Title of Invention

PYRIMIDINE DERIVATIVES USEFUL AS SELECTIVE COX-2-INHIBITORS.

Abstract The invention provides the compounds of formula (I) in which: R1 is selected from the group consisting of H, C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C3-6alkenyl, C3-10cycloalkylC0-6alkyl, C4-12bridged cycloalkyl, A(CR4R5)n and b(CR4R5)n; R2 is C1-2alkyl substituted by one to five fluorine atoms; R3 is selected from the group consisting of C1-6alkyl, NH2 and R7CONH; R4 and R5 are independently selected from H or C1-6alkyl; A is an unsubstituted 5- or 6-membered heteroaryl or an unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or a 6-membered aryl substituted by one or more R6; R6 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl substituted by one or more fluorine atoms, C1-6alkoxy, C1-6alkoxy substituted by one or more F, NH2SO2 and C1-6alkylSO2; B is selected from the group consisting of Formula (i) and (ii) and where (iv) defines the point of attachment of the ring; R7 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, C1-6alkylOC1-6alkyl, phenyl, HO2CC1-6alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1-6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl; and n is 0 to 4. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in treatment of the pain, fever and inflammation of variety of conditions and diseases.
Full Text PYRIMIDINE DERIVATIVES USEFUL AS SELECTIVE COX-2 INHIBITORS
This invention relates to pyrimidine derivatives, to processes for their
preparation, to pharmaceutical compositions containing them and to their use in
medicine.
The enzyme cyclooxygenase (COX) has recently been discovered to exist in two
isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified
constitutive enzyme while COX-2 is rapidly and readily inducible by a number of
agents including mitogens, endotoxin, hormones, cytokines and growth factors.
Prostaglandins generated by the action of COX have both physiological and
pathological roles. It is generally believed that COX-1 is largely responsible for
the important physiological functions such as maintenance of gastrointestinal
integrity and renal blood flow. In contrast the inducible form, COX-2, is believed
to be largely responsible for the pathological effects of prostaglandins where
rapid induction of the enzyme occurs in response to such agents as
inflammatory agents, hormones, growth factors and cytpkines. A selective
inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and
analgesic properties, without the potential side effects associated with inhibition
of COX-1. We have now found a novel group of compounds which are both
potent and selective inhibitors of COX-2.
The invention thus provides the compounds of formula (I)
in which:
R1 is selected from the group consisting of H, C1-6alkyl, C1-2alkyl substituted by
one to five fluorine atoms, C3-6alkenyl, C3-6afkynyl, C3-10cycloalkylC0-6alkyl, C4-
12bridged cycloalkyl, A(CR4R5)n and B(CR4R5)n;
R2 is C1-2alkyl substituted by one to five fluorine atoms;
R3 is selected from the group consisting of C1-6alkyl, NH2 and R7CONH;
R4 and R5 are independently selected from H or C1-6alkyl;
A is an unsubstituted 5- or 6-membered heteroaryl or an unsubstituted 6-
membered aryl, or a 5- or 6-membered heteroaryl or a 6-membered aryl
substituted by one or more R6;
R6 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl
substituted by one more fluorine atoms, C1-6alkoxy, C1-6alkoxy substituted by
one or more F, NH2SO2 and C1-6alkylSO2;
B is selected from the group consisting of
defines the point of attachment of the ring;
R7 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, C1-6alkylOC1-
6alkyl, phenyl, HO2CC1-6alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1-
6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl; and
n is 0 to 4.
The term halogen is used to represent fluorine, chlorine, bromine or iodine.
The term "alkyl" as a group or part of a group means a straight or branched chain
alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or
t-butyl group.
The term 5-membered heteroaryl means a heteroaryl selected from the
following:
The term 6- membered heteroaryl means a heteroaryl selected from the
following:
The term 6-mernbered aryl means:
It is to be understood that the present invention encompasses all isomers of the
compounds ot formula (I) and their pharmaceutically acceptable derivatives,
including all geometric, tautomeric and optical forms, and mixtures thereof (e.g.
racemic mixtures). In particular when the ring B lacks a plane of symmetry the
compounds of formula (I) contain a chiral centre as indicated therein by the
asterisk *. Furthermore, it will be appreciated by those skilled in the art that when
R4 and R5 in formula (I) are different the corresponding compounds contain at
least one chiral centre, by virtue of the asymmetric carbon atom defined thereby,
and that such compounds exist in the form of a pair of optical isomers (i.e.
enantiomers).
In one aspect of the invention R1 is selected from the group consisting of H, C1-
6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C3-6alkenyl, C3-6alkynyl,
C3-10cycloalkylC0-6alkyl, C4-12bridged cycloalkyl and B(CR4R5)n;
In another aspect of the invention R1 is C1-6alkyl or C1-2alkyl substituted by one
to five fluorine atoms. In another aspect R1 is C2-6alkyl (e.g. n-butyl).
In another aspect of the invention R1 is C3-10cycloalkylC0-6alkyl, sucn as
C3-10cycloalkyl (e.g. cyclopentyl or cyclohexyl). In another aspect R1 is C3-
10cycloalkylmethyl, such as C3-7cycloalkylmethyl (e.g. cyclopentylmethyl).
In another aspect of the invention R1 is A(CR4R5)n.
In another aspect of the invention R2 is CHF2, CH2F or CF3. In another aspect
R2 is CF3.
In another aspect of the invention R3 is C1-6alkyl, such as C1-3alkyl (e.g. methyl).
In another aspect of the invention R4 and R5 are independently selected from H
