U.S. patent application number 10/782060 was filed with the patent office on 2004-11-11 for piperidinyl targeting compounds that selectively bind integrins.
Invention is credited to De Corte, Bart, Ghosh, Shyamali, Kinney, William A., Liu, Li, Maryanoff, Bruce E..
Application Number | 20040224986 10/782060 |
Document ID | / |
Family ID | 34911385 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040224986 |
Kind Code |
A1 |
De Corte, Bart ; et
al. |
November 11, 2004 |
Piperidinyl targeting compounds that selectively bind integrins
Abstract
The present invention relates to the synthesis and biological
application of piperidinoyl carboxylic acid integrin antagonists
affinity moiety of IFormula (I): 1 and Formula (II): 2 These
affinity moieties maybe used with imaging agents or liposomes to
target cells that express the .alpha..sub.v.beta..sub.3,
.alpha..sub.v.beta..sub.5, or .alpha..sub.v.beta..sub.6 integrin
receptors.
Inventors: |
De Corte, Bart; (South
Hampton, PA) ; Kinney, William A.; (Newtown, PA)
; Maryanoff, Bruce E.; (Forest Grove, PA) ; Ghosh,
Shyamali; (Norristown, PA) ; Liu, Li;
(Doylestown, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
34911385 |
Appl. No.: |
10/782060 |
Filed: |
February 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10782060 |
Feb 18, 2004 |
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10641964 |
Aug 15, 2003 |
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60404239 |
Aug 16, 2002 |
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Current U.S.
Class: |
514/326 ;
546/207; 546/227 |
Current CPC
Class: |
C07D 405/14 20130101;
A61K 31/4523 20130101; A61K 45/06 20130101; A61P 17/06 20180101;
A61K 51/0459 20130101; C07D 401/14 20130101; C07D 471/04 20130101;
A61P 19/02 20180101; A61K 51/0455 20130101; A61P 19/10 20180101;
A61P 17/00 20180101; A61P 19/00 20180101; Y02P 20/582 20151101;
A61P 35/00 20180101; A61P 27/00 20180101; C07D 401/12 20130101;
A61P 13/12 20180101; A61K 31/4523 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/326 ;
546/207; 546/227 |
International
Class: |
A61K 031/454; C07D
41/02 |
Claims
What is claimed is:
1. A targeting ligand having a formula selected from the group
consisting of Formula (I): 144wherein W is selected from the group
consisting of --C.sub.0-6alkyl(R.sub.1),
--C.sub.1-6alkyl(R.sub.1a), --C.sub.0-6alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-6alkyl-heterocyclyl(R.s- ub.1,R.sub.8),
--C.sub.0-6alkoxy(R.sub.1), --C.sub.0-6alkoxy-aryl(R.sub.1,-
R.sub.8), and --C.sub.0-6alkoxy-heterocyclyl(R.sub.1,R.sub.8);
R.sub.1 is selected from the group consisting of hydrogen,
--N(R.sub.4).sub.2, --N(R.sub.4)(R.sub.5), --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8); R.sub.1a is
selected from the group consisting of
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7)
and --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is selected from the group consisting of hydrogen and
--C.sub.1-8alkyl(R.sub.7); R.sub.5 is selected from the group
consisting of --C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.9), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8); R.sub.6 is selected from the group
consisting of -cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8),
-aryl(R.sub.8) and -heteroaryl(R.sub.8); R.sub.7 is one to two
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-8alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2-C.sub.1-8-alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) and -heteroaryl(R.sub.10); R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.1a),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C.sub.1-8alkoxy(R.sub.9), --O-cycloalkyl(R.sub.1a),
--O-aryl(R.sub.1a), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--C.sub.1-8alkyl(R.sub- .9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .1a), --NHC(.dbd.O)--NH.sub.2,
--NHC(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--NHC(.dbd.O)--NH-aryl(R- .sub.1a),
--NHC(.dbd.O)--O--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--O-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10),
--NHC(.dbd.O)-cycloalkyl(R.sub.10),
--NHC(.dbd.O)-heterocyclyl(R.sub.10), --NHC(.dbd.O)-aryl(R.sub.1a),
--NHC(.dbd.O)-heteroaryl(R.sub.1a), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alk- yl(R.sub.9), --CO.sub.2-aryl(R.sub.1a),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2, --SO.sub.2-aryl(RP
a), --NHSO.sub.2--C.sub.1-8alkyl(R.sub.9)- ,
--NHSO.sub.2-aryl(R.sub.1a), --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10), and -heteroaryl(R.sub.10)
when attached to a carbon atom; R.sub.9 is selected from the group
consisting of hydrogen, --C.sub.1-8alkoxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo; R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl and
--SO.sub.2--N(C.sub.1-8alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C.sub.1-8alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom; q is 0, 1,
2, or 3; R.sub.2a is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkenyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkynyl(R.sub.7)(R.sub.- 11),
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) and -heteroaryl(R.sub.8)(R.sub.12);
R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.14), --O--C.sub.1-8alkyl(R.sub.14),
--NH--C.sub.1-8alkyl(R.sub.14), --S--C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.14),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.14), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--NH--C(.dbd.O)OC.sub.1-8alkyl(- R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alky- lC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 4),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14-
),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14-
),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14)-
,
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14-
),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14-
),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14-
),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).-
sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.s-
ub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O-
).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
SO.sub.2CH.sub.2CH.sub.2O(-
CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.14); R.sub.12 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.14), --O--C.sub.1-8alkyl(R.sub.14),
--NH--C.sub.1-8alkyl(R.sub.14), --S--C.sub.1-8alkyl(R.sub.14),
--CH.sub.2O--C.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C.sub.1-8alkyl(R.sub- .14),
--CH.sub.2S--C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.14), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alk- yl(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R- .sub.14),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--CH.sub.2O--C(.dbd.O)OC.sub.1- -8alkyl(R.sub.14),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)- NHC.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.- sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 4),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2H.sub.2C(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2H.sub.2(R-
.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
CH.sub.2(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2CH.sub.2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2H.sub.2O).sub-
.rCH.sub.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.14), --CH.sub.2
SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).su-
b.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), --CH.sub.2
SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.14),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2CH.sub.2(R.sub.14),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH-
.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
CH.sub.2(R.sub.14),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.14),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.14),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2H.sub.2CO).sub.rCH.sub.2C(.dbd.O-
)(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2O-
(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.14); R.sub.14 when R.sub.11 and R.sub.12 terminates
with a C(.dbd.O) is selected from the group consisting of hydrogen,
OH, --OC.sub.1-4alkyl and NH.sub.2; otherwise R.sub.14 is selected
from the group consisting of --OH, --SH, COOH, and
--COOC.sub.1-4alkyl; Z is selected from the group consisting of
hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-OH, --O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl; and pharmaceutically acceptable salts,
racemic mixtures and enantiomers thereof.
2. The targeting ligand of claim 1 wherein W is selected from the
group consisting of --C.sub.0-4alkyl(R.sub.1) and
--C.sub.0-4alkyl-aryl(R.sub.1- ,R.sub.8).
3. The targeting ligand of claim 1 wherein W is
--C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R.sub.8).
4. The targeting ligand of claim 1 wherein R.sub.1 is selected from
the group consisting of --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8).
5. The targeting ligand of claim 1 wherein R.sub.1 is selected from
the group consisting of --N(R.sub.4)(R.sub.6),
-dihydro-1H-pyrrolo[2,3-b]pyri- dinyl(R.sub.8),
-tetrahydropyrimidinyl(R.sub.8), -tetrahydro-1,8-naphthyri-
dinyl(R.sub.8), -tetrahydro-1H-azepino[2,3-b]pyridinyl(R.sub.8) and
-pyridinyl(R.sub.8).
6. The targeting ligand of claim 1 wherein R.sub.1 is selected from
the group consisting of --N(R.sub.4)(R.sub.6),
-tetrahydropyrimidinyl(R.sub.8- ) and
-tetrahydro-1,8-naphthyridinyl(R.sub.8).
7. The targeting ligand of claim 1 wherein R.sub.1a is selected
from the group consisting of --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
and
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2.
8. The targeting ligand of claim 1 wherein R.sub.4 is selected from
the group consisting of hydrogen and --C.sub.1-4alkyl(R.sub.7).
9. The targeting ligand of claim 1 wherein R.sub.4 is hydrogen.
10. The targeting ligand of claim 1 wherein R.sub.5 is selected
from the group consisting of --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --C(.dbd.O)-cycloalkyl(R.sub.8),
--C(.dbd.O)-heterocyclyl(R.sub.8), --C(.dbd.O)-aryl(R.sub.8),
--C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.9), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8).
11. The targeting ligand of claim 1 wherein R.sub.5 is selected
from the group consisting of --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --CO.sub.2--R.sub.4,
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--SO.sub.2--C.sub.1-4alkyl(R.sub.7) and
--SO.sub.2--N(R.sub.4).sub.2.
12. The targeting ligand of claim 1 wherein R.sub.6 is selected
from the group consisting of -heterocyclyl(R.sub.8) and
-heteroaryl(R.sub.8).
13. The targeting ligand of claim 1 wherein R.sub.6 is selected
from the group consisting of -dihydroimidazolyl(R.sub.8),
-tetrahydropyridinyl(R.s- ub.8), -tetrahydropyrimidinyl(R.sub.8)
and -pyridinyl(R.sub.8).
14. The targeting ligand of claim 1 wherein R.sub.7 is one to two
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.- sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub- .9),
--S--C.sub.1-4alkyl-C.sub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH-- -C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) and -heteroaryl(R.sub.10).
15. The targeting ligand of claim 1 wherein R.sub.7 is one to two
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.- sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, (halo).sub.1-3, hydroxy and
oxo.
16. The targeting ligand of claim 1 wherein R.sub.7 is
hydrogen.
17. The targeting ligand of claim 1 wherein R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.s- ub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.sub- .10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-cycloalkyl(R.sub.10),
--O-aryl(R.sub.10), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl-R- .sub.11).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-4alkyl(R.sub.9- ),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-C.s- ub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH--C.sub.1-4alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10) and -heteroaryl(R.sub.10)
when attached to a carbon atom.
18. The targeting ligand of claim 1 wherein R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9) and --SO.sub.2--NH.sub.2 when
attached to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, cyano, halo, hydroxy, nitro and
oxo when attached to a carbon atom.
19. The targeting ligand of claim 1 wherein R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen and --C.sub.1-4alkyl(R.sub.9) when attached to a nitrogen
atom; and, wherein R.sub.8 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, halo, hydroxy and oxo when
attached to a carbon atom.
20. The targeting ligand of claim 1 wherein R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen and --C.sub.1-4alkyl(R.sub.9) when attached to a nitrogen
atom; and, wherein R.sub.8 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10) and hydroxy when attached to a carbon atom.
21. The targeting ligand of claim 1 wherein R.sub.9 is selected
from the group consisting of hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
--C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo.
22. The targeting ligand of claim 1 wherein R.sub.9 is selected
from the group consisting of hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
--C(.dbd.O)H, --CO.sub.2H, --C(.dbd.O)--C.sub.1-4alkoxy,
(halo).sub.1-3, hydroxy and oxo.
23. The targeting ligand of claim 1 wherein R.sub.9 is selected
from the group consisting of hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
(halo).sub.1-3 and hydroxy.
24. The targeting ligand claim 1 wherein R.sub.10 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkyl, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl and
--SO.sub.2--N(C.sub.1-4alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-4alkyl, --C.sub.1-4alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom.
25. The targeting ligand of claim 1 wherein (R.sub.10).sub.14 is
selected from the group consisting of hydrogen, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--CO.sub.2H, --CO.sub.2--C.sub.1-4alkyl, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, halo, hydroxy,
nitro and oxo when attached to a carbon atom.
26. The targeting ligand of claim 1 wherein R.sub.10 is
hydrogen.
27. The targeting ligand of claim 1 wherein R.sub.2a is selected
from the group consisting of --C.sub.1-4alkyl (R.sub.7)(R.sub.11),
--C.sub.2-4alkenyl(R.sub.7)(R.sub.11),
--C.sub.2-4alkynyl(R.sub.7)(R.sub.- 11),
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12), and -heteroaryl(R.sub.8)(R.sub.12).
28. The targeting ligand of claim 1 wherein R.sub.2a is selected
from the group consisting of -cycloalkyl(R.sub.7)(R.sub.11),
-heterocyclyl(R.sub.8)(R.sub.12), -aryl(R.sub.8)(R.sub.12), and
-heteroaryl(R.sub.8)(R.sub.11).
29. The targeting ligand of claim 1 wherein R.sub.2a is selected
from the group consisting of -cycloalkyl(R.sub.7)(R.sub.11),
-heterocyclyl(R.sub.8)(R.sub.12), -phenyl(R.sub.8)(R.sub.12),
-naphthalenyl(R.sub.8)(R.sub.12), and
-heteroaryl(R.sub.8)(R.sub.11).
30. The targeting ligand claim 1 wherein R.sub.2a is selected from
the group consisting of -tetrahydropyrimidinyl(R.sub.8)(R.sub.12),
-1,3-benzodioxolyl(R.sub.8)(R.sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.su- b.12),
-tetrahydroquinolinyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12- ), -naphthalenyl(R.sub.8)(R.sub.12),
-pyridinyl(R.sub.8)(R.sub.12), -pyrimidinyl(R.sub.8)(R.sub.12), and
-quinolinyl(R.sub.8)(R.sub.12).
31. The targeting ligand of claim 1 wherein R.sub.11 is selected
from the group consisting of --C.sub.1-8alkyl(R.sub.14),
--O--C.sub.1-8alkyl(R.sub- .14), --NH--C.sub.1-8alkyl(R.sub.14),
--S--C.sub.1-8alkyl(R.sub.14), --C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 4),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.14), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R-
.sub.14),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.14),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH-
.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--SO.sub.2NHCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14).
32. The targeting ligand of claim 1 wherein R.sub.11 is selected
from the group consisting of --C.sub.1-8alkyl(R.sub.14),
--O--C.sub.1-8alkyl(R.sub- .14), --NH--C.sub.1-8alkyl(R.sub.14),
--S--C.sub.1-8alkyl(R.sub.14), --C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 4),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.14), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14), and
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14).
33. The targeting ligand of claim 1 wherein R.sub.12 is selected
from the group consisting of --C.sub.1-6alkyl(R.sub.14),
--O--C.sub.1-6alkyl(R.sub- .14), --NH--C.sub.4alkyl(R.sub.14),
--S--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub- .14),
--CH.sub.2S--C.sub.1-6alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-6alkyl(R.s- ub.14),
--O--C(.dbd.O)C.sub.1-6alkyl(R.sub.14), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.14), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-6alk- yl(R.sub.14),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.14),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-6alkyl(R- .sub.14),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.14),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.14),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.-
sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14).
34. The targeting ligand of claim 1 wherein q is 1, 2 or 3.
35. The targeting ligand claim 1 wherein Z is selected from the
group consisting of hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-OH, --O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4a- lkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6a- lkyl,
C.sub.1-8alkyl-OC(O)--C.sub.1-6alkyl, --O--C.sub.1-8alkyl-NH.sub.2,
--O--C.sub.1-8alkyl-NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-N(C.sub.1-8al- kyl).sub.2,
--O--C.sub.1-8alkylamide, C.sub.1-8alkyl-C(O)--NH--C.sub.1-8al-
kyl, --O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
36. The targeting ligand of claim 1 wherein the targeting ligand is
conjugated to an radioactive element.
37. The targeting ligand of claim 1 wherein the targeting ligand is
conjugated to an imagining agent.
38. The targeting ligand of claim 37 wherein the imagining agent is
selected from the group consisting of .sup.99Tc, .sup.125I,
.sup.18F, .sup.11C, and .sup.64Cu.
39. A targeting ligand of Formula (I): 145wherein W is selected
from the group consisting of --C.sub.0-4alkyl(R.sub.1) and
--C.sub.0-4alkyl-phenyl- (R.sub.1,R.sub.8); R.sub.1 is
--NH(R.sub.6); R.sub.2a is selected from the group consisting of
-tetrahydropyrimidinyl(R.sub.8)(R.sub.12),
-1,3-benzodioxolyl(R.sub.8)(R.sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.su- b.12),
-tetrahydroquinolinyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12- ), -naphthalenyl(R.sub.8)(R.sub.12),
-pyridinyl(R.sub.8)(R.sub.12), -pyrimidinyl(R.sub.8)(R.sub.12), and
-quinolinyl(R.sub.8)(R.sub.12). R.sub.6 is selected from the group
consisting of -dihydroimidazolyl(R.sub- .8),
-tetrahydropyridinyl(R.sub.8), -tetrahydropyrimidinyl(R.sub.8) and
-pyridinyl(R.sub.8); R.sub.8 is one to four substituents
independently selected from the group consisting of hydrogen and
--C.sub.1-4alkyl(R.sub.9) when attached to a nitrogen atom; and,
wherein R.sub.8 is one to four substituents independently selected
from the group consisting of hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-aryl(R.sub.10) and hydroxy when
attached to a carbon atom; R.sub.9 is selected from the group
consisting of hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, (halo).sub.1-3 and
hydroxy; R.sub.10 is independently selected from the group
consisting of hydrogen, --C.sub.1-4alkyl, --C.sub.1-4alkoxy,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, halo, hydroxy, nitro and oxo when
attached to a carbon atom; q is 1, 2 or 3; R.sub.12 is selected
from the group consisting of --C.sub.1-6alkyl(R.sub.- 14),
--O--C.sub.1-6alkyl(R.sub.14), --NH--C.sub.1-4alkyl(R.sub.14),
--S--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2S--C.sub.1-6alkyl(R.sub- .14),
--C(.dbd.O)C.sub.1-6alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-6alkyl(R.- sub.14),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14), --CH.sub.2O--C(.dbd.O)C.-
sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.1- 4),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-6alky- l(R.sub.14),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.14),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2H.sub.2C(R.-
sub.14),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.-
sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14);
R.sub.14 when R.sub.11 and R.sub.12 terminates with a C(.dbd.O) is
selected from the group consisting of hydrogen, OH,
--OC.sub.1-4alkyl and NH.sub.2; otherwise R.sub.14 is selected from
the group consisting of --OH, --SH, COOH, and --COOC.sub.1-4alkyl;
Z is slected from the group consisting hydroxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
O--C.sub.1-8alkyl-OH, --O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl; and pharmaceutically acceptable salts,
racemic mixtures and enantiomers thereof.
40. A targeting conjugate having a formula selected from the group
consisting of 146and Formula (II): wherein W is selected from the
group consisting of --C.sub.0-6alkyl(R.sub.1),
--C.sub.1-6alkyl(R.sub.1a), --C.sub.0-6alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-6alkyl-heterocyclyl(R.s- ub.1,R.sub.8),
--C.sub.0-6alkoxy(R.sub.1), --CO.sub.0-6alkoxy-aryl(R.sub.1-
,R.sub.8), and --C.sub.0-6alkoxy-heterocyclyl(R.sub.1,R.sub.8);
R.sub.1 is selected from the group consisting of hydrogen,
--N(R.sub.4).sub.2, --N(R.sub.4)(R.sub.5), --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8); R.sub.1a is
selected from the group consisting of
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7)
and --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is selected from the group consisting of hydrogen and
--C.sub.1-8alkyl(R.sub.7); R.sub.5 is selected from the group
consisting of --C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.9),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8); R.sub.6 is selected from the group
consisting of -cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8),
-aryl(R.sub.8) and -heteroaryl(R.sub.8); R.sub.7 is one to two
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-8alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--C.sub.1-8alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo)-3, hydroxy, nitro, oxo,
-cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10), -aryl(R.sub.10) and
-heteroaryl(R.sub.10); R.sub.8 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl(R.sub.9)- , --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(RP a), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9)- ,
--C.sub.1-8alkoxy(R.sub.9), --O-cycloalkyl(R.sub.1a),
--O-aryl(R.sub.1a), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --NHC(.dbd.O)--NH.sub.2,
--NHC(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--N(C.sub.1-8alk- yl(R.sub.9)).sub.2,
--NHC(.dbd.O)--NH-aryl(R.sub.1a),
--NHC(.dbd.O)--O--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--O-aryl(R.sub.1a- ),
--C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.1a), --C(.dbd.O)-aryl(R.sub.1a),
--C(.dbd.O)-heteroaryl(R.sub.1a),
--NHC(.dbd.O)-cycloalkyl(R.sub.10),
--NHC(.dbd.O)-heterocyclyl(R.sub.10), --NHC(.dbd.O)-aryl(R.sub.10),
--NHC(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.1a), --NHSO.sub.2--C.sub.1-8alkyl(R.sub.9),
--NHSO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub- .9),
--S--C.sub.1-8alkyl-C.sub.1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH-- -C.sub.1-8alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).sub.2,
cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10), and -heteroaryl(R.sub.10)
when attached to a carbon atom; R.sub.9 is selected from the group
consisting of hydrogen, --C.sub.1-8alkoxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo; R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl and
--SO.sub.2--N(C.sub.1-8alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C.sub.1-8alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom; q is 0, 1,
2, or 3; R.sub.2a is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkenyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkynyl(R.sub.7)(R.sub.- 1),
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) and -heteroaryl(R.sub.8)(R.sub.12);
R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.13), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkyl(- R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alky- lC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13)-
,
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13-
),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13-
),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).-
sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.s-
ub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O-
).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13); R.sub.12 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-8alkyl(R.sub- .13),
--CH.sub.2S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alk- yl(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R- .sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--CH.sub.2O--C(.dbd.O)OC.sub.1- -8alkyl(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)- NHC.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.- sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(-
R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2CH.sub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.su-
b.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)CH.sub-
.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH-
.sub.2(R.sub.13),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O-
).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2-
CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
CH.sub.2(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O-
)(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13); wherein when R.sub.11 or R.sub.12 terminates
with a --C(.dbd.O)--, R.sub.13 is selected from 147and when
R.sub.11 or R.sub.12 does not terminate with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of
148149150151152153154155 wherein the unit
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 156 of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer ranging in molecular weight
from 750 to 5000 daltons; r is an integer from 0 to 8; Q and
Q.sup.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and are selected from the group consisting of the
C.sub.11 saturated chain of lauric acid, the C.sub.13 saturated
chain of myristoic acid, the C.sub.15 saturated chain of palmitoic
acid, the C.sub.17 saturated chain of stearoic acid, the C.sub.17
mono-unsaturated chain of oleoic acid, and the C.sub.17
di-unsaturated chain of linoleic acid; Z is selected from the group
consisting of hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-OH, --O--C.sub.1-8alkylC.sub.1-8alkoxy,
O--C.sub.1-8alkylcarbonylC.sub.1-8alk- yl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alk- yl,
--O--C.sub.1-8alkyl-O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.-
2, --O--C.sub.1-8alkyl-NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-N(C.sub.1-8- alkyl).sub.2,
--O--C.sub.1-8alkylamide, --O--C.sub.1-8alkyl-C(O)--NH--C.su-
b.1-8alkyl, O--C.sub.8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2, and
--NHC(O)C.sub.1-8alkyl; and pharmaceutically acceptable salts,
racemic mixtures and enantiomers thereof.
41. The targeting conjugate of claim 40 wherein W is selected from
the group consisting of --C.sub.0-4alkyl(R.sub.1) and
--C.sub.0-4alkyl-aryl(R- .sub.1,R.sub.8).
42. The targeting conjugate of claim 40 wherein W is
--C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R.sub.8).
43. The targeting conjugate of claim 40 wherein R.sub.1 is selected
from the group consisting of --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.9).
44. The targeting conjugate of claim 40 wherein R.sub.1 is selected
from the group consisting of --N(R.sub.4)(R.sub.6),
-dihydro-1H-pyrrolo[2,3-b]- pyridinyl(R.sub.8),
-tetrahydropyrimidinyl(R.sub.8),
-tetrahydro-1,8-naphthyridinyl(R.sub.8),
-tetrahydro-1H-azepino[2,3-b]pyr- idinyl(R.sub.8) and
-pyridinyl(R.sub.8).
45. The targeting conjugate of claim 40 wherein R.sub.1 is selected
from the group consisting of --N(R.sub.4)(R.sub.6),
-tetrahydropyrimidinyl(R.s- ub.8) and
-tetrahydro-1,8-naphthyridinyl(R.sub.8).
46. The targeting conjugate of claim 40 wherein R.sub.1a is
selected from the group consisting of
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
and
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2.
47. The targeting conjugate of claim 40 wherein R.sub.4 is selected
from the group consisting of hydrogen and
--C.sub.1-4alkyl(R.sub.7).
48. The targeting conjugate of claim 40 wherein R.sub.4 is
hydrogen.
49. The targeting conjugate of claim 40 wherein R.sub.5 is selected
from the group consisting of --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub- .2, --C(.dbd.O)-cycloalkyl(R.sub.8),
--C(.dbd.O)-heterocyclyl(R.sub.9), --C(.dbd.O)-aryl(R.sub.8),
--C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.9), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8).
50. The targeting conjugate of claim 40 wherein R.sub.5 is selected
from the group consisting of --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub- .2, --CO.sub.2--R.sub.4,
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--SO.sub.2--C.sub.1-4alkyl(R.sub.7) and
--SO.sub.2--N(R.sub.4).sub.2.
51. The targeting conjugate of claim 40 wherein R.sub.6 is selected
from the group consisting of -heterocyclyl(R.sub.8) and
-heteroaryl(R.sub.8).
52. The targeting conjugate of claim 40 wherein R.sub.6 is selected
from the group consisting of -dihydroimidazolyl(R.sub.8),
-tetrahydropyridinyl(R.sub.8), -tetrahydropyrimidinyl(R.sub.8) and
-pyridinyl(R.sub.8).
53. The targeting conjugate of claim 40 wherein R.sub.7 is one to
two substituents independently selected from the group consisting
of hydrogen, --C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.- sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub- .9),
--S--C.sub.1-4alkyl-C.sub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH-- -C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) and -heteroaryl(R.sub.10).
54. The targeting conjugate of claim 40 wherein R.sub.7 is one to
two substituents independently selected from the group consisting
of hydrogen, --C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.- sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, (halo).sub.13, hydroxy and
oxo.
55. The targeting conjugate of claim 40 wherein R.sub.7 is
hydrogen.
56. The targeting conjugate of claim 40 wherein R.sub.8 is one to
four substituents independently selected from the group consisting
of hydrogen, --C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-cycloalkyl(R.sub.10),
--O-aryl(R.sub.10), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl-R- .sub.11).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.1a),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-4alkyl(R.sub.9- ),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-C.s- ub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH--C.sub.1-4alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10) and -heteroaryl(R.sub.10)
when attached to a carbon atom.
57. The targeting conjugate of claim 40 wherein R.sub.8 is one to
four substituents independently selected from the group consisting
of hydrogen, --C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9) and --SO.sub.2--NH.sub.2 when
attached to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, cyano, halo, hydroxy, nitro and
oxo when attached to a carbon atom.
58. The targeting conjugate of claim 40 wherein R.sub.8 is one to
four substituents independently selected from the group consisting
of hydrogen and --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.8 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.1a), --NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, halo, hydroxy and oxo when
attached to a carbon atom.
59. The targeting conjugate of claim 40 wherein R.sub.8 is one to
four substituents independently selected from the group consisting
of hydrogen and --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.8 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10) and hydroxy when attached to a carbon atom.
60. The targeting conjugate of claim 40 wherein R.sub.9 is selected
from the group consisting of hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
--C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo.
61. The targeting conjugate of claim 40 wherein R.sub.9 is selected
from the group consisting of hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
--C(.dbd.O)H, --CO.sub.2H, --C(.dbd.O)--C.sub.1-4alkoxy,
(halo).sub.1-3, hydroxy and oxo.
62. The targeting conjugate of claim 40 wherein R.sub.9 is selected
from the group consisting of hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
(halo).sub.1-3 and hydroxy.
63. The targeting conjugate claim 40 wherein R.sub.10 is one to
four substituents independently selected from the group consisting
of hydrogen, --C.sub.1-4alkyl, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl and
--SO.sub.2--N(C.sub.1-4alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-4alkyl, --C.sub.1-4alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom.
64. The targeting conjugate of claim 40 wherein (R.sub.10).sub.1-4
is selected from the group consisting of hydrogen,
--C.sub.1-4alkyl, --C.sub.1-4alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, halo, hydroxy, nitro and oxo when
attached to a carbon atom.
65. The targeting conjugate of claim 40 wherein R.sub.10 is
hydrogen.
66. The targeting conjugate of claim 40 wherein R.sub.2a is
selected from the group consisting of --C.sub.1-4alkyl
(R.sub.7)(R.sub.11), --C.sub.2-4alkenyl(R.sub.7)(R.sub.11),
--C.sub.2-4alkynyl(R.sub.7)(R.sub.- 11),
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12), and -heteroaryl(R.sub.8)(R.sub.12).
67. The targeting conjugate of claim 40 wherein R.sub.2a is
selected from the group consisting of
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12), and -heteroaryl(R.sub.8)(R.sub.11).
68. The targeting conjugate of claim 40 wherein R.sub.2a is
selected from the group consisting of
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12), -naphthalenyl(R.sub.8)(R.sub.12), and
-heteroaryl(R.sub.8)(R.sub.11).
69. The targeting conjugate claim 40 wherein R.sub.2a is selected
from the group consisting of
-tetrahydropyrimidinyl(R.sub.8)(R.sub.12),
-1,3-benzodioxolyl(R.sub.8)(R.sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.su- b.12),
-tetrahydroquinolinyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12- ), -naphthalenyl(R.sub.8)(R.sub.12),
-pyridinyl(R.sub.8)(R.sub.12), -pyrimidinyl(R.sub.8)(R.sub.12), and
-quinolinyl(R.sub.8)(R.sub.12).
70. The targeting conjugate of claim 40 wherein R.sub.11 is
selected from the group consisting of --C.sub.1-8alkyl(R.sub.13),
--O--C.sub.1-8alkyl(R.sub.13), --NH--C.sub.1-8alkyl(R.sub.13),
--S--C.sub.1-8alkyl(R.sub.13), --C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.13), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.- dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.1-
3),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.sub-
.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13).
71. The targeting conjugate of claim 40 wherein R.sub.11 is
selected from the group consisting of --C.sub.1-8alkyl(R.sub.13),
--O--C.sub.1-8alkyl(R.sub.13), --NH--C.sub.1-8alkyl(R.sub.13),
--S--C.sub.1-8alkyl(R.sub.13), --C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.13), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.- dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13), and
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.s- ub.13).
72. The targeting conjugate of claim 40 wherein R.sub.12 is
selected from the group consisting of --C.sub.1-6alkyl(R.sub.13),
--O--C.sub.1-6alkyl(R.sub.13), --NH--C.sub.1-4alkyl(R.sub.13),
--S--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl(R.sub- .13),
--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-6alkyl(R.- sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.-
sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.1- 3),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-6alky- l(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH-
.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
wherein when R.sub.11 or R.sub.12 terminates with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 157and when
R.sub.11 or R.sub.12 does not terminate with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 158159
73. The targeting conjugate of claim 40 wherein R.sub.12 is
selected from the group consisting of
--CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl(R.sub- .13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.su- b.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(C-
H.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.s-
ub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.-
dbd.O)(R.sub.13), and
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).su-
b.rCH.sub.2C(.dbd.O)(R.sub.13). wherein when R.sub.11 or R.sub.12
terminates with a --C(.dbd.O)--, R.sub.13 is selected from the
group consisting of 160and when R.sub.11 or R.sub.12 does not
terminate with a --C(.dbd.O)--, R.sub.13 is selected from the group
consisting of 161162
74. The targeting conjugate of claim 40 wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 163of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer ranging in molecular weight
from 2000 to 5000 daltons.
75. The targeting conjugate of claim 40 wherein wherein Q and
Q.sup.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and are selected from the group consisting of the
C.sub.1-5 saturated chain of palmitoic acid, the C.sub.1-7
saturated chain of stearoic acid, and the C.sub.17 mono-unsaturated
chain of oleoic acid.
76. The targeting conjugate of claim 40 wherein W is preferably is
selected from the group consisting of --C.sub.0-4alkyl(R.sub.1),
--C.sub.1-4alkyl(R.sub.1a), --C.sub.0-4alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-4alkyl-heterocyclyl(R.sub.1,R.sub.8),
--C.sub.0-4alkoxy(R.sub.1- ),
--C.sub.0-4alkoxy-aryl(R.sub.1,R.sub.8), and
--C.sub.0-4alkoxy-heterocy- clyl(R.sub.1,R.sub.8); R.sub.1 is
--N(R.sub.4)(R.sub.6), -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8); R.sub.1a is --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is hydrogen or --C.sub.1-4alkyl(R.sub.7); R.sub.5 is
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub- .8),
--C(.dbd.O)--N(R.sub.4)-aryl(R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) or
--SO.sub.2-aryl(R.sub.8); R.sub.6 is -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8); R.sub.7 is one to two substituents
independently selected from hydrogen, --C.sub.1-4alkoxy(R.sub.9),
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4a- lkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.su- b.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub- .9),
--S--C.sub.1-4alkyl-C.sub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH-- -C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo)-3, hydroxy, nitro, oxo,
-cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10), -aryl(R.sub.10) or
-heteroaryl(R.sub.10); R.sub.8 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9) or --SO.sub.2--NH.sub.2 when
attached to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, cyano, halo, hydroxy, nitro or
oxo when attached to a carbon atom; R.sub.9 is hydrogen,
--C.sub.1-4alkoxy, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro or oxo; R.sub.10 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alky- l, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl or
--SO.sub.2--N(C.sub.1-4alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, cyano, halo,
hydroxy, nitro or oxo when attached to a carbon atom; R.sub.2a is
-cycloalkyl(R.sub.8)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) or -heteroaryl(R.sub.8)(R.sub.12); q is 1,
2 or 3. R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.13), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.- dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.1-
3),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13); R.sub.12
is selected from the group consisting of
--C.sub.1-6alkyl(R.sub.13), --O--C.sub.1-6alkyl(R.sub.13),
--NH--C.sub.1-4alkyl(R.sub.13), --S--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl(R.sub- .13),
--C(.dbd.O)C.sub.16alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-6alkyl(R.s- ub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.s-
ub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.1- 3),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-6alky- l(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R)
3),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.-
sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
wherein when R.sub.11 or R.sub.12 terminates with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 164 and when
R.sub.11 or R.sub.12 does not terminate with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 165166said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 167 of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer ranging in molecular weight
from 750 to 5000 daltons; r is an integer from 0 to 8; Q and
Q.sup.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and are selected from the group consisting of the
C.sub.11 saturated chain of lauric acid, the C.sub.15 saturated
chain of palmitoic acid, the C.sub.17 saturated chain of stearoic
acid, the C.sub.17 mono-unsaturated chain of oleoic acid, and the
C.sub.17 di-unsaturated chain of linoleic acid; Z is selected from
the group consisting of hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-OH, --O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4a- lkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6a- lkyl,
--O--C.sub.1-8alkyl-O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.su- b.2,
--O--C.sub.1-8alkyl-NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-N(C.sub.1- -8alkyl).sub.2,
--O--C.sub.1-8alkylamide --O--C.sub.1-8alkyl-C(O)--NH--C.s-
ub.1-8alkyl, --O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
77. The targeting conjugate of claim 40 wherein W is preferably
--C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R.sub.8); R.sub.1 is
--N(R.sub.4)(R.sub.6), -tetrahydropyrimidinyl(R.sub.8) or
-tetrahydro-1,8-naphthyridinyl(R.sub.8); R.sub.1a is
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is hydrogen; R.sub.5 is --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --CO.sub.2--R.sub.4,
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--SO.sub.2--C.sub.1-4alkyl(R.sub.7) or
--SO.sub.2--N(R.sub.4).sub.2; R.sub.6 is
-dihydroimidazolyl(R.sub.8), -tetrahydropyridinyl(R.sub.8),
-tetrahydropyrimidinyl(R.sub.8) or -pyridinyl(R.sub.8); R.sub.7 is
hydrogen; R.sub.8 is one to four substituents independently
selected from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached
to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9)-O-ar-
yl(R.sub.10) or hydroxy when attached to a carbon atom; R.sub.9 is
hydrogen, --C.sub.1-4alkoxy, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, (halo).sub.1-3 or hydroxy; R.sub.10 is
hydrogen; R.sub.2a is -tetrahydropyrimidinyl(R.sub.8)(R.sub.12),
-1,3-benzodioxolyl(R.sub.8)(R.sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.su- b.12),
-tetrahydroquinolinyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12- ), -naphthalenyl(R.sub.8)(R.sub.12),
-pyridinyl(R.sub.8)(R.sub.12), -pyrimidinyl(R.sub.8)(R.sub.12) or
-quinolinyl(R.sub.8)(R.sub.12); q is 1 or 2; R.sub.12 is selected
from the group consisting of
--CH.sub.2--O--(CH.sub.2).sub.4(R.sub.13)--,
--CH.sub.2--NH--(CH.sub.2).s- ub.4(R.sub.13)--,
--CH.sub.2--S--(CH.sub.2).sub.4(R.sub.13)--,
--CH.sub.2--O--(CH.sub.2).sub.6(R.sub.13)--,
--CH.sub.2--NH--(CH.sub.2).s- ub.6(R.sub.13)--,
--CH.sub.2--S--(CH.sub.2).sub.6(R.sub.13)--,
--NH--C(.dbd.O)--(CH.sub.2).sub.4(R.sub.13)--,
--NH--C(.dbd.O)--(CH.sub.2- ).sub.7(R.sub.13)--,
--NH--C(.dbd.O)NH--(CH.sub.2).sub.3(R.sub.13)--,
--NH--C(.dbd.O)NH--(CH.sub.2).sub.6(R.sub.13)--,
--CH.sub.2NH--C(.dbd.O)N- H--(CH.sub.2).sub.2(R.sub.13)--,
--CH.sub.2NH--C(.dbd.O)NH--(CH.sub.2).sub- .5(R.sub.13)--,
--NHC(.dbd.O)--(CH.sub.2).sub.2--C(.dbd.O)(R.sub.13)--,
--NHC(.dbd.O)--(CH.sub.2).sub.3--C(.dbd.O)(R.sub.13)--,
--NHC(.dbd.O)--(CH.sub.2).sub.4--C(.dbd.O)(R.sub.13)--,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--NHCH.sub.2CH.sub.2OCH- .sub.2CH.sub.2(R.sub.13)--,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2C-
H.sub.2(R.sub.13)--,
--NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.-
2(R.sub.13)--, --OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
--NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)---
,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)-
--,
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13-
)--, --CH.sub.2NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
and --NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--; wherein
when R.sub.11 or R.sub.12 terminates with a --C(.dbd.O)--, R.sub.13
is selected from the group consisting of 168and when R.sub.11 or
R.sub.12 does not terminate with a --C(.dbd.O)--, R.sub.13 is
selected from the group consisting of 169wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 170 of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer selected from 2000 (PEG
2000), 3400 (PEG 3400), or 5000 (PEG 5000) Daltons; r is an integer
from 0 to 8; Q and Q.sup.1 of substituents R.sub.12 and R.sub.13
are the same within a given compound and is the C.sub.1-7 saturated
chain of stearoic acid; Z is selected from the group consisting of
hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-OH, --O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4a- lkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6a- lkyl,
--O--C.sub.1-8alkyl-O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.su- b.2,
--O--C.sub.1-8alkyl-NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-N(C.sub.1- -8alkyl).sub.2,
--O--C.sub.1-8alkylamide --O--C.sub.1-8alkyl-C(O)--NH--C.s-
ub.1-8alkyl, --O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
78. A therapeutic liposome composition sensitized to a target cell,
comprising (i) a liposomal composition composed of pre-formed
liposomes having an entrapped therapeutic agent; and (ii) a
plurality of targeting conjugates, each conjugate composed of (a) a
lipid having a polar head group and a hydrophobic tail, (b) a
hydrophilic polymer having a proximal end and a distal end, where
the polymer is attached at its proximal end to the head group of
the lipid, and (c) a targeting ligand attached to the distal end of
the polymer.
79. The liposome of claim 78 wherein the targeting conjugate has a
formula selected from the group consisting of Formula (I):
171wherein W is selected from the group consisting of
--C.sub.0-6alkyl(R.sub.1), --C.sub.1-6alkyl(R.sub.1a),
--C.sub.0-6alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-6alkyl-heterocyclyl(R.sub.1,R.sub.8),
--C.sub.0-6alkoxy(R.sub.1- ),
--C.sub.0-6alkoxy-aryl(R.sub.1,R.sub.8), and
--C.sub.0-6alkoxy-heterocy- clyl(R.sub.1,R.sub.8); R.sub.1 is
selected from the group consisting of hydrogen, --N(R.sub.4).sub.2,
--N(R.sub.4)(R.sub.5), --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8); R.sub.1a is
selected from the group consisting of --C(R.sub.4)(.dbd.N--R.-
sub.4), --C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.- sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7)
and --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is selected from the group consisting of hydrogen and
--C.sub.1-8alkyl(R.sub.7); R.sub.5 is selected from the group
consisting of --C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8); R.sub.6 is selected from the group
consisting of -cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8),
-aryl(R.sub.8) and -heteroaryl(R.sub.8); R.sub.7 is one to two
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-8alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl--S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl--C.s- ub.1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--C.sub.1-8alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) and -heteroaryl(R.sub.10); R.sub.8 is one to four
substituents independently selected from the group consisting of
hydrogen, --C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C.sub.1-8alkoxy(R.sub.9), --O-cycloalkyl(R.sub.10),
--O-aryl(R.sub.10), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--C.sub.1-8alkyl(R.sub- .9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --NHC(.dbd.O)--NH.sub.2,
--NHC(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--NHC(.dbd.O)--NH-aryl(R- .sub.10),
--NHC(.dbd.O)--O--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--O-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10),
--NHC(.dbd.O)-cycloalkyl(R.sub.10),
--NHC(.dbd.O)-heterocyclyl(R.sub.10), --NHC(.dbd.O)-aryl(R.sub.10),
--NHC(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alk- yl(R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --NHSO.sub.2--C.sub.1-8alkyl(R.su- b.9),
--NHSO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl--S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkylC.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl--NH--C.sub.1-8alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10), and -heteroaryl(R.sub.10)
when attached to a carbon atom; R.sub.9 is selected from the group
consisting of hydrogen, --C.sub.1-8alkoxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo; R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
C.sub.1-8alkyl, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl and
--SO.sub.2--N(C.sub.1-8alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C.sub.1-8alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom; q is 0, 1,
2, or 3; R.sub.2a is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkenyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkynyl(R.sub.7)(R.sub.- 11),
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) and -heteroaryl(R.sub.8)(R.sub.12);
R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.13), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkyl(- R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alky- lC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(RI.sub.3),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13)-
,
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13-
),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13-
),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).-
sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.s-
ub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O-
).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13); R.sub.12 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-8alkyl(R.sub- .13),
--CH.sub.2S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alk- yl(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R- .sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--CH.sub.2O--C(.dbd.O)OC.sub.1- -8alkyl(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)- NHC.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.- sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(-
R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2CH.sub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.su-
b.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)CH.sub-
.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH-
.sub.2(R.sub.13),
--CH.sub.2OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.-
2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.-
2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
CH.sub.2(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O-
)(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.-
rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13); wherein when R.sub.11 or R.sub.12 terminates
with a --C(.dbd.O)--, R.sub.13 is selected from 172and when
R.sub.11 or R.sub.12 does not terminate with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of
173174175176wherein the unit --O--(CH.sub.2CH.sub.2O--).sub.p-- or
177 of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG) polymer
ranging in molecular weight from 750 to 5000 daltons; r is an
integer from 0 to 8; Q and Q.sup.1 of substituents R.sub.12 and
R.sub.13 are the same within a given compound and are selected from
the group consisting of the C.sub.11 saturated chain of lauric
acid, the C.sub.13 saturated chain of myristoic acid, the C.sub.15
saturated chain of palmitoic acid, the C.sub.17 saturated chain of
stearoic acid, the C.sub.17 mono-unsaturated chain of oleoic acid,
and the C.sub.17 di-unsaturated chain of linoleic acid; Z is
selected from the group consisting of hydroxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl--OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
O--C.sub.1-8alkylcarbonylC.sub.1-8alk- yl,
--O--C.sub.1-8alkyl--CO.sub.2H,
--O--C.sub.1-8alkyl--C(O)O--C.sub.1-8a-
lkyl, O--C.sub.1-8alkyl--O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--NH.su- b.2,
--O--C.sub.1-8alkyl--NH--C.sub.1-8alkyl,
O--C.sub.1-8alkyl--N(C.sub.1- -8alkyl).sub.2,
--O--C.sub.1-8alkylamide, --O--C.sub.1-8alkyl--C(O)--NH--C-
.sub.1-8alkyl, O--C.sub.1-8alkyl--C(O)--N(C.sub.1-8alkyl).sub.2,
and --NHC(O)C.sub.1-8alkyl; and pharmaceutically acceptable salts,
racemic mixtures and enantiomers thereof.
80. The liposome of claim 79 wherein R.sub.12 is selected from the
group consisting of --C.sub.1-6alkyl(R.sub.13),
--O--C.sub.1-6alkyl(R.sub.13), --NH--C.sub.1-4alkyl(R.sub.13),
--S--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub- .13),
--CH.sub.2S--C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-6alkyl(R.s- ub.13),
--O--C(.dbd.O)C.sub.1-6alkyl(R.sub.13), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-6alk- yl(R.sub.13),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-6alkyl(R- .sub.13),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.-
sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub-
.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2-
CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
wherein when R.sub.11 or R.sub.12 terminates with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 178and when
R.sub.11 or R.sub.12 does not terminate with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 179180
81. The liposome of claim 79 wherein R.sub.12 is selected from the
group consisting of --CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6akyl(R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl(R.sub.- 13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub- .1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(C-
H.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.s-
ub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.-
dbd.O)(R.sub.13), and
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).su-
b.rCH.sub.2C(.dbd.O)(R.sub.13). wherein when R.sub.11 or R.sub.12
terminates with a --C(.dbd.O)--, R.sub.13 is selected from the
group consisting of 181and when R.sub.11 or R.sub.12 does not
terminate with a --C(.dbd.O)--, R.sub.13 is selected from the group
consisting of 182183
82. The liposome of claim 79 wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p- -- or 184of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer ranging in molecular weight
from 2000 to 5000 daltons.
83. The liposome of claim 79 wherein wherein Q and Q.sup.1 of
substituents R.sub.12 and R.sub.13 are the same within a given
compound and are selected from the group consisting of the C.sub.15
saturated chain of palmitoic acid, the C.sub.17 saturated chain of
stearoic acid, and the C.sub.17 mono-unsaturated chain of oleoic
acid.
84. The liposome of claim 79 wherein W is preferably is selected
from the group consisting of --C.sub.0-4alkyl(R.sub.1),
--C.sub.1-4alkyl(R.sub.1a)- ,
--C.sub.0-4alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-4alkyl-heterocyclyl(R.- sub.1,R.sub.8),
--C.sub.0-4alkoxy(R.sub.1), --C.sub.0-4alkoxy-aryl(R.sub.1-
,R.sub.8), and --C.sub.0-4alkoxy-heterocyclyl(R.sub.1,R.sub.8);
R.sub.1 is --N(R.sub.4)(R.sub.6), -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8); R.sub.1a is --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is hydrogen or --C.sub.1-4alkyl(R.sub.7); R.sub.5 is
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub- .8),
--C(.dbd.O)--N(R.sub.4)-aryl(R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) or
--SO.sub.2-aryl(R.sub.8); R.sub.6 is -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8); R.sub.7 is one to two substituents
independently selected from hydrogen, --C.sub.1-4alkoxy(R.sub.9),
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4a- lkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.su- b.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl--S--C.sub.1-4alkyl(R.su- b.9),
--S--C.sub.1-4alkyl--C.sub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--C.sub.1-4al- kyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9- ),
--SO.sub.2--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10)- , cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) or -heteroaryl(R.sub.10); R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9) or --SO.sub.2--NH.sub.2 when
attached to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, cyano, halo, hydroxy, nitro or
oxo when attached to a carbon atom; R.sub.9 is hydrogen,
--C.sub.1-4alkoxy, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro or oxo; R.sub.10 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alky- l, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl or
--SO.sub.2--N(C.sub.1-4alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, cyano, halo,
hydroxy, nitro or oxo when attached to a carbon atom; R.sub.2a is
-cycloalkyl(R.sub.8)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) or -heteroaryl(R.sub.8)(R.sub.12); q is 1,
2 or 3. R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13), --C(.dbd.O)NHC.sub.1-8alkyl(-
R.sub.13), --O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.- dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13-
),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.1-
3),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13); R.sub.12
is selected from the group consisting of
--C.sub.1-6alkyl(R.sub.13), --O--C.sub.1-6alkyl(R.sub.13),
--NH--C.sub.1-4alkyl(R.sub.13), --S.sub.1-6alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl(R.sub- .13),
--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-6alkyl(R.- sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.-
sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.1- 3),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-6alky- l(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.-
sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub-
.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2-
CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
wherein when R.sub.11 or R.sub.12 terminates with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 185and when
R.sub.11 or R.sub.12 does not terminate with a --C(.dbd.O)--,
R.sub.13 is selected from the group consisting of 186187said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 188 of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer ranging in molecular weight
from 750 to 5000 daltons; r is an integer from 0 to 8; Q and
Q.sub.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and are selected from the group consisting of the
C.sub.11 saturated chain of lauric acid, the C.sub.15 saturated
chain of palmitoic acid, the C.sub.17 saturated chain of stearoic
acid, the C.sub.17 mono-unsaturated chain of oleoic acid, and the
C.sub.17 di-unsaturated chain of linoleic acid; Z is selected from
the group consisting of hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--OH, --O--C.sub.1-8alkyl.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4al- kyl,
--O--C.sub.1-8alkyl--CO.sub.2H,
--O--C.sub.1-8alkyl--C(O)O--C.sub.1-6- alkyl,
--O--C.sub.1-8alkyl--O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--NH- .sub.2,
--O--C.sub.1-8alkyl--NH--C.sub.1-8alkyl, --O--C.sub.1-8alkyl--N(C.-
sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide--O--C.sub.1-8alkyl--C(O)--NH-
--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
85. The liposome of claim 79 wherein W is preferably
--C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl--phenyl(R.sub.1,R.sub.8); R.sub.1 is
--N(R.sub.4)(R.sub.6), -tetrahydropyrimidinyl(R.sub.8) or
-tetrahydro-1,8-naphthyridinyl(R.sub.8); R.sub.1a is
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or --C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
R.sub.4 is hydrogen; R.sub.5 is --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --CO.sub.2--R.sub.4,
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--SO.sub.2--C.sub.1-4alkyl(R.sub.7) or
--SO.sub.2--N(R.sub.4).sub.2; R.sub.6 is
-dihydroimidazolyl(R.sub.8), -tetrahydropyridinyl(R.sub.8),
-tetrahydropyrimidinyl(R.sub.8) or -pyridinyl(R.sub.8); R.sub.7 is
hydrogen; R.sub.8 is one to four substituents independently
selected from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached
to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9)--O-a-
ryl(R.sub.10) or hydroxy when attached to a carbon atom; R.sub.9 is
hydrogen, --C.sub.1-4alkoxy, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, (halo).sub.1-3, or hydroxy; R.sub.10 is
hydrogen; R.sub.2a is -tetrahydropyrimidinyl(R.sub.8)(R.sub.12),
-1,3-benzodioxolyl(R.sub.8)(R.sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.su- b.12),
-tetrahydroquinolinyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12- ), -naphthalenyl(R.sub.8)(R.sub.12),
-pyridinyl(R.sub.8)(R.sub.12), -pyrimidinyl(R.sub.8)(R.sub.12) or
-quinolinyl(R.sub.8)(R.sub.12); q is 1 or 2; R.sub.12 is selected
from the group consisting of
--CH.sub.2--O--(CH.sub.2).sub.4(R.sub.13)--,
--CH.sub.2--NH--(CH.sub.2).s- ub.4(R.sub.13)--,
--CH.sub.2--S--(CH.sub.2).sub.4(R.sub.13)--,
--CH.sub.2--O--(CH.sub.2).sub.6(R.sub.13)--,
--CH.sub.2--NH--(CH.sub.2).s- ub.6(R.sub.13)--,
--CH.sub.2--S--(CH.sub.2).sub.6(R.sub.13)--,
--NH--C(.dbd.O)--(CH.sub.2).sub.4(R.sub.13)--,
--NH--C(.dbd.O)--(CH.sub.2- ).sub.7(R.sub.13)--,
--NH--C(.dbd.O)NH--(CH.sub.2).sub.3(R.sub.13)--,
--NH--C(.dbd.O)NH--(CH.sub.2).sub.6(R.sub.13)--,
--CH.sub.2NH--C(.dbd.O)N- H--(CH.sub.2).sub.2(R.sub.13)--,
--CH.sub.2NH--C(.dbd.O)NH--((CH.sub.2).su- b.5(R.sub.13)--,
--NHC(.dbd.O)--(CH.sub.2).sub.2--C(.dbd.O)(R.sub.13)--,
--NHC(.dbd.O)--(CH.sub.2).sub.3--C(.dbd.O)(R.sub.13)--,
--NHC(.dbd.O)--(CH.sub.2).sub.4--C(.dbd.O)(R.sub.13)--,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--NHCH.sub.2CH.sub.2OCH- .sub.2CH.sub.2(R.sub.13)--,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2C-
H.sub.2(R.sub.13)--,
--NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.-
2(R.sub.13)--, --OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
--NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)---
,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)-
--,
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13-
)--, --CH.sub.2NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
and --NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--; wherein
when R.sub.11 or R.sub.12 terminates with a --C(.dbd.O)--, R.sub.13
is selected from the group consisting of 189and when R.sub.11 or
R.sub.12 does not terminate with a --C(.dbd.O)--, R.sub.13 is
selected from the group consisting of 190wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 191 of R.sub.12 and R.sub.13
is a polyethylene glycol (PEG) polymer selected from 2000 (PEG
2000), 3400 (PEG 3400), or 5000 (PEG 5000) Daltons; r is an integer
from 0 to 8; Q and Q.sup.1 of substituents R.sub.12 and R.sub.13
are the same within a given compound and is the C.sub.17 saturated
chain of stearoic acid; Z is selected from the group consisting of
hydroxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--OH, --O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4a- lkyl,
--O--C.sub.1-8alkyl--CO.sub.2H,
--O--C.sub.1-8alkyl--C(O)O--C.sub.1-- 6alkyl,
--O--C.sub.1-8alkyl--O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--NH.sub.2,
--O--C.sub.1-8alkyl--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide--O-
--C.sub.1-8alkyl--C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl--C(O)--N(C- .sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
86. The therapeutic liposome composition of claim 78 wherein the
therapeutic agent is selected from the group consisting of
steroids, immunosuppressants, antihistamines, non-steroidal
anti-asthamtics, non-steroidal anti-inflammatory agents,
cyclooxygenase-2 inhibitors, cytotoxic agents, gene therapy agents,
radiotherapy agents, and imaging agents.
