Title of Invention

NOVEL METHODS FOR THE TREATMENT OF INFLAMMATORY DISEASES

Abstract Method of inhibiting the cytokine or biological activity of Macrophage Migration inhibitory Factor (MIF) com- prising contacting MIF with a compound of formula (I) are provided. The invention also relates to method of treating disease or condition where MIF cytokine or biological activity is implicated comprising administration of compound of formula (I), either alone or as a part of combination therapy, Novel compounds of formula (I) are also provided for.
Full Text WO 2004/089927 PCT/AU2004/0004S3
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NOVEL METHODS FOR THE TREATMENT OF INFLAMMATORY DISEASES
FIELD OF THE INVENTION
The present invention relates generally to the treatment of diseases or conditions resulting
from cellular activation, such as inflammatory or cancerous diseases or conditions. In
particular, the invention relates to the use of phenyl substituted cyclic derivatives to inhibit
the cytokine or biological activity of macrophage migration inhibitory factor (MIF), and
diseases or conditions wherein MIF cytokine or biological activity is implicated.
BACKGROUND TO THE INVENTION
MEF is the first identified T-cell-derived soluble lymphokine. MIF was first described as a
soluble factor with the ability to modify the migration of macrophages(1). The molecule
responsible for the biological actions ascribed to MIF was identified and cloned in 1989 (2).
Initially found to activate macrophages at inflammatory sites, it has been shown to possess
pluripotential actions in the immune system. MIF has been shown to be expressed in
human diseases which include inflammation, injury, ischaemia or malignancy. MIF also
has a unique relationship with glucocarticoids by overriding their anti-inflammatory
effects.
Recent studies have indicated that monoclonal antibody antagonism of MIF may be useful
in the treatment of sepsis, certain types of cancers and delayed type hypersensitivity.
Antibody antagonism of MIF has also been shown to have activity in adjuvant- or
collagen-induced arthritis animal models and other models of inflammatory and immune
diseases.
Although antibody antagonism of MIF is one potential way to provide therapeutic
treatments, such biological molecules can be expensive to prepare on a commercial basis
and further, can be limited in the way they are administered (generally by injection) and do
not readily lend themselves to formulations for administration by other means eg oral
administration.
Small molecule inhibitors may overcome one or more such difficulties connected with the
use of biological therapeutic treatments. There exists a need, therefore, for small molecule
inhibitors of the cytokine or biological activity of MIF. Small molecule inhibitors of the
cytokine or biological activity of MIF would have therapeutic effects in a broad range of
diseases, whether given alone or in combination with other therapies.

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Further, glucocorticoids have been used to treat human diseases for over fifty years and are
effective in a range of diseases which include inflammation, injury, ischaemia or
malignancy. Although debate continues in relation to their impact on disease progression,
their influence on symptoms and signs of inflammation, especially in the short term, can be
dramatic.
Despite their benefits and efficacy, the use of glucocorticoids is limited by universal,
predictable, dose-dependent toxicity. Mimicking Cushing's disease, a disease wherein the
adrenal glands produce excess endogenous glucocorticoids, glucocorticoid treatment is
associated with side effects including immunosuppression (resulting in increased
susceptibility to infections), weight gain, change in body habitus, hypertension, oedema,
diabetes mellitus, cataracts,; osteoporosis, poor wound healing, Running of the skin,
vascular fragility, hirsutism and other features of masculinization (in females). In children,
growth retardation is also noted. These side effects are known as Cushingoid side effects.
Since the side effects of glucocorticoids are dose dependent attempts to reduce the dosage
requirement have been investigated, including combination therapies in which
glucocorticoids are administered with other therapeutic agents. These combination
therapies are sometimes referred to as "steroid-sparing" therapies. However, currently
available combination therapies are non-specific as the other therapeutic agents do not
address biological events which inhibit the effectiveness of glucocorticoids. Such
combination therapies are also typically associated with serious side effects.
Furthermore, glucocorticoids are incompletely effective in a number of disease settings,
leading to the concept of "steroid-resistant" diseases. Agents which amplify or enhance the
effects of glucocorticoids would not only allow the reduction of dose of these agents but
may also potentially render "steroid-resistant" diseases steroid-sensitive.
There is a need for effective therapies which enable a reduction in the dosage level of
glucocorticoids. There is also a need for effective treatment of "steroid-resistant" diseases.
Preferably, such therapies or treatments would address factors which directly limit the
effectiveness of glucocorticoids.
Therapeutic antagonism of MIP may provide "'steroid-sparing" effects or be therapeutic in
"steroid-resistant" diseases. Unlike other pro-inflammatory molecules, such as cytokines,
the expression and/ or release of MIF can be induced by glucocorticoids (3) (4). Moreover,
MIF is able to directly antagonize the effects of glucocorticoids. This has been shown to be
the case for macrophage TNF, IL-1, IL-6 and IL-8 secretion(5) (6), and for T cell proliferation

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and IL-2 release(7). In vivo, MIF exerts a powerful glucocorticoid-antagonist effect in
models including endotoxic shock and experimental arthritis(5)(8). In the context of an
inflammatory or other disease treated with glucocorticoids, then, MIF is expressed but
exerts an effect which prevents the glucocorticoid inhibition of inflammation. It can
therefore be proposed that therapeutic antagonism of MIF would remove MIFs role in
inhibiting the anti-inflammatory effect of. glucocorticoids, thereby allowing glucocorticoids
to prevail, This would be the first example of true "steroid-sparing" therapy. In support of
this hypothesis is the observation that anti-MIF antibody therapy reverses the effect of
adrenaiectomy in rat adjuvant arthritis(9). By neutralizing the natural glucocorticoid
'counter-regulator' effect of MIF, it is envisioned that with MIF antagonism, steroid
dosages could be reduced or even eliminated in inflammatory disease, particularly in those
diseases that are associated with the glucocorticoid resistance (10) (10), There is a need,
therefore, for therapeutic antagonists of the cytokine or biological activity of MIF.
SUMMARY OF THE INVENTION
Throughout this specification and the claims which follow, unless the context requires
otherwise, the word "comprise", and variations such as "comprises" and "comprising", will
be understood to imply the inclusion of a stated integer or step or group of integers or
steps but not the exclusion of any other integer or step or group of integers or steps.
In a first aspect, the present invention provides a compound of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof


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wherein X and X' are independently selected from -C(3R5)2 -O-, -S-, -N(R5)-, or taken
together form -C(R5)-C(R5)-, -C(R5)=N-, -N=C(R5)-, -N(R5)-N(R5)- or -N=N-;
Y and Y' are independently selected from -C(R5)2-, -O-, -S-, -N(R5)- or taken together form
-C(R5)=C(R5)-, -C(R5)=N-, -N=C(R5), -N(R5)-N(R5)- or -N=N-;
Z is -C(R5)2 -O-, -S- or -N(R5)-, or forms a covalent single or double bond between X' and
Y, or Z together with X' or Y forms -C(R3)=C(R5)-, -C(R5)=N-, -N=C(R5)-, -N(R5)-N(R5)- or
wherein when Z is -O-, -S- or -N(R5)-, X' and Y" are -C(R5)2;
when X is-O,-S-or-N(R5)- X1 is-C(R5)2-;
when Y is -O-, -S- or -N(R5)-,Y' is -C(R5)2; or
X or Y together with the carbon atom bearing the phenyl group form a double bond
wherein which ever of X or Y forms part of the double bond is selected from -C(R5)- and
-N-;
R1 is selected from hydrogen;. C1-20alkyl, C2-20alkenyl, C2-20alkynyl (A)nC(O)R6, (A)nC(S)R6,
(A)nS(O)R6 (A)nS(O)2R6 (A)nOR7, (A)nSR,7, (A)nN(R8)2, (A)nC(=NR9)R10 and (A)nR11or when
X or Y together with the carbon atom bearing the phenyl group form a double bond, R1 is
absent;
R2 and R4 are independently selected from hydrogen, C13alkyl and (A)mR12
R3 is selected from C13alkyl, (A)mR12, (A)maryl and (A)mheterocydyl;
R5 is selected from hydrogen, C1-20.alkyl, C1-20alkenyl, C2-20alkynyl, (A)nC(O)R6 (A)nC(S)R6,
(A)nS(O)R6, (A)nS(O)2R6, (A)nOR7, (A)nSR7, (A)pN(R6), (A)nC(=NR9)R10 and (A)nR11;
R6 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, OH, OC1-10alkyl,
OC2-20alkenyl, OC2-10alkynyl, O(A)qR11 SH, SC1-10alkyl, SC2-10alkenyl, SC2-10alkynyl, S(A)qR11,
N(R13)2, [NH-CH(R14)C(O)]8-OH [NH-CH(R14)C(O)]5-OC1-3alkyl, [sugar], and (A)qR11
R7 is selected from hydrogen, C1-20, C2-20alkenyl, C2-20alkynyl, (A)qR11, C(O)H,
C(O)C1-10alkyl C(O)C2-10alkenyl, C(O)C2-10alkynyl C(O)-aryl C(O)(A)qR11C(O)2H,
C(O)2C1-10alkyl C(O)2C2.10alkenyl C2-10alkynyl, C(O)2-aryl, C(O)2(A)q R11C(S)H,
C(S)C1-10alkyl C(S)C2-10alkenyl, C(S)C2-10alkynyl, C(S)-aryl C(S)(A)qR11, C(S)OH
C(S)OC1-10alkyl, C(S)OC2-10alkenyl, C(S)OC2-10alkynyl, C(S)O-aryl C(S)O(A)qR11, S(O)H,

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S(O) A-ioalkyL S(O)A-iaalkenyl, S{0>A-ioa&ynyl, S(O)raryl, S(O)t [CfOjCH^JNH]^ [aOCHCR^NHlrCMoalkyl, [C(O)CH(RH)NH]rCM0aIkenyl
ECCO)CH(R11)NH]fl-Q,toalkynyl/ [C(O)CH(R14)NH]B-aryl, [C(O)CH(RH)NH3s-(A)qRn and
[sugar],
Each R8 is independently selected from R7 and NHC(=NR15)NH2;
R9 is selected from hydrogen and Q1-6alkyl;
R10 is selected from C1-6alkyl, NH2 NH(C1-3alkyl), N(C1-5alkyl)2, OH, OC1-3alkyl SH and
SC1-3alkyl;
R11 is selected from OH, OC1-6alkyl, OC1-3alkyl-O-C1-3alkyl, O-aryl O-heteroclyl,
O[C(O)CH(R14)NH]5H, [sugar]5, SH, SC1-6alkyl, SC1-3alkyl-O-C1-3alkyl, S-aryl, S-heterocyclyl,
S[C(O)CH(R14)NH]8 halo, N(R15)2, C(O)R16, CN, C(R17)3, aryl and heterocyclyl;
R12 is selected from OH, SH, NH2 halo, NO2, C(R17)3, OC(R17)3 and CN;
Each R13 is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and
R14 is the characterising group of an amino acid;
Each R15 is independently selected from hydrogen, C1-6alkyl, C1-3alkoxyC1-3alkyl, aryl and
heterocyclyl;
R16 is selected from C1-3alkyl, OH C1-3alkoxy, aryl, aryloxy, heterocyclyl and
heterocydyloxy;
Each R]7 is independently selected from hydrogen and halogen;
A is optionally substituted methylene wherein when n > 1, any two adjacent A groups are
optionally interrupted by -O-, -S- or -N(R15)-;
where n is .0 or an integer selected from 1 to 20;
m is 0 or an integer selected from 1 to 3;
p is an integer selected from 1 to 20;
q is an integer selected from 1 to 10

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s is an integer selected from 1 to 5;
t is an integer selected from 1 or 2; and
wherein each alkyl, alkenyl, alkynyl, aryl and heterocydyl maybe optionally substituted.
In a further aspect the present invention provides a method of inhibiting cytokine or
biological activity of MIF comprising contacting MIF with a cytokine or biological
inhibiting amount of a compound of formula (I), or a pharmaceutically acceptable salt or
prodrug thereof.
In another aspect, the invention provides a method of treating, preventing or diagnosing a
disease or condition wherein MIF cytokine or biological activity is implicated comprising
the administration of a treatment, prevention or diagnostic effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof to a
subject in need thereof.
In a further aspect, there is provided the use of a compound of formula (I) or a
pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament
for the treatment, prevention or diagnosis of a disease or condition wherein MIF cytokine
or biological activity is implicated.
In particular, the invention provides a method of treating, diagnosing or preventing
autoimmune diseases, tumours, or chronic or acute inflammatory diseases, including a
disease or condition selected from the group comprising:
rheumatic diseases (including but not limited to rheumatoid arthritis, osteoarthritis,
psoriatic arthritis) spondyloarthropathies (including but not limited to ankylosing
spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (including
but not limited to gout pseudogout, calcium pyrophosphate deposition disease),
Lyrne disease, polymyalgia rheumatica;
connective tissue diseases (including but not limited to systemic lupus
erythematosus, systemic sclerosis, polymyositis, dermatomyositis, SjÖgren's
syndrome);
vasculitides (including but not limited to polyarthritis nodosa, Wegener's
gxanulomatosis, Churg-Strauss syndrome);
inflammatory conditions including consequences of trauma or ischaemia,

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sarcoidosis;
vascular diseases including atherosclerotic vascular disease, atherosclerosis, and
vascular occlusive disease (including but not limited to atherosclerosis, ischaemic
heart disease, myocardial infarction, stroke, peripheral vascular disease), and
vascular stent restenosis;
ocular diseases including uveitis, comeal disease, iritis, iridocyclitis, cataracts;
autoimmune diseases (including but not limited to diabetes mellitus, thyroiditis,
myasthenia gravis, sclerosing cholangitis, primary biliary cirrhosis);
pulmonary diseases (including but not limited to diffuse interstitial lung diseases,
pneumoconioses, fibrosing alveolitis, asthma, bronchitis, bronchiectasis, chronic
obstructive pulmonary disease, adult respiratory distress syndrome);
cancers whether primary or metastatic (including but not limited to prostate cancer,
colon cancer, lymphoma, lung cancer, melanoma, multiple myeloma, breast cancer,
stomach cancer, leukaemia, cervical cancer and metastatic cancer);
renal diseases including glomerulonephritis, interstitial nephritis;
disorders of the hypomalamic-pituitary-adrenal axis;.
nervous system disorders including multiple sclerosis, Alzheimer's disease;
diseases characterised by modified angiogenesis (eg diabetic retinopathy,
rheumatoid arthritis, cancer), endometrial function (menstruation, implantation,
endometriosie);
complications of infective disorders including endotoxic (septic) shock, exotoxic
(septic) shock, infective (true septic) shock, malarial complications, other
complications of infection, pelvic inflammatory disease;
transplant rejection, graft-versus-host disease;
allergic diseases including allergies, atopic diseases, allergic rhinitis;
bone diseases (eg osteoporosis, Paget's disease);
skin diseases including psoriasis, atopic dermatitis, UV(B)-induced dermal cell
activation (eg sunburn, skin cancer);

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complications of diabetes mellitus, pain, testicular dysfunctions and wound
healing,
gastrointestinal diseases including inflammatory bowel disease (including but not
limited to ulcerative colitis, Grohn's disease), peptic ulceration, gastritis,
oesophagitis, liver disease (including but not limited to cirrhosis, hepatitis);
comprising the administration of a treatment diagnosis or prevention effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof to a
subject in need thereof.
Preferably, the disease or condition is selected from the group consisitmg of rheumatoid
athritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, multiple
sclerosis, psoriasis, uveitis, atherosclerotic vascular disease, asthma and chronic obstructive
pulmonary disease,
A further aspect of the invention provides for the use of a compound of Formula (I) or a
pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament
for the treatment of a disease or condition as above.
A further aspect of the invention provides a pharmaceutical composition comprising a
compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
In another aspect, the invention provides a method of treating or preventing a disease or
condition wherein MIF cytokine or biological activity is implicated comprising:
administering to a mammal a compound of formula (I) and a second therapeutic
agent.
In another aspect, the present invention provides a method of prophylaxis or treatment of a
disease or condition for which treatment with a glucocorticoid is indicated, said method
comprising:
administering to a mammal a glucocorticoid and a compound of formula (I).
In yet another aspect, the present invention provides a method of treating steroid-resistant
diseases comprising:
administering to a mammal a glucocorticoid and a compound of formula (I),

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In a further aspect, the present invention provides a method of enhancing the effect of a
glucocorticoid in mammals comprising administering a compound of formula (I)
simultaneously, separately or sequentially with said glucocorticoid.
In yet a further aspect; the present invention provides a pharmaceutical composition
comprising a glucocorticoid and a compound of formula (I).
In a further aspect of the invention there is provided a use of a glucocorticoid in the
manufacture of a medicament for administration with a compound of formula (I) for the
treatment or prophylaxis of a disease or condition for which treatment with a
glucocorticoid is indicated.
In yet a further aspect of the invention there is provided a use of a compound of formula (I)
in the manufacture of a medicament for administration with a glucocorticoid for the
treatment or prophylaxis of a disease or condition for which treatment of a glucocorticoid
is indicated.
In yet a further aspect of the invention there is provided a Use of a glueocorticoid and a
compound of formula (I) in the manufacture of a medicament for the treatment or
prophylaxis of a disease or condition for which treatment with a glucocorticoid is
indicated.
In preferred embodiments, the compounds of Formula (I) or a pharmaceutically acceptable
salt or prodrug thereof are used to treat or prevent a disease or condition, particularly in a
human subject.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: graphically depicts inhibition of MIF-induced proliferation of S1 12 human
fibroblasts by 2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methyIphenyl)-l/3-
dioxolane (Compound 1).
Figure 2: graphically depicts inhibition of IL-1 induced COX-2 expression by 2-(2-
dyoxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-dioxolane (Compound 1).
Figure 3: graphically depicts inhibition of IL-1 induced-COX-2 expression by 2-(2-
hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-dioxolane (Compound 1).
Figure 4: graphically depicts inhibition of IL-1 induced COX-2 expression by 2-(2-
hydroxyethoxy)-2-(4'-hydroxyphenyl)-l,3-dioxolane (Compound 2).

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Figure 5: graphically depicts inhibition of antigen-specific T-cell activation by 2-(2-
hydroxyeihoxy)-2-(4-hydroxyphenyl)-1,3-dioxolane (Compound 2).
Figure 6: graphically depicts the enhanced effect of the glucocorticoid dexamethasone in
the presence of 2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-
dioxolane (Compound 1).
Figure 7: graphically depicts the absence of cytotoxic effects of 2-(2-hydroxyethoxy)-2-(4-
hydroxy-3-methylphenyl)-l,3-dioxolane (Compound 1).
Figure 8: graphically depicts the inhibition o£ tnacrophage nitrite release by
l-(3-Methylbutyl)-4-(4-methylphenyl)-lH- pyrazole (Compound 13).
Figure 9: graphically depicts the inhibition of MIF-induced NIH-3T3 fibroblast
proliferation by 2-Methyl-2-(4-methyIphenyl)-l,3-dithiolane (Compound 18)
and other compounds of the invention.
Figure 10: graphically depicts the inhibition of Iipopolysaccharide-induced serum IL-1,
TNF, and IL-6 in mice treated with 2-Hexyl-2-(4-methylphenyl)-l,3-dithiolane
(Compound 17).
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "alkyl" refers to monovalent straight, branched or, where
appropriate, cyclic aliphatic radicals, having 1 to 3,1 to 6,1 to 10 or 1 to 20 carbon atoms,
e.g. methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, t-butyl and
cyclobutyl, n-pentyl, l-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopentyl, n-hexyl, 1-
2- 3- or 4- methylpentyl, 1- 2- or 3-ethylbutyl, 1 or 2- propylpropyl or cyclohexyl.
An alkyl group may be optionally substituted one or more times by halo (eg chloro, fluoro
orbrorno), CN, NO2, CO2H, CO2C1-6alkyl, CO2NH2 CO2NH(C1-6alkyl), CO2N(C1.6alkyl)2,
OH, alkoxy, acyl, acetyl, halomethyl, trifiuoromethyl, benzyloxy, phenoxy, NH2,
NH(C1-6alkyl) or N (C1-6alkyl)2. A preferred optional substituentis a polar substituent
Examples of alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, cydopropoxy, and
butoxy (n-, Sec t- and cydo) pentoxy and hexyloxy. The "alkyl" portion of an alkoxy group
may be substituted as described above.
As used herein, the term "alkenyl" refers to straight branched, or where appropriate, cyclic
carbon containing radicals having one or more double bonds between carbon atoms.
Examples of such radicals include vinyl, alkyl, butenyl, or longer carbon chains such as

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those derived from palrnitoleic, oleic, linoleic, linolenic or arachidonic acids. An alkenyl
group may be optionally substituted one or more times by halo (eg chloro, fluoro or
bromo), CN, NO2, CO2H, CO2C1-6alkyl, CO2NH2 CO2NH(C1-6alkyl), CO2N(C1-6alkyIk OH,
alkoxy, acyl, acetyl, halomethyl, trifluoromeyl, benzyloxy, phenoxy, NH2, NH(C1-6alkyl)
or N(C1-6alkyl)2. A preferred optional substituent is a polar substituent.
As used herein, the term "alkynyl" refers to straight or branched carbon containing radicals
having one or more triple bonds between carbon atoms. Examples of such radicals include
propargyl, butynyl and hexynyl. An alkynyl group may be optionally substituted one or
more times by halo (eg chloro, fluoro or bromo), CN, NO2, CO2H, CO2C1-6alkyl, CO2NH2,
CO2NH(C1-6alkyl), CO2N(C1-6alkyl)2, OH, alkoxy, acyl, acetyl, halomeihyl trifluoromethyl,
benzyloxy, phenoxy, NH2, NH(C1-6alkyl) or N(C1-6alkyl)2 A preferred optional substituent
is a polar substituent.
Examples of suitable NH(alkyl) and N(alkyl)2 include methylamino, ethylamino,
igopropylamino, dimethylamino,n-propylamino/ diethylamino and di-isopropylamino,
The term "halogen" (or "halo") refers to fluorine (fluoro), chlorine (chloro), bromine
(bromo) or iodine (iodd).
The term "sugar" refers to a pyranosyl or furanosyl moiety such as those derived from
glucose, galactose, mannose, allose, altrose, gluose, idose, talose, ribose, arabinose or
xylose. Derivatives of such sugars include deoxy or amino pyranosyl or furanosyl sugar
derivatives. Each sugar moiety is incorporated into the compound of formula (I) through a
hydroxy group of the sugar moiety.
As used herein, "the characterising group of an amino acid" refers to the substituent at C2 of
a natural or unnatural amino add and which defines the amino acid. For example, methyl
is the characterising group of alanine, phenylmethyl is the characterising group of
phenylalanine, hydroxymethyl is the characterising group of serine, hydroxyethyl is the
characterising group of homoserine and n-propyi is the characterising group of norvaline.
An aryl group, as used herein, refers to C6-C10 aryl groups such as phenyi or naphthalene.
Aryl groups may be optionally substituted one or more times by halo (eg, chloro, fluoro or
bromo), CN, NO2, CO2H, CO2C1-6alkyl, CO2NH2 CO2NH(C)1-6alkyl), CO2N(C1-6alkyl) OH,
alkoxy, acyl, acetyl, halomethyl, trifluoromethyl, benzyloxy, phenoxy, NH2 NH(C1-6alkyl)
or N(C1-6alkyl)2.

