U.S. patent application number 13/462068 was filed with the patent office on 2012-08-30 for use of b-aminoalcohols in the treatment of inflammatory disorders and pain.
This patent application is currently assigned to BIOCOPEA LIMITED. Invention is credited to Robin Mark Bannister, Andrew Douglas Baxter, John Brew.
Application Number | 20120219592 13/462068 |
Document ID | / |
Family ID | 36241338 |
Filed Date | 2012-08-30 |
United States Patent
Application |
20120219592 |
Kind Code |
A1 |
Brew; John ; et al. |
August 30, 2012 |
Use of B-Aminoalcohols in the Treatment of Inflammatory Disorders
and Pain
Abstract
A compound for therapeutic use, of the formula ##STR00001##
wherein R.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.5; R.sub.2 is H, alkyl or CH.sub.2OH or forms part of a ring
with R.sub.4; R.sub.3 is H, alkyl or CH.sub.2OH or forms part of a
ring with R.sub.4; R.sub.4 is H, alkyl or (when forming part of a
ring with R.sub.2 or R.sub.3) CH.sub.2; and R.sub.5 is alkyl,
CF.sub.3, OH, Oalkyl, OCOalkyl, CONH.sub.2, CN, halogen, NH.sub.2,
NO.sub.2, NHCHO, NHCONH.sub.2, NHSO.sub.2Me, CONH.sub.2, or SOMe;
or a salt thereof.
Inventors: |
Brew; John; (London, GB)
; Baxter; Andrew Douglas; (London, GB) ;
Bannister; Robin Mark; (London, GB) |
Assignee: |
BIOCOPEA LIMITED
London
GB
|
Family ID: |
36241338 |
Appl. No.: |
13/462068 |
Filed: |
May 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12282259 |
Mar 29, 2009 |
8188150 |
|
|
PCT/GB2007/000816 |
Mar 7, 2007 |
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13462068 |
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Current U.S.
Class: |
424/278.1 ;
514/171; 514/653; 564/342 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
19/10 20180101; A61P 25/04 20180101; A61P 25/06 20180101; A61P
25/24 20180101; A61P 11/06 20180101; A61P 17/06 20180101; A61P
21/02 20180101; A61P 19/00 20180101; A61P 29/00 20180101; A61P 1/02
20180101; A61P 1/04 20180101; A61P 3/10 20180101; A61P 25/08
20180101; A61P 27/04 20180101; A61P 17/00 20180101; A61P 25/00
20180101; A61P 17/04 20180101; A61P 31/00 20180101; A61P 37/04
20180101; A61P 27/02 20180101; A61P 13/12 20180101; A61P 19/02
20180101; A61P 37/00 20180101; A61K 31/137 20130101; A61P 43/00
20180101; A61P 11/00 20180101; A61P 27/00 20180101; A61P 9/00
20180101 |
Class at
Publication: |
424/278.1 ;
514/171; 514/653; 564/342 |
International
Class: |
A61K 45/00 20060101
A61K045/00; A61K 31/135 20060101 A61K031/135; C07C 223/06 20060101
C07C223/06; A61P 29/00 20060101 A61P029/00; A61P 25/00 20060101
A61P025/00; A61P 11/00 20060101 A61P011/00; A61P 1/00 20060101
A61P001/00; A61P 17/00 20060101 A61P017/00; A61P 3/10 20060101
A61P003/10; A61P 27/02 20060101 A61P027/02; A61P 37/04 20060101
A61P037/04; A61P 31/00 20060101 A61P031/00; A61P 25/08 20060101
A61P025/08; A61P 25/24 20060101 A61P025/24; A61P 21/02 20060101
A61P021/02; A61K 31/56 20060101 A61K031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 7, 2006 |
GB |
0604822.7 |
Claims
1. A compound of formula (I) ##STR00005## wherein R.sub.1 is aryl
or heteroaryl optionally substituted with R.sub.5; R.sub.2 is H,
alkyl or CH.sub.2OH or forms part of a ring with R.sub.4; R.sub.3
is H, alkyl or CH.sub.2OH or forms part of a ring with R.sub.4;
R.sub.4 is H, alkyl or (when forming part of a ring with R.sub.2 or
R.sub.3) CH.sub.2; and R.sub.5 is alkyl, CF.sub.3, OH, Oalkyl,
OCOalkyl, CONH.sub.2, CN, halogen, NH.sub.2, NO.sub.2, NHCHO,
NHCONH.sub.2, NHSO.sub.2Me, CONH.sub.2 or SOMe; or a salt
thereof.