87. The therapeutic liposome composition of claim 78 wherein the
therapeutic agent is a cytotoxic drug.
88. The therapeutic liposome composition of claim 87 wherein the
cytotoxic drug is selected from the group consisting of
anthracycline antibiotics, platinum compounds, topoisomerase 1
inhibitors, and vinca alkaloids.
89. The therapeutic liposome composition of claim 87 wherein the
cytotoxic agent is selected from the group consisting of
doxorubicin, daunorubicin, epirubicin, idarubicin, cisplatin,
carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin,
lobaplatin, spiroplatin, ((-)-(R)-2-aminomethylpy- rrolidine
(1,1-cyclobutane dicarboxylato)platinum),
(SP-4-3(R)1,1-cyclobutane-dicarboxylato(2-)-(2-methyl-1,4-butanediamine-N-
,N')platinum), nedaplatin,
(bis-acetato-ammine-dichloro-cyclohexylamine-pl- atinum(IV),
topotecan, irinotecan, (7-(4-methylpiperazino-methylene)-10,11-
-ethylenedioxy-20(S)-camptothecin),
7-(2-(N-isopropylamino)ethyl)-(20S)-ca- mptothecin,
9-aminocamptothecin, 9-nitrocamptothecin, vincristine, vinblastine,
vinleurosine, vinrodisine, vinorelbine, and vindesine.
90. The therapeutic liposome composition of claim 87 wherein the
cytotoxic agent is selected from the group consisting of
doxorubicin, daunorubicin, epirubicin, idarubicin, cisplatin,
including salts.
Description
[0001] This application is a continuation in part of nonprovisional
patent application Ser. No. 10/641,964 filed on Aug. 15, 2003 and
claims benefit of provisional patent application Ser. No.
60/404,239, filed on 16 Aug. 2003, which are all hereby
incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The current invention relates to the preparation of an
affinity moiety or targeting ligand that may be used in imaging or
treating integrin mediated diseases. The targeting ligand of the
present invention is a member of a class of piperidinoyl carboxylic
acid compounds, which possess a high binding affinity for
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5 or
.alpha..sub.v.beta..sub.6 integrin receptors. The current invention
also relates to targeting ligand conjugated with an imaging agent
or a drug delivery vehicle such as a liposome. Also provided are
targeted liposomes as drug delivery vehicle for treating cells and
imaging agents for imaging cells involved in
.alpha..sub.v.beta..sub.4, .alpha..sub.v.beta..sub.5, or
.alpha..sub.v.beta..sub.6-mediated disease states.
BACKGROUND OF THE INVENTION
[0003] Integrins are a family of transmembrane receptors, each of
which is composed of a pair of heterodimeric, noncovalently
associated glycoproteins, designated as a and .beta. chains. The
.alpha. subunit contains heavy and light chains as part of its
extracellular domain, with 3-4 divalent-cation binding sites; the
light chain also contains transmembrane and intracellular domains.
The .beta.-subunit contains a large extracellular domain, as well
as transmembrane and intracellular domains. Integrins are cell
surface receptors, which bind to extracellular matrix adhesive
proteins such as fibrinogen, fibronectin, vitronectin and
osteopontin. These transmembrane glycoproteins are classified by
the .beta. subunits. The .beta.3 class of integrin family has
received the most attention in recent drug discovery efforts (W. J.
Hoekstra, Current Medicinal Chemistry, 1998, 5, 195), however, the
.beta.5 class has also become a focus of attention. Some of the
disease states that have been associated with a strong .beta.3 and
.beta.5 integrin component in their etiologies are thrombosis
(integrin .alpha.2b.beta.3 also called GPIIb/IIIa); unstable angina
(GPIIb/IIIa); restenosis (GPIIb/IIIa and integrin .alpha.v.beta.3);
arthritis, vascular disorders or osteoporosis (.alpha.v.beta.3);
tumor angiogenesis, multiple sclerosis, neurological disorders,
asthma, vascular injury or diabetic retinopathy (.alpha.v.beta.3 or
.alpha.v.beta.5) and tumor metastasis (.alpha.v.beta.3). See S. A.
Mousa, et al., Emerging Therapeutic Targets, 2000, 4(2) 148-149;
and W. H. Miller, et al., Drug Discovery Today, 2000, 5(9), 397-40.
Antibodies and/or low-molecular weight compound antagonists of
.alpha.v.beta.3 have shown efficacy against these respective
disease states in animal models (J. Samanen, Current Pharmaceutical
Design, 1997, 3 545-584) and thereby offer promise as therapeutic
agents. Several patents have described compounds that could
interact with these integrins. For example, U.S. Pat. Nos.
5,919,792 B1, 6,211,191 B1, and WO 01/96334 and WO 01/23376
describe .alpha.v.beta.3 and .alpha.v.beta.5 integrin receptor
antagonists.
[0004] The present invention provides a new class of piperidinyl
compounds, which selective bind to .beta.3, .beta.5 or dual
integrin receptors (e.g. .alpha.v.beta.3 and .alpha.v.beta.5) for
the treatment of a wide variety of integrin mediated disease
states.
[0005] The present invention describes the synthesis and use of
piperidinoyl carboxylic acid integrin antagonists affinity moieties
that may serve as a targeting agent for imaging agents or serve to
direct the liposomes containing therapeutic agents to cells that
express .alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5, or
.alpha..sub.v.beta..sub.6 integrin receptors. The liposome may
carry a number of therapeutic agents, including but not limited to,
steroids, immunosuppressants, antihistamines, non-steroidal
anti-asthamtics, non-steroidal anti-inflammatory agents,
cyclooxygenase-2 inhibitors, cytotoxic agents, gene therapy agents,
radiotherapy agents, imaging agents.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to piperidinyl compounds
of Formula (I): 3
[0007] wherein
[0008] W is selected from the group consisting of
--C.sub.0-6alkyl(R.sub.1- ), --C.sub.1-6alkyl(R.sub.1a),
--C.sub.0-6alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-6alkyl-heterocyclyl(R.sub.1,R.sub.8),
--C.sub.0-6alkoxy(R.sub.1- ),
--C.sub.0-6alkoxy-aryl(R.sub.1,R.sub.8), and
--C.sub.0-6alkoxy-heterocy- clyl(R.sub.1,R.sub.8),
[0009] R.sub.1 is selected from the group consisting of hydrogen,
--N(R.sub.4).sub.2, --N(R.sub.4)(R.sub.5), --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8);
[0010] R.sub.1a is selected from the group consisting of
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7)
and
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
[0011] R.sub.4 is selected from the group consisting of hydrogen
and --C.sub.1-8alkyl(R.sub.7);
[0012] R.sub.5 is selected from the group consisting of
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8);
[0013] R.sub.6 is selected from the group consisting of
-cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8), -aryl(R.sub.8) and
-heteroaryl(R.sub.8);
[0014] R.sub.7 is one to two substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkoxy(R.sub.9),
--NH.sub.2, --NH--C.sub.1-8alkyl(R.sub.9),
--N(C.sub.1-8alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--C.sub.1-8alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo)-3, hydroxy, nitro, oxo,
-cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10), -aryl(R.sub.10) and
-heteroaryl(R.sub.10);
[0015] R.sub.8 is one to four substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C.sub.1-8alkoxy(R.sub.9), --O-cycloalkyl(R.sub.10),
--O-aryl(R.sub.10), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.1a),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-8alkyl(R.sub.9- ),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.s- ub.1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.1a),
-heterocyclyl(R.sub.1a), -aryl(R.sub.1a) and -heteroaryl(R.sub.10)
when attached to a carbon atom;
[0016] R.sub.9 is selected from the group consisting of hydrogen,
--C.sub.1-8alkoxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo;
[0017] R.sub.10 is one to four substituents independently selected
from from the group consisting of hydrogen, --C.sub.1-8alkyl,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl and
--SO.sub.2--N(C.sub.1-8alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C.sub.1-8alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom;
[0018] R.sub.2 is selected from the group consisting of hydrogen,
--C.sub.1-8alkyl(R.sub.7), --C.sub.2-8alkenyl(R.sub.7),
--C.sub.2-8alkynyl(R.sub.7), -cycloalkyl(R.sub.8),
-heterocyclyl(R.sub.8), -aryl(R.sub.8) and
-heteroaryl(R.sub.8);
[0019] q is 0, 1, 2 or 3;
[0020] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
[0021] and pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0022] The present invention is also directed to methods for
producing the instant piperidinyl compounds and pharmaceutical
compositions and medicaments thereof.
[0023] The present invention is further directed to a method for
treating or ameliorating an integrin receptor mediated
disorder.
[0024] In one embodiment of the present invention comprise
targeting ligands of Formula (I): 4
[0025] wherein
[0026] W is selected from the group consisting of
--C.sub.0-6alkyl(R.sub.1- ), --C.sub.1-6alkyl(R.sub.1a),
--C.sub.0-6alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-6alkyl-heterocyclyl(R.sub.1,R.sub.8),
--C.sub.0-6alkoxy(R.sub.1- ),
--C.sub.0-6alkoxy-aryl(R.sub.1,R.sub.8), and
--C.sub.0-6alkoxy-heterocy- clyl(R.sub.1,R.sub.8);
[0027] R.sub.1 is selected from the group consisting of hydrogen,
--N(R.sub.4).sub.2, --N(R.sub.4)(R.sub.5), --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8);
[0028] R.sub.1a is selected from the group consisting of
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7)
and
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
[0029] R.sub.4 is selected from the group consisting of hydrogen
and --C.sub.1-8alkyl(R.sub.7);
[0030] R.sub.5 is selected from the group consisting of
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8);
[0031] R.sub.6 is selected from the group consisting of
-cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8), -aryl(R.sub.8) and
-heteroaryl(R.sub.8);
[0032] R.sub.7 is one to two substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkoxy(R.sub.9),
--NH.sub.2, --NH--C.sub.1-8alkyl(R.sub.9),
--N(C.sub.1-8alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--C.sub.1-8alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo)-3, hydroxy, nitro, oxo,
-cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10), -aryl(R.sub.10) and
-heteroaryl(R.sub.10);
[0033] R.sub.8 is one to four substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.1a), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.1a), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C.sub.1-8alkoxy(R.sub.9), --O-cycloalkyl(R.sub.1a),
--O-aryl(R.sub.1a), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--C.sub.1-8alkyl(R.sub- .9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .1a), --NHC(.dbd.O)--NH.sub.2,
--NHC(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--NHC(.dbd.O)--NH-aryl(R- .sub.1a),
--NHC(.dbd.O)--O--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--O-aryl(R.sub.1a), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10),
--NHC(.dbd.O)-cycloalkyl(R.sub.10),
--NHC(.dbd.O)-heterocyclyl(R.sub.10), --NHC(.dbd.O)-aryl(R.sub.10),
--NHC(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alk- yl(R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --NHSO.sub.2--C.sub.1-8alkyl(R.su- b.9),
--NHSO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10), and -heteroaryl(R.sub.10)
when attached to a carbon atom;
[0034] R.sub.9 is selected from the group consisting of hydrogen,
--C.sub.1-8alkoxy, --NH.sub.2, --NH--C.sub.1-8alkyl,
--N(C.sub.1-8alkyl).sub.2, --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.8alkyl).sub.2, cyano, (halo).sub.13, hydroxy,
nitro and oxo;
[0035] R.sub.10 is one to four substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkyl,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl and
--SO.sub.2--N(C.sub.1-8alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C.sub.1-8alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom;
[0036] q is 0, 1, 2, or 3;
[0037] R.sub.2a is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkenyl(R.sub.7)(R.sub.11- ),
--C.sub.2-8alkynyl(R.sub.7)(R.sub.1),
-cycloalkyl(R.sub.7)(R.sub.1), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) and -heteroaryl(R.sub.8)(R.sub.12);
[0038] R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.14), --O--C.sub.1-8alkyl(R.sub.14),
--NH--C.sub.1-8alkyl(R.sub.14), --S--C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 4),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.14), --O--C(.dbd.O)NHC.sub.1-8alkyl(R) 4),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkyl- (R.sub.14),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2H.sub.2C(R).sub.4),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(-
R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2CH.sub.2(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2H.sub.2O).su-
b.rCH.sub.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2H.-
sub.2CO).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub-
.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2H.sub.2CO).sub.rCH.sub.2C(.dbd.O)-
(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O-
).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.14);
[0039] R.sub.12 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.14), --O--C.sub.1-8alkyl(R.sub.14),
--NH--C.sub.1-8alkyl(R.sub.14), --S--C.sub.1-8alkyl(R.sub.14),
--CH.sub.2O--C.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C.sub.1-8alkyl(R.sub- .14),
--CH.sub.2S--C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.14), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alk- yl(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R- .sub.14),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--CH.sub.2O--C(.dbd.O)OC.sub.1- -8alkyl(R.sub.14),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)- NHC.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.- sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 4),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(-
R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2H.sub.2CO).sub.rCH.sub.-
2CH.sub.2(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.14),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.su-
b.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2SCH.sub.2CH.sub.2.degree-
.(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.14),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2CH.sub.2(R.sub.14),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH-
.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
CH.sub.2(R.sub.14),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.14),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.14),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O-
)(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2O-
(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.114),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rC
H.sub.2C(.dbd.O) (R.sub.14);
[0040] R.sub.14 when R.sub.11 and R.sub.12 terminates with a
C(.dbd.O) is selected from the group consisting of hydrogen, OH,
--OC.sub.1-4alkyl and NH.sub.2; otherwise R.sub.14 is selected from
the group consisting of --OH, --SH, COOH, and
--COOC.sub.1-4alkyl;
[0041] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl;
[0042] and pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0043] In one embodiment of the present invention comprises a
targeting conjugate of Formula (I): 5
[0044] wherein
[0045] W is selected from the group consisting of
--C.sub.0-6alkyl(R.sub.1- ), --C.sub.1-6alkyl(R.sub.1a),
--C.sub.0-6alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-6alkyl-heterocyclyl(R.sub.1,R.sub.8),
--C.sub.0-6alkoxy(R.sub.1- ),
--C.sub.0-6alkoxy-aryl(R.sub.1,R.sub.8), and
--C.sub.0-6alkoxy-heterocy- clyl(R.sub.1,R.sub.8);
[0046] R.sub.1 is selected from the group consisting of hydrogen,
--N(R.sub.4).sub.2, --N(R.sub.4)(R.sub.5), --N(R.sub.4)(R.sub.6),
-heterocyclyl(R.sub.8) and -heteroaryl(R.sub.8);
[0047] R.sub.1a is selected from the group consisting of
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7)
and
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
[0048] R.sub.4 is selected from the group consisting of hydrogen
and --C.sub.1-8alkyl(R.sub.7);
[0049] R.sub.5 is selected from the group consisting of
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-8alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) and
--SO.sub.2-aryl(R.sub.8);
[0050] R.sub.6 is selected from the group consisting of
-cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8), -aryl(R.sub.8) and
-heteroaryl(R.sub.8);
[0051] R.sub.7 is one to two substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkoxy(R.sub.9),
--NH.sub.2, --NH--C.sub.1-8alkyl(R.sub.9),
--N(C.sub.1-8alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--C.sub.1-8alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) and -heteroaryl(R.sub.10);
[0052] R.sub.8 is one to four substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) and
-aryl(R.sub.10) when attached to a nitrogen atom; and, wherein
R.sub.8 is one to four substituents independently selected from the
group consisting of hydrogen, --C.sub.1-8alkyl(R.sub.9),
--C.sub.1-8alkoxy(R.sub.9),
--O-cycloalkyl(R.sub.10).sub.5--O-aryl(R.sub.10), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--C.sub.1-8alkyl(R.sub- .9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --NHC(.dbd.O)--NH.sub.2,
--NHC(.dbd.O)--NH--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--N(C.sub.1-8alkyl(R.sub.9)).sub.2,
--NHC(.dbd.O)--NH-aryl(R- .sub.10),
--NHC(.dbd.O)--O--C.sub.1-8alkyl(R.sub.9),
--NHC(.dbd.O)--O-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10),
--NHC(.dbd.O)-cycloalkyl(R.sub.10),
--NHC(.dbd.O)-heterocyclyl(R.sub.10), --NHC(.dbd.O)-aryl(R.sub.10),
--NHC(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-8alk- yl(R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-8alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --NHSO.sub.2--C.sub.1-8alkyl(R.su- b.9),
--NHSO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-S--C.sub.1-8alkyl(R.sub.9),
--S--C.sub.1-8alkyl-C.sub- .1-8alkoxy(R.sub.9),
--S--C.sub.1-8alkyl-NH--C.sub.1-8alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-8alkyl(R.sub.9), --N(C.sub.1-8alkyl(R.sub.9)).s-
ub.2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.10), -aryl(R.sub.10), and -heteroaryl(R.sub.0)
when attached to a carbon atom; R.sub.9 is selected from the group
consisting of hydrogen, --C.sub.1-8alkoxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-alkyl).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-8alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro and oxo;
[0053] R.sub.10 is one to four substituents independently selected
from the group consisting of hydrogen, --C.sub.1-8alkyl,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl and
--SO.sub.2--N(C.sub.1-8alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from the group consisting of hydrogen,
--C.sub.1-8alkyl, --C.sub.1-8alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-8alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-8alkyl,
--C(.dbd.O)--N(C.sub.1-8alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-8alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-8alkyl,
--SO.sub.2--N(C.sub.1-8alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2, cyano, halo,
hydroxy, nitro and oxo when attached to a carbon atom;
[0054] q is 0, 1, 2, or 3;
[0055] R.sub.2a is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.7)(R.sub.11),
--C.sub.2-8alkenyl(R.sub.7)(R.sub.11- ),
--C.sub.2-8alkynyl(R.sub.7)(R.sub.11),
-cycloalkyl(R.sub.7)(R.sub.11), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) and -heteroaryl(R.sub.8)(R.sub.12);
[0056] R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 3),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.13), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkyl- (R.sub.13),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(-
R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2CH.sub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)-
(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.s-
ub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O-
).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13);
[0057] R.sub.12 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-8alkyl(R.sub- .13),
--CH.sub.2S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.s- ub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.13), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alk- yl(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R- .sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--CH.sub.2O--C(.dbd.O)OC.sub.1- -8alkyl(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)- NHC.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.- sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8al- kylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.1- 3),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13)-
,
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(-
R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.-
2CH.sub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.su-
b.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.-
sub.2(R.sub.13),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
CH.sub.2(R.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--OC(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.-
sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O-
)(R.sub.13), --SO.sub.2
CH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.-
rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.r-
CH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2-
C(.dbd.O)(R.sub.13);
[0058] wherein when R.sub.11 or R.sub.12 terminates with a
--C(.dbd.O)--, R.sub.13 is selected from 6
[0059] and when R.sub.11 or R.sub.12 does not terminate with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
7891011
[0060] wherein the unit --O--(CH.sub.2CH.sub.2O--).sub.p-- or
12
[0061] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer ranging in molecular weight from 750 to 5000 daltons;
[0062] r is an integer from 0 to 8;
[0063] Q and Q.sup.1 of substituents R.sub.12 and R.sub.13 are the
same within a given compound and are selected from the group
consisting of
[0064] the C.sub.11 saturated chain of lauric acid,
[0065] the C.sub.13 saturated chain of myristoic acid,
[0066] the C.sub.15 saturated chain of palmitoic acid,
[0067] the C.sub.17 saturated chain of stearoic acid,
[0068] the C.sub.17 mono-unsaturated chain of oleoic acid, and
[0069] the C.sub.17 di-unsaturated chain of linoleic acid;
[0070] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
O--C.sub.8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2, and
--NHC(O)C.sub.1-8alkyl;
[0071] and pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0072] Another aspect of the present invention includes a
therapeutic liposome composition sensitized to a target cell,
comprising liposomes having an entrapped therapeutic agent, the
liposomes including one or more targeting conjugates. The targeting
conjugates have a structure represented by Formula (D or Formula
(ID, and are comprised of (a) a lipid having a polar head group and
a hydrophobic tail, (b) a hydrophilic polymer having a proximal end
and a distal end, where the polymer is attached at its proximal end
to the head group of the lipid, and (c) a piperidinoyl carboxylic
acid compound attached to the distal end of the polymer.
BRIEF DESCRIPTION OF THE FIGURES
[0073] FIGS. 1A-1B are HPLC chromatograms of a
maleimide-poly(ethylene glycol)-distearoylphosphatidylethanolamine
(Mal-PEG-DSPE) compound before conjugation (FIG. 1A) and after
conjugation (FIG. 1B) to Compound 38b (Example 39) to form a
DSPE-PEG-piperidinoyl carboxylic acid compound conjugate.
DETAILED DESCRIPTION OF THE INVENTION
[0074] 1. Compounds
[0075] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein W is preferably is selected
from the group consisting of --C.sub.0-4alkyl(R.sub.1),
--C.sub.1-4alkyl(R.sub.1a)- ,
--C.sub.0-4alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-4alkyl-heterocyclyl(R.- sub.1,R.sub.8),
--C.sub.0-4alkoxy(R.sub.1), --C.sub.0-4alkoxy-aryl(R.sub.1-
,R.sub.8), and --C.sub.0-4alkoxy-heterocyclyl(R.sub.1,R.sub.8).
[0076] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein W is preferably
--C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-aryl(R.sub.1,R.sub.8).
[0077] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein W is preferably
--C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R.sub.8).
[0078] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.1 is
--N(R.sub.4)(R.sub.6), -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8).
[0079] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.1 is
--N(R.sub.4)(R.sub.6),
-dihydro-1H-pyrrolo[2,3-b]pyridinyl(R.sub.8),
-tetrahydropyrimidinyl(R.su- b.8),
-tetrahydro-1,8-naphthyridinyl(R.sub.8),
-tetrahydro-1H-azepino[2,3-- b]pyridinyl(R.sub.8) or
-pyridinyl(R.sub.8).
[0080] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.1 is
--N(R.sub.4)(R.sub.6), -tetrahydropyrimidinyl(R.sub.8) or
-tetrahydro-1,8-naphthyridinyl(R.sub.8- )-- Aspects of the present
invention include compounds of Formula (I) and Formula (II) wherein
R.sub.1a is --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2.
[0081] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.4 is hydrogen or
--C.sub.1-4alkyl(R.sub.7)- .
[0082] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.4 is hydrogen.
[0083] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.5 is
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.O)-cycloalkyl(R.sub.8), --C(.dbd.O)-heterocyclyl(R.sub.8),
--C(.dbd.O)-aryl(R.sub.8), --C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub- .8),
--C(.dbd.O)--N(R.sub.4)-aryl(R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.9),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.9) or
--SO.sub.2-aryl(R.sub.8).
[0084] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.5 is
--C(.dbd.O)--R.sub.4, --C(.dbd.O)--N(R.sub.4).sub.2,
--CO.sub.2--R.sub.4, --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--N(R.sub.4)--C(R.sub.4)(.dbd.- N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--SO.sub.2--C.sub.1-4alkyl(R.sub.7) or
--SO.sub.2--N(R.sub.4).sub.2.
[0085] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.6 is
-heterocyclyl(R.sub.8) or -heteroaryl(R.sub.8).
[0086] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.6 is
-dihydroimidazolyl(R.sub.- 8), -tetrahydropyridinyl(R.sub.8),
-tetrahydropyrimidinyl(R.sub.8) or -pyridinyl(R.sub.8).
[0087] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.7 is one to two
substituents independently selected from hydrogen,
--C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-C.sub- .1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.s- ub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo)-3, hydroxy, nitro, oxo,
-cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10), -aryl(R.sub.16) or
-heteroaryl(R.sub.10).
[0088] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.7 is one to two
substituents independently selected from hydrogen,
--C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).s-
ub.2, (halo).sub.1-3, hydroxy or oxo.
[0089] A further aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.7 is hydrogen.
[0090] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), -cycloalkyl(R.sub.10) or -aryl(R.sub.10)
when attached to a nitrogen atom; and, wherein R.sub.8 is one to
four substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-cycloalkyl(R.sub.10), --O-aryl(R.sub.10), --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl-R.sub.11).sub.2,
--C(.dbd.O)--NH-aryl(R.sub- .10), --C(.dbd.O)-cycloalkyl(R.sub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10)- , --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --CO.sub.2-aryl(R.sub.1- 0),
--C(.dbd.NH)--NH.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.1-4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl- (R.sub.9),
--S--C.sub.1-4alkyl-C.sub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH--C.sub.1-4alkyl(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).sub.2,
cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R.sub.10),
-heterocyclyl(R.sub.16)- , -aryl(R.sub.10) or -heteroaryl(R.sub.10)
when attached to a carbon atom.
[0091] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.su- b.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9) or --SO.sub.2--NH.sub.2 when
attached to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, cyano, halo, hydroxy, nitro or
oxo when attached to a carbon atom.
[0092] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.8 is one to four
substituents independently selected from hydrogen or
--C.sub.1-4alkyl(R.sub.9) when attached to a nitrogen atom; and,
wherein R.sub.8 is one to four substituents independently selected
from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-aryl(R.sub.10), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).sub.2,
halo, hydroxy or oxo when attached to a carbon atom.
[0093] A further aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.8 is one to four
substituents independently selected from hydrogen or
--C.sub.1-4alkyl(R.sub.9) when attached to a nitrogen atom; and,
wherein R.sub.8 is one to four substituents independently selected
from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9) --O-aryl(R.sub.10) or hydroxy when
attached to a carbon atom.
[0094] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.9 is hydrogen,
--C.sub.1-4alkoxy, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, cyano, (halo), .sub.3,
hydroxy, nitro or oxo.
[0095] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.9 is hydrogen,
--C.sub.1-4alkoxy, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, --C(.dbd.O)H, --CO.sub.2H,
--C(.dbd.O)--C.sub.1-4alkoxy, (halo).sub.1-3, hydroxy or oxo.
[0096] A further aspect of the present invention includes compounds
of Formula (I) wherein R.sub.9 is hydrogen, --C.sub.1-4alkoxy,
--NH.sub.2, --NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
(halo).sub.1-3 or hydroxy.
[0097] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.10 is one to four
substituents independently selected from hydrogen,
--C.sub.1-4alkyl, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl or
--SO.sub.2--N(C.sub.1-4alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, cyano, halo,
hydroxy, nitro or oxo when attached to a carbon atom.
[0098] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein (R.sub.10).sub.14 is
hydrogen, --C.sub.1-4alkyl, --C.sub.1-4alkoxy, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --NH.sub.2, --NH--C.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, halo, hydroxy, nitro or oxo when
attached to a carbon atom.
[0099] A further aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.10 is hydrogen.
[0100] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein R.sub.2 is hydrogen,
--C.sub.1-4alkyl(R.sub.7), --C.sub.2-4alkenyl(R.sub.7),
--C.sub.2-4alkynyl(R.sub.7), -cycloalkyl(R.sub.8),
-heterocyclyl(R.sub.8), -aryl(R.sub.8) or -heteroaryl(R.sub.8).
[0101] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.2 is hydrogen,
-cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8), -aryl(R.sub.8) or
-heteroaryl(R.sub.8).
[0102] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.2 is hydrogen,
-cycloalkyl(R.sub.8), -heterocyclyl(R.sub.8), -phenyl(R.sub.8),
-naphthalenyl(R.sub.8) or -heteroaryl(R.sub.8).
[0103] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein R.sub.2 is hydrogen,
-tetrahydropyrimidinyl(R.sub.8), -1,3-benzodioxolyl(R.sub.8),
-dihydrobenzofuranyl(R.sub.8), -tetrahydroquinolinyl(R.sub.8),
-phenyl(R.sub.8), -naphthalenyl(R.sub.8), -pyridinyl(R.sub.8),
-pyrimidinyl(R.sub.8) or -quinolinyl(R.sub.8).
[0104] For the targeting ligand and targeting conjugates previously
decribed R.sub.2 is replaced by R.sub.2A, which is described
hereinafter.
[0105] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein q is
1, 2 or 3.
[0106] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein Z is
selected from the group consisting of hydroxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4a- lkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6a- lkyl,
--O--C.sub.1-8alkyl-O--C(O)C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.su- b.2, --O--C
C.sub.8alkyl-NH--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-
-8alkyl).sub.2, --C.sub.1-8alkylamide
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.- 1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
[0107] Aspects of the present invention include a composition
comprising compound of Formula (I) 13
[0108] wherein the compound is selected from the group consisting
of:
1 Stereo Cpd W R.sub.1 R.sub.2 q chem Z 1 --CH.sub.2--Ph(3-R.sub.1)
--NH-1,4,5,6- H 0 OH tetrahydro-pyrimidin- 2-yl 2
--(CH.sub.2).sub.2--Ph(3-R.- sub.1) --NH-1,4,5,6- H 0 OH
tetrahydro-pyrimidin- 2-yl 3 --CH.sub.2--Ph(3-R.sub.1)
--NH-1,4,5,6- quinolin-3-yl 0 OH tetrahydro-5-OH- pyrimidin-2-yl 4
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- quinolin-3-yl 0 OH
[1,8]naphthyridin-2- yl 5 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro- 0 OH [1,8]naphthyridin-2-
quinolin-3-yl yl 5-1 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro- 0 Isomer 1 OH
[1,8]naphthyridin-2- quinolin-3-yl yl 5-2
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro-
0 Isomer 2 OH [1,8]naphthyridin-2- quinolin-3-yl yl 5-3
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro-
0 Isomer 3 OH [1,8]naphthyridin-2- quinolin-3-yl yl 5-4
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro-
0 Isomer 4 OH [1,8]naphthyridin-2- quinolin-3-yl yl 6 Ph(3-R.sub.1)
--NH-1,4,5,6- pyridin-3-yl 2 OH tetrahydro-pyrimidin- 2-yl 7
Ph(3-R.sub.1) --NH-1,4,5,6- pyridin-3-yl 2 OH tetrahydro-5-OH-
pyrimidin-2-yl 8 --(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro-
pyridin-3-yl 2 OH [1,8]naphthyridin-2- yl 9
--(CH.sub.2).sub.3--R.sub.1 --NH-pyridin-2-yl pyridin-3-yl 2 OH 10
Ph(3-R.sub.1) --NH-1,4,5,6- (6-OCH.sub.3)-pyridin- 2 OH
tetrahydro-5-OH- 3-yl pyrimidin-2-yl 11 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 1,3-benzodioxol-5- 1 OH [1,8]naphthyridin-2- yl
yl 12 Ph(3-R.sub.1) --NH-1,4,5,6- quinolin-3-yl 2 OH
tetrahydro-pyrimidin- 2-yl 13 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- phenyl 1 OH [1,8]naphthyridin-2- yl 14
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- 1,3-benzodioxol-5-
0 OH [1,8]naphthyridin-2- yl yl 15 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- 1,3-benzodioxol-5- 0 OH [1,8]naphthyridin-2- yl
yl 16 --CH.sub.2--R.sub.1 5,6,7,8-tetrahydro- 1,3-benzodioxol-5- 0
OH [1,8]naphthyridin-2- yl yl 17 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 0 OH
[1,8]naphthyridin-2- 3-yl yl 18 --(CH.sub.2).sub.2--R.sub- .1
5,6,7,8-tetrahydro- 1,4,5,6-tetrahydro- 1 OH [1,8]naphthyridin-2-
2-Me-pyrimidin-5- yl yl 19 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro- 1 OH [1,8]naphthyridin-2-
quinolin-3-yl yl 19-1 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro- 1 Isomer 1 OH
[1,8]naphthyridin-2- quinolin-3-yl yl 19-2
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro-
1 Isomer 2 OH [1,8]naphthyridin-2- quinolin-3-yl yl 19-3
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro-
1 Isomer 3 OH [1,8]naphthyridin-2- quinolin-3-yl yl 19-4
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- 1,2,3,4-tetrahydro-
1 Isomer 4 OH [1,8]naphthyridin-2- quinolin-3-yl yl 20
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- 1,3-benzodioxol-5-
2 OH [1,8]naphthyridin-2- yl yl 21 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 2 OH
[1,8]naphthyridin-2- 3-yl yl 21a --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 2 Isomer a OH
[1,8]naphthyridin-2- 3-yl yl 21b --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 2 Isomer b OH
[1,8]naphthyridin-2- 3-yl yl 22 --(CH.sub.2).sub.3--R.sub.1
--NH-pyridin-2-yl quinolin-3-yl 2 OH 23 --(CH.sub.2).sub.3--R.sub.1
--NH-pyridin-2-yl 1,3-benzodioxol-5- 2 OH yl 24
--(CH.sub.2).sub.3--R.sub.1 --NH-pyridin-2-yl 1,3-benzodioxol-5- 0
OH yl 25 --(CH.sub.2).sub.3--R.sub- .1 --NH-pyridin-2-yl
(6-OCH.sub.3)-pyridin- 2 OH 3-yl 26 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- 1,3-benzodioxol-5- 1 OH [1,8]naphthyridin-2- yl
yl 27 Ph(3-R.sub.1) --NH-1,4,5,6- 1,3-benzodioxol-5- 1 OH
tetrahydro-5-OH- yl pyrimidin-2-yl 28 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 1 OH
[1,8]naphthyridin-2- 3-yl yl 28a --(CH.sub.2).sub.2--R.su- b.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 1 Isomer a OH
[1,8]naphthyridin-2- 3-yl yl 28b --(CH.sub.2).sub.2--R.su- b.1
5,6,7,8-tetrahydro- (6-OCH.sub.3)-pyridin- 1 Isomer b OH
[1,8]naphthyridin-2- 3-yl yl 29 --(CH.sub.2).sub.3--R.sub- .1
5,6,7,8-tetrahydro- quinolin-3-yl 1 OH [1,8]naphthyridin-2-yl 30
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-F)phenyl 1 OH
[1,8]naphthyridin-2- yl 30a --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (3-F)phenyl 1 Isomer a OH [1,8]naphthyridin-2-
yl 30b --(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-F)phenyl
1 Isomer b OH [1,8]naphthyridin-2- yl 31
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- (3-F)phenyl 1 OH
[1,8]naphthyridin-2- yl 32 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- quinolin-3-yl 1 OH [1,8]naphthyridin-2- yl 33
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (4-F)phenyl 1 OH
[1,8]naphthyridin-2- yl 34 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- (4-F)phenyl 1 OH [1,8]naphthyridin-2- yl 35
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (2-CH3)pyrimidin- 1
OH [1,8]naphthyridin-2- 5-yl yl 36 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 2,3-dihydro- 1 OH [1,8]naphthyridin-2-
benzofuran-6-yl yl 36a --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 2,3-dihydro- 1 Isomer a OH [1,8]naphthyridin-2-
benzofuran-6-yl yl 36b --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 2,3-dihydro- 1 Isomer b OH [1,8]naphthyridin-2-
benzofuran-6-yl yl 37 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (3,5-difluoro)- 1 OH [1,8]naphthyridin-2-
phenyl yl 38 --(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro-
(3,5-difluoro)- 1 OH [1,8]naphthyridin-2- phenyl yl 39
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-CF.sub.3)-phenyl
1 OH [1,8]naphthyridin-2- yl 40 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (4-OCF.sub.3)-phenyl 1 OH [1,8]naphthyridin-2-
yl 41 --(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro-
(3-F-4-Ph)-phenyl 1 OH [1,8]naphthyridin-2- yl 42
--(CH.sub.2).sub.2--R.s- ub.1 5,6,7,8-tetrahydro-
(3-F-4-OCH.sub.3)- 1 OH [1,8]naphthyridin-2- phenyl yl 43
--(CH.sub.2).sub.2--R.s- ub.1 5,6,7,8-tetrahydro- (4-Oph)-phenyl 1
OH [1,8]naphthyridin-2- yl 44 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- isoquinolin-4-yl 1 OH [1,8]naphthyridin-2- yl
45 --(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- pyridin-3-yl 1
OH [1,8]naphthyridin-2- yl 46 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- dihydrobenzofuran-5- 1 OH [1,8]naphthyridin-2-
yl yl 47 --(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro-
(2,4-OCH.sub.3)- 1 OH [1,8]naphthyridin-2- pyrimidin-5-yl yl 48
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (2-OCH.sub.3)- 1 OH
[1,8]naphthyridin-2- pyrimidin-5-yl yl 49 Ph(3-R.sub.1)
--NH-1,4,5,6- quinolin-3-yl 2 OH tetrahydro-5-OH- pyrimidin-2-yl 50
Ph(3-R.sub.1) --NH-1,4,5,6- quinolin-3-yl 2 OH
tetrahydro-pyridin-2- yl 51 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- quinolin-3-yl 2 OH [1,8]naphthyridin-2- yl 52
Ph(3-R.sub.1) --NH-3,4,5,6- 1,3-benzodioxol-5- 2 OH
tetrahydro-pyrimidin- yl 2-yl 53 Ph(3-R.sub.1) --NH-3,4,5,6-
1,3-benzodioxol-5- 2 OH tetrahydro-pyridin-2- yl yl 54
Ph(3-R.sub.1) NH-1,4,5,6- 1,3-benzodioxol-5- 2 OH tetrahydro-5-OH-
yl pyrimidin-2-yl 55 --CH.sub.2--R.sub.1 5,6,7,8-tetrahydro-
1,3-benzodioxol-5- 2 OH [1,8]naphthyridin-2- yl yl 56
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- naphthalene-2-yl 1
OH [1,8]naphthyridin-2- yl 56a --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- naphthalen-2-yl 1 Isomer a OH
[1,8]naphthyridin-2- yl 56b --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- naphthalen-2-yl 1 Isomer b OH
[1,8]naphthyridin-2- yl 57 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 5,6,7,8-tetrahydro- 1 racemic OH
[1,8]naphthyridin-2- quinolin-3-yl yl 58a
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- 5,6,7,8-tetrahydro-
0 Isomer a OH [1,8]naphthyridin-2- quinolin-3-yl yl 58b
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8-tetrahydro- 5,6,7,8-tetrahydro-
0 Isomer b OH [1,8]naphthyridin-2- quinolin-3-yl yl 59
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-OCH.sub.3)phenyl
1 racemic OH [1,8]naphthyridin-2- yl 60 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (4-OCH.sub.3)phenyl 1 racemic OH
[1,8]naphthyridin-2- yl 61 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- H 1 OH [1,8]naphthyridin-2- yl 62
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- tetrahydrofuran-3-
1 racemic OH [1,8]naphthyridin-2- yl yl 63
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- thiophen-2-yl 1
racemic OH [1,8]naphthyridin-2- yl 64 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (3-F)phenyl 1 racemic NH.sub.2
[1,8]naphthyridin-2- yl 65 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- 2,3-dihydro- 1 racemic OH [1,8]naphthyridin-2-
benzo[1,4]-dioxin- yl 6-yl 66 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (3-SCH.sub.3)phenyl 1 racemic OH
[1,8]naphthyridin-2- yl 67 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- N-methyl-1,2,3,4- 1 racemic OH
[1,8]naphthyridin-2- tetrahydro- yl quinolin-3-yl 68
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- H 1 --O-ethyl
[1,8]naphthyridin-2- yl 69 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- H 1 --O-2- [1,8]naphthyridin-2- propyl yl 70
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- H 1 --O-t-
[1,8]naphthyridin-2- butyl yl 71 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- H 1 --O-n- [1,8]naphthyridin-2- octyl yl 72
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- H 1 --O-s-
[1,8]naphthyridin-2- butyl yl 73 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- H 1 --O--methyl [1,8]naphthyridin-2- yl 74
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- H 1 racemic
--O--CH.sub.2-- [1,8]naphthyridin-2- OC(O)-t- yl butyl 75
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro-
(3-(NMe.sub.2)phenyl 1 racemic OH [1,8]naphthyridin-2- yl 76
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-OMe-4- 1 racemic
OH [1,8]naphthyridin-2- OH)phenyl yl 76a
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-OMe-4- 1 Isomer
a OH [1,8]naphthyridin-2- OH)phenyl yl 77 Ph(3-R.sub.1)
--NH-4,5-dihydro-1H- (3-F)phenyl 1 racemic OH imidazol-2-yl 78
--(CH.sub.2).sub.2--R.sub.1 5,6,7,8-tetrahydro- (3-NHEt)phenyl 1
racemic OH [1,8]naphthyridin-2- yl 79 --(CH.sub.2).sub.2--R.sub.1
5,6,7,8-tetrahydro- (3-NHMe)phenyl 1 racemic OH
[1,8]naphthyridin-2- yl 80 --(CH.sub.2).sub.3--R.sub.1
5,6,7,8-tetrahydro- dihydrobenzofuran- 0 OH [1,8]naphthyridin-2-
6-yl yl
[0109] Aspects of the present invention include a composition
comprising a compound of Formula (II) 14
[0110] wherein W, R.sub.1, R.sub.2, q and Z are as previously
defined and preferably are
2 Stereo Cpd W R.sub.1 R.sub.2 q chem Z 81
--(CH.sub.2).sub.3--R.sub.1 5,6,7,8- (3-F)phenyl 1 racemic OH
tetra- hydro-[1, 8]naphthy- ridin-2-yl
[0111] Aspects of the present invention include a composition
comprising a compound of Formula (I) wherein the compound is
selected from the group consisting of
[0112] a compound of Formula (I) wherein W is
--CH.sub.2-Ph(3-R.sub.1); R.sub.1 is
--NH-1,4,5,6-tetrahydro-pyrimidin-2-yl; R.sub.2 is H, q is 0 and Z
is OH;
[0113] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2-Ph(3-R.su- b.1); R.sub.1 is
--NH-1,4,5,6-tetrahydro-pyrimidin-2-yl; R.sub.2 is H, q is 0 and Z
is OH;
[0114] a compound of Formula (I) wherein W is
--CH.sub.2-Ph(3-R.sub.1); R.sub.1 is
--NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl; R.sub.2 is
-3-quinolinyl, q is 0 and Z is OH;
[0115] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 0 and Z is OH;
[0116] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,2,3,4-tetrahydro-3-quinolinyl, q is 0 and Z is OH
[0117] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-pyrimidin-2-yl; R.sub.2 is
-3-pyridinyl, q is 2 and Z is OH;
[0118] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl; R.sub.2 is
-3-pyridinyl, q is 2 and Z is OH;
[0119] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -3-pyridinyl,
q is 2 and Z is OH;
[0120] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is --NH-pyridin-2-yl; R.sub.2
is -3-pyridinyl, q is 2, and Z is OH;
[0121] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl; R.sub.2 is
-(6-MeO)pyridin-3-yl, q is 2 and Z is OH;
[0122] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 1 and Z is OH;
[0123] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-pyrimidin-2-yl; R.sub.2 is
-3-quinolinyl, q is 2 and Z is OH;
[0124] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -Ph, q is 1
and Z is OH;
[0125] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 0 and Z is OH;
[0126] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 0 and Z is OH;
[0127] a compound of Formula (I) wherein W is --CH.sub.2--R.sub.1;
R.sub.1 is -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 0 and Z is OH;
[0128] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(6-MeO)pyridin-3-yl, q is 0 and Z is OH;
[0129] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,4,5,6-tetrahydro-2-Me-pyrimidin-5-yl, q is 1 and Z is OH;
[0130] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,2,3,4-tetrahydro-3-quinolinyl, q is 1 and Z is OH;
[0131] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 2 and Z is OH;
[0132] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(6-MeO)pyridin-3-yl, q is 2 and Z is OH;
[0133] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is --NH-pyridin-2-yl; R.sub.2
is -quinolinyl, q is 2 and Z is OH; a compound of Formula (I)
wherein W is --(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
--NH-pyridin-2-yl; R.sub.2 is -1,3-benzodioxol-5-yl, q is 2 and Z
is OH;
[0134] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is --NH-pyridin-2-yl; R.sub.2
is -1,3-benzodioxol-5-yl, q is 0 and Z is OH;
[0135] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is --NH-pyridin-2-yl; R.sub.2
is -(6-MeO)pyridin-3-yl, q is 2 and Z is OH;
[0136] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 1 and Z is OH;
[0137] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-5-OH-2-pyrimidinyl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 1 and Z is OH;
[0138] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(6-MeO)pyridin-3-yl, q is 1 and Z is OH;
[0139] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 1 and Z is OH;
[0140] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -(3-F)Ph, q
is 1 and Z is OH;
[0141] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -(3-F)Ph, q
is 1 and Z is OH;
[0142] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 1 and Z is OH;
[0143] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -(4-F)Ph, q
is 1 and Z is OH;
[0144] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -7(4-F)Ph, q
is 1 and Z is OH;
[0145] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(2-Me)pyrimidin-5-yl, q is 1 and Z is OH;
[0146] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2,3-dihydro-benzofuran-6-yl, q is 1 and Z is OH;
[0147] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(3,5-F.sub.2)Ph, q is 1 and Z is OH;
[0148] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(3,5-F.sub.2)Ph, q is 1 and Z is OH;
[0149] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(3-CF.sub.3)Ph, q is 1 and Z is OH;
[0150] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(4-OCF.sub.3)Ph, q is 1 and Z is OH;
[0151] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(3-F-4-Ph)Ph, q is 1 and Z is OH;
[0152] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(3-F-4-OMe)Ph, q is 1, and Z is OH;
[0153] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -(4-OPh)Ph, q
is 1 and Z is OH;
[0154] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-4-isoquinolinyl, q is 1, and Z is OH;
[0155] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -3-pyridinyl,
q is 1 and Z is OH;
[0156] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-5-dihydrobenzofuranyl, q is 1 and Z is OH;
[0157] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2,4-(OMe).sub.2-pyrimid-5-yl, q is 1 and Z is OH;
[0158] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(2-OMe)pyrimidin-5-yl, q is 1 and Z is OH;
[0159] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl; R.sub.2 is
-3-quinolinyl, q is 2 and Z is OH;
[0160] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-3,4,5,6-tetrahydro-pyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 2 and Z is OH;
[0161] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 2 and Z is OH;
[0162] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-3,4,5,6-tetrahydro-pyrimidin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 2 and Z is OH;
[0163] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-3,4,5,6-tetrahydro-pyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 2 and Z is OH;
[0164] a compound of Formula (I) wherein W is -Ph(3-R.sub.1);
R.sub.1 is --NH-1,4,5,6-tetrahydro-5-OH-pyrimidin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 2 and Z is OH;
[0165] a compound of Formula (I) wherein W is --CH.sub.2--R.sub.1;
R.sub.1 is -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 2 and Z is OH; and, a compound of
Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2-naphthalenyl, q is 1 and Z is OH.
[0166] Another aspect of the present invention includes a
composition comprising a compound of Formula (I) wherein the
compound is selected from the group consisting of:
[0167] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,2,3,4-tetrahydro-3-quinolinyl, q is 0 and Z is OH;
[0168] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 0 and Z is OH;
[0169] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,2,3,4-tetrahydro-3-quinolinyl, q is 1 and Z is OH;
[0170] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(6-MeO)pyridin-3-yl, q is 1 and Z is OH;
[0171] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -(3-F)Ph, q
is 1 and Z is OH;
[0172] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 1 and Z is OH;
[0173] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(2-Me)pyrimidin-5-yl, q is 1 and Z is OH;
[0174] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2,3-dihydro-benzofuran-6-yl, q is 1 and Z is OH;
[0175] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-4-isoquinolinyl, q is 1, and Z is OH;
[0176] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -3-pyridinyl,
q is 1 and Z is OH;
[0177] a compound of Formula (I) wherein W is
--(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2,4-(OMe).sub.2-pyrimid-5-yl, q is 1 and Z is OH; and, a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(2-OMe)pyrimidin-5-yl, q is 1 and Z is OH.
