U.S. patent application number 12/165014 was filed with the patent office on 2009-01-22 for amide substituted imidazoquinolines.
Invention is credited to Patrick L. Coleman, Stephen L. Crooks, George W. Griesgraber, Kyle J. Lindstrom, Bryon A. Merrill, Michael J. Rice.
Application Number | 20090023722 12/165014 |
Document ID | / |
Family ID | 33424856 |
Filed Date | 2009-01-22 |
United States Patent
Application |
20090023722 |
Kind Code |
A1 |
Coleman; Patrick L. ; et
al. |
January 22, 2009 |
AMIDE SUBSTITUTED IMIDAZOQUINOLINES
Abstract
Imidazoquinoline and tetrahydroimidazoquinoline compounds that
contain amide functionality at the 1-position are useful as immune
response modifiers. The compounds and compositions of the invention
can induce the biosynthesis of various cytokines and are useful in
the treatment of a variety of conditions including viral diseases
and neoplastic diseases.
Inventors: |
Coleman; Patrick L.; (Saint
Paul, MN) ; Crooks; Stephen L.; (Mahtomedi, MN)
; Griesgraber; George W.; (Eagan, MN) ; Lindstrom;
Kyle J.; (Houlton, WI) ; Merrill; Bryon A.;
(River Falls, WI) ; Rice; Michael J.; (Oakdale,
MN) |
Correspondence
Address: |
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON
MA
02210-2206
US
|
Family ID: |
33424856 |
Appl. No.: |
12/165014 |
Filed: |
June 30, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10848893 |
May 19, 2004 |
7393859 |
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12165014 |
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10027218 |
Dec 21, 2001 |
6756382 |
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10848893 |
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09589580 |
Jun 7, 2000 |
6451810 |
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10027218 |
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60138365 |
Jun 10, 1999 |
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Current U.S.
Class: |
514/232.8 ;
514/253.03; 514/293 |
Current CPC
Class: |
A61P 33/02 20180101;
A61P 11/06 20180101; A61P 17/02 20180101; A61P 25/00 20180101; A61P
31/08 20180101; A61P 33/08 20180101; A61P 1/16 20180101; A61P 7/04
20180101; A61P 17/04 20180101; A61P 37/02 20180101; A61P 31/10
20180101; A61P 11/02 20180101; A61P 35/02 20180101; A61P 31/12
20180101; A61K 31/4745 20130101; A61P 35/00 20180101; A61P 33/06
20180101; C07D 471/04 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/232.8 ;
514/293; 514/253.03 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/437 20060101 A61K031/437; A61K 31/496
20060101 A61K031/496; A61P 35/00 20060101 A61P035/00; A61P 31/12
20060101 A61P031/12 |
Claims
1.-23. (canceled)
24. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of the formula (Ib): ##STR00226##
wherein R.sub.1 is --C.sub.2-4 alkyl-NR.sub.3--CO--R.sub.4 wherein
R.sub.4 is heterocyclyl which may be unsubstituted or substituted
by one or more substituents selected from the group consisting of:
-alkyl; -alkenyl; -alkynyl, -(alkyl).sub.0-1-aryl;
-(alkyl).sub.0-1-(substituted aryl); -(alkyl).sub.0-1-heterocyclyl;
-(alkyl).sub.0-1-(substituted heterocycyl);
-(alkyl).sub.0-1-heteroaryl; -(alkyl).sub.0-1-(substituted
heteroaryl); --O-alkyl; --O-(alkyl).sub.0-1-aryl;
--O-(alkyl).sub.0-1-(substituted aryl);
--O-(alkyl).sub.0-1-heterocyclyl; --O-(alkyl).sub.0-1-(substituted
heterocyclyl); --O-(alkyl).sub.0-1-heteroaryl;
--O-(alkyl).sub.0-1-(substituted heteroaryl); --CO-aryl;
--CO-(substituted aryl); --CO-heteroaryl; --CO-(substituted
heteroaryl); --COOH; --CO--O-alkyl; --CO-alkyl;
--S(O).sub.0-2-alkyl; --S(O).sub.0-2-(alkyl).sub.0-1-aryl;
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted aryl);
--S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl;
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heterocyclyl);
--S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl;
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl);
--P(O)(OR.sub.3).sub.2; --NR.sub.3--CO--O-alkyl; --N.sub.3;
-halogen; --NO.sub.2; --CN; -haloalkyl; --O-haloalkyl;
--CO-haloalkyl; --OH; --SH; or R.sub.4 is ##STR00227## wherein
R.sub.5 is an aryl, (substituted aryl), heteroaryl, (substituted
heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
R.sub.2 is selected from the group consisting of: -hydrogen;
-alkyl; -alkenyl; -aryl; -(substituted aryl); -heteroaryl;
-(substituted heteroaryl); -heterocyclyl; -(substituted
heterocyclyl); -alkyl-O-alkyl; -alkyl-O-alkenyl; and -alkyl or
alkenyl substituted by one or more substituents selected from the
group consisting of: --OH; -halogen; --N(R.sub.3).sub.2;
--CO--N(R.sub.3).sub.2; --CO--C.sub.1-10alkyl;
--CO--O--C.sub.1-10alkyl; --N.sub.3; -aryl; -(substituted aryl);
-heteroaryl; -(substituted heteroaryl); -heterocyclyl;
-(substituted heterocyclyl); --CO-aryl; and --CO-heteroaryl; each
R.sub.3 is independently selected form the group consisting of
hydrogen; C.sub.1-10alkyl-heteroaryl; C.sub.1-10alkyl-(substituted
heteroaryl); C.sub.1-10alkyl-aryl; C.sub.1-10alkyl-(substituted
aryl) and C.sub.1-10alkyl; n is 0 to 4; and each R present is
independently selected from the group consisting of C.sub.1-10
alkyl, C.sub.1-10alkoxy, halogen and trifluoromethyl, or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable carrier.
25. The pharmaceutical compound of claim 1 wherein R.sub.4 is
heterocyclyl.
26. The pharmaceutical compound of claim 1 wherein R.sub.4 is
substituted heterocyclyl.
Description
FIELD OF THE INVENTION
[0001] This invention relates to imidazoquinoline compounds that
have an amide containing substituent at the 1-position, and to
pharmaceutical compositions containing such compounds. A further
aspect of this invention relates to the use of these compounds as
immunomodulators, for inducing cytokine biosynthesis in animals,
and in the treatment of diseases, including viral and neoplastic
diseases.
BACKGROUND OF THE INVENTION
[0002] The first reliable report on the 1H-imidazo[4,5-c]quinoline
ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950)
describes the synthesis of
1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for
possible use as an antimalarial agent. Subsequently, syntheses of
various substituted 1H-imidazo[4,5-c]quinolines were reported. For
example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968),
synthesized the compound
1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible
anticonvulsant and cardiovascular agent. Also, Baranov et al.,
Chem. Abs. 85, 94362 (1976), have reported several
2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic
Chem. 18, 1537-1540 (1981), have reported certain
2-oxoimidazo[4,5-c]quinolines.
[0003] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and
2-substituted derivatives thereof were later found to be useful as
antiviral agents, bronchodilators and immunomodulators. These are
described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;
4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of
which are incorporated herein by reference.
[0004] There continues to be interest in the imidazoquinoline ring
system. For example, EP 894 797 describes imidazoquinoline
compounds that bear an amide containing substituent at the
1-position. The active compounds of this series require a terminal
amine substituent that may be incorporated into a heterocyclic
ring. As another example, WO 00/09506 describes imidazopyridine and
imidazoquinoline compounds that may have an amide or urea
containing substituent at the 1-position. The compounds described
in this publication as having utility contain a 1-substituent
wherein the amide or urea nitrogen is part of a heterocyclic ring.
Despite these attempts to identify compounds that are useful as
immune response modifiers, there is a continuing need for compounds
that have the ability to modulate the immune response, by induction
of cytokine biosynthesis or other mechanisms.
SUMMARY OF THE INVENTION
[0005] We have found a new class of compounds that are useful in
inducing cytokine biosynthesis in animals. Accordingly, this
invention provides imidazoquinoline-4-amine and
tetrahydroimidazoquinoline-4-amine compounds that have an amide
containing substituent at the 1-position. The compounds which have
been found to be useful inducers of cytokine biosynthesis are
defined by Formulae (I), (Ia), and (Ib), which are defined in more
detail infra. These compounds share the general structural formula
(I):
##STR00001##
wherein R.sub.1, R.sub.2, and R are as defined herein for each
class of compounds having formulas (I), (Ia), and (Ib). The
invention also provides novel compounds of formulas (Ic), (Id), and
(Ie) as defined herein, which compounds are also useful as immune
response modifiers and which also have the same general structural
formula (I) above.
[0006] The compounds of Formulae (I), (Ia), (Ib), (Ic), (Id), and
(Ie) are useful as immune response modifiers due to their ability
to induce cytokine biosynthesis and otherwise modulate the immune
response when administered to animals. This makes the compounds
useful in the treatment of a variety of conditions such as viral
diseases and tumors that are responsive to such changes in the
immune response.
[0007] The invention further provides pharmaceutical compositions
containing the immune response modifying compounds, and methods of
inducing cytokine biosynthesis in an animal, treating a viral
infection in an animal, and/or treating a neoplastic disease in an
animal by administering a compound of Formula (I), (Ia), (Ib),
(Ic), (Id), or (Ie) to the animal.
[0008] In addition, methods of synthesizing the compounds of the
invention and intermediates useful in the synthesis of these
compounds are provided.
DETAILED DESCRIPTION OF THE INVENTION
[0009] As mentioned earlier, we have found that certain compounds
induce cytokine biosynthesis and modify the immune response in
animals. Such compounds are represented by Formulae (I), (Ia),
(Ib), (Ic), (Id), and (Ie), as shown below.
[0010] The invention provides pharmaceutical compositions
containing a therapeutically effective amount of a compound of
Formula (I):
##STR00002##
wherein
[0011] R.sub.1 is -alkyl-NR.sub.3--CO--R.sub.4 or
-alkenyl-NR.sub.3--CO--R.sub.4 wherein R.sub.4 is aryl, heteroaryl,
alkyl or alkenyl, each of which may be unsubstituted or substituted
by one or more substituents selected from the group consisting of:
[0012] -alkyl; [0013] -alkenyl; [0014] -alkynyl; [0015]
-(alkyl).sub.0-1-aryl; [0016] -(alkyl).sub.0-1-(substituted aryl);
[0017] -(alkyl).sub.0-1-heteroaryl; [0018]
-(alkyl).sub.0-1-(substituted heteroaryl); [0019] --O-alkyl; [0020]
--O-(alkyl).sub.0-1-aryl; [0021] --O-(alkyl).sub.0-1-substituted
aryl); [0022] --O-(alkyl).sub.0-1-heteroaryl; [0023]
--O-(alkyl).sub.0-1-(substituted heteroaryl); [0024] --CO-aryl;
[0025] --CO-(substituted aryl); [0026] --CO-heteroaryl; [0027]
--CO-(substituted heteroaryl); [0028] --COOH; [0029] --CO--O-alkyl;
[0030] --CO-alkyl; [0031] --S(O).sub.0-2-alkyl; [0032]
--S(O).sub.0-2-(alkyl).sub.0-1-aryl; [0033]
--S(O).sub.0-2-(alkyl).sub.0-1-substituted aryl); [0034]
--S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl; [0035]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl); [0036]
--P(O)(OR.sub.3).sub.2; [0037] --NR.sub.3--CO--O-alkyl; [0038]
--N.sub.3; [0039] -halogen; [0040] --NO.sub.2; [0041] --CN; [0042]
-haloalkyl; --O-haloalkyl; --CO-haloalkyl; [0043] --OH; [0044]
--SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;
[0045] or R.sub.4 is
##STR00003##
[0046] wherein R.sub.5 is an aryl, (substituted aryl), heteroaryl,
(substituted heteroaryl), heterocyclyl or (substituted
heterocyclyl) group;
[0047] R.sub.2 is selected from the group consisting of: [0048]
-hydrogen; [0049] -alkyl; [0050] -alkenyl; [0051] -aryl; [0052]
-(substituted aryl); [0053] -heteroaryl; [0054] -(substituted
heteroaryl); [0055] -heterocyclyl; [0056] -(substituted
heterocyclyl); [0057] -alkyl-O-alkyl; [0058] -alkyl-O-alkenyl; and
[0059] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of: [0060] --OH; [0061]
-halogen; [0062] --N(R.sub.3).sub.2; [0063] --CO--N(R.sub.3).sub.2;
[0064] --CO--C.sub.1-10 alkyl; [0065] --CO--O--C.sub.1-10 alkyl;
[0066] --N.sub.3; [0067] -aryl; [0068] -(substituted aryl); [0069]
-heteroaryl; [0070] -(substituted heteroaryl); [0071]
-heterocyclyl; [0072] -(substituted heterocyclyl); [0073]
--CO-aryl; and [0074] --CO-heteroaryl;
[0075] each R.sub.3 is independently selected from the group
consisting of hydrogen; C.sub.1-10 alkyl-heteroaryl; C.sub.1-10
alkyl-(substituted heteroaryl); C.sub.1-10 alkyl-aryl; C.sub.1-10
alkyl-(substituted aryl) and C.sub.1-10 alkyl;
[0076] n is 0 to 4;
[0077] and each R present is independently selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkoxy, halogen and
trifluoromethyl, or a pharmaceutically acceptable salt thereof, in
combination with a therapeutically effective carrier.
[0078] The invention also provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
Formula (Ia):
##STR00004##
wherein
[0079] R.sub.1 is -alkyl-NR.sub.3--CO--R.sub.4 or
-alkenyl-NR.sub.3--CO--R.sub.4 wherein R.sub.4 is aryl, heteroaryl,
alkyl or alkenyl, each of which may be unsubstituted or substituted
by one or more substituents selected from the group consisting of:
[0080] -heterocyclyl; [0081] -(substituted heterocyclyl); [0082]
-(alkyl).sub.0-1-heterocyclyl; [0083] -(alkyl).sub.0-1-(substituted
heterocyclyl); [0084] --O-(alkyl).sub.0-1-heterocyclyl; [0085]
--O-(alkyl).sub.0-1(substituted heterocyclyl); [0086]
--S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl; and [0087]
--S(O).sub.0-2-(alkyl).sub.0-1(substituted heterocyclyl);
[0088] R.sub.2 is selected from the group consisting of: [0089]
-hydrogen; [0090] -alkyl; [0091] -alkenyl; [0092] -aryl; [0093]
-(substituted aryl); [0094] -heteroaryl; [0095] -(substituted
heteroaryl); [0096] -heterocyclyl; [0097] -(substituted
heterocyclyl); [0098] -alkyl-O-alkyl; [0099] -alkyl-O-alkenyl; and
[0100] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of: [0101] --OH; [0102]
-halogen; [0103] --N(R.sub.3).sub.2; [0104] --CO--N(R.sub.3).sub.2;
[0105] --CO--C.sub.1-10 alkyl; [0106] --CO--O--C.sub.1-10 alkyl;
[0107] --N.sub.3; [0108] -aryl; [0109] -(substituted aryl); [0110]
-heteroaryl; [0111] -(substituted heteroaryl); [0112]
-heterocyclyl; [0113] -(substituted heterocyclyl); [0114]
--CO-aryl; and [0115] --CO-heteroaryl;
[0116] each R.sub.3 is independently selected from the group
consisting of hydrogen; C.sub.1-10 alkyl-heteroaryl; C.sub.1-10
alkyl-(substituted heteroaryl); C.sub.1-10 alkyl-aryl; C.sub.1-10
alkyl-(substituted aryl) and C.sub.1-10 alkyl;
[0117] n is 0 to 4;
[0118] and each R present is independently selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkoxy, halogen and
trifluoromethyl, or a pharmaceutically acceptable salt thereof, in
combination with a pharmaceutically acceptable carrier.
[0119] The invention further provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
Formula (Ib):
##STR00005##
wherein
[0120] R.sub.1 is -alkyl-NR.sub.3--CO--R.sub.4 or
-alkenyl-NR.sub.3--CO--R.sub.4 wherein R.sub.4 is heterocyclyl
which may be unsubstituted or substituted by one or more
substituents selected from the group consisting of: [0121] -alkyl;
[0122] -alkenyl; [0123] -alkynyl; [0124] -(alkyl).sub.0-1-aryl;
[0125] -(alkyl).sub.0-1-(substituted aryl); [0126]
-(alkyl).sub.0-1-heterocyclyl; [0127] -(alkyl).sub.0-1-(substituted
heterocyclyl); [0128] -(alkyl).sub.0-1-heteroaryl; [0129]
-(alkyl).sub.0-1-(substituted heteroaryl); [0130] --O-alkyl; [0131]
--O-(alkyl).sub.0-1-aryl; [0132] --O-(alkyl).sub.0-1-(substituted
aryl); [0133] --O-(alkyl).sub.0-1-heterocyclyl; [0134]
--O-(alkyl).sub.0-1-(substituted heterocyclyl); [0135]
--O-(alkyl).sub.0-1-heteroaryl; [0136]
--O-(alkyl).sub.0-1-(substituted heteroaryl); [0137] --CO-aryl;
[0138] --CO-(substituted aryl); [0139] --CO-heteroaryl; [0140]
--CO-(substituted heteroaryl); [0141] --COOH; [0142] --CO--O-alkyl;
[0143] --CO-alkyl; [0144] --S(O).sub.0-2-alkyl; [0145]
--S(O).sub.0-2-(alkyl).sub.0-1-aryl; [0146]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted aryl); [0147]
--S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl; [0148]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heterocyclyl); [0149]
--S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl; [0150]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl); [0151]
--P(O)(OR.sub.3).sub.2; [0152] --NR.sub.3--CO--O-alkyl; [0153]
--N.sub.3; [0154] -halogen; [0155] --NO.sub.2; [0156] --CN; [0157]
-haloalkyl; [0158] --O-haloalkyl; [0159] --CO-haloalkyl; [0160]
--OH; [0161] --SH; [0162] or R.sub.4 is
##STR00006##
[0163] wherein R.sub.5 is an aryl, (substituted aryl), heteroaryl,
(substituted heteroaryl), heterocyclyl or (substituted
heterocyclyl) group;
[0164] R.sub.2 is selected from the group consisting of: [0165]
-hydrogen; [0166] -alkyl; [0167] -alkenyl; [0168] -aryl; [0169]
-(substituted aryl); [0170] -heteroaryl; [0171] -(substituted
heteroaryl); [0172] -heterocyclyl; [0173] -(substituted
heterocyclyl); [0174] -alkyl-O-alkyl; [0175] -alkyl-O-alkenyl; and
[0176] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of: [0177] --OH; [0178]
-halogen; [0179] --N(R.sub.3).sub.2; [0180] --CO--N(R.sub.3).sub.2;
[0181] --CO--C.sub.1-10 alkyl; [0182] --CO--O--C.sub.1-10 alkyl;
[0183] --N.sub.3; [0184] -aryl; [0185] -(substituted aryl); [0186]
-heteroaryl; [0187] -(substituted heteroaryl); [0188]
-heterocyclyl; [0189] -(substituted heterocyclyl); [0190]
--CO-aryl; and [0191] --CO-heteroaryl;
[0192] each R.sub.3 is independently selected from the group
consisting of hydrogen; C.sub.1-10 alkyl-heteroaryl; C.sub.1-10
alkyl-(substituted heteroaryl); C.sub.1-10 alkyl-aryl; C.sub.1-10
alkyl-(substituted aryl) and C.sub.1-10 alkyl;
[0193] n is 0 to 4;
[0194] and each R present is independently selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkoxy, halogen and
trifluoromethyl, or a pharmaceutically acceptable salt thereof, in
combination with a pharmaceutically acceptable carrier.
[0195] The invention also provides compounds that are useful as
immune response modifiers. One such class of compounds has
structural Formula (Ic):
##STR00007##
wherein
[0196] R.sub.1 is -alkyl-NR.sub.3--CO--R.sub.4 or
-alkenyl-NR.sub.3--CO--R.sub.4 wherein R.sub.4 is aryl, heteroaryl,
heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted
or substituted by one or more substituents selected from the group
consisting of: [0197] -alkyl; [0198] -alkenyl; [0199] -alkynyl;
[0200] -(alkyl).sub.0-1-aryl; [0201] -(alkyl).sub.0-1-(substituted
aryl); [0202] -(alkyl).sub.0-1-heteroaryl; [0203]
-(alkyl).sub.0-1-(substituted heteroaryl); [0204]
-(alkyl).sub.0-1-heterocyclyl; [0205] -(alkyl).sub.0-1-(substituted
heterocyclyl); [0206] --O-alkyl; [0207] --O-(alkyl).sub.0-1-aryl;
[0208] --O-(alkyl).sub.0-1-(substituted aryl); [0209]
--O-(alkyl).sub.0-1-heteroaryl; [0210]
--O-(alkyl).sub.0-1-(substituted heteroaryl); [0211]
--O-(alkyl).sub.0-1-heterocyclyl; [0212]
--O-(alkyl).sub.0-1-(substituted heterocyclyl); [0213] --CO-aryl;
[0214] --CO-(substituted aryl); [0215] --CO-heteroaryl; [0216]
--CO-(substituted heteroaryl); [0217] --COOH; [0218] --CO--O-alkyl;
[0219] --CO-alkyl; [0220] --S(O).sub.0-2-alkyl; [0221]
--S(O).sub.0-2-(alkyl).sub.0-1-aryl; [0222]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted aryl); [0223]
--S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl; [0224]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl); [0225]
--S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl; [0226]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heterocyclyl); [0227]
--P(O)(OR.sub.3).sub.2; [0228] --NR.sub.6--CO--O-alkyl; [0229]
--N.sub.3; [0230] -halogen; [0231] --NO.sub.2; [0232] --CN; [0233]
-haloalkyl; [0234] --O-haloalkyl; [0235] --CO-haloalkyl; [0236]
--OH; [0237] --SH; and in the case of alkyl, alkenyl, or
heterocyclyl, oxo; [0238] or R.sub.4 is
##STR00008##
[0239] wherein R.sub.5 is an aryl, (substituted aryl), heteroaryl,
(substituted heteroaryl), heterocyclyl or (substituted
heterocyclyl) group;
[0240] R.sub.2 is selected from the group consisting of: [0241]
-hydrogen; [0242] -alkyl; [0243] -alkenyl; [0244] -aryl; [0245]
-(substituted aryl); [0246] -heteroaryl; [0247] -(substituted
heteroaryl); [0248] -heterocyclyl; [0249] -(substituted
heterocyclyl); [0250] -alkyl-O-alkyl; [0251] -alkyl-O-alkenyl; and
[0252] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of: [0253] --OH; [0254]
-halogen; [0255] --N(R.sub.6).sub.2; [0256] --CO--N(R.sub.6).sub.2;
[0257] --CO--C.sub.1-10 alkyl; [0258] --CO--O--C.sub.1-10 alkyl;
[0259] --N.sub.3; [0260] -aryl; [0261] -(substituted aryl); [0262]
-heteroaryl; [0263] -(substituted heteroaryl); [0264]
-heterocyclyl; [0265] -(substituted heterocyclyl); [0266]
--CO-aryl; and [0267] --CO-heteroaryl;
[0268] R.sub.3 is selected from the group consisting of C.sub.1-10
alkyl-heteroaryl; C.sub.1-10 alkyl-(substituted heteroaryl);
C.sub.1-10 alkyl-aryl; C.sub.1-10 alkyl-(substituted aryl) and
C.sub.1-10 alkyl;
[0269] each R.sub.6 is independently selected from the group
consisting of hydrogen; C.sub.1-10 alkyl-heteroaryl; C.sub.1-10
alkyl-(substituted heteroaryl); C.sub.1-10 alkyl-aryl; C.sub.1-10
alkyl-(substituted aryl) and C.sub.1-10 alkyl;
[0270] n is 0 to 4;
[0271] and each R present is independently selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkoxy, halogen and
trifluoromethyl, or a pharmaceutically acceptable salt thereof.
[0272] Another class of compounds provided by the invention is
described by Formula (Id):
##STR00009##
wherein
[0273] R.sub.1 is -alkyl-NR.sub.3--CO--R.sub.4 or
-alkenyl-NR.sub.3--CO--R.sub.4 wherein R.sub.4 is aryl or
heteroaryl which may be unsubstituted or substituted by one or more
substituents selected from the group consisting of: [0274] -alkyl;
[0275] -alkenyl; [0276] -alkynyl; [0277] -(alkyl).sub.0-1-aryl;
[0278] -(alkyl).sub.0-1-(substituted aryl); [0279]
-(alkyl).sub.0-1-heteroaryl; [0280] -(alkyl).sub.0-1-(substituted
heteroaryl); [0281] -(alkyl).sub.0-1-heterocyclyl; [0282]
-(alkyl).sub.0-1-(substituted heterocyclyl); [0283] --O-alkyl;
[0284] --O-(alkyl).sub.0-1-aryl; [0285]
--O-(alkyl).sub.0-1-(substituted aryl); [0286]
--O-(alkyl).sub.0-1-heteroaryl; [0287]
--O-(alkyl).sub.0-1-(substituted heteroaryl); [0288]
--O-(alkyl).sub.0-1-heterocyclyl; [0289]
--O-(alkyl).sub.0-1-(substituted heterocyclyl); [0290] --CO-aryl;
[0291] --CO-(substituted aryl); [0292] --CO-heteroaryl; [0293]
--CO-(substituted heteroaryl); [0294] --COOH; [0295] --CO--O-alkyl;
[0296] --CO-alkyl; [0297] --S(O).sub.0-2-alkyl; [0298]
--S(O).sub.0-2-(alkyl).sub.0-1-aryl; [0299]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted aryl); [0300]
--S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl; [0301]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl); [0302]
--S(O).sub.0-2-(alkyl).sub.0-1-heterocyclyl; [0303]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heterocyclyl); [0304]
--P(O)(OR.sub.3).sub.2; [0305] --NR.sub.3--CO--O-alkyl; [0306]
--N.sub.3; [0307] -halogen; [0308] --NO.sub.2; [0309] --CN; [0310]
-haloalkyl; [0311] --O-haloalkyl; [0312] --CO-haloalkyl; [0313]
--OH; and [0314] --SH;
[0315] R.sub.2 is selected from the group consisting of: [0316]
-hydrogen; [0317] -alkyl; [0318] -alkenyl; [0319] -aryl; [0320]
-(substituted aryl); [0321] -heteroaryl; [0322] -(substituted
heteroaryl); [0323] -heterocyclyl; [0324] -(substituted
heterocyclyl); [0325] -alkyl-O-alkyl; [0326] -alkyl-O-alkenyl; and
[0327] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of: [0328] --OH; [0329]
-halogen; [0330] --N(R.sub.3).sub.2; [0331] --CO--N(R.sub.3).sub.2;
[0332] --CO--C.sub.1-10 alkyl; [0333] --CO--C.sub.1-10 alkyl;
[0334] --N.sub.3; [0335] -aryl; [0336] -(substituted aryl); [0337]
-heteroaryl; [0338] -(substituted heteroaryl); [0339]
-heterocyclyl; [0340] -(substituted heterocyclyl); [0341]
--CO-aryl; and [0342] --CO-heteroaryl;
[0343] each R.sub.3 is independently selected from the group
consisting of hydrogen; C.sub.1-10 alkyl-heteroaryl; C.sub.1-10
alkyl-(substituted heteroaryl); C.sub.1-10 alkyl-aryl; C.sub.1-10
alkyl-(substituted aryl) and C.sub.1-10 alkyl;
[0344] n is 0 to 4;
[0345] and each R present is independently selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkoxy, halogen and
trifluoromethyl, or a pharmaceutically acceptable salt thereof,
[0346] with the proviso that R.sub.4 is not an unsubstituted
benzene ring, and that when R.sub.4 is a substituted benzene ring
the substituents are selected from the group consisting of
C.sub.1-20 alkyl, C.sub.2-20 alkoxy, C.sub.1-20 alkylthio, hydroxy,
haloalkyl, haloalkylcarbonyl, haloalkoxy, C.sub.1-20 alkylcarbonyl,
C.sub.1-20 alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,
heterocycloalkyl, nitrile, C.sub.1-20 alkoxycarbonyl,
C.sub.1-20alkanoyloxy, C.sub.1-20alkanoylthio, oxo and
-(C.sub.1-10-alkyl)-NR.sub.3--(C.sub.1-10-alkyl)-R.sub.5,
[0347] wherein R.sub.5 is an aryl, (substituted aryl), heteroaryl,
(substituted heteroaryl), heterocyclyl or (substituted
heterocyclyl) group.
