U.S. patent application number 13/391207 was filed with the patent office on 2012-06-14 for therapeutic aryl-amido-aryl compounds and their use.
This patent application is currently assigned to KING'S COLLEGE LONDON. Invention is credited to David Reginald Adams, Alan David Borthwick, Jane Theresa Brown, Jonathan Patrick Thomas Corcoran, Sarkis Barret Kalindjian, Jason John Shiers, David Michel Adrien Taddei.
Application Number | 20120149737 13/391207 |
Document ID | / |
Family ID | 41202973 |
Filed Date | 2012-06-14 |
United States Patent
Application |
20120149737 |
Kind Code |
A1 |
Corcoran; Jonathan Patrick Thomas ;
et al. |
June 14, 2012 |
Therapeutic Aryl-Amido-Aryl Compounds and Their Use
Abstract
The present invention pertains generally to the field of
therapeutic compounds, and more specifically to certain
aryl-amido-aryl compounds of the following formula (for
convenience, collectively referred to herein as "AAA compounds"),
which, inter alia, are (selective) retinoic acid receptor .alpha.
(RAR.alpha.) agonists. The present invention also pertains to
pharmaceutical compositions comprising such compounds, and the use
of such compounds and compositions, both in vitro and in vivo, to
(selectively) activate RAR.alpha., and in the treatment of diseases
and conditions that are mediated by RAR.alpha., that are
ameliorated by the activation of RAR.alpha., etc., including
cognitive disorders, memory impairment, memory deficit, senile
dementia, Alzheimer's disease, early stage Alzheimer's disease,
intermediate stage Alzheimer's disease, late stage Alzheimer's
disease, cognitive impairment, and mild cognitive impairment.
Inventors: |
Corcoran; Jonathan Patrick
Thomas; (London, GB) ; Kalindjian; Sarkis Barret;
(London, GB) ; Borthwick; Alan David; (London,
GB) ; Adams; David Reginald; (High Wycombe, GB)
; Brown; Jane Theresa; (Nottingham, GB) ; Taddei;
David Michel Adrien; (Nottingham, GB) ; Shiers; Jason
John; (Nottingham, GB) |
Assignee: |
KING'S COLLEGE LONDON
London
GB
|
Family ID: |
41202973 |
Appl. No.: |
13/391207 |
Filed: |
September 1, 2010 |
PCT Filed: |
September 1, 2010 |
PCT NO: |
PCT/GB2010/001650 |
371 Date: |
February 17, 2012 |
Current U.S.
Class: |
514/357 ;
514/530; 514/563; 514/616; 546/335; 560/45; 562/455; 564/158 |
Current CPC
Class: |
A61P 43/00 20180101;
C07C 2601/14 20170501; C07C 233/75 20130101; A61P 25/28 20180101;
C07C 237/42 20130101; C07C 235/56 20130101; C07C 2601/04 20170501;
C07D 213/30 20130101; C07D 237/24 20130101; C07D 213/80 20130101;
C07D 213/81 20130101; C07C 2601/08 20170501; C07C 235/84 20130101;
C07C 2601/02 20170501 |
Class at
Publication: |
514/357 ;
562/455; 560/45; 546/335; 564/158; 514/563; 514/530; 514/616 |
International
Class: |
A61K 31/4409 20060101
A61K031/4409; C07D 213/56 20060101 C07D213/56; A61P 25/28 20060101
A61P025/28; A61K 31/192 20060101 A61K031/192; A61K 31/235 20060101
A61K031/235; A61K 31/167 20060101 A61K031/167; C07C 235/84 20060101
C07C235/84; C07C 235/56 20060101 C07C235/56 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 1, 2009 |
GB |
0915196.0 |
Claims
1-154. (canceled)
155. A compound of the following formula, or a pharmaceutically
acceptable salt thereof: ##STR00440## wherein: --R.sup.1 is
independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR;
--R.sup.2 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or
--O-L-R.sup.AR; --R.sup.3 is independently --X, --R.sup.X,
--O--R.sup.X, --O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C,
--O--R.sup.AR, or --O-L-R.sup.AR; with the proviso that --R.sup.1,
--R.sup.2, and --R.sup.3 are not all --O--R.sup.A; wherein: each
--X is independently --F, --Cl, --Br, or --I; each --R.sup.A is
saturated aliphatic C.sub.1-6alkyl; each --R.sup.X is saturated
aliphatic C.sub.1-6haloalkyl; each --R.sup.C is saturated
C.sub.3-7cycloalkyl; each --R.sup.AR is phenyl or
C.sub.5-6heteroaryl; each -L- is saturated aliphatic
C.sub.1-3alkylene; and wherein: -J- is --C(.dbd.O)--NR.sup.N--;
--R.sup.N is independently --H or --H or --R.sup.NN; --R.sup.NN is
saturated aliphatic C.sub.1-4alkyl; .dbd.Y-- is .dbd.CR.sup.Y-- and
--Z.dbd. is --CR.sup.Z.dbd.; --R.sup.Y is --H; --R.sup.Z is
independently --H or --R.sup.ZZ; --R.sup.ZZ is independently --F,
--Cl, --Br, --I, --OH, saturated aliphatic C.sub.1-4alkoxy,
saturated aliphatic C.sub.1-4alkyl, or saturated aliphatic
C.sub.1-4haloalkyl; .dbd.W-- is .dbd.CR.sup.W--; --R.sup.W is --H;
--R.sup.O is independently --OH, --OR.sup.E, --NH.sub.2,
--NHR.sup.T1, --NR.sup.T1R.sup.T1 or --NR.sup.T2R.sup.T3; --R.sup.E
is saturated aliphatic C.sub.1-6alkyl; each --R.sup.T1 is saturated
aliphatic C.sub.1-6alkyl; --NR.sup.T2R.sup.T3 is independently
azetidino, pyrrolidino, piperidino, piperizino, N--(C.sub.1-3alkyl)
piperizino, or morpholino; with the proviso that the compound is
not a compound selected from the following compounds, and salts,
hydrates, and solvates thereof:
4-(3,5-dichloro-4-ethoxy-benzoylamino)-benzoic acid (PP-02); and
4-(3,5-dichloro-4-methoxy-benzoylamino)-benzoic acid (PP-03).
156. A compound according to claim 155, wherein: --R.sup.1 is
independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; --R.sup.2 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and --R.sup.3 is
independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; with the proviso that --R.sup.1,
--R.sup.2, and --R.sup.3 are not all --O--R.sup.A.
157. A compound according to claim 155, wherein: --R.sup.1 is
independently --X, --R.sup.X, --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; --R.sup.2 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; and --R.sup.3 is independently --X,
--R.sup.X, --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; with the
proviso that --R.sup.1, --R.sup.2, and --R.sup.3 are not all
--O--R.sup.A.
158. A compound according to claim 155, wherein: --R.sup.1 is
independently --X or --R.sup.X; --R.sup.2 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and --R.sup.3 is
independently --X or --R.sup.X.
159. A compound according to claim 155, wherein: --R.sup.1 is --X;
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and --R.sup.3 is --X.
160. A compound according to claim 155, wherein: --R.sup.1 is --X;
--R.sup.2 is independently --O--R.sup.A or --O--R.sup.C; and
--R.sup.3 is --X.
161. A compound according to claim 155, wherein: --R.sup.1 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C;
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and --R.sup.3 is independently --X or --R.sup.X; or:
--R.sup.1 is independently --X or --R.sup.X; --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
--R.sup.3 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C.
162. A compound according to claim 155, wherein: --R.sup.1 is
independently --O--R.sup.A or --O--R.sup.C; --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C; and --R.sup.3 is
independently --X or --R.sup.X; or: --R.sup.1 is independently --X
or --R.sup.X; --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C.
163. A compound according to claim 155, wherein: --R.sup.1 is
--O--R.sup.A; --R.sup.2 is --O--R.sup.A; and --R.sup.3 is
independently --X or --R.sup.X; or: --R.sup.1 is independently --X
or --R.sup.X; --R.sup.2 is --O--R.sup.A; and --R.sup.3 is
--O--R.sup.A.
164. A compound according to claim 155, wherein: --R.sup.1 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C;
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and --R.sup.3 is --X; or: --R.sup.1 is --X;
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and --R.sup.3 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C.
165. A compound according to claim 155, wherein: --R.sup.1 is
independently --O--R.sup.A or --O--R.sup.C; --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C; and --R.sup.3 is --X;
or: --R.sup.1 is --X; --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C.
166. A compound according to claim 155, wherein: --R.sup.1 is
independently --O--R.sup.A; --R.sup.2 is independently
--O--R.sup.A; and --R.sup.3 is --X; or: --R.sup.1 is --X; --R.sup.2
is independently --O--R.sup.A; and --R.sup.3 is independently
--O--R.sup.A.
167. A compound according to claim 155, wherein: each --X is
independently --F, --Cl, or --Br; each --R.sup.A is saturated
aliphatic C.sub.1-4alkyl; each --R.sup.X is --CF.sub.3; each
--R.sup.C is independently cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl; each --R.sup.AR is independently phenyl, pyridinyl,
pyrimidinyl, or pyridizinyl; and each -L- is independently
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
168. A compound according to claim 155, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
169. A compound according to claim 156, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
170. A compound according to claim 157, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
171. A compound according to claim 158, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
172. A compound according to claim 159, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
173. A compound according to claim 160, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
174. A compound according to claim 161, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
175. A compound according to claim 162, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
176. A compound according to claim 163, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
177. A compound according to claim 164, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
178. A compound according to claim 165, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
179. A compound according to claim 166, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
180. A compound according to claim 167, wherein: --R.sup.ZZ is
independently --F, --Cl, --OH, or -Me; --R.sup.N is --H; and
--R.sup.O is --OH.
181. A compound according to claim 155, which is selected from the
following compounds, or a pharmaceutically acceptable salt thereof:
##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445##
##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450##
##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455##
##STR00456##
182. A composition comprising a compound according to claim 155,
and a pharmaceutically acceptable carrier, diluent, or
excipient.
183. A method of preparing a composition comprising admixing a
compound according to claim 155 and a pharmaceutically acceptable
carrier, diluent, or excipient.
184. A method of treatment of a cognitive disorder, memory
impairment, memory deficit, senile dementia, Alzheimer's disease,
early stage Alzheimer's disease, intermediate stage Alzheimer's
disease, late stage Alzheimer's disease, cognitive impairment, or
mild cognitive impairment comprising administering to a subject in
need of treatment a therapeutically-effective amount of a compound
according to claim 155.
Description
RELATED APPLICATION
[0001] This application is related to United Kingdom patent
application number 0915196.0 filed 1 Sep. 2009, the contents of
which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention pertains generally to the field of
therapeutic compounds, and more specifically to certain
aryl-amido-aryl compounds (for convenience, collectively referred
to herein as "AAA compounds"), which, inter alia, are (selective)
retinoic acid receptor .alpha. (RAR.alpha.) agonists. The present
invention also pertains to pharmaceutical compositions comprising
such compounds, and the use of such compounds and compositions,
both in vitro and in vivo, to (selectively) activate RAR.alpha.,
and in the treatment of diseases and conditions that are mediated
by RAR.alpha., that are ameliorated by the activation of
RAR.alpha., etc., including cognitive disorders, memory impairment,
memory deficit, senile dementia, Alzheimer's disease, early stage
Alzheimer's disease, intermediate stage Alzheimer's disease, late
stage Alzheimer's disease, cognitive impairment, and mild cognitive
impairment.
BACKGROUND
[0003] A number of patents and publications are cited herein in
order to more fully describe and disclose the invention and the
state of the art to which the invention pertains. Each of these
references is incorporated herein by reference in its entirety into
the present disclosure, to the same extent as if each individual
reference was specifically and individually indicated to be
incorporated by reference.
[0004] Throughout this specification, including the claims which
follow, unless the context requires otherwise, the word "comprise,"
and variations such as "comprises" and "comprising," will be
understood to imply the inclusion of a stated integer or step or
group of integers or steps but not the exclusion of any other
integer or step or group of integers or steps.
[0005] It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a pharmaceutical carrier" includes
mixtures of two or more such carriers, and the like.
[0006] Ranges are often expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another embodiment includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by the use of the
antecedent "about," it will be understood that the particular value
forms another embodiment.
[0007] This disclosure includes information that may be useful in
understanding the present invention. It is not an admission that
any of the information provided herein is prior art or relevant to
the presently claimed invention, or that any publication
specifically or implicitly referenced is prior art.
Alzheimer's Disease
[0008] The current licensed treatments for Alzheimer's disease (AD)
improve the symptoms that people experience but do not alter the
progression of the underlying disease changes in the brain. Most of
the attempts to develop new treatments have focused on altering
deposits of the amyloid protein in the brain, but despite more than
a decade of intensive research this has still not yielded any new
therapies in the clinic.
[0009] The only currently approved medications for the treatment of
AD are two groups of drugs, acetylcholinesterase inhibitors (e.g.,
Aricept.TM.) and non-competitive NMDA receptor blockers (e.g.,
Memantine.TM.), which give significant symptomatic improvement but
do not fundamentally prevent or alter disease progression.
[0010] Recent research has concentrated on the mis-processing of
the amyloid precursor protein (APP) and overproduction amyloid
.beta.(A.beta.), as the central causative substrates in the disease
process and the main treatment target. However, despite
considerable effort and research over more than a decade, these
treatments have not yet translated into treatments in the
clinic.
[0011] The inventors have now determined the importance of
RAR.alpha. signalling in processing the APP into the non-amyloidic
pathway, and a key role of this pathway in modulating neuronal
survival.
Retinoic Acid Receptors
[0012] The retinoic acid receptor (RAR) is a type of nuclear
receptor which is activated by both all-trans retinoic acid and
9-cis retinoic acid. There are three retinoic acid receptors, known
as RAR.alpha., RAR.beta., and RAR.gamma..
[0013] The inventors' studies have highlighted a specific retinoic
acid receptor, (RAR).alpha., as a novel and exciting target for the
development of new treatments. This receptor has two potential
mechanisms of action; it regulates amyloid deposits in the brain
and also plays a key role in the survival of neurons.
[0014] The pathological hallmarks of Alzheimer's disease (AD) are
the presence of senile plaques containing amyloid .beta.(A.beta.)
peptide and the formation of neuronal tangles in the cerebral
cortex. In addition, 90% of AD patients have amyloid .beta.
deposits in their cerebral blood vessels (see, e.g., Vinters,
1987). Recently it has been shown that in AD there are genetic
linkages to the disease which are close to genes involved in the
retinoid signalling pathway (see, e.g., Goodman and Pardee, 2003).
This is mediated by retinoic acid receptors (RARs) and retinoid X
receptors (RXRs), both of which have three types .alpha., .beta.,
and .gamma. and various isoforms (see, e.g., Bastien and
Rochette-Egly, 2004). Transcription occurs when the small
lipophilic molecule, retinoic acid (RA) binds to an RAR/RXR
heterodimer which then binds to retinoic acid response elements
(RAREs) located in the regulatory regions of target genes (see,
e.g., Bastien and Rochette-Egly, 2004).
[0015] Vitamin A deficiency in rats leads to A.beta. deposits in
the brain vasculature and a down-regulation of RAR.alpha. in their
cortical neurons; the same receptor deficit is found in the
cortices in pathology samples of AD (see, e.g., Corcoran et al.,
2004). In addition, vitamin A deficiency produces spatial learning
and memory impairments and this cognitive decline, which is a
symptom of AD, can be reversed by normalization of brain retinoid
signalling (see, e.g., Fischer et al., 1989; Cocco et al., 2002).
Similarly, in aged mice, there is a loss of retinoid signalling in
the brain and cognitive decline and this can also be reversed by
supplementing their diet with retinoids (see, e.g., Etchamendy et
al., 2001). Also, vitamin A deficiency in mice can lead to a loss
in hippocampal synaptic plasticity, which can be reversed by the
addition of retinoids to the diet (see, e.g., Misner et al.,
2001).
[0016] It has also been shown that the amyloid precursor protein
(APP), which gives rise to amyloid .beta. protein, can be
differentially spliced depending on the concentration of RA (see,
e.g., Pan et al., 1993). The APP can be cleaved into A.beta.40 and
A.beta.42 by .beta. and .gamma. secretases (see, e.g., Selkoe,
2001). Alternatively, APP can be cleaved by .alpha. secretases into
a soluble neuroprotective fragment (see, e.g., Annaert and De,
2000). Disintegrin-metalloproteinases (ADAMS) have been shown to
act as .alpha. secretases (see, e.g., Lammich et al., 1999; Endres
et al., 2005), and one of these (ADAM10) has been shown to be
regulated by RA (see, e.g., Endres et al., 2005) and this appears
to be direct as the promoter of this gene contains an RARE (see,
e.g., Prinzen et al., 2005).
[0017] Other consistent aspects of AD are defects in the levels of
the neurotransmitter, acetylcholine, which is produced by
cholinergic neurons. In AD, there is a loss of the cholinergic
markers choline acetyltransferase (chAT), which synthesises
acetylcholine and acetylcholinesterase (Ache); Ache breaks down
acetylcholine, and subsequently causes the loss of cholinergic
neurons themselves (see, e.g., Coyle et al., 1983; Perry et al.,
1992; Geula et al., 1998; Ladner and Lee, 1998; Talesa, 2001). It
is the loss in cholinergic function that leads to the memory
deficits in AD (see, e.g., Collerton, 1986; DeKosky et al., 1992;
Bierer et al., 1995; Fischer et al., 1989). RA can also increase
chAT expression (see, e.g., Cervini et al., 1994; Berrard et al.,
1995; Bejanin et al., 1994).
[0018] The inventors' have now shown that RAR.alpha. agonists are
likely to be useful in the treatment of AD. They prevent neuronal
cell death in the presence of A.beta.42; in culture, they
up-regulate chAT, down-regulate APP and increase the expression of
ADAM10. In vivo, the inventors' have shown that feeding RAR.alpha.
agonists to Tg2576 mice (which overexpresses the Swedish mutation
of the human APP leading to amyloid .beta. deposits and cognitive
decline) results in a significant reduction in the levels of both
A.beta.40 and A.beta.42. Studies demonstrating these findings are
described in more detail in the Examples below.
[0019] Certain aryl-amido-aryl compounds are known in the art.
[0020] Teng et al., 1997 (U.S. Pat. No. 5,663,357) describes
certain compounds which apparently have retinoid-like biological
activity. All of the compounds exemplified therein (see Table 1,
spanning column 6 and 7 therein) have the following formula, in
which the ring that is opposite the ring bearing the carboxylic
acid group has two tert-butyl substituents.
##STR00001##
[0021] Shudo, 1987 (U.S. Pat. No. 4,703,110) describes certain
compounds which apparently are useful for diagnosis of leukemia
types, the treatment of dermatological disorders, and as
differentiation-inducing agents for neoplastic cells. Among the
compounds exemplified therein (see Tables 1 and 2 spanning columns
8 to 12 therein) are compounds of the following formula, wherein
--X-- is an amide linkage (see, e.g., the last few compounds in
Table 1, and compounds 15-40, 64, 65, 67, and 68 in Table 2).
However, in each case, the substituents R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and R.sub.5, when not hydrogen, are alkyl (e.g., -Et,
-iPr, -tBu), cycloalkyl (e.g., cyclohexyl), or together form a ring
fused to the parent phenyl ring.
##STR00002##
[0022] Shudo et al., 1996, (U.S. Pat. No. 5,525,618) describes
certain compounds which apparently are useful in osteopathic
treatment. The following compounds are shown in Table 1 (see
columns 8 to 9 therein).
##STR00003##
[0023] Kato et al., 1992 (EP 0 515 684 A1) describes compounds
according to the following general formula. These compounds are
said to be useful in treating arteriosclerosis, peptic ulcer,
cancer, ischemic organ disease, inflammation and pulmonary
silicosis.
##STR00004##
[0024] Of the numerous compounds described therein, Compound 132 on
page 59 has the structure given below.
##STR00005##
[0025] Mizukoshi et al., 1986 (JP 61-233678 A) describes compounds
useful as anti-ulcer agents. Compound 1849-89-4 therein has the
structure shown below.
##STR00006##
[0026] Albright et al., 1998 (U.S. Pat. No. 5,849,735) describes
tricyclic compounds of the following general formula. These
compounds are said to exhibit in vivo vasopressin antagonist
activity and antagonist activity at oxytocin receptors, and to be
useful in treating conditions where decreased vasopressin levels
are desired, such as in congestive heart failure, in disease
conditions with excess renal water reabsorption and in conditions
with increased vascular resistance and coronary
vasoconstriction.
##STR00007##
[0027] Additionally, the document includes, as reference example 65
(see column 53 therein), a compound having the structure shown
below, without attributing any particular activity to the
compound.
##STR00008##
[0028] Schmidt et al., 1975 (GB 1 409 689) describes compounds
referred to as "new penicillin compounds", which are said to be
suitable for treating bacterial infections. Additionally,
4-(3,4,5-trimethoxybenzoylamino)-benzoic acid is mentioned as a
precursor compound (for compound 22; see page 35 therein). This
precursor compound has the structure shown below.
##STR00009##
[0029] Coppola et al., 2005 describes compounds said to have
activity as inhibitors of 11.beta.-HSD1, and suggests that the
compounds may "serve as useful tools to study the effect of
11.beta.-HSD1 inhibition in animal models of diabetes, dyslipidemia
and obesity". Of the compounds described in the document, compound
9a has the structure shown below.
##STR00010##
SUMMARY OF THE INVENTION
[0030] One aspect of the invention pertains to certain
aryl-amido-aryl compounds (for convenience, collectively referred
to herein as "AAA compounds"), as described herein.
[0031] Another aspect of the invention pertains to a composition
(e.g., a pharmaceutical composition) comprising an AAA compound, as
described herein, and a pharmaceutically acceptable carrier or
diluent.
[0032] Another aspect of the invention pertains to method of
preparing a composition (e.g., a pharmaceutical composition)
comprising the step of admixing an AAA compound, as described
herein, and a pharmaceutically acceptable carrier or diluent.
[0033] Another aspect of the present invention pertains to a method
of activating retinoic acid receptor .alpha. (RAR.alpha.), in vitro
or in vivo, comprising contacting RAR.alpha. with an effective
amount of an AAA compound, as described herein.
[0034] Another aspect of the present invention pertains to a method
of selectively activating retinoic acid receptor .alpha.
(RAR.alpha.) (e.g., with respect to RAR.beta. and/or RAR.gamma.),
in vitro or in vivo, comprising contacting RAR.alpha. with an
effective amount of an AAA compound, as described herein.
[0035] Another aspect of the present invention pertains to a method
of activating retinoic acid receptor .alpha. (RAR.alpha.) in a
neuronal cell, in vitro or in vivo, comprising contacting the cell
with an effective amount of an AAA compound, as described
herein.
[0036] Another aspect of the present invention pertains to a method
of selectively activating retinoic acid receptor .alpha.
(RAR.alpha.) (e.g., with respect to RAR.beta. and/or RAR.gamma.) in
a neuronal cell, in vitro or in vivo, comprising contacting the
cell with an effective amount of an AAA compound, as described
herein.
[0037] Another aspect of the present invention pertains to a method
of up-regulating chAT expression in a cortical neuron, comprising
contacting the cortical neuron, in vitro or in vivo, with an
effective amount of an AAA compound, as described herein.
[0038] Another aspect of the present invention pertains to a method
of down-regulating APP expression in a cortical neuron, comprising
contacting the cortical neuron, in vitro or in vivo, with an
effective amount of an AAA compound, as described herein.
[0039] Another aspect of the present invention pertains to a method
of up-regulating ADAM10 expression in a cortical neuron, comprising
contacting the cortical neuron, in vitro or in vivo, with an
effective amount of an AAA compound, as described herein.
[0040] Another aspect of the present invention pertains to a method
of down-regulating A.beta.40 and A.beta.42 expression in a cortical
neuron, comprising contacting the cortical neuron, in vitro or in
vivo, with an effective amount of an AAA compound, as described
herein.
[0041] Another aspect of the present invention pertains to a method
of up-regulating chAT expression in a cortical neuron in a patient,
comprising administering to the patient a therapeutically effective
amount of an AAA compound, as described herein.
[0042] Another aspect of the present invention pertains to a method
of down-regulating APP expression in a cortical neuron in a
patient, comprising administering to the patient a therapeutically
effective amount of an AAA compound, as described herein.
[0043] Another aspect of the present invention pertains to a method
of up-regulating ADAM10 expression in a cortical neuron in a
patient, comprising administering to the patient a therapeutically
effective amount of an AAA compound, as described herein.
[0044] Another aspect of the present invention pertains to a method
of down-regulating A.beta.40 and A.beta.42 expression in a cortical
neuron in a patient, comprising administering to the patient a
therapeutically effective amount of an AAA compound, as described
herein.
[0045] Another aspect of the present invention pertains to a method
of preventing, reducing, or slowing cortical neuronal death in a
patient, comprising administering to the patient a therapeutically
effective amount of an AAA compound, as described herein.
[0046] Another aspect of the present invention pertains to a method
of treatment comprising administering to a subject in need of
treatment a therapeutically-effective amount of an AAA compound, as
described herein, preferably in the form of a pharmaceutical
composition.
[0047] Another aspect of the present invention pertains to an AAA
compound as described herein for use treatment of the human or
animal body by therapy.
[0048] Another aspect of the present invention pertains to use of
an AAA compound, as described herein, in the manufacture of a
medicament for use in treatment.
[0049] In one embodiment, the treatment is treatment of a disease
or condition that is mediated by RAR.alpha..
[0050] In one embodiment, the treatment is treatment of a disease
or condition that is ameliorated by the activation of
RAR.alpha..
[0051] In one embodiment, the treatment is treatment of a disease
or condition that is ameliorated by the selective activation of
RAR.alpha. (e.g., with respect to RAR.beta. and/or RAR.gamma.).
[0052] In one embodiment, the treatment is treatment of a cognitive
disorder, memory impairment, memory deficit, senile dementia,
Alzheimer's disease, early stage Alzheimer's disease, intermediate
stage Alzheimer's disease, late stage Alzheimer's disease,
cognitive impairment, or mild cognitive impairment.
[0053] In one embodiment, the treatment is treatment of Alzheimer's
disease.
[0054] In one embodiment, the treatment is treatment of early stage
Alzheimer's disease.
[0055] In one embodiment, the treatment is treatment of
intermediate stage Alzheimer's disease.
[0056] In one embodiment, the treatment is treatment of late stage
Alzheimer's disease.
[0057] In one embodiment, the treatment is treatment of cognitive
impairment.
[0058] In one embodiment, the treatment is treatment of mild
cognitive impairment.
[0059] Another aspect of the present invention pertains to a kit
comprising (a) an AAA compound, as described herein, preferably
provided as a pharmaceutical composition and in a suitable
container and/or with suitable packaging; and (b) instructions for
use, for example, written instructions on how to administer the
compound.
[0060] Another aspect of the present invention pertains to an AAA
compound obtainable by a method of synthesis as described herein,
or a method comprising a method of synthesis as described
herein.
[0061] Another aspect of the present invention pertains to an AAA
compound obtained by a method of synthesis as described herein, or
a method comprising a method of synthesis as described herein.
[0062] Another aspect of the present invention pertains to novel
intermediates, as described herein, which are suitable for use in
the methods of synthesis described herein.
[0063] Another aspect of the present invention pertains to the use
of such novel intermediates, as described herein, in the methods of
synthesis described herein.
[0064] As will be appreciated by one of skill in the art, features
and preferred embodiments of one aspect of the invention will also
pertain to other aspect of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Compounds
[0065] One aspect of the present invention relates to certain
compounds which are structurally related to the following
compounds:
TABLE-US-00001 1 ##STR00011## 4-Benzoylamino- benzoic acid 2
##STR00012## 6-Benzoylamino- nicotinic acid 3 ##STR00013##
5-Benzoylamino- pyridine-2- carboxylic acid 4 ##STR00014##
6-Benzoylamino- pyridazine- 3-carboxylic acid 5 ##STR00015##
N-Phenyl- terephthalamic acid 6 ##STR00016## 5-Phenylcarbamoyl-
pyridine-2- carboxylic acid 7 ##STR00017## 6-Phenylcarbamoyl-
nicotinic acid 8 ##STR00018## 6-Phenylcarbamoyl- pyridazine-3-
carboxylic acid
[0066] Thus, one aspect of the present invention pertains to
compounds selected from compounds of the following formula, and
pharmaceutically acceptable salts, hydrates, and solvates thereof,
wherein --R.sup.1, --R.sup.2, --R.sup.3, -J-, --W.dbd., --Y.dbd.,
--Z.dbd., and --R.sup.O are as defined herein (for convenience,
collectively referred to herein as "aryl-amido-aryl compounds" or
"AAA compounds"):
##STR00019##
[0067] Some embodiments of the invention include the following:
(1) A compound selected from compounds of the following formula,
and pharmaceutically acceptable salts, hydrates, and solvates
thereof:
##STR00020##
wherein: [0068] --R.sup.1 is independently --X, --R.sup.X,
--O--R.sup.X, --O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C,
--O--R.sup.AR, or --O-L-R.sup.AR; [0069] --R.sup.2 is independently
--X, --R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C,
--O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR; [0070] --R.sup.3
is independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR;
wherein: [0071] each --X is independently --F, --Cl, --Br, or --I;
[0072] each --R.sup.A is independently saturated aliphatic
C.sub.1-6alkyl; [0073] each --R.sup.X is independently saturated
aliphatic C.sub.1-6haloalkyl; [0074] each --R.sup.C is
independently saturated C.sub.3-7cycloalkyl; [0075] each --R.sup.AR
is independently phenyl or C.sub.5-6heteroaryl; [0076] each -L- is
independently saturated aliphatic C.sub.1-3alkylene; and wherein:
[0077] -J- is independently --C(.dbd.O)--NR.sup.N-- or
--NR.sup.N--C(.dbd.O)--; [0078] --R.sup.N is independently --H or
--R.sup.NN; [0079] --R.sup.NN is independently saturated aliphatic
C.sub.1-4alkyl; [0080] .dbd.Y-- is .dbd.CR.sup.Y-- and --Z.dbd. is
--CR.sup.Z.dbd.; or [0081] .dbd.Y-- is .dbd.N-- and --Z.dbd. is
--CR.sup.Z.dbd.; or [0082] .dbd.Y-- is .dbd.CR.sup.Y-- and --Z.dbd.
is --N.dbd.; or [0083] .dbd.Y-- is .dbd.N-- and --Z.dbd. is
--N.dbd.; [0084] --R.sup.Y is independently --H or --R.sup.YY;
[0085] --R.sup.YY is independently --F, --Cl, --Br, --I, or
saturated aliphatic C.sub.1-4alkyl; [0086] --R.sup.Z is
independently --H or --R.sup.ZZ; [0087] --R.sup.ZZ is independently
--F, --Cl, --Br, --I, --OH, saturated aliphatic C.sub.1-4alkoxy,
saturated aliphatic C.sub.1-4alkyl, or saturated aliphatic
C.sub.1-4haloalkyl; [0088] .dbd.W-- is .dbd.CR.sup.W--; [0089]
--R.sup.W is independently --H or --R.sup.WW; [0090] --R' is
independently --F, --Cl, --Br, --I, --OH, saturated aliphatic
C.sub.1-4alkoxy, saturated aliphatic C.sub.1-4alkyl, or saturated
aliphatic C.sub.1-4haloalkyl; [0091] --R.sup.O is independently
--OH, --OR.sup.E, --NH.sub.2, --NHR.sup.T1, --NR.sup.T1R.sup.T1, or
--NR.sup.T2R.sup.T3; [0092] --R.sup.E is independently saturated
aliphatic C.sub.1-6alkyl; [0093] each --R.sup.T1 is independently
saturated aliphatic C.sub.1-6alkyl; [0094] --NR.sup.T2R.sup.T3 is
independently azetidino, pyrrolidino, piperidino, piperizino,
N--(C.sub.1-3alkyl)piperizino, or morpholino.
[0095] For the avoidance of doubt, it is not intended that
--R.sup.1 and --R.sup.2 and --R.sup.3 are attached to one another
other than as shown in the above formula. For example, it is not
intended that --R.sup.1 and --R.sup.2 together form a ring fused to
the benzene ring to which they are attached. Similarly, it is not
intended that --R.sup.2 and --R.sup.3 together form a ring fused to
the benzene ring to which they are attached. Similarly, it is not
intended that --R.sup.1 and --R.sup.3 together form a ring fused to
the benzene ring to which they are attached.
[0096] For the avoidance of doubt, the term "C.sub.1-6haloalkyl"
refers to a C.sub.1-6alkyl group that has one or more (e.g., 1, 2,
3, etc.) halo substituents, and includes, for example, --CF.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2F, etc.
[0097] For the avoidance of doubt, the term "agonist" is intended
to encompass compounds which are partial agonists.
Optional Provisos
[0098] In one or more aspects of the present invention (e.g.,
compounds, compositions, compounds for use in therapy, use of
compounds in the manufacture of a medicament, methods, methods of
treatment, etc.), the compounds are optionally as defined herein,
but with one or more optional provisos, as defined herein.
(2) A compound according to (1), with the proviso that the compound
is not a compound selected from: compounds (PP-01), (PP-02), and
(PP-03), and salts, hydrates, and solvates thereof. (3) A compound
according to (1), with the proviso that the compound is not a
compound selected from: compounds (PP-01), (PP-02), (PP-03),
(PP-04), (PP-05), (PP-06), (PP-07), and (PP-08), and salts,
hydrates, and solvates thereof.
TABLE-US-00002 # Structure Name Registry No. PP-01 ##STR00021##
4-(3,4,5-triethoxy- benzoylamino)- benzoic acid 926257-87-6 PP-02
##STR00022## 4-(3,5-Dichloro-4- ethoxy- benzoylamino)- benzoic acid
690982-75-3 PP-03 ##STR00023## 4-(3,5-Dichloro-4- methoxy-
benzoylamino)- benzoic acid 832094-08-3 PP-04 ##STR00024##
4-(3,4,5- Trimethoxy- benzoylamino)- benzoic acid methyl ester
303796-30-7 PP-05 ##STR00025## 4-(3,4,5- Trimethoxy- benzoylamino)-
benzoic acid ethyl ester 1849-89-4 PP-06 ##STR00026## 6-(3,4,5-
Trimethoxy- benzoylamino)- nicotinic acid 180339-52-0 PP-07
##STR00027## 4-(3,4,5- Trimethoxy- benzoylamino)- benzoic acid
54057-51-1 PP-08 ##STR00028## 3,4,5-Trimethoxy- N-[4-(piperidine-1-
carbonyl)-phenyl]- benzamide 901062-25-7
[0099] It appears that compounds (PP-01), (PP-02), and (PP-03) are
commercially available. However, their usefulness (e.g., as
RAR.alpha. agonists, in method of therapy, etc., as described
herein) has not yet been published.
[0100] In one or more aspects of the present invention (e.g.,
compounds for use in therapy, use of compounds in the manufacture
of a medicament, methods of treatment, etc.), the compounds are
optionally as defined herein, but without the proviso regarding
compounds (PP-01), (PP-02), and (PP-03).
[0101] In one or more aspects of the present invention (e.g.,
compounds for use in therapy, use of compounds in the manufacture
of a medicament, methods of treatment, etc.), the compounds are
optionally as defined herein, but without the proviso regarding
compounds (PP-01), (PP-02), (PP-03), (PP-04), (PP-05), (PP-06),
(PP-07), and (PP-08).
[0102] For example, a reference to a particular group of compounds
"without the recited proviso regarding compounds (PP-01), (PP-02),
and (PP-03)" (e.g., for use in therapy) is intended to be a
reference to the compounds as defined, but wherein the definition
no longer includes the indicated proviso. In such cases, it is as
if the indicated proviso has been deleted from the definition of
compounds, and the definition has been expanded to encompass those
compounds which otherwise would have been excluded by the indicated
proviso.
[0103] In one or more aspects of the present invention (e.g.,
compounds for use in therapy, use of compounds in the manufacture
of a medicament, methods of treatment, etc.), the compounds are
optionally as defined herein, with the proviso regarding compounds
(PP-01), (PP-02), and (PP-03).
[0104] In one or more aspects of the present invention (e.g.,
compounds for use in therapy, use of compounds in the manufacture
of a medicament, methods of treatment, etc.), the compounds are
optionally as defined herein, with the proviso regarding compounds
(PP-01), (PP-02), (PP-03), (PP-04), (PP-05), (PP-06), (PP-07), and
(PP-08).
The Group --R.sup.1
[0105] (4) A compound according to any one of (1) to (3), wherein:
[0106] --R.sup.1 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, or --O-L-R.sup.AR. (5) A
compound according to any one of (1) to (3), wherein: [0107]
--R.sup.1 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C. (6) A compound according
to any one of (1) to (3), wherein: [0108] --R.sup.1 is
independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A, or
--O--R.sup.C. (7) A compound according to any one of (1) to (3),
wherein: [0109] --R.sup.1 is independently --X, --R.sup.X,
--O--R.sup.A, or --O--R.sup.C. (8) A compound according to any one
of (1) to (3), wherein: [0110] --R.sup.1 is independently --X,
--R.sup.X, or --O--R.sup.A. (9) A compound according to any one of
(1) to (3), wherein: [0111] --R.sup.1 is independently --X or
--R.sup.X. (10) A compound according to any one of (1) to (3),
wherein: [0112] --R.sup.1 is independently --X. (11) A compound
according to any one of (1) to (3), wherein: [0113] --R.sup.1 is
independently --R.sup.X. (12) A compound according to any one of
(1) to (3), wherein: [0114] --R.sup.1 is independently
--O--R.sup.X. (13) A compound according to any one of (1) to (3),
wherein: [0115] --R.sup.1 is independently --O--R.sup.A. (14) A
compound according to any one of (1) to (3), wherein: [0116]
--R.sup.1 is independently --O--R.sup.C. (15) A compound according
to any one of (1) to (3), wherein: [0117] --R.sup.1 is
independently --O-L-R.sup.C. (16) A compound according to any one
of (1) to (3), wherein: [0118] --R.sup.1 is independently
--O--R.sup.AR. (17) A compound according to any one of (1) to (3),
wherein: [0119] --R.sup.1 is independently --O-L-R.sup.AR.
The Group --R.sup.2
[0120] (18) A compound according to any one of (1) to (17),
wherein: [0121] --R.sup.2 is independently --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or
--O-L-R.sup.AR. (19) A compound according to any one of (1) to
(17), wherein: [0122] --R.sup.2 is independently --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, or --O-L-R.sup.AR. (20)
A compound according to any one of (1) to (17), wherein: [0123]
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C,
--O-L-R.sup.C, or --O-L-R.sup.AR. (21) A compound according to any
one of (1) to (17), wherein: [0124] --R.sup.2 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C. (22) A compound
according to any one of (1) to (17), wherein: [0125] --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C. (23) A compound
according to any one of (1) to (17), wherein: [0126] --R.sup.2 is
independently --X or --R.sup.X. (24) A compound according to any
one of (1) to (17), wherein: [0127] --R.sup.2 is independently --X.
(25) A compound according to any one of (1) to (17), wherein:
[0128] --R.sup.2 is independently --R.sup.X. (26) A compound
according to any one of (1) to (17), wherein: [0129] --R.sup.2 is
independently --O--R.sup.X. (27) A compound according to any one of
(1) to (17), wherein: [0130] --R.sup.2 is independently
--O--R.sup.A. (28) A compound according to any one of (1) to (17),
wherein: [0131] --R.sup.2 is independently --O--R.sup.C. (29) A
compound according to any one of (1) to (17), wherein: [0132]
--R.sup.2 is independently --O-L-R.sup.C. (30) A compound according
to any one of (1) to (17), wherein: [0133] --R.sup.2 is
independently --O--R.sup.AR. (31) A compound according to any one
of (1) to (17), wherein: [0134] --R.sup.2 is independently
--O-L-R.sup.AR.
