U.S. patent application number 11/807303 was filed with the patent office on 2009-01-29 for pre-organized tricyclic integrase inhibitor compounds.
Invention is credited to James M. Chen, Xiaowu Chen, Maria Fardis, Haolun Jin, Choung U. Kim, Laura N. Schacherer.
Application Number | 20090029939 11/807303 |
Document ID | / |
Family ID | 32110203 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090029939 |
Kind Code |
A1 |
Chen; James M. ; et
al. |
January 29, 2009 |
Pre-organized tricyclic integrase inhibitor compounds
Abstract
Tricyclic compounds according to the structure below, protected
intermediates thereof, and methods for inhibition of HIV-integrase
are disclosed. ##STR00001## A.sup.1 and A.sup.2 are moieties
forming a five, six, or seven membered ring. L is a bond or a
linker connecting a ring atom of Ar to N. X is O, S, or substituted
nitrogen. Ar is aryl or heteroaryl, Q is N, .sup.+NR, or CR.sup.4.
The aryl carbons may be independently substituted with substituents
other than hydrogen. The compounds may include prodrug moieties
covalently attached at any site.
Inventors: |
Chen; James M.; (San Ramon,
CA) ; Chen; Xiaowu; (San Mateo, CA) ; Fardis;
Maria; (San Carlos, CA) ; Jin; Haolun; (Foster
City, CA) ; Kim; Choung U.; (San Carlos, CA) ;
Schacherer; Laura N.; (San Francisco, CA) |
Correspondence
Address: |
GILEAD SCIENCES INC
333 LAKESIDE DR
FOSTER CITY
CA
94404
US
|
Family ID: |
32110203 |
Appl. No.: |
11/807303 |
Filed: |
May 25, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10687373 |
Oct 16, 2003 |
7253180 |
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11807303 |
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60418963 |
Oct 16, 2002 |
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60478783 |
Jun 16, 2003 |
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Current U.S.
Class: |
514/50 ; 435/375;
514/210.18; 514/232.8; 514/253.03; 514/292; 514/81; 540/521;
544/126; 544/361; 546/23; 546/84 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 487/04 20130101; C07D 471/04 20130101; A61P 31/12 20180101;
C07D 207/404 20130101; A61P 31/18 20180101 |
Class at
Publication: |
514/50 ; 546/84;
514/292; 514/232.8; 544/126; 544/361; 514/253.03; 514/210.18;
514/81; 546/23; 435/375; 540/521 |
International
Class: |
A61K 31/7072 20060101
A61K031/7072; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; A61K 31/5377 20060101 A61K031/5377; A61K 31/496
20060101 A61K031/496; A61P 31/18 20060101 A61P031/18; A61K 31/675
20060101 A61K031/675; C07F 9/58 20060101 C07F009/58; C12N 5/06
20060101 C12N005/06; C07D 487/04 20060101 C07D487/04 |
Claims
1. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound having the structure: ##STR00401## wherein: A.sup.1 is
independently selected from C(R.sup.2).sub.2, CR.sup.2OR,
CR.sup.2OC(.dbd.O)R, C(.dbd.O), C(.dbd.S), CR.sup.2SR, and
C(.dbd.NR), A.sup.2 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3) and
C(.dbd.O)C(R.sup.3).sub.2; Q is CR.sup.4; ##STR00402## L is
selected from a bond, O, S, S--S, S(.dbd.O), S(.dbd.O).sub.2,
S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12 alkylene,
C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12 alkenylene,
C.sub.2-C.sub.12 substituted alkenylene, C.sub.2-C.sub.12
alkynylene, C.sub.2-C.sub.12 substituted alkynylene, C(.dbd.O)NH,
OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
is optionally 1, 2, 3, 4, 5, or 6; X is selected from O, S, NH, NR,
N--OR, N--NR.sub.2, N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is
selected from (a) a C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12
substituted carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20
substituted aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20
substituted heteroaryl; or (b) a saturated, unsaturated or aromatic
ring or ring system having a mono- or bicyclic carbocycle or
heterocycle containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and
R.sup.4 are each independently selected from H, F, Cl, Br, I, OH,
--NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof; with the proviso that when Y.dbd.Z
is C.dbd.C(OH), X is O, A.sup.1 is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond; and
further comprising a therapeutically effective amount of an AIDS
treatment agent selected from an HIV inhibitor agent, an
anti-infective agent, and an immunomodulator.
2. The pharmaceutical composition of claim 1 wherein the HIV
inhibitor agent is an HIV-protease inhibitor.
3. The pharmaceutical composition of claim 1 wherein the HIV
inhibitor agent is a nucleoside reverse transcriptase
inhibitor.
4. The pharmaceutical composition of claim 3 wherein said
nucleoside reverse transcriptase inhibitor is
3'-azido-3'-deoxythymidine (zidovudine, AZT),
2'-deoxy-3'-thiacytidine (3TC),
2',3'-dideoxy-2',3'-didehydroadenosine (D4A), 2', 3'-dideoxy-2',
3'-didehydrothymidine (D4T), carbovir (carbocyclic
2',3'-dideoxy-2',3'-didehydroguanosine), 2',3'-dideoxycytidine
(ddC), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI),
PMEA, or PMPA.
5. The pharmaceutical composition of claim 1 wherein the HIV
inhibitor agent is a non-nucleoside reverse transcriptase
inhibitor.
6. A process for making a pharmaceutical composition comprising
combining a pharmaceutically acceptable carrier and a compound
having the structure: ##STR00403## wherein: A.sup.1 is
independently selected from C(R.sup.2).sub.2, CR.sup.2OR,
CR.sup.2OC(.dbd.O)R, C(.dbd.O), C(.dbd.S), CR.sup.2SR, and
C(.dbd.NR), A.sup.2 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3) and
C(.dbd.O)C(R.sup.3).sub.2; Q is CR.sup.4; ##STR00404## L is
selected from a bond, O, S, S--S, S(.dbd.O), S(.dbd.O).sub.2,
S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12 alkylene,
C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C].sub.2 alkenylene,
C.sub.2-C.sub.12 substituted alkenylene, C.sub.2-C.sub.12
alkynylene, C.sub.2-C.sub.12 substituted alkynylene, C(.dbd.O)NH,
OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.20).sub.n, where n
is optionally 1,2, 3, 4, 5, or 6; X is selected from O, S, NH, NR,
N--OR, N--NR.sub.2, N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is
selected from (a) a C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12
substituted carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20
substituted aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20
substituted heteroaryl; or (b) a saturated, unsaturated or aromatic
ring or ring system having a mono- or bicyclic carbocycle or
heterocycle containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and
R.sup.4 are each independently selected from H, F, Cl, Br, I, OH,
--NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof; with the proviso that when Y=Z is
C.dbd.C(OH), X is O, A.sup.1 is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond.
7. A method of inhibiting HIV integrase, comprising the
administration to a mammal in need of such treatment of a
therapeutically effective amount of a compound having the
structure: ##STR00405## wherein: A.sup.1 is independently selected
from C(R.sup.2).sub.2, CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O),
C(.dbd.S), CR.sup.2SR, and C(.dbd.NR), A.sup.2 is independently
selected from C(R.sup.2).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3) and C(.dbd.O)C(R.sup.3).sub.2; Q is
CR.sup.4; ##STR00406## L is selected from a bond, O, S, S--S,
S(--O), S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR,
C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12 substituted alkylene,
C.sub.2-C.sub.12 alkenylene, C.sub.2-C.sub.12 substituted
alkenylene, C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12
substituted alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH,
C(.dbd.O), C(.dbd.O)NH(CH.sub.2).sub.n, or
(CH.sub.2CH.sub.2O).sub.n, where n is optionally 1, 2, 3, 4, 5, or
6; X is selected from O, S, NH, NR, N--OR, N--NR.sub.2,
N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is selected from (a) a
C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl; or (b) a saturated, unsaturated or aromatic ring or
ring system having a mono- or bicyclic carbocycle or heterocycle
containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and R.sup.4 are
each independently selected from H, F, Cl, Br, I, OH, --NH.sub.2,
--NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof, with the proviso that when Y.dbd.Z
is C.dbd.C(OH), X is O, A.sup.1 is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond.
8. A method of treating infection by HIV, or of treating AIDS or
ARC, comprising administration to a mammal in need of such
treatment of a therapeutically effective amount of a compound
having the structure: ##STR00407## wherein: A.sup.1 is
independently selected from C(R.sup.2).sub.2, CR.sup.2OR,
CR.sup.2OC(.dbd.O)R, C(.dbd.O), C(.dbd.S), CR.sup.2SR, and
C(.dbd.NR), A.sup.2 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3) and
C(.dbd.O)C(R.sup.3).sub.2; Q is CR.sup.4; ##STR00408## L is
selected from a bond, O, S, S--S, S(.dbd.O), S(.dbd.O).sub.2,
S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12 alkylene,
C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12 alkenylene,
C.sub.2-C.sub.12 substituted alkenylene, C.sub.2-C.sub.12
alkynylene, C.sub.2-C.sub.12 substituted alkynylene, C(.dbd.O)NH,
OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
is optionally 1, 2, 3, 4, 5, or 6; X is selected from O, S, NH, NR,
N--OR, N--NR.sub.2, N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is
selected from (a) a C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12
substituted carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20
substituted aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20
substituted heteroaryl; or (b) a saturated, unsaturated or aromatic
ring or ring system having a mono- or bicyclic carbocycle or
heterocycle containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and
R.sup.4 are each independently selected from H, F, Cl, Br, I, OH,
--NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof; with the proviso that when Y=Z is
C.dbd.C(OH), X is O, Al is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond.
9. A method of treating a disorder affecting white blood cells,
comprising: administering to a patient in need of white-blood-cell
targeting a phosphonate prodrug of a compound having the structure:
##STR00409## wherein: A.sup.1 is independently selected from
C(R.sup.2).sub.2, CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O),
C(.dbd.S), CR.sup.2SR, and C(.dbd.NR), A.sup.2 is independently
selected from C(R.sup.2).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3) and C(.dbd.O)C(R.sup.3).sub.2; Q is
CR.sup.4; ##STR00410## L is selected from a bond, O, S, S--S,
S(.dbd.O), S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR,
C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12 substituted alkylene,
C.sub.2-C.sub.12 alkenylene, C.sub.2-C.sub.12 substituted
alkenylene, C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12
substituted alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH,
C(.dbd.O), C(.dbd.O)NH(CH.sub.2), or (CH.sub.2CH.sub.2O).sub.n,
where n is optionally 1, 2, 3, 4, 5, or 6; X is selected from O, S,
NH, NR, N--OR, N--NR.sub.2, N--CR.sub.2OR and N--CR.sub.2NR.sub.2;
Ar is selected from (a) a C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl; or (b) a saturated,
unsaturated or aromatic ring or ring system having a mono- or
bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R.sup.2, R.sup.3 and R.sup.4 are each independently selected from
H, F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR,
--NR.sub.2, --NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide,
carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring
sultam, C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof; with the proviso that when Y=Z is
C.dbd.C(OH), X is O, A.sup.1 is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond.
10. A method of targeting a compound to white blood cells,
comprising: (a) selecting a compound having a first structure:
##STR00411## wherein: A.sup.1 is independently selected from
C(R.sup.2).sub.2, CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O),
C(.dbd.S), CR.sup.2SR, and C(.dbd.NR), A.sup.2 is independently
selected from C(R.sup.2).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3) and C(.dbd.O)C(R.sup.3).sub.2; Q is
CR.sup.4; ##STR00412## L is selected from a bond, O, S, S--S,
S(.dbd.O), S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR,
C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12 substituted alkylene,
C.sub.2-C.sub.12 alkenylene, C.sub.2-C.sub.12 substituted
alkenylene, C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12
substituted alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH,
C(.dbd.O), C(.dbd.O)NH(CH.sub.2).sub.n, or
(CH.sub.2CH.sub.2O).sub.n, where n is optionally 1, 2, 3, 4, 5, or
6; X is selected from O, S, NH, NR, N--OR, N--NR.sub.2,
N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is selected from (a) a
C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl; or (b) a saturated, unsaturated or aromatic ring or
ring system having a mono- or bicyclic carbocycle or heterocycle
containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and R.sup.4 are
each independently selected from H, F, Cl, Br, I, OH, --NH.sub.2,
--NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof; with the proviso that when Y=Z is
C.dbd.C(OH), X is O, A.sup.1 is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond; and
having a desired pharmaceutical activity; and (b) modifying said
first structure by replacing one or more atoms of said first
structure with an organic substituent comprising a phosphonate
group or incipient phosphonate group to provide a compound having a
second structure.
11. A method of accumulating an HIV integrase inhibitor compound
inside a white blood cell, comprising: (a) selecting a composition
comprising a compound having a structure: ##STR00413## wherein:
A.sup.1 is independently selected from C(R.sup.2).sub.2,
CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O), C(.dbd.S), CR.sup.2SR,
and C(.dbd.NR), A.sup.2 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3) and
C(.dbd.O)C(R.sup.3).sub.2; Q is CR.sup.4; ##STR00414## L is
selected from a bond, O, S, S--S, S(.dbd.O), S(.dbd.O).sub.2,
S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12 alkylene,
C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12 alkenylene,
C.sub.2-C.sub.12 substituted alkenylene, C.sub.2-C.sub.12
alkynylene, C.sub.2-C.sub.12 substituted alkynylene, C(.dbd.O)NH,
OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O), where n is
optionally 1, 2, 3, 4, 5, or 6; X is selected from O, S, NH, NR,
N--OR, N--NR.sub.2, N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is
selected from (a) a C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12
substituted carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20
substituted aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20
substituted heteroaryl; or (b) a saturated, unsaturated or aromatic
ring or ring system having a mono- or bicyclic carbocycle or
heterocycle containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and
R.sup.4 are each independently selected from H, F, Cl, Br, I, OH,
--NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof; with the proviso that when Y=Z is
C.dbd.C(OH), X is O, A.sup.1 is C(.dbd.O), A.sup.2 is
C(R.sup.2).dbd.C(R.sup.3), and Q is CH, then L is not a bond; and
(b) administering said composition to a sample.
12. A method of claim 11 wherein said sample is a patient.
13. A compound having the structure: ##STR00415## wherein: A.sup.1
is independently selected from C(R.sup.2).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3), C(.dbd.O)C(R.sup.3).sub.2,
C(R.sup.2).sub.2--C(R.sup.3).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3)--C(R.sup.3).sub.2, and
C(R.sup.2).sub.2--C(R.sup.3); A.sup.2 is independently selected
from C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3),
and C(.dbd.O)C(R.sup.3).sub.2; Q is CR.sup.4; ##STR00416## L is
selected from a bond, O, S, S--S, S(.dbd.O), S(.dbd.O).sub.2,
S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12 alkylene,
C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12 alkenylene,
C.sub.2-C.sub.12 substituted alkenylene, C.sub.2-C.sub.12
alkynylene, C.sub.2-C.sub.12 substituted alkynylene, C(.dbd.O)NH,
OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
may be 1, 2, 3, 4, 5, or 6; X is selected from O, S, NH, NR, N--OR,
N--NR.sub.2, N--CR.sub.2OR and N--CR.sub.2NR.sub.2; Ar is selected
from (a) a C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12
substituted carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20
substituted aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20
substituted heteroaryl; or (b) a saturated, unsaturated or aromatic
ring or ring system having a mono- or bicyclic carbocycle or
heterocycle containing 3 to 12 ring atoms; R.sup.2, R.sup.3 and
R.sup.4 are each independently selected from H, F, Cl, Br, I, OH,
--NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety; R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety; R.sup.X2 is
independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group
selected from the group consisting of benzyhydryl (CHPh.sub.2),
trialkylsilyl (R.sub.3Si), 2-trimethylsiloxyethyl, alkoxymethyl
(CH.sub.2OR), and ester (C(.dbd.O)R); and the tautomers, salts,
solvates, resolved enantiomers and purified diastereomers
thereof.
14. A compound of claim 13 selected from the structures:
##STR00417##
15. A compound of claim 13 selected from the structures:
##STR00418##
16. A compound of claim 13 wherein R.sup.1 is selected from R, OR,
NR.sub.2, NHR, NHSO.sub.2R and NRSO.sub.2R.
17. A compound of claim 13 selected from the structures:
##STR00419##
18. A compound of claim 13 wherein R.sup.X2 is a protecting group
selected from the group consisting of benzyhydryl (CHPh.sub.2),
trialkylsilyl (R.sub.3Si), 2-trimethylsiloxyethyl, alkoxymethyl
(CH.sub.2OR), and ester (C(.dbd.O)R).
19. A compound of claim 13 having the structure: ##STR00420##
20. A compound of claim 13 having Formula I: ##STR00421## wherein
R.sup.X2 is H and X is O.
21. A compound of claim 13 wherein L is not a bond.
22. A compound of claim 13 wherein R.sup.4 is H.
23. A compound of claim 13 wherein Ar is C.sub.6-C.sub.20
substituted aryl.
24. A compound of claim 13 having at least one phosphonate
group.
25. A compound of claim 13 wherein substituted alkyl, substituted
alkylene, substituted alkyenylene, substituted alkynylene,
substituted carbocycle, substituted aryl, and substituted
heteroaryl are independently substituted with one or more
substituents selected from F, Cl, Br, I, OH, --NH.sub.2,
--NH.sub.3.sup.+, --NHR, --NR.sub.2, --NR.sub.3.sup.+,
C.sub.1-C.sub.8 alkylhalide, carboxylate, sulfate, sulfamate,
sulfonate, 5-7 membered ring sultam, C.sub.1-C.sub.8
alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.12 carbocycle,
C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heteroaryl,
polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.
26. The compound of claim 13 wherein A.sup.1 is CH.sub.2--CH.sub.2,
C(CH.sub.3).sub.2--CH.sub.2, CH.dbd.CH or
CH.sub.2--CH.sub.2--CH.sub.2.
27. The compound of claim 20 wherein L is CH.sub.2; and Ar is
substituted phenyl.
28. The compound of claim 27 wherein Ar is 4-fluorophenyl.
29. The compound of claim 20 wherein R.sup.2, R.sup.3 and R.sup.4
are each H.
30. The compound of claim 20 wherein A.sup.1 is CH.dbd.CH; and
R.sup.2, R.sup.3 and R.sup.4 are each H.
31. The compound of claim 13 wherein Ar-L is selected from the
structures: ##STR00422##
32. A compound of claim 20 having the formula ##STR00423##
33. A compound of claim 20 having the structure: ##STR00424##
34. A compound of claim 20 wherein Ar-L is para-fluorobenzyl.
35. A compound of claim 13 wherein R.sup.1 is selected from
CR.sub.3, C(.dbd.O)NR.sub.2, OC(.dbd.O)OR, OC(.dbd.O)NR.sub.2,
OC(.dbd.O)R, OSO.sub.2NR.sub.2 (sulfamate), NR.sub.2, NRSO.sub.2R,
SR, S(O)R, SO.sub.2R and SO.sub.2NR.sub.2 (sulfonamide).
36. The compound of claim 35 wherein at least one R is a prodrug
moiety.
37. A compound of claim 13 wherein at least one of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 is selected from the structures:
##STR00425##
38. A compound of claim 13 wherein at least one of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 is selected from the structures:
##STR00426##
39. A compound of claim 13 wherein at least one of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 is selected from the structures:
##STR00427##
40. A compound of claim 13 wherein at least one of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 is a lactam having the structures:
##STR00428## a sultam having the structures: ##STR00429##
41. A compound of claim 13 wherein Ar is selected from the
structures: ##STR00430## where the wavy lineindicates the covalent
attachment site to L.
42. A compound of claim 13 wherein Ar is selected from the
structures: ##STR00431## where n is 1 to 6.
43. A compound of claim 13 wherein Ar is selected from the
structures: ##STR00432##
44. A compound of claim 13 comprising a prodrug moiety selected
from the structures: ##STR00433## wherein R.sup.5 is
--CR.sub.2CO.sub.2R.sup.7 where R.sup.6 and R.sup.7 are
independently H or C.sub.1-C.sub.8 alkyl.
45. The compound of claim 13 comprising a phosphonate or prodrug
moiety having the structure: ##STR00434## wherein: Y.sup.1 is
independently O, S, N(R.sup.x), N(O)(R.sup.x), N(OR.sup.x),
N(O)(OR.sup.x), or N(N(R.sup.x).sub.2; Y.sup.2 is independently a
bond, O, N(R.sup.x), N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x),
N(N(R.sup.x).sub.2), --S(O)-- (sulfoxide), --S(O).sub.2--
(sulfone), --S-- (sulfide), or --S--S-- (disulfide); M2 is 0, 1 or
2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; M12b is 0, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R.sup.y is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl, or a
protecting group, or where taken together at a carbon atom, two
vicinal R.sup.y groups form a carbocycle or a heterocycle; and
R.sub.x is independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
substituted alkyl, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20
substituted aryl, or a protecting group, or the formula:
##STR00435## where M1a, M1c, and M1d are independently 0 or 1, and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
46. The compound of claim 45 wherein the phosphonate or prodrug
moiety has the structure: ##STR00436##
47. The compound of claim 46 wherein the phosphonate or prodrug
moiety has the structure: ##STR00437## where Y.sup.2b is O or
N(R.sup.x).
48. The compound of claim 46 wherein the phosphonate or prodrug
moiety has the structure: ##STR00438## where W.sup.5 is a
carbocycle, and Y.sup.2c is O, N(R.sup.y) or S.
49. The compound of claim 48 wherein W.sup.5 is selected from the
structures: ##STR00439##
50. The compound of claim 46 wherein the phosphonate or prodrug
moiety has the structure: ##STR00440##
51. The compound of claim 13 wherein the phosphonate or prodrug
moiety has the structure: ##STR00441## wherein Y.sup.2b is O or
N(R.sup.x); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R.sup.1 is H or
C.sub.1-C.sub.6 alkyl; and the phenyl carbocycle is substituted
with 0 to 3 R.sup.2 groups where R.sup.2 is C.sub.1-C.sub.6 alkyl
or substituted alkyl.
52. The compound of claim 13 wherein the phosphonate or prodrug
moiety has the structure: ##STR00442##
53. The compound of claim 45 wherein Rx is selected from the
structures: ##STR00443##
54. A compound of claim 13 wherein none of R.sup.2, R.sup.3,
R.sup.4, R, or R.sup.X2 is a prodrug moiety.
55. A compound that is ##STR00444##
56. A compound of claim 13 substituted with a phosphonate or
phosphonate prodrug moiety and capable of accumulating in human
PBMC.
57. The compound of claim 56 wherein the intracellular half-life of
the compound or an intracellular metabolite of the compound in
human PBMC is increased by at least about 50% when compared to the
analog of the compound not having the a phosphonate or phosphonate
prodrug moiety.
58. The compound of claim 57 wherein the half-life is improved by
at least about 100%.
59. The compound of claim 56 wherein the intracellular half-life of
a metabolite of the compound in human PBMC is increased by at least
about 50% when compared to the analog of the compound not having
the a phosphonate or phosphonate prodrug moiety.
60. The compound of claim 59 wherein the half-life is improved by
at least about 100%.
61. The compound of claim 60 wherein the half-life is improved by
greater than 100%.
62. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 13 and a pharmaceutically
acceptable carrier.
63. The pharmaceutical composition of claim 62 further comprising a
therapeutically effective amount of an AIDS treatment agent
selected from an HIV inhibitor agent, an anti-infective agent, and
an immunomodulator.
64. The pharmaceutical composition of claim 63 wherein the HIV
inhibitor agent is an HIV-protease inhibitor.
65. The pharmaceutical composition of claim 63 wherein the HIV
inhibitor agent is a nucleoside reverse transcriptase
inhibitor.
66. The pharmaceutical composition of claim 65 wherein said
nucleoside reverse transcriptase inhibitor is
3'-azido-3'-deoxythymidine (zidovudine, AZT),
2'-deoxy-3'-thiacytidine (3TC),
2',3'-dideoxy-2',3'-didehydroadenosine (D4A),
2',3'-dideoxy-2',3'-didehydrothymidine (D4T), carbovir (carbocyclic
2',3'-dideoxy-2',3'-didehydroguanosine), 2',3'-dideoxycytidine
(ddC), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI),
PMEA, or PMPA.
67. The composition of claim 63 wherein the HIV inhibitor agent is
a non-nucleoside reverse transcriptase inhibitor.
68. A process for making a pharmaceutical composition comprising
combining a compound of claim 13 and a pharmaceutically acceptable
carrier.
69. A method of inhibiting HIV integrase, comprising the
administration to a mammal in need of such treatment of a
therapeutically effective amount of a compound of claim 13.
70. A method of treating infection by HIV, or of treating AIDS or
ARC, comprising administration to a mammal in need of such
treatment of a therapeutically effective amount of a compound of
claim 13.
71. Method of treating a disorder affecting white blood cells,
comprising: administering a compound of claim 13 comprising a
phosphonate prodrug to a patient in need of white-blood-cell
targeting.
72. A method of targeting a compound to white blood cells,
comprising: (a) selecting a compound of claim 13 having a desired
pharmaceutical activity and having a first structure; and (b)
modifying said first structure by replacing one or more atoms of
said first structure with an organic substituent comprising a
phosphonate group or incipient phosphonate group to provide a
compound having a second structure.
73. A method of accumulating an HIV integrase inhibitor compound
inside a white blood cell, comprising: (a) selecting a composition
comprising a compound of claim 13; and (b) administering said
composition to a sample.
74. A method of claim 73 wherein said sample is a patient.
Description
[0001] This non-provisional application is a divisional of
non-provisional application Ser. No. 10/687,373, filed Oct. 16,
2003, that claims the benefit of Provisional Application No.
60/418,963, filed Oct. 16, 2002, and Provisional Application No.
60/478,783, filed Jun. 16, 2003, all of which are incorporated
herein in their entirety by reference as if each were individually
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates generally to compounds with antiviral
activity and more specifically with HIV-integrase inhibitory
properties.
BACKGROUND OF THE INVENTION
[0003] Human immunodeficiency virus (HIV) infection and related
diseases are a major public health problem worldwide. A virally
encoded integrase protein mediates specific incorporation and
integration of viral DNA into the host genome. Integration is
necessary for viral replication. Accordingly, inhibition of HIV
integrase is an important therapeutic pursuit for treatment of HIV
infection of the related diseases.
[0004] Human immunodeficiency virus type 1 (HIV-1) encodes three
enzymes which are required for viral replication: reverse
transcriptase, protease, and integrase. Although drugs targeting
reverse transcriptase and protease are in wide use and have shown
effectiveness, particularly when employed in combination, toxicity
and development of resistant strains have limited their usefulness
(Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman, D. D.
Nature (2001) 410:995-1001). There is a need for new agents
directed against alternate sites in the viral life cycle. Integrase
has emerged as an attractive target, because it is necessary for
stable infection and homologous enzymes are lacking in the human
host (LaFemina, et al J. Virol. (1992) 66:7414-7419). The function
of integrase is to catalyze integration of proviral DNA, resulting
from the reverse transcription of viral RNA, into the host genome,
by a stepwise fashion of endonucleolytic processing of proviral DNA
within a cytoplasmic preintegration complex (termed 3'-processing
or "3'-P") with specific DNA sequences at the end of the HIV-1 long
terminal repeat (LTR) regions, followed by translocation of the
complex into the nuclear compartment where integration of
3'-processed proviral DNA into host DNA occurs in a "strand
transfer" (ST) reaction (Hazuda, et al Science (2000) 287:646-650;
Katzman, et al Adv. Virus Res. (1999) 52:371-395; Asante-Applah, et
al Adv. Virus Res. (1999) 52:351-369). Although numerous agents
potently inhibit 3'-P and ST in extracellular assays that employ
recombinant integrase and viral long-terminal-repeat
oligonucleotide sequences, often such inhibitors lack inhibitory
potency when assayed using fully assembled preintegration complexes
or fail to show antiviral effects against HIV-infected cells
(Pommier, et al Adv. Virus Res. (1999) 52-427-458; Farnet, et al
Proc. Natl. Acad. Sci. U.S.A. (1996) 93:9742-9747; Pommier, et al
Antiviral Res. (2000) 47:139-148.
[0005] Certain HIV integrase inhibitors have been disclosed which
block integration in extracellular assays and exhibit good
antiviral effects against HIV-infected cells (Anthony, et al WO
02/30426; Anthony, et al WO 02/30930; Anthony, et al WO 02/30931;
WO 02/055079; Zhuang, et al WO 02/36734; U.S. Pat. No. 6,395,743;
U.S. Pat. No. 6,245,806; U.S. Pat. No. 6,271,402; Fujishita, et al
WO 00/039086; Uenaka et al WO 00/075122; Selnick, et al WO
99/62513; Young, et al WO 99/62520; Payne, et al WO 01/00578; Jing,
et al Biochemistry (2002) 41:5397-5403; Pais, et al Jour. Med.
Chem. (2002) 45:3184-94; Goldgur, et al Proc. Natl. Acad. Sci.
U.S.A. (1999) 96:13040-13043; Espeseth, et al Proc. Natl. Acad.
Sci. U.S.A. (2000) 97:11244-11249).
[0006] HIV integrase inhibitory compounds with improved antiviral
and pharmacokinetic properties are desirable, including enhanced
activity against development of HIV resistance, improved oral
bioavailability, greater potency and extended effective half-life
in vivo (Nair, V. "HIV integrase as a target for antiviral
chemotherapy" Reviews in Medical Virology (2002) 12(3):179-193).
Three-dimensional quantitative structure-activity relationship
studies and docking simulations (Buolamwini, et al Jour. Med. Chem.
(2002) 45:841-852) of conformationally-restrained cinnamoyl-type
integrase inhibitors (Artico, et al Jour. Med. Chem. (1998)
41:3948-3960) have correlated hydrogen-bonding interactions to the
inhibitory activity differences among the compounds.
[0007] Improving the delivery of drugs and other agents to target
cells and tissues has been the focus of considerable research for
many years. Though many attempts have been made to develop
effective methods for importing biologically active molecules into
cells, both in vivo and in vitro, none has proved to be entirely
satisfactory. Optimizing the association of the inhibitory drug
with its intracellular target, while minimizing intercellular
redistribution of the drug, e.g. to neighboring cells, is often
difficult or inefficient.
[0008] Most agents currently administered parenterally to a patient
are not targeted, resulting in systemic delivery of the agent to
cells and tissues of the body where it is unnecessary, and often
undesirable. This may result in adverse drug side effects, and
often limits the dose of a drug (e.g., cytotoxic agents and other
anti-cancer or anti-viral drugs) that can be administered. By
comparison, although oral administration of drugs is generally
recognized as a convenient and economical method of administration,
oral administration can result in either (a) uptake of the drug
through the cellular and tissue barriers, e.g. blood/brain,
epithelial, cell membrane, resulting in undesirable systemic
distribution, or (b) temporary residence of the drug within the
gastrointestinal tract. Accordingly, a major goal has been to
develop methods for specifically targeting agents to cells and
tissues. Benefits of such treatment includes avoiding the general
physiological effects of inappropriate delivery of such agents to
other cells and tissues, such as uninfected cells. Intracellular
targeting may be achieved by methods and compositions which allow
accumulation or retention of biologically active agents inside
cells.
SUMMARY OF THE INVENTION
[0009] The present invention provides compositions and methods for
inhibition of HIV integrase.
[0010] In one aspect, the invention comprises a compound having the
structure:
##STR00002##
[0011] wherein:
[0012] A.sup.1 and A.sup.2 are independently selected from O, S,
NR, C(R.sup.2).sub.2, CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O),
C(.dbd.S), CR.sup.2SR, C(.dbd.NR),
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3),
C(R.sup.2).sub.2--O, NR--C(R.sup.3).sub.2, N.dbd.C(R.sup.3),
N.dbd.N, SO.sub.2--NR, C(.dbd.O)C(R.sup.3).sub.2, C(.dbd.O)NR,
C(R.sup.2).sub.2--C(R.sup.3).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.(R.sup.3)--C(R.sup.3).sub.2, C(R.sup.2)C(.dbd.O)NR,
C(R.sup.2)C(.dbd.S)NR, C(R.sup.2).dbd.N--C(R.sup.3).sub.2,
C(R.sup.2).dbd.N--NR, and N.dbd.C(R.sup.3)--NR;
[0013] Q is N, .sup.+NR, or CR.sup.4;
##STR00003##
[0014] L is selected from a bond, O, S, S--S, S(.dbd.O),
S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12
alkylene, C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12
alkenylene, C.sub.2-C.sub.12 substituted alkenylene,
C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12 substituted
alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
may be 1, 2, 3, 4, 5, or 6;
[0015] X is selected from O, S, NH, NR, N--OR, N--NR.sub.2,
N--CR.sub.2OR and N--CR.sub.2NR.sub.2;
[0016] Ar is selected from C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl;
[0017] R.sup.1 R.sup.2, R.sup.3 and R.sup.4 are each independently
selected from H, F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+,
--NHR, --NR.sub.2.sup.+, --NR.sub.3.sup.+, C.sub.1-C.sub.8
alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7
membered ring sultam, C.sub.1-C.sub.8 alkylsulfonate,
C.sub.1-C.sub.8 alkylamino, 4-dialkylaminopyridinium,
C.sub.1-C.sub.8 alkylhydroxyl, C.sub.1-C.sub.8 alkylthiol,
dialkylaminopyridinium, --SO.sub.2R, --SO.sub.2Ar, --SOAr, --SAr,
--SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.25-7
membered ring lactam, 5-7 membered ring lactone, --CN, --N.sub.3,
--NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 trifluoroalkyl,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted alkyl,
C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety;
[0018] when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; and
[0019] R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety;
[0020] R.sup.X2 is independently selected from H, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug, a pharmaceutically acceptable
prodrug, a prodrug moiety, a protecting group, and a phosphonate
prodrug moiety;
[0021] and the salts, solvates, resolved enantiomers and purified
diastereomers thereof;
[0022] with the proviso that when Y=Z is C.dbd.C(OH), X is O,
A.sup.1 is C(.dbd.O), A.sup.2 is C(R.sup.2).dbd.C(R.sup.3), and Q
is CH, then L is not a bond.
[0023] In one aspect, the invention is a compound having the
structure:
##STR00004##
[0024] wherein:
[0025] A.sup.1 is independently selected from C(R.sup.2).sub.2,
CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O), C(.dbd.S), CR.sup.2SR,
and C(.dbd.NR),
[0026] A.sup.2 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3), and
C(.dbd.O)C(R.sup.3).sub.2;
[0027] Q is CR.sup.4;
##STR00005##
[0028] L is selected from a bond, O, S, S--S, S(.dbd.O),
S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12
alkylene, C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12
alkenylene, C.sub.2-C.sub.2 substituted alkenylene,
C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12 substituted
alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
is optionally 1, 2, 3, 4, 5, or 6;
[0029] X is selected from O, S, NH, NR, N--OR, N--NR.sub.2,
N--CR.sub.2OR and N--CR.sub.2NR.sub.2;
[0030] Ar is selected from (a) a C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl;
[0031] or (b) a saturated, unsaturated or aromatic ring or ring
system having a mono- or bicyclic carbocycle or heterocycle
containing 3 to 12 ring atoms;
[0032] R.sup.2, R.sup.3 and R.sup.4 are each independently selected
from H, F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR,
--NR.sub.2, --NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide,
carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring
sultam, C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2R.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety;
[0033] when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may from a spiro ring; R.sup.1 is independently selected
from CR.sub.3, NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H,
F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety;
[0034] R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety;
[0035] R.sup.X2 is independently selected from H, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting
group;
[0036] and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof,
[0037] with the proviso that when Y=Z is C.dbd.C(OH), X is O,
A.sup.1 is C(.dbd.O), A.sup.2 is C(R.sup.2).dbd.C(R.sup.3), and Q
is CH, then L is not a bond.
[0038] In another aspect the invention is a compound having the
structure:
##STR00006##
[0039] wherein:
[0040] A.sup.1 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3),
C(.dbd.O)C(R.sup.3).sub.2,
C(R.sup.2).sub.2--C(R.sup.3).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3)--C(R.sup.3).sub.2, and
C(R.sup.2).sub.2--C(R.sup.3).dbd.C(R.sup.3);
[0041] A.sup.2 is independently selected from
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3), and
C(.dbd.O)C(R.sup.3).sub.2;
[0042] Q is CR.sup.4;
##STR00007##
[0043] L is selected from a bond, O, S, S--S, S(.dbd.O),
S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12
alkylene, C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12
alkenylene, C.sub.2-C.sub.12 substituted alkenylene,
C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12 substituted
alkynylene, C(.dbd.O)N--H, OC(.dbd.O)NH, NHC(.dbd.O)NH, C(--O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
may be 1, 2, 3, 4, 5, or 6;
[0044] X is selected from O, S, NH, NR, N--OR, N--NR.sub.9,
N--CR.sub.2OR and N--CR.sub.9NR.sub.2;
[0045] Ar is selected from (a) a C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl;
[0046] or (b) a saturated, unsaturated or aromatic ring or ring
system having a mono- or bicyclic carbocycle or heterocycle
containing 3 to 12 ring atoms;
[0047] R.sup.2, R.sup.3 and R.sup.4 are each independently selected
from H, F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR,
--NR.sub.2, --NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide,
carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring
sultam, C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety;
[0048] when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring;
[0049] R.sup.1 is independently selected from CR.sub.3,
NRSO.sub.2R, OC(.dbd.O)NR.sub.2 OC(.dbd.O)R, SR, H, F, Cl, Br, I,
OH, --NH.sub.2, --NH.sub.3.sup.+, --NHR, --NR.sub.2,
--NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug
moiety;
[0050] R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety;
[0051] R.sup.X2 is independently selected from H, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug moiety, and a protecting group
selected from the group consisting of benzyhydryl (CHPh.sub.2),
trialkylsilyl (R.sub.3Si), 2-trimethylsilylethyl, alkoxymethyl
(CH.sub.2OR), and ester (C(.dbd.O)R);
[0052] and the tautomers, salts, solvates, resolved enantiomers and
purified diastereomers thereof.
[0053] In one aspect, the invention includes tricyclic compounds
represented by the following structure:
##STR00008##
[0054] The compounds of the invention share a tricyclic scaffold
and a potential active site or metal binding motif defined by the
lower side of the Formula above including the amide-type
functionality, i.e. N--C(.dbd.X), of the left ring, the aromatic
hydroxyl of the middle ring, and the nitrogen of the right ring.
The compounds of the invention have binding functionality, e.g.
nitrogen, hydroxyl, and X-carbonyl, in a pre-organized
configuration which may confer optimized inhibitory properties
against HIV integrase.
[0055] A.sup.1 and A.sup.2 are each and independently a moiety
forming a five, six, or seven membered ring. Q is N, substituted
nitrogen (NR), CH, or substituted carbon. L is a bond or a linker
connecting a ring atom of Ar to N. X is O, S, NH, or substituted
nitrogen (NR). Ar is a carbocycle, aryl or heteroaryl group. R is a
substituent including H, alkyl, aryl, heteroaryl and substituted
forms thereof, as well as polyethyleneoxy, phosphonate, phosphate,
or a prodrug moiety. The 5 and 6 positions are represented in the
structure above by Y and Z respectively. The chemical bond between
Y and Z may be a single bond, a double bond, or a bond with enolic,
tautomeric character, depending on the substituent on Z, i.e.
R.sup.1 or X. The Y and Z substructure is represented wherein:
##STR00009##
[0056] The compounds of the invention may include prodrug moieties
covalently attached at any site. The prodrug moiety may be a
phosphonate group.
[0057] The invention also includes a pharmaceutical composition
comprising a therapeutically effective amount of a compound of the
invention, or a pharmaceutically acceptable salt thereof, in
combination with a pharmaceutically acceptable diluent or
carrier.
[0058] The invention also includes a pharmaceutical composition
comprising a therapeutically effective amount of a compound of the
invention, or a pharmaceutically acceptable salt thereof in
combination with a therapeutically effective amount of an AIDS
treatment agent selected from an HIV inhibitor agent, an
anti-infective agent, and an immunomodulator. The HIV inhibitor
agent may include an HIV-protease inhibitor, a nucleoside reverse
transcriptase inhibitor, or a non-nucleoside reverse transcriptase
inhibitor.
[0059] The invention also includes methods of preventing the
proliferation of HIV virus, treating AIDS, delaying the onset of
AIDS or ARC symptoms, and generally inhibiting HIV integrase. The
methods comprise administering to a mammal infected with HIV (HIV
positive) an amount of a compound of the invention, in a
therapeutically effective dose or administration to inhibit the
growth of HIV infected cells of the mammal.
[0060] In another aspect of the invention, the activity of HIV
integrase is inhibited by a method comprising the step of treating
a sample suspected of containing HIV virus with a compound or
composition of the invention.
[0061] The invention also includes processes and novel
intermediates disclosed herein which are useful for preparing
compounds of the invention. Some of the compounds of the invention
are useful to prepare other compounds of the invention.
[0062] This invention also includes methods of increasing cellular
accumulation, bioavailability, or retention of drug compounds, thus
improving their therapeutic and diagnostic value, by administering
a phosphonate prodrug form of a compound of the invention.
[0063] Another aspect of the invention provides a method for
inhibiting the activity of HIV integrase comprising the step of
contacting a sample suspected of containing HIV virus with the
composition embodiments of the invention.
[0064] In other aspects, novel methods for the synthesis, analysis,
separation, isolation, crystallization, purification,
characterization, resolution of isomers including enantiomers and
diastereomers, and testing of the compounds of this invention are
provided.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0065] Reference will now be made in detail to certain embodiments
of the invention, examples of which are illustrated in the
accompanying descriptions, structure and formulas. While the
invention will be described in conjunction with the enumerated
embodiments, it will be understood that they are not intended to
limit the invention to those embodiments. On the contrary, the
invention is intended to cover all alternatives, modifications, and
equivalents, which may be included within the scope of the present
invention as defined by the claims.
DEFINITIONS
[0066] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0067] The terms "phosphonate" and "phosphonate group" mean a
functional group or moiety within a molecule that comprises at
least one phosphorus-carbon bond, and at least one
phosphorus-oxygen double bond. The phosphorus atom is further
substituted with oxygen, sulfur, and nitrogen substituents. These
substituents may be part of a prodrug moiety. As defined herein,
"phosphonate" and "phosphonate group" include molecules with
phosphonic acid, phosphonic monoester, phosphonic diester,
phosphonamidate, phosphondiamidate, and phosphonthioate functional
groups.
[0068] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e. active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s),
photolysis, and/or metabolic chemical reaction(s). A prodrug is
thus a covalently modified analog or latent form of a
therapeutically-active compound.
[0069] "Pharmaceutically acceptable prodrug" refers to a compound
that is metabolized in the host, for example hydrolyzed or
oxidized, by either enzymatic action or by general acid or base
solvolysis, to form an active ingredient. Typical examples of
prodrugs of the compounds of the invention have biologically labile
protecting groups on a functional moiety of the compound. Prodrugs
include compounds that can be oxidized, reduced, aminated,
deaminated, esterified, deesterified, alkylated, dealkylated,
acylated, deacylated, phosphorylated, dephosphorylated, photolyzed,
hydrolyzed, or other functional group change or conversion
involving forming or breaking chemical bonds on the prodrug.
[0070] "Prodrug moiety" means a labile functional group which
separates from the active inhibitory compound during metabolism,
systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of
Prodrugs" in Textbook of Drug Design and Development (1991), P.
Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic
Publishers, pp. 113-19 1). Enzymes which are capable of an
enzymatic activation mechanism with the prodrug compounds of the
invention include, but are not limited to, amidases, esterases,
microbial enzymes, phospholipases, cholinesterases, and phosphases.
Prodrug moieties can serve to enhance solubility, absorption and
lipophilicity to optimize drug delivery, bioavailability and
efficacy. A "prodrug" is thus a covalently modified analog of a
therapeutically-active compound.
[0071] Exemplary prodrug moieties include the hydrolytically
sensitive or labile acyloxymethyl esters
--CH.sub.2OC(.dbd.O)R.sup.9 and acyloxymethyl carbonates
--CH.sub.2OC(.dbd.O)OR.sup.9 where R.sup.9 is C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 substituted alkyl, C.sub.6-C.sub.20 aryl or
C.sub.6-C.sub.20 substituted aryl. The acyloxyalkyl ester was first
used as a prodrug strategy for carboxylic acids and then applied to
phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci.
72: 324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and
5,792,756. In certain compounds of the invention, a prodrug moiety
is part of a phosphonate group. Subsequently, the acyloxyalkyl
ester was used to deliver phosphonic acids across cell membranes
and to enhance oral bioavailability. A close variant of the
acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate),
may also enhance oral bioavailability as a prodrug moiety in the
compounds of the combinations of the invention. An exemplary
acyloxymethyl ester is pivaloyloxymethoxy, (POM)
--CH.sub.2OC(.dbd.O)C(CH.sub.3).sub.3. An exemplary acyloxymethyl
carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC)
--CH.sub.2OC(.dbd.O)OC(CH.sub.3).sub.3.
[0072] The phosphonate group may be a phosphonate prodrug moiety.
The prodrug moiety may be sensitive to hydrolysis, such as, but not
limited to a pivaloyloxymethyl carbonate (POC) or POM group.
Alternatively, the prodrug moiety may be sensitive to enzymatic
potentiated cleavage, such as a lactate ester or a
phosphonamidate-ester group. Exemplary phosphonate prodrug moieties
include by way of example and not limitation groups of the
structure A.sup.3.
[0073] Aryl esters of phosphorus groups, especially phenyl esters,
are reported to enhance oral bioavailability (DeLambert et al
(1994) J. Med. Chem. 37: 498). Phenyl esters containing a
carboxylic ester ortho to the phosphate have also been described
(Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl
esters are reported to generate the parent phosphonic acid. In some
cases, substituents at the ortho-or para-position may accelerate
the hydrolysis. Benzyl analogs with an acylated phenol or an
alkylated phenol may generate the phenolic compound through the
action of enzymes, e.g. esterases, oxidases, etc., which in turn
undergoes cleavage at the benzylic C--O bond to generate the
phosphoric acid and the quinone methide intermediate. Examples of
this class of prodrugs are described by Mitchell et al (1992) J.
Chem. Soc. Perkin Trans. I 2345; Brook et al WO 91/19721. Still
other benzylic prodrugs have been described containing a carboxylic
ester-containing group attached to the benzylic methylene (Glazier
et al WO 91/1972 1). Thio-containing prodrugs are reported to be
useful for tie intracellular delivery of phosphonate drugs. These
proesters contain an ethylthio group in which the thiol group is
either esterified with an acyl group or combined with another thiol
group to form a disulfide. Deesterification or reduction of the
disulfide generates the free thio intermediate which subsequently
breaks down to the phosphoric acid and episulfide (Puech et al
(1993) Antiviral Res. 22: 155-174; Benzaria et al (1996) J. Med.
Chem. 39: 4958). Cyclic phosphonate esters have also been described
as prodrugs of phosphorus-containing compounds (Erion et al, U.S.
Pat. No. 6,312,662).
[0074] "Protecting group" refers to a moiety of a compound that
masks or alters the properties of a functional group or the
properties of the compound as a whole. The chemical substructure of
a protecting group varies widely. One function of a protecting
group is to serve as intermediates in the synthesis of the parental
drug substance. Chemical protecting groups and strategies for
protection/deprotection are well known in the art. See: "Protective
Groups in Organic Chemistry", Theodora W. Greene (John Wiley &
Sons, Inc., New York, 1991, which is incorporated herein by
reference. Protecting groups are often utilized to mask the
reactivity of certain functional groups, to assist in the
efficiency of desired chemical reactions, e.g. making and breaking
chemical bonds in an ordered and planned fashion. Protection of
functional groups of a compound alters other physical properties
besides the reactivity of the protected functional group, such as
the polarity, lipophilicity (hydrophobicity), and other properties
which can be measured by common analytical tools. Chemically
protected intermediates may themselves be biologically active or
inactive.
[0075] Protected compounds may also exhibit altered, and in some
cases, optimized properties in vitro and in vivo, such as passage
through cellular membranes and resistance to enzymatic degradation
or sequestration. In this role, protected compounds with intended
therapeutic effects may be referred to as prodrugs. Another
function of a protecting group is to convert the parental drug into
a prodrug, whereby the parental drug is released upon conversion of
the prodrug in vivo. Because active prodrugs may be absorbed more
effectively than the parental drug, prodrugs may possess greater
potency in vivo than the parental drug. Protecting groups are
removed either in vitro, in the instance of chemical intermediates,
or in viva, in the case of prodrugs. With chemical intermediates,
it is not particularly important that the resulting products after
deprotection, e.g. alcohols, be physiologically acceptable,
although in general it is more desirable if the products are
pharmacologically innocuous. Exemplary protecting groups include by
way of example and not limitation groups of the structure R.sup.X
other than hydrogen.
[0076] Any reference to any of the compounds of the invention also
includes a reference to a physiologically acceptable salt thereof:
Examples of physiologically acceptable salts of the compounds of
the invention include salts derived from an appropriate base, such
as an alkali metal (for example, sodium), an alkaline earth (for
example, magnesium), ammonium and NX.sub.4.sup.+ (wherein X is
C.sub.1-C.sub.4 alkyl). Physiologically acceptable salts of an
hydrogen atom or an amino group include salts of organic carboxylic
acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic,
malonic, malic, isethionic, lactobionic and succinic acids; organic
sulfonic acids, such as methanesulfonic, ethanesulfonic,
benzenesulfonic and p-toluenesulfonic acids; and inorganic acids,
such as hydrochloric, sulfuric, phosphoric and sulfonic acids.
Physiologically acceptable salts of a compound of an hydroxy group
include the anion of said compound in combination with a suitable
cation such as Na.sup.+ and NX.sub.4.sup.+ (wherein X is
independently selected from H or a C.sub.1-C.sub.4 alkyl
group).
[0077] For therapeutic use, salts of active ingredients of the
compounds of the invention will be physiologically acceptable, i.e.
they will be salts derived from a physiologically acceptable acid
or base. However, salts of acids or bases which are not
physiologically acceptable may also find use, for example, in the
preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived form a physiologically
acceptable acid or base, are within the scope of the present
invention.
[0078] "Alkyl" is C.sub.1-C.sub.18 hydrocarbon containing normal,
secondary, tertiary or cyclic carbon atoms. Examples are methyl
(Me, --CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr,
n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(C.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3.
[0079] "Alkenyl" is C.sub.2-C.sub.18 hydrocarbon containing normal,
secondary, tertiary or cyclic carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp.sup.2 double bond.
Examples include, but are not limited to: ethylene or vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
cyclopentenyl (--C.sub.5H.sub.7), and 5-hexenyl (--CH.sub.2
CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2)
[0080] "Alkynyl" is C.sub.2-C.sub.18 hydrocarbon containing normal,
secondary, tertiary or cyclic carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples
include, but are not limited to: acetylenic (--C.ident.CH) and
propargyl (--CH.sub.2C.ident.CH),
[0081] The terms "alkylene" and "akyldiyl" each refer to a
saturated, branched or straight chain or cyclic hydrocarbon radical
of 1-18 carbon atoms, and having two monovalent radical centers
derived by the removal of two hydrogen atoms from the same or two
different carbon atoms of a parent alkane. Typical alkylene
radicals include, but are not limited to: methylene (--CH.sub.2--)
1,2-ethyl (--CH.sub.2CH.sub.2--), 1,3-propyl
(--CH.sub.2CH.sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0082] 37 Alkenylene" refers to an unsaturated, branched or
straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms,
and having two monovalent radical centers derived by the removal of
two hydrogen atoms from the same or two different carbon atoms of a
parent alkene, i.e. double carbon-carbon bond moiety. Typical
alkenylene radicals include, but are not limited to: 1,2-ethylene
(--CH.dbd.CH--).
[0083] "Alkynylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and
having two monovalent radical centers derived by the removal of two
hydrogen atoms from the same or two different carbon atoms of a
parent alkyne, i.e. triple carbon-carbon bond moiety. Typical
alkynylene radicals include, but are not limited to: acetylene
(--C.ident.C--), propargyl (--CH.sub.2C.ident.C--), and 4-pentynyl
(--CH.sub.2CH.sub.2CH.sub.2C.ident.CH--).
[0084] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-20 carbon atoms derived by the removal of one hydrogen atom from
a single carbon atom of a parent aromatic ring system. Typical aryl
groups include, but are not limited to, radicals derived from
benzene, substituted benzene, naphthalene, anthracene, biphenyl,
and the like.
[0085] "Heteroaryl" means a monovalent aromatic radical of one or
more carbon atoms and one or more atoms selected from N, O, S, or
P, derived by the removal of one hydrogen atom from a single atom
of a parent aromatic ring system. Heteroaryl groups may be a
monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to
3 heteroatoms selected from N, O, P, and S) or a bicycle having 7
to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms
selected from N, O, P, and S). Heteroaryl bicycles have 7 to 10
ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected
from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or
[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2
hetero atoms selected from N and S) arranged as a bicyclo [5,6] or
[6,6] system. The heteroaryl group may be bonded to the drug
scaffold through a carbon, nitrogen, sulfur, phosphorus or other
atom by a stable covalent bond.
[0086] Heteroaryl groups include, for example: pyridyl,
dihydropyridyl isomers, pyridazinyl, pyrimidinyl, pyrazinyl,
s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,
pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and
pyrrolyl.
[0087] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethen-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,
2-naphthophenylethan-1-yl and the like. The arylalkyl group
comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including
alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to
6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
[0088] Substituted substituents such as "substituted alkyl",
"substituted aryl", "substituted heteroaryl" and "substituted
arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which
one or more hydrogen atoms are each independently replaced with a
substituent. Typical substituents include, but are not limited to,
--X, --R, --O.sup.-, --OR, --SR, --S.sup.-, --NR.sub.2, --NR.sub.3,
.dbd.NR, --CX.sub.3, --CN, --OCN, --SCN, --N.dbd.C.dbd.O, --NCS,
--NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, NC(.dbd.O)R,
--C(.dbd.O)R, --C(.dbd.O)NRR --S(.dbd.O).sub.2O.sup.-,
--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR,
--S(.dbd.O).sub.2NR, --S(.dbd.O)R, --OP(.dbd.O)O.sub.2RR,
--P(.dbd.O)O.sub.2RR, --P(.dbd.O)(O.sup.-).sub.2,
--P(.dbd.O)(OH).sub.2, --C(.dbd.O)R, --C(.dbd.O)X, --C(S)R,
--C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NRR,
--C(S)NRR, --C(NR)NRR, where each X is independently a halogen: F,
Cl, Br, or I; and each R is independently --H, alkyl, aryl,
heterocycle, protecting group or prodrug moiety. Alkylene,
alkenylene, and alkynylene groups may also be similarly
substituted.
[0089] "Heterocycle" means a saturated, unsaturated or aromatic
ring system including at least one N, O, S, or P. Heterocycle thus
include heteroaryl groups. Heterocycle as used herein includes by
way of example and not limitation these heterocycles described in
Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (W.
A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7,
and 9; "The Chemistry of Heterocyclic Compounds, A series of
Monographs" (John Wiley & Sons, New York, 1950 to present), in
particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R.,
Rees, C. W. and Scriven, E. "Comprehensive Heterocyclic Chemistry"
(Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.
[0090] Examples of heterocycles include by way of example and not
limitation pyridyl, dihydroypyridyl, tetrahydropyridyl(piperidyl),
thiazolyl, tetrahydrothiophenyl, sulfur oxidized
tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,
indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,
piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl,
pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl,
tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and
isatinoyl.
[0091] One embodiment of the bis-tetrahydrofuranyl group is:
##STR00010##
[0092] By way of example and not limitation, carbon bonded
heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine,
position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl.
[0093] By way of example and not limitation, nitrogen bonded
heterocycles are bonded at position 1 of an aziridine, azetidine,
pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,
position 4 of a morpholine, and position 9 of a carbazole, or
.beta.-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,
1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
[0094] "Carbocycle" means a saturated, unsaturated or aromatic ring
system having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon
atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms,
still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7
to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or
[6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or
[6,6] system. Examples of monocyclic carbocycles include
cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,
1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,
1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl,
spiryl and naphthyl. Carbocycle thus includes some aryl groups.
[0095] "Linker" or "link" means a chemical moiety comprising a
covalent bond or a chain of atoms that covalently attaches a
phosphonate group to a drug. Linkers include L interposed between
Ar and the nitrogen of the tricyclic compounds of the invention.
The structures herein may refer to linkers as "link" or "L".
Linkers may also be interposed between a phosphorus-containing
A.sup.3 group and the R.sup.1, R.sup.2, R.sup.3, or R.sup.4
position of the compounds of the invention. Linkers include, but
are not limited to moieties such as O, S, NR, N--OR,
C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12 substituted alkylene,
C.sub.2-C.sub.12 alkenylene, C.sub.2-C.sub.12 substituted
alkenylene, C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12
substituted alkynylene, C(.dbd.O)NH, C(.dbd.O), S(.dbd.O).sub.2,
C(.dbd.O)NH(CH.sub.2).sub.n, and (CH.sub.2CH.sub.2O).sub.n, where n
may be 1, 2, 3, 4, 5, or 6. Linkers also include repeating units of
alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and
alkylamino (e.g. polyethyleneamino, Jeffamine.TM.); and diacid
ester and amides including succinate, succinamide, diglycolate,
malonate, and caproamide.
[0096] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0097] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0098] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0099] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0100] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and I or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or l meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory. For a given
chemical structure, these stereoisomers are identical except that
they are mirror images of one another. A specific stereoisomer may
also be referred to as an enantiomer, and a mixture of such isomers
is often called an enantiomeric mixture. A 50:50 mixture of
enantiomers is referred to as a racemic mixture or a racemate,
which may occur where there has been no stereoselection or
stereospecificity in a chemical reaction or process. The terms
"racemic mixture" and "racemate" refer to an equimolar mixture of
two enantiomeric species, devoid of optical activity.
HIV-Integrase Inhibitor Compounds
[0101] Novel tricyclic compounds with inhibitory activity against
HIV integrase are described, including any pharmaceutically
acceptable salts thereof.
[0102] In one aspect, the invention comprises a compound having the
structure:
##STR00011##
[0103] wherein:
[0104] A.sup.1 and A.sup.2 are independently selected from O, S,
NR, C(R.sup.2).sub.2, CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O),
C(.dbd.S), CR.sup.2SR, C(.dbd.NR),
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3),
C(R.sup.2).sub.2--O, NR--C(R.sup.3).sub.2, N.dbd.C(R.sup.3),
N.dbd.N, SO.sub.2--NR, C(.dbd.O)C(R.sup.3).sub.2, C(.dbd.O)NR,
C(R.sup.2).sub.2--C(R.sup.3).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3)--C(R.sup.3).sub.2, C(R.sup.2)C(.dbd.O)NR,
C(R.sup.2)C(.dbd.S)NR, C(R.sup.2).dbd.N--C(R.sup.3).sub.2,
C(R.sup.2).dbd.N--NR, and N.dbd.C(R.sup.3)--NR;
[0105] Q is N, .sup.-NR, or CR.sup.4;
##STR00012##
[0106] L is selected from a bond, O, S, S--S, S(.dbd.O),
S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12
alkylene, C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12
alkenylene, C.sub.2-C.sub.12 substituted alkenylene,
C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12 substituted
alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
may be 1, 2, 3, 4, 5, or 6;
[0107] X is selected from O, S, NH, NR, N--OR, N--NR.sub.2,
N--CR.sub.2OR and N--CR.sub.2NR.sub.2;
[0108] Ar is selected from C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl;
[0109] R.sup.1 R.sup.2, R.sup.3 and R.sup.4 are each independently
selected from H, F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+,
--NHR, --NR.sub.2, --NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide,
carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring
sultam, C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety;
[0110] when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring; and
[0111] R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety;
[0112] R.sup.X2 is independently selected from H, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug, a pharmaceutically acceptable
prodrug, a prodrug moiety, a protecting group, and a phosphonate
prodrug moiety;
[0113] and the salts, solvates, resolved enantiomers and purified
diastereomers thereof;
[0114] with the proviso that when Y=Z is C.dbd.C(OH), X is O,
A.sup.1 is C(.dbd.O), A.sup.2 is C(R.sup.2).dbd.C(R.sup.3), and Q
is CH, then L is not a bond.
[0115] In one aspect, the invention is a compound having the
structure:
##STR00013##
[0116] or a salt thereof,
[0117] wherein:
[0118] A.sup.1 and A.sup.2 are independently selected from O, S,
NR, C(R.sup.2).sub.2, CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O),
C(.dbd.S), CR.sup.2SR, C(.dbd.NR),
C(R.sup.2).sub.2--C(R.sup.3).sub.2, C(R.sup.2).dbd.C(R.sup.3),
NR--C(R.sup.3).sub.2, N.dbd.C(R.sup.3), N.dbd.N, SO.sub.2--NR,
C(.dbd.O)C(R.sup.3).sub.2, C(.dbd.O)NR,
C(R.sup.2).sub.2--C(R.sup.3).sub.2--C(R.sup.3).sub.2,
C(R.sup.2.dbd.C(R.sup.3)--C(R.sup.3).sub.2, C(R.sup.2)C(.dbd.O)NR,
C(R.sup.2)C(.dbd.S)NR, C(R.sup.2).dbd.N--C(R.sup.3).sub.2,
C(R.sup.2).dbd.N--NR, and N.dbd.C(R.sup.3)--NR;
[0119] Q is N, .sup.+NR, or CR.sup.4;
##STR00014##
[0120] L is selected from a bond, O, S, S--S, S(.dbd.O),
S(.dbd.O).sub.2, S(.dbd.O).sub.2NR, NR, N--OR, C.sub.1-C.sub.12
alkylene, C.sub.1-C.sub.12 substituted alkylene, C.sub.2-C.sub.12
alkenylene, C.sub.2-C.sub.12 substituted alkenylene,
C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12 substituted
alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH, C(.dbd.O),
C(.dbd.O)NH(CH.sub.2).sub.n, or (CH.sub.2CH.sub.2O).sub.n, where n
may be 1, 2, 3, 4, 5, or 6;
[0121] X is selected from O, S, NH, NR, N--OR, N--NR.sub.2,
N--CR.sub.2OR and N--CR.sub.2NR.sub.2;
[0122] Ar is selected from C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl;
[0123] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently
selected from H, F, Cl, Br, I, OH, --NH.sub.2, --NH.sub.3.sup.+,
--NHR, --NR.sub.2, --NR.sub.3.sup.+, C.sub.1-C.sub.8 alkylhalide,
carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring
sultam, C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, --SO.sub.2R, --SO.sub.2Ar, --SOAr,
--SAr, --SO.sub.2NR.sub.2, --SOR, --CO.sub.2R, --C(.dbd.O)NR.sub.2,
5-7 membered ring lactam, 5-7 membered ring lactone, --CN,
--N.sub.3, --NO.sub.2, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
trifluoroalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted
alkyl, C.sub.3-C.sub.12 carbocycle, C.sub.3-C.sub.12 substituted
carbocycle, C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted
aryl, C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug
moiety;
[0124] when taken together on a single carbon, two R.sup.2 or two
R.sup.3 may form a spiro ring;
[0125] R is independently selected from H, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug; and
[0126] P is a protecting group selected from benzyhydryl
(CHPh.sub.2), trialkylsilyl (R.sub.3Si), 2-trimethylsiloxyethyl,
alkoxynethyl (CH.sub.2OR), and ester (C(.dbd.O)R).
[0127] In one aspect, the compounds are pre-organized with
constrained conformations that include an active form for
inhibition of nuclear integration of reverse-transcribed HIV DNA.
The invention includes tricyclic compounds represented by the
following structure:
##STR00015##
[0128] A.sup.1 and A.sup.2 are each and independently any moiety
forming a five, six, or seven membered ring. A.sup.1 and A.sup.2
may be independently selected from O, S, NR, C(R.sup.2).sub.2,
CR.sup.2OR, CR.sup.2OC(.dbd.O)R, C(.dbd.O), C(S), CR.sup.2SR,
C(.dbd.NR), C(R.sup.2).sub.2--C(R.sup.3).sub.2,
--C(R.sup.2).dbd.C(R.sup.3), C(R.sup.2).sub.2--O,
NR--C(R.sup.3).sub.2, N.dbd.C(R.sup.3), N.dbd.N, SO.sub.2--NR,
C(.dbd.O)C(R.sup.3).sub.2, C(.dbd.O)NR,
C(R.sup.2).sub.2--C(R.sup.3).sub.2--C(R.sup.3).sub.2,
C(R.sup.2).dbd.C(R.sup.3)--C(R.sup.3).sub.2, C(R.sup.2)C(.dbd.O)NR,
C(R.sup.2)C(.dbd.S)NR, C(R.sup.2).dbd.N--C(R.sup.3).sub.2,
C(R.sup.2).dbd.N--NR, and N.dbd.C(R.sup.3)--NR. When taken together
on a single carbon, two R.sup.2 or two R.sup.3 may form a spiro
ring.
[0129] Q is N, .sup.-NR, or CR.sup.4.
##STR00016##
[0130] L is a bond or any linker which covalently attaches the Ar
group to the tricyclic scaffold. For example, L may be a bond, O,
S, S--S (disulfide), S(.dbd.O) (sulfoxide), S(.dbd.O).sub.2
(sulfone), S(.dbd.O).sub.2NR (sulfonamide), NR, N--OR,
C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12 substituted alkylene,
C.sub.2-C.sub.12 alkenylene, C.sub.2-C.sub.12 substituted
alkenylene, C.sub.2-C.sub.12 alkynylene, C.sub.2-C.sub.12
substituted alkynylene, C(.dbd.O)NH, OC(.dbd.O)NH, NHC(.dbd.O)NH,
C(.dbd.O), C(.dbd.O)NH(CH.sub.2).sub.n, or
(CH.sub.2CH.sub.2O).sub.n, where n may be 1, 2, 3, 4, 5, or 6.
[0131] Substituted alkylene, substituted alkyenylene, substituted
alkynylene, substituted aryl, and substituted heteroaryl are
independently substituted with one or more substituents selected
from F, Cl, Br, I, OH, amino (--NH.sub.2), ammonium
(--NH.sub.3.sup.+), alkylamino, dialkylamino, trialkylammonium,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, alkylsulfone (--SO.sub.2R), arylsulfone
(--SO.sub.2Ar), arylsulfoxide (--SOAr), arylthio (--SAr),
sulfonamide (--SO.sub.2NR.sub.2), alkylsulfoxide (--SOR), ester
(--CO.sub.2R), amido (--C(.dbd.O)NR.sub.2), 5-7 membered ring
lactam, 5-7 membered ring lactone, nitrile (--CN), azido
(--N.sub.3), nitro (--NO.sub.2), C.sub.1-C.sub.8 alkoxy (--OR),
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.2-C.sub.20 heteroaryl, and C.sub.2-C.sub.20 substituted
heteroaryl, phosphonate, phosphate, polyethyleneoxy, and a prodrug
moiety.
[0132] X may be O, S, NH, NR, N--OR, N--NR.sub.2, N--CR.sub.2OR or
N--CR.sub.2NR.sub.2.
[0133] Ar groups may be any saturated, unsaturated or aromatic ring
or ring system comprising a mono- or bicyclic carbocycle or
heterocycle, e.g. 3 to 12 ring atoms. The rings are saturated when
containing 3 ring atoms, saturated or mono-unsaturated when
containing 4 ring atoms, saturated, or mono- or di-unsaturated when
containing 5 ring atoms, and saturated, mono- or di-unsaturated, or
aromatic when containing 6 ring atoms.
[0134] For example, Ar may be C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, or
C.sub.2-C.sub.20 substituted heteroaryl.
[0135] Exemplary embodiments of C.sub.6-C.sub.20 substituted aryl
groups include halo-substituted phenyl such as 4-fluorophenyl,
4-chlorophenyl, 4-trifluoromethyl, 2-amide phenyl,
3,5-dichlorophenyl, and 3,5-difluorophenyl.
[0136] Ar groups include substituted phenyl groups such as, but not
limited to:
##STR00017##
[0137] Other examples of substituted phenyl groups include:
##STR00018##
where a wavy line in any orientation, indicates the covalent
attachment site to L.
[0138] Ar groups also include disubstituted phenyl groups such as,
but not limited to:
##STR00019##
where n is 1 to 6.
[0139] Ar groups also include carbocycles such as, but not limited
to:
##STR00020##
[0140] Ar groups also include phenyl and substituted phenyl fused
to a carbocycle to form groups including:
##STR00021##
[0141] R.sup.1, R.sup.2, R.sup.3 and R.sup.4, and substituents of
Ar, may independently be H, F, Cl, Br, I, OH, amino (--NH.sub.2),
ammonium (--NH.sub.3.sup.+), alkylamino, dialkylamino,
trialkylammonium, C.sub.1-C.sub.8 alkylhalide, carboxylate,
sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,
C.sub.1-C.sub.8 alkylsulfonate, C.sub.1-C.sub.8 alkylamino,
4-dialkylaminopyridinium, C.sub.1-C.sub.8 alkylhydroxyl,
C.sub.1-C.sub.8 alkylthiol, alkylsulfone (--SO.sub.2R), arylsulfone
(--SO.sub.2Ar), arylsulfoxide (--SOAr), arylthio (--SAr),
sulfonamide (--SO.sub.2NR.sub.2), alkylsulfoxide (--SOR), ester
(--CO.sub.2R), amido (--C(.dbd.O)NR.sub.2), 5-7 membered ring
lactam, 5-7 membered ring lactone, nitrile (--CN), azido
(--N.sub.3), nitro (--NO.sub.2), C.sub.1-C.sub.8 alkoxy (--OR),
C.sub.1-C.sub.8 trifluoroalkyl, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 substituted alkyl, C.sub.3-C.sub.12 carbocycle,
C.sub.3-C.sub.12 substituted carbocycle, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, phosphonate, phosphate,
polyethyleneoxy, and a prodrug moiety.
[0142] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 also include:
--OC(.dbd.O)OR, --OC(.dbd.O)NR.sub.2, --OC(.dbd.S)NR.sub.2,
--OC(.dbd.O)NRNR.sub.2, --OC(.dbd.O)R, --C(.dbd.O)OR,
--C(.dbd.O)NR.sub.2, --C(.dbd.O)NRNR.sub.2, --C(.dbd.O)R,
--OSO.sub.2NR.sub.2 (sulfamate), --NR.sub.2, --NRSO.sub.2R,
--NRC(.dbd.S)NR.sub.2, --SR, --S(O)R, --SO.sub.2R,
--SO.sub.2NR.sub.2 (sulfonamide), --OSO.sub.2R (sulfonate),
--P(.dbd.O)(OR).sub.2, --P(.dbd.O)(OR)(NR.sub.2),
--P(.dbd.O)(NR.sub.2).sub.2, --P(.dbd.S)(OR).sub.2,
--P(.dbd.S)(OR)(NR.sub.2), --P(.dbd.S)(NR.sub.2).sub.2, and
including prodrug substituted forms thereof.
[0143] Exemplary embodiments of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 include the structures:
##STR00022##
where the wavy line indicates the point of covalent attachment on
the tricyclic structure.
[0144] R may be independently selected from H, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl,
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, and a prodrug moiety. Two R groups may form
a ring, such as when the two R groups are bonded to a nitrogen atom
and form a ring such as aziridinyl, azetidinyl, pyrrolidinyl,
pyrazinyl, imidazolyl, piperidyl, piperazinyl, pyridinium, or
morpholino.