[0348] A further class of compounds provided by the invention is
described by Formula (Ie):
##STR00010##
wherein
[0349] R.sub.1 is -alkyl-NR.sub.3--CO--R.sub.4 or
-alkenyl-NR.sub.3--CO--R.sub.4 wherein R.sub.4 is an alkyl or
alkenyl group that is substituted by one or more substituents
selected from the group consisting of: [0350] -alkynyl; [0351]
-(substituted aryl) wherein the substituent(s) are independently
selected from the group consisting of alkyl, alkoxy, alkylthio,
hydroxy, haloalkyl, haloalkylcarbonyl, haloalkoxy, alkylcarbonyl,
alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl,
nitrile, alkoxycarbonyl, alkanoyloxy, and alkanoylthio; [0352]
-(substituted aryl); [0353] -heteroaryl; [0354] -(substituted
heteroaryl); [0355] --O-alkyl; [0356]
--O-(alkyl).sub.0-1-(substituted aryl) wherein the substituent(s)
are independently selected from the group consisting of alkyl,
alkoxy, alkylthio, hydroxy, haloalkyl, haloalkylcarbonyl,
haloalkoxy, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocycloalkyl, nitrile, alkoxycarbonyl,
alkanoyloxy, and alkanoylthio; [0357]
--O-(alkyl).sub.0-1-heteroaryl; [0358]
--O-(alkyl).sub.0-1-(substituted heteroaryl); [0359] --CO-aryl;
[0360] --CO-(substituted aryl); [0361] --CO-heteroaryl; [0362]
--CO-(substituted heteroaryl); [0363] --COOH; [0364] --CC--O-alkyl;
[0365] --CO-alkyl; [0366] --S(O).sub.0-2-alkyl; [0367]
--S(O).sub.0-2-(alkyl).sub.0-1-aryl; [0368]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted aryl); [0369]
--S(O).sub.0-2-(alkyl).sub.0-1-heteroaryl; [0370]
--S(O).sub.0-2-(alkyl).sub.0-1-(substituted heteroaryl); [0371]
--P(O)(OR.sub.3).sub.2; [0372] --NR.sub.3--CO--O-alkyl; [0373]
--N.sub.3; [0374] --NO.sub.2; [0375] --CN; [0376] --O-haloalkyl;
[0377] --CO-haloalkyl; [0378] --OH; [0379] --SH; and oxo;
[0380] R.sub.2 is selected from the group consisting of: [0381]
-hydrogen; [0382] -alkyl; [0383] -alkenyl; [0384] -aryl; [0385]
-(substituted aryl); [0386] -heteroaryl; [0387] -(substituted
heteroaryl); [0388] -heterocyclyl; [0389] -(substituted
heterocyclyl); [0390] -alkyl-O-alkyl; [0391] -alkyl-O-alkenyl; and
[0392] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of: [0393] --OH; [0394]
-halogen; [0395] --N(R.sub.3).sub.2; [0396] --CO--N(R.sub.3).sub.2;
[0397] --CO--C.sub.1-10 alkyl; [0398] --CO--O--C.sub.1-10 alkyl;
[0399] --N.sub.3; [0400] -aryl; [0401] -(substituted aryl); [0402]
-heteroaryl; [0403] -(substituted heteroaryl); [0404]
-heterocyclyl; [0405] -(substituted heterocyclyl); [0406]
--CO-aryl; and [0407] --CO-heteroaryl;
[0408] each R.sub.3 is independently selected from the group
consisting of hydrogen; C.sub.1-10 alkyl-heteroaryl; C.sub.1-10
alkyl-(substituted heteroaryl); C.sub.1-10 alkyl-aryl; C.sub.1-10
alkyl-(substituted aryl) and C.sub.1-10 alkyl;
[0409] n is 0 to 4;
[0410] and each
[0411] R present is independently selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkoxy, halogen and
trifluoromethyl, or a pharmaceutically acceptable salt thereof.
Preparation of the Compounds
[0412] Imidazoquinolines of the invention can be prepared according
to Reaction Scheme I where R, R.sub.1, R.sub.2 and n are as defined
above.
[0413] In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline
of Formula II is reacted with an amine of Formula R.sub.1NH.sub.2
to provide a 3-nitroquinolin-4-amine of Formula III. The reaction
can be carried out by adding amine to a solution of a compound of
Formula II in a suitable solvent such as chloroform or
dichloromethane and optionally heating. Many quinolines of Formula
II are known compounds (see for example, U.S. Pat. No. 4,689,338
and references cited therein).
[0414] In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine
of Formula III is reduced to provide a quinoline-3,4-diamine of
Formula IV. Preferably, the reduction is carried out using a
conventional heterogeneous hydrogenation catalyst such as platinum
on carbon or palladium on carbon. The reaction can conveniently be
carried out on a Parr apparatus in a suitable solvent such as
isopropyl alcohol or toluene.
[0415] In step (3) of Reaction Scheme I a quinoline-3,4-diamine of
Formula IV is reacted with a carboxylic acid or an equivalent
thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula V.
Suitable equivalents to carboxylic acid include acid halides,
orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid
or equivalent is selected such that it will provide the desired
R.sub.2 substituent in a compound of Formula V. For example,
triethyl orthoformate will provide a compound where R.sub.2 is
hydrogen and triethyl orthoacetate will provide a compound where
R.sub.2 is methyl. The reaction can be run in the absence of
solvent or in an inert solvent such as toluene. The reaction is run
with sufficient heating to drive off any alcohol or water formed as
a byproduct of the reaction.
[0416] In step (4) of Reaction Scheme I a
1H-imidazo[4,5-c]quinoline of Formula V is oxidized to provide a
1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI using a
conventional oxidizing agent that is capable of forming N-oxides.
Preferred reaction conditions involve reacting a solution of a
compound of Formula V in chloroform with 3-chloroperoxybenzoic acid
at ambient conditions.
[0417] In step (5) of Reaction Scheme I a
1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI is aminated to
provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula VII which is
a subgenus of Formula I. Step (5) involves (i) reacting a compound
of Formula VI with an acylating agent and then (ii) reacting the
product with an aminating agent. Part (i) of step (5) involves
reacting an N-oxide of Formula VI with an acylating agent. Suitable
acylating agents include alkyl- or arylsulfonyl chlorides (e.g.,
benezenesulfonyl chloride, methanesulfonyl chloride,
p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.
Para-toluenesulfonyl chloride is most preferred. Part (ii) of step
(5) involves reacting the product of part (i) with an excess of an
aminating agent. Suitable aminating agents include ammonia (e.g.,
in the form of ammonium hydroxide) and ammonium salts (e.g.,
ammonium carbonate, ammonium bicarbonate, ammonium phosphate).
Ammonium hydroxide is preferred. The reaction is preferably carried
out by dissolving the N-oxide of Formula VI in an inert solvent
such as dichloromethane, adding the aminating agent to the
solution, and then slowly adding the acylating agent. The product
or a pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
[0418] Alternatively, step (5) may be carried out by (i) reacting
an N-oxide of Formula VI with an isocyanate and then (ii)
hydrolyzing the resulting product. Part (i) involves reacting the
N-oxide with an isocyanate wherein the isocyanato group is bonded
to a carbonyl group. Preferred isocyanates include trichloroacetyl
isocyanante and aroyl isocyanates such as benzoyl isocyanate. The
reaction of the isocyanate with the N-oxide is carried out under
substantially anhydrous conditions by adding the isocyanate to a
solution of the N-oxide in an inert solvent such as chloroform or
dichloromethane. Part (ii) involves hydrolysis of the product from
part (i). The hydrolysis can be carried out by conventional methods
such as heating in the presence of water or a lower alkanol
optionally in the presence of a catalyst such as an alkali metal
hydroxide or lower alkoxide.
##STR00011##
[0419] Compounds of the invention can also be prepared according to
Reaction Scheme II where R, R.sub.2, R.sub.4 and n are as defined
above and m is 1-20.
[0420] In Reaction Scheme II an aminoalkyl substituted
1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with
an acid chloride of Formula IX to provide a compound of Formula X
which is a subgenus of Formula I. The reaction can be carried out
by adding a solution of the acid chloride in a suitable solvent
such as pyridine or dichloromethane to a solution of a compound of
Formula VIII either at ambient temperature or at a reduced
temperature. Many 1H-imidazo[4,5-c]quinolin-4-amines of Formula
VIII are known compounds, see for example U.S. Pat. No. 6,069,149
(Nanba), the disclosure of which is incorporated by reference
herein; others can be readily prepared using known synthetic
methods. Many acid chlorides of Formula IX are commercially
available; others can be readily prepared using known synthetic
methods. The product or a pharmaceutically acceptable salt thereof
can be isolated using conventional methods.
##STR00012##
[0421] Compounds of the invention can also be prepared according to
Reaction Scheme III where R, R.sub.2, R.sub.4 and n are as defined
above and m is 1-20.
[0422] In Reaction Scheme III an aminoalkyl substituted
1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with
an acid of Formula XI to provide a compound of Formula X which is a
subgenus of Formula I. The reaction can be run at ambient
temperature in a solvent such as dichloromethane or pyridine using
a standard coupling reagent such as 1,3-dicyclohexylcarbodiimide or
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide. The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
##STR00013##
[0423] Compounds of the invention can also be prepared according to
Reaction Scheme IV where R, R.sub.2, R.sub.4 and n are as defined
above and m is 1-20.
[0424] In Reaction Scheme IV an aminoalkyl substituted
1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with
an acid anhydride of Formula XII provide a compound of Formula X
which is a subgenus of Formula I. The reaction can be run at
ambient temperature in an inert solvent such as dichloromethane in
the presence of a base such as N,N-diisopropylethylamine or
pyridine. Many acid anhydrides of Formula XII are commercially
available; others may be readily prepared using known synthetic
methods. The product or a pharmaceutically acceptable salt thereof
can be isolated using conventional methods.
##STR00014##
[0425] Tertiary amides of the invention can be prepared according
to Reaction Scheme V where R, R.sub.2, R.sub.3, R.sub.4 and n are
as defined above except that R.sub.3 is other than hydrogen and m
is 1-20.
[0426] In step (1) of Reaction Scheme V an aminoalkyl substituted
1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with
an aldehyde of Formula XIII to provide a secondary amine of Formula
XIV. Preferably, the reductive amination is carried out using
sodium triacetoxyborohydride. The reaction can be carried out by
adding the sodium triacetoxyborohydride to a solution of the amine
and the aldehyde in an inert solvent such as dichloromethane. The
secondary amine or a salt thereof can be isolated using
conventional methods.
[0427] In step (2) of Reaction Scheme V the secondary amine of
Formula XIV is acylated to provide a compound of Formula XV which
is a subgenus of Formula I. The reaction can be carried out by
reacting the secondary amine of Formula XIV with an acid, acid
chloride or an acid anhydride according to the methods of Reaction
Schemes III, II and IV above. The product or a pharmaceutically
acceptable salt thereof can be isolated using conventional
methods.
##STR00015##
[0428] Tetrahydroimidazoquinolines of the invention can be prepared
according to Reaction Scheme VI where R.sub.2, R.sub.3 and R.sub.4
are as defined above and m is 1-20.
[0429] In step (1) of Reaction Scheme VI an aminoalkyl substituted
1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI is reduced to
provide an aminoalkyl substituted
6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula
XVII. Preferably the reduction is carried out by suspending or
dissolving the compound of Formula XVI in trifluoroacetic acid,
adding a catalytic amount of platinum (IV) oxide, and then
subjecting the mixture to hydrogen pressure. The reaction can
conveniently be carried out on a Parr apparatus. The product or a
salt thereof can be isolated using conventional methods.
[0430] In step (2) of Reaction Scheme VI an aminoalkyl substituted
6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula
XVII is reacted to provide a compound of Formula XVIII which is a
subgenus of Formula I. When R.sub.3 is hydrogen, the reaction can
be carried out according to the methods described in Reaction
Schemes II, III and IV above using a tetrahydroimidazoquinoline of
Formula XVII in place of the imidazoquinoline of Formula VIII. When
R.sub.3 is other than hydrogen, then the reaction can be carried
out using the method described in Reaction Scheme V. The product or
a pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
##STR00016##
[0431] Tetrahydroimidazoquinolines of the invention can also be
prepared according to Reaction Scheme VII where R, R.sub.2,
R.sub.3, R.sub.4 and n are as defined above and m is 1-20.
[0432] In step (I) of Reaction Scheme VII a
6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamate
of Formula XIX is hydrolyzed to provide an aminoalkyl substituted
6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XX.
The reaction can be carried out dissolving the compound of Formula
XIX in a mixture of trifluoroacetic acid and acetonitrile and
stirring at ambient temperature. Alternatively, the compound of
Formula XIX can be combined with dilute hydrochloric acid and
heated on a steam bath. Tetrahydro-1H-imidazo[4,5-c]quinolinyl
tert-butylcarbamates of Formula XIX can be prepared using the
synthetic route disclosed in U.S. Pat. No. 5,352,784 (Nikolaides).
The product or a salt thereof can be isolated using conventional
methods.
[0433] In step (2) of Reaction Scheme VII an aminoalkyl substituted
6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XX
is reacted to provide a compound of Formula XXI which is a subgenus
of Formula I. When R.sub.3 is hydrogen, the reaction can be carried
out according to the methods described in Reaction Schemes II, III
and IV above using a tetrahydroimidazoquinoline of Formula XX in
place of the imidazoquinoline of Formula VIII. When R.sub.3 is
other than hydrogen, then the reaction can be carried out using the
method described in Reaction Scheme V. The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
##STR00017##
[0434] Some compounds of Formula I can be readily prepared from
other compounds of Formula I. For example, compounds wherein the
R.sub.4 substituent contains a chloroalkyl group can be reacted
with an amine to provide an R.sub.4 substituent substituted by a
secondary or teriary amino group; compounds wherein the R.sub.4
substituent contains a nitro group can be reduced to provide a
compound wherein the R.sub.4 substituent contains a primary
amine.
[0435] As used herein, the terms "alkyl", "alkenyl", "alkynyl" and
the prefix "-alk" are inclusive of both straight chain and branched
chain groups and of cyclic groups, i.e. cycloalkyl and
cycloalkenyl. Unless otherwise specified, these groups contain from
1 to 20 carbon atoms, with alkenyl and alkynyl groups containing
from 2 to 20 carbon atoms. Preferred groups have a total of up to
10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and
preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic
groups include cyclopropyl, cyclopentyl, cyclohexyl and
adamantyl.
[0436] The term "haloalkyl" is inclusive of groups that are
substituted by one or more halogen atoms, including groups wherein
all of the available hydrogen atoms are replaced by halogen atoms.
This is also true of groups that include the prefix "haloalk-".
Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like.
[0437] The term "aryl" as used herein includes carbocyclic aromatic
rings or ring systems. Examples of aryl groups include phenyl,
naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl"
includes aromatic rings or ring systems that contain at least one
ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups
include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl,
indolyl, isoindolyl, pyrrolyl, tetrazolyl, imidazo, pyrazolo,
oxazolo, thiazolo and so on.
[0438] "Heterocyclyl" includes non-aromatic rings or ring systems
that contain at least one ring hetero atom (e.g., O, S, N).
Exemplary heterocyclic groups include pyrrolidinyl,
tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl,
piperazinyl, thiazolidinyl, and imidazolidinyl.
[0439] Unless otherwise specified, the terms "substituted aryl",
"substituted heteroaryl" and "substituted heterocyclyl" indicate
that the rings or ring systems in question are further substituted
by one or more substituents independently selected from the group
consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen,
haloalkyl, haloalkylcarbonyl, haloalkoxy (e.g., trifluoromethoxy),
nitro, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocycloalkyl, nitrile, alkoxycarbonyl,
alkanoyloxy, alkanoylthio, and, in the case of heterocyclyl,
oxo.
[0440] In structural formulas representing compounds of the
invention certain bonds are represented by dashed lines. These
lines mean that the bonds represented by the dashed line can be
present or absent. Accordingly, the compounds of the invention can
be either imidazoquinoline compounds or tetrahydroimidazoquinoline
compounds.
[0441] The invention is inclusive of the compounds described herein
in any of their pharmaceutically acceptable forms, including
isomers such as diastereomers and enantiomers, salts, solvates,
polymorphs, and the like.
Pharmaceutical Compositions and Biological Activity
[0442] Pharmaceutical compositions of the invention contain a
therapeutically effective amount of a compound of the invention as
described supra in combination with a pharmaceutically acceptable
carrier.
[0443] The term "a therapeutically effective amount" means an
amount of the compound sufficient to induce a therapeutic effect,
such as cytokine induction, antitumor activity and/or antiviral
activity. Although the exact amount of active compound used in a
pharmaceutical composition of the invention will vary according to
factors known to those of skill in the art, such as the physical
and chemical nature of the compound as well as the nature of the
carrier and the intended dosing regimen, it is anticipated that the
compositions of the invention will contain sufficient active
ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 .mu.g/kg to about 5 mg/kg, of the compound to
the subject. Any of the conventional dosage forms may be used, such
as tablets, lozenges, parenteral formulations, syrups, creams,
ointments, aerosol formulations, transdermal patches, transmucosal
patches and the like.
[0444] The compounds of the invention can be administered as the
single therapeutic agent in the treatment regimen, or the compounds
of the invention may be administered in combination with one
another or with other active agents, including additional immune
response modifiers, antivirals, antibiotics, etc.
[0445] The compounds of the invention have been shown to induce the
production of certain cytokines in experiments performed according
to the tests set forth below. These results indicate that the
compounds are useful as immune response modifiers that can modulate
the immune response in a number of different ways, rendering them
useful in the treatment of a variety of disorders.
[0446] Cytokines whose production may be induced by the
administration of compounds according to the invention generally
include interferon-.alpha. (IFN-.alpha.) and/or tumor necrosis
factor-.alpha. (TNF-.alpha.) as well as certain interleukins (IL).
Cytokines whose biosynthesis may be induced by compounds of the
invention include IFN-.alpha., TNF-.alpha., IL-1, 6, 10 and 12, and
a variety of other cytokines. Among other effects, cytokines
inhibit virus production and tumor cell growth, making the
compounds useful in the treatment of viral diseases and tumors.
[0447] In addition to the ability to induce the production of
cytokines, the compounds of the invention affect other aspects of
the innate immune response. For example, natural killer cell
activity may be stimulated, an effect that may be due to cytokine
induction. The compounds may also activate macrophages, which in
turn stimulates secretion of nitric oxide and the production of
additional cytokines. Further, the compounds may cause
proliferation and differentiation of B-lymphocytes.
[0448] Compounds of the invention also have an effect on the
acquired immune response. For example, although there is not
believed to be any direct effect on T cells or direct induction of
T cell cytokines, the production of the T helper type 1 (Th1)
cytokine IFN-.gamma. is induced indirectly and the production of
the T helper type 2 cytokines IL-4, IL-5 and IL-13 are inhibited
upon administration of the compounds. This activity means that the
compounds are useful in the treatment of diseases where
upregulation of the Th1 response and/or downregulation of the Th2
response is desired. In view of the ability of compounds of the
invention to inhibit the Th2 immune response, the compounds are
expected to be useful in the treatment of atopic diseases, e.g.,
atopic dermatitis, asthma, allergy, allergic rhinitis; systemic
lupus erythematosis; as a vaccine adjuvant for cell mediated
immunity; and possibly as a treatment for recurrent fungal diseases
and chlamydia.
[0449] The immune response modifying effects of the compounds make
them useful in the treatment of a wide variety of conditions.
Because of their ability to induce the production of cytokines such
as IFN-.alpha. and/or TNF-.alpha., the compounds are particularly
useful in the treatment of viral diseases and tumors. This
immunomodulating activity suggests that compounds of the invention
are useful in treating diseases such as, but not limited to, viral
diseases including genital warts; common warts; plantar warts;
Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II;
molluscum contagiosum; HIV; CMV; VZV; intraepithelial neoplasias
such as cervical intraepithelial neoplasia; human papillomavirus
(HPV) and associated neoplasias; fungal diseases, e.g. candida,
aspergillus, and cryptococcal meningitis; neoplastic diseases,
e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma,
renal cell carcinoma, squamous cell carcinoma, myelogenous
leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma,
cutaneous T-cell lymphoma, and other cancers; parasitic diseases,
e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis,
toxoplasmosis, trypanosome infection, and leishmaniasis; and
bacterial infections, e.g., tuberculosis, and mycobacterium avium.
Additional diseases or conditions that can be treated using the
compounds of the invention include eczema; eosinophilia; essential
thrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome;
discoid lupus; Bowen's disease; Bowenoid papulosis; and to enhance
or stimulate the healing of wounds, including chronic wounds.
Accordingly, the invention provides a method of inducing cytokine
biosynthesis in an animal comprising administering an effective
amount of a compound or composition of the invention to the
animal.
[0450] An amount of a compound effective to induce cytokine
biosynthesis is an amount sufficient to cause one or more cell
types, such as monocytes, macrophages, dendritic cells and B-cells
to produce an amount of one or more cytokines such as, for example,
IFN-.beta., TNF-.beta., IL-1, 6, 10 and 12 that is increased over
the background level of such cytokines. The precise amount will
vary according to factors known in the art but is expected to be a
dose of about 100 ng/kg to about 50 mg/kg, preferably about 10
.mu.g/kg to about 5 mg/kg. The invention also provides a method of
treating a viral infection in an animal and a method of treating a
neoplastic disease in an animal comprising administering an
effective amount of a compound or composition of the invention to
the animal. An amount effective to treat or inhibit a viral
infection is an amount that will cause a reduction in one or more
of the manifestations of viral infection, such as viral lesions,
viral load, rate of virus production, and mortality as compared to
untreated control animals. The precise amount will vary according
to factors known in the art but is expected to be a dose of about
100 ng/kg to about 50 mg/kg, preferably about 10 .mu.g/kg to about
5 mg/kg. An amount of a compound effective to treat a neoplastic
condition is an amount that will cause a reduction in tumor size or
in the number of tumor foci. Again, the precise amount will vary
according to factors known in the art but is expected to be a dose
of about 100 ng/kg to about 50 mg/kg, preferably about 10 .mu.g/kg
to about 5 mg/kg.
[0451] The invention is further described by the following
examples, which are provided for illustration only and are not
intended to be limiting in any way.
EXAMPLE 1
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-e]quinolin-1-yl)butyl]benzamide
##STR00018##
[0453] A suspension of
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8
mmol) in pyridine (1 L) was warmed to 60.degree. C. to dissolve the
starting material. The solution was cooled to about 30.degree. C.
and then benzoyl chloride (1.1 g, 7.8 mmol) diluted with pyridine
(100 mL) was slowly added. After 1 hour analysis by high
performance liquid chromatography (HPLC) indicated that some
starting material remained. Additional benzoyl chloride (0.3 g) was
added and the reaction was warmed to 50.degree. C. overnight. The
reaction mixture was concentrated under vacuum. The resulting
residue was combined with chloroform (200 mL) and 1% sodium
carbonate (200 mL). The organic layer was separated and then
concentrated under vacuum. The resulting residue was combined with
propyl acetate (30 mL) and heated on a steam bath to dissolve the
residue. The solution was allowed to cool. The resulting
precipitate was isolated by filtration to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide
as a solid, m.p. 210-212.degree. C. Analysis: Calculated for
C.sub.21H.sub.21N.sub.5O: % C, 70.18; % H, 5.89: % N, 19.48; Found:
% C, 69.49; % H, 5.97; % N, 19.64. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.48 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 8.04
(d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H),
7.50 (t, J=8.0 Hz, 1H), 7.43 (m, 3H), 7.21 (t, J=8.0 Hz, 1H), 6.62
(broad s, 2H), 4.64 (t, J=7.0 Hz, 2H), 3.30 (q, J=6.0 Hz, 2H), 1.92
(quintet, J=7.0 Hz, 2H); 1.58 (quintet, J=7.0 Hz, 2H); MS (EI) m/e
359.1746 (359.1746 calcd for C.sub.21H.sub.21N.sub.5O).
EXAMPLE 2
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide
Hydrochloride Hydrate
[0454]
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide
(1 g) was dissolved in isopropanol. Hydrochloric acid (1 eq of 12N)
was added. The resulting precipitate was isolated by filtration to
provide 1 g of
N-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide
hydrochloride hydrate as a solid, m.p. 254-256.degree. C. Analysis:
Calculated for C.sub.21H.sub.21N.sub.5O.HCl 1.5H.sub.2O: % C,
59.63; % H, 5.96; % N, 16.56; Found: % C 59.61; % H, 6.04; % N,
16.64. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.80 (broad s,
1H), 9.15 (broad s, 2H), 8.56 (s, 1H), 8.50 (t, J=6.0 Hz, 1H), 8.23
(d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H),
7.71 (t, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz,
1H), 7.42 (t, J=8.0 Hz, 2H), 4.72 (t, J=7.0 Hz, 2H), 3.30 (q, J=7.0
Hz, 2H), 1.93 (quintet, J=7.0 Hz, 2H), 1.61 (quintet, J=7.0 Hz,
2H).
EXAMPLE 3
N.sup.1-[4-(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamid-
e
##STR00019##
[0456] Using the general method of Example 1,
1-(4-aminobutyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.55
g, 1.8 mmol) was reacted with benzoyl chloride (0.26 g, 1.8 mmol)
to provide
N.sup.1-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzami-
de as a solid, m.p. 173-174.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.80 (broad s, 2H), 8.46 (t, J=6.0 Hz, 1H),
8.20 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.4 Hz,
2H), 7.67 (t, J=7.4 Hz, 1H), 7.49 (m, 2H), 7.43 (t, J=7.5 Hz, 2H),
4.63 (t, J=7.0 Hz, 2H), 3.34 (m, 2H), 2.97 (t, J=7.0 Hz, 2H), 1.85
(m, 4H), 1.72 (quintet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H); MS
(EI) m/e 401.2210 (401.2216 calcd for
C.sub.24H.sub.27N.sub.5O).
EXAMPLE 4
N.sup.1-[4-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamid-
e
##STR00020##
[0458] Using the general method of Example 1,
1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g,
1.8 mmol) was reacted with benzoyl chloride (0.26 g, 1.8 mmol) to
provide
N.sup.1-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzami-
de as a solid, m.p. 164-170.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.47 (t, J=6.0 Hz, 1H), 8.01 (d, J=8.0 Hz,
1H), 7.78 (d, J=8.0 Hz, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (t,
J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (dt, J=8.0, 1.2 Hz,
1H), 7.17 (dt, J=8.0, 1.2 Hz, 1H), 6.48 (broad s, 2H), 4.53 (t,
J=7.0 Hz, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 1.88 (quintet,
J=7.0 Hz, 2H), 1.68 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 373.1903
(373.1903 calcd for C.sub.22H.sub.23N.sub.5O).
