U.S. patent application number 12/131023 was filed with the patent office on 2008-12-11 for sulfonamido ether substituted imidazoquinolines.
This patent application is currently assigned to Coley Pharmaceutical Group, Inc.. Invention is credited to Stephen L. Crooks, George W. Griesgraber, Philip D. Heppner, Bryon A. Merrill, Ralph R. Roberts, Ai-Ping Wei.
Application Number | 20080306252 12/131023 |
Document ID | / |
Family ID | 46150148 |
Filed Date | 2008-12-11 |
United States Patent
Application |
20080306252 |
Kind Code |
A1 |
Crooks; Stephen L. ; et
al. |
December 11, 2008 |
SULFONAMIDO ETHER SUBSTITUTED IMIDAZOQUINOLINES
Abstract
Imidazoquinoline and tetrahydroimidazoquinoline compounds that
contain ether and sulfonamide or sulfamide 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: |
Crooks; Stephen L.;
(Mahtomedi, MN) ; Griesgraber; George W.; (Eagan,
MN) ; Heppner; Philip D.; (Woodbury, MN) ;
Merrill; Bryon A.; (River Falls, WI) ; Roberts; Ralph
R.; (Cottage Grove, MN) ; Wei; Ai-Ping;
(Woodbury, MN) |
Correspondence
Address: |
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON
MA
02210-2206
US
|
Assignee: |
Coley Pharmaceutical Group,
Inc.
New York
NY
|
Family ID: |
46150148 |
Appl. No.: |
12/131023 |
Filed: |
May 30, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11069035 |
Feb 28, 2005 |
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12131023 |
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10696478 |
Oct 29, 2003 |
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11069035 |
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10165443 |
Jun 7, 2002 |
6677347 |
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10696478 |
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10012599 |
Dec 6, 2001 |
6683088 |
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10165443 |
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60254218 |
Dec 8, 2000 |
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Current U.S.
Class: |
534/798 ;
546/118 |
Current CPC
Class: |
A61P 37/02 20180101;
C07D 471/04 20130101; A61P 31/12 20180101 |
Class at
Publication: |
534/798 ;
546/118 |
International
Class: |
C09B 29/36 20060101
C09B029/36; C07D 471/04 20060101 C07D471/04 |
Claims
1.-26. (canceled)
27. A compound selected from the group consisting of: ##STR00072##
##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077##
##STR00078## ##STR00079## ##STR00080## ##STR00081## or a
pharmaceutically acceptable salt thereof.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
10/012,599, filed on Dec. 6, 2001, which claims the benefit of
previously filed Provisional Application Ser. No. 60/254,218, filed
on Dec. 8, 2000.
FIELD OF THE INVENTION
[0002] This invention relates to imidazoquinoline compounds that
have ether and sulfonamide or sulfamide functionality at the
1-position, and to pharmaceutical compositions containing such
compounds. The invention also provides methods of making the
compounds and intermediates useful in their synthesis. 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
[0003] 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.
[0004] 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.
[0005] There continues to be interest in the imidazoquinoline ring
system. Certain 1H-imidazo[4,5-c]naphthyridine-4-amines,
1H-imidazo[4,5-c]pyridin-4-amines, and
1H-imidazo[4,5-c]quinolin-4-amines having an ether containing
substituent at the 1 position are known. These are described in
U.S. Pat. Nos. 5,268,376; 5,389,640; 5,494,916; and WO
99/29693.
[0006] 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
[0007] 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 ether and
sulfonamide or sulfamide containing substituent at the 1-position.
The compounds are defined by Formulas (I) and (II), which are
defined in more detail infra. These compounds share the general
structural formula
##STR00001##
wherein X, R.sub.1, R.sub.2, and R are as defined herein for each
class of compounds having Formulas (I) and (II).
[0008] The compounds of Formulas (I) and (II) 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.
[0009] 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) or (II) to the
animal.
[0010] In addition, the invention provides methods of synthesizing
the compounds of the invention and novel intermediates useful in
the synthesis of these compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0011] As mentioned earlier, we have found certain compounds that
induce cytokine biosynthesis and modify the immune response in
animals. Such compounds are represented by Formulas (I) and (II),
shown below.
[0012] Imidazoquinoline compounds of the invention, which have
ether and sulfonamide or sulfamide functionality at the 1-position
are represented by Formula (I):
##STR00002##
wherein: X is --CHRs--, --CHR.sub.5-alkyl-, or
--CHR.sub.5-alkenyl-; [0013] R.sub.1 is selected from the group
consisting of: [0014] R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkyl;
[0015] R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkenyl; [0016]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-aryl; [0017]
R.sub.4--NR.sub.3--SO.sub.2-heteroaryl; [0018]
R.sub.4--NR.sub.3--SO.sub.2--R-heterocyclyl; [0019]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.7; [0020]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-alkyl; [0021]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-alkenyl; [0022]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-aryl; [0023]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-heteroaryl; [0024]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-heterocyclyl; and
[0025] R.sub.4--NR.sub.3--SO.sub.2--NH.sub.2; [0026] R.sub.2 is
selected from the group consisting of: [0027] hydrogen; [0028]
alkyl; [0029] alkenyl; [0030] aryl; [0031] heteroaryl; [0032]
heterocyclyl; [0033] alkyl-Y-alkyl; [0034] alkyl-Y-alkenyl; [0035]
alkyl-Y-aryl; and [0036] alkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: [0037] OH;
[0038] halogen; [0039] N(R.sub.5).sub.2; [0040]
CO--N(R.sub.5).sub.2; [0041] CO--C.sub.1-10 alkyl; [0042]
CO--O--C.sub.1-10 alkyl; [0043] N.sub.3; [0044] aryl; [0045]
heteroaryl; [0046] heterocyclyl; [0047] CO-aryl; and [0048]
CO-heteroaryl; [0049] Y is --O-- or --S(O).sub.0-2--; [0050]
R.sub.3 is H, C.sub.1-10 alkyl, or arylalkyl; [0051] R.sub.4 is
alkyl or alkenyl, which may be interrupted by one or more
--O-groups; or R.sub.3 and R.sub.4 can join together to form a
ring; [0052] each R.sub.5 is independently H, C.sub.1-10 alkyl, or
C.sub.2-10 alkenyl; [0053] R.sub.6 is a bond, alkyl, or alkenyl,
which may be interrupted by one or more --O-- groups; [0054]
R.sub.7 is C.sub.1-10 alkyl; or R.sub.3 and R.sub.7 can join
together to form a ring; [0055] n is 0 to 4; and [0056] each R
present is independently selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkoxy, hydroxy, halogen and
trifluoromethyl; [0057] or a pharmaceutically acceptable salt
thereof.
[0058] The invention also includes tetrahydroimidazoquinoline
compounds that bear an ether and sulfanomide or sulfamide
containing substituent at the 1-position. Such
tetrahydroimidazoquinoline compounds are represented by Formula
(II):
##STR00003##
wherein: X is --CHR.sub.5--, --CHR.sub.5-alkyl-, or
--CHR.sub.5-alkenyl-; [0059] R.sub.1 is selected from the group
consisting of: [0060] R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkyl;
[0061] R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkenyl; [0062]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-aryl; [0063]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-heteroaryl; [0064]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-heterocyclyl; [0065]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.7; [0066]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-alkyl; [0067]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-alkenyl; [0068]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-aryl; [0069]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-heteroaryl; [0070]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-heterocyclyl; and
[0071] R.sub.4--NR.sub.3--SO.sub.2--NH.sub.2; [0072] R.sub.2 is
selected from the group consisting of: [0073] hydrogen; [0074]
alkyl; [0075] alkenyl; [0076] aryl; [0077] heteroaryl; [0078]
heterocyclyl; [0079] alkyl-Y-alkyl; [0080] alkyl-Y-alkenyl; [0081]
alkyl-Y-aryl; and [0082] alkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: [0083] OH;
[0084] halogen; [0085] N(R.sub.5).sub.2; [0086]
CO--N(R.sub.5).sub.2; [0087] CO--C.sub.1-10 alkyl; [0088]
CO--O--C.sub.1-10 alkyl; [0089] N.sub.3; [0090] aryl; [0091]
heteroaryl; [0092] heterocyclyl; [0093] CO-aryl; and [0094]
CO-heteroaryl; [0095] Y is --O-- or --S(O).sub.0-2--; [0096]
R.sub.3 is H, C.sub.1-10 alkyl, or arylalkyl; [0097] R.sub.4 is
alkyl or alkenyl, which may be interrupted by one or more
--O-groups; or R.sub.3 and R.sub.4 can join together to form a
ring; [0098] each R.sub.5 is independently H, C.sub.1-10 alkyl, or
C.sub.2-10 alkenyl; [0099] R.sub.6 is a bond, alkyl, or alkenyl,
which may be interrupted by one or more --O-- groups; [0100]
R.sub.7 is C.sub.1-10 alkyl; or R.sub.3 and R.sub.7 can join
together to form a ring; [0101] n is 0 to 4; and [0102] each R
present is independently selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkoxy, hydroxy, halogen, and
trifluoromethyl; [0103] or a pharmaceutically acceptable salt
thereof.
Preparation of the Compounds
[0104] Compounds of the invention can be prepared according to
Reaction Scheme I where R, R.sub.1, R.sub.2, X and n are as defined
above.
[0105] In step (1) of Reaction Scheme I a
2,4-dichloro-3-nitroquinoline of Formula X is reacted with an amine
of Formula R.sub.1--O--X--NH.sub.2 to provide a
2-chloro-3-nitroquinolin-4-amine of Formula XI. The reaction can be
carried out by adding the amine to a solution of a compound of
Formula X in a suitable solvent such as chloroform or
dichloromethane and optionally heating. Many quinolines of Formula
XI are known or can be prepared using known synthetic methods, see
for example, Andre et al., U.S. Pat. No. 4,988,815 and references
cited therein. Many amines of Formula R.sub.1--O--X--NH.sub.2 are
known; some are commercially available and others can by prepared
using known synthetic methods.
[0106] In step (2) of Reaction Scheme I a
2-chloro-3-nitroquinolin-4-amine of Formula XI is reduced to
provide a 2-chloroquinoline-3,4-diamine of Formula XII. 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 ethanol, isopropanol or
toluene.
[0107] In step (3) of Reaction Scheme I a
2-chloroquinoline-3,4-diamine of Formula XII is reacted with a
carboxylic acid or an equivalent thereof to provide a
4-chloro-1H-imidazo[4,5-c]quinoline of Formula XIII. Suitable
equivalents to carboxylic acid include 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 XIII. 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.
[0108] Alternatively, step (3) can be carried out by (i) reacting
the diamine of Formula XII with an acyl halide of Formula
R.sub.2C(O)Cl and then (ii) cyclizing. In part (i) the acyl halide
is added to a solution of the diamine in an inert solvent such as
acetonitrile or dichloromethane. The reaction can be carried out at
ambient temperature. The product can be isolated using conventional
methods. In part (ii) the product of part (i) is heated in an
alcoholic solvent in the presence of a base. Preferably the product
of part (i) is refluxed in ethanol in the presence of an excess of
triethylamine or heated with methanolic ammonia.
[0109] In step (4) of Reaction Scheme I a
4-chloro-1H-imidazo[4,5-c]quinoline of Formula XIII is aminated to
provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula I. The
reaction is carried out by heating (e.g., 125-175.degree. C.) a
compound of Formula XIII under pressure in a sealed reactor in the
presence of a solution of ammonia in an alkanol. The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
##STR00004##
[0110] Compounds of the invention containing a sulfonamide group
can be prepared according to Reaction Scheme II where R, R.sub.2,
R.sub.3, R.sub.4, X and n are as defined above, BOC is
tert-butoxycarbonyl and R.sub.11 is --R.sub.6-alkyl,
--R.sub.6-aryl, --R.sub.6-heteroaryl or --R.sub.6-heterocyclyl
where R.sub.6 is as defined above.
[0111] In step (1) of Reaction Scheme II the amino group of an
aminoalcohol of Formula XIV is protected with a tert-butoxycarbonyl
group. A solution of the aminoalcohol in tetrahydrofuran is treated
with di-tert-butyl dicarbonate in the presence of a base such as
sodium hydroxide. Many aminoalcohols of Formula XIV are
commercially available; others can be prepared using known
synthetic methods.
[0112] In step (2) of Reaction Scheme II a protected aminoalcohol
of Formula XV is converted to an iodide of Formula XVI. Iodine is
added to a solution of triphenylphosphine and imidazole in
dichloromethane; then a solution of a protected aminoalcohol of
Formula XV in dichloromethane is added. The reaction is carried out
at ambient temperature.
[0113] In step (3) of Reaction Scheme II a
1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVII is alkylated
with an iodide of Formula XVI to provide a
1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII. The alcohol
of Formula XVII is reacted with sodium hydride in a suitable
solvent such as N,N-dimethylformamide to form an alkoxide. The
iodide is added to the alkoxide solution at ambient temperature.
After the addition is complete the reaction is stirred at an
elevated temperature (.about.100.degree. C.). Many compounds of
Formula XVII are known, see for example, Gerster, U.S. Pat. No.
4,689,338; others can readily be prepared using known synthetic
routes, see for example, Gerster et al., U.S. Pat. No. 5,605,899
and Gerster, U.S. Pat. No. 5,175,296.