2. The compound according to claim 1, which is
.alpha.-[(1,1-dimethyl-2-hydroxyethyl)amino]-4-amino-3,5-dichloroacetophe-
none.
3. A pharmaceutical composition comprising a compound according to
claim 1 and a carrier or diluent.
4. A method of treating an inflammatory condition or a pain
condition, the method comprising the step of administering to an
individual in need thereof a pharmaceutical composition as defined
in claim 3.
5. The method according to claim 4, wherein the inflammatory
condition is a chronic degenerative disease.
6. The method according to claim 4, wherein the inflammatory
condition is a chronic demyelinating disease.
7. The method according to claim 4, wherein the inflammatory
condition is a respiratory disease.
8. The method according to claim 4, wherein the inflammatory
condition is an inflammatory bowel disease (IBD).
9. The method according to claim 4, wherein the inflammatory
condition is a dermatological condition.
10. The method according to claim 4, wherein the inflammatory
condition is a dental disease such as periodontal disease or
gingivitis.
11. The method according to claim 4, wherein the inflammatory
condition is diabetic nephropathy, lupus nephritis, IgA
nephropathy, or glomerulonephritis.
12. The method according to claim 4, wherein the inflammatory
condition is systemic lupus erythematosus.
13. The method according to claim 4, wherein the inflammatory
condition is graft vs host disease.
14. The method according to claim 4, wherein the condition is an
ophthalmic condition.
15. The method according to claim 4, wherein the pain condition is
a chronic pain or an acute pain.
16. The method according to claim 4, wherein the pain condition is
neuropathic pain.
17. The method according to claim 4, wherein the individual is also
administered another therapeutic agent selected from
18. The method according to claim 4, wherein the individual is also
administered an additional therapeutic agent, the additional
therapeutic agent includes a corticosteroid, a cytotoxic, an
antibiotic, an immunosupressant, a non-steroidal anti-inflammatory
drug, a narcotic analgesic, a local anaesthetic, an NMDA
antagonist, a neuroleptic, an anti-convulsant, an anti-spasmodic,
an anti-depressant, or a muscle relaxant.
19. The method according to claim 18, wherein the compound and the
additional therapeutic agent are provided in combination.
Description
PRIORITY CLAIM
[0001] This application is a continuation that claims priority
pursuant to 35 U.S.C. 120 to U.S. Non-Provisional patent
application Ser. No. 12/282,259, filed Mar. 29, 2009, a national
stage entry of PCT/GB2007/000816, filed Mar. 7, 2007, which claims
priority to Great Britain Patent Application No. 0604822.7, filed
Mar. 7, 2006, each of which is hereby incorporated by reference in
its entirety.
BACKGROUND
[0002] 1. Field of the Invention
[0003] This invention relates to the use of beta-aminoalcohols in
the treatment of inflammatory disorders and pain
[0004] 2. Background of the Invention
[0005] Immune-driven inflammatory events are a significant cause of
many chronic inflammatory diseases where prolonged inflammation
causes tissue destruction and results in extensive damage and
eventual failure of the effected organ. The cause of these diseases
is unknown, so they are often called autoimmune, as they appear to
originate from an individual's immune system turning on itself.