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As used herein, the term "heterocyclyl" refers-to a cyclic, aliphatic or aromatic radical
containing at least one heteroatom independently selected from O, N or S. Examples of
suitable heterocydyl groups include furyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl,
pyridinyl, pyrimidinyl, pyrazolyl, piperidinyl, pyrrolyl, thyaphenyl, oxazolyl, imidazolyl,
thiazolyl, isoxazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzofuranyl,
benzothiophenyl, triazolyl, tetrazolyl, oxadiazolyl and purinyl. Heterocyclyl groups may
be optionally substituted one or more times by halo (eg, chloro, fluoro or bromo), CN, NOj.
CO2H, CO2C1-6alkyl, CO2NH2 CO2NH(C1-6alkyl), CO2N(C1-6alky)2, OH, alkoxy, acyl, acetyl
halomethyl trifluoromethyl, benzyloxy, phenoxy, NH2, NH(C1-6alkyl) or N(C1-6alkyl)2.
Each A is an unsubstituted methylene group (-CH2-) or an optionally substituted
methylene group where one or two of the hydrogen atoms of the methylene group may be
replaced by a substituent such as halo (eg. chloro, fluoro or bromo), CN, NO2, CO2H,
CO2C1-6alkyl, CO2NH2, CO2NH(C1-6alkyl), CO2N(C1-6alkyl)2, OH, alkoxy, acyl, acetyl,
halomethyl, trifluoromethyl, benzyloxy, phenoxy, NH2, NH(C1-6alkyl) or N(C1-6alkyl)2. (A)n
may therefore form an optionally substituted methylene group, when n is 1, or an
optionally substituted alkylene group when n is greater than 1. Alternatively, when two or
more A groups appear in adjacent positions, they are optionally interrupted by -O-, -S- or
-N(R15)- (A)n may therefore form, for example, an optionally substituted ether or
polyether.
In a first aspect, the present invention provides a compound of formula (I), or a
pharmaceutically acceptable salt or prodrug thereof


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wherein X and X are independently selected from -C(R5)2, -O-, -S-, -N(R5)-, or taken
together form-C(R5)=C(R5)-, -CR5)=N-, -N=C(R5)-, -N(R5)N(R5)- or -N=N-;
Y and Y' are independently selected from -C(R5)2-, -O-, -S-, -N(R5)-, or taken together form
-C(R5)=C(R5)-, -C(R5)=N-, -N=C(R5)-,-N(R5)-N(R5)- or -N=N-;
Z is -C(R5)2-, -O-, -S- or -N(R5)-, or forms a covalent single or double bond between X' and
Y', or Z together with X' or Y' forma -C(R5)=C(R5)-, -C(R5)=N-, -N=C(R5)-, -N(R5)-N(R5)- or-
N=N-;
wherein when Z is -O-, -S- or -N(R5)-, X' and Y' are -C(R5)2;
when X is -O-, -S- or -N(R5)-, X' is -C(R5)2-;
when Y is -O-, -S- or -N(R5)-, Y' is -C(R5)2-; or
X or Y together with the carbon atom bearing the phenyl group form a double bond
wherein which ever of X or Y forms part of the double bond is selected from -C(R5)- and
-N-;
R1 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (A)nC(O)R6, (A)nC(S)R6
(A)n(O)R6 (A)nS(O)2R6, (A)nOR7, (A)nSR7(A)nN(R8), (A)nC(=NR9)R10 and (A)nR11 or when
X or Y together with the carbon atom bearing the phenyl group form a double bond, R1 is
absent;
R2 and R4 are independently selected from hydrogen, C1-3alkyl and (A)mR12;
R3 is selected from C1-3alkyl, (A)mR12, (A)maryl and (A)mheterocyclyl;
R5 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (A)nC(O)R6, (A)nC(S)R6,
(A)nS(O)R6, (A)nS(O)2R6 (A)nOR7, (A)nSR7, (A)pN(R8), (A)nC(=NR9)R10 and (A)nR11;
R6 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, OH, OC1-10alkyl,
OC2-10alkenyl, OC2-10alkynyl, O(A)qR11 SH, SC1-10alkyl SC2-10alkenyl SC2.10alkynyl, S(A)qR11
N(R13)2, [NH-CH(R14)C(O)]3OH, [NH-CH(R14)C(O)]3OC1-3alkyl [sugar]9 and (A)qRl1;
R7 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (A)qR11, C(O)H,
C(O)C1-10alkyl, C(O)C2-10alkenyl, C(O)C2.10alkynyl, C(O)-aryl, C(O)(A)qR11 C(O)2H,
C(O)2C1-10alkyl, C(O)2C2-10alkenyl, C(O)2C2-10alkynyl C(O)2aryl C(O)2(A)qR11 C(S)H,
C(S)C1-10alkyI, C(S)C2-10alkenyl, C(S)C2-10alkynyl, C(S)-aryI, C(S)(A)qR11, C(S)OH,
C(S)OC1-10alkyl, C(S)OC2-10alkenyl, C(S)OC2-10alkynyI, C(S)O-aryl, C(S)O(A)qR11, S(O),H,

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S(O)tC1-10alkyl S(O)t C2-10alkenyl, S(O)t C2-10alkynyl S(O)taryl, S(O)t(A)qR11,
[C(O)CH(R14)NH],-H, [C(O)CH(R14)NH]9C1-10alkyl, [C(O)CH(R14)NH]8-C2-10alkenyl
[C(O)CHCR14)NH]8-C2.10alkynyl [C(O)CH(R14)NH]5-aryl [C(O)CH(R14)NH]6-(A)qR11 and
[sugar]5;
Each R8 is independently selected from R7 and NHC(=NR15)NH2;
R9 is selected from hydrogen and C1-6alkyl;
R10is selected from C1-6alkyl NH2 NH(C1-3alkyl), N(C1-3alkyl)2 OH, OC1-3alkyl, SH and
SC1-3alkyl;
R11 is selected from OH, OC1-6alkyl, OC1-3alkyl-O-C1-3alkyl, O-aryl, O-heterocyclyl,
O[C(O)CH(R14)NH]8H, [sugar]8, SH, SC1-6alkyl, SC1-3alkyl-O-C1-3alkyl, S-aryl, S-heterocyclyl,
S[C(O)CH(R14)NH]8H, halo, N(R15)2 C(O)R16 CN, C(R17)3,aryl and heterocyclyl;
R12 is selected from OH, SH, NH2 halo, NO2 C(R17)3, OC(R17)3 and CN;
Each R13 is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and
(A)qR11;
R14 is the characterising group of an amino acid;
Each R15 is independently selected from hydrogen, C1-6alkyl, C1-3alkoxyC1-3alkyl, aryl and
heterocyclyl;
R16 is selected from C1-3alkyl OH, C1-3alkoxy, aryl, aryloxy, heterocyclyl and
heterocyclyloxy;
Each R17 is independently selected from hydrogen and halogen;
A is optionally substituted rnethylene wherein when n > 1, any two adjacent A groups are
optionally interrupted by -O-, -S- or -N(R15)-;
where n is 0 or an integer selected from 1 to 20;
m is 0 or an integer selected from 1 to 3;
p is an integef selected from 1 to 20;
q is an integer selected from 1 to 10

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s is an integer selected from 1 to 5;
t is an integer selected from 1 or 2; and
wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted.
In another aspect, the compound of the invention is a compound of formula (II), or a
pharmaceutically acceptable salt or prodrug thereof

wherein X and Y are independently selected from -O-, -S-, -N(R5)- and -C(R5)2;
Z is -C(R5)2- or is a covalent bond between adjacent methylene groups;
R1 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (A)nC(O)R6, (A)nC(S)R6,
(A)nS(O)R6 (A)nS(O)2R6 (A)nOR7, (A)nSR7, (A)nN(R8), (A)nC(=NR9)R10 and (A)nR11;
R2 and R4 are independently selected from hydrogen, C1-3alkyl and (A)mR12;
R3 is selected from C1-3alkyl, (A)mR12, (A)maryl and (A)mheterocydyl;
R5 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, (A)nC(O)R6, (A)nC(S)R6
(A)nS(O)R6(A)nS(O)2R6,(A)nOR7, (A)nSR7, (A)pN(R8)-(A)nC(=NR9)R11and(A)nR11 ,
R6 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, OH, OC1-10alkyl,
OC2-10alkenyl OC2-10alkynyl O(A)qR11,SH, SC1-10alkyl, SC2-10alkenyl, SC2-10alkynyl, S(A)qR11,
N(R13)2 [NH-CH(R14)C(O)]8-OH, [NH-CH(R14)C(O)]6-OC1-3alkyl, [sugar], and (A)qR11;

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R7 is selected from hydrogen, C1-20alkyl C2-20alkenyl, C2-20alkynyl, (A)qR11, C(O)H,
C(O)C1-10alkyl, C(O)C2.10alkenyl, C(O)C2-10alkynyl, C(O)-aryl, C(O)(A)qR11, C(O)2H,
C(O)2C1-10alkyl, C(O)2C2-10alkenyl, C(O)2C2-10alkynyl C(O)2-aryl, C(O)2(A)qR11, C(S)H,
C(S)C1-10alkyl, C(S)C2-10alkenyl C(S)C2-10alkynyI, C(S)-aryl, C(S)(A)qR11, C(S)OH,
C(S)OC1-10alkyl, C(S)alkenyl, C(S)OC2-10alkynyl C(S)O-aryl, C(S)O(A)qR11, S(O)tH,
S(O)tC1-10alkyl, S(O)tC2-10alkenyl, S(O)tC2-10alkynyl S(O)taryl, S(O)t(A)qR11
[C(O)CH(R14)NH]8 -H,[C(O)CH(R14)NH]5-C1.10aIkyl, [C(O)CH(R14)NH]5-C2-10alkenyl
[C(O)CH(R14)NH]5-C2-10alkynyl [C(O)CH(R14)NH]5-aryl, [C(O)CH(R14)NH]5-(A)qR11 and
[sugar]8;
Each R8 is independently selected from R7 and NHC(=NR15)NH2;
R9 is selected from hydrogen and C1-6alkyl;
R10 is selected from C1-6alkyl, NH2 NH(C1-3alkyl), N(C1-3alkyl)2, OH, OC1-3alkyl, SH and
SC1-3alkyl;
R11 is selected from OH, OC1-6alkyl, OC1-3alkyl-O-C1-3alkyl O-aryl, O-heterocyclyl,
O[C(O)CH(R14)NH]8H, [sugar]8, SH, SC1-6alkyl, SC1-3alkyl-O-C1-3alkyl, S-aryl, S-heterocyclyl,
S[C(O)CH(R14)NH]8H, halo, N(R15)2, C(O)R16, CN, C(R17)3, aryl and heterocyclyl;
R12 is selected from OH, SH,NH2, halo, NO2,C(R17)3,OC(R17)3 and CN;
Each R13 is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and
(A)qR11;
R14 is the characterising group of an amino acid;
Each R15 is independently selected from hydrogen, C1-6alkyl, C1-3alkoxyC1-3alkyl aryl and
heterocyclyl;
R16 is selected from C1-3alkyl, OH, C1-3alkoxy, aryl, aryloxy, heterocydyl and
heterocydyloxy;
Each R17 is independently selected fromhydrogen and halogen;
A is optionally substituted methylene wherein when n > 1, any two adjacent A groups are
optionally interrupted by -O-, -S- or -N(R15)-;
where n is 0 or an integer selected from 1 to 20;

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m is 0 or an integer selected from 1 to 3;
p is an integer selected from 1 to 20;
q is an integer selected from 1 to 10
s is an integer selected from 1 to 5;
t is an integer selected from 1 or 2; and
wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted.
In a preferred embodiment one or more of the following definitions apply:
X is -O, -S-, -NH- or -CH2;
Y is-O-, -S- or -NR5
Z forms a covalent bond between adjacent methylene groups;
R1 is selected from C1-20alkyl, C1-20alkenyl, O-(A)qO-C1-6alkyl, O-(A)q-heterocyclyl,
O-(A)q-sugar, O-(A)qO[C(O)CH(R14)NH]8-H (A)nOH, (A)nOC1-20alkyl, (A)nOC1-20alkenyl,
(A)nOC(O)C1-20alkyl (A)nOC(O)C1-20alkenyl (A)nOC(O)aryl, (A)nO[C(O)CH(R14)NH]8-H,
(A)nO[sugar]8, (A)nNHC1-20alkyl (A)nN(C1-20alkyl)2, (A)nNHC1-2Oalkenyl (A)nN(C1-20alkenyl)2,
(A)nNHC(O)C1-20alkyl (A)nNHC(O)C1-20alkenyl, (A)nNHC(O)aryl,
(A)nNH[C(O)CH(R14)NH]-H, (A)n NH-[sugar]5, (A)nSO3H, (A)nSO3C1-20alkyl,
(A)nSO3C1-20alkenyl, (A)nC(O)C1-20alkyl (A)nC(O)C1-20alkenyl, (A)nCO2H, (A)nCO2C1-20alkyl,
(A)nCO2-C1-20alkenyl, (A)nC(O)NHC1-20alkyl (A)nC(O)N(C1-20alkyl)2, (A)nC(O)NHC1-20alkenyl,
(A)nC(O)N(C1-20alkenyl)2, (A)nC(O)[NHCH(R14)C(O)]5-OH, (A)nC(O)[sugar]8; wherein A is
methylene optionally substituted one or two times with a group that is independently
selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, OH, OC1-6alkyl, CO2H
CO2C1-3-alkyl NH2, NHC1-3alkyl, -N(C1-3alkyl)2, CN, NO2, aryl or heterocydyl; R14 is the
characterising group of an amino acid, n is 0 or an integer from 1 to 20 and s is an integer
from 1 to 5;
R2 is hydrogen, C1-3alkyl, OH, SH, NH2 -NO2, CF3 halo or -CN;
R3 is hydrogen, C1-C3alkyl -(CH2)mNH2, -(CH2)m-OH, -(CH2)m-CF3, -(CH2)m-SH or a 5 or 6
membered heterocyclic group, wherein m is 0 or an integer from 1 to 3;
R4 is hydrogen, C1-3alkyl, OH, SH, NH2 NO2, CF3 halo or CN;

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A is unsubstituted methylene or mono-substituted methylene.
In certain preferred forms of the invention, the compounds of Formula (II) include:

wherein
X is-O-,-S-,-NH-;
Y is -O-, -S- or -N(R5)-;
Z forms a covalent bond between adjacent methylene groups;
R1, is C1-C20alkyl C2-C20alkenyl C2-C20alkynyl (A)nC(O)R6, -(A)nC(S)R6, -(A)nS(O)R6,
-(A)nS(O)2R6 -(A)nOK7, -(A)nS7,-(A)nN(R8)2, (A)nC(=NR9)R10 or (A)nR11 where n, R6, R7, R8,
R9, R10 and R11 are defined above;
R2 is hydrogen, methyl, OH, OCH3, SH, NH2, NO2 CF3, halo or CN;
R3 is C1-3alkyl, -(CH2)mNH2, -(CH2)m-OH, -(CH2)mSH or heterocydyl where m is defined
above;
R4 is hydrogen, methyl, OH, OCH3, SH, NH2, NO2, CF3, CF3, halo or CN.

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More preferably the compounds of formula (II) comprise

wherein
X is -O- or NH;
Y is -O- or -N(R18)- where R18 is selected from hydrogen, C1-20alkyl, C1-20alkenyl, C1-20alkenyl,
C1-20alkynyl and (CH2)nR11 where R11 and n are defined above;
Z forms a covalent bond between adjacent methylene groups;
R1 is as defined for R1 above;
R2 is hydrogen, halomethyl, OH, OCH3, SH, NH2, NO2 or CN;
R3 is hydrogen, C1-3alkyl (CH2)mNH2, (CH2)mOH or (CH2)mCF3 or heterocyclyl where m is
defined above;
R4 is hydrogen, methyl, OH, OCH3, SH, NH2, NO2 or CN.

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More preferably, the compounds of Formula (I) are heterocyclic compounds having the
formula (III)

wherein
X is-O- or -NH-;
Y is -O- or -N(R18)- where R18 is defined above;
R1 is as defined for R1 above;
R3 is hydrogen, NH2, OH;
R4 is hydrogen, methyl, OCH3, or OH.
In a preferred embodiment Rl is selected from (A)nOR7 where n is 0 and A and R7 are
defined above.
Further preferred embodiments include:
A compound of formula (I) wherein X is -S-; Y is -N(R5); X' is -C(R5)2-; Y' is -C(R5)2-;;
Z forms a covalentbond between X' and Y. Preferably, Y is -NH-; X' is -CH2-; Y' is
-CH2-; R1 is H.
A compound of formula (I) wherein X and Y are each -O-; X' and Y' are each -
C(R5)2-; Z forms a covalent bond between X' and Y'. Preferably, X' and Y are each
-CH2-;R1 is H.
A compound of formula (I) wherein X and X' taken together form-C(R5)=N-; Y is
-C(R5)- and taken together with the carbon atom bearing the phenyl group forms a

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double bond; Y' is -N(R5)-; Z forms a covalent bond between X' and Y' Preferably,
Y is-CH-;X is-CH-.
A compound of formula (I) wherein X and X' taken together form -C(R5)=N-; 2
together with Y' forms -C(R5)=C(R5)-;Y is -C(R5)- and together withthe carbon atom
bearing the phenyl group forms a double bond. Preferably, X is -C(QGH3); Z
together with Y' forms -C(OCH3)=CH-; Y is -CH-.
A compound of formula (I) wherein X'.is -C(R5)2-; Y' is -C(R5)2-; Z is -C(R5)2-; X and
Y are each -O- Preferably, X', V and Z are each -CH2; R1 is H.
A compound of formula (1) wherein X and Y are each -S-; X' and Y are each
-C(R5)2-; Z forms a covalent bond between X' and Y'. Preferably, X' and Y' are each -
CH2-;R,is H.
A compound of formula (I) wherein X is -S-; Y is -O-; X' and Y' are each -C(R5)2; Z
forms a covalent bond between X' and Y'. Preferably, X' and Y' are each -CH2-.
A compound of formula (I) wherein X and X' taken together form -C(R5)=C(R5)-; Z
together with Y' forms -C(R5)-C(R5)-; Y is -C(R5)- and together with the carbon atom
bearing the phenyl group forms a double bond. Preferably, X and X' taken together
form -CH=CH-; Z together with Y forms -CH=CH-;Y is-CH-.
A compound of formula (I) wherein Y is -N- and taken together with the carbon
atom bearing the phenyl group forms a double bond; X is -O-; X' and Y' are each
-C(R5)2-; Z forms a covalent bond between X' and Y'. Preferably, X' and Y' are each
-CH2-
A compound of formula (I) wherein X and Y are each -C(R5)2; X' and Y' are each -
N(R5)-;Z is C (R5)2
A compound of formula 0) wherein X is -O-; Y' is -N(R5)-; X' and Y are each
A compound of formula (I) wherein X and X' are each -C(R5)2-; Y is -N(R5)-; Y' is
-C(R5)2; Z forms a covalent bond between X' and Y'.
A compound of formula (I) wherein X is -N(R9)-; X' is -C(R5)2-; Y is -C(R5)2-; Y' is
-N(R5)-; Z forms a covalent bond between X' and Y'.

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A compound of formula (I) wherein X and X' are each -C(R5)2- Y is -C(R5)2-; Y' is
-N(R5)-;-Z is -C(R5)2-.
Preferred compounds of formula (I) include 2-(2-hydroxyethoxy)-2-(4-hydroxy-3-
methylphenyl)-l,3-dioxolane;2-(2-hydroxyethoxy)-2-(4-hydroxyphenyl)-l,3-dioxolane;2-
(2-hydroxyethoxy)-2-(3-bromo-4-hydroxy-5-methylphenyl)-l,3-dioxolane;2-(4-
Bromophenyl)-l,3-thazolane;2-(4-Methoxyphenyl)-l,3-thiazolane;4-(l,3-Thiazolidin-2-
yl)benzonitrile;2-(4-Hydroxy-3-methoxyphenyl)-l,3-thiazolane;2-(3,4-Dimethoxyphenyl)-
1,3-thiazolane; Methyl 4-[2-(4-fluorophenyl)4,3-dioxolan-2-yl]butanoate; 4-[2-(4-
Fluorophenyl)-l,3-dioxolan-2-yl]butan-l-ol;2-(4'-Bromophenyl)-2-butyl-l/3-dioxolane;4-
(4-Methoxyphenyl)-1-(3-methylbutyl)-1H-pyrazole;1-(3-Methybutyl)-4-(4-methylphenyl)
1H-pyrazole; 2,6-Dimethoxy-3-[4-(trifluoromethoxy)phenyl]pyridine); 2-[4-(2-
Thienyl)phenyl]-l,3thiazolane;2-Ethyl-2-(4-methoxyphenyl)-l,3-dioxolane;2-Hexyl-2-(4-
methylphenyl)-l,3-dithiolane;2-Methyl-2-(4-methylphenyl)1,3-dithiolane;2-Hexyl-2-(4-
methylphenyl)-l,3-dioxolane; 2-(4-Chlorophenyl)-2-methyl-l,3-dioxane; 2-(4-
Chorophenyl)-2-methyl-l,3-dioxolane;2-Methyl-2-(4-methylphenyl)-l,3-dioxane;2-
Methyl-2-(4-methylphenyl)-l,3-dioxolane;2-(4-Chorophenyl)-2-methyl-l,3-dithiolane;2
(4-Nitrophenyl)-2-methyl-l,3-dioxolane;2-(4-Nitropheny])-2-methyl-l,3-dioxane;2-(4-
Methoxyphenyl)-1,3-oxathiolane;-2-(3,4,5-Trimethoxyphenyl)-1,3-oxathiolane;2-Methoxy-
4-(1,3-oxathiolan-2-yl)phenol;4-(1,3-Oxathiolan-2-yl)benzonitrile;2-(4-Bromophenyl)-2-
ethyl-l,3-oxathiolane;4-(5-Methyl-l,3-oxathiolan-2-yl)benzonitrile;2-(4-Thien-2-ylphenyl)
1,3-oxathiolane;4-(5-Methyl-2-octyl-1,3-oxathiolan-2-yl)phenol;2-Fluoro-5-(5-methyl-1,3-
oxatholan-2-yl)benzenecarbonitrile;4-Methoxy-4'-(trifluoromethoxy)-1,1'-biphenyl;2,6-
Dimethoxy-[4-(trifluoromethyl)phenyl]pyridine;2-(4-bromophenyl)-2-butyl-4-propyl-l,3-
oxathiane;4-(l,3-Dioxolan-2-yl)benzenecarbonitrile;2-(3,5-Dimethoxyphenyl)-2-hexyl-l,3-
dioxolane;2-(4-Chlorophenyl)-2-ethyl-4-methyl-l,3-dioxolane;5-(5,5-Diethyl-l,3-dioxan-2-
yl)-2-fluorobenzenecarbonitrile;2-(4-Chlorophenyl)-4,5-dihydro-l,3-oxazole;2-(4-
Methylphenyl)-4,5-dihydro-l,3-oxazole.
More preferably the compounds are selected from the group consisting of:2-(2-
hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-dioxolane;2-(2-hydroxyethoxy)-2-(4-
hydroxyphenyl)-l,3-dioxolane;2-(2-hydroxyethoxy)-2-(3-bromo-4-hydroxy-5-
methylphenyl)-1,3-dioxolane; Methyl 4-[2-(4-fIuorophenyl)-l,3-dioxolan-2-yl]butanoate; 4-
[2-(4-FluorophenyI)-l,3-dioxolan-2-yl]butan-l-ol;2-(4'-Bromophenyl)-2-butyl-l,3-
dioxolane;4-(4-Methoxyphenyl)-l-(3-methylbutyl)-lH-pyrazole;l-(3-Methylbutyl)-4-(4-
methylphenyl)-lH-pyrazole;2,6-Dimethoxy-3-[4-(trifluorcmethoxy)phenyl]pyridine);2-[4-
(2-Thienyl)phenyl]-l,3-thiazolane;2-Ethyl-2-(4-methoxyphenyl)-l,3-dioxolane;2-Hexyl-2-

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(4-methylphenyl)-l,3-dithiolane;2-Hexyl-2-(4-methylpheny])-l,3-dioxolane;2-(4-
Bromophenyl)-2-ethyl-l,3-oxathiolane;4-(5-Methyl-l,3-oxathiolan-2-yl)benzonitrile;2-(4-
Thien-2-ylphenyl)-l,3-oxathiolane;4-(5-Methyl-2-octyl-1,3-oxathiolan-2-yl)phenol;2-
Fluoro-5-(5-methyl-l,3-oxathiolan-2-yl)benzenecarbonitrile;4-Methoxy-4'-
(trifluoromethoxy)-1,1'-biphenyl;2,6-Dimethoxy-3-[4-(trifluoromethyl)phenyl]pyridine;2-
(4-bromophenyl)-2-butyl-4-propyl-l,3-oxathiane;4-(l,3-Dioxolan-2-yl)benzenecarbonitrile
2-(4-Chlorophenyl)-2-ethyl-4-methyl-l,3-dioxolane;5-(5,5-Diethyl-l,3-dioxan-2-yl)-2-
fluorobenzenecarbonitrile.
In a yet further preferred embodiment the compound of formula (I) is selected from the
group consisting of: 2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-dioxoIane; 4-
(4-Methoxyphenyl)-l-(3-methylbutyl)-lH-pyrazole; l-(3-Methylbutyl)-4-(4-methylphenyl)-
liy-pyrazole;2-Hexyl-2-(4-methylphenyl)-1,3-ditholane;2-Methyl-2-(4-methylphenyl)-l,3-
ditholane;2-(4-Thien-2-ylphenyl)-1,3-oxathiolane;4-Methoxy-4'-(trifluorornethoxy)-l,l'-
biphenyl;2,6-Dimethoxy-3-[4-(trifluoromethyl)phenyl]pyridine.
Examples of suitable compounds may include:

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Compounds of Formula (I) may be prepared using the methods depicted or described
herein or known in the art. It will be understood that minor modifications to methods
described herein or known in the art may be required to synthesize particular compounds
of Formula (I). General synthetic procedures applicable to the synthesis of compounds
may be found in standard references such as Comprehensive Organic Transformations, R,
C. Larock, 1989, VCH Publishers and Advanced Organic Chemistry, J. March, 4th Edition
(1992), Wiley InterScience, and references therein. It will also be recognised that certain
reactive groups may require protection and deprotection during the synthetic process.
Suitable protecting and deprotecting methods for reactive functional groups are known in
the art for example in Protective Groups in Organic Synthesis, T. W. Green & P. Wutz, John
Wiley & Son, 3rd Edition, 1999.
Thus for certain embodiments of the invention, compounds of formula (I), where X and Y
are -O-, X' and Y' are -CH2-, Z is -CH2- or forms a bond between X' and Y' and R1 is alkyl,
alkenyl, alkynyl or an optionally substituted alkylene with terminal functionality, eg
(A)nOMe where n is between 1 and 20, may be prepared by the general method shown in
Scheme 1.

Suitable starting materials may be commercially available or made by methods known in
the art Suitable conditions for this reaction include refluxing the starting material and the
dihydroxy compound in benzene in the presence of acid, eg. tosylate. Other conditions for
performing this reaction to provide selectivity in the presence of other carbonyl groups or
to provide conditions suitable for use in the presence of other functional groups are
provided in Protective Groups in Organic Synthesis, T.W. Green & P. Wutz, John Wiley &

WO 2004/089927 PCT/AU2004/000453
27
Son; 3rd Edition, 1999, pages 312-329. Functionality may be introduced into the dioxolane
group by using a substituted dihydroxy compound.
1,3-dithiane or 1,3-dithiolane derivatives, where X and Y are -5-, X' and Y' are -CH2-, Z is
-CH2- or forms a covalent bond between X' and Y' and R1 is alkyl, alkenyl, alkynyl or an
optionally substituted alkylene with terminal functionality, eg.: (A)nOMe where n is 1 to 20,
may be prepared in a similar mariner as the 1,3-dioxolane derivatives in Scheme 1. Suitable
conditions for this reaction include mixing the starting material and HS-(CH2)b-SH, where b
is 2 or 3, in the presence of BF3-Et2O in dichloromethane at room temperature. Other
conditions for performing this reaction are provided in Protective Groups in Organic
Synthesis, T.W. Green & P. Wutz, John Wiley & Son; 3rd Edition, 1999, pages 333-336.
1,3-oxathiolanes, where one of X and Y is -O- and the other is -S-, X' and Y1 are -CHZ-, Z is
-CH2 or forms a covalent bond between X' and Y' and R1 is alkyl, alkenyl, alkynyl or an
optionally substituted alkylene with terminal functionality, eg.: (A)nOMe where n is 1 to 20,
may be prepared in a similar manner as the 1,3-dioxolane derivatives in Scheme 1. Suitable
conditions include mixing the starting material with HS-(CH2)b-OH where b is 2 or 3, in
dioxane, in the presence of ZnCl2 and AcONa at room temperature. Conditions for
performing this reaction are given in Protective Groups in Organic Synthesis, T.W. Green
& P. Wutz, John Wiley & Son; 3rd Edition, 1999, at page 346.
Compounds where X and Y are -N(R5)-, X' and Y' are -CH2-, Z is -CH2- or forms a covalent
bond between X' and Y' and R1 is alkyl, alkenyl, alkynyl or an optionally substituted
alkylene with terminal functionality, eg.: (A)nOMe where n is 1 to 20, may be prepared as
shown in Scheme 2 (12):


WO 2004/089927 PCT/AU2004/000453
28
Compounds where X is -N(R5)-, X' and Y' are -CH2, Z is -CH2- or forms a covalent bond
between X' and Y', Y together with the carbon atom to which the phenyl group is attached
is a double bond and R1 is absent may be prepared as shown in Scheme 3 (13).

