U.S. patent application number 11/478121 was filed with the patent office on 2006-11-02 for tricyclic protein kinase inhibitors.
Invention is credited to Dan M. Berger, Diane H. Boschelli, Frenel F. DeMorin, Minu D. Dutia, Dennis W. Powell, Hwei-Ru Tsou, Allan Wissner, Biqi Wu, Fei Ye, Nan Zhang.
Application Number | 20060247217 11/478121 |
Document ID | / |
Family ID | 26933817 |
Filed Date | 2006-11-02 |
United States Patent
Application |
20060247217 |
Kind Code |
A1 |
Berger; Dan M. ; et
al. |
November 2, 2006 |
Tricyclic protein kinase inhibitors
Abstract
This invention provides compounds of formula 1, having the
structure ##STR1## which are useful as inhibitors of protein
tyrosine kinase and are antiproliferative agents.
Inventors: |
Berger; Dan M.; (New City,
NY) ; Dutia; Minu D.; (West Nyack, NY) ;
DeMorin; Frenel F.; (Nanuet, NY) ; Boschelli; Diane
H.; (New City, NY) ; Powell; Dennis W.;
(Westchester, NY) ; Tsou; Hwei-Ru; (New City,
NY) ; Wissner; Allan; (Ardsley, NY) ; Zhang;
Nan; (Eastchester, NY) ; Ye; Fei; (Nanuet,
NY) ; Wu; Biqi; (Nanuet, NY) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Family ID: |
26933817 |
Appl. No.: |
11/478121 |
Filed: |
June 29, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10618044 |
Jul 10, 2003 |
7105531 |
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11478121 |
Jun 29, 2006 |
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09751274 |
Dec 29, 2000 |
6638929 |
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10618044 |
Jul 10, 2003 |
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60240905 |
Dec 29, 1999 |
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Current U.S.
Class: |
514/151 ;
514/253.03; 514/292; 544/361; 546/79; 546/82 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 333/66 20130101; C07F 7/0812 20130101; C07D 215/48 20130101;
C07D 219/04 20130101; C07D 513/04 20130101; C07D 219/06 20130101;
C07D 219/08 20130101; C07D 221/08 20130101; C07D 495/04 20130101;
C07D 401/12 20130101; C07D 491/04 20130101; C07D 401/14 20130101;
C07D 215/54 20130101; C07D 333/70 20130101; C07D 215/56
20130101 |
Class at
Publication: |
514/151 ;
514/253.03; 514/292; 544/361; 546/079; 546/082 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/655 20060101 A61K031/655; A61K 31/4745
20060101 A61K031/4745; A61K 31/473 20060101 A61K031/473; C07D
498/02 20060101 C07D498/02; C07D 491/02 20060101 C07D491/02 |
Claims
1. A compound of formula 1 having the structure: ##STR102##
wherein: Ar is cycloalkyl of 3 to 7 carbon atoms, which may be
optionally substituted with one or more alkyl of 1 to 6 carbon
atoms; or Ar is a pyridinyl, pyrimidinyl, or phenyl ring; wherein
the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-,
di-, or tri-substituted with substituent(s) independently selected
from the group consisting of halogen, alkyl of 1-6 carbon atoms,
alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido,
hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7
carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6
carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,
trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7
carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8
carbon atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of
1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,
N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of
3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms,
mercapto, methylmercapto and benzoylamino; or Ar is a bicyclic aryl
or bicyclic heteroaryl ring system of 8 to 12 atoms where the
bicyclic heteroaryl ring may contain 1 to 4 heteroatoms selected
from N, O, and S wherein the bicyclic aryl or bicyclic heteroaryl
ring may be optionally mono-di-, tri, or tetra-substituted with
substituent(s) independently selected from the group consisting of
halogen, oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of
2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl
of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,
alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon
atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8
carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of
2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or Ar
is the radical: ##STR103## A' is a pyridinyl, pyrimidinyl, or
phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may
be optionally mono- or di-substituted with a substituent(s)
independently selected from the group consisting of alkyl of 1-6
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen,
halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of
2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6
carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of
1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,
phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,
alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon
atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8
carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of
2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; T is
substituted on A' at carbon and is --NH(CH.sub.2).sub.m--,
--O(CH.sub.2).sub.m--, --S(CH.sub.2).sub.m--,
--NR(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mNH--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mS--, --SO(CH.sub.2).sub.m--,
--SO.sub.2(CH.sub.2).sub.m--, --CO(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mCO--, --(CH.sub.2).sub.mSO--,
--(CH.sub.2).sub.mSO.sub.2-- or --(CH.sub.2).sub.mNR--; L is a
phenyl ring that is optionally substituted with one, two, or three
substituent(s) independently selected from the group consisting of
alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of
2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen,
halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of
2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6
carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of
1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,
phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,
alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon
atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8
carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of
2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or L
is a 5- or 6-membered heteroaryl ring where the heteroaryl ring
contains 1 to 3 heteroatoms selected from N, O, and S and where the
heteroaryl ring may be optionally mono- or di-substituted with
substituent(s) selected from the group consisting of halogen, oxo,
thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6
carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,
alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon
atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8
carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of
2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; m is
0-3; n is 0-1; X is NH, O, S, or NR; R is alkyl of 1-6 carbon
atoms; Y and Z are both carbon or N; the ring structure of formula
1 then being a fused 5,6,6 or 6,6,6 tricycle; or one of Y and Z is
N, O or S, and the other is a bond between the two end rings; the
ring structure of formula 1 then being a fused 5,5, 6 or 6,5,6
tricycle; or one of Y or Z is N with the other being carbon; the
ring structure of formula 1 then being a fused 5,6,6 or 6,6,6
tricycle; ##STR104## A and D are each, independently, carbon, N, O,
or S; B is carbon or N; the dashed line indicates an optional
double bond; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each,
independently, not present, hydrogen, halogen, hydroxy, amino,
hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon
atoms, alkynyloxy of 2-106 carbon atoms, hydroxyalkyl of 1-6 carbon
atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl
of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8
carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8
carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of
1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms,
alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6
carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon
atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms,
N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino
of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl,
thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of
2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of
3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms,
alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl
group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7
carbons, carboalkoxyalkyl of 3-8 carbon atoms, ##STR105## R.sub.5
is independently hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of
1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,
N,N-dialkylaminoalkyl of 3-12 carbon atoms, N-cycloalkylaminoalkyl
of 4-12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon
atoms, N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms,
morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms,
piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms,
N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon
atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of
1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, or phenyl; V is
(CH.sub.2).sub.m, O, S, or NR.sub.6; R.sub.7 is NR.sub.6R.sub.6,
OR.sub.6, J, N(R.sub.6).sub.3.sup.+, or NR.sub.6(OR.sub.6); M is
NR.sub.6, O, S, N--[(C(R.sub.6).sub.2).sub.pNR.sub.6R.sub.6], or
N--[(C(R.sub.6).sub.2).sub.p--OR.sub.6]; W is NR.sub.6, O, S, or is
a bond; Het is a heterocycle selected from the group consisting of
morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine
S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine,
imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine,
tetrazole, piperazine, furan, thiophene, tetrahydrothiophene,
tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and
tetrahydropyran; wherein the heterocycle is optionally mono- or
di-substituted on carbon or nitrogen with R.sub.6; optionally mono-
or di-substituted on carbon with hydroxy, --N(R.sub.6).sub.2, or
--OR.sub.6; optionally mono or di-substituted on carbon with the
mono-valent radicals --(C(R.sub.6).sub.2).sub.sOR.sub.6 or
--[(C(R.sub.6).sub.2).sub.sN(R.sub.6).sub.2]; or optionally mono or
di-substituted on a saturated carbon with divalent radicals .dbd.O
or --O(C(R.sub.6).sub.2).sub.sO--; Ph is a phenyl ring optionally
mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon
atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl,
alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl,
--N(R.sub.6).sub.2, --OR.sub.6, --(C(R.sub.6).sub.2).sub.sOR.sub.6,
--[(C(R.sub.6).sub.2).sub.sN(R.sub.6).sub.2], or
--(C(R.sub.6).sub.2).sub.kHet; R.sub.6 is hydrogen, alkyl of 1-6
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon
atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6
carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or
carboxyalkyl of 2-7 carbon atoms; or R.sub.6 is phenyl optionally
mono-, di-, or tri-substituted with substituent(s) independently
selected from halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl,
amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon
atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon
atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6
carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon
atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino,
benzylamino; alkanoylamino of 1-6 carbon atoms or alkyl of 1-6
carbon atoms; R.sub.8 and R.sub.9 are each, independently,
--[(C(R.sub.6).sub.2).sub.rNR.sub.6R.sub.6], and
--[(C(R.sub.6).sub.2).sub.r OR.sub.6]; J is independently hydrogen,
chlorine, fluorine, or bromine; g=1-6; k=0-4; p=2-4; q=0-4; r=1-4;
s=1-6; or a pharmaceutically acceptable salt thereof; ##STR106## at
least one of the bonds between A and B or B and D must be a double
bond, with the other being a single bond; at least one of A, B, and
D are not carbon; only one of A, B, or D can be O or S; when A, B,
or D is O or S, the adjacent atoms must be carbon; provided that
when R.sub.5 is bound to a nitrogen atom, the resulting structures
do not include --N--C--N-- or --O--C--N-- radicals; and when
R.sub.5 is bound to an oxygen atom, the resulting structures do not
include an --N--C--O-- radical; provided that when R.sub.6 is
alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, the
alkenyl or alkynyl moieties are bound to a nitrogen or oxygen atom
through a saturated carbon atom in the alkenyl or alkynyl chain;
provided that when V is NR.sub.6 and R.sub.7 is NR.sub.6R.sub.6,
N(R.sub.6).sub.3.sup.+, or NR.sub.6(OR.sub.6), then g=2-6; provided
that when M is O or S and R.sub.7 is OR.sub.6, then p=1-4; provided
that when V is NR.sub.6, O, S, then k=2-4; provided that when V is
O or S and M or W is O or S, then k=1-4 provided that when W is not
a bond with Het bonded through a nitrogen atom then q=2-4; and
finally provided when W is a bond with Het bonded through a
nitrogen atom and V is O or NR.sub.6 or S, then k=2-4.
2. The compound of claim 1, having the structure ##STR107## or a
pharmaceutically acceptable salt thereof.
3. The compound of claim 1, having the structure ##STR108## wherein
X is selected from NH, sulfur or oxygen; or a pharmaceutically
acceptable salt thereof.
4. The compound of claim 1, having the structure ##STR109## wherein
X is selected from NH, sulfur, or oxygen; or a pharmaceutically
acceptable salt thereof.
5. The compound of claim 1, having the structure ##STR110## wherein
R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms,
hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon
atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6
carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6
carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of
1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms,
alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, ##STR111## or a pharmaceutically acceptable salt
thereof.
6. The compound of claim 1, having the structure ##STR112## wherein
R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms,
hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon
atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6
carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6
carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of
1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms,
alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon
atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl
of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
##STR113## or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 wherein R.sub.2 is
hydrogen.
8. The compound of claim 1, having the structure ##STR114## wherein
R.sub.2 and R.sub.3 are hydrogen; or a pharmaceutically acceptable
salt thereof.
9. The compound of claim 1, having the structure ##STR115## wherein
R.sub.3 is hydrogen; or a pharmaceutically acceptable salt
thereof.
10. The compound of claim 1, having the structure ##STR116##
wherein R.sub.2 is hydrogen, amino, hydroxyamino, trifluoromethyl,
alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6
carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms,
alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of
2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano,
carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon
atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon
atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl
of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino
of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl,
thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, dialkylamino
of 2 to 12 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, ##STR117## R.sub.3 is
hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon
atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
hydroxyalkyl of 2-6 carbon atoms; mercaptoalkyl of 2-6 carbon
atoms, phenyl, benzyl, ##STR118## or a pharmaceutically acceptable
salt thereof.
11. The compound of claim 1, having the structure ##STR119##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR120##
R.sub.1 and R.sub.4 are hydrogen; or a pharmaceutically acceptable
salt thereof.
12. The compound of claim 1, having the structure ##STR121##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR122##
R.sub.4 is hydrogen and one or two of the substituents R.sub.1,
R.sub.2 and R.sub.3 are as defined above, the remaining being
hydrogen; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1, having the structure ##STR123##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR124##
R.sub.4 is hydrogen and one or two of the substituents R.sub.1,
R.sub.2 and R.sub.3 are as herein above described, the remaining
being hydrogen; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1, having the structure ##STR125##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR126##
R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms,
hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon
atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6
carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6
carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of
1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms,
alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms,
alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7
carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon
atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl
of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
##STR127## or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1, having the structure ##STR128##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR129##
R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms,
hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon
atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6
carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6
carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of
1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms,
alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms,
alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7
carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon
atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl
of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
##STR130## or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 15 wherein R.sub.2 is
hydrogen.
17. The compound of claim 1, having the structure ##STR131##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alklynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbanoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR132##
R.sub.2 and R.sub.3 are hydrogen; or a pharmaceutically acceptable
salt thereof.
18. The compound of claim 1, having the structure ##STR133##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR134##
R.sub.3 is hydrogen; or a pharmaceutically acceptable salt
thereof.
19. The compound of claim 1, having the structure ##STR135##
wherein Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or Ar is the radical: ##STR136##
R.sub.2 is hydrogen, amino, hydroxyamino, trifluoromethyl, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon
atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6
carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy
of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of
1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of
2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano,
carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon
atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon
atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl
of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino
of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl,
thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, dialkylamino
of 2 to 12 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, ##STR137## R.sub.3 is
hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon
atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
hydroxyalkyl of 2-6 carbon atoms; mercaptoalkyl of 2-6 carbon
atoms, phenyl, benzyl, ##STR138## or a pharmaceutically acceptable
salt thereof.
20. The compound of claim 1, which is: a)
4-(4-phenoxyanilino)benzo[g]quinoline-3-carbonitrile, b)
4-(3-chloro-4-fluoroanilino)benzo[g]quinoline-3-carbonitrile, c)
4-(4-chloro-5-methoxy-2-methylanilino)benzo[g]quinoline-3-carbonitrile,
d)
7,8-dimethoxy-4-(4-phenoxyanilino)benzo[g]quinoline-3-carbonitrile,
e)
4-(4-chloro-5-methoxy-2-methylanilino)-7,8-dimethoxybenzo[g]quinoline--
3-carbonitrile, f)
4-(3-chloro-4-fluoroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitril-
e, g)
4-(2,4-dichloroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitri-
le, h)
4-(2,4-dichloroanilino)-7,8-dihydroxybenzo[g]quinoline-3-carbonitr-
ile, i)
8-(3,4,5-trimethoxyanilino)-3H-[1,2,3]triazolo[4,5-g]quinoline-7--
carbonitrile, j)
9-(4-chloro-5-methoxy-2-methylanilino)pyrido[2,3-g]quinoxaline-8-carbonit-
rile, k)
8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}i-
midazo[4,5-g]quinoline-7-carbonitrile, l)
2-{[2-(4-morpholinyl)ethyl]amino}-8-(3,4,5-trimethoxyanilino)imidazo[4,5--
g]quinoline-7-carbonitrile, m)
2-amino-8-(4-phenoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile,
n) 8-(3-bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile,
o)
8-(2-bromo-4-chlorophenylamino)imidazo[4,5-g]quinoline-7-carbonitrile,
p)
8-(2-bromo-4-chloro-5-methoxyphenylamino)imidazo[4,5-g]quinoline-7-car-
bonitrile, q)
8-(2-chloro-5-methoxyphenylamino)imidazo[4,5-g]quinoline-7-carbonitrile,
r)
8-(3-hydroxy-4-methylphenylamino)imidazo[4,5-g]quinoline-7-carbonitril-
e, s)
8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile,
t) 8-(4-phenoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile, u)
2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-car-
bonitrile, v)
2-(4-morpholinylmethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinolin-
e-7-carbonitrile, w)
8-(4-chloro-5-methoxy-2-methylanilino)-3-[2-(4-morpholinyl)ethyl]-3H-imid-
azo[4,5-g]quinoline-7-carbonitrile, x)
3-[2-(4-morpholinyl)ethyl]-8(4-phenoxyanilino)-3H-imidazo[4,5-g]quinoline-
-7-carbonitrile, y)
8-[(4-chloro-5-methoxy-2-methylphenyl)amino]-thiazolo[4,5-g]quinoline-7-c-
arbonitrile, z)
4-(3-bromophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
aa)
4-(4-chloro-2-fluorophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-car-
bonitrile, bb)
4-(2,4-dichlorophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile-
, cc)
4-(2,4-dichloro-5-methoxyphenylamino)benzo[4,5]thieno[3,2-b]pyridin-
e-3-carbonitrile, dd)
4-(4-phenoxyphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
ee)
4-(3-hydroxy-4-methylphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-ca-
rbonitrile, ff)
4-(4-chloro-2-fluorophenoxy)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitril-
e, gg)
4-(4-chloro-5-methoxy-2-methylphenylamino)-8-nitrobenzo[4,5]thieno-
[3,2-b]pyridine-3-carbonitrile, hh)
8-anilino-4-(4-chloro-5-methoxy-2-methylanilino)[1]benzothieno[3,2-b]pyri-
dine-3-carbonitrile, ii)
4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
jj)
6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitril-
e, kk)
4-(3-bromophenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile-
, ll)
4-(4-chloro-2-fluorophenylamino)benzo[4,5]furo[3,2-b]pyridine-3-car-
bonitrile, mm)
4-(3-hydroxy-4-methylphenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonit-
rile, nn)
4-(4-phenoxyphenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carboni-
trile, oo)
4-(4-chloro-2-fluorophenoxy)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile,
pp)
4-(2,4-dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbo-
nitrile, qq)
4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
rr)
8-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitril-
e, ss)
N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-8-yl]acr-
ylamide, tt)
N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-6-yl]acrylamide-
, uu)
4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile,
vv)
4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile,
ww)
4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile,
xx)
4-(2,4-dichloroanilino)-8-hydroxybenzo[g]quinoline-3-carbonitrile,
yy)
4-(2,4-dichloroanilino)-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline--
3-carbonitrile, zz)
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile, aaa)
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile, bbb)
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, ccc)
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, ddd)
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile, eee)
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile, fff)
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]be-
nzo[g]quinoline-3-carbonitrile, ggg)
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]be-
nzo[g]quinoline-3-carbonitrile, hhh)
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile, iii)
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile, jjj)
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, kkk)
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, lll)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-
-methoxybenzo[g]quinoline-3-carbonitrile, mmm)
8-(2-Chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)pheny-
lamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, nnn)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, ooo)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chloro-
propoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile, ppp)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile, qqq)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile,
rrr)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-meth-
oxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,
sss)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-meth-
oxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,
ttt)
4-(2,4-Dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]qui-
noline-3-carbonitrile, uuu)
8-(3-Chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[-
g]quinoline-3-carbonitrile, vvv)
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propo-
xy)benzo[g]quinoline-3-carbonitrile, www)
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, xxx)
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-1-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, yyy)
4-(2,4-Dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-
-3-carbonitrile, zzz)
8-(2-Chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,-
8]naphthyridine-3-carbonitrile, aaaa)
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]be-
nzo[b][1,8]naphthyridine-3-carbonitrile, bbbb)
8-(2-Chloroethoxy)-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]ani-
lino}-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile, cccc)
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile, dddd)
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-methoxy-8-[-
2-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile,
eeee)
4-(2,4-Dichloroanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carboni-
trile, ffff)
8-(2-Chloroethoxy)-4-(4-chloro-5-methoxy-2-methylanilino)-7-ethoxybenzo[g-
]quinoline-3-carbonitrile, gggg)
8-(2-Chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-7-methoxybenzo[-
g]quinoline-3-carbonitrile, hhhh)
7-(2-Chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-8-methoxybenzo[-
g]quinoline-3-carbonitrile, iiii)
8-(2-Chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-7-methoxybe-
nzo[g]quinoline-3-carbonitrile, jjjj)
7-(2-Chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-8-methoxybe-
nzo[g]quinoline-3-carbonitrile, kkkk)
7-(2-Chloroethoxy)-4-(3-chloro-4-fluoroanilino)-8-methoxybenzo[g]quinolin-
e-3-carbonitrile, llll)
8-(2-Chloroethoxy)-4-(3-chloro-4-fluoroanilino)-7-methoxybenzo[g]quinolin-
e-3-carbonitrile, mmmm)
4-(4-Benzyloxy-3-chlorophenylamino)-7-(2-chloroethoxy)-8-methoxybenzo[g]q-
uinoline-3-carbonitrile, nnnn)
4-(4-Benzyloxy-3-chlorophenylamino)-8-(2-chloroethoxy)-7-methoxybenzo[g]q-
uinoline-3-carbonitrile, oooo)
7-(2-Chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-8-methoxybenzo[g]qui-
noline-3-carbonitrile, pppp)
8-(2-Chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-7-methoxybenzo[g]qui-
noline-3-carbonitrile, qqqq)
4-(4-Chloro-5-methoxy-2-methylanilino)-8-ethoxy-7-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile, rrrr)
4-(4-Chloro-5-methoxy-2-methylanilino)-7-ethoxy-8-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile, ssss)
({2[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-8-ethoxybenzo[g]qu-
inoline-7-yloxy]-ethyl}-ethoxycarbonylmethyl-amino)-acetic acid
ethyl ester, tttt)
({2-[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-7-ethoxybenzo[g]q-
uinoline-8-yloxy]-ethyl}-ethoxycarbonylmethylamino)-acetic acid
ethyl ester, uuuu)
2-(Carbamoylmethyl-{2-[4-(4-chloro-5-methoxy-2-methylphenylamino)-3-cyano-
-7-ethoxybenzo[g]quinolin-8-yloxy]-ethyl}-amino)-acetamide, vvvv)
4-(2,4-Dichloroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g]quin-
oline-3-carbonitrile, wwww)
4-(2,4-Dichloroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g]quin-
oline-3-carbonitrile, xxxx)
8-Methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5-trimethoxyanilino-
)benzo[g]quinoline-3-carbonitrile, yyyy)
7-Methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]-43,4,5-trimethoxyanilino)b-
enzo[g]quinoline-3-carbonitrile, zzzz)
7-Methoxy-8-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)benzo[g]-
quinoline-3-carbonitrile, aaaaa)
8-Methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)benzo[g]-
quinoline-3-carbonitrile, bbbbb)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, ccccc)
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, ddddd)
4-(2-Chloro-5-methoxy-4-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, eeeee)
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-hydroxy-1-piperidinyl)ethoxy]-8-
-methoxybenzo[g]quinoline-3-carbonitrile, fffff)
4-(3-Chloro-4-fluoroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g-
]quinoline-3-carbonitrile, ggggg)
4-(2,4-Dichloro-5-methoxyanilino)-8-[2-(4-hydroxy-1-piperidinyl)ethoxy]-7-
-methoxybenzo[g]quinoline-3-carbonitrile, hhhhh)
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-hydroxy-1-piperi-
dinyl)ethoxy]benzo[g]quinoline-3-carbonitrile, iiiii)
4-(2-Chloro-5-methoxy-4-methylanilino)-7-methoxy-8-[2-(4-hydroxy-1-piperi-
dinyl)ethoxy]benzo[g]quinoline-3-carbonitrile, jjjjj)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, kkkkk)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, lllll)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, mmmmm)
4-(3-Chloro-4-fluoroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g-
]quinoline-3-carbonitrile, nnnnn)
4-(3-Chloro-4-phenoxyphenylamino)-7-methoxy-8-(2-morpholin-4-yl-ethoxy)be-
nzo[g]quinoline-3-carbonitrile, ooooo)
4-(3-Chloro-4-phenoxyphenylamino)-8-methoxy-7-(2-morpholin-4-yl-ethoxy)be-
nzo[g]quinoline-3-carbonitrile, ppppp)
4-(2-Chloro-5-methoxy-4-methylphenylamino)-8-methoxy-7-(2-morpholin-4-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, qqqqq)
4-(2-Chloro-5-methoxy-4-methylphenylamino)-7-methoxy-8-(2-morpholin-4-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, rrrrr)
4-(4-Benzyloxy-3-chlorophenylamino)-8-methoxy-7-(2-morpholin-4-yl-ethoxy)-
benzo[g]quinoline-3-carbonitrile, sssss)
4-(4-Benzyloxy-3-chlorophenylamino)-7-methoxy-8-(2-morpholin-4-yl-ethoxy)-
benzo[g]quinoline-3-carbonitrile, ttttt)
8-(Benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo-
[g]quinoline-3-carbonitrile, uuuuu)
4-[(2-Chloro-4-fluoro-5-methoxyphenyl)amino]-8-hydroxy-7-methoxybenzo[g]q-
uinoline-3-carbonitrile, or a pharmaceutically acceptable salt
thereof.
21. An intermediate compound selected from the group: a)
4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile, b)
4-chlorobenzo[g]quinoline-3-carbonitrile, c)
3-(dimethylaminomethyleneamino)-6,7-dimethoxynaphthalene-2-carboxylic
acid methyl ester, d)
7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile, e)
4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, f)
7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-
-quinolinecarbonitrile, g)
6,7-diamino-4-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydro-quinoli-
ne-3-carbonitrile, h)
8-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,8-dihydro[1,2,3]triazolo[4,5-
-g]quinoline-7-carbonitrile, i)
8-oxo-5,8-dihydro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile, j)
8-chloro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile, k)
2-amino-8-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl-5,8-dihydroimidazo[4,5--
g]quinoline-7-carbonitrile, l)
2-amino-8-oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile, m)
2-amino-8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, n)
8-oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile, o)
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, p)
7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide,
q) 7-cyanoimidazo[4,5-g]quinolin-8-yl(4-phenoxyphenyl)formamide, r)
7-{[2-(4-morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, s)
6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, t)
3-[2-(4-morpholinyl)ethyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7-
-carbonitrile, u)
8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonit-
rile, v)
1,4-dihydro-7-mercapto-6-nitro-4-oxo-1-[[2-(trimethylsilyl)ethox-
y]methyl]-3-quinolinecarbonitrile, w)
8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile, x)
3-(dimethylaminomethyleneamino)benzo[b]thiophene-2-carboxylic acid
methyl ester, y)
4-hydroxybenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, z)
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, aa)
4-hydroxy-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
bb) 4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
cc) 4-chloro-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
dd) 3-(dimethylaminomethyleneamino)benzofuran-2-carboxylic acid
ethyl ester, ee)
4-hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile, ff)
4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile, gg)
7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile, hh)
8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile, ii)
4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile, jj)
4-chloro-8-methoxybenzo[g]quinoline-3-carbonitrile, kk) ethyl
7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate, ll) ethyl
6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate, mm) ethyl
3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate, nn) ethyl
3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate, oo)
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carboni-
trile, pp) 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[
]quinoline-3-carbonitrile, qq)
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile,
rr)
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile-
, ss) 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]
naphthyridine-3-carbonitrile, tt)
4-chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile,
uu)
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine--
3-carbonitrile, and vv)
4-chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carboni-
trile.
22. A method of treating, inhibiting the growth of, or eradicating
a neoplasm in a mammal in need thereof which comprises providing to
said mammal an effective amount of a compound as described in claim
1.
23. The method according to claim 22 wherein the neoplasm is
selected from the group consisting of breast, kidney, bladder,
mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas,
liver, prostate, and skin.
24. The method according to claim 22 wherein the neoplasm expresses
EGFR or erbB2 (Her2).
25. The method according to claim 22 wherein the neoplasm depends,
at least in part, on the MAPK pathway.
26. The method acording to claim 22 wherein the neoplasm depends,
at least in part, on the RAF kinase pathway.
27. The method acording to claim 22 wherein the neoplasm depends,
at least in part, on the SRC kinase pathway.
28. The method according to claim 22 wherein the neoplasm depends,
at least in part, on the ECK/LERK-1 pathway.
29. The method according to claim 22 wherein the neoplasm depends,
at least in part, on the VEGF/KDR pathway.
30. A method of treating, inhibiting the progression of, or
eradicating polycystic kidney disease in a mammal in need thereof
which comprises providing to said mammal an effective amount of a
compound described in claim 1.
31. A method of treating, inhibiting, or eradicating colonic polyps
in a mammal in need thereof which comprises providing to said
mammal an effective amount of a compound described in claim 1.
32. A method of inhibiting the biological effects of a deregulated
protein kinase in a mammal which comprises providing to said mammal
an, effective amount of a compound described in claim 1.
33. A method of treating a disease or inhibiting a disease state
whose etiology is at least in part caused by a defect in a
signaling pathway upstream from a protein kinase; by overexpression
of a protein kinase; or by a dysregulated protein kinase in a
mammal in need thereof which comprises providing to said mammal an
effective amount of a compound described in claim 1.
34. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and a compound described in claim 1.
35. A process for the preparation of a compound as described in the
specification for any of Flowsheets 1'', 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, or 14.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to substituted aromatic tricyclic
compounds containing nicotinonitrile rings as well as the
pharmaceutically acceptable salts thereof. The compounds of the
present invention inhibit the action of certain protein kinases,
thereby inhibiting the abnormal growth of particular cell types.
The compounds of this invention are therefore useful for the
treatment or inhibition of certain diseases that are the result of
deregulation of these protein kinases. The compounds of this
invention are anti-cancer agents and are useful for the treatment
or inhibition of cancer in mammals. In addition, the compounds of
this invention are useful for the treatment and inhbition of
polycystic kidney disease and colonic polyps.
[0002] Protein kinases are a class of enzymes that catalyze the
transfer of a phosphate group from ATP to a tyrosine, serine,
threonine, or histidine residue located on a protein substrate.
Protein kinases clearly play a role in normal cell growth. Many of
the growth factor receptor proteins function as kinases and it is
by this process that they effect signaling. The interaction of
growth factors with these receptors is a necessary event in normal
regulation of cell growth. However, under certain conditions, as a
result of either mutation or over expression, these receptors can
become deregulated; the result of which is uncontrolled cell
proliferation which can lead to tumor growth and ultimately to the
disease known as cancer [Wilks, A. F., Adv. Cancer Res., 60, 43
(1993) and Parsons, J. T.; Parsons, S. J., Important Advances in
Oncology, DeVita, V. T. Ed., J. B. Lippincott Co., Phila., 3
(1993)]. Among the growth factor receptor kinases and their
proto-oncogenes that have been identified and which are targets of
the compounds of this invention are the epidermal growth factor
receptor kinase (EGF-R kinase, the protein product of the erbB
oncogene), and the product produced by the erbB-2 (also referred to
as the neu or HER2) oncogene. Since the phosphorylation event is a
necessary signal for cell division to occur and since overexpressed
or mutated kinases have been associated with cancer, an inhibitor
of this event, a protein tyrosine kinase inhibitor, will have
therapeutic value for the treatment of cancer and other diseases
characterized by uncontrolled or abnormal cell growth. For example,
over expression of the receptor kinase product of the erbB-2
oncogene has been associated with human breast and ovarian cancers
[Slamon, D. J. et al., Science, 244, 707 (1989) and Science, 235,
177 (1987)]. Deregulation of EGF-R kinase has been associated with
epidermoid tumors [Reiss, M., et al., Cancer Res., 51, 6254
(1991)], breast tumors [Macias, A et al., Anticancer Res., 7, 459
(1987)], and tumors involving other major organs [Gullick, W. J.,
Brit. Med. Bull., 47, 87 (1991)]. Because of the importance of the
role played by deregulated receptor kinases in the pathogenesis of
cancer, many recent studies have dealt with the development of
specific PTK inhibitors as potential anti-cancer therapeutic agents
[some recent reviews: Traxler, P., Exp. Opin. Ther. Patents, 8,
1599 (1998) and Bridges, A. J., Emerging Drugs, 3, 279 (1998)].
[0003] It is also known that deregulation of EGF receptors is a
factor in the growth of epithelial cysts in the disease described
as polycystic kidney disease [Du, J., Wilson, P. D., Amer. J.
Physiol., 269 (2 Pt 1), 487 (1995); Nauta, J., et al., Pediatric
Research, 37(6), 755 (1995); Gattone, V. H. et al., Developmental.
Biology, 169(2), 504 (1995); Wilson, P. D. et al., Eur. J. Cell
Biol., 61(1), 131, (1993)]. The compounds of this invention, which
inhibit the catalytic function of the EGF receptors, are
consequently useful for the treatment of this disease.
[0004] The mitogen-activated protein kinase (MAPK) pathway is a
major pathway in the cellular signal transduction cascade from
growth factors to the cell nucleus. The pathway involves kinases at
two levels: MAP kinase kinases (MAPKK), and their substrates MAP
kinases (MAPK). There are different isoforms in the MAP kinase
family. (For review, see Seger, R.; Krebs, E. G., FASEB, 9, 726,
(1995).) The compounds of this invention can inhibit the action of
two of these kinases: MEK, a MAP kinase kinase, and its substrate
ERK, a MAP kinase. MEK is activated by phosphorylation on two
serine residues by upstream kinases such as members of the raf
family. When activated, MEK catalyzes phosphorylation on a
threonine and a tyrosine residue of ERK. The activated ERK then
phosphorylates and activates transcription factors in the nucleus,
such as fos and jun, or other cellular targets with PXT/SP
sequences. ERK, a p42 MAPK, is found to be essential for cell
proliferation and differentiation. Over-expression and/or
over-activation of MEK or ERK has been found to be associated with
various human cancers [For example, Sivaraman, V. S.; Wang, H-Y.;
Nuovo, G. J. Malbon, C. C. J. Clin. Invest., 99, 1478 (1997)]. It
has been demonstrated that inhibition of MEK prevents activation of
ERK and subsequent activation of ERK substrates in cells, resulting
in inhibition of cell growth stimulation and reversal of the
phenotype of ras-transformed cells [Dudley, D. T.; Pang, L.;
Decker, S. J.; Bridges, A. J.; Saltiel, A. R., Proc. Nat. Acad.
Sci., 92, 7686, (1995)]. Since, as demonstrated below, the
compounds of this invention can inhibit the coupled action of MEK
and ERK, they are useful for the treatment of diseases such as
cancer which are characterized by uncontrolled cell proliferation
and which, at least in part, depend on the MAPK pathway.
[0005] As mentioned above, members of the raf family of kinases
phosphorylate serine residues on MEK. There are three
serine/threonine kinase members of the raf family known as a-rat
b-raf and c-raf. While mutations in the raf genes are rare in human
cancers, c-raf is activated by the ras oncogene which is mutated in
a wide number of human tumors. Therefore inhibition of the kinase
activity of c-raf may provide a way to prevent ras mediated tumor
growth [Campbell, S. L., Oncogene, 17, 1395 (1998)].
[0006] The Src family of cytoplasmic protein tyrosine kinases
consists of at least eight members (Src, Fyn, Lyn, Yes, Lck, Fgr,
Hck and Blk) that participate in a variety of signaling pathways
[Schwartzberg, P. L., Oncogene, 17, 1463-1468, (1998)]. The
prototypical member of this tyrosine kinase family is p60.sup.src
(Src). Src is involved in proliferation and migration responses in
many cell types. In limited studies, Src activity has been shown to
be elevated in breast, colon (.about.90%), pancreatic (>90%) and
liver (>90%) tumors. Greatly increased Src activity is also
associated with metastasis (>90%) and poor prognosis. Antisense
Src message impedes growth of colon tumor cells in nude mice
[Staley et al., Cell Growth & Differentiation., 8, 269-74,
(1997)], suggesting that Src inhibitors should slow tumor growth.
In addition to its role in cell proliferation, Src also acts in
stress response pathways, including the hypoxia response, and nude
mice studies with colon tumor cells expressing antisense Src
message have reduced vascularization [Ellis, et al., J. Biol.
Chem., 273, 1052-7 (1998)], which suggests that Src inhibitors
would be anti-angiogenic as well as anti-proliferative.
[0007] In addition to its role in cancer, Src also appears to play
a role in osteoporosis. Mice genetically engineered to be deficient
in src production were found to exhibit osteopetrosis, the failure
to resorb bone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J.
Clin., Invest., 90, 1622 (1992)]. This defect was characterized by
a lack of osteoclast activity. Since osteoclasts normally express
high levels of Src, inhibition of Src kinase activity may be useful
in the treatment of osteoporosis [Missbach, M., Bone, 24, 437
(1999)].
[0008] In addition to EGFr, there are several other RTKs including
FGFr, the receptor for fibroblast growth factor (FGF); flk-1, also
known as KDR, and flt-1, the receptors for vascular endothelial
growth factor (VEGF); and PDGFr, the receptor for platelet derived
growth factor (PDGF). The formation of new blood vessels, a process
known as angiogenesis, is essential for tumor growth. Two natural
angiogenesis inhibitors, angiostatin and endostatin dramatically
inhibited the growth of a variety of solid tumors. [O'Reilly, M.
S., Cell, 79, 315 (1994); O'Reilly, M. S., Nature Medicine, 2, 689
(1996); O'Reilly, M. S., Cell, 88, 277 (1997)]. Since FGF and VEGF
are known to stimulate angiogenesis, inhibition of the kinase
activity of their receptors should block the angiogenic effects of
these growth factors. In addition, the receptor tyrosine kinases
tie-1 and tie-2 also play a key role in angiogenesis [Sato, T. N.,
Nature, 376, 70 (1995)]. Compounds of the invention that inhibit
the kinase activity of FGFr, flk-1, flt-1, tie-1 or tie-2 may
inhibit tumor growth by their effect on angiogenesis. Normal
angiogenesis is required in many physiological conditions such as
wound healing, female reproduction and fetal development. Abnormal
or pathological angiogenesis has been implicated in neoplastic
diseases including solid tumor growth, metastasis, and Karposi's
sarcoma; various eye diseases including diabetic retinopathy, and
macular degeneration; inflammatory conditions including rheumatoid
arthritis, and osteoarthritis; skin diseases including psoriasis,
eczema and scleroderma; as well as ulcerative colitis and childhood
haemangiomas [Toi, M. et al., Breast Cancer Res. And Treat, 36,
192-204 (1995); Folkman, J., Nature Medicine, 1, 27-31 (1995);
Jackson, J. R. et al., FASEB J, 11, 457-465 (1997)]. Inhibition of
VEGF function has been shown to inhibit disease progression in
tumors [Borgstrom, P. et al., Cancer Res., 56, 4032-4039 (1996);
Kim, J. K. et al., Nature, 362, 841-844 (1993)] and retinal
neovascularization [Aiello, L. P. et al., Proc. Nat. Acad. Sci.,
92, 10457-10461 (1995)] as well as vascular dysfunction mediated by
glucose in models of diabetes [Tilton, R. G. et al., J. Clin.
Invest., 99, 2192-2202 (1997)].
[0009] PDGF is a potent growth factor and chemoattractant for
smooth muscle cells (SMCs) and the renarrowing of coronary arteries
following angioplasty is due in part to the enhanced proliferation
of SMCs in response to increased levels of PDGF. Therefore,
compounds that inhibit the kinase activity of PDGFr may be useful
in the treatment of restenosis. In addition, since PDGF and PDGFr
are overexpressed in several types of human gliomas, small
molecules capable of suppressing PDGFr activity, have potential
utility as anticancer therapeutics [Nister, M., J. Biol. Chem. 266,
16755 (1991); Strawn, L. M., J. Biol. Chem. 269, 21215 (1994)].
[0010] In accordance with the present invention, the tricyclic ring
systems described herein will be numbered as indicated in the
representative formulas below (where U=N or O or S): ##STR2##
[0011] No fully aromatic fused tricyclic compounds containing
nicotinonitrile rings have been reported that have biological
activity as inhibitors of protein tyrosine kinases.
3-Cyanoquinoline derivatives described in WO-9843960 have been
disclosed as inhibitors of tyrosine kinase. A 3-cyanoquinoline with
a 4-(2-methyl anilino) substituent having gastric
(H.sup.+/K.sup.+)-ATPase inhibitory activity at high concentrations
has been described [Ife R. J., et al., J. Med. Chem., 35(18), 3413
(1992)]. However, there are no references to any fully aromatic
tricyclic compounds containing nicotinonitrile rings in the above
publications.
[0012] In WO-9713760, a series of fused tricyclic compounds
containing pyridine rings (and pyrimidines) that are reported to be
inhibitors of protein tyrosine kinases is disclosed. However, it is
specified that the position meta to the pyridine nitrogen bears a
hydrogen atom only. No compounds possessing cyano substituents at
this position are claimed. In two patents: AU 8767450 and U.S. Pat.
No. 4,952,584, 4-amino-9H-pyrido-(2,3-b)-indole-3-carboxylic acid
derivatives are disclosed as anxiolytic and antidepressant agents.
No corresponding 3-cyano substituents are claimed. In EP 755934,
fused tricyclic compounds containing nicotinonitrile rings are
disclosed as endothelin receptor antagonists. However, these
derivatives do not have the unique combination of substituents
contained in the compounds of the present invention. In particular,
it is specified that these compounds possess aromatic substituents
directly attached to the position para to the pyridine nitrogen.
Such substituents are not claimed in the present invention.
Similarly, a series of compounds claimed in WO 9705137 do include
tricyclics containing nicotinonitrile rings, but with hydrogen or
simple alkyl chains attached to the position para to the pyridine
nitrogen. Such substituents are not claimed in the present
invention. Several patents exist which disclose substituted
quinoline compounds as tyrosine kinase inhibitors, none of which
possess the 3-cyano substituent: 1. An international patent
WO-9813350 describing 3-fluoroquinoline and quinoline tyrosine
kinase inhibitors. 2. WO-9609294 discloses inhibitors of protein
tyrosine kinases that include 4-anilino quinolines with a large
variety of substituents on positions 5-8 but which must also have a
hydrogen atom at position 3. 3. U.S. Pat. No. 5,480,883 discloses
quinoline derivatives that are inhibitors of protein tyrosine
kinases but these derivatives do not have the unique combination of
substituents, including the 3-cyano group, contained in the
compounds of the present invention.
[0013] In addition to the above-mentioned compounds, certain
tricyclics containing pyrimidine rings are known to be inhibitors
of protein tyrosine kinases. WO-9749688, WO-9519970, U.S. Pat. No.
5,679,683 and the previously-mentioned WO-9713760 disclose a
variety of tricyclic heterocycles which are tyrosine kinase
inhibitors. Other patent applications WO-9802434, WO-9730044 and
EP-837063 describe quinazolines substituted at positions 5 to 8
with one or more optionally substituted 5- or 6-membered
heterocyclic rings.
[0014] In addition to the aforementioned patent applications, a
number of publications describe fused tricyclics containing
4-anilinopyrimidine rings: Rewcastle G. W., et. al., J. Med. Chem.,
39, 918 (1996); Bencteux, E., et. al., J. Heterocycl. Chem., 34,
1375, (1997); Palmer B. D., et. al. J. Med. Chem., 40, 1519 (1997);
and Zhou, H., et. al., Book of Abstracts, 210.sup.th ACS National
Meeting, Chicago, Ill., Aug. 20-24 (1995), Issue Pt. 2, MEDI-017.
There are no publications that describe fused tricyclic tricyclic
compounds containing nicotinonitrile rings as PTK inhibitors.
SUMMARY OF THE INVENTION
[0015] The present invention relates to certain protein kinase
inhibitors of formula 1 having the structure: ##STR3## wherein:
[0016] Ar is cycloalkyl of 3 to 7 carbon atoms, which may be
optionally substituted with one or more alkyl of 1 to 6 carbon
atoms; or [0017] Ar is a pyridinyl, pyrimidinyl, or phenyl ring;
wherein the pyridinyl, pyrimidinyl, or phenyl ring may be
optionally mono-, di-, or tri-substituted with substituents
selected from the group consisting of halogen, alkyl of 1-6 carbon
atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl
of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy
of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,
trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7
carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8
carbon atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of
1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,
N,N-alkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9
carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms,
mercapto, methylmercapto and benzoylamino; or [0018] Ar is a
bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms
where the bicyclic heteroaryl ring may contain 1 to 4 heteroatoms
selected from N, O, and S wherein the bicyclic aryl or bicyclic
heteroaryl ring may be optionally mono-di-, tri, or
tetra-substituted with substituent(s) independently selected from
the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1-6
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl,
alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon
atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,
hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of
2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, phenoxy, phenyl,
thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon
atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino,
benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of
3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl
of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms,
aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon
atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or
[0019] Ar is the radical: ##STR4## [0020] A' is a pyridinyl,
pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or
phenyl ring may be optionally mono- or di-substituted with a
substituent(s) independently selected from the group consisting of
alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of
2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halogen,
halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of
2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6
carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of
1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,
phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,
alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon
atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8
carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of
2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; [0021]
T is substituted on A' at carbon and is --NH(CH.sub.2).sub.m--,
--O(CH.sub.2).sub.m--, --S(CH.sub.2).sub.m--,
--NR(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mNH--, --CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mS--, --SO(CH.sub.2).sub.m--,
--SO.sub.2(CH.sub.2).sub.m--, --CO(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mCO--, --(CH.sub.2).sub.mSO--,
--(CH.sub.2).sub.mSO.sub.2-- or --(CH.sub.2).sub.mNR--; [0022] L is
a phenyl ring that is optionally substituted with one, two, or
three substituent(s) independently selected from the group
consisting of alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6
carbon atoms, halogen, halomethyl, alkoxymethyl of 2-7 carbon
atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon
atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl,
cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl
of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl,
amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12
carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of
3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl
of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; or
[0023] L is a 5- or 6-membered heteroaryl ring where the heteroaryl
ring contains 1 to 3 heteroatoms selected from N, O, and S and
where the heteroaryl ring may be optionally mono- or di-substituted
with substituent(s) selected from the group consisting of halogen,
oxo, thiocarbonyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6
carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,
alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon
atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,
alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon
atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8
carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of
2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms,
N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of
4-10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1-6
carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8
carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, and benzoylamino; [0024]
m is 0-3; [0025] n is 0-1; [0026] X is NH, O, S, or NR; [0027] R is
alkyl of 1-6 carbon atoms; [0028] Y and Z are both carbon or N; the
ring structure of formula 1 then being a fused 5,6,6 or 6,6,6
tricycle; or one of Y and Z is N, O or S, and the other is a bond
between the two end rings; the ring structure of formula 1 then
being a fused 5,5,6 or 6,5,6 tricycle; or one of Y or Z is N with
the other being carbon; the ring structure of formula 1 then being
a fused 5,6,6 or 6,6,6 tricycle; ##STR5## [0029] A and D are each,
independently, carbon, N, O, or S; [0030] B is carbon or N; [0031]
the dashed line indicates an optional double bond; [0032] R.sub.1,
R.sub.2, R.sub.3, and R.sub.4 are each, independently, not present,
hydrogen, halogen, hydroxy, amino, hydroxyamino, trifluoromethyl,
trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl
of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6
carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms,
alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of
2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino
of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms,
alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl
group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7
carbons, carboalkoxyalkyl of 3-8 carbon atoms, ##STR6## [0033]
R.sub.5 is independently hydrogen, alkyl of 1-6 carbon atoms,
aminoalkyl of 1-6 carbon atoms, N-alkylaminoalkyl of 2-9 carbon
atoms, N,N-dialkylaminoalkyl of 3-12 carbon atoms,
N-cycloalkylaminoalkyl of 4-12 carbon atoms,
N-cycloalkyl-N-alkylaminoalkyl of 5-18 carbon atoms,
N,N-dicycloalkylaminoalkyl of 7-18 carbon atoms, morpholino-N-alkyl
wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl
wherein the alkyl group is 1-6 carbon atoms,
N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1-6 carbon
atoms, azacycloalkyl-N-alkyl of 3-11 carbon atoms, hydroxyalkyl of
1-6 carbon atoms, alkoxyalkyl of 2-8 carbon atoms, or phenyl;
[0034] V is (CH.sub.2).sub.m, O, S, or NR.sub.6; [0035] R.sub.7 is
NR.sub.6R.sub.6, OR.sub.6, J, N(R.sub.6).sub.3.sup.+, or
NR.sub.6(OR.sub.6); [0036] M is NR.sub.6, O, S,
N--[(C(R.sub.6).sub.2).sub.pNR.sub.6R.sub.6], or
N--[(C(R.sub.6).sub.2).sub.p--OR.sub.6]; [0037] W is NR.sub.6, O,
S, or is a bond; [0038] Het is a heterocycle selected from the
group consisting of morpholine, thiomorpholine, thiomorpholine
S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine,
aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole,
thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene,
tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane
pyrrole, and tetrahydropyran; wherein the heterocycle is optionally
mono- or di-substituted on carbon or nitrogen with R.sub.6;
optionally mono- or di-substituted on carbon with hydroxy,
--N(R.sub.6).sub.2, or --OR.sub.6; optionally mono or
di-substituted on carbon with the mono-valent radicals
--(C(R.sub.6).sub.2).sub.sOR.sub.6 or
--[(C(R.sub.6).sub.2).sub.sN(R.sub.6).sub.2]; or optionally mono or
di-substituted on a saturated carbon with divalent radicals .dbd.O
or --O(C(R.sub.6).sub.2).sub.sO--; [0039] Ph is a phenyl ring
optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6
carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl,
carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl,
--N(R.sub.6).sub.2, --OR.sub.6, --(C(R.sub.6).sub.2).sub.sOR.sub.6,
--[(C(R.sub.6).sub.2).sub.sN(R.sub.6).sub.2], or
--(C(R.sub.6).sub.2).sub.kHet; [0040] R.sub.6 is hydrogen, alkyl of
1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7
carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of
1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or
carboxyalkyl of 2-7 carbon atoms; or [0041] R.sub.6 is phenyl
optionally mono-, di-, or tri-substituted with substituent(s)
independently selected from halogen, alkoxy of 1-6 carbon atoms,
trifluoromethyl, amino, alkylamino of 1-3 carbon atoms,
dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl,
alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon
atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl,
alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy,
benzoyl, benzyl, phenylamino, benzylamino; alkanoylamino of 1-6
carbon atoms or alkyl of 1-6 carbon atoms; [0042] R.sub.8 and
R.sub.9 are each, independently,
--[(C(R.sub.6).sub.2).sub.rNR.sub.6R.sub.6], and
--[(C(R.sub.6).sub.2).sub.r OR.sub.6]; [0043] J is independently
hydrogen, chlorine, fluorine, or bromine; [0044] g=1-6; [0045]
k=0-4; [0046] p=2-4; [0047] q=0-4; [0048] s=1-6; [0049] or a
pharmaceutically acceptable salt thereof; ##STR7## [0050] at least
one of the bonds between A and B or B and D must be a double bond,
with the other being a single bond; [0051] at least one of A, B,
and D are not carbon; [0052] only one of A, B, or D can be O or S;
[0053] when A, B, or D is O or S, the adjacent atoms must be
carbon; [0054] provided that when R.sub.5 is bound to a nitrogen
atom, the resulting structures do not include --N--C--N-- or
--O--C--N-- radicals; and when R.sub.5 is bound to an oxygen atom,
the resulting structures do not include an --N--C--O-- radical;
[0055] provided that when R.sub.6 is alkenyl of 2-7 carbon atoms or
alkynyl of 2-7 carbon atoms, the alkenyl or alkynyl moieties are
bound to a nitrogen or oxygen atom through a saturated carbon atom
in the alkenyl or alkynyl chain; [0056] provided that when V is
NR.sub.6 and R.sub.7 is NR.sub.6R.sub.6, N(R.sub.6).sub.3.sup.+, or
NR.sub.6(OR.sub.6), then g=2-6; [0057] provided that when M is O or
S and R.sub.7 is OR.sub.6, then p=1-4; [0058] provided that when V
is NR.sub.6, O, S, then k=2-4; [0059] provided that when V is O or
S and M or W is O or S, then k=1-4 [0060] provided that when W is
not a bond with Het bonded through a nitrogen atom then q=2-4; and
[0061] finally provided when W is a bond with Het bonded through a
nitrogen atom and V is O or NR.sub.6 or S, then k=2-4. The present
invention also relates to a method for making compounds of formula
1 and methods of using the compounds of formula 1.
DESCRIPTION OF THE INVENTION
[0062] The present invention relates to substituted aromatic
tricyclic compounds containing nicotinonitrile rings of formula 1
above as well as the pharmaceutically acceptable salts thereof. The
compounds of the present invention inhibit the action of certain
protein kinases, thereby inhibiting the abnormal growth of
particular cell types. The compounds of this invention are
therefore useful for the treatment or inhibition of certain
diseases that are the result of deregulation of these protein
kinases. The compounds of this invention are anti-cancer agents and
are useful for the treatment or inhibition of cancer in mammals. In
addition, the compounds of this invention are useful for the
treatment and inhbition of polycystic kidney disease and colonic
polyps.
[0063] The pharmaceutically acceptable salts are any conventionally
known salts useful in the pharmaceutical industry including those
derived from such organic and inorganic acids such as: acetic,
lactic, citric, tartaric, succinic, maleic, malonic, gluconic,
hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, and similarly known acceptable acids.
[0064] In the present application in those cases in which a
substituent, moiety, or group is di-, tri-, and/or
tetra-substituted, it is understood that the 2, 3, and/or 4
substituents on the substituent, moiety, or group may be the same
or different.
[0065] It is understood by one skilled in the art that the
heteroaryl or bicyclic heteroaryl rings of the compounds of Formula
I do not contain O--O, S--S, or S--O bonds, as they would be
unstable. Preferred bicyclic aryl or bicyclic heteroaryl ring
systems include naphthalene, tetralin, indan, 1-indanone,
1,2,3,4-tetrahydroquinoline, naphthyridine, benzofuran,
3-oxo-1,3-dihydroisobenzofuran, benzothiophene,
1,1-dioxo-benzothiophene, indole, indoline
1,3-dioxo-2,3-dihydro-1H-isoindole, benzotriazole, 1H-indazole,
indoline, indazole, 1,3-benzodioxole, benzoxazole, purine,
phthalimide, coumarin, chromone, quinoline, terahydroquinoline,
isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyridine,
pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine,
pyrido[3,4-b]pyridine, 1H-pyrazole[3,4-d]pyrimidine,
1,4-benzodioxane, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone,
2-oxo-2,3-dihydrobenzthiazole, 1,2-methylenedioxybenzene,
2-oxindole, 1,4-benzisoxazine, benzothiazole, quinoxaline,
quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide,
quinazoline-N-oxide, benzoazine, phthalazine,
1,4-dioxo-1,2,3,4-tetrahydrophthalazine,
2-oxo-1,2-dihydro-quinoline,
2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine,
2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, or
cinnoline.
[0066] When L is a 5 or 6-membered heteroaryl ring, preferred
heteroaryl rings are pyridine, pyrimidine, imidazole, thiazole,
thiazolidine, pyrrole, furan, thiophene, oxazole, or
1,2,4-triazole.
[0067] Either or both rings of the bicyclic aryl or bicyclic
heteroaryl group may be fully unsaturated, partially saturated, or
fully saturated. An oxo substituent on the bicyclic aryl or
bicyclic heteroaryl moiety means that one of the carbon atoms has a
carbonyl group. A thiocarbonyl substituent on the bicyclic aryl or
bicyclic heteroaryl moiety means that one of the carbon atoms has a
thiocarbonyl group.
[0068] When L is a 5 or 6-membered heteroaryl ring, it may be fully
unsaturated, partially saturated, or fully saturated. The
heteroaryl ring can be bound to A' via carbon or nitrogen. An oxo
substituent on the heteroaryl ring means that one of the carbon
atoms has a carbonyl group. A thio substituent on the heteroaryl
ring means that one of the carbon atoms has a thiocarbonyl
group.
[0069] The alkyl portion of the alkyl, alkoxy, alkanoyloxy,
alkoxymethyl, alkanoyloxymethyl, alkylsulphinyl, alkylsulfonyl,
alkylsulfonamido, alkoxycarbonyl, carboxyalkyl, carboalkoxyalkyl,
alkanoylamino, N-alkylcarbamoyl, N,N-dialkylcarbamoyl,
N-alkylaminoalkoxy and N,N-dialkylaminoalkoxy include both straight
chain as well as branched carbon chains. The cycloalkyl portions of
cycloalkyl, N-cycloalkylamino, N-cycloalkyl-N-alkylaminoalkyl,
N,N-dicycloalkylaminoalkyl, cycloalkylthio and azacycloalkyl
substituents include both simple carbocycles as well as carbocycles
containing alkyl substituents. The alkenyl portion of the alkenyl,
alkenyloxy, alkenylsulfonamido, substituents include both straight
chain as well as branched carbon chains and one or more sites of
unsaturation and all possible configurational isomers. The alkynyl
portion of the alkynyl, alkynylsulfonamido, alkynyloxy,
substituents include both straight chain as well as branched carbon
chains and one or more sites of unsaturation. Carboxy is defined as
a --CO.sub.2H radical. Alkoxycarbonyl of 2-7 carbon atoms is
defined as a --CO.sub.2R'' radical, where R'' is an alkyl radical
of 1-6 carbon atoms. Carboxyalkyl is defined as a HO.sub.2C--R'''--
radical where R''' is a divalent alkyl radical of 1-6 carbon atoms.