Conditions include those involving multiple organs, such as
systemic lupus erythematosus (SLE) and scleroderma. Other types of
autoimmune disease can involve specific tissues or organs such as
the musculoskeletal tissue (rheumatoid arthritis, ankylosing
spondylitis), gastro-intestinal tract (Crohn's disease and
ulcerative colitis), the central nervous system (Alzheimer's,
multiple sclerosis, motor neurone disease, Parkinson's disease and
chronic fatigue syndrome), pancreatic beta cells (insulin-dependent
diabetes mellitus), the adrenal gland (Addison's disease), the
kidney (Goodpasture's syndrome, IgA nephropathy, interstitial
nephritis), exocrine glands (Sjogren's syndrome and autoimmune
pancreatitis) and skin (psoriasis and atopic dermatitis).
[0006] In addition, there are chronic inflammatory diseases whose
aetiology is more or less known but whose inflammation is also
chronic and unremitting. These also exhibit massive tissue/organ
destruction and include conditions such as osteoarthritis,
periodontal disease, diabetic nephropathy, chronic obstructive
pulmonary disease, artherosclerosis, graft versus host disease,
chronic pelvic inflammatory disease, endometriosis, chronic
hepatitis and tuberculosis. In these diseases, the tissue
destruction often damages organ function, resulting in progressive
reductions in quality of life and organ failure. These conditions
are a major cause of illness in the developing world and are poorly
treated by current therapies.
[0007] Inflammation of skin structures (dermatitis) is a common set
of conditions which include actinic keratosis, acne rosacea, acne
vulgaris, allergic contact dermatitis, angioedema, atopic
dermatitis, bullous pemiphigoid, cutaneous drug reactions, erythema
multiforme, lupus erythrametosus, photodermatitis, psoriasis,
psoriatic arthritis, scleroderma and urticaria. These diseases are
treated using a wide array of therapies, many of which have very
severe side-effects.
[0008] Current disease-modifying treatments (if any) for
immune-driven conditions include neutralising antibodies,
cytotoxics, corticosteroids, immunosuppressants, antihistamines and
antimuscarinics. These treatments are often associated with
inconvenient routes of administration and severe side-effects,
leading to compliance issues. Moreover, certain drug classes are
only effective for certain types of inflammatory diseases, e.g.
antihistamines for rhinitis.
[0009] It is known that Beta-aminoalcohols have properties which
may be useful in therapy. Other such compounds are known but
without any suggestion of therapeutic utility; see, for example,
WO2005/069930.
SUMMARY OF THE INVENTION
[0010] Surprisingly, it has been found that certain compounds are
inhibitors of cytokines and possess anti-inflammatory properties as
well as reducing pain in pain conditions where cytokines are
involved. According to the present invention, an inflammatory
condition or pain such as acute, chronic or neuropathic pain
(including, but not limited to, pain associated with cancer,
surgery, arthritis, dental surgery, painful neuropathies, trauma,
musculo-skeletal injury or disease, and visceral diseases) and
migraine headache in mammals, can be treated by the use of a
compound of general formula (I)
##STR00002##
Wherein R.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.5; R.sub.2 is H, alkyl or CH.sub.2OH or forms a ring with
R.sub.4; R.sub.3 is H, alkyl or CH.sub.2OH or forms a ring with
R.sub.4; R.sub.4 is H, alkyl or (when forming part of a ring with
R.sub.2 or R.sub.3) CH.sub.2; and R.sub.5 is alkyl, CF.sub.3, OH,
Oalkyl, OCOalkyl, CONH.sub.2, CN, halogen, NH.sub.2, NO.sub.2,
NHCHO, NHCONH.sub.2, NHSO.sub.2Me, CONH.sub.2 or SOMe; or a salt
thereof.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0011] Compounds of formula (I) for use in the invention include
(but are not limited to) novel compounds such as:
[0012]
1-(4-amino-3,5-dichlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamin-
o)ethanone
[0013]
1-(3-chlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)propan-1-o-
ne
[0014]
1-(3-chlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-one
