CA2341440A1 - Novel compounds - Google Patents

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Publication number
CA2341440A1
CA2341440A1 CA002341440A CA2341440A CA2341440A1 CA 2341440 A1 CA2341440 A1 CA 2341440A1 CA 002341440 A CA002341440 A CA 002341440A CA 2341440 A CA2341440 A CA 2341440A CA 2341440 A1 CA2341440 A1 CA 2341440A1
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Prior art keywords
formula
compound
biphenyl
yloxy
nr9r10
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CA002341440A
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French (fr)
Inventor
David Cladingboel
Simon Hirst
David Cheshire
Michael Stocks
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AstraZeneca AB
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    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to novel pyridyl derivatives (I), their use as medicaments, pharmaceutical formulations including them and methods for thei r preparation.

Description

The Swedish Patent Office PST/ S E 9 9 / 0 1 6 0 0 P ,T International Appllcatton NOVEL COMPOUNDS
This invention relates to novel pyridyl derivatives, their use as medicaments, pharmaceutical formulations including them and methods for their preparation.
s PCT Patent Applications PCT/SE98/00423, PCT/SE98/00505 and PCT/SE98/00575 disclose pyridine alkanol derivatives and their use as mast cell inhibitors.
A series of structurally distinct compounds have now been found to be useful for the ~o modulation of inflammatory conditions. In a first aspect the present invention therefore provides a compound of formula I:
OH
A (CR' R2) ~X~Ar' (R)n ~ s (I) wherein;
A is a phenyl or a S- or 6-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R is halogen, nitro, C,~ alkyl, C,~ alkoxy, (CHZ)PR3 where p is 0 to 3 and R3 is hydroxy, or zo NR4R5 where R~ and RS are independently hydrogen or C,~ alkyl or R is CONR4R5;
nis0, l,2or3;
X is O, S or CHz;
R' and R' are independently hydrogen, C,~ alkyl or C3_6 cycloalkyl or R' and RZ together with the carbon atom to which they are attached form a C3_f; cycloalkyl group;
zs Ar' is biphenyl, naphthyl or tetrahydronaphthyl, each Ar' group being optionally substituted by halo, nitro, C,~ alkyl (optionally substituted by one or more fluorine atoms), CN, -Y-NRgC(O)NR9R'°, -O-Y-C(O)NR9R'°, -O-Y-C(S)NR9R'°, -Y-C(O) NR9R'°, -Y-C(S)NR9R'°, -Y-SOzNR9R'°, -Y-NR9R'°, SOzNR9R'°, C(,O)NR9R'°, C(S)NR9R'°, C(O)R", - OC(O)R" , -Y-OR", -Y-COZR", SOZR'3, N(R'Z)SOZR'3, N(R'2)C(O)R'3 or 3o N(R'')COzR'3 where:
Y is a bond, C,_6 alkylene or CZ~ alkenylene;

Amended Sheet F'C~/St99/01600 R9 and R'° are independently hydrogen or C,_6 alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur;
R8, R", R'z and R'3 are independently hydrogen or C,_,° alkyl (optionally substituted by one or more fluorine atoms);
or a salt or solvate thereof, ~ provided that when n is zero then A is not pyridyl or pyrimidinyl.
Alkyl, alkylene and alkenylene groups, whether alone or part of another group, can be ~ o straight chained or branched and can be optionally substituted by one or more fluorine atoms and optionally interrupted by one or more oxygen atoms.
Suitably A is a phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such rings, which can is be saturated or aromatic, include pyridine, pyrimidine, thiazole, pyrrolidone, pyridazine and pyridone. Preferably A is phenyl, pyridine, pyrimidine, thiazole or pyrrolidone.
Suitably n is 0, 1, 2 or 3 such that multiple substituents can be present.
Preferably n is 0, or when A is pyridine n is preferably 1.
Suitably X is O, S or CHZ. Preferably X is O.