Carboalkoxyalkyl is defined as a R''O.sub.2C--R'''-- radical where
R''' is a divalent alkyl radical and where R'' and R''' may be the
same or different, and together have 2-7 carbon atoms. Alkanoyl is
defined as a --COR'' radical, where R'' is an alkyl radical of 1-6
carbon atoms. Alkenoyl is defined as a --COR'' radical, where R''
is an alkenyl radical of 2-6 carbon atoms. Alkanoyloxy is defined
as a --OCOR'' radical, where R'' is an alkyl radical of 1-6 carbon
atoms. Alkanoyloxymethyl is defined as R''CO.sub.2CH.sub.2--
radical, where R'' is an alkyl radical of 1-6 carbon atoms.
Alkoxymethyl is defined as R''OCH.sub.2-- radical, where R'' is an
alkyl radical of 1-6 carbon atoms. Alkylsulphinyl is defined as
R''SO-- radical, where R'' is an alkyl radical of 1-6 carbon atoms.
Alkylsulfonyl is defined as R''SO.sub.2-- radical, where R'' is an
alkyl radical of 1-6 carbon atoms. Alkylsulfonamido,
alkenylsulfonamido, alkynylsulfonamido are defined as
R''SO.sub.2NH-- radical, where R'' is an alkyl radical of 1-6
carbon atoms, an alkenyl radical of 2-6 carbon atoms, or an alkynyl
radical of 2-6 carbon atoms, respectively. N-alkylcarbamoyl is
defined as R''NHCO-- radical, where R'' is an alkyl radical of 1-6
carbon atoms. N,N-dialkylcarbamoyl is defined as R''R'NCO--
radical, where R'' is an alkyl radical of 1-6 carbon atoms, R' is
an alkyl radical of 1-6 carbon atoms and R' and R'' may be the same
or different.
[0070] Het is a heterocycle, as defined above which in some cases
when Het is substituted with .dbd.O (carbonyl), the carbonyl group
can be hydrated. Het may be bonded to W when q=0 via a carbon atom
on the heterocyclic ring, or when Het is a nitrogen containing
heterocycle which also contains a saturated carbon-nitrogen bond,
such heterocycle may be bonded to carbon, via the nitrogen when W
is a bond. When q=0 and Het is a nitrogen containing heterocycle
which also contains an unsaturated carbon-nitrogen bond, that
nitrogen atom of the heterocycle may be bonded to carbon when W is
a bond and the resulting heterocycle will bear a positive charge.
When Het is substituted with R.sub.6, such substitution may be on a
ring carbon, or in the case of a nitrogen containing heterocycle,
which also contains a saturated carbon-nitrogen, such nitrogen may
be substituted with R.sub.6 or in the case of a nitrogen containing
heterocycle, which also contains an unsaturated carbon-nitrogen,
such nitrogen may be substituted with R.sub.6 in which case the
heterocycle will bear a positive charge. Preferred heterocycles
include pyridine, 2,6-disubstituted morpholine, 2,5-disubstituted
thiomorpholine, 2-substituted imidazole, substituted thiazole,
N-substituted imidazole, N-subsitituted 1,4-piperazine,
N-subsitituted piperidine, and N-substituted pyrrolidine.
[0071] The compounds of this invention may contain one or more
asymmetric carbons atoms; in such cases, the compounds of this
invention include the individual diasteromers, the racemates, and
the individual R and S enantiomers thereof. Some of the compounds
of this invention may contain one or more double bonds; in such
cases, the compounds of this invention include each of the possible
configurational isomers as well as mixtures of these isomers.
[0072] Preferred compounds of the invention are selected from:
##STR8## ##STR9## wherein Ar, R.sub.1, R.sub.2, R.sub.3 and R.sub.4
are as defined above.
[0073] More preferred compounds of this invention are described
below. Except as otherwise indicated below, the substituents are as
defined above.
[0074] A Compounds according to the formula 1, having the structure
##STR10## [0075] or a pharmaceutically acceptable salt thereof.
[0076] B. Compounds according to formula 1, having the structure
##STR11## [0077] X is selected from NH sulfur or oxygen; [0078] or
a pharmaceutically acceptable salt thereof.
[0079] C. Compounds according to formula 1, having the structure
##STR12## [0080] X is selected from NH, sulfur, or oxygen; [0081]
or a pharmaceutically acceptable salt thereof.
[0082] D. Compounds according to formula 1, having the structure
##STR13## wherein [0083] R.sub.2 is hydrogen, amino,
trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, alkenyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon
atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl
of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8
carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8
carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of
1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, cyano,
carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon
atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy,
benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon
atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon
atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, ##STR14## [0084] or a pharmaceutically acceptable
salt thereof;
[0085] E. Compounds according to formula 1, having the structure
##STR15## [0086] R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl
of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon
atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6
carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy
of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of
1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, ##STR16##
[0087] F. Compounds according to formula 1 having the structure
##STR17## [0088] R.sub.1 is hydrogen, hydroxymethyl, aminomethyl,
N-alkylaminomethyl of 2-6 carbon atoms, N,N-dialkylaminomethyl of
3-12 carbon atoms, N-cycloalkylaminomethyl of 4-9 carbon atoms,
N-cycloalkyl-N-alkylaminoalkyl of 5-16 carbon atoms,
N,N-dicycloalkylaminomethyl of 7-18 carbon atoms,
morpholino-N-methyl, piperidino-N-methyl,
N-alkyl-piperazino-N-methyl wherein the alkyl group is 1-6 carbon
atoms, azacycloalkyl-N-methyl of 3-6 carbon atoms,
N-(hydroxyalkyl)aminomethyl of 3-7 carbon atoms,
N,N-di(hydroxyalkyl)aminomethyl of 5-12 carbon atoms,
N-(hydroxycycloalkyl)aminomethyl of 4-9 carbon atoms,
N-(hydroxycycloalkyl)-N-(hydroxyalkyl)aminoalkyl of 6-16 carbon
atoms, or N,N-di(hydroxycycloalkyl)aminomethyl of 7-18 carbon
atoms; [0089] R.sub.2 is hydrogen; [0090] R.sub.3 is hydrogen,
alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, hydroxyalkyl of
2-6 carbon atoms; mercaptoalkyl of 2-6 carbon atoms, phenyl,
benzyl, ##STR18## [0091] or a pharmaceutically acceptable salt
thereof.
[0092] G. Compounds according to formula 1, having the structure
##STR19## [0093] R.sub.2 and R.sub.3 are hydrogen; [0094] or a
pharmaceutically acceptable salt thereof.
[0095] H. Compounds according to formula 1, having the structure
##STR20## [0096] R.sub.3 is hydrogen; [0097] or a pharmaceutically
acceptable salt thereof.
[0098] I. Compounds according to formula 1, having the structure
##STR21## [0099] R.sub.2 is hydrogen, amino, hydroxyamino,
trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, alkenyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon
atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl
of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8
carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8
carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of
1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms,
alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6
carbon atoms, cyano, carboxy, alkoxycarbonyl of 2-7 carbon atoms,
alkanoyl of 2-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12
carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino,
alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms,
alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7
carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of
1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, ##STR22##
[0100] R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl
of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, hydroxyalkyl of 2-6 carbon atoms; mercaptoalkyl of
2-6 carbon atoms, phenyl, benzyl, ##STR23## [0101] a
pharmaceutically acceptable salt thereof.
[0102] J. Compounds according to the formula 1, having the
structure ##STR24## [0103] or a pharmaceutically acceptable salt
thereof.
[0104] K. Compounds according to formula 1, having the structure
##STR25##
[0105] Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0106] Ar is the radical:
##STR26## [0107] R.sub.1 and R.sub.4 are hydrogen; [0108] or a
pharmaceutically acceptable salt thereof.
[0109] L. Compounds according to formula 1, having the structure
##STR27## [0110] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0111] Ar is the radical:
##STR28## [0112] R.sub.4 is hydrogen and [0113] one or two of the
substituents R.sub.1, R.sub.2 and R.sub.3 are as defined above, the
remaining being hydrogen; [0114] or a pharmaceutically acceptable
salt thereof.
[0115] M. Compounds according to formula 1, having the structure
##STR29## [0116] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0117] Ar is the radical:
##STR30## [0118] R.sub.4 is hydrogen and [0119] one or two of the
substituents R.sub.1, R.sub.2 and R.sub.3 are as herein above
described, [0120] the remaining being hydrogen; [0121] or a
pharmaceutically acceptable salt thereof.
[0122] N. Compounds according to formula 1, having the structure
##STR31## [0123] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0124] Ar is the radical:
##STR32## [0125] R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl
of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon
atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6
carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy
of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of
1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, ##STR33## [0126] or a pharmaceutically acceptable
salt thereof.
[0127] O. Compounds according to formula 1, having the structure
##STR34## [0128] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0129] Ar is the radical:
##STR35## [0130] R.sub.2 is hydrogen, amino, trifluoromethyl, alkyl
of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon
atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6
carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy
of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of
1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, ##STR36## [0131] or a pharmaceutically acceptable
salt thereof.
[0132] P. Compounds according to formula 1, having the structure
##STR37## [0133] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0134] Ar is the radical:
##STR38## [0135] R.sub.1 is hydrogen, hydroxymethyl, aminomethyl,
N-alkylaminomethyl of 2-6 carbon atoms, N,N-dialkylaminomethyl of
3-12 carbon atoms, N-cycloalkylaminomethyl of 4-9 carbon atoms,
N-cycloalkyl-N-alkylaminoalkyl of 5-16 carbon atoms,
N,N-dicycloalkylaminomethyl of 7-18 carbon atoms,
morpholino-N-methyl, piperidino-N-methyl,
N-alkyl-piperazino-N-methyl wherein the alkyl group is 1-6 carbon
atoms, azacycloalkyl-N-methyl of 3-6 carbon atoms,
N-(hydroxyalkyl)aminomethyl of 3-7 carbon atoms,
N,N-di(hydroxyalkyl)aminomethyl of 5-12 carbon atoms,
N-(hydroxycycloalkyl)aminomethyl of 4-9 carbon atoms,
N-(hydroxycycloalkyl)-N-(hydroxyalkyl)aminoalkyl of 6-16 carbon
atoms, or N,N-di(hydroxycycloalkyl)aminomethyl of 7-18 carbon
atoms; [0136] R.sub.2 is hydrogen; [0137] R.sub.3 is hydrogen,
alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, hydroxyalkyl of
2-6 carbon atoms; mercaptoalkyl of 2-6 carbon atoms, phenyl,
benzyl, ##STR39## [0138] or a pharmaceutically acceptable salt
thereof.
[0139] Q. Compounds according to formula 1, having the structure
##STR40##
[0140] Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0141] Ar is the radical:
##STR41## [0142] R.sub.2 and R.sub.3 are hydrogen; [0143] or a
pharmaceutically acceptable salt thereof.
[0144] R. Compounds according to formula 1, having the structure
##STR42##
[0145] Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0146] Ar is the radical:
##STR43## [0147] R.sub.3 is hydrogen; [0148] or a pharmaceutically
acceptable salt thereof.
[0149] S. Compounds according to formula 1, having the structure
##STR44## [0150] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0151] Ar is the radical:
##STR45## [0152] R.sub.2 is hydrogen, amino, hydroxyamino,
trifluoromethyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon
atoms, alkenyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon
atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl
of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8
carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8
carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of
1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms,
alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6
carbon atoms, cyano, carboxy, alkoxycarbonyl of 2-7 carbon atoms,
alkanoyl of 2-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12
carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino,
alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms,
alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7
carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms,
benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of
1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, ##STR46##
[0153] R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl
of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, hydroxyalkyl of 2-6 carbon atoms; mercaptoalkyl of
2-6 carbon atoms, phenyl, benzyl, ##STR47## [0154] or a
pharmaceutically acceptable salt thereof.
[0155] T. Compounds according to formula 1, having the structure
##STR48## [0156] Ar is a phenyl ring which may be optionally mono-,
di- or tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or [0157] Ar is the radical:
##STR49## [0158] R.sub.1 and R.sub.4 are hydrogen; [0159] or a
pharmaceutically acceptable salt thereof.
[0160] Another group of preferred compounds of the present
invention are those in which:
[0161] 1) Ar is a phenyl ring which may be optionally mono-, di- or
tri-substituted with a substituent selected from the group
consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,
alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms,
dialkylamino of 2-12 carbon atoms, alkanoylamino of 1-6 carbon
atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8
carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8
carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl,
N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13
carbon atoms, and benzoylamino; or
[0162] Ar is the radical: ##STR50##
[0163] 2) X is N, S, or O;
[0164] 3) R.sub.2 is hydrogen, amino, trifluoromethyl alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms,
hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon
atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6
carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6
carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsulphinyl of
1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms,
alkylsulfonamido of 1-6 carbon atoms, cyano, carboxy,
alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms,
phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl,
alkylamino of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon atoms,
alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,
carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms,
N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12
carbon atoms, ##STR51##
[0165] It being especially preferred when R.sub.2 is H;
[0166] 4) R.sub.1 is hydrogen, hydroxymethyl aminomethyl,
N-alkylaminomethyl of 2-6 carbon atoms, N,N-dialkylaminomethyl of
3-12 carbon atoms, N-cycloalkylaminomethyl of 4-9 carbon atoms,
N-cycloalkyl-N-alkylaminoalkyl of 5-16 carbon atoms,
N,N-dicycloalkylaminomethyl of 7-18 carbon atoms,
morpholino-N-methyl, piperidino-N-methyl,
N-alkyl-piperazino-N-methyl wherein the alkyl group is 1-6 carbon
atoms, azacycloalkyl-N-methyl of 3-6 carbon atoms,
N-(hydroxyalkyl)aminomethyl of 3-7 carbon atoms,
N,N-di(hydroxyalkyl)aminomethyl of 5-12 carbon atoms,
N-(hydroxycycloalkyl)aminomethyl of 4-9 carbon atoms,
N-(hydroxycycloalkyl)-N-(hydroxyalkyl)aminoalkyl of 6-16 carbon
atoms, or N,N-di(hydroxycycloalkyl)aminomethyl of 7-18 carbon
atoms; and/or
[0167] 5) R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms,
cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, hydroxyalkyl of 2-6 carbon atoms;
mercaptoalkyl of 2-6 carbon atoms, phenyl, benzyl, ##STR52##
[0168] it being especially preferred when R.sub.3 is hydrogen;
[0169] Specifically preferred compounds of this invention include:
[0170] a) 4-(4-phenoxyanilino)benzo[g]quinoline-3-carbonitrile,
[0171] b)
4-(3-chloro-4-fluoroanilino)benzo[g]quinoline-3-carbonitrile,
[0172] c)
4-(4-chloro-5-methoxy-2-methylanilino)benzo[g]quinoline-3-carbonitrile-
, [0173] d)
7,8-dimethoxy-4-(4-phenoxyanilino)benzo[g]quinoline-3-carbonitrile,
[0174] e)
4-(4-chloro-5-methoxy-2-methylanilino)-7,8-dimethoxybenzo[g]quinoline-3-c-
arbonitrile, [0175] f)
4-(3-chloro-4-fluoroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitril-
e, [0176] g)
4-(2,4-dichloroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile,
[0177] h)
4-(2,4-dichloroanilino)-7,8-dihydroxybenzo[g]quinoline-3-carbonitrile,
[0178] i)
8-(3,4,5-trimethoxyanilino)-3H-[1,2,3]triazolo[4,5-g]quinoline-7-carbonit-
rile, [0179] j)
9-(4-chloro-5-methoxy-2-methylanilino)pyrido[2,3-g]quinoxaline-8-carbonit-
rile, [0180] k)
8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo[4,-
5-g]quinoline-7-carbonitrile, [0181] l)
2-{[2-(4-morpholinyl)ethyl]amino}-8-(3,4,5-trimethoxyanilino)imidazo[4,5--
g]quinoline-7-carbonitrile, [0182] m)
2-amino-8-(4-phenoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile,
[0183] n)
8-(3-bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile,
[0184] o)
8-(2-bromo-4-chlorophenylamino)imidazo[4,5-g]quinoline-7-carbonitrile,
[0185] p)
8-(2-bromo-4-chloro-5-methoxyphenylamino)imidazo[4,5-g]quinoline-7-carbon-
itrile, [0186] q)
8-(2-chloro-5-methoxyphenylamino)imidazo-[4,5-g]quinoline-7-carbonitrile,
[0187] r)
8-(3-hydroxy-4-methylphenylamino)imidazo[4,5-g]quinoline-7-carbonitrile,
[0188] s)
8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile,
[0189] t)
8-(4-phenoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile, [0190]
u)
2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-car-
bonitrile, [0191] v)
2-(4-morpholinylmethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinolin-
e-7-carbonitrile, [0192] w)
8-(4-chloro-5-methoxy-2-methylanilino)-3-[2-(4-morpholinyl)ethyl]-3H-imid-
azo[4,5-g]quinoline-7-carbonitrile, [0193] x)
3-[2-(4-morpholinyl)ethyl]-8-(4-phenoxyanilino)-3H-imidazo[4,5-g]quinolin-
e-7-carbonitrile, [0194] y)
8-[(4-chloro-5-methoxy-2-methylphenyl)amino]-thiazolo[4,5-g]quinoline-7-c-
arbonitrile, [0195] z)
4-(3-bromophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
[0196] aa)
4-(4-chloro-2-fluorophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carboni-
trile, [0197] bb)
4-(2,4-dichlorophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile-
, [0198] cc)
4-(2,4-dichloro-5-methoxyphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-ca-
rbonitrile, [0199] dd)
4-(4-phenoxyphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
[0200] ee)
4-(3-hydroxy-4-methylphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbon-
itrile, [0201] ff)
4-(4-chloro-2-fluorophenoxy)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitril-
e, [0202] gg)
4-(4-chloro-5-methoxy-2-methylphenylamino)-8-nitrobenzo[4,5]thieno[3,2-b]-
pyridine-3-carbonitrile, [0203] hh)
8-amino-4-(4-chloro-5-methoxy-2-methylanilino)[1]benzothieno[3,2-b]pyridi-
ne-3-carbonitrile, [0204] ii)
4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
[0205] jj)
6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
[0206] kk)
4-(3-bromophenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile,
[0207] ll)
4-(4-chloro-2-fluorophenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitr-
ile, [0208] mm)
4-(3-hydroxyl-4-methylphenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carboni-
trile, [0209] nn)
4-(4-phenoxyphenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile,
[0210] oo)
4-(4-chloro-2-fluorophenoxy)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile,
[0211] pp)
4-(2,4-dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitri-
le, [0212] qq)
4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
[0213] rr)
8-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
[0214] ss)
N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-8-yl]acrylamide-
, [0215] tt)
N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-6-yl]acrylamide-
, [0216] uu)
4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile,
[0217] vv)
4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile,
[0218] ww)
4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile,
[0219] xx)
4-(2,4-dichloroanilino)-8-hydroxybenzo[g]quinoline-3-carbonitrile,
[0220] yy)
4-(2,4-dichloroanilino)-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline-3-ca-
rbonitrile, [0221] zz)
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile, [0222] aaa)
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile, [0223] bbb)
4-(4-chloro-5-methoxy-2-methylamino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy-
]benzo[g]quinoline-3-carbonitrile, [0224] ccc)
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, [0225] ddd)
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile, [0226] eee)
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile, [0227] fff)
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]be-
nzo[g]quinoline-3-carbonitrile, [0228] ggg)
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]be-
nzo[g]quinoline-3-carbonitrile, [0229] hhh)
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile, [0230] iii)
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile, [0231] jjj)
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0232] kkk)
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0233] lll)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-
-methoxybenzo[g]quinoline-3-carbonitrile, [0234] mmm)
8-(2-Chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)pheny-
lamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, [0235] nnn)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, [0236]
ooo)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chloro-
propoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile, [0237] ppp)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile, [0238]
qqq)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile,
[0239] rrr)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,
[0240] sss)
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-meth-
oxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile,
[0241] ttt)
4-(2,4-Dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinolin-
e-3-carbonitrile, [0242] uuu)
8-(3-Chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[-
g]quinoline-3-carbonitrile, [0243] vvv)
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propo-
xy)benzo[g]quinoline-3-carbonitrile, [0244] www)
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, [0245] xxx)
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-1-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, [0246] yyy)
4-(2,4-Dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-
-3-carbonitrile, [0247] zzz)
8-(2-Chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,-
8]naphthyridine-3-carbonitrile, [0248] aaaa)
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]be-
nzo[b][1,8]naphthyridine-3-carbonitrile, [0249] bbbb)
8-(2-Chloroethoxy)-4-{3-chloro-4-[(1-methyl-H-imidazol-2-yl)sulfanyl]anil-
ino}-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile, [0250]
cccc)
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile, [0251] dddd)
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-methoxy-8-[-
2-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile,
[0252] eeee)
4-(2,4-Dichloroanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3--
carbonitrile, [0253] ffff)
8-(2-Chloroethoxy)-4-chloro-5-methoxy-2-methylanilino)-7-ethoxybenzo[g]qu-
inoline-3-carbonitrile, [0254] gggg)
8-(2-Chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-7-methoxybenzo[-
g]quinoline-3-carbonitrile, [0255] hhhh)
7-(2-Chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-8-methoxybenzo[-
g]quinoline-3-carbonitrile, [0256] iiii)
8-(2-Chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-7-methoxybe-
nzo[g]quinoline-3-carbonitrile, [0257] jjjj)
7-(2-Chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-8-methoxybe-
nzo[g]quinoline-3-carbonitrile, [0258] kkkk)
7-(2-Chloroethoxy)-4-(3-chloro-4-fluoroanilino)-8-methoxybenzo[g]quinolin-
e-3-carbonitrile, [0259] llll)
8-(2-Chloroethoxy)-4-(3-chloro-4-fluoroanilino)-7-methoxybenzo[g]quinolin-
e-3-carbonitrile, [0260] mmmm)
4-(4-Benzyloxy-3-chlorophenylamino)-7-(2-chloroethoxy)-8-methoxybenzo[g]q-
uinoline-3-carbonitrile, [0261] nnnn)
4-(4-Benzyloxy-3-chlorophenylamino)-8-(2-chloroethoxy)-7-methoxybenzo[g]q-
uinoline-3-carbonitrile, [0262] oooo)
7-(2-Chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-8-methoxybenzo[g]qui-
noline-3-carbonitrile, [0263] pppp)
8-(2-Chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-7-methoxybenzo[g]qui-
noline-3-carbonitrile, [0264] qqqq)
4-(4-Chloro-5-methoxy-2-methylanilino)-8-ethoxy-7-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile, [0265] rrrr)
4-(4-Chloro-5-methoxy-2-methylanilino)-7-ethoxy-8-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile, [0266] ssss)
({2-[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-8-ethoxybenzo[g]q-
uinoline-7-yloxy]-ethyl}-ethoxycarbonylmethyl-amino)-acetic acid
ethyl ester, [0267] tttt)
({2-[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-7-ethoxybenzo[g]q-
uinoline-8-yloxy]-ethyl}-ethoxycarbonylmethylamino)-acetic acid
ethyl ester, [0268] uuuu)
2-(Carbamoylmethyl-{2-[4-(4-chloro-5-methoxy-2-methylphenylamino)-3-cyano-
-7-ethoxybenzo[g]quinolin-8-yloxy]-ethyl}-amino)-acetamide, [0269]
vvvv)
4-(2,4-Dichloroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g]quin-
oline-3-carbonitrile, [0270] wwww)
4-(2,4-Dichloroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g]quin-
oline-3-carbonitrile, [0271] xxxx)
8-Methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5-trimethoxyanilino-
)benzo[g]quinoline-3-carbonitrile, [0272] yyyy)
7-Methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5)
trimethoxyanilino)benzo[g]quinoline-3-carbonitrile, [0273] zzzz)
7-Methoxy-8-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)benzo[g]-
quinoline-3-carbonitrile, [0274] aaaaa)
8-Methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)benzo[g]-
quinoline-3-carbonitrile, [0275] bbbbb)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0276] ccccc)
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0277] ddddd)
4-(2-Chloro-5-methoxy-4-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0278] eeeee)
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-hydroxy-1-piperidinyl)ethoxy]-8-
-methoxybenzo[g]quinoline-3-carbonitrile, [0279] fffff)
4-(3-Chloro-4-fluoroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g-
]quinoline-3-carbonitrile, [0280] ggggg)
4-(2,4-Dichloro-5-methoxyanilino)-8-[2-(4-hydroxy-1-piperidinyl)ethoxy]-7-
-methoxybenzo[g]quinoline-3-carbonitrile, [0281] hhhhh)
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-hydroxy-1-piperi-
dinyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0282] iiiii)
4-(2-Chloro-5-methoxy-4-methylanilino)-7-methoxy-8-[2-(4-hydroxy-1-piperi-
dinyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0283] jjjjj)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, [0284] kkkkk)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile, [0285] lllll)
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile, [0286] mmmmm)
4-(3-Chloro-4-fluoroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g-
]quinoline-3-carbonitrile, [0287] nnnnn)
4-(3-Chloro-4-phenoxyphenylamino)-7-methoxy-8-(2-morpholin-4-yl-ethoxy)be-
nzo[g]quinoline-3-carbonitrile, [0288] ooooo)
4-(3-Chloro-4-phenoxyphenylamino)-8-methoxy-7-(2-morpholin-4-yl-ethoxy)be-
nzo[g]quinoline-3-carbonitrile, [0289] ppppp)
4-(2-Chloro-5-methoxy-4-methylphenylamino)-8-methoxy-7-(2-morpholin-4-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, [0290] qqqqq)
4-(2-Chloro-5-methoxy-4-methylphenylamino)-7-methoxy-8-(2-morpholin-4-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, [0291] rrrrr)
4-(4-Benzyloxy-3-chlorophenylamino)-8-methoxy-7-(2-morpholin-4-yl-ethoxy)-
benzo[g]quinoline-3-carbonitrile, [0292] sssss)
4-(4-Benzyloxy-3-chlorophenylamino)-7-methoxy-8-(2-morpholin-4-yl-ethoxy)-
benzo[g]quinoline-3-carbonitrile, [0293] ttttt)
8-(Benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo-
[g]quinoline-3-carbonitrile, and [0294] uuuuu)
4-[(2-Chloro-4-fluoro-5-methoxyphenyl)amino]-8-hydroxy-7-methoxybenzo[g]q-
uinoline-3-carbonitrile, [0295] or a pharmaceutically acceptable
salt
thereof.
[0296] Also included in the present invention are compounds useful
as intermediates for producing the above compounds of formula 1.
Such intermediates specifically include the following: [0297] a)
4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile, [0298] b)
4-chlorobenzo[g]quinoline-3-carbonitrile, [0299] c)
3-(dimethylaminomethyleneamino)-6,7-dimethoxynaphthalene-2-carboxylic
acid methyl ester, [0300] d)
7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile,
[0301] e) 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile,
[0302] f)
7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-
-quinoline-3-carbonitrile, [0303] g)
6,7-diamino-4-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydro-quinoli-
ne-3-carbonitrile, [0304] h)
8-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,8-dihydro[1,2,3]triazolo[4,5-
-g]quinoline-7-carbonitrile, [0305] i)
8-oxo-5,8-dihydro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile,
[0306] j) 8-chloro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile,
[0307] k)
2-amino-8-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl-5,8-dihydroimidazo[4,5--
g]quinoline-7-carbonitrile, [0308] l)
2-amino-8-oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile,
[0309] m) 2-amino-8-chloroimidazo[4,5-g]quinoline-7-carbonitrile,
[0310] n) 8-oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitride,
[0311] o) 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, [0312] p)
7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide,
[0313] q)
7-cyanoimidazo[4,5-g]quinolin-8-yl(4-phenoxyphenyl)formamide,
[0314] r)
7-{[2-(4-morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, [0315] s)
6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, [0316] t)
3-[2-(4-morpholinyl)ethyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7-
-carbonitrile, [0317] u)
8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonit-
rile, [0318] v)
1,4-dihydro-7-mercapto-6-nitro-4-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-
-3-quinolinecarbonitrile, [0319] w)
8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile, [0320] x)
3-(dimethylaminomethyleneamino)benzo[b]thiophene-2-carboxylic acid
methyl ester, [0321] y)
4-hydroxybenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, [0322] z)
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, [0323] aa)
4-hydroxy-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
[0324] bb)
4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile,
[0325] cc)
4-chloro-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
[0326] dd) 3-(dimethylaminomethyleneamino)benzofuran-2-carboxylic
acid ethyl ester, [0327] ee)
4-hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile, [0328] ff)
4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile, [0329] gg)
7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile, [0330]
hh) 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile,
[0331] ii) 4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile,
[0332] jj) 4-chloro-8-methoxybenzo[g]quinoline-3-carbonitrile,
[0333] kk) ethyl 7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate,
[0334] ll) ethyl 6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate,
[0335] mm) ethyl 3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate,
[0336] nn) ethyl 3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate,
[0337] oo)
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carboni-
trile, [0338] pp)
7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carboni-
trile, [0339] qq)
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile,
[0340] rr)
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile,
[0341] ss)
7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile,
[0342] tt)
4-chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile,
[0343] uu)
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyrid-
ine-3-carbonitrile, and [0344] vv)
4-chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carboni-
trile.
[0345] The compounds and intermediates of this invention
encompassed by Formula 6 may be prepared as described below and in
Flowsheet 1 wherein Ar, X and n are hereinbefore defined. R.sub.1',
R.sub.2', R.sub.3' and R.sub.4' are each, independently, hydrogen,
halogen, hydroxy, amino, hydroxyamino, trifluoromethyl,
trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl
of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6
carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of
1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms,
alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms,
alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon
atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of
2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano,
nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7
carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl,
N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino
of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl,
thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, or
dialkylamino of 2 to 12 carbon atoms;
R.sub.7--C(R.sub.6).sub.2).sub.g--V--,
Ph-(C(R.sub.6).sub.2).sub.q--W--(C(R.sub.6).sub.2).sub.k--V--.
[0346] where V, R.sub.6, R.sub.7, W, Ph, g, k and q are as
hereinabove defined.
[0347] Reaction of 3-amino-2-naphthoic acids (Formula 2) with
dimethylformamide dimethyl acetal, with or without a solvent, gives
intermediates of Formula 3. The reaction of 3 with the lithium
anion of acetonitrile prepared by using a base such as
n-butyllithium or the like in an inert solvent gives
3-cyano-4-oxo-1,4-dihydrobenzo[g]quinolines 4 or the
3-cyano-4-hydroxybenzo[g]quinoline tautomers thereof. Heating 4,
with or without solvent, with a chlorinating agent such as
phosphorus oxychloride or oxalyl chloride provides the
corresponding 4-chloro-3-cyanobenzo[g]quinolines. Condensation of
4-chloro-3-cyanobenzo[g]quinolines with a nucleophilic amine,
aniline, mercaptan, thiophenol, phenol, or alcohol reagent of
Formula 5, HX--(CH.sub.2).sub.n--Ar, wherein Ar, X and n are as
hereinbefore defined, give the 3-cyanobenzo[g]quinolines of Formula
6. The condensation can be accelerated by heating the reaction
mixture together with one equivalent of pyridine hydrochloride or
by using bases such as trialkylamines, sodium hydride in an inert
solvent, sodium or potassium alkoxides in an alcohol solvent, or by
using transition metal catalysts such as
tris(dibenzylideneacetone)dipalladium(0) or the like, together with
ligands such as, but not limited to
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, and
potassium phosphate or the like in an inert solvent. In those cases
where the substituents may contain an asymmetric carbon atom, the
intermediates can be used as the racemate or as the individual R or
S enantiomers in which case the compounds of this invention will be
in the racemic or the R and S optically active forms, respectively.
In cases where the substituents may contain more than one
asymmetric carbon atoms, diastereomers may be present; these can be
separated by methods well known in the art including, but not
limited to, fractional crystallization and chromatographic methods.
When Ar contains primary or secondary amino groups or hydroxyl
groups, it may be necessary to protect these groups prior to the
reaction with the substituted 4-chloro-3-cyanobenzo[g]quinolines.
Suitable protecting groups include, but are not limited to
tert-butoxycarbonyl (BOC), .beta.-trimethylsilylethanesulfonamide
(SES), benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups.
The first protecting group listed above can be removed from the
final products of Formula 6 by treatment with an acid such as
trifluoroactic acid, the second protecting group with a fluoride
salt, such as cesium fluoride or tetrabutylammonium fluoride. The
latter two protecting groups can be removed by catalytic
hydrogenation or sodium in ammonia. In those cases where the Ar
contains hydroxyl groups, the hydroxyl groups may first have to be
protected prior to final product formation. Suitable protecting
groups include, but are not limited to, t-butyldimethylsilyl,
tetrahydropyranyl, or benzyl protecting groups. The first two
protecting groups listed above can be removed from the final
products of Formula 6 by treatment with an acid such as acetic acid
or hydrochloric acid while the latter protecting group can be
removed by catalytic hydrogenation. The 3-amino-2-naphthoic acids
of Formula 2 are commercially available or can be prepared by
procedures known in the art from compounds detailed by the
following references: Zhu, Z.; Drach, J. C.; Townsend, L. B. J.
Org. Chem., 63, 977-983, (1998); Kienzle, F. Helv. Chim. Acta, 63,
2364-2369, (1980), Kobayashi, K.; Kanno, C.; Seko, S.; Suginome, H.
J. Chem. Soc., Perkin Trans. 1., 3111-317, (1992), Levy, L. A.
Synth. Commun., 13, 639-48 (1983) and Moder, K. P.; Leonard, N. J.
J. Am. Chem. Soc., 104, 2613-24 (1982).
[0348] It will be recognized by those skilled in the art that the
4-hydroxy substituent of the benzoquinoline tautomer may be
converted to a leaving group such as halogen, tosyl, mesyl, aryl-
or alkyl-sulfonate, preferably trifluoromethanesulfonate and the
like. ##STR53##
[0349] Intermediate 3 can also be prepared as described below and
in Flowsheet 1'.
[0350] The reaction of substituted naphtho[2,3-c]furan-1,3-dione
compounds (McOmie, John F. W.; Perry, David H. Synthesis (1973),
Issue 7, 416-417) with an alcohol such as methanol, with or without
a base such as sodium hydride, provides substituted
3-(methoxycarbonyl)-2-naphthoic acids as a mixture of geometric
isomers if R.sub.1' differs from R.sub.4' and/or R.sub.2' differs
from R.sub.3'. Treatment of the 3-(methoxycarbonyl)-2-naphthoic
acids with diphenylphosphoryl azide and a base such as
triethylamine in an inert solvent, followed by workup with an
aqueous acetone solution or the like, provides the corresponding
substituted methyl 3-amino-2-naphthoates, which when reacted with
dimethylformamide dimethyl acetal, with or without a solvent,
provides intermediates of Formula 3 (and the geometric isomer 3' if
R.sub.1' differs from R.sub.4' and/or R.sub.2' differs from
R.sub.3'). Separation of the geometric isomers can be carried out
by silica gel chromatography or other purification methods at any
step in the preparation of intermediate of Formula 3. The
above-mentioned chemical transformations can be carried out
separately on each isomer. If a mixture of geometric isomers of
Formula 3 and 3' is converted to compounds of Formula 6, a
chromatographic separation can be carried out on the mixture of
products of Formula 6 or any of the intermediates formed in this
sequence. ##STR54## Intermediate 4 can also be prepared as
described below and in Flowsheet 1''.
[0351] The reaction of phenyl compounds with electron-rich R.sub.2'
and R.sub.3' substituents, such as alkoxy of 1 to 6 carbons or, for
example, a haloalkoxy moiety of the formula
R.sub.7--(C(R.sub.6).sub.2).sub.g--V-- where R.sub.6 is hydrogen,
R.sub.7 is a halogen, V is oxygen and g=2-6, with a solution of
formalin and hydrochloric acid provides substituted
1,2-bis(chloromethyl)benzene intermediates. Heating these
substituted 1,2-bis(chloromethyl)benzene intermediates with sodium
acetate in acetic acid provides the corresponding substituted
1,2-bis(acetyloxymethyl)benzene compounds which can be converted to
the corresponding 1,2-bis(hydroxymethyl)benzene intermediates by
reaction with a ammonia-saturated methanol or aqueous sodium
hydroxide. Oxidation of the substituted
1,2-bis(hydroxymethyl)benzene intermediates by oxalyl chloride,
dimethyl sulfoxide and triethylamine in an inert solvent such as
methylene chloride provides the substituted phthalaldehyde
intermediates. Reaction of the substituted phthalaldehyde
intermediates with an excess of a 3-nitropropanoate ester such as
ethyl 3-nitropropanoate (as described by Kienzle, F. Helv. Chim.
Acta, 63, 2364-2369, (1980)), and sodium ethoxide in ethanol
provides the corresponding ethyl 3-nitro-2-naphthoate intermediates
as a mixture of geometric isomers if R.sub.2' differs from
R.sub.3'. Reduction of the substituted ethyl 3-nitro-2-naphthoate
intermediates by catalytic hydrogenation over palladium-on-carbon
or platinum-on-carbon in tetrahydrofuran provides the substituted
ethyl 3-amino-2-naphthoate intermediates as a mixture of geometric
isomers if R.sub.2' differs from R.sub.3'. Reaction of the
substituted ethyl 3-amino-2-naphthoate intermediates with
dimethylformamide dimethyl acetal, with or without a solvent,
followed by reaction with the lithium anion of acetonitrile
prepared by using a base such as n-butyllithium or the like, in an
inert solvent, gives 3-cyano-4-oxo-1,4-dihydrobenzo[g]quinolines 4
(and the geometric isomer 4' if R.sub.2' differs from R.sub.3') or
the 3-cyano-4-hydroxybenzo[g]quinoline tautomers thereof.
Separation of the geometric isomers can be carried out by silica
gel chromatography or other purification methods at any step in the
preparation of intermediate of Formula 4. The above-mentioned
chemical transformations can be carried out separately on each
isomer. If a mixture of geometric isomers of Formula 4 and 4' is
converted to compounds of Formula 6, a chromatographic separation
can be carried out on the mixture of products of Formula 6 or any
of the intermediates formed in this sequence. ##STR55## ##STR56##
Intermediate 4 can also be prepared as described below and in
Flowsheet 1'''.
[0352] Bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitriles with
R.sub.1', R.sub.2' and R.sub.3' substituents being alkoxy of 1 to 6
carbon atoms, alkyl of 1 to 6 carbon atoms, or benzyloxy moiety of
the formula
Ph-(C(R.sub.6).sub.2).sub.q--W--(C(R.sub.6).sub.2).sub.k--V-- where
R.sub.6 is hydrogen, W is a bond, V is oxygen and k=0, q=1, can be
synthesized in regioisomerically pure form by procedures known in
the art as detailed by the following references: Kametani, T. et al
J. Het. Chem, 11, 179, (1974), Kametani, T.; kondoh, H.; Tsubuki,
M.; Honda, T. J. Chem. Soc Perkin Trans. 1, 5 (1990), Kametani, T.;
Kato, Honda, T. Fukumoto, K. J. Chem. Soc Perkin 1, 2001 (1990),
Kametani, T.; Kajiwara, M.; Takahashi, T.; Fukumoto, K.
Tetrahedron, 31, 949 (1975) and Honda, T. Toya, T. Heterocycles,
33, 291 (1992). The reaction of the substituted
bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitriles with a base such
as sodium (bistrimethylsilyl)amide or n-butyllithium at -78.degree.
C. and the like provides the corresponding anion a to the cyano
group which is then reacted with a suitable electrophile such as a
substituted diphenyl disulfide PhSSPh (where Ph is as hereinabove
defined) to provide substituted
7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-carbonitriles
after warming to room temperature. Reaction of these intermediates
with the magnesium bromide salt of an ester such as, but not
limited to t-butyl acetate at 0.degree. C. in an inert solvent such
as ether or tetrahydrofuran and the like provides the corresponding
substituted
3-amino-3-(7-phenylsulfanyl-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-acrylic
acid tert-butyl esters. Refluxing these adducts in a high boiling
solvent such as dichlorobenzene or the like for 0.5 to 3 hours
provides the substituted 3-amino-naphthalene-2-carboxylic acid
tert-butyl esters. Reaction of the substituted 3-amino-2-naphthoate
tert-butyl ester intermediates with dimethylformamide dimethyl
acetal, with or without a solvent, followed by reaction with the
lithium anion of acetonitrile prepared by using a base such as
n-butyllithium or the like, in an inert solvent, gives
3-cyano-4-oxo-1,4dihydrobenzo[g]quinolines 4 or the
3-cyano-4-hydroxybenzo[g]quinoline tautomers thereof. ##STR57##
[0353] Converting the R.sub.1', R.sub.2', R.sub.3' and R.sub.4'
groups to R.sub.1, R.sub.2, R.sub.3 and R.sub.4 groups can be
accomplished through any conventionally known techniques, for
example:
[0354] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a methoxy group, it can
be converted to the corresponding hydroxy group by reaction with a
demethylating agent such as boron tribromide in an inert solvent or
by heating with pyridinium chloride with or without solvent;
[0355] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 is a benzyloxy group of the formula
Ph-(C(R.sub.6).sub.2).sub.q--W--(C(R.sub.6).sub.2).sub.k--V-- where
R.sub.6 is hydrogen, W is a bond, V is oxygen and k=0, q=1, it can
be converted to the corresponding hydroxy group by reaction with a
debenzylating agent such as boron tribromide in an inert solvent,
trifluoroacetic acid or catalytic hydrogenation with a catalyst
such as palladium-on-carbon;
[0356] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a hydroxy group, it can
be converted to the corresponding alkanoyloxy group of 1-6 carbon
atoms by reaction with an appropriate carboxylic acid chloride,
anhydride, or mixed anhydride in a inert solvent using pyridine or
a trialkylamine as a base;
[0357] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a hydroxy group, it can
be converted to the corresponding alkenoyloxy group of 1-6 carbon
atoms by reaction with an appropriate carboxylic acid chloride,
anhydride, or mixed anhydride in an inert solvent using pyridine or
a trialkylamine as a base;
[0358] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a hydroxy group, it can
be converted to the corresponding alkynoyloxy group of 1-6 carbon
atoms by reaction with an appropriate carboxylic acid chloride,
anhydride, or mixed anhydride in a inert solvent using pyridine or
a trialkylamine as a base;
[0359] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a hydroxy group, it can
be converted to the corresponding groups: ##STR58## wherein R.sub.5
is as defined hereinabove, by the reaction in an inert solvent with
an alkyl or phenyl substituted isocyanate, R.sub.5--N.dbd.C.dbd.O,
or using a base such as pyridine, with a reagent
(R.sub.5).sub.2NCOCl;
[0360] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a hydroxy group, it can
be converted to the corresponding groups: ##STR59## wherein V is
oxygen, R.sub.6, R.sub.7, R.sub.8, R.sub.9, M, W, Het, Ph, p and q
are as defined hereinabove and g=2-6 and k=2-4 by reacting with an
appropriately substituted alcohol using triphenyl phosphine and
diethyl azodicarboxylate in an inert solvent, or alternatively by
first reacting with a reagent such as, but not limited to, a
bromoalkyl chloride or chloroalkyl tosylate to provide an
intermediate haloalkoxy group which can be converted to the above
described groups by subsequent reaction with an appropriately
substituted nucleophile;
[0361] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a hydroxy group, it can
be converted to a alkoxycarbonyl group of 2-7 carbon atoms by first
converting to a trifluoromethanesulfonate using
trifluoromethanesulfonate anhydride or
N-phenyltrifluoromethylsulfonamide and a base such as triethylamine
in an inert solvent, then reacting with carbon monoxide in an
alcoholic solvent of 1-6 carbons in the presence of a palladium (0)
catalyst such as palladium tetrakis triphenylphosphine;
[0362] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an alkoxycarbonyl group
of 2-7 carbon atoms, it can be converted to the corresponding
hydroxymethyl group by reduction with an appropriate reducing agent
such as lithium borohydride, or lithium aluminum hydride in a inert
solvent; the hydroxymethyl group, in turn, can be converted to the
corresponding halomethyl group by reaction in an inert solvent with
a halogenating reagent such as phosphorous tribromide to give a
bromomethyl group, or phosphorus pentachloride to give a
chloromethyl group. The hydroxymethyl group can be acylated with an
appropriate acid chloride, anhydride, or mixed anhydride in an
inert solvent using pyridine or a trialkylamine as a base to give
the compounds of this invention with the corresponding
alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl
group of 2-7 carbon atoms, or alkynoyloxymethyl group of 2-7 carbon
atoms;
[0363] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a halomethyl group, it
can be converted to the corresponding groups: ##STR60## wherein
R.sub.6, R.sub.7, R.sub.8, R.sub.9, M, W, Het, p and q are as
defined hereinabove by reacting with the appropriately substituted
alcohol, amine or mercaptan in an inert solvent such as dioxane or
acetonitrile and a base such as triethylamine or potassium
carbonate;
[0364] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a alkoxycarbonyl group
of 2-7 carbon atoms, it can be converted to the corresponding
carboxy group by reaction with a strong base such as aqueous sodium
hydroxide in an alcoholic solvent such as ethanol;
[0365] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a carboxy group, it can
be converted to a carbamoyl, N-alkylcarbamoyl or
N,N-dialkylcarbamoyl of 4-12 carbon atoms by reaction in an inert
solvent with a halogenating agent such as phosphorus oxychloride or
oxalyl chloride, or alternatively activating by reaction with a
coupling agent such as, but not limited to carbonyl diimidazole in
an inert solvent such as dimethylformamide, followed by reaction
with the appropriate amine;
[0366] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is a carboxy group, it can
be converted to an amino group by heating with diphenyl phosphoryl
azide and t-butanol in an inert solvent such as dioxane, followed
by treatment with a strong acid such as hydrochloric or
trifluoroacetic acid;
[0367] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an amino group, it can
be converted to the corresponding dialkylamino group of 2 to 12
carbon atoms by alkylation with at least two equivalents of an
alkyl halide of 1 to 6 carbon atoms by heating in an inert
solvent;
[0368] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an amino group, it can
be converted to the corresponding alkylsulfonamido,
alkenylsulfonamido, or alkynylsulfonamido group of 2 to 6 carbon
atoms by the reaction with an alkylsulfonyl chloride,
alkenylsulfonyl chloride, or alkylsulfonyl chloride, respectively,
in an inert solvent using a base such as triethylamine or
pyridine;
[0369] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an amino group, it can
be converted to the corresponding alkylamino group of 1 to 6 carbon
atoms by alkylation with one equivalent of an alkyl halide of 1 to
6 carbon atoms by heating in an inert solvent or by reductive
alkylation using an aldehyde of 1 to 6 carbon atoms and a reducing
agent such as sodium cyanoborohydride in a protic solvent such as
water or alcohol, or mixtures thereof;
[0370] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an amino group, it can
be converted to the corresponding groups: ##STR61## wherein R.sub.5
is as defined hereinabove by reacting with the appropriately
substituted carboxylic acid chloride or sulfonyl chloride or mixed
anhydride (which is prepared from the corresponding carboxylic
acid) in an inert solvent such as tetrahydrofuran (THF) in the
presence of an organic base such as pyridine, triethylamine or
N-methyl morpholine;
[0371] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an amino group, it can
be converted to the corresponding groups: ##STR62## wherein R.sub.5
is as defined hereinabove, by the reaction in an inert solvent with
an alkyl or phenyl substituted isocyanate, R.sub.5--N.dbd.C.dbd.O,
or an alkyl or phenyl substituted isothiocyanate,
R.sub.5--N.dbd.C.dbd.S;
[0372] where one or more of R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' of Formula 6 or an intermediate is an amino group, it can
be converted to the corresponding groups: ##STR63## wherein R.sub.5
is as defined hereinabove, by reacting with phosgene in an inert
solvent such as toluene in the presence of a base such as pyridine
to give an isocyanate which, in turn, is treated with an excess of
the alcohol R.sub.5--OH.
[0373] In those cases when the R.sub.1', R.sub.2', R.sub.3' and
R.sub.4' substituents of Formula 6 or an intermediate may contain
an asymmetric carbon atom, the intermediates can be used as the
racemate or as the individual R or S enantiomers in which case the
compounds of this invention will be in the racemic or R and S
optically active forms, respectively. In cases where the
substituents may contain more than one asymmetric carbon atom,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases where
the R.sub.1', R.sub.2', R.sub.3', R.sub.4', R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9 and Het substituents of Formula 6 or an
intermediate contains primary or secondary amino groups or hydroxyl
groups, it may be necessary to protect these groups during the
reaction sequence. The same amine or alcohol protecting groups
described hereinabove can be used and they can be removed from the
products of Formula 6 as previously described.
[0374] The preparation of the compounds and intermediates of this
invention encompassed by Formula 13 is described below and in
Flowsheet 2 where Ar, X and n are as hereinabove defined.
[0375] According to the sequence of reaction outlined in Flowsheet
2, a quinoline-3-carboxylic acid ester of Formula 7 is hydrolyzed
with base to furnish a carboxylic acid of Formula 8. The carboxylic
acid group of 8 is converted to an acyl imidazole by heating it
with carbonyldiimidazole in an inert solvent such as
dimethylformamide (DMF) followed by the addition of ammonia to give
the amide 9. Dehydration of the amide functional group with the
dehydrating agent, cyanuric chloride in dimethylformamide (DMF),
gives the 3-cyano-4-quinolone of Formula 10. Deprotonation of 10
with sodium hydride in anhydrous dimethylformamide (DMF), followed
by reaction with 2-(trimethylsilyl)ethoxymethyl (SEM) chloride
provides a 4-quinolone of Formula 11. By heating 11 with sodium
azide in dimethylsulfoxide (DMSO), it can be converted to an azide,
which is reduced to the diamine of Formula 12 by catalytic
hydrogenation over palladium-on-carbon or platinum-on-carbon in
tetrahydrofuran. Reaction of 12 with nitrous acid provides 13.
Refluxing 13 in formic acid provides the
7-cyano-8-oxo-5,8-dihydrotriazolo[4,5-g]quinoline 14 or the
7-cyano-8-hydroxytriazolo[4,5-g]quinoline tautomer thereof. Heating
14 with or without solvent with a chlorinating agent such as
phosphorus oxychloride or oxalyl chloride provides the
corresponding 7-cyano-8-chlorotriazolo[4,5-g]quinoline.
Condensation of 7-cyano-8-chlorotriazolo[4,5-g]quinoline with a
nucleophilic amine, aniline, mercaptan, thiophenol, phenol, or
alcohol reagent of Formula 5 gives the
7-cyano-triazolo[4,5-g]quinolines of Formula 15; this condensation
can be accelerated by heating the reaction mixture together with
one equivalent of pyridine hydrochloride or by using bases such as
trialkylamines, sodium hydride in an inert solvent, sodium or
potassium alkoxides in alcohol solvents, and the like. In those
cases where the Ar substituents may contain an asymmetric carbon
atom, the intermediates can be used as the racemate or as the
individual R or S enantiomers in which case the compounds of this
invention will be in the racemic or R and S optically active forms,
respectively. In cases where the Ar substituents may contain more
than one asymmetric carbon atoms, diastereomers may be present;
these can be separated by methods well known in the art including,
but not limited to, fractional crystallization and chromatographic
methods. In those cases, in intermediates 5 where Ar contains
primary or secondary amino groups or hydroxyl groups, it may be
necessary to protect these groups prior to the reaction with
7-cyano-8-chlorotriazolo[4,5-g]quinoline. The same amine or alcohol
protecting groups described hereinabove can be used and they can be
removed from the products 15 as previously described.
[0376] The quinoline-3-carboxylic acid ester of Formula 7 needed to
prepare the compounds of this invention are either already known in
the art or can be prepared by procedures known in the art as
detailed in the following reference: Koga, Hiroshi; Itoh, Akira;
Murayama, Satoshi; Suzue, Seigo; Irikura, Tsutomu, J. Med. Chem.,
23, 1358 (1980). ##STR64## ##STR65##
[0377] The preparation of the compounds and intermediates of this
invention encompassed by Formula 19 is described below and in
Flowsheet 3 where Ar, X and n are as hereinabove defined.
[0378] Heating 10 with or without solvent with a chlorinating agent
such as phosphorus oxychloride or oxalyl chloride provides the
intermediate 4,7-dichloro-6-nitro-3-quinolinecarbonitrile.
Condensation of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile with a
nucleophilic amine, aniline, mercaptan, thiophenol, phenol, or
alcohol reagent of Formula 5 gives the
7-cyano-triazolo[4,5-g]quinolines of Formula 16; this condensation
can be accelerated by heating the reaction mixture together with
one equivalent of pyridine hydrochloride or by using bases such as
trialkylamines, sodium hydride in an inert solvent, sodium or
potassium alkoxides in an alcohol solvents, and the like. Heating
16 with sodium azide in dimethylsulfoxide (DMSO), provides the
corresponding azides, which are reduced to the diamines of Formula
17 by catalytic hydrogenation over palladium-on-carbon or
platinum-on-carbon in tetrahydrofuran. Reaction of 17 with
2,3-dihydroxy-1,4-dioxane of Formula 18 in an inert solvent such as
methanol provides the pyrido[2,3-g]quinoxaline-8-carbonitriles of
Formula 19. In those cases where the Ar substituents may contain an
asymmetric carbon atom, the intermediates can be used as the
racemate or as the individual R or S enantiomers in which case the
compounds of this invention will be in the racemic or R and S
optically active forms, respectively. In cases where the Ar
substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 5 where Ar contains primary or secondary amino groups
or hydroxyl groups, it may be necessary to protect these groups
prior to the reaction with 4,7-dichloro-6-nitro-3-quinoline
carbonitrile. The same amine or alcohol protecting groups
hereinabove can be used and they can be removed from the products
19 as previously described. ##STR66##
[0379] The preparation of the compounds and intermediates of this
invention encompassed by Formula 23 is described below and in
Flowsheet 4 where Ar, X and n are as hereinabove defined. G is
selected from the group consisting of: alkyl of 1-6 carbon atoms,
cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, hydroxyalkyl of 2-6 carbon atoms;
mercaptoalkyl of 2-6 carbon atoms, phenyl, benzyl, ##STR67## where
R.sub.6, R.sub.7, R.sub.8, R.sub.9, M, W, Het, Ph, p and q are as
defined hereinabove, g=2-6 and k=2-4.
[0380] Reaction of 17 with an isothiocyanate 20 provides a mixture
of thioureas of Formulas 21 and 22. Heating the mixture of Formulas
21 and 22 with mercury (II) oxide and a catalytic amount of sulfur
in an inert solvent such as dioxane provides the corresponding
substituted 2-amino-7-cyanoimidazo[4,5-g]quinolines of Formula 23.
In those cases where the Ar and/or G substituents may contain an
asymmetric carbon atom, the intermediates can be used as the
racemate or as the individual R or S enantiomers in which case the
compounds of this invention will be in the racemic or R and S
optically active forms, respectively. In cases where the Ar and/or
G substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 20 where G contains primary or secondary amino groups
or hydroxyl groups, it may be necessary to protect these groups
prior to the reaction with 17. The same amine or alcohol protecting
groups defined hereinabove can be used and they can be removed from
the products 23 as previously described. ##STR68##
[0381] The preparation of the compounds and intermediates of this
invention encompassed by Formula 26 is described below and in
Flowsheet 5 where Ar, X and n are as hereinabove defined.
[0382] Reaction of 12 with cyanogen bromide in an inert solvent
such as methanol provides a compound of Formula 24. Refluxing 24 in
formic acid with 4 equivalents of imidazole provides a compound of
formula 25. Heating 25 with or without solvent with a chlorinating
agent such as phosphorus oxychloride or oxalyl chloride provides
the corresponding
2-amino-8-chloroimidazo[4,5-g]quinoline-7-carbonitrile.
Condensation of
2-amino-8-chloroimidazo[4,5-g]quinoline-7-carbonitrile with a
nucleophilic amine, aniline, mercaptan, thiophenol, phenol, or
alcohol reagent of Formula 5 gives the 7-cyano
imidazo[4,5-g]quinolines of Formula 26; this condensation can be
accelerated by heating the reaction mixture together with one
equivalent of pyridine hydrochloride or by using bases such as
trialkylamines, sodium hydride in an inert solvent, sodium or
potassium alkoxides in an alcohol solvents, and the like. In those
cases where the Ar substituents may contain an asymmetric carbon
atom, the intermediates can be used as the racemate or as the
individual R or S enantiomers in which case the compounds of this
invention will be in the racemic or R and S optically active forms,
respectively. In cases where the Ar substituents may contain more
than one asymmetric carbon atoms, diastereomers may be present;
these can be separated by methods well known in the art including,
but not limited to, fractional crystallization and chromatographic
methods. In those cases, in intermediates 5 where Ar contains
primary or secondary amino groups or hydroxyl groups, it may be
necessary to protect these groups prior to the reaction with
2-amino-8-chloro-imidazo[4,5-g]quinoline-7-carbonitrile. The same
amine or alcohol protecting groups described hereinabove can be
used and they can be removed from the products 26 as previously
described. ##STR69##
[0383] The preparation of the compounds and intermediates of this
invention encompassed by Formula 28 is described below and in
Flowsheet 6 where Ar, X and n are as hereinabove defined.