[0114] In step (4) of Reaction Scheme II a
1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII is oxidized
to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XIX
using a conventional oxidizing agent capable of forming N-oxides.
Preferably a solution of a compound of Formula XVIII in chloroform
is oxidized using 3-chloroperoxybenzoic acid at ambient
temperature.
[0115] In step (5) of Reaction Scheme II a
1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XIX is aminated to
provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XX. Step (5)
involves (i) reacting a compound of Formula XIX 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 XIX
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 XIX
in an inert solvent such as dichloromethane or 1,2-dichloroethane
with heating if necessary, adding the animating agent to the
solution, and then slowly adding the acylating agent. Optionally
the reaction can be carried out in a sealed pressure vessel at an
elevated temperature (85-100.degree. C.).
[0116] In step (6) of Reaction Scheme II the protecting group is
removed by hydrolysis under acidic conditions to provide a
1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI. Preferably the
compound of Formula XX is treated with hydrochloric acid/ethanol at
ambient temperature or with gentle heating.
[0117] In step (7) of Reaction Scheme II a
1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI is converted to a
sulfonamide of Formula XXII which is a subgenus of Formula I using
conventional synthetic methods. For example, a compound of Formula
XXI can be reacted with a sulfonyl chloride of Formula
R.sub.11S(O.sub.2)Cl. The reaction can be carried out by adding a
solution of the sulfonyl chloride in a suitable solvent such as
dichloromethane or 1-methyl-2-pyrrolidinone to a solution of a
compound of Formula XXI at ambient temperature. Alternatively, a
compound of Formula XXI can be reacted with a sulfonic anhydride of
Formula R.sub.11S(O.sub.2)OS(O.sub.2)R.sub.11. The reaction can be
run at ambient temperature in an inert solvent such as
dichloromethane in the presence of a base such as pyridine or
N,N-diisopropylethylamine. The product or a pharmaceutically
acceptable salt thereof can be isolated using conventional
methods.
##STR00005##
[0118] Compounds of the invention containing a sulfonamide group
can be prepared according to Reaction Scheme III where R, R.sub.2,
R.sub.3, R.sub.4, R.sub.11, X and n are as defined above and BOC is
tert-butoxycarbonyl.
[0119] In step (1) of Reaction Scheme III the amino group of an
aminoalcohol of Formula XXIII is protected with a
tert-butoxycarbonyl group. A solution of the aminoalcohol in
tetrahydrofuran is treated with di-tert-butyl dicarbonate in the
presence of a base such as sodium hydroxide. Many aminoalcohols of
Formula XXIII are commercially available; others can be prepared
using known synthetic methods.
[0120] In step (2) of Reaction Scheme III a protected amino alcohol
of Formula XXIV is converted to a methanesulfonate of Formula XXV.
A solution of a compound of Formula XXIV in a suitable solvent such
as dichloromethane is treated with methanesulfonyl chloride in the
presence of a base such as triethylamine. The reaction can be
carried out at a reduced temperature (0.degree. C.).
[0121] In step (3a) of Reaction Scheme III a methanesulfonate of
Formula XXV is converted to an azide of Formula XXVI. Sodium azide
is added to a solution of a compound of Formula XXV in a suitable
solvent such as N,N-dimethylformamide or tetrahydrofuran. The
reaction can be carried out at an elevated temperature
(80-100.degree. C.).
[0122] In step (3b) of Reaction Scheme III a compound of Formula
XXVI is alkylated with a halide of Formula Hal-R.sub.3 to provide a
compound of Formula XXVII. In compounds where R.sub.3 is hydrogen
this step is omitted. The compound of Formula XXVI is reacted with
sodium hydride in a suitable solvent such as N,N-dimethylformamide
to form the anion and then combined with the halide. The reaction
can be carried out at ambient temperature.
[0123] In step (4) of Reaction Scheme III an azide of Formula XXVI
or XXVII is reduced to provide an amine of Formula XXVIII.
Preferably, the reduction is carried out using a conventional
heterogeneous hydrogenation catalyst such as palladium on carbon.
The reaction can conveniently be carried out on a Parr apparatus in
a suitable solvent such as methanol or isopropanol.
[0124] In step (5) of Reaction Scheme III a
4-chloro-3-nitroquinoline of Formula XXIX is reacted with an amine
of Formula XXVIII to provide a 3-nitroquinoline of Formula XXX. The
reaction can be carried out by adding an amine of Formula XXVIII to
a solution of a compound of Formula XXIX in a suitable solvent such
as dichloromethane in the presence of a base such as triethylamine.
Many quinolines of Formula XXIX are known compounds or can be
prepared using known synthetic methods, see for example, U.S. Pat.
No. 4,689,338 and references cited therein.
[0125] In step (6) of Reaction Scheme III a 3-nitroquinoline of
Formula XXX is reduced to provide a 3-aminoquinoline of Formula
XXXI. Preferably, the reduction is carried out using a conventional
heterogeneous hydrogenation catalyst such as platinum on carbon.
The reaction can conveniently be carried out on a Parr apparatus in
a suitable solvent such as toluene.
[0126] In step (7) of Reaction Scheme III a compound of Formula
XXXI is reacted with a carboxylic acid or an equivalent thereof to
provide a 1H-imidazo[4,5-c]quinoline of Formula XVIII. Suitable
equivalents to carboxylic acid include 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 XVIII. For example, triethyl orthoformate
will provide a compound where R.sub.2 is hydrogen and triethyl
orthovalerate will provide a compound where R.sub.2 is butyl. 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. Optionally a catalytic amount of pyridine
hydrochloride can be included.
[0127] Alternatively, step (7) can be carried out by (i) reacting a
compound of Formula XXXI with an acyl halide of Formula
R.sub.2C(O)Cl and then (ii) cyclizing. In part (i) the acyl halide
is added to a solution of a compound of Formula XXXI in an inert
solvent such as acetonitrile or dichloromethane. The reaction can
be carried out at ambient temperature or at a reduced temperature.
In part (ii) the product of part (i) is heated in an alcoholic
solvent in the presence of a base. Preferably the product of part
(i) is refluxed in ethanol in the presence of an excess of
triethylamine or heated with methanolic ammonia.
[0128] Steps (8), (9), (10) and (11) are carried out in the same
manner as steps (4), (5), (6) and (7) of Reaction Scheme II.
##STR00006## ##STR00007##
[0129] Compounds of the invention containing a sulfamide group can
be prepared according to Reaction Scheme IV where R, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.11, X and n are as defined
above.
[0130] In step (I) of Reaction Scheme IV a
1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI is reacted with
sulfuryl chloride to generate in situ a sulfamoyl chloride of
Formula XXXII. The reaction can be carried out by adding a solution
of sulfuryl chloride in dichloromethane to a solution of a compound
of Formula XXI in dichloromethane in the presence of 1 equivalent
of 4-(dimethylamino)pyridine. The reaction is preferably carried
out at a reduced temperature (-78.degree. C.).
[0131] In step (2) of Reaction Scheme IV an amine of Formula
HNR.sub.5R.sub.11 is reacted with the sulfamoyl chloride of Formula
XXXII to provide a sulfamide of Formula XXXIII which is a subgenus
of Formula I. The reaction can be carried out by adding a solution
containing 2 equivalents of the amine and 2 equivalents of
triethylamine in dichloromethane to the reaction mixture from step
(1). The addition is preferably carried out at a reduced
temperature (-78.degree. C.). After the addition is complete the
reaction mixture can be allowed to warm to ambient temperature. The
product or a pharmaceutically acceptable salt thereof can be
isolated using conventional methods.
##STR00008##
[0132] Compounds of the invention can be prepared according to
Reaction Scheme V where R, R.sub.2, R.sub.3, R.sub.4, R.sub.11, X
and n are as defined above.
[0133] In step (1) of Reaction Scheme V a
1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI is reduced to
provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of
Formula XXXIV. Preferably the reduction is carried out by
suspending or dissolving a compound of Formula XXI in
trifluoroacetic acid, adding a catalytic amount of platinum (IV)
oxide, and then hydrogenating. The reaction can be conveniently
carried out in a Parr apparatus.
[0134] Step (2) is carried out in the same manner as step (7) of
Reaction Scheme II to provide a
6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula
XXXV which is a subgenus of Formula II. The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
##STR00009##
[0135] Compounds of the invention containing a sulfamide group can
be prepared according to Reaction Scheme VI where R, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.11, X and n are as defined
above.
[0136] In step (1) of Reaction Scheme VI a
1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXIV is reacted with
sulfuryl chloride to generate in situ a sulfamoyl chloride of
Formula XXXVI. The reaction can be carried out by adding a solution
of sulfuryl chloride in dichloromethane to a solution of a compound
of Formula XXXIV in dichloromethane in the presence of 1 equivalent
of 4-(dimethylamino)pyridine. The reaction is preferably carried
out at a reduced temperature (-78.degree. C.).
[0137] In step (2) of Reaction Scheme VI an amine of Formula
HNR.sub.5R.sub.11 is reacted with the sulfamoyl chloride of Formula
XXXVI to provide a sulfamide of Formula XXXVII which is a subgenus
of Formula II. The reaction can be carried out by adding a solution
containing 2 equivalents of the amine and 2 equivalents of
triethylamine in dichloromethane to the reaction mixture from step
(1). The addition is preferably carried out at a reduced
temperature (-78.degree. C.). After the addition is complete the
reaction mixture can be allowed to warm to ambient temperature. The
product or a pharmaceutically acceptable salt thereof can be
isolated using conventional methods.
##STR00010##
[0138] The invention also provides novel compounds useful as
intermediates in the synthesis of the compounds of Formulas (I) and
(II). These intermediate compounds have the structural Formula
(III).
##STR00011##
wherein X is --CHR.sub.5--, --CHR.sub.5-alkyl-, or
--CHR.sub.5-alkenyl-; [0139] R.sub.1 is selected from the group
consisting of: [0140] R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkyl;
[0141] R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkenyl; [0142]
R.sub.4--NR.sub.3--SO.sub.2--R-aryl; [0143]
R.sub.4--NR.sub.3--SO.sub.2--R-heteroaryl; [0144]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-heterocyclyl; [0145]
R.sub.4--NR.sub.3--SO.sub.2--R.sub.7; [0146]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-alkyl; [0147]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-alkenyl; [0148]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-aryl; [0149]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-heteroaryl; [0150]
R.sub.4--NR.sub.3--SO.sub.2--NR.sub.5--R.sub.6-heterocyclyl; and
[0151] R.sub.4--NR.sub.3--SO.sub.2--NH.sub.2; [0152] R.sub.2 is
selected from the group consisting of: [0153] hydrogen; [0154]
alkyl; [0155] alkenyl; [0156] aryl; [0157] heteroaryl; [0158]
heterocyclyl; [0159] alkyl-Y-alkyl; [0160] alkyl-Y-alkenyl; [0161]
alkyl-Y-aryl; and [0162] alkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: [0163] OH;
[0164] halogen; [0165] N(R.sub.5).sub.2; [0166]
CO--N(R.sub.5).sub.2; [0167] CO--C.sub.1-10 alkyl; [0168]
CO--O--C.sub.1-10 alkyl; [0169] N.sub.3; [0170] aryl; [0171]
heteroaryl; [0172] heterocyclyl; [0173] CO-aryl; and [0174]
CO-heteroaryl; [0175] Y is --O-- or --S(O).sub.0-2--; [0176]
R.sub.3 is H, C.sub.1-10 alkyl, or arylalkyl; [0177] R.sub.4 is
alkyl or alkenyl, which may be interrupted by one or more
--O-groups; or R.sub.3 and R.sub.4 can join to form a ring; [0178]
each R.sub.5 is independently H, C.sub.1-10 alkyl, or C.sub.2-10
alkenyl; [0179] R.sub.6 is a bond, or is alkyl or alkenyl, which
may be interrupted by one or more --O-- groups; [0180] R.sub.7 is
C.sub.1-10 alkyl; or R.sub.3 and R.sub.7 can join together to form
a bond; [0181] n is 0 to 4; and [0182] each R present is
independently selected from the group consisting of C.sub.1-10
alkyl, C.sub.1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
[0183] or a pharmaceutically acceptable salt thereof.
[0184] As used herein, the terms "alkyl", "alkenyl" 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 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, cyclopropylmethyl, cyclopentyl, cyclohexyl and
adamantyl.
[0185] In addition, the alkyl and alkenyl portions of --X-- groups
can be unsubstituted or substituted by one or more substituents,
which substituents are selected from the groups consisting of
alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl,
heteroarylalkyl, and heterocyclylalkyl.
[0186] The term "haloalkyl" is inclusive of groups that are
substituted by one or more halogen atoms, including perfluorinated
groups. This is also true of groups that include the prefix
"halo-". Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like.
[0187] 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, triazolyl, pyrrolyl, tetrazolyl, imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl,
carbazolyl, benzoxazolyl, pyrimidinyl, quinoxalinyl,
benzoimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl,
isothiazolyl, quinazolinyl, purinyl, and so on.
[0188] "Heterocyclyl" includes non-aromatic rings or ring systems
that contain at least one ring hetero atom (e.g., O, S, N) and
includes all of the fully saturated and partially unsaturated
derivatives of the above mentioned heteroaryl groups. Exemplary
heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,
morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl,
thiazolidinyl, imidazolidinyl, and the like.
