U.S. patent application number 14/507248 was filed with the patent office on 2015-06-11 for cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes.
The applicant listed for this patent is Jenrin Discovery. Invention is credited to Robert J. Chorvat, John F. McElroy.
Application Number | 20150157605 14/507248 |
Document ID | / |
Family ID | 40588777 |
Filed Date | 2015-06-11 |
United States Patent
Application |
20150157605 |
Kind Code |
A1 |
McElroy; John F. ; et
al. |
June 11, 2015 |
CANNABINOID RECEPTOR ANTAGONISTS/INVERSE AGONISTS USEFUL FOR
TREATING METABOLIC DISORDERS, INCLUDING OBESITY AND DIABETES
Abstract
The present invention provides novel pyrazoles that are useful
as cannabinoid receptor antagonists and pharmaceutical compositions
thereof and methods of using the same for treating obesity,
diabetes, hepatic disorders, and/or cardiometabolic disorders.
Inventors: |
McElroy; John F.;
(Wilmington, DE) ; Chorvat; Robert J.; (West
Chester, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Jenrin Discovery |
Wilmington |
DE |
US |
|
|
Family ID: |
40588777 |
Appl. No.: |
14/507248 |
Filed: |
October 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13414586 |
Mar 7, 2012 |
8853252 |
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14507248 |
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12650947 |
Dec 31, 2009 |
8138216 |
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13414586 |
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12262765 |
Oct 31, 2008 |
7655685 |
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12650947 |
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60984760 |
Nov 2, 2007 |
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Current U.S.
Class: |
514/403 |
Current CPC
Class: |
A61K 31/415 20130101;
A61P 17/02 20180101; A61P 11/00 20180101; A61P 15/02 20180101; A61P
1/00 20180101; A61P 3/04 20180101; A61P 35/00 20180101; A61P 3/00
20180101; A61P 43/00 20180101; A61P 25/28 20180101; A61P 3/06
20180101; C07D 231/06 20130101; A61P 19/02 20180101; A61P 9/12
20180101; A61P 1/16 20180101; A61P 9/00 20180101; A61P 3/10
20180101; A61P 25/20 20180101 |
International
Class: |
A61K 31/415 20060101
A61K031/415 |
Claims
1. A method of treating a disease, comprising: administering to a
mammal in need thereof a therapeutically effective amount of a
compound of Formula I or a stereoisomer or pharmaceutically
acceptable salt thereof, wherein the disease is Type 2 diabetes:
##STR00023## wherein: X, Y, X', Y', X'', and Y'' are independently
selected from: H, C.sub.1-6 alkyl, halogen, CF.sub.3,
O--C.sub.1-.sub.6 alkyl, NO.sub.2, NR.sub.2,
O(CH.sub.2).sub.nCO.sub.2R, O(CH.sub.2).sub.nCN,
OCH.sub.2CH.dbd.CHCO.sub.2R, CH.sub.2O(CH.sub.2).sub.nCO.sub.2R,
CH.sub.2OCH.sub.2CH.dbd.CHCO.sub.2R, O(CH.sub.2).sub.nPO(OR).sub.2,
CH.sub.2O(CH.sub.2).sub.nPO(OR).sub.2,
NR.sup.a(CH.sub.2).sub.nCO.sub.2R,
NR.sup.a(CH.sub.2).sub.nPO(OR).sub.2,
NR.sup.aCH.sub.2CH.dbd.CHCO.sub.2R, NR.sup.aSO.sub.2R,
NR.sup.aCO(CH.sub.2).sub.nCO.sub.2R,
NR.sup.aCO(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
O(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCO.sub.2R,
CH.sub.2O(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
O(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
O(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
CH.sub.2O(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
CH.sub.2O(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
O(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.n-tetrazole,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
CH.sub.2NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCO.sub.2R,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
CH.sub.2NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCONR.sup.a.sub.2,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
CH.sub.2NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.n-tetrazole,
CONHOH, C(NH)NR.sup.a.sub.2, (CH.sub.2).sub.nC(NH)NR.sup.a.sub.2,
O(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC(NH)NR.sup.a.sub.2,
O(CH.sub.2).sub.nC(NOH)NR.sup.a.sub.2,
CH.sub.2O(CH.sub.2).sub.nCONR.sup.a.sub.2,
NR.sup.a(CH.sub.2).sub.nCONR.sup.a.sub.2,
OCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
CH.sub.2OCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
NR.sup.aCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
(CH.sub.2).sub.m-tetrazole, O(CH.sub.2).sub.n-tetrazole,
O(CH.sub.2CH.sub.2O).sub.pR, NR.sup.a(CH.sub.2CH.sub.2O).sub.pR,
and SO.sub.2NHCH.sub.3; Z is selected from: H, C.sub.1-6 alkyl, OH,
O--C.sub.1-6 alkyl, O(CH.sub.2CH.sub.2O).sub.pR, OC(O)-C.sub.1-6
alkyl, O(CH.sub.2).sub.nCO.sub.2R, OCH.sub.2CH.dbd.CHCO.sub.2R,
O(CH.sub.2).sub.nPO(OR).sub.2, O(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC(NH)NH.sub.2,
O(CH.sub.2).sub.nC(NOH)NR.sup.a.sub.2,
OCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
O(CH.sub.2).sub.n-phenyl-(CH.sub.2).sub.mCO.sub.2R, and
O(CH.sub.2).sub.n-phenyl-(CH.sub.2).sub.m-tetrazole; Z' is selected
from H, CO.sub.2R, and CONR.sup.a.sub.2; Q is selected from:
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.3R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mC(NH)NH.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mC(NOH)NH.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(CH.sub.-
2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2,
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCO.sub.2R, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 or
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R, then (a) m is other
than 0, (b) A is other than H, or (c) both (a) and (b); A is
selected from H, C.sub.1-6 alkyl,
(CH.sub.2).sub.mC.sub.3-6-cycloalkyl, OH, CH.sub.2OH,
CH(CH.sub.3)OH, C(CH.sub.3).sub.2OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b,
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2, and (CH.sub.2).sub.m-phenyl,
wherein the phenyl is substituted with 0-3 groups selected from H,
C.sub.1-4 alkyl, halogen, CF.sub.3, O--C.sub.1-4 alkyl, and
NO.sub.2; alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 or
CHA(CH.sub.2).sub.mCO.sub.2R, and (a) A is selected from OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b, and
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2; (b) R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2; or (c) both (a) and (b); A'' is C.sub.1-6
alkyl; M is C.dbd.O or SO.sub.2; R is independently selected from
H, (CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH,
CH(CH.sub.2OH).sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; R.sup.a is independently selected from H,
(CH.sub.2).sub.m(CHR).sub.n(CH.sub.2).sub.mOH, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; R.sup.b is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl; p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
m is selected from 0, 1, 2, 3, and 4; and, n is selected from 1, 2,
3, and 4.
2. The method of claim 1, wherein: M is SO.sub.2.
3. The method of claim 1, wherein the compound is of formula Ia or
a stereoisomer or pharmaceutically acceptable salt thereof:
##STR00024##
4. The method of claim 1, wherein the compound is of formula Ib or
a stereoisomer or pharmaceutically acceptable salt thereof:
##STR00025##
5. The method of claim 1, wherein the compound is of formula Ic or
a stereoisomer or pharmaceutically acceptable salt thereof:
##STR00026##
6. The method of claim 1, wherein the compound is a compound of
formula Ia or a stereoisomer or pharmaceutically acceptable salt
thereof, ##STR00027## wherein: X, Y, X', Y', X'', and Y'' are
individually selected from the following: H, C.sub.1-4 alkyl,
halogen, CF.sub.3, O--C.sub.1-4 alkyl, NO.sub.2,
O(CH.sub.2CH.sub.2O).sub.pR, NR.sup.a(CH.sub.2CH.sub.2O).sub.pR,
and NR.sub.2; Z is selected from: H, C.sub.1-4 alkyl, OH,
O--C.sub.1-4 alkyl, acetyloxy, and propionyloxy; Q is selected
from: (CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(CH.sub.-
2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2,
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCO.sub.2R, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 or
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R, then (a) m is other
than 0, (b) A is other than H, or (c) both (a) and (b); A is
selected from H, C.sub.1-4 alkyl,
(CH.sub.2).sub.mC.sub.3-6-cycloalkyl, OH, CH.sub.2OH,
CH(CH.sub.3)OH, C(CH.sub.3).sub.2OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b,
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2, and (CH.sub.2).sub.m-phenyl,
wherein the phenyl is substituted with 0-3 groups selected from H,
C.sub.1-4 alkyl, halogen, CF.sub.3, O--C.sub.1-4 alkyl, and
NO.sub.2; alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 or
CHA(CH.sub.2).sub.mCO.sub.2R, and A is OH or
(CH.sub.2).sub.nCO.sub.2R.sup.b or R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2; R is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; R.sup.b is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl; p is selected from 2, 3, 4, 5, 6, 7, and 8;
m is independently selected from 0, 1, 2, and 3; and, n is
independently selected from 1, 2, and 3.
7. The method of claim 6, wherein: Q is selected from:
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 then (a) m is
other than 0, (b) A is other than H, or (c) both (a) and (b);
alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 and A is OH or
(CH.sub.2).sub.nCO.sub.2R.sup.b or R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2; M is SO.sub.2; R is independently selected
from H and C.sub.1-4 alkyl; R.sup.b is independently selected from
H and C.sub.1-4 alkyl; m is independently selected from 0, 1, and
2; and, n is independently selected from 1 and 2.
8. The method of claim 1, wherein the compound is a compound of
formula Ib or a stereoisomer or pharmaceutically acceptable salt
thereof, ##STR00028## wherein: X, Y, X', Y', X'', and Y'' are
individually selected from the following: H, C.sub.1-4 alkyl,
halogen, CF.sub.3, O--C.sub.1-4 alkyl, NO.sub.2,
O(CH.sub.2CH.sub.2O).sub.pR, NR.sup.a(CH.sub.2CH.sub.2O).sub.pR,
and NR.sub.2; Z is selected from: H, C.sub.1-4 alkyl, OH,
O--C.sub.1-4 alkyl, acetyloxy, and propionyloxy; Q is selected
from: (CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2)CHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(CH.sub.-
2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2,
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCO.sub.2R, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 or
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R, then (a) m is other
than 0, (b) A is other than H, or (c) both (a) and (b); A is
selected from H, C.sub.1-4 alkyl,
(CH.sub.2).sub.mC.sub.3-6-cycloalkyl, OH, CH.sub.2OH,
CH(CH.sub.3)OH, C(CH.sub.3).sub.2OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b,
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2, and (CH.sub.2).sub.m-phenyl,
wherein the phenyl is substituted with 0-3 groups selected from H,
C.sub.1-4 alkyl, halogen, CF.sub.3, O--C.sub.1-4 alkyl, and
NO.sub.2; alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 or
CHA(CH.sub.2).sub.mCO.sub.2R, and A is OH or
(CH.sub.2).sub.nCO.sub.2R.sup.b or R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2; R is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; R.sup.b is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl; p is selected from 2, 3, 4, 5, 6, 7, and 8;
m is independently selected from 0, 1, 2, and 3; and, n is
independently selected from 1, 2, and 3.
9. The method of claim 8, wherein: Q is selected from:
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 then (a) m is
other than 0, (b) A is other than H, or (c) both (a) and (b);
alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 and A is OH or
(CH.sub.2).sub.nCO.sub.2R.sup.b or R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2; M is SO.sub.2; R is independently selected
from H and C.sub.1-4 alkyl; R.sup.b is independently selected from
H and C.sub.1-4 alkyl; m is independently selected from 0, 1, and
2; and, n is independently selected from 1 and 2.