When R1 includes a -CO2H or -C(S)OH group, the compounds may be further derivatised
to provide ketones, thioketones, esters, thioesters, amides and thioamides by standard
alkylating, esterifying or amide forming methodology. When R1 includes a hydroxy, thiol
or amino group, these groups may be further derivatised to provide esters, thioesters,
amides, ethers, thioethers and N-alkyl groups using standard acylating or alkylating
methodology. Conversion of an amide to C=NH(NH2) can be achieved by aminolysis eg
NH3/dry methanol.
In other embodiments, compounds of Formula (I), where R1 R2, R3 or R4 is a substituted
methyl group, can be prepared by conversion of the methyl substituent into a halomethyl
substituent (eg by treatment with a N-halosuccinimide such as NBS) followed by
nucleophilic substitution by an appropriate nudeophile and/ or insertion of additional
methylene groups by, for example, Wittig reaction (see Scheme 4 where R* can be, for
example, (CH2)xOH, (CH2)xSH, (CH2)xNH2, (CH2)xheterocyclyl, (CH2)xaryl, (CH2)xNO2
where x is 0,1 or 2. Similar reactions could be performed if R1 is CH2Br to provide
subetituents such as (CH2)nC(O)C1-20alkyl, (CH2)nOC(O)C1-10alkyl, (CH2)nOC1-20alkyl,
(CH3)nOphenyl (CH?)nObenzyl, (CH2)nNHC1-20alkyl, (CH2)nN(C1-20alkyl)2, (CH2)nNHphenyl,
(CH2)nNHbenzyl, (CH2)nSC1-20alkyl, (CH2)nSC(O)C1-10alkyl, (CH2)nphenyl, (CH2)nSbenzyl,
(CH2)nNHsugar, (CH2)nSsugar, (CH2)nOsugar, (CH2)nNHC(O)C1-10alkyl,
(CH2)nNHC(O)phenyl,(CH2)nNHC(O)benzyI, (CH2)nNHCO2C1-6alkyl,
(CH2)nNHCO2phenyl or (CH2)nNHCO2benzyl, where n is 0 or 1 to 20),

WO 2004/089927 PCT/AU2004/000453
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WO 2004/089927 PCT/AU2004/000453
30
In other embodiments, compounds where R1, R2, R3 or R4 are CH2halo can be prepared
reaction of a suitable carboxylic acid derivative with a reducing agent such as LiAlH4,
followed by halogenatton, eg treatment with thionyl chloride (Scheme 5).

Coupling of compounds wherein R1, R2, R3 or R4 is CH2halo with an alkylhalide or
halo(CH2)nheterocyclyl in the presence of CuLi affords the corresponding compounds
where the R1, R2, R3 or R4 substituant is alkyl or where R1 or R3 are (CH2)nheterocyclyl where
a is 1-20 in relation to R1 or 1 to 3 in relation to R3
Reaction of CH2halo with NH2-NH-C(=NH)-NH2 in the presence of base affords access to
compounds wherein R1 is CH2-NH-NH-C(=NH)-NH2. Alternatively, reaction of the
CH2halo group with halo(CH2)pNH-NH-C(=NH)-NH2 (where p is 1 or 2), affords the group
(CH2)pNH-NH-C(=NH)-NH2 where p is 2 or 3.

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Compounds where R3 is -OH, -NFR or -CH2CN can be prepared from the compound where
R3 is C1 as shown in Scheme 6

Compounds according to formula (1) in which X' and Y' are each -N(R5)- and Z is -CH2-
can be prepared as is shown in Scheme 7. (Reference: Journal of American Chemical
Society, 123(19), 4451-4458, 2001

WO 2004/089927 PCT/AU2004/000453
32

Compounds in which X is O, Y' is -N(R5)- and Z is -CH2- can be prepared as is shown in
SchemeS.

Compounds in which X and X' are each -C(R5)2-, Z is a bond and Y is -N(R5)- can be
prepared according to scheme 9.

WO 2004/089927 PCT/AU2004/000453
33

Compounds in which X is -N(R5)-, Y is -N(R5)- and Z is a bond can be prepared according
to scheme 10.

Compounds in which X and X' are -C(R5)2- Z is -CH2- and Y' is -N(R5)- can be prepared
according to Scheme 11.

WO 2004/089927 PCT/AU2004/000453
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2-Ethyl-2-(4-methoxyphenyl)-l,3-dioxolane, Compound 16, the synthesis of which is
reported below, is prepared by the following the reaction scheme 12 and it would be
understood by a person skilled in the art that a similar methodology can be used to prepare
other appropriately substituted 1,3-dioxolanes.

2-Hexyl-2-(4-methylphenyl)-l,3-dithiolane, Compound 17, the synthesis of which is
reported below, is prepared by following the reaction scheme 13 and it would be
understood by a person skilled in the art that a similar methodology can be used to prepare
other appropriately substituted 1,3- ditholanes.

WO 2004/089927 PCT7AU2004/000453
35

The term "salt, or prodrug" includes any pharmaceutically acceptable salt, ester, solvate,
hydrate, or any other compound which, upon administration to the recipient is capable of
providing (directly or indirectly) a compound of Formula (I) as described herein. The term
"pro-drug" is used in its broadest sense and encompasses those derivatives that are
converted in vivo to the compounds of the invention. Such derivatives would readily
occur to those skilled in the art, and include, for example, compounds where a free
hydroxy group is converted into an ester, such as an acetate, or where a free amino group
is converted into an amide. Procedures for acylating hydroxy or amino groups of the

WO 2004/089927 PCT/AU2004/000453
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compounds of the invention are well known in the art and may include treatment of the
compound with an appropriate carboxylic acid, anhydride or acylchloride in the presence
of a suitable catalyst or base.
Suitable pharmaceutically acceptable salts include, but are not limited to, salts of
pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric,
nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically
acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic,
fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succirdc, oxalic, phenylacetic,
methanesulphoric, toluenesulphonic, benezenesulphonic, salicydic sulphanilic, aspartic,
glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic tannic, ascorbic and valeric
acids.
Base salts include, but are not limited to, those formed with pharmaceutically acceptable
cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and
alkylammonium.
Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl
halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates like dimethyl and diethyl sulfate; and others.
It will also be recognised that some compounds of formula (I) may possess asymmetric
centres and are therefore capable of existing in more than one stereoisomeric form. The
invention thus also relates to compounds in substantially pure isomeric form at one or
more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or
greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers
may be prepared by asymmetric synthesis, for example using chiral intermediates, or by
chtral resolution.
In a further aspect, the present invention provides a method of inhibiting cytokine or
biological activity of MIF comprising contacting MIF with a cytokine or biological activity
inhibiting effective amount of a compound of formula (I), or a pharmaceutieally acceptable
salt or prodrug thereof.
In another aspect, the invention provides a method of treating, preventing or diagnosing a
disease or condition wherein MIF cytokine or biological activity is implicated comprising
the administration of a treatment, prevention or diagnostic effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof to a
subject in need thereof.

WO 2004/089927 PCT/AU2004/000453
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In a further aspect, there is provided the use of a compound o£ formula (I) or a
pharcnaceutically acceptable salt or prodrug thereof in the manufacture of a medicament
for the treatment, prevention or diagnosis of a disease or condition wherein MIF cytokine
or biological activity is implicated.
As used herein, MIF includes human or other animal MIF and derivatives and naturally
occurring variants thereof which at least partially retain MIF cytokine or biological activity.
Thus, the subject to be treated may be human or other animal such as a mammal.
Non-human subjects include, but are not limited to primates, livestock animals (eg sheep,
cows, horses, pigs, goats), domestic animals (eg, dogs, cats), birds and laboratory test
animals (eg mice rats, guinea pigs, rabbits). MIF i$ also expressed in plants (thus "MIF"
may also refer to plant MIF) and where appropriate, compounds of Formula (I) may be
used in botanical/agricultural applications such as crop control.
Reference herein to "cytokine or biological activity" of MIF includes the cytokine or
biological effect on cellular function via autocrine, endocrine, paracrme, cytokine, hormone
or growth factor activity or via intracellular effects.
In a further aspect of the invention there is provided a method of treating, diagnosing, or
preventing autoimmune diseases, tumours or chronic or acute inflammatory diseases
comprising administration of a treatment, diagnosis or prevention effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof. Such
diseases include:
rheumatic diseases (including but not limited to rheumatoid arthritis, osteoarthritis,
psoriatic arthritis) spondyloarthropathies (including but not limited to ankylosing
spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (including
but not limited to gout, pseudogout, calcium pyrophosphate deposition disease),
Lyme disease, polymyalgia rheuriiatica;
connective tissue diseases (including but not limited to systemic lupus
erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjögren's
syndrome);
vasculitides (including but not limited to polyarteritis nodosa, Wegener's
granulomatosis, Churg-Strauss syndrome);
inflammatory conditions including consequences of trauma or ischaemia,
sarcoidosis;

WO 2004/089927 PCT/AU2004/0004S3
38
vascular diseases including atherosclerotic vascular disease, atherosclerosis, and
vascular occlusive disease (including but not limited to atherosclerosis, ischaemic
heart disease, myoeardial infarction, stroke, peripheral vascular disease), and
vascular stent restenosis;
ocular diseases including uveitis, corneal disease, iritis, iridocyclitis, cataracts;
autoimmune diseases (including but not limited to diabetes mellirus, thyroiditis,
myasthenia gravis, sclerosing cholangitis, primary biliary cirrhosis);
pulmonary diseases (including but not limited to diffuse interstitial lung diseases,
pneumoconioses, fibrosing alveolitis, asthma, bronchitis, bronchiectasis, chronic
obstructive pulmonary disease, adult respiratory distress syndrome);
cancers whether primary or metastatic (including but not limited to prostate cancer,
colon cancer, lymphoma, lung cancer, melanoma,,multiple myeloma, breast cancer,
stomach cancer, leukaemia, cervical cancer and metastatic cancer);
renal diseases including glomerulonephritis, interstitial nephritis;
disorders of the hypothalamic-pituitary-adrenal axis;
nervous system disorders- including multiple sclerosis, Alzheimer's disease;
diseases characterised by modified angiogenesis (eg diabetic retinopathy,
rheumatoid arthritis, cancer), endornerrial function (menstruation, implantation,
endometriosis);
complications of infective disorders including endotoxic (septic) shock, exotoxic
(septic) shock, infective (true septic) shock, malarial complications, other
complications of infection, pelvic inflammatory disease;
transplant rejection, graft-versus-host disease;
allergic diseases including allergies, atopic diseases, allergic rhinitis;
bone diseases (eg osteoporosis, Faget's disease);
skin diseases including psoriasis, atopic dermatitis, UV(B)-induced dermal cell
activation (eg sunburn, skin cancer);
complications of diabetes mellitus, pain, testicular dysfunctions and wound

WO 2004/089927 PCT/AU2004/000453
39
healing,
gastrointestinal diseases including inflammatory bowel disease (including but not
limited to ulcerative colitis, Crohn's disease), peptic ulceration, gastritis,
oesophagitis, liver disease (including but not limited to cirrhosis, hepatitis).
Particularly preferred diseases or conditions include: rheumatoid athritis, systemic lupus
erythematosus, ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis, uveitis,
atherosclerotic vascular disease, asthma and chronic obstructive pulmonary disease.
A further aspect of the invention provides for the use of a compound of Formula (I) or a
pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament
for the treatment of a disease or condition: as above.
As used herein, the term "effective amount" relates to an amount of compound which,
when administered according to a desired dosing regimen, provides the desired MIF
cytokine inhibiting or treatment or therapeutic activity, or disease/condition prevention.
Dosing may occur at intervals of minutes, hours, days, weeks, months or years or
continuously over any one of these periods. A cytokine or biological activity inhibiting
amount is an amount which will at least partially inhibit the cytokine or biological activity
of MIF. A therapeutic, or treatment, effective amount is an amount of the compound
which, when administered according to a desired dosing regimen, is sufficient to at least
partially attain the desired therapeutic effect, or delay the onset of, or inhibit the
progression of or halt or partially or fully reverse the onset or progression of a particular
disease condition being treated. A prevention effective amount is an amount of compound
which when administered according to the desired dosing regimen is sufficient to at least
partially prevent or delay the onset of a particular disease or condition. A diagnostic
effective amount of compound is an amount sufficient to bind to MIF to enable detection of
the MIF-compound complex such that diagnosis of a disease or condition is possible.
Suitable dosages may Be within the range of about 0.1 rig per kg of body weight to 1 g per
kg of body weight per dosage. Thedosage is preferably in the range of 1 g to 1 g per kg of
body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per
dosage. In one embodiment the dosage is in the range of 1 mg to 500 mg per kg of body
weight per dosage. In another embodiment the dosage is in the range of I mg to 250 mg
per kg of body weight per dosage, in yet another preferred embodiment the dosage is in
the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg

WO 2004/089927 PCT/AU2004/000453
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of body weight per dosage. In yet another embodiment, the dosage is in the range of lg
to l mg per kg of body weight per dosage.
Suitable dosage amounts and dosing regimens can be determined by the attending
physician or veterinarian and may depend on the desired level of inhibiting activity, the
particular condition being treated, the severity of the condition as well as the general age,
health and weight of the subject.
The active ingredient may be administered in a single dose or a series of doses. While it is
possible for the active ingredient to be administered alone, it is preferable to present it as a
composition, preferably as a pharmaceutical composition.
In a further aspect of the invention, there is provided a pharmaceutical composition
comprising a compound of formula (I) together with a pharmaceutically acceptable carrier,
diluent or extipient
The formulation of such compositions is well known to those skilled in the art. The
composition may contain pharmaceutically acceptable additives such as carriers, diluents
or excipients. These include, where appropriate, all conventional solvents, dispersion
agents, fillers, solid carriers, coating agents, antifungal and antibacterial agents, dermal
penetration agents, surfactants, iaotonic and absorption agents and the like. It will be
understood that the compositions of the invention may also include other supplementary
physiologically active agents.
The carrier must be pharmaceutically acceptable in the sense of being compatible with the
other ingredients of the composition and not injurious to the subject. Compositions
include those suitable for oral, rectal, inhalational, nasal, transdermal, topical (including
buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular,
intraspinal, intravenous and intradermal) administration, The compositions may
conveniently be presented in unit dosage form and may be prepared by any methods well
known in the art of pharmacy. Such methods include the step of bringing into association
the active ingredient with the carrier which constitutes one or more accessory ingredients.
In general, the compositions are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely divided solid carriers or both,
and then if necessary shaping the product.
Depending on the disease or condition to be treated, it may or may not be desirable for a
compound of Formula (I) to cross the blood/brain barrier. Thus the compositions for use
in the present invention may be formulated to be water or lipid soluble.

WO 2004/089927 PCT/AU2004/000453
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Compositions of the present invention suitable for oral administration may be presented as
discrete units such as capsules, sachets or tablets each containing a predetermined amount
of the active ingredient; as a powder orgranules; as a solution or a suspension in an
aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil
liquid emulsion, the active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing in a suitable machine
the active ingredient in. a free-flowing form such as a powder or granules, optionally mixed
with a binder (eg inert diluent, preservative, disintegrant (eg; sodium starch glycolate,
cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose))
surface-active or dispersing agent. Moulded tablets may be made by moulding in a
suitable machine a mixture of the powdered compound moistened with an inert liquid
diluent. The tablets may optionally be coated or scored and may be formulated so as to
provide slow or controlled release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the desired release
profile. Tablets may optionally be provided with an enteric coating, to provide release in
parts of the gut other than the stomach.
Compositions suitable for topical administration in the mouth include lozenges comprising
the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum;
pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or
sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable
liquid carrier.
The compounds of Formula (I) may also be administered intranasally or via inhalation, for
example by atomiser, aerosol or nebulizer means-
Compositions suitable for topical administration to the skin may comprise the compounds
dissolved or suspended in any suitable carrier or base and may be in the form of lotions,
gel, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene
glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate,
polysorbate 60,cetyl.esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water. Transdermal devices, such as patches, may also be used to administer the
compounds of the invention.
Compositions for rectal administration may be presented as a suppository with a suitable
carrier base comprising, for example, cocoa butter, gelatin, glycerin or polyethylene glycol.

WO 2004/089927 PCT/AU2004/000453
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Compositions suitable for vaginal administration may be presented as pessaries, tampons,
creams, gels, pastes, foams or spray formulations containing in addition to the active
ingredient such carriers as are known in the art to be appropriate.
Compositions suitable for parenteral administration include aqueous and non-aqueous
isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriddes
and solutes which render the composition isotonic with the blood of the intended recipient;
and aqueous and.non-aqueous sterile suspensions which may include suspending agents
and thickening agents. The compositions may be presented in unit-dose or multi-dose
sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried
(lyophilised) condition requiring only trie addition of the sterile liquid carrier, for example
water for injections/ immediately prior to use. Extemporaneous injection solutions and :
suspensions may be prepared from sterile powders, granules and tablets of the kind
previously described.
Preferred unit dosage compositions are those containing a daily dose or unit, daily
sub-dose, as herein above described, or an appropriate fraction thereof, of the active
ingredient
It should be understood that in addition to the active ingredients particularly mentioned
above, the compositions of this invention may.include other agents conventional in the art
having regard to the type of composition in question, for example, those suitable for oral
administration may include such further agents as binders, sweeteners, thickeners,
flavouring agents, disintegrating agents, coating agents, preservatives, lubricants and/or
time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or
saccharine, Suitable disintegrating agents include corn starch, methylcellulose,
polyvinylpyrrolidone, xanthan gum, bentonite, alginic add or agar. Suitable flavouring
agents indude peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
Suitable coating agents indude polymers or copolymers of acrylic add and/or methacrylic
add and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable
preservatives indude sodium benzoate, vitamin E, alpna-tocopherol, ascorbic add, methyl
paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium
stearate, siearic acid, sodium oleate, sodium chloride or talc; Suitable time delay agents
indude glyceryl monostearate or glyceryl distearate.
It will be recognised that other therapeutically active agents such as anti-inflammatory (eg
steroids such as glucocorticoids) or anti-cancer agents may be used in conjunction with a
compound of Formula (I). Compounds of Formula (I) when administered in conjunction

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with other therapeuideally active agents may exhibit an additive or synergistic effect. These
may be administered simultaneously, either as a combined form (ie as a single composition
containing the active agents) or as discrete dosages. Alternatively, the other
therapeutically active agents may be administered sequentially or separately with the
compounds of the invention. Thus, the invention also relates to kits and combinations,
comprising a compound of Formula (I) and one or more other therapeutically active
ingredients for use in the treatment of diseases or conditions described herein. Without
being limiting, examples of agents which could be used in combination with a compound
of Formula (I) include: antirheumatic drugs (including but not limited to methotrexate,
leflunomide, sulphasalazine, hydroxycholorquine, gold salts); immunosuppressive drugs
(including but not limited to cydosporin, mycophenyllate mofetil, azathioprine,
cyclophosphamide); anti-cytokine therapies (including but not limited to antagonists of,
antibodies to, binding proteins for, or soluble receptors for tumor necrosis factor,
interleukin 1, interleukin 3, interleukin 5, interleukin 6, interleukin 8, interleukin 12,
interleukin 18, interleukin 17, and other pro-inflammatory cytokines as may be found
relevant to pathological states); antagonists or inhibitors of mitogen-activated protein
(MAP) kinases (including but not limited to antagonists or inhibitors of extracellular
signal-regulated kinases (ERK), the c-Jun N-terminal kinases/stress-activated protein
kinases (JNK/SAPK), and the p38 MAP kinases, and other kinases or enzymes or proteins
involved in MAP kittaserdependent cell activation):; antagonists or inhibitors of the nuclear
factor kappa-B (NF-B) signal transduction pathway (including but not limited to
antagonists or inhibitors of I-B-kinase, interleukin receptor activated kinase, and other
kinases or enzymes or proteins involved in NF-B-dependent cell activation); antibodies,
protein therapeutics, or small molecule therapeutics interacting with adhesion molecules
and co-stimulatory molecules (including but not limited to therapeutic agents directed
against intercellular adhesion molecule-1, CD40, CD40-ligand, CD28, CD4, CD-3, selectins
such as P-selectin or E-selectin); bronchodilators such as e-adrenoceptor agonists or
anu-cholinergics; antagonists of eicosanoid synthesis pathways such as non-steroidal
anti-inflammatory drugs, cyclooxygenase-2 inhibitors, thromboxane inhibitors, or
lipoxygenase inhibitors; antibodies or other agents directed against leukocyte surface
antigens (including but not limited to antibodies or other agents directed against CD3,
CD4, CD5, CD19, CD20,HLA moleeules); agente used for the freatmenfof inflammatory
bowel disease (including but not limited to sulphasalazine, mesalazine, salicylic acid
derivatives); anti-cancer drugs {including but not limited to cytotoxic drugs, cytolytic
drugs, monoclonal antibodies).

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In another aspect, the invention provides a method of treating or preventing a disease or
condition wherein MIF cytokine or biological activity is implicated comprising:
administering to a mammal a compound o£ formula (I) and a second therapeutic
agent.
In a preferred embodiment of this aspect of the invention/ the second therapeutic agent is a
glucocorticoid compound.
In another aspect, the present invention provides a method of prophylaxis or treatment of a
disease or condition for which treatment with a glucocorticoid is indicated, said method
comprising: administering to a mammal a glucocorticoid and a compound of formula (I).
In yet another aspect the present invention provides a method of treating steroid-resistant
diseases comprising administering to a mammal a glucocorticoid and a compound of
formula (I).
In a further aspect the present invention provides a method of enhancing the effect of a
glucocorticoid in mammals comprising administering a compound of formula (I)
simultaneously, separately or sequentially with said glucocorticoid.
In yet a further aspect the present invention provides a composition comprising a
glucocorticoid and a compound of formula (I).
In a further aspect of the invention there is provided a use of a glucocorticoid in the
manufacture of a medicament for administration with a compound of formula (I) for the
treatment or prophylaxis of a disease or condition for which treatment with a
glucocorticoid is indicated.
In yet a further aspect of the invention there is provided a use of a compound of formula (I)
in the manufacture of a medicament for administration with a glucocorticoid for the
treatment or prophylaxis of a disease or condition for which treatment of a glucocorticoid
is indicated.
In yet a further aspect of the invention mere is provided a use of a glucocorticoid and a
compound of formula (I) in the manufacture of a medicament for the treatment or
prophylaxis of a disease or condition for which treatment with a glucocorticoid is
indicated.

WO 2004/089927 PCT/AU2004/000453
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Preferably the amount of glucocorticoid used in the methods, uses and compositions of the
invention is less than the amount which would be effective in the absence of the compound
of formula (I). In the treatment of steroid-resistant diseases or conditions which are not
responsive to glucocorttcoids, any amount of glucocorticoid which is effective in
combination with a compound of formula (I) is considered less than the amount which
would be effective in the absence of a compound formula (I). Accordingly, the invention
provides a steroid-sparing therapy.
In preferred embodiments of the invention, the glucocorticoid and the compound of
formula (I) are used to treat or prevent a disease or condition in a mammal, preferably in a
human subject.
The term "disease or condition for which treatment with a glucocorticoid is indicated"
refers to diseases or conditions which are capable of being treated by administration of a
glucocorticoid including but not limited to autoimmune diseases, tumours, or chronic or
acute inflammatory diseases. Examples of such diseases or conditions include:
rheumatic diseases (including but not limited to rheumatoid arthritis, osteoarthritis,
psoriatic arthritis) spondyloarthropathies (including but not limited to ankylosing
spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (including
but not limited to gout, pseudogout, calcium pyrophosphate deposition disease),
Lyme disease, polymyalgia rheumatica;
connective tissue diseases (including but not limited to systemic lupus
erythematosus, systemic sclerosis, polyrhyositis, dermatomyositis, Sjögren's
syndrome);
vasculitides (including but not limited to polyarteritis nodosa, Wegener's
granulomatosis, Churg-Strauss syndrome);
inflammatory conditions including consequences of trauma or ischaemia,
sarcoidosis;
vascular diseases, including atherosclerotic vascular disease, atherosclerosis, and
vascular occlusive disease (including but not limited to atherosclerosis, ischaemic
heart disease, myocardial infarction, stroke/ peripheral vascular disease), and
vascular stent restenosis;
ocular diseases including uveitis, cornea! disease, iritis, iridocyclitis, cataracts;

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autoimmune diseases (including but not limited to diabetes mellitus, thyroiditis,
myasthenia gravis, sclerosing cholangitis, primary biliary cirrhosis);
pulmonary diseases (including but not limited to diffuse interstitial lung diseases,
pneumoconioses, fibroaing alveolitis, asthma, bronchitis/ bronchiectasis, chronic
obstructive pulmonary disease, adult respiratory distress syndrome);
cancers whether primary or metastau'c (including but not limited to prostate cancer,
colon cancer, lymphoma, lung cancer, melanoma, multiple myeloma, breast cancer,
stomach cancer, leukaemia, cervical cancer and metastatic cancer);
renal diseases including glomeralonephritis, interstitial nephritis;
disorders of the hypothalamic-pituitary-adrenal axis;
nervous system disorders including multiple sclerosis, Alzheimer's disease;
diseases characterised by modified angiogenesis (eg diabetic retinopathy,
rheumatoid arthritis, cancer), endometrial function (menstruatioiv implantation,
endometrtosis);
complications of infective disorders including endotoxic (septic) shock, exotoxic
(septic) shock, infective (true septic) shock, malarial complications, other
complications of infection, pelvic inflammatory disease;
transplant rejection, graft-versus-host disease;
allergic diseases including allergies, atopic diseases, allergic rhinitis;
bone diseases (eg osteoporosis, Faget's disease);
skin diseases including psoriasis, atopic dermatitis, UV(B)-induced dermal cell
activation (eg sunburn, skin cancer);
complications of diabetes mellitus, pain, testicular dysfunctions and wound
healing,
gastrointestinal diseases including inflammatory bowel disease (including but not
limited to ulcerative colitis, Crohn's disease), peptic ulceration, gastritis,
oesophagitis, liver disease (including but not limited to cirrhosis, hepatitis).