[0145] The following embodiments of A.sup.1 and A.sup.2 in the
compounds of the invention include but are not limited to the
following structures. Various embodiments of A.sup.1 form
5-membered rings in the exemplary structures:
##STR00023## ##STR00024##
[0146] Various embodiments of A.sup.1 form 6-membered rings in the
exemplary structures:
##STR00025## ##STR00026##
[0147] Various embodiments of A.sup.1 form 7-membered rings in the
exemplary structures
##STR00027##
[0148] Various embodiments of A.sup.2 form 5-membered rings in the
exemplary structures:
##STR00028## ##STR00029##
[0149] Other various embodiments of A.sup.2 form 6-membered rings
in the exemplary structures:
##STR00030##
[0150] Other various embodiments of A.sup.2 form 7-membered rings
in the exemplary structures:
##STR00031##
[0151] Compounds of the invention include Formulas I-IV,
represented by the following structures:
##STR00032##
[0152] Formula I compounds thus include the following succinimide
structure:
##STR00033##
[0153] Embodiments of Formula I also include Ia-c where A is
CH.sub.2, CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2,
respectively:
##STR00034##
[0154] Where A forms a seven-membered ring, the 7 membered ring may
be comprised of a second amide group, as shown by exemplary Formula
Id:
##STR00035##
[0155] One aspect of the invention includes compounds with a cyclic
imide group, e.g. 5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione
(Myers, et al U.S. Pat. No. 5,252,560; Robinson, U.S. Pat. No.
5,854,275), where A is C(.dbd.O) and X is O, as in formula Ie.
##STR00036##
[0156] Along with other compounds of the invention, the cyclic
imide group of Formula Ie provides functionality which may be in a
pre-organized state for optimized HIV integrase inhibition relative
to compounds without the cyclic imide group (Anthony, et al WO
02/30931; Zhuang, et al "Design and synthesis of
8-hydroxy-1,6-naphthyridines as novel HIV-1 integrase inhibitors"
Interscience Conference on Antimicrobial Agents and Chemotherapy,
San Diego, Calif., Sep. 27-30, 2002).
[0157] Formula Ia compounds include the following amide
structure:
##STR00037##
[0158] R.sup.1, R.sup.2, R.sup.3, or R.sup.4 may independently
comprise a phosphonate group or phosphonate prodrug moiety. A
tricyclic integrase inhibitor compound of the invention may include
one or more phosphonate group or phosphonate prodrug moiety. For
example, R.sup.1, R.sup.2, R.sup.3, or R.sup.4 may comprise the
structure A.sup.3, where A.sup.3 is:
##STR00038##
[0159] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x).sub.2.
[0160] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x).sub.2),
--S(.dbd.O)-(sulfoxide), --S(.dbd.O).sub.2-(sulfone),
--S-(sulfide), or --S--S-(disulfide).
[0161] M2 is 0, 1 or 2.
[0162] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12.
[0163] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
[0164] R.sup.y is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, aryl, substituted aryl, or a
protecting group. Alternatively, taken together at a carbon atom,
two vicinal R.sup.y groups form a ring, i.e. a spiro carbon. The
ring may be all carbon atoms, for example, cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl, or alternatively, the ring may contain
one or more heteroatoms, for example, piperazinyl, piperidinyl,
pyranyl, or tetrahydrofuryl.
[0165] R.sup.x is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, or a protecting group, or the
formula:
##STR00039##
[0166] M1a, M1c, and M1d are independently 0 or 1.
[0167] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0168] A linker may be interposed between positions R.sup.1,
R.sup.2, R.sup.3 or R.sup.4 and substituent A.sup.3. The linker may
be O, S, NR, N--OR, C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12
substituted alkylene, C.sub.2-C.sub.12 alkenylene, C.sub.2-C.sub.12
substituted alkenylene, C.sub.2-C.sub.12 alkynylene,
C.sub.2-C.sub.12 substituted alkynylene, C(.dbd.O)NH, C(.dbd.O),
S(.dbd.O).sub.2, C(.dbd.O)NH(CH.sub.2).sub.n, and
(CH.sub.2CH.sub.2O).sub.n, where n may be 1, 2, 3, 4, 5, or 6.
Linkers may also be repeating units of alkyloxy (e.g.
polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g.
polyethyleneamino, Jeffamine.TM.); and diacid ester and amides
including succinate, succinamide, diglycolate, malonate, and
caproamide. For example, the linker may comprise propargyl, urea,
or alkoxy groups in the exemplary structures:
##STR00040##
[0169] Embodiments of A.sup.3 include where M2 is 0, such as:
##STR00041##
and where M12b is 1, Y.sup.1 is oxygen, and Y.sup.2b is
independently oxygen (O) or nitrogen (N(R.sup.x)) such as:
##STR00042##
[0170] An embodiment of A.sup.3 includes:
##STR00043##
where W.sup.5 is a carbocycle such as phenyl or substituted phenyl,
and Y.sup.2c is independently O, N(R.sup.y) or S. For example,
R.sup.1 may be H and n may be 1.
[0171] W.sup.5 also includes, but is not limited to, aryl and
heteroaryl groups such as:
##STR00044##
[0172] Another embodiment of A.sup.3 includes:
##STR00045##
[0173] Such embodiments include:
##STR00046##
where Y.sup.2b is O or N(R.sup.x); M12d is 1, 2, 3, 4, 5, 6, 7 or
8; R.sup.1 is H or C.sub.1-C.sub.6 alkyl; and the phenyl carbocycle
is substituted with 0 to 3 R.sup.2 groups where R.sup.2 is
C.sub.1-C.sub.6 alkyl or substituted alkyl. Such embodiments of
A.sup.3 include phenyl phosphonamidate amino acid, e.g. alanate
esters and phenyl phosphonate-lactate esters:
##STR00047##
[0174] Embodiments of R.sup.x include esters, carbamates,
carbonates, thioesters, amides, thioamides, and urea groups:
##STR00048##
[0175] The compounds of the invention may also include one or more
prodrug moieties located as a covalently-attached substituent at
any location or site, e.g. Ar, L, X, A, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, or the 9-hydroxyl. One substituent which may be modified
as a prodrug moiety is a phosphonate, phosphate, phosphinate or
other phosphorus functionality (Oliyai et al Pharmaceutical Res.
(1999) 16:1687-1693; Krise, J. and Stella, V. Adv. Drug Del.
Reviews (1996) 19:287-310; Bischofberger et al, U.S. Pat. No.
5,798,340). Prodrug moieties of phosphorus functionality serve to
mask anionic charges and decrease polarity. The phosphonate prodrug
moiety may be an ester (Oliyai, et al Intl. Jour. Pharmaceutics
(1999) 179:257-265), e.g. POC and POM (pivaloyloxymethyl, Yuan, et
al Pharmaceutical Res. (2000) 17:1098-1 103), or amidate which
separates from the integrase inhibitor compound in vivo or by
exposure in vitro to biological conditions, e.g. cells, tissue
isolates. The separation may be mediated by general hydrolytic
conditions, oxidation, enzymatic action or a combination of
steps.
[0176] Compounds of the invention bearing one or more prodrug
moieties may increase or optimize the bioavailability of the
compounds as therapeutic agents. For example, bioavailability after
oral administration may be preferred and depend on resistance to
metabolic degradation in the gastrointestinal tract or circulatory
system, and eventual uptake inside cells. Prodrug moieties are
considered to confer said resistance by slowing certain hydrolytic
or enzymatic metabolic processes. Lipophilic prodrug moieties may
also increase active or passive transport of the compounds of the
invention across cellular membranes (Darby, G. Antiviral Chem.
& Chemotherapy (1995) Supp. 1, 6:54-63).
[0177] R.sup.X2 is independently selected from H, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heteroaryl, and
C.sub.2-C.sub.20 substituted heteroaryl, polyethyleneoxy,
phosphonate, phosphate, a prodrug, a pharmaceutically acceptable
prodrug, a prodrug moiety, a protecting group, and a phosphonate
prodrug moiety; preferably H, a prodrug or a protecting group; more
preferably, H or a prodrug; more preferably yet R.sup.X2 is H.
[0178] Exemplary embodiments of the invention includes
phosphonamidate and phosphonamidate (collectively "amidate")
prodrug compounds. General formulas for phosphonamidate and
phosphonamidate prodrug moieties include:
##STR00049##
[0179] The phosphorus atom of the phosphonamidate group is bonded
to a carbon atom. The nitrogen substituent R.sup.5 may include an
ester, an amide, or a carbamate functional group. For example,
R.sup.5 may be --CR.sub.2C(.dbd.O)OR' where R' is H,
C.sub.1-C.sub.6 alkyl, C.sub.1C.sub.6 substituted alkyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.2-C.sub.20 heteroaryl, or C.sub.2-C.sub.20 substituted
heteroaryl.
[0180] Exemplary embodiments of phosphonamidate and phosphonamidate
prodrugs include:
##STR00050##
[0181] wherein R.sup.5 is --CR.sub.2CO.sub.2R.sup.7 where R.sup.6
and R.sup.7 are independently H or C.sub.1C.sub.8 alkyl.
[0182] The nitrogen atom may comprise an amino acid residue within
the prodrug moiety, such as a glycine, alanine, or valine ester
(e.g. valacyclovir, see: Beauchamp, et al Antiviral Chem.
Chemotherapy (1992) 3:157-164), such as the general structure:
##STR00051##
where R' is the amino acid side-chain, e.g. H, CH.sub.3,
CH(CH.sub.3).sub.2, etc.
[0183] An exemplary embodiment of a phosphonamidate prodrug moiety
is:
##STR00052##
[0184] Another embodiment of the invention is directed toward an
HIV integrase inhibitor tricyclic compound of the invention which
is capable of accumulating in human PBMC (peripheral blood
mononuclear cells). PBMC refer to blood cells having round
lymphocytes and monocytes. Physiologically, PBMC are critical
components of the mechanism against infection. PBMC may be isolated
from heparinized whole blood of normal healthy donors or huffy
coats, by standard density gradient centrifugation and harvested
from the interface, washed (e.g. phosphate-buffered saline) and
stored in freezing medium. PBMC may be cultured in multi-well
plates. At various times of culture, supernatant may be either
removed for assessment, or cells may be harvested and analyzed
(Smith R. et al (2003) Blood 102(7):2532-2540). The compounds of
this embodiment may further comprise a phosphonate or phosphonate
prodrug. Typically, the phosphonate or phosphonate prodrug has the
structure A.sup.3 as described herein.
[0185] Optionally, the compounds of this embodiment demonstrate
improved intracellular half-life of the compounds or intracellular
metabolites of the compounds in human PBMC when compared to analogs
of the compounds not having the phosphonate or phosphonate prodrug.
Typically, the half-life is improved by at least about 50%, more
typically at least in the range 50-100%, still more typically at
least about 100%, more typically yet greater than about 100%.
[0186] In another embodiment, the intracellular half-life of a
metabolite of the compound in human PBMCs is improved when compared
to an analog of the compound not having the phosphonate or
phosphonate prodrug. In such embodiments, the metabolite may be
generated intracellularly, or it is generated within human PBMC.
The metabolite may be a product of the cleavage of a phosphonate
prodrug within human PBMCs. The phosphonate prodrug may be cleaved
to form a metabolite having at least one negative charge at
physiological pH. The phosphonate prodrug may be enzymatically
cleaved within human PBMC to form a phosphonate having at least one
active hydrogen atom of the form P--OH.
[0187] The compounds of the invention may have pre-organized
binding modes which optimize the binding affinity of other, known
HIV integrase inhibitors. During binding between the inhibitor and
the active site of the target HIV integrase enzyme, the inhibitor
may attain a low energy conformation (also called bound
conformation) in order to interact within an active site.
Generally, ligands of molecules with multiple rotational bonds
exist in many potential conformational states, most of which are
not able to bind to the active site. The greater the number of
possible ligand conformations typically results in a greater
decrease in efficiency of the entropy contribution to the free
energy of binding, and will result in less favorable binding
affinities. One aspect of designing pre-organized binding features
in an integrase inhibitor compound is incorporating conformational
constraints that reduces the total number of conformational states
and places the inhibitor into a correct binding conformation (Lam,
P. Y. S. et al. J. Med. Chem, (1996) 39:3514-3525; Chen, J. M. et
al. Biochemistry (1998) 37:17735-17744; Chen, J. M. et al. Jour.
Amer. Chem. Soc. (2000) 122:9648-9654; Chen, J. M. et al U.S. Pat.
No. 6,187,907; Chen, et al Bio. Org. Med. Chem. Letters (2002)
12:1195-1198). Knowledge of one or more preferred, i.e. low-energy,
binding conformations is important for rational structure design
and avoid inactive lead compounds.
[0188] Those of skill in the art will also recognize that the
compounds of the invention may exist in many different protonation
states, depending on, among other things, the pH of their
environment. While the structural formulae provided herein depict
the compounds in only one of several possible protonation states,
it will be understood that these structures are illustrative only,
and that the invention is not limited to any particular protonation
state--any and all protonated forms of the compounds are intended
to fall within the scope of the invention.
[0189] The compounds of this invention optionally comprise salts of
the compounds herein, especially pharmaceutically acceptable
non-toxic salts containing, for example, Na.sup.+, Li.sup.+,
K.sup.+, Ca.sup.+2 and Mg.sup.+2. Such salts may include those
derived by combination of appropriate cations such as alkali and
alkaline earth metal ions or ammonium and quaternary amino ions
with an acid anion moiety, typically a carboxylic acid. The
compounds of the invention may bear multiple positive or negative
charges. The net charge of the compounds of the invention may be
either positive or negative. Any associated counter ions are
typically dictated by the synthesis and/or isolation methods by
which the compounds are obtained. Typical counter ions include, but
are not limited to ammonium, sodium, potassium, lithium, halides,
acetate, trifluoroacetate, etc., and mixtures thereof. It will be
understood that the identity of any associated counter ion is not a
critical feature of the invention, and that the invention
encompasses the compounds in association with any type of counter
ion. Moreover, as the compounds can exists in a variety of
different forms, the invention is intended to encompass not only
forms of the compounds that are in association with counter ions
(e.g., dry salts), but also forms that are not in association with
counter ions (e.g., aqueous or organic solutions).
[0190] Metal salts typically are prepared by reacting the metal
hydroxide with a compound of this invention. Examples of metal
salts which are prepared in this way are salts containing Li.sup.+,
Na.sup.+, and K.sup.+. A less soluble metal salt can be
precipitated from the solution of a more soluble salt by addition
of the suitable metal compound. In addition, salts may be formed
from acid addition of certain organic and inorganic acids, e.g.,
HCl, HBr, H.sub.2SO.sub.4, H.sub.3PO.sub.4 or organic sulfonic
acids, to basic centers, typically amines, or to acidic groups.
Finally, it is to be understood that the compositions herein
comprise compounds of the invention in their unionized, as well as
zwitterionic form, and combinations with stoichiometric amounts of
water as in hydrates.
[0191] Also included within the scope of this invention are the
salts of the parental compounds with one or more amino acids,
especially the naturally-occurring amino acids found as protein
components. The amino acid typically is one bearing a side chain
with a basic or acidic group, e.g., lysine, arginine or glutamic
acid, or a neutral group such as glycine, serine, threonine,
alanine, isoleucine, or leucine.
[0192] The compounds of the invention can also exist as tautomeric,
resonance isomers in certain cases. Typically, the structures shown
herein exemplify only one tautomeric or resonance form of the
compounds. For example, hydrazine, oxime, hydrazone groups may be
shown in either the syn or anti configurations. The corresponding
alternative configuration is contemplated as well. All possible
tautomeric and resonance forms are within the scope of the
invention.
[0193] One enantiomer of a compound of the invention can be
separated substantially free of its opposing enantiomer by a method
such as formation of diastereomers using optically active resolving
agents (Stereochemisty of Carbon Compounds (1962) by E. L. Eliel,
McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3)
283-302). Separation of diastereomers formed from the racemic
mixture can be accomplished by any suitable method, including: (1)
formation of ionic, diastereomeric salts with chiral compounds and
separation by fractional crystallization or other methods, (2)
formation of diastereomeric compounds with chiral derivatizing
reagents, separation of the diastereomers, and conversion to the
pure enantiomers. Alternatively, enantiomers can be separated
directly under chiral conditions, method (3).
[0194] Under method (1), diastereomeric salts can be formed by
reaction of enantiomerically pure chiral bases such as brucine,
quinine, ephedrine, strychnine,
.alpha.-methyl-.beta.-phenethylamine(amphetamine), and the like
with asymmetric compounds bearing acidic functionality, such as
carboxylic acid and sulfonic acid. The diastereomeric salts may be
induced to separate by fractional crystallization or ionic
chromatography. For separation of the optical isomers of amino
compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid
can result in formation of the diastereomeric salts.
[0195] Alternatively, by method (2), the substrate to be resolved
may be reacted with one enantiomer of a chiral compound to form a
diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry
of Organic Compounds, John Wiley & Sons, Inc., p. 322).
Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents,
such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the free, enantiomerically
enriched xanthene. A method of determining optical purity involves
making chiral esters, such as a menthyl ester or Mosher ester,
.alpha.-methoxy-.alpha.-(trifluoromethyl)phenyl acetate (Jacob III.
(1982) J. Org. Chem. 47:4165), of the racemic mixture, and
analyzing the NMR spectrum for the presence of the two
atropisomeric diastereomers. Stable diastereomers can be separated
and isolated by normal- and reverse-phase chromatography following
methods for separation of atropisomeric naphthyl-isoquinolines
(Hoye, T., WO 96/15111).
[0196] By method (3), a racemic mixture of two asymmetric
enantiomers can be separated by chromatography using a chiral
stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough,
Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution
of dihydropyridine enantiomers by High-performance liquid
chromatography using phenylcarbamates of polysaccharides as a
chiral stationary phase", J. of Chromatogr. 513:375-378).
[0197] Enantiomers can be distinguished by methods used to
distinguish other chiral molecules with asymmetric carbon atoms,
such as optical rotation and circular dichroism.
Synthesis of HIV-Integrase Inhibitor Compounds
[0198] The compounds of the invention may be prepared by a variety
of synthetic routes and methods known to those skilled in the art.
The invention also relates to methods of making the compounds of
the invention. The compounds are prepared by any of the applicable
techniques of organic synthesis. Many such techniques are well
known in the art. However, many of the known techniques are
elaborated in: "Compendium of Organic Synthetic Methods", John
Wiley & Sons, New York, Vol. 1, Ian T. Harrison and Shuyen
Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974;
Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G.
Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6,
Michael B. Smith; as well as March, J., "Advanced Organic
Chemistry", Third Edition, John Wiley & Sons, New York, 1985;
"Comprehensive Organic Synthesis. Selectivity, Strategy &
Efficiency in Modern Organic Chemistry" (9 Volume set) Barry M.
Trost, Editor-in-Chief, Pergamon Press, New York, 1993.
[0199] A number of exemplary methods for the preparation of the
compounds, Formulas I-IV, of the invention are provided herein.
These methods are intended to illustrate the nature of such
preparations are not intended to limit the scope of applicable
methods.
[0200] Deliberate use may be made of protecting groups to mask
reactive functionality and direct reactions regioselectively
(Greene, et al (1991) "Protective Groups in Organic Synthesis", 2nd
Ed., John Wiley & Sons). For example, useful protecting groups
for the 8-hydroxyl group and other hydroxyl substituents include
methyl, MOM (methoxymethyl), trialkylsilyl, benzyl, benzoyl,
trityl, and tetrahydropyranyl. Certain aryl positions may be
blocked from substitution, such as the 2-position as fluorine.
Formula I Compounds
[0201] Exemplary methods of synthesis of Formula I compounds are
described below in Schemes 1-10 and 15-17. One method of synthesis
of Formula I compounds of the invention is cyclization of a
succinimide compound with a pyridine dicarboxylate compound to give
tricyclic compounds (Murray and Semple, Synthesis (1996) 11:80-82;
Jones and Jones, Jour. Chem. Soc., Perkin Transactions I (1973)
26-32), according to Scheme 1.
##STR00053##
[0202] Alternatively, a succinimide with a labile protecting group
(P) on the nitrogen may be reacted with a pyridine dicarboxylate
compound. P may be an acid-labile protecting group, such as
trialkylsilyl. Trialkylsilyl groups may also be removed with
fluoride reagents. After P is removed, a variety of Ar-L groups may
be covalently attached, according to Scheme 2.
##STR00054##
[0203] Imide compounds can be reduced with dissolving metal
reducing agents, e.g. Zn, or hydride reagents, e.g. NaBH.sub.4, to
form a lactam. Exemplary regioselective conversions shown in Scheme
3 include:
##STR00055##
[0204] Imide compounds may also be reduced to the hydroxylactam
under mild conditions. Reductions with sodium borohydride and
cerium or samarium salts have been shown to proceed with
regioselectivity on asymmetric imides (Mase, et al J. Chem. Soc.
Perkin Communication 1 (2002) 707-709), as in Scheme 4, upper.
Grignard reagents and acetylenic anions (Chihab-Eddine, et al
Tetrahedron Lett. (2001) 42:573-576) may also add with
regioselectivity to an imide carbonyl to form alkyl-hydroxylactam
compounds, as in Scheme 4, lower). The phenolic oxygen groups may
be protected and deprotected as necessary to furnish yield
reactions.
##STR00056##
[0205] Another synthetic route to the compounds of the invention
proceeds through substituted quinoline intermediates (Clemence, et
al U.S. Pat. No. 5,324,839; Billhardt-Troughton, et al U.S. Pat.
No. 5,602,146; Matsumura, J. Amer. Chem. Soc. (1935) 57:124-128)
having the general formula:
##STR00057##
[0206] 5,8-Dihydroxy quinoline compounds may be elaborated
according to Scheme 5:
##STR00058##
##STR00059##
[0207] The cyclic anhydride below may be regioselectively
esterified to give the compounds of the invention, for example via
the route in Scheme 6 where MOM is methoxymethyl and X is, for
example, C(.dbd.O), CRC(.dbd.O), C(.dbd.O)C(.dbd.O), and SO.sub.2.
See Ornstein, et al Jour. Med. Chem. (1989) 32:827-833. The same
chemistry can be applied to the 5-membered lactam synthesis to
control the regiochemistry as in Scheme 7:
##STR00060##
[0208] A cyclic imide may be conveniently alkylated, acylated, or
otherwise reacted to form a broad array of compounds with Ar-L
groups:
##STR00061##
[0209] The Ar-L group may be attached as one reactant group, for
example as an alkylating reagent like benzyl bromide (Ar=phenyl,
L=CH.sub.2) or a sulfonating reagent, like 4-methoxyphenyl sulfonyl
chloride (Ar=4-methoxyphenyl, L=S(.dbd.O).sub.2. Alternatively, the
Ar-L group may be attached by a multi step process. For example,
the imide nitrogen may react with a sulfurizing reagent such as
2,2-dipyridyl disulfide to form an N-sulfide intermediate
(Ar=2-pyridyl, L=S). Such an intermediate may be further elaborated
to a variety of Ar-L groups where L is S, S(.dbd.O) or
S(.dbd.O).sub.2.
[0210] Another synthetic route to the compounds of the invention
proceeds through 7-substituted, 8-quinolinol intermediates (Zhuang,
et al WO 02/36734; Vaillancourt, et al U.S. Pat. No. 6,310,211;
Hodel, U.S. Pat. No. 3,113,135) having the general formulas,
including aryl substituted compounds:
##STR00062##
[0211] Annulation of the third, 5-7 membered ring can be conducted
by appropriate selection of aryl substituents on the quinoline ring
system, utilizing known synthetic transformations to give compounds
of Formula I. For example, methods for coupling carboxylic acids
and other activated acyl groups with amines to form carboxamides
are well known in the art (March, J. Advanced Organic Chemistry,
3rd Edition, John Wiley & Sons, 1985, pp. 370-376). An
exemplary cyclization includes the following:
##STR00063##
[0212] Scheme 8 below shows another synthetic route to compounds of
the invention, i.e. Formula 1. This route proceeds by cyclization
of a 2-O-protected, 3 halo-aniline compound with an
(.alpha.,.beta.-unsaturated carbonyl compound to give a
functionalized quinoline. The .alpha.,.beta.-unsaturated carbonyl
compound may be, for example, an aldehyde (X.dbd.H), ketone
(X.dbd.R), ester (X.dbd.OR), amide (X.dbd.NR2), acyl halide
(X.dbd.Cl), or anhydride. Carbonylation via palladium catalysis can
give an ester which may be elaborated to the amide functionality
and cyclization to form a 5, 6, or 7 membered ring. The R group of
phenolic oxygen may be a labile protecting group, e.g.
trialkylsilyl or tetrahydropyranyl, which may be removed at a step
in the synthetic route, or it may be a substituent which is
retained in the putative integrase inhibitor compound.
##STR00064##
[0213] Halo quinoline intermediates may undergo a flexible array of
nucleophilic aromatic substitutions and Suzuki-type reactions, as
shown in Scheme 9 below. Suzuki coupling of aryl halide compounds
with acetylenic and vinylic palladium complexes are carbon-carbon
bond forming reactions under relatively mild conditions. In some
instances it may be necessary to block the 2 position to direct
reaction at the desired aryl position.
##STR00065##
[0214] Formula I compounds with a
5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione were prepared by
selective protection of the C9 phenol in
5,9-dihydroxy-pyrrolo[3,4-g]quinolinie-6,8-dione. The C9 phenol was
protected with a TIPS group and the C5 phenol could then be
alkylated or acylated (Scheme 10)
##STR00066##
Formula III Compounds
[0215] Formula III compounds may be prepared by the following
methods in Schemes 11-14:
##STR00067## ##STR00068##
[0216] The acid 1 (WO02/30930, p. 173) may be reacted with amine 2
(prepared according to the methods described by T. Morie, et al,
Chem. Pharm. Bull., 42, 1994, 877-882; D. Wenninger, et al,
Nucleosides Nucleotides, 16, 1997, 977-982) by the method of
peptide coupling such as described in WO02/30930, p. 173 to form
amide 3. Bromination with NBS generates compound 4. The phenol is
protected with a bulky acyl group such as pivaloyl. Displacement of
bromine at C5 of naphthyridine by Bis-boc protected hydrazine is
achieved using the method reported by J. B. Arteburn, et al, Org.
Lett., 3, 2001, 1351-1354. The silyl protecting group is removed by
TBAF (T. Green and P. Wuts, "Protective Groups in Organic
Synthesis", p. 142, Wiley Science, 1999) and mesylate 7 is formed
by reacting the alcohol formed with methanesulfonyl chloride.
Treatment of compound 7 with TFA followed by heating hydrazino
mesylate in the basic condition affords hydrazono triaza anthracene
8.
##STR00069##
[0217] Compound 8 is converted to many different derivatives, e.g.
carbazones 9 (R.sup.1.dbd.COR.sup.3) are generated by reaction with
acid chlorides or activated carboxylic acids. Carbamates 9
(R.sup.1.dbd.COOR.sup.3) are obtained upon reaction of 8 with
chloro formates ClCOOR.sup.3. Semicarbazones 9
(R.sup.1.dbd.CONR.sup.2R.sup.3) are formed using isocyanates or
N,N-dialkyl chloroformaides. Thiosemicarbazones 9
(R.sup.1.dbd.CSNR.sup.3R.sup.4) are generated with thioisocyanates.
Sulfonyl ureas 9 (R.sup.1.dbd.SO.sub.2NR.sup.3R.sup.4) are obtained
by reaction of 8 with sulfamoyl chlorides using procedures reported
by M. L. Matier, et al, J. Med. Chem., 15, 1972, 538-541. The
simple sulfonamides are produced when 8 reacts with sulfonyl
chlorides. The ester group in compounds 9 is removed upon
saponification to give compound 10.
[0218] Alternatively, many of hydrazone derivatives 9 are subjected
to alkylation followed by saponification to afford compounds
11.
##STR00070##
[0219] Compound 5 from Scheme 11 is reacted with a substituted
hydroxyamine or amine (R.sup.5=Boc; R.sup.6.dbd.OR.sup.a or alkyl)
in a manner similar to that described by L. A., Carpino et al, Org.
Lett., 3, 2001, 2793-2795 to give derivative 12. After transforming
the silyl protected hydroxyl in 12 to a leaving group such as the
mesylate in 13, cyclization is accomplished in the heating
condition and the presence of a base to afford compound 14. Final
deprotection by hydrolysis of 14 gives compound 15.
##STR00071##
[0220] When R.sup.6 in 14 is OR.sup.a, or where R.sup.a can be
removed, oxime 16 is obtained and can be functionalized with many
reagents to yield compound 17. Hydrolysis of ester group affords
18. For example, when 16 is treated with an alkyl halide
(R.sup.7--X) or an alcohol under Mitsunobu condition, an ether 18
is formed. When an isocyanate or thioisocyanate is applied, a
carbamate or thiocarbamate 18 (R.sup.7: C(.dbd.O)NHR.sup.8 or
C(.dbd.S)NHR.sup.8) is generated. An N,N-disubstituted carbamate 18
(R.sup.7: C(.dbd.O)NR.sup.2R.sup.3) is obtained when a
chloroformate ClC(.dbd.O)NR.sup.2R.sup.3 is reacted with 16.
Similarly, treating 16 with a sulfamoyl chlorides affords a
sulfamate 18 (R.sup.7: SO.sub.2NR.sup.1R.sup.2).
##STR00072##
[0221] Scheme 15 depicts one of the methods to prepare a
spiro-cyclopropane-containing lactam fused to quinoline, an
embodiment of Formula I. A differentially protected phenol 19 is
used where R.sup.8 can be a removable ether group such as
trimethylsilyethyl ether and R.sup.9 can be a bulky group such as
diphenylmethyl or t-butyl ether. The carbonyl of C6 is converted to
an olefin regioselectively by treating 19 with methylmagnesium
bromide followed by dehydration of aminal to give 20. Carbene
insertion by Simmons-Smith reaction (for examples Y. Biggs et al,
JOC, 57, 1992, 5568-5573) produces cyclopropane 21. Selective
removal of R.sup.8 by TBAF followed by fuctionalization using the
methods described in many examples leads to compound 24.
##STR00073## ##STR00074##
[0222] A dimethyl substituted lactam can be prepared by reacting 19
with a Grignard reagent followed by converting aminal 25 to acetate
26 and treating 26 with Me.sub.3Al/TMSOTf, a method reported by C.
U. Kim, et al, Tetrahedron Letters, 35, 1994, 3017-3020, to afford
27. An alternative method can be used by reducing cyclopropane 21
with PtO.sub.2/H.sub.2 as reported by C. K. Cheung et al, JOC, 54,
1989, 570-573, to give 27.
##STR00075## ##STR00076##
[0223] Another version of modified lactam can be obtained according
to Scheme 17. Treating 19 with an allyl Grignard reagent gives 30.
Activating aminal 30 by forming acetate 31 followed by treating 31
with allyl trimethylsilane mediated by a Lewis acid such as TMSOTf
affords 32. Cyclization can be achieved by using Grubb's RCM (ring
closure metathesis) method (P. Schwab et al, Angew. Chem. Intl. 34,
1995, 2039). Alternatively, the terminal olefins in 32 can be
converted to aldehydes and reductive amination leads to a
spiro-piperidine.
##STR00077##
##STR00078##
##STR00079##
##STR00080##
##STR00081##
##STR00082##
##STR00083##
[0224] Many tricyclic compounds can bear a heterocycle different
from 9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one, i.e.
Formula IV. Some examples and methods to prepare Formula IV
compounds are depicted in Schemes 18-24 above.
Preparation of the Intermediate Phosphonate Esters Iaa-IVcc.
[0225] The structures of the intermediate phosphonate esters Iaa to
IVcc are shown in Chart 1, in which the substituents R.sup.1,
R.sup.2, R.sup.3, R.sup.4, A.sup.1 and A.sup.2 are as previously
defined. The groups A.sup.1a and A.sup.2a are the same as the
groups A.sup.1 and A.sup.2, except that a substituent
link--P(O)(OR.sup.5).sub.2 is appended. The substituent R.sup.5 is
hydrogen, alkyl, alkenyl, aralkyl, or aryl. Subsequent chemical
modifications to the compounds Iaa to Vcc, as described herein,
permit the synthesis of the final compounds of this invention.
[0226] The intermediate compounds Iaa to IVcc incorporate a
phosphonate moiety (R.sup.5O).sub.2P(O) connected to the nucleus by
means of a variable linking group, designated as "link" in the
attached structures. Chart 2 illustrates examples of the linking
groups present in the structures Iaa-IVcc.
[0227] Schemes A1-A33 illustrate the syntheses of the intermediate
phosphonate compounds of this invention, Iaa-IVcc, and of the
intermediate compounds necessary for their synthesis.
[0228] The methods described for the introduction of phosphonate
substituents are, with modifications made by one skilled in the
art, transferable within the substrates I-V. For example, reaction
sequences which produce the phosphonates Iaa are, with appropriate
modifications, applicable to the preparation of the phosphonates
IIaa, IIIaa, or IVaa. Methods described below for the attachment of
phosphonate groups to reactive substituents such as OH, NH.sub.2,
CH.sub.2Br, COOH, CHO etc are applicable to each of the scaffolds
I-V.
[0229] Scheme A34 illustrates methods for the interconversion of
phosphonate diesters, monoesters and acids.
##STR00084## ##STR00085##
##STR00086## ##STR00087##
Protection of Reactive Substituents.
[0230] Depending on the reaction conditions employed, it may be
necessary to protect certain reactive substituents from unwanted
reactions by protection before the sequence described, and to
deprotect the substituents afterwards, according to the knowledge
of one skilled in the art. Protection and deprotection of
functional groups are described, for example, in Protective Groups
in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley,
Second Edition 1990. Reactive substituents which may be protected
are shown in the accompanying schemes as, for example, [OH], [SH],
etc.
Preparation of the Intermediate Phosphonate Esters 1aa.
[0231] Schemes A1-A5 illustrate methods for the preparation of the
intermediate phosphonate esters Iaa.
[0232] As shown in Scheme A1, the phenolic hydroxyl substituent
present in the tricyclic compound A1.1 is protected to afford the
derivative A1.2. The protection of hydroxyl groups is described in
Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M
Wuts, Wiley, Second Edition 1990, p. 10. For example, hydroxyl
substituents are protected as trialkylsilyloxy, methoxymethyl,
benzyl or tert-butyl ethers. Trialkylsilyl groups are introduced by
the reaction of the phenol with a chlorotrialkylsilane and a base
such as imidazole, for example as described in Protective Groups in
Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second
Edition 1990, p. 10ff. The protected product A1.2 is then reacted,
in the presence of a strong base, with a bromoalkyl phosphonate
A1.3, to give the alkylation product A1.4. The reaction is effected
in a polar organic solvent such as dimethylformamide,
dimethylacetamide, diglyme, tetrahydrofuran and the like, in the
presence of a base such as sodium hydride, an alkali metal
alkoxide, lithium hexamethyldisilazide, and the like, at from
ambient temperature to about 100.degree. C., to yield the alkylated
product A1.4. The phenolic hydroxyl group is then deprotected to
afford the phenol A1.5. Methods for the deprotection of hydroxyl
groups are described in Protective Groups in Organic Synthesis, by
T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p.
10ff.
[0233] For example,
7-(4-fluoro-benzyl)-9-hydroxy-5H-1,7-diaza-anthracene-6,8-dione
A1.6 is reacted with one molar equivalent of
chlorotriisopropylsilane and imidazole in dimethylformamide at
ambient temperature, as described in Tet. Lett., 2865, 1974, to
produce
7-(4-fluoro-benzyl)-9-triisopropylsilanyloxy-5H-1,7-diaza-anthracene-6,8--
dione A1.7. The product is then reacted in dimethylformamide
solution at about 60.degree. C. with one molar equivalent of a
dialkyl 2-bromoethyl phosphonate A1.8 (Aldrich) and lithium
hexamethyldisilazide, to yield the alkylated product A1.9. The
silyl protecting group is then removed by reaction with
tetrabutylammonium fluoride in tetrahydrofuran, as described in J.
Org. Chem., 51, 4941, 1986, to give the phenolic product A1.10.
[0234] Using the above procedures, but employing, in place of the
4-fluorobenzyl-substituted phenol A1.6, different phenols A1.1
and/or different phosphonates A1.3, the corresponding products A1.5
are obtained.
[0235] Scheme A2 illustrates the preparation of phosphonate esters
of structure Iaa in which the phosphonate group is attached by
means of an aryl of heteroaryl ring.
[0236] In this procedure, a hydroxy-substituted phthalimide
derivative A2. 1 (Formula I) is protected, as described above, to
afford the product A2.2. This compound is then reacted with a
bromoaryl magnesium bromide Grignard reagent A2.3, in which the
group Ar.sup.1 is an aromatic or heteroaromatic group such as, for
example, benzene or thiophene, to afford the carbinol A2.4. The
regioselective addition of organometallic derivatives to
phthalimides is described in Scheme 4. The reaction is performed
between approximately equimolar amounts of the reactants in an
ethereal solvent such as diethyl ether, tetrahydrofuran and the
like, at from -40.degree. C. to ambient temperature, to give the
carbinol product A2.4. This material is then reacted with a dialkyl
phosphite A2.5 and a palladium catalyst, to give the phosphonate
A2.6. The preparation of arylphosphonates by means of a coupling
reaction between aryl bromides and dialkyl phosphites is described
in J. Med. Chem., 35, 1371, 1992. The reaction is conducted in a
hydrocarbon solvent such as benzene, toluene or xylene, at about
100.degree. C., in the presence of a palladium (0) catalyst such as
tetrakis(triphenylphosphine)palladium(0), and a tertiary base such
as triethylamine or diisopropylethylamine. The hydroxyl group is
then deprotected to yield the phenolic product A2.7. Optionally,
the benzylic hydroxyl substituent in the product A2.7 is removed by
means of a reductive procedure, as shown on Scheme 4. Benzylic
hydroxyl groups are removed by catalytic hydrogenation, for example
by the use of 10% palladium on carbon in the presence of hydrogen
or a hydrogen donor, or by means of chemical reduction, for example
employing triethylsilane and boron trifluoride etherate.
[0237] For example,
7-(3,5-dichloro-benzyl)-5,9-bis-triisopropylsilanyloxy-pyrrolo[3,4-g]quin-
oline-6,8-dione A2.9, prepared by silylation of the corresponding
diol, which is reacted with one molar equivalent of 4-bromophenyl
magnesium bromide A2.10 in ether at 0.degree. C. to produce the
carbinol A2.11. The latter compound is then reacted, in toluene
solution at reflux, with a dialkyl phosphite A2.5, triethylamine
and tetrakis(triphenylphosphine)palladium(0), as described in J.
Med. Chem., 35, 1371, 1992, to afford the phosphonate product
A2.12. Desilylation, for example by reaction with tetrabutyl
ammonium fluoride, gives the diol product A2.13. Optionally, the
product A2.12 is reduced, for example by reaction in
dichloromethane solution at ambient temperature with ca. four molar
equivalents of triethylsilane and boron trifluoride etherate, as
described in Example 18 to yield after deprotection the reduced
product A2.14.
[0238] Using the above procedures, but employing, in place of the
3,5-dichlorobenzyl-substituted phenol derivative A2.9, different
phenol derivatives A2.1 and/or different bromoaryl Grignard
reagents A2.3, the corresponding products A2.7 and A2.8 are
obtained.
[0239] Scheme A3 illustrates the preparation of phosphonate esters
of structure Iaa in which the phosphonate group is attached by
means of an alkylene chain.
[0240] In this sequence, a 6-aminoquinoline ester A3.1, prepared,
for example, from the corresponding carboxylic acid by means of a
Curtius rearrangement, (Advanced Organic Chemistry, Part B, by F.
A. Carey and R. J. Sundberg, Plenum, 2001, p.646) is reacted, under
reductive amination conditions, with a dialkyl formylalkyl
phosphonate A3.2. The preparation of amines by means of reductive
amination procedures is described, for example, in Comprehensive
Organic Transformations, by R. C. Larock, VCH, p 421, and in
Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.
Sundberg, Plenum, 2001, p 269. In this procedure, the amine
component and the aldehyde or ketone component are reacted together
in the presence of a reducing agent such as, for example, borane,
sodium cyanoborohydride, sodium triacetoxyborohydride or
diisobutylaluminum hydride, optionally in the presence of a Lewis
acid, such as titanium tetraisopropoxide, as described in J. Org.
Chem., 55, 2552, 1990. The product A3.3 is then converted, by
reaction with the amine ArBNH.sub.2 A3.4, or a derivative thereof,
into the amide A3.5. The conversion of esters into amides is
described in Comprehensive Organic Transformations, by R. C.
Larock, VCH, 1989, p. 987. The reactants are combined in the
presence of a base such as sodium methoxide under azeotropic
conditions, or of a dialkyl aluminum or trialkyl tin derivative of
the amine. The use of trimethylaluminum in the conversion of esters
to amides is described in J. Med. Chem. Chim. Ther., 34, 1999,
1995, and Syn. Comm., 25, 1401, 1995. The reaction is conducted in
an inert solvent such as dichloromethane or toluene. The amide
product A3.5 is then cyclized by reaction with a reagent such as
phosgene or a functional equivalent thereof, such as triphosgene or
a dialkyl carbonate, or a reagent such as diiodomethane, to give
the cyclized product A3.6 in which D is CO or CH.sub.2. The
reaction is conducted in an aprotic solvent such as
tetrahydrofuran, in the presence of an inorganic or organic base
such as potassium carbonate or diisopropylethylamine.
[0241] For example, the amine A3.7, prepared by means of a Curtius
rearrangement of the corresponding MOM-protected carboxylic acid,
is reacted in isopropanol solution with a dialkyl formylmethyl
phosphonate A3.8, prepared as described in Zh. Obschei. Khim.,
1987, 57, 2793, sodium cyanoborohydride and acetic acid, to give
the reductive amination product A3.9. The product is then reacted
with an excess of 3,4-dichlorobenzylamine and sodium methoxide in
toluene at reflux, to yield the amide A3.10. The latter compound is
then reacted with one molar equivalent of triphosgene and
N,N-dimethylaminopyridine in dichloromethane, to afford the
cyclized product A3.11. The MOM protecting groups are then removed,
for example by reaction with a catalytic amount of methanolic
hydrogen chloride, as described in J. Chem. Soc., Chem. Comm., 298,
1974, to give the dihydroxy product A3.12.
[0242] Using the above procedures, but employing, in place of the
amine A3.7, different amines A3.1, and/or different aldehydes A3.2,
and/or different amines A3.4, the corresponding products A3.6 are
obtained.
[0243] Scheme A4 illustrates the preparation of phosphonate esters
of structure Iaa in which the phosphonate group is attached by
means of an alkylene chain or an aryl, heteroaryl or aralkyl group
and a heteroatom O, S or N. In this sequence, a tricyclic aminal
A4.1 is reacted in the presence of an acid catalyst with a hydroxy,
mercapto or amino-substituted dialkyl phosphonate A4.2 in which X
is O, S, NH or N-alkyl, and R is alkyl, alkenyl, aryl, heteroaryl
or aralkyl. The reaction is effected at ambient temperature in an
inert solvent such as dichloromethane, in the presence of an acid
such as p-toluenesulfonic acid or trifluoroacetic acid and an
excess of the reagent A4.2. The hydroxyl group is then deprotected
to yield the phenolic product A4.4.
[0244] For example,
7-(4-fluoro-benzyl)-6-hydroxy-5-methoxy-9-triisopropylsilanyloxy-6,7-dihy-
dro-pyrrolo[3,4-g]quinolin-8-one A4.5 (Example 20, Scheme 15) is
reacted at ambient temperature in dichloromethane solution with a
dialkyl 2-mercaptoethyl phosphonate A4.6 (Zh. Obschei. Khim., 1973,
43, 2364) and trifluoroacetic acid to give the thioether product
A4.7, which upon deprotection with tetrabutylammonium fluoride
yields the phenol A4.8.
[0245] As a further example,
6-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-9-triisopropylsilanyloxy-
-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A4.9, prepared
analogously to the 4-fluoro analog A4.5, is reacted, under the same
conditions, with a dialkyl 3-mercaptophenyl phosphonate A4.10 to
give the thioether A4.11 which upon deprotection affords the phenol
A4.12. The phosphonate reagent A4.10 is obtained by palladium (0)
catalyzed coupling reaction, as described in Scheme A2, between a
dialkyl phosphite and an S-protected derivative of
3-bromothiophenol, for example the S-trityl derivative, followed by
removal of the sulfur protecting group. Protection and deprotection
of thiols is described in Protective Groups in Organic Synthesis,
by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p.
277.
[0246] Using the above procedures, but employing, in place of the
carbinols A4.5 and A4.9, different carbinols A4.1, and/or different
alcohols, thiols or amines A4.2, the corresponding products A4.4
are obtained.
[0247] Scheme A5 illustrates the preparation of phosphonate esters
of structure Iaa in which the phosphonate group is attached to a
7-membered ring by means of an alkylene or arylmethylene chain. In
this sequence, a suitable protected quinoline acid ester A5.1 is
subjected to a Curtius rearrangement, as described in Scheme A3 to
yield the amine A5.2. The product is then reductively aminated, as
described in Scheme A3, with a phosphonate aldehyde A5.3, in which
the group R is an alkyl group or an aryl group, to give the amine
product A5.4. This material is then coupled with the glycine
derivative A5.5 to yield the amide A5.6. The preparation of amides
from carboxylic acids and derivatives is described, for example, in
Organic Functional Group Preparations, by S. R. Sandler and W.
Karo, Academic Press, 1968, p. 274, and Comprehensive Organic
Transformations, by R. C. Larock, VCH, 1989, p. 972ff. The
carboxylic acid is reacted with the amine in the presence of an
activating agent, such as, for example, dicyclohexylcarbodiimide or
diisopropylcarbodiimide, optionally in the presence of, for
example, hydroxybenztriazole, N-hydroxysuccinimide or
N-hydroxypyridone, in a non-protic solvent such as, for example,
pyridine, DMF or dichloromethane, to afford the amide.
Alternatively, the carboxylic acid may first be converted into an
activated derivative such as the acid chloride, anhydride, mixed
anhydride, imidazolide and the like, and then reacted with the
amine, in the presence of an organic base such as, for example,
pyridine, to afford the amide. The conversion of a carboxylic acid
into the corresponding acid chloride can be effected by treatment
of the carboxylic acid with a reagent such as, for example, thionyl
chloride or oxalyl chloride in an inert organic solvent such as
dichloromethane, optionally in the presence of a catalytic amount
of dimethylformamide. The product A5.6 is then cyclized, for
example by heating at reflux temperature in toluene in the presence
of a basic catalyst such as sodium methoxide, or by reaction with
trimethylaluminum, as described in Syn. Comm., 25, 1401, 1995, to
afford after deprotection of the hydroxyl groups, the diazepindione
derivative A5.7.
[0248] For example, the MOM-protected amine A3.7 is reductively
aminated by reaction with a dialkyl phosphonoacet aldehyde A5.8
(Aurora) and sodium triacetoxyborohydride, to produce the amine
A5.9. The product is then coupled in dimethylformamide solution, in
the presence of dicyclohexyl carbodiimide, with
(4-fluoro-benzylamino)-acetic acid A5.10, to give the amide A5.11.
This material is converted, by reaction with trimethylaluminum in
dichloromethane, as described above, into the diazepin derivative
A5.12. Removal of the MOM protecting groups, as previously
described, then affords the phenolic product A5.13.
[0249] Using the above procedures, but employing, in place of the
amine A3.7, different amines A5.2, and/or different aldehydes A5.3,
and/or different carboxylic acids A5.5, the corresponding products
A5.7 are obtained.
##STR00088## ##STR00089##
##STR00090## ##STR00091##
##STR00092## ##STR00093##
##STR00094## ##STR00095##
##STR00096## ##STR00097##
Preparation of the Intermediate Phosphonate Esters Ibb.
[0250] Schemes A6-A16 illustrate methods for the preparation of the
phosphonate esters of general structure Ibb.
[0251] Scheme A6 depicts two methods for the preparation of
phosphonate esters in which the phosphonate group is linked by
means of a saturated or unsaturated alkylene chain, or alkylene
chains incorporating carbocyclic, aryl or heteroaryl rings. In this
procedure, a mono-protected phenol A6.1, for example, is reacted
either with a bromo-substituted alkyl phosphonate A6.2, in which
the group R is alkylene, cycloalkyl, alkenyl, aralkyl,
heterarylalkyl and the like, or with an analogous
hydroxyl-substituted dialkyl phosphonate A6.3. The reaction between
the phenol and the bromo compound A6.2 is conducted in a polar
organic solvent such as dimethylformamide, in the presence of a
base such as potassium carbonate, and optionally in the presence of
a catalytic amount of potassium iodide, to afford the ether product
A6.4. Alternatively, the ether compounds A6.4 are obtained by means
of a Mitsunobu reaction between the phenol A6.1 and the hydroxy
compound A6.3. The preparation of aromatic ethers by means of the
Mitsunobu reaction is described, for example, in Comprehensive
Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in
Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.
Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335,
The phenol and the alcohol component are reacted together in an
aprotic solvent such as, for example, tetrahydrofuran, in the
presence of a dialkyl azodicarboxylate and a triarylphosphine, to
afford the ether or thioether products. The procedure is also
described in Org. React., 1992, 42, 335-656. Deprotection of the
phenolic hydroxyl group then affords the phenol A6.5.
[0252] For example,
7-(4-fluoro-benzyl)-5-hydroxy-9-triethylsilanyloxy-pyrrolo[3,4-g]quinolin-
e-6,8-dione A6.6, (Example 12, Scheme 11) is reacted at ambient
temperature in dimethoxyethane solution with one molar equivalent
of a dialkyl 4-bromo-2-butenylphosphonate A6.7 (J. Med. Chem.,
1992, 35, 1371) and potassium carbonate, to yield the ether product
A6.8, which upon deprotection with tetrabutylammonium fluoride
gives the phenol A6.9.
[0253] As a further example,
7-[2-(4-fluoro-phenyl)-ethyl]-5-hydroxy-9-triethylsilanyloxy-pyrrolo[3,4--
g]quinoline-6,8-dione A6.10 prepared by analogous procedures to
those shown is reacted in tetrahydrofuran solution with a dialkyl
3-hydroxypropyl phosphonate A6.11 (Acros), diethyl azodicarboxylate
and triphenylphosphine, to afford the ether product A6.12 which
upon deprotection gives the phenol A6.13.
[0254] Using the above procedures, but employing, in place of the
phenols A6.6 and A6.10, the phenols A6.1, and/or different bromides
A6.2, or alcohols A6.3, the corresponding products A6.5 are
obtained.
[0255] Scheme A7 illustrates the preparation of phosphonate esters
of structure Ibb in which the phosphonate is linked by means of an
aryl or a heteroaryl group.
[0256] In this procedure, a mono-protected phenol A7.1 (Formula I)
is converted into the triflate A7.2 by reaction, in an inert
solvent such as dichloromethane, with trifluoromethanesulfonyl
chloride or anhydride, or with trimethylsilyl triflate and
triethylsilane, in each case in the presence of a tertiary base
such as triethylamine. The triflate is then coupled with a
bromo-substituted arylboronate A7.3, in which the group Ar.sup.1 is
an aromatic or heteroaromatic moiety, to afford the coupled product
A7.4. The Suzuki coupling of aryl triflates and aryl boronic acids
is described in Palladium Reagents and Catalysts by J. Tsuji, Wiley
1995, p 218. The reactants are combined in an inert solvent such as
toluene or dioxan, in the presence of a palladium (0) catalyst such
as tetrakis(triphenylphosphine)palladium and a base such as sodium
bicarbonate. The coupled product A7.4 is then reacted, as described
previously (Scheme A2) with a dialkyl phosphate A7.5, to give the
phosphonate ester A7.6, which upon deprotection yields the phenol
A7.7.
[0257] For example, trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester A7.8 (Example 46) is reacted in dioxan solution
at 70.degree. C. with one molar equivalent of 3-bromophenyl boronic
acid A7.9 (Maybridge), sodium bicarbonate and a catalytic amount of
tri-(o-tolyl)phosphine, to produce the coupled compound A7.10. This
material is then reacted, as described in Scheme A2, with a dialkyl
phosphite and a palladium (0) catalyst, to give the phosphonate
product A7.10. Removal of the benzhydryl protecting group, for
example by treatment with trifluoroacetic acid and anisole in
dichloromethane, as described in Tet. Lett., 25, 3909, 1984, then
affords the phenol A7.11.
[0258] Using the above procedures, but employing, in place of the
phenol A7.8, the phenol A7.1, and/or different boronic acids A7.3,
the corresponding products A7.7 are obtained.
[0259] Scheme A8 illustrates the preparation of phosphonate esters
of structure Ibb in which the phosphonate group is linked by means
of a oxygen, sulfur or nitrogen and an aliphatic or aromatic
moiety.
[0260] In this method, a monoprotected phenol A8.1 (Formula I) is
converted into the corresponding triflate A8.2, as described above
(Scheme A7). The product is then subjected to a nucleophilic
displacement reaction with various carbinols, thiols or amines
A8.3, in which the group R is an acyclic or cyclic saturated or
unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to
afford after deprotection the ether, thioether or amine products
A8.4. The displacement reaction is performed in an inert solvent
such as dichloroethane or dioxan, at from ambient temperature to
about 80.degree. C., in the presence of a tertiary organic base
such as N-methyl morpholine and the like.
[0261] For example, trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4--
g]quinolin-5-yl ester A8.5 (Example 56) is reacted in dioxan at
50.degree. C. with one molar equivalent of a dialkyl
methylaminomethyl phosphonate A8.6 and diisopropylethylamine, to
give the amine product A8.7. Deprotection then affords the phenol
A8.8.
[0262] Using the above procedures, but employing, in place of the
triflate A8.5, different triflates A8.2, and/or different
carbinols, thiols or amines A8.3, the corresponding products A8.4
are obtained.
[0263] Scheme A9 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of a methylamino group and a carbon link R, in which the group R is
an acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety. The compounds are obtained by means
of a reductive alkylation reaction, as described above (Scheme A3)
between the aldehyde A9.1, prepared by the method shown in Example
49, and a dialkyl aminoalkyl or aryl phosphonate A9.2. The
amination product A9.3 is then deprotected to give the phenol
A9.3.
[0264] For example,
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inoline-5-carbaldehyde A9.5 (Example 49) is reacted with a dialkyl
aminopropyl phosphonate A9.6 (Acros), sodium cyanoborohydride and
acetic acid in isopropanol to yield the amination product A9.7,
which is deprotected to produce the phenol A9.8.
[0265] Using the above procedures, but employing, in place of the
aldehyde A9.5, different aldehydes A9.1, and/or different amines
A9.2, the corresponding products A9.4 are obtained.
[0266] Scheme A10 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of an amide linkage and a carbon link R, in which the group R is an
acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety. In this sequence, the aldehyde A10.1,
prepared, for example, as shown in Example 49 is oxidized to the
corresponding carboxylic acid A10.2. The conversion of an aldehyde
to the corresponding carboxylic acid is described in Comprehensive
Organic Transformations, by R. C. Larock, VCH, 1989, p. 838. The
reaction is effected by the use of various oxidizing agents such
as, for example, potassium permanganate, ruthenium tetroxide,
silver oxide or sodium chlorite. The carboxylic acid is then
coupled, as described in Scheme A5, with an amine A10.3 to afford
the amide, which upon deprotection gives the phenolic amide
A10.4.
[0267] For example,
9-benzhydryloxy-7-(4-chloro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4--
g]quinoline-5-carbaldehyde A10.5, prepared using the methods
described in Example 49, is treated with silver oxide in
acetonitrile, as described in Tet. Lett., 5685, 1968, to produce
the corresponding carboxylic acid
9-benzhydryloxy-7-(4-chloro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4--
g]quinoline-5-carboxylic acid A10.6. This material is then coupled,
in dimethylformamide solution, with one molar equivalent of a
dialkyl aminoethyl phosphonate A10.7 (Aurora) and dicyclohexyl
carbodiimide, to afford the amide, which upon deprotection gives
the phenolic product A10.8.
[0268] Using the above procedures, but employing, in place of the
aldehyde A10.5, different aldehydes A10.1, and/or different amines
A10.3, the corresponding products A10.4 are obtained.
[0269] Scheme A11 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of a methylene group. In this procedure, a
hydroxymethyl-substituted O-protected phenol A11.1, prepared by the
method shown in Example 50, is converted into the corresponding
bromomethyl derivative A11.2. The conversion of alcohols into the
corresponding bromides is described, for example, in Comprehensive
Organic Transformations, by R. C. Larock, VCH, 1989, p. 356ff. For
example, benzyl alcohols can be transformed into the bromo
compounds by reaction with bromine and triphenyl phosphite, or by
reaction with trimethylsilyl chloride and lithium bromide, or with
carbon tetrabromide and triphenylphosphine, as described in J. Am.
Chem. Soc., 92, 2139, 1970. The resultant bromomethyl compound
A11.2 is treated with a trialkyl phosphite A11.3 in an Arbuzov
reaction. The preparation of phosphonates by means of the Arbuzov
reaction is described in Handb. Organophosphorus Chem., 1992,
115-72. The bromo compound is heated with an excess of the
phosphite at from about 80.degree. C.-130.degree. C. to produce the
phosphonate product, which upon deprotection affords the phenolic
phosphonate A11.4.
[0270] For example,
9-benzhydryloxy-5-hydroxymethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[-
3,4-g]quinolin-8-one A11.5 prepared by the method shown in Example
50, is reacted in dichloromethane with one molar equivalent of
carbon tetrabromide and triphenylphosphine to produce
9-benzhydryloxy-5-bromomethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,-
4-g]quinolin-8-one A11.6. The product is then heated at 120.degree.
C. with an excess of a trialkyl phosphite A11.3. The resulting
phosphonate is then deprotected to afford the phenolic product
A11.7.
[0271] Using the above procedures, but employing, in place of the
carbinol A11.5, different carbinols A11.1, and/or different
phosphites A11.3, the corresponding products A11.4 are
obtained.
[0272] Scheme A12 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of a methyleneoxy and a variable alkyl moiety. In this procedure, a
protected hydroxymethyl-substituted tricyclic phenol A12.1 prepared
according to the procedure of Example 50, is alkylated with a
dialkyl bromo-substituted phosphonate A12.2, in which the group R
is an acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety. The carbinol is reacted with one
molar equivalent of the bromo compound in a polar aprotic organic
solvent such as dimethylacetamide, dioxan and the like, in the
presence of a strong base such as sodium hydride, lithium
hexamethyldisilazide, or potassium tert. butoxide. The
thus-obtained ether A12.3 is then deprotected to give the phenol
A12.4.
[0273] For example,
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-hydroxymethyl-6,7-dihydro-pyrrolo[3-
,4-g]quinolin-8-one A12.5 (Example 50) is treated in
dimethylformamide solution at ambient temperature with one molar
equivalent of lithium hexamethyldisilazide, followed by one molar
equivalent of a dialkyl 4-(bromomethyl)benzyl phosphonate A12.6
(Tet., 1998, 54, 9341) to yield the alkylated product A12.7.
Deprotection then gives the phenol A12.8.
[0274] Using the above procedures, but employing, in place of the
carbinol A12.5, different carbinols A12.1, and/or different bromo
compounds A12.2, the corresponding products A12.4 are obtained.
[0275] Scheme A13 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of an aryl or heteroaryl ethenyl or ethyl linkage. In this
procedure, a vinyl-substituted OH-protected phenol A13.1, prepared
by the method shown in Example 59, is coupled in a
palladium-catalyzed Heck reaction with a dibromo-substituted
aromatic or heteroaromatic reagent A13.2, in which the group
Ar.sup.1 is an aromatic or heteroaromatic ring. The coupling of
aryl halides with olefins by means of the Heck reaction is
described, for example, in Advanced Organic Chemistry, by F. A.
Carey and R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem.
Res., 12, 146, 1979. The aryl bromide and the olefin are coupled in
a polar solvent such as dimethylformamide or dioxan, in the
presence of a palladium(0) catalyst such as
tetrakis(triphenylphosphine)palladium(0) or a palladium(II)
catalyst such as palladium(II) acetate, and optionally in the
presence of a base such as triethylamine or potassium carbonate.
The coupled product A13.3 is then reacted, as described in Scheme
A7, with a dialkyl phosphite A13.4 and a palladium catalyst, to
afford, after deprotection of the phenolic hydroxyl, the ethenyl
phosphonate ester A13.5. Catalytic or chemical reduction of the
product then yields the saturated analog A13.6. The reduction
reaction is effected chemically, for example by the use of diimide
or diborane, as described in Comprehensive Organic Transformations,
by R. C. Larock, VCH, 1989, p. 5, or catalytically, for example by
the use of a palladium on carbon catalyst in the presence of
hydrogen or a hydrogen donor.
[0276] For example,
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-vinyl-6,7-dihydro-pyrrolo[3,4-g]qui-
nolin-8-one A13.7 (Example 59) is reacted in dimethylformamide with
2,5-dibromothiophene A13.8 and a catalytic amount of palladium (II)
acetate and triethylamine, to give the coupled product A13.9. This
material is then coupled with a dialkyl phosphite, as described
above, to afford after deprotection of the phenol, the
ethenylthienyl phosphonate A13.10. The latter compound is reacted
with diimide, prepared by basic hydrolysis of diethyl
azodicarboxylate, as described in Angew. Chem. Int. Ed., 4, 271,
1965, to yield the saturated product A13.11.
[0277] Using the above procedures, but employing, in place of the
vinyl-substituted compound A13.7, different analogs A13.1, and/or
different dibromo compounds A13.2, the corresponding products A13.5
are obtained.
[0278] Scheme A14 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of an alkoxy chain incorporating an amide linkage. In this
procedure, a mono-protected phenol A14.1 (Example 6) is alkylated
with a methyl bromoalkyl carboxylate A14.2. The alkylation reaction
is conducted under similar conditions to those described in Scheme
A6, to afford the ester ether A14.3. Hydrolysis of the ester group
then gives the carboxylic acid A14.4. Hydrolysis methods for
converting esters into carboxylic acids are described, for example,
in Comprehensive Organic Transformations, by R. C. Larock, VCH,
1989, p 981. The methods include the use of enzymes such as pig
liver esterase, and chemical methods such as the use of alkali
metal hydroxides in aqueous organic solvent mixtures, for example
lithium hydroxide in an aqueous organic solvent.
[0279] The resultant carboxylic acid is then coupled, as described
in Scheme A10, with a dialkyl amino-substituted phosphonate A14.5,
in which the group R is an acyclic or cyclic saturated or
unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to
produce the amide A14.6. Deprotection then yields the phenol
A14.7.
[0280] For example,
5-hydroxy-9-methoxymethoxy-7-(4-methyl-benzyl)-pyrrolo[3,4-g]quinoline-6,-
8-dione A14.8, prepared, for example, by the method shown in
Example 6 is reacted in dimethylformamide solution with methyl
bromoacetate A14.9 and cesium carbonate, to give the ether A14.10.
The ester group is then hydrolyzed by reaction with one molar
equivalent of lithium hydroxide in aqueous glyme, to produce the
carboxylic acid A14.11. The carboxylic acid is then coupled in
dimethylformamide solution in the presence of diisopropyl
carbodiimide with a dialkyl 2-aminoethyl phosphonate A14.12, (J.
Org. Chem., 2000, 65, 676) to form the amide A14.13. Deprotection,
for example by the use of 50% aqueous acetic acid containing a
catalytic amount of sulfuric acid, as described in J. Am. Chem.
Soc., 55, 3040, 1933, then affords the phenol A14.14.
[0281] Using the above procedures, but employing, in place of the
phenol A14.8, different phenols A14.1, and/or different bromoesters
A14.2, and/or different amines A14.5, the corresponding products
A14.7 are obtained.
[0282] Scheme A15 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of an alkylene chain incorporating an amide linkage. In this
procedure, the malonic ester derivative of a protected phenol
A15.1, prepared, for example, by the methods shown in Example 86,
is hydrolyzed and decarboxylated to give the corresponding acetic
acid derivative A15.2. Hydrolysis and decarboxylation of malonic
esters is described, for example, in Advanced Organic Chemistry,
Part B, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 15. The
ester hydrolysis is effected under conventional basic conditions,
and decarboxylation occurs after acidification either spontaneously
or under mild heating. The resultant acetic acid derivative is then
coupled, as described previously, with a dialkyl amino-substituted
phosphonate A15.3, to give the amide product which upon
deprotection affords the phenol A15.4.
[0283] For example,
2-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g-
]quinolin-5-yl]-malonic acid dimethyl ester A15.5 (Example 86) is
reacted at ambient temperature with two molar equivalents of
lithium hydroxide in aqueous dimethoxyethane, and the reaction
mixture is then acidified to pH 4.0 and heated at reflux to effect
decarboxylation and production of the acetic acid derivative A15.6.
The carboxylic acid is then coupled in acetonitrile solution in the
presence of a water-soluble carbodiimide with a dialkyl
4-aminophenyl phosphonate A15.7 (Epsilon) to yield after
deprotection the phenolic amide A15.8.
[0284] Using the above procedures, but employing, in place of the
malonic ester A15.5, different malonic esters A15.1, and/or
different amines A15.3, the corresponding products A15.4 are
obtained.
[0285] Scheme A16 depicts the preparation of phosphonate esters of
structure Ibb in which the phosphonate group is attached by means
of an alkoxy chain and the nucleus incorporates a benzazepin
moiety. In this procedure, a quinoline monoester A16.1 is
decarboxylated to afford the ester A16.2. Decarboxylation of
carboxylic acids is described in Advanced Organic Chemistry, Part
B, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 676 and in
Advanced Organic Chemistry, By J. Marsh, McGraw Hill, 1968, p. 435.
The carboxylic acid is decarboxylated thermally in the presence of
copper powder and quinoline, or by conversion to an ester with
N-hydroxyphthalimide or N-hydroxythiopyridine, followed by
photolysis in the presence of a hydrogen donor. The decarboxylated
product A16.2 is then converted into the allyl ether A16.3 by
reaction with allyl bromide in a polar solvent such as
dimethylformamide in the presence of a base such h as triethylamine
or potassium carbonate. The allyl ester is then subjected to a
thermal Claisen rearrangement to afford the allyl-substituted
phenol A16.4. The Claisen rearrangement of allyl aryl ethers is
described in Advanced Organic Chemistry, By J. Marsh, McGraw Hill,
1968, p. 830 and in Advanced Organic Chemistry, Part B, by F. A.
Carey and R. J. Sundberg, Plenum, 2001, p. 394. The reaction is
conducted in a high-boiling solvent or without solvent at ca.
200.degree. C. The free phenolic hydroxyl group is then protected
to yield the doubly protected product A16.5. The latter compound is
then subjected to a hydroboration procedure to afford the carbinol
A16.6. Hydroboration of alkenes is described, for example, in
Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.
Sundberg, Plenum, 2001, p. 226. The olefin is reacted with diborane
or a substituted borane such as 9-BBN or catechyl borane, and the
resulting borane is oxidized, for example with hydrogen peroxide,
oxygen, sodium peroxycarbonate or a tertiary amine oxide. The
resultant carbinol A16.6 is then converted into the substituted
amine A16.7. The conversion is effected in two stages. In the first
step, the carbinol is converted into a leaving group such as
mesylate, tosylate or bromide by reaction with, for example,
methanesulfonyl chloride, p-toluenesulfonyl chloride or
triphenylphosphine/carbon tetrabromide. In the second step, the
activated intermediate is reacted in a polar solvent such as
N-methylpyrrolidinone or acetonitrile with the amine ArBNH.sub.2 to
give the product A16.7. The aminoester is then cyclized to yield
the azepin derivative A16.8. The cyclization reaction is performed
under similar conditions to those described above (Scheme A5). For
example, the aminoester is heated in xylene at reflux temperature
in the presence of a catalytic amount of sodium isopropoxide. The
doubly protected azepin derivative A16.8 is then selectively
deprotected to give the phenol A16.9. The procedure for the
selective deprotection is dependent on the nature of the protecting
groups. For example, if the phenol A16.1 is protected as the
benzhydryl derivative, the phenol A16.4 is protected as, for
example, the TIPS derivative. Deprotection of the azepin A16.8 is
then effected by treatment with tetrabutylammonium fluoride in
tetrahydrofuran. The phenol A16.9 is then reacted with a dialkyl
hydroxy-substituted phosphonate A16.10, in which the group R is an
alkylene or alkenyl chain, optionally incorporating an aryl or
heteroaryl group. The reaction is performed under the conditions of
the Mitsunobu reaction, as described in Scheme A6. The resultant
ether is then deprotected to afford the phenol A16.11.
[0286] For example, 8-benzhydryloxy-7-methyl-quinolin-5-ol A16.12
prepared as described above from the corresponding carboxyester is
converted, via allylation, rearrangement and
hydroboration/oxidation, as described above, into
3-(8-benzhydryloxy-7-methyl-5-triisopropylsilanyloxy-quinolin-6-yl)-propa-
n-1-ol A16.13. The latter compound is then converted into an
activated derivative which is reacted, as described above, with
3-chloro-4-fluorobenzylamine A16.14 to yield
[3-(8-benzhydryloxy-7-methyl-5-triisopropylsilanyloxy-quinolin-6-yl)-prop-
yl]-(3-chloro-4-fluoro-benzyl)-amine A16.15. Cyclization of the
product, for example by reaction with trimethylaluminum, employing
the conditions described above affords
11-benzhydryloxy-9-(3-chloro-4-fluoro-benzyl)-5-triisopropylsilanyloxy-6,-
7,8,9-tetrahydro-1,9-diaza-cyclohepta[b]naphthalen-10-one A16.16.
The compound is deprotected by reaction with tetrabutylammonium
fluoride, to produce
11-benzhydryloxy-9-(3-chloro-4-fluoro-benzyl)-5-hydroxy-6,7,8,9-t-
etrahydro-1,9-diaza-cyclohepta[b]naphthalen-10-one A16.17. The
product is then reacted with a dialkyl hydroxyethyl phosphonate
A16.18, diethyl azodicarboxylate and triphenylphosphine in
tetrahydrofuran to give after deprotection the phenolic ether
A16.19.
[0287] Using the above procedures, but employing, in place of the
phenol A16.12, different phenols A16.2, and/or different
hydroxyesters A16.10, and/or different amines ArBNH.sub.2, the
corresponding products A16.11 are obtained.
##STR00098## ##STR00099##
##STR00100## ##STR00101##
##STR00102## ##STR00103##
##STR00104## ##STR00105##
##STR00106## ##STR00107##
##STR00108## ##STR00109##
##STR00110## ##STR00111##
##STR00112## ##STR00113##
##STR00114## ##STR00115##
##STR00116## ##STR00117##
##STR00118## ##STR00119## ##STR00120##
Preparation of the Intermediate Phosphonate Esters Icc.
[0288] Scheme A17 illustrates methods for the preparation of
phosphonate esters of structure Icc in which the phosphonate group
is attached by means of a one-carbon link, or by saturated or
unsaturated multicarbon chains optionally incorporating a
heteroatom. In this procedure, a 4-methyl-substituted quinoline
A17.3 is prepared by means of a Doebner-von Miller condensation
between an enone A17.2 and a substituted aniline A17.1. The
preparation of quinolines by means of the Doebner-von Miller
reaction is described in Heterocyclic Chemistry, by T. L.
Gilchrist, Longman, 1992, p. 158. The reaction is performed by
heating equimolar amounts of the reactants in an inert solvent such
as dimethylacetamide. The bromohydroxyquinoline A17.3 is then
transformed, by means of reaction sequence such as that illustrated
in Scheme 8 into the protected tricyclic compound A17.4. Benzylic
bromination of the latter compound, for example by reaction with
N-bromosuccinimide or N-bromoacetamide in an inert solvent such as
ethyl acetate at ca. 60.degree. C., then yields the bromomethyl
derivative A17.5. This compound is then reacted in an Arbuzov
reaction, as described above (Scheme A11), with a trialkyl
phosphite to produce after deprotection the phosphonate ester
A17.8.
[0289] Alternatively, the bromomethyl derivative A17.5 is reacted,
using the conditions described in Scheme A12, with a dialkyl
hydroxy, mercapto or amino-substituted phosphonate A17.6, in which
the group R is an acyclic or cyclic saturated or unsaturated
alkylene, or aryl, aralkyl or heteroaryl moiety, to give after
deprotection the ether, thioether or amino product A17.7.
[0290] Alternatively, the methyl-substituted tricyclic compound
A17.4 is condensed, under basic conditions, with a dialkyl
formyl-substituted phosphonate A17.9. The reaction is conducted
between equimolar amounts of the reactants in a polar solvent such
as dioxan or dimethylformamide, in the presence of a strong base
such as sodium hydride or lithium tetramethyl piperidide. The
procedure affords after deprotection the unsaturated phenol A17.10.