Suitably R is halogen, nitro, C,~ alkyl, C,~ alkoxy, (CHZ)pR3 where p is 0 to 3 and R3 is hydroxy, or NR°R5 where R4 and R5 are independently hydrogen or C,~
alkyl or R is zs CONR'R5. Substituents can be present on carbon or appropriate nitrogen atoms of the ring A. Preferably R is fluoro, nitro, methyl, methoxy, dimethylamino, (CHZ)PR3 where p is 1 and R3 is hydroxy or NR4R5 where R4 is hydrogen and RS is methyl or C,~ alkyl, or R is or R is CONR4R5 where R4 is hydrogen and RS is methyl.
3o Suitably R' and RZ are independently hydrogen, C,~ alkyl or C3_6 cycloalkyl or R' and RZ
together with the carbon atom to which they are attached form a C3_6 cycloalkyl group.
Preferably R' and RZ are both hydrogen.
Suitably Ar' is biphenyl, naphthyl or tetrahydronaphthyl, each Ar' group being optionally 3s substituted by halo, nitro, C,~ alkyl (optionally substituted by one or more fluorine atoms), CN, -Y-NRBC(O)NR9R'°, -O-Y-C(O)NR9R'°, -O-Y-C(S)NR9R'°, -Y-C(O) NR9R'°, Amended Sheet ('CT/SE99/01600 -Y-C(S)NR9R'°, -Y-SOzNR9R'°, -Y-NR9R'°, SOzNR9R'°, C(O)NR9R'°, C(S)NR9R'°, C(O)R", - OC(O)R" , -Y-OR", -Y-COZR", SOzR'3, N(R'z)SOzR'3, N(R'z)C(O)R'3 or N(R'z)COZR'3 where Y is a bond, C,~ alkylene or Cz_6 alkenylene. More than one substituent can be present, preferably one or two substituents are present.
Particularly preferred compounds of the invention include:
(~)-1-(Biphenyl-4-yloxy)-4-(3-(2-fluoro)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(3-(2-methoxy)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(3-(6-fluoro)pyridyl)-2-butanol, 'o (t)-1-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(6( 1 H)-pyridone-3-yl)-2-butanol, 1-(Biphenyl-4-yloxy)-4-[4-(3-fluoro)pyridyl]-2-butanol, 1-(Biphenyl-4-yloxy)-4-[(3-methoxy)-4-pyridyl]-2-butanol, 1-(Biphenyl-4-yloxy)-4-(4-pyridin-2-one)-2-butanol, 's 1-[(Biphenyl-4-yloxy)]-4-(4-pyridazin-3-yl)-2-butanol, 1-[(Biphenyl-4-yloxy)]-4-(pyridazin-4-yl)-2-butanol, 1-[(Biphenyl-4-yloxy)]-4-(pyrimidin-4-yl)-2-butanol, (t)-4-(2-(Hydroxymethyl)phenyl)-1-(2-thionaphthyl)-2-butanol, (t)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzamide, zo (~)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzylamine, (t)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-hydroxybutyl)benzamide, (~)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-hydroxybutyl)benzylamine, (~)-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy))-3-hydroxybutyl)benzyl alcohol, ( 1 S.2RS)-4'-(2-Hydroxy-1-methyl-4-thiazol-2-yl-butoxy)-biphenyl-3-carbonitrile, 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-2-methoxy-phenol, 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-1-methyl-pyrrolidin-2-one, (t)-4-[4-(Biphenyl-4-yloxy)-3-hydroxybutyl]-1-methyl-11~ pyridin-2-one, or salts or solvates thereof.
3o Compounds of the invention can form pharmaceutically acceptable solvates and salts. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example malefic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, trifluoroacetic and methanesulphonic acids. Compounds of the invention may also form alkali metal salts 3a such as magnesium, sodium, potassium and calcium salts.
CA °2341440 2001-02-21 Amended Sheet PCT/St99/01600 Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained s by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof, particularly in the case of compounds where A is pyridyl and R is hydroxy.