[0189] The aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro,
hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio,
arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy,
heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino,
alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl,
alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl,
haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl,
heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,
arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy,
alkanoylthio, arylcarbonyloxy, arylcarbonylthio, arylcarbonylamino,
alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino,
arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino,
alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino,
heteroarylcarbonylamino, heteroarylalkycarbonylamino,
alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino,
arylalkylsulfonylamino, heteroarylsulfonylamino,
heteroarylalkylsulfonylamino, alkylaminocarbonylamino,
alkenylaminocarbonylamino, arylaminocarbonylamino,
arylalkylaminocarbonylamino, heteroarylaminocarbonylamino,
heteroarylalkylcarbonylamino and, in the case of heterocyclyl, oxo.
If any other groups are identified as being "substituted" or
"optionally substituted", then those groups can also be substituted
by one or more of the above enumerated substituents.
[0190] Certain substituents are generally preferred. For example,
preferred R.sub.1 groups include
--R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-alkyl,
--R--NR.sub.3--SO.sub.2--R.sub.6-aryl, and
--R.sub.4--NR.sub.3--SO.sub.2--R.sub.6-heteroaryl wherein the
alkyl, aryl and heteroaryl groups can be unsubstituted or
substituted and R.sub.4 is preferably ethylene or n-butylene.
Thiophene and quinoline are preferred heteroaryl groups Preferably
no R substituents are present (i.e., n is 0). Preferred R.sub.2
groups include hydrogen, alkyl groups having 1 to 4 carbon atoms
(i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl.
For substituted groups such as substituted alkyl or substituted
aryl groups, preferred substituents include halogen, nitrile,
methoxy, trifluoromethyl, and trifluoromethoxy. One or more of
these preferred substituents, if present, can be present in the
compounds of the invention in any combination.
[0191] The invention is inclusive of the compounds described herein
in any of their pharmaceutically acceptable forms, including
isomers (e.g., diastereomers and enantiomers), salts, solvates,
polymorphs, and the like. In particular, if a compound is optically
active, the invention specifically includes each of the compound's
enantiomers as well as racemic mixtures of the enantiomers.
Pharmaceutical Compositions and Biological Activity
[0192] Pharmaceutical compositions of the invention contain a
therapeutically effective amount of a compound of the invention as
described above in combination with a pharmaceutically acceptable
carrier.
[0193] 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, 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.
[0194] 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.
[0195] 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.
[0196] 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, IL-6, IL-10 and
IL-12, and a variety of other cytokines. Among other effects, these
and other cytokines can inhibit virus production and tumor cell
growth, making the compounds useful in the treatment of viral
diseases and tumors. 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.
[0197] Certain compounds of the invention have been found to
preferentially induce the expression of IFN-.alpha. in a population
of hematopoietic cells such as PBMCs (peripheral blood mononuclear
cells) containing pDC2 cells (precursor dendritic cell-type 2)
without concomitant production of significant levels of
inflammatory cytokines.
[0198] 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.
[0199] 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 (Th2) 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.
[0200] 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; variola, particularly variola major; HIV;
CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza;
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 actinic keratosis; eczema; eosinophilia; essential
thrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome;
discoid lupus; Bowen's disease; Bowenoid papulosis; alopecia
areata; the inhibition of keloid formation after surgery and other
types of post-surgical scars. In addition, these compounds could
enhance or stimulate the healing of wounds, including chronic
wounds. The compounds may be useful for treating the opportunistic
infections and tumors that occur after suppression of cell mediated
immunity in, for example, transplant patients, cancer patients and
HIV patients.
[0201] 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-.alpha., TNF-.alpha., IL-1, IL-6, IL-10 and IL-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 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.
[0202] 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.
[0203] In the examples below some of the compounds were purified
using semi-preparative HPLC. A Waters Fraction Lynx automated
purification system was used. The semi-prep HPLC fractions were
analyzed using a Micromass LC-TOFMS and the appropriate fractions
were combined and centrifuge evaporated to provide the
trifluoroacetate salt of the desired compound.
[0204] Column: Phenomenex Luna C18(2), 10.times.50 mm, 5 micron
particle size, 100 .ANG. pore; flow rate: 25 mL/min.; gradient
elution from 5-65% B in 4 min., then 65 to 95% B in 0.1 min, then
hold at 95% B for 0.4 min., where A=0.05% trifluoroacetic
acid/water and B=0.05% trifluoroacetic acid/acetonitrile; fraction
collection by mass-selective triggering.
EXAMPLE 1
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}-
ethyl)methanesulfonamide
##STR00012##
[0205] Part A
[0206] A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol)
in 180 mL of tetrahydrofuran (THF), under N.sub.2, was cooled to
0.degree. C. and treated with 140 mL of 2N NaOH solution. A
solution of di-tert-butyl dicarbonate (60.2 g, 0.276 mol) in 180 mL
of THF was then added dropwise over 1 h to the rapidly stirred
solution. The reaction mixture was then allowed to warm to room
temperature and was stirred an additional 18 h. The THF was then
removed under reduced pressure and the remaining aqueous slurry was
brought to pH 3 by addition of 150 mL of 1M H.sub.2SO.sub.4
solution. This was then extracted with ethyl acetate (300 mL, 100
mL) and the combined organic layers were washed with H.sub.2O
(2.times.) and brine. The organic portion was dried over
Na.sub.2SO.sub.4 and concentrated to give tert-butyl
2-(2-hydroxyethoxy)ethylcarbamate as a colorless oil (47.1 g).
Part B
[0207] A rapidly stirred solution of tert-butyl
2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of
anhydrous CH.sub.2Cl.sub.2 was cooled to 0.degree. C. under N.sub.2
and treated with triethylamine (48.0 mL, 0.345 mol).
Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added
dropwise over 30 min. The reaction mixture was then allowed to warm
to room temperature and was stirred an additional 22 h. The
reaction was quenched by addition of 500 mL saturated NaHCO.sub.3
solution and the organic layer was separated. The organic phase was
then washed with H.sub.2O (3.times.500 mL) and brine. The organic
portion was dried over Na.sub.2SO.sub.4 and concentrated to give
2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a
brown oil (63.5 g).
Part C
[0208] A stirred solution of
2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate
(63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was
treated with NaN.sub.3 (16.1 g, 0.247 mol) and the reaction mixture
was heated to 90.degree. C. under N.sub.2. After 5 h, the solution
was cooled to room temperature and treated with 500 mL of cold
H.sub.2O. The reaction mixture was then extracted with Et.sub.2O
(3.times.300 mL). The combined organic extracts were washed with
H.sub.2O (4.times.100 mL) and brine (2.times.100 mL). The organic
portion was dried over MgSO.sub.4 and concentrated to give 52.0 g
of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown
oil.
Part D
[0209] A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate
(47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on
carbon and shaken under H.sub.2 (3 Kg/cm.sup.2) for 24 h. The
solution was then filtered through a Celite pad and concentrated to
give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as
a colorless liquid that was used without further purification.
Part E
[0210] A stirred solution of 4-chloro-3-nitroquinoline (31.4 g,
0.151 mol) in 500 mL of anhydrous CH.sub.2Cl.sub.2, under N.sub.2,
was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl
2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring
overnight, the reaction mixture was washed with H.sub.2O
(2.times.300 mL) and brine (300 mL). The organic portion was dried
over Na.sub.2SO.sub.4 and concentrated to give a bright yellow
solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of
tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate
as bright yellow crystals.
Part F
[0211] A solution of tert-butyl
2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g,
20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and
shaken under H.sub.2 (3 Kg/cm.sup.2) for 24 h. The solution was
then filtered through a Celite pad and concentrated to give 6.92 g
of crude tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellow
syrup.
Part G
[0212] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g,
29.5 mmol) in 250 mL of anhydrous CH.sub.2Cl.sub.2 was cooled to
0.degree. C. and treated with triethylamine (4.18 mL, 30.0 mmol).
Methoxypropionyl chloride (3.30 mL, 30.3 mmol) was then added
dropwise over 5 min. The reaction was then warmed to room
temperature and stirring was continued for 1 h. The reaction
mixture was then concentrated under reduced pressure to give an
orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of
triethylamine was added. The mixture was heated to reflux and
stirred under N.sub.2 overnight. The reaction was then concentrated
to dryness under reduced pressure and treated with 300 mL of
Et.sub.2O. The mixture was then filtered and the filtrate was
concentrated under reduced pressure to give a brown solid. The
solid was dissolved in 200 mL of hot MeOH and treated with
activated charcoal. The hot solution was filtered and concentrated
to give 11.1 g of tert-butyl
2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarba-
mate as a yellow syrup.
Part H
[0213] A solution of tert-butyl
2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarba-
mate (10.22 g, 24.7 mmol) in 250 mL of CHCl.sub.3 was treated with
3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). After
stirring 30 min, the reaction mixture was washed with 1%
Na.sub.2CO.sub.3 solution (2.times.75 mL) and brine. The organic
layer was then dried over Na.sub.2SO.sub.4 and concentrated to give
10.6 g of tert-butyl
2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hylcarbamate as an orange foam that was used without further
purification.
Part I
[0214] A solution of tert-butyl
2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane
was heated to 60.degree. C. and treated with 10 mL of concentrated
NH.sub.4OH solution. To the rapidly stirred solution was added
solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min
period. The reaction mixture was treated with an additional 1 mL
concentrated NH.sub.4OH solution and then sealed in a pressure
vessel and heating was continued for 2 h. The reaction mixture was
then cooled and treated with 100 mL of CHCl.sub.3. The reaction
mixture was then washed with H.sub.2O, 1% Na.sub.2CO.sub.3 solution
(2.times.) and brine. The organic portion was dried over
Na.sub.2SO.sub.4 and concentrated to give 10.6 g of tert-butyl
2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hylcarbamate as a brown foam.
Part J
[0215] Tert-butyl
2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hylcarbamate (10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl
in EtOH and the mixture was heated to reflux with stirring. After
1.5 h, the reaction mixture was cooled and filtered to give a gummy
solid. The solid was washed EtOH and Et.sub.2O and dried under
vacuum to give the hydrochloride salt as a light brown solid. The
free base was made by dissolving the hydrochloride salt in 50 mL of
H.sub.2O and treating with 10% NaOH solution. The aqueous
suspension was then concentrated to dryness and the residue was
treated with CHCl.sub.3. The resulting salts were removed by
filtration and the filtrate was concentrated to give 3.82 g of
1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quino-
lin-4-amine as a tan powder.
[0216] MS 330 (M+H).sup.+;
[0217] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.10 (d, J=8.1
Hz, 1H); 7.66 (d, J=8.2 Hz, 1H); 7.40 (m, 1H); 7.25 (m, 1H); 6.88
(br s, 2H); 4.78 (t, J=5.4 Hz, 2H); 3.89 (t, J=4.8 Hz, 2H); 3.84
(t, J=6.9 Hz, 2H); 3.54 (t, J=5.4 Hz, 2H); 3.31 (s, 3H); 3.23 (t,
J=6.6 Hz, 2H); 2.88 (t, J=5.3 Hz, 2H).
Part K
[0218]
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quin-
olin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of
anhydrous CH.sub.2Cl.sub.2 and cooled to 0.degree. C. under
N.sub.2. To the stirred solution were added Et.sub.3N (0.64 mL,
4.56 mmol) and methanesulfonyl chloride (176 .mu.L, 2.28 mmol) and
the reaction was allowed to warn to room temperature over 2 h. The
reaction mixture was then quenched by addition of saturated
NaHCO.sub.3 solution (30 mL). The organic layer was separated and
washed with H.sub.2O (3.times.25 mL) and brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give a
tan foam. The foam was dissolved in a minimum amount of MeOH and
Et.sub.2O was added and a solid precipitated from the solution. The
off-white solid was isolated by filtration and dried to yield 385
mg of
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy-
}ethyl)methanesulfonamide. m.p. 114.0-117.0.degree. C.;
[0219] MS 408 (M+H).sup.+;
[0220] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.05 (d, J=7.6
Hz, 1H); 7.61 (d, J=8.5 Hz, 1H); 7.42 (t, J=8.5 Hz, 1H); 7.24 (t,
J=7.0 Hz, 1H); 6.99 (t, J=4.4 Hz, 1H); 6.51 (s, 2H); 4.76 (t, J=5.0
Hz, 2H); 3.88-3.81 (m, 4H); 3.41 (t, J=5.4 Hz, 2H); 3.31 (s, 3H);
3.23 (t, J=6.9 Hz, 2H); 3.04-2.99 (m, 2H); 2.81 (s, 3H); .sup.13C
(75 MHz, DMSO-d.sub.6) 151.9, 145.0, 132.7, 126.7, 126.6, 121.5,
120.5, 115.1, 70.5, 70.2, 69.3, 58.5, 45.4, 42.4, 27.6.