Reduction of the double bond, as described above (Scheme A13) then
produces the saturated analog A17.11.
[0291] For example, benzoic acid
7-cyclopent-3-enylmethyl-4-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quin-
olin-9-yl ester A17.12 is reacted with N-bromosuccinimide in
refluxing ethyl acetate to afford benzoic acid
4-bromomethyl-7-cyclopent-3-enylmethyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g-
]quinolin-9-yl ester A17.13. This compound is heated to 120.degree.
C. with an excess of a trialkyl phosphite to give after
deprotection the phenolic phosphonate ester A17.14.
[0292] As a further example,
4-bromomethyl-7-(4-fluoro-benzyl)-9-triisopropylsilanyloxy-6,7-dihydro-py-
rrolo[3,4-g]quinolin-8-one A17.15, prepared by bromination of the
corresponding methyl compound is reacted with a dialkyl
2-mercaptoethyl phosphonate A17.16 (Zh. Obschei. Khim., 1973, 43,
2793) and cesium carbonate in acetonitrile, to give the thioether
product A17.17. Deprotection yields the corresponding phenol
A17.18.
[0293] As a further example,
7-(3-chloro-4-fluoro-benzyl)-9-methoxymethoxy-4-methyl-6,7-dihydro-pyrrol-
o[3,4-g]quinolin-8-one A17.19 is condensed in dioxan solution with
a dialkyl formylmethyl phosphonate A17.20 (Aurora) in the presence
of lithium tetramethylpiperidide to form the unsaturated product
A17.21. Deprotection then yields the phenol A17.22; reduction of
the double bond then gives the saturated analog A17.23.
[0294] Using the above procedures, but employing, in place of the
starting materials A17.12, A17.15 and A17.19, different starting
materials A17.4 or A17.5, and/or different carbinols, thiols or
amines A17.6 or aldehydes A17.9, the corresponding products A17.7,
A17.8, A17.10 and A17.11 are obtained.
##STR00121## ##STR00122##
Preparation of the Intermediate Phosphonate Esters IIaa.
[0295] Schemes A18 and A19 illustrate the preparation of
phosphonate esters of structure IIaa. Scheme A18 depicts the
preparation of phosphonate esters of structure IIaa in which the
phosphonate group is attached by means of an alkoxy, alkylthio or
alkylamino group. In this procedure, an alkoxyethene triester A18.1
(JP 61289089) and a 3-aminopyridine A18.2 are reacted together, as
described in JP 61289089 and GB 1509695, to produce the
pyridylamino triester A18.3. The reaction is performed using
equimolar amounts of the reactants at a temperature of about
150.degree. C. The product is then cyclized to afford the
1,5-naphthyridine derivative A18.4. The reaction is performed in a
high-boiling solvent such as diphenyl ether at a temperature of
about 250.degree. C. The diester is then converted to the
anhydride, and the later compound is transformed by reaction with
the amine ArBNH.sub.2, and protection of the phenolic hydroxyl
group, into the cyclic imide A18.5. This material is then reduced,
as described in Example 20, for example by the use of sodium
borohydride, to afford the hydroxylactam A18.6. The latter compound
is then reacted, in the presence of an acid catalyst, as described
in Scheme A4, with a dialkyl hydroxy, mercapto or amino-substituted
phosphonate A18.7, in which the group R is an acyclic or cyclic
saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl
moiety, to yield after deprotection of the phenolic hydroxy group,
the ether, thioether or amino product A18.8.
[0296] For example, the triester A18.1 is reacted with
3-aminopyridine A18.9 to afford the pyridylamino triester A18.10.
The product is heated in diphenyl ether at 250.degree. C. to form
the 1,5-naphthyridine A18.11. The latter compound is then
transformed, as described above, into
7-(4-fluoro-benzyl)-6-hydroxy-9-triisopropylsilanyloxy-6,7-dihydro-pyrrol-
o[3,4-b][1,5]naphthyridin-8-one A18.12. The hydroxylactam is then
reacted in dichloromethane solution with a dialkyl 4-hydroxybutyl
phosphonate A18.13 (J. Med. Chem., 1996, 39, 949) and
trifluoroacetic acid, by a similar reaction as Example 23, to
generate the phosphonate product A18.14.
[0297] Using the above procedures, but employing, in place of the
pyridine A18.9, different pyridines A18.2, and/or different
phosphonates A18.7, the corresponding products A18.8 are
obtained.
[0298] Scheme A19 depicts the preparation of phosphonate esters of
structure IIaa in which the phosphonate group is attached by means
of variable carbon linkage, and the nucleus is a
1,3,5,9-tetraazaanthracene. In this procedure, the
1,5-naphthyridine A18.4 is converted into the phenol-protected
analog A19.1. The product is then subjected to a selective partial
hydrolysis, for example by reaction with one molar equivalent of a
base such as lithium hydroxide in an aqueous organic solvent
mixture, to produce the carboxy ester A19.2. The product is then
subjected to a Curtius rearrangement, as described in Scheme A3, to
afford the amine A19.3. The product is then reductively aminated,
as described in Scheme A3, by reaction with a dialkyl
formyl-substituted phosphonate A19.4, in which the group R is an
acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety, to give the amine A19.5. The ester
group is then transformed, as described previously (Scheme A3),
into the amide A19.6, by reaction with the amine ArBNH.sub.2. The
product is then cyclized to afford, after deprotection of the
phenolic hydroxyl, the tricyclic product, A19.7, in which A is, for
example, CO or CH.sub.2, by reaction respectively with phosgene or
an equivalent thereof, or with diiodomethane or a similar
reagent.
[0299] For example,
2-amino-4-hydroxy-[1,5]naphthyridine-3-carboxylic acid methyl ester
A19.8, prepared as described in Scheme A18 by the reaction between
3-aminopyridine and 1,2,2-tris-(carbomethoxy)-1-ethoxyethene, is
converted, as described above, into
2-amino-4-benzyloxy-[1,5]naphthyridine-3-carboxylic acid methyl
ester A19.9. The amine is then reacted in isopropanol solution with
a dialkyl 3-formylphenyl phosphonate A19.10 ( J. Med. Chem., 1984,
27, 654) and sodium triacetoxyborohydride, to yield the amine
A19.11. The ester group of the latter compound is then transformed
into the amide by reaction with
3,5-dichlorophenethylamine-trimethyl aluminum, as described
previously, to afford the amide A19.12. The product is then reacted
with triphosgene in pyridine solution at 80.degree. C. to give the
cyclized product A19.13. Deprotection then yields the phenol
A19.14.
[0300] Using the above procedures, but employing, in place of the
amine A19.9, different amines A19.3, and/or different formyl
phosphonates A19.4, the corresponding products A19.7 are
obtained.
##STR00123## ##STR00124##
##STR00125## ##STR00126## ##STR00127##
Preparation of the Intermediate Phosphonate Esters IIcc.
[0301] Scheme A20 illustrates the preparation of phosphonate esters
of structure IIcc, in which the phosphonate group is attached by
means of a one-carbon or multicarbon link, or by means of a
heteroatom and a variable carbon linkage. In this procedure, the
triester A18.1 is reacted, as described in Scheme A18, with a
3-amino-4-methylpyridine A20.1 to give the substituted pyridine
product A20.2. The latter compound is then transformed, as
described previously, into the methyl-substituted tricyclic
compound A20.3. This compound is then subjected to benzylic
bromination, for example by reaction with N-bromosuccinimide, to
form the bromomethyl product A20.4. This compound is subjected to
an Arbuzov reaction with a trialkyl phosphite, as described in
Scheme A11, to afford after deprotection the phosphonate A20.5.
[0302] Alternatively, the bromomethyl compound A20.4 is reacted
with a dialkyl phosphonate A20.6 in which X is O, S, NH or N-alkyl,
and R is an acyclic or cyclic saturated or unsaturated alkylene, or
aryl, aralkyl or heteroaryl moiety, using the procedures described
in Scheme A17, to give, after deprotection of the phenolic
hydroxyl, the ether, thioether or amine products A20.7.
[0303] Alternatively, the methyl compound A20.3 is subjected, as
described in Scheme A17, to a base-catalyzed condensation reaction
with a dialkyl formyl-substituted phosphonate A20.8, in which R is
an acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety, to generate after deprotection of the
phenolic hydroxyl, the unsaturated product A20.9. The double bond
is then reduced, as described in Scheme A17, to afford the
saturated analog A20.10.
[0304] For example, condensation between the triester A18.1 and
3-amino-4-methylpyridine A20.11 gives the pyridine product A20.12.
The compound is then transformed, as described above, into
7-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-4-methyl-9-triisopropylsilanyloxy--
pyrrolo[3,4-b][1,5]naphthyridine-6,8-dione A20.13. The latter
compound is then reacted with a dialkyl formylethyl phosphonate
A20.14 (Zh. Obschei. Mum., 1987, 57, 2793) and lithium
tetramethylpiperidide in tetrahydrofuran to afford after
deprotection the unsaturated product A20.15. The product is then
reduced with diimide, as described above, (Scheme A13) to yield the
saturated analog A20.16.
[0305] As a further example,
7-[1-(4-fluoro-phenyl)-cyclopropyl]-4-methyl-9-triisopropylsilanyloxy-pyr-
rolo[3,4-b][1,5]naphthyridine-6,8-dione A20.17, prepared according
to the procedures described above, is reacted with
N-bromosuccinimide in refluxing ethyl acetate to give
4-bromomethyl-7-[1-(4-fluoro-phenyl)-cyclopropyl]-9-triisopropylsilanylox-
y-pyrrolo[3,4-b[1,5]naphthyridine-6,8-dione A20.18. The product is
then heated at 120.degree. C. with excess of a trialkyl phosphite
to give after deprotection the phosphonate A20.19.
[0306] As a further example,
4-bromomethyl-7-(3-chloro-4-fluoro-benzyl)-9-triisopropylsilanyloxy-pyrro-
lo[3,4-b][1,5]naphthyridine-6,8-dione A20.20, prepared according to
the procedures described above, is reacted in dimethylformamide
solution with a dialkyl methylaminomethyl phosphonate
A20.21(AsInEx) and potassium carbonate, to afford after
deprotection the displacement product A20.22.
[0307] Using the above procedures, but employing, in place of the
starting materials A20.13, A20.17 and A20.20, different starting
materials A20.3 or A20.4, and/or different carbinols, thiols or
amines A20.6 or aldehydes A20.8, the corresponding products A20.5,
A20.7, A20.9 and A20.10 are obtained.
##STR00128## ##STR00129## ##STR00130##
Preparation of the Intermediate Phosphonate Esters IIIaa.
[0308] Scheme A21 illustrates methods for the preparation of
phosphonates of structure IIIaa in which the phosphonate group is
attached by means of a heteroatom and a variable carbon link. In
this sequence, a carbomethoxymethyl derivative of the amine
ArBNH.sub.2, A21.1 is coupled with the 1,6-naphthyridine carboxylic
acid A21.2, prepared as described in WO 0230930, using the methods
described previously, to prepare the amide A21.3. Bromination, for
example using N-bromosuccinimide, yields the 5-bromo derivative
A21.4. Protection of the phenolic hydroxyl group, followed by
displacement of the bromine with a hydrazine or hydroxylamine
nucleophile, as described for example in Example 69, affords the
5-imino derivative A21.5 in which X is NH.sub.2 or OH. Lactam
formation, for example by the use of potassium tert. butoxide in
refluxing xylene, or by the use of trimethylaluminum, then gives
the tricyclic product A21.6, which upon protection of the X
substituent gives the product A21.7. Reduction of this material,
for example by treatment with sodium borohydride, for example as in
Example 20, then gives the aminol A21.8. The latter compound is
reacted with a dialkyl hydroxy, mercapto, or amino-substituted
phosphonate A21.9, in which the group R is an acyclic or cyclic
saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl
moiety, in the presence of an acid such as trifluoroacetic acid, as
described in Scheme A4, to yield the ether, thioether or amine
product A21.10. Deprotection then gives the phenol A21.11.
[0309] For example, (4-fluoro-benzylamino)-acetic acid methyl ester
A21.12 is coupled in tetrahydrofuran solution with one molar
equivalent of 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid
A21.13, (WO 0230930) in the presence of diisopropyl carbodiimide,
to form
[(4-fluoro-benzyl)-(8-hydroxy-[1,6]naphthyridine-7-carbonyl)-amino]-aceti-
c acid methyl ester A21.14. The latter compound is then
transformed, by bromination, displacement and cyclization, as
described above into the tricyclic product,
9-benzyloxy-7-(4-fluoro-benzyl)-10-hydrazono-6,7-dihydro-10H-1,7,10a-tria-
za-anthracene-5,8-dione A21.15. The hydrazono compound is then
converted into the N,N-dibenzyl derivative A21.16. The conversion
of amines into dibenzylamines, for example by treatment with benzyl
bromide in a polar solvent such as acetonitrile or aqueous ethanol,
in the presence of a base such as triethylamine or sodium
carbonate, is described in Protective Groups in Organic Synthesis,
by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p.
364. The tribenzylated compound is then reduced with a limited
amount of sodium borohydride in isopropanol to afford the aminal
A21.17. This compound is reacted with a dialkyl 2-mercaptoethyl
phosphonate A21.18 (Zh. Obschei. Khim., 1973, 43, 2364), and
trifluoroacetic acid in dichloromethane, to give the thioether
A21.19. Debenzylation, for example by the use of 5% palladium on
carbon in the presence of ammonium formate, as described in Tet.
Lett, 28, 515, 1987, then affords the hydrazono phenol A21.20.
[0310] Using the above procedures, but employing, in place of the
amide A21.14, different amides A21.3, and/or different phosphonates
A21.9, the corresponding products A21.11 are obtained.
##STR00131## ##STR00132## ##STR00133## ##STR00134##
Preparation of the Intermediate Phosphonate Esters IIIbb.
[0311] Schemes A22-A24 illustrate methods for the preparation of
phosphonate esters of structure IIIbb.
[0312] Scheme A22 illustrates methods for the preparation of
phosphonates of structure IIIbb in which the phosphonate group is
attached by means of a variable carbon linkage. In this sequence,
the naphthyridine carboxylic acid A21.2 is coupled, as described
previously, with the amine derivative A22.1, following a procedure
similar to Example 28, to form the amide A22.2. Bromination, as
described above, yields the 5-bromo derivative A22.3, which upon
protection of the phenolic hydroxyl yields the compound A22.4.
Displacement of the bromine, by reaction with a dialkyl
amino-substituted phosphonate A22.5, in which the group R is an
acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety, affords the amine A22.6. The reaction
is performed in a polar organic solvent such as dimethylformamide
in the presence of a base such as potassium carbonate. Deprotection
of the alcoholic hydroxyl group affords the carbinol A22.7, which
upon activation and cyclization, for example as described in Scheme
11 then gives the tricyclic product A22.8, which upon deprotection
affords the phenol A22.9.
[0313] For example, acetic acid
5-bromo-7-[(4-fluoro-benzyl)-propyl-carbamoyl]-[1,6]naphthyridin-8-yl
ester A22.10, is reacted with one molar equivalent of a dialkyl
aminopropyl phosphonate A22.11, (Acros) to yield the amine A22.12.
Deprotection and activation of the alcoholic hydroxyl group, for
example by conversion to the mesylate, followed by cyclization
under basic conditions, and deprotection of the phenolic hydroxyl
group, then affords the enol A22.13.
[0314] Using the above procedures, but employing, in place of the
bromide A22.10, different bromides A22.4, and/or different
aminophosphonates A22.5, the corresponding products A22.9 are
obtained.
[0315] Scheme A23 illustrates methods for the preparation of
phosphonates of structure IIIbb in which the phosphonate group is
attached by means of a nitrogen and a variable carbon linkage. In
this sequence, a tricyclic imine A23.1 (Scheme 12) is reacted with
a dialkyl bromoalkyl phosphonate A23.2 to give the alkylated
product A23.3. The reaction is performed in a polar organic solvent
such as acetonitrile or dimethylsulfoxide, in the presence of a
base such as diisopropylethylamine or 2,6-lutidine.
[0316] Alternatively, the imine A23.1 is converted into a hydrazone
A23.5 by reaction with a dialkyl formyl-substituted phosphonate
A23.4 in which the group R is an acyclic or cyclic saturated or
unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety. The
hydrazone is prepared by the reaction of equimolar amounts of the
reactants in a polar organic solvent such as ethanol, optionally in
the presence of a catalytic amount of an acid such as acetic acid.
Optionally, the hydrazone product A23.5 is reduced, for example by
treatment with sodium borohydride, to give the dihydro derivative
A23.6.
[0317] For example, acetic acid
7-(4-fluoro-benzyl)-10-hydrazono-8-oxo-6,7,8,10-tetrahydro-5H-1,7,10a-tri-
aza-anthracen-9-yl ester A23.7 (Scheme 12) is reacted at 60.degree.
C. in dimethylformamide solution containing potassium carbonate
with one molar equivalent of a dialkyl 2-bromoethyl phosphonate
A23.8 (Aldrich), to prepare the alkylated product which upon
deprotection yields the enol A23.9.
[0318] As a further example, the hydrazone A23.7 is reacted in
ethanol solution at ambient temperature with one molar equivalent
of a dialkyl 2-formylphenyl phosphonate A23.10 (Epsilon) to give
the hydrazone product A23.11. Reduction of the double bond, by
treatment with sodium cyanoborohydride in isopropanol, followed by
deprotection, affords the enol product A23.12.
[0319] Using the above procedures, but employing, in place of the
hydrazone A23.7, different hydrazones A23.1, and/or different
bromophosphonates A23.2, or formyl phosphonates A23.4 the
corresponding products A23.3, A23.5 and A23.6 are obtained.
[0320] Scheme A24 illustrates methods for the preparation of
phosphonates of structure IIIbb in which the phosphonate group is
attached by means of a hydroxyimino linkage. In this sequence, a
tricyclic oxime A24.1 (Scheme 14) is reacted with a dialkyl
bromo-substituted phosphonate A24.2 in which the group R is an
acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety. The reaction is performed in a polar
organic solvent in the presence of a base such as sodium hydride or
lithium hexamethyldisilazide. Deprotection then yields the enol
A24.4.
[0321] For example, acetic acid
7-(4-fluoro-benzyl)-10-hydroxyimino-8-oxo-6,7,8,10-tetrahydro-5H-1,7,10a--
triaza-anthracen-9-yl ester A24.5 (Scheme 14) is reacted in
dimethylformamide solution with one molar equivalent of sodium
hydride, followed by the addition of one molar equivalent of a
dialkyl 4-(bromomethyl)phenyl phosphonate A24.6 (Tet., 1998, 54,
9341) to afford after deprotection the iminoether A24.7.
[0322] Using the above procedures, but employing, in place of the
oxime A24.5, different oximes A24.1, and/or different phosphonates
A24.2, the corresponding products A24.4 are obtained.
##STR00135## ##STR00136##
##STR00137## ##STR00138##
##STR00139##
Preparation of the Intermediate Phosphonate Esters IIIcc.
[0323] Scheme A25 illustrates methods for the preparation of
phosphonates of structure IIIcc. The conversion of
pyridine-2,3-dicarboxylic anhydride (A25.1, R.dbd.H) into the
naphthyridine A25.2, R.dbd.H, is described in WO 0255079. Using the
same procedure, 4-methylpyridine-2,3-dicarboxylic anhydride A25.1,
R=Me, (J. Org. Chem., 1961, 26, 808) is converted into the
naphthyridine A25.2, R=Me. This compound is then transformed, as
described in Scheme 12, into the imine A25.3. Protection of the
hydroxyl and amino groups then furnishes the derivative A25.4. The
product is then condensed under basic conditions, as described in
Scheme A20, with a dialkyl formyl-substituted phosphonate A25.5, in
which the group R is an acyclic or cyclic saturated or unsaturated
alkylene, or aryl, aralkyl or heteroaryl moiety. After
deprotection, the product A25.6 is optionally reduced, as described
in Scheme A20, to give the saturated analog A25.17.
[0324] Alternatively, the methyl-substituted tricycle A25.4 is
brominated, for example by reaction with N-bromosuccinimide, to
give the bromomethyl product A25.7. The compound is then subjected
to a Arbuzov reaction with a trialkyl phosphite, to yield after
deprotection the phosphonate A25.8.
[0325] Alternatively, the bromomethyl compound A25.7 is reacted, as
described previously (Scheme A20) with a dialkyl hydroxy, mercapto
or amino-substituted phosphonate A25.18, in which the group R is an
acyclic or cyclic saturated or unsaturated alkylene, or aryl,
aralkyl or heteroaryl moiety, to give after deprotection the ether,
thioether or amine product A25.9.
[0326] For example, acetic acid
7-[2-(4-fluoro-phenyl)-ethyl]-10-hydrazono-4-methyl-8-oxo-6,7,8,10-tetrah-
ydro-5H-1,7,10a-triaza-anthracen-9-yl ester A25.10, prepared
according to the procedures described above, is converted into the
phthalimido derivative by reaction with one molar equivalent of
phthalic anhydride, as described in J. Org. Chem., 43, 2320, 1978.
The protected product is then reacted with N-bromosuccinimide in
hexachloroethane to give the bromomethyl derivative A25.12. This
compound is heated to 120.degree. C. with an excess of a trialkyl
phosphite to produce the phosphonate A25.13. Deprotection, for
example by reaction with ethanolic hydrazine, as described in J.
Org. Chem., 43, 2320, 1978, then affords the phosphonate
A25.14.
[0327] As a further example, the phthalimido-protected
methyl-substituted tricycle A25.11 is reacted in dioxan solution
with a dialkyl formylphosphonate A25.12 (Tet., 1994, 50, 10277) and
lithium tetramethyl piperidide, to yield, after removal of the
protecting groups, the unsaturated phosphonate A25.13. Reduction of
the double bond then gives the saturated analog A25.14.
[0328] As a further example, the bromomethyl derivative A25.12 is
reacted in acetonitrile solution with one molar equivalent of a
dialkyl 2-mercaptopropyl phosphonate A25.15 (WO 007101) and
diisopropylethylamine, to produce after deprotection the
phosphonate A25.16.
[0329] Using the above procedures, but employing, in place of the
starting materials A25.10, A25.11 or A25.12, different starting
materials A25.4 and A25.7, and/or different aldehydes A25.5 or
alcohols, thiols or amines A25.18, the corresponding products
A25.6, A25.8, A25.9 and A25.17 are obtained.
##STR00140## ##STR00141## ##STR00142##
Preparation of the Intermediate Phosphonate Esters IVaa.
[0330] Schemes A29 and A30 illustrates the preparation of
phosphonate esters of structure IVaa.
[0331] Scheme A29 illustrates the preparation of compounds in which
phosphonate is attached by means of an ether, tioether of amine
linkage. In this procedure, a substituted succinimide A29.1 is
condensed, as described in Scheme 1 and Example 2, with a
heterocyclic diester A29.2 to afford after protection the tricyclic
product A29.3. Reduction with sodium borohydride then yields the
aminal A29.4, which upon acid-catalyzed reaction with a dialkyl
hydroxy, mercapto or amino-substituted phosphonate A29.S, in which
the group R is an acyclic or cyclic saturated or unsaturated
alkylene, or aryl, aralkyl or heteroaryl moiety, to give after
deprotection the ether, thioether or amine products A29.6.
[0332] For example,
1-[2-(4-fluoro-phenyl)-cyclopropyl]-pyrrolidine-2,5-dione A29.7,
prepared from 4-fluorophenylcyclopropylamine (J. Med. Chem., 1996,
39, 1485) and succinic anhydride, is reacted with
4,5-dicarbomethoxyisoxazole A29.8 (Chem Ber., 97, 1414, 1964) to
afford after protection
6-[2-(4-fluoro-phenyl)-cyclopropyl]-4,8-bis-methoxymethoxy-oxazolo[4,5-f]-
isoindole-5,7-dione A29.9. Reduction with sodium borohydride then
gives the aminal A29.10, which upon reaction with a dialkyl
3-mercaptopropyl phosphonate A29.11 (WO 0077101) and
trifluoroacetic acid in dichloromethane yields the phosphonate
thioether A29.12.
[0333] Using the above procedures, but employing, in place of the
starting materials A29.7 and A29.8, different starting materials
A29.1 and A29.2, and/or different phosphonates A29.5, the
corresponding products A29.6 are obtained.
Preparation of the Intermediate Phosphonate Esters IVaa.
[0334] Scheme A30 illustrates the preparation of phosphonate esters
of structure IVaa in which the phosphonate is attached by means of
a variable carbon linkage. In this procedure, dimethyl succinate
A30.1 is condensed, under base catalysis, for example using the
procedure described on Scheme 1 and Example 2 with a heterocyclic
diester A30.2, to yield after protection of the phenolic hydroxyl
groups, the diester A30.3. Partial basic hydrolysis, for example by
reaction with one molar equivalent of lithium hydroxide in aqueous
dimethoxyethane, then affords the monoacid A30.4. The carboxylic
acid is homologated to produce the corresponding acetic acid A30.5.
The transformation is effected by means of the Arndt Eistert
reaction. In this procedure, which is described in Advanced Organic
Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum, 2001,
p. 641, and in Advanced Organic Chemistry, By J. Marsh, McGraw
Hill, 1968, p. 809, the carboxylic acid is converted into the acid
chloride, which is reacted with diazomethane to give the
corresponding diazoketone. Silver-catalyzed Wolff rearrangement of
the diazoketone in an alcoholic solvent then yields the acetic acid
ester, which upon hydrolysis yields the acetic acid A30.5. This
material is coupled with the amine A30.6 to give the amide A30.7.
Base-catalyzed thermal cyclization of the latter compound, for
example by refluxing in xylene with sodium methoxide, then gives
the cyclized product A30.8. The latter compound is then alkylated,
as described above, (Scheme A10) with a dialkyl bromo-substituted
phosphonate A30.9, in which the group R is an acyclic or cyclic
saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl
moiety, to afford after deprotection the phosphonate A30.10.
[0335] For example, condensation between dimethyl succinate and
methyl 1-methylimidazole-4,5-dicarboxylate A30.11 (Eqypt. J. Chem.,
1985, 28, 139) yields, after protection of the phenolic hydroxyl
groups,
4,7-bis-methoxymethoxy-1-methyl-1H-benzoimidazole-5,6-dicarboxylic
acid dimethyl ester A30.12. Partial hydrolysis then gives the
monocarboxylic acid A30.13, and this compound is subjected to Arndt
Eistert homologation to give the corresponding acetic acid A30.14.
The carboxylic acid is coupled, in the presence of dicyclohexyl
carbodiimide, with cyclohexylmethylamine A30.15 to give the amide
A30.16. Cyclization is effected as described above to prepare
6-cyclohexylmethyl-4,9-bis-methoxymethoxy-1-methyl-1,5,6,8-tetrahydro-1,3-
,6-triaza-cyclopenta[b]naphthalen-7-one A30.17. The product is then
reacted in dioxan solution with a dialkyl bromoethyl phosphonate
A30.18 (Aldrich) and lithium hexamethyldisilazide, to give after
deprotection the phosphonate A30.19.
[0336] Using the above procedures, but employing, in place of the
starting materials A30.1 and A30.11, different starting materials
A30.1 and A30.2, and/or different phosphonates A30.9, the
corresponding products A30.10 are obtained.
##STR00143## ##STR00144##
##STR00145## ##STR00146##
Preparation of the Intermediate Phosphonate Esters IVbb.
[0337] Schemes A31 and A32 illustrates the preparation of
phosphonate esters of structure IVbb. Scheme A31 illustrates the
preparation of phosphonate esters in which the phosphonate is
attached by means of a variable carbon linkage linkage. In this
procedure, the doubly protected phenol A29.3 is selectively
deprotected to give the phenol A31.1. The product is converted into
the triflate A31.2 and this material is reacted with a dialkyl
hydroxy, mercapto or amino-substituted phosphonate A31.3, in which
the group R is an acyclic or cyclic saturated or unsaturated
alkylene, or aryl, aralkyl or heteroaryl moiety, in the presence of
a base, as described in Scheme A8, to afford the displacement
product A31.4, which upon deprotection gives the phenol A31.5.
[0338] For example, 2-naphthylmethylsuccinimide A31.6 is reacted
with dimethyl pyrimidine 4,5-dicarboxylate A31.7 (Chem. Ber., 1975,
108, 3877) to afford after differential protection, as describe in
Scheme 1 and Example 2 and triflate formation,
trifluoro-methanesulfonic acid
7-naphthalen-2-ylmethyl-6,8-dioxo-9-triisopropylsilanyloxy-7,8-dihydro-6H-
-pyrrolo[3,4-g]quinazolin-5-yl ester A31.8. The compound is then
reacted with a dialkyl 3-hydroxyphenyl phosphonate A31.9 (Aurora)
and triethylamine in dichloromethane to give the phosphonate
A31.10.
[0339] Using the above procedures, but employing, in place of the
starting materials A31.6 and A31.7, different starting materials
A29.3 and/or different phosphonates A31.3, the corresponding
products A31.5 are obtained.
[0340] Scheme A32 depicts the preparation of phosphonate esters of
structure Vbb in which the phosphonate is attached by means of an
ether linkage. In this procedure, dimethyl succinate A32.1 is
condensed under basic conditions, with a heterocyclic dicarboxylic
ester A32.2 to afford the bicyclic product A32.3. Hydrolysis of the
ester groups, followed by anhydride formation and selective
protection of the phenolic hydroxyl groups, then gives the product
A32.4. The anhydride is then reacted, as described with the
substituted hydrazine A32.5, to yield the tricyclic product A32.6.
Selective deprotection then affords the phenol A32.7, and this
compound is then reacted with a dialkyl hydroxy-substituted
phosphonate A32.8, in which the group R is an acyclic or cyclic
saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl
moiety, under the conditions of the Mitsonobu reaction, as
described in Scheme A6, to form after deprotection the phenol
A32.9.
[0341] For example, condensation between dimethyl succinate and
dimethyl 1,3,4-triazine-5,6-dicarboxylate A32.10 (J. Org. Chem.,
23, 1931, 1958) affords after selective silylation, following a
procedure similar to Example 12,
6-(4-fluoro-benzyl)-9-hydroxy-10-triisopropylsilanyloxy-6,7-dihydro-1,2,4-
,6,7-pentaaza-anthracene-5,8-dione A32.11. The product is then
reacted in tetrahydrofuran with a dialkyl hydroxyethyl phosphonate
A32.12, (Epsilon) diethyl azodicarboxylate and triphenyl phosphine
to yield after deprotection the phenolic phosphonate A32.13.
[0342] Using the above procedures, but employing, in place of the
starting material A32.10 different starting materials A32.2 and/or
different phosphonates A32.8, the corresponding products A32.9 are
obtained.
##STR00147## ##STR00148##
##STR00149## ##STR00150##
Preparation of the Intermediate Phosphonate Esters IVcc.
[0343] Scheme A33 illustrates the preparation of phosphonate esters
of structure IVcc in which the phosphonate is attached by means of
a carbon linkage. In this procedure, a substituted succinimide
A33.1 is reacted with a heterocyclic diester A33.2 to afford after
protection the bicyclic product A33.3. The amino group of the
product is then alkylated by reaction with a dialkyl
bromo-substituted phosphonate A33.4 to yield after deprotection the
phenolic phosphonate A33.5.
[0344] For example,
1-(6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidine-2,5-dione
A33.6, prepared by the reaction of
2-amino-7-fluoro-1,2,3,4-tetrahydronaphthalene (U.S. Pat. No.
5,538,988) and succinic anhydride, is reacted with dimethyl
1,2,3-triazole-4,5-dicarboxylate A33.7 (Interchim) to afford after
silylation of the phenolic hydroxyl groups
6-(6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-4,8-bis-triisopropylsilan-
yloxy-1H-pyrrolo[3',4':4,5]benzo[1,2-d][1,2,3]triazole-5,7-dione
A33.8. The product is then reacted, in dimethylformamide solution
with one molar equivalent of sodium hydride and a dialkyl
4-bromobutyl phosphonate A33.9 (Syn., 1994, 9, 909) to afford after
deprotection the phosphonate A33.10.
[0345] Using the above procedures, but employing, in place of the
starting materials A33.6 and A33.7 different starting materials
A33.1 and A33.2 and/or different phosphonates A33.4, the
corresponding products A33.5 are obtained.
##STR00151##
Interconversions of the Phosphonates R-link-P(O)(OR.sup.5).sub.2,
R-link-P(O)(OR.sup.5)(OH) and R-link-P(O)(OH).sub.2.
[0346] Schemes A1-A33 described the preparations of phosphonate
esters of the general structure R-link-P(O)(OR.sup.5).sub.2, in
which the groups R.sup.5 may be the same or different. The R.sup.5
groups attached to a phosphonate esters Iaa-IVcc, or to precursors
thereto, may be changed using established chemical transformations.
The interconversions reactions of phosphonates are illustrated in
Scheme A34. The group R in Scheme A34 represents the substructure
to which the substituent link-P(O)(OR.sup.5).sub.2 is attached,
either in the compounds Iaa-Ivcc or in precursors thereto. The
R.sup.5 group may be changed, using the procedures described below,
either in the precursor compounds, or in the esters Iaa-IVcc. The
methods employed for a given phosphonate transformation depend on
the nature of the substituent R.sup.5. The preparation and
hydrolysis of phosphonate esters is described in Organic Phosphorus
Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
9ff.
[0347] The conversion of a phosphonate diester A34.1 into the
corresponding phosphonate monoester A34.2 (Scheme A34, Reaction 1)
can be accomplished by a number of methods. For example, the ester
A34.1 in which R.sup.5 is an aralkyl group such as benzyl, can be
converted into the monoester compound A34.2 by reaction with a
tertiary organic base such as diazabicyclooctane (DABCO) or
quinuclidine, as described in J. Org. Chem., 1995, 60, 2946. The
reaction is performed in an inert hydrocarbon solvent such as
toluene or xylene, at about 11.degree. C. The conversion of the
diester A34.1 in which R.sup.5 is an aryl group such as phenyl, or
an alkenyl group such as allyl, into the monoester A34.2 can be
effected by treatment of the ester A34.1 with a base such as
aqueous sodium hydroxide in acetonitrile or lithium hydroxide in
aqueous tetrahydrofuran. Phosphonate diesters A34.1 in which one of
the groups R.sup.5 is aralkyl, such as benzyl, and the other is
alkyl, can be converted into the monoesters A34.2 in which R.sup.5
is alkyl by hydrogenation, for example using a palladium on carbon
catalyst. Phosphonate diesters in which both of the groups R.sup.5
are alkenyl, such as allyl, can be converted into the monoester
A34.2 in which R.sup.5 is alkenyl, by treatment with
chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in
aqueous ethanol at reflux, optionally in the presence of
diazabicyclooctane, for example by using the procedure described in
J. Org. Chem., 38, 3224, 1973 for the cleavage of allyl
carboxylates.
[0348] The conversion of a phosphonate diester A34.1 or a
phosphonate monoester A34.2 into the corresponding phosphonic acid
A34.3 (Scheme A34, Reactions 2 and 3) can effected by reaction of
the diester or the monoester with trimethylsilyl bromide, as
described in J. Chem. Soc., Chem. Comm., 739, 1979. The reaction is
conducted in an inert solvent such as, for example,
dichloromethane, optionally in the presence of a silylating agent
such as bis(trimethylsilyl)trifluoroacetamide, at ambient
temperature. A phosphonate monoester A34.2 in which R.sup.5 is
aralkyl such as benzyl, can be converted into the corresponding
phosphonic acid A34.3 by hydrogenation over a palladium catalyst,
or by treatment with hydrogen chloride in an ethereal solvent such
as dioxan. A phosphonate monoester A34.2 in which R.sup.5 is
alkenyl such as, for example, allyl, can be converted into the
phosphonic acid A34.3 by reaction with Wilkinson's catalyst in an
aqueous organic solvent, for example in 15% aqueous acetonitrile,
or in aqueous ethanol, for example using the procedure described in
Helv. Chim. Acta., 68, 618, 1985. Palladium catalyzed
hydrogenolysis of phosphonate esters A34.1 in which R.sup.5 is
benzyl is described in J. Org. Chem., 24,434, 1959.
Platinum-catalyzed hydrogenolysis of phosphonate esters A34.1 in
which R.sup.5 is phenyl is described in J. Am. Chem. Soc., 78,
2336, 1956.
[0349] The conversion of a phosphonate monoester A34.2 into a
phosphonate diester A34.1 (Scheme A34, Reaction 4) in which the
newly introduced R.sup.5 group is alkyl, aralkyl, haloalkyl such as
chloroethyl, or aralkyl can be effected by a number of reactions in
which the substrate A34.2 is reacted with a hydroxy compound
R.sup.5OH, in the presence of a coupling agent. Suitable coupling
agents are those employed for the preparation of carboxylate
esters, and include a carbodiimide such as
dicyclohexylcarbodiimide, in which case the reaction is preferably
conducted in a basic organic solvent such as pyridine, or
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PYBOP, Sigma), in which case the reaction is performed in a polar
solvent such as dimethylformamide, in the presence of a tertiary
organic base such as diisopropylethylamine, or Aldrithiol-2
(Aldrich) in which case the reaction is conducted in a basic
solvent such as pyridine, in the presence of a triaryl phosphine
such as triphenylphosphine. Alternatively, the conversion of the
phosphonate monoester A34.2 to the diester A34.1 can be effected by
the use of the Mitsonobu reaction, as described above (Scheme A6).
The substrate is reacted with the hydroxy compound R.sup.5OH, in
the presence of diethyl azodicarboxylate and a triarylphosphine
such as triphenyl phosphine. Alternatively, the phosphonate
monoester A34.2 can be transformed into the phosphonate diester
A34.1, in which the introduced R.sup.5 group is alkenyl or aralkyl,
by reaction of the monoester with the halide R.sup.5Br, in which
R.sup.5 is as alkenyl or aralkyl. The alkylation reaction is
conducted in a polar organic solvent such as dimethylformamide or
acetonitrile, in the presence of a base such as cesium carbonate.
Alternatively, the phosphonate monoester can be transformed into
the phosphonate diester in a two step procedure. In the first step,
the phosphonate monoester A34.2 is transformed into the chloro
analog RP(O)(OR.sup.5)Cl by reaction with thionyl chloride or
oxalyl chloride and the like, as described in Organic Phosphorus
Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and
the thus-obtained product RP(O)(OR.sup.5)Cl is then reacted with
the hydroxy compound R.sup.5OH, in the presence of a base such as
triethylamine, to afford the phosphonate diester A34.1.
[0350] A phosphonic acid R-link-P(O)(OH).sub.2 can be transformed
into a phosphonate monoester RP(O)(OR.sup.5)(OH) (Scheme A34,
Reaction 5) by means of the methods described above of for the
preparation of the phosphonate diester R-link-P(O)(OR.sup.5).sub.2
A34.1, except that only one molar proportion of the component
R.sup.5OH or R.sup.5Br is employed.
[0351] A phosphonic acid R-link-P(O)(OH).sub.2 A34.3 can be
transformed into a phosphonate diester R-link-P(O)(OR.sup.5).sub.2
A34.1 (Scheme A34, Reaction 6) by a coupling reaction with the
hydroxy compound R.sup.5OH, in the presence of a coupling agent
such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction
is conducted in a basic solvent such as pyridine. Alternatively,
phosphonic acids A34.3 can be transformed into phosphonic esters
A34.1 in which R.sup.5 is aryl, by means of a coupling reaction
employing, for example, dicyclohexylcarbodiimide in pyridine at ca
70.degree. C. Alternatively, phosphonic acids A34.3 can be
transformed into phosphonic esters A34.1 in which R.sup.5 is
alkenyl, by means of an alkylation reaction. The phosphonic acid is
reacted with the alkenyl bromide R.sup.5Br in a polar organic
solvent such as acetonitrile solution at reflux temperature, the
presence of a base such as cesium carbonate, to afford the
phosphonic ester A34.1.
##STR00152##
Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,
Monoamidates, Diesters and Monoesters.
[0352] A number of methods are available for the conversion of
phosphonic acids into amidates and esters. In one group of methods,
the phosphonic acid is either converted into an isolated activated
intermediate such as a phosphoryl chloride, or the phosphonic acid
is activated in situ for reaction with an amine or a hydroxy
compound.
[0353] The conversion of phosphonic acids into phosphoryl chlorides
is accomplished by reaction with thionyl chloride, for example as
described in J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim.,
1958, 28, 1063, or J. Org. Chem., 1994, 59, 6144, or by reaction
with oxalyl chloride, as described in J. Am. Chem. Soc., 1994, 116,
3251, or J. Org. Chem., 1994, 59, 6144, or by reaction with
phosphorus pentachloride, as described in J. Org. Chem., 2001, 66,
329, or in J. Med. Chem., 1995, 38, 1372. The resultant phosphoryl
chlorides are then reacted with amines or hydroxy compounds in the
presence of a base to afford the amidate or ester products.
[0354] Phosphonic acids are converted into activated imidazolyl
derivatives by reaction with carbonyl diimidazole, as described in
J. Chem. Soc., Chem. Comm., 1991, 312, or Nucleosides Nucleotides
2000, 19, 1885. Activated sulfonyloxy derivatives are obtained by
the reaction of phosphonic acids with trichloromethylsulfonyl
chloride, as described in J. Med. Chem. 1995, 38, 4958, or with
triisopropylbenzenesulfonyl chloride, as described in Tet. Lett.,
1996, 7857, or Bioorg. Med. Chem. Lett., 1998, 8, 663. The
activated sulfonyloxy derivatives are then reacted with amines or
hydroxy compounds to afford amidates or esters.
[0355] Alternatively, the phosphonic acid and the amine or hydroxy
reactant are combined in the presence of a diimide coupling agent.
The preparation of phosphonic amidates and esters by means of
coupling reactions in the presence of dicyclohexyl carbodiimide is
described, for example, in J. Chem. Soc., Chem. Comm., 1991, 312,
or J. Med. Chem., 1980, 23, 1299 or Coll. Czech. Chem. Comm., 1987,
52, 2792. The use of ethyl dimethylaminopropyl carbodiimide for
activation and coupling of phosphonic acids is described in Tet.
Lett., 2001, 42, 8841, or Nucleosides Nucleotides, 2000, 19,
1885.
[0356] A number of additional coupling reagents have been described
for the preparation of amidates and esters from phosphonic acids.
The agents include Aldrithiol-2, and PYBOP and BOP, as described in
J. Org. Chem., 1995, 60, 5214, and J. Med. Chem., 1997, 40, 3842,
mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described
in J. Med. Chem., 1996, 39, 4958, diphenylphosphoryl azide, as
described in J. Org. Chem., 1984, 49, 1158,
1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT)
as described in Bioorg. Med. Chem. Lett., 1998, 8, 1013,
bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), as
described in Tet. Lett., 1996, 37, 3997,
2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described in
Nucleosides Nucleotides 1995, 14, 871, and diphenyl
chlorophosphate, as described in J. Med. Chem., 1988, 31, 1305.
[0357] Phosphonic acids are converted into amidates and esters by
means of the Mitsonobu reaction, in which the phosphonic acid and
the amine or hydroxy reactant are combined in the presence of a
triaryl phosphine and a dialkyl azodicarboxylate. The procedure is
described in Org. Lett., 2001, 3, 643, or J. Med. Chem., 1997, 40,
3842.
[0358] Phosphonic esters are also obtained by the reaction between
phosphonic acids and halo compounds, in the presence of a suitable
base. The method is described, for example, in Anal. Chem., 1987,
59, 1056, or J. Chem. Soc. Perkin Trans., I, 1993, 19, 2303, or J.
Med. Chem., 1995, 38, 1372, or Tet. Lett., 2002, 43, 1161.
[0359] Schemes 1-5 illustrate the conversion of phosphonate esters
and phosphonic acids into carboalkoxy-substituted
phosphorobisamidates (Scheme 1), phosphoroamidates (Scheme 2),
phosphonate monoesters (Scheme 3) and phosphonate diesters, (Scheme
4)
[0360] Scheme 1 illustrates various methods for the conversion of
phosphonate diesters 1.1 into phosphorobisamidates 1.5. The diester
1.1, prepared as described previously, is hydrolyzed, either to the
monoester 1.2 or to the phosphonic acid 1.6. The methods employed
for these transformations are described above. The monoester 1.2 is
converted into the monoamidate 1.3 by reaction with an aminoester
1.9, in which the group R.sup.2 is H or alkyl, the group R.sup.4 is
an alkylene moiety such as, for example, CHCH.sub.3, CHPr.sup.1,
CH(CH.sub.2Ph), CH.sub.2CH(CH.sub.3) and the like, or a group
present in natural or modified amino acids, and the group R.sup.5
is alkyl. The reactants are combined in the presence of a coupling
agent such as a carbodiimide, for example dicyclohexyl
carbodiimide, as described in J. Am. Chem. Soc., 1957, 79, 3575,
optionally in the presence of an activating agent such as
hydroxybenztriazole, to yield the amidate product 1.3. The
amidate-forming reaction is also effected in the presence of
coupling agents such as BOP, as described in J. Org. Chem., 1995,
60, 5214, Aldrithiol, PYBOP and similar coupling agents used for
the preparation of amides and esters. Alternatively, the reactants
1.2 and 1.9 are transformed into the monoamidate 1.3 by means of a
Mitsonobu reaction. The preparation of amidates by means of the
Mitsonobu reaction is described in J. Med. Chem., 1995, 38, 2742.
Equimolar amounts of the reactants are combined in an inert solvent
such as tetrahydrofuran in the presence of a triaryl phosphine and
a dialkyl azodicarboxylate. The thus-obtained monoamidate ester 1.3
is then transformed into amidate phosphonic acid 1.4. The
conditions used for the hydrolysis reaction depend on the nature of
the R.sup.1 group, as described previously. The phosphonic acid
amidate 1.4 is then reacted with an aminoester 1.9, as described
above, to yield the bisamidate product 1.5, in which the amino
substituents are the same or different.
[0361] An example of this procedure is shown in Scheme 1, Example
1. In this procedure, a dibenzyl phosphonate 1.14 is reacted with
diazabicyclooctane (DABCO) in toluene at reflux, as described in J.
Org. Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate
1.15. The product is then reacted with equimolar amounts of ethyl
alaninate 1.16 and dicyclohexyl carbodiimide in pyridine, to yield
the amidate product 1.17. The benzyl group is then removed, for
example by hydrogenolysis over a palladium catalyst, to give the
monoacid product 1.18. This compound is then reacted in a Mitsonobu
reaction with ethyl leucinate 1.19, triphenyl phosphine and
diethylazodicarboxylate, as described in J. Med. Chem., 1995, 38,
2742, to produce the bisamidate product 1.20.
[0362] Using the above procedures, but employing, in place of ethyl
leucinate 1.19 or ethyl alaninate 1.16, different aminoesters 1.9,
the corresponding products 1.5 are obtained.
[0363] Alternatively, the phosphonic acid 1.6 is converted into the
bisamidate 1.5 by use of the coupling reactions described above.
The reaction is performed in one step, in which case the
nitrogen-related substituents present in the product 1.5 are the
same, or in two steps, in which case the nitrogen-related
substituents can be different.
[0364] An example of the method is shown in Scheme 1, Example 2. In
this procedure, a phosphonic acid 1.6 is reacted in pyridine
solution with excess ethyl phenylalaninate 1.21 and
dicyclohexylcarbodiimide, for example as described in J. Chem.
Soc., Chem. Comm., 1991, 1063, to give the bisamidate product
1.22.
[0365] Using the above procedures, but employing, in place of ethyl
phenylalaninate, different aminoesters 1.9, the corresponding
products 1.5 are obtained.
[0366] As a further alternative, the phosphonic acid 1.6 is
converted into the mono or bis-activated derivative 1.7, in which
Lv is a leaving group such as chloro, imidazolyl,
triisopropylbenzenesulfonyloxy etc. The conversion of phosphonic
acids into chlorides 1.7 (Lv=Cl) is effected by reaction with
thionyl chloride or oxalyl chloride and the like, as described in
Organic Phosphorus Compounds, G. M. Kosolapoff L. Maeir, eds,
Wiley, 1976, p. 17. The conversion of phosphonic acids into
monoimidazolides 1.7 (Lv=imidazolyl) is described in J. Med. Chem.,
2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.
Alternatively, the phosphonic acid is activated by reaction with
triisopropylbenzenesulfonyl chloride, as described in Nucleosides
and Nucleotides, 2000, 10, 1885. The activated product is then
reacted with the aminoester 1.9, in the presence of a base, to give
the bisamidate 1.5. The reaction is performed in one step, in which
case the nitrogen substituents present in the product 1.5 are the
same, or in two steps, via the intermediate 1.11, in which case the
nitrogen substituents can be different.
[0367] Examples of these methods are shown in Scheme 1, Examples 3
and 5. In the procedure illustrated in Scheme 1, Example 3, a
phosphonic acid 1.6 is reacted with ten molar equivalents of
thionyl chloride, as described in Zh. Obschei Khim., 1958, 28,
1063, to give the dichloro compound 1.23. The product is then
reacted at reflux temperature in a polar aprotic solvent such as
acetonitrile, and in the presence of a base such as triethylamine,
with butyl serinate 1.24 to afford the bisamidate product 1.25.
[0368] Using the above procedures, but employing, in place of butyl
serinate 1.24, different aminoesters 1.9, the corresponding
products 1.5 are obtained.
[0369] In the procedure illustrated in Scheme 1, Example 5, the
phosphonic acid 1.6 is reacted, as described in J. Chem. Soc. Chem.
Comm., 1991, 312, with carbonyl diimidazole to give the imidazolide
1.32. The product is then reacted in acetonitrile solution at
ambient temperature, with one molar equivalent of ethyl alaninate
1.33 to yield the monodisplacement product 1.34. The latter
compound is then reacted with carbonyl diimidazole to produce the
activated intermediate 1.35, and the product is then reacted, under
the same conditions, with ethyl N-methylalaninate 1.33a to give the
bisamidate product 1.36.
[0370] Using the above procedures, but employing, in place of ethyl
alaninate 1.33 or ethyl N-methylalaninate 1.33a, different
aminoesters 1.9, the corresponding products 1.5 are obtained.
[0371] The intermediate monoamidate 1.3 is also prepared from the
monoester 1.2 by first converting the monoester into the activated
derivative 1.8 in which Lv is a leaving group such as halo,
imidazolyl etc, using the procedures described above. The product
1.8 is then reacted with an aminoester 1.9 in the presence of a
base such as pyridine, to give an intermediate monoamidate product
1.3. The latter compound is then converted, by removal of the
R.sup.1 group and coupling of the product with the aminoester 1.9,
as described above, into the bisamidate 1.5.
[0372] An example of this procedure, in which the phosphonic acid
is activated by conversion to the chloro derivative 1.26, is shown
in Scheme 1, Example 4. In this procedure, the phosphonic
monobenzyl ester 1.15 is reacted, in dichloromethane, with thionyl
chloride, as described in Tet. Let., 1994, 35, 4097, to afford the
phosphoryl chloride 1.26. The product is then reacted in
acetonitrile solution at ambient temperature with one molar
equivalent of ethyl 3-amino-2-methylpropionate 1.27 to yield the
monoamidate product 1.28. The latter compound is hydrogenated in
ethylacetate over a 5% palladium on carbon catalyst to produce the
monoacid product 1.29. The product is subjected to a Mitsonobu
coupling procedure, with equimolar amounts of butyl aluminate 1.30,
triphenyl phosphine, diethylazodicarboxylate and triethylamine in
tetrahydrofuran, to give the bisamidate product 1.31.
[0373] Using the above procedures, but employing, in place of ethyl
3-amino-2-methylpropionate 1.27 or butyl alaninate 1.30, different
aminoesters 1.9, the corresponding products 1.5 are obtained.
[0374] The activated phosphonic acid derivative 1.7 is also
converted into the bisamidate 1.5 via the diamino compound 1.10.
The conversion of activated phosphonic acid derivatives such as
phosphoryl chlorides into the corresponding amino analogs 1.10, by
reaction with ammonia, is described in Organic Phosphorus
Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976. The
diamino compound 1.10 is then reacted at elevated temperature with
a haloester 1.12, in a polar organic solvent such as
dimethylformamide, in the presence of a base such as
dimethylaminopyridine or potassium carbonate, to yield the
bisamidate 1.5.
[0375] An example of this procedure is shown in Scheme 1, Example
6. In this method, a dichlorophosphonate 1.23 is reacted with
ammonia to afford the diamide 1.37. The reaction is performed in
aqueous, aqueous alcoholic or alcoholic solution, at reflux
temperature. The resulting diamino compound is then reacted with
two molar equivalents of ethyl 2-bromo-3-methylbutyrate 1.38, in a
polar organic solvent such as N-methylpyrrolidinone at ca.
150.degree. C., in the presence of a base such as potassium
carbonate, and optionally in the presence of a catalytic amount of
potassium iodide, to afford the bisamidate product 1.39.
[0376] Using the above procedures, but employing, in place of ethyl
2-bromo-3-methylbutyrate 1.38, different haloesters 1.12 the
corresponding products 1.5 are obtained.
[0377] The procedures shown in Scheme 1 are also applicable to the
preparation of bisamidates in which the aminoester moiety
incorporates different functional groups, Scheme 1, Example 7
illustrates the preparation of bisamidates derived from tyrosine.
In this procedure, the monoimidazolide 1.32 is reacted with propyl
tyrosinate 1.40, as described in Example 5, to yield the
monoamidate 1.41. The product is reacted with carbonyl diimidazole
to give the imidazolide 1.42, and this material is reacted with a
further molar equivalent of propyl tyrosinate to produce the
bisamidate product 1.43.
[0378] Using the above procedures, but employing, in place of
propyl tyrosinate 1.40, different aminoesters 1.9, the
corresponding products 1.5 are obtained. The aminoesters employed
in the two stages of the above procedure can be the same or
different, so that bisamidates with the same or different amino
substituents are prepared.
[0379] Scheme 2 illustrates methods for the preparation of
phosphonate monoamidates.
[0380] In one procedure, a phosphonate monoester 1.1 is converted,
as described in Scheme 1, into the activated derivative 1.8. This
compound is then reacted, as described above, with an aminoester
1.9, in the presence of a base, to afford the monoamidate product
2.1.
[0381] The procedure is illustrated in Scheme 2, Example 1. In this
method, a monophenyl phosphonate 2.7 is reacted with, for example,
thionyl chloride, as described in J. Gen. Chem. USSR., 1983, 32,
367, to give the chloro product 2.8. The product is then reacted,
as described in Scheme 1, with ethyl alaninate 2.9, to yield the
amidate 2.10.
[0382] Using the above procedures, but employing, in place of ethyl
alaninate 2.9, different aminoesters 1.9, the corresponding
products 2.1 are obtained.
[0383] Alternatively, the phosphonate monoester 1.1 is coupled, as
described in Scheme 1, with an aminoester 1.9 to produce the
amidate 2.1. If necessary, the R.sup.1 substituent is then altered,
by initial cleavage to afford the phosphonic acid 2.2. The
procedures for this transformation depend on the nature of the
R.sup.1 group, and are described above. The phosphonic acid is then
transformed into the ester amidate product 2.3, by reaction with
the hydroxy compound R.sup.3OH, in which the group R.sup.3 is aryl,
heteroaryl, alkyl, cycloalkyl, haloalkyl etc, using the same
coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsonobu
reaction etc) described in Scheme 1 for the coupling of amines and
phosphonic acids.
##STR00153## ##STR00154## ##STR00155##
[0384] Examples of this method are shown in Scheme 2, Examples and
2 and 3. In the sequence shown in Example 2, a monobenzyl
phosphonate 2.11 is transformed by reaction with ethyl alaninate,
using one of the methods described above, into the monoamidate
2.12. The benzyl group is then removed by catalytic hydrogenation
in ethylacetate solution over a 5% palladium on carbon catalyst, to
afford the phosphonic acid amidate 2.13. The product is then
reacted in dichloromethane solution at ambient temperature with
equimolar amounts of 1-(dimethylaminopropyl)-3-ethylcarbodiimide
and trifluoroethanol 2.14, for example as described in Tet. Lett.,
2001, 42, 8841, to yield the amidate ester 2.15.
[0385] In the sequence shown in Scheme 2, Example 3, the
monoamidate 2.13 is coupled, in tetrahydrofuran solution at ambient
temperature, with equimolar amounts of dicyclohexyl carbodiimide
and 4-hydroxy-N-methylpiperidine 2.16, to produce the amidate ester
product 2.17.
[0386] Using the above procedures, but employing, in place of the
ethyl alaninate product 2.12 different monoacids 2.2, and in place
of trifluoroethanol 2.14 or 4-hydroxy-N-methylpiperidine 2.16,
different hydroxy compounds R.sup.3OH, the corresponding products
2.3 are obtained.
[0387] Alternatively, the activated phosphonate ester 1.8 is
reacted with ammonia to yield the amidate 2.4. The product is then
reacted, as described in Scheme 1, with a haloester 2.5, in the
presence of a base, to produce the amidate product 2.6. If
appropriate, the nature of the R.sup.1 group is changed, using the
procedures described above, to give the product 2.3. The method is
illustrated in Scheme 2, Example 4. In this sequence, the
monophenyl phosphoryl chloride 2.18 is reacted, as described in
Scheme 1, with ammonia, to yield the amino product 2.19. This
material is then reacted in N-methylpyrrolidinone solution at
170.degree. C. with butyl 2-bromo-3-phenylpropionate 2.20 and
potassium carbonate, to afford the amidate product 2.21.
[0388] Using these procedures, but employing, in place of butyl
2-bromo-3-phenylpropionate 2.20, different haloesters 2.5, the
corresponding products 2.6 are obtained.
[0389] The monoamidate products 2.3 are also prepared from the
doubly activated phosphonate derivatives 1.7. In this procedure,
examples of which are described in Synlett., 1998, 1, 73, the
intermediate 1.7 is reacted with a limited amount of the aminoester
1.9 to give the mono-displacement product 1.11. The latter compound
is then reacted with the hydroxy compound R.sup.3OH in a polar
organic solvent such as dimethylformamide, in the presence of a
base such as diisopropylethylamine, to yield the monoamidate ester
2.3.
[0390] The method is illustrated in Scheme 2, Example 5. In this
method, the phosphoryl dichloride 2.22 is reacted in
dichloromethane solution with one molar equivalent of ethyl
N-methyl tyrosinate 2.23 and dimethylaminopyridine, to generate the
monoamidate 2.24. The product is then reacted with phenol 2.25 in
dimethylformamide containing potassium carbonate, to yield the
ester amidate product 2.26.
[0391] Using these procedures, but employing, in place of ethyl
N-methyl tyrosinate 2.23 or phenol 2.25, the aminoesters 1.9 and/or
the hydroxy compounds R.sup.3OH, the corresponding products 2.3 are
obtained.
##STR00156## ##STR00157##
[0392] Scheme 3 illustrates methods for the preparation of
carboalkoxy-substituted phosphonate diesters in which one of the
ester groups incorporates a carboalkoxy substituent.
[0393] In one procedure, a phosphonate monoester 1.1, prepared as
described above, is coupled, using one of the methods described
above, with a hydroxyester 3.1, in which the groups R.sup.4 and
R.sup.5 are as described in Scheme 1. For example, equimolar
amounts of the reactants are coupled in the presence of a
carbodiimide such as dicyclohexyl carbodiimide, as described in
Aust. J. Chem., 1963, 609, optionally in the presence of
dimethylaminopyridine, as described in Tet., 1999, 55, 12997. The
reaction is conducted in an inert solvent at ambient
temperature.
[0394] The procedure is illustrated in Scheme 3, Example 1. In this
method, a monophenyl phosphonate 3.9 is coupled, in dichloromethane
solution in the presence of dicyclohexyl carbodiimide, with ethyl
3-hydroxy-2-methylpropionate 3.10 to yield the phosphonate mixed
diester 3.11.
[0395] Using this procedure, but employing, in place of ethyl
3-hydroxy-2-methylpropionate 3.10, different hydroxyesters 3.1, the
corresponding products 3.2 are obtained.
[0396] The conversion of a phosphonate monoester 1.1 into a mixed
diester 3.2 is also accomplished by means of a Mitsonobu coupling
reaction with the hydroxyester 3.1, as described in Org. Lett.,
2001, 643. in this method, the reactants 1.1 and 3.1 are combined
in a polar solvent such as tetrahydrofuran, in the presence of a
triarylphosphine and a dialkyl azodicarboxylate, to give the mixed
diester 3.2. The R.sup.1 substituent is varied by cleavage, using
the methods described previously, to afford the monoacid product
3.3. The product is then coupled, for example using methods
described above, with the hydroxy compound R.sup.3OH, to give the
diester product 3.4.
[0397] The procedure is illustrated in Scheme 3, Example 2. In this
method, a monoallyl phosphonate 3.12 is coupled in tetrahydrofuran
solution, in the presence of triphenylphosphine and
diethylazodicarboxylate, with ethyl lactate 3.13 to give the mixed
diester 3.14. The product is reacted with tris(triphenylphosphine)
rhodium chloride (Wilkinson catalyst) in acetonitrile, as described
previously, to remove the allyl group and produce the monoacid
product 3.15. The latter compound is then coupled, in pyridine
solution at ambient temperature, in the presence of dicyclohexyl
carbodiimide, with one molar equivalent of 3-hydroxypyridine 3.16
to yield the mixed diester 3.17.
[0398] Using the above procedures, but employing, in place of the
ethyl lactate 3.13 or 3-hydroxypyridine, a different hydroxyester
3.1 and/or a different hydroxy compound R.sup.3OH, the
corresponding products 3.4 are obtained.
[0399] The mixed diesters 3.2 are also obtained from the monoesters
1.1 via the intermediacy of the activated monoesters 3.5. In this
procedure, the monoester 1.1 is converted into the activated
compound 3.5 by reaction with, for example, phosphorus
pentachloride, as described in J. Org. Chem., 2001, 66, 329, or
with thionyl chloride or oxalyl chloride (Lv=Cl), or with
triisopropylbenzenesulfonyl chloride in pyridine, as described in
Nucleosides and Nucleotides, 2000, 19, 1885, or with carbonyl
diimidazole, as described in J. Med. Chem., 2002, 45, 1284. The
resultant activated monoester is then reacted with the hydroxyester
3.1, as described above, to yield the mixed diester 3.2.
[0400] The procedure is illustrated in Scheme 3, Example 3. In this
sequence, a monophenyl phosphonate 3.9 is reacted, in acetonitrile
solution at 70.degree. C., with ten equivalents of thionyl
chloride, so as to produce the phosphoryl chloride 3.19. The
product is then reacted with ethyl 4-carbamoyl-2-hydroxybutyrate
3.20 in dichloromethane containing triethylamine, to give the mixed
diester 3.21.
[0401] Using the above procedures, but employing, in place of ethyl
4-carbamoyl-2-hydroxybutyrate 3.20, different hydroxyesters 3.1,
the corresponding products 3.2 are obtained.
[0402] The mixed phosphonate diesters are also obtained by an
alternative route for incorporation of the R.sup.3O group into
intermediates 3.3 in which the hydroxyester moiety is already
incorporated. In this procedure, the monoacid intermediate 3.3 is
converted into the activated derivative 3.6 in which Lv is a
leaving group such as chloro, imidazole, and the like, as
previously described. The activated intermediate is then reacted
with the hydroxy compound R.sup.3OH, in the presence of a base, to
yield the mixed diester product 3.4.
[0403] The method is illustrated in Scheme 3, Example 4. In this
sequence, the phosphonate monoacid 3.22 is reacted with
trichloromethanesulfonyl chloride in tetrahydrofuran containing
collidine, as described in J. Med. Chem., 1995, 38, 4648, to
produce the trichloromethanesulfonyloxy product 3.23. This compound
is reacted with 3-(morpholinomethyl)phenol 3.24 in dichloromethane
containing triethylamine, to yield the mixed diester product
3.25.
[0404] Using the above procedures, but employing, in place of with
3-(morpholinomethyl)phenol 3.24, different carbinols R.sup.3OH, the
corresponding products 3.4 are obtained.
[0405] The phosphonate esters 3.4 are also obtained by means of
alkylation reactions performed on the monoesters 1.1. The reaction
between the monoacid 1.1 and the haloester 3.7 is performed in a
polar solvent in the presence of a base such as
diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056,
or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or
in a non-polar solvent such as benzene, in the presence of
18-crown-6, as described in Syn. Comm., 1995, 25, 3565.
[0406] The method is illustrated in Scheme 3, Example 5. In this
procedure, the monoacid 3.26 is reacted with ethyl
2-bromo-3-phenylpropionate 3.27 and diisopropylethylamine in
dimethylformamide at 80.degree. C. to afford the mixed diester
product 3.28.
[0407] Using the above procedure, but employing, in place of ethyl
2-bromo-3-phenylpropionate 3.27, different haloesters 3.7, the
corresponding products 3.4 are obtained.
##STR00158## ##STR00159##
[0408] Scheme 4 illustrates methods for the preparation of
phosphonate diesters in which both the ester substituents
incorporate carboalkoxy groups.
[0409] The compounds are prepared directly or indirectly from the
phosphonic acids 1.6. In one alternative, the phosphonic acid is
coupled with the hydroxyester 4.2, using the conditions described
previously in Schemes 1-3, such as coupling reactions using
dicyclohexyl carbodiimide or similar reagents, or under the
conditions of the Mitsonobu reaction, to afford the diester product
4.3 in which the ester substituents are identical.
[0410] This method is illustrated in Scheme 4, Example 1. In this
procedure, the phosphonic acid 1.6 is reacted with three molar
equivalents of butyl lactate 4.5 in the presence of Aldrithiol-2
and triphenyl phosphine in pyridine at ca. 70.degree. C., to afford
the diester 4.6.
[0411] Using the above procedure, but employing, in place of butyl
lactate 4.5, different hydroxyesters 4.2, the corresponding
products 4.3 are obtained.
[0412] Alternatively, the diesters 4.3 are obtained by alkylation
of the phosphonic acid 1.6 with a haloester 4.1. The alkylation
reaction is performed as described in Scheme 3 for the preparation
of the esters 3.4.
[0413] This method is illustrated in Scheme 4, Example 2. In this
procedure, the phosphonic acid 1.6 is reacted with excess ethyl
3-bromo-2-methylpropionate 4.7 and diisopropylethylamine in
dimethylformamide at ca. 80.degree. C., as described in Anal.
Chem., 1987, 59, 1056, to produce the diester 4.8.
[0414] Using the above procedure, but employing, in place of ethyl
3-bromo-2-methylpropionate 4.7, different haloesters 4.1, the
corresponding products 4.3 are obtained.
[0415] The diesters 4.3 are also obtained by displacement reactions
of activated derivatives 1.7 of the phosphonic acid with the
hydroxyesters 4.2. The displacement reaction is performed in a
polar solvent in the presence of a suitable base, as described in
Scheme 3. The displacement reaction is performed in the presence of
an excess of the hydroxyester, to afford the diester product 4.3 in
which the ester substituents are identical, or sequentially with
limited amounts of different hydroxyesters, to prepare diesters 4.3
in which the ester substituents are different.
[0416] The methods are illustrated in Scheme 4, Examples 3 and 4.
As shown in Example 3, the phosphoryl dichloride 2.22 is reacted
with three molar equivalents of ethyl
3-hydroxy-2-(hydroxymethyl)propionate 4.9 in tetrahydrofuran
containing potassium carbonate, to obtain the diester product
4.10.
[0417] Using the above procedure, but employing, in place of ethyl
3-hydroxy-2-(hydroxymethyl)propionate 4.9, different hydroxyesters
4.2, the corresponding products 4.3 are obtained.
[0418] Scheme 4, Example 4 depicts the displacement reaction
between equimolar amounts of the phosphoryl dichloride 2.22 and
ethyl 2-methyl-3-hydroxypropionate 4.11, to yield the monoester
product 4.12. The reaction is conducted in acetonitrile at
70.degree. C. in the presence of diisopropylethylamine. The product
4.12 is then reacted, under the same conditions, with one molar
equivalent of ethyl lactate 4.13, to give the diester product
4.14.
[0419] Using the above procedures, but employing, in place of ethyl
2-methyl-3-hydroxypropionate 4.11 and ethyl lactate 4.13,
sequential reactions with different hydroxyesters 4.2, the
corresponding products 4.3 are obtained.
##STR00160## ##STR00161##
[0420] 2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can
be prepared by the route in Scheme 5. Condensation of
2-methyl-2-propanesulfinamide with acetone give sulfinyl imine 11
(J. Org. Chem. 1999, 64, 12). Addition of dimethyl
methylphosphonate lithium to 11 afford 12. Acidic methanolysis of
12 provide amine 13. Protection of amine with Cbz group and removal
of methyl groups yield phosphonic acid 14, which can be converted
to desired 15 (Scheme 5a) using methods reported earlier on. An
alternative synthesis of compound 14 is also shown in Scheme 5b.
Commercially available 2-amino-2-methyl-1-propanol is converted to
aziridines 16 according to literature methods (J. Org. Chem. 1992,
57, 5813; Syn. Lett. 1997, 8, 893). Aziridine opening with
phosphite give 17 (Tetrahedron Lett. 1980, 21, 1623). Reprotection)
of 17 affords 14.
##STR00162##
Biological Activity of HIV-Integrase Inhibitor Compounds
[0421] Representative compounds of the invention were tested for
biological activity by methods including anti-HIV assay, measuring
inhibition of HIV-integrase strand transfer catalysis, and
cytotoxicity. See: Wolfe, et al J. Virol. (1996) 70:1424-143 2;
Hazuda, et al Nucleic Acids Res. (1994) 22:1121-22; Hazuda, et al
J. Virol. (1997) 71:7005-7011; Hazuda, et al Drug Design and
Discovery (1997) 15.17-24; and Hazuda, et al Science (2000)
287:646-650. The antiviral activity of a compound of the invention
can be determined using pharmacological models which are well known
in the art. While many of the compounds of the present invention
demonstrate inhibition of integration of HIV reverse-transcribed
DNA, there may be other mechanisms of action whereby HIV
replication or proliferation is affected. The compounds of the
invention may be active via inhibition of HIV-integrase or other
enzymes associated with HIV infection, AIDS, or ARC. Furthermore,
the compounds of the invention may have significant activity
against other viral diseases. Thus, the specific assays embodied in
Examples x-y are not meant to limit the present invention to a
specific mechanism of action.
Pharmaceutical Formulations and Routes of Administration
[0422] The compounds of the invention may be formulated with
conventional carriers and excipients, which will be selected in
accord with ordinary practice. Tablets will contain excipients,
glidants, fillers, binders and the like. Aqueous formulations are
prepared in sterile form, and when intended for delivery by other
than oral administration generally will be isotonic. Formulations
optionally contain excipients such as those set forth in the
"Handbook of Pharmaceutical Excipients" (1986) and include ascorbic
acid and other antioxidants, chelating agents such as EDTA,
carbohydrates such as dextrin, hydroxyalkylcellulose,
hydroxyalkylmethylcellulose, stearic acid and the like.
[0423] Compounds of the invention and their physiologically
acceptable salts (hereafter collectively referred to as the active
ingredients) may be administered by any route appropriate to the
condition to be treated, suitable routes including oral, rectal,
nasal, topical (including ocular, buccal and sublingual), vaginal
and parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural). The preferred route of
administration may vary with for example the condition of the
recipient.
[0424] While it is possible for the active ingredients to be
administered alone it is preferably to present them as
pharmaceutical formulations. The formulations, both for veterinary
and for human use, of the present invention comprise at least one
active ingredient, as above defined, together with one or more
pharmaceutically acceptable carriers therefor and optionally other.
therapeutic ingredients. The carrier(s) must be "acceptable" in the
sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
[0425] The formulations include those suitable for oral, rectal,
nasal, topical (including buccal and sublingual), vaginal or
parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural) administration. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0426] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient, as a powder or granules; as solution or a
suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0427] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent. The tablets may optionally
be coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredient therein.
[0428] For infections of the eye or other external tissues e.g.
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and
most preferably 0.5 to 10% w/w. When formulated in an ointment, the
active ingredients may be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredients
may be formulated in a cream with an oil-in-water cream base.
[0429] If desired, the aqueous phase of the cream base may include,
for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs.