[0015]
1-(3-chlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0016] 1-phenyl-2-(1-hydroxy-2-propan-2-ylamino)propan-1-one
[0017]
1-(2-chlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)propan-1-o-
ne
[0018]
1-(2-chlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-one
[0019]
1-(2-chlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0020]
1-(3,4-dichlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)propan-
-1-one
[0021]
1-(3,4-dichlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-one
[0022]
1-(3,4-dichlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0023]
2-(1-hydroxy-2-methylpropan-2-ylamino)-1-(4-hydroxy-3-hydroxymethyl-
-phenyl) butan-1-one
[0024]
1-(4-hydroxy-3-hydroxymethyl-phenyl)-2-(1-hydroxy-2-methylpropan-2--
ylamino) ethanone
[0025]
1-(4-amino-phenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)butan-1-on-
e
[0026]
1-(3,5-dimethylcarbamoyl-phenyl)-2-(1-hydroxy-2-methylpropan-2-ylam-
ino)propan-1-one
[0027]
2-(1-hydroxy-2-methylpropan-2-ylamino)-1-(phenyl)ethanone
[0028]
1-(3,4-dihydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-on-
e
[0029]
1-(2,3-dihydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-on-
e
[0030]
1-(2,3,4-dihydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1--
one
[0031]
1-(5,6,7,8-tetrahydro-2-naphthyl)-2-(1-hydroxy-2-butan-2-ylamino)et-
hanone
[0032]
1-(2,5-dimethoxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-on-
e
[0033]
1-(4-hydroxy-3-ureylphenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)e-
thanone
[0034]
1-(4-amino-3,-cyanophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0035]
1-(2-chlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0036]
1-(3,4-dihydroxyphenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethan-
one
[0037]
1-(4-hydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0038]
1-(3,4-diacetylphenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0039]
1-(3,4-dichlorophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0040]
1-(3,4-dichlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethano-
ne
[0041]
1-(2,5-dimethoxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-on-
e
[0042]
1-(3,4-dihydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)butan-1-one
[0043]
1-(4-hydroxy-3-methoxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethan-
one
[0044]
1-(3-hydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0045]
1-(4-nitrophenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0046]
1-(3-hydroxyquinolin-5-yl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0047]
1-(4-hydroxy-3-methanesulphonamidephenyl)-2-(1-hydroxy-2-propan-2-y-
lamino) ethanone
[0048]
1-(4-methanesulphonamidephenyl)-2-(1-hydroxy-2-propan-2-ylamino)eth-
anone
[0049]
1-(2-chloro-4-hydroxyphenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)-
ethanone
[0050]
1-(2-fluorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethanone
[0051]
1-(3-fluorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethanone
[0052]
1-(4-fluorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethanone
[0053]
1-(4-fluorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)propan-1on-
e
[0054]
1-(4-bromophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethanone
[0055]
1-(4-bromophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)propan-1-on-
e
[0056]
1-(3,5-ditertbutylcarbonyloxyphenyl)-2-(1-hydroxy-2-methylpropan-2--
ylamino) ethanone
[0057]
1-(3,5-dihydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0058]
1-(3,5-dihydroxyphenyl)-2-(1-hydroxy-2-propan-2-ylamino)propan-1-on-
e
[0059]
1-(3-chloro-4-amino-5-trifluoromethylphenyl)-2-(1-hydroxy-2-propan--
2-ylamino) propan-1-one
[0060]
1-(2-naphthalenyl)-2-(1-hydroxy-2-propan-2-ylamino)ethanone
[0061] It is understood that the invention refers to salts, e.g.
the hydrochloride of compounds (I). The compounds may also be
provided as metabolites and pro-drugs thereof. The compounds are
chiral, and the invention includes substantially single
diastereomers and enantiomers of (I). Aryl and heteroaryl groups
are know, and typically have up to 12 atoms.