[0384] Refluxing 12 in formic acid with 4 equivalents of imidazole
provides a compound of formula 27. Heating 27 with or without
solvent with a chlorinating agent such as phosphorus oxychloride or
oxalyl chloride provides the corresponding
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile. Condensation of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile with a nucleophilic
amine, aniline, mercaptan, thiophenol, phenol, or alcohol reagent
of Formula 5 gives the 7-cyano-imidazo[4,5-g]quinolines of Formula
28; this condensation can be accelerated by heating the reaction
mixture together with one equivalent of pyridine hydrochloride or
by using bases such as trialkylamines, sodium hydride in an inert
solvent, sodium or potassium alkoxides in an alcohol solvents, and
the like. In those cases where the Ar substituents may contain an
asymmetric carbon atom, the intermediates can be used as the
racemate or as the individual R or S enantiomers in which case the
compounds of this invention will be in the racemic or R and S
optically active forms, respectively. In cases where the Ar
substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 5 where Ar contains primary or secondary amino groups
or hydroxyl groups, it may be necessary to protect these groups
prior to the reaction with
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile. The same amine or
alcohol protecting groups described hereinabove can be used and
they can be removed from the products 28 as previously described.
##STR70##
[0385] An alternative preparation of the compounds and
intermediates of this invention encompassed by Formula 28 is
described below and in Flowsheet 7 where Ar, X and n are as
hereinabove defined.
[0386] Refluxing intermediates of Formula 17 in diethoxymethyl
acetate provides the 7-cyano-imidazo[4,5-g]quinolines of Formula 28
when X is oxygen or sulfur. When X is nitrogen with a hydrogen
substituent, the corresponding
7-cyanoimidazo[4,5-g]quinolin-8-ylformamides are formed. Heating
the 7-cyanoimidazo[4,5-g]quinolin-8-ylformamides with potassium
carbonate in a solvent such as methanol or ethanol provides the
compounds of Formula 28. In those cases where the Ar substituents
may contain an asymmetric carbon atom, the intermediates can be
used as the racemate or as the individual R or S enantiomers in
which case the compounds of this invention will be in the racemic
or R and S optically active forms, respectively. In cases where the
Ar substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 17 where Ar contains primary or secondary amino
groups or hydroxyl groups, it may be necessary to protect these
groups prior to the reaction with diethoxymethyl acetate. The same
amine or alcohol protecting groups described hereinabove can be
used and they can be removed from the products 28 as previously
described. ##STR71##
[0387] The preparation of the compounds and intermediates of this
invention encompassed by Formula 32 is described below and in
Flowsheet 8 where Ar, X and n are as hereinabove defined; and
[0388] G' is selected from the group consisting of: hydrogen, alkyl
of 1-6 carbon atoms, trifluoromethyl, cycloalkyl of 3-8 carbon
atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
thiol, hydroxyalkyl of 1-6 carbon atoms; mercaptoalkyl of 1-6
carbon atoms; halomethyl, alkoxycarbonyl of 2-7 carbon atoms,
phenyl, benzyl, phenoxy; R.sub.7--C(R.sub.6).sub.2).sub.g--V--,
Ph-(C(R.sub.6).sub.2).sub.q--W--(C(R.sub.6).sub.2).sub.k--V--.
where g, k q, R.sub.6, R.sub.7, V, W and Ph are as defined
hereinabove.
[0389] Reaction of 17 with a carboxylic acid chloride of Formula 29
with a base such as pyridine, diethylaniline or triethylamine with
or without an inert solvent such as tetrahydrofuran (THF) provides
mixtures of compounds of Formula 30 and 31. Heating the mixture of
Formulas 30 and 31 in formic acid or acetic acid provides the
corresponding substituted 7-cyano-imidazo[4,5-g]quinolines of
Formula 32. Alternatively, intermediates 17 can be directly
converted to substituted 7-cyano-imidazo[4,5-g]quinolines of
Formula 32 by reaction with G'-C(L').sub.3, where L' is chloro,
hydroxy, alkoxy, alkylthio, phenoxy, thiophenoxy or dimethylamine,
or two L' groups can be taken together to form .dbd.S, .dbd.NH,
.dbd.O or .dbd.Se substituents, using acidic conditions (Hagen, H;
Kohler, R.-D.; Fleig, H. Liebigs Ann. Chem., 1216 (1980), or basic
reaction conditions (Webb, R. L. et al, J. Heterocycl. Chem., 24,
275 (1987), McKee, R. L.; Mckee, M. K.; Bost, R. W. J. Am. Chem.
Soc., 68, 1904 (1946), Allen, J. A.; Deacon, B. D. Org. Synth., 30,
56 (1950)) or by using a strongly dehydrating solvent such as
polyphosphoric acid (Hein, D. W.; Leavitt, J. J. J. Am. Chem. Soc.,
79, 427 (1957), or by using agents such as
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (Corrol, F. I.;
Coleman, M. C. J. Med. Chem., 18, 318 (1975)) or by heating in an
inert solvent (Cohen, V. I.; Pourabass, J. Heterocycl. Chem., 14,
1321 (1977)). In those cases, in intermediates 29 or G'-C(L').sub.3
where G' contains primary or secondary amino groups or hydroxyl
groups, it may be necessary to protect these groups prior to the
reaction with 17. The same amine or alcohol protecting groups as
defined hereinabove can be used and they can be removed from the
products 32 as previously described. In those cases where the Ar
and/or G' substituents may contain an asymmetric carbon atom, the
intermediates can be used as the racemate or as the individual R or
S enantiomers in which case the compounds of this invention will be
in the racemic or R and S optically active forms, respectively. In
cases where the substituents may contain more than one asymmetric
carbon atoms, diastereomers may be present; these can be separated
by methods well known in the art including, but not limited to,
fractional crystallization and chromatographic methods.
##STR72##
[0390] Converting the G' groups of Formula 32 to R.sub.2 groups can
be accomplished through any conventionally known techniques.
[0391] The preparation of the compounds and intermediates of this
invention encompassed by Formula 36 is described below and in
Flowsheet 9 where Ar, X, G' and n are as hereinabove defined;
and
[0392] G'' is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of
3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, hydroxyalkyl of 2-6 carbon atoms; mercaptoalkyl of
2-6 carbon atoms, phenyl, benzyl, ##STR73## where R.sub.6, R.sub.7,
R.sub.8, R.sub.9, M, W, Het, Ph, p and q are as hereinabove defined
and g 2-6 and k=2-4.
[0393] By heating 11 with amines of Formula 33 in an inert solvent
such as acetonitrile or dimethyl sulfoxide (DMSO), followed by
catalytic hydrogenation over palladium on carbon in tetrahydrofuran
and ethanol, it can be converted to compounds of Formula 34. The
compounds of Formula 34 can be converted to compounds of Formula 35
by reaction with G'-C(L').sub.3, where L' is chloro, hydroxy,
alkoxy, alkylthio, phenoxy, thiophenoxy or dimethylamine, or two L'
groups can be taken together to form .dbd.S, .dbd.NH, .dbd.O or
.dbd.Se substituents, using acidic conditions (Hagen, H; Kohler,
R.-D.; Fleig, H. Liebigs Ann. Chem., 1216 (1980), or basic reaction
conditions (Webb, R. L. et al, J. Heterocycl Chem., 24, 275 (1987),
McKee, R. L.; Mckee, M. K.; Bost, R W. J. Am. Chem. Soc., 68, 1904
(1946), Allen, J. A.; Deacon, B. D. Org. Synth., 30, 56 (1950)) or
by using a strongly dehydrating solvent such as polyphosphoric acid
(Hein, D. W.; Leavitt, J. J. J. Am. Chem. Soc., 79, 427 (1957), or
by using agents such as
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (Corrol, F. I.;
Coleman, M. C. J. Med. Chem., 18, 318 (1975)) or by heating in an
inert solvent (Cohen, V. I.; Pourabass, J. Heterocycl. Chem., 14,
1321 (1977)). Heating 35 with or without solvent with a
chlorinating agent such as phosphorus oxychloride or oxalyl
chloride provides the corresponding
8-chloroimidazo[4,5-g]quinoline-7-carbonitriles. Condensation of
8-chloroimidazo[4,5-g]quinoline-7-carbonitriles with a nucleophilic
amine, aniline, mercaptan, thiophenol, phenol, or alcohol reagent
of Formula 5 gives the 7-cyano-imidazo[4,5-g]quinolines of Formula
36; this condensation can be accelerated by heating the reaction
mixture together with one equivalent of pyridine hydrochloride or
by using bases such as trialkylamines, sodium hydride in an inert
solvent, sodium or potassium alkoxides in an alcohol solvent, and
the like. In those cases where the Ar and/or G' and/or G''
substituents may contain an asymmetric carbon atom, the
intermediates can be used as the racemate or as the individual R or
S enantiomers in which case the compounds of this invention will be
in the racemic or R and S optically active forms, respectively. In
cases where the Ar and/or G' and/or G'' substituents may contain
more than one asymmetric carbon atoms, diastereomers may be
present; these can be separated by methods well known in the art
including, but not limited to, fractional crystallization and
chromatographic methods. In those cases, in intermediates 33 where
G'' contains primary or secondary amino groups or hydroxyl groups,
it may be necessary to protect these groups prior to the reaction
with 11. In those cases, in intermediates 5 where Ar contains
primary or secondary amino groups or hydroxyl groups, it may be
necessary to protect these groups prior to the reaction with
8-chloroimidazo[4,5-g]quinoline-7-carbonitriles. The same amine or
alcohol protecting groups described hereinabove can be used and
they can be removed from the products 36 as previously described.
##STR74##
[0394] Converting the G' groups of Formula 36 or Formula 35 to
R.sub.2 groups and the G'' groups of Formula 36 or Formula 35 to
R.sub.3 groups can be accomplished through any conventionally known
techniques.
[0395] The preparation of the compounds and intermediates of this
invention encompassed by Formula 39 is described below and in
Flowsheet 10 where Ar, X, G' and n are as hereinabove defined.
[0396] By heating 11 with sodium sulfide in dimethylsulfoxide
(DMSO), followed by catalytic hydrogenation over palladium on
carbon in tetrahydrofuran and ethanol, it can be converted to a
compound of Formula 37. Refluxing 37 in formic acid with 4
equivalents of imidazole provides a compound of formula 38. The
compounds of Formula 37 can be converted to compounds of Formula 38
by reaction with G'-C(L').sub.3, where L' is chloro, hydroxy,
alkoxy, alkylthio, phenoxy, thiophenoxy or dimethylamine, or two L'
groups can be taken together to form .dbd.S, .dbd.NH, .dbd.O or
.dbd.Se substituents, using acidic conditions (Hagen, E; Kohler,
R.-D.; Fleig, H. Liebigs Ann. Chem., 1216 (1980), or basic reaction
conditions (Tawins, A.; Hsiu, R. K.-C. Can. J. Chem., 49, 4054
(1971)) or by using a strongly dehydrating solvent such as
polyphosphoric acid (Hein, D. W.; Leavitt, J. J. J. Am. Chem. Soc.,
79, 427 (1957), or by using agents such as phosphorus oxychloride
(Davis, C. S. J. Pharm. Sci., 51, 1111 (1962)) or by heating in an
inert solvent (Campaigne, E.; Van Verth, J. E. J. Org. Chem., 23,
1344 (1958), George, B.; Papadopoulos, E. P. J. Org. Chem., 42,
2530 (1977). Heating 38 with or without solvent with a chlorinating
agent such as phosphorus oxychloride or oxalyl chloride provides
the corresponding 7-cyano-8-chlorothiazolo[4,5-g]quinoline.
Condensation of a substituted
7-cyano-8-chlorothiazolo[4,5-g]quinoline with a nucleophilic amine,
aniline, mercaptan, thiophenol, phenol, or alcohol reagent of
Formula 5 gives the 7-cyanothiazolo[4,5-g]quinolines of Formula 39;
this condensation can be accelerated by heating the reaction
mixture together with one equivalent of pyridine hydrochloride or
by using bases such as trialkylamines, sodium hydride in an inert
solvent, sodium or potassium alkoxides in an alcohol solvent, and
the like. In those cases where Ar and/or G' may contain an
asymmetric carbon atom, the intermediates can be used as the
racemate or as the individual R or S enantiomers in which case the
compounds of this invention will be in the racemic or R and S
optically active forms, respectively. In cases where the
substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 5 where Ar contains primary or secondary amino groups
or hydroxyl groups, it may be necessary to protect these groups
prior to the reaction with
7-cyano-8-chlorothiazolo[4,5-g]quinoline. The same amine or alcohol
protecting groups described hereinabove can be used and they can be
removed from the products 39 as previously described. ##STR75##
[0397] Converting the G' groups of Formula 39 to R.sub.2 groups can
be accomplished through any conventionally known techniques.
[0398] The preparation of the compounds and intermediates of this
invention encompassed by Formula 44 is described below and in
Flowsheet 11 where Ar, X and n are as hereinabove defined.
[0399] Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4 are each,
independently, hydrogen, halogen, hydroxy, amino, hydroxyamino,
trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms,
alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms,
mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7
carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon
atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon
atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6
carbon atoms, alkylsulfonamido of 1-6 carbon atoms,
alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6
carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon
atoms, alkanoyl of 2-7 carbon atoms, N-alkylcarbamoyl,
N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon
atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino,
benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of
1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, ##STR76##
where V, R.sub.6, R.sub.7, R.sub.8, R.sub.9, M, W, Het, Ph, g, k, p
and q are as hereinabove defined.
[0400] By reacting substituted 2-nitrobenzonitriles of Formula 40
with methyl thioglycolate and a base such as potassium hydroxide or
triethylamine in an inert solvent such as dimethyl sulfoxide (DMSO)
or aqueous dimethyl formamide (DMF) with or without heating
provides compounds of Formula 41. Heating the substituted aniline
of Formula 41 with dimethylformamide dimethyl acetal with or
without a solvent gives intermediates of Formula 42. The reaction
of 42 with from one to ten equivalents of acetonitrile using a base
such as n-butyllithium, sodium methoxide or the like in an inert
solvent gives the
4-oxo-1,4-dihydro[1]benzothieno[3,2-b]pyridine-3-carbonitrile 43,
or the 4-hydroxy[1]benzothieno[3,2-b]pyridine-3-carbonitriles
tautomers thereof. Heating 43 with or without solvent with a
chlorinating agent such as phosphorus oxychloride or oxalyl
chloride provides the corresponding
4-chloro[1]benzothieno[3,2-b]pyridine-3-carbonitriles. Condensation
of 4-chloro[1]benzothieno[3,2-b]pyridine-3-carbonitriles with a
nucleophilic amine, aniline, mercaptan, thiophenol, phenol, or
alcohol reagent of Formula 5 gives the
benzothieno[3,2-b]pyridine-3-carbonitriles of Formula 44; this
condensation can be accelerated by heating the reaction mixture
together with one equivalent of pyridine hydrochloride or by using
bases such as trialkylamines, sodium hydride in an inert solvent,
sodium or potassium alkoxides in an alcohol solvents, and the like.
In those cases where the Ar and/or Q.sub.1, Q.sub.2, Q.sub.3 and
Q.sub.4 substituents may contain an asymmetric carbon atom, the
intermediates can be used as the racemate or as the individual R or
S enantiomers in which case the compounds of this invention will be
in the racemic or R and S optically active forms, respectively. In
cases where the Ar and/or Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4
substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 40 where Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4
contain primary or secondary amino groups or hydroxyl groups, it
may be necessary to protect these groups prior to the reaction with
methyl thioglycolate. In those cases, in intermediates 5 where Ar
contains primary or secondary amino groups or hydroxyl groups, it
may be necessary to protect these groups prior to the reaction with
the 4-chloro[1]benzothieno[3,2-b]pyridine-3-carbonitriles. The same
amine or alcohol protecting groups described hereinabove can be
used and they can be removed from the products 44 as previously
described.
[0401] The 2-nitrobenzonitriles of Formula 40 are either
commercially available, or are already known to the art or can be
prepared by procedures known in the art. ##STR77##
[0402] Converting the Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4 groups
to R.sub.1, R.sub.2, R.sub.3 and R.sub.4 groups can be accomplished
through any conventionally known techniques, for example:
[0403] Where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a nitro group, it can be converted to the
corresponding amino group by reduction using a reducing agent such
as iron in acetic acid;
[0404] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is an amino group, it can be converted to the
corresponding dialkylamino group of 2 to 12 carbon atoms by
alkylation with at least two equivalents of an alkyl halide of 1 to
6 carbon atoms by heating in an inert solvent;
[0405] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a methoxy group, it can be converted to the
corresponding hydroxy group by reaction with a demethylating agent
such as boron tribromide in an inert solvent or by heating with
pyridinium chloride with or without solvent;
[0406] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is an amino group, it can be converted to the
corresponding alkylsulfonamido, alkenylsulfonamido, or
alkynylsulfonamido group of 2 to 6 carbon atoms by the reaction
with an alkylsulfonyl chloride, alkenylsulfonyl chloride, or
alkynylsulfonyl chloride, respectively, in an inert solvent using a
base such as triethylamine or pyridine;
[0407] where two of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of Formula
44 are contiguous methoxy groups, the corresponding compound with
contiguous hydroxy groups can be prepared by using a demethylating
agent such as boron tribromide in an inert solvent or by heating
with pyridinium chloride with or without solvent.
[0408] Where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is an amino group, it can be converted with or without
heating to the corresponding alkylamino group of 1 to 6 carbon
atoms by alkylation with one equivalent of an alkyl halide of 1 to
6 carbon atoms or by reductive alkylation using an aldehyde of 1 to
6 carbon atoms and a reducing agent such as sodium cyanoborohydride
in a protic solvent such as water or alcohol, or mixtures
thereof;
[0409] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is hydroxy, it can be converted to the corresponding
alkanoyloxy, group of 1-6 carbon atoms by reaction with an
appropriate carboxylic acid chloride, anhydride, or mixed anhydride
in a inert solvent using pyridine or a trialkylamine as a base;
[0410] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is hydroxy, it can be converted to the corresponding
alkenoyloxy group of 1-6 carbon atoms by reaction with an
appropriate carboxylic acid chloride, anhydride, or mixed anhydride
in an inert solvent using pyridine or a trialkylamine as a
base;
[0411] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is hydroxy, it can be converted to the corresponding
groups: ##STR78## wherein V is oxygen, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, M, W, Het, Ph, p and q are as hereinabove defined and
g=2-6 and k=2-4 by reacting with the appropriately substituted
alcohol using triphenyl phosphine and diethyl azodicarboxylate in
an inert solvent, or alternatively by first reacting with a reagent
such as, but not limited to, a bromoalkyl chloride or chloroalkyl
tosylate to provide an intermediate haloalkoxy group which can be
converted to the above described groups by subsequent reaction with
an appropriately substituted nucleophile;
[0412] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a HO--(CH.sub.2).sub.q-- group, it can be converted
to the corresponding groups: ##STR79## wherein q and R.sub.5 are as
defined above, by the reaction in an inert solvent with an alkyl or
phenyl substituted isocyanate, R.sub.5--N.dbd.C.dbd.O, or using a
base such as pyridine, with a reagent (R.sub.5).sub.2NCOCl;
[0413] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is carboxy or a alkoxycarbonyl group of 2-7 carbon
atoms, it can be converted to the corresponding hydroxymethyl group
by reduction with an appropriate reducing agent such as lithium
borohydride, or lithium aluminum hydride in a inert solvent; the
hydroxymethyl group, in turn, can be converted to the corresponding
halomethyl group by reaction in an inert solvent with a
halogenating reagent such as phosphorus tribromide to give a
bromomethyl group, or phosphorus pentachloride to give a
chloromethyl group. The hydroxymethyl group can be acylated with an
appropriate acid chloride, anhydride, or mixed anhydride in an
inert solvent using pyridine or a trialkylamine as a base to give
the compounds of this invention with the corresponding
alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl
group of 2-7 carbon atoms, or alkynoyloxymethyl group of 2-7 carbon
atoms;
[0414] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a halomethyl group, it can be converted to the
corresponding groups: ##STR80## wherein R.sub.6, R.sub.7, R.sub.8,
R.sub.9, M, W, Het, p and q are as hereinabove defined by reacting
with the appropriately substituted alcohol, amine or mercaptan in
an inert solvent such as dioxane or acetonitrile and a base such as
triethylamine or potassium carbonate;
[0415] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR81## wherein R.sub.5
and q are as hereinabove defined, by reacting with the
appropriately substituted acid chloride or mixed anhydride (which
is prepared from the corresponding carboxylic acid) in an inert
solvent such as tetrahydrofuran (THF) in the presence of an organic
base such as pyridine, triethylamine or N-methyl morpholine;
[0416] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR82## wherein R.sub.5
and q are as hereinabove defined, by reacting with phosgene in an
inert solvent such as toluene in the presence of a base such as
pyridine to give an isocyanate which, in turn, is treated with an
excess of the alcohol R.sub.5--OH
[0417] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR83## wherein R.sub.5
and q are as hereinabove defined, by the reaction in an inert
solvent with an alkyl or phenyl substituted isocyanate,
R.sub.5--N.dbd.C.dbd.O, or by reacting with phosgene in an inert
solvent such as toluene in the presence of a base such as pyridine
to give an isocyanate which, in turn, is treated with an excess of
amine (R.sub.5).sub.2NH;
[0418] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 44 is a H.sub.2N(CH.sub.2).sub.q group, it can be converted
to the corresponding groups: ##STR84## wherein R.sub.5 and q are as
hereinabove defined, by the reaction in an inert solvent with an
alkyl or phenyl substituted isothiocyanate, R.sub.5--N.dbd.C.dbd.S,
or by reacting with 1,1'-thiocarbonyldiimidazole in an inert
solvent such as toluene in the presence of a base such as pyridine
to give an isothiocyanate which, in turn, is treated with an excess
of amine (R.sub.5).sub.2NH.
[0419] Intermediate 43 can also be prepared as described below and
in Flowsheet 12.
[0420] By reacting substituted 2-fluorobenzonitriles of Formula 45
with methyl thioglycolate and a base such as potassium hydroxide or
triethylamine in an inert solvent such as dimethyl sulfoxide (DMSO)
or aqueous dimethyl formamide (DMF) with or without heating
provides compounds of Formula 41. Heating the substituted anilines
of Formula 41 with N-methyl piperazine in an inert solvent such as
N-methyl pyrrolidine (NMP) provides intermediates 46. Treatment of
46 with ethyl (ethoxymethylene)cyanoacetate gives intermediates 47.
Cyclization of 47 in refluxing 1:3 biphenyl/diphenyl ether to
provide compounds of Formula 43, or the
4hydroxy[1]benzothieno[3,2-b]pyridine-3-carbonitriles tautomers
thereof, which can be converted to the compounds of this invention
using the procedures outlined in Flowsheet 11.
[0421] The 2-fluorobenzonitriles of Formula 45 are either
commercially available, or are already known to the art or can be
prepared by procedures known in the art. ##STR85##
[0422] The preparation of the compounds and intermediates of this
invention encompassed by Formula 52 is described below and in
Flowsheet 13 where Ar, X Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4 and
n are as hereinabove defined.
[0423] Reaction of substituted 2-nitrophenols of Formula 48 with
ethyl bromoacetate and a base such as potassium carbonate in an
inert solvent such as dimethyl formamide (DMF) with or without
heating, followed by further treatment with potassium t-butoxide in
an inert solvent such as tetrahydrofuran (THF) provides compounds
of Formula 49. Heating the substituted aniline of Formula 49 with
dimethylformamide dimethyl acetal with or without a solvent gives
intermediates of Formula 50. The reaction of 50 with from one to
ten equivalents of acetonitrile using a base such as
n-butyllithium, sodium methoxide or the like in an inert solvent
gives the
4-oxo-1,4-dihydro[1]benzofuro[3,2-b]pyridine-3-carbonitrile 51, or
the 4-hydroxy[1]benzofuro[3,2-b]pyridine-3-carbonitriles tautomers
thereof. Heating 51 with or without solvent with a chlorinating
agent such as phosphorus oxychloride or oxalyl chloride provides
the corresponding
4-chloro[1]benzofuro[3,2-b]pyridine-3-carbonitriles. Condensation
of 4-chloro[1]benzofuro[3,2-b]pyridine-3-carbonitriles with a
nucleophilic amine, aniline, mercaptan, thiophenol, phenol, or
alcohol reagent of Formula 5 gives the
benzofuro[3,2-b]pyridine-3-carbonitriles of Formula 52; this
condensation can be accelerated by heating the reaction mixture
together with one equivalent of pyridine hydrochloride or by using
bases such as trialkylamines, sodium hydride in an inert solvent,
sodium or potassium alkoxides in alcohol solvents, and the like. In
those cases where the Ar and/or Q.sub.1, Q.sub.2, Q.sub.3 and
Q.sub.4 substituents may contain an asymmetric carbon atom, the
intermediates can be used as the racemate or as the individual R or
S enantiomers in which case the compounds of this invention will be
in the racemic or R and S optically active forms, respectively. In
cases where the Ar and/or Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4
substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 48 where Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4
contains primary or secondary amino groups or hydroxyl groups, it
may be necessary to protect these groups prior to the reaction with
ethyl bromoacetate. In those cases, in intermediates 5 where Ar
contains primary or secondary amino groups or hydroxyl groups, it
may be necessary to protect these groups prior to the reaction with
the 4-chloro[1]benzofuro[3,2-b]pyridine-3-carbonitriles. The same
amine or alcohol protecting groups hereinabove described can be
used and they can be removed from the products 54 as previously
described.
[0424] The 2-nitrophenols of Formula 48 are either commercially
available, or are already known to the art or can be prepared by
procedures known in the art. ##STR86##
[0425] Converting the Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4 groups
to R.sub.1, R.sub.2, R.sub.3 and R.sub.4 groups can be accomplished
through any conventionally known techniques, for example:
[0426] Where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a nitro group, it can be converted to the
corresponding amino group by reduction using a reducing agent such
as iron in acetic acid;
[0427] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is an amino group, it can be converted to the
corresponding dialkylamino group of 2 to 12 carbon atoms by
alkylation with at least two equivalents of an alkyl halide of 1 to
6 carbon atoms by heating in an inert solvent;
[0428] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a methoxy group, it can be converted to the
corresponding hydroxy group by reaction with a demethylating agent
such as boron tribromide in an inert solvent or by heating with
pyridinium chloride with or without solvent;
[0429] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is an amino group, it can be converted to the
corresponding alkylsulfonamido, alkenylsulfonamido, or
alkynylsulfonamido group of 2 to 6 carbon atoms by the reaction
with an alkylsulfonyl chloride, alkenylsulfonyl chloride, or
alkynylsulfonyl chloride, respectively, in an inert solvent using a
base such as triethylamine or pyridine;
[0430] where two of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of Formula
52 are contiguous methoxy groups, the corresponding compound with
contiguous hydroxy groups can be prepared by using a demethylating
agent such as boron tribromide in an inert solvent or by heating
with pyridinium chloride with or without solvent;
[0431] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is an amino group, it can be converted to the
corresponding alkylamino group of 1 to 6 carbon atoms by alkylation
with one equivalent of an alkyl halide of 1 to 6 carbon atoms by
heating in an inert solvent or by reductive alkylation using an
aldehyde of 1 to 6 carbon atoms and a reducing agent such as sodium
cyanoborohydride in a protic solvent such as water or alcohol, or
mixtures thereof,
[0432] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is hydroxy, it can be converted to the corresponding
alkanoyloxy, group of 1-6 carbon atoms by reaction with an
appropriate carboxylic acid chloride, anhydride, or mixed anhydride
in a inert solvent using pyridine or a trialkylamine as a base;
[0433] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is hydroxy, it can be converted to the corresponding
alkenoyloxy group of 1-6 carbon atoms by reaction with an
appropriate carboxylic acid chloride, anhydride, or mixed anhydride
in an inert solvent using pyridine or a trialkylamine as a
base;
[0434] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is hydroxy, it can be converted to the corresponding
groups: ##STR87## wherein V is oxygen, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, M, W, Het, Ph, p and q are as hereinabove defined and
g=2-6 and k=2-4, by reacting with the appropriately substituted
alcohol using triphenyl phosphine and diethyl azodicarboxylate in
an inert solvent;
[0435] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a HO--(CH.sub.2).sub.q-- group, it can be converted
to the corresponding groups: ##STR88## wherein q and R.sub.5 are as
hereinabove defined, by the reaction in an inert solvent with an
alkyl or phenyl substituted isocyanate, R.sub.5--N.dbd.C.dbd.O, or
using a base such as pyridine, with a reagent
(R.sub.5).sub.2NCOCl;
[0436] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is carboxy or a alkoxycarbonyl group of 2-7 carbon
atoms, it can be converted to the corresponding hydroxymethyl group
by reduction with an appropriate reducing agent such as lithium
borohydride, or lithium aluminum hydride in an inert solvent; the
hydroxymethyl group, in turn, can be converted to the corresponding
halomethyl group by reaction in an inert solvent with a
halogenating reagent such as phosphorus tribromide to give a
bromomethyl group, or phosphorus pentachloride to give a
chloromethyl group. The hydroxymethyl group can be acylated with an
appropriate acid chloride, anhydride, or mixed anhydride in an
inert solvent using pyridine or a trialkylamine as a base to give
the compounds of this invention with the corresponding
alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl
group of 2-7 carbon atoms, or alkynoyloxymethyl group of 2-7 carbon
atoms;
[0437] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a halomethyl group, it can be converted to the
corresponding groups: ##STR89## wherein R.sub.6, R.sub.7, R.sub.8,
R.sub.9, M, W, Het, p and q are as hereinabove defined by reacting
with the appropriately substituted alcohol, amine or mercaptan in
an inert solvent such as dioxane or acetonitrile and a base such as
triethylamine or potassium carbonate;
[0438] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR90## wherein R.sub.5
and q are as hereinabove defined by reacting with the appropriately
substituted acid chloride or mixed anhydride (which is prepared
from the corresponding carboxylic acid) in an inert solvent such as
tetrahydrofuran (THF) in the presence of an organic base such as
pyridine, triethylamine or N-methylmorpholine;
[0439] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR91## wherein R.sub.5
and q are as hereinabove defined, by reacting with phosgene in an
inert solvent such as toluene in the presence of a base such as
pyridine to give an isocyanate which, in turn, is treated with an
excess of the alcohol R.sub.5--OH;
[0440] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR92## wherein R.sub.5
and q are as hereinabove defined, by the reaction in an inert
solvent with an alkyl or phenyl substituted isocyanate,
R.sub.5--N.dbd.C.dbd.O, or by reacting with phosgene in an inert
solvent such as toluene in the presence of a base such as pyridine
to give an isocyanate which, in turn, is treated with an excess of
amine (R.sub.5).sub.2NH
[0441] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 52 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR93## wherein R.sub.5
and q are as hereinabove defined, by the reaction in an inert
solvent with an alkyl or phenyl substituted isothiocyanate,
R.sub.5--N.dbd.C.dbd.S, or by reacting with
1,1'-thiocarbonyldiimidazole in an inert solvent such as toluene in
the presence of a base such as pyridine to give an isothiocyanate
which, in turn, is treated with an excess of amine
(R.sub.5).sub.2NH.
[0442] The preparation of the compounds and intermediates of this
invention encompassed by Formula 59 is described below and in
Flowsheet 14 where Ar, X, Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4 and
n are as hereinabove defined.
[0443] Reaction of substituted benzaldehydes (Formula 53) with a
nitrating agent such as, but not limited to fuming nitric acid,
provides substituted nitrobenzaldehyde intermediates of Formula 54.
The condensation reaction of the substituted nitrobenzaldehyde
intermediates 54 with methyl cyanoacetate and a base such as
piperidine in an alcoholic solvent such as methanol, with or
without heating, provides the corresponding substituted
2-cyano-3-(2-nitrophenyl)acrylic acid methyl esters 55. Reduction
of the substituted 2-cyano-3-(2-nitrophenyl)acrylic acid methyl
esters 55 a reducing agent such as, but not limited to, iron (0) in
an alcoholic solvent provides the substituted
2-aminoquinoline-3-carboxylic acid methyl ester intermediates of
Formula 56. Heating the substituted 2-aminoquinoline-3-carboxylic
acid methyl ester intermediates of Formula 56 with
dimethylformamide dimethyl acetal with or without a solvent gives
intermediates of Formula 57. The reaction of 57 with from one to
ten equivalents of acetonitrile using a base such as
n-butyllithium, sodium methoxide or the like in an inert solvent
gives the
4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitriles 58, or
the 4-hydroxy-benzo[b][1,8]naphthyridine-3-carbonitrile tautomers
thereof. Heating 58 with or without solvent with a chlorinating
agent such as phosphorus oxychloride or oxalyl chloride provides
the corresponding
4-chlorobenzo[b][1,8]naphthyridine-3-carbonitriles. Condensation of
4-chlorobenzo[b][1,8]naphthyridine-3-carbonitriles with a
nucleophilic amine, aniline, mercaptan, thiophenol, phenol, or
alcohol reagent of Formula 5 gives the
benzo[b][1,8]naphthyridine-3-carbonitriles of Formula 59; this
condensation can be accelerated by heating the reaction mixture
together with one equivalent of pyridine hydrochloride or by using
bases such as trialkylamines, sodium hydride in an inert solvent,
sodium or potassium alkoxides in alcohol solvents, and the like. In
those cases where the Ar and/or Q.sub.1, Q.sub.2, Q.sub.3 and
Q.sub.4 substituents may contain an asymmetric carbon atom, the
intermediates can be used as the racemate or as the individual R or
S enantiomers in which case the compounds of this invention will be
in the racemic or R and S optically active forms, respectively. In
cases where the Ar and/or Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4
substituents may contain more than one asymmetric carbon atoms,
diastereomers may be present; these can be separated by methods
well known in the art including, but not limited to, fractional
crystallization and chromatographic methods. In those cases, in
intermediates 54 where Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4
contains primary or secondary amino groups or hydroxyl groups, it
may be necessary to protect these groups prior to the reaction with
methyl cyanoacetate. In those cases, in intermediates 5 where Ar
contains primary or secondary amino groups or hydroxyl groups, it
may be necessary to protect these groups prior to the reaction with
the 4-chlorobenzo[b][1,8]naphthyridine-3-carbonitriles. The same
amine or alcohol protecting groups hereinabove described can be
used and they can be removed from the products 59 as previously
described. The benzaldehydes of Formula 53 are either commercially
available, or are already known to the art or can be prepared by
procedures known in the art. ##STR94##
[0444] Converting the Q.sub.1, Q.sub.2, Q.sub.3 and Q.sub.4 groups
to R.sub.1, R.sub.2; R.sub.3 and R.sub.4 groups can be accomplished
through any conventionally known techniques, for example:
[0445] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a nitro group, it can be converted to the
corresponding amino group by reduction using a reducing agent such
as iron in acetic acid;
[0446] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is an amino group, it can be converted to the
corresponding dialkylamino group of 2 to 12 carbon atoms by
alkylation with at least two equivalents of an alkyl halide of 1 to
6 carbon atoms by heating in an inert solvent;
[0447] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a methoxy group, it can be converted to the
corresponding hydroxy group by reaction with a demethylating agent
such as boron tribromide in an inert solvent or by heating with
pyridinium chloride with or without solvent;
[0448] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is an amino group, it can be converted to the
corresponding alkylsulfonamido, alkenylsulfonamido, or
alkynylsulfonamido group of 2 to 6 carbon atoms by the reaction
with an alkylsulfonyl chloride, alkenylsulfonyl chloride, or
alkynylsulfonyl chloride, respectively, in an inert solvent using a
base such as triethylamine or pyridine;
[0449] where two of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of Formula
59 are contiguous methoxy groups, the corresponding compound with
contiguous hydroxy groups can be prepared by using a demethylating
agent such as boron tribromide in an inert solvent or by heating
with pyridinium chloride with or without solvent;
[0450] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is an amino group, it can be converted to the
corresponding alkylamino group of 1 to 6 carbon atoms by alkylation
with one equivalent of an alkyl halide of 1 to 6 carbon atoms by
heating in an inert solvent or by reductive alkylation using an
aldehyde of 1 to 6 carbon atoms and a reducing agent such as sodium
cyanoborohydride in a protic solvent such as water or alcohol, or
mixtures thereof;
[0451] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is hydroxy, it can be converted to the corresponding
alkanoyloxy, group of 1-6 carbon atoms by reaction with an
appropriate carboxylic acid chloride, anhydride, or mixed anhydride
in a inert solvent using pyridine or a trialkylamine as a base;
[0452] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is hydroxy, it can be converted to the corresponding
alkenoyloxy group of 1-6 carbon atoms by reaction with an
appropriate carboxylic acid chloride, anhydride, or mixed anhydride
in an inert solvent using pyridine or a trialkylamine as a
base;
[0453] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is hydroxy, it can be converted to the corresponding
groups: ##STR95## wherein V is oxygen, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, M W, Het, Ph, p and q are as hereinabove defined and g=2-6
and k=2-4, by reacting with the appropriately substituted alcohol
using triphenyl phosphine and diethyl azodicarboxylate in an inert
solvent;
[0454] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a HO--(CH.sub.2).sub.q-- group, it can be converted
to the corresponding groups: ##STR96## wherein q and R.sub.5 are as
hereinabove defined, by the reaction in an inert solvent with an
alkyl or phenyl substituted isocyanate, R.sub.5--N.dbd.C.dbd.O, or
using a base such as pyridine, with a reagent
(R.sub.5).sub.2NCOCl;
[0455] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is carboxy or a alkoxycarbonyl group of 2-7 carbon
atoms, it can be converted to the corresponding hydroxymethyl group
by reduction with an appropriate reducing agent such as lithium
borohydride, or lithium aluminum hydride in an inert solvent; the
hydroxymethyl group, in turn, can be converted to the corresponding
halomethyl group by reaction in an inert solvent with a
halogenating reagent such as phosphorus tribromide to give a
bromomethyl group, or phosphorus pentachloride to give a
chloromethyl group. The hydroxymethyl group can be acylated with an
appropriate acid chloride, anhydride, or mixed anhydride in an
inert solvent using pyridine or a trialkylamine as a base to give
the compounds of this invention with the corresponding
alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl
group of 2-7 carbon atoms, or alkynoyloxymethyl group of 2-7 carbon
atoms;
[0456] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a halomethyl group, it can be converted to the
corresponding groups: ##STR97## wherein R.sub.6, R.sub.7, R.sub.8,
R.sub.9, M, W, Het, p and q are as hereinabove defined by reacting
with the appropriately substituted alcohol, amine or mercaptan in
an inert solvent such as dioxane or acetonitrile and a base such as
triethylamine or potassium carbonate;
[0457] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR98## wherein R.sub.5
and q are as hereinabove defined by reacting with the appropriately
substituted acid chloride or mixed anhydride (which is prepared
from the corresponding carboxylic acid) in an inert solvent such as
tetrahydrofuran (THF) in the presence of an organic base such as
pyridine, triethylamine or N-methylmorpholine;
[0458] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR99## wherein R.sub.5
and q are as hereinabove defined, by reacting with phosgene in an
inert solvent such as toluene in the presence of a base such as
pyridine to give an isocyanate which, in turn, is treated with an
excess of the alcohol R.sub.5--OH;
[0459] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR100## wherein R.sub.5
and q are as hereinabove defined, by the reaction in an inert
solvent with an alkyl or phenyl substituted isocyanate,
R.sub.5--N.dbd.C.dbd.O, or by reacting with phosgene in an inert
solvent such as toluene in the presence of a base such as pyridine
to give an isocyanate which, in turn, is treated with an excess of
amine (R.sub.5).sub.2NH;
[0460] where one or more of Q.sub.1, Q.sub.2, Q.sub.3 or Q.sub.4 of
Formula 59 is a H.sub.2N(CH.sub.2).sub.q-- group, it can be
converted to the corresponding groups: ##STR101## wherein R.sub.5
and q are as hereinabove defined, by the reaction in an inert
solvent with an alkyl or phenyl substituted isothiocyanate,
R.sub.5--N.dbd.C.dbd.S, or by reacting with
1,1'-thiocarbonyldiimidazole in an inert solvent such as toluene in
the presence of a base such as pyridine to give an isothiocyanate
which, in turn, is treated with an excess of amine
(R.sub.5).sub.2NH.
[0461] Compounds of this invention are evaluated in several
standard pharmacological test procedures that showed that the
compounds of this invention possess significant activity as
inhibitors of protein kinases and are antiproliferative agents.
Among the disease states which can be treated or inhibited by
protein kinase inhibitors include those in which the etiology is at
least in part caused by a defect upstream in a signaling pathway
from a protein kinase (e.g., colon cancer); those in which the
etiology is at least in part caused by an overexpressed protein
kinase (e.g., lung cancer and colonic polyps); and those in which
the etiology is at least in part caused by a dysregulated protein
kinase (gene turned on at all times; glioblastoma).
[0462] Based on the activity shown in the standard pharmacological
test procedures, the compounds of this invention are therefore
useful as antineoplastic agents. In particular, these compounds are
useful in treating, inhibiting the growth of, or eradicating
neoplasms such as those of the breast, kidney, bladder, mouth,
larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver,
prostate and skin.
[0463] In addition to having antineoplastic properties, the
compounds of the present invention are useful in treating or
inhibiting a variety of protein tyrosine kinase-associated
disorders including: polycystic kidney disease, colonic polyps,
restenosis; atherosclerosis; angiofibromas; hemangiomas; diabetes;
acute and chronic nephropathies; Kaposi's sarcoma;
neovascularization associated with macular degeneration; rheumatoid
arthritis; osteoarthritis; transplant rejection; psoriasis; lupus;
graft versus host disease; glomerulonephritis; respiratory and skin
allergies; autoimmune alopecia; Autoimmune Hyperthyroidism;
multiple sclerosis; atopic dermatitis; and systemic sclerosis; and
are useful as antibacterial and antiviral agents.
[0464] As used in accordance with this invention, the term
providing an effective amount of a compound means either directly
administering such compound, or administering a prodrug,
derivative, or analog which will form an effective amount of the
compound within the body.
[0465] The test procedures used and results obtained are shown
below.
Inhibition of Epidermal Growth Factor Receptor Kinase (EGF-R) Using
Recombinant Enzyme
[0466] Representative test compounds are evaluated in a standard
pharmacological test procedure to measure their ability to inhibit
the phosphorylation of the tyrosine residue of a peptide substrate
catalyzed by the enzyme epidermal growth factor receptor kinase.
The peptide substrate (RR-SRC) has the sequence
arg-arg-leu-ile-glu-asp-ala-glu-tyr-ala-ala-arg-gly.
[0467] The enzyme used in this assay is the His-tagged cytoplasmic
domain of EGFR. A recombinant baculovirus (vHcEGFR52) is
constructed containing the EGFR cDNA encoding amino acids 645-1186
preceded by Met-Ala-(His).sub.6. Sf9 cells in 100 mm plates are
infected at a multiplicity of infection of 10 pfu/cell and cells
are harvested 48 h post infection. A cytoplasmic extract is
prepared using 1% Triton X-100 and applied to Ni-NTA column. After
washing the column with 20 mM imidazole, HcEGFR is eluted with 250
mM imidazole (in 50 mM Na.sub.2HPO.sub.4, pH 8.0, 300 mM NaCl).
Fractions collected are dialyzed against 10 mM HEPES, pH 7.0, 50 mM
NaCl, 10% glycerol, 1 ug/mL antipain and leupeptin and 0.1 mM
Pefabloc SC. The protein is frozen in dry ice/methanol and stored
-70.degree. C.
[0468] Test compounds are made into 10 mg/mL stock solutions in
100% dimethylsulfoxide (DMSO). Prior to experiment, stock solutions
are diluted to 500 uM with 100% DMSO and then serially diluted to
the desired concentration with HEPES buffer (30 mM HEPES pH
7.4).
[0469] For the enzyme reaction, 10 uL of each inhibitor (at various
concentrations) are added to each well of a 96-well plate. To this
is added 3 uL of enzyme (1:10 dilution in 10 mM HEPES, pH 7.4 for
final conc. of 1:120). This is allowed to sit for 10 min on ice and
is followed by the addition of 5 ul peptide (80 uM final conc.), 10
ul of 4.times. Buffer containing 50 mM HEPES (pH 7.4), 200 mM
Na.sub.3VO.sub.4, 40 mM MnCl, 80 uM ATP, 0.25 uL .sup.33P-ATP
(>2500 Ci/mmol; Amersham) and 12 uL H.sub.2O. The reaction is
allowed to run for 90 min at room temperature and is followed by
spotting the entire volume onto precut P81 filter papers. The
filter discs are washed 2.times. with 0.5% phosphoric acid and
radioactivity is measured using a liquid scintillation counter.
[0470] The inhibition data for representative compounds of the
invention are shown below in TABLE 1. The IC.sub.50 is the
concentration of test compound needed to reduce the total amount of
phosphorylated substrate by 50%. The % inhibition of the test
compound is determined for at least three different concentrations
and the IC.sub.50 value is evaluated from the dose response curve.
The % inhibition is evaluated with the following formula: %
inhibition=100-[CPM(drug)/CPM(control)].times.100
[0471] where CPM(drug) is in units of counts per minute and is a
number expressing the amount of radiolabled ATP (.gamma.-.sup.33P)
incorporated onto the RR-SRC peptide substrate by the enzyme after
90 minutes at room temperature in the presence of test compound as
measured by liquid scintillation counting. CPM(control) is in units
of counts per minute and is a number expressing the amount of
radiolabled ATP (.gamma.-.sup.33P) incorporated into the RR-SRC
peptide substrate by the enzyme after 90 minutes at room
temperature in the absence of test compound as measured by liquid
scintillation counting. The CPM values are corrected for the
background counts produced by ATP in the absence of the enzymatic
reaction. TABLE-US-00001 TABLE 1 Inhibition of EGF-R Kinase
(recombinant enzyme) Example IC50 (.mu.M) 37 0.0015 (a) 4 0.005 85
1 65 1 (a) 91 10 92 10 93 10 94 0.1 124 3.0 129 1.5 205 0.25 212
1.89 216 0.29 218 0.0053 (a) Average of two tests.
Inhibition of Kinase insert Domain containing Receptor (KDR; the
Catalytic Domain of the VEGF Receptor)
[0472] KDR protein is mixed, in the presence or absence of a
inhibitor compound, with a substrate peptide to be phosphorylated
(a copolymer of glutamic acid and tyrosine, E:Y::4:1) and other
cofactors such as Mg.sup.++ and sodium vanadate (a protein tyrosine
phosphatase inhibitor) in an appropriate buffer to maintain pH
(7.2). ATP and a radioactive tracer (either P.sup.32- or
P.sup.33-labeled ATP) is then added to initiate phosphorylation.
After incubation, the radioactive phosphate associated with the
acid-insoluble fraction of the test procedure mixture is then
quantified as reflection of substrate phosphorylation. This
radioactive format is used to identify inhibitors of KDR tyrosine
kinase activity where the IC.sub.50 is the concentration of drug
that inhibits substrate phosphorylation by 50%. The results
obtained for representative compounds of this invention are listed
in Table 2.
Mitogen Activated Protein Kinase (MAPK) Test Procedure
[0473] To evaluate inhibitors of the MAP (mitogen activated
protein) kinase a two component coupled standard pharmacological
test procedure, which measures phosphorylation of a
serine/threonine residue in an appropriate sequence in the
substrate in the presence and absence of a putative inhibitor, is
used. Recombinant human MEK 1 (MAPKK) is first used to activate
recombinant human ERK2 (MAPK) and the activated MAPK (ERK) is
incubated with substrate (myelin basic protein peptide (MBPP) or
Myc peptide) in the presence of ATP, Mg.sup.+2 and radiolabeled
.sup.33P ATP. The phosphorylated peptide is captured on a P 81
phosphocellulose filter (paper filter or embedded in microtiter
plate) washed and counted by scintillation methods.
[0474] The peptide substrates used in the assay are MBPP, peptide
substrate (APRTPGGRR), or synthetic Myc substrate,
(KKFELLPTPPLSPSRR-5 TFA). The recombinant enzymes used are prepared
as GST fusion proteins of human ERK 2 and human MEK 1. Inhibitor
samples are prepared as 10.times. stocks in 10% DMSO and an
appropriate aliquot is used to deliver either 10 ug/ml for a single
point screening dose or 100 to 0.0001 uM final concentration for a
dose response curve. Final DMSO concentrations are less than or
equal to 1%.
[0475] The reaction is run as follows in 50 mM Tris kinase buffer,
pH 7.4 in a reaction volume of 50 ul. The appropriate volume of
kinase buffer and inhibitor sample is added to the tube.
Appropriate dilution of enzyme is delivered to give 2-5 ug
recombinant MAPK (Erk) per tube. The inhibitor is incubated with
MAPK (Erk) for 30 min at 0 deg. C. Recombinant Mek (MAPKK) (0.5-2.5
ug) or fully activated Mek (0.05-0.1 units) is added to activate
the Erk and incubated for 30 min at 30.degree. C. Then substrate
and .gamma..sup.33P ATP are added to give a final concentration of
0.5-1 mM MBPP or 250-500 uM Myc; 0.2-0.5 uCi gamma P 33 ATP/tube;
50 .mu.M ATP final concentration. Samples are incubated at
30.degree. C. for 30 minutes and the reaction is stopped by adding
25 .mu.l of ice cold 10% trichloroacetic acid (TCA). After samples
are chilled on ice for 30 min, 20 .mu.l of sample is transferred
onto P 81 phosphocellulose filter. Filter papers are washed 2 times
with a large volume of 1% acetic acid, then 2 times with water. The
filters are briefly air dried before addition of scintillant and
samples are counted in the appropriate scintillation counter set up
for reading .sup.33P isotope. Samples include a positive control
(activated enzyme plus substrate); a no enzyme control; a no
substrate control; samples with different concentrations of
putative inhibitor, and samples with reference inhibitors (other
active compounds or non-specific inhibitors such as staurosporine
or K252 B).
[0476] The raw data is captured as cpm. Sample replicates are
averaged and corrected for background count. Mean cpm data is
tabulated by group and % inhibition by a test compound is
calculated as (corrected cpm control-corrected. cpm
sample/control).times.100=% inhibition). If several concentrations
of inhibitor are tested, IC.sub.50 values (the concentration which
gives 50% inhibition) are determined graphically. The results
obtained for representative compounds of this invention are listed
in Table 2.
Src Kinase Test Procedrue
[0477] Inhibitors of p60.sup.c-arc (partially purified preparation
purchased from Upstate Biotechnologies) tyrosine kinase activity
are analyzed in an Elisa format. The Boehringer Mannheim Tyrosine
Kinase Assay Kit (Catalog number 1-534505) with a cdc2 substrate
peptide containing Tyr15 is used for the assay. HRP-conjugated
anti-phosphotyrosine is used to detect phosphorylated peptide via a
color reaction. Conditions recommended by the manufacturer are
employed.
[0478] Reaction conditions: Five microliter aliquots of each
compound prepared fresh at the time of the assay are added as a
solution in 10 mM HEPES pH 7.5, 10% DMSO to the reaction well.
Thirty-five microliters of reaction mix containing Src, buffer and
peptide/bovine serum albumin mix are added to the compound wells
and incubated at 30.degree. C. for 10 minutes (reaction buffer: 50
mM Tris HCl pH 7.5, 10 mM MgCl.sub.2, 0.1 mM EGTA, 0.5 mM
Na.sub.3VO.sub.4). The reaction is started by addition of 10
microliters of ATP, incubated at 30.degree. C. for 1 hour, and
stopped by addition of 20 microliters of 0.5M EDTA. The reaction
mixture with the phosphorylated peptide is then transferred to a
streptavidin-coated microtiter plate (provided in the kit) and
allowed to bind for 20 minutes. Unbound peptide and reaction
mixture is decanted and the plate is washed with PBS six times.
Horseradish peroxidase-conjugated phosphotyrosine antibody supplied
in the kit is incubated with the plate for one hour, then decanted.
The plate is again washed with PBS six times. Substrate (provided
in the kit) is added and absorbance at 405 nm is measured.
[0479] Activity is determined as % inhibition as calculated by the
formula: (1-Abs/Abs(max)).times.100=% inhibition. Where multiple
concentrations of the test agent are used, an IC.sub.50
(concentration which gives 50% inhibition) could be determined.
[0480] The results obtained for representative compounds of this
invention are listed in Table 2. TABLE-US-00002 TABLE 2 Inhibition
of Kinase insert Domain containing Receptor (KDR), Mitogen
Activated Protein Kinase (Mek-Erk) and p60.sup.c-src (Src) KDR
Mek-Erk Src Example % Inh (10 .mu.M) IC50 (.mu.M) IC50 (.mu.M) %
Inh dose (.mu.M) 38 1.3 0.075(a) 39 1.3 0.016(a) 40 0.5 0.03(a) 57
0.028(a) 58 >10 3 0.2 5 0.012 12 0.0015(b) 14 0.018(a) 15 10
0.01 85 53 10 44 10 86 54 10 46 10 87 32 0 10 88 >100 69 3 70 22
42 0.012 44 0.03 61 0.281 65 7 10 67 0 10 7 10 68 4.2 75 0 10 90 0
1 103 30 0.1 104 30 0.1 105 0.094 106 0.19 107 0.40 124 0.00019(c)
125 0.0021(d) 128 0.0013 129 0.00035(d 130 0.0011(d) 131 0.00029(d
132 0.0014(d) 133 0.00031(d 157 0.0019(d) 158 0.00049 159 0.00018
165 0.22(a) 172 0.053 173 0.13 33 0.1 175 0.074 177 30 5 178 2.78
179 0.0029 190 0.0025 191 0.00072 192 0.0062 193 0.0029 194 0.0017
90 0.0015 195 0.0018 196 0.052 197 0.0027 198 0.00057 199 0.00022
200 0.00051 201 0.00077 202 0.00043 100 0.15 203 0.0042 204 0.0034
205 0.29 206 0.0027 207 0.002 208 0.00039 209 0.0049 210 0.00083
211 0.0011 212 0.15 215 0.0029 216 0.001(e) (a)Average of two runs
(b)Average of four runs (c)Average of six runs (d)Average of three
runs (e)Average of five runs
Cell Proliferation Test Procedure
[0481] HT-29 cells: Compound effectiveness at inhibiting cell
proliferation on plastic is performed in a 96-well format by
plating 5000 cells per well in appropriate medium on day one,
followed by compound addition on day 2 in serial two-fold
dilutions. On day five, compound is washed away and medium
containing MTS reagent (Promega) is added. Relative cell number is
determined by reading the absorbance at 490 nm of a dye produced by
an NAD-dependent cellular enzymatic reaction. These data are shown
below in Table 3.
[0482] Anchorage Independent Src-transformed Fibroblast
Proliferation Test Procedure: Rat2 fibroblasts stably transformed
with a plasmid containing a CMV promotor controlled v-Src/Hu c-Src
fusion gene in which the catalytic domain of human c-Src is
inserted in place of the v-Src catalytic domain in the v-Src gene
are used for the measurement of src dependent suspension growth.
Ultra-low cluster plates (Costar # 3474) are seeded with 10,000
cells per well on Day 1. Compound is added in serial two-fold
dilutions from 10 micromolar to 0.009 micromolar on Day 2 and MTS
reagent (Promega) is added on Day 5 (100 microliters of MTS/medium
mix+100 microliters of medium already on the cells and the
absorbance is measured at 490 nm. The results are analyzed as
follows to yield an IC.sub.50 for proliferation (micromolar units)
as follows: % inhibition=(Abs490 nm sample-blank)/(Abs490 nm no
cmpd control-blank).times.100%. These data are shown below in Table
3. TABLE-US-00003 TABLE 3 Inhibition of Cancer Cell Growth HT-29
prolif Src TF prolif @ dose IC.sub.50 @ dose IC.sub.50 Example %
Inh (.mu.M) (.mu.M) % Inh (.mu.M) (.mu.M) 40 10 10 0 10 39 35 10 25
10 38 25 10 0 10 57 0 10 42 0 10 50 0.22 124 >10 0.012(a) 128
0.23 129 >10 0.015(b) 130 0.26 131 0.056(b) 132 0.30 133 8.595
0.047(b) 157 0.038(c) 158 0.067(c) 159 0.073(c) 165 >10 172
1.875 173 3.74(d) 190 0.17 191 >10 0.022(b) 194 >10 195 0.286
196 1.781 197 2.071 198 0.353 199 0.023(c) 200 0.24 201 0.175(b)
202 0.068 203 0.071(b) 204 1.598(b) 206 0.307(b) 207 0.929 208
0.096 209 0.309 210 0.046 211 0.128 212 >10 215 0.105 216 9.95
0.004 (a)Average of five runs (b)Average of two runs (c)Average of
three runs (d)Average of four runs
Inhibition of Cancer Cell Growth as Measured by Cell Number
[0483] Human tumor cell lines are plated in 96-well plates (250
.mu.l/well, 1-6.times.10.sup.4 cells/ml) in RPMI 1640 medium,
containing 5% FBS (Fetal Bovine Serum). Twenty four hours after
plating, test compounds are added at various concentrations. After
48 hours exposure to test compounds, cells are fixed with
trichloroacetic acid, and stained with Sulforhodamine B. After
washing with trichloroacetic acid, bound dye is solubilized in 10
mM Tris base and optical density is determined using plate reader.