or methyl. In another aspect R4 and R5 are both H.
In another aspect of the invention A is selected from the group consisting of
defines the point of attachment of the ring
and A is unsubstituted or substituted by one or two R6.
In another aspect of the invention R6 is selected from the group consisting of
halogen (e.g. F), C1-3alkyl (e.g. methyl), C1-3alkyl substituted by one to three
fluorine atoms (e.g. CF3), and C1-3alkoxy (e.g. methoxy).
In another aspect of the invention R7 is selected from the group consisting of C1-
6alkyl (e.g. ethyl), phenyl and aminomethyl.
In another aspect of the invention n is 1 to 4.
In another aspect of the invention n is 0 to 2 (e.g. 0).
It is to be understood that the invention covers all combinations of particular
aspects of the invention as described hereinabove. ,
Within the invention there is provided one group of compounds of formula (I)
(group A) wherein: R1 is C1-6alkyl (e.g. n-butyl); R2 is CF3; and R3 is C1-6alkyl,
such as C1-3alkyl (e.g. methyl).
Within the invention there is provided another group of compounds of formula (I)
(group B) wherein: R1 is C3-10cycloalkylC0-6alkyl, such as C3-10cycloalkyl (e.g.
cyclopentyl or cyclohexyl); R2 is CF3; and R3 is C1-6alky!, such as C1-3alkyl (e.g.
methyl).
Within the invention there is provided another group of compounds of formula (I)
(group C) wherein: R1 is C3-10ocycloalkylmethyl, such as C3-7cycloalkylmethyl (e.g.
cyclopentylmethyl); R2 is CF3; and R3 is C1-6alkyl, such as C1-3alkyl (e.g. methyl).
Within the invention there is provided another group of compounds of formula (I)
(group D) wherein: R1 is A(CR4R5)n; R2 is CF3; R3 is C1-6alkyl, such as C1-3alkyl
(e.g. methyl); R4 and R5 are independently selected from H or methyl; A is
selected from the group consisting of
and A is unsubstituted or substituted by one or two R6; R6 is selected from the
group consisting of halogen (e.g. F), C1-3alkyl (e.g. methyl), C1-3alkyl substituted
by one to three fluorine atoms (e.g. CF3), and C1-3alkoxy (e.g. methoxy); and n is
0 to 2 (e.g. 0).
Within group D, there is provided a further group of compounds (group D1)
wherein: R1 is A(CR4R5)n; R2 is CF3; R3 is methyl; R4 and R5 are both H; A is
selected from the group consisting of
and A is unsubstituted or substituted by one or two R6; R6 is selected from the
group consisting of fluorine, chlorine, methyl, CF3 and methoxy; and n is 0 or 1.
In a preferred aspect the invention provides the following compounds:
2-(4-fluorophenoxy)-4-[4-(methylsulfonyl)phenyl]-6](trifiuoromethyl)pyrimidine;
2-(4-methoxyphenoxy)-4-[4-(methylsulfonyl)phenyI]-6-trifluoromethyl)pyrimidine;"
2-butoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine;
2-[(5-chloropyridin-3-yl)oxy]-4-[4-(methylsulfony)phenyl]-6-
(trifluoromethyl)pyrirnidine;
2-(cyclohexyloxy)-4-[4-(methyIsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine.
In a more preferred aspect the invention provides the following compound:
2-butoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine.
Since the compounds of the present invention, in particular compounds of
formula (I), are intended for use in pharmaceutical compositions, it will be
understood that they are each provided in substantially pure form, for example at
least 50% pure, more suitably at least 75% pure and preferably at least 95%
pure (% are on a wt/wt basis). Impure preparations of the compound of formula
(I) may be used for preparing the more pure forms used in pharmaceutical
compositions. Although the purity of intermediate compounds of the present
invention is less critical, it will be readily understood that the substantially pure
form is preferred as for the compounds of formula (I). Preferably, whenever
possible, the compounds of the present invention are available in crystalline
form.
When some of the compounds of this invention are allowed to crystallise or are
recrysallised from organic solvents, solvent of recrystallisation may be present in
the crystalline product. This invention includes within its scope such solvates.
Similarly, some of the compounds of this invention may be crystallised or
recrystallised from solvents containing water. In such cases water of hydration
may be formed. This invention includes within its scope stoichiometric hydrates
as well as compounds containing variable amounts of water that may be
produced by processes such as lyophilisation. In addition, different
crystallisation conditions may lead to the formation of different polymorphic
forms of crystalline products. This invention includes within its scope all the
polymorphic forms of the compounds of formula (I).
Compounds of the invention are potent and selective inhibitors of COX-2. This
activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.
In view of their selective COX-2 inhibitory activity, the compounds of the present
invention are of interest for use in human and veterinary medicine, particularly in
the treatment of the pain (both chronic and acute), fever and inflammation of a
variety of conditions and diseases mediated by selective inhibition of COX-2.
Such conditions and diseases are well known in the art and include rheumatic
fever; symptoms associated with influenza or other viral infections, such as the
common cold; lower back and neck pain; headache; toothache; sprains and
strains; myositis; sympathetically maintained pain; synovitis; arthritis, Including
rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout
and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as
psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and
those arising from surgical and dental procedures.
The compounds of the invention are also useful for the treatment of neuropathic
pain. Neuropathic pain syndromes can develop following neuronal injury and the
resulting pain may persist for months or years, even after the original injury has
healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal
cord or certain regions in the brain. Neuropathic pain syndromes are
traditionally classified according to the disease or event that precipitated them.
Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific
lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy;
neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia; and pain
resulting from physical trauma, amputation, cancer, toxins or chronic
inflammatory conditions. These conditions are difficult to treat and although
several drugs are known to have limited efficacy, complete pain control is rarely
achieved. The symptoms of neuropathic pain are incredibly heterogeneous and
are often described as spontaneous shooting and lancinating pain, or ongoing,
burning pain. In addition, there is pain associated with normally non-painful
sensations such as "pins and needles" (paraesthesias and dysesthesias),
increased sensitivity to touch (hyperesthesia), painful sensation following
innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity
to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain
sensation after removal of the stimulation (hyperpathia) or an absence of or
deficit in selective sensory pathways (hypoalgesia).
The compounds of the invention are also useful for the treatment of other
conditions mediated by selective inhibition of COX-2.
For example, the compounds of the invention inhibit cellular and neoplastic
transformation and metastatic tumour growth and hence are useful in the
treatment of certain cancerous diseases, such as colonic cancer and prostate
cancer. The compounds of the invention are also useful in reducing the number
of adenomatous colorectal polyps and thus reduce the risk of developing colon
cancer. The compounds of the invention are also useful in the treatment of
cancer associated with overexpression of HER-2/neu, in particular breast
cancer.
Compounds of the invention also prevent neuronal injury by inhibiting the
generation of neuronal free radicals (and hence oxidative stress) and therefore
are of use in the treatment of stroke; epilepsy; and epileptic seizures (including
grand mal, petit mal, myoclonic epilepsy and partial seizures).
Compounds of the invention also inhibit prostanoid-induced smooth muscle
contraction and hence are of use in the treatment of dysmenorrhoea and
premature labour.
Compounds of the invention are also useful in the treatment of liver disease,
such as inflammatory liver disease, for example chronic viral hepatitis B, chronic
viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune
hepatitis, nonalcoholic steatohepatitis and liver transplant rejection.
Compounds of the invention inhibit inflammatory processes and therefore are of
use in the treatment of asthma, allergic rhinitis and respiratory distress
syndrome; gastrointestinal conditions such as inflammatory bowel disease,
Crohn"s disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the
inflammation in such diseases as vascular disease, migraine, periarteritis
nodosa, thyroiditis, aplastic anaemia, Hodgkin"s disease, sclerodoma, type I
diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome,
Bechet"s syndrome, polymyositis, gingivitis, conjunctivitis and myocardial
ischemia.
Compounds of the invention are also useful in the treatment of ophthalmic
diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye
tissue.
Compounds of the invention are also useful for the treatment of cognitive
disorders such as dementia, particularly degenerative dementia (including senile
dementia, Alzheimer"s disease, Pick"s disease, Huntington"s chorea, Parkinson"s
disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-
infarct dementia), as well as dementia associated with intracranial space
occupying lesions, trauma, infections and related conditions (including HIV
infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive
impairment associated with ageing, particularly Age Associated Memory
Impairment.
Compounds of the invention are also useful in the treatment of disorders
ameliorated by a gastroprokinetic agent. Disorders ameliorated by
gastroprokinetic agents include ileus, for example post-operative ileus and ileus
during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD);
gastroparesis, such as diabetic gastroparesis; and other functional bowel
disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain
(NCCP).
According to a further aspect of the invention, we provide a compound of
formula (I) for use in human or veterinary medicine.
According to another aspect of the invention, we provide a compound of
formula (I) for use in the treatment of a condition which is mediated by COX-2.
According to a further aspect of the invention, we provide a method of treating a
human or animal subject suffering from a condition which is mediated by COX-2
which comprises administering to said subject an effective amount of a
compound of formula (I).
According to a further aspect of the invention, we provide a method of treating a
human or animal subject suffering from an inflammatory disorder, which method
comprises administering to said subject an effective amount of a compound of
formula (I).
According to another aspect of the invention, we provide the use of a compound
of formula (I) for the manufacture of a therapeutic agent for the treatment of a
condition which is mediated by COX-2.
According to another aspect of the invention, we provide the use of a compound
of formula (I) for the manufacture of a therapeutic agent for the treatment of an
inflammatory disorder.
It is to be understood that reference to treatment includes both treatment of
established symptoms and prophylactic treatment, unless explicitly stated
otherwise.
It will be appreciated that the compounds of the invention may advantageously