[0221] Anal. Calcd for
C.sub.18H.sub.25N.sub.5O.sub.4S.0.23H.sub.2O: % C, 52.52; % H,
6.23; % N, 17.01. Found: % C, 52.55; % H, 6.17; % N, 16.66
EXAMPLE 2
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]qu-
inolin-1-yl]ethoxy}ethyl)methanesulfonamide
##STR00013##
[0222] Part A
[0223]
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quin-
olin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of
trifluoroacetic acid and treated with PtO.sub.2 (1.0 g). The
reaction mixture was shaken under H.sub.2 (3 Kg/cm.sup.2). After 4
d, an additional 0.5 g of PtO.sub.2 was added and hydrogenation was
continued for an additional 3 d. The reaction was then filtered
through Celite and concentrated under reduced pressure to give a
brown oil. The oil was dissolved in 200 mL of H.sub.2O then made
basic (pH.about.11) by addition of 10% NaOH solution. This was then
extracted with CHCl.sub.3 (5.times.75 mL) and the combined organic
layers were dried over Na.sub.2SO.sub.4 and concentrated to give
5.17 g of
1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydr-
o-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
[0224] MS 334 (M+H).sup.+;
[0225] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.19 (s, 2H); 4.49
(t, J=5.4 Hz, 2H); 3.84 (t, J=6.6 Hz, 2H); 3.71 (t, J=5.4 Hz, 2H),
3.36 (t, J=5.2 Hz, 2H); 3.28 (s, 3H); 3.15 (t, J=6.6 Hz, 2H); 2.95
(m, 2H); 2.82 (m, 2H); 2.76 (t, J=5.1 Hz, 2H); 1.84 (m, 4H), 1.47
(br s, 2H).
Part B
[0226]
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-
-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.00 mmol) was dissolved
in 30 mL of anhydrous CH.sub.2Cl.sub.2 and cooled to 0.degree. C.
under N2. To the stirred solution were added Et.sub.3N (0.84 mL,
6.00 mmol) and methanesulfonyl chloride (232 .mu.L, 3.00 mmol) and
the reaction was allowed to warm to room temperature overnight. The
reaction mixture was then quenched by addition of saturated
NaHCO.sub.3 solution (30 mL). The organic layer was separated and
washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give a yellow solid. The
solid was triturated with Et.sub.2O and a few drops of MeOH. The
resulting white powder was isolated by filtration and further
purified by column chromatography (SiO.sub.2, 3% MeOH/CHCl.sub.3
saturated with aqueous NH.sub.4OH) to give 389 mg of
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]q-
uinolin-yl]ethoxy}ethyl)methanesulfonamide as a white powder. m.p.
151.0-153.0.degree. C.;
[0227] MS 412 (M+H).sup.+;
[0228] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.00 (t, J=5.4
Hz, 1H); 5.68 (s, 2H); 4.44 (t, J=5.1 Hz, 2H); 3.77 (t, J=6.8 Hz,
2H); 3.68 (t, J=5.0 Hz, 2H); 3.39 (t, J=5.8 Hz, 2H); 3.28 (s, 3H);
3.11-2.99 (m, 4H); 2.92 (m, 2H), 2.82 (s, 3H); 2.65 (m, 2H); 1.75
(m, 4H);
[0229] .sup.13C (75 MHz, DMSO-d.sub.6) 151.3, 149.3, 146.3, 138.4,
124.9, 105.6, 70.6, 70.5, 70.1, 44.5, 42.4, 32.7, 27.6, 23.8, 23.1,
23.0.
[0230] Anal. Calcd for C.sub.18H.sub.29N.sub.5O.sub.4S: % C, 52.54;
% H, 7.10; % N, 17.02. Found: % C, 52.47; % H, 7.22; % N,
16.83.
EXAMPLE 3
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}-
ethyl)-N-methylmethanesulfonamide
##STR00014##
[0231] Part A
[0232] Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was
placed in a round bottom flask and washed with hexanes (3.times.)
under N.sub.2. The dried sodium hydride was treated with 800 mL of
anhydrous THF. A solution of tert-butyl
2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF
was then added to the stirred sodium hydride solution over 40 min.
After addition was complete, the reaction was stirred an additional
20 min followed by addition of methyl iodide (13.6 mL, 218 mmol).
After stirring overnight, the reaction was quenched with 300 mL of
saturated NaHCO.sub.3 solution. The reaction mixture was then
treated with 200 mL of H.sub.2O and 1 L of Et.sub.2O. The organic
phase was separated and washed with H.sub.2O and brine. The organic
portion was then dried over MgSO.sub.4 and concentrated under
reduced pressure to give 41.9 g of tert-butyl
2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.
Part B
[0233] A solution of tert-butyl
2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600
mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken
under H.sub.2 (3 Kg/cm.sup.2) for 24 h. The solution was then
filtered through a Celite pad and concentrated to give 37.2 g of
crude tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light
yellow liquid.
Part C
[0234] A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155
mmol) in 400 mL of anhydrous CH.sub.2Cl.sub.2, under N.sub.2, was
treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl
2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After
stirring overnight, the reaction mixture was washed with H.sub.2O
(2.times.300 mL) and brine (300 mL). The organic portion was dried
over Na.sub.2SO.sub.4 and concentrated to give a brown oil. Column
chromatography (SiO.sub.2, 33% ethyl acetate/hexanes-67% ethyl
acetate/hexanes) gave 46.7 g of tert-butyl
methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as
a yellow solid.
Part D
[0235] A solution of tert-butyl
methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate
(6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.5 g of
5% Pt on carbon and shaken under H.sub.2 (3 Kg/cm.sup.2) for 24 h.
The solution was then filtered through a Celite pad and
concentrated to give 6.8 g of crude tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate as
an orange syrup which was carried on without further
purification.
Part E
[0236] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate
(6.05 g, 16.8 mmol) in 200 mL of anhydrous CH.sub.2Cl.sub.2 was
cooled to 0.degree. C. and treated with triethylamine (2.40 mL,
17.2 mmol). Methoxypropionyl chloride (1.72 mL, 17.2 mmol) was then
added dropwise over 5 min. The reaction was then warmed to room
temperature and stirring was continued for 3 h. The reaction
mixture was then concentrated under reduced pressure to give an
orange solid. This was dissolved in 200 mL of EtOH and 7.2 mL of
triethylamine was added. The mixture was heated to reflux and
stirred under N.sub.2 overnight. The reaction was then concentrated
to dryness under reduced pressure and treated with 300 mL of
Et.sub.2O. The mixture was then filtered and the filtrate was
concentrated under reduced pressure to give a brown solid. This was
dissolved in 300 mL of CH.sub.2Cl.sub.2 and washed with H.sub.2O
and brine. The organic portion was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to give a brown oil. The oil
was dissolved in 100 mL of hot MeOH and treated with activated
charcoal. The hot solution was filtered and concentrated to give
7.20 g of tert-butyl
2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(meth-
yl)carbamate as a yellow syrup.
Part F
[0237] A solution of tert-butyl
2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(meth-
yl)carbamate (7.20 g, 16.8 mmol) in 200 mL of CH.sub.2Cl.sub.2 was
treated with MCPBA (77%, 4.32 g, 19.3 mmol). After stirring 6 h,
the reaction mixture was treated with saturated NaHCO.sub.3
solution and the layers were separated. The organic portion was
washed with H.sub.2O and brine then dried over Na.sub.2SO.sub.4 and
concentrated to give 7.05 g of tert-butyl
2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hyl(methyl)carbamate as a light brown solid.
Part G
[0238] A solution of tert-butyl
2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of
1,2-dichloroethane was heated to 80.degree. C. and treated with 5
mL of concentrated NH.sub.4OH solution. To the rapidly stirred
solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5
mmol) over a 10 min period. The reaction mixture was treated with
an additional 5 mL concentrated NH.sub.4OH solution and then sealed
in a pressure vessel and heating was continued for 4 h. The
reaction mixture was then cooled and treated with 100 mL of
CH.sub.2Cl.sub.2. 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 6.50 g of tert-butyl
2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hyl(methyl)carbamate as a brown oil
Part H
[0239] Tert-butyl
2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hyl(methyl)carbamate (6.50 g, 14.7 mmol) was dissolved in 100 mL of
EtOH and treated with 20 mL of 2M HCl in EtOH and the mixture was
heated to reflux with stirring. After 6 h, the reaction mixture was
cooled and filtered to give a gummy solid. The solid was washed
with EtOH and Et.sub.2O and dried under vacuum to give the
hydrochloride salt as a light brown powder. The free base was made
by dissolving the hydrochloride salt in 50 mL of H.sub.2O and
treating with 5 mL of concentrated NH.sub.4OH. The aqueous
suspension was extracted with CHCl.sub.3 (5.times.50 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated to give 3.93 g of
2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]qu-
inolin-4-amine as a tan powder.
[0240] MS 344 (M+H).sup.+;
[0241] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.07 (d, J=7.7
Hz, 1H); 7.62 (dd, J=1.0, 8.3 Hz, 1H); 7.42 (ddd, J=1.0, 7.1, 8.2
Hz, 1H); 7.22 (ddd, J=1.1, 7.1, 8.2 Hz, 1H); 6.49 (s, 2H); 4.75 (t,
J=5.1 Hz, 2H); 3.83 (t, J=6.8 Hz, 4H); 3.35 (t, J=5.6 Hz, 2H); 3.30
(s, 3H); 3.21 (t, J=6.9 Hz, 2H); 2.45 (t, J=5.6 Hz, 2H); 2.12 (s,
3H).
Part I
[0242]
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,-
5-c]quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of
anhydrous CH.sub.2Cl.sub.2 and cooled to 0.degree. C. under
N.sub.2. To the stirred solution were added Et.sub.3N (0.81 mL,
5.81 mmol) and methanesulfonyl chloride (226 .mu.L, 2.92 mmol) and
the reaction was allowed to warm to room temperature overnight. The
reaction mixture was then quenched by addition of saturated
NaHCO.sub.3 solution (30 mL) and CH.sub.2Cl.sub.2 (30 mL). The
organic layer was separated and washed with H.sub.2O and brine,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Crystallization of the residue from EtOAc and
CH.sub.2Cl.sub.2 gave 756 mg of
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy-
}ethyl)-N-methylmethanesulfonamide as tan crystals. m.p.
145.0-146.5.degree. C.;
[0243] MS 422 (M+H).sup.+;
[0244] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.06 (d, J=7.8
Hz, 1H); 7.61 (dd, J=0.9, 8.3 Hz, 1H); 7.42 (t, J=7.2 Hz, 1H); 7.23
(ddd, J=1.0, 7.0, 8.0 Hz, 1H); 6.50 (s, 2H); 4.77 (t, J=5.0 Hz,
2H); 3.87 (t, J=5.0 Hz, 2H), 3.83 (t, J=6.8 Hz, 2H); 3.48 (t, J=5.5
Hz, 2H); 3.30 (s, 3H); 3.22 (t, J=6.8 Hz, 2H); 3.13 (t, J=5.5 Hz,
2H); 2.77 (s, 3H); 2.63 (s, 3H);
[0245] .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 153.9, 153.8,
147.0, 134.6, 128.6, 128.5, 123.4, 122.5, 117.0, 72.4, 71.2, 60.4,
51.1, 47.3, 37.3, 37.2, 29.6.
[0246] Anal. Calcd for C.sub.19H.sub.27N.sub.5O.sub.4S: % C, 54.14;
% H, 6.46; % N, 16.61. Found: % C, 53.92; % H, 6.32; % N,
16.47.
EXAMPLE 4
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]qu-
inolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide
##STR00015##
[0247] Part A
[0248]
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-H-imidazo[4,5-
-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of
trifluoroacetic acid and treated with PtO.sub.2 (0.5 g). The
reaction mixture was shaken under H.sub.2 (3 Kg/cm.sup.2). After 4
d, an additional 0.5 g of PtO.sub.2 was added and hydrogenation was
continued for an additional 3 d. The reaction mixture was then
filtered through Celite and concentrated under reduced pressure to
give a yellow oil. The yellow oil was dissolved in 50 mL of
H.sub.2O and extracted with 50 mL of CHCl.sub.3. The organic
portion was removed and discarded. The aqueous portion was then
made basic (pH.about.12) by addition of 10% NaOH solution. This was
then extracted with CHCl.sub.3 (6.times.50 mL) and the combined
organic layers were dried over Na.sub.2SO.sub.4 and concentrated to
a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and
treated with 1 g of activated charcoal. The hot solution was
filtered through Celite and concentrated to dryness. The resulting
gummy solid was concentrated several times with Et.sub.2O to give
3.19 g of
2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro--
1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
[0249] MS 348 (M+H).sup.+;
[0250] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.84 (s, 2H); 4.48
(t, J=5.7 Hz, 2H); 3.84 (t, J=6.7 Hz, 2H); 3.70 (t, J=5.7 Hz, 2H);
3.46 (t, J=1.1 Hz, 2H); 3.36 (s, 3H); 3.14 (t, J=6.7 Hz, 2H); 2.96
(m, 2H); 2.83 (m, 2H); 2.65 (t, J=5.1 Hz, 2H); 2.36 (s, 3H); 1.85
(m, 4H).
Part B
[0251]
(2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetr-
ahydro-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.16 mmol) was
dissolved in 30 mL of anhydrous CH.sub.2Cl.sub.2 and cooled to
0.degree. C. under N.sub.2. To the stirred solution were added
Et.sub.3N (0.60 mL, 4.32 mmol) and methanesulfonyl chloride (167
.mu.L, 2.16 mmol) and the reaction was allowed to warm to room
temperature over 3 h. The reaction mixture was then quenched by
addition of saturated NaHCO.sub.3 solution (30 mL) and
CH.sub.2Cl.sub.2 (30 mL). The organic layer was separated and
washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification by column
chromatography (SiO.sub.2, 3-5% MeOH/CHCl.sub.3 saturated with
aqueous NH.sub.4OH) gave the product as a colorless glass. The
material was then concentrated with iso-propyl alcohol to give a
syrup which solidified upon standing in the freezer. The solid was
dried under vacuum to give 437 mg of
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imida-
zo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide as
off-white crystals.
