U.S. patent application number 13/830042 was filed with the patent office on 2013-08-29 for imidazoquinolines with immuno-modulating properties.
This patent application is currently assigned to Dainippon Sumitomo Pharma Co., Ltd.. The applicant listed for this patent is AstraZeneca AB, Dainippon Sumitomo Pharma Co., Ltd.. Invention is credited to Roger Victor Bonnert, Thomas McInally, Stephen Thom, Hiroki Wada.
Application Number | 20130225555 13/830042 |
Document ID | / |
Family ID | 39596464 |
Filed Date | 2013-08-29 |
United States Patent
Application |
20130225555 |
Kind Code |
A1 |
Bonnert; Roger Victor ; et
al. |
August 29, 2013 |
Imidazoquinolines with Immuno-Modulating Properties
Abstract
The present invention provides compounds of formula (I)
##STR00001## wherein R.sup.a, R.sup.1, R.sup.2, R.sup.3, X.sup.1,
Y.sup.1, Z.sup.1, A, n and m are as defined in the specification,
and pharmaceutically acceptable salts thereof, as well as processes
for their preparation, pharmaceutical compositions containing them
and their use in therapy.
Inventors: |
Bonnert; Roger Victor;
(Leicestershire, GB) ; McInally; Thomas;
(Leicestershire, GB) ; Thom; Stephen;
(Leicestershire, GB) ; Wada; Hiroki;
(Leicestershire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AstraZeneca AB;
Dainippon Sumitomo Pharma Co., Ltd.; |
|
|
US
US |
|
|
Assignee: |
Dainippon Sumitomo Pharma Co.,
Ltd.
Osaka
JP
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
39596464 |
Appl. No.: |
13/830042 |
Filed: |
March 14, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12596817 |
Apr 30, 2010 |
8436178 |
|
|
PCT/GB08/50328 |
May 6, 2008 |
|
|
|
13830042 |
|
|
|
|
60916586 |
May 8, 2007 |
|
|
|
61024957 |
Jan 31, 2008 |
|
|
|
Current U.S.
Class: |
514/210.21 ;
514/211.15; 514/217.07; 514/218; 514/232.8; 514/252.18; 514/253.03;
514/293 |
Current CPC
Class: |
A61P 37/00 20180101;
A61P 17/00 20180101; A61P 27/14 20180101; A61P 37/02 20180101; A61P
11/06 20180101; A61P 31/00 20180101; A61P 31/18 20180101; A61P
31/12 20180101; A61P 31/14 20180101; A61P 31/20 20180101; C07D
471/04 20130101; A61P 31/04 20180101; A61P 11/00 20180101; A61P
35/00 20180101; A61P 11/02 20180101; A61P 37/08 20180101 |
Class at
Publication: |
514/210.21 ;
514/293; 514/253.03; 514/232.8; 514/252.18; 514/217.07; 514/211.15;
514/218 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Goverment Interests
NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT
[0001] The subject matter claimed in this application was made as a
result of activities undertaken within the scope of a joint
research agreement dated Dec. 19, 2003, between AstraZeneca AB and
Sumitomo Pharmaceuticals Co., Ltd. All of the rights and
obligations of Sumitomo Pharmaceuticals Co., Ltd. as defined in the
joint research agreement between AstraZeneca AB and Sumitomo
Pharmaceuticals Co., Ltd. were assumed by Dainippon Sumitomo Pharma
Co., Ltd., a company created by the merger of Dainippon
Pharmaceuticals Co., Ltd. and Sumitomo Pharmaceuticals Co., Ltd.
effective Oct. 3, 2005.
Claims
1.-17. (canceled)
18. A method of treating, or reducing the risk of, a disease or
condition in which modulation of TLR7 activity is beneficial which
comprises administering to a patient in need thereof a
therapeutically effective amount of a compound of formula (I):
##STR00090## wherein: R.sup.1 represents a straight chain
C.sub.1-C.sub.6 alkyl, optionally substituted by one or more
substituents independently selected from halogen, cyano, hydroxyl
and C.sub.1-C.sub.3 alkoxy; Z.sup.1 represents a C.sub.2-C.sub.6
alkylene group; X.sup.1 represents NR.sup.5 or >N--COR.sup.5;
Y.sup.1 represents C.sub.1-C.sub.6 alkylene; each R.sup.2 is
independently selected from halogen, cyano, hydroxy, thiol,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 hydroxyalkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkoxy, C.sub.1-3alkylthio, C.sub.1-3alkylsulfonyl and
C.sub.1-3alkylsulfinyl; R.sup.3 represents C.sub.1-6alkyl
optionally substituted by C.sub.1-6alkoxy; each R.sup.a is
independently selected from halogen, cyano, hydroxy, thiol,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 hydroxyalkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkoxy, C.sub.1-3alkylthio, C.sub.1-3alkylsulfonyl and
C.sub.1-3alkylsulfinyl; R.sup.5 represents hydrogen, a 3- to
8-membered saturated heterocyclic ring comprising a ring group O,
S(O).sub.p or NR.sup.10, a C.sub.1-C.sub.6 alkyl group or
C.sub.3-C.sub.6 cycloalkyl group, the latter two groups being
optionally substituted by one or more substituents independently
selected from NR.sup.7R.sup.8 or R.sup.9, or R.sup.5 is a
C.sub.1-C.sub.6 alkylene which may be linked to a carbon atom
within a C.sub.2-C.sub.6alkylene group Z.sup.1 so as to form a
saturated 4-7 membered nitrogen containing ring; R.sup.7 and
R.sup.8 each independently represent hydrogen, a 3- to 8-membered
saturated heterocyclic ring comprising a ring group O, S(O).sub.p
or NR.sup.10a, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl,
the latter two groups being optionally substituted by one or more
groups independently selected from halogen, cyano,
S(O).sub.qR.sup.11, OR.sup.12, CO.sub.2R.sup.12, OC(O)R.sup.12,
SO.sub.2NR.sup.12R.sup.13, CONR.sup.12R.sup.13, NR.sup.12R.sup.13,
NR.sup.12SO.sub.2R.sup.14, NR.sup.12COR.sup.13, or a 3- to
8-membered saturated heterocyclic ring comprising a ring group O,
S(O).sub.p or NR.sup.10b, or R.sup.7 and R.sup.8 together with the
nitrogen atom to which they are attached form a 3- to 8-membered
saturated heterocyclic ring comprising a ring nitrogen atom and
optionally one or more further heteroatoms independently selected
from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring
being optionally substituted by one or more substituents
independently selected from halogen, cyano, S(O).sub.qR.sup.15,
OR.sup.15, CO.sub.2R.sup.15, COR.sup.15, OC(O)R.sup.15,
SO.sub.2NR.sup.15R.sup.16, CONR.sup.15R.sup.16, NR.sup.15R.sup.16,
NR.sup.15SO.sub.2R.sup.17, NR.sup.15COR.sup.16,
NR.sup.15CO.sub.2R.sup.16, heteroaryl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl and C.sub.1-C.sub.6 alkyl, the latter
two groups being optionally substituted by one or more groups
independently selected from cyano, S(O).sub.qR.sup.18, OR.sup.18,
CO.sub.2R.sup.18, SO.sub.2NR.sup.18R.sup.19, CONR.sup.18R.sup.19 or
NR.sup.18R.sup.19; R.sup.9 represents halogen, cyano,
CO.sub.2R.sup.20, S(O).sub.qR.sup.20, OR.sup.20,
SO.sub.2NR.sup.20R.sup.22, CONR.sup.20R.sup.22,
NR.sup.20SO.sub.2R.sup.21, NR.sup.20CO.sub.2R.sup.21,
NR.sup.20COR.sup.22 or a 3- to 8-membered saturated heterocyclic
ring comprising a ring group NR.sup.10c; R.sup.10, R.sup.10a,
R.sup.10b and R.sup.10c independently represent hydrogen,
CO.sub.2R.sup.23, S(O).sub.qR.sup.23, COR.sup.24, or a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.3-C.sub.8 cycloalkyl group, each of which may be
optionally substituted by one or more substituents independently
selected from halogen, cyano, OR.sup.25 or NR.sup.25R.sup.26;
R.sup.11, R.sup.12, R.sup.13, R.sup.15, R.sup.16, R.sup.18,
R.sup.19, R.sup.20, R.sup.22, R.sup.24, R.sup.25 and R.sup.26 each
independently represent hydrogen, C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl; R.sup.14, R.sup.17, R.sup.21 and
R.sup.23 each independently represent C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl; m, n, p and q each independently
represent an integer 0, 1 or 2; and A represents a monocyclic or
bicyclic C.sub.6-C.sub.10 aryl; or a pharmaceutically acceptable
salt thereof.
19. The method of claim 18 wherein the disease or condition is
selected from the group consisting of allergic diseases, viral
diseases, asthma, COPD, allergic rhinitis, allergic conjunctivitis,
atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV,
bacterial infections and dermatosis.
20. The method of claim 19 wherein the disease or condition is
asthma.
21. The method of claim 19 wherein the disease or condition is
COPD.
22. The method of claim 19 wherein the disease or condition is
allergic rhinitis.
Description
[0002] The present invention relates to imidazoquinoline
derivatives, processes for their preparation, pharmaceutical
compositions containing them and their use in therapy.
[0003] The immune system is comprised of innate and acquired
immunity, both of which work cooperatively to protect the host from
microbial infections. It has been shown that innate immunity can
recognize conserved pathogen-associated molecular patterns through
toll-like receptors (TLRs) expressed on the cell surface of immune
cells. Recognition of invading pathogens then triggers cytokine
production (including interferon alpha (IFN.alpha.)) and
upregulation of co-stimulatory molecules on phagocytes, leading to
modulation of T cell function. Thus, innate immunity is closely
linked to acquired immunity and can influence the development and
regulation of an acquired response.
[0004] TLRs are a family of type I transmembrane receptors
characterized by an NH.sub.2-terminal extracellular leucine-rich
repeat domain (LRR) and a COOH-terminal intracellular tail
containing a conserved region called the Toll/IL-1 receptor (TIR)
homology domain. The extracellular domain contains a varying number
of LRR, which are thought to be involved in ligand binding. Eleven
TLRs have been described to date in humans and mice. They differ
from each other in ligand specificities, expression patterns, and
in the target genes they can induce.
[0005] Ligands which act via TLRs (also known as immune response
modifiers (IRMS)) have been developed, for example, the
imidazoquinoline derivatives described in U.S. Pat. No. 4,689,338
which include the product Imiquimod for treating genital warts, and
the adenine derivatives described in WO 98/01448 and WO
99/28321.
[0006] This patent application describes a class of
imidazoquinoline compounds having immuno-modulating properties
which act via TLR7 that are useful in the treatment of viral or
allergic diseases and cancers.
[0007] In accordance with the present invention, there is therefore
provided a compound of formula (I)
##STR00002## [0008] wherein [0009] R.sup.1 represents a straight
chain C.sub.1-C.sub.6 alkyl, optionally substituted by one or more
substituents independently selected from halogen, cyano, hydroxyl
and C.sub.1-C.sub.3 alkoxy; [0010] Z.sup.1 represents a
C.sub.2-C.sub.6 alkylene or C.sub.3-C.sub.8 cycloalkylene group;
[0011] X.sup.1 represents NR.sup.5, >N--COR.sup.5, CONR.sup.5,
NR.sup.5CO, SO.sub.2NR.sup.5, >N--SO.sub.2R.sup.5,
NR.sup.5SO.sub.2, NR.sup.5CONR.sup.6 or NR.sup.6CONR.sup.5,
S(O).sub.p or O; [0012] Y.sup.1 represents a single bond or
C.sub.1-C.sub.6 alkylene; [0013] each R.sup.2 is independently
selected from halogen, cyano, hydroxy, thiol, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 hydroxyalkyl, C.sub.1-C.sub.3 haloalkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy,
C.sub.1-3alkylthio, C.sub.1-3alkylsulfonyl and
C.sub.1-3alkylsulfinyl; [0014] R.sup.3 represents C.sub.1-6alkyl
optionally substituted by C.sub.1-6alkoxy; [0015] each R.sup.a is
independently selected from halogen, cyano, hydroxy, thiol,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 hydroxyalkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkoxy, C.sub.1-3alkylthio, C.sub.1-3alkylsulfonyl and
C.sub.1-3alkylsulfinyl; [0016] R.sup.5 represents hydrogen, a 3- to
8-membered saturated heterocyclic ring comprising a ring group O,
S(O).sub.p or NR.sup.10, a C.sub.1-C.sub.6 alkyl group or
C.sub.3-C.sub.6 cycloalkyl group, the latter two groups being
optionally substituted by one or more substituents independently
selected from NR.sup.7R.sup.8 or R.sup.9, [0017] or R.sup.5 is a
C.sub.1-C.sub.6 alkylene which may be linked to a carbon atom
within a C.sub.2-C.sub.6alkylene group Z.sup.1 so as to form a
saturated 4-7 membered nitrogen containing ring; [0018] provided
that when X.sup.1 is >N--SO.sub.2R.sup.5, R.sup.5 does not
represent hydrogen; [0019] R.sup.7 and R.sup.8 each independently
represent hydrogen, a 3- to 8-membered saturated heterocyclic ring
comprising a ring group O, S(O).sub.p or NR.sup.10a,
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl, the latter two
groups being optionally substituted by one or more groups
independently selected from halogen, cyano, S(O).sub.qR.sup.11,
OR.sup.12, CO.sub.2R.sup.12, OC(O)R.sup.12,
SO.sub.2NR.sup.12R.sup.13, CONR.sup.12R.sup.13, NR.sup.12R.sup.13,
NR.sup.12SO.sub.2R.sup.14, NR.sup.12R.sup.13, or a 3- to 8-membered
saturated heterocyclic ring comprising a ring group O, S(O).sub.p
or NR.sup.10b, [0020] or R.sup.7 and R.sup.8 together with the
nitrogen atom to which they are attached form a 3- to 8-membered
saturated heterocyclic ring comprising a ring nitrogen atom and
optionally one or more further heteroatoms independently selected
from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring
being optionally substituted by one or more substituents
independently selected from halogen, cyano, S(O).sub.qR.sup.15,
OR.sup.15, CO.sub.2R.sup.15, COR.sup.15, OC(O)R.sup.15,
SO.sub.2NR.sup.15R.sup.16, CONR.sup.15R.sup.16, NR.sup.15R.sup.16,
NR.sup.15SO.sub.2R.sup.17, NR.sup.15COR.sup.16,
NR.sup.15CO.sub.2R.sup.16, heteroaryl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl and C.sub.1-C.sub.6 alkyl, the latter
two groups being optionally substituted by one or more groups
independently selected from cyano, S(O).sub.qR.sup.18, OR.sup.18,
CO.sub.2R.sup.18, SO.sub.2NR.sup.18R.sup.19, CONR.sup.18R.sup.19 or
NR.sup.18R.sup.19; [0021] R.sup.9 represents halogen, cyano,
CO.sub.2R.sup.20, S(O).sub.qR.sup.20, OR.sup.20,
SO.sub.2NR.sup.20R.sup.22, CONR.sup.20R.sup.22,
NR.sup.20SO.sub.2R.sup.21, NR.sup.20CO.sub.2R.sup.21,
NR.sup.20COR.sup.22 or a 3- to 8-membered saturated heterocyclic
ring comprising a ring group NR.sup.10c; [0022] R.sup.10,
R.sup.10a, R.sup.10b and R.sup.10c independently represent
hydrogen, CO.sub.2R.sup.23, S(O).sub.qR.sup.23, COR.sup.24, or a
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or C.sub.3-C.sub.8 cycloalkyl group, each of which may be
optionally substituted by one or more substituents independently
selected from halogen, cyano, OR.sup.25 or NR.sup.25R.sup.26;
[0023] R.sup.6, R.sup.11, R.sup.12, R.sup.13, R.sup.15, R.sup.16,
R.sup.18, R.sup.19, R.sup.20, R.sup.22, R.sup.24, R.sup.25 and
R.sup.26 each independently represent hydrogen, C.sub.1-C.sub.6
alkyl or C.sub.3-C.sub.6 cycloalkyl; [0024] R.sup.14, R.sup.17,
R.sup.21 and R.sup.23 each independently represent C.sub.1-C.sub.6
alkyl or C.sub.3-C.sub.6 cycloalkyl; [0025] m, n, p and q each
independently represent an integer 0, 1 or 2; and [0026] A
represents a monocyclic or bicyclic C.sub.6-C.sub.10 aryl or a
monocyclic or bicyclic C.sub.5-C.sub.12 heteroaryl group containing
1-3 heteroatoms; or a pharmaceutically acceptable salt thereof.
[0027] In the context of the present specification, unless
otherwise stated, an alkyl substituent group or an alkyl moiety in
a substituent group may be linear or branched. They may for example
contain from 1 to 6 carbon atoms. Examples of C.sub.1-C.sub.6 alkyl
groups/moieties include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Similarly, an
alkylene group/moiety may be linear or branched. Examples of
C.sub.1-C.sub.6 alkylene groups/moieties include methylene,
ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene,
1-methylethylene, 2-methylethylene, 1,2-dimethylethylene,
1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and
1-, 2- or 3-ethylpropylene. An alkenyl or alkynyl group is an
unsaturated linear or branched group, containing for example from 2
to 6 carbon atoms. It should be appreciated that, in formula (I),
if more than one substituent contains a group or moiety S(O).sub.p
or S(O).sub.q or if a substituent contains two or more S(O).sub.p
or S(O).sub.q, then each "p" or each "q" independently represents
an integer 0, 1 or 2. For example, if R.sup.7 represents a
C.sub.3-C.sub.6 cycloalkyl group substituted by two groups
S(O).sub.qR.sup.11, then each "q" may be the same or different. In
the same way, each group "R.sup.11", where there is more than one
such group, may be the same or different.
[0028] Cycloalkyl or carbocycle groups are rings containing, for
example, from 3 to 8 carbon atoms and are saturated.
[0029] Heterocyclic groups are rings which may be saturated,
partially unsaturated or unsaturated, and contain from 3 to 20
atoms, at least one and suitably from 1 to 4 atoms are heteroatoms
selected from oxygen, sulphur and nitrogen. Rings may be
monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring
system(s). Monocyclic heterocyclic rings contain from about 3 to 12
ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S,
and suitably from 3 to 7 member atoms, in the ring. Bicyclic
heterocycles contain from 7 to 17 member atoms, suitably 7 to 12
member atoms, in the ring. Bicyclic heterocycles contain from about
7 to about 17 ring atoms, suitably from 7 to 12 ring atoms.
Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring
systems.
[0030] Examples of heterocyclic groups which are saturated or
partially saturated include cyclic ethers (oxiranes) such as
ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic
ethers. Heterocycles containing nitrogen include, for example,
azetidine, pyrrolidine, piperidine, piperazine, tetrahydrotriazine,
tetrahydropyrazole, and the like. Typical sulfur containing
heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol-2-yl,
and hexahydrothiepin-4-yl. Other heterocycles include
dihydro-oxathiol-4-yl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,
tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,
tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,
tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,
octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For
heterocycles containing sulfur, the oxidized sulfur heterocycles
containing SO or SO.sub.2 groups are also included. Examples
include the sulfoxide and sulfone forms of tetrahydrothiophene. A
suitable value for a heterocyclyl group which bears 1 or 2 oxo or
thioxo substituents is, for example, 2-oxopyrrolidinyl,
2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl,
2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or
2,6-dioxopiperidinyl.
[0031] Heterocyclic groups which are aromatic in nature are
referred to as "heteroaryl" groups. These groups are aromatic
mono-, bi-, or polycyclic heterocyclic ring incorporating one or
more (for example 1-4) heteroatoms selected from N, O, and S. The
term heteroaryl includes both monovalent species and divalent
species. Examples of heteroaryl groups include furyl, pyrrolyl,
thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl,
benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl,
benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl,
benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,
cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl,
benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl,
2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl,
1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl,
pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl,
imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also covers ring
systems wherein at least one ring is an aromatic ring containing 1
or more heteroatoms selected from O, S and N and one or more of the
other rings is a non-aromatic, saturated or partially unsaturated
ring optionally containing one or more heteroatoms selected from O,
S and N, for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl,
1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.
[0032] A preferred heteroaryl group is a 5-7 member aromatic ring
or 6,6- or 6,5-fused bicyclic ring containing one or more ring
heteroatoms selected from N, S, O. Examples include pyridine,
pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan,
isoxazole, pyrrole, isothiazole and azulene, naphthyl, indene,
quinoline, isoquinoline, indole, indolizine, benzo[b]furan,
benzo[b]thiophene, 1H-indazole, benzimidazole, benzthiazole,
benzoxazole, purine, 4H-quinolizine, cinnoline, phthalazine,
quinazoline, quinoxaline, 1,8-naphthyridine, pteridine and
quinolone.
[0033] Preferably R.sup.1 represents a straight chain
C.sub.1-6alkyl group optionally substituted by C.sub.1-3alkoxy, for
example, methyl, ethyl, n-propyl, n-butyl, methoxymethyl or
methoxyethyl. In a particular embodiment R.sup.1 is methyl.
[0034] In a particular embodiment. Z.sup.1 is a C.sub.2-6alkylene,
in particular a straight chain C.sub.2-6alkylene group, for example
a straight chain C.sub.2-4alkylene group. A particular example of
Z.sup.1 is n-propylene.
[0035] In a particular embodiment, X.sup.1 represents NR.sup.5,
>N--COR.sup.5, NR.sup.5CO, NR.sup.5SO.sub.2 or
>N--SO.sub.2R.sup.5. (For the avoidance of doubt, within the
definition of X.sup.1, the first atom appearing is linked to the
Z.sup.1 group. Thus, when X.sup.1 is SO.sub.2NR.sup.5, the sulphur
atom is linked to the Z.sup.1 group and the nitrogen atom is linked
to the Y.sup.1 group.)
[0036] In another embodiment, X.sup.1 represents NR.sup.5 or
>N--COR.sup.5.
[0037] Where R.sup.6 is present in any group X.sup.1, it is
suitably selected from hydrogen or C.sub.1-6 alkyl such as
methyl.
[0038] A particular example of X.sup.1 is a group NR.sup.5.
[0039] Another particular example of an X.sup.1 group is
>N--COR.sup.5.
[0040] Particular examples of R.sup.5 groups include hydrogen or a
C.sub.1-6alkyl optionally substituted by one or more substituents
independently selected from NR.sup.7R.sup.8 or R.sup.9, where
R.sup.7, R.sup.8 and R.sup.9 are as defined above.
[0041] For instance, R.sup.5 represents a C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.4 alkyl optionally substituted by one or more
substituents independently selected from NR.sup.7R.sup.8 or
R.sup.9, where R.sup.7, R.sup.8 and R.sup.9 are as defined
above.
[0042] In particular, R.sup.5 is a C.sub.1-C.sub.6 alkyl,
particularly C.sub.1-C.sub.3 alkyl such as methyl, ethyl or
n-propyl, optionally substituted by one or more substituents
independently selected from NR.sup.7R.sup.8 where R.sup.7 and
R.sup.8 are as defined above.
[0043] In yet a further embodiment, R.sup.5 is a C.sub.1-C.sub.6
alkylene which may be linked to a carbon atom within a
C.sub.2-C.sub.6 alkylene group Z.sup.1 so as to form a saturated
4-7 membered nitrogen containing ring. In particular, R.sup.5 is
linked to a carbon atom in the Z.sup.1 chain so as to form for
example, where X.sup.1 is a group NR.sup.5, a piperidine ring.
[0044] In a particular embodiment, Y.sup.1 represents
C.sub.1-C.sub.6 alkylene, such as a CH.sub.2 group.
[0045] In a further embodiment, where A is a heteroaryl group, it
is suitably a monocyclic ring containing six atoms, one or two of
which are nitrogen. Thus particular examples of heteroaryl groups A
include pyridyl and pyrimidinyl, suitably pyridyl.
[0046] A particular example of ring A is phenyl.
[0047] Where present, R.sup.2 is suitably halogen such as fluoro or
chloro, cyano, hydroxy, thiol, C.sub.1-C.sub.3 alkyl such as
methyl, C.sub.1-C.sub.3 hydroxyalkyl such as hydroxymethyl,
C.sub.1-C.sub.3 haloalkyl such as trifluoromethyl, C.sub.1-C.sub.3
alkoxy such as methoxy or ethoxy, C.sub.1-C.sub.3 haloalkoxy such
as trifluoromethoxy, C.sub.1-3alkylthio such as methylthio,
C.sub.1-3alkylsulfonyl such as methylsulfonyl or
C.sub.1-3alkylsulfinyl such as methylsulfinyl.