[0062] The compounds of formula (I) according to the invention are
used to treat inflammatory diseases including, but not exclusive
to, autoimmune diseases involving multiple organs, such as systemic
lupus erythematosus (SLE) and scleroderma, specific tissues or
organs such as the musculoskeletal tissue (rheumatoid arthritis,
ankylosing spondylitis), gastro-intestinal tract, (Crohn's disease
and ulcerative colitis), the central nervous system (Alzheimers,
Multiple sclerosis, motor neurone disease, Parkinson's disease and
chronic fatigue syndrome), pancreatic beta cells (insulin dependent
diabetes mellitus), the adrenal gland (Addison's diseae), the
kidney (Goodpasture's syndrome, IgA nephropathy, interstitial
nephritis) exocrine glands (Sjogrens syndrome and autoimmune
pancreatitis) and skin (psoriasis and atopic dermatitis), chronic
inflammatory diseases such as osteoarthritis, periodontal disease,
diabetic nephropathy, chronic obstructive pulmonary disease,
artherosclerosis, graft versus host disease, chronic pelvic
inflammatory disease, endometriosis, chronic hepatitis and
tuberculosis, IgE mediated (Type I) hypersensitivities such as
rhinitis, asthma, anaphylaxis, dermatitis and ophthalmic
conditions. Dermatitis conditions include; actinic keratosis, acne
rosacea, acne vulgaris, allergic contact dermatitis, angioedema,
atopic dermatitis, bullous pemiphigoid, cutaneous drug reactions,
erythema multiforme, lupus erythrametosus, photodermatitis,
psoriasis, psoriatic arthritis, scleroderma and urticaria.
Opthalmic conditions include age related macular degeneration,
diabetic retinopathy, choroidal neovascular membrane, cystoid
macular edema, epi-retinal membrane, macular hole, dry eye and
uveitis.
[0063] These compounds may be used according to the invention when
the patient is also administered or in combination with another
therapeutic agent selected from corticosteroids (examples including
cortisol, cortisone, hydrocortisone, dihydrocortisone,
fludrocortisone, prednisone, prednisolone, deflazacort,
flunisolide, beconase, methylprednisolone, triamcinolone,
betamethasone, and dexamethasone), disease modifying anti-rheumatic
drugs (DMARDs) (examples including, azulfidine, aurothiomalate,
bucillamine, chlorambucil, cyclophosphamide, leflunomide,
methotrexate, mizoribine, penicillamine and sulphasalazine),
immunosuppressants (examples including azathioprine, cyclosporin,
mycophenolate,) COX inhibitors (examples including aceclofenac,
acemetacin, alcofenac, alminoprofen, aloxipirin, amfenac,
aminophenazone, antraphenine, aspirin, azapropazone, benorilate,
benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacine,
choline salicylate, chlometacin, dexketoprofen, diclofenac,
diflunisal, emorfazone, epirizole, etodolac, feclobuzone, felbinac,
fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl
salicylate, ibuprofen, indometacin, indoprofen, ketoprofen,
ketorolac, lactyl phenetidin, loxoprofen, mefenamic acid,
metamizole, mofebutazone, mofezolac, nabumetone, naproxen,
nifenazone, oxametacin, phenacetin, pipebuzone, pranoprofen,
propyphenazone, proquazone, rofecoxib, salicylamide, salsalate,
sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid,
zomepirac) neutralising antibodies (examples including, etanercept
and infliximab), antibiotics (examples including, doxycycline and
minocycline).
[0064] Compounds of formula (I) exhibit analgesic activity in
animal models. The activity of these compounds may be determined by
the use of the appropriate in vivo assay.
[0065] This invention also relates to a method of treatment for
patients (including man and/or mammalian animals raised in the
dairy, meat or fur industries or as pets) suffering from chronic,
acute or neuropathic pain; and more specifically, a method of
treatment involving the administration of the analgesic of formula
(I) as the active constituent.
[0066] Accordingly, the compounds of formula (I) can be used among
other things in the treatment of pain conditions such as acute and
chronic pain (as well as, but not limited to, pain associated with
cancer, surgery, arthritis, dental surgery, trauma,
musculo-skeletal injury or disease, visceral diseases) and migraine
headache. Additionally the painful conditions can be neuropathic
(post-herpetic neuralgia, diabetic neuropathy, drug induced
neuropathy, HIV mediated neuropathy, sympathetic reflex dystrophy
or causalgia, fibromyalgia, myofacial pain, entrapment neuropathy,
phantom limb pain, trigeminal neuralgia. Neuropathic conditions
include central pain related to stroke, multiple sclerosis, spinal
cord injury, arachnoiditis, neoplasms, syringomyelia, Parkinson's
and epilepsia.