be used in conjunction with one or more other therapeutic agents. Examples of
suitable agents for adjunctive therapy include a 5HT1 agonist, such as a triptan
(e.g. sumatriptan or naratriptan); an adenosine A1 agonist; an EP ligand; an
NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e.g.
lamotrigine); a substance P antagonist (e.g. an NK1 antagonist); a cannabinoid;
acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotriene receptor
antagonist; a DMARD (e.g. methotrexate); gabapentin and related compounds; a
tricyclic antidepressant (e.g. amitryptilline); a neurone stabilising antiepileptic
drug; a mono-aminergic uptake inhibitor (e.g. venlafaxine); a matrix
metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor, such as an
iNOS or an nNOS inhibitor; an inhibitor of the release, or action, of tumour
necrosis factor a; an antibody therapy, such as a monoclonal antibody therapy;
an antiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or an immune
system modulator (e.g. interferon); an opioid analgesic; a local anaesthetic; a
stimulant, including caffeine; an H2-antagonist (e.g. ranitidine); a proton pump
inhibitor (e.g. omeprazole); an antacid (e.g. aluminium or magnesium hydroxide;
an antiflatulent (e.g. simethicone); a decongestant (e.g. phenylephrine,
phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine,
naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine); an
antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane, or
dextramethorphan); a diuretic; or a sedating or non-sedating antihistamine. It is
to be understood that the present invention covers the use of a compound of
formula (I) in combination with one or more other therapeutic agents.
The compounds of formula (I) are conveniently administered in the form of
pharmaceutical compositions. Thus, in another aspect of the invention, we
provide a pharmaceutical composition comprising a compound of formula (I)
adapted for use in human or veterinary medicine. Such compositions may
conveniently be presented for use in conventional manner in admixture with one
or more physiologically acceptable carriers or excipients.
The compounds of formula (I) may be formulated for administration in any
suitable manner. They may, for example, be formulated for topical
administration or administration by inhalation or, more preferably, for oral,
transdermal or parenteral administration. The pharmaceutical composition may
be in a form such that it can effect controlled release of the compounds of
formula (I).
For oral administration, the pharmaceutical composition may take the form of, for
example, tablets (including sub-lingual tablets), capsules, powders, solutions,
syrups or suspensions prepared by conventional means with acceptable
excipients.
For transdermal administration, the pharmaceutical composition may be given in
the form of a transdermal patch, such as a transdermal iontophoretic patch.
For parenteral administration, the pharmaceutical composition may be given as
an injection or a continuous infusion (e.g. intravenously, intravascularly or
subcutaneously). The compositions may take such forms as suspensions,
solutions or emulsions in oily or aqueous vehicles and may contain formulatory
agents such as suspending, stabilising and/or dispersing agents. For
administration by injection these may take the form of a unit dose presentation or
as a multidose presentation preferably with an added preservative.
Alternatively for parenteral administration the active ingredient may be in powder
form for reconstitution with a suitable vehicle.
The compounds of the invention may also be formulated as a depot preparation.
Such long acting formulations may be administered by implantation (for example
subcutaneously or intramuscularly) or by intramuscular injection. Thus, for
example, the compounds of the invention may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in an
acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for
example, as a sparingly soluble salt.
As stated above, the compounds of the invention may also be used in
combination with other therapeutic agents. The invention thus provides, in a
further aspect, a combination comprising a compound of formula (I) together with
a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in
the form of a pharmaceutical formulation and thus pharmaceutical formulations
comprising a combination as defined above together with a pharmaceutically
acceptable carrier or excipient comprise a further aspect of the invention. The
individual components of such combinations may be administered either
sequentially or simultaneously in separate or combined pharmaceutical
formulations.
When a compound of formula (I) is used in combination with a second
therapeutic agent active against the same disease state the dose of each
compound may differ from that when the compound is used alone. Appropriate
doses will be readily appreciated by those skilled in the art.
A proposed daily dosage of a compound of formula (I) for the treatment of man
is 0.01mg/kg to 500mg/kg, such as 0.05mg/kg to 100mg/kg, e.g. 0.1mg/kg to
50mg/kg, which may be conveniently administered in 1 to 4 doses. The precise
dose employed will depend on the age and condition of the patient and on the
route of administration. Thus, for example, a daily dose of 0.25mg/kg to
10mg/kg may be suitable for systemic administration.
Compounds of formula (I) may be prepared by any method known in the art for
the preparation of compounds of analogous structure.
Compounds of formula (I) may be prepared by a process which comprises:
reacting an alcohol R1OH of formula (II) or a protected derivative thereof with a
compound of formula (III)
and thereafter and if necessary,
interconverting a compound of formula (I) into another compound of formula (I);
and/or
deprotecting a protected derivative of compound of formula (I).