[0048] Preferably however, n is 0.
[0049] In a particular embodiment, R.sup.3 represents a
C.sub.1-6alkyl group optionally substituted by a C.sub.1-4alkoxy
group. Examples of alkyl groups include methyl, ethyl, iso-propyl,
n-propyl, and n-butyl. A particular example of R.sup.3 is n-butyl.
Particular examples of an alkoxy substituted alkyl group R.sup.3
are ethoxymethyl and methoxyethyl.
[0050] Where present, each R.sup.a suitably independently
represents halogen such as chloro or fluoro, cyano, hydroxy, thiol,
C.sub.1-C.sub.3 alkyl such as methyl, C.sub.1-C.sub.3 hydroxyalkyl
such as hydroxymethyl, C.sub.1-C.sub.3 haloalkyl such as
trifluoromethyl, C.sub.1-C.sub.3 alkoxy such as methoxy or ethoxy,
C.sub.1-C.sub.3 haloalkoxy such as trifluoromethoxy,
C.sub.1-3alkylthio such as methylthio, C.sub.1-3alkylsulfonyl such
as methylsulfonyl or C.sub.1-3alkylsulfinyl such as
methylsulfinyl.
[0051] Suitably however, m is 0.
[0052] R.sup.7 and R.sup.8 each independently represent hydrogen, a
3- to 8- or 5- to 6-membered saturated heterocyclic ring comprising
a ring group O, S(O).sub.p or NR.sup.10a, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.6 or
C.sub.5-C.sub.6 cycloalkyl, the latter two groups being optionally
substituted by one or more (e.g. one, two, three or four) groups
independently selected from halogen (e.g. fluorine, chlorine,
bromine or iodine), cyano, S(O).sub.qR.sup.11, OR.sup.12
CO.sub.2R.sup.12, OC(O)R.sup.12, SO.sub.2NR.sup.12R.sup.13,
CONR.sup.12R.sup.13, NR.sup.12R.sup.13, NR.sup.12SO.sub.2R.sup.14,
NR.sup.12COR.sup.13, or a 3- to 8- or 5- to 6-membered saturated
heterocyclic ring comprising a ring group O, S(O).sub.p or
NR.sup.10b, or R.sup.7 and R.sup.8 together with the nitrogen atom
to which they are attached form a 3- to 8-membered saturated
heterocyclic ring comprising a ring nitrogen atom and optionally
one or more (e.g. one, two or three) further heteroatoms
independently selected from nitrogen, oxygen, sulphur and sulphonyl
(such as piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl),
the heterocyclic ring being optionally substituted by one or more
(e.g. one, two, three or four) substituents independently selected
from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano,
S(O).sub.qR.sup.15, OR.sup.15, CO.sub.2R.sup.15, COR.sup.15,
OC(O)R.sup.15, SO.sub.2NR.sup.15R.sup.16, CONR.sup.15R.sup.16,
NR.sup.15R.sup.16, NR.sup.15SO.sub.2R.sup.17, NR.sup.15COR.sup.16,
NR.sup.15CO.sub.2R.sup.16, heteroaryl (particularly pyrimidinyl),
C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or C.sub.1-C.sub.2 haloalkyl
(e.g. trifluoromethyl, trifluoromethoxy or pentafluoroethyl),
C.sub.3-C.sub.8 or C.sub.5-C.sub.6 cycloalkyl and C.sub.1-C.sub.6,
or C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkyl, the latter two groups
being optionally substituted by one or more (e.g. one, two, three
or four) groups independently selected from cyano,
S(O).sub.qR.sup.18, OR.sup.18, CO.sub.2R.sup.18,
SO.sub.2NR.sup.18R.sup.19, CONR.sup.18R.sup.19 or
NR.sup.18R.sup.19.
[0053] In one embodiment, R.sup.7 and R.sup.8 each independently
represent hydrogen, a 5- to 6-membered saturated heterocyclic ring
comprising a ring group O or NR.sup.10a, or a C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkyl group optionally
substituted by one or more (e.g. one, two, three or four) groups
independently selected from halogen (e.g. fluorine, chlorine,
bromine or iodine), cyano, S(O).sub.qR.sup.11, OR.sup.12,
CO.sub.2R.sup.12, OC(O)R.sup.12, SO.sub.2NR.sup.12R.sup.13,
CONR.sup.12R.sup.13, NR.sup.12R.sup.13, NR.sup.12SO.sub.2R.sup.14,
NR.sup.12COR.sup.13, or a 3- to 8- or 5- to 6-membered saturated
heterocyclic ring comprising a ring group O, S(O).sub.p or
NR.sup.10b.
[0054] In another embodiment, R.sup.7 and R.sup.8 each
independently represent hydrogen, a 5- to 6-membered saturated
heterocyclic ring comprising a ring group O or N.sup.10a, or a
C.sub.1-C.sub.4 alkyl group optionally substituted by one or two
groups independently selected from halogen (e.g. fluorine,
chlorine, bromine or iodine), cyano, S(O).sub.qR.sup.11, OR.sup.12,
CO.sub.2R.sup.12, OC(O)R.sup.12, SO.sub.2NR.sup.12R.sup.13,
CONR.sup.12R.sup.13, NR.sup.12R.sup.13, NR.sup.12SO.sub.2R.sup.14,
NR.sup.12COR.sup.13, or a 3- to 8- or 5- to 6-membered saturated
heterocyclic ring comprising a ring group O, S(O).sub.p or
NR.sup.10b.
[0055] In a further embodiment, R.sup.7 and R.sup.8 each
independently represent a 5- to 6-membered saturated heterocyclic
ring comprising a ring group O or NR.sup.10a (such as
tetrahydropyranyl or N-acetylpiperidinyl) or a C.sub.1-C.sub.4
alkyl group optionally substituted by OR.sup.12.
[0056] In an alternative embodiment, R.sup.7 and R.sup.8 together
with the nitrogen atom to which they are attached form a 3- to
8-membered, particularly 4- to 7- or 5- to 6-membered, saturated
heterocyclic ring comprising a ring nitrogen atom and optionally
one or more further heteroatoms independently selected from
nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring
being optionally substituted by one or more (e.g. one, two, three
or four) substituents independently selected from halogen (e.g.
fluorine, chlorine, bromine or iodine), cyano, S(O).sub.qR.sup.15,
OR.sup.15, CO.sub.2R.sup.15, COR.sup.15, CONR.sup.15R.sup.16,
NR.sup.15CO.sub.2R.sup.16, heteroaryl and C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkyl, the alkyl group being
optionally substituted by one or more (e.g. one, two, three or
four) groups independently selected from cyano, S(O).sub.qR.sup.18,
OR.sup.18, CO.sub.2R.sup.18, SO.sub.2NR.sup.18R.sup.19,
CONR.sup.18R.sup.19 or NR.sup.18R.sup.19.
[0057] According to a further embodiment, R.sup.7 and R.sup.8
together with the nitrogen atom to which they are attached form a
4- to 7-membered saturated heterocyclic ring comprising a ring
nitrogen atom and optionally one further heteroatom selected from
nitrogen and oxygen, the heterocyclic ring being optionally
substituted by one or two substituents independently selected from
S(O).sub.qR.sup.15, OR.sup.15, CO.sub.2R.sup.15, COR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15CO.sub.2R.sup.16, pyrimidinyl and
C.sub.1-C.sub.2 alkyl, the alkyl group being optionally substituted
by one or two groups independently selected from OR.sup.18 and
CO.sub.2R.sup.18.
[0058] Examples of compounds of the invention include: [0059]
Methyl
2-(4-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamino)meth-
yl)phenyl)acetate, [0060] Methyl
2-(3-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamino)meth-
yl)phenyl)acetate, [0061] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, [0062] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, [0063] Methyl
2-(3-((4-((4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)meth-
yl)piperidin-1-yl)methyl)phenyl)acetate di-trifluoroacetate salt,
[0064] Methyl
[4-({[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl][2--
(dimethylamino)ethyl]amino}methyl)phenyl]acetate, [0065] Methyl
2-(3-((N-(3-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)prop-
yl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate, [0066] Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(1-methy-
lpiperidin-4-yl)amino)methyl)phenyl)acetate, [0067] Methyl
2-(4-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(1-methy-
lpiperidin-4-yl)amino)methyl)phenyl)acetate, [0068] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate, [0069] Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-(dime-
thylamino)propyl)amino)methyl)phenyl)acetate, [0070] Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-morph-
olinopropyl)amino)methyl)phenyl)acetate, [0071] Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-(ethy-
l(methyl)amino)propyl)amino)methyl)phenyl)acetate, [0072] Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-(4-me-
thylpiperazin-1-yl)propyl)amino)methyl)phenyl)acetate, [0073]
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(me-
thylsulfonyl)acetamido)methyl)phenyl)acetate, [0074] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)acetam-
ido)methyl)phenyl)acetate, [0075] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-mor-
pholinoacetamido)methyl)phenyl)acetate, [0076] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-((2-
-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate, [0077]
Methyl
2-(4-((2-(4-acetylpiperazin-1-yl)-N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]-
quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate, [0078]
(R)-Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(3--
hydroxypyaolidin-1-yl)acetamido)methyl)phenyl)acetate, [0079]
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(pyrimidin-2-yl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0080] Ethyl
4-(2-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(4--
(2-methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)piperazine-1-carboxylate,
[0081] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(ethylsulfonyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0082] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate, [0083] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(tert-butoxycarbonylamino)piperidin-1-yl)acetamido)methyl)phenyl)acetate,
[0084] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(tert-butoxycarbonylmethyl)amino)piperidin-1-yl)acetamido)methyl)phenyl)ac-
etate, [0085] Ethyl
2-(1-(2-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(4-(2--
methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)piperidin-4-yl)acetate,
[0086] Methyl
1-(2-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(4-
-(2-methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)piperidine-4-carboxylate,
[0087] Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate, [0088]
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate, [0089]
Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate, [0090]
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-((2-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate,
[0091] Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-3-(piperidin-1-yl)propanamido)methyl)phenyl)acetate, [0092]
Methyl
2-(4-(((3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)prop-
yl)(3-morpholinopropyl)amino)methyl)phenyl)acetate, [0093]
(S)-Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(2-(methoxymethyl)pyrrolidin-1-yl)acetamido)methyl)phenyl)acetate,
[0094] (R)-Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(2-(methoxymethyl)pyrrolidin-1-yl)acetamido)methyl)phenyl)acetate,
[0095] Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(pyrrolidin-1-yl)acetamido)methyl)phenyl)acetate, [0096]
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-((2-hydroxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate,
[0097] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-((2-
-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate, [0098]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(bu-
tyl(methyl)amino)acetamido)methyl)phenyl)acetate, [0099] Methyl
3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(dipro-
pylamino)acetamido)methyl)phenyl)acetate, [0100] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(bi-
s(2-hydroxyethyl)amino)acetamido)methyl)phenyl)acetate, [0101]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(me-
thyl(tetrahydro-2H-pyran-4-yl)amino)acetamido)methyl)phenyl)acetate,
[0102] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(az-
etidin-1-yl)acetamido)methyl)phenyl)acetate, [0103] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(3--
hydroxyazetidin-1-yl)acetamido)methyl)phenyl)acetate, [0104] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(py-
rrolidin-1-yl)acetamido)methyl)phenyl)acetate, [0105] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(3--
hydroxypyrrolidin-1-yl)acetamido)methyl)phenyl)acetate, [0106]
(R)-Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(3--
hydroxypyrrolidin-1-yl)acetamido)methyl)phenyl)acetate, [0107]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(pi-
peridin-1-yl)acetamido)methyl)phenyl)acetate, [0108] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
hydroxypiperidin-1-yl)acetamido)methyl)phenyl)acetate, [0109]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
methoxypiperidin-1-yl)acetamido)methyl)phenyl)acetate, [0110]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(dimethylcarbamoyl)piperidin-1-yl)acetamido)methyl)phenyl)acetate,
[0111] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-morpholinoacetamido)methyl)phenyl)acetate, [0112] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-((2-
S,6R)-2,6-dimethylmorpholino)acetamido)methyl)phenyl)acetate,
[0113] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate, [0114]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(2-hydroxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0115] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0116] Methyl
2-(3-((2-(4-acetylpiperazin-1-yl)-N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]-
quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate, [0117] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(methylsulfonyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0118] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-(azepan-1-yl)acetamido)methyl)phenyl)acetate, [0119] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(1,-
4-oxazepan-4-yl)acetamido)methyl)phenyl)acetate, [0120] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
methyl-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate, [0121]
Methyl
2-(3-((2-(4-acetyl-1,4-diazepan-1-yl)-N-(3-(4-amino-2-butyl-1H-imidazo[4,-
5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate, [0122]
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(ethylcarbamoyl)-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate,
[0123] Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-(4-(methylsulfonyl)-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate,
[0124] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(4--
(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0125] Methyl
2-(4-((2-(4-acetyl-1,4-diazepan-1-yl)-N-(3-(4-amino-2-butyl-1H-imi-
dazo[4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate,
[0126] Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl-
)-2-(4-(methylsulfonyl)-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate,
[0127] Methyl
2-(4-((2-((1-acetylpiperidin-4-yl)(methyl)amino)-N-(3-(4-amino-2-butyl-1H-
-imidazo[4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate,
[0128] Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0129] Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin--
1-yl)propyl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)a-
cetate, [0130] Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)pr-
opyl)-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate,
[0131] Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin--
1-yl)propyl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)a-
cetate. and pharmaceutically acceptable salts of any one
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0132] FIG. 1A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, monosaccharin
salt.
[0133] FIG. 1B is a table that corresponds to the XRPD trace in
FIG. 1A.
[0134] FIG. 2A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, disaccharin salt.
[0135] FIG. 2B is a table that corresponds to the XRPD trace in
FIG. 2A.
[0136] FIG. 3A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate,
di-1-hydroxy-2-naphthoic acid salt--polymorph A.
[0137] FIG. 3B is a table that corresponds to the XRPD trace in
FIG. 3A.
[0138] FIG. 3C shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate,
di-1-hydroxy-2-naphthoic acid salt--polymorph B.
[0139] FIG. 3D is a table that corresponds to the XRPD trace in
FIG. 3C.
[0140] FIG. 4A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, dibenzenesulfonic acid
salt.
[0141] FIG. 4B is a table that corresponds to the XRPD trace in
FIG. 4A.
[0142] FIG. 5A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, mandelic acid
salt.
[0143] FIG. 5B is a table that corresponds to the XRPD trace in
FIG. 5A.
[0144] FIG. 6A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, fumaric acid salt.
[0145] FIG. 6B is a table that corresponds to the XRPD trace in
FIG. 6A.
[0146] FIG. 7A shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, dimethane sulfonic
acid salt--polymorph A.
[0147] FIG. 7B is a table that corresponds to the XRPD trace in
FIG. 7A.
[0148] FIG. 7C shows an XRPD trace for methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-(di-
methylamino)acetamido)methyl)phenyl)acetate, dimethane sulfonic
acid salt--polymorph B.
[0149] FIG. 7D is a table that corresponds to the XRPD trace in
FIG. 7C.
[0150] The present invention further provides a process for the
preparation of a compound of formula (I) or a pharmaceutically
acceptable salt thereof as defined above which comprises
either:
a) where X.sup.1 is a group NR.sup.5, reacting a compound of
formula (II)
##STR00003##
wherein Z.sup.1, R.sup.3, R.sup.a and m are as defined in formula
(I) and L.sup.1 is a leaving group, with a compound of formula
(III)
##STR00004##
where Y.sup.1, R.sup.1, R.sup.2, R.sup.5, A and n are as defined in
formula (I); or (b) where X.sup.1 is a group NR.sup.5 and Y.sup.1
is C.sub.1-C.sub.6 alkylene, reacting a compound of formula
(IV)
##STR00005##
where R.sup.a, R.sup.3, R.sup.5, Z.sup.1 and m are as defined in
formula (I), with a compound of formula (V)
##STR00006##
where R.sup.1, R.sup.2, A and n are as defined in formula (I) and
Y.sup.2 is a bond or a C.sub.1-5alkylene group in the presence of a
suitable reducing agent (e.g. sodium triacetoxyborohydride); or (c)
where X.sup.1 is a group NR.sup.5, O or S, reacting a compound of
formula (VI)
##STR00007##
wherein X.sup.3 is a group NR.sup.5, O or S, and Z.sup.1, R.sup.3,
R.sup.5, R.sup.a and m are as defined in formula (I), with a
compound of formula (VII)
##STR00008##
where Y.sup.1, R.sup.1, R.sup.2, A and n are as defined in formula
(I) and L.sup.2 is a leaving group; or (d) where X.sup.1 is a group
S(O).sub.p where p is 1 or 2, oxidation of a compound of formula
(I) where X.sup.1 is S; or (e) where X.sup.1 is a group NR.sup.5CO,
NR.sup.5SO.sub.2, NR.sup.5CONR.sup.6 or NR.sup.6CONR.sup.5,
reacting a compound of formula (IVA)
##STR00009##
where R.sup.a, R.sup.3, Z.sup.1 and m are as defined in relation to
formula (I) and R.sup.5a is a group R.sup.5 or R.sup.6 as defined
in relation to formula (I), with a compound of formula (VIII)
##STR00010##
where L.sup.3 is a leaving group such as halo, X.sup.2 is a CO,
SO.sub.2, CONR.sup.6 or CONR.sup.5 group respectively, and Y.sup.1,
R.sup.1, R.sup.2, A and n are as defined in relation to formula
(I); or (f) where X.sup.1 is CONR.sup.5 or SO.sub.2NR.sup.5,
reacting a compound of formula (IX)
##STR00011##
where X.sup.4 is an activated acid such as an acid chloride or
SO.sub.2Cl, R.sup.a, R.sup.3, Z.sup.1 and m are as defined in
formula (I), with a compound of formula (III) as defined above; or
(h) where X.sup.1 is >N--COR.sup.5 or >N--SO.sub.2R.sup.5,
reacting a compound of formula (I) where X.sup.1 is NR.sup.5 where
R.sup.5 is hydrogen with a compound of formula (X) or (XI)
respectively
L.sup.4-COR.sup.5 (X)
L.sup.4-SO.sub.2R.sup.5 (XI)
where L.sup.4 is a leaving group such as halo for instance chloro,
and R.sup.5 is defined in relation to formula (I); and thereafter,
if desired or necessary, carrying out one or more of the following
steps: [0151] converting the compound obtained to a further
compound of formula (I) [0152] removal of any protecting groups
[0153] forming a pharmaceutically acceptable salt of the
compound.
[0154] In reaction (a) and (c) above, suitable leaving groups
L.sup.1 and L.sup.2 are halogen atoms such as bromine, or chlorine,
as well as an activated alcohol such as mesylate or tosylate. The
reactions may conveniently be carried out in an organic solvent
such as acetonitrile, 1-methyl-2-pyrrolidinone or
N,N-dimethylformamide at a temperature, for example, in the range
from 0 to 150.degree. C. The reaction may be suitably effected by
the presence of a base (e.g. sodium carbonate or potassium
carbonate).
[0155] In process (b), the reaction may conveniently be carried out
in an organic solvent such as 1-methyl-2-pyrrolidinone,
1,2-dichloroethane or tetrahydrofuran at a temperature, for
example, in the range from 0 to 100.degree. C.
[0156] Compounds of formula (II) may be prepared as illustrated in
the reaction scheme A:
##STR00012##
where R.sup.a, m, R.sup.3 and Z.sup.1 are as defined in relation to
formula (I) and P is a protecting group.
[0157] The compound of formula (B) is prepared by nitration of a
compound of formula (A). Suitable nitrating agents include nitric
acid. The reaction is suitably effected in an organic solvent such
as an organic acid such as propionic acid. The reaction may be
carried out at elevated temperature, for example from room
temperature to 150.degree. C.
[0158] Compounds of formula (C) may be prepared by reacting the
compound of formula (B) with a mixture of thionyl chloride and DMF
to give the aryl chloride which can then be displaced with an
aminoalkanol. The chlorination is suitably carried out in a solvent
such as dichloromethane, preferably at elevated temperature. The
displacement of the chloride with an aminoalkanol, is suitably
carried out in the presence of a base for example triethylamine or
Hunigs base and in an organic solvent such as dichloromethane, at a
temperature in the range from 0 to 40.degree. C.
[0159] Compounds of formula (D) are prepared by adding a suitable
protecting group to the hydroxy terminal group. This can be
effected using conventional chemistry as outlined for example in
`Protective Groups in Organic Synthesis` by Theodora Green
(publisher: John Wiley & Sons). A suitable protecting group P
for the hydroxy group is, for example, an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl, or a silyl group for example
tert-butyl(dimethyl)silyl. Compounds of formula (D) may also be
prepared by adding a protected aminoalkanol to a compound of
formula (B), using the same conditions as above.
[0160] The compound of formula (D) is then reduced to form a
compound of formula (E). Suitable reducing agents include iron
powder in a suitable solvent such as acetic acid or sodium
borohydride in the presence of a suitable catalyst such as a 15% of
nickel chloride in a suitable solvent such as methanol or
hydrogenation. Suitable hydrogenation conditions include the use of
hydrogen gas at elevated pressure, for example at 2-5 Bar in the
presence of a suitable catalyst such as a 1% platinum on carbon
catalyst. The reaction is suitably effected at room
temperature.
[0161] Compounds of formula (E) are then cyclised to form the
compound of formula (F). Suitable cyclisation conditions include
reaction with an acid chloride in the presence of a base such as
triethylamine in a suitable solvent such as N-methylpyrrolidinone
or an acid in the presence of a coupling reagent such as
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphat
purum (HATU) in the presence of a base such as triethylamine in a
suitable solvent such as N-methylpyrrolidine. Alternatively the
compound of formula (F) may be prepared by cyclisation reaction
with an orthoester in a suitable solvent such as N-methyl
pyrrolidinonein the presence of a suitable catalyst such as 10 mol
% of toluensulphuric acid. The reaction is suitably effected at
elevated temperatures, for example from 30-150.degree. C.
[0162] Compounds of formula (F) may be oxidised to compounds of
formula (G) by reaction with an oxidising agent such as
meta-chloroperoxybenzoic acid or hydrogen peroxide. The reaction is
suitably effected in an organic solvent such as dichloromethane or
ethanol at reduced temperatures for example in the range of
-10.degree. C. to room temperature.
[0163] Subsequently, the compound of formula (G) is reacted with
p-toluenesulphonyl chloride and aqueous ammonia to convert it to
the compound of formula (H). The reaction is suitably effected in
an organic solvent such as dichloromethane. Temperatures in the
range from 0-40.degree. C. and conveniently at room temperature are
suitably employed.
[0164] Deprotection of the resultant compound of formula (H) yields
a compound of formula (J). The deprotection conditions for the
above protecting groups necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or alkoxycarbonyl group or an aroyl group may be removed
for example, by hydrolysis with a suitable base such as an alkali
metal hydroxide, for example lithium or sodium hydroxide.
Alternatively a benzyl group may be removed, for example, by
hydrogenation over a catalyst such as palladium-on-carbon.
[0165] The product of formula (J) is then converted to a compound
of formula (II) by formation of a suitable leaving group such as
halo, for instance chloro or bromo, or an activated alcohol such as
a mesylate or tosylate. For example, the chloride may be formed by
reacting the compound of formula (J) with thionyl chloride.
Preferably in a solvent such as dichloromethane at a temperature
between 20-40.degree. C.
[0166] Compounds of formulae (IV) and (IVA) may be prepared by an
analogous route as illustrated in Scheme B.
##STR00013##
where R.sup.a, m, R.sup.3 and Z.sup.1 are as defined in relation to
formula (I), R.sup.5a is as defined in relation to formula (IVA)
and P.sup.1 is an amino protecting group.
[0167] Compounds of formula (K) or (L) may be prepared by reacting
the compound of formula (B) with a mixture of thionyl chloride and
DMF to give the aryl chloride which can then be displaced with a
di-amino alkane, or a protected form thereof. The chlorination is
suitably carried out in a solvent such as dichloromethane,
preferably at elevated temperature. The displacement of the
chloride with a di-amino alkane, or a protected form thereof, is
suitably carried out in the presence of a base for example
triethylamine or Hunigs base and in an organic solvent such as
dichloromethane, at a temperature in the range from 0 to 40.degree.
C.
[0168] Where a diaminoalkane is used, a compound of formula (K) is
prepared which may be subsequently protected to form a compound of
formula (L) using conventional methods.
[0169] A suitable protecting group P.sup.1 is for example, a group
such as an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl. A suitable alternative
protecting group for a primary amino group is, for example, a
phthaloyl group.
