WO 2006/093548 2 PCT/US2005/044713
SPIRO-HETEROCYCLIC CHROMANS. THIOCHROMANS AND DIHYDROQUINOUNES
Cross-Reference to Related Applications
[0001] This application claims the benefit under 35 U.S.C. §119(e) of United States Provisional
Application Serial No. 60/656,748 filed on February 25, 2005 and Serial No. 60/656,711 also filed on
February 25, 2005, both of which are incorporated by reference in their entirety.
Background Information
[0002] The present invention relates to certain novel spiro-heterocyclic chroman, thiochroman
and dihydroquinoline derivatives of Formula I as depicted below, pharmaceutical formulations containing
them, and their uses as therapeutic agents, and syntheses therefore. Their uses as therapeutic agents
that may act as lipoxygenase inhibitors include but are not limited to prevention or treatment of diseases
involving apoptosis in cancer cells; diseases involving hypoxia or anoxia; diseases involving
inflammation; disorders of the airways; and diseases involving the autoimmune system.
[0003] The use of compounds having a chroman moiety as lipoxygenase inhibitors has been
disclosed, for example, in US Patents 5,059,609; US 4,950,684; US 5,015,661; US 4,780,469; US
5,591,772; US 5,925,673; US 5,250,547; US 5,393,775; US 4,814,346; US 5,939,452, US 6,051,601;
US6.117.874; and US 6,133.286.
[0004] Arachidonic acid is an essential fatty acid that exists within the cell membrane and can
be released from phosphoiipids by the action of phospholipase. The released arachidonic acid is
metabolized through three major enzymatic pathways, i.e. the lipoxygenase pathway, to form
substances such as prostaglandins which are associated with inflammatory responses, and
thromboxanes which are associated with the formation of thrombus, or leukotrienes which induce
allergic reactions.
[0005] Lipoxygenases are non-heme iron-containing enzymes that catalyze the oxidation of
polyunsaturated fatty acids and esters thereof. They were originally classified based on their substrate
specificity for insertion of molecular oxygen into arachidonic acid at carbon positions 5,12 and 15, but
more recently a phylogenetic classification is being used. This separates the mammalian enzymes In
four main subtypes, 5-Lipoxygenase, 12/15-Lipoxygenases, platelet 12-Lipoxygenases and epidermis-
type lipoxygenases. The 12/15 family of lipoxygenases includes two sub-families with a high degree of
sequence homology, the reticulocyte 15-Lipoxygenases (found in rabbit and humans) and the leukocyte
12-Lipoxygenases (found in mouse, pig, rat, and rabbit). This type of lipoxygenase shares more
homology to reticulocyte 15-Lipoxygenase and leukocyte 12-Lipoxygenase, than to platelet 12-
Upoxygenases.
[0006] It is believed that oxidative metabolites of the 12/15-Lipoxygenase or the 15-
Lipoxygenase cascade have been implicated in the potentiation of thrombin induced platelet activation
(Setty et al. Blood, (1992), 2765-2773); in the progression of various cancers (Kelavkar et al, Curr. Urol.

WO 2006/093548 3 PCT/US2005/044713
Rep. Vol. 3 no. 3 (2002),: pp. 207-214) and related pathologies (Tisdale et al., Science Vol. 289 no.
5488 (2000) pp. 2293-4). It has also been shown that treatment with a 15-Lipoxygerase inhibitor
suppresses atherogenesis In rabbits fed a high-fat diet (Bocan et al., Atherosclerosis, Vol. 136 (1998)
pp. 203-16). There is increasing evidence that certain lipoxygenase enzymes are involved in the
pathogenesis and acceleration of atherosclerosis by inducing oxidation of LDL to its atherogenlc form
(Sparrow, C. P., et al., J. Lipid Res. Vol. 29 (1988) pp. 745-753. and Steinberg, D., New Eng. J. Med.
Vol. 320(1989) pp. 915-924). It has also been reported that 12-Lipoxygenase enzyme plays a role in
mediating angiotensin II Induced vascular and adrenal actions (Natarajan, R., et al., Endocrinology Vol.
131 (1992) pp. 1174-1180). Recent studies (Klein, R. et al., Science Vol. 303 no. 5655 (2004) 329-332)
have also shown the role of 15-Lipoxygenase enzyme in the regulation of bone density.
[0007] The enzyme 5-Lipoxygenase converts arachidonic acid to 5-
hydroperoxyeicosatetraenoic acid (5-HPETE). This Is the first step in the metabolic pathway yielding 5-
hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes. Evidence
of the role of leukotrienes in the pathology of certain diseases has been described, for example in Cloud
et al., J. Allergy Clin. Immunol., Vol. 79 (1987) pp. 256 (asthma); Turnbull et al., Lancet II, (1977) pp.
526-9 (chronic bronchitis); Cromwell et al., Lancet II, (1981) pp. 164-5 (cystic fibrosis); Davidson et al.,
J. Pharm. Pharmacol. Vol. 34 no. 61(982) pp. 410 (rheumatoid arthritis); Rae et al., Lancet. Vol. 2 no.
8308 (1982) pp. 1122-4. Cook et al., J. Pharmacol. Exp. Then, 235, (1985) pp. 470-474 (cardiovascular
conditions); Tsuji et al., Biochem. Pharmacol. Vol. 55 no. 3: (1998); pp. 297-304 (dermatitis such as
psoriasis).
[0008] It has also been shown in co-owned US application Serial No. 11/251,423 filed
October 13, 2005, titled Methods for Treating Diabetes, herein incorporated by reference In its entirety,
that dual 5-Lipoxygenase and 12/15-Lipoxygenase inhibitors or 5-Lipoxygenase and 15-Lipoxygenase
inhibitors are superior in the prevention of treatment of subjects susceptible to diabetes, are able to
improve glucose control in animal models of diabetes, and have demonstrated a significant lowering of
the baseline serum glucose levels compared to selective 5-Lipoxygenase, 15-Lipoxygenase and 12/15-
Llpoxygenase inhibitors.
[0009] The compositions, formulations and methods of this invention are particularly applicable
in preventing and/or treating diseases or disorders mediated, at least in part, by one or more
lipoxygenase enzymes, such as 5-Lipoxygenase enzyme and/or 12/15-Lipoxygenase enzyme.
SUMMARY OF THE INVENTION
[0010] The present invention Is concerned with certain novel derivatives of Formula I, which
may be useful in the manufacture of pharmaceutical compositions for treating disorders mediated by
lipoxygenases.
[0011] In a first aspect, the present invention concerns the compounds represented by Formula

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wherein,
X is O, S(O)0-2, or NR;
R1, R3, and R4 are independently selected from the group consisting of hydrogen, alky], cycloalkyl,
halogen, nitro, cyano, amino, aminosulfonyl, sulfanyl, aryl, heterocyclyl, hydroxy, alkoxy, carboxy,
alkoxycarbonyl, and aminocarbonyl;
R2 is selected from the group consisting of hydroxy, amino, aminocarbonyl, alkoxy, -O-alkenyl,-O-
acyl, -O-alkylene-amino, -O-C(O)-alkylene-COORa; -O-C(O)-alkylene-amino; -O-C(O)-alkylene-
heterocyclyl; -O-glucoside; -O-phosphoryl, -O-alkylene-phosphoryl; -O-C(O)-AA, wherein AA is
an amino acid, or a di-, tri- or tetra-peptide;
R5 and R6 are
• independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy,
carboxy, alkylcarbonyl, amino, amido, aminosulfonyl, sulfonylamino, sulfanyl, nitro, cyano,
halogen, -NRdORa, and -NRd-NRbRc or
■ together with the carbon atom to which they are attached form C=O, C=NORa, C=N-NRbRc,
optionally substituted (C3-C8)cycloalkyl ring, an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
R7 and R8 are
• independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy,
carboxy, alkylcarbonyl, amino, amido, aminosulfonyl, sulfonylamino, suffanyl, nitro, cyano,
halogen, -NRdORa, and -NRd-NRbR°; or
■ together with the carbon atom to which they are attached form C=O, C=NORa, C=N-NRbR°,
optionally substituted (C3-C8)cycloalkyl ring, an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
R9 and R10 are
■ independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy,
carboxy, alkyl carbonyl, amino, amido, aminosulfonyl, sulfonylamino, sulfanyl, nitro, cyano,
halogen, -NRdORa, and -NRd-NRbRc; or
• together with the carbon atom to which they are attached form C=O, C=NORa, C=N-NRbRc an
optionally substituted (C3-C6)cycloalkyl ring, an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, acyl,
aminocarbonyl, heterocyclyl and aryl;

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Ra is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl, heterocyclyl, and
aryl;
Rb and R° are
■ independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
■ together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 N, O, or S atoms;
Rd is hydrogen or alkyl; and
with the proviso that
■ at least one of -CR5R8, -CR7R8, and -CR9R10 is an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
[0012] In one embodiment, R2 is hydroxy, and in another embodiment R2 is hydroxy and R1,
R3, and R4 are independently of each other hydrogen, halogen, or alkyl. In yet another embodiment, R2
is hydrqxy, R1, R3, and R4 are independently of each other hydrogen, halogen, or alkyl, and CRrR8 is an
optionally substituted azetidine ring or an optionally substituted oxetan. In another embodiment, R2 is
hydroxy, R1, R3, and R4 are independently of each other hydrogen, halogen, or alkyl, and CR9R10 is
optionally substituted an optionally substituted azetidine ring; or an optionally substituted oxetan. In
another embodiment, R2 is hydroxy, R1, R3, and R4 are independently of each other hydrogen, halogen,
or alkyl, and CR5R6 is optionally substituted an optionally substituted azetidine ring; or an optionally
substituted oxetan ring. In one embodiment R5 and R8 are both hydrogen.
[0013] In some embodiments, R6 is hydroxy, -NRdORa, or -NRd-NRbR°.
[0014] In one embodiment X is O or S. In another embodiment X is NR, R2 is hydroxy, R3 is
alkyl and R1, R3 and R4 are independently of each other hydrogen or alkyl, and in a particular
embodiment R is alkyl substituted with an amido, a sulfonylamino or an aminosulfonyl group and in
another embodiment R is -(CH2)2-6-NRdS(O)2-aryl, •{CH2)2-6-S(O)2NRd-aryl; -(CH2NRdC(O)-aryl or
-(CH2)2-6C(O)NRd-aryl; illustrated by alkylbenzenesulfonaminoethyl, or alkylbenzenesulfonamlnopropyl.
[0015] It is contemplated that in embodiments where R2 is selected from alkoxy, -O-alkenyl.-O-
acyl, -O-alkylene-amino, -O-C(O)-alkylene-COORa; -O-C(O)-alkylene-amino; -O-C(O)-alkylene-
heterocyclyl; -O-glucoside; -O-phosphoryl, -O-alkylene-phosphoryl; -O-C(O)-AA, wherein AA is an.amino
acid, or a di-, tri- or tetra-peptide, then the compound will hydrolyze in vivo to form the active hydroxy.
[0016] In another aspect, the invention relates to a pharmaceutical composition containing a
therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt
thereof admixed with at least one pharmaceutically acceptable excipient. In some examples, the
pharmaceutical compositions comprise a compound of Formula I and a pharmaceutically acceptable
excipient; and the compound is selected from the illustrative compounds and stereoisomers, mixture of
stereoisomers or pharmaceutically acceptable salts thereof.
[0017] In another aspect, the invention relates to a method of inhibiting a lipoxygenase,