10. The method of claim 1, wherein the compound is selected from
Table B or a stereoisomer or a pharmaceutically acceptable salt
thereof: TABLE-US-00007 TABLE B ##STR00029## Number Q Y'' X'' X 1
CH.sub.2CH.sub.2CH(OH)CO.sub.2Me 4-Cl H Cl 2
CH(CH.sub.2CO.sub.2tBu)CO.sub.2Me 4-Cl H Cl 3
C(CH.sub.3).sub.2CO.sub.2H 4-Cl H Cl 4
C(CH.sub.3).sub.2CONH--CH(CH.sub.3)CO.sub.2Me 4-Cl H Cl 5
CH(CH(CH.sub.3).sub.2)--CONHCH.sub.2CH.sub.2OH 4-OMe H Cl 6
CH.sub.2CH(OH)CH.sub.2CONH.sub.2 4-Cl H Cl 7
CHCH(CH.sub.3).sub.2CONH--CH(CH.sub.2OH).sub.2 4-Cl H Cl 8
CH.sub.2CH.sub.2CH(OH)CONH.sub.2 4-Cl H Cl 9
CHCH(CH.sub.3).sub.2CONH--CH(CH.sub.2OH).sub.2 4-OMe H Cl 10
CH(CH.sub.2CONH.sub.2)CONH.sub.2 4-Cl H Cl 11
CH.sub.2CONHCH.sub.2CONH.sub.2 4-Cl H Cl 12
CH.sub.2CONHCH.sub.2CONH.sub.2 4-OMe H Cl 13
CH.sub.2CONH--CH(CHCH.sub.3OH)CONH.sub.2 4-OMe H Cl 14
CHCH.sub.3CONHCH.sub.2CONH.sub.2 4-Cl H Cl 15
CHCH.sub.3CONH--CH.sub.2CONH.sub.2 4-OMe H Cl 16
CHCH(CH.sub.3).sub.2CONH--CH.sub.2CONH.sub.2 4-Cl H Cl 17
CHCH(CH.sub.3).sub.2CONH--CHCH.sub.3CONH.sub.2 4-Cl H Cl 18
CHCH.sub.3CONH--CHCH.sub.2OHCONH.sub.2 4-Cl H Cl 19
CHCH.sub.3CONH--CHCH.sub.3CONH.sub.2 4-Cl H Cl 20 ##STR00030## 4-Cl
H Cl 21 CH.sub.2CH.sub.2SO.sub.2NH.sub.2 4-Cl H Cl
11. A method of treating a disease, comprising: administering to a
mammal in need thereof a therapeutically effective amount of a
compound selected from the compounds of Table A and C or a
stereoisomer or a pharmaceutically acceptable salt thereof, wherein
the disease is Type 2 diabetes: TABLE-US-00008 TABLE A ##STR00031##
Num- ber Q Y'' X'' X 1 CH(CH.sub.3)CH.sub.2CO.sub.2Et 4-Cl H Cl 2
CH(CH.sub.3)CH.sub.2CO.sub.2H 4-Cl H Cl 3 CH.sub.2CO.sub.2Me 4-Cl H
Cl 4 CH.sub.2CO.sub.2H 4-Cl H Cl 5 CH(CH.sub.3)CO.sub.2Me 4-Cl H Cl
6 CH(CHOHCH.sub.3)CO.sub.2Me 4-Cl H Cl 7
CH(C(CH.sub.3).sub.3)CO.sub.2Me 4-Cl H Cl 8 CH.sub.2CO.sub.2Me
4-OMe 3- Cl OMe 10 CH.sub.2CO.sub.2Me 4-OMe 3-Cl Cl 11
CH(CH.sub.2OH)CO.sub.2Me 4-Cl H Cl 12
CH.sub.2CONHCH.sub.2CO.sub.2Me 4-Cl H Cl 13
CH(CH.sub.3)CONH--CH.sub.2CO.sub.2Me 4-Cl H Cl 14
CH(CH(CH.sub.3).sub.2)CONH--CH.sub.2CO.sub.2Me 4-Cl H Cl 15
CH.sub.2CONHCH.sub.2CO.sub.2Me 4-OMe H Cl 16 CH.sub.2CONH.sub.2
4-Cl H Cl 16 CH(CH.sub.3)CONH.sub.2 4-Cl H Cl 17
CH.sub.2CH.sub.2CONH.sub.2 4-Cl H Cl 18
CH(CH.sub.3)CH.sub.2CONH.sub.2 4-Cl H Cl 19
CH(C(CH.sub.3).sub.3)CONH.sub.2 4-Cl H Cl 20
CH(CH(CH.sub.3).sub.2)CONH.sub.2 4-Cl H Cl 21
CHCH(CH.sub.3).sub.2)--CONHCH.sub.3 4-Cl H Cl 22
CH(CHOHCH.sub.3)CONH.sub.2 4-Cl H Cl 23 CH.sub.2CONH.sub.2 4-OMe H
Cl 24 CH(CH.sub.3)CONH.sub.2 4-OMe H Cl 25 CH(CH.sub.3)CONH.sub.2
4-OCH.sub.2--CN H Cl 26 C(CH.sub.3).sub.2CONH.sub.2 4-Cl H Cl 27
CH.sub.2CH(CH.sub.3)CONH.sub.2 4-Cl H Cl 28 CH(CH.sub.3)CONH.sub.2
4-OMe 4- Cl OMe 29 CH(CH.sub.3)CONH.sub.2 4-OMe 3-Cl Cl 30
CH.sub.2CONH.sub.2 4-Cl H OMe 31 CH(CH(CH.sub.3).sub.2)CONH.sub.2
3-OMe H Cl 32 CH.sub.2CH.sub.2CONH.sub.2 4-Cl H Cl
TABLE-US-00009 TABLE C ##STR00032## Number Q Y'' X'' X 1 Me
4-OCH.sub.2CO.sub.2Et H Cl 2 Me 4-CONHOH Cl Cl
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. The method of claim 1, wherein the compound is: ##STR00033## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
22. The method of claim 1, wherein the compound is: ##STR00034## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
23. The method of claim 1, wherein the compound is: ##STR00035## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
24. The method of claim 1, wherein the compound is: ##STR00036## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
25. The method of claim 1, wherein the compound is: ##STR00037## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
26. The method of claim 1, wherein the compound is: ##STR00038## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
27. The method of claim 1, wherein the compound is: ##STR00039## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
28. The method of claim 1, wherein the compound is: ##STR00040## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
29. The method of claim 1, wherein the compound is: ##STR00041## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
30. The method of claim 1, wherein the compound is: ##STR00042## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
31. The method of claim 1, wherein the compound is: ##STR00043## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
32. The method of claim 1, wherein the compound is: ##STR00044## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
33. The method of claim 1, wherein the compound is: ##STR00045## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
34. The method of claim 1, wherein the compound is: ##STR00046## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
35. The method of claim 1, wherein the compound is: ##STR00047## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
36. The method of claim 1, wherein the compound is: ##STR00048## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
37. The method of claim 1, wherein the compound is: ##STR00049## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
38. The method of claim 1, wherein the compound is: ##STR00050## or
a stereoisomer or a pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority benefit under 35
U.S.C. .sctn.119(e) of U.S. Provisional Patent Application Ser. No.
60/984,760 filed Nov. 2, 2007. The disclosure this application is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention provides cannabinoid receptor
antagonists/inverse agonists and pharmaceutical compositions
thereof and methods of using the same for treating obesity,
diabetes, hepatic disorders, and/or cardiometabolic disorders. The
present invention also relates to a novel method for treating
obesity, diabetes, hepatic disorders, and/or cardiometabolic
disorders using a pyrazoline.
BACKGROUND OF THE INVENTION
[0003] Obesity is associated with an increase in the overall amount
of adipose tissue (i.e., body fat), especially adipose tissue
localized in the abdominal area. Obesity has reached epidemic
proportions in the United States. The prevalence of obesity has
steadily increased over the years among all racial and ethnic
groups. The most recent data from the Centers for Disease Control
and Prevention, and the National Center for Health Statistics
report 66% of the adult population overweight (BMI, 25.0-29.9), 31%
obese (BMI, 30-39.9), and 5% extremely obese (BMI, .gtoreq.40.0).
Among children aged 6 through 19 years, 32% were overweight and 17%
were obese. This translates to 124 million Americans medically
overweight, and 44 million of these deemed obese. Obesity is
responsible for more than 300,000 deaths annually, and will soon
overtake tobacco usage as the primary cause of preventable death in
the United States. Obesity is a chronic disease that contributes
directly to numerous dangerous co-morbidities, including type 2
diabetes, cardiometabolic diseases, hepatic disorders,
cardiovascular disease, inflammatory diseases, premature aging, and
some forms of cancer. Type 2 diabetes, a serious and
life-threatening disorder with growing prevalence in both adult and
childhood populations, is currently the 7.sup.th leading cause of
death in the United States. Since more than 80% of patients with
type 2 diabetes are overweight, obesity is the greatest risk factor
for developing type 2 diabetes. Increasing clinical evidence
indicates that the best way to control type 2 diabetes is to reduce
weight.
[0004] The most popular over-the counter drugs for the treatment of
obesity, phenylpropanolamine and ephedrine, and the most popular
prescription drug, fenfluramine, were removed from the marketplace
as a result of safety concerns. Drugs currently approved for the
long-term treatment of obesity fall into two categories: (a) CNS
appetite suppressants such as sibutramine and rimonabant, and (b)
gut lipase inhibitors such as orlistat. CNS appetite suppressants
reduce eating behavior through activation of the `satiety center`
in the brain and/or by inhibition of the `hunger center` in the
brain. Gut lipase inhibitors reduce the absorption of dietary fat
from the gastrointestinal (GI) tract. Although appetite
suppressants and gut lipase inhibitors work through very different
mechanisms, they share in common the same overall goal of reducing
body weight secondary to reducing the amount of calories that reach
the systemic circulation. Unfortunately, these indirect therapies
produce only a modest initial weight loss (approximately 5%
compared to placebo) that is usually not maintained. After one or
two years of treatment, most patients return to or exceed their
starting weight. In addition, most approved anti-obesity
therapeutics produce undesirable and often dangerous side effects
that can complicate treatment and interfere with a patient's
quality of life.
[0005] The lack of therapeutic effectiveness, coupled with the
spiraling obesity epidemic, positions the `treatment of obesity` as
one of the largest and most urgent unmet medical needs. There is,
therefore, a real and continuing need for the development of
improved medications that treat or prevent obesity.
[0006] The endocanabinoid system, comprised of the canabinoid
receptors (CB1 and CB2) and their endogenous ligands (e.g.,
anandamide, 2-AG), plays a prominent role in the control of food
intake and energy metabolism. CB1 receptors are widely expressed in
the brain, including cortex, hippocampus, amygdala, pituitary and
hypothalamus. CB1 receptors have also been identified in numerous
peripheral organs and tissues, including thyroid gland, adrenal
gland, reproductive organs, adipose tissue, liver, muscle,
pancreas, and gastrointestinal tract. CB2 receptors are localized
almost exclusively in immune and blood cells [Endocrine Reviews
2006, 27, 73].
[0007] The plant-derived cannabinoid agonist
.DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC), the main
psychoactive component of marijuana, binds to both CB1 and CB2
receptors. .DELTA..sup.9-THC is widely reported to increase
appetite and food intake (hyperphagia) in humans and in animals.
This hyperphagic effect is largely blocked by pretreatment with
selective CB1 receptor blockers (i.e., CB1 blockers)(e.g.,
rimonabant (SR141716A, Acomplia.RTM.)), strongly supporting the
belief that CB1 receptor activation mediates the hyperphagic effect
of .DELTA..sup.9-THC, [Endocrine Reviews 2006, 27, 73].
[0008] In humans, rimonabant produces a clinically meaningful
weight loss in obese patients. Obese patients also experience
improvements in diabetic and cardiometabolic risk factors
associated with obesity, including an increase in the level of high
density lipoprotein cholesterol (HDL), and decreases in
triglycerides, glucose, and hemoglobin Alc (HbAlc, a marker of
cumulative exposure to glucose) levels. Rimonabant also produces
greater reductions in abdominal fat deposits, which are a known
risk factor for diabetes and heart disease [Science 2006, 311,
323]. Taken together, these improvements in adiposity and
cardiometabolic risk factors produce an overall decrease in the
prevalence of the metabolic syndrome [Lancet 2005, 365, 1389 and
NEJM 2005, 353, 2121].
[0009] In patients with type 2 diabetes not currently treated with
other anti-diabetic medications, rimonabant was shown to
significantly improve blood sugar control and weight, as well as
other risk factors such as HDL and triglycerides, when compared to
placebo (International Diabetes Federation World Diabetes Congress,
Cape Town, South Africa, 2006). After six months of treatment,
HbAlc levels were significantly lowered by 0.8% from a baseline
value of 7.9 as compared to a reduction of 0.3% in the placebo
group. These results are consistent with preclinical studies that
demonstrate improved glycemic and lipid control in diabetic and
dyslipedemic mice, rats, and dogs (Pharmacology Biochemistry &
Behavior, 2006, 84, 353; American Journal of Physiology, 2003, 284,
R345; American Diabetes Association Annual Meeting, 2007; Abstract
Number 0372-OR).
[0010] The beneficial effects of rimonabant on diabetic and
cardiometabolic risk factors such as high blood pressure, insulin
resistance, and elevated triglycerides cannot be explained by
diet-related weight loss alone. For example, in patients receiving
20 mg of rimonabant, only approximately 50% of the beneficial
effects on triglycerides, fasting insulin, and insulin resistance
can be accounted for by weight loss secondary to reduced food
intake. These results suggest a direct pharmacological effect of
CB1 antagonists on glucose and lipid metabolism, in addition to
indirect effects on metabolism secondary to hypophagia-mediated
weight loss [Science 2006, 311, 323 and JAMA 2006, 311, 323]. Taken
together, these results suggest that CB1 antagonists might be
effective in the treatment of diabetes, dyslipidemia,
cardiovascular disorders (e.g., atherosclerosis, hypertension), and
hepatic disorders (e.g., cirrhosis, fatty liver diseases), even in
patients that are not clinically overweight or obese.
[0011] The CB1 receptor is one of the most abundant and widely
distributed G protein-coupled receptors in the mammalian brain. It
is believed that the appetite-suppressant properties of CB1
antagonists are mediated through an interaction with CB1 receptors
in the hypothalamus (regulation of food intake), and in the
mesolimbic region (rewarding properties of food). However, CB1
receptors are far more broadly distributed in brain (e.g.,
neocortex, hippocampus, thalamus, cerebellum, and pituitary), and
while interacting with targeted CB1 receptors in hypothalamus and
mesolimbic regions to suppress appetite, CB1 antagonists have equal
access to non-targeted CB1 receptors that have little if any role
in appetite control. Binding to non-targeted receptors can often
lead to unwanted side effects of CNS drugs [Endocrine Reviews 2006,
27: 73]. The CB1 blockers rimonabant and taranabant produce
psychiatric and neurological side effects. These include depressed
mood, anxiety, irritability, insomnia, dizziness, headache,
seizures, and suicidality.
[0012] These side effects are dose-related and appear pronounced at
the most efficacious weight-reducing doses of rimonabant and
taranabant (JAMA 2006, 311, 323; Cell Metabolism 2008, 7, 68). The
occurrence of therapeutic efficacy (appetite suppression) and side
effects over the same dose range strongly suggest that both effects
are mediated through concurrent antagonism of CB1 receptors in both
`targeted` and `non-targeted` brain regions. Brain-penetrant CB1
blockers do not selectively target CB1 receptors in efficacy brain
regions, while ignoring CB1 receptors in side effect brain
regions.
[0013] The beneficial effects of the CB1 antagonist rimonabant on
body weight, adiposity, and diabetic and cardiometabolic risk
factors such as high blood pressure, insulin resistance and blood
lipids cannot be explained by weight loss derived from CNS-mediated
appetite suppression alone [JAMA 2006, 311, 323]. Approximately 50%
of the benefit is likely derived from an interaction with CB1
receptors in peripheral tissues known to play an active role in
metabolism. These include adipose tissue, liver, muscle, pancreas,
and gastrointestinal tract.
[0014] In view of the above, it is highly desirable to find
effective and highly selective CB1 receptor blockers with limited
or no CNS adverse side effects, including mood disorders.
Particularly, it is desirable to find compounds that preferentially
target CB1 receptors in peripheral tissues (e.g., adipose tissue,
liver, muscle, pancreas, and gastrointestinal tract), while sparing
CB1 receptors in brain. In this way, peripherally-mediated
beneficial effects of CB1 blockers should be maintained, whereas
CNS side effects should be reduced or eliminated. This should
provide a novel opportunity to develop safer alternatives to highly
brain penetrant CB1 blockers for the prevention or treatment of
obesity, diabetes, dyslipidemia, cardiovascular disorders, and/or
hepatic disorders.
SUMMARY OF THE INVENTION
[0015] Accordingly, in an aspect, the present invention provides
novel pyrazolines or pharmaceutically acceptable salts thereof that
are CB1 receptor antagonists/inverse agonists.
[0016] In another aspect, the present invention provides novel
pharmaceutical compositions, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of at
least one of the compounds of the present invention or a
pharmaceutically acceptable salt form thereof.
[0017] In another aspect, the present invention provides novel
methods for treating obesity, diabetes (e.g., insulin resistance,
inadequate glucose tolerance, Type I diabetes, and Type II
diabetes), dyslipidemia (e.g., elevated triglyerides and low HDL),
cardiovascular disorders (e.g., atherosclerosis and hypertension),
and/or hepatic disorders (e.g., cirrhosis and fatty liver disease),
comprising: administering to a mammal in need of such treatment a
therapeutically effective amount of at least one of the compounds
of the present invention or a pharmaceutically acceptable salt form
thereof.