[0170] Reduction of the product of formula (L) using for example
analogous conditions to those described above for the reduction of
the compound of formula (D), will yield a compound of formula (M).
This in turn may be cyclised to a compound of formula (N) using
conditions analogous to those described above for the cyclisation
of the compound of formula (E), oxidised to a compound of formula
(Q) using conditions analogous to those described above for the
oxidation of the compound of formula (F), and the product reacted
with p-toluenesulphonyl chloride and aqueous ammonia to form the
compound of formula (S) using for example conditions analogous to
those described above for the preparation of the compound of
formula (H).
[0171] Deprotection of the resultant compound of formula (S) yields
a compound of formula (IV). The deprotection conditions for the
above protecting groups necessarily vary with the choice of
protecting group. Thus, for example, an alkoxycarbonyl group may be
removed for example, by hydrolysis with a suitable base such as an
alkali metal hydroxide, for example lithium or sodium hydroxide.
Alternatively an alkoxycarbonyl group such as a t-butoxycarbonyl
group may be removed, for example, by treatment with a suitable
acid as hydrochloric, sulfuric or phosphoric acid or
trifluoroacetic acid and an arylmethoxycarbonyl group such as a
benzyloxycarbonyl group may be removed, for example, by
hydrogenation over a catalyst such as palladium-on-carbon, or by
treatment with a Lewis acid for example boron
tris(trifluoroacetate). A phthaloyl protecting group which be
removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0172] Suitably in Scheme B, R.sup.5 is hydrogen, which may be
converted to a different R.sup.5 group later, for example once the
compound of formula (IV) has been converted to a compound of
formula (I).
[0173] Compounds of formula (VI) where X.sup.1 is NR.sup.5 may be
prepared by reacting compounds of formula (II) with compounds of
formula (XII)
R.sup.5NH.sub.2 (XII)
[0174] Coupling conditions will be similar to those described above
for the reactions (a) and (c).
[0175] Compounds of formula (I) may be coverted to other compounds
of formula (I) using conventional methods. For example, in process
(h) above, compounds where R.sup.5 is hydrogen may be reacted with
compounds of formula (X) or (XI);
L.sup.4-COR.sup.5 or (X)
L.sup.4-SO.sub.2R.sup.5 (XI)
where L.sup.4 is a leaving group such as halo for instance chloro,
and R.sup.5 is defined in relation to formula (I). The reaction is
suitably carried out in an organic solvent such as acetonitrile,
dimethylformamide and/or dichloromethane optionally in the presence
of a base such as triethylamine. Temperatures in the range from 0
to 150.degree. C. are suitably employed.
[0176] Similarly, oxidation of compounds of formula (I) during
process (d) above can be carried out under conventional conditions,
for example by reaction with an oxidising agent such as
meta-chloroperoxybenzoic acid or hydrogen peroxide. The reaction is
suitably effected in an organic solvent such as dichloromethane or
ethanol at temperatures for example in the range of 0-40.degree.
C.
[0177] Compounds of formula (IX) above where X.sup.4 is an
activated acid such as an acid chloride are suitably prepared by a
reaction as set out in Scheme C.
##STR00014##
[0178] Conditions used for the reactions shown in Scheme C are
generally similar to those used in analogous steps in Scheme B. A
compound of formula Y may be converted to a compound of formula Z
with a base such as lithium or sodium hydroxide, in a suitable
solvent such as tetrahydrofuran or methanol and water.
Alternatively the ester may be hydrolysed under acidic conditions
such as aqueous HCl, preferably at elevated temperature. A compound
of formula (I) may be prepared from a compound of formula (Z) by
activation of the acid to an acyl halide, such as chloride with a
reagent such as thionyl chloride then treated with a compound of
formula (III). The formation of the acid chloride may conveniently
be carried out neat or in an organic solvent such as
dichloromethane at a temperature, for example, in the range from 0
to 80.degree. C. The activated acid is then treated with a compound
of formula (III), the reaction may conveniently be carried out in
an organic solvent such as tetrahydrofuran or dimethylformamide,
with a base such as triethylamine at a temperature, for example, in
the range from 0 to 80.degree. C. Alternatively the acid may be
activated with a coupling agent such as
1,3-dicyclohexylcarbodiimide or
benzotriazol-1-yloxytripyrrolidinophosphonium
hexafluorophosphate.
[0179] Compounds of formula (IX) above where X.sup.4 is SO.sub.2Cl
may be prepared by reacting a compound of formula (II) with sodium
sulphite, then treatment of the sulphonate with a chlorinating
reagent such as thionyl chloride or phosphorous pentachloride to
give the sulphonyl chloride. The suphonyl chloride may then be
reacted with a compound of formula (III) to give a compound of
formula (I). The reaction may conveniently be carried out in an
organic solvent such as tetrahydrofuran or dichloromethane, with a
base such as triethylamine at a temperature, for example, in the
range from 0 to 80.degree. C.
[0180] A compound of formula (I) in which X.sup.1 is NR.sup.5 and
R.sup.5 is hydrogen may be converted to a corresponding compound of
formula (I) in which R.sup.5 is --COCH.sub.2NR.sup.7R.sup.8 by
reaction with chloroacetyl chloride followed by an amine of formula
R.sup.7R.sup.8NH where R.sup.7 and R.sup.8 are as defined above.
The first stage is suitably carried out in an organic solvent such
as dichloromethane or acetonitrile, with one equivalent of
chloroacetyl chloride. Temperatures in the range from 0.degree. C.
to 50.degree. C. are suitably employed. In the second stage the
reaction is suitably carried out in an organic solvent such as
dichloromethane or acetonitrile, with excess of an amine
R.sup.7R.sup.8NH. Temperatures in the range from 0.degree. C. to
100.degree. C. are suitably employed.
[0181] A compound of formula (I) in which X.sup.1 is NR.sup.5 and
R.sup.5 is hydrogen may also be converted to a corresponding
compound of formula (I) in which R.sup.5 is a C.sub.1-C.sub.6 alkyl
(e.g. propyl) group substituted by NR.sup.7R.sup.8 by reaction with
a compound of formula (XX), L.sup.10-R.sup.5, where L.sup.10 is a
leaving group such as halo for instance chloro and R.sup.5 is as
defined above. The reaction is suitably carried out in an organic
solvent such as dimethylformaldehyde or acetonitrile, with
preferably one equivalent of formula (XX) compound optionally in
the presence of a base such as triethylamine and a salt such as
sodium iodide or potassium iodide. Temperatures in the range from
0.degree. C. to 100.degree. C. are suitably employed.
[0182] A compound of formula (I) in which X.sup.1 is NR.sup.5 and
R.sup.5 is a C.sub.1-C.sub.6 alkyl (e.g. propyl) group substituted
by NR.sup.7R.sup.8 may also be prepared by reacting a compound of
formula (XIII)
##STR00015##
where L.sup.5 is a leaving group for example chloro or mesylate and
m R.sup.a, R.sup.1, n, R.sup.2, R.sup.3, A, Z.sup.1 and Y.sup.1 are
as defined above, with an amine of formula (XXI), R.sup.7R.sup.8NH,
where R.sup.7 and R.sup.8 are as defined above. The reaction may be
carried out using an excess of the amine R.sup.7R.sup.8NH in an
organic solvent such as DMF or dioxane at a temperature in the
range of, for example, 40.degree. C.-150.degree. C. Sodium iodide
may be used as an additive in the reaction.
[0183] A compound of formula (XIII) may be prepared from a
corresponding compound of formula (XIV)
##STR00016##
[0184] The alcohol may be converted into a leaving group using
conventional methods, for example, by reaction with thionyl
chloride in an appropriate solvent such as DCM at a temperature
from 20-100.degree. C.
[0185] A compound of formula (XIV) may be formed using the route in
scheme A and the chemistry above.
[0186] Compounds of formulae (III), (V), (VII), (VIII), A, (XII),
(XX) and (XXI) are known compounds or can be prepared from known
compounds by conventional methods.
[0187] It will be appreciated by those skilled in the art that in
the processes of the present invention certain functional groups
such as hydroxyl or amino groups in the reagents may need to be
protected by protecting groups. Thus, the preparation of the
compounds of formula (I) may involve, at an appropriate stage, the
removal of one or more protecting groups.
[0188] The protection and deprotection of functional groups is
described in `Protective Groups in Organic Chemistry`, edited by J.
W. F. McOmie, Plenum Press (1973) and `Protective Groups in Organic
Synthesis`, 3.sup.rd edition, T. W. Greene and P. G. M. Wuts,
Wiley-Interscience (1999).
[0189] The compounds of formula (I) above may be converted to a
pharmaceutically acceptable salt thereof, preferably an acid
addition salt such as a hydrochloride, hydrobromide,
trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate,
tartrate, lactate, citrate, pyruvate, succinate, oxalate,
methanesulphonate or p-toluenesulphonate. Preferred salts include
dimethane sulphonic acid, monosaccharin, disaccharin,
di-1-hydroxy-2-naphthoic acid (di-xinafoate), dibenzenesulphonic
acid (di-besylate), mandelic and fumaric acid salts.
[0190] Compounds of formula (I) are capable of existing in
stereoisomeric forms. It will be understood that the invention
encompasses the use of all geometric and optical isomers (including
atropisomers) of the compounds of formula (I) and mixtures thereof
including racemates. The use of tautomers and mixtures thereof also
form an aspect of the present invention. Enantiomerically pure
forms are particularly desired.
[0191] The compounds of formula (I) and their pharmaceutically
acceptable salts have activity as pharmaceuticals, in particular as
modulators of toll-like receptor (especially TLR7) activity, and
thus may be used in the treatment of:
1. respiratory tract: obstructive diseases of the airways
including: asthma, including bronchial, allergic, intrinsic,
extrinsic, exercise-induced, drug-induced (including aspirin and
NSAID-induced) and dust-induced asthma, both intermittent and
persistent and of all severities, and other causes of airway
hyper-responsiveness; chronic obstructive pulmonary disease (COPD);
bronchitis, including infectious and eosinophilic bronchitis;
emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's
lung and related diseases; hypersensitivity pneumonitis; lung
fibrosis, including cryptogenic fibrosing alveolitis, idiopathic
interstitial pneumonias, fibrosis complicating anti-neoplastic
therapy and chronic infection, including tuberculosis and
aspergillosis and other fungal infections; complications of lung
transplantation; vasculitic and thrombotic disorders of the lung
vasculature, and pulmonary hypertension; antitussive activity
including treatment of chronic cough associated with inflammatory
and secretory conditions of the airways, and iatrogenic cough;
acute and chronic rhinitis including rhinitis medicamentosa, and
vasomotor rhinitis; perennial and seasonal allergic rhinitis
including rhinitis nervosa (hay fever); nasal polyposis; acute
viral infection including the common cold, and infection due to
respiratory syncytial virus, influenza, coronavirus (including
SARS) and adenovirus; 2. skin: psoriasis, atopic dermatitis,
contact dermatitis or other eczematous dermatoses, and delayed-type
hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic
dermatitis, dermatitis herpetiformis, lichen planus, lichen
sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid
lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa,
urticaria, angioedema, vasculitides, toxic erythemas, cutaneous
eosinophilias, alopecia areata, male-pattern baldness, Sweet's
syndrome, Weber-Christian syndrome, erythema multiforme;
cellulitis, both infective and non-infective; panniculitis;
cutaneous lymphomas, non-melanoma skin cancer and other dysplastic
lesions; drug-induced disorders including fixed drug eruptions; 3.
eyes: blepharitis; conjunctivitis, including perennial and vernal
allergic conjunctivitis; iritis; anterior and posterior uveitis;
choroiditis; autoimmune, degenerative or inflammatory disorders
affecting the retina; ophthalmitis including sympathetic
ophthalmitis; sarcoidosis; infections including viral, fungal, and
bacterial; 4. genitourinary: nephritis including interstitial and
glomerulonephritis; nephrotic syndrome; cystitis including acute
and chronic (interstitial) cystitis and Hunner's ulcer; acute and
chronic urethritis, prostatitis, epididymitis, oophoritis and
salpingitis; vulvo-vaginitis; Peyronie's disease; erectile
dysfunction (both male and female); 5. allograft rejection: acute
and chronic following, for example, transplantation of kidney,
heart, liver, lung, bone marrow, skin or cornea or following blood
transfusion; or chronic graft versus host disease; 6. other
auto-immune and allergic disorders including rheumatoid arthritis,
irritable bowel syndrome, systemic lupus erythematosus, multiple
sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's
disease, diabetes mellitus, idiopathic thrombocytopaenic purpura,
eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid
syndrome and Sazary syndrome; 7. oncology: treatment of common
cancers including prostate, breast, lung, ovarian, pancreatic,
bowel and colon, stomach, skin and brain tumors and malignancies
affecting the bone marrow (including the leukaemias) and
lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's
lymphoma; including the prevention and treatment of metastatic
disease and tumour recurrences, and paraneoplastic syndromes; and,
8. infectious diseases: virus diseases such as genital warts,
common warts, plantar warts, hepatitis B, hepatitis C, herpes
simplex virus, molluscum contagiosum, variola, human
immunodeficiency virus (HIV), human papilloma virus (HPV),
cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus,
adenovirus, coronavirus, influenza, para-influenza; bacterial
diseases such as tuberculosis and mycobacterium avium, leprosy;
other infectious diseases, such as fungal diseases, chlamydia,
candida, aspergillus, cryptococcal meningitis, pneumocystis carnii,
cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome
infection and leishmaniasis.
[0192] The compounds of formula (I) and their pharmaceutically
acceptable salts have antedrug properties. An antedrug is defined
as an active synthetic derivative that is designed to undergo
biotransformations to a readily excretable less active form upon
entry into the systemic circulation, therefore minimizing systemic
side-effects. Thus, on administration, a compound of the invention
is rapidly degraded enzymatically to yield a degradation product
having a substantially reduced medical effect. A medical effect as
defined herein means a pharmacological activity of the compound of
the invention, including specifically interferon inducing activity
and/or suppression of IL-4/IL-5 production activity.
[0193] The medical effect of the degradation product is preferably
10 times, more preferably 100 times less than that of the compound
of the invention (i.e. parent compound).
[0194] The pharmacological activity can be measured using methods
known in the art, preferably using in vitro evaluation methods such
as commercially available ELISA kits or the biological assay
described in Example 7 of the present specification.
[0195] Thus, the present invention provides a compound of formula
(I) or a pharmaceutically-acceptable salt thereof as hereinbefore
defined for use in therapy.
[0196] In a further aspect, the present invention provides the use
of a compound of formula (I) or a pharmaceutically acceptable salt
thereof as hereinbefore defined in the manufacture of a medicament
for use in therapy.
[0197] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0198] Prophylaxis is expected to be particularly relevant to the
treatment of persons who have suffered a previous episode of, or
are otherwise considered to be at increased risk of, the disease or
condition in question. Persons at risk of developing a particular
disease or condition generally include those having a family
history of the disease or condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the disease or condition.
[0199] In particular, the compounds of the invention may be used in
the treatment of asthma, COPD, allergic rhinitis, allergic
conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis
C, HIV, HPV, bacterial infections and dermatosis.
[0200] The anti-cancer treatment defined hereinbefore may be
applied as a sole therapy or may involve, in addition to the
compound of the invention, conventional surgery or radiotherapy or
chemotherapy. Such chemotherapy may include one or more of the
following categories of anti-tumour agents:--
(i) other antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, oxaliplatin, carboplatin,
cyclophosphamide, nitrogen mustard, melphalan, chlorambucil,
busulphan, temozolamide and nitrosoureas); antimetabolites (for
example gemcitabine and antifolates such as fluoropyrimidines like
5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine
arabinoside, and hydroxyurea); antitumour antibiotics (for example
anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,
epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);
antimitotic agents (for example vinca alkaloids like vincristine,
vinblastine, vindesine and vinorelbine and taxoids like taxol and
taxotere and polokinase inhibitors); and topoisomerase inhibitors
(for example epipodophyllotoxins like etoposide and teniposide,
amsacrine, topotecan and camptothecin); (ii) cytostatic agents such
as antioestrogens (for example tamoxifen, fulvestrant, toremifene,
raloxifene, droloxifene and iodoxyfene), antiandrogens (for example
bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH
antagonists or LHRH agonists (for example goserelin, leuprorelin
and buserelin), progestogens (for example megestrol acetate),
aromatase inhibitors (for example as anastrozole, letrozole,
vorazole and exemestane) and inhibitors of 5.alpha.-reductase such
as finasteride; (iii) anti-invasion agents (for example c-Src
kinase family inhibitors like
4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)-
ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530;
International Patent Application WO 01/94341) and
N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-met-
hylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib,
BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and
metalloproteinase inhibitors like marimastat, inhibitors of
urokinase plasminogen activator receptor function or antibodies to
Heparanase); (iv) inhibitors of growth factor function: for example
such inhibitors include growth factor antibodies and growth factor
receptor antibodies (for example the anti-erbB2 antibody
trastuzumab [Herceptin.TM.], the anti-EGFR antibody panitumumab,
the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth
factor or growth factor receptor antibodies disclosed by Stern et
al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp
11-29); such inhibitors also include tyrosine kinase inhibitors,
for example inhibitors of the epidermal growth factor family (for
example EGFR family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, ZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazol-
in-4-amine (CI-1033), erbB2 tyrosine kinase inhibitors such as
lapatinib, inhibitors of the hepatocyte growth factor family,
inhibitors of the platelet-derived growth factor family such as
imatinib, inhibitors of serine/threonine kinases (for example
Ras/Raf signalling inhibitors such as farnesyl transferase
inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of
cell signalling through MEK and/or AKT kinases, inhibitors of the
hepatocyte growth factor family, c-kit inhibitors, abl kinase
inhibitors, IGF receptor (insulin-like growth factor) kinase
inhibitors; aurora kinase inhibitors (for example AZD1152,
PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459)
and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4
inhibitors; (v) antiangiogenic agents such as those which inhibit
the effects of vascular endothelial growth factor, [for example the
anti-vascular endothelial cell growth factor antibody bevacizumab
(Avastin.TM.) and VEGF receptor tyrosine kinase inhibitors such as
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)qu-
inazoline (ZD6474; Example 2 within WO 01/32651),
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-
quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib
(PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814),
compounds such as those disclosed in International Patent
Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354
and compounds that work by other mechanisms (for example linomide,
inhibitors of integrin .alpha.v.beta.3 function and angiostatin)];
(vi) vascular damaging agents such as Combretastatin A4 and
compounds disclosed in International Patent Applications WO
99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO
02/08213; (vii) antisense therapies, for example those which are
directed to the targets listed above, such as ISIS 2503, an
anti-ras antisense; (viii) gene therapy approaches, including for
example approaches to replace aberrant genes such as aberrant p53
or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and (ix)
immunotherapy approaches, including for example ex-vivo and in-vivo
approaches to increase the immunogenicity of patient tumour cells,
such as transfection with cytokines such as interleukin 2,
interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell anergy, approaches using transfected
immune cells such as cytokine-transfected dendritic cells,
approaches using cytokine-transfected tumour cell lines and
approaches using anti-idiotypic antibodies.
[0201] The invention still further provides a method of treating,
or reducing the risk of, an obstructive airways disease or
condition (e.g. asthma or COPD) which comprises administering to a
patient in need thereof a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof as hereinbefore defined.
[0202] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary with the compound employed, the
mode of administration, the treatment desired and the disorder
indicated. For example, the daily dosage of the compound of the
invention, if inhaled, may be in the range from 0.05 micrograms per
kilogram body weight (.mu.g/kg) to 100 micrograms per kilogram body
weight (.mu.g/kg). Alternatively, if the compound is administered
orally, then the daily dosage of the compound of the invention may
be in the range from 0.01 micrograms per kilogram body weight
(.mu.g/kg) to 100 milligrams per kilogram body weight (mg/kg).
[0203] The compounds of formula (I) and pharmaceutically acceptable
salts thereof may be used on their own but will generally be
administered in the form of a pharmaceutical composition in which
the formula (I) compound/salt (active ingredient) is in association
with a pharmaceutically acceptable adjuvant, diluent or carrier.
Conventional procedures for the selection and preparation of
suitable pharmaceutical formulations are described in, for example,
"Pharmaceuticals--The Science of Dosage Form Designs", M. E.
Aulton, Churchill Livingstone, 1988.
[0204] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% w (percent by
weight), more preferably from 0.05 to 80% w, still more preferably
from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of
active ingredient, all percentages by weight being based on total
composition.
[0205] The present invention also provides a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof as hereinbefore defined,
in association with a pharmaceutically acceptable adjuvant, diluent
or carrier.
[0206] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula (I) or a pharmaceutically acceptable
salt thereof as hereinbefore defined with a pharmaceutically
acceptable adjuvant, diluent or carrier.
[0207] The pharmaceutical compositions may be administered
topically (e.g. to the skin or to the lung and/or airways) in the
form, e.g., of creams, solutions, suspensions, heptafluoroalkane
(HFA) aerosols and dry powder formulations, for example,
formulations in the inhaler device known as the Turbuhaler.RTM.; or
systemically, e.g. by oral administration in the form of tablets,
capsules, syrups, powders or granules; or by parenteral
administration in the form of a sterile solution, suspension or
emulsion for injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion); or by rectal
administration in the form of suppositories.
[0208] Dry powder formulations and pressurized HFA aerosols of the
compounds of the invention (including pharmaceutically acceptable
salts) may be administered by oral or nasal inhalation. For
inhalation, the compound is desirably finely divided. The finely
divided compound preferably has a mass median diameter of less than
10 micrometres (.mu.m), and may be suspended in a propellant
mixture with the assistance of a dispersant, such as a
C.sub.8-C.sub.20 fatty acid or salt thereof, (for example, oleic
acid), a bile salt, a phospholipid, an alkyl saccharide, a
perfluorinated or polyethoxylated surfactant, or other
pharmaceutically acceptable dispersant.
[0209] The compounds of the invention may also be administered by
means of a dry powder inhaler. The inhaler may be a single or a
multi dose inhaler, and may be a breath actuated dry powder
inhaler.
[0210] One possibility is to mix the finely divided compound of the
invention with a carrier substance, for example, a mono-, di- or
polysaccharide, a sugar alcohol, or another polyol. Suitable
carriers are sugars, for example, lactose, glucose, raffinose,
melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and
starch. Alternatively the finely divided compound may be coated by
another substance. The powder mixture may also be dispensed into
hard gelatine capsules, each containing the desired dose of the
active compound.
[0211] Another possibility is to process the finely divided powder
into spheres which break up during the inhalation procedure. This
spheronized powder may be filled into the drug reservoir of a
multidose inhaler, for example, that known as the Turbuhaler.RTM.
in which a dosing unit meters the desired dose which is then
inhaled by the patient. With this system the active ingredient,
with or without a carrier substance, is delivered to the
patient.
[0212] For oral administration the compound of the invention may be
admixed with an adjuvant or a carrier, for example, lactose,
saccharose, sorbitol, mannitol; a starch, for example, potato
starch, corn starch or amylopectin; a cellulose derivative; a
binder, for example, gelatine or polyvinylpyrrolidone; and/or a
lubricant, for example, magnesium stearate, calcium stearate,
polyethylene glycol, a wax, paraffin, and the like, and then
compressed into tablets. If coated tablets are required, the cores,
prepared as described above, may be coated with a concentrated
sugar solution which may contain, for example, gum arabic,
gelatine, talcum and titanium dioxide. Alternatively, the tablet
may be coated with a suitable polymer dissolved in a readily
volatile organic solvent.
[0213] For the preparation of soft gelatine capsules, the compound
of the invention may be admixed with, for example, a vegetable oil
or polyethylene glycol. Hard gelatine capsules may contain granules
of the compound using either the above-mentioned excipients for
tablets. Also liquid or semisolid formulations of the compound of
the invention may be filled into hard gelatine capsules.
[0214] Liquid preparations for oral application may be in the form
of syrups or suspensions, for example, solutions containing the
compound of the invention, the balance being sugar and a mixture of
ethanol, water, glycerol and propylene glycol. Optionally such
liquid preparations may contain colouring agents, flavouring
agents, saccharine and/or carboxymethylcellulose as a thickening
agent or other excipients known to those skilled in art.
[0215] The compounds of the invention may also be administered in
conjunction with other compounds used for the treatment of the
above conditions.
[0216] The invention therefore further relates to combination
therapies wherein a compound of the invention or a pharmaceutical
composition or formulation comprising a compound of the invention
is administered concurrently or sequentially or as a combined
preparation with another therapeutic agent or agents, for the
treatment of one or more of the conditions listed.