WO 2006/093548 6 PCT/US2005/044713
comprising contacting a cell with an effective amount of a compound of Formula I.
[0018] In one embodiment, the compound Inhibits one or more lipoxygenase enzymes selected
from 5-Lipoxygenase, 15-Lipoxygenase, 12/15-Lipoxygenase enzymes and combinations thereof. In
some embodiments the compound inhibits 5-Lipoxygenase, and in other embodiments the compound
inhibits both 5-Lipoxygenase and 15-Lipoxygenase or both 5-Lipoxygenase and 12/15-Lipoxygenase.
[0019] In some embodiments, the invention relates to a method of treating a subject with a
lipoxygenase mediated disorder such as but not limited to apoptosis in cancer cells including prostatic
cancer, gastric cancer, breast cancer, pancreatic cancer, colorectal or esophageal cancer and airways
carcinoma; diseases involving hypoxia or anoxia including atherosclerosis, myocardial infarction,
cardiovascular disease, heart failure (including chronic and congestive heart failure), cerebral ischemia,
retinal ischemia, myocardial ischemia, post surgical cognitive dysfunction and other ischemias; diseases
involving inflammation, including diabetes, arterial inflammation, inflammatory bowel disease, Crohn's
disease, renal disease, pre-menstrual syndrome, asthma, allergic rhinitis, gout, cardiopulmonary
inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue and inflammatory disorders of the skin
including acne, dermatitis and psoriasis; disorders of the airways including asthma, chronic bronchitis,
human airway carcinomas, mucus hypersecretion, chronic obstructive pulmonary disease (COPD)
pulmonary fibrosis caused by chemotherapy or other drugs, idiopathic pulmonary fibrosis, cystic fibrosis
and adult respiratory distress syndrome; diseases involving central nervous system (CNS) disorders
including psychiatric disorders including anxiety and depression; neurodegeneration and
neuroinflammation including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy
including spinal chord injury, head injury and surgical trauma, and allograft tissue and organ transplant
rejection; diseases involving the autoimmune system including psoriasis, eczema, rheumatoid arthritis,
and diabetes; and disorders involving bone loss or bone formation. In an illustrative example, the
invention relates to a method of treating a subject with a lipoxygenase mediated disorder, such as but
not limited to diabetes, arthritis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD),
asthma, allergic rhinitis, Crohn's disease, and/or atherosclerosis.
[0020] In some of the embodiments, the compositions, methods of treatment and uses In the
manufacture of pharmaceutical compositions therefor, may relate to compounds of Formula I such as:
■ 5,7,8-trimethylspiroJchroman-2,3'-oxetan]-6-ol;
■ 5,7-diethylspiro[chroman-2,3'-oxetan]-6-ol;

• 5,7-diethy!spiro[chroman-2,2'-oxetan]-6-ol;
• 5,7'-diethylspirotazetidine-3,2'-chroman]-6'-ol;

■ 5,7-diethyl-4-(methoxyam ino)spiro[chroman-2,3'-oxetan]-6-ol;
■ 5,7-diethyl-4-(methoxyamino)spiro[chroman-2,2'-oxetan]-6-ol;
• 5',71-diethyl-4'-(methoxyamino)spiro[azetidine-3,2'-chroman]-6'-ol;
■ 5,7-diethyispiro[chroman-2,3'-oxetane]-4,6-diol;
• 5-ethyl-7-isopropylspiro[chroman-2,3'-oxetane]-4,6-dlol
■ 7-isopropyl-5-methylspiro[chroman-2,3'-oxetane]-4,6-diol

WO 2006/093548 7 PCT/US2005/044713
■ 5,7-diethyl-6-hydroxyspiro[chroman-2,3'-oxetan]-4-one;
■ 5,7-diethylspiro[chroman-2,2'-oxetane]-4,6-diol;
■ 5,7'-dimethylspirotazetidine-3,2'-chromanl]4,6'-diol;
■ 5,7'-diethyl-6'-hydroxyspiro[fazetidine-3,2'-chroman]-4'-one;
■ 7'-isopropyl-5'-methylspirolazetidine-3,2'-chromanl]-4,6'-diol
■ 5,7-diethylspiro[chroman-4,3'oxetan]-6-ol;
■ 5',7'-dimethylspirolazetidlne-3,4'-chromanl-6'-ol;
■ 5',7'-dimethylspirofchroman-4,2'-oxetanl-6'-ol;
■ 5,'7'-dimethylspirolazetidine-2.4'-chromanl-6'-ol;
■ 5',7'-dimethylspiroIchroman-3.3'-oxetanl-6-ol;
■ 5',7'-dimethylspirotazetidine-3,3'-chromanl-6'-ol;
■ 5',7'-dimethyl-1'-methyl-2',4'-dihydro-1'H-spiro[azetidine-3,3'-quinolinl-6'-ol;
■ 5',7'-dimethyl-1'-methyl-2',4'-dihydro-1'H-splrotoxetane-3,3'-quinolin]-6'-ol;
■ N-(3-(6'- hydroxy-5',7'-dimethyl-2',4'-dihydro-1'H-splro[oxetane-3,3'-quinoline]-1'-yl)propyl)benzene-
sulfonamide;
■ N-(3-(6'- hydroxy-5',7'-dimethyl-2',4'-dihydro-1'H-splro[oxetane-3,3'-quinoline]-1'-yl)propyl)benzene-
sulfonamide;
■ N-(3-(6'- hydroxy-5',7'-dimethyl-2',4'-dihydro-1'H-splro[oxetane-3,3'-quinoline]-1-
yl)propyl)benzamide;
■ N-(3-(6'-hydroxy-5',7'-dimethyt-2',4'-dihydro-1'H-spirotoxetane-3,3'-quinoline]-1'-yl)propyl)benzamide;
■ N-(3-(6'- hydroxy-5',7'-dimethyl-2',4'-dihydro-1'H-splro[oxetane-3,3'-quinoline]-1'-yl)propyl)benzene-
sulfonamide; and
■ N-(3-(6'- hydroxy-5',7'-dimethyl-2',4'-dihydro-1'H-splro[oxetane-3,3'-quinoline]-1'-yl)propyl)benzene-
sulfonamide.
[0021] Another aspect of this invention is the processes for preparing compounds of Formula I
and is set forth in "Description of the Invention".
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0022] As used in the present specification, the following words and phrases are generally
intended to have the meanings as set forth below, except to the extent that the context in which they are
used indicates otherwise.
[0023] The term "optional" or "optionally" means that the subsequently described event or
circumstance may or may not occur, and that the description includes instances where said event or
circumstance occurs and instances in which it does not.
[0024] it will be understood by those skilled in the art with respect to any group containing one
or more substituents that such groups are not intended to introduce any substitution or substitution
patterns that are sterically impractical and/or physically non-feasible.

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[0025] The term "acyl" refers to the groups -C(O)-H, -C(O)-(alkyl), -C(O)-(cycloalkyl), -C(O)-
(alkenyl), -C(O)-(cycloalkenyl), -C(O)-(aryl), and -C(O)-(heterocyclyl).
[0026] The term "acyloxy" refers to the moiety -O-acyl, including, for example, -O-C(O)-alkyl.
[0027] The term "alkenyl" refers to a monoradical branched or unbranched, unsaturated or
polyunsaturated hydrocarbon chain, having from about 2 to 20 carbon atoms, for example 2 to 10
carbon atoms. This term is exemplified by groups such as ethenyl, but-2-enyl, 3-methyl-but-2-eny! (also
referred to as "prenyl", octa-2,6-dienyl, 3,7-dimethyl-octa-2,6-dienyl (also referred to as "geranyl"), and
the like. The term also includes substituted alkenyl groups, and refers to an alkenyl group in which 1 or
more, for example, 1 to 3 hydrogen atoms is replaced by a substituent independently selected from the
group: =O, =S,'acyi, acyloxy, alkoxy, amino (wherein the amino group may be a cyclic amine), aryl,
heterocyclyl, carboxyl, carbonyl, amido, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro,
sulfamoyl (-SO2NH2), sulfanyl, sulfinyl (-S(O)H), sulfonyl (-SO2H), and sulfonic acid (-SO2OH). One of
the optional substituents for alkenyl may be heterocyclyl, exemplified by 2-quinolyl-2-vinyl.
[0028] The term "alkenylene" refers to a diradical derived from the above defined monoradical,
alkenyl.
[0029] The term "alkoxy" refers to the groups: -O-alkyl, -O-alkenyl, -O-cycloalkyl, -O-
cycloalkenyl, and -O-alkynyl. Alkoxy groups that are -O-alkyl include, by way of example, methoxy,
ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-dimethylbutoxy, and the like. The term "alkoxy" also includes substituted alkoxy groups and refers to
the groups -O-(substituted alkyl), -O-(substituted alkenyl), -O-(substituted cycloalkyl), -O-(substituted
cycloalkenyl), -©-(substituted alkynyl) and -O-(optionally substituted alkylene)-alkoxy.
[0030] The term "alky!" refers to a monoradical branched or unbranched saturated hydrocarbon
chain having from about 1 to 20 carbon atoms. The term "alkyl" also means a combination of linear or
branched and cyclic saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms. This
term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-
decyl, tetradecyl, and the like. The term " alkyl" also includes substituted alkyl and refers to an alkyl
group in which 1 or more, such as 1 to 5, hydrogen atoms Is replaced by a substituent independently
selected from the group: =O, =S, acyl, acyloxy, alkoxy, alkoxyamino, hydroxyamino, amino (wherein the
amino group may be a cyclic amine), aryl, heterocyclyl, azldo, carboxyl, alkoxycarbonyl, amido, cyano,
cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro, sulfonylamino, aminosulfonyl, sulfanyl, sulfinyl,
sulfonyl, and sulfonic acid. One of the optional substituents for alkyl may be hydroxy or amino,
exemplified by hydroxyalkyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl,
4-hydroxybutyl, and the like; dihydroxyalkyl groups (glycols), such as 2,3-dihydroxypropyl,
3,4-dihydroxybutyl, 2,4-dihydroxybutyl, and those compounds known as polyethylene glycols,
polypropylene glycols and polybutylene glycols, and the like; or aminoalkyl groups exemplified by groups
such as aminomethyi, dimethylaminomethyl, diethylaminomethyl, ethylaminomethyl, piperidinylmethyl,
morpholinylmethyl, and the like. Another substituent for alkyl may be halogen, such as trifluoromethyl.
Another substituent may be hydroxyamino or alkoxyamino, exemplified by groups such as

