U.S. patent application number 09/780657 was filed with the patent office on 2001-10-18 for heterocyclic compounds and their therapeutic use.
Invention is credited to Dyke, Hazel Joan, Lowe, Christopher, Montana, John Gary.
Application Number | 20010031777 09/780657 |
Document ID | / |
Family ID | 9885480 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031777 |
Kind Code |
A1 |
Dyke, Hazel Joan ; et
al. |
October 18, 2001 |
Heterocyclic compounds and their therapeutic use
Abstract
A compound of the formula 1 wherein R.sub.1 is C.sub.1-3 alkyl
optionally substituted with one or more fluorines; R.sub.2 is
CH.sub.2OCH.sub.3 or 2 or 3-tetrahydrofuranyl; R.sub.3 is a
pyrazole, imidazole or isoxazole group of partial formula (A), (B)
or (C) 2 R.sub.4 is C.sub.1-3 alkyl; and R.sub.5 and R.sub.6, which
may be the same or different, each represents C.sub.1-3 alkyl,
halogen, CF.sub.3 or CN; or a pharmaceutically-acceptable salt
thereof.
Inventors: |
Dyke, Hazel Joan;
(Cambridge, GB) ; Lowe, Christopher; (Cambridge,
GB) ; Montana, John Gary; (Cambridge, GB) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK
A PROFESSIONAL ASSOCIATION
2421 N.W. 41ST STREET
SUITE A-1
GAINESVILLE
FL
326066669
|
Family ID: |
9885480 |
Appl. No.: |
09/780657 |
Filed: |
February 9, 2001 |
Current U.S.
Class: |
514/378 ;
514/397; 514/406; 548/247; 548/311.4; 548/364.4 |
Current CPC
Class: |
A61P 17/06 20180101;
A61P 21/00 20180101; A61P 11/06 20180101; C07D 405/12 20130101;
A61P 1/00 20180101; C07D 413/12 20130101; A61P 27/14 20180101; A61P
43/00 20180101; A61P 25/00 20180101; A61P 3/10 20180101; A61P 19/02
20180101; A61P 29/00 20180101; A61P 17/00 20180101; A61P 37/02
20180101; A61P 9/08 20180101; A61P 11/00 20180101; A61P 13/12
20180101; A61P 7/00 20180101; A61P 19/08 20180101; A61P 27/02
20180101; A61P 31/00 20180101; A61P 37/08 20180101; A61P 27/16
20180101; A61P 25/24 20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/378 ;
514/397; 514/406; 548/311.4; 548/364.4; 548/247 |
International
Class: |
C07D 261/06; C07D
233/02; A61K 031/4178; A61K 031/42; A61K 031/4155 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 11, 2000 |
GB |
0003257.3 |
Claims
1. A compound of the formula 8wherein R.sub.1 is C.sub.1-3 alkyl
optionally substituted with one or more fluorines; R.sub.2 is
CH.sub.2OCH.sub.3 or 2 or 3-tetrahydrofuranyl; R.sub.3 is a
pyrazole, imidazole or isoxazole group of partial formula (A), (B)
or (C) 9R.sub.4 is C.sub.1-3 alkyl; and R.sub.5 and R.sub.6, which
may be the same or different, each represents C.sub.1-3 alkyl,
halogen, CF.sub.3 or CN; or a pharmaceutically-acceptable salt
thereof.
2. A compound of claim 1, wherein R.sub.1 is CH.sub.3 or
CHF.sub.2.
3. A compound of claim 1 or claim 2, wherein R.sub.3 is a pyrazole
or isoxazole group.
4. A compound of claim 3, wherein R.sub.3 is a pyrazole group,
R.sub.4 is CH.sub.3 and R.sub.5 is CN, CH.sub.3, Cl or
CF.sub.3.
5. A compound of claim 3, wherein R.sub.3 is an isoxazole group,
R.sub.5 is CH.sub.3, CF.sub.3 or CN and R.sub.5 is CH.sub.3,
CF.sub.3 or CN.
6. A compound of claim 1, selected from
7-methoxy-2-(tetrahydrofuran-3-yl)- -benzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide,
7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic
acid (4-cyano-2-methyl-2-H-pyrazol-3-yl)-amide,
7-methoxy-2-methoxymethylbenzo- furan-4-carboxylic acid
(5-cyano-3-methyl-3H-imidazol-4-yl)-amide
7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,
7-methoxy-2-(tetrahydrofuran-3-y- l)-benzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,
7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,
7-methoxy-2-methoxymethylbenzofu- ran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,
7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic
acid (3,5-dimethylisoxazol-4-yl)-amide,
7-methoxy-2-(tetrahydrofuran-2-yl)-ben- zofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide,
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide,
7-methoxy-2-methoxymethylbenzofuran-4-- carboxylic acid
(4-chloro-2-methyl-2H-pyrazol-3-yl)-amide,
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(2-methyl-2H-pyrazol-3-yl)-amide,
7-methoxy-2-methoxymethylbenzofuran-4-c- arboxylic acid
(2-ethyl-2H-pyrazol-3-yl)-amide, 7-methoxy-2-methoxymethylb-
enzofuran-4-carboxylic acid (2,4-dimethyl-2H-pyrazol-3-yl)-amide,
and 7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide.
7. A composition for use in therapy, comprising a compound of any
preceding claim and a pharmaceutically acceptable carrier or
diluent.
8. Use of a compound of any of claims 1 to 6, for the manufacture
of a medicament for use in the treatment of a disease state that is
capable of being modulated by inhibition of phosphodiesterase IV or
Tumour Necrosis Factor, or that is a pathological condition
associated with a function of phosphodiesterase IV, eosinophil
accumulation or a function of the eosinophil.
9. The use of claim 8, wherein the disease state is an inflammatory
disease or autoimmune disease.
10. The use of claim 8, wherein the disease state is selected from
asthma, chronic bronchitis, chronic pulmonary inflammatory disease,
chronic obstructive airways disease, atopic dermatitis, allergic
rhinitis, psoriasis, arthritis, rheumatoid arthritis, joint
inflammation, ulcerative colitis, Crohn's disease, atopic eczema,
stroke, bone resorption disease, multiple sclerosis and
inflammatory bowel disease.
11. The use of claim 8, wherein the disease state is selected from
urticaria, allergic conjunctivitis, vernal conjunctivitis,
inflammation of the eye, allergic responses in the eye,
eosinophilic granuloma, gouty arthritis and other arthritic
conditions, adult respiratory distress syndrome, diabetes
insipidus, keratosis, cerebral senility, multi-infarct dementia,
senile dementia, memory impairment associated with Parkinson's
disease, depression, cardiac arrest, intermittent claudication,
rheumatoid spondylitis, osteoarthritis, sepsis, septic shock,
endotoxic shock, gram negative sepsis, toxic shock syndrome, acute
respiratory distress syndrome, cerebral malaria, silicosis,
pulmonary sarcoidosis, reperfusion injury, graft vs host reaction,
allograft rejection, infection-related fever or myalgia, malaria,
HIV, AIDS, ARC, cachexia, keloid formation, scar tissue formation,
pyresis, systemic lupus erythematosus, type 1 diabetes mellitus,
Bechet's disease, anaphylactoid purpura nephritis, chronic
glomerulonephritis, leukaemia, tarditive dyskinesia, yeast or
fungal infection, conditions requiring gastroprotection, and
neurogenic inflammatory disease associated with irritation and
pain.