[0217] In particular, for the treatment of the inflammatory
diseases COPD, asthma and allergic rhinitis the compounds of the
invention may be combined with agents such as tumour necrosis
factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal
antibodies (for example Remicade, CDP-870 and adalimumab) and TNF
receptor immunoglobulin molecules (such as Enbrel); non-selective
cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or
systemically (such as piroxicam, diclofenac, propionic acids such
as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen,
fenamates such as mefenamic acid, indomethacin, sulindac,
azapropazone, pyrazolones such as phenylbutazone, salicylates such
as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib,
rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib);
glucocorticosteroids (whether administered by topical, oral,
intramuscular, intravenous, or intra-articular routes);
methotrexate, lefunomide; hydroxychloroquine, d-penicillamine,
auranofin or other parenteral or oral gold preparations.
[0218] The present invention still further relates to the
combination of a compound of the invention and a leukotriene
biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or
5-lipoxygenase activating protein (FLAP) antagonist such as;
zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175;
Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide;
2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such
as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted
2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline
compound such as L-746,530; or an indole or quinoline compound such
as MK-591, MK-886, and BAY x 1005.
[0219] The present invention further relates to the combination of
a compound of the invention and a receptor antagonist for
leukotrienes (LT B4, LTC4, LTD4, and LTE4) selected from the group
consisting of the phenothiazin-3-1s such as L-651,392; amidino
compounds such as CGS-25019c; benzoxalamines such as ontazolast;
benzenecarboximidamides such as BIIL 284/260; and compounds such as
zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),
RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
[0220] The present invention still further relates to the
combination of a compound of the invention and a phosphodiesterase
(PDE) inhibitor such as a methylxanthanine including theophylline
and aminophylline; a selective PDE isoenzyme inhibitor including a
PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor
of PDE5.
[0221] The present invention further relates to the combination of
a compound of the invention and a histamine type 1 receptor
antagonist such as cetirizine, loratadine, desloratadine,
fexofenadine, acrivastine, terfenadine, astemizole, azelastine,
levocabastine, chlorpheniramine, promethazine, cyclizine, or
mizolastine; applied orally, topically or parenterally.
[0222] The present invention still further relates to the
combination of a compound of the invention and a gastroprotective
histamine type 2 receptor antagonist.
[0223] The present invention further relates to the combination of
a compound of the invention and an antagonist of the histamine type
4 receptor.
[0224] The present invention still further relates to the
combination of a compound of the invention and an alpha-1/alpha-2
adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as
propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine,
pseudoephedrine, naphazoline hydrochloride, oxymetazoline
hydrochloride, tetrahydrozoline hydrochloride, xylometazoline
hydrochloride, tramazoline hydrochloride or ethylnorepinephrine
hydrochloride.
[0225] The present invention further relates to the combination of
a compound of the invention and an anticholinergic agent including
muscarinic receptor (M1, M2, and M3) antagonists such as atropine,
hyoscine, glycopyrrolate, ipratropium bromide, tiotropium bromide,
oxitropium bromide, pirenzepine or telenzepine.
[0226] The present invention still further relates to the
combination of a compound of the invention together with a
beta-adrenoceptor agonist (including beta receptor subtypes 1-4)
such as isoprenaline, salbutamol, formoterol, salmeterol,
terbutaline, orciprenaline, bitolterol mesylate, and
pirbuterol.
[0227] The present invention further relates to the combination of
a compound of the invention and a chromone, such as sodium
cromoglycate or nedocromil sodium.
[0228] The present invention still further relates to the
combination of a compound of the invention together with an
insulin-like growth factor type I (IGF-1) mimetic.
[0229] The present invention still further relates to the
combination of a compound of the invention and a glucocorticoid,
such as flunisolide, triamcinolone acetonide, beclomethasone
dipropionate, budesonide, fluticasone propionate, ciclesonide or
mometasone furoate.
[0230] The present invention still further relates to the
combination of a compound of the invention together with an
inhibitor of matrix metalloproteases (MMPs), i.e., the
stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; especially collagenase-1 (MMP-1), collagenase-2
(MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3),
stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and
MMP-12.
[0231] The present invention still further relates to the
combination of a compound of the invention together with modulators
of chemokine receptor function such as antagonists of CCR1, CCR2,
CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and
CCR11 (for the C--C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5
(for the C--X--C family) and CX3CR1 for the C--X3-C family.
[0232] The present invention still further relates to the
combination of a compound of the invention together with a cytokine
or modulator of cytokine function, including alpha-, beta-, and
gamma-interferon; interleukins (IL) including IL1 to 15, and
interleukin antagonists or inhibitors, including agents which act
on cytokine signalling pathways.
[0233] The present invention still further relates to the
combination of a compound of the invention together with an
immunoglobulin (Ig) or Ig preparation or an antagonist or antibody
modulating Ig function such as anti-IgE (omalizumab).
[0234] The present invention further relates to the combination of
a compound of the invention and another systemic or
topically-applied anti-inflammatory agent, such as thalidomide or a
derivative thereof, a retinoid, dithranol or calcipotriol.
[0235] The present invention further relates to the combination of
a compound of the invention together with an antibacterial agent
such as a penicillin derivative, a tetracycline, a macrolide, a
beta-lactam, a fluoroquinolone, metronidazole, an inhaled
aminoglycoside; an antiviral agent including acyclovir,
famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine,
rimantadine, ribavirin, zanamavir and oseltamavir; a protease
inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir;
a nucleoside reverse transcriptase inhibitor such as didanosine,
lamivudine, stavudine, zalcitabine or zidovudine; or a
non-nucleoside reverse transcriptase inhibitor such as nevirapine
or efavirenz.
[0236] A compound of the invention can also be used in combination
with an existing therapeutic agent for the treatment of cancer, for
example suitable agents include:
(i) an antiproliferative/antineoplastic drug or a combination
thereof, as used in medical oncology, such as an alkylating agent
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an
antimetabolite (for example an antifolate such as a
fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed,
methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or
paclitaxel); an antitumour antibiotic (for example an anthracycline
such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,
idarubicin, mitomycin-C, dactinomycin or mithramycin); an
antimitotic agent (for example a vinca alkaloid such as
vincristine, vinblastine, vindesine or vinorelbine, or a taxoid
such as taxol or taxotere); or a topoisomerase inhibitor (for
example an epipodophyllotoxin such as etoposide, teniposide,
amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent
such as an antioestrogen (for example tamoxifen, toremifene,
raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down
regulator (for example fulvestrant), an antiandrogen (for example
bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH
antagonist or LHRH agonist (for example goserelin, leuprorelin or
buserelin), a progestogen (for example megestrol acetate), an
aromatase inhibitor (for example as anastrozole, letrozole,
vorazole or exemestane) or an inhibitor of 5.alpha.-reductase such
as finasteride; (iii) an agent which inhibits cancer cell invasion
(for example a metalloproteinase inhibitor like marimastat or an
inhibitor of urokinase plasminogen activator receptor function);
(iv) an inhibitor of growth factor function, for example: a growth
factor antibody (for example the anti-erbb2 antibody trastuzumab,
or the anti-erbb1 antibody cetuximab [C225]), a farnesyl
transferase inhibitor, a tyrosine kinase inhibitor or a
serine/threonine kinase inhibitor, an inhibitor of the epidermal
growth factor family (for example an EGFR family tyrosine kinase
inhibitor such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-4-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) or
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), an inhibitor of the platelet-derived growth
factor family, or an inhibitor of the hepatocyte growth factor
family; (v) an antiangiogenic agent such as one which inhibits the
effects of vascular endothelial growth factor (for example the
anti-vascular endothelial cell growth factor antibody bevacizumab,
a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO
98/13354), or a compound that works by another mechanism (for
example linomide, an inhibitor of integrin .alpha.v.beta.3 function
or an angiostatin); (vi) a vascular damaging agent such as
combretastatin A4, or a compound disclosed in WO 99/02166, WO
00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(vii) an agent used in antisense therapy, for example one directed
to one of the targets listed above, such as ISIS 2503, an anti-ras
antisense; (viii) an agent used in a gene therapy approach, for
example approaches to replace aberrant genes such as aberrant p53
or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; or (ix) an
agent used in an immunotherapeutic approach, for example ex-vivo
and in-vivo approaches to increase the immunogenicity of patient
tumour cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell anergy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0237] The present invention will be further explained by reference
to the following illustrative examples.
EXPERIMENTAL
[0238] Unless otherwise stated organic solutions were dried over
magnesium sulphate. RPHPLC means reversed phase preparative HPLC
using Waters Symmetry C8, Xterra, Xbridge or Phenomenex Gemini
columns using acetonitrile and either aqueous ammonium acetate,
ammonia, formic acid or trifluoroacetic acid as buffer where
appropriate. Column chromatography was carried out on silica gel.
Treating with SCX means the mixture was absorbed on SCX and eluted
with an appropriate solvent such as methanol or acetonitrile then
the free base product eluted with aqueous ammonia/methanol.
[0239] The following abbreviations are used; [0240] EtOAc ethyl
acetate [0241] DCM dichloromethane [0242] NMP N-methylpyrrolidinone
[0243] NBS N-bromosuccinimide [0244] DMF N,N-dimethylformamide
[0245] DMSO dimethylsulfoxide [0246] THF tetrahydrofuran [0247]
MeOH methanol [0248] TFA trifluoroacetic acid [0249] HCl hydrogen
chloride [0250] K.sub.2CO.sub.3 potassium carbonate [0251]
NaHCO.sub.3 sodium hydrogen carbonate [0252] TEA triethylamine
[0253] MeCN acetonitrile [0254] HATU
O-(7-azabezotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0255] EDCI
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0256]
HOBt 1-hydroxybenzotriazole [0257] rt room temperature [0258] h
hours [0259] min minutes [0260] M molar [0261] MS mass spectrometry
[0262] PyBop Benzotriazol-1-yloxytripyrrolidinophosphonium
hexafluorophosphate [0263] APCI atmospheric chemical ionisation
method [0264] ESI electron spray ionisation method [0265] NMR
nuclear magnetic resonance
Instrument Details:
[0266] XRPD--PANalytical CubiX PRO machine in O-O configuration
over the scan range 2.degree. to 40.degree. 2O with 100-second
exposure per 0.02.degree. increment. The X-rays were generated by a
copper long-fine focus tube operated at 45 kV and 40 mA. The
wavelength of the copper X-rays was 1.5418 .ANG.. The Data was
collected on zero background holders on which .about.2 mg of the
compound was placed. The holder was made from a single crystal of
silicon, which had been cut along a non-diffracting plane and then
polished on an optically flat finish. The X-rays incident upon this
surface were negated by Bragg extinction.
[0267] DSC thermograms were measured using a TA Q1000 Differential
Scanning calorimeter, with aluminium pans and pierced lids. The
sample weights varied between 0.3 to 5 mg. The procedure was
carried out under a flow of nitrogen gas (50 mL/min) and the
temperature studied from 25 to 300.degree. C. at a constant rate of
temperature increase of 10.degree. C. per minute.
Example 1
Methyl
2-(4-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamin-
o)methyl)phenyl)acetate
##STR00017##
[0268] (i) 3-Nitroquinolin-4-ol
[0269] 4-Hydroxyquinoline (22.2 g) and propionic acid (200 mL) were
combined and heated to 125.degree. C. Nitric acid (21.5 mL) was
added dropwise over 1.5 h. The reaction mixture was stirred at
reflux temperature for a further 15 min and cooled to rt. The
mixture was diluted with ethanol and the solid was collected by
vacuum filtration. The solid was washed with ethanol, water then
ethanol. The residue was refluxed in ethanol and the hot mixture
was filtered and dried to give the subtitle compound. Yield: 22
g
[0270] .sup.1H NMR .delta. (DMSO-d.sub.6) 13.00 (1H, s), 9.19 (1H,
s), 8.26 (1H, m), 7.81 (1H, ddd), 7.75-7.71 (1H, m), 7.53 (1H,
ddd)
(ii) tert-Butyl
{3-[(3-nitroquinolin-4-yl)amino]propyl}carbamate
[0271] To a stirred solution of 3-nitroquinolin-4-ol (8.15 g) in
DCM (100 mL) was added DMF (3.33 mL) and thionyl chloride (3.47 mL)
and the reaction mixture was refluxed for 2.5 h when all solids
dissolved. The solution was cooled to 0.degree. C. and a solution
of (3-aminopropyl)-carbamic acid tert-butyl ester (8.3 g) and
Et.sub.3N (6.5 mL) in DCM (20 mL) was added dropwise. The reaction
mixture was stirred overnight then poured into saturated sodium
bicarbonate solution and the product extracted using DCM. The
combined organic layer were washed with brine, water, dried,
filtered and the solvents evaporated. The residue was trituated
with diethylether to leave the subtitle compound (13 g).
[0272] .sup.1H NMR .delta. (CDCl.sub.3) 9.66 (1H, s), 9.36 (1H, s),
8.32 (1H, d), 8.00 (1H, d), 7.77 (1H, t), 7.49 (1H, ddd), 4.65 (1H,
s), 4.01 (2H, dd), 3.33 (2H, q), 2.02 (2H, quintet), 1.40 (9H,
s)
[0273] MS: APCI (+ve): 347
(iii) tert-Butyl
{3-[(3-aminoquinolin-4-yl)amino]propyl}carbamate
[0274] The product from step (ii) (12 g) was dissolved in dry THF
(250 mL), 1% Pt/C catalyst (3 g) was added and the reaction mixture
hydrogenated (H.sub.2 pressure: 3 bar) for 72 h at rt. The product
was filtered through a glass fibre filter paper and purified via
neutral Aluminum oxide column eluting with 4% MeOH in DCM and
further purified via RPHPLC to give subtitle compound, yield 1.3
g.
[0275] .sup.1H NMR .delta. (CD.sub.3OD) 8.34 (1H, s), 8.09-8.02
(1H, m), 7.80-7.74 (1H, m), 7.44-7.38 (2H, m), 3.34-3.30 (2H, m),
3.21-3.10 (2H, m), 1.78-1.67 (2H, m), 1.42 (9H, s)
(iv) tert-Butyl
[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate
[0276] The product from step (iii) (1.23 g) was dissolved in NMP
(25 mL) and valeryl chloride (0.46 mL) was added dropwise. The
reaction mixture was stirred for 1.5 h at rt, heated to 50.degree.
C. for 24 h then heated to 80.degree. C. for 2 days. The solvent
was evaporated and the reaction mixture poured into DCM. The solid
precipitate was filtered off and the filtrate was purified on
silica eluting with 10% MeOH in DCM to give subtitle compound (0.9
g).
[0277] .sup.1H NMR .delta. (CDCl.sub.3) 9.29 (1H, s), 8.28 (1H,
dd), 8.20 (1H, d), 7.72-7.59 (2H, m), 4.80-4.69 (1H, m), 4.60 (2H,
t), 3.03-2.92 (2H, m), 2.72 (1H, s), 2.21-2.09 (2H, m), 1.57-1.50
(2H, m), 1.48 (9H, s), 1.02 (3H, t) 2H under NMP peak
[0278] MS: APCI (+ve): 383
(v) tert-Butyl
[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate
[0279] The product from step (iv) (0.9 g) was dissolved in DCM (25
mL) and cooled to 5.degree. C. 3-Chloroperoxybenzoic acid (0.203 g)
was added and the reaction was allowed to warm to rt. The reaction
mixture was stirred for 2 h, more 3-chloroperoxybenzoic acid (0.30
g) was added and the reaction mixture stirred for a further 2 h.
The reaction mixture was poured into saturated sodium bisulfate
solution, extracted with DCM, dried, filtered and evaporated to
give the subtitle (0.9 g).
[0280] MS: APCI (+ve): 399
(vi) tert-Butyl
[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate
[0281] p-Toluenesulphonyl chloride (0.43 g) was added portionwise
to a vigourously stirred mixture of the product from step (v) (0.9
g) in DCM (25 mL) and ammonium hydroxide solution (35%, 2.5 mL) at
0.degree. C. The mixture was allowed to warm to rt over 2 h then
partioned between water/DCM, washed with saturated sodium
bicarbonate solution, dried, filtered and the solvent evaporated.
The solid product was triturated with diethylether to give the
subtitle compound (0.6 g).
[0282] MS: APCI (+ve): 398
(vii)
1-(3-Aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine
[0283] The product from step (vi) (0.6 g) was dissolved in DCM (5
mL) and TFA (5 mL) was added. The reaction mixture was stirred for
20 min, the solvents were evaporated and the product purified via
SCX resin, eluting with ammonia in MeOH solution (3.5%). Yield 380
mg.
[0284] .sup.1H NMR .delta. (CDCl.sub.3) 8.06 (1H, d), 7.83 (1H, d),
7.50 (1H, t), 7.33 (1H, t), 4.59 (2H, t), 3.02-2.80 (4H, m),
2.15-1.97 (2H, m), 1.96-1.77 (2H, m), 1.60-1.41 (2H, m), 1.01 (3H,
t).
[0285] MS: APCI (+ve): 298
(viii) Methyl
2-(4-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamino)meth-
yl)phenyl)acetate
[0286] The product from step (vii) (55 mg) was combined with methyl
(4-formylphenyl)acetate (0.0329 g) and stirred in THF (15 mL) for
16 h. Sodium borohydride (0.015 g) was added followed by MeOH (3
drops) and the reaction mixture was stirred for 1 h. The reaction
mixture was diluted with MeOH and purified via RPHPLC to give the
title compound.
[0287] Yield 17 mg.
[0288] .sup.1H NMR .delta. (DMSO-d.sub.6) 8.12 (1H, d), 7.60 (1H,
d), 7.40 (1H, t), 7.30 (2H, d), 7.23-7.16 (3H, m), 6.41 (2H, s),
4.58 (2H, t), 3.71-3.63 (4H, m), 3.60 (3H, s), 2.93 (2H, t),
2.63-2.57 (2H, m), 2.02-1.92 (2H, m), 1.83-1.73 (2H, m), 1.47-1.37
(2H, m), 1.00-0.89 (3H, m).
[0289] MS: APCI (+ve): 460
Example 2
Methyl
2-(3-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamin-
o)methyl)phenyl)acetate
##STR00018##
[0291] The title compound was prepared by the method of example 1
using methyl (3-formylphenyl)acetate (34 mg) to afford the title
compound, 13 mg as a white solid.
[0292] .sup.1H NMR .delta. (DMSO-d.sub.6) 8.13 (1H, d), 7.60 (1H,
d), 7.40 (1H, t), 7.28-7.23 (3H, m), 7.21-7.16 (1H, m), 7.15-7.11
(1H, m), 6.41 (2H, s), 4.62-4.54 (2H, m), 3.69 (2H, s), 3.65 (2H,
s), 3.60 (3H, s), 2.94 (2H, t), 2.63-2.58 (2H, m), 2.02-1.91 (2H,
m), 1.84-1.73 (2H, m), 1.44 (2H, q), 0.95 (3H, t)
[0293] MS: APCI (+ve): 460
Example 3
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate
##STR00019##
[0295] The product from example 1 (15 mg) was dissolved in a
mixture of DMF:DCM, 1:1 (5 mL) and N,N-dimethylglycyl chloride
hydrochloride salt (8 mg) and Et.sub.3N (0.01 mL) were added. The
reaction mixture was stirred for 72 h. More N,N-dimethylglycyl
chloride hydrochloride salt (0.050 g) and Et.sub.3N (0.06 mL) were
added, the mixture was stirred for a further 16 h. The product was
purified via RPHPLC.
[0296] .sup.1H NMR .delta. (CD.sub.3OD) 8.05-7.96 (1H, m),
7.73-7.66 (1H, m), 7.54-7.45 (1H, m), 7.38-7.29 (1H, m), 7.17-7.01
(4H, m), 4.63-4.45 (4H, m), 3.63 (3H, s), 3.56 (2H, s), 3.51-3.33
(2H, m), 3.01 (1H, s), 2.94-2.85 (2H, m), 2.28 (3H, s), 2.22-2.13
(1H, m), 2.04 (4H, s), 1.88-1.78 (2H, m), 1.52-1.42 (2H, m),
1.35-1.25 (1H, m), 1.00 (3H, s)
[0297] MS: APCI (+ve): 545
Example 4
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate
##STR00020##
[0299] The title compound was prepared by the method of example 3
using the product from example 2 (27 mg) to afford the title
compound 3 mg as a colourless gum.
[0300] .sup.1H NMR .delta. (CD.sub.3OD) 8.04-7.95 (1H, m),
7.73-7.65 (1H, m), 7.53-7.44 (1H, m), 7.37-7.30 (1H, m), 7.20-7.13
(1H, m), 7.11-6.98 (3H, m), 4.62 (1H, s), 4.57-4.44 (3H, m),
3.63-3.55 (2H, m), 3.55-3.39 (3H, m), 3.26 (1H, s), 3.01 (1H, s),
2.94-2.83 (2H, m), 2.28 (3H, s), 2.22-2.11 (1H, m), 2.07-1.95 (4H,
m), 1.88-1.77 (2H, m), 1.52-1.41 (2H, m), 1.35-1.24 (2H, m),
1.02-0.91 (3H, m)
[0301] MS: APCI (+ve): 545
Example 5
Methyl
2-(3-((4-((4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-y-
l)methyl)piperidin-1-yl)methyl)phenyl)acetate di-trifluoroacetate
salt
##STR00021##
[0302] (i)
2-(Ethoxymethyl)-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quin-
olin-4-amine, di-trifluoroacetate salt
[0303] The subtitle compound was prepared by the method of example
1 steps (i)-(vii) using tert-butyl
4-(aminomethyl)piperidine-1-carboxylate and ethoxyacetyl
chloride.
[0304] MS: APCI (+ve): 340
(ii) Methyl
2-(3-((4-((4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)meth-
yl)piperidin-1-yl)methyl)phenyl)acetate di-trifluoroacetate
salt
[0305] A mixture of the product from step (i) (0.14 g), methyl
[3-(bromomethyl)phenyl]acetate (0.07 g) and K.sub.2CO.sub.3 (0.25
g) in DMF (5 mL) were stirred at rt for 18 h. The mixture was
filtered then purified by RPHPLC. The product was dissolved in
methanol/TFA mixture (4 mL 10/1), the solvent evaporated under
reduced pressure and the residue triturated with diethylether,
yield 25 mg.
[0306] .sup.1H NMR .delta. (DMSO-d.sub.6) 14.06 (1H, brs); 9.69
(1H, brs); 8.25 (1H, d); 7.83 (1H, d); 7.75 (1H, t); 7.58 (1H, t);
7.44-7.34 (4H, m); 4.79 (2H, s); 4.65 (2H, s); 4.21 (2H, s); 3.70
(2H, s); 3.63-3.55 (5H, m); 3.33 (2H, d); 2.90-2.75 (2H, m); 2.18
(1H, brs); 1.79-1.62 (4H, m); 1.18 (3H, t)
[0307] MS: APCI (+ve): 502
Example 6
Methyl
[4-({[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl][2-(-
dimethylamino)ethyl]amino}methyl)phenyl]acetate
##STR00022##
[0308] (i)
N-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-3-nitroquinolin-4--
amine
[0309] To a stirred solution of 3-nitro-quinolin-4-ol (5 g) in DCM
(70 mL) was added DMF (2.3 mL) then thionyl chloride (2.1 mL) and
the reaction mixture was refluxed for 3 h. The solution was cooled
to 0.degree. C. and
3-{[tert-butyl(dimethyl)silyl]oxy}propan-1-amine (6 g) was added
followed by dropwise addition of Et.sub.3N (12 mL). The reaction
mixture was stirred at rt for 2 h, then partitioned between DCM and
saturated NaHCO.sub.3 solution. The organic layer was washed with
water, dried, and the solvent evaporated under reduced pressure.
The residue was triturated with iso-hexane to leave the subtitle
compound (8.7 g).
[0310] MS: ESI (+ve): 362
(ii)
N.sup.4-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)quinoline-3,4-diami-
ne
[0311] A mixture of the product from step (i) (8.5 g), iron powder
(14 g) in acetic acid was stirred at rt for 3 h the partitioned
between EtOAc/water. The organics were separated, washed with
saturated NaHCO.sub.3 solution, brine, dried and evaporated under
reduced pressure, yield 4.85 g.
[0312] MS: ESI (+ve): 332
(iii) 3-(2-Butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl
pentanoate
[0313] Valeryl chloride was added to a solution of the product from
step (ii) (4.85 g) in NMP at rt. The mixture was stirred at rt for
15 min, heated at 100.degree. C. for 6 h, cooled, and partitioned
between EtOAc/saturated NaHCO.sub.3 solution. The organics were
separated washed with water, dried and evaporated under reduced
pressure. The residue was purified by chromatography on silica
eluting with EtOAc, yield 2.15 g.