WO 2006/093548 9 PCT/US2005/044713

hydroxyaminomethyl, methoxyaminomethyl or ethoxyaminomethyl. Another substituent may be sulfanyl,
exemplified by groups such as methyl (2-methylthioacetate). Another substituent may be aryl or
heterocyclyl exemplified by methylbenzoate, propylisoindoline-1,3-dione, quinoline-methyl or 2-quinolyl-
2-ethyl. Another substituent may be amido, aminosulfonyl or sulfonylamino, exemplified by 4-
propylben2ensulfonamide-2-ethyl;4-methylbenzene-sulfonamide-2-ethy, 4-propylbenzensulfonamide-3-
propyl; 4-methylbenzenesulfonamide-3-propyl, or methyl-N-methylacetamide. Another substituent may
be aminocarbonyloxy (-OC(O)amino), such as -OC(O)NH2 or-OC(O)-substituted amino.
[0031] The term "alkylene" refers to a diradical alkyl group, whereby alkyl is as defined above.
[0032] The term "alkynyl" refers to a monoradical branched or unbranched, unsaturated or
polyunsaturated hydrocarbon chain, having from about 2 to 20 carbon atoms, for example 2 to 10
carbon atoms and comprising at least one triple bond, and preferably 1 to 3. The term also includes
substituted alkynyl groups, and refers to an alkynyl group in which 1 or more hydrogen atoms is
replaced by a substituent independently selected from the group: acyl, acyloxy, alkoxy, amino (wherein
the amino group may be a cyclic amine), aryl, heterocyclyl, carboxyl, carbonyl, amido, cyano, cycloalkyl,
cycloalkenyl, halogen, hydroxyl, nltro, sulfamoyl, sulfanyl, sulfinyi, sulfonyl, and sulfonic acid.
10033] The term "amido" refers to the moieties -C(O)-NR100R101 and -NR10DC(O)R101, wherein
R100 and R101 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl, provided that R100 and R101 are
not aryl or heteroaryl.
[0034] The term "amino" refers to the group -NH2 as well as to the substituted amines such as
-NHRX or -NRXRX where each R" is independently selected from the group: alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, heterocyclyl, acyl, optionally substituted alkoxy, carboxy and alkoxycarbonyl,
and where -NRXRX may also be a cyclic saturated or unsaturated amine, optionally incorporating one or
more, for example 1 to 3, additional atoms chosen form N, O or S, and optionally substituted with a
substituent selected from the group consisting of =O, =S, alkyl, hydroxy, acyloxy, halo, cyano, nitro,
sulfanyl, alkoxy, and phenyl. This term is exemplified by such groups as amino, cyclopropylamino,
dimethylamlno, diethylamino, hexylamino. The term "cyclic amine" or "cyclic amino" is exemplified by
the group morpholinyl. The term "alkoxyamino" refers to embodiments wherein at least one of R" Is
alkoxy. The term "hydroxyamino" refers to embodiments wherein at least one of Rx is hydroxy.
[0035] "Amino acid" refers to any of the naturally occurring amino acids, as well as synthetic
analogs (e.g., D-stereoisomers of the naturally occurring amino acids, such as D-threonine) and
derivatives thereof. a-Amino acids comprise a carbon atom to which is bonded an amino group, a
carboxyl group, a hydrogen atom, and a distinctive group referred to as a "side chain". The side chains
of naturally occurring amino acids are well known in the art and include, for example, hydrogen (e.g., as
in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in
threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arglnine,
and lysine), arylalkyl or aralkyl (e.g., as in phenylalanine and tryptophan), substituted arylalkyi (e.g., as

WO 2006/093548 10 PCT/US2005/044713

in tyrosine), and heteroarylalkyl (e.g., as in histidine). The term "naturally occurring amino acids" refers
to these amino acids.
[0036] Unnatural amino acids are also known in the art, as set forth in, for example, Williams
(ed.), Synthesis of Optically Active .alpha.-Amino Acids, Pergamon Press (1989); Evans et al., J. Amer.
Chem. Soc, 112:4011-4030 (1990); Pu etal., J. Org Chem., 56:1280-1283(1991); Williams etal., J.
Amer. Chem. Soc, 113:9276-9286 (1991); and all references cited therein.
[0037] The term "peptide" refers to any of various natural or synthetic compounds containing
two or more amino acids linked by the carboxyl group of one amino acid to the amino group of another.
A "dipeptide" refers to a peptide that contains 2 amino acids. A "tripeptide" refers to a peptide that
contains 3 amino acids. A "tetrapeptide" refers to a peptide that contains 4 amino acids.
[0038] The term "aromatic" refers to a cyclic or polycyclic moiety having a conjugated
unsaturated (4n + 2) % electron system (where n is a positive integer), sometimes referred to as a
delocalized % electron system.
[0039] The term "aryl" refers to an aromatic cyclic hydrocarbon group of from 6 to 20 carbon
atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
Aryts include phenyl, naphthyl and the like. The term "aryl" also includes substituted aryl rings and
refers to an aryl group as defined above, which unless otherwise constrained by the definition for the
aryl substituent, is substituted with one or more, such as 1 to 5, substituents, independently selected
from the group consisting of: hydroxy, acyl, acyloxy, alkenyl, alkoxy, alkyl, alkynyt, amino, aryl, aryloxy,
azido, carboxyl, alkoxycarbonyl, amido, cyano, cycloalkyl, cycloalkenyl, halogen, heterocyclyl,
heterocyclyloxy, nitro, sulfonylamino, aminosulfonyl, sulfanyl, sulfinyl, sulfonyl, and sulfonic acid.
[0040] The term "aryloxy" refers to the group -O-aryl.
[0041] The term "aralkyl" refers to the group -alkylene-aryl, wherein alkylene and aryl are
defined herein.
[0042] The term "carbonyl" refers to the dkadical "C=O", which is also illustrated as m-C(O)-".
This moiety is also referred as "keto."
[0043] The term "alkylcarbonyl" refers to the groups: -C(O) -(alkyl), -C(O) -(cycloalkyl), -C(O)
-(alkenyl), and -C(O) -(alkynyl).
[0044] The term "alkoxycarbonyl" refers to the groups: -C(O)O-(aikyi), -CfOJCKcycloalkyl),
-C(O)O-(alkenyl), and -C(O)O-(alkynyl). These moieties may also be referred to as esters.
[0045] The term "aminosulfonyl" refers to the group -S(O)2-(amino). The term "sulfonylamino"
refers to the group -(amino) -S(0)rRy, wherein Ry is alkyl, cycloalkyl, alkenyl, aryl or heterocyclyl.
[0046] The term "amlnocarbonyT refers to the group -C(O)-( amino) and the term
"cabonylamino" refers to the group -amino-C(O)-Ry, wherein Ry is alkyl, cycloalkyl, alkenyl, aryl or
heterocyclyl and the term amino is as described herein.
[0047] The term "carboxy" or "carboxyl" refers to the moiety "-C(O)OH," which is also illustrated
as"-COOH." The salts of-COOH are also included.

WO 2006/093548 11 PCT/US2005/044713

[0048] The term "cycloalkyl" refers to non-aromatic cyclic hydrocarbon groups having about 3
to 12 carbon atoms having a single ring or multiple condensed or bridged rings. Such cycloalkyl groups
include, byway of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyt,
cyclohexyl, and the like, or multiple ring structures such as adamantyl, and the like. The term
"cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom
in common with another ring. The term "cycloalkyl" also includes substituted cycloalkyl rings and refers
to a cycloalkyl group substituted with one or more, such as 1 to 5, substituents, independently selected
from the group consisting of: =O, =S, acyl, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy,
azido, carboxyl, alkoxycarbonyl, amido, cyano, cycloalkyl, cycloalkenyl, halogen, heterocyclyl,
heterocyclyloxy, hydroxyl, nitro, sulfonylamlno, amlnosulfonyl, sulfanyl, sulflnyl, sulfonyl, and sulfonic
acid. A cycloalkyl ring substituted with an alkyl group is also referred as "alkylcycloalkyl."
[0049] The term "cycloalkenyl" refers to cyclic alkenyl groups of from 3 to 10 carbon atoms
having single or multiple cyclic rings. This also includes substituted cycloalkenyl which includes
substituents as those listed with cycloalkyl.
[0050] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0051] The term "heteroaryl" refers to an aromatic carbocyclic radical having one or more, such
as 1 to 3, rings incorporating one or more, such as 1 to 4, heteroatoms within the ring (chosen from
nitrogen, oxygen, and/or sulfur). This term excludes saturated carbocyclic radical having one or more
rings incorporating one or more heteroatoms within the ring (chosen from nitrogen, oxygen, and/or
sulfur).
[0052] The terms "heterocycle," "heterocycllc," "heterocyclo," and "heterocyclyl" refer to a
monovalent, saturated, partially unsaturated or fully unsaturated (aromatic) carbocyclic radical having
one or more, such as 1 to 3, rings Incorporating one or more, such as 1 to 4, heteroatoms within the ring
(chosen from nitrogen, oxygen, and/or sulfur). Heterocycles include morpholine, piperidine, piperazine,
thlazole, thiazolidine, isothiazole, oxazole, isoxazole, pyrazole, pyrazolidine, pyrazoline, imidazole,
imidazolidine, benzothiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, pyrrolidine, quinoline,
quinazoline, purine, carbazole, benzimldazole, thiophene, benzothlophene, pyran, tetrahydropyran,
benzopyran, furan, tetrahydrofuran, Indole, Indollne, indazole, xanthene, thioxanthene, acridine,
quinuclidine, and the like. The terms "heterocycle," "heterocyclic," "heterocyclo," and "heterocvclyT also
include substituted rings and refer to a heterocycle group as defined above, which unless otherwise
constrained by the definition for the heterocycle, is substituted with one or more, such as 1 to 5,
substituents, independently selected from the group consisting of: hydroxy, acyl, acyloxy, alkenyl,
alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, azido, carboxyl, alkoxycarbonyl, amido, cyano, cycloalkyl,
cycloalkenyl, halogen, heterocyclyl, heterocyclo-oxy, nitro, sulfonylamino, aminosulfonyl, sulfanyl,
sulfinyl, sulfonyl, and sulfonic acid. This term is exemplified by 4,5-dihydroisoxazole-5-
methylcarboxylate, 5-butylisoxazol, pyrrolidinyl, morpholinyl, imidazolyl, 5-hydroxypyridin-2-yl,
dlmethylaminopyrldin-3-yl, isoindolinedione, trifluoromethyloxazolyl, 2-bromophenyl-1H-tetrazol-5-yl,
methylthiazolyl, phenylthiazolyl, and benzothiazolyl.