The Group --R.sup.3
[0135] (32) A compound according to any one of (1) to (31),
wherein: [0136] --R.sup.3 is independently --X, --R.sup.X,
--O--R.sup.X, --O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, or
--O-L-R.sup.AR. (33) A compound according to any one of (1) to
(31), wherein: [0137] --R.sup.3 is independently --X, --R.sup.X,
--O--R.sup.X, --O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C. (34) A
compound according to any one of (1) to (31), wherein: [0138]
--R.sup.3 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, or --O--R.sup.C. (35) A compound according to any one
of (1) to (31), wherein: [0139] --R.sup.3 is independently --X,
--R.sup.X, --O--R.sup.A, or --O--R.sup.C. (36) A compound according
to any one of (1) to (31), wherein: [0140] --R.sup.3 is
independently --X, --R.sup.X, or --O--R.sup.A. (37) A compound
according to any one of (1) to (31), wherein: [0141] --R.sup.3 is
independently --X or --R.sup.X. (38) A compound according to any
one of (1) to (31), wherein: [0142] --R.sup.3 is independently --X.
(39) A compound according to any one of (1) to (31), wherein:
[0143] --R.sup.3 is independently --R.sup.X. (40) A compound
according to any one of (1) to (31), wherein: [0144] --R.sup.3 is
independently --O--R.sup.X. (41) A compound according to any one of
(1) to (31), wherein: [0145] --R.sup.3 is independently
--O--R.sup.A. (42) A compound according to any one of (1) to (31),
wherein: [0146] --R.sup.3 is independently --O--R.sup.C. (43) A
compound according to any one of (1) to (31), wherein: [0147]
--R.sup.3 is independently --O-L-R.sup.C. (44) A compound according
to any one of (1) to (31), wherein: [0148] --R.sup.3 is
independently --O--R.sup.AR. (45) A compound according to any one
of (1) to (31), wherein: [0149] --R.sup.3 is independently
--O-L-R.sup.AR.
Examples of Some Particular Combinations of --R.sup.1, --R.sup.2,
and --R.sup.3
[0150] (46) A compound according to any one of (1) to (3), wherein:
[0151] --R.sup.1 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or
--O-L-R.sup.AR; [0152] --R.sup.2 is independently --X, --R.sup.X,
--O--R.sup.X, --O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C,
--O--R.sup.AR, or --O-L-R.sup.AR; [0153] --R.sup.3 is independently
--X, --R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C,
--O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR; [0154] with the
proviso that --R.sup.1, --R.sup.2, and --R.sup.3 are not all
--O-Me; and [0155] with the proviso that --R.sup.1, --R.sup.2, and
--R.sup.3 are not all --O-Et. (47) A compound according to any one
of (1) to (3), wherein: [0156] --R.sup.1 is independently --X,
--R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C,
--O--R.sup.AR, or --O-L-R.sup.AR; [0157] --R.sup.2 is independently
--X, --R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C,
--O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR; [0158] --R.sup.3
is independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR;
[0159] with the proviso that if: --R.sup.1, --R.sup.2, and
--R.sup.3 are all --O--R.sup.A, [0160] then: --R.sup.1, --R.sup.2,
and --R.sup.3 are not all the same. (48) A compound according to
any one of (1) to (3), wherein: [0161] --R.sup.1 is independently
--X, --R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C,
--O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR; [0162] --R.sup.2
is independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or --O-L-R.sup.AR;
[0163] --R.sup.3 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, --O-L-R.sup.C, --O--R.sup.AR, or
--O-L-R.sup.AR; [0164] with the proviso that --R.sup.1, --R.sup.2,
and --R.sup.3 are not all --O--R.sup.A. (49) A compound according
to any one of (1) to (3), wherein: [0165] --R.sup.1 is
independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; [0166] --R.sup.2 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and [0167] --R.sup.3
is independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C. (50) A compound according to any
one of (1) to (3), wherein: [0168] --R.sup.1 is independently --X,
--R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; [0169] --R.sup.2 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; and [0170] --R.sup.3 is
independently --X, --R.sup.X, --O--R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; [0171] with the proviso that
--R.sup.1, --R.sup.2, and --R.sup.3 are not all --O-Me; and [0172]
with the proviso that --R.sup.1, --R.sup.2, and --R.sup.3 are not
all --O-Et. (51) A compound according to any one of (1) to (3),
wherein: [0173] --R.sup.1 is independently --X, --R.sup.X,
--O--R.sup.X, --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0174]
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and [0175] --R.sup.3 is independently --X,
--R.sup.X, --O--R.sup.X, --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; [0176] with the proviso that if: --R.sup.1,
--R.sup.2, and --R.sup.3 are all --O--R.sup.A, [0177] then:
--R.sup.1, --R.sup.2, and --R.sup.3 are not all the same. (52) A
compound according to any one of (1) to (3), wherein: [0178]
--R.sup.1 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0179] --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
[0180] --R.sup.3 is independently --X, --R.sup.X, --O--R.sup.X,
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0181] with the
proviso that --R.sup.1, --R.sup.2, and --R.sup.3 are not all
--O--R.sup.A. (53) A compound according to any one of (1) to (3),
wherein: [0182] --R.sup.1 is independently --X, --R.sup.X,
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0183] --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
[0184] --R.sup.3 is independently --X, --R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C. (54) A compound according to any
one of (1) to (3), wherein: [0185] --R.sup.1 is independently --X,
--R.sup.X, --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0186]
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and [0187] --R.sup.3 is independently --X,
--R.sup.X, --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0188]
with the proviso that --R.sup.1, --R.sup.2, and --R.sup.3 are not
all --O-Me; and [0189] with the proviso that --R.sup.1, --R.sup.2,
and --R.sup.3 are not all --O-Et. (55) A compound according to any
one of (1) to (3), wherein: [0190] --R.sup.1 is independently --X,
--R.sup.X, --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0191]
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and [0192] --R.sup.3 is independently --X,
--R.sup.X, --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0193]
with the proviso that if: --R.sup.1, --R.sup.2, and --R.sup.3 are
all --O--R.sup.A, [0194] then: --R.sup.1, --R.sup.2, and --R.sup.3
are not all the same. (56) A compound according to any one of (1)
to (3), wherein: [0195] --R.sup.1 is independently --X, --R.sup.X,
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0196] --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
[0197] --R.sup.3 is independently --X, --R.sup.X, --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; [0198] with the proviso that
--R.sup.1, --R.sup.2, and --R.sup.3 are not all --O--R.sup.A. (57)
A compound according to any one of (1) to (3), wherein: [0199]
--R.sup.1 is independently --X or --R.sup.X; [0200] --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
[0201] --R.sup.3 is independently --X or --R.sup.X; (58) A compound
according to any one of (1) to (3), wherein: [0202] --R.sup.1 is
independently --X; [0203] --R.sup.2 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; and [0204] --R.sup.3 is
independently --X. (59) A compound according to any one of (1) to
(3), wherein: [0205] --R.sup.1 is independently --X; [0206]
--R.sup.2 is independently --O--R.sup.A or --O--R.sup.C; and [0207]
--R.sup.3 is independently --X. (60) A compound according to any
one of (1) to (3), wherein: [0208] --R.sup.1 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0209] --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
[0210] --R.sup.3 is independently --X or --R.sup.X; [0211] or:
[0212] --R.sup.1 is independently --X or --R.sup.X; [0213]
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and [0214] --R.sup.3 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C. (61) A compound according to any
one of (1) to (3), wherein: [0215] --R.sup.1 is independently
--O--R.sup.A or --O--R.sup.C; [0216] --R.sup.2 is independently
--O--R.sup.A or --O--R.sup.C; and [0217] --R.sup.3 is independently
--X or --R.sup.X; [0218] or: [0219] --R.sup.1 is independently --X
or --R.sup.X; [0220] --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and [0221] --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C. (62) A compound according to any one of (1) to (3),
wherein: [0222] --R.sup.1 is independently --O--R.sup.A; [0223]
--R.sup.2 is independently --O--R.sup.A; and [0224] --R.sup.3 is
independently --X or --R.sup.X; [0225] or: [0226] --R.sup.1 is
independently --X or --R.sup.X; [0227] --R.sup.2 is independently
--O--R.sup.A; and [0228] --R.sup.3 is independently --O--R.sup.A.
(63) A compound according to any one of (1) to (3), wherein: [0229]
--R.sup.1 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; [0230] --R.sup.2 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; and [0231] --R.sup.3 is
independently --X; [0232] or: [0233] --R.sup.1 is independently
--X; [0234] --R.sup.2 is independently --O--R.sup.A, --O--R.sup.C,
or --O-L-R.sup.C; and [0235] --R.sup.3 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C. (64) A compound
according to any one of (1) to (3), wherein: [0236] --R.sup.1 is
independently --O--R.sup.A or --O--R.sup.C; [0237] --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C; and [0238] --R.sup.3 is
independently --X; [0239] or: [0240] --R.sup.1 is independently
--X; [0241] --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and [0242] --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C. (65) A compound according to any one of (1) to (3),
wherein: [0243] --R.sup.1 is independently --O--R.sup.A; [0244]
--R.sup.2 is independently --O--R.sup.A; and [0245] --R.sup.3 is
independently --X; [0246] or: [0247] --R.sup.1 is independently
--X; [0248] --R.sup.2 is independently --O--R.sup.A; and [0249]
--R.sup.3 is independently --O--R.sup.A. (66) A compound according
to any one of (1) to (3), wherein: [0250] --R.sup.1 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0251]
--R.sup.2 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; and [0252] --R.sup.3 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C. (67) A compound according to any
one of (1) to (3), wherein: [0253] --R.sup.1 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0254] --R.sup.2 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and
[0255] --R.sup.3 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; [0256] with the proviso that --R.sup.1, --R.sup.2,
and --R.sup.3 are not all --O-Me; and [0257] with the proviso that
--R.sup.1, --R.sup.2, and --R.sup.3 are not all --O-Et. (68) A
compound according to any one of (1) to (3), wherein: [0258]
--R.sup.1 is independently --O--R.sup.A, --O--R.sup.C, or
--O-L-R.sup.C; [0259] --R.sup.2 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; and [0260] --R.sup.3 is
independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; [0261]
with the proviso that if: --R.sup.1, --R.sup.2, and --R.sup.3 are
all --O--R.sup.A, [0262] then: --R.sup.1, --R.sup.2, and --R.sup.3
are not all the same. (69) A compound according to any one of (1)
to (3), wherein: [0263] --R.sup.1 is independently --O--R.sup.A,
--O--R.sup.C, or --O-L-R.sup.C; [0264] --R.sup.2 is independently
--O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C; and [0265] --R.sup.3
is independently --O--R.sup.A, --O--R.sup.C, or --O-L-R.sup.C;
[0266] with the proviso that --R.sup.1, --R.sup.2, and --R.sup.3
are not all --O--R.sup.A. (70) A compound according to any one of
(1) to (3), wherein: [0267] --R.sup.1 is independently --O--R.sup.A
or --O--R.sup.C; [0268] --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and [0269] --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C. (71) A compound according to any one of (1) to (3),
wherein: [0270] --R.sup.1 is independently --O--R.sup.A or
--O--R.sup.C; [0271] --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and [0272] --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C; [0273] with the proviso that --R.sup.1, --R.sup.2,
and --R.sup.3 are not all --O-Me; and [0274] with the proviso that
--R.sup.1, --R.sup.2, and --R.sup.3 are not all --O-Et. (72) A
compound according to any one of (1) to (3), wherein: [0275]
--R.sup.1 is independently --O--R.sup.A or --O--R.sup.C; [0276]
--R.sup.2 is independently --O--R.sup.A or --O--R.sup.C; and [0277]
--R.sup.3 is independently --O--R.sup.A or --O--R.sup.C; [0278]
with the proviso that if: --R.sup.1, --R.sup.2, and --R.sup.3 are
all --O--R.sup.A, [0279] then: --R.sup.1, --R.sup.2, and --R.sup.3
are not all the same. (73) A compound according to any one of (1)
to (3), wherein: [0280] --R.sup.1 is independently --O--R.sup.A or
--O--R.sup.C; [0281] --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; and [0282] --R.sup.3 is independently --O--R.sup.A or
--O--R.sup.C; [0283] with the proviso that --R.sup.1, --R.sup.2,
and --R.sup.3 are not all --O--R.sup.A.
The Group --X
[0284] (74) A compound according to any one of (1) to (73),
wherein: [0285] each --X, if present, is independently --F, --Cl,
or --Br. (75) A compound according to any one of (1) to (73),
wherein: [0286] each --X, if present, is independently --F or --Cl.
(76) A compound according to any one of (1) to (73), wherein:
[0287] each --X, if present, is independently --Cl or --Br. (77) A
compound according to any one of (1) to (73), wherein: [0288] each
--X, if present, is independently --F. (78) A compound according to
any one of (1) to (73), wherein: [0289] each --X, if present, is
independently --Cl. (79) A compound according to any one of (1) to
(73), wherein: [0290] each --X, if present, is independently
--Br.
The Group --R.sup.A
[0291] (80) A compound according to any one of (1) to (79),
wherein: [0292] each --R.sup.A, if present, is independently
saturated aliphatic C.sub.1-4alkyl. (81) A compound according to
any one of (1) to (79), wherein: [0293] each --R.sup.A, if present,
is independently -Me, -Et, -nPr, or -iPr. (82) A compound according
to any one of (1) to (79), wherein: [0294] each --R.sup.A, if
present, is independently -Me. (83) A compound according to any one
of (1) to (79), wherein: [0295] each --R.sup.A, if present, is
independently -Et. (84) A compound according to any one of (1) to
(79), wherein: [0296] each --R.sup.A, if present, is independently
-iPr.
The Group --R.sup.X
[0297] (85) A compound according to any one of (1) to (84),
wherein: [0298] each --R.sup.X, if present, is independently
saturated aliphatic C.sub.1-4haloalkyl. (86) A compound according
to any one of (1) to (84), wherein: [0299] each --R.sup.X, if
present, is independently --CF.sub.3, --CH.sub.2CF.sub.3, or
--CH.sub.2CH.sub.2F. (87) A compound according to any one of (1) to
(84), wherein: [0300] each --R.sup.X, if present, is independently
--CF.sub.3.
The Group --R.sup.C
[0301] (88) A compound according to any one of (1) to (87),
wherein: [0302] each --R.sup.C, if present, is independently
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (89) A
compound according to any one of (1) to (87), wherein: [0303] each
--R.sup.C, if present, is independently cyclopropyl, cyclobutyl, or
cyclopentyl. (90) A compound according to any one of (1) to (87),
wherein: [0304] each --R.sup.C, if present, is independently
cyclopropyl. (91) A compound according to any one of (1) to (87),
wherein: [0305] each --R.sup.C, if present, is independently
cyclobutyl. (92) A compound according to any one of (1) to (87),
wherein: [0306] each --R.sup.C, if present, is independently
cyclopentyl.
The Group --R.sup.AR
[0307] (93) A compound according to any one of (1) to (92),
wherein: [0308] each --R.sup.AR, if present, is independently
phenyl or C.sub.6heteroaryl. (94) A compound according to any one
of (1) to (92), wherein: [0309] each --R.sup.AR, if present, is
independently phenyl, pyridinyl, pyrimidinyl, or pyridizinyl. (95)
A compound according to any one of (1) to (92), wherein: [0310]
each --R.sup.AR, if present, is independently phenyl or pyridinyl.
(96) A compound according to any one of (1) to (92), wherein:
[0311] each --R.sup.AR, if present, is independently phenyl. (97) A
compound according to any one of (1) to (92), wherein: [0312] each
--R.sup.AR, if present, is independently pyridinyl.
The Group -L-
[0313] (98) A compound according to any one of (1) to (97),
wherein: [0314] each -L-, if present, is independently --CH.sub.2--
or --CH.sub.2CH.sub.2--. (99) A compound according to any one of
(1) to (97), wherein: [0315] each -L-, if present, is independently
--CH.sub.2--.
The Groups Y and Z
[0316] (100) A compound according to any one of (1) to (99),
wherein: [0317] .dbd.Y-- is .dbd.CR.sup.Y-- and --Z.dbd. is
--CR.sup.Z.
##STR00029##
[0317] (101) A compound according to any one of (1) to (99),
wherein: [0318] .dbd.Y-- is .dbd.N-- and --Z.dbd. is
--CR.sup.Z.
##STR00030##
[0318] (102) A compound according to any one of (1) to (99),
wherein: [0319] .dbd.Y-- is .dbd.CR.sup.Y-- and --Z.dbd. is
--N.dbd..
##STR00031##
[0319] (103) A compound according to any one of (1) to (99),
wherein: [0320] .dbd.Y-- is .dbd.N-- and --Z.dbd. is --N.dbd..
##STR00032##
[0320] The Groups --R.sup.Y and --R.sup.YY
[0321] (104) A compound according to any one of (1) to (103),
wherein: [0322] --R.sup.Y, if present, is independently --H. (105)
A compound according to any one of (1) to (103), wherein: [0323]
--R.sup.Y, if present, is independently --R.sup.YY. (106) A
compound according to any one of (1) to (105), wherein: [0324]
--R.sup.YY, if present, is independently --F, --Cl, --Br, --I, -Me,
or -Et. (107) A compound according to any one of (1) to (105),
wherein: [0325] --R.sup.YY, if present, is independently --F, --Cl,
or -Me. (108) A compound according to any one of (1) to (105),
wherein: [0326] --R.sup.YY, if present, is independently --F or
--Cl. (109) A compound according to any one of (1) to (105),
wherein: [0327] --R.sup.YY, if present, is independently --F. (110)
A compound according to any one of (1) to (105), wherein: [0328]
--R.sup.YY, if present, is independently --Cl. (111) A compound
according to any one of (1) to (105), wherein: [0329] --R.sup.YY,
if present, is independently -Me.
The Groups --R.sup.Z and --R.sup.ZZ
[0330] (112) A compound according to any one of (1) to (111),
wherein: [0331] --R.sup.Z, if present, is independently --H. (113)
A compound according to any one of (1) to (111), wherein: [0332]
--R.sup.Z, if present, is independently --R.sup.ZZ. (114) A
compound according to any one of (1) to (113), wherein: [0333]
--R.sup.ZZ, if present, is independently --F, --Cl, --Br, --I,
--OH, --OMe, --OEt, -Me, -Et, or --CF.sub.3. (115) A compound
according to any one of (1) to (113), wherein: [0334] --R.sup.ZZ,
if present, is independently --F, --Cl, --Br, --I, --OH, saturated
aliphatic C.sub.1-4alkyl. (116) A compound according to any one of
(1) to (113), wherein: [0335] --R.sup.ZZ, if present, is
independently --F, --Cl, --Br, --I, --OH, -Me or -Et. (117) A
compound according to any one of (1) to (113), wherein: [0336]
--R.sup.ZZ, if present, is independently --F, --Cl, --Br, --I, or
saturated aliphatic C.sub.1-4alkyl. (118) A compound according to
any one of (1) to (113), wherein: [0337] --R.sup.ZZ, if present, is
independently --F, --Cl, --Br, --I, -Me, or -Et. (119) A compound
according to any one of (1) to (113), wherein: [0338] --R.sup.ZZ,
if present, is independently --F, --Cl, -Me, or --OH. (120) A
compound according to any one of (1) to (113), wherein: [0339]
--R.sup.ZZ, if present, is independently --F, -Me, or --OH. (121) A
compound according to any one of (1) to (113), wherein: [0340]
--R.sup.ZZ, if present, is independently --F, --Cl, or -Me. (122) A
compound according to any one of (1) to (113), wherein: [0341]
--R.sup.ZZ, if present, is independently -Me. (123) A compound
according to any one of (1) to (113), wherein: [0342] --R.sup.ZZ,
if present, is independently --F. (124) A compound according to any
one of (1) to (113), wherein: [0343] --R.sup.ZZ, if present, is
independently --OH. (125) A compound according to any one of (1) to
(113), wherein: [0344] --R.sup.ZZ, if present, is independently
--Cl.
The Groups --R.sup.W and --R.sup.WW
[0345] (126) A compound according to any one of (1) to (125),
wherein: [0346] --R.sup.W, if present, is independently --H. (127)
A compound according to any one of (1) to (125), wherein: [0347]
--R.sup.W, if present, is independently --R.sup.WW. (128) A
compound according to any one of (1) to (127), wherein: [0348]
--R.sup.WW, if present, is independently --F, --Cl, --Br, --I,
--OH, --OMe, --OEt, -Me, -Et, or --CF.sub.3. (129) A compound
according to any one of (1) to (127), wherein: [0349] --R.sup.WW,
if present, is independently --F, --Cl, --Br, --I, or saturated
aliphatic C.sub.1-4alkyl. (130) A compound according to any one of
(1) to (127), wherein: [0350] --R.sup.WW, if present, is
independently --F, --Cl, --Br, --I, -Me, or -Et. (131) A compound
according to any one of (1) to (127), wherein: [0351] --R.sup.WW,
if present, is independently --F, --Cl, or -Me. (132) A compound
according to any one of (1) to (127), wherein: [0352] --R.sup.WW,
if present, is independently --F. (133) A compound according to any
one of (1) to (127), wherein: [0353] --R.sup.WW, if present, is
independently --Cl. (134) A compound according to any one of (1) to
(127), wherein: [0354] --R.sup.WW, if present, is independently
-Me.
The Group -J-
[0355] (135) A compound according to any one of (1) to (134),
wherein: [0356] -J- is independently --C(.dbd.O)--NR.sup.N--.
##STR00033##
[0356] (136) A compound according to any one of (1) to (134),
wherein: [0357] -J- is independently --NR.sup.N--C(.dbd.O)--.
##STR00034##
[0357] The Groups --R.sup.N and --R.sup.NN
[0358] (137) A compound according to any one of (1) to (136),
wherein: [0359] --R.sup.N is independently --H. (138) A compound
according to any one of (1) to (136), wherein: [0360] --R.sup.N is
independently --R.sup.NN. (139) A compound according to any one of
(1) to (138), wherein: [0361] R.sup.NN, if present, is
independently -Me or -Et. (140) A compound according to any one of
(1) to (138), wherein: [0362] --R.sup.NN, if present, is
independently -Me.
The Group --R.sup.O
[0363] (141) A compound according to any one of (1) to (140),
wherein: [0364] --R.sup.O is independently --OH, --OR.sup.E,
--NH.sub.2, or --NHR.sup.T1. (142) A compound according to any one
of (1) to (140), wherein: [0365] --R.sup.O is independently --OH or
--OR.sup.E. (143) A compound according to any one of (1) to (140),
wherein: [0366] --R.sup.O is independently --OH.
The Group --R.sup.E
[0367] (144) A compound according to any one of (1) to (143),
wherein: [0368] --R.sup.E, if present, is independently saturated
aliphatic C.sub.1-4alkyl. (145) A compound according to any one of
(1) to (143), wherein: [0369] --R.sup.E, if present, is
independently -Me or -Et. (146) A compound according to any one of
(1) to (143), wherein: [0370] --R.sup.E, if present, is
independently -Me.
The Group --R.sup.T1
[0371] (147) A compound according to any one of (1) to (146),
wherein: [0372] each --R.sup.T1, if present, is independently
saturated aliphatic C.sub.1-4alkyl. (148) A compound according to
any one of (1) to (146), wherein: [0373] each --R.sup.T1, if
present, is independently -Me or -Et. (149) A compound according to
any one of (1) to (146), wherein: [0374] each --R.sup.T1, if
present, is independently -Me.
The Group --NR.sup.T2R.sup.T3
[0375] (150) A compound according to any one of (1) to (149),
wherein: [0376] --NR.sup.T2R.sup.T3 is independently piperidino,
piperizino, N--(C.sub.1-3alkyl)piperizino, or morpholine.
Molecular Weight
[0377] (151) A compound according to any one of (1) to (150),
wherein the compound has a molecular weight of from 295 to 1200.
(152) A compound according to (151), wherein the bottom of range is
300, 325, 350, or 400. (153) A compound according to (151) or
(152), wherein the top of range is 1100, 1000, 900, 800, 700, or
600. (154) A compound according to any one of (1) to (150), wherein
the compound has a molecular weight of range from 325 to 600.
Activity and Selectivity
[0378] (155) A compound according to any one of (1) to (154),
wherein the compound has a RAR.alpha. activity ratio (with respect
to atRA) of less than about 200; or less than about 70; or less
than about 30; or less than about 10; or less than about 5. (156) A
compound according to any one of (1) to (155), wherein the compound
is selective for RAR.alpha., as compared to RAR.beta.. (157) A
compound according to any one of (1) to (155), wherein the compound
is selective for RAR.alpha., as compared to RAR.gamma.. (158) A
compound according to any one of (1) to (155), wherein the compound
is selective for RAR.alpha., as compared to both RAR.beta. and
RAR.gamma.. (159) A compound according to any one of (1) to (158),
wherein the compound has a ratio of RAR.alpha. activity ratio (with
respect to atRA) to RAR.beta. activity ratio (with respect to atRA)
of at least 10; or at least 20; or at least 50; or at least 100; or
at least 200.
Specific Compounds
[0379] (160) A compound according to (1), selected from compounds
of the following formulae and pharmaceutically acceptable salts,
hydrates, and solvates thereof:
TABLE-US-00003 Code No. Synthesis Structure AAA- 001 1 ##STR00035##
AAA- 002 1 ##STR00036## AAA- 003 2 ##STR00037## AAA- 004 3
##STR00038## AAA- 005 4 ##STR00039## AAA- 006 5 ##STR00040## AAA-
007 6 ##STR00041## AAA- 008 7 ##STR00042## AAA- 009 8 ##STR00043##
AAA- 010 9 ##STR00044## AAA- 011 10 ##STR00045## AAA- 012 11
##STR00046## AAA- 013 12 ##STR00047## AAA- 014 13 ##STR00048## AAA-
015 14 ##STR00049## AAA- 016 15 ##STR00050## AAA- 017 16
##STR00051## AAA- 018 17 ##STR00052## AAA- 0019 18 ##STR00053##
AAA- 020 19 ##STR00054## AAA- 021 20 ##STR00055## AAA- 022 21
##STR00056## AAA- 023 22 ##STR00057## AAA- 024 23 ##STR00058## AAA-
025 24 ##STR00059## AAA- 026 25 ##STR00060## AAA- 027 26
##STR00061## AAA- 028 (PP-01) 27 ##STR00062## AAA- 029 (PP-02) 28
##STR00063## AAA- 030 (PP-03) 29 ##STR00064##
(161) A compound according to (1), selected from compounds of the
following formulae and pharmaceutically acceptable salts, hydrates,
and solvates thereof: AAA-001 to AA-027. (162) A compound according
to (1), selected from compounds of the following formulae and
pharmaceutically acceptable salts, hydrates, and solvates
thereof:
TABLE-US-00004 Code No. Synthesis Structure AAA- 031 33
##STR00065## AAA- 032 34 ##STR00066## AAA- 033 35 ##STR00067## AAA-
034 36 ##STR00068## AAA- 035 37 ##STR00069## AAA- 036 38
##STR00070## AAA- 037 39 ##STR00071## AAA- 038 40 ##STR00072## AAA-
039 41 ##STR00073## AAA- 040 42 ##STR00074## AAA- 041 43
##STR00075## AAA- 042 44 ##STR00076## AAA- 043 45 ##STR00077## AAA-
044 46 ##STR00078## AAA- 045 47 ##STR00079## AAA- 046 48
##STR00080## AAA- 047 49 ##STR00081## AAA- 048 50 ##STR00082## AAA-
049 51 ##STR00083## AAA- 050 52 ##STR00084## AAA- 051 53
##STR00085## AAA- 052 54 ##STR00086## AAA- 053 55 ##STR00087## AAA-
054 56 ##STR00088## AAA- 055 57 ##STR00089## AAA- 056 58
##STR00090## AAA- 057 59 ##STR00091## AAA- 058 60 ##STR00092## AAA-
059 61 ##STR00093## AAA- 060 62 ##STR00094## AAA- 061 63
##STR00095## AAA- 062 64 ##STR00096## AAA- 063 65 ##STR00097## AAA-
064 66 ##STR00098## AAA- 065 67 ##STR00099## AAA- 066 68
##STR00100## AAA- 067 69 ##STR00101## AAA- 068 70 ##STR00102## AAA-
069 71 ##STR00103## AAA- 070 72 ##STR00104## AAA- 071 73
##STR00105## AAA- 072 74 ##STR00106## AAA- 073 75 ##STR00107## AAA-
074 76 ##STR00108## AAA- 075 77 ##STR00109## AAA- 076 78
##STR00110## AAA- 077 79 ##STR00111## AAA- 078 80 ##STR00112## AAA-
079 81 ##STR00113## AAA- 080 82 ##STR00114## AAA- 081 83
##STR00115## AAA- 082 84 ##STR00116## AAA- 083 85 ##STR00117## AAA-
084 86 ##STR00118## AAA- 085 87 ##STR00119## AAA- 086 88
##STR00120## AAA- 087 89 ##STR00121## AAA- 088 90 ##STR00122## AAA-
089 91 ##STR00123## AAA- 090 92 ##STR00124## AAA- 091 93
##STR00125## AAA- 092 94 ##STR00126## AAA- 093 95 ##STR00127## AAA-
094 96 ##STR00128## AAA- 095 97 ##STR00129## AAA- 096 98
##STR00130## AAA- 097 99 ##STR00131## AAA- 098 100 ##STR00132##
AAA- 099 101 ##STR00133## AAA- 100 102 ##STR00134## AAA- 101 103
##STR00135## AAA- 102 104 ##STR00136## AAA- 103 105 ##STR00137##
AAA- 104 106 ##STR00138## AAA- 105 107 ##STR00139## AAA- 106 108
##STR00140## AAA- 107 109 ##STR00141## AAA- 108 110 ##STR00142##
AAA- 109 111 ##STR00143## AAA- 110 112 ##STR00144## AAA- 111 113
##STR00145## AAA- 112 114 ##STR00146## AAA- 113 115 ##STR00147##
AAA- 114 116 ##STR00148## AAA- 115 117 ##STR00149## AAA- 116 118
##STR00150## AAA- 117 119 ##STR00151## AAA- 118 120 ##STR00152##
AAA- 119 121 ##STR00153## AAA- 120 122 ##STR00154##
(163) A compound according to (1), selected from compounds of the
following formulae and pharmaceutically acceptable salts, hydrates,
and solvates thereof: AAA-01 to AA-027 and AA-031 to M-120.
Combinations
[0380] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable sub-combination.
All combinations of the embodiments pertaining to the chemical
groups represented by the variables (e.g., --R.sup.1, --R.sup.2,
--R.sup.3, -J-, --W.dbd., --Y.dbd., --Z.dbd., --R.sup.O, --X,
--R.sup.X, --R.sup.A, --R.sup.C, -L-, --R.sup.N, --R.sup.NN,
--R.sup.W, --R.sup.WW, --R.sup.Y, --R.sup.YY, --R.sup.Z,
--R.sup.ZZ, --R.sup.E, --R.sup.T1, --NR.sup.T2R.sup.T3, etc.) are
specifically embraced by the present invention and are disclosed
herein just as if each and every combination was individually and
explicitly disclosed, to the extent that such combinations embrace
compounds that are stable compounds (i.e., compounds that can be
isolated, characterised, and tested for biological activity). In
addition, all sub-combinations of the chemical groups listed in the
embodiments describing such variables are also specifically
embraced by the present invention and are disclosed herein just as
if each and every such sub-combination of chemical groups was
individually and explicitly disclosed herein.
Substantially Purified Forms
[0381] One aspect of the present invention pertains to AAA
compounds, as described herein, in substantially purified form
and/or in a form substantially free from contaminants.
[0382] In one embodiment, the compound is in substantially purified
form and/or in a form substantially free from contaminants.
[0383] In one embodiment, the compound is in a substantially
purified form with a purity of least 50% by weight, e.g., at least
60% by weight, e.g., at least 70% by weight, e.g., at least 80% by
weight, e.g., at least 90% by weight, e.g., at least 95% by weight,
e.g., at least 97% by weight, e.g., at least 98% by weight, e.g.,
at least 99% by weight.
[0384] Unless specified, the substantially purified form refers to
the compound in any stereoisomeric or enantiomeric form. For
example, in one embodiment, the substantially purified form refers
to a mixture of stereoisomers, i.e., purified with respect to other
compounds. In one embodiment, the substantially purified form
refers to one stereoisomer, e.g., optically pure stereoisomer. In
one embodiment, the substantially purified form refers to a mixture
of enantiomers. In one embodiment, the substantially purified form
refers to an equimolar mixture of enantiomers (i.e., a racemic
mixture, a racemate). In one embodiment, the substantially purified
form refers to one enantiomer, e.g., optically pure enantiomer.
[0385] In one embodiment, the compound is in a form substantially
free from contaminants wherein the contaminants represent no more
than 50% by weight, e.g., no more than 40% by weight, e.g., no more
than 30% by weight, e.g., no more than 20% by weight, e.g., no more
than 10% by weight, e.g., no more than 5% by weight, e.g., no more
than 3% by weight, e.g., no more than 2% by weight, e.g., no more
than 1% by weight.
[0386] Unless specified, the contaminants refer to other compounds,
that is, other than stereoisomers or enantiomers. In one
embodiment, the contaminants refer to other compounds and other
stereoisomers. In one embodiment, the contaminants refer to other
compounds and the other enantiomer.
[0387] In one embodiment, the compound is in a substantially
purified form with an optical purity of at least 60% (i.e., 60% of
the compound, on a molar basis, is the desired stereoisomer or
enantiomer, and 40% is undesired stereoisomer(s) or enantiomer),
e.g., at least 70%, e.g., at least 80%, e.g., at least 90%, e.g.,
at least 95%, e.g., at least 97%, e.g., at least 98%, e.g., at
least 99%.
Isomers
[0388] Certain compounds may exist in one or more particular
geometric, optical, enantiomeric, diasteriomeric, epimeric,
atropic, stereoisomeric, tautomeric, conformational, or anomeric
forms, including but not limited to, cis- and trans-forms; E- and
Z-forms; c-, t-, and r-forms; endo- and exo-forms; R--, S--, and
meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms;
keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal-
and anticlinal-forms; .alpha.- and .beta.-forms; axial and
equatorial forms; boat-, chair-, twist-, envelope-, and
halfchair-forms; and combinations thereof, hereinafter collectively
referred to as "isomers" (or "isomeric forms").
[0389] Note that, except as discussed below for tautomeric forms,
specifically excluded from the term "isomers," as used herein, are
structural (or constitutional) isomers (i.e., isomers which differ
in the connections between atoms rather than merely by the position
of atoms in space). For example, a reference to a methoxy group,
--OCH.sub.3, is not to be construed as a reference to its
structural isomer, a hydroxymethyl group, --CH.sub.2OH. Similarly,
a reference to ortho-chlorophenyl is not to be construed as a
reference to its structural isomer, meta-chlorophenyl. However, a
reference to a class of structures may well include structurally
isomeric forms falling within that class (e.g., C.sub.1-7alkyl
includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-,
and tert-butyl; methoxyphenyl includes ortho-, meta-, and
para-methoxyphenyl).
[0390] The above exclusion does not pertain to tautomeric forms,
for example, keto-, enol-, and enolate-forms, as in, for example,
the following tautomeric pairs: keto/enol (illustrated below),
imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
##STR00155##
[0391] Note that specifically included in the term "isomer" are
compounds with one or more isotopic substitutions. For example, H
may be in any isotopic form, including .sup.1H, .sup.2H (D), and
.sup.3H (T); C may be in any isotopic form, including .sup.12C,
.sup.13C, and .sup.14C; O may be in any isotopic form, including
.sup.16O and .sup.18O; and the like.
[0392] Unless otherwise specified, a reference to a particular
compound includes all such isomeric forms, including mixtures
(e.g., racemic mixtures) thereof. Methods for the preparation
(e.g., asymmetric synthesis) and separation (e.g., fractional
crystallisation and chromatographic means) of such isomeric forms
are either known in the art or are readily obtained by adapting the
methods taught herein, or known methods, in a known manner.
Salts
[0393] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding salt of the compound, for example, a
pharmaceutically-acceptable salt. Examples of pharmaceutically
acceptable salts are discussed in Berge et al., 1977,
"Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp.
1-19.
[0394] For example, if the compound is anionic, or has a functional
group which may be anionic (e.g., --COOH may be --COO.sup.-)), then
a salt may be formed with a suitable cation. Examples of suitable
inorganic cations include, but are not limited to, alkali metal
ions such as Na.sup.+ and K.sup.+, alkaline earth cations such as
Ca.sup.2+ and Mg.sup.2+, and other cations such as Al.sup.3+.
Examples of suitable organic cations include, but are not limited
to, ammonium ion (i.e., NH.sub.4.sup.+) and substituted ammonium
ions (e.g., NH.sub.3R.sup.+, NH.sub.2R.sub.2.sup.+,
NHR.sub.3.sup.+, NR.sub.4.sup.+). Examples of some suitable
substituted ammonium ions are those derived from: ethylamine,
diethylamine, dicyclohexylamine, triethylamine, butylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine,
benzylamine, phenylbenzylamine, choline, meglumine, and
tromethamine, as well as amino acids, such as lysine and arginine.
An example of a common quaternary ammonium ion is
N(CH.sub.3).sub.4.sup.+.
[0395] If the compound is cationic, or has a functional group which
may be cationic (e.g., --NH.sub.2 may be --NH.sub.3.sup.+), then a
salt may be formed with a suitable anion. Examples of suitable
inorganic anions include, but are not limited to, those derived
from the following inorganic acids: hydrochloric, hydrobromic,
hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and
phosphorous.
[0396] Examples of suitable organic anions include, but are not
limited to, those derived from the following organic acids:
2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic,
ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic,
glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic,
lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic,
oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic,
phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic,
sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of
suitable polymeric organic anions include, but are not limited to,
those derived from the following polymeric acids: tannic acid,
carboxymethyl cellulose.
[0397] Unless otherwise specified, a reference to a particular
compound also includes salt forms thereof.
Hydrates and Solvates
[0398] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding solvate of the compound. The term "solvate"
is used herein in the conventional sense to refer to a complex of
solute (e.g., compound, salt of compound) and solvent. If the
solvent is water, the solvate may be conveniently referred to as a
hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate,
etc.
[0399] Unless otherwise specified, a reference to a particular
compound also includes solvate and hydrate forms thereof.
Chemically Protected Forms
[0400] It may be convenient or desirable to prepare, purify, and/or
handle the compound in a chemically protected form. The term
"chemically protected form" is used herein in the conventional
chemical sense and pertains to a compound in which one or more
reactive functional groups are protected from undesirable chemical
reactions under specified conditions (e.g., pH, temperature,
radiation, solvent, and the like). In practice, well known chemical
methods are employed to reversibly render unreactive a functional
group, which otherwise would be reactive, under specified
conditions. In a chemically protected form, one or more reactive
functional groups are in the form of a protected or protecting
group (also known as a masked or masking group or a blocked or
blocking group). By protecting a reactive functional group,
reactions involving other unprotected reactive functional groups
can be performed, without affecting the protected group; the
protecting group may be removed, usually in a subsequent step,
without substantially affecting the remainder of the molecule. See,
for example, Protective Groups in Organic Synthesis (T. Greene and
P. Wuts; 4th Edition; John Wiley and Sons, 2006).
[0401] A wide variety of such "protecting," "blocking," or
"masking" methods are widely used and well known in organic
synthesis. For example, a compound which has two nonequivalent
reactive functional groups, both of which would be reactive under
specified conditions, may be derivatized to render one of the
functional groups "protected," and therefore unreactive, under the
specified conditions; so protected, the compound may be used as a
reactant which has effectively only one reactive functional group.
After the desired reaction (involving the other functional group)
is complete, the protected group may be "deprotected" to return it
to its original functionality.
[0402] For example, a hydroxy group may be protected as an ether
(--OR) or an ester (--OC(.dbd.O)R), for example, as: a t-butyl
ether; a benzyl, benzhydryl (diphenylmethyl), or trityl
(triphenylmethyl)ether; a trimethylsilyl or t-butyldimethylsilyl
ether; or an acetyl ester (--OC(.dbd.O)CH.sub.3, --OAc).
[0403] For example, an aldehyde or ketone group may be protected as
an acetal (R--CH(OR).sub.2) or ketal (R.sub.2C(OR).sub.2),
respectively, in which the carbonyl group (>C.dbd.O) is
converted to a diether (>C(OR).sub.2), by reaction with, for
example, a primary alcohol. The aldehyde or ketone group is readily
regenerated by hydrolysis using a large excess of water in the
presence of acid.