According to the invention there is also provided a process for the preparation of io compounds of formula (I) as hereinbefore defined which comprises:
(a) reduction of a compound of formula (II):
O
A (CR' R2) ~X ~Ar' (R)n (II) ~s wherein A, R, n, R', R2, X and Ar' is as defined in formula (I) or are protected derivatives thereof;
(b) for compounds of formula (I), wherein Ar' is a group R6-R', forming the R6-R' bond by reaction of a compound of formula (III):
OR'6 (CR~R2 /X~Rs~R
A v ) (R)n (III) with a compound of formula (IV):
RoR~s (IV) where A, R, n, R', RZ, R6, R' and are as defined in formula (II), R'6 is a hydroxy protecting group, and one of R"/R'g is triflate or halo and the other is B(OH)z or ZnHal;
or Amended Sheet ~'CT/ F 9 9 / 0 1 6 0 0 (c) for compounds of formula (I) where R' and Rz are both hydrogen, reaction of a compound of formula (V):
O
A
(V) where A, R and n are as defined in formula (II), with a compound of formula (VI):
MYAr' (VI) io where Y is O, S or CHz, M is Li, Na, K, Cs or MgHal where Hal is halogen and Ar' is as defined in formula (I);
or with a compound of formula (VII):
HYAr' (VII) 's where Y is as defined in formula (VI) in the presence of a base; or (d) for compounds of formula (I), where R' and Rz are both hydrogen, and X
represents O
or S, reaction of a compound of formula (V) or (VI), as hereinbefore defined, with a suitably protected and activated derivative of a diol of formula (VIII):
zo OH
OH
A
(R)" (VIII) where R, n and A are as defined in formula (II); or (e) preparation of compounds of formula (I) wherein X represents O, from a compound of z, formula (IX):
CA 02341440 2001-02-21 Amended Sheet PCT/ S ~ 9 9 / 0 1 6 0 0 R' R2)~OH
(R)n (Ix) in which R, n, A, R', R2, and R'6 are as defined in process (b) by reaction with a compound of formula (VII) wherein Y represents O; or s (f) reaction of a compound of formula (X):
Hal A
(R)n (x) in which A, R and n are as defined in formula (II) and Hal is halogen with a compound of io formula (XI):
OH
CR' R2 ~X~Ar' ( ) (XI) in which R', RZ, X and Ar' are as defined in formula (II) in the presence of a suitable is catalyst, or (g) preparation of compounds of formula (I) wherein X represents O, from a compound of formula (XII):
O
~~OAr' (XII) Zo in which Ar' is as defined in formula (II) with a compound of formula (XIII):
A jCH2M
R)n (XIII) R~s '(C

Amended Sheet Pt;T/SE 99 / 0 1 600 in which R and n are as defined in formula (II) and M is a metal, or (h) preparation of compounds of formula (I) wherein X represents O from a compound of formula (XIV):
O
OAr~
s Ph3P (XIV) in which Ar' is as defined in formula (II) with a compound of formula (XV):
jCHO
A
R)n (XV) io in which R and n are as defined in formula (II), followed by hydrogenation of the resulting product using a suitable catalyst and optionally thereafter process (a) to (h):
~ removing any protecting groups converting a compound of formula (I) into a further compound of formula (I) ~ s ~ forming a pharmaceutically acceptable salt or solvate.
Reduction of a compound of formula (II) can be carried out with a suitable reducing agent (e.g. sodium borohydride) for example at room temperature in the presence of a suitable organic solvent (e.g. ethanol).
Reaction of compounds of formulae (III) and (IV) can be carried out under the conditions of the Suzuki reaction (Synthetic Communications 11 (7), 51. 3-519, 1981 ) for example at 100 °C in the presence of a suitable catalyst and base (e.g.
tetrakis(triphenylphosphine)-palladium(0) and aqueous sodium carbonate) in a suitable solvent (e.g.
ethanol/toluene).
Reaction of a compound of formula (V), examples of which are (~)-3-(2-oxiranylethyl)pyridine or a-(chloromethyl)-3-pyridinepropanol, with a compound of formula (VI) can be carried out in the presence of a base such as sodium hydroxide in a suitable solvent such as aqueous ethanol.