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These diseases or conditions may also include steroid-resistant diseases or conditions
where treatment with a glucocorticoid is indicated, but where the glucocorticoid is
ineffective or is not as effective as expected.
The methods of the invention are preferably performed in a steroid-sparing mariner. The
term "steroid-sparing" refers to a combination therapy method that allows a reduction in
the amount of glucocorticoid administered while still providing an effective therapy for the
disease or condition being treated or prevented.
Steroid-resistant diseases or conditions are diseases or conditions for which treatment with
a glucocorticoid is indicated, but where the glucocorticoid is ineffective or is not as
effective as expected. This term encompasses diseases or conditions for which the effective
dose of glucocorticoid results in unacceptable side effects and/or toxidty. Some
steroid-resistant diseases or conditions may require a dosage of glucocorticoid so large that
they are considered non-responsive and therefore are not able to be successfully treated
with glucocorticoids. Some steroid-resistant diseases or conditions may require a large
dosage of glucocorticoid to achieve only a small effect on the symptoms of the disease or
condition. Furthermore, some patients, diseases or conditions present with symptoms that
do not respond to treatment with a glucocorticoid, or may become less sensitive to
glucocorticoid treatment over time.
Glucocorticoids are a group of steroid hormones, which are used to treat or prevent a wide
range of diseases or conditions. Suitable glucocorticoids may be synthetic or naturally
occurring and include but are not limited to prednisolone, prednisone, cortisone acetate,
beclamethasone, flutiasone, hydrocortisone, dexamethasone, methyl prednisolone,
triamcinolone, budesonide and betamethasone.
In preferred embodiments of the invention, the glucocorticoid used is selected from
predrtisone, prednisolone, hydrocortisone, fluticasone, beclamethasone, betamethasone,
methyl prednisolone, budesorride, triamcinolone, dexamethasone and cortisone. Most
preferably, the glucocorticoid is selected from prednisone, prednisolone, methyl
prednisolone, fluticasone and beclamethasone. Bedamethasane and fluticasone are
particularly preferred for treating asthma, Prednisone, prednisolone and methyl
prednisolone are particularly preferred in the treatment of systemic or local inflammatory
diseases.
The amounts of glucocorticoid and compound of formula (I) are selected such that in
combination they provide complete or partial treatment or prophylaxis of a disease or


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condition for which a glucocorticoid is indicated. The amount of compound formula (I) is
preferably an amount that will at least partially inhibit the cytokine or biological activity of
MIF. The amount of glucocorticoid is preferably less than the amount required in the
absence of the compound of formula (I). The amounts of glucocorticoid and compound of
formula (I) used in a treatment or therapy are selected such that in combination they at
least partially attain the desired therapeutic effect or delay onset of, or inhibit the
progression of, or halt or partially or fully reverse the onset or progression of the disease or
condition being treated. The amounts of glucocorticoid and compound of formula (I) used
in the prophylaxis of a disease or condition are selected such that in combination they at
least partially prevent or delay the onset of the disease or condition. Dosing may occur at
intervals of minutes, hours, days, weeks, months or years or continuously over any one of g,
these periods.
Suitable doses of a compound of formula (I) may lie within the range of about 0.1 ng per kg
of body weight to 1 g per kg of body weight per dosage. The dosage is preferably in the
range of 1 jxg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g
per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg
to 500 mg per kg of body weight per dosage. In another embodiment, the dosage is in the
range of 1 mg to 250 mg per kg of body weight per dosage. In yet another preferred
embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per
dosage, such as up to 50 mg per kg of body weight per dosage. In yet another
embodiment, the dosage is in the range of l g to l mg per kg of body weight per dosage.
Suitable dosage amounts of glucocorticoids will depend, in part, on the mode of
administration and whether the dosage is being administered in a single, daily or divided
dose, or as a continuous infusion. When administered orally, intravenously,
intramuscularly, intralesionally or intracavity (eg. intra-articular, intrathecal, intrathoracic),
dosages are typically between 1 mg to 1000 mg, preferably 1 mg to 100 mg, more
preferably 1 mg to 50 mg or 1 mg to 10 mg per dose. When administered topically or by
inhalation as a single, daily or divided dose, dosages are typically 1 ng to 1 g 1 ng to 1 mg
or 1 pg to 1 g.
Suitable dosage amounts and! dosing regimens can be determined by the attending
physician or veterinarian and may depend on the desired level of inhibiting activity, the
particular condition being treated, the severity of the condition as well as the general age,
health and weight of the subject.

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The glucocorticoid and compound of formula (I) may be administered simultaneously or
sequentially. The active ingredients may be administered alone but are preferably
administered as a pharmaceutically acceptable composition or separate pharmaceutically
acceptable compositions.
The formulation of such compositions is well known to those skilled in the art and are
described above in relation to compounds of formula (I). The composition or compositions
may containpharmaceutically acceptable additives such as carriers/ diluents or excipients.
These include, where appropriate, all conventional solvents, dispersion agents, fillers, solid
carriers, coating agents, antifungal and antibacterial agents, dermal penetration agents,
surfactants, isotonic and absorption agents and the like. It wilt be understood that the
compositions of the invention may also include other supplementary physiologically active
agents.
Preferred unit dosage compositions are those containing a daily dose or unit, daily
sub-dose, as herein above described, or an appropriate fraction thereof, of the
glucocortioids and/or compound of formula (I) which inihibit the cytokine or biological
activity of MIF
The compounds of formula (I), either as the only active agent or together with another
active agent, eg: a glucocorqrticod, may also be presented for use in veterinary compositions.
These may be prepared by any suitable means known in the art. Examples of such
compositions include those adapted for:
oral administration external application (eg drenches including aqueous and
non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pellets
for admixture with feedstuffs, pastes for application to the tongue;
parenteral administration, eg subcutaneous, intramuscular or intravenous injection
as a sterile solution or suspension; and

topical application eg creams, ointments, gels, lotions, etc.
By virtue of their ability to bind to or antagonize MIF, compounds of Formula (I) or salts or
derivatives thereof may be used as laboratory or diagnostic or in vivo imaging reagents.
Typically, for such use the compounds would be labelled in some way, for example, radio
isotope, fluorescence or colorimetric labelling, or be chelator conjugated. In particular,
compounds of Formula (I) could be used as part of an assay system for MIF or as controls
in screens for identifying other inhibitors. Those skilled in the art are familiar with such

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screens and could readily establish such screens using compounds of Formula (I). Those
skilled in the art will also be familiar with the use of chelate conjugated molecules for in
vivo diagnostic imaging.
Inhibitors of MIF may also be used in implantable devices such as stents. Accordingly, in a
further aspect the present invention provides an implantable device, preferably a stent,
comprising:
(i) a reservoir containing at least one compound of formula (I); and
(ii) means to release or elute the inhibitor from the reservoir
There is further provided a method for inhibiting the cytokine or biological activity of MIF
in a subject comprising the step of implanting an implantable device according to the
invention in the subject.
Preferably, the method is for inhibiting the cytokine or biological activity Of MIF in a local
region of the subject and the device is implanted within or proximate to the local region of
the subject.
In a,yet further aspect, the present invention provides a method of treating, preventing or
diagnosing a disease or condition wherein MIF cytokine activity is implicated comprising
the step of implanting an implantable device according to the invention in a subject in need
thereof.
Preferably, the disease or condition is confined to a local region of the subject and the
device is implanted within or proximate to the local region.
The present invention further provides an angioplastic stent for inhibiting the onset of
restenosis, which comprises an angioplastic stent operably coated with a prophylactically
effective dose of a composition comprising at least one compound of formula (I).
Angioplastic stents/ also: known by other terms such as "intravascular stents" or simply
"stents", are well known in the art. They are routinely used to prevent vascular closure due
tophysical anomalies such as unwanted inward growth of vascular tissue due to surgical
trauma. They often Have a tubular, expanding lattice-type structure appropriate for their
function, and can optionally be biodegradable.
In this invention, the stent can be operably coated with at least one compound of formula
(I) using any suitable means known in the art. Here, "operably coating" a stent means

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coating it in a way that permits the timely release of the compound(s) of formula (I)into the
surrounding tissue to be treated once the coated stent is administered. Such coating
methods, for example, can use the polymer polypyrrole.
The present invention further provides a method for inhibiting the onset of restenosis in a
subject undergoing angioplasty, which comprises topically administering a stent according
to the present invention to the subject at around the time of the angioplasty.
As used herein, administration "at around the time of angioplasty" can be performed
during the procedure, or immediately before or after the procedure. The administering can
be performed according to known methods such as cameter delivery.
There is further provided a method of reducing the severity of stent restenosis in the
vicinity of a stent comprising the use of a stent according to the present invention.
The construction of stents that release or elute a pharmaceutical active is known to those
skilled in the art. The standard approach is to use current highly refined metallic stent
designs with polymer materials that release the active in a controlled manner. Several
polymer materials have been used for the coating of stents to permit the elution of drugs.
These include bioerodible polymers such as poly-L lactic acid, biostable polymers such as
polyurethane derivatives and slilicone-based polymers, as well as hydrogels. It will be
recognised by those skilled in the art that the function of a drug-eluting stent requires the
drug to be bound to the stent or its polymer or other coating in such a way as to allow
steady release of drug over a period of time, and that the drug is able to be locally absorbed
into cells in the vessel and stent lumen. The optimum stent coating material and delivery
parameters vary according to the tissue retention of the drug, such that rapid release of a
tissue-retained drug can have long lasting effects, whereas a drug retained in tissues for a
shorter time would need to be released over a longer period. A person skilled in the art
would be able to select appropriate materials and conformations of stent for a particular
purpose and particular small molecule inhibitor.
Unless the context indicates otherwise, reference to any prior art in this specification is not,
and should not be taken as, an acknowledgment or any form of suggestion that that prior
art forms part of the common general knowledge in Australia.
Those skilled in the art will appreciate that the invention, described herein is susceptible to
variations and modifications other than those specifically described. It is to be understood
that the invention includes all such variations and modifications which fall within the spirit
and scope. The invention also includes all of the steps, features, compositions and

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compounds referred to or indicated in this specification, individually or collectively, and
any and all combinations of any two or more of said steps or features.
The invention will now be described with reference to the following examples which are
included for the purpose of illustration only and are not intended to limit the generality of
the invention hereinbefore described.
EXAMPLES
Example 1: Preparation of
2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l/3-dioxolarie (Compound 1)

A mixture of 3-methyl-p-hydroxybenzaldehyde (05 g, 3.6 mmol), ethylene glycol (0.34 g,
5.5 mmol) and p-toluenesulfonic acid (0.07 g, 0.36 mmol) in toluene was heated under
'
reflux. After 24 h, the reaction mixture was cooled to room temperature, TLC showed no
starting material. The toluene was removed in vacuo and saturated solution of sodium
hydrogen carbonate (20 ml) was added to the residue, which was then extracted with ethyl
acetate (3 x 20 ml). The organic layer was washed with water (20 ml), dried over anhydrous
sodium sulf ate and the solvent was removed in vacuo. The residue was then reerystallised
from an ethyl acetate and hexane mixture to give the product as a brown solid in 24%
yield.
H NMK (CDC13): 2.21 (s, 3H), 3.62 (t, 2H, J = 4.5 Hz), 3.70 (t, 2H, J = 4.2 Hz), 3.81 (t, 2H, J =
4.7 Hz), 4.42 (t, 2H, J = 4.7 Hz), 6.74 (d, 1H J = 8.4 Hz), 7.21 (d, 1H, J = 8.4 Hz) and 7.78 (s,
1H). MS: m/e 263 (M+ + Na), 179 (M+ - OCH2CH2OH), 147,135,118 and 107.
12C NMR (CDC13): 15.7,61.1,635,69.1,72.4,114,0,120.5,124.5,128.4,135.6,159.8 and 167.1.

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Example 2: Preparation of 2-(2-hydroxyethoxy)-2-(4-hydioxyphenyI)-l/3-dioxoIane
(Compound 2)

To a solution of p-hydroxybenzaldehyde (1g, 8.18 mmol) in anhydrous toluene (100 mL)
was added ethylene glycol (0.68 mL, 12.28 mmol), pyridinium toluene sulphonate (0.2 g,
0.88 mmol) and p-toluene sulphonic add monohydrate (0.16 g, 0.88 mmol). The solution
was refluxed overnight before concentrating the solvent to furnish an amber gum.
Saturated sodium bicarbonate (50 mL) was then added to the reaction mixture, and
extracted with ethyl acetate (3x 50 mL). The organic extracts were dried over magnesium
sulphate, filtered, and concentrated to furnish a dark brown gum. The gum was
chromatographed on silica (ether/methanol, 9.5:05) ta furnish the title compound as a
dark brown solid (173 mg, 9%).
H NMK (CDCI3): 7.88 (d, 2H, 2x ArCH, J 8.7 Hz), 7.49 (bs, 1H, phenolic hydroxyl), 6.82 (d,
2H, 2x ArCH, J 8.7 Hz), 4.46,3.84 (2x appt, 2x 2H, 2x ethoxy CH2, Jvic 4.5 Hz), 3.74 (m, 2H,
dioxolan CH2), 3.66 (appt 2H, dioxolan CH2, Jvic 4.8 Hz);
LRMS (ESI): m/z 227 [M+H+]; C11H14O5:226.23

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Example 3: Preparation of
2-(2-hydioxyethoxy)-2-(3-bromo-4-hydroxy-5-meihylphenyI)-l,3-dioxolane (compound3)

A mixture of compound 1 (109 mg; 0.4 mmol), N-bromosuccinarnide (80 mg; 0.4 irtmol)
and AIBN (7.3 mg; 0.045 mmol) in dry carbon tetrachloride was refluxed for 5 hrs, TLC did
not show any of the starting material. The reaction mixture was cooled to room
temperature and then concentrated to dryness. The residue was dissolved in ethyl acetate
(2 x 10 ml). The clear solution was washed with distilled water (5 x 10 ml), dried over
anhydrous Na2SO4 and evaporated to dryness. This gave a 47% yield of compound 3.
H NMR (CDCl3): 2.32 (s, 3H), 3.65 (t,2H, J - 4.4 Hz), 3.74 (t, 2H, J - 4.3 Hz), 3.83 (t, 2H, J=
4.7 Hz), 4.46 (t, 2H, J = 4.S Hz), 7.80 (s, 1H) and 8.02 (s, 1H).

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Example 4; Preparation of 2-(4-Bromophenyl)-l,3-thiazolane (compound 4)

Melting Point Ref: UK patent GB2010827A.
To a solution of 4-bromobenzaldehyde (2.5 g, 13.5 mmol) in EtOH (15 ml) was added a
solution of cysteamine HC1 (0.5 g,.44.mmQl) in water (5 ml) drppwise with stirring. The
solution was then stirred at RT for 18 h before the bulk of the EtOH was removed by rotary
evaporator. The residue was diluted with water (15 ml) and extracted with ether (3x20 ml)
to remove excess aldehyde. The acidic aqueous layer was then basified with the slow
addition of solid sodium carbonate (0.3 g) to give a heavy white precipitate, which was
filtered and washed carefully with water (3x10 ml). The solid was dried in a vacuum
desiccator to give 2-(4-bromophenyI)-l,3~thiazolane (4) as a white crystalline solid (0.73 g,
68%), mp 107° (Hi mp, 105-107°). 1H nmr (d6-dmso, 300 MHz) 2.4, br s, NH; 3.05-3.2, m,
H4,4,5; 3.5-3.6, m, H5; 5.55, s, H2; 7.38, d (6.4 Hz), ArH; 7.47, d (8.4), ArH ESI (+ve) MS
m/z 287/285 (M+MeCN+H, 30%), 246/244 (M+H, 100).

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Example 5: Preparation of 2-(4-Methoxyphenyl)-l,3-lhiazolane (compound 5)

Melting Point Kef: US patent 4616025
To a solution of p-methoxybenzaldehyde (1,81 g, 13.3 mrnol) in ethanol (15 ml) was added
dropwise a solution of cysteamine HO (0.5 g, 4.4 mmol) in water (5 ml) and the solution
stirred at RT for 18 h. The bulk of the ethanol was removed by rotary evaporator and the
residue was diluted with water (15 ml) and extracted with diethyl ether (3x20 ml) to
remove excess aldehyde. The aqueous layer was bagified by addition of solid sodium
carbonate (0.3 g) causing the product to precipitate out of solution. The precipitate was
filtered, washed carefully with water (3x20 ml) and dried in a vacuum desiccator to give
2-(4-methoxyphenyI)-l,3-thiazo!ane (5) as a white solid (0.55 g, 69%), mp 94-95° (lit mp,
93-94°). 1H nmr (CDCl3 300 MHz) 251, s, NH; 3.05-3.20, m, H4,4,5; 3.64, m, H5; 3.80, s,
OMe; 5.23, s, H2; 6.87, d (87 Hz), H3',5'; 7.44, d (8.7), H2'H61. ESI (+ve) MS m/z 196 (M+H,
100%).

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Example 6: Preparation of 4-(l,3-ThiazoIidin-2-yl)benzonitriIe (compound 6)

To a solution of 4-cyanobenzaldehyde (0.86 g, 6.6 mmol) in ethanol (15 mi) was added a
solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT
for 18 h. The bulk of the ethanol was removed by rotary evaporator and the residue was
treated with water (15 ml) and extracted with diethyl ether (3x20 ml) to remove excess
aldehyde. The aqueous layer was basified with solid sodium carbonate (0.3 g) resulting in
the formation of an oil. The mixture was extracted with ether (2x25 ml), washed with brine
(1x50 ml), dried (MgSO4) and evaporated to give a clear oil that solidified on standing (0.62
g). Column chromatography (silica gel, 100% chloroform) afforded pure
4-(1,3-thiazolidin-2-yl)benzonitrile (6) (0.56 g, 67%) as clear oil that solidified on standing,
mp 57-58°. 1H nmr (CDCI3,300 MHz) 3.05-3.15, m, H4,4; 3.2-3.35, m, H5; 3.4-3.5, m,H5;
5.64, s, H2; 7.63, app. s, H2',3',5l,6'. ESI (+ve) MS m/z 191 (M+H, 100%).

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Example 7; Preparation of 2-(4-Hydroxy-3-meflioxyphenyl)-1,3-thiazolane (compound


Melting Point Kef: Chem. Pharm. Bull. 1988,36,1110-1116.
To a solution of vanillin (2.0 g, 13.2 mmol) in ethanol (15 ml) was added dropwise a
solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (S ml) and the solution stirred at RT
for 16.5 h. The bulk of the ethanol was removed by rotary evaporator and the residue was
diluted with water (15 ml) and extracted with diethyl ether (3x20 ml) to remove excess
aldehyde. The aqueous layer was basified by addition of solid sodium carbonate (0.3 g)
causing the product to precipitate out of solution. The precipitate was filtered, washed
carefully with water (3x20 ml) and dried in a vacuum desiccator to give
2-(44iydroxy-3-methoxyphenyl)-1,3-thiazolane (7) as a white solid (0.62 g, 67%), mp
158-161° (lit mp, 182-183°). JH nmr (d6-dmso, 300 MHz) 2.8-3.0, m, H4,4,5; 3.12, br s, NH;
3.4-3.6, m, H5; 3.76, s, OMe; 5.34, s, H2; 6.70, d (8.0 Hz), H5; 6.84, dd (1.8, 8.1 Hz), H6; 7.04,
d (1.8 Hz), H21; 8.91, s, OH. ESI (+ve) MS m/z 212 (M+H, 100%).

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Example 8: Preparation of 2-(3,4-DimethoxyphenyI)-l,3-thiazolane (compound 8)

To a solution of 3,4-dimethoxybenzaldehyde (2.19 g, 13.2 mmol) in ethanal (15 ml) was
added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the
solution stirred at RT for 40 h. The bulk of the ethanol was removed by rotary evaporator
and the residue was diluted with water (15 ml) and extracted with diethyl ether (3x20 ml)
to remove excess aldehyde; The aqueous layer was basified with solid sodium carbonate
(0.3 g) resulting in the formation of an oil. The mixture was extracted with ether (2x25 ml),
washed with brine (1x50 ml), dried .(MgSO4) and evaporated to give a clear oil that
solidified on standing (0.77 g). The material was triturated with hexane (3x5 ml) to give
2-(3,4-dimethoxyphenyl)-l,3-thiazoIane (8) as a friable white solid (0.65 g, 66%), mp 54-56°.
1H nmr (d6-dmso, 300 MHz) 2.3-3.2, m, H4,4,5; 3.5, m, H5; 3.73, s, OMe; 3.74, s, Ome; 5.37, d
(10.2 Hz), H2; 6.87, d (8.1 Hz), H5; 6.96, dd (1.7,8.1 Hz), H6; 7.06, d (1.5 Hz), H2. ESI (+ve)
MSm/z226(M+H,100%).

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Example 9: Preparation of Methyl 4-[2-(4-fluorophenyl)-l/3-dioxolan-2-yllbutanoate
(compound 9)

Methyl 5-(4-fluorophenyl)-5-oxopentanoate
To a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid (3.0 g, 14.3 mmol) in dry MeOH (50
ml) was added concentrated sulfuric acid (50 mg) and the mixture refluxed under nitrogen
for 16 h. The bulk of the MeOH was removed by rotary evaporator and the residue treated
with sodium bicarbonate solution (5%, 100 ml) and extracted with ethyl acetate (3x50 ml).
The organic extract was washed with water (1x100 ml), brine (1x100 ml), dried (Na2SO4)
and evaporated to give methyl 5-(4-fluorophenyl)-5-oxopentanoate (2.69 g, 84%) as a white
crystalline solid.
Methyl 4-F2-(4rfluorophenyl)-l,3-dioxolan-2-ynbutanoate (9)
To a solution of 5-(4-ftuorophenyl)-5-oxopentanoate (2.26 g, 10 mmol) in toluene (60 ml)
was added ethylene glycol (1.95 ml, 35 mmol) and p-toluenesulfonic acid monohydrate (60
mg, 0.32 mmol) and the mixture refluxed in a Dean-Stark apparatus under nitrogen for 17
h. The toluene was removed by rotary evaporator and the residue treated with sodium
bicarbonate solution (5%, 50 ml) and extracted with ether (2x50 ml). The ether extract was
washed with brine (1x50 ml), dried (Na2SO4) and evaporated to give methyl
4-[2-(4-fiuorophenyl)-l,3-dioxolan-2-yl]butanoate (9) as a pale yellow oil (2.47 g, 91%). !H
nmr (CDCl3 300 MHz) 1.6-1.7, m, H3; 1.9, m, H4; 2.30, t (75 Hz), H2; 3.64, s, OMe; 3.7-3.8,
m, CH2O; 3.95-4.05, m, CBA 7.01, m, H3',5'; 7.41, m, H2',6'. ESI (+ve) MS m/z 269 (M+H,
45%).

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Example 10: Preparation of 442-(4-Fluorophenyl)-l,3-dioxolan-2-yl]butan-l-ol
(compound 10)

To a suspension of lithium aluminium hydride (0.167 g, 4.4 mmol) in dry tetrahydrofuran
(10 ml) was added dropwise a solution of methyl
4-[2-(4-fluorophenyl)-l,3-dioxoIan-2-yl]butanoate (9) (0.50 g, 1.86 mmol) in dry
tetrahydrofuran (10 ml) with stirring under nitrogen. Once the addition was complete
stirring was continued at RT for 2 h following by refluxing under nitrogen for 1 h. Water
was cautiously added to destroy excess hydride men the reaction mixture tipped into
sodium carbonate solution (1.7%, 150 ml) and extracted with ethyl acetate (2x50 ml). The
ethyl acetate extract was washed with brine (1x50 ml), dried (Na2SO4) and evaporated to
give a yellow oil (0.394 g). Purification by column chromatography (silica gel 80:3
chloroform/n-propanol) afforded 4-[2-(4-fluorophenyl)-l/3-dioxolan-2-yl]butan-l-ol (10)
(0.252 g, 56%) as a clear colourless oil. 1H nmr (CDCl3 300 MHz) 1.35-1.50, m, H3; 1.55,
quin (6.9 Hz), H2; 1.90, m, H4; 3.60, m, HI; 3.76, m, CH2O; 4.01, m, CH2O; 7.01, m, H3',5';
7.41, m, H2',6\ ESI (+ve) MS m/z 179 (M-C2H5O2, 90%).

