U.S. patent application number 12/186308 was filed with the patent office on 2008-12-11 for ep4 receptor antagonists.
This patent application is currently assigned to Asterand UK Limited. Invention is credited to David Edward Clark, Kenneth Lyle Clark, Robert Alexander Coleman, Richard Jon Davis, Garry Fenton, Neil Victor Harris, George Hynd, Alexander William Oxford, Keith Alfred James Stuttle, Jonathan Mark Sutton.
Application Number | 20080306117 12/186308 |
Document ID | / |
Family ID | 29559424 |
Filed Date | 2008-12-11 |
United States Patent
Application |
20080306117 |
Kind Code |
A1 |
Clark; David Edward ; et
al. |
December 11, 2008 |
EP4 RECEPTOR ANTAGONISTS
Abstract
A compound of formula (I): ##STR00001## or a salt, solvate and
chemically protected form thereof, wherein one of R.sup.2 and
R.sup.5 is: (i) H or an optionally substituted C.sub.1-4 alkyl
group; or (ii) an optionally substituted C.sub.5-7 aryl; and the
other of R.sup.2 and R.sup.5 is the other group; m and n can be 0
or 1, and m+n=1 or 2 R.sup.N is H or optionally substituted
C.sub.1-4 alkyl R.sup.3 is either: (i) carboxy; (ii) a group of
formula (II): ##STR00002## (iii) a group of formula (III):
##STR00003## wherein R is optionally substituted C.sub.1-7 alkyl,
C.sub.5-20 aryl, or NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4
are independently selected from optionally substituted C.sub.1-4
alkyl; or (iv) tetrazol-5-yl.
Inventors: |
Clark; David Edward; (Essex,
GB) ; Harris; Neil Victor; (Essex, GB) ;
Fenton; Garry; (Essex, GB) ; Hynd; George;
(Essex, GB) ; Stuttle; Keith Alfred James; (Essex,
GB) ; Sutton; Jonathan Mark; (Essex, GB) ;
Oxford; Alexander William; (Hertfordshire, GB) ;
Davis; Richard Jon; (Hertfordshire, GB) ; Coleman;
Robert Alexander; (Hertfordshire, GB) ; Clark;
Kenneth Lyle; (Hertfordshire, GB) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
Asterand UK Limited
Hertfordshire
GB
|
Family ID: |
29559424 |
Appl. No.: |
12/186308 |
Filed: |
August 5, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10964831 |
Oct 15, 2004 |
7417068 |
|
|
12186308 |
|
|
|
|
60512200 |
Oct 20, 2003 |
|
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|
Current U.S.
Class: |
514/336 ;
514/378; 514/471; 546/284.7; 548/247; 549/487 |
Current CPC
Class: |
A61P 19/00 20180101;
A61P 25/06 20180101; A61P 25/04 20180101; A61P 37/02 20180101; A61P
43/00 20180101; A61P 19/02 20180101; C07D 307/68 20130101; A61P
29/00 20180101; A61P 25/00 20180101 |
Class at
Publication: |
514/336 ;
549/487; 514/471; 548/247; 514/378; 546/284.7 |
International
Class: |
A61K 31/443 20060101
A61K031/443; C07D 307/34 20060101 C07D307/34; A61K 31/341 20060101
A61K031/341; C07D 261/06 20060101 C07D261/06; A61P 29/00 20060101
A61P029/00; A61K 31/422 20060101 A61K031/422; C07D 405/02 20060101
C07D405/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 16, 2003 |
GB |
0324269.0 |
Claims
1. A compound of formula (I): ##STR00046## or a salt, solvate and
chemically protected form thereof, wherein: either R.sup.2 is H or
an optionally substituted C.sub.1-4 alkyl group and R.sup.5 is an
optionally substituted C.sub.5-7 aryl; or R.sup.5 is H or an
optionally substituted C.sub.1-4 alkyl group and R.sup.2 is an
optionally substituted C.sub.5-7 aryl; m and n can be 0 or 1, and
m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl
R.sup.3 is either carboxy or tetrazol-5-yl.
2. A compound according to claim 1, wherein R.sup.5 is the
optionally substituted C.sub.5-7 aryl group and R.sup.2 is H or the
optionally substituted C.sub.1-4 alkyl group.
3. A compound according to claim 2, wherein R.sup.2 is selected
from H or an optionally substituted C.sub.1-3 alkyl group.
4. A compound according to claim 3, wherein R.sup.2 is a methyl
group.
5. A compound according to claim 2, wherein R.sup.5 is a C.sub.6
aryl group.
6. A compound according to claim 5, wherein R.sup.5 is phenyl.
7. A compound according to claim 1 wherein the C.sub.5-7 aryl group
is substituted by substituents selected from C.sub.1-7 alkoxy
groups.
8. A compound according to claim 1, wherein n+m=1.
9. A compound according to claim 8, wherein n is 0 and m is 1.
10. A compound according to claim 1, wherein R.sup.N is H or
methyl.
11. A pharmaceutical composition comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof together with
a pharmaceutically acceptable carrier or diluent.
12. A method of treating a condition which can be alleviated by
antagonism of an EP.sub.4 receptor, which method comprises
administering to a patient in need of treatment an effective amount
of a compound of claim 1, or a pharmaceutically acceptable salt
thereof.
13. A method according to claim 12, wherein the condition which can
be alleviated by antagonism of an EP.sub.4 receptor is a primary
headache disorder.
14. A method according to claim 13, wherein the primary headache
disorder is a migraine.
15. A method of treating a condition which can be alleviated by
antagonism of an EP.sub.4 receptor, which method comprises
administering to a patient in need of treatment an effective amount
of a compound of claim formula (I), ##STR00047## or a
pharmaceutically acceptable salt thereof, wherein: either R.sup.2
is H or an optionally substituted C.sub.1-4 alkyl group and R.sup.5
is an optionally substituted C.sub.5-7 aryl; or R.sup.5 is H or an
optionally substituted C.sub.1-4 alkyl group and R.sup.2 is an
optionally substituted C.sub.5-7 aryl; m and n can be 0 or 1, and
m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl
R.sup.3 is either: (i) carboxy; (ii) a group of formula (II):
##STR00048## (iii) a group of formula (III): ##STR00049## wherein R
is optionally substituted C.sub.1-7 alkyl, C.sub.5-20 aryl, or
NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4 are independently
selected from optionally substituted C.sub.1-4 alkyl; or (iv)
tetrazol-5-yl.
16. A method of claim 15, wherein R.sup.5 is the optionally
substituted C.sub.5-7 aryl group and R.sup.2 is H or the optionally
substituted C.sub.1-4 alkyl group.
17. A method according to claim 16, wherein R.sup.2 is selected
from H or an optionally substituted C.sub.1-3 alkyl group.
18. A method according to claim 17, wherein R.sup.2 is a methyl
group.
19. A method according to claim 16, wherein R.sup.5 is a C.sub.6
aryl group.
20. A method according to claim 19, wherein R.sup.5 is phenyl.
21. A method according to claim 15 wherein the C.sub.5-7 aryl group
is substituted by substituents selected from C.sub.1-7 alkoxy
groups.
22. A method according to claim 15 wherein R.sup.3 is either: (i) a
group of formula (II): ##STR00050## (ii) a group of formula (III):
##STR00051##
23. A method according to claim 22, wherein R is selected from an
optionally substituted C.sub.5-20 aryl group, and an optionally
substituted C.sub.5-20 aryl-C.sub.1-7 alkyl group.
24. A method according to claim 22, wherein R is a C.sub.1-7 alkyl
group.
25. A method according to claim 15, wherein n+m=1.
26. A method according to claim 25, wherein n is 0 and m is 1.
27. A method according to claim 15, wherein R.sup.N is H or methyl.
Description
[0001] The present application is a divisional application of
application Ser. No. 10/964,831, filed Oct. 15, 2004 (allowed)
which claims benefit of U.S. provisional application Ser. No.
60/512,200, filed 20 Oct. 2003, and GB 0324269.0, filed 16 Oct.
2003, the entire contents of each of which is hereby incorporated
by reference.
[0002] This invention relates to EP.sub.4 receptor antagonists,
pharmaceutical compositions comprising such compounds, and the use
of such compounds and compositions to treat various diseases.
BACKGROUND TO THE INVENTION
[0003] Prostanoids comprise prostaglandins (PGs) and thromboxanes
(Txs) and their receptors fall into five different classes (DP, EP,
FP, IP and TP) based on their sensitivity to the five naturally
occurring prostanoids, PGD.sub.2, PGE.sub.2, PGF.sub.2.alpha.,
PGI.sub.2 and TxA.sub.2, respectively (Coleman, R. A., Prostanoid
Receptors. IUPHAR compendium of receptor characterisation and
classification, 2.sup.nd edition, 338-353, ISBN 0-9533510-3-3,
2000). EP receptors (for which the endogenous ligand is PGE.sub.2)
have been subdivided into four types termed EP.sub.1, EP.sub.2,
EP.sub.3 and EP.sub.4. These four types of EP receptors have been
cloned and are distinct at both a molecular and pharmacological
level (Coleman, R. A., 2000)
[0004] EP.sub.4 antagonists have been shown to be useful in the
treatment of pain, and in particular, in the treatment of primary
headache disorders, which include migraines, and secondary headache
disorders, such as drug-induced headaches (WO 00/18405 and WO
01/72302). Dilation of the cerebral vasculature and the subsequent
stimulation of pain stimulating, perivascular trigeminal sensory
afferent nerves is recognised to play an important role in the
pathophysiology of migraine. A sterile inflammatory response,
associated with activation of cycloxygenase and the generation of
PGE.sub.2, is also implicated in the pathophysiology of migraine.
PGE.sub.2 levels have been shown to be raised during migraine
attacks and PGE.sub.2 contributes to the pain of migraine by
directly dilating cerebral arteries and by stimulating the release
of vasoactive/pro-inflammatory peptides from the trigeminal nerves.
These effects of PGE.sub.2 are mediated in whole or in part by
EP.sub.4 receptors. Thus, by binding to and preventing the
stimulation of EP.sub.4 receptors, EP.sub.4 antagonists may be used
to treat the pain of migraine.