Under conditions of the assay the optical density is proportional
to the number of cells in the well. IC.sub.50s (concentrations
causing 50% inhibition of cell growth) are determined from the
growth inhibition plots. The test procedure is described in detail
by Philip Skehan et. al, J. Natl. Canc. Inst., 82, 1107-1112
(1990). These data are shown below in Table 4. Information about
some of the cell lines used in these test procedures is available
from the American Type Tissue Collection: Cell Lines and
Hybridomas, 1994 Reference Guide, 8th Edition. TABLE-US-00004 TABLE
4 Inhibition of Cancer Cell Growth as Measured by Cell Number
(IC.sub.50 .mu.g/mL) Example MDA-MB-435 A431 SK-BR3 SW620 4 1.65
0.332 1.01 1.08 15 0.85 0.58 >5 0.38 33 >5 4.88 >5 >5
37 3.48 (a) 0.58 (a) 0.6 (a) 3.72 (a) 65 >5 >5 >5 >5 85
>5 >5 >5 >5 90 0.46 0.41 0.59 0.67 92 >5 >5 >5
>5 93 1.69 0.838 0.224 1 94 3.9 1.11 1.09 >5 129 0.88 0.62
0.93 1.3 212 -- 0.76 0.04 0.36 218 33.5 4.7 3.5 11.6 (a) Average of
three runs
Raf1 Kinase Cascade Assay Procedure
[0484] Raf-1 (c-Raf) is used to phosphorylate and activate inactive
GST-MEK1 which then can phosphorylate and activate inactive p42
GST-MAPK, which subsequently is measured for phosphorylation of the
TEY sequence (aa's 202-204) by a phospho-specific antibody from
Sigma (cat. # 77439219041) Reagents: Sf9 insect cell lysate
containing full length 6his-tagged recombinant human c-Raf.
(Specific Activity: .about.200 U/ml). Human Non-active Mek-1-GST
and human GST-MAP kinase (recombinant proteins produced in E.
coli).
Stock Solutions Raf Assay:
1. Assay Dilution Buffer (ADB): 20 mM MOPS, pH 7.2, 25 mM
.beta.-glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1
mM dithiothreitol.
2. Magnesium/ATP Cocktail: 500 .mu.M cold ATP and 75 mM magnesium
chloride in ADB.
4. Active Kinase: Human Active c-Raf: Use at 0.4 U per assay
point.
5. Non-active GST-MEK1: Use at 0.1 .mu.g per assay point.
6. Non-active GST-p42 MAP Kinase: Use at 1.0 .mu.g per assay
point.
Stock Solutions ELISA:
1. TBST--Tris (50 mM, pH 7.5), NaCl (150 mM), Tween-20 (0.05%)
2. Superblock (Pierce)
3. Anti-GST Ab (Pharmacia)
4. Anti-Phospho MAPK (Sigma)
5. Anti-Mouse Ab/Europium conjugate (Wallac)
Assay Procedure:
First Stage: c-Raf Dependent Activation of GST-MEK and GST-MAPK
1. Add 20 ml of ADB per assay (i.e. per well of a 96 well
plate)
2. Add 10 ml of 0.5 mM cold ATP and 75 mM magnesium chloride in
ADB.
3. Add 2 ml of c-Raf (0.4 U/assay), in conjunction with 1.6 ml
non-active MEK1 (0.4 mg/assay).
4. Add 4 ml of non-active GST-p42 MAP Kinase (1.0 mg/assay).
5. Incubate for 60 minutes at 30.degree. C. in a shaking
incubator.
6. Transfer this mixture to an anti-GST Ab coated 96 well plate
(Nunc Immunosorb plates coated o/n with a-GST, then blocked with
Pierce Superblock).
7. Incubate for 60 minutes at 30.degree. C. in a shaking incubator
Wash 3.times. with TBST, add Anti-Phospho MAPK (Sigma) (1:3000)
6. Incubate for 60 minutes at 30.degree. C. in a shaking
incubator
7. Wash 3.times. with TBST, add Anti-Mouse Ab/Europium conjugate
(Wallac) (1:500)
8. Incubate for 60 minutes at 30.degree. C. in a shaking
incubator
9. Wash 3.times. with TBST, Read plates in Wallac Victor model
Plate Reader.
10. Collect data analyze in Excel for single point and IC50
determinations.
[0485] Single point assay--% inhibition at 10 mg/ml (%
Inhibition=1-cpd.treated sample/untreated control). IC.sub.50
determinations--done on compounds from single point assays with
>80% inhibition. Typically Raf-1 assay is run at compound
concentrations from 10 .mu.M to 1 nM in half log dilutions. (%
inhibition is determined for each compound concentration). The
results obtained for representative compounds of this invention are
listed in Table 2.
Cell Based Screen for Inhibitors of Raf Kinase.
Materials
[0486] Cell Lines: Human adenocarcinoma cell line LoVo which is
known to be growth inhibited by low nM concentrations of a
reference standard inhibitor of Ras and human adenocarcinoma cell
line CaCo-2, which is known to be growth resistant to the same
reference compound.
Cell Media: RPMI 1640 with 10% Fetal Bovine Serum supplemented with
L-glutamine and Pennicilin/Streptomycin.
Compounds: Supplied usually as a 10 mM stock in 100% DMSO.
Normal Saline: 150 mM NaCl
Trichloroacetic Acid (TCA): 50% (w/v) in water
Sulforhodamine B (SRB): 0.4% (w/v) in 1% Acetic Acid
Tris Base: 10 mM in water
Methods
[0487] Cells are plated at 2000 cells per well for cell line LoVo
and 1500 cells for cell line CaCo-2 in 96 well plates. Cells are
plated in media (200 .mu.l) and allowed to adhere overnight at
37.degree. C. At 24 hours post plating, compounds are added
directly at a volume of 0.5 .mu.l. For the qualitative screen
(compounds screened at compound is added directly to cells. For the
quantitative screen, compound is first diluted in DMSO to generate
concentrations of compound or reference standard of: 1, 5, 10 and
25 .quadrature.M. It is advisable to make the dilutions in an
identical 96 well plate so that compounds can be added using a
multichannel micropipettor set at 0.5 .mu.l. The cells are then
incubated for four days after which the media is removed using a 12
well manifold by first tipping the plate forward at a 45 degree
angle and then inserting the manifold in an upright orientation to
prevent the tips of the manifold from disturbing cells at the
bottom of the plate. 200 .mu.l of normal saline is then added to
each well using an 8 well multichannel pipettor, followed by the
careful addition of 50 .mu.l of 50% TCA The plates are then
incubated for 2 hours at 4.degree. C., after which the supernatant
is removed using the same technique as above and the plated washed
twice with 200 .mu.l water. The plates are then air dried and 50
.mu.l of SRB stock solution is carefully added so that the entire
bottom of each well is covered. This again can be used using an 8
well multichannel pipettor. The SRB is incubated with fixed cells
for 15 minutes at room temperature after which the SRB is removed
with the manifold as described above and the plates washed twice
with 350 .mu.l of 1% acetic acid per well each time. The plates are
then air dried after which the bound SRB is released from protein
by the addition of 200 .mu.l of Tris base. Resolubilizing the SRB
is aided by placing the plates on a rotator for 15-30 minutes. The
absorbance of each well is determined at 550 or 562 nm using a
microtiter plate reader.
[0488] Each compound or dilution thereof is performed in
triplicate. Outliers are identified by visual inspection of the
data. Each plate should have a "0" control (vehicle only).
[0489] Qualitative screen: To calculate % inhibition of a compound
at 25 .mu.M, the following formula is used: 1-(experimental
absorbance @ 25 .mu.M compound/"0" control absorbance).times.100=%
inhibition at 25 .mu.M. Compounds having >50% inhibition at 25
.mu.M are placed in the quantitative assay.
[0490] Quantitative Assay: A standard curve is constructed by
plotting the concentration of compound against the average
absorbance calculated at that concentration. A curve is plotted and
the concentration at which the curve passes through the 50% the
absorbance mark seen in the "0" control well is the IC.sub.50
calculated for that compound. Multiple entries for a given compound
indicate that it is tested multiple times. The results obtained for
representative compounds of this invention are listed in Table 5.
TABLE-US-00005 TABLE 5 raf LoVo BxPC3 LnCAP CaCo-2 Example
IC.sub.50 .mu.M IC.sub.50 .mu.M IC.sub.50 .mu.M IC.sub.50 .mu.M
IC.sub.50 .mu.M 3 0.09 39 0.9 40 0.7 44 0.009 0.85(a) 9.2(a) 124
0.13 129 0.3 149 0.004 0.006(c) 0.037(b) 0.053(b) 0.9(c) 151 0.007
0.0085 0.04 0.012 0.7 152 0.008 0.029 0.04 0.032 >1 153 0.012
0.0094 0.038 0.019 >1 154 0.008 0.043 0.04 >1 174 >10 0.44
4 176 2.995 3.5 10 213 0.027 0.3 1.4 214 0.31 0.25 8 217 >10
0.48 4.8 218 0.66 0.43 6 (a)Average of two runs (b)Average of three
runs (c)Average of five runs
The results shown in tables 1, 2, 3, 4 and 5 demonstrate that the
compounds of this invention are potent inhibitors of protein
kinases, and are useful as described above.
[0491] The compounds of this invention may be formulated neat or
may be combined with one or more pharmaceutically acceptable
carriers for administration. For example, solvents, diluents and
the like, and may be administered orally in such forms as tablets,
capsules, dispersible powders, granules, or suspensions containing,
for example, from about 0.05 to 5% of suspending agent, syrups
containing, for example, from about 10 to 50% of sugar, and elixirs
containing, for example, from about 20 to 50% ethanol, and the
like, or parenterally in the form of sterile injectable solution or
suspension containing from about 0.05 to 5% suspending agent in an
isotonic medium. Such pharmaceutical preparations may contain, for
example, from about 0.05 up to about 90% of the active ingredient
in combination with the carrier, more usually between about 5% and
60% by weight.
[0492] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration and the severity of the condition being treated.
However, in general, satisfactory results are obtained when the
compounds of the invention are administered at a daily dosage of
from about 0.5 to about 1000 mg/kg of animal body weight,
optionally given in divided doses two to four times a day, or in
sustained release form. For most large mammals the total daily
dosage is from about 1 to 1000 mg, preferably from about 2 to 500
mg. Dosage forms suitable for internal use comprise from about 0.5
to 1000 mg of the active compound in intimate admixture with a
solid or liquid pharmaceutically acceptable carrier. This dosage
regimen may be adjusted to provide the optimal therapeutic
response. For example, several divided doses may be administered
daily or the dose may be proportionally reduced as indicated by the
exigencies of the therapeutic situation.
[0493] The compounds of this invention may be administered orally
as well as by intravenous, intramuscular, or subcutaneous routes.
Solid carriers include starch, lactose, dicalcium phosphate,
microcrystalline cellulose, sucrose and kaolin, while liquid
carriers include sterile water, polyethylene glycols, non-ionic
surfactants and edible oils such as corn, peanut and sesame oils,
as are appropriate to the nature of the active ingredient and the
particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents,
preserving agents, and antioxidants, for example, vitamin E,
ascorbic acid, BHT and BHA.
[0494] The preferred pharmaceutical compositions from the
standpoint of ease of preparation and administration are solid
compositions, particularly tablets and hard-filled or liquid-filled
capsules. Oral administration of the compounds is preferred.
[0495] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol.
[0496] The compounds of this invention may also be administered
parenterally or intraperitoneally. Solutions or suspensions of
these active compounds as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a
surfactant such as hydroxy-propylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in oils. Under ordinary conditions of storage and use,
these preparation contain a preservative to prevent the growth of
microorganisms.
[0497] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0498] For the treatment of cancer, the compounds of this invention
can be administered in combination with other antitumor substances
or with radiation therapy. These other substances or radiation
treatments can be given at the same or at different times as the
compounds of this invention. These combined therapies may effect
synergy and result in improved efficacy. For example, the compounds
of this invention can be used in combination with mitotic
inhibitors such as taxol or vinblastine, alkylating agents such as
cisplatin or cyclophosamide, antimetabolites such as 5-fluorouracil
or hydroxyurea, DNA intercalators such as adriamycin or bleomycin,
topoisomerase inhibitors such as etoposide or camptothecin,
antiangiogenic agents such as angiostatin, and antiestrogens such
as tamoxifen.
[0499] The preparation of representative examples of the compounds
of this invention is described below.
EXAMPLE 1
4-Oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
[0500] A suspension of 5.6 g (30 mmol) of 3-amino-2-napthoic acid
in 30 mL of N,N-dimethylformamide dimethyl acetal is refluxed for 6
hours. Removal of the solvent yields 7.06 g (86.4%) of methyl
3-{[(dimethylamino)methylidene]amino}-2-naphthoate as a dark oil
residue. To a solution of 20.8 mL (52 mmol) of n-butyllithium (2.5M
in hexane) in 18 mL of tetrahydrofuran (THF) is added dropwise a
solution of 5.97 mL (114 mmol) of acetonitrile in 100 mL of THF at
-78.degree. C. After completion of addition, the suspension is
stirred for 15 minutes. To this is added 7.02 g (26 mmol) of
3-{[(dimethylamino)methylidene]amino}-2-naphthoate in 50 mL of THF
dropwise. The resulting reaction mixture is stirred at -78.degree.
C. for 1 hour. Then 7.8 g (130 mmol) of acetic acid is added
dropwise. The reaction mixture is warmed up to room temperature and
diluted with water. The precipitate is collected by filtration and
washed with water and ethyl acetate. After drying in vacuo, this
yields 3.80 g (67%) of the product as a yellow solid,
mp>260.degree. C.
[0501] .sup.1HNMR(DMSO-d.sub.6): .delta. 7.58 (t, J=6.8, 1H); 7.68
(t, J=6.8, 1H); 8.09 (d, J=8.2, 1H); 8.14 (s, 1H); 8.23 (d, 1H);
8.80 (s, 1H); 8.85 (s, 1H); 12.85 (bs,1H).
[0502] MS (ES, positive ion mode): m/z calcd for
C.sub.14H.sub.8N.sub.2O: 220.23, found: 221.2 (M+H).sup.+.
[0503] Analysis for C.sub.14H.sub.8N.sub.2O.0.15H.sub.2O
[0504] Calcd: C, 75.42; H, 3.75; N, 12.56.
[0505] Found: C, 75.38; H, 3.68; N, 12.52.
EXAMPLE 2
4-Chlorobenzo[g]quinoline-3-carbonitrile
[0506] A reaction mixture of 3.5 g (16 mmol) of
4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 35 mL of
phosphorus oxychloride and 22 drops of N,N-dimethylformamide (DMF)
is heated at 100-110.degree. C. for 5 hours. After cooling, the
mixture is concentrated to dryness in vacuo to give a dark residue.
The residue is partitioned between methylene chloride and
ice-cooled saturated aqueous sodium carbonate solution. The organic
layer is washed with ice-cooled brine and dried over sodium
sulfate. The organic solvent is passed through a short column of
silica gel, and further eluted with additional methylene chloride.
Removal of the solvent yields 1.89 g (49.5%) of the product as a
bright yellow solid, mp 253-255.degree. C.
[0507] .sup.1HNMR(DMSO-d.sub.6): .delta. 7.77 (m, 2H); 8.33 (d,
3=9.3, 1H); 8.39 (d, 3=9.5, 1H); 8.91 (s, 1H); 9.08 (s, 1H); 9.18
(s, 1H).
[0508] MS (ES, positive ion mode): m/z calcd for
C.sub.14H.sub.7ClN.sub.2: 238.68, found: 239.2 (M+H).sup.+.
[0509] Analysis for C.sub.14H.sub.7ClN.sub.2
[0510] Calcd: C, 70.45; H, 2.96; N, 11.74.
[0511] Found: C, 70.16; H, 3.04; N, 11.55.
EXAMPLE 3
4-(4-Phenoxyanilino)benzo[g]quinoline-3-carbonitrile
[0512] A reaction mixture of 141.8 mg (0.59 mmol) of
4-chlorobenzo[g]quinoline-3-carbonitrile, 111.1 mg (0.60 mmol) of
4-phenoxyaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride
in 8 ml of 2-ethoxyethanol is heated at 110-120.degree. C. for 1
hour. After cooling, the mixture is diluted with water and made
basic by addition of 125.0 mg (1.18 mmol) of sodium carbonate. The
precipitate is collected by filtration and washed with water.
Drying in vacuo yields the crude product. The crude product is
purified by chromatography, eluting with a methylene
chloride/methanol gradient from 100:0 to 86:14, to provide 167.8 mg
(73.4%) of the pure product as a yellow solid, mp 250-251.degree.
C.
[0513] .sup.1HNMR(DMSO-d.sub.6): .delta. 7.05 (s, 1H); 7.08 (s,
1H); 7.14 (m, 3H); 7.43 (m, 4H); 7.66 (m, 2H); 8.11 (d, J=8.1, 1H);
8.19 (d, J=7.8, 1H); 8.55 (d, 2H); 9.24 (s, 1H); 10.22 (bs,
1H).
[0514] MS (ES, positive ion mode): m/z calcd for
C.sub.26H.sub.17N.sub.3O: 387.44, found: 388.2 (M+H).sup.+.
[0515] Analysis for C.sub.26H.sub.17N.sub.3O.0.2H.sub.2O
[0516] Calcd: C, 79.86; H, 4.48; N, 10.74.
[0517] Found: C, 79.87; H, 4.44; N, 10.70.
EXAMPLE 4
4-(3-Chloro-4-fluoroanilino)benzo[g]quinoline-3-carbonitrile
[0518] Following the procedure of Example 3, the reaction mixture
of 141.8 mg (0.60 mmol) of
4-chlorobenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of
3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine
hydrochloride in 8.0 mL of 2ethoxyethanol is heated at
110-120.degree. C. for 1 hour to yield 162.5 mg (77.9%) of the
product as a bright yellow solid, mp 257-259.degree. C.
[0519] .sup.1HNMR(DMSO-d.sub.6): .delta. 7.51 (m, 2H); 7.67 (m,
2H); 8.13 (d, J=8.1, 1H); 8.20 (d, J=8.1 1H); 8.61 (s, 2H); 9.19
(s, 1H); 10.24 (s, 1H); 12.25 (bs, 1H).
[0520] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.11ClFN.sub.3: 347.78, found: 348.3
[0521] Analysis for C.sub.20H.sub.11ClFN.sub.3.0.2H.sub.2O
[0522] Calcd: C, 68.36; H, 3.27; N, 11.96.
[0523] Found: C, 68.60; H, 3.29; N, 11.70.
EXAMPLE 5
4-(4-Chloro-5-methoxy-2-methylanilino)benzo[g]quinoline-3-carbonitrile
[0524] Following the procedure of Example 3, the reaction mixture
of 141.8 mg (0.60 mmol) of
4-chlorobenzo[g]quinoline-3-carbonitrile, 102.9 mg (0.60 mmol) of
4-chloro-5-methoxy-2-methylaniline (can be prepared by the
procedure disclosed in WO 85/01939, which is hereby incorporated by
reference) and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0
mL of 2-ethoxyethanol is heated at 130-135.degree. C. for 1.5 hours
to yield the crude product. Purification of the crude product on
preparative TLC (developing solvent: 95:5 methylene
chloride/methanol) yields 159.3 mg (72.2%) of the pure product as a
yellow solid, mp 195-197.degree. C.
[0525] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.16 (s, 3H); 3.82 (s,
3H); 7.22 (s, 1H); 7.46 (s, 1H); 7.67 (m, 2H); 8.12 (d, J=8.1, 1H);
8.19 (d, J=8.1, 1H); 8.54 (d, J=14.7, 2H); 9.29 (s, 1H); 10.11 (s,
1H).
[0526] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.16ClN.sub.3O: 373.84, found: 374.3 (M+H).sup.+.
[0527] Analysis for C.sub.22H.sub.16ClN.sub.3O.0.55H.sub.2O
[0528] Calcd: C, 68.86; H, 4.49; N, 10.95.
[0529] Found C, 68.70; H, 4.64; N, 10.41.
EXAMPLE 6
6,7-Dimethoxy-3-(methoxycarbonyl)-2-naphthoic acid
[0530] To 20 mL of methanol at room temperature is added 200 mg
(5.0 mmol) of 60% sodium hydride in mineral oil. The solution is
stirred for 5 minutes, and then added to a suspension of 516 mg
(2.0 mmol) of 6,7-dimethoxy-2,3-naphthalenedicarboxylic anhydride
(McOmie, John F. W.; Perry, David H. Synthesis (1973), Issue 7,
416-417) in 30 mL of methanol. The mixture is stirred at room
temperature for 10 minutes, and concentrated. The residue is
partitioned between ethyl acetate and saturated sodium carbonate
solution. The aqueous layer is separated and neutralized with
concentrated hydrochloric acid to pH 1. The product is extracted
with ethyl acetate, dried over magnesium sulfate, and concentrated
in vacuo. The waxy solid thus obtained is washed with ethyl acetate
to yield the product as 406 mg (70%) of an off-white solid, mp
181-183.degree. C.
[0531] .sup.1HNMR(DMSO-d.sub.6): .delta. 13.10 (s, 1H), 8.21 (s,
1H), 8.07 (s, 11, 7.54 (s, 1H), 7.51 (s, 1H), 3.91 (s, 6H), 3.81
(s, 3H).
[0532] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.14O.sub.6: 290.3, found: 291.3 (M+H).sup.+.
[0533] Analysis for C.sub.15H.sub.14O.sub.6.0.1H.sub.2O
[0534] Calcd: C, 61.12; H, 4.96.
[0535] Found: C, 61.03; H, 4.99.
EXAMPLE 7
3-Amino-6,7-dimethoxy-2-naphthalene-2-carboxylic acid methyl
ester
[0536] A mixture of 290 mg (1.0 mmol) of
6,7-dimethoxy-3-(methoxycarbonyl)-2-naphthoic acid, 1.0 g of
diphenylphosphoryl azide, and 1 mL of triethylamine in 10 mL of
toluene is refluxed for 15 minutes and added dropwise to a solution
of 80 mL of acetone and 10 mL of water at 80.degree. C. The mixture
is heated at 80.degree. C. for 1 hour and concentrated. The residue
is partitioned between ethyl acetate and saturated sodium chloride
solution. The organic layer is dried over magnesium sulfate and
concentrated. The residue is chromatographed over silica gel,
eluted with 1:1 ethyl acetate/hexanes to yield 105 mg (40%) of a
yellow solid, mp 125-127.degree. C.
[0537] .sup.1HNMR (DMSO): .delta. 8.25 (s, 1H), 7.19 (s, 1H), 6.91
(s, 2H), 6.25 (brs, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79 (s,
3H).
[0538] MS (ES, positive ion mode): m/z calcd for
C.sub.14H.sub.15NO.sub.4: 261.3, found: 262.3 (M+H).sup.+.
[0539] Analysis for C.sub.14H.sub.15NO.sub.4
[0540] Calcd: C, 64.36; H, 5.79; N, 5.36.
[0541] Found: C, 64.08; H, 5.64; N, 5.39.
EXAMPLE 8
3-(Dimethylamino-methyleneamino)-6,7-dimethoxy-naphthalene-2-carboxylic
acid methyl ester
[0542] A suspension of 1.95 g (7.46 mmol) of
3-amino-6,7-dimethoxy-2-naphthalene-2-carboxylic acid methyl ester
in 40 mL of N,N-dimethylformamide dimethyl acetal is refluxed for
1.5 hours. Removal of the solvent yields a solid residue which is
washed with diethyl ether and ethyl acetate, affording 1.99 g
(83.8%) of the product as an off-white solid, mp 180-182.degree.
C.
[0543] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.00 (bs, 6H); 3.77 (s,
3H); 3.84 (s, 3H); 3.86 (s, 3H); 7.12 (s, 1H); 7.17 (s, 1H); 7.29
(s, 1H); 7.65 (s,1H); 7.93(s, 1H).
[0544] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.20N.sub.2O.sub.4: 316.36, found: 317.1
(M+H).sup.+.
[0545] Analysis for C.sub.17H.sub.20N.sub.2O.sub.4
[0546] Calcd: C, 64.54; H, 6.37; N, 8.86.
[0547] Found: C, 64.37; H, 6.31; N, 8.74.
EXAMPLE 9
7,8-Dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
[0548] To a solution of 2.6 mL (6.3 mmol) of n-butyllithium (2.5M
in hexane) in 2.0 ml of THF is added dropwise a solution of 0.36 mL
(6.9 mmol) of acetonitrile in 6 mL of THF at -78.degree. C. After
completion of addition, the suspension is stirred for 15 minutes.
To this is added 496.7 mg (1.57 mmol) of
3-(dimethylaminomethyleneamino)-6,7-dimethoxy-naphthalene-2-carboxylic
acid methyl ester in 15 mL of THF dropwise. The resulting reaction
mixture is stirred at -78.degree. C. for 1.5 hours. Then 942.8 mg
(15.7 mmol) of acetic acid is added dropwise. The reaction mixture
is warmed to room temperature and is diluted with water. The
precipitate is collected by filtration and washed with water and
methanol. After drying in vacuo, this yields 406.0 mg (92.3%) of
the product as a light brown solid, mp>265.degree. C.
[0549] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.91 (s, 3H); 3.95 (s,
3H); 7.45 (s, 1H); 7.59 (s, 1H); 7.94 (s, 1H); 8.62 (s, 1H); 8.70
(s, 1H); 12.75 (bs,1H).
[0550] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.12N.sub.2O.sub.3: 280.28, found: 279.3
(M+H).sup.+.
[0551] Analysis for C.sub.16H.sub.12N.sub.2O.sub.3.0.75H.sub.2O
[0552] Calcd: C, 65.41; H, 4.63; N, 9.53.
[0553] Found: C, 65.29; H, 4.43; N, 9.40.
EXAMPLE 10
4-Chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile
[0554] A mixture of 356.2 mg (1.3 mmol) of
7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in
5 mL of phosphorus oxychloride and 4 drops of DMF is heated at
100-110.degree. C. for 4.5 hours. After cooling, the mixture is
concentrated to dryness in vacuo to give a dark residue. The
residue is partitioned between methylene chloride and ice-cooled
saturated aqueous sodium carbonate solution. The organic layer is
washed with cooled brine and dried over sodium sulfate. The organic
solvent is passed through a short column of silica gel, and the
column is first eluted with additional methylene chloride, then a
99:1 methylene chloride/ethyl acetate soltion. Removal of the
solvent yields 187.0 mg (49.4%) of the product as a bright yellow
solid, mp>265.degree. C.
[0555] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.99 (s, 3H); 4.00 (s,
3H); 7.65 (s, 1H); 7.74 (s, 1H); 8.63 (s, H); 8.80 (s, 1H); 9.06
(s, 1H).
[0556] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.11ClN.sub.2O.sub.2: 298.73, found: 299.2
(M+H).sup.+.
[0557] Analysis for
C.sub.16H.sub.11ClN.sub.2O.sub.2.0.5H.sub.2O
[0558] Calcd: C, 62.44; H, 3.93; N, 9.10.
[0559] Found: C, 62.41; H, 3.81; N, 8.91.
EXAMPLE 11
7,8-Dimethoxy-4-(4-phenoxyanilino)benzo[g]quinoline-3-carbonitrile
[0560] A mixture of 75.5 mg (0.25 mmol) of
4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 56.2 mg
(0.30 mmol) of 4-phenoxyaniline and 28.9 mg (0.25 mmol) of pyridine
hydrochloride in 5 mL of 2-ethoxyethanol is heated at
120-125.degree. C. for 2 hours. After cooling, the mixture is
diluted with water and neutralized by the addition of 53.0 mg (0.5
mmol) of sodium carbonate. The precipitate is collected by
filtration and washed with water, diethyl ether and methanol.
Drying in vacuo yields 83.2 mg (63.5%) of the product as a yellow
solid, mp>265.degree. C.
[0561] .sup.1HNMR (DMSO-d.sub.6): .delta. 4.00 (s, 3H); 4.02 (s,
3H); 7.07-7.20 (m, 5H); 7.36 (s, 1H); 7.42 (dd, J=8.34, J=11.13,
2H); 7.53 (s, 1H); 7.56 (s, 1H); 7.65 (s, 1H); 8.37 (s, 1H); 9.01
(s, 1H); 9.27 (s, 1H); 11.50 (bs, 1H).
[0562] MS (ES, positive ion mode): m/z calcd for
C.sub.28H.sub.21N.sub.3O.sub.3: 447.49, found: 448.3
(M+H).sup.+.
[0563] Analysis for C.sub.28H.sub.21N.sub.3O.sub.3.2 HCl
[0564] Calcd: C, 64.62; H, 4.46; N, 8.07.
[0565] Found: C, 64.55; H, 4.75; N, 7.95.
EXAMPLE 12
4-(4-Chloro-5-methoxy-2-methylanilino)-7,8-dimethoxybenzo[g]quinoline-3-ca-
rbonitrile
[0566] Following the procedure of Example 11, a mixture of 75.8 mg
(0.25 mmol) of
4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 51.5 mg
(0.30 mmol) of 4-chloro-5-methoxy-2-methylaniline and 28.9 mg (0.25
mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is
heated at 120-130.degree. C. for 2 hours to yield the crude
product. Purification of the crude product on preparative TLC
(developing solvent: 95:5 methylene chloride/methanol) yields 88.7
mg (82.1%) of the pure product as a yellow solid, mp
171-173.degree. C.
[0567] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.13 (s, 3H); 3.80 (s,
3H); 3.96 (s, 3H); 3.97 (s, 3H); 7.15 (s, 1H); 7.33 (s, 1H); 7.41
(s, 1H); 7.52 (s, 1H); 8.32 (s, 1H); 8.43 (s, 1H); 9.01 (s, 1H);
9.94 (bs, 1H).
[0568] MS (ES, positive ion mode): m/z cacld for
C.sub.24H.sub.20ClN.sub.3O.sub.3: 433.89, found: 434.3
(M+H).sup.+.
[0569] Analysis for C.sub.24H.sub.20ClN.sub.3O.sub.3
[0570] Calcd: C, 66.44; H, 4.65; N, 9.68.
[0571] Found: C, 65.06; H, 4.80; N, 9.46.
EXAMPLE 13
4-(3-Chloro-4-fluoroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile
[0572] Following the procedure of Example 11, a mixture of 149.4 mg
(0.50 mmol) of
4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 87.3 mg
(0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of
pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at
100-110.degree. C. for 1.0 hour to yield 184.4 mg (83.0%) of the
product as a yellow solid, mp>280.degree. C.:
[0573] .sup.1HNMR (DMSO-d.sub.4): .delta. 3.99 (s, 3H); 4.02 (s,
3H); 7.36 (s, 1H); 7.58 (m, 2H); 7.65 (s, 1H); 7.85 (d, J=4.5, 1H);
8.40 (s, 1H); 9.05 (s, 1H); 9.30 (s, 1H); 11.70 (bs, 1H).
[0574] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.15ClFN.sub.3O.sub.2: 407.83, found: 408.2
(M+H).sup.+.
[0575] Analysis for C.sub.22H.sub.15ClFN.sub.3O.sub.2,
HCl.0.5H.sub.2O
[0576] Calcd: C, 58.29; H, 3.78; N, 9.27.
[0577] Found: C, 58.05; H, 3.94; N, 9.10.
EXAMPLE 14
4-(2,4-Dichloroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile
[0578] A mixture of 178.2 mg (1.1 mmol) of 2,4-dichloroaniline and
44.0 mg (1.1 mmol) of sodium hydride in anhydrous DMF is stirred at
room temperature for 0.5 hours. To the mixture is added 149.4 mg
(0.5 mmol) of
4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile. The
resulting mixture is heated at 50-60.degree. C. for 1 hour. After
cooling, the mixture is diluted with water and extracted with ethyl
acetate. The organic phase is washed with brine and dried over
sodium sulfate. Removal of the solvent yields a dark residue which
is purified on preparative TLC (developing solvent: 97:3 methylene
chloride/methanol), giving a yellow foam. Trituration of the foam
with diethyl ether containing several drops of methanol yields
126.1 mg (59.5%) of the product as a yellow solid, mp
271-273.degree. C.
[0579] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.95 (s, 6H); 7.54 (m,
5H); 8.34 (s, 1H); 8.84 (s, 1H); 10.05 (bs 1H); 12.40 (bs, 1H).
[0580] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.15Cl.sub.2N.sub.3O.sub.2: 424.3, found: 426.1
[0581] Analysis for
C.sub.22H.sub.15Cl.sub.2N.sub.3O.sub.2.0.6H.sub.2O
[0582] Calcd: C, 60.73; H, 3.75; N, 9.66.
[0583] Found: C, 60.69; H, 3.70; N, 9.51.
EXAMPLE 15
4-(2,4-Dichloroanilino)-7,8-dihydroxybenzo[g]quinoline-3-carbonitrile
[0584] A mixture of 252.6 mg (0.6 mmol) of
4-(2,4-dichloroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile
and 5.0 g of pyridine hydrochloride is heated at 215-220.degree. C.
for 40 minutes under nitrogen. After cooling, the mixture is
neutralized with 3% ammonium hydroxide aqueous solution and stirred
for 30 minutes. The precipitate is collected, washed with water and
dried in vacuo. The crude product is passed through a short column
of silica gel, eluting with a gradient of methylene
chloride/methanol 90:10 to 50:50, to provide 122.8 mg (51.7%) of
the product as a brown solid, mp>260.degree. C.
[0585] .sup.1HNMR (DMSO-d.sub.6+TFA): .delta. 7.44 (d, J=9, 2H);
7.68 (dd, J=3, J=6, 1H); 7.79 (d, J=6, 1H); 7.95, (s 1H); 8.23 (s,
1H); 9.15 (s, 1H); 9.17 (s, 1H).
[0586] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.11Cl.sub.2N.sub.3O.sub.2: 396.2, found: (M+H).sup.+
396.1.
[0587] Analysis for
C.sub.20H.sub.11Cl.sub.2N.sub.3O.sub.2.0.6H.sub.2O
[0588] Calcd: C, 59.02; H, 3.02; N, 10.32.
[0589] Found: C, 59.10; H, 3.21; N, 10.12.
7-Chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
[0590] A mixture of 12.0 g (40.5 mmol) of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl
ester (J. Med. Chem. 23, 1358 (1980)) and 60.0 mL of 2.5 N sodium
hydroxide in 160.0 mL of ethanol is heated at reflux temperature
for 1.5 hours. After allowing the reaction mixture to cool to room
temperature, it is further cooled in an ice bath, brought to pH 4
with 4.0 N hydrochloric acid and stirred for 0.5 hour. The solid is
collected by filtration, washed with water and dried in vacuo to
yield 10.1 g of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a
tan solid, mp 294-297.degree. C.
[0591] .sup.1HNMR (DMSO-d.sub.4):.delta. 9.71(s, 1H); 8.70 (s, 1H);
8.09 (s, 1H).
[0592] MS (ES, negative mode): m/z calcd for
C.sub.10H.sub.5ClN.sub.2O.sub.5: 268, found: 266.8 (M-H).sup.-.
[0593] Analysis for C.sub.10H.sub.5ClN.sub.2O.sub.5
[0594] Calcd: C, 44.72; H, 1.88; N, 10.43.
[0595] Found: C, 44.38; H, 2.05; N, 10.22.
EXAMPLE 17
7-Chloro-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
amide
[0596] A mixture of 10.1 g (37.61 mmol) of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and
14.0 g (86.34 mmol) of 1-1'-carbonyldiimidazole in 110 mL of
N,N-dimethylformamide is heated at 60.degree. C. for 50 minutes
under nitrogen. The mixture is cooled in an ice bath and ammonia
gas is bubbled through the solution for 7 minutes. After further
stirring for 0.5 hours, the reaction mixture is poured on to ice.
The solid is collected by filtration, washed with water and dried
to yield 9.75 g of yellow solid. A 0.17 g sample is purified by
silica gel chromatography utilizing a gradient of methylene
chloride/methanol (98:2 to 92:8) to yield 0.12 g of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid amide
as beige solid, mp 298-300.degree. C.
[0597] .sup.1HNMR (DMSO-d.sub.6): .delta. 13.0 (br s, 14); 8.96 (d,
1H, J=3.3 Hz); 8.81 (s, 1H); 8.74 (s, 1H); 7.97 (s, 1H); 7.65 (d,
1H, J=3.6 Hz).
[0598] MS (ES, positive mode):m/z calcd for
C.sub.10H.sub.6ClN.sub.3O.sub.4: 267, found 268 (M+H).sup.+.
[0599] Analysis for C.sub.10H.sub.6ClN.sub.3O.sub.4.0.3H.sub.2O
[0600] Calcd: C, 43.98; H, 2.44; N, 15.39.
[0601] Found: C, 44.13; H, 2.53; N, 14.99.
EXAMPLE 18
7-Chloro-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile
[0602] To a suspension of 9.58 g (35.77 mmol) of
7-chloro-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
amide in 60.0 mL of N,N-dimethylformamide is added 4.0 g (21.7
mmol) of cyanuric chloride and the resulting clear solution is
stirred at room temperature for 0.5 hours under nitrogen. The
mixture is heated at 50.degree. C. for 10 minutes, stirred at room
temperature for an extra 10 minutes and then poured on to ice. The
solid is collected by filtration, washed with water and dried to
yield 8.9 g of a brown solid. A 0.17 g sample is purified by silica
gel chromatography utilizing a gradient of methylene
chloride/methanol (97:3 to 95:5) to yield 0.12 g of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile as beige
solid, mp>300.degree. C.
[0603] .sup.1HNMR (DMSO-d.sub.6): .delta. 13.2 (bs, 1H); 8.91(s,
1H); 8.71 (s, 1H); 7.88 (s, 1H).
[0604] MS (ES, negative mode): m/z calcd for
C.sub.10H.sub.4ClN.sub.3O.sub.3: 249, found: 248 (M-H).sup.-.
[0605] Analysis for C.sub.10H.sub.4ClN.sub.3O.sub.3.0.2H.sub.2O
[0606] Calcd: C, 47.43; H, 1.75; N, 16.60.
[0607] Found: C, 47.70; H, 1.96; N, 16.34.
EXAMPLE 19
7-Chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl)-1,4-dihydro-3--
quinolinecarbonitrile
[0608] To a cold suspension of 1.67 g (41.75 mmol) of sodium
hydride (60% in oil) in 70.0 mL of N,N-dimethylformamide is added
8.73 g (34.98 mmol) of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile in
portions over a period of 20 minutes under nitrogen. The resulting
mixture is stirred at 5.degree. C. for 20 minutes and then 7.5 mL
(42.37 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride is added
dropwise. After stirring at 5.degree. C. for 20 minutes, the
mixture is poured on to ice. The solid is collected by filtration,
washed with water and dried to yield 13.3 g of a brown solid. The
solid is purified by silica gel chromatography, utilizing a
gradient of methylene chloride/methanol (99.5:0.5 to 98:2) to yield
10.5 g of
7-chloro-6-nitro-4-oxo-1-{([2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro--
3-quinolinecarbonitrile as white solid, mp 200-202.degree. C.
[0609] .sup.1HNMR (DMSO-d.sub.6): .delta. 9.12(s, 1H); 8.74 (s,
1H); 8.27 (s, 1H); 5.71 (s, 2H); 3.63 (dd, 2H, J=5.2, 10.5
Hz);).0.88 (dd, 2H, J=5.0, 8.1 Hz); 0.07 (s, 9H).
[0610] MS (ES, positive mode):m/z calcd for
C.sub.16H.sub.18ClN.sub.3O.sub.4Si: 379, found: 380
(M+H).sup.+.
[0611] Analysis for C.sub.16H.sub.18ClN.sub.3O.sub.4Si
[0612] Calcd: C, 50.59; H, 4.78; N, 11.06.
[0613] Found: C, 50.57; H, 4.97; N, 11.02.
EXAMPLE 20
6,7-Diamino-4-oxo-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydro-quinoline-
-3-carbonitrile
[0614] To a solution of 6.0 g (15.8 mmol) of
7-chloro-6-nitro-4-oxo-1-([2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-
-quinolinecarbonitrile in 120 mL of dimethyl sulfoxide is added
5.13 g (79.0 mmol) of sodium azide and the resulting mixture is
stirred at room temperature for 3 hours. The mixture is then heated
at 60.degree. C. for 10 minutes, room temperature for 1 hour and
then poured on to ice. The solid is collected by filtration, washed
thoroughly with water and dried in vacuo to yield 6.1 g of
7-azido-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3--
quinolinecarbonitrile as a yellow solid.
[0615] A mixture of 6.1 g (15.8 mmol) of
7-azido-6-nitro-4-oxo-1-([2-(trimethylsilyl)
ethoxy]methyl)-1,4-dihydro-3-quinolinecarbonitrile, 1.2 g of 10%
palladium on carbon in 80 mL of ethanol and 150 mL of
tetrahydrofuran is reacted in a Parr shaker at 30 psi for 3 hours.
The mixture is filtered through a pad of diatomaceous earth, washed
with 700 mL of tetrahydrofuran and 300 mL of methanol. The filtrate
is evaporated to yield 1.23 g of brown solid. The diatomaceous
earth pad is further washed with 300 mL of N,N-dimethylformamide
and the filtrate is poured on ice. The crude product is collected
by filtration, washed with water and dried to yield 3.36 g of a
brown solid. The combined solid (4.59 g) is used directly in the
next step. A 0.15 g portion of sample is purified by silica gel
chromatography utilizing a gradient of methylen chloride/methanol
(99:1 to 96:4) to yield 0.1 g of
6,7-diamino-4-oxo-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydro-quinolin-
e-3-carbonitrile as a pink solid, mp>300.degree. C.
[0616] .sup.1HNMR (DMSO-d.sub.6):.delta. 8.65 (s, 1H); 7.27 (s,
1H); 6.84 (s, 1H); 5.86 (s, 2H); 5.50 (s, 2H); 5.19 (s, 2H); 3.60
(t, 2H, J=5.1, 10.2 Hz);) 0.88 (t, 2H, J=5.0, 8.4 Hz); 0.011 (s,
9H).
[0617] MS (ES, positive mode): m/z calcd for
C.sub.16H.sub.22N.sub.4O.sub.2Si: 330, found: 331 (M+H).sup.+.
[0618] Analysis for C.sub.16H.sub.22N.sub.4O.sub.2Si
[0619] Calcd: C, 58.15; H, 6.71; N, 16.95
[0620] Found: C, 57.91; H, 6.82; N, 16.75.
EXAMPLE 21
8-Oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,8-dihydro[1,2,3]triazolo[4,5--
g]quinoline-7-carbonitrile
[0621] A 0.5 g portion of
6,7-diamino-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quin-
olinecarbonitrile (1.5 mmol) is dissolved in 130 mL of dioxane and
125 mL of 0.1 N hydrochloric acid and cooled in an ice bath. A
solution of 0.11 g (1.6 mmol) of sodium nitrile in 5 mL of water is
added in one portion and the mixture stirred at 0.degree. C. for 45
minutes. Solids precipitated out of solution and are collected by
filtration and washed with water to yield a brown solid. The solid
is dissolved in 50 mL of 0.01 N sodium hydroxide and washed with
3.times.100 mL of methylene chloride. The aqueous layer is
acidified to pH=5 and the solids collected by filtration and washed
with water. After drying, 0.4 g of a brown solid is obtained that
could be recrystallized from methanol to yield a tan needles, mp
249-251.degree. C. with gas evolution.
[0622] .sup.1HNMR(DMSO-d.sub.6):.delta. 9.1(s, 1H); 8.78 (brs, 1H);
8.35 (brs, 1H); 5.78 (s, 2H); 3.64 (t, 21, J=8.0 Hz); 0.87 (t, 2H,
J=8.0 Hz).
[0623] MS (ES, positive mode): m/z calcd for
C.sub.16H.sub.19N.sub.5O.sub.2Si: 341, found: 342 (M+H).sup.+.
[0624] Analysis for C.sub.16H.sub.19N.sub.5O.sub.2Si
[0625] Calcd: C, 56.28; H, 5.61; N, 20.51.
[0626] Found: C, 56.14; H, 5.54; N, 20.41.
EXAMPLE 22
8-Oxo-5,8-dihydro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile
[0627] A mixture of 0.357 g (1.04 mmol) of
8-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,8-dihydro[1,2,3]triazolo[4,5-
-g]quinoline-7-carbonitrile and 0.35 g of imidazole (5.2 mmol) in
10 mL of formic acid is heated to 110.degree. C. for 6 hours. The
solution is cooled to room temperature and the volatiles are
removed at reduced pressure. The residue is suspended in 20 mL of
water, filtered and washed with water. After drying, 0.2 g of a
brown solid is obtained, mp>300.degree. C.
[0628] .sup.1HNMR (DMSO-d.sub.6):.delta. 9.1(s, 1H); 8.78 (br s,
1H); 8.35 (br s, 1H); 5.78 (s, 2H); 3.64 (t, 2H, J=8.0 Hz); 0.87
(t, 2H, J=8.0 Hz).
[0629] MS (ES, negative mode): m/z calcd for
C.sub.10H.sub.5N.sub.5O: 211, found (M-H).sup.-210.
[0630] Analysis for C.sub.10H.sub.5N.sub.5O
[0631] Calcd: C, 56.28; H, 5.61; N, 20.51.
[0632] Found: C, 56.14; H, 5.54; N, 20.41.
EXAMPLE 23
8-Chloro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile
[0633] A solution of 0.3 g of
8-oxo-5,8-dihydro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile
(1.4 mmol), is suspended in 10 mL of 2 M oxalyl chloride (in
methylene chloride). One mL of DMF is added dropwise and the
solution heated to reflux for 6 hours. The solution is cooled to
room temperature and the volatiles are removed at reduced pressure.
Ice water is added to the residue, and the solids are filtered and
washed with water. After drying a brown solid, 0.2 g, is
obtained.
[0634] MS (ES, negative mode): m/z calcd for
C.sub.10H.sub.4ClN.sub.5: 229.6, found (M-H).sup.-228.2.
EXAMPLE 24
8-(3,4,5-trimethoxyanilino)[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile
[0635] A solution of 0.07 g of
8-chloro[1,2,3]triazolo[4,5-g]quinoline-7-carbonitrile (0.3 mmol),
0.035 g of pyridine hydrochloride (0.3 mmol), and 0.83 g of 3,4,5
trimethoxyaniline (0.45 mmol) are dissolved in 3 mL of
2-ethoxyethanol and heated to 110.degree. C. for 3 hours. The
solution is cooled to room temperature, filtered and the orange
solids are washed with diethyl ether. This yields 0.07 of pure
compound as the hydrochloride salt. This material could be
recrystallized from methanol to afford yellow fine needles, mp
280.degree. C. with decomposition.
[0636] .sup.1HNMR (DMSO-d.sub.6):.delta. 10.2 (br s, 1H); 9.4 (br
s, 1H); 8.56 (s, 1H); 8.3 (br s, 1H); 6.7 (s, 2H); 3.78 (s, 6H); 37
(s, 3H).
[0637] MS (ES, positive mode): m/z calcd for
C.sub.19H.sub.6N.sub.6O.sub.3: 376, found: 377 (M+H).sup.+.
[0638] Analysis for C.sub.19H.sub.16N.sub.6O.sub.3.0.7 HCl.0.4
CH.sub.3OH
[0639] Calcd: C, 56.19; H, 4.45; N, 20.27
[0640] Found: C, 55.80; H, 4.8; N, 19.94.
EXAMPLE 25
4,7-Dichloro-6-nitro-3-quinolinecarbonitrile
[0641] A mixture of 1.18 g (4.74 mmol) of
7-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile, 60 mL
of 2M oxalyl chloride (in methylene chloride) and 25 drops of
N,N-dimethylformamide is refluxed for 5.5 hours. After cooling, the
mixture is concentrated to dryness and the residue is taken into
ice water. The aqueous suspension is neutralized to pH 7 with an
aqueous solution of saturated sodium carbonate. The solid is
collected by filtration and washed with ice water, and then dried
in vacuo, giving 1.20 g of the product as a light brown solid.
[0642] An analytical sample is obtained by column chromatography,
eluting with a gradient of hexane/ethyl acetate (from 98:2 to
90:10) to afford a light yellow solid, mp 159-161.degree. C.
[0643] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.70 (s, 1H); 9.09 (s,
1H); 9.41 (s, 1H).
[0644] MS (ES, negative ion mode): m/z calcd for
C.sub.10H.sub.3Cl.sub.2N.sub.3O.sub.2: 268.1, found:
(M-H).sup.-267.0.
[0645] Analysis for C.sub.10H.sub.3Cl.sub.2N.sub.3O.sub.2.0.2
AcOEt
[0646] Calcd: C, 45.40; H, 1.62; N, 14.70.
[0647] Found: C, 45.76; H, 1.68; N, 14.59.
EXAMPLE 26
7-Chloro-4-(chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitr-
ile
[0648] To a stirred suspension of 0.9 g (3.3 mmol) of
4,7-dichloro-6-nitro-3-quinolinecarbonitrile and pyridine
hydrochloride (0.381 g, 3.3 mmol) in 2-ethoxyethanol (10 mL) under
nitrogen, is added 0.634 g (3.69 mmol) of
4-chloro-5-methoxy-2-methylaniline (WO 8501939 A1). The reaction is
stirred at 120.degree. C. for 4 hours. The mixture is then cooled
to room temperature and solid sodium bicarbonate is added until
foaming subsided. Water is added to the reaction mixture (40 mL),
which is subsequently extracted with 3.times.30 mL ethyl acetate.
After combining the organic portions and drying with sodium
sulfate, the solvents are removed in vacuo. The residue obtained is
purified by flash chromatography, eluting with 99.5:0.5 methylene
chloride/methanol. The solid obtained is recrystallized from hot
ethyl acetate to afford 1.1 g of an orange crystalline solid, mp
217-219.degree. C.
[0649] .sup.1HNMR(DMSO-d.sub.6): .delta. 10.27 (s,1H); 9.42 (s,1H);
8.68 (s, 1H); 8.23 (s, 1H); 7.43 (s, 1H); 7.18 (s, 1H); 3.79 (s,
3H); 2.13 (s, 3H).
[0650] MS (ES, positive ion mode): m/z calcd for:
C.sub.18H.sub.12Cl.sub.2N.sub.4O.sub.3 403.22, found: 403.2
(M+H).sup.+.
[0651] Elemental analysis calculated for:
C.sub.18H.sub.12Cl.sub.2N.sub.4O.sub.3.1
CH.sub.3CO.sub.2C.sub.2H.sub.5
[0652] Calcd: C, 53.77; H, 4.07; N, 11.39.
[0653] Found: C, 53.79; H, 4.46; N, 11.40.
EXAMPLE 27
6,7-Diamino-4-(4-chloro-5-methoxy-2-methylanilino)-3-quinolinecarbonitrile
[0654] To 1.1 g (2.7 mmol) of
7-chloro-4-(4-chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbon-
itrile in 5 mL of anhydrous dimethyl sulfoxide (DMSO) is added 1.77
g (27 mmol) of sodium azide under a flow of nitrogen. The mixture
is stirred at 55.degree. C. for 3 hours. The reaction is cooled to
room temperature and poured onto 30 g of crushed ice. This mixture
is stirred for 30 minutes and the suspended solid collected by
filtration. After drying, a 1 g portion of
7-azido-4-(4-chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarboni-
trile is obtained as a dark solid. The solid is dissolved in a 1:1
mixture of ethanol/tetrahydrofuran (50 mL) and to this is added 200
mg of 10% palladium on carbon under a flow of nitrogen. After
hydrogenation of the mixture for 1.5 hours using a Parr shaker at
40 psi, the crude product is filtered through diatomaceous earth
and the filtrate evaporated in vacuo. The residue obtained is
purified by flash chromatography, eluting with 85:15 methylene
chloride/methanol to provide a 0.638 g of a brown solid, mp
232-235.degree. C.
[0655] .sup.1HNMR(DMSO-d.sub.6): .delta. 8.72 (s,1H); 8.122 (s,1H);
7.31 (s, 1H); 7.23 (s, 1H); 6.90 (s, 1H); 6.83 (s, 1H); 5.76 (s,
2H); 5.20 (s, 2H); 3.73 (s, 3H); 2.07 (s, 3H).
[0656] MS (positive ion mode): m/z calcd for
C.sub.18H.sub.16ClN.sub.5O: 353.81, found: 354.2 (M-H).sup.-.
[0657] Elemental analysis calculated for: C.sub.18H.sub.16
ClN.sub.5O.1.5H.sub.20
[0658] Calcd: C, 56.76; H, 5.04; N, 17.36.
[0659] Found: C, 56.82; H, 5.04; N, 17.54.
EXAMPLE 28
9-(4-Chloro-5-methoxy-2-methylanilino)pyrido[2,3-g]quinoxaline-8-carbonitr-
ile
[0660] A mixture of 0.120 g (0.34 mmol) of
6,7-diamino-4-(4-chloro-5-methoxy-2-methylanilino)-3-quinolinecarbonitril-
e and 0.408 g of 1,4-dioxane-2,3-diol (3.4 mmol) in 5 mL of
anhydrous methanol is stirred at room temperature under a flow of
nitrogen for 2 hours. The reaction is concentrated in vacuo and the
residue purified by flash chromatography, eluting with 92:8
CH.sub.2Cl.sub.2/MeOH. This yields 0.108 g of a yellow solid, mp
158-160.degree. C.
[0661] .sup.1HNMR(DMSO-d.sub.6): .delta. 10.34 (s, 1H); 9.53
(s,1H); 9.11 (s, 1H); 9.08 (s, 1H); 8.64 (s, 1H); 8.61 (s, 1H);
7.46 (s, 2H); 7.26 (s, 2H); 3.82 (s, 3H); 2.27 (s, 3H).
[0662] MS (positive ion mode): m/z calcd for
C.sub.20H.sub.14ClN.sub.5O: 375.8, found: 376.2 (M-H).sup.-.
[0663] Analysis for C.sub.20H.sub.14ClN.sub.5O.0.2H.sub.2O.0.8
CH.sub.3OH
[0664] Calcd: C, 61.67; H, 4.38; N, 17.27.
[0665] Found: C, 61.35; H, 4.11; N, 16.88.
EXAMPLE 29
7-Chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile
[0666] A mixture of 0.9 g (3.36 mmol) of
4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 0.55 g (4.0 mmol) of
5-methoxy-2-methylaniline, 0.46 g (4.0 mmol) of pyridine
hydrochloride in 10.0 mL of 2-ethoxyethanol is heated at
115.degree. C. for 1 hour, cooled and poured into a saturated
solution of sodium bicarbonate. The oil is extracted with methylene
chloride, dried over anhydrous sodium sulfate and the solvent is
evaporated to yield a foam. This is purified by silica gel
chromatography, eluting with methylene chloride/methanol (99.5:0.5)
to yield 0.77 g of
7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile
as a yellow solid, mp 180-182.degree. C.
[0667] .sup.1HNMR (DMSO-d.sub.6): .delta. 10.25 (s, 1H); 9.43 (s
1H); 8.67 (s, 1H); 8.23 (s, 1H); 7.24 (d, 1H J=8.7 Hz); 6.92 (d,
2H, J=7.5 Hz); 3.73 (s, 3H); 2.13 (s, 3H).
[0668] MS (ES, positive mode): m/z calcd for
C.sub.18H.sub.13ClN.sub.4O.sub.3: 368, found: 369 (M+H).sup.+.
[0669] Analysis for C.sub.18H.sub.13ClN.sub.4O.sub.3
[0670] Calcd: C, 58.63; H, 3.55; N, 15.19.
[0671] Found: C, 58.55; H, 3.56; N, 15.06.
EXAMPLE 30
6,7-Diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile
[0672] A mixture of 0.7 g (1.9 mmol) of
7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile
and 0.62 g (9.5 mmol) of sodium azide is heated at 60.degree. C.
under nitrogen for 24 hours. The mixture is cooled and poured onto
ice. The solid is collected by filtration, washed with water and
dried to yield 0.65 g of
7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbon-
itrile as a yellow solid.
[0673] A mixture of 0.65 g (1.73 mmol) of
7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile
and 0.12 g of 10% palladium on carbon in a 1:1 mixture of
ethanol/tetrahydrofuran is shaken on Parr apparatus with hydrogen
gas at 40 psi for 2 hours. The mixture is filtered through a pad of
diatomaceous earth, washed with methanol and tetrahydrofuran, then
dried to provide a dark solid. The crude product is purified by
silica gel chromatography, utilizing a gradient of methylene
chloride/methanol (95:5 to 88:12) to yield 0.4 g of
6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile
as a dark solid, mp 245.degree. C. (dec).
[0674] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.56 (s, 1H); 8.12 (s
1H); 7.22 (s, 1H); 7.13 (d, 1H, J=8.5 Hz); 6.91 (s, 1H); 6.70 (d,d,
1H, J=2.6 Hz, 8.4 Hz), 6.55(d, 1H, J=2.6 Hz); 5.74 (s, 2H); 5.18
(s, 2H); 3.67 (s, 3H); 2.08 (s, 3H).
[0675] MS (ES, positive mode): m/z calcd for
C.sub.18H.sub.17N.sub.5O: 319, found: 320 (M+H).sup.+.