WO 2006/093548 12 PCT/US2005/044713
[0053] The term "heterocyclyloxy" refers to the moiety -O-heterocyclyl.
[0054] The term "inflammation," "inflammatory conditions," or "inflammation conditions"
includes but is not limited to muscle fatigue, osteoarthritis, rheumatoid arthritis, inflammatory bowel
syndrome or disorder, Crohn's disease, skin inflammation, such as atopic dermatitis, contact dermatitis,
allergic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, atherosclerosis, thermal and
radiation burns, acne, oily skin, wrinkles, excessive cellulite, excessive pore size, intrinsic skin aging,
photo aging, photo damage, harmful UV damage, keratinization abnormalities, irritation including retinoid
induced irritation, hirsutism, alopecia, dysplgmentation, Inflammation due to wounds, scarring or stretch
marks, loss of elasticity, skin atrophy, and gingivitis.
[0055] The term "ischemia" refers to deficiency of blood to an organ or tissue due to functional
constriction or actual obstruction of a blood vessel.
[0056] The term "isomers" or "stereoisomers" relates to compounds that have identical
molecular formulae but that differ in the arrangement of their atoms in space. Stereoisomers that are not
mirror images of one another are termed "diastereoisomers" and stereoisomers that are non-
superimposable mirror images are termed "enantiomers," or sometimes optical isomers. A mixture of
equal amounts of stereoisomers of a molecule is termed a "racemate" or a "racemic mixture." A carbon
atom bonded to four non-identical substituents is termed a "chiral center." Certain compounds of the
present invention have one or more chiral centers and therefore may exist as either individual
stereoisomers or as a mixture of stereoisomers. Configurations of stereoisomers that owe their
existence to hindered rotation about double bonds are differentiated by their prefixes cis and trans, (or Z
and E), which indicate that the groups are on the same side (cis or Z) or on opposite sides (trans or E) of
the double bond in the molecule according to the Cahn-lngold-Prelog rules. This invention includes all
possible stereoisomers as individual stereoisomers, racemates, or mixtures of stereoisomers.
[0057] A "lipoxygenase-mediated condition" or a "disorder mediated by lipoxygenases" means
any condition, disorder or disease mediated, at least in part, by a lipoxygenase enzyme. This includes
disorders related to or otherwise associated with a lipoxygenase enzyme or the inhibition thereof,
including, by way of example and without limitation, diseases involving apoptosis in cancer cells such as
prostatic cancer, gastric cancer, breast cancer, pancreatic cancer, colorectal or esophageal cancer and
airways carcinoma; diseases involving hypoxia, or anoxia such as atherosclerosis, myocardial infarction,
cardiovascular disease, heart failure (including chronic and congestive heart failure), cerebral ischemia,
retinal ischemia, myocardial ischemia, post surgical cognitive dysfunction and other ischemias; diseases
involving inflammation, including diabetes, arterial inflammation, inflammatory bowel disease, Crohn's
disease, renal disease, pre-menstrual syndrome, asthma, allergic rhinitis, gout; cardiopulmonary
inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue and inflammatory disorders of the skin
including acne, dermatitis and psoriasis; disorders of the airways such as asthma, chronic bronchitis,
human airway carcinomas, mucus hypersecretion, chronic obstructive pulmonary disease (COPD),
pulmonary flbrosis caused by chemotherapy or other drugs, idiopathic pulmonary fibrosis, cystic fibrosis,
and adult respiratory distress syndrome; diseases involving central nervous system (CNS) disorders

WO 2006/093548 13 PCT/US2005/044713
including psychiatric disorders including anxiety and depression; neurodegeneration and
neuroinflammation including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy
including spinal chord injury, head injury and surgical trauma, and allograft tissue and organ transplant
rejection; diseases involving the autoimmune system such as psoriasis, eczema, rheumatoid arthritis,
and diabetes; and disorders involving bone loss or bone formation.
[0058] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable
excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents,
isotonic and absorption delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be incorporated into the compositions.
[0059] The term "pharmaceutically acceptable salt" refers to salts which retain the biological
effectiveness and properties of the compounds of this invention and which are not biologically or
otherwise undesirable, in some cases, the compounds of this invention are capable of forming acid
and/or base salts by virtue of the presence of phenolic, amino and/or carboxyl groups or groups similar
thereto. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic
bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium,
ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited
to, salts of primary, secondary and tertiary amines, such as alky) amines, dialkyl amines, trialkyl amines,
substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alky!) amines, alkenyl amines,
dialkenyl amines, trialkeny] amines, substituted alkenyl amines, di(substituted alkenyl) amines,
tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines,
cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,
disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl
amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines
where at least two of the substituents on the amine are different and are selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic, and the like. Also included are amines where
the two or three substituents, together with the amino nitrogen, form a heterocyclic group.
[0060] Specific examples of suitable amines include, by way of example only, isopropylamine,
trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-
dimethylaminoethanol, tromethamine, lysine, arginine, histldine, caffeine, procaine, hydrabamlne,
choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromlne, purines, piperazine,
piperidine, morpholine, N-ethylpiperidlne, and the like.
[0061] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and
organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid,

WO 2006/093548 14 PCT/US2005/044713
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, malelc
acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0062] It should be understood that for the purpose of this invention, all references to
acceptable salts also include solvent addition forms (solvates) or polymorphs (crystal forms). "Solvate*
means solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.
Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid
state, thus forming a solvate. If the solvent is water the solvate formed is a "hydrate," when the solvent
is alcohol, the solvate formed is an "alcoholate." "Polymorphs" (or "crystal forms") means crystal
structures in which a compound can crystallize in different crystal packing arrangements, all of which
have the same elemental composition. Different crystal forms usually have different X-ray diffraction
patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical
properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature,
and other factors may cause one crystal form to dominate.
[0063] The term "prodrug" refers to an inactive form of a compound which must be metabolized
in vivo, e.g., by biological fluids or enzymes, by a subject after administration into an active form of the
parent compound in order to produce the desired pharmacological effect. The prodrug can be
metabolized before absorption, during absorption, after absorption, or at a specific site. Prodrug forms
of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such
as masking or reducing unpleasant characteristics such as a bitter taste, odor, or gastrointestinal
irritability, alter solubility, provide for prolonged or sustained release or delivery, improve ease of
formulation, or provide site-specific delivery of the compound.
[0064] Prodrugs of a compound of this invention are prepared by modifying one or more
functional group(s) present in the compound in such a way that the modification(s) may be cleaved in
vivo to release the parent compound. Prodrugs include compounds wherein a hydroxyl group in a
compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free
hydroxyl, amino. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and
benzoate derivatives), carbamates (e.g., W,A/-dimethylaminocarbonyl) of hydroxy functional groups in
compounds of the invention, see Bundegaard, H. Design of Prodrugs. New York-Oxford: Elsevier, 1985,
pp. 1-92., and the like. Reference to a compound herein includes prodrug forms of said compound.
[0065] The term 'subject" includes, but is not limited to, humans and animals, such as farm
animals (cattle, horses, sheep, goats, and swine) and domestic animals (rabbits, dogs, cats, rats, mice
and guinea pigs. The term "subject" does not denote a particular age or sex.
[0066] The term "sulfanyl" or "thio" refers to the groups: -S-H, -S-(alkyl), -S-(aryl), or
-S-(heterocyclyl). The term is exemplified by groups such as isopropylthio and methyl thioacetate.
[0067] The term "therapeutically effective amount" refers to that amount of a compound of this
invention that is sufficient to effect treatment, as defined below, when administered to a subject in need
of such treatment. The therapeutically effective amount will vary depending upon the subject and

WO 2006/093548 15 PCT/US2005/044713
disease condition being treated, the weight and age of the subject, the severity of the disease condition,
the particular compound chosen, the dosing regimen to be followed, timing of administration, the manner
of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
[0068] The term "treatment" or "treating" means any treatment of a disease or disorder in a
subject, including:
• preventing or protecting against the disease or disorder, that is, causing the clinical symptoms
not to develop;
• inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical
symptoms; and/or
• relieving the disease or disorder that is, causing the regression of clinical symptoms.
[0069] It will be understood by those skilled in the art that in human medicine, it is not always
possible to distinguish between "preventing" and "suppressing" since the ultimate inductive event or
events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the
event or events. Therefore, as used herein the term "prophylaxis" is intended as an element of
"treatment" to encompass both "preventing" and "suppressing" as defined herein. The term "protection,"
as used herein, is meant to include "prophylaxis."
Nomenclature
[0070] In general, the nomenclature used in this Application was generated using or with the
help of the naming package within the ChemDrawUltra® version 9.0.1 suite of programs by
CambridgeSoft Corp. (Cambridge, MA).
Synthesis of the Compounds of the Invention
Synthetic Reaction Parameters
[0071] The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under
the conditions of the reaction being described in conjunction therewith. Solvents employed in synthesis
of the compounds of the invention include, for example, methanol ("MeOH"), acetone, water, acetonitrile,
1,4-dioxane, dimethylformamlde ("DMF"), benzene, toluene, tetrahydrofuran ("THF"), chloroform,
methylene chloride (also named dichloromethane ("DCM")), dlethyl ether, ethyl acetate ("EtOAc"),
pyridine and the like, as well as mixtures thereof. Unless specified to the contrary, the solvents used in
the reactions of the present invention are inert organic solvents.
[0072] Unless specified to the contrary, the reactions described herein take place at
atmospheric pressure within a temperature range from -10°C to 110°C. and in some cases at "room" or
"ambient" temperature, e.g., 20°C. Further, unless otherwise specified, the reaction times and
conditions are intended to be approximate.
[0073] Isolation and purification of the compounds and intermediates described herein can be
effected, if desired, by any suitable separation or purification procedure such as, for example, filtration,
extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer
chromatography, or a combination of these procedures. Specific illustrations of suitable separation and
isolation procedures can be had by reference to the examples herein below. However, other equivalent

WO 2006/093548 16 PCT/US2005/044713
separation or isolation procedures can also be used.
Reaction Scheme 1

[0074] Scheme 1 describes a synthesis for compounds of Formula I of the present invention
wherein X=S, CR5R6 form an azetidine or an oxetan ring, R7, R8, R9, R10 are hydrogen, and R1, R3, R4
are as described herein. Compound 101 can be treated with an ally! halide of formula 102, wherein Hal
is halide such as a bromide, A is a heteroatom such as O or N, n is 0 to 2, m is 0 to 2, and n+m =2, to
give a compound 103 wherein Pro is a protective group. Intramolecular cyclization catalyzed with a
Lewis acid such as boron trifluoride, followed by deprotection may yield a compound 104 wherein A is a
heteroatom such as O or N, n is 0 to 2, m is 0 or 2, and n+m =2.
Reaction Scheme 2

[0075] Scheme 2 describes a synthesis for compounds of Formula I, wherein X is O, R9 and
R10 form an azetidine or an oxetan ring, RB is hydrogen, and R1 to R4, and R5 to R7are as described
herein. The vinyl-cycloalcohol of formula 202, which may be prepared by Grignard reaction of a vinyl
magnesium bromide of formula CR5R6l=CR7MgBr with azetidinone or an oxetanone, under inert
conditions in a solvent such as tetrahydrofuran, may react with the phenol of formula 201 in the
presence of a Lewis acid, such as BF3-ether, methane sulfonic acid, p-toluene sulfonic acid, or
aluminum chloride, to give the compound of formula 203, wherein A is a heteroatom such as O or N, n is
0 to 2, m is 0 to 2, and n+m =2.