[0252] m.p. 115.3-117.8.degree. C.;
[0253] MS 426 (M+H).sup.+;
[0254] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.65 (s, 2H);
4.44 (t, J=5.2 Hz, 2H); 3.76 (t, J=6.9 Hz, 2H), 3.70 (t, J=5.3 Hz,
2H); 3.47 (t, J=5.5 Hz, 2H); 3.27 (s, 3H); 3.15 (t, J=5.5 Hz, 2H);
3.08 (t, J=6.9 Hz, 2H); 2.93 (m, 2H); 2.78 (s, 3H); 2.65 (s, 3H);
2.64 (m, 2H); 1.74 (m, 4H);
[0255] .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 151.2, 149.3,
146.3, 138.5, 124.9, 105.6, 70.6, 70.5, 69.2, 58.4, 49.2, 44.5,
35.4, 35.2, 32.7, 27.6, 23.8, 23.1, 23.0.
[0256] Anal. Calcd for C.sub.19H.sub.27N.sub.5O.sub.4S.0.40
C.sub.3H.sub.8O: % C, 53.97; % H, 7.67; % N, 15.58. Found: % C,
53.71; % H, 7.48; % N, 15.77.
EXAMPLE 5
2-Butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4-
,5-c]quinolin-4-amine
##STR00016##
[0258] Under a nitrogen atmosphere, chloropropylsulfonyl chloride
(0.05 ml, 0.46 mmol) was added dropwise to a solution of
1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine
(0.12 g, 0.37 mmol) and triethylamine (0.065 ml, 0.46 mmol) in
dichloromethane (5 ml). The reaction was stirred for 20 hours
followed by removal of the solvent in vacuo. The resulting
off-white solid was dissolved in N,N-dimethylformamide (5 mL) and
1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 ml, 0.58 mmol) was added.
The reaction was stirred for 18 hours under an atmosphere of
nitrogen and then quenched with water and extracted with
dichloromethane (2.times.). The organic fractions were combined,
washed with water followed by brine, dried (Na.sub.7SO.sub.4),
filtered, and concentrated in vacuo to provide an off-white solid.
Recrystallization from ethyl acetate yielded 0.068 g of
2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imida-
zo[4,5-c]quinolin-4-amine as off-white crystals, m.p.
152-154.degree. C.
[0259] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. 8.06 (d, J=8.1
Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.23 (t,
J=7.5 Hz, 1H), 6.52 (s, 2H), 4.73 (t, J=4.99 Hz, 2H), 3.86 (t,
J=5.0 Hz, 2H), 3.46 (t, J=5.3 Hz, 2H), 3.07 (t, J=7.66 Hz, 2H),
2.97-2.87 (m, 6H), 2.04 (quintet, J=6.8 Hz, 2H), 1.81 (quintet,
J=7.6 Hz, 2H), 1.46 (sextet, J=7.4 Hz, 2H), 0.96 (t, J=7.3 Hz,
3H);
[0260] .sup.13C-NMR (75 MHz, DMSO-d.sub.6): .delta. 154.6, 152.9,
145.1, 133.0, 126.8, 126.6, 121.6, 120.8, 115.3, 69.2, 69.1, 47.0,
45.5, 45.0, 43.7, 29.3, 26.2, 21.9, 18.1, 13.7;
[0261] Anal calcd for C.sub.21H.sub.29N.sub.5O.sub.3S*0.25H.sub.2O:
% C, 57.84; % H, 6.82; % N, 16.06; % S, 7.35. Found: % C, 57.90; %
H, 6.79; % N, 15.92; % S, 7.55.
EXAMPLES 6-26
Part A
[0262] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g,
10.0 mmol) in 50 mL of toluene was treated with
triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture
was heated to reflux. A 25 mg portion of pyridinium hydrochloride
was then added and refluxing was continued for 4 h. The reaction
was then concentrated to dryness under reduced pressure. The
residue was dissolved in 50 mL of CH.sub.2Cl.sub.2 and washed with
saturated NaHCO.sub.3, H.sub.2O and brine. The organic portion was
dried over Na.sub.2SO.sub.4 and concentrated to give a green oil.
The green oil was dissolved in 50 mL of hot MeOH and treated with
activated charcoal. The hot solution was filtered and concentrated
to give 4.12 g of tert-butyl
2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
as a yellow oil.
Part B
[0263] A solution of tert-butyl
2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
(4.12 g, 10.0 mmol) in 50 mL of CH.sub.2Cl.sub.2 was treated with
3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After
stirring for 5 h, the reaction mixture was treated with saturated
NaHCO.sub.3 solution and the layers were separated. The organic
portion was washed with H.sub.2O and brine then dried over
Na.sub.2SO.sub.4 and concentrated to give 3.68 g of tert-butyl
2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e as a light brown foam.
Part C
[0264] A solution of tert-butyl
2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to
80.degree. C. and treated with 10 mL of concentrated NH.sub.4OH
solution. To the rapidly stirred solution was added solid
p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min
period. 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 100 mL of CH.sub.2Cl.sub.2. 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 3.68 g of tert-butyl
2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e as a light brown foam.
Part D
[0265] Tert-butyl
2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e (3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and
the mixture was heated to reflux with stirring. After 3 h, the
reaction mixture was concentrated to give a solid. The solid was
triturated with hot EtOH (50 mL) and filtered to give 2.90 g of the
product as the hydrochloride salt. The free base was made by
dissolving the hydrochloride salt in 50 mL of H.sub.2O and treating
with 5 mL of concentrated NH.sub.4OH. The aqueous suspension was
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4 and concentrated to
give
1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine
as a tan powder.
[0266] MS 328 (M+H);
[0267] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.95 (d, J=8.3 Hz,
1H); 7.83 (d, J=8.4 Hz, 1H); 7.50 (m, 1H); 7.30 (m, 1H); 5.41 (s,
2H); 4.69 (t, J=5.6 Hz, 2H); 3.93 (t, J=5.6 Hz, 2H); 3.39 (t, J=5.1
Hz, 2H); 2.97 (t, J=7.9 Hz, 2H); 2.76 (t, J=5.1 Hz, 2H); 1.89 (m,
2H); 1.52 (m, 2H); 1.26 (br s, 2H); 1.01 (t, J=7.3 Hz, 3H).
Part E
[0268] The compounds in the table below were prepared according to
the synthetic method of step (7) of Reaction Scheme II above using
the following general method.
[0269] The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.)
was added to a test tube containing a solution of
1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine
(25 mg) in dichloromethane (5 mL). The test tube was capped and
then placed on a shaker at ambient temperature for 18-20 hr. The
solvent was removed by vacuum centrifugation. The residue was
purified by semi-preparative HPLC using the method described above.
The products were verified by accurate mass and .sup.1H NMR. The
table below shows the structure of the free base and the observed
accurate mass (M+H).
TABLE-US-00001 Example Accurate Mass Number Structure of Free Base
(obs.) 6 ##STR00017## 420.2077 7 ##STR00018## 434.2234 8
##STR00019## 435.2196 9 ##STR00020## 448.2387 10 ##STR00021##
468.2075 11 ##STR00022## 474.1625 12 ##STR00023## 482.2214 13
##STR00024## 486.1967 14 ##STR00025## 493.2009 15 ##STR00026##
493.2025 16 ##STR00027## 498.2195 17 ##STR00028## 504.1861 18
##STR00029## 518.2210 19 ##STR00030## 518.2243 20 ##STR00031##
519.2158 21 ##STR00032## 536.1917 22 ##STR00033## 544.2384 23
##STR00034## 546.1852 24 ##STR00035## 552.1874 25 ##STR00036##
615.2848 26 ##STR00037## 542.2779
EXAMPLES 27-39
Part A
[0270] Using the general method of Part A of Examples 6-26,
4-piperidineethanol (10 g, 77.4 mmol) was reacted with
di-tert-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of
tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear
oil.
Part B
[0271] Iodine (7.97 g) was added in three portions to a solution of
imidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1
mmol) in dichloromethane (350 mL). After 5 minutes a solution of
the material from Part A in dichloromethane (70 mL) was added. The
reaction mixture was stirred at ambient temperature overnight. More
iodine (7.97 g) was added and the reaction was stirred at ambient
temperature for 1 hr. The reaction mixture was washed with
saturated sodium thiosulfate (2.times.) and brine, dried over
sodium sulfate, filtered and then concentrated under reduced
pressure to provide an oily residue. The residue was purified by
column chromatography (silica gel eluting with 20% ethyl acetate in
hexanes) to provide 15.52 g of tert-butyl
4-(2-iodoethyl)piperidine-1-carboxylate as a pale yellow oil.
Part C
[0272] Under a nitrogen atmosphere,
2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (6.5 g, 26.9 mmol) was
added in three portions to a suspension of sodium hydride (1.4 g of
60%, 35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction
mixture was allowed to stir for 45 minutes by which time gas
evolution had ceased. Tert-butyl
4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol) was
added dropwise over a period of 15 minutes. The reaction mixture
was allowed to stir at ambient temperature for 2.5 hrs; then it was
heated to 100.degree. C. and stirred overnight. Analysis by HPLC
showed that the reaction was about 35% complete. Saturated ammonium
chloride solution was added, the resulting mixture was allowed to
stir for 20 minutes and then it was extracted with ethyl acetate
(2.times.). The ethyl acetate extracts were washed with water
(2.times.) and then with brine, combined, dried over sodium
sulfate, filtered and then concentrated under reduced pressure to
provide a brown oil. The oil was purified by column chromatography
(silica gel eluting sequentially with 30% ethyl acetate in hexanes,
50% ethyl acetate in hexanes, and ethyl acetate) to provide 2.2 g
of tert-butyl
4-{2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxy-
late.
Part D
[0273] Using the general method of Examples 6-26 Part H, the
material from Part C was oxidized to provide tert-butyl
4-{2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-
-carboxylate as an oil.
Part E
[0274] Ammonium hydroxide solution (20 mL) was added to a solution
of the material from Part D in dichloromethane (20 mL). A solution
of tosyl chloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was
added over a period of 5 minutes. The resulting biphasic reaction
mixture was allowed to stir overnight. The reaction mixture was
diluted with chloroform and saturated sodium bicarbonate solution.
The layers were separated. The organic layer was dried over sodium
sulfate, filtered and then concentrated under reduced pressure to
provide a brown glass. This material was purified by column
chromatography (silica gel eluting first with 50% ethyl acetate in
hexanes and then with ethyl acetate) to provide 1.0 g of tert-butyl
4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-
-carboxylate as pale yellow glassy foam.
Part F
[0275] Under a nitrogen atmosphere, tert-butyl
4-{2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-
-carboxylate (1.00 g, 2.1 mmol) and 2N ethanolic hydrochloric acid
(10 ml, 20 mmol) were combined and the solution was stirred at
ambient temperature for 14 hours. The solvent was removed in vacuo
and the resulting tan solid was dissolved in water. Saturated
aqueous sodium carbonate was added until the pH reached 10. After
extraction with dichloromethane (3.times.), the organic fractions
were combined, washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and the majority of the solvent was removed in vacuo.
Hexane was added to form a precipitate. Vacuum filtration yielded
0.5 g of
1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4--
amine as a tan powder.
[0276] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.34 (bs, 1H),
8.19 (d, J=8.49, 1H), 7.61 (dd, J=8.31, 1.13, 1H), 7.45-7.39 (m,
1H), 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80
(m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H),
2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, 5H), 0.95-0.7
(m, 5H);
[0277] .sup.13C-NMR (75 MHz, DMSO-d.sub.6): .delta. 152.8, 145.8,
140.6, 133.0, 127.8, 127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1,
58.4, 46.1, 36.3, 33.1, 32.7, 24.5, 9.9;
[0278] MS (CI) m/e 368.2459 (368.2450 calcd for
C.sub.21H.sub.30N.sub.5O).
Part G
[0279] The compounds in the table below were prepared according to
the synthetic method of step (7) of Reaction Scheme II above using
the following general method.
[0280] The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.)
was added to a test tube containing a solution of
1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-c]quinolin-4--
amine (25 mg) in dichloromethane (5 mL). The test tube was capped
and then placed on a shaker at ambient temperature for 20 hr. The
solvent was removed by vacuum centrifugation. The residue was
purified by semi-preparative HPLC using the method described above.
The products were verified by accurate mass and .sup.1H NMR. The
table below shows the structure of the free base and the observed
accurate mass (M+H).