[0404] For example, an amine group may be protected, for example,
as an amide (--NRCO--R) or a urethane (--NRCO--OR), for example,
as: a methyl amide (--NHCO--CH.sub.3); a benzyloxy amide
(--NHCO--OCH.sub.2C.sub.6H.sub.5, --NH-Cbz); as a t-butoxy amide
(--NHCO--OC(CH.sub.3).sub.3, --NH-Boc); a 2-biphenyl-2-propoxy
amide (--NHCO--OC(CH.sub.3).sub.2C.sub.6H.sub.4C.sub.6H.sub.5,
--NH-Bpoc), as a 9-fluorenylmethoxy amide (--NH-Fmoc), as a
6-nitroveratryloxy amide (--NH-Nvoc), as a 2-trimethylsilylethyloxy
amide (--NH-Teoc), as a 2,2,2-trichloroethyloxy amide (--NH-Troc),
as an allyloxy amide (--NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy
amide (--NH-Psec); or, in suitable cases (e.g., cyclic amines), as
a nitroxide radical (>N--O ).
[0405] For example, a carboxylic acid group may be protected as an
ester for example, as: an C.sub.1-7alkyl ester (e.g., a methyl
ester; a t-butyl ester); a C.sub.1-7haloalkyl ester (e.g., a
C.sub.1-7trihaloalkyl ester); a
triC.sub.1-7alkylsilyl-C.sub.1-7alkyl ester; or a
C.sub.5-20aryl-C.sub.1-7alkyl ester (e.g., a benzyl ester; a
nitrobenzyl ester); or as an amide, for example, as a methyl
amide.
[0406] For example, a thiol group may be protected as a thioether
(--SR), for example, as: a benzyl thioether; an acetamidomethyl
ether (--S--CH.sub.2NHC(.dbd.O)CH.sub.3).
Prodruqs
[0407] It may be convenient or desirable to prepare, purify, and/or
handle the compound in the form of a prodrug. The term "prodrug,"
as used herein, pertains to a compound which, when metabolised
(e.g., in vivo), yields the desired active compound. Typically, the
prodrug is inactive, or less active than the desired active
compound, but may provide advantageous handling, administration, or
metabolic properties.
[0408] For example, some prodrugs are esters of the active compound
(e.g., a physiologically acceptable metabolically labile ester).
During metabolism, the ester group (--C(.dbd.O)OR) is cleaved to
yield the active drug. Such esters may be formed by esterification,
for example, of any of the carboxylic acid groups (--C(.dbd.O)OH)
in the parent compound, with, where appropriate, prior protection
of any other reactive groups present in the parent compound,
followed by deprotection if required.
[0409] Also, some prodrugs are activated enzymatically to yield the
active compound, or a compound which, upon further chemical
reaction, yields the active compound (for example, as in ADEPT,
GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar
derivative or other glycoside conjugate, or may be an amino acid
ester derivative.
Chemical Synthesis
[0410] Several methods for the chemical synthesis of compounds of
the present invention are described herein. These and/or other well
known methods may be modified and/or adapted in known ways in order
to facilitate the synthesis of additional compounds within the
scope of the present invention.
[0411] In one approach, certain compounds of the invention (where
-J- is --C(.dbd.O)--NR.sup.N--) may conveniently be prepared by
coupling a suitably substituted benzoic acid with a suitably
protected para-amino benzoic acid compound. Deprotection gives the
corresponding carboxylic acid compound, which can be converted to
the corresponding amide.
[0412] For example, coupling a suitably substituted benzoic acid
(e.g., (1)(i)) with a suitably protected para-amino benzoic acid
compound (e.g., (1)(ii), wherein --R.sup.P denotes a protecting
group, such as -Me), gives the corresponding amide (e.g.,
(1)(iii)). Coupling may be carried out using a variety of agents,
for example oxalyl chloride in the presence of
diisopropylethylamine, triethylamine or catalytic quantities of
dimethylformamide in a solvent such as dichloromethane where
coupling proceeds via the acid chloride, or by using agents such as
HATU, EEDQ, PyBOP, PyBrOP, EDC, or CDI under usual conditions.
[0413] If necessary or desired, the protecting group can be removed
using conventional methods to give the carboxylic acid compound
(e.g., (1)(iv)). For example, if the protecting group (e.g.,
--R.sup.P) is alkyl, then hydrolysis can be achieved using lithium
hydroxide in a mixture of THF or dioxane and water. If the
protecting group (e.g., --R.sup.P) is benzyl, it may be removed by
hydrogenation, for example by using hydrogen over a metal
catalyst.
[0414] If necessary or desired, the carboxylic acid compound (e.g.,
(1)(iv)) can be converted to a corresponding amide compound (e.g.,
(1)(v)), for example, by reaction with a suitable amine.
[0415] An example of such a method is illustrated in the following
scheme.
##STR00156##
[0416] In another approach, certain compounds of the invention
(where -J- is --NR.sup.N--C(.dbd.O)--) may conveniently be prepared
by coupling a suitably substituted aniline with a suitably
protected and activated terephthalic acid compound. Deprotection
gives the corresponding carboxylic acid compound, which can be
converted to the corresponding amide.
[0417] For example, coupling a suitably substituted aniline (e.g.,
(2)(i)) with a suitably protected terephthalic acid compound (e.g.,
(2)(ii), wherein --R.sup.P denotes a protecting group and -LG
denotes a leaving group), gives the corresponding amide (e.g.,
(2)(iii)). An example of a suitable leaving group is halogen (e.g.,
Cl), and the corresponding compound may be prepared, for example,
from the corresponding benzoic acid by treatment with a variety of
reagents including thionyl chloride and oxalyl chloride. In this
case, coupling may be achieved, for example, by mixing the two
components in a suitable solvent such as dichloromethane in the
presence of a base such as triethylamine or diisopropylethylamine.
Another example of a suitable leaving group is --OH. In this case,
coupling may be achieved, for example, using oxalyl chloride, HATU,
EEDQ, PyBOP, PyBrOP, CDI or EDC under usual conditions.
[0418] If necessary or desired, the protecting group can be removed
using conventional methods to give the carboxylic acid compound
(e.g., (2)(iv)). For example, if the protecting group (e.g.,
--R.sup.P) is alkyl, then hydrolysis can be achieved using lithium
hydroxide in a mixture of THF or dioxane and water. If the
protecting group (e.g., --R.sup.P) is benzyl, it may be removed by
hydrogenation, for example by using hydrogen over a metal
catalyst.
[0419] If necessary or desired, the carboxylic acid compound (e.g.,
(2)(iv)) can be converted to a corresponding amide compound (e.g.,
(2)(v)), for example, by reaction with a suitable amine.
[0420] An example of such a method is illustrated in the following
scheme.
##STR00157##
[0421] The benzoic acids (e.g., (1)(i)) are often commercially
available, but if not, the requisite material can be prepared from
commercially available starting materials in a few steps using
conventional methods. For example, suitably protected
hydroxyl-benzoic acids may be alkylated. Deprotection gives the
corresponding substituted benzoic acid.
[0422] For example, suitably protected hydroxyl-benzoic acid (e.g.,
(3)(i)) may be alkylated using a base such as potassium carbonate
or sodium hydride in a suitable solvent to form the phenolate
anion, which is then quenched with the requisite halide, to give
the corresponding substituted protected benzoic acid compound
(e.g., (3)(ii)). The carboxylic acid protecting group may be
removed using conventional methods to give the desired substituted
benzoic acid compound (e.g., (3)(iii)). For example, if the
protecting group (e.g., --R.sup.P) is alkyl, then hydrolysis can be
achieved using lithium hydroxide in a mixture of THF or dioxane and
water. If the protecting group (e.g., --R.sup.P) is benzyl, it may
be removed by hydrogenation, for example by using hydrogen over a
metal catalyst.
[0423] An example of such a method is illustrated in the following
scheme.
##STR00158##
[0424] The amines (e.g., (1)(ii)) are often commercially available,
but if not, the requisite material can be prepared from
commercially available starting materials in a few steps using
conventional methods. For example, compounds where --R.sup.N is
other than --H can be prepared by reductive amination of a suitably
protected 4-aminobenzoic acid derivative.
[0425] In another approach, one or more of the groups --R.sup.1,
--R.sup.2, and --R.sup.3 may be changed after coupling. For
example, debenzylation of a pendant --OCH.sub.2Ph group gives a
corresponding --OH group, which can then be alkylated.
[0426] For example, in a method similar to Scheme 1 above, when one
of --R.sup.1, --R.sup.2, and --R.sup.3 in the starting material
(e.g., (4)(i)) is --OCH.sub.2Ph, then, following coupling (e.g., to
give (4)(iii)), debenzylation (for example, using boron
trichloride) converts this --OCH.sub.2Ph group to --OH (e.g.,
(4)(iv)). This --OH group may be then be alkylated, for example,
using a base such as potassium carbonate or sodium hydride in a
suitable solvent to form the phenolate anion, which is then
quenched with the requisite halide, to give the corresponding
alkylated compound (e.g., (4)(v)).
[0427] Again, if necessary or desired, the protecting group can be
removed using conventional methods to give the carboxylic acid
compound (e.g., (4)(iv)). For example, if the protecting group
(e.g., --R.sup.P) is alkyl, then hydrolysis can be achieved using
lithium hydroxide in a mixture of THF or dioxane and water. If the
protecting group (e.g., --R.sup.P) is benzyl, it may be removed by
hydrogenation, for example by using hydrogen over a metal
catalyst.
[0428] Again, if necessary or desired, the carboxylic acid compound
(e.g., (4)(vi)) can be converted to a corresponding amide compound
(e.g., (4)(vii)), for example, by reaction with a suitable
amine.
[0429] An example of such a method is illustrated in the following
scheme.
##STR00159## ##STR00160##
[0430] In another approach, one or more of the groups --R.sup.1,
--R.sup.2, and --R.sup.3 may be changed after coupling. For
example, a pendant --OH may be alkylated.
[0431] For example, in a method similar to that described in Scheme
2 above, one of --R.sup.1, --R.sup.2, and --R.sup.3 in the starting
material (e.g., (5)(i)) is --OH. Following coupling (e.g., to give
(5)(iii)), this --OH group may be then be alkylated, for example,
using a base such as potassium carbonate or sodium hydride in a
suitable solvent to form the phenolate anion, which is then
quenched with the requisite halide, to give the corresponding
alkylated compound (5)(iv).
[0432] Again, if necessary or desired, the protecting group can be
removed using conventional methods to give the carboxylic acid
compound (e.g., (5)(v)). For example, if the protecting group
(e.g., --R.sup.P) is alkyl, then hydrolysis can be achieved using
lithium hydroxide in a mixture of THF or dioxane and water. If the
protecting group (e.g., --R.sup.C) is benzyl, it may be removed by
hydrogenation, for example by using hydrogen over a metal
catalyst.
[0433] Again, if necessary or desired, the carboxylic acid compound
(e.g., (5)(v)) can be converted to a corresponding amide compound
(e.g., (5)(vi)), for example, by reaction with a suitable
amine.
[0434] An example of such a method is illustrated in the following
scheme.
##STR00161##
[0435] In the above methods, the core 1,4-phenylene group of the
protected para-amino benzoic acid compound (e.g., (1)(ii) and
(4)(ii)) and of the activated terephthalic acid compound (e.g.,
(2)(ii) and (5)(ii)) may bear additional substituents (e.g.,
--R.sup.YY, --R.sup.ZZ, --R.sup.WW), or may be replaced with a
pyridine-diyl group (e.g., .dbd.Y-- is .dbd.N-- or --Z.dbd. is
--N.dbd.), which may itself bear additional substituents (e.g.,
--R.sup.YY, --R.sup.ZZ, --R.sup.WW).
Compositions
[0436] One aspect of the present invention pertains to a
composition (e.g., a pharmaceutical composition) comprising an AAA
compound, as described herein, and a pharmaceutically acceptable
carrier, diluent, or excipient.
[0437] Another aspect of the present invention pertains to a method
of preparing a composition (e.g., a pharmaceutical composition)
comprising admixing an AAA compound, as described herein, and a
pharmaceutically acceptable carrier, diluent, or excipient.
Uses
[0438] The compounds described herein are useful, for example, in
the treatment of diseases and conditions that are ameliorated by
the (selective) activation of RAR.alpha., such as, for example,
Alzheimer's disease.
Use in Methods of Activating Retinoic Acid Receptor .alpha.
(RAR.alpha.)
[0439] One aspect of the present invention pertains to a method of
activating retinoic acid receptor .alpha. (RAR.alpha.), in vitro or
in vivo, comprising contacting RAR.alpha. with an effective amount
of an AAA compound, as described herein.
[0440] One aspect of the present invention pertains to a method of
selectively activating retinoic acid receptor .alpha. (RAR.alpha.)
(e.g., with respect to RAR.beta. and/or RAR.gamma.), in vitro or in
vivo, comprising contacting RAR.alpha. with an effective amount of
an AAA compound, as described herein.
[0441] In one embodiment, the method is performed in vitro.
[0442] In one embodiment, the method is performed in vivo.
[0443] One aspect of the present invention pertains to a method of
activating retinoic acid receptor .alpha. (RAR.alpha.) in a
neuronal cell, in vitro or in vivo, comprising contacting the cell
with an effective amount of an AAA compound, as described
herein.
[0444] One aspect of the present invention pertains to a method of
selectively activating retinoic acid receptor .alpha. (RAR.alpha.)
(e.g., with respect to RAR.beta. and/or RAR.gamma.) in a neuronal
cell, in vitro or in vivo, comprising contacting the cell with an
effective amount of an AAA compound, as described herein.
[0445] In one embodiment, the AAA compound is provided in the form
of a pharmaceutically acceptable composition.
[0446] Suitable assays for determining RAR.alpha. activation are
described herein and/or are known in the art.
Use in Methods of Up-Regulating chAT, Etc.
[0447] The AAA compounds described herein are useful in the
up-regulation of chAT expression in cortical neurons; the
down-regulation of APP expression in cortical neurons, the
up-regulation of ADAM10 expression in cortical neurons; and the
down-regulation of A.beta.40 and A.beta.42 expression in cortical
neurons.
[0448] One aspect of the present invention pertains to a method of
up-regulating chAT expression in a cortical neuron, comprising
contacting the cortical neuron, in vitro or in vivo, with an
effective amount of an AAA compound, as described herein.
[0449] One aspect of the present invention pertains to a method of
down-regulating APP expression in a cortical neuron, comprising
contacting the cortical neuron, in vitro or in vivo, with an
effective amount of an AAA compound, as described herein.
[0450] One aspect of the present invention pertains to a method of
up-regulating ADAM10 expression in a cortical neuron, comprising
contacting the cortical neuron, in vitro or in vivo, with an
effective amount of an MA compound, as described herein.
[0451] One aspect of the present invention pertains to a method of
down-regulating A.beta.40 and A.beta.42 expression in a cortical
neuron, comprising contacting the cortical neuron, in vitro or in
vivo, with an effective amount of an AAA compound, as described
herein.
[0452] In one embodiment, the method is performed in vitro.
[0453] In one embodiment, the method is performed in vivo.
[0454] One aspect of the present invention pertains to a method of
up-regulating chAT expression in a cortical neuron in a patient,
comprising administering to the patient a therapeutically effective
amount of an AAA compound, as described herein.
[0455] One aspect of the present invention pertains to a method of
down-regulating APP expression in a cortical neuron in a patient,
comprising administering to the patient a therapeutically effective
amount of an AAA compound, as described herein.
[0456] One aspect of the present invention pertains to a method of
up-regulating ADAM10 expression in a cortical neuron in a patient,
comprising administering to the patient a therapeutically effective
amount of an AAA compound, as described herein.
[0457] One aspect of the present invention pertains to a method of
down-regulating A.beta.40 and A.beta.42 expression in a cortical
neuron in a patient, comprising administering to the patient a
therapeutically effective amount of an AAA compound, as described
herein.
[0458] In one embodiment, the AAA compound is provided in the form
of a pharmaceutically acceptable composition.
[0459] Suitable assays for determining up-regulation of chAT
expression; down-regulation of APP expression; up-regulation of
ADAM10 expression; and down-regulation of A.beta.40 and A.beta.42
expression; are described herein and/or are known in the art.
Use in Methods of Preventing Cortical Neuronal Death
[0460] The AAA compounds described herein are useful in preventing,
reducing, or slowing cortical neuronal death.
[0461] One aspect of the present invention pertains to a method of
preventing, reducing, or slowing cortical neuronal death in a
patient, comprising administering to the patient a therapeutically
effective amount of an AAA compound, as described herein.
Use in Methods of Therapy
[0462] Another aspect of the present invention pertains to an AAA
compound, as described herein, for treatment of the human or animal
body by therapy.
Use in the Manufacture of Medicaments
[0463] Another aspect of the present invention pertains to use of
an AAA compound, as described herein, in the manufacture of a
medicament for use in treatment.
[0464] In one embodiment, the medicament comprises the AAA
compound.
Methods of Treatment
[0465] Another aspect of the present invention pertains to a method
of treatment comprising administering to a patient in need of
treatment a therapeutically effective amount of an AAA compound, as
described herein, preferably in the form of a pharmaceutical
composition.
Conditions Treated--Conditions Mediated by RAR.alpha.
[0466] In one embodiment (e.g., of use in methods of therapy, of
use in the manufacture of medicaments, of methods of treatment),
the treatment is treatment of a disease or condition that is
mediated by RAR.alpha..
Conditions Treated--Conditions Ameliorated by the Activation of
RAR.alpha.
[0467] In one embodiment (e.g., of use in methods of therapy, of
use in the manufacture of medicaments, of methods of treatment),
the treatment is treatment of: a disease or condition that is
ameliorated by the activation of RAR.alpha..
[0468] In one embodiment (e.g., of use in methods of therapy, of
use in the manufacture of medicaments, of methods of treatment),
the treatment is treatment of: a disease or condition that is
ameliorated by the selective activation of RAR.alpha. (e.g., with
respect to RAR.beta. and/or RAR.gamma.).
Conditions Treated
[0469] In one embodiment (e.g., of use in methods of therapy, of
use in the manufacture of medicaments, of methods of treatment),
the treatment is treatment of a cognitive disorder, memory
impairment, memory deficit, senile dementia, Alzheimer's disease,
early stage Alzheimer's disease, intermediate stage Alzheimer's
disease, late stage Alzheimer's disease, cognitive impairment, or
mild cognitive impairment.
[0470] In one embodiment, the treatment is treatment of Alzheimer's
disease.
[0471] In one embodiment, the treatment is treatment of early stage
Alzheimer's disease.
[0472] In one embodiment, the treatment is treatment of
intermediate stage Alzheimer's disease.
[0473] In one embodiment, the treatment is treatment of late stage
Alzheimer's disease.
[0474] In one embodiment, the treatment is treatment of cognitive
impairment.
[0475] In one embodiment, the treatment is treatment of mild
cognitive impairment.
Treatment
[0476] The term "treatment," as used herein in the context of
treating a condition, pertains generally to treatment and therapy,
whether of a human or an animal (e.g., in veterinary applications),
in which some desired therapeutic effect is achieved, for example,
the inhibition of the progress of the condition, and includes a
reduction in the rate of progress, a halt in the rate of progress,
alleviation of symptoms of the condition, amelioration of the
condition, and cure of the condition. Treatment as a prophylactic
measure (i.e., prophylaxis) is also included. For example, use with
patients who have not yet developed the condition, but who are at
risk of developing the condition, is encompassed by the term
"treatment" (that is, treatment of condition encompasses reducing
the risk of that condition).
[0477] For example, treatment includes the prophylaxis of
Alzheimer's disease, reducing the risk of Alzheimer's disease,
alleviating the symptoms of Alzheimer's disease, etc.
[0478] The term "therapeutically-effective amount," as used herein,
pertains to that amount of a compound, or a material, composition
or dosage form comprising a compound, which is effective for
producing some desired therapeutic effect, commensurate with a
reasonable benefit/risk ratio, when administered in accordance with
a desired treatment regimen.
Combination Therapies
[0479] The term "treatment" includes combination treatments and
therapies, in which two or more treatments or therapies are
combined, for example, sequentially or simultaneously.
[0480] For example, the compounds described herein may also be used
in combination therapies, e.g., in conjunction with other agents.
Examples of treatments and therapies include, but are not limited
to, chemotherapy (the administration of active agents, including,
e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs
(e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery;
radiation therapy; photodynamic therapy; gene therapy; and
controlled diets.
[0481] For example, it may be beneficial to combine treatment with
a compound as described herein with one or more other (e.g., 1, 2,
3, 4) agents or therapies, e.g., that treat Alzheimer's
disease.
[0482] One aspect of the present invention pertains to a compound
as described herein, in combination with one or more additional
therapeutic agents, as described below.
[0483] The particular combination would be at the discretion of the
physician who would select dosages using his common general
knowledge and dosing regimens known to a skilled practitioner.
[0484] The agents (i.e., the compound described herein, plus one or
more other agents) may be administered simultaneously or
sequentially, and may be administered in individually varying dose
schedules and via different routes. For example, when administered
sequentially, the agents can be administered at closely spaced
intervals (e.g., over a period of 5-10 minutes) or at longer
intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer
periods apart where required), the precise dosage regimen being
commensurate with the properties of the therapeutic agent(s).
[0485] The agents (i.e., the compound described here, plus one or
more other agents) may be formulated together in a single dosage
form, or alternatively, the individual agents may be formulated
separately and presented together in the form of a kit, optionally
with instructions for their use.
Other Uses
[0486] The AAA compounds described herein may also be used as cell
culture additives to activate RAR.alpha., e.g., to up-regulate chAT
expression; to down-regulate APP expression; to up-regulate ADAM10
expression; to down-regulate A.beta.40 and A.beta.42 expression; to
prevent, reduce, or slow cortical neuronal death.
[0487] The AAA compounds described herein may also be used, for
example, as part of an in vitro assay, for example, in order to
determine whether a candidate host is likely to benefit from
treatment with the compound in question.
[0488] The AAA compounds described herein may also be used as a
standard, for example, in an assay, in order to identify other
compounds, other RAR.alpha. agonists, etc.
Kits
[0489] One aspect of the invention pertains to a kit comprising (a)
an AAA compound as described herein, or a composition comprising an
AAA compound as described herein, e.g., preferably provided in a
suitable container and/or with suitable packaging; and (b)
instructions for use, e.g., written instructions on how to
administer the compound or composition.
[0490] The written instructions may also include a list of
indications for which the active ingredient is a suitable
treatment.
Routes of Administration
[0491] The AAA compound or pharmaceutical composition comprising
the AAA compound may be administered to a subject by any convenient
route of administration, whether systemically/peripherally or
topically (i.e., at the site of desired action).
[0492] Routes of administration include, but are not limited to,
oral (e.g., by ingestion); buccal; sublingual; transdermal
(including, e.g., by a patch, plaster, etc.); transmucosal
(including, e.g., by a patch, plaster, etc.); intranasal (e.g., by
nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by
inhalation or insufflation therapy using, e.g., via an aerosol,
e.g., through the mouth or nose); rectal (e.g., by suppository or
enema); vaginal (e.g., by pessary); parenteral, for example, by
injection, including subcutaneous, intradermal, intramuscular,
intravenous, intraarterial, intracardiac, intrathecal, intraspinal,
intracapsular, subcapsular, intraorbital, intraperitoneal,
intratracheal, subcuticular, intraarticular, subarachnoid, and
intrasternal; by implant of a depot or reservoir, for example,
subcutaneously or intramuscularly.
The Subject/Patient
[0493] The subject/patient may be a chordate, a vertebrate, a
mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a
rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine
(e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a
bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a
horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g.,
a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g.,
marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang,
gibbon), or a human.
[0494] Furthermore, the subject/patient may be any of its forms of
development, for example, a foetus.
[0495] In one preferred embodiment, the subject/patient is a
human.
Formulations
[0496] While it is possible for the AAA compound to be administered
alone, it is preferable to present it as a pharmaceutical
formulation (e.g., composition, preparation, medicament) comprising
at least one AAA compound, as described herein, together with one
or more other pharmaceutically acceptable ingredients well known to
those skilled in the art, including, but not limited to,
pharmaceutically acceptable carriers, diluents, excipients,
adjuvants, fillers, buffers, preservatives, anti-oxidants,
lubricants, stabilisers, solubilisers, surfactants (e.g., wetting
agents), masking agents, colouring agents, flavouring agents, and
sweetening agents. The formulation may further comprise other
active agents, for example, other therapeutic or prophylactic
agents.
[0497] Thus, the present invention further provides pharmaceutical
compositions, as defined above, and methods of making a
pharmaceutical composition comprising admixing at least one AAA
compound, as described herein, together with one or more other
pharmaceutically acceptable ingredients well known to those skilled
in the art, e.g., carriers, diluents, excipients, etc. If
formulated as discrete units (e.g., tablets, etc.), each unit
contains a predetermined amount (dosage) of the compound.
[0498] The term "pharmaceutically acceptable," as used herein,
pertains to compounds, ingredients, materials, compositions, dosage
forms, etc., which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of the subject in
question (e.g., human) without excessive toxicity, irritation,
allergic response, or other problem or complication, commensurate
with a reasonable benefit/risk ratio. Each carrier, diluent,
excipient, etc. must also be "acceptable" in the sense of being
compatible with the other ingredients of the formulation.
[0499] Suitable carriers, diluents, excipients, etc. can be found
in standard pharmaceutical texts, for example, Remington's
Pharmaceutical Sciences, 18th edition, Mack Publishing Company,
Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th
edition, 2005.
[0500] The formulations may be prepared by any methods well known
in the art of pharmacy. Such methods include the step of bringing
into association the compound with a carrier which constitutes one
or more accessory ingredients. In general, the formulations are
prepared by uniformly and intimately bringing into association the
compound with carriers (e.g., liquid carriers, finely divided solid
carrier, etc.), and then shaping the product, if necessary.
[0501] The formulation may be prepared to provide for rapid or slow
release; immediate, delayed, timed, or sustained release; or a
combination thereof.
[0502] Formulations may suitably be in the form of liquids,
solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous,
non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),
elixirs, syrups, electuaries, mouthwashes, drops, tablets
(including, e.g., coated tablets), granules, powders, losenges,
pastilles, capsules (including, e.g., hard and soft gelatin
capsules), cachets, pills, ampoules, boluses, suppositories,
pessaries, tinctures, gels, pastes, ointments, creams, lotions,
oils, foams, sprays, mists, or aerosols.
[0503] Formulations may suitably be provided as a patch, adhesive
plaster, bandage, dressing, or the like which is impregnated with
one or more compounds and optionally one or more other
pharmaceutically acceptable ingredients, including, for example,
penetration, permeation, and absorption enhancers. Formulations may
also suitably be provided in the form of a depot or reservoir.
[0504] The compound may be dissolved in, suspended in, or admixed
with one or more other pharmaceutically acceptable ingredients. The
compound may be presented in a liposome or other microparticulate
which is designed to target the compound, for example, to blood
components or one or more organs.
[0505] Formulations suitable for oral administration (e.g., by
ingestion) include liquids, solutions (e.g., aqueous, non-aqueous),
suspensions (e.g., aqueous, non-aqueous), emulsions (e.g.,
oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets,
granules, powders, capsules, cachets, pills, ampoules, boluses.
[0506] Formulations suitable for buccal administration include
mouthwashes, losenges, pastilles, as well as patches, adhesive
plasters, depots, and reservoirs. Losenges typically comprise the
compound in a flavored basis, usually sucrose and acacia or
tragacanth. Pastilles typically comprise the compound in an inert
matrix, such as gelatin and glycerin, or sucrose and acacia.
Mouthwashes typically comprise the compound in a suitable liquid
carrier.
[0507] Formulations suitable for sublingual administration include
tablets, losenges, pastilles, capsules, and pills.
[0508] Formulations suitable for oral transmucosal administration
include liquids, solutions (e.g., aqueous, non-aqueous),
suspensions (e.g., aqueous, non-aqueous), emulsions (e.g.,
oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as
well as patches, adhesive plasters, depots, and reservoirs.
[0509] Formulations suitable for non-oral transmucosal
administration include liquids, solutions (e.g., aqueous,
non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions
(e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels,
pastes, ointments, creams, lotions, oils, as well as patches,
adhesive plasters, depots, and reservoirs.
[0510] Formulations suitable for transdermal administration include
gels, pastes, ointments, creams, lotions, and oils, as well as
patches, adhesive plasters, bandages, dressings, depots, and
reservoirs.
[0511] Tablets may be made by conventional means, e.g., compression
or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the compound in a free-flowing form such as a powder or
granules, optionally mixed with one or more binders (e.g.,
povidone, gelatin, acacia, sorbitol, tragacanth,
hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose,
microcrystalline cellulose, calcium hydrogen phosphate); lubricants
(e.g., magnesium stearate, talc, silica); disintegrants (e.g.,
sodium starch glycolate, cross-linked povidone, cross-linked sodium
carboxymethyl cellulose); surface-active or dispersing or wetting
agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl
p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid);
flavours, flavour enhancing agents, and sweeteners. Moulded tablets
may be made by moulding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent. The
tablets may optionally be coated or scored and may be formulated so
as to provide slow or controlled release of the compound therein
using, for example, hydroxypropylmethyl cellulose in varying
proportions to provide the desired release profile. Tablets may
optionally be provided with a coating, for example, to affect
release, for example an enteric coating, to provide release in
parts of the gut other than the stomach.
[0512] Ointments are typically prepared from the compound and a
paraffinic or a water-miscible ointment base.
[0513] Creams are typically prepared from the compound and an
oil-in-water cream base. If desired, the aqueous phase of the cream
base may include, for example, at least about 30% w/w of a
polyhydric alcohol, i.e., an alcohol having two or more hydroxyl
groups such as propylene glycol, butane-1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol and mixtures thereof.
The topical formulations may desirably include a compound which
enhances absorption or penetration of the compound through the skin
or other affected areas. Examples of such dermal penetration
enhancers include dimethylsulfoxide and related analogues.
[0514] Emulsions are typically prepared from the compound and an
oily phase, which may optionally comprise merely an emulsifier
(otherwise known as an emulgent), or it may comprises a mixture of
at least one emulsifier with a fat or an oil or with both a fat and
an oil. Preferably, a hydrophilic emulsifier is included together
with a lipophilic emulsifier which acts as a stabiliser. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabiliser(s) make up the so-called
emulsifying wax, and the wax together with the oil and/or fat make
up the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0515] Suitable emulgents and emulsion stabilisers include Tween
60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl
monostearate and sodium lauryl sulfate. The choice of suitable oils
or fats for the formulation is based on achieving the desired
cosmetic properties, since the solubility of the compound in most
oils likely to be used in pharmaceutical emulsion formulations may
be very low. Thus the cream should preferably be a non-greasy,
non-staining and washable product with suitable consistency to
avoid leakage from tubes or other containers. Straight or branched
chain, mono- or dibasic alkyl esters such as di-isoadipate,
isocetyl stearate, propylene glycol diester of coconut fatty acids,
isopropyl myristate, decyl oleate, isopropyl palmitate, butyl
stearate, 2-ethylhexyl palmitate or a blend of branched chain
esters known as Crodamol CAP may be used, the last three being
preferred esters. These may be used alone or in combination
depending on the properties required. Alternatively, high melting
point lipids such as white soft paraffin and/or liquid paraffin or
other mineral oils can be used.
[0516] Formulations suitable for intranasal administration, where
the carrier is a liquid, include, for example, nasal spray, nasal
drops, or by aerosol administration by nebuliser, include aqueous
or oily solutions of the compound.
[0517] Formulations suitable for intranasal administration, where
the carrier is a solid, include, for example, those presented as a
coarse powder having a particle size, for example, in the range of
about 20 to about 500 microns which is administered in the manner
in which snuff is taken, i.e., by rapid inhalation through the
nasal passage from a container of the powder held close up to the
nose.
[0518] Formulations suitable for pulmonary administration (e.g., by
inhalation or insufflation therapy) include those presented as an
aerosol spray from a pressurised pack, with the use of a suitable
propellant, such as dichlorodifluoromethane,
trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide,
or other suitable gases.
[0519] Formulations suitable for ocular administration include eye
drops wherein the compound is dissolved or suspended in a suitable
carrier, especially an aqueous solvent for the compound.
[0520] Formulations suitable for rectal administration may be
presented as a suppository with a suitable base comprising, for
example, natural or hardened oils, waxes, fats, semi-liquid or
liquid polyols, for example, cocoa butter or a salicylate; or as a
solution or suspension for treatment by enema.
[0521] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the compound, such
carriers as are known in the art to be appropriate.
[0522] Formulations suitable for parenteral administration (e.g.,
by injection), include aqueous or non-aqueous, isotonic,
pyrogen-free, sterile liquids (e.g., solutions, suspensions), in
which the compound is dissolved, suspended, or otherwise provided
(e.g., in a liposome or other microparticulate). Such liquids may
additional contain other pharmaceutically acceptable ingredients,
such as anti-oxidants, buffers, preservatives, stabilisers,
bacteriostats, suspending agents, thickening agents, and solutes
which render the formulation isotonic with the blood (or other
relevant bodily fluid) of the intended recipient. Examples of
excipients include, for example, water, alcohols, polyols,
glycerol, vegetable oils, and the like. Examples of suitable
isotonic carriers for use in such formulations include Sodium
Chloride Injection, Ringer's Solution, or Lactated Ringer's
Injection. Typically, the concentration of the compound in the
liquid is from about 1 ng/mL to about 10 .mu.g/mL, for example from
about 10 ng/ml to about 1 .mu.g/mL. The formulations may be
presented in unit-dose or multi-dose sealed containers, for
example, ampoules and vials, and may be stored in a freeze-dried
(lyophilised) condition requiring only the addition of the sterile
liquid carrier, for example water for injections, immediately prior
to use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules, and tablets.
Dosage
[0523] It will be appreciated by one of skill in the art that
appropriate dosages of the AAA compounds, and compositions
comprising the AAA compounds, can vary from patient to patient.
Determining the optimal dosage will generally involve the balancing
of the level of therapeutic benefit against any risk or deleterious
side effects. The selected dosage level will depend on a variety of
factors including, but not limited to, the activity of the
particular AAA compound, the route of administration, the time of
administration, the rate of excretion of the AAA compound, the
duration of the treatment, other drugs, compounds, and/or materials
used in combination, the severity of the condition, and the
species, sex, age, weight, condition, general health, and prior
medical history of the patient. The amount of AAA compound and
route of administration will ultimately be at the discretion of the
physician, veterinarian, or clinician, although generally the
dosage will be selected to achieve local concentrations at the site
of action which achieve the desired effect without causing
substantial harmful or deleterious side-effects.
[0524] Administration can be effected in one dose, continuously or
intermittently (e.g., in divided doses at appropriate intervals)
throughout the course of treatment. Methods of determining the most
effective means and dosage of administration are well known to
those of skill in the art and will vary with the formulation used
for therapy, the purpose of the therapy, the target cell(s) being
treated, and the subject being treated. Single or multiple
administrations can be carried out with the dose level and pattern
being selected by the treating physician, veterinarian, or
clinician.
[0525] In general, a suitable dose of the AAA compound is in the
range of about 10 .mu.g to about 250 mg (more typically about 100
.mu.g to about 25 mg) per kilogram body weight of the subject per
day. Where the compound is a salt, an ester, an amide, a prodrug,
or the like, the amount administered is calculated on the basis of
the parent compound and so the actual weight to be used is
increased proportionately.
EXAMPLES
[0526] The following examples are provided solely to illustrate the
present invention and are not intended to limit the scope of the
invention, as described herein.
Abbreviations
[0527] AcOH=glacial acetic acid aq.=aqueous Boc=tert-butoxycarbonyl
br=broad CDI=1,1-carbonyldiimidazole d=doublet
DCM=dichloromethane
DIPEA=N,N-diisopropylethylamine
DMA=N,N-dimethylacetamide
[0528] DMAP=4-dimethylaminopyridine
DMF=N,N-dimethylformamide
[0529] DMSO=dimethylsulfoxide
EDC=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
eq.=no. of molar equivalents EtOAc=ethyl acetate h=hour(s)
HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
HOBt=N-hydroxybenzotriazole
[0530] HPLC=high performance liquid chromatography IPA=isopropanol
m=multiplet MeOH=methanol min=minute(s) NMR=nuclear magnetic
resonance PTSA=toluene-4-sulfonic acid quin=quintet RT=room
temperature s=singlet sat.=saturated SAX=solid supported strong
anion exchange resin SCX=solid supported strong cation exchange
resin sep=septet t=triplet T3P=2-propanephosphonic acid anhydride
TBAF=tetrabutylammonium fluoride TEA=triethylamine
TFA=trifluoroacetic acid THF=tetrahydrofuran
TMSCl=trimethylchlorosilane
General Procedures
[0531] All starting materials and solvents were either obtained
from commercial sources or prepared according to literature
conditions.
[0532] Hydrogenations were performed either on a Thales H-cube flow
reactor or with a suspension of the catalyst under a balloon of
hydrogen.
[0533] Microwave reactions were carried out on a Personal Chemistry
SmithSynthesizer Workstation with a 300 W single mode microwave
cavity.
[0534] SCX was purchased from Sigma Aldrich and washed with
methanol prior to use. The reaction mixture to be purified was
first dissolved in methanol and then loaded directly onto the SCX
and washed with methanol. The desired material was then eluted by
washing with 1% NH.sub.3 in methanol.
[0535] Column chromatography was performed on Silicycle pre-packed
silica (230-400 mesh, 40-63 .mu.M) cartridges.
Analytical Methods
Preparative HPLC:
[0536] The system consisted of a Gilson HPLC and an Agilent 5 .mu.m
Prep-C18 21.2.times.50 mm column. Detection was achieved using a UV
detector at 254 nm. Mobile phase A: 0.1% aqueous formic acid,
Mobile phase B: 0.1% formic acid in methanol.
[0537] Method 1: Flow rate 40 mL/min. Gradient: 0.0-0.8 min 5% B;
0.8-7.3 min 5-95% B; 7.3-8.3 min 95% B; 8.3-8.4 min 95-5% B.
.sup.1H NMR Spectroscopy:
[0538] NMR spectra were recorded using a Bruker Avance III.TM. 400
MHz instrument, using either residual non-deuterated solvent or
tetra-methylsilane as reference.
Chemical Synthesis
Synthesis 1
4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoic acid (AAA-001)
and Methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate
(AAA-002)
##STR00162##
[0539] Step (i): Methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate
(2)
##STR00163##
[0541] Methyl 3,5-dichloro-4-hydroxybenzoate (1) (1.00 g, 4.52
mmol) was dissolved in DMF (8 mL) and treated with
bromocyclopentane (534 .mu.L, 4.98 mmol), followed by potassium
carbonate (937 mg, 6.79 mmol). The mixture was stirred at
80.degree. C. for 3 h and then partitioned between EtOAc (100 mL)
and H.sub.2O (100 mL). The aqueous phase was extracted with EtOAc
(50 mL) and the combined organic phases washed successively with
water (5.times.50 mL) and brine (50 mL), then dried over MgSO.sub.4
and filtered. The solvent was removed in vacuo to afford methyl
3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.10 g, 84%): .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.97 (2H, s), 5.04 (1H, m), 3.90
(3H, s), 2.04-1.91 (4H, m), 1.82-1.75 (2H, m), 1.69-1.60 (2H,
m).
Step (ii): 3,5-Dichloro-4-(cyclopentyloxy)benzoic acid (3)
##STR00164##
[0543] Methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.05 g,
3.63 mmol) and lithium hydroxide (174 mg, 7.26 mmol) were combined
in THF (10 mL) and water (ca. 1.5 mL) was added dropwise until a
solution formed. The resultant mixture was stirred at RT for 12 h.
The THF was removed in vacuo and the residue acidified using
aqueous HCl (1 M). The resultant precipitate was filtered to afford
3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (820 mg, 82%): m/z
273 (M-H).sup.- (ES.sup.-).