[0676] Analysis for C.sub.18H.sub.17N.sub.5O
[0677] Calcd: C, 65.83; H, 5.53; N, 21.33.
[0678] Found: C, 65.71; H, 5.32; N, 21.32.
EXAMPLE 31
8-(5-Methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo
[4,5-g]quinoline-7-carbonitrile
[0679] A mixture of 0.1 g (0.3 mmol) of
6,7-diamino-4-(5-methoxy-2-methylamino)-3-quinolinecarbonitrile and
0.11 g (0.62 mmol) of 2-(4-morpholino)ethylisothiocyanate in 0.3 mL
of dioxane is heated at 100.degree. C. for 2 hours under nitrogen.
The mixture is cooled and solvent is evaporated to dryness to yield
an oil consisting of
N-[7-amino-3-cyano-4-(5-methoxy-2-methylanilino)-6-quinolinyl]-N'-[2-(4-m-
orpholinyl)-ethyl]thiourea and
N-[6-amino-3-cyano-4-(5-methoxy-2-methylanilino)-7-quinolinyl]-N-[2-(4-mo-
rpholinyl)ethyl]thiourea. The oil is dissolved in 3.0 mL of
ethanol. To this is added 0.3 g of mercuric oxide and 20 mg of
sulphur powder and the resulting mixture is heated at reflux
temperature for 2 hours. The product mixture is filtered hot
through diatomaceous earth, washed with methanol and solvent is
evaporated to yield an oil. The oil is purified by silica gel
chromatography, utilizing a gradient of methylene chloride/methanol
(95:5 to 85:15) to yield 0.062 g of
8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo[4,-
5-g]quinoline-7-carbonitrile as a pink solid, mp 148-150.degree. C.
(shrinks at 140.degree. C.).
[0680] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.17
(s, 1H); 8.72 (s 1H); 8.04 (s, 1H); 7.34 (d, 1H, J=8.37 Hz);
7.11-7.05 (m,2H); 4.02-3.91(m, 2H); 3.91-3.81 (m, 2H); 3.80 (s,
3H); 3.76-3.71 (m, 1H); 3.57-3.53 (m, 2H); 3.44-3.33 (m, 4H);
3.21-3.19 (m, 1H); 2.21 (s, 3H).
[0681] MS (ES, positive mode):m/z calcd for
C.sub.25H.sub.27N.sub.7O.sub.2: 457, found: 458 (M+H).sup.+.
[0682] Analysis for C.sub.25H.sub.27N.sub.7O.sub.2.2H.sub.2O
[0683] Calcd: C, 60.83; H, 6.33; N, 19.87.
[0684] Found: C, 60.56; H, 6.10; N, 19.70.
EXAMPLE 32
7-Chloro-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
[0685] A mixture of 500 mg (1.86 mmol) of
4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 342.0 mg (1.86 mmol)
of 3,4,5-trimethoxyaniline and 215.5 mg (1.86 mmol) of pyridine
hydrochloride in 25 mL of 2-ethoxyethanol is heated at
100-110.degree. C. for 1.5 hours. After cooling, the mixture is
diluted with water and neutralized with an aqueous solution of
saturated sodium carbonate. The solid is collected by filtration
and is washed with water. After drying in vacuo, this yields 621.0
mg (80.5%) of the product as a deep yellow solid.
[0686] An analytical sample is obtained by column chromatography,
eluting with 5:95 methanol/methylene chloride. An orange solid is
obtained, mp 215-217.degree. C.
[0687] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.69 (s, 3H); 3.77 (s,
6H); 6.73 (s, 2H); 8.25 (s, 1H); 8.73 (s, 1H); 9.38 (s, 11; 10.37
(bs, 1H).
[0688] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.15ClN.sub.4O.sub.5: 414.1, found: 415.2
(M+H).sup.+.
[0689] Analysis for C.sub.19H.sub.15ClN.sub.4O.sub.5
[0690] Calcd: C, 55.02; H, 3.64; N, 13.51.
[0691] Found: C, 54.86; H, 3.65; N, 13.43.
EXAMPLE 33
2-{[2-(4-Morpholinyl)ethyl]amino}-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g-
]quinoline-7-carbonitrile
[0692] A mixture of 506.1 mg (1.2 mmol) of
7-chloro-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
and 390.0 mg (6.0 mmol) of sodium azide in 10.0 mL of DMSO is
heated at 40-50.degree. C. for 5 hours, and then at room
temperature for 15 hours. The mixture is poured into ice water and
extracted with ethyl acetate. The organic phase is washed with
brine and dried over sodium sulfate. Removal of the solvent yields
493.4 mg (97.7%) of
7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
as a yellow solid which is used in the next reaction without
further purification.
[0693] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.15N.sub.7O.sub.5: 421.11, found: 422.4
(M+H).sup.+.
[0694] A solution of 493.4 mg (1.17 mmol) of
7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
in 15 mL of THF and 5 mL of ethanol is hydrogenated at 30 psi for 1
hour in the presence of 100.0 mg of 10% palladium-on-carbon. The
catalyst is removed by filtration and the solvent removed in vacuo
to give 422.1 mg (98.8%) of
6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile as
a deep yellow solid which is used directly in the next step.
[0695] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.19N.sub.5O.sub.3: 365.16, found: 366.3
(M+H).sup.+.
[0696] A mixture of 0.15 g (0.41 mmol) of
6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile and
0.14 g (0.82 mmol) of 2-(4-morpholino)ethylisothiocyanate in 0.4 mL
of tetrahydrofuran is heated at 100.degree. C. for 1.5 hours under
nitrogen. The mixture is cooled and purified by silica gel
chromatography, utilizing a gradient of methylene chloride/methanol
(97:3 to 85:15) to yield 0.038 g of
2-{[2-(4-morpholinyl)ethyl]amino}-8-(3,4,5-trimethoxyanilino)imidazo[4,5--
g]quinoline-7-carbonitrile as a yellow solid, mp 175-178.degree. C.
(shrinks at 165.degree. C.).
[0697] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.17
(s, 1H); 8.63 (s 1H); 7.98 (s, 1H); 6.89 (s, 2H); 3.96-3.94(m, 2H);
3.89-3.82 (m, 2H); 3.80 (s, 6H); 3.69 (s, 3H); 3.62 (m, 2H); 3.60
(m, 3H); 3.58-3.41 (m, 2H); 3.32-3.30 (m, 1H).
[0698] MS (ES, positive mode):m/z calcd for
C.sub.26H.sub.29N.sub.7O.sub.4: 503, found: 504 (M+H).sup.+.
[0699] Analysis for C.sub.26H.sub.29N.sub.7O.sub.4-2.6
CH.sub.3OH
[0700] Calcd: C, 58.52; H, 6.76; N, 16.71.
[0701] Found: C, 58.40; H, 6.03; N, 16.35.
EXAMPLE 34
2-Amino-8-(4-phenoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile
[0702] To a stirred mixture of 0.5 g (1.5 mmol) of
6,7-diamino-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quin-
olinecarbonitrile in 10 mL of anhydrous methanol is added 0.174 g
(1.65 mmol) of cyanogen bromide at 0.degree. C. The ice bath is
then removed and the reaction stirred at room temperature under a
flow of nitrogen. The reaction is placed in an oil bath and heated
to 70.degree. C. After two hours at that temperature, the oil bath
is removed and another 0.174 g (1.65 mmol) of cyanogen bromide is
added. The reaction is then stirred at 70.degree. C. for 15 hours.
At that point, TLC analysis showed that no starting material
remained. The reaction is cooled down to room temperature and
brought to pH 10 with aqueous ammonium hydroxide. After evaporation
of the mixture in vacuo, the resulting residue is suspended in
methanol. The resulting precipitate is collected by filtration and
dried in a vacuum oven at 50.degree. C. to yield 0.5 g of
2-amino-8-oxo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5,8-dihydroimidazo[4,5-
-g]quinoline-7-carbonitrile as an off-white solid.
[0703] To this solid (0.5 g, 1.4 mmole) in a round bottom flask is
added 5 mL of formic acid and 0.57 g (8.4 mmole) of imidazole. This
mixture is stirred at reflux temperature for 2 hours. The reaction
is then reduced in vacuo and then neutralized with aqueous ammonium
hydroxide. The resulting solid is collected by filtration, washed
with water and dried in a vacuum oven at 50.degree. C. to yield 0.3
g of
2-amino-8-oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile as
a yellow solid. To the above solid is added 10 mL of 2M oxalyl
chloride (in methylene chloride) and 1 mL of DMF. The reaction
mixture is stirred at reflux until the disappearance of starting
material is observed by thin layer chromatography. The reaction is
cooled to room temperature, concentrated in vacuo and neutralized
with cold aqueous 1N NaOH. A precipitate formed, which is collected
by filtration, washed with water and dried in a vacuum oven at
50.degree. C. to yield 0.35 g of
2-amino-8-chloroimidazo[4,5-g]quinoline-7-carbonitrile as a yellow
solid.
[0704] To a stirred mixture 0.150 g (0.5 mmol) of
2-amino-8-chloroimidazo[4,5-g]quinoline-7-carbonitrile in 5 mL of
ethoxyethanol and 0.063 mg (0.55 mmol) pyridine hydrochloride, is
added 0.102 g (0.55 mmol) of 4-phenoxyaniline under a positive flow
of nitrogen. The reaction is heated to 120.degree. C. and stirring
is continued for 2 hours. Upon cooling, a solid precipitated out of
solution. The solid is collected by filtration, washed with
ethanol, then stirred with a solution of saturated solution sodium
bicarbonate for 30 minutes. The resulting solid is filtered, washed
with water and dried in a vacuum oven at 50.degree. C. to yield
0.128 mg of a yellow solid, mp>300.degree. C.
[0705] .sup.1HNMR(DMSO-d.sub.6): .delta. 9.18 (s, 1H); 8.66 (s,
1H); 7.96 (s, 1H); 7.54 (d, 2H, J=8.79 Hz); 7.42 (t, 2, J=8.43),
7.21 (m, 3H), 7.11 (d, 2H, J=7.71).
[0706] MS (positive ion mode): m/z calcd for
C.sub.23H.sub.16N.sub.6O: 392.419, found: 393.33 (M-H).sup.+.
[0707] Analysis for C.sub.23H.sub.16N.sub.6O.1.7H.sub.2O.1 HCl
[0708] Calcd: C, 60.08; H, 4.48; N, 17.25.
[0709] Found: C, 60.15; H, 4.67; N, 17.46.
EXAMPLE 35
8-Oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile
[0710] A mixture of 4.41 g (13.36 mmol) of
6,7-diamino-4-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydroquinolin-
e-3-carbonitrile and 4.41 g (56.54 mmol) of imidazole in 50 mL of
formic acid is heated at reflux temperature for 6 hours, then
cooled to room temperature. The solvent is evaporated to dryness to
yield a residue which is suspended in water, neutralized to pH 7
with ammonium hydroxide and stirred for 0.5 hours. The solid is
collected by filtration, washed with water and dried under vacuum
to yield 2.8 g of an orange-brown solid. A portion (0.17 g) of the
sample is purified by silica gel chromatography utilizing a
gradient of methylene chloride/methanol (93:7 to 80:20) to yield
0.11 g of 8-Oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile
as an orange solid, mp>300.degree. C.
[0711] .sup.1HNMR (DMSO-d.sub.6): .delta. 12.80 (s, 1H); 12.78 (s,
1H); 8.76 (d, 1H, J=6.5 Hz); 8.55 (s, 1H); 8.34 (s, 1H); 7.88 (s,
1H).
[0712] MS (ES, positive mode): m/z calcd for C.sub.11N.sub.4O: 210,
found: 211 (M+H).sup.+.
[0713] Analysis for C.sub.11H.sub.6N.sub.4O.1.0H.sub.2O
[0714] Calcd: C, 57.89; H, 3.53; N, 24.55.
[0715] Found: C, 57.68; H, 3.60; N, 24.15.
EXAMPLE 36
8-Chloroimidazo[4,5-g]quinoline-7-carbonitrile
[0716] To a suspension of 2.65 g (12.61 mmol) of
8-oxo-5,8-dihydroimidazo[4,5-g]quinoline-7-carbonitrile in 60.0 mL
of 2.0 M solution of oxalyl chloride in methylene chloride is added
4 drops of N,N-dimethylformamide and resulting mixture is heated at
reflux temperature for 0.5 hours. While refluxing, additional 0.3
mL portions of N,N-dimethylformamide are added every hour until the
reaction is complete (5 hours). After cooling the reaction mixture,
the solvent is evaporated to yield a residue which is placed in an
ice bath and cautiously neutralized with a solution of saturated
sodium bicarbonate to pH 7. This is further stirred with cooling
for 0.5 hours. The solid is collected by filtration, washed with
water and dried to yield 2.9 g of a brown solid. The solid is
purified by silica gel chromatography utilizing a gradient of
methylene chloride/methanol (93:7 to 80:20) to yield 1.32 g of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile as a pink solid,
mp>300.degree. C.
[0717] .sup.1HNMR(DMSO-d.sub.6): .delta. 9.79 (s, 1H); 8.89 (s,
1H); 8.56 (s, 1H); 8.15 (s, 1H).
[0718] MS (ES, positive mode): m/z calcd for
C.sub.11H.sub.5ClN.sub.4: 228, found: 229 (M+H).sup.+.
[0719] Analysis for C.sub.11H.sub.5ClN.sub.4.0.27H.sub.2O
[0720] Calcd: C, 56.58; H, 2.39; N, 23.99.
[0721] Found: C, 56.95; H, 2.64; N, 23.59.
EXAMPLE 37
8-(3-Bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
[0722] A mixture of 0.2 g (0.87 mmol) of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.12 mL (1.1 mmol)
of 3-bromoaniline, and 0.1 g (0.87 mmol) of pyridine hydrochloride
in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 45
minutes, then cooled to room temperature. The product mixture is
poured into a saturated solution of sodium bicarbonate and stirred
for 0.5 hour. The solid is collected by filtration, washed with
water and dried. The solid is purified by silica gel
chromatography, utilizing a gradient of methylene chloride/methanol
(98:2 to 93:7) to yield 0.20 g of
8-(3-bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as
pink solid, mp 286-288.degree. C.
[0723] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 13.2
(bs, 2H); 9.31 (s, 1H); 9.29 (s, 1H); 9.19 (s, 1H); 8.35 (s, 1H);
7.83 (t,1H, J=1.77 Hz); 7.69 (dt, 1H, J=7.68, 1.60 Hz); 7.56 (m,
2H).
[0724] MS (ES, positive mode): m/z calcd for
C.sub.17H.sub.10BrN.sub.5: 364, found: 365 (M+H).sup.+.
[0725] Analysis for C.sub.17H.sub.10BrN.sub.5.1.2H.sub.2O
[0726] Calcd: C, 52.92; H, 3.24; N, 18.15.
[0727] Found: C, 52.85; H, 3.23; N, 17.92.
EXAMPLE 38
8-(2-Bromo-4-chlorophenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
[0728] A mixture of 0.25 g (1.10 mmol) of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.27 g (1.3 mmol)
of 2-bromo-4-chloroaniline, and 0.13 g (1.12 mmol) of pyridine
hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at reflux
temperature for 1 hour, cooled to room temperature, poured into a
saturated solution of sodium bicarbonate and stirred for 0.5 hour.
The solid is collected by filtration, washed with water and dried.
The solid is purified by silica gel chromatography utilizing a
gradient of methylene chloride/methanol (97:3 to 90:10) to yield
0.10 g of
8-(2-bromo-4-chloro-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
as an yellow solid, mp 244-246.degree. C. (shrinks at 200.degree.
C.).
[0729] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.46
(s, 1H); 9.30 (s, 1H); 9.27 (s, 1H); 8.40 (s, 1H); 8.06 (d, 1H,
J=2.2 Hz); 7.77 (d, 1H, J=8.5 Hz); 7.69 (dd, H, J=2.2, 8.5 Hz).
[0730] MS (ES, positive mode): m/z calcd for
C.sub.17H.sub.9BrClN.sub.5: 399, found: 400 (M+H).sup.+.
[0731] Analysis for C.sub.17H.sub.9BrClN.sub.5.1.0H.sub.2O
[0732] Calcd: C, 49.00; H, 2.66; N, 16.81.
[0733] Found: C, 48.96; H, 2.65; N, 16.13.
EXAMPLE 39
8-(2-Bromo-4-chloro-5-methoxyphenylamino)imidazo[4,5-g]quinoline-7-carboni-
trile
[0734] A mixture of 0.12 g (0.52 mmol) of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.2 g (0.63 mmol)
of 2-bromo-4-chloro-5-methoxyanline hydrobromide and 0.06 g (0.52
mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is
heated at reflux temperature for 1 hour, cooled to room
temperature, poured into a saturated solution of sodium bicarbonate
and stirred for 0.5 hour. The solid is collected by filtration,
washed with water and dried. The solid is purified by silica gel
chromatography utilizing a gradient of methylene chloride/methanol
(97:3 to 90:10) to yield 0.1 g of
8-(2-bromo-4-chloro-5-methoxy-phenylamino)imidazo[4,5-g]quinoline-7-carbo-
nitrile as a yellow solid, mp 257.degree. C. (dec).
[0735] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.40
(s, 1H); 9.28 (d, 2H, J=5.3 Hz) 8.39 (s, 1H); 8.0 (s, 1H); 7.60 (s,
1H); 3.9 (s, 3H).
[0736] MS (ES, positive mode): m/z calcd for
C.sub.18H.sub.11BrClN.sub.5O: 429, found: 430 (M+H).sup.+.
[0737] Analysis for C.sub.18H.sub.11BrClN.sub.5O.0.4H.sub.2O
[0738] Calcd: C, 49.60; H, 2.73; N, 16.07.
[0739] Found: C, 49.59; H, 2.93; N, 15.73.
EXAMPLE 40
8-(2-Chloro-5-methoxy-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
[0740] A mixture of 0.2 g (0.87 mmol) of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.22 g (1.04 mmol)
of 2-chloro-5-methoxyaniline hydrochloride and 0.1 g (0.87 mmol) of
pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at
reflux temperature for 1 hour, cooled to room temperature, poured
into a saturated solution of sodium bicarbonate and stirred for 0.5
hour. The solid is collected by filtration, washed with water and
dried. The solid is purified by silica gel chromatography utilizing
a gradient of methylene chloride/methanol (97:3 to 90:10) to yield
0.19 g of
8-(2-chloro-5-methoxy-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
as beige solid, mp 296-298.degree. C.
[0741] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.42
(s, 1H); 9.29 (d, 2H, J=5.5 Hz); 8.40 (s, 1H); 7.61 (d, 1H, J=8.9
Hz); 7.37 (d, 1H, J=3.0 Hz); 7.19 (dd, 1H, J=3.0, 3.0 Hz); 3.84 (s,
3H).
[0742] MS (ES, positive mode): m/z calcd for
C.sub.18H.sub.12ClN.sub.5O: 349, found: 350 (M+H).sup.+.
[0743] Analysis for C.sub.18H.sub.12ClN.sub.5O.1.5H.sub.2O
[0744] Calcd: C, 57.37; H, 4.01; N, 18.59.
[0745] Found: C, 57.31; H, 3.86; N, 18.21.
EXAMPLE 41
8-(3-Hydroxy-4-methylphenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
[0746] A mixture of 0.15 g (0.66 mmol) of
8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.1 g (0.78 mmol)
of 5-amino-o-cresol and 0.075 g (0.66 mmol) of pyridine
hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux
temperature for 1 hour, cooled to room temperature, poured into a
saturated solution of sodium bicarbonate and stirred for 0.5 hour.
The solid is collected by filtration, washed with water, diethyl
ether, methylene chloride, tetrahydrofuran and dried in vacuo to
yield 0.17 g of
8-(3-hydroxy-4-methyl-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile
as white solid, mp 257-260.degree. C. (dec).
[0747] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.38
(s, 1H); 9.23 (d, 2H, J=3.3 Hz); 8.33 (s, 1H); 7.22 (d, 1H, J=8.0
Hz); 6.89 (m, 2H); 3.18 (s, 3H).
[0748] MS (ES, positive mode): m/z calcd for
C.sub.18H.sub.13N.sub.5O: 315, found: 316 (M+H).sup.+.
[0749] Analysis for C.sub.18H.sub.13N.sub.5O.0.5H.sub.2O
[0750] Calcd: C, 66.65; H, 4.35; N, 21.59.
[0751] Found: C, 66.75; H, 4.45; N, 21.56.
EXAMPLE 42
8-(3,4,5-Trimethoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile
[0752] A 422.1 mg (1.16 mmol) portion of
6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
(intermediate from Example 33) is heated at reflux temperature in 2
mL of diethoxymethyl acetate at 120.degree. C. for 2 hours. After
cooling, the solution is diluted with water and extracted with
ethyl acetate. The separated organic phase is washed with brine and
dried over sodium sulfate. After filtration and removal of the
solvent, the residue is flash chromatographed (elution with 93:7
methylene chloride/methanol) to give 169.9 mg (36.3%) of
7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide
as a deep beige solid, mp 156.degree. C. (dec.).
[0753] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.65 (s, 3H); 3.71 (s,
6H); 6.73 (s, 2H); 8.27 (bs, 1H); 8.41 (bs, 1H); 8.75 (s, 1H); 9.12
(s, 1H); 9.23 (s, 1H); 13.10 (bs, 1H).
[0754] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.17N.sub.5O.sub.4: 403.4, found: 404.2
(M+H).sup.+.
[0755] HRMS m/z calcd 403.1281 for C.sub.21H.sub.17N.sub.5O.sub.4,
found: 404.1343 (M+H).sup.+.
[0756] A suspension of 138.6 mg (0.34 mmol) of
7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide
and 229.1 mg (1.66 mmol) of potassium carbonate in 10 mL of
methanol is refluxed for 2 hours. After cooling, the solution is
diluted with water and neutralized to pH 7 with AcOH. The
precipitate is collected by filtration and washed with water,
diethyl ether and ethyl acetate. After drying in vacuo, this yields
a crude product. Purification of the crude product by flash
chromatography (elution with 95:5 methylene chloride/methanol)
yields 87.3 mg (68.5%) of the final product as a yellow solid,
mp>260.degree. C.
[0757] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 3.73
(s, 3H); 3.81 (s, 6H); 6.90 (s, 2H); 8.20 (s, 1H); 8.85 (s, 1H);
9.13 (s, 1H); 9.15 (s, 1H); 11.40 (bs, 1H).
[0758] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.17N.sub.5O.sub.3: 375.4, found: 376.3
(M+H).sup.+.
[0759] Analysis for C.sub.20H.sub.17N.sub.5O.sub.3.0.9H.sub.2O
[0760] Calcd: C, 61.34; H, 4.84; N, 17.88.
[0761] Found: C, 61.03; H, 4.82; N, 17.76.
EXAMPLE 43
7-Chloro-6-nitro-4-(4-phenoxyanilino)-3-quinolinecarbonitrile
[0762] A mixture of 722.7 mg (2.70 mmol) of
4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 100.1 mg (2.70 mmol)
of 4-phenoxyaniline and 312.1 mg (2.70 mmol) of pyridine
hydrochloride in 30 mL of 2-ethoxyethanol is heated at
110-120.degree. C. for 3 hours. After cooling, the mixture is
diluted with water, neutralized with an aqueous solution of
saturated sodium carbonate, and extracted with ethyl acetate. The
separated organic layer is washed with brine and dried over sodium
sulfate. Removal of the solvent yields a solid residue which is
purified by flash chromatography (elution with 99:1 methylene
chloride/methanol), giving 831.0 mg (73.9%) of the product as a
deep yellow solid, mp 220-222.degree. C.
[0763] .sup.1HNMR(DMSO-d.sub.6): .delta. 7.14 (m, 5H); 7.40 (m,
4H); 8.24 (s, 1H); 8.71 (s, 1H); 9.38 (s, 1H); 10.42 (bs, 1H).
[0764] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.13ClN.sub.4O.sub.3: 416.8, found: 417.2
(M+H).sup.+.
[0765] Analysis for C.sub.22H.sub.13ClN.sub.4O.sub.3
[0766] Calcd: C, 63.39; H, 3.14; N, 13.44.
[0767] Found: C, 63.12; H, 3.19; N, 13.22.
EXAMPLE 44
8-(4-Phenoxyanilino)imidazo[4,5-g]quinoline-7-carbonitrile
[0768] Following the procedure of
7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
(intermediate from Example 33), 728.4 mg (1.75 mmol) of
7chloro-6-nitro-4-(4-phenoxyanilino)-3-quinolinecarbonitrile in 12
mL of DMSO is reacted with 568.1 mg (8.74 mmol) of sodium azide to
yield 736.0 mg (99.5%) of
7-azido-6-nitro-4-(4-phenoxyanilino)-3-quinolinecarbonitrile.
[0769] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.13N.sub.7O.sub.3: 423.1, found: 424.0
(M+H).sup.+.
[0770] Following the procedure of
6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile
(intermediate from Example 33), hydrogenation of a suspension of
736.0 mg (1.74 mmol) of
7-azido-6-nitro-4-(4-phenoxyanilino)-3-quinolinecarbonitrile and
147.2 mg of 10% palladium-on-carbon in 21 mL of THF and 6 mL of
ethanol yields 765.1 mg of crude
6,7-diamino-4-(4-phenoxyanilino)-3-quinolinecarbonitrile.
[0771] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.17N.sub.5O: 367.1, found: 368.3 (M+H).sup.+.
[0772] Following the procedure of
7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide
(intermediate from Example 42), treatment of 765.1 mg (2.08 mmol)
of the crude
6,7-diamino-4-(4-phenoxyanilino)-3-quinolinecarbonitrile with
diethoxymethyl acetate at 120.degree. C. for 3 hours, followed by
the same work up yields a dark oil residue which is flash
chromatographed (elution with a gradient of 99:1 to 82:18 methylene
chloride/methanol), yielding 263.8 mg (31.3%) of
7-cyanoimidazo[4,5-g]quinolin-8-yl(4-phenoxyphenyl)formamide as a
beige solid, mp 266.degree. C. (dec.).
[0773] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.08 (m, 5H); 7.39 (m,
4H); 8.36 (bs, 2H); 8.74 (s, 1H); 9.12 (s, 1H); 9.24 (s, 1H); 13.10
(bs, 1H).
[0774] MS (ES, positive ion mode): m/z calcd for
C.sub.24H.sub.15N.sub.5O.sub.2: 405.4, found: 406.2
(M+H).sup.+.
[0775] Analysis for C.sub.24H.sub.15N.sub.5O.sub.2.0.3H.sub.2O
[0776] Calcd: C, 70.16; H, 3.83; N, 17.05.
[0777] Found: C, 70.23; H, 3.81; N, 17.23.
[0778] A suspension of 211.8 mg (0.52 mmol) of
7-cyano-3H-imidazo[4,5-g]quinolin-8-yl(4-phenoxyphenyl)formamide
and 288.9 mg (2.09 mmol) of potassium carbonate in 15 mL of
methanol is refluxed for 2.5 hours. The solution is concentrated
and the residue is diluted with water followed by neutralization to
pH 7-8 with acetic acid. The precipitate is collected by filtration
and washed with water and dried in vacuo, giving a deep yellow
solid. The solid is purified by flash chromatography (elution with
a gradient of 98:2 to 90:10 methylene chloride/methanol) yields
137.4 mg (70.0%) of the final product as a yellow solid,
mp>270.degree. C.
[0779] .sup.1HNMR(DMSO-d.sub.6): .delta. 7.11 (m, 5H); 7.39 (m,
4H); 8.05 (bs, 1H); 8.47 (s, 1H); 8.60 (bs, 1H); 8.89 (bs, 2H);
9.85 (bs, 1H).
[0780] MS (ES, positive ion mode): m/z calcd for
C.sub.23H.sub.15N.sub.5O: 377.4, found: 378.2 (M+H).sup.+.
[0781] Analysis for C.sub.23H.sub.15N.sub.5O.0.9H.sub.2O
[0782] Calcd: C, 70.18; H, 4.30; N, 17.79.
[0783] Found: C, 70.11; H, 4.11; N, 17.79.
EXAMPLE 45
N-[7-Amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]-2-chloroaceta-
mide and
EXAMPLE 46
N-[6-Amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]-2-chloroaceta-
mide
[0784] To an ice-cooled mixture of 0.12 g (0.33 mmol) of
6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile and
0.5 mL of N,N-diethylaniline in 3.0 mL of tetrahydrofuran is added
dropwise 0.052 mL (0.66 mmol) of chloroacetyl chloride, which is
further stirred for 15 minutes at 0.degree. C. The mixture is
diluted with water and stirred for 20 minutes, while warming to
room temperature. The solid is collected by filtration and dried.
Purification by silica gel chromatography, utilizing a gradient of
methylene chloride/methanol (97:3 to 90:10), yields 0.11 g of a
yellow solid consisting 1 of a 1:1 mixture of
N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]-2-chloroa-
cetamide and
N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]-2-chloroacet-
amide.
[0785] .sup.1HNMR(DMSO-d.sub.6): .delta. 9.69 (s, 0.5H); 9.42 (s,
0.5H); 8.36 (s, 0.5H); 8.23 (s, 0.5H); 7.04 (s, 1H); 6.53 (s, 2H);
6.01 (s, 2H); 4.34 (s, 2H); 3.74 (s, 6H); 3.65 (s, 3H).
[0786] MS (ES, positive mode): m/z calcd for
C.sub.21H.sub.20ClN.sub.5O.sub.4: 441, found: 442 (M+H).sup.+.
[0787] Analysis for
C.sub.21H.sub.20ClN.sub.5O.sub.4.1.3H.sub.2O
[0788] Calcd: C, 54.21; H, 4.90; N, 15.05.
[0789] Found: C, 54.23; H, 4.96; N, 14.94.
EXAMPLE 47
2-(Chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-carb-
onitrile
[0790] A of 0.11 g (0.25 mmol) sample of product from Example 46 in
3.0 mL of glacial acetic acid is heated at 100.degree. C. for 15
minutes, then cooled to room temperature. Following evaporation of
the solvent in vacuo, the residue is suspended in water and
neutralized with solid sodium carbonate. The solid is collected by
filtration, washed with water and dried to yield 0.1 g of
2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-car-
bonitrile as a yellow solid.
[0791] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.20
(s, 1H); 9.13 (s, 1H); 8.20 (s, 1H); 6.93 (s, 2H); 5.12 (d, 2H,
J=4.2 Hz); 3.83 (s, 6H); 3.76 (s, 3H).
[0792] MS (ES, positive mode): m/z calcd for
C.sub.21H.sub.18ClN.sub.5O.sub.3: 423, found: 424 (M+H).sup.+.
[0793] Analysis for
C.sub.21H.sub.18ClN.sub.5O.sub.3.0.6H.sub.2O
[0794] Calcd: C, 58.02; H, 4.45; N, 16.11.
[0795] Found: C, 57.90; H, 4.30; N, 15.79.
EXAMPLE 48
2-(4-Morpholinylmethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-
-7-carbonitrile
[0796] A mixture of 0.09 g (0.2 mmol) of
2-(chloromethyl)-8-(3,4,5-trimethoxyanilino)imidazo[4,5-g]quinoline-7-car-
bonitrile, 0.2 mL (2.3 mmol) of morpholine and 0.3 g (2.2 mmol) of
anhydrous potassium carbonate in 5 mL of ethanol is stirred at room
temperature overnight. The product mixture is filtered to remove
the inorganic salts and the filtrate is evaporated to dryness to
yield an oil. The oil is purified by silica gel chromatography
utilizing a gradient of methylene chloride/methanol (97:3 to 90:10)
to yield 0.087 g of
2-(4-morpholinylmethyl)-8-(3,4,5-trimethoxyanilino)-3H-imidazo[4,5-g]q-
uinoline-nylmethyl)-8-(3,4,5-trimethoxyanilino)-3H-imidazo[4,5-g]quinoline-
-7-carbonitrile as a yellow solid, mp 258-260.degree. C. (dec).
[0797] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 9.23
(s, 1H); 9.15 (s, 1H); 8.27 (s, 1H); 6.92 (s, 2H); 4.93 (s, 2H);
3.94 (bs, 4H); 3.82 (s, 6H); 3.75 (s, 3H); 3.56 (bs, 4H).
[0798] MS (ES, positive mode): m/z calcd for
C.sub.25H.sub.26N.sub.6O.sub.4: 474, found: 475 (M+H).sup.+.
[0799] Analysis for C.sub.26N.sub.6O.sub.4.1.2H.sub.2O
[0800] Calcd: C, 60.52; H, 5.77; N, 16.94.
[0801] Found: C, 60.20; H, 5.77; N, 16.80.
EXAMPLE 49
N-[7-Amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]acrylamide
and
EXAMPLE 50
N-[6-Amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]acrylamide
[0802] To a cold mixture of 0.12 g (0.33 mmol) of
6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile and
0.4 mL of N,N-diethylaniline in 3.0 mL of tetrahydrofuran is added,
dropwise, 0.054 mL (0.66 mmol) of acryloyl chloride and the mixture
is stirred cold for 20 minutes. The mixture is diluted with water
and stirred for 20 minutes. The solid is collected by filtration,
dried and purified by silica gel chromatography utilizing a
gradient of methylene chloride/methanol (97:3 to 90:10) to yield
0.03 g of a yellow solid as a 1:1 mixture of
N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]acrylamide
and
N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]acrylamid-
e.
[0803] .sup.1HNMR (DMSO-d.sub.6+trifluoroacetic acid): .delta. 8.89
(s, 1H); 8.65 (d, 1H, J=4.2 Hz); 7.03 (s, 1H); 8.23 (s, 0.5H); 6.78
(s, 2H); 6.55 (q, 1H, J=10.2 Hz); 6.30 (dd, 1H, J=2.0 Hz, J=10.0
Hz); 5.83 (dd, 1H, J=1.8 Hz, J=10.2 Hz); 3.748(s, 6H); 3.70 (s,
3H).
[0804] MS (ES, positive mode): m/z calcd for
C.sub.22H.sub.21N.sub.5O.sub.4: 419, found: 420 (M+H).sup.+.
[0805] Analysis for C.sub.22H.sub.21N.sub.5O.sub.4.1.4H.sub.2O
[0806] Calcd: C, 59.42; H, 5.40; N, 15.75.
[0807] Found: C, 59.59; H, 5.13; N, 15.40.
EXAMPLE 51
N-[7-Amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]-3-(4-morpholi-
nyl propanamide and
EXAMPLE 52
N-[6-Amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]-3-(4-morpholi-
nyl)propanamide
[0808] A mixture of 0.025 g (0.06 mmol) of
N-[7-amino-3-cyano-4-3,4,5-trimethoxyanilino)-6-quinolinyl]acrylamide
and
N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]acrylamide
and 0.05 mL (6.0 mmol) of morpholine in 0.2 mL of
N,N-dimethylformamide is stirred at room temperature overnight and
the solvent is evaporated to dryness to yield an oil. The oil is
triturated with diethyl ether several times and dried to yield 0.03
g of
N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]-3-(4-morphol-
inyl)propanamide and
N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]-3-(4-morphol-
inyl)propanamide as a yellow solid.
[0809] MS (ES, positive mode): m/z calcd for
C.sub.26H.sub.30N.sub.6O.sub.5: 506, found: 507 (M+H).sup.+.
[0810] Analysis for C.sub.26H.sub.30N.sub.6O.sub.5.2.0H.sub.2O
[0811] Calcd: C, 57.55; H, 6.32; N, 15.49.
[0812] Found: C, 57.91; H, 6.06; N, 15.40.
EXAMPLE 53
7-{[2-(4-Morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-1-{[2-(trimethylsilyl)et-
hoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile
[0813] A mixture of 1.25 g (3.29 mmol) of
7-chloro-6-nitro-4-oxo-1-{[2-(trimethysilyl)-ethoxy]methyl}-1,4-dihydro-3-
-quinolinecarbonitrile and 1.07 g (8.2 mmol) of
4-(2-aminoethyl)-morpholine in 21 mL of acetonitrile is heated at
reflux temperature for 17 hours. After cooling, the mixture is
concentrated under reduced pressure and the residue is partitioned
between methylene chloride and brine. The separated organic layer
is dried over sodium sulfate and filtered. Removal of the solvent
yields a residue which is flash chromatographed (elution with
methylene chloride, then a gradient of 99:1 to 98:2 methylene
chloride/methanol), giving 966 mg (61.9%) of the product as a
yellow solid, mp 294-216.degree. C.
[0814] .sup.1HNMR (DMSO-d.sub.6): .delta. 0.045 (s, 9H); 0.93 (t,
J=8.4 Hz, 2H); 2.51 (t, J=6 Hz, 2H); 2.72 (t, J=6 Hz, 2H); 3.53 (m,
2H); 3.66 (m, 6H); 5.66(s, 2H); 7.01 (s, 1H); 8.59 (t, 1H); 8.87
(s, 1H); 8.97 (s, 1H).
[0815] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.31N.sub.5O.sub.5Si: 473.6, found: 474.3
(M+H).sup.+.
[0816] Analysis for C.sub.19H.sub.15ClN.sub.4O.sub.5
[0817] Calcd: C, 55.79; H, 6.60; N, 14.79.
[0818] Found: C, 55.84; H, 6.65; N, 14.96.
EXAMPLE 54
6-Amino-7-{[2-(4-morpholinyl
ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl
ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile
[0819] A suspension of 916.4 mg (1.93 mmol) of
7-{[2-(4-morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile in 52 mL of THF and
19 mL of ethanol is hydrogenated in a Parr apparatus at 40 psi for
6 hours in the presence of 183.3 mg of 10% palladium-on-carbon. The
catalyst is removed by filtration and the solvent is evaporated in
vacuo to give 944.0 mg of
6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile as a deep yellow
solid which is used directly in the next step.
[0820] For analysis, 100 mg of the crude product is purified on
preparative thin layer chromatography (TLC), developing solvent:
9:1 methylene chloride/methanol, to afford 64.7 mg of the pure
product as a light yellow solid, mp 236-238.degree. C.
[0821] .sup.1HNMR (DMSO-d.sub.6): .delta. 0.06 (s, 9H); 0.92 (t,
J=8.1 Hz, 2H); 2.52(t, J=4.5 Hz, 2H); 2.67(t, J=6.9 Hz, 2H); 3.36
(t, 2H); 3.65 (m, 6H); 5.26 (bs, 2H); 5.63 (s, 2H); 5.72 (t, J=3
Hz, 1H); 6.67 (s, 1H); 7.31(s, 1H); 8.67 (s, 1H).
[0822] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.33N.sub.5O.sub.3Si: 443.6, found: 444.2
(M+H).sup.+.
[0823] Analysis for C.sub.22H.sub.33N.sub.5O.sub.3Si:
[0824] Calcd: C, 59.56; H, 7.50; N, 15.79.
[0825] Found: C, 59.17; H, 7.46; N, 15.63.
EXAMPLE 55
3-[2-(4-Morpholinyl)ethyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7--
carbonitrile
[0826] A mixture of 422 mg (0.95 mmol) of
6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile, 258.7 mg (3.80
mmol) of imidazole in 6 mL of 96% formic acid is refluxed for 6.5
hours. After cooling, the mixture is concentrated under reduced
pressure and the residue is diluted with water. Undissolved solid
is filtered off and washed with water. The combined filtrate and
water washes are brought to pH 8 with 28% ammonium hydroxide
aqueous solution. The precipitate is collected by filtration and
washed with water. After drying in vacuo, this yields 190.0 mg of
the crude product as a yellow solid. The crude product is purified
by flash chromatography (elution with methylene chloride, then a
gradient of 99:1 to 88:12 methylene chloride/methanol) to give
151.6 mg (49.3%) of the pure product as an off-white solid,
mp>270.degree. C.
[0827] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.44 (t, J=4.4 Hz, 4H);
2.72 (t, J=6.0 Hz, 2H); 3.53 (t, J=4.45 Hz, 4H); 4.42(t, J=6 Hz,
2H); 7.74(s, 1H); 8.38 (s, 1H); 8.51(s, 1H); 8.70 (s, 1H); 12.85
(bs, 1H).
[0828] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.17N.sub.5O.sub.2: 323.4, found: 324.2
(M+H).sup.+.
[0829] Analysis for C.sub.17H.sub.17N.sub.5O.sub.2.0.3H.sub.2O
[0830] Calcd: C, 62.11; H, 5.39; N, 21.30.
[0831] Found: C, 62.23; H, 5.15; N, 21.47.
EXAMPLE 56
8-Chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitr-
ile
[0832] A suspension of 190.0 mg (0.59 mmol) of
3-[2-(4-morpholinyl)ethyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7-
-carbonitrile, 5.45 mL of 2M oxalyl chloride (in methylene
chloride) and 5 drops of DMF is heated at reflux temperature for
1.5 hours. After cooling, the solvent is evaporated to dryness. The
residue is cooled in an ice bath and neutralized to pH 7 by slow
addition of ice-cooled, aqueous saturated sodium bicarbonate
solution. The aqueous solution is extracted with methylene
chloride. The organic phase is washed with cold brine and dried
over sodium sulfate. Removal of the solvent in vacuo gives the
crude product. Purification of the crude product by preparative TLC
(developing solvent: 5:95 methanol/methylene chloride) gives 122.8
mg (61%) of the product as a yellow solid, mp 205-207.degree.
C.
[0833] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.45 (t, J=4.5 Hz, 4H);
2.76 (t, J=5.9 Hz, 2H); 3.50 (t, J=4.5 Hz, 4H); 4.47 (t, J=5.9 Hz,
2H); 8.52(s, 1H); 8.60 (s, 1H); 8.76 (s, 1H); 9.11 (s, 1H).
[0834] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.16ClN.sub.5O: 341.8, found 342.3 (M+H).sup.+.
[0835] Analysis for C.sub.17H.sub.16ClN.sub.5.0.4H.sub.2O
[0836] Calcd: C, 58.50; H, 4.85; N, 20.06.
[0837] Found: C, 58.47; H, 4.76; N, 19.93.
EXAMPLE 57
8-(4-Chloro-5-methoxy-2-methylanilino)-3-[2-(4-morpholinyl)ethyl]-3H-imida-
zo[4,5-g]quinoline-7-carbonitrile
[0838] A mixture of 86.5 mg (0.25 mmol) of
8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonit-
rile, 67.2 mg (0.39 mmol) of 4-chloro-5-methoxy-2-methyl aniline
and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 3 mL of
2-ethoxyethanol is heated at 130-135.degree. C. for 11 hours. After
cooling, the mixture is diluted with water and neutralized with 2
equivalents of sodium carbonate, and then extracted with ethyl
acetate. The separated organic layer is washed with brine and dried
over sodium sulfate. Removal of the solvent yields a residue which
is purified on preparative TLC (developing solvent: 1:9
methanol/methylene chloride), giving 83.3 mg (69.9%) of the product
as a beige solid, mp 246-248.degree. C.
[0839] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.13 (s, 3H); 2.47(t,
J=4.3 Hz, 4H); 2.75 (t, J=5.9 Hz, 2H); 3.52 (t, J=4.5 Hz, 4H); 3.81
(s, 3H); 4.50 (t, J=5.9 Hz, 2H); 7.13 (s, 1H); 7.42 (s, 1H); 8.16
(s, 1H); 8.45 (s, 1H); 8.57 (s, 1H); 8.94 (s, 1H); 9.70 (bs,
1H).
[0840] MS (ES, positive ion mode): m/z calcd for
C.sub.25H.sub.25ClN.sub.6O.sub.2: 476.97, found: 477.3
(M+H).sup.+.
[0841] Analysis for C.sub.25H.sub.25ClN.sub.6O.sub.50.5H.sub.2O
[0842] Calcd: C, 61.79; H, 5.39; N, 17.29.
[0843] Found: C, 61.91; H, 5.21; N, 17.06.
EXAMPLE 58
3-[2-(4-Morpholinyl)ethyl]-8-(4-phenoxyanilino)-3H-imidazo[4,5-g]quinoline-
-7-carbonitrile
[0844] Following the procedure of Example 7, a mixture of 82.2 mg
(0.24 mmol) of
8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-
-carbonitrile, 53.3 mg (0.29 mmol) of 4-phenoxyaniline and 33.5 mg
(0.29 mmol) of pyridine hydrochloride in 3.5 mL of 2-ethoxyethanol
is heated at 130-135.degree. C. for 1 hour to yield 81.2 mg (69%)
of the product as a yellow solid, mp>260.degree. C.
[0845] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.46 (t, J=4.4 Hz, 4H);
2.76 (t, J=5.9 Hz, 2H); 3.52 (t, J=4.5 Hz, 4H); 4.50 (t, J=5.9 Hz,
2H); 7.11 (m, 5H); 7.40 (m, 4H); 8.17 (s, 1H); 8.49 (s, 1H); 8.57
(s, 1H); 8.88 (s, 1H); 9.84 (s, 1H).
[0846] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.26N.sub.6O.sub.2: 490.6, found: 491.3
(M+H).sup.+.
[0847] Analysis for C.sub.29H.sub.26N.sub.6O.sub.2.0.3H.sub.2O
[0848] Calcd: C, 70.23; H, 5.41; N, 16.94.
[0849] Found: C, 70.35; H, 5.56; N, 16.84.
EXAMPLE 59
1,4-Dihydro-7-mercapto-6-nitro-4-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]--
3-quinolinecarbonitrile
[0850] A solution of 100 mg (0.26 mmol) of
7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-
-quinolinecarbonitrile and 63 mg (0.26 mmol) of sodium sulfide
nonahydrate in 1 mL of dimethyl sulfoxide is stirred at room
temperature for 17 hours and poured into 50 mL of water. To this is
added 0.27 mL of 1 N HCl. The product is collected by filtration,
washed with water, and dried to yield 81 mg (83%) of a tan solid,
mp 200.degree. C. (decomposed).
[0851] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.86 (s, 1H), 7.91 (s,
2H), 5.47 (s, 2H), 3.51 (t, 2H), 0.77 (t, 2H), -0.09 (s, 9H).
[0852] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.86 (s, 1H), 7.91 (s,
2H), 5.47 (s, 2H), 3.51 (t, 2H), 0.77 (t, 2H), -0.09 (s, 9H).
[0853] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.19N.sub.3O.sub.4SSi: 377.5, found: 378.4
(M+H).sup.+.
[0854] Analysis for
C.sub.16H.sub.19N.sub.3O.sub.4SSi.0.1DMSO.1.4H.sub.2O
[0855] Calcd: C, 47.40; H, 5.50; N, 10.23.
[0856] Found: C, 47.04; H, 5.02; N, 10.15.
EXAMPLE 60
8-Hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile
[0857] A mixture of 377 mg (1.0 mmol) of
1,4-dihydro-7-mercapto-6-nitro-4-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-
-3-quinolinecarbonitrile and 200 mg of 20%
palladium-hydroxide-on-carbon in 50 mL of tetrahydrofuran and 10 mL
of methanol is hydrogenated in a Parr apparatus at 40 psi for 30
minutes. The mixture is filtered and concentrated in vacuo. The
residue is dissolved in 5 mL of 98% formic acid, and 200 mg of
imidazole is added to the solution. The solution is refluxed for 2
hours and cooled to room temperature. To this solution is added a
mixture of 100 mL ethyl acetate and 50 mL of hexanes. The solids
thus formed are filtered, washed with ethyl acetate, and dried to
yield 125 mg (55%) of a tan solid, mp 200.degree. C.
(decomposed).
[0858] .sup.1HNMR (DMSO-d.sub.6): .delta. 13.1 (brs, 1H), 9.53 (s,
1H), 8.81 (s, 1H), 8.73 (s, 1H), 8.45 (s, 1H).
[0859] MS (ES, positive ion mode): m/z calcd for
C.sub.11H.sub.5N.sub.3OS: 227.2, found: 226.3 (M-H).sup.-.
[0860] HRMS (ESI): Calc for C.sub.11H.sub.5N.sub.3OS (2M-H).sup.-:
453.0233, found: 453.0224.
EXAMPLE 61
8-[(4-Chloro-5-methoxy-2-methylphenyl)amino]thiazolo[4,5-g]quinoline-7-car-
bonitrile
[0861] To a mixture of 100 mg (0.44 mmol) of
8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile in 5 mL of
phosphoryl chloride is added five drops of N,N-dimethylformamide.
The mixture is heated at reflux temperature for 30 minutes and then
concentrated in vacuo. To the residue at 0.degree. C. is added 50
mL of water. The solids are collected, washed with water, and dried
in vacuo. To a mixture of this compound in 2 mL of 2-ethoxyethanol
are added 76 mg (0.44 mmol) of 4-chloro-5-methoxy-2-methylaniline
and 20 mg of pyridine hydrochloride. The mixture is refluxed for
one hour and concentrated. The residue is chromatographed by silica
gel chromatography, eluting with 9:1 methylene chloride/methanol to
yield 26 mg (16%) of product as a dark oil.
[0862] .sup.1HNMR (DMSO-d.sub.6): .delta. 9.99 (s, 1H), 9.60 (s,
1H), 9.39 (s, 1H), 8.77 (s, 1 .mu.l), 8.56 (s, 1H), 7.44 (s, 1H),
7.20 (s, 1H), 3.82 (s, 3H), 2.15 (s, 3H).
[0863] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.13ClN.sub.4OS: 380.9, found: 381.4 (M+H).sup.+.
[0864] HRMS (EI): Calc for C.sub.19H.sub.13N.sub.4OSCl: 380.0499,
found: 380.0493.
EXAMPLE 62
3-(Dimethylaminomethyleneamino)benzo[b]thiophene-2-carboxylic acid
methyl ester
[0865] A mixture of 3.38 g (16.32 mmol) of methyl
3-aminobenzo[b]thiophene-2-carboxylate (J. Org. Chem. 37, 3224
(1972)) in 8 mL of N,N,-dimethylformamide dimethyl acetal is heated
at reflux temperature for 2 hours, then cooled to room temperature.
The solid is collected by filtration, washing with hexane and ethyl
acetate to provide 3.96 g (93%) of a white solid, mp 73-74.degree.
C.
[0866] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.06 (s, 6H), 3.75 (s,
3H), 7.47 (t, 1H), 7.50 (t, 1H), 7.78 (d, 1H), 7.82-7.89 (m,
2H).
[0867] MS (ES, positive ion mode): m/z calcd for
C.sub.13H.sub.14N.sub.2O.sub.2S: 262.3, found: 262.9
(M+H).sup.+
[0868] Analysis for C.sub.13H.sub.14N.sub.2O.sub.2S
[0869] Calcd: C, 59.52; H, 5.38; N, 10.68.
[0870] Found: C, 59.25; H, 5.32; N, 10.58.
EXAMPLE 63
4-Hydroxybenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0871] A solution of 1.6 mL (30.6 mmol) of acetonitrile in 10 mL of
tetrahydrofuran is added to a -78.degree. C. solution of 12.5 mL of
2.5 M n-butyllithium (31.2 mmol) in 40 mL of tetrahydrofuran. After
stirring at -78.degree. C. for 10 min, a solution of 4.0 g (15.2
mmol) of
3-(dimethylaminomethyleneamino)benzo[b]thiophene-2-carboxylic acid
methyl ester in 40 mL of tetrahydrofuran is added dropwise over 1
hour. After stirring at -78.degree. C. for 30 minutes, the reaction
mixture is allowed to warm to room temperature and then stirred at
room temperature for 1 hour. The reaction mixture is cooled to
-50.degree. C. and 2.1 mL of acetic acid is added. The solution is
concentrated in vacuo and poured into water. The aqueous solution
is extracted with ethyl acetate and then aqueous HCl is added to
the aqueous layer. The product is extracted into ethyl acetate and
the organic layer is dried over magnesium sulfate, filtered and
concentrated in vacuo. Ethyl acetate and hexane are added to the
residue and the resulting tan solid is collected to provide 2.20 g
(64%) of product. An analytical sample is obtained by
recrystallization from diethyl ether and hexane, mp>300.degree.
C.
[0872] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.65 (m, 2H), 8.17 (d,
1H), 8.44 (d, 1H), 8.84 (s, 1H).
[0873] MS (ES, negative ion mode): m/z calcd for
C.sub.12H.sub.6N.sub.2OS: 226.3, found: 224.9 (M-H).sup.-
[0874] Analysis for C.sub.12H.sub.6N.sub.2OS.0.25H.sub.2O
[0875] Calcd: C, 62.46; H, 2.84; N, 12.14.
[0876] Found: C, 62.52; H, 2.93; N, 12.00.
EXAMPLE 64
4-Chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0877] A mixture of 1.01 g (4.47 mmol) of
4-hydroxybenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 7 mL of
phosphorous oxychloride is heated at reflux temperature for 40
minutes, then cooled to room temperature. Hexane is added and the
solid is collected by filtration, dissolved in ethyl acetate and
washed with saturated sodium bicarbonate. The organic layer is
dried over magnesium sulfate, filtered and concentrated in vacuo to
a small volume. The solids are collected by filtration to give 696
mg (64%) of product, mp 305-308.degree. C.
[0878] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.70 (t, 1H), 7.80 (t,
1H), 8.26 (d, 1H), 8.45 (d, 1H), 9.20 (s, 1H).
[0879] MS (ES, positive ion mode): m/z calcd for
C.sub.12H.sub.5ClN.sub.2S: 244.7, found: 244.6 (M+H).sup.+.
[0880] Analysis for C.sub.12H.sub.5ClN.sub.2S.0.2H.sub.2O
[0881] Calcd: C, 58.05; H, 2.19; N, 11.28.
[0882] Found: C, 58.29; H, 2.13; N, 11.27.
EXAMPLE 65
4-(3-Bromophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0883] A solution of 150 mg (0.61 mmol) of
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 3 mL of
2-ethoxyethanol containing 80 mg (0.74 mmol) of 3bromoaniline and
71 mg of pyridine hydrochloride is heated at reflux temperature for
4 hours, then allowed to stir at room temperature for 3 days. The
reaction mixture is partitioned between ethyl acetate and saturated
sodium bicarbonate and the organic layer is dried over magnesium
sulfate, filtered and concentrated in vacuo. Diethyl ether is added
to the residue and the resultant solid is collected by filtration
to give 139 mg (58%) of a white solid, mp 240-242.degree. C.
[0884] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.24 (d, 1H), 7.31-7.43
(m, 3H), 7.52-7.68 (m, 2H), 8.06 (d, 1H), 8.37 (d, 1H), 8.83 (s,
1H), 9.84 (s, 1H).
[0885] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.10BrN.sub.3S: 380.3, found: 379.9 (M+H).sup.+.
[0886] Analysis for C.sub.18H.sub.10BrN.sub.3S.0.5H.sub.2O
[0887] Calcd: C, 55.54; H, 2.85; N, 10.79.
[0888] Found: C, 55.84; H, 2.79; N, 10.73.
EXAMPLE 66
4-(4-Chloro-2-fluorophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonit-
rile
[0889] A solution of 237 mg (0.97 mmol) of
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 6 mL of
2-ethoxyethanol containing 0.15 mL (1.36 mmol) of
4-chloro-2-fluoroaniline and 112 mg of pyridine hydrochloride is
heated at reflux temperature for 30 hours. The reaction mixture is
cooled to room temperature and partitioned between ethyl acetate
and saturated sodium bicarbonate. The organic layer is dried over
magnesium sulfate, filtered and concentrated in vacuo. Diethyl
ether is added to the residue and the resultant solid is collected
by filtration, washing with hexane to give 225 mg (66%) of an
off-white solid, mp 250-251.degree. C.
[0890] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.40 (d, 1H), 7.50-7.69
(m, 4H), 8.08 (d, 1H), 8.37 (d, 1H), 8.80 (s, 1H), 9.68 (s,
1H).
[0891] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.9ClFN.sub.3S: 353.8, found: 353.8 (M+H).sup.+.
[0892] Analysis for C.sub.18H.sub.9ClFN.sub.3S
[0893] Calcd: C, 61.11; H, 2.56; N, 11.88.
[0894] Found: C, 61.50; H, 2.58; N, 11.65.
EXAMPLE 67
4-(2,4-Dichlorophenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0895] A mixture of 250 mg (1.02 mmol) of
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 530 mg
(3.27 mmol) of 2,4-dichloroaniline and 112 mg of pyridine
hydrochloride is heated until no
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile remained as
measured by thin layer chromatography. The reaction mixture is
cooled to room temperature and the solid is treated with methanol
and then partitioned between ethyl acetate and saturated sodium
bicarbonate. The organic layer is dried over magnesium sulfate,
filtered and concentrated in vacuo. Diethyl ether is added to the
residue and the solid is collected by filtration to give 225 mg
(66%) of a yellow solid. An analytical sample is obtained by column
chromatography, eluting with 6:1 hexane/ethyl acetate, to provide a
light yellow solid, mp 260-262.degree. C.
[0896] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.55-7.72 (m, 4H), 7.83
(s, 1H), 8.06 (d, 1H), 8.35 (d, 1H), 8.79 (s, 1H), 9.76 (s,
1H).
[0897] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.9Cl.sub.2N.sub.3S: 370.3, found: 369.8 (M+H).sup.+.
Analysis for C.sub.18H.sub.9Cl.sub.2N.sub.3S.0.25H.sub.2O
[0898] Calcd: C, 57.68; H, 2.55; N, 11.21.