12. The use of claim 8, wherein the disease state is asthma.
13. The use of claim 8, wherein the disease state is chronic
obstructive airways disease or chronic bronchitis.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel heterocyclic
compounds and to their formulation and use as pharmaceuticals.
BACKGROUND OF THE INVENTION
[0002] The modes of action of phosphodiesterases and also tumour
necrosis factor (TNF), and the therapeutic utilities of inhibitors
thereof, are described in WO-A-97/44337 and U.S. Pat. Nos.
5,925,636 and 5,972,936, the contents of which are incorporated
herein by reference. These reference describe benzofurans having
such activity.
SUMMARY OF THE INVENTION
[0003] This invention provides novel compounds having therapeutic
utility, in particular for the treatment of disease states
associated with proteins which mediate cellular activity, for
example by inhibiting TNF and/or PDE IV. According to the
invention, the compounds are of formula (i): 3
[0004] wherein R.sub.1 is C.sub.1-3 alkyl optionally substituted
with one or more fluorines;
[0005] R.sub.2 is CH.sub.2OCH.sub.3 or 2 or
3-tetrahydrofuranyl;
[0006] R.sub.3 is a pyrazole, imidazole or isoxazole group of
partial formula (A), (B) or (C) 4
[0007] R.sub.4 is C.sub.1-3 alkyl; and
[0008] R.sub.5 and R.sub.6, which may be the same or different,
each represents C.sub.1-3 alkyl, halogen, CF.sub.3 or CN,
[0009] or a pharmaceutically-acceptable salt thereof.
[0010] In summary, the compounds of the invention represent a
selection within the scope of WO-A-97/44337. The novel compounds
have superior in vivo activity.
[0011] This invention provides also a method for mediating or
inhibiting the enzymatic activity or catalytic activity of PDE IV
in a mammal in need thereof and for inhibiting the production of
TNF in a mammal in need thereof, which comprises administering to
said mammal an effective amount of a compound of Formula (i) or a
pharmaceutically-acceptable salt thereof.
DESCRIPTION OF THE INVENTION
[0012] The term "C.sub.1-3 alkyl" means methyl, ethyl, propyl or
isopropyl.
[0013] One group of compounds of the invention is of formula (i) in
which R.sub.1 is CH.sub.3 or CHF.sub.2.
[0014] R.sub.3 may in particular be a pyrazole of partial formula
(A) or an isoxazole of partial formula (C). When R.sub.3 is a
pyrazole moiety, R.sub.4 is especially CH.sub.3 and R.sub.5 is
particularly CN, CH.sub.3, Cl or CF.sub.3. Where R.sub.3 is an
isoxazole moiety, R.sub.5 is especially CH.sub.3, CF.sub.3 or CN
and R.sub.6 is particularly CH.sub.3, CF.sub.3 or CN.
[0015] The compounds of the Examples are especially preferred.
[0016] It will be appreciated by those skilled in the art that
compounds of formula (i) in which R.sub.2 represents
tetrahydrofuran contain a chiral centre. This invention extends to
both enantiomers and all mixtures thereof, including racemic
mixtures.
[0017] Certain of the compounds of formula (i) which contain a
basic group form acid addition salts. Suitable acid addition salts
include pharmaceutically-acceptable inorganic salts such as the
sulphate, nitrate, phosphate, borate, hydrochloride and
hydrobromide, and pharmaceutically-acceptable organic acid addition
salts such as acetate, tartrate, maleate, citrate, succinate,
benzoate, ascorbate, methanesulphate, .alpha.-ketoglutarate,
.alpha.-glycerophosphate and glucose-1-phosphate. The
pharmaceutically-acceptable salts of the compounds of formula (i)
are prepared using conventional procedures.
[0018] Compounds of the invention may be prepared by reaction of an
appropriate carboxylic acid of formula (ii) with a suitable amine
of formula (iii) as described in WO 97/44337. Carboxylic acids of
formula (ii) may be conveniently prepared from compounds of formula
(iv) by bromination followed by palladium-catalysed carbonylation
as described in WO 97/44337. Amines of formula (iii) are either
commercially available, previously described compounds, or are
prepared using standard conditions known to those skilled in the
art.
[0019] Compounds of formula (iv) in which R.sub.1 represents methyl
and R.sub.2 represents CH.sub.2OCH.sub.3 may be conveniently
prepared from o-vanillin as shown below. o-Vanillin is treated with
bromoacetaldehyde dimethyl acetal in the presence of a base, such
as potassium carbonate, in a suitable solvent such as
N,N-dimethylformamide, favourably at elevated temperature. The
resultant acetal can then be cyclised, for example by heating in
acetic acid, to provide 7-methoxybenzofuran-2-carba- ldehyde. The
aldehyde may be reduced using any suitable reducing agent known to
those skilled in the art, such as sodium borohydride. The resultant
alcohol may be methylated using any appropriate methylating agent,
such as methyl iodide, in the presence of an appropriate base, such
as sodium hydride. 5
[0020] Compounds of formula (iv) in which R.sub.1 represents methyl
and R.sub.2 represents 3-tetrahydrofuranyl may be prepared from
7-methoxybenzofuran as depicted below. 7-Methoxybenzofuran may be
deprotonated by treatment with any suitable base, such as
butyllithium, and the resultant anion added to
tetrahydrofuran-3-one. The resultant alcohol may be converted to a
leaving group, such as a mesylate, and then eliminated. The alkene
thus formed may be reduced using any suitable reducing agent, such
as Raney nickel and hydrogen. 6
[0021] Compounds of formula (iv) in which R.sub.1 represents methyl
and R.sub.2 represents 2-tetrahydrofuranyl may be prepared from
7-methoxybenzofuran-2-carbaldehyde as shown below. A suitably
protected Grignard reagent derived from 1,3-propanediol may be
added to 7-methoxybenzofuran-2-carbaldehyde, and the protecting
group may then be removed. A suitable protecting group may be
tert-butyldimethylsilyl, which may be removed using any standard
conditions known to those skilled in the art, for example
tetrabutylammonium fluoride. Cyclisation of the resultant diol may
be achieved using any appropriate conditions, such as
p-toluenesulphonic acid and molecular sieves in a suitable solvent
such as dicloromethane. 7
[0022] Compounds of formula (iv) in which R.sub.1 represents
difluoromethoxy may be prepared by demethylation, and subsequent
difluoromethylation, of suitable intermediates in which R.sub.1
represents methyl. Such demethylation may be carried out using any
suitable conditions known to those skilled in the art. Suitable
conditions include the use of ethane thiolate in an appropriate
solvent, such as N,N-dimethylformamide, at a suitable temperature.
Suitable temperatures include elevated temperatures, favourably
140.degree. C. Difluoromethylation of the resultant phenols may be
carried out using any suitable conditions known to those skilled in
the art. Suitable conditions include the use of
chlorodifluoromethane and a suitable base in an appropriate solvent
at an appropriate temperature. Favourably, the reaction is
conducted in dioxane as solvent using aqueous sodium hydroxide as
base. Elevated temperatures, such as reflux temperature, may be
employed.