Step (iii): Methyl
4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002)
##STR00165##
[0545] A solution of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid
(3) (100 mg, 363 .mu.mol) in DCM (5 mL), cooled to 0.degree. C.,
was treated with oxalyl chloride (63.6 .mu.L, 727 .mu.mol),
followed by a drop of DMF. The resultant mixture was stirred for 1
h at RT. The solvent was evaporated in vacuo and the residue
dissolved in DCM (5 mL), and then treated with a solution of methyl
4-aminobenzoate (54.9 mg, 363 .mu.mol) and DIPEA (190 .mu.L, 1.09
mmol) in DCM (5 mL). The reaction mixture was stirred for 12 h at
RT and then partitioned between DCM (20 mL) and aqueous HCl (20 mL,
1 M). The phases were separated and the organic phase was washed
successively with water (2.times.20 mL), and brine (20 mL), dried
over MgSO.sub.4, filtered and then the solvent was removed in
vacuo. The residue was purified by silica gel chromatography (12 g,
0-100% EtOAc in isohexane) to afford methyl
4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002) (30
mg, 20%): m/z 406 (M-H).sup.- (ES.sup.-). NMR (400 MHz, CDCl.sub.3)
.delta.: 8.06 (2H, d), 7.85 (1H, br s), 7.82 (2H, s), 7.71 (2H, d),
5.05 (1H, m), 3.92 (3H, s), 2.10-1.90 (4H, m), 1.85-1.70 (2H, m),
1.70-1.60 (2H, m).
Step (iv): 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)benzoic acid
(AAA-001)
##STR00166##
[0547] 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)benzoic acid
(AAA-001) (15.0 mg, 51%) was prepared from methyl
4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002)
(30.0 mg, 74 .mu.mol) using a procedure essentially the same as in
Step (ii): m/z 392 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.77 (1H, s), 10.58 (1H, s), 8.07 (2H, s),
7.93 (2H, d), 7.88 (2H, d), 5.02 (1H, m), 1.90-1.60 (8H, m).
Synthesis 2
4-(3,5-Dichloro-4-propoxybenzamido)benzoic acid (AAA-003)
##STR00167##
[0549] 4-(3,5-Dichloro-4-propoxybenzamido)benzoic acid (AAA-003)
(34 mg, 71% for final step) was prepared in essentially the same
manner as in Steps (iii) and (iv) for AAA-001 except that
3,5-dichloro-4-propoxybenzoic acid was used instead of
3,5-dichloro-4-(cyclopentyloxy)-benzoic acid in step (iii): m/z 366
(M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, MeOH-d.sub.4)
.delta.: 7.99 (4H, s), 7.85 (2H, d), 4.07 (2H, s), 3.89 (3H, s),
1.89 (2H, s), 1.12 (3H, s).
Synthesis 3
4-(3,5-Dichloro-4-isopropoxybenzamido)benzoic acid (AAA-004)
##STR00168##
[0551] 4-(3,5-Dichloro-4-isopropoxybenzamido)benzoic acid (AAA-004)
(48.5 mg, 53% for final step) was prepared in essentially the same
manner as AAA-001 except that isopropyl bromide was used instead of
cyclopentyl bromide in step (i): m/z 366 (M-H).sup.- (ES.sup.-),
368 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, MeOH-d.sub.4)
.delta.: 8.03 (4H, m), 7.83 (2H, d), 4.77 (1H, m), 1.38 (6H,
s).
Synthesis 4
4-(4-(Benzyloxy)-3,5-dichlorobenzamido)benzoic acid (AAA-005)
##STR00169##
[0553] 4-(4-Benzyloxy-3,5-dichlorobenzamido)benzoic acid (AAA-005)
(21 mg, 46% for final step) was prepared in essentially the same
manner as for AAA-001 except that benzyl bromide was used instead
of cyclopentyl bromide in step (i): m/z 414 (M-H).sup.- (ES.sup.-).
.sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta.: 8.03 (4H, d), 7.83
(2H, d), 7.53 (2H, d), 7.38 (3H, m), 5.15 (2H, s).
Synthesis 5
4-(3-Chloro-4-(cyclopentyloxy)-5-methoxybenzamido)benzoic acid
(AAA-006)
##STR00170##
[0555] 4-(3-Chloro-4-(cyclopentyloxy)-5-methoxybenzamido)benzoic
acid (AAA-006) (56 mg, 57% for final step) was prepared in
essentially the same manner as in Steps (iii) and (iv) for AAA-001
except that 3-chloro-4-(cyclopentyloxy)-5-methoxybenzoic acid was
used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step
(iii): m/z 388 (M-H).sup.- (ES.sup.-), 390 (M+H).sup.+ (ES.sup.+).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 12.68 (1H, s), 10.41
(1H, s), 7.86 (2H, d), 7.82 (2H, d), 7.63 (1H, d), 7.49 (1H, d),
4.95 (1H, m), 3.85 (3H, s), 1.80-1.47 (8H, m).
Synthesis 6
4-(3,5-Dichloro-4-ethoxybenzamido)-2-fluorobenzoic acid
(AAA-007)
##STR00171##
[0557] 4-(3,5-Dichloro-4-ethoxybenzamido)-2-fluorobenzoic acid
(AAA-007) (380 mg, 48% for final step) was prepared in essentially
the same manner as for AAA-001 except that ethyl iodide was used
instead of cyclopentyl bromide in step (i) and methyl
4-amino-2-fluorobenzoate (prepared by the action of hydrogen and
10% Pd/C on methyl 2-fluoro-4-nitrobenzoate) was used instead of
methyl 4-aminobenzoate in step (iii): m/z 370 (M-H).sup.-
(ES.sup.-), 372 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta.: 8.01 (2H, s), 7.92 (1H, t), 7.79 (1H, d),
7.53 (1H, d), 4.18 (2H, q), 1.46 (3H, t).
Synthesis 7
4-(4-Ethoxy-3,5-diisopropoxybenzamido)benzoic acid (AAA-008)
##STR00172##
[0559] 4-(4-Ethoxy-3,5-diisopropoxybenzamido)benzoic acid (AAA-008)
(288 mg, 57% for final step) was prepared in essentially the same
manner as in Steps (iii) and (iv) for AAA-001 except that
4-ethoxy-3,5-diisopropoxybenzoic acid (prepared in 3 steps from
methyl 3,4,5-trihydroxybenzoate by sequential treatment with ethyl
iodide and base, isopropyl bromide and base and then lithium
hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 400
(M-H).sup.- (ES.sup.-), 402 (M+H).sup.+ (ES.sup.+). .sup.1H NMR
(400 MHz, MeOH-d.sub.4) .delta.: 8.02 (2H, d), 7.85 (2H, d), 7.28
(2H, s), 4.70 (2H, m), 4.10 (2H, q), 1.37 (15H, m).
Synthesis 8
4-(3,4-Diethoxy-5-isopropoxybenzamido)benzoic acid (AAA-009)
##STR00173##
[0561] 4-(3,4-Diethoxy-5-isopropoxybenzamido)benzoic acid (AAA-009)
(5 mg, 15% for final step) was prepared in essentially the same
manner as in Steps (iii) and (iv) for AAA-001 except that
3,4-diethoxy-5-diisopropoxybenzoic acid (prepared in 3 steps from
methyl 3,4,5-trihydroxybenzoate by sequential treatment with ethyl
iodide and base, isopropyl bromide and base and then lithium
hydroxide, the product being a by-product of the preparation of
4-ethoxy-3,5-diisopropoxybenzoic acid shown in the synthesis of
AAA-008) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic
acid in step (iii): m/z 386 (M-H).sup.- (ES.sup.-), 388 (M+H).sup.+
(ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.12 (2H,
d), 7.75 (2H, d), 7.08 (2H, d), 4.63 (1H, m), 4.13 (4H, m), 1.47
(3H, t), 1.40-1.36 (9H, m).
Synthesis 9
4-(3,5-Dichloro-4-(cyclopropylmethoxy)benzamido)benzoic acid
(AAA-010)
##STR00174## ##STR00175##
[0562] Step (i): Methyl 4-(benzyloxy)-3,5-dichlorobenzoate (2)
##STR00176##
[0564] Crude methyl 4-(benzyloxy)-3,5-dichlorobenzoate (2) (16.9 g)
was prepared from methyl 3,5-dichloro-4-hydroxybenzoate (1) (10 g,
45.2 mmol) and benzyl bromide (15.5 g, 90 mmol) using a procedure
essentially the same as in Step (0 for AAA-001, except that the
mixture was stirred at RT for 18 h. The crude product was partially
purified by silica gel chromatography (330 g, 0-10%
EtOAc/isohexane) to afford a white solid. The material was used in
the next step without further purification.
Step (ii): 4-(Benzyloxy)-3,5-dichlorobenzoic acid (3)
##STR00177##
[0566] 4-(Benzyloxy)-3,5-dichlorobenzoic acid (3) (12.8 g, 96% over
2 steps) was prepared from crude 4-(benzyloxy)-3,5-dichlorobenzoate
(2) (16.9 g) using a procedure essentially the same as in Step (iv)
for AAA-001: m/z 295 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 7.88 (2H, s), 7.51 (2H, d), 7.44-7.37 (3H,
m), 5.05 (2H, s).
Step (iii): Methyl 4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate
(4)
##STR00178##
[0568] Methyl 4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate (4)
(9.81 g, 51%) was prepared from 4-(benzyloxy)-3,5-dichlorobenzoic
acid (3) (12.8 g, 43.2 mmol) using a procedure essentially the same
as in Step (iii) for AAA-001, except the crude product was
crystallised from isohexane/EtOAc to afford the product as a white
solid. m/z 428 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 8.07 (2H, d), 7.84 (2H, s), 7.73 (2H, d), 7.54
(2H, d), 7.44-7.36 (3H, m), 5.13 (2H, s), 3.92 (3H, s).
Step (iv): Methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate
(5)
##STR00179##
[0570] A solution of methyl
4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate (4) (8.8 g, 20.5
mmol) in DCM (500 mL) was cooled to 0.degree. C. and treated
dropwise with boron trichloride (20.5 mL, 20.5 mmol, 1 M in DCM).
The mixture was then allowed to stir at RT for 12 h. The mixture
was cooled in an ice bath then quenched by addition of water (150
mL). The resultant mixture was partitioned between EtOAc (200 mL)
and H.sub.2O (100 mL). The aqueous phase was extracted with EtOAc
(2.times.75 mL) and the combined organic phases washed successively
with water (50 mL) and brine (50 mL), then dried over MgSO.sub.4
and filtered. The solvent was removed in vacuo. The residue was
crystallised from isohexane/EtOAc to afford methyl
4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (5.81 g, 84%): m/z
338 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 11.06 (1H, s), 10.52 (1H, s), 8.06 (2H, s), 8.00 (2H, d),
7.95 (2H, d), 3.88 (3H, s).
Step (v): Methyl
4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)benzoate (6)
##STR00180##
[0572] Methyl
4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)benzoate (6) (120
mg, 100%) was prepared from methyl
4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (100 mg, 294
.mu.mol) and (bromomethyl)cyclopropane (57 .mu.L, 588 .mu.mol)
using a procedure essentially the same as in Step (i) for AAA-001
except the mixture was stirred at 50.degree. C. for 18 h: m/z 392
(M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 7.99 (4H, d), 7.85 (2H, d), 3.99 (2H, d), 3.90 (3H, s),
1.49-1.29 (1H, m), 0.65-0.60 (2H, m), 0.37-0.34 (2H, m).
Step (vi): 4-(3,5-Dichloro-4-(cyclopropylmethoxy)benzamido)benzoic
acid (AAA-010)
##STR00181##
[0574] 4-(3,5-Dichloro-4-(cyclopropylmethoxy)benzamido)benzoic acid
(AAA-010) (82 mg, 71%) was prepared from methyl
4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)-benzoate (6) (120
mg, 304 .mu.mol) using a procedure essentially the same as in Step
(iv) for AAA-001: m/z 378 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400
MHz, MeOH-d.sub.4) .delta.: 8.01 (4H, d), 7.83 (2H, d), 3.98 (2H,
d), 1.40-1.30 (1H, m), 0.64-0.60 (2H, m), 0.37-0.33 (2H, m).
Synthesis 10
4-(3,5-Dichloro-4-cyclobutoxybenzamido)benzoic acid (AAA-011)
##STR00182##
[0576] 4-(3,5-Dichloro-4-cyclobutoxybenzamido)benzoic acid
(AAA-011) (23 mg, 31% for final step) was prepared in essentially
the same manner as in Steps (v) and (vi) for AAA-010 except that
bromocyclobutane was used instead of (bromomethyl)cyclopropane in
step (v): m/z 378 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta.: 8.01 (4H, d), 7.85 (2H, s), 4.78-4.71 (1H,
m), 2.4-2.35 (4H, m) 1.8-1.75 (1H, m), 1.64-1.49 (1H, m).
Synthesis 11
4-(3,5-Dichloro-4-(pyridin-4-ylmethoxy)benzamido)benzoic acid
(AAA-012)
##STR00183##
[0578] 4-(3,5-Dichloro-4-(pyridin-4-ylmethoxy)benzamido)benzoic
acid (AAA-012) (47 mg, 63% for final step) was prepared in
essentially the same manner as in Steps (v) and (vi) for AAA-010
except that 4-(chloromethyl)pyridine was used instead of
(bromomethyl)cyclopropane in step (v): m/z 415 [M-H].sup.-
(ES.sup.-), 417 [M+H].sup.+ (ES.sup.+), 1H NMR (400 MHz,
MeOH-d.sub.4) .delta.: 10.43 (1H, s), 8.92 (2H, d), 8.30 (2H, d),
8.13 (2H, s), 8.04 (2H, d), 7.86 (2H, d), 5.54 (2H, s).
Synthesis 12
4-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-013)
##STR00184##
[0579] Step (i): 4-(3,5-Dichloro-4-hydroxyphenylcarbamoyl)benzoic
acid (4)
##STR00185##
[0581] A mixture of 4-(chlorocarbonyl)benzoic acid methyl ester (1)
(600 mg, ca. 3.02 mmol) contaminated with
4-(methoxycarbonyl)benzoic acid was suspended in DCM (5 mL) and
cooled to 0.degree. C. The mixture was treated with oxalyl chloride
(529 .mu.L, 6.04 mmol) and DMF (1 drop). The resultant mixture was
warmed to RT, stirred for 2 h, and then concentrated in vacuo. The
residue was dissolved in DCM (3 mL) and a suspension of
4-amino-2,6-dichlorophenol (2) (511 mg, 2.9 mmol) in DCM (18 mL)
was added. The resultant suspension was treated with DIPEA (1.58
mL, 9.06 mmol) and was stirred at RT overnight. The solvent was
removed in vacuo and the residue partitioned between EtOAc/DCM and
aqueous HCl (1 M). The layers were separated and the organic layer
was washed with water and brine. The organic layer was dried over
MgSO.sub.4, filtered and then the solvent evaporated in vacuo to
afford a pale brown solid (930 mg), which was triturated in hot
acetonitrile/methanol (9:1) and filtered. The precipitate and
filtrate were recombined, the solvent was evaporated in vacuo and
then the residue was dissolved in THF (40 mL). Water (10 mL) was
added and the mixture treated with lithium hydroxide (340 mg, 14.2
mmol). The mixture was stirred overnight and then partitioned
between EtOAc and aqueous HCl (1 M). The organic layer was washed
successively with water (2.times.50 mL), brine, dried over
MgSO.sub.4, filtered and then concentrated in vacuo to afford crude
4-(3,5-dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (3) as a pale
brown solid. This material was used in the subsequent reaction step
without purification.
Step (ii): Ethyl 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoate
(4)
##STR00186##
[0583] Crude 4-(3,5-dichloro-4-hydroxyphenylcarbamoyl)benzoic acid
(3) (450 mg) was dissolved in DMF (15 mL) and treated with
potassium carbonate (829 mg, 6.00 mmol) and iodoethane (436 .mu.L,
5.4 mmol). The mixture was stirred at 65.degree. C. overnight.
Iodoethane (200 .mu.L, 2.48 mmol) was added and the reaction
mixture stirred at 70.degree. C. for 3 h. The mixture was
partitioned between EtOAc (150 mL) and aqueous HCl (100 mL, 1 M).
The layers were separated and the organic layer was washed
successively with saturated aqueous NaHCO.sub.3 and water. The
organic layer was dried over MgSO.sub.4, filtered and the solvent
evaporated in vacuo. The residue was purified by silica gel
chromatography (10-25% EtOAc/isohexane) to afford Ethyl
4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoate (4) (500 mg, 75%
over 2 steps) as a pale pink solid: m/z 380 (M-H).sup.+
(ES.sup.-).
Step (iii): 4-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)benzoic acid
(AAA-013)
##STR00187##
[0585] Ethyl 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoate (6)
(109 mg, 285 .mu.mol) in THF (5 mL) was treated with aqueous
lithium hydroxide (1.43 mL, 1 M, 1.43 mmol) and the mixture was
stirred at RT for 5 h. The reaction mixture was partitioned between
EtOAc and aqueous HCl (1 M). The organic layer was separated and
washed successively with water and brine. The organic layer was
dried over MgSO.sub.4, filtered and then concentrated in vacuo to
afford 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoic acid
(AAA-013) (89 mg, 88%) as a pale lilac solid: m/z 352 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.30 (1H,
s), 10.58 (1H, s), 8.08 (2H, d), 8.03 (2H, d), 7.94 (2H, d), 4.04
(2H, q), 1.37 (3H, t).
Synthesis 13
4-(3,5-Dibromo-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-014)
##STR00188##
[0586] Step (i): 3,5-Dibromo-4-ethoxyaniline (2)
##STR00189##
[0588] 4-Amino-2,6-dibromophenol (1) (1.00 g, 3.75 mmol) was
dissolved in anhydrous DMF (10 mL) and cooled to 0.degree. C.
Sodium hydride (165 mg, 4.12 mmol) was added portionwise. The dark
blue solution was stirred for 1 h at RT before iodoethane (318
.mu.L, 3.93 mmol) was added. The mixture was stirred at RT for 3
days and then partitioned between EtOAc and aqueous NaOH (1 M). The
organic layer was washed successively with water and brine, then
dried over MgSO.sub.4 and filtered. The solvent was evaporated in
vacuo and the residue purified by silica gel chromatography (10%
EtOAc/isohexane) to afford 3,5-dibromo-4-ethoxyaniline (2) (790 mg,
72%) as a dark orange solid: m/z 296 (M+H).sup.+ (ES.sup.+).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 6.82 (2H, s), 3.99 (2H,
q), 3.58 (2H, s), 1.54 (3H, s), 1.44 (3H, t).
Step (ii): Methyl 4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate
(4)
##STR00190##
[0590] 3,5-Dibromo-4-ethoxyaniline (2) (100 mg, 339 .mu.mol) was
dissolved in DCM (2.5 mL) and treated with triethylamine (143
.mu.L, 1.02 mmol). 4-(Chlorocarbonyl)benzoic acid methyl ester (3)
(135 mg, 678 .mu.mol) was added in one portion and the resultant
dark orange mixture was stirred at RT for 3 h then partitioned
between EtOAc and aqueous 1M HCl. The organic layer was washed
successively with saturated aqueous NaHCO.sub.3, water and brine.
The organic layer was then dried over MgSO.sub.4, filtered and the
solvent evaporated in vacuo. The residue was triturated from
Et.sub.2O and filtered. The filtered solid was washed with methanol
and the washings were concentrated in vacuo to provide methyl
4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate (4) (141 mg, 73%)
as a pale brown solid: m/z 456 [M-H].sup.- (ES.sup.-).
Step (iii): 4-(3,5-Dibromo-4-ethoxyphenylcarbamoyl)benzoic acid
(AAA-014)
##STR00191##
[0592] 4-(3,5-Dibromo-4-ethoxyphenylcarbamoyl)benzoic acid
(AAA-014) (31 mg, 71%) was prepared from methyl
4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate (4) (45 mg, 98
.mu.mol) using a procedure essentially the same as in Step (iii)
for AAA-013, except the mixture was stirred overnight: m/z 442
[M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.31 (1H, s), 10.59 (1H, s), 8.15 (2H, s), 8.05 (2H, d),
8.03 (2H, d), 4.01 (2H, q), 1.40 (3H, t).
Synthesis 14
4-(4-Ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoic acid
(AAA-015)
##STR00192##
[0593] Step (i): 2-Ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene
(2)
##STR00193##
[0595] Ethanol (20 mL, 343 mmol) was treated with potassium
hydroxide (956 mg, 17.0 mmol) and the mixture was stirred at RT for
1 h. A solution of 2-chloro-5-nitro-1,3-bis(trifluoromethyl)benzene
(1) (1.00 g, 3.41 mmol) in DMSO (10 mL) was added drop-wise. The
resultant mixture was stirred at RT for 1 h. The mixture was
partitioned between EtOAc and water and the aqueous phase was
extracted twice with EtOAc. The combined organic phases were washed
with brine, dried over MgSO.sub.4, filtered and the solvent removed
in vacuo to afford 2-ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene
(2) (1.00 g, 93%) as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 8.72 (2H, s), 4.21 (2H, q), 1.41 (3H,
t).
Step (ii): 4-Ethoxy-3,5-bis(trifluoromethyl)aniline (3)
##STR00194##
[0597] 2-Ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2) (1.00
g, 3.30 mmol) was dissolved in MeOH (150 mL) and passed through a
Thales `H-cube` cartridge (10% Pd/C) at a flow rate of 1 mL/min at
30.degree. C. under H.sub.2 (full H.sub.2 mode). The solvent was
removed in vacuo and the residue was dissolved in EtOH (20 mL) and
then treated with 10% Pd/C (182 mg, 171 .mu.mol). Hydrogen gas was
bubbled through the mixture, with stirring at RT for 2 h. The
mixture was then filtered through Celite and concentrated in vacuo.
The residue was purified by silica gel chromatography (15% EtOAc in
isohexane) to afford 4-ethoxy-3,5-bis(trifluoromethyl)aniline (3)
(460 mg, 56%) as a white solid: m/z 273 [M+H].sup.+ (ES.sup.+).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.09 (2H, s), 5.76
(2H, s), 3.87 (2H, q), 1.29 (3H, t).
Step (iii): Methyl
4-(4-ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoate
(5)
##STR00195##
[0599] 4-(Methoxycarbonyl)benzoic acid (4) (246 mg, 1.37 mmol) was
dissolved in DCM (15 mL) and treated with EDC (654 mg, 3.41 mmol)
and DMAP (33 mg, 273 .mu.mol). The resultant mixture was stirred at
RT for 15 min. 4-Ethoxy-3,5-bis(trifluoromethyl)aniline (3) (360
mg, 1.32 mmol) was added and the resultant mixture was stirred at
RT for 20 h. The mixture was diluted with EtOAc and washed three
times with 1 M HCl and then three times with NaHCO.sub.3 solution.
The organic phase was washed with brine, dried over MgSO.sub.4,
filtered and the solvent removed in vacuo. The residue was purified
by silica gel chromatography (10% EtAOc in isohexane) to afford
methyl 4-(4-ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoate
(5) (150 mg, 28%): m/z 436 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 10.88 (1H, s), 8.48 (2H, s), 8.11 (4H,
m), 4.04 (2H, q), 3.90 (3H, s), 1.37 (3H, t).
Step (iv):
4-(4-Ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoic acid
(AAA-015)
##STR00196##
[0601] 4-(4-Ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoic
acid (AAA-015) (107 mg, 70%) was prepared from methyl
4-(4-ethoxy-3,5-bis(trifluoromethyl)phenyl carbamoyl)benzoate (5)
(150 mg, 345 .mu.mol) using a procedure essentially the same as in
Step (vi) for AAA-010: m/z 422 [M+H].sup.+ (ES.sup.+). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 13.39 (1H, bs), 10.92 (1H, s),
8.55 (2H, s), 8.15 (4H, m), 4.11 (2H, q), 1.44 (3H, t).
Synthesis 15
N-(4-Carbamoylphenyl)-3,5-dichloro-4-ethoxybenzamide (AAA-016)
##STR00197##
[0603] 3,5-Dichloro-4-ethoxybenzoic acid (1) (100 mg, 425 .mu.mol)
was dissolved in DCM (2 mL) and treated with EDC (204 mg, 1.06
mmol) and DMAP (10 mg, 85 .mu.mol). The resultant mixture was
stirred at RT for 30 min. 4-Aminobenzamide (2) (58 mg, 425 .mu.mol)
was added and the resultant mixture was stirred at RT for 4 h. The
mixture was filtered and the solid washed with DCM to afford
N-(4-carbamoylphenyl)-3,5-dichloro-4-ethoxybenzamide (AAA-016) (98
mg, 64%) as a white solid: m/z 355 [M+H].sup.+ (ES.sup.+). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.51 (1H, bs), 8.08 (2H, s),
7.84 (5H, m), 7.27 (1H, bs), 4.14 (2H, q), 1.40 (3H, t).
Synthesis 16
Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-chlorobenzoate
(AAA-017)
##STR00198##
[0605] Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-chlorobenzoate
(AAA-017) (175 mg, 39%) was prepared in essentially the same manner
as in Step (iii) for AAA-001, except that
3,5-dichloro-4-ethoxybenzoic acid was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl
4-amino-2-chlorobenzoate was used instead of methyl
4-aminobenzoate: m/z 402 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.93 (2H, d), 7.85 (1H, s), 7.83 (1H, d),
7.80 (2H, s), 4.18 (2H, q), 3.93 (3H, s), 1.49 (3H, t).
Synthesis 17
2-Chloro-4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid
(AAA-018)
##STR00199##
[0607] 2-Chloro-4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid
(AAA-018) (39 mg, 39% for the final step) was prepared in
essentially the same manner as in Steps (iii) and (iv) for AAA-001,
except that 3,5-dichloro-4-ethoxybenzoic acid was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl
4-amino-2-chlorobenzoate was used instead of methyl 4-aminobenzoate
in Step (iii): m/z 386 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 13.18 (1H, s), 10.65 (1H, s), 8.07 (2H,
s), 8.00 (1H, d), 7.88 (1H, d), 7.78 (1H, dd), 4.13 (2H, q), 1.39
(3H, t).
Synthesis 18
4-(3,5-Dichloro-4-ethoxybenzamido)-2-methylbenzoic acid
(AAA-019)
##STR00200##
[0608] Step (i): Methyl
4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3)
##STR00201##
[0610] A solution of 3,5-dichloro-4-ethoxybenzoic acid (1) (285 mg,
1.21 mmol) and DIPEA (1.05 mL, 6.05 mmol) in DMF (2.5 mL) was added
to HATU (690 mg, 1.82 mmol) and the orange mixture was stirred for
5 min prior to the addition of methyl 4-amino-2-methylbenzoate (2)
(200 mg, 1.21 mmol) in DMF (1 mL). The resulting dark orange
solution was stirred overnight for 18 h. 2 M HCl (10 mL) was added
and stirring continued for 10 min, and then the mixture was
extracted with diethyl ether. The organic layer was washed with
water (3.times.15 mL), dried over MgSO.sub.4, filtered and the
solvent was evaporated in vacuo. The yellow residue was purified by
silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to
afford methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate
(3) (267 mg, 56%): m/z 380 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.97 (1H, s), 7.80 (3H, m), 7.54 (1H,
dd), 7.51 (1H, d), 4.18 (2H, q), 3.89 (3H, s), 2.63 (3H, s), 1.49
(3H, t).
Step (ii): 4-(3,5-Dichloro-4-ethoxybenzamido)-2-methylbenzoic acid
(AAA-019)
##STR00202##
[0612] Lithium hydroxide (60 mg, 2.51 mmol) in water (1 mL) was
added dropwise to a stirring solution of methyl
4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3) (267 mg,
56%) (240 mg, 0.628 mmol) in THF (5 mL) and the resulting yellow
solution was stirred for 5 days at RT. The solvent was evaporated
in vacuo and dissolved in water (5 mL), then acidified with 2 M
HCl. The resultant mixture was extracted with EtOAc. The organic
layer was washed with water, dried over MgSO.sub.4 and filtered and
pre-adsorbed on silica. Silica gel chromatography (40 g, 0-10% IPA
in DCM) provided 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoic
acid (AAA-019) (52 mg, 22%): m/z 366 (M-H).sup.- (ES.sup.-).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.66 (1H, s), 10.49
(1H, s), 8.08 (2H, s), 7.87 (1H, d), 7.71 (1H, dd), 7.68 (1H, d),
4.14 (2H, q), 2.54 (3H, s), 1.40 (2H, t).
Synthesis 19
6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid
(AAA-020)
##STR00203##
[0613] Step (i): 3,5-Dichloro-4-ethoxyaniline (2)
##STR00204##
[0615] 4-Amino-2,6-dichlorophenol (1) (1.00 g, 5.62 mmol) was
dissolved in dry DMF (9 mL) and cooled to 0.degree. C. Sodium
hydride (142 mg, 5.90 mmol) was added to the mixture portionwise.
The dark purple solution was stirred for 1 h at RT, then iodoethane
(468 .mu.L, 5.79 mmol) was added. The reaction mixture was stirred
for 3 h and partitioned between EtOAc and aqueous NaOH (1 M). The
organic layer was washed successively with water and brine, and
then dried over MgSO.sub.4, filtered and the solvent evaporated in
vacuo. The residue was purified by silica gel chromatography (5%
EtOAc/isohexane) to afford 3,5-dichloro-4-ethoxyaniline (2) (460
mg, 40%): m/z 206 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 6.60 (2H, s), 4.01 (2H, q), 3.60 (2H, s), 1.42
(3H, t).
Step (ii): Methyl
6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3)
##STR00205##
[0617] 5-(Methoxycarbonyl)-2-pyridine carboxylic acid (50 mg, 276
.mu.mol) was dissolved in DMF (2 mL) and treated with CDI (60 mg,
370 .mu.mol). The reaction mixture was stirred at RT for 2 h.
3,5-Dichloro-4-ethoxyaniline (2) (57 mg, 276 .mu.mol) and DIPEA (96
.mu.L, 552 .mu.mol) were added sequentially and the reaction
mixture was stirred at RT overnight, then at 70.degree. C. for 19
h. The reaction mixture was partitioned between EtOAc and aqueous
HCl (1 M). The organic layer was washed successively with water and
brine, and then dried over MgSO.sub.4, filtered and concentrated in
vacuo. The residue was crystallised from methanol to afford methyl
6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (46 mg, 45%)
as a white solid: m/z 369 [M+H].sup.+ (ES.sup.+). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H,
dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 3.94 (3H, s), 1.37
(3H, t).
Step (iii): 6-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid
(AAA-020)
##STR00206##
[0619] 6-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid
(AAA-020) (19 mg, 109%) was prepared from methyl
6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (18 mg, 49
.mu.mol) using a procedure essentially the same as in Step (iii)
for AAA-013, except methanol (0.5 mL) was also added and the
reaction mixture was stirred at RT overnight: m/z 353 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.12 (1H,
s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06
(2H, q), 1.37 (3H, t).
Synthesis 20
4-(4-Ethoxy-3,5-difluorophenylcarbamoyl)benzoic acid (AAA-021)
##STR00207##
[0621] 4-(4-Ethoxy-3,5-difluorophenylcarbamoyl)benzoic acid
(AAA-021) (7 mg, 17%) was prepared was prepared in essentially the
same manner as in Steps (ii) and (iii) for AAA-014, except that
3,5-difluoro-4-ethoxyaniline was used instead of
3,5-dibromo-4-ethoxyaniline in step (ii) and purification was
effected by trituration with Et.sub.2O/EtOAc 8:1 and purification
by preparative HPLC (Method 1): m/z 320 [M-H].sup.- (ES.sup.-).
.sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta.: 8.42 (1H, s), 8.10
(2H, d), 7.94 (2H, d), 7.45 (2H, d), 4.14 (2H, q), 1.35 (3H,
t).
Synthesis 21
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2,6-difluorobenzoic
acid (AAA-022)
##STR00208##
[0623]
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2,6-difluorobenz-
oic acid (AAA-022) (5 mg, 7% for final step) was prepared in
essentially the same manner as in Steps (iii) and (iv) for AAA-001,
except that 3-chloro-4-ethoxy-5-trifluoromethylbenzoic acid
(prepared in 3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid
by sequential treatment with sulfuryl chloride, ethyl iodide and
base and then lithium hydroxide) and ethyl
2,6-difluoro-4-aminobenzoate were used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl
4-aminobenzoate respectively in step (iii): m/z 422 (M-H).sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, MeOD) .delta.: 8.32 (d, 1H), 8.21
(d, 1H), 7.49 (d, 2H), 4.24 (q, 2H), 1.48 (t, 3H).
Synthesis 22
4-(3,5-Dibromo-4-ethoxybenzamido)benzoic acid (AAA-023)
##STR00209##
[0625] 4-(3,5-Dibromo-4-ethoxybenzamido)benzoic acid (AAA-023) (42
mg, 87% for final step) was prepared in essentially the same manner
as in Steps (iii) and (iv) for AAA-001, except that
3,5-dibromo-4-ethoxybenzoic acid (prepared in 2 steps from methyl
3,5-dibromo-4-hydroxybenzoate by sequential treatment with ethyl
iodide and base and then lithium hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 442
(M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, CDCl.sub.3) 10.59
(1H, s), 8.24 (2H, s), 7.94 (2H, d), 7.87 (2H, d), 4.10 (2H, q),
1.43 (3H, t).
Synthesis 23
4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid (AAA-024)
##STR00210##
[0627] 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid
(AAA-024) (80 mg, 79% for final step) was prepared in essentially
the same manner as in Steps (iii) and (iv) for AAA-001, except that
3-chloro-4-ethoxy-5-methoxybenzoic acid was used instead of
3,5-dichloro-4-(cyclopentyloxy)-benzoic acid in step (iii): m/z 348
(M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO) 12.76 (1H, br
s), 10.46 (1H, br s), 7.93 (2H, d), 7.87 (2H, d), 7.69 (1H, d),
7.56 (1H, d), 4.19 (2H, q), 3.85 (3H, s), 1.39 (3H, t).
Synthesis 24
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-025)
##STR00211##
[0629] 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-025) (17 mg, 34% for final step) was prepared in
essentially the same manner as in Steps (iii) and (iv) for AAA-001,
except that 3-chloro-4-ethoxy-5-(trifluoromethyl)benzoic acid was
used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step
(iii): m/z 386 (M-H).sup.- ES.sup.-. .sup.1H NMR (400 MHz, DMSO)
12.78 (1H, br s), 10.69 (1H, br s), 8.42 (1H, d), 8.22 (1H, d),
7.95 (2H, d), 7.87 (2H, d), 3.37 (2H, q), 1.41 (3H, t).
Synthesis 25
5-(3,5-Dichloro-4-ethoxybenzamido)picolinic acid (AAA-026)
##STR00212##
[0631] 5-(3,5-Dichloro-4-ethoxybenzamido)picolinic acid (AAA-026)
(20 mg, quant. for final step) was prepared in essentially the same
manner as in Steps (iii) and (iv) for AAA-001, except that
3,5-dichloro-4-ethoxybenzoic acid and methyl 5-aminopicolinate
(prepared by treating 5-aminopyridine-2-carboxylic acid with acetyl
chloride and methanol) were used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl
4-aminobenzoate respectively in step (iii): m/z 355 (M+H).sup.+
(ES.sup.+). .sup.1H NMR 400 MHz, DMSO-d.sub.6) .delta.: 10.9 (1H,
s), 9.0 (1H, d), 8.4 (1H, dd), 8.2 (2H, s), 8.1 (1H, d), 4.1 (2H,
q), 1.4 (3H, t). (The final compound was isolated as a
hydrochloride salt.
Synthesis 26
6-(3,5-Dichloro-4-ethoxybenzamido)nicotinic acid (AAA-027)
##STR00213##
[0633] 6-(3,5-Dichloro-4-ethoxybenzamido)nicotinic acid (AAA-027)
(28 mg, 29% for final step) was prepared in essentially the same
manner as in Steps (iii) and (iv) for AAA-001, except that
3,5-dichloro-4-ethoxybenzoic acid and methyl 6-aminonicotinate were
used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and
methyl 4-aminobenzoate respectively in step (iii): m/z 353
(M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 11.3 (1H, s), 8.9 (1H, d), 8.3 (1H, dd), 8.2 (1H, d), 8.1
(2H, s), 4.1 (2H, q), 1.4 (3H, t).
Synthesis 27
4-(3,4,5-Triethoxybenzamido)benzoic acid (AAA-028) (PP-01)
##STR00214##
[0635] 4-(3,4,5-Triethoxybenzamido)benzoic acid (AAA-028) (42 mg,
68% for final step) was prepared in essentially the same manner as
in Steps (iii) and (iv) for AAA-001, except that
3,4,5-triethoxybenzoic acid was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 374
(M+H).sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.3 (1H, s), 7.9 (2H, d), 7.8 (2H, d), 7.2 (2H, s), 4.1
(4H, q), 4.0 (2H, q), 1.4 (6H, t), 1.2 (3H, t).
Synthesis 28
4-(3,5-Dichloro-4-ethoxybenzamido)benzoic acid (AAA-029)
(PP-02)
##STR00215##
[0637] The title compound was obtained from commercial sources.
Synthesis 29
4-(3,5-Dichloro-4-methoxybenzamido)benzoic acid (AAA-030)
(PP-03)
##STR00216##
[0639] The title compound was obtained from commercial sources.
Synthesis 30 (Comparison Compound)
4-(4-Ethoxy-3-(trifluoromethyl)benzamido)benzoic acid (XXX-01)
##STR00217##
[0641] 4-(4-Ethoxy-3-(trifluoromethyl)benzamido)benzoic acid
(XXX-01) (14 mg, 49% for final step) was prepared in essentially
the same manner as in Steps (iii) and (iv) for AAA-001, except that
4-ethoxy-3-(trifluoromethyl)benzoic acid (prepared in 2 steps from
4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential treatment
with ethyl iodide and base and then lithium hydroxide) was used
instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step
(iii): m/z 352 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO)
12.75 (1H, br s) 10.54 (1H, br s), 8.26 (1H, d), 8.24 (1H, d), 7.94
(2H, d), 7.88 (2H, d), 7.41 (1H, d), 4.27 (2H, q), 1.36 (3H,
t).
Synthesis 31 (Comparison Compound)
4-(4-Ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid
(XXX-02)
##STR00218##
[0642] Step (i): 4-Amino-2,6-difluorobenzoic acid (2)
##STR00219##
[0644] Ethyl 4-amino-2,6-difluorobenzoate (1) (3.26 g, 16.2 mmol)
was dissolved in THF (40 mL) and treated with lithium hydroxide
(1.94 g, 81 mmol), followed by water (10 mL). The resultant mixture
was stirred at RT for 20 h. Methanol (4 mL) was added and the
resultant mixture was stirred at RT for 20 h. The solvent was
removed in vacuo. The residue was twice dissolved in toluene and
the solvent removed in vacuo. The material was divided into three
equal portions and each was dissolved in AcOH (5 mL) and then
partitioned between EtOAc and water. The phases were separated and
the organic phase was washed successively with water and brine,
then dried over MgSO.sub.4, filtered and the solvent removed in
vacuo. The residues were combined to afford
4-amino-2,6-difluorobenzoic acid (2) (2.46 g, 88%) as a pale yellow
solid: m/z 173 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) a: 12.59 (1H, br s), 6.31 (1H, s), 6.16 (2H, dt).
Step (iv): Benzyl 4-amino-2,6-difluorobenzoate (3)
##STR00220##
[0646] 4-Amino-2,6-difluorobenzoic acid (5) (900 mg, 5.20 mmol) was
dissolved in DMF (15 mL) and treated with potassium carbonate (790
mg, 5.72 mmol). Benzyl bromide (617 .mu.L, 5.20 mmol) was added
over 5 min. The resultant mixture was stirred at RT for 2 h. The
mixture was then partitioned between EtOAc (150 mL) and water. The
phases were separated and the aqueous phase extracted with EtOAc.
The combined organic phases were washed successively with water (4
times) and then brine. The organic phase was then dried over
MgSO.sub.4, filtered and the solvent removed in vacuo. The residue
was purified by silica gel chromatography (100% DCM). The resultant
material was dissolved in the minimum volume of EtOAc and added
dropwise to isohexane (150 mL). The resultant white precipitate was
collected by filtration to afford benzyl
4-amino-2,6-difluorobenzoate (6) (910 mg, 64%) as a white solid:
m/z 264 (M+H).sup.+ (ES.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.44 (2H, dd), 7.39-7.29 (3H, m), 6.16 (2H, dt), 5.34 (2H,
s), 4.18 (2H, br s).