TABLE-US-00002 Example Accurate Mass Number Structure of Free Base
(obs.) 27 ##STR00038## 474.2531 28 ##STR00039## 475.2483 29
##STR00040## 488.2647 30 ##STR00041## 508.2349 31 ##STR00042##
514.1924 32 ##STR00043## 526.2241 33 ##STR00044## 533.2315 34
##STR00045## 538.2477 35 ##STR00046## 544.2166 36 ##STR00047##
559.2493 37 ##STR00048## 586.2166 (1) 38 ##STR00049## 592.2144 39
##STR00050## 655.3173
EXAMPLES 40-49
Part A
[0281] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g,
20.0 mmol) in 100 mL of toluene was treated with
triethylorthoformate (4.65 mL, 28.0 mmol) and the reaction mixture
was heated to reflux. A 100 mg portion of pyridinium hydrochloride
was then added and refluxing was continued for 2 h. The reaction
was then concentrated to dryness under reduced pressure. The
residue was dissolved in 200 mL of CH.sub.2Cl.sub.2 and washed with
saturated NaHCO.sub.3, H.sub.2O and brine. The organic portion was
dried over Na.sub.2SO.sub.4 and concentrated to give a green oil.
The green oil was dissolved in 200 mL of hot MeOH and treated with
10 g of activated charcoal. The hot solution was filtered and
concentrated to give 5.25 g of tert-butyl
2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a
light yellow syrup.
Part B
[0282] A solution of tert-butyl
2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g,
14.7 nmol) in 200 mL of CH.sub.2Cl.sub.2 was treated with MCPBA
(77%, 3.63 g, 16.3 mmol). After stirring overnight, the reaction
mixture was treated with saturated NaHCO.sub.3 solution and the
layers were separated. The organic portion was washed with H.sub.2O
and brine then dried over Na.sub.2SO.sub.4 and concentrated to give
4.60 g of tert-butyl
2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
as a light brown foam.
Part C
[0283] A solution of tert-butyl
2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
(4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to
80.degree. C. and treated with 10 mL of concentrated NH.sub.4OH
solution. To the rapidly stirred solution was added solid
p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min
period. The reaction mixture was treated with an additional 2 mL of
concentrated NH.sub.4OH solution and then sealed in a pressure
vessel and heating was continued for 3 h. The reaction mixture was
then cooled and treated with 100 mL of CH.sub.2Cl.sub.2. 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 4.56 g of tert-butyl
2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
as a light brown foam.
Part D
[0284] Tert-butyl
2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
(4.56 g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated
with 30 mL of 2M HCl in EtOH and the mixture was heated to reflux
with stirring. After 3 h, the reaction mixture was concentrated to
give a solid. The solid was triturated with hot EtOH (100 mL) and
filtered to give the product as the hydrochloride salt. The free
base was made by dissolving the hydrochloride salt in 50 mL of
H.sub.2O and treating with 5 mL of concentrated NH.sub.4OH. The
aqueous suspension was extracted with CH.sub.2Cl.sub.2 (5.times.50
mL). The combined organic layers were dried over Na.sub.2SO.sub.4
and concentrated to give 1.35 g of
1-[2-(2-aminoethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as a
tan powder.
[0285] MS 272 (M.sup.+;
[0286] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.98 (d, J=8.2 Hz,
1H); 7.88 (s, 1H); 7.84 (d, J=8.4 Hz, 1H); 7.54 (m, 1H); 7.32 (m,
1H); 5.43 (s, 2H); 4.74 (t, J=5.2 Hz, 2H); 3.97 (t, J=5.2 Hz, 2H);
3.42 (t, J=5.1 Hz, 2H); 2.78 (t, J=5.1 Hz, 2H); 1.10 (br s,
2H).
Part E
[0287] The compounds in the table below were prepared according to
the synthetic method of step (7) of Reaction Scheme II above using
the following general method.
[0288] 1-[2-(2-Aminoethoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine
(20 mg) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a test
tube and then heated and sonicated to provide a solution. The
sulfonyl chloride (1.1 eq.) was then added to the test tube. The
test tube was capped and then placed on a shaker at ambient
temperature for 20 hr. The solvent was removed by vacuum
centrifugation. The residue was purified by semi-preparative HPLC
using the method described above. The products were verified by
accurate mass and .sup.1H NMR. The table below shows the structure
of the free base and the observed accurate mass (M+H).
TABLE-US-00003 Example Accurate Mass Number Structure of Free Base
(obs.) 40 ##STR00051## 392.1781 41 ##STR00052## 412.1468 42
##STR00053## 430.1348 43 ##STR00054## 442.1572 44 ##STR00055##
448.1259 45 ##STR00056## 462.1571 46 ##STR00057## 480.1274 47
##STR00058## 488.1722 48 ##STR00059## 490.1224 49 ##STR00060##
496.1230
EXAMPLE 50
N-[10-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,7-dioxadecyl]-5--
dimethylaminonaphthalene-1-sulfonamide
##STR00061##
[0289] Part A
[0290] 4,7-Dioxadecane-1,10-diamine (32.6 g, 0.185 mole) in
acetonitrile (100 mL) was chilled in an ice bath. To this was
slowly added dropwise dansyl chloride (5 g, 0.0185 mole) dissolved
in acetonitrile (60 mL) over a 20 min. period. Stirring in an ice
bath was continued for 1.5 hr. The reaction mixture was poured into
water (about 300 mL) and extracted with dichloromethane
(2.times.100 mL). The combined extracts were washed with water and
dried to give an oil. The oil was purified by column chromatography
(silica gel eluting with acetonitrile containing increasing amounts
of ethanol) to provide 4.6 g of
N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide
as a viscous oil.
[0291] .sup.1H-NMR (500 MHz, CDCl.sub.3) 1.65 (2H, quin), 1.75 (2H,
quin), 2.80 (2H, t, 6.59 Hz), 2.87 (6H, s), 3.03 (2H, t, 6.1 Hz),
3.43 (2H, m), 3.47 (2H, m), 3.52 (2H, m), 3.59 (2H, t, 6.22 Hz),
7.18 (1H, d, J=7.08 Hz)), 7.56-7.49 (overlapping multiplets, 2H),
8.24 (dd, 1H, J=1.2, 7.3 Hz), 8.31 (d, 1H), 8.53 (d, 1H).
Part B
[0292] A solution of 2,4-dichloro-3-nitroquinoline (2.71 g, 0.0115
mole) in toluene (100 mL) was cooled to 0-5.degree. C. in an ice
bath. Triethylamine (1.5 g) was added in one portion. A solution of
N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide
(4.6 g, 0.01159 mole) in toluene (60 mL) was added dropwise while
maintaining the temperature below 10.degree. C. The reaction was
stirred at 2-5.degree. C. for 4 hrs and at a room temperature of
21.degree. C. overnight (18 hours). Thin layer chromatography
(dichloromethane: ethanol) showed a trace of the amine starting
material, but was mostly a bright yellow spot at the solvent front
assumed to be the addition product. The toluene was removed by
rotary evaporation to provide a viscous oil. The oil was purified
by column chromatography (silica gel, dichloromethane/ethanol) to
provide 2.4 g of
N-[10-(2-chloro-3-nitro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylamin-
onaphthalene-1-sulfonamide.
[0293] .sup.1H-NMR (CDCl.sub.3) 1.62 (2H, quin), 2.05 (2H, quin),
2.87 (6H, s), 3.03 (2H, m), 3.47 (4H, m), 3.55 (2H, m), 3.65 (2H,
m), 3.73 (2H, t, 5.37 Hz), 5.75 (1H, t, 4.39 Hz, NH), 6.91 (1H, t,
4.76 Hz, NH), 7.15 (1H, d, 7.32 Hz), 7.30 (1H, m), 7.50 (2H,
overlapping t), 7.62 (1H, m), 7.82 (1H, d, 7.44 Hz), 7.88 (1H, d,
8.54 Hz), 8.22 (1H, m), 8.29 (1H, d, 8.42), 8.52 (1H, d, 8.06
Hz).
Part C
[0294] Material from Part B (2.2 g, 0.00357 mole) was dissolved in
ethanol (150 mL). Catalyst (about 1 g of 5% Pt/C) was added and the
mixture was hydrogenated using a Parr apparatus for 30 minutes.
Thin layer chromatography (ethyl acetate:hexane 1:1) showed that
the reaction was complete. The reaction mixture was filtered to
remove the catalyst and the filtrate was evaporated to provide a
sticky solid which was shown by NMR to be crude
N-[10-(3-amino-2-chloro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylamin-
onaphthalene-1-sulfonamide. It was used without further
purification.
[0295] .sup.1H-NMR (500 MHz, CDCl.sub.3) 1.60 (2H, quin), 1.90 (2H,
quin), 2.87 (6H, s, NMe.sub.2), 3.00 (2H, br s), 3.45 (4H, m), 3.53
(2H, m), 3.62 (2H, t, 5.62 Hz), 3.71 (4.30 (2H, br s, NH.sub.2),
5.85 (1H, br s, NH), 7.11 (1H, d, J=7.32 Hz), 7.35 (1H, m),
7.44-7.48 (3H, m), 7.82 (1H, d), 8.18 (1H, dd, J=1.1, 7.2 Hz), 8.30
(1H, d, 8.66 Hz), 8.49 (1H, d, 8.54 Hz).
[0296] .sup.13C-NMR (125 MHz) 28.48 (CH.sub.2), 30.08 (CH.sub.2),
41.93 (CH.sub.2), 45.27 (CH.sub.3), 45.28 (CH.sub.2), 69.75
(CH.sub.2), 69.83 (CH.sub.2), 70.08 (CH.sub.2), 70.38 (CH.sub.2),
114.99 (CH), 118.84 (CH), 120.84 (CH), 123.02 (CH), 123.50 (C),
125.67 (CH), 126.22 (CH), 128.01 (CH), 128.57 (C) 128.67 (CH),
129.22 (CH), 129.52 (C), 129.74 (C), 130.09 (CH), 134.72 (C),
137.17 (C), 141.82 (C), 142.03 (C), 151.75 (C).
Part D
[0297] A portion (1 g, 1.78 mmol) of the material from Part C was
dissolved in tetrahydrofuran (30 mL) and then cooled in an ice-bath
to about 5.degree. C. Freshly distilled acetyl chloride (0.13 g,
1.78 mmol) was added with stirring. The yellow solid which
immediately precipitated was isolated by filtration and washed with
tetrahydrofuran. Standing in air gave an oily solid (possibly
hygroscopic). FAB (fast atom bombardment) mass spectrum suggested
that this was the desired
N-[10-(3-acetamido-2-chloro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethyl-
aminonaphthalene-1-sulfonamide hydrochloride together with an
undetermined amount of starting material. This solid was carried on
to Part E without additional purification.
Part E
[0298] The crude salt from Part D was dissolved in dry methanol
containing 7% ammonia (20 mL). The solution was heated at
150.degree. C. in a bomb for 61/2 hrs. The reaction mixture was
cooled and then concentrated. The residue was combined with
acetone. Undissolved material was removed by filtration. The
filtrate was concentrated and the residue was purified by column
chromatography (silica gel; ethanol/dichloromethane) to provide
0.45 g of a brown oil.
[0299] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.53 (2H, t, 7.08 Hz),
2.05 (2H, m), 2.45 (3H, s), 2.70 (6H, s), 2.90 (2H, t, 5.98 Hz),
3.30 (8H, br, m), 4.40 (2H, t, 6.59 Hz), 5.75 (2H, br s NH.sub.2),
6.65 (1H, br s NHSO.sub.2), 7.00 (1H, d, 7.54 Hz), 7.14 (1H, t,
8.06 Hz), 7.30 (3H, m), 7.64 (1H, d, 8.30 Hz), 7.88 (1H, d, 8.18
Hz), 8.06 (1H, d, 7.33 Hz), 8.24 (1H, d, 8.54 Hz), 8.36 (1H, d,
8.55 Hz).
[0300] This material was then purified by high performance liquid
chromatography using a Bondapak C18 12.5 nm reverse phase column
(available from Waters, Milford, Mass.) eluting with a composite
gradient of acetonitrile in water to provide the desired
product.
EXAMPLE 51
1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine
##STR00062##
[0301] Part A
[0302] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (12.05 g,
34.8 mmol) in 200 mL of 1,2-dichloroethane was treated with
trimethyl orthoacetate (5.50 mL, 43.2 mmol) and the reaction
mixture was heated to reflux. A 100 mg portion of pyridinium
hydrochloride was then added and refluxing was continued for 4 h.
The reaction was then cooled and washed with water and brine. The
organic portion was dried over Na.sub.2SO.sub.4 and concentrated to
give an orange foam. The foam was triturated with ether and
filtered to yield 10.76 g of tert-butyl
2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
as a tan solid.
Part B
[0303] A solution of tert-butyl
2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
(10.75 g, 29.0 mmol) in 150 mL of CHCl.sub.3 was chilled in an ice
water bath. The solution was treated with 3-chloroperoxybenzoic
acid (MCPBA, 70%, 10.73 g, 43.5 mmol). After stirring for 1.5 h,
the reaction mixture was washed with 1% Na.sub.2CO.sub.3 (3.times.)
solution and the layers were separated. The organic portion was
washed with H.sub.2O and brine then dried over Na.sub.2SO.sub.4 and
concentrated to give a sticky brown solid. The solid was triturated
with ether to yield 11.21 g of tert-butyl
2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbama-
te as a light tan solid.