[0023] The invention includes the prevention and treatment of
TNF-mediated disease or disease states, by which is meant any and
all disease states in which TNF plays a role, either by production
of TNF itself, or by TNF causing another cytokine to be released,
such as but not limited to IL-1 or IL-6. A disease state in which
IL-1, for instance, is a major component, and whose production or
action is exacerbated or secreted in response to TNF, would
therefore be considered a disease state mediated by TNF. As
TNF-.beta. (also known as lymphotoxin) has close structural
homology with TNF-.alpha. (also known as cachectin), and since each
induces similar biological responses and binds to the same cellular
receptor, both TNF-.alpha. and TNF-.beta. are inhibited by
compounds of the present invention and thus are herein referred to
collectively as "TNF" unless specifically delineated otherwise.
[0024] PDE IV inhibitors are useful in the treatment of a variety
of allergic and inflammatory diseases, including: asthma, chronic
bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic
rhinitis, allergic conjunctivitis, vernal conjunctivitis,
inflammation of the eye, allergic responses in the eye,
eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis,
anaphylactoid purpura nephritis, joint inflammation, arthritis,
rheumatoid arthritis and other arthritic conditions such as
rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative
colitis, Crohn's disease, reperfusion injury of the myocardium and
brain, chronic glomerulonephritis, endotoxic shock and adult
respiratory distress syndrome. In addition, PDE IV inhibitors are
useful in the treatment of diabetes insipidus and conditions
associated with cerebral metabolic inhibition, such as cerebral
senility, senile dementia (Alzheimer's disease), memory impairment
associated with Parkinson's disease, depression and multi-infarct
dementia. PDE IV inhibitors are also useful in conditions
ameliorated by neuroprotectant activity, such as cardiac arrest,
stroke and intermittent claudication. Additionally, PDE IV
inhibitors could have utility as gastroprotectants. A special
embodiment of the therapeutic methods of the present invention is
the treatment of asthma.
[0025] The viruses contemplated for treatment herein are those that
produce TNF as a result of infection, or those which are sensitive
to inhibition, such as by decreased replication, directly or
indirectly, by the TNF inhibitors of Formula (i). Such viruses
include, but are not limited to HIV-1, HIV-2 and HIV-3,
cytomegalovirus (CMV), influenza, adenovirus and the Herpes group
of viruses, such as, but not limited to, Herpes zoster and Herpes
simplex.
[0026] This invention more specifically relates to a method of
treating a mammal, afflicted with a human immunodeficiency virus
(HIV), which comprises administering to such mammal an effective
TNF inhibiting amount of a compound of Formula (i) or a
pharmaceutically-acceptable salt thereof.
[0027] The compounds of this invention may be also be used in
association with the veterinary treatment of animals, other than
humans, in need of inhibition of TNF production. TNF mediated
diseases for treatment, therapeutically or prophylactically, in
animals include disease states such as those noted above, but in
particular viral infections. Examples of such viruses include, but
are not limited to feline immunodeficiency virus (FIV) or other
retroviral infection such as equine infectious anaemia virus,
caprine arthritis virus, visna virus, maedi virus and other
lentiviruses.
[0028] The compounds of this invention are also useful in treating
parasite, yeast and fungal infections, where such yeast and fungi
are sensitive to upregulation by TNF or will elicit TNF production
in vivo. A preferred disease state for treatment is fungal
meningitis.
[0029] The compounds of formula (i) are preferably in
pharmaceutically-acceptable form. By pharmaceutically-acceptable
form is meant, inter alia, a pharmaceutically-acceptable level of
purity excluding normal pharmaceutical additives such as diluents
and carriers, and including no material considered toxic at normal
dosage levels. A pharmaceutically-acceptable level of purity will
generally be at least 50% excluding normal pharmaceutical
additives, preferably 75%, more preferably 90% and still more
preferably 95%. When used herein the term
"pharmaceutically-acceptable" encompasses materials suitable for
both human and veterinary use.
[0030] A compound of formula (i) or where appropriate a
pharmaceutically-acceptable salt thereof and/or a
pharmaceutically-accept- able solvate thereof, may be administered
per se or, preferably, as a pharmaceutical composition also
comprising a pharmaceutically-acceptable carrier.
[0031] Accordingly, the present invention provides a pharmaceutical
composition comprising a compound of formula (i) or where
appropriate a pharmaceutically-acceptable salt thereof and/or a
pharmaceutically-accept- able solvate thereof, and a
pharmaceutically-acceptable carrier.
[0032] The active compound may be formulated for administration by
any suitable route, the preferred route depending upon the disorder
for which treatment is required, and is preferably in unit dosage
form or in a form that a human patient may administer to himself in
a single dosage. Advantageously, the composition is suitable for
oral, rectal, topical, parenteral administration or through the
respiratory tract. Preparations may be designed to give slow
release of the active ingredient.
[0033] The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasternal injection or
infusion techniques. In addition to the treatment of warm-blooded
animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc,
the compounds of the invention are effective in the treatment of
humans.
[0034] The compositions of the invention may be in the form of
tablets, capsules, sachets, vials, powders, granules, lozenges,
suppositories, reconstitutable powders, or liquid preparations such
as oral or sterile parenteral solutions or suspensions. Topical
formulations are also envisaged where appropriate.
[0035] In order to obtain consistency of administration it is
preferred that a composition of the invention is in the form of a
unit dose. Unit dose presentation forms for oral administration may
be tablets and capsules and may contain conventional excipients
such as binding agents, for example syrup, acacia, gelatin,
sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example
microcrystalline cellulose, lactose, sugar, maize-starch, calcium
phosphate, sorbitol or glycine; tabletting lubricants, for example
magnesium stearate; disintegrants, for example starch,
polyvinylpyrrolidone, sodium starch glycollate or microcrystalline
cellulose; or pharmaceutically-acceptable wetting agents such as
sodium lauryl sulphate.
[0036] Solid oral compositions may be prepared by conventional
methods of blending, filling, tabletting or the like. Repeated
blending operations may be used to distribute the active agent
throughout those compositions employing large quantities of
fillers.
[0037] Such operations are of course conventional in the art. The
tablets may be coated according to methods well known in normal
pharmaceutical practice, in particular with an enteric coating.
[0038] Oral liquid preparations may be in the form of, for example,
emulsions, syrups or elixirs, or may be presented as a dry product
for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, for example sorbitol, syrup, methyl cellulose,
gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium
stearate gel, hydrogenated edible fats; emulsifying agents, for
example lecithin, sorbitan monooleate, or acacia, non-aqueous
vehicles (which may include edible oils), for example almond oil,
fractionated coconut oil, oily esters such as esters of glycerine,
propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired
conventional flavouring or colouring agents.
[0039] Compositions may also suitably be presented for
administration to the respiratory tract as a snuff or an aerosol or
solution for a nebuliser, or as a microfine powder for
insufflation, alone or in combination with an inert carrier such as
lactose. In such a case the particles of active compound suitably
have diameters of less than 50 .mu.m, such as from 0.1 to 50 .mu.m,
preferably less than 10 .mu.m, for example from 1 to 10 .mu.m, 1 to
5 .mu.m or from 2 to 5 .mu.m. Where appropriate, small amounts of
other anti-asthmatics and bronchodilators for example
sympathomimetic amines such as isoprenaline, isoetharine,
salbutamol, phenylephrine and ephedrine; corticosteroids such as
prednisolone and adrenal stimulants such as ACTH may be
included.
[0040] For parenteral administration, fluid unit dosage forms are
prepared utilizing the compound and a sterile vehicle, and,
depending on the concentration used, can be either suspended or
dissolved in the vehicle. In preparing solutions, the compound can
be dissolved in water for injection and filter-sterilised before
filling into a suitable vial or ampoule and sealing.