EXAMPLE 5
N.sup.1-[4-(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide
##STR00021##
[0460] Using the general method of Example 1,
1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g,
1.76 mmol) was reacted with benzoyl chloride (0.25 g, 1.76 mmol) to
provide
N.sup.1-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamid-
e as a solid, m.p. 203-206.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz,
1H), 7.79 (d, J=8.0 Hz, 2H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.50 (t,
J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.17
(t, J=8.0 Hz, 1H), 6.47 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.32
(q, J=6.0 Hz, 2H), 2.95 (q, J=7.0 Hz, 2H), 1.87 (quintet, J=7.0 Hz,
2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H); MS (EI)
m/e 387.2058 (387.2059 calcd for C.sub.23H.sub.25N.sub.5O).
EXAMPLE 6
N.sup.1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide
##STR00022##
[0462] 1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine
(0.5 g, 1.6 mmol) was combined with pyridine (50 mL) and heated to
50.degree. C. Benzoyl chloride (0.22 g, 1.6 mmol) was added via a
pipette. After 1 hour analysis by HPLC indicated that all of the
starting material was gone and that several products had formed.
The reaction mixture was concentrated under vacuum. The residue was
combined with dichloromethane and aqueous sodium bicarbonate. The
organic layer was separated and then concentrated under vacuum. The
residue was dissolved in dichloromethane and placed on a silica gel
column. The column was eluted with 5% methanol in dichloromethane
and then with 10% methanol in dichloromethane. The 10% methanol in
dichloromethane fractions were combined and concentrated under
vacuum to provide
N.sup.1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamid-
e as a solid, m.p. 174-175.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.48 (t, J=6.0 Hz, 1-H), 8.00 (d, J=8.0 Hz,
1H), 7.78 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0
Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.18 (t,
J=8.0 Hz, 1H), 6.50 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.32 (m,
2H), 2.91 (t, J=7.0 Hz, 2H), 1.86 (quintet, J=7.0 Hz, 2H), 1.77
(quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.41
(sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H); MS (CI) m/e 416
(M+H).
EXAMPLE 7
N.sup.1-[4-(4-Amino
-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-(chloromethyl)benzamide
##STR00023##
[0463] Part A
[0464] Oxalyl chloride (4.4 mL of 2M in chloroform, 8.8 mmol) was
added to a suspension of 4-(chloromethyl)benzoic acid (1 g, 5.7
mmol) in dichloromethane. N,N-dimethylformamide (4 drops) was added
to catalyze the reaction. After 1 hour analysis by HPLC indicated
100% clean conversion. The reaction mixture was concentrated under
vacuum to provide 4-(chloromethyl)benzoyl chloride.
Part B
[0465] A solution of 4-(chloromethyl)benzoyl chloride (1.06 g, 5.6
mmol) in dichloromethane was added to a suspension of
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.9
mmol) in pyridine (250 mL). After 1 hour HPLC analysis indicated
that the reaction was complete. The reaction mixture was
concentrated under vacuum. The residue was combined with saturated
aqueous sodium bicarbonate. A solid was isolated by filtration then
dissolved in chloroform containing a small amount of methanol. The
solution was washed with saturated aqueous sodium bicarbonate. The
organic layer was concentrated under vacuum. The resulting residue
was purified by column chromatography (silica gel eluting with 10%
methanol in dichloromethane) to provide N.sup.1-[4-(4-amino
-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-(chloromethyl)benzamide as
a solid, m.p. 240-300 (dec.). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.49 (t, J=6.0 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=8.0 Hz,
1H); 7.76 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0
Hz, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.80
(broad s, 2H), 4.78 (s, 2H), 4.62 (t, J=7.0 Hz, 2H), 3.28 (q, J=6.0
Hz, 2H), 1.89 (quintet, J=7.0 Hz, 2H), 1.56 (quintet, J=7.0 Hz,
2H); MS (CI) m/e 408 (M+H).
EXAMPLE 8
N.sup.1-[4-(4-Amino
-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-[(2-tetrahydro-1H-1-pyrrolyl-1H--
benzo[d]imidazol-1-yl)methyl]benzamide
##STR00024##
[0466] Part A
[0467] 2-Hydroxy-1H-benzimidazole (62 g, 0.46 mole) was added to
phosphorous oxychloride (200 mL) and the mixture was refluxed for
4.5 hours. The resulting solution was poured over 4 L of ice and
the mixture was made strongly basic with ammonium hydroxide. The
resulting solid was isolated by filtration, washed with water and
dried to provide crude 2-chloro-1H-benzimidazole.
Part B
[0468] 2-Chloro-1H-benzimidazole (10.0 g, 0.066 mol), pyrrolidine
(18.5 g, 0.26 mol), and ethanol (100 mL) were combined. The
resulting solution was heated at 160-170.degree. C. for 6 hours and
then the solvent was evaporated. The resulting residue was mixed
with water. The mixture was made strongly acidic with hydrochloric
acid and then made basic with ammonium hydroxide. The resulting
solid was isolated by filtration, washed with water and then air
dried to provide 11.8 g of crude product as a tan powder. This
material was recrystallized from ethyl acetate/methanol to provide
4.9 g of 2-pyrrolidino-1H-benzimidazole. Analysis: Calculated for
C.sub.11H.sub.13N.sub.3: % C, 70.56; % H, 7.00; % N, 22.44; Found:
% C, 70.13; % H, 7.05; % N, 22.70.
Part C
[0469] Sodium hydride (402 mg, 11 mmol) was added to a suspension
of 2-pyrrolidino-1H-benzimidazole (1.9 g, 10.1 mmol) in dry
N,N-dimethylformamide (30 mL). All solids dissolved. The solution
was allowed to stir at ambient temperature for 15 minutes following
the cessation of foaming. The solution was cooled to 5.degree. C.
and a solid formed. Methyl 4-(bromomethyl)benzoate (2.1 g, 01 mol)
was added to the suspension and all the solids dissolved. The
solution was allowed to stir at ambient temperature and a solid
formed. The mixture was stirred at ambient temperature overnight
and then it was poured into cold water. A solid was isolated by
filtration, washed with water and dried to provide 3.0 g of crude
product as an off-white solid. This material was recrystallized
from methanol to provide methyl
4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate. Analysis:
Calculated for C.sub.20H.sub.21N.sub.3O.sub.2: % C, 71.62; % H,
6.31; % N, 12.53; Found: % C, 71.44; % H, 6.41; % N, 12.50.
Part D
[0470] Methyl
4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate (2.5 g, 7.5
mmol) was added to a solution of sodium hydroxide (1.8 g, 45 mmol)
in water (30 mL) and methanol (10 mL). The mixture was heated on a
steam bath until all of the ester dissolved. Heating was continued
for an additional 15 minutes and then the solution was diluted with
an equal volume of water and neutralized with hydrochloric acid.
The resulting precipitate was isolated by filtration, washed with
water and dried to provide 1.9 g of crude product. This material
was recrystallized from N,N-dimethylformamide to provide
4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoic acid.
Analysis: Calculated for C.sub.19H.sub.19N.sub.3O.sub.2: % C,
71.01; % H, 5.96; % N, 13.07; Found: % C, 70.01; % H, 6.14; % N,
13.32.
Part E
[0471] Oxalyl chloride (4 mL) was added to a suspension of
4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoic acid (0.28 g,
0.872 mmol) in chloroform (50 mL). The mixture was heated at reflux
for 1 hour and then concentrated under vacuum. The residue was
diluted with toluene, concentrated under vacuum and then dried
under vacuum at ambient temperature over the weekend to provide
crude 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoyl
chloride.
Part F
[0472] 1-(4-Aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.20 g,
0.783 mmol) was added to a mixture of the acid chloride from Part E
and pyridine (20 mL). After 10 minutes analysis by HPLC indicated
that the reaction mixture contained product plus about 10% each of
the acid chloride and the amine. The reaction mixture was
concentrated under vacuum. The residue was combined with water,
treated with 0.1 N sodium hydroxide and then extracted with
dichloromethane. The dichloromethane extract was purified by column
chromatography (silica gel eluting with 5-10% methanol in
dichloromethane) to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-[(2-tetrahydr-
o-1H -1-pyrrolyl-1H-benzo[d]imidazol-1-yl)methyl]benzamide as a
solid, m.p. 150-153.degree. C. MS (EI) m/e 558.2865 (558.2855 calcd
for C.sub.33H.sub.34N.sub.8O).
EXAMPLE 9
N.sup.1-[5-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzami-
de
##STR00025##
[0473] Part A
[0474] Under an argon atmosphere, 1,5-diaminopentane (25 g, 0.24
mol) and benzamide (9.9 g, 0.081 mol) were combined and heated at
reflux overnight. The reaction mixture was concentrated under
vacuum to remove the excess diamine. The residue was distilled at
about 210.degree. C. at 12 torr (16.times.10.sup.2 pascals) to
provide 11.8 g of N-(5-aminopentyl)benzamide as a colorless
oil.
Part B
[0475] Triethylamine (1 eq.) was added to a suspension of
4-chloro-3-nitroquinoline hydrochloride (13 g, 53 mmol) in
chloroform. A suspension of N-(5-aminopentyl)benzamide (11 g, 53
mmol) in chloroform was added and the reaction mixture was heated
to reflux. Progress of the reaction was monitored by HPLC. The
reaction mixture was concentrated under vacuum. The residue was
diluted with toluene, heated to reflux and then filtered while
still hot. The filtrate was allowed to cool. The resulting
precipitate was isolated by filtration to provide 16.9 g of
N-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide as a yellow
solid, m.p. 130-132.degree. C. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.07 (s, 1H), 9.02 (broad s, 1H), 8.53 (d, J=8.0 Hz, 1H),
8.43 (t, J=6.0 Hz, 1H), 7.89 (dd, J=8.0, 1.2 Hz, 1H), 7.83 (dt,
J=8.0, 1.2 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.57 (dt, J=8.0, 1.2
Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 3.63 (q,
J=6.0 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz,
2H), 1.55 (quintet, J=7.0 Hz, 2H), 1.39 (quintet, J=7.0 Hz,
2H).
Part C
[0476] A catalytic amount of platinum on carbon was added to a
suspension of
N.sup.1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide (3.4 g, 9
mmol) in isopropyl alcohol (250 mL). The reaction mixture was
placed under a hydrogen atmosphere at 50 psi (3.4.times.10.sup.4
pascals) on a Parr apparatus. After 2 hours the reaction mixture
was filtered to remove the catalyst. The filtrate was concentrated
under vacuum to provide crude
N'-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide. This material
was combined with triethylorthoacetate (1.4 g, 9 mmol) and toluene
(200 mL). The reaction mixture was heated overnight on a steam bath
with a Vigreux column. The toluene was decanted from the reaction
mixture and concentrated under vacuum to provide
N.sup.1-[5-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide
as an oil.
Part D
[0477] 3-Chloroperoxybenzoic acid (3 g, 9 mmol) was added to a
solution of the oil from Part C in methyl acetate (50 mL). The
reaction mixture was stirred at ambient temperature overnight and
then diluted with diethyl ether (50 mL). The resulting precipitate
was isolated by filtration and then washed with diethyl ether to
provide 1.6 g of
1-(5-benzamidopentyl)-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide.
Part E
[0478] Ammonium hydroxide (50 mL) was added to a solution of
1-(5-benzamidopentyl)-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide
(1.6 g, 4.12 mmol) in dichloromethane (150 mL). Tosyl chloride
(0.78 g, 4.12 mmol) was slowly added with rapid stirring of the
reaction mixture. After 1 hour the organic layer was separated,
washed with 1% sodium carbonate and then concentrated under vacuum.
The resulting residue was combined with 1N-hydrochloric acid (30
mL), treated with charcoal and then filtered. The filtrate was
neutralized. An oil precipitated out. The oil solidified overnight
to provide 0.63 g of
N.sup.1-[5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzam-
ide as a solid, m.p. 110-120.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.50 (t, J=5.5 Hz, 1H), 8.12 (d, J=8.0 Hz,
1H), 7.82 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.5 Hz, 1H), 7.63 (broad s,
2H), 7.55 (t, J=8.5 Hz, 1H), 7.51 (t, J=8.3 Hz, 1H), 7.46 (t, J=8.0
Hz, 2H), 7.40 (t, J=8.0 Hz, 1H), 4.52 (t, J=7.5 Hz, 2H), 3.28 (q,
J=6.0 Hz, 2H), 2.64 (s, 3H), 1.87 (quintet, J=7.0 Hz, 2H), 1.79
(quintet, J=7.0 Hz, 2H), 1.48 (quintet, J=7.0 Hz, 2H); MS (CI) m/e
388 (M+H).
EXAMPLE 10
N.sup.1-[5-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide
Hydrochloride
##STR00026##
[0479] Part A
[0480] A catalytic amount of platinum on carbon was added to a
suspension of N'-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide
(5 g, 13.2 mmol) in toluene (250 mL). The reaction mixture was
placed under a hydrogen atmosphere at 50 psi (3.4.times.10.sup.4
pascals) on a Parr apparatus. After about 2 hours an oily ball had
formed in the bottom of the Parr bottle. Magnesium sulfate and
additional catalyst were added and the hydrogenation was continued
overnight. The reaction mixture was filtered to remove the
catalyst. The residue in the Parr bottle was combined with
isopropyl alcohol (150 mL), heated on a steam bath and then
filtered. HPLC analysis indicated that both filtrates contained
product so they were combined and concentrated under vacuum to
provide crude N'-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide.
This material was combined with toluene (250 mL).
Triethylorthoformate (4 g, 26.4 mmol) was added and the reaction
mixture was heated at reflux with a Vigreux column for 2 hours. The
reaction mixture was allowed to cool to ambient temperature. The
resulting precipitate was isolated by filtration to provide 3.4 g
of N.sup.1-[5-(1H.imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide as a
solid, m.p. 171.5-172.5.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.43 (t, J=6.0 Hz, 2H), 8.38
(m, 1H), 8.18 (m, 1H), 7.80 (d, J=7.0 Hz, 2H), 7.73 (m, 2H), 7.51
(t, J=7.0 Hz, 1H), 7.45 (t, J=7.0 Hz, 2H), 4.72 (t, J=7.5 Hz, 2H),
3.25 (q, J=6.0 Hz, 2H), 1.94 (quintet, J=7.5 Hz, 2H), 1.58
(quintet, J=7.5 Hz, 2H), 1.40 (quintet, J=8.5 Hz, 2H).
Part B
[0481] 3-Chloroperoxybenzoic acid (1.9 g, 5.58 mmol) was added to a
solution of
N.sup.1-[5-(1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide (2.0 g,
5.58 mmol) in chloroform. After 4 hours HPLC analysis indicated
that the reaction was complete. The reaction was washed twice with
1% sodium carbonate (50 mL) and then concentrated under vacuum to
provide
1-(5-benzamidopentyl)-1H-imidazo[4,5-c]quinoline-5N-oxide.
Part C
[0482] Ammonium hydroxide was added to a solution of
1-(5-benzamidopentyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (2.1 g,
5.58 mmol) in dichloromethane. Tosyl chloride (1.06 g, 5.58 mmol)
was slowly added with rapid stirring of the reaction mixture. After
1 hour the reaction was diluted with dichloromethane. The organic
layer was separated, washed with 1% sodium carbonate and then
concentrated under vacuum. The resulting residue was dissolved in
isopropyl alcohol (100 mL) and then 6N hydrochloric acid (0.93 mL)
was added. The resulting precipitate was suspended in water (150
mL), heated to reflux, treated with charcoal and then filtered. The
filtrate was allowed to cool. The resulting precipitate was
isolated by filtration and dried to provide 0.9 g of
N.sup.1-[5-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide
hydrochloride as a white crystalline solid, m.p. 217-219.degree. C.
Analysis: Calculated for C.sub.22H.sub.23N.sub.5O.HCl.1/2H.sub.2O:
% C, 52.85; % H, 6.85; % N, 14.01; Found: % C, 52.62; % H, 6.44%; %
N, 13.87. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.84 (broad
s, 1H), 9.24 (broad s, 2H), 8.51 (s, 1H), 8.43 (t, J=6.0 Hz, 1H),
8.22 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz,
2H), 7.70 (t, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.49 (t, J=8.0
Hz, 1H), 7.42 (t, J=8.0 Hz, 2H), 4.66 (t, J=7.0 Hz, 2H), 3.23 (q,
J=6.0 Hz, 2H), 1.90 (quintet, J=7.0 Hz, 2H), 1.56 (quintet, J=7.0
Hz, 2H), 1.38 (quintet, J=7.0 Hz, 2H); MS (CI) m/e 374 (M+H).
EXAMPLE 11
N.sup.1-[3-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide
Hydrochloride
##STR00027##
[0483] Part A
[0484] Benzamide (25 g, 0.20 mol) and 1,3-diaminopropane (45.9 g,
0.60 mol) were combined in a Parr vessel and heated to 150.degree.
C. for 15 hours. The vessel was cooled and the reaction mixture was
concentrated under vacuum to remove excess diamine. The residue was
dissolved in water (500 mL) and concentrated hydrochloric acid was
added to adjust the pH to <1. The resulting precipitate
(starting benzamide and diacylated product) was removed by
filtration. The filtrate was washed with dichloromethane. The
aqueous layer was made strongly basic by the addition of 50% sodium
hydroxide and then it was extracted with dichloromethane
(4.times.300 mL). The extracts were combined, washed with brine
(300 mL), dried over sodium sulfate and then concentrated under
vacuum to provide 11.9 g of N-(3-aminopropyl)benzamide as an
oil.
Part B
[0485] Triethylamine (9.3 mL, 67 mmol) was added to a mixture of
4-chloro-3-nitroquinoline hydrochloride (16.4 g, 67 mmol) and
dichloromethane (400 mL). A solution of N-(3-aminopropyl)benzamide
(11.9 g, 67 mmol) in dichloromethane (100 mL) was added all a once.
The reaction mixture was stirred at ambient temperature for 1 hour
and then heated on a steam bath for 1 hour. The resulting
precipitate was isolated by filtration to provide 6 g of
N.sup.1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide as a
yellow solid, m.p. 209-211.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.07 (broad s, 1H), 9.05 (s, 1H), 8.54 (t,
J=6.0 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.82
(t, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.55 (t, J=8.0 Hz, 1H),
7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 3.69 (q, J=6.0 Hz,
2H), 3.35 (q, J=6.0 Hz, 2H), 2.00 (quintet, J=7.0 Hz, 2H).
Part C
[0486] A suspension of
N.sup.1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (1.0 g,
2.8 mmol) in isopropyl alcohol (120 mL) was warmed to dissolve some
of the material. A catalytic amount of platinum on carbon was added
and the reaction mixture was placed under a hydrogen atmosphere at
50 psi (3.4.times.10.sup.4 pascals) on a Parr apparatus. After 3
hours the reaction mixture was filtered to remove catalyst. The
filtrate was concentrated under vacuum to provide crude
N.sup.1-[3-[(3-aminoquinolin-4-yl)amino]propyl]benzamide as an oil.
Toluene (100 mL) was added to the oil followed by the addition of
triethylorthoformate (0.8 g, 5.6 mmol). The reaction mixture was
heated on a steam bath overnight. The reaction mixture was allowed
to cool to ambient temperature. The resulting precipitate was
isolated by filtration to provide 0.53 g of
N'-[3-(1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as an off
white solid, m.p. 188-190.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.67 (t, J=5.5 Hz, 1H), 8.50 (s, 1H), 8.37
(d, J=7.5 Hz, 1H), 8.17 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (d, J=7.0 Hz,
2H), 7.71 (dt, J=7.5, 1.5 Hz, 1H), 7.56 (dt, J=7.5, 1.0 Hz, 1H),
7.54 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.0 Hz, 2H), 4.78 (t, J=7.0 Hz,
2), 3.38 (q, J=6.0 Hz, 2H), 2.18 (quintet, J=7.0 Hz, 2H).
Part D
[0487] 3-Chloroperoxybenzoic acid (0.55 g, 1.6 mmol) was slowly
added at ambient temperature to a solution of
N.sup.1-[3-(1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide (0.53
g, 1.6 mmol) in chloroform (50 mL). After 3 hours the reaction was
washed with 1% sodium carbonate (2.times.30 mL) and then
concentrated under vacuum to provide 0.32 g of
1-(3-benzamidopropyl)-1H-imidazo[4,5-c]quinoline-5N-oxide as a
solid.
Part E
[0488] Ammonium hydroxide (20 mL) was added to a solution of
1-(3-benzamidopropyl)-1H-imidazo[4,5-c]quinoline-5N-oxide (0.32 g,
0.92 mmol) in dichloromethane (100 mL). Tosyl chloride (0.17 g,
0.92 mmol) was slowly added. The reaction mixture was stirred
overnight at ambient temperature and then it was concentrated under
vacuum to remove the dichloromethane. The resulting precipitate was
isolated by filtration and then washed with water. This material
was dissolved in isopropyl alcohol (20 mL/g). Concentrated
hydrochloric acid (1 eq.) was added and then the volume of the
reaction mixture was reduced by 10-20%. The resulting precipitate
was isolated by filtration and washed with isopropyl alcohol to
provide 0.25 g of
N.sup.1-[3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide
hydrochloride as a solid, m.p. 265-270.degree. C. Analysis:
Calculated for C.sub.20H.sub.19N.sub.5O.HCl.1/2H.sub.2O: % C,
61.46; % H, 5.42; % N, 17.92; Found: % C, 61.79; % H, 5.34; % N,
17.61. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.74 (broad s,
1H), 9.30 (broad s, 2H), 8.73 (t, J=6.0 Hz, 1H), 8.61 (s, 1H), 8.22
(d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 1H),
7.71 (t, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz,
2H), 7.43 (t, J=8.0 Hz, 1H), 4.75 (t, J=7.0 Hz, 2H), 3.39 (q, J=6.0
Hz, 2H), 2.17 (t, J=7.0 Hz, 2H); MS (EI) m/e 345.1593 (345.1590
calcd for C.sub.20H.sub.19N.sub.5O).
EXAMPLE 12
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-morpholinonico-
tinamide
##STR00028##
[0489] Part A
[0490] Carbonyl diimidazole (18.6 g, 0.115 mol) was added to a
suspension of 6-chloronicotinic acid (16.6 g, 0.105 mol) in
dichloromethane (250 mL). After all of the solid had dissolved the
reaction solution was stirred at ambient temperature for 1 hour and
then isopropyl alcohol (100 mL) was added. The dichloromethane was
removed under vacuum. A catalytic amount of sodium isopropoxide was
added to the solution and the solution was heated at reflux for 1
hour. The solution was then concentrated under vacuum. The
resulting residue was slurried with water and then extracted with
diethyl ether. The extract was dried over magnesium sulfate and
then concentrated under vacuum to provide 23.9 g of isopropyl
6-chloronicotinate.
Part B
[0491] A solution of isopropyl 6-chloronicotinate (6.0 g, 0.03 mol)
and morpholine (13 mL, 0.15 mol) in isopropyl alcohol (60 mL) was
heated at reflux for 72 hours. The solution was allowed to cool to
ambient temperature overnight. The resulting precipitate was
isolated by filtration, washed with isopropyl alcohol and dried to
provide isopropyl 6-morpholinonicotinate. The filtrate was diluted
with water. The resulting precipitate was isolated by filtration,
washed with water and dried to provide isopropyl
6-morpholinonicotinate. The combined yield was 8.3 g. The isopropyl
6-morpholinonicotinate was combined with 1 N sodium hydroxide (40
mL) and the resulting suspension was stirred at 50-60.degree. C.
until all of the solid had dissolved. The solution was stirred at
ambient temperature overnight during which time a precipitate
formed. This material was isolated by filtration and identified as
starting material. The filtrate was neutralized with concentrated
hydrochloric acid. The resulting precipitate was isolated by
filtration, washed with water and dried to provide 3.3 g of crude
product. This material was recrystallized from
methanol/dichloromethane to provide 6-morpholinonicotinic acid as a
solid, m.p. 259-261.degree. C. Analysis: Calculated for
C.sub.10H.sub.12N.sub.2O.sub.3: % C, 57.19; % H, 5.81; % N, 13.48;
Found: % C, 57.50; % H, 5.71; % N, 13.53.
Part C
[0492] N,N-Dimethylformamide (1 mL) was slowly added to a solution
of oxalyl chloride (0.13 g, 1 mmol) in chloroform (5 mL).
6-Morpholinonicotinic acid (0.21 g, 1 mmol) was added and the
reaction mixture was stirred for 15 minutes. The reaction mixture
was concentrated under vacuum, diluted with toluene and then
concentrated under vacuum to provide 6-morpholinonicotinoyl
chloride. This material was kept under vacuum at ambient
temperature overnight and then used in the next step.
Part D
[0493] The acid chloride from Part C was dissolved in pyridine (20
mL) and then added all at once to a warm solution of
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.25 g, 1 mmol)
in pyridine (25 mL). The reaction mixture was concentrated under
vacuum at 40.degree. C. to remove the pyridine. The resulting
residue was combined with water and 1N sodium hydroxide (25 mL).
The mixture was extracted with dichloromethane. The extract was
concentrated under vacuum. The resulting residue was recrystallized
from isopropyl alcohol to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-morpholinonic-
otinamide as a solid, m.p. 160-170.degree. C. (dec.). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.55 (d, J=2.5 Hz, 1H), 8.52 (s,
1H), 8.28 (t, J=6.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.90 (dd,
J=8.0, 2.5 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H),
7.52 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.70 (t, J=7.0 Hz,
2H), 3.69 (t, J=5.0 Hz, 4H), 3.54 (t, J=5.0 Hz, 4H), 3.27 (q, J=6.0
Hz, 2H), 1.91 (quintet, J=7.0 Hz, 2H), 1.58 (t, J=6.0 Hz, 2H); MS
(EI) m/e 445.2209 (445.2226 calcd for
C.sub.24H.sub.27N.sub.7O.sub.2).
EXAMPLE 13
N.sup.1-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]benzamide
##STR00029##
[0494] Part A
[0495] Triethylamine (66.8 g, 0.33 mol) was added to a solution of
tert-butyl N-(2-aminoethyl)carbamate (55.0 g, 0.34 mol) in
anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline was
slowly added and the reaction exothermed. The reaction mixture was
allowed to stir at ambient temperature overnight. The resulting
precipitate was isolated by filtration to provide product as a
yellow solid. The filtrate was washed with water, dried over
magnesium sulfate and then concentrated under vacuum. The resulting
residue was slurried with hexane and filtered to provide additional
product as a yellow solid. The two crops were combined to provide
10 g of tert-butyl N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate
as a yellow solid, m.p. 157-158.
Part B
[0496] Platinum on carbon (1 g of 10%) and sodium sulfate (2 g)
were added to a slurry of tert-butyl
N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate (100 g, 0.30 mol)
in toluene (500 mL). The mixture was placed under a hydrogen
atmosphere at 50 psi (3.4.times.10.sup.4 pascals) on a Parr
apparatus at ambient temperature overnight. The reaction mixture
was filtered. The filtrate was concentrated to provide 73 g of
tert-butyl N-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate as a
dark gold oil.
Part C
[0497] Triethyl orthoformate (11.3 g, 73.4 mmol) was added to a
solution of tert-butyl
N-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate (21 g, 69.4 mmol)
in anhydrous toluene (250 mL). The reaction mixture was heated at
reflux for 5 hours and then allowed to slowly cool to ambient
temperature. The resulting precipitate was isolated by filtration
and dried to provide 17.6 g of tert-butyl
N-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a light tan
solid, m.p. 154-155.degree. C.