Amended Sheet PCT; S E 9 9 / 0 1 6 0 0 ~ s -~o- zooo Reaction of a compound of formula (V) with a compound of formula (VII) carried out at ambient or reduced temperature in a suitable solvent such as dimethylformamide or tetrahydrofuran.
s Process (d) is carried out at elevated temperature, for example at about 60°C, in the presence of suitable base (e.g. sodium hydride) and an appropriate organic solvent (e.g.
dimethylformamide). Suitably protected and activated derivatives include the carbonate compounds of formula (VIIIa):
O
A
(R)n (VIIIa) Processes (e) is carried out under the conditions of the Mitsonobu reaction, for example at approximately 0-25°C in the presence of diethyl azodicarboxylate and triphenylphosphine in an appropriate solvent (e.g. toluene).
~s Process (f) is carried out in the presence of a suitable catalyst such as a palladium catalyst, for example palladium acetate.
In process (g) M is a metal such as lithium or magnesium.
zo Compounds of formula (III) wherein R" is B(OH)2, can be prepared from a compound in which R" is bromine or iodine by, for example, treatment with n-butyllithium and tri-isopropylborate in an appropriate solvent (e.g. tetrahydrofuran), at low temperature (e.g. -78°C).
zs An alternative preparation of compounds of formula (III) wherein X represents O is from compounds of formula (VII) as defined above by reaction with a compound of formula (XVI), in which R" is triflate, or halogen:

Amended Sheet PCT/ St 99 / 0 'i 600 R' ~
I \
(XVI) under the conditions of the Mitsonobu reaction as described above.
s Compounds of formula (IX) can be prepared by reduction of a compound of formula (XVII) OR'6 ' A \ (CR'R2)~O \
(R)n (XVII) ~o in which R', R' and R'6 are as defined above using conventional procedures, for example hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate, followed by debenzylation using conventional methods such as those described in 'Protective Groups in Organic Synthesis', 2"d Edition, T.W. Greene & P.G.M. Wuts, Wiley-Interscience (1991).
~s Compounds of formula (XVII) can be prepared by the reaction of compound (XVIII):
O
H~(CR'R2)~O \
(XVIII) 2o reported by Reetz et. al. Angew. Chem. Suppl., ( 1983), 1511.) in which R' and Rz are as defined above with a compound of formula (XIX):
M
A
(R)n (XIX) Amended Sheet PC./St=99/01600 l0 1 6 -10- 2000 in which A, R and n are as defined above and M is lithium, sodium, potassium, MgX or ZnX, where X is halogen, optionally in the presence of additives such as boron trifluoride.
It will be appreciated by those skilled in the art that in the process described above the s functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include organosilyl groups (e.g.
to tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydro-pyranyl. Suitable protecting groups for amino include tert-butoxycarbonyl or benzyloxy carbonyl. Suitable protecting groups for carboxylic acid include C,~ alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after a reaction step.
The use of protecting groups is fully described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1991).
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures known in the art such as reduction, alkylation, esterification etc.
Novel intermediates form a further aspect of the invention.
2s Diastereoisomers may be separated using conventional techniques, e.g.
chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
The compounds of the invention are useful because they possess pharmacological activity and more particularly activity in the modulation of inflammatory and allergic conditions, for example as shown in the test described below. The compounds of the invention inhibit the activation of a range of cell types from haematopoetic lineage, including mast cells, 3s neutrophils and eosinophils.