[0430] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0431] Emulgents and emulsion stabilizers suitable for use in the
formulation of the present invention include Tween.TM. 60, Span.TM.
80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl
mono-stearate and sodium lauryl sulfate.
[0432] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0433] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10% particularly about 1.5% w/w.
[0434] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0435] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0436] Formulations suitable for nasal administration wherein the
carrier is a solid include a coarse powder having a particle size
for example in the range 20 to 500 microns (including particle
sizes in a range between 20 and 500 microns in increments of 5
microns such as 30 microns, 35 microns, etc), which is administered
in the manner in which snuff is taken, i.e. by rapid inhalation
through the nasal passage from a container of the powder held close
up to the nose. Suitable formulations wherein the carrier is a
liquid, for administration as for example a nasal spray or as nasal
drops, include aqueous or oily solutions of the active ingredient.
Formulations suitable for aerosol administration may be prepared
according to conventional methods and may be delivered with other
therapeutic agents such as pentamidine for treatment of
pneumocystis pneumonia.
[0437] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0438] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents. The
formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of an active ingredient.
[0439] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0440] The present invention further provides veterinary
compositions comprising at least one active ingredient as above
defined together with a veterinary carrier therefor. Veterinary
carriers are materials useful for the purpose of administering the
composition and may he solid, liquid or gaseous materials which are
otherwise inert or acceptable in the veterinary art and are
compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally or by any
other desired route.
[0441] Compounds of the invention can be used to provide controlled
release pharmaceutical formulations containing as active ingredient
one or more compounds of the invention ("controlled release
formulations") in which the release of the active ingredient can be
controlled and regulated to allow less frequency dosing or to
improve the pharmacokinetic or toxicity profile of a given
invention compound. Controlled release formulations adapted for
oral administration in which discrete units comprising one or more
compounds of the invention can be prepared according to
conventional methods. Controlled release formulations may be
employed for the treatment or prophylaxis of various microbial
infections particularly human bacterial, human parasitic protozoan
or human viral infections caused by microbial species including
Plasmodium, Pneumocystis, herpes viruses (CMV, HSV 1, HSV 2, VZV,
and the like), retroviruses, adenoviruses and the like. The
controlled release formulations can be used to treat HIV infections
and related conditions such as tuberculosis, malaria, pneumocystis
pneumonia, CMV retinitis, AIDS, AIDS-related complex (ARC) and
progressive generalized lymphadeopathy (PGL), and AIDS-related
neurological conditions such as multiple sclerosis, and tropical
spastic paraparesis. Other human retroviral infections that may be
treated with the controlled release formulations according to the
invention include Human T-cell Lymphotropic virus (HTLV)-I and IV
and HIV-2 infections. The invention accordingly provides
pharmaceutical formulations for use in the treatment or prophylaxis
of the above-mentioned human or veterinary conditions and microbial
infections.
Combination Therapy
[0442] The compounds of the invention may be employed in
combination with other therapeutic agents for the treatment or
prophylaxis of the infections or conditions indicated above.
Examples of such further therapeutic agents include agents that are
effective for the treatment or prophylaxis of viral, parasitic or
bacterial infections or associated conditions or for treatment of
tumors or related conditions include 3'-azido-3'-deoxythymidine
(zidovudine, AZT), 2'-deoxy-3'-thiacytidine (3TC),
2',3'-dideoxy-2',3'-didehydroadenosine (D4A),
2',3'-dideoxy-2',3'-didehydrothymidine (D4T), carbovir (carbocyclic
2',3'-dideoxy-2',3'-didehydroguanosine),
3'-azido-2',3'-dideoxyuridine, 5-fluorothymidine,
(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU),
2-chlorodeoxyadenosine, 2-deoxycoformycin, 5-fluorouracil,
5-fluorouridine, 5-fluoro-2'-deoxyuridine,
5-trifluoromethyl-2'-deoxyuridine, 6-azauridine, 5-fluoroorotic
acid, methotrexate, triacetyluridine,
1-(2'-deoxy-2'-fluoro-1-.beta.-arabinosyl)-5-iodocytidine (FIAC))
tetrahydro-imidazo(4,5,1-jk)-(1,4)-benzodiazepin-2(1H)-thione
(TIBO), 2'-nor-cyclicGMP, 6-methoxypurine arabinoside (ara-M),
6-methoxypurine arabinoside 2'-O-valerate, cytosine arabinoside
(ara-C), 2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine
(ddC), 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI),
acyclic nucleosides such as acyclovir, penciclovir, famciclovir,
ganciclovir, HPMPC, PMEA, PMEG, PMPA, PMPDAP, FPMPA, HPMPA,
HPMPDAP,
(2R,5R)-9.fwdarw.tetrahydro-5-(phosphonomethoxy)-2-furanyladenine,
(2R,5R)-1.fwdarw.tetrahydro-5-(phosphonomethoxy)-2-furanylthymine,
other antivirals including ribavirin (adenine arabinoside),
2-thio-6-azauridine, tubercidin, aurintricarboxylic acid,
3-deazaneoplanocin, neoplanocin, rimantidine, adamantine, and
foscarnet (trisodium phosphonoformate), antibacterial agents
including bactericidal fluoroquinolones (ciprofloxacin, pefloxacin
and the like), aminoglycoside bactericidal antibiotics
(streptomycin, gentamicin, amicacin and the like) .beta.-lactamase
inhibitors (cephalosporins, penicillins and the like), other
antibacterials including tetracycline, isoniazid, rifampin,
cefoperazone, claithromycin and azithromycin, antiparasite or
antifungal agents including pentamidine
(1,5-bis(4'-aminophenoxy)pentane), 9-deaza-inosine,
sulfamethoxazole, sulfadiazine, quinapyramine, quinine,
fluconazole, ketoconazole, itraconazole, Amphotericin B,
5-fluorocytosine, clotrimazole, hexadecylphosphocholine and
nystatin, renal excretion inhibitors such as probenicid, nucleoside
transport inhibitors such as dipyridamole, dilazep and
nitrobenzylthioinosine, immunomodulators such as FK506, cyclosporin
A, thymosin .alpha.-1, cytokines including TNF and TGF-.beta.,
interferons including IFN-.alpha., IFN-.beta., and IFN-.gamma.,
interleukins including various interleukins, macrophage/granulocyte
colony stimulating factors including GM-CSF, G-CSF, M-CSF, cytokine
antagonists including anti-TNF antibodies, anti-interleukin
antibodies, soluble interleukin receptors, protein kinase C
inhibitors and the like.
EXAMPLES
Example 1
N-4-fluorobenzyl-succinimide 1
##STR00163##
[0444] Freshly ground potassium carbonate, K.sub.2CO.sub.3 (31 g,
225 mmol) was added to dry acetone (200 ml) in a 3-necked flask
equipped with drying tube, condenser, and mechanical stirrer.
Succinimide (7.43 g, 75 mmol) and 4-fluorobenzylbromide (11.21 mL,
90 mmol) were added. The mixture was refluxed for 19 hours and
filtered through Celite. Acetone was removed under vacuum, diluted
with EtOAc, washed with saturated aqueous sodium bicarbonate and
also with brine, dried (MgSO.sub.4), filtered and concentrated to
give crude. Crude product was chromatographed (EtOAc/Hexane) on
silica gel to give N-4-fluorobenzyl-succinimide 1 as white solid
(13.22 g, 85%). .sup.1H NMR (CDCl.sub.3) .delta. 7.4 (dd, 2H), 7.0
(t, 2H), 4.6 (s, 1H), 2.7 (s, 4 H).
Example 2
5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 2
##STR00164##
[0446] N-4-fluorobenzyl-succinimide 1 (8 g, 38.6 mmol) and
2,3-pyridine carboxylic acid dimethyl ester (7.9 g, 40.6 mmol) were
dissolved in dry tetrahydrofuran (THF, 78 mL) and dry methanol
(MeOH, 1.17 mL) in a 3-necked flask with mechanical stirrer and
condenser. Sodium hydride (NaH, 60% in mineral oil, 3.4 g, 85 mmol)
was added slowly in four portions. The mixture was stirred until
bubbling ceased, then refluxed for 24 hours. HCl (30 mL 6 M) was
then added to the mixture while in an ice bath, with stirring for
15 minutes. Diethylether (100 mL) was added. The precipitate was
filtered, washed with diethylether and H.sub.2O, and dried under
vacuum at 100.degree. C. Crude product was then recrystallized from
1 L refluxing dioxane and dried under vacuum at 100.degree. C. to
give solid
5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 2 (8.6
g, 66%). .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.05 (d, 1H),
8.75 (d, 1H), 7.79 (dd, 1 H), 7.37 (dd, 2 H), 7.17 (t, 2H), 4.73
(s, 2 H). mp: 281.9-284.0.
Example 3
5-O-Propanoate,
8-hydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 3
##STR00165##
[0448] 5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline
2 is acylated with propanoyl chloride to give 5-O-propanoate,
8-hydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 3.
Example 4
Carbonic acid ethyl ester
7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quin-
olin-5-yl ester 4
##STR00166##
[0450] 5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline
(300 mg, 0.887 mmol) 2 was suspended in 1,4 dioxane (5 mL) and
water (20 mL). An aqueous solution of NaOH (0.567 M, 3.1 mL) was
added slowly to form red solution which was then cooled in an
ice-water bath. Ethyl chloroformate (0.093 mL, 0.975 mmol) was
added and the mixture was stirred at room temperature for 30
minutes. Dichloromethane and 1N aqueous HCl were added to the
mixture in a separate. The aqueous layer was extracted with
dichloromethane two more times. The combined organic solution was
washed with brine, dried (MgSO4) and concentrated. The crude
product was crystallized from EtOAc to give carbonic acid ethyl
ester
7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quin-
olin-5-yl ester 4 (136 mg, 37%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (d, 1H), 8.5 (d, 1H), 7.7 (dd, 1H), 7.5
(t, 2H), 7.4 (t, 2 H), 7.0 (t, 2 H), 4.8 (s, 2H), 4.5 (q, 2 H), 1.5
(t, 3H); MS: 409 (M-1)
Example 5
Carbonic acid ethyl ester
7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinolin-5-yl ester 5
##STR00167##
[0452] Carbonate (23.6 mg, 0.08 mmol) 4 was dissolved in
acetonitrile (2 mL). Chloromethyl methyl ether (0.03 mL, 0.17 mmol)
and Cs.sub.2CO.sub.3 (74 mg, 0.23 mmol) were added consecutively.
The mixture was stirred at room temperature for 30 minutes when
most of the starting material was consumed as indicated by TLC.
Dichloromethane was added and the solution was washed with 1N HCl
and brine, dried (MgSO.sub.4) and concentrated. The crude product
was chromatographed on silica gel column, eluting with
EtOAc/hexanes to give the product, carbonic acid ethyl ester
7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinolin-5-yl ester 5 as a white solid (18 mg, 70%). .sup.1H NMR
(CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.5 (dd, 1H), 7.7 (dd, 1H), 7.4
(dd, 2H), 7.0 (t, 2H), 5.9 (s, 2H), 4.8 (s, 2H), 4.5 (q, 2H), 3.7
(s, 1H), 1.5 (t, 3H).
Example 6
7-(4-Fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-
-dione 6
##STR00168##
[0454] To the ethyl carbonate methoxymethyl ether 5 (70.9 mg, 0.156
mmol) in THF (7.6 mL) at room temperature was added a solution (5
mL) of K.sub.2CO.sub.3 (215 mg, 1.56 mmol) in water and
4-dimethylaminopyridine (3.8 mg, 0.03 mmol). The yellow solution
was stirred at room temperature under nitrogen atmosphere
overnight. Most of THF was removed under reduced pressure at
30-40.degree. C. and the remaining solution was diluted with
dichloromethane, washed with 1N HCl and brine, dried (MgSO.sub.4)
and concentrated to give solid crude product (51 mg, 85%), which is
triturated in diethylether/hexane to afford the product,
7-(4-fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,-
8-dione 6 as a yellow solid (34 mg). .sup.1H NMR (CDCl.sub.3)
.delta. 9.1 (dd, 1H), 8.7 (dd, 1H), 7.6 (dd, 1H), 7,4 (dd, 2H), 7.0
(t, 2H), 5.8 (s, 2H), 4.8 (s, 2H), 3.7 (s, 1H). MS: 383 (M+1); 381
(M-1).
Example 7
Trifluoro-methanesulfonic acid
7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinolin-5-yl ester 7
##STR00169##
[0456] To the methoxymethyl ether 6 (13.7 mg, 0.036 mmol) in
dichloromethane (1 mL) at -78.degree. C. were added
N,N-diisopropylethylamine (0.019 mL, 0.1 mmol) and
trifluoromethanesulfonic anhydride (0.012 mL, 0.054 mmol)
successively. The solution was stirred at the same temperature for
30 minutes and diluted with dichloromethane, washed with water and
brine, dried (MgSO.sub.4) and concentrated. The mixture was
chromatographed on a silica gel column, eluting with EtOAc/hexanes
to afford the product, trifluoro-methanesulfonic acid
7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinolin-5-yl ester 7 (6 mg, 33%). .sup.1H NMR (CDCl.sub.3)
.delta. 9.1 (dd, 1H), 8.5 (dd, 1H), 7.8 (dd, 1H), 7.5 (dd, 2H), 7.0
(t, 2H), 5.9 (s, 2H), 4.9 (s, 2H), 3.7 (s, 1H). .sup.19F NMR
(CDCl.sub.3) .delta. -72.8.
[0457] The reaction was repeated, where monophenol 6 (0.0444 g,
0.116 mmol) was dissolved in 2 mL dry dichloromethane. To this was
added diisopropylethylamine (0.06 mL, 0.348 mmol.) After cooling to
-78.degree. C., triflic anhydride was added (0.029 mL, 0.342 mmol)
and was stirred at this temperature for thirty minutes. Reaction
was then complete by TLC, diluted with dichloromethane, washed with
1M HCl, saturated NaHCO.sub.3 solution, dried (MgSO.sub.4) and
organics concentrated to give product, trifluoro-methanesulfonic
acid
7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinolin-5-yl ester 7 (0.06 g, 0.116 mmol, 100%) which was used
as crude for the next reaction. .sup.1H NMR (CDCl.sub.3) .delta.
9.15 (dd, 1H), 8.46 (d, 1H), 7.47 (dd, 1H), 7.01 (t, 2H), 5.92 (s,
2H), 4.87 (s, 2H.), 3.67 (s, 3H); MS: 537 (M+Na).
Example 8
7-(4-Fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-
-dione 8
##STR00170##
[0459] Methoxymethyl ether 6 (0.02 g, 0.052 mmol) was dissolved in
2 mL dry dichloromethane at 0.degree. C. An excess of a
diazomethane solution in diethylether was added. After about 20
minutes, all starting 6 was consumed. The mixture was concentrated
in vacuo to give crude
7-(4-fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,-
8-dione 8 (0.0223 g, 0.0527 mmol). .sup.1H NMR (CDCl.sub.3) .delta.
9.1 (dd, 1H), 8.7 (dd, 1H), 7.6 (dd, 1H), 7.5 (t, 2H), 7.0 (t, 2H),
5.8 (s, 2 H), 4.8 (s, 2 H), 4.4 (s, 3H), 3.7 (s, 3H). MS: 397
(M+1); 419 (M+23).
Example 9
7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione
9
##STR00171##
[0461] Crude diether 8 (0.0223 g, 0.0527 mmol) was dissolved in 1
mL dichloromethane. Ten equivalents of tuifluoroacetic acid was
added. The mixture was stirred at room temperature for 45 minutes.
The reaction mixture was concentrated and azeotroped with toluene
(2.times.) to give crude
7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-
-dione 9 which was triturated with 8 mL of 1:1 diethylether/hexane
and filtered to give 9 (0.0161 g, 0.0456 mmol, 83% for two steps).
.sup.1H NMR (CDCl.sub.3) .delta. 9.0 (br s, 1 H), 8.7 (d, 1 H), 7.7
(d, 1 H), 7.5 (m, 2 H), 7.0 (t, 2 H), 4.8 (s, 2H), 4.4 (s, 3H). MS:
353 (M+1).
Example 10
5-Allyloxy-7-(4-fluoro-benzyl)-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,-
8-dione 10
##STR00172##
[0463] Methoxymethyl ether 6 (0.0172 g, 0.045 mmol) was dissolved
in 1.5 mL dry dimethylformamide (DMF). Ground
K.sub.2CO.sub.3(0.0186 g, 0.135 mmol) was added, followed by allyl
bromide (0.0077 mL, 0.09 mmol). The mixture was stirred at room
temperature overnight, then diluted with 100 mL of ethylacetate,
washed with saturated NH.sub.4Cl solution, dried (MgSO.sub.4), and
concentrated to give crude 10. The crude product 10 was
chromatographed on silica gel, elating with ethylacetate and
hexanes to give white solid allyl, methoxymethyl diether 10:
(0.0063 g, 33%). .sup.1H NMR (CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.8
(dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.8
(s, 2H), 5.5 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS:
423 (M+1); 445 (M+23).
Example 11
5-Allyloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoline-6,8-dione
11
##STR00173##
[0465]
5-Allyloxy-7-(4-fluoro-benzyl)-9-methoxymethoxy-pyrrolo[3,4-g]quino-
line-6,8-dione 10 was dissolved in 1 mL dichloromethane. Ten
equivalents of trifluoroacetic acid was added and the mixture was
stirred at room temperature. After one hour another 10 equivalents
of trifluoroacetic acid was added. The mixture was then stirred
overnight, concentrated in vacuo, and azeotroped with toluene
(2.times.), to give crude 11 which was triturated with 2 mL of 1:1
diethylether/hexane two times to give allyl ether 11 (0.0025 g,
0.0066 mmol, 44%). .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (s, 1H),
8.7 (d, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.0 (t, 2H), 6.1 (m, 1H),
5.4 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 379
(M+1).
Example 12
7-(4-Fluoro-benzyl)-5-hydroxy-9-triisopropylsilanyloxy-pyrrolo[3,4-g]quino-
line-6,8-dione 12
##STR00174##
[0467] A solution of
7-(4-fluoro-benzyl)-5,9-dihydroxy-pyrrolo[3.4-g]quinoline-6,8-dione
2 (1.039 g, 3.07 mmol) in 31 mL of DMF was stirred with imidazole
(314 mg, 4.62 mmol) and triisopropylsilylchloride (TIPSCl, 0.723
mL, 3.38 mmol) under a N.sub.2 atmosphere for 1.5 days when most of
the starting materials was converted to the regiospecific mono TIPS
(triisopropylsilyl) protected compound. The solid bisphenol left in
the reaction was filtered and recycled. The mother liquor was dried
and the residue was suspended in EtOAc. The organic layer was
washed with water and dried. The resulted solid 12 was carried to
the next step. EI MS (m/z) 495.6 [MH.sup.+], 517.4 [M+Na].
Example 13
7-(4-Fluoro-benzyl)-5-methoxy-9-triisopropylsilanyloxy-pyrrolo[3,4-g]quino-
line-6,8-dione 13
[0468] A mixture of 12 from the monosilylation reaction was heated
at 40.degree. C. in anhydrous acetonitrile with K.sub.2CO.sub.3
(1.64 g, 11.8 mmol) and methyl iodide (4.2 g, 29.6 mmol) for 5
hours. The reaction mixture was worked up by addition of H.sub.2O
and EtOAc. The organic layer was washed with H.sub.2O and the
solvent was removed in vacuo. The residue was purified by column
chromatography using a gradient of 10% EtOAc-Hex to elute the
product 13 as a yellow solid (72% for two steps). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 1.13 (d, 18H, J=8 Hz), 1.53 (septet, 3H,
J=7 Hz), 4.29 (s, 3H), 4.84 (s, 2H), 7.00 (t, 2H, J=8 Hz), 7.48
(dd, 2H, J=5, 8 Hz), 7.58 (dd, 1H, J=4, 8 Hz), 8.65 (dd, 1H, J=2, 8
Hz), 8.93 (dd, 1H, J=2, 4 Hz); EI MS (m/z) 509.7 [MH.sup.+], 531.4
[M+Na].
##STR00175##
Example 14
7-(4-Fluoro-benzyl)-6-hydroxy-5-methoxy-6-phenyl-9-triisopropylsilanyloxy--
6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 14
[0469] A mixture of 13 (36 mg, 0.071 mmol) in 0.35 mL of dry THF
was cooled to 0.degree. C. A 26 .mu.L aliquot of a 3 M solution of
phenyl magnesium bromide in ether (0.078 mmol) was added to the
mixture and the reaction was allowed to warm up to room
temperature. The reaction was worked up in 30 minutes when the
reaction was complete as indicated by TLC. The mixture was diluted
with EtOAc and washed with water. The product 14 was purified by
column chromatography using 20% EtOAc-Hex solvent system to provide
33 mg (80%) of the product as a solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.20 (s, 18H), 1.52-1.68 (m, 3H), 2.95 (s, 1H),
3.93 (s, 3H), 4.08 (d, 1H, J=15 Hz), 4.77 (d, 1H, J=15 Hz), 6.85
(t, 2H, J=9 Hz), 7.19-7.25 (m, 2H), 7.25-7.35 (m, 3H), 7.39-7.49
(m, 3H), 8.26 (d, 1H, J=8 Hz,), 8.84 (br d, 1H, J=4 Hz); .sup.19F
NMR (282.6 MHz, CDCl.sub.3) .delta. -76.2, 60.7; EI MS (m/z) 587.5
[MH.sup.+], 609.4 [M+Na].
Example 15
7-(4-Fluoro-benzyl)-6,9-dihydroxy-5-methoxy-6-phenyl-6,7-dihydro-pyrrolo[3-
,4-g]quinolin-8-one 15
[0470] A mixture of 14 (27 mg, 0.046 mmol) in THF (0.46 mL) and
tetrabutyl ammonium fluoride (50 .mu.L, 0.050 mmol) was stirred at
room temperature under a N.sub.2 atmosphere for 2 hours when
reaction was complete as demonstrated by LCMS analysis. The organic
solvent was removed in vacuo and the residue was suspended in
EtOAc. The organic layer was washed with water and dried. The solid
was washed with hexane and dried to provide 15 mg (76%) of the
product 15 as a light orange solid. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 3.54 (s, 3H), 4.36 (d, 1H, J=15 Hz), 4.48 (d,
1H, J=15 Hz), 6.84 (t, 2H, J=9Hz), 7.17-7.23 (m, 2H), 7.24-7.26 (m,
3H), 7.35-7.46 (m, 2H), 7.62 (dd, 1H, J=4, 9 Hz), 8.44 (d, 1H, J=9
Hz), 8.89 (d, 1H, J=3 Hz); .sup.19F NMR (282.6 MHz, CDCl.sub.3)
.delta. 58.5; EI MS (m/z) 431.2 [MH.sup.+], 453.2 [M+Na].
##STR00176##
Example 16
7-(4-Fluoro-benzyl)-6-hydroxy-5-methoxy-6-methyl-9-triisopropylsilanyloxy--
6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 16
[0471] Under a nitrogen atmosphere, a solution of 13 (90 mg, 0.18
mmol) was dissolved in 0.885 mL of dry THF. A solution of 3 M of
methylmagnesium bromide in ether (71 .mu.L, 0.213 mmol) was added.
The solution was allowed to stir at ambient temperature for 2 hours
when TLC indicated complete consumption of starting materials. The
reaction mixture was diluted with EtOAc and washed with water and
saturated aqueous NH.sub.4Cl. The organic layer was reduced in
vacuo to 1 mL and cooled to get the product 16 to crystallize from
the solvent (92 mg, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.16 (d, 18H, J=8 Hz), 1.55 (septet, 3H, J=8 Hz), 1.78 (s, 3H),
2.29 (s, 1H), 4.04 (s, 3H), 4.72 (ABqt, 2H, J=13 Hz), 6.99 (t, 2H,
J=9 Hz), 7.38 (dd, 2H, J=6, 9 Hz), 7.52 (dd, 1H, J=4, 9 Hz), 8.42
(dd, 1H, J=2, 8 Hz), 8.87 (dd, 1H, J=2, 4 Hz); .sup.19F NMR (282.6
MHz, CDCl.sub.3) .delta. 60.8.
Example 17
7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-6-methylene-6,7-dihydro-pyrrolo[3,-
4-g]quinolin-8-one 17
[0472] A solution of 16 (10 mg, 0.019 mmol) in 3 mL of
CH.sub.2Cl.sub.2 and TFA (30 .mu.L, 0.389 mmol) was aged for 18
hours. Analysis of the reaction demonstrated complete conversion of
starting materials to the product. The solvents were removed under
reduced pressure. The residue was dissolved in EtOAc and
precipitated with hexanes. The mother liquor was removed and the
solid residue was washed with hexanes and subsequently with
Et.sub.2O to yield the product 17 as a solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 3.97 (s, 3H), 4.99 (s, 2H), 5.04 (d, 1H, J=2
Hz), 5.63 (d, 1H, J=2 Hz), 6.90 (br s, 1H), 7.04 (t, 2H, J=8 Hz),
7.31 (dd, 2H, J=5, 8 Hz), 7.71 (dd, 1H, J=4, 8 Hz), 8.64 (dd, 1H,
J=2, 9 Hz), 9.11 (d, 1H, J=3 Hz); .sup.19F (282.6 MHz, CDCl.sub.3)
.delta. 62.1; EI MS (m/z) 351.5 [MH.sup.+], 383.3 [M+Na].
Example 18
7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-6-methyl-6,7-dihydro-pyrrolo[3,4-g-
]quinolin-8-one 18
[0473] To a solution of 16 (52 mg, 0.099 mmol) in 1.4 mL of dry
CH.sub.2Clunder a N.sub.2 atmosphere, was added BF.sub.3.OEt.sub.2
(49 .mu.L, 0.397 mmol) followed by triethylsilane (63 .mu.L, 0.397
mmol). The solution was allowed to stir at ambient temperature for
1 day when LCMS indicated a clean conversion of starting materials
to the desired product. The reaction was worked up by removing the
solvent and dissolving the residue in EtOAc. The organic layer was
washed with water and the solvent removed under reduced pressure.
The residue was dissolved in 1 mL of EtOAc and triturated by
addition of hexanes to provide the product 18. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 1.60 (d, 3H, J=7 Hz), 3.93 (s, 3H), 4.28
(d, 1H, J=15 Hz), 4.65 (q, 1H, J=7 Hz), 5.25 (d, 1H, J=15 Hz), 7.06
(t, 2H, J=8 Hz), 7.32 (dd, 2H, J=6, 8 Hz), 7.67 (dd, 1H, J=4, 8
Hz), 8.59 (br s, 1H), 8.61 (d, 1H, J=8 Hz), 9.11 (br s, 1H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 16.9, 42.8, 54.5, 61.9,
113.9, 115.7, 116.0, 122.7, 126.6, 129.8, 129.9, 130.8, 132.1,
133.1, 136.7, 142.4, 147.8, 148.3, 162.3 (d, J=245 Hz), 168.1;
.sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 62.5; EI MS (m/z)
353.5 [MH.sup.+], 385.4 [M+Na].
##STR00177##
Example 19
Isoxazole 19
[0474] The exocyclic olefin in 17 can be utilized toward a
cycloaddition reaction. Under a nitrogen atmosphere, a TIPS
protected analog 17a (17 mg, 0.033 mmol) was suspended in 0.17 mL
of dry CH.sub.2Cl.sub.2. To this solution was added
4-chlorophenylglyoxyl-O-hydroxamyl chloride (7.3 mg, 0.034 mmol)
and TEA (4.7 .mu.L, 0.034 mmol). The solution was stirred at room
temperature for 12 hours. The reaction was worked up by diluting
the solution with EtOAc and washing the organic layer with water.
The organic layer was removed under reduced pressure. The residue
was dissolved in EtOAc and diluted with hexanes. The solution was
filtered and the mother liquor was dried to provide 18 mg (100%) of
the product 19 as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.31 (d, 1H, J=19 Hz), 3.94 (s, 3H), 4.01 (d, 1H, J=19 Hz),
4.36 (d, 1H, J=16 Hz), 4.96 (d, 1H, J=15 Hz), 6.95 (t, 2H, J=9 Hz),
7.29 (dd, 2H, J=5, 9 Hz), 7.55 (d, 2H, J=9 Hz), 7.65 (dd, 1H, J=4,
8 Hz), 8.29 (d, 2H, J=9 Hz), 8.45 (dd, 1H, J=2, 9 Hz), 8.99 (dd,
1H, J=2, 4 Hz); .sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 62.8;
EI MS (m/z) 532.6 [MH.sup.+].
##STR00178##
Example 20
7-(4-Fluoro-benzyl)-6,9-dihydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quin-
olin-8-one 20
[0475] To a solution of 13 (0.699 g, 1.38 mmol) in 14 mL of a 1:1
solution of dry MeOH:CH.sub.2Cl.sub.2 under a N.sub.2 atmosphere
was added sodium borohydride (NaBH.sub.4, 156 mg, 4.13 mmol). The
reaction mixture was dried after 5 hours and the residue was loaded
onto a silica column. The product was eluted with a 10% EtOAc-Hex
to provide the product 20. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 1.10 (d, 9H, J=8 Hz), 1.16 (d, 9H, J=7 Hz), 1.52 (septet,
3H, J=8 Hz), 3.72 (d, 1H, J=11 Hz), 4.11 (s, 3H), 4.23 (d, 1H, J=15
Hz), 4.85 (d, 1H, J=15 Hz), 5.79 (d, 1H, J=11 Hz), 6.97 (t, 1H, J=9
Hz), 7.27 (dd, 2H, J=6.9 Hz), 7.43 (dd, 1H, J=4. 8 Hz), 8.43 (dd,
1H. J=2, 8 Hz), 8.81 (dd, 1H, J=2, 4 Hz); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 14.8. 18.2, 41.3, 61.6, 78.6, 115.3, 115.6,
116.6, 122.3, 126.0, 126.8, 130.1, 130.2, 131.1, 132.8, 143.1,
143.8, 148.3, 162.1 (d, J=244 Hz), 165.2; EI MS (m/z) 511.5
[MH.sup.+], 533.4 [M+Na].
Example 21
7-(4-Fluoro-benzyl)-6,9-dihydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quin-
olin-8-one 21
[0476] A solution of 20 (35 mg, 0.069 mmol) was stirred in 0.69 mL
of dry THF and 75 .mu.L of a 1 M solution of tetra-butylammonium
fluoride (THF, 0.075 mmol) under a N.sub.2 atmosphere for 2 hours
at ambient temperature. The solution was diluted with EtOAc and the
organic layer was washed with water The organic layer was removed
in vacuo to leave a yellow residue. The solid was washed with
hexanes and dried to give 27 mg (100%) of the product 21. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. 4.13 (s, 3H), 4.46 (d, 1H, J=15
Hz), 5.04 (d, 1H, J=15 Hz), 6.01 (s, 1H), 7.09 (t, 2H, J=9 Hz),
7.42-7.47 (m, 2H), 7.65 (dd, 1H, J=4, 9 Hz), 8.61 (d, 1H, J=8 Hz),
8.89 (d, 1H, J=3 Hz); .sup.13C NMR (75 MHz, CD.sub.3OD) .delta.
41.1, 79.3, 60.0, 111.6, 115.0, 115.4, 122.4, 125.1, 125.9, 129.6,
130.0, 131.5, 132.9, 139.5, 142.8, 148.8, 161.8 (d, J=245 Hz),
166.7; .sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 59.4; EI MS
(m/z) 355.4 [MH.sup.+].
Example 22
7-(4-Fluoro-benzyl)-9-hydroxy-5,6-dimethoxy-6,7-dihydro-pyrrolo[3,4-g]quin-
olin-8-one 22
[0477] A solution of 21 (6.7 mg, 0.019 mmol) in a 1:1 solution of
CH.sub.2Cl.sub.2:MeOH was stirred with TFA (3 .mu.L, 0.038 mmol) at
room temperature for 2 hours when complete conversion was observed
by LCMS. The solution was dried in vacuo and the residue was washed
with hexanes to yield 7 mg of the product 22. EI MS (m/z) 355.4
[MH.sup.+].
##STR00179##
Example 23
3-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,-
4-g]quinolin-6-ylsulfanyl]-propionic acid methyl ester 23
[0478] To a solution of 20 (215 mg, 0.422 mmol) in CH.sub.2Cl.sub.2
(4.2 mL) and TFA (98 .mu.L, 1.26 mmol) was added
methyl-3-mercaptopropionate (56 .mu.L, 0.506 mmol). The solution
was stirred at ambient temperature for 5 hours when LCMS analysis
indicated complete conversion of the starting materials to the
products. The solution was dried under reduced pressure and
azeotroped with CH.sub.2Cl.sub.2 three times to provide the product
23 as a yellow solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.30-2.38 (m, 4H), 3.63 (s, 3H), 4.04 (s, 3H), 4.42 (d, 1H, J=15
Hz), 5.33 (d, 1H, J=15 Hz), 5.49 (s, 1H), 7.05 (t, 2H, J=9 Hz),
7.38 (dd, 2H, J=5, 8 Hz), 7.59 (dd, 1H, J=4, 9 Hz), 8.53 (d, 1H,
J=8 Hz), 8.91-9.01 (m, 1H); .sup.19F NMR (282.6 MHz, CDCl.sub.3)
.delta. 62.6; EI MS (m/z) 457.3 [MH.sup.+], 479.2 [M-Na].
Example 24
3-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,-
4-g]quinolin-6-ylsulfanyl]-propionic acid 24
[0479] A solution of 23 (150 mg, 0.329 mmol) in 3.29 mL of a 1:2:3
solution of H.sub.2O:MeOH:THF was stirred with LiOH. H.sub.2O (69
mg, 1.65 mmol) for 1 hour when LCMS demonstrated complete
conversion of starting materials to product. The reaction mixture
was dried under reduced pressure and the residue was suspended in
water and the pH was adjusted to 11 with aqueous 1N NaOH solution.
The aqueous layer was washed with EtOAc twice. The pH of the
aqueous layer was then adjusted to 5 using 1N HCl and the product
was extracted with CH.sub.2Cl.sub.2 under continuous extraction
conditions. The organic layer was dried in vacuo to yield the
product 24 as an orange solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 2.1 (s, 1H), 2.25-2.45 (m, 4H), 4.04 (s, 3H), 4.43 (d, 1H,
J=15 Hz), 5.32 (dd, 1H, J=3, 14 Hz), 5.49 (s, 1H), 7.03 (t, 2H, J=9
Hz), 7.35 (dd, 2H, J=5, 8 Hz), 7.57 (dd, 1H, J=4, 8 Hz), 8.52 (dd,
1H, J=2, 8 Hz), 8.98 (dd, 1H, J=2, 5 H); .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 21.4, 33.6, 41.9, 61.8, 61.9, 112.3, 115.7,
116.0, 123.1, 125.0, 126.5, 130.4, 130.5, 131.8, 131.8, 139.3,
142.6, 148.3, 149.6, 162.4 (d, J=245 Hz), 167.2, 175.3; .sup.19F
NMR (282.6 MHz, CDCl.sub.3) .delta. 62.6; EI MS (m/z) 441.4
[M-H].sup.-, 883.1 [2M-2H].sup.-.
##STR00180##
Example 25
N,N-Diethyl-3-[7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6-
H-pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionamide 25
[0480] A solution of 24 (10.7 mg, 0.024 mmol) in CH.sub.2Cl.sub.2
(0.24 mL) was stirred with EDC (14 mg, 0.73 mmol) and diethyl amine
(10 .mu.L, 0.097 mmol) for 1 day at ambient temperature. The
product 25 was purified by reverse phase HPLC using 5-95% A. Buffer
A contained CH.sub.3CN-- 1% HOAc and B contained H.sub.2O-- 1%
HOAc. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.984 (t, 3H, J=6
Hz), 1.05 (t, 3H, J=7 Hz), 2.23-2.45 (m, 4H), 3.04 (q, 2H, J=7 Hz),
3.29 (q, 2H, J=8 Hz), 4.06 (s, 3H), 4.47 (d, 1H, J=14 Hz), 5.31 (d,
1H, J=15 Hz), 5.50 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.36-7.44 (m,
2H), 7.55-7.62 (m, 1H), 8.53 (d, 1H, J=9 Hz), 8.95-9.00 (m, 1H); EI
MS (m/z) 520.2 [MH.sup.+], 1016.9 [2M+Na].
Example 26
({3-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[-
3,4-g]quinolin-6-ylsulfanyl]-propionylamino}-methyl)-phosphonic
acid diethyl ester 26
[0481] To a solution of 24 (15 mg, 0.035 mmol) in 0.35 mL of
CH.sub.2Cl.sub.2 (0.35 mL) was added
diethyl(aminomethyl)phosphonate oxalate (27 mg, 0.105 mmol), EDC
(20 mg, 0.105 mmol) and TEA (15 .mu.L, 0.105 mmol). The solution
was stirred at room temperature for 1 day when the same amount of
the aminomethyl phosphonate, EDC and TEA were added. The reaction
was stirred for another day when complete conversion of starting
materials to the desired product was observed by LCMS. The product
26 was purified by reverse phase HPLC using 5-95% A. Buffer A
contained CH.sub.3CN-- 1% HOAc and buffer B was H.sub.2O-- 1% HOAc.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.33-1.40 (m, 6H),
2.37-2.45 (m, 4H), 3.60-3.72 (m, 2H), 4.05 (s, 3H), 4.06-4.18 (m,
4H), 4.44 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=14 Hz), 5.49 (s, 1H),
6.17 (br s, 1H), 6.98-7.08 (m, 2H), 7.33-7.43 (m, 2H), 7.55-7.63
(m, 1H), 8.50-8.57 (br d, 1H), 8.97 (br s, 1H); .sup.31P (121.4
MHz, CDCl.sub.3) .delta. 22.7; .sup.19F NMR (282.6 MHz, CDCl.sub.3)
.delta. 62.6; EI MS (m/z) 590.4 [M-H].sup.-, 614.2 [M+Na].
##STR00181##
Example 27
(tert-Butoxycarbonyl-carboxymethyl-amino)-acetic acid 27
[0482] A mixture of iminodiacetic acid (5.1 g, 38.3 mmol) and
sodium hydrogen carbonate (NaHCO.sub.3, 12.9 g, 153 mmol) were
dissolved in 50 mL of water. Once the bubbling subsided, 50 mL of
THF was added followed by 10.0 g (46.0 mmol) of BOC.sub.2O. The
mixture was stirred at ambient temperature for 2 days when starting
materials were completely consumed as detected by ESI. The reaction
was worked up by removing THF and washing the aqueous layer with
Et.sub.2O twice. The pH of the aqueous layer was then adjusted to 1
using conc. HCl. The product was extracted with EtOAc and solvent
removed in vacuo to provide the product as a white solid. The
product was purified by crystallization from EtOAc to give 8.04 g
(90%) of clear crystals of 27. ES MS [M-H].sup.- 232.1.
Example 28
4-(4-Fluoro-benzyl)-3,5-dioxo-piperazine-1-carboxylic acid
tert-butyl ester 28
[0483] A solution of 27 (547 mg, 2.35 mmol) and carbonyl
diimidazole (837 mg, 5.16 mmol) in 4.7 mL of dry THF under a
N.sub.2 atmosphere was refluxed for 5 minutes. Once the reaction
cooled down to room temperature 4-fluorobenzyl amine (0.295 mL,
2.58 mmol) was added and the mixture was heated to reflux
overnight. The reaction mixture was then concentrated and
re-dissolved in EtOAc. The organic layer was washed with an aqueous
0.5 N HCl solution and the solvent was removed in vacuo. The
product was purified by column chromatography eluting with
CH.sub.2Cl.sub.2 to provide clean product 28 as a clear oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.47 (s, 9H), 4.39 (s,
4H), 4.92 (s, 2H), 6.99 (t, 2H, J=9 Hz), 7.40 (dd, 2H, J=5, 9 Hz);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 28.1, 42.0, 47.1, 82.3,
115.2, 115.5, 131.1, 131.2, 132.0, 153.0, 162.7 (d, J=245 Hz),
168.0; .sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 62.5; EI MS
(m/z) 340.5 [M+Na].
Example 29
4-(4-Fluoro-benzyl)-3,5-dioxo-piperazin-1-ium; Trifluoro-Acetate
29
[0484] A solution of 28 (26 mg, 0.080 mmol) in 2 mL of
CH.sub.2Cl.sub.2 was stirred with 1 mL of TFA for 1.5 hours when
TLC indicated complete conversion to the product. The solution was
dried in vacuo to yield a white solid. The product was purified by
crystallization using CH.sub.2Cl.sub.2. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 4.18 (s, 4H), 4.95 (s, 2H), 5.01 (s, 2H), 7.01
(dt, 2H, J=2, 9 Hz), 7.41 (ddd, 21, J=2, 5, 9 Hz); .sup.19F NMR
(282.6 MHz, CDCl.sub.3) .delta. -77.5, 60.0.
Example 30
Pyridine-2,3-dicarboxylic acid 2-isopropyl ester 30
[0485] A mixture of 2,3-pyridine carboxylic anhydride (100 g, 0.67
mol) in 500 mL of i-PrOH was heated at reflux for 1 day according
to the procedure of Ornstein, P. et. al. J. Med. Chem. (1989) 32,
4, 827. The reaction mixture was then dried in vacuo to provide the
product 30 as a white solid. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 1.37 (d, 6H, J=7 Hz), 5.27 (septet, 1H, J=6 Hz), 7.63 (dd,
1H, J=5, 8 Hz), 8.34 (dd, 1H, J=1, 8 Hz), 8.71 (d, 1H, J=5 Hz); EI
MS (m/z) 210.0 [MH.sup.+].
Example 31
3-4-(4-Fluoro-benzyl)-3,5-dioxo-piperazine-1-carbonyl]-pyridine-2-carboxyl-
ic acid isopropyl ester 31
[0486] A solution of 29 (54 mg, 0.16 mmol), 30 (34 mg, 0.16 mmol),
EDC (92 mg, 0.48 mmol), dimethylaminopyridine (20 mg, 0.16 mmol),
triethylamine (67 .mu.L, 0.48 mmol) in 1.6 mL of a 1:1 mixture of
CH.sub.2Cl.sub.2:DMF was stirred for 1 day at ambient temperature.
The reaction mixture was directly loaded onto a silica column and
the product was eluted with a gradient of 1:1 Hex-EtOAc to EtOAc
followed by 10% MeOH-EtOAc. The product 31 was obtained as a clear
oil. EI MS (m/z) 414.7 [MH.sup.+], 436.4 [M+Na].
Example 32
7-(4-Fluoro-benzyl)-9-hydroxy-1,7,10a-triaza-anthracene-6,8,10-trione
32
[0487] A solution of 31 (5 mg, 0.01 mmol) in 0.3 mL of dry 0.5 M
NaOMe was stirred at ambient temperature for 15 minutes when a
yellow precipitate formed. The solvent was removed in vacuo and the
solid was dissolved in a mixture of CH.sub.2Cl.sub.2-- 1N HCl. The
layers were separated and the aqueous layer was washed with
CH.sub.2Cl.sub.2. The organic solvent was removed to provide an
off-white solid. The product 32 was purified by trituration using
CH.sub.2Cl.sub.2 and hexane. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 5.01 (s, 2H), 5.16 (s, 2H), 7.02 (dt, 2H, J=2, 9 Hz), 7.51
(ddd, 2H, J=2, 5, 9 Hz), 7.79 (dd, 1H, J=8, 5 Hz), 8.61 (dd, 1H,
J=8, 2 Hz), 9.13 (dd, 1H, J=4, 2 Hz), 12.35 (s, 1H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 42.4, 46.1, 107.0, 115.5, 115.8,
126.7, 127.1, 130.8, 131.4, 131.5, 132.5, 143.2, 148.4, 153.7,
156.0, 162.2 (d, J=249 Hz), 163.9, 164.0; EI MS (m/z) 354.6
[MH.sup.+].
##STR00182##
Example 33
3-Oxo-piperazine-1-carboxylic acid tert-butyl ester 33
[0488] To a mixture of piperazine-2-one (1.037 g, 10.4 mmol) in 52
mL of CH.sub.2Cl.sub.2, was added BOC.sub.2O (2.5 g, 11.4 mmol).
The reaction became homogeneous after 3 hours when the starting
material was completely consumed. The reaction was diluted with
CH.sub.2Cl.sub.2 and the organic layer was washed with water The
solvent was removed in vacuo to yield quantitative amount of
product 33 as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 1.48 (s, 9H), 3.35-3.44 (m, 2H), 3.64 (t, 2H, J=5 Hz), 4.10
(s, 2H), 6.41 (br s, 1H).
Example 34
4-(4-Fluoro-benzyl)-3-oxo-piperazine-1-carboxylic acid tert-butyl
ester 34
[0489] To a heterogeneous solution of 33 (1.6 g, 8.1 mmol) in 16.2
mL of dry THF under a N.sub.2 atmosphere was added 0.211 g (8.80
mmol) of 95% NaH. Once the bubbling subsided, 4-fluorobenzylbromide
(1.2 mL, 9.7 mmol) was added dropwise to the solution. After 1
hour, when the reaction was complete as judged by TLC, the reaction
was quenched by addition of water and the organic layer was diluted
with EtOAc. The organic layer was washed with water and the solvent
removed in vacuo. The product was purified by column chromatography
using 1:1 EtOAc-Hex solvent system to provide 2.3 g (93%) of the
product 34 as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 1.47 (s, 9H), 3.24 (t, 2H, J=5 Hz), 3.60 (t, 2H, J=5 Hz),
4.16 (s, 2H), 4.59 (s, 2H), 7.03 (t, 2H, J=9 Hz), 7.26 (dd, 2H,
J=5.8 Hz); .sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 62.2.
Example 35
4-(4-Fluoro-benzyl)-3-oxo-piperazin-1-ium trifluoroacetate salt
35
[0490] A solution of 34 (1.4 g, 4.5 mmol) in 6 mL of a 1:1 solution
of CH.sub.2Cl.sub.2:TFA was stirred at ambient temperature for 2
hours when all of the starting materials were consumed as judged by
TLC. The reaction mixtures were dried in vacuo to yield 1.5 g of 35
as a thick oil which was used in the next reaction without
purification.
Example 36
3-[4-(4-Fluoro-benzyl)-3-oxo-piperazine-1-carbonyl]-pyridine-2-carboxylic
acid isopropyl ester 36
[0491] A solution of 35 (1.46 g, 4.55 mmol) was dissolved in 20 mL
of a 1:1 solution of CH.sub.2Cl.sub.2:DMF. To this solution was
added 0.95 g (4.55 mmol) of 30, EDC (1.74 g, 9.10 mmol) and
triethylamine (1.90 mL, 13.7 mmol). The solution was stirred at
room temperature for 4 hours when the reaction was complete. The
solution was diluted with CH.sub.2Cl.sub.2 and washed with water.
The organic layer was subsequently washed with aq. saturated
solution of NH.sub.4Cl and the solvent was removed. The yellow
residue was purified by column chromatography using EtOAc--10% MeOH
gradient to yield 1.8 g (100%) of the product 36 as a clear oil. EI
MS (m/z) 400.5 [MH.sup.+], 422.3 [M+Na].
Example 37
7-(4-Fluoro-benzyl)-9-hydroxy-6,7-dihydro-5H-1,7,10a-triaza-anthracene-8,1-
0-dione 37
[0492] To a solution of 36 (0.900 g, 2.26 mmol) in 12 mL of dry
MeOH under a N.sub.2 atmosphere was added 12.5 mL of a 0.5 M sodium
methoxide (NaOMe). The solution was stirred at ambient temperature
for 2.5 hours. The reaction was worked up by removing the solvent
and dissolving the residue in CH.sub.2Cl.sub.2. The organic layer
was washed with a saturated aqueous solution of NH.sub.4Cl and
dried to provide 610 mg of the product 37 as a yellow solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.58 (t, 2H, J=6 Hz),
4.308 (t, 2H, J=5 Hz), 4.77 (s, 2H), 7.09 (t, 2H, J=8 Hz), 7.34 (t,
2H, J=8 Hz), 7.61 (dd, 1H, J=5, 8 Hz), 8.73 (d, 1H, J=8 Hz), 9.12
(d, 1H, J=3 Hz), 13.00 (s, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 38.8, 43.9, 49.5, 111.9, 115.9, 116.2, 124.7, 130.0, 130.1,
131.0, 136.4, 146.8, 147.2, 154.7, 157.3, 163.0 (d, J=245 Hz),
163.7; .sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 63.2; EI MS
(m/z) 340.5 [MH.sup.+], 362.3 [M+Na].
##STR00183##
Example 38
Diphenyldiazomethane 38
[0493] Benzophenone hydrazone (25 g, 122.3 mmol) and sodium sulfate
(anhydrous) (26 g, 183.5 mmol) were suspended in ether (anhydrous,
400 mL). To this mixture, a potassium hydroxy (powder) saturated
ethanol solution (10 mL) was added, followed by mercury oxide (66.2
g, 305.8 mmol) to form a red solution. This solution was shaken at
room temperature for 1.5 hours. The solid was filtered off. The
filtrate was concentrated to a residue, which was redissolved in
200 mL of hexane and placed in a cold room overnight. The
solidified solution was evaporated to dryness, which gave
diphenyldiazomethane 38 as a red solid (24.7 g, 99.7%).
##STR00184##
Example 39
[0494] Mono carbonate 4 (8.9 g, 21.7 mmol) was dissolved in
1,2-dichloroethane (400 mL). Diphenyldiazomethane 38 (8.4 g, 43.4
mmol) was added in one portion. The mixture was stirred at
70.degree. C. for 3 hours. The reaction was monitored by TLC
(EtOAc/Hexane=3/7). After completion of the reaction, the solution
was cooled down to room temperature. The solvent was evaporated.
The crude product is chromatographed on a silica gel column,
eluting with EtOAc/hexane to give the product 39 as a white solid
(10.1 g, 80%). .sup.1H NMR (CDCl.sub.3): .delta. 9.1 (d, 1H), 8.4
(d, 1H), 8.0 (s, 1H), 7.6 (dd, 1H), 7.6 (d, 4H), 7.4 (dd, 2H),
7.2-7.3 (m, 6H), 7.0 (t, 2H), 4.8 (s, 2H), 4.4 (q, 2H), 1.4 (t,
3H). MS: 577 (M+23).
[0495] The reaction was repeated, where mono-carbonate 4 (2 g,
0.4878 mmol) was dissolved in 9 mL of dichloroethane. To this was
added diphenyldiazomethane (0.189 g, 0.9756 mmol) and stirred at
70.degree. C. for two hours. After starting material consumed,
concentrated off some solvent, and chromatographed (25%
ethylacetate/hexanes) to give product 39 (0.2653 g, 0.4598 mmol,
94%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.14 (d, 1H), 8.47 (d, 1H),
7.99 (s, 1H), 7.61 (m, 5H), 7.43 (dd, 2H), 7.27 (m, 6H), 7.02 (dd,
2H), 4.82 (s, 2H), 4.45 (q, 2H), 1.47 (t, 3H) MS: 577 (M+1)
##STR00185##
Example 40
[0496] A solution of K.sub.2CO.sub.3 (24.2 g, 175.2 mmol) in water
(120 mL) and 4-dimethylaminopyridine (4.24 g, 35.0 mmol) was added
to the ethyl carbonate 39 (10.1 g, 17.5 mmol) in THF (180 mL). The
mixture is stirred at room temperature under nitrogen atmosphere
overnight. Most of THF is removed under reduced pressure at
30-40.degree. C. and the remaining solution is diluted with
dichloromethane. To this, it is acidified with 1N HCl to pH about
4. The organic phase was separated and washed with brine, dried
(MgSO.sub.4) and concentrated to give a yellow solid crude product
40 (9.9 g, 100%). .sup.1H NMR (CDCl.sub.3): .delta. 9.1 (d, 1H),
8.6 (d, 1H), 8.4 (s, 1H, (OH)), 7.8 (s, 1H), 7.6 (dd, 1H), 7.6 (dd,
4H), 7.4 (d, 2H), 7.2-7.3 (m, 6H), 7.0 (t, 2H), 4.8 (s, 2H). LC/MS:
527 (M+23).
##STR00186##
Example 41
[0497] 2-(Trimethylsilyl) ethanol (2.4 mL, 16.7 mmol),
triphenylphosphine (3.5 g, 13.4 mmol) and diethyl azodicarboxylate
(92.1 mL, 13.4 mmol) was added to the phenol 40 (3.37 g, 6.7 mmol)
in anhydrous THF (70 mL). The solution was stirred at room
temperature for 3 hours under nitrogen. TLC indicated the
completion of the reaction. The solvent was evaporated and the
residue oil was purified by silica gel chromatography, eluting with
EtOAc/hexane to afford the product 41 (3.3 g, 82%). .sup.1H NMR
(CDCl.sub.3): .delta. 9.1 (d, 1H), 8.6 (d, 1H), 7.9 (s, 1H), 7.6
(dd, 1H), 7.6 (d, 4H), 7.4 (d, 2H), 7.2-7.3 (m, 6H), 7.0 (t, 2H),
4.8 (s, 2H), 4.6 (t, 2H), 1.2 (t, 2H). MS: 605 (M+1), 627
(M+23).
##STR00187##
Example 42
[0498] Compound 41 (3.3 g, 5.46 mmol) was dissolved in the mixture
of THF (40 mL), isopropanol (20 mL) and water (10 mL) and chilled
to 0.degree. C. in an ice-bath. To this was added lithium
borohydride (373.0 mg, 16.4 mmol) slowly. The mixture was stirred
at 0.degree. C. for 1 hour and at room temperature for 1 hour under
nitrogen. TLC indicated the completion of the reaction. A solution
of 1N HCl (30 mL) was added and the mixture was extracted twice
with CH.sub.2Cl.sub.2 (2.times.50 mL). The organic layer was washed
with saturated NaHCO.sub.3 and dried over Mg.sub.2SO.sub.4 and
evaporated to dryness to give 42 as an oil (3.3 g).
Example 43
[0499] Crude product 42 was dissolved in anhydrous dichloromethane
(50 mL). N-dimethylaminopyridine (66.7 mg, 0.546 mmol),
N,N-diisopropylethylamine (2.85 mL, 16.4 mmol) and acetic anhydride
(1.03 mL, 109 mmol) were added. The mixture was stirred at room
temperature under nitrogen overnight. TLC indicated the completion
of the reaction. The reaction was quenched with 1N HCl (30 mL) and
extracted with CH.sub.2Cl.sub.2 twice (2.times.50 mL). The organic
layer was washed with saturated NaHCO.sub.3, dried
(Mg.sub.2SO.sub.4) and concentrated to give crude product 43 (3.5
g).
Example 44
[0500] Crude product 43 was dissolved in anhydrous dichloromethane
(60 mL) under nitrogen. To this solution was added 2,6-lutidine
(3.2 mL, 23.7 mmol), triethylsilane (10 mL), then trimethylsilyl
triflate (1.5 mL, 8.2 mmol) slowly. The mixture was stirred at room
temperature for 3 hours. TLC indicated the completion of the
reaction. It was quenched with 1N HCl (30 mL) and extracted with
CH.sub.2Cl.sub.2 twice (2.times.50 mL). The organic layer was
washed with saturated NaHCO.sub.3, dried (Mg.sub.2SO.sub.4) and
concentrated. The residue was chromatographed on a silica gel
column, eluting with EtOAc/Hexane to afford 44 (1.4 g, 43.4% in 3
steps from 41). .sup.1H NMR (CDCl.sub.3): .delta. 9.0 (d, 1H), 8.4
(d, 1H), 8.0 (s, 1H), 7.7 (d, 4H), 7.4 (dd, 1H), 7.1-7.3 (m, 8H),
7.0 (t, 2H), 4.8 (s, 2H), 4.2 (s, 2H), 4.1 (t, 2H), 1.1 (t, 2H),
0.1 (s, 9H). MS: 591 (M+1).
##STR00188##
Example 45
[0501] To
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-trimethylsilanyl-ethoxy-
)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 44 (300.8 mg, 0.509
mmol) in anhydrous THF (20 mL), was added tetrabutylammonium
fluoride hydrate (500 mg, 1.02 mmol). The reaction mixture turned
to red and was stirred at room temperature under nitrogen for 1
hour. The reaction was monitored by TLC (EtOAc/Hexane=3/7). After
completion of the reaction, it was diluted with EtOAc (50 mL) and
washed with 1N HCl, saturated NaHCO.sub.3 and brine. The organic
layer was dried (MgSO.sub.4) and concentrated to give a crude
product 45 (280 mg).
[0502] The reaction was repeated whereby, to a solution of lactam
44 (0.026 g, 0.044 mmol) in THF (0.441 mL) was added triethylamine
(0.025 mL, 0.176 mmol) and tetrabutylammonium fluoride in 1M THF
(0.066 mL). The reaction mixture was stirred at room temperature
under an inert atmosphere for 30 minutes, monitored to completion
by MS. The mixture was diluted with dichloromethane, washed with
saturated NH.sub.4Cl, dried (MgSO.sub.4), and concentrated in
vacuo. The crude material 45 was taken forward immediately with no
further purification or characterization: MS: 491 (M+1).
[0503] Alternatively, to a solution of
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-trimethylsilanyl-ethoxy)-6,7-dih-
ydro-pyrrolo[3,4-g]quinolin-8-one 44 (30 mg, 0.051 mmol) dissolved
in THF (1 mL) was added tetrabutylammonium fluoride hydrate (1M in
THF, 150 .mu.L). The reaction mixture turned to red and was stirred
at room temperature for 1/2 hours under an inert atmosphere, which
generated
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-hydroxy-6,7-dihydro-pyrrolo[3,4-g]q-
uinolin-8-one 45. TLC was used to monitor the reaction.
Example 46
[0504] Crude compound 45 was dissolved in dichloromethane (20 mL).
To this was added cesium carbonate (200 mg, 0.611 mmol) and
N-phenyltrifluoromethane sulfonimide (220 mg, 0.611 mmol). The
mixture was stirred at room temperature under nitrogen for 16
hours. The reaction was monitored by TLC (EtOAc/Hexane=3/7). After
completion of the reaction, it was diluted with EtOAc (50 mL) and
washed with 1N HCl, saturated NaHCO.sub.3 and brine. The organic
layer was dried (MgSO.sub.4) and concentrated. The residue was
chromatographed on a silica gel column, eluting with EtOAc/Hexane
to afford the clean product 46 (135 mg, 42.6% in 2 steps). .sup.1H
NMR (CDCl.sub.3): .delta. 9.1 (d, 1H), 8.3 (d, 1H), 8.0 (s, 1H),
7.7 (d, 4H), 7.6 (dd, 1H), 7.2-7.4 (m, 8H), 7.1 (t, 2H), 4.8 (s,
2H), 4.4 (s, 2H), MS: 623 (M+1), 645(M+23).
##STR00189##
Example 47
[0505] To the triflate 46 (66.6 mg, 0.107 mmol) in toluene (2.8
mL)/ethanol (1.2 mL)/water (0.8 mL) was added potassium carbonate
(37 mg, 0.268 mmol), trans-phenylvinylboronic acid (24.5 mg, 0.160
mmol) and tetrakis(triphenylphosphine)-palladium (0) (18.5 mg,
0.016 mmol). The mixture in the flask was flushed with argon three
times and heated to 120.degree. C. under argon for 3 hours. The
mixture was cooled to room temperature, diluted with EtOAc and
washed with 1N HCl, saturated NaHCO.sub.3 and brine. The organic
phase was dried (MgSO.sub.4) and concentrated. The residue was
chromatographed on a silica gel column, eluting with EtOAc/Hexane
to afford the product 47 (51.4 mg, 83%). .sup.1H NMR (CDCl.sub.3):
.delta. 9.0 (d, 1H), 8.4 (d, 1H), 8.1 (s, 1H), 7.7 (d, 4H), 7.2-7.5
(m, 14H), 7.1 (d, 1H), 7.0 (dd, 2H), 6.8 (d, 1H), 4.8 (s, 2H),
4.4(s, 2H). MS: 577 (M+1), 599 (M+23).
##STR00190##
Example 48
[0506] The compound 47 (12 mg, 0.02 mmol) was dissolved in
dichloromethane (1 mL) at room temperature under nitrogen.
Triethylsilane (200 .mu.L) was added followed by TFA (100 .mu.L)
slowly. The mixture became smoke and dark. It was stirred at room
temperature for 30 min. The solvent was removed under reduced
pressure. The crude product was triturated in diethylether/hexane
to afford a yellow solid 48 (9 mg, 90%). .sup.1H NMR (CDCl.sub.3):
.delta. 9.0 (d, 1H), 8.6 (d, 1H), 7.5 (m, 3H), 7.2-7.4 (m, 6H), 7.1
(m, 2H), 6.8 (d, 1H), 4.8 (s, 2H), 4.5 (s, 2H). MS: 411 (M+1).
##STR00191##
Example 49
[0507] Compound 47 (405 mg, 0.7 mmol) in dichloromethane (150 mL)
was chilled to -78.degree. C. Ozone (O.sub.3) was passed slowly
into the solution over 30 min. TLC indicated the completion of the
reaction. Nitrogen was bubbled into the mixture for 10 min to expel
excess O.sub.3. Dimethyl sulfate (10 mL) was then added the mixture
at -78.degree. C. and the mixture was warmed to room temperature
slowly with stirring. After 16 hours, the mixture was evaporated to
dryness and the residue was purified by chromatography on a silica
gel column, eluting with methanol/dichloromethane to give product
of 49 (166.5 mg) and its hydrate form (122 mg), total yield of
80.8%. .sup.1H NMR (CDCl.sub.3): .delta. 10.7 (s, 1H, CHO), 9.1 (m,
2H), 8.4 (s, 1H), 7.7 (d, 4H), 7.6 (dd, 2H), 7.2-7.4 (m, 8H), 7.0
(t, 2H), 4.6 (s, 2H). MS: 503 (M+1), 525 (M+23).
##STR00192##
Example 50
[0508] The aldehyde 49 (23 g, 0.046 mmol) was dissolved in
anhydrous THE (1 mL) and MeOH (0.1 mL) at room temperature. To this
was added sodium borohydride (5.2 mg, 0.14 mmol) slowly. The
mixture was stirred at room temperature for 30 min under nitrogen.
TLC indicated the completion of the reaction. The mixture was
diluted with water (5 mL). The insoluble material was collected by
filtration and washed with hexane and air-dried to give product 50
(13.5 mg, 59%). .sup.1H NMR (CD.sub.3OD): .delta. 9.3 (d, 1H), 9.1
(4, 1H), 8.1 (dd, 1H), 8.0 (s, 1H), 7.5 (d, 4H), 7.4 (dd, 2H), 7.3
(m, 6H), 7.1 (t, 2H), 5.0 (s, 2H), 4.9 (s, 2H), 4.7 (s, 2H). MS:
505 (M+1), 527(M+23).
##STR00193##
Example 51
[0509] The aldehyde 49 (121 mg, 0.24 mmol) was dissolved in
anhydrous THF (5 mL) and MeOH (0.5 mL) at room temperature. To this
was added sodium borohydride (27 mg, 0.72 mmol) slowly. The mixture
was stirred at room temperature for 30 min under nitrogen. It was
diluted with 1N HCl (10 mL), and stirred for 10 min. The phases
were separated and the aqueous phase was lyophilized to give a
yellow solid, which was washed with water and ether. The solid was
dried to give 50 mg of product 51. .sup.1H NMR (DMSO-d.sub.6):
.delta. 9.0 (d, 1H), 8.8 (d, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m,
2H), 5.0 (s, 1H, PhOH), 4.8 (s, 2H), 4.7 (s, 2H), 4.5 (s, 2H). MS:
339 (M+1).
[0510] The organic phase was concentrated. The residue was
dissolved in DMF (2 mL) 1 and purified by Prep-HPLC to give 10 mg
of product 52. HPLC condition: mobile phase A (1% AcOH in water),
mobile phase B (1% AcOH in AcCN); gradient: 20% to 50% B in 30 min;
flow rate: 20 mL/min; column: Phenomenex, Luna 5.mu., C18 (2), 150
mm.times.21.2 mm. .sup.1H NMR (DMSO-d.sub.6): .delta. 9.5 (d, 1H),
89.0 (d, 1H), 7.7 (m, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 4.7 (s, 2H),
4.6 (s, 2H), 4.5 (s, 2H), 3.5 (s, 3H, under water peak). MS: 353
(M+1).
##STR00194##
Example 52
[0511] The aldehyde 49 (118 mg, 0.23 mmol) was dissolved in
anhydrous THF (5 mL) and MeOH (0.5 mL) at room temperature. To this
was added sodium borohydride (27 mg, 0.72 mmol) slowly. The mixture
was stirred at room temperature for 30 min under nitrogen. It was
diluted with 1N HCl (10 mL), and stirred for 10 min. The phases
were separated and the aqueous phase was lyophilized to give a
yellow solid as product 51.
[0512] The alcohol 51 (crude from reduction) was suspended in
dichloromethane (10 mL) at room temperature under nitrogen.
Triethylsilane (3 mL) was added followed by TFA (1 mL) slowly. The
mixture became homogeneous and was stirred at room temperature
overnight under nitrogen. The solvent was removed under reduced
pressure. The crude product was dissolved in 2 mL of DMF then
purified by prep-HPLC to gave a clean product of 53 (22.4 mg, 30%).
HPLC condition: mobile phase A (1% TFA in water), mobile phase B
(1% TFA in AcCN); gradient-5% to 100% B in 20 min; flow rate: 20
mL/min; column: Phenomenex, Luna 5.mu., C18 (2), 150 mm.times.21.2
mm. .sup.1H NMR (CD.sub.3OD): .delta. 9.0 (d, 1H), 8.9 (d, 1H), 7.9
(dd, 1H), 7.4 (d, 4H), 7.1 (t, 2H), 4.8 (s, 2H), 4.9 (s, 2H), 4.5
(s, 2H), 2.5 (s, 3H). MS: 323 (M+1).
##STR00195##
Example 53
[0513] To the compound 44 (350.0 mg, 0.592 mmol) in anhydrous THF
(20 mL), was added tetrabutylammonium fluoride (1M in THF, 651
.mu.l, 0.651 mmol) and triethylamine (330 .mu.l, 2.37 mmol). The
reaction mixture turned to red and was stirred at room temperature
under nitrogen for 1 hour. The reaction forming 45 was monitored by
TLC (EtOAc/Hexane=3/7).
Example 54
[0514] Triethylamine (330 .mu.L, 2.37 mmol) was added to the
reaction mixture followed by a catalytic amount of DMAP, and
N,N-dimethylsulfamoyl chloride (160 .mu.L, 1.5 mmol). The mixture
was stirred at room temperature under nitrogen for 16 hours. After
completion of the reaction, it was diluted with dichloromethane (50
mL) and washed with 1N HCl, saturated NaHCO.sub.3 and brine. The
organic layer was dried (MgSO.sub.4) and concentrated. The residue
was chromatographed on a silica gel column, eluting with
EtOAc/Hexane to afford the product 54 (205.4 mg, 58% in 2 steps).
.sup.1H NMR (CDCl.sub.3): .delta. 9.0 (d, 1H), 8.4 (d, 1H), 8.0 (s,
1H), 7.7 (d, 4H), 7.5 (dd, 1H), 7.1-7.3 (m, 8H), 7.0 (t, 2H), 4.8
(s, 2H), 4.4 (s, 2H), 3.0 (s, 3H). MS: 598 (M+1).
Example 55
[0515] The compound 54 ((205.4 mg, 0.344 mmol) was dissolved in
dichloromethane (6 mL) at room temperature under nitrogen.
Triethylsilane (2 mL) was added followed by TFA (1 mL) slowly. The
mixture became smoky and dark and was stirred at room temperature
for 30 min. The solvent was removed under reduced pressure. The
crude product was triturated in diethylether/hexane to afford a
yellow solid 55, 169 mg, 93%. .sup.1H NMR (CD.sub.3OD): .delta. 9.0
(d, 1H), 8.6 (d, 1H), 7.8 (dd, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 4.8
(s, 2H), 4.6 (s, 2H), 3.1 (s, 6H). MS: 432 (M+1).
##STR00196##
Example 56
[0516] The phenol 40 (1.0 g, 1.984 mmol) and DIEA (1.04 mL, 6.0
mmol) in dichloromethane (20 mL) was chilled to -78.degree. C. To
this was added trifluoromethanesulfonic anhydride (0.78 mL, 3.0
mmol) slowly under the nitrogen. The reaction was completed in 1
hour. It was quenched with 1.5 mL of methanol and stirred for 5 min
more. Warmed to room temperature, it was washed with 1N HCl,
saturated NaHCO.sub.3 and brine. The organic phase was dried
(MgSO.sub.4) and concentrated to afford the forming product 56 (1.2
g, 95%).
[0517] The reaction was repeated, where monophenol 40 (0.1807 g,
0.358 mmol) was dissolved in 4 mL dry dichloromethane. To this was
added diisopropylethylamine (0.182 mL, 1.074 mmol.) After cooling
to -78.degree. C., triflic anhydride was added (0.14 mL, 0.537
mmol) and was stirred at this temperature for twenty minutes.
Reaction was then complete by TLC, diluted with dichloromethane,
washed with 1M HCl, saturated NaHCO.sub.3 solution, dried
(MgSO.sub.4) and organics concentrated to give product (0.2518 g,
0.396 mmol, 100%) which was stored crude as a solution in 10 mL dry
benzene. .sup.1H NMR (CDCl.sub.3) .delta. 9.2 (dd, 1H), 8.46 (d,
1H), 8.068 (s, 1H), 7.75 (dd, 1H), 7.6 (d, 4H), 7.47 (dd, 1H), 7.27
(m, 7H), 7.19, dd, 2H), 4.87 (s, 2H.) MS: 637 (M+1)
##STR00197##
Example 57
[0518] To the triflate 56 (78.0 mg, 0.122 mmol) in toluene (2.8
mL)/ethanol (1.2 mL)/water (0.8 mL) was added potassium carbonate
(42 mg, 0.306 mmol), 1-octeneboronic acid (29.0 mg, 0.184 mmol) and
tetrakis (triphenylphosphine)-palladium (0) (21.0 mg, 0.018 mmol).
The mixture in the flask was flushed with argon three times. It was
heated to 120.degree. C. under argon for 3 hours. Cooling to room
temperature, it was diluted with EtOAc and washed with 1N HCl,
saturated NaHCO.sub.3 and brine. The organic phase was dried
(MgSO.sub.4) and concentrated. The residue was chromatographed on a
silica gel column, eluting with EtOAc/Hexane to afford the product
57 (11.4 mg, 15.6%).
Example 58
[0519] The compound 57 (6 mg, 0.01 mmol) was dissolved in
dichloromethane (1 mL) at room temperature under nitrogen.
Triethylsilane (200 .mu.L) was added followed by TFA (100 .mu.L)
slowly. The mixture became smoky and dark and was stirred at room
temperature for 30 min. The solvent was removed under reduced
pressure. The crude product was triturated in diethylether/hexane
to afford a yellow solid TFA salt of 58, 3 mg, 57%. .sup.1H NMR
(CD.sub.3OD): .delta. 9.0 (d, 1H), 8.8 (d, 1H), 7.8 (dd, 1H), 7.4
(dd, 2H), 7.1 (d, 1H), 7.0 (dd, 2H), 6.2 (m, 1H), 4.8 (s, 2H), 2.4
(m, 2H), 1.6 (m, 2H), 1.3-1.5 (m, 6H), 0.9 (t, 3H). MS: 433
(M+1).
##STR00198##
Example 59
[0520] To the triflate 56 (100 mg, 0.157 mmol) in toluene (2.8
mL)/ethanol (1.2 mL)/water (0.8 mL) was added potassium carbonate
(54 mg, 0.392 mmol), vinylboronic acid (17 mg, 0.235 mmol) and
tetrakis (triphenylphosphine)-palladium (0) (27.0 mg, 0.023 mmol).
The mixture in the flask was flushed with argon three times. It was
heated to 120.degree. C. under argon for 3 hours. Cooling to room
temperature, it was diluted with EtOAc and washed with 1N HCl,
saturated NaHCO.sub.3 and brine. The organic phase was dried
(MgSO.sub.4) and concentrated. The residue was chromatographed on a
silica gel column, eluting with EtOAc/Hexane to afford the product
59 (32.3 mg, 40%).