[0005] EP.sub.4 antagonists may also be useful in treating a number
of other conditions and diseases. For example, they may be used
in:
the treatment of pain associated with rheumatoid arthritis,
osteoarthritis, rheumatoid spondylitis, gouty arthritis and
juvenile arthritis; the treatment of musculoskeletal pain, lower
back and neck pain, sprains and strains, neuropathic pain,
sympathetically mediated pain, myositis, pain associated with
cancer and fibromyalgia, pain associated with influenza or other
viral infections, such as the common cold, rheumatic fever; pain
associated with bowel disorders such as non-ulcer dyspepsia,
irritable bowel syndrome; non-cardiac chest pain, pain associated
with myocardial ischaemia, post-operative pain, headache, toothache
and dysmenorrhea. Neuropathic pain syndromes include diabetic
neuropathy, sciatica, non-specific lower back pain, multiple
sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic
neuralgia, trigeminal neuralgia and pain resulting from physical
trauma; the treatment of inflammatory diseases including rheumatoid
and osteoarthritis, psoriasis, dermatitis, retinitis,
conjunctivitis, asthma, bronchitis, chronic obstructive pulmonary
disease, inflammatory bowel disease, colitis, nephritis, gingivitis
and hepatitis; the treatment of cancers including familial
adenomatous polyposis, endometrial carcinoma, colorectal and
cervical cancer; the treatment of bone disorders involving altered
bone formation or resorption such as osteoporosis; women's health
for the treatment of myometrial and endometrial disorders; the
treatment of gastrointestinal disease including diarrhoea; the
treatment of immunological disorders such as autoimmune disease,
immunological deficiency diseases, organ transplantation and
increasing the latency of HIV infection; the treatment of diseases
of abnormal platelet function. (e.g. occlusive vascular diseases);
the preparation of a drug with diuretic properties to treat or
prevent various oedema, hypertension, premenstrual tension, urinary
calculus, oliguria, hyperphosphaturia, mesangial proliferative
glomerulonephritis, chronic renal failure or the like; the
treatment of impotence or erectile dysfunction, and female sexual
dysfunction; the treatment of hair growth disorders; the treatment
of sleep disorders such as narcolepsy and insomnia; the treatment
of cardiovascular diseases and shock states associated with
hypotension (e.g. septic shock); the treatment of neurodegenerative
diseases and for preventing neuronal damage following stroke,
cardiac arrest, cardiopulmonary bypass, traumatic brain injury or
spinal cord injury; the treatment of tinnitus; the treatment of
dependence; and the treatment of complications of diabetes.
[0006] Although EP.sub.4 antagonists are known, it is desired to
find novel EP.sub.4 antagonists, and in particular, EP.sub.4
antagonists which are selective against other EP receptors, i.e.
EP.sub.1, EP.sub.2 and EP.sub.3.
SUMMARY OF THE INVENTION
[0007] A first aspect of the present invention provides a compound
of formula (I):
##STR00004##
or a salt, solvate and chemically protected form thereof,
wherein:
one of R.sup.2 and R.sup.5 is:
[0008] (i) H or an optionally substituted C.sub.1-4 alkyl group; or
(ii) an optionally substituted C.sub.5-7 aryl; and the other of
R.sup.2 and R.sup.5 is the other group; m and n can be 0 or 1, and
m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl
R.sup.3 is either: (i) carboxy; (ii) a group of formula (II):
##STR00005##
(iii) a group of formula (III):
##STR00006##
wherein R is optionally substituted C.sub.1-7 alkyl, C.sub.5-20
aryl, or NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4 are
independently selected from optionally substituted C.sub.1-4 alkyl;
or (iv) tetrazol-5-yl.
[0009] The compound is preferably not
N-(5-phenyl-2-methyl-3-furoyl)-p-aminophenylacetic acid, i.e.
R.sup.2=CH.sub.3, R.sup.5=phenyl, R.sup.N.dbd.H, n=0, m=1 and
R.sup.3=carboxy.
[0010] A second aspect of the present invention provides a compound
of formula (I) or a pharmaceutically acceptable salt thereof for
use in a method of therapy.
[0011] A third aspect of the present invention provides a
pharmaceutical composition comprising a compound of formula (I) as
defined in the first aspect or a pharmaceutically acceptable salt
thereof together with a pharmaceutically acceptable carrier or
diluent.
[0012] A further aspect of the present invention provides the use
of a compound of formula (I) or a pharmaceutically acceptable salt
thereof in the preparation of a medicament for the treatment of a
condition alleviated by antagonism of an EP.sub.4 receptor.
[0013] Another aspect of the present invention provides a method of
treating a condition which can be alleviated by antagonism of an
EP.sub.4 receptor, which method comprises administering to a
patient in need of treatment an effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt thereof.
[0014] Conditions which can be alleviated by antagonism of an
EP.sub.4 receptor are discussed above, and particularly include
primary headache disorders, most particularly migraines.
[0015] The present invention also provides methods of antagonizing
EP.sub.4 receptors, in vitro or in vivo, comprising contacting a
cell with an effective amount of a compound of formula (I).
[0016] In some embodiments, the compounds described above may be
selective as against antagonism of the other three EP receptors,
i.e. EP.sub.1, EP.sub.2 and EP.sub.3. This selectivity allows for
targeting of the effect of the compounds of the invention, with
possible benefits in the treatment of certain conditions.
DEFINITIONS
Monodentate Groups
[0017] (i.e groups with one point of covalent attachment)
[0018] Alkyl: The term "alkyl" as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from a
carbon atom of a hydrocarbon compound having from 1 to 7 carbon
atoms (unless otherwise specified), which may be aliphatic or
alicyclic, and which may be saturated or unsaturated. Thus, the
term "alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cylcoalkynyl, etc., discussed below.
[0019] In the context of alkyl groups, the prefixes (e.g.
C.sub.1-4, C.sub.1-7) denote the number of carbon atoms, or range
of number of carbon atoms. For example, the term "C.sub.1-4 alkyl"
as used herein, pertains to an alkyl group having from 1 to 4
carbon atoms. Examples of groups of alkyl groups include C.sub.1-4
alkyl ("lower alkyl") and C.sub.1-7 alkyl. Note that the first
prefix may vary according to other limitations; for example, for
unsaturated alkyl groups, the first prefix must be at least 2; for
cyclic alkyl groups, the first prefix must be at least 3; etc.
[0020] Examples of saturated alkyl groups include, but are not
limited to, methyl (C.sub.1), ethyl (C.sub.2), propyl (C.sub.3),
butyl (C.sub.4), pentyl (C.sub.5), hexyl (C.sub.6) and heptyl
(C.sub.7).
[0021] Examples of saturated linear alkyl groups include, but are
not limited to, methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), n-butyl (C.sub.4), n-pentyl (amyl) (C.sub.5), n-hexyl
(C.sub.6), and n-heptyl (C.sub.7).
[0022] Examples of saturated branched alkyl groups include
iso-propyl (C.sub.3), iso-butyl (C.sub.4), sec-butyl (C.sub.4),
tert-butyl (C.sub.4), iso-pentyl (C.sub.5), and neo-pentyl
(C.sub.5).
[0023] Alkenyl: The term "alkenyl" as used herein, pertains to an
alkyl group having one or more carbon-carbon double bonds. Examples
of alkenyl groups include C.sub.2-4 alkenyl and C.sub.2-7 alkenyl.
Examples of alkenyl groups include, but are not limited to, ethenyl
(vinyl, --CH.dbd.CH.sub.2), 1-propenyl (--CH.dbd.CH--CH.sub.3),
2-propenyl (allyl, --CH--CH.dbd.CH.sub.2), isopropenyl
(1-methylvinyl, --C(CH.sub.3).dbd.CH.sub.2), butenyl (C.sub.4),
pentenyl (C.sub.5), and hexenyl (C.sub.6).
[0024] Alkynyl: The term "alkynyl" as used herein, pertains to an
alkyl group having one or more carbon-carbon triple bonds. Examples
of groups of alkynyl groups include C.sub.2-4 alkynyl and C.sub.2-7
alkynyl. Examples of alkynyl groups include, but are not limited
to, ethynyl (ethinyl, --C.ident.CH) and 2-propynyl (propargyl,
--CH.sub.2--C.ident.CH).
[0025] Cycloalkyl: The term "cycloalkyl" as used herein, pertains
to an alkyl group which is also a cyclyl group; that is, a
monovalent moiety obtained by removing a hydrogen atom from an
alicyclic ring atom of a carbocyclic ring of a carbocyclic
compound, which carbocyclic ring may be saturated or unsaturated,
which moiety has from 3 to 7 carbon atoms (unless otherwise
specified), including from 3 to 7 ring atoms. Thus, the term
"cycloalkyl" includes the sub-classes cycloalkenyl and
cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms.
Examples of groups of cycloalkyl groups include C.sub.3-7
cycloalkyl.
[0026] Examples of cycloalkyl groups include, but are not limited
to, those derived from: [0027] saturated monocyclic hydrocarbon
compounds: cyclopropane (C.sub.3), cyclobutane (C.sub.4),
cyclopentane (C.sub.5), cyclohexane (C.sub.6), cycloheptane
(C.sub.7), methylcyclopropane (C.sub.4), dimethylcyclopropane
(C.sub.5), methylcyclobutane (C.sub.5), dimethylcyclobutane
(C.sub.6), methylcyclopentane (C.sub.6), dimethylcyclopentane
(C.sub.7), methylcyclohexane (C.sub.7); [0028] unsaturated
monocyclic hydrocarbon compounds: cyclopropene (C.sub.3),
cyclobutene (C.sub.4), cyclopentene (C.sub.5), cyclohexene
(C.sub.6), methylcyclopropene (C.sub.4), dimethylcyclopropene
(C.sub.5), methylcyclobutene (C.sub.5), dimethylcyclobutene
(C.sub.6), methylcyclopentene (C.sub.6), dimethylcyclopentene
(C.sub.7), methylcyclohexene (C.sub.7);
[0029] Heterocyclyl: The term "heterocyclyl" as used herein,
pertains to a monovalent moiety obtained by removing a hydrogen
atom from a ring atom of a heterocyclic compound, which moiety has
from 3 to 20 ring atoms (unless otherwise specified), of which from
1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7
ring atoms, of which from 1 to 4 are ring heteroatoms.
[0030] In this context, the prefixes (e.g. C.sub.3-20, C.sub.3-7,
C.sub.5-6, etc.) denote the number of ring atoms, or range of
number of ring atoms, whether carbon atoms or heteroatoms. For
example, the term "C.sub.5-6 heterocyclyl" as used herein, pertains
to a heterocyclyl group having 5 or 6 ring atoms. Examples of
groups of heterocyclyl groups include C.sub.3-20 heterocyclyl,
C.sub.5-20 heterocyclyl, C.sub.3-15 heterocyclyl, C.sub.5-15
heterocyclyl, C.sub.3-12 heterocyclyl, C.sub.5-12 heterocyclyl,
C.sub.3-10 heterocyclyl, C.sub.5-10 heterocyclyl, C.sub.3-7
heterocyclyl, C.sub.5-7 heterocyclyl, and C.sub.5-6
heterocyclyl.
[0031] Examples of monocyclic heterocyclyl groups include, but are
not limited to, those derived from:
N.sub.1: aziridine (C.sub.3), azetidine (C.sub.4), pyrrolidine
(tetrahydropyrrole) (C.sub.5), pyrroline (e.g., 3-pyrroline,
2,5-dihydropyrrole) (C.sub.5), 2H-pyrrole or 3H-pyrrole
(isopyrrole, isoazole) (C.sub.5), piperidine (C.sub.6),
dihydropyridine (C.sub.6), tetrahydropyridine (C.sub.6), azepine
(C.sub.7); O.sub.1: oxirane (C.sub.3), oxetane (C.sub.4), oxolane
(tetrahydrofuran) (C.sub.5), oxole (dihydrofuran) (C.sub.5), oxane
(tetrahydropyran) (C.sub.6), dihydropyran (C.sub.6), pyran
(C.sub.6), oxepin (C.sub.7); S.sub.1: thiirane (C.sub.3), thietane
(C.sub.4), thiolane (tetrahydrothiophene) (C.sub.5), thiane
(tetrahydrothiopyran) (C.sub.6), thiepane (C.sub.7); O.sub.2:
dioxolane (C.sub.5), dioxane (C.sub.6), and dioxepane (C.sub.7);
O.sub.3: trioxane (C.sub.6); N.sub.2: imidazolidine (C.sub.5),
pyrazolidine (diazolidine) (C.sub.5), imidazoline (C.sub.5),
pyrazoline (dihydropyrazole) (C.sub.5), piperazine (C.sub.6);
N.sub.1O.sub.1: tetrahydrooxazole (C.sub.5), dihydrooxazole
(C.sub.5), tetrahydroisoxazole (C.sub.5), dihydroisoxazole
(C.sub.5), morpholine (C.sub.6), tetrahydrooxazine (C.sub.6),
dihydrooxazine (C.sub.6), oxazine (C.sub.6); N.sub.1S.sub.1:
thiazoline (C.sub.5), thiazolidine (C.sub.5), thiomorpholine
(C.sub.6); N.sub.2O.sub.1: oxadiazine (C.sub.6); O.sub.1S.sub.1:
oxathiole (C.sub.5) and oxathiane (thioxane) (C.sub.6); and,
N.sub.1O.sub.1S.sub.1: oxathiazine (C.sub.6).