Amended Sheet PCT/ ~E 9 9 / 0 1 600 In a further aspect the invention therefore provides a compound of formula (IA) OH
A (CR' RZ)~X~Ar' (R)n (I) wherein;
A is a phenyl or a S- or 6-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R is halogen, nitro, C,~ alkyl, C,~ alkoxy, (CHZ)PR~ where p is 0 to 3 and R3 is hydroxy, or ~o NR4R5 where R4 and RS are independently hydrogen or C,~ alkyl or R is CONR4R5;
nis0, l,2or3;
X is O, S or CH2;
R' and RZ are independently hydrogen, C,~ alkyl or C3_6 cycloalkyl or R' and RZ together with the carbon atom to which they are attached form a C3_6 cycloalkyl group;
~s Ar' is a fused bicyclic ring system optionally containing one or more heteroatoms, a fused tricyclic ring system optionally containing an oxygen atom, or Ar' is a group R6-R' where one of R6/R' is a phenyl ring and the other is phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms, each Ar' group being optionally substituted by halo, nitro, C,~ alkyl (optionally substituted by one or more fluorine atoms), CN, 20 -Y-NRgC(O)NR9R'°, -O-Y-C(O)NR9R'°, -O-Y-C(S)NR9R'°, -Y-C(O) NR9R'°, -Y-C(S)NR9R'°, -Y-SOzNR9R'°, -Y-NR9R'°, SOZNR9R'°, C(O)NR9R'°, C(S)NR9R'°, C(O)R", - OC(O)R" ,-Y-OR", -Y-COzR", SOZR'3, N(R'z)SOzR'3, N(R'Z)C(O)R'3 or N(R'Z)COZR'3 where:
Y is a bond, C,_6 alkylene or CZ_6 alkenylene;
2s R9 and R'° are independently hydrogen or C,~ alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur;
R8, R", R'z and R'3 are independently hydrogen or C,_,° alkyl (optionally substituted by one or more fluorine atoms);
30 or a pharmaceutically acceptable salt or solvate thereof for use as a therapeutic agent, ~ provided that when n is zero then A is not pyridyl.
CA °234144° 2001-02-21 Amended Sheet PCT/ S ~ 9 9 / 0 1 6 0 0 The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory, auto-immune, proliferative and hyper-proliferative diseases.
The compounds of the invention are also indicated in the treatment and prevention of s allergic, inflammatory or auto-immune conditions of the lung, including reversible obstructive airways diseases which includes asthma (e.g. bronchial, allergic, intrinsic asthma, extrinsic and chronic asthma), and associated manifestations of the disease (late responses, hyper-responsiveness), also farmer's lung and related diseases, fibrosis, ideopathic interstitial pneumonia, chronic obstructive airways disease (COPD), io bronchiectasis, cystic fibrosis, eosinophilic pneumonias, adult respiratory distress syndrome CARDS), emphysema and alveolitis, for example cryptogenic fibrosing alveolitis.
Further, the compounds of the invention are indicated in the treatment or prevention of is allergic, inflammatory or auto-immune conditions in the nose including all conditions characterised by inflammation of the nasal mucous membrane such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, scrofulous rhinitis, seasonal 2o rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis. Of particular interest are allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever). The compounds are also indicated for the treatment of nasal polyps and allergic menifestations of the nasopharynx other than those described hereintofore.
zs The compounds of the invention are also indicated the treatment or prevention of allergic, inflammatory or auto-immune conditions of the eye such as conjunctivitis (allergic, acute, vernal, of hay fever, chronic), inflammation disorders of the eyelids, cornea, uveal tract and retina.
3o The compounds of the invention are also indicated in the treatment and prevention of allergic, inflammatory and auto-immune conditions of the gastrointestinal tract such as food allergy and food intolerance, ulcerative colitis, Crohn's disease, irritable bowel disease, gastric ulcers, and food related allergic diseases which have symptomatic manifestations remote from the gastrointestinal tract, for example migraine, rhinitis and 3s eczema.

Amended Sheet PCT/ ~ E 9 9 / 0 I 6 7 0 The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory or auto-immune conditions of the skin such as psoriasis, atopical dermatitis, contact dermatitis/dermatitis herpetiformis, erythema nodosum, urticaria, cutaneous eosinophilias, acne, Alopecia areata, eosinophilic fascitis dermatomyositis, photoallergic sensitivity and periodontal disease.
The compounds of the invention are therefore indicated for use in the treatment or prevention of allergic, inflammatory or auto-immune conditions of the joints and connective tissue, including osteoarthritis, rheumatoid arthritis, systemic lupus io erythematosis, vasculitis, Wegener's granulomatosis, polyarthritis nodosa, bursitis, tendonitis, gout, Behcet's syndrome, ankylosing sponditis, Reiter's syndrome and psoriatic arthritis.