Example 60
[0521] The compound 59 (11 mg, 0.01 mmol) was dissolved in
dichloromethane (1 mL) at room temperature under nitrogen.
Triethylsilane (200 .mu.L) was added followed by TFA (100 .mu.L)
slowly. The mixture became smoky and dark and was stirred at room
temperature for 30 min. The solvent was removed under reduced
pressure. The crude product was triturated in diethylether/hexane
to afford a yellow solid TFA salt of 60, 2.3 mg, 31.4%. .sup.1H NMR
(CDCl.sub.3): .delta. 9.0 (d, 1H), 8.8 (d, 1H), 7.7 (dd, 1H), 7.5
(m, 2H), 7.0 (m, 2H), 6.0 (d, 1H), 5.6 (d, 1H), 5.3 (s, 1H, OH),
4.8 (s, 2H). MS: 349 (M+1).
##STR00199##
Example 61
[0522] The compound 59 (157 g, 0.11 mmol) was dissolved in
anhydrous THF (5 mL) and MeOH (0.5 mL) at room temperature. To this
was added sodium borohydride (13 mg, 0.33 mmol) slowly. The mixture
was stirred at room temperature for 1 hour under nitrogen. It was
diluted with EtOAc (50 mL), and washed with 1N HCl, saturated
NaHCO.sub.3 and brine. The organic phase was dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel prep-TLC,
eluting with EtOAc/Hexane (3/7) to afford the product 61 (12.5 mg,
22%).
Example 62
[0523] The compound 61 (11 mg, 0.01 mmol) was dissolved in
dichoromethane (1 mL) at room temperature under nitrogen.
Triethylsilane (200 .mu.L) was added followed by TFA (100 .mu.L)
slowly. The mixture became smoky and dark and was stirred at room
temperature for 30 min. The solvent was removed under reduced
pressure. The crude product was triturated in diethylether/hexane
to afford a yellow solid TFA salt of 62, 8 mg, 75%. .sup.1H NMR
(CDCl.sub.3): .delta. 9.0 (d, 1H), 8.5 (d, 1H), 7.7 (dd, 1H), 7.5
(dd, 2H), 7.0 (m, 2H), 4.8 (s, 2H), 3.5 (q, 2H), 1.3 (t, 3H). MS:
451 (M+1).
##STR00200##
Example 63
[0524] Mono-phenol 6 (0.02 g, 0.052 mmol) was added to 1.5 mL dry
dimethylformamide. To this was added benzyl bromide (0.0124 ml,
0.104 mmol) and K.sub.2CO.sub.3 (0.0215 g, 0.156 mmol) and stirred
at 50.degree. C. After 1.5 hrs reaction completed by TLC. Diluted
with 100 mL ethylacetate, washed with saturated NH.sub.4Cl solution
and brine. The organic phase was dried (MgSO.sub.4), concentrated,
and chromatographed (25% ethylacetate/hexanes) to give product 63
(0.013 g, 0.0275 mmol, 53%.). .sup.1H NMR (CDCl.sub.3) .delta. 9.03
(dd, 1H), 8.6 (d, 1H), 7.54 (m, 6H), 7.4 (m, 2H), 7.05 (dd, 2H),
5.8 (s, 2H), 5.6 (s, 2H), 4.9 (s, 2H), 3.7 (s, 3H). MS: 473
(M+1)
##STR00201##
Example 64
[0525] Benzyl ether (0.013 g, 0.0275 mmol) was dissolved in 1 mL
dry dichloromethane. To this was added trifluoroacetic acid (0.0213
mL, 0.275 mmol) and stirred 2.5 hrs. Concentrated off volatiles,
azeotroped with toluene (2.times.), concentrated to give crude
product. Triturated with 1:1 diethylether/hexanes to give product
64 (0.0078 g, 0.0182 mmol, 66%). .sup.1H NMR (CDCl.sub.3) .delta.
8.96 (dd, 1H), 8.6 (d, 1H), 7.6 (dd, 1H), 7.5 (m, 5H), 7.37 (m,
2H), 7.05 (dd, 2H), 5.6 (s, 2H), 4.88 (s, 2H). MS: 429 (M+1), 427
(M-1)
##STR00202##
Example 65
[0526] Monophenol 6 (0.04 g, 0.1047 mmol) was dissolved in 2 mL of
dry dimethylformamide. To this was added 2-bromomethyl pyridine HBr
salt (0.0529 g, 0.209 mmol) and K.sub.2CO.sub.3 (0.144 g, 1.047
mmol.) Stirred at 50.degree. C. for twelve hours. Diluted with
ethylacetate, washed with brine (saturated NaCl) and 1M HCl, dried
(MgSO.sub.4,), and concentrated. The crude product was
chromatographed (20 to 50% ethylacetate/hexanes) to give product
65: (0.0032 g, 0.0067 mmol, 6.5%.) .sup.1H NMR (CDCl.sub.3) .delta.
9.03 (d, 1H), 8.72 (d, 1H), 8.6 (d, 1H), 7.8 (dd, 1H), 7.7 (dd,
1H), 7.57 (dd, 1H), 7.48 (dd, 2H), 7.0 (dd, 2H), 5.8 (s, 2H), 5.65
(s, 2H), 4.86 (s, 2H), 3.72 (s, 3H.) MS: 488 (M+1)
##STR00203##
Example 66
[0527] Pyridyl ether 65 (0.0032 g, 0.0067 mmol) was dissolved in 1
mL dry dichloromethane. To this was added trifluoroacetic acid
(0.0052 mL, 0.0676 mmol) and stirred 12 hrs. Concentrated off
volatiles, azeotroped with toluene (2.times.), concentrated to give
crude product. Triturated with 1:1 diethylether/hexanes to give
product 66 (0.0012 g, 0.0028 mmol, 42%.) .sup.1H NMR (CDCl.sub.3)
.delta. 8.96 (d, 1H), 8.73 (d, 1H), 8.6 (d, 1H), 7.8 (dd, 1H), 7.7
(d, 1H), 7.63 (dd, 1H), 7.5 (dd, 2H), 7.3 (m, 1H) 7.04 (dd, 2H),
5.67 (s, 2H), 4.87 (s, 2H.) MS: 430 (M+1), 428 (M-1)
##STR00204##
Example 67
[0528] Triflate 46 in benzene was concentrated to give (0.0225 g,
0.0353 mmol) and dissolved in 3 mL of dichloroethane. To this was
added triethylamine (0.0073 mL, 0.0529 mmol) and morpholine (0.0092
ml, 0.118 mmol) and reaction stirred at 65.degree. C. After 15 hrs,
reaction still incomplete by TLC, added another 0.118 mL of
morpholine. After 21 hrs reaction time concentrated off volatiles
and chromatographed (10 to 25% ethylacetate/hexanes) to give
product 67 (0.0061 g, 0.01, 30%). .sup.1H NMR (CDCl.sub.3) .delta.
9.09 (dd, 1H), 8.89 (d, 1H), 8.03 (s, 1H), 7.65 (m, 5H), 7.49 (dd,
1H), 7.27 (m, 7H), 7.06 (dd, 2H), 4.85 (s, 2H), 3.92 (dd, 4H), 3.92
(br m, 4H). MS: 574 (M+1)
##STR00205##
Example 68
[0529] Tertiary amine 67 was dissolved in 0.5 mL of
dichloromethane. To this was added 0.2 mL of triethylsilane and 0.1
mL of trifluoroacetic acid. Stirred at room temperature and after
ten minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene, solidified with hexane and concentrated to give
crude. Triturated with 1:1 diethylether/hexanes to give product 68
(0.002 g, 0.0049 mmol, 49%). .sup.1H NMR (CDCl.sub.3) .delta. 8.98
(m, 2H), 7.7 (dd, 1H), 7.53 (dd, 2H), 7.05 (dd, 2H), 4.86 (s, 2H),
3.96 (dd, 4H), 3.35 (br m, 4H). MS: 408 (M+1), 406 (M-1)
Example 69
[0530] Triflate 46 in benzene was concentrated to give (0.045 g,
0.0706 mmol) and dissolved in 3 mL of dichloroethane. To this was
added triethylamine (0.0147 mL, 0.1059 mmol) and morpholine (0.0209
ml, 0.2118 mmol) and reaction stirred at 70.degree. C. After 15 hrs
of stirring, concentrated off volatiles and chromatographed (8 to
10% ethylacetate/hexanes) to give product 69 (0.0085 g, 0.01488,
44%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.068 (dd, 1H), 8.79 (d,
1H), 7.8 (s, 1H), 7.6 (d, 4H), 7.57 (dd, 1H), 7.46 (dd, 2H), 7.27
(m, 6H), 7.06 (dd, 2H), 4.84 (s, 2H), 3.24 (br s, 4H), 1.73 (br s,
6H.) MS: 572 (M+1)
##STR00206##
Example 70
[0531] Tertiary amine 69 was dissolved in 0.5 mL of
dichloromethane. To this was added 0.2 mL of triethylsilane and 0.1
mL of trifluoroacetic acid. Stirred at room temperature and after
ten minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene, solidified with hexane and concentrated to give
crude. Triturated with 1:1 diethylether/hexanes to give product 70
(0.0043 g, 0.0106 mmol, 72%,) .sup.1H NMR (CDCl.sub.3) .delta. 8.96
(dd, 1H), 8.85 (d, 1H), 7.66 (dd, 1H), 7.5 (m, 2H), 7.04 (dd, 2H),
4.85 (s, 2H), 3.29 (br s, 4H), 1.77 (br s, 6H.) MS: 406 (M+1), 404
(M-1)
Example 71
[0532] Monophenol 45 (0.03 g, 0.0595 mmol) was dissolved in 2 mL
dry dimethylformamide. To this was added ethyl bromoacetate (0.0131
mL, 0.119 mmol) and freshly ground K.sub.2CO.sub.3 (0.025 g, 0.178
mmol.) Stirred at 50.degree. C., for two hours until starting
material consumed. Concentrated off some solvent, diluted with
ethylacetate, washed with saturated NH.sub.4Cl solution,
concentrated organics to give crude product. Chromatographed (10 to
25% ethylacetate/hexanes) to give product 71 (0.0321 g, 0.054 mmol,
91%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.1 (dd, 1 H), 8.96 (d, 1H),
7.9 (s, 1H), 7.62 (d, 4H), 7.445 (m, 2H), 7.27 (m, 7 H), 7.059 (dd,
2H), 5.21 (s, 2H), 4.83 (s, 2H), 4.22 (q, 2H), 1.23 (t, 3H). MS:
591 (M+1).
##STR00207##
Example 72
[0533] Ethyl ester 71 was dissolved in 0.5 mL of dichloromethane.
To this was added 0.2 mL of triethylsilane and 0.1 mL of
trifluoroacetic acid. Stirred at room temperature and after ten
minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated with 1:1
diethylether/hexanes to give product 72 (0.0209 g, 0.049 mmol,
91%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (m, 2H), 7.7 (dd, 1H),
7.5 (dd, 2H), 7.04 (dd, 2H), 5.33 (s, 2H), 4.84 (s, 2H), 4.24 (q,
2H), 1.28 (t, 3H.) MS: 425 (M+1), 423 (M-1)
##STR00208##
Example 73
[0534] Monophenol 45 (0.03 g, 0.0595 mmol) was dissolved in 2 mL
dry dimethylformamide. To this was added t-butyl bromoacetate
(0.0175 mL, 0.119 mmol) and freshly ground K.sub.2CO.sub.3 (0.025
g, 0.178 mmol.) Stirred at 50.degree. C., for one hour until
starting material consumed. Concentrated off some solvent, diluted
with ethylacetate, washed with saturated NH.sub.4Cl solution,
concentrated organics to give crude product. Chromatographed (10 to
15% ethylacetate/hexanes) to give product 73 (0.0309 g, 0.05 mmol,
84%.) .sup.1 H NMR (CDCl.sub.3) .delta. 9.09 (dd, 1H), 8.97 (d,
1H), 7.92 (s, 1H), 7.62 (d, 4H), 7.44 (m, 2H), 7.27 (m, 7 H), 7.05
(dd, 2H), 5.12 (s, 2H), 4.83 (s, 2H), 1.38 (s, 9H.) MS: 619
(M+1)
##STR00209##
Example 74
[0535] Tertiary Butyl ester 73 was dissolved in 0.5 mL of
dichloromethane. To this was added 0.2 mL of triethylsilane and 0.1
mL of trifluoroacetic acid. Stirred at room temperature and after
ten minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated with 1:1
diethylether/hexanes to give product 74 (0.0189 g, 0.042 mmol,
84%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.05 (m, 2H), 7.72 (dd, 1H),
7.5 (dd, 2H), 7.04 (dd, 2H), 5.22 (s, 2H), 4.84 (s, 2H), 1.44 (s,
9H.) MS: 453 (M+1), 451 (M-1)
Example 75
[0536] Monophenol 45 (0.04 g, 0.079 mmol) was dissolved in 1 mL dry
dimethylformamide. To this was added 2-bromoacetamide (0.022 g
0.158 mmol) and freshly ground K.sub.2CO.sub.3 (0.0345 g, 0.25
mmol.) Stirred at 60.degree. C., for three hours until starting
material nearly consumed. Concentrated off some solvent, diluted
with ethylacetate, washed with saturated NaHCO.sub.3 solution,
concentrated organics to give crude product. Chromatographed (10 to
50% ethylacetate/hexanes) to give product 75 (0.0204 g, 0.0355
mmol, 46%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.15 (dd, 1H), 8.53
(d, 1H), 7.96 (s, 1H), 7.6 (m, 4H), 7.45 (dd, 2H), 7.27 (m, 7H),
7.06 (dd, 2H), 5.73 (br s, 1H), 4.84 (s, 2H), 4.77 (s, 2H.) MS: 562
(M-1)
##STR00210##
Example 76
[0537] Amide 75 was dissolved in 0.5 mL of dichloromethane. To this
was added 0.2 mL of triethylsilane and 0.1 mL of trifluoroacetic
acid. Stirred at room temperature and after ten minutes complete by
TLC. Concentrated off volatiles, azeotroped with toluene to give
crude. Triturated with 1:1 diethylether/hexanes to give product 76
(0.0095 g, 0.024 mmol, 67%.) .sup.1H NMR (CD.sub.3SOCD.sub.3)
.delta. 9.08 (dd, 1H), 8.93 (d, 1H), 7.87 (dd, 1H), 7.73 (br s,
1H), 7.41 (dd, 2H), 7.19 (dd, 2H), 4.86 (s, 2H), 4.75 (s, 2H.) MS:
396 (M-1), 394 (M-1)
##STR00211##
Example 77
[0538] Monophenol 45 (2.9 g, 5.75 mmol) was dissolved in 20 mL dry
dimethylformamide. To this was added methyl iodide (3.58 mL, 57.5
mmol) and freshly ground K.sub.2CO.sub.3 (3.17 g, 23 mmol.) Stirred
at 40.degree. C. for one hour, until starting material consumed.
Diluted with dichloromethane, washed with saturated NH.sub.4Cl
solution, 2.5% LiCl solution, concentrated organics to give crude
product. Chromatographed (15 to 55% ethylacetate/hexanes to give
product 77 (2.54 g, 4.9 mmol, 85%.) .sup.1H NMR (CDCl.sub.3)
.delta. 9.1 (dd, 1H), 8.64 (dd, 1H), 7.91 (s, 1H), 7.62 (m, 5H),
7.46 (dd, 2H), 7.27 (m, 7H), 7.05 (dd, 2H), 4.84 (s, 2H), 4.28 (s,
3H.) MS: 519 (M+1)
##STR00212##
Example 78
[0539] Methyl ether 77 was dissolved in 115 mL of dry
tetrahydrofuran and 25 mL of dry methanol. To this was added three
equivalents of a 0.5 M solution of NaBH4 (29.4 mL, 14.7 mmol) in
2-methoxyethyl ether. After 15 hrs at room temperature,
concentrated off some solvent, diluted with dichloromethane, washed
with 1M HCl solution with NaCl added, concentrated, chromatographed
(15-66% ethlylacetate/hexanes) to give oil. Triturated with hexane
to give product 78 (1.3 g, 2.5 mmol, 68%.) .sup.1H NMR
(CD.sub.3SOCD.sub.3) .delta. 9.08 (dd, 1H), 8.5 (d, 1H), 7.89 (s,
1H), 7,75 (d, 2H), 7.69 (dd, 1H), 7.63 (d, 2H), 7.42 (dd, 2H), 7.27
(m, 7H), 6.9 (d, 1H), 5.92 (dd, 1H), 4.97 (d J=15 Hz, 1H), 4.45 (d
J=15 Hz, 1H), 4.04 (s, 3H.) MS: 521 (M+1)
##STR00213##
Example 79
[0540] Aminal 78 was dissolved in 15 mL of dichloromethane. To this
was added 2 mL of triethylsilane and 1 mL of trifluoroacetic acid.
Stirred at room temperature and after ten minutes complete by TLC.
Concentrated off volatiles, azeotroped with toluene to give crude.
Triturated with 1:1 diethylether/hexanes to give reduced product.
Dissolved in 30 mL of dichloromethane and cooled to 0.degree. C. To
this was added 4 mL of triethylsilane and trimethylsilyltriflate
(1.36 mL, 7.5 mmol.) Stirred vigorously for three minutes, then
concentrated off volatiles, diluted with dichloromethane, washed
quickly with saturated NaHCO.sub.3 solution, concentrated organics
to give crude product 79. Triturated with 1:1 diethylether/hexanes
to give product (0.806 g, 2.38 mmol, 95% for two steps.) .sup.1H
NMR (CDCl.sub.3) .delta. 8.96 (dd, 1H), 8.50 (d, 1H), 7.56 (dd,
1H), 7.37 (dd, 2H), 7.09 (dd, 2H), 4.78 (s, 2H), 4.51 (s, 2H), 3.98
(s, 3H). MS: 339 (M+1), 337 (M-1).
##STR00214##
Example 80
[0541] Monophenol 45 (0.02 g, 0.0396 mmol) was dissolved in 1 mL
dry dichloromethane. To this was added at 0.degree. C.
triethylamine (0.0165 mL, 0.1188 mmol) and dimethylcarbamoyl
chloride (0.0054 mL, 0.0594 mmol). Catalytic amount of DMAP was
also added. Stirred at room temperature overnight. Dilute with
dichloromethane, washed with saturated NaHCO.sub.3 solution and
saturated NH.sub.4Cl solution, concentrated to give crude.
Triturated with 1:1 diethylether/hexanes and chromatographed (10%
methanol/45% ethylacetate/45% hexanes) to give product 80 (0.012 g,
0.0198 mmol, 50%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.12 (s, 1H),
8.4 (d, 1H), 7.97 (s, 1H), 7.62 (d, 4H), 7.43 (dd, 2H), 7.27 (m,
7H), 7.05 (dd, 2H), 4.81 (s, 2H), 3.26 (s, 3H), 3.09 (s, 3H.) MS:
576 (M+1)
##STR00215##
Example 81
[0542] Carbamate 80 (0.012 g, 0.0198 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated with 1:1
diethylether/hexanes to give product 81 (0.0054 g, 0.013 mmol,
67%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.98 (s, 1H), 8.49 (d, 1H),
7.7 (dd, 1H), 7.46 (dd, 2H), 7.03 (dd, 2H), 4.83 (s, 2H), 3.31 (s,
3H), 3.12 (s, 3H). MS: 410 (M+1), 408 (M-1).
##STR00216##
Example 82
[0543] Monophenol 45 (0.035 g, 0.0694 mmol) was dissolved in 1 mL
dry dichloroethane. To this was added triethylamine (0.038 mL,
0.277 mmol) and
3-chlorocarbonyl-1-methanesulfonyl-2-imidazolidinone (0.0314 g,
0.1388 mmol Stirred at room temperature for five minutes. Dilate
with dichloromethane, washed with saturated NaHCO.sub.3 solution
and saturated NH.sub.4Cl solution, dried (MgSO.sub.4), concentrated
to give crude. Chromatographed (10% methanol/45% ethylacetate/45%
hexanes) to give product 82 (0.036 g, 0.0518 mmol, 75%.) .sup.11
NMR (CDCl.sub.3) 9.16 (dd, 1H), 8.49 (dd, 1H), 8.00 (s, 1H), 7.66
(dd, 1H), 7.61 (d, 4H), 7.40 (dd, 2H), 7.27 (m, 6H), 7.05 (dd, 2H),
4.81 (s, 2H), 4.2 (dd, 2H), 4.08 (dd, 2H), 3.92 (s, 3H). MS: 695
(M+1).
##STR00217##
Example 83
[0544] Carbamate 82 (0.036 g, 0.0518 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated with 1:1
diethylether/hexanes to give product 83 (0.025 g, 0.047 mmol, 91%.)
.sup.1H NMR (CDCl.sub.3) .delta. 9.04 (d, 1H), 8.58 (d, 1H), 7.75
(dd, 1H), 7.43 (dd, 2H), 7.04 (dd, 2H), 4.82 (s, 2H), 4.22 (dd,
2H), 4.10 (dd, 2H). MS: 529 (M+1), 527 (M-1).
##STR00218##
Example 84
[0545] Monophenol 45 (0.045 g, 0.089 mmol) was dissolved in 1 mL
dry dichloroethane. To this was added triethylamine (0.049 mL,
0.356 mmol) and 4-morpholine carbonyl chloride (0.0207 mL, 0.178
mmol.) Stirred at room temperature for 1.5 hours. Dilute with
dichloromethane, washed with saturated NaHCO.sub.3, concentrated to
give crude. Chromatographed (15% to 60% ethylacetate/hexanes) to
give product 84 (0.039 g, 0.063 mmol, 71%.) .sup.1H NMR
(CDCl.sub.3) 9.13 (dd, 1H), 8.40 (d, 1H), 7.98 (s, 1H), 7.62 (dd,
4H), 7.4 (dd, 2H), 7.27 (m, 7H), 7.05 (dd, 2H), 4.81 (s, 2H), 3.84
(br s, 6H), 3.62 (br s, 2H.) MS: 618 (M+1)
##STR00219##
Example 85
[0546] Carbamate 84 (0.039 g, 0.063 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated with 1:1
diethylether/hexanes to give product 85 (0.014 g, 0.032 mmol, 51%.)
.sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.48 (d, 1H), 7.72
(dd, 1H), 7.49 (dd, 2H), 7.04 (dd, 2H), 4.83 (s, 2H), 3.88 (br s,
6H), 3.66 (br s, 2H.) MS: 452 (M+1), 450 (M-1)
##STR00220##
Example 86
[0547] Triflate 46 in benzene concentrated to give (0.048 g, 0.075
mmol) and dissolved in 1 mL dry tetrahydrofuran. To this was added
freshly ground K.sub.2CO.sub.3 (0.069 , 0.5 mmol) and
dimethylmalonate (0.017 mL, 0.15 mmol) and stirred at 500 C. After
15 hours, starting material consumed, concentrated to give oil.
Chromatographed (5% to 30% ethylacetate/hexanes) to give product 86
(0.012 g, 0.0195 mmol, 26%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.09
(d, 1H), 8.51 (d, 1H), 8.12 (s, 1H), 7.65 (d, 4H), 7.57 (dd, 1H),
7.48 (dd, 2H), 7.27 (m, 6H), 7.07 (dd, 2H), 4.85 (s, 2H), 3.72
(6H.) MS: 619 (M+1)
##STR00221##
Example 87
[0548] Di-ester 86 (0.008 g, 0.0129 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 87 (0.0022 g, 0,0049 mmol,
38%.) 3H NMR (CDCl.sub.3) .delta. 8.95 (d, 1H), 8.60 (d, 1H), 7.70
(dd, 1H), 7.55 (dd, 2H), 7.05 (dd, 2H), 4.87 (s, 2H), 3.76 (s, 6H.)
MS: 453 (M+1), 451 (M-1)
##STR00222##
Example 88
[0549] Mono-phenol 12 (0.03 g, 0.06 mmol) was dissolved in 1 mL of
dichloroethane. To this was added triethylamine (0.033 mL, 0.24
mmol) and 2-oxo-1-imidazolidinecarbonyl chloride (0.0178 g, 0.12
mmol.) Catalytic amount of DMAP added, and stirred at room
temperature for three hours. Diluted with dichloromethane, washed
with saturated NH.sub.4Cl solution, concentrated to give crude.
Chromatographed (10% ethylacetate/hexane to 10% medmanol/45%
ethylacetate/45% hexanes) to give product 88 (0.0247 g, 0.0395
mmol, 68%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.96 (s, 1H), 8.53 (d,
1H), 7.63 (dd, 1H), 7.43 (dd, 2H), 7.03 (dd, 2H), 4.81 (s, 2H),
4.25 (dd, 2H), 3.69 (dd, 2H), 1.55 (m, 3H), 1.14 (d, 18H.) MS: 607
(M+1)
##STR00223##
Example 89
[0550] Urea 88 (0.024 g, 0.0395 mmol) was dissolved in 1 mL of dry
dichloromethane. To this was added ten equivalents (0.03 mL, 0.395
mmol) of trifluoroacetic acid. Stirred at room temperature, for
fifteen hours. Concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Crude product triturated
with 1:1 diethylether/hexanes to give product 89 (0.0119 g, 0.026
mmol, 67%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (d, 1H), 8.58 (d,
1H), 7.73 (dd, 1H), 7.47 (dd, 2H), 7.03 (dd, 2H), 4.83 (s, 2H),
4.28 (dd, 2H), 3.70 (dd, 2H.) MS: 451 (M+1), 449 (M-1)
##STR00224##
Example 90
[0551] Mono-phenol 12 (0.04 g, 0.08 mmol) was dissolved in 1.5 mL
dry tetrahydrofuran. To this was added triethylamine (0.0445 mL,
0.32 mmol) and bispentafluorophenyl carbonate (0.063 g, 0.16 mmol)
and catalytic dimethylaminopyridine. Stirred at room temperature.
After three hours, added methyl piperazine (0.04 mL, 0.36 mmol.)
After two hours TLC indicated product formed however TIPSCl was
removed. Diluted with dichloromethane, washed with saturated
NH.sub.4Cl solution, concentrated organics to give crude. Dissolved
in 1.5 mL dichloroethane, added triethylamine (0.11 mL, 0.8 mmol)
and TIPSCl (0.085 mL, 0.4 mmol) and stirred at 50.degree. C.
Stirred for four hours until starting material was consumed.
Diluted with dichloromethane, washed with saturated brine,
concentrated organics to give crude. Chromatographed (50%
ethylacetate/hexanes to 20% methanol/60% ethylacetate/20%hexanes)
to give product 90 (0.027 g, 0.0435 mmol, 54% for two steps.)
.sup.1H NMR (CDCl.sub.3) .delta. 9.05 (d, 1H), 8.60 (d, 1H), 7.61
(dd, 1H), 7.41 (dd, 2H), 7.03 (dd, 2H), 4.81 (s, 2H), 3.71 (br m,
8H), 2.43 (s, 3H), 1.60 (m, 3H), 1.15 (d, 18H.) MS: 621 (M+1)
##STR00225##
Example 91
[0552] Mono-carbamate 90 (0.027 g, 0.0435 mmol) was dissolved in 1
mL of dichloromethane. To this was added trifluoroacetic acid
(0.067 mL, 0.87 mmol) and stirred at room temperature. After twenty
hours, concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Triturate with 1:1
diethylether/hexanes to give product 91 (0.0177 g, 0.038 mmol,
87%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.09 (s, 1H), 8.71
(d, 1H), 7.67 (dd, 1H), 7.42 (dd, 2H), 7.07 (dd, 2H), 4.81 (s, 2H),
3.45 (br m, 8H), 2.90 (s, 3H.) MS: 465 (M+1), 463 (M-1)
##STR00226##
Example 92
[0553] Mono-phenol 12 (0.04 g, 0.08 mmol) was dissolved in 1.5 mL
dichloromethane. To this was added triethylamine (0.044 mL, 0.32
mmol), dimethylsulfamoyl chloride (0.017 mL, 0.16 mmol) and
catalytic dimethylaminopyridine. Stirred at room temperature for 30
minutes. Diluted with dichloromethane, washed with saturated NH4Cl
solution, concentrated organics to give crude. Chromatographed (25%
ethylacetate/hexanes) to give product 92 (0.017 g, 0.02828 mmol,
35%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.95 (d, 1H), 8.79 (d, 1H),
7.66 (dd, 1H), 7.45 (dd, 2H), 7.03 (dd, 2H), 4.84 (s, 2H), 3.24 (s,
6H), 1.55 (m, 3H), 1.14 (d, 18H.) MS: 602 (M+1)
##STR00227##
Example 93
[0554] Mono-carbamate 92 (0.017 g, 0.02828 mmol) was dissolved in 1
mL of dichloromethane. To this was added trifluoroacetic acid
(0.044 mL, 0.5657 mmol) and stirred at room temperature. After
twenty hours, concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Triturate with 1.1
diethylether/hexanes to give product 93 (0.0081 g, 0.018 mmol,
64%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (d, 1H), (8.84 (d, 1H),
7.76 (dd, 1H), 7.49 (dd, 2H), 7.03 (dd, 2H), 4.86 (s, 2H), 3.24 (s,
6H.) MS: 446 (M+1), 444 (M-1)
##STR00228##
Example 94
[0555] Mono-phenol 45 (0.04 g, 0.08 mmol) was dissolved in 1.5 mL
tetrahydrofuran. To this was added diisopropylethylamine (0.052 mL,
0.3 mmol), bis-pentafluorophenyl carbonate (0.047 g, 0.119 mmol)
and catalytic dimethylaminopyridine. Stirred at room temperature.
After 75 minutes, cooled to 0.degree. C., n-butylamine (0.079 mL,
0.08 mmol) added. Stirred for 1.5 hours, then diluted with
dichloromethane, washed with saturated brine, 1 M HCl, concentrated
organics to give crude. Chromatographed (25% ethylacetate/hexanes
to give product 94 (0.0028 g, 0.0048 mmol, 6%.) .sup.1H NMR
(CDCl.sub.3) .delta. 9.12 (d, 1H), 8.41 (d, 1H), 7.98 (s, 1H), 7.61
(d, 4H), 7.43 (dd, 2H), 7.27 (m, 7H), 7.043 (dd, 2H), 5.37 (m, 1H),
4.82 (s, 2H), 3.35 (q, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 1.01 (t,
3H.) MS: 604 (M+1)
##STR00229##
Example 95
[0556] Carbamate 94 (0.006 g, 0.0099 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude which was triturated twice
with 1:1 diethylether/hexanes to give product 95 (0.0014 g, 0.003
mmol, 32%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.98 (s, 1H), 8.49 (d
1H), 7.68 (dd, 1H), 7.47 (dd, 2H), 7.03 (dd, 2H), 5.40 (m, 1H),
4.83 (s, 2H), 3.38 (q, 2H), 3.15 (m, 2H), 1.49 (m, 2H), 1.03 (t,
3H.) MS: 438 (M+1), 436 (M-1)
Example 96
[0557] Monophenol 45 (0.05 g, 0.099 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added triethylamine (0.03 mL, 0.2
mmol) and pyrrolidine carbonyl chloride (0.0214 mL, 0.2 mmol.)
Stirred at 30.degree. C. for fifteen hours. Diluted with
dichloromethane, washed with 1 M HCl solution, concentrated
organics to give crude. Chromatographed (20% to 50%
ethylacetate/hexanes) to give product 96 (0.033 g, 0.0555 mmol,
57%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.11 (dd, 1H), 8.45 (d, 1H),
7.97 (s, 1H), 7.62 (d, 5H), 7.40 (dd, 2H), 7.27 (m, 6H), 7.05 (dd,
2H), 4.81 (s, 2H), 3.75 (dd, 2H), 3.54 (dd, 2H), 2.05 (m, 4H.) MS:
602 (M+1)
##STR00230##
Example 97
[0558] Carbamate 96 (0.033 g, 0.055 mmol) was dissolved in 0.5 mL
of dichloromethane. Triethylsilane (0.2 mL) and of trifluoroacetic
acid (0.1 mL) were added. The mixture was stirred at room
temperature and was complete after ten minutes by TLC. The mixture
was concentrated in vacuo and azeotroped with toluene to give a
crude residue which was triturated twice with 1:1
diethylether/hexanes to give product 97 (0.0123 g, 0.028 mmol,
51%). .sup.1H NMR (CDCl.sub.3) .delta. 8.98 (d, 1H), 8.51 (d, 1H),
7.70 (dd, 1H), 7.46 (dd, 2H), 7.03 (dd, 2H), 4.82 (s, 2H), 3.81
(dd, 2H), 3.57 (dd, 2H), 2.09 (m, 4H.) MS: 436 (M+1), 434 (M-1)
##STR00231##
Example 98
[0559] Monophenol 45 (0.03 g, 0.06 mmol) was dissolved in 1.5 mL of
dichloromethane. Triethylamine (0.033 mL, 0.238 mmol) and
diethylcarbamoyl chloride (0.015 mL, 0.119 mmol) were added. The
mixture was stirred at 60.degree. C. for five hours. The mixture
was diluted with dichloromethane, washed with 1 M HCl solution, and
concentrated to give crude product. The crude product was
chromatographed (20% to 50% ethylacetate/hexanes) to give product
98 (0.0237 g, 0.040 mmol, 66%.) .sup.1H NMR (CDCl.sub.3) .delta.
9.12 (s, 1H), 8.34 (d, 1H), 7.97 (s, 1H), 7.63 (d, 4H), 7.40 (dd,
2H), 7.27 (m, 7H), 7.01 (dd, 2H), 4.81 (s, 2H), 3.61 (dd, 2H), 3.50
(q, 2H), 1.41 (t, 3H), 1.37 (t, 3H.) MS: 604 (M+1)
##STR00232##
Example 99
[0560] Carbamate 98 (0.023 g, 0.04 mmol) was dissolved in 0.5 mL of
dichloromethane. Triethylsilane (0.2 mL) and trifluoroacetic acid
(0.1 mL) were added. The mixture was stirred at room temperature
and after ten minutes was complete by TLC. Concentrated off
volatiles, azeotroped with toluene to give crude. Triturated twice
with 1:1 diethylether/hexanes to give product 99 (0.01 g, 0.024
mmol, 60%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.98 (d, 1H), 8.45 (d,
1H), 7.70 (dd, 1H), 7.48 (dd, 2H), 7.03 (dd, 2H), 4.82 (s, 2H),
3.67 (q, 2H), 3.48 (q, 2H), 1.46 (t, 3H), 1.32 (t, 3H.) MS: 438
(M+1), 436 (M-1)
##STR00233##
Example 100
[0561] Trimethylsilyl ether 44 (0.022 g, 0.0373 mmol) was dissolved
in 0.5 mL dry tetrahydrofuran. To this was added triethylamine
(0.031 mL, 0.2238 mmol) and 1 M tetrabutylammonium fluoride
solution in tetrahydrofuran (0.0559 mL, 0.0559 mmol.) Stirred at
room temperature 10 minutes until starting material consumed. Then
added catalytic amount of dimethylaminopyridine and
2-oxo-1-imidazolidinecarbonyl chloride (0.022 g, 0.1492 mmol.)
Stirred at room temperature for three hours, then diluted with
dichloromethane, washed with 1M HCl solution, saturated
NaHCO.sub.3, saturated brine, concentrated to give crude.
Chromatographed (50% ethylacetate/hexanes to 1:1:1 methanol,
ethylacetate, hexanes) to give product 100 (0.0197 g, 0.031 mmol,
88%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.04 (dd, 1H), 8.31 (d, 1H),
8.02 (s, 1H), 7.73 (d, 4H), 7.53 (dd, 1H), 7.27 (m, 6H), 7.04 (dd,
2H), 5.00 (s, 1H) 4.80 (s, 2H), 4.10 (dd, 2H), 3.64 (dd, 2H.) MS:
603 (M+1)
##STR00234##
Example 101
[0562] Carbamate 100 (0.019 g, 0.031 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 101 (0.006 g, 0.011 mmol,
35%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 8.98 (s, 1H), 8.48
(d, 1H), 7.77 (dd, 1H), 7.72 (s, 1H), 7.36 (dd, 2H), 7.22 (dd, 2H),
4.70 (s, 2H), 4.37 (s, 2H), 4.03 (dd, 2H), 3.41 (dd, 2H.) .sup.19F
NMR: -74.6 MS: 437 (M+1), 435 (M-1)
##STR00235##
Example 102
[0563] Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. Triethylamine (0.042 mL,
0.3048 mmol) and 1 M tetrabutylammonium fluoride solution in
tetrahydrofuran (0.1016 mL, 0.1016 mmol) were added and stirred at
room temperature for 10 minutes until starting material was
consumed. A catalytic amount of dimethylaminopyridine was added,
followed by diethylcarbamoyl chloride (0.026 mL, 0.2032 mmol). The
mixture was stirred at room temperature for four hours, then
diluted with dichloromethane, washed with 1M HCl solution,
saturated NaHCO.sub.3, saturated brine, and concentrated to the
crude product. Chromatographed (25% to 50% ethylacetate/hexanes) to
give product 102 (0.014 g, 0.024 mmol, 47%.) .sup.1H NMR
(CDCl.sub.3) .delta. 9.04 (s, 1H), 8.11 (d, 1H), 8.03 (s, 1H), 7.76
(d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H), 7.08 (dd, 2H), 4.80 (s, 2H),
4.21 (s, 2H), 3.53 (q, 2H), 3.40 (q, 2H), 1.33 (t, 3H), 1.23 (t,
3H.) MS: 590 (M+1)
##STR00236##
Example 103
[0564] Carbamate 102 (0.01 g, 0.0169 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 103 (0.0073 g, 0.014 mmol,
80%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.01 (s, 1H), 8.23 (d, 1H),
7.60 (dd, 1H), 7.33 (dd, 2H), 7.09 (dd, 2H), 4.77 (s, 2H), 4.37 (s,
2H), 3.56 (q, 2H), 3.43 (q, 2H), 1.37 (t, 3H), 1.26 (t, 3H.)
.sup.19F NMR: -76.2 MS: 424 (M+1), 422 (M-1)
##STR00237##
Example 104
[0565] Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.042 mL, 0.3048 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.1016 mL, 0.1016 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Then added catalytic amount of dimethylaminopyridine and
dimethylcarbamoyl chloride (0.0187 mL, 0.2032 mmol.) Stirred at
room temperature for six hours, then diluted with dichloromethane,
washed with 1 M HCl solution, saturated NaHCO.sub.3, saturated
brine, concentrated to give crude. Chromatographed (20% to 50%
ethylacetate/hexanes) to give product 104 (0.014 g, 0.024 mmol,
48%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.04 (d, 1H), 8.14 (d, 1H),
8.03 (s, 1H), 7.75 (d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H), 7.16 (dd,
2H), 4.80 (s, 2H0, 4.23 (s, 2H), 3.19 (s, 3H), 3.02 (s, 3H.) MS:
562 (M+1)
##STR00238##
Example 105
[0566] Carbamate 104 (0.012 g, 0.021 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 105 (0.0068 g, 0.017 mmol,
82%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.96 (s, 1H), 8.25 (d, 1H),
7.59 (dd, 1H), 7.36 (dd, 2H), 7.09 (dd, 2H), 4.77 (s, 2H), 4.38 (s,
2H), 3.24 (s, 3H), 3.06 (s, 3H.) MS: 396 (M+1), 394 (M-1)
##STR00239##
Example 106
[0567] Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.0282 mL, 0.2032 mmol) and 1M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.076 mL, 0.076 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. After fifteen minutes, diluted with dichloromethane,
washed with washed with 1M HCl solution, saturated NaHCO.sub.3,
saturated brine, concentrated to give crude. Diluted in 1 mL
dichloromethane. To this was added triethylamine (0.028 mL, 0.2032
mmol), para-nitrochloroformate (0.02 g, 0.1016 mmol) and catalytic
dimethylaminopyridine. Stirred at room temperature for 30 minutes,
then diluted with dichloromethane, washed with saturated NH.sub.4Cl
solution, concentrated organics to give crude. Chromatographed (50%
ethylacetate/hexanes) to give product 106 (0.009 g, 0.0137 mmol,
27%) .sup.1H NMR (CDCl.sub.3) .delta. 9.10 (s, 1H), 8.16 (d, 2H),
8.10 (s, 1H), 7.71 (d, 4H), 7.53 (dd, 1H), 7.27 (m, 9H), 7.09 (dd,
2H), 6.93 (d, 2H), 4.79 (s, 2H), 4.23 (s, 2H.) MS: 656 (M+1)
##STR00240##
Example 107
[0568] Carbonate 106 (0.009 g, 0.0137 mmol) was dissolved in 0.5 mL
dichloromethane. To this was added triethylamine (0.0282 mL, 0.2032
mmol) and n-butylamine (0.01 mL, 0.1016 mmol) and stirred at room
temperature. After 15 minutes, starting material consumed. Diluted
with dichloromethane, washed with 1M HCl solution, saturated brine,
concentrated to give crude. Chromatographed (30%
ethylacetate/hexanes) to give product 107 (0.0075 g, 0.012 mmol,
88%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.02 (s, 1H), 8.15 (d, 1H),
8.04 (s, 1H), 7.75 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 6H), 7.08 (dd,
2H), 5.18 (s, 1H), 4.80 (s, 2H), 4.21 (s, 2H), 3.31 (q, 2H), 1.59
(m, 2H), 1.41 (m, 2H), 0.99 (t, 3H.) MS: 590 (M+1)
##STR00241##
Example 108
[0569] Carbamate 107 (0.007 g, 0.012 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 108 (0.0028 g, 0.0066 mmol,
56%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.98 (s, 1H), 8.27 (d, 1H),
7.59 (dd, 1H), 7.31 (dd, 2H), 7.06 (dd, 2H), 5.19 (s, 1H), 4.77 (s,
2H), 4.37 (s, 2H), 3.32 (q, 2H), 1.65 (m, 2H), 1.44 (m, 2H), 1.01
(t, 3H) MS: 424 (M+1), 422 (M-1)
##STR00242##
Example 109
[0570] Trimethylsilylethyl ether 44 (0.01 g, 0.0169 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.014 mL, 0.0339 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.0339 mL, 0.0339 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated NaHCO.sub.3, saturated brine, concentrated
to give crude. Dissolved in 0.5 mL dichloromethane, added catalytic
dimethylaminopyridine, triethylamine (0.042 mL, 0.1017 mmol) and
cooled to 0.degree. C. To this was added a 1 M solution of
triphosgene in dichloromethane (0.1017 mL, 0.1017 mmol) and stirred
30 minutes. Methyl piperazine (0.0168 mL, 0.1521 mmol) was then
added and stirred at room temperature for fifteen minutes. Diluted
with dichloromethane, washed with brine, concentrated volatiles to
give crude. Chromatographed (50% ethylacetate/hexanes to 10%
methanol/ethylacetate) to give product 109 (0.0055 g, 0.009 nmmol,
53%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.04 (d, 1H), 8.10 (d, 1H),
8.03 (s, 1H), 7.75 (d, 4H), 7.52 (dd, 1H), 7.27 (m, 8H), 7.05 (dd,
2H), 4.80 (s, 2H), 4.22 (s, 2H), 3.77 (br s, 2H), 3.58 (br s, 2H),
2.48 (br s, 4H), 2.37 (s, 3H) MS: 617 (M+1)
##STR00243##
Example 110
[0571] Carbamate 109 (0.007 g, 0.01136 mmol) was dissolved in 0.5
mL of dichloromethane. To this was added 0.2 mL of triethylsilane
and 0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 110 (0.004 g, 0.007 mmol,
63%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (s, 1H), 8.11 (d, 1H),
7.59 (dd, 1H), 7.35 (dd, 2H), 7.08 (dd, 2H), 4.78 (s, 2H), 4.35 (s,
2H), 3.50 (br m, 8H), 2.93 (s, 3H.), .sup.19F NMR: -76.2 MS: 451
(M+1), 449 (M-1)
##STR00244##
Example 111
[0572] Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. Triethylamine (0.0188 mL,
0.135 mmol) and 1 M tetrabutylammonium fluoride solution in
tetrahydrofuran (0.0678 mL, 0.0678 mmol) were added. The mixture
was stirred at room temperature for 10 minutes until starting
material consumed. The mixture was diluted with dichloromethane,
washed with 1M HCl solution, saturated NaHCO.sub.3, saturated
brine, and concentrated to give crude. The crude residue was
dissolved in 0.5 mL dichloromethane, and catalytic
dimethylaminopyridine, triethylamine (0.0188 mL, 0.135 mmol) and
ethyl isocyanatoacetate (Aldrich, St. Louis, Mo., 0.011 mL, 0.1017
mmol) were added and stirred at room temperature (Satchell and
Satchell, Chem. Soc. Rev. (1975) 4:231-250; R. G. Arnold et al.,
Chem. Soc. (1957) 57:47-76). After four hours, starting material
was consumed. The mixture was diluted with dichloromethane, washed
with 1M HCl, brine, and concentrated in vacuo to give crude
product. The crude product was chromatographed on silica gel (10%
to 50% ethylacetate/hexanes) to give product 111 (0.0118 g, 0.156
mmol, 46%) .sup.1H NMR (CDCl.sub.3) .delta. 9.07 (d, 1H), 8.73 (s,
1H), 8.17 (d, 1H), 8.08 (s, 1H), 7.76 (d, 4H), 7.57 (dd, 1H), 7.27
(m, 8H), 7.08 (dd, 2H), 4.81 (s, 2H), 4.74 (s, 2H), 4.20 (m, 4H),
4.07 (d, 4H), 1.27 (m, 6H). MS: 749 (M+1), 747 (M-1).
##STR00245##
Example 112
[0573] Carbamate 111 (0.01 g, 0.0177 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 112 (0.0056 g, 0.0095 mmol,
54%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.99 (s, 1H), 8.76 (s, 1H),
8.27 (d, 1H), 7.63 (dd, 1H), 7.35 (dd, 2H), 7.09 (dd, 2H), 4.79 (d,
4H), 4.33 (d, 2H), 4.23 (m, 4H), 4.09 (d, 2H), 1.30 (m, 6H.) MS:
583 (M+1), 581 (M-1)
##STR00246##
Example 113
[0574] Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.019 mL, 0.14 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.0678 mL, 0.0678 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated NaHCO.sub.3, saturated brine, concentrated
to give crude. Dissolved in 0.5 mL dichloromethane, added catalytic
dimethylaminopyridine, triethylamine (0.019 mL, 0.14 mmol) and
cooled to 0.degree. C. To this was added a 1M solution of
triphosgene in dichloromethane (0.0678 mL, 0.0678 mmol) and stirred
60 minutes. Morpholine (0.009 mL, 0.1016 mmol) was then added and
stirred at room temperature for 30 minutes. Diluted with
dichoromethane, washed with 1M HCl, brine, concentrated volatiles
to give crude. Chromatographed (40% ethylacetate/hexanes to 60%
ethylacetate/hexanes) to give product 113 (0.0176 g, 0.028 mmol,
86%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.05 (d, 1H), 8.09 (d, 1H),
8.04 (s, 1H), 7.75 (d, 4H), 7.53 (dd, 1H), 7.27 (m, 8H), 7.06 (dd,
2H), 4.81 (s, 1H), 4.23 (s, 2H), 3.78 (br s, 6H), 3.56 (br s, 2H.)
MS: 604 (M+1), 602 (M-1)
##STR00247##
Example 114
[0575] Carbamate 113 (0.017 g, 0.028 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 114 (0.0085 g, 0.015 mmol,
55%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.02 (s, 1H), 8.24 (d, 1H),
7.62 (dd, 1H), 7.33 (dd, 2H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.39 (s,
2H), 3.82 (br s, 6H), 3.60 (br s, 2H.) .sup.19F NMR: -76.2 MS: 438
(M+1), 436 (M-1)
##STR00248##
Example 115
[0576] Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
diisopropylethylamine (0.024 mL, 0.135 mmol) and 1 M
tetrabutylammonium fluoride solution in tetrahydrofuran (0.0678 mL,
0.0678 mmol.) Stirred at room temperature 10 minutes until starting
material consumed. Diluted with dichoromethane, washed with washed
with 1M HCl solution, saturated NaHCO.sub.3, saturated brine,
concentrated to give crude. Dissolved in 0.5 mL dichloromethane,
added catalytic dimethylaminopyridine, diisopropylethylamine (0.024
mL, 0.135 mmol) and cooled to 0.degree. C. To this was added a 1M
solution of triphosgene (bis[trichloromethyl]carbonate) in
dichloromethane (0.0678 mL, 0.0678 mmol) and stirred 45 minutes.
Dimethylhydrazine (0.01 mL, 0.135 mmol) was then added and stirred
at room temperature for 20 minutes. Diluted with dichloromethane,
washed with saturated NH.sub.4Cl solution, concentrated volatiles
to give crude. Chromatographed (10% ethylacetate/hexanes to 60%
ethylacetate/hexanes) and purified by preparatory TLC plate (60%
ethylacetate/hexanes) to give product 115 (0.004 g, 0.0069 mmol,
20%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.05 (d, 1H), 8.11 (d, 1H),
8.04 (s, 1H), 7.75 (d, 4H), 7.5 (dd, 1H), 7.27 (m, 8H), 7.07 (dd,
2H), 6.14 (s, 1H), 4.80 (s, 2H), 4.23 (s, 2H), 2.70 (6H.) MS: 577
(M+1)
##STR00249##
Example 116
[0577] Carbamate 115 (0.009 g, 0.0156 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 116 (0.003 g, 0.0057 mmol,
37%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.96 (s, 1H), 8.24 (d, 1H),
7.56 (dd, 1H), 7.33 (dd, 2H), 7.06 (dd, 2H), 4.76 (s, 2H), 4.39 (s,
2H), 2.74 (s, 3H.) .sup.19F NMR: -76.1 MS: 411 (M+1), 409 (M-1)
##STR00250##
Example 117
[0578] Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.0188 mL, 0.135 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.0678 mL, 0.0678 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated, saturated brine, concentrated to give
crude. Dissolved in 0.5 mL dichoromethane, added catalytic
dimethylaminopyridine.sub.7 triethylamine (0.0188 mL, 0.135 mmol)
and methyl (s)-(-)-2-isocyanato-3-methyl butyrate (0.0048 mL,
0.0339 mmol) and stirred at room temperature. After 4.5 hours,
starting material consumed. Diluted with dichloromethane, washed
with saturated NH.sub.4Cl solution, concentrated organics to give
crude. Chromatographed (10% to 50% ethylacetate/hexanes) to give
product 117 (0.0085 g, 0.013 mmol, 39%.) .sup.1H NMR (CDCl.sub.3)
.delta. 9.03 (s, 1H), 8.17 (d, 1H), 8.05 (s, 1H), 7.75 (4H), 7.52
(dd, 1H), 7.27 (m, 8H), 7.07 (dd, 2H), 5.70 (d, 1H), 4.80 (s, 2H),
4.21 (s, 2H), 3.79 (s, 3H), 2.28 (dsp, 1H), 1.03 (d, 3H), 0.98 (d,
3H.) MS: 649 (M+1)
##STR00251##
Example 118
[0579] Carbamate 117 (0.004 g, 0.006 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 118(0.0027 g, 0,0046 mmol,
76%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (S, 1H), 8.31 (d, 1H),
7.60 (dd, 1H), 7.33 (dd, 2H), 7.09 (dd, 2H), 5.76 (d, 1H), 4.77 (s,
2H), 4.36 (s, 2H), 3.81 (s, 3H), 2.28 (dsp, 1H), 1.06 (d, 3H), 1.00
(d, 3H.) .sup.19F NMR: -76.2 MS: 482 (M+1), 480 (M-1)
##STR00252##
Example 119
[0580] Trimethylsilylethyl ether 44 (0.2 g, 0.339 mmol) was
dissolved in 3 mL dry tetrahydrofuran. To this was added
triethylamine (0.139 mL, 1 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.0678 mL, 0.0678 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated brine, concentrated to give crude.
Dissolved in 3 mL dichloromethane, added catalytic
dimethylaminopyridine, triethylamine (0.754 mL, 5.4 mmol) and
cooled to 0.degree. C. To this was added a 1M solution of
triphosgene in dichloromethane (0.1356 mL, 0.1356 mmol) and stirred
50 minutes. BOC-piperazine (0.37 g, 2 mmol) was then added and
stirred at room temperature for 30 minutes. Diluted with
dichloromethane, washed with 1M HCl, brine, concentrated volatiles
to give crude. Chromatographed (10% to 30% acetone/toluene) to give
product 119 (0.1158 g, 0.166 mmol, 49%.) .sup.1H NMR (CDCl.sub.3)
.delta. 9.04 (d, 1H), 8.09 (d, 1H), 8.04 (s, 1H), 7.75 (d, 4H),
7.50 (dd, 1H), 7.27 (m, 8H), 7.05 (dd, 2H), 4.80 (s, 2H), 4.22 (s,
2H), 3.73 (br s, 2H), 3.53 (br s, 4H), 1.51 (s, 9H.) MS: 688
(M+1)
##STR00253##
Example 120
[0581] Carbamate 119 (0.057 g, 0.082 mmol) was dissolved in 1 L of
dichloromethane. To this was added 0.4 mL of triethylsilane and 0.2
mL of trifluoroacetic acid. Stirred at room temperature and after
ten minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene to give crude. Then dissolved in 1 mL dichloromethane,
1 ml trifluoroacetic acid. Stirred at room temperature for one
hour. Concentrated off volatiles, azeotroped with toluene to give
crude. Triturated twice with 1:1 diethylether/hexanes to give
product 120 (0.0317 g, 0.059 mmol, 72%.) .sup.1H NMR
(CD.sub.3SOCD.sub.3) .delta. 8.97 (br m, 2H), 8.40 (d, 1H), 7.75
(dd, 1H), 7.35 (dd, 2H), 7.23 (dd, 2H), 4.71 (s, 2H), 4.38 (s, 2H),
3.91 (br s, 2H), 3.24 (br s, 4H.) .sup.19F NMR: -74.5 MS: 437
(M+1), 435 (M-1)
##STR00254##
Example 121
[0582] Trimethylsilylethyl ether 44 (0.035 g, 0.0596 mmol) was
dissolved in 0.8 mL dry tetrahydrofuran. To this was added
triethylamine (0.05 mL, 0.358 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.119 mL, 0.119 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated brine, concentrated to give crude.
Dissolved in 0.8 mL dichloromethane, added triethylamine (0.05 mL,
0.358 mmol) and ethyl isocyanate (0.0046 mL, 0.0595 mmol) and
stirred at room temperature. After 6 hours, starting material
consumed. Diluted with dichloromethane, washed with saturated
brine, concentrated organics to give crude. Chromatographed (10% to
50% ethylacetate/hexanes) to give product 121 (0.0112 g, 0.023
mmol, 39%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.05 (s, 1H), 8.17 (d,
1H), 8.04 (s, 1H), 7.76 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 8H), 7.05
(dd, 2H), 4.80 (s, 2H), 4.23 (s, 2H), 3.33 (q, 2H), 1.27 (t, 3H.)
MS: 562 (M+1)
##STR00255##
Example 122
[0583] Carbamate 121 (0.0112 g, 0.023 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 122 (0.0033 g, 0.0076 mmol,
33%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.06 (s, 1H), 8.37 (d, 1H),
7.64 (dd, 1H), 7.33 (dd, 2H), 7.06 (dd, 2H), 5.24 (s, 1H), 4.77 (s,
2H), 4.39 (s, 2H), 3.38 (q, 2H), 1.30 (t, 3H.) .sup.19F NMR: -76.2
MS: 397 (M+1), 395 (M-1)
##STR00256##
Example 123
[0584] N-Methyl piperazine (0.33 mL, 3 mmol) was added slowly and
with caution to a mixture of sulfuryl chloride (0.72 mL, 9 mmol) in
6 mL of acetonitrile. The solution was heated to reflux for 15
hours. After starting material consumed, solution concentrated to
oil, azeotroped with toluene (2.times.), concentrated to give crude
product which was triturated with diethylether to give the product
123 as a pale brown solid (0.5 g, 71%.) .sup.1H NMR
(CD.sub.3SOCD.sub.3) .delta. 3.90 (br s, 2H), 3.59 (br s, 2H.),
3.38 (br. S, 4H), 2.67 (s, 3H); MS: 200 (M+1).
##STR00257##
Example 124
[0585] Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. Triethylamine (0.021 mL,
0.1525 mmol) and 1 M tetrabutylammonium fluoride solution in
tetrahydrofuran (0.1016 mL, 0.1016 mmol.) were added. The mixture
was stirred at room temperature 10 minutes until starting material
was consumed, then diluted with dichloromethane, washed with washed
with 1 M HCl solution, saturated brine, and concentrated. The crude
product was dissolved in 0.5 mL dichloromethane. Catalytic
diethylaminopyridine, triethylamine (0.035 mL, 0.254 mmol) and
methyl piperazine sulfamoyl chloride HCl salt 123 (0.024 g, 0.1016
mmol) were added and stirred at room temperature. After 15 hours,
starting material was consumed. The mixture was diluted with
dichloromethane, washed with saturated brine, and concentrated
organics to give crude product which was chromatographed (1% to 10%
methanol/dichloromethane) to give product 124 (0.016 g, 0.0246
mmol, 48%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.07 (s, 1H), 8.38 (d,
1H), 8.08 (s, 1H), 7.75 (d, 4H), 7.55 (dd, 1H), 7.27 (m, 8H), 7.08
(dd, 2H), 4.81 (s, 2H), 4.46 (s, 2H), 3.51 (br s, 4H), 2.54 (br s,
4H), 3.35 (s, 3H.) MS: 653 (M+1)
##STR00258##
Example 125
[0586] Sulfamate 124 (0.016 g, 0.0246 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 125 (0.008 g, 0.0133 mmol,
54%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.02 (s, 1H), 8.37 (d, 1H),
7.67 (dd, 1H), 7.33 (dd, 2H), 7.06 (dd, 2H), 4.80 (s, 2H), 4.57 (s,
2H), 3.95 (br s, 4H), 3.29 (br s, 4H), 2.89 (s, 3H.) .sup.19F NMR:
-76.2 MS: 487 (M+1), 485 (M-1)
##STR00259##
Example 126
[0587] Morpholine (0.436 mL, 5 mmol) was added slowly and with
caution to a mixture of sulfinyl chloride (1.205 mL, 15 mmol) in 5
mL acetonitrile. Heated to reflux and stirred for 24 hours. After
starting material consumed, solution concentrated to oil,
azeotroped with toluene (2.times.), concentrated to give crude
product 126 stored as a 2M solution in dichloromethane (0.999 g, 5
mmol, 100%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 3.80 (br s,
4H), 3.28 (br s, 4H.) MS: 186 (M+1)
##STR00260##
Example 127
[0588] Trimethylsilylethyl ether 44 (0.027 g, 0.0457 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.025 mL, 0.1828 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.0915 mL, 0.0915 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated brine, concentrated to give crude.
Dissolved in 0.5 mL dichloromethane, added catalytic
dimethylaminopyridine, triethylamine (0.025 mL, 0.1828 mmol) and 2
M morpholine sulfamoyl chloride solution 126 in dichloromethane
(0.05 g, 0.10 mmol) and stirred at room temperature. After 1.5
hours, starting material consumed. Diluted with dichloromethane,
washed with saturated brine, concentrated organics to give crude.
Chromatographed (10% to 40% ethylacetate/hexanes) to give product
127 (0.0199 g, 0.031 mmol, 68%.) .sup.1H NMR (CDCl.sub.3) .delta.
9.07 (s, 1H), 8.35 (d, 1H), 8.09 (s, 1H), 7.75 (d, 4H), 7.56 (dd,
1H), 7.27 (m, 8H), 7.05 (dd, 2H), 4.82 (s, 2H), 4.46 (s, 2H), 3.81
(m, 4H), 3.75 (m, 4H), 3.48 (m, 4H), 3.27 (m, 4H.) MS: 790
(M+1)
##STR00261##
Example 128
[0589] Sulfamate 127 (0.095 g, 0.012 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 128 (0.0054 g, 0.0086 mmol,
71%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (s, 1H), 8.45 (d, 1H),
7.65 (dd, 1H), 7.33 (dd, 2H), 7.10 (dd, 2H), 4.79 (s, 2H), 4.59 (s,
2H), 3.86 (m, 4H), 3.76 (m, 4H), 3.59 (m, 4H), 3.28 (m, 4H.) MS:
624 (M+1), 622 (M-1)
##STR00262##
Example 129
[0590] Trimethylsilylethyl ether 44 (0.1 g, 0.169 mmol) was
dissolved in 2 mL dry tetrahydrofuran. To this was added
triethylamine (0.094 mL, 0.676 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.339 mL, 0.339 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated brine, concentrated to give crude.
Dissolved in 1.5 mL dichloromethane, added catalytic
dimethylaminopyridine, triethylamine (0.139 mL, 1 mmol) and cooled
to 0.degree. C. To this was added triphosgene (0.1 g, 0.339 mmol)
and stirred 40 minutes. BOC-aminopiperidine (0.135 g, 0.678 mmol)
was then added and stirred at room temperature for 10 minutes.
Diluted with dichloromethane, washed with 1M HCl, brine,
concentrated volatiles to give crude. Chromatographed (10% to 50%
ethylacetale/hexanes) to give product 129 (0.072 g, 0.097 mmol,
59%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.04 (dd, 1H), 8.07 (d, 1H),
8.04 (s, 1H), 7.74 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 8H), 7.06 (dd,
2H), 4.80 (s, 2H), 4.48 (br s, 1H), 4.28 (m, 1H), 4.21 (s, 3H),
3.71 (br s, 2H), 3.21 (dd, 2H), 3.03 (dd, 2H), 1.48 (s, 9H.) MS:
717 M+1)
##STR00263##
Example 130
[0591] Carbamate 129 (0.07 g, 0.097 mmol) was dissolved in 2 mL of
dichloromethane. To this was added 0.5 mL of triethylsilane and 0.2
mL of trifluoroacetic acid. Stirred at room temperature and after
ten minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene to give crude. Then dissolved in 1.5 mL
dichloromethane, 1.5 ml trifluoroacetic acid. Stirred at room
temperature for one hour. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 130 (0.0329 g, 0.058 mmol,
60%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 8.98 (s, 1H), 8.22
(d, 1H), 7.95 (s, 2H), 7.74 (dd, 1H), 7.35 (dd, 2H), 7.19 (dd, 2H),
4.70 (s, 2H), 4.35 (s, 3H), 4.00 (br s, 1H), 3.44 (br s, 7H.)
.sup.19F NMR: -74.1 MS: 451 (M+1), 449 (M-1)
##STR00264##
Example 131
[0592] Triphosgene (0.06 g, 0.2032 mmol) was added to 0.5 mL
dichloromethane and cooled to 0.degree. C. To this was slowly added
glycine tertiary-butyl ester HCl salt (0.034 g, 0.2032 mmol) and
triethylamine (0.14 mL, 1 mmol) and stirred at 0.degree. C. Stirred
thirty minutes until starting material consumed. Simultaneously, in
a separate flask trimethylsilylethyl ether compound 44 was
dissolved in 0.5 mL tetrahydrofuran. To this was added
triethylamine (0.028 mL, 0.2032 mmol) and 1M tetrabutylammonium
fluoride in tetrahydrofuran (0.1016 mL, 0.1016 mmol) and stirred at
room temperature. After 20 minutes, diluted with dichoromethane,
washed with 1M HCl solution and brine, concentrated to give crude.
At 0.degree. C., crude dissolved in 0.5 mL dichloromethane and
added to the glycine isocyanate prepared in situ above. Stirred at
0.degree. C. for 5 minutes, then stirred for one hour at room
temperature. Diluted with dichloromethane, washed with 1 M HCl
solution, brine, concentrated to give crude. Chromatographed (10%
to 40% ethylacetate/hexanes) to give product 131 (0.017 g, 0.026
mmol, 52%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.03 (d, 1H), 8.20
(dd, 1H), 8.05 (s, 1H), 7.75 (d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H),
7.04 (dd, 2H), 5.66 (s, 1H), 4.79 (s, 2H), 4.23 (s, 2H), 3.93 (d,
2H), 1.5 (s, 9H.) MS: 648 (M+1)
##STR00265##
Example 132
[0593] Carbamate 131 (0.017 g, 0.026 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.2 mL of triethylsilane and
0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Then dissolved in 0.5 mL
dichloromethane, 0.2 mL triethylsilane, 0.2 ml trifluoroacetic
acid. Stirred at room temperature for three hours. Concentrated off
volatiles, azeotroped with toluene to give crude. Triturated with
1:1 diethylether/hexanes to give product 132 (0.0088 gm, 0.021
mmol, 80%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 8.97 (s, 1H),
8.40 (s, 1H), 8.30 (d, 1H), 7.74 (dd, 1H), 7.37 (m, 2H), 7.23 (m,
2H), 4.69 (s, 2H0, 4.32 (s, 2H), 3.76 (d, 2H.) .sup.19F NMR: -74.3
MS: 426 (M+1), 424 (M-1)
##STR00266##
Example 133
[0594] Carbamate 120 (0.019 g, 0.0435 mmol) was dissolved in 0.5 mL
of dichloroethane. To this was added triethylamine (0.072 mL, 0.52
mmol) and triisopropylsilyl chloride (0.058 mL, 0.26 mmol) and
stirred at 50.degree. C. After 19 hours, starting material
consumed, diluted with dichloromethane, washed with 1M HCl
solution, brine and concentrated to give crude. Chromatographed to
give product 133 (0.012 g, 0.0203 mmol, 47%.) .sup.1H NMR
(CDCl.sub.3) .delta. 8.86 (s, 1H), 8.06 (d, 1H), 7.54 (dd, 1H),
7.33 (dd, 2H), 7.08 (dd, 2H), 4.78 (s, 2H), 4.21 (s, 4H), 4.01 (br
s, 2H), 3.35 (br s, 4H), 11.58 (m, 1H), 1.16 (d, 18H.) MS: 593
(M+1)
##STR00267##
Example 134
[0595] Piperazine carbamate 133 (0.012 g, 0.0203 mmol) was
dissolved 0.5 mL of acetonitrile and 0.2 mL dichloromethane. To
this was added Cs.sub.2CO.sub.3 (0.0325 g, 0.1 mmol) and
2-bromoacetamide (0.009 g, 0.0608 mmol.) Stirred at room
temperature for 3.5 days, until starting material was consumed.
Diluted with dichloromethane, washed with saturated NH.sub.4Cl
solution, concentrated to give product 134 (0.0037 g, 0.0057, 28%.)
.sup.1H NMR (CDCl.sub.3) .delta. 8.87 (dd, 1H), 8.11 (d, 1H), 7.73
(s, 1H), 7.53 (dd, 1H), 7.34 (dd, 2H), 7.07 (dd, 2H), 4.78 (s, 2H),
4.23 (s, 2H), 3.84 (br s, 2H), 3.64 (br s, 2H), 3.14 (s, 2H), 2.62
(br s, 4H), 1.58 (m, 3H), 1.17 (d, 18H.) MS: 650 (M+1)
##STR00268##
Example 135
[0596] Mono-carbamate 134 (0.0037 g, 0.0057 mmol) was dissolved in
0.2 mL of dichloromethane. To this was added trifluoroacetic acid
(0.009 mL, 0.114 mmol) and stirred at room temperature. After
twenty hours, concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Triturate with 1:1
diethylether/hexanes to give product 135 (0.0015 g, 0.0024 mmol,
43%.) .sup.1H NMR (CD.sub.3OD) .delta. 8.96 (s, 1H), 8.38 (s, 1H),
7.75 (m, 2H), 7.39 (dd, 2H), 7.11 (dd, 2H), 4.87 (s, 2H), 4.42 (s,
2H), 4.0 (br m, 8H), 3.3 (s, 2H.) .sup.19F: -77.73 MS: 494 (M+1),
492 (M-1)
##STR00269##
Example 136
[0597] Piperazine carbamate 133 (0.033 g, 0.056 mmol) was dissolved
in 0.5 mL dichloromethane. To this was added catalytic
dimethylaminopyridine, triethylamine (0.031 mL, 0.225 mmol) and
methanesulfonyl chloride (0.0087 mL, 0.112 mmol) at 0.degree. C.
After five minutes, continued stirring at room temperature. After
one hour starting material consumed. Diluted with dichloromethane,
washed with saturated NH.sub.4Cl solution, dried (Na.sub.2SO.sub.4)
concentrated to give crude. Chromatographed (10% to 60%
ethylacetate/hexanes) to give product 136 (0.013 g, 0.019 mmol,
35%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.88 (dd, 1H), 8.08 (d, 1H),
7.53 (dd, 1H), 7.33 (dd, 2H), 7.05 (dd, 2H), 4.79 (s, 2H), 4.23 (s,
2H), 3.93 (br s, 2H), 3.72 (br s, 2H), 3.37 (br s, 4H), 2.88 (s,
3H), 1.58 (m, 3H), 1.17 (d, 18H.) MS: 671 (M+1)
##STR00270##
Example 137
[0598] Mono-carbamate 136 (0.013 g, 0.019 mmol) was dissolved in
0.5 mL of dichloromethane. To this was added trifluoroacetic acid
(0.056 mL, 0.72 mmol) and stirred at room temperature. After twenty
hours, concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Triturate with 1:1
diethylether/hexanes to give product 137 (0.0066 g, 0.013 mmol,
68%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.01 (s, 1H), 8.17 (s, 1H),
7.61 (s, 1H), 7.27 (dd, 2H), 7.07 (dd, 2H), 4.79 (s, 2H), 4.37 (s,
2H), 3.93 (br s, 2H), 3.72 (br s, 2H), 3.39 (br s, 4H), 2.89 (s,
3H.) MS: 515 (M+1), 513 (M-1)
##STR00271##
Example 138
[0599] Piperazine carbamate 133 (0.033 g, 0.056 mmol) was dissolved
in 0.5 mL dichloromethane. To this was added catalytic
dimethylaminopyridine, triethylamine (0.031 mL, 0.225 mol) and
methanesulfonyl chloride (0.0087 mL, 0.112 mmol) at 0.degree. C.
After five minutes, continued stirring at room temperature. After
one hour starting material consumed. Diluted with dichloromethane,
washed with saturated NH.sub.4Cl solution, dried Na.sub.2SO.sub.4)
concentrated to give crude. Chromatographed (10% to 50%
ethylacetate/hexanes) to giveproduct 138 (0.012 g, 0.017 mmol,
31%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.87 (dd, 1H), 8.09 (d, 1H),
7.53 (dd, 1H), 7.31 (dd, 2H), 7.07 (dd, 2H), 4.79 (s, 2H), 4.23 (s,
2H), 3.87 (br s, 2H), 3.66 (br s, 2H), 3.35 (br s, 4H), 2.89 (s,
6H), 1.56 (m, 3H), 1.17 (d, 18H.) MS: 700 (M+1)
##STR00272##
Example 139
[0600] Mono-carbamate 138 (0.012 g, 0.017 mmol) was dissolved in
0.5 mL of dichloromethane. To this was added trifluoroacetic acid
(0.056 mL, 0.72 mmol) and stirred at room temperature. After twenty
hours, concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Triturate with 1:1
diethylether/hexanes to give product 139 (0.0039 g, 0.007 mmol,
42%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (s, 1H), 8.18 (d, 1H),
7.60 (s, 1H), 7.27 (dd, 2H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.36 (s,
2H), 3.88 (br s, 2H), 3.67 (br s, 2H), 3.35 (br s, 4H), 2.89 (s,
6H.) MS: 544 (M+1), 542 (M-1)
##STR00273##
Example 140
[0601] Piperazine carbamate 133 (0.033 g, 0.056 m-mol) was
dissolved in 0.5 mL dichloromethane. To this was added catalytic
dimethylaminopyridine, triethylamine (0.031 mL, 0.225 mmol) and
methanesulfonyl chloride (0.0087 mL, 0.112 mmol) at 0.degree. C.