[0314] MS: ESI (+ve): 368
(iv) 3-(2-Butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl
pentanoate
[0315] 3-Chloroperoxybenzoic acid (1.6 g) was added to a solution
of the product from step (iii) (2.15 g) in DCM (30 mL) at 5.degree.
C. The reaction mixture was allowed to warm to rt, stirred for 18 h
and partitioned between DCM/saturated sodium bisulfate solution.
The organics were separated washed with saturated NaHCO.sub.3
solution, water, dried and evaporated under reduced pressure. Yield
1.77 g
[0316] MS: ESI (+ve): 384
(v)
3-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol
[0317] p-Toluenesulphonyl chloride (0.93 g) was added portionwise
to a vigourously stirred mixture of the product from step (iv)
(1.77 g) in DCM (50 mL) and ammonium hydroxide solution (35%, 5 mL)
at rt. The reaction mixture was stirred for 3 h then partioned
between water/DCM. The organics were washed with saturated
NaHCO.sub.3 solution, water, dried, and the solvent evaporated
under reduced pressure. The residue was dissolved in MeOH (40 mL),
water (20 mL) then 6M NaOH solution (2 mL) added and the mixture
stirred at rt for 18 h. The solid formed was filtered off washed
with water and dried, yield 965 mg.
[0318] MS: ESI (+ve): 299
(vi)
N'-[3-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N,N-dim-
ethylethane-1,2-diamine
[0319] A mixture of the product from step (v) (0.96 g) and thionyl
chloride (10 mL) in DCM (20 mL) was heated under reflux for 6 h
then evaporated under reduced pressure. The residue was dissolved
in acetonitrile (20 mL) then N,N-dimethylethylenediamine (10 mL)
added and the mixture heated under reflux for 24 h. The solvent was
removed under reduced pressure and the residue purified by RPHPLC,
yield 0.512 g.
[0320] MS: APCI (+ve): 369
(vii) Methyl
[4-({[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl][2-(dimeth-
ylamino)ethyl]amino}methyl)phenyl]acetate
[0321] A mixture of the product from step (vi) (0.25 g), methyl
(4-formylphenyl)acetate (0.15 g) and sodium triacetoxyborohydride
(0.2 g) in NMP (10 mL) was stirred at rt for 18 h then heated at
45.degree. C. for 3 h. A further portion of methyl
(4-formylphenyl)acetate (0.1 g) and sodium triacetoxyborohydride
(0.2 g) were added then stirred at 45.degree. C. for 6 h. The
mixture was purified by RPHPLC, yield 0.035 g.
[0322] .sup.1H NMR .delta. (DMSO-d.sub.6) 8.02 (1H, d); 7.62 (1H,
d); 7.40 (1H, t); 7.28 (2H, d); 7.21 (2H, d); 7.13 (1H, t); 6.47
(2H, s); 4.49-4.45 (2H, m); 3.66 (2H, s); 3.60 (2H, s); 3.59 (2H,
s); 2.89 (2H, t); 2.61 (2H, t); 2.35 (2H, t); 2.07 (6H, s);
1.96-1.90 (2H, m); 1.82-1.74 (2H, m); 1.47-1.38 (2H, m); 0.94 (3H,
t)
[0323] MS: APCI (+ve): 531
Example 7
Methyl
2-(3-((N-(3-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-y-
l)propyl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate
##STR00023##
[0324] (i) tert-Butyl
[3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate
[0325] The product from example 1 step (iii) (790 mg) was dissolved
in NMP (5 mL), then EDCI (1.44 g), HOBt (1 g), methoxyacetic acid
(0.71 mL) and Et.sub.3N (1 mL) were added. The mixture was stirred
at 40.degree. C. for 15 h then heated at 60.degree. C. for 5 h.
After cooling to rt, the crude mixture was dissolved in diethyl
ether, washed with brine, dried and evaporated under reduced
pressure, which afforded 600 mg of the subtitle product.
[0326] MS APCI +ve: 385
(ii) tert-Butyl
[3-(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamat-
e
[0327] The subtitle compound was prepared by the method of example
1 step (v) using the product from step (i).
[0328] MS APCI +ve: 401
(iii) tert-Butyl
[3-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamat-
e
[0329] The subtitle compound was prepared by the method of example
1 step (vi) using the product from step (ii).
[0330] MS APCI +ve: 400
(iv)
1-(3-Aminopropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine
[0331] The subtitle compound was prepared by the method of example
1 step (vii) using the product from step (iii)
[0332] MS APCI +ve: 300
(v) Methyl
2-(3-((3-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1--
yl)propylamino)methyl)phenyl)acetate
[0333] Methyl 2-(3-formylphenyl)acetate (199 mg) was added to the
product of step (iv) (334 mg) in THF (20 mL) at 25.degree. C. under
nitrogen. The resulting solution was stirred at rt for 6 h. Sodium
triacetoxyborohydride (1183 mg) was added to the reaction mixture
at rt under nitrogen and the mixture was stirred at rt for 15 h.
The reaction mixture was quenched with water and dissolved in MeOH.
The product was purified via RPHPLC, which afforded 25 mg of the
desired product as a white solid.
[0334] MS APCI +ve: 462
(vi) Methyl
2-(3-((N-(3-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)prop-
yl)-2-chloroacetamido)methyl)phenyl)acetate
[0335] Chloroacetyl chloride (0.059 mL) was added to the product of
step (v) (25 mg) in MeCN (2 mL) at rt under nitrogen. The resulting
solution was stirred at rt for 2 h, then concentrated in vacuo and
azeotroped with toluene, yield 30 mg.
[0336] MS APCI +ve: 538
(vii) Methyl
(3-{[[3-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl](N,-
N-dimethylglycyl)amino]methyl}phenyl)acetate
[0337] The product from step (vi) (30 mg) was dissolved in DMF (2
mL) then a solution of dimethylamine (2M in THF, 0.279 mL) was
added at rt under nitrogen. The resulting solution was stirred at
rt for 16 h. The mixture was purified by RPHPLC to give the title
compound, yield 4.5 mg.
[0338] .sup.1H NMR .delta. (CD.sub.3OD) 8.05-7.95 (1H, m),
7.75-7.65 (1H, m), 7.50-7.44 (1H, m), 7.39-7.35 (1H, m), 7.20-7.15
(1H, m), 7.14-7.07 (3H, m), 4.87-4.57 (8H, m), 3.64-3.54 (6H, m),
3.33-3.05 (4H, m), 2.31-2.05 (7H, m), 1.26-1.00 (3H, m)
[0339] MS APCI +ve: 547
Example 8
Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(1-
-methylpiperidin-4-yl)amino)methyl)phenyl)acetate
##STR00024##
[0340] (i)
2-Butyl-1-(3-(1-methylpiperidin-4-ylamino)propyl)-1H-imidazo[4,-
5-c]quinolin-4-amine
[0341] Sodium triacetoxyborohydride (1.07 g) was added to a stirred
mixture of the product from example 1 step (vii) (502 mg) and
1-methylpiperidin-4-one (0.21 mL) in NMP (2 mL) at rt. The
resulting solution was stirred at 50.degree. C. for 3 h, then
purified by SCX, yield 335 mg.
[0342] MS: APCI (+ve): 395
(ii) Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(1-methy-
lpiperidin-4-yl)amino)methyl)phenyl)acetate
[0343] A solution of methyl 2-(3-formylphenyl)acetate (0.15 g)
dissolved in NMP (10 mL) was added to a stirred solution of the
product from step (i) (0.36 g) in NMP (10 mL) at rt. Sodium
triacetoxyborohydride (0.90 g) was added to the mixture, the
temperature was increased to 50.degree. C. and the reaction mixture
stirred for 24 h. The resulting solution was dissolved in methanol
(0.5 mL), acidified with acetic acid (0.5 mL) and purified by SCX.
The crude product was further purified by RPHPLC to give the title
product, yield 22 mg.
[0344] .sup.1H NMR .delta. (DMSO-d.sub.6) 7.95 (1H, d); 7.59 (1H,
d); 7.38 (1H, m); 7.27-7.04 (5H, m); 6.41 (2H, brs); 4.34 (2H, m);
3.62 (3H, m); 3.50 (2H, s); 3.29 (3H, s); 2.90-2.65 (4H, m);
2.30-2.40 (4H, m); 1.85-1.24 (9H, m); 0.92 (3H, t)
[0345] MS: APCI (+ve): 557
Example 9
Methyl
2-(4-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(1-
-methylpiperidin-4-yl)amino)methyl)phenyl)acetate
##STR00025##
[0346] (i)
2-(4-(((3-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propy-
l)(1-methylpiperidin-4-yl)amino)methyl)phenyl)acetic acid
[0347] A solution of 2-(4-formylphenyl)acetic acid (0.14 g)
dissolved in NMP (10 mL) was added to a stirred solution of the
product from example 8 step (i) (0.34 g) in NMP (10 mL) at rt.
Sodium triacetoxyborohydride (0.90 g) was added and the mixture
heated at 50.degree. C. for 24 h. The resulting solution was
dissolved in methanol (0.5 mL), acidified with acetic acid (0.5 mL)
and purified by SCX. The crude product was further purified by
RPHPLC to give the subtitle product, yield 0.25 g.
[0348] MS: APCI (+ve): 543
(ii) Methyl
2-(4-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(1-methy-
lpiperidin-4-yl)amino)methyl)phenyl)acetate
[0349] Sulfuric acid (1 mL) was added to the product from step (i)
(250 mg) in MeOH (10 mL). The mixture was stirred at rt for 15 h,
then the solvent evaporated under reduced pressure. The residue was
purified by RPHPLC to afford the title compound, yield 6.2 mg.
[0350] .sup.1H NMR .delta. (CD.sub.3OD) 8.05 (1H, d); 7.72 (1H, d);
7.45 (1H, m); 7.25-7.20 (5H, m); 3.70-3.62 (5H, m); 3.35-2.70 (8H,
m); 2.29 (3H, s); 2.15-1.24 (13H, m); 0.92 (3H, t)
[0351] MS: APCI (+ve): 557
Example 10
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00026##
[0353] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 and methyl
piperazine.
[0354] .sup.1H NMR .delta. (DMSO-d.sub.6) 8.05 (1H, m), 7.65 (1H,
m), 7.45 (1H, m), 7.15-7.05 (5H, m), 4.65-4.40 (7H, m), 3.71-3.60
(5H, m), 3.45-2.20 (15H, m), 2.00-1.25 (5H, m), 0.95 (3H, t)
[0355] MS: APCI (+ve): 600
Example 11
Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-
-(dimethylamino)propyl)amino)methyl)phenyl)acetate
##STR00027##
[0356] (i) 3-(3-Nitroquinolin-4-ylamino)propan-1-ol
[0357] Thionyl chloride (6.3 mL) was added to a mixture of
3-nitroquinolin-4-ol (15 g) and DMF (6.9 mL) in DCM (200 mL). The
mixture was heated under reflux for 3 h then cooled to 0.degree. C.
3-Amino-1-propanol (7.3 mL) was added slowly followed by dropwise
addition of TEA (36 mL) and the mixture stirred at rt for 3 h. The
precipitate was filtered, washed with DCM then water. The DCM
filtrate was washed with water and evaporated under reduced
pressure then combined with the filtered solid. The combined solids
were triturated with ether and filtered to give a yellow solid,
19.2 g
[0358] MS: APCI (+ve): 248
(ii)
N-(3-(tert-Butyldimethylsilyloxy)propyl)-3-nitroquinolin-4-amine
[0359] tert-Butyldimethylchlorosilane (18 g) was added to a mixture
of the product from step (ii) (19.2 g) and imidazole (15 g) in DMF
(200 mL). The mixture was stirred at rt for 16 h then partitioned
between diethyl ether and water. The organics were separated,
washed with water, dried, and evaporated under reduced pressure.
The residue was triturated with isohexane and filtered to give 21.8
g of a yellow solid.
[0360] MS: APCI (+ve): 362
(iii)
N.sup.4-(3-(tert-Butyldimethylsilyloxy)propyl)quinoline-3,4-diamine
[0361] Iron powder (10 g) was added to a solution of the product
from step (ii) (20 g) in acetic acid (200 mL) and MeOH (100 mL).
The mixture was stirred at rt for 30 min then evaporated under
reduced pressure. The residue was partitioned between DCM and
water, the organics separated, washed with aq NaHCO.sub.3 solution,
water, dried, and evaporated under reduced pressure. The residue
was purified by chromatography on silica eluting with 3-5% MeOH in
DCM to give a brown oil, 10.1 g.
[0362] MS: APCI (+ve): 332
(iv)
2-Butyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-imidazo[4,5-c]qui-
noline
[0363] Pentanoyl chloride (3.7 mL) was added dropwise to a stirred
solution of the product from step (iii) (10 g) and TEA (5 mL) in
NMP (110 mL) at rt under nitrogen. The mixture was stirred at rt
for 2 h then heated to 100.degree. C. for 6 h. After cooling, the
reaction mixture was partitioned between diethyl ether/water, the
organics were separated, washed with water, dried, and evaporated
under reduced pressure. The residue was purified by chromatography
on silica eluting with 50-70% EtOAc/isohexane, yield 6.58 g.
[0364] .sup.1H NMR .delta. (CDCl.sub.3) 9.29 (s, 1H); 8.34-8.26 (m,
2H); 7.69-7.58 (m, 2H); 4.68 (t, 2H); 3.78 (t, 2H); 3.00 (t, 2H);
2.20-2.11 (m, 2H); 2.00-1.90 (m, 2H); 1.59-1.47 (m, 2H); 1.02 (H,
3H); 0.99 (s, 9H); 0.14 (s, 6H)
(v)
2-Butyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-imidazo[4,5-c]quin-
olin-4-amine
[0365] 3-Chloroperoxybenzoic acid (4 g) was added portionwise to a
solution of the product from step (iv) (6.5 g) in DCM (100 mL) at
0-5.degree. C. The mixture was warmed to rt, stirred for 3 h then
partitioned between DCM and aq sodium metabisulphite solution. The
organics were separated, washed with aq NaHCO.sub.3 solution,
water, dried, and evaporated under reduced pressure. The residue
was dissolved in DCM (100 mL) then 0.88 aq ammonia (12 mL) was
added followed by p-toluenesulphonyl chloride (3.24 g) portionwise
with vigorous stirring over 5 min. The mixture was stirred for 3 h
then partitioned between DCM and water, the organics were
separated, washed with aq NaHCO.sub.3 solution, brine, dried, and
evaporated under reduced pressure. Yield 6.7 g.
[0366] MS: APCI (+ve): 414
(vi) 3-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol,
dihydrochloride 4M HCl in dioxane (12 mL) was added to a solution
of the product from step (v) (6.7 g) in MeOH (100 mL) and stirred
at rt for 18 h. The solvent was evaporated under reduced pressure,
the residue triturated with diethyl ether, filtered and dried.
Yield 5.53 g.
[0367] MS: APCI (+ve): 299
(vii)
3-(3-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamino)pro-
pan-1-ol
[0368] A mixture of the product from step (vi) (5.53 g) and thionyl
chloride (15 mL) in DCM (100 mL) was heated under reflux for 3 h
then evaporated under reduced pressure. To the residue was added
DMSO (10 mL), acetonitrile (80 mL) and 3-amino-1-propanol (25 mL)
and the mixture heated under reflux for 4 h. The mixture was cooled
and partitioned between water and EtOAc, the aqueous layer was
extracted with EtOAc (4.times.400 mL), the organics were combined,
dried, and evaporated under reduced pressure. The residue was
triturated with ether and filtered, yield 4.21 g.
[0369] MS: APCI (+ve): 356
(viii) Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-hydro-
xypropyl)amino)methyl)phenyl)acetate
[0370] A mixture of the product from step (vii) (2 g), methyl
2-(3-(bromomethyl)phenyl)acetate (1.4 g) and potassium carbonate
(2.1 g) in DMF (20 mL) was stirred at rt under nitrogen for 24 h.
The mixture was partitioned between DCM/water, the organics
separated, washed with water, dried, and evaporated under reduced
pressure. The residue was purified by chromotography on silica
eluting with DCM/MeOH/Et.sub.3N (1000/50/3). Yield 2.43 g of
solid.
[0371] MS: APCI (+ve): 518
(ix) Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-chlor-
opropyl)amino)methyl)phenyl)acetate
[0372] A mixture of the product from step (viii) (2.43 g) and
thionyl chloride (10 mL) in DCM (30 mL) was stirred at rt for 4 h
then evaporated under reduced pressure to give the subtitle
compound. Used crude in next step.
[0373] MS: APCI (+ve): 536/8
(x) Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propy-
l)(3-(dimethylamino)propyl)amino)methyl)phenyl)acetate
[0374] A solution of dimethylamine in THF (2M, 6 mL) was added to a
mixture of the product from step (ix) (1.17 mmol) and sodium iodide
(250 mg) in DMF (5 mL) at rt. The mixture was heated at 55.degree.
C. in a sealed vessel for 24 h, cooled, filtered and the filtrate
purified by RPHPLC. The fractions containing the desired compound
were evaporated to dryness and the residue triturated with
ether/isohexane, 270 mg.
[0375] .sup.1H NMR DMSO-d6: .delta. 8.00 (d, 1H); 7.60 (d, 1H);
7.38 (t, 1H); 7.29-7.21 (m, 3H); 7.15-7.09 (m, 2H); 6.42 (s, 2H);
4.46 (t, 1H); 3.64 (s, 2H); 3.58 (s, 2H); 3.54 (s, 3H); 2.89 (t,
2H); 2.58 (t, 2H); 2.42 (t, 2H); 2.16 (t, 2H); 2.05 (s, 6H);
1.96-1.91 (m, 2H); 1.81-1.73 (m, 2H); 1.63-1.56 (m, 2H); 1.46-1.37
(m, 2H); 0.93 (t, 3H).
[0376] MS: Multimode+: 545.
Example 12
Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-
-morpholinopropyl)amino)methyl)phenyl)acetate
##STR00028##
[0378] The title compound was prepared by the method of example 11
step (x) using the product from example 11 step (ix) (627 mg) and
morpholine (1 ml) to give product as a white solid 165 mg.
[0379] .sup.1H NMR DMSO-d6: .delta. 8.01 (d, 1H); 7.60 (d, 1H);
7.39 (t, 1H); 7.27-7.12 (m, 5H); 6.46 (s, 2H); 4.47 (t, 2H); 3.64
(s, 2H); 3.57 (s, 2H); 3.55 (s, 3H); 3.47-3.45 (t, 4H); 2.89 (t,
2H); 2.58 (t, 2H); 2.42 (t, 2H); 2.23-2.19 (m, 6H); 1.99-1.91 (m,
2H); 1.81-1.74 (m, 2H); 1.63-1.56 (m, 2H); 1.46-1.37 (m, 2H); 0.93
(t, 3H).
[0380] MS: Multimode+: 587
Example 13
Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-
-(ethyl(methyl)amino)propyl)amino)methyl)phenyl)acetate
##STR00029##
[0382] The title compound was prepared by the method of example 11
step (x) using the product of example 11 step (ix) (627 mg) and
N-ethylmethylamine (1 ml) as a white solid 65 mg.
[0383] .sup.1H NMR DMSO-d6: .delta. 8.01 (d, 1H); 7.60 (d, 1H);
7.39 (t, 1H); 7.29-7.09 (m, 5H); 6.43 (s, 2H); 4.45 (t, 2H); 3.64
(s, 2H); 3.57 (s, 2H); 3.54 (s, 3H); 2.89 (t, 2H); 2.58 (t, 2H);
2.41 (t, 2H); 2.28-2.21 (m, 4H); 2.04 (s, 3H); 1.96-1.92 (m, 2H);
1.81-1.74 (m, 2H); 1.63-1.56 (m, 2H); 1.44-1.39 (m, 2H); 0.93 (t,
3H); 0.89 (t, 3H).
[0384] MS: Multimode+: 559
Example 14
Methyl
2-(3-(((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(3-
-(4-methylpiperazin-1-yl)propyl)amino)methyl)phenyl)acetate
##STR00030##
[0386] The title compound was prepared by the method of example 11
step (x) using the product of example 11 step (ix) (627 mg) and
N-methylpiperazine (1 ml) as a colourless gum 120 mg.
[0387] .sup.1H NMR DMSO-d6: .delta. 8.00 (d, 1H); 7.60 (d, 1H);
7.38 (t, 1H); 7.29-7.10 (m, 5H); 6.42 (s, 2H); 4.46 (t, 2H); 3.64
(s, 2H); 3.57 (s, 2H); 3.54 (s, 3H); 2.89 (t, 2H); 2.58 (t, 2H);
2.41 (t, 2H); 2.33-2.13 (brm, 10H); 2.08 (s, 3H); 1.98-1.90 (m,
2H); 1.81-1.73 (m, 2H); 1.63-1.55 (m, 2H); 1.46-1.37 (m, 2H); 0.94
(t, 3H).
[0388] MS: Multimode+: 600
Example 15
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(methylsulfonyl)acetamido)methyl)phenyl)acetate
##STR00031##
[0390] To a solution of the product from example 1 (221 mg) in DCM
(10 mL) was added 2-(methylsulfonyl)acetic acid (66.4 mg) followed
by TEA (0.201 mL) and HATU (201 mg). The reaction mixture was
stirred at rt for 16 h then the solvents were evaporated. The crude
product was purified by RPHPLC to afford the title compound (120
mg) as a white solid.
[0391] .sup.1H NMR DMSO-d6: .delta. 8.07-7.93 (m, 1H), 7.66-7.56
(m, 1H), 7.47-7.37 (m, 1H), 7.29-7.04 (m, 5H), 6.43 (s, 2H), 4.71
(s, 1H), 4.59-4.37 (m, 5H), 3.67-3.55 (m, 5H), 3.15 (s, 3H),
2.93-2.80 (m, 2H), 2.72 (s, 1H), 2.10-1.93 (m, 2H), 1.84-1.68 (m,
2H), 1.49-1.32 (m, 2H), 1.30-1.19 (m, 1H), 0.95 (t, 3H)
[0392] MS: 580 ES+
Example 16
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
acetamido)methyl)phenyl)acetate
##STR00032##
[0394] The product from example 1 (142 mg) was dissolved in DCM (5
mL) and TEA (0.065 mL) was added. The reaction mixture was cooled
to 0.degree. C. Acetyl chloride (0.029 mL) was added and the
reaction mixture stirred for 30 min. The solvents were evaporated
and the residue was taken up in MeOH and purified by RPHPLC to
afford the title compound (40 mg) as a white solid.
[0395] .sup.1H NMR DMSO-d6: .delta. 8.02-7.91 (m, 1H), 7.66-7.56
(m, 1H), 7.47-7.36 (m, 1H), 7.28-7.18 (m, 2H), 7.17-7.07 (m, 3H),
6.43 (d, 2H), 4.58 (s, 1H), 4.49-4.38 (m, 2H), 3.65 (s, 1H),
3.62-3.56 (m, 3H), 3.49-3.40 (m, 2H), 3.17 (d, 1H), 2.92-2.81 (m,
2H), 2.07 (d, 2H), 2.04-1.94 (m, 2H), 1.81-1.71 (m, 2H), 1.47-1.39
(m, 2H), 1.26-1.22 (m, 2H), 0.95 (t, 3H)
[0396] MS: 502 ES+
Example 17
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-morpholinoacetamido)methyl)phenyl)acetate
##STR00033##
[0398] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (500 mg) and
morpholine (0.9 ml), to give a yellow gum (102 mg).
[0399] .sup.1H NMR DMSO-d6: .delta. 8.06-7.93 (m, 1H), 7.64-7.58
(m, 1H), 7.46-7.40 (m, 1H), 7.26-7.20 (m, 2H), 7.16 (d, 2H),
7.11-7.05 (m, 1H), 6.43 (d, 2H), 4.67 (s, 1H), 4.59-4.50 (m, 1H),
4.48-4.38 (m, 2H), 4.11-4.04 (m, 1H), 3.66-3.61 (m, 2H), 3.60 (s,
3H), 3.51-3.37 (m, 8H), 2.90-2.81 (m, 2H), 2.27-2.21 (m, 1H),
2.14-2.05 (m, 1H), 2.03-1.91 (m, 1H), 1.79-1.72 (m, 2H), 1.46-1.38
(m, 2H), 1.29-1.21 (m, 2H), 0.98-0.90 (m, 3H)
[0400] MS: 587 ES+
Example 18
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-((2-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate
##STR00034##
[0402] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (500 mg) and
N-(2-methoxyethyl)methylamine (0.97 mg), to give a yellow gum (62
mg).