[0032] Aryl: The term "aryl" as used herein, pertains to a
monovalent moiety obtained by removing a hydrogen atom from an
aromatic ring atom of an aromatic compound, which moiety has from 3
to 20 ring atoms (unless otherwise specified). Preferably, each
ring has from 5 to 7 ring atoms.
[0033] In this context, the prefixes (e.g. C.sub.3-20, C.sub.5-7,
C.sub.5-6, etc.) denote the number of ring atoms, or range of
number of ring atoms, whether carbon atoms or heteroatoms. For
example, the term "C.sub.5-6 aryl" as used herein, pertains to an
aryl group having 5 or 6 ring atoms. Examples of groups of aryl
groups include C.sub.3-20 aryl, C.sub.5-20 aryl, C.sub.5-15 aryl,
C.sub.5-12 aryl, C.sub.5-10 aryl, C.sub.5-7 aryl, C.sub.5-6 aryl,
C.sub.5 aryl, and C.sub.6 aryl.
[0034] The ring atoms may be all carbon atoms, as in "carboaryl
groups". Examples of carboaryl groups include C.sub.3-20 carboaryl,
C.sub.5-20 carboaryl, C.sub.5-15 carboaryl, C.sub.5-12 carboaryl,
C.sub.5-10 carboaryl, C.sub.5-7 carboaryl, C.sub.5-6 carboaryl,
C.sub.5 carboaryl, and C.sub.6 carboaryl.
[0035] Examples of carboaryl groups include, but are not limited
to, those derived from benzene (i.e. phenyl) (C.sub.6), naphthalene
(C.sub.10), azulene (C.sub.10), anthracene (C.sub.14), phenanthrene
(C.sub.14), naphthacene (C.sub.18), and pyrene (C.sub.16).
[0036] Examples of aryl groups which comprise fused rings, at least
one of which is an aromatic ring, include, but are not limited to,
groups derived from indane (e.g., 2,3-dihydro-1H-indene) (C.sub.9),
indene (C.sub.9), isoindene (C.sub.9), tetraline
(1,2,3,4-tetrahydronaphthalene (C.sub.10), acenaphthene (C.sub.12),
fluorene (C.sub.13), phenalene (C.sub.13), acephenanthrene
(C.sub.15), and aceanthrene (C.sub.16).
[0037] Alternatively, the ring atoms may include one or more
heteroatoms, as in "heteroaryl groups". Examples of heteroaryl
groups include C.sub.3-20 heteroaryl, C.sub.5-20 heteroaryl,
C.sub.5-15 heteroaryl, C.sub.5-12 heteroaryl, C.sub.5-10
heteroaryl, C.sub.5-7 heteroaryl, C.sub.5-6 heteroaryl, C.sub.5
heteroaryl, and C.sub.6 heteroaryl.
[0038] Examples of monocyclic heteroaryl groups include, but are
not limited to, those derived from:
N.sub.1: pyrrole (azole) (C.sub.5), pyridine (azine) (C.sub.6);
O.sub.1: furan (oxole) (C.sub.5); S.sub.1: thiophene (thiole)
(C.sub.5); N.sub.1O.sub.1: oxazole (C.sub.5), isoxazole (C.sub.5),
isoxazine (C.sub.6); N.sub.2O.sub.1: oxadiazole (furazan)
(C.sub.5); N.sub.3O.sub.1: oxatriazole (C.sub.5); N.sub.1S.sub.1:
thiazole (C.sub.5), isothiazole (C.sub.5); N.sub.2: imidazole
(1,3-diazole) (C.sub.5), pyrazole (1,2-diazole) (C.sub.5),
pyridazine (1,2-diazine) (C.sub.6), pyrimidine (1,3-diazine)
(C.sub.6), pyrazine (1,4-diazine) (C.sub.6); N.sub.3: triazole
(C.sub.5), triazine (C.sub.6); and, N.sub.4: tetrazole
(C.sub.5).
[0039] Examples of heteroaryl groups which comprise fused rings,
include, but are not limited to: [0040] C.sub.9 (with 2 fused
rings) derived from benzofuran (O.sub.1), isobenzofuran (O.sub.1),
indole (N.sub.1), isoindole (N.sub.1), indolizine (N.sub.1),
indoline (N.sub.1), isoindoline (N.sub.1), purine (N.sub.4) (e.g.,
adenine, guanine), benzimidazole (N.sub.2), indazole (N.sub.2),
benzoxazole (N.sub.1O.sub.1), benzisoxazole (N.sub.1O.sub.1),
benzodioxole (O.sub.2), benzofurazan (N.sub.2O.sub.1),
benzotriazole (N.sub.3), benzothiofuran (S.sub.1), benzothiazole
(N.sub.1S.sub.1), benzothiadiazole (N.sub.2S); [0041] C.sub.10
(with 2 fused rings) derived from chromene (O.sub.1), isochromene
(O.sub.1), chroman (O.sub.1), isochroman (O.sub.1), benzodioxan
(O.sub.2), quinoline (N.sub.1), isoquinoline (N.sub.1), quinolizine
(N.sub.1), benzoxazine (N.sub.1O.sub.1), benzodiazine (N.sub.2),
pyridopyridine (N.sub.2), quinoxaline (N.sub.2), quinazoline
(N.sub.2), cinnoline (N.sub.2), phthalazine (N.sub.2),
naphthyridine (N.sub.2), pteridine (N.sub.4); [0042] C.sub.11 (with
2 fused rings) derived from benzodiazepine (N.sub.2); [0043]
C.sub.13 (with 3 fused rings) derived from carbazole (N.sub.1),
dibenzofuran (O.sub.1), dibenzothiophene (S.sub.1), carboline
(N.sub.2), perimidine (N.sub.2), pyridoindole (N.sub.2); and,
[0044] C.sub.14 (with 3 fused rings) derived from acridine
(N.sub.1), xanthene (O.sub.1), thioxanthene (S.sub.1), oxanthrene
(O.sub.2), phenoxathiin (O.sub.1S.sub.1), phenazine (N.sub.2),
phenoxazine (N.sub.1O.sub.1), phenothiazine (N.sub.1S.sub.1),
thianthrene (S.sub.2), phenanthridine (N.sub.1), phenanthroline
(N.sub.2), phenazine (N.sub.2).
[0045] If a heteroaryl or heterocyclyl group contains a nitrogen
ring atom, this ring atom, where possible, may be in a oxidised
state, as an N-oxide.
[0046] The above groups, whether alone or part of another
substituent, may themselves optionally be substituted with one or
more groups selected from themselves, the additional monodentate
substituents listed below and alkoxylene.
[0047] Halo: --F, --Cl, --Br, and --I.
[0048] Hydroxy: --OH.
[0049] Ether: --OR, wherein R is an ether substituent, for example,
a C.sub.1-7 alkyl group (also referred to as a C.sub.1-7 alkoxy
group, discussed below), a C.sub.3-20 heterocyclyl group (also
referred to as a C.sub.3-20 heterocyclyloxy group), or a C.sub.5-20
aryl group (also referred to as a C.sub.5-20 aryloxy group),
preferably a C.sub.1-7 alkyl group.
[0050] C.sub.1-7 alkoxy: --OR, wherein R is a C.sub.1-7 alkyl
group. Examples of C.sub.1-7 alkoxy groups include, but are not
limited to, --OMe (methoxy), --OEt (ethoxy), --O(nPr) (n-propoxy),
--O(iPr) (isopropoxy), --O(nBu) (n-butoxy), --O(sBu) (sec-butoxy),
--O(iBu) (isobutoxy), and --O(tBu) (tert-butoxy).
[0051] Oxo (keto, -one): .dbd.O.
[0052] Thione (thioketone): .dbd.S.
[0053] Imino (imine): .dbd.NR, wherein R is an imino substituent,
for example, hydrogen, C.sub.1-7 alkyl group, a C.sub.3-20
heterocyclyl group, or a C.sub.5-20 aryl group, preferably hydrogen
or a C.sub.1-7 alkyl group. Examples of imino groups include, but
are not limited to, .dbd.NH, .dbd.NMe, .dbd.NEt, and .dbd.NPh.
[0054] Formyl (carbaldehyde, carboxaldehyde): --C(.dbd.O)H.
[0055] Acyl (keto): --C(.dbd.O)R, wherein R is an acyl substituent,
for example, a C.sub.1-7 alkyl group (also referred to as C.sub.1-7
alkylacyl or C.sub.1-7 alkanoyl), a C.sub.3-20 heterocyclyl group
(also referred to as C.sub.3-20 heterocyclylacyl), or a C.sub.5-20
aryl group (also referred to as C.sub.5-20 arylacyl), preferably a
C.sub.1-7 alkyl group. Examples of acyl groups include, but are not
limited to, --C(.dbd.O)CH.sub.3 (acetyl),
--C(.dbd.O)CH.sub.2CH.sub.3 (propionyl),
--C(.dbd.O)C(CH.sub.3).sub.3 (t-butyryl), and --C(.dbd.O)Ph
(benzoyl, phenone).
[0056] Carboxy (carboxylic acid): --C(.dbd.O)OH.
[0057] Thiocarboxy (thiocarboxylic acid): --C(.dbd.S)SH.
[0058] Thiolocarboxy (thiolocarboxylic acid): --C(.dbd.O)SH.
[0059] Thionocarboxy (thionocarboxylic acid): --C(.dbd.S)OH.
[0060] Imidic acid: --C(.dbd.NH)OH.
[0061] Hydroxamic acid: --C(.dbd.NOH)OH.
[0062] Ester (carboxylate, carboxylic acid ester, oxycarbonyl):
--C(.dbd.O)OR, wherein R is an ester substituent, for example, a
C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a
C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples
of ester groups include, but are not limited to,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3,
--C(.dbd.O)OC(CH.sub.3).sub.3, and --C(.dbd.O)OPh.
[0063] Acyloxy (reverse ester): --OC(.dbd.O)R, wherein R is an
acyloxy substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of acyloxy groups
include, but are not limited to, --OC(.dbd.O)CH.sub.3 (acetoxy),
--OC(.dbd.O)CH.sub.2CH.sub.3, --OC(.dbd.O)C(CH.sub.3).sub.3,
--OC(.dbd.O)Ph, and --OC(.dbd.O)CH.sub.2Ph.
[0064] Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide):
--C(.dbd.O)NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are
independently amino substituents, as defined for amino groups.