Part D
[0498] 3-Chloroperoxybenzoic acid (17.4 g, 60.6 mmol) was added in
small portions to a solution of tert-butyl
N-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (17.2 g, 55.1
mmol) in chloroform (250 mL). The reaction was maintained at
ambient temperature overnight and then quenched with 5% sodium
carbonate solution. The layers were separated. The organic layer
was dried over magnesium sulfate and then concentrated under vacuum
to provide 15.0 g of
1-[2-(tert-butylcarbamyl)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide
as an off white solid, m.p. 213-215.degree. C.
Part E
[0499] Trichloroacetyl isocyanate (9.5 g, 50.2 mmol) was slowly
added to a stirred solution of
1-[2-(tert-butylcarbamyl)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide
(15.0 g, 45.7 mmol) in chloroform (200 mL). After 2 hours the
reaction was quenched with concentrated ammonium hydroxide (100
mL). Water (100 mL) was added and the layers were separated. The
aqueous layer was extracted with chloroform. The organic layers
were combined, dried over magnesium sulfate and then concentrated
under vacuum to provide a white solid. This material was slurried
in warm methyl acetate and then filtered to provide 15 g of
tert-butyl
N-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a
white solid, m.p. 215.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.13 (t, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.61
(d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H),
7.06 (t, J=6.0 Hz, 1H), 6.56 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H),
3.43 (q, J=6.0 Hz, 2H), 1.32 (s, 9H); MS (EI) m/e 327.1696
(327.1695 calcd for C.sub.17H.sub.21N.sub.5O.sub.2)
Part F
[0500] Tert-butyl
N-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.8
g, 45.2 mmol), trifluoroacetic acid (100 mL) and acetonitrile (100
mL) were combined and maintained at ambient temperature overnight.
The acetonitrile was removed and the reaction mixture was heated at
reflux for 2 hours. The reaction mixture was concentrated under
vacuum to provide a tan solid. This material was dissolved in a
minimal amount of hot water. The solution was adjusted to pH 14 and
allowed to cool. The solution was concentrated under vacuum. The
resulting residue was extracted with refluxing ethanol. The ethanol
extract was concentrated under vacuum to provide 3.0 g of
1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid,
m.p. 265.degree. C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.14 (s, 1H), 8.08 (dd, J=8.0, 1.5 Hz, 1H), 7.62 (dd, J=8.0, 1.5
Hz, 1H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.25 (dt, J=8.0, 1.5 Hz,
1H), 6.58 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.01 (t, J=7.0 Hz,
2H), 1.60 (broad s, 2H); MS (EI) m/e 227.1171(227.1171 calcd for
C.sub.12H.sub.13N.sub.5)--
Part G
[0501] A mixture of
1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 1.76
mmol) and anhydrous pyridine (60 mL) was heated until a clear
solution was obtained. The solution was then cooled with an ice
bath. Benzoyl chloride (0.25 g, 1.76 mmol) was added. The reaction
mixture was maintained at ambient temperature overnight and then
concentrated under vacuum. The residue was slurried with water (200
mL) and a solid was isolated by filtration. This material was
recrystallized from isopropyl alcohol to provide 0.15 g of
N.sup.1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]benzamide
as a white powder, m.p. 295.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.50 (t, J=6.0 Hz, 1H), 8.23 (d, J=8.0 Hz,
1H), 8.04 (s, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz, 1H),
7.49 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0, 1H), 7.41 (t, J=8.0 Hz,
2H), 7.25 (t, J=8.0 Hz, 1H), 6.28 (broad s, 2H), 4.80 (t, J=7.0 Hz,
2H), 3.80 (q, J=6.0 Hz, 2H); MS (EI) m/e 331.1429 (331.1433 calcd
for C.sub.19H.sub.17N.sub.5O).
EXAMPLE 14
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxybenzami-
de
##STR00030##
[0503] Under a nitrogen atmosphere, a mixture of
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.125 g, 0.49
mmol) and anhydrous pyridine (40 mL) was warmed with a heat gun to
dissolve the solid. The resulting solution was allowed to cool to
ambient temperature. A solution of 2-phenoxybenzoyl chloride (0.11
g, 0.47 mmol) in pyridine (5 mL) was added. The reaction mixture
was maintained at ambient temperature for 18 hours and then
concentrated under vacuum. The resulting solid residue was purified
by flash chromatography (silica gel eluting with 9:1
dichloromethane:methanol) to provide 0.12 g of
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxybenzam-
ide as a white solid, m.p. 93-94.degree. C. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.23 (t, J=6.0 Hz, 1H), 8.14 (s, 1H), 8.00
(d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.0, 1.5 Hz,
1H), 7.43 (dt, J=8.0, 1.5 Hz, 1H), 7.42 (dt, J=8.0, 1.5 Hz, 1H),
7.30 (t, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz,
1H), 7.07 (t, J=8.0 Hz, 1H), 6.89 (m, 3H), 6.59 (broad s, 2H), 4.55
(t, J=7.0 Hz, 2H), 3.23 (q, J=6.0 Hz, 2H), 1.81 (quintet, J=7.0 Hz,
2H), 1.47 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 451.2004 (451.2008
calcd for C.sub.27H.sub.25N.sub.5O.sub.2).
EXAMPLE 15
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-benzoylbenzami-
de
##STR00031##
[0505] Using the method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78
mmol) was reacted with 3-benzoylbenzoyl chloride (0.18 g, 0.73
mmol) to provide 0.19 g of
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-ben-
zoylbenzamide as a white crystalline solid, m.p. 103-105.degree. C.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.70 (t, J=6.0 Hz, 1H),
8.22 (s, 1H), 8.16 (broad s, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.03 (d,
J=8.0 Hz, 0.1H), 7.85 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H),
7.70 (t, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz,
1H), 7.57 (t, J=8.0 Hz, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.19 (t, J=8.0
Hz, 1H), 6.67 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.32 (q, J=6.0
Hz, 2H), 1.91 (quintet, J=7.0 Hz, 2H), 1.59 (quintet, J=7.0 Hz,
2H); MS (EI) m/e 463.2022 (463.2008 calcd for
C.sub.28H.sub.25N.sub.5O.sub.2).
EXAMPLE 16
N'-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenylpropanamide
##STR00032##
[0507] Using the method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78
mmol) was reacted with hydrocinnamoyl chloride (0.11 mL, 0.74 mmol)
to provide 0.14 g of
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenylpr-
opanamide as a white solid, m.p. 148-150.degree. C.
[0508] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H),
8.03 (d, J=8.0 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.63 (d, J=8.0 Hz,
1H), 7.45 (t, J=8.0 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.22 (t, J=8.0
Hz, 2H), 7.15 (m, 3H), 6.66 (broad s, 2H), 4.58 (t, J=7.0 Hz, 2H),
3.06 (q, J=6.0 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.31 (t, J=7.0 Hz,
2H), 1.79 (quintet, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 2H); MS (EI)
m/e 387.2067 (387.2059 calcd for C.sub.23H.sub.25N.sub.5O).
EXAMPLE 17
N.sup.1-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-phenylpropanam-
ide
##STR00033##
[0510] Using the method of Example 14,
1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (100 mg, 0.44
mmol) was reacted with hydrocinnamoyl chloride (0.065 mL, 0.44
mmol) to provide 0.06 g of
N'-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-phenylpr-
opanamide as a white solid, m.p. 254-256.degree. C. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.16 (d, J=8.0 Hz, 1H), 8.07 (t,
J=6.0 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J=8.0, 1.0 Hz, 1H), 7.45
(dt, J=8.0, 1.0 Hz, 1H), 7.26 (m, 3H), 7.16 (m, 3H), 6.6 (broad s,
2H), 4.61 (t, J=7.0 Hz, 2H), 3.54 (q, J=6.0 Hz, 2H), 2.75 (t, J=7.0
Hz, 2H), 2.31 (t, J=7.0 Hz, 2H); MS (EI) m/e 359.1745 (359.1746
calcd for C.sub.21H.sub.21N.sub.5O).
EXAMPLE 18
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-benzoylphen-
oxy)acetamide
##STR00034##
[0512] 1-(4-Aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (99.6 mg,
0.39 mmol) and 2-(4-benzoylphenoxy)acetic acid (100 mg, 0.39 mmol)
were combined in pyridine (10 mL). The mixture was warmed until
homogeneous and then allowed to cool.
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (82
mg, 0.43 mole) was added. The reaction mixture was maintained at
ambient temperature overnight and then concentrated under vacuum.
The residue was partitioned between chloroform and saturated
potassium carbonate solution. The layers were separated. The
aqueous layer was extracted with chloroform. The organic layers
were combined, dried over magnesium sulfate and then concentrated
under vacuum to provide a gold oil. The oil was purified by column
chromatography (silica gel eluting with 10% methanol in
dichloromethane) to provide about 70 mg of
N'-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-benzoylpheno-
xy)acetamide as a white solid, m.p. 73-98.degree. C. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.22 (t, J=6.0 Hz, 1H), 8.18 (s,
1H), 8.03 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0
Hz, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.55
(t, J=8.0 Hz, 2H), 7.42 (dt, J=8.0, 1.0 Hz, 1H), 7.25 (t, J=8.0,
1.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.58 (broad s, 2H), 4.61 (t,
J=7.0 Hz, 2H), 4.56 (s, 2H), 3.18 (q, J=6.0 Hz, 2H), 1.86 (quintet,
J=7.0 Hz, 2H), 1.50 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 493.2106
(493.2114 calcd for C.sub.29H.sub.27N.sub.5O.sub.3).
EXAMPLE 19
N-[4-Amino-1H-imidazo[4,5-c]quinolin-1-yl]butyl-5-[(2-oxo-2,3-dihydro-1H-b-
enzo[d]imidazol-5-yl)oxy]pentamide
##STR00035##
[0514] Using the general method of Example 18,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (100 mg, 0.392
mmol) was coupled with
5-[(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy]pentanoic acid
(98.1 mg, 0.392 mmol) to provide 20 mg of
N-[4-amino-1H-imidazo[4,5-c]quinolin-1-yl]butyl-5-[(2-oxo-2,3-dihydro-1H--
benzo[d]imidazol-5-yl)oxy]pentamide as an off-white solid, m.p.
150-157.degree. C. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.51 (s, 1H), 10.36 (s, 1H), 8.23 (s, 1H), 8.05 (d, J=8.0 Hz, 1H),
7.81 (t, J=6.0 Hz, 1H), 7.64 (t, J=6.0 Hz, 1H), 7.47 (t, J=8.0 Hz,
1H), 7.29 (t, J=8.0 Hz, 1H), 6.93 (broad s, 2H), 6.78 (d, J=8.0 Hz,
1H), 6.48 (s, 1H), 6.47 (d, J=8.0 Hz, 1H), 4.61 (t, J=7.0 Hz, 2H),
3.82 (broad s, 2H), 3.08 (q, J=6.0 Hz, 2H), 2.05 (t, J=7.0 Hz, 2H),
1.84 (quintet, J=7.0 Hz, 2H), 1.58 (broad s, 4H), 1.44 (quintet,
J=7.0 Hz, 2H); MS (EI) m/e 487.2329 (487.2332 calcd for
C.sub.26H.sub.29N.sub.7O.sub.3).
EXAMPLE 20
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin
1-yl)butyl]-4-benzoylbenzamide
##STR00036##
[0516] Using the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.51 g, 2.0
mmol) was reacted with 4-benzoylbenzoyl chloride (2.0 mmol) to
provide 0.15 g of
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin1-yl)butyl]-4-benzoylbenzami-
de as a white solid, m.p. 159-161.degree. C. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.06 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.91 (d,
J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 7.76
(d, J=8.0 Hz, 2H), 7.60 (m, 2H), 7.49 (t, J=8.0 Hz, 2H), 7.48 (t,
J=8.0 Hz, 1H), 7.24 (broad s, 1H), 6.86 (broad s, 1H), 6.60 (t, J=6
Hz, 1H), 4.69 (t, J=7.0 Hz, 2H), 3.62 (q, J=6.0 Hz, 2H), 2.14
(quintet, J=7.0 Hz, 2H), 1.82 (quintet, J=7.0 Hz, 2H); MS (EI) m/e
463.2002 (463.2008 calcd for C.sub.28H.sub.25N.sub.5O.sub.2).
EXAMPLE 21
N.sup.6-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-quinolinecarbo-
xamide
##STR00037##
[0518] Using the general method of Example 18,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.96
mmol) was coupled with 6-quinolinecarboxylic acid (0.34 g, 1.96
mmol) to provide 0.08 g of
N.sup.6-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-qui-
nolinecarboxamide as a tan powder, m.p. 122-127.degree. C.
(foaming). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.98 (m,
1H), 8.73 (t, J=5.4 Hz, 1H), 8.43 (m, 2H), 8.23 (s, 1H), 8.13-8.03
(m, 3H), 7.60 (m, 2H), 7.40 (m, 1H), 7.20 (m, 1H), 6.58 (broad s,
2H), 4.66 (t, J=6.7 Hz, 2H), 3.37 (m, 2H), 1.96 (m, 2H), 1.64 (m,
2H); MS (EI) m/e 410.1847 (410.1855 calcd for
C.sub.24H.sub.22N.sub.6O).
EXAMPLE 22
N.sup.1-[3-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzami-
de
##STR00038##
[0519] Part A
[0520] Using the general method of Example 11 Part C,
N.sup.1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (2.0 g,
5.7 mmol) was reduced to the diamine and then reacted with
triethylorthoacetate to provide 0.74 g of
N.sup.1-[3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide
as a sticky dark yellow solid.
Part B
[0521] Using the general method of Example 11 Part D, the material
from Part A was oxidized to provide 0.35 g of
1-(3-benzamidopropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide
as a solid.
Part C
[0522] Ammonium hydroxide (20 mL) was added to a solution of
1-(3-benzamidopropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-5N-oxide
(0.35 g, 0.97 mmol) in dichloromethane (100 mL). Tosyl chloride
(0.185 g, 0.97 mmol) was slowly added with vigorous stirring. The
reaction mixture was stirred overnight at ambient temperature and
then it was concentrated under vacuum to remove the
dichloromethane. The resulting solid was recrystallized from
dichloromethane to provide 0.1 g of
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide
as a solid, m.p. 230-231.4.degree. C.
EXAMPLE 23
N.sup.1-[6-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)hexyl]benzamide
##STR00039##
[0523] Part A
[0524] Using the general method of Example 9 Part A,
hexamethylenediamine (348.63 g, 3 mol) was reacted with benzamide
(121.14 g, 1 mole) to provide 136.5 g of
N-(6-aminohexyl)benzamide.
Part B
[0525] Using the general method of Example 9 Part B,
4-chloro-3-nitroquinoline hydrochloride (10 g, 41 mmol) was reacted
with N-(6-aminohexyl)benzamide to provide 12.85 g of
N'-{6-[(3-nitroquinolin-4-yl)amino]hexyl}benzamide as a yellow
crystalline solid.
Part C
[0526] Using the general method of Example 9 Part C, 12.3 g of the
material from part B was reduced and then reacted with
triethylorthoformate (8.94 g, 6 mmol) to provide 6.4 g of
N.sup.1-[6-(1H-imidazo[4,5-c]quinolin-1-yl)hexyl]benzamide as a
brown oil.
Part D
3-Chloroperoxybenzoic acid (5.9 g, 17 mmol) was slowly added to a
solution of the material from Part C in chloroform. The solution
turned orange. After 2 hours the reaction mixture was washed twice
with aqueous sodium carbonate and then concentrated under vacuum to
provide 6.0 g of
1-(6-benzamidohexyl)-1H-imidazo[4,5-c]quinoline-5N-oxide as an
orange oil.
Part E
[0527] Ammonium hydroxide was added to a solution of the material
from Part D in dichloromethane. Tosyl chloride (2.94 g, 15 mmol)
was slowly added with vigorous stirring. The reaction mixture was
allowed to stir at ambient temperature overnight and then it was
concentrated under vacuum. The resulting crude material was
recrystallized from propyl acetate to provide 0.91 g of
N.sup.1-[6-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)hexyl]benzamide
as a beige crystalline solid, m.p. 146-155.degree. C.
EXAMPLE 24
N.sup.1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(2-oxo-
perhydrothieno[3,4-d]imimidazol-4-yl)pentanamide
##STR00040##
[0529] D-biotinyl N-hydroxysuccinimide (0.57 g, 1.67 mmol) was
added to a solution of
1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.52 g,
1.67 mmol) in pyridine (25 mL). The reaction was maintained at
ambient temperature overnight and then concentrated to dryness. The
residue was partitioned between dichloromethane and aqueous
saturated potassium carbonate. The organic layer was dried over
magnesium sulfate and then concentrated to provide 0.4 g of
N.sup.1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-5-(2-oxoperhy-
drothieno[3,4-d]imidazol-4-yl)pentamide as a solid, m.p.
214-215.degree. C. Analysis: Calculated for
C.sub.28H.sub.39N.sub.7O.sub.2S: % C, 62.54; % H, 7.31; % N, 18.23;
Found: % C, 61.67; % H, 7.37; % N, 17.62.
EXAMPLE 25
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(2-oxoperhydro-
thieno[3,4-d]imidazol-4-yl)pentanamide
##STR00041##
[0531] A solution of
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.38 g, 1.49
mmol) in pyridine-(20 mL) was added to a solution of
N-hydroxysuccinimidobiotin (0.51 g, 1.49 mmol) in pyridine (20 mL).
The reaction was maintained at ambient temperature overnight and
then concentrated to dryness. The residue was partitioned between
dichloromethane and aqueous saturated potassium carbonate. The
organic layer was dried over magnesium sulfate and then
concentrated to provide 0.58 g of
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-5-(2-oxoper-
hydrothieno[3,4-d]imidazol-4-yl)pentamide as a solid, m.p.
104-106.degree. C. High resolution mass spec: Theoretical
mass=481.2260, Measured mass=481.2261.
EXAMPLE 26
N.sup.1-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-imi-
noperhydrothieno[3,4-d]imidazol-4-yl)pentanamide
##STR00042##
[0533] A solution of N-hydroxysuccinimidoiminobiotin (0.74 g, 1.76
mmol) in pyridine (10 mL) was slowly added to a solution of
1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g,
1.76 mmol) in pyridine (30 mL). The reaction was maintained at
ambient temperature overnight and then concentrated to dryness. The
residue was partitioned between dichloromethane and aqueous
saturated potassium carbonate. The organic layer was dried over
magnesium sulfate and then concentrated to dryness. The residue was
recrystallized from ethanol to provide 0.5 g of
N'-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-iminope-
rhydrothieno[3,4-d]imidazol-4-yl)pentanamide as a solid, m.p.
95-96.degree. C. High resolution mass spec: Theoretical
mass=508.2733, Measured mass=508.2723.
EXAMPLE 27
N.sup.1-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydro-
thieno[3,4-a]imidazol-4-yl)pentanamide
##STR00043##
[0535] Using the general method of Example 24,
N-hydroxysuccinimidobiotin (0.6 g, 1.76 mmol) was reacted with
1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.76
mmol) to provide 0.6 g of
N.sup.1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydr-
othieno[3,4-d]imidazol-4-yl)pentanamide as a solid, m.p.
169.degree. C.
EXAMPLE 28
N'-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhy-
drothieno[3,4-d]imidazol-4-yl)pentanamide
##STR00044##
[0537] Using the general method of Example 25,
1-(4-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g,
1.47 mmol) was reacted with N-hydroxysuccinimidobiotin (0.5 g, 1.47
mmol) to provide 0.44 g of
N'-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperh-
ydrothieno[3,4-d]imidazol-4-yl)pentanamide as a white solid, m.p.
124-126.degree. C. High resolution mass spec: Theoretical
mass=509.25, Measured mass 509.2580.
EXAMPLE 29
N.sup.1-[2-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-
-5-(2-oxoperhydrothieno[3,4-d](imidazol-4-yl)pentanamide
Ditrifluoroacetate
##STR00045##
[0539] Triethylamine (1.2 g, 11.4 mmol) was added in a single
portion to a slurry of
1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-a-
mine hydrochloride (3.39 g, 10.53 mmol) in chloroform (150 mL). The
reaction mixture became clear. N-hydroxysuccinimidobiotin (3.0 g,
8.79 mmol) was then slowly added. After 2 hours the turbid reaction
mixture was heated to reflux. The reaction mixture was maintained
at reflux overnight and became clear. The reaction mixture was
allowed to cool to ambient temperature and then it was quenched
with water. The layers were separated. The organic layer was dried
over magnesium sulfate and then concentrated to provide an
off-white solid. This material was recrystallized from 8:2
ethanol:water to provide a white solid. A portion of this material
was purified by prep HPLC eluting with
water/acetonitrile/trifluoroacetic acid to provide 0.6 g of
N-[2-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-
-oxoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as the
ditrifluoroacetate salt, m.p. 171-175.degree. C. Analysis:
Calculated for: C.sub.25H.sub.33N.sub.7O.sub.3S 2
C.sub.2HF.sub.3O.sub.2: % C, 47.09; % H, 4.77; % N, 13.26; Found: %
C, 47.06; % H, 5.17; % N, 13.31.
EXAMPLE 30
N.sup.1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-(5-met-
hyl-2-oxo-4-imidazolinyl)hexaneamide
##STR00046##
[0541] 1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine
(0.13 g, 0.47 mmol), D-desthiobiotin (0.10 g, 0.47 mmol) and
chloroform (200 mL) were combined and stirred at ambient
temperature until a clear solution was obtained.
1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.094
g, 0.49 mmol) was added and the reaction mixture was maintained at
ambient temperature overnight. The reaction mixture was poured onto
a silica gel column. The chloroform was allowed to run off and then
the column was eluted with 10% methanol in dichloromethane. The
pure fractions were combined and concentrated to provide
N'-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-(5-methyl--
2-oxo-4-imidazolinyl)hexaneamide as a white solid.
EXAMPLE 31
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethoxy-1-napht-
hamide
##STR00047##
[0543] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
2-ethoxy-1-naphthoyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethoxy-1-naph-
thamide as a white powder, m.p. 219.degree. C. (decomposition).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.33 (t, J=5.8 Hz, 1H),
8.22 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H),
7.87-7.84 (m, 1H), 7.64-7.56 (m, 2H), 7.47-7.22 (m, 5H), 6.60 (s,
2H), 4.69 (t, J=7.2 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.37 (m, 2H),
2.01 (m, 2H), 1.64 (m, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) m/e
453.2157 (453.2165 calcd for C.sub.27H.sub.27N.sub.5O.sub.2).
EXAMPLE 32
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-cyanobenzamide
##STR00048##
[0545] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
4-cyanobenzoyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-cyanobenzamid-
e as a white powder, m.p. 222.8-225.3.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.73 (t, J=5.7 Hz, 1H), 8.22 (s, 1H),
8.03 (d, J=8.1 Hz, 1H), 7.93 (s, 4H), 7.61 (dd, J=8.4, 1.2 Hz, 1H),
7.43 (dt, J=7.6, 1.5 Hz, 1H), 7.21 (dt, J=7.6, 1.2 Hz, 1H), 6.61
(s, 2H), 4.64 (t, J=7.2 Hz, 2H), 3.33 (m, 2H), 1.96 (quintet, J=7.2
Hz, 2H), 1.58 (quintet, J=7.2 Hz, 2H); IR (KBr) 3441, 3337, 3136,
2945, 2228, 1641, 1545, 1531, 1481, 1396, 1309, 1257, 857, 755
cm.sup.-1; MS (EI) m/e 384.1699 (384.1699 calcd for
C.sub.22H.sub.20N.sub.6O).
EXAMPLE 33
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-cyanobenzamide
##STR00049##
[0547] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
3-cyanobenzoyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-cyanobenzamid-
e as a white crystalline solid, m.p. 200.0-201.0.degree. C.
(decomposition). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.68
(t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.10-7.97
(m, 3H), 7.69-7.60 (m, 2H), 7.42 (dt, J=7.5, 1.2 Hz, 1H), 7.20 (dt,
J=7.5, 1.5 Hz, 1H), 6.62 (s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.32 (m,
2H), 1.91 (quintet, J=7.5 Hz, 2H), 1.59 (quintet, J=7.5 Hz, 2H); IR
(KBr) 3455, 3295, 3072, 2941, 2231, 1638, 1581, 1527, 1479, 1396,
1312, 1251, 1205 cm.sup.-1; MS (EI) m/e 384.1699 (384.1699 calcd
for C.sub.22H.sub.20N.sub.6O).
EXAMPLE 34
N'-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenylbenzamide
##STR00050##
[0549] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
4-biphenylcarbonyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenylbenzami-
de as a white powder, m.p. 215.4.degree. C. (decomposition).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.54 (t, J=5.7 Hz, 1H),
8.22 (s, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.88 (d, J=5.4 Hz, 2H),
7.75-7.70 (m, 4H), 7.62 (dd, J=8.4, 1.5 Hz, 1H), 7.52-7.38 (m, 4H),
7.22 (dt, J=7.5, 1.2 Hz, 1H), 6.61 (s, 2H), 4.65 (t, J=7.2 Hz, 2H),
3.30 (m, 2H), 1.93 (quintet, J=7.5 Hz, 2H), 1.60 (quintet, J=7.5
Hz, 2H); MS (EI) m/e 435.2054 (435.2059 calcd for
C.sub.27H.sub.25N.sub.5O).
EXAMPLE 35
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxyacetami-
de
##STR00051##
[0551] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
phenoxyacetyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxyacetam-
ide as an off white powder, m.p. 61.5.degree. C. (decomposition).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H), 8.12 (t,
J=6.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz,
1H), 7.44 (dt, J=7.5, 1.2 Hz, 1H), 7.29-7.21 (m, 3H), 6.96-6.88 (m,
3H), 6.62 (s, 2H), 4.60 (t, J=7.2 Hz, 2H), 4.42 (s, 2H), 3.16 (q,
J=6.9 Hz, 2H), 1.83 (quintet, J=7.2 Hz, 2H), 1.47 (quintet, J=7.2
Hz, 2H); IR (KBr) 3311, 3180, 2937, 1664, 1618, 1583, 1527, 1493,
1480, 1396, 1244, 755 cm.sup.-1; MS (EI) m/e 389.1844 (389.1852
calcd for C.sub.22H.sub.23N.sub.5O.sub.2).
EXAMPLE 36
N'-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethylhexanamide
##STR00052##
[0553] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
2-ethylhexanoyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethylhexanami-
de as a tan powder, m.p. 163.0-164.0.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H), 8.03 (d, J=8.1 Hz, 1H),
7.79 (m, 1H), 7.61 (dd, J=8.1, 1.2 Hz 1H), 7.44 (dt, J=7.5, 1.2 Hz,
1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.63 (s, 2H), 4.61 (t, J=6.9 Hz,
2H), 3.12-3.05 (m, 2H), 1.94-1.82 (m, 3H), 1.49-1.03 (m, 10H), 0.76
(t, J=7.2 Hz, 3H), 0.67 (t, J=7.2 Hz, 3H); MS (EI) m/e 381.2533
(381.2529 calcd for C.sub.22H.sub.31N.sub.5O).
EXAMPLE 37
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-(trans)-2-phenyl-
cyclopropane-1-carboxamide
##STR00053##
[0555] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
trans-2-phenyl-1-cyclopropanecarbonyl chloride were combined to
provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-(trans)-2-pheny-
lcyclopropane-1-carboxamide as an off white solid, m.p.
77.0.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.90
(dd, J=8.1, 1.2 Hz, 1H), 7.81 (dd, J=8.1, 1.2 Hz, 1H), 7.78 (s,
1H), 7.50 (dt, J=8.1, 1.5 Hz, 1H), 7.33-7.15 (m, 4H), 7.05-7.02 (m,
2H), 5.84 (broad s, 1H), 5.51 (s, 2H), 4.52 (t, J=7.2 Hz, 2H), 3.32
(q, J=6.6 Hz, 2H), 2.49-2.43 (m, 1H), 2.07-1.95 (m, 3H), 1.64-1.51
(m, 3H), 1.25-1.18 (m, 1H); IR (KBr) 3304, 3179, 2939, 1640, 1582,
1527, 1479, 1396, 1250, 755, 735, 689 cm.sup.-1; MS (EI) m/e
399.2059 (399.2059 calcd for C.sub.24H.sub.25N.sub.5O).