[0403] .sup.1H NMR DMSO-d6: .delta. 8.03-7.93 (m, 1H), 7.64-7.58
(m, 1H), 7.46-7.39 (m, 1H), 7.29-7.19 (m, 2H), 7.19-7.07 (m, 3H),
6.43 (s, 2H), 4.70 (s, 1H), 4.54-4.37 (m, 3H), 3.67-3.55 (m, 5H),
3.52-3.37 (m, 2H), 3.31-3.17 (m, 3H), 3.16-3.07 (m, 3H), 2.86 (td,
2H), 2.59-2.54 (m, 1H), 2.24 (s, 2H), 2.14-2.02 (m, 3H), 2.00-1.88
(m, 1H), 1.82-1.70 (m, 2H), 1.49-1.38 (m, 2H), 1.29-1.18 (m, 1H),
0.94 (t, 3H)
[0404] MS: 589 ES+
Example 19
Methyl
2-(4-((2-(4-acetylpiperazin-1-yl)-N-(3-(4-amino-2-butyl-1H-imidazo[-
4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate
##STR00035##
[0406] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (500 mg) and
1-acetylpiperazine (1.2 g), to give a white solid (152 mg).
[0407] .sup.1H NMR DMSO-d6: .delta. 8.06-7.92 (m, 1H), 7.64-7.57
(m, 1H), 7.46-7.39 (m, 1H), 7.28-7.13 (m, 4H), 7.12-7.04 (m, 1H),
6.48-6.40 (m, 2H), 4.69-4.61 (m, 1H), 4.59-4.52 (m, 1H), 4.49-4.38
(m, 2H), 3.66-3.62 (m, 2H), 3.60 (s, 3H), 3.49-3.38 (m, 2H),
3.28-3.23 (m, 4H), 2.91-2.81 (m, 2H), 2.70-2.61 (m, 2H), 2.45-2.33
(m, 2H), 2.23 (d, 2H), 1.98 (s, 3H), 1.77 (s, 2H), 1.43 (t, 2H),
0.94 (m, 3H)
[0408] MS: Multimode+: 628
Example 20
(R)-Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pro-
pyl)-2-(3-hydroxypyrrolidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00036##
[0410] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (500 mg) and
R-(+)-pyrrolidin-3-ol (813 mg), to give a white solid (25 mg).
[0411] .sup.1H NMR DMSO-d6: .delta. 8.02-7.93 (m, 1H), 7.64-7.59
(m, 1H), 7.46-7.39 (m, 1H), 7.27-7.19 (m, 2H), 7.18-7.14 (m, 2H),
7.12-7.08 (m, 1H), 6.46-6.41 (m, 2H), 4.69-4.64 (m, 1H), 4.55-4.50
(m, 1H), 4.45-4.39 (m, 2H), 3.62 (s, 3H), 3.50-3.35 (m, 2H),
3.25-3.13 (m, 4H), 2.89-2.83 (m, 2H), 2.79-2.77 (m, 1H), 2.70-2.64
(m, 1H), 2.42-2.24 (m, 2H), 2.10-2.01 (m, 2H), 1.99-1.90 (m, 2H),
1.82-1.73 (m, 2H), 1.56-1.35 (m, 3H), 0.98-0.91 (m, 3H)
[0412] MS: Multimode+: 587
Example 21
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(pyrimidin-2-yl)piperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00037##
[0414] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (1.06 mg) and
2-(piperazin-1-yl)pyrimidine (0.32 mg) to give 40 mg as a white
solid.
[0415] .sup.1H NMR DMSO-d6: .delta. 8.34 (dd, 2H), 8.05-7.94 (m,
1H), 7.66-7.55 (m, 1H), 7.46-7.34 (m, 1H), 7.30-7.16 (m, 3H),
7.11-7.07 (m, 1H), 6.66-6.57 (m, 1H), 6.50-6.41 (m, 2H), 4.74-4.66
(m, 1H), 4.61-4.52 (m, 1H), 4.50-4.39 (m, 2H), 3.66-3.50 (m, 3H),
3.53-3.30 (m, 6H), 3.27 (s, 3H), 3.13 (s, 2H), 2.86 (t, 2H),
2.39-2.28 (m, 2H), 2.18-2.08 (m, 1H), 2.04-1.94 (m, 3H), 1.82-1.72
(m, 2H), 1.47-1.35 (m, 2H), 1.29-1.18 (m, 1H), 0.99-0.85 (m,
3H)
[0416] MS: Multimode +: 664
Example 22
Ethyl
4-(2-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(4-(-
2-methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)piperazine-1-carboxylate
##STR00038##
[0418] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
ethyl piperazine-1-carboxylate (339 mg). The crude product was
purified by RPHPLC and the resulting residue was triturated with a
1:1 mixture of ethyl aceate:ether to give the title compound as a
white solid (74 mg).
[0419] .sup.1H NMR DMSO-d6: .delta. 8.04-7.94 (m, 1H), 7.64-7.58
(m, 1H), 7.44-7.39 (m, 1H), 7.27-7.21 (m, 1H), 7.18-7.12 (m, 3H),
7.07 (d, 1H), 6.46-6.40 (m, 2H), 4.66 (s, 1H), 4.54 (s, 1H),
4.47-4.38 (m, 2H), 4.07-3.95 (m, 3H), 3.64-3.58 (m, 4H), 3.47-3.37
(m, 3H), 3.25-3.20 (m, 3H), 3.05-3.02 (m, 2H), 2.88-2.81 (m, 2H),
2.42-2.36 (m, 2H), 2.26-2.20 (m, 2H), 2.14-2.04 (m, 2H), 2.03-1.92
(m, 2H), 1.81-1.71 (m, 2H), 1.48-1.36 (m, 2H), 1.16 (dt, 3H), 0.94
(td, 3H)
[0420] MS: Multimode +: 658
Example 23
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(ethylsulfonyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00039##
[0422] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
1-(ethylsulfonyl)piperazine (382 mg). The crude product was
purified as in example 22 to give the title compound as a white
solid (72 mg).
[0423] .sup.1H NMR DMSO-d6: .delta. 8.00 (dd, 1H), 7.64-7.55 (m,
1H), 7.47-7.38 (m, 1H), 7.31-7.22 (m, 1H), 7.21-7.12 (m, 3H),
7.13-7.04 (m, 1H), 6.51-6.39 (m, 2H), 4.69-4.60 (m, 1H), 4.61-4.52
(m, 1H), 4.47-4.38 (m, 2H), 3.68-3.56 (m, 5H), 3.48-3.38 (m, 2H),
3.28-3.23 (m, 2H), 3.11-3.00 (m, 4H), 2.99-2.91 (m, 4H), 2.89-2.82
(m, 2H), 2.36-2.30 (m, 3H), 2.15-1.92 (m, 2H), 1.81-1.73 (m, 2H),
1.46-1.38 (m, 2H), 1.20-1.12 (m, 3H), 0.98-0.90 (m, 3H)
[0424] MS: Multimode+: 678
Example 24
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00040##
[0426] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
piperidine (183 mg). The crude product was purified by RPHPLC and
the resulting residue was triturated with ethyl acetate to give the
title compound as a white solid (25 mg).
[0427] .sup.1H NMR DMSO-d6: .delta. 8.03-7.92 (m, 1H), 7.60 (d,
1H), 7.45-7.40 (m, 1H), 7.26-7.20 (m, 2H), 7.19-7.14 (m, 2H),
7.11-7.03 (m, 1H), 6.45-6.40 (m, 1H), 4.72-4.66 (m, 1H), 4.57-4.51
(m, 1H), 4.48-4.37 (m, 2H), 3.65-3.58 (m, 5H), 3.53-3.35 (m, 2H),
3.14-3.08 (m, 2H), 2.97-2.91 (m, 2H), 2.90-2.78 (m, 3H), 2.38-2.30
(m, 2H), 2.16-1.87 (m, 2H), 1.84-1.72 (m, 3H), 1.49-1.19 (m, 8H),
0.94 (td, 3H).
[0428] MS: Multimode+: 585
Example 25
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(tert-butoxycarbonylamino)piperidin-1-yl)acetamido)methyl)phenyl)ace-
tate
##STR00041##
[0430] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
tert-butyl piperidin-4-ylcarbamate (430 mg). The crude product was
purified by RPHPLC and the resulting residue was triturated with
ethyl acetate to give the title compound as a white solid (87
mg).
[0431] .sup.1H NMR DMSO-d6: .delta. 8.05-7.93 (m, 1H), 7.66-7.54
(m, 1H), 7.48-7.36 (m, 1H), 7.27-7.14 (m, 3H), 7.08-7.03 (m, 1H),
6.75-6.63 (m, 1H), 6.46-6.40 (m, 2H), 4.65-4.60 (m, 1H), 4.58-4.48
(m, 1H), 4.47-4.36 (m, 2H), 3.65-3.58 (m, 2H), 3.48-3.35 (m, 2H),
3.18-3.10 (m, 2H), 2.89-2.81 (m, 3H), 2.80-2.73 (m, 1H), 2.69-2.62
(m, 2H), 2.11-2.01 (m, 4H), 1.97-1.87 (m, 2H), 1.82-1.72 (m, 2H),
1.67-1.56 (m, 2H), 1.48-1.40 (m, 2H), 1.37 (t, 9H), 1.30-1.23 (m,
3H), 0.94 (t, 3H).
[0432] MS: Multimode+: 700
Example 26
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(tert-butoxycarbonylmethyl)amino)piperidin-1-yl)acetamido)methyl)phe-
nyl)acetate
##STR00042##
[0434] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
tert-butyl methyl(piperidin-4-yl)carbamate (440 mg). The crude
product was purified by RPHPLC and the resulting residue was
triturated with ethyl acetate to give the title compound as a white
solid (40 mg).
[0435] .sup.1H NMR DMSO-d6: .delta. 8.05-7.94 (m, 1H), 7.64-7.58
(m, 1H), 7.45-7.39 (m, 1H), 7.29-7.20 (m, 1H), 7.19-7.14 (m, 3H),
7.10-7.06 (m, 1H), 6.45-6.40 (m, 2H), 4.70-4.66 (m, 1H), 4.58-4.51
(m, 2H), 4.48-4.38 (m, 2H), 3.65 (s, 3H), 3.61 (s, 3H), 3.51-3.38
(m, 3H), 3.18-3.14 (m, 1H), 2.98-2.95 (m, 1H), 2.89-2.81 (m, 3H),
2.68-2.59 (m, 2H), 2.16-1.86 (m, 6H), 1.85-1.71 (m, 2H), 1.53-1.38
(m, 6H), 1.39-1.34 (m, 9H), 0.94 (td, 3H).
[0436] MS: Multimode+: 714
Example 27
Ethyl
2-(1-(2-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(-
4-(2-methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)piperidin-4-yl)acetate
##STR00043##
[0438] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
ethyl 2-(piperidin-4-yl)acetate (75 mg). The crude product was
purified by RPHPLC and the resulting residue was triturated with
ethyl acetate to give the title compound as a white solid (25
mg).
[0439] .sup.1H NMR DMSO-d6: .delta. 8.03-7.92 (m, 1H), 7.64-7.58
(m, 1H), 7.42 (s, 1H), 7.27-7.20 (m, 1H), 7.18-7.14 (m, 3H),
7.09-7.05 (m, 1H), 6.44-6.40 (m, 2H), 4.69-4.64 (m, 1H), 4.56-4.50
(m, 1H), 4.46-4.38 (m, 2H), 4.03 (q, 2H), 3.65-3.62 (m, 2H),
3.61-3.59 (m, 3H), 3.50-3.38 (m, 2H), 3.14 (s, 1H), 2.97 (s, 1H),
2.88-2.82 (m, 2H), 2.80-2.75 (m, 2H), 2.16-2.06 (m, 3H), 2.04-1.91
(m, 3H), 1.89-1.72 (m, 3H), 1.60-1.47 (m, 3H), 1.46-1.38 (m, 2H),
1.20-1.12 (m, 4H), 1.12-1.07 (m, 2H), 0.94 (td, 3H).
[0440] MS: Multimode+: 671
Example 28
Methyl
1-(2-((3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)(4--
(2-methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)piperidine-4-carboxylate
##STR00044##
[0442] The title compound was prepared by the method of example 7
steps (vi)-(vii) using the product from example 1 (230 mg) and
methyl piperidine-4-carboxylate (61 mg). The crude product was
purified by RPHPLC and the resulting residue was triturated with
diethyl ether to give the title compound as a white solid (16
mg).
[0443] .sup.1H NMR DMSO-d6: .delta. 8.02-7.92 (m, 1H), 7.64-7.58
(m, 1H), 7.45-7.39 (m, 1H), 7.26-7.20 (m, 2H), 7.18-7.14 (m, 2H),
7.07-7.05 (m, 1H), 6.44-6.40 (m, 2H), 4.69-4.66 (m, 1H), 4.56-4.51
(m, 1H), 4.46-4.39 (m, 2H), 3.64-3.62 (m, 2H), 3.60-3.58 (m, 3H),
3.48-3.37 (m, 2H), 3.29-3.28 (m, 3H), 3.17-3.10 (m, 1H), 3.00-2.93
(m, 1H), 2.89-2.82 (m, 2H), 2.80-2.74 (m, 2H), 2.63-2.58 (m, 2H),
2.29-2.18 (m, 1H), 2.14-1.89 (m, 4H), 1.82-1.69 (m, 4H), 1.54-1.37
(m, 4H), 0.94 (td, 3H).
[0444] MS: Multimode+: 643
Example 29
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00045##
[0445] i) tert-Butyl
3-(2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate
[0446] To the product of example 1 step (iii) (1.9 g) in NMP (25
mL), 3-methoxypropanoic acid (0.678 mL, 7.21 mmol) was added
followed by HATU (2.74 g) and TEA (0.837 mL) under nitrogen. The
resulting solution was stirred at 60.degree. C. for 15 h. The
reaction mixture was diluted with diethyl ether (300 mL) and EtOAc
(300 mL), and washed with water (300 mL), sat. NaHCO.sub.3 (200
mL), and saturated brine (200 mL). The organic was dried, filtered
and evaporated to afford the subtitle product (3.5 g).
[0447] MS APCI +ve 385
ii)
1-(3-(tert-Butoxycarbonylamino)propyl)-2-(2-methoxyethyl)-1H-imidazo[4-
,5-c]quinoline 5-oxide
[0448] The subtitle compound was prepared by the method of example
1 step (v) using the product from step (i).
[0449] MS APCI +ve: 401
iii) tert-Butyl
3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbam-
ate
[0450] The subtitle compound was prepared by the method of example
1 step (vi) using the product from step (ii).
[0451] MS APCI +ve: 400
iv)
1-(3-Aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine
[0452] The subtitle compound was prepared by the method of example
1 step (vii) using the product of step (iii).
[0453] MS APCI +ve: 300
v) Methyl
2-(4-((3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propylamino)methyl)phenyl)acetate
[0454] To the product from step (iv) (1.25 g) in THF (100 mL),
methyl 2-(4-formylphenyl)acetate (0.818 g) was added followed by
sodium triacetoxyborohydride (0.885 g) and acetic acid (3 drops)
and stirred at rt for 16 h. The reaction was quenched with water,
extracted with DCM washed with sat. NaHCO.sub.3 (200 mL), dried and
solvent removed. The resulting residue was dissolved in methanol
and purified on SCX to give the subtitle compound (0.73 g).
[0455] MS APCI +ve 462
vi) Methyl
2-(4-((3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin--
1-yl)propylamino)methyl)phenyl)acetate
[0456] To the product from step (v) (180 mg) in MeCN (5 mL),
2-chloroacetyl chloride (44.0 mg) was added at 0.degree. C. and
stirred for 7 h. Piperidine (332 mg) was added and stirred at rt
for 15 h. The solvent was removed and the crude product was
purified by RPHPLC. The resulting residue was triturated with
diethyl ether to afford the title compound as a white solid (22
mg).
[0457] .sup.1H NMR DMSO-d6: .delta. 8.03-7.93 (m, 1H), 7.64-7.59
(m, 1H), 7.45-7.40 (m, 1H), 7.28-7.20 (m, 1H), 7.19-7.15 (m, 3H),
7.11-7.07 (m, 1H), 6.47-6.43 (m, 2H), 4.70 (s, 1H), 4.61-4.55 (m,
1H), 4.45 (d, 2H), 3.80 (q, 2H), 3.63 (d, 2H), 3.60 (d, 3H),
3.52-3.46 (m, 1H), 3.44-3.37 (m, 1H), 3.16-3.08 (m, 3H), 2.97 (s,
1H), 2.39-2.31 (m, 3H), 2.23-2.17 (m, 2H), 2.15-2.08 (m, 1H),
2.00-1.92 (m, 1H), 1.46-1.39 (m, 3H), 1.36-1.23 (m, 7H).
[0458] MS: Multimode+: 587
Example 30
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate
##STR00046##
[0460] The title compound was prepared by the method of example 29
step (vi) with the product of example 29 step (v) (180 mg) and a 2M
THF solution of dimethylamine (0.2 ml). The title compound was
obtained as a white solid (15 mg).
[0461] .sup.1H NMR DMSO-d6: .delta. 8.04-7.94 (m, 1H), 7.65-7.59
(m, 1H), 7.46-7.40 (m, 1H), 7.27-7.20 (m, 2H), 7.19-7.09 (m, 3H),
6.48-6.42 (m, 2H), 4.70-4.67 (m, 1H), 4.58-4.52 (m, 1H), 4.48-4.42
(m, 2H), 3.84-3.77 (m, 2H), 3.65-3.62 (m, 2H), 3.61 (s, 3H),
3.49-3.38 (m, 2H), 3.28 (s, 3H), 3.17-3.09 (m, 3H), 3.01-2.98 (m,
1H), 2.21 (s, 3H), 2.15-2.07 (m, 2H), 2.02 (s, 3H), 1.98-1.94 (m,
2H).
[0462] MS: Multimode+: 547
Example 31
Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate
saccharin salt
##STR00047##
[0463] i) Methyl
2-(3-((3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)propy-
lamino)methyl)phenyl)acetate
[0464] The subtitle compound was prepared by the method of example
29 step (v) using methyl 2-(4-formylphenyl)acetate. The subtitle
compound was obtained as a white solid.
[0465] MS APCI +ve 462
ii) Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinol-
in-1-yl)propyl)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate
saccharin salt
[0466] The title compound was prepared by the method of example 29
step (vi) using the product from step (i) (95 mg) and piperidine
(18 mg). The crude product was purified by RPHPLC to give the free
base as a gum 44 mg, which was dissolved in 1 ml of MeOH. A
solution of saccharin (13.9 mg) in 1 ml of MeOH was added and
evaporated to dryness, EtOAc (2 ml) was added and the suspension
stirred at rt for 2 days. The solid was collected by filtration and
dried to afford the title compound as a white solid (22 mg).
[0467] .sup.1H NMR DMSO-d6: .delta. 8.17-8.13 (m, 1H), 7.85-7.83
(m, 1H), 7.70-7.06 (m, 10H), 4.64-4.55 (m, 6H), 4.31-4.10 (brm,
2H), 3.86-3.80 (m, 2H), 3.64 (s, 2H), 3.58 (s, 3H), 3.50-3.46 (m,
2H), 3.32-3.17 (m, 9H), 2.07-1.71 (m, 6H).
[0468] MS: Multimode+: 587
Example 32
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-((2-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)aceta-
te
##STR00048##
[0470] The title compound was prepared by the method of example 29
step (vi) using 2-methoxy-N-methylethanaminein (455 mg) and the
product of example 29 step (v) (549 mg). The title compound was
obtained as a white solid (52 mg).
[0471] .sup.1H NMR DMSO-d6: .delta. 8.03-7.96 (m, 1H), 7.64-7.61
(m, 1H), 7.44 (m, 1H), 7.28-7.10 (m, 5H), 6.46 (brs, 2H), 4.72-4.67
(m, 4H), 3.80 (q, 2H), 3.63 (m, 2H), 3.51 (s, 3H), 3.42-3.11 (m,
13H), 2.58-2.50 (m, 2H), 2.25-1.98 (m, 4H), 1.11 (t, 2H).
[0472] MS: Multimode+: 591
Example 33
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-3-(piperidin-1-yl)propanamido)methyl)phenyl)acetate
##STR00049##
[0474] To the product from step (v) of example 29 (480 mg, 1.04
mmol) in DMF (5 mL), 3-(piperidin-1-yl)propanoic acid (196 mg, 1.25
mmol) and HATU (475 mg, 1.25 mmol) were added at rt and stirred for
2 hours. After adding 1 mL of methanol, the crude product was
purified by RPHPLC and the resulting residue was triturated with
diethyl ether:EtOAc (5:1). The suspension was filtered to afford
the title compound as a white solid (72 mg).
[0475] .sup.1H NMR DMSO-d6: .delta. 8.03-7.96 (m, 1H), 7.63-7.60
(m, 1H), 7.45-7.40 (m, 1H), 7.28-7.10 (m, 5H), 6.46 (brs, 2H),
4.63-4.47 (m, 4H), 3.80 (t, 2H), 3.65-3.59 (m, 5H), 3.48 (m, 2H),
3.29-3.27 (m, 7H), 3.15 (q, 2H), 2.27-2.00 (m, 6H), 1.39-1.31 (m,
6H).
[0476] MS: Multimode+: 601
Example 34
Methyl
2-(4-(((3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-y-
l)propyl)(3-morpholinopropyl)amino)methyl)phenyl)acetate
##STR00050##
[0478] The product from step (v) of example 29 (360 mg, 0.78 mmol)
was dissolved in MeCN (10 mL) and 4-(3-chloropropyl)morpholine
hydrochloride (187 mg, 0.94 mmol) added at rt. Anhydrous
K.sub.2CO.sub.3 (323 mg, 2.34 mmol) and sodium iodide (117 mg, 0.78
mmol) were added. The mixture was refluxed for 15 h. After cooling
to room temperature, the crude product was purified by RPHPLC and
the resulting residue was triturated with diethyl ether:EtOAc (5:1)
at 0.degree. C. The suspension was filtered to afford the title
compound as a pale yellow solid (31 mg).
[0479] .sup.1H NMR DMSO-d6: .delta. 8.03-8.00 (m, 1H), 7.61-7.58
(m, 1H), 7.42-7.37 (m, 1H), 7.29-7.26 (m, 2H), 7.19-7.14 (m, 2H),
7.14-7.09 (m, 1H), 6.45 (brs, 2H), 4.52 (m, 2H), 3.79 (t, 2H),
3.66-3.56 (m, 5H), 3.45 (m, 4H), 3.32-3.27 (m, 5H), 3.16 (t, 2H),
2.58-2.36 (m, 6H), 2.27-2.18 (m, 4H), 1.99-1.59 (m, 4H).
[0480] MS: Multimode+: 589.
Example 35
(S)-Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinol-
in-1-yl)propyl)-2-(2-(methoxymethyl)pyrrolidin-1-yl)acetamido)methyl)pheny-
l)acetate disaccharin salt
##STR00051##
[0482] The title compound was prepared by the method of example 29
step (vi) using (S)-2-(methoxymethyl)pyrrolidine (235 mg) and the
product from example 29 step (v) (549 mg) to give the free base as
a gum 97 mg. This was dissolved in MeOH (1 ml) and a solution of
saccharin (59 mg) in MeOH (1 ml) was added and evaporated to
dryness, diethyl ether (2 ml) was added and stirred at rt for 15 h.
The solid was collected by filtration and to afford the title
compound as a white solid 22 mg.
[0483] .sup.1H NMR DMSO-d6: .delta. 8.17-8.22 (m, 1H), 7.88-7.85
(m, 1H), 7.74-7.56 (m, 10H), 7.26-7.13 (m, 4H), 4.64-4.55 (m, 6H),
4.31-4.10 (brm, 2H), 3.86-3.80 (m, 4H), 3.61-3.14 (m, 18H),
2.32-1.71 (m, 6H).
[0484] MS: Multimode+: 617
Example 36
(R)-Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinol-
in-1-yl)propyl)-2-(2-(methoxymethyl)pyrrolidin-1-yl)acetamido)methyl)pheny-
l)acetate disaccharin salt
##STR00052##
[0486] The title compound was prepared by the method of example 29
step (vi) using (S)-2-(methoxymethyl)pyrrolidine (117 mg) and the
product from example 29 step (v) (549 mg) to give the free base as
a gum. The dissaccharin salt was formed as in example 35 to give
the title compound as a white solid 68 mg.
[0487] .sup.1H NMR DMSO-d6: .delta. 8.17-8.22 (m, 1H), 7.88-7.85
(m, 1H), 7.74-7.56 (m, 10H), 7.26-7.13 (m, 4H), 4.64-4.55 (m, 6H),
3.86-3.80 (m, 4H), 3.61-3.14 (m, 18H), 2.42-1.71 (m, 6H).