[0178] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,2,3,4-tetrahydro-3-quinolinyl, q is 0 and Z is OH.
[0179] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.3--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,3-benzodioxol-5-yl, q is 0 and Z is OH.
[0180] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-1,2,3,4-tetrahydro-3-quinolinyl, q is 1 and Z is OH.
[0181] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(6-MeO)pyridin-3-yl, q is 1 and Z is OH.
[0182] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -(3-F)Ph, q
is 1 and Z is OH.
[0183] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-3-quinolinyl, q is 1 and Z is OH.
[0184] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(2-Me)pyrimidin-5-yl, q is 1 and Z is OH.
[0185] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2,3-dihydro-benzofuran-6-yl, q is 1 and Z is OH.
[0186] Another aspect of the present invention includes a compound
of Formula (I wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-4-isoquinolinyl, q is 1 and Z is OH.
[0187] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is -3-pyridinyl,
q is 1 and Z is OH.
[0188] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-2,4-(OMe).sub.2-pyrimid-5-yl, q is 1 and Z is OH.
[0189] Another aspect of the present invention includes a compound
of Formula (I) wherein W is --(CH.sub.2).sub.2--R.sub.1; R.sub.1 is
-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl; R.sub.2 is
-(2-OMe)pyrimidin-5-yl, q is 1 and Z is OH.
[0190] Aspects of the present invention include a compound of
Formula (I): 15
[0191] wherein W, R.sub.1, R.sub.2, R.sub.6, R.sub.8, R.sub.9, q
and Z are as previously defined; and, preferably, wherein
[0192] W is --C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R- .sub.8);
[0193] R.sub.1 is --NH(R.sub.6);
[0194] R.sub.2 is hydrogen, -tetrahydropyrimidinyl(R.sub.8),
-1,3-benzodioxolyl(R.sub.8), -dihydrobenzofuranyl(R.sub.8),
-tetrahydroquinolinyl(R.sub.8), -phenyl(R.sub.8),
-naphthalenyl(R.sub.8), -pyridinyl(R.sub.8), -pyrimidinyl(R.sub.8)
or -quinolinyl(R.sub.8);
[0195] R.sub.6 is -dihydroimidazolyl(R.sub.8),
-tetrahydropyridinyl(R.sub.- 8), -tetrahydropyrimidinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0196] R.sub.8 is one to four substituents independently selected
from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.8 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-aryl(R.sub.10) or hydroxy when
attached to a carbon atom;
[0197] R.sub.9 is hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, (halo).sub.13 or
hydroxy; and,
[0198] q is 1, 2 or 3;
[0199] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, ---N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl;
[0200] and pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0201] Aspects of the present invention include a compound of
Formula (I) wherein the compound is a compound of Formula (I.2):
16
[0202] wherein W, R.sub.1, R.sub.6, R.sub.8, R.sub.9, q and Z are
as previously defined; and, preferably, wherein
[0203] W is --C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R- .sub.8);
[0204] R.sub.1 is --NH(R.sub.6),
-dihydro-1H-pyrrolo[2,3-b]pyridinyl(R.sub- .8),
-tetrahydropyrimidinyl(R.sub.8),
-tetrahydro-1,8-naphthyridinyl(R.sub- .8),
-tetrahydro-1H-azepino[2,3-b]pyridinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0205] R.sub.6 is -dihydroimidazolyl(R.sub.8),
-tetrahydropyridinyl(R.sub.- 8), -tetrahydropyrimidinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0206] R.sub.8 is one to four substituents independently selected
from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.9 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-aryl(R.sub.10) or hydroxy when
attached to a carbon atom;
[0207] R.sub.9 is hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, (halo).sub.13 or
hydroxy; and,
[0208] q is 1, 2 or 3;
[0209] Z is selected from the group consisting hydroxy, --NH.sub.2,
--NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl;
[0210] and pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0211] Another aspect of the present invention includes compounds
of Formula (I.2) wherein R.sub.1 is --NH(R.sub.6),
-tetrahydropyrimidinyl(R.- sub.8) or
-tetrahydro-1,8-naphthyridinyl(R.sub.8); and, all other variables
are as previously defined.
[0212] Aspects of the present invention include a compound of
Formula (I) wherein the compound is a compound of Formula (I1.3):
17
[0213] wherein W, R.sub.1, R.sub.2, R.sub.6, R.sub.8, R.sub.9 and Z
are as previously defined; and, preferably, wherein
[0214] W is --C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R- .sub.8);
[0215] R.sub.1 is --NH(R.sub.6),
-dihydro-1H-pyrrolo[2,3-b]pyridinyl(R.sub- .8),
-tetrahydropyrimidinyl(R.sub.8),
-tetrahydro-1,8-naphthyridinyl(R.sub- .8),
-tetrahydro-1H-azepino[2,3-b]pyridinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0216] R.sub.2 is hydrogen, -tetrahydropyrimidinyl(R.sub.8),
-1,3-benzodioxolyl(R.sub.8), -dihydrobenzofuranyl(R.sub.8),
-tetrahydroquinolinyl(R.sub.8), -phenyl(R.sub.8),
-naphthalenyl(R.sub.8), -pyridinyl(R.sub.8), -pyrimidinyl(R.sub.8)
or -quinolinyl(R.sub.8);
[0217] R.sub.6 is -dihydroimidazolyl(R.sub.8),
-tetrahydropyridinyl(R.sub.- 8), -tetrahydropyrimidinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0218] R.sub.8 is one to four substituents independently selected
from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.8 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-aryl(R.sub.10) or hydroxy when
attached to a carbon atom; and,
[0219] R.sub.9 is hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, (halo).sub.13 or
hydroxy;
[0220] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl;
[0221] and pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0222] Another aspect of the present invention includes compounds
of Formula (I.3) wherein R.sub.1 is --NH(R.sub.6),
-tetrahydropyrimidinyl(R.- sub.8) or
-tetrahydro-1,8-naphthyridinyl(R.sub.8); and, all other variables
are as previously defined.
[0223] Aspects of the present invention include a compound of
Formula (I) wherein the compound is a compound of Formula (I.4):
18
[0224] wherein R.sub.2 and Z are as previously defined; and,
further, R.sub.2 is selected from the group consisting of
-2-benzofuranyl, -3-benzofuranyl, -4-benzofuranyl, -5-benzofuranyl,
-6-benzofuranyl, -7-benzofuranyl, -benzo[b]thien-2-yl,
-benzo[b]thien-3-yl, -benzo[b]thien-4-yl, -benzo[b]thien-5-yl,
-benzo[b]thien-6-yl, -benzo[b]thien-7-yl, -1H-indol-2-yl,
-1H-indol-3-yl, -1H-indol-4-yl, -1H-indol-5-yl, -1H-indol-6-yl,
-1H-indol-7-yl, -2-benzoxazolyl, -4-benzoxazolyl, -5-benzoxazolyl,
-6-benzoxazolyl, -7-benzoxazolyl, -2-benzothiazolyl,
-3-benzothiazolyl, -4-benzothiazolyl, -5-benzothiazolyl,
-6-benzothiazolyl, -7-benzothiazolyl, -1H-benzimidazolyl-2-yl,
-1H-benzimidazolyl-4-yl, -1H-benzimidazolyl-5-yl- ,
-1H-benzimidazolyl-6-yl, -1H-benzimidazolyl-7-yl, -2-quinolinyl,
-3-quinolinyl, -4-quinolinyl, -5-quinolinyl, -6-quinolinyl,
-7-quinolinyl, -8-quinolinyl, -2H-1-benzopyran-2-yl,
-2H-1-benzopyran-3-yl, -2H-1-benzopyran-4-yl,
-2H-1-benzopyran-5-yl, -2H-1-benzopyran-6-yl,
-2H-1-benzopyran-7-yl, -2H-1-benzopyran-8-yl,
-4H-1-benzopyran-2-yl, -4H-1-benzopyran-3-yl,
-4H-1-benzopyran-4-yl, -4H-1-benzopyran-5-yl,
-4H-1-benzopyran-6-yl, -4H-1-benzopyran-7-yl,
-4H-1-benzopyran-8-yl, -1H-2-benzopyran-1-yl,
-1H-2-benzopyran-3-yl,-1H-2- -benzopyran-3-yl,
-1H-2-benzopyran-5-yl, -1H-2-benzopyran-6-yl,
-1H-2-benzopyran-7-yl, -1H-2-benzopyran-8-yl,
-1,2,3,4-tetrahydro-1-napht- halenyl,
-1,2,3,4-tetrahydro-2-naphthalenyl, -1,2,3,4-tetrahydro-5-naphtha-
lenyl, -1,2,3,4-tetrahydro-6-naphthalenyl,
-2,3-dihydro-2-benzofuranyl, -2,3-dihydro-3-benzofuranyl,
-2,3-dihydro-4-benzofuranyl, -2,3-dihydro-5-benzofuranyl,
-2,3-dihydro-6-benzofuranyl, -2,3-dihydro-7-benzofuranyl,
-2,3-dihydrobenzo[b]thien-2-yl, -2,3-dihydrobenzo[b]thien-3-yl,
-2,3-dihydrobenzo[b]thien-4-yl, -2,3-dihydrobenzo[b]thien-5-yl,
-2,3-dihydrobenzo[b]thien-6-yl, -2,3-dihydrobenzo[b]thien-7-yl,
-2,3-dihydro-1H-indol-2-yl, -2,3-dihydro-1H-indol-3-yl,
-2,3-dihydro-1H-indol-4-yl, -2,3-dihydro-1H-indol-5-yl,
-2,3-dihydro-1H-indol-6-yl, -2,3-dihydro-1H-indol-7-yl,
-2,3-dihydro-2-benzoxazolyl, -2,3-dihydro-4-benzoxazolyl,
-2,3-dihydro-5-benzoxazolyl, -2,3-dihydro-6-benzoxazolyl,
-2,3-dihydro-7-benzoxazolyl, -2,3-dihydro-1H-benzimidazol-2-yl,
-2,3-dihydro-1H-benzimidazol-4-yl,
-2,3-dihydro-1H-benzimidazol-5-yl,
-2,3-dihydro-1H-benzimidazol-6-yl,
-2,3-dihydro-1H-benzimidazol-7-yl, -3,4-dihydro-1 (2H)-quinolinyl,
-1,2,3,4-tetrahydro-2-quinolinyl, -1,2,3,4-tetrahydro-3-quinolinyl,
-1,2,3,4-tetrahydro-4-quinolinyl, -1,2,3,4-tetrahydro-5-quinolinyl,
-1,2,3,4-tetrahydro-6-quinolinyl, -1,2,3,4-tetrahydro-7-quinolinyl,
-1,2,3,4-tetrahydro-8-quinolinyl,
-3,4-dihydro-2H-1-benzopyran-2-yl,
-3,4-dihydro-2H-1-benzopyran-3-yl,
-3,4-dihydro-2H-1-benzopyran-4-yl,
-3,4-dihydro-2H-1-benzopyran-5-yl,
-3,4-dihydro-2H-1-benzopyran-6-yl,
-3,4-dihydro-2H-1-benzopyran-7-yl,
-3,4-dihydro-2H-1-benzopyran-8-yl,
-3,4-dihydro-4H-1-benzopyran-2-yl,
-3,4-dihydro-4H-1-benzopyran-3-yl,
-3,4-dihydro-4H-1-benzopyran-4-yl,
-3,4-dihydro-4H-1-benzopyran-5-yl,
-3,4-dihydro-4H-1-benzopyran-6-yl,
-3,4-dihydro-4H-1-benzopyran-7-yl,
-3,4-dihydro-4H-1-benzopyran-8-yl,
-3,4-dihydro-1H-2-benzopyran-2-yl,
-3,4-dihydro-1H-2-benzopyran-3-yl,
-3,4-dihydro-1H-2-benzopyran-4-yl,
-3,4-dihydro-1H-2-benzopyran-5-yl,
-3,4-dihydro-1H-2-benzopyran-6-yl,
-3,4-dihydro-1H-2-benzopyran-7-yl and
-3,4-dihydro-1H-2-benzopyran-8-yl optionally substituted when
allowed by available valences with up to 7 substituents
independently selected from methyl when attached to a nitrogen
atom; and, independently selected from methyl, methoxy or fluoro
when attached to a carbon atom;
[0225] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-8alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-8alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide,
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl;
[0226] pharmaceutically acceptable salts, racemic mixtures and
enantiomers thereof.
[0227] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts" (Ref: International
J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1977 (Jan), 66, 1,
1). Other salts may, however, be useful in the preparation of
compounds according to this invention or of their pharmaceutically
acceptable salts. Representative organic or inorganic acids
include, but are not limited to, hydrochloric, hydrobromic,
hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic,
propionic, glycolic, lactic, succinic, maleic, fumaric, malic,
tartaric, citric, benzoic, mandelic, methanesulfonic,
hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,
2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,
salicylic, saccharinic or trifluoroacetic acid. Representative
organic or inorganic bases include, but are not limited to, basic
or cationic salts such as benzathine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, procaine, aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc.
[0228] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the subject. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0229] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. Where the processes for the
preparation of the compounds according to the invention give rise
to mixtures of stereoisomers, these isomers may be separated by
conventional techniques such as preparative chromatography. The
compounds may be prepared in racemic form or as individual
enantiomers or diasteromers by either stereospecific synthesis or
by resolution. The compounds may be resolved into their component
enantiomers or diasteromers by standard techniques. It is to be
understood that all stereoisomers, racemic mixtures, diastereomers
and enantiomers thereof are encompassed within the scope of the
present invention.
[0230] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known in the
art.
[0231] Furthermore, some of the crystalline forms for the compounds
may exist as polymorphs and as such are intended to be included in
the present invention. In addition, some of the compounds may form
solvates with water (i.e., hydrates) or common organic solvents and
such solvates are also intended to be encompassed within the scope
of this invention.
[0232] As used herein, the following underlined terms are intended
to have the following meanings:
[0233] The term "C.sub.a-b" (where a and b are integers referring
to a designated number of carbon atoms) refers to an alkyl,
alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl
portion of a radical in which alkyl appears as the prefix root
containing from a to b carbon atoms inclusive. For example,
C.sub.1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
[0234] The term "alkyl" refers to an optionally substituted
saturated or partially unsaturated, branched, straight-chain or
cyclic monovalent hydrocarbon radicals derived by the removal of
one hydrogen atom from a single carbon atom of an alkane molecule,
thus forming the point of attachment. The term "alkenyl" refers to
an optionally substituted partially unsaturated branched or
straight-chain monovalent hydrocarbon radical having at least one
carbon-carbon double bond and derived by the removal of one
hydrogen atom from a single carbon atom of an alkene molecule, thus
forming the point of attachment. The radical may be in either the
cis or trans conformation about the double bond(s). The term
"alkynyl" refers to an optionally substituted partially unsaturated
branched or straight-chain monovalent hydrocarbon radical having at
least one carbon-carbon triple bond and derived by the removal of
one hydrogen atom from a single carbon atom of an alkyne molecule,
thus forming the point of attachment. The term "alkoxy" refers to
an optionally substituted saturated or partially unsaturated,
branched, straight-chain monovalent hydrocarbon radical derived by
the removal of the hydrogen atom from the single oxygen atom of an
alkane, alkene or alkyne molecule, thus forming the point of
attachment. An alkyl alkenyl, alkynyl or alkoxy radical is
optionally substituted within the radical or on a terminal carbon
atom (for a chain) with that amount of substituents allowed by
available saturated valences.
[0235] The term "--C.sub.1-8alkyl(R.sub.x)" (where x is an integer
referring to a designated substitutent group) refers to an R.sub.x
substituent group which may be substituted within an alykl chain,
on a terminal carbon atom and may be similarly substituted on an
alkenyl, alkynyl or alkoxy radical with a designated amount of
substituents where allowed by available chemical bond valences. The
term "--C.sub.0-8alkyl(R.sub.x)" refers to an R.sub.x substituent
group which may also be directly substituted on a point of
attachment without an alkyl linking group (wherein C.sub.0 is a
placeholder for the R.sub.x substituent with a direct bond to the
point of attachment).
[0236] The term "cycloalkyl" refers to saturated or partially
unsaturated cyclic monovalent hydrocarbon radical consistent with
the definitions of alkyl, alkanyl, alkenyl and alkynyl.
Specifically included within the definition of cycloalkyl are fused
polycyclic ring systems in which one or more rings are aromatic and
one or more rings are saturated or partially unsaturated (it being
understood that the radical may also occur on the aromatic ring).
For example, the cycloalkyl groups are saturated or partially
unsaturated or monocyclic alkyl radicals of from 3-8 carbon atoms
(derived from a molecule such as cyclopropane, cyclobutane,
cyclopentane, cyclohexane or cycloheptane); saturated or partially
unsaturated fused or benzofused cyclic alkyl radicals of from 9 to
12 carbon atoms; or, saturated or partially unsaturated fused or
benzofused tricyclic or polycyclic alkyl radicals of from 13 to 20
carbon atoms.
[0237] The term "heterocyclyl" refers to a saturated or partially
unsaturated cyclic alkyl radical in which one or more carbon atoms
are independently replaced with the same or different heteroatom.
Specifically included within the definition of heterocyclyl are
fused polycyclic ring systems in which one or more rings are
aromatic and one or more rings are saturated or partially
unsaturated (it being understood that the radical may also occur on
the aromatic ring). Typical heteroatoms to replace the carbon
atom(s) include, but are not limited to, N, O, S and the like. For
example, the heterocyclyl group is a saturated or partially
unsaturated five membered monocyclic alkyl ring of which at least
one member is replaced by a N, O or S atom and which optionally
contains one additional O atom replacing an additional member of
the alkyl ring or one additional N atom replacing a member of the
alkyl ring; a saturated or partially unsaturated six membered
monocyclic alkyl ring of which one, two or three members of the
alkyl ring are replaced by a N atom and optionally one member of
the alkyl ring is replaced by a O or S atom or two members of the
alkyl ring are replaced by O or S atoms; a saturated or partially
unsaturated 5-6 membered heterocylic ring as previously defined
fused to a heteroaryl as hereinafter defined; a saturated,
partially unsaturated or benzofused nine or 10 membered bicyclic
alkyl wherein at least one member of the ring is replaced by N, O,
or S atom and which optionally one or two additional members of the
bicyclic alkyl are replaced by N, O or S atoms; or, a saturated,
partially unsaturated or benzofused 11 to 20 membered polycyclic
alkyl of which at least one member is replaced by a N, O or S atom
and which optionally one, two or three additional members of the
polycyclic alkyl are replaced by N atoms. Examples of saturated or
partially unsaturated heterocyclyl radicals include, but are not
limited to, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,
1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, dihydroimdazolyl,
2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,
tetrahydropyrimidinyl, piperazinyl,
dihydro-1H-pyrrolo[2,3-b]pyridinyl, tetrahydro-1,8-naphthyri-
dinyl, tetrahydro-1H-azepino[2,3-b]pyridinyl, 1,3-benzodioxol-5-yl,
1,2,3,4-tetrahydro-3-quinolinyl or dihydrobenzofuranyl.
[0238] The term "aryl" refers to a monovalent aromatic hydrocarbon
radical derived by the removal of one hydrogen atom from a single
carbon atom of an aromatic ring system, thus forming the point of
attachment for the radical. For example, the aryl group is derived
from an unsaturated aromatic monocyclic ring system containing 5 to
6 carbon atoms (such as phenyl, derived from benzene); an
unsaturated aromatic bicyclic ring system containing 9 to 10 carbon
atoms (such as naphthyl, derived from naphthalene); or, an
unsaturated aromatic tricyclic ring system containing 13 to 14
hydrogen carbon atoms (such as anthracenyl, derived from
anthracene). The term "aromatic ring system" refers to an
unsaturated cyclic or polycyclic ring system having an "aromatic"
conjugated n electron system. Specifically excluded from the
definition of aryl are fused ring systems in which one or more
rings are saturated or partially unsaturated. Typical aryl groups
include, but are not limited to, anthracenyl, naphthalenyl,
azulenyl, benzenyl and the like
[0239] The term "heteroaryl" refers to a monovalent heteroaromatic
radical derived by the removal of one hydrogen atom from a single
atom of a heteroaromatic ring system, thus forming the point of
attachment for the radical. The term "heteroaromatic ring system"
refers to an aromatic ring system in which one or more carbon atoms
are each independently replaced with a heteroatom. Typical
heteratoms to replace the carbon atoms include, but are not limited
to, N, O, S, and the like. Specifically excluded from the
definition of heteroaromatic ring system are fused ring systems in
which one or more rings are saturated or partially unsaturated. For
example, the heteroaryl group is derived from a heteroaromatic
monocyclic ring system containing five members of which at least
one member is a N, O or S atom and which optionally contains one,
two or three additional N atoms; a heteroaromatic monocyclic ring
system having six members of which one, two or three members are an
N atom; a heteroaromatic fused bicyclic ring system having nine
members of which at least one member is a N, O or S atom and which
optionally contains one, two or three additional N atoms; a
heteroaromatic fused bicyclic ring system having ten members of
which one, two or three members are a N atom; a heteroaromatic
fused tricyclic ring system containing 13 or 14 members of which at
least one member is a N, O or S atom and which optionally contains
one, two or three additional N atoms; or, a heteroaromatic fused
polycyclic ring system containing 15 to 20 members of which at
least one member is a N, O or S atom and which optionally contains
one, two or three additional N atoms. Typical heteroaryls include,
but are not limited to, cinnolinyl, furanyl, imidazolyl, indazolyl,
indolyl, indolinyl, indolizinyl, isobenzofuranyl, isoquinolinyl,
isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl,
phenanthridinyl, phenanthrolinyl, purinyl, pyranyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxalinyl, tetrazole, thiadiazole,
thiazole, thiophene, triazole and the like.
[0240] The term "independently" means that when a group is
substituted with more than one substituent that the substituents
may be the same or different. The term "dependently" means that the
substituents are specified in an indicated combination of structure
variables.
[0241] Under standard nomenclature rules used throughout this
disclosure, the terminal portion of the designated side chain is
described first followed by the adjacent functionality toward the
point of attachment. Thus, for example, a
"phenylC.sub.1-6alkylamidoC.sub.1-6alkyl" substituent refers to a
group of the formula: 19
[0242] A substituent's point of attachment may also be indicated by
a dashed line to indicate the point(s) of attachment, followed by
the adjacent functionality and ending with the terminal
functionality such as, for
example,_--(C.sub.1-6)alkyl-carbonyl-NH--(C.sub.1-6)alkyl-phenyl.
[0243] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0244] Integrins are a widely expressed family of calcium or
magnesium dependent aX or .beta. heterodimeric cell surface
receptors, which bind to extracellular matrix adhesive proteins
such as fibrinogen, fibronectin, vitronectin and osteopontin. The
integrin receptors are transmembrane glycoproteins (GP's) known for
their large extracellular domains and are classified by at least 8
known .beta. subunits and 14 .alpha. subunits (S. A. Mousa, et al.,
Emerging Theraupeutic Targets, 2000, 4, (2), 143-153).
[0245] For example, the .beta.1 subfamily has the largest number of
integrins wherein the various .alpha. subunits associate with
various .beta. subunits: .beta.3, .beta.5, .beta.6 and .beta.8 (S.
A. Mousa, et al., Emerging Theraupeutic Targets, 2000, 4, (2),
144-147). Some of the disease states that have a strong
.alpha.v.beta.3, .alpha.v.beta.5 and .alpha.IIb.beta.3 (also
referred to as GPIIb/IIIa) integrin component in their etiologies
are unstable angina, thromboembolic disorders or atherosclerosis
(GPIIb/IIIa); thrombosis or restenosis (GPIIb/IIIa or
.alpha.v.beta.3); restenosis (dual .alpha.v.beta.3/GPIIb/IIIa);
rheumatoid arthritis, vascular disorders or osteoporosis
(.alpha.v.beta.3); tumor angiogenesis, tumor metastasis, tumor
growth, multiple sclerosis, neurological disorders, asthma,
vascular injury or diabetic retinopathy (.alpha.v.beta.3 or
.alpha.v.beta.5); and, angiogenesis (dual
.alpha.v.beta.3/.alpha.v.beta.5) (S. A. Mousa, et al., Emerging
Theraupeutic Targets, 2000, 4, (2), 148-149; W. H. Miller, et al.,
Drug Discovery Today 2000, 5 (9), 397-407; and, S. A. Mousa, et
al., Exp. Opin. Ther. Patents, 1999, 9(9), 1237-1248). The .beta.3
subunit has received significant attention in recent drug discovery
efforts. (W. J. Hoekstra, Current Medicinal Chemistry 1998, 5,
195). Antibodies and/or low-molecular weight compound antagonists
of .alpha.v.beta.3 have shown efficacy in animal models (J.
Samanen, Current Pharmaceutical Design 1997, 3, 545) and, thereby,
offer promise as medicinal agents.
[0246] Integrin antagonists have typically been designed after the
bioactive arginine-glycine-aspartate (RGD) conformation of peptides
derived from the primary ligand vitronectin. The RGD motif is the
general cell attachment sequence of many extracellular matrix,
blood and cell surface proteins, as half of the approximately 20
known integrins bind the RGD-containing adhesion ligands. To
discover RGD peptides with integrin selectivity, peptides with both
restricted conformations and alterations of flanking residues have
been studied. In particular, the structural requirements for
interaction of the RGD sequence with GPIIb/IIIa and the inhibitory
potential of a series of nonpeptidic mimetics on platelet
aggregation and interactions with the extracellular matrix have
been described (D. Varon, et al., Thromb. Haemostasis, 1993, 70(6),
1030-1036). Iterative synthesis of cyclic and alicyclic peptides
and computer modelling have provided potent, selective agents as a
platform for nonpeptide .alpha.v (as in .alpha.v.beta.3) integrin
antagonist design.
[0247] Integrin antagonists have been implicated as useful for
inhibiting bone resorption (S. B. Rodan and G. A. Rodan, Integrin
Function In Osteoclasts, Journal of Endocrinology, 1997, 154:
S47-S56). In vertebrates, bone resorption is mediated by the action
of cells known as osteoclasts, large multinucleated cells of up to
about 400 mm in diameter that resorb mineralized tissue, chiefly
calcium carbonate and calcium phosphate. Osteoclasts are actively
motile cells that migrate along the surface of bone and can bind to
bone, secrete necessary acids and proteases, thereby causing the
actual resorption of mineralized tissue from the bone. More
specifically, osteoclasts are believed to exist in at least two
physiological states, namely, the secretory state and the migratory
or motile state. In the secretory state, osteoclasts are flat,
attach to the bone matrix via a tight attachment zone (sealing
zone), become highly polarized, form a ruffled border and secrete
lysosomal enzymes and protons to resorb bone. The adhesion of
osteoclasts to bone surfaces is an important initial step in bone
resorption. In the migratory or motile state, osteoclasts migrate
across bone matrix and do not take part in resorption until they
again attach to bone.
[0248] Integrins are involved in osteoclast attachment, activation
and migration. The most abundant integrin receptor on osteoclasts
(e.g., on rat, chicken, mouse and human osteoclasts) is the
.alpha.v.beta.3 integrin receptor, which is thought to interact in
bone with matrix proteins that contain the RGD sequence. Antibodies
to .alpha.v.beta.3 block bone resorption in vitro, indicating that
this integrin plays a key role in the resorptive process. There is
increasing evidence to suggest that .alpha.v.beta.3 ligands can be
used effectively to inhibit osteoclast mediated bone resorption in
vivo in mammals.
[0249] The current major bone diseases of public concern are
osteoporosis, hypercalcemia of malignancy, osteopenia due to bone
metastases, periodontal disease, hyperparathyroidism, periarticular
erosions in rheumatoid arthritis, Paget's disease,
immobilization-induced osteopenia and glucocorticoid-induced
osteoporosis. All of these conditions are characterized by bone
loss, resulting from an imbalance between bone resorption, i.e.
breakdown and bone formation, which continues throughout life at
the rate of about 14% per year on the average. However, the rate of
bone turnover differs from site to site; for example, it is higher
in the trabecular bone of the vertebrae and the alveolar bone in
the jaws than in the cortices of the long bones. The potential for
bone loss is directly related to turnover and can amount to over 5%
per year in vertebrae immediately following menopause, a condition
that leads to increased fracture risk.
[0250] In the United States, there are currently about 20 million
people with detectable fractures of the vertebrae due to
osteoporosis. In addition, there are about 250,000 hip fractures
per year attributed to osteoporosis. This clinical situation is
associated with a 12% mortality rate within the first two years,
while 30% of the patients require nursing home care after the
fracture. Individuals suffering from all the conditions listed
above would benefit from treatment with agents that inhibit bone
resorption.
[0251] Additionally, .alpha.v.beta.3 ligands have been found to be
useful in treating and/or inhibiting restenosis (i.e. recurrence of
stenosis after corrective surgery on the heart valve),
atherosclerosis, diabetic retinopathy, macular degeneration and
angiogenesis (i.e. formation of new blood vessels) and inhibiting
viral disease.
[0252] Moreover, it has been postulated that the growth of tumors
depends on an adequate blood supply, which in turn is dependent on
the growth of new vessels into the tumor; thus, inhibition of
angiogenesis can cause tumor regression in animal models
(Harrison's Principles of Internal Medicine, 1991, 12.sup.th ed.).
Therefore, .alpha.v.beta.3 antagonists, which inhibit angiogenesis
can be useful in the treatment of cancer by inhibiting tumor growth
(Brooks et al., Cell, 1994, 79, 1157-1164). Evidence has also been
presented suggesting that angiogenesis is a central factor in the
initiation and persistence of arthritic disease and that the
vascular integrin .alpha.v.beta.3 may be a preferred target in
inflammatory arthritis. Therefore, .alpha.v.beta.3 antagonists that
inhibit angiogenesis may represent a novel therapeutic approach to
the treatment of arthritic disease, such as rheumatoid arthritis
(C. M. Storgard, et al., Decreased Angiogenesis and Arthritic
Disease in Rabbits Treated with an .alpha.v.beta.3 Antagonist, J.
Clin. Invest., 1999, 103, 47-54).
[0253] Inhibition of the .alpha.v.beta.5 integrin receptor can also
prevent neovascularization. A monoclonal antibody for
.alpha.v.beta.5 has been shown to inhibit VEGF-induced angiogenesis
in rabbit cornea and the chick chorioallantoic membrane model (M.
C. Friedlander, et al., Science, 1995, 270, 1500-1502). Thus,
.alpha.v.beta.5 antagonists are useful for treating and preventing
macular degeneration, diabetic retinopathy, cancer and metastatic
tumor growth.
[0254] Inhibition of .alpha.v integrin receptors can also prevent
angiogenesis and inflammation by acting as antagonists of other
.beta. subunits, such as .alpha.v.beta.6 and .alpha.v.beta.8 (Melpo
Christofidou-Solomidou, et al., Expression and Function of
Endothelial Cell on Integrin Receptors in Wound-Induced Human
Angiogenesis in Human Skin/SCID 25 Mice Chimeras, American Journal
of Pathology, 1997, 151, 975-83; and, Xiao-Zhu Huang, et al.,
Inactivation of the Integrin .beta.6 Subunit Gene Reveals a Role of
Epithelial Integrins in Regulating Inflamnation in the Lungs and
Skin, Journal of Cell Biology, 1996, 133, 921-28).
[0255] An antagonist to the .alpha.v integrin can act to inhibit or
minimize adhesions that result from either wounding or surgical
adhesions. Post-surgical adhesions result as an anomaly of the
wound healing process. Cell adhesion and the migration of
fibroblasts are major players in this process. Trauma caused by the
wounding, a surgical procedure, normal tissue manipulation in
surgery, or bleeding during a surgical procedure can act to disrupt
the peritoneum and expose the underlying stroma leading to the
release of inflammatory mediators and an increase in capillary
permeability. Inflammatory cells are subsequently liberated and the
formation of a fibrin clot ensues. Adhesions are formed and
intensify as fibroblasts and inflammatory cells continue to
infiltrate this extracellular matrix rich in fibrin. The
extracellular matrix is composed of adhesive proteins which act as
ligands for the .alpha.v integrin. To inhibit post-surgical
adhesion development, application of an av antagonist could be
parenteral, subcutaneous, intravenous, oral, topical or
transdermal. The .alpha.v integrin antagonist can be administered
before, during or after a surgical procedure. When administered
during a surgical procedure the antagonists can be administered by
aerosol, in a pad, gel, film, sponge, solution, suspension or
similar suitable pharmaceutically acceptable carrier to the area in
which the surgery is performed.
[0256] An aspect of the invention is a composition or medicament
comprising a pharmaceutically appropriate carrier and any of the
compounds of the present invention. Illustrative of the invention
is a composition or medicament made by mixing an instant compound
and a pharmaceutically appropriate carrier. Another illustration of
the invention is a process for making a composition or medicament
comprising mixing any of the compounds described above and a
pharmaceutically appropriate carrier. Further illustrative of the
present invention are compositions or medicaments comprising one or
more compounds of this invention in association with a
pharmaceutically appropriate carrier.
[0257] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts for treating or ameliorating an .alpha.v
integrin mediated disorder or for use as a medicament.
[0258] The compounds of the present invention are .alpha.v integrin
inhibitors useful for treating or ameliorating an .alpha.v integrin
mediated disorder. An aspect of the invention includes compounds
that are selective inhibitors of an .alpha.v integrin receptor, or
subtype thereof. In another aspect of the invention, the inhibitor
is independently selective to the .alpha.v.beta.3 integrin receptor
or the .alpha.v.beta.5 integrin receptor. An aspect of the
invention also includes compounds that are inhibitors of a
combination of .alpha.v integrin receptors, or subtypes thereof. In
another aspect of the invention, the compound inhibitor
simultaneously antagonizes both the .alpha.v.beta.3 integrin and
the .alpha.v.beta.5 integrin receptor subtypes.
[0259] An aspect of the present invention includes a method for
treating or ameliorating an .alpha.v integrin mediated disorder in
a subject in need thereof comprising administering to the subject a
therapeutically effective amount of a compound of Formula (I) or
composition thereof.
[0260] The term "therapeutically effective amount" or "effective
amount," as used herein, means that amount of active compound or
pharmaceutical agent that elicits the biological or medicinal
response in a tissue system, animal or human, that is being sought
by a researcher, veterinarian, medical doctor, or other clinician,
which includes alleviation of the symptoms of the disease or
disorder being treated.
[0261] An aspect of the present invention includes a prophylactic
method for preventing an .alpha.v integrin mediated disorder in a
subject in need thereof comprising administering to the subject a
prophylactically effective amount of a compound of Formula (I) or
composition thereof.
[0262] Another aspect of the present invention includes the
preparation of a medicament comprising a therapeutically effective
amount of a compound of Formula (I) for use in preventing, treating
or ameliorating an .alpha.v integrin mediated disorder in a subject
in need thereof.
[0263] The term "administering" is to be interpreted in accordance
with the methods of the present invention whereby an individual
compound of the present invention or a composition thereof can be
therapeutically administered separately at different times during
the course of therapy or concurrently in divided or single
combination forms. Prophylactic administration can occur prior to
the manifestation of symptoms characteristic of an .alpha.v
integrin mediated disease or disorder such that the disease or
disorder is prevented or, alternatively, delayed in its
progression. The instant invention is therefore to be understood as
embracing all such regimes of simultaneous or alternating
therapeutic or prophylatic treatment.
[0264] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, which has been the
object of treatment, observation or experiment and is at risk of
(or susceptible to) developing a disease or disorder or having a
disease or disorder related to expression of an .alpha.v integrin,
or subtype thereof.
[0265] The term ".alpha.v integrin mediated disorder" refers to
disorders and diseases associated with pathological unregulated or
disregulated cell proliferation resulting from expression of an
.alpha.v integrin, or subtype thereof.
[0266] The term "unregulated" refers to a breakdown in the process
of regulating cell proliferation, as in a tumor cell. The term
"disregulated" refers to inappropriate cell growth as a result of
pathogenesis. The term "subtype" refers to a particular .alpha.v
integrin receptor selected from those receptors making up the class
of .alpha.v integrins, such as an .alpha.v.beta.3 integrin receptor
or an .alpha.v.beta.5 integrin receptor.
[0267] The term "disorders and diseases associated with unregulated
or disregulated cell proliferation" refers to disorders wherein
cell proliferation by one or more subset of cells in a
multicellular organism results in harm (such as discomfort or
decreased life expectancy) to the organism. Such disorders can
occur in different types of animals and humans and include, and are
not limited to, cancers, cancer-associated pathologies,
atherosclerosis, transplantation-induced vasculopathies, neointima
formation, papilloma, lung fibrosis, pulmonary fibrosis,
glomerulonephritis, glomerulosclerosis, congenital multicystic
renal dysplasia, kidney fibrosis, diabetic retinopathy, macular
degeneration, psoriasis, osteoporosis, bone resorption,
inflammatory arthritis, rheumatoid arthritis, restenosis or
adhesions.
[0268] The term "cancers" refers to, and is not limited to, glioma
cancers, lung cancers, breast cancers, colorectal cancers, prostate
cancers, gastric cancers, esophageal cancers, leukemias, melanomas,
basal cell carcinomas and lymphomas. The term "cancer-associated
pathologies" refers to, and is not limited to, unregulated or
disregulated cell proliferation, tumor growth, tumor
vascularization, angiopathy and angiogenesis. The term
"angiogenesis" refers to, and is not limited to, unregulated or
disregulated proliferation of new vascular tissue including, but
not limited to, endothelial cells, vascular smooth muscle cells,
pericytes and fibroblasts. The term "osteoporosis" refers to, and
is not limited to, formation or activity of osteoclasts resulting
in bone resorption. The term "restenosis" refers to, and is not
limited to, in-stent stenosis and vascular graft restenosis.
[0269] The term ".alpha.v integrin expression" refers to expression
of an .alpha.v integrin, or subtype thereof, which leads to
unregulated or disregulated cell proliferation:
[0270] 1. by cells which do not normally express an .alpha.v
integrin, or subtype thereof,
[0271] 2. by neoplastic cells,
[0272] 3. in response to stimulation by a growth factor, hypoxia,
neoplasia or a disease process,
[0273] 4. as a result of mutations which lead to constitutive
expression of an O.alpha.v integrin, or subtype thereof.
[0274] The expression of an .alpha.v integrin, or subtype thereof,
includes selective expression of an .alpha.v integrin or subtype
thereof, selective expression of the .alpha.v.beta.3 integrin or
the .alpha.v.beta.5 integrin subtypes, expression of multiple
.alpha.v integrin subtypes or simultaneous expression of the
.alpha.v.beta.3 integrin and the .alpha.v.beta.5 integrin subtypes.
Detecting the expression of an .alpha.v integrin, or subtype
thereof, in inappropriate or abnormal levels is determined by
procedures well known in the art.
[0275] Another aspect of the present invention includes a method
for treating or ameliorating a selective .alpha.v.beta.3 integrin
mediated disorder in a subject in need thereof comprising
administering to the subject a therapeutically effective amount of
a compound of Formula (I) or composition thereof.
[0276] Another aspect of the present invention includes a method
for treating or ameliorating a selective .alpha.v.beta.5 integrin
mediated disorder in a subject in need thereof comprising
administering to the subject a therapeutically effective amount of
a compound of Formula (I) or composition thereof.
[0277] Another aspect of the present invention includes a method
for treating or ameliorating a disorder simultaneously mediated by
an .alpha.v.beta.3 and .alpha.v.beta.5 integrin in a subject in
need thereof comprising administering to the subject a
therapeutically effective amount of a compound of Formula (I) or
composition thereof.
[0278] An aspect of the present invention includes a method for
inhibiting .alpha.v integrin mediated neoplastic activity
comprising administering to a neoplasm or to the microenvironment
around the neoplasm an effective amount of a compound of Formula
(I) or composition thereof.
[0279] The term "neoplastic activity" refers to unregulated or
disregulated cell proliferation and the process of angiogenesis or
the formation of new vasculature supporting a neoplasm in the
endothelial microenvironment around the neoplasm.
[0280] The term "neoplasm" refers to tumor cells are cells having
unregulated or disregulated proliferation as a result of genetic
instability or mutation and an endothelium wherein the endothelial
cells have unregulated or disregulated proliferation as a result of
a pathogenic condition. Within the scope of the present invention,
a neoplasm is not required to express the .alpha.v integrin, or
subtype thereof, by itself and is not limited to a primary tumor of
origin but also to secondary tumors occurring as a result of
metastasis of the primary tumor. The term "administering to a
neoplasm" refers to administering a compound of Formula (I) or
composition thereof to the surface of a neoplasm, to the surface of
a neoplastic cell or to the endothelial microenvironment around a
neoplasm.
[0281] The term "inhibiting .alpha.v integrin mediated neoplastic
activity" includes attenuating a tumor's growth by limiting its
blood supply and, further, preventing the formation of new
supportive vasculature by preventing the process of
angiogenesis.
[0282] An aspect of the present invention includes a method for
treating or ameliorating a disease mediated by cells pathologically
expressing an .alpha.v integrin, or subtype thereof.
[0283] The term "disease mediated by cells pathologically
expressing an .alpha.v integrin" refers to, and is not limited to,
a disorders selected from cancers, cancer-associated pathologies,
diabetic retinopathy, macular degeneration, osteoporosis, bone
resorption, inflammatory arthritis, rheumatoid arthritis or
restenosis.
[0284] An aspect of the present invention includes a method for
sustained neoplasm regression in a subject in need thereof
comprising administering to the subject an effective amount of a
compound of Formula (I) or composition thereof; wherein the
compound or composition thereof is conjugated with and delivers a
therapeutic agent to to a neoplasm or to the microenvironment
around the neoplasm; and, wherein the therapeutic agent induces
apoptosis or attenuates unregulated or disregulated cell
proliferation.
[0285] The terms "conjugated with" and "delivers a therapeutic
agent" refers to a compound of Formula (D or composition thereof
bound to a therapeutic agent by a conjugation means known to those
skilled in the art; wherein the compound or composition thereof
acts as a targeting agent for antagonizing the .alpha.v integrin
receptors of a neoplasm or the microenvironment thereof; and,
wherein the conjugation means facilitates and selectively delivers
the therapeutic agent to the neoplasm or the microenvironment
thereof.
[0286] The term "therapeutic agent," including but not limited to
Technetium.sup.99, refers to imaging agents known to those skilled
in the art.
[0287] An aspect of the present invention includes a method for use
of a compound of Formula (I) or composition thereof advantageously
co administered in one or more tumor or cell anti-proliferation
therapies including chemotherapy, radiation therapy, gene therapy
or immunotherapy for preventing, treating or ameliorating an
.alpha.v integrin mediated disorder.
[0288] The combination therapy can include:
[0289] 1. co-administration of a compound of Formula (I) or
composition thereof and a chemotherapeutic agent for preventing,
treating or ameliorating an .alpha.v integrin mediated
disorder,
[0290] 2. sequential administration of a compound of Formula (I) or
composition thereof and a chemotherapeutic agent for preventing,
treating or ameliorating an .alpha.v integrin mediated
disorder,
[0291] 3. administration of a composition containing a compound of
Formula (I) and a chemotherapeutic agent for preventing, treating
or ameliorating an .alpha.v integrin mediated disorder, or,
[0292] 4. simultaneous administration of a separate composition
containing a compound of Formula (I) and a separate composition
containing a chemotherapeutic agent for preventing, treating or
ameliorating an .alpha.v integrin mediated disorder.
[0293] For example, the compounds of this invention are useful in
combination therapies with at least one other chemotherapeutic
agent for the treatment of a number of different cancers and
advantageously appear to facilitate the use of a reduced dose of
the chemotherapeutic agent that is recommended for a particular
cancer or cell proliferation disorder. Therefore, it is
contemplated that the compounds of this invention can be used in a
treatment regime before the administration of a particular
chemotherapeutic agent recommended for the treatment of a
particular cancer, during administration of the chemotherapeutic
agent or after treatment with a particular chemotherapeutic
agent.
[0294] The term "chemotherapeutic agents" includes, and is not
limited to, anti-angiogenic agents, anti-tumor agents, cytotoxic
agents, inhibitors of cell proliferation and the like. The term
"treating or ameliorating" includes, and is not limited to,
facilitating the eradication of, inhibiting the progression of or
promoting stasis of a malignancy. For example, an inhibitor
compound of the present invention, acting as an anti-angiogenic
agent can be administered in a dosing regimen with at least one
other cytotoxic compound, such as a DNA alkylating agent.
[0295] Preferred anti-tumor agents are selected from the group
consisting of cladribine (2-chloro-2'-deoxy-(beta)-D-adenosine),
chlorambucil (4-(bis(2-chlorethyl)amino)benzenebutanoic acid),
DTIC-Dome (5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide),
platinum chemotherapeutics and nonplatinum chemotherapeutics.
Platinum containing anti-tumor agents include, and are not limited
to, cisplatin (CDDP) (cis-dichlorodiamineplatinum). Non-platinum
containing anti-tumor agents include, and are not limited to,
adriamycin (doxorubicin), aminopterin, bleomycin, camptothecin,
carminomycin, combretastatin(s), cyclophosphamide, cytosine
arabinoside, dactinomycin, daunomycin, epirubicin, etoposide
(VP-16), 5-fluorouracil (5FU), herceptin actinomycin-D,
methotrexate, mitomycin C, tamoxifen, taxol, taxotere, thiotepa,
vinblastine, vincristine, vinorelbine and derivatives and prodrugs
thereof. Each anti-tumor agent is administered in a therapeutically
effective amount, which varies based on the agent used, the type of
malignancy to be treated or ameliorated and other conditions
according to methods well known in the art.
[0296] As will be understood by those skilled in the art, the
appropriate doses of chemotherapeutic agents will be generally
around those already employed in clinical therapies wherein the
chemotherapeutics are administered alone or in combination with
other chemotherapeutics. By way of example only, agents such as
cisplatin and other DNA alkylating are used widely to treat cancer.
The efficacious dose of cisplatin used in clinical applications is
about 20 mg/m.sup.2 for 5 days every three weeks for a total of
three courses. Cisplatin is not absorbed orally and must therefore
be delivered via injection intravenously, subcutaneously,
intratumorally or intraperitoneally. Further useful agents include
compounds that interfere with DNA replication, mitosis and
chromosomal segregation. Such chemotherapeutic agents include
adriamycin (doxorubicin), etoposide, verapamil or podophyllotoxin
and the like and are widely used in clinical settings for tumor
treatment. These compounds are administered through bolus
injections intravenously at doses ranging from about 25 to about 75
mg/m.sup.2 at 21 day intervals (for adriamycin) or from about 35 to
about 50 mg/m.sup.2 (for etoposide) intravenously or at double the
intravenous dose orally. Agents that disrupt the synthesis and
fidelity of polynucleotide precursors such as 5-fluorouracil (5-FU)
are preferentially used to target tumors. Although quite toxic,
5-FU is commonly used via intravenous administration with doses
ranging from about 3 to about 15 mg/kg/day.
[0297] Another aspect of the present invention includes a method
for administering a compound of the present invention in
combination with radiation therapy. As used herein, "radiation
therapy" refers to a therapy that comprises exposing the subject in
need thereof to radiation. Such therapy is known to those skilled
in the art. The appropriate scheme of radiation therapy will be
similar to those already employed in clinical therapies wherein the
radiation therapy is used alone or in combination with other
chemotherapeutics.
[0298] An aspect of the present invention includes a method for
administering a compound of the present invention in combination
with a gene therapy or for use of a compound of the present
invention as a gene therapy means. The term "gene therapy" refers
to a therapy targeting angiogenic endothelial cells or tumor tissue
during tumor development. Gene therapy strategies include the
restoration of defective cancer-inhibitory genes, cell transduction
or transfection with antisense DNA (corresponding to genes coding
for growth factors and their receptors) and the use of "suicide
genes." The term "gene therapy means" refers to the use of a
targeting vector comprising a combination of a cationic
nanoparticle coupled to an .alpha.v-targeting ligand to influence
blood vessel biology; whereby genes are selectively delivered to
angiogenic blood vessels (as described in Hood, J. D., et al, Tumor
Regression by Targeted Gene Delivery to the Neovasculature,
Science, 2002, 28 June, 296, 2404-2407).
[0299] Another aspect of the present invention includes a method
for treating or ameliorating an .alpha.v integrin mediated neoplasm
in a subject in need thereof comprising administering to the
subject an effective amount of a gene therapy combination product
comprising a compound of Formula (I) or composition thereof and a
gene therapeutic agent; wherein the product is delivered or
"seeded" directly to a neoplasm or the microenvironment thereof by
antagonizing the .alpha.v integrin receptors of the neoplasm or
microenvironment thereof.
[0300] The term "delivered or `seeded` directly to a neoplasm"
includes using a compound of Formula (I) or composition thereof as
a gene therapy means whereby the compound or composition thereof
functions as a targeting agent which directs the conjugate to its
intended site of action (i.e., to neoplastic vascular endothelial
cells or to tumor cells). Because of the specific interaction of
the .alpha.v integrin inhibitor as a targeting agent and its
corresponding .alpha.v integrin receptor site, a compound of this
invention can be administered with high local concentrations at or
near a targeted .alpha.v integrin receptor, or subtype thereof,
thus treating the .alpha.v integrin mediated disorder more
effectively.
[0301] Another aspect of the present invention includes a method
for administering a compound of the present invention in
combination with an immunotherapy. As used herein, "immunotherapy"
refers to a therapy targeted to a particular protein involved in
tumor development via antibodies specific to such protein. For
example, monoclonal antibodies against vascular endothelial growth
factor have been used in treating cancers.
[0302] An aspect of the present invention includes a method for
tumor imaging in a subject in need thereof comprising
advantageously coadministering to the subject an effective amount
of a compound of Formula (I) or composition thereof, wherein the
compound or composition thereof is conjugated with and delivers a
non-invasive tumor imaging agent to a tumor or to the
microenvironment around the tumor.
[0303] The terms "conjugated with" and "delivers a non-invasive
tumor imaging agent" refers to a compound of Formula (I) or
composition thereof bound to an imaging agent by a conjugation
means known to those skilled in the art; wherein the compound or
composition thereof acts as a targeting agent for antagonizing the
.alpha.v integrin receptors of a neoplasm or the microenvironment
thereof, and, wherein the conjugation means facilitates and
selectively delivers the imaging agent to the neoplasm or the
microenvironment thereof (as described in PCT Application
WO00/35887, WO00/35492, WO00/35488 or WO99/58162). The term
"imaging agent," including but not limited to Technetium.sup.99,
refers to imaging agents known to those skilled in the art. The
term "conjugation means," including but not limited to appending a
compound to a linking group followed by conjugation with an imaging
agent chelating group, refers to means known to those skilled in
the art.