Part C
[0304] A solution of tert-butyl
2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbama-
te (11.21 g, 29.0 mmol) in 75 mL of CH.sub.2Cl.sub.2 was treated
with 75 mL of concentrated NH.sub.4OH solution. The mixture was
chilled in an ice water bath. To the rapidly stirred mixture was
added solid p-toluenesulfonyl chloride (5.53 g, 29.0 mmol) over a
10 min period. The reaction mixture was then warmed to room
temperature and treated with 75 mL of CH.sub.2Cl.sub.2 and 75 mL of
water. The organic portion was then washed with 1% Na.sub.2CO.sub.3
solution (3.times.) and brine. The organic portion was dried over
Na.sub.2SO.sub.4 and concentrated and triturated in ether to yield
7.13 g of tert-butyl
2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbama-
te as a light green solid.
Part D
[0305] Tert-butyl
2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbama-
te (7.13 g, 18.5 mmol) was suspended in 100 mL of 2M HCl in EtOH
and the mixture was heated to reflux with stirring. After 3 h, the
reaction mixture was chilled in an ice water bath and a filtered.
The resulting solid was washed with small portions of ether to give
the product as the hydrochloride salt. The free base was made by
dissolving the hydrochloride salt in 100 mL of H.sub.2O and
treating with 20 mL of concentrated NH.sub.4OH. The aqueous
suspension was extracted with CH.sub.2Cl.sub.2 (3.times.75 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated to give 5.10 g of
1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amineas
a tan powder.
[0306] mp 155-157.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.07 (d, J=7.5 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.41 (t,
J=7.0 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.50 (s, 2H), 4.70 (t, J=5.2
Hz, 2H), 3.85 (t, J=5.2 Hz, 2H), 3.27 (t, J=5.4 Hz, 2H), 3.03 (bs,
2H), 2.61 (s, 3H), 2.53 (t, J=5.6 Hz, 2H); .sup.13C NMR (75 MHz,
DMSO-d.sub.6) .delta. 152.0, 150.9, 145.1, 132.8, 126.6, 121.3,
120.5, 115.1, 73.6, 69.4, 45.8, 41.6, 14.1; MS m/z 286 (M+H).sup.+;
Anal. Calcd for C.sub.15H.sub.19N.sub.5O: C, 63.14, H, 6.71, N,
24.54. Found: C, 62.74, H, 6.68, N, 24.55.
EXAMPLE 52
1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine
##STR00063##
[0307] Part A
[0308] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (32.0 g,
92.0 mmol) in 300 mL of CH.sub.2Cl.sub.2 was treated with
triethylamine (19.2 mL, 138.0 mmol). The reaction was chilled in an
ice water bath and then propionyl chloride (9.40 mL, 108.2 mmol)
was added dropwise. After stirring for 18 h, the reaction was
treated with water (150 mL) and the layers were separated. The
aqueous portion was extracted with CH.sub.2Cl.sub.2 (3.times.50
mL). The combined organic portions were washed with 1%
Na.sub.2CO.sub.3, water, brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield a red sticky solid. The solid
was triturated with ether and filtered to yield 16.5 g of
tert-butyl
2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamnate
as an off white powder.
Part B
[0309] A solution of tert-butyl
2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate
(15.00 g, 37.3 mmol) in 200 mL of EtOH was treated with
triethylamine (13.0 mL, 93.2 mmol). The reaction was heated to
reflux with stirring. After 3 days, the reaction was concentrated,
triturated with ether and filtered to yield 13.78 g of tert-butyl
2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
as an off white solid.
Part C
[0310] A solution of tert-butyl
2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate
(13.78 g 35.8 mmol) in 175 mL of CHCl.sub.3 was treated with
3-chloroperoxybenzoic acid (MCPBA, 70%, 10.28 g, 41.7 mmol). After
stirring for 3 h, the reaction mixture was treated with water (100
mL) and CHCl.sub.3 (50 mL) and the layers were separated. The
organic portion was washed with 1% Na.sub.2CO.sub.3 solution
(2.times.), water and brine then dried over Na.sub.2SO.sub.4 and
concentrated to give 14.35 g tert-butyl
2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e as a sticky tan solid.
Part D
[0311] A solution of tert-butyl
2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e (14.3 g, 35.8 mmol) in 90 mL of CH.sub.2Cl.sub.2 was treated with
90 mL of concentrated NH.sub.4OH solution. The mixture was chilled
in an ice water bath. To the rapidly stirred mixture was added
solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min
period. The reaction mixture was then warmed to room temperature.
After 30 min, the reaction was treated with 90 mL of
CH.sub.2Cl.sub.2 and 90 mL of water. The organic portion was then
washed with 0.1% Na.sub.2CO.sub.3 solution (2.times.), water,
brine, dried over Na.sub.2SO.sub.4 and concentrated. The resulting
solid was triturated in ether and filtered to yield 9.35 g of
tert-butyl
2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e as a light tan solid.
Part E
[0312] Tert-butyl
2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamat-
e (9.35 g, 23.4 mmol) was suspended in 150 mL of 2M HCl in EtOH and
the mixture was heated to reflux with stirring. After 2 h, the
reaction was cooled to room temperature and the HCl salt of the
product was collected by vacuum filtration and rinsed with ether.
The free base was made by dissolving the HCl salt in water and
treating with 10% NaOH solution until the mixture was pH 12. The
aqueous suspension was extracted with CH.sub.2Cl.sub.2 (10.times.50
mL). The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give 6.62 g of
1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4--
amine as a light yellow solid.
[0313] mp 144-146.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.07 (d, J=7.5 Hz, 1H), 7.61 (dd, J=1.0, 8.3 Hz, 1H),
7.43-7.38 (m, 1H), 7.25-7.17 (m, 1H), 6.45 (s, 2H), 4.71 (t, J=5.2
Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.27 (t, J=5.7 Hz, 2H), 2.97 (q,
J=7.5 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H), 1.37 (t, J=7.5 Hz, 3H), 1.25
(bs, 2H); .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 155.2, 152.1,
145.1, 132.8, 126.6, 126.6, 121.3, 120.5, 115.2, 73.8, 69.4, 45.4,
41.6, 20.4, 12.2; MS m/z 300 (M+H).sup.+; Anal. Calcd for
C.sub.16H.sub.21N.sub.5O: C, 64.19; H, 7.07; N, 23.39; Found: C,
63.98; H, 6.96; N, 23.27.
EXAMPLE 53
1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-am-
ine
##STR00064##
[0314] Part A
[0315] A solution of tert-butyl
2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (18.04 g,
52.1 mmol) in 180 mL of pyridine was treated with 50 mg of
4-dimethylaminopyridine and chilled in an ice water bath.
2-ethoxyacetyl chloride (6.44 g, 52.6 mmol) was added dropwise to
the solution. The reaction was stirred at room temperature for 3 h.
The reaction was then heated to reflux with stirring. After 18 h
the reaction was cooled and then concentrated. The residue was
partitioned between CHCl.sub.3 (150 mL) and water (150 mL) and the
layers were separated. The aqueous portion was extracted with
CHCl.sub.3 (3.times.50 mL). The combined organic portions were
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to yield 15.47 g of tert-butyl
2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbama-
te as a sticky yellow solid.
Part B
[0316] A solution of tert-butyl
2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbama-
te (15.47 g, 37.3 mmol) in 150 mL of CHCl.sub.3 was treated with
3-chloroperoxybenzoic acid (MCPBA, 70%, 15.12 g, 61.3 mmol). After
stirring for 1.5 h, the reaction mixture was treated with water
(100 mL) and CHCl.sub.3 (50 mL) and the layers were separated. The
organic portion was washed with 2% Na.sub.2CO.sub.3 solution
(2.times.), H.sub.2O and brine then dried over Na.sub.2SO.sub.4 and
concentrated to give 16.06 g of tert-butyl
2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethy-
lcarbamate as a yellow solid.
Part C
[0317] A solution of tert-butyl
2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethy-
lcarbamate (16.06 g, 37.3 mmol) in 75 mL of CH.sub.2Cl.sub.2 was
treated with 75 mL of concentrated NH.sub.4OH solution. The mixture
was chilled in an ice water bath. To the rapidly stirred mixture
was added solid p-toluenesulfonyl chloride (7.82 g, 41.0 mmol) over
a 10 min period. The reaction mixture was then warmed to room
temperature. After 30 min, the reaction was treated with 75 mL of
CH.sub.2Cl.sub.2 and 75 mL of water and the layers were separated.
The organic portion was then washed with 1% Na.sub.2CO.sub.3
solution (2.times.), water, brine, dried over Na.sub.2SO.sub.4 and
concentrated to give 14.95 g of tert-butyl
2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethy-
lcarbamate as a yellow solid.
Part D
[0318] Tert-butyl
2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethy-
lcarbamate (14.45 g, 33.6 mmol) was dissolved in 50 mL of 2M HCl in
EtOH and the mixture was heated to reflux with stirring. After 3 h,
the reaction was cooled to room temperature and treated with ether
(100 mL). The HCl salt of the product was collected by vacuum
filtration. The free base was made by dissolving the hydrochloride
salt in 75 mL of water and treating with concentrated NH.sub.4OH
until pH 12 was reached. The aqueous suspension was extracted with
CH.sub.2Cl.sub.2 (4.times.50 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4 and concentrated to give a thick orange
oil. The oil was dissolved in MeOH (100 mL), treated with 2 g of
activated charcoal and heated to reflux. After 2 h, the mixture was
filtered through a pad of Celite and rinsed with portions of MeOH.
The filtrate was concentrated to yield
1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-a-
mine as a sticky orange solid.
[0319] MS 330 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.13 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.44 (m,
1H), 7.25 (m, 1H), 6.58 (s, 2H), 4.85 (t, J=5.5 Hz, 2H), 4.80 (s,
2H), 3.86 (t, J=5.5 Hz, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.30 (t, J=5.5
Hz, 2H), 2.54 (t, J=5.6 Hz, 2H), 1.17 (t, J=7.0 Hz, 3H).
EXAMPLE 54
N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}meth-
anesulfonamide
##STR00065##
[0321] A solution of the compound of Example 51,
1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine
(1.570 g, 5.50 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was
treated with triethylamine (1.53 mL, 11.0 mmol). With vigorous
stirring, methanesulfonyl chloride (0.426 mL, 5.50 mmol) was added
dropwise. After 18 h, the reaction was treated with 50 mL of water
and then concentrated to yield a solid. The solid was purified by
column chromatography (SiO.sub.2, 90:10:0.5
CHCl.sub.3:MeOH:NH.sub.4OH) to yield 244 mg of
N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}met-
hanesulfonamide as a white solid.
[0322] mp=152-155.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.13 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.51 (t,
J=7.2 Hz, 1H), 7.34 (t, J=7.2 Hz, 1H), 7.27 (s, 2H), 7.02 (m, 1H),
4.74 (t, J=5.0 Hz, 2H), 3.89 (t, J=5.0 Hz, 2H), 3.42 (t, J=5.7 Hz,
2H), 3.02 (m, 2H), 2.81 (s, 3H), 2.65 (s, 3H); .sup.13C NMR (75
MHz, DMSO-d.sub.6) .delta. 152.2, 151.0, 141.3, 133.6, 127.6,
125.9, 124.0, 122.6, 121.0, 114.4, 70.2, 69.2, 45.9, 42.4, 14.2; MS
m/z 364 (M+H).sup.+; Anal. Calcd for
C.sub.16H.sub.21N.sub.5O.sub.3S: C, 52.88; H, 5.82; N, 19.27;
Found: C, 52.56; H, 5.75; N, 19.21.
EXAMPLE 55
N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}prop-
ane-2-sulfonamide
##STR00066##
[0324] A solution of the compound of Example 51,
1-[2-(2-aminoethoxy)ethyl]-2-methyl
1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.50 mmol) in 30 mL of
pyridine was chilled in an ice water bath. The stirred solution was
treated dropwise with isopropylsulfonyl chloride (0.39 mL, 3.50
mmol) and the reaction was allowed to gradually warm to room
temperature. After 18 h, the reaction was concentrated. The crude
product was purified by column chromatography (SiO.sub.2, 90:10:0.5
CHCl.sub.3:MeOH:NH.sub.4OH) and then triturated in hexanes to give
314 mg of
N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-
propane-2-sulfonamide as a white solid.
[0325] mp=172-175.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.04 (d, J=7.5 Hz, 1H), 7.62 (dd, J=1.1, 8.4 Hz, 1H), 7.40
(m, 1H), 7.22 (m, 1H), 6.97 (t, J=5.2 Hz, 1H), 6.48 (s, 2H), 4.71
(t, J=5.2 Hz, 2H), 3.88 (t, J=5.1 Hz, 2H), 3.42-3.35 (m, 2H),
3.07-2.95 (m, 3H), 2.61 (s, 3H), 1.11 (d, J=6.8 Hz, 6H); .sup.13C
NMR (75 MHz, DMSO-d.sub.6) .delta. 151.6, 150.5, 144.6, 132.3,
126.1, 120.9, 119.9, 114.7, 70.1, 68.9, 51.3, 45.3, 42.0, 16.1,
13.7; MS m/z 392 (M+H).sup.+; Anal. Calcd for
C.sub.18H.sub.25N.sub.5O.sub.3S: C, 55.22; H, 6.44; N, 17.89.
Found: C, 55.37; H, 6.52; N, 17.66.