After five minutes, continued stirring at room temperature. After
one hour starting material consumed. Diluted with dichloromethane,
washed with saturated NH.sub.4Cl solution, dried (Na.sub.2SO.sub.4)
concentrated to give crude. Chromatographed (50% to 100%
ethylacetate/hexanes) to give product 140 (0.012 g, 0.018 mmol,
32%.) .sup.1H NMR (CDCl.sub.3) .delta. 8.85 (dd, 1H), 8.11 (d, 1H),
7.52 (dd, 1H), 7.31 (dd, 2H), 7.07 (dd, 2H), 4.79 (s, 2H), 4.23 (s,
2H), 3.82 (br s, 2H), 3.60 (br s, 2H), 3.34 (br s, 4H), 2.91 (s,
6H), 1.56 (m, 3H), 1.17 (d, 18H.) MS: 664 (M+1)
##STR00274##
Example 141
[0602] Mono-carbamate 140 (0.012 gm, 0.018 mmol) was dissolved in
0.5 mL of dichloromethane. To this was added trifluoroacetic acid
(0.056 mL, 0.72 mmol) and stirred at room temperature. After twenty
hours, concentrated off volatiles, azeotroped with toluene
(2.times.), concentrated to give crude. Triturate with 1:1
diethylether/hexanes to give product 141 (0.0051 g, 0.0083 mmol,
46%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (s, 1H), 8.21 (s, 1H),
7.60 (s, 1H), 7.27 (dd, 2H), 7.07 (dd, 2H), 4.76 (s, 2H), 4.37 (s,
2H), 3.83 (br s, 2H), 3.61 (br s, 2H), 3.35 (br s, 4H), 2.92 (s,
6H.) .sup.19F: -76.3 MS: 508 (M+1), 506 (M-1)
##STR00275##
Example 142
[0603] Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was
dissolved in 0.5 mL dry tetrahydrofuran. To this was added
triethylamine (0.028 mL, 0.2032 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.1016 mL, 0.1016 mmol.)
Stirred at room temperature 10 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated brine, dried (Na.sub.2SO.sub.4,)
concentrated to give crude. Dissolved in 0.5 mL dichloromethane,
added catalytic dimethylaminopyridine, triethylamine (0.08 mL, 0.6
mmol) and cooled to 0.degree. C. To this was added triphosgene
(0.03 g, 0.1016 mmol) and stirred 30 minutes. Azetid-3-yl carbamic
acid t-butyl ester (0.035 g, 0.2032 mmol) and triethylamine (0.08
mL, 0.6 mmol) was then added and stirred at room temperature for 50
minutes. Diluted with dichloromethane, washed with 1M HCl, brine,
dried (Na.sub.2SO.sub.4,) concentrated volatiles to give crude.
Chromatographed (10% to 50% ethylacetate/lexanes) to give product
142 (0.024 g, 0.035 mmol, 69%.) .sup.1H NMR (CDCl.sub.3) .delta.
9.04 (dd, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.74 (d, 4H), 7.51 (dd,
1H), 7.27 (m, 8H), 7.08 (dd, 2H), 5.00 (m, 1H), 4.80 (s, 2H), 4.52
(m, 2H), 4.23 (s, 2H), 3.91 (m, 2H), 1.48 (s, 9H.) MS: 689
(M+1)
##STR00276##
Example 143
[0604] Carbamate 142 (0.024 g, 0.035 mmol) was dissolved in 0.5 mL
of dichloromethane. To this was added 0.4 mL of triethylsilane and
0.2 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Then dissolved in 0.75 mL
dichloromethane, 0.75 ml trifluoroacetic acid. Stirred at room
temperature for one hour. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated twice with 1:1
diethylether/hexanes to give product 143 (0.0128 g, 0.024 mmol,
68%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.00 (s, 1H), 8.38
(br s, 3H), 7.75 (s, 1H), 7.36 (br s, 2H), 7.22 (br s, 2H), 4.72
(s, 2H), 4.32 (br m, 5H), 3.14 (br s, 2H.) .sup.19F NMR: -74.0 MS:
423 (M+1), 421 (M-1)
##STR00277##
Example 144
[0605] To crude triflate 7 (0.025 g, 0.048 mmol) in 1 mL of
dichloroethane was added triethylamine (0.014 mL, 0.096 mmol) and
benzenethiol (0.008 ml, 0.072 mmol) and the solution stirred at
room temperature. After 15 hrs, the mixture was concentrated and
chromatographed on silica gel eluting with EtOAc/hexanes to give
compound 144 (0.01 g, 44%) as a yellow oil. .sup.1H NMR
(CDCl.sub.3) .delta. 9.2 (m, 2H), 7.6 (dd, 1H), 7.06 (m, 5H), 7.0
(t, 2 H), 5.97 (s, 2H), 4.85 (s, 2H), 3.72 (s, 3H); MS: 474
(M+1)
Example 145
[0606] MOM ether 144 (0.009 g, 0.019 mmol) in 1 mL of
dichloromethane was treated with TFA (0.015 mL, 0.19 mmol) at room
temperature for 15 hrs. The volatiles were removed in vacuo and the
residue was triturated with diethylether to afford
7-(4-fluoro-benzyl)-9-hydroxy-5-phenylsulfanyl-pyrrolo[3,4-g]quinoline-6,-
8-dione 145 as a yellow solid. .sup.1H NMR (CDCl.sub.3) .delta.
9.31 (d, 2H), 7.81 (m, 1H), 7.46 (dd, 2H), 7.17 (m, 5H), 7.04 (t, 2
H), 5.97 (s, 2H), 4.88 (s, 2H); MS: 430 (M+1).
##STR00278##
Example 146
[0607] To the triflate 5 (0.045 g, 0.07 mmol) in toluene (0.7
mL)/ethanol (0.3 mL)/water (0.2 mL) were added potassium carbonate
(0.037 g, 0.175 mmol), trans-phenylvinylbronic acid (0.016 g, 0.105
mmol) and tetrakis (triphenylphosphine)-palladium (0) (0.012 g,
0.011 mmol). The mixture in the flask was flushed with argon three
times. It was heated to 120.degree. C. under argon for 3 hours.
Cooling to room temperature, it was diluted with EtOAc and washed
with 1N HCl, saturated NaHCO3 and brine. The organic phase was
dried (MgSO.sub.4) and concentrated. The residue was
chromatographed on a silica gel column, eluting with EtOAc/Hexane
to afford the product 146 (0.031 g, 75%). MS: 613 (M+Na).
Example 147
[0608] Compound 146 (8 mg, 0.013 mmol) was dissolved in
dichloromethane (1 mL) at room temperature under nitrogen.
Triethylsilane (0.034 mL) was added followed by TFA (0.02 mL)
slowly. The mixture was stirred at room temperature for 30 min. The
solvent was removed at reduced pressure. The crude product was
triturated in diethylether/hexane to afford a yellow solid
7-(4-fluoro-benzyl)-9-hydroxy-5-styryl-pyrrolo[3,4-g]quinoline-6,8--
dione 147 (0.005 g, 88%. .sup.1H NMR (CDCl.sub.3): .delta. 8.99 (d,
1H), 8.88 (d, 1H), 8.05 (d, 1H), 7.67 (m, 3H), 7.36-7.52 (m, 5H),
7.01 (m, 3H), 4.87 (s, 2H); MS: 425 (M+1).
##STR00279##
Example 148
[0609] To a solution of trifluoromethanesulfonic acid
diethoxyphosphorylmethyl ester (D. P. Phillion, et al, Tetra.
Lett., 27 (1986) 1477-1480, 0.040 g, 0.104 mmol) dissolved in
acetonitrile (0.75 mL) was added the phenol 6 (0.044 g, 0.146 mmol)
and CsCO.sub.3 (0.102 g, 0.314 mmol). The reaction mixture was
stirred at room temperature for 3 hours under an inert atmosphere
then filtered and concentrated in vacuo. The residue was purified
by silica gel chromatography (3/1--ethylacetate/hexane) to afford
the product 148 (0.014 g, 25%) as a solid: .sup.1H NMR (CDCl.sub.3)
.delta. 9.1 (d, 1H), 8.9 (d, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0
(t, 2H), 5.8 (s, 2H), 5.0 (d, 2H), 4.8 (s, 2H), 4.2 (m, 4H), 3.7
(s, 3H), 1.3 (t, 6H); .sup.31P NMR (CDCl.sub.3) .delta. 19.0; MS:
533 (M+1).
##STR00280##
Example 149
[0610] A solution of the phosphonate 148 (0.014 g, 0.026 mmol) in
dichloromethane (0.96 mL) was treated with trifluoroacetic acid
(0.020 mL, 0.260 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere for 3 hours. The volatiles
were removed in vacuo with toluene. The solid was triturated in
diethylether/hexane to afford the product 149 (0.11 g, 86%) as a
TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.9 (d,
1H), 7.7 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 5.0 (d, 2H), 4.9 (s,
2H), 4.2 (m, 4H), 1.3 (s, 6H); .sup.31P NMR (CDCl.sub.3) .delta.
19.2; MS: 489 (M+1), 487 (M-1).
##STR00281##
Example 150
[0611] Dibenzyl hydroxymethyl phosphonate triflate was prepared
from dibenzyl hydroxymethyl phosphonate (M. Krecmerova, et al,
Czech. Chem. Commun., 55, 1990, 2521-2536) by the method of: Y. Xu,
et al, J. Org. Chem., 61 (1996) 7697-7701. To a solution of
dibenzyl hydroxymethyl phosphonate triflate (0.050 g, 0.131 mmol)
dissolved in acetonitrile (1.87 mL) was added the phenol 6 (0.078
g, 0.183 mmol) and CsCO.sub.3 (0.102 g, 0.314 mmol). The reaction
mixture was stirred at room temperature for 3 hours under an inert
atmosphere then filtered and concentrated in vacuo. The residue was
purified by silica gel chromatography (1/1--ethylacetate/hexane) to
afford the product 150 (0.030 g, 35%) as a solid: .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (d, 1H), 8.65 (d, 1H), 7.5 (dd, 2H), 7.4
(dd, 1H), 7.3 (m, 10H), 7.0 (t, 2H), 5.8 (s, 2H), 5.1 (m, 4H), 4.9
(d, 2H), 4.8 (s, 2H), 3.7 (s, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 20.1; MS: 657 (M+1).
##STR00282##
Example 151
[0612] A solution of the phosphonate 150 (0.029 g, 0.044 mmol) in
dichloromethane (1.6 mL) was treated with trifluoroacetic acid
(0.034 mL, 0.44 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere for 3 hours. The volatiles
were removed in vacuo with toluene. The solid was triturated in
diethylether/hexane to afford the product 151 (0.024 g, 89%) as a
TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 8.9 (d, 1H), 8.6 (d,
1H), 7.5 (dd, 2H), 7.45 (dd, 1H), 7.3-7.2 (m, 10H), 7.0 (t, 2H),
5.1-5.0 (m, 4H), 5.0 (d, 2H), 4.8 (s, 2H); .sup.31P NMR
(CDCl.sub.3) .delta. 20.3; MS: 613 (M-1), 611 (M-1).
##STR00283##
Example 152
[0613] To a solution of diallyl hydroxymethyl phosphonate triflate
(prepared by a method similar to: D. P. Phillion, et al, Tetra.
Lett., 27 (1986) 1477-1480 and Y. Xu, et al, J. Org. Chem., 61
(1996) 7697-7701, 0.153 g, 0.471 mmol) dissolved in acetonitrile
(6.7 mL) was added
7-(4-fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,-
8-dione 6 (0.060 g, 0.157 mmol) and CsCO.sub.3 (0.154 g, 0.471
mmol). The reaction mixture was stirred at room temperature for 2
hours under an inert atmosphere ten filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography
(3/1--ethylacetate/hexane) to afford
[7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyr-
rolo[3,4-g]quinolin-5-yloxymethyl]-phosphonic acid diallyl ester
152 (0.051 g, 59%) as a solid: .sup.1H NMR (CDCl.sub.3) .delta.
9.05 (d, 1H), 8.85 (d, 1H), 7.6 (dd, 1H), 7.45 (dd, 2H), 7.0 (t,
2H), 5.9 (m, 2H), 5.8 (s, 2H), 5.3 (d, 2H), 5.2 (d, 2H), 5.0 (d,
2H), 4.8 (s, 2H), 4.6 (m, 4H), 3.7 (s, 3H); .sup.31P NMR
(CDCl.sub.3) .delta. 19.9; MS: 557 (M+1).
##STR00284##
Example 153
[0614] A solution of the phosphonate 152 (0.0065 g, 0.0117 mmol) in
dichloromethane (0.425 mL) was treated with trifluoroacetic acid
(0.009 mL, 0.117 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere for 1 hour. The volatiles
were removed in vacuo with toluene. The solid was triturated in
diethylether/hexane to afford the product 153 (0.006 g, 100%) as a
TFA salt: .sup.1H MR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.9 (d, 1H),
7.7 (dd, 2H), 7.5 (dd, 1H), 7.0 (t, 2H), 5.9 (m, 2H), 5.3 (d, 2H),
5.2 (d, 2H), 5.0 (d, 2H), 4.85 (s, 2H), 4.6 (m, 4H); .sup.31P NMR
(CDCl.sub.3) .delta. 20.0; MS: 513 (M+1), 511 (M-1).
##STR00285##
Example 154
[0615] Diethyl hydroxymethyl phosphonate triflate was prepared from
diethyl hydroxymethyl phosphonate (Aldrich, St. Louis, Mo.,) by the
method of: D. P. Phillion, et al, Tetra. Lett., 27, 1986,
1477-1480. To a solution of diethyl hydroxymethyl phosphonate
triflate (0.61 g, 0.202 mmol) dissolved in acetonitrile (2.9 mL)
was added the phenol 12 (0.100 g, 0.202 mmol) and CsCO.sub.3 (0.198
g, 0.607 mmol). The reaction mixture was stirred at room
temperature for 3 hours under an inert atmosphere then filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography (1/1--ethylacetate/hexane) to afford the product 154
(0.130 g, 100%) as a solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.95
(d, 1H), 8.9 (d, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.9
(d, 2H), 4.8 (s, 2H), 4.2 (m, 4H), 1.5 (m, 3H), 1.3 (t, 6H), 1.2
(d, 18H); .sup.31P NMR (CDCl.sub.3) .delta. 19.5; MS: 645
(M+1).
##STR00286##
Example 155
[0616] A solution of the phosphonate 154 (0.020 g, 0.031 mmol) in
dichloromethane (0.311 mL) was treated with trimethylsilane bromide
(0.0246 mL, 0.186 mmol). The reaction mixture was stirred at room
temperature overnight under an inert atmosphere. The volatiles were
removed in vacuo with methanol. The solid was washed with
dichloromethane to afford the diacid 155 (0.010 g, 77%): .sup.1H
NMR (CD.sub.3OD) .delta. 9.5 (d, 1H), 9.2 (d, 1H), 8.2 (dd, 1H),
7.5 (dd, 2H), 7.1 (t, 2H), 5.0 (d, 2H), 4.9 (s, 2H); .sup.31P NMR
(CD.sub.3OD) .delta. 16.2; MS: 433 (M+1), 431 (M-1).
##STR00287##
Example 156
[0617] To a solution of the phosphonate 154 (0.038 g, 0.059 mmol)
dissolved in dichloromethane (0.297 mL) and ethanol (0.297 mL) was
added sodium borohydride (0.475 mL, 0.237 mmol). The reaction
mixture stirred at room temperature overnight under an inert
atmosphere and then was concentrated in vacuo. The residue was
dissolved in ethylacetate and washed with saturated NH.sub.4Cl and
brine. The organic phase was dried (MgSO.sub.4) then concentrated
in vacuo. The residue was purified by silica gel chromatography
(1/99--methanol/dichloromethane) to afford the product 156 (0.022
g, 59%): .sup.1H NMR (CDCl.sub.3) .delta. 8.9 (d, 1H), 8.4 (d, 1H),
7.5 (dd, 1H), 7.4 (dd, 2H), 7.0 (t, 2H), 6.0 (s, 1H), 5.8 (bs, 1H),
5.2 (d, 1H), 4.6-4.4 (m, 2H), 4.4 (d, 1H), 4.3-4.2 (m, 4H), 1.6 (m,
3H), 1.4 (m, 6H), 1.15 (d, 18H); .sup.31P NMR (CDCl.sub.3) .delta.
20.95; MS: 647 (M+1).
##STR00288##
Example 157
[0618] A solution of the phosphonate 156 (0.025 g, 0.039 mmol) in
dichloromethane (1.41 mL) was treated with trifluoroacetic acid
(0.030 mL, 0.390 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere overnight. The volatiles were
removed in vacuo, azeotroping to dryness with toluene. The solid
was triturated in diethylether/hexane to afford the product 157
(0.021 g, 100%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 9.0
(d, 1H), 8.6 (d, 1H), 7.6 (dd, 1H), 7.4 (dd, 2H), 7.0 (t, 2H), 6.2
(bs, 1H), 6.0 (s, 1H), 5.1 (d, 1H), 4.7-4.5 (m, 2H), 4.5 (d, 1H),
4.25 (m, 4H), 1.4 (m, 6H); .sup.31P NMR (CDCl.sub.3) .delta. 20.1;
MS: 491 (M+1), 489 (M-1).
##STR00289##
Example 158
[0619] A solution of phosphonate 157 (0.0185 g, 0.0378 mmol) in
dichloromethane (0.455 mL) was cooled to 0.degree. C.
Triethylsilane (0.0603 mL, 0.378 mmol) and then trimethylsilane
triflate (0.0205 mL, 0.113 mmol) were added. The reaction stirred
for 15 minutes under an inert atmosphere. The mixture was
partitioned between dichloromethane and water. The organic phase
was washed with saturated NaHCO.sub.3 then dried (MgSO.sub.4) and
concentrated in vacuo. The solid was triturated in
diethylether/hexane to afford the product 158 (0.015 g, 84%):
.sup.1H NMR (CDCl.sub.3) .delta. 9.0 (dd, 1H), 8.6 (dd, 1H), 7.6
(dd, 1H), 7.35 (dd, 2H), 7.15 (t, 2H), 4.8 (s, 2H), 4.5 (s, 2H),
4.3 (d, 2H), 4.2 (m, 4H), 1.3 (t, 6H); .sup.31P NMR (CDCl.sub.3)
.delta. 18.7; MS: 475 (M+1).
##STR00290##
Example 159
[0620] To a solution of phenol 6 (0.063 g, 0.165 mmol) dissolved in
THF (0.86 mL) was added dimethyl hydroxyethyl phosphonate (0.076 g,
0.495 mmol), triphenylphosphine (0.108 g, 0.412 mmol), and diethyl
azodicarboxylate (0.039 mL, 0.247 mmol). The reaction mixture
stirred at room temperature under an inert atmosphere overnight.
The residue was purified directly by silica gel chromatography
(5/95--methanol/ethylacetate) to afford the product 159 (0.022 g,
26%): .sup.1H NMR (CDCl.sub.3) .delta. 9.05 (d, 1H), 8.9 (d, 1H),
7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 5.8 (s, 2H), 4.8 (d, 2H),
4.75 (m, 2H), 3.8 (d, 6H), 3.7 (s, 3H), 2.5 (m, 2H); .sup.31P NMR
(CDCl.sub.3) .delta. 30.2; MS. 519 (M+1).
##STR00291##
Example 160
[0621] A solution of the phosphonate 159 (0.012 g, 0.024 mmol) in
dichloromethane (0.863 mL) was treated with trifluoroacetic acid
(0.018 mL, 0.240 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere overnight. The volatiles were
removed in vacuo with toluene. The solid was triturated in
diethylether/hexane to afford the product 160 (0.0095 g, 84%) as a
TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.9 (d,
1H), 7.7 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.85 (d, 2H), 4.8 (m,
2H), 3.8 (d, 6H), 2.5 (m, 2H); .sup.31P NMR (CDCl.sub.3) .delta.
30.3; MS: 475 (M+1), 473 (M-1).
##STR00292##
Example 161
[0622] A solution of diethyl phosphonacetic acid (0.700 g, 3.57
mmol) dissolved in THF was cooled to 0.degree. C. Borane-THF
complex (7.14 mL) in 1M THF was added dropwise. The reaction
mixture was stirred for 3 hours under an inert atmosphere then
concentrated in vacuo. The residue was directly purified by silica
gel chromatography (5/95--methanol/ethylacetate) to afford the
product, diethyl hydroxyethyl phosphonate, 161 (0.583 g, 90%) as an
oil: .sup.1H NMR (CDCl.sub.3) .delta. 4.1 (m, 4H), 3.9 (m, 2H), 2.1
(m, 2H), 1.3 (t, 6H); .sup.31P NMR (CDCl.sub.3) .delta. 30.4; MS:
183 (M+1).
Example 162
[0623] To a solution of phenol 12 (0.023 g, 0.046 mmol) dissolved
in THF (0.24 mL) was added diethyl hydroxyethyl phosphonate 161
(0.025 g, 0.137 mmol), triphenylphosphine (0.030 g, 0.114 mmol),
and diethyl azodicarboxylate (0.011 mL, 0.069 mmol). The reaction
mixture stirred at room temperature under an inert atmosphere
overnight. The residue was purified directly by silica gel
chromatography (75/25--ethylacetate/hexane). The residue was
purified again by silica gel chromatography
(80/20--toluene/acetone) to afford the product 162 (0.032 g, 48%):
.sup.1H NMR (CDCl.sub.3) .delta. 8.9 (d, 1H), 8.8 (d, 1H), 7.6 (dd,
1H), 7.45 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.7 (m, 2H), 4.15 (m,
4H), 2.5 (m, 2H), 1.5 (m, 3H), 1.3 (g, 6H), 1.2 (d, 18H); .sup.31P
NMR (CDCl.sub.3) .delta. 27.6; MS: 659 (M+1).
Example 163
[0624] A solution of the phosphonate 162 (0.012 g, 0.018 mmol) in
dichloromethane (0.663 mL) was treated with trifluoroacetic acid
(0.014 mL 0.180 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere overnight. The volatiles were
removed in vacuo with toluene. The solid was triturated in
diethylether/hexane to afford the product 163 (0.008 g, 89%) as a
TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (dd, 1H), 8.9 (dd,
1H), 7.7 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.75 (m,
2H), 4.15 (m, 4H), 2.45 (m, 2H), 1.3 (t, 6H); .sup.31P NMR
(CDCl.sub.3) .delta. 27.5; MS: 503 (M+1), 501 (M-1).
##STR00293##
Example 164
[0625] To a solution of phenol 12 (0.097 g, 0.196 mmol) dissolved
in THF (1.02 mL) was added (2-hydroxyethyl)-phosphonic acid
dimethyl ester (0.091 g, 0.589 mmol), triphenylphosphine (0.129 g,
0.491 mmol), and diethyl azodicarboxylate (0.046 mL, 0.295 mmol).
The reaction mixture stirred at room temperature under an inert
atmosphere overnight. The residue was purified directly by silica
gel chromatography (85/15--ethylacetate/hexane) to afford a mixture
of product 164 and triphenylphosphine oxide (0.160 g): .sup.1H NMR
(CDCl.sub.3) .delta. 8.95 (d, 1H), 8.75 (d, 1H), 7.7-7.4 (m, 12H),
7.0 (t, 2H), 4.8 (s, 2H), 4.7 (m, 2H), 3.8 (d, 6H), 2.5 (m, 2H),
1.5 (m, 3H), 1.2 (d, 18H); .sup.31P NMR (CDCl.sub.3) .delta. 30.5
(triphenylphosphine oxide), 29.3; MS: 631 (M+1).
##STR00294##
Example 165
[0626] A solution of the phosphonate 164 (0.025 g, 0.040 mmol) in
dichloromethane (0.397 mL) was treated with trimethylsilane bromide
(0.0314 mL, 0.24 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere overnight. The volatiles were
removed in vacuo with methanol. The solid was washed with
dichloromethane to afford the diacid 165 (0.0094 g, 53%): .sup.1H
NMR (CD.sub.3OD) .delta. 9.4 (dd, 1H), 9.1 (dd, 1H), 8.05 (dd, 1H),
7.5 (dd, 2H), 7.1 (t, 2H), 4.9 (s, 21), 4.8 (m, 2H), 2.45 (m, 2H);
.sup.31P NMR (CD.sub.3OD) .delta. 24.7; MS: 447 (M+1), 445
(M-1).
##STR00295##
Example 166
[0627] To a solution of allylphosphonic dichloride (4 g, 25.4 mmol)
and phenol (5.2 g, 55.3 mmol) in CH.sub.2Cl.sub.2 (40 mL) at
0.degree. C. was added triethylamine (TEA, 8.4 ML, 60 mmol). After
stirring at room temperature for 1.5 h, the mixture was diluted
with hexane-ethylacetate and washed with HCl (0.3 N) and water. The
organic phase was dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. The residue was filtered through a pad of
silica gel (eluted with 2:1 hexane-ethyl acetate) to afford crude
product diphenol allylphosphonate (7.8 g, containing the excessive
phenol) as an oil which was used directly without any further
purification. The crude material was dissolved in CH.sub.3CN (60
mL), and NaOH (4.4N, 15 mL) was added at 0.degree. C. The resulting
mixture was stirred at room temperature for 3 h, then neutralized
with acetic acid to pH=8 and concentrated under reduced pressure to
remove most of the acetonitrile. The residue was dissolved in water
(50 mL) and washed with CH.sub.2Cl.sub.2 (three 25 mL portions).
The aqueous phase was acidified with concentrated HCl at 0.degree.
C. and extracted with ethyl acetate. The organic phase was dried
over MgSO.sub.4, filtered, evaporated and co-evaporated with
toluene under reduced pressure to yield desired monophenol
allylphosphonate (4.75 g. 95%) as an oil.
[0628] To a solution of monophenol allylphosphonate (4.75 g, 24
mmol) in toluene (30 mL) was added SOCl.sub.2 (5 mL, 68 mmol) and
DMF (0.05 mL). After stirring at 65.degree. C. for 4 h, the
reaction was complete as shown by .sup.31P NMR. The reaction
mixture was evaporated and co-evaporated with toluene under reduced
pressure to give the mono chloride (5.5 g) as an oil. To a solution
of the mono chloride in CH.sub.2Cl.sub.2 (25 mL) at 0.degree. C.
was added ethyl (S)-lactate (3.3 mL, 28.8 mmol), followed by TEA.
The mixture was stirred at 0.degree. C. for 5 min, then at room
temperature for 1 h, and concentrated under reduced pressure. The
residue was partitioned between ethylacetate and HCl (0.2N), the
organic phase was washed with water, dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel to afford the allyl
monolactate (5.75 g, 80%) as an oil (2:1 mixture of two isomers):
.sup.1H NMR (CDCl.sub.3) .delta. 7.1-7.4 (m, 5H), 5.9 (m, 1H), 5.3
(m, 2H), 5.0 (m, 1H), 4.2 (m, 2H), 2.9 (m, 2H), 1.6; 1.4 (d, 3H),
1.25 (m, 3H); .sup.31P NMR (CDCl.sub.3) .delta. 25.4, 23.9.
[0629] A solution of the ally) monolactate (2.5 g, 8.38 mmol) in
CH.sub.12Cl.sub.2 (30 mL) was bubbled with ozone air at -78.degree.
C. until the solution became blue, then bubbled with nitrogen until
the blue color disappeared. Methyl sulfide (3 mL) was added at
-78.degree. C. The mixture was warmed up to room temperature,
stirred for 16 h and concentrated under reduced pressure to give
desired aldehyde 166 (3.2 g, as a 1:1 mixture of DMSO): .sup.1H NMR
(CDCl.sub.3) .delta. 9.8 (m, 1H), 7.1-7.4 (m, 5H), 5.0 (m, 1H), 4.2
(m, 2H), 3.4 (m, 2H), 1.6; 1.4 (d, 3H), 1.25 (m, 3H). .sup.31P NMR
(CDCl.sub.3) .delta. 17.7, 15.4.
##STR00296##
Example 167
[0630] To a solution of
2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl
ester; aldehyde 166 (0.082 g, 0.218 mmol) in a 1: mixture of DMSO
and 1,2-dichloroethane was added acetic acid (0.050 mL, 0.870 mmol)
then sodium cyanoborohydride (0.027 g, 0.435 mmol). The reaction
mixture stirred at room temperature for three hours under an inert
atmosphere. Saturated NaHCO.sub.3 was added to the reaction mixture
and was stirred for five more minutes. The mixture was concentrated
in vacuo to remove most of the dichloroethane. Brine was added and
then the crude product was extracted into ethylacetate. The organic
phase was dried (MgSO.sub.4) and concentrated. The residue was
purified by silica gel chromatography
(5/95--methanol/dichloromethane) to afford the product 167 (0.047
g, 73%), an oil as a mixture of two diastereomers: .sup.1H NMR
(CDCl.sub.3) .delta. 7.1-7.4 (m, 5H), 5.1 (m, 1H), 4.25 (m, 2H),
4.1 (m, 2H), 2.3 (m, 4H), 1.6 & 1.4 (d, 3H), 1.25 (m, 3H);
.sup.31P NMR (CDCl.sub.3) .delta. 29.0, 26.8.
Example 168
[0631] To a solution of phenol 40 (0.033 g, 0.065 mmol) dissolved
in THF (0.34 mL) was added ethyl-lactate phosphonate alcohol 167
(0.029 g, 0.097 mmol), triphenylphosphine (0.043 g, 0.162 mmol),
and diethyl azodicarboxylate (0.015 mL, 0.097 mmol). The reaction
mixture stirred at room temperature under an inert atmosphere
overnight. The residue was purified directly by silica gel
chromatography (50/50--ethylacetate/hexane) to afford the product
168 (0.027 g, 53%). Separation of the diastereomers by
chromatography allowed for characterization of 168a (0.016 g):
.sup.1H NMR (CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.8 (dd, 1H), 7.9
(s, 1H), 7.6 (m, 4H), 7.55 (m, 1H), 7.4 (dd, 2H), 7.1-7.4 (m, 11H),
7.0 (t, 2H), 5.0 (m, 1H), 4.9 (s, 2H), 4.8 (m, 2H), 4.1 (q, 3H),
2.75 (m, 2H), 1.4 (d, 3H), 1.2 (t, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 26.05; MS: 790 (M+1)--and 168b (0.011 g): .sup.1H NMR
(CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.8 (dd, 1H), 7.95 (s, 1H), 7.6
(m, 4H), 7.55 (m, 1H), 7.40 (dd, 2H), 7.1-7.4 (m, 11H), 7.05 (t,
2H), 5.05 (m, 1H), 4.85 (s, 2H), 4.8 (m, 2H), 4.15 (q, 3H), 2.7 (m,
2H), 1.55 (d, 3H), .sup.31P NMR (CDCl.sub.3) .delta. 24.37; MS: 790
(M+1)
##STR00297##
Example 169a
[0632] A solution of the phosphonate 168a (0.013 g, 0.0165 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1
mL) and triethylsilane (0.2 mL). The reaction mixture was stirred
at room temperature under an inert atmosphere for 20 minutes. The
volatiles were removed in vacuo with toluene. The solid was
triturated in diethylether/hexane to afford the product 169a (0.008
g, 80%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 8.95 (dd,
1H), 8.9 (dd, 1H), 7.6 (m, 1H), 7.5 (dd, 2H), 7.1-7.4 (m, 5H), 7.0
(t, 2H), 5.0 (m, 1H), 5.0 (m, 2H), 4.85 (s, 2H), 4.15 (q, 3H), 2.8
(m, 2H), 1.4 (d, 3H), 1.25 (t, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 26.13; MS: 623 (M+1), 621 (M-1).
Example 169b
[0633] A solution of the phosphonate 168b (0.011 g, 0.014 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1
mL) and triethylsilane (0.2 mL). The reaction mixture was stirred
at room temperature under an inert atmosphere for 20 minutes. The
volatiles were removed in vacuo with toluene. The solid was
triturated in diethylether/hexane to afford the product 169b (0.005
g, 60%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 8.95 (dd,
1H), 8.9 (dd, 1H), 7.65 (m, 1H), 7.5 (dd, 2H), 7.1-7.4 (m, 5H), 7.0
(t, 2H), 5.1 (m, 2H), 4.9 (m, 1H), 4.85 (s, 2H), 4.15(q, 3H), 2.7
(m, 2H), 1.55 (d, 3H), 1.2 (t, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 24.44; MS: 623 (M+1), 621 (M-1).
##STR00298##
Example 170
[0634] A solution of ethyl-lactate phosphonate 169 (0.021 g, 0.034
mmol) in DMSO (0.675 mL) and phosphate buffer saline (3.38 ml) was
heated to 40.degree. C. The reaction mixture was treated with
esterase--from porcine liver (0.200 mL) and stirred overnight.
Another equivalent of esterase was added the following day and the
mixture stirred another day. The mixture was concentrated and
purified by reversed phase HPLC to afford the product 170 (0.008 g,
46%) as a solid: .sup.1H NMR (CD.sub.3OD) .delta. 8.95 (dd, 1H),
8.9 (dd, 1H), 7.75 (m, 1H), 7.45 (dd, 2H), 7.05 (t, 2H), 4.9 (s,
2H), 4.85 (m, 3H), 2.5 (m, 2H), 1.5 (d, 3H); .sup.31P NMR
(CD.sub.3OD) .delta. 26.26; MS: 519 (M+1), 517 (M-1).
##STR00299##
Example 171
[0635] To a solution of phenol 4 (1.14 g, 2.79 mmol) dissolved in
dioxane (27.9 mL) was added 2-(trimethylsilyl)-ethanol (0.600 mL,
4.18 n-mol), triphenylphosphine (1.46 g, 5.57 mmol), and diethyl
azodicarboxylate (0.88 mL, 5.57 mmol). The reaction mixture stirred
at room temperature under an inert atmosphere overnight. The
residue was purified directly by silica gel chromatography
(30/70--ethylacetate/hexane) to afford the product 171 (0.240 g,
67%): .sup.1H NMR (CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.5 (dd, 1H),
7.65 (dd, 1H), 7.45 (dd, 2H), 7.0 (t, 2H), 4.9 (m, 2H), 4.8 (s,
2H), 4.45 (q, 2H), 1.5 (t, 3H), 1.4 (m, 2H), 0.1 (s, 9H; MS: 510
(M+1).
##STR00300##
Example 172
[0636] To the ethyl carbonate 171 (0.716 g, 1.4 mmol) in THF (70.2
mL) was added a solution (45 mL) of K.sub.2CO.sub.3 (1.94 g, 14
mmol) in water and 4-dimethylaminopyridine (0.035 g, 0.281 mmol).
The yellow solution was stirred at room temperature under an inert
atmosphere overnight. Most of THF was removed in vacuo and the
remaining solution was diluted with dichloromethane, washed with 1N
HCl and brine, then dried (MgSO.sub.4) and concentrated. The crude
product was triturated in diethylether/hexane to afford the yellow
solid product 172 (0.428 g, 70%): .sup.1H NMR (CDCl.sub.3) .delta.
9.1 (dd, 1H), 8.65 (dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t,
2H), 4.85 (s, 2H), 4.85 (m, 2H), 1.35 (m, 2H), 0.1 (s, 9H); MS: 438
(M+1).
##STR00301##
Example 173
[0637] To a solution of (2-benzyloxy-ethyl)-phosphonic acid
dibenzyl ester (0.200 g, 0.543 mmol) in THF was added a solution of
NaOH (1.36 mL, 1M) in water. The reaction mixture was stirred at
room temperature for 3 hours. Most of THF was removed in vacuo and
the residue was dissolved in water. The aqueous solution was washed
with ethylacetate three times then acidified with 1N HCl (to pH=1)
then extracted with ethylacetate. The organic phase was dried
(MgSO.sub.4), concentrated and co-evaporated with toluene in vacuo
to afford the mono-acid, (2-benzyloxy-ethyl)-phosphonic acid
monobenzyl ester, 173 (0.160 g. 100%) as an oil with no further
purification: .sup.1H NMR (CDCl.sub.3) .delta. 9.25 (bs, 1H),
7.4-7.1 (m, 10OH), 4.5 (s, 2H), 3.8 (m, 2H), 2.25 (m, 2H); .sup.31P
NMR (CDCl.sub.3) .delta. 28.63.
Example 174
[0638] To a solution of the mono-acid 173 (0.160 g, 0.576 mmol)
dissolved in acetonitrile (3.84 mL) was added thionyl chloride
(0.42 mL, 5.76 mmol). The reaction mixture was heated to 70.degree.
C. and stirred for 3 hours at which point the reaction was
completed as shown by .sup.31P NMR (CDCl.sub.3) .delta. 36.7. The
reaction mixture was concentrated as such to afford the
intermediate mono-chloridate as an oil which was immediately
dissolved in dichloromethane (2.88 mL) and treated with
triethylamine (0.321 mL, 2.30 mmol). The reaction mixture was
cooled to 0.degree. C. and L-alanine ethyl ester (0.265 g, 1.73
mmol) was added. The mixture was stirred overnight at room
temperature under an inert atmosphere and then was concentrated in
vacuo. The residue was partitioned between ethylacetate and
saturated NH.sub.4Cl, and the organic phase was washed with brine,
dried (MgSO.sub.4) then concentrated in vacuo. The residue was
purified by chromatography on silica gel washed with methanol prior
to use (1/1--ethylacetate/hexane) to afford the amidate 174 (0.095
g, 45%) as an oil with a 1:1.2 mixture of diastereomers: .sup.1H
NMR (CDCl.sub.3) .delta. 7.1-7.4 (m, 10H), 4.6 (s, 2H), 4.1 (q,
2H), 3.8 (m, 2H), 3.65 (m, 1H), 2.3 (m, 2H), 1.3 & 1.2 (d, 3H),
1.25 (t, 3H); .sup.31P NMR (CDCl.sub.3) .delta. 29.51, 28.70.
Example 175
[0639] To a solution of the amidate 174 (0.095 g, 0.243 mmol)
dissolved in ethanol (4.9 mL) was added palladium (on carbon). The
reaction was purged under a vacuum then submitted to hydrogen gas
(via balloon attached to the reaction vessel). After several purges
between gas and vacuum the reaction mixture was stirred at room
temperature for 4 hours. The mixture was filtered with Celite and
concentrated in vacuo to afford the alcohol 175 (0.74 g, 100%) as
an oil with a 1:1.2 mixture of diastereomers without further
purification: .sup.1H NMR (CDCl.sub.3) .delta. 7.4-7.1 (m, 5H),
4.15 (m, 2H), 3.7 (q, 2H), 3.5 (m, 1H ), 2.2 (m, 2H), 1.35 &
1.25 (d, 3H), 1.25 (m, 3H); .sup.31P NMR (CDCl.sub.3) .delta.
30.82, 30.54.
Example 176
[0640] To a solution of phenol 172 (0.073 g, 0.167 mmol) dissolved
in THF (1.67 mL) was added the alcohol 175 (0.075 g, 0.25 mmol),
triphenylphosphine (0.087 g, 0.33 mmol), and diethyl
azodicarboxylate (0.042 mL, 0.33 mmol). The reaction mixture
stirred at room temperature under an inert atmosphere overnight.
The residue was purified directly by chromatography on silica gel
washed with methanol prior to use (80/20--toluene/acetone) to
afford the product 176 (0.065 g, 54%) with a 1:1.2 mixture of
diastereomers: .sup.1H NMR (CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.8
(dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.4-7.1 (m, 5H), 7.0 (t, 2H),
4.85 (s, 2H), 4.85-4.7 (m, 4H), 4.2 (q, 1H), 4.15 (m, 2H), 4.0-3.8
(m, 1H), 2.65 (m, 2H), 1.4 & 1.25 (d, 3H), 1.3 (m, 2H), 1.2 (m,
3H), 0.10 (s, 9H); .sup.31P NMR (CDCl.sub.3) .delta. 27.84, 26.96;
MS: 722 (M+1),
##STR00302##
Example 177
[0641] A solution of the phosphonate 176 (0.030 g, 0.042 mmol) in
dichloromethane (0.832 mL) was treated with trifluoroacetic acid
(0.064 mL, 0.84 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere for 45 minutes. The volatiles
were removed in vacuo with toluene. The solid was triturated in
diethylether/hexane to afford the product 177 (0.022 g, 85%) as a
TFA salt with a 1:1.2 mixture of diastereomers: .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (dd, 1H), 8.85 (dd, 1H), 7.65 (dd, 1H),
7.5 (dd, 2H), 7.4-7.1 (m, 5H), 7.0 (t, 2H), 4.85 (s, 2H), 4.85 (m,
2H), 4.15 (m, 1H), 4.15 (m, 1H), 4.1 (m, 2H), 3.8 (m, 1H), 2.65 (m,
2H), 1.35 & 1.30 (d, 3H), 1.2 (m, 3H); .sup.31P NMR
(CDCl.sub.3) .delta. 27.86, 27.05; MS: 622 (M+1), 620 (M-1).
##STR00303##
Example 178
[0642] A solution of (2-ethoxy-ethyl)-phosphonic acid diethyl ester
(0.500 g, 2.1 mmol) in ether (8.5 mL) and THF (1.5 mL) was treated
with lithium borohydride. The reaction mixture stirred at room
temperature for 1 hour and was then concentrated in vacuo. The
crude mixture was partitioned between dichloromethane and water.
The organic phase was washed with saturated NaHCO.sub.3 and brine,
dried (MgSO4), then concentrated in vacuo. The residue was purified
by silica gel chromatography (5/95--methanol/dichloromethane) to
afford (3-hydroxy-propyl)-phosphonic acid diethyl ester 178 (0.100
g, 24%) as an oil: .sup.1H NMR (CDCl.sub.3) .delta. 4.1 (m, 4H),
3.7 (m, 2H), 2.95 (bs, 1H), 1.85 (m, 4H), 1.30 (t, 3H); .sup.31P
NMR (CDCl.sub.3) .delta. 33.26; MS: 197 (M+1).
Example 179
[0643] To a solution of phenol 40 (0.023 g, 0.046 mmol) dissolved
in THF (0.45 mL) was added the alcohol 178 (0.013 g, 0.068 mmol),
triphenylphosphine (0.024 g, 0.091 mmol), and diethyl
azodicarboxylate (0.014 mL, 0.091 mmol). The reaction mixture
stirred at room temperature under an inert atmosphere overnight.
The residue was purified directly by silica gel chromatography
(90/10--ethylacetate/hexane) to afford the product 179 (0.024 g,
76%): .sup.1H NMR (CDCl.sub.3) .delta. 9.1 (dd, 1H), 8.6 (dd, 1H),
7.9 (dd, 1H), 7.6 (m, 6H), 7.4 (dd, 2H), 7.2 (m, 6H), 7.0 (t, 2H),
4.8 (s, 2H), 4.5 (t, 2H), 4.15 (m, 2H), 2.2 (m, 2H), 2.0 (m, 2H),
1.35 (t, 3H); .sup.31P NMR (CDCl.sub.3) .delta. 31.48; MS: 684
(M+1).
##STR00304##
Example 180
[0644] A solution of the phosphonate 179 (0.028 g, 0.041 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1
mL) and triethylsilane (0.2 mL). The reaction mixture was stirred
at room temperature under an inert atmosphere for 20 minutes. The
volatiles were removed in vacuo with toluene. The solid was
triturated in diethylether/hexane to afford the product 180 (0.020
g, 95%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (dd,
1H) 8.7 (dd, 1H), 7.65 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.85
(s, 2H), 4.6 (t, 2H), 4.15 (m, 2H), 2.25 (m, 2H), 2.05 (m, 2H),
1.35 (t, 3H); .sup.31P NMR (CDCl.sub.3) .delta. 31.45; MS: 517
(M+1)) 51.6 (M-1).
##STR00305##
Example 181
[0645] To a solution of 1-BOC-piperazine (0.200 g, 1.08 mmol) in
acetonitrile (10.4 mL) was added CsCO.sub.3 (1.05 g, 3.23 mmol) and
then cooled to 0.degree. C. Trifluoromethanesulfonic acid
diethoxyphosphorylmethyl ester (0.387 g, 1.29 mmol) dissolved in
acetonitrile (5 mL) was added in a dropwise manner. The reaction
mixture was stirred at room temperature for 1 hour upon which it
was concentrated in vacuo. The reaction mixture was taken into
ethylacetate then washed with saturated NH.sub.4Cl and brine, dried
(MgSO.sub.4), then concentrated in vacuo. The residue was purified
using silica gel chromatography (3/97--methanol/dichloromethane) to
afford the product 181 (0.310 g, 86%) as an oil: .sup.1H NMR
(CDCl.sub.3) .delta. 4.15 (m, 4H), 3.45 (t, 4H), 2.8 (d, 2H), 2.6
(m, 4H), 1.45 (s, 9H), 1.35 (t, 6H); .sup.31P NMR (CDCl.sub.3)
.delta. 24.03; MS, 337 (M+1).
Example 182
[0646] A solution of the BOC protected piperazine linker
phosphonate 181 (0,310 g, 0.923 mmol) in dichloromethane (6.15 mL)
was treated with trifluoroacetic acid (0.711 mL, 9.23 mmol). The
reaction mixture was stirred at room temperature under an inert
atmosphere overnight. The volatiles were removed in vacuo with
toluene to afford the free piperazine linker phosphonate 182 (0.323
g, 100%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 11.0 (bs,
1H), 4.2 (m, 4H), 3.45 (t, 4H), 3.35 (m, 4H), 3.2 (d, 2H), 1.4 (t,
6H); .sup.31P NMR (CDCl.sub.3) .delta. 19.16 MS: 237 (M+1).
Example 183
[0647] A solution of the phenol intermediate 45 (0.044 mmol) in
dichloromethane (0.441 mL) was treated with triethylamine (0.025
mL, 0.176 mmol) and cat. 4-dimethylaminopyridine. The reaction
mixture was cooled to 0.degree. C. then triphosgene (0.026 g, 0.088
mmol) in a 1M solution of dichloromethane was added. The mixture
stirred at room temperature under an inert atmosphere for 2 hours,
then the free piperazine linker phosphonate 182 (0.046 g, 0.132
mmol) in a 1M solution of dichloromethane treated with
triethylamine (0.025 mL, 0.176 mmol) was added, and the mixture was
stirred overnight. The mixture was partitioned between
dichloromethane and water. The organic phase was washed with
saturated NH.sub.4Cl and brine, dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by silica gel
chromatography (3/97--methanol/dichloromethane) to afford the
product 183 (0.016 g, 64%): .sup.1H NMR (CDCl.sub.3) .delta. 9.05
(dd, 1H), 8.1 (dd, 1H), 8.0 (s, 1H), 7.75 (d, 4H), 7.5 (dd, 1H),
7.4-7.m, 8H), 7.05 (t, 2H), 4.8 (s, 2H), 4.2 (s, 2H), 4.15 (m, 4H),
3.75 (m, 2H), 3.6 (m, 2H), 2.85 (d, 2H), 2.8 (m, 2H), 2.75 (m, 2H),
1.35 (t, 6H); .sup.31P NMR (CDCl.sub.3) .delta. 23.57; MS: 753
(M+1).
##STR00306##
Example 184
[0648] A solution of the phosphonate 183 (0.016 g, 0.021 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1
mL) and triethylsilane (0.2 mL). The reaction mixture was stirred
at room temperature under an inert atmosphere for 20 minutes. The
volatiles were removed in vacuo with toluene. The solid was
triturated in diethylether/hexane to afford the product 184 (0.0125
g, 100%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (dd,
1H), 8.2 (dd, 1H), 7.6 (dd, 1H), 7.3 (m, 2H), 7.05 (t, 2H), 4.75
(s, 2H), 4.35 (s, 2H), 4.2 (m, 4H), 3.95 (m, 2H), 3.75 (m, 2H), 3.2
(d, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 1.4 (t, 6H); .sup.31P NMR
(CDCl.sub.3) .delta. 19.93; MS: 587 (M+1), 585 (M-1).
##STR00307##
Example 185
[0649] To a solution of (2-hydroxy-ethyl)-phosphonic acid dimethyl
ester (0.250 g, 1.62 mmol) in dichloromethane (4 mL) was added
2,6-lutidine (0.284 mL, 2.44 mmol). The reaction mixture was cooled
to 40.degree. C. and trifluoromethanesulfonic anhydride (0.355 mL,
2.11 mmol) was added. The mixture stirred in the cold bath under an
inert atmosphere for 2 hours at which point the reaction was
completed as shown by .sup.31P NMR (CDCl.sub.3) .delta. 25.7. The
mixture was partitioned between dichloromethane and water both
cooled by an ice-water bath. The organic phase was washed with
brine, dried (MgSO.sub.4), and concentrated in vacuo to afford
trifluoromethanesulfonic acid dimethoxy-phosphoryl-2-ethyl ester
185 as an oil which was immediately carried forward with no further
purification or characterization.
Example 186
[0650] To a solution of 1-BOC-piperazine (0.252 g, 1.35 mmol) in
acetonitrile (14.3 mL) was added CsCO.sub.3 (1.32 g, 4.06 mmol) and
then cooled to 0.degree. C. Trifluoromethanesulfonic acid
dimethoxy-phosphoryl-2-ethyl ester 185 (0.464 g, 1.62 mmol)
dissolved in acetonitrile (5 mL) was added in a dropwise manner.
The reaction mixture was stirred at room temperature overnight upon
which it was concentrated in vacuo. The reaction mixture was taken
into ethylacetate then washed with saturated NH.sub.4Cl and brine,
dried (MgSO.sub.4), then concentrated in vacuo. The residue was
purified using silica gel chromatography
(5/95-methanol/dichloromethane) to afford the BOC protected
piperazine linker phosphonate 186 (0.162 g, 31% over 2 steps) as an
oil: .sup.1H NMR (CDCl.sub.3) .delta. 3.75 (d, 6H), 3.4 (m, 4H),
2.65 (m, 2H), 2.4 (m, 4H), 1.95 (m, 2H), 1.45 (s, 9H); .sup.31P NMR
(CDCl.sub.3) .delta. 33.06; MS: 323 (M+1).
Example 187
[0651] A solution of the BOC protected piperazine linker
phosphonate 186 (0.162 g, 0.503 mmol) in dichloromethane (3.35 mL)
was treated with trifluoroacetic acid (0.388 mL, 5.03 mmol). The
reaction mixture was stirred at room temperature under an inert
atmosphere overnight. The volatiles were removed in vacuo with
toluene to afford the free piperazine linker phosphonate 187 (0.169
g, 100%) as a TFA salt: .sup.1H NMR (CD.sub.3OD) .delta. 3.8 (d,
6H), 3.45 (m, 4H), 3.2 (m, 4H), 3.15 (m, 2H), 2.3 (m, 2H); .sup.31P
NMR (CDCl.sub.3) .delta. 30.92; MS: 223 (M+1).
Example 188
[0652] A solution of the phenol intermediate 45 (0.046 mmol) in
dichloromethane (0.458 mL) was treated with triethylamine (0.026
mL, 0.183 mmol) and a catalytic amount of 4-dimethylaminopyridine.
The reaction mixture was cooled to 0.degree. C. then triphosgene
(0.027 g, 0.092 mmol) in a 1M solution of dichloromethane was
added. The mixture was stirred at room temperature under an inert
atmosphere for 2 hours, then the free piperazine linker phosphonate
187 (0.046 g, 0.137 mmol) in a 1M solution of dichloromethane
treated with triethylamine (0.026 mL, 0.183 mmol) was added
dropwise. The mixture was stirred overnight and then partitioned
between dichloromethane and water. The organic phase was washed
with saturated NH.sub.4Cl and brine, dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by silica gel
chromatography (8/92-methanol/ethylacetate) to afford the product
188 (0.019 g, 56%): .sup.1H NMR (CDCl.sub.3) .delta. 9.05 (dd, 1H),
8.1 (dd, 1H), 8.05 (s, 1H), 7.75 (m, 4H), 7.5 (dd, 1H), 7.4-7.1 (m,
8H), 7.1 (t, 2H), 4.8 (s, 2H), 4.2 (s, 2H), 3.8 (d, 6H), 3.6 (m,
4H), 2.75 (m, 2H), 2.55 (m, 4H), 2.1 (m, 2H); .sup.31P NMR
(CDCl.sub.3) .delta. 32.65; MS: 739 (M+1).
##STR00308##
Example 189
[0653] A solution of the phosphonate 188 (0.019 g, 0.026 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1
mL) and triethylsilane (0.2 mL). The reaction mixture was stirred
at room temperature under an inert atmosphere for 20 minutes. The
volatiles were removed in vacuo with toluene. The solid was
triturated in diethylether/hexane to afford the product 189 (0.013
g, 74%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 8.9 (dd,
1H), 8.15 (dd, 1H), 7.55 (dd, 1H), 7.35 (m, 2H), 7.05 (t, 2H), 4.75
(s, 2H), 4.35 (s, 2H), 4.2 (m, 2H), 3.95 (m, 2H), 3.8 (d, 6H), 3.4
(m, 4H), 3.35 (m, 2H), 2.4 (m, 2H); .sup.31P NMR (CDCl.sub.3)
.delta. 27.31; MS: 573 (M+1).
##STR00309##
Example 190
[0654] A solution of the phosphonate 189 (0.006 g, 0.009 mmol) in
dichloromethane (0.088 mL) was treated with trimethylsilane bromide
(0.007 mL, 0.053 mmol). The reaction mixture was stirred at room
temperature overnight under an inert atmosphere. The volatiles were
removed in vacuo with methanol. The solid was washed with
dichloromethane to afford the diacid 190 (0.006 g, 100%): .sup.1H
NMR (CD.sub.3OD) .delta. 9.3 (dd, 1H), 9.2 (dd, 1H), 8.2 (dd, 1H),
7.4 (m, 2H), 7.1 (t, 2H), 4.8 (s, 2H), 4.6 (s, 2H), 3.6-3.2 (m,
10H), 2.35 (m, 2H); .sup.31P NMR (CD.sub.3OD) .delta. 21.43; MS:
545 (M+1), 543 (M-1).
##STR00310##
Example 191
[0655] To a solution of
2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl
ester, aldehyde 166, as a 1:1 mixture of DMSO (0.050 g, 0.167 mmol)
and 1-BOC-piperazine (0.034 g, 0.183 mmol) dissolved in ethanol
(1.67 mL) was added acetic acid (0.038 mL, 0.667 mmol). The
reaction mixture was stirred at room temperature for 2.5 hours then
sodium cyanoborohydride (0.021 g, 0.333 mmol) was added. The
reaction mixture stirred at room temperature overnight. Saturated
NaHCO.sub.3 was added to the reaction mixture and was stirred for
five more minutes. The mixture was concentrated in vacuo to remove
most of the ethanol. Brine was added and then the crude product was
extracted into ethylacetate. The organic phase was dried
(MgSO.sub.4) and concentrated. The residue was purified by silica
gel chromatography (5/95-methanol/dichloromethane) to afford the
product 191 (0.050 g, 64%), an oil as a mixture of diastereomers:
.sup.1H NMR (CDCl.sub.3) .delta. 7.4-7.1 (m, 5H), 5.0 (m, 1H), 4.2
(m, 2H), 3.4 (m, 4H), 2.8 (m, 2H), 2.4 (m, 4H), 2.2 (m, 2H), 1.6
& 1.35 (d, 3H), 1.4 (s, 9H), 1.2 (t, 3H); .sup.31P NMR
(CDCl.sub.3) .delta. 28.83, 27.18; MS: 471 (M+1).
[0656] Alternatively, a solution of
2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester
166, as a 1:1 mixture with DMSO (0.500 g, 1.67 mmol), and
piperazine-1-carboxylic acid tert-butyl ester (1-BOC-piperazine,
0.340 g, 1.83 mmol) dissolved in ethanol (1.67 mL) was added 4
.ANG. molecular sieves (0.300 g) and acetic acid (0.400 mL, 6.8
mmol). The reaction mixture was stirred at room temperature for 1.5
hours then sodium cyanoborohydride (0.212 g, 3.33 mmol) was added.
The reaction mixture stirred at room temperature for 3 hours and
was concentrated in vacuo then redissolved in chloroform. The
mixture was washed with saturated NaHCO.sub.3 and brine, dried
(NaSO.sub.4), filtered and concentrated. The residue was treated
with diethyl ether. Solid precipitate was filtered off, and the
filtrate was concentrated to afford
4-{2-[(1-Ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-c-
arboxylic acid tert-butyl ester 191 (0.600 g, 77%) as an oil
(mixture of two diastereomers).
Example 192
[0657] A solution of
4-{2-[(1-ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-c-
arboxylic acid tert-butyl ester 191 (0.050 g, 0.106 mmol) in
dichloromethane (0.709 mL) was treated with trifluoroacetic acid
(0.082 mL, 1.06 mol). The reaction mixture was stirred at room
temperature under an inert atmosphere for 4 hours. The volatiles
were removed in vacuo with toluene to afford the free piperazine
linker phosphonate 192 (0.051 g, 100%) as a TFA salt (mixture of
two diastereomers): .sup.1H NMR (CDCl.sub.3) .delta. 10.8 (bs, 1H),
7.5-7.1 (m, 5H), 5.0 (m, 1H), 4.2 (m, 4H), 3.7 (m, 8H), 2.65 (m,
2H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 25.58, 20.86; MS: 371 (M+1).
[0658] Alternatively a solution of
4-{2-[(1-ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-c-
arboxylic acid tert-butyl ester 191 (0.100 g, 0.212 mmol) in
methylene chloride (2 mL) was treated with trifluoroacetic acid
(0.340 mL, 4.41 mmol). The reaction mixture was stirred at room
temperature under an inert atmosphere for 6 hours. The volatiles
were removed in vacuo with ethyl acetate to afford the
trifluoroacetate salt of
2-[phenoxy-(2-piperazin-1-yl-ethyl)-phosphinoyloxy]-propionic acid
ethyl ester 192 (0.103 g, 100%) (mixture of two diastereomers).
Example 193
[0659] A solution of the phenol intermediate 45 (0.039 mmol) in
dichloromethane (0.386 mL) was treated with triethylamine (0.022
mL, 0.155 mmol) and cat. 4-dimethylaminopyridine. The reaction
mixture was cooled to 0.degree. C. then triphosgene (0.023 g, 0.077
mmol) in a 1M solution of dichloromethane was added. The mixture
stirred at room temperature under an inert atmosphere for 2 hours,
then the free piperazine linker phosphonate 192 (0.056 g, 0.115
mmol) in a 1M solution of dichloromethane treated with
triethylamine (0.022 mL, 0.155 mmol) was added, and the mixture was
stirred overnight. The mixture was partitioned between
dichloromethane and water. The organic phase was washed with
saturated NH.sub.4Cl and brine, dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by silica gel
chromatography (5/95-methanol/dichloromethane) to afford the
product 193 (0.013 g, 50%) as a mixture of diastereomers: .sup.1H
NMR (CDCl.sub.3) .delta. 9.05 (dd, 1H), 8.1 (dd, 1H), 8.05 (s, 1H),
7.75 (d, 4H), 7.5 (dd, 1H), 7.4-7.1 (m, 11H), 7.05 (t, 2H), 5.1 (m,
1H), 4.8 (s, 2H), 4.2 (s, 2H), 4.15 (m, 2H), 3.8-3.4 (m, 4H),
3.0-2.2 (m, 8H), 1.6 & 1.4 (d, 3H), 1.2 (t, 3H); .sup.31P NMR
(CDCl.sub.3) .delta. 28.30, 26.59; MS: 887 (M+1).
##STR00311##
Example 194
[0660] A solution of the phosphonate 193 (0.013 g, 0.015 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1
mL) and triethylsilane (0.2 mL). The reaction mixture was stirred
at room temperature under an inert atmosphere for 20 minutes. The
volatiles were removed in vacuo with toluene. The solid was
triturated in diethylether/hexane to afford the product 194 (0.010
g, 80%) as a TFA salt: .sup.1H NMR (CDCl.sub.3) .delta. 8.95 (dd,
1H), 8.15 (dd, 1H), 7.55 (dd, 1H), 7.35 (m, 2H), 7.3-7.1 (m, 5H),
7.05 (t, 2H), 5.0 (m, 1H), 4.75 (s, 2H), 4.35 (s, 2H), 4.2 (m,
21H), 3.8-3.6 (m, 4H), 3.4-3.0 (m, 6H), 2.5-2.7 (m, 2H), 1.6 &
1.4 (d, 3H), 1.25 (t, 3H); .sup.31P NMR (CDCl.sub.3) .delta. 22.29,
21.67; MS: 721 (M+1).
##STR00312##
Example 195
[0661] To a solution of 2-aminoethylphosphonic acid (1.26 g, 10.1
mmol) in 2N NaOH (10.1 mL, 20.2 mmol) was added benzyl
chloroformate (1.7 mL, 12.1 mmol). After the reaction mixture was
stirred for 2 d at room temperature, the mixture was partitioned
between Et.sub.2O and water. The aqueous phase was acidified with
6N HCl until pH=2. The resulting colorless solid was dissolved in
MeOH (75 mL) and treated with Dowex 50WX8-200 (7 g). After the
mixture was stirred for 30 minutes, it was filtered and evaporated
under reduced pressure to give carbobenzoxyaminoethyl phosphonic
acid (2.37 g, 91%) as a colorless solid.
[0662] To a solution of carbobenzoxyaminoethyl phosphonic acid
(2.35 g, 9.1 mmol) in pyridine (40 mL) was added phenol (8.53 g,
90.6 mmol) and 1,3-dicyclohexylcarbodiimide (7.47 g, 36.2 mmol).
After the reaction mixture was warmed to 70.degree. C. and stirred
for 5 h, the mixture was diluted with CH.sub.3CN and filtered. The
filtrate was concentrated under reduced pressure and diluted with
EtOAc. The organic phase was washed with sat. NH.sub.4Cl, sat.
NaHCO.sub.3, and brine, then dried over Na.sub.2SO.sub.4, filtered,
and evaporated under reduced pressure. The crude product was
chromatographed on silica gel twice (eluting 40-60% EtOAc/hexane)
to give diphenyl 2-aminoethyl phosphonic acid (2.13 g, 57%) as a
colorless solid.
[0663] To a solution of diphenyl 2-aminoethyl phosphonic acid (262
mg, 0.637 mmol) in iPrOH (5 mL) was added TFA (0.05 mL, 0.637 mmol)
and 10% Pd/C (26 mg). After the reaction mixture was stirred under
H.sub.2 atmosphere (balloon) for 1 h, the mixture was filtered
through Celite. The filtrate was evaporated under reduced pressure
to give diphenyl carbobenzoxyaminoethyl phosphonate 195 (249 mg,
100%) as a colorless oil.
##STR00313##
Example 196
[0664] To a solution of benzyloxymethyl phosphonic acid (520 mg,
2.57 mmol) in CH.sub.3CN (5 mL) was added thionyl chloride (0.75
mL, 10.3 mmol) and heated to 70.degree. C. in an oil bath. After
the reaction mixture was stirred for 2 h at 70.degree. C., the
mixture was concentrated and azeotroped with toluene. To a solution
of the crude chloridate in toluene (5 mL) was added tetrazole (18
mg, 0.26 mmol) at 0.degree. C. To this mixture was added phenol
(121 mg, 1.28 mmol) and triethylamine (0.18 mL, 1.28 mmol) in
toluene (3 mL) at 0.degree. C. After the reaction mixture was
warmed to room temperature and stirred for 2 h, ethyl lactate (0.29
mL, 2.57 mmol) and triethylamine (0.36 mL, 2.57 mmol) in toluene
(2.5 mL) were added. The reaction mixture was stirred for 16 hours
at room temperature, at which time the mixture was partitioned
between EtOAc and sat. NH.sub.4Cl. The organic phase was washed
with sat. NH.sub.4Cl, 1M NaHCO.sub.3, and brine, then dried over
Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure.
The crude product was chromatographed on silica gel (eluting 20-40%
EtOAc/hexane) to give two diastereomers (isomer A and isomer B) of
2-(benzyloxymethyl-phenoxy-phosphinoyloxy)-propionic acid ethyl
ester 196 (66 mg, 109 mg, 18% total) as colorless oils.
Example 197a
[0665] To a solution of benzyl phosphonate 196 isomer A (66 mg,
0.174 mmol) in EtOH (2 mL) was added 10% Pd/C (13 mg). After the
reaction mixture was stirred under H.sub.2 atmosphere (balloon) for
6 h, the mixture was filtered through Celite. The filtrate was
evaporated under reduced pressure to give alcohol 197a isomer A (49
mg, 98%) as a colorless oil.
Example 197b
[0666] To a solution of benzyl phosphonate 196 isomer B (110 mg,
0.291 mmol) in EtOH (3 mL) was added 10% Pd/C (22 mg). After the
reaction mixture was stirred under H.sub.2 atmosphere (balloon) for
6 h, it was filtered through Celite. The filtrate was evaporated
under reduced pressure to give alcohol 197b isomer B (80 mg, 95%)
as a colorless oil.
Example 198a
[0667] To a solution of alcohol 197a isomer A (48 mg, 0.167 mmol)
in CH.sub.2Cl.sub.2 (2 mL) was added 2,6-lutidine (0.03 mL, 0.250
mmol) and trifluoromethanesulfonic anhydride (0.04 mL, 0.217 mmol)
at -40.degree. C. (dry ice-CH.sub.3CN bath). After the reaction
mixture was stirred for 15 min at -40.degree. C., the mixture was
warmed to 0.degree. C. and partitioned between Et.sub.2O and 1M
H.sub.3PO.sub.4. The organic phase was washed with 1M
H.sub.3PO.sub.4 (3 times), dried over Na.sub.2SO.sub.4, filtered,
and evaporated under reduced pressure to give triflate 198a isomer
A (70 mg, 100%) as a pale yellow oil.
Example 198b
[0668] To a solution of alcohol 197b isomer B (80 mg, 0.278 mmol)
in CH.sub.2Cl.sub.2 (3 mL) was added 2,6-lutidine (0.05 mL, 0.417
mmol) and trifluoromethanesulfonic anhydride (0.06 mL, 0.361 mmol)
at -40.degree. C. (dry ice-CH.sub.3CN bath). After the reaction
mixture was stirred for 15 min at -40.degree. C., the mixture was
warmed to 0.degree. C. and partitioned between Et2O and 1M
H.sub.3PO.sub.4. The organic phase was washed with 1M
H.sub.3PO.sub.4 (3 times), dried over Na.sub.2SO.sub.4, filtered,
and evaporated under reduced pressure to give triflate 198b isomer
B (115 mg, 98%) as a pale yellow oil.
##STR00314##
Example 199
[0669] To a stirred solution of phenyl 2-carbobenzoxyaminoethyl
phosphonate (1 g, 3 mmol) in 30 mL of acetonitrile at room
temperature under N.sub.2 was added thionyl chloride (0.67 mL, 9
mmol). The resulted mixture was stirred at 60-70.degree. C. for 0.5
h. After cooled to room temperature, the solvent was removed under
reduced pressure, and the residue was added 30 mL of DCM, followed
by DIEA (1.7 mL, 10 mmol), L-alanine butyric acid ethyl ester
hydrochloride (1.7 g, 10 mmol) and TEA (1.7 mL, 12 mmol). After 4 h
at room temperature, the solvent was removed under reduced
pressure, and the residue was diluted with DCM and washed with
brine and water, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by chromatography on silica
gel (Hexane/EtOAc 1:1) to give 199 (670 mg, 50%) as a yellow oil.
.sup.1NMR (CDCl.sub.3) .delta. 7.33-7.11 (m, 10H), 5.70 (m, 1H),
5.10 (s, 2H), 4.13-3.53 (m, 5H), 2.20-2.10 (m, 2H), 1.76-1.55 (m,
2H), 1.25-1.19 (m, 3H), 0.85-0.71 (m, 3H); .sup.31P NMR
(CDCl.sub.3) .delta. 30.2 and 29.9; MS (ESI) 471 (M+Na).
Example 200
[0670] A solution of compound 199 (450 mg) was dissolved in 9 mL of
EtOH, then 0.15 mL of acetic acid and 10% Pd/C (90 mg) was added.
The resulted mixture was stirred under H2 atmosphere (balloon) for
4 h. After filtration through Celite, the filtered was evaporated
under reduced pressure to afford the compound 200 (300 mg, 95%) as
a colorless oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.29-7.12 (m,
5H), 4.13-3.53 (m, 5H), 2.20-2.10 (m, 2H), 1.70-1.55 (m, 2H),
1.24-1.19 (m, 3H), 0.84-0.73(m, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 29.1 and 28.5; MS (ESI) 315 (M+1).
##STR00315##
Example 201
[0671] A THF solution (30 mL) of NaH (3.4 g of 60% oil dispersion,
85 mmol) was cooled to -10.degree. C., followed by the addition of
diethyl(cyanomethyl)phosphonate (5 g, 28.2 mmol) and iodomethane
(17 g, 112 mmol). The resulting solution was stirred at -10.degree.
C. for 2 hr, then 0.degree. C. for 1 hr, was worked up, and
purified to give diethyl(cyano(dimethyl)methyl)phosphonate (5 g,
86%).
[0672] Diethyl(cyano(dimethyl)methyl)phosphonate was reduced to the
amine derivative by the described procedure (J. Med. Chem. 1999,
42, 5010-5019) whereby a solution of ethanol (150 mL) and 1N HCl
aqueous solution (22 mL) of
diethyl(cyano(dimethyl)methyl)phosphonate (2.2 g, 10.7 mmol) was
hydrogenated at 1 atmosphere in the presence of PtO.sub.2 (1.25 g)
at room temperature overnight. The catalyst was filtered through a
Celite pad. The filtrate was concentrated to dryness, to give crude
diethyl 2-amino-1,1-dimethyl-ethyl phosphonate (2.5 g, as HCl
salt).
[0673] Crude diethyl 2-amino-1,1-dimethyl-ethyl phosphonate (2.5 g)
in 30 mL CH.sub.3CN was cooled to 0.degree. C., and treated with
TMSBr (8 g, 52 mmol) for 5 hr. The reaction mixture was stirred
with methanol for 1.5 hr at room temperature, concentrated,
recharged with methanol, concentrated to dryness to give crude
2-Amino-1,1-dimethyl-ethyl phosphonic acid which was used for next
reaction without further purification.
[0674] 2-Amino-1,1-dimethyl-ethyl phosphonic acid was protected
with CBZ, followed by the reaction with thionyl chloride at
70.degree. C. The CBZ protected dichloridate was reacted with
phenol in the presence of DIPEA. Removal of one phenol, follow by
coupling with ethyl L-lactate gave N-CBZ-2-amino-1,1-dimethyl-ethyl
phosphonate derivative. Hydrogenation of N-CBZ derivative at 1
atmosphere in the presence of 10% Pd/C and 1 eq. of TFA gave
lactate phenyl (2-amino-1,1-dimethyl-ethyl)phosphonate 201 as the
TFA salt.
##STR00316##
Example 202
[0675] Powdered magnesium tert-butoxide (2.05 g, 12.02 mmol) was
added to a solution of dibenzyl trifluoromethane sulfonic
hydroxymethyl phosphonate (4.10 g, 9.66 mmol) and anhydrous
ethylene glycol (5.39 mL, 96.6 mmol) in anhydrous DMF (30 mL) at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for
1.5 h, then concentrated. The residue was partitioned between EtOAc
and H.sub.2O and washed with 1 N HCl, saturated NaHCO.sub.3
solution, and brine. Organic layer dried (MgSO.sub.4), concentrated
and purified (silica gel, 4% MeOH/CH.sub.2Cl.sub.2) to give
(2-hydroxy-ethoxymethyl)-phosphonic acid dibenzyl ester 202 as a
colorless oil (1.55 g, 48%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.37 (s, 10 H, Ar), 5.40-5.05 (m, 4 H, CH.sub.2Ph), 3.84
(d, J=8.1 Hz, 2 H, PCH.sub.2O), 3.70-3.60 (m, 4 H,
OCH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2O); .sup.31P NMR (121 MHz,
CDCl.sub.3): .delta. 22.7.
##STR00317##
Example 203
[0676] A solution of 24 (Example 24) (38 mg, 0.086 mmol) in
CH.sub.2Cl.sub.2 (0.86 mL) was stirred with EDC (33 mg, 0.172
mmol), TEA (12 .mu.L, 0.086 mmol), and 1-Boc-piperazine (19 mg,
0.103 mmol) at ambient temperature for 15 h when LCMS analysis
demonstrated completion of the reaction. The reaction mixture was
worked up by dilution of the mixture with CH.sub.2Cl.sub.2 and
washing the organic layer with H.sub.2O. The organic layer was
dried in vacuo and the residue,
4-{3-[7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrol-
o[3,4-g]quinolin-6-ylsulfanyl]-propionyl}-piperazine-1-carboxylic
acid tert-butyl ester 203 was carried forward for deprotection.