[0067] It will often be advantageous to use compounds of formula
(I) in combination with another drug used for pain therapy. Such
another drug may be an opiate or a non-opiate such as baclofen.
Especially for the treatment of neuropathic pain, coadministration
with gabapentin is preferred. Other compounds that may be used
include acetaminophen, a non-steroidal anti-inflammatory drug, a
narcotic analgesic, a local anaesthetic, an NMDA antagonist, a
neuroleptic agent, an anti-convulsant, an anti-spasmodic, an
anti-depressant or a muscle relaxant.
[0068] Any suitable route of administration can be used. For
example, any of oral, topical, parenteral, ocular, rectal, vaginal,
inhalation, buccal, sublingual and intranasal delivery routes may
be suitable. The dose of the active agent will depend on the nature
and degree of the condition, the age and condition of the patient
and other factors known to those skilled in the art. A typical dose
is 1.0-100 mg given one to three times per day.
[0069] The compounds of the invention may be prepared via a
multistep synthetic route of a type familiar to those skilled in
the art, and it is assumed that functional groups present in the
molecules can be protected and deprotected as needed. The synthesis
begins with a substituted acetophenone or analogue which is reacted
initially with bromine to give the bromo derivative, and then the
amino alcohol to generate the target molecule. The final compounds
are generally isolated via precipitation which may require
purification via a technique such as recrystallisation.
[0070] The following Examples illustrate the preparation of
compounds of the invention.
EXAMPLE 1
1-(4-Amino-3,5-dichlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethan-
one (3)
##STR00003##
[0071] Bromo-(-4-amino-3,5-dichloro)acetophenone (2)
[0072] Bromine (63 ml, 1.22 mol) was added to a mixture of
4-amino-3,5-dichloroacetophenone (1) (250 g, 1.22 mol) in
CHCl.sub.3 (3 L ml) at room temperature. The mixture was stirred
for 1 h then EtOH (500 ml) was added. The mixture was cooled to
0.degree. C. and stirred for 1 h. The precipitate was filtered and
air-dried (4.7 g, 67%).
[0073] .sup.1H NMR (400 MHz, DMSO): 4.77 (2H, s), 6.61 (2H, bs),
7.86 (2H, s); .sup.13C NMR (100 MHz, DMSO): 63.39, 117.89, 128.57,
129.75, 146.17, 195.99.
1-(4-Amino-3,5-dichlorophenyl)-2-(1-hydroxy-2-methylpropan-2-ylamino)ethan-
one (3)
[0074] 2-Amino-2-methyl-propan-1-ol (180 ml, 2.49 mol) was added to
a mixture of bromo-(-4-amino-3,5-dichloro)acetophenone (2) (237 g,
0.83 mol) in chloroform (650 ml). The mixture was stirred at room
temperature for 2 h, then water (380 ml) was added. The mixture was
stirred for 1 h, and then the solid was filtered. The solid was
triturated with water (1 L) to give the desired compound (3) (223
g, 91%).
[0075] .sup.1H NMR (400 MHz, DMSO): 0.94 (6H, s), 3.18 (2H, d J=4.4
Hz), 3.93 (2H, s), 4.55 (1H, m), 6.40 (2H, s), 7.84 (2H, s);
.sup.13C NMR (100 MHz, DMSO): 24.21, 48.87, 53.73, 68.52, 117.92,
124.57, 125.79, 128.62, 146.07, 195.30; LC-MS: 291, 292, 293
(M+H.sup.+).
EXAMPLE 2
2-(1-hydroxy-2-methylpropan-2-ylamino)-1-(3-chlorophenyl)propan-1-one
(4)
##STR00004##
[0076] Bromo-3'-chloropropiophenone
[0077] Bromine (6.07 ml, 0.12 mol) was added to a solution of
3'-chloropropiophenone (20 g, 0.12 mol) in chloroform (250 ml) at
room temperature. The reaction was followed by TLC in DCM. When all
of the starting material was consumed the mixture was washed with a
saturated solution of sodium bicarbonate. The organic phase was
dried over magnesium sulphate, filtered and evaporated.