[0018] In another aspect, the present invention provides processes
for preparing novel compounds.
[0019] In another aspect, the present invention provides novel
compounds or pharmaceutically acceptable salts for use in
therapy.
[0020] In another aspect, the present invention provides the use of
novel compounds for the manufacture of a medicament for the
treatment of obesity, diabetes, dyslipidemia, cardiovascular
disorders, and/or hepatic disorders.
[0021] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery that the presently claimed compounds or
pharmaceutically acceptable salt forms thereof are expected to be
effective CB1 receptor blockers.
DETAILED DESCRIPTION OF THE INVENTION
[0022] All references cited herein are hereby incorporated in their
entirety herein by reference.
[0023] A CB1 blocker is a neutral CB1 receptor antagonist and/or a
CB1 receptor inverse agonist.
[0024] The present invention is based on the finding that a CB1
receptor blocker has beneficial effects on cardiometabolic
disorders including obesity, diabetes, and dyslipidemia that cannot
be explained by weight loss derived from CNS-mediated appetite
suppression alone, and that this effect is mediated, at least in
part, through interaction at peripheral CB1 receptors. To this end,
the present invention provides compounds that are designed to
preferentially target CB1 receptors in peripheral tissues (e.g.,
adipose tissue, liver, muscle, pancreas, and gastrointestinal
tract), while sparing CB1 receptors in brain. With these types of
compounds, peripherally-mediated beneficial effects of CB1 blockers
should be maintained, whereas CNS side effects should be reduced or
eliminated.
[0025] The compounds of the present invention have been designed to
have reduced CNS exposure by virtue of their inability or limited
ability to penetrate the blood-brain barrier (BBB), or by their
participation in active transport systems, thus reducing centrally
mediated side-effects, a potential problem with many anti-obesity
agents. It is expected that the peripherally restricted compounds
of the present invention will have no or very limited CNS effects,
including mood disorders, seizures, and suicidality. Thus, their
peripherally mediated CB1 antagonistic properties should provide
therapeutic agents with greater safety.
[0026] Moreover, if the maximum dosage of a drug used in the
treatment of obesity, diabetes, dyslipidemia, cardiovascular
disorders, and/or hepatic disorders is limited as a result of CNS
side effects (e.g., seizures, depression, anxiety, suicidality,
movement disorders, and hyperactivity), incorporation of a
peripherally restricting group in such a drug would lower the brain
concentration of the drug relative to the concentration in the
systemic circulation, thereby affording the opportunity to increase
the dosage employed to treat the peripheral disorder (e.g.,
obesity, diabetes, dyslipidemia, cardiovascular disorders, and/or
hepatic disorders). The increased dosage may provide greater
therapeutic efficacy, as well as a more rapid onset of therapeutic
action.
[0027] [1] In another embodiment, the present invention provides
novel compound of Formula I or a stereoisomer or pharmaceutically
acceptable salt thereof:
##STR00001##
[0028] wherein:
[0029] X, Y, X', Y', X'', and Y'' are independently selected from:
H, C.sub.1-6 alkyl, halogen, CF.sub.3, O--C.sub.1-6 alkyl,
NO.sub.2, NR.sub.2, O(CH.sub.2).sub.nCO.sub.2R,
O(CH.sub.2).sub.nCN, OCH.sub.2CH.dbd.CHCO.sub.2R,
CH.sub.2O(CH.sub.2).sub.nCO.sub.2R,
CH.sub.2OCH.sub.2CH.dbd.CHCO.sub.2R, O(CH.sub.2).sub.nPO(OR).sub.2,
CH.sub.2O(CH.sub.2).sub.nPO(OR).sub.2,
NR.sup.a(CH.sub.2).sub.nCO.sub.2R,
NR.sup.a(CH.sub.2).sub.nPO(OR).sub.2,
NR.sup.aCH.sub.2CH.dbd.CHCO.sub.2R, NR.sup.aSO.sub.2R,
NR.sup.aCO(CH.sub.2).sub.nCO.sub.2R,
NR.sup.aCO(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
O(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCO.sub.2R,
CH.sub.2O(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
O(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
O(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
CH.sub.2O(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
CH.sub.2O(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
O(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.n-tetrazole,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
CH.sub.2NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CO.sub.2R,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCO.sub.2R,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
CH.sub.2NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4CONR.sup.a.sub.2,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.nCONR.sup.a.sub.2,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
CH.sub.2NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4-tetrazole,
NR.sup.a(CH.sub.2).sub.nC.sub.6H.sub.4(CH.sub.2).sub.n-tetrazole,
CONHOH, C(NH)NR.sup.a.sub.2, (CH.sub.2).sub.nC(NH)NR.sup.a.sub.2,
O(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC(NH)NR.sup.a.sub.2,
O(CH.sub.2).sub.nC(NOH)NR.sup.a.sub.2,
CH.sub.2O(CH.sub.2).sub.nCONR.sup.a.sub.2,
NR.sup.a(CH.sub.2).sub.nCONR.sup.a.sub.2,
OCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
CH.sub.2OCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
NR.sup.aCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
(CH.sub.2).sub.m-tetrazole, O(CH.sub.2).sub.n-tetrazole,
O(CH.sub.2CH.sub.2O).sub.pR, NR.sup.a(CH.sub.2CH.sub.2O).sub.pR,
and SO.sub.2NHCH.sub.3;
[0030] Z is selected from: H, C.sub.1-6 alkyl, OH, O--C.sub.1-6
alkyl, O(CH.sub.2CH.sub.2O).sub.pR, OC(O)--C.sub.1-6 alkyl,
O(CH.sub.2).sub.nCO.sub.2R, OCH.sub.2CH.dbd.CHCO.sub.2R,
O(CH.sub.2).sub.nPO(OR).sub.2, O(CH.sub.2).sub.nCONR.sup.a.sub.2,
O(CH.sub.2).sub.nC(NH)NH.sub.2,
O(CH.sub.2).sub.nC(NOH)NR.sup.a.sub.2,
OCH.sub.2CH.dbd.CHCONR.sup.a.sub.2,
O(CH.sub.2).sub.n-phenyl-(CH.sub.2).sub.mCO.sub.2R, and
O(CH.sub.2).sub.n-phenyl-(CH.sub.2).sub.m-tetrazole;
[0031] Z' is selected from H, CO.sub.2R, and CONR.sup.a.sub.2;
[0032] Q is selected from:
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.3R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mC(NH)NH.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mC(NOH)NH.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(CH.sub.-
2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2,
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCO.sub.2R, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
[0033] provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 or
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R, then (a) m is other
than 0, (b) A is other than H, or (c) both (a) and (b);
[0034] A is selected from H, C.sub.1-6 alkyl,
(CH.sub.2).sub.mC.sub.3-6-cycloalkyl, OH, CH.sub.2OH,
CH(CH.sub.3)OH, C(CH.sub.3).sub.2OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b,
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2, and (CH.sub.2).sub.m-phenyl,
wherein the phenyl is substituted with 0-3 groups selected from H,
C.sub.1-4 alkyl, halogen, CF.sub.3, O--C.sub.1-4 alkyl, and
NO.sub.2;
[0035] alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 or
CHA(CH.sub.2).sub.mCO.sub.2R, and (a) A is selected from OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b, and
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2; (b) R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2; or (c) both (a) and (b);
[0036] A'' is C.sub.1-6 alkyl;
[0037] M is C.dbd.O or SO.sub.2;
[0038] R is independently selected from H,
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH,
CH(CH.sub.2OH).sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl;
[0039] R.sup.a is independently selected from H,
(CH.sub.2).sub.m(CHR).sub.n(CH.sub.2).sub.mOH, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl;
[0040] R.sup.b is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl;
[0041] p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12;
[0042] m is selected from 0, 1, 2, 3, and 4; and,
[0043] n is selected from 1, 2, 3, and 4.
[0044] In another embodiment, the present invention provides novel
compounds wherein:
[0045] M is SO.sub.2.
[0046] [2] In another embodiment, the present invention provides
novel compounds of formula Ia or a stereoisomer or pharmaceutically
acceptable salt thereof,
##STR00002##
[0047] [3] In another embodiment, the present invention provides
novel compounds of formula Ib or a stereoisomer or pharmaceutically
acceptable salt thereof,
##STR00003##
[0048] [4] In another embodiment, the present invention provides
novel compounds of formula Ic or a stereoisomer or pharmaceutically
acceptable salt thereof,
##STR00004##
[0049] [5] In another embodiment, the present invention provides
novel compounds of formula Ia or a stereoisomer or pharmaceutically
acceptable salt thereof,
##STR00005##
[0050] wherein:
[0051] X, Y, X', Y', X'', and Y'' are individually selected from
the following: H, C.sub.1-4 alkyl, halogen, CF.sub.3, O--C.sub.1-4
alkyl, NO.sub.2, O(CH.sub.2CH.sub.2O).sub.pR,
NR.sup.a(CH.sub.2CH.sub.2O).sub.pR, and NR.sub.2;
[0052] Z is selected from: H, C.sub.1-4 alkyl, OH, O--C.sub.1-4
alkyl, acetyloxy, and propionyloxy;
[0053] Q is selected from:
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(CH.sub.-
2).sub.mCO.sub.2R,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2,
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCO.sub.2R, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
[0054] provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 or
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCO.sub.2R, then (a) m is other
than 0, (b) A is other than H, or (c) both (a) and (b);
[0055] A is selected from H, C.sub.1-4 alkyl,
(CH.sub.2).sub.mC.sub.3-6-cycloalkyl, OH, CH.sub.2OH,
CH(CH.sub.3)OH, C(CH.sub.3).sub.2OH,
(CH.sub.2).sub.nCO.sub.2R.sup.b,
(CH.sub.2).sub.nC(O)NR.sup.b.sub.2, and (CH.sub.2).sub.m-phenyl,
wherein the phenyl is substituted with 0-3 groups selected from H,
C.sub.1-4 alkyl, halogen, CF.sub.3, O--C.sub.1-4 alkyl, and
NO.sub.2;
[0056] alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 or
CHA(CH.sub.2).sub.mCO.sub.2R, and A is OH or
(CH.sub.2).sub.nCO.sub.2R.sup.b or R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2;
[0057] R is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl;
[0058] R.sup.b is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl;
[0059] p is selected from 2, 3, 4, 5, 6, 7, and 8;
[0060] m is independently selected from 0, 1, 2, and 3; and,
[0061] n is independently selected from 1, 2, and 3.
[0062] [5] In another embodiment, the present invention provides
novel compounds of formula Ia or a stereoisomer or pharmaceutically
acceptable salt thereof, wherein:
[0063] Q is selected from:
(CH.sub.2).sub.nCHA(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mSO.sub.2NR.sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.sub.-
2,
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONR.sup.a.-
sub.2,
(CH.sub.2).sub.mCHA(CH.sub.2).sub.mCONHCHA(CH.sub.2).sub.mCONHCHA(C-
H.sub.2).sub.mCONR.sup.a.sub.2, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCO.sub.2R, C.sub.3-C.sub.6-cyclic
amino-(CH.sub.2).sub.mCONR.sup.a.sub.2, and
C.sub.3-C.sub.6-cycloalkylene-(CH.sub.2).sub.mCONR.sup.a.sub.2;
[0064] provided that when Q is
(CH.sub.2).sub.mCAA''(CH.sub.2).sub.mC(O)NR.sub.2 then (a) m is
other than 0, (b) A is other than H, or (c) both (a) and (b);
[0065] alternatively, Q is CHA(CH.sub.2).sub.mC(O)NR.sub.2 and A is
OH or (CH.sub.2).sub.nCO.sub.2R.sup.b or R is
(CH.sub.2).sub.m(CHR.sup.b).sub.n(CH.sub.2).sub.mOH or
CH(CH.sub.2OH).sub.2;
[0066] M is SO.sub.2;
[0067] R is independently selected from H and C.sub.1-4 alkyl;
[0068] R.sup.b is independently selected from H and C.sub.1-4
alkyl;
[0069] m is independently selected from 0, 1, and 2; and,
[0070] n is independently selected from 1 and 2.
[0071] In another embodiment, the present invention provides novel
pharmaceutical compositions, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt form thereof.
[0072] In another embodiment, the present invention provides a
novel method of modulating the activity of CB1 receptors (e.g.,
periperhal CB1 receptors) in a patient, comprising: administering
to a patient in need thereof a therapeutically effective amount of
a compound of the present invention or a pharmaceutically
acceptable salt form thereof.
[0073] In another embodiment, the present invention provides a
novel method of treating a disease characterized by an
inappropriate activation of peripheral CB1 receptors, comprising:
administering to a patient in need thereof a therapeutically
effective amount of a compound of the present invention or a
pharmaceutically acceptable salt form thereof.
[0074] In another embodiment, the present invention provides a
novel method for treating a disease mediated by the CB.sub.1
receptor in a patient, comprising: administering to a patient in
need thereof a therapeutically effective amount of a compound of
the present invention or a pharmaceutically acceptable salt form
thereof. In an example, the disease is mediated by peripheral
CB.sub.1 receptors. In another example, the CB.sub.1 receptors that
are blocked are peripheral CB.sub.1 receptors.
[0075] In another embodiment, the present invention provides a
novel method for treating a disease, comprising: administering to a
patient in need thereof a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt form thereof, wherein the disease is selected from obesity,
diabetes, dyslipidemia, cardiovascular disorders, hepatic
disorders, and a combination thereof.
[0076] In another embodiment, the diabetes disorder is selected
from Type 1 diabetes, Type 2 diabetes, inadequate glucose
tolerance, and insulin resistance.
[0077] In another embodiment, the dyslipidemia disorder is selected
from undesirable blood lipid levels, including elevated LDL and
triglyceride levels, and lowered HDL levels.
[0078] In another embodiment, the cardiovascular disorder is
selected from atherosclerosis, hypertension, stroke and heart
attack.
[0079] In another embodiment, the hepatic disorder is selected from
cirrhosis and fatty liver diseases.
[0080] In another embodiment, the present invention provides a
novel method for treating a co-morbidity of obesity, comprising:
administering to a patient in need thereof a therapeutically
effective amount of a compound of the present invention or a
pharmaceutically acceptable salt form thereof.
[0081] In another embodiment, the co-morbidity is selected from
diabetes, dyslipidemia, Metabolic Syndrome, dementia,
cardiovascular, and hepatic disease.
[0082] In another embodiment, the co-morbidity is selected from
hypertension; gallbladder disease; gastrointestinal disorders;
menstrual irregularities; degenerative arthritis; venous statis
ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring;
coronary artery disease; arterial sclerotic disease; pseudotumor
cerebri; accident proneness; increased risks with surgeries;
osteoarthritis; high cholesterol; and, increased incidence of
malignancies of the ovaries, cervix, uterus, breasts, prostrate,
and gallbladder.