Step (v): Benzyl
4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate
(4)
##STR00221##
[0648] Benzyl
4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4)
(172 mg, 37%) was prepared from 4-ethoxy-3-(trifluoromethyl)benzoic
acid (250 mg, 1.07 mmol) and benzyl 4-amino-2,6-difluorobenzoate
(4) (255 mg, 970 .mu.mol) using a procedure essentially the same as
in Step (iii) for AAA-001, except the reaction mixture was stirred
at RT for 16 h and then heated at 35.degree. C. for 1 h. The crude
product was partially purified by silica gel chromatography (15-20%
EtOAc/isohexane) followed by trituration successively with 10%
EtOAc/isohexane and then diethyl ether. The filtered solid was
dissolved in EtOAc and washed twice with NaHCO.sub.3, then
successively with water and brine. The organic phase was dried over
MgSO.sub.4, filtered and the solvent removed in vacuo. The residue
was further purified by silica gel chromatography (50%
DCM/isohexane): m/z 477.8 (M-H).sup.- (ES.sup.-). .sup.1H NMR (400
MHz, MeOD) .delta.: 8.22 (1H, d), 8.18 (1H, dd), 7.55 (2H, dt),
7.46-7.44 (2H, m), 7.41-7.36 (3H, m), 7.29 (1H, d), 5.37 (2H, s),
4.25 (2H, q), 1.46 (3H, t).
Step (vi):
4-(4-Ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid
(XXX-02)
##STR00222##
[0650] Benzyl
4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4)
(25 mg, 52 .mu.mol) was dissolved in methanol (10 mL) and was
passed through a Thales `H-cube` cartridge (10% Pd/C) at a flow
rate of 1 mL/min at 25.degree. C. under H.sub.2 (10 bar). The
solvent was removed in vacuo to afford
4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid
(XXX-02) (20 mg, 97%) as a white solid: m/z 388.1 (M-H).sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, MeOD) a: 8.23 (1H, d), 8.19 (1H,
dd), 7.53 (2H, dt), 7.30 (1H, d), 4.26 (2H, q), 1.46 (3H, t).
Synthesis 32 (Comparison Compound)
4-(3,5-Dichlorobenzamido)benzoic acid (XXX-03)
##STR00223##
[0652] The title compound was obtained from commercial sources.
Synthesis 33
4-(4-(tert-Butoxy)-3,5-dichlorobenzamido)benzoic acid (AAA-031)
##STR00224##
[0653] Step (i): Methyl
4-(4-(tert-butoxy)-3,5-dichlorobenzamido)benzoate (2)
##STR00225##
[0655] A stirred suspension of methyl
4-(3,5-dichloro-4-hydroxybenzamido)benzoate (1) (Synthesis 9) (100
mg, 294 .mu.mol) in toluene (2 mL) was heated at 80.degree. C.
until homogenous. The resultant solution was treated with
1,1-di-tert-butoxy-N,N-dimethylmethanamine
(141 .mu.L, 588 .mu.mol) and the mixture heated at 80.degree. C.
for 3 h, and then at RT for 18 h. Additional
1,1-di-tert-butoxy-N,N-dimethylmethanamine (141 .mu.L, 588 .mu.mol)
was added and mixture was heated at 80.degree. C. for 5 h. The
reaction mixture was cooled to RT and solvent was removed in vacuo.
The residue was diluted with water and extracted with Et.sub.2O.
The organic layer was dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was partially purified by silica
gel chromatography (12 g, 0-50% EtOAc in isohexane) to afford
methyl 4-(4-(tert-butoxy)-3,5-dichlorobenzamido)benzoate (2) (82
mg, 71%). The material was used in the next step without further
purification.
Step (ii): 4-(4-(tert-Butoxy)-3,5-dichlorobenzamido)benzoic acid
(AAA-031)
##STR00226##
[0657] 4-(4-(tert-Butoxy)-3,5-dichlorobenzamido)benzoic acid
(AAA-031) (39 mg, 51%) was prepared from methyl
4-(4-(tert-butoxy)-3,5-dichlorobenzamido)benzoate (2) (82 mg, 294
.mu.mol) using a procedure essentially the same as in step (ii) for
AAA-001: m/z 380 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.79 (1H, s), 10.60 (1H, s), 8.06 (2H, s),
7.94 (2H, d), 7.87 (2H, d), 1.49 (9H, s).
Synthesis 34
4-(3,5-Dichloro-4-isopropoxybenzamido-2-methylbenzoic acid
(AAA-032)
##STR00227##
[0659] 4-(3,5-Dichloro-4-isopropoxybenzamido-2-methylbenzoic acid
(AAA-032) (30 mg, 41% for final step) was prepared in essentially
the same manner as for (AAA-001) except that isopropyl bromide was
used instead of cyclopentyl bromide in step (i) and methyl
4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate
in step (iii): m/z 383 (M+H).sup.+ (ES.sup.+); .sup.1H NMR (400
MHz, DMSO) 12.61 (1H, bs), 10.46 (1H, s), 8.07 (2H, s), 7.86 (1H,
m), 7.69 (2H, m), 4.66 (1H, m), 2.53 (3H, s), 1.33 (6H, d).
Synthesis 35
4-(3,5-Dichloro-4-ethoxybenzamido)-2-(trifluoromethyl)benzoic acid
(AAA-033)
##STR00228##
[0661]
4-(3,5-Dichloro-4-ethoxybenzamido)-2-(trifluoromethyl)benzoic acid
(AAA-033) (12 mg, 10% for final step) was prepared in essentially
the same manner as for AAA-001 except that ethyl iodide was used
instead of cyclopentyl bromide in step (i) and methyl
4-amino-2-(trifluoromethyl)benzoate (prepared from
4-amino-2-(trifluoromethyl)benzoic acid by reaction with MeOH and
TMSCl) was used instead of methyl 4-aminobenzoate in step (iii):
m/z 422 [M+H].sup.+ (ES.sup.+); 420 [M-H].sup.- (ES.sup.-); .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.77 (1H, s), 8.26 (1H, s),
8.14 (1H, d), 8.10 (2H, s), 7.88 (1H, d), 7.15 (1H, br s), 4.14
(2H, q), 1.40 (3H, t).
Synthesis 36
4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-034)
##STR00229##
[0663]
4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-034) (35 mg, 38% for final step) was prepared in essentially
the same manner as in steps (iii) and (iv) for AAA-001 except that
3-chloro-4-isopropoxy-5-(trifluoromethyl)benzoic acid (prepared in
3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid by
sequential treatment with sulfuryl chloride, isopropyl bromide and
base and then lithium hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 400
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.80 (1H, br s), 10.69 (1H, s), 8.39 (1H, d), 8.22 (1H,
d), 7.94 (2H, m), 7.87 (2H, m), 5.06 (1H, m), 1.28 (6H, d).
Synthesis 37
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-035)
##STR00230##
[0665] 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-035) (5 mg, 73% for final step) was prepared in
essentially the same manner as in steps (iii) and (iv) for AAA-001
except that 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid
(prepared in 3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid
by sequential treatment with sulfuryl chloride, methyl iodide and
base and then lithium hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 374
[M+H].sup.+ (ES.sup.+), 372 [M-H].sup.- (ES.sup.-); .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.79 (1H, bs), 10.70 (1H, s),
8.44 (1H, d), 8.23 (1H, d), 7.96 (2H, d), 7.88 (2H, d), 3.98 (3H,
s).
Synthesis 38
4-(3-Chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-036)
##STR00231##
[0666] Step (i) 3-Chloro-4-hydroxy-5-(trifluoromethyl)benzoic acid
(2)
##STR00232##
[0668] 4-Hydroxy-3-(trifluoromethyl)benzoic acid (1) (2.00 g, 9.70
mmol) was dissolved in AcOH (40 mL) and treated with sulfuryl
chloride (2.37 mL, 29.1 mmol). The mixture was stirred at
60.degree. C. for 20 h. The reaction mixture was allowed to cool to
RT and then poured into water (100 mL). The product was extracted
with EtOAc (75 mL) and the organic solution was washed with water
(2.times.75 mL) and brine (75 mL), then dried over MgSO.sub.4 and
filtered. The solvent was removed in vacuo and the residue was
purified by silica gel chromatography (120 g, 0-100%
EtOAc/isohexane) to afford
3-chloro-4-hydroxy-5-(trifluoromethyl)benzoic acid (2) (1.87 g,
80%) as a white solid: m/z 241 [M+H].sup.+ (ES.sup.+), 239
[M-H].sup.- (ES.sup.-).
Step (ii): Methyl
4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)benzoate (4)
##STR00233##
[0670] Methyl
4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)benzoate (4)
(178 mg, 22%) was prepared in essentially the same manner as in
step (iii) for AAA-001 except that
3-chloro-4-hydroxy-5-trifluoromethylbenzoic acid was used instead
of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid: m/z 374 [M+H].sup.+
(ES.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 11.43 (1H,
br s), 10.50 (1H, s), 8.33 (1H, d), 8.16 (1H, d), 7.97 (2H, m),
7.91 (2H, m), 3.84 (3H, s).
Step (iii): Methyl
4-(3-chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoate
(5)
##STR00234##
[0672] Methyl
4-(3-chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoate (5)
(105 mg, 51%) was prepared in essentially the same manner as in
steps (i) for AAA-001 except that cyclobutyl bromide and
tetrabutylammonium iodide were used instead of cyclopentylbromide
and that the reaction was carried out at 90.degree. C.: m/z 428
[M+H].sup.+ (ES.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.72 (1H, s), 8.40 (1H, d), 8.20 (1H, d), 7.90 (2H, m),
7.97 (2H, m) 4.72 (1H, m), 3.84 (3H, s), 2.36 (2H, m), 2.27 (2H,
m), 1.69 (1H, m), 1.44 (1H, m).
Step (iv):
4-(3-Chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-036)
##STR00235##
[0674]
4-(3-Chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoic acid
(96 mg, 91%) was prepared in essentially the same manner as in step
(ii) for AAA-001 except that 1,4-dioxane was used instead of THF:
m/z 412 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.81 (1H, br s), 10.70 (1H, s), 8.41 (1H, d), 8.20 (1H,
d), 7.95 (2H, m), 7.88 (2H, m), 4.73 (1H, m), 2.36 (2H, m), 2.27
(2H, m), 1.69 (1H, m), 1.44 (1H, m).
Synthesis 39
4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-037)
##STR00236##
[0676]
4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-037) (27 mg, 39% for final step) was prepared in
essentially the same manner as for AAA-031 except that
methyl-4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)benzoate
(Synthesis 38 steps (i) and (ii)) was used instead of methyl
4-(3,5-dichloro-4-hydroxybenzamido)benzoate in step (i): m/z 416
[M+H].sup.+ (ES.sup.+), 414 [M-H].sup.- (ES.sup.-); .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, s), 10.69 (1H, s), 8.40
(1H, d), 8.21 (1H, d), 7.95 (2H, m), 7.88 (2H, m), 1.48 (9H,
s).
Synthesis 40
4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-038)
##STR00237##
[0678]
4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)-2-methylb-
enzoic acid (AAA-038) (10 mg, 32% for final step) was prepared in
essentially the same manner as for AAA-031 except that methyl
4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)-2-methylbenzoate
was used instead of methyl
4-(3,5-dichloro-4-hydroxybenzamido)benzoate in step (i). Methyl
4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)-2-methylbenzoate
was prepared essentially as in synthesis 38 steps (i) and (ii)
except that and methyl 4-amino-2-methylbenzoate was used instead of
methyl 4-aminobenzoate in step (ii): m/z 430 [M+H].sup.+
(ES.sup.+), 428 [M-H].sup.- (ES.sup.-); .sup.1H-NMR (400 MHz,
d.sub.4-MeOH) .delta.: 8.30 (1H, d), 8.20 (1H, d), 7.95 (1H, d),
7.68-7.65 (2H, m), 2.60 (3H, s), 1.54 (9H, s).
Synthesis 41
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-039)
##STR00238##
[0680]
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-039) (36 mg, 53% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-chloro-4-ethoxy-5-trifluoromethylbenzoic acid was used instead of
3,5-dichloro-4-ethoxybenzoic acid in step (i) and 1,4-dioxane (5
mL) was used instead of THF in step (ii): m/z 402 [M+H].sup.+
(ES.sup.+), 400 [M-H].sup.- (ES.sup.-); .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.65 (1H, br s), 10.59 (1H, s), 8.42 (1H,
d), 8.23 (1H, d), 7.88 (1H, d), 7.74-7.68 (2H, m), 4.20 (2H, q),
2.55 (3H, s), 1.42 (3H, t).
Synthesis 42
4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-040)
##STR00239##
[0682]
4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-methylbenz-
oic acid (AAA-040) (36 mg, 65% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-chloro-4-isopropoxy-5-trifluoromethylbenzoic acid was used
instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i) and
1,4-dioxane (5 mL) was used instead of THF in step (ii): m/z 416
[M+H].sup.+ (ES.sup.+), 414 [M-H].sup.- (ES.sup.-); .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.57 (1H, br s), 10.56 (1H, s),
8.39 (1H, d), 8.22 (1H, d), 7.88 (1H, d), 7.73-7.67 (2H, m), 5.06
(2H, sep), 2.54 (3H, s), 1.29 (6H, d).
Synthesis 43
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-041)
##STR00240##
[0684]
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-041) (28 mg, 57% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-chloro-4-methoxy-5-trifluoromethylbenzoic acid was used instead
of 3,5-dichloro-4-ethoxybenzoic acid in step (i) and 1,4-dioxane
(2.5 mL) was used instead of THF in step (ii): m/z 388 [M+H].sup.+
(ES.sup.+), 386 [M-H].sup.- (ES.sup.-); .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.62 (1H, br s), 10.59 (1H, s), 8.43 (1H,
d), 8.23 (1H, d), 7.88 (1H, d), 7.73-7.67 (2H, m), 3.97 (3H, s),
2.54 (3H, s).
Synthesis 44
4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-042)
##STR00241##
[0686] 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-042) (35 mg, 60% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-bromo-4-ethoxy-5-trifluoromethylbenzoic acid (prepared in 3 steps
from 4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential
treatment with bromine in acetic acid, ethyl iodide and base and
then lithium hydroxide) was used instead of
3,5-dichloro-4-ethoxybenzoic acid and methyl 4-aminobenzoate was
used instead of methyl 4-amino-2-methylbenzoate in step (i) and
1,4-dioxane (2.5 mL) was used instead of THF in step (ii): m/z 434
[M+H].sup.+ (ES.sup.+), 432 [M-H].sup.- (ES.sup.-); .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.81 (1H, br s), 10.71 (1H, s),
8.56 (1H, d), 8.26 (1H, d), 7.96 (2H, d), 7.88 (2H, d), 4.18 (2H,
q), 1.43 (3H, t).
Synthesis 45
4-(3-Chloro-4-(cyclopentyloxy)-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-043)
##STR00242##
[0688]
4-(3-Chloro-4-(cyclopentyloxy)-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-043) (20 mg, 26% for final step) was prepared in
essentially the same manner as for AAA-036 except that cyclopentyl
iodide was used instead of cyclobutyl iodide in step (iii): m/z 426
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.71 (1H, br s), 10.69 (1H, s), 8.40 (1H, d), 8.22 (1H,
d), 7.96 (2H, m), 7.88 (2H, m), 5.27 (1H, q), 1.86 (4H, m), 1.75
(2H, m), 1.59 (2H, m).
Synthesis 46
4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic acid
(AAA-044)
##STR00243## ##STR00244##
[0689] Step (i): 3-Chloro-4,5-dihydroxybenzoic acid (2)
##STR00245##
[0691] Tribromoborane (7.86 mL, 82 mmol) was added dropwise to a
stirring mixture of 3-chloro-4-hydroxy-5-methoxybenzoic acid (1)
(6.61 g, 32.6 mmol) in DCM (50 mL) under nitrogen at 0.degree. C.
The resulting orange mixture was stirred at the same temperature
for 2 h then poured portionwise onto ice/brine (250 mL). The
aqueous phase was extracted with EtOAc (2.times.150 mL) and the
combined organic extracts were dried over MgSO.sub.4 and filtered.
The solvent was removed in vacuo to give
3-chloro-4,5-dihydroxybenzoic acid (2) (5.11 g, 79%): m/z 187
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.69 (1H, br s), 10.14 (2H, br s), 7.35 (1H, d), 7.32
(1H, d).
Step (ii): Methyl 3-chloro-4,5-dihydroxybenzoate (3)
##STR00246##
[0693] A solution of 3-chloro-4,5-dihydroxybenzoic acid (2) (3.16
g, 16.76 mmol) and chlorotrimethylsilane (6.36 mL, 50.3 mmol) in
MeOH (50 mL) was stirred at 50.degree. C., under nitrogen
overnight. The solvent was removed in vacuo and the residue was
partitioned between brine (75 mL) and EtOAc (75 mL). The organic
layer was washed with brine (75 mL), dried over MgSO.sub.4 and
filtered. The solvent was removed in vacuo to give methyl
3-chloro-4,5-dihydroxybenzoate (3) (3.26 g, 13.68 mmol, 82% yield):
m/z 201 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.17 (2H, br s), 7.38 (1H, d), 7.35 (1H, d), 3.78 (3H,
s).
Step (iii): Methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4)
##STR00247##
[0695] A mixture of methyl 3-chloro-4,5-dihydroxybenzoate (3) (300
mg, 1.48 mmol), iodocyclopentane (558 .mu.L, 4.44 mmol) and
potassium carbonate (614 mg, 4.44 mmol) in DMF (10 mL) was stirred
at 70.degree. C. for 46 h. The reaction mixture was cooled to room
temperature and then partitioned between 1M HCl (75 mL) and EtOAc
(100 mL). The phases were separated and the organic phase was
washed with brine (2.times.75 mL) then dried over MgSO.sub.4 and
filtered. The solvent was removed in vacuo and the residue was
purified by silica gel chromatography (40 g, 0-100% EtOAc in
isohexane) to give methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate
(4) (427 mg, 1.26 mmol, 85% yield): m/z 339 [M+H].sup.+ (ES.sup.+);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.66 (1H, d), 7.45 (1H,
d), 5.05-4.98 (1H, m), 4.87-4.83 (1H, m), 3.89 (3H, s), 1.95-1.55
(16H, m).
Step (iv): 3-Chloro-4,5-bis(cyclopentyloxy)benzoic acid (5)
##STR00248##
[0697] 3-Chloro-4,5-bis(cyclopentyloxy)benzoic acid (5) (380 mg,
99%) was prepared from methyl
3-chloro-4,5-bis(cyclopentyloxy)benzoate (4) (400 mg, 1.18 mmol)
using a procedure essentially the same as in Step (ii) for AAA-001,
except that 1,4-dioxane (10 mL) was used instead of THF: m/z 323
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.07 (1H, br s), 7.52 (1H, d), 7.45 (1H, d), 4.97-4.91
(2H, m), 1.99-1.90 (2H, m), 1.70-1.57 (14H, m).
Step (v): Methyl
4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7)
##STR00249##
[0699] Methyl 4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate
(7) (155 mg, 49%) was prepared from
3-chloro-4,5-bis(cyclopentyloxy)benzoic acid (5) (200 mg, 0.616
mmol) using a procedure essentially the same as in Step (iii) for
AAA-001: m/z 458 [M+H].sup.+ (ES.sup.+), 456 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.06 (2H,
d), 7.84 (1H, br s), 7.71 (2H, d), 7.38 (2H, d), 5.02 (1H, m), 4.88
(1H, m), 3.92 (3H, s), 1.95-1.63 (16H, m).
Step (vi): 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic
acid (AAA-044)
##STR00250##
[0701] 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic acid
(AAA-044) (55 mg, 72%) was prepared from methyl
4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7) (75 mg,
0.16 mmol) using a procedure essentially the same as in Step (ii)
for AAA-001, except that 1,4-dioxane (2.5 mL) was used instead of
THF: m/z 442 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.74 (1H, br s), 10.45 (1H, s), 7.94 (2H,
d), 7.88 (2H, d), 7.69 (1H, d), 7.52 (1H, d), 4.97 (2H, m),
1.99-1.93 (2H, m), 1.73-1.48 (14H, m).
Synthesis 47
4-(3,4-bis(benzyloxy)-5-chlorobenzamido)benzoic acid (AAA-045)
##STR00251##
[0703] 4-(3,4-bis(Benzyloxy)-5-chlorobenzamido)benzoic acid
(AAA-045) (48 mg, 96% for final step) was prepared in essentially
the same manner as for AAA-044 except that benzyl bromide was used
instead of cyclopentyl iodide in step (iii) and stirring was
carried out at 40.degree. C. in step (v): m/z 486 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.76 (1H,
br s), 10.51 (1H, s), 7.95 (2H, m), 7.89 (2H, m), 7.74 (2H, d),
7.52 (2H, d), 7.44-7.32 (8H, m), 5.31 (2H, s), 5.11 (2H, s).
Synthesis 48
4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)-2-methylbenzoic acid
(AAA-046)
##STR00252##
[0705]
4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)-2-methylbenzoic acid
(AAA-046) (65 mg, 85% for final step) was prepared in essentially
the same manner as for AAA-044 except that methyl
4-amino-2-methylbenzoate (prepared from 4-amino-2-methylbenzoic
acid by reaction with methanol and chlorotrimethylsilane) was used
instead of methyl 4-aminobenzoate in Step (v): m/z 456 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.63 (1H,
br s), 10.33 (1H, s), 7.86 (1H, d), 7.72-7.68 (3H, m), 7.52 (1H,
d), 4.98 (2H, m), 2.54 (3H, s), 1.99-1.91 (2H, m), 1.78-1.58 (14H,
m).
Synthesis 49
4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic acid
(AAA-047)
##STR00253## ##STR00254##
[0706] Step (i): Methyl 4-(benzyloxy)-3-chloro-5-hydroxybenzoate
(2)
##STR00255##
[0708] (Bromomethyl)benzene (1.41 mL, 11.9 mmol) was added dropwise
to a stirring suspension of methyl 3-chloro-4,5-dihydroxybenzoate
(1) (product step ii, Synthesis 46 (2.00 g, 9.87 mmol) and
potassium carbonate (1.50 g, 10.9 mmol) in DMF (10 mL) at
5-10.degree. C. The resulting mixture was stirred for 2 h at RT and
then partitioned between 1M HCl (50 mL) and EtOAc (50 mL). The
phases were separated and the organic solution was washed with
water (2.times.40 mL), dried over MgSO.sub.4 and filtered. The
solvent was removed in vacuo and residue was purified by silica gel
chromatography (80 g, 0-50% EtOAc in iso-hexanes) to give methyl
4-(benzyloxy)-3-chloro-5-hydroxybenzoate (2) (1.66 g, 54% yield):
m/z 291 [M-H] (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.50 (1H, s), 7.49 (2H, m), 7.46 (1H, d), 7.40-7.33 (4H,
m), 5.14 (2H, s), 3.82 (3H, s).
Step (ii): Methyl 4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoate
(2)
##STR00256##
[0710] Diisopropylazo dicarboxylate (807 .mu.L, 4.10 mmol) was
added dropwise to a stirring mixture of methyl
4-(benzyloxy)-3-chloro-5-hydroxybenzoate (2) (300 mg, 1.03 mmol),
cyclohexanol (434 .mu.L, 4.10 mmol) and triphenylphosphine (1.08 g,
4.10 mmol) in THF (5 mL) and the mixture was stirred at RT for 20
h. The reaction was quenched with MeOH (10 mL) and the solvent was
removed in vacuo. The residue was purified by silica gel
chromatography (80 g, 0-20% EtOAc in iso-hexane) to afford methyl
4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoate (2) (350 mg, 9%):
.sup.1H NMR (400 MHz, CDCl3) .delta.: 7.66 (1H, d), 7.51 (3H, m),
7.38-7.33 (3H, m), 5.14 (2H, s), 4.38 (1H, m) 3.90 (3H, s) 2.01
(2H, m), 1.80 (2H, m), 1.62-1.50 (3H, m), 1.45-1.35 (3H, m).
Step (iii): 4-(Benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoic acid
(4)
##STR00257##
[0712] 4-(Benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoic acid (4)
(329 mg, 97%) was prepared from methyl
4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoate (3) (350 mg, 0.934
mmol) using a procedure essentially the same as in Step (ii) for
AAA-001, except that 1,4-dioxane (5 mL) was used instead of THF:
m/z 359 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.19 (1H, s), 7.51 (2H, m), 7.48 (2H, m), 7.42-7.33 (3H,
m), 5.10 (2H, s), 4.51 (1H, m), 1.94 (2H, m), 1.72 (2H, m),
1.59-1.49 (3H, m), 1.46-1.27 (3H, m).
Step (iv): Methyl
4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate
(6)
##STR00258##
[0714] Methyl
4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate (6)
(323 mg, 70%) was prepared from
4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoic acid (4) (325 mg,
0.901 mmol) using a procedure essentially the same as in Step (iii)
for AAA-001: m/z 494 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (400-MHz,
DMSO-d.sub.6) .delta.: 10.51 (1H, br s), 7.97 (2H, d), 7.91 (2H,
d), 7.68 (1H, d), 7.58 (1H, d), 7.50 (2H, m), 7.42-7.36 (3H, m),
5.12 (2H, s), 4.57 (1H, m), 3.84 (3H, s), 1.98 (2H, m), 1.73 (2H,
m), 1.62-1.51 (3H, m), 1.47-1.31 (3H, m).
Step (v): Methyl
4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7)
##STR00259##
[0716] 45% hydrogen bromide in acetic acid (26 .mu.L, 0.20 mmol)
was added to a stirring mixture of methyl
4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate (6)
(20 mg, 40 .mu.mol) in TFA (3 mL) and the mixture was stirred at RT
for 1 h. The mixture was partitioned between water (15 mL) and
EtOAc (15 mL) and the phases were separated. The organic solution
was washed with water (10 mL), dried over MgSO.sub.4 and the
solvent was removed in vacuo to give methyl
4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (16
mg, 92%): m/z 402 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400-MHz,
DMSO-d.sub.6) .delta.: 10.37 (1H, s), 7.94 (4H, m), 7.68 (1H, d),
7.54 (1H, d), 4.40 (1H, m), 3.84 (3H, s), 1.94 (2H, m), 1.83-1.73
(2H, m), 1.57-1.45 (3H, m), 1.40-1.20 (3H, m).
Step (vi): Methyl
4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8)
##STR00260##
[0718] Diisopropylazo dicarboxylate (63 .mu.L, 0.32 mmol) was added
dropwise to a stirring mixture of methyl
4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (65
mg, 161 .mu.mol), cyclohexanol (34 .mu.L, 0.32 mmol) and
triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) and the
resulting yellow mixture was stirred at RT for 20 h. The reaction
was quenched with MeOH (5 mL) and the solvent was removed in vacuo.
The residue was purified by silica gel chromatography (40 g, 0-15%
EtOAc in iso-hexane) to give the desired methyl
4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg,
100%): m/z 486 [M+H].sup.+ (ES.sup.+); .sup.1H NMR (400-MHz,
DMSO-d.sub.6) .delta.: 10.48 (1H, s), 7.97 (2H, d), 7.91 (2H, d),
7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36 (1H, m), 3.84 (3H,
m), 1.92 (4H, m), 1.80-1.70 (4H, m), 1.60-1.40 (6H, m), 1.30-1.05
(6H, m).
Step (vii): 4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic
acid (AAA-047)
##STR00261##
[0720] 4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic acid
(AAA-047) (15 mg, 19%) was prepared from methyl
4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg,
0.17 mmol) using a procedure essentially the same as in Step (ii)
for AAA-001, except that 1,4-dioxane (6 mL) was used instead of
THF: m/z 470 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.72 (1H, br s), 10.44 (1H, s), 7.94 (2H,
d), 7.87 (2H, d), 7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36
(1H, m), 1.98-1.82 (4H, m), 1.80-1.65 (4H, m), 1.58-1.20 (12H,
m).
Synthesis 50
4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid (AAA-048)
##STR00262##
[0721] Step (i): 3,4-Di-tert-butoxy-5-chlorobenzoic acid (3)
##STR00263##
[0723] N,N-Dimethylformamide di-tert-butyl acetal (2) (5.92 mL,
24.7 mmol) was added to a solution of methyl
3-chloro-4,5-dihydroxybenzoate (1) (500 mg, 2.47 mmol) in toluene
(10 mL) and the reaction mixture was stirred at RT under nitrogen
for 21 h. The solvent was removed in vacuo and the residue was
purified by silica gel chromatography (40 g, 0-20% EtOAc in
iso-hexane) to give the bis-alkylated intermediate, which was
dissolved in 1,4-dioxane/water (20 mL, 1:1) and treated with
lithium hydroxide (591 mg, 24.7 mmol). The mixture was stirred 18 h
at RT. The mixture was poured into 10% aqueous citric acid (100 mL)
and the precipitate was collected by filtration. The solid was
washed with water and dried to give
3,4-di-tert-butoxy-5-chlorobenzoic acid (2) (534 mg, 70%): m/z 299
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.13 (1H, br s), 7.67 (1H, s), 7.53 (1H, s), 1.39 (9H,
s), 1.32 (9H, s).
Step (ii): Methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate
(5)
##STR00264##
[0725] Methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5)
(185 mg, 50%) was prepared from 3,4-di-tert-butoxy-5-chlorobenzoic
acid (3) (250 mg, 0.831 mmol) using a procedure essentially the
same as in Step (i) for AAA-019 except that methyl 4-aminobenzoate
was used instead of methyl 4-amino-2-methylenzoate and TEA (579
.mu.L, 4.16 mmol) was used as base instead of DIPEA: m/z 432
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.54 (1H, s), 7.96 (2H, d), 7.91 (2H, d), 7.86 (1H, d),
7.60 (1H, d), 3.84 (3H, s), 1.41 (9H, s), 1.32 (9H, s).
Step (iii): 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid
(AAA-048)
##STR00265##
[0727] 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid
(AAA-048) (110 mg, 64%) was prepared from methyl
4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5) (175 mg, 0.403
mmol) using a procedure essentially the same as in Step (ii) for
AAA-001, except that 1,4-dioxane (6 mL) was used instead of THF:
m/z 418 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.78 (1H, br s). 10.49 (1H, s), 7.93 (2H, d), 7.87 (2H,
d), 7.85 (1H, d), 7.59 (1H, d), 1.40 (9H, s), 1.34 (9H, s).
Synthesis 51
4-(3,4-Di-tert-butoxy-5-chlorobenzamido)-2-methylbenzoic acid
(AAA-049)
##STR00266##
[0729] 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)-2-methylbenzoic
acid (AAA-049) (86 mg, 49% for final step) was prepared in
essentially the same manner as for AAA-048 except that methyl
4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate
in step (ii): m/z 432 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.60 (1H, br s), 10.38 (1H, s), 7.86 (2H,
m), 7.72 (1H, br d), 7.70 (1H, br s), 7.60 (1H, d), 2.45 (3H, s),
1.41 (9H, s), 1.32 (9H, s).
Synthesis 52
4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-050)
##STR00267##
[0731] 4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-050)
(134 mg, 74% for final step) was prepared in essentially the same
manner as AAA-044 except isopropyl bromide was used instead of
cyclopentyl iodide and the reaction performed at 80.degree. C. in
step (iii): m/z 390 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.78 (1H, br s), 10.46 (1H, s), 7.94 (2H,
d), 7.87 (2H, d), 7.68 (1H, d), 7.54 (1H, d), 4.76 (1H, m), 4.59
(1H, m), 1.33 (6H, d), 1.28 (6H, d).
Synthesis 53
4-(3-Chloro-4,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-051)
##STR00268##
[0733] 4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-051)
(103 mg, 48% for final step) was prepared in essentially the same
manner as AAA-044 except isopropyl bromide was used instead of
cyclopentyl iodide and the reaction performed at 80.degree. C. in
step (iii) and that methyl 4-amino-2-methylbenzoate was used
instead of methyl 4-aminobenzoate in step (v): m/z 404 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.62 (1H,
br s), 10.34 (1H, s), 7.87 (1H, d), 7.73 (1H, dd), 7.68 (2H, d),
7.54 (1H, d), 4.76 (1H, m), 4.59 (1H, m), 2.54 (3H, s), 1.33 (6H,
d), 1.28 (6H, d).
Synthesis 54
4-(3,5-Dibromo-4-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-052)
##STR00269##
[0735] 4-(3,5-Dibromo-4-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-052) (166 mg, 56% for final step) was prepared in essentially
the same manner as for AAA-019 except that
3,5-dibromo-4-isopropoxybenzoic acid (prepared in 2 steps from
3,5-dibromo-4-hydroxybenzoic acid by sequential treatment with
isopropyl bromide and base followed by lithium hydroxide) was used
instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 470
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.61 (1H, br s), 10.47 (1H, s), 8.25 (2H, s), 7.87 (1H,
m), 7.71 (1H, m), 7.68 (1H, m), 4.75 (1H, m), 2.54 (3H, s), 1.35
(6H, d).
Synthesis 55
4-(3,5-Dibromo-4-ethoxybenzamido)-2-methylbenzoic acid
(AAA-053)
##STR00270##
[0737] 4-(3,5-Dibromo-4-ethoxybenzamido)-2-methylbenzoic acid
(AAA-053) (57 mg, 64% for final step) was prepared in essentially
the same manner as for AAA-019 except that
3,5-dibromo-4-ethoxybenzoic acid (prepared in 2 steps from
3,5-dibromo-4-hydroxybenzoic acid by sequential treatment with
ethyl iodide and base followed by lithium hydroxide) was used
instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i) m/z 456
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.64 (1H, br s), 10.48 (1H, s), 8.25 (2H, s), 7.87 (1H,
m), 7.71 (1H, m), 7.67 (1H, m), 4.10 (2H, q), 2.54 (3H, s), 1.43
(3H, t).
Synthesis 56
4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)-2-methylbenzoic acid
(AAA-054)
##STR00271##
[0739] 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)-2-methylbenzoic
acid (AAA-054) (137 mg, 46% for final step) was prepared in
essentially the same manner as AAA-001 except that methyl
4-amino-2-methylbenzoate, HATU and DIPEA were used instead of
methyl 4-aminobenzoate, oxalyl chloride, DIPEA and DMF in step
(iii): m/z 406 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.63 (1H, br s), 10.46 (1H, s), 8.07 (2H,
s), 7.87 (1H, m), 7.72-7.68 (2H, m), 5.02 (1H, m), 2.54 (3H, s),
1.91-1.78 (6H, m), 1.63-1.60 (2H, m).
Synthesis 57
4-(3,5-Dichloro-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-055)
##STR00272##
[0741] 4-(3,5-Dichloro-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-055) (53 mg, 18% for final step) was prepared in essentially
the same manner as AAA-001 except that methyl iodide was used
instead of cyclopentyl bromide in step (i) and methyl
4-amino-2-methylbenzoate, HATU and DIPEA were used instead of
methyl 4-aminobenzoate, oxalyl chloride, DIPEA and DMF in step
(iii): m/z 352 [M-H].sup.- (ES.sup.-), 354 [M+H].sup.+ (ES.sup.+);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.65 (1H, br s),
10.48 (1H, s), 8.09 (2H, s), 7.87 (1H, m), 7.73-7.68 (2H, m), 3.91
(3H, s), 2.89 (3H, s).
Synthesis 58
4-(4-tert-Butoxy-3,5-dichlorobenzamido)-2-methylbenzoic acid
(AAA-056)
##STR00273##
[0743] 4-(4-tert-Butoxy-3,5-dichlorobenzamido)-2-methylbenzoic acid
(AAA-056) (73 mg, 24% for final step) was prepared in essentially
the same manner as AAA-048 except that 5 eq. of
N,N-dimethylformamide di-tert-butyl acetal was reacted with methyl
3,5-dichloro-4-hydroxybenzoate in step (i) and the product reacted
with methyl 4-amino-2-methylbenzoate instead of methyl
4-aminobenzoate in step (ii): m/z 394 [M-H].sup.- (ES.sup.-), 396
[M+H].sup.+ (ES.sup.+); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.64 (1H, br s), 10.48 (1H, s), 8.07 (2H, s), 7.87 (1H,
m), 7.72-7.68 (2H, m), 2.54 (3H, s), 1.50 (9H, s).
Synthesis 59
4-(3,5-Dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid
(AAA-057)
##STR00274##
[0744] Step (i): tert-Butyl 2-methoxy-4-nitrobenzoate (2)
##STR00275##
[0746] 1,1-di-tert-Butoxy-N,N-dimethylmethanamine (608 .mu.L, 2.54
mmol) was added dropwise to a solution of 2-methoxy-4-nitrobenzoic
acid (1) (250 mg, 1.27 mmol) in toluene (7.5 mL) at 80.degree. C.
The reaction mixture was heated at 80.degree. C. for 3 h, then a
further quantity of 1,1-di-tert-butoxy-N,N-dimethylmethanamine (608
.mu.L, 2.54 mmol) was added. The reaction mixture was heated at
80.degree. C. for 16 h, then diluted with water (10 mL) and
extracted with Et.sub.2O (3.times.10 mL). The combined organic
phases were washed with brine (30 mL), dried over MgSO.sub.4,
filtered and then concentrated in vacuo to afford tert-butyl
2-methoxy-4-nitrobenzoate (2) (271 mg, 78%) as a pale yellow solid.
The material was used in the next step without further
purification.
Step (ii): tert-Butyl 4-amino-2-methoxybenzoate (3)
##STR00276##
[0748] tert-Butyl 2-methoxy-4-nitrobenzoate (2) (271 mg, 1.07 mmol)
was dissolved in MeOH (270 mL) and passed through a Thales `H-cube`
cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25.degree. C.
under full H.sub.2 mode. The solvent was removed in vacuo to afford
tert-butyl 4-amino-2-methoxybenzoate (3) (234 mg, 92%) as a pale
yellow solid: m/z 222 [M-H].sup.- (ES.sup.-); .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 7.41 (1H, d), 6.16 (1H, d), 6.09 (1H, dd),
5.82 (2H, br s), 3.68 (3H, s), 1.45 (9H, s).
Step (iii): tert-Butyl
4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5)
##STR00277##
[0750] 3,5-Dichloro-4-ethoxybenzoic acid (4) (75 mg, 0.32 mmol) in
DCM (5 mL) was treated with oxalyl chloride (56 .mu.L, 0.64 mmol)
dropwise, followed by a drop of DMF. The reaction mixture was
stirred at RT for 1 h, and then the solvent was removed in vacuo.
The residue was dissolved in DCM (5 mL) and TEA (133 .mu.L, 957
.mu.mol) was added. The mixture was added to tert-butyl
4-amino-2-methoxybenzoate (3) (71 mg, 0.32 mmol) and stirred at RT
for 16 h. The mixture was sequentially washed with sat. aq.
NaHCO.sub.3 (5 mL) and 1 M HCl (5 mL), and the organic phase was
concentrated in vacuo. The residue was purified by silica gel
chromatography (12 g, 0-100% EtOAc in isohexane) to afford
tert-butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5)
(59 mg, 42%) as a white solid: m/z 384 [M-.sup.tBu+2H].sup.+
(ES.sup.+); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.51 (1H,
s), 8.09 (2H, s), 7.63 (1H, d), 7.60 (1H, d), 7.43 (1H, dd), 4.15
(2H, q), 3.81 (3H, s), 1.51 (9H, s), 1.41 (3H, t).
Step (iv): 4-(3,5-Dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid
(AAA-057)
##STR00278##
[0752] A solution of tert-butyl
4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5) (55 mg,
0.13 mmol) in DCM (5 mL) was cooled to 0.degree. C. and treated
dropwise with a solution of 1 M boron trichloride in DCM (349
.mu.L, 349 .mu.mol). The reaction mixture was stirred at 0.degree.
C. for 1 h and then at RT for 2 h. The reaction mixture was cooled
to 0.degree. C. and water (0.5 mL) and sat. aq. NaHCO.sub.3 (2 mL)
were added. The resulting white precipitate was collected by
filtration and washed with water (2 mL). The solid was dried, then
purified by capture and release on SAX, eluting with 5% AcOH in THF
to afford 4-(3,5-dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid
(AAA-057) (11 mg, 24%) as a white solid: m/z 370 [M+H].sup.+
(ES.sup.+), 368 [M-H].sup.- (ES.sup.-); .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.51 (1H, s), 8.06 (2H, s), 7.76 (1H, d),
7.48 (1H, d), 7.28 (1H, dd), 4.14 (2H, q), 1.91 (1H, s), 1.40 (3H,
t), 1.35 (1H, s).