EXAMPLE 38
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-naphthamide
##STR00054##
[0557] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 1-naphthoyl
chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-naphthamide
as an off white powder, m.p. 174.5.degree. C. (decomposition).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.52 (t, J=5.6 Hz, 1H),
8.49 (s, 1H), 8.24 (m, 3H), 8.10 (d, J=8.1 Hz, 1H), 7.97 (m, 2H),
7.80 (d, J=8.2 Hz, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.57-7.41 (m, 5H),
4.75 (t, J=6.9 Hz, 2H), 2.03-1.98 (m, 2H), 1.69-1.64 (m, 2H); MS
(EI) m/e 409.1903 (409.1903 calcd for
C.sub.25H.sub.23N.sub.5O).
EXAMPLE 39
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenoxybenzami-
de
##STR00055##
[0559] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
3-phenoxybenzoyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenoxybenzam-
ide as a white powder, m.p. 105.0-107.0.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.54 (t, J=5.4 Hz, 1H), 8.34 (s, 1H),
8.10 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.1, 1.2 Hz, 1H), 7.58-7.29 (m,
9H), 7.19-7.13 (m, 2H), 7.04-6.99 (m, 2H), 4.65 (t, J=7.2 Hz, 2H),
3.28 (m, 2H), 1.89 (quintet, J=7.2 Hz, 2H), 1.58 (quintet, J=7.2
Hz, 2H); MS (EI) m/e 451.2012 (451.2008 calcd for
C.sub.27H.sub.25N.sub.5O.sub.2).
EXAMPLE 40
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-quinolinecarbo-
xamide
##STR00056##
[0561] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
quinoline-3-carbonyl chloride were combined to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-quinolinecarb-
oxamide as a white crystalline solid, m.p. 116.0-118.0.degree. C.
(decomposition). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.24
(d, J=2.1 Hz, 1H), 8.86 (t, J=5.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H),
8.25 (s, 1H), 8.09-8.05 (m, 3H), 7.86 (dt, J=7.5, 1.0 Hz, 1H), 7.69
(t, J=7.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H),
7.21 (t, J=7.5 Hz, 1H), 6.68 (s, 2H), 4.67 (t, J=6.9 Hz, 2H), 1.97
(quintet, J=7.2 Hz, 2H), 1.65 (quintet, J=7.2 Hz, 2H); MS (EI) m/e
410.1864 (410.1855 calcd for C.sub.24H.sub.22N.sub.6O).
EXAMPLE 41
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxypropana-
mide
##STR00057##
[0563] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
2-phenoxypropionyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxypropan-
amide as a white powder, m.p. 85.0-87.5.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.15 (s, 1H), 8.07 (t, J=6.0 Hz, 1H),
8.00 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (dt,
J=7.5, 1.2 Hz, 1H), 7.28-7.16 (m, 3H), 6.91-6.81 (m, 3H), 6.57 (s,
2H), 4.62-4.53 (m, 3H), 3.10 (q, J=6.9 Hz, 2H), 1.76 (quintet,
J=7.1 Hz, 2H), 1.43 (quintet, J=7.1 Hz, 2H), 1.33 (d, J=6.6 Hz,
3H); MS (EI) m/e 403.2005 (403.2008 calcd for
C.sub.23H.sub.25N.sub.5O.sub.2).
EXAMPLE 42
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzyl-1H-3-in-
dolecarboxamide
##STR00058##
[0565] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
1-benzylindole-3-carbonyl chloride were combined to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzyl-1H-3-i-
ndolecarboxamide as a white powder, m.p. 139.0.degree. C.
(decomposition). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.24
(s, 1H), 8.14 (t, J=7.8 Hz, 1H), 8.04 (m, 2H), 7.93 (m, 1H), 7.62
(d, J=8.4 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.44-7.09 (m, 9H), 6.63
(s, 2H), 5.44 (s, 2H), 4.66 (t, J=6.6 Hz, 2H), 1.97-1.92 (m, 2H),
1.62-1.57 (m, 2H); MS (EI) m/e 488.2326 (488.2325 calcd for
C.sub.30H.sub.28N.sub.6O).
EXAMPLE 43
N.sup.2-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-naphthamide
##STR00059##
[0567] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-naphthoyl
chloride were combined to provide
N.sup.2-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-naphthamide
as a white powder, m.p. 257.0.degree. C. (decomposition). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 8.85 (broad s, 2H), 8.69 (broad
s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=8.4 Hz, 1H),
7.99-7.80 (m, 5H), 7.75-7.50 (m, 4H), 4.75 (t, J=6.9 Hz, 2H), 3.39
(m, 2H), 1.98 (quintet, J=7.2 Hz, 2H), 1.68 (quintet, J=7.2 Hz,
2H); MS (EI) m/e 409.1909 (409.1903 calcd for
C.sub.25H.sub.23N.sub.5O).
EXAMPLE 44
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2,6-dimethoxynic-
otinamide
##STR00060##
[0569] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
2,6-dimethoxynicotinoyl chloride were combined to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2,6-dimethoxyni-
cotinamide as an off white powder, m.p. 175.0-177.0.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.21 (s, 1H), 8.11-8.02
(m, 3H), 7.62 (d, J=8.2 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.20 (t,
J=7.5 Hz, 1H), 6.58 (broad s, 2H), 6.46 (d, J=8.3 Hz, 1H), 4.63 (t,
J=7.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.30 (m, 2H), 1.90 (m,
2H), 1.57 (m, 2H); MS (EI) m/e 420.1909 (420.1910 calcd for
C.sub.22H.sub.24N.sub.6O.sub.3).
EXAMPLE 45
N.sup.8-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-8-quinolinecarbo-
xamide
##STR00061##
[0571] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
quinoline-8-carbonyl chloride were combined to provide
N.sup.8-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-8-quinolinecarb-
oxamide as a tan powder, m.p. 91.0-93.0.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 10.80 (t, J=5.5 Hz, 1H), 8.79 (dd,
J=4.3, 1.8 Hz, 1H), 8.55-8.49 (m, 2H), 8.24 (s, 1H), 8.17 (dd,
J=8.1, 1.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H),
7.63-7.59 (m, 2H), 7.40 (dt J=7.1, 1.2 Hz, 1H), 7.14 (dt, J=7.1,
1.2 Hz, 1H), 6.57 (broad s, 2H), 4.68 (t, J=7.0 Hz, 2H), 3.51 (m,
2H), 2.02 (m, 2H), 1.69 (m, 2H); MS (EI) m/e 410.1858 (410.1855
calcd for C.sub.24H.sub.22N.sub.6O).
EXAMPLE 46
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-isobutylphe-
nyl)propanamide
##STR00062##
[0573] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
4-isobutyl-.alpha.-methylphenylacetyl chloride were combined to
provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-isobutylph-
enyl)propanamide as a white powder, m.p. 172.0-173.0.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.14 (s, 1H), 8.01 (d,
J=7.6 Hz, 1H), 7.90 (t, J=5.6 Hz, 1H), 7.63 (dd, J=8.1, 1.0 Hz,
1H), 7.44 (dt, J=7.0, 1.0 Hz, 1H), 7.25 (dt, J=7.0 Hz, 1H), 7.14
(d, J=8.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 6.58 (broad s, 2H), 4.55
(t, J=7.0 Hz, 2H), 3.47 (q, J=7.1 Hz, 1H), 3.06 (m, 2H), 2.34 (d,
J=7.1 Hz, 2H), 1.80-1.69 (m, 3H), 1.44 (m, 2H), 1.24 (d, J=7.0 Hz,
3H), 0.82 (d, J=6.6 Hz, 6H); MS (EI) m/e 443.2687 (443.2685 calcd
for C.sub.27H.sub.33N.sub.5O).
EXAMPLE 47
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide
##STR00063##
[0575] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and nicotinoyl
chloride hydrochloride were combined to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide
as a white powder, m.p. 188.6-189.5.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.95 (dd, J=2.2, 0.7 Hz, 1H), 8.70-8.65
(m, 2H), 8.22 (s, 1H), 8.11 (dt, J=8.3, 2.0 Hz, 1H), 8.04 (dd,
J=8.2, 0.9 Hz, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.50-7.39 (m,
2H), 7.23-7.18 (m, 1H), 6.58 (broad s, 2H), 4.64 (t, J=7.0 Hz, 2H),
3.30 (m, 2H), 1.93 (m, 2H), 1.60 (m, 2H); MS (EI) m/e 360.1696
(360.1699 calcd for C.sub.20H.sub.20N.sub.6O).
EXAMPLE 48
N.sup.4-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]
isonicotinamide
##STR00064##
[0577] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
isonicotinoyl chloride hydrochloride were combined to provide
N.sup.4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isonicotinamide
as a white crystalline solid, m.p. 213.0-213.7.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 8.76 (m, 1H), 8.69 (d, J=5.6
Hz, 2H), 8.22 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.67 (d, J=5.7 Hz,
2H), 7.62 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.5
Hz, 1H), 6.62 (broad s, 2H), 4.64 (t, J=6.8 Hz, 2H), 3.30 (m, 2H),
1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 360.1699 (360.1699 calcd
for C.sub.20H.sub.20N.sub.6O).
EXAMPLE 49
N.sup.4-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-quinolinecarbo-
xamide
##STR00065##
[0579] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
quinoline-4-carbonyl chloride were combined to provide
N.sup.4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-quinolinecarb-
oxamide as a white crystalline solid, m.p. 214.5-215.2.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.89 (d, J=4.3 Hz, 1H),
8.76 (t, J=5.6 Hz, 1H), 8.24 (s, 1H), 8.10-8.01 (m, 3H), 7.78 (ddd,
J=8.4, 6.9, 1.5 Hz, 1H), 7.64 (dd, J=8.4, 1.1 Hz, 1H), 7.56 (ddd,
J=8.3, 6.9, 1.4 Hz, 1H), 7.44 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.34
(d, J=4.3 Hz, 1H), 7.24 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 6.60 (broad
s, 2H), 4.68 (t, J=6.9 Hz, 2H), 3.38 (q, J=7.0 Hz, 2H), 2.00 (m,
2H), 1.63 (m, 2H); MS (EI) m/e 410.1860 (410.1855 calcd for
C.sub.24H.sub.22N.sub.6O).
EXAMPLE 50
N.sup.4-[4-(4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)buty-
l]-2-phenyl-4-quinolinecarboxamide
##STR00066##
[0581] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (0.57 g, 3.0 mmol) was added dropwise to a chilled
(0.degree. C.) solution of 2-phenyl-4-quinolinecarboxylic acid (0.5
g, 3.7 mmol), 1-hydroxybenzotriazole (0.5 g, 3.7 mmol), pyridine
(2.2 ml), and dichloromethane (20 ml). The reaction was maintained
for 15 min followed by the dropwise addition of
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(0.8 g, 2.55 mmol) in dichloromethane (100 ml). The reaction was
maintained at room temperature overnight. The solvent was removed
in vacuo and the residue was purified by flash column
chromatography (silica gel, 9:1 dichloromethane\methanol). The
fractions containing product were combined, washed with saturated
aqueous sodium bicarbonate, dried (MgSO.sub.4), filtered, and
concentrated to provide 0.62 g of
N.sup.4-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)but-
yl]-2-phenyl-4-quinolinecarboxamide as a yellow crystalline solid,
m.p. 118.degree. C. (decomposition). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.88 (t, J=5.7 Hz, 1H), 8.24-8.21 (m, 2H),
8.13-8.01 (m, 4H), 7.83-7.78 (m, 1H), 7.62-7.48 (m, 5H), 7.36 (m,
1H), 7.20 (dt, J=7.6, 1.2 Hz, 1H), 6.54 (broad s, 2H), 4.62 (t,
J=7.2 Hz, 2H), 3.83 (t, J=6.7 Hz, 2H), 3.45 (m, 2H), 3.29-3.20 (m,
5H), 1.96 (m, 2H), 1.79 (m, 2H); MS (EI) m/e 544.2589 (544.2587
calcd for C.sub.33H.sub.32N.sub.6O.sub.2).
EXAMPLE 51
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(pentylsulfany-
l)nicotinamide
##STR00067##
[0583] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
2-(n-pentylthio)pyridine-3-carbonyl chloride were combined to
provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(pentylsulfan-
yl)nicotinamide as a tan powder, m.p. 158.0-161.0.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.47-8.41 (m, 2H), 8.21
(s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.3, 1.1 Hz, 1H), 7.54
(dd, J=7.6, 1.8 Hz, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 1H), 7.08
(dd, J=7.5, 4.8 Hz, 1H), 6.57 (broad s, 2H), 4.64 (t, J=6.9 Hz,
2H), 3.27 (m, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.96 (m, 2H), 1.62-1.46
(m, 4H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.1 Hz, 3H); MS (EI) m/e
462.2196 (462.2202 calcd for C.sub.25H.sub.30N.sub.6OS).
EXAMPLE 52
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-cyanonicotinam-
ide
##STR00068##
[0585] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
6-cyanopyridine-3-carbonyl chloride were combined to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-cyanonicotina-
mide as an off white powder, m.p. 125.0-129.0.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 9.05 (dd, J=2.1, 0.8 Hz, 1H),
8.88 (t, J=5.6 Hz, 1H), 8.31 (dd, J=8.1, 2.1 Hz, 1H), 8.21 (s, 1H),
8.14 (dd, J=8.1, 0.8 Hz, 1H), 8.03 (m, 1H), 7.62 (dd, J=8.3, 1.1
Hz, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.59 (broad s, 2H), 4.64 (t,
J=6.9 Hz, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.59 (m, 2H); MS (EI)
m/e 385.1648 (385.1651 calcd for C.sub.21H.sub.19N.sub.7O).
EXAMPLE 53
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-chloronicotina-
mide
##STR00069##
[0587] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
6-chloropyridine-3-carbonyl chloride were combined to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-chloronicotin-
amide as an off white crystalline solid, m.p. 144.0-148.0.degree.
C. (decomposition). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.77 (dd, J=2.5, 0.6 Hz, 1H), 8.73 (t, J=5.6 Hz, 1H), 8.22 (s, 1H),
8.16 (dd, J=8.3, 2.5 Hz, 1H), 8.03 (m, 1H), 7.63 (d, J=0.5 Hz, 1H),
7.60 (d, J=0.5 Hz, 1H), 7.45-7.40 (m, 1H), 7.23-7.18 (m, 1H), 6.61
(broad s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.92 (m, 2H),
1.58 (m, 2H). MS (EI) m/e 394.1298 (394.1309 calcd for
C.sub.20H.sub.19N.sub.6OCl).
EXAMPLE 54
N.sup.3-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-(2,2,2-trifluo-
roethoxy)nicotinamide
##STR00070##
[0589] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
6-(2,2,2-trifluoroethoxy)pyridine-3-carbonyl chloride were combined
to provide
N.sup.3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-6-(2,2,-
2-trifluoroethoxy)nicotinamide as a white crystalline solid, m.p.
192.0-194.0.degree. C. (decomposition). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.62 (d, J=1.9 Hz, 1H), 8.58 (t, J=5.6 Hz,
1H), 8.25 (s, 1H), 8.15 (dd, J=8.6, 2.4 Hz, 1H), 8.06 (d, J=7.6 Hz,
1H), 7.64 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.1 Hz, 1H), 7.24 (t, J=7.1
Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.82 (broad s, 2H), 5.06 (q, J=9.1
Hz, 2H), 4.64 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 1.91 (m, 2H), 1.60
(m, 2H); MS (EI) m/e 458.1678 (458.1678 calcd for
C.sub.22H.sub.21N.sub.6O.sub.2F.sub.3).
EXAMPLE 55
N.sup.2-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-2-quinolinecarboxamide
##STR00071##
[0591] According to the general method of Example 14,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and quinoline-2-carbonyl chloride were combined in dichloromethane
and triethylamine (3 equivalents) to provide
N.sup.2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-2-quinolinecarboxamide as a white solid, m.p. 78.1-79.9.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.02 (t, J=6.1 Hz,
1H), 8.55 (d, J=8.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.10 (t, J=7.6
Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.75-7.70 (m,
1H), 7.58 (dd, J=8.3, 1.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.18-7.13 (m,
2H), 6.48 (broad s, 2H), 4.58 (m, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.44
(m, 2H), 3.22 (m, 5H), 1.91-1.78 (m, 4H); MS (EI) m/e 468.2276
(468.2274 calcd for C.sub.27H.sub.28N.sub.6O.sub.2).
EXAMPLE 56
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(2-fluoro-4-bi-
phenylyl)propanamide
##STR00072##
[0593] According to the general method of Example 14,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and 2-(2-fluoro-4-biphenylyl)propionyl chloride were combined to
provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(2-fluoro-4-b-
iphenylyl)propanamide as a white powder, m.p. 76.1-79.9.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.17 (s, 1H), 8.03 (m,
2H), 7.62 (d, J=8.3 Hz, 1H), 7.49-7.14 (m, 10H), 6.59 (broad s,
2H), 4.58 (t, J=6.9 Hz, 2H), 3.59 (q, J=7.0 Hz, 1H), 3.09 (pentet,
J=6.7 Hz, 2H), 1.82 (m, 2H), 1.45 (m, 2H), 1.30 (d, J=7.0 Hz, 3H);
MS (EI) m/e 481.2268 (481.2278 calcd for
C.sub.29H.sub.28FN.sub.5O).
EXAMPLE 57
N.sup.1-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-1-isoquinolinecarboxamide
##STR00073##
[0595] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and isoquinoline-1-carboxylic acid were combined to provide
N.sup.1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-1-isoquinolinecarboxamide as a yellow crystalline solid, m.p.
61.0-63.0.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.94 (t, J=5.9 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 8.51 (d, J=5.6 Hz,
1H), 8.05-7.96 (m, 3H), 7.84-7.96 (m, 1H), 7.70-7.65 (m, 1H), 7.61
(dd, J=8.3, 1.1 Hz, 1H), 7.37 (dt, J=7.7, 1.0 Hz, 1H), 7.19 (dt,
J=7.6, 1.2 Hz, 1H), 6.53 (broad s, 2H), 4.60 (t, J=7.2 Hz, 2H),
3.81 (t, J=6.7 Hz, 2H), 3.41 (m, 2H), 3.28-3.12 (m, 5H), 1.92-1.76
(m, 4H); MS (EI) m/e 468.2261 (468.2274 calcd for
C.sub.27H.sub.28N.sub.6O.sub.2).
EXAMPLE 58
N.sup.2-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-5-butyl-2-pyridinecarboxamide
##STR00074##
[0597] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and fusaric acid were combined to provide
N.sup.2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-5-butyl-2-pyridinecarboxamide as a tan solid, m.p.
54.9-55.2.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.81 (t, J=6.1 Hz, 1H), 8.44 (m, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.94
(dd, J=8.0, 0.7 Hz, 1H), 7.80 (dd, J=8.0, 2.2 Hz, 1H), 7.60 (dd,
J=8.3, 1.2 Hz, 1H), 7.39-7.34 (m, 1H), 7.16-7.10 (m, 1H), 6.52
(broad s, 2H), 4.55 (t, J=6.9 Hz, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.23
(s, 3H), 3.18 (t, J=6.7 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.83-1.72
(m, 4H), 1.63-1.53 (m, 2H), 1.34-1.24 (m, 2H), 0.90 (t, J=7.3 Hz,
3H); MS (EI) m/e 474.2750 (474.2743 calcd for
C.sub.27H.sub.34N.sub.6O.sub.2).
EXAMPLE 59
N.sup.3-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-3-indolecarboxamide
##STR00075##
[0599] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and indole-3-carboxylic acid were combined to provide
N.sup.3-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-3-indolecarboxamide as a white powder, m.p. 225.5-227.4.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.50 (broad s, 1H),
8.13 (d, J=7.9 Hz, 1H), 8.06 (d, J=10.2 Hz, 1H), 7.95-7.89 (m, 2H),
7.61 (d, J=8.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.20-7.05 (m, 3H), 6.48
(broad s, 2H), 4.58 (t, J=7.2 Hz, 2H), 3.80 (t, J=6.6 Hz, 2H), 3.33
(m, 2H), 3.24-3.18 (m, 5H), 1.88 (m, 2H), 1.70 (m, 2H); .sup.13C
NMR (75 MHz, DMSO-d.sub.6) .delta. 165.0, 152.0, 151.0, 145.1,
136.4, 132.6, 127.8, 126.8, 126.6, 126.4, 122.1, 121.5, 121.4,
120.6, 120.3, 115.1, 112.1, 111.0, 70.5, 58.4, 45.1, 38.2, 27.7,
27.5, 27.0; MS (EI) m/e 456.2282 (456.2274 calcd for
C.sub.26H.sub.28N.sub.6O.sub.2).
EXAMPLE 60
N.sup.1-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-4-(1-pyrrolyl)benzamide
##STR00076##
[0601] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and 4-(1-pyrrolyl)benzoic acid were combined to provide
N.sup.1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-4-(1-pyrrolyl)benzamide as an off white powder, m.p.
173.0-174.9.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.52 (t, J=5.5 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.90 (d, J=8.7 Hz,
2H), 7.67 (d, J=8.7 Hz, 2H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.48 (t,
J=2.2 Hz, 2H), 7.39 (m, 1H), 7.19 (dt, J=7.6, 1.1 Hz, 1H), 6.53
(broad s, 2H), 6.30 (t, J=2.2 Hz, 2H), 4.57 (t, J=7.0 Hz, 2H), 3.82
(t, J=6.7 Hz, 2H), 3.33 (m, 2H), 3.26 (s, 3H), 3.20 (t, J=6.7 Hz,
2H), 1.87 (m, 2H), 1.71 (m, 2H); MS (EI) m/e 482.2421 (482.2430
calcd for C.sub.28H.sub.30N.sub.6O.sub.2).
EXAMPLE 61
[0602]
N.sup.2-{4-[4-Amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-
-yl]butyl}-2-quinolinecarboxamide
##STR00077##
[0603] Quinoline-2-carbonyl chloride (0.28 g in 10 ml
dichloromethane, 1.46 mmol) was added dropwise to a stirring
solution of
1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine
(0.49 g, 1.3 mmol), dichloromethane (140 ml) and triethylamine (0.5
ml). The reaction was maintained for 17 hours and then concentrated
in vacuo. The yellow residue was partitioned between
dichloromethane and saturated aqueous sodium bicarbonate. The
organic fraction was dried (MgSO.sub.4), filtered, and
concentrated. The crude residue was purified by flash column
chromatography (silica gel, gradient elution using dichloromethane
to 95:5 dichloromethane\methanol) to provide 0.19 g of
N.sup.2-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]bu-
tyl}-2-quinolinecarboxamide as an off white solid, m.p.
95.1-97.4.degree. C. .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta.
8.97 (t, J=6.0 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.16-8.07 (m, 3H),
7.96 (d, J=7.7 Hz, 1H), 7.87 (m, 1H), 7.72 (m, 1H), 7.58 (dd,
J=8.3, 1.1 Hz, 1H), 7.31 (m, 1H), 7.23 (d, J=8.7 Hz, 2H), 7.08 (m,
1H), 6.82 (d, J=8.7 Hz, 2H), 6.58 (broad s, 2H), 4.50 (m, 2H), 4.33
(s, 2H), 3.63 (s, 3H), 3.34 (m, 2H), 1.65 (m, 4H); MS (EI) m/e
530.2431 (530.2430 calcd for C.sub.32H.sub.30N.sub.6O.sub.2)--
EXAMPLE 62
N.sup.3-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-6-(1-pyrrolyl)nicotinamide
##STR00078##
[0605] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and 2-pyrrolopyridine-5-carboxylic acid were combined to provide
N.sup.3-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-6-(1-pyrrolyl)nicotinamide as a yellow crystalline solid, m.p.
77.0-80.0.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.72
(d, J=2.3 Hz, 1H), 8.07 (dd, J=8.4, 2.4 Hz, 1H), 7.92 (d, J=7.3 Hz,
1H), 7.82 (d, J=7.4 Hz, 1H), 7.55 (t, J=2.2 Hz, 2H), 7.49 (m, 1H),
7.37 (m, 2H), 6.39 (d, J=2.2 Hz, 2H), 6.20 (m, 1H), 5.42 (broad s,
2H), 4.59 (t, J=7.5 Hz, 2H), 3.90 (t, J=7.4 Hz, 2H), 3.56 (q, J=6.7
Hz, 2H), 3.36 (s, 3H), 3.20 (t, J=6.4 Hz, 2H), 2.05 (m, 2H), 1.82
(m, 2H); MS (EI) m/e 483.2376 (483.2383 calcd for
C.sub.27H.sub.29N.sub.7O.sub.2).
EXAMPLE 63
N.sup.5-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-5-indolecarboxamide
##STR00079##
[0607] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and indole-5-carboxylic acid were combined to provide
N.sup.5-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-5-indolecarboxamide as an off white solid. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.31 (s, 1H), 8.34 (t, J=5.5 Hz, 1H),
8.06 (m, 2H), 7.63-7.58 (m, 2H), 7.42-7.38 (m, 3H), 7.22 (t, J=7.1
Hz, 1H), 6.67 (broad s, 2H), 6.50 (s, 1H), 4.58 (m, 2H), 3.81 (t,
J=6.6 Hz, 2H), 3.34 (m, 2H), 3.25 (s, 3H), 3.21 (t, J=6.6 Hz, 2H),
1.89 (m, 2H), 1.72 (m, 2H); MS (EI) m/e 456.2264 (456.2274 calcd
for C.sub.26H.sub.28N.sub.6O.sub.2)--
EXAMPLE 64
N.sup.1-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenoxybenzami-
de
##STR00080##
[0609] According to the general method of Example 14,
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and
4-phenoxybenzoyl chloride were combined to provide
N.sup.1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenoxybenzam-
ide as a white powder, m.p. 90.5-91.5.degree. C. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.42 (t, J=5.7 Hz, 1H), 8.21 (s, 1H),
8.03 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.62 (d, J=7.9 Hz,
1H), 7.45-7.40 (m, 3H), 7.21 (m, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.99
(d, J=8.9 Hz, 2H), 6.61 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.25
(m, 2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 451.2008 (451.2008
calcd for C.sub.27H.sub.25N.sub.5O.sub.2).
EXAMPLE 65
N.sup.5-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]buty-
l}-5-(2-phenyl-1-ethynyl)nicotinamide
##STR00081##
[0611] According to the general method of Example 50,
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
and 5-(phenylethynyl)pyridine-3-carboxylic acid were combined to
provide
N.sup.5-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]but-
yl}-5-(2-phenyl-1-ethynyl)nicotinamide as a yellow solid, m.p.
76.0-78.0.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.95 (d, J=2.1 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.79 (t, J=2.1 Hz,
1H), 8.31 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.61 (m, 3H),
7.48 (m, 3H), 7.40 (m, 1H), 7.19 (m, 1H), 6.56 (broad s, 2H), 4.57
(t, J=7.4 Hz, 2H), 3.82 (t, J=6.7 Hz, 2H), 3.37 (m, 2H), 3.27 (s,
3H), 3.21 (t, J=6.7 Hz, 2H), 1.89 (m, 2H), 1.72 (m, 2H); MS (CI)
m/e 519 (M+H).