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Example 11: Preparation of 2-(4'-Bramophenyl)-2-butyl-1,3-dioxolane (compound 11)

To a solution of 4'-bromovalerophenone (2.41 g, 10 mmol) in benzene (60 ml) was added
ethylene glycol (2.0 ml, 36 mmol), p-toluenesulfonic add monohydrate (100 mg, 0.53
mmol) and the mixture refluxed under nitrogen in a Dean-Stark apparatus for 16 h. The
reaction mixture was washed with sodium bicarbonate solution (5%, 50 ml), brine (1x50
ml), dried (Na2SO4 and evaporated to give2-(4-bromophenyl)-2-butyl-l,3-dioxolane (11)
as a dear oil (2.61 g, 92%). H nmr (CDCl3 300 MHz) 0.88, t (6.9 Hz), H4"; 1.2-1.4, m,
H2",3"; 1.88, m, H1"; 3.7-3.8, m, CH2O; 40-4.1, m, CH2O; 7.34, d (8.4 Hz), H2',6'; 7.49, d (8.4
Hz),H3',5'. ESI(+ve)MSin/z285/287(M+H 8%).

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Example 12: Preparation of 4-(4-Methoxyphenyl)-I-(3-methylbutyl)-lHpyrazole
(compound 12)

To p-bromoanisole (0.25 g, 1.33 mmol) was added a solution of
l-(3-methyIbuutyl)-4-(4,4,5,5-teiramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.41 g, 1.55
mmol) intetrahydrofuran (10ml), potassium carbonate (0.29 g, 2.1 mmol) and
[l,l-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (12 mg, 0.023 mmol) and the
mixture refluxed under nitrogen for 17 h. Water (50 ml) was added to the reaction mixture
and stirring continued at RT for 15 min followed by extraction with ether (2x50 ml), drying
(MgSO4) and evaporation of the ether extract to give a brown oil (0.414 g). Purification by
column chromatography (silica gel, 100% chloroform) afforded
4-(4-methoxyphenyl)-l-(3-methyIbutyl)-1H-pyrazole (12) as a waxy pale yellow solid (37
mg, 11%). H nmr (CDCl3 300 MHz) 0.97, d (6.6 Hz), 2xMe; 1.64, sept (6.6 Hz), H3"; 1.80,
dt (7.2 Hz), H2"; 3.82, s, OMe; 4.15, t (7.5 Hz), HI"; 6.90, d (8.7 Hz), H3',5'; 7.39, d (8.7 Hz),
H2',6'; 7.54, s, H3 or HS; 7.69, s, H5 or H3. ESI (+ve) MS m/z245 (M+H, 100%).

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Example 13: Preparation of l-(3-Methylbutyl)-4-(4-methylphenyl)-1H-pyrazole
(compound 13)

To a solution of p-bromotoluene (0.66 g, 3.86 mmol) in tetrahydrofuran (20 ml) was added
a solution of l-(3-methylbutyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
(0.41 g, 1.55 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0 mmol),
[l,l-bis(diphenylphosphino)ferrocene} dichloropalladium (II) (40 mg, 0.077 mmol) and
water (40 μl) and the mixture refluxed under nitrogen for 43 h. Water (50 ml) was added to
the reaction mixture and stirring continued at RT for 10 min followed by extraction with
ether (2x50 ml). The ether extract was men dried (MgSO4) and evaporated to give a brown
oil (056 g) that solidified on standing. Purification by column chromatography (silica gel,
100% chloroform) afforded l-(3-methylbutyl)-4-(4-methylphenyl)-lH-pyrazole (13) as a
waxy pale yellow solid (0.216 g, 53%). lH nmr (CDCl3, 300 MHz) 0.97, d (6.3 Hz), 2xMe;
1.62, m, H3"; 1.80, dt (7.3 Hz), H2"; 2.35, s, 4'-Me; 4.16, t (7.5 Hz), HI"; 7.16, d (8.1 Hz),
H3',5'; 7.37, d (8.1 Hz), H2',6'; 7.59, s, H3 or H5; 7.74, s, H5 or H3. ESI (+ve) MS m/z229
(M+H, 100%).

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Example 14: Preparation of 2,6-0imethoxy-3-[4-(trifluoromethoxy)phenyl]pyridine
(compound 14)

To a solution of l-bromo-4-(trifIuoromethoxy)benzene (0.92 g, 3.86 mmol) in
tetrahydrofuran (20 ml) was added a solution of
2,6-dimethoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)pyridine (0.40 g, 1.50 mmol)
in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0 mmol),
[l,l-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (40 mg, 0.077 mmol) and
water (40 μl) and the mixture refluxed under nitrogen for 43 h. Water (50 ml) was added to
the reaction mixture and stirring continued at RT for 10 min followed by extraction with
ether (2x50 mi). The ether extract was then dried (MgSO4) and evaporated to give a dark
mobile oil (0.504 g). Purification by column chromatography (silica gel, 3:1
hexane/dichloromethane) afforded 2,6-dimethoxy-3-it4-(trifluoromethoxy)phenyl]pyridine
(14) as a clear, colourless oil (0.372 g, 83%). 1H nmr (CDCI3 300 MHz) 3.97, s, 2x OMe; 6.40,
d (8.1 Hz), H5; 7.24, d (8.4Hz), H3',5'; 7.55, m, H2,2',6'. ESI (+ve) MS m/z300 (M+H,
100%).

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Example 15: Preparation of 2-[4-(2-ThienyI)phenyl]-1,3-thiazoIane (compound 15)

To a solution of 4-(2-thienyl)benzaIdehyde (500.0 mg> 2.66 mmol) in EtOH (5.0 mL) was
added a solution of cysteamine HCI (101.0 mg, 0.89 mmol) in water (2.0 mL) dropwise with
stirring. The solution was then stirred at room temperature for 18 hours before the bulk of
the EtOKwas removed by rotary evaporator. The resulting residue was diluted with
water (15.0 mL) and extracted with ether. (3x30.0 mL) to remove excess aldehyde. The
acidic aqueous layer was then basified with the slow addition of solid sodium carbonate
(300.0 mg) to afford a white precipitate, which was filtered andwashed carefully with
water (3.x 20.0 mL). The solid was dried under reduced pressure to afford
2-[4-(2-truenyl)phenyl]-l,3-thiazolane (15) as a yellow powder (30 mg, 4.6%). 1H nmr
(CDCl3 300 MHz) 3.14, m, H4,4,5; 3.64, m, H5; 5.95, s, H2; 7.08, m, thienyl-H; 7.31, m, 2 x
thienyl-H; 7.50, d (8.1 Hz), 2 x phenyl-H; 7.59, d (8.4 Hz), 2 x phenyl-H. ESI (+ve) MS m/z
248 (M+H, 100%).

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Example 16: Preparation of 2-EthyI-2-(4-methoxyphenyI)-l,3-dioxolane (compound 16)

4'-Methoxypropiophenone
To a solution of 4'-hydroxypropiophenone (1.0 g, 6.67 mmol) in acetonitrile (50.0 mL) was
added potassium carbonate (7.17 g, 66.7 mmol) and the mixture heated to reflux for 90 min.
After this time the reaction mixture was allowed to cool to room temperature and dimethyl
sulphate (l".05 mL, 11.1 mmol) was added and the reaction mixture was heated to reflux for
a further 19 h. After cooling the acetonitrile was evaporated under reduced pressure and
the residue taken up in water and extracted with dichloromethane. The dichloromethane
extract was dried (MgSO4) and evaporated under reduced pressure to give
4'-methoxypropiophenone as a yellow oil, (970 mg, 89 %) 1H nmr (d6-DMSO, 300 MHz)
1.06, t (7.2 Hz), CH3; 2.95/ q (7.2 Hz), CH2; 3.83, s, OMe; 7.02, d (6.9 Hz), H3',5'; 7.93, d (6.9
Hz), H2',6'. ESI (+ve) MS m/z165 (M+H, 100%).
2-Ethyl-2-(4-methoxyphenyl)-l,3-dioxolane(16)
To a solution of 4'-methoxypropiophenone (250.0 mg, 1,52 mmol) in toluene (20.0 mL) was
added ethylene glycol (255.0 μL, 4.57 mmol) and p-tohienesulfonic add monohydrate (13.0
mg, 0.04 mmol) and the reaction mixture refluxed overnight using a Dean-Stark apparatus.
The reaction mixture was cooled to room temperature, then washed with saturated
aqueous aodium bicarbonate solution followed by water. The toluene solution was then
dried (MgSO4) and evaporated under reduced pressure to afford
2-ethyl-2-(4-methoxyphenyl)-l,3-dioxolane (16) as a yellow oil (184 mg, 58%). 1H nmr
(CDCI3,300 MHz) 0.76, t (6.6 Hz), CH3 1.78, q (6.9 Hz), CH2;3.65, m, CH2O, 3.73, s, 4'-OMe;


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3.95, m, CH2O- 6.88, d (7.2 Hz), H3',5'; 7.02, d, (75 Hz), H2',6', ESI (+ve) MS m/z209
(M+H,100%).
Example 17: Preparation of 2-Hexyl-2-(4-methylphenyl)-l,3-dithiolane (compound 17)

α-Hexyl-4-methyl-berizenemethanol
(Ref: Liang, X,; Bols, M.J, Chem. Soc, Parkin Trans. 12002,503-508.)
1-Iodohexane was added dropwise to a stirred suspension of magnesium turnings (987 mg,
40.6 rrintol, 2.0 equiv.) in anhydrous diethyl ether (40 mL), Cooled in an ice-water bath arid
under an atmosphere of dry nitrogen. The addition was followed by a vigorous exotherm
after which a cloudy suspension resulted. Stirring was continued at ambient temperature
for 2 hours before recooling to 0 °C. 4-ToluaIdehyde (1.21 mL, 10.2 rnmol, 0.5 eq.) was
added dropwise and the reaction mixture was stirred at ambient temperature for 2 hours
prior to careful quenching with saturated aqueous ammonium chloride solution (20 mL).
The biphasic mixture was stirred for 10 minutes, the organic phase was isolated and the
aqueous phase was twice extracted with diethyl ether. The organic phases were combined,
dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a colourless
oil which was purified by flash chrotnatography on silica gel, eluting with hexane-ethyl
acetate (4:1) to give the desired benzylic alcohol (2.10 g, 100%). 1H nmr (200 MHz, CDC13)
0.83-1.79 (m, 13H, (CH2)5CH3), 2.34 (s, 3H, ArCH3), 4.61 (t, J = 3.8 Hz, 2H, CHOH), 7.14 (d, J
= 4.0 Hz, 2H, 2 x ArH), 7.23 (d, J - 4.2 Hz, 2H, 2 x ArH).
l-(4-Methylphenyl)-l-heptanone
To a stirred solution of a-hexyl-4-rnethyI-benzenemethanol (2.10 g, 10.2 mmol.) in
anhydrous dichloromethane (45 mL) under an atmosphere of dry nitrogen was added

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pyridinium chlorochromate (3.08 g, 14.3 mmol., 1.4 eq.). Stirring was continued at room
temperature for 3 hours after which time analysis by thin layer chromatography revealed
complete conversion of the starling alcohol. Following evaporation of the reaction solvent
the desired ketone (1.929 g, 93%) was isolated by flash chromatography on silica gel,
eluting with hexane-ethyl acetate (4:1). 1H nmr (200 MHz, CDC13) 0.86-1.76 (m, 3H,
(CH2)5CH3), 2.41 (s, 3H, ArCH3), 2.93 (t, J = 3.6 Hz, 2H, COCH2), 7.25 (d, J = 4.2 Hz, 2H, 2 x
ArH), 7.86 (d, J = 4.2 Hz, 2H, 2 x ArH),
2-Hexyl-2-(4-methylphenyn-1.3-dithiolane (l7)
(Ref: Banik et al. Tetrahedron Lett. 2001,42, 4425-4427.)
To a stirred solution of l-(4-methylphenyl)-l-heptanone (500 mg, 2.45 mmol) and
1,2-ethanedithiol (250 L, 2.94 rninol., 1.2 eq.) in anhydrous tetrahydrofuran (5.0 mL) under
an atmosphere of dry nitrogen was added iodine (62 mg, 0.245 mmol., 0.10 eq.). The
reaction mixture was stirred at ambient temperature for several days after which time
analysis by thin layer chromatography revealed a mixture of starting material and a new
less polar compound which stained positively towards phosphomolybdic acid.
Evaporation of the solvent gave a strong smelling crude oil which was purified by flash
chromatography on silica gel, eluting with hexane-dichloromethane (2:1) to afford the
. desired dithiolane (17; 300 mg, 44% isolated) as a colourless oil. 1H nmr (200 MHz, CDC13)
0.80-0.86 (m, 3H, CH2CH3), 1.21-1.29 [m, 10H, (CHa)5], 2.32 (s, 3H, ArCH3), 3.16-3.41 (m, 4H,
SCH2), 7.01 (d, J = 4.0 Hz, 2H, 2 x ArH), 7.56 (d, J = 4.1 Hz, 2H, 2 x ArH).
(Ref: Banik et al. Tetrahedron Lett. 2001,42,4425-4427.)
Example 18: Preparation of 2-Methyl-2-(4-methylphenyI)-l,3-dithiolane (compound 18)


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To a stirred solution of the 4-methylacetophenone (1.34 mL, 10.0 mmol) and 1,2-
ethanedithiol (838 L,10.0 mmol., 1.0 eq.) in anhydrous tetrahydrofuran (20.0 mL) under
an atmosphere of dry nitrogen was added iodine (253 mg, 1.0 mmol., 0.10 equiv.). The
reaction mixture was stirred at ambient temperature for five days after which time analysis
by thin layer chromatography revealed a mixture of starting material and a new less-polar
compound which stained positively towards phosphomolybdic add. Evaporation of the
solvent gave a strong smelling crude oil which was purified by flash chromatography on
silica gel, eluting with hexane-ethyl acetate (4:1) to afford the desired dithiolane (558 mg,
27% isolated) as a pale yellow oil (a low melting solid). 1H nmr (200 MHz, CDCl3) 2.14 (s,
3H, CH3), 2.33 (s, 3H, ArCH3), 3.32-3.53 (m, 4H, SCH2CH2S), 7.12 (d, j== 8.5 Hz, 2H, 2 x
ArH), 7.63 (dd, j= 8.5,1.9 Hz, 2H, 2 x ArH). ,
Example 19: Preparation of 2-Hexyl-2-(4-methyIphenyI)-l,3-dioxolane (compound 19)

(Ref: A. Srikishna and R. Viswajanani, Tetrahedron, 1995,51, 3339.)
A mixture of l-(4-methy!phenyl)-l-heptanone (200 mg, 0.980 mmol), p-toluenesulfonic acid
(17 mg, 0.098 mmol) and ethylene glycol (0.16 mL, 2.9 mmol) in dry toluene (10 mL) was
heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was
allowed to cool to room temperature and the solvent was evaporated in vacuo. The
residue was taken up in ether (20 mL) and the solution was washed with saturated sodium
carbonate solution (2 x 10 mL) and brine (1 x 10 mL), then dried (Na2SO4) and concentrated
under reduced pressure. Flash column chromatography of the residue, eluting with
dichloromethane/hexane (1:2) afforded 2-hexyl-2-(4-methylphenyl)-l-3-dioxolane (19) as a
tan-coloured oil (162 mg, 67 %). 1H nmr (200 MHz, ODC13) 0.80-0.92 (m, 3H, CH2CH3),
1.18-1.40 [m, 8H, (CH2),] 1.84-1.89 (m, 2H, CCH2), 2.34 (s, 3H, ArCH3), 3.73-3.81 (m, 2H,

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OCH2), 3.94-4.02 (m, 2H, OCH2), 7.13 (d, j= 8.2 Hz, 2H, 2 x ArH), 7.32 (d, j= 8.2 Hz, 2H, 2 x
ArH).
Example 20: Preparation of 2-(4-Chlorophenyl)-2-methyl-l,3-dioxane (compound 20)

(Ref. B. Karimi, G. R. Ebrahimian and H. Sheradj, Org. Lett., 1999,1,1737.)
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL,
12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry CH2C12 (50
mL) was added NBS (53 mg, 0.30 mmol): This mixture was protected from light and stirred
at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was
washed with saturated aqueous sodium bicarbonate solution (20 mL), the aqueous phase
was extracted with dichloromethane (3 x 30 mL). The combined organic solution was
washed with water (2 x 20 mL), brine (1 x 20 mL), then dried (Na2SO4) and concentrated
under reduced pressure. Hash column chromatography of the residue, eluting with 37%
aqueous ammonia:ether:hexane (0.02:1:6) afforded
2-(4-chlorophenyl)-2-methyl-1,3-dioxane (20) as a colourless oil (1.1 g, 52%). 1H nmr (200
MHz, CDC13) 1.49 (s, 3H, CH3) 1.98-2.25 (m, 2H, OCH2CH2CH2O), 3.65-4.10 (m, 4H,
OCH2CH2CH2O), 7.30-7.50 (m, 4H, 4 x ArH).

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Example 21: Preparation of 2-(4-Chlorophenyl)-2-methyl-l/3-dioxoIane (compound 21)

To a stirred mixture of 4-chIoroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL,
12 mmol), ethylene glycol (1.7 mL, 30 mmol) and dry methanol (1.2 mL) in dry
dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected
from light and starred at room temperature under an inert atmosphere of nitrogen for 70 h.
After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the
aqueous phase was extracted with dichloromethane (3 x 30 mL). The combined organic
solution, was washed with water (2 x 20 mL), brine (1 x 20 mt), then dried (Na2SO4) and
concentrated under reduced pressure. Flash column chromatography of the residue,
eluting with 37% aqueous ammonia:ethenhexane (0.02:1:6) afforded
2-(4-chlorophenyl)-2-methyl-l,3-dioxoIane (21) as a colourless oil (1.1 g, 51%). 1H nmr (300
MHz, CDCI3) 1.63 (s, 3H, CH3), 3.72-3.82 (m, 2H, OCH2), 3.98-4.09 (m, 2H, OCH2), 7.42 (d, j
= 8.6 Hz, 2H, 2 x ArH), 7.30 (d, j= 8.6 Hz, 2H, 2 x ArH).

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Example 22: Preparation of 2-Methyl-2-(4-methylphenyI)-l,3-dioxane (compound 22)

To a stirred mixture of 4-methylacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL,
12 mmol), l,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 rnL) in dry
dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected
from light and stirred at room temperature tinder an inert atmosphere of nitrogen for 70 h.
After the mixture was washed with saturated sodium bicarbonate solution (20 ml), the
aqueous phase was extracted with dichioromethane (3 x 30 mL). The combined organic
solution was washed with water (2 x 20 mL), brine (1 x 20 mL), then dried (Na2SO4) and
concentrated under reduced pressure. Flash column chromatography of the residue,
eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded
2-methyl-2-(4-methylpheny1)-l,3-dioxane (22) as a colourless oil (480 mg, 24%). lH nmr
(200 MHz, CDCI3) 1.50 (s, 3H, CH3) 1.96-2.25 (m, 2H, OCH2CH2CH20), 2.37 (s, 3H, ArCH3),
3.70-4.00 (rn, 4H, OCH2CH2CH2O), 7.23 (d, j= 8.3 Hz, 2H, 2 x ArH), 7.33 {d, j= 8.3 Hz, 2H,
2xArH).

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Example 23: Preparation of 2-Mefhyl-2-(4-methyIphenyl)-l,3-dioxolane (compound 23)

A mixture of 4-methylacetophenone (1.00 g, 7.45 mmol), p-toluenesulfonic acid (133 mg,
0.745 mmol) and ethylene glycol (1.20 mL/ 22.4mmol) in dry toluene-(20 mL) was heated at
reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to
cool to room temperature and the solvent was evaporated in vacuo. The residue was taken
up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate
solution (2 x 10 mL) and brine (1 x 10 mL), then dried (Na2SO4) and concentrated under
reduced pressure Flash column chromatography of the residue, eluting with 37% aqueous
ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-l,3-dioxolane (23)
as a colourless oil (1.05 g, 59%). 1Hninr (200 MHz, CDC13) 1.65 (s, 3H, CH3), 2.35 (s, 3H,
ArCH3) 3,74-3.86 (m, 2H, OCH2), 3.94-4.06 (m, 2H, OCH2), 7.15 (d, j= 8.2 Hz, 2H, 2 x ArH),
7.37 (d, j= 8.2 Hz, 2H, 2 x ArH).

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Example 24: Preparation of 2-(4-ChlorophenyI)-2-methyl-l/3-dithiolane (compound 24)

(Ref. S. Samajdar, M. K. Basu, F. F. Becker and B. K. Banik, Tetrahedron Lett., 2001,42,
4425.)
A mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), iodine (250 mg, 1 mmol),
1,2-ethanedithiol (0.85 mL, 10 mmol) in dry tetrahydrofuran (20 mL) was heated at reflux
under an atmosphere of nitrogen for 16 h. The mixture was allowed to cool to room
temperature and concentrated in vacuo and the residue taken up in ether (20 mL). The
organic solution was washed with water (2 x 10 mL) and brine (1 x 10 mL), then dried
(Na2SO4) and evaporated under reduced pressure. Flash column chromatography of the
residue, eluting with 37% aqueous ammonia: ethenhexane (0.02:1:6) afforded
2-(4-chlorophenyi)-2-methyl-l,3-dithiolane (24) as a colourless oil (1,11 g, 48%). 1H nmr
(300 MHz, CDC13) 2.13 (a, 3H, CH3), 3.31-3.53 (m, 4H, SCH2CH2S), 7.27 (d, j= 8.7 Hz, 2H, 2
x ArH), 7.69 (d, j= 8.7 Hz, 2H, 2 x ArH).

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Example 25: Preparation of 2-(4-NittophenyI)-2-methyI-l,3-dioxoIane (compound 25)

A mixture of 4-nitroacetophenone (1.65 g, 10.0 mmol), p-toluenesulfonic arid (172 mg, 1.00
mmol) and ethylene glycol (1-7 mL, 30 mmol) in dry toluene (20 mL) was heated at reflux
with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to
room temperature and the solvent was evaporated in vacuo. The residue was taken up in
ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2
x 10 mL) and brine (1 x 10 mL), then dried (Na2SO4) and concentrated under reduced
pressure. Recrystallisationfrom.ether and hexanes afforded
2-(4rnitrophenyl)-2-methyI-l-3-dioxolane (25) as a pale yellow crystals (152 g, 73 %; yield
based from the first crop of crystals). 1H nmr (300 MHz, CDCI3) 1.66 (s, 3H, CH3), 3-71-3.83
(m, 2H, OCH2) 4.02-4.13 (m, 2H, OCH2), 7.63-7.73 (d, j= 8.8 Hz, 2H, 2 x ArH), 8.16-8.26 (d,
j=8.8Hz/2H,2xArH).

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Example 26: Preparation of 2-(4-NitrophenyI)-2-methyl-1,3-dioxane (compound 26)

A mixture of 4-nitroacetophenone (1.65 g, 10.0 rnmol), p-toluertesulfonk acid (172 mg, 1.00
mmol) and 1,3-propanediol (2.3 mL, 30 mmol) in dry toluene (20 mL) was heated at reflux
with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to
room temperature and the solvent was evaporated in vacao. The residue was taken up in
ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2
x 10 mL) and brine (1 x 10 mL), then dried (Na2SO4) and concentrated under reducecl
pressure. Recrystallisarion from ether and hexane afforded
2-(4-nitrophenyl)-2-methyI-l,3-dioxane (26) as a pale yellow crystals (1.60 g, 72 %; yield
based from the first crop of crystals). lH nmx (300 MHz, CDCI3) 1.52 (s, 3H, CH3), 2.08-2.22
(m, 2H, OCH2CH2O) 3.65-3.80 (m, 2H, OCH2), 3.88-4.00 (m, 2H, OCH2), 7.63 (d, j= 8.9
Hz, 2H, 2 x ArH), 8.26 (d, j== 8.9 Hz, 2H, 2 x ArH).

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Example 27: Preparation of 2-(4-Methoxyphenyl)-l,3-oxathiolane (compound 27)

A mixture of anisaldehyde (273 mg, 2.00 mmol), freshly distilled 2-mercaptoethanol (625
mg, 8.00 mmol), sodium sulfate (852 mg, 6.00 mmol) and freshly fused zinc chloride (818
mg, 6.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under nitrogen at room temperature
for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added and the phases separated.
The ethyl acetate layer was washed with more water (10 ml) followed by saturated
aqueous sodium chloride solution (10 ml). The solution was then dried (Na2SO4), filtered
and the solvent removed in vacuo to give a colourless, oil (528 mg). To 260 mg of the oil
were added toluene (20 ml) and p-toluenesulfbnic acid monohydrate (5 mg, 26 mol) and
the mixture was refiuxed for 3 h. After cooling the toluene was removed in vacuo and the
residual oil subjected to flash chromatography (ether/hexane gradient) to give
2-(4-methoxyphenyl)-l/3-6xathiolane (27) (74 mg, 39%) as a colourless oil. 1H nmr
(d5-dmso, 300 MHz)  3.18 (m, 2H); 3.81 (m, 1H); 4.45 (m, 1H); 5.98, (s, 1H); 6.90 (d, j8.7 Hz,
2H); 7.36 (d, j8.7 Hz, 2H). ESI (+ve) MS m/z 197 (M+H, 100%).

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Example 28: Preparation of 2-(3,4,5-Trimethoxyphenyl)-l,3-oxathioIane (compound 28)

A mixture of 3,4,5-trimethoxybenzaldehde (393 mg, 2.00 mmol), freshly distilled
2-mercaptoethanol (469 mg, 6-00 mmol), sodium sulfate (568 mg, 4.00 mmol) and freshly
fused zinc chloride (545 mg, 4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under
nitrogen at room temperature for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added
and the phases separated. The ethyl; acetate layer was washed with more water (10 ml)
followed by saturated aqueous sodium chloride solution (10 ml). The solution was then
dried (sodium sulfate), filtered, and the.solvent removed in vacuoto give a colourless oil
(513 mg). To the oil was added toluene (20 ml), p-toluenesulfonic acid monohydrate (5 mg,
26 mol) and the mixture was refluxed for 2 h. After cooling, the toluene was removed in
vacua and the residual oil subjected to flash chromatography (ether/hexane gradient) to
give 2-(3,4,5-trimethoxyphenyl)-l,3-oxathiolane (28) (174 mg, 34%) as a colourless oil. 1H
nmr (d6-dmso, 300 MHz) 5 3.17 (m, 2H); 3.64 (s, 3H); 3.75 (s, 6H); 3.84 (m, 1H); 448 (m, 1H);
5.98, (s, 1H); 6.72 (s, 2H). ESI (+ve) MS m/z257 (M+H 100%).