The compounds of the invention are indicated in the treatment and prevention of allergic, i s inflammatory, and auto-immune conditions of the circulatory system including atheroma, reperfusion injury (e.g. on angioplasty), myocardial infarction, thrombosis and vascular and tissue damage caused by ischaemic disease or injury.
The compounds of the invention are indicated in the treatment and prevention of allergic, zo inflammatory or auto-immune conditions of the CNS including Parkinson's disease, Alzheimers and other dementias, stroke and subarachnoid haemorrhage. The compounds of the invention are indicated in the treatment and prevention of inflammatory conditions of the liver for example hepatitis, cirrhosis and glomerulonephritis.
zs The compounds of the invention are indicated in the treatment and prevention of allergic, inflammatory or auto-immune conditions of the bladder and uro-genital tract including cystitis.
The compounds of the invention are indicated in the treatment and prevention of tumours so and other proliferative diseases.
Of particular interest amongst the above indications is use of the compounds of the invention in a reversible obstructive airways disease, most particularly asthma and especially the treatment and prophylaxis of asthma and rhinitis.

Amended Sheet 14 1 6 -10- 20~U
According to a further aspect of the invention there is thus provided the use of a compound of formula I, as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of the above diseases, in particular reversible obstructive airways disease.
Administration of the compounds of the invention may be topical (for example by inhalation to the lung). The compounds of the invention may be inhaled as a dry powder which may be pressurised or non-pressurised.
io In non-pressurised powder compositions, the active ingredient in finely divided form may be used in admixture with a larger sized pharmaceutically acceptable inert carrier.
The composition may alternatively be pressurised and contain a compressed gas, e.g.
nitrogen, or a liquefied gas propellant. In such pressurised compositions, the active is ingredient is preferably finely divided. The pressurised composition may also contain a surface active agent. The pressurised compositions may be made by conventional methods.
The compounds of the invention may be administered systemically (for example by oral administration to the gastrointestinal tract). The active ingredient may be formulated together with known adjuvants, diluents or carriers using conventional techniques to 2o produce tablets or capsules for oral administration to the gastrointestinal tract.
Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, 2s sodium bicarbonate and/or gelatin.
According to a further aspect of the invention there is provided a pharmaceutical composition including a compound of formula I or a salt or solvate thereof as hereinbefore defined in assuciation with a pharmaceutically acceptable adjuvant, diluent or carrier.
Suitable doses for such oral administration are in the range from 0.3 to 30 mg kg' day-', for example 3 mg kg-' day-'.
According to a further aspect of the present invention, there is provided a method of 3s treatment or prophylaxis of a reversible obstructive airways disease, in particular asthma, which method comprises administration of a therapeutically effective amount of a CA 02341440 2001-02-21 Amended Sheet Is 1 6 -10- 2000 compound of formula I as hereinbefore defined, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to, the disease.
The invention is illustrated by the following Examples.
CA 02341440 2001-02-21 Amended Sheet Example 1 (t)-1-(Biphenyl-4-yloxyr4-(3-(2-fluoro)pyridyl)-2-butanol a) (t)-I-(Biphenyl-4-yloxy)-but-3-en-2-of s A solution of 1-allyloxybiphenyl (15 g) in dry dichloromethane (500 ml), at -78°C, under nitrogen, was treated with an ozone rich stream of oxygen over a period of 1.5 hours.
Excess ozone was removed, and the reaction quenched by the addition of triphenyl phosphine ( I 8.7 g), and allowed to warm to room temperature with stirring overnight.
The solution was recooled to -78°C and a solution of vinylmagnesium chloride (142m1, IM
io in tetrahydrofuran) was added dropwise. The resulting mixture was allowed to warm to room temperature over 2 hours, and the reaction quenched by the addition of saturated ammonium chloride solution (250 ml). The organic phase was separated, and the aqueous extracted with dichloromethane (2x200 ml). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced ~s pressure. The residue was purified by column chromatography over silica, eluting with isohexane/diethyl ether (1:1) to give the sub-title compound as a pale yellow solid (10 g).