EXAMPLE 56
N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}metha-
nesulfonamide
##STR00067##
[0327] A solution of the compound of Example 52,
1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine
(800 mg, 2.67 mmol) in 30 mL of CH.sub.2Cl.sub.2 was treated with
triethylamine (1.10 mL, 8.00 mmol). With vigorous stirring, the
solution was treated dropwise with methanesulfonyl chloride (0.217
mL, 2.80 mmol). After 18 h, the reaction was treated with 50 mL of
water and the layers were separated. The aqueous portion was
extracted with CHCl.sub.3 (3.times.30 mL). The combined organic
portions were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield an off white solid. Purification
by column chromatography (SiO.sub.2, 95:5:0.5
CHCl.sub.3:MeOH:NH.sub.4OH) gave 463 mg of
N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}meth-
anesulfonamide as a white solid.
[0328] mp=169-171.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.05 (d, J=7.5 Hz, 1H), 7.62 (dd, J=1.1, 7.3 Hz, 1H),
7.45-7.37 (m, 1H), 7.22 (m, 1H), 7.03-6.95 (m, 1H), 6.44 (s, 2H),
4.71 (t, J=5.3 Hz, 2H), 3.87 (t, J=5.2 Hz, 2H), 3.40 (t, J=5.9 Hz,
2H), 3.05-2.95 (m, 4H), 2.81 (s, 3H), 1.38 (t, J=7.4 Hz, 3H);
.sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 155.2, 152.1, 132.8,
126.6, 121.4, 120.5, 115.2, 70.2, 69.3, 45.3, 42.4, 20.4, 12.2; MS
m/z 378 (M+H).sup.+; Anal. Calcd for
C.sub.17H.sub.23N.sub.5O.sub.3S: C, 54.09; H, 6.14; N, 18.55;
Found: C, 54.16; H, 6.25; N, 18.37.
EXAMPLE 57
N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hyl)methanesulfonamide
##STR00068##
[0330] A solution of the compound of Example 53,
1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-a-
mine (980 mg, 2.98 mmol) in 20 mL of CH.sub.2Cl.sub.2 was treated
with triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water
bath. With vigorous stirring, the solution was treated dropwise
with methanesulfonyl chloride (0.242 mL, 3.13 mmol). After 18 h,
the reaction was treated with 40 mL CH.sub.2Cl.sub.2, mL
CHCl.sub.3, 25 mL water and the layers were separated. The organic
portion was washed with 1% Na.sub.2CO.sub.3 solution, water and
brine. The organic portion was then dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield a yellow foam. Purification by
column chromatography (SiO.sub.2, 90:10:0.5
CHCl.sub.3:MeOH:NH.sub.4OH) followed by recrystallization from
CH.sub.2Cl.sub.2 gave 282 mg of
N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}e-
thyl)methanesulfonamide as light yellow crystals.
[0331] mp=152-155.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.09 (d, J=7.4 Hz, 1H), 7.63 (dd, J=1.1, 8.4 Hz, 1H), 7.44
(m, 1H), 7.25 (m, 1H), 7.01 (t, =5.5 Hz, 1H), 6.58 (s, 2H), 4.83
(t, J=5.5 Hz, 2H), 4.81 (s, 2H), 3.87 (t, J=5.5 Hz, 2H), 3.55 (q,
J=7.0 Hz, 2H), 3.42 (t, J=5.5 Hz, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.82
(s, 3H), 1.17 (t, J=6.9 Hz, 3H); .sup.13C NMR (75 MHz,
DMSO-d.sub.6) .delta. 152.3, 149.9, 145.6, 133.5, 127.2, 126.7,
121.5, 120.8, 115.0, 70.2, 69.3, 65.7, 64.8, 45.6, 42.4, 15.3; MS
m/z 408 (M+H).sup.+; Anal. Calcd for
C.sub.18H.sub.25N.sub.5O.sub.4S: C, 53.06; H, 6.18; N, 17.19;
Found: C, 52.84; H, 5.84; N, 17.14.
EXAMPLE 58
N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}et-
hyl)propane-2-sulfonamide
##STR00069##
[0333] A solution of the compound of Example 53,
1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-a-
mine (980 mg, 2.98 mmol) in 20 mL CH.sub.2Cl.sub.2 was treated with
triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water
bath. With vigorous stirring, the solution was treated dropwise
with isopropylsulfonyl chloride (0.351 mL, 3.13 mmol). After 18 h,
the reaction was treated with 25 mL CH.sub.2Cl.sub.2 and 25 mL
water and the layers were separated. The organic portion was washed
with 1% Na.sub.2CO.sub.3 solution, water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield a yellow foam.
Purification by column chromatography (SiO.sub.2, 90:10:0.5
CHCl.sub.3:MeOH:NH.sub.4OH) followed by recrystallization from
CH.sub.2Cl.sub.2/hexanes gave 308 mg of
N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}e-
thyl)propane-2-sulfonamide as a light yellow solid.
[0334] mp 139-142.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.09 (d, J=7.7 Hz, 1H), 7.63 (dd, J=1.0, 8.3 Hz, 1H), 7.44
(m, 1H), 7.26 (m, 1H), 6.98 (t, J=5.6 Hz, 1H), 6.58 (s, 2H), 4.82
(t, J=5.5 Hz, 2H), 4.81 (s, 2H), 3.88 (t, J=5.5 Hz, 2H), 3.55 (q,
J=7.0 Hz, 2H), 3.40 (t, J=5.7 Hz, 2H), 3.06-2.96 (m, 3H), 1.17 (t,
J=7.0 Hz, 3H), 1.11 (d, J=6.7 Hz, 6H); .sup.13C NMR (75 MHz,
DMSO-d.sub.6) .delta. 152.3, 149.9, 145.6, 133.5, 127.2, 126.6,
121.5, 120.8, 115.0, 70.5, 69.3, 65.7, 64.8, 51.7, 45.6, 42.4,
16.5, 15.3; MS m/z 436 (M+H).sup.+;
[0335] Anal. Calcd for C.sub.20H.sub.29N.sub.5O.sub.4S: C, 55.15;
H, 6.71; N, 16.08; Found: C, 55.00; H, 6.77; N, 16.04.
EXAMPLE 59
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}-
ethyl)-N-methylpropane-2-sulfonamide
##STR00070##
[0337]
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,-
5-c]quinolin-4-amine (965 mg, 2.81 mmol) was dissolved in 30 mL of
anhydrous CH.sub.2Cl.sub.2 and cooled to 0.degree. C. under
N.sub.2. To the stirred solution were added Et.sub.3N (0.78 mL,
5.63 mmol) and isopropylsulfonyl chloride (316 .mu.L, 2.81 mmol)
and the reaction was allowed to warm to room temperature overnight.
The reaction mixture was then quenched by addition of saturated
NaHCO.sub.3 solution (30 mL) and CH.sub.2Cl.sub.2 (30 mL). The
organic layer was separated and washed with H.sub.2O and brine,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Column chromatography (3% MeOH/CHCl.sub.3 saturated with
NH.sub.4OH) gave 0.28 g of sticky solid. Crystallization from
EtOAc/CH.sub.2Cl.sub.2 gave 120 mg of
N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy-
}ethyl)-N-methylpropane-2-sulfonamide as amber crystals. m.p.
129.7-130.2.degree. C. MS m/z 450 (M+H).sup.+; .sup.1H NMR (300
MHz, d.sub.6-DMSO) .varies. 8.07 (d, J=7.6 Hz, 1H); 7.61 (dd,
J=1.1, 8.3 Hz, 1H); 7.41 (ddd, J=1.1, 7.0, 8.1 Hz, 1H); 7.23 (ddd,
J=1.2, 6.9, 8.2 Hz, 1H); 6.47 (s, 2H); 4.77 (t, J=5.0 Hz, 2H); 3.87
(t, J=5.0 Hz, 2H), 3.83 (t, J=6.8 Hz, 2H); 3.47 (t, J=5.4 Hz, 2H);
3.30 (s, 3H); 3.23-3.13 (m, 5H); 2.69 (s, 3H); 1.07 (d, J=6.8 Hz,
6H); .sup.13C NMR (75 MHz, d.sub.6-DMSO) .varies.152.0, 151.8,
145.2, 132.7, 126.7, 121.4, 120.6, 115.1, 70.4, 69.6, 69.3, 58.5,
52.0, 49.2, 45.4, 35.7, 27.7, 16.6. Anal. Calcd for
C.sub.21H.sub.31N.sub.5O.sub.4S: C, 56.10; H, 6.95; N, 15.58.
Found: C, 56.25; H, 6.89; N, 15.51.
EXAMPLE 60
1-{2-[2-(1,1-Dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-2-methyl-1H-imidazo[-
4,5-c]quinolin-4-amine
##STR00071##
[0339] Using the general method of Example 5, chloropropylsulfonyl
chloride (0.13 ml, 1.05 mmol) was reacted with
1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine
(0.3 g, 1.05 mmol). Recrystallization from 2-propanol yielded 0.2 g
of
1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-2-methyl-1H-imidazo-
[4,5-c]quinolin-4-amine as an off-white powder, m.p.
186.0-187.0.degree. C.
[0340] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.06 (d, J=7.6
Hz, 1H), 7.61 (dd, J=8.3, 1.0 Hz, 1H), 7.41 (dt, J 7.6, 1.0 Hz,
1H), 7.23 (dt, J=7.6, 1.2 Hz, 1H), 6.56 (s, 2H), 4.72 (t, J=5.0 Hz,
2H), 3.87 (t, J=5.0 Hz, 2H), 3.46 (t, J=5.3 Hz, 2H), 3.07 (t, J=7.7
Hz, 2H), 2.95-2.86 (m, 4H), 2.61 (s, 3H), 2.03 (quintet, J=6.9 Hz,
2H);
[0341] .sup.13C NMR (75 Hz, DMSO-d.sub.6) .delta. 151.5, 150.8,
144.4, 132.5, 126.3, 126.1, 126.0, 121.0, 120.2, 114.7, 68.9, 46.9,
45.5, 45.3, 43.7, 18.2, 13.7;
[0342] MS (CI) m/e 390.1607 (390.1600 calcd for
C.sub.18H.sub.23N.sub.5O.sub.3S, M+H).
[0343] Anal calcd for C.sub.18H.sub.23N.sub.5O.sub.3S: % C, 55.51;
% H, 5.95; % N, 17.98; % S, 8.23. Found: % C, 55.26; % H, 5.87; %
N, 17.87; % S, 8.13.
Cytokine Induction in Human Cells
[0344] An in vitro human blood cell system is used to assess
cytokine induction. Activity is based on the measurement of
interferon and tumor necrosis factor (a) (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
[0345] Whole blood from healthy human donors is collected by
venipuncture into EDTA vacutainer tubes. Peripheral blood
mononuclear cells (PBMC) are separated from whole blood by density
gradient centrifugation using Histopaque)-1077. Blood is diluted
1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's
Balanced Salts Solution (HBSS). The PBMC layer is collected and
washed twice with DPBS or HBSS and resuspended at 4.times.10.sup.6
cells/mL in 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
[0346] 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. The compounds are generally
tested at concentrations ranging from 30-0.014 .mu.M.
Incubation
[0347] The solution of test compound is added at 60 .mu.M to the
first well containing RPMI complete and serial 3 fold dilutions are
made in the wells. The PBMC suspension is then added to the wells
in an equal volume, bringing the test compound concentrations to
the desired range (30-0.014 .mu.M). The final concentration of PBMC
suspension is 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
[0348] Following incubation the plates are centrifuged for 10
minutes at 1000 rpm (.about.200.times.g) at 4.degree. C. The
cell-free 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 ELISA and for
tumor necrosis factor (a) by ELISA or IGEN Assay
Interferon (.alpha.) and Tumor Necrosis Factor (.alpha.) Analysis
by ELISA
[0349] Interferon (.alpha.) concentration is determined by ELISA
using a Human Multi-Species kit from PBL Biomedical Laboratories,
New Brunswick, N.J. Results are expressed in pg/mL.
[0350] Tumor necrosis factor (a) (TNF) concentration is determined
using ELISA kits available from Biosource International, Camarillo,
Calif. Alternately, the TNF concentration can be determined by
Origeno.RTM. M-Series Immunoassay and read on an IGEN M-8 analyzer
from IGEN International, Gaithersburg, Md. The immunoassay uses a
human TNF capture and detection antibody pair from Biosource
International, Camarillo, Calif. Results are expressed in
pg/mL.
[0351] 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; generally
the highest concentration tested was 10 or 30 .mu.M.
TABLE-US-00004 Cytokine Induction in Human Cells Example Lowest
Effective Concentration (.mu.M) Number Interferon Tumor Necrosis
Factor 3 0.01 0.12 6 0.001 1 7 0.01 1 8 0.01 1 9 0.1 1 10 1 10 11 1
10 12 0.1 10 13 1 10 14 1 10 15 10 10 16 1 10 17 1 10 18 * 10 19 *
10 20 1 10 21 10 10 22 0.0001 10 23 0.0001 10 24 0.0001 10 25
0.0001 * 26 0.01 10 27 0.1 1 28 0.1 1 29 1 10 30 1 10 31 1 10 32 1
1 33 1 1 34 1 1 35 1 1 36 1 10 37 0.1 1 38 * * 39 1 * 41 10 1 42 10
1 43 10 10 44 1 10 45 * * 46 * * 47 * * 48 * 10 49 * 10 50 1.11
*
* * * * *