[0041] Advantageously, adjuvants such as a local anaesthetic, a
preservative and buffering agents can be dissolved in the vehicle.
To enhance the stability, the composition can be frozen after
filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same
manner, except that the compound is suspended in the vehicle
instead of being dissolved, and sterilisation cannot be
accomplished by filtration. The compound can be sterilised by
exposure to ethylene oxide before suspending in the sterile
vehicle. Advantageously, a surfactant or wetting agent is included
in the composition to facilitate uniform distribution of the
compound.
[0042] The compositions may contain from 0.1% to 99% by weight,
preferably from 10-60% by weight, of the active material, depending
on the method of administration.
[0043] Compounds of formula (i), or if appropriate a
pharmaceutically-acceptable salt thereof and/or a
pharmaceutically-accept- able solvate thereof, may also be
administered as a topical formulation in combination with
conventional topical excipients.
[0044] Topical formulations may be presented as, for instance,
ointments, creams or lotions, impregnated dressings, gels, gel
sticks, spray and aerosols, and may contain appropriate
conventional additives such as preservatives, solvents to assist
drug penetration and emollients in ointments and creams. The
formulations may contain compatible conventional carriers, such as
cream or ointment bases and ethanol or oleyl alcohol for
lotions.
[0045] Suitable cream, lotion, gel, stick, ointment, spray or
aerosol formulations that may be used for compounds of formula (i)
or if appropriate a pharmaceutically-acceptable salt thereof, are
conventional formulations well known in the art, for example, as
described in standard text books such as Harry's Cosmeticology
published by Leonard Hill Books, Remington's Pharmaceutical
Sciences, and the British and US Pharmacopoeias.
[0046] Suitably, the compound of formula (i), or if appropriate a
pharmaceutically-acceptable salt thereof, will compromise from
about 0.5 to 20% by weight of the formulation, favourably from
about 1 to 10%, for example 2 to 5%.
[0047] The dose of the compound used in the treatment of the
invention will vary in the usual way with the seriousness of the
disorders, the weight of the sufferer, and the relative efficacy of
the compound. However, as a general guide suitable unit doses may
be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg,
for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be
administered more than once a day, for example 2, 3, 4, 5 or 6
times a day, but preferably 1 or 2 times per day, so that the total
daily dosage for a 70 kg adult is in the range of about 0.1 to 1000
mg, that is in the range of about 0.001 to 20 mg/kg/day, such as
0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg/day,
for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2
mg/kg/day, and such therapy may extend for a number of weeks or
months.
Assay Methods
[0048] The assays used to confirm the phosphodiesterase IV
inhibitory activity of compounds of formula (I) are standard assay
procedures as disclosed by Schilling et al, Anal. Biochem. 216:154
(1994), Thompson and Strada, Adv. Cycl. Nucl. Res. 8:119 (1979) and
Gristwood and Owen, Br. J. Pharmacol. 87:91P (1986).
[0049] Compounds of formula (i) have exhibited activity at levels
consistent with those believed to be useful in treating
phosphodiesterase IV related disease states in those assays.
[0050] The ability of compounds of formula (i) to inhibit TNF
production in human peripheral blood mononuclear cells (PMBC's) is
measured as follows. PMBC's are prepared from freshly taken blood
or "Buffy coats" by standard procedures. Cells are plated out in
RPMI1640+1% foetal calf serum in the presence and absence of
inhibitors. LPS (Lipopolysaccharide (endotoxin); 100 ng/ml) is
added and cultures are incubated for 22 h at 37.degree. C. in an
atmosphere of 95% air/5% CO.sub.2. Supernatants are tested for
TNF.alpha. by ELISA (Enzyme linked immunosorbent assay) using
commercially available kits.
[0051] Activity in a guinea pig lung model is measured using the
procedures described by Mauser et al, Am. Rev. Respir. Dis.
148:1623 (1993), and Am. J. Respir. Crit. Care Med. 152:467
(1995).
[0052] The compound of Example 2 of WO-A-97/44337 exhibits 41%
inhibition of eosinophilia in the guinea pig model when dosed at 30
mg/kg. Example 10 herein (representative of the present invention)
achieves 35% inhibition when dosed at 3 mg/kg.
[0053] The following Examples illustrate the invention.
[0054] Intermediate 1 2-(2-Formyl-6-methoxyphenoxy)acetaldehyde,
dimethyl acetal
[0055] o-Vanillin (20 g) and potassium carbonate (18 g) were
stirred in N,N-dimethylformamide (80 ml) at room temperature for 30
minutes. Bromoacetaldehyde dimethyl acetal (24 g) was added
dropwise ensuring that the temperature did not rise above
50.degree. C. The mixture was then heated at reflux for 4 hours
then cooled to room temperature. Diethyl ether (30 ml) was added
and the mixture was filtered. The solid was washed with ether
(2.times.30 ml) and the combined organic phases were concentrated
in vacuo to give the title compound (33 g) as a green oil.
[0056] TLC R.sub.f0.66 (50% ethyl acetate in hexane).
[0057] Intermediate 2 7-Methoxybenzofuran-2-carbaldehyde
[0058] 2-(2-Formyl-6-methoxyphenoxy)acetaldehyde, dimethyl acetal
(31 g) was heated to reflux in glacial acetic acid (120 ml)
overnight. The mixture was then cooled and the solvent removed in
vacuo to give a red oil. Purification by Kugelrohr distillation
gave the title compound (17 g) as a pale yellow oil which
solidified on standing.
[0059] TLC R.sub.f 0.71 (dichloromethane).
[0060] Intermediate 3 7-Methoxybenzofuran-2-yl-methanol
[0061] Sodium borohydride (0.462 g) was added in one portion to a
stirred solution of 7-methoxybenzofuran-2-carbaldehyde (2.15 g) in
methanol (50 ml) at room temperature and the reaction was stirred
for 3 hours. The reaction mixture was then diluted with water (100
ml) and extracted with dichloromethane (3.times.30 ml). The organic
extracts were combined, washed with water (30 ml), dried over
magnesium sulphate, filtered and the solvent removed in vacuo to
afford the title compound (2.10 g) as a pale orange liquid.
[0062] TLC R.sub.f 0.51 (2% methanol in dichloromethane).
[0063] Intermediate 4 7-Methoxy-2-methoxymethylbenzofuran
[0064] Sodium hydride (3.82 g, 60% in mineral oil) was added to a
solution of 7-methoxybenzofuran-2-ylmethanol (11.21 g) in dry
tetrahydrofuran (300 ml) under an atmosphere of dry nitrogen at
room temperature. After 10 minutes iodomethane (15.67 ml) was added
and the reaction was left to stir overnight. The solvent was
removed in vacuo and the residue partitioned between ethyl acetate
(100 ml) and water (50 ml). The organic extract was washed with
water (50 ml), followed by brine (50 ml), dried over magnesium
sulphate, filtered and the solvent removed in vacuo to afford the
title compound (13.32 g) as a yellow oil.
[0065] TLC R.sub.f 0.70 (50% ethyl acetate in hexane).