[0304] Since, cell adhesion molecules .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 play a pivotal role in certain disorders
such as tumor angiogenesis and metastasis, and are only present at
very low levels in normal non-proliferative tissue,
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5 integrin
receptor antagonists are potentially useful tools in non-invasive
imaging and treatment. The ability to visualize and quantify
integrin expression may provide a better understanding of disease
progression such as tumor growth and efficiency of current methods
of treatment.
[0305] The .alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5
integrin receptor antagonists and more preferably the targeting
ligands of the present invention may be labeled with radioactive
elements such as .sup.125I, .sup.18F, .sup.11C, .sup.64Cu, and the
like for use in imaging such as positron emission tomography (PET)
imaging or for radioactive treatment of patients. The targeting
ligands or affinity moieties described herein may be reacted with
an appropriate functionalized radioactive reagents using
conventional chemistry to provide a radiolabeled affinity moiety.
For example radiopharmaceutical molecules may be synthesized using
Compound A1, wherein R.sub.2A comprises an aryl ring substituted
with R.sub.15, and said R.sub.15 is a PEG chain containing a
reactive functional group such as amine, alcohol, or carboxylic
acid. Compound A1 may be coupled with a variety of activated
radio-labeled molecules or other diagnostic agents that contain a
reactive functional group, such as p-.sup.18F-benzoic acid, to
provide Compound A2. 20
[0306] Similarly, Compound A1 may be coupled with p-hydroxybenzoic
acid using reagents, protecting groups, and methods known to those
skilled in the art, followed by the alkylation of the phenolic
hydroxyl group with a radiolabeled electrophile such as
.sup.18fluoroethyltosylate or .sup.18fluoroethylbromide to afford
compound B1. 21
[0307] Other methods for incorporation of imaging molecules
include, but are not limited to, alkylation, acylation with
anhydrides and acid chlorides, coupling reactions with various
carboxylic acids, reductive amination with aldehydes and ketones,
and the like.
[0308] One skilled in the art will recognize that the foregoing
examples describing the inclusion of desired radiolabels into the
compounds of Formula (I) and (II) are not intended to be all
inclusive, but rather are intended to provide examples of known
chemistry using known synthetic methods.
[0309] An aspect of the present invention includes a composition
comprising a compound of Formula (I), or pharmaceutically
acceptable salt thereof, in association with a pharmaceutically
acceptable carrier. Compositions contemplated within this invention
can be prepared according to conventional pharmaceutical
techniques. A pharmaceutically acceptable carrier may also (but
need not necessarily) be used in the composition of the
invention.
[0310] The term "pharmaceutically acceptable" refers to molecular
entities and compositions that do not produce an adverse, allergic
or other untoward reaction when administered to an animal, or a
human, as appropriate. Veterinary uses are equally included within
the invention and "pharmaceutically acceptable" formulations
include formulations for both clinical and/or veterinary use.
[0311] The composition may take a wide variety of forms depending
on the form of preparation desired for administration including,
but not limited to, intravenous (both bolus and infusion), oral,
nasal, transdermal, topical with or without occlusion, and
injection intraperitoneally, subcutaneously, intramuscularly,
intratumorally or parenterally, all using forms well known to those
of ordinary skill in the pharmaceutical arts. The composition may
comprise a dosage unit such as a tablet, pill, capsule, powder,
granule, sterile parenteral solution or suspension, metered aerosol
or liquid spray, drop, ampoule, auto-injector device or
suppository; for administration orally, parenterally, intranasally,
sublingually or rectally or by inhalation or insufflation.
Compositions suitable for oral administration include solid forms
such as pills, tablets, caplets, capsules (each including immediate
release, timed release and sustained release formulations),
granules and powders; and, liquid forms such as solutions, syrups,
elixirs, emulsions and suspensions. Forms useful for parenteral
administration include sterile solutions, emulsions and
suspensions. Alternatively, the composition may be presented in a
form suitable for once-weekly or once-monthly administration; for
example, an insoluble salt of the active compound, such as the
decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. In preparing the compositions in oral
dosage form, one or more of the usual pharmaceutical carriers may
be employed, including necessary and inert pharmaceutical
excipients, such as water, glycols, oils, alcohols, flavoring
agents, preservatives, coloring agents, syrup and the like; in the
case of oral liquid preparations, carriers such as starches,
sugars, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like may be employed.
[0312] The dosage unit (tablet, capsule, powder, injection,
suppository, measured liquid dosage and the like) containing the
pharmaceutical compositions herein will contain an amount of the
active ingredient necessary to deliver a therapeutically effective
amount as described above. The composition may contain from about
0.001 mg to about 5000 mg of the active compound or prodrug thereof
and may be constituted into any form suitable for the mode of
administration selected for a subject in need.
[0313] An aspect of the present invention contemplates a
therapeutically effective amount in a range of from about 0.001 mg
to 1000 mg/kg of body weight per day. Another aspect of the present
invention includes a range of from about 0.001 to about 500 mg/kg
of body weight per day. A further aspect of the present invention
includes a range of from about 0.001 to about 300 mg/kg of body
weight per day. The compounds may be administered according to a
dosage regimen of from about 1 to about 5 times per day and still
more preferably 1, 2 or 3 times a day.
[0314] For oral administration, the compositions are preferably
provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5,
1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500
milligrams of the active ingredient for the symptomatic adjustment
of the dosage to the patient to be treated. Optimal dosages to be
administered may be readily determined by those skilled in the art
and will vary depending factors associated with the particular
patient being treated (age, weight, diet and time of
administration), the severity of the condition being treated, the
compound being employed, the mode of administration and the
strength of the preparation. The use of either daily administration
or post-periodic dosing may be employed.
[0315] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier,
e.g. conventional tableting ingredients such as corn starch,
lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums and other pharmaceutical diluents, e.g.
water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit
dosage forms of the type described above containing from 0.001 to
about 5000 mg of the active ingredient of the present invention.
The tablets or pills of the composition can be coated or otherwise
compounded to provide a dosage form affording the advantage of
prolonged action. For example, the tablet or pill can comprise an
inner dosage and an outer dosage component, the latter being in the
form of an envelope over the former. The two components can be
separated by an enteric layer that serves to resist disintegration
in the stomach and permits the inner component to pass intact into
the duodenum or to be delayed in release. A variety of material can
be used for such enteric layers or coatings, such materials
including a number of polymeric acids with such materials as
shellac, acetyl alcohol and cellulose acetate.
[0316] For oral administration in the form of a tablet or capsule,
the active drug component can be optionally combined with an oral,
non-toxic pharmaceutically acceptable inert carrier such as
ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0317] The liquid forms in which the compound of formula (I) may be
incorporated for administration orally or by injection include,
aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions and flavored emulsions with edible oils such as
cottonseed oil, sesame oil, coconut oil or peanut oil, as well as
elixirs and similar pharmaceutical vehicles. Suitable dispersing or
suspending agents for aqueous suspensions, include synthetic and
natural gums such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or
gelatin. The liquid forms in suitably flavored suspending or
dispersing agents may also include the synthetic and natural gums,
for example, tragacanth, acacia, methyl-cellulose and the like. For
parenteral administration, sterile suspensions and solutions are
desired. Isotonic preparations that generally contain suitable
preservatives are employed when intravenous administration is
desired.
[0318] As is also known in the art, the compounds may alternatively
be administered parenterally via injection of a formulation
consisting of the active ingredient dissolved in an inert liquid
carrier. The injectable formulation can include the active
ingredient mixed with an appropriate inert liquid carrier.
Acceptable liquid carriers include vegetable oils such as peanut
oil, cottonseed oil, sesame oil and the like, as well as organic
solvents such as solketal, glycerol and the like. As an
alternative, aqueous parenteral formulations may also be used. For
example, acceptable aqueous solvents include water, Ringer's
solution and an isotonic aqueous saline solution. Further, a
sterile non-volatile oil can usually be employed as a solvent or
suspending agent in the aqueous formulation. The formulations are
prepared by dissolving or suspending the active ingredient in the
liquid carrier such that the final formulation contains from 0.005
to 10% by weight of the active ingredient. Other additives
including a preservative, an isotonizer, a solubilizer, a
stabilizer and a pain-soothing agent may adequately be
employed.
[0319] Advantageously, compounds of Formula (I) may be administered
in a single daily dose, or the total daily dosage may be
administered in divided doses of two, three or four times daily.
Furthermore, compounds of the present invention can be administered
in intranasal form via topical use of suitable intranasal vehicles,
or via transdermal routes, using those forms of transdermal skin
patches well known to those of ordinary skill in that art. To be
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
[0320] Because of their ease of administration, tablets and
capsules represent an advantageous oral dosage unit form, wherein
solid pharmaceutical carriers are employed. If desired, tablets may
be sugarcoated or enteric-coated by standard techniques. If
desired, tablets may be sugar coated or enteric coated by standard
techniques. For parenterals, the carrier will usually comprise
sterile water, though other ingredients, for example, for purposes
such as aiding solubility or for preservation, may be included.
Injectable suspensions may also be prepared, in which case
appropriate liquid carriers, suspending agents and the like may be
employed.
[0321] The compositions of the present invention also include a
composition for slow release of the compound of the invention. The
composition includes a slow release carrier (typically, a polymeric
carrier) and a compound of the invention. In preparation for slow
release, a slow release carrier, typically a polymeric carrier and
a compound of the invention are first dissolved or dispersed in an
organic solvent. The obtained organic solution is then added into
an aqueous solution to obtain an oil-in-water-type emulsion.
Preferably, the aqueous solution includes surface-active agent(s).
Subsequently, the organic solvent is evaporated from the
oil-in-water-type emulsion to obtain a colloidal suspension of
particles containing the slow release carrier and the compound of
the invention. Slow release biodegradable carriers are also well
known in the art. These are materials that may form particles that
capture therein an active compound(s) and slowly degrade/dissolve
under a suitable environment (e.g., aqueous, acidic, basic, etc)
and thereby degrade/dissolve in body fluids and release the active
compound(s) therein. The particles are preferably nanoparticles
(i.e., in the range of about 1 to 500 nm in diameter, preferably
about 50-200 nm in diameter and most preferably about 100 nm in
diameter).
[0322] The present invention also provides methods to prepare the
pharmaceutical compositions of this invention. A compound of
Formula (I) as the active ingredient is intimately admixed with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques, which carrier may take a wide variety of
forms depending on the form of preparation desired for
administration. In preparing the compositions in oral dosage form,
any of the usual pharmaceutical media may be employed. For solid
oral dosage forms, suitable carriers and additives include
starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. For liquid oral
preparations, suitable carriers and additives include water,
glycols, oils, alcohols, flavoring agents, preservatives, coloring
agents and the like. Additionally, liquid forms of the active drug
component can be combined in suitably flavored suspending or
dispersing agents such as the synthetic and natural gums, including
for example, tragacanth, acacia, methyl-cellulose and the like.
Other dispersing agents that may be employed include glycerin and
the like.
[0323] The compounds of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes containing delivery systems as
well known in the art are formed from a variety of phospholipids,
such as cholesterol, stearylamine or phosphatidylcholines.
[0324] 2. Targeting Ligands and Targeting Conjugates
[0325] Another embodiment of the present invention relates to the
synthesis and biological application of piperidinoyl carboxylic
acid integrin antagonists targeting ligands. These targeting
ligands maybe used with imaging agents (radioactive labeling
reagents and the like) or liposomes to target cells that express
the .alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5, or
.alpha..sub.v.beta..sub.6 integrin receptors.
[0326] The targeting ligands and targeting conjugates of the
present invention will employ any of the previously defined
substituents for W, R.sub.1, R.sub.1a, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10, q, and Z in any combination,
with the appropriate substitutions of R.sub.2a, R.sub.14, R.sub.11,
R.sub.12, and R.sub.13, for the targeting ligand and targeting
conjugate respectively. Preferred embodiments for R.sub.2a
R.sub.14, R.sub.11, R.sub.12, and R.sub.13, are provided
hereinafter.
[0327] Aspects of the present invention include targeting ligands
and targeting conjugates of Formula (I) and Formula (II) wherein
the variables of the formulas are as previously described and
R.sub.2a is --C.sub.1-4alkyl(R.sub.7)(R.sub.1a),
--C.sub.2-4alkenyl(R.sub.7)(R.sub.11- ),
--C.sub.2-4alkynyl(R.sub.7)(R.sub.11),
-cycloalkyl(R.sub.8)(R.sub.12), -heterocyclyl(R.sub.8)(R.sub.12),
-aryl(R.sub.8)(R.sub.12) or -heteroaryl(R.sub.8)(R.sub.12).
[0328] Another aspect of the present invention includes targeting
ligands and targeting conjugates of Formula (I) and Formula (II)
wherein the variables of the formulas are as previously described
and R.sub.2a is -cycloalkyl(R.sub.8)(R.sub.12),
-heterocyclyl(R.sub.8)(R.sub.12), -aryl(R.sub.8)(R.sub.12) or
-heteroaryl(R.sub.8)(R.sub.12).
[0329] Another aspect of the present invention includes targeting
ligands and targeting conjugates of Formula (I) and Formula (II)
wherein the variables of the formulas are as previously described
and R.sub.2a is -cycloalkyl(R.sub.8)(R.sub.11),
-heterocyclyl(R.sub.8)(R.sub.12), -phenyl(R.sub.8)(R.sub.12),
-naphthalenyl(R.sub.8)(R.sub.12) or
-heteroaryl(R.sub.8)(R.sub.12).
[0330] Another aspect of the present invention includes targeting
ligands and targeting conjugates of Formula (I) and Formula (II)
wherein the variables of the formulas are as previously described
and R.sub.2a is -tetrahydropyrimidinyl(R.sub.8)(R.sub.12),
-1,3-benzodioxolyl(R.sub.8)(R.- sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.sub.12), -tetrahydroquinolinyl(R.-
sub.8)(R.sub.12), -phenyl (R.sub.8)(R.sub.12),
-naphthalenyl(R.sub.8)(R.su- b.12), -pyridinyl(R.sub.8)(R.sub.12),
-pyrimidinyl(R.sub.8)(R.sub.12) or
-quinolinyl(R.sub.8)(R.sub.12).
[0331] A further aspects of the present invention include targeting
ligands as previously defined of Formula (I) and Formula (II)
wherein the variables are as previously defined and R.sub.1 is
selected from the group consisting of --C.sub.1-8alkyl(R.sub.14),
--O--C.sub.1-8alkyl(R.sub- .14), --NH--C.sub.1-8alkyl(R.sub.14),
--S--C.sub.1-8alkyl(R.sub.14), --C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 4),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.14), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R-
.sub.14), --C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2
0).sub.rCH.sub.2C(.dbd.O) (R.sub.14),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2H.sub.2O).sub.rCH.sub.-
2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).s-
ub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2-
CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--SO.sub.2NHCH.sub.2CH.su-
b.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14).
[0332] Aspects of the present invention include targeting ligands
of Formula (I) and Formula (II) wherein the variables are as
previously defined and R.sub.11 is selected from the group
consisting of --C.sub.1-8alkyl(R.sub.14),
--O--C.sub.1-8alkyl(R.sub.14), --NH--C.sub.1-8alkyl(R.sub.14),
--S--C.sub.1-8alkyl(R.sub.14), --C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 4),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.14),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.14), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.14),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.14),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14), and
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14).
[0333] Aspects of the present invention include targeting ligands
of Formula (I) and Formula (II) wherein the variables are as
previously defined and R.sub.12 is selected from the group
consisting of --C.sub.1-6alkyl(R.sub.14),
--O--C.sub.1-6alkyl(R.sub.14), --NH--C.sub.1-4alkyl(R.sub.14),
--S--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.14),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub- .14),
--CH.sub.2S--C.sub.1-6alkyl(R.sub.14),
--C(.dbd.O)C.sub.1-6alkyl(R.s- ub.14),
--O--C(.dbd.O)C.sub.1-6alkyl(R.sub.14), --NH--C(.dbd.O)C.sub.1-8al-
kyl(R.sub.14), --CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.14),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.14),
--C(.dbd.O)OC.sub.1-6alk- yl(R.sub.14),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.14),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--O--C(.dbd.O)NHC.sub.1-6alkyl(R- .sub.14),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.14),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.14),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.14- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2H.sub.2O).sub.rCH.sub-
.2CH.sub.2(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).-
sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.su-
b.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2-
O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.14),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.14),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.14),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.14),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2-
O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.su-
b.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--NHC(.dbd.O)NHCH.sub.2CH.-
sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.14),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.14),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.14).
[0334] In another aspect of the present invention includes
targeting ligands of Formula (I) and Formula (II) wherein the
variables of the formula are as previously defined and R.sub.14
when R.sub.11 and R.sub.12 terminates with a C(.dbd.O) is selected
from the group consisting of hydrogen, OH, --OC.sub.1-4alkyl and
NH.sub.2; otherwise R.sub.14 is selected from the group consisting
of --OH, --SH, COOH, and --COOC.sub.1-4alkyl.
[0335] A further aspects of the present invention include targeting
conjugates as previously defined of Formula (I) and Formula (II)
wherein the variables are as previously defined and R.sub.11 is
selected from the group consisting of --C.sub.1-8alkyl(R.sub.13),
--O--C.sub.1-8alkyl(R.sub- .13), --NH--C.sub.1-8alkyl(R.sub.13),
--S--C.sub.1-8alkyl(R.sub.13), --C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 3),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.13), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R-
.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub-
.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH-
.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13).
[0336] Aspects of the present invention include targeting
conjugates of Formula (I) and Formula (II) wherein the variables
are as previously defined and R.sub.11 is selected from the group
consisting of --C.sub.1-8alkyl(R.sub.13),
--O--C.sub.1-8alkyl(R.sub.13), --NH--C.sub.1-8alkyl(R.sub.13),
--S--C.sub.1-8alkyl(R.sub.13), --C(.dbd.O)C.sub.1-8alkyl(RP 3),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub- .13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkyl- (R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R) 3),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13), and
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13).
[0337] Aspects of the present invention include targeting
conjugates of Formula (I) and Formula (II) wherein the variables
are as previously defined and R.sub.12 is selected from the group
consisting of --C.sub.1-6alkyl(R.sub.13),
--O--C.sub.1-6alkyl(R.sub.13), --NH--C.sub.1-4alkyl(R.sub.13),
--S--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub- .13),
--CH.sub.2S--C.sub.16alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-6alkyl(R.su- b.13),
--O--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alk- yl(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-6alk- yl(R.sub.13),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-6alkyl(R- .sub.13),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(O)(R.sub.13),
OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rC-
H.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.-
rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(-
CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
[0338] wherein when R.sub.11 or R.sub.12 terminates with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
22
[0339] and when R.sub.11 or R.sub.12 does not terminate with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
2324
[0340] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein the variables are as
previously defined and R.sub.12 is selected from the group
consisting of
[0341] --CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
[0342] --CH.sub.2NH--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl- (R.sub.13),
[0343] --NH--C(.dbd.O)C.sub.8alkyl(R.sub.13),
[0344] --CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
[0345] --NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
[0346] --NH--C(.dbd.O)C.sub.1-6alkylC(.dbd.O)(R.sub.13),
[0347]
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub-
.13),
[0348]
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.su-
b.13),
[0349]
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.su-
b.13),
[0350]
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.s-
ub.13),
[0351]
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub-
.2(R.sub.13),
[0352]
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.su-
b.2 (R.sub.13),
[0353]
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub-
.2(R.sub.13),
[0354]
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.13), and
[0355]
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.d-
bd.O)(R.sub.13).
[0356] wherein when R.sub.11 or R.sub.12 terminates with a
C(.dbd.O)--, R.sub.13 is selected from the group consisting of
25
[0357] and when R.sub.11 or R.sub.12 does not terminate with a
--(.dbd.O)--, R.sub.13 is selected from the group consisting of
2627
[0358] Aspects of the pre sent invention include targeting
conjugates of Formula (I) and Formula (II) wherein the variables
are as previously defined and R.sub.12 is selected from the group
consisting of
[0359] --CH.sub.2--O--(CH.sub.2).sub.4(R.sub.13)--,
[0360] --CH.sub.2--NH--(CH.sub.2).sub.4(R.sub.13)--,
[0361] --CH.sub.2--S--(CH.sub.2).sub.4(R.sub.13)--,
[0362] --CH.sub.2--O--(CH.sub.2).sub.6(R.sub.13)--,
[0363] --CH.sub.2--NH--(CH.sub.2).sub.6(R.sub.13)--,
[0364] --CH.sub.2--S--(CH.sub.2).sub.6(R.sub.13)--,
[0365] --NH--C(.dbd.O)--(CH.sub.2).sub.4(R.sub.13)--,
[0366] --NH--C(.dbd.O)--(CH.sub.2).sub.7(R.sub.13)--,
[0367] --NH--C(.dbd.O)NH--(CH.sub.2).sub.3(R.sub.13)--,
[0368] --NH--C(.dbd.O)NH--(CH.sub.2).sub.6(R.sub.13)--,
[0369] --CH.sub.2NH--C(.dbd.O)NH--(CH.sub.2).sub.2(R.sub.13)--,
[0370] --CH.sub.2NH--C(.dbd.O)NH--(CH.sub.2).sub.5(R.sub.13)--,
[0371] --NHC(.dbd.O)--(CH.sub.2).sub.2--C(.dbd.O)(R.sub.13)--,
[0372] --NHC(.dbd.O)--(CH.sub.2).sub.3--C(.dbd.O)(R.sub.13)--,
[0373] --NHC(.dbd.O)--(CH.sub.2).sub.4--C(.dbd.O)(R.sub.13)--,
[0374] --OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0375] --NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0376]
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0377]
--NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0378] --OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
[0379]
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
[0380] --NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0381]
--NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)---
,
[0382]
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0383]
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0384]
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0385]
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub-
.13)--,
[0386]
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.su-
b.13)--,
[0387]
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub-
.13)--,
[0388] --CH.sub.2NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)-,
and
[0389] --NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--;
[0390] wherein when R.sub.11 or R.sub.12 terminates with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
28
[0391] and when R.sub.11 or R.sub.12 does not terminate with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
29
[0392] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 30
[0393] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer ranging in molecular weight from 750 to 5000 daltons.
[0394] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 31
[0395] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer ranging in molecular weight from 2000 to 5000 daltons.
[0396] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein said
--O--(CH.sub.2CH.sub.2O--).sub.p-- or 32
[0397] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer selected from 2000 (PEG 2000), 3400 (PEG 3400), or 5000
(PEG 5000) daltons.
[0398] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein r is
an integer from 0 to 8.
[0399] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein Q and
Q.sup.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and are selected from the group consisting of
[0400] the C.sub.11 saturated chain of lauric acid,
[0401] the C.sub.15 saturated chain of palmitoic acid,
[0402] the C.sub.17 saturated chain of stearoic acid,
[0403] the C.sub.17 mono-unsaturated chain of oleoic acid, and
[0404] the C.sub.17 di-unsaturated chain of linoleic acid.
[0405] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein Q and
Q.sup.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and are selected from the group consisting of
[0406] the C.sub.15 saturated chain of palmitoic acid,
[0407] the C.sub.17 saturated chain of stearoic acid, and
[0408] the C.sub.17 mono-unsaturated chain of oleoic acid.
[0409] Aspects of the present invention include a composition
comprising a compound of Formula (I) and Formula (II) wherein Q and
Q.sup.1 of substituents R.sub.12 and R.sub.13 are the same within a
given compound and is
[0410] the C.sub.17 saturated chain of stearoic acid.
[0411] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein
[0412] W is preferably is selected from the group consisting of
--C.sub.0-4alkyl(R.sub.1), --C.sub.1-4alkyl(R.sub.1a),
--C.sub.0-4alkyl-aryl(R.sub.1,R.sub.8),
--C.sub.0-4alkyl-heterocyclyl(R.s- ub.1,R.sub.8),
--C.sub.0-4alkoxy(R.sub.1), --C.sub.0-4alkoxy-aryl(R.sub.1,-
R.sub.8), and --C.sub.0-4alkoxy-heterocyclyl(R.sub.1,R.sub.8);
[0413] R.sub.1 is --N(R.sub.4)(R.sub.6), -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8);
[0414] R.sub.1a is --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(- R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or --C(--N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
[0415] R.sub.4 is hydrogen or --C.sub.1-4alkyl(R.sub.7);
[0416] R.sub.5 is --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --C(.dbd.O)-cycloalkyl(R.sub.8),
--C(.dbd.O)-heterocyclyl(R.sub.8), --C(.dbd.O)-aryl(R.sub.8),
--C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(--N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) or
--SO.sub.2-aryl(R.sub.8);
[0417] R.sub.6 is -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8);
[0418] R.sub.7 is one to two substituents independently selected
from hydrogen, --C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.- sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2,
--C(.dbd.O)--NH-aryl(R.sub.10), --C(.dbd.O)-cycloalkyl(R.s- ub.10),
--C(.dbd.O)-heterocyclyl(R.sub.10), --C(.dbd.O)-aryl(R.sub.10),
--C(.dbd.O)-heteroaryl(R.sub.10), --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl- (R.sub.9), --CO.sub.2-aryl(R.sub.10),
--C(.dbd.NH)--NH.sub.2, --SH, --S--C.sub.1-4alkyl(R.sub.9),
--S--C.sub.1-4alkyl-S--C.sub.1-4alkyl(R.sub- .9),
--S--C.sub.1-4alkyl-C.sub.1-4alkoxy(R.sub.9),
--S--C.sub.1-4alkyl-NH-- -C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--SO.sub.2--NH--C.sub.1-4alkyl(R.sub.9),
--SO.sub.2--N(C.sub.4alkyl(R.sub.9)).sub.2,
--SO.sub.2-aryl(R.sub.10), cyano, (halo).sub.1-3, hydroxy, nitro,
oxo, -cycloalkyl(R.sub.10), -heterocyclyl(R.sub.10),
-aryl(R.sub.10) or -heteroaryl(R.sub.10);
[0419] R.sub.8 is one to four substituents independently selected
from hydrogen, --C.sub.1-4alkyl(R.sub.9), --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl(R.sub.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R- .sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9) or --SO.sub.2--NH.sub.2 when
attached to a nitrogen atom; and, wherein R.sub.8 is one to four
substituents independently selected from hydrogen,
--C.sub.4alkyl(R.sub.9), --C.sub.1-4alkoxy(R.sub.9),
--O-aryl(R.sub.10), --C(.dbd.O)H, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl(R.su- b.9),
--C(.dbd.O)--N(C.sub.1-4alkyl(R.sub.9)).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl(R.sub.9), --SO.sub.2--NH.sub.2,
--NH.sub.2, --NH--C.sub.1-4alkyl(R.sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, cyano, halo, hydroxy, nitro or
oxo when attached to a carbon atom;
[0420] R.sub.9 is hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, --C(.dbd.O)H,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, cyano, (halo).sub.1-3,
hydroxy, nitro or oxo;
[0421] R.sub.10 is one to four substituents independently selected
from hydrogen, --C.sub.1-4alkyl, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-4alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl or
--SO.sub.2--N(C.sub.1-4alkyl).sub.2 when attached to a nitrogen
atom; and, wherein R.sub.10 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH--C.sub.1-4alkyl,
--C(.dbd.O)--N(C.sub.1-4alkyl).sub.2, --CO.sub.2H,
--CO.sub.2--C.sub.1-4alkyl, --SO.sub.2--C.sub.1-4alkyl,
--SO.sub.2--NH.sub.2, --SO.sub.2--NH--C.sub.1-4alkyl,
--SO.sub.2--N(C.sub.1-4alkyl).sub.2, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, cyano, halo,
hydroxy, nitro or oxo when attached to a carbon atom;
[0422] R.sub.2a is -cycloalkyl(R.sub.8)(R.sub.11),
-heterocyclyl(R.sub.8)(- R.sub.12), -aryl(R.sub.8)(R.sub.12) or
-heteroaryl(R.sub.8)(R.sub.12);
[0423] q is 1, 2 or 3.
[0424] R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkyl(R.sub.1- 3),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.- sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13), --O--C(.dbd.O)OC.sub.1-8al-
kyl(R.sub.13), --O--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8- alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1- -8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13)- ,
--O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R-
.sub.13),
--C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R-
.sub.13),
--OC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C-
(.dbd.O) (R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).su-
b.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2C-
H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--SO.sub.2NHCH.sub.2CH.sub-
.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
[0425] R.sub.12 is selected from the group consisting of
[0426] --C.sub.1-6alkyl(R.sub.13), --O--C.sub.1-6alkyl(R.sub.13),
--NH--C.sub.1-4alkyl(R.sub.13), --S--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl(R.sub- .13),
-C.sub.12S--C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-6alkyl(R.su- b.13),
--O--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alk- yl(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-6alk- yl(R.sub.13),
--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-6alkyl(R- .sub.13),
--NH--C(.dbd.O)OC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC- (.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13- ),
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2O--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--CH.sub.2NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13)-
,
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2-
(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.-
2(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2CH.sub.2(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2CH.sub.2CH.sub.2O(CH.sub.2CH.s-
ub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--SO.sub.2NHCH.sub.2CH.sub.2O(CH.s-
ub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.-
2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.su-
b.2C(.dbd.O)(R.sub.13),
--OC(.dbd.O)NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O)-
.sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2H.sub.2O-
).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub-
.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NHC(.dbd.O)NHCH.sub.2CH.s-
ub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--CH.sub.2C(.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.-
sub.13),
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(-
.dbd.O)(R.sub.13),
--CH.sub.2NHC(.dbd.O)OCH.sub.2CH.sub.2O(CH.sub.2CH.sub.-
2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13), and
--CH.sub.2NHC(.dbd.O)NHCH.sub.2C-
H.sub.2O(CH.sub.2H.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13);
[0427] wherein when R.sub.11 or R.sub.12 terminates with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
33
[0428] and when R.sub.11 or R.sub.12 does not terminate with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
3435
[0429] said --O--(CH.sub.2CH.sub.2O--).sub.p-- or 36
[0430] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer ranging in molecular weight from 750 to 5000 daltons;
[0431] r is an integer from 0 to 8.
[0432] Q and Q.sup.1 of substituents R.sub.12 and R.sub.13 are the
same within a given compound and are selected from the group
consisting of
[0433] the C.sub.11 saturated chain of lauric acid,
[0434] the C.sub.15 saturated chain of palmitoic acid,
[0435] the C.sub.17 saturated chain of stearoic acid,
[0436] the C.sub.17 mono-unsaturated chain of oleoic acid, and
[0437] the C.sub.17 di-unsaturated chain of linoleic acid;
[0438] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
[0439] Aspects of the present invention include compounds of
Formula (I) and Formula (II) wherein:
[0440] W is preferably --C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-aryl(R.sub.1,R.sub.8);
[0441] R.sub.1 is --N(R.sub.4)(R.sub.6),
-dihydro-1H-pyrrolo[2,3-b]pyridin- yl(R.sub.8),
-tetrahydropyrimidinyl(R.sub.8), -tetrahydro-1,8-naphthyridin-
yl(R.sub.8), -tetrahydro-1H-azepino[2,3-b]pyridinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0442] R.sub.1a is --C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(- R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
[0443] R.sub.4 is hydrogen or --C.sub.1-4alkyl(R.sub.7);
[0444] R.sub.5 is --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --C(.dbd.O)-cycloalkyl(R.sub.9),
--C(.dbd.O)-heterocyclyl(R.sub.8), --C(.dbd.O)-aryl(R.sub.8),
--C(.dbd.O)-heteroaryl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-cycloalkyl(R.sub.8),
--C(.dbd.O)--N(R.sub.4)-aryl- (R.sub.8), --CO.sub.2--R.sub.4,
--CO.sub.2-cycloalkyl(R.sub.8), --CO.sub.2-aryl(R.sub.8),
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2,
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.- 4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6- ),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.sub.4).sub.2-
, --N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.-
sub.7),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4)-
.sub.2, --SO.sub.2--C.sub.1-4alkyl(R.sub.7),
--SO.sub.2--N(R.sub.4).sub.2, --SO.sub.2-cycloalkyl(R.sub.8) or
--SO.sub.2-aryl(R.sub.8).
[0445] R.sub.6 is -heterocyclyl(R.sub.8) or
-heteroaryl(R.sub.8);
[0446] R.sub.7 is one to two substituents independently selected
from hydrogen, --C.sub.1-4alkoxy(R.sub.9), --NH.sub.2,
--NH--C.sub.1-4alkyl(R.- sub.9),
--N(C.sub.1-4alkyl(R.sub.9)).sub.2, (halo).sub.1-3, hydroxy or
oxo;
[0447] R.sub.8 is one to four substituents independently selected
from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.8 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9), --O-aryl(R.sub.10), --NH.sub.2,
--NH--C.sub.4alkyl(R.sub.9), --N(C.sub.1-4alkyl(R.sub.9)).sub.2,
halo, hydroxy or oxo when attached to a carbon atom;
[0448] R.sub.9 is hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, --C(.dbd.O)H,
--CO.sub.2H, --C(.dbd.O)--C.sub.1-4alkoxy, (halo).sub.13, hydroxy
or oxo; (R.sub.10).sub.14 is hydrogen, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4alkyl,
--CO.sub.2H, --CO.sub.2--C.sub.1-4alkyl, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, halo, hydroxy,
nitro or oxo when attached to a carbon atom;
[0449] R.sub.2a is -cycloalkyl(R.sub.7)(R.sub.11),
-heterocyclyl(R.sub.8)(- R.sub.12), -phenyl(R.sub.8)(R.sub.12),
-naphthalenyl (R.sub.8)(R.sub.12) or
-heteroaryl(R.sub.8)(R.sub.12);
[0450] q is 1, 2 or 3;
[0451] R.sub.11 is selected from the group consisting of
--C.sub.1-8alkyl(R.sub.13), --O--C.sub.1-8alkyl(R.sub.13),
--NH--C.sub.1-8alkyl(R.sub.13), --S--C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--O--C(=.degree.)C.sub.1-8alkyl (R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkyl(R.sub.1- 3),
--O--C(.dbd.O)OC.sub.1-8alkyl(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8alky- l(R.sub.13),
--O--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)C.sub.1-8alk- ylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--NH--C(.dbd.O)OC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.sub.13),
--O--C(.dbd.O)NHC.sub.1-8- alkylC(.dbd.O)(R.sub.13), and
--NH--C(.dbd.O)NHC.sub.1-8alkylC(.dbd.O)(R.s- ub.13).
[0452] R.sub.12 is selected from the group consisting of
[0453] --CH.sub.2O--C.sub.1-6alkyl(R.sub.13),
--CH.sub.2NH--C.sub.1-6alkyl- (R.sub.13),
--CH.sub.2S--C.sub.1-6alkyl (R.sub.13),
--NH--C(.dbd.O)C.sub.1-8alkyl(R.sub.13),
--CH.sub.2NH--C(.dbd.O)C.sub.1-6- alkyl(R.sub.13),
--NH--C(.dbd.O)NHC.sub.1-6alkyl(R.sub.13),
--NH--C(.dbd.O)C.sub.1-6alkylC(.dbd.O)(R.sub.13),
--OCH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--NHCH.sub.2CH.sub.2O(CH-
.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--OCH.sub.2CH.sub.2O(CH.-
sub.2CH.sub.2O).sub.rCH.sub.2C(.dbd.O)(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(C-
H.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2OCH.sub.2CH.s- ub.2O(CH.sub.2CH.sub.2
0).sub.rCH.sub.2CH.sub.2(R.sub.13),
--CH.sub.2NHCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2(R.-
sub.13),
--CH.sub.2SCH.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.s-
ub.2(R.sub.13),
--NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).sub.rCH.sub.2C(.-
dbd.O)(R.sub.13), and
--CH.sub.2NH(C.dbd.O)CH.sub.2O(CH.sub.2CH.sub.2O).su-
b.rCH.sub.2C(.dbd.O)(R.sub.13);
[0454] wherein when R.sub.11 or R.sub.12 terminates with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
37
[0455] and when R.sub.11 or R.sub.12 does not terminate with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
3839
[0456] wherein said --O--(CH.sub.2CH.sub.2O--).sub.p-- or 40
[0457] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer ranging in molecular weight from 2000 to 5000 daltons.
[0458] r is an integer from 0 to 8.
[0459] Q and Q.sup.1 of substituents R.sub.12 and R.sub.13 are the
same within a given compound and are selected from the group
consisting of
[0460] the C.sub.15 saturated chain of palmitoic acid,
[0461] the C.sub.17 saturated chain of stearoic acid, and
[0462] the C.sub.17 mono-unsaturated chain of oleoic acid.
[0463] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl, --O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkylamide
--O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)--N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
[0464] Another aspect of the present invention includes compounds
of Formula (I) and Formula (II) wherein:
[0465] W is preferably --C.sub.0-4alkyl(R.sub.1) or
--C.sub.0-4alkyl-phenyl(R.sub.1,R.sub.8);
[0466] R.sub.1 is --N(R.sub.4)(R.sub.6),
-tetrahydropyrimidinyl(R.sub.8) or
-tetrahydro-1,8-naphthyridinyl(R.sub.8); R.sub.1a is
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--C(.dbd.N--R.sub.4)--N(R.sub.- 4)--C(.dbd.O)--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--C(.dbd.O)--N(R.s- ub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--CO.sub.2--R.sub.4,
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--C.sub.1-4alkyl(R.sub.7)
or
--C(.dbd.N--R.sub.4)--N(R.sub.4)--SO.sub.2--N(R.sub.4).sub.2;
[0467] R.sub.4 is hydrogen;
[0468] R.sub.5 is --C(.dbd.O)--R.sub.4,
--C(.dbd.O)--N(R.sub.4).sub.2, --CO.sub.2--R.sub.4,
--C(R.sub.4)(.dbd.N--R.sub.4),
--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--C(.dbd.N--R.sub.4)--N(R.sub.4)(- R.sub.6),
--N(R.sub.4)--C(R.sub.4)(.dbd.N--R.sub.4),
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4).sub.2,
--N(R.sub.4)--C(.dbd.N--R.sub.4)--N(R.sub.4)(R.sub.6),
--SO.sub.2--C.sub.1-4alkyl(R.sub.7) or
--SO.sub.2--N(R.sub.4).sub.2;
[0469] R.sub.6 is -dihydroimidazolyl(R.sub.8),
-tetrahydropyridinyl(R.sub.- 8), -tetrahydropyrimidinyl(R.sub.8) or
-pyridinyl(R.sub.8);
[0470] R.sub.7 is hydrogen;
[0471] R.sub.8 is one to four substituents independently selected
from hydrogen or --C.sub.1-4alkyl(R.sub.9) when attached to a
nitrogen atom; and, wherein R.sub.8 is one to four substituents
independently selected from hydrogen, --C.sub.1-4alkyl(R.sub.9),
--C.sub.1-4alkoxy(R.sub.9)--O-a- ryl(R.sub.10) or hydroxy when
attached to a carbon atom;
[0472] R.sub.9 is hydrogen, --C.sub.1-4alkoxy, --NH.sub.2,
--NH--C.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, (halo).sub.1-3 or
hydroxy;
[0473] R.sub.10 is hydrogen;
[0474] R.sub.2a is -tetrahydropyrimidinyl(R.sub.8)(R).sub.2),
-1,3-benzodioxolyl(R.sub.8)(R.sub.12),
-dihydrobenzofuranyl(R.sub.8)(R.su- b.12),
-tetrahydroquinolinyl(R.sub.8)(R.sub.12),
-phenyl(R.sub.8)(R.sub.12- ), -naphthalenyl(R.sub.8)(R.sub.12),
-pyridinyl(R.sub.8)(R.sub.12), -pyrimidinyl(R.sub.8)(R.sub.12) or
-quinolinyl(R.sub.8)(R.sub.12);
[0475] q is 1 or 2;
[0476] R.sub.12 is selected from the group consisting of
[0477] --CH.sub.2--O--(CH.sub.2).sub.4(R.sub.13)--,
[0478] --CH.sub.2--NH--(CH.sub.2).sub.4(R.sub.13)--,
[0479] --CH.sub.2--S--(CH.sub.2).sub.4(R.sub.13)--,
[0480] --CH.sub.2--O--(CH.sub.2).sub.6(R.sub.13)--,
[0481] --CH.sub.2--NH--(CH.sub.2).sub.6(R.sub.13)--,
[0482] --CH.sub.2--S--(CH.sub.2).sub.6(R.sub.13)--,
[0483] --NH--C(.dbd.O)--(CH.sub.2).sub.4(R.sub.13)--,
[0484] --NH--C(.dbd.O)--(CH.sub.2).sub.7(R.sub.13)--,
[0485] --NH--C(.dbd.O)NH--(CH.sub.2).sub.3(R.sub.13)--,
[0486] --NH--C(.dbd.O)NH--(CH.sub.2).sub.6(R.sub.13)--,
[0487] --CH.sub.2NH--C(.dbd.O)NH--(CH.sub.2).sub.2(R.sub.13)--,
[0488] --CH.sub.2NH--C(.dbd.O)NH--(CH.sub.2).sub.5(R.sub.13)--,
[0489] --NHC(.dbd.O)--(CH.sub.2).sub.2--C(.dbd.(O)(R.sub.13)--,
[0490] --NHC(.dbd.O)--(CH.sub.2).sub.3--C(.dbd.O)(R.sub.13)--,
[0491] --NHC(.dbd.O)--(CH.sub.2).sub.4--C(.dbd.O)(R.sub.13)--,
[0492] --OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0493] --NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0494]
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0495]
--NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0496] --OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
[0497]
--OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
[0498] --NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0499] --NHC(.dbd.O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2
(R.sub.13)--,
[0500]
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0501]
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0502]
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub.13)--,
[0503]
--CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub-
.13)--,
[0504]
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.su-
b.13)--,
[0505]
--CH.sub.2SCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2(R.sub-
.13)--,
[0506] --CH.sub.2NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--,
and
[0507] --NHC(.dbd.O)CH.sub.2OCH.sub.2C(.dbd.O)(R.sub.13)--;
[0508] wherein when R.sub.11 or R.sub.12 terminates with a
--C(.dbd.O)--, R.sub.13 is selected from the group consisting of
41
[0509] and when R.sub.11 or R.sub.12 does not terminate with a
C(.dbd.O)--, R.sub.13 is selected from the group consisting of
42
[0510] wherein said --O--(CH.sub.2CH.sub.2O--).sub.p-- or 43
[0511] of R.sub.12 and R.sub.13 is a polyethylene glycol (PEG)
polymer selected from 2000 (PEG 2000), 3400 (PEG 3400), or 5000
(PEG 5000) Daltons;
[0512] r is an integer from 0 to 8;
[0513] Q and Q.sup.1 of substituents R.sub.12 and R.sub.13 are the
same within a given compound and is the C.sub.17 saturated chain of
stearoic acid;
[0514] Z is selected from the group consisting of hydroxy,
--NH.sub.2, --NH--C.sub.1-8alkyl, --N(C.sub.1-8alkyl).sub.2,
--O--C.sub.1-8alkyl, --O--C.sub.1-8alkyl-OH,
--O--C.sub.1-8alkylC.sub.1-4alkoxy,
--O--C.sub.1-8alkylcarbonylC.sub.1-4alkyl,
--O--C.sub.1-8alkyl-CO.sub.2H,
--O--C.sub.1-8alkyl-C(O)O--C.sub.1-6alkyl,
--O--C.sub.1-8alkyl-O--C(O)C.s- ub.1-8alkyl,
--O--C.sub.1-8alkyl-NH.sub.2, --O--C.sub.1-8alkyl-NH--C.sub.1-
-8alkyl,
--O--C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2--O--C.sub.1-8alkylami-
de --O--C.sub.1-8alkyl-C(O)--NH--C.sub.1-8alkyl,
--O--C.sub.1-8alkyl-C(O)-- -N(C.sub.1-8alkyl).sub.2 and
--NHC(O)C.sub.1-8alkyl.
[0515] 3. Liposomes
[0516] In a further aspect of the present invention is providing
targeted liposomes.
[0517] Another aspect of the present invention includes a
therapeutic liposome composition sensitized to a target cell,
comprising
[0518] (i) a liposomal composition composed of pre-formed liposomes
having an entrapped therapeutic agent; and
[0519] (ii) a plurality of conjugates, each conjugate composed
of
[0520] (a) a lipid having a polar head group and a hydrophobic
tail, (b) a hydrophilic polymer having a proximal end and a distal
end, where the polymer is attached at its proximal end to the head
group of the lipid, and (c) a targeting ligand attached to the
distal end of the polymer. The therapeutic, target-cell sensitized
liposome composition is formed by combining the liposomal
composition with a conjugate selected from the plurality of
conjugates.
[0521] Targeted liposomes, when administered systemically, are
useful for carrying therapeutic agents to target cells. An
advantage of targeted liposomes is that they may be directed to a
specific region of diseased cells while avoiding exposure of normal
tissues to the chemotherapeutic agent. In particular, stable long
circulating liposomes (LCLs) are formulated with a coat of
flexible, water soluble polymeric chains which prevent the uptake
of the liposomes by the mononuclear phagocyte system, particularly
the liver and spleen. Often an extended lifetime is necessary in
order for the liposomes to reach their desired target region or
cell from the site of injection.
[0522] To date, applications of targeted liposomes include the
following: long-circulating, polyethylene glycol-grafted
immunoliposomes (Allen, T. M. et al. Journal of Controlled Release,
91, (2003) 115-122); RGD-peptides coupled to the distal end of
poly(ethylene glycol)-coated long-circulating liposomes (Storm, et
al. Journal of Controlled Release, 39, (1996) 153-161).
[0523] Efforts have focused on ways to achieve site specific
delivery of long-circulating liposomes. In one approach, targeting
ligands, such as are described herein, are attached to the
liposomes' surfaces. This approach, where the targeting ligand is
bound to the polar head group residues of liposomal lipid
components, results in interference by the surface-grafted polymer
chains, inhibiting the interaction between the bound ligand and its
intended target (Klibanov, A. L., et al., Biochim. Biophys. Acta.,
1062:142-148 (1991); Hansen, C. B., et al., Biochim. Biophys. Acta,
1239:133-144 (1995)).
[0524] In another approach, the targeting ligand is attached to the
free ends of the polymer chains forming the surface coat on the
liposomes (Allen. T. M., et al., Biochim. Biophys. Acta,
1237:99-108 (1995); Blume, G. et al., Biochim. Biophys. Acta,
1149:180-184 (1993)). Two approaches have been described for
preparing a liposome having a targeting ligand attached to the
distal end of the surface polymer chains. One approach involves
preparation of lipid vesicles which include an end-functionalized
lipid-polymer derivative; that is, a lipid-polymer conjugate where
the free polymer end is reactive or "activated". Such an activated
conjugate is included in the liposome composition and the activated
polymer ends are reacted with a targeting ligand after liposome
formation. The disadvantage to this approach is the difficulty in
reacting all of the activated ends with a ligand. The approach also
requires a subsequent step for separation of the unreacted ligand
from the liposome composition.
[0525] In another approach, the lipid-polymer-ligand conjugate is
included in the lipid composition at the time of liposome
formation. This approach has the disadvantage that some of the
valuable ligand faces the inner aqueous compartment of the liposome
and is unavailable for interaction with the intended target.
[0526] 3.A Liposome Definitions and Nomenclature
[0527] Unless otherwise noted, the term "incubating" refers to
conditions of time, temperature and liposome lipid composition
which allow for penetration and entry of a selected component, such
as a lipid or lipid conjugate, into the lipid bilayer of a
liposome.
[0528] Unless otherwise noted, the term "pre-formed liposomes"
refers to intact, previously formed unilamellar or multilamellar
lipid vesicles.
[0529] Unless otherwise noted, the term "sensitized to a cell" or
"target-cell sensitized" refers to a liposome which includes a
ligand or affinity moiety covalently bound to the liposome and
having binding affinity for a receptor expressed on a particular
cell.
[0530] Unless otherwise noted, the term "therapeutic liposome
composition" refers to liposomes which include a therapeutic agent
entrapped in the aqueous spaces of the liposomes or in the lipid
bilayers of the liposomes.
[0531] Unless otherwise noted, the term "vesicle-forming lipid"
refers to any lipid capable of forming part of a stable micelle or
liposome composition and typically including one or two
hydrophobic, hydrocarbon chains or a steroid group and may contain
a chemically reactive group, such as an amine, acid, ester,
aldehyde or alcohol, at its polar head group.
[0532] 3.B Targeted Liposomes
[0533] Liposomes are spherical vesicles comprised of concentrically
ordered lipid bilayers that encapsulate an aqueous phase. Liposomes
serve as a delivery vehicle for therapeutic agents contained in the
aqueous phase or in the lipid bilayers. Delivery of drugs in
liposome-entrapped form can provide a variety of advantages,
depending on the drug, including, for example, a decreased drug
toxicity, altered pharmacokinetics, or improved drug solubility.
Liposomes when formulated to include a surface coating of
hydrophilic polymer chains, so-called Stealth.RTM. or
long-circulating liposomes, offer the further advantage of a long
blood circulation lifetime, due in part to reduced removal of the
liposomes by the mononuclear phagocyte system. Often an extended
lifetime is necessary in order for the liposomes to reach their
desired target region or cell from the site of injection.
[0534] Targeted liposomes, also referred to as immunoliposomes,
have targeting ligands or affinity moieties attached to the surface
of the liposomes. When administered systemically targeted liposomes
are delivery the entrapped therapeutic agent to a target tissue,
region or, cell. Because targeted liposomes are directed to a
specific region or cell, healthy tissue is not exposed to the
therapeutic agent. Such targeting ligands can be attached directly
to the liposomes' surfaces by covalent coupling of the targeting
ligand to the polar head group residues of liposomal lipid
components (see, for example, U.S. Pat. No. 5,013,556). This
approach, however, is suitable primarily for liposomes that lack
surface-bound polymer chains, as the polymer chains interfere with
interaction between the targeting ligand and its intended target
(Klibanov, A. L., et al., Biochim. Biophys. Acta., 1062:142-148
(1991); Hansen, C. B., et al., Biochim. Biophys. Acta, 1239:133-144
(1995)).
[0535] Alternatively, the targeting ligands can be attached to the
free ends of the polymer chains forming the surface coat on the
liposomes (Allen. T. M., et al., Biochim. Biophys. Acta,
1237:99-108 (1995); Blume, G. et al., Biochim. Biophys. Acta,
1149:180-184 (1993)). In this approach, the targeting ligand is
exposed and readily available for interaction with the intended
target.
[0536] Accordingly, in another aspect, the invention includes a
liposome composition comprised of liposomes that include a
piperidinoyl carboxylic acid compound as a targeting ligand. The
piperidinoyl carboxylic acid compound is incorporated into the
liposomes in the form of a lipid-polymer-compound conjugate, also
referred to herein as a lipid-polymer-ligand conjugate. As noted
above, the piperidinoyl carboxylic acid compounds act as
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5, and/or
.alpha..sub.v.beta..sub.6 integrin receptor antagonists and target
the liposomes to cells that express one or more of these receptors.