WO 2006/093548 16 PCT/US2005/044713
Reaction Scheme 3

[0076] Scheme 3 describes the synthesis for compounds of Formula I wherein R9 and R10 form
an azetidine or an oxetan ring; R5, Re, R7, R8 are hydrogen, R2 is hydroxy, R1, R3, and R4 are as
described herein, and X is S or NR, starting from compound of formula 301, wherein Pro is a protective
group, A is a heteroatom such as O or N, n is 0 to 2, m is 0 to 2, and n+m =2, and treating it with a
cycloalkylidene carboxylate of formula 302 to give a compound of formula 303. Intramolecular
cyclization in the presence of a Lewis acid may give compound of formula 304. Deprotection of
compound 304 may give the compound 305 that can be treated with alkoxyamine followed by reduction
with borane/pyridine complex to give a compound of formula 306. Compound 304 may also be reduced
with sodium borohydride followed by deprotection to yield compound of formula 307, which can be
further reduced under acidic conditions, such as with sodium borohydride in the presence of
trifluoroacetic aced to yield a compound of formula 308.
[0077] If X is NH, any of the compounds of formula 305, 306, 307 or 308 can be coupled with a
compound RL wherein R is as described herein but not hydrogen, and L is a leaving group such as an
halide for example a chloride, a bromide or an iodide to yield a derivative of Formula I wherein X is
substituted nitrogen.

WO 2006/093548 18 PCT/US2005/044713
3:
Scheme 4

[0078] Scheme 4 describes the synthesis for compounds of Formula I, wherein R9 and R10 form an
azetidine or an oxetan ring, R5, R6. R7, R8, are hydrogen and X is O, starting from a hydroquinone of
formula 401 wherein R1, R3 and R4 are as described herein, and treating it with acetylchloride to give
the diacetate which after work-up was further treated with boron trifluoride-acetic acid complex in the
presence of pyrrolidine to give the acetylacetate of formula 402. Treatment with azetidinone or
oxetanone of formula 403 wherein A is a heteroatom such as O or N, n is 0 to 2, m is 0 to 2, and n+m
=2, may give a compound of formula 404 that can be treated with alkoxyamine followed by reduction
with sodium/pyridine complex to give a compound 405. compound 404 may also be reduced with
sodium borohydride in methanol to yield a compound 406, which can be further reduced under acidic
conditions such as with sodium borohydride in the presence of trifluoroacetic aced to yield a compound
of formula 407.
Preferred Compounds
[0079] The compounds of Formula I encompass the derivatives of the invention as disclosed,
and/or the pharmaceutically acceptable salts of such compounds. In addition, the compounds of this
invention include the Individual stereochemlcal isomers and mixtures thereof, arising from the selection
of substituent groups. It will be understood by those skilled in the art with respect to any group
containing one or more substituents that such groups are not intended to introduce any substitution or
substitution patterns that are sterically impractical and/or synthetically non-feasible.

WO 2006/093548 19 PCT/US2005/044713
Utility, Testing and Administration
General Utility
[0080] Without subscribing to a particular theory or mechanism of action, compounds of the
invention may target certain enzymes known as "oxidoreductases" that function widely across a variety
of physiological processes, for example, certain compounds of the present invention may target
llpoxygenases such as 5-Lipoxygenase, 12-Lipoxygenase, 15-Lipoxygenase, and/or 12/15-
Lipoxygenase. In particular, oxidoreductases catalyze reactions in which two molecules interact so that
one molecule is oxidized and the other is reduced. Alterations in oxidoreductases are thought to
account for as many as 3% of all known human genetic diseases. Abnormalities in oxidoreductase
activity may underlie such disorders as congestive heart failure, respiratory chain defects (e.g.,
abnormalities associated with enzymes of the respiratory chain, acute respiratory distress syndrome
(ARDS)), glycogen storage disease, end-stage renal disease, and rheumatoid arthritis. Inhibitors of
lipoxygenases are known to be useful in the prevention or treatment of, for example, disorders selected
from apoptosis in cancer cells including prostatic cancer, gastric cancer, breast cancer, pancreatic
cancer, colorectal or esophageal cancer and airways carcinoma; diseases involving hypoxla or anoxia,
including atherosclerosis, myocardia! infarction, cardiovascular disease, heart failure (including chronic
and congestive heart failure), cerebral ischemia, retinal ischemia, myocardial ischemia, post surgical
cognitive dysfunction and other ischemias; diseases involving inflammation, including diabetes, arterial
inflammation, inflammatory bowel disease, Crohn's disease, renal disease, pre-menstrual syndrome,
asthma, allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle
fatigue and inflammatory disorders of the skin including acne, dermatitis and psoriasis; disorders of the
airways including asthma, chronic bronchitis, human airway carcinomas, mucus hypersecretlon, chronic
obstructive pulmonary disease (COPD), pulmonary fibrosls caused by chemotherapy or other drugs,
idiopathic pulmonary flbrosis, cystic fibrosis, and adult respiratory distress syndrome; diseases .involving
central nervous system (CNS) disorders including psychiatric disorders including anxiety and
depression; neurodegeneration and neuroinflammation including Alzheimer's, dementia and Parkinson's
disease; peripheral neuropathy including spinal chord injury, head injury and surgical trauma, and
allograft tissue and organ transplant rejection; diseases involving the autoimmune system including
psoriasis, eczema, rheumatoid arthritis, and diabetes; and disorders involving bone loss or bone
formation
[0081] Certain compounds of the present invention are also useful in treating conditions falling
with the group of dermatologic conditions, such as prevention and protection of skin tissue against age-
related damage or damage resulting from insults such as harmful ultraviolet (UV) radiation, use of
retinoids, wearing diapers, stress and fatigue, and in the treatment of contact dermatitis, skin irritation,
skin pigmentation, psoriasis, or acne.
Testing
[0082] This section describes how compositions incorporating compositions of the present

WO 2006/093548 20 PCT/US2005/044713
invention are selected, using in vitro and/or in vivo models, and used as therapeutic interventions in the
exemplary indications in support of the present invention.
[0083] The 5-Lipoxygenase pathway Is a major synthetic pathway relevant to human
inflammatory disease. The enzyme 5-Lipoxygenase catalyses the two first steps in the oxygenation of
arachidonlc acid (a polyunsaturated 20-carbon fatty acid) to leukotrienes. Leukotrienes are known to be
important mediators of inflammatory and allergic reactions. The first step in the synthesis of
leukotrienes, which is catalyzed by 5-Lipoxygenase, is the formation of 5-HPETE. The rearrangement of
5-HPETE to form the unstable LTAi, the rate-limiting step in the synthesis of the leukotrienes, Is also
catalyzed by 5-Lipoxygenase. LTA4 is then converted to either LTB4 or LTC4. LTC4 is rapidly
metabolized to LTD4 and then to LTE4. LTC4, LTD4and LTE4 are collectively referred to as the cysteinyl
(Cys) leukotrienes.
[0084] Biosynthesis of LTB4, LTC4, LTD4 and LTE4 occurs predominantly in leukocytes, in
response to a variety of immunological stimuli. The primary target of LTB4 is the leukocyte where it elicits
enzyme release, chemotaxis, adherence, and aggregation in nM concentrations. LTB4 modulates
immune responses and participates in the host-defense against infections. Hence, LTB4 is an important
chemical mediator in the development and maintenance of inflammatory reactions and disease states.
[0085] Endogenous lipoxygenase metabolites may also be involved in enhanced cytoklne
tumor necrosis factor a (TNF-α) production following certain stimuli such as silica, asbestos and
lipopolysaccharides (Rola-Pleszczynski, M et al. Mediators of Inflammation 1 : 5-8 (1992)). Consistent
with selective lipoxygenase inhibitory effect, certain compounds of the present invention have also
shown to have an inhibitory effect on TNF-Α. synthesis and/or release. The TNF-α" has a broad
spectrum of biological activities, plays an important role in coordinating the body's response to infection,
and serves as an Important mediator of inflammation. It is known that inflammatory cytokines have been
shown to be pathogenic in several diseases including, but not limited to asthma (N. M. Cembrzynska et
al., Am. Rev. Respir. Dis., 147, 291 (1993)), Adult Respiratory Distress Syndrome (ARDS). (Miller et al.,
Lancet 2 (8665); 712-714 (1989) and Ferrai-Baliviera et al., Arch. Surg. 124 (12): 1400-1405 (1989)),
lung flbrosis (Piguet et al., Nature, 344:245-247 (1990) and Bissonnette et al., Inflammation 13 (3): 329-
339 (1989)), bone resorption diseases (Bertolini et al., Nature 319: 516-518 (1986) and Johnson et al.,
Endocrinology 124 (3): 1424-1427 (1989)), auto-immune diseases (W. Fiers, FEBS Lett., 1991, 285, p.
199). It will be therefore appreciated that compounds of the present invention showing an inhibitory
effect on both 5-Lipoxygenase and TNF-o should be superior in the treatment or amelioration of for
example diseases such as respiratory disorders, antiprolilferative disorders or autoimmune disorders.
[0086] In vitro evaluation of the ability of a composition to inhibit the enzymes 5-Lipoxygenase,
15-Lipoxygenase, or 12/15-Lipoxygenase as described in Walidge, N.B. et al. Anal. Biochem., Vol. 231
(1995), pp. 354-358 using a high throughput colorimetric method; as well as In vitro evaluation of
inhibiting LTB4 is described in Examples.
[0087] In v'rtro cell-based assays for Inflammation are well known in the art, for example, e-
selectin (also named Endothelial Leukocyte Adhesion Molecule or ELAM) or C-reactive protein (CRP).