Example 204
[0677] A solution of 203 (52 mg, 0.085 mmol) in 0.8 mL of
trifluoroacetic acid and 0.8 mL of CH.sub.2Cl.sub.2 was stirred at
room temperature for 1 h when the starting material was completely
consumed as detected by LCMS. The solution was dried in vacuo and
redissolved in 1:1 mixture of MeOH--H.sub.2O. The product 204 was
purified by RP-HPLC using a 5-95% A. Buffer A contained
CH.sub.3CN-1% TFA and buffer B was H.sub.2O-1% TFA. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 2.19-2.40 (m, 4H), 3.06-3.20 (m, 4H),
3.43-3.56 (m, 2H), 3.63-3.74 (m, 2H), 4.08 (s, 3H), 4.62 (d, 1H,
J=15 Hz), 5.16 (d, 1H, J=15 Hz), 5.76 (s, 1H), 7.10 (t, 2H, J=9
Hz), 7.46 (t, 2H, J=8 Hz), 7.74 (dd, 1H, J=4, 8 Hz), 8.69 (d, 1H,
J=8 Hz), 8.96 (d, 1H, J=4 Hz); .sup.19F NMR (282.6 MHz, CD.sub.3OD)
.delta. -77.7, 60.0; EI MS (m/z) 511.0 [M+H.sup.+.
##STR00318##
Example 205
[0678] Grignard product 16 (Example 16) was worked up by addition
of ethyl acetate and stirring of the organic layer with aqueous 1N
HCl for 30 minutes. The layers were separated and the organic layer
was washed with the 1N HCl solution 2 more times. The organic layer
was checked with LCMS to assure complete elimination of the alcohol
resulted from the Grignard reaction to the eliminated product 205.
The organic layer was dried in vacuo and the residue was purified
by column chromatography using CH.sub.2Cl.sub.2 to give 205.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.15 (d, 18H, J=8 Hz),
1.56 (septet, 3H, J=8 Hz), 3.95 (s, 3H), 4.82 (s, 1H), 4.99 (s,
2H), 5.53 (s, 1H), 7.01 (t, 2H, J=8 Hz), 7.28 (dd, 2H, J=5, 9 Hz),
7.54 (dd, 1H, J=4, 8 Hz), 8.46 (d, 1H, J=8 Hz), 8.87 (d, 1H, J=3
Hz); .sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 61.06; EI MS
(m/z) 507.4 [M+H].sup.+.
Example 206
[0679] A solution of diethylzinc (0.134 mmol, 134 .mu.L of a 1M
mixture) and 134 .mu.L of CH.sub.2Cl.sub.2 was added to TFA (0.134
mmol, 10.4 .mu.L) under a N.sub.2 atmosphere at 0.degree. C. The
mixture was stirred at cooled temperature for 15 minutes, then a
solution of CH.sub.2I.sub.2 (0.134 mmol, 11 .mu.L) in 100 .mu.L of
CH.sub.2Cl.sub.2 was added. After 10 minutes, a solution of 205 in
100 .mu.L of CH.sub.2Cl.sub.2 was added and the ice bath removed.
The reaction mixture was stirred at ambient temperature for 1 hour
when LCMS analysis demonstrated complete consumption of the
starting materials. The product 206 was purified by RP-HPLC using a
20-80% A. Buffer A contained CH.sub.3CN-1% TFA and buffer B was
H.sub.2O-1% TFA. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.58 (t,
2H, J=5 Hz), 1.79 (t, 2H, J=5 Hz), 3.95 (s, 3H), 4.61 (s, 2H), 7.07
(t, 2H, J=9 Hz), 7.32 (dd, 2H, J=5, 8 Hz), 7.84 (dd, 1H, J=4, 8
Hz), 8.77 (d, 1H, J=8 Hz), 8.98 (d, 1H, J=4 Hz); .sup.19F NMR
(282.6 MHz, CD.sub.3OD) .delta. -78.0, 59.3; EI MS (m/z) 365.3
[M+H].sup.+, 387.3 [M+Na].sup.+.
##STR00319##
Example 207
[0680] A solution of 12 (Example 12, 65 mg, 0.131 mmol) in 1.3 mL
of CH.sub.2Cl.sub.2 was stirred with dimethyl sulfamoyl chloride
(38 mg, 0.262 mmol), TEA (73 .mu.L, 0.63 mmol), and DMAP (2 mg,
0.013 mmol) for 2 hours at room temperature when LCMS analysis
demonstrated complete consumption of the starting materials. The
reaction was worked up by dilution with CH.sub.2Cl.sub.2 and
washing the organic layer with H.sub.2O. The solvent was removed
under reduced pressure and the product was purified by column
chromatography to yield 59 mg of 207 (75%) as a white solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.12 (d, 18H, J=8 Hz),
1.53 (septet 3H, J=8 Hz), 3.23 (s, 6H), 4.84 (s, 2H), 7.00 (t, 2H,
J=8 Hz), 7.45 (dd, 2H, J=6, 9 Hz), 7.65 (dd, 1H, J=4, 8 Hz), 8.77
(dd, 1H, J=2, 8 Hz), 8.94 (dd, 1H, J=2, 4 Hz); .sup.19F NMR (282.6
MHz, CDCl.sub.3) .delta. 62.0; EI MS (m/z) 624.2 [M+Na].sup.+.
Example 208
[0681] A solution of 207 (30 mg, 0.050 mmol) in 0.25 mL of THF was
stirred with 33 .mu.L (0.10 mmol) of methylmagnesium bromide for 1
hour at room temperature. The solution was diluted with
CH.sub.2Cl.sub.2 and stirred with aqueous 1N HCl for 30 minutes.
Removal of the solvent in vacuo yielded 26 mg (87%) of the product
208 as a green oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.14
(d, 18H, J=8 Hz), 1.56 (septet, 3H, J=8 Hz), 2.97 (s, 6H), 4.94 (s,
1H), 5.00 (s, 2H), 5.59 (s, 1H), 7.00 (t, 2H, J=8 Hz), 7.21-7.32
(m, 2H), 7.55-7.62 (m, 1H), 8.50 (d, 1H, J=8 Hz), 8.88 (br s, 1H);
.sup.19F NMR (282.6 MHz, CDCl.sub.3) .delta. 61.3; EI MS (m/z)
600.2 [M+H].sup.+, 622.2 [M+Na].sup.+.
##STR00320##
Example 209
[0682] A solution of 208 (13 mg, 0.022 mmol) and TFA (0.11 mL) and
CH.sub.2Cl.sub.2 (0.11 mL) was allowed to stir at room temperature
overnight. The solvent was removed in vacuo and the residue was
purified by RP-HPLC using a 20-80% A to give product 209. Buffer A
contained CH.sub.3CN-1% TFA and buffer B was H.sub.2O-1% TFA.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.06 (s, 3H), 3.07 (s,
3H), 5.00 (s, 2H), 5.12 (s, 1H), 5.71 (s, 1H), 6.96-7.07 (m, 2H),
7.22-7.33 (m, 2H), 7.71 (dd, 1H, J=4, 9 Hz), 8.67 (d, 1H, J=8
Hz),9.05 (br s, 1H); .sup.19F NMR (282.6 MHz, CDCl.sub.3) -76.2,
62.1; EI MS (m/z) 444.2 [M+H].sup.+, 466.1 [M+Na].sup.+.
Example 210
[0683] Under a N.sub.2 atmosphere, a solution of 208 (14 mg, 0.023
mmol) in CH.sub.2Cl.sub.2 (0.23 mL) was stirred with triethylsilane
(15 .mu.L, 0.093 mmol) and boron trifluoride diethyletherate
(BF.sub.3OEt.sub.2, 20 .mu.L, 0.164 mmol) at ambient temperature
overnight. The reaction mixture was worked up by removing the
solvent under reduced pressure and precipitation from EtOAc-Hex to
provide 7.5 mg of the product 210 as a yellow solid. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.56 (d, 3H, J=7 Hz), 3.16 (s, 6H),
4.42 (d, 1H, J=15 Hz), 5.02 (q, 1H, J=6 Hz), 5.09 (d, 1H, J=15 Hz),
7.06 (t, 2H, J=8 Hz), 7.33(dd, 2H, J=5, 9 Hz), 7.72-7.79 (m, 1H),
8.62 (d, 1H, J=9 Hz), 9.15 (br s, 1H); .sup.19F NMR (282.6 MHz,
CDCl.sub.3) .delta. -76.2, 62.5; EI MS (m/z) 446.2 [M+H].sup.+,
468.2 [M+Na].sup.+.
Example 211
[0684] Under a N.sub.2 atmosphere, to a solution of diethylzine
(0.074 mmol, 74 .mu.L of a 1M mixture) and 74 .mu.L of
CH.sub.2Cl.sub.2 was added TFA (0.074 mmol, 5.7 .mu.L) at 0.degree.
C. This mixture was stirred at cooled temperature for 15 minutes
when a solution of CH.sub.2I.sub.2 (0.074 mmol, 6 .mu.L) in 50
.mu.L of CH.sub.2Cl.sub.2 was added. After 10 minutes, a solution
of 208 in 50 .mu.L of CH.sub.2Cl.sub.2 was added and the ice bath
removed. The reaction mixture was stirred at ambient temperature
for 1 hour when LCMS analysis demonstrated complete consumption of
the starting materials. The product 211 was purified by RP-HPLC
using a 20-80% A. Buffer A contained CH.sub.3CN-1% TFA and buffer B
was H.sub.2O-1% TFA. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.46
(br t, 2H), 2.10 (br t, 2H), 3.14 (s, 6H), 4.55 (s, 2H), 7.02 (t,
2H, J=9 Hz), 7.21-7.31 (m, 2H), 7.60-7.68 (m, 1H), 8.58-8.65 (m,
1H), 9.05-9.08 (m:, 1H); EI MS (m/z) 458.2 [M+H].sup.+, 480.1
[M+Na].sup.+.
##STR00321##
Example 212
[0685] To trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (1.48 g, 2.39 mmol) and
1,3-bis(diphenylphosphino)propane (DPPP) (295 mg, 0.7 mmol) in DMF
(20 mL) and water (1 mL) in a two-necked round bottom flask were
added Pd(OAc).sub.2 (107 mg, 0.48 mmol). The solution was degassed
under high vacuum and flushed with carbon monoxide from a balloon.
The flushing was repeated five times. TEA (0.733 mL, 3.26 mmol) was
introduced. The mixture was heated under CO atmosphere for 2.5
hours and cooled down to the room temperature. MeI (0.74 mL, 12
mmol) and Cs.sub.2CO.sub.3 were added and stirring was continued
under a nitrogen atmosphere for 45 minutes. The mixture was diluted
with EtOAc (300 mL), washed with water, 1N aqueous HCl and brine,
dried over MgSO.sub.4 and concentrated. The crude product was
purified by chromatography on a silica gel column eluting with 15%
to 35% of EtOAc in hexane to afford
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inoline-5-carboxylic acid methyl ester 212, (0.9 g, 1.69 mmol, 70%)
as a yellow solid. .sup.1H NMR (CDCl.sub.3): .delta.9.25 (d, 1H),
9.05 (m, 1H), 7.80 (d, 4H), 7.56 (dd, 1H), 7.0-7.4 (m, 11H), 4.85
(s, 2H), 4.55 (s, 2H), 3.95 (s, 3H); MS: 555 (M+Na).
##STR00322##
Example 213
[0686] A solution of
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inoline-5-carboxylic acid methyl ester 212 (54 mg, 0.10 mmol) in
1.0 mL of a 1:1:1 mixture of THF: MeOH: H.sub.2O was stirred with
LiOH (9.7 mg, 0.41 mmol) overnight when the starting materials were
completely consumed as judged by TLC (DPM=benzhydryl,
Ph.sub.2CH--). The reaction mixture was dried under reduced
pressure and the residue was dissolved in EtOAc. The organic layer
was stirred with saturated aqueous NH.sub.4Cl for 30 minutes. The
aqueous layer was checked by TLC to assure complete transfer of the
products to the organic layer. The organic layer was dried in vacuo
to yield 45.5 mg (87%) of
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolio[3,4-g]q-
uinoline-5-carboxylic acid 213 as a white solid. The product was
carried on without purification. MS (m/z) 519.2 [M+H].sup.+, 541.2
[M+Na].sup.+.
[0687] Alternatively, methyl ester 212 (0.071 g, 0.1334 mmol) was
dissolved in 2.4 mL of tetrahydrofuran and 0.6 mL of DI H.sub.2O.
To this was added LiOH (0.013 g, 0.5338 mmol) and mixture stirred
at room temperature. After 15 hours, starting material consumed.
Diluted with dichloromethane, washed with 1M HCl solution, dried
(Na.sub.2SO.sub.4), concentrated to give 213 (0.068 g, 0.1313 mmol,
98%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.25 (d, 1H), 9.12
(dd, 1H), 8.17 (s, 1H), 7.75 (d, 5H), 7.37 (dd, 2H), 7.24 (m, 6H),
4.82 (s, 2H), 4.59 (s, 2H.) MS: 517 (M-1.)
Example 214
[0688] A solution of the oxalate salt (HO.sub.2CCO.sub.2.sup.-) of
diethyl(aminoethyl)phosphonate (12 mg, 0.042 mmol) in 0.21 mL of
DMF was mixed with DIEA (15 .mu.L, 0.084 mmol) until the reaction
became clear. To this solution was added 213 (11 mg, 0.021 mmol)
and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) (16 mg, 0.042 mmol). This mixture was
stirred at room temperature for 2 hours when it was warmed to
60.degree. C. with a heat gun for 1 minute. LCMS analysis
demonstrated complete consumption of the starting materials. The
reaction mixture was directly loaded onto a silica gel column and
the product was quickly eluted with a gradient of EtOAc-10%
MeOH/EtOAc to provide 12.7 mg (88%) of the product 214. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 1.29 (t, 6, J=7 Hz), 2.18 (dt, 2H,
J'7, 18 Hz), 3.53-3.65 (m, 2H), 4.08 (septet, 4H, J=7 Hz), 4.46 (s,
2H), 4.83 (s, 2H), 7.06-7.25 (m, 8H), 7.40 (dd, 2H, J=5, 9 Hz),
7.61-7.68 (m, 6H), 8.04 (s, 1H), 8.44 (d, 1H, J=7 Hz), 9.04-9.09
(m, 1H); .sup.31P (121.4 MHz, CD.sub.3OD) .delta. 29.5; MS (m/z)
682.1 [M+H].sup.-, 704.2 [M+Na].sup.+.
Example 215
[0689] A solution of 214 (12.7 mg, 0.019 mmol) in 0.19 mL of
CH.sub.2Cl.sub.2 was stirred with TFA (144 .mu.L, 1.9 mmol) and TES
(304 .mu.L, 1.9 mmol) for 45 minutes under a N.sub.2 atmosphere.
TLC and LCMS analysis indicated complete reaction at that time. The
reaction was worked up by removing the solvent under reduced
pressure. The residue was purified by crystallization from
EtOAc-Hex to yield 8.6 mg (71%) of
(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qui-
noline-5-carbonyl]-amino}-ethyl)-phosphonic acid diethyl ester 215
as a yellow solid. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 1.33
(t, 6H, J=7 Hz), 2.24 (dt, 2H, J=19, 7 Hz), 3.70 (septet, 2H, J=8
Hz), 4.09-4.17 (m, 4H), 4.61 (s, 2H), 4.78 (s, 2H), 7.10 (t, 2H,
J=9 Hz), 7.41 (dd, 2H, J=6, 8 Hz), 7.76 (br d, 1H, J=5 Hz), 8.71
(d, 1H, J=9 Hz), 8.95 (br s, 1H); .sup.31P (121.4 MHz, CD.sub.3OD)
.delta. 29.5; MS (m/z) 516.3 [M+H].sup.+, 1030.9 [2M].sup.+, 1053.0
[2M+Na].sup.+.
##STR00323##
Example 216
[0690] A solution of oxalate salt of
diethyl(aminomethyl)phosphonate (8 mg, 0.031 mmol) in 0.31 mL of
DMF and DIEA (22 .mu.L, 0.124 mmol) was added to 213 (16 mg, 0.031
mmol) and HATU (24 mg, 0.062 mmol). The solution was stirred at
ambient temperature for 2 hours when another batch of the amine and
the coupling reagent equivalent to the above amounts were added.
The reaction was heated with a heat gun to 60.degree. C. for 1
minute and the reaction was analyzed by LCMS. The reaction mixture
was loaded onto a flash column and
({[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g-
]quinoline-5-carbonyl]-amino}-methyl)-phosphonic acid diethyl ester
216 was eluted with EtOAc-10% MeOH to provide 20 mg (97%) of a
clear oil. MS (m/z) 668.1 [M+H].sup.+, 690.3 [M+Na].sup.+.
Example 217
[0691] A solution of 216 (20 mg, 0.030 mmol) in 0.30 nL of
CH.sub.2Cl.sub.2 was stirred with TFA (231 .mu.L, 3.00 mmol) and
TES (479 .mu.L, 3.00 mmol) for 30 minutes when the starting
materials were completely consumed as judged by TLC and LCMS. The
reaction was worked up by removal of the solvent in vacuo and
crystallizing the product from EtOAc-Hex to provide 10 mg (66%) of
({[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quino-
line-5-carbonyl]-amino}-methyl)-phosphonic acid diethyl ester 217
as a yellow solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.32
(t, 6H, J=7 Hz), 3.96 (d, 2H, J=12 Hz), 4.16 (septet, 4H, J=7 Hz),
4.56 (s, 2H), 4.79 (s, 2H), 7.10 (t, 2H, J=9 Hz), 7.39 (dd, 2H, J=9
Hz), 7.76 (br s, 1H), 8.66 (d, 1H, J=8 Hz), 8.95 (br s, 1H);
.sup.31P (121.4 MHz, CD.sub.3OD) .delta. 23.2; .sup.19F NMR (282.6
MHz, CD.sub.3OD) .delta.-76.2, 59.9; MS (m/z) 502.5 [M+H].sup.+,
1003.0 [2M].sup.+, 1025.1 [2M+Na].sup.+.
##STR00324##
Example 218
[0692] S-lactate ester 218
Example 219
[0693] A solution of
2-[(2-benzyloxycarbonylamino-ethyl)-phenoxy-phosphinoyloxy]-propionic
acid ethyl ester 218 (240 mg, 0.551 mmol) with approximately 50%
purity and a ratio of 2:1 of diastereomers was dissolved in 5.5 mL
of ethanol with acetic acid (63 .mu.L, 1.10 mmol). To this solution
was added 36 mg of 10% Pd/C and the solution was degassed under a
hydrogen atmosphere three times. The solution was vigorously
stirred at room temperature for 3 hours when TLC showed complete
consumption of the starting materials. The mixture was filtered
through a pad of Celite and dried to provide 174 mg (87%) of
2-[(2-amino-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl
ester; compound with acetic acid 219 as a clear oil.
Example 220
[0694] A solution of 13.5 mg of 213 in 0.13 mL of DMF was stirred
with HATU (20 mg, 0.052 mmol) at room temperature for 10 minutes.
To this solution was added a premixed solution of 219 (28 mg, 0.078
mmol) of approximately 50% purity in 0.130 mL of DMF and DIEA (13.4
mg, 0.104 mmol). The reaction mixture was gently heated with a heat
gun for 30 seconds and then the reaction was allowed to proceed at
room temperature for 2 hours when LCMS demonstrated complete
consumption of the carboxylic acid. The reaction mixture was loaded
onto a silica gel column and purified with EtoAc-10% MeOH to
provide 9.5 mg of
3-[(2-{[9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[-
3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyl]-2-methyl-pr-
opionic acid ethyl ester 220 which was carried on to the next
step.
Example 221
[0695] A solution of 220 (9.5 mg, 11.8 .mu.mol) was stirred with
0.12 mL of dry dichloromethane with trifluoroacetic acid (93 .mu.L,
1.18 mmol) and triethylsilane (189 .mu.L, 1.18 mmol) for 1 hour at
room temperature when TLC showed complete consumption of the
starting materials. The reaction mixture was dried in vacuo and
azeotroped from dichloromethane three times. The solid product was
triturated with EtOAc-Hex to get 6 mg of
2-[(2-{[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyloxy]-propionic
acid ethyl ester 221 as a pale yellow solid. The NMR of the two
diastereomers in CDCl.sub.3 is broad and indicates presence of
rotamers. VT NMR in DMSO at 85.degree. C. resulted in drastic
sharpening of the peaks. .sup.1H NMR (300 MHz, DMSO-d6, 85.degree.
C.) .delta. 1.15-1.26 (m, 3H), 1.35 and 1.47 (d, 3H, J=7 Hz),
2.23-2.45 (m, 2H), 3.58-3.57 (m, 2H), 4.08-4.19 (m, 2H), 4.56 (s,
2H), 4.69 (s, 2H), 4.93-5.04 (n, 1IH), 7.14 (t, 2H, J=9 Hz),
7.18-7.23 (m, 3H), 7.35-7.42 (m, 4H), 7.65 (dd, 1H, J=4, 8 Hz),
8.42 (br s, 1H), 8.55 (d, 1H, J=9 Hz), 8.92 (d, 1H, J=4H); .sup.31P
(121.4 MHz, DMSO-d6, 85.degree. C.) .delta. 26.1, 28.3; MS (m/z)
636.5 [M+H].sup.+.
##STR00325##
Example 222
[0696] A solution of the trifluoroacetate salt of
4-{2-[(1-ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-c-
arboxylic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 194 (0.045 g, 0.054 mmol) in acetonitrile (ACN, 0.68
mL) and water (0.68 mL) was treated with an aqueous solution of
NaOH (0.162 mL, 1M). The reaction mixture was stirred at room
temperature for 3 hours. The mixture was cooled to 0.degree. C.,
then acidified with a 2N aqueous solution of HCl to pH=1.
Acetonitrile was removed in vacuo then purified by reversed phase
HPLC to afford the trifluoroacetate salt of
4-{2-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-ethyl}-piperazine-1-carboxyl-
ic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]q-
uinolin-5-yl ester; compound with trifluoro-acetic acid 222 (0.032
g, 80%): .sup.1H NMR (CD.sub.3OD) .delta. 9.0 (d, 1H), 8.5 (d, 1H),
7.75 (dd, 1H), 7.4 (dd, 2H), 7.1 (t, 2H), 4.8 (s, 2H), 4.45 (s,
2H), 4.3-3.7 (m, 4H), 3.7-3.35 (m, 6H), 2.2 (m, 2H), 1.55 (d, 3H);
.sup.31P NMR (CDCl.sub.3) .delta. 19.8; MS: 617 (M+1).
##STR00326##
Example 223
[0697] A solution of the
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inoline-5-carboxylic acid 213 (0.415 g, 0.80 mmol) and HATU (0.608
g, 1.60 mmol) in N,N-dimethylformamide (DMF) (2.5 mL) was stirred
under an inert atmosphere at room temperature for 5 minutes. To the
solution was added a premixed solution of
2-[phenoxy-(2-piperazin-1-yl-ethyl)-phosphinoyloxy]-(S)-propionic
acid ethyl ester: compound with trifluoroacetic acid 192 (0.580 g,
1.20 mmol), N,N-Diisopropylethylamine (DIPEA) (0.700 mL, 4.0 mmol)
in DMF (3.5 mL). The reaction mixture was stirred at room
temperature for 5 hours. The mixture was diluted with ethyl
acetate, washed with saturated NaHCO.sub.3 (twice), water (twice)
and brine (twice), dried (NaSO.sub.4), and concentrated. The
residue was purified by silica gel chromatography
(5/95-methanol/methylene chloride) to afford
2-[(2-{4-[9-benzyhydryloxy-7-(4-fluoro-benzyl-8-oxo-7,8-dihydro-6H-pyrrol-
o[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phenoxy-phosphinoylox-
y]-(S)-propionic acid ethyl ester 223 (0.625 g, 90%) as mixture of
diastereomers: .sup.1H NMR (CDCl.sub.3) .delta. 9.07 (dd, 1H), 8.15
(s, 1H), 8.05 (dd, 1H), 7.75 (d, 4H), 7.52 (dd, 1H), 7.4-7.1 (m,
13H), 7.05 (t, 2H), 5.02 (m, 1H), 5.0-4.6 (dd, 2H), 4.4-4.0 (dd,
2H), 4.17 (m, 2H), 4.0-3.5 (m, 3H), 3.0 (m, 2H), 2.7-2.5 (m, 3H),
2.4-2.1 (m, 4H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H) ; .sup.31P NMR
(CDCl.sub.3) .delta. 28.3, 26.5; MS: 871 (M+1).
##STR00327##
Example 224
[0698] A solution of
2-[(2-{4-[9-benzyhydryloxy-7-(4-fluoro-benzyl-8-oxo-7,8-dihydro-6H-pyrrol-
o[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phenoxy-phosphinoylox-
y]-propionic acid ethyl ester 223 (0.420 g, 0.483 mmol) in
methylene chloride (2 mL) was treated with trifluoroacetic acid
(0.4 mL) and triethylsilane (0.8 mL). The reaction mixture was
stirred at room temperature under an inert atmosphere for 40
minutes. The volatiles were removed in vacuo with toluene. The
product was triturated in diethyl ether/hexane with sonicaton to
afford the trifluoroacetate salt of
2-{[2-4-2-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-
-g]quinolin-5-yl]-acetyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-p-
ropionic acid ethyl ester 224 (0.370 g, 94%): .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (d, 1H), 8.15 (dd, 1H), 7.67 (dd, 1H),
7.35-7.1 (m, 7H), 7.05 (t, 2H), 5.0 (m, 1H), 5.0-4.6 (m, 2H),
4.6-4.25 (m, 2H), 4.25-3.95 (m, 5H), 3.7-2.8 (m, 8H), 2.7-2.5 (m,
2H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H); .sup.31P NMR (CDCl.sub.3)
.delta. 23.0, 21.0; MS: 705 (M+1).
##STR00328##
Example 225
[0699] Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was
dissolved in 2 mL dry tetrahydrofuran. To this was added
triethylamine (0.028 mL, 0.2032 mmol) and 1 M tetrabutylammonium
fluoride solution in tetrahydrofuran (0.1016 mL, 0.1016 mmol.)
Stirred at room temperature I0 minutes until starting material
consumed. Diluted with dichloromethane, washed with washed with 1M
HCl solution, saturated brine, concentrated to give crude.
Dissolved in 1.5 mL dichloromethane, added catalytic
dimethylaminopyridine, triethylamine (0.16 mL, 0.6 mmol) and cooled
to 0.degree. C. To this was added triphosgene (0.03 g, 0.1016 mmol)
and stirred 40 minutes. BOC-aminopyrrolidine (0.038 g, 0.2032 mmol)
was then added and stirred at room temperature for 10 minutes. The
mixture was diluted with dichloromethane, washed with 1M HCl,
brine, concentrated volatiles to give crude product.
Chromatographed (10% to 30% acetone/toluene) to give 225 (0.0108 g,
0.0153 mmol, 30%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.03 (dd, 1H),
8.11 (d, 1H), 8.03 (s, 1H), 7.74 (d, 4H), 7.50 (dd, 1H), 7.27 (m,
8H), 7.07 (dd, 2H), 4.80 (s, 2H), 4.65 (br s, 1H), 4.30 (hr s, 1H),
4.24 (s, 2H), 3.95 (br s, 1H), 3.74 (m, 2H), 3.58 (m, 2H), 1.48 (s,
9H) MS: 703 M+1)
##STR00329##
Example 226
[0700] Carbamate 225 (0.0108 g, 0.0153 mmol) was dissolved in 0.5
mL of dichloromethane. To this was added 0.2 mL of triethylsilane
and 0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Then dissolved in 0.3 mL
dichloromethane, 0.3 ml trifluoroacetic acid. Stirred at room
temperature for one hour. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated twice with 1:1 diethyl
ether/hexanes to give the trifluoroacetate salt of
3-amino-pyrrolidine-1-carboxylic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 226 (0.0057 g, 0.0104 mmol, 68%.) .sup.1H NMR
(CD.sub.3SOCD.sub.3) .delta. 9.00 (s, 1H), 8.41 (s, 1H), 8.21 (s,
1H), 7.76 (dd, 1H), 7.36 (dd, 2H), 7.22 (dd, 2H), 4.72 (s, 2H),
4.36 (s, 2H), 3.93-3.35 (m, 7H) .sup.19F NMR: -73.9 MS: 437 (M+1),
435 (M-1)
##STR00330##
Example 227
[0701] 2-Amino-1,2,4 thiadiazole (0.006 g, 0.06 mmol) and
triethylamine (0.0376 mL, 0.27 mmol) were added to 1 mL
dichloromethane and cooled to 0.degree. C. To this was slowly added
chlorosulfonylisocyanate (0.007 mL, 0.08 mmol) at 0.degree. C.
Stirred thirty minutes until starting material consumed.
Simultaneously, in a separate flask trimethylsilylethyl ether 44
was dissolved in 0.5 mL tetrahydrofuran. To this was added
triethylamine (0.0376 mL, 0.27 mmol) and 1M tetrabutylammonium
fluoride in tetrahydrofuran (0.135, 0.135 mmol) and stirred at room
temperature. After 20 minutes, diluted with dichloromethane, washed
with 1M HCl solution and brine, concentrated to give crude. At
0.degree. C., dissolved in 0.5 mL dichloromethane and added to the
solution prepared in situ above. Stirred at 0.degree. C. for 5
minutes, catalytic DMAP added, then stirred for one hour at room
temperature. Diluted with dichloromethane, washed with 1M HCl
solution, brine, concentrated to give crude. Chromatographed (5 to
30% methanol/dichloromethane) to give dimethylaminopyridine adduct
227 (0.033 g, 0.046 mmol, 68%.) .sup.1H NMR (CDCl.sub.3) .delta.
8.97 (dd, 1H), 8.54 (d, 2H), 8.19 (d, 1H), 8.00 (s, 1H), 7.72 (d,
4H), 7.42 (dd, 1H), 7.26-7.14 (m, 7H), 7.02 (dd, 2H), 6.52 (d, 2H),
4.74 (s, 2H), 4.17 (s, 2H), 3.22 (s, 6H.) MS: 718 (M+1).
##STR00331##
Example 228
[0702] Carbamate 227 (0.007 gm, 0.0097 mmol) was dissolved in 0.25
mL of dichloromethane. To is was added 0.1 mL of triethylsilane and
0.05 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethyl ether/hexanes to give 228 (0.004 g, 0.0073 mmol, 75%.)
.sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.22 (d, 1H), 9.09 (s,
1H), 8.47 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.37 (s, 2H), 7.19
(s, 1H), 6.96 (s, 2H), 4.76 (s, 2H), 4.45 (s, 2H), 3.21 (d, 6H.)
.sup.19F NMR: -75.95 MS: 552 (M+1), 550 (M-1)
##STR00332##
Example 229
[0703] Carboxylic acid 213 (0.015 g, 0.029 mmol) was dissolved in
0.8 mL of dimethylformamide. To this was added BOC-piperazine
(0.0116 g, 0.058 mmol), triethylamine (0.012 mL, 0.087 mmol),
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.011
g, 0.058 mmol), 1-Hydroxybenzotriazole hydrate (0.0059 g, 0.0435
mmol) and stirred at room temperature. After 15 hours, starting
material was consumed. Dilute with dichloromethane, washed with 1M
HCl solution, saturated brine solution, dried (Na.sub.2SO.sub.4),
concentrated to give crude product. Chromatographed (10 to 50%
ethyl acetate/hexanes) to give
4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g-
]quinoline-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl
ester 229 (0.009 g, 0.013 mmol, 45%.) .sup.1H NMR (CDCl.sub.3)
9.075 (s, 1H), 8.15 (s, 1H), 8.03 (d, 1H), 7.74 (dd, 4H), 7.53 (dd,
1H), 7.27 (m, 8H), 7.04 (dd, 2H), 4.91 (d, J=17 Hz, 1H), 4.69 (d,
J=17Hz, 1H), 4.41 (d, J=17 Hz, 1H), 4.055 (d, J=17 Hz, 1H),
3.55-2.96 (br m, 8 H), 1.44 (s, 9H.) MS: 687 (M+1).
##STR00333##
Example 230
[0704] Carboxamide 229 (0.0108 g, 0.0153 mmol) was dissolved in 1
mL of dichloromethane. To this was added 0.4 mL of triethylsilane
and 0.2 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Then dissolved in 0.6 mL
dichloromethane, 0.6 ml trifluoroacetic acid. Stirred at room
temperature for one hour. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated twice with 1:1 diethyl
ether/hexanes to give
7-(4-fluoro-benzyl)-9-hydroxy-5-(piperazine-1-carbonyl)-6,7-dihydro-pyrro-
lo[3,4-g]quinolin-8-one 230 (0.039 g, 0.0682 mmol, 100%.) .sup.1H
NMR (CD.sub.3SOCD.sub.3) .delta. 98.97 (s, 2H), 8.32 (d, 1H), 7.74
(s, 1H), 7.36 (dd, 2H), 7.19 (dd, 2H), 4.86 (d, 1H), 4.58 (d, 1H),
4.42 (d, 1H), 4.34 (d, 1H), 3.9-2.90 (m, 8H.) .sup.19F NMR: -74.202
MS: 421 (M+1), 419 (M-1)
##STR00334##
Example 231
[0705] Carboxylic acid 213 (0.010 g, 0.0193 mmol) was dissolved in
0.3 mL of dimethylformamide. To this was added
2-aminomethylpyridine (0.004 g, 0.0386 mmol), triethylamine (0.008
mL, 0.058 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.074 g, 0.0386 mmol), 1-Hydroxybenzotriazole
hydrate (0.0039 g, 0.029 mmol) and stirred at room temperature.
After 15 hours, starting material was consumed. Dilute with
dichloromethane, washed with 1M HCl solution, saturated brine
solution, dried (Na.sub.2SO.sub.4), concentrated to give crude
product. Chromatographed (0 to 8% methanol/dichloromethane) to give
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inoline-5-carboxylic acid (pyridin-2-ylmethyl)-amide 231 (0.007 g,
0.011 mmol, 59%.) .sup.1H NMR (CDCl.sub.3) 8.94 (s, 1H), 8.45 (d,
2H), 8.05 (s, 1H), 7.70 (d, 4H), 7.57-7.17 (m, 12H), 7.05 (d, 2H),
4.78 (s, 1H), 4.69 (d, J=5Hz, 1H), 4.38 (s, 1H). MS: 609 (M+1).
##STR00335##
Example 232
[0706] Carboxamide 231 (0.225 g, 0.355 mmol) was dissolved in 1 mL
of dichloromethane. To this was added 0.5 mL of triethylsilane and
0.25 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethyl ether/hexanes to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qui-
noline-5-carboxylic acid (pyridin-2-ylmethyl)-amide 232 (0.11 g,
0.20 mmol, 56%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.18 (s,
1H), 8.96 (d, 1H), 8.65 (dd, 2H), 8.09 (dd, 1H), 7.76 (dd, 1H),
7.64 (dd, 1H), 7.36 (dd, 2H), 7.22 (dd, 2H), 4.70 (S, 4H), 4.54 (s,
2H). .sup.19F NMR: -75.37 MS: 443 (M+1), 441 (M-1)
##STR00336##
Example 233
[0707] Carboxylic acid 213 (0.010 g, 0.0193 mmol) was dissolved in
0.3 mL of dimethylformamide. To this was added
4-aminomethylpyridine (0.004 mL, 0.0386 mmol), triethylamine (0.008
mL, 0.058 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.074 g, 0.0386 mmol), 1-Hydroxybenzotriazole
hydrate (0.0039 g, 0.029 mmol) and stirred at room temperature.
After 15 hours, starting material was consumed. Dilute with
dichloromethane, washed with 1M HCl solution, saturated brine
solution, dried (Na.sub.2SO.sub.4), concentrated to give crude
product. Chromatographed (0 to 8% methanol/dichloromethane) to give
233 (0.0048 g, 0.008 mmol, 41%.) .sup.1H NMR (CDCl.sub.3) .delta.
8.71 (s, 1H), 8.66 (d, 2H), 7.99 (dd, 2H), 7.65 (s, 1H), 7.51 (s,
4H), 7.34 (m, 9H), 7.05 (dd, 2H), 4.69 (s, 2H), 4.25 (d, 2H), 4.00
(s, 2H). MS: 609 (M+1).
##STR00337##
Example 234
[0708] Carboxamide 233 (0.137 g, 0.225 mmol) was dissolved in 1 mL
of dichloromethane. To this was added 0.5 mL of triethylsilane and
0.25 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethyl ether/hexanes to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qui-
noline-5-carboxylic acid (pyridin-4-ylmethyl)-amide 234 (0.114 g,
0.20 mmol, 91%.) .sup.1H NMR (CD.sub.3SOCD.sub.3) .delta. 9.24 (dd,
1H), 8.98 (d, 1H), 8.77 (dd, 2H), 8.53 (d, 1H), 7.79 (dd, 3H), 7.40
(dd, 2H), 7.23 (dd, 2H), 4.71 (s, 4H), 4.56 (s, 2H). .sup.19F NMR:
-74.906 MS: 443 (M+1), 441 (M-1)
##STR00338##
Example 235
[0709] Carboxylic acid 213 (0.020 g, 0.0386 mmol) was dissolved in
0.4 mL of dimethylformamide. To this was added methyl piperazine
(0.0085 mL, 0.077 mmol), diisopropylethylamine (0.027 mL, 0.154
mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.029 g, 0.0777 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed. Dilute
with dichloromethane, washed with saturated brine solution, dried
(Na.sub.2SO.sub.4), concentrated to give crude product.
Chromatographed (0 to 8% methanol/dichloromethane) to give 235
(0.017 g, 0.028 mmol, 73%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.06
(dd, 1H), 8.13 (s, 1H), 8.05 (dd, 1H), 7.76 (dd, 4H), 7.53 (dd,
1H), 7.27 (m, 8H), 7.06 (dd, 2H), 4.93 (d, J=15 Hz, 1H), 4.72 (d,
J=15 Hz, 1H), 4.36 (d, J=15 Hz, 1H), 4.066 (d, J=15 Hz, 1H),
3.88-2.97 (m, 8H), 2.28 (s, 3H.) MS: 601 (M+1).
##STR00339##
Example 236
[0710] Carboxamide 235 (0.015 g, 0.025 mmol) was dissolved in 0.5
mL of dichloromethane. To this was added 0.2 mL of triethylsilane
and 0.1 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethyl ether/hexanes to give
7-(4-fluoro-benzyl)-9-hydroxy-5-(4-methyl-piperazine-1-carbonyl)-6,7-dihy-
dro-pyrrolo[3,4-g]quinolin-8-one 236 (0.0135 g, 0.227 mmol, 91%.)
.sup.1H NMR 90 0.degree. C.(CD.sub.3SOCD.sub.3) .delta. 8.98 (dd,
1H), 8.28 (d, 1H), 7.74 (dd, 1H), 7.40 (dd, 2H), 7.21 (dd, 2H),
4.72 (s, 4H), 4.40 (s, 4H), 3.5 (br s, 4H), 2.81 (s, 3H.) .sup.19F
NMR: -74.688 MS: 436 (M+1), 434 (M-1)
##STR00340##
Example 237
[0711] Carboxylic acid 213 (0.10 g, 0.193 mmol) was dissolved in 2
mL of dimethylformamide. To this was added morpholine (0.0337 mL,
0.386 mmol), diisopropylethylamine (0.135 mL, 0.772 mmol),
O-(7-azabenzotiazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU, 0.146 g, 0.386 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed. Dilute
with dichloromethane, washed with 1M HCl solution, saturated brine
solution, dried (Na.sub.2SO.sub.4), concentrated to give crude
product. Chromatographed (0 to 5% methanol/dichloromethane) to give
pure product (0.06 g, 0.102 mmol, 53%.) .sup.1H NMR (CDCl.sub.3)
.delta. 9.08 (dd, 1H), 8.15 (s, 1H), 8.06 (dd, 1H), 7.76 (dd, 4H),
7.55 (dd, 1H), 7.30 (m, 8H), 7.07 (dd, 2H), 4.95 (d, J=15 Hz, 1H),
4.70 (d, J=15 Hz, 1H), 4.42 (d, J=15 Hz, 1H), 4.14 (d, J=15 Hz,
1H), 3.94-3.79 (m, 4H), 3.41 (m, 2H), 2.99 (m, 2H.) MS: 588
(M+1).
##STR00341##
Example 238
[0712] Carboxamide 237 (0.06 g, 0.102 mmol) was dissolved in 1 mL
of dichloromethane. To this was added 0.4 mL of triethylsilane and
0.2 mL of trifluoroacetic acid. Stirred at room temperature and
after ten minutes complete by TLC. Concentrated off volatiles,
azeotroped with toluene to give crude. Triturated twice with 1:1
diethyl ether/hexanes to give
7-(4fluoro-benzyl)-9-hydroxy-5-(morpholine-4-carbonyl)-6,7dihydro-pyrrolo-
[3,4-g]quinolin-8-one 238 (0.0459 g, 0.109 mmol, 100%.) .sup.1H NMR
(CDCl.sub.3) .delta. 9.05 (dd, 1H), 8.20 (d, 1H), 7.64 (dd, 1H),
7.35 (m, 2H), 7.08 (dd, 2H), 4.91 (d, J=15 Hz, 1H), 4.68 (d, J=15
Hz, 1H), 4.59 (d, J=15 Hz, 1 Hz), 4.24 (d, J=15 Hz, 1H), 3.99 (m,
3H), 3.5 (s, 2H), 3.18 (s, 2H.) MS: 436 (M+1), 434 (M-1)
##STR00342##
Example 239
[0713] Carboxylic acid 213 (0.018 g, 0.0347 mmol) was dissolved in
0.5 mL of dimethylformamide. To this was added piperidine (0.0068
mL, 0.0695 mmol), diisopropylethylamine (0.024 mL, 0.1399 mmol),
HATU (0.027 g, 0.0695 mmol) and stirred at room temperature. After
2.5 hours, starting material was consumed. Dilute with ethyl
acetate, washed with 2.5% LiCl solution, saturated brine solution,
dried (Na.sub.2SO.sub.4), concentrated to give crude 239. .sup.1H
NMR (CDCl.sub.3) .delta. 9.04 (dd, 1H), 8.12 (s, 1H), 8.06 (d, 1H),
7.75 (dd, 4H), 7.52 (dd, 1H), 7.30 (m, 8H), 7.06 (dd, 2H), 4.94 (d,
J=15 Hz, 1H), 4.69 (d, J=15 Hz, 1H), 4.40 (d, J=15 Hz, 1H), 4.07
(d, J=15 Hz, 1H), 3.91 (s, 1H), 3.71 (s, 1H), 3.28 (s, 1H), 3.18
(s, 1H), 2.0-1.28 (m, 6H.) MS: 586 (M+1).
##STR00343##
Example 240
[0714] Carboxamide 239 (crude) was dissolved in 0.5 mL of
dichloromethane. To this was added 0.2 mL of triethylsilane and 0.1
mL of trifluoroacetic acid. Stirred at room temperature and after
ten minutes complete by TLC. Concentrated off volatiles, azeotroped
with toluene to give crude. Triturated twice with 1:1 diethyl
ether/hexanes to give
7-(4-fluoro-benzyl)-9-hydroxy-5-piperidine-1-carbonyl)-6,7-dihydro-pyrrol-
o[3,4-g]quinolin-8-one 240 (0.0084 g, 0.02 mmol, 58% for 2 steps.)
.sup.1H NMR (CDCl.sub.3) .delta. 8.97 (dd, 1H), 8.17 (d, 1H), 7.60
(dd, 1H), 7.34 (dd, 2H), 7.07 (dd, 2H), 4.91 (d, J=15 Hz, 1H), 4.66
(d, J=15 Hz, 1H), 4.56 (d, J=15 Hz, 1 Hz), 4.22 (d, J=15 Hz, 1H),
3.91 (s, 1H), 3.75 (s, 1H), 3.11 (s, 2H), 1.7-1.3 (m, 6H.) MS: 420
(M+1), 418 (M-1)
##STR00344##
Example 241
[0715] To a mixture of pyrazine-2,3-dicarboxylic acid (20 g, 119
mmol, 1 equiv.) was added MeOH (80 mL) followed by dropwise
addition of concentrated H.sub.2SO.sub.4 (36 mL, 680 mmol, 5.7
equiv.) over 45 minutes. This method is similar to that that cited
for a different substrate (J. Am. Chem. Soc., 73, 1951, 5614-5616).
The reaction was heated at 75.degree. C. for 16 hours and then
cooled and quenched with water (200 mL). It was extracted with
EtOAc (4.times.60 mL) and the organic layer washed several times
with water (3.times.50 ml), saturated NaHCO.sub.3 (50 ml), brine
solution (50 mL). It was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to yield pyrazine-2,3-dicarboxylic acid
methyl ester 241 as a brown solid (47%, 10.97 g, 55.9 mmol).
.sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 8.79 (d, J=2.7 Hz, 2 H),
4.05 (s, 3 H), 4.04 (s, 3 H). TLC Rf: 0.7 ethyl acetate/methanol
(9/1)
##STR00345##
Example 242
[0716] Into a flask containing pyrazine-2,3-dicarboxylic acid
methyl ester 241 (10.70 g, 54.6 mmol, 1 equiv.) was added THF (150
mL) under a nitrogen atmosphere followed by
1-(4-Fluoro-benzyl)-pyrrolidine-2,5-dione 1 (11.30 g, 54.6 mmol, 1
equiv.). MeOH (1.8 mL) was then added and at 0.degree. C. was added
NaH (4.8 g, 120.1 mmol, 2.2 equiv.) carefully in four portions.
Refluxing was carried out for 20 hours after which the reaction was
cooled and placed in a 0.degree. C. icebath. HCl (6 N, 30 mL,
H.sub.2O) was slowly added while vigorously stirring. The resulting
solid was filtered, and washed thoroughly with water followed by
ether. It was then dried in a vacuum oven (60.degree. C., 12 hours)
to realize 8.7 gm (47%, 25.66 mmol) of
7-(4-fluoro-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione
242. .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 7.15-7.33 (m, 5 H),
5.91 (s, 2 H), 3.96 (s, 3 H), 3.88 (s, 3 H). MS: 340.3 (M+1).
##STR00346##
Example 243
[0717] 7-(4-Fluoro-benzyl)-5,9-dihydroxy-pyrrolo [3,4-g]
quinoxaline-6,8-dione 242 (1 g, 2.95 mmol, 1 equiv.) was dissolved
in DMF (30 ml, 0.11 M) and pyridine (477 .mu.L, 5.89 mmol, 2
equiv.) before ethyl chloroformate was added (237 .mu.L, 2.95 mmol,
1 equiv.). The reaction was stirred for 16 hours before being
quenched with HCl (30 ml, 1 N) and extracted with ethyl acetate
(2.times.30 mL). The organic layer washed several times with water
(4.times.30 mL), saturated NaHCO.sub.3 (50 mL), brine solution (50
mL). It was dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. Recrystallization was carried out in ethyl acetate and
Hexanes to yield carbonic acid ethyl ester
7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quin-
oxalin-5-yl ester 243 as a light brown solid (98%, 1.20 g, 2.89
mmol). .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 9.09 (d, J=6 Hz, 1
H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H),
7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H), 4.04 (q, J=2.8 Hz, 2 H),
1.43 (q, J=2.8 Hz, 3 H). MS: 412.6 (M+1).
##STR00347##
Example 244
[0718] Carbonic acid
mono-[1-(1-benzyl-4-methylene-2,5-dioxo-pyrrolidin-3-ylidene)-ethyl]
ester 243 (1.1 g, 2.68 mmol, 1 equiv.) was dissolved in 1,2
dichloroethane (50 mL, 0.055 M) and to this was added
diphenyldiazomethane (1.05 g, 5.35 mmol, 2 equiv.) and heated at
70.degree. C. under a nitrogen atmosphere for 24 hours. The
reaction was concentrated in vacuo and purified by silica gel
chromatography using 4/1 Hexanes/Ethyl acetate to obtain carbonic
acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4--
g]quinoxalin-5-yl ethyl ester 244 (70%, 1085 mg, 1.87 mmol).
.sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 9.09 (d, J=6 Hz, 1 H),
8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H),
7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H), 4.04 (q, J=2.8 Hz, 2 H),
1.43 (q, J=2.8 Hz, 3 H). MS: 600.2 (M+23). TLC R.sub.f: 0.3
Hexanes/Ethyl acetate (7/3)
##STR00348##
Example 245
[0719] Carbonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4--
g]quinoxalin-5-yl ester ethyl ester 244 (500 mg, 0.87 mmol) was
dissolved in THE (9 mL, 0.1 M) along with DMAP (211 mg, 1.73 mmol,
2 equiv.). A solution of K.sub.2CO.sub.3 (1.20 g, 8.66 mmol, and 10
equiv.) was dissolved separately in H.sub.2O (6 mL) before being
transferred to the reaction mixture. The reaction was allowed to
stir for 18 hours and quenched with HCl (20 mL, 1 N) and extracted
with ethyl acetate (2.times.30 mL). The organic layer was washed
with saturated NH.sub.4Cl solution (25 mL), brine solution (25 mL)
and dried over Na.sub.2SO.sub.4 and concentrated in vacuo to yield
5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6-
,8-dione 245 (94%, 413 mg, 0.82 mmol).
[0720] .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 9.08 (d, J=1.5 Hz,
1 H), 8.92 (d, J=1.5 Hz, 1 H), 7.67 (s, 1 H), 7.67-7.42 (dd,
J.sub.1=1.5 Hz, J.sub.2=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27
(m, 7 H), 7.03-7.20 (m, 1 H), 4.86 (s, 2 H). MS: 528.0 (M+23). TLC
R.sub.f: 0.2 Hexanes/Ethyl acetate (8/2)
##STR00349##
Example 246
[0721] Into a flask containing
5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6-
,8-dione 245 (350 mg, 0.69 mmol, 1 equiv.) was added DMF (20 mL)
followed by K.sub.2CO.sub.3 (478 mg, 3.46 mmol, 5 equiv.). To this
was added MeI (983 .mu.L, 6.93 mmol, 10 equiv.) under a nitrogen
atmosphere and stirred for 16 hours. To the reaction was then added
water (50 mL) and extracted with ethyl acetate (2.times.40 mL). The
organic layer was washed several times with water (3.times.30 mL),
saturated NaHCO.sub.3 (40 mL), brine solution (30 mL). It was dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo before
being purified by silica gel chromatography using 3/2 Hexanes/ethyl
acetate to obtain
5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6-
,8-dione 246 (78%, 280 mg, 0.54 mmol) as a yellow solid, .sup.1H
NMR (300 MHz) CDCl.sub.3 .delta. 9.03 (d, J=1.5 Hz, 1 H), 8.97 (d,
J=1.5 Hz, 1 H), 7.75 (s, 1 H), 7.60 (dd, J.sub.1=1.5 Hz,
J.sub.2=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27 (m, 7 H),
7.03-7.20 (m, 1 H), 4.86 (s, 2 H), 4.37 (s, 3 H). MS: 542.0 (M+23).
TLC R.sub.f: 0.5 Hexanes/Ethyl acetate (1/1)
##STR00350##
Example 247
[0722]
5-Benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxa-
line-6,8-dione 246 (10 mg, 0.019 mmol, 1 equiv.) was dissolved in
CH.sub.2Cl.sub.2 (0.2 mL) and MeOH (0.5 mL) under a nitrogen
atmosphere at 0.degree. C. Sodium borohydride (NaBH.sub.4) was
added (115 .mu.L, 0.057 mmol, 3 equiv., 0.5 M). The reaction was
allowed to stir for 1 hour and then quenched with water (5 mL) and
extracted with ethyl acetate (2.times.5 mL). The organic layer was
washed several times with water (2.times.10 mL), brine solution (10
mL). It was dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo and purified by preparatory thin-layer chromatography
(PTLC) using 3/2 Hexanes/Ethyl acetate to obtain
5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrro-
lo[3,4-g]quinoxalin-6-one 247a (34%, 3 mg) and reduced species:
5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-1,2,3,4,7,8-hexah-
ydro-pyrrolo[3,4-g]quinoxalin-6-one 247b (21%, 2 mg) and
5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-1,2,3,4tetrahydro-pyrrolo
3,4-g]quinoxaline-6,8-dione 247c (34%, 3.4 mg).
[0723] 247a: .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 8.86 (d,
J=1.8 Hz, 1 H), 8.82 (d, J=1.8 Hz, 1 H), 7.69 (s, 1 H), 7.69-7.56
(m, 1 H), 7.54-7.56 (m, 1 H), 7.16-7.32 (m, 10 H), 7.01-7.17 (s, 2
H), 5.78 (bs, 1 H), 5.18 (d, J=14.7 Hz, 1 H), 4.38 (d, J=13.5 Hz, 1
H), 4.18 (s, 3 H), 3.83 (s, 2 H). MS: 544.0(M+23). TLC R.sub.f: 0.3
Hexanes/Ethyl acetate (3/2)
[0724] 247b: .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 7.27-7.7.40
(m, 12 H), 6.95-7.01 (m, 2 H), 4.70 (s, 2 H), 4.01 (s, 3 H), 3.32
(t, J=3.9 Hz, 2 H), 3.13 (t, J=5.1 Hz, 2 H), 2.75 (s, 2 H). MS:
545.9 (M+23). TLC R.sub.f: 0.25 Hexanes/Ethyl acetate (1/1)
[0725] 247c: .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 7.27-7.7.40
(m, 12 H), 5.58 (bs, 1 H), 5.01 (d, J=14.1 Hz, 1 H), 4.21 (d, J=9.6
Hz, 1 H), 3.85 (s, 3 H), 3.32-3.45 (m, 2 H), 3.02-3.05 (t, J=5.1
Hz, 2 H), 1.63 (bs, 2 H). R.sub.f: 0.2 Hexanes/Ethyl acetate
(1/1)
##STR00351##
Example 248
[0726] Into a flask containing
5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrro-
lo[3,4-g]quinoxalin-6-one 247a (20 mg, 0.038 mmol, 1 equiv.) was
added CH.sub.2Cl.sub.2 (1 mL) under a nitrogen atmosphere.
Triethylsilane (200 .mu.L) was added followed by trifluoroacetic
acid (200 .mu.L). The reaction was allowed to stir for 1 hour and
then concentrated in vacuo until thoroughly dried. To the oil was
Hexanes/Ethyl ether (15 mL, 1/1 ratio) and sonicated. The resulting
solid was then filtered, washed in hexanes, and air dried to give
7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxa-
lin-6-one 248 (38%, 7.2 mg, 0.0.14 mmol). .sup.1H NMR (300 MHz)
CDCl.sub.3 .delta. 8.95 (d, J=13.8 Hz, 2 H), 7.23-7.27 (m, 2 H),
6.96-7.05 (s, 2 H), 4.79 (2 H), 4.55 (s, 2 H), 4.14 (s, 3 H).
.sup.19F NMR (300 MHz) CDCl.sub.3 .delta. 62.80. MS: 340.1
(M+1)
##STR00352##
Example 249
[0727] Into a flask containing
5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6-
,8-dione 246 (10 mg, 0.019 mmol, 1 equiv.) was added
CH.sub.2Cl.sub.2 (1 mL) and under a nitrogen atmosphere was added
triethylsilane (200 .mu.L) followed by trifluoroacetic acid (200
.mu.L). The reaction was allowed to stir for 1.5 hours and
concentrated in vacuo until thoroughly dried. To the oil was added
Hexanes/Ethyl ether (20 mL, 1/1 ratio) and sonicated. The resulting
solid was filtered, washed in hexanes and air dried to give
7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dio-
ne 249 (67%, 4.6 mg, 0.015 mmol). .sup.1H NMR (300 MHz) CDCl.sub.3
.delta. 9.07 (d, J=1.8 Hz 1 H), 8.97 (d, J=1.8 Hz, 1 H), 7.23-7.27
(m, 2 H), 6.96-7.05 (s, 2 H), 4.87 (s, 2 H), 4.46 (s, 3 H).
.sup.19F NMR (300 MHz) CDCl.sub.3 .delta. 62.77 MS: 354.0 (M+1)
##STR00353##
Example 250
[0728] To commercially available,
1-benzyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid (4.5 g, 18.2
mmol, 1 equiv.) was added MeOH (30 mL) followed by dropwise
addition of H.sub.2SO.sub.4 (5.5 mL, 103.75 mmol, 5.7 equiv.) over
20 minutes by a method similar to J. Am. Chem. Soc., 73, 1951,
5614-5616. The reaction was heated at 85.degree. C. for 2 h. The
reaction was cooled and quenched with water (100 mL). It was
extracted with ethyl acetate (4.times.40 mL) and the organic layer
washed several times with water (3.times.50 mL), saturated
NaHCO.sub.3 (50 mL), brine solution (50 mL). It was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield
1-Benzyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester
250 as a brown solid (76%, 3.85 g, 55.9 mmol). .sup.1H NMR (300
MHz) CDCl.sub.3 .delta.7.15-7.33 (m, 5 H), 5.41 (s, 2 H), 3.92 (s,
3 H), 3.84 (s, 3 H).
##STR00354##
Example 251
[0729] Into a flask containing
1-benzyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester
250 (3.75 g, 13.64 mmol, 1 equiv.) was added THF (150 mL) under a
nitrogen followed by 1-(4-fluoro-benzyl)-pyrrolidine-2,5-dione 1
(2.82 g, 13.64 mmol, 1 equiv.). Methanol (MeOH, 1.1 mL) was added
and at 0.degree. C. was added NaH (1.20 g, 29.99 mmol, 2.2 equiv.,
60% dispersion) carefully in four portions. Refluxing was carried
out for 20 hours after which the reaction was cooled and placed in
a 0.degree. C. icebath. HCl (6 N, 20 mL, H.sub.2O) was slowly added
while vigorously stirring. The resulting solid was filtered, and
washed thoroughly with water followed by ether. It was then dried
in a vacuum oven (60.degree. C., overnight) to realize 3.34 gm
(60%, 8.18 mmol) of
1-benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-pyrrolo[3',4':4,5]benzo[1,2-
-d][1,2,3]triazole-5,7-dione 251. .sup.1H NMR (300 MHz) CD.sub.3OD
.delta. 9.51 (b, 1 H), 7.45-7.35 (m, 8 H), 7.15-7.33 (m, 2 H), 5.92
(s, 2 H), 4.78 (s, 2 H).
##STR00355##
Example 252
[0730] 1H-Imidazole-4,5-dicarboxylic acid dimethyl ester (2 g,
10.87 mmol, 1 equiv.) was dissolved in THF (55 mL, 0.2 M) and DMAP
(1.46 g, 11.95 mmol, 1.1 equiv.) before Di-tert-butyl dicarbonate
(3.50 g, 16.29 mmol, 1.4 equiv.) was added. The reaction was
stirred for 16 hours before being quenched with saturated
NH.sub.4Cl (30 mL) and extracted with ethyl acetate (2.times.30 mL)
and the organic layer washed several times with water (4.times.30
mL), brine solution (50 mL). It was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Imidazole-1,4,5-tricarboxylic
acid 1-tert-butyl ester 4,5-dimethyl ester 252 (3.85 g, 100%, 10.87
mmol). .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 8.02 (s, 1 H), 3.99
(s, 3 H), 3.92 (s, 3 H). MS: 306.8 (M+23). TLC R.sub.f: 0.6
Hexanes/Ethyl acetate (1/1)
##STR00356##
Example 253
[0731] Into a flask containing imidazole-1,4,5-tricarboxylic acid
1-tert-butyl ester 4,5-dimethyl ester 252 (3.85 g, 13.55 mmol, 1
equiv.) was added THF (55 mL) under a nitrogen atmosphere followed
by 1-(4-fluoro-benzyl)-pyrrolidine-2,5-dione 1(2.80 g, 13.55 mmol,
1 equiv.). MeOH (0.4 mL) was added and at 0.degree. C. was added
NaH (1.20 g, 29.81 mmol, 2.2 equiv., 60% dispersion) carefully in
four portions. Refluxing was carried out for 20 hours after which
the reaction was cooled and placed in a 0.degree. C. icebath. HCl
(6 N, 30 mL, H.sub.2O) was slowly added while vigorously stirring.
The resulting solid was filtered, and washed thoroughly with water
followed by ether. It was then dried in a vacuum oven (60.degree.
C., overnight) to realize 2.70 gm of a crude solid which was
recrystallized with dioxane (650 mL).
6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione
253 1.65 g, 5.01 mmol). .sup.1H NMR (300 MHz) DMSO d.sub.6 .delta.
8.64 (s, 1 H), 7.25-7.35 (m, 2 H), 7.10-7.29 (m, 2 H), 4.66 (s, 2
H). .sup.19F NMR (300 MHz) CDCl.sub.3 .delta. 61.34. MS: 328.1
(M+1)
##STR00357##
Example 254
[0732] 1H-Imidazole-4,5-dicarboxylic acid dimethyl ester (1.5 g,
8.15 mmol, 1 equiv.) was dissolved in MeOH (10 mL) and benzyl
bromide (1.16 mL, 9.77 mmol, 1.1 equiv.) before sodium hydride (360
mg, 1.1 equiv., 60% dispersion) and sodium iodide (200 mg) was
added. The reaction was stirred for 16 hours before being quenched
with saturated NH.sub.4Cl (30 mL) and extracted with ethyl acetate
(2.times.30 mL) and the organic layer washed several times with
water (4.times.30 mL), brine solution (50 mL). It was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
1-Benzyl-1H-imidazole-4,5-dicarboxylic acid dimethyl ester 254
(2.01 g, 90%, 7.33 mmol). .sup.1H NMR (300 MHz) CDCl.sub.3 .delta.
7.58 (s, 1 H), 7.33-7.42 (m, 3 H), 7.14-7.18 (m, 2 H), 5.41 (s, 2
H), 3.92 (s, 3 H), 3.84 (s, 3 H). MS: 275.1 (M+1)
##STR00358##
Example 255
[0733] Into a flask containing
1-benzyl-1H-imidazole-4,5-dicarboxylic acid dimethyl ester 254
(2.80 g, 10.22 mmol, 1 equiv.) was added THF (35 mL) under a
nitrogen atmosphere followed by
1-(4-Fluoro-benzyl)-pyrrolidine-2,5-dione 1 (2.2 g, 10.22 mmol, 1
equiv.). MeOH (0.5 mL) was then added and at 0.degree. C. was added
NaH (940 mg, 23.49 mmol, 2.2 equiv.) carefully in four portions.
Refluxing was carried out for 20 hours after which the reaction was
cooled and placed in a 0.degree. C. icebath. HCl (6 N, 30 mL,
H.sub.2O) was slowly added while vigorously stirring. The resulting
solid was filtered, and washed thoroughly with water followed by
ether. It was then dried in a vacuum oven (60.degree. C., 12 hours)
to realize 4.20 gm of a crude solid. It was recrystallized with
dioxane (700 ml) to realize
1-benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-
-dione 255 (1.74 g, 41%, 4.19 mmol). .sup.1H NMR (300 MHz) DMSO
d.sub.6 .delta. 10.40 (bs, 1 H), 8.73 (s, 1 H), 7.22-7.7.43 (m, 3
H), 7.05-7.18 (m, 2 H), 5.65 (s, 2 H), 4.60 (s, 2 H). MS: 418.1
(M+1).
##STR00359##
Example 256
[0734]
1-Benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indace-
ne-5,7-dione 255 (1 g, 2.39 mmol, 1 equiv.) was dissolved in a
flask containing DMF (24 mL, 0.1 M) and pyridine (290 .mu.L, 2.88
mmol, 1.5 equiv.). Ethyl chloroformate was added (231 .mu.L, 2.88
mmol, 1.2 equiv.) under a nitrogen atmosphere. The reaction was
stirred for 16 hours before being quenched with saturated
NH.sub.4Cl (30 mL) and extracted with ethyl acetate (2.times.30 mL)
and the organic layer washed several times with water (4.times.30
mL), saturated NaHCO.sub.3 (50 mL), brine solution (50 mL). It was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Trituration was carried out with Hexanes/Ethyl acetate (1/4, 100
mL) to remove the corresponding biscarbonate to give carbonic acid
3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-
-triaza-s-indacen-4-yl ester ethyl ester 256 (13%, 145 mg, 0.296
mmol). .sup.1H NMR (300 MHz) DMSO d.sub.6 .delta. 8.63 (s, 1 H),
7.45-7.35 (m, 6 H), 7.15-7.33 (m, 4H), 5.59 (s, 2H), 4.63 (s, 2 H),
3.98 (q, J=6.9 Hz, 2 H), 1.17 (t, J=6.9 Hz, 3 H). MS: 490.2 (M+1).
TLC R.sub.f: 0.6 Ethyl acetate.
##STR00360##
Example 257
[0735] Carbonic acid
3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-
-triaza-s-indacen-4-yl ester ethyl ester 256 (140 mg, 0.28 mmol, 1
equiv.) was dissolved in 1,2 dichloroethane (20 mL) and to this was
added diphenyldiazomethane (72 mg, 0.37 mmol, 1.3 equiv.) and
heated at 70.degree. C. under a nitrogen atmosphere for 24 hours.
The reaction was then concentrated in vacuo and purified by silica
gel chromatography using 7/3 Hexanes/Ethyl acetate to obtain
carbonic acid
8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-
-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 257 (78%, 135 mg,
0.22 mmol). .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 8.17 (s, 1 H),
7.91 (s, 1 H), 7.68 (d, J=7.2 Hz, 4 H), 7.21-7.42 (m, 12 H),
6.95-7.06 (s, 4 H), 5.49 (s, 2 H), 4.76 (s, 2 H), 4.11 (q, J=6.9
Hz, 2 H), 1.17 (t, J=6.9 Hz, 3 H). MS: 678.1 (M+23). TLC R.sub.f:
0.3 Hexanes/Ethyl acetate (7/3)
##STR00361##
Example 258
[0736] Carbonic acid
8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-
-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 257 (130 mg, 0.20
mmol) was dissolved in THF (5 mL, 0.1 M) along with DMAP (24 mg,
0.40 mmol, 2 equiv.). A solution of K.sub.2CO.sub.3 (276 mg, 1.99
mmol, 10 equiv.) was dissolved separately in H.sub.2O) (6 mL)
before transferring to the reaction mixture. The reaction was
allowed to stir for 18 hr and quenched with HCl (20 mL, 1 N) and
extracted with ethyl acetate (2.times.30 ml). The organic layer was
washed with saturated NH.sub.4Cl solution (25 mL), brine solution
(25 mL) and dried over Na.sub.2SO.sub.4 and concentrated in vacuo
to yield
4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s--
indacene-5,7-dione 258 (94%, 103 mg, 0.188 mmol) as an off white
oil. .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 8.28 (bs, 1 H), 7.94
(s, 1 H), 7.89 (s, 1 H), 7.64-7.43 (m, 4 H), 7.17-7.43 (m, 12 H),
6.98-7.04 (s, 2 H), 5.57 (s, 2 H), 4.77 (s, 2 H). MS: 584.1
(M+1).
##STR00362##
Example 259
[0737]
Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaz-
a-s-indacene-5,7-dione 258 (103 mg, 0.177 mmol, 1 equiv.) was added
to a flask containing DMF (4 mL) followed by K.sub.2CO.sub.3 (122
mg, 0.88 mmol, 5 equiv.). To this was added methyl iodide (MeI, 109
.mu.L, 1.76 mmol, 10 equiv.) under a nitrogen atmosphere and
stirred for 16 hours. To the reaction was added water (50 mL) and
extracted with ethyl acetate (2.times.40 mL). The organic layer was
washed several times with water (3.times.30 mL), saturated
NaHCO.sub.3 (40 mL), brine solution (30 mL). It was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo and purified
by silica gel chromatography using 7/3 Hexanes/Ethyl acetate to
obtain
4-benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-
-triaza-s-indacene-5,7-dione 259 (73%, 75 mg, 0.125 mmol). .sup.1H
NMR (300 MHz) CDCl.sub.3 .delta. 8.09 (s, 1 H), 7.94 (s, 1 H), 7.88
(s, 1 H), 7.64-7.43 (m, 4 H), 7.41-7.46 (m, 2 H), 7.17-7.43 (m, 10
H), 6.98-7.04 (m, 3 H), 5.56 (s, 2 H), 4.80 (s, 2 H), 3.84 (s, 3
H). MS: 620.1 (M+23). TLC R.sub.f: 0.6 Hexanes/Ethyl acetate
(1/1).
##STR00363##
Example 260
[0738]
4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-tri-
aza-s-indacene-5,7-dione 259 (54 mg, 0.092 mmol, 1 equiv.) was
dissolved in CH.sub.2Cl.sub.2 (2 mL) and MeOH (0.5 mL) and under a
nitrogen atmosphere. Sodium borohydride (NaBH.sub.4, 736 .mu.L,
0.37 mmol, 4 equiv., 0.5 M) was added. The reaction was allowed to
stir for 1 hour at room temperature and heated to 65.degree. C. for
2 hours before being quenched with water (5 mL) and extracted with
ethyl acetate (2.times.5 mL). The organic layer was washed several
times with water (2.times.10 mL), brine solution (10 mL). It was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo and
purified by preparatory thin-layer chromatography (PTLC) using 3/2
Hexanes/Ethyl acetate to obtain 260 (51%, 28 mg, 0.047 mmol).
[0739] .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 7.86 (d, J=7.2 Hz,
2 H), 7.59 (d, J=7.2 Hz, 2 H), 7.46-7.32 (m, 4 H), 7.32-7.21 (m, 4
H), 7.03-7.18 (m, 6 H), 6.91-7.01 (m, 2 H), 5.95 (bs, 1 H), 5.56
(s, 2 H), 5.62-5.52 (m, 1 H), 5.28 (d, J=15.9 Hz, 1 H), 5.14 (d,
J=15.9 Hz, 1 H), 4.49 (d, J=15.9 Hz, 1 H), 3.37 (s, 3 H). MS: 622.0
(M+23). TLC R.sub.f: 0.25 Hexanes/Ethyl acetate (3/2)
##STR00364##
Example 261
[0740]
4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-7-hydroxy-8-methoxy-6,-
7-dihydro-1H-1,3,6-triaza-s-indacen-5-one 260 (28 mg, 0.047 mmol, 1
equiv.) was added to CH.sub.2Cl.sub.2 (1 mL) under a nitrogen
atmosphere. Triethylsilane (200 .mu.L) was added, followed by
trifluoroacetic acid (200 .mu.L). The reaction was allowed 1 hour
and concentrated in vacuo until thoroughly dried. Hexanes/Ethyl
ether (15 mL, 1/1 ratio) was added to the oil and sonicated. The
resulting solid was then filtered and washed in Hexanes and air
dried to give
7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxa-
lin-6-one 261 (100%, 20 mg, 0.047 mmol) as a light gray powder.
[0741] .sup.1H NMR (300 MHz) CDCl.sub.3 .delta. 9.11 (bs 1 H), 7.8S
(s, 1 H), 7.33-7.23 (m, 5 H), 7.01-7.07 (s, 4 H), 5.57 (s, 2 H),
4.71 (s, 2 H), 4.37 (s, 2 H), 3.57 (s, 3 H). .sup.19F NMR (300 MHz)
CDCl.sub.3 .delta. 62.25. MS: 418.2 (M+1)
##STR00365##
Example 262
[0742] To 0.051 mmol crude 45 was added triethylamine (100 .mu.L),
DMAP (catalytic amount) and isopropylsulfonyl chloride (18 .mu.l,
0.154 mmol). The reaction mixture was stirred at room temperature
for 24 hours under an inert atmosphere. The reaction was monitored
by TLC (EtOAc/hexane 3/7) (R.sub.f44=0.5, R.sub.f 45=0, R.sub.f
262=0.2) and LC/MS. After completion of the reaction, the mixture
was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated
NaHCO.sub.3 and brine. The organic phase was dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
silica gel chromatography (ethylacetate/hexane--3/7) to afford
propane-2-sulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 262 (8.7 mg, 29%).