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Example 29: Preparation of 2-Methoxy-4-(l/3-oxathiolan-2-yI)phenol (compound 29)

A mixture of vanillin (304 mg, 2.00 mmol), freshly distilled 2-mercaptoethanoi (469 mg,
6.00 mmol), sodium sulfate (568 mg, 4.00 mmol) and freshly fused zinc chloride (545 mg,
4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under nitrogen at room temperature for 16
h. Water (10 ml) and ethyl acetate (20 ml) were added and the phases separated. The ethyl
acetate layer was washed with more water (10 ml) followed by saturated aqueous sodium
chloride solution (10 ml). The solution was then dried (sodium sulfate), filtered and the
. solvent removed inyacuo to give a. colourless oil (507 mg),. To the oil was added toluene
(20 ml) and p-toluenesulfonic acid monohydrate (6 mg, 31 mol) and the mixture was
refluxed for 1 h. After cooling the toluene was removed in vacuo and the residual oil
subjected to flash chromatography (ether/hexane gradient) to give
2-methoxy-4-(l,3-oxathiolan-2-yl)phenoI (29) (34 mg, 8%) as a colourless oil which ;
solidified upon standing. 1H nmr (d6-dmso, 300 MHz)  3.17 (m, 2H); 3.74 (s, 3H); 3.78 (m,
1H); 4.45 (m, 1H);5.93, (s, 1H); 6.72 (d, j7.8 Hz, 1H); 6.84 (dd, j7.8,1.8 Hz, 1H); 6.97 (d, j1.8
Hz, 1H). ESI (+ve) MS m/z213 (M+H, 65%).

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Example 30: Preparation of 4-(l,3-Oxathiolart-2-yl)benzonitrile (compound 30)

A mixture of 4-cyanobenzaldehyde (262 mg, 2.00 mmol), freshly distilled
2-mercaptoethanol (469 mg, 6.00 mmol), sodium sulfate (568 mg, 4.00 mmol) and freshly
fused zinc chloride (545 mg, 4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under
nitrogen at room temperature for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added
and the phases separated. The ethyl acetate layer was washed with more water (10 ml)
followed by saturated aqueous sodium chloride solution (10 ml). The solution was then
dried, (sodium sulfate),. filtered and the solvent removed in. vacao to give a.colourless Oil
(512 mg). To the oil was added toluene (25 ml) and p-toluenesulfonic acid monohydrate (6
mg, 31 mol) and the mixture was refluxed for Ih. After cooling, the toluene was removed
in vacuo and the residual oil subjected.to flash chromatography (ether/hexane gradient) to
give 4-(l,3-oxathiolan-2-yI)benzordtrile (30) (106 mg, 28%) as a colourless oil. 1H nmr
(d6-dmso, 300 MHz)  3.20 (m, 2H); 3.92 (m, 1H); 4.49 (m, 1H); 6.16, (s, 1H); 7.59 (d, j8.1 Hz,
2H);7.82(d,j8.1Hz,2H).

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Example 31: Preparation of 2-(4-BromophenyI)-2-efltyl-l,3-oxathioIane (compound 31)

A mixture of p-bromopropiophenone (426 mg, 2.00 mmol), freshly distilled
2-mercaptoethanol (469-mg, 6.00 mmol), sodium sulfate (568 mg, 4.00 mmol) and freshly
fused zinc chloride (545 mg, 4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under
nitrogen at room temperature for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added
and the phases separated. The ethyl acetate layer was washed with more water (10 ml)
followed by saturated aqueous sodium chloride solution (10 ml). The solution was then
dried (sodium sulfate),. filtered and the solvent removed in.vacua to. give a, colourless oil
(560 mg). The oil was subjected to flash chromatography (ether/hexane gradient) to give
2-(4-bromophenyl)-2-ethyl-l,3-oxathiolane (31) (214 mg/ 39%) as a colourless oil. 1H nmr
(d6-dmso, 300 MHz) 5 0.77 (t, J7.2 Hz, 3H); 2.05 (q, j7.2 Hz, 2H); 3.07 (m, 2H); 3.86 (m, 1H);
4.30 (m, 1H); 731 (d, j8.7 Hz, 2H); 7.51 (d, j8.4 Hzr 2H).

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Example 32: Preparation of 4-(5-Methyl-1,3-oxathiolan-2-yI)benzonitriIe (compound 32)

A mixture of 4-cyanobenzaldehyde (131 mg, 1.00 mmol), l-mercapto-2-propanol (276 mg,
3.00 mmol), sodium sulfate (284 mg, 2.00 mmol) and freshly fused zinc chloride (273 mg,
2.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under nitrogen at room temperature for 16
h. Water (10 ml) and ethyl acetate (20 ml) were added and the phases separated. The ethyl
acetate layer was washed with more water (10 ml) followed by saturated aqueous sodium
chloride solution (10 ml). The solution was then dried (sodium sulfate), filtered and the
solvent removed in vacuo to give a colourless oil (284 mg). To the oil was added toluene
(25 ml) and p-toluenesulfonic acid monohydrate (6 mg, 31mol) and the mixture was
refluxed for 70 min. After cooling the toluene was removed in vacuo and the residual oil
subjected to flash chromatography (ether/hexane gradient) to give a diasteromeric mixture
of 4-(5-methyl-l/3-oxathiolan-2-yl)benzonitrile (32) (76 mg, 37%) as a colourless oil. 1H nmr
(d6-dmso, 300 MHz) .32 & 1.43 (each d,j6.0 Hz, total 3H); 2.83 & 3.29 (each m, total 2H);
4.21 & 4.60 (each m, total 1H); 6.17 & 6.30 (each s, total 1H); 7.58 {m, 2H); 7.82 (m, 2H).

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Example 33: Preparation of 2-(4-Thien-2-ylphenyl)-l/3-oxathioIane (compound 33)

A mixture of 4-(2~thienyl)benzaIdehyde (188 mg, 2.00 mmol), freshly distilled
2-mercaptoethanor(234 mg, 3.00 mmol), sodium sulfate (284 mg, 2.00 mmol) and freshly
fused zinc chloride (273 mg, 2.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under
nitrogen at room temperature for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added
and the phases separated. The ethyl acetate layer was washed with more water (10 ml)
followed by saturated aqueous sodium chloride solution (10 ml). The solution was then
dried (sodium sulfate), filtered and the solvent removed in vacuo to give a yellow-green
solid (323 mg). A solution of the solid and p-toluenesulfonic acid monohydrate (6 mg, 31
mol) in toluene (25 ml) was refluxed for 70 min. After cooling, the toluene was removed
in vacuo and the residual solid subjected to flash chromatography (ether/ hexane gradient)
to give 2-(4-thien-2-ylphenyl)-l/3-oxathiolane (33) (49 mg, 20%) as a white powder. 1H nmr
(c6-dmso, 300 MHz)  3.21 (m, 2H); 3.88 (m, 1H); 4.49 (m, 1H); 6.07, (s, 1H); 7.13 (dd, J5.1,
4.8 Hz, 1H); 7.45 (d, j8.4 Hz, 2H); 751 (dd, j4.8,1.1 Hz, 1H); 7.54 (dd, j5.1,1.1 Hz, 1H);
7.64 (d, j8.4 Hz, 2H). ESI (+ve) MS m/z249 (M+H, 70%).

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Example 34: Preparation of 4-(5-Methyl-2-octyl-l,3-oxathioIan-2-yl)phenol (compound
34)

A mixture of 4'-hydroxynonanophenone (468 mg, 2.00 mmol), l-mercapto-2-propanol (553
mg, 6.00 mrnol), sodium sulfate (568 mg, 4.00 mmol) and freshly fused zinc chloride (545
mg, 4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under nitrogen at room temperature
for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added and the phases separated.
The ethyl acetate layer was washed with more water (10 ml) followed by saturated
aqueous sodium chloride solution (10 ml). The solution was then dried (sodium sulfate),
filtered and the solvent removed in vacuoto give a colourless oil (688 mg). A portion of
the oil (410 mg) was subjected to flash chromatography (ether/hexane gradient) to give a
mixture of the two diastereoisomers of 4-(5-methyl-2-octyl-l/3-oxathiolan-2-yl)phenol (34)
(117 mg, 32%) as a colourless oil. 1H mmr (cVdmso, 300 MHz) S 0.82 (t j6.6 Hz, 3H); 1.16
(br. s, 12H); 1.33 (m, 2H); 1.96 (m, 2H); 2.6 & 3.1 (each m, total 2H); 3.99 & 4.11 (each m,
total 1H); 6.67 (m, 2H); 7.16 (m, 2H). ESI (+ve) MS m/z309 (M+H, 25%).

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Example 35: Preparation of
2-Fluoro-5-(5-methyl-l/3-oxathiolan-2-yl)benzenecarbonitrile (compound 35)

A mixture of 2-fluoro-5-formylbenzonitrile (298 mg, 2.00 rnrnol), l-mercapto-2-propanol
(553 mg, 6.00 mmol), sodium sulfate (568 mg, 4.00 mmol) and freshly fused zinc chloride
(545 mg, 4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under nitrogen at room
temperature for 16 h. Water (10 ml) and ethyl acetate (20 ml) were added and the phases
separated. The ethyl acetate layer was washed with more water (10 ml) followed by
saturated aqueous sodium chloride solution (10 ml). The solution was then dried (sodium
sulfate), filtered and the solvent removed in vacuoto give a colourless oil (717 mg). To this
oil was added toluene (25 ml) and p-toluenesuIfonic acid monohydrate (8 mg, 41 mol)
and the mixture was refluxed for 1.5 h. After cooling the toluene was removed in vacuo
and the residual oil subjected to flash chromatography (ether/hexane gradient) to give a
mixture of the two diastereoisomers of
2-fluoro-5-(5-methyl-l,3-oxathiolan-2-yl)benzenecarbonitrile (35) (295 mg, 66%) as a
colourless oil. 1H nmr (d6-dmso, 300 MHz) 1.31 & 1.42 (each d, j6.0 Hz, total 3H); 2.85 &
3.30 (each m, total 2H); 4.18 & 4.61 (each m, total 1H); 6.11 & 6.25 (each s, total 1H); 7.51 (m,
1H); 7.83 (m, 1H); 7.93 (m 1H).

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Example 36: 4-Methoxy-4'-(trifluorometlioxy)-lrl'-biphenyl (compound 36)

To a solution of l-bromo-4-(trifluoromethoxy)benzene (0.90 g, 3.7 mmol) in
tetrahydrofuran (20 ml) was added a solution of 2-(4-methoxyphenyI)-4,4,5,5-tetrarnethyl-
1,3,2-dioxaborolane (0.36 g, 1.54 mrnol) in tetrahydrofuran (10 ml), potassium carbonate
(0.42 g, 3.0 mmol), [l,l-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (40 mg,
0.077 mmol) and water (0.20 ml) and the mixture refluxed under nitrogen for 19 h. The
reaction mixture was tipped into water (150 ml) and extracted with ether (2x50 ml), the
ether extract then dried (MgSO4) and evaporated to give a tan semi-solid (0.801 g).
Purification by column chrornatography (silica gel, 4:1 hexane/ chloroform) afforded 4-
methoxy-4'-(trifluoromethoxy)-1,1'-biphenyi (36) as a white solid (0.33 g, 80%). 1H nmr
(CDCI3, 300 MHz) 3.86, s, 4-OMe; 6.99, d (8.7 Hz), H3,5; 7.26, d (8.1 Hz), H3',5'; 7.49, d (8.7
Hz), H2,6 or H2',6'; 7.55, d (8.7 Hz), H2',6' or H2,6. APCI (+ve) MS m/z 268 (M+, 80%).


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Example 37: 2,6-Dimethoxy-3-4-(trifluoromethyl)phenyl]pyridine (compound 37)

To a solution of 4-bromobenzotrifioudde (0.85 g, 3.78 mmol) in tetrahydrofuran (20 ml)
was added a solution of 2,6-dimethoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)pyridine (0.41 g, 1.55 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0
mmol), [1,l-bis(diphenylphosphino)ferroeene3 dichloropalladium (II) (40 mg, 0.077 mmol)
and water (0.2 ml) and the mixture refluxed under nitrogen for 19 h. The reaction mixture
was tipped into water (150 ml) and extracted with ether (2x50 ml), the ether extract then
dried (MgSO4) and evaporated to give a light brown oil (0.537 g). Purification by column
chromatography (silica gel, 2:1 hexane/ chloroform) afforded 2,6-dimethoxy-3-[4-
(trifluoromethyl)phenyI3pyridme (37) as a clear, colourless oil (0.359 g, 82%). 1H nmr
(CDCI3,300 MHz) 4,00, s, 2x OMe; 6,44, d (8.1 Hz), H5; 7.60, d (8.1 Hz), H4; 7.66, m,
H2',3',5',6'. ESI (+ve) MS m/z284 (M+H, 100%).

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Example 38 and 39: Diastereomers of 2-(4-bromophenyl)-2-butyl-4-propyl-l,3-
oxathiane (compound 38) and (compound 39)

A mixture of 4-bromovalerophenone (482 mg, 2.00 mmol), 3-mercapto-1-hexanol (805 mg,
6.00 mmol), sodium sulfate (568 mg, 4.00 mmol) and freshly fused zinc chloride (545 mg,
4.00 mmol) in dry 1,4-dioxane (1 ml) was stirred under nitrogen at room temperature for 16
h. Water (10 ml) and ethyl acetate (20 ml) were added and the phases separated. The ethyl
acetate layer was washed with more water (3x10 ml) followed by saturated aqueous
sodium chloride solution (10 ml). The solution was then dried (sodium sulfate), filtered
and the solvent removed in vacuo to give a colourless oil (1.112g). To 467 mg of this oil
were added toluene (25 ml) and p-toluenesulfonic acid monohydrate (75 mg, 39 mol) and
the mixture was refluxed for 5 h. After cooling, the toluene was removed in vacuo and the
residual oil subjected to flash chromatography (ether/hexane gradient) to give a colourless
oil (254 mg), consisting of the starting ketone and the two diasteroisomers of 2-(4-
bromophenyl)-2-butyl-4-propyl-l,3-oxathiane (38/39). Further flash chromatography
(dichloromethane/hexane gradient) gave in order of elution, the first diastereomer (38) as a
colourless oil (36 mg), followed by the second diastereomer (39), also as a colourless oil (43
mg). The 1H nmr data for the separated diastereomers is given below.
(38) 1H nmr (d6-dmso, 300 MHz) 6 076 (t, J 7.2 Hz, 3H); 0.85 (t, J 6.9 Hz, 3H); 0.9-1.5
(complex, 9H); 1.83 (dd, J 13.5,2.7 Hz, 1H); 2.00 (ddd, J 15.0,11.4,4,2 Hz, 1H); 2.76 (ddd, J
15.0,11.7,4.2 Hz, 1H); 3,35 (m, 1H); 3.89 (dt, J 11.7,1.8 Hz, 1H); 3.98 (m, 1H); 7.38 (d, J 8.7
Hz, 2H); 7.52 (d, J 8.7 Hz, 2H).

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(39) 1H nmr (d6dmso, 300 MHz) 8 0.74 (t, J 7.2 Hz, 3H); 0.84 (t, J 6.9 Hz, 3H); 0.9-1.3
(complex, 4H); 1.3-1.9 (complex, 8H); 2.61 (m, 1H); 3,40 (apparent dt, J 12.3,2.4 Hz); 3.83
(ddd, J 12,3,3.6,1.5 Hz); 7.49 (d, J 8.7 Hz, 2H); 7.60 (d, J 8.7 Hz, 2H).
Example 40: 4-(l,3-Dioxolan-2-yl)benzenecarbonitrile (compound 40)

4-Cyanobenzaldehyde (500 mg, 3.81 mmol), ethylene glycol (828 mg, 1334 mmol) and a
catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 mL)
overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the
residue dissolved in chloroform (50 ml) and washed with saturated sodium bicarbonate
solution (2x 25 mL) and brine (1x 25 mL). The organic phase was then dried (Na2SO4) and
evaporated to give 4-(l,3-dioxolan-2-yl)benzenecarbonitrile (40) as an oil which solidified
to a white solid (633 mg, 95%). 1H NMR (CDCl3, 300 MHz): 5 4.04, t (1.8 Hz), OCH2;4.07, t
(2.0 Hz), OCH2; 5.82. s, H2; 7.64, d (1.4 Hz), 2xArH; 7.73, d (1.3 Hz), 2xArH ESI (+ve) MS:
m/z176(M+H,12%).

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Example 41s 2-(3/S-Dimethoxyphenyl)-2-hexyl-1,3-dioxolane (compound 41)

l-(3,5-Dimethoxyphenyl)heptan-l-one (200 mg, 0.80 mmol), ethylene glycol (173 mg, 2.80
mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in
toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then
concentrated and the residue dissolved in chloroform (50 mL) and washed with saturated
sodium bicarbonate solution (2x 25 mL) then brine (1x 25 mL). The organic phase was
dried (Na2SO1) and evaporated to give 2-(3,5-dimethoxyphenyl)-2-hexyl-l,3-dioxolane (41)
as a light yellow oil (215 mg, 90%). 1H NMR (CDCl3, 300 MHz):  0.94, (6.5 Hz), CH3; 1.31,
m, methylene envelope; 1.89, m, CH2; 3.79-3.83, m, 2x OMe, OCH2; 4.04, m, OCH2; 6.46, m,
H4'; 6.63, m, H2',6'. ESI (+ve) MS: m/z 295 (M+H, 62%).

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Compound 42
pChloropropriophenone (250 mg, 1.48 mmol), propylene glycol (395 mg, 5.19 mmol) and a
catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in toluene (25 ml)
overnight in a Dean-Stark apparatus. The reaction mixture was then concentrated and the
residue dissolved in chloroform (50 mL) and washed with saturated sodium bicarbonate
solution (2x 25 mL) then brine (1x 25 rnL). The organic phase was dried (Na2SO4) and
evaporated to give a 2:1 diasteromeric mixture of 2-(4-chlorophenyl)-2-ethyl-4-methyl-1,3-
dioxolane (42) as an oil (329 mg, 98%). 1H NMR (CDCl3,300 MHz): 5 0.88, t (7.4 Hz),
CH2CH3 (minor); 0.92, t (7.4 Hz), CH2CH3 (major); 1.19, d (6.1 Hz), C4-Me (minor); 1.32, d
(6.0 Hz), C4-Me (major); 1.87, m, CH2CH3 (both); 3.27, t (8.0 Hz), H5 (minor); 3.53, t (7.2
Hz), H5 (major); 3.92, t (7.3 Hz), H5 (major); 4.05, app q (6.3 Hz), H4 (major); 4.20, dd (5.8,
8.1 Hz), H5 (minor); 4.33, m, H4 (minor), 7.3-73, m, 4xArH (both). ESI (+ve) MS: m/z244

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Compound 43
2-Fluoro-5-formylbenzonitrile (250 mg, 1.68 mmol), 2,2-diethyl-l,3-propanediol (776 mg,
5.87 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate were refluxed in
toluene (25 mL) overnight in a Dean-Stark apparatus. The reaction mixture was then
concentrated and the residue dissolved in chloroform (50 mL) and washed with saturated
sodium bicarbonate solution (2x 25 mL) then brine (1x 25 mL). The organic phase was
dried (Na2SO4) and evaporated to give an oil. The oil was then chromatographed on silica
gel (4:1 hexane/ ethyl acetate) to give 5-(5,5-diethyl-l,3-dioxan-2-yl)-2-
fluorobenzenecarborutrile (43) as a light yellow oil (401 mg, 91%). 1H NMR (MeOD, 300
MHz):  0.90, t (7.7 Hz), CH2CH3; 0.97, t (75 Hz), CH2CH3; 1.25, q (7.6 Hz), CH2CH3; 1.86, q
(7.6 Hz), CH2CH3; 3.72, d (11.5 Hz), CH2;4.02, d (11.4 Hz), CH2O; 5.52, s, H2; 7.42, t (9.3
Hz), H3; 7.86, m, H4,6. ESI (+ve) MS: m/z 264(M+H, 11%).

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Compound 44
p-Chlorobenzoic acid (05 g, 3.19 mmol) was suspended in thionyl chloride (25 mL) and
refluxed overnight. The excess thionyl chloride was removed in vacuo to furnish the acid
chloride as a light brown solid. The solid was then dissolved in dichloromethane (25 mL),
cooled on an ice bath and ethanolamine (0.40 mL, 6.4 mmol) added to the mixture,
followed by the addition of triethylamine (2.3 mL, 16 mmol) and the mixture was then
stirred overnight at room temperature. The mixture was then diluted with chloroform (50
mL) and washed with 1M hydrochloric acid (2x 25 mL) and brine (1x 25 mL) before
concentrating the solvent to give the crude amide as an oil, which solidified to an off-white
solid. Without further purification the crude amide was then dissolved in ethyl acetate (10
mL) to which was added dropwise, a solution of thionyl chloride (0.7 mL, 6.4 mmol) in
ethyl acetate (3 mL) and the mixture stirred overnight at room temperature before
concentrating to furnish the solid chloro-amide. After dissolving in dichloromethane (10
mL) and addition of DBU (1 mL, 6.4 mmol) the mixture was refluxed overnight
Concentration of the solvent and flash chromatography of the resulting gum furnished 2-
(4-chlorophenyl)-4,5-dihydro-l,3-oxa2ole (44) as a white crystalline solid (327 mg. 56 %
overall yield).
1H NMR (d4-MeOH 300 MHz): 8 409, t (9.6 Hz), H4; 4,57, t (95 Hz), H5; 7.54, d (8.6 Hz),
2xArH; 7.95, d (8.6 Hz), 2xArH. ESI (+ve) MS: m/z 182/184 (M+H, 100%/32%).

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Compound 45
p-Toluic acid (05 g, 3.67 mmol) was suspended in thionyl chloride (25 mL) and refluxed
overnight. The excess thionyl chloride was removed in vacuo to furnish the acid chloride
as a light brown solid. The solid was then dissolved in dichloromethane (25 mL), cooled
on an ice bath and ethanolamine (0.45 mL, 73 mmol) added to the mixture, followed by the
addition of triethylamine (2.6 mL, 18.4 mmol) and the mixture was then stirred overnight
at room temperature. The mixture was then diluted with chloroform (50 mL) and washed
with 1M hydrochloric acid (2x 25 mL) and brine (1x 25 mL) before concentrating the
solvent to give the crude amide as art oil, which solidified to an off-white solid. Without
further purification the crude amide was then dissolved in ethyl acetate (10 mL) to which
was added dropwise, a solution of thionyl chloride (0.8 mL, 7.3 mmol) in ethyl acetate (3
mL) and the mixture stirred overnight at room temperature before concentrating to give
the chloro-amide as a brown solid. After dissolving in dichloromethane (10 mL) and
addition of DBU (11 mL, 7.3 mmol) the mixture was refluxed overnight Concentration of
the solvent and flash chromatography of the resulting gum furnished 2-(4-methylphenyl)-
4,5-dihydro-l,3-oxazole (45) as a white crystalline solid (236 mg, 40 % overall yield).
1H NMR (d4MeOH, 300 MHz); 5 2.45, s, Me; 4.07, t (9.6 Hz), H4; 4.54, t (9.5 Hz), H5; 7.33, d
(7.9 Hz), 2xArH; 7.86, d (7.9 Hz), 2xArH. ESI (+ve) MS: m/zl62 (M+H, 100%).

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BIOLOGICAL EXAMPLES
Biological Example 1: MIF-induced human fibroblast proliferation.
Methods
The activity of a compound of formula (I) was studied in a bioassay utilising MIF-induced
proliferation of human dermal fibroblasts. The proliferation of human fibroblasts has been
demonstrated to be a phenomenon inducible by MIF(16). S112 human dermal fibroblasts
were propagated in RPMI/10% foetal calf serum (FCS). Prior to experimentation, cells were
seeded at 105 cells/ml in RPMI/0.1% BSA for 18 hours. Cells were treated with
recombinant human macrophage migration inhibitory factor (MOP) 50 ng/ml and/ or a
compound of the invention at a concentration of 1 nM. The compound was combined with
MIF at time point -30 minutes, prior to adding to cell culture at time point zero. At time
point zero, culture medium was replaced with RPMI/10% FCS and treatments
administered. At time point 30 hours, cells were pulsed with 1 Ci 3H-thymidine. At time
point 48 hours, cells were harvested using a semi-automated cell harvester. The
radioactivity incorporated into DNA was determined by liquid scintillation counting, with
results expressed as 3H-thymidine incorporation.
Significant inhibition of MIF-induced proliferation was determined by the demonstration
of a significant P value (P Results
2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-dioxolane (Compound 1) (cpd 1),
when used in the method above, significantly inhibited the induction of S112 human
fibroblast proliferation (P MIF (+MIF) induced proliferation, but this was prevented by pre-incubating MIF with
Compound 1 (1 nM) (+MIF +cpd 1) (*P compounds exerting inhibitory effects on the biological activity of MIF.