Examples of amido groups include, but are not limited to,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --C(.dbd.O)NHCH.sub.2CH.sub.3, and
--C(.dbd.O)N(CH.sub.2CH.sub.3).sub.2, as well as amido groups in
which R.sup.1 and R.sup.2, together with the nitrogen atom to which
they are attached, form a heterocyclic structure as in, for
example, piperidinocarbonyl, morpholinocarbonyl,
thiomorpholinocarbonyl, and piperazinocarbonyl.
[0065] Acylamino: --NR.sup.1C(.dbd.O)R.sup.2, wherein R.sup.1 is an
amide substituent, for example, hydrogen, a C.sub.1-7 alkyl group,
a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably hydrogen or a C.sub.1-7 alkyl group, and R.sup.2 is an
acyl substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably hydrogen or a C.sub.1-7 alkyl group. Examples of
acylamide groups include, but are not limited to,
--NHC(.dbd.O)CH.sub.3, --NHC(.dbd.O)CH.sub.2CH.sub.3, and
--NHC(.dbd.O)Ph. R.sup.1 and R.sup.2 may together form a cyclic
structure, as in, for example, succinimidyl, maleimidyl, and
phthalimidyl:
##STR00007##
[0066] Thioamido (thiocarbamyl): --C(.dbd.S)NR.sup.1R.sup.2,
wherein R.sup.1 and R.sup.2 are independently amino substituents,
as defined for amino groups. Examples of thioamido groups include,
but are not limited to, --C(.dbd.S)NH.sub.2, --C(.dbd.S)NHCH.sub.3,
--C(.dbd.S)N(CH.sub.3).sub.2, and
--C(.dbd.S)NHCH.sub.2CH.sub.3.
[0067] Ureido: --N(R.sup.1)CONR.sup.2R.sup.3 wherein R.sup.2 and
R.sup.3 are independently amino substituents, as defined for amino
groups, and R.sup.1 is a ureido substituent, for example, hydrogen,
a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a
C.sub.5-20 aryl group, preferably hydrogen or a C.sub.1-7 alkyl
group. Examples of ureido groups include, but are not limited to,
--NHCONH.sub.2, --NHCONHMe, --NHCONHEt, --NHCONMe.sub.2,
--NHCONEt.sub.2, --NMeCONH.sub.2, --NMeCONHMe, --NMeCONHEt,
--NMeCONMe.sub.2, and --NMeCONEt.sub.2.
[0068] Guanidino: --NH--C(.dbd.NH)NH.sub.2.
[0069] Tetrazolyl: a five membered aromatic ring having four
nitrogen atoms and one carbon atom,
##STR00008##
[0070] Amino: --NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are
independently amino substituents, for example, hydrogen, a
C.sub.1-7 alkyl group (also referred to as C.sub.1-7 alkylamino or
di-C.sub.1-7 alkylamino), a C.sub.3-20 heterocyclyl group, or a
C.sub.5-20aryl group, preferably H or a C.sub.1-7 alkyl group, or,
in the case of a "cyclic" amino group, R.sup.1 and R.sup.2, taken
together with the nitrogen atom to which they are attached, form a
heterocyclic ring having from 4 to 8 ring atoms. Amino groups may
be primary (--NH.sub.2), secondary (--NHR.sup.1), or tertiary
(--NHR.sup.1R.sup.2), and in cationic form, may be quaternary
(--.sup.+NR.sup.1R.sup.2R.sup.3). Examples of amino groups include,
but are not limited to, --NH.sub.2, --NHCH.sub.3,
--NHC(CH.sub.3).sub.2, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, and --NHPh. Examples of cyclic amino
groups include, but are not limited to, aziridino, azetidino,
pyrrolidino, piperidino, piperazino, morpholino, and
thiomorpholino.
[0071] Amidine (amidino): --C(.dbd.NR)NR.sub.2, wherein each R is
an amidine substituent, for example, hydrogen, a C.sub.1-7 alkyl
group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably H or a C.sub.1-7 alkyl group. Examples of amidine groups
include, but are not limited to, --C(.dbd.NH)NH.sub.2,
--C(.dbd.NH)NMe.sub.2, and --C(.dbd.NMe)NMe.sub.2.
[0072] Nitro: --NO.sub.2.
[0073] Nitroso: --NO.
[0074] Cyano (nitrile, carbonitrile): --CN.
[0075] Sulfhydryl (thiol, mercapto): --SH.
[0076] Thioether (sulfide): --SR, wherein R is a thioether
substituent, for example, a C.sub.1-7 alkyl group (also referred to
as a C.sub.1-7 alkylthio group), a C.sub.3-20 heterocyclyl group,
or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group.
Examples of C.sub.1-7 alkylthio groups include, but are not limited
to, --SCH.sub.3 and --SCH.sub.2CH.sub.3.
[0077] Disulfide: --SS--R, wherein R is a disulfide substituent,
for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl
group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl
group (also referred to herein as C.sub.1-7 alkyl disulfide).
Examples of C.sub.1-7 alkyl disulfide groups include, but are not
limited to, --SSCH.sub.3 and --SSCH.sub.2CH.sub.3.
[0078] Sulfine (sulfinyl, sulfoxide): --S(.dbd.O)R, wherein R is a
sulfine substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of sulfine groups
include, but are not limited to, --S(.dbd.O)CH.sub.3 and
--S(.dbd.O)CH.sub.2CH.sub.3.
[0079] Sulfone (sulfonyl): --S(.dbd.O).sub.2R, wherein R is a
sulfone substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group, including, for example, a
fluorinated or perfluorinated C.sub.1-7 alkyl group. Examples of
sulfone groups include, but are not limited to,
--S(.dbd.O).sub.2CH.sub.3 (methanesulfonyl, mesyl),
--S(.dbd.O).sub.2CF.sub.3 (triflyl),
--S(.dbd.O).sub.2CH.sub.2CH.sub.3 (esyl),
--S(.dbd.O).sub.2C.sub.4F.sub.9 (nonaflyl),
--S(.dbd.O).sub.2CH.sub.2CF.sub.3 (tresyl),
--S(.dbd.O).sub.2CH.sub.2CH.sub.2NH.sub.2 (tauryl),
--S(.dbd.O).sub.2Ph (phenylsulfonyl, besyl), 4-methylphenylsulfonyl
(tosyl), 4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl
(brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl),
and 5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).
[0080] Sulfinic acid (sulfino): --S(.dbd.O)OH, --SO.sub.2H.
[0081] Sulfonic acid (sulfo): --S(.dbd.O).sub.2OH, --SO.sub.3H.
[0082] Sulfinate (sulfinic acid ester): --S(.dbd.O)OR; wherein R is
a sulfinate substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of sulfinate groups
include, but are not limited to, --S(.dbd.O)OCH.sub.3
(methoxysulfinyl; methyl sulfinate) and
--S(.dbd.O)OCH.sub.2CH.sub.3 (ethoxysulfinyl; ethyl sulfinate).
[0083] Sulfinyloxy: --OS(.dbd.O)R, wherein R is a sulfinyloxy
substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20
heterocyclyl group, or a C.sub.5-20 aryl group, preferably a
C.sub.1-7 alkyl group. Examples of sulfinyloxy groups include, but
are not limited to, --OS(.dbd.O)CH.sub.3 and
--OS(.dbd.O)CH.sub.2CH.sub.3.
[0084] Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide):
--S(.dbd.O)NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are
independently amino substituents, as defined for amino groups.
Examples of sulfamyl groups include, but are not limited to,
--S(.dbd.O)NH.sub.2, --S(.dbd.O)NH(CH.sub.3),
--S(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)NH(CH.sub.2CH.sub.3),
--S(.dbd.O)N(CH.sub.2CH.sub.3).sub.2, and --S(.dbd.O)NHPh.
[0085] Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide)
--S(.dbd.O).sub.2NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are
independently amino substituents, as defined for amino groups.
Examples of sulfonamido groups include, but are not limited to,
--S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2NH(CH.sub.3),
--S(.dbd.O).sub.2N(CH.sub.3).sub.2,
--S(.dbd.O).sub.2NH(CH.sub.2CH.sub.3),
--S(.dbd.O).sub.2N(CH.sub.2CH.sub.3).sub.2, and
--S(.dbd.O).sub.2NHPh.
[0086] Sulfonamino: --NR.sup.1S(.dbd.O).sub.2R, wherein R.sup.1 is
an amino substituent, as defined for amino groups, and R is a
sulfonamino substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of sulfonamino groups
include, but are not limited to, --NHS(.dbd.O).sub.2CH.sub.3 and
--N(CH.sub.3)S(.dbd.O).sub.2C.sub.6H.sub.5.
[0087] Sulfinamino: --NR.sup.1S(.dbd.O)R, wherein R.sup.1 is an
amino substituent, as defined for amino groups, and R is a
sulfinamino substituent, for example, a C.sub.1-7 alkyl group, a
C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group,
preferably a C.sub.1-7 alkyl group. Examples of sulfinamino groups
include, but are not limited to, --NHS(.dbd.O)CH.sub.3 and
--N(CH.sub.3)S(.dbd.O)C.sub.6H.sub.5.
[0088] As already mentioned, the above described groups may be
substituted, and particular examples include, but are not limited
to, C.sub.3-20 aryl-C.sub.1-7 alkyl groups, which include benzyl
(phenylmethyl, PhCH.sub.2--), benzhydryl (Ph.sub.2CH--), trityl
(triphenylmethyl, Ph.sub.3C--), phenethyl (phenylethyl,
Ph-CH.sub.2CH.sub.2--), styryl (Ph-CH.dbd.CH--) and cinnamyl
(Ph-CH.dbd.CH--CH.sub.2--).
Bidentate Groups
[0089] (i.e. groups with two points of covalent attachment; linking
groups)
[0090] Alkylene: The term "C.sub.1-3 alkylene", as used herein,
pertains to a bidentate moiety obtained by removing two hydrogen
atoms from each of two different carbon atoms, of a linear
hydrocarbon compound having from 1 to 3 carbon atoms, which may be
saturated or unsaturated. Thus, the term "alkylene" includes the
sub-classes alkenylene and alkynylene.
[0091] In this context, the prefix C.sub.1-3 denotes the number of
carbon atoms, or range of number of carbon atoms.
[0092] Examples of saturated C.sub.1-3 alkylene groups include
--CH.sub.2-(methylene), --CH.sub.2CH.sub.2-- (ethylene) and
--CH.sub.2CH.sub.2CH.sub.2-- (propylene).
[0093] Examples of unsaturated C.sub.1-3 alkylene groups (which may
be termed "C.sub.2-3 alkenylene" or "C.sub.2-3 alkynylene", as
appropriate) include --CH.dbd.CH-- (vinylene),
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--, --C.ident.C--,
--C.ident.C--CH.sub.2-- and --CH.sub.2--C.ident.C--.
[0094] The C.sub.1-3 alkylene group may be substituted by any
monodentate substituent described above.
[0095] Alkoxylene: The term "alkoxylene," as used herein, pertains
to a bidentate group of formula --O(CH.sub.2).sub.nO--, where n is
1 or 2.
Includes Other Forms
[0096] Unless otherwise specified, included in the above are the
well known ionic, salt, solvate, and protected forms of these
substituents. For example, a reference to carboxylic acid (--COOH)
also includes the anionic (carboxylate) form (--COO.sup.-), a salt
or solvate thereof, as well as conventional protected forms.