The overall synthesis of a compound of formula (I) is shown in Scheme 1 below
in which, R1 and R2 are as defined in formula (I) above unless otherwise stated,
R3 is C1-6alkyl; THF is tetrahydrofuran; MTBE is methyl t-butyl ether; and alkyl is
a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-
propyl, n-butyl, s-butyl or t-butyl group.
Referring to Scheme 1, the preparation of compounds of formula (I) may
conveniently be achieved by the treatment of compounds of formula (III) with an
alcohol of formula (II) in the presence of sodium hydride. The reaction is
conveniently carried out in a solvent such as THF and at between ambient
temperature and reflux.
Conveniently the oxidation shown in Scheme 1 is effected using a
monopersulfate compound, such as potassium peroxymonosulfate (known as
Oxone™) and the reaction is carried out in a solvent, such as an aqueous
alcohol, (e.g. aqueous methanol), and at between -78°C and ambient
temperature.
Alternatively, the oxidation shown in Scheme 1 may be effected using hydrogen
peroxide in the presence of catalytic sodium tungstate dihydrate. The reaction
may be carried out in a solvent such as acetic acid and at between ambient
temperature and reflux (e.g. 50°C).
Referring to Scheme 1, the cyclisation of diones of formula (VI) to give the
corresponding pyrimidines of formula (IV) is conveniently carried out employing
a thioronium salt such as a 2-methyl-2-thiopseudourea sulfate and under reflux.
It will be appreciated by those skilled in the art that certain of the procedures
described in Scheme 1 for the preparation of compounds of formula (I) or
intermediates thereto may not be applicable to some of the possible
substituents.
It will be further appreciated by those skilled in the art that it may be necessary
or desirable to carry out the transformations described in Scheme 1 in a different
order from that described, or to modify one or more of the transformations, to
provide the desired compound of formula (I).
In one variation of Scheme 1, compounds of formula (III) wherein R3 is C1-6alkyl
or NH2 may be prepared by oxidising a compound of formula (IV)A;
under oxidation conditions described hereinabove. Compounds of formula (1V)A
may be prepared according to the general procedures of Scheme 1 by
employing sulphonyl derivatives in place of the corresponding sulfide
compounds of formulae (VI) and (VII).
It will be appreciated by those skilled in the art that compounds of formula (I)
may be prepared by interconversion, utilising other compounds of formula (I) as
precursors. Suitable interconversions, such as alkylations, are well known to
those skilled in the art and are described in many standard organic chemistry
texts, such as "Advanced Organic Chemistry" by Jerry March, fourth edition
(Wiley, 1992), incorporated herein by reference. For example, compounds of
formula (I) wherein R1 is C1-6alkyl, C1-2alkyl substituted by one to five fluorine
atoms, C3-6alkenyl, C3-6alkynyl, C3-10cycloalkylC0-6alkyl, C4-12bridged cycloalkane,
A(CR4R5)n (with the proviso that n is not zero) and B(CR4R5)n may be prepared
by alkylating the corresponding compound of formula (I) wherein R1 is H.
Acylation of compounds of formula (I) wherein R3 is NH2, to provide compounds
of formula (I) wherein R3 is R7CONH, may be carried out by conventional means,
for example by employing conventional acylating agents such as those
described in "Advanced Organic Chemistry", pp 417-424, incorporated herein by
reference.
As will be appreciated by those skilled in the art it may be necessary or desirable
at any stage in the synthesis of compounds of formula (I) to protect one or more
sensitive groups in the molecule so as to prevent undesirable side reactions.
The protecting groups used in the preparation of compounds of formula (I) may
be used in conventional manner. See, for example, those described in
"Protective Groups in Organic Synthesis" by Theodora W Green and Peter G M
Wuts, second edition, (John Wiley and Sons, 1991), incorporated herein by
reference, which also describes methods for the removal of such groups.
Alcohols of formula (II) are either known compounds or may be prepared by
literature methods, such as those described in "Comprehensive Organic
Transformations: a guide to functional group preparations" by Richard Larock
(VCH, 1989), incorporated herein by reference.
Thioronium salts of formula (V) are either known compounds or may be
prepared by literature methods, such as those described in A H Owens et al,
Eur J Med Chem, 1988, 23(3), 295-300, incorporated herein by reference.
Acetophenones of formula (VII) are either known compounds or may be
prepared by conventional chemistry.
Certain intermediates described above are novel compounds, and it is to be
understood that all novel intermediates herein form further aspects of the
present invention. Compounds of formulae (III) and (IV) are key intermediates
and represent a particular aspect of the present invention.
Solvates (e.g. hydrates) of a compound of the invention may be formed during
the work-up procedure of one of the aforementioned process steps.
The Intermediates and Examples that follow illustrate the invention but do not
limit the invention in any way. All temperatures are in °C. Flash column
chromatography was carried out using Merck 9385 silica. Solid Phase
Extraction (SPE) chromatography was carried out using Varian Mega Bond
Elut(Si) cartridges (Anachem) under 15mmHg vacuum. Thin layer
chromatography (Tlc) was carried out on silica plates. In addition to those
already defined, the following abbreviations are used: Me, methyl; Ac, acyl;
DMSO, dimethylsulphoxide; TFA, trifluoroacetic acid; DME, dimethoxyethane;
DCM, dichloromethane; NMP, N- methyl pyrrolidone; and MTBE, methyl t-butyl
ether.
Intermediate 1
4,4,4-Trifluoro-1-[4-(methylthio)phenyl]butane-1,3-dione