[0899] Found: C, 57.64; H, 2.48; N, 10.94.
EXAMPLE 68
4-(2,4-Dichloro-5-methoxyphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-car-
bonitrile
[0900] A mixture of 230 mg (1.2 mmol) of
2,4-dichloro-5-methoxyaniline (WO 8501939A1) and 48 mg (1.2 mmol)
of 60% sodium hydride in mineral oil in 10 mL of tetrahydrofuran is
heated at reflux temperature. The reaction mixture is cooled and
200 mg (0.82 mmol) of
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile is added.
The mixture is heated at reflux for 4 hours, then cooled to room
temperature and partitioned between ethyl acetate and water. The
organic layer is washed with water, dried over magnesium sulfate,
filtered and concentrated in vacuo. Diethyl ether is added to the
residue and the resultant solid is collected by filtration and
purified by column chromatography, eluting with 3:1 hexane/ethyl
acetate, to provide 89 mg (27%) of a white solid, mp
234-236.degree. C.
[0901] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.86 (s, 3H), 7.21 (s,
1H), 7.56-7.67 (m, 2H), 7.78 (s, 1H), 8.07 (d, 1H), 8.37 (d, 1H),
8.79 (s, 1H), 9.79 (s, 1H).
[0902] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.11Cl.sub.2N.sub.3OS: 400.3, found: 400.1
(M+H).sup.+.
[0903] Analysis for C.sub.19H.sub.11Cl.sub.2N.sub.3OS.0.2
CH.sub.3CO.sub.2C.sub.2H.sub.5
[0904] Calcd: C, 56.90; H, 3.04; N, 10.05.
[0905] Found: C, 56.99; H, 3.37; N, 10.07.
EXAMPLE 69
4-(4-Phenoxyphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0906] A mixture of 250 mg (1.02 mmol) of
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 210 mg
(1.12 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is
heated at reflux temperature for 4 hours then stirred at room
temperature for 3 days. The reaction mixture is then heated at
reflux temperature for an additional 6 hours, then cooled to room
temperature and partitioned between ethyl acetate and saturated
sodium bicarbonate. The organic layer is dried over sodium sulfate,
filtered and concentrated in vacuo to provide 240 mg (60%) of a
beige solid, mp 230-233.degree. C.
[0907] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.06-7.19 (m, 5H),
7.32-7.47 (m, 4H), 7.55-7.86 (m, 2H), 8.05 (s, 1H), 8.34(s, 1H),
8.75 (s, 1H), 9.65 (s, 1H).
[0908] MS (ES, positive ion mode): m/z calcd for
C.sub.24H.sub.15N.sub.3OS: 393.5, found: 393.9 (M+H).sup.+.
[0909] Analysis for C.sub.24H.sub.15N.sub.3OS.0.5H.sub.2O
[0910] Calcd: C, 71.61; H, 3.98; N, 10.44.
[0911] Found: C, 71.99; H, 3.80; N, 10.56.
EXAMPLE 70
4-(3-Hydroxy-4-methylphenylamino)benzo[4,5]thieno[3,2-b]pyridine-3-carboni-
trile
[0912] A mixture of 300 mg (1.20 mmol) of
4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 160 mg
(1.32 mmol) of 5-amino-o-cresol in 5 mL of 2-ethoxyethanol is
heated at reflux temperature for 8 hours, then stirred at room
temperature overnight. The reaction mixture is partitioned between
ethyl acetate and saturated sodium bicarbonate. The organic layer
is dried over sodium sulfate, filtered and concentrated in vacuo to
provide 220 mg (55%) of a light yellow solid, mp 260.degree. C.
dec.
[0913] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.17 (s, 3H), 6.63 (dd,
1H). 6.69 (d, 1H), 7.09 (s, 1H), 7.52-7.67 (m, 2H), 8.01 (d, 1H),
8.33 (d, 1H), 8.76 (s, 1H), 9.55 (s, 1H).
[0914] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.13N.sub.3OS: 331.4, found: 331.8 (M+H).sup.+.
[0915] Analysis for C.sub.19H.sub.13N.sub.3OS.0.2H.sub.2O
[0916] Calcd: C, 68.11; H, 4.03; N, 12.54.
[0917] Found: C, 68.20; H, 3.95; N, 12.31.
EXAMPLE 71
4-(4-Chloro-2-fluorophenoxy)benzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0918] A mixture of 0.59 mL (5.5 mmol) of 4-chloro-2-fluorophenol
and 100 mg (1.78 mmol) of potassium hydroxide is heated until a
homogeneous solution is formed. To this is added 245 mg (1.00 mmol)
of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and the
mixture is heated for 2 hours. Ethyl acetate is added and the
solution is washed with 1 N NaOH. The organic layer is dried over
sodium sulfate, filtered and concentrated in vacuo. The solid is
collected and recrystallized from ethyl acetate to give 195 mg
(55%) of a light beige solid, mp 174-175.degree. C.:
[0919] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.49 (m, 1H), 7.64-7.77
(m, 3H), 7.86 (dd, 1H), 8.15 (d, 1H), 8.46 (d, 1H), 9.19 (s,
1H).
[0920] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.8ClFN.sub.2OS: 354.8, found: 354.8 (M+H).sup.+.
[0921] Analysis for C.sub.18H.sub.8ClFN.sub.2OS.0.3H.sub.2O
[0922] Calcd: C, 60.02; H, 2.41; N, 7.78.
[0923] Found: C, 60.32; H, 2.38; N, 7.25.
EXAMPLE 72
3-Amino-5-nitrobenzo[b]thiophene
[0924] A solution of 23.00 g (91.26 mmol) of methyl
3-amino-5-nitrobenzo[b]thiophene-2-carboxylate (J. Hetero. Chem.,
34(4), 1163 (1997)) in 100 mL of 1-methyl-2-pyrrolidinone and 30 mL
of 1-methylpiperazine is heated at 180.degree. C. for 2 hours. The
reaction is cooled to room temperature and poured into water. The
resultant solid is collected by filtration and washed with water.
The solid is dissolved in a mixture of ethyl acetate and diethyl
ether and the solution is washed with water twice. The organic
layer is dried over magnesium sulfate, filtered and concentrated in
vacuo. Diethyl ether and hexane are added to the residue and the
dark red solid is collected by filtration to provide 11.17 g (63%),
mp 155-158.degree. C.
[0925] .sup.1HNMR (DMSO-d.sub.6): .delta. 5.67 (s, 2H, NH2), 6.39
(s, 1H), 8.05-8.14 (m, 2H), 8.88 (s, 1H).
[0926] MS (ES, positive ion mode): m/z calcd for
C.sub.8H.sub.6N.sub.2O.sub.2S: 194.2, found: 194.9 (M+H).sup.+.
[0927] Analysis for C.sub.8H.sub.6N.sub.2O.sub.2S
[0928] Calcd: C, 49.48; H, 3.11; N, 14.42.
[0929] Found: C, 49.73; H, 3.25; N, 14.13.
EXAMPLE 73
4-Hydroxy-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0930] A mixture of 9.00 g (46.34 mmol) of
3-amino-5-nitrobenzo[b]thiophene and 8.65 g (51.12 mmol) of
ethyl(ethoxymethylene)cyanoacetate in 100 mL of toluene is heated
at reflux for 2 hours. The reaction mixture is cooled to room
temperature and the precipitate is collected by filtration washing
with diethyl ether to provide 11.50 g (78%) of a bright yellow
solid.
[0931] A 2.33 g portion of this solid is added to 40 mL of 1:3
biphenyl/diphenyl ether and the mixture is heated at reflux for 4
hours. The mixture is cooled slightly and the precipitate is
collected by filtration, washing with diethyl ether and hexane to
give 925 mg (46%) of a brown solid, mp>305.degree. C.
[0932] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.43 (s, 2H), 8.95 (s,
1H), 9.45 (s, 1H).
[0933] MS (ES, negative ion mode): m/z calcd for
C.sub.12H.sub.5N.sub.3O.sub.3S: 271.3, found: 270.2
(M-H).sup.-.
[0934] Analysis for C.sub.12H.sub.5N.sub.3O.sub.3S
[0935] Calcd: C, 53.14; H, 1.86; N, 15.49.
[0936] Found: C, 52.81; H, 2.07; N, 15.31.
EXAMPLE 74
4-Chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile
[0937] A mixture of 1.22 g (4.49 mmol) of
4-hydroxy-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in
20 mL of phosphorous oxychloride is heated at reflux temperature
for 3 hours, then cooled to room temperature. The solid is
collected by filtration, then washed with hexane followed by water.
The solid is dried to give 947 mg (73%) of a dark brown solid, mp
softens at 270.degree. C.
[0938] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.59 (s, 2H), 9.09 (s,
1H), 9.34 (s, 1H).
[0939] MS (ES, positive ion mode): m/z calcd for
C.sub.12H.sub.4ClN.sub.3O.sub.2S: 289.7, found: 289.6
(M+H).sup.+.
[0940] Analysis for
C.sub.12H.sub.4ClN.sub.3O.sub.2S.1.0H.sub.2O
[0941] Calcd: C, 46.83; H, 1.97; N, 13.66.
[0942] Found: C, 47.10; H, 1.63; N, 13.54.
EXAMPLE 75
4-(4-Chloro-5-methoxy-2-methylphenylamino)-8-nitrobenzo[4,5]thieno[3,2-b]p-
yridine-3-carbonitrile
[0943] A solution of 286 mg (0.99 mmol) of
4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in
10 mL of 2-ethoxyethanol containing 131 mg (1.42 mmol) of
4-chloro-5-methoxy-2-methylaniline (WO 8501939A1) and 131 mg of
pyridine hydrochloride is heated at reflux temperature overnight.
The reaction mixture is cooled slightly and an additional 100 mg
(0.58 mmol) of 4-chloro-5-methoxy-2-methylaniline is added and the
reaction mixture is heated at reflux temperature overnight. The
mixture is cooled to room temperature and the solid is collected by
filtration, then suspended in methanol. Aqueous ammonium hydroxide
is added and the mixture is partitioned between ethyl acetate and
water. The organic layer is washed with water, then dried over
magnesium sulfate, filtered and concentrated in vacuo. Diethyl
ether is added to the residue and the resultant solid is collected
by filtration, and washed with diethyl ether to give 110 mg (26%)
of a tan solid, mp>305.degree. C.
[0944] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.10 (s, 3H), 3.78 (s,
3H), 7.23 (s, 1H), 7.49 (s, 1H), 8.33 (d, 1H), 8.39 (d, 1H), 8.83
(s,1H), 9.00 (s, 1H), 9.70 (s, 1H).
[0945] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.13ClN.sub.4O.sub.3S: 424.9, found: 425.0
(M+H).sup.+.
[0946] Analysis for C.sub.20H.sub.13ClN.sub.4O.sub.3S
[0947] Calcd: C, 56.54; H, 3.08; N, 13.19.
[0948] Found: C, 56.34; H, 3.31; N, 12.81.
EXAMPLE 76
8-Amino-4-(4-chloro-5-methoxy-2-methylanilino)[1]benzothieno[3,2-b]pyridin-
e-3-carbonitrile
[0949] A mixture of 476 mg (1.12 mmol) of
4-(4-chloro-5-methoxy-2-methylphenylamino)-8-nitrobenzo[4,5]thieno[3,2-b]-
pyridine-3-carbonitrile, 180 mg (3.22 mmol) of iron powder and 180
mg (3.36 mmol) of ammonium chloride in 20 mL of 50% aqueous
methanol is heated at reflux temperature for 2 hours. An additional
80 mg (1.42 mmol) of iron powder and 100 mg (1.87 mmol) of ammonium
chloride are added and the reaction mixture is heated at reflux
temperature for 2 hours, then stirred at room temperature
overnight. The reaction mixture is heated at reflux for 4 hours
then cooled slightly and filtered. The solid residue is extracted
with several portions of hot ethyl acetate followed by hot
methanol. All the organic layers are combined and washed with
water. The organic layer is dried over magnesium sulfate, filtered
and concentrated in vacuo. The residue is purified by flash
chromatography eluting with a gradient of 1:1 hexane/ethyl acetate
to only ethyl acetate to give 165 mg (37%) of a tan solid, mp
266-268.degree. C. dec.
[0950] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.07 (s, 3H), 3.77 (s,
3H), 5.38 (d, 2H), 6.90 (dd, 1H), 7.13 (s, 1H), 7.46 (s, 1H), 7.46
(d, 1H), 7.58 (d, 1H), 8.63 (s, 1H), 9.30 (s, 1H).
[0951] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.15ClN.sub.4OS: 394.9, found: 395.1 (M+H).sup.+.
[0952] Analysis for
C.sub.20H.sub.15ClN.sub.4OS.0.25CH.sub.3CO.sub.2C.sub.2H.sub.5
[0953] Calcd: C, 60.50; H, 4.11; N, 13.44.
[0954] Found: C, 60.30; H, 4.17; N, 13.26.
EXAMPLE 77
7-Nitro-1-benzothiophen-3-amine
[0955] A mixture of 4.82 g (19.1 mmol) methyl
3-amino-7-nitro-1-benzothiophene-2-carboxylate (WO 9738983),
1-methyl-2-pyrrolidinone (23 mL) and 1-methylpiperazine (6.5 mL) is
stirred at 185-190.degree. C. for 4 hours, then cooled to room
temperature. The precipitate is filtered, washed with diethyl
ether, and dried to give 7-nitro-1-benzothiophen-3-amine (3.3 g,
89% A) as a red-brown solid, m.p. 188-191.degree. C.
[0956] .sup.1HNMR (DMSO-d.sub.6): .delta. 5.55 (s, br, 2H), 6.40
(s, 1H), 7.64 (t, 1H), 8.34 (d, 1H), 8.41 (d, 1H).
[0957] MS (ES, positive ion mode): m/z calcd for
C.sub.8H.sub.6N.sub.2O.sub.2S: 194.2, found: 195.1 (M+H).sup.+.
[0958] Analysis for C.sub.8H.sub.6N.sub.2O.sub.2S.0.3
C.sub.2H.sub.5OC.sub.2H.sub.5
[0959] Calcd: C, 51.05; H, 4.19; N, 12.96.
[0960] Found: C, 51.14; H, 3.95; N, 13.21.
EXAMPLE 78
Ethyl (Z,E)-2-cyano-3-[(7-nitro-1-benzothien-3-yl
amino]-2-propenoate
[0961] A mixture of 7-nitro-1-benzothiophen-3-amine (3.3 g, 17.0
mmol) and ethyl(ethoxymethylene)cyanoacetate (3.16 g, 18.7 mmol) in
toluene (30 mL) is heated at reflux temperature with stirring for
two hours under nitrogen, then cooled, filtered, washed with
diethyl ether, dried, and purified by column chromatography on
silica gel, elution with chloroform/methanol 20:1. Ethyl (Z,
E)-2-cyano-3-[(7-nitro-1-benzothien-3-yl)amino]-2-propenoate (4.5
g, 83%) is obtained as a yellow solid, m.p. 249-250.degree. C. The
ratio of Z and E isomers, determined by .sup.1HNMR, is 1:1.
[0962] .sup.1HNMR (DMSO-d.sub.6): .delta. 1.24 and 1.30 (t, 3H),
4.19 and 4.29 (q, 2H), 7.78 and 7.80 (t, 1H), 8.01 and 8.05 (s,
1H), 8.22 (s, 1H), 8.50 (m, 2H), 11.05 (d, 1H).
[0963] MS (ES, negative ion mode): m/z calcd for
C.sub.14H.sub.11N.sub.3O.sub.4S: 317.3, found: 316.2
(M-H).sup.-.
[0964] Analysis for C.sub.14H.sub.11N.sub.3O.sub.4S
[0965] Calcd: C, 52.99; H, 3.49; N, 13.24.
[0966] Found: C, 52.85; H, 3.61; N, 13.11.
EXAMPLE 79
4-Chloro-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile
[0967] A suspension of ethyl (Z,
E)-2-cyano-3-[(7-nitro-1-benzothien-3-yl)amino]-2-propenoate (3.17
g, 10.0 mmol) in 45 mL of 1:3 biphenyl/diphenyl ether is heated at
255.degree. C. for 20 hours, then cooled, filtered, the precipitate
thoroughly washed with diethyl ether and dried to give 1.1 g of
6-nitro-4-oxo-1,4-dihydro[1]benzothieno[3,2-b]pyridine-3-carbonitrile.
This compound is dissolved in 25 mL of dichloromethane, and to the
formed solution are added sequentially oxalyl chloride (4.0 mL of
2M solution in dichloromethane) and DMF (0.8 mL). The formed
mixture is stirred for 4 hours at 40.degree. C., then cooled and
concentrated in vacuo. The residue is suspended in 5 mL of water,
extracted with chloroform, and the extract dried over sodium
sulfate. After the solvent evaporation the desired product is
isolated by column chromatography on silica gel, elution with
chloroform. The product is washed with diethyl ether and ethyl
acetate, then dried in vacuo to provide
4-chloro-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.6
g, 20%) as a light-brown solid, m.p. 258-260.degree. C.
[0968] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.02 (t, 1H), 8.77 (dd,
1H), 8.96 (dd, 1H), 9.36 (s, 1H).
[0969] MS (ES, positive ion mode): m/z calcd for
C.sub.12H.sub.4ClN.sub.3O.sub.2S: 289.7, found: 289.0
(M+H).sup.+.
[0970] Analysis for
C.sub.12H.sub.4ClN.sub.3O.sub.2S.0.5CH.sub.3CO.sub.2C.sub.2H.sub.5
[0971] Calcd: C, 50.38; H, 2.42; N, 12.59.
[0972] Found: C, 50.21; H, 2.33; N, 12.51.
EXAMPLE 80
4-(3-Bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile
[0973] A mixture of
4-chloro-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.27
g, 0.9 mmol), 3-bromoaniline (3.16 g, 18.4 mmol), and pyridine
hydrochloride (0.06 g) in 15 mL of DMSO is stirred in the microwave
(PROLABO unit) at 140.degree. C., power range 0-10%, for one hour.
The final reaction mixture is cooled, dissolved in 100 mL of
chloroform, washed with 2N HCl (2.times.50 mL), then with saturated
aqueous sodium bicarbonate (50 mL), and dried over sodium sulfate.
The solvent is evaporated, and the desired compound purified by
silica gel chromatography, eluting with 9:1 chloroform/methanol.
After washing with diethyl ether and ethyl acetate,
4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile
(0.215 g, 55%) is obtained as a yellow solid, m. p. 288-290.degree.
C.
[0974] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.33 (d, 1H), 7.40 (t,
1H), 7.52 (m, 2H), 7.90 (t, 1H), 8.68 (d, 1H), 8.83 (d, 1H), 8.91
(s, 1H), 10.04 (s, br, 1H).
[0975] MS (ES, positive ion mode): m/z calcd for
C.sub.18BrN.sub.4O.sub.2S: 425.3, found: 427.0 (M+H).sup.+.
[0976] Analysis for
C.sub.18H.sub.9BrN.sub.4O.sub.2S.0.5HCl.0.5CH.sub.3CO.sub.2C.sub.2H.sub.5
[0977] Calcd: C, 49.27; H, 2.79; N, 11.49.
[0978] Found: C, 49.02; H, 2.42; N, 11.18.
EXAMPLE 81
6-Amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile
[0979] A mixture of
4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile
(0.213 g, 0.5 mmol), iron powder (0.168 g, 3.0 mmol) ammonium
chloride (0.325 g, 6.0 mmol), methanol (90 mL) and water (90 mL) is
heated at reflux temperature with vigorous stirring under nitrogen
for 12 hours. The final mixture is concentrated, and the residue is
extracted with ethyl acetate (5.times.20 mL). The extract is dried
over sodium sulfate, evaporated, and re-dissolved in a small volume
of chloroform/methanol/DMSO. Purification by silica gel
chromatography, eluting with 20:1 chloroform/methanol, yields
6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile
as a brown solid, m. p. 256-258.degree. C.
[0980] .sup.1HNMR (DMSO-d.sub.6): .delta. 5.60 (s, br, 2H), 6.89
(d, 1H), 7.18 (d, 1H), 7.32 (m, 4H), 7.65 (d, 1H), 8.83 (s, 1H),
9.76 (s, 1H).
[0981] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.11BrN.sub.4S: 395.3, found: 397.0 (M+H).sup.+.
[0982] Analysis for
C.sub.18H.sub.11BrN.sub.4S.1CH.sub.3SOCH.sub.3
[0983] Calcd: C, 50.74; H, 3.61; N, 11.83.
[0984] Found: C, 50.90; H, 3.24; N, 11.93.
EXAMPLE 82
3-(Dimethylaminomethyleneamino)benzofuran-2-carboxylic acid ethyl
ester
[0985] A mixture of 4.2 g (20.0 mmol) of ethyl
3-amino-2-benzo[b]furancarboxylate (EP 187487 A1) in 10 mL of
N,N-dimethylformamide dimethyl acetal is heated at reflux
temperature for 1.5 hours, then cooled to room temperature and
concentrated in vacuo. The residue is partitioned between ethyl
acetate and water. The organic layer is washed with water, dried
over sodium sulfate, passed through a pad of diatomaceous earth and
concentrated in vacuo. The solid is collected by filtration to
provide 3.90 g (75%) of a white solid, mp 89-90.degree. C.
[0986] .sup.1HNMR (DMSO-d.sub.6): .delta. 1.3 (t, 3H), 3.04 (s,
3H), 3.06 (s, 3H), 4.25 (t, 2H), 7.38 (t, 1H), 7.49 (t, 1H), 7.57
(d, 1H), 7.68 (d, 1H), 7.99 (s, 1H).
[0987] MS (ES, positive ion mode): m/z calcd for
C.sub.14H.sub.16N.sub.2O.sub.3: 260.3, found: 260.9
(M+H).sup.+.
[0988] Analysis for C.sub.14H.sub.16N.sub.2O.sub.3
[0989] Calcd: C, 64.60; H, 6.20; N, 10.76.
[0990] Found: C, 64.45; H, 6.04; N, 10.64.
EXAMPLE 83
4-Hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile
[0991] A solution of 1.5 mL (30.0 mmol) of acetonitrile in 30 mL of
tetrahydrofuran is added to a -78.degree. C. solution of 11.4 mL of
2.5 M n-butyllithium (29.00 mmol) in 35 mL of tetrahydrofuran.
After stirring at -78.degree. C. for 15 min a solution of 3.7 g
(14.2 mmol) of
3-(dimethylaminomethyleneamino)benzofuran-2-carboxylic acid ethyl
ester in 50 mL of tetrahydrofuran is added dropwise. After stirring
at -78.degree. C. for 30 minutes, the reaction mixture is allowed
to warm to 0.degree. C. The reaction mixture is cooled to
-78.degree. C. and 3 mL of acetic acid is added. The solution is
warmed to room temperature and the resulting precipitate is
collected. This solid is combined with 20 mL of acetic acid and
heated at reflux temperature for 1.5 hours. The mixture is cooled
to room temperature and the solid is collected by filtration
washing with saturated sodium bicarbonate, water, diethyl ether and
ethyl acetate to provide 2.45 g of a red solid, mp>310.degree.
C.
[0992] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.53 (t, 1H), 7.72 (t,
1H), 7.86 (d, 1H), 8.13 (d, 1H), 8.80(s, 1H).
[0993] MS (ES, positive ion mode): m/z calcd for
C.sub.12H.sub.6N.sub.2O.sub.2: 210.2, found: 210.8 (M+H).sup.+.
[0994] Analysis for C.sub.12H.sub.6N.sub.2O.sub.2.0.50 H.sub.2O
[0995] Calcd: C, 65.52; H, 3.21; N, 12.71.
[0996] Found: C, 65.51; H, 3.19; N, 12.94.
EXAMPLE 84
4-Chlorobenzo[4,5]furo[3,2-b]pyridine-3 carbonitrile
[0997] A mixture of 2.10 g (11.0 mmol) of
4-hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile in 15 mL of
phosphorous oxychloride is heated at reflux temperature for 1.5
hours, then cooled to room temperature. Hexane is added and the
solid is collected by filtration, dissolved in ethyl acetate and
washed with cold 1 N NaOH. The organic layer is dried over sodium
sulfate, filtered through a pad of diatomaceous earth and
concentrated in vacuo to give 1.55 g (65%) of a red solid, mp
229-231.degree. C.
[0998] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.64 (t, 1H), 7.87 (t,
1H), 8.00 (d, 1H), 8.28 (d, 1H), 9.14(s, 1H).
[0999] MS (ES, positive ion mode): m/z calcd for
C.sub.12H.sub.5ClN.sub.2O: 228.6, found: 228.9 (M+H).sup.+.
[1000] Analysis for C.sub.12H.sub.5ClN.sub.2O
[1001] Calcd: C, 63.04; H, 2.20; N, 12.25.
[1002] Found: C, 62.83; H, 2.26; N, 12.12.
EXAMPLE 85
4-(3-Bromophenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile
[1003] A solution of 300 mg (1.30 mmol) of
4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.160 mL
(1.43 mmol) of 3-bromoaniline in 8 mL of 2-ethoxyethanol is heated
at reflux temperature for 24 hours. The reaction mixture is
partitioned between ethyl acetate and saturated sodium bicarbonate.
The organic layer is washed with saturated sodium bicarbonate,
followed by brine, then dried over sodium sulfate, filtered through
a pad of diatomaceous earth and concentrated in vacuo. The
resultant solid is collected by filtration to give 300 mg (42%) of
a beige solid, mp 242-245.degree. C.
[1004] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.21-7.57 (m, 5H), 7.70
(d, 2H), 8.18 (d, 1H), 8.74 (s, 1H), 9.93 (s, 1H).
[1005] MS (ES, negative ion mode): m/z calcd for
C.sub.18H.sub.10BrN.sub.3O: 362.4, found: 361.8 (M-H).sup.-.
[1006] Analysis for C.sub.18H.sub.10BrN.sub.3O
[1007] Calcd: C, 59.36; H, 2.77; N, 11.54.
[1008] Found: C, 59.01; H, 2.97; N, 11.36.
EXAMPLE 86
4-(4-Chloro-2-fluorophenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitri-
le
[1009] A mixture of 200 mg (0.88 mmol) of
4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.11 mL
(0.97 mmol) of 4-chloro-2-fluoroaniline in 6 mL of 2-ethoxyethanol
is heated at reflux temperature for 4 days. A catalytic amount of
pyridine hydrochloride is added and the reaction mixture is heated
at reflux temperature overnight then cooled to room temperature.
The reaction mixture is partitioned between ethyl acetate and
water. The organic layer is dried over sodium sulfate, filtered
through a pad of diatomaceous earth and concentrated in vacuo to
provide 120 mg (40%) of a beige solid, mp 259-261.degree. C.
[1010] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.24-7.39 (m, 2H),
7.43-7.53 (m, 2H), 7.61 (d, 2H), 8.09 (d, 1H), 8.49 (s, 1H), 10.07
(s, 1H).
[1011] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.9ClFN.sub.3O: 337.7, found: 337.8 (M+H).sup.+.
[1012] Analysis for C.sub.18H.sub.9ClFN.sub.3O.1.0H.sub.2O
[1013] Calcd: C, 60.77; H, 3.12; N, 11.81.
[1014] Found: C, 60.41; H, 2.70; N, 11.60.
EXAMPLE 87
4-(3-Hydroxy-4-methylphenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitr-
ile
[1015] A mixture of 200 mg (0.88 mmol) of
4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 120 mg
(0.97 mmol) of 5-amino-o-cresol in 6 mL of 2-ethoxyethanol is
heated at 80.degree. C. for 15 hours and then at reflux temperature
for 10 hours. The reaction mixture is cooled to room temperature
and partitioned between ethyl acetate and saturated sodium
bicarbonate. The organic layer is washed with saturated sodium
bicarbonate, dried over sodium sulfate and filtered through a pad
of diatomaceous earth. Concentration in vacuo yields 200 mg (72%)
of a beige solid, mp 240.degree. C. dec.
[1016] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.13 (s, 3H), 6.61 (dd,
1H), 6.68 (d, 1H), 7.03 (d, 1H), 7.51 (t, 1H), 7.63-7.74 (m, 2H),
8.15 (d, 1H), 8.62 (s, 1H), 9.40 (s, 1H), 9.66 (s, 1H).
[1017] MS (ES, positive ion mode): m/z calcd for
C.sub.19H.sub.13N.sub.3O.sub.2: 315.3, found: 315.9
(M+H).sup.+.
[1018] Analysis for C.sub.19H.sub.13N.sub.3O.sub.2.0.2H.sub.2O
[1019] Calcd: C, 71.54; H, 4.22; N, 13.17.
[1020] Found: C, 71.39; H, 4.31; N, 12.99.
EXAMPLE 88
4-(4-Phenoxyphenylamino)benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile
[1021] A mixture of 200 mg (0.88 mmol) of
4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 180 mg
(0.96 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is
heated at reflux temperature for 3 hours. The reaction mixture is
cooled to room temperature and partitioned between ethyl acetate
and saturated sodium bicarbonate. The organic layer is washed with
saturated sodium bicarbonate, followed by brine, then dried over
sodium sulfate and filtered through a pad of diatomaceous earth.
Concentration in vacuo yields 115 mg (35%) of a beige solid, mp
175-179.degree. C.
[1022] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.01-7.18 (m, 5H),
7.31-7.45 (m, 4H), 7.54 (dt, 11, 7.65-7.73 (m, 2H), 8.15 (d, 1H),
8.62 (s, 1H), 9.83 (s, 1H).
[1023] MS (ES, positive ion mode): m/z calcd for
C.sub.24H.sub.15N.sub.3O.sub.2: 377.4, found: 377.9
(M+H).sup.+.
[1024] Analysis for C.sub.24H.sub.15N.sub.3O.sub.2
[1025] Calcd: C, 76.38; H, 4.01; N, 11.13.
[1026] Found: C, 76.13; H, 3.96; N, 11.14.
EXAMPLE 89
4-(4-Chloro-2-fluorophenoxy)-benzo[4,5]furo[3,2-b]pyridine-3-carbonitrile
[1027] A mixture of 0.530 mL (4.1 mmol) of 4-chloro-2-fluorophenol
and 70 mg (1.25 mmol) of potassium hydroxide is heated until a
homogeneous solution is formed. To this is added 170 mg (0.74 mmol)
of 4-chlorobenzo[4,5]-furo[3,2-b]pyridine-3-carbonitrile and the
mixture is heated for 1 hour. Ethyl acetate is added and the
solution is washed with 1 N NaOH. The organic layer is dried over
sodium sulfate, filtered through a pad of diatomaceous earth and
concentrated in vacuo. The solid is collected to give 115 mg (46%)
of a beige solid, mp 138-140.degree. C.
[1028] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.41 (d, 1H), 7.57-7.85
(m, 5H), 8.25 (d, 1H), 9.10 (s, 1H).
[1029] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.8ClFN.sub.2O.sub.2: 338.7, found: 338.8
(M+H).sup.+.
[1030] Analysis for
C.sub.18H.sub.8ClFN.sub.2O.sub.2.0.5H.sub.2O
[1031] Calcd: C, 62.16; H, 2.61; N, 8.06.
[1032] Found: C, 62.00; H, 2.34; N, 7.71.
EXAMPLE 90
4-(2,4-Dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitril-
e
[1033] A mixture of 160 mg (4.00 mmol) of sodium hydride (60%
dispersion in oil) and 648 mg (4.00 mmol) of 2,4-dichloroaniline in
10 mL of dimethylformamide is stirred at room temperature for 1
hour.
4-Chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 578
mg (2.00 mmol), is added and the suspension is heated at
130.degree. C. overnight. The reaction mixture is cooled to room
temperature and partitioned between ethyl acetate and water. The
organic layer is washed with water then dried over magnesium
sulfate, filtered and concentrated in vacuo. Diethyl ether is added
to the residue and the resultant solid is collected by filtration.
The solid is suspended in diethyl ether and filtered. The filtrate
is concentrated to a small volume and filtered to give 80 mg (29%)
of
4-(2,4-dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitri-
le as an off-white solid, mp 210-213.degree. C.
[1034] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.58 (dd, J=8 Hz, J=2 Hz,
1H), 7.65 (d, J=8 Hz, 1H), 7.85 (d, J=2 Hz, 1H), 8.36-8.45 (m, 2H),
8.87 (s, 1H), 9.01 (d, J=2 Hz, 1H), 9.97 (s, 1H).
[1035] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.8Cl.sub.2N.sub.4O.sub.2S: 415.3, found: 415.0, 417.0
(M+H).sup.+.
[1036] Analysis for C.sub.18H.sub.8Cl.sub.2N.sub.4O.sub.2S.0.2
C.sub.2H.sub.5OC.sub.2H.sub.5
[1037] Calcd: C, 52.50; H, 2.34; N, 13.03.
[1038] Found: C, 52.27; H, 2.46; N, 13.00.
EXAMPLE 91
4-(3-Bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile
[1039] A solution of 400 mg (1.38 mmol) of
4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 8
mL of 2-ethoxyethanol containing 160 mg (1.38 mmol) of pyridine
hydrochloride and 0.180 mL (1.65 mmol) of 3-bromoaniline is heated
at reflux for 4 hours. The reaction mixture is filtered hot and the
solid is stirred with methanol and ammonium hydroxide. The mixture
is poured into water and the solid is collected, washing with ethyl
acetate to give 363 mg (62%) of
4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile
as a brown solid, mp>300.degree. C.
[1040] .sup.1HNMR (DMSO-d.sub.6): .delta. 7.32 (d, J=8 Hz, 1H),
7.40 (t, J=8 Hz, 1H), 7.52 (m, 2H), 8.37 (d, J=8 Hz, 1H), 8.43 (dd,
J=8 Hz, 3=2 Hz, 1H), 8.92 (s, 1H), 9.01 (d, 3=2 Hz, 1H), 10.03 (s,
1H).
[1041] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.9BrN.sub.4O.sub.3S: 425.3, found: 425.0, 427.1
(M+H).sup.+.
[1042] Analysis for C.sub.18H.sub.9BrN.sub.4O.sub.3S
[1043] Calcd: C, 50.84; H, 2.13; N, 13.17.
[1044] Found: C, 50.77; H, 2.47; N, 13.01.
EXAMPLE 92
8-Amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile
[1045] A mixture of 436 mg (1.03 mmol) of
4-(3-bromoanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile,
291 mg (5.19 mmol) of iron powder and 416 mg (7.77 mmol) of
ammonium chloride in 160 mL of methanol and 110 mL of water is
heated at reflux for 5.5 hours. The reaction mixture is filtered
hot and the solid residue is extracted with several portions of hot
ethyl acetate followed by hot methanol. All the organic layers are
combined and washed with water. The organic layer is dried over
magnesium sulfate, filtered and concentrated in vacuo. Diethyl
ether and hexane are added and the solid is collected by filtration
to provide 87 mg of
8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile.
The filtrate is concentrated and purified by flash chromatography,
eluting with a gradient of 1:1 hexane/ethyl acetate to 100% ethyl
acetate to give an additional 56 mg of 8-amino-4-(3-bromoanilino)-[
]benzothieno[3,2-b]pyridine-3-carbonitrile as a bright yellow
solid, mp 295-300.degree. C. dec.
[1046] .sup.1HNMR (DMSO-d.sub.6): .delta. 5.43 (s, 2H), 6.95 (dd,
J=8 Hz, J=2 Hz, 1H), 7.21 (m, 1H), 7.29-7.40 (m, 3H), 7.51 (d, J=2
Hz, 1H), 7.64 (d, J=8 Hz, 1H), (8.77 (s, 1H), 9.67 (s, 1H).
[1047] MS (ES, positive ion mode): m/z calcd for
C.sub.18H.sub.11BrN.sub.4S: 395.3, found: 395.2, 397.2
(M+H).sup.+.
[1048] Analysis for C.sub.18H.sub.11BrN.sub.4S
[1049] Calcd: C, 54.69; H, 2.80; N, 14.17.
[1050] Found: C, 54.37; 1, 2.85; N, 13.98.
EXAMPLE 93
N-[4-(3-Bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-8-yl]acrylamide
[1051] To a 0.degree. C. solution of 164 mg (0.417 mmol) of
8-amino-4-(3-bromoanilino)-[1]benzothieno[3,2-b]pyridine-3-carbonitrile
and 120 mg (0.626 mmol) of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 2
mL of dimethylformamide and 2 mL of tetrahydrofuran is added 0.045
mL (0.656 mmol) of acrylic acid followed by 0.110 mL (0.633 mmol)
of diisopropylethylamine. The reaction mixture is stirred at room
temperature for 4 hours then partitioned between methylene chloride
and water. The aqueous layer is extracted with additional methylene
chloride and the organic layers are combined, dried over magnesium
sulfate, filtered and concentrated in vacuo. The residue is
purified by flash chromatography, eluting with a gradient of 95:5
methylene chloride/methanol to 9:1 methylene chloride/methanol, to
provide 69 mg of
N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-8-yl]acrylamide
as a light tan solid, mp>300.degree. C. dec.
[1052] .sup.1HNMR (DMSO-d.sub.6): .delta. 5.81 (dd, J=10 Hz, J=2
Hz, 1H), 6.32 (dd, J=17 Hz, J=2 Hz, 1H), 6.49 (dd, J=17 Hz, J=10
Hz, 1H), 7.25 (m, 1H), 7.30-7.47 (m, 2H), 7.80 (dd, J=9 Hz, J=2 Hz,
1H), 8.00 (d, J=9 Hz, 1H), 8.84 (s, 1H), 8.90 (d, J=2 Hz, 1H), 9.81
(s, 1H), 10.46 (s, 1H).
[1053] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.13BrN.sub.4OS: 449.3, found: 449.1, 451.2
(M+H).sup.+.
[1054] Analysis for C.sub.21H.sub.13BrN.sub.4OS
[1055] Calcd: C, 56.13; H, 2.92; N, 12.47.
[1056] Found: C, 55.91; H, 3.08; N, 12.18.
EXAMPLE 94
N-[4-(3-Bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-6-yl]acrylamide
[1057] A 0.138 g (0.349 mM) portion of
6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile
is dissolved in 2 mL of tetrahydrofuran and 2 mL of
dimethylformamide at 0.degree. C. To this is added 0.042 g (0.583
mM) of acrylic acid, 0.105 g (0.575 mM) of
N,N-diisopropylethylamine and 0.106 g (0.554 mM) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride with
stirring under nitrogen. The reaction mixture is stirred for 48
hours at room temperature, and the solvent is removed under reduced
pressure. The residue is worked up with water (3 mL) and extracted
with methylene chloride (10 mL), dried with sodium sulfate and
evaporated. Purification of the product is carried out by silica
gel chromatography, eluting with 20:1 chloroform/methanol. Further
purification is achieved by preparative thin layer chromatography,
eluting with the same solvent system. Finally, the product is
washed with ether to provide 0.068 g (43%) of
N-[4-(3-bromoanilino)-3-cyano[1]benzothieno[3,2-b]pyridin-6-yl]acrylamide-
, m.p. 286-287.degree. C.
[1058] .sup.1H NMR (DMSO-d.sub.6): .delta. 5.63 (d, 1H), 6.30 (d,
1H), 6.54 (dd, 1H), 7.22 (d, 1H), 7.36 (m, 2H), 7.44 (s, 1H), 7.63
(t, 1H), 7.74 (d, 1H), 8.26 (d, 1H), 8.85 (s, 1H), 9.83 (s, 1H),
10.38 (s, 1H).
[1059] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.13BrN.sub.4OS: 449.32, found: 451.3 (M+H).sup.+
[1060] Analysis for
C.sub.21H.sub.13BrN.sub.4OS.C.sub.4H.sub.10O.0.8H.sub.2O
[1061] Calcd: C, 55.82; H, 4.61; N, 10.42.
[1062] Found: C, 56.19; H, 4.86; N, 10.47.
EXAMPLE 95
Methyl 3-amino-6-methoxy-2-naphthoate and
EXAMPLE 96
Methyl 3-amino-7-methoxy-2-naphthoate
[1063] To 100 mL of methanol at room temperature is added 2.20 g
(55 mmol) of 60% sodium hydride in mineral oil. The solution is
stirred for 5 minutes, and added to a suspension of 5.0 g (21.9
mmol) 6-methoxynaphtho[2,3-c]furan-1,3-dione (Frank K. Brown, Peter
J. Brown, D. Mark Bickett, C. Lynn Chambers, H. Geoff Davies, David
N. Deaton, David Drewry, Michael Foley, Andrew B. McElroy, Michael
Gregson, Gerald M. McGeehan, Peter L. Myers, David Norton, James M.
Salovich, Frank J. Schoenen, and Peter Ward, J. Med. Chem., 1994,
37, 674-688) in 100 mL of methanol. The mixture is stirred at room
temperature for 10 minutes, and concentrated. The residue is
partitioned between ethyl acetate and saturated sodium carbonate
solution. After separation of the layers, the aqueous layer is
neutralized with concentrated hydrochloric acid to pH 1. The
product is extracted with ethyl acetate, dried over magnesium
sulfate, and concentrated. A solution of this residue, 10 g of
diphenylphosphoryl azide, and 10 mL of triethylamine in 100 mL of
toluene is refluxed for 15 minutes and added dropwise to a mixture
of 800 mL of acetone and 100 mL of water at 80.degree. C. After
continuing heating at 80.degree. C. for 1 hour, the mixture is
concentrated in vacuo. The residue is partitioned between ethyl
acetate and saturated sodium chloride solution. Following
separation of the layers, the organic layer is dried over magnesium
sulfate and concentrated. The residue is chromatographed over
silica gel, eluting with a gradient of 95:5 hexane/diethyl ether to
70:30 hexane/diethyl ether, providing 365 mg of (7.2%) methyl
3-amino-6-methoxy-2-naphthoate as a yellow solid, mp
152-154.degree. C., and 466 mg of (9.2%) methyl
3-amino-7-methoxy-2-naphthoate as a yellow solid, mp
115-117.degree. C.
[1064] Methyl 3-amino-6-methoxy-2-naphthoate: .sup.1HNMR
(CDCl.sub.3): .delta. 3.89 (s, 3H); 3.93 (s, 3H); 5.59 (br s, 2H);
6.79 (d, J=1.3, 1H); 6.84 (m, 2H); 7.59 (d, J=6.6, 1H); 8.40 (s,
1H).
[1065] MS (ES, positive ion mode): m/z calcd for
C.sub.13H.sub.13O.sub.3: 231.25, found: 232.2 (M+H).sup.+.
[1066] Analysis for C.sub.13H.sub.13O.sub.3
[1067] Calcd: C, 67.52; H, 5.67; N, 6.06.
[1068] Found: C, 67.23; H, 5.61; N, 5.89.
[1069] Methyl 3-amino-7-methoxy-2-naphthoate: .sup.1HNMR
(CDCl.sub.3): .delta. 3.87 (s, 3H); 3.94 (s, 3H); 5.42 (br s, 2H);
6.95 (s, 1H); 7.02 (d, J=1.8 Hz, 1H); 7.11 (dd, J=6.7 Hz, J=1.8 Hz,
1H); 7.45 (d, J=6.7 Hz, 1H); 8.40 (s, 1H).
[1070] MS (ES, positive ion mode): m/z calcd for
C.sub.13H.sub.13O.sub.3: 231.25, found: 232.2 (M+H).sup.+.
[1071] Analysis for C.sub.13H.sub.13O.sub.3-0.3H.sub.2O
[1072] Calcd: C, 65.98; H, 5.79; N, 5.92.
[1073] Found: C, 65.79; H, 5.36; N, 5.78.
EXAMPLE 97
Methyl
3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate
[1074] A suspension of 1.2 g (5.2 mmol) of methyl
3-amino-7-methoxy-2-naphthoate in 30 mL of dimethylformamide
dimethylacetal is refluxed for 2.5 hours. The mixture is cooled to
room temperature. The resulting precipitate is collected by
filtration and washed with ether. After drying in vacuo, this
yields 1.28 g (85.9%) of methyl
3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate as
a light yellow solid, mp 160-162.degree. C.
[1075] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.93 (br s, 3H); 3.00 (br
s, 3H); 3.79 (s, 3H); 3.84 (s, 3H); 7.15 (dd, J=8.91 Hz, J=2.55 Hz,
1H); 7.24 (s, 1H); 7.31 (d, J=2.52 Hz, 1H); 7.68 (d, 3=9.0 Hz, 1H);
7.71 (s, 1H); 7.94 (s, 1H).
[1076] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.18N.sub.2O.sub.3: 286.33, found: 287.3
(M+H).sup.+.
[1077] Analysis for C.sub.16H.sub.18N.sub.2O.sub.3
[1078] Calcd: C, 67.12; H, 6.34; N, 9.78.
[1079] Found: C, 67.10; H, 6.35; N, 9.70.
EXAMPLE 98
Methyl
3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate
[1080] According to the procedure of example 97, the reaction
mixture of 1.05 g (4.54 mmol) of methyl
3-amino-6-methoxy-2-naphthoate in 20 mL of dimethylformamide
dimethylacetal is refluxed for 2.5 hours to give 840.5 mg (64.6%)
of methyl
3-{[(F)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate as
a beige solid, mp 122-124.degree. C.
[1081] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.95 (br s, 3H); 3.09 (br
s, 3H); 3.78 (s, 3H); 3.85 (s, 3H); 7.00 (dd, J=8.94 Hz, J=2.52 Hz,
1H); 7.14 (d, J=2.4 Hz, 1H); 7.17 (s, 1H); 7.70 (s, 1H); 7.79 (d,
J=8.94 Hz, 1H); 8.01 (s, 1H).
[1082] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.18N.sub.2O.sub.3: 286.3, found: 287.3
(M+H).sup.+.
[1083] Analysis for C.sub.16H.sub.18N.sub.2O.sub.3.0.1H.sub.2O
[1084] Calcd: C, 66.69; H, 6.37; N, 9.72.
[1085] Found: C, 66.68; H, 6.45; N, 9.42.
EXAMPLE 99
7-Methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
[1086] To a solution of 4.75 mL (11.88 mmol) of n-butyllithium
(2.5M in hexane) in 4.0 mL of tetrahydrofuran at -78.degree. C. is
added dropwise a solution of 0.68 mL (13.1 mmol) of acetonitrile in
6.8 mL of tetrahydrofuran. After completion of addition, the
suspension is stirred for 10 minutes. To this is added 1.36 g (4.75
mmol) of methyl
3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate in
32 mL of tetrahydrofuran dropwise. The resulting reaction mixture
is stirred at -78.degree. C. for 1 hour, at -5.degree. C. for 1
hour and at room temperature for 15 minutes. The reaction mixture
is again cooled to -78.degree. C. and 1.72 g (28.6 mmol) of acetic
acid is added dropwise. After addition of the acetic acid, the
reaction mixture is allowed to warm to room temperature. The
precipitate is collected by filtration and washed sequentially with
water, acetonitrile and methanol. After drying in vacuo, this
yields 796.9 mg (67%) of
7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a
deep yellow solid, mp>260.degree. C.
[1087] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.91 (s, 3H); 7.35 (dd,
J=9.0 Hz, J=2.7 Hz, 1H); 7.62 (d, J=2.4 Hz, 1H); 8.03 (d, J=9.0 Hz,
1H); 8.23 (m, 1H); 8.09 (s, 1H); 8.71 (s, 1H); 8.75 (s,1H).
[1088] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.10N.sub.2O.sub.2: 250.3, found: 251.1
(M+H).sup.+.
[1089] Analysis for
C.sub.15H.sub.10N.sub.2O2.0.3H.sub.2O.0.3CH.sub.3CN
[1090] Calcd: C, 69.92; H, 4.33; N, 12.02.
[1091] Found: C, 70.25; H, 4.06; N, 11.89.
EXAMPLE 100
8-Methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
[1092] To a solution of 2.81 mL (7.03 mmol) of n-butyllithium (2.5M
in hexane) in 2.0 mL of tetrahydrofuran at -78.degree. C. is added
dropwise a solution of 0.448 mL (8.44 mmol) of acetonitrile in 4.4
mL of tetrahydrofuran. After completion of addition, the suspension
is stirred for 10 minutes. To this is added 804.5 mg (2.81 mmol) of
methyl
3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate in
18 mL of tetrahydrofuran dropwise. The resulting reaction mixture
is stirred at -78.degree. C. for 1 hour and at -5.degree. C. for 1
hour. The reaction mixture is again cooled to -78.degree. C. and
4.0 mL (69.9 mmol) of acetic acid is added dropwise. The reaction
mixture is warmed up to room temperature and stirred overnight. The
precipitate is collected by filtration and washed sequentially with
water, acetonitrile and methanol. After drying in vacuo, this
yields 468.6 mg (67%) of
8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a
yellow solid, mp>265.degree. C.
[1093] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.93 (s, 3H); 7.22 (dd,
J=9.12 Hz, J=2.46 Hz, 1H); 7.45 (d, J=2.34 Hz, 1H); 7.98 (s, 1H);
8.13 (d, J=9.18 Hz, 1H); 8.74 (s, 1H); 8.75 (s, 1H).
[1094] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.10N.sub.2O.sub.2: 250.2567, found: 249.1
(M-H).sup.-.
[1095] Analysis for C.sub.15H.sub.10N.sub.2O.sub.2.0.2H.sub.2O
[1096] Calcd: C, 70.97; H, 4.14; N, 11.03.
[1097] Found: C, 70.74; H, 3.96; N, 11.14.
EXAMPLE 101
4-Chloro-7-methoxybenzo[g]quinoline-3-carbonitrile
[1098] A reaction mixture of 767.7 mg (3.1 mmol) of
7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 12
mL of phosphorus oxychloride and 5 drops of N,N-dimethylformamide
(DMF) is refluxed for 2 hours. After cooling, the mixture is
concentrated to dryness in vacuo to give a dark residue. The
residue is partitioned between methylene chloride and ice-cooled
saturated aqueous sodium carbonate solution. The organic layer is
washed with ice-cooled brine and dried over sodium sulfate. The
crude product is passed through a short column of silica gel, and
further eluted with additional methylene chloride, followed by 95:5
methylene chloride/ethyl acetate. Removal of the solvent in vacuo
yields 532.0 mg (64.7%) of
4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile as a bright
yellow solid, mp 242-243.degree. C.
[1099] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.98 (s, 3H); 7.45 (dd,
J=9.21 Hz, J=2.4 Hz, 1H); 7.75 (d, J=2.04 Hz, 1H); 8.24 (d, J=9.27
Hz, 1H); 8.83 (s, 1H); 8.89 (s, 1H); 9.10 (s, 1H).
[1100] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.10ClN.sub.2O: 268.7, found: 269.1 (M+H).sup.+.
[1101] Analysis for C.sub.15H.sub.10N.sub.2O.sub.2.0.1H.sub.2O
[1102] Calcd: C, 66.60; H, 3.43; N, 10.35.
[1103] Found: C, 66.52; H, 3.15; N, 10.32.
EXAMPLE 102
4-Chloro-8-methoxybenzo[g]quinoline-3-carbonitrile
[1104] According to the procedure of example 101, 446.7 mg (1.8
mmol) of
8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile is
refluxed in 102 mL of phosphorus oxychloride and 4 drops of
N,N-dimethylformamide (DMF) for 1.5 hours to give 389.0 mg (81.6%)
of 4-chloro-8-methoxy-benzo[g]quinoline-3-carbonitrile as a bright
yellow solid, mp 258-260.degree. C.
[1105] .sup.1HNMR (DMSO-d.sub.6): .delta. 3.99 (s, 3H); 7.41 (dd,
J=9.24 Hz, J=2.43 Hz, 1H); 7.75 (d, J=2.22 Hz, 1H); 8.32 (d, J=9.3
Hz, 1H); 8.70 (s, 1H); 8.99 (s, 1H); 9.13 (s, 1H).
[1106] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.9ClN.sub.2O: 268.7, found: 269.1 (M+H).sup.+.
[1107] Analysis for C.sub.15H.sub.10N.sub.2O.sub.2.0.1H.sub.2O
[1108] Calcd: C, 66.60; H, 3.43; N, 10.35.
[1109] Found: C, 66.56; H, 3.22; N, 10.33.
EXAMPLE 103
4-(2,4-Dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile
[1110] According to the procedure of Example 14, a reaction mixture
of 657.8 mg (4.06 mmol) of 2,4-dichloroaniline and 162.4 mg (4.06
mmol) of sodium hydride in 18 mL of anhydrous DMF is stirred at
room temperature for 0.5 hour. To the mixture is added 494.0 mg
(1.84 mmol) of 4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile.
The resulting mixture is heated at 55.degree. C. for 1 hour. After
work up, 624.6 mg (86.2%) of
4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile
is obtained as a yellow solid, mp 215-217.degree. C.
[1111] .sup.1HNMR (DMSO-di/TFA): .delta. 3.99 (s, 3H); 7.49 (d,
J=2.28 Hz, 1H); 7.62 (dd, J=9.18 Hz, J=2.43 Hz, 1H); 7.68 (dd,
J=8.55 Hz, J=2.28 Hz, 1H); 7.81 (d, J=8.55 Hz, 1H); 7.94 (d, J=2.25
Hz, 1H); 8.18 (d, J=9.27 Hz, 1H); 8.59 (s, 1H); 9.28 (s, 1H); 9.40
(s, 1H).
[1112] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.13Cl.sub.2N.sub.3O: 394.3, found: 394.1, 396.1
(M+H).sup.+.
[1113] Analysis for C.sub.21H.sub.13Cl.sub.2N.sub.3O
[1114] Calcd: C, 63.98; H, 3.32; N, 10.66.
[1115] Found: C, 66.89; H, 3.35; N, 10.44.
EXAMPLE 104
4-(2,4-Dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile
[1116] According to the procedure of Example 14, a reaction mixture
of 487.7 mg (3.01 mmol) of 2,4-dichloroaniline and 120.6 mg (3.01
mmol) of sodium hydride in 15 mL of anhydrous DMF is stirred at
room temperature for 0.5 hour. To the mixture is added 367.0 mg
(1.37 mmol) of 4-chloro-8-methoxybenzo[g]quinoline-3-carbonitrile.
The resulting mixture is heated at 55.degree. C. for 0.5 hour.
After work up, 443.3 mg (82.1%) of
4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile
is obtained as a yellow solid, mp>260.degree. C.
[1117] .sup.1HNMR (DMSO-dr/TFA): .delta. 4.02 (s, 3H); 7.47 (dd,
J=9.15 Hz, J=2.28 Hz, 1H); 7.66 (m, 2H); 7.81 (d, J=8.55 Hz, 1H);
7.91 (d, J=2.28 Hz, 1H); 8.17 (d, J=9.24 Hz, 1H); 8.47 (s, 1H);
8.28 (s, 1H); 9.49 (s, 1H).
[1118] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.13Cl.sub.2N.sub.3O: 394.3, found: 394.1, 396.1
(M+H).sup.+.
[1119] Analysis for
C.sub.21H.sub.13Cl.sub.2N.sub.3O.0.2H.sub.2O
[1120] Calcd: C, 63.40; H, 3.39; N, 10.56.
[1121] Found: C, 63.40; H, 3.43; N, 10.35.
EXAMPLE 105
4-(2,4-Dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile
[1122] A reaction mixture of 566.5 mg (1.44 mmol) of
4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile
and 10 g of pyridine hydrochloride is stirred at 215.degree. C. for
50 min under nitrogen. After cooling, the mixture is neutralized
with 40 mL of a 3% ammonium hydroxide solution and stirred for 0.5
hour. The separated solid is filtered off and washed with water and
ether. After drying in vacuo, this yields 527.9 mg (96.5%) of
4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile
as a salmon color solid, mp>300.degree. C.
[1123] .sup.1HNMR (DMSO-d.sub.6/TFA): .delta. 7.47 (s, 1H);
7.53(dd, J=9.06 Hz, J=2.28 Hz, 1H); 7.67 (dd, J=8.55 Hz, J=2.25 Hz,
1H); 7.81 (d, J=8.52 Hz, 1H); 7.92 (d, J=2.22 Hz, 1H); 8.23 (d,
J=9.15 Hz, 1H); 8.55 (s, 1H); 9.24 (s, 1H); 9.30 (s, 1H).
[1124] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.11Cl.sub.2N.sub.3O: 380.2, found: 380.2, 382.1
(M+H).sup.+.
[1125] Analysis for
C.sub.20H.sub.11Cl.sub.2N.sub.3O.1.3H.sub.2O
[1126] Calcd: C, 59.51; H, 3.40; N, 10.41.
[1127] Found: C, 59.63; H, 3.30; N, 10.50.
EXAMPLE 106
4-(2,4-Dichloroanilino)-8-hydroxybenzo[g]quinoline-3-carbonitrile
[1128] According to the procedure of example 105, the reaction
mixture of 373.9 mg (0.954 mmol) of
4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile
and 10 g of pyridine hydrochloride is stirred at 215.degree. C. for
1 hour under N.sub.2. After cooling, the mixture is neutralized
with 40 mL of a 3% ammonium hydroxide solution and stirred for 0.5
hour. The separated solid is filtered off and washed with water and
ether. After drying in vacuo, this yields 333.4 mg (92.6%) of
4-(2,4-dichloroanilino)-8-hydroxybenzo[g]quinoline-3-carbonitrile
as a yellow solid, mp 267-269.degree. C.