EXAMPLE 66
N.sup.3-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotina-
mide
##STR00082##
[0612] Part A
[0613] A solution of benzoyl chloride (5.3 g, 37.7 mmol) in
dichloromethane (100 mL) was slowly added to a solution of
tert-butyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (12.5
g, 37.7 mmol) in dichloromethane (250 mL) at ambient temperature.
The reaction mixture was maintained at ambient temperature
overnight. The resulting precipitate was isolated by filtration and
dried to provide 11.0 g of tert-butyl
N-(4-{[3-(benzoylamino)quinolin-4-yl]amino}butyl)carbamate
hydrochloride as a white solid.
Part B
[0614] Triethylamine (7.26 g, 71.7 mmol) was added to a solution of
the material from Part A in ethanol (200 mL) and heated at reflux
for 2 days. The reaction mixture was concentrated to provide an
orange syrup. HPLC mass spec analysis showed that the syrup
contained the desired product and starting material. The syrup was
taken up in dichloromethane (100 mL) and then cooled in an ice
bath. Triethylamine (5 mL) and benzoyl chloride (1.9 mL) were
added. The reaction mixture was maintained at ambient temperature
for 2 days at which time analysis by HPLC indicated that the
reaction was not complete. The reaction mixture was concentrated
under vacuum. The residue was taken up in isopropyl alcohol (150
mL). Triethylamine (5 mL) was added and the reaction mixture was
heated at reflux overnight. The reaction mixture was concentrated
under vacuum. The residue was purified by flash chromatography
(silica gel; eluting with 10% methanol in dichloromethane). The
fractions containing product were combined and concentrated under
vacuum. The residue was recrystallized from acetonitrile to provide
6.7 g of tert-butyl
N-[4-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a
solid, m.p. 158-159.degree. C.
Part C
[0615] 3-Chloroperoxybenzoic acid (1.05 eq of 65%) was slowly added
in small portions to a solution of tert-butyl
N-[4-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (6.56
g, 15.75 mmol) in dichloromethane (120 mL). After 3 hours the
reaction was quenched with 1% aqueous sodium bicarbonate (200 mL).
The layers were separated. The aqueous layer was extracted with
dichloromethane (2.times.50 mL). The organic fractions were
combined, dried over magnesium sulfate and then concentrated under
vacuum to provide a pale orange syrup. The syrup was triturated
with diethyl ether to provide 6.8 g of
1-[4-(tert-butylcarbamyl)butyl]-2-phenyl-1H-imidazo[4,5-c]quinoline--
5N-oxide as a pale tan solid, m.p. 178-181.degree. C.
Part D
[0616] A solution of
1-[4-(tert-butylcarbamyl)butyl]-2-phenyl-1H-imidazo[4,5-c]quinoline-5N-ox-
ide (6.8 g, 15.75 mmol) in dichloromethane (100 mL) was chilled in
an ice bath. Concentrated ammonium hydroxide (30 mL) was added.
Tosyl chloride (3.0 g, 15.75 mmol) was added in small portions over
a period of 30 minutes. The reaction mixture was allowed to warm to
ambient temperature overnight. The reaction was quenched with water
(350 mL). The layers were separated. The aqueous layer was
extracted with dichloromethane. The organic fractions were
combined, dried over magnesium sulfate and then concentrated under
vacuum to provide a tan solid. This material was purified by flash
chromatography (silica gel eluting with 10% methanol in
dichloromethane) to provide 4.8 g of product. The bulk of the
material was carried on to the next step. A small portion was
recrystallized from toluene to provide tert-butyl
N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate
as a solid, m.p. 182-183.degree. C. Analysis: Calculated for
C.sub.25H.sub.29N.sub.5O.sub.2: % C, 69.58; % H, 6.77; % N, 16.22;
Found: % C, 69.86; % H, 6.95; % N, 15.80.
Part E
[0617] The material from Part D was dissolved in methanol (15 mL)
and 1 N hydrochloric acid (100 mL) and then heated at reflux for 2
hours. The reaction mixture was concentrated under vacuum to a
volume of about 50 mL. Addition of concentrated ammonium hydroxide
to pH 12 did not produce a precipitate. The pH was adjusted to 7
with 1 N hydrochloric acid. The mixture was extracted with
dichloromethane and then with ethyl acetate. The aqueous layer was
concentrated to dryness. The residue was dissolved in water (50 mL)
and then extracted continuously with refluxing chloroform for 36
hours. The chloroform extract was concentrated under vacuum to
provide a light tan solid. This material was recrystallized from
acetonitrile to provide 2.5 g of
1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an
off white solid, m.p. 175-177.degree. C. Analysis: Calculated for
C.sub.20H.sub.21N.sub.5: % C, 72.48; % H, 6.39; % N, 21.13; Found:
% C, 72.72; % H, 6.32; % N, 20.71.
Part F
[0618] According to the general method of Example 61,
1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and
nicotinoyl chloride hydrochloride were combined to provide
N.sup.3-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotin-
amide as a white crystalline solid, m.p. 84.5-86.1.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.91 (s, 1H), 8.69 (m,
1H), 8.56 (m, 1H), 8.07 (m, 2H), 7.75-7.41 (m, 8H), 7.21 (m, 1H),
6.72 (broad s, 2H), 4.60 (m, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.86 (m,
2H), 1.40 (m, 2H); MS (CI) m/e 437 (M+H).
EXAMPLE 67
N.sup.2-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-quino-
linecarboxamide
##STR00083##
[0620] According to the general method of Example 61,
1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and
quinoline-2-carbonyl chloride were combined to provide
N.sup.2-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-quin-
olinecarboxamide as an off white crystalline solid, m.p.
81.1-83.9.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.90 (t, J=6.0 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.12-8.07 (m, 4H),
7.90-7.84 (m, 1H), 7.75-7.54 (m, 7H), 7.36 (t, J=7.5 Hz, 1H), 7.18
(t, J=7.5 Hz, 1H), 6.70 (broad s, 2H), 4.61 (m, 2H), 3.23 (m, 2H),
1.88 (m, 2H), 1.49 (m, 2H); MS (CI) m/e 487 (M+H).
EXAMPLES 68-102
[0621] The compounds shown in the table below were prepared using
the synthetic method described in Reaction Scheme II above.
[0622] A solution of
1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (36 .mu.mol) in
10 mL of dichloromethane in a screw-capped test tube was cooled
down to -5.degree. C. The acid chloride (45 .mu.mol) was added as a
0.3 M solution in dichloromethane. Argon was bubbled through the
mixture during addition and for an additional 15 seconds, and the
mixture was allowed to stand at -5.degree. C. Overnight. To this
mixture was added approximately 90 mg of an aminomethyl polystyrene
resin (0.62 meq/g, 100-200 mesh), and the mixture was warmed to
reflux and shaken at 600 rpm for 3 hours. The compounds were
purified by eluting through a short plug of silica gel with 10:1
dichloromethane-methanol, collecting ca. 1 mL fractions and pooling
the product fractions (fractions analyzed by tlc in 9:1
dichloromethane-methanol to identify product). Compounds were
analyzed by 500 MHz .sup.1H nmr and APCI-MS (plug injection or an
LC/MS protocol).
TABLE-US-00001 Example APCI-MS No. Structure m/e 500 MHz .sup.1H
NMR 68 ##STR00084## 450.10 (DMSO-d.sub.6) .delta. 8.93(t, J = 5.2
Hz, 1H), 8.23 (s, 1H), 8.06(d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.5
Hz, 1H),7.46 (t, J = 7.8 Hz, 1H),7.27 (t, J = 7.6 Hz, 1H), 6.75
(bs, 2H),4.65 (t, J = 7 Hz, 2H), 3.31(q, J = 6 Hz, 2H), 1.92
(quintet, J = 8 Hz, 2H), 1.56(quintet, J = 7 Hz, 2H) 69
##STR00085## 394.12 (DMSO-d.sub.6) .delta. 8.40(t, J = 5.8 Hz, 1H),
8.23 (s, 1H), 8.08(d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.5 Hz,
1H),7.47 (t, J = 8.2 Hz, 1H),7.43 (d, J = 7.9 Hz, 1H), 7.39 (dt,J =
1.5 Hz, J = 7 Hz, 1H), 7.30(t, J = 6.4 Hz, 1H), 7.28 (t, J = 10.4
Hz,1H), 7.23 (dd, J = 1.5 Hz,J = 7.3 Hz, 1H), 6.75 (bs, 2H), 4.65
(t,J = 7 Hz, 2H), 3.26(q, J = 6 Hz, 2H), 1.95(quintet, J = 8 Hz,
2H), 1.56(quintet, J = 7.5 Hz, 2H) 70 ##STR00086## 428.07
(DMSO-d.sub.6) .delta. 8.47 (t, J = 5.8Hz, 1H), 8.22 (s, 1H),
8.07(d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.63(d, J = 2.1
Hz, 1H), 7.47 (t,J = 8.2 Hz, 1H), 7.40 (dd, J = 2.1 Hz,J = 10.4 Hz,
1H), 7.29 (t, J = 7.0 Hz, 1H), 7.26(d, J = 8.2 Hz, 1H),6.75 (bs,
2H), 4.65 (t, J = 5.5 Hz, 2H), 3.25(q, J = 6.5 Hz, 2H),1.94
(quintet, J = 8 Hz, 2H), 1.54(quintet, J = 7 Hz, 2H), 71
##STR00087## 428.06 (DMSO-d.sub.6) .delta. 8.65 (t, J = 6.1 Hz,1H),
8.23 (s, 1H), 8.08(d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.2 Hz,
1H),7.47 (t, J = 7.9 Hz, 1H),7.43 (d, J = 9 Hz, 1H), 7.44 (d, J = 7
Hz, 1H), 7.38(dd, J = 9.2 Hz, J = 7 Hz, 1H), 7.28 (t,J = 7.9 Hz,
1H), 6.8 (bs, 2H),4.65 (t, J = 6.5 Hz, 2H), 3.28 (m, 2H),
1.96(quintet, J = 7.5 Hz, 2H), 1.57 (quintet, J = 8 Hz, 2H) 72
##STR00088## 378.11 (DMSO-d.sub.6) .delta. 8.50 (t, J = 5.8 Hz,1H),
8.23 (s, 1H), 8.04(d, J = 8.2 Hz, 1H), 7.84 (dd, J = 2.1 Hz,J = 5.8
Hz, 2H), 7.62(d, J = 7.3 Hz, 1H), 7.44 (t, J = 7 Hz, 1H),7.26 (t, J
= 6.7 Hz, 2H),7.22 (t, J = 8.2 Hz, 1H), 6.74 (bs, 2H), 4.63(t, J =
7 Hz, 2H), 3.28(m, 2H), 1.91 (quintet, J = 7.5 Hz, 2H),
1.57(quintet, J = 8 Hz, 2H) 73 ##STR00089## 394.07 (DMSO-d.sub.6)
.delta. 8.56 (t, J = 5.6 Hz,1H), 8.24 (s, 1H), 8.05(d, J = 7.9 Hz,
1H), 7.79 (d, J = 8.5 Hz, 2H), 7.63(d, J = 8.2 Hz, 1H), 7.50 (d, J
= 8.9 Hz, 2H), 7.46(t, J = 7.6 Hz, 1H),7.23 (t, J = 7.6 Hz, 1H),
6.8 (bs, 2H), 4.64 (t,J = 7 Hz, 2H), 3.29(q, J = 6.5 Hz, 2H), 1.91
(quintet,J = 7.5 Hz, 2H), 1.57(quintet, J = 7.5 Hz, 2H) 74
##STR00090## 390.13 (DMSO-d.sub.6) .delta. 8.33 (t, J = 5.6 Hz,1H),
8.24 (s, 1H), 8.05(d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H),
7.63(d, J = 8.2 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.24 (t,J = 7.9
Hz, 1H),6.95 (d, J = 8.8 Hz, 2H), 6.81 (bs,2H), 4.64 (t, J = 7 Hz,
2H),3.80 (s, 3H), 3.28 (quintet, J = 5.5 Hz, 2H), 1.90(quintet, J =
8 Hz, 2H), 1.57 (quintet, J = 8.5 Hz, 2H) 75 ##STR00091## 428.10
(DMSO-d.sub.6) .delta. 8.71 (t, J = 5.6 Hz,1H), 8.27 (s, 1H),
8.06(d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.64(d, J = 7.9
Hz, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.46(t, J = 7.3 Hz, 1H),7.25 (t,
J = 7 Hz, 1H), 6.9 (bs, 2H),4.65 (t, J = 7 Hz, 2H), 3.31(m, 2H),
1.92 (quintet, J = 8 Hz, 2H), 1.59(quintet, J = 7.5 Hz, 2H) 76
##STR00092## 416.22 (DMSO-d.sub.6) .delta. 8.54 (s, 1H), 8.39 (t,J
= 5.5 Hz, 1H), 8.22(d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.2 Hz,
1H),7.70 (t, J = 4 Hz, 1H),7.68 (d, J = 4.3 Hz, 2H), 7.52 (t, J = 8
Hz, 1H), 7.43(d, J = 7.8 Hz, 2H), 4.72 (t, J = 7 Hz, 2H),3.30 (q, J
= 6.5 Hz, 2H),1.91 (quintet, J = 7.5 Hz, 2H), 1.59 (quintet,J = 7.5
Hz, 2H), 1.29(s, 9H) 77 ##STR00093## 374.18 (DMSO-d.sub.6) .delta.
8.54 (s, 1H), 8.38 (t,J = 5.8 Hz, 1H), 8.23(d, J = 8.2 Hz, 1H),7.82
(d, J = 8.6 Hz, 1H), 7.71 (t, J = 8.2 Hz, 1H),7.659 (d, J = 8.2 Hz,
2H), 7.54 (t,J = 8.2 Hz, 1H), 7.22(d, J = 7.9 Hz, 2H), 4.71 (t, J =
6.5 Hz,2H), 3.28 (q, J = 6 Hz, 2H),2.34 (s, 3H), 1.92 (quintet, J =
8 Hz, 2H), 1.60(quintet, J = 7.5 Hz, 2H) 78 ##STR00094## 374.18
(DMSO-d.sub.6) .delta. 8.50 (s, 1H), 8.22 (d,J = 8.2 Hz, 1H),
8.06(t, J = 5.8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H),7.74 (t, J = 7
Hz, 1H),7.58, (t, J = 7.6 Hz, 1H), 7.21(m, 2H), 7.18 (m, 3H),
4.67(t, J = 7 Hz, 2H), 3.33 (s, 2H),3.09 (q, J = 6 Hz, 2H),
1.84(quintet, J = 8 Hz, 2H), 1.48 (quintet, J = 7.5 Hz, 2H) 79
##STR00095## 386.15 (DMSO-d.sub.6) .delta. 8.55 (s, 1H), 8.24 (d,J
= 8.2 Hz, 1H), 8.16(t, J = 5.8 Hz, 1H), 7.82 (d, J = 8.6 Hz,1H),
7.72 (t, J = 7.3 Hz, 1H),7.58 (t, J = 73 Hz, 1H), 7.53 (d,J = 6.7
Hz, 2H), 7.40 (m, 4H),6.57 (d, J = 15.9 Hz, 1H), 4.72 (t, J = 7 Hz,
2H), 3.23(q, J = 6 Hz, 2H), 1.91 (quintet, J = 7.5 Hz, 2H),
1.55(quintet, J = 7.5 Hz, 2H) 80 ##STR00096## 354.19 (DMSO-d.sub.6)
.delta. 8.53 (s, 1H), 8.24 (d,J = 8.2 Hz, 1H), 7.83(d, J = 8.2 Hz,
1H), 7.74 (m, 2H),7.58 (t, J = 7.8, 1H), 4.70(t, J = 7 Hz, 2H),
3.06 (q, J = 6Hz, 2H), 1.86 (s, 2H), 1.86(quintet, J = 8.5 Hz, 2H),
1.44 (quintet,J = 7.5 Hz, 2H), 0.84(s, 9H) 81 ##STR00097## 324.15
(DMSO-d.sub.6) .delta. 8.53 (s, 1H), 8.23 (d,J = 8.5 Hz, 1H),
8.06(t, J = 5.5 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H),7.74 (t, J = 8.2
Hz, 1H),7.59 (t, J = 8.2 Hz, 1H), 4.69 (t, J = 7 Hz, 2H), 3.09(q, J
= 6 Hz, 2H), 1.86 (quintet, J = 7Hz, 2H), 1.47 (m, 3H), 0.59(m, 4H)
82 ##STR00098## 352.16 (DMSO-d.sub.6) .delta. 8.52 (s, 1H), 8.23
(d,J = 7.9 Hz, 1H), 7.83(d, J = 8.2 Hz, 1H), 7.74 (m, 2H),7.60 (t,
J = 7.6 Hz, 1H), 4.69(t, J = 7.5 Hz, 2H), 3.06 (q, J = 6 Hz, 2H),
2.42(quintet, J = 8 Hz, 1H), 1.84 (quintet,J = 7.5 Hz, 2H), 1.59(m,
2H), 1.55 (m, 2H), 1.48 (m, 6H) 83 ##STR00099## 380.16
(DMSO-d.sub.6) .delta. 8.52 (s, 1H), 8.22 (d,J = 8.2 Hz, 1H),
7.83(d, J = 8.2 Hz, 1H), 7.77 (t, J = 5.8 Hz, 1H),7.73 (t, J = 8.2
Hz, 1H),7.58 (t, J = 8.2 Hz, 1H), 4.68 (t, J = 7 Hz, 2H), 3.06(q, J
= 6 Hz, 2H), 1.98 (t, J = 8 Hz, 2H), 1.84(quintet, J = 7.5 Hz, 2H),
1.62(m, 3H), 1.48 (m, 8H), 0.97(m, 2H) 84 ##STR00100## 366.15
(DMSO-d.sub.6) .delta. 9.2 (b, 2H), 8.52 (s, 1H),8.22 (d, J = 8.2
Hz, 1H),7.83 (d, J = 8.5 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.65(t,
J = 5.8 Hz, 1H), 7.58 (t, J = 7.9 Hz,1H), 4.68 (t, J = 7 Hz,
2H),3.04 (q, J = 6.5 Hz, 2H), 1.95 (m, 1H), 1.83(quintet, J = 8 Hz,
2H), 1.60 (m,3H), 1.50 (m, 2H), 1.43(quintet, J = 7.5 Hz, 2H), 1.14
(m, 5H) 85 ##STR00101## 350.18 (DMSO-d.sub.6) .delta. 9.0 (bs, 2H),
8.54 (s, 1H), 8.39 (t,J = 5 Hz, 1H),8.22 (d, J = 5 Hz, 1H), 7.82
(d, J = 10Hz, 1H), 7.80. (s, 1H), 7.72(t, J = 10 Hz, 1H), 7.54 (t,
J = 10 Hz,1H), 7.02 (dd, J = 1 Hz,J = 3 Hz, 1H), 6.60 (dd, J =
1.7Hz, J = 3.5 Hz, 1H), 4.70(t, J = 7.5 Hz, 2H), 3.25 (q, J = 6 Hz,
2H), 1.90(quintet, J = 7.5 Hz, 2H), 1.58 (quintet, J = 7 Hz, 2H) 86
##STR00102## 366.25 (DMSO-d.sub.6) .delta. 8.51 (t, J = 5.5 Hz,1H),
8.32 (s, 1H), 8.10(d, J = 8.6 Hz, 1H), 7.72 (dd, J = 0.9Hz, J = 4.9
Hz, 1H), 7.68(m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.34 (bs, 2H),
7.31(t, J = 7.9 Hz, 1H), 7.11 (dd, J = 4Hz, J = 4.9 Hz, 1H),
4.66(t, J = 7.5 Hz, 2H), 3.27 (q, J = 6 Hz, 2H), 1.91(quintet, J =
7.5 Hz, 2H), 1.58 (quintet, J = 8 Hz, 2H) 87 ##STR00103## 405.21
(DMSO-d.sub.6) .delta. 8.80 (t, J = 5.8 Hz,1H), 8.28 (s, 1H),
8.27(d, J = 8.6 Hz, 2H), 8.07 (d, J = 8 Hz, 1H),7.98 (d, J = 8.9
Hz, 2H),7.65 (d, J = 8.6 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.27(t,
J = 7.9 Hz, 1H), 7.07 (bs, 2H), 4.66 (t,J = 7 Hz, 2H),
1.93(quintet, J = 8 Hz, 2H), 1.60 (quintet, J = 7.5 Hz, 2H) 88
##STR00104## 298.16 (DMSO-d.sub.6) .delta. 8.33 (s, 1H), 8.11 (d, J
= 8.1Hz, 1H), 7.83(t, J = 6 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H),7.56
(t, J = 8.1 Hz, 1H),7.39 (t, J = 7.8 Hz, 1H), 4.63 (t, J = 7 Hz,
2H), 3.05(q, J = 6.5 Hz, 2H), 1.85 (quintet,J = 7.5 Hz, 2H), 1.74
(s, 3H),1.44 (quintet, J = 7.5 Hz, 2H) 89 ##STR00105## 439.30
(DMSO-d.sub.6) .delta. 8.59 (t, 1H), 8.43 (s, 1H), 8.16(d, J = 7.6
Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H),7.75 (t, J = 6.8 Hz, 2H),7.71 (d,
J = 8.1 Hz, 1H), 7.60 (m, 1H),7.40 (t, J = 7.8 Hz, 2H),4.68 (t, J =
6.5 Hz, 2H), 3.30 (q, J = 6 Hz, 2H), 1.91(quintet, J = 6 Hz, 2H),
1.59 (quintet, J = 6 Hz, 2H) 90 ##STR00106## 418.28 (DMSO-d.sub.6)
.delta. 8.29 (s, 1H), 8.08 (d, J = 8.5Hz, 1H), 7.68(d, J = 7.8 Hz,
1H), 7.53 (t, J = 7.6 Hz, 1H),7.36 (t, J = 7.3 Hz, 1H),7.30 (t, J =
5.9 Hz, 1H), 4.62 (t, J = 6.5 Hz, 2H), 3.05(q, J = 6.5 Hz, 2H),
1.86 (m, 5H), 1.60 (m, 12H), 1.41(quintet, J = 7 Hz, 2H) 91
##STR00107## 462.21 (DMSO-d.sub.6) .delta. 8.25 (s, 1H), 8.06 (d, J
= 8.3Hz, 1H), 7.70(d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.8 Hz,
1H),7.49 (t, J = 5.6 Hz, 1H),7.37 (t, J = 7.3 Hz, 1H), 7.24 (s,
4H), 4.57(t, J = 7 Hz, 2H), 3.01(q, J = 6 Hz, 2H), 2.38 (m,
2H),1.68 (m, 4H), 1.49 (m, 2H), 1.40(m, 4H) 92 ##STR00108## 422.28
(DMSO-d.sub.6) .delta. 8.36 (s, 1H), 8.13 (d, J = 8.8Hz, 1H),
7.86(b, 2H), 7.76 (t, J = 6 Hz, 1H),7.74 (d, J = 8.5 Hz, 1H),
7.59(t, J = 8.1 Hz, 1H), 7.43 (t,J = 7.5 Hz, 1H), 5.77 (m, 1H),
4.98(dd, J = 2 Hz, J = 17 Hz, 1H), 4.92 (dd , J = 1.5Hz, J = 10 Hz,
1H),4.64 (t, J = 7 Hz, 2H), 3.07 (q, J = 5.5 Hz, 2H), 1.97(m, J =
7.5 Hz, 4H), 1.84 (quintet,J = 7 Hz, 2H), 1.45(quintet, J = 8 Hz,
2H), 1.40 (quintet, J = 6.5 Hz, 2H), 1.30(quintet, J = 7 Hz, 2H),
1.18 (m, 8H) 93 ##STR00109## 450.19 (DMSO-d.sub.6) .delta. 8.43 (t,
J = 5.6 Hz, 1H), 8.31(s, 1H), 8.08(d, J = 7.8 Hz, 1H), 7.67 (d, J =
8.1 Hz, 1H),7.50 (t, J = 7.3 Hz, 1H),7.29 (t, J = 7.8 Hz, 1H), 7.11
(s, 2H), 4.67(t, J = 7 Hz, 2H), 3.78(s, 6H), 3.69 (s, 3H), 3.29 (q,
J = 6 Hz, 2H), 1.91(quintet, J = 7.5 Hz, 2H), 1.58(quintet, J = 7.5
Hz, 2H) 94 ##STR00110## 402.25 (DMSO-d.sub.6) .delta. 8.24 (s, 1H),
8.19 (t, J = 5.9 Hz, 1H), 8.08(d, J = 8 Hz, 1H), 7.65 (d, J = 8.3
Hz,1H), 7.48 (t, J = 8.3 Hz, 1H),7.29 (t, J = 7.8 Hz, 1H),6.87 (bs,
2H), 6.77 (s, 2H), 4.65(t, J = 6.5 Hz, 2H), 3.26 (q, J = 6.5Hz,
2H), 2.19 (s, 3H), 2.02(s, 6H), 1.92 (quintet, J = 8 Hz, 2H),1.54
(quintet, J = 8.5 Hz, 2H) 95 ##STR00111## 398.21 (DMSO-d.sub.6)
.delta. 8.28 (s, 1H),8.08 (d, J = 7.6 Hz, 1H), 7.79(t, J = 5.9 Hz,
1H), 7.68 (d, J = 7.8 Hz, 1H),7.52 (t, J = 7.6 Hz, 1H),7.35 (t, J =
7.1 Hz, 1H), 7.2 (bs, 2H),4.62 (t, J = 7 Hz, 2H), 3.56(s, 3H), 3.06
(q, J = 5.5 Hz, 2H), 2.24 (m, 2H), 1.99(quintet, J = 6.5 Hz, 2H),
1.84(quintet, J = 8 Hz, 2H), 1.43(m, 6H) 96 ##STR00112## 395.12
(DMSO-d.sub.6) .delta. 8.88 (t, J = 5.6Hz, 1H), 8.25 (s, 1H),
8.05(d, J = 8.3 Hz, 1H), 7.72 (d, J = 3.9 Hz, 1H), 7.63(d, J = 8.3
Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H),7.32 (d, J = 3.9 Hz, 1H),7.26 (t,
J = 7.1 Hz, 1H), 6.93 (bs, 2H),4.64 (t, J = 7 Hz, 2H), 3.28(q, J =
6 Hz, 2H), 1.90 (quintet, J = 7 Hz, 2H), 1.56(quintet, J = 8 Hz,
2H) 97 ##STR00113## 395.20 (DMSO-d.sub.6) .delta. 8.57 (t, J = 5.6
Hz,1H), 8.42 (dd, J = 1.9 Hz,J = 4.6 Hz, 1H), 8.25 (s, 1H), 8.12(d,
J = 8.0 Hz, 1H), 7.70(dd, J = 2 Hz, J = 7.6 Hz, 1H),7.65 (d, J =
8.5 Hz, 1H), 7.49(t, J = 7.6 Hz, 1H), 7.41 (dd, J = 4.9Hz, J = 7.6
Hz, 1H), 7.30(t, J = 7.6 Hz, 1H), 6.90 (bs, 2H),4.66 (t, J = 7 Hz,
2H), 3.27(q, J = 6.5 Hz, 2H), 1.96 (quintet,J = 8.5 Hz, 2H),
1.56(quintet, J = 7.5 Hz, 2H) 98 ##STR00114## 404.18 (DMSO-d.sub.6)
.delta. 8.36 (s, 1H), 8.14 (d,J = 8.3 Hz, 1H), 7.97(t, J = 5.6 Hz,
1H), 7.76 (d, J = 8.3 Hz, 1H),7.62 (t, J = 7.8 Hz, 1H),7.45 (t, J =
7.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.76(d, J = 8.8 Hz, 2H),
4.63 (t, J = 7Hz, 2H), 3.70 (s, 3H), 3.25(s, 2H), 3.08 (q, J = 6
Hz, 2H), 1.83(quintet, J = 7.5 Hz, 2H), 1.46(quintet, J = 7 Hz, 2H)
99 ##STR00115## 366.22 (DMSO-d.sub.6) .delta. 8.35 (s, 1H), 8.2
(bs, 1H), 8.13(d, J = 7.8 Hz, 1H), 7.75 (t, J = 5.6Hz, 1H), 7.73
(d, J = 8.8 Hz, 1H),7.59 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz,
1H), 4.65(t, J = 7 Hz, 2H), 3.06 (q, J = 6 Hz,2H), 2.02 (m, J = 7.5
Hz, 1H),1.96 (d, J = 7.5 Hz, 2H), 1.84(quintet, J = 8 Hz, 2H),
1.55(quintet, J = 5 Hz, 2H), 1.46 (m, J = 7.5 Hz, 6H), 1.00(m, J =
12 Hz, 2H) 100 ##STR00116## 418.11 (DMSO-d.sub.6) .delta. 9.6-8.5
(b, 2H), 8.66 (t,J = 5.5 Hz, 1H), 8.54(s, 1H), 8.23 (d, J = 8.0 Hz,
1H),8.00 (d, J = 8.0 Hz, 2H), 7.87(d, J = 8.0 Hz, 2H), 7.81 (d, J =
8 Hz, 1H),7.70 (t, J = 8.0 Hz, 1H),7.53 (t, J = 8.0 Hz, 1H), 4.72
(t, J = 7.0Hz, 2H), 3.88 (s, 3H), 3.31(q, J = 5.5 Hz, 2H), 1.93
(quintet, J = 7.0, 2H), 1.61(quintet, J = 7.0 Hz, 2H) 101
##STR00117## 454.19 (DMSO-d.sub.6) .delta. 9.6-8.6 (b, 2H), 8.51
(s, 1H), 8.22 (d,J = 8.5 Hz, 1H), 7.84 (d, J = 8.5 Hz,1H), 7.78 (t,
J = 5.5Hz, 1H), 7.73 (t, J = 8.5 Hz, 1H),7.58 (t, J = 8.5 Hz, 1H),
4.68(t, J = 7.0 Hz, 2H), 3.57 (s, 3H),3.07 (q, J = 5.5 Hz, 2H),
2.26(t, J = 7.0 Hz, 2H), 1.84 (quintet, J = 7.0 Hz, 2H),
1.48(sextet, J = 7.0 Hz, 4H), 1.38 (quintet,J = 7.0 Hz, 2H),
1.71(m,8H) 102 ##STR00118## 444.11 Compound is trifluoroacetate
salt
EXAMPLES 103-107
[0623] The compounds shown in the Table below were prepared
according to the synthetic method described below.