[0083] In another embodiment, the present invention also provides a
method of preventing or reversing the deposition of adipose tissue
in a mammal by the administration of a compound of the present
invention. By preventing or reversing the deposition of adipose
tissue, compound of the present invention are expected to reduce
the incidence or severity of obesity, thereby reducing the
incidence or severity of associated co-morbidities.
[0084] In another embodiment, the present invention provides a
compound of the present invention for use in therapy.
[0085] In another embodiment, the present invention provides the
use of the present invention for the manufacture of a medicament
for the treatment of obesity, diabetes, dyslipidemia,
cardiovascular disorders, hepatic disorders, and a combination
thereof.
[0086] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. This invention encompasses all combinations of aspects of
the invention noted herein. It is understood that any and all
embodiments of the present invention may be taken in conjunction
with any other embodiment or embodiments to describe additional
embodiments. It is also to be understood that each individual
element of the embodiments is intended to be taken individually as
its own independent embodiment. Furthermore, any element of an
embodiment is meant to be combined with any and all other elements
from any embodiment to describe an additional embodiment.
[0087] Definitions
[0088] The examples provided in the definitions present in this
application are non-inclusive unless otherwise stated. They include
but are not limited to the recited examples.
[0089] The compounds herein described may have asymmetric centers,
geometric centers (e.g., double bond), or both. All chiral,
diastereomeric, racemic forms and all geometric isomeric forms of a
structure are intended, unless the specific stereochemistry or
isomeric form is specifically indicated. Compounds of the present
invention containing an asymmetrically substituted atom may be
isolated in optically active or racemic forms. It is well known in
the art how to prepare optically active forms, such as by
resolution of racemic forms, by synthesis from optically active
starting materials, or through use of chiral auxiliaries. Geometric
isomers of olefins, C.dbd.N double bonds, or other types of double
bonds may be present in the compounds described herein, and all
such stable isomers are included in the present invention.
Specifically, cis and trans geometric isomers of the compounds of
the present invention may also exist and may be isolated as a
mixture of isomers or as separated isomeric forms. All processes
used to prepare compounds of the present invention and
intermediates made therein are considered to be part of the present
invention. All tautomers of shown or described compounds are also
considered to be part of the present invention.
[0090] "Alkyl" includes both branched and straight-chain saturated
aliphatic hydrocarbon groups having the specified number of carbon
atoms. C.sub.1-6 alkyl, for example, includes C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkyl groups. Examples of
alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, and s-pentyl.
[0091] "Alkenyl" includes the specified number of hydrocarbon atoms
in either straight or branched configuration with one or more
unsaturated carbon-carbon bonds that may occur in any stable point
along the chain, such as ethenyl and propenyl. C.sub.2-6 alkenyl
includes C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkenyl
groups.
[0092] "Alkynyl" includes the specified number of hydrocarbon atoms
in either straight or branched configuration with one or more
triple carbon-carbon bonds that may occur in any stable point along
the chain, such as ethynyl and propynyl. C.sub.2-6 Alkynyl includes
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkynyl groups.
[0093] "Cycloalkyl" includes the specified number of hydrocarbon
atoms in a saturated ring, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. C.sub.3-8
cycloalkyl includes C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7,
and C.sub.8 cycloalkyl groups.
[0094] "Cyclic amine" is a hydrocarbon ring wherein one carbon atom
of the ring has been replaced by a nitrogen atom. The cyclic amine
can be unsaturated, partially saturated, or fully saturated. The
cyclic amine can also be bicyclic, tricyclic, and polycyclic.
Examples of cyclic amine include pyrrolidine and piperdine.
[0095] Halo" or "halogen" refers to fluoro, chloro, bromo, and
iodo.
[0096] "Counterion" is used to represent a small, negatively
charged species, such as chloride, bromide, hydroxide, acetate, and
sulfate.
[0097] The group "C.sub.6H.sub.4" represents a phenylene.
[0098] "Aryl" refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13
membered monocyclic, bicyclic, or tricyclic ring, wherein at least
one ring, if more than one is present, is aromatic. Examples of
aryl include fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and
tetrahydronaphthyl.
[0099] "Heteroaryl" refers to any stable 5, 6, 7, 8, 9, 10, 11, or
12 membered monocyclic, bicyclic, or tricyclic heterocyclic ring
that is aromatic, and which consists of carbon atoms and 1, 2, 3,
or 4 heteroatoms independently selected from the group consisting
of N, O, and S. If the heteroaryl group is bicyclic or tricyclic,
then at least one of the two or three rings must contain a
heteroatom, though both or all three may each contain one or more
heteroatoms. If the heteroaryl group is bicyclic or tricyclic, then
only one of the rings must be aromatic. The N group may be N, NH,
or N-substituent, depending on the chosen ring and if substituents
are recited. The nitrogen and sulfur heteroatoms may optionally be
oxidized (e.g., S, S(O), S(O).sub.2, and N--O). The heteroaryl ring
may be attached to its pendant group at any heteroatom or carbon
atom that results in a stable structure. The heteroaryl rings
described herein may be substituted on carbon or on a nitrogen atom
if the resulting compound is stable.
[0100] Examples of heteroaryl includes acridinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,
carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,
oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl,
phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,
quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
1,3,4-triazolyl, and xanthenyl.
[0101] "Mammal" and "patient" cover warm blooded mammals that are
typically under medical care (e.g., humans and domesticated
animals). Examples include feline, canine, equine, bovine, and
human, as well as just human.
[0102] "Treating" or "treatment" covers the treatment of a
disease-state in a mammal, and includes: (a) preventing the
disease-state from occurring in a mammal, in particular, when such
mammal is predisposed to the disease-state but has not yet been
diagnosed as having it; (b) inhibiting the disease-state, i.e.,
arresting it development; and/or (c) relieving the disease-state,
i.e., causing regression of the disease state until a desired
endpoint is reached.
[0103] "Pharmaceutically acceptable salts" refer to derivatives of
the disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include, but are not limited to, those derived from inorganic and
organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic,
2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic,
benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic,
ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic,
glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,
hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,
hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,
maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,
pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,
propionic, salicyclic, stearic, subacetic, succinic, sulfamic,
sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
[0104] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound that contains
a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, non-aqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are useful. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
18th ed., Mack Publishing Company, Easton, Pa., 1990, p 1445, the
disclosure of which is hereby incorporated by reference.
[0105] "Therapeutically effective amount" includes an amount of a
compound of the present invention that is effective when
administered alone or in combination to treat obesity or another
indication listed herein. "Therapeutically effective amount" also
includes an amount of the combination of compounds claimed that is
effective to treat the desired indication. The combination of
compounds can be a synergistic combination. Synergy, as described,
for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,
22:27-55, occurs when the effect of the compounds when administered
in combination is greater than the additive effect of the compounds
when administered alone as a single agent. In general, a
synergistic effect is most clearly demonstrated at sub-optimal
concentrations of the compounds. Synergy can be in terms of lower
cytotoxicity, increased effect, or some other beneficial effect of
the combination compared with the individual components.
[0106] Obesity is defined as having a body mass index (BMI) of 30
or above. The index is a measure of an individual's body weight
relative to height. BMI is calculated by dividing body weight (in
kilograms) by height (in meters) squared. Normal and healthy body
weight is defined as having a BMI between 20 and 24.9. Overweight
is defined as having a BMI.gtoreq.25. Obesity has reached epidemic
proportions in the U.S., with 44 million obese Americans, and an
additional eighty million deemed medically overweight.
[0107] Obesity is a disease characterized as a condition resulting
from the excess accumulation of adipose tissue, especially adipose
tissue localized in the abdominal area. It is desirable to treat
overweight or obese patients by reducing their amount of adipose
tissue, and thereby reducing their overall body weight to within
the normal range for their sex and height. In this way, their risk
for co-morbidities such as diabetes and cardiovascular disease will
be reduced. It is also desirable to prevent normal weight
individuals from accumulating additional, excess adipose tissue,
effectively maintaining their body weights at a BMI<25, and
preventing the development of co-morbidities. It is also desirable
to control obesity, effectively preventing overweight and obese
individuals from accumulating additional, excess adipose tissue,
reducing the risk of further exacerbating their co-morbidities.
[0108] Type 2 Diabetes or Diabetes mellitus type 2 or (formerly
called non-insulin-dependent diabetes mellitus (NIDDM), or
adult-onset diabetes) is a metabolic disorder that is primarily
characterized by insulin resistance, relative insulin deficiency,
and hyperglycemia. The World Health Organization definition of
diabetes is for a single raised glucose reading with symptoms
otherwise raised values on two occasions, of either fasting plasma
glucose.gtoreq.7.0 mmol/l (126 mg/dl) or with a Glucose tolerance
test: two hours after the oral dose a plasma glucose.gtoreq.11.1
mmol/l (200 mg/dl). Type 2 Diabetes is rapidly increasing in the
developed world and there is some evidence that this pattern will
be followed in much of the rest of the world in coming years. CDC
has characterized the increase as an epidemic (Diabetes, Atlanta:
Centres for Disease Control, Atlanta, Report no. 2007-05-24). In
addition, whereas this disease used to be seen primarily in adults
over age 40 (in contrast to Diabetes mellitus type 1), it is now
increasingly seen in children and adolescents, an increase thought
to be linked to rising rates of obesity in this age group.
[0109] Insulin resistance means that body cells do not respond
appropriately when insulin is present. Unlike insulin-dependent
diabetes mellitus (Type 1), the insulin resistance is generally
"post-receptor", meaning it is a problem with the cells that
respond to insulin rather than a problem with insulin production.
Type 2 diabetes is presently of unknown etiology (i.e., origin).
About 90-95% of all North American cases of diabetes are type 2,
and about 20% of the population over the age of 65 has diabetes
mellitus Type 2 (Nature, 2001, 414, 6865). Diabetes affects over
150 million people worldwide and this number is expected to double
by 2025. About 55 percent of type 2 diabetics are obese-chronic
obesity leads to increased insulin resistance that can develop into
diabetes (Morbidity and Mortality Weekly Report 2008, 53, 1066).
Type 2 diabetes is often associated with obesity, hypertension,
elevated cholesterol (combined hyperlipidemia), and with the
condition often termed Metabolic syndrome (it is also known as
Syndrome X, Reavan's syndrome, or CHAOS). There are several drugs
available for Type 2 diabetics, including metformin,
thiazolidinediones, which increase tissue insulin sensitivity,
.alpha.-glucosidase inhibitors which interfere with absorption of
some glucose containing nutrients, and peptide analogs that must be
injected.
[0110] Dyslipidemia is the presence of abnormal levels of lipids
and/or lipoproteins in the blood. Lipids (fatty molecules) are
transported in a protein capsule, and the density of the lipids and
type of protein determines the fate of the particle and its
influence on metabolism. Lipid and lipoprotein abnormalities are
extremely common in the general population, and are regarded as a
highly modifiable risk factor for cardiovascular disease due to the
influence of cholesterol, one of the most clinically relevant lipid
substances, on atherosclerosis. In addition, some forms may
predispose to acute pancreatitis.
[0111] In western societies, most dyslipidemias are
hyperlipidemias; that is, an elevation of lipids in the blood,
often due to diet and lifestyle. The prolonged elevation of insulin
levels can also lead to dyslipidemia. The most prevalent
hyperlipidemias include: hypercholesterolemia, characterized by
elevated cholesterol (usually LDL), hypertriglyceridemia,
characterized by elevated triglycerides (TGs);
hyperlipoproteinemia, characterized by elevated lipoproteins;
hyperchylomicronemia, characterized by elevated chylomicrons; and
combined hyperlipidemia, characterized by elevated LDL and
triglycerides. Abnormal decreases in the levels of lipids and/or
lipoproteins in the blood also can occur. These include
hypocholesterolemia, characterized by lowered cholesterol (usually
high density lipoprotein, or HDL); and abetalipoproteinemia,
characterized by lowered beta lipoproteins.
[0112] Dyslipidemia contributes to the development of
atherosclerosis. Causes may be primary (genetic) or secondary.
Diagnosis is by measuring plasma levels of total cholesterol, TGs,
and individual lipoproteins. Treatment is dietary changes,
exercise, and lipid-lowering drugs. A linear relation probably
exists between lipid levels and cardiovascular risk, so many people
with "normal" cholesterol levels benefit from achieving still lower
levels. Normal and abnormal lipid levels have been defined in the
Third Report of the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults. National Institutes
of Health, National Heart, Lung, and Blood Institute, 2001.
[0113] The treatment of choice for dyslipidemias is lifestyle
change, including diet and exercise. Drugs are the next step when
lifestyle changes are not effective. Lipid lowering drugs include
statins, nicotinic acid, bile acid sequestrants, fibrates,
cholesterol absorption inhibitors, and combination treatments
(e.g., niacin and a statin). These agents are not without adverse
effects, including flushing and impaired glucose tolerance
(nicotinic acid), bloating, nausea, cramping, and constipation
(bile acid sequestrants). Bile acid sequestrants may also increase
TGs, so their use is contraindicated in patients with
hypertriglyceridemia. Fibrates potentiate muscle toxicity when used
with statins, and may increase LDL in patients with high TGs.
[0114] Drugs enter the CNS from the systemic circulation by
crossing the blood-brain barrier (BBB). The BBB is a highly
specialized `gate-keeper` that protects the brain by preventing the
entry of many potentially harmful substances into the CNS from the
systemic circulation. Much is known about the BBB, and of the
physical-chemical properties required for compounds transported
across it.
[0115] Drugs that do not cross the BBB into the CNS or that are
readily eliminated through transport mechanisms (J. Clin. Invest.
1996, 97, 2517) are known in the literature and have low CNS
activity due to their inability to develop brain levels necessary
for pharmacological action. The BBB has at least one mechanism to
remove drugs prior to their accumulation in the CNS.
P-Glycoproteins (P-gp) localized in plasma membrane of the BBB can
influence the brain penetration and pharmacological activity of
many drugs through translocation across membranes. The lack of
accumulation into the brain by some drugs can be explained by their
active removal from the brain by P-gp residing in the BBB. For
example, the typical opioid drug loperamide, clinically used as an
antidiarrheal, is actively removed from the brain by P-gp, thus
explaining its lack of opiate-like CNS effects. Another example is
domperidone, a dopamine receptor blocker that participates in the
P-gp transport (J. Clin. Invest. 1996, 97, 2517). Whereas dopamine
receptor blockers that cross the BBB can be used to treat
schizophrenia, the readily-eliminated domperidone can be used to
prevent emesis, without the likelihood of producing adverse CNS
effects.