Synthesis 60
4-(3,5-Bis(cyclopentyloxy)-4-ethoxybenzamido)benzoic acid
(AAA-058)
##STR00279##
[0754] 4-(3,5-Bis(cyclopentyloxy)-4-ethoxybenzamido)benzoic acid
(AAA-058) (75 mg, 55% for final step) was prepared in essentially
the same manner as in Steps (iii) and (iv) for AAA-001 except that
3,5-bis(cyclopentyloxy)-4-ethoxybenzoic acid (prepared in 3 steps
from methyl 3,4,5-trihydroxybenzoate by sequential reaction with
ethyl iodide and base, cyclopentyl bromide and base and then
lithium hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step m/z 454
[M+H].sup.+ (ES.sup.+), 452 [M-H].sup.- (ES.sup.-); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 8.12 (2H, d), 7.83 (1H, s), 7.75
(2H, d), 7.04 (2H, s), 4.87 (2H, m), 4.06 (2H, q), 2.00-1.50 (16H,
m), 1.35 (3H, t).
Synthesis 61
4-(3,4,5-Triisopropoxybenzamido)benzoic acid (AAA-059)
##STR00280##
[0756] 4-(3,4,5-Triisopropoxybenzamido)benzoic acid (AAA-059) (194
mg, 91% for final step) was prepared in essentially the same manner
as in Steps (iii) and (iv) for AAA-001 except that
3,4,5-triisopropoxybenzoic acid (prepared in 2 steps from methyl
3,4,5-trihydroxybenzoate by sequential reaction with 2-bromopropane
and base and then lithium hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (110: m/z 416
[M+H].sup.+ (ES.sup.+), 414 [M-H].sup.- (ES.sup.-); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 8.13 (2H, d), 7.87 (1H, s), 7.75
(2H, d), 7.08 (2H, s), 4.64 (2H, heptet), 4.46 (1H, heptet), 1.36
(12H, d), 1.32 (6H, d).
Synthesis 62
4-(3,4,5-Tri-tert-butoxybenzamido)benzoic acid (AAA-060)
##STR00281##
[0758] 4-(3,4,5-Tri-tert-butoxybenzamido)benzoic acid (AAA-060) (53
mg, 84% for final step) was prepared in essentially the same manner
as in Steps (iii) and (iv) for AAA-001 except that
3,4,5-tri-tert-butoxybenzoic acid (prepared in 2 steps from methyl
3,4,5-trihydroxybenzoate by sequential reaction with
1,1-di-tert-butoxy-N,N-dimethylmethanamine and then lithium
hydroxide) was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 458
[M+H].sup.+ (ES.sup.+), 456 [M-H].sup.- (ES.sup.-); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 8.12 (2H, d), 7.84 (1H, s), 7.75
(2H, d), 7.30 (2H, s), 1.38 (27H, s).
Synthesis 63
4-(4-Ethoxy-3,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-061)
##STR00282##
[0760] 4-(4-Ethoxy-3,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-061) (30 mg, 31% for final step) was prepared in essentially
the same manner as in steps (iii) and (iv) for AAA-001 except that
4-ethoxy-3,5-diisopropoxybenzoic acid was used instead of
3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl
4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate
in step (iii): m/z 416 (M+H).sup.+ (ES.sup.+); .sup.1H NMR (400
MHz, DMSO) 12.60 (1H, bs), 10.19 (1H, s), 7.86 (1H, d), 7.70 (1H,
dd), 7.66 (1H, d), 7.23 (2H, s), 4.67-4.61 (2H, m), 3.99 (2H, q),
2.53 (3H, s), 1.29 (12H, d), 1.25 (3H, t).
Synthesis 64
4-(3,5-Diisopropoxy-4-methoxybenzamido)benzoic acid (AAA-062)
##STR00283##
[0762] 4-(3,5-Diisopropoxy-4-methoxybenzamido)benzoic acid
(AAA-062) (223 mg, 77% for final step) was prepared in essentially
the same manner as for AAA-019 except that
3,5-diisopropoxy-4-methoxybenzoic acid (prepared in 3 steps from
methyl 3,4,5-trihydroxybenzoate by sequential treatment with methyl
iodide and base, isopropyl bromide and base and then lithium
hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid
and methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (i): m/z 388 [M+H].sup.+
(ES.sup.+), 386 [M-H].sup.- (ES.sup.-). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.77 (1H, br s), 10.32 (1H, s), 7.92 (2H,
d), 7.87 (2H, d), 7.24 (2H, s), 7.88 (2H, d), 4.66 (2H, sep), 3.73
(3H, s), 1.30 (12H, d).
Synthesis 65
4-(3,5-Diisopropoxy-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-063)
##STR00284##
[0764] 4-(3,5-Diisopropoxy-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-063) (207 mg, 69% for final step) was prepared in essentially
the same manner as for AAA-019 except that
3,5-diisopropoxy-4-methoxybenzoic acid was used instead of
3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 402 [M+H].sup.+
(ES.sup.+), 400 [M-H].sup.- (ES.sup.-). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.62 (1H, br s), 10.21 (1H, s), 7.86 (1H,
d), 7.73-7.66 (2H, m), 7.25 (2H, s), 4.66 (2H, sep), 3.74 (3H, s),
2.54 (3H, s), 1.30 (12H, d).
Synthesis 66
4-(3,5-Diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic acid
(AAA-064)
##STR00285##
[0765] Step (i): Methyl
4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate
##STR00286##
[0767] A mixture of 3,5-diisopropoxy-4-ethoxybenzoic acid (1) (300
mg, 1.06 mmol), methyl 4-amino-2-fluorobenzoate (2) (189 mg, 1.12
mmol) and TEA (149 .mu.L, 1.06 mmol) in EtOAc (2.5 mL) was treated
with T3P (50% wt. in EtOAc, 1.69 mL, 2.66 mmol). The reaction
mixture was stirred at 60.degree. C. for 1 h, and then allowed to
cool to RT. The mixture was diluted with DCM (5 mL) and washed
sequentially with 1M HCl (5 mL) and satd. NaHCO.sub.3 (5 mL). The
solvent was removed in vacuo and the residue was purified by silica
gel chromatography (12 g, 0-30% EtOAc in isohexane) to afford
methyl 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate (3)
(326 mg, 56%): m/z 434 [M+H].sup.+ (ES.sup.+), 432 [M-H].sup.-
(ES.sup.-). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.93 (1H,
t), 7.82 (1H, br s), 7.73 (1H, dd), 7.27 (1H, dd), 7.04 (2H, s),
4.60 (2H, sep), 4.09 (2H, q), 3.91 (3H, s), 1.39-1.34 (15H, m).
Step (ii) 4-(3,5-Diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic
acid (AAA-064)
##STR00287##
[0769] 2 M Lithium hydroxide (554 .mu.L, 1.11 mmol) was added to a
solution of 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate
(3) (320 mg, 0.740 mmol) in THF (5 mL) and the mixture was stirred
at RT for 20 h. The mixture was partitioned between 1M HCl (5 mL)
and DCM (10 mL) and the phases were separated. The organic solvent
was removed in vacuo and the residue was purified by silica gel
chromatography (40 g, 0-20% IPA in isohexane) to afford
4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic acid
(AAA-064) as a white solid (176 mg, 56%): m/z 420 [M+H].sup.+
(ES.sup.+), 418 [M-H].sup.- (ES.sup.-). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.03 (1H, br s), 10.45 (1H, s), 7.88 (1H,
t), 7.81 (1H, dd), 7.61 (1H, dd), 7.22 (2H, s), 4.65 (2H, sep),
4.00 (2H, q), 1.29 (12H, d), 1.26 (3H, t).
Synthesis 67
6-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)nicotinic acid
(AAA-065)
##STR00288##
[0771] 6-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)nicotinic
acid (AAA-065) (65 mg, 48% for final step) was prepared in
essentially the same manner as in steps (iii) and (iv) for AAA-001
except that 3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was
used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid, methyl
6-aminonicotinate was used instead of methyl 4-aminobenzoate and
pyridine was used instead of TEA in step (iii) and 1,4-dioxane was
used instead of THF in step (iv): m/z 375 [M+H].sup.+ (ES.sup.+),
373 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.24 (1H, br s), 11.54 (1H, s), 8.90 (1H, dd), 8.48 (1H,
d), 8.39-8.24 (3H, m), 3.97 (3H, s).
Synthesis 68
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-066)
##STR00289##
[0773]
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-066) (30 mg, 42% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead
of 3,5-dichloro-4-ethoxybenzoic acid, methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate and TEA was used instead of DIPEA in step
(i): m/z 392 [M+H].sup.+ (ES.sup.+), 390 [M-H].sup.- (ES.sup.-).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.11 (1H, br s),
10.85 (1H, s), 8.43 (1H, d), 8.22 (1H, d), 7.89 (1H, t), 7.79 (1H,
dd), 7.61 (1H, dd), 3.98 (3H, s).
Synthesis 69
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-3-fluorobenzoic
acid (AAA-067)
##STR00290##
[0775]
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-3-fluorobenzoic
acid (AAA-067) (11 mg, 31% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead
of 3,5-dichloro-4-ethoxybenzoic acid, methyl
4-amino-3-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate and TEA was used instead of DIPEA in step
(i): m/z 392 [M+H].sup.+ (ES.sup.+), 390 [M-H].sup.- (ES.sup.-).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.35 (1H, br s),
10.62 (1H, s), 8.42 (1H, d), 8.24 (1H, d), 7.83-7.73 (3H, m), 3.98
(3H, s).
Synthesis 70
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-068)
##STR00291##
[0777]
4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-068) (11 mg, 31% for final step) was prepared in
essentially the same manner as for AAA-064 except that
3-chloro-4-ethoxy-5-(trifluoromethyl)benzoic acid was used instead
of 3,5-diisopropoxy-4-ethoxybenzoic acid in step (i): m/z 404
[M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.06 (1H, br s), 10.83 (1H, s), 8.41 (1H, d), 8.21 (1H,
d), 7.90 (1H, t), 7.80 (1H, dd), 7.61 (1H, dd), 4.20 (2H, q), 1.41
(3H, t).
Synthesis 71
4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-069)
##STR00292##
[0779]
4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-fluorobenz-
oic acid (AAA-069) (155 mg, 67% for final step) was prepared in
essentially the same manner as for AAA-064 except that
3-chloro-4-isopropoxy-5-(trifluoromethyl)benzoic acid was used
instead of 3,5-diisopropoxy-4-ethoxybenzoic acid in step (i): m/z
418 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 13.02 (1H, br s), 10.81 (1H, s), 8.38 (1H, d), 8.21 (1H,
d), 7.90 (1H, t), 7.80 (1H, dd), 7.61 (1H, dd), 5.06 (1H, sep),
1.28 (6H, d).
Synthesis 72
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-hydroxybenzoic
acid (AAA-070)
##STR00293##
[0781]
4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-hydroxybenzoi-
c acid (AAA-070) (73 mg, 58% for final step) was prepared in
essentially the same manner as for AAA-064 except that
3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead
of 3,5-diisopropoxy-4-ethoxybenzoic acid and methyl
4-amino-2-hydroxybenzoate (prepared from methyl
4-amino-2-hydroxybenzoic acid by treatment with H.sub.2SO.sub.4 and
MeOH) was used instead of methyl 4-amino-2-fluorobenzoate in step
(i): m/z 388 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.77 (1H, br s), 11.39 (1H, br s), 10.65
(1H, s), 8.43 (1H, d), 8.22 (1H, d), 7.80 (1H, d), 7.51 (1H, d),
7.31 (1H, dd), 3.99 (3H, s).
Synthesis 73
4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-071)
##STR00294##
[0783]
4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic
acid (AAA-071) (20 mg, 52% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-bromo-4-ethoxy-5-trifluoromethylbenzoic acid was used instead of
3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 446 and 448
[M+H].sup.+ (ES.sup.+), 444 and 446 [M-H].sup.- (ES.sup.-).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.66 (1H, br s),
10.60 (1H, s), 8.56 (1H, d), 8.26 (1H, d), 7.88 (1H, d), 7.73 (1H,
dd), 7.68 (1H, d) 4.17 (2H, q), 2.55 (3H, s) 1.43 (3H, t).
Synthesis 74
4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-072)
##STR00295##
[0785]
4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic
acid (AAA-072) (95 mg, 64% for final step) was prepared in
essentially the same manner as for AAA-019 except that
3-bromo-4-ethoxy-5-trifluoromethylbenzoic acid was used instead of
3,5-dichloro-4-ethoxybenzoic acid and methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (i): m/z 451 [M+H].sup.+
(ES.sup.+), 449 [M-H].sup.- (ES.sup.-). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.08 (1H, br s), 10.85 (1H, s), 8.56 (1H,
d), 8.26 (1H, d), 7.92 (1H, t), 7.82 (1H, dd), 7.63 (1H, dd), 4.18
(2H, q1.44 (3H, t).
Synthesis 75
4-(4-Ethoxy-3,5-difluorobenzamido)benzoic acid (AAA-073)
##STR00296##
[0787] 4-(4-Ethoxy-3,5-difluorobenzamido)benzoic acid (AAA-073) (74
mg, 80% for final step) was prepared in essentially the same manner
as for AAA-019 except that 4-ethoxy-3,5-difluorobenzoic acid
(prepared in 3 steps from 3,5-difluoro-4-methoxybenzoic acid by
sequential treatment with BBr.sub.3, ethyl iodide and base and then
lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic
acid, methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate and TEA was used instead of DIPEA in step
(i): m/z 322 [M+H].sup.+ (ES.sup.+), 320 [M-H].sup.- (ES).sup.-.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.82 (1H, br s),
10.53 (1H, s), 7.98-7.93 (2H, m), 7.92-7.87 (2H, m), 7.84-7.76 (2H,
m), 4.30 (2H, q), 1.34 (3H, t).
Synthesis 76
4-(3-Chloro-5-fluoro-4-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-074)
##STR00297##
[0789] 4-(3-Chloro-5-fluoro-4-isopropoxybenzamido)-2-methylbenzoic
acid (AAA-074) (52 mg, 12% for final step) was prepared in
essentially the same manner as for AAA-019 except that
4-(3-chloro-5-fluoro-4-isopropoxybenzoic acid (prepared in 3 steps
from 3-chloro-5-fluoro-4-methoxybenzoic acid by sequential
treatment with BBr.sub.3, isopropyl bromide and base and then
lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic
acid and TEA was used instead of DIPEA in step (i): m/z 366
[M+H].sup.+ (ES.sup.+), 364 [M-H].sup.- (ES).sup.-. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.75 (1H, br s), 10.44 (1H, s),
7.99-7.96 (1H, m), 7.91-7.83 (2H, m), 7.69 (2H, m), 4.58 (1H, sep),
2.52 (3H, s), 1.33 (6H, d).
Synthesis 77
4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-075)
##STR00298## ##STR00299##
[0790] Step (i): Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate
(2)
##STR00300##
[0792] Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2) (3.00
g, 94%) was prepared from methyl
4-(benzyloxy)-3-chloro-5-hydroxybenzoate (1) (Synthesis 49 (2.73 g,
9.33 mmol) using a procedure essentially the same as in step (i)
for AAA-001 except that isopropyl bromide was used instead of
cyclopentyl bromide: m/z 335 [M+H].sup.+ (ES.sup.+). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.68 (1H, d), 7.56-7.47 (3H, m),
7.43-7.28 (3H, m), 5.12 (2H, s), 4.66 (1H, sep), 3.90 (3H, s), 1.38
(6H, d).
Step (ii): Methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3)
##STR00301##
[0794] Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2) (3.00
g, 8.96 mmol) was dissolved in a mixture of MeOH (100 mL), DCM (10
mL) and AcOH (0.1 mL) and the solution was passed through a Thales
`H-cube` cartridge (10% Pd/C) at a flow rate of 1 mL/min at
25.degree. C. under H.sub.2 (full H.sub.2 mode). The solvents were
removed in vacuo to afford methyl
3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (2.03 g, 89%): m/z 245
[M+H].sup.+ (ES.sup.+), 243 [M-H].sup.- (ES.sup.-).
Step (iii): Methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4)
##STR00302##
[0796] Methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g,
95%) was prepared from methyl
3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (1.00 g, 4.09 mmol)
using a procedure essentially the same as in step (i) for AAA-001
except that methyl iodide was used instead of cyclopentyl bromide
and the mixture was stirred at RT for 18 h.
Step (iv): 3-Chloro-5-isopropoxy-4-methoxybenzoic acid (5)
##STR00303##
[0798] 3-Chloro-5-isopropoxy-4-methoxybenzoic acid (5) (0.93 g,
89%) was prepared from methyl
3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g, 4.10 mmol)
using a procedure essentially the same as in step (ii) for AAA-001
except that MeOH instead of water was added dropwise until a
solution formed: m/z 243 [M-H].sup.- (ES.sup.-).
Step (v): Methyl
4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate
(7)
##STR00304##
[0800] A mixture of 3-chloro-5-isopropoxy-4-methoxybenzoic acid (5)
(250 mg, 1.02 mmol), methyl 4-amino-2-methylbenzoate (6) (177 mg,
1.07 mmol) and TEA (150 .mu.L, 1.07 mmol) in EtOAc (2.5 mL) was
treated with T3P (50% in EtOAc) (1.63 mL, 2.55 mmol) and the
mixture was heated at 60.degree. C. for 5 h. The mixture was
diluted with DCM (5 mL) and washed with 1M HCl (5 mL) followed by
satd. NaHCO.sub.3 solution (5 mL). The organic solvents were
removed in vacuo and the residue purified by silica gel
chromatography (12 g, 0-100% EtOAc in isohexane to yield methyl
4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7)
(167 mg, 40%): m/z 392 [M+H].sup.+ (ES.sup.+), 390 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.98 (1H,
d), 7.78 (1H, s), 7.59-7.50 (2H, m), 7.40 (2H, dd), 4.67 (1H, sep),
3.94 (3H, s), 3.89 (3H, s), 2.62 (3H, s), 1.40 (6H, d).
Step (vi):
4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-075)
##STR00305##
[0802] 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic
acid (AAA-075) (94 mg, 57%) was prepared from methyl
4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7)
(167 mg, 4.10 mmol) using a procedure essentially the same as in
step (ii) for AAA-001 except that MeOH was added dropwise until a
solution formed and the mixture was stirred at 40.degree. C. for 18
h: m/z 378 [M+H].sup.+ (ES.sup.+), 376 [M-H].sup.- (ES.sup.-).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.63 (1H, br s),
10.34 (1H, s), 7.86 (1H, d), 7.75-7.63 (3H, m), 7.57 (1H, d), 4.77
(1H, sep), 3.83 (3H, s), 2.53 (3H, s), 1.34 (6H, d).
Synthesis 78
4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)benzoic acid
(AAA-076)
##STR00306##
[0804] 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)benzoic acid
(AAA-076) (47 mg, 56% for final step) was prepared in essentially
the same manner as AAA-075 except that methyl 4-aminobenzoate was
used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z
364 [M+H].sup.+ (ES.sup.+), 362 [M-H].sup.- (ES.sup.-). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.78 (1H, br s), 10.47 (1H, s),
7.94 (2H, d), 7.88 (2H, d), 7.69 (1H, d), 7.58 (1H, d), 4.78 (1H,
sep), 3.83 (3H, s), 1.33 (6H, d).
Synthesis 79
4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-fluorobenzoic acid
(AAA-077)
##STR00307##
[0806] 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-fluorobenzoic
acid (AAA-077) (116 mg, 76% for final step) was prepared in
essentially the same manner as AAA-075 except that methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 380 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.03 (1H,
br s), 10.60 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.69 (1H, d),
7.63 (1H, dd), 7.57 (1H, d), 4.78 (1H, sep), 3.85 (3H, s), 1.35
(6H, d).
Synthesis 80
4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)benzoic acid
(AAA-078)
##STR00308##
[0808] 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)benzoic acid
(AAA-078) (145 mg, 80% for final step) was prepared in essentially
the same manner as AAA-075 except that ethyl iodide was used
instead of methyl iodide in step (iii) and methyl 4-aminobenzoate
was used instead of methyl 4-amino-2-methylbenzoate in step (v):
m/z 378 [M+H].sup.+ (ES.sup.+), 376 [M-H].sup.- (ES.sup.-). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.77 (1H, br s), 10.46 (1H,
s), 7.97-7.90 (2H, m), 7.90-7.84 (2H, m), 7.68 (1H, d), 7.55 (1H,
d), 4.75 (1H, sep), 4.11 (2H, q), 1.35-1.28 (9H, m).
Synthesis 81
4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-fluorobenzoic acid
(AAA-079)
##STR00309##
[0810] 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-fluorobenzoic
acid (AAA-079) (120 mg, 78% for final step) was prepared in
essentially the same manner as AAA-075 except that ethyl iodide was
used instead of methyl iodide in step (iii) and methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 394 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.02 (1H,
br s), 10.60 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.69 (1H, d),
7.63 (1H, dd), 7.55 (1H, d), 4.76 (1H, sep), 4.13 (2H, q),
1.38-1.27 (9H, m).
Synthesis 82
4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-080)
##STR00310##
[0812] 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic
acid (AAA-080) (155 mg, 74% for final step) was prepared in
essentially the same manner as AAA-075 except that ethyl iodide was
used instead of methyl iodide in step (iii): m/z 392 [M+H].sup.+
(ES.sup.+), 390 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.64 (1H, br s), 10.34 (1H, s), 7.86 (1H,
d), 7.74-7.63 (3H, m), 7.55 (1H, d), 4.75 (1H, sep), 4.10 (2H, q),
2.52 (3H, s), 1.37-1.26 (9H, m).
Synthesis 83
4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-hydroxybenzoic acid
(AAA-081)
##STR00311##
[0814] 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-hydroxybenzoic
acid (AAA-081) (29 mg, 37% for final step) was prepared in
essentially the same manner as AAA-075 except that ethyl iodide was
used instead of methyl iodide in step (iii) and methyl
4-amino-2-hydroxybenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 394 [M+H].sup.+
(ES.sup.+), 392 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.78 (1H, br s), 11.40 (1H, br s), 10.40
(1H, s), 7.77 (1H, d), 7.67 (1H, d), 7.52 (2H, dd), 7.30 (1H, dd),
4.77 (1H, sep), 4.12 (2H, q), 1.37-1.28 (9H, m).
Synthesis 84
6-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)pyridazine-3-carboxylic
acid (AAA-082)
##STR00312##
[0816]
6-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)pyridazine-3-carboxylic
acid (AAA-082) (25 mg, 43% for final step) was prepared in
essentially the same manner as AAA-075 except that ethyl iodide was
used instead of methyl iodide in step (iii) and methyl
6-aminopyridazine-3-carboxylate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 380 [M+H].sup.+
(ES.sup.+), 378 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.73 (1H, br s), 11.91 (1H, s), 8.55 (1H,
d), 8.26 (1H, d), 7.79 (2H, dd), 4.85 (1H, sep), 4.14 (2H, q),
1.42-1.27 (9H, m).
Synthesis 85
4-(3-Chloro-4-isopropoxy-5-methoxybenzamido)benzoic acid
(AAA-083)
##STR00313##
[0818] 4-(3-Chloro-4-isopropoxy-5-methoxybenzamido)benzoic acid
(AAA-083) (116 mg, 55% for final step) was prepared in essentially
the same manner as AAA-075 except that methyl iodide at RT was used
instead of isopropyl bromide in step (i), isopropyl bromide at
60.degree. C. was used instead of methyl iodide in step (iii) and
methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 364 [M+H].sup.+
(ES.sup.+), 362 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.76 (1H, br s), 10.50 (1H, s), 8.03-7.80
(4H, m), 7.70 (1H, d), 7.56 (1H, d), 4.59 (1H, sep), 3.92 (3H, s),
1.27 (6H, d).
Synthesis 86
4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid (AAA-084)
##STR00314##
[0820] 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid
(AAA-084) (16 mg, 46% for final step) was prepared in essentially
the same manner as AAA-019 except that
3-chloro-4-ethoxy-5-methoxybenzoic acid (prepared in 3 steps from
methyl 4-hydroxy-3-methoxybenzoate by sequential treatment with
sulfuryl chloride, ethyl iodide and base and then lithium
hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid
and methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (i): m/z 350 [M+H].sup.+
(ES.sup.+), 348 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.75 (1H, br s), 10.48 (1H, s), 7.91 (4H,
dd), 7.70 (1H, d), 7.57 (1H, d), 4.09 (2H, q), 3.92 (3H, s), 1.31
(3H, t).
Synthesis 87
4-(3-Chloro-4-ethoxy-5-methoxybenzamido)-2-methylbenzoic acid
(AAA-085)
##STR00315##
[0822] 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)-2-methylbenzoic
acid (AAA-085) (97 mg, 52% for final step) was prepared in
essentially the same manner as AAA-019 except that
3-chloro-4-ethoxy-5-methoxybenzoic acid (prepared in 3 steps from
methyl 4-hydroxy-3-methoxybenzoate by sequential treatment with
sulfuryl chloride, ethyl iodide and base and then lithium
hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid in
step (i): m/z 364 [M+H].sup.+ (ES.sup.+), 362 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.65 (1H,
br s), 10.39 (1H, s), 7.88 (1H, d), 7.76-7.66 (3H, m), 7.58 (1H,
d), 4.10 (2H, q), 3.93 (3H, s), 2.55 (3H, s), 1.32 (3H, t).
Synthesis 88
4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)benzoic acid
(AAA-086)
##STR00316##
[0824] 4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)benzoic acid
(AAA-086) (10 mg, 4% for final step) was prepared in essentially
the same manner as AAA-075 except that ethyl iodide at RT was used
instead of isopropyl bromide in step (i), isopropyl bromide at
60.degree. C. was used instead of methyl iodide in step (iii) and
methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 378 [M+H].sup.+
(ES.sup.+), 376 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.70 (1H, br s), 10.39 (1H, s), 7.93-7.73
(4H, m), 7.61 (1H, d), 7.47 (1H, d), 4.51 (1H, sep), 4.09 (2H, q),
1.31 (3H, t), 1.20 (6H, d).
Synthesis 89
4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-087)
##STR00317##
[0826] 4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)-2-methylbenzoic
acid (AAA-087) (129 mg, 56% for final step) was prepared in
essentially the same manner as AAA-075 except that ethyl iodide at
RT was used instead of isopropyl bromide in step (i) and isopropyl
bromide at 60.degree. C. was used instead of methyl iodide in step
(iii): m/z 390 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.68 (1H, s), 10.40 (1H, s), 7.92 (1H, d),
7.81-7.69 (3H, m), 7.59 (1H, d), 4.64 (1H, sep), 4.21 (2H, q), 2.58
(3H, s), 1.45 (3H, t), 1.33 (6H, d).
Synthesis 90
4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)benzoic acid
(AAA-088)
##STR00318##
[0828] 4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)benzoic acid
(AAA-088) (112 mg, 41% for final step) was prepared in essentially
the same manner as AAA-075 except that cyclobutyl bromide was used
instead of isopropyl bromide in step (i), ethyl iodide was used
instead of methyl iodide in step (iii) and methyl 4-aminobenzoate
was used instead of methyl 4-amino-2-methylbenzoate in step (v):
m/z 388 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.75 (1H, br s), 10.46 (1H, s), 7.95-7.86 (4H, m), 7.71
(1H, d), 7.37 (1H, d), 4.85 (1H, quin), 4.14 (2H, q), 2.49-2.42
(2H, m), 2.19-2.01 (2H, m), 1.92-1.58 (2H, m), 1.33 (3H, t).
Synthesis 91
4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)benzoic acid
(AAA-089)
##STR00319##
[0830] 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)benzoic
acid (AAA-089) (255 mg, 90% for final step) was prepared in
essentially the same manner as AAA-075 except that
bromomethylcyclopropane was used instead of isopropyl bromide in
step (i), ethyl iodide was used instead of methyl iodide in step
(iii) and methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 388 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.76 (1H
br s), 10.46 (1H, s), 7.92 (4H, dd), 7.70 (1H, d), 7.55 (1H, d),
4.17 (2H, q), 4.00 (2H, d), 1.34 (3H, t), 1.31-1.24 (1H, m),
0.66-0.55 (2H, m), 0.42-0.31 (2H, m).
Synthesis 92
4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-hydroxybenzoic
acid (AAA-090)
##STR00320##
[0832]
4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-hydroxybenz-
oic acid (AAA-090) (76 mg, 90% for final step) was prepared in
essentially the same manner as AAA-075 except that
bromomethylcyclopropane was used instead of isopropyl bromide in
step (i), ethyl iodide was used instead of methyl iodide in step
(iii) and methyl 4-amino-2-hydroxybenzoate was used instead of
methyl 4-amino-2-methylbenzoate in step (v): m/z 406 [M+H].sup.+
(ES.sup.+), 404 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.72 (1H, br s), 11.40 (1H, br s), 10.39
(1H, s), 7.77 (1H, d), 7.68 (1H, d), 7.52 (2H, dd), 7.30 (1H, dd),
4.17 (2H, q), 4.00 (2H, d), 1.34 (3H, t), 1.31-1.24 (1H, m),
0.68-0.54 (2H, m), 0.44-0.31 (2H, m).
Synthesis 93
4-(3-Chloro-4,5-diisopropoxybenzamido)-2-hydroxybenzoic acid
(AAA-091)
##STR00321##
[0834] 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-hydroxybenzoic acid
(AAA-091) (43 mg, 63% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
3-chloro-4,5-diisopropoxybenzoic acid (Synthesis 52) was used
instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-amino-2-hydroxybenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 408 [M+H].sup.+
(ES.sup.+), 406 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.75 (1H, br s), 11.40 (1H, br s), 10.39
(1H, s), 7.77 (1H, d), 7.67 (1H, d), 7.52 (2H, dd), 7.30 (1H, dd),
4.77 (1H, sep), 4.60 (1H, sep), 1.33 (6H, d), 1.28 (6H, d).
Synthesis 94
4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)benzoic acid
(AAA-092)
##STR00322##
[0836] 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)benzoic acid
(AAA-092) (137 mg, 54% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
3-chloro-4,5-di(cyclobutyloxy)benzoic acid (prepared in 4 steps
from 3-chloro-4-hydroxy-5-methoxybenzoic acid by sequential
treatment with BBr.sub.3, TMSCl and MeOH, cyclobutyl bromide and
base and then lithium hydroxide) was used instead of
3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate
in step (v): m/z 414 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.76 (1H, br s), 10.46 (1H, s), 7.98-7.83
(4H, m), 7.70 (1H, d), 7.34 (1H, d), 4.83 (1H, quin), 4.71 (1H,
quin), 2.49-2.42 (2H, m), 2.36-2.01 (6H, m), 1.92-1.61 (3H, m),
1.57-1.37 (1H, m).
Synthesis 95
4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-methylbenzoic acid
(AAA-093)
##STR00323##
[0838] 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-methylbenzoic
acid (AAA-093) (83 mg, 99% for final step) was prepared in
essentially the same manner as in steps (v) and (vi) for AAA-075
except that 3-chloro-4,5-di(cyclobutyloxy)benzoic acid (Synthesis
94) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic in
step (v): m/z 428 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.62 (1H, br s), 10.35 (1H, s), 7.87 (1H,
d), 7.73-7.66 (3H, m), 7.35 (1H, d), 4.84 (1H, quin), 4.72 (1H,
quin), 2.55 (3H, s), 2.49-2.41 (2H, m), 2.22-2.06 (6H, m),
1.84-1.65 (3H, m), 1.54-1.42 (1H, m).
Synthesis 96
4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-hydroxybenzoic acid
(AAA-094)
##STR00324##
[0840] 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-hydroxybenzoic
acid (AAA-094) (33 mg, 75% for final step) was prepared in
essentially the same manner as in steps (v) and (vi) for AAA-075
except that 3-chloro-4,5-di(cyclobutyloxy)benzoic acid (Synthesis
94) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid
and methyl 4-amino-2-hydroxybenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 432 [M+H].sup.+
(ES.sup.+), 430 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.39 (1H, s), 7.76 (1H, d), 7.69 (1H, d),
7.49 (1H, d), 7.35-7.25 (2H, m), 4.88-4.80 (1H, m), 4.76-4.67 (1H,
m), 2.48-2.43 (2H, m), 2.29-2.05 (6H, m), 1.87-1.81 (1H, m),
1.76-1.65 (2H, m), 1.53-1.44 (1H, m).
Synthesis 97
4-(3-Chloro-4,5-diisopropoxybenzamido)-2-fluorobenzoic acid
(AAA-095)
##STR00325##
[0842] 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-fluorobenzoic acid
(AAA-095) (207 mg, 93% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
3-chloro-4,5-diisopropoxybenzoic acid (Synthesis 52) was used
instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 410 [M+H].sup.+
(ES.sup.+), 408 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.05 (1H, br s), 10.61 (1H, s), 7.90 (1H,
t), 7.82 (1H, dd), 7.69 (1H, d), 7.63 (1H, dd), 7.54 (1H, d), 4.77
(1H, sep), 4.61 (1H, sep), 1.34 (6H, d), 1.28 (6H, d).
Synthesis 98
4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)-2-methylbenzoic acid
(AAA-096)
##STR00326##
[0844]
4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)-2-methylbenzoic acid
(AAA-096) (127 mg, 69% for final step) was prepared in essentially
the same manner as AAA-075 except that cyclobutyl bromide was used
instead of isopropyl bromide in step (i) and ethyl iodide was used
instead of methyl iodide in step (iii): m/z 402 [M-H]- (ES.sup.-).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.62 (1H, br s),
10.35 (1H, s), 7.87 (1H, d), 7.76-7.66 (3H, m), 7.38 (1H, d), 4.86
(1H, quin), 4.14 (2H, q), 2.53 (3H, s), 2.50-2.43 (2H, m),
2.19-2.03 (2H, m), 1.84 (1H, q), 1.69 (1H, dq), 1.34 (3H, t).
Synthesis 99
4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-methylbenzoic
acid (AAA-097)
##STR00327##
[0846]
4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-methylbenzo-
ic acid (AAA-097) (105 mg, 56% for final step) was prepared in
essentially the same manner as AAA-075 except that
bromomethylcyclopropane was used instead of isopropyl bromide in
step (i) and ethyl iodide was used instead of methyl iodide in step
(iii): m/z 402 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.65 (1H, br s), 10.35 (1H, s), 7.88 (1H,
d), 7.75-7.65 (3H, m), 7.55 (1H, d), 4.17 (2H, q), 4.00 (2H, d),
2.54 (3H, s), 1.34 (3H, t), 1.31-1.25 (1H, m), 0.65-0.58 (2H, m),
0.43-0.35 (2H, m).
Synthesis 100
4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)benzoic acid
(AAA-098)
##STR00328##
[0848] 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)benzoic acid
(AAA-098) (232 mg, 78% for final step) was prepared in essentially
the same manner as AAA-075 except that cyclobutyl bromide was used
instead of isopropyl bromide in step (i) and methyl 4-aminobenzoate
was used instead of methyl 4-amino-2-methylbenzoate in step (v):
m/z 374 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.79 (1H, br s), 10.49 (1H, s), 8.11-7.82 (4H, m), 7.73
(1H, d), 7.39 (1H, d), 4.87 (1H, quin), 3.87 (3H, s), 2.49-2.43
(2H, m), 2.30-1.97 (2H, m), 1.83 (1H, q), 1.69 (1H, dq).
Synthesis 101
4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-099)
##STR00329##
[0850]
4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-methylbenzoic acid
(AAA-099) (170 mg, 75% for final step) was prepared in essentially
the same manner as AAA-075 except that cyclobutyl bromide was used
instead of isopropyl bromide in step (i): m/z 388 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.64 (1H,
br s), 10.37 (1H, s), 7.88 (1H, d), 7.75-7.66 (3H, m), 7.39 (1H,
d), 4.87 (1H, quin), 3.87 (3H, s), 2.53 (3H, s), 2.50-2.43 (2H, m),
2.19-2.05 (2H, m), 1.83 (1H, q), 1.76-1.62 (1H, m).
Synthesis 102
4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-fluorobenzoic acid
(AAA-100)
##STR00330##
[0852]
4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-fluorobenzoic acid
(AAA-100) (274 mg, 84% for final step) was prepared in essentially
the same manner as AAA-075 except that cyclobutyl bromide was used
instead of isopropyl bromide in step (i) and methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 392 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.06 (1H,
br s), 10.62 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.73 (1H, d),
7.63 (1H, dd), 7.38 (1H, d), 4.87 (1H, quin), 3.87 (3H, s),
2.50-2.42 (2H, m), 2.20-2.05 (2H, m), 1.83 (1H, q), 1.69 (1H,
dq).
Synthesis 103
4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)benzoic acid
(AAA-101)
##STR00331##
[0854] 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)benzoic
acid (AAA-101) (232 mg, 97% for final step) was prepared in
essentially the same manner as AAA-075 except that 3-bromopentane
was used instead of isopropyl bromide in step (i) and methyl
4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate
in step (v): m/z 390 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.80 (1H, br s), 10.49 (1H, s), 8.01-7.84
(4H, m), 7.69 (1H, d), 7.55 (1H, d), 4.45 (1H, quin), 3.85 (3H, s),
1.79-1.61 (4H, m), 0.95 (6H, t).
Synthesis 104
4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic
acid (AAA-102)
##STR00332##
[0856]
4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic
acid (AAA-102) (156 mg, 60% for final step) was prepared in
essentially the same manner as AAA-075 except that 3-bromopentane
was used instead of isopropyl bromide in step (i): m/z 404
[M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.63 (1H, br s), 10.36 (1H, s), 7.87 (1H, d), 7.75-7.65
(3H, m), 7.54 (1H, d), 4.43 (1H, quin), 3.85 (3H, s), 2.54 (3H, s),
1.76-1.62 (4H, m), 0.94 (6H, t).
Synthesis 105
4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic
acid (AAA-103)
##STR00333##
[0858]
4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic
acid (AAA-103) (253 mg, 90% for final step) was prepared in
essentially the same manner as AAA-075 except that 3-bromopentane
was used instead of isopropyl bromide in step (i) and methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 410 [M+H].sup.+
(ES.sup.+), 408 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 13.03 (1H, br s), 10.61 (1H, s), 7.89 (1H,
t), 7.81 (1H, dd), 7.68 (1H, d), 7.62 (1H, dd), 7.53 (1H, d), 4.44
(1H, quin), 3.85 (3H, s), 1.77-1.60 (4H, m), 0.94 (6H, t).
Synthesis 106
4-(3-Chloro-4-methoxy-5-(2-methoxyethoxy)benzamido)-2-fluorobenzoic
acid (AAA-104)
##STR00334##
[0860]
4-(3-Chloro-4-methoxy-5-(2-methoxyethoxy)benzamido)-2-fluorobenzoic
acid (AAA-104) (18 mg, 14% for final step) was prepared in
essentially the same manner as AAA-075 except that 2-methoxyethyl
bromide was used instead of isopropyl bromide in step (i) and
methyl 4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 398 [M+H].sup.+
(ES.sup.+), 396 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.97 (1H, br s), 10.62 (1H, s), 7.89 (1H,
t), 7.81 (1H, dd), 7.70 (1H, d), 7.62 (1H, dd), 7.59 (1H, d),
4.33-4.23 (2H, m), 3.87 (3H, s), 3.78-3.69 (2H, m), 3.34 (3H,
s).
Synthesis 107
4-(3-Chloro-4-methoxy-5-(neopentyloxy)benzamido)benzoic acid
(AAA-105)
##STR00335##
[0862] 4-(3-Chloro-4-methoxy-5-(neopentyloxy)benzamido)benzoic acid
(AAA-105) (83 mg, 45% for final step) was prepared in essentially
the same manner as AAA-075 except that neopentyl bromide,
Cs.sub.2CO.sub.3 and NMP at (130.degree. C., microwave, 20 min)
were used instead of isopropyl bromide, K.sub.2CO.sub.3 and DMF in
step (i) and methyl 4-aminobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 390 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.45 (1H,
s), 7.90 (4H, m), 7.71 (1H, d), 7.58 (1H, d), 3.91 (3H, s), 3.81
(2H, s), 1.06 (9H, s).
Synthesis 108
4-(4-Bromo-3,5-diethoxybenzamido)benzoic acid (AAA-106)
##STR00336##
[0864] 4-(4-Bromo-3,5-diethoxybenzamido)benzoic acid (AAA-106) (300
mg, 62% for final step) was prepared in essentially the same manner
as in steps (v) and (vi) for AAA-075 except that
4-bromo-3,5-diethoxybenzoic acid (prepared in 2 steps from
4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with
ethyl iodide and base and then lithium hydroxide) was used instead
of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate
in step (v): m/z 408 [M+H].sup.+ (ES.sup.+), 406 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.61 (1H,
br s), 10.29 (1H, s), 7.80-7.71 (2H, m), 7.71-7.63 (2H, m), 7.05
(2H, s), 4.01 (4H, q), 1.20 (6H, t).