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Table 1.
Untreated cells MIF-treated cells MIF-treated cells +
cpdl at 1 nM
Mean (cpm) 3245 4415 2994*
Standard error 393.1 403.5 410.7
Number of
experiments 9 9 9
* P Biological Example 2: MIF-dependent IL-1 induced fibroblast cyclboxygenase-2
expression.
Methods
The activity of the compounds of formula (I) were further studied in a bioassay utilising
MIF-dependent activation of human dermal fibroblasts. Sampey et al have shown that
induction of the expression of cyclooxygenase-2 (COX-2) by the cytokine interleukin 1 (IL-
1) is dependent upon the presence of MIF, i.e. can be prevented using specific anti-MIF
monoclonal antibody(17). IL-1-induced COX-2 expression is therefore a MIF-dependent
event
S112 human dermal fibroblasts were propagated in RPMI/10% foetal calf serum (FCS).
Prior to experimentation, cells were seeded at 2x105 cells/ml in RPMI/0.1% BSA for 18
hours, Cells were treated with compound at 1-100 uM and 30 minutes later with
recombinant human IL-1 (0.1 ng/ml). After 6 hours, cells were collected and intracellular
COX-2 protein determined by permeabilisation flow cytometry, as described by Sampey et
al(18). Cells permeabilised with 02% saponin were sequentially labelled with a mouse anti-
human COX-2 monoclonal antibody and with sheep-anti-mouse F{ab)2 fragment labelled
with fluorOseein isothiocyanate. Cellular fluorescence was determined using a flow
cytometer. At least 5000 events were counted for each reading, each of which was
performed in duplicate, and the results expressed in mean fluorescence intensity (MFI)
after subtraction of negative control-labelled cell fluorescence.
In Table 2 and Figure 2, the effect of each concentration of 2-(2-hydroxyethoxy)-2-(4-
hydroxy-3-methylphenyl)-l,3-dioxolane (Compound 1) was determined by subtracting the
IL-1+compound-treated cell MFI from the IL-1-treated cell MFI, and expressed as %

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inhibition. Significant inhibition of IL-induced COX-2 expression was determined by the
demonstration of a significant P value (P Results
As shown in Figure 2, cells treated with Compound 1 exhibited a significant reduction in
COX-2 expression as measured by flow cytometry (P inhibition of the induction of COX-2 expression by IL-1 in human S112 fibroblast cells was
demonstrated when cells were treated with Compound 1 (cpd 1) 50 M (*P As shown in Table 2 and Figure 3, cells treated with 2-(2-hydroxyethoxy)-2-(4-hydroxy~3-
methyIphenyl)-l,3-dioxolane (Compound 1) exhibited a dose-dependent reduction in
COX-2 expression as measured by flow cytometry. These data are consistent with these
compounds exerting inhibitory effects on the biological activity of MIF.

Table 2.
Concentration of
Compound 1
(M) Mean%
inhibition COX2
expression Standard error Number of experiments
0.01 10.5 9.6 4
0.1 13.2 9.5 4
1 15.6* 8.1 4
10 19.5* 3.9 6
50
*P In Figure 4, the effect of 2-(2-hydroxyethoxy)-2-(4rhydroxyphenyl)-l,3-dioxolane
(Compound 2) is expressed as mean fluorescence intensity (MFI), after deducting the MFI
of control-labelled cells. Significant inhibition of IL-induced COX-2 expression was
determined by the demonstration of a significant P value (P Significant inhibition of IL-induced COX-2 expression in human S112 fibroblast cells was
demonstrated in cells treated with Compound 2 (IL-l+cpd2) compared to cells treated with
IL-1 (*P
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Biological Example 3: MIF-dependent antigen-specific T cell activation.
Methods
The activity of compounds of formula (I) was further studied in a bioassay utilising MIF-
dependent activation of murine T cell activation. The activation of T lymphocytes in
response to exposure to a recall antigen is known to be dependent on the presence of MIF,
i.e. can be prevented using specific anti-MIF monoclonal antibody(7). Antigen-induced T
cell activation is therefore a MIF-dependent phenomenon.
Splenocytes were obtained by Hank's buffered saline flushing of spleens obtained from
C57B1/6 mice previously immunized with methylated bovine serum albumin (mBSA,
Sigma Chemical Co., Castle Hill Australia). Mice were immunized on day 0 with 200 g
mBSA emulsified in 0.2 ml of Freund's complete adjuvant (FCA) injected subcutaneously
into the flank skin. On day 7, the mice received 100g mBSA/0.1,ml FCA by intradermal
injection at the base of the tail. Spleens were removed on day 14 after first immunisation
and a single cell suspension was prepared in DMEM containing 5% FCS and 0,05% 2-
mercaptoethanol. 1 x 105 cells /2001 were cultured in triplicate in the presence of mBSA (10
g /ml) with or without the addition of 2-(2-hydroxyethoxy)-2-(4-hydroxyphenyl)-l,3-
dioxolane (Compound 2) at a concentration of 100 nM -10 M, 30 minutes before the
addition of mBSA- The T cell proliferation response was determined by measuring the
amount of [3H] thymidine incorporation during the final 18 hr. The cells were harvested
and radioactivity incorporation into the DNA was measured with a Wallac 1409 liquid
scintillation counter (Pharmacia, Turku, Finland). Significant inhibition of T cell activation
was determined by the demonstration of a significant P value (P test
Results,
Treatment of spleen cells with 2-(2-hydroxyethoxy)-2-(4rhydroxyphenyI)-l,3-dioxolane
(Compound 2) (cpd2) resulted in a significant dose-dependent reduction in antigen-specific
T cell activation, compared to cells exposed to mBSA without Compound 2 (*P (Figure 5). These data are consistent with these compounds exerting inhibitory effects on
the biological activity of MIF.

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Biological Example 4: Combination of MIF-antagonist with glucocorticoid;
effects on MIF-dependent IL-1 induced fibroblast
cyclooxygenase-2 expression.
A particular aspect of the biological function of MIF relates to its ability to antagonise the
anti-inflammatory effects of glucocorticoids such as dexamethasone, as recently reviewed
by Morand et al.(4). This property of MIF suggests that MIF antagonists might exert
"steroid-sparing" effects, that is, their use in combination with glucocorticoids might
permit the achievement of a greater therapeutic effect with a given dose of glucocorticoids.
Thus, in the presence of MIF antagonists, low doses of glucocorticoids could exert a
therapeutic effect otherwise requiring a higher dose of glucocorticoids. As the adverse
effects of glucocorticoids are in general dose-dependent the ability to reduce the
requirement for glucocorticoids is clinically desirable.
The potential for a MIF antagonist to be '"steroid-sparing", therefore, could be
demonstrated by the observation of enhanced effectiveness of a given dose of
glucocorticoids in the presence of a MIF antagonist.
Methods
The above in vitro assay (Biological Example 2) for analysing the effect of MIF antagonists
on IL-1 induced COX-2 expression was performed using 2-(2-hydroxyethoxy)-2-(4'-
hydroxy-3'-methylphenyl)-1,3-dioxolane (Compound 1) (50 M), dexamethasone (1 M) or
a combination of dexamethasone (1 M) and Compound 1 (50 M), COX-2 expression was
expressed as the mean fluorescence intensity (MFI) as measured by flow cytometry, after
deduction of the MFI for control-labelled samples, as described by Sampey et al.(18). The
results are shown in Table 3 and Figure 6.
Results
Significant enhancement of the inhibitory effects of the glucocorticoid dexamethasone was
determined by the demonstration of a significant P value (P compared to the effect of dexamethasone alone, Compared to the inhibition of IL-1-
induced COX-2 expression achieved with 1 M dexamethasone alone (IL-1+DEX), a
significantly greater inhibition of IL-1-induced COX-2 expression was observed when cells
were treated with 1 nM dexamethasone together with Compound 150 M (IL-
1+DEX+cpdl) (P inhibitory effects on the biological activity of MIF.

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Table 3.
Control IL-1 IL-1 + DEX IL-1+DEX+cpdl
MeanCOX-2
expression
(MFI) 0.7400 49.37 15.13 6.013*
Standard
error 0.4413 2.412 1.770 2.906
N 4 4 4 4
*P Biological Example 5; Lack of cytotoxicity.
A valuable characteristic of a therapeutic material is a lack of toxicity. The compounds of
formula (I) may have low toxicity towards cells. To examine this in vitro, the ability of 2-(2-
hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-1,3-dioxolane (Compound 1) to induce
apoptosis ("programmed cell death) was investigated. A lack of cytotoxicity would be
evidenced by the finding of equivalent proportions of apoptotic and viable cells in control-
and compound-treated cells.
Methods
To examine the cytotoxicity of compounds of formula (I), S112 human dermal fibroblasts
were exposed to a therapeutic concentration (50 M) of
2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l,3-dioxolane (Compound 1) or
vehicle (control) and analysed for apoptosis by flow cytometric analysis of annexin V and
propidium iodide staining, as described by Leech et al,(19), Toxicity was assessed by
analysis of apoptosis using flow cytometric detection of cell surface Annexin V binding and
propidium iodide staining. At least 5000 events were analysed for each experiment. Cells
positive for both Annexin V and propidium iodide were designated as'apoptotic and cells
negative for both Annexin V and propidium iodide were designated as viable. Results are
expressed as the percentage (%) of cells with each of these labels.
Results.
The results of cytotoxicity analysis are shown in Figure 7. No significant increase (ns) in
apoptotic cell numbers, and no significant decrease (ns) in viable cell numbers, was

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observed in cells treated with
2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-1,3-dioxolane(Compoundl)
compared to control-treated cells.
Biological Example 6: MIF-dependent nitrite production in peritoneal
macrophages
MIF is able to induce or facilitate the expression and release of a wide variety o£ pro-
inflammatory and/ or destructive molecules, including the release of macrophage nitric
oxide (NO)(20). A compound with the ability to inhibit the cytokine or biological function of
MIF might be expected to inhibit the activation of NO production by macrophages.
Methods
C57BL6/J male mice were injected intraperitoneally with 2ml of thioglycolate. Three days
later peritpneal macrophages were collected by lavaging the peritoneum with 3ml of cold
Hank's buffered saline solution. Cells from several mice were pooled, washed and re-
suspended in DMEM supplemented with 5%FCS, Cells were plated in 96 well plastic tissue
culture plates at 1x105 cells/well. Cells were treated in triplicate wells with compound or
vehicle for 1 hour in a 5% CO2 incubator at 37 °C. Cells were then treated with LPS (10
ng/ml) and recombinant human interferon- (10 units/ ml) and incubated for 24 hours.
After 24 hours, 50 l of supernatant from each well was carefully removed and transferred
to ELISA plates. The production of NO was measured by analysing the concentration of
nitrite in culture supernatants, as measured by the Greiss assay(21). The results were
calculated as the percentage inhibition of nitrite concentration in compound-treated cell
culture supernatants, compared to that of vehicle-treated cells.
Results
Treatment of cells with l-(3-Methylbutyl)-4-(4-methylphenyl)-1H-pyrazole (Compound 13)
0.5 -100 M resulted in a dose-responsive inhibition of LPS-IFN-induced nitrite
production (Figure 8).
Table 4 displays the results for other compounds tested in this assay. Marked reductions in
nitrite concentration were observed in the supernatants of cells treated with thee
compounds. These data are consistent with these compounds exerting inhibitory effects on
the biological activity of MTP.

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Significant inhibition of nitrite production was determined by the demonstration of a
significant P value (P
TABLE 4
Compound % Inhibition of nitrite
(±SD) Compound concentration
(MM)
4 22±1* 100
5 22±2 100
7 15±1 100
9 16±1 1
11 19±1* 33
12 78±9* 100
13 91±8* 100
14 27±3* 100
15 12±1* 100
17 69±2* 100
18 40±1 100
24 21±2* 33
25 7±1 33
27 24±1* 100
29 9±1* 100
30 31±2* 100
31 35±3* 100
32 14±4 100
33 47±4* 100
34 24±1 100
35 18±2* 100

WO 2004/089927 PCT/AU2004/000453
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36 57±1 100
37 24±1* 100
38 35* 100
40 7±2 100
41 26±1* 100
43 34±1* 100
45 7±1 100
*F Biological Example 7: MIF-induced proliferation in mouse fibroblasts
Methods
The activity of compounds was studied in a bioassay utilising MIF-induced proliferation of
mouse NIH 3T3 fibroblasts. The proliferation of NIH3T3 fibroblasts has been demonstrated
to be a phenomenon inducible by MIF(22), and MIF-induced proliferation has been linked to
the pathology of diseases such as rheumatoid arthritis (16) NIH 3T3 cells were propagated
in DMEM/10% foetal calf serum (FCS). Prior to experimentation, cells were seeded at 104
cells/ well in 96-well plates in DMEM/10% FCS for 18 hours. The media was then replaced
with DMEM/0.1% FCS and the cells incubated for a further 18 hr. At time point -1 hr,
culture medium was replaced with DMEM/0.1% FCS and cells were treated with a
compound of the invention at a final concentration of 10 M or vehicle. At time point zero,
cells were treated with MIF at a final concentration of 50 ng/ml. At time point 6 hr the cells
were pulsed with 1 Ci/we11 of 3H-thymidine. At time point 24 hours, cells were harvested
using a semi-automated cell harvester. The radioactivity incorporated into DNA was
determined by liquid scintillation counting, with results expressed as 3H-thymidine
incorporation (cpm). Statistical significance was analysed using the Mann-Whitney test.
Results
Compounds of the invention were inhibitory of MIF-induced proliferation. Treatment of
cells with MIF induced a significant increase in proliferation (P = 0.006). Treatment with
2-Methyl-2-(4-methylphenyl)-l,3-dithiolane (Compound 18) 10 M resulted in significant
inhibition of MIF-induced proliferation (*P treatment of cells with MIF again induced a significant increase in proliferation (P = 0.004).

WO 2004/089927 PCT/AU2004/000453
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Other compounds of the invention resulted in significant inhibition of MIF-induced
proliferation (*P Table 5 displays the results for other compounds tested using this methodology.
Reductions in MIF-induced proliferation were observed in cells treated with all
compounds listed; where indicated these results were statistically significant. These data
are consistent with these compounds exerting direct inhibitory effects on the biological
activity of MIF.

TABLE 5
Mean cpm Std. Error P value (compared
to nil)
nil 1087 48.04
MIF + vehicle 1452 60.15 0.006
Compound (10x10-6M) Mean cpm Std. Error P value (compared
to MIF + Vehicle)
7 1281 108.1
3 1238 95.07
9 1071 8958 0.0253
10 1187 60.35 0.0257
11 1245 185.1
13 1015 60.51 0.0253
14 1420 93
15 955.6 88.32 0.0253
16 1335 159.6
17 933.2 216.5 0.0253
19 1209 51.21 0.0257
20 1214 8757 0.0485

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21 1220 107.2
22 1310 1671
23 1344 126.8
24 1318 139.3
25 1117 101.4 0.0253
26 1141 125.2 0.0356
28 1219 46.09 0.0364
29 1157 192.4
32 1196 98.5 0.0485
36 1033 35.98 0.0364
37 1045 11.19 0.0364
39 956.1 102.6 0.0253
40 1143 30.89 0.0364
42 1168 99.8
43 1106 106.4 0.0116
44 1294 32.62 0.0485
Biological Example 8: Mouse endotoxic shock model
The activity of compounds was studied in the murine endotoxic shock model. In this
model, features of shock, characterised by increased serum levels of cytokines such as IL-1,
tumor necrosis factor (INF), and interleukin 6 (IL-6), are induced by the injection of
bacterial lipoloysaccharide (LPS). The in vivo produetion of IL-1, IL-6, and TNF in response
to endotoxin has been previously shown to-be dependent on MIF(23). Treatment of mice
with a compound with inhibitory effects on the biological or cytokine activity of MIF could
be expected to produce inhibition of serum IL-1, TNF, and/or IL-6 levels.
Methods
Groups of four mice were used in each experiment Endotoxaemia was induced by intra-
peritoneal injection of lipopolysaccharide (LPS) (5 mg/kg) in 300 l saline. Mice injected

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with saline alone were used as a control group. Treatments were administered by intra-
peritoneal injection at intervals 24 hours and 1 hour before intra-peritoneal LPS injection.
Mice were treated with saline, compounds dissolved in DMSO/saline vehicle at a dose of
5-15 mg/kg body weight, or vehicle (containing matching concentrations of DMSO).
After 1.5 hours mice were humanely killed by CO2 inhalation then neck dislocation.
Serum was obtained from blood obtained by cardiac puncture prior to death and measured
for the concentration of cytokines including IL-1, TNF, and/or IL-6, by ELISA. Statistical
significance was analysed using the Mann-Whitney test.
Results
Treatment with 2-Hexyl-2-(4-methylphenyl)-l,3-dithiolane (Compound 17) was assessed.
The mean ± standard error of serum IL-1, IL-6, and TNF concentrations at a time-point 1.5h
after administration of LPS are presented in Figure 10. Compared to saline, LPS injection
induced a significant cytokinaemia for each of IL-1, IL-6, and TNF (P 2-Hexyl-2-(4-methylphenyl)-l,3-dithiolane (Compound 17) (shown as cpd 17) at 5 and 15
mg/ kg (as shown in brackets) was associated with marked inhibition of LPS-induced
serum IL-1 (Figure 10a), IL-6 (Figure 10b), and TNF (Figure 10c). In the case of IL-1, the
inhibition was statistically significant (*P compound exerting inhibitory effects on the biological activity of MIF.
The effect of additional compounds is presented in Table 6, in which the mean ± standard
error of serum IL-1, IL-6, and TNF concentrations are presented.
4-(4-Methoxyphenyl)-1-(3-methylbuty)-1H-pyrazole (Compound 12),
l-(3-Methylbutyl)-4-(4-methylphenyl)-1H-pyrazole (Compound 13), and
2-(4-Thien-2-ylphenyl)-l,3-oxathiolane (Compound 33) were tested. An inhibitory effect of
treatment with Compounds 12,13, and 33 on serum IL-1 was observed at a dose of 5
mg/kg. An inhibitory effect of treatment with Compounds 12,13, and 33 on serum IL-6
and TNF was observed at a dose of 15 mg/kg. These data are consistent with these
compounds exerting inhibitory effects on the biological activity of MIF.


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TABLE 6
Cytokine Saline UPS plus
vehicle Compound
12
5 mg/kg Compound
13
5 mg/kg Compound
33
5 mg/kg
IL-1 (pg/ml) 175 ± 43 428 ±168 286 ±102 305±51 360 ±72
Cytokine Saline LPS plus
vehicle Compound
12
15 mg/kg Compound
13
15 mg/kg Compound
33
15 mg/kg
rL-6(ng/ml) 4±4 118 ±30 80 ±16 92±7 95±14
TNF(pg/ml) 189 ±69 2022 ±1245 1636 ± 468 1067 ±191 1152 ±317


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References
(1) David, J. Proc. Nail. Acad. Sd., USA, (1966), 56,72-77.
(2) Weiser, W.Y., et al., Proc. Natl. Acad. Sri., USA, (1989), 86,7522-7526.
(3) Leech M, Metz-CN, Smith M, Weedon H, Holdsworth SR, Bucala R, et al.
Macrophage migration inhibitory factor (MtF) in rheumatoid arthritis: Evidence for
pro-inflammatory function and regulation by glucocorticoids. Arthritis &
Rheumatism 1999; 42:1601-1608.
(4) Morahd EF, Bucala R, Leech M. Macrophage migration inhibitory factor (MIF): An
emerging therapeutic target in rheumatoid arthritis. Arthritis & Rheumatism 2003;
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(5) Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, et al. MEF as
a glucocorticoid-induced modulator of cytokine production. Nature 1995; 377:68-71.
(6) Donnelly SC, Haslett C Reid PT, Grant IS, Wallace WAH, Metz CN, I. Regulatory
role for macrophage migration inhibitory factor in acute respiratory distress
syndrome. Nature Medicine 1997; 3:320-323.
(7) Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, et al. An essential
regulatory role for macrophage migration inhibitory factor in T-cell activation.
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(8) Santos LL, Hall P, Metz CN, Bucala R, Morand EF. Role of macrophage migration
inhibitory factor (MIF) in murine antigen-induced arthritis: Interaction with
glucocorticoids. ain.Explmrnunol. 2001; 123:309-314.
(9) Leech M, Santos LL, Metz C, Holdsworth SR, Bucala R, Morand EF. Control of
macrophage migration, inhibitory factor (MIF) by endogenous glucocorticoids in rat
adjuvant arthritis. Arthritis & Rheumatism 2000; 43:827-833.
(10) Bucala R. MIF rediscovered: cytokine, pituitary hormone, and
glucocorticoid-induced regulator of the immune response. FASEB J. 1996;
10:1607-1613.
. (11) Sabroe I, Pease JE, Williams Tj, Asthma and MIF: innately Thl and Th2. Clin Exp
Allergy 2000; 30(9):1194-6.

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(12) Eur. J. Med. Chem - Chim. Ther., 17(3), 235-43, (1982).
(13) Synthetic Communications, 30(6), 1083-1094, (2000).
(14) J. Am. Pharm. Assoc, 38,9-11, (1949).
(15) J. Org. Chem., 63 (12), 4116-4119, (1998).
(16) Lacey D, Sampey A, Mitchell R, Bucala R, Santos L, Leech M. Morand EF. Control
o£ fibroblast-like synoviocyte proliferation by macrophage migration inhibitory
factor (MIF). Arthritis Rheum 48:103-9,2003.
(17) Sampey A, Hall P, Morand EF. Regulation of Synoviocyte FLA2 and COX2 By
Macrophage Migration Inhibitory Factor. Arthritis Rheum 44:1273-1280,2001.
(18) Sampey A, Morand EF. Annexin I inhibition of human synoviocyte phospholipase
A2 but not cydooxygenase-2 activity. Mediators of Inflammation 9:125-132,2000.
(19) Leech M, Lacey D, Xue JR, Santos t, Hutchinson P, Wolvetang E, David JR, Bucala
R, Morand EF. Macrophage migration inhibitory factor (MIF) regulates p53 in
inflammatory arthritis. Arthritis Rheum 2003.

(20) Jurtner S, Bernhagen J, Metz CN, Rollihghoff M, Bucala R, Gessner A. Migration
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(21) Santos LL, Morand EFy Holdsworth SR. Suppression of adjuvant arthritis and
synovial macrophage inducible nitric oxide by N-iminoethyl-1-ornithine, a nitric
oxide synthase inhibitor. Inflammation 1997,-21:299-311.
(22) Mitchell RA, Metz CN, Peng T, Bucala R. Sustained mitogen-activated protein
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CLAIMS
1. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof

wherein X and X' are independently selected from -CR5)2 -O-, -S-, -N(R5)-, or
taken together form -C(R5)=C(R5)- ,-C(R5)=N-, -N=C(R5)-, -N(R5)-N(R5)-or- or -N=N-;
Y and Y' are independenily selected from -C(R5)2 -,-O-, -S-, -N(R5)-, or taken
together form-C(R5)=C(R5), -C(R5=N-, -N=C(R5)-,-N(R5)-N(R5)- or-N=N-;
Z is -C(R5)2-V, -O-, -S- or -N(R5)-, or forms a covalent single or double bond between
X' and Y', or 2 together with X' or Y' forms -C(R5)=C(R5) -C(R5)=-N-, -N=0(R5)-,
-N(R5)-N(R5)-or-N=N-;
wherein when Z is -O-, -S- or -N(R5)-,X' and Y' are -C(R5)2-;
when X is -O-, -S- or -N(R5)-, X' is -C(R5)2-;
when Y is -O-, -S- or -N(R5)-, Y' is -C(R5)-; or
X or Y together with the carbon atom bearing the phenyl group form a double bond
wherein which ever of X or Y forms part of the double bond is selected from -C(R5)-
and -N-;
R1 is selected from hydrogen/ C1-20alkyl, C2-20.alkenyl, C2-20alkynyl, (A)nC(O)R6,
(A)nC(S)R6 (A)nS(O)R6 (A)nS(O)2R6, (A)nOR7/ (A)nSR7, (A)nN(R8), (A)nC(=NR9,)R10 and

WO 2004/089927 PCT/AU2004/000453
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(A)nRn, or when X or Y together with the carbon atom bearing the phenyl group
form a double bond, R11 is absent;
R2 and R4 are independently selected from hydrogen, C1-3alkyl and (A)mR12i;
R3 is selected from C1-3alkyl (A)mR12, (A)maryl and (A)mheterocyclyl;
Rs is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2.20alkynyl, (A)nC(O)R6'
(A)nC(S)R6 (A)n.S(O)R6, (A)nS(O)2R6 (A)nOR, (A)nSR, (A)ppN(R8), (A)nC(=NR9)R10 and
(A)nR11
R6 is selected from hydrogen, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, OH, OC1-20aIkyl,
OC2.10alkenyl, OC2_10alkynyI, O(A)R SH, SC1-20alkyl, SC2.10alkenyI, SC2-20alkynyl,
S(A)qR11, N(R13)2, [NH-CH(RI4)C(O)]rOH, [NH-CH(R14)C(O)]fl-OC1.3alkyl/ [sugar],
and (A)qR11;
R7 is selected from hydrogen, C2-20fiSkyl, Q^oalkenyl, C2.aoalkynyl, (A)qRn, C{O)H,
C(O)Cx.walkyI, CCOCHoalkenyl C(O)Q.10aIkynyl C(O)-aryl C(OXA),Rtl/ C(O)2H,
C(O)A-i0alkyl CCO^CwoaUcfinyl, C(O)2CM0aikynyl C(O)2-aryI, OPUA^ C(S)H,
C(S)CMOalkyl, C(S)Q.IQalkenyl, C(S)CMoaBcynyl, C(S)-aryl asXA)^,, C(S)OH,
C(S)OCMOalkyi CtSPCMoalkenyl C(S)OC2.10alkynyl, C(S)O-aryl, as^A^Rn,
S(Om, StOXCMoalkyiS^A-ioalfcenyl StOXq^alkynyl/SCOr^ryLSfOXCA)^,,
[CCOjCHCRuJNHlrH [aojCHCRxJNI-fl.-CMoalkyl, [qOCHCR^NHL-Q^alkenyl
[C(O)CH(R14)NH|a-C2.10alkyny], [qOjCHtR^NHl^aryl [C(O)CH(R14)NH]a-(A)11Ru
and [sugar],,;
each Rs is independently selected from R? and NHC(==NRiS)NH2;
R9 is selected from hydrogen and C^alkyl;
R10 is selected from C^alkyl, NH^ NHfC^alkyl), NCCLgalkyDi, OH, OC^alkyl, SH
and SC^alkyl;
Rn is selected from OH, OC^alkyl, OQ.galkyl-O-Q.aalkyl O-aryl, O-heterocydyl,
OrCCOICHCR^NH]^, tsugaxL SH, SQ^alkjd, SCMalkyI-O-Cwa!kyL S-aryl,
S-heterocydyl, SLCtOjCHfR^NHJsH, halo, N(R15)2, C(O)Ri6, CN, CfR^j, aryl and
heterocydyl;
Ru is selected from OH, SH NHa, halo, NOj, C(R17)3, OC(R17)3 and CN;