[0488] MS: Multimode+: 617
Example 37
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(pyrrolidin-1-yl)acetamido)methyl)phenyl)acetate
disaccharin salt
##STR00053##
[0490] The title compound was prepared by the method of example 29
step (vi) using pyrrolidine (73 mg) and the product of example 29
step (v) (55 mg) to afford the free base as a gum. The dissaccharin
salt was formed as in example 35 to give the title compound as a
white solid 29 mg.
[0491] .sup.1H NMR DMSO-d6: .delta. 8.18-8.22 (m, 1H), 7.88-7.85
(m, 1H), 7.75-7.60 (m, 10H), 7.23-7.13 (m, 4H), 4.64-4.40 (m, 6H),
3.82 (m, 4H), 3.61-3.14 (m, 14H), 2.44-1.82 (m, 6H).
[0492] MS: Multimode+: 573
Example 38
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-((2-hydroxyethyl)(methyl)amino)acetamido)methyl)phenyl)aceta-
te disaccharin salt
##STR00054##
[0494] The title compound was prepared by the method of example 29
step (vi) using the product of example 29 step (v) (549 mg) and
2-(methylamino)ethanol (81 mg) to give the free base as a gum. The
dissaccharin salt was formed as in example 35 to give the title
compound as a white solid 27 mg.
[0495] .sup.1H NMR DMSO-d6: .delta. 8.17-8.22 (m, 1H), 7.88-7.85
(m, 1H), 7.90-7.56 (m, 10H), 7.26-7.13 (m, 4H), 4.64-4.55 (m, 6H),
3.86-3.80 (m, 4H), 3.61-3.14 (m, 13H), 2.32-1.71 (m, 6H).
[0496] MS: Multimode+: 573
Example 39
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-((2-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate
##STR00055##
[0497] (i) Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)
2-chloroacetamido)methyl)phenyl)acetate
[0498] Chloroacetyl chloride (0.434 mL, 5.44 mmol) was added to the
product of example 2 (2.50 g) in CHCl.sub.3 (75 mL) at 0.degree. C.
The resulting solution was stirred at 0.degree. C. for 1 h, then
0.2 N HCl aq. (100 mL) was added and extracted with CHCl.sub.3 (100
mL). The organic layer was dried and concentrated in vacuo.
[0499] .sup.1H NMR (CDCl.sub.3) .delta. 8.00 (1H, d), 7.96 (1H, d),
7.64 (1H, dd), 7.55 (1H, dd), 7.33 (1H,), 7.23 (1H, d), 7.12 (1H,
s), 7.08 (1H, d), 4.70 (2H, s), 4.51 (2H, dd), 4.16 (2H, s), 3.70
(3H, s), 3.66-3.62 (2H, m), 3.62 (2H, s), 2.88 (2H, dd), 2.18-2.10
(2H, m), 1.93-1.85 (2H, m), 1.57-1.48 (2H, m), 1.03 (3H, t).
(ii) Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2-((2-
-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate
[0500] Acetonitrile (75 ml) was added to the residue, then excess N
2-methoxyethylmethylamine was added at 0.degree. C. The resulting
solution was stirred at rt for 4 h. The solvent was evaporated. To
the residue, 0.2N HCl aq. (100 mL) was added and extracted with
CHCl.sub.3/MeOH=20/1 (100 mL). The water layer was neutralized with
NH.sub.3 aq. and then extracted with EtOAc/hexane=2/1 (100 ml). The
combined organic layer was washed with brine, dried and
concentrated in vacuo to give the title compound 266 mg as a
gum.
[0501] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.00 (0.5H, d), 8.00
(0.5H, d), 7.66 (1H, dd), 7.45-7.39 (1H, m), 7.27-7.20 (2H, m),
7.16-7.00 (3H, m), 6.46 (2H, brs), 4.72 (1H, s), 4.52-4.38 (3H, m),
3.64 (1H, s), 3.60 (1H, s), 3.57 (1.5H, s), 3.56 (1.5H, s), 3.51
(1H, t), 3.42 (1H, t), 3.33-3.28 (2H, m), 3.23 (1H, s), 3.19 (1H,
s), 3.13 (1.5H, s), 3.09 (1.5H, s), 2.90-2.81 (2H, m), 2.55 (1H,
t), 2.47 (1H, t), 2.22 (1.5H, s), 2.12 (1.5H, s), 2.12-2.05 (1H,
m), 2.01-1.92 (1H, m), 1.82-1.71 (2H, m), 1.46-1.38 (2H, m), 0.94
(3H, t).
[0502] MS: ESI 589 (M+1)
Example 40
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(butylmethyl)amino)acetamido)methyl)phenyl)acetate
##STR00056##
[0504] The title compound was prepared by the method of example 39
using 312 mg of the product from step (i) and N-butyl-N-methylamine
to give the title compound 276 mg as a gum.
[0505] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.00 (0.5H, d), 7.96
(0.5H, d), 7.60 (1H, dd), 7.42 (1H, dd), 7.27-7.22 (2H, m),
7.15-7.02 (3H, m), 6.45 (2H, brs), 4.71 (1H, s), 4.50 (1H, t), 4.47
(1H, s), 4.42 (1H, t), 3.64 (1H, s), 3.60 (1H, s), 3.58 (1.5H, s),
3.57 (1.5H, s), 3.51 (1H, t), 3.42 (1H, t), 3.15 (1H, s), 3.06 (1H,
s), 2.85 (2H, t), 2.32 (1H, t), 2.24-2.16 (1H, m), 2.17 (1.5H, s),
2.13-2.05 (1H, m), 2.01 (1.5H, s), 2.00-1.91 (1H, m), 1.82-1.71
(2H, m), 1.47-1.38 (2H, m), 1.31-1.10 (4H, m), 0.94 (3H, t), 0.78
(3H, m).
[0506] MS: ESI 587 (M+1)
Example 41
Methyl
3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-2--
(dipropylamino)acetamido)methyl)phenyl)acetate
##STR00057##
[0508] The title compound was prepared by the method of example 39
using 308 mg of the product from step (i) and dipropylamine to give
the title compound 250 mg as gum
[0509] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.00-7.94 (1H, m), 7.60
(1H, dd), 7.45-7.40 (1H, m), 7.27-7.20 (2H, m), 7.18-7.02 (3H, m),
6.46 (2H, brs), 4.73 (1H, s), 4.49-4.38 (3H, m), 3.64 (1H, s), 3.59
(1H, s), 3.58 (1.5H, s), 3.57 (1.5H, s), 3.55-3.51 (1H, m), 3.42
(1H, t), 3.22 (1H, s), 3.20 (1H, s), 2.85 (2H, t), 2.38 (2H, t),
2.27 (2H, t), 2.20-2.10 (1H, m), 2.03-1.92 (1H, m), 1.82-1.71 (2H,
m), 1.45-1.38 (2H, m), 1.31-1.22 (4H, m), 0.94 (3H, t), 0.73 (6H,
m)
[0510] MS: ESI 601 (M+1)
Example 42
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(bis(2-hydroxyethyl)amino)acetamido)methyl)phenyl)acetate
##STR00058##
[0512] The title compound was prepared by the method of example 39
using 240 mg of the product from step (i) and diethanolamine to
give the title compound 130 mg as a gum.
[0513] .sup.1H NMR (CDCl.sub.3) .delta. 7.80 (2H, m), 7.47-7.51
(1H, m), 6.93-7.31 (5H, m), 5.79 (2H, brs), 4.40-4.53 (3H, m), 3.68
(3H, s), 3.53-3.58 (7H, m), 3.40 (1H, m), 2.82-2.85 (5H, m),
2.57-2.59 (1H, m), 2.08-2.13 (4H, m), 1.79-1.85 (3H, m), 1.45-1.50
(2H, m), 1.25 (2H, m), 0.98 (3H, t).
[0514] MS: ESI 605 (M+1)
Example 43
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)acetamido)methyl)phenyl)acetate
##STR00059##
[0516] The title compound was prepared by the method of example 39
using 260 mg of the product from step (i) and
N-methyl-N-tetrahydro-2H-pyran-4-ylamine to give the title compound
180 mg as a gum.
[0517] .sup.1H NMR (CDCl.sub.3) .delta. 7.85 (2H, t,), 7.52 (1H,
m), 6.83-7.26 (5H, m), 5.65 (2H, brs), 4.71 (2H, s), 4.38-4.57 (2H,
m), 3.96-4.00 (2H, m), 3.68 (3H, s), 3.50-3.58 (4H, m), 3.35 (3H,
s), 2.83-2.87 (2H, m), 2.60 (1H, m), 2.07 (2H, m), 1.80-1.87 (6H,
m), 1.67 (2H, m), 1.46-1.57 (4H, m), 1.25 (2H, m), 0.99 (3H, t)
[0518] MS: ESI 615 (M+1)
Example 44
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(azetidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00060##
[0520] The title compound was prepared by the method of example 39
using 267 mg of the product from step (i) and azetidine to give the
title compound 107 mg as a solid.
[0521] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.03 (1/2H, d), 7.96
(1/2H, d, J), 7.61-7.56 (1H, m), 7.43 (1H, dd, 7.2, 7.9), 7.31-7.21
(2H, m), 7.17-7.01 (3H, m), 6.47 (1H, brd), 4.63 (1H, s), 4.52 (1H,
brt), 4.44 (1H, s), 4.45-4.38 (1H, m), 3.66 (1H, s), 3.61 (1H, s),
3.58 (3H, s), 3.45-3.35 (2H, m), 3.24 (1H, s), 3.17 (2H, t), 3.08
(1H, s), 3.02 (2H, t), 2.89-2.83 (2H, m), 2.11-2.02 (1H, m),
1.99-1.91 (2H, m), 1.86-1.73 (3H, m), 1.43 (2H, q), 0.95 (3H,
t).
[0522] MS: ESI 557 (M+1)
Example 45
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(3-hydroxyazetidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00061##
[0524] The title compound was prepared by the method of example 39
using 202 mg of the product from step (i) and 3-azetidinol to give
the title compound 193 mg as a gum.
[0525] .sup.1H NMR (CDCl.sub.3) .delta. 7.87-7.83 (2H, m),
7.54-7.50 (1H, m), 7.36-7.32 (1H, m), 7.26-7.23 (1H, m), 7.17-7.13
(1H, m), 7.05-7.03 (1H, m), 7.00-6.97 (1H, m), 5.61-5.57 (2H, m),
4.54-4.41 (4H, m), 3.82-3.78 (2H, m), 3.68 (3H, s), 3.57-3.50 (4H,
m), 3.41 (2H, s), 3.20-3.16 (0.5H, m), 3.09-3.06 (1.5H, m),
2.86-2.83 (2H, m), 2.20-2.15 (0.5H, m), 2.11-2.04 (1.5H, m),
1.85-1.74 (4H, m), 1.51-1.45 (2H, m), 0.99 (3H, t,).
[0526] MS: ESI 573 (M+1)
Example 46
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(pyrrolidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00062##
[0528] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and pyrrolidine to give
the title compound 289 mg as a gum.
[0529] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.01 (0.5H, d), 7.95
(0.5H, d), 7.62-7.59 (1H, m), 7.42 (1H, dd), 7.29-7.20 (2H, m),
7.15-7.05 (3H, m), 6.45 (2H, d), 4.69 (1H, s), 4.52 (1H, t), 4.48
(1H, s), 4.41 (1H, t), 3.63 (1H, s), 3.61 (1H, s), 3.57 (1.5H, s),
3.56 (1.5H, s), 3.51-3.46 (1H, m), 3.42 (1H, t), 3.28 (1H, s), 3.12
(1H, s), 2.84 (2H, t), 2.51-2.45 (2H, m), 2.34-2.28 (2H, m),
2.12-2.03 (1H, m), 2.02-1.91 (1H, m), 1.81-1.72 (2H, m), 1.66-1.60
(2H, m), 1.54-1.48 (2H, m), 0.94 (1.5H), 0.93 (1.5H, t).
[0530] MS: ESI 571 (M+1)
Example 47
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(3-hydroxypyrrolidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00063##
[0532] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and DL-3-pyrroldinol to
give the title compound 300 mg as a solid.
[0533] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.99 (0.5H, d), 7.94
(0.5H, d), 7.60 (1H, dd), 7.43-7.39 (1H, m), 7.28-7.20 (2H, m),
7.14-7.02 (3H, m), 6.45 (2H, brs), 4.68-4.66 (2H, m), 4.65-4.39
(3H, m), 4.15-4.00 (1H, m), 3.63 (1H, s), 3.59 (1H, s), 3.57 (1.5H,
s), 3.55 (1.5H, s), 3.52-3.32 (2H, m), 3.26 (1H, s), 3.22-3.11 (1H,
m), 2.85-2.74 (2.5H, m), 2.70-2.62 (0.5H, m), 2.58-2.49 (0.5H, m),
2.37-2.24 (1.5H, m), 2.10-2.00 (1H, m), 1.98-1.72 (4H, m),
1.54-1.37 (3H, m), 0.93 (3H, t).
[0534] MS: ESI 587 (M+1)
Example 48
(R)-Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pro-
pyl)-2-(3-hydroxypyrrolidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00064##
[0536] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and (R)-3-pyrrolidinol to
give the title compound 169 mg as a solid.
[0537] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.99 (0.5H, d), 7.94
(0.5H, d), 7.60 (1H, dd), 7.43-7.39 (1H, m), 7.28-7.20 (2H, m),
7.14-7.02 (3H, m), 6.45 (2H, brs), 4.68-4.66 (2H, m), 4.65-4.39
(3H, m), 4.15-4.00 (1H, m), 3.63 (1H, s), 3.59 (1H, s), 3.57 (1.5H,
s), 3.55 (1.5H, s), 3.52-3.32 (2H, m), 3.26 (1H, s), 3.22-3.11 (1H,
m), 2.85-2.74 (2.5H, m), 2.70-2.62 (0.5H, m), 2.58-2.49 (0.5H, m),
2.37-2.24 (1.5H, m), 2.10-2.00 (1H, m), 1.98-1.72 (4H, m),
1.54-1.37 (3H, m), 0.93 (3H, t).
[0538] MS: ESI 587 (M+1)
Example 49
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00065##
[0540] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and piperidine to give
the title compound 300 mg as a gum.
[0541] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.01 (0.5H, d), 7.95
(0.5H, d), 7.63-7.59 (1H, m), 7.42 (1H, dd), 7.29-7.20 (2H, m),
7.15-7.09 (2H, m), 7.04-7.01 (1H, m), 6.46 (2H, brs), 4.69 (1H, s),
4.53 (1H, t), 4.48 (1H, s), 4.40 (1H, t), 3.63 (1H, s), 3.60 (1H,
s), 3.58 (1.5H, s), 3.56 (1.5H, s), 3.50 (1H, t), 3.40 (1H), 3.10
(1H, s), 2.93 (1H, s), 2.87-2.81 (2H, m), 2.38-2.32 (2H, m),
2.21-2.14 (2H, m), 2.14-2.06 (1H, m), 1.99-1.90 (1H, m), 1.82-1.71
(2H, m), 1.47-1.31 (8H, m), 0.94 (1.5H, t), 0.93 (1.5H).
[0542] MS: ESI 585 (M+1)
Example 50
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-hydroxypiperidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00066##
[0544] The title compound was prepared by the method of example 39
using 600 mg of the product from step (i) and 4-hydroxypiperidine
to give the title compound 660 mg as a solid.
[0545] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.01 (0.5H, d), 7.93
(0.5H, d), 7.60 (1H, dd), 7.43-7.38 (1H, m), 7.26-7.19 (2H, m),
7.13-7.10 (2H, m), 7.00 (1H, brs), 6.45 (2H, brs), 4.68 (1H, s),
4.54-4.50 (2H, m), 4.46 (1H, s), 4.41-4.37 (1H, m), 3.63 (1H, s),
3.59 (1H, s), 3.56 (1.5H, s), 3.55 (1.5H, s), 3.52-3.43 (1H, m),
3.41-3.28 (1H, m), 3.11 (1H, s), 2.95 (1H, s), 2.85-2.80 (2H, m),
2.68-2.58 (1H, m), 2.51-2.47 (1H, m), 2.16-2.12 (2H, m), 2.00-1.88
(2H, m), 1.79-1.68 (2H, m), 1.65-1.53 (2H, m), 1.48-1.33 (2H, m),
1.32-1.23 (2H, m), 0.95-0.90 (3H, m).
[0546] MS: ESI 601 (M+1)
Example 51
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-methoxypiperidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00067##
[0548] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and 4-methoxypiperidine
to give the title compound 230 mg as a gum.
[0549] .sup.1H NMR (DMSO-d6) .delta. 8.00 (0.5H, d), 7.93 (0.5H,
d), 7.61-7.58 (1H, m), 7.43-7.37 (1H, m), 7.26-7.19 (2H, m),
7.13-7.09 (2H, m), 7.00 (1H, brs), 6.45 (2H, brd), 4.67 (1H, s),
4.54-4.50 (1H, m), 4.46 (1H, s), 4.41-4.37 (1H, m), 3.62 (1H, s),
3.59 (1H, s), 3.57 (1.5H, s), 3.55 (1.5H, s), 3.52-3.36 (2H, m),
3.17 (1.5H, s), 3.16 (1.5H, s), 3.13 (1H, s), 3.12-3.00 (1H, m),
2.94 (1H, s), 2.86-2.81 (2H, m), 2.68-2.63 (1H, m), 2.53-2.49 (1H,
m), 2.18-2.00 (2H, m), 1.98-1.88 (2H, m), 1.80-1.63 (4H, m),
1.44-1.25 (4H, m), 0.95-0.90 (3H, m).
[0550] MS: ESI 615 (M+1)
Example 52
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(dimethylcarbamoyl)piperidin-1-yl)acetamido)methyl)phenyl)acetate
##STR00068##
[0552] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and
N,N-dimethylpiperidine-4-carboxamide to give the title compound 265
mg as a gum.
[0553] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.00 (0.5H, d), 7.93
(0.5H, d), 7.61-7.58 (1H, m), 7.43-7.38 (1H, m), 7.27-7.19 (2H, m),
7.16-7.09 (2H, m), 7.00-6.99 (1H, m), 6.45 (2H, brs), 4.67 (1H, s),
4.54-4.50 (1H, m), 4.46 (1H, s), 4.41-4.37 (1H, m), 3.64 (1H, s),
3.58 (1H, s), 3.57 (1.5H, s), 3.55 (1.5H, s), 3.50-3.47 (1H, m),
3.41-3.37 (1H, m), 3.33 (1H, s), 3.14 (1H, s), 2.98 (1.5H, s), 2.95
(1.5H, s), 2.93 (1H, s), 2.86-2.74 (6H, m), 2.68-2.64 (1H, m),
2.07-1.84 (4H, m), 1.78-1.70 (2H, m), 1.55-1.37 (6H, m), 0.95-0.90
(3H, m MS: ESI 656 (M+1)
Example 53
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-morpholinoacetamido)methyl)phenyl)acetate
##STR00069##
[0555] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and morpholine to give
the title compound 294 mg as a solid.
[0556] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.03 (0.5H, d), 7.95
(0.5H, d), 7.63-7.59 (1H, m), 7.42 (1H, dd), 7.30-7.20 (2H, m),
7.15-7.08 (2H, m), 7.04-7.01 (1H, m), 6.46 (2H, d), 4.68 (1H, s),
4.55 (1H, t), 4.47 (1H, s), 4.41 (1H, t), 3.64 (1H, s), 3.60 (1H,
s), 3.58 (1.5H, s), 3.57 (1.5H, s), 3.51-3.39 (6H, m), 3.17 (1H,
s), 2.98 (1H, s), 2.88-2.82 (2H, m), 2.41-2.37 (2H, m), 2.25-2.20
(2H, m), 2.15-2.06 (1H, m), 2.00-1.91 (1H, m), 1.82-1.72 (2H, m),
1.47-1.37 (2H, m), 0.94 (1.5H, t), 0.93 (1.5H, t)
[0557] MS: ESI 587 (M+1)
Example 54
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-((2S,6R)-2,6-dimethylmorpholino)acetamido)methyl)phenyl)acetate
##STR00070##
[0559] The title compound was prepared by the method of example 39
using 206 mg of the product from step (i) and
cis-2,6-dimethylmorpholine to give the title compound 232 mg as a
solid.
[0560] .sup.1H NMR (CDCl.sub.3) .delta. 7.86-7.84 (2H, m),
7.55-7.51 (1H, m), 7.35-7.31 (1H, m), 7.25-7.21 (1H, m), 7.14-7.12
(1H, m), 7.03-6.99 (2H, m), 5.73 (1.5H, brs), 5.56 (0.5H, brs),
4.63 (1.5H, s), 4.57 (0.5H, s), 4.42 (2H, t), 3.68-3.64 (5H, m),
3.58-3.49 (4H, m), 3.22 (1.5H, s), 2.92 (0.5H, s), 2.86-2.75 (4H,
m), 2.24-2.05 (2H, m), 1.89-1.81 (4H, m), 1.51-1.45 (2H, m),
1.12-1.10 (6H, m), 0.99 (3H, t).
[0561] MS: ESI 615 (M+1)
Example 55
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00071##
[0563] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and 1-methylpiperazine to
give the title compound 320 mg as a gum.
[0564] .sup.1H NMR (CDCl.sub.3) .delta. 7.85 (1H, m), 7.53 (1H, m),
7.36 (1H, m), 7.23 (2H, m), 7.13 (1H, m), 7.04-7.00 (2H, m), 5.61
(2H, brs), 4.66 (2H, s), 4.44 (2H, t, J=7.6 Hz), 3.67 (3H, s), 3.56
(2H, s), 3.51 (2H, t), 3.25 (2H, s), 2.84 (2H, t), 2.67-2.25 (6H,
m), 2.21 (3H, s), 2.20-2.03 (4H, m), 1.87-1.79 (2H, m), 1.52-1.44
(2H, m), 1.00 (3H, t).
[0565] MS: ESI 600 (M+1)
Example 56
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00072##
[0567] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and 1-piperazineethanol
to give the title compound 337 mg as a solid.
[0568] .sup.1H NMR (CDCl.sub.3) .delta. 7.86 (1H, m), 7.54 (1H, m),
7.37 (1H, m), 7.24 (2H, m), 7.13 (1H, m), 7.08-6.99 (2H, m), 5.81
(2H, brs), 4.66 (2H, s), 4.45 (2H, t), 3.67 (3H, s), 3.58 (2H, s),
3.52 (2H, t), 3.48 (1H, brs), 3.26 (2H, s), 2.85 (2H, t), 2.67-2.03
(14H, m), 1.88-1.81 (2H, m), 1.52-1.45 (2H, m), 1.00 (3H, t).
[0569] MS: ESI 630 (M+1)
Example 57
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00073##
[0571] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and
1-(2-methoxyethyl)piperazine to give the title compound 354 mg as a
gum.
[0572] .sup.1H NMR (CDCl.sub.3) .delta. 7.87 (1H, m), 7.54 (1H, m),
7.38 (1H, m), 7.24 (2H, m), 7.14 (1H, m), 7.06-6.99 (2H, m), 5.93
(2H, brs), 4.67 (2H, s), 4.43 (2H, t), 3.67 (3H, s), 3.57 (2H, s),
3.56-3.46 (4H, m), 3.32 (3H, s), 3.25 (2H, s), 2.84 (2H, t),
2.59-2.20 (10H, m), 2.12-2.05 (2H, m), 1.87-1.80 (2H, m), 1.52-1.45
(2H, m), 1.00 (3H, t).
[0573] MS: ESI 644 (M+1)
Example 58
Methyl
2-(3-((2-(4-acetylpiperazin-1-yl)-N-(3-(4-amino-2-butyl-1H-imidazo[-
4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate
##STR00074##
[0575] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and 1-acetylpiperazine to
give the title compound 333 mg as a solid.
[0576] .sup.1H NMR (CDCl.sub.3) .delta. 7.85 (1H, m), 7.54 (1H, m),
7.33 (1H, m), 7.24 (2H, m), 7.14 (1H, m), 7.04-6.97 (2H, m), 5.72
(2H, brs), 4.67 (2H, s), 4.43 (2H, t,), 3.67 (3H, s), 3.63-3.27
(6H, m), 3.56 (2H, s), 3.28 (2H, s), 2.85 (2H, t), 2.56-2.07 (6H,
m), 2.06 (3H, s), 1.86-1.81 (2H, m), 1.52-1.45 (2H, m), 1.00 (3H,
t).