[0066] Intermediate 5
4-(tert-Butyldimethylsilanyloxy)-1-(7-methoxybenzofu-
ran-2-yl)-butan-1-ol
[0067] A suspension of dried magnesium turnings (0.42 g) in
anhydrous tetrahydrofuran (20 ml) was treated with 2 ml of
(3-Bromopropoxy)-tert-bu- tyldimethylsilane (4.4 g) in anhydrous
tetrahydrofuran (10 ml) at room temperature under a dry nitrogen
atmosphere. Initiation was achieved by the addition of catalytic
iodine and warming to 80.degree. C. The remaining solution (8 ml)
was then added carefully. The reaction was cooled to -5.degree. C.
and a solution of 7-methoxybenzofuran-2-carbaldeh- yde (3 g) in
anhydrous tetrahydrofuran (20 ml) was added carefully. After
stirring at ambient temperature overnight the solvent was removed
in vacuo. The residue was partitioned between ethyl acetate (100
ml) and saturated aqueous ammonium chloride solution (100 ml). The
organic extract was dried over magnesium sulphate, filtered and
preadsorbed onto silica. Purification by column chromatography on
silica eluting with 10% ethyl acetate in hexane afforded the title
compound as a yellow oil (4.88 g).
[0068] TLC R.sub.f 0.75 (20% ethyl acetate).
[0069] Intermediate 6
1-(7-Methoxybenzofuran-2-yl)-butane-1,4-diol
[0070] Tetrabutylammonium fluoride (1 2 ml, 1M in tetrahydrofuran)
was added to a stirred solution of
4-(tert-butyldimethylsilanyloxy)-1-(7-meth-
oxybenzofuran-2-yl)-butan-1-ol (4 g) in tetrahdrofuran (50 ml) at
0.degree. C. After stirring cooled for 2 hours the reaction was
warmed to room temperature and allowed to stir for a further 1
hour. The solvent was removed in vacuo and the residue partitioned
between ethyl acetate (100 ml) and water (50 ml). The organic
extract was dried over magnesium sulphate, filtered and preadsorbed
onto silica. Purification by column chromatography on silica
eluting with ethyl acetate yielded the title compound as a tan oil
(2.34 g).
[0071] TLC R.sub.f 0.15 (50% ethyl acetate in hexane).
[0072] Intermediate 7
7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran
[0073] A solution of 1-(7-methoxybenzofuran-2-yl)-butane-1,4-diol
(0.88 g) was treated with p-toluenesulfonic acid monohydrate (10
mg) and 3.ANG. molecular sieves in dichloromethane (10 ml) at
ambient temperature. After stirring for 1 hour the solvent was
removed in vacuo. The residue was purified by column chromatography
on silica eluting with 20% ethyl acetate in hexane to give the
title compound as a yellow oil (0.58 g).
[0074] TLC R.sub.f 0.35 (20% ethyl acetate in hexane).
[0075] Intermediate 8
3-(7-Methoxybenzofuran-2-yl)-tetrahydrofuran-3-ol
[0076] Methyl sulfoxide (1.16 ml) was added dropwise to a stirred
solution of oxalyl chloride (0.71 ml) in dry dichloromethane (15
ml) at -60.degree. C. under an inert atmosphere. After stirring at
this temperature for 30 minutes a solution of
3-hydroxytetrahydrofuran (0.55 ml) in dry dichloromethane was added
carefully. After a further 30 minutes triethylamine was added
dropwise and the reaction allowed to warm to room temperature. The
reaction was poured onto water (40 ml) and extracted with
dichloromethane (30 ml). The organic phase was washed with water
(50 ml), brine (2.times.50 ml) and saturated aqueous sodium
hydrogen carbonate solution (2.times.50 ml). After drying over
magnesium sulphate the solvent was removed in vacuo to afford
tetrahydro-furan-3-one as a yellow gum (0.19 g). n-Butyllithium
(0.72 ml, 1.6M in hexanes) was added dropwise to a stirred solution
of 7-methoxybenzofuran (0.15 g) in dry tetrahydrofuran (5 ml) at
-78.degree. C. under a dry nitrogen atmosphere. After stirring for
20 minutes a solution of tetrahydrofuran-3-one (90 mg) in dry
tetrahydrofuran (2 ml) was added carefully. After stirring for a
further 15 minutes at -78.degree. C. the reaction was allowed to
warm to room temperature. The reaction was carefully quenched with
water and the solvent removed in vacuo. The residue was partitioned
between ethyl acetate (2.times.15 ml) and water (15 ml). The
combined organic extracts were dried over magnesium sulphate,
filtered and concentrated in vacuo. The residue was purified by
column chromatography on silica eluting with 50% ethyl acetate in
hexane to give the title compound as an orange gum (64 mg).
[0077] TLC R.sub.f0.37 (50% ethyl acetate in hexane).
[0078] Intermediate 9
7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran
[0079] Triethylamine (0.19 ml) was added to a stirred solution of
3-(7-methoxybenzofuran-2-yl)-tetrahydrofuran-3-ol (0.15 g) in dry
dichloromethane (8 ml) at room temperature under a dry nitrogen
atmosphere. Methanesulfonyl chloride (0.08 ml) was then added
followed by a catalytic amount of 4-(dimethylamino)pyridine. After
stirring at room temperature overnight the solvent was removed in
vacuo. The residue was purified by column chromatography on silica
eluting with 50% ethyl acetate in hexane to give a mixture of
2-(4,5-dihydrofuran-3-yl)-7-methox- ybenzofuran and
2-(2,5-dihydrofuran-3-yl)-7-methoxybenzofuran (85 mg) as a yellow
solid.
[0080] A solution of the alkene mixture (85 mg) in ethanol (10 ml)
was treated with Raney Nickel and hydrogenated at atmospheric
pressure for 1 hour. The reaction mixture was filtered through
celite and the solvent was removed in vacuo to give the title
compound as a white solid (80 mg).
[0081] TLC R.sub.f 0.49 (33% ethyl acetate in hexane).
[0082] Intermediate 10 2-(Tetrahydrofuran-3-yl)-benzofuran-7-ol
[0083] Sodium hydride (0.19 g, 60% in mineral oil) was added to a
stirred solution of ethane thiol (0.34 ml) in N,N-dimethylformamide
(6 ml) at room temperature under a dry nitrogen atmosphere. After
stirring for 15 minutes 7-methoxy-2-(tetrahydrofuran-3-yl)
benzofuran (0.5 g) in N,N-dimethylformamide (6 ml) was added and
the reaction heated to 140.degree. C. for 2 hours. After cooling to
room temperature the solvent was removed in vacuo. The residue was
partitioned between ethyl acetate (50 ml) and water (50 ml). The
organic extract was dried over magnesium sulphate, filtered and
preadsorbed onto silica. Purification by column chromatography on
silica eluting with 50% ethyl acetate in heptane afforded the title
compound as a brown oil (0.37 g).
[0084] TLC R.sub.f 0.38 (50% ethyl acetate in heptane).
[0085] Intermediate 11
tert-Butyldimethyl-[2-(tetrahydrofuran-3-yl)-benzof-
uran-7-yloxy]-silane
[0086] Sodium hydride (80 mg, 60% dispersion in mineral oil) was
added to a stirred solution of
2-(tetrahydrofuran-3-yl)-benzofuran-7-ol (0.37 g) in dry
tetrahydrofuran (10 ml) at room temperature under a dry nitrogen
atmosphere. After stirring for 10 minutes tert-butyldimethylsilyl
chloride (0.27 g) was added and the reaction stirred for 90
minutes. The reaction mixture was partitioned between ethyl acetate
(30 ml) and water (2.times.25 ml). The combined aqueous washings
were extracted with ethyl acetate (30 ml). The organic extracts
were combined, dried over magnesium sulphate, filtered and
concentrated in vacuo to give the title compound as a yellow oil
(0.58 g).