The following sections describe the liposome components, including
the liposome lipids and therapeutic agents, preparation of
liposomes bearing a targeting ligand, and methods of using the
liposomal composition for treatment of disorders characterized by
cellular expression of .alpha..sub.v.beta..sub.3,
.alpha..sub.v.beta..sub- .5, and/or .alpha..sub.v.beta..sub.6
integrin receptors.
[0537] 3.C. Liposome Lipid Components
[0538] Liposomes suitable for use in the composition of the present
invention include those composed primarily of vesicle-forming
lipids. Such a vesicle-forming lipid is one which can form
spontaneously into bilayer vesicles in water, as exemplified by the
phospholipids, with its hydrophobic moiety in contact with the
interior, hydrophobic region of the bilayer membrane, and its head
group moiety oriented toward the exterior, polar surface of the
membrane. Lipids capable of stable incorporation into lipid
bilayers, such as cholesterol and its various analoges, can also be
used in the liposomes.
[0539] The vesicle-forming lipids are preferably lipids having two
hydrocarbon chains, typically acyl chains, and a head group, either
polar or nonpolar. There are a variety of synthetic vesicle-forming
lipids and naturally-occurring vesicle-forming lipids, including
the phospholipids, such as phosphatidylcholine,
phosphatidylethanolamine, phosphatidic acid, phosphatidylinositol,
and sphingomyelin, where the two hydrocarbon chains are typically
between about 14-22 carbon atoms in length, and have varying
degrees of unsaturation. The above-described lipids and
phospholipids whose acyl chains have varying degrees of saturation
can be obtained commercially or prepared according to published
methods. Other suitable lipids include glycolipids, cerebrosides
and sterols, such as cholesterol.
[0540] Cationic lipids are also suitable for use in the liposomes
of the invention, where the cationic lipid can be included as a
minor component of the lipid composition or as a major or sole
component. Such cationic lipids typically have a lipophilic moiety,
such as a sterol, an acyl or diacyl chain, and where the lipid has
an overall net positive charge. Preferably, the head group of the
lipid carries the positive charge. Exemplary cationic lipids
include 1,2-dioleyloxy-3-(trimethylamino) propane (DOTAP);
N-[1-(2,3,-ditetradecyloxy)propyl]-N,N-dimethyl-N-hydrox-
yethylammonium bromide (DMRWE);
N-[1-(2,3,-dioleyloxy)propyl]-N,N-dimethyl- -N-hydroxy
ethylammonium bromide (DORIE); N-[1-(2,3-dioleyloxy)
propyl]-N,N,N-trimethylammonium chloride (DOTMA); 3
[N--(N',N'-dimethylaminoethane) carbamoly] cholesterol (DC-Chol);
and dimethyldioctadecylammonium (DDAB). The cationic
vesicle-forming lipid may also be a neutral lipid, such as
dioleoylphosphatidyl ethanolamine (DOPE) or an amphipathic lipid,
such as a phospholipid, derivatized with a cationic lipid, such as
polylysine or other polyamine lipids. For example, the neutral
lipid (DOPE) can be derivatized with polylysine to form a cationic
lipid.
[0541] The vesicle-forming lipid can be selected to achieve a
specified degree of fluidity or rigidity, to control the stability
of the liposome in serum, to control the conditions effective for
insertion of the targeting conjugate, as will be described, and/or
to control the rate of release of the entrapped agent in the
liposome. Liposomes having a more rigid lipid bilayer, or a liquid
crystalline bilayer, are achieved by incorporation of a relatively
rigid lipid, e.g., a lipid having a relatively high phase
transition temperature, e.g., up to 60.degree. C. Rigid, i.e.,
saturated, lipids contribute to greater membrane rigidity in the
lipid bilayer. Other lipid components, such as cholesterol, are
also known to contribute to membrane rigidity in lipid bilayer
structures.
[0542] On the other hand, lipid fluidity is achieved by
incorporation of a relatively fluid lipid, typically one having a
lipid phase with a relatively low liquid to liquid-crystalline
phase transition temperature, e.g., at or below room
temperature.
[0543] The liposomes also include a vesicle-forming lipid
derivatized with a hydrophilic polymer. As has been described, for
example in U.S. Pat. No. 5,013,556, including such a derivatized
lipid in the liposome composition forms a surface coating of
hydrophilic polymer chains around the liposome. The surface coating
of hydrophilic polymer chains is effective to increase the in vivo
blood circulation lifetime of the liposomes when compared to
liposomes lacking such a coating.
[0544] Vesicle-forming lipids suitable for derivatization with a
hydrophilic polymer include any of those lipids listed above, and,
in particular phospholipids, such as distearoyl
phosphatidylethanolamine (DSPE).
[0545] Hydrophilic polymers suitable for derivatization with a
vesicle-forming lipid include polyvinylpyrrolidone,
polyvinylmethylether, polymethyloxazoline, polyethyloxazoline,
polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide,
polymethacrylamide, polydimethylacrylamide,
polyhydroxypropylmethacrylate, polyhydroxyethylacrylate,
hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol,
polyaspartamide and hydrophilic peptide sequences. The polymers may
be employed as homopolymers or as block or random copolymers.
[0546] A preferred hydrophilic polymer chain is polyethyleneglycol
(PEG), preferably as a PEG chain having a molecular weight between
500-10,000 daltons, more preferably between 750-10,000 daltons,
still more preferably between 750-5000 daltons. Methoxy or
ethoxy-capped analogues of PEG are also preferred hydrophilic
polymers, commercially available in a variety of polymer sizes,
e.g., 120-20,000 daltons.
[0547] Preparation of vesicle-forming lipids derivatized with
hydrophilic polymers has been described, for example in U.S. Pat.
No. 5,395,619. Preparation of liposomes including such derivatized
lipids has also been described, where typically between 1-20 mole
percent of such a derivatized lipid is included in the liposome
formulation (see, for example, U.S. Pat. No. 5,013,556).
[0548] 3.D. Liposome Preparation
[0549] Various approaches have been described for preparing
liposomes having a targeting ligand attached to the distal end of
liposome-attached polymer chains. One approach involves preparation
of lipid vesicles which include an end-functionalized lipid-polymer
derivative; that is, a lipid-polymer conjugate where the free
polymer end is reactive or "activated" (see, for example, U.S. Pat.
Nos. 6,326,353 and 6,132,763). Such an activated conjugate is
included in the liposome composition and the activated polymer ends
are reacted with a targeting ligand after liposome formation. In
another approach, the lipid-polymer-ligand conjugate is included in
the lipid composition at the time of liposome formation (see, for
example, U.S. Pat. Nos. 6,224,903, 5,620,689). In yet another
approach, a micellar solution of the lipid-polymer-ligand conjugate
is incubated with a suspension of liposomes and the
lipid-polymer-ligand conjugate is inserted into the pre-formed
liposomes (see, for example, U.S. Pat. Nos. 6,056,973,
6,316,024).
[0550] Liposomes carrying an entrapped agent and bearing
surface-bound targeting ligands, i.e., targeted, therapeutic
liposomes, are prepared by any of these approaches. A preferred
method of preparation is the insertion method, where pre-formed
liposomes and are incubated with the targeting conjugate to achieve
insertion of the targeting conjugate into the liposomal bilayers.
In this approach, liposomes are prepared by a variety of
techniques, such as those detailed in Szoka, F., Jr., et al., Ann.
Rev. Biophys. Bioeng., 9:467 (1980), and specific examples of
liposomes prepared in support of the present invention will be
described below. Typically, the liposomes are multilamellar
vesicles (MLVs), which can be formed by simple lipid-film hydration
techniques. In this procedure, a mixture of liposome-forming lipids
of the type detailed above dissolved in a suitable organic solvent
is evaporated in a vessel to form a thin film, which is then
covered by an aqueous medium. The lipid film hydrates to form MLVs,
typically with sizes between about 0.1 to 10 microns.
[0551] The liposomes can include a vesicle-forming lipid
derivatized with a hydrophilic polymer to form a surface coating of
hydrophilic polymer chains on the liposomes surface. Addition of a
lipid-polymer conjugate is optional, since after the insertion
step, described below, the liposomes will include
lipid-polymer-targeting ligand. Additional polymer chains added to
the lipid mixture at the time of liposome formation and in the form
of a lipid-polymer conjugate result in polymer chains extending
from both the inner and outer surfaces of the liposomal lipid
bilayers. Addition of a lipid-polymer conjugate at the time of
liposome formation is typically achieved by including between 1-20
mole percent of the polymer-derivatized lipid with the remaining
liposome forming components, e.g., vesicle-forming lipids.
Exemplary methods of preparing polymer-derivatized lipids and of
forming polymer-coated liposomes have been described in U.S. Pat.
Nos. 5,013,556, 5,631,018 and 5,395,619, which are incorporated
herein by reference. It will be appreciated that the hydrophilic
polymer may be stably coupled to the lipid, or coupled through an
unstable linkage, which allows the coated liposomes to shed the
coating of polymer chains as they circulate in the bloodstream or
in response to a stimulus.
[0552] The liposomes also include a therapeutic or diagnostic
agent, and exemplary agents are provided below. The selected agent
is incorporated into liposomes by standard methods, including (i)
passive entrapment of a water-soluble compound by hydrating a lipid
film with an aqueous solution of the agent, (ii) passive entrapment
of a lipophilic compound by hydrating a lipid film containing the
agent, and (iii) loading an ionizable drug against an
inside/outside liposome pH gradient. Other methods, such as
reverse-phase evaporation, are also suitable.
[0553] After liposome formation, the liposomes can be sized to
obtain a population of liposomes having a substantially homogeneous
size range, typically between about 0.01 to 0.5 microns, more
preferably between 0.03-0.40 microns. One effective sizing method
for REVs and MLVs involves extruding an aqueous suspension of the
liposomes through a series of polycarbonate membranes having a
selected uniform pore size in the range of 0.03 to 0.2 micron,
typically 0.05, 0.08, 0.1, or 0.2 microns. The pore size of the
membrane corresponds roughly to the largest sizes of liposomes
produced by extrusion through that membrane, particularly where the
preparation is extruded two or more times through the same
membrane. Homogenization methods are also useful for down-sizing
liposomes to sizes of 100 nm or less (Martin, F. J., in SPECIALIZED
DRUG DELIVERY SYSTEMS--MANUFACTURING AND PRODUCTION TECHNOLOGY, P.
Tyle, Ed., Marcel Dekker, New York, pp. 267-316 (1990)).
[0554] After formation of the liposomes, a targeting ligand is
incorporated to achieve a target-cell sensitized, therapeutic
liposome. The targeting ligand is incorporated by incubating the
pre-formed liposomes with the lipid-polymer-ligand conjugate,
prepared as described above. The pre-formed liposomes and the
conjugate are incubated under conditions effective to achieve
insertion of the conjugate into the liposome bilayer. More
specifically, the two components are incubated together under
conditions which achieve insertion of the conjugate in such a way
that the targeting ligand is oriented outwardly from the liposome
surface, and therefore available for interaction with its cognate
receptor. It will be appreciated that the conditions effective to
achieve insertion of the targeting conjugate into the liposome are
determined based on several variables, including, the desired rate
of insertion, where a higher incubation temperature may achieve a
faster rate of insertion, the temperature to which the ligand can
be safely heated without affecting its activity, and to a lesser
degree the phase transition temperature of the lipids and the lipid
composition. It will also be appreciated that insertion can be
varied by the presence of solvents, such as amphipathic solvents
including polyethyleneglycol and ethanol, or detergents.
[0555] The targeting conjugate, in the form of a
lipid-polymer-ligand conjugate, will typically form a solution of
micelles when the conjugate is mixed with an aqueous solvent. The
micellar solution of the conjugates is mixed with a suspension of
pre-formed liposomes for insertion of the conjugate into the
liposomal lipid bilayers. The invention includes, in another
aspect, a plurality of targeting conjugates, such as a micellar
solution of targeting conjugates, for use in preparing a targeted,
therapeutic liposome composition. Each conjugate is composed of (i)
a lipid having a polar head group and a hydrophobic tail, (ii) a
hydrophilic polymer having a proximal end and a distal end, where
the polymer is attached at its proximal end to the head group of
the lipid, and (iii) a targeting ligand attached to the distal end
of the polymer.
[0556] The invention also contemplates a method of formulating a
therapeutic liposome composition having sensitivity to a target
cell. The method includes the steps of (i) providing a liposome
formulation composed of pre-formed liposomes having an entrapped
therapeutic agent; (ii) providing a targeting conjugate composed of
(a) a lipid having a polar head group and a hydrophobic tail, (b) a
hydrophilic polymer having a proximal end and a distal end, where
the polymer is attached at its proximal end to the head group of
the lipid, and (c) a piperidinoyl carboxylic acid compound as a
targeting ligand attached to the distal end of the polymer; (iii)
combining the liposome formulation and the targeting conjugate to
form the therapeutic, target-cell sensitive liposome composition.
In one embodiment, combining includes incubating under conditions
effective to achieve insertion of the selected targeting conjugate
into the liposomes of the selected liposome formulation.
[0557] 3.E. Therapeutic Uses and Agents
[0558] The liposomes include a therapeutic or diagnostic agent in
entrapped form. Entrapped is intended to include encapsulation of
an agent in the aqueous core and aqueous spaces of liposomes as
well as entrapment of an agent in the lipid bilayer(s) of the
liposomes. Agents contemplated for use in the composition of the
invention are widely varied, and examples of agents suitable for
therapeutic and diagnostic applications are given below.
[0559] The targeting ligand included in the liposomes serve to
direct the liposomes to a region, tissue, or cell bearing
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5, and/or
.alpha..sub.v.beta..sub.6 integrin receptors. Targeting the
liposomes to such a region achieves site specific delivery of the
entrapped agent. Disease states having a strong
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5, and
.alpha.IIb.beta.3 (also referred to as GPIIb/IIIa) integrin
component in their etiologies include, but are not limited to,
unstable angina, thromboembolic disorders or atherosclerosis
(GPIIb/IIIa); thrombosis or restenosis (GPIIb/IIIa or
.alpha..sub.v.beta..sub.3); restenosis (dual
.alpha..sub.v.beta..sub.3/GPIIb/IIIa); rheumatoid arthritis,
vascular disorders or osteoporosis (.alpha..sub.v.beta..sub.3);
tumor angiogenesis, tumor metastasis, tumor growth, multiple
sclerosis, neurological disorders, asthma, vascular injury or
diabetic retinopathy (.alpha..sub.v.beta..sub.3 or
.alpha..sub.v.beta..sub.5); and, angiogenesis (dual
.alpha..sub.v.beta..sub.3/.alpha..sub.v.beta..sub.5).
[0560] Additionally, .alpha..sub.v.beta..sub.3 ligands have been
found to be useful in treating and/or inhibiting restenosis (i.e.
recurrence of stenosis after corrective surgery on the heart
valve), atherosclerosis, diabetic retinopathy, macular degeneration
and angiogenesis (i.e. formation of new blood vessels) and
inhibiting viral disease. Consequently the delivery of an
appropriate therapeutic agent to would be expected to enhance this
effect.
[0561] Moreover, the growth of tumors depends on an adequate blood
supply, which in turn is dependent on the growth of new vessels
into the tumor; thus, inhibition of angiogenesis can cause tumor
regression in animal models (Harrison's Principles of Internal
Medicine, 1991, 12.sup.th ed.). Therefore,
.alpha..sub.v.beta..sub.3 targeted liposome containing a
therapeutic agent, which inhibit angiogenesis can be useful in the
treatment of cancer by inhibiting tumor growth (Brooks et al.,
Cell, 79:1157-1164 (1994)). Evidence has also been presented
suggesting that angiogenesis is a central factor in the initiation
and persistence of arthritic disease and that the vascular integrin
.alpha..sub.v.beta..sub.- 3 may be a preferred target in
inflammatory arthritis. Therefore, .alpha..sub.v.beta..sub.3
targeted liposome that delivers an anti-angiogenesis or appropriate
therapeutic to treat arthritis may represent a novel therapeutic
approach to the treatment of arthritic disease, such as rheumatoid
arthritis (C. M. Storgard, et al., J. Clin. Invest., 103:47-54
(1999)).
[0562] Inhibition of the .alpha..sub.v.beta..sub.5 integrin
receptor can also prevent neovascularization. A monoclonal antibody
for .alpha..sub.v.beta..sub.5 has been shown to inhibit
VEGF-induced angiogenesis in rabbit cornea and the chick
chorioallantoic membrane model (M. C. Friedlander, et al., Science,
270:1500-1502 (1995)). Thus, .alpha..sub.v.beta..sub.5 targeted
liposomes containing an appropriate therapeutic agent would be
useful for treating and preventing macular degeneration, diabetic
retinopathy, cancer, and metastatic tumor growth.
[0563] Inhibition of .alpha.v integrin receptors can also prevent
angiogenesis and inflammation by acting as antagonists of other
.beta. subunits, such as .alpha.v.beta.6 and .alpha.v.beta.8 (Melpo
Christofidou-Solomidou, et al., American Journal of Pathology,
151:975-83 (1997); Xiao-Zhu Huang, et al., Journal of Cell Biology,
133:921-28 (1996)), again suggesting in disease states where
angiogenesis or inflammation is to be treated that a
.alpha..sub.v.beta..sub.6 targeted liposome containing an
appropriate therapeutic agent would provide a novel therapy.
[0564] An antagonist to the .alpha.v integrin can act to inhibit or
minimize adhesions that result from either wounding or surgical
adhesions. Post-surgical adhesions result as an anomaly of the
wound healing process. Cell adhesion and the migration of
fibroblasts are major players in this process. Trauma caused by the
wounding, a surgical procedure, normal tissue manipulation in
surgery, or bleeding during a surgical procedure can act to disrupt
the peritoneum and expose the underlying stroma leading to the
release of inflammatory mediators and an increase in capillary
permeability. Inflammatory cells are subsequently liberated and the
formation of a fibrin clot ensues. Adhesions are formed and
intensify as fibroblasts and inflammatory cells continue to
infiltrate this extracellular matrix rich in fibrin. The
extracellular matrix is composed of adhesive proteins which act as
ligands for the .alpha.v integrin. The .alpha.v integrin targeted
liposome containing an appropriate therapeutic agent can be
administered before, during or after a surgical procedure.
[0565] Therapeutic agents include natural and synthetic compounds
having the following therapeutic activities including but not
limited to, steroids, immunosuppressants, antihistamines,
non-steroidal anti-asthamtics, non-steroidal anti-inflammatory
agents, cyclooxygenase-2 inhibitors, cytotoxic agents, gene therapy
agents, radiotherapy agents, and imaging agents may be used in the
targeted liposomes.
[0566] Examples of these compounds include (a) steroids such as
beclomethasone, methylprednisolone, betamethasone, prednisone,
dexamethasone, and hydrocortisone; (b) immunosuppressants such as
FK-506 type immunosuppressants; (c) antihistamines (H1-histamine
antagonists) such as bromopheniramine, chlorpheniramine,
dexchlorpheniramine, triprolidine, clemastine, diphenhydraamine,
diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,
promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,
pheniramine pyrilamine, astemizole, terfenadine, loratadine,
cetirizine, fexofenadine, descarboethoxyloratadine, and the like;
(d) non-steroidal anti-asthmatics such as b2-agonists (terbutaline,
metaproterenol, fenoterol, isoetharine, albuterol, bitolterol,
salmeterol and pirbuterol), theophylline, cromolyn sodium,
atropine, ipratropium bromide, leukotriene antagonists
(zafirlukast, montelukast, pranlukast, iralukast, pobilukast,
SKB-106,203), leukotriene biosynthesis inhibitors (zileuton,
BAY-1005); (e) non-steroidal antiinflammatory agents (NSAIDs) such
as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic
acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,
ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,
pirprofen, pranoprofen, suprofen, tiaprofenic acid, and
tioxaprofen), acetic acid derivatives (indomethacin, acemetacin,
alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,
fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac,
tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid
derivatives (flufenamic acid, meclofenamic acid, mefenamic acid,
niflumic acid and tolfenamic acid), biphenylcarboxylic acid
derivatives (diflunisal and flufenisal), oxicams (isoxicam,
piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic
acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon,
feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (f)
cyclooxygenase-2 (C OX-2) inhibitors such as celecoxib, rofecoxib,
and parecoxib; (g) cholesterol lowering agents such as HMG-CoA
reductase inhibitors (lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, and other statins), sequestrants
(cholestyramine and colestipol), nicotinic acid, fenofibric acid
derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate),
and probucol; (h) anti-diabetic agents such as insulin,
sulfonylureas, biguanides (metformin), a-glucosidase inhibitors
(acarbose) and glitazones (troglitazone, pioglitazone, englitazone,
MCC-555, BRL49653 and the like); (1) agents that interfere with TNF
such as antibodies to TNF (REMICADE.RTM.) or soluble TNF receptor
(e.g. ENBREL.RTM.); (h) anticholinergic agents such as muscarinic
antagonists (ipratropium nad tiatropium); (i) antimetabolites such
as azathioprine and 6-mercaptopurine, and cytotoxic cancer
chemotherapeutic agents.
[0567] The entrapped therapeutic agent is, in one embodiment, a
cytotoxic drug. The drug can be an anthracycline antibiotic,
including but not limited to doxorubicin, daunorubicin, epirubicin,
and idarubicin, including salts and analogs thereof. The cytotoxic
agent can also be a platinum compound, such as cisplatin,
carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin,
lobaplatin, spiroplatin, ((-)--(R)-2-aminomethylpyrrolidine
(1,1-cyclobutane dicarboxylato)platinum),
(SP-4-3(R)-1,1-cyclobutane-dicarboxylato(2-)-(2--
methyl-1,4-butanediamine-N,N')platinum), nedaplatin and
(bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV)). The
cytotoxic agent can also be a topoisomerase 1 inhibitor, including
but not limited to topotecan, irinotecan,
(7-(4-methylpiperazino-methylene)-10,11-ethylen-
edioxy-20(S)-camptothecin),
7-(2-(N-isopropylamino)ethyl)-(20S)-camptothec- in,
9-aminocamptothecin and 9-nitrocamptothecin. The cytotoxic agent
can also be a vinca alkaloid such as vincristine, vinblastine,
vinleurosine, vinrodisine, vinorelbine, and vindesine. The
entrapped therapeutic agent can also be an angiogenesis inhibitor,
such as angiostatin, endostatin and TNF.alpha..
[0568] Nucleic acids are also contemplated for use as the
therapeutic agent. DNA and RNA based nucleic acids, including
fragments and analogues, can be used for treatment of various
conditions, and coding sequences for specific genes of interest can
be retrieved from DNA sequence databanks, such as GenBank or EMBL.
For example, polynucleotides for treatment of viral, malignant and
inflammatory diseases and conditions, such as, cystic fibrosis,
adenosine deaminase deficiency and AIDS, have been described.
Treatment of cancers by administration of tumor suppressor genes,
such as APC, DPC4, NF-1, NF-2, MTS1, RB, p53, WT1, BRCA1, BRCA2 and
VHL, are contemplated. Administration of the following nucleic
acids for treatment of the indicated conditions are also
contemplated: HLA-B7, tumors, colorectal carcinoma, melanoma; IL-2,
cancers, especially breast cancer, lung cancer, and tumors; IL-4,
cancer; TNF, cancer; IGF-1 antisense, brain tumors; IFN,
neuroblastoma; GM-CSF, renal cell carcinoma; MDR-1, cancer,
especially advanced cancer, breast and ovarian cancers; and HSV
thymidine kinase, brain tumors, head and neck tumors, mesothelioma,
ovarian cancer.
[0569] The polynucleotide can be an antisense DNA oligonucleotide
composed of sequences complementary to its target, usually a
messenger RNA (mRNA) or an mRNA precursor. The mRNA contains
genetic information in the functional, or sense, orientation and
binding of the antisense oligonucleotide inactivates the intended
mRNA and prevents its translation into protein. Such antisense
molecules are determined based on biochemical experiments showing
that proteins are translated from specific RNAs and once the
sequence of the RNA is known, an antisense molecule that will bind
to it through complementary Watson-Crick base pairs can be
designed. Such antisense molecules typically contain between 10-30
base pairs, more preferably between 10-25, and most preferably
between 15-20. The antisense oligonucleotide can be modified for
improved resistance to nuclease hydrolysis, and such analogues
include phosphorothioate, methylphosphonate, phosphodiester and
p-ethoxy oligonucleotides (WO 97/07784). The entrapped agent can
also be a ribozyme or catalytic RNA.
[0570] 3.F. Exemplary Liposome Compositions
[0571] Liposomes were prepared in support of the invention as
described in Example 40. The liposomes included a
lipid-polymer-ligand conjugated having the structure of Formula
1(a): 44
[0572] It is recognized that there are two enantiomers of the
targeting ligand or targeting conjugate and although the absolute
configuration of the enantiomers is not known. It is recognized
that one of the enantiomers is significantly more active that the
other. The enantiomers can be resolved using conventional chiral
separation techniques and the most active enantiomer will
preferably be employed for the practice of the present
invention.
[0573] where Q and Q.sup.1 correspond to C17 of stearoic acid and
the 45
[0574] moiety corresponds to poly(ethylene glycol) with a molecular
weight of 3400 Daltons.
[0575] As described in Example 40, pre-formed liposomes were
prepared from the lipids HSPC, cholesterol, and mPEG-DSPE. The
therapeutic agent doxorubicin was loaded into the liposomes by
remote loading against an ammonium ion gradient. The Formula (1a)
targeting conjugate was inserted to the pre-formed liposomes by
incubation of the conjugate at various concentrations with a fixed
amount of liposomes. Three liposome formulations were prepared,
differing only in the number of targeting ligands inserted into the
outermost lipid bilayers of the pre-formed liposomes. As described
in Example 40, liposomes having 18, 31, and 63 ligands per lipo
some were prepared.
[0576] Compounds having a structure represented by Formula (1b) are
also suitable for use as liposomal targeting conjugates and for
transfer via insertion into pre-formed liposomes: 46
[0577] wherein R.sub.8, the 47
[0578] moiety, Q, and Q.sup.1 can be:
3 Targeting Conjugate No. R.sub.8 48 Q/Q.sup.1 TA-1 OCH.sub.3 PEG
2000 C17 of stearoic acid TA-2 OCH.sub.3 PEG 5000 C17 of stearoic
acid TA-3 OCH.sub.3 PEG 2000 C15 of palmitoic acid TA-4 OCH.sub.3
PEG 3400 C15 of palmitoic acid TA-5 OCH.sub.3 PEG 5000 C15 of
palmitoic acid TA-6 H PEG 2000 C17 of stearoic acid TA-7 H PEG 3400
C17 of stearoic acid TA-8 H PEG 5000 C17 of stearoic acid
[0579] Compounds having a structure represented by Formula (1c) are
also suitable for use as liposomal targeting conjugates and for
transfer via insertion into pre-formed liposomes: 49
[0580] wherein the 50
[0581] moiety, Q, and Q.sup.1 can be:
4 Targeting Conjugate No. 51 Q and Q.sup.1 TA-9 PEG 2000 C17 of
stearoic acid TA-10 PEG 5000 C17 of stearoic acid TA-11 PEG 2000
C17 of oleoic acid TA-12 PEG 3400 C17 of stearoic acid TA-13 PEG
5000 C17 of oleoic acid
[0582] Compounds having a structure represented by Formula (1d) are
also suitable for use as liposomal targeting conjugates and for
transfer via insertion into pre-formed liposomes: 52
[0583] wherein the 53
[0584] moiety, Q, and Q.sup.1 can be:
5 TARGETING AGENT 54 Q and Q.sup.1 TA-14 PEG 3400 C17 of stearoic
acid TA-15 PEG 3400 C15 of palmitoic acid TA-16 PEG 2000 C17 of
stearoic acid
[0585] Compounds having a structure represented by Formula (1e) are
also suitable for use as liposomal targeting conjugates and for
transfer via insertion into pre-formed liposomes: 55
[0586] wherein the 56
[0587] moiety, Q, and Q.sup.1 can be:
6 Targeting Conjugate No. 57 Q and Q.sup.1 TA-17 PEG 5000 C17 of
stearoic acid TA-18 PEG 3400 C17 of stearoic acid TA-19 PEG 2000
C17 of stearoic acid
[0588] Compounds having a structure represented by Formula (1f) are
also suitable for use as liposomal targeting conjugates and for
transfer via insertion into pre-formed liposomes: 58
[0589] wherein the 59
[0590] moiety, Q, and Q.sup.1 can be:
7 Targeting Conjugate No. 60 Q and Q.sup.1 TA-20 PEG 5000 C17 of
stearoic acid TA-21 PEG 3400 C17 of stearoic acid TA-22 PEG 2000
C17 of stearoic acid
[0591] Compounds having a structure represented by Formula (1g) are
also suitable for use as liposomal targeting conjugates and for
transfer via insertion into pre-formed liposomes: 61
[0592] wherein the 62
[0593] moiety, Q, and Q.sup.1 can be:
8 Targeting Conjugate No. 63 Q and Q.sup.1 TA-23 PEG 5000 C17 of
stearoic acid TA-24 PEG 3400 C17 of stearoic acid TA-25 PEG 2000
C17 of stearoic acid
[0594] Compounds having structures represented by Formulas
(1a)-(1g) can be inserted into pre-formed liposomes by the method
described in Example 40.
[0595] The invention also contemplates, in another aspect, a
composition comprised of compound selected from compounds
represented by Formula (1a)-(1g) and a solvent, to form a micellar
solution of the compound. Such a micellar solution can be
used-during preparation of therapeutic, target-cell sensitized
liposomes by the manufacturer, the clinician, the pharmacist, or
the patient.
[0596] As described above, the therapeutic, target-cell sensitized
liposomes can be administered to patients suffering from a disorder
having an .alpha.v.beta.3, .alpha.v.beta.5, and/or
.alpha.IIb.beta.3 (also referred to as GPIIb/IIIa) integrin
component in its etiology. The targeting ligand, i.e., the
piperidinoyl carboxylic acid compound, directs the drug-laden
liposomes to cells expressing one or more of these integrin
receptors. Biological Example 5 describes administration of
liposomes, targeted with Cpd 39 (Example 39) and loaded with
doxorubicin to mice.
[0597] Abbreviations used in the instant specification,
particularly the Schemes and Examples, are as follows:
9 Boc tert-butoxycarbonyl BSA Bovine Serum Albumen Cod
Cyclooctadiene d/hr/min/rt day(s)/hour(s)/minute(s)/room
temperature DBC 2,6-Dichlorobenzoylchloride DCM Dichloromethane
DIEA Diisopropylethylamine DMA Dimethylacetamide DMAP
Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl
sulfoxide EDC N-ethyl-N'-dimethylaminopropylcarbodiimide
hydrochloride Et.sub.2O Diethyl ether EtOAc Ethyl acetate EtOH
Ethanol HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
Hexafluorophosphate HBTU O-Benzotriazol-1-yl-N,N,N',N'-tetramethyl-
uronium Hexafluorophosphate HCl Hydrochloric acid HOBt
1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography
LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilylamide
Me Methyl MeOH Methanol MeCN Acetonitrile NaHMDS sodium
hexamethyldisilylamide NaOH Sodium hydroxide ND Not Determined NMM
N-Methylmorpholine PBS Phosphate Buffer Solution Ph Phenyl RP-HPLC
Reverse Phase High Performance Liquid Chromatography rt Room
Temperature SDS Sodium dodecasulfate TEA Triethylamine TFA
Trifluoroacetic acid THF Tetrahydrofuran Thi Thienyl TMS
Tetramethylsilane TFA Trifluoroacetic acid Tol Toluene
General Synthetic Methods
[0598] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated more particularly in the
schemes that follow. Since the schemes are illustrations whereby
intermediate and target compounds of the present invention may be
prepared, the invention should not be construed as being limited by
the chemical reactions and conditions expressed. Additional
representative compounds and stereoisomers, racemic mixtures,
diastereomers and enantiomers thereof can be synthesized using the
intermediates prepared in accordance with these schemes and other
materials, compounds and reagents known to those skilled in the
art. All such compounds, stereoisomers, racemic mixtures,
diastereomers and enantiomers thereof are intended to be
encompassed within the scope of the present invention. The
preparation of the various starting materials used in the schemes
is well within the skill of persons versed in the art.
Scheme A
[0599] Scheme A describes a method for preparing a target compound
of Formula (I) (wherein R.sub.1 and W are as previously defined
within the scope of the invention. Removal of the Boc-protective
group from a R.sub.a substituted (wherein R.sub.a is
C.sub.1-4alkyl) Compound A1 was accomplished under acidic
conditions (by using an acid such as an acidic mixture of TFA and
DCM or an inorganic acid in an appropriate solvent such as dioxane)
and resulted in formation of a piperidine Compound A2. Coupling of
the piperidine Compound A2 with a carboxylic acid Compound A3 under
standard coupling conditions (by using a mixture of coupling agents
such as HOBt/EDC, HOBT/HBTU or isobutyl chloroformate in the
presence of a suitable base such as NMM or DIEA) afforded the ester
Compound A4. Hydrolysis of the ester Compound A4 under acidic or
basic conditions yielded a target compound Formula (I). The
individual isomers of Formula (I) can be achieved through the
chiral separation of intermediate A1-A4, and elaboration of the
chiral intermediates to compounds of Formula (I). 64
Scheme B
[0600] Scheme B describes an alternative method for preparing a
target compound of Formula (I) (wherein R.sub.1 is --NH(R.sub.6)
and W is --(CH.sub.2).sub.0-4alkyl-). Condensation of a Compound A2
with a Compound B1 (wherein R.sub.1 is H) possessing a suitable
leaving group such as a halogen or a mesylate or tosylate under
standard coupling conditions (by using a mixture of coupling agents
such as HOBt/EDC, HOBT/HBTU or isobutyl chloroformate in the
presence of a suitable base such as NMM or DIEA) resulted in the
formation of Compound B2. Reaction of Compound B2 with a
substituted amine Compound B3 in the presence of an appropriate
base such as LiHMDS, NaHMDS or LDA resulted in the formation of
Compound B4. Treatment of Compound B4 with aqueous hydrochloric
acid resulted in hydrolysis of the ester to yield a target compound
of Formula (I). 65 66
Scheme C
[0601] Scheme C describes an alternative method whereby a Compound
A1 may be prepared. Carboxylic acid Compound C1 was transformed
into an amide Compound C2 using N-methyl-O-methylhydroxylamine in
the presence of an appropriate activating agent such as HOBt, HBTU,
HATU, isobutyl chloroformate or the like. Reaction of the amide
Compound C2 with an in situ prepared aryl lithium species, a
Grignard reagent or the like resulted in the formation of a ketone
Compound C3. The ketone Compound C3 was converted to a mixture of
cis and trans isomers of an .alpha.,.beta.-unsaturated ester
Compound C5 upon reaction with an appropriately substituted
phosphorane or phosphonate Compound C4 in the presence of a base
such as LiHMDS, NaHMDS, LDA or the like. Conversion of Compound C5
to Compound A1 was accomplished under hydrogenolysis conditions
(wherein a hydrogen overpressure of from about 10 to about 50 psi
was used) in the presence of an appropriate catalyst such as 5 or
10% palladium on carbon. 67
Scheme D
[0602] Scheme D describes an alternative method for the synthesis
of a Compound A1 in which (CH.sub.2).sub.q is (CH.sub.2).sub.2-3.
Reaction of an amide Compound C2 with an appropriate reducing agent
such as lithium aluminum hydride or the like resulted in the
formation of an aldehyde Compound D1. Condensation of an in situ
generated acetylide Compound D2 with the aldehyde Compound D1 at a
low temperature resulted in formation of a propargylic alcohol
Compound D3. The alkyne Compound D3 was selectively reduced to a
cis-olefin Compound D4 under hydrogenolysis conditions using
Lindlar's catalyst in pyridine. Condensation of the allylic alcohol
Compound D4 with an R.sub.a substituted 3-chloro-3-oxopropionate
Compound D5 in the presence of a base such as TEA, DIEA or the like
resulted in the formation of a mixed ester Compound D6. Treatment
of Compound D6 with chlorotrimethylsilane in the presence of a
suitable base such as sodium hydride, potassium hydride, LDA or the
like gave rise to an intermediate silyl ketene acetal which
rearranged upon heating in a suitable solvent such as THF or
Et.sub.2O to a mixed ester Compound D7. Decarboxylation of the
ester Compound D7 to form Compound D8 was accomplished upon heating
Compound D7 under vacuum. Reduction of the double bond in Compound
D8 was accomplished under standard hydrogenation conditions,
applying a hydrogen overpressure (of from about 10 to about 50 psi)
in the presence of an appropriate catalyst such as 5 or 10%
palladium on carbon resulted in formation of a target compound
Compound A1 in which (CH.sub.2).sub.q is (CH.sub.2).sub.2-3. 68
Scheme E
[0603] Scheme E describes an alternative method for the synthesis
of a target compound of Formula (I.2) (wherein R.sub.2 for a
compound of Formula (I) is hydrogen, R.sub.1 and W are as
previously defined. Condensation of an aldehyde Compound E1 using
an appropriate carbalkoxymethylene triphenylphosphorane (Wittig
reaction) or a trialkyl phosphonoacetate (Horner-Emmons reaction)
resulted in the formation of an .alpha.,.beta.-unsaturated ester
Compound E2. Treatment of Compound E2 under acidic conditions
(using an acid such as a 1:1 mixture of TFA in DCM, 4N HCl in
dioxane or the like) resulted in the removal of the Boc-protective
group, resulting in formation of a substituted piperidine Compound
E3. Coupling of the piperidine Compound E3 with a carboxylic acid
Compound A3 under standard coupling conditions (using a mixture of
coupling agents such as HOBt/EDC, HOBT/HBTU or isobutyl
chloroformate in the presence of a suitable base such as NMM or
DIEA) resulted in an ester Compound E4. Hydrolysis of the ester
Compound E4 under acidic or basic conditions yielded an
.alpha.,.beta.-unsaturated acid Compound E5. Reduction of the
double bond in Compound E5 was accomplished under standard
hydrogenation conditions, applying hydrogen overpressure (of from
about 10 to about 50 psi) in the presence of an appropriate
catalyst such as 5 or 10% palladium on carbon and resulted in the
formation of a target compound of Formula (I.2). 69
Scheme F
[0604] Scheme F describes an alternative method whereby a target
Compound A1 may be prepared. A racemic E/Z-mixture of an
.alpha.,.beta.-unsaturate- d ester Compound E2 was reacted with an
R.sub.2 substituted boronic acid Compound F1 in the presence of an
appropriate transition metal catalyst such as Rhodium or Indium to
yield a target Compound A1. 70
Scheme G
[0605] Scheme G describes an alternative method for the synthesis
of a target compound of Formula (I.3) (wherein (CH.sub.2).sub.q for
a compound of Formula (I) is --(CH.sub.2).sub.2-3--, R.sub.1 is as
previously defined and W is --(CH.sub.2).sub.0-4alkyl-). The
Boc-protecting group on Compound D8 was removed under acidic
conditions (using an acid such as a 1:1 mixture of TFA in DCM, 4N
HCl in dioxane or the like) to yield a substituted piperidine
Compound G1. Coupling of the piperidine Compound G1 with a
carboxylic acid Compound A3 under standard coupling conditions
(using a mixture of coupling agents such as HOBt/EDC, HOBT/HBTU or
isobutyl chloroformate in the presence of a suitable base such as
NMM or DIEA) led to formation of an ester Compound G2. The ester
Compound G2 was be converted to Compound G3 upon exposure to strong
acidic or basic aqueous conditions (in the presence of a strong
acid or base such as concentrated HCl or NaOH). The double bond in
Compound G3 was reduced using standard hydrogenation conditions,
applying hydrogen overpressure (of from about 10 to about 50 psi)
in the presence of an appropriate catalyst such as 5 or 10%
palladium on carbon and resulted in the formation of a target
compound of Formula (I.3). 71
Scheme H
[0606] Scheme H describes a method for the synthesis of a target
compound of Formula (I.3a) (wherein R.sub.1 for a compound of
Formula (I.3) is --NH(R.sub.5), W is --(CH.sub.2).sub.0-4alkyl- and
an R.sub.5 heteroaryl subtituent is reduced to a partially
unsaturated heterocyclyl substituent) by reduction of the double
bond in a Compound G3a (wherein R.sub.1 in a Compound G3 is
--NH(R.sub.5)) using standard hydrogenation conditions, applying
hydrogen overpressure (of from about 10 to about 50 psi) in the
presence of an appropriate catalyst such as 5 or 10% palladium on
carbon, accompanied by standard reduction of R.sub.5 to yield a
target compound of Formula (I.3a). 72
Scheme I
[0607] Scheme I describes an alternative method for the synthesis
of a target Compound B4a (wherein (CH.sub.2).sub.q for the Compound
B4 is not limited to --(CH.sub.2).sub.2-3--, R.sub.6 is as
previously defined, R.sub.1 is H, and W is
--(CH.sub.2).sub.0-4alkyl-). Condensation of a Compound A2 under
standard coupling conditions (using a mixture of coupling agents
such as HOBt/EDC, HOBT/HBTU or isobutyl chloroformate in the
presence of a suitable base such as NMM or DIEA) with a protected
amino acid Compound I1 resulted in the formation of a target
Compound B4a. 73
Scheme J
[0608] Scheme J describes a method for the synthesis of a target
Compound A1a (wherein R.sub.2 in a Compound A1 is a heteroaryl
subtituent that has been reduced to a partially or fully
unsaturated heterocyclyl substituent). The double bond in Compound
C5a (wherein R.sub.2 in a Compound C5 is a unsaturated heteroaryl
subtituent) was reduced under standard hydrogenation conditions,
applying hydrogen overpressure (of from about 10 to about 50 psi)
in the presence of an appropriate catalyst such as 5 or 10%
palladium on carbon, accompanied by standard reduction of R.sub.2
to yield a target Compound A1a. Compound A1a can be separated into
its individual optical isomers by chiral chromatography at this
stage. In addition, Compound A1a can be alkylated on the R.sub.2
heteroatom using the appropriate alkylating agent such as
iodomethane and the appropriate base such as
2,6-di-tert-butylpyridine to yield A1b. 74
Scheme K
[0609] Scheme K describes a method for preparing a target compound
of Formula 14. Treatment of a compound of Formula I with an
appropriate alcohol in the presence of a coupling agent such as
1,3-dicyclohexylcarbodiimide and an activating agent such as
dimethylaminopyridine or the like resulted in the formation of
target compound of Formula (I4). Alternatively, a compound of
Formula I may be treated with an alkyl halide in the presence of a
suitable base such as NMM or DIEA to yield a target compound of
Formula I4. 75
Scheme L
[0610] Scheme L describes a method for the synthesis of a target
compound of Formula A1b (wherein R.sub.2 in a Compound A1b is a
hydroxyaryl, aminoaryl, or thiophenyl substituent that has been
deprotected). The double bond in Compound C5b (wherein R.sub.2 in a
Compound C5 is an O-protected hydroxyaryl, N-protected anilino, or
S-protected thioaryl substituent) was reduced under standard
hydrogenation conditions, applying hydrogen overpressure (of from
about 10 to about 50 psi) in the presence of an appropriate
catalyst such as 5% or 10% palladium on carbon, accompanied by
removal of the protective group to yield hydroxyaryl or anilino
compound A1b. Alternatively, the protective group can be removed
via basic or acidic hydrolysis in a subsequent step. 76
Scheme M
[0611] Scheme M describes a method for preparing a target compound
of Formula (I5) (wherein R1 and W are as previously defined). The
ketone Compound C3 was converted to a mixture of cis and trans
isomers of an .alpha.,.beta.-unsaturated nitriles Compound M2 upon
reaction with an appropriately substituted phosphorane or
phosphonate Compound M1 in the presence of a base such as LiHMDS,
NaHMDS, LDA or the like. Conversion of Compound M2 to Compound M3
was accomplished under hydrogenolysis conditions (wherein a
hydrogen overpressure of about 5 psi was used) in the presence of
an appropriate catalyst such as 5 or 10% palladium on carbon.
Removal of the Boc-protective group from Compound M3 was
accomplished under acidic conditions (by using an acid such as an
acidic mixture of TFA and DCM or an inorganic acid in an
appropriate solvent such as dioxane) and resulted in formation of a
piperidine Compound M4. Coupling of the piperidine Compound M4 with
a carboxylic acid Compound A3 under standard coupling conditions
(by using a mixture of coupling agents such as HOBt/EDC, HOBT/HBTU
or isobutyl chloroformate in the presence of a suitable base such
as NMM or DIEA) afforded the nitrile Compound M5. Hydrolysis of the
nitrile Compound M5 under acidic conditions yielded a target
compound of Formula (I5). 7778
Scheme N
[0612] Scheme N describes a method for the synthesis of a target
compound of Formula (II) (wherein W is defined as
C.sub.1-4alkyl(R.sub.1)). Carboxylic acid Compound A3 was
transformed into alcohol Compound N1 using an appropriate reducing
agent such as lithium aluminum hydride or the like. Alchol Compound
N1 was transformed into aldehyde Compound N2 using an appropriate
oxidizing agent such as pyridinium chlorochromate or the like.
Coupling of the aldehyde Compound N2 with a piperidine Compound A2
under standard reductive amination conditions using a reducing
agent such as sodium triacetoxyborohydride or the like afforded the
ester Compound N3. Hydrolysis of the ester Compound N3 under acidic
or basic conditions yielded a target compound Formula (II). 79
Targeting Compounds
[0613] The following schemes describe general synthetic methods
whereby intermediate and target compounds of the present invention
may be prepared. Additional representative compounds and
stereoisomers, racemic mixtures, diasteromers and enantiomers
thereof can be synthesized using the intermediates prepared in
accordance to the general schemes and other materials, compounds
and reagents known to those skilled in the art. All such compounds,
stereoisomers, racemic mixtures, diasteromers and enantiomers
thereof are intended to be encompassed within the scope of the
present invention. Those skilled in the art will recognize that the
construction of compounds of the present invention may require
manipulation of the reaction sequences presented herein so as to
accommodate sensitive or reactive functional groups. Likewise,
during any of the processes for preparation of the compounds
described herein, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned.
This may be achieved by means of conventional protecting groups,
such as those described in Protective Groups in Organic Chemistry,
ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P.
G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley
& Sons, 1991. The protecting groups may be removed at a
convenient subsequent stage using methods known in the art.
Scheme O
[0614] Scheme O describes a general method for the synthesis of
compounds of the present invention. Compound O1 is a compound
wherein R.sub.2a is a reactive form of R.sub.2, meaning that it is
equipped with a reactive functional group such as hydroxy or the
like. Similarly, T as used herein is an activated precursor to
R.sub.11 or R.sub.12 which possesses reactive functional groups at
one or both of its ends. As demonstrated in Scheme O, the hydroxy
functional group of Compound O.sub.2 may be reacted with Compound
O3, wherein LG is a leaving group such as chloride, bromide,
iodide, or a sulfonate ester such as methane sulfonate,
para-toluene sulfonate, or benzene sulfonate. Such compounds are
commercially available or may be prepared using reagents and
methods known to those skilled in the art. Alkylation of Compound
O.sub.2 under anhydrous basic conditions provides Compound O4 which
may then be converted to azide Compound O5 via displacement of the
leaving group (LG) by azide anion in a polar aprotic solvent.
Compound O5 may be deprotected under suitable acidic conditions to
afford a free amine Compound O6. Subsequent acylation with Compound
O7 (wherein W.sub.a is an activated precursor to W of the present
invention) using previously described chemistry yields Compound O8.
The azide functionality of Compound O8 may be reduced to its
corresponding primary amine using catalytic hydrogenation in an
alcoholic solvent in the presence of a palladium catalyst and under
a hydrogen pressure ranging from atmospheric pressure to 65 psi.
Saponification of the ester under basic or acidic conditions, or
using other chemistry for the deprotection of esters known to those
skilled in the art, affords Compound O9.
[0615] Compound O9 may be reacted with a variety of activated
precursors of R.sub.13, such as Compound O10, to provide compounds
of Formula (I). Activated precursors of R.sub.13 are either
commercially available from suppliers (Avanti Polar Lipids, Inc.,
Alabaster Ala.; Nektar Therapeutics AL, Huntsville Ala.) or may be
synthesized (Zalipsky, S. et al, J Control Release, 1996, 39,
153-161).
[0616] More specifically, Scheme O shows the acylation of the
primary amine of O9 with a hydroxyimide-activated ester, Compound
O10, to give amide Compound O11. An amide linkage may also be
accomplished using standard coupling reactions with appropriately
activated R.sub.13 precursors. Those skilled in the art will
recognize that intermediate Compound O9 may be acylated with a
variety of other R.sub.13 precursors activated with functional
groups such as acid chlorides, formyl chlorides, anhydrides,
.alpha.-halo-carbonyls, .alpha./.beta.-unsaturated carbonyls,
isocyanates, and the like. 8081
Scheme P
[0617] Compounds of the present invention may join R.sub.11 or
R.sub.12 to R.sub.13 via a sulfur ether linkage. One method for the
preparation of this class of compounds is shown in Scheme P which
is a modification of Scheme O. The first step of Scheme P involves
the deprotection of Compound O1 to provide Compound P1, with
subsequent coupling of the free amine with Compound O7 to give
Compound P2. Upon removal of the protecting group, Compound
.beta..sub.2 may be alkylated with Compound O3 as described herein,
followed by treatment with the sodium or potassium salt of
thioacetic acid in an alcoholic or polar aprotic solvent (DMF or
DMSO) to yield Compound P3. Saponification of the esters of
Compound .beta..sub.3 gives the free thiol, Compound P4. 82
[0618] Those skilled in the art will recognize that the thiol of
Compound P4 may be reacted with a number of activated precursors of
R.sub.13 to yield compounds of the present invention. Examples of
functional groups on the R.sub.13 terminus that would be reactive
with a thiol are maleimido substituents, .alpha.-halo-carbonyls,
.alpha./.beta.-unsaturate- d carbonyls, disulfides, and the
like.
Scheme Q
[0619] Scheme Q shows a means for preparing of compounds of the
present invention wherein R.sub.2a is joined to R.sub.11 or
R.sub.12 precursor, T, via an ester linkage. The hydroxy
functionality of Compound O.sub.2 may be reacted with a precursor
of R.sub.11 or R.sub.12 activated with an acyl functional group
such as an acid chloride, activated ester, or the like, to give
Compound Q2, which may then be converted to azide Compound Q3 using
chemistry discussed above. Compound Q3 may be further elaborated
using chemistry described herein to prepare a compound of Formula
(I).