Similarly, a reference to an amino group includes the protonated
form (--N.sup.+HR.sup.1R.sup.2), a salt or solvate of the amino
group, for example, a hydrochloride salt, as well as conventional
protected forms of an amino group. Similarly, a reference to a
hydroxyl group also includes the anionic form (--O.sup.-), a salt
or solvate thereof, as well as conventional protected forms of a
hydroxyl group.
Isomers, Salts, Solvates and Protected Forms
[0097] Certain compounds may exist in one or more particular
geometric, optical, enantiomeric, diasteriomeric, epimeric,
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").
[0098] 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).
[0099] 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/hyroxyazo, and nitro/aci-nitro.
##STR00009##
[0100] 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.
[0101] Unless otherwise specified, a reference to a particular
compound includes all such isomeric forms, including (wholly or
partially) racemic and other 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.
[0102] Unless otherwise specified, a reference to a particular
compound also includes ionic, salt, solvate, and protected forms of
thereof, for example, as discussed below.
[0103] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding salt of the active compound, for example, a
pharmaceutically-acceptable salt. Examples of pharmaceutically
acceptable salts are discussed in Berge, et al., J. Pharm. Sci.,
66, 1-19 (1977).
[0104] 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.+.
[0105] 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.
[0106] 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, glucoheptonic, 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.
[0107] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding solvate of the active compound. The term
"solvate" is used herein in the conventional sense to refer to a
complex of solute (e.g., active compound, salt of active 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.
[0108] It may be convenient or desirable to prepare, purify, and/or
handle the active 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. Green and
P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
[0109] 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.
[0110] 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).
[0111] 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.
[0112] For example, an amine group may be protected, for example,
as an amide (--NRCO--R) or a urethane (--NRCO--OR), for example,
as: an acetamide (--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.).
[0113] For example, a carboxylic acid group may be protected as an
ester for example, as: an C.sub.1-7 alkyl ester (e.g., a methyl
ester; a t-butyl ester); a C.sub.1-7 haloalkyl ester (e.g., a
C.sub.1-7 trihaloalkyl ester); a triC.sub.1-7 alkylsilyl-C.sub.1-7
alkyl ester; or a C.sub.5-20 aryl-C.sub.1-7 alkyl ester (e.g. a
benzyl ester; a nitrobenzyl ester); or as an amide, for example, as
a methyl amide.
[0114] 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).
[0115] 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,
amelioration of the condition, and cure of the condition. Treatment
as a prophylactic measure (i.e. prophylaxis) is also included.
[0116] The term "therapeutically-effective amount", as used herein,
pertains to that amount of an active compound, or a material,
composition or dosage form comprising an active 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.
Suitable dose ranges will typically be in the range of from 0.01 to
20 mg/kg/day, preferably from 0.1 to 10 mg/kg/day.
Compositions and their Administration
[0117] Compositions may be formulated for any suitable route and
means of administration. Pharmaceutically acceptable carriers or
diluents include those used in formulations suitable for oral,
rectal, nasal, topical (including buccal and sublingual), vaginal
or parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural) administration. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0118] For solid compositions, conventional non-toxic solid
carriers include, for example, pharmaceutical grades of mannitol,
lactose, cellulose, cellulose derivatives, starch, magnesium
stearate, sodium saccharin, talcum, glucose, sucrose, magnesium
carbonate, and the like may be used. The active compound as defined
above may be formulated as suppositories using, for example,
polyalkylene glycols, acetylated triglycerides and the like, as the
carrier. Liquid pharmaceutically administrable compositions can,
for example, be prepared by dissolving, dispersing, etc, an active
compound as defined above and optional pharmaceutical adjuvants in
a carrier, such as, for example, water, saline aqueous dextrose,
glycerol, ethanol, and the like, to thereby form a solution or
suspension. If desired, the pharmaceutical composition to be
administered may also contain minor amounts of non-toxic auxiliary
substances such as wetting or emulsifying agents, pH buffering
agents and the like, for example, sodium acetate, sorbitan
monolaurate, triethanolamine sodium acetate, sorbitan monolaurate,
triethanolamine oleate, etc. Actual methods of preparing such
dosage forms are known, or will be apparent, to those skilled in
this art; for example, see Remington's Pharmaceutical Sciences,
20th edition, pub. Lippincott, Williams & Wilkins, 2000. The
composition or formulation to be administered will, in any event,
contain a quantity of the active compound(s) in an amount effective
to alleviate the symptoms of the subject being treated.
[0119] Dosage forms or compositions containing active ingredient in
the range of 0.25 to 95% with the balance made up from non-toxic
carrier may be prepared.
[0120] For oral administration, a pharmaceutically acceptable
non-toxic composition is formed by the incorporation of any of the
normally employed excipients, such as, for example, pharmaceutical
grades of mannitol, lactose, cellulose, cellulose derivatives,
sodium crosscarmellose, starch, magnesium stearate, sodium
saccharin, talcum, glucose, sucrose, magnesium carbonate, and the
like. Such compositions take the form of solutions, suspensions,
tablets, pills, capsules, powders, sustained release formulations
and the like. Such compositions may contain 1%-95% active
ingredient, more preferably 2-50%, most preferably 5-8%.
[0121] Parenteral administration is generally characterized by
injection, either subcutaneously, intramuscularly or intravenously.
Injectables can be prepared in conventional forms, either as liquid
solutions or suspensions, solid forms suitable for solution or
suspension in liquid prior to injection, or as emulsions. Suitable
excipients are, for example, water, saline, dextrose, glycerol,
ethanol or the like. In addition, if desired, the pharmaceutical
compositions to be administered may also contain minor amounts of
non-toxic auxiliary substances such as wetting or emulsifying
agents, pH buffering agents and the like, such as for example,
sodium acetate, sorbitan monolaurate, triethanolamine oleate,
triethanolamine sodium acetate, etc.
[0122] The percentage of active compound contained in such parental
compositions is highly dependent on the specific nature thereof, as
well as the activity of the compound and the needs of the subject.
However, percentages of active ingredient of 0.1% to 10% in
solution are employable, and will be higher if the composition is a
solid which will be subsequently diluted to the above percentages.
Preferably, the composition will comprise 0.2-2% of the active
agent in solution.
Acronyms
[0123] For convenience, many chemical moieties are represented
using well known abbreviations, including but not limited to,
methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl
(nBu), sec-butyl (sBu), iso-butyl (iBu), tert-butyl (tBu), n-hexyl
(nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl
(Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz),
and acetyl (Ac).
[0124] For convenience, many chemical compounds are represented
using well known abbreviations, including but not limited to,
methanol (MeOH), ethanol (EtOH), iso-propanol (i-PrOH), methyl
ethyl ketone (MEK), ether or diethyl ether (Et.sub.2O), acetic acid
(AcOH), dichloromethane (methylene chloride, DCM), acetonitrile
(ACN), trifluoroacetic acid (TFA), dimethylformamide (DMF),
tetrahydrofuran (THF), and dimethylsulfoxide (DMSO).
General Synthesis Methods
[0125] Compounds of the invention wherein R.sup.3 is of formula
(II):
##STR00010##
may be synthesised from the analogous compound of the invention
wherein R.sup.3 is carboxy, by reaction with a compound of formula
1:
##STR00011##
in basic conditions, preferably aided by a coupling agent, for
example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride.
[0126] Compounds of the invention wherein R.sup.3 is of formula
(III):
##STR00012##
may be synthesized from a compound of formula 2:
##STR00013##
by reaction with a compound of formula 3:
##STR00014##
wherein X is either OH or halo, where if X is OH, the use of basic
conditions and a coupling agent is preferred.
[0127] Compounds where R.sup.3 is tetrazol-5-yl may be synthesised
from compounds of formula 4:
##STR00015##
by treatment with sodium azide in the presence of a base. Compounds
of formula 4 may be synthesised by coupling compounds of Formula 5
and Formula 6a.
##STR00016##
[0128] Such a coupling step may be carried out using a coupling
agent, for example,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
[0129] Compounds where R.sup.3 is carboxy, may be synthesised from
compounds of formula 7:
##STR00017##
where R.sup.O is typically a C.sub.1-4 alkyl group, by a hydrolysis
reaction, for example, using sodium hydroxide.
[0130] Compounds of formula 7 can be synthesised by coupling
compounds of formula 5 and 6b:
##STR00018##
[0131] Such a coupling step may be carried out as described above,
by using a coupling agent, for example,
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
[0132] In compounds of formula 5, if R.sup.5 is an aryl group, then
these may be synthesised from compounds of formula 8:
##STR00019##
by a Suzuki coupling of a compound of formula 9a (or equivalent
ester of formula 9b):
##STR00020##
[0133] The Suzuki coupling may be achieved using, for example,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) as the
palladium catalyst.
[0134] Compounds of Formula 8 may be synthesised from compounds of
formula 10:
##STR00021##
by treating the compound of formula 10 with a brominating agent,
such as pyridinium tribromide.
[0135] Compounds where R.sup.2 or R.sup.5 is a phenyl group
substituted by --O--CHF.sub.2, can be synthesised from the
corresponding compound where the phenyl group is substituted by
--OH, by treating this compound with a base and
chlorodifluoromethane.
Preferences
[0136] The following preferences may be combined with one another,
and may be different for each aspect of the present invention.
[0137] R.sup.5 is preferably the optionally substituted C.sub.5-7
aryl group and R.sup.2 is preferably H or the optionally
substituted C.sub.1-4 alkyl group.
[0138] R.sup.2 is preferably selected from H or an optionally
substituted C.sub.1-3 alkyl group, more preferably H, methyl,
CF.sub.3 or iso-propyl, and most preferably R.sup.2 is a methyl
group.
[0139] R.sup.5 is preferably a C.sub.6 aryl group, and is more
preferably phenyl. R.sup.5 may be substituted, and preferred
substituents include C.sub.1-7 alkoxy groups, more preferably
C.sub.1-4 alkoxy groups, e.g. --OMe, --OCF.sub.3, --OEt,
--OCHF.sub.2, with --OCHF.sub.2 being the most preferred.
[0140] R.sup.3 is preferably either:
(i) a group of formula (II):
##STR00022##
(ii) a group of formula (III):
##STR00023##
with a group of formula (II) being more preferred. In some
embodiments, R.sup.3 is preferably carboxy.
[0141] Where R.sup.3 is of formula (II) or (III), R is preferably
selected from an optionally substituted C.sub.5-20 aryl group, and
an optionally substituted C.sub.5-20 aryl-C.sub.1-7 alkyl group,
wherein the C.sub.1-7 alkyl group is more preferably methyl. In
these groups the C.sub.5-20 aryl group is preferably a C.sub.6 aryl
group. Such groups may preferably be substituted with C.sub.1-4
alkyl groups, such as methyl and hydroxy or halo groups, for
example, fluoro. Thus, preferred R groups include, but are not
limited to: phenyl; benzyl; 2-fluoro-phenyl; 4-hydroxy-phenyl;
2-trifluoromethyl-phenyl; 5-methyl-pyrid-2-yl.
[0142] If R in formula (II) or (III) is a C.sub.1-7 alkyl group, it
is more preferably a C.sub.1-4 alkyl group, for example methyl or
propyl.
[0143] Preferably n+m=1, and more preferably n is 0 and m is 1.
[0144] R.sup.N is preferably H or methyl, and is more preferably
H.