[0087] TLC R.sub.f 0.7 (50% ethyl acetate in heptane).
[0088] Intermediate 12
4-Bromo-7-methoxy-2-methoxymethylbenzofuran
[0089] A solution of 7-methoxy-2-methoxymethylbenzofuran (13.32 g)
in acetonitrile (500 ml) was stirred at room temperature.
N-bromosuccinimide (11.04 g) was added and stirring continued for 2
days after which the solvent was removed in vacuo. The resulting
oil was partitioned between ethyl acetate (100 ml) and sodium
metasulfite solution (50 ml), the organic extract washed with more
sodium metasulfite solution (2.times.50 ml), followed by brine (50
ml). The organic layer was separated, dried over magnesium
sulphate, filtered and the solvent removed in vacuo to afford the
title compound as a yellow oil (18.61 g).
[0090] TLC R.sub.f 0.73 (50% ethyl acetate in hexane).
[0091] The following compounds were prepared in a similar
manner.
[0092] Intermediate 13
4-Bromo-7-methoxy-2-(tetrahydrofuran-2-yl)-benzofur- an
[0093] Starting from 7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran
(0.58 g). The title compound was obtained as a yellow oil (0.8
g).
[0094] TLC R.sub.f 0.35 (20% ethyl acetate in hexane).
[0095] Intermediate 14
4-Bromo-7-methoxy-2-(tetrahydrofuran-3-yl)-benzofur- an
[0096] Starting from 7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran
(80 mg). The title compound was obtained as a brown oil (65
mg).
[0097] TLC R.sub.f 0.46 (33% ethyl acetate in hexane).
[0098] Intermediate 15
[4-Bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-ylox-
y]-tert-butyldimethylsilane
[0099] Starting from
tert-Butyldimethyl-[2-(tetrahydrofuran-3-yl)-benzofur-
an-7-yloxy]-silane (0.59 g). Purification by column chromatography
on silica eluting with 20% ethyl acetate in heptane afforded the
title compound as a brown oil (0.31 g).
[0100] TLC R.sub.f 0.48 (20% ethyl acetate in heptane).
[0101] Intermediate 16
4-Bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-ol
[0102] Tetrabutylammonium fluoride (8.1 ml, 1M in tetrahydrofuran)
was added to a stirred solution of
[4-bromo-2-(tetrahydrofuran-3-yl)-benzofur-
an-7-yloxy]-tert-butyldimethylsilane (2.69 g) in dry
tetrahydrofuran (80 ml) at 0.degree. C. under a dry nitrogen
atmosphere. After stirring at this temperature for 45 minutes the
solvent was removed in vacuo. The residue was partitioned between
ethyl acetate (75 ml) and water (75 ml). The organic extract was
dried over magnesium sulphate, filtered and concentrated in vacuo.
Purification by column chromatography on silica eluting with 50%
ethyl acetate in heptane afforded the title compound as a clear oil
(1 g).
[0103] TLC R.sub.f 0.39 (50% ethyl acetate in heptane).
[0104] Intermediate 17 4-Bromo-2-methoxymethylbenzofuran-7-ol
[0105] To a stirred solution of sodium hydride (334 mg, 60% in
mineral oil) in dry N,N-dimethylformamide (25 ml) under an
atmosphere of dry nitrogen at room temperature was added dropwise
ethane thiol (0.586 ml). After stirring for 20 minutes a solution
of 4-bromo-7-methoxy-2-methoxyme- thylbenzofuran(2.04 g) in
N,N-dimethyl-formamide (7 ml) was added dropwise and the reaction
mixture was heated at 160.degree. C. for 2 hours. The reaction was
cooled and the solvent removed in vacuo. The residue was dissolved
in ethyl acetate (70 ml) and washed with ammonium chloride solution
(70 ml). The organic extract was dried over magnesium sulphate,
filtered and the solvent removed in vacuo. Purification by column
chromatography on silica eluting with 50% ethyl acetate in hexane
afforded the title compound as a white solid (1.21 g).
[0106] TLC R.sub.f0.65 (50% ethyl acetate in hexane).
[0107] Intermediate 18
4-Bromo-7-difluoromethoxy-2-methoxymethylbenzofuran
[0108] To a solution of 4-bromo-2-methoxymethylbenzofuran-7-ol in
1,4-dioxane (25 ml) heated to 100.degree. C. was added dropwise a
solution of sodium hydroxide (0.76 g) in water (2 ml).
Chlorodifluoromethane was bubbled through the reaction mixture for
2 hours after which it was allowed to cool to room temperature and
the organic solvent removed in vacuo. The resulting aqueous slurry
was extracted with ethyl acetate (3.times.25 ml). The organic
extracts were dried over magnesium sulphate, filtered and the
solvent removed in vacuo. Purification by column chromatography on
silica eluting with 20% ethyl acetate in hexane afforded the title
compound as an off-white solid (1.24 g).
[0109] TLC R.sub.f 0.73 (20% ethyl acetate in hexane).
[0110] The following compound was prepared in a similar manner.
[0111] Intermediate 19
4-Bromo-7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-- benzofuran
[0112] Starting from
4-bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-ol (1 g).
Purification by column chromatography on silica eluting with 30%
ethyl acetate in heptane gave the title compound as a pale yellow
solid (0.8 g).
[0113] TLC R.sub.f 0.64 (50% ethyl acetate in heptane).
[0114] Intermediate 20
7-Methoxy-2-methyoxymethylbenzofuran-4-carboxylic acid
[0115] 4-Bromo-7-methoxy-2-methoxymethylbenzofuran (18.61 g),
Pplladuim chloride (3.09 g), bis-diphenylphosphinopropane (6.60 g),
triethylamine (49.65 ml), tetrahydrofuran (200 ml), and water
(50ml) were combined in a Parr pressure reactor. The vessel was
purged with carbon monoxide 3 times before being charged with
carbon monoxide at 140 psi. The vessel was then heated at
90.degree. C. for 3 days before cooling and release of the
pressure. The reaction mixture was concentrated in vacuo and the
residue taken up in 2N sodium hydroxide solution (250 ml). The
reaction mixture was washed with ethyl acetate (2.times.300 ml) and
then the aqueous layer was acidified to pH 5 with 10N hydrochloric
acid. The resulting mixture was extracted with dicloromethane
(2.times.100 ml), the combined organic extracts dried over
magnesium sulphate, filtered and the solvent removed in vacuo to
afford the title compound as a yellow solid (14.24 g).
[0116] TLC R.sub.f 0.31 (50% ethyl acetate in hexane).
[0117] The following compounds were prepared in a similar manner.
Intermediate 21
7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid
[0118] Starting from
4-bromo-7-difluoromethoxy-2-methoxymethylbenzofuran (1.24 g). After
carbonylation the reaction mixture was concentrated in vacuo to
remove organic solvent and the subsequent aqueous residue extracted
with dichloromethane (50 ml). The aqueous layer was acidified to
pH4 with glacial acetic acid and extracted with ethyl acetate
(2.times.100 ml). The combined organic extracts were dried over
magnesium sulphate, filtered and the solvent removed in vacuo to
afford the title compound as a white solid.
[0119] TLC R.sub.f 0.63 (50% ethyl acetate in hexane).
[0120] Intermediate 22
7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-car- boxylic
acid
[0121] Starting from
4-bromo-7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran (1.9 g). The
title compound was obtained as an orange solid (1.18 g).