[0620] Accordingly, Compound Q2 may be treated with the sodium or
potassium salt of thioacetic acid and further elaborated using
conventional reagents and methods known to those skilled to provide
a terminal thiol. The resulting thiol may be reacted with an
activated precursor of R.sub.13 as discussed herein to give
compounds of the present invention. 83
Scheme R
[0621] As shown in Scheme R, compounds of the present invention may
be made via an intermediate wherein R.sub.2a is activated with a
terminal aldehyde. The hydroxy substituent of Compound R1 may be
oxidized using conventional oxidation chemistry, such as the Swern
oxidation to afford aldehyde Compound R2. Compound R2 may be
further elaborated through reductive amination with a suitable
amine in the presence of a hydride source to arrive at compounds
wherein R.sub.2a and T are linked through an alkylamino linkage.
The terminal amino group may be reacted with acid chlorides, formyl
chlorides, carbamates, and the like to obtain amide, carbamate, or
urea linkages between R.sub.2a and T. In addition, Compound R2 may
undergo Wittig chemistry to yield a new carbon bond linkage. 84
[0622] Furthermore, the hydroxy substituent of Compound R1 may be
oxidized to its corresponding carboxylic acid using a strong
oxidizing agent, such as Jones reagent or PCC in DMF or the like.
The resulting carboxylic acid may take part in a variety of known
chemical transformations such as the Curtius rearrangement followed
by either hydrolysis or treatment with benzyl alcohol and
hydrogenation, leading to compounds wherein R.sub.2a is activated
with a terminal amino group for further elaboration as discussed
herein.
Scheme S
[0623] Scheme S describes the preparation of compounds of the
present invention. Aldehyde R2 may be treated with Compound S1 and
an organometallic base such as n-butyllithium to provide
intermediate Compound S2. Subsequent treatment of Compound S2 with
sodium mercury amalgam, aluminum mercury amalgam, or Raney Nickel
in aqueous alcoholic solvent results in removal of the phenyl
sulfone functionality. Oxidation of Compound S3 using standard
oxidation chemistry affords ketone Compound S4. Upon removal of the
protecting group, the hydroxy group may be reacted with number of
activated precursors of R.sub.13 possessing functional groups such
as formyl chlorides to make carbonates, isocyanates to afford
carbamates, activated esters and the like. 85
[0624] The terminal hydroxy group on T may be oxidized using Swem
or Moffat chemistry to afford T functionalized with an aldehyde.
The aldehyde may be reductively aminated with precursors to
R.sub.13 activated with amines to form secondary amines, or with
precursors to R.sub.13 activated with acyl hydrazines to form acyl
hydrazones.
[0625] Furthermore, the terminal hydroxy group on T may be oxidized
using conventional chemistry to yield a T with a terminal carboxy
group. The terminal carboxy group may be coupled with precursors to
R.sub.13 that possess a hydroxyl functionality to form an ester
linkage using standard peptide coupling or esterification methods,
such as treatment with DCC and a catalytic amount of DMAP in DMF
(Zlatkov, A. et al., Arch. Pharm (Weinheim), 1998, 331 (10),
313-318).
[0626] Similarly, the terminal carboxy group on T may be coupled
with precursors to R.sub.13 that possess an amino functionality to
form an amide linkage. Typical reagents used for such coupling
reactions are PyBroP in DMP with a catalytic amount of DMAP. An
alternative method uses BOP with a trialkylamine base in DMP
(Scherer, M. et al. Chem Commun, 1998, (1), 85-86; Bendavid, A. et
al. J. Org. Chem. 2001, 66 (11), 3709-3718).
[0627] Once the group R.sub.13 has been installed on compounds of
the present invention, it is suitably functionalized for
incorporated into a pegylated liposome. Several methods have been
developed to accomplish this transformation. The least complex
method involves the incubation of compounds of Fomula (I) with a
fully formed pegylated liposome. With this procedure, compounds of
Formula (I) form a micellar suspension in water which, upon
addition of pre-formed pegylated liposomes loaded with a certain
therapeutic agent, effects the ordered insertion of compounds of
Formula (I) into the lipid bilayer of the liposome (Zalipsky, S et
al., Bioconjugate Chem. 1997, (8) 111-118). In the insertion
process, the phospholipid portion of R.sub.13 acts as an anchor in
the lipid bilayer of the pegylated liposome. The oligomeric PEG
portion of R.sub.13 extends outward from the liposome and serves to
display the remainder of the compound of Formula (I) at the
interface of the pegylated region of the liposome and the solvent.
By controlling the concentration, this composition can be composed
of ten to several thousand molecules of a compound of Formula (I)
inserted into the bilayer of the pegylated liposome and displayed
at the liposome: solvent interface. This incubation is run at
temperatures ranging from ambient to 37.degree. C. for up to 48
h.
[0628] Another means for the incorporation of compounds of Formula
(I) into a liposomal formulation involves mixing compounds of
Formula (I) with the appropriate lipid components and forming
unilamellar liposomes from this mixture. The method is carried out
by dissolving defined proportions of a phospholipid, such as
dipalmitoylphosphatidylcholine, cholesterol, a pegylated
phospholipid, such as PEG-2000 disteroylphosphatidylethanolamine in
chloroform:methanol, and a predetermined measure of a compound of
Formula (I). A lipid film is prepared, then hydrated, the
therapeutic agent is added and finally extruded several times
through polycarbonate membranes until the liposomes form from the
extrusion at the desired size (Lee, R. J.; Low, P. S., Biochim.
Biophys. Acta, 1995 (1233) 134-144.
[0629] A third method involves forming the liposome by the second
method discussed herein substituting a molecule derived from the
precursor of R.sub.13. The liposome decorated with these reactive
head groups on the phospholipid is then capable of reacting with
precursors of Formula (I) wherein T is activated with a
complementary functional group and the liposome with the reactive
phospholipid head groups interact with these intermediates in the
same manner as described for Schemes O through S (Lee, R. J., Low,
P. S., J. Biol. Chem., 1994, 269 (5), 3198-3204; Gyongyossy-Issa,
M. I. C. et al., Arch. Biochem. Biophys., 1998, 353 (1),
101-108).
Specific Synthetic Methods
[0630] Specific compounds which are representative of this
invention were prepared as per the following examples and reaction
sequences; the examples and the diagrams depicting the reaction
sequences are offered by way of illustration, to aid in the
understanding of the invention and should not be construed to limit
in any way the invention set forth in the claims which follow
thereafter. The instant compounds may also be used as intermediates
in subsequent examples to produce additional compounds of the
present invention. No attempt has been made to optimize the yields
obtained in any of the reactions. One skilled in the art would know
how to increase such yields through routine variations in reaction
times, temperatures, solvents and/or reagents.
[0631] Reagents were purchased from commercial sources.
Microanalyses were performed at Robertson Microlit Laboratories,
Inc., Madison, N.J. and are expressed in percentage by weight of
each element per total molecular weight. Nuclear magnetic resonance
(NMR) spectra for hydrogen atoms were measured in the indicated
solvent with (TMS) as the internal standard on a Bruker Avance (300
MHz) spectrometer. The values are expressed in parts per million
downfield from TMS. The mass spectra (MS) were determined on a
Micromass Platform LC spectrometer as (ESI) m/z (M+H.sup.+) using
an electrospray technique. Stereoisomeric compounds may be
characterized as racemic mixtures or as separate diastereomers and
enantiomers thereof using X-ray crystallography and other methods
known to one skilled in the art. Unless otherwise noted, the
materials used in the examples were obtained from readily available
commercial suppliers or synthesized by standard methods known to
one skilled in the art of chemical synthesis. The substituent
groups, which vary between examples, are hydrogen unless otherwise
noted.
EXAMPLE 1
1-[[3-[(1,4,5,6-Tetrahydro-2-pyrimidinyl)amino]phenyl]acetyl]-4-piperidine-
propanoic acid (Cpd 1)
[0632] Methyl iodide (3.21 mL, 51.6 mmol) was added to a solution
of 3,4,5,6-tetrahydro-2-pyrimidinethiol Compound 1a (6.00 g, 51.6
mmol) in absolute ethanol (45 mL). The mixture was refluxed for 3
h, concentrated and dried in vacuo to yield Compound 1b as a
colorless oil. MS (ES+) m/z 172 (M+41). .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 1.89 (m, 2H), 2.61 (s, 3H), 3.61 (m, 4H), 9.56 (s,
1H).
[0633] Boc.sub.2O (11.33 g, 51.91 mmol) was added to a solution of
Compound 1b (13.4 g, 51.9 mmol) and TEA (7.23 mL, 51.9 mmol) in DCM
(70 mL) at 0.degree. C. and the mixture was stirred at rt for 2 d.
The organic layer was washed with water (2.times.75 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give Compound 1c. MS (ES+)
m/z 231 (M+H.sup.+).
[0634] A solution of Compound 1c (0.91 g, 3.95 mmol) and
3-aminophenylacetic acid Compound 1d (0.59 g, 3.95 mmol) in DMA (5
mL) was heated to 80-85.degree. C. for 4 d. The mixture was cooled
to rt and diluted with MeCN. The solid was filtered and washed with
MeCN and Et.sub.2O, then dried in vacuo. Water was added and the pH
was adjusted to pH 1-2 by adding conc. HCl dropwise. The resulting
solution was lyophilized to give Compound 1e as a light yellow
solid. MS (ES+) m/z 234 (M+H.sup.+).
[0635] Boc.sub.2O (19 g, 87 mmol) and TEA (13 mL, 96 mmol) were
added to a solution of 4-piperidinemethanol Compound 1f (10 g, 87
mmol), DMAP (catalytic amount), dioxane (90 mL) and water (45 mL)
at 5.degree. C. The reaction mixture was stirred overnight at rt
and diluted with DCM (100 mL). The organic layer was washed with
saturated NH.sub.4Cl, dried (Na.sub.2SO.sub.4) and concentrated to
give Compound 1g. MS (ES+) m/z 216 (M+H.sup.+).
[0636] DMSO (4.28 mL, 60.38 mmol) was added over a 15 min period to
a solution of oxalyl chloride (2.63 mL, 30.19 mmol) in DCM (110 mL)
at -78.degree. C. After stirring at -78.degree. C. for 30 min, a
solution of Compound 1g (5.0 g, 23.2 mmol) in DCM (10 mL) was added
dropwise. The resulting mixture was stirred at -78-.degree. C. for
2 h. TEA (19.42 mL, 139.3 mmol) was added dropwise and the mixture
was warmed to rt and quenched with water. The organic layer was
separated, washed sequentially with saturated NH.sub.4Cl (75 mL),
water (75 mL), saturated NaHCO.sub.3 (75 mL) and saturated brine
(75 mL), then dried (Na.sub.2SO.sub.4) and concentrated to give
Compound 1h. MS (ES+) m/z 214 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.4 (s, 9H), 1.89 (m, 4H), 2.58 (m,
1H), 3.85 (m, 4H), 9.65 (s, 1H).
[0637] A solution of Compound 1h (2.29 g, 10.7 mmol) in DCM (15 mL)
was added dropwise to a solution of carbethoxymethylene
triphenylphosphorane (4.11 g, 10.7 mmol) in DCM (20 mL) at
0.degree. C. The resulting mixture was warmed to rt and stirred
overnight. The mixture was concentrated and the residue was
purified by flash chromatography (silica gel, 15-30% ethyl
acetate/hexane) to give Compound 1i. MS (ES+) m/z 284 (M+H.sup.+).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.2 (t, J=7 Hz, 3H),
1.39 (s, 9H), 1.69 (m, 2H), 2.36 (m, 1H), 2.74 (m, 2H), 3.94 (m,
2H), 4.11 (q, J=7 Hz, 2H), 5.86 (d, J=15 Hz, 2H), 6.82 (dd, J=15, 7
Hz, 2H).
[0638] A mixture of Compound 1i (1.6 g, 5.6 mmol), TFA (10 mL) and
anisole (1 drop) in DCM (10 mL) was stirred at rt for 1.5 h. The
mixture was concentrated and dried in vacuo to give Compound 1j as
a TFA salt. MS (ES+) m/z 184 (M+H.sup.+).
[0639] NMM (0.22 mL, 2.07 mmol), Compound 1e (0.29 g, 1.04 mmol),
NMM (0.114 mL, 1.04 mmol), HOBT (0.07 g, 0.51 mmol) and HBTU (0.46
g, 1.24 mmol) were added sequentially to a solution of Compound 1j
(0.308 g, 1.04 mmol) in MeCN (20 mL) and DMF (2 mL). The mixture
was stirred at 0.degree. C. for 1 h, then at rt overnight, quenched
with saturated NH.sub.4Cl, concentrated and extracted with EtOAc.
The organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, 110% EtOH/1.5% NH.sub.4OH/DCM to 16%
EtOH/1.5% NH.sub.4OH/DCM) to yield Compound 1k as a colorless
solid. MS (ES+) m/z 399 (M+H.sup.+).
[0640] Compound 1k (0.27 g) was dissolved in ice cold 6N HCl (20
mL) at 0.degree. C. and stirred at rt for 2 d. The mixture was
concentrated and MeCN (3.times.20 mL) was used as an azeotrope. The
resulting solid was triturated with Et.sub.2O and DCM and purified
by RP-HPLC (10-90% MeCN/water, 0.1% TFA) to yield Compound 11 as a
TFA salt. MS (ES+) m/z 371 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 1.07 (m, 2H), 1.65 (m, 4H), 1.7 (m, 2H), 2.41 (m,
1H), 3.05 (m, 2H), 3.72 (s, 2H), 3.91 (m, 2H), 4.37 (m, 2H), 5.74
(d, J=16 Hz, 1H), 6.75 (m, 1H), 7.15 (m, 3H), 7.42 (m, 1H), 8.15
(br s, 1H), 9.76 (s, 1H). Anal. Calcd for
C.sub.20H.sub.26N.sub.4O.sub.3.1.57CF.sub.3COOH-0.38H.sub.2O: C,
49.96; H, 5.14; N, 10.08; F, 16.09; H.sub.20, 1.24. Found: C,
49.62; H, 5.00; N, 9.97; F, 15.98; H.sub.2O, 1.25.
[0641] 10% Palladium on carbon (85 mg) was added to a solution of
Compound 1l (0.05 g) in warm EtOH (10 mL) under argon and the
mixture was hydrogenated (40 psi) in a Parr apparatus. The mixture
was filtered through celite and concentrated at reduced pressure to
yield Compound 1 as a sticky solid. MS (ES+) m/z 373 (M+H.sup.+).
8687
EXAMPLE 2
1-[1-Oxo-3-[3-[(1,4,5,6-tetrahydro-2-pyrimidinyl)amino]phenyl]propyl]-4-pi-
peridinepropanoic acid (Cpd 2)
[0642] Compound 1c (0.84 g, 3.65 mmol) was added to a solution of
3-(3-aminophenyl)propionic acid Compound 2a (0.60 g, 3.65 mmol) in
DMA (5 mL). The reaction mixture was stirred at 80-85.degree. C.
for 3 d, cooled to rt, diluted with MeCN (30 mL) and filtered.
Water was added to the filtrate and the pH was adjusted to 1-2 by
adding conc. HCl dropwise. The resulting solution was lyophilized
to yield Compound 2b. MS (ES+) m/z 248 (M+H.sup.+).
[0643] A solution of 4N HCl in dioxane (8 mL) was added dropwise to
a solution of Compound 2c (1.0 g, 3.9 mmol) in MeOH (20 mL) at
0.degree. C. The resulting mixture was stirred overnight at rt and
concentrated using MeCN (3.times.20 mL) as an azeotrope. The solid
was triturated with Et.sub.2O and hexane, dissolved in water and
lyophilized to yield Compound 2d as a colorless solid. MS (ES+) m/z
172 (M+H.sup.+).
[0644] NMM (0.23 mL, 2.11 mmol) was added to a solution of Compound
2d (0.20 g, 0.70 mmol) in MeCN (25 mL) and DMF (2 mL). Compound 2b
(0.15 g, 0.70 mmol), NMM (0.15 mL, 1.40 mmol), HOBT (0.05 g, 0.35
mmol) and HBTU (0.32 g, 0.84 mmol) were then added and the mixture
was stirred for 1 h at 0.degree. C., followed by overnight at rt.
Saturated NH.sub.4Cl was added and the reaction mixture was
concentrated and extracted with EtOAc (25 mL). The organic layer
was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The crude mixture was purified by RP-HPLC (10-90% MeCN/water, 0.1%
TFA) to yield Compound 2e. MS (ES+) m/z 401 (M+H.sup.+). Compound
2e (0.21 g) was dissolved in 4N HCl (20 mL) at 0.degree. C. and the
mixture was stirred overnight at rt. The mixture was concentrated
using MeCN (3.times.25 mL) as an azeotrope and triturated with
Et.sub.2O to yield Compound 2 as an HCl salt. MS (ES+) m/z 387
(M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.93 (m,
4H), 1.46 (m, 4H), 1.67 (s, 1H), 1.88 (m, 2H), 2.25 (m, 2H), 2.66
(m, 2H), 2.82 (m, 4H), 3.39 (m, 2H), 3.82 (d, J=13 Hz, 1H), 4.39
(d,J=13 Hz, 1H), 7.15 (m, 3H), 7.39 (m, 1H), 7.97 (br s, 1H), 9.45
(br s, 1H). Anal. Calcd for C.sub.21H.sub.30N.sub.4O.sub.3.1.85
HCl-1'.15H.sub.2O: C, 53.14; H, 7.26; N, 11.82; H.sub.2O, 4.37.
Found: C, 53.19; H. 7.14; N, 11.91; H.sub.2O, 4.62. 88
EXAMPLE 3
.beta.-[1-[[3-[(1,4,5,6-Tetrahydro-5-hydroxy-2-pyrimidinyl)amino]phenyl]ac-
etyl]-4-piperidinyl]-3-quinolinepropanoic acid (Cpd 3)
[0645] N,O-Dimethylhydroxylamine hydrochloride (98%, 2.55 g, 26.17
mmol), NMM (14.39 mL, 130.8 mmol), HOBT (1.47 g, 10.90 mmol) and
HBTU (9.83 g, 26.16 mmol) were added to a solution of Compound 3a
(5.00 g, 21.80 mmol) in MeCN (75 mL). The mixture was stirred for 1
h at 0.degree. C. and overnight at rt, quenched with saturated
NH.sub.4Cl, concentrated and extracted with EtOAc (3.times.75 mL).
The organic layer was dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The crude product was purified by flash column
chromatography (silica gel, 30-60% ethyl acetate/hexane with a few
drops of TEA) to give Compound 3b as a liquid. MS (ES+) m/z 273
(M+H.sup.+).
[0646] n-BuLi (2.5M in hexane, 7.34 mL, 18.35 mmol) was added
dropwise to a stirred solution of 3-bromoquinoline (3.81 g, 18.35
mmol) in anhydrous Et.sub.2O (65 mL) at -78.degree. C. over a
period of 30 min. The mixture was stirred at -78.degree. C. for 30
min and a solution of Compound 3b (1.0 g, 3.67 mmol) in Et.sub.2O
(20 mL) was added dropwise over a period of 10 min. The resulting
mixture was stirred for 30 min -78.degree. C. and allowed to warm
to rt. After stirring for 2 h at rt, the mixture was quenched with
a saturated NH.sub.4Cl solution and diluted with EtOAc. The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The residue was purified via chromatography
(silica gel, 15-25% ethyl acetate/hexane) to give Compound 3c as a
liquid. MS (ES+) m/z 341 (M+H.sup.+).
[0647] A solution of NaHMDS (1M, 3.17 mL, 3.17 mmol) in THF was
added over a period of 15 min to a stirred solution of trimethyl
phosphonoacetate (0.51 mL, 3.17 mmol) in THF (15 mL) at 0.degree.
C. under argon. After the resulting mixture was stirred for 20 min,
a solution of Compound 3c-(0.27 g, 0.79 mmol) in THF (3 mL) was
added over a period of 15 min. The mixture was stirred at 0.degree.
C. for 30 min, refluxed for 2.5 h, cooled to rt, diluted with
Et.sub.2O (30 mL) and washed with a saturated NaHCO.sub.3 solution
(2.times.25 mL) and brine (2.times.25 mL). The aqueous layer was
extracted with Et.sub.2O and the combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, 10-30% ethyl
acetate/hexane) to give Compound 3d as a mixture of E- and
Z-isomers. MS (ES+) m/z 397 (M+H.sup.+).
[0648] A mixture of the E- and Z-isomers of Compound 3d (0.25 g,
0.63 mmol) and 10% Pd/C (0.12 g) in MeOH (15 mL) was shaken
overnight under hydrogen pressure (5 psi) in a Parr apparatus. The
mixture was filtered through celite and concentrated under vacuum.
The crude product was purified by flash chromatography (70% ethyl
acetate in hexane) to yield Compound 3e as an oil. MS (ES+) m/z 399
(M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.38 (m,
4H), 1.41 (s, 9H), 1.80 (m, 1H), 2.53 (m, 2H), 3.18 (m, 2H), 3.51
(s, 3H), 3.71 (m, 1H), 4.13 (m, 2H), 7.54 (t,J=8 Hz, 1H), 7.69
(t,J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.89 (s, 1H), 8.09 (d, J=8
Hz, 1H), 8.75 (s, 1H).
[0649] Compound 3e (0.11 g) was dissolved in dioxane (3 mL), one
drop of anisole was added and 4N HCl in dioxane (3 mL) was added
dropwise. The mixture was stirred at rt for 2 h and concentrated
using MeCN as an azeotrope. The resulting solid was triturated with
Et.sub.2O and hexane and dried to give Compound 3f as a sticky
solid. MS (ES+) m/z 299 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 1.34 (m, 4H), 1.94 (m, 1H), 2.67 (m, 2H), 3.01 (m,
2H), 3.24 (m, 2H), 3.43 (s, 3H), 3.68 (m, 1H), 7.79 (t, J=8 Hz,
1H), 7.94 (t, J=8 Hz, 1H), 8.13 (d, J=8 Hz, 1H), 8.23 (d, J=8 Hz,
1H), 8.48 (m, 1H), 8.70 (m, 1H). Anal. Calcd for
C.sub.18H.sub.22N.sub.2O.sub.2.2.2 TFA-0.4H.sub.2O: C, 48.36; H,
4.53; N, 5.04; F, 22.54. Found: C, 48.24; H, 4.42; N, 4.99; F,
22.56.
[0650] 1,3-Diamino-2-hydroxypropane Compound 3i (10.0 g, 111 mmol)
was dissolved in ethanol (30 m-L) and deionized water (30 mL).
Carbon disulfide (6.67 mL, 110.95 mmol) was added dropwise via an
addition funnel over a period of 35 min while the temperature was
maintained at 25-33.degree. C. to afford a milky white mixture. The
resulting mixture was refluxed for 2 h to afford a yellow solution.
After cooling the mixture in ice water, concentrated HCl (7 mL) was
added dropwise while maintaining the mixture's temperature at
25-26.degree. C. The temperature of the mixture was then raised to
79.degree. C. After stirring for 21 h, the mixture was cooled to
2.degree. C. and filtered via vacuum filtration. A white solid was
collected, washed three times with a 1:1 mixture of cold ethanol
and water and dried in vacuo at 40.degree. C. to give Compound 3j.
MS (ES.sup.+) m/z 174 (M.sup.+MeCN). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 82.96 (d, J=15 Hz, 2H), 3.15 (d, J=13 Hz, 2H), 3.33 (m, 1H),
3.89 (m, 1H).
[0651] Methyl iodide (2.9 mL, 46 mmol) was added to a stirred
solution of Compound 3j (6.1 g, 46 mmol) in absolute ethanol (35
mL) and the mixture was refluxed for 1 h and cooled to rt. After
concentration, the residue was triturated with Et.sub.2O and dried
in vacuo to give Compound 3k as a white solid. MS (ES.sup.+) m/z
188 (M+MeCN). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.59 (s,
3H), 3.23 (d, J=13 Hz, 2H), 3.43 (d, J=13 Hz, 2H), 4.16 (m,
1H).
[0652] TEA (6.91 mL, 49.61 mmol) was added to a solution of
Compound 3k (13.06 g, 49.61 mmol) in DCM (50 mL) and DMA (5 mL).
The mixture was cooled in an ice bath and Boc.sub.2O (10.82 g,
49.61 mmol) was added at 4.degree. C. The mixture was heated at
41-43.degree. C. for 18 h to afford a light yellow solution. The
resulting solution was washed with water (3.times.75 mL), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to yield Compound 31
as a solid. MS (ES+) m/z 247(M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 1.46 (s, 9H), 1.95 (s, 3H), 2.14 (m, 2H), 2.94 (m,
2H), 3.51 (m, 1H).
[0653] 3-Aminophenyl acetic acid Compound 1d (2.60 g, 17.25 mmol)
was added to a solution of Compound 31 (5.1 g, 21 mmol) in DMA (5
mL). The mixture was heated at 100.degree. C. for 2 d, cooled to rt
and diluted with MeCN (75 mL). The resulting precipitate was
filtered and washed with MeCN and Et.sub.2O, taken up in water and
acidified with conc. HCl. After lyophilization, Compound 3m was
obtained as a white solid. MS (ES+) m/z 250 (M+H.sup.+). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.16 (d, J=13 Hz, 2H), 3.33 (d,
J=13 Hz, 2H), 3.59 (s, 2H), 7.12 (m, 3H), 7.35 (m, 1H), 8.14 (s,
1H).
[0654] Using the procedure described in Example 2 for converting
Compound 2d to Compound 2e, Compound 3m was converted to provide
Compound 3n as a solid. MS (ES+) m/z 530 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.92 (m, 4H), 1.33 (m, 2H), 1.90
(m, 1H), 2.88 (m, 4H), 3.17 (m, 3H), 3.33 (m, 2H), 3.43 (s, 3H),
4.06 (m, 2H), 4.32 (m, 1H), 6.98 (m, 3H), 7.27 (m, 1H), 7.48 (m,
1H), 7.66 (m, 1H), 7.79 (m, 1H), 8.01 (m, 3H), 8.25 (br s, 1H),
8.83 (br s, 1H).
[0655] Using the procedure described in Example 2 for converting
Compound 2e to Compound 2, Compound 3n was converted to provide
Compound 3 as a solid. MS (ES+) m/z 516 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.92 (m, 4H), 1.33 (m, 1H), 1.90
(m, 2H), 2.88 (m, 4H), 3.17 (m, 1H), 3.33 (m, 4H), 4.06 (m, 2H),
4.32 (m, 1H), 6.98 (m, 3H), 7.24 (m, 1H), 7.77 (m, 1H), 7.72 (m,
1H), 8.03 (m, 1H), 8.10 (m, 1H), 8.18 (m, 1H), 8.65 (m, 1H), 9.21
(br s, 1H). 899091
EXAMPLE 4
.beta.-[1-[1-Oxo-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]-4-pipe-
ridinyl]-3-quinolinepropanoic acid (Cpd 4)
[0656] Compound 4a was prepared as described in WO 99/31061. Using
the procedure described in Example 2 for converting Compound 2d to
Compound 2e, Compound 4a was converted and purified by RP-HPLC
(10-70% acetonitrile/water, 0.1% TFA) to provide Compound 4b. MS
(ES+) m/z 501 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 1.02 (m, 4H), 1.33 (m, 1H), 2.86 (m, 4H), 2.29 (m, 2H),
2.61 (m, 2H) 2.72 (m, 2H), 2.86 (m, 2H), 2.98 (m, 2H), 3.17 (m,
1H), 3.44 (s, 3H), 3.78 (m, 2H), 4.35 (m, 2H), 6.52 (d, J=7 Hz,
1H), 7.56 (d, J=7 Hz, 1H), 7.78 (m, 2H), 7.99 (m, 2H), 8.41 (s,
1H), 8.91 (s, 1H).
[0657] Using the procedure described in Example 2 for converting
Compound 2e to Compound 2, Compound 4b was converted to provide
Compound 4 as a sticky solid. MS (ES+) m/z 487 (M+H.sup.+). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.99 (m, 4H), 1.49 (m, 1H),
2.86 (m, 4H), 2.30 (m, 2H), 2.69 (m, 2H), 2.81 (m, 1H), 2.92 (m,
2H), 3.13 (m, 2H), 3.33 (m, 1H), 3.79 (m, 2H), 4.41 (m, 2H), 6.55
(d, J=7 Hz, 1H), 7.56 (d, J=7 Hz, 1H), 7.86 (m, 1H), 7.98 (m, 2H),
8.72 (m, 2H), 8.83 (s, 1H), 9.15 (s, 1H). Anal. Calcd for
C.sub.29H.sub.34N.sub.4O.sub.3.3.5 HCl-H.sub.2O: C, 55.09; H. 6.30;
N, 8.86; H.sub.2O, 3.24. Found: C, 54.83; H, 6.53; N, 9.08;
H.sub.2O, 3.24. 9293
[0658] Using the procedure of Example 4 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
10 MS Cpd Name (m/z) 14
.beta.-(1,3-benzodioxol-5-yl)-1-[1-oxo-3-(5,6,7,8- 466
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4- piperidinepropanoic
acid 15 .beta.-(1,3-benzodioxol-5-yl)-1-[1-oxo-4-(5,6,7,8- 480
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4- piperidinepropanoic acid
16 .beta.-(1,3-benzodioxol-5-yl)-1-[(5,6- ,7,8- 452
tetrahydro-1,8-naphthyridin-2-yl)acetyl]- 4-piperidinepropanoic
acid 17 6-methoxy-.beta.-[1-[1-oxo-4-(5,6,7- ,8- 467
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4-
piperidinyl]-3-pyridinepropanoic acid 82 3-(2,3-Dihydro-benzofura-
n-6-yl)-3-[1-4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
yl)butyl]-4-piperidinyl]-propanoic acid
[0659] and pharmaceutically acceptable salts thereof.
EXAMPLE 5
3,4-Tetrahydro-.beta.-[1-[1-oxo-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-
l)butyl]-4-piperidinyl]-3-quinolinepropanoic acid (Cpd 5)
[0660] Compound 3d (0.49 g) was combined with 10% Pd/C (0.6 g) in
methanol (40 mL) and water (1.5 mL), and hydrogenated at 50 psi of
H.sub.2 for 3 d. After filtration of catalyst, the evaporated
material was purified by flash chromatography (gradient 20-30%
ethyl acetate in heptane with a few drops of triethylamine) to
provide Compounds 5a (0.23 g, 47%) and 5b (0.16 g, 32%). Cpd 5a: MS
(ES+) m/z 403 (M+H.sup.+). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.2-1.7 (m, 4H), 1.45 (s, 9H), 1.9-2.4 (m, 4H), 2.5-3.1 (m,
5H), 3.27 (m, 1H), 3.68 (s, 3H), 3.84 (m, 1H), 4.13 (m, 2H), 6.48
(d,J=8 Hz, 1H), 6.61-6.69 (m, 1H), 6.92-6.99 (m, 2H). Cpd 5b: MS
(ES+) m/z 403.5 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 0.8-1.3 (m, 4H), 1.35 (s, 9H), 1.6-1.8 (m, 4H), 2.6-2.8 (m,
10H), 3.45 (s, 3H), 3.8-4.0 (m, 2H), 7.27 (m, 1H), 8.08 (m,
1H).
[0661] Using the procedure described in Example 3 for converting
Compound 3e to Compound 3f, Compound 5a was converted to provide
Compound 5c as a solid. MS (ES+) m/z 303 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.61 (m, 4H), 1.82 (m, 1H), 2.32
(m, 1H), 2.44 (m, 2H), 2.78 (m, 2H), 3.25 (m, 2H), 3.35 (m, 2H),
3.62 (s, 3H), 3.78 (m, 3H), 7.16 (m, 2H), 8.76 (m, 2H).
[0662] Using the procedure described in Example 2 for converting
Compound 2d to Compound 2e, Compound 4a was reacted with Compound
5c and purified by RP-HPLC (10-70% acetonitrile/water, 0.1% TFA) to
provide Compound 5d. MS (ES+) m/z 505 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.11 (m, 4H), 1.56 (m, 1H), 1.79
(m, 6H), 2.32 (m, 4H), 2.66 (m, 2H), 2.77 (m, 2H), 2.91 (m, 2H),
3.16 (m, 2H), 3.5 (m, 2H), 3.62 (s, 3H), 3.82 (m, 2H), 4.43 (m,
2H), 6.58 (m, 3H), 7.63 (d,J=7 Hz, 1H), 7.93 (m, 2H).
[0663] Using the procedure described in Example 2 for converting
Compound 2e to Compound 2, Compound 5d was converted to provide
Compound 5 as an HCl salt. MS (ES+) m/z 491 (M+H.sup.+). .sup.1HNMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.13 (m, 4H), 1.54 (m, 2H), 1.77
(m, 4H), 2.21 (m, 4H), 2.37 (m, 1H), 2.64 (m, 2H), 2.71 (m, 2H),
2.96 (m, 2H), 3.23 (m, 2H), 3.45 (s, 2H), 3.84 (m, 2H), 4.45 (m,
2H), 6.54 (m, 3H), 6.98 (m, 2H), 7.61 (d, J=8 Hz, 1H), 8.01 (br s,
1H). 9495
[0664] Using the procedure of Example 5 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
11 MS Cpd Name (m/z) 18
1,4,5,6-tetrahydro-2-methyl-.beta.-[[1-[1-oxo-3- 456
(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)propyl]-4-piperidinyl-
]methyl]-5- pyrimidinepropanoic acid 19
1,2,3,4-tetrahydro-.beta.-[[1-[1-oxo-3-(5,6,7,8- 491
tetrahydro-1,8-naphthyridin-2-yl)propyl]-
4-piperidinyl]methyl]-3-quinolinepropanoic acid 57
5,6,7,8-tetrahydro-.beta.-[[1-[1-oxo-3-(5,6,7,8- 491
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-
piperidinyl]methyl]-3-quinolinepropanoic acid
[0665] and pharmaceutically acceptable salts thereof.
EXAMPLE 6
.beta.-[2-[1-[3-[(1,4,5,6-Tetrahydro-2-pyrimidinyl)amino]benzoyl]-4-piperi-
dinyl]ethyl]-3-pyridinepropanoic acid (Cpd 6)
[0666] Using the procedure described in Example 3 for converting
Compound 3a to Compound 3b, N-Boc-piperidin-4-propionic acid
Compound 2c was converted to Compound 6a (colorless liquid;
purified by flash chromatography (on silica gel, eluted with 30-50%
ethyl acetate/hexane with a few drops of TEA). MS (ES+) m/z 301
(M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (m,
4H), 1.45 (s, 9H), 1.62 (m, 1H), 1.68 (m, 2H), 2.44 (t, J=7.5 Hz,
2H), 2.63 (m, 2H), 3.18 (s, 3H), 3.68 (s, 3H), 4.08 (m, 2H).
[0667] Using the procedure described in Example 3 for converting
Compound 3b to Compound 3c, Compound 6a was converted to Compound
6b (purified by flash chromatography on silica gel, eluted with
30-50% ethyl acetate/hexane with a few drops of TEA). MS (ES+) m/z
319 (M+H.sup.+).
[0668] Using the procedure described in Example 3 for converting
Compound 3c to Compound 3d, Compound 6b was converted to Compound
6c (purified by flash chromatography on silica gel, eluted with
30-50% ethyl acetate/hexane with a few drops of TEA). MS (ES+) m/z
375 (M+H.sup.+).
[0669] Using the procedure described in Example 3 for converting
Compound 3d to Compound 3e, Compound 6c was converted to Compound
6d (purified by flash chromatography on silica gel, eluted with
15-35% ethyl acetate/hexane with a few drops of TEA). MS (ES+) m/z
377 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.91
(m, 4H), 1.12 (m, 2H), 1.29 (m, 1H), 1.41 (s, 9H), 1.53 (m, 3H),
2.63 (m, 2H), 3.98 (m, 2H), 3.35 (s, 3H), 3.48 (m, 1H), 3.88 (m,
2H), 7.34 (m, 1H), 7.68 (m, 1H), 8.43 (m, 2H).
[0670] Using the procedure described in Example 3 for converting
Compound 3e to Compound 3f, Compound 6d was converted to Compound
6e (white solid). MS (ES+) m/z 277 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.91 (m, 2H), 1.19 (m, 4H), 1.44
(m, 1H), 1.71 (m, 2H), 2.71 (m, 2H), 2.82 (m, 2H), 3.08 (m, 2H),
3.21 (m, 1H), 3.49 (s, 0.3H), 7.51 (m, 1H), 7.94 (m, 1H), 8.53 (m,
2H).
[0671] Using the procedure described in Example 1 for converting
Compound 1e to Compound 1e, Compound 1c was reacted with
3-aminobenzoic acid Compound 6f to provide Compound 6g as a white
amorphous solid. MS (ES+) m/z 220 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 4.13 (m, 2H), 5.42 (t, J=5 Hz, 4H),
6.81 (m, 4H).
[0672] Using the procedure described in Example 1 for converting
Compound 1j to Compound 1k, Compound 6g was reacted with Compound
6e to produce Compound 6h (purified via RP-HPLC: 5-50%
acetonitrile/water, 0.1% TFA). MS (ES+) m/z 478 (M+H.sup.+).
[0673] Using the procedure described in Example 2 for converting
Compound 2e to Compound 2, Compound 6h was converted to Compound 6
(purified via RP-HPLC: 5-50% acetonitrile/water, 0.1% TFA). MS
(ES+) m/z 464 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 1.11 (m, 2H), 1.19 (m, 2H), 1.49 (m, 4H), 1.68 (m, 1H),
1.72 (m, 4H), 2.72 (m, 4H), 3.15 (m, 1H), 3.65 (m, 2H), 4.38 (m,
2H), 7.12-7.51 (m, 4H), 7.73 (m, 1H), 8.21 (m, 1H), 8.65 (m, 2H).
969798
EXAMPLE 7
.beta.-[2-[1-[3-[(1,4,5,6-Tetrahydro-5-hydroxy-2-pyrimidinyl)amino]benzoyl-
]-4-piperidinyl]ethyl]-3-pyridinepropanoic acid (Cpd 7)
[0674] Using the procedure described in Example 3 for converting
Compound 3l to Compound 3m, Compound 3l was reacted with
3-aminobenzoic acid Compound 6f to provide Compound 7a as a white
amorphous solid. MS (ES+) m/z 235 (M+H.sup.+). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 3.18 (d, J=12 Hz, 2H), 3.35 (d,
J=12 Hz, 2H), 4.09 (m, 1H), 7.55 (m, 2H), 7.84 (m, 2H).
[0675] Using the procedure described in Example 3 for converting
Compound 3m to Compound 3n, Compound 7a was reacted with Compound
6e to produce Compound 7b (white solid; purified by RP-HPLC: 2-30%
acetonitrile/water, 0.1% TFA). MS (ES+) m/z 494 (M+H.sup.+).
[0676] Using the procedure described in Example 3 for converting
Compound 3n to Compound 3, Compound 7b was converted to provide
Compound 7 as a white solid. MS (ES+) m/z 480 (M+H.sup.+). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.03 (m, 2H), 2.22 (m, 4H),
1.49 (m, 1H), 1.66 (m, 2H), 2.65 (m, 2H), 2.76 (m, 2H), 3.06 (m,
2H), 3.18 (m, 4H), 3.34 (m, 1H), 4.13 (s, 1H), 7.12-8.78 (m, 8H),
9.91 (s, 1H). 99
EXAMPLE 8
.beta.-[2-[1-[1-Oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-4--
piperidinyl]ethyl]-3-pyridinepropanoic acid (Cpd 8)
[0677] The acid Compound 8a was derived from the corresponding
ethyl ester as described in WO99/31061, the synthesis of which was
described in WO 00/72801.
[0678] Using the procedure described in Example 5 for converting
Compound 4a to Compound 5c, Compound 8a was reacted with Compound
6e to yield Compound 8b (purified by RP-HPLC: 10-90%
acetonitrile/water, 0.1% TFA). MS (ES+) m/z 465 (M+H.sup.+).
[0679] Using the procedure described in Example 5 for converting
Compound 5c to Compound 5, Compound 8b was converted to provide
Compound 8 as an HCl salt. MS (ES+) m/z 451 (M+H.sup.+). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.03 (m, 2H), 1.19 (m, 2H),
1.49 (m, 4H), 1.68 (m, 1H), 1.72 (m, 4H), 2.72 (m, 2H), 2.98 (m,
2H), 3.18 (m, 1H), 3.65 (m, 2H), 4.33 (m, 2H), 7.25 (m, 2H), 7.51
(m, 1H), 7.73 (m, 1H), 8.21 (m, 1H), 8.31 (s, 1H), 8.65 (m, 2H).
100
[0680] Using the procedure of Example 8 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
12 MS Cpd Name (m/z) 20
.beta.-(1,3-benzodioxol-5-yl)-1-[1-oxo-3-(5,6,7,8- 494
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4- piperidinepentanoic
acid 21 6-methoxy-.beta.-[2-[1-[1-oxo-3-(5,6,7,8- 481
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-
piperidinyl]ethyl]-3-pyridinepropanoic acid
[0681] and pharmaceutically acceptable salts thereof.
EXAMPLE 9
.beta.-[2-[1-[1-Oxo-4-(2-pyridinylamino)butyl]-4-piperidinyl]ethyl]-3-pyri-
dinepropanoic acid (Cpd 9)
[0682] A mixture of Compound 6e (0.14 g, 0.44 mmol) in DCM (10 mL)
and NMM (0.09 mL, 0.89 mmol) was stirred for 0.5 h at rt then
cooled in an ice bath. 4-Bromobutyrylchloride Compound 9a (0.06 mL,
0.58 mmol) and NMM (0.09 mL, 0.89 mmol) were added and the reaction
mixture was stirred for 6 h at 0.degree. C. and overnight at rt.
The reaction mixture was washed with saturated NH.sub.4Cl solution
(5 mL), water (5 mL) and 1N HCl (3.times.10 mL). The organic layer
was dried (Na.sub.2SO.sub.4) and concentrated in vacuo to yield
Compound 9b as a viscous oil. MS (ES+) m/z 345 (M-Br).
[0683] DIEA (0.73 mL, 4.23 mmol) was added to a stirred solution of
Compound 9b (0.60 g, 1.41 mmol) and 2-aminopyridine Compound 9c
(0.39 g, 4.23 mmol) in toluene (10 mL). The mixture was refluxed
overnight and concentrated in vacuo. The residue was purified by
RP-HPLC (2-30% acetonitrile/water, 0.1% TFA) to give Compound 9d as
an oil. MS (ES+) m/z 439 (M+H.sup.+).
[0684] Using the procedure described in Example 6 for converting
Compound 6h to Compound 6, Compound 9d was converted to Compound 9
(purified by RP-HPLC: 2-30% acetonitrile/water, 0.1% TFA). MS (ES+)
m/z 425 (M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
1.01 (m, 2H), 1.11 (m, 4H), 1.36 (m, 1H), 1.69 (m, 4H), 2.16 (m,
2H), 2.39 (m, 2H), 3.21 (m, 2H), 3.76 (m, 2H), 4.26 (m, 2H), 4.61
(m, 1H), 7.31-8.72 (m, 8H). 101
[0685] Using the procedure of Example 9 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
13 MS Cpd Name (m/z) 22
.beta.-[2-[1-[1-oxo-4-(2-pyridinylamino)butyl]-4- 475
piperidinyl]ethyl]-3-quinolinepropanoic acid 23
.beta.-(1,3-benzodioxol-5-yl)-1-[1-oxo-4-(2- 468
pyridinylamino)butyl]-4-piperidinepentanoic acid 24
.beta.-(1,3-benzodioxol-5-yl)-1-[1-oxo-4-(2- 440
pyridinylamino)butyl]-4-piperidinepropanoic acid 25
6-methoxy-.beta.-[2-[1-[1-oxo-4-(2- 455 pyridinylamino)butyl]-4-p-
iperidinyl]ethyl]- 3-pyridinepropanoic acid
[0686] and pharmaceutically acceptable salts thereof.
EXAMPLE 10
6-Methoxy-.beta.-[2-[1-[3-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)ami-
no]benzoyl]-4-piperidinyl]ethyl]-3-pyridinepropanoic acid (Cpd
10)
[0687] Using the procedure described in Example 6 for converting
Compound 6c to Compound 6d, Compound 10a was converted to Compound
10b (colorless liquid; purified by flash chromatography on silica
gel, 10-15% ethyl acetate/hexane with a few drops of TEA). MS (ES+)
m/z 407 (M+H.sup.+) as a racemic mixture that was enantiomerically
separated using a chiralcel OJ column eluting with hexane/ethanol
(75:25). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.04 (m, 4H),
1.19 (m, 2H), 1.47 (s, 9H), 1.61 (m, 1H), 1.73 (m, 2H), 2.66 (m,
4H), 3.02 (m, 2H), 3.61 (s, 3H), 3.92 (s, 3H), 4.01 (m, 1H), 6.81
(d, J=7 Hz, 1H), 7.38 (d, J=7 Hz, 1H), 8.05 (s, 1H).
[0688] Using the procedure described in Example 6 for converting
Compound 6d to Compound 6e, Compound 10b was converted to provide
Compound 10c as an HCl salt. MS (ES+) m/z 307 (M+H.sup.+). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.98 (m, 2H), 1.18 (m, 1H),
1.53 (m, 4H), 1.81 (m, 2H), 2.62 (m, 2H), 2.81 (m, 4H), 3.22 (m,
1H), 3.53 (s, 3H), 3.83 (s, 3H), 6.76 (d, J=9 Hz, 1H), 7.63 (m,
1H), 8.04 (m, 1H). Anal. Calcd for
C.sub.17H.sub.26N.sub.2O.sub.3-1.63 CF.sub.3COOH-0.2H.sub.2O: C,
49.08; H, 5.70; N, 5.65; H.sub.2O, 0.73. Found: C, 49.10; H, 5.66;
N, 5.65; H.sub.2O, 0.93.
[0689] Using the procedure described in Example 7 for converting
Compound 7a to Compound 7b, Compound 7a was reacted with Compound
10c to produce Compound 10d. Using the procedure described in
Example 3 for converting Compound 3n to Compound 3, Compound 10d
was converted to produce Compound 10 as an HCl salt (purified by
RP-HPLC: 5-50% acetonitrile/water, 0.1% TFA). MS (ES+) m/z 510
(M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.99 (m,
2H), 1.14 (m, 1H), 1.53 (m, 6H), 1.67 (m, 2H), 2.58 (m, 2H), 2.94
(m, 1H), 3.15 (d, J=11 Hz, 2H), 3.33 (d, J=12 Hz, 2H), 3.81 (s,
3H), 3.86 (m, 2H), 4.09 (m, 1H), 6.75 (d,J=9 Hz, 1H), 7.12-7.29 (m,
4H), 7.63 (m, 1H), 8.03 (m, 1H). 102
EXAMPLE 11
[0690] Using the procedures described in Examples 6 and 8 for
preparing Compound 8, the enantiomers of Compound 21 were produced
from the enantiomers of 10b.
[0691] The two pure chiral intermediates 10b-1 (isomer 1: faster
eluting) and 10b-2 (isomer 2: slower eluting) were obtained by
chiral HPLC chromatography (stationary phase: 500 g of Chiralcel
OJ; eluent: hexane/ethanol 75/25; wavelength: 220 nm). Compounds
10b-1 and 10b-2 were converted individually to 21a and 21b,
respectively, by the same methods used to convert 6d to 8 in
Examples 6 and 8. Using the procedure of Example 11 and the
appropriate solvents, columns, reagents and starting materials
known to those skilled in the art, other compounds of the present
invention may be prepared including, but not limited to:
14 MS Cpd Name (m/z) 28a
6-methoxy-.beta.-[[1-[1-oxo-3-(5,6,7,8-tetrahydro- 467
1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-
3-pyridinepropanoic acid 28b 6-methoxy-.beta.-[[1-[1-oxo-3-(5,6,7,-
8-tetrahydro- 467 1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]meth-
yl]- 3-pyridinepropanoic acid
EXAMPLE 12
.beta.-(1,3-Benzodioxol-5-yl)-1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyri-
din-2-yl)propyl]-4-piperidinebutanoic acid (Cpd 11)
[0692] To a solution of Compound 12a (5 g, 20.55 mmol) and NMM
(4.96 mL, 45.11 mmol) in anhydrous THF (50 mL) at -20.degree. C.
under nitrogen, isobutyl chloroformate (2.67 mL, 20.58 mmol) was
added via syringe. The mixture was stirred for 30 min and
N,O-dimethylhydroxylamine (2 g, 20.5 mmol) was added in one
portion. The mixture was warmed slowly to rt and stirred for 2 d.
After concentration in vacuo, the residue was partitioned between
EtOAc and 1N HCl. The organic phase was separated, washed with
H.sub.2O and saturated NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to afford Compound 12b as an oil. Compound
12b was used in the next reaction without further purification.
Butyllithium (2.5M in hexane, 4.19 mL, 10.48 mmol) was added
dropwise to a solution of 4-bromo-1,2-(methylenedioxy)benzene
Compound 12c (1.26 mL, 10.48 mmol) in THF (40 mL) at -78.degree. C.
The mixture was stirred at -78.degree. C. for 30 min and a solution
of Compound 12b (2 g, 6.98 mmol) in THF (10 mL) was added dropwise.
After the mixture was stirred at -78.degree. C. for 30 min, the
cooling bath was removed. The mixture was stirred an additional 2 h
at rt and quenched with a saturated NH.sub.4Cl solution. The
organic phase was separated, washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified via
RP-HPLC to yield Compound 12d as an oil.
[0693] Sodium hexamethyldisilazide (1.0M in THF, 2.07 mL, 2.07
mmol) was added dropwise to a solution of trimethyl
phosphonoacetate (0.33 mL, 2.07 mmol) in THF (10 mL) at 0.degree.
C. The mixture was stirred at 0.degree. C. for 30 min and a
solution of Compound 12d (0.18 g, 0.52 mmol) in THF (5 mL) was
added dropwise. The mixture was heated to reflux for 16 h then
stirred at rt for additional 24 h, cooled, diluted with Et.sub.2O
(30 mL) and washed with sat. NaHCO.sub.3 and brine. The organic
layer was dried (Na.sub.2SO.sub.4) and concentrated. The residue
was purified via RP-HPLC to give Compound 12e. A solution of
Compound 12e (0.5 g, 1.24 mmol) in MeOH (20 mL) was hydrogenated at
40 psi of H.sub.2 in the presence of 10% palladium on carbon (0.2
g) for 16 h. The catalyst was removed by filtration over celite.
The filtrate was concentrated in vacuo to yield Compound 12f as an
oil. Compound 12f was used in the next reaction without further
purification. TFA (5 mL) was added to a solution of Compound 12f
(0.37 g, 0.91 mmol) in DCM (20 mL). The mixture was stirred at rt
for 30 min, concentrated in vacuo and the residue was purified via
RP-HPLC to give Compound 12g as an oil.