[0145] Particularly preferred compounds of the present invention
include: [0146]
(4-{[5-(4-Methoxy-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amin-
o}-phenyl)-acetic acid (4); [0147]
(4-{[5-(4-Methoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-phenyl)-aceti-
c acid (6); [0148]
{4-[(5-Phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid (10);
[0149]
(4-{[5-(4-Difluoromethoxy-phenyl)-furan-3-carbonyl]-amino}-phenyl)-acetic
acid (13); [0150]
(4-{[5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-pheny-
l)-acetic acid (18); [0151]
4-{[(5-Methyl-2-phenyl-furan-3-carbonyl)-amino]-methyl}-benzoic
acid (20); [0152] 2-Methyl-5-phenyl-furan-3-carboxylic acid
[4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (21); [0153]
5-(4-Methoxy-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid
[4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (22); [0154]
5-(4-Methoxy-phenyl)-2-methyl-furan-3-carboxylic acid
[4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (23); [0155]
5-Phenyl-furan-3-carboxylic acid
{4-[2-oxo-2-(toluene-2-sulfonylamino)-ethyl]-phenyl}-amide (24);
[0156] 5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic
acid [4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (25);
[0157] 5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic
acid {4-[2-oxo-2-(toluene-2-sulfonylamino)-ethyl]-phenyl}-amide
(26); [0158]
5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic acid
{4-[2-oxo-2-(propane-1-sulfonylamino)-ethyl]-phenyl}-amide (27);
[0159] 5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic
acid
{4-[2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-2-oxo-ethyl]-phenyl}-amide
(28); [0160]
5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic acid
{4-[2-oxo-2-(thiophene-2-sulfonylamino)-ethyl]-phenyl}-amide (29);
[0161] 5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic
acid
{4-[2-(5-methyl-pyridine-2-sulfonylamino)-2-oxo-ethyl]-phenyl}-amide
(30); [0162]
5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic acid
[4-(2-oxo-2-phenylmethanesulfonylamino-ethyl)-phenyl]-amide (31);
[0163] 5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic
acid
{4-[2-oxo-2-(2-trifluoromethyl-benzenesulfonylamino)-ethyl]-phenyl}-amide
(32); [0164]
5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic acid
{4-[2-(4-hydroxy-benzenesulfonylamino)-2-oxo-ethyl]-phenyl}-amide
(35); and [0165]
5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic acid
{4-[2-(2-fluoro-benzenesulfonylamino)-2-oxo-ethyl]-phenyl}-amide
(36).
[0166] The selectivity of the compound for antagonising EP.sub.4
receptors over the other EP receptors (i.e. EP.sub.1, EP.sub.2,
EP.sub.3) can be quantified by dividing the Ki for EP.sub.4 (see
below) by the Ki for the other EP receptors (see below). The
resulting ratio is preferably 10 or more, more preferably 100 or
more.
SYNTHESIS EXAMPLES
General Experimental Details
[0167] All reactions were carried out under an inert atmosphere of
nitrogen.
[0168] Where products were purified by flash chromatography the
stationary phase used was silica gel for chromatography, 0.035 to
0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60). An applied
pressure of nitrogen of .about.10 psi was used to accelerate column
elution. Thin layer chromatography (TLC) was carried out on
aluminium foil plates coated with silica gel containing a
fluorescent indicator (254 nm) (e.g. Fluka 60778).
[0169] Petroleum ether refers to that fraction with a boiling point
of 40-60.degree. C.
[0170] Organic solutions were dried over magnesium sulphate unless
otherwise specified.
[0171] PS-TsCl refers to Polystyrene scavenger resin (loading 1.97
mmol/g)--Argonaut Technologies (P/N 800277)
Preparative HPLC System
[0172] Preparative HPLC was carried out on a C18-reverse-phase
column (10.times.2.1 cm i.d Genesis column with 7 .mu.m particle
size), eluting with a gradient of acetonitrile (containing 0.1%
trifluoroacetic acid) in water (containing 0.1% trifluoroacetic
acid) at a flow rate of 5 ml/min. The gradient was started at 50%
acetonitrile, and was increased at a rate of 1% per minute up to
90% acetonitrile/water unless otherwise stated. UV detection at 230
nm was used unless otherwise stated.
LC/MS Systems
[0173] The Liquid Chromatography Mass Spectroscopy (LC/MS) systems
used are as follows.
[0174] LC/MS System A: [0175] Mass Spectrometer--Platform LC with
electrospray source operating in positive and negative ion mode.
HP1100 system running at 2.0 mL/min, 200 mL/min split to the ESI
source with inline HP1100 DAD detection and SEDEX ELS detection.
[0176] Mobile Phase [0177] A) Water 0.1% Formic Acid [0178] B)
acetonitrile 0.1% Formic Acid
TABLE-US-00001 [0178] Gradient Time Flow (min) (mL/min) % A % B
0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.00 2.0 5 95 5.50 2.0 95
5
[0179] Column--Luna 3u C18(2) 30.times.4.6 mm
LC/MS System B:
[0179] [0180] Mass Spectrometer--Platform II with electrospray
source operating in negative ion mode. HP1100 system running at 2.0
mL/min, 200 .mu.L/min split to the ESI source with inline HP1100
DAD detection and SEDEX ELS detection. [0181] Mobile Phase [0182]
A) Water 0.1% Diethylamine [0183] B) acetonitrile
TABLE-US-00002 [0183] Gradient Time Flow (min) (mL/min) % A % B
0.00 2.0 95 5 0.50 2.0 95 5 4.00 2.0 5 95 4.50 2.0 5 95 5.00 2.0 95
5 20.00 2.0 95 5
[0184] Column--XTerra MS C18 3.5 .mu.m 4.6.times.30 mm
LCMS System C:
[0184] [0185] Mass Spectrometer--Finnigan TSQ700 with electrospray
source operating in negative ion mode. [0186] HP1050 system running
at 2.0 mL/min, 200 .mu.L/min split to the ESI source with inline
HP1050 Single wavelength UV detector at 254 nm. [0187] Mobile Phase
[0188] A) Water 0.1% Diethylamine [0189] B) acetonitrile
TABLE-US-00003 [0189] Gradient Time Flow (min) (mL/min) % A % B
0.00 2.0 95 5 1.00 2.0 95 5 15.00 2.0 5 95 17.00 2.0 5 95 18.00 2.0
95 5 20.00 2.0 95 5
[0190] Column--XTerra MS C18 3.5.quadrature.m 4.6.times.30 mm
LC/MS System D:
[0190] [0191] Mass Spectrometer--Finnigan TSQ700 with electrospray
source operating in positive or negative ion mode. HP1050 system
running at 2.0 mL/min, 200 .mu.L/min split to the ESI source with
inline HP1050 Single Wavelength UV detector at 254 nm. [0192]
Mobile Phase [0193] A) Water 0.1% formic Acid [0194] B)
acetonitrile 0.1% formic Acid
TABLE-US-00004 [0194] Gradient Time Flow (min) (mL/min) % A % B
0.00 2.0 95 5 1.00 2.0 95 5 15.00 2.0 5 95 17.00 2.0 5 95 18.00 2.0
95 5 20.00 2.0 95 5
[0195] Column--Higgins Clipius C18 5.quadrature.m 100.times.3.0
mm
Example 1
Synthesis of [(alkyl-phenyl-furan-3-carbonyl)-amino]-phenyl-acetic
acids
(a) {4-[(2-Methyl-5-phenyl-furan-3-carbonyl)-amino}-phenyl]-acetic
acid (2)
##STR00024##
[0197] (i) Diispropylethylamine (427 mg) was added to a stirred
solution of 2-methyl-5-phenyl-furan-3-carboxylic acid (334 mg, 1.6
mmol) and ethyl-4-aminophenyl acetate (296 mg, 1.65 mmoles) in
N,N-dimethylformamide (30 ml).
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (628 mg, 1.65 mmoles) was added and the
solution was stirred at room temperature for 18 hours. The solvent
was evaporated, the residue was dissolved in dichloromethane and
washed with water, 10% aqueous sodium carbonate, 1M aqueous
hydrochloric acid and finally dried (MgSO.sub.4). After evaporation
of the solvent, the residue was triturated with cyclohexane and
dried to afford
{4-[(2-Methyl-5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid
ethyl ester (1) (466 mg) as a gum. LC/MS System D; R.sub.t=
[0198] (ii) A solution of sodium hydroxide (150 mg) in water (5 ml)
was added to a stirred solution of
{4-[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid
ethyl ester (1) (150 mg, 0.41 mmoles) in ethanol (20 ml) and the
mixture was stirred at room temperature for 1 hour. The solvent was
evaporated and the residue was diluted with water (10 ml) and
acidified to pH2 with 1M aqueous hydrochloric acid. The precipitate
was collected, washed with water and the residue was triturated
with cyclohexane. Recrystallisation from isopropanol afforded
compound (2) (135 mg) as a white solid. LC/MS System C;
R.sub.t=4.06 mins, m/z (ES.sup.-)=334 (M-H for
C.sub.20H.sub.17NO.sub.4).
(b)
(4-[(5-(4-Methoxy-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino)-p-
henyl)-acetic acid (4)
##STR00025##
[0200] (i) In an analogous manner to example 1(a)(i),
(4-{[5-(4-Methoxy-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-phen-
yl)-acetic acid ethyl ester (3) was synthesised from
5-(4-methoxy-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid (160
mg, 0.56 mmol) and ethyl-4-aminophenyl acetate (100 mg, 0.56
mmoles). 190 mg of the product was obtained as a gum. LC/MS System
A; R.sub.t=4.15 mins, m/z (ES.sup.+)=448 (M+H for
C.sub.23H.sub.20F.sub.3NO.sub.5).
[0201] (ii) In an analagous manner to example 1(a)(ii), compound
(4), was synthesised from
(4-{[5-(4-methoxy-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-phen-
yl)-acetic acid ethyl ester (3) (180 mg, 0.403 mmoles). The
resulting precipitate was collected, washed with water and the
residue was triturated with cyclohexane to afford compound (4) (140
mg) as a white solid. LC/MS System D; R.sub.t=8.07 mins, m/z
(ES.sup.+)=420 (M+H for C.sub.21H.sub.16F.sub.3NO.sub.5).
(c)
(4-([5-(4-Methoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino)-phenyl)-ac-
etic acid (6)
##STR00026##
[0203] (i) In an analogous manner to example 1(a)(i),
(4-{[5-(4-Methoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-phenyl)-aceti-
c acid ethyl ester (5) was synthesised from
5-(4-methoxy-phenyl)-2-methyl-furan-2-carboxylic acid (250 mg,
1.077 mmol) and ethyl-4-aminophenyl acetate (193 mg, 1.077 mmoles).
80 mg of the compound was obtained as a gum. LC/MS System A;
R.sub.t=4.03 mins, m/z (ES.sup.+)=394 (M+H for
C.sub.23H.sub.23NO.sub.5).
[0204] (ii) In an analagous manner to example 1(a)(ii), compound
(6), was synthesised from
{4-[(5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl
ester (5) (50 mg, 0.143 mmoles). The resulting precipitate was
collected, washed with water and the residue was triturated with
cyclohexane to afford compound (6) (14 mg) as a white solid. LC/MS
System D; R.sub.t=7.25 mins, m/z (ES.sup.+)=322 (M+H for
C.sub.19H.sub.15NO.sub.4).