To a solution of ethyl trifluoroacetate (7.95ml, 11eq) in MTBE (125ml) was
added dropwise 25% sodium methoxide in methanol (16ml, 1.2eq).
4-Methyithioacetophenone (Aldrich, 10g, 0.06mol) was added portionwise and
the mixture stirred at ambient temperature overnight. 2N Hydrochloric acid
(40ml) was added cautiously and the organic phase separated, washed with
brine and dried (Na2SO4) to give an orange solid. The orange solid was
recrystallised from hot isopropanol to give the title compound as a yellow
crystalline solid (11.25g, 71%).
MH- 261
Intermediate 2
2-(Methylthio)-4-[4-(methvlthio)phenyl]-6-(trifluoromethyl)pyrimidine
To a mixture of 4,4,4-trifluoro-1-[4-(methylthio)phenyl]butane~1,3-dione (5g) and
2-methyl-2-thiopseudourea sulfate (5.1g, 0.98eq) in acetic acid (100ml) was
added sodium acetate (3g, 2eq) and heated under reflux for 8h. The mixture
was concentrated in vacuo and water (100mI) added to give a solid, which was
isolated by filtration to give the title compound as a yellow solid (5.8g,
quantitative).
MH+317
Intermediate 3
2-(Methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine
To a solution of 2-(methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl)
pyrimidine (5.78g) in MeOH (500ml) was added a solution of OXONE™ (Aldrich,
56.23g, 5eq) in water (200ml). The mixture was stirred at ambient temperature
overnight, concentrated in vacuo and the residue partitioned between water and
ethyl acetate (2 x 100ml). The combined organic phases were dried and
concentrated in vacuo to an off-white solid which was triturated with hot
isopropanol to give the title compound as a white solid (5.6g, 80%).
MH+ 381
Tic SiO2 Ethyl acetate:cyclohexane (1:1) Rf 0.45
Example 1
2-(4-Fluorophenoxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine.
To a stirred solution of 4-fluorophenol (37mg, 0.33mmole) in dry tetrahyrofuran (10ml)
was added, under an atmosphere of nitrogen, sodium hydride (60% dispersion in oil,
13mg, 0.33mmole) and the resulting mixture stirred at 20 for 30min. To the stirred
reaction mixture was added 2-(methylsulfonyl)-4[4-(methylsulfonyl)phenyl]-6-
trifluoromethyl)pyrimidine (114mg, 0.33mmole) in a single portion, and stirring was
continued for 2h. The solvent was evaporated, and the residue partitioned between
dichloromethane and 2N sodium hydroxide. The dried organic phase was evaporated
to dryness. The residue was purified on a silica gel SPE cartridge eluting with
chloroform to afford the title compound as a colourless solid (99mg, 80%).
MH+ 413.
Examples 2 to 10
• Examples 2 to 10, as shown in Table 1 that follows, were prepared in the
manner described for Example 1.
Table 1
Example 11
2-Butoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine
Sodium methoxide (6.6kg of a 30%w/w solution in methanol) was added over at
least 30min to a solution of 4-(methylthio)acetophenone (5.0kg) and methyl
trifluoroacetate (4.25kg) in tert-butylmethylether (40L) at 40±3°C. The solution
was heated at 40±3°C for at least 3h. Acetic acid (55L) was added, followed by
S-methyl 2-thiopseudourea sulfate (5.45kg) and the mixture concentrated to ca.
45L. The mixture was heated at about 110°C for at least a further 8h (overnight)
then acetic acid (20L) was added before cooling to 50±3°C. A solution of
sodium tungstate dihydrate (0.2kg) in water (2.5L) was added, followed by
hydrogen peroxide (20.7kg of 30%w/v solution), which was added over at least
3h, maintaining the temp at ca. 50°. The mixture is heated at ca. 50°C for at
least 12h before cooling to 20±3°C. A solution of sodium sulphite (3.45kg) in
water (28L) was then added over at least 30min whilst maintaining the
temperature at 20±3°. The mixture was aged at 20±3°C for ca. 1h and 2-
(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine
collected by filtration, washed with water (3x15L) and dried at up to 60° in vacuo.
Yield, 9.96kg, 90% of theory.
A suspension of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyrimidine (525g) in n-butanol (5.25L) was treated with
potassium carbonate (210g) at 20±5°C. The mixture was heated to 50±5°C
overnight until the reaction was complete by HPLC. Acetic acid (1.57L) was
added dropwise, to control any gas evolution, keeping the temperature at
50±5°C. Water (3.67L) was then added over 30min keeping the temperature at
50±5°C to allow full crystallisation to occur. The slurry was then cooled to 20-
25°C and aged for at least 1 hour. The resulting product was then filtered under
vacuum and washed with a mixture of n-butanol (787mL), acetic acid (236mL),
and water (551 mL) followed by water (2x1.57L). The product was then dried at
up to ca50°C under vacuum to yield the title compound. Yield, 457g, 88.4% of
theory. The title compound was found to be identical to that of Example 10.
1H NMR (CDCI3) 5: 8.33(2H, d, para-di-substituted CH); 8.11(2H, d, para-di-
substituted CH); 7.70(1H, s, aromatic CH); 4.54(2H, t, butyl CH2); 3.12(3H, s,
sulphone CH3); 1.88(2H, m, butyl CH2); 1.55(2H, m, butyl CH2); 1.01(3H, t, butyl
CH3).
Biological Data
Celt Based Assay
Inhibitory activity against human COX-1 and COX-2 was assessed in COS cells
which had been stably transfected with cDNA for human COX-1 and human
COX-2. 24 Hours prior to experiment, COS cells were transferred from the
175cm2 flasks in which they were grown, onto 24-well cell culture plates using
the following procedure. The incubation medium (Dulbecco"s modified eagles
medium (DMEM) supplemented with heat-inactivated foetal calf serum (10%v/v),
penicillin (100 lU/ml), streptomycin (100µg/ml) and geneticin (600µg/ml)) was
removed from a flask of confluent cells (1 flask at confluency contains
approximately 1x107 cells). 5ml of phosphate buffered saline (PBS) was added
to the flask to wash the cells. Having discarded the PBS, cells were then