[0694] To a solution of Compound 8a (0.28 g, 1.15 mmol) in DMF (40
mL), 1-HOBt (0.135 g, 1.0 mmol), EDC (0.192 g, 1.0 mmol) and DIEA
(0.35 mL, 2 mmol) were added under Argon at rt. The mixture was
stirred at rt for 45 min. A solution of Compound 12g (0.28 g, 0.067
mmol) and DIEA (0.35 mL, 2 mmol) in DMF (10 mL) was added to the
mixture containing Compound 8a. The resulting mixture was stirred
overnight at rt. Water (2 mL) was added, followed by DCM (20 mL).
The organic layer was separated, dried (Na.sub.2SO.sub.4) and
concentrated. The resulting crude Compound 12h was used as such in
the next reaction. The crude Compound 12h was dissolved in MeOH (20
mL) and 3N aqueous NaOH (6 mL) was added. The mixture was stirred
at rt for 5 h and neutralized with 2N HCl. After the solvent was
evaporated, the residue was purified via RP-HPLC to yield Compound
11. MS (ES+) m/z 480 (M+H.sup.+). .sup.1H-NMR of Compound 11:
.sup.1HNMR (CDCL.sub.3, 300 MHz) .delta. 1.09 (m, 2H,), 1.30 (m,
1H), 1.4-1.7 (m, 3H), 1.86 (m, 1H), 1.94 (m, 2H), 2.47 (m, 1H),
2.58 (d,J=7.5 Hz, 2H), 2.7-3.1 (m, 7H), 3.15 (m, 1H), 3.51 (br s,
2H), 3.99 (dd, J=5.3 Hz, 14.3 Hz, 2H), 4.49 (dd, J=5.3 Hz, 14.3 Hz,
2H), 5.97 (s, 2H), 6.45 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H),
6.69, (s, 1H), 6.75 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 9.82
(s, 2H), 15.0 (s, 1H). 103104
[0695] Using the procedure of Example 12 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
15 MS Cpd Name (m/z) 26
.beta.-(1,3-benzodioxol-5-yl)-1-[1-oxo-4-(5,6,7,8- 494
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4- piperidinebutanoic acid
27 .beta.-(1,3-benzodioxol-5-yl)-1-[3-[(1,4,5,6- 509
tetrahydro-5-hydroxy-2-pyrimidinyl)amino]benzoyl]-
4-piperidinebutanoic acid 28 6-methoxy-.beta.-[[1-[1-oxo-3-(5,6,7,-
8- 467 tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-
piperidinyl]methyl]-3-pyridinepropanoic acid 29
.beta.-[[1-[1-oxo-4-(5,6,7,8-tetrahydro-1,8- 501
naphthyridin-2-yl)butyl]-4-piperidinyl]methyl]-
3-quinolinepropanoic acid 30 .beta.-(3-fluorophenyl)-1-[1-oxo-3-(5-
,6,7,8-tetrahydro-1,8- 454 naphthyridin-2-yl)propyl]-4-piperidineb-
utanoic acid 31 .beta.-(3-fluorophenyl)-1-[1-oxo-4-(5,6,7,8- 468
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4- piperidinebutanoic acid
32 .beta.-[[1-[1-oxo-3-(5,6,7,8-tetrahydro- -1,8- 487
naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-
quinolinepropanoic acid 33 .beta.-(4-fluorophenyl)-1-[1-oxo-3-(5-
,6,7,8-tetrahydro-1,8- 454 naphthyridin-2-yl)propyl]-4-piperidineb-
utanoic acid 34 .beta.-(4-fluorophenyl)-1-[1-oxo-4-(5,6,7,8- 468
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4- piperidinebutanoic acid
35 2-methyl-.beta.-[[1-[1-oxo-3-(5,6,7,8- 452
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-
piperidinyl]methyl]-5-pyrimidinepropanoic acid 36
.beta.-(2,3-dihydro-6-benzofuranyl)-1-[1-oxo-3- 478
(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)propyl]-4-piperidinebu-
tanoic acid 37 .beta.-(3,5-difluorophenyl)-1-[1-oxo-3-(5,6,7,8- 472
tetrahydro-1,8-naphthyridin-2-yl)propyl]- 4-piperidinebutanoic acid
38 .beta.-(3,5-difluorophenyl)-1-[1-oxo-- 4-(5,6,7,8- 486
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4- piperidinebutanoic acid
39 1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8- 504
naphthyridin-2-yl)propyl]-.beta.-[3-
(trifluoromethyl)phenyl]-4-piperidinebutanoic acid 40
1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8- 520 naphthyridin-2-yl)propyl]-
-.beta.-[4- (trifluoromethoxy)phenyl]-4-piperidinebutanoic acid 41
.beta.-(2-fluoro[1,1'-biphenyl]-4-yl)-1-[1-oxo-3- 530
(5,6,7,8-tetrahydro-1,8-naphthyridin-2-
yl)propyl]-4-piperidinebutanoic acid 42 .beta.-(3-fluoro-4-methoxy-
phenyl)-1-[1-oxo-3- 484 (5,6,7,8-tetrahydro-1,8-naphthyridin-2-
yl)propyl]-4-piperidinebutanoic acid 43
1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8- 528 naphthyridin-2-yl)propyl]-
-.beta.-(4- phenoxyphenyl)-4-piperidinebutanoic acid 44
.beta.-[[1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8- 487
naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-
4-isoquinolinepropanoic acid 45 .beta.-[[1-[1-oxo-3-(5,6,7,8-tetra-
hydro-1,8- 437 naphthyridin-2-yl)propyl]-4-
piperidinyl]methyl]-3-pyridinepropanoic acid 46
.beta.-(2,3-dihydro-5-benzofuranyl)-1-[1-oxo-3- 478
(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)propyl]-4-piperidinebu-
tanoic acid 47 2,4-dimethoxy-.beta.-[[1-[1-oxo-3- 498
(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)propyl]-4-piperidinyl]-
methyl]-5- pyrimidinepropanoic acid 48
2-methoxy-.beta.-[[1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8- 468
naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-
5-pyrimidinepropanoic acid
EXAMPLE 13
.beta.-[2-[1-[3-[(1,4,5,6-Tetrahydro-2-pyrimidinyl)amino]benzoyl]-4-piperi-
dinyl]ethyl]-3-quinolinepropanoic acid (Cpd 12)
[0696] A suspension of lithium aluminum hydride (3.11 g, 0.082 mol)
in Et.sub.2O (250 mL) was cooled at -55.degree. C. under Argon. A
solution of Compound 3b (18.5 g, 0.068 mol) in Et.sub.2O (75 mL)
was added dropwise over a period of 15 min so that the temperature
did not exceed -50.degree. C. The cooling bath was removed and the
mixture was warmed up to 5.degree. C., cooled again to -35.degree.
C. and celite (50 g) was added. The mixture was quenched slowly
with bisulphate solution (15.30 g in 43 mL of H.sub.2O) while the
temperature was kept at -30.degree. C. The resulting mixture was
warmed to 0.degree. C., filtered over celite and the solid residue
on the filter was washed with EtOAc (750 mL) and H.sub.2O (500 mL).
The organic layer was separated, washed with 0.5N HCl (100 mL),
saturated NaHCO.sub.3 (100 mL) and brine (100 mL). The aqueous
layer was extracted with EtOAc (500 mL) and the combined organic
layers were dried, filtered and evaporated. The resulting residue
was purified by Kugelrohr distillation (120-140.degree. C. at 1.5-2
mm Hg) to yield Compound 13a as a colorless oil.
[0697] A mixture of 3-bromoquinoline (10.40 g, 0.05 mol),
trimethylsilylacetylene (8.48 mL, 0.06 mol), cuprous iodide (0.5 g)
and trans-dichlorobis(triphenylphosphine)palladium (1 g) and TEA
(15 mL) was heated at 70.degree. C. in a sealed tube for 1 h.
H.sub.2O (150 mL) was added, followed by Et.sub.2O (300 mL). The
organic layer was separated and the aqueous layer extracted with
Et.sub.2O (200 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified by
flash column chromatography (eluent: 100% DCM) to give
3-(trimethylsilylethynyl) quinoline as a brown oil.
3-(Trimethylsilylethynyl) quinoline was dissolved in anhydrous MeOH
(100 mL) and K.sub.2CO.sub.3 (0.69 g, 5 mmol) was added. The
mixture was stirred at rt for 1 h and DCM (250 mL) was added. The
mixture was filtered over celite. The filtrate was evaporated and
the residue was purified by flash column chromatography to give
Compound 13b as an off-white solid.
[0698] Butyllithium (2.5M in hexane, 9.44 mL, 23.6 mmol) was added
dropwise to a solution of Compound 13b (3.62 g, 23.6 mmol) in THF
(150 mL) under argon, such that the temperature did not exceed
-60.degree. C., then the mixture was cooled to -70.degree. C. The
mixture was stirred at -70.degree. C. for 15 min and a solution of
Compound 13a in THF (40 mL) was added dropwise while maintaining
the temperature between -60 and -70.degree. C. After stirring at
-70.degree. C. for 30 min, the mixture was warmed to 0.degree. C.
over a period of 20 min and H.sub.2O (1 mL) was added. The
resulting mixture was dried over K.sub.2CO.sub.3, filtered and
evaporated. The residue was purified by flash column chromatography
(eluent gradient: DCM/MeOH: 100:0 to 95:5) to yield Compound 13c as
an oil. A mixture of Compound 13c (6.05 g) in pyridine (100 mL) was
hydrogenated in the presence of Lindlar's catalyst (1 g) at 1 psi
of hydrogen for 7 h. The catalyst was removed by filtration over
celite and the solvent was evaporated. The residue was purified by
flash column chromatography (eluent gradient: hexane/EtOAc: 9:1 to
1:1) to yield Compound 13d as a solid.
[0699] A solution of methyl 3-chloro-3-oxopropionate (1.24 mL,
11.53 mmol) in DCM (20 mL) was added dropwise over a period of 30
min to a solution of Compound 13d (4.25 g, 11.53 mmol) and TEA
(1.81 mL, 13 mmol) in DCM (80 mL) at 0.degree. C. under argon. The
mixture was stirred overnight at rt. Aqueous NH.sub.4Cl solution
(50 mL) and DCM (150 mL) were added. The organic layer was
separated and washed with sat. NaHCO.sub.3 (100 mL) and brine (100
mL), dried (Na.sub.2SO.sub.4), filtered and evaporated. The residue
was purified by flash column chromatography (eluent gradient:
hexane/EtOAc: 4:1 to 1:1) to yield Compound 13e as an oil.
[0700] A solution of Compound 13e (4.45 g, 9.5 mmol) in THF (20 mL)
was added dropwise to a flask containing sodium hydride (60% in
mineral oil, 0.57 g, 14.25 mmol, triple washed with hexane
(3.times.25 mL)) at 60.degree. C. under argon. The mixture was
heated to 60.degree. C. for 15 min. Chlorotrimethylsilane (2.41 g,
19 mmol) was added via syringe and the mixture was heated for 4 h
at 60.degree. C. H.sub.2O (0.5 mL) was added and the mixture was
stirred overnight at rt. The reaction mixture was evaporated, DCM
(250 mL) was added and the mixture was dried (Na.sub.2SO.sub.4).
After filtration and evaporation, the residue was heated at
130.degree. C. for 2 h under vacuum. Purification by flash column
chromatography (eluent: 1% MeOH in DCM) gave Compound 13f as a
yellow oil.
[0701] A solution of Compound 13f (0.375 g, 0.88 mmol) in MeOH (50
mL) was hydrogenated in the presence of 10% palladium on carbon
(120 mg) at 1 psi of hydrogen for 2 h. The catalyst was removed by
filtration over celite and the solvent was evaporated to give a
crude Compound 13g, which was used as such for the next reaction.
TFA (10 mL) was added to a solution of Compound 13g (0.35 g, 0.82
mmol) in DCM (10 mL). The mixture was stirred at rt for 1 h and
concentrated under vacuum to give crude Compound 13h, which was
used as such for the next reaction.
[0702] Isobutyl chloroformate (0.118 mL, 0.90 mmol) was added to a
solution of Compound 6g (230 mg, 0.90 mmol) and NMM (0.385 mL, 3.5
mmol) in DMF (8 mL) under argon at 0.degree. C. The mixture was
stirred at 0.degree. C. for 5 min and a solution of Compound 13h
(0.455 g, 0.82 mmol) in DMF (7 mL) was added dropwise. After the
addition was complete, the cooling bath was removed. The mixture
was stirred at rt overnight. H.sub.2O (0.5 mL) was added and the
mixture was concentrated under high vacuum at 80.degree. C. The
residue was purified by RP-HPLC to yield Compound 13i as a white
powder.
[0703] 1N aqueous NaOH (10 mL) was added to a solution of Compound
13i (0.15 g, 0.2 mmol) in 1,4-dioxane (10 mL). The reaction mixture
was stirred for 20 h at rt and neutralized with 1N HCl (10 mL).
Purification by RP-HPLC yielded Compound 12 as a white powder after
lyophilization. MS (ES+) m/z 514 (M+H.sup.+). .sup.1H-NMR of
Compound 12: .sup.1HNMR (DMSO-d.sub.6, 300 MHz) .delta. 0.97-1.86
(m, 18H), 2.66 (m, 2H), 2.90 (m, 1H), 3.55 (m, 1H), 7.14 (s, 1H),
7.18 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.44 (t,J=7.6 Hz,
1H), 7.65 (t,J=7.6 Hz, 1H), 7.78 (t,J=7.6 Hz, 1H), 8.01 (t,J=8.5
Hz, 2H), 8.19 (s, 1H), 8.35 (s, 1H), 8.91 (s, 1H). 105106107
[0704] Using the procedure of Example 13 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
16 MS Cpd Name (m/z) 49
.beta.-[2-[1-[3-[(1,4,5,6-tetrahydro-5-hydroxy-2- 530
pyrimidinyl)amino]benzoyl]-4-piperidinyl]ethyl]-3-
quinolinepropanoic acid 50 .beta.-[2-[1-[3-[(3,4,5,6-tetrahydro-2-
513 pyridinyl)amino]benzoyl]-4- piperidinyl]ethyl]-3-quin-
olinepropanoic acid 51
.beta.-[2-[1-[1-oxo-3-(5,6,7,8-tetrahydro-1,- 8- 501
naphthyridin-2-yl)propyl]-4-piperidinyl]ethyl]-
3-quinolinepropanoic acid 52 .beta.-[2-[1-[1-oxo-3-(5,6,7,8-tetrah-
ydro-1,8- 507 naphthyridin-2-yl)propyl]-4-piperidinyl]ethyl]-3-
quinolinepropanoic acid 53 .beta.-(1,3-benzodioxol-5-yl)-1-[3-
-[(3,4,5,6- 506 tetrahydro-2-pyridinyl)amino]benzoyl]-4-
piperidinepentanoic acid 54 .beta.-(1,3-benzodioxol-5-yl)-1-[3-[(1-
,4,5,6- 523 tetrahydro-5-hydroxy-2-pyrimidinyl)amino]benzoyl]-
4-piperidinepentanoic acid 55 .beta.-(1,3-benzodioxol-5-yl)-1--
[(5,6,7,8-tetrahydro- 480 1,8-naphthyridin-2-yl)acetyl]-4-piperidi-
nepentanoic acid
EXAMPLE 14
1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-.beta.-phenyl-
-4-piperidinebutanoic acid (Cpd 13)
[0705] Di-tert-butyl dicarbonate (41.25 g, 189 mmol) was added in
one portion to a solution of 4-(2-hydroxyethyl)piperidine Compound
14a (24.42 g, 189 mmol) in DMF (200 mL) at 0.degree. C. After 1
hour, the cooling bath was removed and the reaction mixture was
allowed to stir for 20 h at RT. The reaction mixture was treated
with Et.sub.2O (200 mL) and H.sub.2O (500 mL). The organic layer
was separated, washed with sat NH.sub.4Cl (200 mL) and brine (200
mL) and dried MgSO.sub.4). After filtration and evaporation,
Compound 14b was obtained as a transparent oil and used as such
without further purification.
[0706] A solution of DMSO (14 g, 179 mmol) in DCM (80 mL) was added
dropwise over a period of 1.5 h to a 2M solution of oxalyl chloride
(62.8 mL, 125.6 mmol) in dry DCM (200 mL) at -78.degree. C., such
that the temperature did not exceed -60.degree. C. A solution of
Compound 14a in DCM (30 mL) was added dropwise at -78.degree. C.
over a 50 min period. After stirring 30 min at -78.degree. C., the
cooling bath was removed and the temperature of the reaction
mixture was allowed to rise to -30.degree. C. over a 30 min period.
TEA (25.41 g, 251 mmol) was added and the reaction mixture was
allowed to stir for 1 h at rt. The solid precipitate that had
formed was removed by filtration and the filtrate was washed with
0.3N HCl (2.times.100 mL) and brine (200 mL). The organic phase was
dried (Na.sub.2SO.sub.4), evaporated and the residue was purified
via flash column chromatography (eluent gradient: hexane/EtOAc
100/0 to 70/30) to yield Compound 14c.
[0707] A 1M solution of LiHMDS (73 mL, 73 mmol) was added via
syringe to a solution of trimethyl phosphonoacetate (13.29 g, 73
mmol) in THF (200 mL) at -78.degree. C. under argon. The reaction
mixture was then stirred for 20 min at -78.degree. C. and a
solution of Compound 14c (8.3 g, 36.5 mmol) in THF (50 mL) was
added over a 30 min period. After stirring for 15 min at
-78.degree. C., the cooling bath was removed and the reaction
mixture was heated to reflux for 2. The reaction mixture was
allowed to cool to room temperature and a saturated NH.sub.4Cl
solution (40 mL) was added. Et.sub.2O (200 mL) was added, the
organic layer was separated and washed with brine (140 mL) and
dried (Na.sub.2SO.sub.4). After filtration and evaporation, the
residue was purified via flash column chromatography (eluent
gradient: hexane/EtOAc: 100/0 to 85/15), yielding a mixture of E-
and Z-isomers of Compound 14d.
[0708] Compound 14d, phenyl boronic acid (1.55 g, 12.32 mmol),
[RhCl(Cod)]2 (0.1 g, 0.227 mmol) and Cod (0.557 g, 5.15 mmol) were
combined in H.sub.2O (15 mL) and heated to 100.degree. C. for 3 h
under a nitrogen atmosphere. Phenylboronic acid (1.0 g, 8.2 mmol)
was added again and the reaction mixture was heated to 100.degree.
C. for another 6 h. The reaction mixture was allowed to cool to rt,
Et.sub.2O (100 mL) was added and the organic layer was separated.
The aqueous layer was washed with Et.sub.2O (2.times.100 mL) and
the combined organic layers were dried (Na.sub.2SO.sub.4), filtered
and evaporated. The residue was purified via flash column
chromatography, yielding Compound 14e.
[0709] TFA (6 mL) was added to a solution of Compound 14e (1.48 g,
4.09 mmol) in DCM (14 mL). The mixture was stirred at rt for 20
min, concentrated under vacuum and purified via RP-HPLC to yield
Compound 14f as a trifluoroacetate salt.
[0710] HOBt (0.333 g, 2.46 mmol), EDC (0.47 g, 2.46 mmol) and NMM
(0.68 g, 5.28 mmol) were added to a solution of Compound 8a (0.64
g, 2.64 mmol) in DMF (30 mL) under argon. The mixture was stirred
at rt for 1 h, then a solution of Compound 14f (0.66 g, 1.76 mmol)
and NMM (0.68 g, 5.28 mmol) in DMF (10 mL) was added. The resulting
mixture was stirred overnight at rt. Water (2 mL) was added,
followed by DCM (20 mL). The organic layer was separated, dried
(Na.sub.2SO.sub.4) and concentrated. The resulting crude Compound
14g was used as such in the next reaction. To a solution of
Compound 14g in dioxane (2 mL) and H.sub.2O (1 mL) was added NaOH
(0.78 g, 19.5 mmol). The mixture was stirred at rt for 5 h and
neutralized with 2N HCl. After the solvent was evaporated, the
residue was purified by RP-HPLC to give Compound 13 after
lyophilization. 108
[0711] Using the procedure of Example 14 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
17 MS Cpd Name (m/z) 56
.beta.-(2-naphthalenyl)-1-[1-oxo-3-(5,6,7,8- 486
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4- piperidinebutanoic
acid
[0712] and pharmaceutically acceptable salts thereof.
EXAMPLE 15
Isomers 1, 2, 3, and 4 of
1,2,3,4-tetrahydro-.beta.-[[1-[1-oxo-3-(5,6,7,8--
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-quinoline-
propanoic acid (Cpd 19-1, 19-2, 19-3, 194)
[0713] To a stirred solution of the Weinreb amide 12b (3.00 g,
10.48 mmol) and 3-bromoquinoline Compound 15a (10.9 g, 52.38 mmol)
in THF (120 mL) were added dropwise n-BuLi (2.5 M solution in
hexane; 21.0 mL, 52.38 mmol) over a period of 20 min at -78.degree.
C. The reaction mixture was kept below -74.degree. C. during the
addition. After the addition, the mixture was stirred for 30 min at
-78.degree. C., and then the cooling bath was removed. The reaction
mixture was allowed to warm up to rt over a period of 1 h. The
reaction mixture was quenched by the addition of saturated
NH.sub.4Cl in water (50 mL), and it was extracted with EtOAc (100
mL). The organic layer was washed with brine (10 mL), and dried
over MgSO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography (30%
EtOAc/hexane) to give the ketone Compound 15b as an amber foam. MS
(ES+) m/z 355.4 (M+H.sup.+). .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 1.26 (m, 2H), 1.46 (s, 9H), 1.78 (m, 2H), 2.22 (m, 1H),
2.77 (m, 2H), 3.02 (d, J=7 Hz, 2H), 4.08-4.18 (m, 2H), 7.64 (t, J=7
Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.17 (d, J=8
Hz, 1H), 8.70 (br s, 1H), 9.42 (br s, 1H).
[0714] To a THF (166 mL) solution of trimethyl phosphonoacetate
(11.65 mL, 80.58 mmol) was added dropwise NaHMDS (1.0M in THF; 67.2
mL, 67.15 mmol) over a period of min at -78.degree. C. The
resulting partially solidified mixture was stirred at -50.degree.
C. for 20 min. To the resulting thick solidified mixture, a THF
(119 mL) solution of the ketone Compound 15b (4.76 g, 13.43 mmol)
was added at -50.degree. C. over a period of 5 min. After the
addition, the cooling bath was changed to a water bath and it was
stirred for min. The reaction mixture was then refluxed for 2.5 h.
The reaction was monitored by HPLC. After cooling to rt, the
mixture was diluted with EtOAc (400 mL) and it was washed with
saturated NaHCO.sub.3 (50 mL.times.2), and brine (50 mL). The
organic layer was dried over MgSO.sub.4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (100 g, 6.5.times.5 cm, 20% to 30% EtOAc/hexane) to
give the olefin Compound 15c as an amber-red syrup, mixture of
E,Z-isomers. MS (ES+) m/z 411.3 (M+H.sup.+).
[0715] A MeOH (150 mL) solution of the olefin Compound 15c (2.76 g,
6.72 mmol) was added to 10% Pd/C (5.52 g as is, 50% water wet). The
solution was vacuum/N.sub.2 degassed and then pressurized to 60 psi
H.sub.2 pressure. The reaction was agitated at rt for 22 h. The
reaction mixture was filtered and the filtrates were concentrated
under reduced pressure. The residue was purified by flash-column
chromatography (70 g, 3.times.25 cm column, eluting with 30%
EtOAc/hexane) to afford the hydroquinoline Compound 15d as a light
yellow gum) and Compound 15e as a minor product.
[0716] Alternatively, toluene can be used as the solvent. A
solution of Compound 15c (17.14 g, mmol), was combined with 10%
Pd/C (8.6 g) in toluene (210 mL) with TEA (2.1 mL). The reaction
mixture was shaken on a Parr apparatus at 50.degree. C. and 50 psi
for about 28 h. It was stopped when the hydrogen uptake slowed.
After chromatography Compound 15d was isolated. MS (ES+) m/z 417.1
(M+H.sup.+). .sup.1HNMR (CDCl.sub.3, 300 MHz) .delta. 1.0-1.6 (m,
6H), 1.45 (s, 9H), 2.0-2.7 (m, 8H), 3.00 (m, 1H), 3.26 (m, 1H),
3.67 (s, 3H), 3.83 (m, 1H), 4.11 (m, 2H), 6.49 (d, J=8 Hz, 1H),
6.62 (t,J=7 Hz, 1H), 6.97 (m, 2H).
[0717] The individual enantiomers of Compound 19 were prepared by
separating the isomers of 15d and taking them to final product
Compounds 19-1, 19-2, 19-3, and 194, by the same method that
Compound 5a was converted to Compound 5 in Example 5, but using the
tetrahydronaphthyridine Compound 8a instead of 4a.
[0718] The four isomers of Compound 15d were separated by
sequential chiral chromatography. The UV triggered preparative HPLC
work was accomplished using a Dynamic Axial Compression type
Prochrom LC50 column, which was filled with 500 grams of stationary
phase. A Prep LC 4000 (Waters) quaternary gradient low pressure
mixing pump, a K-2500 UV detector (KNAUER), a 233 XL auto injector
(Gilson), a 402 Syringe pump (Gilson), a 202 fraction collector
(Gilson), an rh.7030L fraction collector valve (Gilson), and
Unipoint control software (Gilson) were utilized. Isomers (numbered
based on elution order: isomer 1 first eluting) 15d-1 and 15d-2
were separated from isomers 15d-3 and 15d4 using a Chiralpak.RTM.
OD column: Cellulose tris-(3,5-dimethylphenylcarbamate) coated on a
20 .mu.m silica-gel, 5 cm ID; 41 cm length; using methanol as
eluent: 100 vol % at 80 mL/min. and a wavelength 220 nM. This
resulted in 15d-1 and 15d-2 as a mixture and 15d-3 and 15d4 as a
mixture. The isomers 15d-1 and 15d-2 were separated on a chiral
column: ChiralpakS AD: Amylose tris-(3,5-dimethylphenylcarbamate)
coated on a 20 .mu.m silica-gel, 5 cm ID, 41 cm length; using
ethanol as eluent: 100 vol % at 80 mL/min.; wavelength 220 nM. This
results in two pure isomers 15d-1 and 15d-2, which were
individually converted to 19-1 and 19-2, respectively, by the
methods described in Example 5 with the appropriate reagents and
starting materials.
[0719] The isomers 15d-3 and 15d4 were separated on a chiral
column: Chiralpak.RTM. AD, Amylose
tris-(3,5-dimethylphenylcarbamate) coated on a 20 .mu.m silica-gel,
500 gr; 5 cm ID; 41 cm length and as eluent using ethanol: 100 vol
% at 80 mL/min.; wavelength 220 nM. This resulted in two pure
isomers 15d-3 and 15d4, which were individually converted to 19-3
and 19-4, respectively, by the methods described in Example 5 with
the appropriate reagents and starting materials.
[0720] Cpds 19-1, 19-2, 19-3, 194: .sup.1H-NMR (DMSO-d.sub.6, 300
MHz) .delta. 0.86-2.95 (m, 24H), 3.22 (br d, 1H), 3.41 (br s, 2H),
3.82 (br d, 1H), 4.37 (br d, 1H), 6.65 (m, 3H), 6.95 (m, 2H), 7.61
(d, J=7 Hz, 1H), 7.95 (br s, 1H).
18 Optical Rotation of Optical Rotation of Compound No. 15d (in
MeOH) Compound No. 19 (in MeOH) 15d-1 +30.degree. 19-1
+15.85.degree. 15d-2 +62.03.degree. 19-2 +24.15.degree. 15d-3
-64.57.degree. 19-3 -24.78.degree. 15d-4 -30.99.degree. 19-4
-14.57.degree. 109 110 111 112
[0721] Using the procedures of Example 19 and the appropriate
solvents and starting materials known to those skilled in the art,
other individual isomers of the compounds of the present invention
may be prepared including, but not limited to:
19 MS Cpd Name (m/z) 5-1,
1,2,3,4-Tetrahydro-.beta.-[1-[1-oxo-4-(5,6,7,8- 491 5-2,
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4- 5-3,
piperidinyl]-3-quinolinepropanoic acid 5-4 58a
5,6,7,8-Tetrahydro-.beta.-[1-[1-oxo-4-(5,6,7,8- 491
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4-
piperidinyl]-3-quinolinepropanoic acid 58b
5,6,7,8-Tetrahydro-.beta.-[1-[1-oxo-4-(5,6,7,8- 491
tetrahydro-1,8-naphthyridin-2-yl)butyl]-4-
piperidinyl]-3-quinolinepropanoic acid
[0722] and pharmaceutically acceptable salts thereof.
20 Compound Optical Rotation Compound Optical Rotation No. of 5a
(in MeOH) No. of 5 (in MeOH) 5a-3 -62.degree. 5-3 -26.41.degree.
5a-4 -46.degree. 5-4 -19.57.degree.
EXAMPLE 16
N-Methyl-1,2,3,4-tetrahydro-.beta.-[[1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8-na-
phthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-quinolinepropanoic
acid (Cpd 67)
[0723] Compound 67 was prepared by the same method used to convert
Compound 15d to Compound 19 as described in Example 15, except in
this case the intermediate Compound 15d was alkylated prior to the
Boc deprotection step. The alkylated product Compound 16a was
converted to Compound 67 in the same manner Compound 15d was
converted to Compound 19. Compound 15d (280 mg, 0.67 mmol) was
dissolved in anhydrous DMF (10 mL) and treated with
2,6-di-tert-butylpyridine (0.181 mL, 0.81 mmol) and iodomethane
(0.050 mL, 0.81 mmol) and left at rt for 20 h. The crude reaction
mixture was evaporated and then purified by flash chromatography
(20% EtOAc in hexane, few drops of triethyl amine) to yield 16a (90
mg, 31%) as a glassy solid. MS (ES+) m/z 431 (M+H.sup.+). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.0-1.7 (m, 7H), 1.45 (s, 9H),
2.0-2.7 (m, 8H), 2.88 (s, 3H), 3.01 (m, 1H), 3.09 (m, 1H), 3.67 (s,
3H), 4.01 (m, 2H), 6.4-6.6 (m, 2H), 6.96 (d, J=7 Hz, 1H), 7.08 (t,
J=8 Hz, 1H).
21 Cpd Name MS (m/z) 67
N-Methyl-1,2,3,4-tetrahydro-.beta.-[[1-[1-oxo-3-(5,6,7,8- 505
tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]
methyl]-3-quinolinepropanoic acid 113
EXAMPLE 17
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl-propionyl)-piperidin-4-y-
l]-butyric acid tert-butyl ester (Cpd 70)
[0724] Using the procedure described in Example 3 for converting
Compound 3d to Compound 3e, Compound 14d was converted to Compound
17a. MS (ES+) m/z 286 (M+H.sup.+).
[0725] Using the procedure described in Example 3 for converting
Compound 3e to Compound 3f, Compound 17a was converted to Compound
17b. MS (ES+) m/z 186 (M+H.sup.+).
[0726] Using the procedure described in Example 14 for converting
Compound 14f to Compound 14g, Compound 17b was reacted with
Compound 8a to yield Compound 17c. MS (ES+) m/z 374.2
(M+H.sup.+).
[0727] 3N NaOH (3.21 mL, 9.63 mmol) was added to a solution of
Compound 17c (1.8 g, 4.82 mmol) in MeOH (9 mL). The resulting
mixture was stirred for 4.5 h at rt. 2N HCl (4.82 mL, 9.64 mmol)
was added, and the mixture was concentrated under reduced pressure.
DCM was added to the residue, and the solid was removed via
filtration. The filtrate was evaporated to yield Compound 17d. MS
(ES+) m/z 360.3 (M+H.sup.+).
[0728] t-Butanol (0.476 mL, 4.98 mmol),
1,3-dicyclohexylcarbodiimide (1M in DCM; 1 mL, 1 mmol), and DMAP
(1M in DCM; 0.11 mL, 0.11 mmol) were added to a solution of
Compound 17d (0.3 g, 0.83 mmol) in DCM (2 mL). The resulting
mixture was stirred overnight at rt. The mixture was filtered and
concentrated at reduced pressure and the residue was purified by
RP-HPLC (10-90% MeCN/water, 0.1% TFA) to yield C Compound 70. MS
(ES+) m/z 388.4 (M+H.sup.+). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 0.98-1.86 (m, 9H), 1.42 (s, 9H), 1.93 (m, 2H), 2.20
(t,J=7.5 Hz, 2H), 2.58 (t,J=7.5 Hz, 1H), 2.68-3.10 (m, 7H), 3.50
(t, J=5.4 Hz, 2H), 4.05 (d, J=12.3 Hz, 1H), 4.54 (d, J=12.3 Hz,
1H), 6.49 (d, J=6.9 Hz, 1H), 7.33 (d, J=6.9 Hz, 1H). 114115
[0729] Using the procedure of Example 17 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
22 MS Cpd Name (m/z) 68
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2- 388.4
yl-propionyl)-piperidin-4-yl]-butyric acid ethyl ester 69
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2- 402.3
yl-propionyl)-piperidin-4-yl]-butyric acid isopropyl ester 71
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2- 472.5
yl-propionyl)-piperidin-4-yl]-butyric acid octyl ester 72
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2- 416.4
yl-propionyl)-piperidin-4-yl]-butyric acid isobutyl ester 73
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2- 374.2
yl-propionyl)-piperidin-4-yl]-butyric acid methyl ester
EXAMPLE 18
4-[1-(3-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl-propionyl)-piperidin-4-y-
l]-butyric acid 2,2-dimethyl-propionyloxymethyl ester (Cpd 74)
[0730] 3N NaOH (3.21 mL, 9.63 mmol) was added to a solution of
Compound 17c (1.8 g, 4.82 mmol) in MeOH (10 mL). The resulting
mixture was stirred for 4 h at rt and concentrated at reduced
pressure to yield 18a. MS (ES+) m/z 360.3 (M+H.sup.+).
[0731] Chloromethyl pivalate (0.21 mL, 1.46 mmol) and 25% aqueous
NaI (0.13 mL) were added to a suspension of Compound 18a (0.5 g,
1.3 mmol) in acetone (10 mL) and the resulting mixture was heated
to reflux for 5 h. The solvent was removed at reduced pressure and
the residue was purified by RP-HPLC (10-90% MeCN/water, 0.1% TFA)
to yield Compound 74. MS (ES+) m/z 474.3 (M+H.sup.+). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.05 (m, 2H), 1.20 (s, 9H), 1.27 (m,
2H), 1.50 (m, 1H), 1.67 (m, 2H), 1.77 (m, 2H), 1.95 (m, 2H), 2.37
(t, J=7.8 Hz, 2H), 2.57 (t, J=13.2 Hz, 1H), 2.75 (t, J=7.5 Hz, 2H),
2.82 (m, 2H), 2.95-3.10 (m, 3H), 3.51 (t, J=6 Hz, 2H), 4.05 (d,
J=13.2 Hz, 1H), 4.56 (d, J=13.2 Hz, 1H), 5.76 (s, 2H), 6.50 (d,
J=7.5 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H). 116
EXAMPLE 19
3-(2,3-Dihydro-benzofuran-6-yl)-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyrid-
in-2-yl-propionyl)-piperidin-4-yl]-butyric acid (Cpd 36a)
[0732] Using the procedure described in Example 12 for converting
Compound 12b to Compound 12d, Compound 12b was converted to
Compound 19b upon reaction with n-BuLi and
6-bromo-2,3-dihydrobenzofuran 19a (Compound 19a was obtained in
three steps from 1,4-dibromo-2-fluorobenzene as described in
Organic Letters (2001), 3(21), 3357-3360). MS (ES+) m/z 368.4
(M+Na.sup.+).
[0733] Using the procedure described in Example 12 for converting
Compound 12d to Compound 12e, Compound 19b was converted to
Compound 19c. MS (ES+) m/z 424.4 (M+Na.sup.+).
[0734] Using the procedure described in Example 12 for converting
Compound 12e to Compound 12f, Compound 19c was converted to
Compound 19d. MS (ES+) m/z 426.5 (M+Na.sup.+).
[0735] Racemic Compound 19d was separated into the two
enantiomerically pure Compounds 19e and 19f on a chiral column
using methanol as eluent (Stationary phase: Chiralpak AD 20 .mu.m
(Daicel); eluent: methanol; column diameter: 50 mm; detector: 0.5
mm Knauer superpreparative cell; wavelength: 225 nm). Compound 19f
(second eluting isomer): [.alpha.].sup.20.sub.D-24.3 (c 0.717,
MeOH). Compound 19e (first eluting isomer):
[.alpha.].sup.20.sub.D+24.8 (c 0.775, MeOH).
[0736] Using the procedure described in Example 12 for converting
Compound 12f to Compound 12g, Compound 19f was converted to
Compound 19g. MS (ES+) m/z 304.4 (M+H.sup.+).
[0737] Using the procedure described in Example 12 for converting
Compound 12g to Compound 12h, Compound 19g was converted to
Compound 19h. MS (ES+) m/z 492 (M+H.sup.+).
[0738] The crude Compound 19h was dissolved in MeOH (20 mL) and 3N
aqueous NaOH (6 mL) was added. The mixture was stirred at rt for 5
h and neutralized with 2N HCl. After the solvent was evaporated,
the residue was purified via RP-HPLC to yield Compound 36a. MS
(ES+) m/z 478.8 (M+H.sup.+). .sup.1HNMR (CDCl.sub.3, 300 MHz)
.delta. 1.09 (1.07 (m, 2H), 1.27 (m, 1H), 1.40-1.86 (m, 3H),
1.73-2.0 (m, 3H), 2.42 (t,J=12.5 Hz, J=4.4 Hz, 1H), 2.55 (d, J=7.3
Hz, 2H), 2.67-3.24 (m, 10H), 3.5 (br s, 2H), 3.93 (dd, J=19.8
Hz,J=16.2 Hz, 1H), 4.43 (dd,J=16.2 Hz,J=14.7 Hz, 1H), 4.57 (t,J=7.5
Hz, 1H), 6.62 (s, 1H), 6.67 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz,
1H), 7.33 (d, J=7.5 Hz, 1H), 8.41 (br s, 1H). Anal. Calcd for
C.sub.28H.sub.35N.sub.3O.sub.4-1.05 HCl-0.6H.sub.2O: C, 63.86; H,
7.13; N, 7.98; Cl, 7.07; H.sub.2O, 2.06. Found: C, 63.67; H, 7.32;
N, 8.12; Cl, 6.94; H.sub.20, 1.91. [.alpha.].sup.20.sub.D-31.1 (c
0.675, MeOH).
[0739] Enantiomer 36b was obtained from the fast moving enantiomer
Compound 19e using procedures described for converting 19f to
Compound 36a. 117118119
EXAMPLE 20
3-(4-Hydroxy-3-methoxy-phenyl)-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyridi-
n-2-yl-propionyl)-piperidin-4-yl]-butyric acid (Cpd 76)
[0740] To a solution of bromo-methoxyphenol Compound 20a (10 g,
49.2 mmol) and N,N-diethyl-N-diisopropylamine (0.7 g, 54.2 mmol) in
dry DCM (100 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride
(9.03 g, 54.2 mmol). The resulting mixture was stirred for 2 h at
rt, and water and brine were added. The organic layer was separated
and dried over Na.sub.2SO.sub.4. The solvent was removed under
reduced pressure and the residue was purified via flash column
chromatography (silica gel; eluent:hexane:EtOAc; 9:1) to yield
Compound 20b. MS (ES+) m/z 396/398 (M+H.sup.+).
[0741] Using the procedure described in Example 12 for converting
Compound 12b to Compound 12d, Compound 12b was converted to
Compound 20c. MS (ES+) m/z 502.2 (M+Na.sup.+).
[0742] Using the procedure described in Example 12 for converting
Compound 12d to Compound 12e, Compound 20c was converted to
Compound 20d. MS (ES+) m/z 558.2 (M+Na.sup.+).
[0743] Using the procedure described in Example 12 for converting
Compound 12e to Compound 12f, Compound 20d was converted to
Compound 20e. MS (ES+) m/z 408.3 (M+H.sup.+).
[0744] Using the procedure described in Example 12 for converting
Compound 12f to Compound 12g, Compound 20e was converted to
Compound 20f. MS (ES+) m/z 308.1 (M+H.sup.+).
[0745] Using the procedure described in Example 12 for converting
Compound 12g to Compound 12h, Compound 20f was converted to
Compound 20g. MS (ES+) m/z 496.8 (M+H.sup.+).
[0746] Using the procedure described in Example 12 for converting
Compound 12h to Compound 11, Compound 20g was converted to Compound
76. MS (ES+) m/z 482.4 (M+H.sup.+). .sup.1HNMR (DMSO-d.sub.6, 300
MHz) .delta. 0.93 (m, 2H), 1.25 (m, 1H), 1.5 (m, 3H), 1.8 (m, 3H),
2.47 (m, 6H), 2.72 (m, 3H), 2.83 (d, J=7.3 Hz, 2H), 2.99 (m, 1H),
3.40 (br s, 2H), 3.74 (s, 3H), 3.77 (dd, J=14.7 Hz, J=14.3 Hz, 1H),
4.28 (dd, J=14.7 Hz, J=14.3 Hz, 1H), 6.60 (d, J=8.1 Hz, 1H), 6.63
(d, J=7.2 Hz, 1H), 6.66 d, J=8.1 Hz, 1H), 6.77 (br s, 1H), 7.59 (d,
J=7.2 Hz, 1H), 8.04 (br s, 1H). 120121122
[0747] Derivatives in which the hydroxyl substituent of Compound 76
is alkylated or acylated can be made using general methods,
starting materials, and reagents known to one skilled in the
art.
EXAMPLE 21
3-(3-Methylamino-phenyl)-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-
-propionyl)-piperidin-4-yl]-butyric acid (Cpd 79)
[0748] A solution of 3-bromoaniline Compound 21a (2 mL, 18.4 mmol),
di-tert-butyl dicarbonate (4.05 g, 18.6 mmol) in THF (20 mL) was
heated to reflux for 30 h under N.sub.2. The mixture was evaporated
under reduced pressure, and the residue was dissolved in EtOAc. The
solution was washed with saturated NaHCO.sub.3 solution and brine.
The organic layer was dried over MgSO.sub.4, filtered, and
evaporated, to yield Compound 21b. MS (ES+) m/z 256.8/258.8
(M-CH.sub.3).
[0749] Sodium hydride (60% in oil; 0.78 g, 19.5 mmol) was added in
small portions to a solution of Compound 21b (4.18 g, 15.4 mmol)
and methyl iodide (1.21 mL, 19.5 mmol) in DMF (50 mL) at 0.degree.
C. The resulting mixture was allowed to warm to rt and stirred for
1 h. The mixture was poured in ice-water and extracted with EtOAc.
The organic layer was separated, dried over MgSO.sub.4, filtered,
and evaporated under reduced pressure to yield Compound 21c. MS
(ES+) m/z 270.9/272.9 (M-CH.sub.3).
[0750] Using the procedure described in Example 12 for converting
Compound 12b to Compound 12d, Compound 21c was converted to
Compound 21d. MS (ES+) m/z 455.0 (M+Na.sup.+).
[0751] Using the procedure described in Example 12 for converting
Compound 12d to Compound 12e, Compound 21d was converted to
Compound 21e. MS (ES+) m/z 510.9 (M+Na.sup.+).
[0752] Using the procedure described in Example 12 for converting
Compound 12e to Compound 12f, Compound 21e was converted to
Compound 21f. MS (ES+) m/z 512.8 (M+Na.sup.+).
[0753] Using the procedure described in Example 12 for converting
Compound 12f to Compound 12g, Compound 21f was converted to
Compound 21g. MS (ES+) m/z 291.0 (M+H.sup.+).
[0754] Using the procedure described in Example 12 for converting
Compound 12g to Compound 12h, Compound 21g was converted to
Compound 21h. MS (ES+) m/Z 479.0 (M+H.sup.+).
[0755] Using the procedure described in Example 12 for converting
Compound 12h to Compound 11, Compound 21h was converted to Compound
79. MS (ES+) m/z 465.0 (M+H.sup.+). .sup.1HNMR (DMSO-d.sub.6, 300
MHz) .delta. 0.99 (m, 2H), 1.21 (m, 1H), 1.4-1.65 (m, 3H), 1.72 (m,
1H), 1.86 (m, 2H), 2.3-3.0 (m, 13H), 3.17 (m, 1H), 3.42 (m, 2H),
3.87 (dd, J=17.7 Hz, J=15.2 Hz, 1H), 4.40 (dd,J=15.2 Hz, J=11.6 Hz,
1H), 6.41 (d, J=7.5 Hz, 1H), 7.1-7.4 (m, 5H). 123124125
[0756] Using the procedure of Example 21 and the appropriate
reagents and starting materials known to those skilled in the art,
other compounds of the present invention may be prepared including,
but not limited to:
23 Cpd Name MS (m/z) 78 3-(3-Ethylamino-phenyl)-4-[1- 479.0
(3-5,6,7,8-tetrahydro-[1,8]na- phthyridin-
2-yl-propionyl)-piperidin-4-yl]-butyric acid
EXAMPLE 22
3-Naphthalen-2-yl-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-propio-
nyl) -piperidin-4-yl]-butyric acid (Cpd 56a)
[0757] Using the procedure described in Example 19 for converting
Compound 12b to Compound 19b, Compound 12b was converted to
Compound 22a upon reaction with 2-bromonaphthalene. MS (ES+) m/z
376 (M+Na.sup.+).
[0758] Using the procedure described in Example 19 for converting
Compound 19b to Compound 19c, Compound 22a was converted to
Compound 22b. MS (ES+) m/z 432.1 (M+Na.sup.+).
[0759] Using the procedure described in Example 19 for converting
Compound 19c to Compound 19d, Compound 22b was converted to
Compound 22c. MS (ES+) m/z 434.1 (M+Na.sup.+).
[0760] Racemic Compound 22c was separated into the two
enantiomerically pure Compounds 22d and 22e on a chiral column
using ethanol as eluent (Stationary phase: Chiralpak AD 20 .mu.m
(Daicel); column diameter: 50 mm; detector: 0.5 mm Knauer
superpreparative cell; wavelength: 225 nm). 22d (first eluting
isomer): [.alpha.].sup.20.sub.D+0.177 (c 0.75, MeOH). 22e (second
eluting isomer): [.alpha.].sup.20.sub.D-0.167 (c 0.683, MeOH).
[0761] Using the procedure described in Example 19 for converting
Compound 19f to Compound 19g, Compound 22e was converted to
Compound 22f. MS (ES+) m/z 312.0 (M+H.sup.+).
[0762] Using the procedure described in Example 19 for converting
Compound 19g to Compound 19h, Compound 22f was reacted with
Compound 8a to yield Compound 22g. MS (ES+) m/z 500.0
(M+H.sup.+).
[0763] Using the procedure described in Example 19 for converting
Compound 19h to Compound 36a, Compound 22g was converted to
Compound 56a. MS (ES+) m/z 486.0(M+H.sup.+). .sup.1HNMR
(CDCl.sub.3, 300 MHz) .delta. 0.95-1.35 (m, 3H), 1.44-2.0 (m, 6H),
2.35 (t, J=12.7 Hz, 1H), 2.55-3.1 (m, 9H), 3.40 (m, 3H), 3.89 (m,
1H), 4.42 (m, 1H), 6.45 (d, J=7.4 Hz, 1H), 7.24 (d, J=7.4 Hz, 1H),
7.35 (d, J=8.1 Hz, 1H), 7.45 (m, 2H), 7.65 (s, 1H), 6.45 (d, J=7.4
Hz, 1H), 7.7-7.85 (m, 3H). Anal. Calcd for
C.sub.30H.sub.35N.sub.3O.sub.3-1.1 HCl-0.75H.sub.2O: C, 66.83; H,
7.03; N, 7.80; Cl, 7.24; H.sub.2O, 2.51. Found: C, 66.53; H, 7.26;
N, 8.15; Cl, 7.27; H.sub.2O, 2.39. [.alpha.].sup.20.sub.D-0.193 (c
0.717, MeOH).
[0764] Enantiomer 56b was obtained from the fast moving enantiomer
22d using procedures described for converting 22e to Compound 56a.
126127
EXAMPLE 23
3-(3-Fluoro-phenyl)-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-prop-
ionyl) -piperidin-4-yl]-butyramide (Cpd 64)
[0765] Using the procedure described in Example 12 for converting
Compound 12b to Compound 12d, Compound 12b was converted to
Compound 23a upon reaction with 1-bromo-3-fluorobenzene. MS (ES+)
m/z 344 (M+Na.sup.+).
[0766] Using the procedure described in Example 12 for converting
Compound 12d to Compound 12e, Compound 23a was converted to
Compound 23b upon reaction with Diethyl cyanomethylphosphonate. MS
(ES+) m/z 367.4 (M+Na.sup.+).
[0767] A solution of of Compound 23b (2.06 g, 5.98 mmol) in EtOH
(50 mL) was hydrogenated at 5 psi in the presence of 10% palladium
on carbon (200 mg) for 40 h. The catalyst was removed by filtration
over celite. The filtrate was concentrated in vacuo to yield
Compound 23c. MS (ES+) m/z 369.5 (M+Na.sup.+).
[0768] Using the procedure described in Example 12 for converting
Compound 12f to Compound 12g, Compound 23c was converted to
Compound 23d. MS (ES+) m/z 247 (M+H.sup.+).
[0769] Using the procedure described in Example 12 for converting
Compound 12g to Compound 12h, Compound 23d was reacted with
Compound 8a to yield Compound 23e. MS (ES+) m/z 435
(M+H.sup.+).
[0770] A mixture of Compound 23e (150 mg, 0.345 mmol) and 12N HCl
(10 mL) was heated to 40.degree. C. for 3 h. The mixture was
evaporated to dryness and further dried by lyophilization to yield
Compound 64. MS (ES+) m/z 453.5 (M+Na.sup.+). .sup.1HNMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.8-1.1 (m, 2H), 1.25 (m, 1H),
1.4-1.65 (m, 3H), 1.7-1.9 (m, 4H), 2.25-2.5 (m, 4H), 2.7-2.9 (m,
8H), 3.21 (m, 1H), 3.82 (t, J=13.6 Hz, 1H), 4;31 (t, J=13.6 Hz,
1H), 6.66 (d, J=7.3 Hz, 1H), 6.71 (br s, 1H), 6.95-7.15 (m, 3H),
7.25 (br s, 1H), 7.36 (dd, J=15.1 Hz, J=7.3 Hz, 1H), 7.63 (d, J=7.3
Hz, 1H), 7.98 (br s, 11H), 13.77 (br s, 1H). 128
EXAMPLE 24
3-(3-Fluoro-phenyl)-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-prop-
yl]-piperidin-4-yl]-butyric acid (Cpd 81)
[0771] Lithium aluminum hydride (1.0M in THF; 16.5 mL, 16.5 mmol)
was added slowly to a suspension of Compound 8a (2.0 g, 8.2 mmol)
in dry THF (60 mL) at 0.degree. C. The cooling bath was removed,
and the mixture was stirred for 24 hr at rt. The mixture was
quenched with water and celite was added. The mixture was extracted
with Et.sub.2O and EtOAc. The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure, yielding Compound 24a. MS (ES+) m/z 193.2
(M+H.sup.+).