[0577] MS: ESI 628 (M+1)
Example 59
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(methylsulfonyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00075##
[0579] The title compound was prepared by the method of example 39
using 297 mg of the product from step (i) and
1-methanesulfonyl-piperazine to give the title compound 286 mg as a
solid.
[0580] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.03 (0.5H, d), 7.96
(0.5H, d), 7.61 (1H, d), 7.43 (1H, dd), 7.30-7.21 (2H, m),
7.15-7.06 (2H, m), 7.04-7.02 (1H, m), 6.51 (1H, brs), 6.48 (1H,
brs), 4.66 (1H, s), 4.55 (1H, t), 4.47 (1H, s), 4.43 (1H, t), 3.66
(1H, s), 3.61 (1H, s), 3.58 (1.5H, s), 3.57 (1.5H, s), 3.50-3.42
(2H, m), 3.31 (2H, s), 3.25 (1H, s), 3.04 (1H, s), 2.98-2.90 (4H,
m), 2.89-2.82 (2H, m), 2.78 (1.5H, s), 2.77 (1.5H, s), 2.36-2.30
(2H, m), 2.12-2.05 (1H, m), 2.02-1.94 (1H, m), 1.82-1.73 (2H, m),
1.46-1.38 (2H, m), 0.96-0.91 (3H, m).
[0581] MS: ESI 664 (M+1)
Example 60
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(azepan-1-yl)acetamido)methyl)phenyl)acetate
##STR00076##
[0583] The title compound was prepared by the method of example 39
using 201 mg of the product from step (i) and homopiperidine to
give the title compound 221 mg as a gum.
[0584] .sup.1H NMR (CDCl.sub.3) .delta. 7.87 (0.5H, d), 7.84 (1.5H,
d), 7.54-7.50 (1H, m), 7.32-7.30 (1H, m), 7.22 (1H, d), 7.14-7.12
(1H, m), 7.03-7.01 (2H, m), 5.59 (1.5H, brs), 5.50 (0.5H, brs),
4.73 (1.5H, s), 4.57 (0.5H, s), 4.43 (2H, t), 3.67 (3H, s), 3.57
(2H, s), 3.52 (2H, t), 3.38 (1.5H, s), 3.23 (0.5H, s), 2.87-2.78
(2H, m), 2.71 (3H, t), 2.57 (1H, t), 2.25-2.04 (2H, m), 1.85-1.81
(2H, m), 1.68-1.53 (8H, m), 1.51-1.45 (2H, m), 0.99 (3H, t).
[0585] MS: ESI 599 (M+1)
Example 61
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(1,4-oxazepan-4-yl)acetamido)methyl)phenyl)acetate
##STR00077##
[0587] The title compound was prepared by the method of example 39
using 257 mg of the product from step (i) and homomorphorine to
give the title compound 276 mg as a solid.
[0588] .sup.1H NMR (CDCl.sub.3) .delta. 8.02 (1/2H, d), 7.96 (1/2H,
d), 7.63-7.60 (1H, m), 7.45-7.40 (1H, m), 7.30-7.21 (2H, m),
7.16-7.01 (3H, m), 6.46 (2H, brs), 4.68 (1H, s), 4.57-4.51 (1H, m),
4.48 (1H, s), 4.44-4.39 (1H, m), 3.68-3.29 (7H, m), 3.58 (3/2H, s),
3.57 (3/2H, s), 3.16 (1H, s), 2.89-2.81 (2H, m), 2.78-2.65 (5H, m),
2.17-2.08 (1H, m), 2.01-1.92 (1H, m), 1.81-1.61 (5H, m), 1.48-1.37
(2H, m), 0.94 (3/2H, t), 0.94 (3/2H, t).
[0589] MS: ESI 601 (M+1)
Example 62
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-methyl-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate
##STR00078##
[0591] The title compound was prepared by the method of example 39
using 200 mg of the product from step (i) and
N-methylhomopiperazine to give the title compound 200 mg as a
gum.
[0592] .sup.1H NMR (CDCl.sub.3) .delta. 7.86-7.82 (2H, m),
7.53-7.49 (1H, m), 7.33-7.31 (1H, m), 7.25-7.21 (1H, m), 7.14-7.12
(1H, m), 7.02-6.99 (2H, m), 5.46 (2H, brs), 4.65 (1.5H, s), 4.56
(0.5H, s), 4.43 (2H, t), 3.67 (3H, s), 3.57-3.49 (4H, m), 3.41
(1.5H, s), 3.16 (0.5H, s), 2.87-2.80 (5H, m), 2.66-2.56 (5H, m),
2.35 (2.25H, s), 2.34 (0.75H, s), 2.22-2.04 (4H, m), 1.85-1.81 (4H,
m), 0.99 (3H, t).
[0593] MS: ESI 614 (M+1)
Example 63
Methyl
2-(3-((2-(4-acetyl-1,4-diazepan-1-yl)-N-(3-(4-amino-2-butyl-1H-imid-
azo[4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate
##STR00079##
[0595] The title compound was prepared by the method of example 39
using 270 mg of the product from step (i) and
N-acetylhomopiperazine to give the title compound 290 mg as a
solid.
[0596] .sup.1H NMR (CDCl.sub.3) .delta. 7.82-7.86 (2H, m), 7.52
(1H, m), 7.15-7.32 (4H, m), 6.81-7.00 (1H, m), 5.59 (2H, brs), 4.60
(2H, d), 4.43 (2H, t,), 3.40-3.69 (13H, m), 2.73-2.86 (5H, m),
1.81-2.07 (12H, m), 1.46-1.52 (2H, m), 1.25 (2H, m), 0.98-1.01 (3H,
m).
[0597] MS: ESI 642 (M+1)
Example 64
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(ethylcarbamoyl)-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate
##STR00080##
[0599] The title compound was prepared by the method of example 39
using 300 mg of the product from step (i) and
N-ethyl-1,4-diazepane-1-carboxamide to give the title compound 146
mg as a solid.
[0600] .sup.1H NMR (CDCl.sub.3) .delta. 7.83-7.86 (2H, m), 7.52
(1H, t), 6.97-7.33 (5H, m), 5.59 (2H, brs), 4.55 (2H, s), 4.40-4.45
(2H, m), 3.68 (3H, d), 3.55-3.59 (5H, m), 3.38 (4H, m), 3.22-3.25
(2H, m), 2.73-2.78 (3H, m), 1.81-2.05 (9H, m), 1.47-1.49 (2H, m),
1.26-1.28 (2H, m), 1.10 (3H, t), 0.99 (3H, t).
[0601] MS: ESI 671 (M+1)
Example 65
Methyl
2-(3-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(methylsulfonyl)-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate
##STR00081##
[0603] The title compound was prepared by the method of example 39
using 301 mg of the product from step (i) and
1-(methylsulfonyl)-1,4-diazepane to give the title compound 239 mg
as a solid.
[0604] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.02 (0.5H, d), 7.98
(0.5H, d), 7.61 (1H, d), 7.45-7.40 (1H, m), 7.29-7.20 (2H, m),
7.15-7.06 (2H, m), 7.04-7.01 (1H, m), 6.48 (1H, brs), 6.46 (1H,
brs), 4.64 (1H, s), 4.53 (1H, t), 4.47 (1H, s), 4.44 (1H, t), 3.65
(1H, s), 3.61 (1H, s), 3.58 (1.5H, s), 3.57 (1.5H, s), 3.43-3.40
(3H, m), 3.30 (1H, s), 3.27-3.21 (3H, m), 3.17 (1H, t), 3.12-3.08
(1H, m), 2.88-2.84 (2H, m), 2.83 (1.5H, s), 2.82 (1.5H, s),
2.75-2.66 (2H, m), 2.60-2.51 (1H, m), 2.12-2.06 (1H, m), 2.00-1.94
(1H, m), 1.78-1.72 (2H, m), 1.70-1.65 (1H, m), 1.65-1.57 (1H, m),
1.46-1.38 (2H, m), 0.96-0.91 (3H, m).
[0605] MS: ESI 678 (M+1)
Example 66
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00082##
[0607] The title compound was prepared by the method of example 39
using the product of example 1, step (i). Reaction of this product
(204 mg) and 1-(2-methoxyethyl)piperazine gave the title compound
(223 mg) as a gum.
[0608] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.00 (0.5H, d, 7.93
(0.5H, d), 7.61-7.59 (1H, m), 7.41 (1H, t), 7.30-7.14 (4H, m), 7.06
(1H, d), 6.45 (2H, brs), 4.66 (1H, s), 4.53 (1H, t), 4.44 (1H, s),
4.40 (1H, t), 3.63 (1H, s), 3.62 (1H, s), 3.59 (3H, s), 3.48-3.37
(2H, m), 3.36-3.31 (4H, m), 3.19 (1.5H, s), 3.17 (1.5H, s), 3.13
(1H, s), 2.97 (1H, s), 2.87-2.81 (2H, m), 2.38-2.29 (4H, m),
2.27-2.19 (4H, m), 2.15-2.08 (1H, m), 1.98-1.90 (1H, m), 1.80-1.70
(2H, m), 1.46-1.37 (2H, m), 0.95-0.91 (3H, m)
[0609] MS: ESI 644 (M+1)
Example 67
Methyl
2-(4-((2-(4-acetyl-1,4-diazepan-1-yl)-N-(3-(4-amino-2-butyl-1H-imid-
azo[4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate
##STR00083##
[0611] The title compound was prepared by the method of example 39
using the product of example 1, step (i). Reaction of this product
(290 mg) and N-acetylhomopiperazine gave the title compound (220
mg) as a solid.
[0612] .sup.1H NMR (CDCl.sub.3) .delta. 7.83-7.86 (2H, m), 7.52
(1H, t), 7.18-7.33 (3H, m), 7.02-7.08 (2H, m), 5.69 (2H, brs), 4.59
(2H, d), 3.70 (3H, s), 3.40-3.64 (9H, m), 2.73-2.87 (5H, m),
2.05-2.09 (5H, m), 1.80-1.87 (11H, m), 1.46-1.52 (2H, m), 1.26 (2H,
m), 0.99 (3H, t)
[0613] MS: ESI 642 (M+1)
Example 68
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(4-(methylsulfonyl)-1,4-diazepan-1-yl)acetamido)methyl)phenyl)acetate
##STR00084##
[0615] The title compound was prepared by the method of example 39
using the product of example 1, step (i). Reaction of this product
(293 mg) and 1-(methylsulfonyl)-1,4-diazepane gave the title
compound (291 mg) as a solid.
[0616] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.02 (0.5H, d), 7.96
(0.5H, d), 7.61 (1H, d), 7.43 (1H, dd), 7.27-7.21 (2H, m),
7.17-7.13 (2H, m), 7.09-7.05 (1H, m), 6.51 (2H, brs), 4.63 (1H, s),
4.54 (1H, t), 4.44 (1H, s), 4.42 (1H, t), 3.64 (1H, s), 3.62 (1H,
s), 3.60 (3H, s), 3.43-3.40 (3H, m), 3.32 (1H, s), 3.27-3.21 (3H,
m), 3.17 (1H, t), 3.12-3.08 (1H, m), 2.90-2.83 (2H, m), 2.83 (3H,
s), 2.75-2.66 (2H, m), 2.60-2.51 (1H, m), 2.12-2.05 (1H, m),
2.00-1.95 (1H, m), 1.78-1.72 (2H, m), 1.70-1.65 (1H, m), 1.65-1.57
(1H, m), 1.46-1.38 (2H, m), 0.94 (3H, t).
[0617] MS: ESI 678 (M+1)
Example 69
Methyl
2-(4-((2-((1-acetylpiperidin-4-yl)(methyl)amino)-N-(3-(4-amino-2-bu-
tyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)acetamido)methyl)phenyl)acetate
##STR00085##
[0619] The title compound was prepared by the method of example 39
using the product of example 1, step (i). Reaction of this product
(329 mg) and 1-acetyl-N-methylpiperidine-4-amine gave the title
compound (63 mg) as a gum.
[0620] .sup.1H NMR .delta. (DMSO-d.sub.6) 8.00 (0.5H, d), 7.94
(0.5H, d), 7.62-7.58 (1H, m), 7.43-7.38 (1H, m), 7.24-7.08 (5H, m),
6.49 (2H, brs), 4.66 (1H, s), 4.53-4.49 (1H, m), 4.46-4.30 (3H, m),
3.76-3.70 (1H, m), 3.63 (1H, s), 3.62 (1H, s), 3.58 (3H, s),
3.48-3.33 (2H, m), 3.27 (1H, s), 3.14 (1H, s), 2.86-2.81 (3H, m),
2.65-2.30 (2H, m), 2.18 (1.5H, s), 2.17-2.08 (1H, m), 2.00 (1.5H,
s), 1.99-1.91 (4H, m), 1.76-1.72 (2H, m), 1.68-1.54 (1H, m),
1.52-1.38 (3H, m), 1.30-1.02 (2H, m), 0.93 (3H, t).
[0621] MS: ESI 656 (M+1)
Example 70
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00086##
[0623] The title compound was prepared by the method of example 29
step (vi) using N-methylpiperazine (193 mg) and the product of
example 29 step (v) (207 mg). The title compound was obtained as a
white solid. 51 mgs
[0624] .sup.1H NMR (DMSO-d6) .delta. 8.03-7.91 (m, 1H), 7.63-7.60
(m, 1H), 7.45-7.41 (m, 1H), 7.26-7.07 (m, 5H), 6.45 (brs, 2H),
4.68-4.46 (m, 4H), 3.83-3.78 (m, 2H), 3.64-3.63 (m, 2H), 3.60 (s,
3H), 3.51-3.39 (m, 2H), 3.31-3.27 (m, 5H), 3.15-3.01 (m, 4H),
2.42-1.92 (m, 11H).
[0625] MS: MULTIMODE+: 602
Example 71
Methyl
2-(4-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)ac-
etate
##STR00087##
[0627] The title compound was prepared by the method of example 29
step (vi) using 1-(2-methoxyethyl)piperazine (241 mg) and the
product of example 29 step (v) (180 mg). The title compound was
obtained as a colourless solid. 14 mgs
[0628] .sup.1H NMR (DMSO-d6) .delta. 8.02-7.94 (m, 1H), 7.62 (d,
1H), 7.45-7.41 (m, 1H), 7.29-7.14 (m, 4H), 7.09 (d, 1H), 6.46 (s,
2H), 4.71-4.34 (m, 4H), 3.86-3.75 (m, 2H), 3.65-3.62 (m, 2H),
3.61-3.58 (m, 3H), 3.53-3.38 (m, 2H), 3.38-3.25 (m, 8H), 3.21-3.18
(m, 3H), 3.17-3.09 (m, 3H), 2.43-2.17 (m, 8H), 2.16-1.90 (m,
2H)
[0629] MS: MULTIMODE+: 646
Example 72
Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate
##STR00088##
[0631] The title compound was prepared by the method of example 29
step (vi) using N-methylpiperazine (125 mg) and the product of
example 31 step (i) (115 mg). The title compound was obtained as a
gum. 26 mgs
[0632] .sup.1H NMR (DMSO-d6) .delta. 8.03-7.92 (m, 1H), 7.63-7.61
(m, 1H), 7.45-7.41 (m, 1H), 7.27-7.23 (m, 1H), 7.21-7.12 (m, 1H),
7.03 (m, 1H), 6.45 (brs, 2H), 4.68-4.48 (m, 4H), 3.83-3.77 (m, 2H),
3.64-3.60 (m, 2H), 3.59-3.57 (m, 3H), 3.56-3.39 (m, 2H), 3.31-3.27
(m, 5H), 3.16-3.00 (m, 4H), 2.42-1.94 (m, 11H).
[0633] MS: MULTIMODE+: 602
Example 73
Methyl
2-(3-((N-(3-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-
-yl)propyl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamido)methyl)phenyl)ac-
etate
##STR00089##
[0635] The title compound was prepared by the method of example 29
step (vi) using 1-(2-methoxyethyl)piperazine (180 mg) and the
product of example 31 step (i) (115 mg). The title compound was
obtained as a gum. 34 mgs
[0636] .sup.1H NMR (DMSO-d6) .delta. 8.02-7.92 (m, 1H), 7.62-7.60
(m, 1H), 7.45-7.41 (m, 1H), 7.27-7.21 (m, 1H), 7.15-7.11 (m, 1H),
7.03 (m, 1H), 6.45 (brs, 2H), 4.70-4.41 (m, 4H), 3.83-3.77 (m, 2H),
3.64-3.59 (m, 5H), 3.56-3.39 (m, 2H), 3.31-3.98 (m, 9H), 2.41-1.92
(m, 10H).
[0637] MS: MULTIMODE+: 646
Example 74
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, dimethane
sulfonic acid salt
[0638] Methane sulfonic acid (0.048 mL, 0.73 mmol) was added to a
solution of the product from example 3 (0.2 g) in MeCN (10 mL). The
suspension was stirred for 3 hours and the solvent was evaporated.
The resulting solid was suspended in MeCN (2 mL) and stirred for 7
days. The mixture was filtered using a centrifuge, dried at rt and
a XRPD was run confirming that Polymorph A was formed.
Example 75
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, monosaccharin
salt
[0639] Saccharin (53 mg) in MeOH (1 mL) was added to a solution of
the product from example 3 (160 mg) in MeOH (1 mL) and stirred at
rt for 1 hr and the solvent removed. The resulting residue was
dissolved in THF (1 mL) and MeCN (1 mL) was added and stirred for 9
days. The solid was filtered off using a centrifuge, dried and a
XRPD was run (see FIG. 1A). The same polymorph was also formed when
slurried in water, MeCN and MeOH.
[0640] DSC: 167.degree. C..+-.2.degree. C.
Example 76
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, disaccharin
salt
[0641] Saccharin (106 mg) in MeOH (1 mL) was added to a solution of
the product of example 3 (160 mg) in methanol (1 mL). The resulting
residue was dissolved in THF (2 mL) and stirred for 9 days. The
solid was filtered off using a centrifuge, dried and a XRPD was run
(see FIG. 2A). The same polymorph was also formed when slurried in
dioxane, 1:1 EtOAc:ether, MeCN, 1:1 EtOAc:MeCN and 1:1
THF:MeCN.
[0642] DSC: 200.degree. C..+-.2.degree. C.
Example 77
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, di
1-hydroxy-2-naphthoic acid salt
[0643] 1-hydroxy-2-naphthoic acid (138 mg,) in MeOH (5 mL) was
added to the product from example 3 (200 mg) in MeOH (10 mL) and
the solution was stirred for 2 h at rt. The solvents were
evaporated, EtOAc (6 mL) was added and the mixture was stirred for
40 h at rt. The solid was filtered and dried and a XRPD was run
(see FIG. 3A). The same polymorph (A) was also formed when slurried
in MeOH and EtOH. A second polymorph (B) was formed with slurring
in acetone, DCM, water and isohexane (see FIG. 3C). DSC (Polymorph
A): Undergoes a phase transition at 120.degree. C..+-.5.degree. C.
(onset). The resulting phase C melts at 153.degree. C..+-.2.degree.
C. (onset).
[0644] DSC (Polymorph B): Melt onset 152.degree. C..+-.2.degree.
C.
Example 78
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate,
dibenzenesulfonic acid salt
[0645] Benzenesulfonic acid (116 mg) in MeCN (5 mL) was added to
the product from example 3 (200 mg) in MeCN (10 mL). The solvent
was evaporated and EtOAc (12 mL) was added and the resulting
solution was stirred for 5 days at room temperature. The solid was
filtered dried and a XRPD was run (see FIG. 4A).
Example 79
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, mandelic acid
salt
[0646] Mandelic acid (56 mg) was added to the product from example
3 (200 mg,) in MeCN (5 mL). The solvent was evaporated and the
resulting gum was slurried in diethyl ether for 4 days. The solid
was filtered, dried and a XRPD was run (see FIG. 5A).
[0647] DSC: Melt onset 104.degree. C..+-.2.degree. C.
Example 80
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, fumaric acid
salt
[0648] Fumaric acid (85 mg) dissolved in MeOH (10 mL) was added to
the product of example 3 in MeOH (10 mL) and stirred for 20 mins.
The solvent was removed and the resulting gum was stirred in a
mixture of EtOAc (5 mL) and THF (5 mL) for 10 days, then filtered
and a XRPD was run (see FIG. 6A).
[0649] DSC: Melt onset 175.degree. C..+-.2.degree. C.
Example 81
Methyl
2-(4-((N-(3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl)-
-2-(dimethylamino)acetamido)methyl)phenyl)acetate, dimethane
sulfonic acid salt
[0650] Methane sulfonic acid (0.024 mL) was added to the product
from example 3 (0.2 g) in acetonitrile (10 mL). The mixture was
stirred for 3 hours, the solid filtered, dried and a XRPD was run
to give polymorph A (see FIG. 7A). Slurring this solid in EtOAc (10
mL) for 2 days at rt gave polymorph B (see FIG. 7C).
[0651] DSC (Polymorph A): Melt onset 218.degree. C..+-.2.degree.
C.
Biological Assay
Human TLR7 Assay
[0652] The most common variant sequence of human TLR7 (represented
by the EMBL sequence AF240467) was cloned into the mammalian cell
expression vector pUNO and transfected into a HEK293 cell line
already stably expressing the pNiFty2-SEAP reporter plasmid;
integration of the reporter gene was maintained by selection with
the antibiotic zeocin. Transfectants with stable TLR7 expression
were selected using the antibiotic blasticidin. In this reporter
cell-line, expression of secreted alkaline phosphatase (SEAP) is
controlled by an NFkB/ELAM-1 composite promoter comprising five
NFkB sites combined with the proximal ELAM-1 promoter. TLR
signaling leads to the translocation of NFkB and activation of the
promoter results in expression of the SEAP gene. TLR7-specific
activation was assessed by determining the level of SEAP produced
following overnight incubation of the cells at 37.degree. C. with
the standard compound in the presence of 0.1% (v/v)
dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP
production by compounds was expressed as the concentration of
compound which produced half of the maximal level of SEAP induction
for that compound (pEC.sub.50).
TABLE-US-00001 Example no pEC.sub.50 Example no. pEC.sub.50 1 6.5 2
6.4 3 7.1 4 7.4 5 6.5 6 6.6 7 6.4 8 6.5 9 6.2 10 6.3 11 6.6 12 6.6
13 6.8 14 6.6 15 6.4 16 6.9 17 6.8 18 7.2 19 6.6 20 6.6 21 6.2 22
6.2 23 6.6 24 7.1 25 6.7 26 6.5 27 7.4 28 6.7 29 7.0 30 6.7 31 6.8
32 6.8 33 6.8 34 6.5 35 6.7 36 6.7 37 6.4 38 5.8 39 6.8 40 6.9 41
7.1 42 5.8 43 6.9 44 6.6 45 5.8 46 7.2 47 6.4 48 6.4 49 7.1 50 6.3
51 6.7 52 6.2 53 6.1 54 6.0 55 7.1 56 6.3 57 7.3 58 5.9 59 6.1 60
7.1 61 6.4 62 6.6 63 6.3 64 5.9 65 6.2 66 6.8 67 6.3 68 6.3 69 6.4
70 6.4 71 6.7 72 6.3 73 6.3
Effect of the Compound of Example 3 on Antigen-Induced Pulmonary
Inflammation in a Rat Asthma Model
[0653] Rats were sensitised and challenged to produce allergic
airway inflammation in a similar manner to that described by
Underwood et al (British Journal of Pharmacology 2002; 137:
263-275, 2002). Male Brown Norway rats were sensitized
subcutaneously with ovalbumin (OVA) and aluminum hydroxide on day
0, and challenged with aerosolized OVA solution on day 14. The
compound of Example 3 was administered twice intratracheally 24
hours before and 24 hours after the OVA-challenge and
bronchoalveolar lavage fluid (BALF) was collected 48 hours after
the OVA-challenge. Then eosinophiles and Th2 cytokines (IL-5 and
IL-13) in the BALF were measured to evaluate efficacy of the
compound of Example 3. The results obtained are shown in the
following table.
TABLE-US-00002 Eosinophiles and Th2 cytokines in BALF IL-13 Group
Dose Eosinophiles IL-5 (pg/ml (n = 8) (mg/kg) (cells/BALF) (pg/ml
BALF) BALF) Normal control -- 7.5 .+-. 3.5 3.8 .+-. 3.8 <4.9
OVA-challenge -- 476.7 .+-. 142.8 418.9 .+-. 151.0 103.2 .+-. 50.5
contr Example 3 0.1 67.2 .+-. 16.3 18.0 .+-. 8.7 <4.9 Example 3
1 36.2 .+-. 11.3 11.3 .+-. 7.5 <4.9 Mean .+-. SE (n = 8)
* * * * *