Recrystallisation from chloroform gives the desired compound in 60%
yield as a pale yellow solid (18 g, 73 mmol).
[0078] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.99 (1H, m), 7.89 (1H,
m), 7.55 (1H, m), 7.43 (m), 5.21 (1H, q J=6.5HZ), 1.9 (3H,
J=6.5Hz)
2-(1-hydroxy-2-methylpropan-2-ylamino)-1-(3-chlorophenyl)propan-1-one
(4)
[0079] 2-Amino-1-methyl-propan-1-ol (14 ml, 0.15 mol) was added to
.alpha.-bromo-3'chloro propiophenone (18 g, 73 mmol) in suspension
in chloroform (50 ml), with two crystals of sodium iodide. The
reaction was heated under reflux overnight. After filtration the
organic phase was extracted twice with a 2M HCl solution
(2.times.100 ml). The aqueous phase wash washed with DCM then
neutralised with sodium carbonate. The aqueous layer was extracted
with DCM. The organic phase was dried over magnesium sulphate,
filtered and evaporated. Recrystallisation from chloroform gives
the desired compound in 55% yield as a white solid (10.2 g, 40
mmol).
[0080] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.57 (1H, m), 7.27-7.26
(2H, m), 3.77-3.74 (1H, m), 3.37-3.34 (1H, m), 3.14-3.11 (1H, m),
1.37 (3H, s), 1.04 (3H, s), 0.76 (3H, s)..sup.13C NMR (100 MHz,
CHCl.sub.3): 16.23, 22.69, 27.06, 49.85, 53.41, 69.33, 95.91,
124.52, 126.62, 128.04, 129.34, 134.05, 144.11. LC-MS: 256
(M+H.sup.+).
[0081] The following Assays illustrate the utility of the
invention.
Beta2 Agonism Functional Assay
[0082] Guinea-pig trachea ring preparations were suspended in
Kreb's solution containing indomethacin. After 15 minutes
stabilisation, the preparations were repeated contracted using
carbachol and simultaneously treated with increasing cumulative
doses test compounds (0.1 nM to 0.1 .mu.M). Beta2 agonism for each
test compound was determined by its dose dependant inhibition of
carbachol stimulated tracheal muscle twitch.
[0083] Compound (3) was a very poor beta2 agonist, with an IC50 of
13 .mu.M.
LPS Mouse Assay
[0084] 7 week old Balb C ByJ mice (24-28 g) were administered,
either by i.p. (5 ml/kg) or oral (10 ml/kg) administration, with
vehicle or test article. 30 minutes later these animals were
challenged with an intraperitoneal injection of 1 mg/kg LPS. 2
hours after LPS challenge blood samples were collected under light
isoflurane anaesthesia into normal tubes by retro-orbital puncture.
Samples were allowed to clot at room temperature and then spun at
6000 g for 3 min at 4.degree. C. Serum was stored at -20.degree. C.
until use. Serum TNF.alpha. and IL-10 levels were analysed in
duplicate by ELISA technique.
[0085] Compound (3) had strong inhibitory effects on TNF.alpha. and
potentiating effects on IL-10. These effects are unlikely to be due
to beta2 agonism.
Carrageenan Paw Assay
[0086] Fasted (18 hour) male Wistar rats (105-130 g) were weighed
and a basal mercury plethysmometer reading was taken of the right
hind paw by submerging the paw in the mercury up to the tibiotarsal
joint. Subsequently, vehicles, reference items and test articles
were administered by oral gavage (10 ml/kg). Half an hour after
treatment 0.1 ml of 2% carrageenan in 0.9% saline was injected into
the subplanatar area of the right hind paw. The right paw was
measured again with the plethysmometer at 1, 2, 3, 4 and 5 hours
after carrageenan administration.
[0087] Compound (3) had a dose-dependant inhibitory effect on
inflammation induced by carrageenan paw injection.
* * * * *