[0122] TLC R.sub.f 0.58 (ethyl acetate).
[0123] Intermediate 23
7-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofur-
an-4-carboxylic acid
[0124] Starting from
4-bromo-7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-be- nzofuran
(0.8 g). The title compound was obtained as a cream solid (0.72
g).
[0125] TLC R.sub.f 0.24 (50% ethyl acetate in heptane).
[0126] Intermediate 24
7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-car- boxylic
acid
[0127] Starting from
4-bromo-7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran (0.8 g). The
title compound was obtained as an off white solid (0.63 g).
[0128] TLC R.sub.f 0.13 (20% ethyl acetate in hexane).
[0129] Intermediate 25
7-Methoxy-2-methoxymethylbenzofuran-4-carboyxlic acid 4-nitrophenyl
ester
[0130] 7-Methoxy-2-methyoxymethylbenzofuran-4-carboxylic acid (0.42
g), p-nitrophenol (0.29 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.4 g)
and 4-dimethylaminopyridine (catalytic) in dry dichloromethane (30
ml) were stirred overnight at room temperature. The reaction
mixture was washed with water (40 ml) and the aqueous layer
extracted with dichloromethane (40 ml). The organic extracts were
combined, washed with water (80 ml), dried over magnesium sulphate,
filtered and the solvent removed in vacuo. The residue was
triturated with ethyl acetate and diethyl ether to afford the title
compound as a cream solid (0.42 g).
[0131] TLC R.sub.f 0.61 (50% ethyl acetate in hexane).
[0132] The following compounds were prepared in a similar
manner.
[0133] Intermediate 26
7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carbo- xylic acid
4-nitrophenyl ester
[0134] Starting from
7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxy- lic acid
(118 mg). Purification by trituration with diethyl ether afforded
the title compound as a pale yellow solid (83 mg).
[0135] TLC R.sub.f 0.54 (50% ethyl acetate in heptane).
[0136] Intermediate 27
7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-car- boxylic acid
4-nitrophenyl ester
[0137] Starting from
7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carbo- xylic acid
(1.16 g). The title compound was obtained as a brown solid (1.76
g).
[0138] TLC R.sub.f 0.82 (5% methanol in dichloromethane).
[0139] Intermediate 28
7-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofur-
an-4-carboxylic acid 4-nitrophenyl ester
[0140] Starting from
7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-
-4-carboxylic acid (0.3 g). Purification by column chromatography
on silica eluting with 50% ethyl acetate in heptane gave the title
compound as a white solid (0.38 g).
[0141] TLC R.sub.f 0.55 (50% ethyl acetate in heptane).
[0142] Intermediate 29
7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-car- boxylic acid
4-nitrophenyl ester
[0143] Starting from
7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carbo- xylic acid
(0.3 g). Purification by column chromatography on silica eluting
with 50% ethyl acetate in heptane gave the title compound as a
cream solid (0.37 g).
[0144] TLC R.sub.f 0.48 (50% ethyl acetate in heptane).
[0145] Intermediate 30 4-Chloro-2-methyl-2H-pyrazol-3-ylamine
[0146] To a solution of 2-methyl-2H-pyrazol-3-ylamine (0.30 g) in
conc. hydrochloric acid (4 ml) heated to 85.degree. C. was added
dropwise hydrogen peroxide (0.67 ml of a 30% solution in water).
Heating continued for 60 mins. After cooling to 0.degree. C. the
solution was taken to pH 11 using 46/48% w/w sodium hydroxide
solution. The solid formed was filtered off and the filtrate
extracted with ethyl acetate (4.times.50 ml). The combined organic
layers were dried over magnesium sulphate, filtered and
concentrated in vacuo. The resulting product was combined with the
previously collected product to afford the title compound as a
brown solid (0.13 g).
[0147] TLC R.sub.f 0.50 (10% methanol in dichloromethane).
EXAMPLE 1
7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide
[0148] To a stirred solution of 3,5-dimethylisoxazol-4-ylamine (88
mg) in N,N-dimethylformamide (7 ml) under an atmosphere of dry
nitrogen at room temperature was added sodium
bis(trimethylsilyl)amide (0.78 ml, 1.0M solution in
tetrahydrofuran). The reaction was stirred for 5 minutes.
7-Methoxy-2-(tetrahydro-furan-3-yl)-benzofuran-4-carboxylic acid
4-nitrophenyl ester (200 mg) was then added and stirring continued
for 15 minutes. Water (1 ml) was added and the solvent was removed
in vacuo. The resulting residue was purified by column
chromatography on silica eluting with 50% ethyl acetate in heptane
followed by trituration with diethyl ether affording the title
compound as a cream solid (52 mg).
[0149] TLC R.sub.f 0.60 (50% ethyl acetate in heptane).
[0150] Mp 183.5-185.2.degree. C.
[0151] The following compounds were prepared in a similar
manner.
EXAMPLE 2
7-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic
acid (4-cyano-2-methyl-2-H-pyrazol-3-yl)-amide
[0152] Prepared from
7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-
-4-carboxylic acid 4-nitrophenyl ester (380 mg) and
5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (220 mg). The reaction
was stirred for 2 hours at room temperature. Water (1 ml) was added
and the solvent removed in vacuo. The residue was dissolved in
ethyl acetate (50 ml) and washed with water (2.times.40 ml),
followed by 1N hydrochloric acid (40 ml). The organic extract was
dried over magnesium sulphate, filtered and preadsorbed onto
silica. Purification by column chromatography on silica eluting
with 70% ethyl acetate in heptane, followed by trituration with
diethyl ether afforded the title compound as a white solid (170
mg).
[0153] TLC R.sub.f 0.63 (ethyl acetate).
[0154] Mass spectrum m/z 403 [M+H].
EXAMPLE 3
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(5cyano-3-methyl-3H-imidazol-4-yl)-amide
[0155] Prepared from
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid 4-nitrophenyl
ester (250 mg) and 5-amino-1-methyl-1-H-imidazole-4-carboni- trile
(171 mg). The reaction was stirred for 1 hour and 40 minutes. Water
(1 ml) was added and the solvent removed in vacuo. Purification by
column chromatography on silica eluting with 10% methanol in
dichloromethane afforded the title compound as a pale yellow solid
(178 mg).
[0156] TLC R.sub.f0.35 (10% methanol in dichloromethane).
[0157] Mass spectrum m/z 339[M-H]
EXAMPLE 4
7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide
[0158] Prepared from
7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxy- lic acid
4-nitrophenyl ester (83 mg) and 5-amino-1-methyl-1-H-pyrazole-4-c-
arbonitrile (52 mg) at 0.degree. C. The reaction was stirred for 90
minutes at room temperature. Water (1 ml) was added and the solvent
removed in vacuo. Purification by column chromatography on silica
eluting with 70% ethyl acetate in heptane, followed by trituration
with diethyl ether afforded the title compound (21 mg).
[0159] TLC R.sub.f0.35 (70% ethyl acetate in heptane).
[0160] Mp 118-120.degree. C.
EXAMPLE 5
7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide
[0161] Prepared from 7-methoxy-2-(tetrahydrofuran-3
-yl)-benzofuran-4-carboxylic acid 4-nitrophenyl ester (200 mg) and
5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (127 mg) at 0.degree.
C. The reaction was stirred for 60 minutes at room temperature.
Water (1 ml) was added and the solvent removed in vacuo.