incubated with 5ml trypsin for 5 minutes in an incubator (37°). The flask was
then removed from the incubator and 5ml of fresh incubation medium was
added. The contents of the flask was transferred to a 250ml sterile container
and the volume of incubation medium subsequently made up to 100ml. 1ml cell
suspension was pipetted into each well of 4x24-well cell culture plates. The
plates were then placed in an incubator (37°C, 95% air/5% CO2) overnight. If
more than 1 flask of cells were required, the cells from the individual flasks were
combined before being dispensed into the 24-well plates.
Following the overnight incubation, the incubation medium was completely
removed from the 24-well cell culture plates and replaced with 250ml fresh
DMEM (37°C). The test compounds were made up to 250x the required test
concentration in DMSO and were added to the wells in a volume of 1µl. Plates
were then mixed gently by swirling and then placed in an incubator for 1 hour
(37°C, 95% air/5% CO2). Following the incubation period, 10µl of arachidonic
acid (75µM) was added to each well to give a final arachidonic acid
concentration of 30µM. Plates were then incubated for a further 10 minutes,
after which the incubation medium was removed from each well of the plates
and stored at -20°C, prior to determination of prostaglandin E2 (PGE2) levels
using enzyme immunoassay. The inhibitory potency of the test compound was
expressed as an IC50 value, which is defined as the concentration of the
compound required to inhibit the PGE2 release from the cells by 50%. The
selectivity ratio of inhibition of COX-1 versus COX-2 was calculated by
comparing respective IC50 values.
The following IC50 values for inhibition of COX-2 and COX-1 were obtained from
the cell based assay for compounds of the invention:
Microsomal Assay
Inhibitory activity against microsomal h-COX2 was assessed against a
microsomal preparation from baculovirus infected SF9 ceils. An aliquot of
microsomal preparation was thawed slowly on ice and a 1/40,000 dilution
prepared from it into the assay buffer (sterile water, degassed with argon
containing 100mM HEPES (pH 7.4), 10mM EDTA (pH7.4), 1mM phenol, 1mM
reduced glutathione, 20mg/ml gelatin and 0.001mM Hematin). Once diluted the
enzyme solution was then sonicated for 5 seconds (Branson sonicator, setting 4,
1cm tip) to ensure a homogeneous suspension. 155µl enzyme solution was
then added to each well of a 96-welI microtitre plate containing either 5µl test
compound (40x required test concentration) or 5µl DMSO for controls. Plates
were then mixed and incubated at room temperature for 1 hour. Following the
incubation period, 40µl of 0.5µM arachidonic acid was added to each well to give
a final concentration of 0.1µM. Plates were then mixed and incubated for
exactly 10 minutes (room temperature) prior to addition of 25µl 1M HCI
(hydrochloric acid) to each well to stop the reaction. 25µl of 1M NaOH (sodium
hydroxide) was then added to each well to neutralise the solution prior to
determination of PGE2 levels by enzyme immunoassay (EIA).
The following IC50 values for inhibition of COX-2 and COX-1 were obtained from
the microsomal assay for compounds of the invention:
WE CLAIM:
1. 2-Butoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine
2. A process for the preparation of 2-butoxy-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyrimidine as claimed in claim 1 which comprises:
(A), reacting n-butanol with a compound of formula (III)
3. A pharmaceutical composition comprising 2-butoxy-4-[4-
(methylsulfonyl)phenyl]-6-(trifluoromethyI)pyrimidine as claimed in claim 1
adapted for use in human or veterinary medicine.
4. A pharmaceutical composition as claimed in claim 3 in the form of a tablet
or capsule.
5. Z-Butoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine as
claimed in claim 1 for use in human or veterinary medicine.
6. A pharmaceutical composition as claimed in claim 3, capable of being used
for the manufacture of a therapeutic agent for the treatment of chronic and
acute pain, fever, inflammation, neuropathic pain, cellular and neoplastic
transformation, metastatic tumour growth, neuronal injury, prostanoid-
induced smooth muscle contraction, liver disease, ophthalmic diseases
cognitive disorders, ileus and gastroesophageal reflux disease.
7. A pharmaceutical composition as claimed in claim 3, capable of being used
for the treatment of an inflammatory disorder.
8. A pharmaceutical composition as claimed in claim 3, capable of being used
for the treatment of lower back and neck pain, rheumatoid arthritis and
osteoarthritis.
The invention provides the compounds of formula (I) in which: R1 is selected from the group consisting of
H, C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C5-6alkenyl, C3-10cycloaIkylC0-6aIkyI, C4-12bridged cycloalkyl,
A(CR4R5)n and b(CR4R5)n; R2 is C1-2alkyl substituted by one to five fluorine atoms; R3 is selected from the group consisting of
C1-6alkyl, NH2 and R7CONH; R4 and R5 are independently selected from H or C1-6alkyl; A is an unsubstituted 5- or 6-membered
heteroaryl or an unsubstituted 6-membered aryl, or a 5- or 6-membered heteroaryl or a 6-membered aryl substituted by one or more
R6; R6 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl substituted by one or more fluorine atoms, C1-6alkoxy,
C1-6alkoxy substituted by one or more F, NH2SO2 and C1-6alkylSO2; B is selected from the group consisting of Formula (i) and (ii)
and where (iv) defines the point of attachment of the ring; R7 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy,
C1-6alkylOC1-6alkyl, phenyl. HO2OC1-6alkyl, C1-6alkyiOCOC1-6alkyl, C1-6alkylOCO, H2NC1-6alkyl, C1-6alkylOCONHC1-6alkyl and
C1-6alkylCONHC1-6alkyl; and n is 0 to 4. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in
treatment of the pain, fever and inflammation of variety of conditions and diseases.