(d) {4-[(5-Phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid
(10)
##STR00027##
[0206] (i) To a stirred solution of pyridinium tribromide (14.3 g,
44.6 mmoles) in acetic acid (20 ml) was added 3-furoic acid (5 g,
44.6 mmoles). The resulting mixture was heated at 40.degree. C. for
16 hours. The acetic acid was evaporated; the residue was dissolved
in dichloromethane (50 ml), washed with water (3.times.50 ml) and
dried (MgSO.sub.4). The solvent was evaporated and the residue was
purified by HPLC (gradient: 20% acetonitrile/80% water containing
0.1% trifluoroacetic acid to 80% acetonitrile/20% water at a rate
of 1%/min) to afford 5-Bromo-furan-3-carboxylic acid (7) as a white
solid. LC/MS System A; R.sub.t=2.52 mins, m/z (ES.sup.-)=189/191
(M-H for C.sub.5H.sub.3BrO.sub.3).
[0207] (ii) In an analogous manner to example 1(a)(i),
{4-[(5-bromo-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl
ester (8) was synthesised from 5-bromo-furan-3-carboxylic acid (7)
(225 mg, 1.18 mmol) and ethyl-4-aminophenyl acetate (213 mg, 1.18
mmoles). 403 mg of the product was obtained as a brown solid. LC/MS
System A; R.sub.t=3.49 mins, m/z (ES.sup.+)=352/354 (M+H for
C.sub.15H.sub.14BrNO.sub.4).
[0208] (iii) A solution of
{4-[(5-bromo-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl
ester (8) (200 mg, 0.57 mmoles), phenyl boronic acid (69.2 mg, 0.57
mmoles),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg,
0.06 mmoles) and 2M aqueous cesium carbonate (1.2 ml, 2.4 mmoles)
in toluene (20 ml) was refluxed for 16 hours. The solvent was
evaporated, the residue diluted with water (20 ml) and then
extracted with ethyl acetate (3.times.20 ml). The combined organic
layers were concentrated in vacuo. The residue was purified by
flash chromatography (gradient elution with 90% cyclohexane/10%
ethyl acetate to 50% cyclohexane/50% ethyl acetate) to afford
{4-[(5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl
ester (9) (53 mg). LC/MS System A; R.sub.t=3.84 mins, m/z
(ES.sup.+)=(M+H for C.sub.21H.sub.19NO.sub.4).
[0209] (iv) In an analagous manner to example 1(a)(ii), compound
(10), was synthesised from
{4-[(5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl
ester (9) (50 mg, 0.143 mmoles). The resulting precipitate was
collected, washed with water and the residue was triturated with
cyclohexane to afford compound (10) (14 mg) as a white solid. LC/MS
System D; R.sub.t=7.25 mins, m/z (ES.sup.+)=322 (M+H for
C.sub.19H.sub.15NO.sub.4).
(e)
(4-([5-(4-Difluoromethoxy-phenyl)-furan-3-carbonyl]-amino)-phenyl)-ace-
tic acid (13)
##STR00028##
[0211] (i) A solution of
{4-[(5-Bromo-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl
ester (828 mg, 2.35 mmoles) (8),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (518 mg,
2.35 mmoles),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg)
and 2M aqueous cesium carbonate (3.5 ml, 3.5 mmoles) in
N,N-dimethylformamide (20 ml) was heated in a microwave reactor at
100.degree. C. for 15 minutes. The solvent was evaporated, and the
residue was purified by flash chromatography (gradient elution with
100% cyclohexane to 50% cyclohexane/50% ethyl acetate) to afford
(4-{[5-(4-hydroxy-phenyl)-furan-3-carbonyl]-amino}-phenyl)-acetic
acid ethyl ester (11) (328 mg). LC/MS System A; R.sub.t=3.35 mins,
m/z (ES.sup.+)=366 (M+H for C.sub.21H.sub.19NO.sub.5).
[0212] (ii) To a stirred solution of
(4-{[5-(4-hydroxy-phenyl)-furan-3-carbonyl]-amino}-phenyl)-acetic
acid ethyl ester (328 mg, 0.898 mmoles) (11) in
N,N-dimethylformamide (15 ml) was added potassium carbonate (190
mg, 1.35 mmoles) and potassium iodide (75 mg, 0.449 mmoles).
Chlorodifluoromethane was bubbled through the solution at
80.degree. C. for 5 hours, and then discontinued. The reaction
mixture was stirred at 80.degree. C. for 16 hours. The reaction was
cooled to room temperature and quenched by the addition of water
until no effervescence was observed. The resulting solution was
extracted with ethyl acetate and the combined organic layers washed
with brine, dried over MgSO.sub.4 and concentrated in vacuo. The
residue was purified by flash chromatography (gradient: 100%
cyclohexane to 50% cyclohexane/50% ethyl acetate) to afford
(4-{[5-(4-Difluoromethoxy-phenyl)-furan-3-carbonyl]-amino}-phenyl)-acetic
acid ethyl ester (12) (60 mg) as a yellow solid. LC/MS System A;
R.sub.t=3.91 mins, m/z (ES.sup.+)=416 (M+H for
C.sub.22H.sub.19F.sub.2NO.sub.5).
[0213] (iii) In an analagous manner to example 1(a)(ii), compound
(13), was synthesised from
(4-{[5-(4-difluoromethoxy-phenyl)-furan-3-carbonyl]-amino}-phenyl)-acetic
acid ethyl ester (12) (55 mg, 0.132 mmoles). The resulting
precipitate was collected, washed with water and the residue was
triturated with cyclohexane to afford the compound (13) (41.8 mg)
as a white solid. LC/MS System D; R.sub.t=8.86 mins, m/z
(ES.sup.+)=388 (M+H for C.sub.2H.sub.15F.sub.2NO.sub.5).
(f)
(4-([5-(4-Difluoromethoxy-phenyl)-furan-3-carbonyl]-amino)-phenyl)-ace-
tic acid (18)
##STR00029##
[0215] (i) A solution of sodium hydroxide (4.5 g) in water (10 ml)
was added to a stirred solution of
5-bromo-2-methyl-furan-3-carboxylic acid methyl ester (5 g, 23
mmoles) in methanol (70 ml) and the mixture was stirred at room
temperature for 16 hours. The solvent was evaporated and the
residue was diluted with water (10 ml) and acidified to pH2 with 1M
aqueous hydrochloric acid. The precipitate was collected, washed
with water, dried at 40.degree. C. to afford
5-Bromo-2-methyl-furan-3-carboxylic acid (14) (4 g). LC/MS System
A; R.sub.t=2.86 min.
[0216] (ii) In an analogous manner to example 1(a)(i),
{4-[(5-bromo-2-methyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid
ethyl ester (15) was synthesised from
5-bromo-2-methyl-furan-3-carboxylic acid (14) (1.8 g, 8.78 mmoles)
and (4-amino-phenyl)-acetic acid ethyl ester (1.6 g, 8.9 mmoles).
3.08 g of the product was obtained as a gum. LC/MS System A;
R.sub.t=3.73 mins, m/z (ES.sup.+)=367 (M+H for
C.sub.16H.sub.16BrNO.sub.4).
[0217] (iii) A solution of
{4-[(5-bromo-2-methyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid
ethyl ester (3 g, 8.19 mmoles) (15),
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.8 g,
8.19 mmoles),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (300
mg, 10%) and 2M aqueous cesium carbonate (15 ml, 15 mmoles) in
N,N-dimethylformamide (35 ml) was heated in a microwave reactor at
100.degree. C. for 15 minutes. The solvent was evaporated, and the
residue was purified by flash chromatography (gradient elution with
100% cyclohexane to 100% ethyl acetate) to afford
(4-{[5-(4-hydroxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-phenyl)-aceti-
c acid ethyl ester (16) (1.9 g). LC/MS System A; R.sub.t=3.54 mins,
m/z (ES.sup.+)=380 (M+H for C.sub.22H.sub.21NO.sub.5).
[0218] (iv) To a stirred solution of
(4-{[5-(4-hydroxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-phenyl)-aceti-
c acid ethyl ester (1.9 g, 5 mmoles) (16) in N,N-dimethylformamide
(70 ml) was added potassium carbonate (1.04 g, 7.5 mmoles) and
potassium iodide (416 mg, 2.5 mmoles). Chlorodifluoromethane was
bubbled through the solution at 80.degree. C. for 5 hours, and then
discontinued. The reaction mixture was stirred at 80.degree. C. for
16 hours. The reaction was cooled to room temperature and quenched
by the addition of water until no effervescence was observed. The
resulting solution was extracted with ethyl acetate (3.times.150
ml) and the combined organic layers washed with brine (200 ml),
dried over MgSO.sub.4 and concentrated in vacuo. The residue was
purified by flash chromatography (gradient: 100% cyclohexane to 50%
cyclohexane/50% ethyl acetate) to afford
(4-{[5-(4-difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-pheny-
l)-acetic acid ethyl ester (17) (694 mg) as a white solid. LC/MS
System A; R.sub.t=4.13 mins, m/z (ES.sup.+)=430 (M+H for
C.sub.23H.sub.21F.sub.2NO.sub.5).
[0219] (v) In an analagous manner to example 1(a)(ii), compound
(18), was synthesised from
(4-{[5-(4-difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-pheny-
l)-acetic acid ethyl ester (17) (694 mg, 1.62 mmoles). The
resulting precipitate was collected, washed with water and the
residue was triturated with cyclohexane to afford compound (18)
(643 mg) as a white solid. LC/MS System D; R.sub.t=9.46 mins, m/z
(ES.sup.+)=402 (M+H for C.sub.21H.sub.17F.sub.2NO.sub.5).
Example 2
Synthesis of
4-{[(5-Methyl-2-phenyl-furan-3-carbonyl)-amino]-methyl}-benzoic
acid (20)
##STR00030##
[0221] (i) In an analogous manner to example 1(a)(i),
4-{[(5-methyl-2-phenyl-furan-3-carbonyl)-amino]-methyl}-benzoic
acid ethyl ester (19) was synthesised from
5-methyl-2-phenyl-furan-3-carboxylic acid (79 mg, 0.39 mmol) and
4-aminomethyl benzoic acid ethyl ester (70 mg, 0.39 mmoles). 99 mg
of the product was obtained as a gum. LC/MS System A; R.sub.t=3.88
mins, m/z (ES.sup.+)=364 (M+H for C.sub.22H.sub.21NO.sub.4).
[0222] (ii) In an analagous manner to example 1(a)(ii), compound
(20), was synthesised from
4-{[(5-methyl-2-phenyl-furan-3-carbonyl)-amino]-methyl}-benzoic
acid ethyl ester (19) (90 mg, 0.247 mmoles). The resulting
precipitate was collected, washed with water and the residue was
triturated with cyclohexane to afford compound (20) (51 mg) as a
white solid. LC/MS System D; R.sub.t=6.82 mins, m/z (ES.sup.+)=336
(M+H for C.sub.20H.sub.17NO.sub.4).