[0116] In addition to the above compounds, agents possessing
structural characteristics that retard or prevent BBB penetration
or contribute to participation in active elimination processes have
been identified in various classes of therapeutics. These include
antihistamines (Drug Metab. Dispos. 2003, 31, 312), beta-adrenergic
receptor antagonists (Eur. J. Clin. Pharmacol. 1985, 28, Suppl: 21;
Br. J. Clin. Pharmacol., 1981, 11, 549), non-nucleoside reverse
transcriptase inhibitors (NNRTIs, J. Pharm. Sci., 1999, 88, 950),
and opioid antagonists. This latter group has been tested in
relation to their activity in the gastrointestinal tract. These
peripherally selective opioid antagonists are described in various
US patents as being useful in the treatment of non-CNS pathologies
in mammals, in particular those of the gastrointestinal tract [see
U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S. Pat. No.
5,159,081; and U.S. Pat. No. 5,270,238].
[0117] Other types of non-brain penetrant compounds can be prepared
through the creation of a charge within the molecule. Thus, the
addition of a methyl group to the tertiary amine functionality of
the drugs scopolamine or atropine, unlike the parent molecules,
prevents their passage across the BBB through the presence of a
positive charge. However, the new molecules (methyl-scopolamine and
methyl-atropine) retain their full anticholinergic pharmacological
properties. As such, these drugs can also be used to treat
peripheral diseases, without the concern of adverse CNS effects.
The quaternary ammonium compound methylnaltrexone is also used for
the prevention and/or treatment of opioid-induced gastrointestinal
side effects associated with opioid administration (J. Pharmacol.
Exp. Ther. 2002, 300, 118).
[0118] The discovery that the anti-obesity activity of cannabinoid
receptor blockers may in part be mediated by a non-CNS mechanism
could make it beneficial for the compounds of the present invention
to be peripherally restricted (i.e., have an inability or limited
ability to cross the BBB, or be readily eliminated from the brain
through active transport systems). It may be desirable for the
compounds of the present invention to be peripherally restricted,
which in turn will result in no or very limited CNS effects.
Compounds that provide peripherally mediated anti-obesity,
anti-diabetic, or anti-dyslipidemic properties should result in
therapeutic agents with greater safety. It can be desirable that
the compounds of the present invention, when administered in a
therapeutically effective amount, have no or very limited CNS
effects. It can also be desirable that the lack of CNS effects is a
result of the compounds of the present invention having minimal
brain concentrations when administered in therapeutically effective
amounts. In this context, minimal brain concentrations means levels
that are too low to be therapeutically effective for the treatment
of a CNS indication or too low to cause significant or measurable
deleterious or undesired side effects, or both.
[0119] SLV319 (Compound I when X and X'' are 4-Cl; X', Y, Y', Y'',
Z, and Z' are H; Q is CH.sub.3; and M is SO.sub.2) is a drug that
crosses the BBB and is indicated for the treatment of obesity. It
is believed that SLV319 works to treat obesity via a CNS mechanism.
Compounds like SLV319 and compound AA have been described in
various publications including J. Med. Chem. 2004, 47(3), 627 and
U.S. Pat. No. 6,476,060.
##STR00006##
In compound AA, one of X, Y, X', Y', X'', Y, Z, Z', or Q is a group
capable of reducing or limiting the CNS activity of compound AA.
This reduced or limited CNS activity occurs via at least one of X,
Y, X', Y', X'', Y, Z, Z', and Q being a group that either limits
compound AA's ability to cross the BBB relative to that of SLV319
or enables it to be actively removed from the brain at a rate
greater than that of SLV319. Examples of the amount of compound AA
present in the brain can include (a) from 50, 55, 60, 65, 70, 75,
80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than
SLV319, (b) from 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100%
lower than SLV319, and (c) from 98, 99, to 100% lower than SLV319,
when administered at the same dosage.
[0120] The compounds of the present invention are expected to be
cannabinoid receptor antagonists or inverse agonists (e.g., have
activity at .ltoreq.10 .mu.M). Representative compounds have been
tested and shown to be active (e.g., see Tables A, B, and C).
[0121] An inverse agonist is a compound that not only blocks the
action of the endogenous agonist at the receptor, but also exhibits
its own activity which is usually the opposite of that shown by the
agonist. Inverse agonists are also effective against certain types
of receptors (e.g. certain histamine receptors/GABA receptors) that
have intrinsic activity without the interaction of a ligand upon
them (also referred to as `constitutive activity`).
[0122] Most methods of treating obesity are dependent on a
significant reduction in energy intake, either by a decrease in
food intake (e.g., sibutramine) or by inhibition of fat absorption
(e.g., orlistat). In the present invention, adipose tissue may be
reduced in the absence of a significant reduction in food intake.
The weight loss, as a result of the present invention, comes from
the treatment with a compound of the present invention, largely
independent of, though not totally dissociated from, appetite and
food intake. It can be desirable that adipose tissue loss occurs
while food intake is maintained, increased or (a) about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% below
the normal range of the subject prior to being treated in
accordance with the present invention (i.e., its pre-administration
level), (b) about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or
15% below its pre-administration level, (c) about 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10% below its pre-administration level, or (d) about 1,
2, 3, 4, or 5% below its pre-administration level.
[0123] In some cases, loss of adipose tissue can be accompanied by
a concomitant loss of lean muscle mass. This is particularly
evident in cancer patients who show a generalized wasting of body
tissues, including adipose tissue and lean muscle mass. In the
present invention, however, it can be desirable for body fat to be
significantly reduced in the absence of a significant reduction in
lean body mass. Adipose tissue loss comes from treatment with a
compound of the present invention, independent of a significant
change in lean body mass. Thus, adipose tissue loss can occur while
lean body mass is maintained, increased, or (a) is no more than
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the
normal range of the subject prior to being treated in accordance
with the present invention (i.e., its pre-administration level),
(b) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, or 15% below pre-administration levels, (c) is no more than
about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration
levels, or (d) is no more than about 1, 2, 3, 4, or 5% below
pre-administration levels.
[0124] In some cases, loss of adipose tissue can be accompanied by
a concomitant loss of water mass. This is particularly evident with
diet regimens that promote dehydration. In the present invention,
it can be desirable for body fat to be significantly reduced in the
absence of a significant reduction in water mass. In other words,
adipose tissue loss comes from treatment with a compound of the
present invention, independent of a significant change in water
mass. It can be desirable that adipose tissue loss occurs while
water mass is maintained, increased, or (a) is no more than about
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal
range of the subject prior to being treated in accordance with the
present invention (i.e., its pre-administration level), (b) is no
more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or
15% below pre-administration levels, (c) is no more than about 1,
2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels, or
(d) is no more than about 1, 2, 3, 4, or 5% below
pre-administration levels.
[0125] Sibutramine and orlistat are currently marketed for use in
the treatment of obesity, albeit weight loss is achieved through
entirely different mechanism of action. Sibutramine inhibits the
neuronal reuptake of serotonin and noradrenaline, and orlistat
inhibits gut lipase enzymes that are responsible for breaking down
ingested fat.
[0126] Cannabinoid receptor blockers can promote weight loss
through inhibition of peripheral cannabinoid receptors, a mechanism
entirely different from appetite suppressants, gut lipase
inhibitors, and other agents with similar indications (e.g.,
serotonin agonists, leptin, fatty acid synthase inhibitors, and
monoamine oxidase (MAO) inhibitors). Co-administration of a
cannabinoid receptor blocker together with one or more other agents
that are useful for treating the indications described above (e.g.,
obesity, diabetes, dyslipidemia, cardiovascular disorders, hepatic
disorders, and a combination thereof) is expected to be beneficial,
by producing, for example, either additive or synergistic effects.
Examples of additional agents include an appetite suppressant, a
lipase inhibitor, and a MAO inhibitor (e.g., MAO-B and a
combination of MAO-A/B). Therefore, the present invention provides
a method of treating obesity, diabetes, dyslipidemia,
cardiovascular disorders, and/or hepatic disorders, and a
combination thereof, comprising administering a therapeutically
effective amount of a compound of the present invention and a
second component effective for treating the desired indication.
[0127] Examples of second components include anti-obesity agents,
which include, but are not limited to: 1) growth hormone
secretagogues; 2) growth hormone secretagogue receptor
agonists/antagonists; 3) melanocortin agonists; 4) Mc4r
(melanocortin 4 receptor) agonists; 5) .beta.-3 agonists; 7) 5HT2C
(serotonin receptor 2C) agonists; 8) orexin antagonists; 9) melanin
concentrating hormone antagonists; 10) melanin-concentrating
hormone 1 receptor (MCH1R) antagonists; 11) melanin-concentrating
hormone 2 receptor (MCH2R) agonist/antagonists; 12) galanin
antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin-A)
agonists; 16) corticotropin-releasing hormone agonists; 17) NPY 5
antagonists; 18) NPY 1 antagonists; 19) histamine receptor-3 (H3)
modulators; 20) histamine receptor-3 (H3) blockers; 21)
.beta.-hydroxy steroid dehydrogenase-1 inhibitors (.beta.-HSD-1);
22) PDE (phosphodiesterase) inhibitors; 23) phosphodiesterase-3B
(PDE3B) inhibitors; 24) NE (norepinephrine) transport inhibitors;
25) non-selective serotonin/norepinephrine transport inhibitors,
such as sibutramine, phentermine, or fenfluramine; 26) ghrelin
antagonists; 28) leptin derivatives; 29) BRS3 (bombesin receptor
subtype 3) agonists; 30) CNTF (Ciliary neurotrophic factors); 31)
CNTF derivatives, such as axokine (Regeneron); 32) monoamine
reuptake inhibitors; 33) UCP-1 (uncoupling protein-1), 2, or 3
activators; 34) thyroid hormone .beta. agonists; 35) FAS (fatty
acid synthase) inhibitors; 37) DGAT2 (diacylglycerol
acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2)
inhibitors; 39) glucocorticoid antagonists; 40) acyl-estrogens; 41)
lipase inhibitors, such as orlistat (Xenical.RTM.); 42) fatty acid
transporter inhibitors; 43) dicarboxylate transporter inhibitors;
44) glucose transporter inhibitors; 45) phosphate transporter
inhibitors; 46) serotonin reuptake inhibitors; 47) Metformin
(Glucophage.RTM.); 48) Topiramate (Topimax.RTM.); 49) opiate
antagonists such as naltrexone, 50) the non-selective transport
inhibitor bupropion, and/or 51) MAO inhibitors.
[0128] Examples of MAO inhibitors include Moclobemide; Brofaromine;
BW A616U; Ro 41-1049; RS-2232; SR 95191; Harmaline; Harman;
Amiflamine; BW 1370U87; FLA 688; FLA 788; Bifemelane; Clorgyline;
LY 51641; MDL 72,394;
544-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one;
5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazoles; Lazabemide; Ro
16-6491; Almoxatone; XB308; RS-1636; RS-1653; NW-1015; SL 340026;.
L-selegiline; Rasagiline; Pargyline; AGN 1135; MDL 72,974; MDL
72,145; MDL 72,638; LY 54761; MD 780236; MD 240931; Bifemelane;
Toloxatone; Cimoxatone; Iproniazid; Phenelzine; Nialamide;
Phenylhydrazine; 1-Phenylcyclopropylamine; Isocarboxazid; and,
Tranylcypromine. Additional examples of MAO inhibitors can be found
in USPA 2007/0004683; U.S. Ser. No. 11/445,044; USPA 2007/0015734;
and U.S. Ser. No. 11/424,274.
[0129] Examples of diabetes disorders include treating Type 1
diabetes, Type 2 diabetes, inadequate glucose tolerance, and
insulin resistance.
[0130] Examples of second components useful for treating diabetes
include (a) insulin sensitizers including (i) PPAR-.gamma. agonists
such as the glitazones (e.g. troglitazone, pioglitazone,
englitazone, MCC-555, rosiglitazone), and compounds disclosed in
WO97/27857, 97/28115, 97/28137, and 97/27847; and (ii) biguanides
such as metformin and phenformin; (b) insulin or insulin mimetics;
(c) sulfonylureas such as tolbutamide and glipizide, or related
materials; (d) .alpha.-glucosidase inhibitors (e.g., acarbose); (e)
cholesterol lowering agents such as (i) HMG-CoA reductase
inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, rivastatin, and other statins), (ii) sequestrants
(e.g., cholestyramine, colestipol, and dialkylaminoalkyl
derivatives of a cross-linked dextran), (iii) nicotinyl alcohol,
nicotinic acid or a salt thereof, (iv) PPAR-.alpha. agonists (e.g.,
fenofibric acid derivatives including gemfibrozil, clofibrate,
fenofibrate, and bezafibrate), (v) inhibitors of cholesterol
absorption (e.g., .beta.-sitosterol) and acyl CoA: cholesterol
acyltransferase inhibitors (e.g., melinamide), and (vi) probucol;
(f) PPAR-.alpha./.gamma. agonists; (g) antiobesity compounds
(described previously); (h) ileal bile acid transporter inhibitors;
(i) insulin receptor activators, (j) dipeptidyl peptidase IV, or
DPP-4 inhibitors (sitagliptin, vildagliptin and other DPP-4
inhibitors (k) exenatide, (l) pramLintide, (m) FBPase inhibitors,
(n) glucagon receptor antagonists, (o) glucagon-like peptide -1,
and (p) the glucagon-like peptide -1 analogues (liraglutide, and
others).
[0131] The compounds of the present invention are expected to be
CB1 receptor blockers and are expected to be useful for treating
diseases mediated by the CB.sub.1 receptor. The compounds of the
present are expected to possess an affinity in vitro for the
central and/or peripheral cannabinoid receptors under the
experimental conditions described by Devane et al., Molecular
Pharmacology, 1988, 34, 605-613. The compounds according to the
invention are also expected to possess an affinity for the
cannabinoid receptors present on preparations of electrically
stimulated isolated organs. These tests can be performed on
guinea-pig ileum and on mouse vas deferens according to Roselt et
al., Acta Physiologica Scandinavia 1975, 94, 142-144, and according
to Nicolau et al., Arch. Int. Pharmacodyn, 1978, 236, 131-136.
[0132] CB1 receptor affinities can be determined using membrane
preparations of Chinese hamster ovary (CHO) cells in which the
human cannabinoid CB1 receptor is stably transfected (Biochem J.
1991, 279, 129-134) in conjunction with [3H]CP-55,940 as
radioligand. After incubation of a freshly prepared cell membrane
preparation with the [3H]-radioligand, with or without addition of
test compound, separation of bound and free ligand is performed by
filtration over glass fiber filters. Radioactivity on the filter is
measured by liquid scintillation counting. The IC.sub.50 values can
be determined from at least three independent measurements.