MS (ESI) 240(M)+
'H NMR (CDCl3) 7.6-7.5(4H, m); 7.41(2H, t); 7.3(1H, t); 7.0(2H, dd); 6.05-5.95(1H, m); 5.45( 1 H, d); 5.3( I H, d); 4.63-4.55( 1 H, m); 4.07( 1 H, d), 3.93( 1 H, t); 2.41 ( I H, d).
Zo b) (t)-1-(Biphenyl-4-yloxy)-4-(3-(2-fluoro)pyridyl)-2-butanol A mixture of (~)-1-(biphenyl-4-yloxy)-but-3-en-2-of (1.4183 g), acetonitrile (12 ml), triethylamine (4 ml), 2-fluoro-3-iodopyridine (1.32 g,,LOrg.Chem., 1988, 53{12), 2740), tri-o-tolylphosphine (0.37 g) and palladium (II) acetate (0.13 g) were combined in that is order then heated in a sealed tube at 100°C for 90 minutes. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography over silica eluting with ethyl acetate : hexane (1:4) to give a solid which was a mixture of (~)-1-(biphenyl-4-yloxy)-4-(3-(2-fluoro)pyridyl)-but-3-en-2-of aad (t)-1-(biphenyl-4-yloxy)-but-3-en-2-of and an oil which was 1-(biphenyl-4-yloxy)-4-(3-(2-fluoro)pyridyl)-2-3o butanone. The latter ketone was dissolved in methanol (30 ml) and dichloromethane (IO
ml) and treated with solid sodium borohydride (0.18 g). After 5 minutes the reaction was concentrated under reduced pressure and the residue purified by column chromatography over silica eluting with ethyl acetate : hexane (3:7) to give a product (0.35 g) which was crystallised from ether : hexane to give the title compound.
ss mp 91-93°C
MS (APCI) 338 (M+H)+

'H NMR (DMSO-d6) 8.15(1H, d); 7.96(1H, t}; 7.68(4H, t); 7.51(2H, t); 7.45-7.35(2H, m); 7.10(2H, d); 5.19( I H, d); 4.01 (2H, d); 3.95-3.8( i H, m); 3.0-2.85( 1 H, m); 2.85-2. 7( 1 H, m); 2.0-1.85(1H, m); 1.85-1.75(1H, m).
s Example 2 (t)-1-(Biphenyl-4-yloxy)-4-(3-(2-methoxy)pyridyl)-2-butanol A mixture of (t)-1-(biphenyl-4-yloxy)-but-3-en-2-of (1.44 g, Example la), acetonitrile (12 ml), triethylamine (4 ml), 3-iodo-2-methoxypyridine (0.44 g, J.Org.Chem., 1988, 53(12), io 2740), tri-o-tolylphosphine (0.37 g) and palladium (II) acetate (0.18 g) were heated in a sealed tube at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography over silica to give a mixture of (+)-1-(biphenyl-4-yloxy)-4-(3-(2-methoxy)pyridyl)-but-3-en-2-of and i-(biphenyl-4-yloxy)-4-(3-(2-methoxy)pyridyl)-2-butanone. This mixture of compounds was dissolved in is methanol (100 m1) and sodium borohydride (0.25 g) was added. When the reaction was complete it was concentrated under reduced pressure and the residue partitioned between dichIoromethane and water. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and was hydrogenated at 1.5 atmospheres pressure for 3 hours using zo palladium on carbon (10%, I70 m g) as catalyst. The reaction was filtered and concentrated under reduced pressure to give a solid ( 1.75 g). This was purified by column chromatography over silica eluting with dichloromethane : ethyl acetate (9:1) to give a colourless solid (1.70 g). A sample was crystallised from aqueous methanol.