[1129] .sup.1HNMR (DMSO-d.sub.6/TA): .delta. 7.44 (s, 1H); 7.47 (d,
J=2.22 Hz, 1H); 7.67 (dd, J=8.49 Hz, J=2.28 Hz, 1H); 7.80 (d,
J=8.52 Hz, 1H); 7.94 (d, J=2.25 Hz, 1H); 8.15 (d, J=9.78 Hz, 1H);
8.30 (s, 1H); 9.25 (s, 1H); 9.44 (s, 1H).
[1130] MS (ES, positive ion mode): m/z calcd for
C.sub.20H.sub.11Cl.sub.2N.sub.3O: 380.2, found: 380.2, 382.1
(M+H).sup.+.
[1131] Analysis for C.sub.20H.sub.11Cl.sub.2N.sub.3O.1H.sub.2O
[1132] Calcd: C, 60.31; H, 3.29; N, 10.55.
[1133] Found: C, 60.22; H, 3.23; N, 10.32.
EXAMPLE 107
4-(2,4-Dichloroanilino-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline-3-carb-
onitrile
[1134] To a suspension of 189.1 mg (0.50 mmol) of
4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile,
207.2 mg (0.79 mmol) of triphenylphosphine and 66.9 mg (0.75 mmol)
of 2-(dimethylamino)-ethanol in 3.0 mL of anhydrous methylene
chloride at 0.degree. C. is added dropwise diethyl
azodicarboxylate. The resulting reaction mixture is stirred at room
temperature under nitrogen for 2 days. The solvent is concentrated
in vacuo and the residue is purified on preparative thin layer
chromatography (developing solvent: 9:1 methylene
chloride/methanol) to provide 46.3 mg (20.5%) of
4-(2,4-dichloroanilino)-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline-3-ca-
rbonitrile as a yellow solid, mp 115-117.degree. C.
[1135] .sup.1HNMR (DMSO-d.sub.6): .delta. 2.50 (s, 6H); 2.72(m,
2H); 4.21 (m, 1H); 4.38(m, 1H); 6.98 (d, J=8.46 Hz, 1H); 7.31 (m,
2H); 7.51 (d, J=2.01 Hz, 1H); 7.60 (s, 1H); 8.02 (d, J=9.18 Hz,
1H); 8.20 (s, 1H); 8.27 (s, 1H); 8.33 (s, 1H); 8.98 (d, J=15.72 Hz,
1H).
[1136] MS (ES, positive ion mode): m/z calcd for
C.sub.24H.sub.20Cl.sub.2N.sub.4O: 451.4, found: 451.2, 453.3
(M+H).sup.+,
[1137] Analysis for
C.sub.20H.sub.11Cl.sub.2N.sub.3O.1.3H.sub.2O
[1138] Calcd: C, 60.71; H, 4.80; N, 11.80.
[1139] Found: C, 60.62; H, 4.92; N, 12.20.
EXAMPLE 108
1-(2-Chloroethoxy)-2-methoxybenzene
[1140] A mixture of 52.88 g (0.426 mole) of guaiacol, 100 g (0.426
mole) of chloroethyl tosylate, 88.3 g (0.639 mole) of powdered
potassium carbonate and 600 mL of 2-butanone is stirred
mechanically and refluxed for 2 days. The reaction is filtered and
the solid is rinsed with 2-butanone. The filtrate is evaporated and
the residue taken up in ether and washed with 1N NaOH to remove
unreacted guaiacol. The ether layer is dried over sodium sulfate,
filtered and evaporated to give an oil which slowly crystallized.
The solid is isolated with cold cyclohexane to give 41.47 g (52%)
of 1-(2-Chloroethoxy)-2-methoxybenzene as a white solid, m.p.
42-3.degree. C.
[1141] .sup.1HNMR (CDCl.sub.3): .delta. 6.85-7.02 (m, 4H); 4.28 (t,
J=6.3 Hz, 2H); 3.87 (s, 3H); 3.84 (t, J=6.3 Hz, 2H).
[1142] MS (ES, positive ion mode): m/z calcd for
C.sub.9H.sub.11ClO.sub.2: 186.64, found: 187.4 (M+H).sup.+.
[1143] Analysis for C.sub.9H.sub.11ClO.sub.2
[1144] Calcd: C, 57.92; H, 5.94.
[1145] Found: C, 57.80; H, 5.94.
EXAMPLE 109
1-(2-chloroethoxy)-4,5-bis(chloromethyl)-2-methoxybenzene
[1146] To a solution of the 55.99 g (300 mmol) of
1-(2-Chloroethoxy)-2-methoxybenzene in 250 mL 1,4-dioxane is added
40 mL of concentrated hydrochloric acid while stirring at 0.degree.
C. While bubbling in HCl gas, 30 mL of 35% formalin is added. After
45 minutes, another equal volume of formalin is added. The addition
of HCl gas is continued for 6 hours, the ice-bath is removed after
2 hours and allowed to warm to ambient temperature. The reaction
mixture is stirred overnight at ambient temperature. The green
reaction mixture is then cooled in an ice bath and the resulting
solid is filtered and washed with cold dioxane/water (2.5:1). The
solid is chromatographed on silica gel eluting with 2:1
hexanes/dichloromethane to give 36.35 g (42%) of
1-(2-chloroethoxy)-4,5-bis(chloromethyl)-2-methoxybenzene as a
white solid, m.p. 117-8.degree. C.,
[1147] .sup.1HNMR (CDCl.sub.3): .delta. 6.92 (s, 1H); 6.91 (s, 1H);
4.70 (s, 2H); 4.69 (s, 2H); 4.29 (t, J=6.2 Hz, 2H); 3.90 (s, 3H);
3.84 (t, J=6.2 Hz, 2H)
[1148] MS (ES, positive ion mode): m/z calcd for
C.sub.11H.sub.13Cl.sub.3O.sub.2: 282.00, found: 282.0
(M+H).sup.+.
[1149] Analysis for C.sub.11H.sub.13Cl.sub.3O.sub.2
[1150] Calcd: C, 46.59; H, 4.62.
[1151] Found: C, 46.59; H, 4.70.
EXAMPLE 110
2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl
acetate
[1152] To a solution of 5.67 g (0.020 mole) of
1-(2-chloroethoxy)-4,5-bis(chloromethyl)-2-methoxybenzene in 75 ml
acetic acid is added a solution of 3.5 g of anhydrous sodium
acetate in 100 ml acetic acid. This mixture is refluxed with
stirring for 2 hours. Solids are removed by filtration and washed
with acetic acid. The filtrate is evaporated to approximately 30
ml, then poured into water and extracted with ether. The organic
phase is washed with aqueous sodium carbonate, water and brine.
After drying over sodium sulfate, the solution is filtered and
evaporated to give 5.69 g (86%) of
2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl acetate as
a white solid, m.p. 79-80.degree. C.
[1153] .sup.1HNMR (CDCl.sub.3): .delta. 6.96 (s, 1H); 6.94 (s, 1H);
5.14 (s, 2H); 5.12 (s, 2H); 4.29 (t, J=6.2 Hz, 2H); 3.89 (s, 3H);
3.84 (t, J=6.2 Hz, 2H); 2.09 (s, 3H); 2.08 (s, 3H).
[1154] MS (EI): m/z calcd for C.sub.15H.sub.19ClO.sub.6: 330.09,
found: 329.72 (M.sup.+).
[1155] Analysis for C.sub.15H.sub.19ClO.sub.6
[1156] Calcd: C, 54.47; H, 5.79.
[1157] Found: C, 54.61; H, 5.59.
EXAMPLE 111
[4-(2-chloroethoxy)-2-hydroxymethyl)-5-methoxyphenyl]methanol
[1158] A solution of 14.0 g of the
2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl acetate in
600 mL of methanol is stirred and cooled in an ice bath while
ammonia gas is bubbled in, until the solution is saturated. The
flask is stoppered and stored in the refrigerator for 15 hours. The
reaction mixture is evaporated to give a white solid which is dried
and chromatographed on a silica gel column eluting with 2:1
hexanes/ethyl acetate, to give 9.87 g of
[4-(2-chloroethoxy)-2-(hydroxymethyl)-5-methoxyphenyl]methanol as a
white solid, m.p. 934.degree. C.
[1159] .sup.1HNMR (CDCl.sub.3): .delta. 6.94 (s, 1H); 6.93 (s, 1H);
4.68 (br s, 4H); 4.29 (t, J=6.2 Hz, 2H); 3.88 (s, 3H); 3.83 (t,
J=6.2 Hz, 2H); 2.77 (br s, 1H); 2.71 (br s,1H).
[1160] MS (ES, positive ion mode): m/z calcd for
C.sub.11H.sub.15ClO.sub.4: 246.1, found: 264.10
(M+NH.sub.4).sup.+.
[1161] Analysis for C.sub.11H.sub.15ClO.sub.4
[1162] Calcd: C, 53.56; H, 6.13.
[1163] Found: C, 53.86; H, 6.11.
EXAMPLE 112
4-(2-chloroethoxy)-5-methoxyphthalaldehyde
[1164] To a 500 mL 3-neck round bottom flask fitted with mechanical
stirrer, thermometer and addition funnel is added 100 mL dry
methylene chloride and 8 mL of oxalyl chloride under nitrogen. This
is cooled to -78.degree. C. in a dry ice/acetone bath, then 13.6 mL
DMSO in 25 mL dry methylene chloride is added dropwise. After
complete addition it is further stirred for 5 minutes. Then 9.87 g
of [4-(2-chloroethoxy)-2-(hydroxymethyl)-5-methoxyphenyl]methanol
in 10 mL of dry methylene chloride (with enough DMSO added to
dissolve the solid) is added dropwise. The reaction mixture is
stirred for an additional 30 minutes, then 100 mL of triethylamine
is added slowly at -78.degree. C. The solution is stirred for 10
minutes, allowed to warm to room temperature and then 200 mL of
ice/water is added. The aqueous layer is extracted with methylene
chloride (2.times.100 mL). The organic layer is dried over
MgSO.sub.4, filtered and evaporated to give the crude product as a
solid. This solid is slurried with cold methanol and filtered,
washed with cold methanol, then dried to give 6.37 g of
4-(2-chloroethoxy)-5-methoxyphthalaldehyde as a yellowish solid,
m.p. 113-4.degree. C.
[1165] .sup.1HNMR (CDCl.sub.3): .delta. 7.49 (s, 1H); 7.47 (s, 1H);
4.43 (t, 3=5.9 Hz, 2H); 4.03 (s, 3H); 3.91 (t, J=5.9 Hz, 2H).
[1166] MS (ES, positive ion mode): m/z calcd for
C.sub.11H.sub.11ClO.sub.4: 242.03, found: 242.0 (M+H).sup.+.
[1167] Analysis for C.sub.11H.sub.11ClO.sub.4
[1168] Calcd: C, 54.45; H, 4.57.
[1169] Found: C, 54.32; H, 4.21.
EXAMPLE 113
Ethyl 3-nitropropionate
[1170] A mixture of 25 g (0.21 mole) of 3-nitropropionic acid, 300
mL of absolute ethanol and 10 drops of concentrated sulfuric acid
is refluxed overnight. The reaction mixture is evaporated, and the
residue partitioned between water and ether. The ether layer is
washed with water, aqueous sodium bicarbonate solution and brine,
then dried over sodium sulfate. The ether is removed in vacuo and
the product distilled as a clear liquid to provide 21.54 g (69%) of
Ethyl 3-nitropropionate as a clear oil, b.p. 160-165.degree. C. at
120 mm Hg.
[1171] .sup.1HNMR (CDCl.sub.3): .delta. 4.66 (t, J=6.1 Hz, 2H);
4.18 (q, J=7.1 Hz, 2H); 2.98 (t, J=6.1 Hz, 2H); 1.28 (t, J=7.1 Hz,
3H).
EXAMPLE 114
ethyl 7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate and
EXAMPLE 115
ethyl 6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate
[1172] To a solution of 2.43 g of ethyl 3-nitropropionate in 15 ml
of absolute ethanol cooled using an ice bath, is added 20 mL of 1 N
sodium ethoxide in ethanol dropwise over 10 minutes keeping the
temperature at 0-5.degree. C. A slurry of
4-(2-chloroethoxy)-5-methoxyphthalaldehyde in 5 mL of ethanol is
added. The ice bath is removed and the reaction allowed to warm to
room temperature and stirred for 16 hours. The reaction is
transferred to a beaker with 300 mL of water and neutralized with
acetic acid to pH 4. The solid is collected and washed first with
water, then with 40 mL of cold ethanol. The solid is dried to
provide 2.48 g (70%) of ethyl
7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate and ethyl
6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate (1:1 mixture) as
a yellow solid, m.p. 119-29.degree. C. dec.
[1173] .sup.1HNMR (CDCl.sub.3): .delta. 8.27 (s, 1H); 8.05 (s, 1H);
7.24 and 7.23 and 7.22 (3s, 2H); 4.37-4.45 (m, 4H); 4.03 (s, 3H);
3.95 (t, J=6.0 Hz, 2H); 1.38 (t, J=7.1 Hz, 3H).
[1174] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.16ClNO.sub.6: 353.1, found: 354.2 (M+H).sup.+.
[1175] Analysis for C.sub.16H.sub.16ClNO.sub.6
[1176] Calcd: C, 54.32; H, 4.56; N, 3.96.
[1177] Found: C, 53.96; H, 4.43; N, 3.71.
EXAMPLE 116
ethyl 3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate and
EXAMPLE 117
ethyl 3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate
[1178] A 1.60 g portion of ethyl
7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate and ethyl
6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate (1:1 mixture) is
heated in 100 mL absolute ethanol until dissolved. The solution is
allowed to cool to room temperature and 0.2 g of 10% palladium on
carbon is added. Hydrogenation is carried out in a Parr apparatus
at 50 psi for 2 hours. The reaction mixture is filtered through
celite and the filter cake is rinsed with ethanol. The filtrate and
washes are combined and evaporated to give ethyl
3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate and ethyl
3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate (1:1 mixture) as
a greenish yellow solid, 1.28 g (87%), m.p. 104-8.degree. C.
[1179] .sup.1HNMR (CDCl.sub.3): .delta. 8.34 and 8.32 (2s, 1H);
7.06 and 7.03 (2s, 1H); 6.85 and 6.84 (2s, 1H); 6.82 (s, 1H); 5.52
(br s, 2H); 4.30-4.43 (m, 4H); 3.97 and 3.93 (2s, 3H); 3.89 (t,
J=6.6 Hz, 2H); 1.44 (t, J=7.1 Hz, 3H).
[1180] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.18ClNO.sub.4: 323.1, found: 324.3 (M+H).sup.+.
[1181] Analysis for C.sub.16H.sub.19ClNO.sub.4
[1182] Calcd: C, 59.35; H, 5.60; N, 4.33.
[1183] Found: C, 59.54; H, 5.74; N, 4.08.
EXAMPLE 118
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonit-
rile and
EXAMPLE 119
7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonit-
rile
[1184] A 648 mg portion of ethyl
3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate and ethyl
3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate (1:1 mixture) and
5 mL of dimethylformamide dimethylacetal is heated to reflux using
an oil bath. The reaction is kept at reflux overnight. Solvent is
removed in vacuo to provide crude ethyl
6-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2--
naphthoate and ethyl
7-(2-chloroethoxy)-3-{[(E)-(dimethylamino)-methylidene]amino}-6-methoxy-2-
-naphthoate (1:1 mixture) as a dark red mixture.
[1185] To 2.5 mL of dry tetrahydrofuran at -78.degree. C. is added
1.8 mL of 2.5 M n-butyllithium (4.4 mmol). Then 0.24 mL of dry
acetonitrile in 4.5 mL of dry tetrahydrofuran is added dropwise
over 10 minutes. This is stirred and additional 15 minutes at
-78.degree. C., then the ethyl
6-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]-amino}-7-methoxy-2-
-naphthoate and ethyl
7-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2--
naphthoate (1:1 mixture) is dissolved in 3 mL of tetrahydrofuran
and added dropwise over 15 minutes. The reaction mixture is stirred
for 30 minutes at -78.degree. C., then quenched with 0.57 mL of
glacial acetic acid, and warmed to room temperature. To the yellow
mixture is added 10 mL of water. The solids are filtered, washed
with water and dried to give 0.502 g of
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-ca-
rbonitrile and
7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carboni-
trile (1:1 mixture) as a yellow green solid (76%), m.p.
260-73.degree. C. dec.
[1186] .sup.1HNMR (DMSO-d.sub.6): .delta. 8.68 (s, 1H); 8.62 and
8.61 (2s, 1H); 7.95 and 7.94 (2s, 1H); 7.62 and 7.61 (2s, 1H); 7.49
and 7.47 (2s, 1H); 4.37-4.47 (m, 2H); 4.00-4.11 (m, 2H); 3.96 and
3.93 (2s, 3H).
[1187] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.13ClN.sub.2O.sub.3: 328.1, found: 329.5
(M+H).sup.+.
EXAMPLE 120
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
EXAMPLE 121
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
[1188] To a slurry of 1.11 g of
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carboni-
trile and
7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline--
3-carbonitrile (1:1 mixture) and 5 mL of phosphorus oxychloride is
added 0.15 mL of anhydrous dimethylformamide. This is stirred and
heated to reflux for 20 minutes using an oil bath, followed
concentration in vacuo. The dark residue is quenched with 30 mL of
cold water. The solid formed is collected, washed with water and
dried to give 1.02 g (87%) of
4-chloro-7-methoxy-8(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture) as a greenish yellow solid, m.p. 195-209.degree. C.
dec.
[1189] .sup.1HNMR (CDCl.sub.3): .delta. 8.88 (s, 1H); 8.66 and 8.65
(2s, 1H); 8.52 and 8.51 (2s, 1H); 7.33 (s, 1H); 7.30 and 7.29 (2s,
1H); 4.46-4.52 (m, 2H); 4.09 and 4.08 (2s, 3H); 3.96-4.00 (m,
2H).
[1190] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.12Cl.sub.2N.sub.2O.sub.2: 346.0, found: 347.3
(M+H).sup.+.
[1191] Analysis for C.sub.17H.sub.12Cl.sub.2N.sub.2O.sub.2
[1192] Calcd: C, 58.81; H, 3.48; N, 8.07.
[1193] Found: C, 58.51; H, 3.19; N, 7.95.
EXAMPLE 122
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]q-
uinoline-3-carbonitrile and
EXAMPLE 123
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]q-
uinoline-3-carbonitrile
[1194] A mixture of 248 mg (0.714 mmol) of
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture), 10 mg of pyridine hydrochloride, 150 mg (0.874 mmol)
of 4-chloro-5-methoxy-2-methylaniline and 5 mL of 2-ethoxyethanol
is stirred and heated to 135.degree. C. After 1 hour, the reaction
is cooled to room temperature, quenched with 0.2 mL of
triethylamine and concentrated in vacuo. The residue is dissolved
in 1:1 hexane/ethyl acetate with a little dichloromethane and
chromatographed on silica gel eluting with 1:1 hexane/ethyl
acetate, then ethyl acetate to provide 0.282 g of
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile and
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile (1:1 mixture) as a dull yellow solid
(81%), m.p. 132-68.degree. C. dec.
[1195] .sup.1HNMR (CDCl.sub.3): .delta. 8.66 and 8.65 (2s, 1H);
8.41 and 8.40 (2s, 1H); 8.19 and 8.17 (2s, 1H); 7.36 (s, 1H); 7.25
and 7.24 (2s, 1H); 7.12 (s, 1H); 7.02 (br s, 1H); 6.76 (s, 1H);
4.48 and 4.41 (2H, J=6.1 Hz, 2H); 4.07 and 4.01 (2s, 3H); 3.95 and
3.98 (2H, J=6.1 Hz, 2H); 3.77 (s, 3H); 2.28 (s, 3H).
[1196] MS (ES, positive ion mode): m/z calcd for
C.sub.25H.sub.21Cl.sub.2N.sub.3O.sub.3: 481.1, found: 482.0
(M+H).sup.+.
[1197] Analysis for
C.sub.25H.sub.21Cl.sub.2N.sub.3O.sub.3.H.sub.2O
[1198] Calcd: C, 60.16; H, 4.64; N, 8.42.
[1199] Found C, 60.33; H, 4.46; N, 8.03
EXAMPLE 124
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile and
EXAMPLE 125
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile
[1200] A mixture of 318 mg (0.66 mmol) of
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile and
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile (1:1 mixture), 100 mg of sodium acetate
and 5 mL of morpholine is stirred and heated to 130.degree. C.
using an oil bath. After 30 minutes the reaction is allowed to cool
to room temperature. The reaction mixture is concentrated in vacuo
and the residue purified by silica gel chromatography, eluting with
95:5 methylene chloride/methanol to yield 82 mg (23%) of
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile as a yellow wax and 153 mg of
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-morpholinyl)etho-
xy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp
191-194.degree. C. dec.
[1201]
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-morpholin-
yl)ethoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR(CDCl.sub.3):
.delta. 8.57 (s, 1H); 8.40 (s, 1H); 8.30 (s, 1H); 7.76 (br s, 1H);
7.25 (s, 1H); 7.18 (s, 1H); 7.08 (s, 1H);
[1202] 6.80 (s, 1H); 4.32 (t, J=5.7 Hz, 2H); 3.92 (s, 3H); 3.75 (s,
3H), 3.74-3.77 (m, 4H); 2.95 (t, J=5.7 Hz, 2H); 2.60-2.67 (br s,
4H); 2.19 (s, 3H).
[1203] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.29ClN.sub.4O.sub.4: 532.19, found: 533.1
(M+H).sup.+.
[1204]
4-(4-chloro-5-methoxy-2-methylamino)-8-methoxy-7-[2-(4-morpholinyl-
)ethoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR (CDCl.sub.3):
.delta. 8.65 (s, 1H); 8.39 (s, 1H); 8.17 (s, 1H); 7.35 (br s, 1H);
7.27 (s, 1H); 7.22 (s, 1H); 7.10 (s, 1H); 6.75 (s, 1H); 4.28 (t,
J=5.7 Hz, 2H); 4.05 (s, 3H); 3.75 (s, 3H), 3.73-3.78 (m, 4H); 2.94
(t, J=5.7 Hz, 2H); 2.62-2.67 (br s, 4H); 2.27 (s, 3H).
[1205] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.29ClN.sub.4O.sub.4: 532.2, found: 533.1
(M+H).sup.+.
[1206] Analysis for C.sub.29H.sub.29ClN.sub.4O.sub.4.H.sub.2O
[1207] Calcd: C, 63.21; H, 5.67; N, 10.17.
[1208] Found C, 62.90; H, 5.74; N, 9.99
EXAMPLE 126
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinol-
ine-3-carbonitrile and
EXAMPLE 127
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinol-
ine-3-carbonitrile
[1209] A mixture of 1.10 g (3.17 mmol) of
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture), 50 mg of pyridine hydrochloride, 742 mg (3.86 mmol)
of 2,4-dichloro-5-methoxyaniline and 25 mL of 2ethoxyethanol is
stirred and heated to 135.degree. C. After 1 hour, the reaction is
cooled to room temperature, quenched with 1.0 mL of triethylamine
and concentrated in vacuo. The residue is dissolved in 95:5
methylene chloride/methanol and chromatographed on silica gel,
eluting with 1:1 hexane/ethyl acetate. The product is precipitated
from ethyl acetate to provide 0.760 g (48%) of
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile and
4-(2,4-dichloro-5-methoxy-anilino)-8-methoxy-7(chloroethoxy)benzo[g]quino-
line-3-carbonitrile (1:1 mixture) as a dull yellow solid, m.p.
239-55.degree. C. dec.
[1210] .sup.1HNMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 8.94 (br s,
1H); 8.77 (br s, 1H); 8.59 (br s, 1H); 8.36 (br s, 1H), 7.54 (br s,
1H); 7.28 (br s, 1H); 7.26 (br s, 1H); 6.96 (br s, 1H); 4.40-4.49
(m, 2H); 3.94-4.07 (m, 5H); 3.86 (s, 3H).
[1211] MS (ES, positive ion mode): m/z calcd for
C.sub.24H.sub.18Cl.sub.3N.sub.3O.sub.3: 501.0, found: 502.2
(M+H).sup.+.
[1212] Analysis for
C.sub.24H.sub.18Cl.sub.3N.sub.3O.sub.3.0.3H.sub.2O
[1213] Calcd: C, 56.92; H, 3.70; N, 8.30.
[1214] Found C, 56.67; H, 3.48; N, 8.16
EXAMPLE 128
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]ben-
zo[g]quinoline-3-carbonitrile and
EXAMPLE 129
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl
ethoxy]benzo[g]quinoline-3-carbonitrile
[1215] A mixture of 0.436 g (0.87 mmol) of
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile and
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile (1:1 mixture), 2.0 mL (23.0 mmol) of morpholine
and 0.05 g of sodium iodide in 2.0 mL of ethylene glycol dimethyl
ether is heated at 90.degree. C. for 3.5 hours under nitrogen. The
mixture is cooled, solvent is removed in vacuo and the resulting
residue is stirred with a saturated solution of sodium bicarbonate.
The crude solid is collected by filtration, washed with water, and
dried in vacuo. Purification is carried out by silica gel
chromatography, eluting with a gradient of 97:3 to 90:10 ethyl
acetate/methanol to yield 0.241 g of
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]be-
nzo[g]quinoline-3-carbonitrile as a yellow solid, mp
210-212.degree. C. and 0.203 g of
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]be-
nzo[g]quinoline-3-carbonitrile as a yellow solid, mp
207-214.degree. C.
[1216]
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)et-
hoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR (DMSO-d6+TFA):
.delta. 9.35 (s, 1H); 9.25 (s 1H); 8.43 (s, 1H); 7.91 (s, 1H); 7.78
(s 1H); 7.63 (s, 1H); 7.53 (s, 1H); 4.65 (m, 2H); 4.06 (s, 3H);
4.04-3.97 (m, 2H); 3.91 (s, 3H); 3.84-3.63 (m, 6H); 3.34 (t,
J=10.56 Hz, 2H).
[1217] MS (ES, positive mode): m/z calcd for
C.sub.28H.sub.26Cl.sub.2N.sub.4O.sub.4: 553, found (M+H).sup.+
553
[1218] Analysis for
C.sub.28H.sub.26Cl.sub.2N.sub.4O.sub.4.0.15CH.sub.3CO.sub.2C.sub.2H.sub.5
[1219] Calcd: C, 60.67; H, 4.84; N, 9.89.
[1220] Found: C, 60.31; H, 4.97; N, 9.55.
[1221]
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)et-
hoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR (DMSO-d6+TFA):
.delta. 9.35 (s, 1H); 9.24 (s 1H); 8.42 (s, 1H); 7.91 (s, 1H); 7.82
(s 1H); 7.61 (s, 1H); 7.48 (s, 1H); 4.66 (m, 2H); 4.07 (s, 3H);
4.04-3.97 (m, 2H); 3.90 (s, 3H); 3.83-3.63 (m, 6H); 3.34 (m,
2H).
[1222] MS (ES, positive mode): m/z calcd for
C.sub.29H.sub.26Cl.sub.2N.sub.4O.sub.4: 553, found (M+H).sup.+
553
[1223] Analysis for
C.sub.28H.sub.26Cl.sub.2N.sub.4O.sub.4.2.0H.sub.2O
[1224] Calcd: C, 57.05; H, 5.13; N, 9.50.
[1225] Found: C, 56.88; H, 4.96; N, 9.10.
EXAMPLE 130
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)e-
thoxy]benzo[g]quinoline-3-carbonitrile and
EXAMPLE 131
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)e-
thoxy]benzo[g]quinoline-3-carbonitrile
[1226] A mixture of 0.4 g (0.8 mmol) of
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile and
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quino-
line-3-carbonitrile (1:1 mixture), 1.25 ml (11.27 mmol) of 1-methyl
piperazine and 0.05 g of sodium iodide in 2.0 mL of ethylene glycol
dimethyl ether is heated at 90.degree. C. for 2 hours under
nitrogen. The mixture is cooled, the solvent is removed in vacuo
and the resulting residue is stirred with saturated solution of
sodium bicarbonate. The crude solid is collected by filtration,
washed with water, and dried in vacuo. Purification is carried out
by silica gel chromatography, eluting with a gradient of 92:8 to
85:15 methylene chloride/methanol to yield 0.149 g of
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp
141-150.degree. C. and 0.203 g of
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp
132-135.degree. C.
[1227]
4-(2,4-dichloro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piper-
azinyl)ethoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR
(DMSO-d6+TA): .delta. 9.34 (s, 1H); 9.23 (s 1H); 8.42 (s, 1H); 7.91
(s, 1H); 7.77 (s 1H); 7.61 (s, 1H); 7.51 (s, 1H); 4.63 (m, 2H);
4.03 (s, 3H); 3.90 (s, 3H); 3.81-3.31 (m, 10H); 2.94 (s, 3H).
[1228] MS (ES, positive mode): m/z calcd for
C.sub.29H.sub.29Cl.sub.2N.sub.5O.sub.3: 566, found (M+H).sup.+
566
[1229] Analysis for C.sub.29H.sub.29Cl.sub.2N.sub.5O.sub.3.0.9
CH.sub.2Cl.sub.2
[1230] Calcd: C, 55.85; H, 4.83; N, 10.89.
[1231] Found: C, 55.98; H, 5.14; N, 11.17.
[1232]
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piper-
azinyl)ethoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR
(DMSO-d6+TFA): .delta. 9.35 (s, 1H); 9.23 (s 1H); 8.42 (s, 1H);
7.91 (s, 1H); 7.80 (s 1H); 7.60 (s, 1H); 7.48 (s, 1H); 4.64 (m,
2H); 4.03 (s, 3H); 3.90 (s, 3H); 3.81-3.4 (m, 10H); 2.94 (s,
3H).
[1233] MS (ES, positive mode): m/z calcd for
C.sub.29H.sub.29Cl.sub.2N.sub.5O.sub.3: 566, found (M+H).sup.+
566
[1234] Analysis for C.sub.29H.sub.29Cl.sub.2N.sub.5O.sub.3.0.5
CH.sub.2Cl.sub.2
[1235] Calcd: C, 58.18; H, 4.97; N, 11.50.
[1236] Found: C, 58.22; H, 5.27; N, 11.69.
EXAMPLE 132
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperazi-
nyl)ethoxy]benzo[g]quinoline-3-carbonitrile and
EXAMPLE 133
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperazi-
nyl ethoxy]benzo[g]quinoline-3-carbonitrile
[1237] A mixture of 205 mg (0.425 mmol) of
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile and
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]-
quinoline-3-carbonitrile (1:1 mixture), 0.15 mL (1.35 mmol) of
1-methyl piperazine and 0.05 g of sodium iodide in 5 mL of ethylene
glycol dimethyl ether is heated at 90.degree. C. for 4 days under
nitrogen. The mixture is cooled, the solvent is removed in vacuo
and the resulting residue is stirred with saturated solution of
sodium bicarbonate. The crude solid is collected by filtration,
washed with water, and dried in vacuo. Purification is carried out
by silica gel chromatography, eluting with a gradient of 92:8 to
85:15 methylene chloride/methanol to yield 0.10 g of
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-methyl-
-1-piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow
solid, mp 121-135.degree. C. and 0.068 g of
4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperaz-
inyl)ethoxy]benzo-[g]quinoline-3-carbonitrile as a yellow solid, mp
122-137.degree. C.
[1238]
4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-[2-(4-methyl-1--
piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR
(DMSO-d.sub.6): .delta. 9.86 (s, 1H); 9.01 (s 1H); 8.42 (s, 1H);
8.32 (s, 1H); 7.57 (s, 1H); 7.43 (s 1H); 7.31 (s, 1H); 7.16 (s,
1H); 4.27 (t, J=5.6 Hz, 2H); 3.96 (s, 3H); 3.81 (s, 3H); 2.81 (t,
J=5.8 Hz, 2H); 2.54 (m, 4H); 2.37 (br s, 4H); 2.18 (s, 3H); 2.14
(s, 3H).
[1239] MS (ES, positive mode): m/z calcd for
C.sub.30H.sub.32ClN.sub.5O.sub.3: 546, found (M+H).sup.+ 546
[1240] Analysis for C.sub.30H.sub.32ClN.sub.5O.sub.3 1.6
CH.sub.2Cl.sub.2
[1241] Calcd: C, 62.67; H, 6.17; N, 12.18.
[1242] Found: C, 62.41; H, 5.96; N, 11.89.
[1243]
4-(4-chloro-5-methoxy-2-methylamino)-7-methoxy-8-[2-(4-methyl-1-pi-
perazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile: .sup.1HNMR
(DMSO-d6): .delta. 9.86 (s, 1H); 9.0 (s 1H); 8.43 (s, 1H); 8.34 (s,
1H); 7.53 (s, 1H); 7.43 (s 1H); 7.33 (s, 1H); 7.16 (s, 1H); 4.27
(t, J=5.6 Hz, 2H); 3.97 (s, 3H); 3.81 (s, 3H); 2.81 (t, J=5.8 Hz,
2H); 2.55 (m, 4H); 2.36 (br s, 4H); 2.17 (s, 3H); 2.14 (s, 3H).
[1244] MS (ES, positive mode): m/z calcd for
C.sub.30H.sub.32ClN.sub.5O.sub.3: 546, found (M+H).sup.+ 546
[1245] Analysis for C.sub.30H.sub.32ClN.sub.5O.sub.3 1.0
CH.sub.2Cl.sub.2
[1246] Calcd: C, 59.00; H, 5.43; N, 11.10.
[1247] Found: C, 59.02; H, 5.36; N, 11.26.
EXAMPLE 134
5-(Benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene
[1248] 4-Benzyloxy-3-methoxybenzyl alcohol (1 g, 4.1 mmol) is
dissolved in acetic acid (3 ml) and cooled to 10.degree. C. in a
water/ice bath. A solution of bromine (0.25 ml, 4.92 mmol) in
acetic acid (0.25 ml) is added dropwise to the reaction mixture
while stirring. The reaction is allowed to warm to room temperature
and stirred for 18 hours. The reaction is diluted with water and
the resulting precipitate is collected by filtration. The
precipitate is washed well with water and recrystallized from a
small amount of methanol to yield 1.3 g of
5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene as a white
solid, mp 103-105.degree. C.
[1249] .sup.1HNMR (d.sup.6-DMSO): .delta. 7.5 (m, 7H); 5.09 (s,
2H); 4.69 (s, 2H); 3.77 (s, 3H)
[1250] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.14Br.sub.2O.sub.2: 386.08, found (M+H).sup.+
387.1
[1251] Analysis for
C.sub.15H.sub.14Br.sub.2O.sub.2.0.3CH.sub.3OH
[1252] Calcd: C, 47.60; H, 3.84.
[1253] Found: C, 47.44; H, 3.77.
EXAMPLE 135
3-(4-Benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile
[1254] To a solution of n-butyllithium (1.8 mL of a 2.5 M solution
in hexane, 4.5 mmol) in 5 mL of tetrahydrofuran is added a solution
of acetonitrile (1.0 mL, 19.1 mmol) in 5 mL of tetrahydrofuran. The
reaction mixture is stirred at -78.degree. C. for 15 min. A
solution of 5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene
(0.7 g, 1.8 mmol) in 3 mL of tetrahydrofuran is added and stirring
is continued for 1 hour at -78.degree. C. The reaction is quenched
by the addition of 15 mL of water and the mixture is allowed to
warm to room temperature. The mixture is extracted with ethyl
acetate and the organic layers combined, then dried with sodium
sulfate. After reducing in vacuo, the crude product is purified by
flash chromatography using a gradient of 95:5 to 4:1 hexanes/ethyl
acetate as an eluent. The clean fractions are combined, reduced in
vacuo and dried to yield 0.343 g of
3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile as a white
solid, mp 52-53.degree. C.
[1255] .sup.1HNMR (d.sup.6-DMSO): .delta. 7.39 (m, 5H); 7.33
(s,1H); 7.08 (s, 1H); 5.09 (s, 2H); 3.77 (s, 3H); 2.92 (t, 2H;
J=5.49), 2.78 (t, 2H; J=5.07).
[1256] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.6BrNO.sub.2: 346.22, found (M+H).sup.+ 347.1
[1257] Analysis for C.sub.17H.sub.16BrNO.sub.2
[1258] Calcd: C, 58.98; H, 4.66; N, 4.05.
[1259] Found: C, 58.77; H, 4.71; N, 3.89.
EXAMPLE 136
4-Benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile
[1260] A suspension of sodium amide is prepared from 100 mL of
liquid ammonia, sodium (0.52 g, 22.8 mmol) and a catalytic amount
of ferric nitrate. To this is added
3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile (2 g, 5.7
mmol) in portions and the reaction stirred at -33.degree. C. for 45
minutes. The reaction is then cooled down to -78.degree. C. and
quenched with ammonium chloride. The liquid ammonia is allowed to
evaporate and the resulting solid residue is washed with water. The
tan solid obtained is purified by flash chromatography, using 4:1
hexanes/ethyl acetate as an eluent. The clean fractions are
combined and reduced in vacuo to yield 1 g of
4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile
as a clear oil that solidified into a white solid upon standing, mp
85.degree. C.
[1261] .sup.1HNMR (d.sup.6-DMSO): .delta.7.39 (m, 5H); 7.04 (s,1H);
6.89 (s, 1H); 5.08 (d, 1H, J=12.15); 5.05 (d. 1H, J=12.12); 4.45
(dd, 1H, J=1.74, 3.93), 3.74 (s, 3H); 3.6 (dd, 1H, J=3.99, 10.29),
3.35 (d, 1H, J=1.77)
[1262] MS (ES, positive ion mode): m/z calcd for
C.sub.17H.sub.15NO.sub.2: 265.31, found (M+H).sup.+ 266.1
[1263] Analysis for C.sub.17H.sub.15NO.sub.2
[1264] Calcd: C, 76.96; H, 5.70; N, 5.28.
[1265] Found: C, 76.87; H, 5.97; N, 5.01.
EXAMPLE 137
4-Benzyloxy-7-(4-chlorophenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-t-
riene-7-carbonitrile
[1266] To a solution of
4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile
(1.0 g, 3.7 mmol) in anhydrous tetrahydrofuran (10 mL) at
-78.degree. C. is added sodium bis(trimethylsilyl)amide (5.65 mL of
a 1M solution in tetrahydrofuran, 5.6 mmol) over a period of 4
minutes, followed by the addition of 4,4'-dichlorodiphenyl
disulfide in one portion. The reaction is stirred at -78.degree. C.
for 15 minutes and then at room temperature for one hour. The
reaction is then diluted and extracted with ethyl acetate. The
organic layer is collected and dried with sodium sulfate. After
reducing in vacuo, the crude material is purified by flash
chromatography using 4:1 hexanes/ethyl acetate. The clean fractions
are combined, reduced and dried to yield 1.3 g of
4-benzyloxy-7-(4-chlorophenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5--
triene-7-carbonitrile as an off-white solid, mp 114-115.degree.
C.
[1267] .sup.1HNMR (d.sup.6-DMSO): .delta.7.62-7.54 (m, 4H); 7.41
(m, 4H); 7.36 (m,1H); 6.97 (s,1H); 6.83 (s, 1H); 5.08 (dd, 2H,
J=9.07,10.53); 3.98 (d, 1H, J=10.47), 3.78 (s, 3H); 3.60 (d, 1H,
J=10.5)
[1268] MS (ES, positive ion mode): m/z calcd for
C.sub.23H.sub.18ClNO.sub.2S: 408.92, found (M+H).sup.+ 408.1
[1269] Analysis for C.sub.23H.sub.18ClNO.sub.2S
[1270] Calcd: C, 67.72; H, 4.45; N, 3.43.
[1271] Found: C, 67.99; H, 4.63; N, 3.33.
EXAMPLE 138
4-Benzyloxy-3-methoxy-7-phenylsulfanylbiocylo[4.2.0]octa-1,3,5-triene-7-ca-
rbonitrile
[1272] To a solution of
4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile
(7.22 g, 3.7 mmol) in anhydrous tetrahydrofuran (60 mL) at
-78.degree. C. is added sodium bis(trimethylsilyl)amide (41.0 mL of
a 1M solution in tetrahydrofuran, 41.0 mmol) over a period of 4
minutes, followed by the addition of 11.9 g (54.5 mmol) of phenyl
disulfide in one portion. The reaction is stirred at -78.degree. C.
for 15 minutes and then at room temperature for one hour. The
reaction is quenched with water and extracted with ethyl acetate.
The organic layers are combined and dried with sodium sulfate.
After reducing in vacuo, the crude material is purified by flash
chromatography using 4:1 hexanes/ethyl acetate. The clean fractions
are combined, reduced and dried to yield 7.0 g of
4-benzyloxy-3-methoxy-7-phenylsulfanylbicyclo[4.2.0]octa-1,3,5-triene-7-c-
arbonitrile as a white solid, mp 109-110.degree. C.
[1273] .sup.1HNMR (d.sup.6-DMSO): .delta. 7.60-7.52 (m, 2H);
7.51-7.48 (m, 3H); 7.42-7.34 (m, 5H); 6.97 (s,1H); 6.80 (s, 1H);
5.03 (dd, 2H, J=9.0 Hz, 11.4 Hz); 4.01 (d, 1H, J=10.5 Hz); 3.78 (s,
3H); 3.60 (d, 1H, J=10.5)
[1274] MS (ES, positive ion mode): m/z calcd for
C.sub.23H.sub.19NO.sub.2S: 373.5, found (M+H).sup.+ 374.0
[1275] Analysis for C.sub.23H.sub.19NO.sub.2S
[1276] Calcd: C, 73.97; H, 5.13; N, 3.75.
[1277] Found: C, 73.83; H, 5.16; N, 3.53.
EXAMPLE 139
3-Amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicylo[4.2.0]o-
cta-1,3,5-trien-7-yl]-acrylic acid tert-butyl ester
[1278] To a stirred solution of ethylmagnesium bromide (3.26 mL of
a 3M solution in diethyl ether, 9.8 mmol) in anhydrous
tetrahydrofuran (10 mL) at 0.degree. C. under nitrogen is added
diisopropylamine (2.75 mL, 19.6 mmol). The mixture is stirred at
0.degree. C. for 1 hour. t-Butyl acetate (0.5 mL, 3.6 mmol) and a
solution of 1.0 g (2.45 mmol) of
4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-
-triene-7-carbonitrile in anhydrous tetrahydrofuran (10 mL) are
added successively, and the resulting mixture is stirred for an
additional hour. The reaction is quenched with aqueous ammonium
chloride and the product mixture is extracted with ethyl acetate.
The ethyl acetate extract is washed with brine, dried over
anhydrous sodium sulfate and passed through a plug of silica to
give
3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0-
]octa-1,3,5-trien-7-yl]-acrylic acid tert-butyl ester as a clear
oil, that solidified upon standing, mp 112-115.degree. C.
[1279] .sup.1HNMR (d.sup.6-DMSO): .delta. 7.60-7.29 (m, 9H); 6.81
(s,1H); 6.72 (s, 1H); 5.08 (dd, 2H, J=9.09,11.82 Hz); 4.15 (s, 1H);
3.73 (s, 3H); 3.48 (d, 1H, J=10.7 Hz); 3.30 (d, 1H, J=10.6 Hz);
1.36 (s, 9H)
[1280] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.30ClNO.sub.4S: 524.1, found (M+H).sup.+ 523.9
[1281] Analysis for C.sub.29H.sub.30ClNO.sub.4S
[1282] Calcd: C, 66.46; H, 5.77; N, 2.67.
[1283] Found: C, 66.31; H, 5.91; N, 2.61.
EXAMPLE 140
3-Amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid
tert-butyl ester
[1284] Nitrogen gas is bubbled through a solution of
3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0-
]octa-1,3,5-trien-7-yl]-acrylic acid tert-butyl ester (0.6 g, 1.1
mmol) in 1,2-dichlorobenzene (100 mL) for 1 hour and the reaction
is heated to 179.degree. C. After one hour the reaction is cooled
and reduced in vacuo. The residue is washed with ether, dissolved
in methylene chloride and purified through a plug of silica eluting
with methylene chloride. The filtrate is reduced and dried to
afford 0.321 g of
3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid
tert-butyl ester as a yellow solid, mp 179-180.degree. C.
[1285] .sup.1HNMR (d.sup.6-DMSO): .delta. 8.18 (s, 1H); 7.4 (m,
5H); 7.18 (s, 1H); 7.01 (s, 1H); 6.85 (s, 1H); 6.21(s, 2H), 5.17
(s, 2H); 3.74 (s, 3H), 1.58 (s, 9H)
[1286] MS (ES, positive ion mode): m/z calcd for
C.sub.23H.sub.25NO.sub.4: 379.45, found (M+H).sup.+ 379.9
[1287] Analysis for C.sub.23H.sub.25NO.sub.4.0.7H.sub.2O
[1288] Calcd: C, 70.50; H, 6.08; N, 3.57.
[1289] Found: C, 70.45; H, 6.24; N, 3.40.
EXAMPLE 141
8-Benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
[1290] In a round bottom flask containing 10 mL of toluene is added
3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid
tert-butyl ester (3.0 g, 7.9 mmol) and dimethylformamide dimethyl
acetal (5.4 mL, 31.6 mmol) under a positive nitrogen flow. The
mixture is stirred at 120.degree. C. for 1.5 hour, then cooled to
room temperature. The volatiles are removed under reduced pressure
and the resulting residue dried in vacuo for 15 h to yield 3.0 g of
6-benzyloxy-3-(dimethylamino-methyleneamino)-7-methoxy-naphthalene-2-carb-
oxylic acid tert-butyl ester as a dark oil.
[1291] To a solution of n-butyllithium (7.68 mL of a 2.5 M solution
in hexane, 19.2 mmol) in 30 mL of tetrahydrofuran is added a
solution of acetonitrile (3.34 mL, 64.0 mmol) in 50 mL of
tetrahydrofuran. The reaction mixture is stirred at -78.degree. C.
for 15 min. A solution of
6-benzyloxy-3-dimethylamino-methyleneamino)-7-methoxy-naphthalene-2-carbo-
xylic acid tert-butyl ester obtained in the previous step (2.8 g,
6.4 mmol) in 30 mL of tetrahydrofuran is added and stirring is
continued for 1 h at -78.degree. C. The reaction is quenched by the
addition of 10 mL of glacial acetic acid and the mixture is allowed
to warm up to room temperature. The volatiles are removed under
reduced pressure and the resulting residue washed with water, then
ethyl acetate and dried in a vacuum oven to yield 1.9 g of
8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
as a yellow solid, mp>300.degree. C.
[1292] .sup.1HNMR (d.sup.6-DMSO+TFA): .delta. 8.71 (s, 1H); 8.63
(s, 1H); 7.93 (s, 1H); 7.61 (s, 1H); 7.58 (s, 1H); 7.43 (m, 5H);
5.27 (s, 2H), 3.74 (s, 3H)
[1293] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.15N.sub.2O.sub.2: 356.38, found (M+H).sup.+ 357.1
[1294] Analysis for C.sub.22H.sub.15N.sub.2O.sub.2.0.2H.sub.2O
[1295] Calcd: C, 73.45; H, 4.54; N, 7.77.
[1296] Found: C, 73.49; H, 4.49; N, 7.65.
EXAMPLE 142
3-Amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid
tert-butyl ester
[1297] A solution of 4.7 g (12.0 mmol) of
3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid
tert-butyl ester and 2.0 g of 10% Pd/C in 40 mL of DMF and 100 mL
of methanol is shaken on Parr shaker at 40 psi for 18 hours. The
catalyst is filtered through a pad of Celite, washed with methanol
and solvent is evaporated to yield a residue which is dissolved in
methylene chloride. This is then filtered through a short pad of
Magnesol and washed with methylene chloride and ethyl acetate. The
filtrate is evaporated to yield 3.4 g of
3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid
tert-butyl ester as a yellow solid, mp 262-263.degree. C.
[1298] .sup.1HNMR (d.sup.6-DMSO): .delta. 9.61 (bs, 1H); 8.15 (s,
1H); 7.13 (s, 1H); 6.74 (d, 2H, J=2.7); 6.12 (s, 2H); 3.82 (s, 3H),
1.58 (s, 9H)
[1299] MS (ES, positive ion mode): m/z calcd for
C.sub.16H.sub.19NO.sub.4: 289.33, found (M+H).sup.+ 289.9
[1300] Analysis for
C.sub.16H.sub.19NO.sub.4.0.1CH.sub.3CO.sub.2C.sub.2H.sub.5
[1301] Calcd: C, 66.06; H, 6.69; N, 4.70.
[1302] Found: C, 66.30; H, 6.96; N, 4.30.
EXAMPLE 143
3-Amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic
acid tert-butyl ester
[1303] To a solution of 0.72 g (2.49 mmol) of
3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid
tert-butyl ester in 7.5 ml of tetrahydrofuran is added 0.46 mL
(3.74 mmol) of 4-(2-hydroxyethyl)morpholine, followed by the
addition of 1.34 g (4.98 mmol) of diphenyl-2-pyridylphosphine and
0.6 mL (3.87 mmol) of diethyl azadicarboxylate. The resulting
mixture is stirred at room temperature for 1.5 hours, quenched with
water, diluted with ethyl acetate and the two layers are separated.
The organic layer is extracted with 0.2N hydrochloric acid. After
neutralizing the aqueous layer with a saturated solution of sodium
bicarbonate, it is extracted with ethyl acetate. The ethyl acetate
extract is dried over anhydrous sodium sulfate, filtered and
evaporated to yield a brown oil. The oil is purified by silica gel
chromatography, utilizing a gradient of ethyl acetate/hexane (85:15
to 100:0), to give 0.7 g of
3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic
acid tert-butyl ester as an orange solid, mp 125-127.degree. C.
[1304] .sup.1HNMR(CDCl.sub.3): .delta. 8.24 (s, 1H); 7.00 (s, 1H);
6.81 (d, 2H, J=2.34 Hz); 5.47 (bs, 2H); 4.26 (t, 2H, J=4.5 Hz);
3.92 (s, 3H); 3.75 (t, 41, J=3.45 Hz); 2.93 (t, 21, J=4.5 Hz); 2.65
(bs, 4H); 1.63 (s, 9H).
[1305] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.30N.sub.2O.sub.5: 402.4, found (M+H).sup.+ 403.3
[1306] Analysis for C.sub.22H.sub.30N.sub.2O.sub.5
[1307] Calcd: C, 65.65; H, 7.51; N, 6.96.
[1308] Found: C, 65.65; H, 7.30; N, 6.98.
EXAMPLE 144
7-Methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-
-carbonitrile
[1309] A mixture of 0.69 g (1.7 mmol) of
3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic
acid tert-butyl ester and 2.4 mL of N,N-dimethylformamide dimethyl
acetal in 7.0 mL of toluene is heated under reflux for 1.5 hours.
The solvent is evaporated and the residue is dried on high vacuum
to yield
3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)nap-
hthalene-2-carboxylic acid tert-butyl ester as purple white
foam.
[1310] To 15 mL of tetrahydrofuran at -78.degree. C. is added 2.6
mL of n-butyllithium (1.6M in hexane) and the reaction mixture is
stirred for 5 minutes. To this is added 0.36 mL (6.8 mmol) of
acetonitrile dropwise, followed by stirring for 15 minutes.
Finally, a solution of
3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)nap-
hthalene-2-carboxylic acid tert-butyl ester in 5 mL of
tetrahydrofuran is added dropwise over a period of 15 minutes. The
resulting mixture is stirred at -78.degree. C. for 1 hour, then at
room temperature for 1 hour. After cooling again to -78.degree. C.,
the reaction is quenched with 0.5 mL of glacial acetic acid, the
dry ice bath is removed and the resulting thick slurry is stirred
for 1 hour. The solid is collected by filtration, washed with ethyl
acetate and dried. Purification is carried out by silica gel
chromatography, utilizing a gradient of 95:5 to 89:11 of methylene
chloride/methanol to give 0.38 g of
7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline--
3-carbonitrile as a yellow solid, mp 275.degree. C. (dec).
[1311] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 8.74
(s, 1H); 8.69 (s, 1H); 8.00 (s, 1H); 7.65 (s, 1H); 7.59 (s, 1H);
4.59 (t, 2H, J=3.3 Hz,); 4.05 (d, 2H, J=9.2 Hz); 3.97 (s, 3H); 3.75
(m, 4H); 3.66 (d, 2H, J=9.3 Hz); 3.34 (t, 2H, J=7.0 Hz).
[1312] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.21N.sub.3O.sub.4: 379.4, found (M+H).sup.+ 380.2
[1313] Analysis for C.sub.21H.sub.21N.sub.3O.sub.4. 2.5H.sub.2O
[1314] Calcd: C, 60.71; H, 6.07; N, 10.12.
[1315] Found: C, 60.93; H, 6.11; N, 9.76.
EXAMPLE 145
8-Hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
[1316] A solution of 3.6 g (7.3 mmol) of
8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
and 0.7 g of 10% Pd/C in 240 mL of dimethyl formamide is
hydrogenated in a Parr shaker at 40 psi for 24 hours. The catalyst
is filtered through a pad of Celite, washed with dimethyl formamide
and the solvent is reduced in vacuo to yield a solid. The crude
product is suspended in ether, collected by filtration, further
washed with ether and dried to yield 3.0 g of
8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitril-
e as a yellow solid, mp>300.degree. C.
[1317] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 8.67
(s, 1H); 8.64 (s, 1H); 7.84 (s, 1H); 7.57 (s, 1H); 7.29 (s, 1H);
3.98 (s, 3H).
[1318] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.10N.sub.2O.sub.3: 266.3, found (M+H).sup.+ 266.8.
[1319] Analysis for C.sub.15H.sub.10N.sub.2O.sub.3.1.0
(CH.sub.3).sub.2NCHO.0.8H.sub.2O
[1320] Calcd: C, 61.11; H, 5.30; N, 11.88.
[1321] Found: C, 61.08; H, 4.81; N, 11.82.
EXAMPLE 146
4-Chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile
[1322] A mixture of 3.0 g (11.3 mmol) of
8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
and 20.0 mL of phosphorus oxychloride is heated under reflux for
0.5 hour, then cooled to room temperature. Excess phosphorus
oxychloride is evaporated to yield a residue, to which toluene is
added and the resulting solution is reduced in vacuo. Toluene is
added and evaporated twice more. The resulting residue is cooled
with ice bath, neutralized with cold saturated solution of sodium
bicarbonate and stirred. The solid is collected by filtration,
washed with cold water and dried to yield 2.83 g of
4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a
yellow solid. A sample of the material is purified by silica gel
chromatography, eluting with 97:3 methylene chloride/methanol to
yield a yellow solid, mp. >300.degree. C.
[1323] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 8.68
(s,1H); 8.64 (s,1H); 7.83 (s, 1H); 7.58 (s,1H); 7.27 (s, 1H); 3.96
(s, 3H).
[1324] MS (ES, positive ion mode): m/z calcd for
C.sub.15H.sub.9ClN.sub.2O.sub.2: 284.7, found (M+H).sup.+ 284.7
[1325] Analysis for C.sub.15H.sub.9ClN.sub.2O.sub.2.
0.6H.sub.2O
[1326] Calcd: C, 61.11; H, 5.30; N, 11.88.
[1327] Found: C, 61.08; H, 4.81; N, 11.82.
EXAMPLE 147
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7--
methoxybenzo[g]quinoline-3-carbonitrile
[1328] A mixture of 1.0 g (3.53 mmol) of
4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.93
g (3.88 mmol) of
3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.41
g (3.52 mmol) of pyridine hydrochloride in 20 mL of 2-ethoxyethanol
is heated at 120.degree. C. for 2 hours, then cooled to room
temperature. The product mixture is diluted with a saturated
solution of sodium carbonate, stirred for 15 minutes and the solid
is collected by filtration. The solid is washed with water and
dried in vacuo. The crude product is purified by silica gel
chromatography, utilizing a 95:5 to 9:1 gradient of methylene
chloride/methanol to give 1.13 g of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-
-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow
solid, mp>300.degree. C.
[1329] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.22
(d, 21, J=5.1); 8.28 (s, 1H); 8.06 (d, 1H, J=1.5 Hz); 7.98(d, 1H,
J=1.5 Hz); 7.92 (d,1H, J=1.6 Hz); 7.58 (dd,1H, J=1.7 Hz, J=8.07
Hz); 7.49 (s, 1H); 7.44 (s, 1H); (d, 11, J=6.4 Hz); 4.05 (s, 3H);
3.88 (s, 3H).
[1330] MS (ES, positive ion mode): m/z calcd for
C.sub.25H.sub.18ClN.sub.5O.sub.2S: 487.9, found (M+H).sup.+
487.7
[1331] Analysis for
C.sub.25H.sub.18ClN.sub.5O.sub.2S.0.3H.sub.2O
[1332] Calcd: C, 60.86; H, 3.80; N, 14.20.
[1333] Found: C, 60.82; H, 3.66; N, 14.03.