[0133] Formulations and Dosages
[0134] In the present invention, the compound(s) of the present
invention can be administered in any convenient manner (e.g.,
enterally or parenterally). Examples of methods of administration
include orally and transdermally. One skilled in this art is aware
that the routes of administering the compounds of the present
invention may vary significantly. In addition to other oral
administrations, sustained release compositions may be favored.
Other acceptable routes may include injections (e.g., intravenous,
intramuscular, subcutaneous, and intraperitoneal); subdermal
implants; and, buccal, sublingual, topical, rectal, vaginal, and
intranasal administrations. Bioerodible, non-bioerodible,
biodegradable, and non-biodegradable systems of administration may
also be used. Examples of oral formulations include tablets, coated
tablets, hard and soft gelatin capsules, solutions, emulsions, and
suspensions.
[0135] If a solid composition in the form of tablets is prepared,
the main active ingredient can be mixed with a pharmaceutical
vehicle, examples of which include silica, starch, lactose,
magnesium stearate, and talc. The tablets can be coated with
sucrose or another appropriate substance or they can be treated so
as to have a sustained or delayed activity and so as to release a
predetermined amount of active ingredient continuously. Gelatin
capsules can be obtained by mixing the active ingredient with a
diluent and incorporating the resulting mixture into soft or hard
gelatin capsules. A syrup or elixir can contain the active
ingredient in conjunction with a sweetener, which is typically
calorie-free, an antiseptic (e.g., methylparaben and/or
propylparaben), a flavoring, and an appropriate color.
Water-dispersible powders or granules can contain the active
ingredient mixed with dispersants or wetting agents or with
suspending agents such as polyvinylpyrrolidone, as well as with
sweeteners or taste correctors. Rectal administration can be
effected using suppositories, which are prepared with binders
melting at the rectal temperature (e.g., cocoa butter and/or
polyethylene glycols). Parenteral administration can be effected
using aqueous suspensions, isotonic saline solutions, or injectable
sterile solutions, which contain pharmacologically compatible
dispersants and/or wetting agents (e.g., propylene glycol and/or
polyethylene glycol). The active ingredient can also be formulated
as microcapsules or microspheres, optionally with one or more
carriers or additives. The active ingredient can also be presented
in the form of a complex with a cyclodextrin, for example .alpha.-,
.beta.-, or .gamma.-cyclodextrin,
2-hydroxypropyl-.beta.-cyclodextrin, and/or
methyl-.beta.-cyclodextrin.
[0136] The dose of the compound of the present invention
administered daily will vary on an individual basis and to some
extent may be determined by the severity of the disease being
treated (e.g., obesity, diabetes, and cardiometabolic disorders).
The dose of the compound of the present invention will also vary
depending on the compound administered. Examples of dosages of
compounds of the present invention include from about 0.01, 0.02,
0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5,
0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100
mg/kg of mammal body weight. The compound can be administered in a
single dose or in a number of smaller doses over a period of time.
The length of time during which the compound is administered varies
on an individual basis, and can continue until the desired results
are achieved (i.e., reduction of body fat, or prevention of a gain
in body fat). Therapy could, therefore, last from 1 day to weeks,
months, or even years depending upon the subject being treated, the
desired results, and how quickly the subject responds to treatment
in accordance with the present invention.
[0137] A possible example of a tablet of the present invention is
as follows.
TABLE-US-00001 Ingredient mg/Tablet Active ingredient 100 Powdered
lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na
carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250
[0138] A possible example of a capsule of the present invention is
as follows.
TABLE-US-00002 Ingredient mg/Tablet Active ingredient 50
Crystalline lactose 60 Microcrystalline cellulose 34 Talc 5
Magnesium stearate 1 Capsule fill weight 150
[0139] In the above capsule, the active ingredient has a suitable
particle size. The crystalline lactose and the microcrystalline
cellulose are homogeneously mixed with one another, sieved, and
thereafter the talc and magnesium stearate are admixed. The final
mixture is filled into hard gelatin capsules of suitable size.
[0140] A possible example of an injection solution of the present
invention is as follows.
TABLE-US-00003 Ingredient mg/Tablet Active substance 1.0 mg 1N HCl
20.0 .mu.l acetic acid 0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1N NaOH
q.s. ad pH 5 H.sub.2O q.s. ad 1 mL
Synthesis
[0141] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic synthesis
(e.g., see U.S. Pat. No. 6,476,060 B2, J Med Chem 2004, 47, 627).
The compounds of the present invention can be synthesized using the
methods described below, together with synthetic methods known in
the art of synthetic organic chemistry, or by variations thereon as
appreciated by those skilled in the art. Preferred methods include,
but are not limited to, those described below. The reactions are
performed in a solvent appropriate to the reagents and materials
employed and suitable for the transformations being effected. It
will be understood by those skilled in the art of organic synthesis
that the functionality present on the molecule should be consistent
with the transformations proposed. This will sometimes require a
judgment to modify the order of the synthetic steps or to select
one particular process scheme over another in order to obtain a
desired compound of the invention. It will also be recognized that
another major consideration in the planning of any synthetic route
in this field is the judicious choice of the protecting group used
for protection of the reactive functional groups present in the
compounds described in this invention. An authoritative account
describing the many alternatives to the trained practitioner is
Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and
Sons, 1991). All references cited herein are hereby incorporated in
their entirety herein by reference.
##STR00007##
[0142] Scheme 1 shows how to convert 2'-, 3'-, or
4'-(carbo-t-butoxymethoxy)-2-phenylacetophenones, prepared from
commercially available 2'-, 3'- or 4'-methoxy-2-phenylacetophenones
via O-demethylation using HBr/HOAc or BBr.sub.3/CH.sub.2Cl.sub.2
and alkylation of the resultant phenol with t-butyl bromoacetate in
the presence of base, in 37% aqueous formaldehyde containing
piperidine under reflux to the corresponding acrylophenones (step
a). Treatment of the acrylophenones with hydrazine hydrate in
ethanol can produce the 3,4-diarylpyrazolines (step b). The
diarylpyrazolines can be further treated with
arylsulfonyldithioimidocarbonic acid methyl esters, prepared from
the corresponding aryl sulfonamides, CS.sub.2 and MeI (see J. Med
Chem., 47, 627 (2004); Chem. Ber. 1966, 99, 2885), in a solvent
(e.g., acetonitrile) in the presence of triethylamine at reflux to
yield the pyrazole-1-carboximidothioic acid methyl ester (step c).
Further exposure of these iminothioethers to an aqueous solution of
methylamine and methylene chloride at room temperature should
afford the pyrazoline-1-carboxamidines (step d). Hydrolysis of the
ester using TFA/CH.sub.2Cl.sub.2 should produce the carboxylic acid
(step e).
##STR00008##
[0143] Scheme 2 describes how 2-(2'-, 3'- or
4'-carbo-t-butoxymethoxyphenyl)acetophenones (prepared similarly to
scheme 1) should provide the corresponding acrylophenones (step a).
Treatment of the acrylophenones with hydrazine hydrate in ethanol
can produce the 3,4-diarylpyrazolines (step b). The
diarylpyrazolines can be further treated with
arylsulfonyldithioimidocarbonic acid methyl esters in a solvent
like acetonitrile in the presence of triethylamine at reflux to
yield pyrazole-1-carboximidothioic acid methyl esters (step c).
Further exposure of these iminothioethers to an aqueous solution of
methylamine and methylene chloride at room temperature should
afford the pyrazoline-1-carboxamidines (step d). Hydrolysis of the
ester using TFA/CH.sub.2Cl.sub.2 should produce the carboxylic acid
(step e).
##STR00009##
[0144] Scheme 3 shows the conversion of
4'-chloro-2-phenylacetophenone in 37% aqueous formalin and MeOH
containing piperidine and acetic acid at reflux that should occur
affording the acrylophenone (J. Agric. Food Chem. 1979, 27(2), 406)
(step a). Treatment of the acrylophenone with hydrazine hydrate in
ethanol can produce the 3,4-diarylpyrazolines (step b). The
diarylpyrazolines can be further treated with
arylsulfonyldithioimidocarbonic acid methyl esters in a solvent
like acetonitrile in the presence of triethylamine at reflux to
yield the pyrazole-1-carboximidothioic acid methyl ester (step c).
Further exposure of these iminothioethers to beta-alanine t-butyl
ester in ethanol and methylene chloride containing triethylamine
should yield the pyrazoline-esters (step d). Hydrolysis of the
ester using TFA/CH.sub.2Cl.sub.2 should produce the carboxylic acid
(step e). Treatment of the ester with anhydrous ammonia in methanol
at about 0.degree. to room temperature can afford the carboxamido
compound (step f). Alternatively, the iminothioethers can be
coupled with other amino acid esters to give adducts (step g) that
can be hydrolyzed to the carboxylic acids (step h). These acids may
be converted to the carboxamides using oxalyl chloride in
dichloroethane followed by anhydrous ammonia, or Boc.sub.2O in
pyridine/THF followed by anhydrous ammonia (step i).
##STR00010##
[0145] Scheme 4 illustrates how oxidation of
4'-chloro-2-phenylacrylophenone in methylene chloride with
m-chloroperbenzoic acid should provide the epoxide (step a), which
upon treatment with hydrazine hydrate in ethanol solution at about
35-40.degree. C. can give the 3,4-diarylpyrazoline alcohol (step
b). The pyrazoline can be protected using di-t-butyl-dicarbonate
(t-Boc anhydride) in the presence of a base to give the
N-t-BOC-pyrazoline (step c). The carbamate alcohol can then be
deprotonated with sodium hydride in a solvent like DMF followed by
alkylation with ethyl 4-bromocrotonate to yield the ester (step d).
Removal of the t-BOC group can be achieved via treatment with TFA
(step e). The pyrazoline can then be reacted with
arylsulfonyldithioimidocarbonic acid methyl esters in a solvent
like acetonitrile in the presence of triethylamine at reflux to
yield the pyrazole-1-carboximidothioic acid methyl ether (step f).
Further exposure of these iminothioethers to an aqueous solution of
methylamine and methylene chloride at room temperature can afford
the pyrazoline-1-carboxamidines (step g), and hydrolysis of the
ester using LiOH in aqueous THF solution can produce the carboxylic
acid (step h). The carbxoamides can be prepared by treatment of the
ester with anhydrous ammonia in alcohol at -20.degree. C. to
ambient temperature (step i).
##STR00011##
[0146] Scheme 5 shows how heating a solution of the
3,4-diarylpyrazoline and S-methylisothiourea in pyridine can form
the pyrazoline-1-carboxamidine (step a). Treatment of this amidine
with t4-cyanobenzenesulfonyl choride in acetonitrile in the
presence of N.N-dimethyl-4-aminopyridine and triethylamine can give
the carboxamidine-coupled sulfonamide derivative (step b).
Conversion of the nitrile to the phenylcarboxamidine can be
accomplished using HCl (gas) in MeOH at 0.degree. C. to room
temperature, followed by ammonium carbonate or anhydrous ammonia in
MeOH at about 0.degree. C. to room temperature (step c).
##STR00012##
[0147] Scheme 6 describes how the reaction of a freshly prepared
anhydrous acetonitrile solution of 4-chlorobenzoylisothiocyanate,
made from 4-chlorobenzoylchloride and ammonium isocyanate (see J
Heterocycl. Chem. 1991, 28, 1645), and a 3,4-diarylpyrazoline
stirred in the cold can afford the pyrazoline--adduct (step a).
Treatment of this thiocarboxamide with amino compounds such as
ethyl beta-alanine in the presence of HgCl.sub.2 can produce the
benzoyl guanidines (step b). Hydrolysis of the ester using LiOH in
aqueous THF solution can produce the carboxylic acid (step c).
Further conversion of the acid to the acid chloride followed by
treatment with anhydrous ammonia should afford the carboxamide
(step d).
##STR00013##
[0148] Scheme 7 depicts how condensation of a solution of
4'-nitro-2-phenylacetophenone in 37% aqueous formalin and MeOH
containing piperidine and acetic acid should afford after heating
at reflux, the corresponding acrylophenone (step a). Treatment of
the acrylophenone with hydrazine hydrate in ethanol can produce the
3,4-diarylpyrazoline (step b). The pyrazoline can then be reacted
with arylsulfonyldithioimidocarbonic acid methyl esters in a
solvent like acetonitrile in the presence of triethylamine at
reflux to yield the corresponding pyrazole-1-carboximidothioic acid
methyl ester (step c). The nitro group can be reduced using sodium
dithionite in aqueous basic solution to produce the aniline
compound (step d). Acylation of the aniline with ethyl malonyl
chloride in the presence of base should produce the amide (step e).
Treatment of the amidoester with amines such as methylamine or
anhydrous ammonia in a solvent such as methanol or methylene
chloride at zero degrees to room temperature should afford the
pyrazole-1-carboxamidines with the terminal carboxamido group (step
f). Alternatively, the aniline compound can be treated with
methanesulfonyl chloride to give the sulfonamide (step g), which
upon exposure to an aqueous solution of methylamine and methylene
chloride at room temperature should afford the
pyrazoline-1-carboxamidines (step h).
##STR00014##
[0149] Scheme 8 illustrates how treatment of
4'-cyano-2-phenylacrylophenone with hydrazine hydrate in ethanol
will produce the 3,4-diarylpyrazoline (step a). The pyrazoline can
then be reacted with tri-n-butyltin azide, conveniently prepared in
situ by the reaction of one equivalent of sodium azide and one
equivalent of tri-n-butyltin chloride (see J. Med. Chem. 1991, 56,
2395), in reluxing toluene or xylene to afford the
tri-n-butyltin-tetrazole adduct (step b). The tri-n-butyltin-adduct
can be converted to the trityl-tetrazole adduct by treatment with
one equivalent of aqueous sodium hydroxide solution and one
equivalent of trityl chloride at room temperature (step c).
Reaction of this adduct with arylsulfonyldithioimidocarbonic acid
methyl esters in a solvent like acetonitrile in the presence of
triethylamine at reflux should yield the
pyrazole-1-carboximidothioic acid methyl ester (step d). Treatment
of the iminothioether with aqueous methylamine and methylene
chloride at room temperature should afford the
pyrazole-1-carboxamidines (step e). Removal of the trityl group
with aqueous TFA in THF at room temperature should yield the
unprotected tetrazole (step f).