[0772] Compound 24a (0.5 g, 2.6 mmol) was added to a suspension of
pyridinium chlorochromate (0.67 g, 3.12 mmol) in DCM (5 mL). The
mixture was stirred overnight at rt. Diethyl ether was added, and
the mixture was filtered. The filtrate was dried over
Na.sub.2SO.sub.4. After removal of the drying agent via filtration,
the solvent was removed under reduced pressure, yielding a mixture
of 24a and 24b that was used as such for the next reaction.
Compound 24b: MS (ES+) m/z 191.1 (M+H.sup.+).
[0773] Sodium triacetoxyborohydride (25.6 mg, 0.074 mmol) was added
to a mixture of 24a and 24b (0.01 g, 0.05 mmol) and piperidine
Compound 24c (0.015 g, 0.05 mmol; obtained using the procedure
described in Example 12 for converting Compound 12a to Compound
12g, and wherein bromo-3-fluorobenzene was substituted for the
4-bromo-1,2-(methylenedioxy- )benzene (Compound 12c) and was
reacted to form a 3-fluorophenyl compound analogous to compound
12f) in DCM (0.2 mL) and the mixture was stirred for 4 hr at rt.
Diethyl ether was added, and the organic layer was separated and
dried over Na.sub.2SO.sub.4. The drying agent was removed by
filtration, and the solvent was removed under reduced pressure. The
residue was purified via column chromatography (eluent gradient:
DCM:MeOH:NH.sub.4OH; 100:0:0 to 90:9:1) to yield Compound 24d. MS
(ES+) m/z 454.4 (M+H.sup.+).
[0774] Using the procedure described in Example 12 for converting
Compound 12h to Compound 11, Compound 24d was converted to Compound
81. MS (ES+) m/z 440.5 (M+H.sup.+). 129
EXAMPLE 25
.beta.-(3-fluorophenyl)-1-[1-oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2--
yl)propyl]-4-piperidinebutanoic acid (Cpd 30a and 30b)
[0775] Compound 30 was synthesized following the process set forth
in Example 12 wherein bromo-3-fluorobenzene was substituted for the
4-bromo-1,2-(methylenedioxy)benzene (Compound 12c) and was reacted
to form a 3-fluorophenyl compound analogous to compound 12f.
[0776] Additional Compound 30 was resolved into two isomers (Cpd
30a and Cpd 30b) by generally following the procedure set in
Example 19, wherein the stationary phase was Chiralcel OD; eluent:
hexane/EtOH: 95/5; wavelength: 220 nm. The isomer of most interest
was the second eluting isomer. The separated isomers were converted
into Compounds 30a and 30b by completion of the synthesis from
Compound 12f on as set forth in Example 12 to yield Compounds 30a
and 30b.
PROSPECTIVE EXAMPLE 26
3-(2,3-Dihydro-benzofuran-6-yl)-4-[1-(3-5,6,7,8-tetrahydro-[1,8]naphthyrid-
in-2-yl-butyl)-piperidin-4-yl]-propanoic acid (Cpd 80)
[0777] Using the procedure described in Example 3 for converting
Compound 3b to Compound 3c, Compound 3b may be converted to provide
Compound 26a when reacted with 6-bromo-2,3-dihydrobenzofuran.
[0778] Using the procedure described in Example 3 for converting
Compound 3c to Compound 3d, Compound 26a may be converted to
provide Compound 26b.
[0779] Using the procedure described in Example 3 for converting
Compound 3d to Compound 3e, Compound 26b may be converted to
provide Compound 26c.
[0780] Using the procedure described in Example 3 for converting
Compound 3e to Compound 3f, Compound 26c may be converted to
provide Compound 26d.
[0781] Using the procedure described in Example 3 for converting
Compound 3f to Compound 3g, Compound 26d may be converted to
provide Compound 26e.
[0782] Using the procedure described in Example 4 for converting
Compound 4a to Compound 4b, Compound 26e may be converted to
provide Compound 26f.
[0783] Using the procedure described in Example 4 for converting
Compound 4b to Compound 4, Compound 26f may be converted to provide
Compound 80. 130
EXAMPLE 27
[0784] 131
[0785] A sample of Compound 27a (78.2 g, 385 mmol) and
diisopropylethylamine (DIEA) (54.8 g, 424 mmol, 73.8 mL) was
dissolved into dry CH.sub.2Cl.sub.2 (700 mL) and Compound 27b (70.7
g, 424 mmol, 75 mL) was added dropwise. After 16 h while stirring
at ambient temperature, brine (500 mL) was added. The phases were
separated and the aqueous phase extracted with CH.sub.2Cl.sub.2
(300 mL). The organic phases were combined and dried over sodium
sulfate. The mixture was concentrated and the residue, an orange
semisolid, was applied to a flash column (silica gel, 6.times.20
cm). The residue was eluted with heptane (500 mL), followed by 10%
EtOAc/heptane (2 L) in 500 mL fractions. Fractions 1 and 2 gave
pure Compound 27c. A second purification was required on fractions
3 and 4 using the chromatography conditions described above. The
crops were combined to give 112 g of Compound 27c: .sup.1H NMR
(CDCl.sub.3) .delta.: 7.1-7.0 (m, 3H), 3.9 (s, 3H), 3.8 (t, 2H) 0.9
(t, 2H) and 0.0 ppm (s, 9H).
EXAMPLE 28
[0786] 132
[0787] Compound 27c (112.2 g, 330.7 mmol) was dissolved in dry THF
(1.3 L). The colorless solution was cooled down to -75.degree. C.
and 2.5M n-butyllithium (120.3 mL, 300.6 mmol) in hexanes was added
through an addition funnel. After 15 min stirring at -75.degree.
C., a solution of Compound 28a (86.09 g, 300.6 mmol) in dry THF
(500 mL) was added dropwise over 2 h with an addition funnel at
-75.degree. C. During the addition, the colorless solution turned
light green, and then became yellow. HPLC analysis indicated that
the reaction had gone to completion 20 min after complete addition
of Compound 28a. The reaction was quenched with saturated ammonium
chloride (100 mL), then allowed to come to ambient temperature
overnight. The organic phase was isolated, washed with brine (250
mL), and the aqueous phase was extracted with diethyl ether
(2.times.150 mL). The combined organic phases were dried over
sodium sulfate and then concentrated. The resultant pale yellow
residue was divided into two batches and applied separately to a
flash chromatography column (silica gel, 10 cm for the first
batch/8 cm for the second; fritted funnel 6 cm wide) with applied
vacuum. The first batch of Compound 28b was eluted with heptane (2
L), followed by a gradient of heptane/EtOAc: 95/5 (2 L), 90/10 (4
L), 80/20 (4 L), and 70/30 (4 L). The second batch was eluted with
heptane (1 L), followed by heptane/EtOAc 9/1 (2 L), 85/15 (2 L),
and 80/20 (2 L). The fractions were combined and evaporated to give
109 g of Compound 28b: .sup.1H NMR (CDCl.sub.3) .delta.: 7.5 (m,
2H), 7.2 (d, 1H), 4.2-4.0 (broad m, 2H), 3.95 (s, 3H), 3.8 (t, 2H),
2.85 (d, 2H), 2.8-2.7 (broad t, 2H), 2.15 (broad m, 1H), 1.7 (broad
d, 2H), 1.45 (s, 9H), 1.3-1.1 (broad m, 2H), 0.9 (t, 2H) and 0.0
ppm (s, 9H).
EXAMPLE 29
[0788] 133
[0789] Compound 29a (trimethyl phosphonoacetate) (124.12 g, 681.6
mmol, 112.5 mL) in 50 mL of dry THF was cooled to 0.degree. C. and
NaHMDS in THF (1.0 M, 681.6 mL) was added at 0.degree. C. in three
equal portions with mechanical stirring. After the addition of the
first portion, the solution became a thick beige slurry and the
consistency remained unchanged throughout the duration of the
addition. The slurry was stirred at 0.degree. C. for 1 h after
which time Compound 28b (109.0 g, 227.2 mmol) was added in one
portion as a suspension in dry THF (250 mL). The reaction mixture
was then heated to reflux for 96 h. At this time the reaction was
cooled to ambient temperature and saturated ammonium chloride (400
mL) was added. The phases were separated and the aqueous phase
washed with ether (2.times.300 mL). The combined organic phases
were dried over sodium sulfate, filtered and the solvent
evaporated. The resulting residue was poured onto a fritted glass
funnel containing a pad of flash silica gel (diameter: 15 cm,
height: 8 cm). The compound was isolated by first eluting with pure
heptane (2 L) then with a gradient of heptane/EtOAc: 90/10 (2 L),
80/20 (4 L), and 70/30 (4 L), collecting in fractions of 1.8 L.
Compound 29b was isolated as a mixture of E/Z isomers, and was
contaminated with unreacted Compound 28b (33% by HPLC, 120 g total
of mixture). The mixture was carried on to the next step without
further purification.
EXAMPLE 30
[0790] 134
[0791] The mixture of Cpd 29b and Cpd 28b (120 g total), as
prepared in Example 29, was dissolved in MeOH (1 L) and, under a
stream of Argon, 10% Pd-C catalyst (3.0 g) was added. The mixture
was-shaken in a Parro apparatus under an atmosphere of H.sub.2 gas
(35 psi) for 18 h at ambient temperature. At this time, LC/MS
analysis of the reaction indicated that Compound 29b had been
converted to Compound 30a. After thoroughly purging with Argon gas,
the reaction mixture was filtered through a pad of Celite and the
solvent was removed in vacuo. The resultant residue was applied to
a flash column (silica gel, 15 cm.times.8 cm) in a fritted glass
funnel and eluted with a gradient of pure heptane (2 L) followed by
mixtures of heptane/EtOAc: 90/10 (2 L), 80/20 (4 L), 70/30 (4 L),
collecting in 1.8 L fractions. Upon evaporation, Compound 30a was
isolated as a white foam (47.5 g). .sup.1H NMR (CDCl.sub.3)
.delta.: 6.9-6.6 (m, 3H), 5.6 (s, 1H), 4.2-4.0 (m, 2H), 3.9 (s,
3H), 3.6 (s, 3H) 3.2-3.1 (m, 1H), 2.6-2.5 (m, 4H), 1.8-1.0 (m, 7H)
and 1.4 ppm (s, 9H).
[0792] Compound 30a was separated into its pure enantiomers by
chiral chromatography according to the method described herein. The
separation of Compound 30a was performed on a 5 cm Chiralpak AD
column at a flow of 1 mL/min. Monitoring was performed at
.lambda.=220 nm, and the eluent was a mixture of heptane/EtOH/MeOH
(92:4:4). The faster eluting enantiomer of Compound 30a, Compound
30a-1 (12.96 g) proved to be the less avid binding ligand for the
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5 receptors
while the slower eluting enantiomer of Compound 4a, Compound 30a-2
(17.62 g) gave the more potent binding ligands (see the section
below). Therefore, the slower eluting enantiomer Compound 30a-2 was
carried forward for use in the preparation of subsequent optically
active compounds, unless noted otherwise.
EXAMPLE 31
[0793] 135
[0794] Compound 30a-1 (12.96 g) was dissolved into 25 mL of dry DCM
and TFA (10.0 mL) was added. After stirring for 1 h at ambient
temperature, the reaction mixture was evaporated. The residue was
co-evaporated with chloroform (3.times.) and DCM (2.times.) to give
Compound 31a as a TFA salt (12.56 g).
EXAMPLE 32
[0795] 136
[0796] A mixture of Compound 32a (3.77 g, 15.55 mmol), Compound 31a
(5.46 g, 12.96 mmol), HOBt (1.93 g, 14.25 mmol), DIEA (8.14 g, 63.0
mmol, 11.0 mL) and EDC (2.73 g, 14.25 mmol) were dissolved into dry
DMF (200 mL). After 96 h at ambient temperature, the reaction was
diluted with water (500 mL) and the mixture was extracted with
EtOAc (4.times.300 mL). The combined organic phases were washed
with brine (5.times.300 mL) then dried over sodium sulfate and
evaporated. The residue was purified on a flash column (silica gel,
6.times.20 cm) by eluting with DCM (1 L), followed by a gradient of
DCM/10% NH.sub.4OH in MeOH: 95/5 (2 L), 90/10 (2 L), 85/15 (2 L).
The fractions were collected in the following volumes: 1 to 3:500
mL each, 4 to 19:200 mL each, and 20:500 mL. Compound 32b was
isolated as a foam.
[0797] Compound 32b (325 mg) was dissolved in 1N NaOH (1.3 mL) and
MeOH (2.6 mL). After stirring for 18 h at room temperature, the
solution was neutralized with 2N HCl (0.400 mL). The reaction
mixture was transferred to a test tube, rinsing with MeOH, and
purified in several separate runs by HPLC (12 min per run; 35
mL/min) eluting with 15-35% CH.sub.3CN: H.sub.2O/0.1% TFA on a C18
reverse phase column (100.times.30 mm). Compound 32c was obtained
as a light yellow powder (195 mg): LRMS m/z 481.26; .sup.1H NMR
(CDCl.sub.3) .delta.: 9.5 (broad s, 1H), 7.5-7.3 (m, 5H), 6.8 (d,
1H), 6.7 (s, 2H), 6.45 (d, 1H), 4.45 (t, 1H), 4.1-3.9 (m, 1H), 3.8
(s, 3H), 3.5 (broad s, 2H), 3.1 (broad m, 1H), 3.0-2.6 (m, 4H),
2.55 (d, 2H), 2.45 (t, 1H), 1.9 (broad s, 3H), 1.7-1.4 (m, 3H),
1.25 (m, 1H) and 1.1-0.9 ppm (m, 2H).
[0798] Compound 32c was tested in the .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 binding assays described in Biological
Example 4 with the following results:
24 ASSAY RESULT FOR Cpd 32c .alpha..sub.v.beta..sub.3 Binding
Affinity IC.sub.50 = 104 nM .alpha..sub.v.beta..sub.5 Binding
Affinity IC.sub.50 = 2,313 nM
[0799] Based on the poor receptor binding affinity of Compound 32c
relative to Compound 35c (see below), Compound 32c was not
investigated any further for its potential as a targeting
ligand.
EXAMPLE 33
[0800] 137
[0801] Compound 30a-2 (17.6 g, 43.3 mmol), the slower eluting
enantiomer of Example 30, was dissolved into 30 mL of dry DCM and
TFA (15.0 mL) was added. After 1.5 h of stirring at ambient
temperature, the reaction mixture was evaporated. The residue was
co-evaporated with chloroform (3.times.) and DCM (2.times.) and
stored in vacuo to obtain Compound 33a as its TFA salt as a yellow
solid (16.5 g).
EXAMPLE 34
[0802] 138
[0803] A mixture of Compound 32a (11.75 g, 48.41 mmol), HOBt (5.99
g, 44.33 mmol), DIEA (13.02 g, 100.8 mmol, 17.55 mL) and EDC (8.49
g, 44.3 mmol) were dissolved into dry DMF (200 mL). This mixture
was stirred at ambient temperature for 1.5 h then a solution of
Compound 33a (17.0 g, 40.3 mmol) and. DIEA (13.02 g, 100.75 mmol,
17.55 mL) in DMF (100 mL) was added. After 140 h (.about.6 d) of
stirring at ambient temperature, the reaction mixture was diluted
with water (900 mL). The diluted reaction mixture was extracted
with EtOAc (4.times.300 mL). The combined organic phases were
washed with brine (5.times.300 mL) then dried over sodium sulfate
and evaporated. The residue was purified on a flash chromatography
column (silica gel, 6.times.20 cm), eluting first with DCM (800 mL)
and then with a gradient of DCM/10% NH.sub.4OH (0.1%, aq) in MeOH
in the following proportions: 95/5 (2 L), 90/10 (2 L), 80/20 (2 L).
The fractions were collected in 300 mL volumes. The fractions were
concentrated to give 980 mg of Compound 34b as a red oil. An impure
sample of Compound 34b was recovered from other fractions (6.17
g).
[0804] Compound 34b (435 mg) was stirred with 3N NaOH (0.700 mL) in
MeOH (2.0 mL). After 15 h of stirring at ambient temperature, 2N
HCl was added to neutralize the solution (1.0 mL). The red solution
was transferred into a test tube, rinsing with MeOH, and purified
in several separate HPLC runs (12 min per run; 35 mL/min) eluting
with a gradient of 15-35% CH.sub.3CN: H.sub.2O/0.1% TFA on a C18
reverse phase column (100.times.30 mm). Lyophilization of the
fractions provided Compound 34c (378 mg) as a light yellow powder:
LRMS m/z: 481.26; .sup.1H NMR (CDCl.sub.3) .delta.: 9.7 (broad s,
1H), 7.3 (d, 1H), 6.9 (d, 1H), 6.7 (d, 1H), 6.7 (s, 1H), 6.5 (d,
1H), 6.4-6.0 (broad s, 3H), 4.5 (t, 1H), 4.1-3.9 (m, 1H), 3.9 (s,
3H), 3.5 (broad s, 2H), 3.1 (m, 1H), 3.0-2.7 (m, 6H), 2.6 (d, 2H),
2.5 (t, 1H), 2.0-1.8 (m, 3H), 1.7-1.4 (m, 3H), 1.3 (m, 1H) and
1.2-0.9 ppm (m, 2H).
[0805] Compound 34c was tested in the .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 binding assays described in Biological
Example 4 with the following results:
25 ASSAY RESULT FOR Cpd 34c .alpha..sub.v.beta..sub.3 Binding
Affinity IC.sub.50 = 1.1 nM .alpha..sub.v.beta..sub.5 Binding
Affinity IC.sub.50 = 17 nM
[0806] Based on the strong receptor binding affinity of Compound
34c relative to Compound 34c, Compound 34c was chosen for the
preparation of targeting ligands.
EXAMPLE 35
[0807] 139
[0808] Dibromoethyl ether (2.5 g, 1.35 mL, 10.76 mmol) was added to
a solution of Compound 34b (0.48 g, 0.97 mmol) and 1.0 M potassium
t-butoxide/propanol in dry THF (1.5 mmol, 1.5 mL), and the mixture
was heated to 70.degree. C. The reaction reached approximately 50%
conversion in the first 30 min and continued to stir. After 5 h,
additional 1.0 M potassium t-butoxide solution was added (0.95
mmol, 0.95 mL), and the reaction was completed after 30 min at
70.degree. C. The reaction was quenched with water and the mixture
was extracted with diethyl ether (2.times.100 mL) and DCM
(2.times.50 mL). The combined-organic extracts were dried over
sodium sulfate, evaporated, and the resulting residue was purified
by flash column chromatography (silica gel, 4.times.16 cm) by
eluting with a gradient of DCM (500 mL), followed by DCM/10%
NH.sub.4OH (0.1% aq) in MeOH: 97/3 (1 L), then 95/5 (1 L). The
first fraction collected was a volume of 400 mL, followed by 100 mL
fractions for collections 2-15. Concentration of the fractions gave
Compound 35a (318 mg) as an oil;
[0809] LRMS: 645.24 m/z; .sup.1H NMR (CDCl.sub.3) .delta.: 7.1 (d,
1H), 6.85 (d, 1H), 6.7 (d, 1H), 6.7 (s, 1H), 6.4 (d, 1H), 4.8
(broad s, 1H) 4.5 (t, 1H), 3.9 (t, 4H), 3.8 (s, 3H), 3.6 (s, 3H),
3.5 (s, 3H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9-2.8 (m, 3H), 2.7-2.6 (m,
4H), 2.5 (d, 2H) 2.4 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6-1.4 (m,
3H) 1.2-1.1 (m, 1H) and 1.0 ppm (m, 2H).
EXAMPLE 36
[0810] 140
[0811] Potassium thioacetate (0.28 g, 2.46 mmol) was added to a
solution of Compound 35a (0.159 g, 0.246 mmol) in dry DMF (1 mL)
and the mixture was heated to 60.degree. C. After stirring for 1 h
at 60.degree. C., the reaction was cooled to ambient temperature,
diluted with water (100 mL), and extracted with EtOAc (3.times.50
mL). The organic phase was dried over sodium sulfate, evaporated,
and the resultant residue was purified by flash chromatography
(silica gel, 4.times.10 cm). The column was first eluted with EtOAc
(3.times.100 mL fractions) then DCM (5.times.100 mL fractions), and
finally a gradient of DCM/10% NH.sub.4OH (0.1% aq) in MeOH: 98/2
(10.times.50 mL), then 95/5 (10.times.50 mL) to yield Compound 36a
(80 mg): LRMS: 641.31 m/z.
[0812] Compound 36a (approximately 80 mg) was dissolved into MeOH
(0.800 mL) and 3N NaOH (0.400 mL) was added. After stirring for 18
h at ambient temperature, the mixture was neutralized with 2N HCl.
Purification was performed using several separate HPLC runs (12 min
per run, 35 mL/min), eluting with a gradient of 25-45% CH.sub.3CN:
H.sub.2O/0.1% TFA on a C18 reverse phase column (100.times.30 mm).
Upon lyophilization, Compound 36b (60 mg) was obtained as a
yellowish powder: LRMS 585.2 m/z; .sup.1H NMR (CDCl.sub.3) .delta.
9.6 (broad s, 1H), 7.4 (d, 1H), 6.9 (d, 1H), 6.7 (d, 1H), 6.7 (s,
1H), 6.5 (d, 1H), 5.4 (br s, 3H), 4.5 (t, 1H), 4.2 (m, 2H), 4.1-3.7
(m, 4H), 3.8 (s, 3H), 3.5 (m, 2H), 3.1 (m, 1H), 3.0-2.9 (m, 5H),
2.8-2.7 (m, 4H), 2.6-2.4 (m, 3H), 2.0-1.8 (m, 3H), 1.7-1.4 (m, 3H),
1.3-1.2 (m, 1H), and 1.1-1.0 ppm (m, 2H).
[0813] Compound 36b was tested in the .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 binding assays described in Biological
Example 4 with the following results:
26 ASSAY RESULT FOR Cpd 36b .alpha..sub.v.beta..sub.3 Binding
Affinity IC.sub.50 = 0.8 nM .alpha..sub.v.beta..sub.5 Binding
Affinity IC.sub.50 = 4.8 nM
EXAMPLE 37
[0814] 141
[0815] Compound 37a (7.7 g, 41.2 mmol) was added to a solution of
Compound 35a (2.0 g, 4.0 mmol) and 1.0M potassium
t-butoxide/propanol in dry THF (13.0 mL, 13 mmol). The mixture was
heated at 70.degree. C. for 2 h, at which time the reaction mixture
was diluted with brine (100 mL), and then extracted with diethyl
ether (2.times.100 mL) and DCM (2.times.50 mL). The combined
organic layers were dried over sodium sulfate, evaporated, and the
resultant residue was purified by flash column chromatography
(silica gel, 4.times.16 cm). The column was eluted with DCM (500
mL), followed by DCM/10% NH.sub.4OH (0.1% aq) in MeOH: 98/2 (0.5
L), 95/5 (1 L), and 90/10 (1 L). The fractions were concentrated to
give 1.11 g of Compound 37b: LRMS: 645.32 m/z; .sup.1H NMR
(CDCl.sub.3) 6:7.1 (d, 1H), 6.9 (d, 1H), 6.7 (d, 1H), 6.7 (s, 1H),
6.4 (d 1H), 4.7 (broad s, 1H), 4.55 (t, 1H), 4.2 (t, 2H), 3.9 (t,
2H), 3.85 (s, 3H), 3.8-3.7 (m, 6H), 3.65 (t, 2H), 3.6 (s, 3H) 3.4
(m, 2H), 3.1 (m, 1H), 2.85 (q, 2H), 2.7 (m, 3H), 2.5 (d, 2H), 2.4
(m, 1H) 1.9 (m, 2H), 1.8 (m, 1H), 1.6-1.4 (m, 3H), 1.3 (m, 1H) and
1.0 ppm (m, 2H).
EXAMPLE 38
[0816] 142
[0817] Potassium thioacetate (1.94 g, 17.0 mmol) was added to a
solution of Compound 37b (1.1 g, 1.7 mmol) in dry DMF (11 mL). The
reaction was complete after 1.5 h of stirring at 70.degree. C. The
mixture was to cooled, diluted with water (300 mL), and the mixture
was extracted with EtOAc (3.times.100 mL). The organic phase was
washed with brine (5.times.100 mL), dried over sodium sulfate,
evaporated, and the resultant residue was purified by flash
chromatography (silica gel, 4.times.20 cm), eluting first with pure
EtOAc (500 mL), then pure DCM (500 mL), followed by DCM/10%
NH.sub.4OH (0.1% aq) in MeOH: 98/2 (1 L), 95/5 (1 L) and 90/10 (1
L). Upon concentration of the fractions, Compound 38a was isolated
(1.07 g) as a yellow oil.
[0818] Compound 38a (1.0 g, 1.5 mmol) was treated with of 3N NaOH
(1.46 mL, 4.37 mmol) in MeOH (4.4 mL). After 21 h of stirring at
ambient temperature, 2N HCl (approx. 1.0 mL) was added to achieve
pH 7. The reaction mixture was transferred into a test tube, using
MeOH for rinsing, and purified by several separate HPLC runs (12
min per run, 35 mL/min), eluting with a gradient of 25-45%
CH.sub.3CN: H.sub.2O/0.1% TFA on a C18 reverse phase column
(100.times.30 mm). Upon lyophilization, Compound 38b was obtained
as a white powder: LRMS: 629.31 m/z; .sup.1H NMR (CDCl.sub.3) 9.8
(br 5, 1H), 7.3 (d, 1H), 6.95 (br s, 2H), 6.8 (d, 1H), 6.7 (d, 1H),
6.7 (s, 1H), 6.4 (d, 1H), 4.5 (t, 1H), 4.0-3.8 (m, 3H), 3.8 (s,
3H), 3.7 (m, 2H), 3.7-3.6 (m, 6H), 3.5 (m, 2H), 3.1 (m, 1H), 3.0
(m, 3H), 2.8-2.6 (m, 4H), 2.1 (d, 2H), 2.5 (t, 1H), 2.0-1.8 (m,
3H), 1.6 (t, 2H), 1.5 (m, 1H), 1.3 (m, 1H), and 1.0 ppm (m,
2H).
[0819] Compound 12b was tested in the .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 binding assays described in Biological
Example 4 with the following results:
27 ASSAY RESULT FOR Cpd 12b .alpha..sub.v.beta..sub.3 Binding
Affinity IC.sub.50 = 1.8 nM .alpha..sub.v.beta..sub.5 Binding
Affinity IC.sub.50 = 9.6 nM
EXAMPLE 39
[0820] 143
[0821] Compound 39 was characterized by high pressure liquid
chromatography (HPLC) using the conditions summarized in Table 1.
The results are shown in FIGS. 1A-1B, where FIG. 1A shows the HPLC
chromatogram for a Mal-PEG-DSPE (PEG molecular weight 3400 Daltons)
before conjugation to Cpd 38b. The Mal-PEG-DSPE compound yields
three peaks, one each at 20.42 minutes, which represents 78% of the
total, at 23.73 minutes and 23.90 minutes, which together are about
22% of the total. FIG. 1B shows the Mal-PEG-DSPE compound after
reaction with Cpd 38b, to yield Cpd 39. Conjugation of Mal-PEG-DSPE
resulted in the peak at 20.42 minutes to shift to conjugate peaks
of 19.02 minutes and 19.82 minutes. The Mal-PEG-DPSE peaks at 23.73
minutes and 23.90 minutes shifted to conjugate peaks at 22.13
minutes and 22.78 minutes. The peaks at 23.42 minutes and 23.90
minutes are non-reacted Mal-PEG-DPSE (about 1.85% percent of the
total). The peak at 19.02 minutes represents about 5% of the total
conjugate, and the peak at 19.82 minutes represents about 73% of
the total conjugate, while the peaks at 22.13 minutes and 22.78
minutes represent about 20% of the total conjugate.
28TABLE 1 HPLC conditions. mobile phase 100% = MeOH:THF:0.17 M
NH4Ac, 94:5:1 20% = H2O:MeOH:THF:0.17 M NH.sub.4Ac, 79:19:1:1
column Waters C-18, 5 micron, 15.0 .times. 0.46 cm oven 35.degree.
C. run time 12.5 min flow rate 1 mL/min detection UV 216, 340 nm %
grad. 50%-100%
EXAMPLE 40
[0822] Liposomes comprised of hydrogenated soy phosphatidylcholine,
cholesterol, and methoxy-poly(ethylene
glycol)-distearolyphosphatidyletha- nolamine (HSPE:Chol:mPEG-DSPE,
56.4:38.3:53 molar ratio, mPEG molecular weight 2000 Daltons) and
containing entrapped doxorubicin (Doxil.RTM./Caelyx.RTM.) were
prepared as described in the art (see, for example, U.S. Pat. Nos.
5,103,556; 5,213,804).
[0823] Micellar solutions of the targeting conjugate identified as
Formula (Ia) or Formula (1b) were prepared by hydrating a dried
lipid film of the conjugate with buffer to yield a solution of
ligand conjugates at varying concentrations.
[0824] The transfer of the lipid-polymer-ligand conjugate into the
pre-formed Doxil.RTM. liposomes was initiated by mixing a 60 .mu.L
aliquot of a micellar solution of the targeting conjugates to
provide 2.756 .mu.g, 5.513 .mu.g, and 11.026 .mu.g of the ligand
conjugate with 1 mL of the pre-formed liposomes. The mixtures were
incubated at 60.degree. C. for 1 hour.
[0825] Analysis showed the ratios of ligand/liposome were 18, 36,
and 72 for the ligand conjugate/liposome solutions having ligand
conjugate amounts of 2.756 .mu.g, 5.513 .mu.g, and 11.026 .mu.g,
respectively. The insertion efficiency of each was determined to be
100%, 87.41%, and 87.96% in each solution, respectively.
Biological Experimental Examples
[0826] As demonstrated by biological studies described hereinafter,
as shown in Table I, the compounds of the present invention are
.alpha.v.beta.3 and .alpha.v.beta.5 integrin receptor antagonists
useful in treating an integrin mediated disorder.
EXAMPLE 1
[0827] In Vitro Solid Phase Purified .alpha.v.beta.3 Binding
Assay
[0828] The vitronectin/.alpha.v.beta.3 binding assay methods were
derived from Mehta et al. (Biochem J, 1998, 330, 861). Human
.alpha.v.beta.3 (Chemicon International Inc., Temecula, Calif.), at
a concentration of 1 .mu./ml dissolved in Tris buffer (20 mM Tris,
1 mM CaCl.sub.2, 1 mM MgCl.sub.2, 10 .mu.M MnCl.sub.2, 150 mM
NaCl), was immobilized on Immulon 96 well plates (Dynex
Technologies, Chantilly, Va.) overnight at 4.degree. C. Plates were
washed and treated with blocking buffer (3% BSA in Tris buffer) for
2 h at 37.degree. C. Plates were then rinsed 2 times with assay
buffer comprised of Tris buffer. Synthesized compounds were added
to wells in duplicate immediately prior to the addition of 2 nM
vitronectin (Sigma, St. Louis, Mo.). Following a 3 hour incubation
at 37.degree. C., plates were washed 5 times in assay buffer. An
anti-human vitronectin IgG rabbit polyclonal antibody (Calbiochem,
San Diego, Calif.) was added (1:2000) and plates were incubated for
1 hour at room temperature. VectaStain ABC peroxidase kit reagents
(Vector Laboratories, Burlingame, Calif.) employing a biotin
labeled anti-rabbit IgG, were utilized for detection of bound
antibody. Plates were read at 490 nm on a Molecular Devices
(Sunnyvale, Calif.) microplate reader. Table 1 shows the results of
the in vitro solid phase purified .alpha..sub.v.beta..sub.- 3
binding assay for representative compounds of the present
invention.
EXAMPLE 2
[0829] In Vitro Solid Phase Purified GP IIb/IIIa Binding Assay
[0830] A 96 well Immulon-2 microtiter plate (Dynatech-Immulon) was
coated with 50 .mu.L/well of RGD-affinity purified GP IIb/IIIa
(effective range 0.5-10 .mu.g/mL) in 10 mM HEPES, 150 mM NaCl, 1 mM
MgCl.sub.2 at pH 7.4. The plate was covered and incubated overnight
at 4.degree. C. The GP IIb/IIIa solution was discarded and 150
.mu.L of 5% BSA was added and incubated at RT for 1-3 h. The plate
was washed extensively with modified Tyrodes buffer. Biotinylated
fibrinogen (25 .mu.L/well) at 2.times. final concentration was
added to the wells that contain the test compounds (25 .mu.L/well).
The plate was covered and incubated at RT for 2-4 h. Twenty minutes
prior to incubation completion, one drop of Reagent A (VectaStain
ABC Horseradish Peroxidase kit, Vector Laboratories, Inc.) and one
drop Reagent B were added with mixing to 5 mL modified Tyrodes
buffer mix and let stand. The ligand solution was discarded and the
plate washed (5.times.200 .mu.L/well) with modified Tyrodes buffer.
Vecta Stain HRP-Biotin-Avidin reagent (50 .mu.L/well, as prepared
above) was added and incubated at RT for 15 min. The Vecta Stain
solution was discarded and the wells washed (5.times.200 .mu./well)
with modified Tyrodes buffer. Developing buffer (10 mL of 50 mM
citrate/phosphate buffer @ pH 5.3, 6 mg o-phenylenediamine, 6 .mu.L
30% H.sub.2O.sub.2; 50 .mu.L/well) was added and incubated at RT
for 3-5 min and then 2 N H.sub.2SO.sub.4 (50 .mu.L/well) was added.
The absorbance was read at 490 nM. Table 1 shows the results of the
in-vitro solid phase purified GP IIb/IIIa binding assay for
representative compounds of the present invention.
EXAMPLE 3
[0831] In Vitro Solid Phase Purified .alpha.v.beta.5 Binding
Assay
[0832] The vitronectin/.alpha..sub.v.beta..sub.5 binding assay
method was performed in the same manner as the
vitronectin/.alpha..sub.v.beta..sub.3 binding assay of Example 2,
with the difference that 1 .mu.g/mL of human purified
.alpha..sub.v.beta..sub.5 (Chemicon International, Inc.) was
immobilized onto Immulon 96 well plates (Dynex Technologies)
instead of .alpha..sub.v.beta..sub.3. All other aspects of the
assay including buffers, reagents and incubation times remain
unchanged.
29TABLE 1 Cpd .alpha..sub.v.beta..sub.3IC.sub.50(uM- )
.alpha..sub.v.beta..sub.5IC.sub.50(uM)
.alpha..sub.IIb.beta..sub.3IC.sub- .50(uM) 1 0.0560 .+-. 0.007 N =
2 4.33 .+-. 0.15 N = 2 >5 ND 2 5.4000 .+-. N = 1 4.78 .+-. 1.013
N = 2 3 0.0036 .+-. 0.0004 N = 5 2.5 0.21 N = 1 4 0.0005 .+-.
0.0001 N = 3 0.0355 .+-. 0.0089 N = 4 0.87 .+-. 0.19 N = 2 5 0.0037
.+-. 0.0014 N = 3 0.2607 .+-. 0.0569 N = 3 14.84 .+-. 0.68 N = 2
5-3 0.1613 N = 1 >5 N = 1 ND 5-4 0.0054 .+-. 0.0002 N = 3 0.1616
.+-. 0.0627 N = 3 9.82 N = 1 6 0.0076 .+-. 0.0021 N = 2 0.54 N = 1
1.62 .+-. 0.05 N = 2 7 0.0082 .+-. 0.0014 N = 2 0.0395 .+-. 0.0085
N = 2 1.67 .+-. 0.74 N = 2 8 0.0179 .+-. 0.0034 N = 4 0.253 N = 1
1.36 .+-. 0.43 N = 2 9 >1 N = 1 ND 8.51 .+-. 2.36 N = 2 10
0.0024 .+-. 0.0013 N = 2 0.0335 .+-. 0.0075 N = 2 1.67 N = 1 11
0.0011 .+-. 0.0002 N = 3 0.0023 .+-. 0.0009 N = 3 2.52 .+-. 0.30 N
= 2 12 0.0042 .+-. 0.0014 N = 3 0.078 .+-. 0.017 N = 2 0.136 .+-.
0.003 N = 2 13 0.0032 .+-. 0.0006 N = 2 0.036 .+-. 0.0133 N = 2
11.09 .+-. 3.40 N = 2 14 0.0361 .+-. 0.0001 N = 2 0.108 .+-. 0.034
N = 1 5.04 N = 1 15 0.0019 .+-. 0.0002 N = 4 0.0334 .+-. 0.0063 N =
4 4.03 .+-. 0.43 N = 2 16 0.2810 N = 1 0.775 N = 1 25.38 N = 1 17
0.0008 .+-. 0.0001 N = 4 0.0313 .+-. 0.0060 N = 4 6.60 .+-. 1.42 N
= 2 18 >5 N = 1 >5 N = 1 >50 N = 1 19 0.0025 .+-. 0.0004 N
= 3 0.0171 .+-. 0.0025 N = 3 13.77 .+-. 9.69 N = 2 19-1 0.0367 N =
1 1.12 N = 1 >50 N = 1 19-2 0.0013 .+-. 0.0001 N = 2 0.0092 .+-.
0.0004 N = 2 12.9 N = 1 19-3 0.0447 .+-. 0.0204 N = 2 1.17 .+-.
0.02 N = 2 ND 19-4 0.0013 .+-. 0.0007 N = 3 0.0075 .+-. 0.0018 N =
3 4.86 N = 1 20 0.1417 .+-. 0.027 N = 3 0.995 N = 1 1.80 N = 1 21
0.0280 .+-. 0.0031 N = 3 0.78 N = 1 1.80 .+-. 0.63 N = 2 21b 0.405
N = 1 0.28 N = 1 1.97 N = 1 21a 0.0213 .+-. 0.0019 N = 3 0.8413
.+-. 0.4054 N = 3 5.31 N = 1 22 0.0046 .+-. 0.0008 N = 3 0.195 N =
1 0.43 .+-. 0.07 N = 2 23 0.2980 .+-. 0.1460 N = 2 2.010 N = 1 4.93
N = 1 24 0.3070 N = 1 0.387 N = 1 19.30 N = 1 25 0.0456 .+-. 0.0066
N = 2 0.773 .+-. 0.118 N = 2 8.67 .+-. 1.72 N = 2 26 0.0277 .+-.
0.0053 N = 2 0.5 N = 1 5.92 N = 1 27 0.0480 N = 1 0.81 N = 1 1.62
.+-. 0.56 N = 2 28 0.0007 .+-. 0.0002 N = 3 0.0027 .+-. 0.0008 N =
4 6.10 .+-. 2.44 N = 2 28a 0.0003 .+-. 0.0002 N = 2 0.0042 .+-.
0.0018 N = 2 1.83 .+-. 0.57 N = 2 28b 0.0208 .+-. 0.0053 N = 2
0.1262 .+-. 0.0448 N = 2 24.26 N = 1 29 0.0022 .+-. 0.0008 N = 3
0.119 .+-. 0.0150 N = 3 1.74 .+-. 0.89 N = 2 30 0.0010 .+-. 0.0002
N = 3 0.0028 .+-. 0.0001 N = 3 14.39 .+-. 5.98 N = 2 30a 0.0004
.+-. 0.0002 N = 3 0.0019 .+-. 0.0004 N = 3 2.93 .+-. 1.86 N = 2 30b
0.0317 .+-. 0.0147 N = 2 0.0482 .+-. 0.0028 N = 2 >50 N = 1 31
0.0330 N = 1 0.3 N = 1 21.57 .+-. 4.87 N = 2 32 0.0008 .+-. 0.0002
N = 3 0.0022 .+-. 0.0007 N = 3 1.055 .+-. 0.56 N = 2 33 0.0013 .+-.
0.0004 N = 3 0.0226 .+-. 0.0052 N = 3 >50 N = 1 34 0.1476 .+-.
0.1004 N = 2 1.041 .+-. 0.109 N = 2 >50 N = 1 35 0.0007 .+-.
0.0004 N = 2 0.0007 .+-. 0.0002 N = 3 0.965 .+-. 0.07 N = 2 36
0.0008 .+-. 0.00006 N = 4 0.0007 .+-. 0.0002 N = 3 3.11 .+-. 0.04 N
= 2 36a 0.0004 N = 3 0.0009 .+-. 0.0006 N = 2 0.79 .+-. 0.05 N = 3
36b 0.084 N = 1 0.129 N = 1 >50 N = 1 37 0.0158 .+-. 0.0043 N =
2 0.0897 .+-. 0.0116 N = 3 >50 N = 1 38 0.4840 N = 1 2.11 N = 1
>50 N = 1 39 0.0066 .+-. 0.0018 N = 2 0.0287 .+-. 0.0133 N = 2
>50 N = 1 40 0.0052 .+-. 0.0002 N = 2 0.308 .+-. 0.0630 N = 2
23.95 .+-. 9.89 N = 2 41 0.0018 .+-. 0.0010 N = 2 0.8725 .+-.
0.1575 N = 2 19.3 .+-. 2.60 N = 2 42 0.0007 .+-. 0.0003 N = 3
0.0189 .+-. 0.0046 N = 3 5 .+-. 0.74 N = 2 43 0.0079 .+-. 0.0007 N
= 2 0.2225 .+-. 0.0885 N = 2 28.82 .+-. 15.8 N = 2 44 0.0022 .+-.
0.0009 N = 3 0.002 .+-. 0.0006 N = 3 5.44 .+-. 1.1 N = 2 45 0.0008
.+-. 0.0001 N = 3 0.0017 .+-. 0.0003 N = 3 6.61 .+-. 2.85 N = 2 46
0.0035 .+-. 0.0006 N = 2 0.0659 .+-. 0.0171 N = 2 13.64 .+-. 1.33 N
= 2 47 0.0014 .+-. 0.0007 N = 3 0.0046 .+-. 0.0017 N = 3 1.47 .+-.
0.37 N = 2 48 0.0010 .+-. 0.0005 N = 3 0.0033 .+-. 0.0014 N = 3
1.21 .+-. 0.20 N = 2 49 0.0018 .+-. 0.0005 N = 3 0.0895 .+-. 0.0255
N = 2 0.16 .+-. 0.02 N = 3 50 0.0156 .+-. 0.0044 N = 4 0.676 N = 1
0.19 .+-. 0.04 N = 2 51 0.0030 .+-. 0.0006 N = 4 0.169 .+-. 0.019 N
= 2 0.48 .+-. 0.01 N = 2 52 0.0064 .+-. 0.0014 N = 4 >50 N = 1
0.57 .+-. 0.04 N = 2 53 0.0298 .+-. 0.0137 N = 5 0.1375 .+-. 0.0415
N = 2 0.94 .+-. 0.05 N = 2 54 0.0017 .+-. 0.0005 N = 3 0.0347 .+-.
0.0117 N = 3 0.24 N = 1 55 0.0950 N = 1 0.737 N = 1 15.59 N = 1 56
0.0019 .+-. 0.0006 N = 3 0.0245 .+-. 0.0065 N = 2 39.12 .+-. 0.785
N = 2 56a 0.0005 .+-. 0.0002 N = 3 0.0265 .+-. 0.0034 N = 3 14.66 N
= 1 56b 0.3263 .+-. 0.0894 N = 3 0.8096 .+-. 0.1045 N = 3 ND 57
0.0016 .+-. 0.0007 N = 3 0.0109 .+-. 0.0042 N = 3 3.04 .+-. 0.55 N
= 2 58a 0.0004 .+-. 0.0003 N = 3 0.0323 .+-. 0.0082 N = 3 1.44 .+-.
0.39 N = 2 58b 0.083 .+-. 0.020 N = 2 0.5760 .+-. 0.1490 N = 2 35.5
N = 1 59 0.0026 .+-. 0.0014 N = 2 0.0096 .+-. 0.0038 N = 2 7.805
.+-. 4.67 N = 2 60 0.0010 .+-. 0.0008 N = 2 0.0309 .+-. 0.0006 N =
2 4.53 .+-. 2.47 N = 2 61 0.0045 .+-. 0.0007 N = 3 0.0253 .+-.
0.0073 N = 3 37.45 .+-. 31.58 N = 2 62 0.0900 .+-. 0.0020 N = 2
0.1700 .+-. 0.0810 N = 2 >50 N = 1 63 0.0018 .+-. 0.0008 N = 3
0.0070 .+-. 0.0008 N = 3 10.23 .+-. 6.41 N = 2 64 0.0615 .+-.
0.0055 N = 2 0.1473 .+-. 0.0847 N = 2 >50 N = 1 65 0.0008 N = 2
0.0346 .+-. 0.0002 N = 2 3.84 N = 1 66 0.0012 .+-. 0.0001 N = 3
0.0103 .+-. 0.0014 N = 3 28.27 N = 1 67 0.048 .+-. 0.0030 N = 2
0.176 .+-. 0.0350 N = 2 7.82 N = 1 68 0.413 N = 1 >1 N = 1 35.6
N = 1 69 >0.5 N = 1 >1 N = 1 >50 N = 1 70 >0.5 N = 1
>1 N = 1 >50 N = 1 71 >0.5 N = 1 >1 N = 1 >50 N = 1
72 >0.5 N = 1 >1 N = 1 >50 N = 1 73 >0.5 N = 1 >1 N
= 1 >50 N = 1 74 0.193 N = 1 >1 N = 1 >50 N = 1 75 0.0053
.+-. 0.0010 N = 2 0.0419 .+-. 0.0052 N = 3 >50 N = 1 76 0.0018
.+-. 0.0003 N = 2 0.0397 .+-. 0.0121 N = 2 5.38 N = 1 76a 0.0011
.+-. 0.0002 N = 2 0.0169 .+-. 0.0021 N = 2 10.38 N = 1 77 0.138 N =
1 0.789 .+-. 0.065 N = 2 ND 78 0.0057 .+-. 0.0001 N = 2 0.0260 .+-.
0.0030 N = 2 24.72 N = 1 79 0.0035 .+-. 0.0015 N = 3 0.025 .+-.
0.0060 N = 2 40.23 N = 1 81 0.0067 .+-. 0.0002 N = 3 0.0101 .+-.
0.0017 N = 3 22.73 N = 1
[0833] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
EXAMPLE 4
[0834] Ligand and Targeting Conjugate Binding Assay
[0835] The ability of compounds to inhibit binding of
.alpha..sub.v.beta..sub.3 or .alpha..sub.v.beta..sub.5 to
vitronectin was measured as previously described in Luci, D. K.;
Santulli, R. J.; Gauthier, D. A.; Ghosh, S.; Kinney, W. A.;
DeCorte, B.; Galemmo, R. A. Jr.; Lewis, J. M.; Proost, J. C.;
Tounge, B. A.; Dorsch, W. E.; Wagaman, M. W.; Damiano, B. P.;
Maryanoff, B. E. Heterocycles 2004, 62, 543-557. Human
.alpha..sub.v.beta..sub.3 or .alpha..sub.v.beta..sub.5 (Chemicon
International Inc.) dissolved in Tris buffer (20 mM Tris, 1 mM
CaCl.sub.2, 1 mM MgCl.sub.2, 10 .mu.M MnCl.sub.2, 150 mM NaCl) was
immobilized (1 .mu.g/mL) on Immulon 96 well plates (Dynex
Technologies) overnight at 4.degree. C. Plates were blocked with 3%
BSA in Tris buffer for 2 h at 37.degree. C. Plates were then rinsed
2.times. in assay buffer (Tris buffer with 0.3% BSA and 0.2%
Tween-20). Five minutes prior to the addition of 4 nM vitronectin
(Sigma Chemical Co.), compounds were added to wells in duplicate.
Following 3 h at 37.degree. C., plates were washed 5.times. in
assay buffer. An anti-human vitronectin IgG rabbit polyclonal
antibody (Calbiochem Inc.) was added (1:2000) and plates were
incubated for 1 h at room temperature. VectaStain ABC peroxidase
kit reagents (Vector Laboratories) employing a biotin labeled
anti-rabbit IgG, were utilized for detection of bound antibody (490
nm).
[0836] Adhesion of endothelial cells to vitronectin is both
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5 mediated.
The ability of the liposome conjugates to inhibit human
microvascular endothelial cell (HMVEC) adhesion to vitronectin was
evaluated. Cytomatrix cell adhesion strips coated with vitronectin
(Chemicon) were rehydrated with 200 .mu.l of PBS for at least 15
minutes at room temperature and then aspirated. HMVECs (Clonetics)
were trypsinized to disperse cells from culture flask and dissolved
in DPBS with 0.1% BSA (assay buffer). Cells were fluorescently
labeled with 5 .mu.M Calcein AM (Molecular Probes) and incubated in
the dark for 30 min @ 37.degree. C. After incubation, cells were
washed 2.times. in assay buffer and cell number adjusted to
1.times.10.sup.6/mL. A 50 .mu.L sample of compound was added to
each well followed by 50 .mu.L of the cell suspension. Plates are
incubated for 1 h @ 37.degree. C., 5% CO.sub.2. After 1 h, plates
were washed gently with warm assay buffer and adherent cells lysed
for 15 min in 100 .mu.L of 1 M Tris pH 8.0 with 1% SDS. Fluorescent
Intensity was determined using a Cytoflluor 2300 plate reader
(Applied Biosytems) set at 485 excitation and 530 emission.
[0837] HT-29 colon carcinoma cells adhere to fibronectin via the
integrin .alpha..sub.v.beta..sub.6 as described in Kraft, S.;
Diefenbach, B.; Mehta, R.; Jonczyk, A; Luckenbach, G. A.; Goodman,
S. L. J. Biol. Chem. 1999, 274, 1979-1985. To determine if the
liposome-conjugated can inhibit this interaction the following
adhesion assay was utilized. The ability of compounds to block
adhesion of HT-29 cells was carried out in a similar fashion to the
HMVEC/vitronectin assay described above. The only differences in
protocol were that 1) Cytomatrix cell adhesion strips coated with
fibronectin (Chemicon) were utilized and 2) HT-29 cells (ATCC) were
the cell used in all experiments (same density, same labeling
procedure).
PROSPECTIVE EXAMPLE 5
[0838] Young (4-6 week) female severe combined immune deficient
(SCID) mice are injected with a tumor cell line expressing
.alpha.5.beta.3 integrin receptors in the subcutaneous tissue of
the flank or of the mammary fat pad. When palpable tumors achieve a
size of about 300 mm3 (typically 14 days post inoculation),
therapeutic, target-cell sensitized liposomes prepared as described
in Example 40 and additionally inducing a suitable label are
administered by a single intravenous injection via the tail vein,
in a volume of approximately 200 .mu.L contining approximately 1
.mu.mole total lipid. Animals are sacrificed at designated times
post-injection, organs perfused with saline in situ, and tissues
excised for analysis. Biodistribution of the liposomes is
determined via detection of the liposome label or by quantitative
localization of doxorubicin delivered by the liposomes.
* * * * *