Example 263
[0743] To a solution of 262 (8.7 mg, 0.015 mmol) dissolved in
dichloromethane (1 mL) was added trifluoroacetic acid (100 .mu.l)
and triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 30 min under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford the trifluoroacetate salt of
propane-2-sulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 263 (5.3 mg, 0.010 mmol, 68%) as a yellow solid:
.sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.4 (d, 1H), 7.6 (m,
1H), 7.3 (m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.6(s, 2H), 3.7 (m,
1H), 1.7 (m, 6H); MS: 431 (M+1).
##STR00366##
Example 264
[0744] Triethylamine (100 .mu.l), DMAP (catalytic amount) and
p-tosyl-chloride (30 mg, 0.154 mmol) were added to 0.051 mmol 45,
The reaction mixture was stirred at room temperature for 24 hours
under an inert atmosphere. The reaction was monitored by TLC
(EtOAc/hexane 3/7) (R.sub.f 44=0.5, R.sub.f 45=0, R.sub.f 264=0.3)
and LC/MS. After completion of the reaction, the mixture was
diluted with EtOAc (20 mL) and washed with 1N HCl, saturated
NaHCO.sub.3 and brine. The organic phase was dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
silica gel chromatography (ethylacetate/hexane--3/7) to afford
toluene-4-sulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 264 (15.3 mg, 47%).
Example 265
[0745] To a solution of 264 (15.3 mg, 0.015 mmol) dissolved in
dichloromethane (1 mL) was added trifluoroacetic acid (100 .mu.l)
and triethysilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford the trifluoroacetate salt of
toluene-4-sulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 265 (11.6 mg, 0.020 mmol, 83%) as a yellow solid:
.sup.1H NMR (CDCl.sub.3) .delta. 8.9 (d, 1H), 8.0 (d, 1H), 7.8 (m,
1H), 7.3 (m, 6H), 7.0 (t, 2H), 5.3 (s, 1H, OH), 4.7 (s, 2H), 4.4
(s, 2H), 2.4 (s, 3H); MS. 479 (M+1).
##STR00367##
Example 266
[0746] Triethylamine (50 .mu.l), DMAP (catalytic amount) and
6-Morpholin-4-yl-pyridine-3-sulfonyl chloride (26.3 mg, 0.10 mmol)
were added to 0.034 mmol 45. The reaction mixture was stirred at
room temperature for 18 hours under an inert atmosphere. The
reaction was monitored by TLC (EtOAc/hexane 3/7) (R.sub.f44=0.5,
R.sub.f 45=0, R.sub.f 266=0.3) and LC/MS. After completion of the
reaction, the mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography
(ethylacetate/hexane--3/7) to afford
6-morpholin-4-yl-pyridine-3-sulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 266 (14.6 mg, 59%).
Example 267
[0747] To a solution of 266 (14.6 mg, 0.020 mmol) dissolved in
dichloromethane (1 mL) was added trifluoroacetic acid (100 .mu.l)
and triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford the TFA salt of
6-morpholin-4-yl-pyridine-3-sulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 267 (9.0 mg, 68%) as a yellow solid: .sup.1H NMR
(CDCl.sub.3) .delta. 8.9 (d, 1H), 8.6 (s, 1H), 8.0 (dd, 1H), 7.7
(dd, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 6.5 (d, 2H), 4.8
(s, 2H), 4.6 (s, 2H), 3.7 (d, 4H), 3.6 (d, 4H); MS: 551 (M+1).
##STR00368##
Example 268
[0748] Triethylamine (50 .mu.l), DMAP (catalytic amount) and
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride
(27.4 mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction
mixture was stirred at room temperature for 18 hours under an inert
atmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7)
(R.sub.f 44=0.5, R.sub.f 45=0, R.sub.f 268=0.4) and LC/MS. After
completion of the reaction, the mixture was diluted with EtOAc (20
mL) and washed with 1N HCl, saturated NaHCO.sub.3 and brine. The
organic phase was dried (MgSO.sub.4), filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography
(ethylacetate/hexane--3/7) to afford
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 268 (12.2 mg, 50%).
Example 269
[0749] To a solution of 268 (12.2 mg, 0.017 mmol) dissolved in
dichloromethane (1 mL) was added trifluoroacetic acid (100 .mu.l)
and triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 269, TFA salt, (9.0 mg, 76%) as a yellow solid: .sup.1H
NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.5 (dd, 1H), 7.9 (m, 2H),
7.8 (m, 2H), 7.7 (m, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 4.8 (s, 2H),
4.6 (s, 2H), 4.4 (q, 2H), 3.9 (q, 2H); MS: 562 (M+1).
##STR00369##
Example 270
[0750] Triethylamine (50 .mu.l), DMAP (catalytic amount) and
1-methyl-1H-imidazole-4-sulfonyl chloride (18.1 mg, 0.10 mmol) were
added to 0.034 mmol crude 45. The reaction mixture was stirred at
room temperature for 18 hours under an inert atmosphere. The
reaction was monitored by TLC (EtOAc/hexane 3/7) (R.sub.f 44=0.5,
R.sub.f 45=0, R.sub.f 270=0.05) and LC/MS. After completion of the
reaction, the mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo to give the
crude mixture of 1-methyl-1H-imidazole-4-sulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 270.
Example 271
[0751] To a solution of crude 270 dissolved in dichloromethane (1
mL) was added trifluoroacetic acid (100 .mu.l) and triethylsilane
(200 .mu.l). The reaction mixture was stirred at room temperature
for 1/2 hours under an inert atmosphere then concentrated in vacuo.
The residue was purified by HPLC to afford
1-methyl-1H-imidazole-4-sulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 271, TFA salt, (2.5 mg) as a yellow solid: .sup.1H NMR
(CD.sub.3OD) .delta. 8.9 (d, 1H), 8.4 (d, 1H), 7.85 (s, 1H), 7.78
(s, 1H), 7.6 (m, 1H), 7.4 (m, 2H), 7.1 (t, 2H), 4.8 (s, 2H), 4.5(s,
2H), 3.8 (s, 3H); MS: 469 (M+1). HPLC conditions: mobile phase A
was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH.sub.3CN;
gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min;
column was Phenomenex, luna 5.mu., C18(2), 150 mm.times.21.1
mm.
##STR00370##
Example 272
[0752] Triethylamine (50 .mu.l), DMAP (catalytic amount) and
2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (25.5 mg, 0.10
mmol) were added to 0.034 mmol 45. The reaction mixture was stirred
at room temperature for 18 hours under an inert atmosphere. The
reaction was monitored by TLC (EtOAc/hexane 3/7) (R.sub.f 44=0.5,
R.sub.f 45=0, R.sub.f272=0.2) and LC/MS. After completion of the
reaction, the mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography
(ethylacetate/hexane--3/7) to afford
2-acetylamino-4-methyl-thiazole-5-sulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 272 (18.9 mg, 79%).
Example 273
[0753] To a solution of 272 (18.9 mg, 0.027 mmol) dissolved in
dichloromethane (1 mL) was added trifluoroacetic acid (100 .mu.l)
and triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford
2-acetylamino-4-methyl-thiazole-5-sulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
-5-yl ester 273, TFA salt, (13.2 mg, 74%) as a yellow solid:
.sup.1H NMR (CD.sub.3OD) .delta. 8.9 (d, 1H), 8.2 (d, 1H), 7.6 (m,
1H), 7.4 (m, 2H), 7.1 (t, 2H), 4.7 (s, 2H), 4,4 (s, 2H), 2.23 (s,
3H), 2.21 (s, 3H); MS: 543 (M+1).
##STR00371##
Example 274
[0754] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,
8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (28 mg, 0.045
mmol) dissolved in dichloromethane (2 mL) was added trifluoroacetic
acid (100 .mu.l) and triethylsilane (200 .mu.l). The reaction
mixture was stirred at room temperature for 1/2 hours under an
inert atmosphere then concentrated in vacuo. The residue was
triturated with diethyl ether/hexane (1/1) to afford
trifluoro-methanesulfonic acid
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,
8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 274, (13.7 mg, 0.03
mmol, 67%) as a yellow solid: .sup.1H NMR (CDCl.sub.3) .delta. 9.0
(d, 1H), 8.4 (d, 1H), 7.7 (dd, 1H), 7.3 (dd, 2H), 7.1 (t.sub.7 2H),
4.8 (s, 2H), 4.6 (s, 2H); MS: 457 (M+1).
##STR00372##
Example 275
[0755] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (40 mg, 0.064 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (27
mg, 0.192 mmol), 4-ethoxyphenolboronic acid (22 mg, 0.128 mmol) and
tetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.013 mmol). The
reaction mixture in the flask was flashed with argon three tires.
It was then heated to 120.degree. C. under argon 3 hours. The
reaction was monitored by TLC (EtOAc/hexane 3/7) (R.sub.f46=0.6,
R.sub.f275=0.4) and LC/MS. After cooling to room temperature, the
mixture was diluted with EtOAc (20 mL) and washed with 1N HCl,
saturated NaHCO.sub.3 and brine. The organic phase was dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by silica gel chromatography (ethylacetate/hexane--1/3) to
afford
9-benzhydryloxy-5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrro-
lo[3,4-g]quinolin-8-one 275 (8.0 mg, 21%) as a solid: .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (d, 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8-7.5
(dd, 4H), 7.5 (s, 1H), 7.4 (dd, 2H), 7.3-7.1 (m, 10H), 7.0 (t, 2H),
4.8 (s, 2H), 4.1 (m, 2H), 4.0 (s, 1H), 1.4 (t, 3H); MS: 595
(M+1).
Example 276
[0756] To a solution of
9-benzhydryloxy-5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrro-
lo[3,4-g]quinolin-8-one 275 (8 mg, 0.013 mmol) dissolved in
dichloromethane (1 mL) was added trifluoroacetic acid (100 .mu.l)
and triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford
5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrr-
olo[3,4-g]quinolin-8-one 276, TFA salt, (1.8 mg, 0.003 mmol, 25%)
as a yellow solid: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H),
8.1 (d, 1H), 7.7 (m, 2H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.2 (dd, 2H),
7.1 (t, 2H), 4.7 (s, 2H), 4.2(s, 2H), 4.1 (m, 2H), 1.5 (t, 3H); MS:
429 (M+1).
##STR00373##
Example 277
[0757] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (43 mg, 0.07 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (29
mg, 0.21 mmol), (3-ethoxycarbonylphenyl)boronic acid (28 mg, 0.14
mmol) and tetrakis-(triphenylphosphine)-palladium(0) (16 mg, 0.014
mmol). The reaction mixture in the flask was flashed with argon
three times. It was then heated to 120.degree. C. under argon 3
hours. The reaction was monitored by TLC (EtOAc/hexane 3/7)
(R.sub.f 46=0.6, R.sub.f277=0.3) and LC/MS. After cooling to room
temperature, the mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo to afford
crude
3-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g-
]quinolin-5-yl]-benzoic acid ethyl ester 277.
Example 278
[0758] To a solution of 277 dissolved in dichloromethane (2 mL) was
added trifluoroacetic acid (200 .mu.l) and triethylsilane (400
.mu.l). The reaction mixture was stirred at room temperature for
1/2 hours under an inert atmosphere then concentrated in vacuo. The
residue was redissolved in DMSO (1 mL) and purified by prep-HPLC to
afford
3-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo
[3,4-g]quinolin-5-yl] benzoic acid ethyl ester 278, TFA salt, (25
mg, 0.003 mmol, 44% in two steps) as a yellow solid: .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (d, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.7 (m,
1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (m, 2H), 7.1 (t, 2H), 4.7 (dd,
2H), 4.4(q, 2H), 4.3 (dd, 2H), 1.4 (t, 3H); MS: 457 (M+1). HPLC
conditions: mobile phase A was 0.1% TFA in water, mobile phase b
was 0.1% TFA in CH.sub.3CN; gradient from 5% to 60% B in 20 min;
flow rate was 20 mL/min; column was Phenomenex, luna 5.mu., C18
(2), 150 mm.times.21.1 mm.
##STR00374##
Example 279
[0759] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (23.6 mg, 0.038 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (16
mg, 0.11 mmol), 3,5-dimethylisoxazole-4-boronic acid (11 mg, 0.076
mmol) and tetrakis-(triphenylphosphine)-palladium(0) (9 mg, 0.007
mmol). The reaction mixture in the flask was flashed with argon
three times. It was then heated to 120.degree. C. under argon 3
hours. The reaction was monitored by LC/MS. After cooling to room
temperature, the mixture was diluted with EtOAc (201 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo to afford
crude
9-benzhydryloxy-5-(3,5-dimethyl-isoxazol-4-yl)-7-(4-fluoro-benzyl)-6,7-di-
hydro-pyrrolo[3,4-g]quinolin-8-one 279.
Example 280
[0760] To a solution of 279 dissolved in dichloromethane (1 mL) was
added trifluoroacetic acid (100 .mu.l) and triethylsilane (200
.mu.l). The reaction mixture was stirred at room temperature for
1/2 hours under an inert atmosphere then concentrated in vacuo. The
residue was dissolved in DMSO (1 mL) and purified by prep-HPLC to
remove Ph.sub.3PO. The crude mixture was diluted with EtOAC and
extracted with 1N HCl. The aqueous phase containing product 280 was
re-purified by HPLC to afford
5-(3,5-dimethyl-isoxazol-4-yl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro--
pyrrolo[3,4-g]quinolin-8-one 280, (0.4 mg) as a TFA salt solid:
.sup.1H NMR (CD.sub.3OD) .delta. 9.0 (d, 1H), 8.1 (d, 1H), 8.0 (s,
1H), 7.7 (m, 1H), 7.4 (dd, 1H), 7.1 (t, 2H), 4.8 (s, 2H), 4.2(s,
2H), 2.0 (s, s, 2.times.3H); MS: 404 (M+1). HPLC conditions: mobile
phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in
CH.sub.3CN; gradient from 5% to 60% B in 20 min; flow rate was 20
mL/min; column was Phenomenex, luna 5.mu., C18 (2), 150
mm.times.21.1 mm.
##STR00375##
Example 281
[0761] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (33.5 mg, 0.05 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (22
mg, 0.15 mmol), (2-ethoxycarbonylphenyl)boronic acid (22 mg, 0.10
mmol) and tetrakis-(triphenylphosphine)-palladium(0) (12.5 mg, 0.01
mmol). The reaction mixture in the flask was flashed with argon
three times. It was then heated to 120.degree. C. under argon 3
hours. The reaction was monitored by TLC (EtOAc/hexane 3/7)
(R.sub.f46=0.6, R.sub.f 281=0.5) and LC/MS. After cooling to room
temperature, the mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel with
EtOAc/Hexane (3/7) to afford pure
2-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g-
]quinolin-5-yl]-benzoic acid ethyl ester 281, 9 mg, 26.8%.
Example 282
[0762] To a solution of 281 dissolved in dichloromethane (2 mL) was
added trifluoroacetic acid (200 .mu.l) and triethylsilane (400
.mu.l). The reaction mixture was stirred at room temperature for
1/2 hours under an inert atmosphere then concentrated in vacuo. The
residue was triturated with diethyl ether/hexane (1/1) to afford
2-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quino-
lin-5-yl]-benzoic acid ethyl ester 282, TEA salt, (2.5 mg) as a
yellow solid: .sup.1H NMR (CD.sub.3OD) .delta. 8.9 (d, 1H), 8.0 (d,
1H), 8.0 (s, 1H), 7.8-7.6 (m, 3H), 7.5 (dd, 1H), 7.3 (m, 2H+1H),
7.0 (t, 2H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.7 (m, 2H), 0.6 (t 3H);
MS: 457 (M+1).
##STR00376##
Example 283
[0763] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (40 mg, 0.064 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (29
mg, 0.16 mmol), (2,6-difluorophenyl)boronic acid (20 mg, 0.128
mmol) and tetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.0
1mmol). The reaction mixture in the flask was flashed with argon
three times. It was then heated to 120.degree. C. under argon for 3
hours. The reaction was monitored by TLC (EtOAc/hexane 3/7)
(R.sub.f46=0.6, R.sub.f 283a=0.4, R.sub.f 283b=0.3) and LC/MS.
After cooling to room temperature, the mixture was diluted with
EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO.sub.3 and
brine. The organic phase was dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel with EtOAc/Hexane (3/7) to separate
pure
9-benzhydryloxy-5-(2,6-difluoro-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-p-
yrrolo[3,4-g]quinolin-8-one 283a, 6 mg, 17%; and pure
9-benzhydryloxy-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8--
one 283b, 11.0 mg, 36%.
Example 284
[0764] To a solution of 283a (9 mg) dissolved in dichloromethane (1
mL) was added trifluoroacetic acid (100 .mu.l) and triethylsilane
(200 .mu.l). The reaction mixture was stirred at room temperature
for 1/2 hours under an inert atmosphere then concentrated in vacuo.
The residue was triturated with diethyl ether/hexane (1/1) to
afford
5-(2,6-difluoro-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo-
[3,4-g]quinolin-8-one 284, TFA salt, (3.2 mg) as a yellow solid:
.sup.1H NMR (CDCl,) .delta. 9.0 (d, 1H), 8.0 (d, 1H), 7.6 (m, 1H),
7.5 (dd, 1H), 7.2 (m, 2H), 7.1 (m, 4H), 4.7 (s, 2H), 4.2(s, 2H);
MS: 421 (M+1).
Example 285
[0765] To a solution of 283b (11 mg) dissolved in dichloromethane
(1 mL) was added trifluoroacetic acid (100 .mu.l) and
triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was triturated with diethyl
ether/hexane (1/1) to afford
7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one
285, TFA salt, (3.9 mg) as a yellow solid: .sup.1H NMR (CDCl.sub.3)
.delta. 9.1 (d, 1H), 8.3 (d, 1H), 7.6 (m, 1H), 7.35 (s, 1H), 7.33
(m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.4(s, 2H); MS: 309 (M+1).
##STR00377##
Example 286
[0766] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (40 mg, 0.064 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (29
mg, 0.16 mmol), 2-fluoropyridine-3-boronic acid (18 mg, 0.128 mmol)
and tetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.01 mmol).
The reaction mixture in the flask was flashed with argon three
times. It was then heated to 120.degree. C. under argon 3 hours.
The reaction was monitored by TLC (EtOAc/hexane 3/7) (R.sub.f
46=0.6, R.sub.f 286=0.1) and LC/MS. After cooling to room
temperature, die mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel with
EtOAc/Hexane (1/1) to afford pure
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-fluoro-pyridin-3-yl)-6,7-dihydro-
-pyrrolo[3,4-g]quinolin-8-one (15), 10.6 mg, 29%.
Example 287
[0767] To a solution of 286 (10.6 mg) dissolved in dichloromethane
(1 mL) was added trifluoroacetic acid (100 .mu.l) and
triethylsilane (200 .mu.l). The reaction mixture was stirred at
room temperature for 1/2 hours under an inert atmosphere then
concentrated in vacuo. The residue was purified by HPLC to afford
7-(4-fluoro-benzyl)-5-(2-fluoro-pyridin-3-yl)-9-hydroxy-6,7-dihydro-pyrro-
lo[3,4-g]quinolin-8-one 287, TFA salt, (3.2 mg) as a yellow solid:
.sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.4 (d, 1H), 7.9 (d,
1H), 7.8 (dd, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 2H), 7.0 (t,
2H), 4.7 (dd, 2H), 4.2(dd, 2H); MS: 404 (M+1). HPLC conditions:
mobile phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA
in CH.sub.3CN; gradient from 5% to 60% B in 20 min; flow rate was
20 mL/min; column was Phenomenex, luna 5.mu., C18(2), 150
mm.times.21.1 mm.
##STR00378##
Example 288
[0768] To a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (40 mg, 0.064 mmol) dissolved in toluene (3
mL)/ethanol (0.6 mL)/water (0.4 mL) was added K.sub.2CO.sub.3 (29
mg, 0.16 mmol), 2-methoxypyridine-3-boronic acid (20 mg, 0.128
mmol) and tetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.01
mmol). The reaction mixture in the flask was flashed with argon
three times. It was then heated to 120.degree. C. under argon 3
hours. The reaction was monitored by TLC (EtOAc/hexane 3/7)
(R.sub.f 46=0.6, R.sub.f 288=0.1) and LC/MS. After cooling to room
temperature, the mixture was diluted with EtOAc (20 mL) and washed
with 1N HCl, saturated NaHCO.sub.3 and brine. The organic phase was
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel with
EtOAc/Hexane (1/1) to afford pure
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydr-
o-pyrrolo[3,4-g]quinolin-8-one (17), 18.0 mg, 48%.
[0769] Alternatively, according to a modified Suzuki coupling
method of C. H. Chen; Tetrahedron Letter; EN; 44; 5747-5750; 2003,
to a solution of trifluoro-methanesulfonic acid
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inolin-5-yl ester 46 (266.2 mg, 0.428 mmol) dissolved in toluene (5
mL) was added Na.sub.2CO.sub.3 (2M in water, 500 .mu.l),
2-methoxypyridine-3-boronic acid (164 mg, 1.07 mmol) and
tetrakis-(triphenylphosphine)-palladium(0) (100 mg, 0.086 mmol).
The reaction mixture in the flask was flashed with argon three
times. It was then heated to 120.degree. C. under argon 4 hours.
The reaction was monitored by TLC (EtOAc/hexane 3/7) (R.sub.f1=0.6,
R.sub.f17=0.1) and LC/MS. After cooling to room temperature, the
mixture was diluted with EtOAc (20 mL) and washed with 1N HCl,
saturated NaHCO.sub.3 and brine. The organic phase was dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel with EtOAc/Hexane
(1/1) to afford pure
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydr-
o-pyrrolo[3,4-g]quinolin-8-one 288, 125 mg, 50%. .sup.1H NMR
(CDCl.sub.3) .delta. 9.0 (dd, 1H), 8.3 (dd, 1H), 8.2 (s, 1H), 7.8
(dd, 4H), 7.7 (dd, 1H), 7.4 (dd, 1H), 7.3-7.1 (m, 8H), 7.0 (m,
2H+1H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.8 (s, 1H), MS: 582 (M+1).
Example 289
[0770] To a solution of 288 (18 mg) dissolved in dichloromethane (1
mL) was added trifluoroacetic acid (100 .mu.l) and triethylsilane
(200 .mu.l). The reaction mixture was stirred at room temperature
for 1/2 hours under an inert atmosphere then concentrated in vacuo.
The residue was purified by HPLC to afford
7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-9-hydroxy-6,7-dihydro-pyrr-
olo[3,4-g]quinolin-8-one 289, TFA salt, (11.6 mg, 68%) as a yellow
solid: .sup.1H NMR (CDCl.sub.3) .delta. 9.0 (d, 1H), 8.3 (d, 1H),
7.9 (d, 1H), 7.5 (m, 2H), 7.2 (m, 1H+1H), 7.0 (m, 2H+1H), 4.7 (dd,
2H), 4.1(dd, 2H), 3.8 (s, 1H); MS: 416 (M+1). HPLC conditions:
mobile phase A was 0.1I% TFA in water, mobile phase b was 0.1% TFA
in CH.sub.3CN; gradient from 5% to 60% B in 20 mm; flow rate was 20
mL/min; column was Phenomenex, luna 5.mu., C18(2), 150
mm.times.21.1 mm.
##STR00379##
Example 290
[0771] To a solution of
9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydr-
o-pyrrolo[3,4-g]quinolin-8-one 288 (99 mg, 0.17 mmol) dissolved in
methanol (20 mL) was added p-toluenesulfonic acid monohydrate (390
mg, 2.05 mmol) and lithium iodide (1.37 g, 10.26 mmol). The
reaction mixture was heated to 120.degree. C. under nitrogen for 10
hours. The reaction was monitored by LC/MS. After cooling to room
temperature, the solvent was removed under reduced pressure. The
residue was dissolved in 2 mL DMSO and 100 .mu.l of TFA. It was
purified by HPLC to afford
7-(4-fluoro-benzyl)-9-hydroxy-5-(2-hydroxy-pyridin-3-yl)-6,7-dihydro-pyrr-
olo[3,4-g]quinolin-8-one 290, TFA salt, (44.4 mg, 51%) as a yellow
solid: .sup.1H NMR (CD.sub.3OD) .delta. 8.9 (dd, 1H), 8.2(dd, 1H),
7.7 (m, 1H+1H), 7.6 (d, 2H), 7.4 (m, 2H), 7.1 (m, 2H), 6.6 (t, 1H),
4.8 (dd, 2H), 4.3(d, 2H); HPLC conditions: mobile phase A was 0.1%
TFA in water, mobile phase b was 0.1% TFA in CH.sub.3CN; gradient
from 5% to 60% B in 20 min; flow rate was 20 mL/min; column was
Phenomenex, luna 5.mu., C18(2), 150 mm.times.21.1 mm.
##STR00380##
Example 291
[0772] To a solution of the trifluoroacetate salt of
(2-piperazin-1-yl-ethyl)-phosphonic acid dimethyl ester 187 (0.023
g, 0.077 mmol) in 1 ml DMF was added diisopropylethylamine (33
.mu.L, 0.192 mmol). This mixture was added to a solution of
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo
[3,4-g]quinoline-5-carboxylic acid 213 (0.020 g, 0.038 mmol) that
had been mixed with HATU (0.0293 g, 0.077 mmol) in 1 ml of DMF. The
reaction was stirred at rt under inert atmosphere for 3 h, at which
time TLC in 100% EtOAc showed complete consumption of starting
material. The reaction mixture was introduced directly onto silica
gel (99/1 EtOH/Et.sub.3N) to give 20 mg of
(2-{4-[9-benzhydryloxy-7-(4-fluoro-ben7.yl)-8-oxo-7,8-dihydro-6H-pyrrolo[-
3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid
dimethyl ester 291 after flash chromatography.
Example 292
[0773] An excess of trimethylsilyl bromide (TMSBr, 0.015 g, 0.1
mmol) was added to
(2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H--
pyrrolo
[3,4-g]quinolin-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid
dimethyl ester 291 in 1 mL of CH.sub.2Cl.sub.2. After stirring at
room temperature (rt) for 16 h, volatiles were removed under vacuum
and the residue was triturated with Et.sub.2O to provide pure the
HBr salt of
(2-{4-[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo
[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid
292 (12 mg, 95%) as a yellow solid. .sup.1H NMR (DMSO) .delta.:
8.95 (d, 1H), 8.75 (d, 1H), 8.54 (1H, d), 8.35 (bm, 1H), 7.78 (m,
2H), 7.52 (m, 2H), 7.4-7.32 (bm, 2H), 7.15 (t, 2H), 4.85 (bm, 1H)
4.45 (bm, 2H) 2.04 (bm, 2H); .sup.31P NMR (DMSO) .delta. 19.9; MS:
529 (M+H).
##STR00381##
Example 293
[0774] To a solution of
2-[(2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrol-
o[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phenoxy-phosphinoylox-
y]-propionic acid ethyl ester 223 (15 mg, 0.017 mmol) in 1 ml
CH.sub.2Cl.sub.2 at rt was added an excess of TFA (10 .mu.L, 0.085
mmol) and triethylsilane (30 .mu.L, 0.17 mmol). The reaction was
stirred under N.sub.2 with monitoring via LC/MS. After 8 h, the
volatiles were removed by vacuum and the residue dissolved in 1 mL
of a 1/1 mixture of acetonitrile/water. 50 .mu.L of 1M NaOH was
added and the reaction was stirred at rt overnight. At this time,
the product was introduced directly onto reverse phase HPLC to
afford, after lyophilization,
2-[(2-{4-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4--
g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-hydroxy-phosphinoyloxy]-pro-
pionic acid as the trifluoroacetate salt, 293 (5 mg, 39%). .sup.1H
NMR (D.sub.2O) .delta.: 9.10 (d, 1H), 8.95-8.72 (bm, 1H), 8.14 (bs,
1H), 7.20-7.3 (bm, 2H), 6.92-7.08 (bs, 2H), 4.65-4.25 (m, 4H),
3.78-3.65 (bs, 1H), 3.62-3.10 (bm, 9H), 2.75 (d, 2H), 1.95 (m, 2H),
1.35 (d, 3H); .sup.31P NMR (D.sub.2O) .delta. 19.5; MS: 629
(M+H).
##STR00382##
Example 294
[0775] To
(2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H--
pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic
acid dimethyl ester 291 (5 mg, 0.0069 mmol) in 1 mL
CH.sub.2Cl.sub.2 is added CF.sub.3CO.sub.2H (6 .mu.L, 0.035 mmol)
and triethylsilane (12 .mu.L, 0.07 mmol). After 2 h, the volatile
reaction components were removed by vacuum and the residue was
washed with diethyl ether to give
(2-{4-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]q-
uinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid 294 as
the trifluoroacetate salt (4.5 mg, 97%): .sup.1H NMR (CD.sub.3OD)
.delta.: 8.90 (d, 0.7H) 8.74 (d, 0.3H), 8.45 (d, 0.3H), 8.31 (d,
0.7H), 7.75 (dd, 0.7H), 7.55 (dd, 0.3H), 7.40 (m, 2H), 7.12 (m,
2H), 4.54 (s, 2H), 4.15 (bs, 1H), 3.85 (s, 3H), 3.75 (s, 3H),
3.62-3.40 (bs, 2H), 3.12 (bs, 2H), 2.45-2.30(m, 2H); .sup.19F NMR
(CD.sub.3OD) .delta. .sup.-78, .sup.-127; .sup.31P NMR (CD.sub.3OD)
.delta. 29; MS: 556 (M+H).
##STR00383##
Example 295
[0776] Imidazole (0.74 g, 10.8 mmol) and chlorotriisopropylsilane
(TIPSCl, 1.15 g, 6.0 mmol) were added to
5,8-dihydroxy-quinoline-6,7-dicarboxylic acid dimethyl ester
(prepared by the method in Oguchi, S. Bulletin of the Chemical
Society of Japan 1974, 47, 1291, 1.5 g, 5.4 mmol) in 20 mL DMF. The
reaction was stirred for 48 h at rt and then the reaction was
partitioned between 0.5 L methyl t-butyl ether and 150 mL saturated
aq. LiCl. The organic layer was dried over Na.sub.2SO.sub.4 and the
solvent removed by rotary evaporation. The residue (1.4 g, 3.2
mmol) was redissolved in 25 mL DMF and treated with K.sub.2CO.sub.3
(0.66 g, 4.8 mmol) followed by methyl iodide (MeI, 0.6 g, 4.8 mL)
at rt. After 2 h, the reaction mixture was concentrated and
purified by introduction of the reaction mixture onto silica gel
for flash chromatography (4/1 hexanes/ethyl acetate) to give
5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic acid
dimethyl ester (1.4 g, 59% overall yield): .sup.1H NMR (CDCl.sub.3)
.delta. 8.85 (d, 1H), 8.45 (d, 1H), 7.50 (dd, 1H), 4.05 (s, 3H),
3.95 (s, 3H), 3.90 (s, 3H), 1.45 (septet, 3H), 1.05 (d, 9H); MS:
448 (M+H).
[0777] A 1M solution of TBAF in THF (4 ml) was added to
5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic acid
dimethyl ester (0.85 g, 1.9 mmol) in 20 ml dry THF. The reaction
was stirred at rt for 1 h, at which time the reaction mixture was
concentrated and the residue dissolved in 100 mL diethyl ether and
washed with 25 mL 1N HCl, followed by 25 mL of saturated aq. NaCl.
The organic layer was concentrated and the residue was dissolved in
40 mL dichloroethane. Diphenyldiazomethane (0.7 g, 3.8 mmol) was
added and the reaction temperature was raised to 70.degree. C. for
24 h. The reaction mixture was concentrated and the residue
chromatographed on silica gel (1/1 hexanes/EtOAc) to give
8-benzhydryloxy-5-methoxy-quinoline-6,7-dicarboxylic acid dimethyl
ester (0.8 g, 61% yield overall). .sup.1H NMR (CDCl.sub.3) .delta.
8.85 (d, 1H), 8.45 (d, 1H), 7.45 (dd, 1B), 3.98 (s, 3H), 3.85 (s,
3H), 3.74 (s, 3H); MS: 480 (M+Na).
[0778] Lithium hydroxide (LiOH, 0.07 g, 2.95 mmol) was added to
8-benzhydryloxy-5-methoxy-quinoline-6,7-dicarboxylic acid dimethyl
ester (0.27 g, 0.59 mmol) in 1 mL 3/1 THF/H.sub.2O. The reaction
was heated at 45.degree. C. and after 24 h, the reaction was
diluted with 50 mL dichloromethane and acidified with 1 mL 0.1 M
HCl. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to give 180 mg of an oil which was dissolved in 5 mL
THF, triethylamine (0.168 g, 1.2 mmol) and ethyl chloroformate
(0.064 g, 0.6 mmol). After 2 h, the reaction was diluted with
diethyl ether and washed with brine. The organic layer was dried
over Na.sub.2SO.sub.4 and the organic layer decanted from drying
agent. The ether layer was cooled to 0.degree. C. and a solution of
ca. 0.3 M diazomethane in diethyl ether (4 mL, ca. 1.2 mmol) was
added dropwise. After stirring for 24 h to effect diazotization,
the ether layer was removed along with excess diazomethane via
rotary evaporation. The resulting residue was dissolved in 4 mL of
1/1 THF/water, and silver(I) oxide (0.035 g, 0.15 mmol) was added.
The reaction was heated to 60.degree. C. for a period of 4 h, then
the reaction mixture was diluted with 50 mL EtOAc and acidified
with 10 ml 1N HCl. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The resulting residue was then
taken up in 2 mL THF, and treated with hydroxybenzotriazole (HOBt,
0.08 g, 0.6 mmol), dicyclohexylcarbodiimide (DCC, 0.12 g, 0.6 mmol)
and 4-fluorobenzylamine (0.07 g, 0.6 mmol). After a period of 16 h,
the reaction was introduced directly to chromatography on silica
gel (100% diethyl ether) to give
8-benzhydryloxy-6-[(4-fluoro-benzylcarbamoyl)-methyl]-5-methoxy-quinoline-
-7-carboxylic acid methyl ester (0.12 g, 38% overall yield):
.sup.1H NMR (CDCl.sub.3) .delta. 8.85 (d, 1H), 8.35 (d, 1H),
7.60-6.8 (cm, 12H), 6.15 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 3.75
(s, 3H), 3.65 (s, 2H), 3.54 (t, 1H); MS: 587 (M+Na).
[0779] A 60% sodium hydride (NaB) mineral oil dispersion (0.002 g,
0.06 mmol was added to a solution of
8-benzhydryloxy-6-[(4-fluoro-benzylcarbamoyl)-methyl]-5-methoxy-quinoline-
-7-carboxylic acid methyl ester (0.020 g, 0.04 mmol) in 1 mL of
anhydrous DMF. The resulting indigo-tinted solution was stirred at
rt for a period of 30 min, and then diluted with diethyl ether (50
ml) and washed with sat. aq. NH.sub.4Cl (25 mL). The organic layer
was dried over Na.sub.2SO.sub.4 and solvent was removed by rotary
evaporation. The residue was purified by silica gel chromatography
(1/1 hexanes/diethyl ether and then 100% MeOH to elute product
fractions) to give
9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,-
8-dione 295 (9 mg, 48%).
##STR00384##
Example 296
[0780] 9-Benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5
H-1,7-diaza-anthracene-6,8-dione 295 (6 mg, 0.01 mmol) in 1 mL
CH.sub.2Cl.sub.2 was treated with 0.1 mL trifluoroacetic acid and
0.05 mL triethylsilane. After 1 h, volatiles were removed and the
product was purified via trituration with diethyl ether to give the
trifluoroacetate salt of
7-(4-Fluoro-benzyl)-9-hydroxy-10-methoxy-5H-1,7-diaza-anthracene--
6,8-dione 296 (5 mg, 62%): .sup.1H NMR (CDCl.sub.3) .delta. 12.98
(s, 1H), 9.10 (d, 1H), 8.35 (d, 1H), 7.65 (m, 1H), 7.55 (m, 2H),
7.04 (t, 2H), 5.2 (s, 2H), 4.75 (s, 1H), 4.20 (s, 1H), 3.95 (s,
3H); MS: 367 (M+Na).
##STR00385##
Example 297
[0781] Sodium borohydride (NaBH.sub.4, 0.021 g, 0.56 mmol) was
added to
9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,-
8-dione 295 (30 mg, 0.056 mmol) in 1 mL EtOH at .sup.-5.degree. C.
The reaction was stirred at low temperature for a period of 2 h,
then the reaction was diluted with CH.sub.2Cl.sub.2 (25 mL) and
washed with 10 mL sat. aq. sodium bicarbonate solution. The aqueous
layer was then washed twice with 25 ml portions of CH.sub.2Cl.sub.2
and the combined organic layers washed with brine and dried over
Na.sub.2SO.sub.4. The reduction product was purified on silica gel
(100% Et.sub.2O) to give 6 mg of
9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6--
hydroxy, 8-one 297.
Example 298
[0782]
9-Benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthrac-
ene-6-hydroxy, 8-one 297 (6 mg, 0.01 mmol) was dissolved in 1 mL
CH.sub.2Cl.sub.2 and treated with 0.1 mL trifluoroacetic acid and
0.1 mL triethylsilane. After 1 hr, volatiles were removed and the
product was purified via trituration with diethyl ether to give the
trifluoroacetate salt of
7-(4-Fluoro-benzyl)-9-hydroxy-10-methoxy-7H-1,7-diaza-anthracen-8-
-one 298 (2 mg, 38%). .sup.1H NMR (CD.sub.3OD) .delta. 9.35 (d,
1H), 8.75 (d, 1H), 7.80 (dd, 1H), 7.33 (m, 2H), 7.08 (m, 3H), 6.85
(d, 1H), 5.15 (s, 2H), 3.95 (s, 3H); MS: 351 (M+H).
##STR00386##
Example 299
[0783] To 2,4-dimethoxybenzyl-alcohol (4.3 g, 25.6 mmol) and
pyrrolidine-2,5-dione (succinimide, 1.2 g, 12.2 mmol) dissolved in
tetrahydrofuran (25 ml) and dichloromethane (25 ml) was added
triphenyphosphine (6.4 g, 24.4 mmol). After cooling to 0.degree.
C., diethylazidodicarboxylate (DEAD, 4.25 g, 24.4 mmol) was added
dropwise to the reaction mixture. The reaction mixture was then
allowed to warm to room temperature and kept at room temperature
with stirring overnight. Following concentration in vacuo, 100 ml
of a (1:1)hexane/ether solution was added and this mixture was
stored at 0.degree. C. overnight. The resulting solid precipitate
was filtered off and the filtrate was concentrated in vacuo. The
resulting residue was purified by silica gel chromatography
(3/1--ethyl acetate/hexane) to afford
1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6
mmol, 46%). .sup.1H NMR (CDCl.sub.3) .delta. 7.07 (d, 1H), 6.38 (m,
2H), 4.60 (s, 2H), 3.76 (s, 3H), 2.62 (s, 4H).
Example 300
[0784] To 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4
g, 5.6 mmol) and pyridine-2,3-dicarboxylic acid dimethyl ester
(1.13 g, 5.8 mmol) dissolved in tetrahydrofuran (60 ml) and
methanol (7.0 ml) was added a 60% dispersion of sodium hydride in
mineral oil (NaH, 492 mg, 12.3 mmol). The reaction mixture was
warmed to 80.degree. C. and kept at 80.degree. C. with stirring
overnight. The reaction mixture was placed in an ice bath and
titrated to a pH of 4 with 1 M HCl. 200 ml of ether was added and
the resulting yellow solid was collected by filtration. The solid
was washed twice with ether, twice with water, and dried under high
vacuum with heating to provide
7-(2,4-dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione
300 (1.1 g, 52%). .sup.1H NMR (d-DMSO) .delta. 10.8 (broad, 2H),
9.0 (d, 1H), 8.67 (d, 1H), 7.72 (m, 1H), 6.90 (d, 1H), 6.5 (d, 1H),
6.38 (dd, 1H), 4.58 (s, 2H), 3.76 (s, 3H), 3.66 (s, 3H). MS: 382.1
(M+1)
##STR00387##
Example 301
[0785] 7-(2,4-Dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo
[3,4-g]quinoline-6,8-dione 300 (1.1 g, 2.9 mmol) was dissolved in
dioxane (14.5 ml) and H.sub.2O (9.7 ml) and cooled to 0.degree. C.
To this reaction mixture was added 1.0 M NaOH (5.8 ml, 5.8 mmol),
followed by ethylchloroformate (347.3 mg, 3.2 mmol). After stirring
at 0.degree. C. for 30 minutes, dioxane (10 ml) and
ethylchloroformate (51 mg, 0.5 mmol) were added and the reaction
stirred for another 30 minutes at 0.degree. C. The reaction mixture
was quenched with the addition of acetic acid (0.6 ml) and
concentrated in vacuo. The crude mixture was diluted with ethyl
acetate and washed once with 5% citric Acid (aqueous), twice with
water, once with brine, and dried over magnesium sulfate. The
resulting residue was dissolved in 1,2-dichloroethane (30 ml) and
diphenyl-methanediazonium 38 (diphenyldiazomethane, 1.1 g, 5.6
mmol) was added. The reaction mixture was then stirred overnight at
room temperature. Following dilution with dichloromethane, the
reaction mixture was washed with once with water, once with brine,
dried over magnesium sulfate, and concentrated in vacuo. The
residue was purified by silica gel chromatography
(1/1--Hexanes/Ethyl Acetate) to afford carbonic acid
9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-6,8-dioxo-7,8-dihydro-6H-py-
rrolo[3,4-g]quinolin-5-yl ester ethyl ester 301 (1.2 g, 1.9 mmol,
66%). .sup.1H NMR (CDCl.sub.3) .delta. 9.10 (dd, 1H), 8.40 (dd,
1H), 7.95 (s, 1H), 7.68 (m, 1H), 7.60 (d, 4H), 7.15 (m, 6H), 7.0
(d, 1H), 6.40 (d, 1H), 6.36 (d, 1H), 4.80 (s, 2H), 4.35 (q, 2H),
3.75 (s, 3H), 3.73 (s, 3H), 1.31 (t, 3H). MS: 641.2 (M+23).
Example 302
[0786] Potassium carbonate (2.6 g, 19.0 mmol) and
N,N-dimethyl-aminopyridine (DMAP, 0.464 g, 3.8 mmol) were added to
carbonic acid
9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo-
[3,4-g]quinolin-5-yl ester ethyl ester 301 (1.2 g, 1.9 mmol)
dissolved in tetrahydrofuran (40 ml) and water (20 ml) was added.
After stirring overnight at room temperature, the reaction mixture
was concentrated in vacuo and diluted with ethyl acetate. It was
washed twice with 5% citric Acid (aqueous), twice with water, once
with brine, dried over magnesium sulfate, and concentrated in
vacuo. The resulting residue was dissolved in dimethylformamide (10
ml). To this reaction mixture was added potassium carbonate (1.24
g, 9.0 mmol) and iodomethane (methyl iodide, MeI, 2.55 g, 18.0
mmol). After stirring overnight at room temperature, the reaction
mixture was diluted with ethyl acetate, washed twice with 5% citric
acid, twice with water, once with brine, and concentrated in vacuo
to afford
9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-5-methoxy-pyrrolo[3,4--
g]quinoline-6,8-dione 302 (1.1 g, 1.9 mmol, 100%). .sup.1H NMR
(d-DMSO) .delta. 9.16 (dd, 1H), 8.60 (dd, 1H), 7.82 (s, 1H), 7.75
(m, 1H), 7.54 (d, 4H), 7.16 (m, 6H), 6.82 (d,1H), 6.56 (d, 1H),
6.44 (dd, 1H), 4.66 (s, 2H), 4.10 (s, 3H), 3.76 (s, 3H), 3.70 (s,
3H). MS: 583.2 (M+23).
##STR00388##
Example 303
[0787]
9-Benzhydryloxy-7-(2,4-dimethoxy-benzyl)-5-methoxy-pyrrolo[3,4-g]qu-
inoline-6,8-dione 302 (500 mg, 0.89 mmol) was dissolved in
tetrahydrofuran (6.0 ml), water (1.2 ml), and isopropanol (2.4 ml)
and cooled to 0.degree. C. Lithium borohydride (LiBH.sub.4, 96.9
mg, 4.45 mol) was then added and the reaction mixture was removed
from the ice bath and stirred at room temperature for 2 hours.
After quenching with acetic acid (0.5 ml), the reaction mixture was
diluted with ethyl acetate, washed with twice with water, once with
brine, and concentrated in vacuo. The resulting residue was
dissolved in dichloromethane (9.2 ml) and triethylsilane (1.8
ml).sub.3, and cooled to 0.degree. C. After adding trifluoroacetic
acid (3.6 ml), the reaction mixture was warmed to room temperature
and stirred at room temperature for 1 hour. The mixture was
concentrated in vacuo and the resulting residue was redissolved in
trifluoroacetic acid (10 ml) and triethylsilane (2 ml). It was then
warmed to 75.degree. C. and stirred at 75.degree. C. for 2 hours.
The reaction mixture was concentrated in vacuo and azeotroped three
times with a (1:1) toluene/tetrahydrofuran solution. The resulting
residue was triturated three times with a (3:1) hexane/ether
mixture. The remaining solid in the filter funnel and reaction
flask was dissolved in methanol, combined, and concentrated in
vacuo to afford
9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one
303(240 mg, 113%) .sup.1HNMR (d-DMSO) .delta. 8.84(dd, 1H), 8.58
(broad, 1H),8.50 (dd, 1H), 7.60 (m, 1H), 4.60 (s, 2H), 3.94 (s,
3H). MS: 231.1 (M+1).
Example 304
[0788] Potassium carbonate (60.1 mg, 0.435 mmol),
4-methoxybenzylchloride (41 mg, 0.26 mmol), and sodium iodide (6.3
mg, 0.043 mmol) were added to
9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 303
(20 mg, 0.087 mmol) dissolved in dimethylformamide 8 (0.4 ml). The
reaction mixture was warmed to 60.degree. C. and stirred at
60.degree. C. for one hour. After cooling the reaction mixture to
0.degree. C., acetic acid (0.06 ml) was added and the mixture was
concentrated in vacuo. The residue was diluted with ethyl acetate
and washed once with 5% Citric Acid, twice with water, once with
brine, and concentrated in vacuo. The residue was purified by
silica gel chromatography (9/1--dichloromethane/methanol) to afford
5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-on-
e 304 (16 mg, 0.046 mmol, 53%). .sup.1H NMR (CDCl.sub.3) .delta.
9.0 (dd, 1H), 8.64 (dd, 1H), 7.51 (d, 2H), 7.46 (m, 1H), 6.80 (d,
2H), 6.50 (broad, 1H), 5.60 (s, 2H), 3.98 (s, 3N), 3.72 (s, 3H).
MS: 351.1 (M+1).
Example 305
[0789]
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinoli-
n-8-one 304 (25.4 mg, 0.073 mmol,) was dissolved in
dimethylformamide (0.4 ml) and cooled to 0.degree. C. Sodium
hydride (3.6 mg, 0.095 mmol) was added, followed by stirring at
0.degree. C. for 5 minutes. 4-trifluoromethyl-benzylbromide (21.0
mg, 0.088 mmol) was added and the reaction mixture was allowed to
warm to room temperature and kept at room temperature with stirring
for 5 minutes. It was cooled to 0.degree. C., quenched with acetic
acid (0.030 ml), and concentrated in vacuo. The mixture was diluted
with ethyl acetate, washed twice with water. once with brine, dried
over magnesium sulfate, and concentrate in vacuo. The residue was
purified by silica gel chromatography (99/1--ethyl acetate/acetic
acid) to afford
5-Methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydr-
o-pyrrolo[3,4-g]quinolin-8-one 305 (13 mg, 0.026 mmol, 35%).
.sup.1H NMR .delta. 9.15 (dd, 1H), 8.60 (dd, 1H), 7.60 (m, 4H),
7.40 (d, 2H), 6.80 (d, 2H), 5.85 (s, 2H), 4.80 (s, 2H), 4.42 (s,
2H), 3.98 (s, 3H), 3.86 (s, 3H). MS: 509.2 (M+1).
Example 306
[0790] To
5-methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6-
,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 305 (13 mg, 0.026 mmol)
dissolved in dicloromethane (0.200 ml) was added triethylsilane
(TES, 0.05 ml) and trifluoroacetic acid (TFA, 0.100 ml), After
stirring at room temperature for 15 minutes, the reaction mixture
was concentrated in vacuo and azeotroped three times with a (1:1)
tetrahydrofuran to toluene mixture. The resulting residue was then
triturated three times with a (3:1) hexane to ether mixture to
afford
9-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4--
g]quinolin-8-one 306 (7 mg, 0.014 mmol, 54%). .sup.1H NMR
(CD.sub.3OD) .delta. 9.0 (dd, 1H), 8.58 (dd, 1H), 7.60 (d, 2H),
7.40 (d, 2H), 4.80 (s, 2H), 4.50 (s, 2H), 3.95 (s, 3H). .sup.19F
NMR .delta.-63, -76.2. MS: 389.1 (M+1).
##STR00389##
Example 307
[0791]
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinoli-
n-8-one 304 (17 mg, 0.049 mmol) was dissolved in dimethylformamide
(0.3 ml) and cooled to 0.degree. C. After adding sodium hydride
(2.5 mg, 0.064 mmol), the reaction was stirred for 5 minutes at
0.degree. C. 3,5-Dichlorobenzylchloride (11.5 mg, 0.059 mmol) and a
catalytic amount of sodium iodide were then added. The reaction
mixture was warmed to room temperature and stirred at room
temperature for 30 minutes. It was then cooled to 0.degree. C.,
acidified with acetic acid (0.030 ml), and concentrated in vacuo.
The resulting residue was diluted with ethyl acetate, washed twice
with water, once with brine, and concentrated in vacuo. The residue
was purified by silica gel chromatography (99/1--ethyl
acetate/acetic acid) to afford
7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyr-
rolo[3,4-g]quinolin-8-one 307 (7 mg, 40%). .sup.1H NMR (CDCl.sub.3)
.delta. 9.0 (dd, 1H), 8.40 (dd, 1H), 7.60 (d, 2H), 7.55 (m, 1H),
7.20 (m, 3H), 6.80 (d, 2H), 5.60 (s, 2H), 4.75(s, 2H), 4.40 (s,
2H), 3.95 (s, 3H), 3.75 (s, 3H). MS: 509.1 (M+1).
Example 308
[0792] In a manner similar to the protocol described in Example
306,
7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyr-
rolo[3,4-g]quinolin-8-one 307 (17 mg, 0.049 mmol) was deprotected
to provide
7-(3,5-dichloro-benzyl)-9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3-
,4-g]quinolin-8-one 308 (10 mg, 0.020 mmol, 41%). .sup.1H NMR
(CD.sub.3OD) .delta. 9.0 (dd, 1H), 8.60 (d, 1H), 7.60 (m, 1H), 7.20
(m, 3H) 4.75 (s, 2H), 4.45 (s, 2H), 4.0 (s, 3H). .sup.19F
.delta.-76. MS: 390.1 (M+1).
##STR00390##
Example 309
[0793] To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg,
3.7 mmol) and pyrroldine-2,5-dione (succinimide, 733.3 mg, 7.4
mmol) in dimethylformamide (15 ml) was added potassium carbonate
(2.0 g, 14.8 mmol) and sodium iodide (277 mg, 1.9 mmol). The
reaction mixture was warmed to 60.degree. C. and kept at 60.degree.
C. overnight with stirring. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The concentrate was diluted
with ethyl acetate and washed twice with a saturated sodium
bicarbonate aqueous solution, twice with water, once with brine,
and concentrated in vacuo. The residue was purified by silica gel
chromatography (100% ethylacetate) to afford
1-[2-(4-fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (570 mg,
2.6 mmol, 70%) as a solid. .sup.1H NMR (CDCl.sub.3) .delta. 7.14
(m, 2H), 6.94 (t, 2H), 3.68 (t, 2H), 2.84 (t, 2H), 2.63 (s,
4H).
Example 310
[0794] To 1-[2-(4-Fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309
(270 mg, 1.22 mmol and pyridine-2,3-dicarboxylic acid dimethyl
ester (261.6 mg, 1.34 mmol) dissolved in tetrahydrofuran (12.0 ml)
and methanol (1.4 ml) was added a 60% dispersion of sodium hydride
in mineral oil (108 mg, 2.7 mmol). The reaction mixture was warmed
to 80.degree. C. and kept at 80.degree. C. with stirring overnight.
The reaction mixture was then placed in an ice bath and titrated to
a pH of 4 with 1 M HCl. Two hundred (200) ml of diethylether was
then added and the resulting yellow solid was collected by
filtration. The solid was washed twice with ether, twice with
water, and dried under high vacuum with heating to provide
7-[2-(4-fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-d-
ione 310 (250 mg, 0.71 mmol, 58%). .sup.1H NMR (d-DMSO) .delta.
10.7 (broad, 1H), 8.98 (dd, 1H), 8.66 (dd, 1H), 7.73 (m, 1H), 7.18
(m, 2H), 7.04 (t, 2H), 3.72 (t, 2H), 2.86 (t, 2H). MS: 353.1
(M+1).
##STR00391##
Example 311
[0795]
7-[2-(4-Fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-
-6,8-dione 310 (250 mg, 0.71 mmol) was dissolved in dioxane (3.6
ml) and H.sub.2O (2.4 ml) and cooled to 0.degree. C. After 1.0 M
NaOH (1.42 ml, 1.42 mmol) and ethylchloroformate (84.6 mg, 0.78
mmol) were added, the reaction was stirred at 0.degree. C. for one
hour. The reaction mixture was quenched with the addition of acetic
acid (0.6 ml) and concentrated in vacuo. The crude mixture was
diluted with ethyl acetate and washed once with 5% Citric Acid
(aqueous), twice with water, once with brine, dried over magnesium
sulfate, and concentrated in vacuo. The resulting residue was
dissolved in 1,2-dichloroethane (4.0 ml) and to this was added
diphenyl-methanediazonium 38 (252 mg, 1.3 mmol). The reaction
mixture was then stirred overnight at room temperature. Following
dilution with dichloromethane, the reaction mixture was washed with
once with water, once with brine, dried over magnesium sulfate, and
concentrated in vacuo. The residue was then purified by silica gel
chromatography (1/1--hexane/ethyl acetate) to afford carbonic acid
9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-6,8-dioxo-7,8-dihydro-6H-py-
rrolo[3,4-g]quinolin-5-yl ester ethyl ester 311 (251 mg, 0.425
mmol,65%). .sup.1H NMR (d-DMSO) .delta. 9.19 (dd, 1H), 8.52 (dd,
1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.54 (m, 4H), 7.20 (m, 8H), 7.02
(t, 2H), 4.24 (q, 2H), 3.79 (t, 2H), 2.90 (t, 2H), 1.25 (t, 3H).
MS: 599.2 (M+23).
Example 312
[0796] To carbonic acid
9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-6,8-dioxo-7,8-dihydro-6H-py-
rrolo[3,4-g]quinolin-5-yl ester ethyl ester 311 (140 mg, 0.24 mmol)
dissolved in tetrahydrofuran (0.50 ml) and water (0.25 ml) was
added potassium carbonate (345.4 mg, 2.5 mmol) and
N,N-dimethyl-aminopyridine (DMAP, 29.3 mg, 3.8 mmol). After
stirring overnight at room temperature, the reaction mixture was
concentrated in vacuo and diluted with ethyl acetate. It was then
washed twice with 5% citric Acid (aqueous), twice with water, once
with brine, dried over magnesium sulfate, and concentrated in
vacuo. The resulting residue was dissolved in dimethylformamide
(3.0 ml). To this solution was added potassium carbonate (179 mg,
1.3 mmol) and iodomethane (319 mg, 2.6 mmol). After stirring
overnight at room temperature, the reaction mixture was diluted
with ethyl acetate. It was then washed twice with 5% citric Acid,
twice with water, once with brine, and concentrated in vacuo to
afford
9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-5-methoxy-pyrrolo[3,4-g]qui-
noline-6,8-dione 312 (130 mg, 0.24 mmol, 100%). .sup.1H NMR
(CDCl.sub.3) .delta. 9.16 (dd, 1H), 8.58 (dd, 1H), 7.82 (s, 1H),
7.74 (m, 1H), 7.55 (m, 4H), 7.20 (m, 8H), 7.0 (t, 2H), 4.04 (s,
3H), 3.87 (t, 2H), 2.91 (t, 2H). MS: 555.2 (M+23).
Example 313
[0797]
9-Benzhydryloxy-7-(2,4-dimethoxybenzyl)-5-methoxy-pyrrolo[3,4-g]qui-
noline-6,8-dione 312 (130 mg, 0.24 mmol) was dissolved in
tetrahydrofuran (1.6 ml), water (0.64 ml), and isopropanol (0.32
ml) and cooled to 0.degree. C. Lithium borohydride (26.6 mg, 1.22
mmol) was then added and the reaction mixture was removed from the
ice bath and stirred at room temperature for 2 hours. After
quenching with acetic acid (0.12 ml), the reaction mixture was
diluted with ethyl acetate. It was then washed with twice with
water, once with brine, and concentrated in vacuo. The resulting
residue was dissolved in dichloromethane (1.2 ml) and
triethylsilane (0.6 ml) and trifluoroacetic acid (3.6 ml). The
reaction mixture was then stirred at room temperature for 1 hour.
The mixture was then concentrated in vacuo and azeotroped three
times with a (1:1) toluene/tetrahydrofuran solution. The resulting
residue was triturated three times with a (3:1) hexane/ether
mixture and the remaining solid in the filter funnel and reaction
flask was dissolved in methanol, combined, and concentrated in
vacuo to afford
7-[2-(4-Fluoro-phenyl)-ethyl]-9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-
-g]quinolin-8-one 313 (40 mg, 0.086 mmol, 36%). .sup.1H NMR
(d-DMSO) .delta. 8.85 (dd, 1H), 8.648 (dd, 1H), 7.65 (m, 1H), 7.28
(t, 2H), 7.06 (t, 2H), 4.60 (s, 2H), 3.95 (s, 3H), 3.68 (t, 2H),
2.95 (t, 2H). .sup.19F NMR .delta. 60.0-75.6. MS: 353.1 (M+1).
##STR00392##
Example 314
[0798] To
(2-{[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-py-
rrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phosphonic acid
diethyl ester 214 (16 mg, 0.023 mmol) dissolved in dichloromethane
(0.30 ml) was added trimethylsilylbromide (TMS-Br, 39 mg, 0.25
mmol). After 4 hours of stirring at room temperature, more
trimethylsilylbromide (24 mg, 0.16 mmol) was added and the reaction
mixture stirred for another 2 hours. The reaction mixture was
cooled to 0.degree. C., quenched with methanol (1.0 ml), and
concentrated in vacuo. It was then triturated three times
(3/1--hexane/ether) and the remaining residue in the flask and
filter was dissolved in methanol, combined, and concentrated in
vacuo. The residue was dissolved in dimethysulfoxide (0.40 ml),
filtered through a glass plug, and purified by reverse-phase
preparatory HPLC to provide
(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qui-
noline-5-carbonyl]-amino}-ethyl)-phosphonic acid 314 (7 mg, 0.012
mmol, 52%). .sup.1H NMR (CD.sub.3OD) .delta. 8.96 (d, 1H), 8.77 (d,
1H), 7.78 (m, 1H), 7.42 (m, 2H), 7.10 (t, 2H), 4.80 (s, 2H), 4.63
(s, 2H), 3.72 (m, 2H), 2.16 (m, 2H). .sup.31P .delta. 25.0.
.sup.19F .delta. -78.0-116.0. MS: 460.1 (M+1).
##STR00393##
Example 315
[0799] To
2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrro-
lo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyloxy]-propi-
onic acid ethyl ester 221 (15 mg, 0.024 mmol) dissolved in
acetonitrile (0.10 ml) and water (0.05 ml) was added 1.0 M NaOH
(0.072 ml). The reaction mixture was stirred at room temperature
for 3 hours, cooled to 0.degree. C., and quenched with 1.0 M HCl
(0.1 ml). The mixture was concentrated in vacuo and the resulting
residue was redissolved in dimethylsulfoxide, filtered through a
glass plug, and purified by reverse phase preparatory HPLC to
afford
2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]-
quinoline-5-carbonyl]-amino}-ethyl)-hydroxy-phosphinoyloxy]-propionic
acid 315 (9 mg, 0.014 mmol, 60%). .sup.1H NMR (CD.sub.3OD) .delta.
9.0 (d, 1H), 8.80 (d, 1H), 7.80 (m, 1H), 7.42 (M, 2H), 7.10 (t,
2H), 4.80 (d, 2H), 4.62 (s, 2H), 3.75 (m, 2H), 2.20 (m, 2H), 1.46
(d, 3H). .sup.31P .delta. 27.8. .sup.19F .delta. -78.0, -118.0. MS:
532.1 (M+1).
##STR00394##
Example 316
[0800] To a solution of
9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]qu-
inoline-5-carboxylic acid methyl ester 212 (3 mg, 0056 mmol) in
dichloromethane (1 mL) were added TFA (0.1 mL) and triethylsilane
(0.2 mL). Stirring was continued at the room temperature for 1 hour
and the volatiles were evaporated in vacuo. The residue was
triturated in Et.sub.2O/hexane to afford
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
e-5-carboxylic acid methyl ester 316 (2.0 mg, 100%) as a yellow
solid: .sup.1H NMR (CDCl.sub.3) .delta. 9.5 (d, 1H), 9.0 (m, 1H),
7.66 (dd, 1H), 7.35 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.7 (s,
2H), 4.0 (s, 3H); MS: 365 (M-1).
##STR00395##
Example 317
[0801] To a solution of
9-benzlhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]q-
uinoline-5-carboxylic acid 213 (6 mg, 0.0116 mmol) in DMF (0.5 mL)
at the room temperature were added triethylamine (TEA, 5 .mu.L,
0.034 mmol), cyclohexylamine (2.3 .mu.L, 0.022 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
4.4 mg, 0.022 mmol) and 1-hydroxybenzotriazole (HOBt, 2.3 mg,
0.0174 mmol). The solution was stirred under a nitrogen atmosphere
for 5 hours and diluted with EtOAc. The organic layer was washed
with water, 1N aqueous HCl, saturated aqueous NaHCO.sub.3 and
brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude
product was chromatographed on a silica gel column eluting with
EtOAc/hexane to afford the protected final product, which was
treated in dichloromethane (1 mL) with TFA (0.1 mL) and
triethylsilane (0.2 mL) at the room temperature for 1 hour. The
volatiles were evaporated in vacuo and the residue was triturated
in Et.sub.2O/hexane to afford
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo
[3,4-g]quinoline-5-carboxylic acid cyclopentylamide 317 (2.6 mg,
54%) as yellow solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.96 (dd,
1H), 8.53 (d, 1H), 7.62 (dd, 1H), 7.27 (m, 2H), 7.04 (t, 2H), 6.34
(m, 1H), 4.63 (s, 2H), 4.48 (m, 3H), 2.2 (m, 2H), 1.50-1.90 (m,
6H); MS: 418 (M-1).
##STR00396##
Example 318
[0802] 9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,
8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g,
0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this
was added 2-methylaminopyridine (0.0079 mL, 0.0772 mmol),
diisopropylethylamine (0.027 mL, 0.1544 mmol),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed.
Purified by reverse phase HPLC (0.1% TFA, H.sub.2O/ACN) to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
e-5-carboxylic acid methyl-pyridin-2-yl-amide 318 (0.0017 g, 0.003
mmol, 8%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.02 (dd, 11H), 8.50
(d, 1H), 8.18 (d, 1H), 7.65 (dd, 1H), 7.38 (m, 5H), 7.08 (dd, 2H),
4.94 (dd, J=15 Hz, 11Hz, 2H), 4.49 (d, J=17 Hz, 1H), 4.19 (d,
J=17Hz, 1H), 3.61 (s, 3H.) MS: 443 (M+1).
##STR00397##
Example 319
[0803]
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo
[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was
dissolved in 0.3 mL of dimethylformamide. To this was added
2-aminothiazole (0.0077 mL, 0.0772 mmol), diisopropylethylamine
(0.027 mL, 0.1544 mmol),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed.
Purified by reverse phase HPLC (0.1% TFA, H.sub.2O/ACN) to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
e-5-carboxylic acid thiazol-2-ylamide 319 (0.01 g, 0.023 mmol,
60%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.02 (dd, 1H), 8.61 (d, 1H),
7.65 (dd, 1H), 7.55 (d, 1H), 7.38 (dd, 2H), 7.21 (d, 1H), 7.07 (dd,
2H), 4.78 (s, 2H), 4.67 (s, 2H.) MS: 435 (M+1).
##STR00398##
Example 320
[0804]
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,-
4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was
dissolved in 0.3 mL of dimethylformamide. To this was added
2-amino-1,3,4-thiadiazole (0.0078 mL, 0.0772 mmol),
diisopropylethylamine (0.027 mL, 0.1544 mmol),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed.
Purified by reverse phase HPLC (0.1% TFA, H.sub.2O/ACN) to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
e-5-carboxylic acid [1,3,4]thiadiazole-2-ylamide 320 (0.0066 g,
0.015 mmol, 40%.) .sup.1H NMR (CDCl.sub.3) .delta. 9.02 (dd, 1H),
8.81 (s, 1H), 8.65 (d, 1H), 7.65 (dd, 1H), 7.38 (dd, 2H), 7.05 (dd,
2H), 4.74 (s, 2H), 4.64 (s, 2H.) MS: 436 (M+1).
##STR00399##
Example 321
[0805]
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,-
4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was
dissolved in 0.3 mL of dimethylformamide. To this was added
dimethylamine (2M in THF) (0.0386 mL, 0.0772 mmol),
diisopropylethylamine (0.027 mL, 0.1544 mmol),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed.
Purified by reverse phase HPLC (0.1% TFA, H.sub.2O/ACN) to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-
e-5-carboxylic acid dimethylamide 321 (0.014 g, 0.037 mmol, 97%.)
.sup.1H NMR (CDCl.sub.3) .delta. 9.07 (dd, 1H), 8.18 (d, 1H), 7.65
(dd, 31H), 7.03(dd, 2H), 4.79 (dd, 2H), 4.53 (d, J=17Hz, 1H), 4.25
(d, J=17Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H.) MS: 380 (M+1).
##STR00400##
Example 322
[0806]
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,-
4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was
dissolved in 0.3 mL of dimethylformamide. To this was added
diethylamine (0.0056 mL, 0.0772 mmol), diisopropylethylamine (0.027
mL, 0.1544 mmol),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room
temperature. After 15 hours, starting material was consumed.
Purified by reverse phase HPLC (0.1% TFA, H.sub.2O/ACN) to give
7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dilhydro-6H-pyrrolo[3,4-g]quinoli-
ne-5-carboxylic acid diethylamide 322 (0.0134 g, 0.033 mmol, 86%.)
.sup.1H NMR (CDCl.sub.3) .delta. 9.07 (dd, 1H), 8.18 (d, 1H), 7.65
(m, 3H), 7.07(dd, 2H), 4.72 (dd, 2H), 4.56 (d, J=1 7Hz, 1H), 4.23
(d, J=17 Hz, 1H), 3.66 (q, 2H), 3.11 (q, 2H), 1.35 (t, 3H), 0.965
(t, 3H.) MS: 408 (M+1).
Example 323
HIV Integrase Assay (IC.sub.50 Determination)
[0807] IC50 is the inhibitory concentration that reduces the strand
transfer activity of recombinant integrase by 50%.
[0808] HIV Integrase assay was carried out in Reacti-Bind High
Binding Capacity Streptavidin coated plates (Pierce # 15502) in 100
.mu.l reactions following the method of Hazuda et al Nucleic Acids
Res. (1994) 22:1121-22. The wells of the plate are rinsed once with
PBS. Each well is then coated at room temperature for 1 h with 100
.mu.l of 0.14 .mu.M double-stranded donor DNA of Hazuda et al.
[0809] After coating, the plate was washed twice with PBS.
3'processing of the donor DNA is started by adding 80 .mu.l of
Integrase/buffer mixture (25 mM HEPES, pH 7.3, 12.5 mM DTT, 93.75
mM NaCl, 12.5 mM MgCl.sub.2, 1.25% Glycerol, 0.3125 .mu.M
integrase) to each well. 3'-Processing was allowed to proceed for
30 min at 37.degree. C., after which, 10 .mu.l of test compound and
10 .mu.l of 2.5 .mu.M digoxigenin (DIG)-labeled, double-stranded
Target DNA, according to Hazuda etal, were added to each well to
allow strand transfer to proceed for 30 min at 37.degree. C. The
plate was then washed three times with 2.times.SSC for 5 min and
rinsed once with PBS. For detection of integrated product, 100
.mu.l of a 1/2000 dilution of HRP-conjugated anti-DIG antibody
(Pierce #31468) were added to each well and incubated for 1 hour.
The plate was then washed three times for 5 min each, with 0.05%
Tween-20 in PBS. For signal development and amplification, 100
.mu.l of SuperSignal ELISA Femto Substrate (Pierce #37075) were
added to each well, Chemiluminescence (in relative light units) was
read immediately at 425 nm in the SPECTRAmax GEMINI Microplate
Spectrophotometer using the end point mode at 5 sec per well. For
IC.sub.50 determinations, eight concentrations of test compounds in
a 1/2.2 dilution series were used. Certain compounds of the
invention, including those in Tables 1-5, had a strand transfer
IC.sub.50 less than about 10 .mu.M.
Example 324
Anti-HIV Assay (EC.sub.50 Determination)
[0810] EC50 (also commonly referred to as ED50 or IC50) is the
effective concentration that inhibits 50% of viral production, 50%
of viral infectivity, or 50% of the virus-induced cytopathic
effect.
[0811] Anti-HIV assay was carried out in 96-well Clear Bottom Black
Assay Plate (Costar # 3603) in 100 .mu.l of culture medium, using
the CellTiter-Glo.TM. Reagent (Promega # G7570) for signal
detection. MT-2 cells (1.54.times.10.sup.4 cells) were infected
with wild-type virus at an m.o.i. of about 0.025, and grown in the
presence of various drug concentrations (serial 5-fold dilutions)
in 100 .mu.l of RPMI medium containing 10% FBS, 2% glutamine, 1%
HEPES and 1% penicillin/streptomycin for 5 days. At the end of the
incubation period, 100 .mu.l of CellTiter-Glo.TM. Reagent was added
to each well in the Assay Plate and the chemiluminescence (in
relative light units) was measured after 10 mins of incubation with
the Wallac Victor.sup.2 1420 MultiLabel Counter. Certain compounds
of the invention, including those in Tables 1-5, had an anti-HIV
MT2 EC.sub.50 less than about 10 .mu.M.
Example 325
Cytotoxicity Assay (CC.sub.50 Determination)
[0812] For the determination of compound cytotoxicity, the plate
and reagents are the same as those of anti-HIV assay. Uninfected
MT-2 cells (1.54.times.10.sup.4 cells)were grown in the presence of
various drug concentrations (serial 3-fold dilutions) in 100 .mu.l
of RPMI medium containing 10% FBS, 2% glutamine, 1% HEPES and 1%
penicillin/streptomycin for 5 days. At the end of the incubation
period, 100 .mu.l of CellTiter-Glo.TM. Reagent was added to each
well in the assay plate and the chemiluminescence (in relative
light units) was measured after 10 mins of incubation with the
Wallac Victor.sup.2 1420 MultiLabel Counter. Certain compounds of
the invention, including those in Tables 1-5, had cytotoxicity MT2
CC.sub.50 less than about 10 .mu.M.
[0813] The foregoing specification teaches the principles of the
present invention, with Examples provided for the purpose of
illustration, and fully discloses how to make and use the present
invention. The invention is not limited to the particular
embodiments described herein but includes all modifications within
the scope of the appended claims and their equivalents. Those
skilled in the art will recognize through routine experimentation
that various changes and modifications can be made without
departing from the scope of this invention.
[0814] All publications, including, but not limited to, patents and
patent applications cited in this specification, are herein
incorporated by reference as if each individual publication were
specifically and fully set forth.
* * * * *