##STR00015##
[0150] Scheme 9 shows how to convert 2'-, 3'-, or
4'-polyethoxylated analogs of 2-phenylacetophenones, prepared from
commercially available 2'-, 3'- or 4'-methoxy-2-phenylacetophenones
via O-demethylation using HBr/HOAc or BBr.sub.3/CH.sub.2Cl.sub.2
and alkylation of the resultant phenols with alkyl-capped or
TBDMS-capped halides prepared as described in Nuclear Medicine and
Biology, 32, 799 (2005). Treatment of these polyether ketones in
37% aqueous formaldehyde containing piperidine under reflux should
give the corresponding acrylophenones (step a). Treatment of the
acrylophenones with hydrazine hydrate in ethanol can produce the
3,4-diarylpyrazolines (step b). The diarylpyrazolines can be
further treated with arylsulfonyldithioimidocarbonic acid methyl
esters, prepared from the corresponding aryl sulfonamides, CS.sub.2
and MeI (see J. Med Chem., 47, 627 (2004); Chem. Ber. 1966, 99,
2885), in a solvent (e.g., acetonitrile) in the presence of
triethylamine at reflux to yield the pyrazole-1-carboximidothioic
acid methyl ester (step c). Further exposure of these
iminothioethers to an aqueous solution of methylamine and methylene
chloride at room temperature should afford the
pyrazoline-1-carboxamidines (step d). Removal of the TBDMS-capping
group using anhydrous tetrabutylammonium fluoride in THF should
produce the hydroxyl-PEG analog (step e).
[0151] One stereoisomer of a compound of the present invention may
be a more potent cannabinoid receptor antagonist than its
counterpart(s). Thus, stereoisomers are included in the present
invention. When required, separation of the racemic material can be
achieved by HPLC using a chiral column or by a resolution using a
resolving agent such as described in Wilen, S. H. Tables of
Resolving Agents and Optical Resolutions 1972, 308 or using
enantiomerically pure acids and bases. A chiral compound of the
present invention may also be directly synthesized using a chiral
catalyst or a chiral ligand, e.g., Jacobsen, E. Acc. Chem. Res.
2000, 33, 421-431 or using other enantio- and diastereo-selective
reactions and reagents known to one skilled in the art of
asymmetric synthesis. Examples of stereoisomers include compounds
shown below.
##STR00016## ##STR00017##
[0152] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments that
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
[0153] Tables A, B, and C show a variety of examples of compounds
of the present invention synthesized using the route described
below.
[0154] The following examples are representative of the procedures
used to prepare the preferred compounds in this application.
[0155] Abbreviations:
[0156] MeOH-methanol
[0157] DCM-dichloromethane
[0158] EtOAc-ethyl acetate
[0159] HCl-hydrochloric acid
[0160] PE-petroleum ether
[0161] NMM-N-methylmorpholine
[0162] IBCF-iso-butylchloroformate
[0163] TEA-triethylamine
[0164] The preparation of the diphenyl pyrazolines with optional
substituents on the 3-phenyl group were prepared according to the
procedures previously described [J. Med Chem., 47, 627(2004); J.
Agric. Food Chem., 27, 406 (1979)]. The pyrazolines were condensed
with sulfonylated carbamic acid methyl esters obtained from the
appropriately substituted sulfonamide and methyl chloroformate as
previously described. Chlorination of the product acylsulfonamides
with phosphorus pentachloride in heated cholorbenzene produced the
imidoylchlorides which were readily converted to the various amino
ester adducts as previously described [J. Med Chem., 47,
627(2004)]. Conversion of these esters to acids, carboxamides,
substituted carboxamides, or di-amino acid variants were carried
via conventional methodology, and procedures representative of this
chemistry are described below.
##STR00018##
Example 1
[0165] To 10 mmoles of imidoyl chloride suspended in 20 mL of DCM
was added dropwise to a cooled solution of 12 mmols of glycine
methyl ester hydrochloride salt and 25 mmoles of TEA in 50 mL DCM,
after the addition, the reaction mixture was allowed to warm to
ambient temperature. After stirring for about one hour, the solvent
was removed in vacuo and water (50 mL) was added and the mixture
was extracted with EtOAc. The combined extracts were washed with
brine, and then dried over anhydrous Na.sub.2SO.sub.4. After
solvent removal in vacuo the residue was purified by silica gel
column chromatogram (PE/EtOAc: 2/1) to afford the carboxamidine
(50-80% yields).
Example 2
[0166] Lithium hydroxide monohydrate (10 mmoles) and 5 mmoles of
carboxamidine ester in THF (50 mL) and water (16 mL) was stirred at
room temperature for 5-7 hrs. The pH of the solution was then
adjusted to .about.1-2 by the addition of 1N HCl solution, and the
solvent was removed under reduced pressure. Water (15 mL) was added
to the residue which was then extracted with EtOAc. The combined
extracts were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. The carboxylic acid products (70-95% yields) were
obtained by evaporation of the solvent in vacuo.
Example 3
[0167] The carboxylic acids (1 mmol), obtained from the ester by
the procedure described in Example 2, in 40 mL of dry DCM
containing NMM (3 mmol) was cooled to about -15.degree. C. with a
salt ice bath. A solution of IBCF (1.1 mmol) in dry DCM (20 mL) was
added dropwise over a 5 min period and after stirring for 20 mins
in an ice-brine bath, dry ammonia/THF solution was added in one
portion, and the reaction mixture was then allowed to slowly warm
to rt where it was stirred for 20 mins. The solvent was removed by
evaporation, and the residue was diluted with 20 mL of water and
extracted with EtOAc. The combined extracts were washed with 15 mL
of 1N HCl solution and 30 mL of brine, and then dried over
anhydrous Na.sub.2SO.sub.4. After filtration of the solution and
removal of the solvent in vacuo, the residue was purified by silica
gel chromatography to give the carboxamide adduct (60-80%
yields).
TABLE-US-00004 TABLE A ##STR00019## Number Q Y'' X'' X NMR ppm 1
CH(CH.sub.3)CH.sub.2CO.sub.2Et 4-Cl H Cl (CDCl.sub.3) 1.28, 3H, dq,
Me 1.35, 3H, dd, Me 2.65, 2H, dd, CH.sub.2 4.13-4.18, 3H, m, CH;
OCH.sub.2 4.60, 2H, m, CHs 5.20, 1H, m, CH 7.11-7.90, 13H, aromatic
Hs 2 CH(CH.sub.3)CH.sub.2CO.sub.2H 4-Cl H Cl (CD.sub.3OD) 1.30. 3H,
dd, Me 2.60, 2H, brd d, CH.sub.2 4.06, 1H, m, CH 4.53, 2H, m, CHs
4.90, 1H, m, CH 7.17-7.90, 13H, aromatic Hs 3 CH.sub.2CO.sub.2Me
4-Cl H Cl (CDCl.sub.3) 3.77, 3H, s, OMe 4.11, 1H, m, CH 4.43, 2H,
m, CH.sub.2 4.53, 1H, t, CH 4.64, 1H, m, CH 7.11-7.90, 13H,
aromatic Hs 4 CH.sub.2CO.sub.2H 4-Cl H Cl (CD.sub.3OD) 4.08, 1H, m,
CH 4.24, 2H, m, CH.sub.2 4.53, 1H, m, CH 4.90, 1H, m, CH 7.11-7.90,
13H, aromatic Hs 5 CH(CH.sub.3)CO.sub.2Me 4-Cl H Cl (CDCl.sub.3)
1.55, 3H, dd, Me, 3.71, 3H, s, OMe 4.16, 1H, m, CH 4.61, 2H, m, CHs
4.94, 1H, m, CH 7.09-7.90, 13H, aromatic Hs 6
CH(CHOHCH.sub.3)CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 1.36, 3H, m, Me,
3.73, 3H, d, OMe 4.15, 1H, m, CH 4.42, 1H, m, CH 4.60, 2H, m, CHs
4.85, 1H, m, CH 7.09-7.90, 13H, aromatic Hs 7
CH(C(CH.sub.3).sub.3)CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 1.14, 9H,
brd s, CH.sub.3 3.67, 3.69, 3H, 2s, OMe 3.90-4.95, 4H, 4brd s, CHs
7.22-7.89, 13H, aromatic Hs 8.30, 1H, brd s, NH 8
CH.sub.2CO.sub.2Me 4-OMe 3-OMe Cl (CDCl.sub.3) 3.77, 3H, s, OMe
3.88, 3.90, 6H, 2s, OMe s 4.12, 1H, dd, CH 4.45, 2H, d, CH.sub.2
4.53, 1H, t, CH 4.62, 1H, m, CH 6.85-7.58, 12H, aromatic Hs 7.77,
1H, brd s, NH 10 CH.sub.2CO.sub.2Me 4-OMe 3-Cl Cl (CDCl.sub.3)
3.79, 3H, s, OMe 3.93, 3H, s, OMe 4.12, 1H, dd, CH 4.44, 2H, d,
CH.sub.2 4.53, 1H, t, CH 4.63, 1H, m, CH 6.92-7.93, 12H, aromatic
Hs 11 CH(CH.sub.2OH)CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 3.76, 3.77,
3H, 2s, OMe 4.10, 3H, m, CH.sub.2OH, CH 4.52-4.70, 2H, brd m, CHs
5.02, 1H, m, CH 7.09-7.88, 13H, aromatic Hs 7.93, 1H, brd s, NH 12
CH.sub.2CONHCH.sub.2CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 3.74, 3H, s,
OMe 4.05, 1H, dd, CH 4.11, 2H, d, CH.sub.2CO 4.42, 2H, d,
CH.sub.2CO 4.49, 1H, t, CH 4.65, 1H, dd, CH 6.77, 1H, t, NH 7.78,
1H, brd s, NH 7.11-7.78, 13H, aromatic Hs 13
CH(CH.sub.3)CONH--CH.sub.2CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 1.57,
3H, d, CH.sub.3 3.71, 3H, s, OMe 3.93-4.23, 3H, overlap ms,
CH.sub.2, CH 4.58, 1H, m, CH 4.49, 1H, t, CH 4.65, 1H, m, CH 4.77,
4.83, 1H, 2t, CH 6.82, 1H, brd s, NH 7.09-7.89, 13H, aromatic Hs 14
CH(CH(CH.sub.3).sub.2)CONH--CH.sub.2CO.sub.2Me 4-Cl H Cl
(CDCl.sub.3) 1.12, 6H, m, CH.sub.3 2.37, 1H, brd s, CH 3.90-4.23,
3H, brd m, CH.sub.2, CH 4.41-4.80, 3H, brd m, CH.sub.2, CH 6.80,
1H, brd s, NH 7.08-7.88, 13H, aromatic Hs 15
CH.sub.2CONHCH.sub.2CO.sub.2Me 4-OMe H Cl (CDCl.sub.3) 3.72, 3H, s,
OMe 3.82, 3H, s, OMe 4.08, 1H, dd, CH 4.09, 2H, d, CH.sub.2CO 4.41,
2H, d, CH.sub.2CO 4.51, 1H, t, CH 4.63, 1H, dd, CH 6.83, 1H, t, NH
7.79, 1H, brd s, NH 6.88-7.88, 13H, aromatic Hs 16
CH.sub.2CONH.sub.2 4-Cl H Cl (CDCl.sub.3) 3.99, 1H, m, CH 4.40, 2H,
m, CH.sub.2 4.45, 1H, m, CH 4.65, 1H, m, CH 5.97, 1H, brd s, NH
6.50, 1H, brd s, NH 7.09-7.85, 13H, aromatic Hs 16
CH(CH.sub.3)CONH.sub.2 4-Cl H Cl (CDCl.sub.3) 1.57, 3H, dd, Me
3.97/4.13, 1H, 2m, CH 4.53, 1H, dq, CHMe 4.65, 1H, m, CH 4.73/4.80,
1H, 2m, CH 5.62, 1H, brd s, NH 6.45, 1H, brd s, NH 7.09-7.85, 13H,
aromatic Hs 17 CH.sub.2CH.sub.2CONH.sub.2 4-Cl H Cl (CDCl.sub.3)