EXAMPLE 148
8-(2-Chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenyl-
amino]-7-methoxybenzo[g]quinoline-3-carbonitrile
[1334] A mixture of 0.8 g (1.64 mmol) of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-
-methoxybenzo[g]quinoline-3-carbonitrile, 0.48 g (2.05 mmol) of
2-chloroethyl p-toluene sulfonate and 0.8 g (2.46 mmol) of cesium
carbonate in 15 mL of dry dimethyl formamide is heated at
40.degree. C. for 2 hours. To this is added 0.2 g (0.85 mmol) of
2-chloroethyl p-toluene sulfonate and 0.4 g (1.22 mmol) of cesium
carbonate and the reaction mixture is further heated for 2 hours.
After cooling to room temperature, the mixture is poured on to ice.
The solid is collected by filtration, washed with water and ether,
and dried to yield 1.0 g of dark yellow solid. A sample of the
solid is purified by preparatory thin layer chromatography, eluting
with 95:5% methylene chloride/methanol to give
8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)pheny-
lamino]-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow
solid, mp. 275-280.degree. C.
[1335] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.25
(d, 2H, J=7.3 Hz); 8.41 (s, 1H); 8.06 (d, 1H, J=1.5 Hz); 7.98 (d,
1H, J=1.5 Hz); 7.93 (d, 1H, J=1.7 Hz); 7.78 (s, 1H); 7.58 (dd, 1H,
J=1.7 Hz, 9.9 Hz); 7.45 (s, 1H); 7.33 (d,1H, J=6.4 Hz); 4.55 (t,
2H, J=3.6 Hz): 4.11 (t, 2H, J=3.9 Hz); 4.04 (s, 3H); 3.85 (s,
3H).
[1336] MS (ES, positive ion mode): m/z calcd for
C.sub.27H.sub.21Cl.sub.2N.sub.5O.sub.2S: 550.5, found (M+H).sup.+
549.7
[1337] Analysis for
C.sub.27H.sub.21Cl.sub.2N.sub.5O.sub.2S.1.7H.sub.2O
[1338] Calcd: C, 55.80; H, 4.23; N, 12.05.
[1339] Found: C, 56.05; H, 4.14; N, 11.70.
EXAMPLE 149
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8--
(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile
Procedure 1:
[1340] A mixture of 1.27 g (2.3 mmol) of
8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)pheny-
lamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 4.0 mL of
morpholine and 0.1 g of sodium iodide in 10 mL of
1,2-dimethoxyethane is heated under reflux for 16 hours. After
allowing the reaction to cool, the solvent is evaporated to yield a
residue, which is stirred with saturated sodium bicarbonate. The
solid is collected by filtration, washed with water and dried. The
crude product is purified by silica gel chromatography, utilizing a
gradient of 98:2 to 90:10 of methylene chloride/methanol to give
0.53 g of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a
yellow solid, mp>300.degree. C.
Procedure 2:
[1341] A mixture of 2.32 g (6.11 mmol) of
7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline--
3-carbonitrile and 35 mL of phosphorus oxychloride is heated under
reflux for 1 hour, then cooled to room temperature. Excess
phosphorus oxychloride is evaporated to yield a residue, to which
toluene is added and the resulting solution is reduced in vacuo.
Toluene is added and evaporated twice more. The resulting residue
is cooled with ice bath, neutralized with cold saturated solution
of sodium bicarbonate and stirred. The solid is collected by
filtration, washed with cold water and dried to yield 1.989 g of
4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carboni-
trile as a yellow solid.
[1342] MS (ES, positive ion mode): m/z calcd for
C.sub.21H.sub.20ClN.sub.3O.sub.4397.9, found (M+H).sup.+ 398.2
[1343] A mixture of 1.98 g (4.98 mmol) of
4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carboni-
trile, 1.31 g (5.47 mmol) of
3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.6 g
(5.2 mmol) of pyridine hydrochloride in 2-ethoxyethanol is heated
at 120.degree. C. for 1.25 hours, then cooled. The crude mixture is
poured into a solution of saturated sodium bicarbonate/ice and
stirred for 45 minutes. The resulting solid is collected by
filtration, then washed with water, ether and ethyl acetate
successively. After drying in vacuo, the solid is purified by
silica gel chromatography, using a 94:6 to 9:1 gradient of
methylene chloride/methanol to provide a yellow solid. This solid
is suspended in ether, filtered, and further washed with ether.
After drying in vacuo, 1.77 g of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is
obtained as a yellow solid, mp. >300.degree. C.
[1344] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.28
(s, 2H); 8.45 (s, 1H); 8.06 (d, 1H, J=1.5 Hz); 7.98 (d, 1H, J=1.5
Hz); 7.93 (d, 13, J=1.7 Hz); 7.83 (s, 1H); 7.58 (dd, 1H, J=1.7 Hz,
6.4 Hz); 7.48 (s, 1H); 7.35 (d, 1H, J=6.4 Hz); 4.67 (t, 2H, J=3.6
Hz); 4.06 (m, 2H); 4.04 (s, 3H); 3.87 (s, 3H); 3.77 (m, 4H); 3.67
(d, 2H, J=9.3 Hz); 3.36 (t, 2H, J=3.6 Hz).
[1345] MS (ES, positive ion mode): m/z calcd for
C.sub.31H.sub.29ClN.sub.6O.sub.3S: 601.1, found (M+H).sup.+
601.2
[1346] Analysis for
C.sub.31H.sub.29ClN.sub.6O.sub.3S.1.7H.sub.2O
[1347] Calcd: C, 55.80; H, 4.23; N, 12.05.
[1348] Found: C, 56.05; H, 4.14; N, 11.70.
EXAMPLE 150
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chlorop-
ropoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile
[1349] Following the procedure of Example 148, 0.3 g (0.61 mmol) of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-
-methoxybenzo[g]quinoline-3-carbonitrile is reacted with 0.19 g
(0.77 mmol) of 3-chloropropyl p-toluene sulfonate and 0.3 g of
(0.92 mmol) of cesium carbonate, then an additional 0.05 g (0.2
mmol) of 3-chloropropyl p-toluene sulfonate and 0.07 g (0.2 mmol)
of cesium carbonate in 5 mL of dry dimethyl formamide to provide
0.3 g of a beige solid. A sample of the solid is purified by silica
gel chromatography, utilizing a 99:1 to 95:5 gradient of methylene
chloride/methanol to give
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-(3-chloro-
propoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile as an orange
solid, mp>300.degree. C.
[1350] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.25
(d, 2H, J=8.6 Hz); 8.42 (s, 1H); 8.06 (d, 1H, J=1.5 Hz); 7.98(d,
1H, J=1.5 Hz); 7.93 (d, 1H, J=1.7 Hz); 7.78 (s, 1H); 7.57 (dd, 1H,
J=1.7 Hz, 6.4 Hz); 7.44 (s, 1H); 7.33 (d, 1H, J=6.4); 4.39 (t, 2H,
J=4.5 Hz); 4.03 (s, 3H); 3.87(m, 2H); 3.86 (s, 3H); 2.35 (m,
2H).
[1351] MS (ES, positive ion mode): m/z calcd for
C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.2S: 564.5, found (M+H).sup.+
563.6
[1352] Analysis for
C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.2S.2.0H.sub.2O
[1353] Calcd: C, 56.51; H, 4.53; N, 11.66.
[1354] Found: C, 56.51; H, 4.04; N, 11.37.
EXAMPLE 151
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8--
(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile
[1355] Following procedure 1 of Example 149, a mixture of 0.13 g
(0.22 mmol) of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8--
(3-chloropropoxy)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.3 mL
of morpholine and 0.01 g of sodium iodide is heated under reflux
for 16 hours, to provide 0.054 g of a yellow solid. A sample of the
solid is purified by silica gel chromatography, utilizing a 97:3 to
90:10 gradient of methylene chloride/methanol to give
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile as a
yellow solid, mp 230-235.degree. C.
[1356] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.26
(s, 2H); 8.42 (s, 1H); 8.05 (d, 1H, J=1.2 Hz); 7.97 (d, 1H, J=1.2
Hz); 7.92 (d, 1H J=1.6 Hz); 7.73 (s, 1H); 7.57 (dd, 1H, J=1.6 Hz,
6.3 Hz); 7.46 (s, 1H); 7.33 (d, 1H, J=6.4 Hz); 4.36 (t, 2H, J=3.6
Hz); 4.07 (m, 2H); 4.02 (s, 3H); 3.85 (s, 3H); 3.71 (t, 2, J=9.1
Hz); 3.58 (d, 2H, J=9.1 Hz); 3.38 (t, 2H, J=5.4 Hz); 3.19 (t, 2H,
J=8.0 Hz); 2.33 (m, 2H).
[1357] MS (ES, positive ion mode): m/z calcd for
C.sub.32H.sub.31ClN.sub.6O.sub.3S: 615.2, found
(M+H).sup.+614.7
[1358] Analysis for
C.sub.32H.sub.31ClN.sub.6O.sub.3S.1.5H.sub.2O
[1359] Calcd: C, 59.85; H, 5.34; N, 13.09.
[1360] Found: C, 59.78; H, 5.04; N, 12.98.
EXAMPLE 152
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8--
[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile
[1361] Following procedure 1 of Example 149, a mixture of 0.15 g
(0.3 mmol) of
8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfa-
nyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.5 mL
of 1-methylpiperazine and 0.02 g of sodium iodide is heated under
reflux for 16 hours. Purification of the material is carried out by
silica gel flash chromatography, utilizing a 90:10 to 85:15
gradient of methylene chloride/methanol to give 0.052 g of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile
as a yellow solid, mp 184-186.degree. C.
[1362] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.28
(d, 2H, J=1.9 Hz); 8.45 (s, 1H); 8.06 (d, 1H, J=1.4 Hz); 7.8 (d,
1H, J=1.4 Hz); 7.93 (d, 1H, J=1.7 Hz); 7.82 (s, 1H); 7.57 (dd, 1H,
3=1.7 Hz, 6.4 Hz); 7.49 (s, 1H); 7.34 (d, 1H, J=6.4 Hz); 4.67 (m,
2H); 4.03 (s, 3H); 3.89 (m, 2H); 3.86(s, 3H); 3.71-3.25 (m, 6H);
3.2(m, 2H); 2.97 (s, 3H).
[1363] MS (ES, positive ion mode): m/z calcd for
C.sub.32H.sub.32ClN.sub.7O.sub.2S: 614.2, found (M+2H).sup.2+
307.6
[1364] Analysis for
C.sub.32H.sub.32ClN.sub.7O.sub.2S.3.5H.sub.2O
[1365] Calcd: C, 56.74; H, 5.80; N, 14.48.
[1366] Found: C, 56.57; H, 5.46; N, 14.12.
EXAMPLE 153
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8--
(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile
and
EXAMPLE 154
4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl
phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline--
3-carbonitrile
[1367] A mixture of 0.3 g (0.55 mmol) of
8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)pheny-
lamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.32 mL (5.5
mmol) of 1H-1,2,3-triazole and 0.1 g (2.5 mmol) of sodium hydroxide
powder in 5 mL of N,N-dimethyl formamide is heated at 80.degree. C.
for 4.5 hours, then cooled and poured on to ice. The solid is
collected by filtration, washed with water and dried. The two
isomers are separated by silica gel chromatography, utilizing a
99:1 to 85:15 gradient of ethyl acetate/methanol. The less polar
material, 0.062 g of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is
obtained as yellow solid, mp 235-237.degree. C.
[1368] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.22
(d, 2H, J=11.5 Hz); 8.4 (s, 1H); 8.04 (d, 1H, J=1.4 Hz); 7.96 (d,
1H, J=1.4 Hz); 7.92 (d, 1H, J=1.7 Hz); 7.81 (m, 3H); 7.55 (dd, 1H,
J=1.7 Hz, 6.4 Hz); 7.43 (s, 1H); 7.30 (d, 1H, J=6.4 Hz); 4.98 (t,
2H, J=3.8 Hz); 4.79 (t, 2H, J=3.8 Hz); 3.96 (s, 3H); 3.84 (s,
3H).
[1369] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.23ClN.sub.8O.sub.2S: 583.1, found (M+H).sup.+
582.7
[1370] Analysis for C.sub.29H.sub.23ClN.sub.8O.sub.2S.1H.sub.2O
[1371] Calcd: C, 57.94; H, 4.19; N, 18.64.
[1372] Found: C, 57.73; H, 4.10; N, 18.65.
[1373] The more polar material, 0.087 g of
4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-
-(2-[1,2,3]triazol-1-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, is
obtained as an orange solid, mp 201-207.degree. C.
[1374] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.24
(d, 2H J=8.9 Hz); 8.4 (s,1H); 8.24 (s,1H); 8.06 (d,1H, J=1.2 Hz);
7.98 (d,1H, J=1.2 Hz); 7.93 (d,1H, J=1.5 Hz); 7.78 (d, 2H, J=5.1
Hz); 7.57 (dd,1H, J=1.5 Hz, 6.3 Hz); 7.43 (s,1H); 7.33 (d,1H, J=6.4
Hz); 4.99 (t, 2H, J=4.0 Hz); 4.71 (t, 2H, J=3.6 Hz); 4.00 (s, 3H);
3.86 (s, 3H).
[1375] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.23ClN.sub.8O.sub.2S: 583.1, found (M+H).sup.+
582.7
[1376] Analysis for C.sub.29H.sub.23ClN.sub.8O.sub.2S.2H.sub.2O
[1377] Calcd: C, 56.26; H, 4.40; N, 18.10.
[1378] Found: C, 56.34; H, 4.19; N, 17.83.
EXAMPLE 155
4-(2,4-Dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-
-3-carbonitrile
[1379] A mixture of 0.7 g (2.46 mmol) of
4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.57
g (2.95 mmol) of 2,4-dichloro-5-methoxyaniline and 0.28 g (2.46
mmol) of pyridine hydrochloride in 7 mL of 2-ethoxyethanol is
heated at 120.degree. C. for 2 hours, then cooled to room
temperature. The product mixture is diluted with saturated solution
of sodium bicarbonate and stirred for 15 minutes. The resulting
solid is collected by filtration, washed with water and dried. The
crude product is purified by silica gel chromatography, utilizing a
98:2 to 90:10 gradient of methylene chloride/methanol to give 0.71
g of
4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinolin-
e-3-carbonitrile as a yellow solid, mp, 238-240.degree. C.
[1380] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.31
(s, 1H); 9.22 (s, 1H); 8.28 (s, 1H); 7.89 (s, 1H); 7.64 (s, 1H);
7.44 (s, 1H); 7.41 (s, 1H); 4.03 (s, 3H); 3.91 (s, 3H);
[1381] MS (ES, positive ion mode): m/z calcd for
C.sub.22H.sub.15Cl.sub.2N.sub.3O.sub.3: 440.3, found (M+H).sup.+
439.7
[1382] Analysis for
C.sub.22H.sub.15Cl.sub.2N.sub.3O.sub.3.1.0H.sub.2O
[1383] Calcd: C, 57.65; H, 3.74; N, 9.17.
[1384] Found: C, 57.80; H, 3.94; N, 8.82.
EXAMPLE 156
8-(3-Chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g-
]quinoline-3-carbonitrile
[1385] Following the procedure of Example 148, 0.43 g (0.98 mmol)
of L20350-72-A is reacted with 0.31 g (1.25 mmol) of 3-chloropropyl
p-toluene sulfonate and 0.48 g of (1.47 mmol) of cesium carbonate,
then an additional 0.05 g (0.2 mmol) of 3-chloropropyl p-toluene
sulfonate and 0.07 g (0.2 mmol) of cesium carbonate in 6 mL of dry
dimethyl formamide. The crude product is purified by silica gel
flash chromatography, utilizing a 99.5:0.5 to 99:1 gradient of
methylene chloride/methanol to give 0.71 g of
8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[-
g]quinoline-3-carbonitrile as a yellow solid, mp 220-223.degree.
C.
[1386] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.35
(s, 1H); 9.25 (s, 1H); 8.44 (s, 1H); 7.87 (s, 1H); 7.77 (s, 1H);
7.61 (s, 1H); 7.47 (s, 1H); 4.41 (t, 2H, J=4.5 Hz); 4.06 (s, 3H);
3.93 (s, 31; 3.88 (t, 2H, J=4.8 Hz); 2.35 (m, 2H).
[1387] MS (ES, positive ion mode): m/z calcd for
C.sub.25H.sub.20Cl.sub.3N.sub.3O.sub.3: 516.8, found (M+H).sup.+
517.6
[1388] Analysis for
C.sub.23H.sub.20Cl.sub.3N.sub.3O.sub.3.0.5H.sub.2O
[1389] Calcd: C, 57.10; H, 4.03; N, 7.99.
[1390] Found: C, 57.01; H, 4.00; N, 7.86.
EXAMPLE 157
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl
propoxy)benzo[g]quinoline-3-carbonitrile
[1391] Following procedure 1 of Example 149, a mixture of 0.105 g
(0.20 mmol) of
8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-meth-
oxybenzo[g]quinoline-3-carbonitrile, 0.3 mL of morpholine and 0.01
g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under
reflux for 7 hours. The resulting solid is purified by silica gel
chromatography, utilizing a 98:2 to 94:6 gradient of methylene
chloride/methanol to give 0.089 g of
4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholinyl-propoxy)-
benzo[g]quinoline-3-carbonitrile as a yellow solid, mp
205-208.degree. C.
[1392] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.37
(s, 1H); 9.26 (s, 1H); 8.44 (s, 1H); 7.88 (s, 1H); 7.73 (s, 1H);
7.63 (s, 1H); 7.49 (s, 1H); 4.39 (t, 2H, J=5.5 Hz); 4.09 (m, 2H);
4.05 (s, 3H); 3.93 (s, 3H); 3.75 (t, 2H, J=11.7 Hz); 3.60 (d, 2H,
J=12.2 Hz); 3.42 (t, 2H, J=7.0 Hz); 3.21 (t, 2H, J=9.3 Hz); 2.35
(m, 2H).
[1393] MS (ES, positive ion mode): m/z calcd for
C.sub.29H.sub.28Cl.sub.2N.sub.4O.sub.4: 567.5, found (M+H).sup.+
566.7
[1394] Analysis for
C.sub.29H.sub.28Cl.sub.2N.sub.4O.sub.4.1.7H.sub.2O
[1395] Calcd: C, 58.23; H, 5.29; N, 9.37.
[1396] Found: C, 57.91; H, 5.15; N, 9.12.
EXAMPLE 158
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl-e-
thoxy)benzo[g]quinoline-3-carbonitrile and
EXAMPLE 159
4-(2,4-Dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-1-yl-e-
thoxy)benzo[g]quinoline-3-carbonitrile
[1397] Following the procedure of Example 148, 0.28 g (0.64 mmol)
of
4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinolin-
e-3-carbonitrile is reacted with 0.18 g (0.76 mmol) of
2-chloroethyl p-toluene sulfonate and 0.3 g of (0.92 mmol) of
cesium carbonate, then an additional 0.05 g (0.2 mmol) of
2chloroethyl p-toluene sulfonate and 0.07 g (0.2 mmol) of cesium
carbonate in 5 mL of dry dimethyl formamide. This yields 0.31 g of
8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g-
]quinoline-3-carbonitrile as a brown solid.
[1398] MS (ES, positive ion mode): m/z calcd for
C.sub.28H.sub.23Cl.sub.2N.sub.5O.sub.2S: 502.8, found (M+H).sup.+
503.7
[1399] A mixture of 0.31 g (0.62 mmol) of
8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g-
]quinoline-3-carbonitrile, 0.36 mL (6.1 mmol) of 1H-1,2,3-triazole
and 0.11 g (2.8 mmol) of sodium hydroxide powder in 5 mL of
N,N-dimethyl formamide is heated at 80.degree. C. for 4.5 hours,
then cooled and poured on to ice. The solid is collected by
filtration, washed with water and dried. The two isomers are
separated by silica gel flash chromatography, using first 7:3 ethyl
acetate/hexane, then a 100:0 to 9:1 gradient of ethyl
acetate/methanol. The less polar material, 0.071 g of
4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, is obtained as yellow
solid, mp 285-287.degree. C.
[1400] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.34
(s, 1H); 9.22 (s,1H); 8.44 (s, 1H); 7.84(s, 1H); 7.79 (s, 2H); 7.77
(s, 1H); 7.60(s, 1H); 7.46 (s, 1H); 5.01 (t, 2H, J=3.8 Hz); 4.84
(t, 2H, J=3.7 Hz); 4.00 (s, 3H); 3.94 (s, 3H).
[1401] MS (ES, positive ion mode): m/z calcd for
C.sub.26H.sub.20Cl.sub.2N.sub.6O.sub.3: 535.4, found (M+H).sup.+
534.6
[1402] Analysis for
C.sub.26H.sub.20Cl.sub.2N.sub.6O.sub.3.0.5H.sub.2O
[1403] Calcd: C, 57.36; H, 3.89; N, 15.44.
[1404] Found: C, 57.45; H, 3.86; N, 15.14.
[1405] The more polar material, 0.053 g of
4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-1-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile, is obtained as brown
solid, mp 245.degree. C. (dec).
[1406] .sup.1HNMR (d.sup.6-DMSO+trifluoroacetic acid): .delta. 9.35
(s, 1H); 9.27 (s, 1H); 8.42 (s, 1H); 8.25 (d, 1 .mu.l, J=0.6 Hz);
7.89 (s, 1H); 7.79 (d, 2H, J=3.3 Hz); 7.64 (s, 1H); 7.44 (s, 1H);
5.0 (t, 2H, J=3.8 Hz); 4.72 (t, 2H, J=3.7 Hz); 4.03 (s, 3H); 3.91
(s, 3H).
[1407] MS (ES, positive ion mode): m/z calcd for
C.sub.26H.sub.20Cl.sub.2N.sub.6O.sub.3: 535.4, found (M+H).sup.+
534.6
[1408] Analysis for
C.sub.26H.sub.20Cl.sub.2N.sub.6O.sub.3.1.3H.sub.2O
[1409] Calcd: C, 55.88; H, 4.08; N, 15.04.
[1410] Found: C, 55.97; H, 4.05; N, 14.86.
EXAMPLE 160
Methyl 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate
[1411] To a mixture of 7.00 g (33.15 mmol) of 6-nitroveratraldehyde
(80%) and 3.4 mL (38.42 mmol) of methyl cyanoacetate in 70 mL of
methanol is added 0.7 mL of piperidine. An additional 100 mL of
methanol is added and the thick suspension is warmed slightly until
the mixture stirred freely. After stirring at room temperature for
1 hour, the solids are collected by filtration washing with
methanol followed by diethyl ether to give 7.57 g (78%) of methyl
2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate as a pale
yellow solid, mp 162-164.degree. C.
[1412] MS 292.1 (M+H).sup.+
[1413] Analysis for C.sub.13H.sub.12N.sub.2O.sub.6
[1414] Calcd: C, 53.43; H, 4.14; N, 9.59.
[1415] Found: C, 53.03; H, 4.02; N, 9.59.
EXAMPLE 161
Methyl 2-amino-6,7-dimethoxy-3-quinolinecarboxylate
[1416] To methyl
2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate (7.00 g, 23.97
mmol) in 100 mL of acetic acid is added 5.00 g (89.6 mmol) of iron.
The mixture is heated at reflux for 10 minutes, cooled slightly,
filtered, and washed with ethyl acetate. The filtrate is
concentrated in vacuo and partitioned between ethyl acetate and
saturated sodium bicarbonate. The organic layer is dried over
magnesium sulfate, filtered and concentrated in vacuo to provide
652 mg (10%) of product as a pale yellow solid. The aqueous layer
is acidified with acetic acid and the resultant solid is collected
by filtration, washing with water and ethyl acetate to provide 1.57
g (25%) of methyl 2-amino-6,7-dimethoxy-3-quinolinecarboxylate as a
pale yellow solid, mp 227-229.degree. C.
[1417] MS 263.1 (M+H).sup.+
[1418] Analysis for C.sub.13H.sub.14N.sub.2O.sub.4
[1419] Calcd: C, 59.54; H, 5.38; N, 10.68.
[1420] Found: C, 59.56; H, 5.46; N, 10.55.
EXAMPLE 162
Methyl
2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinoline-
carboxylate
[1421] A mixture of methyl
2-amino-6,7-dimethoxy-3-quinolinecarboxylate (3.60 g, 13.04 mmol)
and 4.10 g of dimethylformamide dimethylacetal in 60 mL of toluene
containing 40 mg of p-toluenesulfonic acid is heated at reflux for
2 hours. Upon cooling to room temperature a solid formed and is
collected by filtration to provide 736 mg of methyl
2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarbox-
ylate as an off-white solid, mp 166-168.degree. C.
[1422] MS 318.1, 319.0 (M+H).sup.+
[1423] Analysis for C.sub.16H.sub.19N.sub.3O.sub.4
[1424] Calcd: C, 60.56; H, 6.03; N, 13.24.
[1425] Found: C, 60.63; H, 6.08; N, 13.32.
[1426] The filtrate is concentrated in vacuo to provide an
additional 2.86 g of methyl
2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarbox-
ylate.
EXAMPLE 163
7,8-Dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile
[1427] Acetonitrile (1.3 mL, 24.9 mmol) is added to a -78.degree.
C. solution of 9.0 mL of 2.5 M n-butyllithium (22.5 mmol) in 40 mL
of tetrahydrofuran. After stirring at -78.degree. C. for 15 min a
solution of 2.86 g (9.02 mmol) of methyl
2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarbox-
ylate in 100 mL of tetrahydrofuran is added dropwise over 30
minutes. After stirring at -78.degree. C. for 30 minutes, the
reaction mixture is allowed to warm to room temperature and then
stirred at room temperature for 1 hour. The reaction mixture is
cooled to -78.degree. C. and 3.0 mL of acetic acid is added. The
mixture is then stirred at room temperature for 40 min. The solids
are collected by filtration washing with water, methanol and ethyl
acetate to provide 1.11 g (44%) of
7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile
as a light yellow solid, mp>300.degree. C.
[1428] MS 281.9 (M+H).sup.+
[1429] Analysis for C.sub.15H.sub.11N.sub.3O.sub.3.0.65H.sub.2O
[1430] Calcd: C, 61.49; H, 4.23; N, 14.34.
[1431] Found: C, 61.40; H, 4.40; N, 14.70.
EXAMPLE 164
4-Chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile
[1432] A mixture of
7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile
(500 mg, 1.78 mmol) and 5 mL of phosphorous oxychloride is heated
at reflux for one hour then cooled to room temperature. Hexane (20
mL) is added and the resultant solids are collected by filtration
washing with hexane, water, methanol and ethyl acetate to provide
258 mg (49%) of
4-chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile as
a brown solid, mp>300.degree. C.
[1433] MS 299.9, 302.0 (M+H).sup.+
[1434] Analysis for
C.sub.15H.sub.10ClN.sub.3O.sub.2.0.40H.sub.2O
[1435] Calcd: C, 58.70; H, 3.55; N, 13.69.
[1436] Found: C, 58.85; H, 3.33; N, 13.97.
EXAMPLE 165
4-(2,4-Dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine--
3-carbonitrile
[1437] A mixture of
4-chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile
(150 mg, 0.50 mmol), 2,4-dichloro-5-methoxyaniline (160 mg, 0.83
mmol) and pyridine hydrochloride (70 mg, 0.60 mmol) in 15 mL of
2-ethoxyethanol is heated at reflux for 25 minutes then cooled to
room temperature. The solution is partitioned between ethyl acetate
and saturated sodium bicarbonate. The organic layer is dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
is partitioned between ethyl acetate and an aqueous solution of
sodium hydroxide and sodium bicarbonate (pH 14). The organic layer
is dried over magnesium sulfate, filtered and concentrated in
vacuo. Diethyl ether is added to the residue and the resultant
bright orange solid is collected to provide 86 mg (38%) of
4-(2,4-dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyrid-
ine-3-carbonitrile, mp 297.degree. C. dec.
[1438] MS 455.0, 457.00 (M+H).sup.+
[1439] Analysis for C.sub.22H.sub.16Cl.sub.2N.sub.4O.sub.3
[1440] Calcd: C, 58.04; H, 3.54; N, 12.31.
[1441] Found: C, 57.86; H, 3.48; N, 12.30.
EXAMPLE 166
4-(2-Chloroethoxy)-5-methoxy-2-nitrobenzaldehyde
[1442] Fuming nitric acid (10 mL) is added dropwise to a
-40.degree. C. suspension of 5.00 g (23.36 mmol) of
4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et.
al., J. Med. Chem., 42(4), 649-658, 1999) in 23 mL of
1,2-dichloroethane. The reaction mixture is slowly allowed to warn
to -10.degree. C. The mixture is poured onto 300 mL of ice water
and then extracted with ethyl acetate. The organic layer is dried
over magnesium sulfate, filtered and concentrated in vacuo. Diethyl
ether is added to the residue and the pale yellow solid is
collected by filtration to provide 2.43 g (40%) of
4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp
148-150.degree. C.
[1443] MS 260.1, 262.1 (M+H).sup.+
[1444] Analysis for C.sub.10H.sub.10ClNO.sub.5
[1445] Calcd: C, 46.26; H, 3.88; N, 5.39.
[1446] Found: C, 46.64; H, 3.60; N, 5.21.
EXAMPLE 167
Methyl
(2E)-2-cyano-3-(4-[2-chloroethoxy]-5-methoxy-2-nitrophenyl)-2-prope-
noate
[1447] To a mixture of 3.00 g (11.58 mmol) of
4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde and 1.5 mL (16.95
mmol) of methyl cyanoacetate in 30 mL of methanol is added 0.3 mL
of piperidine. The mixture is heated at reflux for 5 minutes then
cooled slightly and the thick suspension is collected by filtration
washing with ethyl acetate followed by diethyl ether to give 1.07 g
(27%) of methyl
(2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate
as a yellow solid, mp softens at 121.degree. C., melts at
157-160.degree. C.
[1448] MS 340.1, 342.1 (M+H).sup.+
[1449] Analysis for C.sub.14H.sub.13ClN.sub.2O.sub.6
[1450] Calcd: C, 49.35; H, 3.85; N, 8.22.
[1451] Found: C, 49.56; H, 3.90; N, 8.26.
EXAMPLE 168
Methyl
2-Amino-7-[2-chloroethoxy-6-methoxy-3-quinolinecarboxylate
[1452] To methyl
(2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate
(19.3 g, 56.6 mmol) in 250 mL of acetic acid is added portionwise
12.0 g (215.0 mmol) of iron. The mixture is heated at reflux for 20
minutes, cooled slightly and filtered washing with ethyl acetate.
The filtrate is concentrated in vacuo and water is added to the
residue. The resulting yellow solid is collected by filtration
washing with water to provide 14.6 g of methyl
2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate. An
analytical sample is obtained by stirring a portion of the product
with a mixture of methanol and aqueous ammonium hydroxide. The
undissolved solids are removed by filtration. Upon standing solids
appeared in the filtrate and are collected to provide methyl
2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate as
light yellow crystals, mp 145-157.degree. C.
[1453] MS 311.0, 313.0 (M+H).sup.+
[1454] Analysis for C.sub.14H.sub.15ClN.sub.2O.sub.4
[1455] Calcd: C, 54.11; H, 4.87; N, 9.02.
[1456] Found: C, 53.88; H, 4.84; N, 8.99.
EXAMPLE 169
Methyl
7-(2-chloroethoxy)-2-{[(1E)-(dimethylamino)methylidene]amino}-6-met-
hoxy-3-quinolinecarboxylate
[1457] A mixture of methyl
2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate (5.00
g, 16.09 mmol) and 5.10 g of dimethylformamide dimethylacetal in 75
mL of toluene containing 50 mg of p-toluenesulfonic acid is heated
at reflux for 10 minutes then cooled to room temperature. Diethyl
ether is added and the solids are collected by filtration to
provide 3.81 g of methyl
7-(2-chloroethoxy)-2-{[(1E)-(dimethylamino)methylidene]amino}-6-methoxy-3-
-quinolinecarboxylate as a pale yellow solid, mp 108-110.degree.
C.
[1458] MS 366.1, 368.1 (M+H).sup.+
[1459] Analysis for
C.sub.17H.sub.20ClN.sub.3O.sub.4.0.5H.sub.2O
[1460] Calcd: C, 54.47; H, 5.65; N, 11.21.
[1461] Found: C, 54.86; H, 5.62; N, 10.89.
EXAMPLE 170
8-(2-Chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-
-carbonitrile
[1462] Acetonitrile (1.4 mL, 26.8 mmol) is added to a -78.degree.
C. solution of 9.6 mL of 2.5 M n-butyllithium (24.0 mmol) in 50 mL
of tetrahydrofuran. After stirring at -78.degree. C. for 15 min, a
solution of 3.50 g (9.02 mmol) of methyl
7-(2-chloroethoxy)-2-{[(1E)-dimethylamino)methylidene]amino}-6-methoxy-3--
quinolinecarboxylate in 100 mL of tetrahydrofuran is added dropwise
over 35 minutes. After stirring at -78.degree. C. for 30 minutes,
the reaction mixture is allowed to warm to room temperature and
then stirred at room temperature for 1 hour. The reaction mixture
is cooled to -78.degree. C. and 3.2 mL of acetic acid is added. The
mixture is stirred at room temperature for 35 minutes. The solids
are collected by filtration washing with water, methanol and ethyl
acetate to provide 1.59 g (50%) of product. An analytical sample is
obtained by heating a portion of the product with methanol and
filtering the hot solution to provide
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine--
3-carbonitrile as a tan solid, mp 280.degree. C. dec.
[1463] MS 327.6 (M+H).sup.+
[1464] Analysis for
C.sub.16H.sub.12ClN.sub.3O.sub.3.2.0H.sub.2O
[1465] Calcd: C, 52.54; H, 4.41; N, 11.49.
[1466] Found: C, 52.26; H, 4.47; N, 11.49.
EXAMPLE 171
4-Chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonit-
rile
[1467] A mixture of
8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine--
3-carbonitrile (2.29 g, 6.96 mmol) and 15 mL of phosphorous
oxychloride is heated at reflux for one hour then cooled to room
temperature. The resultant solids are collected by filtration
washing with hexane, water, methanol and ethyl acetate to provide
929 mg (38%) of product. Upon standing, an additional 155 mg of
product is obtained from the filtrate. This solid is stirred in
methanol, filtered and washed with methanol and ethyl acetate to
provide an analytical sample of
4-chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carboni-
trile as a mustard yellow solid, mp 265.degree. C. dec.
[1468] MS 348.0, 350.0 (M+H).sup.+
[1469] Analysis for
C.sub.16H.sub.11Cl.sub.2N.sub.3O.sub.2.0.50H.sub.2O
[1470] Calcd: C, 53.80; H, 3.39; N, 11.76.
[1471] Found: C, 54.16; H, 3.19; N, 12.10.
EXAMPLE 172
8-(2-Chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,8-
]naphthyridine-3-carbonitrile
[1472] A mixture of
4-chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carboni-
trile (500 mg, 1.43 mmol) and 2,4-dichloro-5-methoxyaniline (460
mg, 2.39 mmol) in 40 mL of 2-ethoxyethanol is heated at reflux for
20 minutes then cooled to room temperature. The solution is
partitioned between ethyl acetate and saturated sodium bicarbonate.
The organic layer is dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue is partitioned between ethyl
acetate and an aqueous solution of sodium hydroxide and sodium
bicarbonate (pH 14). The organic layer is dried over magnesium
sulfate, filtered and concentrated in vacuo. Ethyl acetate and
diethyl ether are added to the residue and the resultant orange
solid is collected by filtration to provide 297 mg (41%) of
8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,-
8]naphthyridine-3-carbonitrile, mp 227-230.degree. C. dec.
[1473] MS 502.8, 504.6, 505.0 (M+H).sup.+
[1474] Analysis for
C.sub.23H.sub.17Cl.sub.3N.sub.4O.sub.3.0.50H.sub.2O
[1475] Calcd: C, 53.87; H, 3.54; N, 10.93.
[1476] Found: C, 54.09; H, 3.36; N, 10.91.
EXAMPLE 173
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]ben-
zo[b][1,8]naphthyridine-3-carbonitrile
[1477] A mixture of
8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,-
8]naphthyridine-3-carbonitrile (202 mg, 0.40 mmol) and sodium
iodine (70 mg, 0.47 mmol) in 4 mL of morpholine is heated at reflux
for 2 hours. The reaction mixture is concentrated in vacuo and
partitioned between ethyl acetate and water. The organic layer is
washed with saturated sodium bicarbonate, dried over magnesium
sulfate, filtered and concentrated in vacuo. Ethyl acetate is added
to the residue and the orange solid is collected by filtration to
provide 105 mg (47%) of
4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]be-
nzo[b][1,8]naphthyridine-3-carbonitrile, mp 242-244.degree. C.
dec.
[1478] MS 553.8, 555.8 (M+H).sup.+
[1479] Analysis for C.sub.27H.sub.25Cl.sub.2N.sub.5O.sub.4
[1480] Calcd: C, 58.49; H, 4.54; N, 12.63.
[1481] Found: C, 58.41; H, 4.23; N, 12.48.
[1482] The following compound is made by the method of example
172:
EXAMPLE 174
8-(2-Chloroethoxy-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anili-
no}-7-methoxybenzo[b]1,8]naphthyridine-3-carbonitrile
[1483]
8-(2-Chloroethoxy)-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfa-
nyl]anilino}-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile is
obtained as a yellow solid, mp>250.degree. C. dec.
[1484] MS 552.7 (M+H).sup.+
[1485] The following compounds are made by the method of example
173:
EXAMPLE 175
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)e-
thoxy]benzo[b][1,8]naphthyridine-3-carbonitrile
[1486]
4-(2,4-Dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piper-
azinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile is obtained
as a yellow solid, mp 240-243.degree. C. dec.
[1487] MS 566.9 (M+H).sup.+
EXAMPLE 176
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-methoxy-8-[2-
-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile
[1488]
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-meth-
oxy-8-[2-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile
is obtained as a red solid, mp 160-162.degree. C. dec.
[1489] MS 601.7 (M+H).sup.+
[1490] The following compounds are made by the method of example
165:
EXAMPLE 177
4-(2,4-Dichloroanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonit-
rile
[1491]
4-(2,4-Dichloroanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3--
carbonitrile is obtained as a yellow-orange solid, mp
266-270.degree. C. dec.
[1492] MS 424.7 (M+H).sup.+
EXAMPLE 178
7,8-Dimethoxy-4-(3,4,5-trimethoxyanilino)benzo[b][1,8]naphthyridine-3-carb-
onitrile
[1493]
7,8-Dimethoxy-4-(3,4,5-trimethoxyanilino)benzo[b][1,8]naphthyridin-
e-3-carbonitrile is obtained as an orange solid, mp 250-252.degree.
C. dec.
[1494] MS 446.7 (M+H).sup.+
[1495] The following compounds are made by the method of examples
122 and 123:
EXAMPLE 179
8-(2-Chloroethoxy)-4-(4-chloro-5-methoxy-2-methylanilino)-7-ethoxybenzo[g]-
quinoline-3-carbonitrile
[1496] After purification by silica gel chromatography,
8-(2-chloroethoxy)-4-(4-chloro-5-methoxy-2-methylanilino)-7-ethoxybenzo[g-
]quinoline-3-carbonitrile is obtained as yellow crystals, mp
129-130.degree. C.
[1497] MS 496.1 (M+H).sup.+
EXAMPLE 180
8-(2-Chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-7-methoxybenzo[g-
]quinoline-3-carbonitrile and
EXAMPLE 181
7-(2-Chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-8-methoxybenzo[g-
]quinoline-3-carbonitrile
[1498] The reaction of 2-chloro-4-fluoro-5-methoxyaniline (prepared
by the procedure described in WO 8501939) with
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture), yields a 1:1 mixture of
8-(2-chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-7methoxybenzo[g-
]quinoline-3-carbonitrile and
7-(2-chloroethoxy)-4-(2-chloro-4-fluoro-5-methoxyanilino)-8-methoxybenzo[-
g]quinoline-3-carbonitrile as a yellow solid,
[1499] mp 193-204.degree. C.
[1500] MS (M+H).sup.+ 486.1
EXAMPLE 182
8-(2-Chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-7-methoxyben-
zo[g]quinoline-3-carbonitrile and
EXAMPLE 183
7-(2-Chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-8-methoxyben-
zo[g]quinoline-3-carbonitride
[1501] The reaction of 2-chloro-5-methoxy-4-methylaniline (prepared
by the procedure described in Theodoridis, G., Pesticide Science,
30(3), 259 (1990)) with
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture), yields a 1:1 mixture of
8-(2-chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-7-methoxybe-
nzo[g]quinoline-3-carbonitrile and
7-(2-chloroethoxy)-4-(2-chloro-5-methoxy-4-methylphenylamino)-8-methoxybe-
nzo[g]quinoline-3-carbonitrile as a yellow solid, mp
222-236.degree. C.
[1502] MS (M+H).sup.+ 482.0
EXAMPLE 184
7-(2-Chloroethoxy)-4-(3-chloro-4-fluoroanilino)-8-methoxybenzo[g]quinoline-
-3-carbonitrile and
EXAMPLE 185
8-(2-Chloroethoxy)-4-(3-chloro-4-fluoroanilino)-7-methoxybenzo[g]quinoline-
-3-carbonitrile
[1503] A 1:1 mixture of
7-(2-chloroethoxy)-4-(3-chloro-4-fluoroanilino)-8-methoxybenzo[g]quinolin-
e-3-carbonitrile and
8-(2-chloroethoxy)-4-(3-chloro-4-fluoroanilino)-7-methoxybenzo[g]quinolin-
e-3-carbonitrile is obtained as a yellow solid, mp 137-159.degree.
C.
[1504] MS (M+H).sup.+ 456.1
EXAMPLE 186
4-(4-Benzyloxy-3-chlorophenylamino)-7-(2-chloroethoxy)-8-methoxybenzo[g]qu-
inoline-3-carbonitrile and
EXAMPLE 187
4-(4-Benzyloxy-3-chlorophenylamino)-8-(2-chloroethoxy)-7-methoxybenzo[g]qu-
inoline-3-carbonitrile
[1505] The reaction of 4-benzyloxy-3-chloroaniline (prepared by the
procedure described in WO 9609294) with
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture), yields a 1:1 mixture of
4-(4-benzyloxy-3-chlorophenylamino)-7-(2-chloroethoxy)-8-methoxybenzo[g]q-
uinoline-3-carbonitrile and
4-(4-benzyloxy-3-chlorophenylamino)-8-(2-chloroethoxy)-7-methoxybenzo[g]q-
uinoline-3-carbonitrile as a white solid, mp 182-185.degree. C.
[1506] Analysis for C.sub.30H.sub.23Cl.sub.2N.sub.3O.sub.3
[1507] Calcd: C, 66.18; H, 4.26; N, 7.72.
[1508] Found: C, 65.82; H, 4.27; N, 7.63.
EXAMPLE 188
7-(2-Chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-8-methoxybenzo[g]quin-
oline-3-carbonitrile and
EXAMPLE 189
8-(2-Chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-7-methoxybenzo[g]quin-
oline-3-carbonitrile
[1509] The reaction of 3-chloro-4-phenoxyaniline (prepared by the
procedure described in WO 9615118) with
4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
and
4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile
(1:1 mixture), yields a 1:1 mixture of
7-(2-chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-8-methoxybenzo[g]qui-
noline-3-carbonitrile and
8-(2-chloroethoxy)-4-(3-chloro-4-phenoxyphenylamino)-7-methoxybenzo[g]qui-
noline-3-carbonitrile as a white solid.
[1510] MS (M+H).sup.+ 529.9, 531.9
[1511] The following compounds (examples 190-218) are made by the
method of examples 124 and 125:
EXAMPLE 190
4-(4-Chloro-5-methoxy-2-methylanilino)-8-ethoxy-7-[2-(4
morpholinyl)ethoxy]benzo[g]quinoline-3-carbonitrile
[1512]
4-(4-Chloro-5-methoxy-2-methylamino)-8-ethoxy-7-[2-(4-morpholinyl)-
ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as yellow
crystals, mp 195-196.degree. C.
[1513] MS 547.1 (M+H).sup.+
EXAMPLE 191
4-(4-Chloro-5-methoxy-2-methylanilino)-7-ethoxy-8-[2-(4-morpholinyl)ethoxy-
]benzo[g]quinoline-3-carbonitrile
[1514]
4-(4-Chloro-5-methoxy-2-methylanilino)-7-ethoxy-8-[2-(4-morpholiny-
l)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as yellow
crystals, mp 201-203.degree. C.
[1515] MS 547.1 (M+H).sup.+
EXAMPLE 192
({2[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-8-ethoxybenzo[g]qui-
noline-7-yloxy]-ethyl}-ethoxycarbonylmethyl-amino)-acetic acid
ethyl ester
[1516]
({2[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-8-ethoxyben-
zo[g]quinoline-7-yloxy]-ethyl}-ethoxycarbonylmethyl-amino)-acetic
acid ethyl ester is obtained as yellow crystals, mp 70-71.degree.
C.
[1517] MS 649.2 (M+H).sup.+
EXAMPLE 193
({2-[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-7-ethoxybenzo[g]qu-
inoline-8-yloxy]-ethyl}-ethoxycarbonylmethylamino)-acetic acid
ethyl ester
[1518]
({2-[4-(4-Chloro-5-methoxy-2-methylphenylamino)-3-cyano-7-ethoxybe-
nzo[g]quinoline-8-yloxy]-ethyl}-ethoxycarbonylmethylamino)-acetic
acid ethyl ester is obtained as yellow crystals, mp 85-86.degree.
C.
[1519] MS 649.2 (M+H).sup.+
EXAMPLE 194
2-(Carbamoylmethyl-{2-[4-(4-chloro-5-methoxy-2-methylphenylamino)-3-cyano--
7-ethoxybenzo[g]quinolin-8-yloxy]-ethyl}-amino)-acetamide
[1520]
2-(Carbamoylmethyl-{2-[4-(4-chloro-5-methoxy-2-methylphenylamino)--
3-cyano-7-ethoxybenzo[g]quinolin-8-yloxy]-ethyl}-amino)-acetamide
is obtained as yellow crystals, mp 168-170.degree. C.
[1521] MS 591.1 (M+H).sup.+
EXAMPLE 195
4-(2,4-Dichloroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g]quino-
line-3-carbonitrile
[1522]
4-(2,4-Dichloroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo-
[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp
250-252.degree. C. dec.
[1523] MS 522.7 (M+H).sup.+
EXAMPLE 196
4-(2,4-Dichloroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g]quino-
line-3-carbonitrile
[1524]
4-(2,4-Dichloroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo-
[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp
115-19.degree. C. dec.
[1525] MS 522.7 (M+H).sup.+
EXAMPLE 197
8-Methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)-
benzo[g]quinoline-3-carbonitrile
[1526]
8-Methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5-trimethoxy-
anilino)benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid, mp 115-120.degree. C. dec.
[1527] MS 558.3 (M+H).sup.+
EXAMPLE 198
7-Methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)-
benzo[g]quinoline-3-carbonitrile
[1528]
7-Methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]-4-(3,4,5-trimethoxy-
anilino)benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid, mp 95-97.degree. C. dec.
[1529] MS 558.2 (M+H).sup.+
EXAMPLE 199
7-Methoxy-8-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)benzo[g]q-
uinoline-3-carbonitrile
[1530]
7-Methoxy-8-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)b-
enzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp
127-130.degree. C. dec.
[1531] MS 544.9 (M+H).sup.+
EXAMPLE 200
8-Methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)benzo[g]q-
uinoline-3-carbonitrile
[1532]
8-Methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(3,4,5-trimethoxyanilino)b-
enzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp
135-138.degree. C. dec.
[1533] MS 544.9 (M+H).sup.+
EXAMPLE 201
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1-piperazi-
nyl)ethoxy]benzo[g]quinoline-3-carbonitrile
[1534]
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-methyl-1--
piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as
a yellow solid, mp 170-173.degree. C.
[1535] MS (M+H).sup.+ 550.2
EXAMPLE 202
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-methyl-1-piperazi-
n)ethoxy]benzo[g]quinoline-3-carbonitrile
[1536]
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-methyl-1--
piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as
a yellow solid, mp 220-227.degree. C.
[1537] MS (M+H).sup.+ 546.2
EXAMPLE 203
4-(2-Chloro-5-methoxy-4-methylamino)-7-methoxy-8-[2-(4-methyl-1-piperaziny-
l)ethoxy]benzo[g]quinoline-3-carbonitrile
[1538]
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-methyl-1--
piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as
a yellow solid, mp 218-235.degree. C.
[1539] MS (M+H).sup.+ 545.9
EXAMPLE 204
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-hydroxy-1-piperidinyl)ethoxy]-8--
methoxybenzo[g]quinoline-3-carbonitrile
[1540]
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-hydroxy-1-piperidinyl)et-
hoxy]-8-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a
yellow solid, mp 150-160.degree. C.
[1541] MS (M+H).sup.+ 566.7
EXAMPLE 205
4-(3-Chloro-4-fluoroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[g]-
quinoline-3-carbonitrile
[1542]
4-(3-Chloro-4-fluoroanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]-
benzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp
237-242.degree. C.
[1543] MS (M+H).sup.+ 506.8
EXAMPLE 206
4-(2,4-Dichloro-5-methoxyanilino)-8-[2-(4-hydroxy-1-piperidinyl)ethoxy]-7--
methoxybenzo[g]quinoline-3-carbonitrile
[1544]
4-(2,4-Dichloro-5-methoxyanilino)-8-[2-(4-hydroxy-1-piperidinyl)et-
hoxy]-7-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a
yellow solid, mp 193-198.degree. C.
[1545] MS (M+H).sup.+ 566.8
EXAMPLE 207
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-hydroxy-1-piperid-
inyl)ethoxy]benzo[g]quinoline-3-carbonitrile
[1546]
4-(2-Chloro-5-methoxy-4-methylanilino)-8-methoxy-7-[2-(4-hydroxy-1-
-piperidinyl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as
a yellow solid, mp 205-235.degree. C.
[1547] MS (M+H).sup.+ 546.8
EXAMPLE 208
4-(2-Chloro-5-methoxy-4-methylanilino)-7-methoxy-8-[2-(4-hydroxy
1-piperidinyl ethoxy]benzo[g]quinoline-3-carbonitrile
[1548]
4-(2-Chloro-5-methoxy-4-methylanilino)-7-methoxy-8-[2-(4-hydroxy-1-
-piperidinyl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as
a yellow solid, mp 210-215.degree. C.
[1549] MS (M+H).sup.+ 546.8
EXAMPLE 209
4-(2-Chloro-4-fluoro-5-methoxyanilino)-8-methoxy-7-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile
[1550]
4-(2-Chloro-4-fluoro-5-methoxyamino)-8-methoxy-7-[2-(4-morpholinyl-
)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid, mp 204-214.degree. C.
[1551] MS (M+H).sup.+ 536.8
EXAMPLE 210
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethox-
y]benzo[g]quinoline-3-carbonitrile
[1552]
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholin-
yl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid, mp 206-222.degree. C.
[1553] MS (M+H).sup.+ 537.1
EXAMPLE 211
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1-piperazi-
nyl)ethoxy]benzo[g]quinoline-3-carbonitrile
[1554]
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-methoxy-8-[2-(4-methyl-1--
piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile is obtained as
a yellow solid, mp 197-205.degree. C.
[1555] MS (M+H).sup.+ 550.2
EXAMPLE 212
4-(3-Chloro-4-fluoroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]benzo[g]-
quinoline-3-carbonitrile
[1556]
4-(3-Chloro-4-fluoroanilino)-8-methoxy-7-[2-(4-morpholinyl)ethoxy]-
benzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp
205-210.degree. C.
[1557] MS (M+H).sup.+ 506.8
EXAMPLE 213
4-(3-Chloro-4--phenoxyphenylamino)-7-methoxy-8-(2-morpholin-4-yl-ethoxy)be-
nzo[g]quinoline-3-carbonitrile
[1558]
4-(3-Chloro-4-phenoxyphenylamino)-7-methoxy-8-(2-morpholin-4-yl-et-
hoxy)benzo[g]quinoline-3-carbonitrile is obtained as an orange
solid, mp 190-194.degree. C.
[1559] MS (M+H).sup.+ 581.2
EXAMPLE 214
4-(3-Chloro-4-phenoxphenylamino)-8-methoxy-7-(2-morpholin-4-yl-ethoxy)benz-
o[g]quinoline-3-carbonitrile
[1560]
4-(3-Chloro-4-phenoxyphenylamino)-8-methoxy-7-(2-morpholin-4-yl-et-
hoxy)benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid, mp 251-253.degree. C.
[1561] MS (M+H).sup.+ 581.3
EXAMPLE 215
4-(2-Chloro-5-methoxy-4-methylphenylamino)-8-methoxy-7-(2-morpholin-4-yl-e-
thoxy)benzo[g]quinoline-3-carbonitrile
[1562]
4-(2-Chloro-5-methoxy-4-methylphenylamino)-8-methoxy-7-(2-morpholi-
n-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as a
yellow solid, mp 240-241.degree. C.
MS (M+H).sup.+ 533
EXAMPLE 216
4-(2-Chloro-5-methoxy-4-methylphenylamino)-7-methoxy-8-(2-morpholin-4-yl-e-
thoxy)benzo[g]quinoline-3-carbonitrile
[1563]
4-(2-Chloro-5-methoxy-4-methylphenylamino)-7-methoxy-8-(2-morpholi-
n-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as a
yellow solid, mp 220-222.degree. C.
[1564] MS (M+H).sup.+ 533
EXAMPLE 217
4-(4-Benzyloxy-3-chlorophenylamino)-8-methoxy-7-(2-morpholin-4-yl-ethoxy)b-
enzo[g]quinoline-3-carbonitrile
[1565]
4-(4-Benzyloxy-3-chlorophenylamino)-8-methoxy-7-(2-morpholin-4-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid.
[1566] Analysis for
C.sub.34H.sub.31ClN.sub.4O.sub.4.0.3H.sub.2O
[1567] Calcd: C, 68.00; H, 5.30; N, 9.33.
[1568] Found: C, 67.67; H, 5.14; N, 9.29.
[1569] MS (M+H).sup.+ 595.1
EXAMPLE 218
4-(4-Benzyloxy-3-chlorophenylamino)-7-methoxy-8-(2-morpholin-4-yl-ethoxy)b-
enzo[g]quinoline-3-carbonitrile
[1570]
4-(4-Benzyloxy-3-chlorophenylamino)-7-methoxy-8-(2-morpholin-4-yl--
ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as a yellow
solid.
[1571] Analysis for
C.sub.34H.sub.31ClN.sub.4O.sub.4.1.5H.sub.2O
[1572] Calcd: C, 65.64; H, 5.51; N, 9.01.
[1573] Found: C, 65.85; H, 5.28; N, 8.99.
[1574] MS (M+H).sup.+ 595.1
EXAMPLE 219
8-(Benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[-
g]quinoline-3-carbonitrile
[1575] A mixture of
8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile
(11.4 g, 31.9 mmol) and phosphorus oxychloride (147 g, 959 mmol) is
heated under reflux for one hour. After cooling to room
temperature, the reaction mixture is evaporated under vacuum to
remove the volatiles. The residue is carefully slurried in cold
saturated aqueous sodium bicarbonate solution (500 mL). The solids
are collected by filtration, washed thoroughly with saturated
aqueous sodium bicarbonate solution and water and dried to give
11.7 grams of crude
8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile as
a light orange solid.
[1576] A mixture of
8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile
(1.00 g, 2.7 mmol), 2-chloro-4-fluoro-5-methoxyaniline (560 mg, 3.2
mmol), tris(dibenzylideneacetone)dipalladium(0) (240 mg, 0.26
mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (330
mg, 0.84 mmol) and K.sub.3PO.sub.4 (860 mg, 4.1 mmol) in 15 mL of
ethylene glycol dimethyl ether is heated at 80.degree. C. for 3
hours. An additional 5% of all reagents is added and the mixture is
heated at 80.degree. C. for 2 hours then cooled to room temperature
and partitioned between aqueous sodium bicarbonate and methylene
chloride. The organic layer is dried over magnesium sulfate,
filtered and concentrated in vacuo. Purification by column
chromatography eluting with 1:1 hexane/ethyl acetate yields 500 mg
(36%) of
8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo-
[g]quinoline-3-carbonitrile as a yellow solid, mp 248-250.degree.
C. dec.
[1577] MS 514.2 (M+H).sup.+
EXAMPLE 220
4-[(2-Chloro-4-fluoro-5-methoxyphenyl
amino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile
[1578] A mixture of
8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo-
[g]quinoline-3-carbonitrile (1.88 g, 3.70 mmol) and 280 mg of 15%
Pd on carbon in a mixture of 50 mL of methylene chloride and 70 mL
of N,N-dimethylformamide is hydrogenated at 50-40 psi for 15 hours.
The mixture is filtered through Celite and concentrated in vacuo to
a small volume. The yellow solid is collected by filtration to
provide 1.50 g (95%) of
4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-8-hydroxy-7-methoxy-
benzo[g]quinoline-3-carbonitrile, mp 239-242.degree. C. dec.
[1579] MS 424.2 (M+H).sup.+
* * * * *