Purification by column chromtography on silica eluting with 10%
methanol in dichloromethane followed by gradient preparative HPLC
on a Phenomenex LUNA(2).TM. C18 column eluting with 0.05%
trifluoroacetic acid in 20%-65% acetonitrile in water afforded the
title compound (19 mg) as a white solid.
[0162] TLC R.sub.f 0.47 (ethyl acetate).
[0163] Mp 186-188.8.degree. C.
EXAMPLE 6
7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide
[0164] Prepared from
7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carbo- xylic acid
4-nitrophenyl ester (370 mg) and 5-amino-1-methyl-1-H-pyrazole-- 4
carbonitrile (122 mg). The residue obtained from removing solvent
in vacuo was dissolved in ethyl acetate (50 ml) and washed with
water (50 ml) followed 1N hydrochloric acid (25 ml). The organic
extract was dried over magnesium sulphate, filtered and preadsorbed
onto silica. Purification by column chromatography on silica
eluting with ethyl acetate afforded the title compound as a white
solid (166 mg).
[0165] TLC R.sub.f0.56 (ethyl acetate).
[0166] Mp 114.5-116.degree.0 C.
EXAMPLE 7
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(4-cyano-2-methyl-2-pyrazol-3-yl)-amide
[0167] Oxalyl chloride (0.07 ml) was added to a stirred solution of
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (100 mg) in
dry dichloromethane (20 ml) at room temperature under a dry
nitrogen atmosphere. N,N-dimethylformamide (catalytic amount) was
added and the reaction allowed to stir overnight. The solvent was
removed in vacuo to afford the corresponding acid chloride as an
oily yellow solid.
[0168] To a stirred solution of
5-amino-1-methyl-1-H-pyrazole-4-carbonitri- le (155 mg) in
N,N-dimethylformamide (7 ml) under an atmosphere of nitrogen at
0.degree. C. was added sodium hydride (51 mg, 60% dispersion in
mineral oil). The reaction was stirred at 0.degree. C. for 5
minutes. A solution of the acid chloride in N,N-dimethylformamide
(8 ml) was added and the reaction stirred at room temperature for 2
hours. Water (1 ml) was added and the solvent removed in vacuo.
Purification by column chromatography on silica eluting with 1%
methanol in dichloromethane followed by trituration with 50%
diethyl ether in hexane afforded the title compound as a pale
yellow solid (4 mg).
[0169] TLC R.sub.f 0.52 (10% methanol in dichloromethane).
[0170] Mass spectrum m/z 339[M-H]
EXAMPLE 8
7-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic
acid (3,5-dimethylisoxazol-4-yl)-amide
[0171] Oxalyl chloride (0.09 ml) was added to a stirred solution of
7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic
acid (0.15 g) in dry dichloromethane (20 ml) at room temperature
under a dry nitrogen atmosphere. N,N-dimethylformamide (catalytic
amount) was added and the reaction allowed to stir for 2 hours. The
solvent was removed in vacuo to furnish the corresponding acid
chloride as a yellow oil.
[0172] 3,5-Dimethylisoxazol-4-ylamine (0.11 g) was added to a
stirred solution of the acid chloride in dry dichloromethane (30
ml) at room temperature under a dry nitrogen atmosphere.
Triethylamine (0.14 ml) was added and the reaction allowed to stir
at room temperature for 2 hours. The reaction was washed with water
(30 ml) and 1N hydrochloric acid (30 ml). The organic phase was
dried over magnesium sulphate, filtered and preadsorbed onto
silica. Purification by column chromatography on silica eluting
with 30% heptane in ethyl acetate yielded the title compound as a
white solid (0.16 g).
[0173] TLC R.sub.f 0.17 (50% ethyl acetate in heptane)
[0174] Mp 155.5-156.5.degree. C.
[0175] The following compounds were prepared in a similar
manner.
EXAMPLE 9
7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide
[0176] Starting from
7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carbo- xylic acid
(262 mg) and 3,5-dimethylisoxazol-4-ylamine (120 mg). Purification
by column chromatography on silica eluting with 30% ethyl acetate
in hexane afforded the title compound as an off-white solid (238
mg).
[0177] TLC R.sub.f 0.36 (50% ethyl acetate in hexane)
[0178] Mass spectrum m/z 357 [M+H].
EXAMPLE 10
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide
[0179] Starting from
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.19 g) and
3,5-dimethylisoxazol-4-ylamine (88 mg). Purification by column
chromatography on silica eluting with ethyl acetate afforded the
title compound as a cream solid (0.18 g).
[0180] TLC R.sub.f 0.17 (5% methanol in dichloromethane)
[0181] Mp 168.5-169.5.degree. C.
EXAMPLE 11
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(4-chloro-2-methyl-2H-pyrazol-3-yl)-amide
[0182] Starting from
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.14 g) and
4-chloro-2-methyl-2H-pyrazol-3-ylamine (78 mg). Purification by
column chromatography on silica eluting with 50%-75% ethyl acetate
in hexane afforded the title compound as an off white solid (34
mg).
[0183] TLC R.sub.f 0.57 (ethyl acetate)
[0184] Mp 158-160.degree. C.
EXAMPLE 12
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(2-methyl-2H-pyrazol-3-yl)-amide
[0185] Starting from
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (93 mg) and
2-methyl-2H-pyrazol-3-ylamine (40 mg). Purification by column
chromatography on silica eluting with ethyl acetate afforded the
title compound as a white solid (43 mg).
[0186] TLC R.sub.f 0.4 (ethyl acetate).
[0187] Mp 148-150.degree. C.
EXAMPLE 13
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(2-ethyl-2H-pyrazol-3-yl)-amide
[0188] Starting from
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.15 g) and
2-ethyl-2H-pyrazol-3-ylamine (85 mg). Purification by column
chromatography on silica eluting with 50% ethyl acetate in heptane
increasing to ethyl acetate afforded the title compound as a yellow
solid (35 mg).
[0189] TLC R.sub.f 0.35 (ethyl acetate)
[0190] Mp 97-99.degree. C.
EXAMPLE 14
7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(2,4-dimethyl-2H-pyrazol-3-yl)-amide
[0191] Starting from
7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.1 g) and
2,4-dimethyl-2H-pyrazol-3-ylamine (56 mg). Purification by column
chromatography on silica eluting with 20% heptane in ethyl acetate
and gradient preparative HPLC on a Phenomenex LUNA(2).TM. C18
column eluting with 0.05% trifluoroacetic acid in 20%-65%
acetonitrile in water gave the title compound as a pale yellow
solid (39 mg).
[0192] TLC R.sub.f 0.33 (ethyl acetate)
[0193] Mass spectrum m/z 328 [M-H].
EXAMPLE 15
7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid
(3,5-dimethylisoxazol-4-yl)-amide
[0194] Cyanuric chloride (19 mg) and triethylamine (0.05 ml) were
added to a stirred solution of
7-difluoromethoxy-2-methoxymethylbenzofuran-4-carbo- xylic acid (85
mg) in dry dichloromethane at room temperature under a dry nitrogen
atmosphere. After stirring for 20 minutes
3,5-dimethylisoxazol-4-ylamine (42 mg) was added and the reaction
left overnight. The reaction was mixture was preadsorbed onto
silica. Purification by column chromatography on silica eluting
with 30% ethyl acetate in hexane gave the title compound as a cream
solid (33 mg)
[0195] TLC R.sub.f 0.52 (50% ethyl acetate in hexane)
[0196] Mass spectrum m/z 367 [M+H].
* * * * *