Example 3
Synthesis of alkyl-phenyl-furan-3-carboxylic acid
[4-(2-sulphonylamino-2-oxo-ethyl)-phenyl] amides
(a) 2-Methyl-5-phenyl-furan-3-carboxylic acid
[4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (21)
##STR00031##
[0224] A stirred solution of
{4-[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid
(2) (10 mg, 0.030 mmoles),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.7
mg, 0.030 mmoles), and 4-(N,N-dimethylamino)-pyridine (3.5 mg) in
dichloromethane (10 ml), was treated with benzenesulphonamide (9
mg, 0.060 mmoles). The mixture was stirred at room temperature for
18 hours. The reaction mixture was concentrated in vacuo and the
residue was dissolved in ethyl acetate, washed with 0.1M aqueous
hydrochloric acid, and brine and finally dried (MgSO.sub.4). After
evaporation of the solvent, the residue was purified by HPLC
(gradient: 20% acetonitrile/80% water containing 0.1%
trifluoroacetic acid to 80% acetonitrile/20% water at a rate of
1%/min) to afford compound (21) (10 mg) as a white solid. LC/MS
System D; R.sub.t=9.98 mins, m/z (ES.sup.+)=475 (M+H for
C.sub.26H.sub.22N.sub.2O.sub.5S).
(b) 5-(4-Methoxy-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid
[4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (22)
##STR00032##
[0226] In an analogous way to example 3(a), compound (22) was
synthesised from
(4-{[5-(4-methoxy-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-
-phenyl)-acetic acid (4) (40 mg, 0.095 mmoles). The reaction
mixture was concentrated in vacuo and the residue was dissolved in
dichloromethane, washed with 0.1M aqueous hydrochloric acid, and
brine and finally dried (MgSO.sub.4). After evaporation of the
solvent, the residue was triturated with cyclohexane and a white
solid filtered off, which was purified by HPLC (gradient: 20%
acetonitrile/80% water containing 0.1% trifluoroacetic acid to 80%
acetonitrile/20% water at a rate of 1%/min) to afford compound (22)
(12 mg) as a white solid. LC/MS System D; R.sub.t=9.08 mins, m/z
(ES.sup.+)=559 (M+H for
C.sub.27H.sub.21F.sub.3N.sub.2O.sub.6S).
(c) 5-(4-Methoxy-phenyl)-2-methyl-furan-3-carboxylic acid
[4-(2-benzenesulfonylamino-2-oxo-ethyl)-phenyl]-amide (23)
##STR00033##
[0228] In an analogous way to example 3(a), compound (23) was
synthesised from
(4-{[5-(4-methoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-phenyl)--
acetic acid (6) (100 mg, 0.273 mmoles). The reaction mixture was
concentrated in vacuo and the residue was dissolved in
dichloromethane, washed with 0.1M aqueous hydrochloric acid, and
brine and finally dried (MgSO.sub.4). After evaporation of the
solvent, the residue was triturated with cyclohexane and a white
solid filtered off, which was then purified by HPLC (gradient: 20%
acetonitrile/80% water containing 0.1% trifluoroacetic acid to 80%
acetonitrile/20% water at a rate of 1%/min) to afford compound (23)
(50 mg) as a white solid. LC/MS System D; R.sub.t=8.58 mins, m/z
(ES.sup.+)=405 (M+H for C.sub.27H.sub.24N.sub.2O.sub.6S).
(d) 5-Phenyl-furan-3-carboxylic acid
{4-[2-oxo-2-(toluene-2-sulfonylamino)-ethyl]-phenyl}-amide (24)
##STR00034##
[0230] In an analogous way to example 3(a), compound (24) was
synthesised from
{4-[(5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid (10) (40
mg, 0.125 mmoles) and replacing benzene-sulfonamide with
toluene-2-sulfonamide. The reaction mixture was concentrated in
vacuo and the residue purified by HPLC (gradient: 20%
acetonitrile/80% water containing 0.1% trifluoroacetic acid to 80%
acetonitrile/20% water at a rate of 1%/min) to afford compound (24)
(4 mg) as an off-white solid. LC/MS System D; R.sub.t=9.85 mins,
m/z (ES.sup.+)=475 (M+H for C.sub.26H.sub.22N.sub.2O.sub.5S).
(e) Compounds derived from
(4-{[5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-3-phe-
nyl)-acetic acid (18)
##STR00035##
[0232] A stirred solution of
(4-{[5-(4-difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-pheny-
l)-acetic acid (18) (20 mg, 0.050 mmoles),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.1
mg, 0.010 mmoles), and 4-(N,N-dimethylamino)-pyridine (6 mg, 0.050
mmoles) in dichloromethane (10 ml), was treated with a sulphonamide
(R.sup.SS(.dbd.O).sub.2NH.sub.2) (0.055 mmoles). The mixture was
stirred at room temperature for 1.5 hours (compounds 25 and 26), 2
hours (compound 31) or 16 hours (compounds 27 to 30, 32 and 36).
The reaction mixture was concentrated in vacuo and the residue
purified by HPLC (gradient: 20% acetonitrile/80% water containing
0.1% trifluoroacetic acid to 80% acetonitrile/20% water at a rate
of 1%/min) to afford the desired compound.
TABLE-US-00005 LC/MS R.sub.t (mins) m/z Compound R.sup.S Yield (mg)
System D (ES.sup.-) 25 ##STR00036## 20 10.51 539 26 ##STR00037## 12
10.79 553 27 ##STR00038## 12.5 9.98 505 28 ##STR00039## 37.8 10.38
558 29 ##STR00040## 33 10.22 545 30 ##STR00041## 45 9.87 554 31
##STR00042## 38 10.57 553 32 ##STR00043## 42.8 10.78 607 36
##STR00044## 60 10.32 557
(f) 5-(4-Difluoromethoxy-phenyl)-2-methyl-furan-3-carboxylic acid
{4-[2-(4-hydroxy-benzenesulfonylamino)-2-oxo-ethyl]-phenyl}-amide
(35)
##STR00045##
[0234] (i) A solution of sodium hydroxide (116 mg, 2.9 mmoles) in
water (10 ml) was added to a stirred solution of
4-hydroxy-benzenesulphonamide (500 mg, 2.9 mmoles) in water (30
ml). This mixture was treated with acetic anhydride (295 mg, 2.9
mmoles) and stirred at room temperature for 4.5 hours. The reaction
mixture was filtered off and the resulting solid washed with water
to afford acetic acid 4-sulphamoyl-phenyl ester (33) (348 mg) as a
yellow solid. LC/MS System A; R.sub.t 2.06 mins.
[0235] (ii) In an analogous way to example 3(e),
(4-{[5-(4-difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-pheny-
l)-acetic acid (18) (50 mg, 0.125 mmoles) was treated with acetic
acid 4-sulphamoyl-phenyl ester (33) (29.2 mg, 0.137 mmoles). The
mixture was stirred at room temperature for 16 hours. The reaction
mixture was concentrated and the product (34) used as described in
step (iii) without further purification. LC/MS System A; R.sub.t
3.89 mins, m/z (ES.sup.+)=599 (M+H for
C.sub.29H.sub.24F.sub.2N.sub.2O.sub.8S).
[0236] (iii) Sodium methoxide (6.8 mg, 0.125 mmoles) and water (1
ml) were added to a stirred solution of acetic acid
4-[2-(4-{[5-(4-difluoromethoxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}--
phenyl)-acetylsulphamoyl]-phenyl ester (34) (74.5 mg, 0.125 mmoles)
in methanol (10 ml). The reaction mixture was stirred at room
temperature for 30 minutes, concentrated and the residue was
purified by HPLC (gradient: 20% acetonitrile/80% water containing
0.1% trifluoroacetic acid to 80% acetonitrile/20% water at a rate
of 1%/min) to afford compound (35) (18 mg) as a white solid. LC/MS
System D; R.sub.t=9.48 mins, m/z (ES.sup.-)=555 (M-H for
C.sub.27H.sub.22F.sub.2N.sub.2O.sub.7S).
Example 4
Biological Results
Binding Ability to Human EP Receptors
[0237] Membranes were prepared from cells stably transfected with
human EP receptor cDNA. In brief, cells were cultured to
confluency, scraped from culture flasks, and centrifuged (800 g, 8
minutes, 4.degree. C.). Cells were twice washed in ice cold
homogenisation buffer containing 10 mM Tris-HCl, 1 mM EDTA.2Na, 250
mM sucrose, 1 mM PMSF, 0.3 mM indomethacin, pH 7.4, homogenised and
re-centrifuged as before. The supernatant was stored on ice and
pellets re-homogenised and re-spun. Supernatants were pooled and
centrifuged at 40000 g, 10 minutes, 4.degree. C. Resultant membrane
pellets were stored at -80.degree. C. until use.
[0238] For assay, membranes expressing human EP.sub.4, EP.sub.3,
EP.sub.2 or EP, receptors were incubated in Millipore (MHVBN45)
plates containing assay buffer, radiolabelled [.sup.3H]PGE.sub.2
and 0.1 to 10 000 nM concentrations of compounds. Incubations were
performed at suitable temperatures and for suitable times to allow
equilibrium to be reached. Non-specific binding was determined in
the presence of 10 uM PGE.sub.2. Bound and free radiolabel was
separated by vacuum manifold filtration using appropriate wash
buffers, and bound radiolabel was determined by scintillation
counting. Constituents of each of the buffers are included in table
1 below.
[0239] The affinity or pK.sub.i of each compound for each receptor
was calculated from the concentration causing 50% radioligand
displacement (IC.sub.50) using the Cheng-Prusoff equation:
Ki = IC 50 1 + ( radioligand concentration radioligand KD )
##EQU00001##
[0240] This approach follows that set out in Kenakin, T. P.,
Pharmacologic analysis of drug receptor interaction. Raven Press,
New York, 2.sup.nd edition.
TABLE-US-00006 TABLE 1 Receptor EP.sub.1 EP.sub.2 EP.sub.3 EP.sub.4
Protein/well 6.5 .mu.g 8 .mu.g 5 .mu.g 5 .mu.g Final 3.6 nM 3 nM
2.5 nM 1 nM [.sup.3H-PGE.sub.2] Buffer Assay 10 mM MES pH 6.0; 10
mM MES 10 mM MES pH 10 mM MES 10 mM MgCl.sub.2; 1 mM pH 6.0; 10 mM
6.0; 10 mM pH 6.0; 10 mM EDTA, 3 uM MgCl.sub.2; 1 mM MgCl2; 1 mM
MgCl.sub.2; 1 mM Indomethacin EDTA EDTA, 100 uM EDTA, 3 uM
GTP-gamma-S Indomethacin Wash 10 mM MES pH 6.0; 10 mM MES 10 mM MES
pH 10 mM MES 10 mM MgCl.sub.2 pH 6.0; 10 mM 6.0; 10 mM MgCl.sub.2
pH 6.0; 1 mM MgCl.sub.2 EDTA
[0241] The results are presented as pK.sub.i values in table 2
below.
TABLE-US-00007 TABLE 2 Compound EP.sub.4 EP.sub.2 EP.sub.3 4 >5
<5 <5 6 >6 <5 <5 10 >6 <5.5 <5 13 >6
<5 <5 18 >6 <5.5 <5 20 >5 <5 <5 21 >7
<6 <5 22 >6 <6 <5 23 >7 <6 <5 24 >6
<7 <5 25 >7 <6 <5 26 >7 <6.5 <5 27 >6
<5 <5 28 >6 <5 <5 29 >7 <5.5 <5 30 >7
<6 <5 31 >7 <6 <5 32 >7 <5.5 <5.5 35 >7
<5.5 <5 36 >7 <6 <5
* * * * *