Documents:

1463-kolnp-2003-granted-abstract.pdf

1463-kolnp-2003-granted-assignment.pdf

1463-kolnp-2003-granted-claims.pdf

1463-kolnp-2003-granted-correspondence.pdf

1463-kolnp-2003-granted-description (complete).pdf

1463-kolnp-2003-granted-examination report.pdf

1463-kolnp-2003-granted-form 1.pdf

1463-kolnp-2003-granted-form 18.pdf

1463-kolnp-2003-granted-form 3.pdf

1463-kolnp-2003-granted-form 5.pdf

1463-kolnp-2003-granted-gpa.pdf

1463-kolnp-2003-granted-letter patent.pdf

1463-kolnp-2003-granted-reply to examination report.pdf

1463-kolnp-2003-granted-specification.pdf


Patent Number 214076
Indian Patent Application Number 01463/KOLNP/2003
PG Journal Number 05/2008
Publication Date 01-Feb-2008
Grant Date 30-Jan-2008
Date of Filing 11-Nov-2003
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREENFORD, MIDDLESEX UB6 ONN
Inventors:
# Inventor's Name Inventor's Address
1 NAYLOR ALAN GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HERTFORDSHIRE SG1 2NY
2 PEGG, NEIL ANTHONY -DO-
3 PAYNE JEREMY JOHN -DO-
PCT International Classification Number C 07 D 239/34
PCT International Application Number PCT/GB02/02415
PCT International Filing date 2002-05-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0112802.4 2001-05-25 U.K.