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each R13 is independently selected from hydrogen, Q.6alkyl, Q^alkenyl, Q^alkynyl
and (A)qRn;
Ru is the characterising group of art amino acid;
each R15 is independently selected from hydrogen, Q^alkyl, CLsalkoxyC^alkyl, aryl
and heterocydyl;
R16 is selected from C^alkyl, OH, Q^alkoxy, aryl, aryloxy, heterocydyl and
heterocydyloxy;
each Ri? is independently selected from hydrogen and halogen;
A is optionally substituted methylene wherein when n > 1, any two adjacent A
groups are optionally interrupted by -O-, -S- or -NfRos)-;
where n is 0 or an integer selected from 1 to 20;
m is 0 or an integer selected from 1 to 3;
p is an integer selected from 1 to 20;
q is an integer selected from 1 to 10
s is an integer selected from 1 to 5;
t is an integer selected from 1 or 2; and
wherein each alkyl, alkenyl, alkynyl, aryl and heterocydyl may be optionally
substituted.
A compound according to daim 1 of formula (n), or a pharmaceuticaliy acceptable
salt or prodrug thereof

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114

wherein X and Y are independently selected from --O-, -S-, -NCRj)- and -C(Rg)2-;
Z Is ~C(R5)2- or is a covalent bond between adjacent methylene groups;
Rj is selected from hydrogen, Q^alkyl, Cj^alkenyl, C^^alkynyl/ (A)nC(O)R6y
(A)»C(S)R* (A)nS(O)R^ (A^OjA, (AX.OR,, (A^SR* (A)nN(Rg), (A)nC(«NR,)RM and
(A)nRli;
R2 and R4 are independently selected from hydrogen, C^alkyl and (AJ^R^-
K3 is selected from C^alkyl, (A)mRj2, (A)maryl and {A)mheterocydyl;
Es is selected from hydrogen, Ciaalkyl, Q^alkenyl, Czzaaikynyl, (A)nCfO)Rtf,
(A)nC(S)R^ (A)nS(O)Re, (A^SfO)^ (A^OR,, (A^SR,, (A)^), (A)nC(-NR9)R10 and
(A)nRn;
Rfi is selected from hydrogen, Cj.^alkyl, C2.20alkenyI, Ca-zoalkynyl, OH, OCMOaIkyl,
OQ.^alkenyl, OQ^oalkynyl, O(A)qRn/ SH, SC^oalkyl SQ.loalkenyl SCMOalkynyl,
SCA)^, N(R13)> ENH-CHCR:4)C(O)]g-OH, [NH-CHOR^CCOJL-OC^alkyl [sugar]s
and (AjqRn;
R7 is selected from hydrogen, Q.20alkyl, Qi-aalkenyly Cj-aoalkynyl, (A)qRiV C(Q)H,
C(O)CM0alkyi aOJQ^alkenyl, C(O)CM0alkynyl, C(O)-aryl qOXA)^ C(O)2H,
C(O)2C].10alkyl/ C{0)2C2-ioalkenyI, CfOJA-ioalkynyL CfOVaryl, CtO^AJ^R^ C(S)H,
C(S)CMoalkyl CiS^roaikenyi C(S)Q.10alkynyl C(S)-aryl, C(S){A\Rnr C(S)Oa
C{S)OClA{^kylr C(S)OC2.ualkenyl C(S)OQ.10alkynyl C(S)O-aryl, aslOCA^u,
SfOJtH, S(O)tCW0alkyI, S(0)tC2-ioaIkenyl, S(0),CMoalkynyL S(O)raryl SfQ^A)^

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IC(O)CH(R«)KHL-a [CCOjCHfR^NHl-CMoalkyl, [CCOCHtR^NHL-C^alkenyl,
[C(O)OHCR,4)NHI1-Ct,flalkynyl [C(O)CH(RM)NHli-atyL [aOCHORj^NHL-tA)^
and [sugar],;
each Rg is independently selected from R? and NHC(=NRi5)NH2;
R9 is selected from hydrogen and Chalky!;
R1B is selected from C^alkyl, NH^ NH(C,^alkyI), NCQ^alkyl)^ OH, OC^alkyl, SH
and SCi.3alkyl;
Ru is selected from OH, OC^alkyl, OC^alkyl-O-C^alkyl O-aryl, O-heterocydyl,
O[C(O)CH(RM)NHLHt, [sugar],, SH, SC^ky!, SC,_3alkyl-O~Q.3alkyI, S-aryl,
S-heterocyclyl, S[C(O)CH0Ru)NMtFi halo, NtR^ C(O)R16, CN, Cmn)y aryl and
heterocydyl;
RK is selected from OH, SH, NH^ halo, NO2, C(R17)3, OC(R17)3 and CN;
each Ro is independently selected from hydrogen, C^alkyl, Q6alkenyl, C2^alkynyl
and (A)qRn;
RH is the characterising group of an amino add;
each R15 is independently selected from hydrogen, Cwalkyl, Cj.galkoxyd.aalkyt aryl
and heterocydyl;
R16 is selected from C^alkyl, OH, C^alkoxy, aryl, aryloxy, heterocydyl and
heterocydyloxy;
each R17 is independently selected from hydrogen and halogen;
A is optionally substituted methylene wherein when n > 1, any two adjacent A
groups are optionally interrupted by -G-, -S- or ~N(RH)~;
where n is 0 or an integer selected from 1 to 20;
m is 0 or an integer selected from 1 to 3;
P is an integer selected from 1 to 20;
q is an integer selected from 1 to 10

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s is an integer selected from 1 to 5;
t is an integer selected from 1 or 2; and
wherein each alkyl, alkenyl, aBcynyi aryl and heterocydyl may be optionally
substituted.
3, A compound according to claim 2 wherein
X is -O, -S-, -NH- or -CH2-;
Yis-O-,-S-or-NRr;
Z forms a covalent bond between adjacent methylene groups;
R! is selected from C^oalkyJ, C1.20alkenyl, O-{A)qO-Cj^alkyl, 0-(A)q-heterocydyl,
O-(A)q-sugar, O-(A)qO[C(O)CH(Ru)NH]fl-H, (A)ROH, (A^OC^alkyl
(A)nOQ.2Dalkenyl (A^OqOK^alkyL (A^OCCOQ^alkenyl, (A)nOC(O)aryl
(A)nO[C(O)CH(Ru)NH]s-H (A)nO[sugar)y (A)nNHQ.20alkyl (AWC^alkyl)^
(A)nNHCwoalkenyl, (A^C^alkenyl)^ (AjJ^JHCtOiC^aikyl
(A)llNHC(O)C1.2Dalkenyl/ (A)nNHC(O)aryl, (A)nNH[C(O)GH(R14)NH]a-H/
(A)^4sugar^(A)nSO3Hv(A)nSO3C1.2^kyl,(A)nSO3C1.20alkenyl/
(A)nC(O)Q.20alkyl (AJ^fOjC^alkenyl (A^CCVH, (A)nCO2CVMalkyl,
(A^COjC^alkenyl, (A)nC(O)NHCW0alkyl (A^C^MC^alkyl)^
(A^C^NHC^lkenyl, (A^qONfCMoalkenyl)^ (A)tlCCO)[NHCH(R14)C(O)3s-OH/
(A)nC(O)[sugar]8; wherein A is methylene optionally substituted one or two times ,
with a group that is independently selected from Q^alkyl, Q.galkenyl, C2^alkynyl,
halogen, OH, OC^alkyi CO2H, COsQ^alkyl, NH^ NHQ.3aIkyl, -N^^alkyDa, CN,
NO^ aryl or heterocydyl; Rw is the characterising group of an amino add, n is 0 or
an integer from 1 to 20 and s is an integer from 1 to 5;
R2 is hydrogen, C^alkyl, OH, SH, NH^ -NO^ CFg, halo or -CN;
R3 is hydrogen, Q-Qalkyl, -(CH^NH^ -(CH^^OH, -(CH,)m-a?3, -(CH2)m-SHor a 5
or 6 membered heterocydic group, wherein m is 0 or an integer from 1 to 3;
R4 is hydrogen, Q.3alkyl OH, SH, NH;, NOz, CFg, halo or CN;
A is unaubstituted methylene or mono-substituted methylene.
4. A compound according to daim 2 wherein

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Xis-O-,-S-,-NH-;
Yis-O-,-S-or-N(R9)-;
Z forms a covalent bond between adjacent methylene groups;
Rt is d-Caoalkyl CrC^alkfinyl CrC20alkynyI, (A)nC(O)Rs, -(A^CtSjR* -(A^SCOR*,
-(A^SCO)^ -(A^OR* -(A\$&,, -(A)MR*)* (A)nC(=NR,)R10 or (A)nRn where n, R*
R7, Ra, Ra, Rio and Ru are defined above;
R; is hydrogen, methyl OH, OCHg, SH, NHa, NO^ CFa, halo or CN;
Ra is C^alkyl -(CH^JSTH^ -(CBjJm-OH, -(CH2)mSH or heterocydyl where m is
defined above;
R* is hydrogen, methyl OH, OCH3, SH, NHj, NO& CF3, OF* halo or CN.
5. A compound according to claim 2 wherein
Xis-O~orNH;
Y is -O- or -N{R18)- where R18 is selected from hydrogen, Ci_20alkyl C^oalkenyl
Gi,20alkenyl Q^alkynyl and (CH3)nRi: where Rtl and n are defined above;
Z forms a covalent bond between adjacent methylene groups;
Rj is hydrogen, halomethyl OH, OCH3, SH, NHj, NO2 or CN;
R3 is hydrogen, Q^alkyl (CH2)raNH2, (CH2)mOH or (CH2)mCF3 or heterocydyl where
m is defined above;
R^ is hydrogen, methyl OH OCH^ SH, NHj, NO2 or CN.
6. A compound according to daim 1 of formula (HI)

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wherein
X is -O- or -NH-;
Y is -O or -N(R18)- where R18 is defined above;
R3 is hydrogen, NH^ OH;
Ri is hydrogen methyl OCH3, or OH.
7: A compound according to claim 6 wherein Rj is selected from (A)nOR7 where n is 0.
8. A compound according to claim 1 wherein
X is -S-;
Yi8-N(R5)-;
X'is-COWr;
Y'is-C(Rs)r;
Z forms a covalent bond between X' and Y'.
9. A compound according to claim 8 wherein
Yis-NH-;
X'is-CHr;
Y'is«CH2-;

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RTISH.
10. A compound according to claim 1 wherein
X and Y are each -O-;
X' and V are each-COR^;
Z forms a covalentbond between X' and Y'.
11. A compound according to claim 10 wherein
X' and Y1 are each -CHf, ^ is H.
12. A compound according to claim 1 wherein
X and X1 taken together form -C(Rs)=N-;
Y is -C(Rs)- and taken together with the carbon atom bearing the phenyl group
forms a double bond;
Y'iS-N(R5)-;
Z forms a covaleritbond between X and Y13. A compound according to claim 12 wherein
Yis-CH-;
Xis-CH-.
14- A compound according to claim 1 wherein
X and X' taken together form -COR^N-;
Z together with Y' forms -C(R5)~C(Rs)-;
Y is -Ctiy- and together with the carbon atom bearing the phenyl group forms a
double bond.
15. A compound according to claim 14 wherein
Xis-C(OCH3);

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Z together with Y forms -C(OCH3)=CH-;
Yis-CH-.
16. A compound according to claim 1 wherein
X'ta-OOWr;
Y'is-COWr;
Zis-C(Rs)z-;
X and Y are each -O-.
17. A compound according to claim 16 wherein
■A
X', Y1 and Z are each -CHr; Rx is H.
18. A compound according to claim 1 wherein
X and Y are each -S-;
XI and Y1 are each-C(R,)2-;
Z forms a covalent bond between X1 and Y19. A compound according to claim 18 wherein
X' and Y1 are each -CH2-; Ri is H.
20. A compound according to claim 1 wherein
A IS "■*O**/
Yis-O-;
X' and V are each -CCRgV;
Z forms a covalent bond between X1 and Y1.
21. A compound according to claim 20 wherein
X1 and Y' are each -CHr.

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22. A compound according to claim 1 wherein
X and X' taken 'together form -CCR^CR,)-;
Z together with Y forms -C(R^=C(Rs)~;
Y is -C(R3)- and together with the carbon atom bearing the phenyl group forms a
double bond.
23. A compound according to claim 22 wherein
X and X1 taken together form -CH«CH-;
Z together with Y forms -CH=CH-;
Yis-CH-.
24. A compound according to claim 1 wherein
Y is -N- and taken together with the carbon atom bearing the phenyl group forms a
double bond;
X is -O-;
X' and Yr are each -C(V$r
Z forms a covalent bond between X1 and Yr.
25. A compound according to claim 24 wherein
X'and Y1 are each-CHa-.
26. A compound according to claim 1 wherein
X and Y are each ~C(Rg)r;
XI and Y1 are each -N(R5)-;
ZisC(Rs)2.
27. A compound according to claim 1 wherein
Xis-O-;

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Y is-NOW-;
X' and Y are each -C(]y2-.
28. A compound according to claim 1 wherein
X and X1 are each -C(Rs)2-;
Yis-NCRs)-;
YisCCEWr;
Z forms a covalentbond between X' and Y.
29. A compound according to claim 1 wherein
Xis-N(R9)-;
X'is-CCRsV;
Yis-C{R5)r;
Yis-NCRaV;
Z forms a covalent bond between X' and Y.
30. A compound according to claim 1 wherein
X and X1 are each -C(Rg)2-
Yis-CORJr;
Yis-NfRg)-;
Zis-C(R5)2-
31. A compound according to claim 1 selected from the group consisting of:
2-(2-hydroxyemoxy)-2-(4-hydroxy-3-mefhylphenyl)-l/3-dioxolane;
2-(2-hydroxyetiioxy)-2~(4-hydroxyphenyl)-l/3-dioxolane;
2-(2-hydroxyethoxy)-2-(3-bromo-4rhydroxy-5-methylphenyl)-l,3-dioxoIane;

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2-(4-Bromophenyl)- 1,3-thiazolane;
2-(4~Methoxyphenyl)-l,3-iHazolane;
4-( l^TMazoUdin-2-yl)benzotiitrile;
2-(4-Hydroxy-3-methoxypKenyl)-l,3-thiazolane;
2-(3/4-t>imethoxyphenyl)-l,3-thiazolane;
Methyl 4-[2-(4-fluorophenyl)-l,3-dioxolan~2-yl]butanoate;
4r[2-(4-Huorophenyl)-l/3-dioxolan-2-yl]butan-l-ol;
2-(4'-Bromophenyl)-2-buiyl-l/3-dioxolane;
4-(4-Methoxyphenyl)-l-(3-methylbutyI)-lii^pyrazole;
l-CS-MethylbutylJ^^methylphenyO-li^-pyrazole;
2/6-Dimethoxy-3-[4-(tri£ltxoromethoxy)phenyl]pyridine);
2-[4-(2-Thienyl)phenyl]-l,3-thiazolane;
2-Ethyl-2-(4-methoxyphenyl)-l/3-dioxolane;
2-HexyI-2-(4-methylphenyl)-l/3-dithiolane;
2-MethyI-2-(4-methylphenyl)-l,3-dithiGlane;
2-Hexyi-2-(4-methylphenyI)-13-dioxolane;
2-(4-C2iIo]rophenyl)-2-ine1iiy]-l/3-dioxane;
2-(4-Chlorophenyl)-2-methyl-l,3-dioxolane;
2-MethyI-2-(4-metiiylphenyI)-l/3^dioxane;
2-Methyl-2-(4-methylphenyl)-l,3- 2-(4r-Chlorophfinyl)-2-methyH>-clithiolane;
2-(4-Nitrophenyl)-2-methyl-l/3-dioxoIane;

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2-(4-Nitrophenyl)-2-metnyl-l,3-dioxane;
2-(4-MethoxyphenylM/3-oxathiolane;
2-(3A5~Trimethoxyphenyl)4,3-oxathioIane;
2-Methoxy-4-(l,3-oxathiolan-2-yl)phenol;
4-(ly3-Oxathiolan-2-yI)benzonitdle;
2-(4-Bromophenyl)-2-ethyI-l,3K>xathiolane;
4-(5-MethyI-l/3-oxathiolan-2-yl)benzoratrile;
2-(4-Thien-2-ylpKenyl)-l/3-oxathiolane;
4-(5-Methyl-2-octyl-l,3-oxathiolan-2-yI)phenol;
2-Fluoro-5-(5-methyI-l,3-oxathiolan-2-yl)benzenecarbonitrile;
4-Methoxy-4'-(trifluoromethoxy)-l/l'-biphenyl;
2,6-Dimethoxy-3-[4-(trifIuoromethyl)pKenyl]pyridine;
2-(4-bromophenyl)-2-butyI-4-propyl-l,3-oxaiiiiane;
4~(l/3-Dioxolan-2-yI)ben2enecarbonitrile;
2-(3/S-Dimethoxyphenyl)-2-hexyl-l/3-dioxolane;
2-(4-Chlorophenyl)-2-ethyl-4-metiiyI-l,3-dioxoIane;
5-(5/5-DiethyH,3-dioxan-2-yi)-2-£luorobenzenecarbonitrile;
2-(4~Chlorophenyl)-4v5-dihydro-ly3-oxazoIe;
2-(4-MethylphenyI)-4/5-dihydro-l/3-oxazok.
A compound according to claim 31 selected from the group consisting of:
2-(2-hydroxyethoxy)-2-(4r-Kydroxy-3-methylphenyI)*l/3-dioxolane;
2-(2-hydroxyethoxy)-2-(4rhydroxyphenyl)-l,3-dioxolane;

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2-(2-hydn3xye(hoxy)-2-(3-bromc>4-hydroxy-5--methylphenyl)-l,3-dioxolane;
Methyl 4-[2-(4-fiuorophenyl)-l/3-dioxolan-2-yI]butanoate;
4-[2-{^HuorophenyI)-l,3-dioxoIan-2-yI]butan-l-oI;
2-(4'-Bromophenyl)-2-butyl-lr3-dioxolane;
-i-t^MetiiiOxyphenylJ-l-CS-methylbutyli-li^pyTazole;
l-(3-MethyIbutyl)-4-(4-methylphenyl)-liifpyrazole;
2,6-0imethoxy-3-[4-CtrifItioromethoxy)phenyl]pyridine);
2-[^(2-Thienyl)phenyl]-l/3-thiazolane;
2-Ethyl-2-(4-methoxyphenyl)-l,3-dioxoIane;
2-Hexyl-2-(4-methylphenyl)-l,3-dithiolane;
2-Hexyl-2-(4-methylphenyl)-I,3-dioxoIane;
2-(4~Bromophenyi)-2-ethyl-l,3-oxatluolane;
4-(5-MethyI-lr3-oxathiolan-2-yl)benzordtrile;
2-(4r-Thien-2-ylphenyI)-l,3-oxathioIane;
4-(5-Methyl-2-odyI-l,3-oxathioIan-2i-yl)phenol;
2-Fluoro-5-(5-methyl-l/3-oxathiolan-2-yI)ben2enecarboratrile;
4-Methoxy-4'-(trifluoromethoxy)-l,l'-biphenyl;
2/6-Dimeth6xy-3-[4r(trifiubromethyl)phenyI]pyridine;
2-(4-bromophenyI)-2-butyi-4-propyl-l/3-oxatihiane;
4-(X3-Dioxolan-2-yi)benzenecarbonitrile;
2-{4-Chlorophenyl)-2-ethyl-4-methyI-l/3-dioxolane;
S-fS^S-Diethyl-l^-dioxan^-y^^-fitiorobenzenecarbonitrile.

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33. A compound according to claim 1 selected from the group consisting of:
2-(2-hydroxyethoxy)-2-(4-hydroxy-3-methylphenyl)-l/3-dioxolane;
^(4-MethoxyphenylMK3-memylbutyl)-li£pyrazole;
l~(3-Memylbutyl)-4-(4-methyIphenyl)-li£pyrazole;
2-Hexyl-2-(4-me&ylpheny])-l,3-dithiolarie;
2-Methyl-2-(4-methylphenyl)-l/3-ditMolane;
2-(4-TBen-2-ylphenyl)-l,3~oxathlolane;
4-Memoxy-4'-(trifiuoromethoxy5-l,l'-t>ipKenyl;
2/6-Dimetihoxy~3-[4-(trifluoroinethyl)phenyl]pyridine.
34. A method of inhibiting cytokine or biological activity of ME? comprising contacting
MTF with a cytokine or biological inhibiting amount of a compound according to
any one of claims 1 to 33.
35. A rnethod of treating, preventing or diagnosing a disease or condition wherein MIF
cytokine or biological activity is implicated comprising the administration of a
treatment, prevention or diagnostic effective amount of a compound according to
any one of claims 1 to 33 to a subject in need thereof.
36. The use of a compound according to any one of claims 1 to 33 in the manufacture of
a medicament for the treatment prevention or diagnosis of a disease or condition
wherein MIF cytokine or biological activity is implicated.
37. A method according to claim 35 or a use according to claim 36 wherein the disease
or condition is selected from the group consisting of autoimmune diseases, tumours
. or chronic or acute inflammatory diseases.
38. A method or use according1 to claim 37 wherein- the disease or condition is selected
from the group consisting of. rheumatoid athiitis, systemic lupus eryhtematosus,
ulceraiive colitis/ Crohn's disease, multiple sclerosis, psoriasis, uveitis,
atherosclerotic vascular disease, asthma and chronic obstructive pulmonary
disease.

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39. A method according to claim 35 wherein the subject is a human subject.
40. A pharmaceutical composition comprising a compound according to any one of
claims 1 to 33 and a pharmaceutLcally acceptable carrier, diluent or excipient
41. A pharmaceutical composition according to claim 40 further comprising a
glucocorticoid.
42. A method of treating or preventing a disease or condition wherein MIF cytokine or
biological activity is implicated comprising:
administering to a mammal a compound according to any one of claims 1 to 33 or a
pharmaceutically acceptable salt or prodrug thereof and a second therapeutic agent.
43. A method according to claim 42 wherein the second therapeutic agent is a
glucocorticoid.
44. A method of prophylaxis or treatment of a disease or condition for which treatment
with a glucocorticoid is indicated, said method comprising:
administering to a mammal a glucocorticoid and a compound according to any one
of claims 1 to 33 or a pharmaceutically acceptable salt or prodrug thereof.
45. A method of treating a steroid-resistant disease or condition comprising:
administering to a mammal a glucocorticoid and a compound according to any one
of claims 1 to 33or a pharmaceutically acceptable salt or prodrug thereof.
46. A method of enhancing the effect of a glucocorticoid in mammals comprising
administering according to any one of claims 1 to 33 simultaneously, separately or
sequentially with said glucocorticoid.



Method of inhibiting the cytokine or biological activity of Macrophage Migration inhibitory Factor (MIF) com-
prising contacting MIF with a compound of formula (I) are provided. The invention also relates to method of treating disease or
condition where MIF cytokine or biological activity is implicated comprising administration of compound of formula (I), either
alone or as a part of combination therapy, Novel compounds of formula (I) are also provided for.

Documents:

02068-kolnp-2005-abstract.pdf

02068-kolnp-2005-claims.pdf

02068-kolnp-2005-description complete.pdf

02068-kolnp-2005-drawings.pdf

02068-kolnp-2005-form 1.pdf

02068-kolnp-2005-form 3.pdf

02068-kolnp-2005-form 5.pdf

02068-kolnp-2005-international publication.pdf

2068-kolnp-2005-granted-abstract.pdf

2068-kolnp-2005-granted-assignment.pdf

2068-kolnp-2005-granted-claims.pdf

2068-kolnp-2005-granted-correspondence.pdf

2068-kolnp-2005-granted-description (complete).pdf

2068-kolnp-2005-granted-drawings.pdf

2068-kolnp-2005-granted-examination report.pdf

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2068-kolnp-2005-granted-form 13.pdf

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2068-kolnp-2005-granted-form 5.pdf

2068-kolnp-2005-granted-gpa.pdf

2068-kolnp-2005-granted-reply to examination report.pdf

2068-kolnp-2005-granted-specification.pdf

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Patent Number 239877
Indian Patent Application Number 2068/KOLNP/2005
PG Journal Number 15/2010
Publication Date 09-Apr-2010
Grant Date 06-Apr-2010
Date of Filing 21-Oct-2005
Name of Patentee CORTICAL PTY LTD.
Applicant Address 27-31 WRIGHT STREET, CLAYTON, VIC
Inventors:
# Inventor's Name Inventor's Address
1 ISKANDER MAGDY NAGUIB 158 BEACH ROAD, SANDRINGHAM, VIC 3191
2 MORAND ERIC FRANCIS 107 RUSKIN STREET, ELWOOD, VIC 3184
3 SKENE COLIN EDWARD UNIT 1, 10 SHIRLEY AVENUE, GLEN WAVERLEY VIC 3150
PCT International Classification Number C07D 317/20
PCT International Application Number PCT/AU2004/000453
PCT International Filing date 2004-04-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2003906773 2003-12-08 Australia
2 2003901579 2003-04-07 Australia