[0624] A 10 mg (25 .mu.mol) portion of
N'-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-(chloromethyl)benz-
amide (example 7) was dissolved in 1 mL of N,N-dimethylformamide in
a screw-cap tube, and the appropriate amine (2 eq) was added, along
with ca. 70 mg (270 .mu.mol) of
N,N-(diisopropyl)aminomethylpolystyrene beads (PS-DIEA, 3.86 meq/g,
Argonaut). The mixture was heated to 50.degree. C. and was vortexed
overnight at 500 rpm. Another 1-2 eq of amine was added and then
heating and vortexing was continued for a second night. The product
was isolated by injection of the filtered reaction mixture onto a
semi-prep HPLC system (Shimadzu LC-6A pumps, Rainin Microsorb C18
column, 21.4.times.250 mm, 8 micron particle size, 60 A pore, 9.9
mL/min., gradient elution from 2-95% B in 25 min., hold at 95% B
for 5 min., where A=0.1% trifluoroacetic acid/water and B=0.1%
trifluoroacetic acid/acetonitrile, peak detection at 254 nm,
collected 5 mL fractions). The semi-prep hplc fractions were
analyzed by reversed-phase hplc and the appropriate fractions were
dried in vacuo to provide the compound as a trifluoroacetate salt.
The compound was dissolved in ca. 3-5 mL of 2:1
dichloromethane-methanol and shaken with ca. 80 mg (300 .mu.mol) of
diisopropylaminomethyl-polystyrene resin (Argonaut PS-DIEA, 3.86
mmol/g) for 1-2 h to liberate the free amine, and then filtered and
dried in vacuo to give the compound as an amorphous solid. Each
amine product was analyzed by LC/APCI-MS.
TABLE-US-00002 Example APCI-MS No. Structure of the Free Base m/e
103 ##STR00119## 459.26 104 ##STR00120## 624.51 105 ##STR00121##
480.34 106 ##STR00122## 523.31 107 ##STR00123## 508.32
EXAMPLE 108
N.sup.1-(4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-2-(2-thienyl)ace-
tamide
##STR00124##
[0626] This compound was prepared according to the method of
Examples 68-102. (DMSO-d.sub.6) .delta. 8.28 (s, 1H), 8.09 (m, 2H),
7.70 (d, J=7.9 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.36 (t, J=7.3 Hz,
1H), 7.28 (dd, J=0.9 Hz, J=5.2 Hz, 1H), 6.88 (dd, J=3.4 Hz, J=5.2
Hz, 1H), 6.82 (d, J=3.1 Hz, 1H), 4.63 (t, J=7 Hz, 2H), 3.56 (s,
2H), 3.10 (q, J=6.5 Hz, 2H), 1.85 (quintet, J=7.5 Hz, 2H), 1.46
(quintet, J=7.5 Hz, 2H) MS (APCI) m/e 380.22 (M+H).
EXAMPLES 109-119
[0627] The examples in the table below were prepared using the
synthetic method described in Reaction Scheme III.
[0628] 1-(4-Aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (10 mg,
0.04 mmol) was suspended in 10 mL of dichloromethane in a threaded
test tube. The acid (0.05 mmol) was added and the mixture was
briefly vortexed. To the mixture was added
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC,
10 mg, 0.05 mmol) and the mixture was shaken overnight at ambient
temperature. To the tube was added about 90 mg of
aminomethylpolystrene resin (Bachem, .about.1 meq/g, 100-200 mesh)
and the mixtures were heated to reflux and shaken overnight. The
mixture was then filtered to remove the resin, and was purified by
semi-preparative reversed-phase HPLC (Rainin Microsorb C18 column,
21.4.times.250 mm, 8 micron particle size, 60 A pore, 10 mL/min.,
gradient elution from 2-95% B in 25 min., hold at 95% B for 5 min.,
where A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroacetic
acid/acetonitrile, peak detection at 254 nm for triggering fraction
collection). The semi-prep HPLC fractions were analyzed by
LC-APCI/MS and the appropriate fractions were combined and
lyophilized to provide the trifluoroacetate salt of the desired
amide. The compounds were analyzed by LC-MS (APCI).
TABLE-US-00003 Example Observed Number Structure of Free Base Mass
109 ##STR00125## 464.18 110 ##STR00126## 364.15 111 ##STR00127##
427.98,429.97 112 ##STR00128## 323.19 113 ##STR00129## 370.18 114
##STR00130## 452.10 115 ##STR00131## 336.16 116 ##STR00132## 338.20
117 ##STR00133## 384.20 118 ##STR00134## 368.28 119 ##STR00135##
420.30
EXAMPLES 120-146
[0629] The Examples in the table below were prepared using the
synthetic method described in Reaction Scheme V above.
Part A
[0630] 1-(4-Aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (25 mg,
0.1 mmol) was suspended in 5 mL of dichloromethane in a threaded
test tube and the aldehyde (about 0.1 mmol) was added. The mixture
was heated to reflux and was vortexed at 500 rpm for half an hour.
The mixture was allowed to cool for a few minutes and then sodium
triacetoxyborohydride (38 mg, 0.18 mmol) was added. The mixture was
shaken at ambient temperature for 3 days, then was quenched with
0.5 mL of methanol and evaporated to dryness. The mixture was
purified by semi-preparative reversed-phase HPLC (Rainin Microsorb
C18 column, 21.4.times.250 mm, 8 micron particle size, 60 A pore,
10 mL/min., gradient elution from 2-95% B in 25 min., hold at 95% B
for 5 min., where A=0.1% trifluoroacetic acid/water and B=0.1%
trifluoroacetic acid/acetonitrile, peak detection at 254 nm for
triggering fraction collection). The semi-prep HPLC fractions were
analyzed by LC-APCI/MS and the appropriate fractions were combined
and lyophilized to provide the trifluoroacetate salt of the desired
secondary amine. The compounds were analyzed by LC-MS (APCI).
Part B
[0631] The secondary amines from Part A (about 3-30 .mu.mol as the
di-trifluoroacetate salt) were each dissolved in 1 mL of pyridine,
and about 10 equivalents of a 0.1 M solution of acetic anhydride in
dichloromethane was added. The mixtures were allowed to stand for 1
hour and then 200 .mu.L of methanol was added. The mixtures were
evaporated to dryness in a vacuum centrifuge. The mixtures were
purified by semi-preparative reversed-phase HPLC as in Part A. The
compounds were analyzed by LC-MS (APCI).
TABLE-US-00004 Ex- Ob- ample served Number Structure of Free Base
Mass 120 ##STR00136## 418.1 121 ##STR00137## 466.0,468.0 122
##STR00138## 482.0,484 123 ##STR00139## 460.1 124 ##STR00140##
422.0 125 ##STR00141## 467.0,469.0 126 ##STR00142## 467.0,469.0 127
##STR00143## 530.0 128 ##STR00144## 456.0,458.0 129 ##STR00145##
424.0 130 ##STR00146## 448.1 131 ##STR00147## 448.1 132
##STR00148## 416.1 133 ##STR00149## 406.1 134 ##STR00150## 378.0
135 ##STR00151## 378.0 136 ##STR00152## 416.1 137 ##STR00153##
410.0 138 ##STR00154## 438.0 139 ##STR00155## 468.1 140
##STR00156## 433.0 141 ##STR00157## 433.0 142 ##STR00158## 512.0
143 ##STR00159## 389.0 144 ##STR00160## 402.1 145 ##STR00161##
478.1 146 ##STR00162## 478.1
EXAMPLES 147-159
[0632] The compounds in the table below were prepared using the
synthetic method of Reaction Scheme II above.
[0633]
1-(4-Aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine
(50 mg) was placed in a 2 dram (7.4 mL) vial. Diisopropylethylamine
(1.2 eq) and dichloromethane (1 mL) were added. A solution
containing the carboxylic acid chloride (1.1 eq) in dichloromethane
(1 mL) was added. The vial was placed on a shaker for about 2 hours
at ambient temperature. The reaction mixture was analyzed by LC/MS
to confirm the formation of the desired product. The solvent was
removed and the residue was purified by semi-preparative HPLC
(Capcell PakC18 column, 35.times.20 mm, 5 micron particle size, 20
mL/min., gradient elution from 5-95% B in 10 min., hold at 95% B
for 2 min., where A=0.1% trifluoroacetic acid/water and B=0.1%
trifluoroacetic acid/acetonitrile, peak detection at 254 nm for
triggering fraction collection). The semi-prep HPLC fractions were
analyzed by LC-APCI/MS and the appropriate fractions were combined
and lyophilized to provide the trifluoroacetate salt of the desired
amide.
TABLE-US-00005 Example APCI-MS # Structure of the Free Base m/e 147
##STR00163## 384.2 148 ##STR00164## 396.2 149 ##STR00165## 410.2
150 ##STR00166## 424.2 151 ##STR00167## 432.2 152 ##STR00168##
432.3 153 ##STR00169## 458.2 154 ##STR00170## 468.2 155
##STR00171## 468.2 156 ##STR00172## 474.2 157 ##STR00173## 476.3
158 ##STR00174## 478.3 159 ##STR00175## 484.30
EXAMPLES 160-168
[0634] The compounds in the table below were prepared using the
synthetic method of Reaction Scheme III above.
[0635]
1-(4-Aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine
(50 mg), the carboxylic acid (1.0 eq.) and dichloromethane (3 mL)
were placed in a 2 dram (7.4 mL) vial. A solution containing
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.1
eq) in dichloromethane (1 mL) was added. The vial was placed on a
shaker for about 2 hours at ambient temperature. The reaction
mixture was analyzed by LC/MS to confirm the formation of the
desired product. The solvent was removed and the residue was
purified by semi-preparative HPLC (Capcell Pak C18 column,
35.times.20 mm, 5 micron particle size, 20 mL/min., gradient
elution from 5-95% B in 10 min., hold at 95% B for 2 min., where
A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroacetic
acid/acetonitrile, peak detection at 254 nm for triggering fraction
collection). The semi-prep HPLC fractions were analyzed by
LC-APCI/MS and the appropriate fractions were combined and
lyophilized to provide the trifluoroacetate salt of the desired
amide.
TABLE-US-00006 Example APCI-MS # Structure of Free Base m/e 160
##STR00176## 381.2 161 ##STR00177## 382.2 162 ##STR00178## 408.3
163 ##STR00179## 426.2 164 ##STR00180## 434.2 165 ##STR00181##
440.2 166 ##STR00182## 478.2 167 ##STR00183## 492.3 168
##STR00184## 500.2,502.2
EXAMPLE 169
N.sup.1-[4-(4-Amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl)but-
yl]acetamide Trifluoroacetate
##STR00185##
[0637] Using the method of Examples 147-159 above,
1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine
was reacted with acetyl chloride to provide
N.sup.1-[4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl)bu-
tyl]acetamide Trifluoroacetate. APCI-MS m/e 418.2.
EXAMPLES 170 & 171
[0638] The examples in the table below were prepared by reacting
1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine
with the appropriate carboxylic acid using the method of Example
160-168.
TABLE-US-00007 Ex- APCI-MS ample # Structure of the Free Base m/e
170 ##STR00186## 481.2 171 ##STR00187## 481.2
EXAMPLES 172-174
[0639] The examples in the table below were prepared according to
the synthetic method described in Reaction Scheme VI above.
Part A
[0640] A catalytic amount of platinum (IV) oxide was added toga
solution of
1-(4-aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine
(7.7 g, 24.5 mmol) in trifluoroacetic acid (250 mL). The reaction
mixture was hydrogenated at 50 psi (3.44.times.10.sup.5 Pa) on a
Parr apparatus. The progress of the reaction was monitored by
LC/MS. Additional catalyst was added 7, 11, and 17 days after the
start of the reaction. After 25 days the reaction was complete. The
reaction mixture was filtered through a layer of Celite.RTM. filter
aid to remove the catalyst and the filtrate was concentrated under
vacuum. The residue was combined with 1 N hydrochloric acid (100
mL) and stirred overnight. The mixture was made basic (pH=11) with
ammonium hydroxide and then extracted with dichloromethane
(3.times.300 mL). The extracts were combined and concentrated under
vacuum to provide 3.5 g of
1-(4-aminobutyl)-6,7,8,9-tetrahydro-2-methoxyethyl-1H-imidazo[4,5-c]quino-
lin-4-amine as a solid.
Part B
[0641] Using the method of Examples DC 147-159 above. The material
from Part A was reacted with the appropriate acid chloride to give
the desired amide.
TABLE-US-00008 Ex- APCI-MS ample # Structure of the Free Base m/e
172 ##STR00188## 422.2 173 ##STR00189## 423.1 174 ##STR00190##
436.2
EXAMPLES 175-180
[0642] The Examples in the table below were prepared according to
the synthetic method of Reaction Scheme III above using the general
method of Examples 160-168.
TABLE-US-00009 Ex ample # Structure of the Free Base mass 175
##STR00191## 408.2 176 ##STR00192## 419.1 177 ##STR00193## 438.2
178 ##STR00194## 446.2 179 ##STR00195## 453.2 180 ##STR00196##
480.2
EXAMPLE 181
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}
isoquinoline-3-carboxamide
##STR00197##
[0644] Under a nitrogen atmosphere isoquinoline-3-carboxylic acid
(1.32 g, 7.63 mmol), 1-hydroxybenzotriazole (1.12 g, 8.27 mmol),
and dichloromethane (60 mL) were combined, allowed to stir for
several minutes and then cooled to 0.degree. C.
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was
added. Pyridine (1.8 mL) was added and the resulting mixture was
allowed to stir for at least 60 minutes. A solution of
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(2.0 g, 6.37 mmol) in dichloromethane (250 mL) was added dropwise.
The reaction mixture was allowed to stir at ambient temperature
overnight. The reaction mixture was washed with sodium bicarbonate,
dried over magnesium sulfate, filtered and then concentrated under
reduced pressure. The crude material was purified by column
chromatography (40 g silica gel eluting with
dichloromethane/methanol 9/1) followed by recrystallization from
methanol to provide 882 mg of
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}iso-
quinoline-3-carboxamide as a yellow crystalline solid, m.p.
199-200.degree. C. Analysis: Calculated for
C.sub.27H.sub.28N.sub.6O.sub.2: % C, 69.21; % H, 6.02; % N, 17.94;
Found: % C, 69.03; % H, 5.99; % N, 18.11.
EXAMPLE 182
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}quin-
oline-3-carboxamide
##STR00198##
[0646] Using the general method of Example 181
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(2.0 g, 6.37 mmol) was reacted with quinoline-3-carboxylic acid
(1.33 g, 7.66 mmol) to provide 850 mg of
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}qui-
noline-3-carboxamide as a yellow solid, m.p. 114-116.degree. C.
Analysis: Calculated for C.sub.27H.sub.28N.sub.6O.sub.2
0.2H.sub.2O: % C, 68.68; % H, 6.06; % N, 17.80; Found: % C, 68.68;
% H, 5.85; % N, 17.76.
EXAMPLE 183
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}quin-
oxaline-2-carboxamide
##STR00199##
[0648] Using the general method of Example 181
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(1.5 g, 4.78 mmol) was reacted with 2-quinoxalinecarboxylic acid
(1.0 g, 5.74 mmol) to provide 270 mg of
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}qui-
noxaline-2-carboxamide as a yellow crystalline solid, m.p.
85-87.degree. C. Analysis: Calculated for
C.sub.26H.sub.27N.sub.7O.sub.2: % C, 66.51; % H, 5.80; % N, 20.88;
Found: % C, 66.12; % H, 5.70; % N, 20.62.
EXAMPLE 184
(2S,3S)--N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]b-
utyl}-1-methyl-5-oxo-2-pyridin-3-ylpyrrolidine-3-carboxamide
##STR00200##
[0650] Using the general method of Example 181
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(400 mg, 1.28 mmol) was reacted with trans-4-cotinecarboxylic acid
(338 mg, 1.54 mmol) to provide 25 mg of
(2S,3S)--N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-
butyl)}-1-methyl-5-oxo-2-pyridin-3-ylpyrrolidine-3-carboxamide as a
light gray powder.
[0651] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.53 (dd, J=3.2,
1.6 Hz, 1H), 8.43 (d, J=1.9 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.72
(d, J=7.5 Hz, 1H), 7.48-7.39 (m, 2H), 7.29-7.23 (m, 2H), 6.24 (t,
J=5.6 Hz, 1H), 5.68 (s, 2H), 4.71 (d, J=7.9 Hz, 1H), 4.47 (t, J=7.5
Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.35 (s, 3H), 3.27 (m, 2H), 3.13
(t, J=6.3 Hz, 2H), 2.74-2.63 (m, 3H), 2.59 (s, 3H), 1.87 (m, 2H),
1.61 (m, 2H);
[0652] .sup.13CNMR (75 MHz, CDCl.sub.3) 173.1, 170.8, 151.3, 150.9,
150.1, 148.6, 143.6, 135.0, 134.3, 133.3, 127.3, 126.7, 126.5,
124.1, 122.6, 119.5, 115.1, 70.7, 64.8, 59.0, 48.3, 45.2, 39.3,
34.6, 28.4, 28.3, 27.5, 26.7;
[0653] MS (EI) m/e 515.2654 (515.2645 calcd for
C.sub.28H.sub.33N.sub.7O.sub.3).
EXAMPLE 185
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-[-
(4-tert-butylphenyl)sulfonyl]-L-prolinamide
##STR00201##
[0655] Using the general method of Example 181
1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(400 mg, 1.28 mmol) was reacted with
N-(4-tert-butylphenylsulfonyl)-L-proline (477 mg, 1.53 mmol) to
provide 123 mg of
N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl-
]butyl}-1-[(4-tert-butylphenyl)sulfonyl]-L-prolinamide as a brown
oil.
[0656] .sup.1HNMR (300 MHz, DMSO-d.sub.6) .delta. 8.01 (d, J=8.2
Hz, 1H), 7.93 (t, J=5.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.62-7.59
(m, 3H), 7.42 (t, J=7.4 Hz, 1H), 7.26 (t, J=7.4 Hz, 1H), 6.49 (s,
2H), 4.54 (t, J=7.2 Hz, 2H), 3.93-3.89 (m, 1H) 3.83 (t, J=6.7, 2H)
3.35 (m, 3H), 3.22-3.06 (m, 5H), 1.82 (m, 2H), 1.61 (m, 5H), 1.38
(m, 2H), 1.30 (s, 9H);
[0657] .sup.13CNMR (75 MHz, DMSO-d.sub.6) 171.4, 156.5, 151.9,
151.1, 144.9, 134.3, 132.6, 127.7, 126.9, 126.7, 126.5, 126.4,
121.7, 120.3, 115.1, 70.5, 70.2, 62.0, 58.4, 49.4, 45.1, 38.4,
35.2, 31.1, 27.5, 26.6, 24.4;
[0658] MS (EI) m/e 606.2969 (606.2988 calcd for
C.sub.32H.sub.42N.sub.6O.sub.4S).
EXAMPLE 186
N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide
##STR00202##
[0660] A solution of
1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g,
3.26 mmol) and triethylamine (500 .mu.L, 3.59 mmol) in
dichloromethane (30 mL) was cooled to 0.degree. C. Benzoyl chloride
(380 .mu.L, 3.26 mmol) was slowly added dropwise. The reaction
mixture was allowed to slowly warm to ambient temperature. After
several hours the reaction mixture was washed with distilled water
(1.times.50 mL) and brine (2.times.50 mL), dried over sodium
sulfate and then concentrated under reduced pressure to provide 1.5
g of crude orange gooey material. This material was purified by
column chromatography (65 g of silica gel, eluting with 7.5%
methanol in dichloromethane). The purified material was dissolved
in a small amount of dichloromethane and the solution was diluted
with hexane to precipitate a white powder. This material was
isolated by filtration, washed with hexanes and then dried in a
vacuum oven at 60.degree. C. overnight to provide 0.72 g of
N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide
as a white powder, m.p. 149.5-151.3.degree. C. Analysis: Calculated
for C.sub.29H.sub.37N.sub.5O: % C, 73.85; % H, 7.91; % N, 14.85;
Found: % C, 73.46; % H, 7.79; % N, 14.56.
[0661] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.42 (t, J=5.4
Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.82 (m, 2H), 7.61 (dd, J=8.3, 1.5
Hz, 1H), 7.51-7.41 (m, 4H), 7.25 (m, 1H), 6.51 (s, 2H), 4.48 (t,
J=7.3 Hz, 2H), 3.23 (m, 2H), 2.91 (m, 2H), 1.79 (m, 4H), 1.43 (m,
6H), 1.30 (m, 6H), 0.95 (t, J=7.3 Hz, 3H);
[0662] .sup.13C NMR (125 MHz, DMSO-d.sub.6) 165.9, 152.9, 151.5,
144.4, 134.6, 132.1, 130.8, 128.1, 127.0, 126.3, 126.2, 126.1,
121.1, 119.8, 114.7, 44.7, 39.1, 29.64, 29.60, 29.0, 28.54, 28.49,
26.3, 26.1, 25.7, 21.9, 13.7
[0663] MS m/z 472 (M+1)
EXAMPLE 187
N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benz-
amide
##STR00203##
[0665] Using the general method of Example 186
1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(0.84 g, 2.27 mmol) was reacted with benzoyl chloride (260 .mu.L,
2.27 mmol) to provide 0.48 g of
N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}ben-
zamide as a tan powder, m.p. 133.4-137.5.degree. C. Analysis:
Calculated for C.sub.28H.sub.35N.sub.5O.sub.2: % C, 71.01; % H,
7.45; % N, 14.79; Found: % C, 71.41; % H, 7.35; % N, 14.48.
[0666] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.42 (m, 1H),
8.01 (d, J=8.3 Hz, 1H), 7.82 (d, J=6.8 Hz, 2H), 7.61 (d, J=7.8 Hz,
1H), 7.51-7.39 (m, 4H), 7.25 (m, 1H), 6.48 (s, 2H), 4.51 (t, J=7.3
Hz, 2H), 3.82 (t, J=6.4 Hz, 2H), 3.29 (s, 3H), 3.25-3.16 (m, 4H),
1.80 (m, 2H), 1.50-1.30 (m, 10H);
[0667] .sup.13CNMR (125 MHz, DMSO-d.sub.6) 166.4, 152.0, 151.0,
145.1, 135.1, 132.5, 131.3, 128.5, 127.4, 126.9, 126.7, 121.5,
120.3, 115.1, 70.5, 58.5, 45.3, 39.5, 30.1, 29.4, 29.0, 27.6, 26.7,
26.2
[0668] MS m/z 474 (M+1)
EXAMPLE 188
N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]isoquinoline-3-
-carboxamide
##STR00204##
[0670] Isoquinoline-3-carboxylic acid (1.05 g, 6.05 mmol) was
stirred in 1-methyl-2-pyrrolidinone (50 mL). 1-Hydroxybenzotriazole
(885 mg, 6.55 mmol) was added in a single portion. This solution
was stirred for 15-20 minutes and then cooled in an ice bath.
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.26
g, 6.55 mmol) was added in small portions over a period of 10
minutes. The solution was stirred for 1 hour and then added
dropwise to a solution of
1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine-(1.50
g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (100 mL). After 3 hours
the reaction mixture was poured into distilled water (800 mL). A
solid precipitated. This material was stirred for 5 hours, isolated
by filtration and then air dried over the weekend. The solid was
taken up in chloroform (100 mL) and then purified by column
chromatography (silica gel eluting sequentially with chloroform (1
L), 1% methanol in chloroform (1 L) and 5% methanol in chloroform
(1 L)). The purified material was slurried with hot acetonitrile,
cooled, isolated by filtration and then dried in a vacuum oven to
provide 1.72 g of
N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]isoquinoline--
3-carboxamide as a solid, m.p. 203.8-205.3.degree. C. Analysis:
Calculated for C.sub.27H.sub.28N.sub.6O: % C, 71.66; % H, 6.24; %
N, 18.57; Found: % C, 71.63; % H, 6.17; % N, 18.57.
EXAMPLE 189
N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide
##STR00205##
[0672] Under a nitrogen atmosphere triethylamine (765 mg, 7.56
mmol) was added to a solution of
1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50
g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (50 mL). Benzoyl chloride
(972 mg, 5.55 mmol) was added dropwise. When analysis by HPLC
indicated that the reaction was complete, the reaction solution was
poured into distilled water (500 mL). The pH was adjusted to 10
using solid potassium carbonate. A solid was isolated by
filtration, rinsed with water and then dried in a vacuum oven. This
material was stirred with chloroform (500 mL) and then filtered.
The filtrate was loaded onto a silica gel column. The column was
eluted with 1-5% methanol in chloroform. The purified material was
dried in a vacuum oven to provide 800 mg of
N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide
as a solid, m.p. 189.4-190.0.degree. C. Analysis: Calculated for
C.sub.24H.sub.27N.sub.5O.0.82H.sub.2O: % C, 69.25; % H, 6.93; % N,
16.82; Found: % C, 69.50; % H, 7.15; % N, 17.02.
EXAMPLE 190
N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimet-
hylpropyl}benzamide
##STR00206##
[0674] A solution containing
1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinol-
in-4-amine (1.0 g, 3.05 mmol) and triethylamine (470 .mu.L, 3.36
mmol) in 1-methyl-2-pyrrolidinone (30 mL) was cooled to 0.degree.