2.68, 2H, t, CH.sub.2 3.94, 2H, q, CH.sub.2 4.05, 1H, m, CH 4.52,
1H, t, CH 4.68, 2H, m, CH 5.57, 1H, brd s, NH 5.92, 1H, brd s, NH
7.70, 1H, brd s, NH 7.10-7.90, 13H, aromatic Hs 18
CH(CH.sub.3)CH.sub.2CONH.sub.2 4-Cl H Cl (CDCl.sub.3) 1.38, 3H, dd,
CH.sub.3 1.60, 2H, brd m, CH.sub.2 4.04, 1H, m, CH 4.50, 1H, m, CH
4.67, 1H, m, CH 5.80, 1H, brd s, NH 6.38, 1H, brd s, NH 7.75, 1H,
brd m, NH 7.11-7.90, 13H, aromatic Hs 19
CH(C(CH.sub.3).sub.3)CONH.sub.2 4-Cl H Cl (CD.sub.3).sub.2SO 0.90,
0.99 9H, ds, tBu 3.78, 0.5H, brd s 4.11, 0.5H, brd s 4.40, 1H, m
4..55, 0.5H, m 4.79, 0.5H, brd s 4.92, 0.5H, brd s 5.21, 0.5H, brd
s 5.80, 1H, brd s, NH 7.21-7.95, 13H, aromatic Hs 20
CH(CH(CH.sub.3).sub.2)CONH.sub.2 4-Cl H Cl CD.sub.3OD 1.02, 6H, m,
i-Pr 4.00, 1H, brd m 4.52, 1H, brd m 7.18-7.95, 13H, aromatic Hs 21
CHCH(CH.sub.3).sub.2)--CONHCH.sub.3 4-Cl H Cl (CDCl.sub.3) 1.05,
6H, d, CH.sub.3 1.60, 2H, brd m, CH.sub.2 4.04, 1H, m, CH 4.50, 1H,
m, CH 4.67, 1H, m, CH 5.80, 1H, brd s, NH 6.38, 1H, brd s, NH 7.75,
1H, brd m, NH 7.11-7.90, 13H, aromatic Hs 22
CH(CHOHCH.sub.3)CONH.sub.2 4-Cl H Cl (CD.sub.3OD) 1.20, 3H, dd,
CH.sub.3 4.00, 1H, brd m, CH 4.34, 1H, m, mCH 4.53, 2H, m, CHs
7.19-7.91, 13H, aromatic Hs 23 CH.sub.2CONH.sub.2 4-OMe H Cl
(CDCl.sub.3) 3.80, 3H, s, OCH.sub.3 4.01, 1H, dd, CH 4.37, 2H, d,
CH.sub.2 4.47, 1H, t, CH 4.62, 1H, dd, CH 5.95, 1H, brd s, NH 6.63,
1H, brd s, NH 6.86-7.85, 13H, aromatic Hs 24 CH(CH.sub.3)CONH.sub.2
4-OMe H Cl CDCl.sub.3 1.58, 3H, d, CH.sub.3 3.83, 3H, s, OCH.sub.3
4.00, 4.13, 1H, 2 dd, CH 4.51, 1H, m, CH 4.62, 1H, m, CH 4.70,
4.82, 1H, 2 t, CH 5.52, 1H, brd s, NH 6.48, 1H, brd s, NH
6.90-7.86, 13H, aromatic Hs 25 CH(CH.sub.3)CONH.sub.2
4-OCH.sub.2--CN H Cl CDCl.sub.3 1.55, 3H, d, CH.sub.3 4.00, 4.12,
1H, 2m, CH 4.50, 1H, m, CH 4.65, 1H, m, CH 4.75, 1H, m, CH 4.80,
2H, d, OCH.sub.2 5.85, 1H, brd s, NH 6.50, 1H, brd s, NH 6.87-7.92,
13H, aromatic Hs 26 C(CH.sub.3).sub.2CONH.sub.2 4-Cl H Cl
CDCl.sub.3 1.55, 3H, s, CH.sub.3 1.56, 3H, s, CH.sub.3 4.29, 1H, m,
CH 4.72, 2H, m, CHs 5.47, 1H, brd s, NH 6.13, 1H, brd s, NH
7.10-7.84, 13H, aromatic Hs 27 CH.sub.2CH(CH.sub.3)CONH.sub.2 4-Cl
H Cl CDCl.sub.3 1.25, 3H, dd, CH.sub.3 2.85, 1H, m, CH 3.73, 2H,
dm, CHs 4.02, 1H, dd, CH 4.54, 1H, t, CH 4.66, 1H, m, CH 5.50, 1H,
brd s, NH 6.02, 1H, brd s, NH 7.10-7.86, 13H, aromatic Hs 28
CH(CH.sub.3)CONH.sub.2 4-OMe 4-OMe Cl CDCl.sub.3 1.57, 3H, dd,
CH.sub.3 3.86, 3.87, 3.90, 3.91, 6H, 4s, OMe s 4.02, 0.5H, dd, CH
4.50, 1H, dt, CH 4.65, 1H, m, CH 4.75, 4.85, 1H, 2m, CH 5.60, 1H,
brd s, NH 6.47, 1H, brd s, NH 6.85-7.60, 12H, aromatic Hs 29
CH(CH.sub.3)CONH.sub.2 4-OMe 3-Cl Cl CDCl.sub.3 1.58, 3H, dd,
CH.sub.3 3.92, 3.93, 3H, 2s, OMe 4.00, 4.10, 1H, 2dd, CH
4.50, 1H, dt, CH 4.65, 1H, m, CH 4.73, 4.82, 1H, 2t, CH 5.67, 1H,
d, NH 6.43, 1H, brd s, NH 6.91-7.92, 12H, aromatic Hs 30
CH.sub.2CONH.sub.2 4-Cl H OMe CDCl.sub.3 3.77, 3H, s, OMe 4.02, 1H,
dd, CH 4.38, 2H, q, CH.sub.2CO 4.45, 1H, t, CH 4.65, 1H, dd, CH
5.63, 1H, brd s, NH 6.28, 1H, brd s, NH 7.70, 1H, t, NH 6.78-7.85,
13H, aromatic Hs 31 CH(CH(CH.sub.3).sub.2)CONH.sub.2 3-OMe H Cl
CDCl.sub.3 1.10, 6H, m, CH.sub.3 3.79, 3.83, 3H, 2s, OCH.sub.3
3.99, 4.12, 1H, 2 m, CH 4.45, 1H, m, CH 4.57, 1H, dd, CH 4.65, 1H,
brd s, CH 5.80, 1H, brd m, NH 6.47, 1H, brd s, NH 7.00-7.52, 13H,
aromatic Hs 32 CH.sub.2CH.sub.2CONH.sub.2 4-Cl H Cl (CDCl.sub.3)
2.68, 2H, t, CH.sub.2 3.94, 2H, q, CH.sub.2 4.05, 1H, m, CH 4.52,
1H, t, CH 4.68, 2H, m, CH 5.57, 1H, brd s, NH 5.92, 1H, brd s, NH
7.70, 1H, brd s, NH 7.10-7.90, 13H, aromatic Hs
TABLE-US-00005 TABLE B ##STR00020## Number Q Y'' X'' X NMR ppm 1
CH.sub.2CH.sub.2CH(OH)CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 1.97, 1H,
m, CH.sub.2, 2.19, 1H, m, CH.sub.2 3.78, 2H, m, CH.sub.2NH 3.81,
3H, s, OMe 4.14, 1H, m, CH 4.34, 1H, m, CH 4.58, 2H, m, CHOH 4.66,
1H, m, CH 7.11-7.90, 13H, aromatic Hs 2
CH(CH.sub.2CO.sub.2tBu)CO.sub.2Me 4-Cl H Cl (CDCl.sub.3) 1.46, 9H,
s, CH.sub.3 3.00, 2H, m, CH.sub.2CO 4.10-4.35, 1H, brd m, CH 4.68,
2H, brd s, CHs 7.11-7.89, 13H, aromatic Hs 3
C(CH.sub.3).sub.2CO.sub.2H 4-Cl H Cl (CD.sub.3OD) 1.47, 1.48, 6H,
2s, CH.sub.3 4.35, 1H, m, CH 4.67, 1H, t, CH 4.96, 1H, m, CH
7.22-7.88, 13H, aromatic Hs 4
C(CH.sub.3).sub.2CONH--CH(CH.sub.3)CO.sub.2Me 4-Cl H Cl
(CDCl.sub.3) 1.56, 1.57, 6H, 2 s, CH.sub.3 3.55, 3.63, 3H, 2s, OMe
4.28, 1H, brd s, CH 4.50, 1H, t, CH 4.71, 2H, brd s, CHs 6.65, 1H,
t, NH 7.68, 1H, brd s, NH 7.08-7.86, 13H, aromatic Hs 8.30, 1H, brd
s, NH 5 CH(CH(CH.sub.3).sub.2)--CONHCH.sub.2CH.sub.2OH 4-OMe H Cl
(CD.sub.3OD) 1.01, 3H, dd, CH.sub.3 3.36, 2H, brd m, N--CH.sub.2
3.57, 2H, m, O--CH.sub.2 3.82, 3.83, 3H, 2s, OCH.sub.3 3.85, 3.92,
3H, 2m, CH 4.50, 1H, m, CH 4.90, 2 H, brd m 6.96-7.84, 13H,
aromatic Hs 6 CH.sub.2CH(OH)CH.sub.2CONH.sub.2 4-Cl H Cl CDCl.sub.3
2.48, 2H, m, CH.sub.2CO 3.68, 1H, m, NCH 3.82, 1H, m, NCH 4.03, 1H,
2 dd, CH 4.30, 1H, brd s, OCH 4.48, 1H, q, CH 4.66, 1H, m, CH 5.77,
1H, brd s, NH 6.39, 1H, brd s, NH 6.89-7.84, 13H, aromatic Hs 7
CHCH(CH.sub.3).sub.2CONH--CH(CH.sub.2OH).sub.2 4-Cl H Cl CD.sub.3OD
1.02, 6H, m, CH.sub.3 3.63, 4H, m, CH.sub.2OH 3.96, 2H, m, CHs
4.47, 1H, t, CH 4.90, 2 H, brd m 7.17-7.90, 13H, aromatic Hs 8
CH.sub.2CH.sub.2CH(OH)CONH.sub.2 4-Cl H Cl CDCl.sub.3 1.80, 1H, brd
s, CH 1.97, 1H, brd s, CH 3.75, 1H, brd s, NCH 3.90, 1H, brd s, NCH
4.02, 1H, m, CH 4.30, 1H, brd s, CHO 4.50, 1H, 2 t, CH 4.67, 1H,
brd s, CH 6.05, 1H, brd s, NH 7.01,l 1H, brd s, NH 7.45, 1H, brd s,
NH 7.08-7.83, 13H, aromatic Hs 9
CHCH(CH.sub.3).sub.2CONH--CH(CH.sub.2OH).sub.2 4-OMe H Cl
CD.sub.3OD 1.02, 6H, m, CH.sub.3 3.60, 4H, m, CH.sub.2O 4.83, 3H,
2s, OMe 3.95, 2H, m, CH 4.45, 1H, t, CH 4.90, 2 H, brd m 6.99-7.90,
13H, aromatic Hs 10 CH(CH.sub.2CONH.sub.2)CONH.sub.2 4-Cl H Cl
CDCl.sub.3 2.77, 1H, brd m, CHCO 3.10, 1H, brd m, CHCO 3.99, 4.11,
1H, 2 brd s, CH 4.55, 1H, brd s, CH 4.66, 1H, brd s, CH 5.08, 1H,
brd s, CH 6.20, 1H, brd s, NH 6.42, 1H, brd s, NH 6.70, 1H, brd s,
NH 7.48, 1H, brd s, NH 8.47, 1H, brd s, NH 7.08-7.83, 13H, aromatic
Hs 11 CH.sub.2CONHCH.sub.2CONH.sub.2 4-Cl H Cl CDCl.sub.3 3.93, 1H,
dd, CH 4.02, 2H, dd, CH.sub.2 4.41, 1H, d, CH 4.45, 2H, m, CH.sub.2
4.64, 1H, brd s, CH 6.14, 1H, brd s, NH 7.61, 1H, brd s, NH 7.90,
1H, brd s, NH 7.06-7.80, 13H, aromatic Hs 12
CH.sub.2CONHCH.sub.2CONH.sub.2 4-OMe H Cl CDCl.sub.3 3.75, 1H, s,
OCH.sub.3 3.94-4.07, 3H, m, CH.sub.2, CH 4.42, 3H, m, CH.sub.2, CH
4.45, 2H, m, CH.sub.2 4.60, 1H, m, CH 6.28, 1H, brd s, NH 6.91, 1H,
brd s, NH 7.95, 1H, brd s, NH 6.80-7.80, 13H, aromatic Hs 13
CH.sub.2CONH--CH(CHCH.sub.3OH)CONH.sub.2 4-OMe H Cl CDCl.sub.3
1.13, 3H, dd, CH.sub.3 3.75, 1H, s, OCH.sub.3 3.78, 1H, brd m, CH
3.93, 1H, m, CH 4.30-4.65, 5H, brd overlap ms, CH.sub.2, CH 4.62,
1H, m, CH 4.61, 1H, brd s, CH 6.48, 1H, brd d, NH 7.93, 1H, brd s,
NH 7.00, 2H, brd s, NHs 6.88-7.75, 13H, aromatic Hs 14
CHCH.sub.3CONH--CH.sub.2CONH.sub.2 4-Cl H Cl CDCl.sub.3 1.56, 3H,
dd, CH.sub.3 3.93, 1H, m, CH 4.10, 2H, overlap m, CHs 4.50, 1H, 2t,
CH 4.68, 1H, m, CH 4.85, 1H, m, CH 5.80, 1H, brd s, NH 6.73, 1H,
brd s, NH 7.05-7.82, 13H, aromatic Hs 15
CHCH.sub.3CONH--CH.sub.2CONH.sub.2 4-OMe H Cl CDCl.sub.3 1.56, 3H,
dd, CH.sub.3 3.79, 3.80, 3H, 2s, OMe 3.83-4.16, 3H, m, CH.sub.2, CH
4.45, 4.53, 1H, 2t, CH 4.64, 1H, m, CH 4.83, 1H, m, CH 5.60, 1H,
brd d, NH 6.60, 1H, brd s, NH 6.86-7.82, 13H, aromatic Hs 16
CHCH(CH.sub.3).sub.2CONH--CH.sub.2CONH.sub.2 4-Cl H Cl CD.sub.3OD
1.04, 6H, dd, CH.sub.3 2.30, 1H, brd m, CH 3.90, 3.5H, brd m, CHs
4.18, 0.5H, m, CH 4.60, 1H, brd m, CH 7.15-7.96, 13H, aromatic Hs
17 CHCH(CH.sub.3).sub.2CONH--CHCH.sub.3CONH.sub.2 4-Cl H Cl
CD.sub.3OD 1.03, 6H, dd, CH.sub.3 1.32, 3H, m, CH.sub.3 2.32, 1H,
brd m, CH 3.95, 1H, brd m, CH 4.45, 2H, brd m, CHs 7.15-7.90, 13H,
aromatic Hs 18 CHCH.sub.3CONH--CHCH.sub.2OHCONH.sub.2 4-Cl H Cl
CD.sub.3OD 1.48, 3H, dd, CH.sub.3 3.78, 2H, m, OCH.sub.2 3.95,
4.09, 1H, 2m, CH 4.40-4.60, 2H, m, CHs 4.80-4.95, 2H, brd m, CHs
7.18-7.89, 13H, aromatic Hs 19 CHCH.sub.3CONH--CHCH.sub.3CONH.sub.2
4-Cl H Cl CDCl.sub.3 1.39, 3H, dd, CH.sub.3 1.57, 3H, dd, CH.sub.3
3.89, 1H, dd, CH 4.15, 1H, m, CH 4.50, 2H, m, CHs 4.66, 1H, m, CH
4.85, 1H, m, CH 5.60, 1H, 2brd s, NH 6.47, 6.67, 1H, 2brd s, NH
7.06-7.86, 13H, aromatic Hs 20 ##STR00021## 4-Cl H Cl 1.97, 1H, brd
s, CH 2.12, 3H, brd s, CHs 2.80, 1H, brd s, CH 2.89, 1H, brd s, CH
4.08, 1H, brd m, CH 4.51, 1H, brd m, CH 4.62, 1H, brd s, CH 5.51,
1H, brd s, NH 6.24, 1H, brd s, NH 8.1o, 1H, brd s, NH 7.03-7.90,
13H, aromatic Hs 21 CH.sub.2CH.sub.2CO.sub.2NH.sub.2 4-Cl H Cl
(CDCl3) 3.54, 2H, t, CH2 4.03, 1H, dd, CH 4.15, 2H, brd s, CH2
4.49, 1H, t, CH 4.68, 2H, , CH 5.36, 2H, s, NH 7.63, 1H, brd s, NH
7.09-7.84, 13H, aromatic Hs
TABLE-US-00006 TABLE C ##STR00022## Number Q Y'' X'' X NMR ppm 1 Me
4-OCH.sub.2CO.sub.2Et H Cl 1.29, 3H, t, Me 3.23, 3H, d, NMe 4.10,
1H, m, CH 4.26, 2H, q, OCH.sub.2 4.52, 1H, m, CH 4.60, 1H, m, CH
4.62, 2H, s, OCH.sub.2COEt 6.89-7.90, m, 13H, aromatic Hs 2 Me
4-CONHOH Cl Cl (CD.sub.3OD) 3.05, 3H, s, NMe 3.95 1H, m, CH 4.44,
1H, t, CH 4.90, 1H, m, CH 7.14-7.94, m, 13H, aromatic Hs
[0168] Numerous modifications and variations of the present
invention are possible in light of the above teachings. It is
therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise that as
specifically described herein.
* * * * *