WO 2006/093548 21 PCT/US2005/044713
The ELAM assay measures in vitro activity of the test compounds in reducing expression of ELAM in
activated endothelial cells. Briefly, endotheliai cells are created by adding known activators such as
lipopolysaccharides, TNF or IL-1β, alone or in some combination. Activated cells produce ELAM, which
can be measured using, for example, an E-selectin monoclonal antibody-based ELISA assay.
[0088] In vivo evaluation of anti-inflammatory activity can be determined by well characterized
assays measuring Carrageenan-lnduced Paw Edema, by Mouse Ear Inflammatory Response to Topical
Arachidonic Acid (Gabor, M. Mouse Ear Inflammation Models and their Pharmacological Applications
(2000)), or by the in vivo murine Zymosan peritonitis assay. Carrageenan-lnduced Paw Edema is a
model of inflammation, which causes time-dependent edema formation following carrageenan
administration into the Intraplantar surface of a rat paw. The application of arachidonic acid to the ears
of mice produces immediate vasodilation and erythema, followed by the abrupt development of edema,
which is maximal at 40 to 60 min. The onset of edema coincides with the extravasations of protein and
leukocytes. After one hour the edema wanes rapidly and the inflammatory cells leave the tissue so that
at 6 hours the ears have returned to near normal.
[0089] Administration of Zymosan-A, a purified polysaccharide fraction of yeast cell wall has
been used since the 1980s to Induce acute inflammatory response in rodents. The inflammatory
response is characterized by marked induction of pro-inflammatory cytokines, influx of inflammatory
cells and biosynthesis of arachidonic acid metabolites as early as five minutes after the Zymosan
injection. The purpose of this model is to evaluate the ability of compounds to reduce inflammatory
response induced by administration of Zymosan-A and assessed by the level of inflammatory cytokines
and arachidonic metabolites in the fluid exudates.
[0090] These assays, as described in the Examples, measure a test compound's ability to treat
these inflammatory processes via systemic and topical routes of administration.
10091] Protection against redox stress can be evaluated in cell culture using high glutamate
induced oxidative stress (HGOS) in mouse dopaminergic cell lines. The cytotoxic effect of glutamate is
not due to excitotoxicity, as this cell line is devoid of inotropic glutamate receptors. Rather, the
glutamate-lnduced toxicity of dopaminergic cells is associated with an inhibition of cystine transport
which subsequently leads to depletion of intracellular glutathione (GSH) levels (Murphy T. H., et al.
Neuron, Vol. 2 (1989), pp. 1547-1558), activation of neuronal 12-Lipoxygenase (Li, Y. et al. Neuron, Vol.
19 (1997), pp. 453-463), increased ROS production (Tan S. et al. J. Cell BioI., Vol. 141 (1998), pp.
1423-1432) and elevated intracellular Ca2+ (Li, Y. et al. see supra). Some molecules were measured for
their ability to protect cells against glutamate-induced stress and the assay is detailed in Examples.
[0092] Further validation of neuroantiinflammatory activity of compounds can be assessed in
vitro by the inhibition of IL-1 .beta, release from a microglial cell line.
[0093] lnterleukin-1 (IL-1) is a pro-inflammatory cytokine that exists in two separate forms that
share 30% sequence homology (alpha and beta). Constitutive expression of IL-1 is low in the brain but
levels of both forms of this cytokine increase dramatically after injury. There is substantial evidence that
IL-1 is an important mediator of neurodegeneration induced by cerebral ischemia (Touzani, O. et al. J.

WO 2006/093548 22 PCT/US2005/044713
Neurolmmunol., Vol. 100 (1999), pp. 203-215). Both IL-1 forms are rapidly induced in experimental
models of stroke and administration of recomblnant IL-1β enhances ischemic injury (see Hill J.K., et al.
Brain Res., Vol. 820 (1999), pp. 45-54); Hillhouse E.W. et al. Neurosci. Lett. Vol. 249 (1998), pp. 177-
179; LoddickS.A. etal. J. Cereb. Blood Flow Metab. Vol. 16(1996), pp. :932-940; StroemerR-P. et a/.
J. Cereb. Blood Flow Metab. Vol. 18 (1998), pp. 833-839). Conversely, blocking IL-1 actions with a
receptor antagonist or a neutralizing antibody markedly reduces neuronal death and inflammation in
models of ischemic damage (see Betz, A.L., J. Cereb. Blood Flow Metab. Vol. 15(1995), pp. 547-551;
Relton, J.K., Brain Res. Bull. Vol. 29 (1992), pp. 243-246; Yamasaki, Y. et al. Stoke, Vol. 26 (1995), pp.
676-680). Furthermore, mice with decreased IL-1/? production (caspase-1 knockouts) are significantly
protected from ischemic injury (Schlelke, G.P. et al. J. Cereb. Blood Flow Metab. Vol. 18 (1998), pp.
180-185) and IL-1" and p double knockouts exhibit dramatically reduced ischemic infarct volumes
compared with wild-type mice (87% reduction in cortex) (Boutin, H. et al. J. Neurosci. Vol. 21 (2001), pp.
5528-5534).
[0094] In addition to a role in Ischemic damage, IL-1 elevation has been associated with many
neurodegenerative diseases. There is increasing evidence for a role of IL-1 in Alzheimer's disease (AD)
(Mrak, R.E. et al. Neurobiol. Aging, Vol. 22, no. 6 (2001), pp. 903-908). Elevated levels of IL-1/? have
been shown to surround amyloid plaques in the disease and recent genetic studies have indicated that a
polymorphism in IL-1" is linked to an increased risk of AD (3-6 fold increase) (Griffin, W.S. et al. J.
Leukoc. Biol. Vol. 72, no. 2 (2002), pp. 233-238). This polymorphism has also been correlated with rate
of cognitive decline in AD patients (Murphy, G.M. et al. Neurology, Vol. 56, no. 11 (2001), pp. 1595-
1597). The risk of AD is increased even further when the polymorphism in IL-1 .alpha. Is found in
combination with another polymorphism in IL-1/? (see Griffin, W.S., supra), providing convincing
evidence that these cytokines play an important role in the pathology of the disease.
[0095] This assay measures the release of IL-1β from a mouse microglial cell line following an
inflammatory challenge with LPS and interferon-gamma. The ability of test articles to inhibit microglial
cell activation and IL-1β release is determined by co-incubation of the test article with the inflammatory
challenge.
[0096] Cerebral ischemic insults are modeled In animals by occluding vessels to, or within, the
cranium (Molinari, G.F. in: Barnett, H.J.M. et al. (Eds.), Stroke: Pathophysiology, Diagnosis and
Management, Vol. 1 (New York, Churchill Livingstone, 1986). The rat middle cerebral artery occlusion
(MCAO) model is one of the most widely used techniques to induce transient focal cerebral ischemia
approximating cerebral ischemic damage in humans, e.g., those who suffer from a stroke. The middle
cerebral artery used as the ischemic trigger in this model is the most affected vessel In human stroke.
The model also entails a period of reperfuslon, which typically occurs in human stroke victims. MCAO
involving a two-hour occlusion has been found to produce the maximum size of cortical infarction
obtainable without Increased mortality at twenty-four hours.
Administration
[0097] The compounds of the invention are administered at a therapeutlcally effective dosage,

WO 2006/093548 23 PCT/US2005/044713
e.g., a dosage sufficient to provide treatment for the disease states previously described. Administration
of the compounds of the invention or the pharmaceutically acceptable salts thereof can be via any of the
accepted modes of administration for agents that serve similar utilities.
[0098] While human dosage levels have yet to be optimized for the compounds of the
Invention, a dose may be from about 1 mg to 1 g, preferably 10 mg to 500 mg and most preferably 10
mg to 100 mg per administration. The amount of active compound administered will, of course, be
dependent on the subject and disease state being treated, the severity of the affliction, the manner and
schedule of administration, and the judgment of the prescribing physician.
[0099] In employing the compounds of this invention for treatment of the above conditions, any
pharmaceutically acceptable mode of administration can be used. The compounds of this invention can
be administered either alone or in combination with other pharmaceutically acceptable exclpients,
including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets, capsules,
powders, liquids, suspensions, suppositories, aerosols or the like. The compounds of this invention can
also be administered in sustained or controlled release dosage forms, including depot injections,
osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the prolonged
administration of the compound at a predetermined rate, for example, in unit dosage forms suitable for
single administration of precise dosages. The compositions will typically include a conventional
pharmaceutical carrier or excipient and a compound of this invention or a pharmaceutically acceptable
salt thereof. In addition, these compositions may include other medicinal agents, pharmaceutical
agents, carriers, adjuvants, and the like, including, but not limited to, anticoagulants, blood clot
dissolvers, permeability enhancers, and slow release formulations.
[0100] Generally, depending on the intended mode of administration, the pharmaceutically
acceptable composition will contain about 0.1% to 90%, for example about 0.5% to 50%, by weight of a
compound or salt of this invention, the remainder being suitable pharmaceutical excipients, carriers, etc.
[0101] One manner of administration for the conditions detailed above is oral, using a
convenient daily dosage regimen which can be adjusted according to the degree of affliction. For such
oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the incorporation
of any of the normally employed excipients, such as, for example, mannitol, lactose, starch, magnesium
stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose,
magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets,
dispersible tablets, pills, capsules, powders, sustained release formulations, and the like.
[0102] Certain compositions will take the form of a pill or tablet and thus the composition will
contain, along with the active Ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the
like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia,
polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
[0103] Liquid pharmaceutically administrate compositions can, for example, be prepared by
dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants
in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the