Synthesis 109
4-(4-Bromo-3,5-diisopropoxybenzamido)benzoic acid (AAA-107)
##STR00337##
[0866] 4-(4-Bromo-3,5-diisopropoxybenzamido)benzoic acid (AAA-107)
(338 mg, 63% for final step) was prepared in essentially the same
manner as in steps (v) and (vi) for AAA-075 except that
4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from
4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with
isopropyl iodide and base and then lithium hydroxide) was used
instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate
in step (v): m/z 436 [M+H].sup.+ (ES.sup.+), 434 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.67 (1H,
br s), 10.33 (1H, s), 7.83 (2H, d), 7.75 (2H, d), 7.12 (2H, s),
4.65 (2H, sep), 1.20 (12H, d).
Synthesis 110
4-(4-Bromo-3,5-diisopropoxybenzamido)-2-fluorobenzoic acid
(AAA-108)
##STR00338##
[0868] 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-fluorobenzoic acid
(AAA-108) (51 mg, 37% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from
4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with
isopropyl iodide and base and then lithium hydroxide) was used
instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-amino-2-fluorobenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 452 and 454 [M-H].sup.-
(ES.sup.-). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.05 (1H,
br s), 10.59 (1H, s), 7.91 (1H, t), 7.82 (1H, dd), 7.62 (1H, dd),
7.24 (2H, s), 4.78 (2H, sep), 1.34 (12H, d).
Synthesis 111
4-(4-Bromo-3,5-diisopropoxybenzamido)-2-hydroxybenzoic acid
(AAA-109)
##STR00339##
[0870] 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-hydroxybenzoic acid
(AAA-109) (68 mg, 55% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from
4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with
isopropyl iodide and base and then lithium hydroxide) was used
instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl
4-amino-2-hydroxybenzoate was used instead of methyl
4-amino-2-methylbenzoate in step (v): m/z 452 [M+H].sup.+
(ES.sup.+), 450 [M-H].sup.- (ES.sup.-). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
13.75 (1H, br s), 11.40 (1H, br s), 10.38 (1H, s), 7.79 (1H, d),
7.51 (1H, d), 7.30 (1H, dd), 7.23 (2H, s), 4.78 (2H, sep), 1.34
(12H, d).
Synthesis 112
4-(4-Bromo-3,5-diethoxybenzamido)-2-methylbenzoic acid
(AAA-110)
##STR00340##
[0872] 4-(4-Bromo-3,5-diethoxybenzamido)-2-methylbenzoic acid
(AAA-110) (275 mg, 56% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
4-bromo-3,5-diethoxybenzoic acid (prepared in 2 steps from
4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with
ethyl iodide and base and then lithium hydroxide) was used instead
of 3-chloro-5-isopropoxy-4-methoxybenzoic acid in step (v): m/z 422
[M+H].sup.+ (ES.sup.+), 420 [M-H].sup.- (ES.sup.-). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.45 (1H, br s), 10.18 (1H, s),
7.69 (1H, d), 7.56-7.50 (1H, m), 7.47 (1H, d), 7.06 (2H, s), 4.01
(4H, q), 2.35 (3H, s), 1.20 (6H, t).
Synthesis 113
4-(4-Bromo-3,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-111)
##STR00341##
[0874] 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-111) (306 mg, 52% for final step) was prepared in essentially
the same manner as in steps (v) and (vi) for AAA-075 except that
4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from
4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with
isopropyl iodide and base and then lithium hydroxide) was used
instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid in step (v):
m/z 450 [M+H].sup.+ (ES.sup.+), 448 [M-H].sup.- (ES.sup.-). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.64 (1H, br s), 10.34 (1H,
s), 7.88 (1H, d), 7.71 (1H, dd), 7.66 (1H, d), 7.24 (2H, s), 4.77
(2H, sep), 2.54 (3H, s), 1.32 (12H, d).
Synthesis 114
4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid (AAA-112)
##STR00342## ##STR00343##
[0875] Step (i): Methyl 3,5-dihydroxy-4-nitrobenzoate (2)
##STR00344##
[0877] Tetrabutylammonium nitrate (10.9 g, 35.7 mmol) was dissolved
in DCM (125 mL) and treated with TFAA (5.04 mL, 35.7 mmol). The
resultant solution was added dropwise to an ice cooled solution of
methyl 3,5-dihydroxybenzoate (1) (6.0 g, 36 mmol) in DCM (100 mL),
keeping the temperature below 5.degree. C. The resultant mixture
was allowed to warm to RT and stirred for 18 h. The mixture was
filtered through silica, washing through with 20% EtOAc in DCM (500
mL). The solvent was removed in vacuo and the residue was purified
by silica gel chromatography (120 g, 0-5% EtOAc in DCM) to afford
methyl 3,5-dihydroxy-4-nitrobenzoate (2) (0.36 g, 5% yield) as a
bright orange solid: m/z 212 [M-H].sup.- (ES.sup.-).
Step (ii): Methyl 3,5-diisopropoxy-4-nitrobenzoate (3)
##STR00345##
[0879] Methyl 3,5-diisopropoxy-4-nitrobenzoate (3) (610 mg, 97%)
was prepared from methyl 3,5-dihydroxy-4-nitrobenzoate (2) (430 mg,
2.02 mmol) using a procedure essentially the same as in step (i)
for AAA-001 except that isopropyl bromide was used instead of
cyclopentyl bromide: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.25 (2H, s), 4.66 (2H, sep), 3.92 (3H, s), 1.32 (12H, d).
Step (iii): Methyl 4-amino-3,5-diisopropoxybenzoate (4)
##STR00346##
[0881] Methyl 3,5-diisopropoxy-4-nitrobenzoate (3) (594 mg, 2.00
mmol) was dissolved in a mixture of MeOH (40 mL) and formic acid (5
mL) and was passed through a Thales `H-cube` cartridge (10% Pd/C)
at a flow rate of 1 mL/min at 40.degree. C. under H.sub.2 (full
H.sub.2 mode). The solvents were removed in vacuo to yield methyl
4-amino-3,5-diisopropoxybenzoate (4) (398 mg, 72%) as a pale yellow
oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.20 (2H, s), 4.59
(2H, sep), 4.23 (2H, br s), 3.83 (3H, s), 1.33 (12H, d).
Step (iv): Methyl 4-chloro-3,5-diisopropoxybenzoate (5)
##STR00347##
[0883] A suspension of copper (I) chloride (129 mg, 1.31 mmol) and
tert-butyl nitrite (155 .mu.L, 1.31 mmol) in anhydrous MeCN (2 mL)
was stirred at 65.degree. C. A solution of methyl
4-amino-3,5-diisopropoxybenzoate (4) (233 mg, 0.872 mmol) in
anhydrous MeCN (1 mL) was added dropwise. Once the addition was
complete the mixture was allowed to cool to RT and poured on to 20%
HCl (5 mL). The mixture was partitioned between DCM (10 mL) and aq.
ammonia (35%, 5 mL), the phases were separated and the organic
solution was further washed with ammonia solution (17.5%, 10 mL),
and brine (2.times.20 mL). The solvent was removed in vacuo and the
residue was purified by silica gel chromatography (40 g, 0-100%
EtOAc in isohexane) to afford methyl
4-chloro-3,5-diisopropoxybenzoate (93 mg, 36% yield) as a
colourless oil: m/z 287 [M+H].sup.+ (ES.sup.+).
Step (v): 4-Chloro-3,5-diisopropoxybenzoic acid (6)
##STR00348##
[0885] Methyl 4-chloro-3,5-diisopropoxybenzoate (5) (93 mg, 0.32
mmol) was suspended in 2M sodium hydroxide (1.6 mL, 3.2 mmol) and
stirred at 100.degree. C. for 3 h. After cooling to RT the mixture
was acidified by the addition of 1M HCl. The resulting precipitate
was collected by filtration and dried in vacuo to afford
4-chloro-3,5-diisopropoxybenzoic acid (6) (60 mg, 66% yield) as a
white solid. This material was used in the subsequent reaction step
without purification.
Step (vi): Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate
(8)
##STR00349##
[0887] Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8)
(86 mg, 96%) was prepared from 4-chloro-3,5-diisopropoxybenzoic
acid (6) (60 mg, 0.22 mmol) using a procedure essentially the same
as in step (i) for AAA-064 except that DIPEA was used instead of
TEA, and methyl 4-aminobenzoate was used instead of methyl
4-amino-2-fluorobenzoate: m/z 406 [M+H].sup.+ (ES).sup.+, 404
[M-H].sup.- (ES).sup.-.
Step (vii): 4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid
(AAA-112)
##STR00350##
[0889] 4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid (AAA-112)
(40 mg, 46%) was prepared from methyl
4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8) (86 mg, 0.21
mmol) using a procedure essentially the same as in step (ii) for
AAA-001 except that MeOH was added dropwise to obtain a solution
and the mixture was heated at 50.degree. C. for 2 h then at RT for
15 h: m/z 390 [M-H].sup.- (ES.sup.-), .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.74 (1H, br s), 10.44 (1H, s), 8.01-7.84
(4H, m), 7.29 (2H, s), 4.78 (2H, sep), 1.33 (12H, d).
Synthesis 115
4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-113)
##STR00351## ##STR00352##
[0890] Step (i) Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2)
##STR00353##
[0892] A solution of methyl 4-hydroxy-3-methoxybenzoate (1) (10 g,
55 mmol) in DCM (100 mL) was cooled to -60.degree. C. and fuming
nitric acid (24.5 mL, 549 mmol) was added dropwise over 30 min. The
reaction mixture was stirred at -60.degree. C. for 2 h then added
slowly to iced water (200 mL) with stirring. The precipitate was
collected, washed with ice cold water and dried under suction to
afford methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 35%
yield) as a bright yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 11.08 (1H, d), 8.45 (1H, d), 7.77 (1H, d), 4.01 (3H, s),
3.95 (3H, s).
Step (ii): Methyl 4-chloro-3-methoxy-5-nitrobenzoate (3)
##STR00354##
[0894] A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2)
(4.4 g, 19 mmol) in DMF (30 mL) at 0.degree. C. was treated with
oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then
stirred at 80.degree. C. for 3 h under a CaCl.sub.2 drying tube.
The mixture was allowed to cool to RT, poured in to iced water (100
mL) and stirred for 15 min. The precipitate was collected by
filtration and washed with water and MeOH to afford methyl
4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65% yield) as a
yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.04 (1H,
d), 7.77 (1H, d), 4.04 (3H, s), 3.97 (3H, s).
Step (iii) Methyl 3-amino-4-chloro-5-methoxybenzoate (4)
##STR00355##
[0896] A suspension of methyl 4-chloro-3-methoxy-5-nitrobenzoate
(3) (900 mg, 3.66 mmol) and iron powder (614 mg, 11.0 mmol) in a
mixture of EtOH (15 mL) and water (15 mL) was heated to 70.degree.
C. and degassed with nitrogen for 20 min. Conc. HCl (44.5 .mu.L,
1.47 mmol) was added and the reaction mixture was stirred at
70.degree. C. for 3 h. Celite (1 g) was added and the suspension
stirred for 10 min then filtered through a celite pad. The solvent
was removed in vacuo and the residue was partitioned between EtOAc
(15 mL) and water (15 mL). The phases were separated and the
organic solution was washed with brine (2.times.15 mL). The solvent
was removed in vacuo to afford methyl
3-amino-4-chloro-5-methoxybenzoate (0.82 g, 100% yield) as a yellow
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.10 (1H, d),
6.78 (1H, d), 5.68 (2H, s), 3.81 (6H, m).
Step (iv): Methyl 3,4-dichloro-5-methoxybenzoate (5)
##STR00356##
[0898] A suspension of copper (II) chloride (0.97 g, 7.2 mmol) and
tert-butyl nitrite (1.07 mL, 9.04 mmol) in anhydrous MeCN (5 mL)
was warmed to 65.degree. C. A solution of methyl
3-amino-4-chloro-5-methoxybenzoate (4) (1.3 g, 6.0 mmol) in
anhydrous MeCN (3 mL) was added dropwise. Once the addition was
complete the mixture was allowed to cool to RT and poured on to 1M
HCl (15 mL). The acidic mixture was neutralized with satd.
NaHCO.sub.3 solution and aq. ammonia (35%, 5 mL) was added. The
product was extracted with DCM (25 mL) and then washed with aq.
ammonia (17.5%, 20 mL) and brine (2.times.20 mL). The solvent was
removed in vacuo and the residue was triturated with 10% EtOAc in
isohexane to afford methyl 3,4-dichloro-5-methoxybenzoate (5) (1.17
g, 79% yield) as a brown solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 7.72 (1H, d), 7.57 (1H, d), 3.98 (3H, s), 3.89 (3H,
s).
Step (v): 3,4-Dichloro-5-hydroxybenzoic acid (6)
##STR00357##
[0900] Methyl 3,4-dichloro-5-methoxybenzoate (5) (518 mg, 2.34
mmol) was suspended in DCM (10 mL) under a reflux condenser fitted
with a CaCl.sub.2 drying tube. BBr.sub.3 (554 .mu.L, 5.86 mmol) was
added and the reaction mixture was stirred at RT for 15 h. The
reaction mixture was cautiously poured in to iced water (20 mL) and
the mixture stirred for 10 min. The product was extracted with
EtOAc (50 mL), then the organic solution was washed with brine
(2.times.50 mL) and dried over MgSO.sub.4 and filtered. The solvent
was removed in vacuo and the residue purified by silica gel
chromatography (40 g, 0-100% EtOAc in isohexane) to afford
3,4-dichloro-5-hydroxybenzoic acid (6) (260 mg, 51% yield) as a
white solid: m/z 205 [M-H].sup.- (ES.sup.-).
Step (vi): Isopropyl 3,4-dichloro-5-isopropoxybenzoate (7)
##STR00358##
[0902] Isopropyl 3,4-dichloro-5-isopropoxybenzoate (7) (342 mg,
87%) was prepared from 3,4-dichloro-5-hydroxybenzoic acid (6) (260
mg, 1.26 mmol) using a procedure essentially the same as in step
(i) for AAA-001 except that isopropyl bromide was used instead of
cyclopentyl bromide.
Step (vii): 3,4-Dichloro-5-isopropoxybenzoic acid (8)
##STR00359##
[0904] 3,4-Dichloro-5-isopropoxybenzoic acid (8) (199 mg, 63%) was
prepared from isopropyl 3,4-dichloro-5-isopropoxybenzoate (7) (340
mg, 1.17 mmol) using a procedure essentially the same as in step
(v) for AAA-112 except that the reaction was stirred for 15 h: m/z
247 [M-H].sup.- (ES.sup.-).
Step (viii): Methyl
4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10)
##STR00360##
[0906] Methyl
4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (237
mg, 68%) was prepared from 3,4-dichloro-5-isopropoxybenzoic acid
(8) (200 mg, 800 .mu.mol) using a procedure essentially the same as
in step (i) for AAA-064 except that DIPEA was used instead of TEA,
and methyl 4-amino-2-methylbenzoate (9) was used instead of methyl
4-amino-2-fluorobenzoate: m/z 396 [M+H].sup.+ (ES.sup.+), 394
[M-H].sup.- (ES.sup.-), .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.51 (1H, s), 7.89 (1H, d), 7.81 (1H, d), 7.77-7.72 (2H,
m), 7.64 (1H, d), 4.85 (1H, sep), 3.81 (3H, s), 2.54 (3H, s), 1.35
(6H, d).
Step (ix): 4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic
acid (AAA-113)
##STR00361##
[0908] 4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid
(AAA-113) (85 mg, 41%) was prepared from methyl
4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (210
mg, 0.530 mmol) using a procedure essentially the same as in step
(ii) for AAA-001 except that MeOH was added dropwise to obtain a
solution and the mixture was stirred at 40.degree. C. for 20 h: m/z
380 [M-H].sup.- (ES.sup.-), .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.66 (1H, br s), 10.48 (1H, s), 7.88 (1H, d), 7.81 (1H,
d), 7.75-7.66 (2H, m), 7.64 (1H, d), 4.86 (1H, sep), 2.54 (3H, s),
1.35 (6H, d).
Synthesis 116
4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic acid
(AAA-114)
##STR00362## ##STR00363##
[0909] Step (i): 4-Chloro-3,5-dimethoxyaniline (2)
##STR00364##
[0911] N-Chlorosuccinimide (15.7 g, 118 mmol) was added to a
solution of 3,5-dimethoxyaniline (1) (20.0 g, 131 mmol) in AcOH
(150 mL) and the reaction mixture was left to stir at RT for 3 h.
The reaction mixture was diluted with water (200 mL) and EtOAc (200
mL). The phases were separated and the organic solution was washed
with brine (200 mL). The solvent was removed in vacuo and the
residue was purified by silica gel chromatography (120 g, 0-70%
EtOAc in isohexanes) to afford 4-chloro-3,5-dimethoxyaniline (2)
(6.61 g, 26%) as a colourless solid: m/z 188 [M+H].sup.+
(ES.sup.+).
Step (ii): 2-Chloro-5-iodo-1,3-dimethoxybenzene (3)
##STR00365##
[0913] 4-Chloro-3,5-dimethoxyaniline (2) (6.61 g, 35.2 mmol) was
added to a mixture of sulfuric acid (9.39 mL, 176 mmol) and
H.sub.2O (100 mL) at 0.degree. C. Sodium nitrite (3.16 g, 45.8
mmol) was added and the reaction mixture was stirred at 0.degree.
C. for 30 min. The mixture was added to a pre-warmed mixture of
sodium iodide (21.1 g, 141 mmol), iodine (4.47 g, 17.6 mmol),
sulphuric acid (8 mL) and H.sub.2O (100 mL) at 80.degree. C. and
the resulting mixture was heated at reflux for 30 min. The mixture
was allowed to cool to RT and then 40% sodium thiosulfate solution
(200 mL) was added. The product was extracted with EtOAc (300 mL),
the solvent was removed in vacuo and the residue was purified by
silica gel chromatography (120 g, 0-50% EtOAc in isohexanes) to
afford 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.16 g, 67%
yield).
Step (iii): 2-Chloro-5-iodobenzene-1,3-diol (4)
##STR00366##
[0915] A solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.15
g, 23.9 mmol) in DCM (20 mL) was cooled to 0.degree. C. Boron
tribromide (11.3 mL, 120 mmol) was added dropwise over 30 min and
the reaction mixture was allowed to slowly warm to RT and stirred
for 20 h. The reaction mixture was cautiously added to iced water
(30 mL) with stirring. The phases were separated and the organic
solution was washed with brine (3.times.30 mL). The solvent was
removed in vacuo to afford 2-chloro-5-iodobenzene-1,3-diol (4)
(4.17 g, 64% yield) as a white solid: m/z 269 [M-H].sup.-
(ES.sup.-).
Step (iv): 2-Chloro-5-iodo-1,3-phenylene diacetate (5)
##STR00367##
[0917] A solution of 2-chloro-5-iodobenzene-1,3-diol (4) (4.12 g,
15.2 mmol) and DIPEA (7.98 mL, 45.7 mmol) in anhydrous DCM (15 mL)
was cooled to 0.degree. C. before acetyl chloride (2.28 mL, 32.0
mmol) was added dropwise. The reaction mixture was allowed to
slowly warm to RT and stirred for 20 h. The reaction mixture was
diluted with DCM (15 mL), washed sequentially with water (20 mL),
1M HCl (20 mL) and brine (3.times.20 mL) and then dried over
MgSO.sub.4. The solvent was removed in vacuo to afford
2-chloro-5-iodo-1,3-phenylene diacetate (5) (5.16 g, 96% yield) as
a white solid: m/z 372 [M+H.sub.2O].sup.+ (ES.sup.+).
Step (v): 2-Chloro-3-hydroxy-5-iodophenyl acetate (6)
##STR00368##
[0919] A mixture of 2-chloro-5-iodo-1,3-phenylene diacetate (5)
(5.16 g, 14.5 mmol) and 1M lithium hydroxide (29.1 mL, 29.1 mmol)
in H.sub.2O (5 mL) and dioxane (20 mL) was stirred at 60.degree. C.
for 4 h then at RT for 20 h. The reaction mixture was acidified by
the addition of 1M HCl and the product was extracted with EtOAc
(150 mL). The organic solution was dried over MgSO.sub.4 and the
solvent was removed in vacuo. The resulting oil was slurried with
1:1 DCM: isohexanes and the solvents were removed in vacuo to yield
2-chloro-3-hydroxy-5-iodophenyl acetate (6) (4.88 g, 86%) as a
brown solid: m/z 311 [M-H].sup.- (ES.sup.-).
Step (vi): 2-Chloro-3-ethoxy-5-iodophenol (7)
##STR00369##
[0921] Iodoethane (0.78 mL, 9.6 mmol) and K.sub.2CO.sub.3 (1.3 g,
9.6 mmol) were added to a solution of
2-chloro-3-hydroxy-5-iodophenyl acetate (6) (2.0 g, 6.4 mmol) in
DMF (5 mL) and the mixture was stirred at 60.degree. C. for 1 h.
The reaction mixture was cooled to RT, diluted with diethyl ether
(100 mL) and washed with brine (3.times.100 mL). The solvent was
removed in vacuo and the residue was dissolved in MeOH (20 mL).
K.sub.2CO.sub.3 (1.0 g, 7.2 mmol) was added and the mixture was
stirred at RT for 20 h. The solvent was removed in vacuo and the
residue was partitioned between EtOAc (100 mL) and water (100 mL).
The organic layer was washed with water (100 mL) and evaporated in
vacuo. The residue was purified by silica gel chromatography (40 g,
0-30% EtOAc in isohexane) to afford 2-chloro-3-ethoxy-5-iodophenol
(7) (1.1 g, 58% yield) as a colourless solid: m/z 297 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.45 (1H,
s), 6.89 (2H, d), 4.04 (2H, br s), 1.32 (3H, br s).
Step (vii): 2-Chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene
(8)
##STR00370##
[0923] 2-Chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8) (1.2
g, 79%) was prepared from 2-chloro-3-ethoxy-5-iodophenol (7) (1.1
g, 3.7 mmol) using a procedure essentially the same as in step (i)
for AAA-001 except that 3-bromopentane was used instead of
cyclopentyl bromide.
Step (viii): 4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzoic acid
##STR00371##
[0925] n-Butyllithium (1.3 mL, 3.3 mmol) was slowly added to a
stirred solution of
2-chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8) (1.2 g, 3.3
mmol) in anhydrous THF at -78.degree. C. After 5 min CO.sub.2 gas
was bubbled through the mixture via a CaCl.sub.2 drying tube. The
solution was allowed to warm to RT under a constant stream of
CO.sub.2 gas. 1M NaOH, followed by diethyl ether (50 mL) were added
to the mixture and the phases were separated. The organic phase was
retained. The aqueous phase was acidified by the addition of 1M HCl
and then shaken with EtOAc (50 mL). The phases were separated and
the organic phase was evaporated to give 100 mg of the desired
acid. The organic solution retained from the initial separated
mixture was diluted further with diethyl ether and shaken with 1M
HCl and the phases were separated. The organic solution was dried
over MgSO.sub.4 and the solvent was removed in vacuo, the solid
obtained was combined with the 100 mg obtained previously to give
4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzoic acid (9) (0.76 g, 76%)
as a white solid: m/z 285 [M-H].sup.- (ES.sup.-).
Step (ix): Methyl
4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11)
##STR00372##
[0927] Methyl
4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11) (76
mg, 51%) was prepared from
4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzoic acid (9) (100 mg, 0.349
mmol) using a procedure essentially the same as in step (iii) for
AAA-001: m/z 420 [M+H].sup.+ (ES.sup.+), 418 [M-H].sup.-
(ES.sup.-).
Step (x): 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic
acid (AAA-114)
##STR00373##
[0929] 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic
acid (AAA-114) (50 mg, 65%) was prepared from methyl
4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11) (76
mg, 0.18 mmol) using a procedure essentially the same as in step
(ii) for AAA-001 except that dioxane (2 mL) was used instead of THF
and the mixture was stirred at 50.degree. C. for 2 h: m/z 406
[M+H].sup.+ (ES.sup.+), 404 [M-H].sup.- (ES.sup.-); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 12.79 (1H, br s), 10.46 (1H, s),
7.99-7.93 (2H, m), 7.91-7.82 (2H, m), 7.27 (2H, dd), 4.46 (1H,
quin), 4.20 (2H, q), 1.71-1.64 (4H, m), 1.39 (3H, t), 0.93 (6H,
t).
Synthesis 117
4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic
acid (AAA-115)
##STR00374##
[0931]
4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic
acid (AAA-115) (57 mg, 78% for final step) was prepared in
essentially the same manner as AAA-114 except that methyl
4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate
in step (ix): m/z 420 [M+H].sup.+ (ES.sup.+), 418 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.62 (1H,
br s), 10.35 (1H, s), 7.88 (1H, d), 7.72 (1H, dd), 7.66 (1H, d),
7.32-7.24 (2H, m), 4.45 (1H, quin), 4.20 (2H, q), 2.55 (3H, s),
1.73-1.61 (4H, m), 1.39 (3H, t), 0.93 (6H, t).
Synthesis 118
4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic
acid (AAA-116)
##STR00375##
[0933]
4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic
acid (AAA-116) (44 mg, 81% for final step) was prepared in
essentially the same manner as AAA-114 except that methyl
4-amino-2-fluorobenzoate was used instead of methyl 4-aminobenzoate
in step (ix): m/z 424 [M+H].sup.+ (ES.sup.+), 422 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.05 (1H,
br s), 10.60 (1H, s), 7.91 (1H, t), 7.82 (1H, dd), 7.61 (1H, dd),
7.26 (2H, dd), 4.46 (1H, quin), 4.20 (2H, q), 1.73-1.61 (4H, m),
1.39 (3H, t), 0.92 (6H, t).
Synthesis 119
4-(4-Chloro-3,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-117)
##STR00376## ##STR00377##
[0934] Step (i): Ethyl 4-chloro-3,5-dimethoxybenzoate (2)
##STR00378##
[0936] A solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (1) (3.4
g, 11 mmol) in anhydrous THF (100 mL) was cooled to -70.degree. C.
and treated with n-butyllithium (5.5 mL, 12 mmol). The reaction
mixture was stirred at -70.degree. C. for 45 min then ethyl
chloroformate (1.6 mL, 17 mmol) was added dropwise and the reaction
mixture was allowed to warm to RT and stirred for 20 h. The
reaction mixture was poured on to ice (100 mL) and the product was
extracted with EtOAc (2.times.100 mL). The organic solution was
washed with brine (3.times.100 mL) and the solvent was removed in
vacuo. The residue was purified by silica gel chromatography (120
g, 0-50% EtOAc in isohexane) to afford ethyl
4-chloro-3,5-dimethoxybenzoate (2) (0.12 g, 4%): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.30 (2H, s), 4.40 (2H, q), 3.96 (6H, s),
1.42 (3H, t).
Step (ii): 4-Chloro-3,5-dihydroxybenzoic acid (3)
##STR00379##
[0938] Tribromoborane (318 .mu.L, 3.29 mmol) was added dropwise to
a solution of ethyl 4-chloro-3,5-dimethoxybenzoate (2) (115 mg,
0.470 mmol) in DCM (1.5 mL) at 0.degree. C. and the mixture was
stirred at the same temperature for 4 h. The reaction mixture was
allowed to warm to RT and then poured cautiously in to iced water
(5 mL). The mixture was extracted with EtOAc (3.times.5 mL), and
the combined organic extracts were washed with brine (2.times.5
mL), dried over MgSO.sub.4 and evaporated in vacuo to give
4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 78%) as a brown
solid: m/z 187 [M-H].sup.- (ES.sup.-).
Step (iii): Isopropyl 4-chloro-3,5-diisopropoxybenzoate (4)
##STR00380##
[0940] Isopropyl 4-chloro-3,5-diisopropoxybenzoate (4) (43 mg, 0.12
mmol) was prepared from 4-chloro-3,5-dihydroxybenzoic acid (3) (72
mg, 0.38 mmol) using a procedure essentially the same as in step
(i) for AAA-001 except that isopropyl bromide (8 eq.) was used
instead of cyclopentyl bromide and the mixture was stirred at
50.degree. C. for 20 h: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.25 (2H, s), 5.23 (1H, sep), 4.63 (2H, sep), 1.38 (18H, m).
Step (iv): 4-Chloro-3,5-diisopropoxybenzoic acid (5)
##STR00381##
[0942] 4-Chloro-3,5-diisopropoxybenzoic acid (5) (36 mg, 95%) was
prepared from isopropyl 4-chloro-3,5-diisopropoxybenzoate (4) (43
mg, 0.14 mmol) using a procedure essentially the same as in step
(ii) for AAA-001 except that the mixture was stirred at 40.degree.
C. for 20 h: m/z 271 [M-H].sup.- (ES.sup.-).
Step (v): Methyl
4-(4-chloro-3,5-diisopropoxybenzamido)-2-methylbenzoate (7)
##STR00382##
[0944] Methyl
4-(4-chloro-3,5-diisopropoxybenzamido)-2-methylbenzoate (7) (29 mg,
52%) was prepared from 4-chloro-3,5-diisopropoxybenzoic acid (5)
(36 mg, 0.13 mmol) using a procedure essentially the same as in
step (v) for AAA-075 except that the mixture was stirred at
60.degree. C. for 90 min: m/z 420 [M+H].sup.+ (ES.sup.+), 418
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.98 (1H, d), 7.88 (1H, br s), 7.61-7.52 (2H, m), 7.06 (2H, s),
4.71-4.59 (2H, m), 3.89 (3H, s), 2.64 (3H, s), 1.41 (12H, d).
Step (vi): 4-(4-Chloro-3,5-diisopropoxybenzamido)-2-methylbenzoic
acid (AAA-117)
##STR00383##
[0946] 4-(4-Chloro-3,5-diisopropoxybenzamido)-2-methylbenzoic acid
(AAA-117) (21 mg, 83%) was prepared from methyl
4-(4-chloro-3,5-diisopropoxybenzamido)-2-methylbenzoate (7) (25 mg,
60 .mu.mol) using a procedure essentially the same as in step (ii)
for AAA-001 except that the mixture was stirred at 40.degree. C.
for 20 h: m/z 404 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.61 (1H, br s), 10.33 (1H, s), 7.88 (1H,
d), 7.71 (2H, dd), 7.26 (2H, d), 4.78 (2H, sep), 2.55 (3H, s), 1.33
(12H, d).
Synthesis 120
4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid
(AAA-118)
##STR00384##
[0947] Step (i): 2-Chloro-5-iodo-3-methoxyphenol (2)
##STR00385##
[0949] Tribromoborane (156 .mu.L, 1.65 mmol) was added to a
solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (1) (380 mg, 1.27
mmol) in DCM (5 mL) and the mixture was stirred at RT for 1 h. The
mixture was poured into iced water (20 mL) and made basic by the
addition of 2M NaOH (50 mL). The aqueous mixture was washed with
DCM (50 mL) and then acidified by the addition of 4M HCl. The
product was then extracted into DCM (50 mL), the organic solution
was dried over MgSO.sub.4 and the solvent was removed in vacuo to
give 2-chloro-5-iodo-3-methoxyphenol (2) (290 mg, 78%) as a
colourless oil: m/z 283 [M-H].sup.- (ES.sup.-).
Step (ii): 2-Chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3)
##STR00386##
[0951] 2-Chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3) (270 mg,
77%) was prepared from 2-chloro-5-iodo-3-methoxyphenol (2) (290 mg,
1.02 mmol) using a procedure essentially the same as in step (i)
for AAA-001 except that isopropyl bromide was used instead of
cyclopentyl bromide.
Step (iii) Methyl
4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5)
##STR00387##
[0953] n-Butyllithium (364 .mu.l, 0.909 mmol) was slowly added to a
solution of 2-chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3) (270
mg, 0.827 mmol) in anhydrous THF (5 mL) at -78.degree. C. After
stirring for 15 min at this temperature a solution of methyl
4-isocyanatobenzoate (176 mg, 0.992 mmol) in anhydrous THF (5 mL)
was added dropwise. The solution was allowed to warm to RT and
stirred for a further 20 h. The reaction mixture was partitioned
between DCM (40 mL) and brine (100 mL). The phases were separated
and the organic solution was dried over MgSO.sub.4, filtered and
the solvent was removed in vacuo. The residue was purified by
silica gel chromatography (40 g, 0-40% EtOAc in isohexane) to
afford methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate
(5) (20 mg, 6%) as a colourless oil: m/z 376 [M-H].sup.-
(ES.sup.-).
Step (iv): 4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid
(AAA-118)
##STR00388##
[0955] 4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid
(AAA-118) (10 mg, 55%) was prepared from methyl
4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5) (20 mg, 48
.mu.mol) using a procedure essentially the same as in step (ii) for
AAA-001 except that dioxane (3 mL) was used instead of THF: m/z 362
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 12.80 (1H, br s), 10.47 (1H, s), 7.99-7.92 (2H, m),
7.90-7.83 (2H, m), 7.31 (2H, dd), 4.79 (1H, sep), 3.94 (3H, s),
1.33 (6H, d).
Synthesis 121
4-(4-Fluoro-3,5-diisopropoxybenzamido)benzoic acid (AAA-119)
##STR00389## ##STR00390##
[0957] Step (i): tert-Butyl(4-fluorobenzyloxy)dimethylsilane
(2)
##STR00391##
[0958] A solution of (4-fluorophenyl)methanol (1) (8.6 mL, 79 mmol)
in anhydrous DMF (40 mL) was cooled to 0.degree. C. before
imidazole (5.9 g, 87 mmol) was added portionwise, followed by
tert-butylchlorodimethylsilane (13 g, 87 mmol). The reaction
mixture was allowed to warm to RT and stirred for 20 h. The
reaction mixture was diluted with EtOAc (200 mL) and the organic
solution was washed with satd NaHCO.sub.3 (3.times.200 mL) and then
brine (4.times.300 mL). The organic solution was dried over
MgSO.sub.4 and the solvent was removed in vacuo. The residue was
purified by silica gel chromatography (120 g, 0-10% EtOAc in
isohexane) to afford tert-butyl(4-fluorobenzyloxy)dimethylsilane
(2) (15.4 g, 81%) as a clear oil: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 7.38-7.28 (2H, m), 7.16 (2H, dd), 4.68 (2H,
s), 0.89 (9H, s), 0.07 (6H, s).
Step (ii): 5-((tert-Butyldimethylsilyloxy)methyl)-2-fluorophenol
(3)
##STR00392##
[0960] sec-Butyllithium (20.7 mL, 29.0 mmol) was added dropwise to
a solution of tert-butyl(4-fluorobenzyloxy)dimethylsilane (2) (6.33
g, 26.3 mmol) in THF (30 mL) over 30 min, at -78.degree. C.
Trimethyl borate (2.99 mL, 26.3 mmol) was added dropwise over 30
min while the temperature was maintained at -78.degree. C. The
reaction mixture was allowed to warm to 0.degree. C. and AcOH (2.26
mL, 39.5 mmol) was added dropwise, followed by hydrogen peroxide
(2.48 mL, 29.0 mmol). The mixture was stirred at 0.degree. C. for
30 min then allowed to warm to RT and stirred for 1 h. The reaction
mixture was diluted with diethyl ether (100 mL) and washed with 2M
NaOH (100 mL) and brine (100 mL). The organic solution was dried
over MgSO.sub.4, filtered and the solvent was removed in vacuo to
give 5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (3) (4.0
g, 50%) as a colourless oil: m/z 255 [M-H].sup.- (ES.sup.-).
Step (iii):
tert-Butyl(3-(tert-butyldimethylsilyloxy)-4-fluorobenzyloxy)dimethylsilan-
e (4)
##STR00393##
[0962]
tert-Butyl(3-(tert-butyldimethylsilyloxy)-4-fluorobenzyloxy)dimethy-
lsilane (4) (4.9 g, 81%) was prepared from
5-(tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (3) (4.00 g,
15.6 mmol) using a procedure essentially the same as in step
(i).
Step (iv):
3-(tert-Butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)m-
ethyl)-2-fluorophenol (5)
##STR00394##
[0964]
3-(tert-Butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methy-
l)-2-fluorophenol (5) (2.1 g, 80%) was prepared from
tert-butyl(3-(tert-butyldimethylsilyloxy)-4-fluorobenzyloxy)-dimethylsila-
ne (4) (2.0 g, 5.4 mmol) using a procedure essentially the same as
in step (ii): m/z 385 [M-H].sup.- (ES.sup.-).
Step (v):
tent-Butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane
(6)
##STR00395##
[0966] 2-Bromopropane (0.90 mL, 9.5 mmol) and K.sub.2CO.sub.3 (1.49
g, 10.8 mmol) were added to a stirred solution of
3-(tert-butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-2-f-
luorophenol (5) (2.08 g, 4.30 mmol) in DMF (3 mL) and the mixture
was stirred at 60.degree. C. for 2 h. The reaction mixture was
allowed to cool to RT and diluted with diethyl ether (50 mL). The
organic solution was washed with brine (3.times.50 mL), dried over
MgSO.sub.4, filtered and the solvent was removed in vacuo to afford
tert-butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane (6)
(0.6 g, 31%). This material was used in the subsequent reaction
step without purification.
Step (vi): (4-Fluoro-3,5-diisopropoxyphenyl)methanol (7)
##STR00396##
[0968] TBAF (1 M in THF) (1.35 mL, 1.35 mmol) was added to a
solution of
tert-butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane (6)
(600 mg, 1.35 mmol) in THF at 0.degree. C. and the mixture was
stirred at this temperature for 1 h. The mixture was partitioned
between NH.sub.4Cl (satd. aq.) (50 mL) and EtOAc (100 mL). The
phases were separated and the organic solution was washed with
brine (50 mL), then dried over MgSO.sub.4 and filtered. The solvent
was removed in vacuo and the residue was purified by silica gel
chromatography (40 g, 0-50% EtOAc in isohexane) to afford
(4-fluoro-3,5-diisopropoxyphenyl)methanol (7) (382 mg, 100%) as a
colourless oil.
Step (vii): 4-Fluoro-3,5-diisopropoxybenzoic acid (8)
##STR00397##
[0970] TEMPO (12 mg, 79 .mu.mol) was added to
(4-fluoro-3,5-diisopropoxyphenyl)methanol (7) (382 mg, 1.58 mmol)
in a mixture of MeCN (10 mL) and sodium phosphate buffer at
35.degree. C. Sodium chlorite (285 mg, 3.15 mmol) in water (5 mL)
and sodium hypochlorite (97 .mu.l, 1.6 mmol) were added cautiously
(portionwise, 20% of one then the other every 10 min until the
addition was complete). Once the reaction was complete the mixture
was basified to pH 9 by the addition of NaOH (15 mL). Sodium
sulfite (aq., 20 mL) was added and the aqueous mixture was washed
with diethyl ether (50 mL). The aqueous layer was acidified by the
addition of 4M HCl and the product was extracted into EtOAc (50
mL). The organic solution was dried over MgSO.sub.4, filtered and
the solvent was removed in vacuo. The residue was purified by
silica gel chromatography (12 g, 0-40% EtOAc in isohexane) to
afford 4-fluoro-3,5-diisopropoxybenzoic acid (8) (50 mg, 12%) as a
white solid: m/z 255 [M-H].sup.- (ES.sup.-).
Step (viii): Methyl 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate
(10)
##STR00398##
[0972] A mixture of 4-fluoro-3,5-diisopropoxybenzoic acid (8) (54
mg, 0.21 mmol), DIPEA (110 .mu.L, 0.632 mmol) and T3P (50% solution
in EtOAc) (310 .mu.L, 0.527 mmol) in EtOAc (1 mL) was stirred at RT
for 10 min before a solution of methyl 4-aminobenzoate (9) (35 mg,
0.23 mmol) in EtOAc (1 mL) was added dropwise and the mixture was
stirred at 40.degree. C. for 20 h. The reaction mixture was
adsorbed on to silica and purified by silica gel chromatography (4
g, 0-100% EtOAc in isohexane), then (4 g, 0-10% MeOH in DCM) to
afford methyl 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate (10)
(32 mg, 51% purity). The material was taken on in the subsequent
reaction step without further purification.