C. Benzoyl chloride (345 .mu.L, 3.05 mmol) was slowly added
dropwise. The reaction mixture was allowed to slowly warm to
ambient temperature overnight. The reaction mixture was combined
with 1% aqueous sodium bicarbonate solution (150 mL) and then
stirred overnight. A fine white precipitate was isolated by
filtration and washed with hexanes. The material was dissolved in
dichloromethane, methanol and toluene. The solution was
concentrated under vacuum. The material was purified by column
chromatography (60 g silica gel eluting with 7.5% methanol in
dichloromethane) and then dried in a vacuum oven at 50.degree. C.
for 2 days to provide 0.82 g of
N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dime-
thylpropyl}benzamide as an off white powder, m.p. 103-125.degree.
C. Analysis: Calculated for
C.sub.25H.sub.29N.sub.5O.sub.2.0.30H.sub.2O: % C, 68.72; % H, 6.83;
% N, 16.03; Found: % C, 68.50; % H, 6.55; % N, 16.02.
[0675] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.75 (m, 1H),
8.22 (d, J=8.3 Hz, 1H), 7.97 (m, 2H), 7.59-7.52 (m, 4H), 7.33 (m,
1H), 6.87 (m, 1H), 6.54 (s, 2H), 4.89 (broad s, 1H), 4.45 (broad s,
1H), 3.82 (broad s, 2H), 3.40 (m, 4H), 0.97 (broad s, 3H), 0.77
(broad s, 3H);
[0676] .sup.13C NMR (75 MHz, DMSO-d.sub.6) 167.7, 152.8, 152.3,
145.5, 135.1, 134.1, 131.9, 129.0, 128.0, 127.0, 126.8, 121.4,
120.8, 116.0, 71.3, 58.7, 52.3, 48.3, 28.6, 25.7, 23.3
[0677] MS m/z 432 (M+1)
EXAMPLE 191
N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide
##STR00207##
[0679] Using the general method of Example 186
1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was
reacted with benzoyl chloride (450 .mu.L, 3.85 mmol) to provide
0.45 g of
N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide as an
off white powder, m.p. 133.1-136.7.degree. C. Analysis: Calculated
for C.sub.25H.sub.29N.sub.5O.0.25H.sub.2O: % C, 71.49; % H, 7.08; %
N, 16.67; Found: % C, 71.37; % H, 7.05; % N, 16.62.
[0680] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.42 (m, 1H),
8.20 (s, 1H), 8.03 (d, J=8.3, 1H), 7.83 (m, 2H), 7.62 (d, J=8.3 Hz,
1H), 7.48-7.42 (m, 4H), 7.26 (m, 1H), 6.62 (s, 2H), 4.58 (m, 2H),
3.23 (m, 2H), 1.85 (m, 2H), 1.49 (m, 2H), 1.29 (m, 8H);
[0681] .sup.13CNMR (125 MHz, DMSO-d.sub.6) 168.1, 154.2, 146.9,
144.9, 136.9, 133.7, 133.0, 130.3, 130.2, 129.2, 128.8, 128.2,
123.3, 122.6, 116.9, 48.6, 41.2, 31.8, 31.1, 30.7, 30.5, 28.4,
27.8.
[0682] MS m/z 416 (M+1).
EXAMPLE 192
N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}iso-
quinoline-3-carboxamide
##STR00208##
[0684] Using the general method of Example 188
isoquinoline-3-carboxylic acid (1.05 g, 6.06 mmol) was reacted with
1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(1.50 g, 5.01 mmol) to provide 1.30 g of
N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}is-
oquinoline-3-carboxamide as a white foam, m.p. 198.0-198.5.degree.
C. Analysis: Calculated for C.sub.26H.sub.26N.sub.6O.sub.2: % C,
68.71; % H, 5.77; % N, 18.49; Found: % C, 68.39; % H, 5.83; % N,
18.63.
EXAMPLE 193
N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-
-bromobenzamide
##STR00209##
[0686] Using the general method of Example 189,
1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine
(2.0 g, 5.32 mmol) was reacted with 4-bromobenzoyl chloride (880
mg, 5.86 mmol) to provide 1.8 g of
N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}--
4-bromobenzamide as a light yellow solid, m.p. 186.2-186.7.degree.
C. Analysis: Calculated for C.sub.29H.sub.28BrN.sub.5O.sub.2: % C,
62.37; % H, 5.05; % N, 12.54; Found: % C, 62.18; % H, 5.16; % N,
12.43.
EXAMPLE 194
N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}be-
nzamide
##STR00210##
[0688] Benzoyl chloride (1.03 g, 5.86 mmol) was added to a
refluxing solution of
1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine
(2.0 g, 5.32 mmol) and triethylamine (1.11 mL, 7.98 mmol) in
chloroform (150 mL). When analysis by HPLC indicated that the
reaction was complete, it was quenched with aqueous 1% sodium
carbonate solution. The layers were separated. The organic layer
was washed with aqueous 1% sodium carbonate solution (2.times.100
mL). The aqueous layers were combined and then extracted with
chloroform (2.times.30 mL). The organics were combined, dried over
sodium sulfate, filtered and then concentrated under reduced
pressure to provide 2.63 g of a solid. The solid was dissolved in
methanol, solid sodium carbonate was added and the mixture was
brought to reflux. After 2 hours analysis indicated that conversion
from the bis amide to the desired product was complete. The
reaction mixture was cooled and filtered. Distilled water (20 mL)
was added to the filtrate and the filtrate was concentrated under
reduced pressure to provide a solid. This material was dissolved in
dichloromethane and then washed with distilled water (2.times.100
mL). The aqueous layers were combined and then extracted with
dichloromethane (2.times.100 mL). The organics were combined, dried
over sodium sulfate, filtered and then concentrated under reduced
pressure to provide a solid. This material was purified by column
chromatography (silica gel eluting with a methanol/chloroform
gradient) to provide a yellow foam. The foam was triturated with
acetonitrile and the resulting solid was isolated by filtration and
then dried in a vacuum oven overnight to provide 1.55 g of
N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}b-
enzamide as a light yellow crystalline solid, m.p.
192.0-194.0.degree. C. Analysis: Calculated for
C.sub.29H.sub.29N.sub.5O.sub.2: % C, 72.63; % H, 6.10; % N, 14.60;
Found: % C, 72.43; % H, 6.06; % N, 14.82.
EXAMPLE 195
N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quino-
lin-1-yl]propyl}benzamide
##STR00211##
[0690] Benzoyl chloride (900 mg, 6.40 mmol) was added in a single
portion to a cooled (0.degree. C.) solution of
1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]-
quinolin-4-amine (1.9 g, 6.26 mmol) and triethylamine (2 mL) in
1-methyl-2-pyrrolidinone (100 mL). When analysis by HPLC indicated
that the reaction was complete, it was diluted with diethyl ether
(1 L). The product was salted out by adding 3.3 eq. of a 1.0 M
solution of hydrochloric acid in diethyl ether. The solid was
isolated by filtration and then dissolved in water. The solution
was neutralized using solid potassium carbonate and then extracted
with dichloromethane. The extract was concentrated under reduced
pressure to provide a solid. This material was recrystallized from
1,2-dichloroethane, slurried with diethyl ether, filtered and then
dried in a vacuum oven to provide 1.47 g of
N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quin-
olin-1-yl]propyl}benzamide as a white solid, m.p.
167.8-169.6.degree. C. Analysis: Calculated for
C.sub.23H.sub.29N.sub.5O.sub.2: % C, 67.05; % H, 7.22; % N, 17.00;
Found: % C, 67.17; % H, 7.24; % N, 16.98.
EXAMPLE 196
N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}ben-
zamide
##STR00212##
[0692] Using the general method of Example 186 except that
chloroform was used as the solvent,
1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
(1.50 g, 5.01 mmol) was reacted with benzoyl chloride (972 mg, 5.55
mmol) to provide 700 mg of
N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}be-
nzamide as a white solid, m.p. 183.0-186.0.degree. C. Analysis:
Calculated for C.sub.23H.sub.25N.sub.5O.sub.2.0.5H.sub.2O: % C,
66.97; % H, 6.35; % N, 16.98; Found: % C, 67.16; % H, 6.18; % N,
17.07.
EXAMPLE 197
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecar-
boxamide
##STR00213##
[0694] A solution of
1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g,
3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) in chloroform (100
mL) was cooled with an acetone/ice bath. Cyclopentanecarbonyl
chloride (0.47 mL, 3.9 mmol) was slowly added. The reaction was
complete within 10 minutes. The reaction mixture was washed with
water (1.times.100 mL) and brine (1.times.100 mL). The organic
layer was dried over magnesium sulfate, filtered and then
concentrated under reduced pressure. The residue was slurried with
acetonitrile. The resulting solid was isolated by filtration and
dried in an oven overnight to provide 1.01 g of
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentaneca-
rboxamide as a light brown solid, m.p. 178.6-179.5.degree. C.
Analysis: Calculated for C.sub.22H.sub.29N.sub.5O.0.25H.sub.2O: %
C, 68.81; % H, 7.74; % N, 18.24; Found: % C, 68.77; % H, 7.87; % N,
18.19.
EXAMPLE 198
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecar-
boxamide
##STR00214##
[0696] Using the general method of Example 197,
17-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00
g, 3.7 mmol) was reacted with cyclohexanecarbonyl chloride (0.55
mL, 4.1 mmol) to provide 1.07 g of
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexaneca-
rboxamide as an off white solid, m.p. 191.6-192.6.degree. C.
Analysis: Calculated for C.sub.22H.sub.29N.sub.5O.0.25H.sub.2O: %
C, 68.81; % H, 7.74; % N, 18.24; Found: % C, 68.85; % H, 7.75; % N,
17.95.
EXAMPLE 199
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropan-
amide
##STR00215##
[0698] Using the general method of Example 197,
1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g,
3.5 mmol) was reacted with isobutyl chloride (0.41 mL, 3.9 mmol) to
provide 0.34 g of
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-m-
ethylpropanamide as an off white solid, m.p. 155.4-156.3.degree.
C.
[0699] Analysis: Calculated for
C.sub.20H.sub.27N.sub.5O.0.75H.sub.2O: % C, 65.46; % H, 7.83; % N,
19.08; Found: % C, 65.84; % H, 7.87; % N, 18.73.
EXAMPLE 200
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide
##STR00216##
[0701] Using the general method of Example 197,
1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g,
3.5 mmol) was reacted with butyryl chloride (0.40 mL, 3.9 mmol) to
provide 0.77 g of
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]buta-
namide as a light brown solid, m.p. 147.7-148.8.degree. C.
Analysis: Calculated for C.sub.20H.sub.27N.sub.5O.0.4H.sub.2O: % C,
66.60; % H, 7.77; % N, 19.42; Found: % C, 66.84; % H, 7.77; % N,
19.36.
EXAMPLE 201
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentaneca-
rboxamide
##STR00217##
[0703] Using the general method of Example 197,
1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00
g, 3.7 mmol) was reacted with cyclopentanecarbonyl chloride (0.50
mL, 4.1 mmol) to provide 0.71 g of
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanec-
arboxamide as a white solid, m.p. 168.6-169.8.degree. C.
EXAMPLE 202
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropa-
namide
##STR00218##
[0705] Using the general method of Example 197,
1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00
g, 3.7 mmol) was reacted with isobutyryl chloride (0.43 mL, 4.1
mmol) to provide 0.56 g of
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2--
methylpropanamide as an off white solid, m.p. 159.7-160.7.degree.
C.
EXAMPLE 203
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide
##STR00219##
[0707] Using the general method of Example 197,
1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00
g, 3.7 mmol) was reacted with butyryl chloride (0.43 mL, 4.1 mmol)
to provide 0.65 g of
N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]but-
anamide as an off white solid, m.p. 169.4-170.5.degree. C.
EXAMPLE 204
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecarb-
oxamide
##STR00220##
[0709] Using the general method of Example 197,
1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g,
3.5 mmol) was reacted with cyclohexanecarbonyl chloride (0.52 mL,
3.9 mmol) to provide 1.16 g of
N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecar-
boxamide as a light brown solid, m.p. 201.7-202.5.degree. C.
EXAMPLE 205
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexaneca-
rboxamide
##STR00221##
[0711] Using the general method of Example 195 except that the acid
chloride was added in a dropwise fashion,
1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00
g, 7.83 mmol) was reacted with cyclohexanecarbonyl chloride (1.14
g, 7.83 mmol) to provide 1.34 g of
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanec-
arboxamide as a white powder, m.p. 234.4-235.4.degree. C. Analysis:
Calculated for C.sub.21H.sub.27N.sub.5O: % C, 69.01; % H, 7.45; %
N, 19.16; Found: % C, 68.70; % H, 7.39; % N, 19.24.
EXAMPLE 206
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopentanec-
arboxamide
##STR00222##
[0713] Using the general method of Example 205,
1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00
g, 7.83 mmol) was reacted with cyclopentanecarbonyl chloride (1.04
g, 7.83 mmol) to provide 1.67 g of
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopentane-
carboxamide as a solid, m.p. 207.8-208.9.degree. C. Analysis:
Calculated for C.sub.20H.sub.25N.sub.5O: % C, 68.35; % H, 7.17; %
N, 19.93; Found: % C, 68.09; % H, 7.19; % N, 20.09.
EXAMPLE 207
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-2-methylprop-
anamide
##STR00223##
[0715] Using the general method of Example 205,
1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00
g, 7.83 mmol) was reacted with isobutyryl chloride (835 mg, 7.83
mmol). The product was recrystallized from methyl acetate to
provide 1.11 g of
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-2-methylpro-
panamide as an off white powder, m.p. 239.0-240.1.degree. C.
Analysis: Calculated for C.sub.18H.sub.23N.sub.5O.0.20
C.sub.3H.sub.6O.sub.2: % C, 65.66; % H, 7.17; % N, 20.58; Found: %
C, 65.51; % H, 7.05; % N, 20.71.
EXAMPLE 208
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]butanamide
##STR00224##
[0717] Using the general method of Example 205,
1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00
g, 7.83 mmol) was reacted with butyryl chloride (835 mg, 7.83
mmol). The product was recrystallized from methanol to provide 1.07
g of
N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]butanamide
as a white powder, m.p. 221.8-223.3.degree. C. Analysis: Calculated
for C.sub.18H.sub.23N.sub.5O.0.25 CH.sub.4O: % C, 65.74; % H, 7.26;
% N, 21.00; Found: % C, 65.79; % H, 7.14; % N, 21.25.
EXAMPLE 209
N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethy-
lethyl}-2-ethoxyacetamide
##STR00225##
[0718] Part A
[0719] A stirred solution of 4-chloro-3-nitroquinoline (2.08 g,
10.0 mmol) in 20 mL of anhydrous CH.sub.2Cl.sub.2, under N.sub.2,
was treated with triethylamine (2.79 mL, 20.0 mol) and
1,2-diamino-2-methylpropane (1.15 mL, 11.0 mmol). After stirring
for 2 d, the reaction mixture was diluted with 100 mL of CHCl.sub.3
washed with H.sub.2O (3.times.50 mL) and brine (50 mL). The organic
portion was dried over Na.sub.2SO.sub.4 and concentrated to give
2-methyl-N.sup.1-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.45 g)
as a bright yellow solid.
Part B
[0720] A solution of
2-methyl-N'-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.45 g, 9.42
mmol), in 100 mL of toluene and 50 mL of isopropanol was treated
with 0.5 g of 5% Pt on carbon and shaken under H.sub.2 (3 atm, 3
Kg/cm.sup.2) for 3 h. The solution was then filtered through a
Celite pad and concentrated to give 2.17 g of crude
N.sup.4-(2-amino-2-methylpropyl)quinoline-3,4-diamine as a light
brown foam.
Part C
[0721] A solution of
N.sup.4-(2-amino-2-methylpropyl)quinoline-3,4-diamine (2.17 g, 9.43
mmol) in 100 mL of CH.sub.2Cl.sub.2 was cooled to 0.degree. C. and
treated with triethylamine (1.31 mL, 9.43 mmol) and ethoxyacetyl
chloride (1.00 mL, 9.93 mmol). After 2 h, the reaction mixture was
concentrated under reduced pressure. The resulting syrup was taken
up in 100 mL of EtOH and treated with 4 mL of triethylamine. The
solution was heated to reflux overnight. The reaction mixture was
then concentrated and redissolved in 100 mL of toluene and treated
with pyridinium hydrochloride (100 mg) and the mixture was heated
to reflux overnight. The reaction mixture was concentrated and
taken up in 100 mL of CH.sub.2Cl.sub.2 and washed with H.sub.2O
(2.times.) and brine. The organic portion was dried over
Na.sub.2SO.sub.4 and concentrated. The resulting syrup was purified
by column chromatography (SiO.sub.2, 3% MeOH/CHCl.sub.3) to give
2-ethoxy-N-{2-[2-(ethoxymethy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimeth-
ylethyl}acetamide (1.01 g) as a brown syrup.
Part D
[0722] A solution of
2-ethoxy-N-{2-[2-(ethoxymethy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimeth-
ylethyl}acetamide (998 mg, 2.60 mmol) in 20 mL of CH.sub.2Cl.sub.2
was treated with 3-chloroperoxybenzoic acid (77%, 668 mg, 2.99
mmol). After stirring for 3 h, the reaction mixture was treated
with 30 mL of additional CH.sub.2Cl.sub.2 and was washed with 1%
Na.sub.2CO.sub.3 solution (2.times.50 mL), H.sub.2O and brine. The
organic portion was then dried over Na.sub.2SO.sub.4 and
concentrated to give
2-ethoxy-N-{2-[2-(ethoxymethy)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,-
1-dimethylethyl}acetamide (910 mg) as a light brown oil.
Part E
[0723] A solution of
2-ethoxy-N-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1-
,1-dimethylethyl}acetamide (910 mg, 2.28 mmol) in 10 mL of
1,2-dichloroethane was heated to 60.degree. C. and treated with 1
mL of concentrated NH.sub.4OH solution. To the rapidly stirred
solution was added solid p-toluenesulfonyl chloride (477 mg, 2.50
mmol). The reaction mixture was then sealed in a pressure vessel
and heating was continued for 2 h. The reaction mixture was then
cooled and treated with 50 mL of CHCl.sub.3. The reaction mixture
was then washed with H.sub.2O, 1% Na.sub.2CO.sub.3 solution
(3.times.) and brine. The organic portion was dried over
Na.sub.2SO.sub.4 and concentrated to give the product as a light
brown oil. The resulting oil was purified by column chromatography
(SiO.sub.2, 3% MeOH/CHCl.sub.3) to give
N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimeth-
ylethyl}-2-ethoxyacetamide (900 mg) as a light brown oil.
[0724] MS m/z 400 (M+H).
[0725] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.28 (dd, J=0.8,
8.3 Hz, 1H), 7.80 (dd, J=1.0, 8.4 Hz, 1H), 7.50 (ddd, J=1.2, 7.1,
8.3 Hz, 1H), 7.32 (ddd, J=1.2, 7.1, 8.3 Hz, 1H), 6.46 (s, 1H), 5.50
(s, 2H), 5.15 (s, 2H), 4.85 (br s, 2H), 3.80 (s, 2H), 3.60 (q,
J=7.0 Hz, 2H), 3.43 (q, J=7.0 Hz, 2H), 1.41 (br s, 6H), 1.24 (t,
J=7.0 Hz, 3H), 1.13 (t, J=7.0 Hz, 3H);
[0726] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 170.3, 151.8,
150.9, 145.6, 135.4, 127.8, 127.5, 127.3, 122.2, 121.0, 116.2,
70.4, 67.4, 66.8, 65.6, 55.7, 52.1, 26.4, 15.4, 15.3.
Cytokine Induction in Human Cells
[0727] An in vitro human blood cell system was used to assess
cytokine induction by compounds of the invention. Activity is based
on the measurement of interferon and tumor necrosis factor
(.alpha.) (IFN and TNF, respectively) secreted into culture media
as described by Testerman et. al. In "Cytokine Induction by the
Immunomodulators Imiquimod and S-27609", Journal of Leukocyte
Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture
[0728] Whole blood is collected by venipuncture into EDTA
vacutainer tubes from healthy human donors. Peripheral blood
mononuclear cells (PBMCs) are separated from whole blood by density
gradient centrifugation using Histopaque.RTM.--1077 (Sigma
Chemicals, St. Louis, Mo.). The PBMCs are suspended at
3-4.times.10.sup.6 cells/mL in RPMI 1640 medium containing 10%
fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin
solution (RPMI complete). The PBMC suspension is added to 48 well
flat bottom sterile tissue culture plates (Costar, Cambridge, Mass.
or Becton Dickinson Labware, Lincoln Park, N.J.) containing an
equal volume of RPMI complete media containing test compound.
Compound Preparation
[0729] The compounds are solubilized in dimethyl sulfoxide (DMSO).
The DMSO concentration should not exceed a final concentration of
1% for addition to the culture wells.
Incubation
[0730] The solution of test compound is added at 60 .mu.M to the
first well containing RPMI complete and serial (three fold or ten
fold) dilutions are made. The PBMC suspension is then added to the
wells in an equal volume, bringing the test compound concentrations
to the desired range. The final concentration of PBMC suspension is
1.5-2.times.10.sup.6 cells/mL. The plates are covered with sterile
plastic lids, mixed gently and then incubated for 18 to 24 hours at
37.degree. C. in a 5% carbon dioxide atmosphere.
Separation
[0731] Following incubation the plates are centrifuged for 5-10
minutes at 1000 rpm (.about.200.times.g) at 4.degree. C. The cell
culture supernatant is removed with a sterile polypropylene pipet
and transferred to sterile polypropylene tubes. Samples are
maintained at -30 to -70.degree. C. until analysis. The samples are
analyzed for interferon (.alpha.) by either ELISA or bioassay and
for tumor necrosis factor (.alpha.) by ELISA
Interferon Bioassay Analysis
[0732] Interferon is determined by bioassay using A549 human lung
carcinoma cells challenged with encephalomyocarditis. The details
of the bioassay method have been described by G. L. Brennan and L.
H. Kronenberg in "Automated Bioassay of Interferons in Micro-test
Plates", Biotechniques, June/July, 78, 1983, incorporated herein by
reference. Briefly stated the method is as follows: A549 cells are
incubated with dilutions of samples or a standard interferon at
37.degree. C. for 24 hours. The incubated cells are then infected
with an inoculum of encephalomyocarditis virus. The infected cells
are incubated for an additional 24 hours at 37.degree. C. before
evaluating for viral cytopathic effect. The viral cytopathic effect
is quantified by staining with crystal violet followed by visual
scoring of the plates. Results are expressed as alpha reference
units/mL based on the value obtained for NIH Human Leukocyte IFN
standard.
Interferon (.alpha.) and Tumor Necrosis Factor (.alpha.) Analysis
by ELISA
[0733] Interferon (.alpha.) concentration is determined by ELISA
using a Human Multi-Species kit from PBL Biomedical Laboratories,
New Brunswick, N.J.
[0734] Tumor necrosis factor (.alpha.) (TNF) concentration is
determined using ELISA kits available from Genzyme, Cambridge,
Mass.; R&D Systems, Minneapolis, Minn.; or Pharmingen, San
Diego, Calif.
[0735] The table below lists the lowest concentration found to
induce interferon and the lowest concentration found to induce
tumor necrosis factor for each compound. A "**" indicates that no
induction was seen at any of the tested concentrations (0.12, 0.37,
1.11, 3.33, 10 and 30 .mu.M). A "***" indicates that no induction
was seen at any of the tested concentrations (0.0001, 0.001, 0.01,
0.1, 1 and 10 .mu.M). Unless otherwise indicated, the interferon
biosynthesis was determined by ELISA.
TABLE-US-00010 Cytokine Induction in Human Cells Lowest Effective
Concentration (.mu.M) Example Tumor Necrosis Number Interferon
Factor 1 0.37 10 3 0.37 1.11 4 0.04 0.37 5 0.04 0.37 6 0.12 1.11 7
1.11 ** 8 0.04 ** 9 0.37 3.33 10 3.33 ** 11 1.11 ** 12 3.33 ** 13
1.11 3.33 14 3.33 ** 15 3.33 ** 16 1.11 30 17 3.33 10 18 3.33 ** 19
10 ** 20 3.33 ** 21 0.12 1.11 22 0.37 10 23 1.11 ** 24 0.12 3.33 25
3.33 ** 26 0.37 10 27 ** ** 28 0.12 ** 29 0.12 ** 31 1.11 ** 32
3.33 ** 33 0.37 ** 34 ** 3.33 35 1.11 ** 36 1.11 10 37 0.37 ** 38
0.12 3.33 39 3.33 ** 40 0.37 30 41 1.11 ** 42 30 3.33 43 0.12 ** 44
1.11 ** 45 3.33 ** 46 ** 10 68* 1.11 10 69* 0.12 1.11 70* 0.37 3.33
71* 0.12 3.33 72* 0.37 10 73* 0.37 10 74* 0.37 10 75* 1.11 ** 76*
3.33 ** 77* 1.11 10 78* 0.12 10 79* 0.37 ** 80* 1.11 10 81* 3.33 30
82* 0.12 10 83* 1.11 ** 84* 0.12 10 85 1.11 10 86 1.11 10 87 3.33
30 88 10 ** 89 1.11 10 90 3.33 10 91 3.33 ** 92 3.33 ** 93 1.11 30
94 0.04 3.33 95 3.33 30 96 0.37 10 97 0.12 3.33 98 1.11 10 99 0.37
3.33 100 10 3.33 101 3.33 ** 102 3.33 ** 103 0.37 10 104 ** ** 105
0.12 10 106 3.33 ** 107 0.12 10 108 0.12 10 109 ** ** 110 1.11 3.33
111 1.11 ** 112 10 ** 113 3.33 ** 114 1.11 10 115 1.11 30 116 0.37
10 117 3.33 ** 118 1.11 ** 119 ** ** 120 0.37 ** 121 1.11 ** 122
3.33 ** 123 3.33 ** 124 1.11 3.33 125 1.11 ** 126 3.33 ** 127 ** **
128 3.33 1.11 129 3.33 ** 130 1.11 10 131 3.33 ** 132 1.11 3.33 133
3.33 ** 134 0.37 ** 135 0.12 ** 136 1.11 ** 137 10 ** 138 1.11 **
139 ** ** 140 1.11 ** 141 0.37 ** 142 3.33 ** 143 0.12 ** 144 1.11
** 145 1.11 ** 146 3.33 ** 148 0.01 1 149 0.001 1 150 0.001 0.1 151
0.0001 *** 153 0.0001 0.1 154 0.0001 *** 155 0.0001 1 155 0.01 0.1
156 0.001 1 158 0.001 1 159 0.01 1 172 0.0001 1 173 0.001 1 174
0.001 1 181 0.01 1.11 182 0.01 0.01 183 0.01 0.04 184 0.12 1.11 185
1.11 3.33 186 0.04 0.12 187 0.01 0.01 188 0.37 1.11 189 0.04 0.12
190 0.01 0.01 191 ** ** 192 0.12 0.37 194 ** 10 196 0.01 0.37
*Interferon determined using the bioassay method
[0736] The present invention has been described with reference to
several embodiments thereof. The foregoing detailed description and
examples have been provided for clarity of understanding only, and
no unnecessary limitations are to be understood therefrom. It will
be apparent to those skilled in the art that many changes can be
made to the described embodiments without departing from the spirit
and scope of the invention. Thus, the scope of the invention should
not be limited to the exact details of the compositions and
structures described herein, but rather by the language of the
claims that follow.
* * * * *