WO 2006/093548 24 PCT/US2005/044713
like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be
administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents,
emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, sodium acetate,
sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine
oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those
skilled in this art; for example, see Remington's Pharmaceutical Sciences, 15th Edition, Easton, PA,
Mack Publishing Company, 1975. The composition or formulation to be administered will, in any event,
contain a quantity of the active compound in an amount effective to alleviate the symptoms of the
subject being treated. Dosage forms or compositions containing active ingredient in the range of
0.005% to 95% with the balance made up from non-toxic carrier may be prepared.
[0104] For a solid dosage form, the solution or suspension in for example, propyiene
carbonate, vegetable oils or trigiycerides, is encapsulated in a gelatin capsule. Such diester solutions,
and the preparation and encapsulation thereof, are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239;
and 4,410,545. For a liquid dosage form, the solution, e.g. in a polyethylene glycol, may be diluted with a
sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for
administration.
[0105] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or
dispersing the active compound or salt in vegetable oils, glycols, trigiycerides, propyiene glycol esters
(e.g. propyiene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft
gelatin capsule shells.
[0100] The formulation can be administered in a single unit dosage form for continuous
treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. For
example, the formulation may be administered as a bolus or as a continuous intravenous infusion after
onset of symptoms of stroke, myocardial infarction or chronic heart failure.
[0101] Another manner of administration is the topical administration. Topical administration"
refers to application of the present compositions by spreading, spraying, etc. onto the surface of the
skin. The typical amount applied may vary from about 0.1 mg of composition per square centimeter of
skin to about 25 mg of composition per square centimeter of skin. Certain compounds of the present
invention may be formulated for topical administration to the epidermis as ointments, creams or lotions,
or as transdermal patch. Formulations suitable for topical administration in the mouth include lozenges,
pastilles and mouthwashes.
[0102] Parenteral administration is generally characterized by injection, either subcutaneously,
intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid
solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as
emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In
addition, if desired, the pharmaceutical compositions to be administered may also contain minor
amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents,
solubility enhancers, and the like, such as, for example, sodium acetate, sorbitan monolaurate,

WO 2006/093548 25 PCT/US2005/044713
triethanolamine oleate, cyclodextrins, etc.
[0103] Another approach for parenteral administration employs the implantation of a
slow-release or sustained-release system, such that a constant level of dosage Is maintained. The
percentage of active compound contained in such parenteral compositions is highly dependent on the
specific nature thereof, as well as the activity of the compound and the needs of the subject However,
percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the
composition is a solid which will be subsequently diluted to the above percentages.
[0104] Nasal solutions of the active compound alone or In combination with other
pharmaceutically acceptable excipients can also be administered.
[0105] Formulations of the active compound or a salt may also be administered to the
respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone
or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation
have diameters of less than 50 microns, for example less than 10 microns.
EXAMPLES
[0106] The following preparations and examples are given to enable those skilled in the art to
more clearly understand and to practice the present invention. They should not be considered as
limiting the scope of the invention, but merely as being Illustrative and representative thereof.
General Characterization Methods
[0107] Nuclear Magnetic Resonance (NMR) spectra is recorded on a Bruker DTX 300 ■
spectrometer using, in most cases, tetramethyl silane (TMS) as the internal reference. Mass spectra is
obtained on an Agilent 1100 LC/MSD Instrument using either electrospray ionization (positive or.
negative mode) (ESI) or atmospheric pressure chemical ionization (positive or negative mode) (APCI).
[0108] Further, abbreviations used throughout the specification have the following meanings:
DMSO = dimethyl sulfoxide
ELISA = enzyme-linked immunosorbant assay
FBS = fetal bovine serum
h = hour
IC50 = The molar concentration of a drug, which produces 50% of the maximum
possible inhibition for that drug
M = Molar
M = molar
mg = milligram
min = minute
mL = milliliter
mM = millimolar
mmol = millimole
PBS = phosphate buffered saline

WO 2006/093548 26 PCT/US2005/044713
pg = picograms
ΜL = microliter
μM = micromolar
Example 1
5-Llpoxygenase Enzyme Assay
[0109] This procedure is used for measuring the enzymatic activity of human recombinant 5-
lipoxygenase using a colorimetric method based on the ferric oxidation of xylenol orange.
Materials
- 96 well flat bottom microfilter plates (VWR, Catalog # 62402-933 9295)
- Lipoxygenase screening assay buffer (Cayman, Catalog # 760710)
- Human recombinant 5-Lipoxygenase (Cayman, Catalog # 60402)
- Arachidonic Acid (Sigma, Catalog # A3555)
- Xylenol orange tetrasodlum salt (Aldrich, Catalog # 227854)
- Iron (II) sulfate heptahydrate (Sigma, Catalog # F7002)
- Sulfuric acid (95-98%) [18 M]
- Methanol
Procedure
[0110] Human recombinant 5-lipoxygenase (Cayman Cat # 60402) Is used in this assay. The
test compound and/or vehicle is added to 0.5μL 5-lipoxygenase in 50 mM Tris-HCI buffer, pH 7.4. The
reaction is initiated by addition of 70 μM arachidonic acid in Trls-HCI buffer, pH 7.4, and terminated after
a 10 minute incubation at room temperature by addition of FOX reagent (25 mM sulfuric acid, 100μM
xylenol orange, 100μM iron (II) sulphate, methanokwater 9:1). The yellow color of acidified xylenol
orange Is converted to a blue color by the lipid hydroperoxlde-mediated oxidation of Fe2+ Ions and the
interaction of the resulting Fe3+ ions with the dye. The complex is allowed to form during a 1 hour
incubation at room temperature with shaking. Absorbance of the Fe3+ complex was then measured at
620 nM using a spectrophotometer.
[0111] Negative controls contained enzyme during the incubation step but substrate Is not
added until after the FOX reagent. Compounds are screened at 5 concentrations In triplicate starting at
10 μM.
[0112] Certain compounds of the present invention when tested by this method may show
Inhibition of 5-Llpoxygenase enzyme.

WO 2006/093548 27 PCT/US2005/044713
Example 2
12/15-Llpoxygenase Enzyme Assay
[0113] This procedure is used for measuring the enzymatic activity of porcine leukocyte 12/15-
lipoxygenase using a colorimetric method based on the ferric oxidation of xylenol orange.
Materials
- 96 well flat bottom microfilter plates (VWR, Catalog # 62402-933 9296)
- Lipoxygenase screening assay buffer (Cayman, Catalog # 760710)
- Porcine leukocyte 12/15-lipoxygenase (Cayman, Catalog # 60300)
- Arachldonic Acid (Sigma, Catalog # A3555)
- Xylenol orange tetrasodium salt (Aldrich, Catalog # 227854)
- Iron (II) sulfate heptahydrate (Sigma, Catalog # F7002)
- Sulfuric acid (95-98%) [18 M]
Methanol
Procedure
[0114] Porcine Leukocyte 12/15-lipoxygenase (Cayman Cat # 60300) is used in this assay.
Test compound and/or vehicle are added to 1.3 μL 12/15-lipoxygenase in 50 mM Tris-HCI buffer,
pH 7.4. The reaction is initiated by addition of 70 μM arachidonic acid in Tris-HCI buffer, pH 7.4, and
terminated after a 10 minute incubation at room temperature by addition of FOX reagent (25 mM sulfuric
add, 100μM xylenol orange, 100 μM iron (II) sulphate, methanokwater 9:1). The yellow color of acidified
xylenol orange Is converted to a blue color by the lipid hydroperoxide-mediated oxidation of Fe2+ ions
and the interaction of the resulting Fe3+ ions with the dye. The complex is allowed to form during a
1 hour incubation at room temperature with shaking. Absorbance of the Fe3* complex is then measured
at 620 nM using a spectrophotometer.
[0115] Negative controls contained enzyme during the incubation step but substrate is not
added until after the FOX reagent. Compounds are screened at 5 concentrations in triplicate starting at
10 μM.
[0116] Certain compounds of the present invention may show inhibition of 12/15-Lipoxygenase
enzyme when tested by this method.
Example 3
Inhibition of LTB4 Production in Blood
[0117] The following materials are used for this protocol-
Materials
Human whole blood (Na citrate) (Stanford Blood Center)
A23187, (Sigma, Cat # C-7522)
Leukotriene B4 El A reagents (Cayman Chemical, Cat # 520111)
BWA4C (Sigma, Cat # B7559)

WO 2006/093548 28 PCT/US2005/044713
Procedure
Preparation of A23187:
[0118] A23187 is prepared as a 10 mM stock solution in DMSO (aliquots can be stored at -
20°C). On the day of the assay the stock solution is diluted as follows: 70 μL 10 mM stock added to
1.6 mL plasma to give a working concentration of 0.42 mM.
Preparation of test articles:
[0119] From a 30 mM stock solution in DMSO, test articles are diluted to a working
concentration of 600 uM in PBS (i.e. 10 μl stock solution and 490 μI PBS). This Is the highest
concentration (gives a final testing concentration of 30 μM). From this 600 uM solution test articles are
serially diluted 1:3 in PBS to give a dose-response curve. 10μl of each concentration of test article Is
then added to 4 wells of a 96-well plate (i.e. testing in quadruplicate). A positive control compound,
BWA4C is used in every assay.
Blood stimulation procedure
[0120] Human whole blood is added to the plates containing compounds (190 μl per well) and
mixed well. The blood is incubated with compound at 37 °C for 15 minutes. Following this incubation, 10
μ\ of 0.42 mM A23187 is added to each well except the negative control wells, to give a final calcium
ionophore concentration of 20 ΜM. The plates are then incubated at 37 °C for 60 minutes. After the
incubation period, plates are centrifuged for 15 min at 2000 g at 4 °C in sealed microplate buckets.
Plasma is then removed for quantitation of LTB4 levels by ELISA.
Measurement of LTB4 levels by ELISA
[0121] LTB4 levels in the plasma are determined using a commercially available ELISA kit from
Cayman Chemicals. The ELISA is run according to the manufacturer's instructions. The LTB4 levels in
the vehicle control sample are then compared to those in which the test article has been added. From
this a percent inhibition of LTB4 production by each concentration of test article is calculated and the ICso
is determined.
[0122] Certain compounds of this invention when tested as described above, may show activity
in this assay.
Example 4
LTB4-Cell Assay
[0123] This procedure is used for measuring the release of the leukotrlene LTB4 from a
neutrophii cell line using a competitive ELISA technique.
Materials and Equipments
Materials for cell preparation and experiment
MPRO cell line (ATCC, Catalog # CRL-11422)
Calcium ionophore (A23187) (Sigma, Catalog # C7522)