Step (ix): 4-(4-Fluoro-3,5-diisopropoxybenzamido)benzoic acid
(AAA-119)
##STR00399##
[0974] A suspension of methyl
4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate (10) (32 mg, 51%
purity, 82 .mu.mol) in THF (1 mL) and 2M LiOH (0.16 mL, 0.33 mmol)
was stirred at RT for 20 h, then at 45.degree. C. for 2 h. The
mixture was allowed to cool to RT and was acidified by the addition
of 1M HCl. The mixture was partitioned between EtOAc (10 mL) and
water (10 mL) and the phases were separated. The organic solution
was washed with brine (3.times.10 mL), then dried over MgSO.sub.4
and filtered. The solvent was removed in vacuo and the residue was
purified by reverse phase HPLC to afford
4-(4-fluoro-3,5-diisopropoxybenzamido)benzoic acid (AAA-119) (8 mg,
38%) as a white solid: m/z 376 [M+H].sup.+ (ES.sup.+), 374
[M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.: 10.37 (1H, s), 7.93 (2H, d), 7.83 (2H, d), 7.35 (2H, d),
4.73 (2H, sep), 1.32 (12H, d). NB acid proton not visible.
Synthesis 122
4-(3,4-Diisopropoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-120)
##STR00400## ##STR00401##
[0975] Step (i): 2-Methoxy-6-(trifluoromethyl)phenol (2)
##STR00402##
[0977] A solution of n-butyllithium (20.4 mL, 51.1 mmol) and TMEDA
(9.00 mL, 59.6 mmol) in anhydrous THF (50 mL) was cooled to
-78.degree. C. 1-Methoxy-3-(trifluoromethyl)benzene (1) (10 g, 57
mmol) was added dropwise and the reaction mixture was stirred at
-78.degree. C. for 15 min then allowed to warm to RT and stirred
for 10 min. The reaction mixture was cooled to -78.degree. C. and
trimethyl borate (16.1 mL, 142 mmol) was added slowly, dropwise,
and the reaction mixture was stirred at -78.degree. C. for 15 min
then allowed to warm to RT and stirred for 20 h. 7N NH.sub.3/MeOH
(20 mL) was added and the solvent was removed in vacuo. The residue
was dissolved in formic acid (20 mL) and cooled to 0.degree. C.
before hydrogen peroxide (6.00 mL, 68.5 mmol) was added and the
solution was allowed to warm to RT and stirred for 2 h. The product
was extracted with EtOAc (3.times.50 mL), and then the combined
organics were shaken with NaOH (2.times.50 mL). The aq phase was
acidified with 1M HCl and the product was extracted with DCM
(2.times.30 mL). The organic solution was washed with brine
(2.times.30 mL), dried over MgSO.sub.4 and filtered. The solvent
was removed in vacuo and the residue was purified by silica gel
chromatography (120 g, 0-5% MeOH in DCM) to afford
2-methoxy-6-(trifluoromethyl)phenol (2) (4.95 g, 45%) as a
colourless oil: m/z 191 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.15-7.09 (1H, m), 7.04-6.98 (1H, m),
6.89 (1H, td), 6.14 (1H, br s), 3.91 (3H, s).
Step (ii): 4-Hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde
(3)
##STR00403##
[0979] A mixture of 2-methoxy-6-(trifluoromethyl)phenol (2) (2.5 g,
13 mmol) and hexamethylenetetramine (1.8 g, 13 mmol) in TFA (40 mL)
was stirred under reflux for 3 h. The solvent was removed in vacuo
and the residue was dissolved in 1M HCl (20 mL). The product was
extracted with DCM (3.times.20 mL), the combined organics were
washed with brine (2.times.20 mL) and then the solvent was removed
in vacuo. The residue was purified by silica gel chromatography (80
g, 0-100% EtOAc in isohexane) to afford
4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3) (1.03 g,
34%) as a white solid: m/z 219 [M-H].sup.- (ES.sup.-).
Step (iii): 4-Hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid
(4)
##STR00404##
[0981] A suspension of
4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (1.03 g, 4.68
mmol) and Oxone.TM. (3.45 g, 5.61 mmol) in DMF (10 mL) was stirred
at RT for 2 h. The reaction mixture was diluted with EtOAc (40 mL)
and the solution was washed sequentially with 1M HCl (40 mL) and
brine (4.times.40 mL). The solvent was removed in vacuo and the
residue was purified by silica gel chromatography (80 g, 0-10% MeOH
in DCM) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic
acid (4) (392 mg, 35%) as a white solid: m/z 235 [M-H].sup.-
(ES.sup.-); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.01 (1H,
br s), 10.74 (1H, br s), 7.68 (2H, dd), 3.92 (3H, s).
Step (iv): 3,4-Dihydroxy-5-(trifluoromethyl)benzoic acid (5)
##STR00405##
[0983] Boron tribromide (392 .mu.L, 4.15 mmol) was added to a
suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid
(4) (392 mg, 1.66 mmol) in DCM (10 mL) at 0.degree. C. The reaction
mixture was allowed to warm to RT and stirred for 70 h. The
reaction mixture was cautiously added to stirring iced water (50
mL) and stirred for 10 min. The product was extracted with DCM
(2.times.20 mL), and then the combined organic extracts were washed
with brine (2.times.20 mL). The solvent was removed in vacuo and
the residue was purified by silica chromatography (12 g, 0-10% MeOH
in DCM) to afford 3,4-dihydroxy-5-(trifluoromethyl)benzoic acid (5)
(257 mg, 68%) as a white solid: m/z 221 [M-H].sup.- (ES.sup.-);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.83 (1H, br s),
10.45 (2H, br d), 7.56 (2H, dd).
Step (v): 3,4-Diisopropoxy-5-(trifluoromethyl)benzoic acid (6)
##STR00406##
[0985] 2-Bromopropane (380 .mu.L, 4.05 mmol) was added to a
suspension of 3,4-dihydroxy-5-(trifluoromethyl)benzoic acid (5)
(257 mg, 1.16 mmol) and K.sub.2CO.sub.3 (560 mg, 4.05 mmol) in DMF
(10 mL) and the reaction mixture was stirred at 80.degree. C. for
20 h. The reaction mixture was diluted with EtOAc (30 mL) and
washed sequentially with 1M HCl (30 mL) and brine (5.times.30 mL),
and then the solvent was removed in vacuo. The residue was
suspended in 2M sodium hydroxide (5.8 mL, 12 mmol) and the mixture
was stirred at 80.degree. C. for 4 h. Dioxane (10 mL) was added and
the mixture continued to stir at 80.degree. C. for a further 20 h.
The solvents were removed in vacuo and the residue was partitioned
between EtOAc (50 mL) and 1M HCl (50 mL). The phases were separated
and the organic solution was washed with brine (3.times.40 mL), and
then dried over MgSO.sub.4, and filtered. The solvent was removed
in vacuo and the residue was purified by silica chromatography (40
g, 0-15% MeOH in DCM) to afford
3,4-diisopropoxy-5-(trifluoromethyl)benzoic acid (6) (118 mg, 33%)
as a yellow solid.
Step (vi): Methyl
4-(3,4-diisopropoxy-5-(trifluoromethyl)benzamido)benzoate (8)
##STR00407##
[0987] Methyl
4-(3,4-diisopropoxy-5-(trifluoromethyl)benzamido)benzoate (8) (11
mg, 19%) was prepared from
3,4-diisopropoxy-5-(trifluoromethyl)benzoic acid (6) (40 mg, 0.13
.mu.mol) using a procedure essentially the same as in step (i) for
AAA-064 except that methyl 4-aminobenzoate (7) was used instead of
methyl 4-amino-2-fluorobenzoate: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 10.59 (1H, s), 8.02-7.88 (4H, m), 7.87-7.80
(2H, m), 5.12-5.01 (1H, m), 4.90-4.78 (1H, m), 3.85 (3H, s), 1.37
(6H, d), 1.24 (7H, d).
Step (vii):
4-(3,4-Diisopropoxy-5-(trifluoromethyl)benzamido)benzoic acid
(AAA-120)
##STR00408##
[0989] 4-(3,4-Diisopropoxy-5-(trifluoromethyl)benzamido)benzoic
acid (AAA-120) (8 mg, 71%) was prepared from methyl
4-(3,4-diisopropoxy-5-(trifluoromethyl)benzamido)benzoate (8) (11
mg, 25 .mu.mol) using a procedure essentially the same as in step
(ii) for AAA-001 except the mixture was stirred at 40.degree. C.
for 20 h: m/z 424 [M-H].sup.- (ES.sup.-); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.79 (1H, br s), 10.55 (1H, s), 7.95 (2H,
d), 7.87-7.82 (4H, m), 5.07 (1H, m), 4.85 (1H, m), 1.37 (6H, d),
1.24 (6H, d).
Biological Methods
Studies of Retinoic Acid Receptors
[0990] The inventors' have shown that RAR.alpha. agonists are
likely to be useful in the treatment of AD. They prevent neuronal
cell death in the presence of A.beta.42; in culture, they
up-regulate choline acetyltransferase (chAT), down-regulate amyloid
precursor protein (APP), and increase the expression of
disintegrin-metalloproteinases 10 (ADAM10). In vivo, the inventors'
have shown that feeding RAR.alpha. agonists to Tg2576 mice (which
overexpresses the Swedish mutation of the human APP leading to
amyloid .beta. deposits and cognitive decline) results in a
significant reduction in the levels of both A.beta.40 and
A.beta.42, as well as positive behavioural changes.
Materials and Methods:
Culture of Cortical Neurons and Survival Assays:
[0991] Neuronal cultures were prepared from embryonic E19 mouse
embryos. Fetal brain cortices were dissected and freed from
meninges. The cortices were placed in ice cold PBS containing 0.25%
glucose and triturated with fire polished Pasteur pipettes.
Cortical cells (1.times.10.sup.5) were plated onto poly-L-lysine
(10 .mu.g/mL) coated glass coverslips in 24-well tissue culture
plates. They were cultured in Neurobasal medium containing B27
supplement, 2 mM glutamine, 20 .mu.g/mL penicillin stepromycin, and
0.25% glucose. They were maintained for 7 days before been treated.
For each treatment, 3 coverslips were used and the experiment was
repeated 3 times.
[0992] Treatments consisted of 10 .mu.M A.beta.42 in the presence
of increasing dose of agonist: all-trans retinoic acid (atRA), BMS
194753 (RAR.alpha.), AM 580 (RAR.alpha.), CD 2019 (RAR.beta.), or
CD 437 (RAR.gamma.).
TABLE-US-00005 TABLE 1 RAR Agonists ##STR00409## ##STR00410##
##STR00411## ##STR00412## ##STR00413##
[0993] After 3 days of culture, media was removed and Hoechst 33342
(10 .mu.M) and propidium iodide (10 .mu.M) in PBS was added to the
wells for 15 minutes. Only neurons positive for Hoechst 33342 but
negative for propidium iodide were counted as surviving
neurons.
[0994] In addition, cortical cultures were treated with agonist
alone (0.1 .mu.M) and assayed for chAT, APP, and ADAM10. The
antibodies used were a chAT (1:200, Chemicon.TM.), .alpha. APP
(1:100, Chemicon.TM.) and a ADAM10 (1:200, Chemicon.TM.). Secondary
antibody used was anti-rabbit Cy3 or Cy5 conjugated (Jackson.TM.,
used at 1:1000). The nuclear marker DAPI (1 .mu.g/mL) was used to
stain all cells. Cell counts were carried out in 31 mm.sup.2 areas
per coverslip by an investigator who did not know the
treatments.
Animal Treatments:
[0995] Twenty seven 3 month old Tg2576 mice (Taconic.TM.) were
split into 3 groups of 9. One group was fed normal chow, the other
groups were fed with 1 mg/Kg RAR.alpha. agonist, either AM580 or
BMS194753. Animals were analysed at 6 and 9 months of age.
Tissue Preparation:
[0996] Animals were perfused with PBS. The brain was dissected and
one hemisegment was fixed in 4% PFA overnight, 20% sucrose for 3
days, embedded in OCT compound and stored frozen. The cortex was
removed form the other hemisegment and the protein extracted.
A.beta. Levels:
[0997] To measure A.beta.40 and A.beta.42 levels, a sandwich ELISA
assay kit (Biosource.TM.) was used according to the manufactures
instructions. A 1:5000 of the guanidine-soluble extracts were made
with TBS containing 5% BSA and 1.times. protease inhibitor
(Calbiochem.TM.) and centrifuged at 16000.times.g for 20 minutes at
4.degree. C. Samples were diluted 1:10000 in sample diluent
provided by the manufacturer. Samples were loaded in triplicate
(100 mL) and the plate read at 420 nm, by an investigator who did
not know the treatments.
Graphs and Statistics:
[0998] Graphs were plotted using Sigma Plot.TM.. Data were
expressed as mean+/-S.E.M and statistical analysis was carried out
using student's t test.
Results:
[0999] RAR.alpha. signalling prevents neuronal death in the
presence of A.beta.42:
[1000] Cortical cultures were treated after 7 days with 10 .mu.M
A.beta.42 and supplemented with 0.01-1 .mu.M of agonist. After 3
days, the number of surviving cells was determined. In the presence
of atRA, there was an increase in cell survival with increasing
dose of atRA as compared to the control cultures (treated only with
A.beta.42). As atRA is a weak pan-agonist of all the RARs, it was
decided to identify the specific receptor involved in this process
using RAR specific agonists. Neuronal survival was notably better
for each of two RAR.alpha.selective agonists (AM 580 and BMS
194753) but notably worse for RAR.beta. and RAR.gamma. selective
agonists (CD 2019 and CD 437, respectively). The data are
summarised in the following table. This suggests that it is
RAR.alpha. signalling that is required for neuronal survival in the
presence of A.beta.42.
TABLE-US-00006 TABLE 2 Effect of Increasing Dose of RAR Agonists on
Survival of Cortical Neurons in the Presence of 10 .mu.M A.beta.42
% Surviving Neurons 0.01 .mu.M 0.1 .mu.M 1.0 .mu.M Agonist agonist
agonist agonist atRA (pan-RAR) 53 .+-. 4 69 .+-. 4 82 .+-. 4 AM 580
(RAR.alpha.) 52 .+-. 7 70 .+-. 6 99 .+-. 9 BMS 194753 (RAR.alpha.)
57 .+-. 7 69 .+-. 3 88 .+-. 4 CD 2019 (RAR.beta.) 52 .+-. 3 58 .+-.
5 60 .+-. 5 CD 437 (RAR.gamma.) 53 .+-. 3 30 .+-. 11 26 .+-. 10
Control 1 (no A.beta.42) 100 .+-. 6 Control 2 (A.beta.42; 52 .+-. 7
no agonist)
RAR.alpha. Signalling Up-Regulates Chat Expression in Cultures of
E17 Cortical Neurons:
[1001] Cortical cultures were treated after 7 days with 0.1 .mu.M
of agonist, and analysed 3 days later. Only in the presence of
RAR.alpha. agonist was there a significant increase in choline
acetyltransferase (chAT) expression (and so an increase in the
number of chAT expressing neurons). The data are summarised in the
following table.
TABLE-US-00007 TABLE 3 Effect of Agonists on chAT Expression in
Cortical Neurons Agonist (0.01 .mu.M) Number of chAT Neurons
Control (no agonist) 5 .+-. 1 atRA 16 .+-. 2 BMS 194753
(RAR.alpha.) 37 .+-. 3 CD 2019 (RAR.beta.) 8 .+-. 1 CD 437
(RAR.gamma.) 2 .+-. 1
RAR.alpha. Signalling Down-Regulates App Expression in Cultures of
E17 Cortical Neurons:
[1002] Cortical cultures were treated after 7 days with 0.1 .mu.M
of agonist, and analysed 3 days later. Only in the presence of the
RAR.alpha. agonist was there a significant decrease in amyloid
precursor protein (APP) expression (and so a decrease in the number
of APP expressing neurons). The data are summarised in the
following table.
TABLE-US-00008 TABLE 4 Effect of Agonists on APP Expression in
Cortical Neurons Agonist (0.01 .mu.M) Number of APP Neurons Control
(no agonist) 27 .+-. 2 atRA 15 .+-. 2 BMS 194753 (RAR.alpha.) 10
.+-. 2 AM 580 (RAR.alpha.) 11 .+-. 2 CD 2019 (RAR.beta.) 23 .+-. 2
CD 437 (RAR.gamma.) 22 .+-. 3
RAR.alpha. signalling up-regulates ADAM10 expression in cultures of
E17 cortical neurons:
[1003] Cortical cultures were treated after 7 days with 0.1 .mu.M
of agonist, and analysed 3 days later. Only in the presence of the
RAR.alpha. agonist was there a significant increase in
disintegrin-metalloproteinases 10 (ADAM10) expression (and so an
increase in the number of ADAM10 expressing neurons). The data are
summarised in the following table.
TABLE-US-00009 TABLE 5 Effect of Agonists on APP Expression in
Cortical Neurons Agonist (0.01 .mu.M) Number of APP Neurons Control
(no agonist) 2 .+-. 0.5 atRA 11 .+-. 1.5 BMS 194753 (RAR.alpha.) 20
.+-. 2 AM 580 (RAR.alpha.) 19 .+-. 3 CD 2019 (RAR.beta.) 1 .+-. 0.5
CD 437 (RAR.gamma.) 2 .+-. 0.75
Oral Dosing of RAR.alpha. Agonist Down-Regulates A.beta.40 and
A.beta.42 Expression in the Tg2576 Mouse:
[1004] The above data taken together suggest that RAR.alpha.
signalling as opposed to RAR.beta. and RAR.gamma. signalling
regulates a number of genes involve in AD. In order to demonstrate
the usefulness of a RAR.alpha. agonists in vivo, a mouse model was
employed which shows many aspects of AD. These are Tg2576 mice,
which over-express the Swedish mutation of APP. These mice
overproduce A.beta.40 and A.beta.42. Three month old mice were fed
for 3 months with normal chow or chow supplemented with 1 mg/kg of
agonist. At six months of age, there is a dramatic decrease in both
A.beta.40 and A.beta.42 levels in the mice fed with the RAR.alpha.
agonist, as compared to the normal fed mice.
TABLE-US-00010 TABLE 6 Effect of Oral RAR.alpha. Agonist on
A.beta.40 and A.beta.42 in Tg2576 Mice Agonist % of A.beta.40 % of
A.beta.42 Control (no agonist) 100 .+-. 2 100 .+-. 4 AM 580
(RAR.alpha.) 4 .+-. 1 8 .+-. 1 BMS 194753 (RAR.alpha.) .sup. 3 .+-.
0.5 7 .+-. 1
Behavioural Outcomes:
[1005] It is well known in the field that the Tg2576 mice become
very aggressive with age and that this is one of the symptoms of
AD. It was noted in the above studies, that while it was necessary
to cage the control mice individually during the course of the
experiment due to their aggression, the mice treated with
RAR.alpha. agonist displayed little or no aggression such that they
could be caged together and displayed increased sexual activity.
These data suggest that orally administered RAR.alpha. agonist is
of therapeutic value in the treatment of AD.
Transactivation Assays for RAR.alpha., RAR.beta., and RAR.gamma.
Receptors
[1006] Transcriptional transactivation assays were performed with
gal4 fusion receptor constructs, created using each of the RAR
ligand binding domains, co-transfected with the pFR-luc
(Stratagene.TM.) reporter construct in COS-7 cells. Thus,
transfected cells will constitutively express the gal4-RAR fusion
protein which in turn may be transactivated by all trans retinoic
acid (atRA) to induce the expression of the luciferase that is
driven by a gal4UAS.
[1007] Briefly, on day 1, 96 well plates were seeded with 8000
cells per well then left to recover overnight. On day 2, the cells
were co-transfected with 100 ng of reporter plasmid and 10 ng of
the appropriate receptor plasmid per well using lipofectamine
(Invitrogen.TM.). On day 3, the lipofectamine containing media was
replaced by a DMEM without phenol red, followed by the addition of
test compound dissolved in 1 .mu.L of DMSO to each well's 100 .mu.L
total volume. Finally, on day 4, the cells were lysed and their
luciferase substrate was provided by the BrightGlo.TM. reagent
(Promega.TM.), the plates were then read on the MicroBeta
TriLux.TM. (Perkin Elmer.TM.)
[1008] On each plate, an 8 point dose-response curve of atRA was
run in duplicate and dose-response curves of test compounds were
also generated in duplicate.
[1009] EC.sub.50 data both for test compounds and atRA was
generated by fitting dose-response curves using GraphPad Prism.TM..
Data for test compounds are quoted as a ratio of the test compound
EC.sub.50 to that of atRA obtained on the same plate. Where
replicate data has been generated, the data are quoted as a ratio
of the mean EC.sub.50 from the separate experiments.
Biological Data
[1010] A number of compounds of the invention were examined using
the transactivation assay for RAR alpha, the transactivation assay
for RAR beta, and the transactivation assay for RAR gamma, as
described above.
[1011] For comparison purposes, data for several reference
compounds, XXX-01, XXX-02, and XXX-03, were also obtained. A key
structural feature of the compounds of the present invention is the
presence of particular subsituents (i.e., --R.sup.1, --R.sup.2, and
--R.sup.3) at the positions meta, para, and meta to the amide
linkage (i.e., -J-). The comparison compounds described herein were
selected because they are structurally similar to the compounds of
the present invention, but lack one of these three
substituents.
TABLE-US-00011 Comparison Compounds Code Number Structure XXX-01
##STR00414## XXX-02 ##STR00415## XXX-03 ##STR00416##
The data are summarised in the following table.
TABLE-US-00012 RAR.alpha. RAR.beta. RAR.alpha./ RAR.gamma. Code
activity activity RAR.beta. activity Number ratio ratio ratio (*)
ratio atRA 1 1 1 1 XXX-01 327 2570 7.9 inactive XXX-02 2242 -- --
-- XXX-03 90 642 7.1 inactive AAA-001 11 342 31.1 4700 AAA-002 50
2900 58.0 inactive AAA-003 15 139 9.3 1200 AAA-004 7 1420 202.9 820
AAA-005 68 3570 52.5 3770 AAA-006 14 1054 75.3 5840 AAA-007 25 2010
80.4 inactive AAA-008 26 4560 175.4 56900 AAA-009 29 2450 84.5 960
AAA-010 102 2530 24.8 inactive AAA-011 34 2960 87.1 21800 AAA-012
533 1300 2.4 inactive AAA-013 30 355 11.8 inactive AAA-014 58 1350
23.3 inactive AAA-015 20 540 27.0 inactive AAA-016 500 -- --
AAA-017 140 inactive >500 -- AAA-018 151 9660 64.0 inactive
AAA-019 0.9 74 82.2 136 AAA-020 108 214 2.0 inactive AAA-021 760 --
-- AAA-022 448 inactive >50 inactive AAA-023 5 404 80.8 62370
AAA-024 66 805 12.2 27200 AAA-025 5 131 26.2 inactive AAA-026 180
4920 27.3 inactive AAA-027 260 inactive >5 -- AAA-028 370 64000
173.0 inactive (PP-01) AAA-029 24 1920 80 inactive (PP-02) AAA-030
29 9525 328 5850 (PP-03) AAA-031 7 2930 420 6250 AAA-032 61 2700 44
16875 AAA-033 13 19 1.5 148 AAA-034 2 244 122 1250 AAA-035 0.30
2620 8700 87000 AAA-036 7.0 215 31 2438 AAA-037 0.25 324 1300
>2600 AAA-038 0.50 49 98 0.36 AAA-039 3.0 177 59 2985 AAA-040
1.1 60 55 194 AAA-041 5.4 238 44 31340 AAA-042 5.4 369 68 6000
AAA-043 2 53 27 688 AAA-044 1.7 55 32 571 AAA-045 7.3 283 39 3651
AAA-046 2.8 121 43 698 AAA-047 11 22 2 270 AAA-048 0.86 38 44 162
AAA-049 0.64 8460 13200 82 AAA-050 1.7 89 52 1386 AAA-051 0.97 43
45 2859 AAA-052 0.25 21 84 1923 AAA-053 4.2 1410 336 414 AAA-054
0.59 21 36 51 AAA-055 18 1926 107 69000 AAA-056 3.1 >770 >250
22 AAA-057 33 1226 37 4920 AAA-058 29 4200 145 550 AAA-059 27 2600
96 225 AAA-060 45 2267 50 30 AAA-061 44 5200 118 1531 AAA-062 85
714 8 5328 AAA-063 76 1686 22 6429 AAA-064 81 >3500 >40 1977
AAA-065 15 140 9 3521 AAA-066 32 7558 236 AAA-067 50 279 6 6047
AAA-068 7 976 140 60833 AAA-069 1.2 505 421 3380 AAA-070 3.4 2386
701 >62500 AAA-071 5.2 160 31 13333 AAA-072 9.4 2333 248 29474
AAA-073 19 117 6 220 AAA-074 154 32400 210 14500 AAA-075 4.7 1134
241 2394 AAA-076 5.3 1500 283 10833 AAA-077 6.7 4082 609 117857
AAA-078 0.7 103 147 8083 AAA-079 1.1 536 487 6786 AAA-080 1.6 318
200 17460 AAA-081 9.0 1453 161 >27000 AAA-082 25 6885 275
>56000 AAA-083 9 90 10 4390 AAA-084 26 6087 234 >1400 AAA-085
33 6923 210 >8300 AAA-086 2.1 7 3.1 1203 AAA-087 7 2000 286
11725 AAA-088 1.0 115 115 1706 AAA-089 1.3 510 392 2647 AAA-090 5.0
1250 250 367000 AAA-091 1.6 216 135 75000 AAA-092 2 53 27 1059
AAA-093 2.0 92 46 10833 AAA-094 0.23 656 2852 20000 AAA-095 2.7 92
34 812 AAA-096 3.2 215 67 7895 AAA-097 2.6 151 58 100000 AAA-098 12
433 36 2955 AAA-099 11 655 59 89 AAA-100 33 3273 99 11818 AAA-101
1.7 39 23 375 AAA-102 2.2 73 33 833 AAA-103 2.6 57 21 583 AAA-104
19 10164 535 5000 AAA-105 0.66 8.4 13 941 AAA-106 66 2245 34 2326
AAA-107 4.8 647 135 2833 AAA-108 5.1 1727 338 32500 AAA-109 4 1583
396 792000 AAA-110 16 1921 120 >12000 AAA-111 10 712 71 50000
AAA-112 2 2464 1212 1268 AAA-113 3.9 900 231 11093 AAA-114 4.4 100
23 22759 AAA-115 2.6 150 58 25172 AAA-116 4.5 208 46 55172 AAA-117
4 273 68 29730 AAA-118 36 1700 47 933333 AAA-119 26 5000 192
>42000 AAA-120 0.89 142 157 2162 (*) The ratio of the
"RAR.alpha. activity ratio" to the "RAR.beta. activity ratio" is
referred to as "RAR.alpha./RAR.beta. ratio" and reflects the
fold-selectivitity for RAR.alpha. over RAR.beta.. (In the above
table, "inactive" means that no agonist action was seen at the
highest concentration tested.)
[1012] All of the above AAA compounds were found to be agonists of
RAR.alpha.. Most of the AAA compounds have a RAR.alpha. activity
ratio (with respect to atRA) of less than about 200. Many of the
AAA compounds have a RAR.alpha. activity ratio of less than about
70. Many of the AAA compounds have a RAR.alpha. activity ratio of
less than about 30. Many of the AAA compounds have a RAR.alpha.
activity ratio of less than about 10. Many of the AAA compounds
have a RAR.alpha. activity ratio of less than about 5.
[1013] In addition, all of the above AAA compounds were found to be
selective for RAR.alpha. as compared to RAR.beta.. For most of the
AAA compounds, the selectivity for RAR.alpha. as compared to
RAR.beta. is by a factor or at least about 10 (e.g., the ratio of
the RAR.alpha. activity ratio to the RAR.beta. activity ratio is at
least about 10). For many of the AAA compounds, the selectivity for
RAR.alpha. as compared to RAR.beta. is by a factor of at least
about 20. For many of the AAA compounds, the selectivity for
RAR.alpha. as compared to RAR.beta. is by a factor of at least
about 50. For many of the AAA compounds, the selectivity for
RAR.alpha. as compared to RAR.beta. is by a factor of at least
about 100. For many of the AAA compounds, the selectivity for
RAR.alpha. as compared to RAR.beta. is by a factor of at least
about 200.
[1014] Indeed, many of the AAA compounds (e.g., AAA-001, AAA-004,
AAA-006, AAA-007, AAA-008, AAA-009, AAA-015, AAA-019, AAA-023,
AAA-025) provide at least a 3-fold increase in activity towards
RAR.alpha. (i.e., a RAR.alpha. activity ratio of less than about
30), as compared to the three reference compounds, while
simultaneously providing at least a 3-fold increase in RAR.alpha.
versus RAR.beta. selectivity (i.e., a RAR.alpha./RAR.beta. ratio
greater than about 25) as compared to the three reference
compounds.
[1015] In a comparison with compound XXX-01, compound AAA-025
provides a 65-fold increase in RAR.alpha. activity (i.e., 5 versus
327) while simultaneously providing a 3-fold increase in RAR.alpha.
versus RAR.beta. selectivity (i.e., 26.2 versus 7.9).
TABLE-US-00013 RAR.alpha. RAR.beta. RAR.alpha./ Code activity
activity RAR.beta. Number ratio ratio ratio (*) XXX-01 327 2570 7.9
AAA-025 5 131 26.2 (*) The ratio of the "RAR.alpha. activity ratio"
to the "RAR.beta. activity ratio" is referred to as
"RAR.alpha./RAR.beta. ratio" and reflects the fold-selectivitity
for RAR.alpha. over RAR.beta..
TABLE-US-00014 Code Number Structure XXX-01 ##STR00417## AAA-025
##STR00418##
[1016] Similarly, in a comparison with compound XXX-02, compound
AAA-022 provides a 5-fold increase in RAR.alpha. activity (i.e.,
448 versus 2242) while simultaneously providing a very high
selectivity for RAR.alpha. as compared to RAR.beta. selectivity
(i.e., >50).
TABLE-US-00015 RAR.alpha. RAR.beta. RAR.alpha./ Code activity
activity RAR.beta. Number ratio ratio ratio (*) XXX-02 2242 -- --
AAA-022 448 inactive >50 (*) The ratio of the "RAR.alpha.
activity ratio" to the "RAR.beta. activity ratio" is referred to as
"RAR.alpha./RAR.beta. ratio" and reflects the fold-selectivitity
for RAR.alpha. over RAR.beta..
TABLE-US-00016 Code Number Structure XXX-02 ##STR00419## AAA-022
##STR00420##
[1017] Similarly, in a comparison with compound XXX-03, each of
compounds AAA-001, AM-003, AAA-004, AAA-005, AAA-010, AAA-011,
AAA-019, AAA-029 (PP-02), and AAA-030 (PP-03) provides a comparable
or improved activity towards RAR.alpha. (i.e., from 0.9 to 102,
versus 90), while simultaneously providing improved RAR.alpha.
versus RAR.beta. selectivity (i.e., from 9.3 to 328, versus
7.1).
TABLE-US-00017 RAR.alpha. RAR.beta. RAR.alpha./ Code activity
activity RAR.beta. Number ratio Improvement ratio ratio (*)
Improvement XXX-03 90 -- 642 7.1 -- AAA-001 11 ~8.2-fold 342 31.1
~4.4-fold AAA-003 15 ~6.0-fold 139 9.3 ~1.3-fold AAA-004 7 ~13-fold
1420 203 ~29-fold AAA-005 68 ~1.3-fold 3570 52.5 ~7.4-fold AAA-010
102 ~0.9-fold 2530 24.8 ~3.5-fold AAA-011 34 ~2.6-fold 2960 87.1
~12-fold AAA-019 0.9 ~100-fold 74 82.2 ~12-fold AAA-029 24
~3.8-fold 1920 80.0 ~11-fold (PP-02) AAA-030 29 ~3.1-fold 9525 328
~46-fold (PP-03) (*) The ratio of the "RAR.alpha. activity ratio"
to the "RAR.beta. activity ratio" is referred to as
"RAR.alpha./RAR.beta. ratio" and reflects the fold-selectivitity
for RAR.alpha. over RAR.beta..
[1018] It may be noted that some of the compounds (e.g., AAA-001,
AAA-004, AAA-011, AAA-029, and AAA-030) provide both substantially
improved activity towards RAR.alpha. (i.e., from 7 to 34, versus
90), while simultaneously providing substantially improved
RAR.alpha. versus RAR.beta. selectivity (i.e., from 31 to 328,
versus 7.1).
TABLE-US-00018 Code Number Structure XXX- 003 ##STR00421## AAA- 001
##STR00422## AAA- 003 ##STR00423## AAA- 004 ##STR00424## AAA- 005
##STR00425## AAA- 010 ##STR00426## AAA- 011 ##STR00427## AAA- 019
##STR00428## AAA- 029 (PP-02) ##STR00429## AAA- 030 (PP-03)
##STR00430##
[1019] And so, for example, one preferred group of compounds (e.g.,
compounds for use in therapy, use of compounds in the manufacture
of a medicament, methods of treatment, etc.) are selected from
compounds of the following formula, and pharmaceutically acceptable
salts, hydrates, and solvates thereof:
##STR00431##
wherein: [1020] --R.sup.1 is independently --X or --R.sup.X; [1021]
--R.sup.2 is independently --O--R.sup.A or --O--R.sup.C; [1022]
--R.sup.3 is independently --X or --R.sup.X; wherein: [1023]
--Z.dbd. is --CR.sup.Z.dbd.; [1024] --R.sup.ZZ is independently --H
or --R.sup.ZZ; [1025] --R.sup.ZZ is independently saturated
aliphatic C.sub.1-4alkyl, --OH, or --F; wherein: [1026] each --X is
independently --Cl or --Br; [1027] each --R.sup.X is independently
saturated aliphatic C.sub.1-6haloalkyl; [1028] each --R.sup.A is
independently saturated aliphatic C.sub.1-6alkyl; [1029] each
--R.sup.C is independently saturated C.sub.3-7cycloalkyl.
[1030] In a further embodiment of the above, --R.sup.ZZ is
independently saturated aliphatic C.sub.1-4alkyl.
[1031] Similarly, for example, one preferred group of compounds
(e.g., compounds for use in therapy, use of compounds in the
manufacture of a medicament, methods of treatment, etc.) are
selected from compounds of the following formula, and
pharmaceutically acceptable salts, hydrates, and solvates
thereof:
##STR00432##
wherein: [1032] --R.sup.1 is independently --X; [1033] --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C; [1034] --R.sup.3 is
independently --X; wherein: [1035] --Z.dbd. is --CR.sup.Z.dbd.;
[1036] --R.sup.Z is independently --H or --R.sup.ZZ; [1037]
--R.sup.ZZ is independently saturated aliphatic C.sub.1-4alkyl,
--OH, or --F; wherein: [1038] each --X is independently --Cl or
--Br; [1039] each --R.sup.A is independently saturated aliphatic
C.sub.1-6alkyl; [1040] each --R.sup.C is independently saturated
C.sub.3-7cycloalkyl.
[1041] In a further embodiment of the above, --R.sup.ZZ is
independently saturated aliphatic C.sub.1-4alkyl.
[1042] Similarly, for example, one preferred group of compounds
(e.g., compounds for use in therapy, use of compounds in the
manufacture of a medicament, methods of treatment, etc.) are
selected from compounds of the following formula, and
pharmaceutically acceptable salts, hydrates, and solvates
thereof:
##STR00433##
wherein: [1043] --R.sup.1 is independently --X; [1044] --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C; [1045] --R.sup.3 is
independently --X; wherein: [1046] each --X is independently --Cl
or --Br; [1047] each --R.sup.A is independently saturated aliphatic
C.sub.1-6alkyl; [1048] each --R.sup.C is independently saturated
C.sub.3-7cycloalkyl.
[1049] It may be noted that some of the compounds (e.g., AAA-050,
AAA-051, AAA-080) provide both substantially improved activity
towards RAR.alpha. (i.e., from 0.97 to 1.7, versus 90), while
simultaneously providing substantially improved RAR.alpha. versus
RAR.beta. selectivity (i.e., from 45 to 200, versus 7.1).
TABLE-US-00019 AAA-050 ##STR00434## AAA-051 ##STR00435## AAA-080
##STR00436##
[1050] And so, for example, one preferred group of compounds (e.g.,
compounds for use in therapy, use of compounds in the manufacture
of a medicament, methods of treatment, etc.) are selected from
compounds of the following formula, and pharmaceutically acceptable
salts, hydrates, and solvates thereof:
##STR00437##
wherein: [1051] --R.sup.1 is independently --O--R.sup.A or
--O--R.sup.C; [1052] --R.sup.2 is independently --O--R.sup.A or
--O--R.sup.C; [1053] --R.sup.3 is independently --X; [1054] or:
[1055] --R.sup.1 is independently --X; [1056] --R.sup.2 is
independently --O--R.sup.A or --O--R.sup.C; [1057] --R.sup.3 is
independently --O--R.sup.A or --O--R.sup.C; wherein: [1058]
--Z.dbd. is --CR.sup.Z.dbd.; [1059] --R.sup.Z is independently --H
or --R.sup.ZZ; [1060] --R.sup.ZZ is independently saturated
aliphatic C.sub.1-4alkyl, --OH, or --F; wherein: [1061] each --X is
independently --Cl or --Br; [1062] each --R.sup.A is independently
saturated aliphatic C.sub.1-6alkyl; and [1063] each --R.sup.C is
independently saturated C.sub.3-7cycloalkyl.
[1064] In a further embodiment of the above, --R.sup.ZZ is
independently saturated aliphatic C.sub.1-4alkyl.
[1065] Similarly, for example, one preferred group of compounds
(e.g., compounds for use in therapy, use of compounds in the
manufacture of a medicament, methods of treatment, etc.) are
selected from compounds of the following formula, and
pharmaceutically acceptable salts, hydrates, and solvates
thereof:
##STR00438##
wherein: [1066] --R.sup.1 is independently --O--R.sup.A; [1067]
--R.sup.2 is independently --O--R.sup.A; [1068] --R.sup.3 is
independently --X; [1069] or: [1070] --R.sup.1 is independently
--X; [1071] --R.sup.2 is independently --O--R.sup.A; [1072]
--R.sup.3 is independently --O--R.sup.A; wherein: [1073] --Z.dbd.
is --CR.sup.Z.dbd.; [1074] --R.sup.Z is independently --H or
--R.sup.ZZ; [1075] --R.sup.ZZ is independently saturated aliphatic
C.sub.1-4alkyl, --OH, or --F; wherein: [1076] each --X is
independently --Cl or --Br; and [1077] each --R.sup.A is
independently saturated aliphatic C.sub.1-6alkyl.
[1078] In a further embodiment of the above, --R.sup.ZZ is
independently saturated aliphatic C.sub.1-4alkyl.
[1079] Similarly, for example, one preferred group of compounds
(e.g., compounds for use in therapy, use of compounds in the
manufacture of a medicament, methods of treatment, etc.) are
selected from compounds of the following formula, and
pharmaceutically acceptable salts, hydrates, and solvates
thereof:
##STR00439##
wherein: [1080] --R.sup.1 is independently --O--R.sup.A; [1081]
--R.sup.2 is independently --O--R.sup.A; [1082] --R.sup.3 is
independently --X; [1083] or: [1084] --R.sup.1 is independently
--X; [1085] --R.sup.2 is independently --O--R.sup.A; [1086]
--R.sup.3 is independently --O--R.sup.A; wherein: [1087] --Z.dbd.
is --CR.sup.Z.dbd.; [1088] --R.sup.Z is independently --H or
--R.sup.ZZ; [1089] --R.sup.ZZ is independently -Me, --OH, or --F;
wherein: [1090] each --X is independently --Cl; and [1091] each
--R.sup.A is independently saturated aliphatic C.sub.1-4alkyl.
[1092] In a further embodiment of the above, --R.sup.ZZ is
independently -Me.
[1093] The foregoing has described the principles, preferred
embodiments, and modes of operation of the present invention.
However, the invention should not be construed as limited to the
particular embodiments discussed. Instead, the above-described
embodiments should be regarded as illustrative rather than
restrictive, and it should be appreciated that variations may be
made in those embodiments by workers skilled in the art without
departing from the scope of the present invention.
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