WO 2006/093548 29 PCT/US2005/044713
Nordihydroguaiaretic acid (NDGA) (BioMol .Catalog # EM 01 -0001)
Retinoic Acid (all-trans) (ATRA) (Sigma, Catalog # 95152)
Sterile, tissue-culture treated 96-well plates (Corning, Catalog # 3614)
Materials for LTB4 ELISA
Precoated (Mouse Anti-Rabbit IgG) EIA 96 Well Strip Plates (Cayman, Catalog # 400004)
Leukotriene B4 AChE Tracer (Cayman Catalog # 420110)
Leukotrlene B4 EIA Antiserum (Cayman Catalog # 420112)
Ellman's Reagent (Cayman Catalog # 400050)
EIA Buffer Concentrate (1 OX) (Cayman Catalog # 400060)
Wash Buffer Concentrate (400X) (Cayman Catalog # 400062)
Plastic plate covers (Cayman Catalog # 400012)
Procedure
[0124] A mouse promyelocytic cell line (MPRO) is used in this assay. These cells are
committed immature neutrophils that can be differentiated into mature neutrophils by treatment with
10 M all-trans retinoic acid for 72 hours.
[0125] Following 72 hours of differentiation, cells are stimulated with 1 M of a calcium
ionophore (A23187) in the presence or absence of test compound or vehicle for 1 hour at 37 °C. After
this time, supernatant is removed from the cells and the LTB4 levels are determined following
manufacturer's Instructions, using a Leukotriene B4 EIA kit from Cayman (Cat # 520111).
[0126] The negative controls are media samples from differentiated but unstimulated cells.
The compounds are screened at 5 concentrations in quadruplicate starting at 10 A. Certain
compounds of this invention when tested as described above, may show activity in this assay.
Example 5
Inflammation assay - Cell-ELAM Assay
[0127] Endothelial-Leukocyte Adhesion Molecule (ELAM), also known as E-selectin, is
expressed on the surface of endothelial cells. In this assay, lipopolysaccharide (LPS) and IL-1 are
used to stimulate the expression of ELAM; test agents are tested for their abilities to reduce this
expression, in accordance with studies showing that reduction of leukocyte adhesion to endothelial cell
surface is associated with decreased cellular damage (e.g., Takada, M., et al., Transplantation 64:1520-
25,1997; Steinberg, J.B., et al., J. Heart Lung Trans. 13:306-313, 1994).
[0128] Endothelial cells may be selected from any of a number of sources and cultured
according to methods known in the art; including, for example, coronary artery endothelial cells, human
brain microvascular endothelial cells (HBMEC; Hess, D.C., et al., Neuroscl. Lett. 213(1): 37-40,1996),
or lung endothelial cells. Cells are conveniently cultured in 96-well plates. Cells are stimulated by
adding a solution to each well containing 10 g/mL LPS and 100 pg/mL IL-1 for 6 hours in the
presence of test agent (specific concentrations and time may be adjusted depending on the cell type).
Treatment buffer is removed and replaced with pre-warmed Fixing Solution® (100/l/well) for 25 minutes

WO 2006/093548 29 PCT/US2005/044713
at room temperature. Cells are then washed 3X, then incubated with Blocking Buffer (PBS + 2% FBS)
for 25 minutes at room temperature. Blocking Buffer containing Monoclonal E-Selectin Antibody (1:750,
Sigma Catalog #S-9555) is added to each well. Plates are sealed and stored at 4 "C overnight Plates
are washed 4X with 160 L Blocking Buffer per well. Second Antibody-HRP diluted 1:5000 in Blocking
Buffer is then added (100 L/well), and plates are incubated at room temperature (protected from light)
for two hours. Plates are then washed 4X with Blocking Buffer before addition of 100 /L of ABTS
Substrate solution at room temperature (Zymed, Catalog #00-2024). Wells are allowed to develop for
35 minutes, before measurement at 402 nm in a Fluoroskan® Reader with shake program for 10
seconds. Positive results are recorded as a decrease in ELAM concentration in tested wells, as
compared to control wells.
[0129] Certain compounds of this invention when tested as described above, may show activity
in this assay.
[0130] While the present invention has been described with reference to the specific
embodiments thereof, it should be understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the true spirit and scope of the
invention. In addition, many modifications may be made to adapt a particular situation, material,
composition of matter, process, process step or steps, to the objective, spirit and scope of the present
invention. Ail such modifications are intended to be within the scope of the claims appended hereto. Ail
patents and publications cited above are hereby incorporated by reference.

WO 2006/093548 31 PCT/US2005/044713
1. A compound represented by Formula I:

Formula I
wherein,
X is 0, S(O)0-2, or NR;
R1, R3, and R4 are independently selected from the group consisting of hydrogen, alky),
cycloalkyl, halogen, nitro, cyano, amino, aminosulfonyl, sutfanyi, aryl, heterocyclyl, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, and aminocarbonyl;
R2 is selected from the group consisting of hydroxy, amino, aminocarbonyl, alkoxy, -O-
alkenyl,-O-acyl, -O-alkylene-amlno, -O-C(O)-alkylene-COORa; -O-C(O)-alkylene-amino; -O-
C(O)-alkylene-heterocyclyl; -O-glucoside; -O-phosphoryl, -O-alkylene-phosphoryl; -O-C(O)-
AA, wherein AA is an amino acid, or a di-, tri- or tetra-peptide;
R5 and R6 are
• independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkylcarbonyl, amino, amido, aminosulfonyl, sulfonylamino, sulfanyl, nitro,
cyano, halogen, -NRdORa, and -NRd-NRbRc; or
• together with the carbon atom to which they are attached form C=O, C=NORa, C=N-NRbRc,
optionally substituted (C3-C8)cycloalkyl ring, an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
R7 and R8 are
independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkylcarbonyl, amino, amido, aminosulfonyl, sulfonylamino, sulfanyl, nitro,
cyano, halogen, -NRdORa, and -NRd-NRbRc; or
■ together with the carbon atom to which they are attached form C=O, C=NORa, C=N-NRbRc,
optionally substituted (C3-C8)cycloalkyl ring, an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
R9 and R10 are
■ independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy,
alkoxy, carboxy, alkyl carbonyl, amino, amido, aminosulfonyl, sulfonylamino, sulfanyl, nitro,
cyano, halogen, -NRdORa, and -NRd-NRbRc; or
■ together with the carbon atom to which they are attached form C=O, C=NORa, C=N-NRbRc an
optionally substituted (C3-C8)cycloalkyl ring, an optionally substituted azetidine ring or an
optionally substituted oxetan ring;

WO 2006/093548 32 PCT/US2005/044713
R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, aikynyl, acyl,
aminocarbonyl, heterocycly! and aryl;
Ra is selected from the group consisting of hydrogen, alkyi, cycloalkyl, alkenyl, acyl,
heterocycly), and aryl;
RbandRcare
■ independently selected from the group consisting of hydrogen, alkyi, cycloalkyl, alkenyl, acyl,
aminocarbonyl, heterocyclyl and aryl; or
■ together with the nitrogen atom to which they are attached form an optionally substituted,
saturated or unsaturated 3-8 membered ring optionally incorporating 1 to 3 N, O, or S atoms;
Rd is hydrogen or alkyl; and
with the proviso that
• at least one of-CR5R8, -CR7R8, and -CR9R10 is an optionally substituted azetidine ring or an
optionally substituted oxetan ring;
or single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts
thereof.
2. The compound of Claim 1, wherein R2 is hydroxy, and R1, R3, and R4 are independently
hydrogen or alkyl.
3. The compound of Claim 2, wherein -CR5R6 is an optionally substituted azetidine ring or an
optionally substituted oxetan ring.
4. The compound of Claim 2, wherein -CR7R8 is an optionally substituted azetidine ring or an
optionally substituted oxetan ring.
5. The compound of Claim 2, wherein -CR9R10 is an optionally substituted azetidine ring or an
optionally substituted oxetan ring.
6. The compound of Claim 2, wherein X is O or S.

7. The compound of Claim 6, wherein R5 is selected from the group consisting of hydroxy,
-NRdORa, or-NRd-NRbRc and R8 is hydrogen.
8. The compound of claim 2, wherein R5 and R8 are both hydrogen.
9. The compound of Claim 2, wherein X is NR.

WO 2006/093548 PCT/US2005/044713
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10. The compound of Claim 9, wherein R is substituted with an amido, a sulfonytamino or an
amlnosuffonyl group.
11. The compound of Claim 10, wherein R is -(CH2)2-6-NRdS(O)2-aryl, -(CH2)2-6-S(O)2NRd-aryl;
-(CH2WNRdC(O)-aryl or -(CH2)2-C(O)NRd-aryl.
12. A pharmaceutical composition comprising a compound of Claim 1 admixed with a
pharmaceutically acceptable exclpient.
13. A method of treating a subject with a lipoxygenase mediated condition comprising administering
to said subject a therapeutlcally effective amount of a compound of Claim 1.
14. The method of Claim 13, wherein the subject is a mammal suffering from diseases selected
from the group consisting of apoptosis in cancer cells including prostatic cancer, gastric cancer,
breast cancer, pancreatic cancer, colorectal or esophageal cancer and airways carcinoma;
diseases involving hypoxia or anoxia including atherosclerosis, myocardlal infarction,
cardiovascular disease, heart failure (including chronic and congestive heart failure), cerebral
ischemia, retinal ischemia, myocardial ischemia, post surgical cognitive dysfunction and other
ischemias; diseases involving inflammation, including diabetes, arterial inflammation,
inflammatory bowel disease, Crohn's disease, renal disease, pre-menstrual syndrome, asthma,
allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle
fatigue and inflammatory disorders of the skin including acne, dermatitis and psoriasis; disorders
of the airways including asthma, chronic bronchitis, human airway carcinomas, mucus
hypersecretion, chronic obstructive pulmonary disease (COPD) pulmonary fibrosis caused by
chemotherapy or other drugs, Idiopathic pulmonary fibrosis, cystic fibrosis and adult respiratory
distress syndrome; diseases involving central nervous system (CNS) disorders including
psychiatric disorders including anxiety and depression; neurodegeneration and
neuroinflammation including Alzheimer's, dementia and Parkinson's disease; peripheral
neuropathy including spinal chord injury, head injury and surgical trauma, and allograft tissue
and organ transplant rejection; diseases involving the autoimmune system including psoriasis,
eczema, rheumatoid arthritis, and diabetes; and disorders involving bone loss or bone
formation.
The method of Claim 13, wherein the subject Is a mammal suffering from diabetes, arthritis,
rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, or
atherosclerosis.
A compound, represented by Formula I; a pharmaceutical composition; a method
of treating a subject with a lipoxygenase mediated condition substantially as
herein described with reference to the siven examples.

The present invention is concerned with certain derivatives of Formula:(I). wherein R. R1 to R10
are as described in the specification, and at least one of CR5R6, or CR7R8, or CR9R10 is a an
optionally substituted azetidine ring or an optionally substituted oxetan ring, which may be
useful in the manufacture of pharmaceutical compositions for treating disorders mediated by
lipoxygenases. They may also be useful in the manufacture of pharmaceutical formulations for
the treatment of lipoxygenase mediated disorders.