mp 115°C
is MS (APCI) 350 (M+H)+
'H NMR (DMSO-d6) 8.01(1H, dd); 7.65-7.5(5H, m); 7.43(2H, t); 7.30(1H, t);
7.02(2H, t); 6.91(1H, dd); 5.03(1H, d); 3.92(2H, d); 3.87(3H, s); 3.85-3.75(1H, m); 2.85-2.70(1H, m); 2.65-2.50(IH, m); 1.9-1.75(1H, m); 1.75-1.60(IH, m).
so Example 3 (t)-1-(Biphenyl-4-yloxy)-4-(3-(6-fluoro)pyridyl)-2-butanol a) 3-Bromo-6-fluoropyridine A solution of 2-amino-5-bromopyridine (1 g) in chloroform (20 ml) was added to a slurry 3s of nitrosonium fluoroborate (0.745 g) in chloroform (10 ml) at 0°C.
The mixture was stirred at this temperature for 30 minutes, followed by the addition of 1,2-dichlorobenzene w0 00/15614 PCTlSE99/01600 s io (10 ml). The mixture was heated allowing the chloroform to distil. Heating at 150°C was continued for 2 hours. The reaction was cooled, poured onto water and made basic by the addition of 2N sodium hydroxide. The aqueous phase was extracted into ethyl acetate (3x100 ml), the extracts combined and dried over magnesium sulfate. The dried organics were filtered, and the filtrate concentrated under reduced pressure to give an orange oil, which was further purified by column chromatography over silica, eluting with petrol then 5% ethyl acetate in 40-60 petrol to give the sub-title compound as a yellow oil (0.6 g).
MS (ESI) 175/177 (M)+
b) 1-(Biphenyl-4-yloxy)-4-(3-(6-fluoro)pyridyl)-2-butanone A mixture of (t)-1-(biphenyl-4-yloxy)-but-3-en-2-of (0.68 g, Example la), acetonitrile (10 ml), triethylamine (4 ml), 3-bromo-6-fluoropyridine (0.5 g), tri-o-tolylphosphine (0.173 g) and palladium (II) acetate (0.064 g) were combined in that order then heated in ~s a sealed tube at 120°C for 8 hours. The reaction mixture was filtered through cotton wool and then concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with 50:50 ethyl acetate/isohexane to give the sub-title compound as a yellow gum, which crystallised on standing (0.266 g).
MS (APCI) 336 (M+H)+
zo 'H NMR (DMSO-d6) 8.10(1H, s); 7.86(1H, td); 7.62-7.52(4H, m); 7.42(2H, t);
7.31 ( 1 H, t); 7.11 ( 1 H, dd); 6.95 (2H, d); 4.88(2H, s); 2.95-2.82(4H; m).
c) (t)-1-(Biphenyl-4-yloxy)-4-(3-(6-fluoro)pyridyl)-2-butanol Sodium borohydride (0.03 g) was added to a stirred solution of 1-(Biphenyl-4-yloxy)-zs 4-(3-(6-fluoro)pyridyl)-2-butanone (0.26 g) in ethanol (i0 ml) at 0°C. Allowed to warm up to room temperature, with stirring, and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane (SOmI of each). The organic phase was separated, and the aqueous extracted with dichloromethane (2x50 ml).
The combined organics were washed with saturated brine, dried over magnesium sulfate and 3o filtered. The filtrate was concentrated under reduced pressure, and the resudue further purified by column chromatography eluting with 3:1 ethyl acetate/isohexane to give the title compound, after trituration under diethyl ether, as a colourless solid (0.14 g).
m.p. 80-81 °C
MS (APCl7 338 (M+H)+

'NMR (DMSO-d6) 8.1(1H, s); 7.87(1H, td); 7.65-7.55(4H, m); 7.43(2H, t);
7.30(1H, t); 7.10( 1 H; dd); 7.01 (2H, d); 5.09( 1 H, d); 3.92(2H, d); 3.85-3.72( 1 H, m); 2.90-2.72(2H, m); 1.90-1.63(2H, m).
Example 4 s (t)-Z-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanol a) 3-Iodo-6-methoxypyridine 5-Amino-2-methoxypyridine (5 g) was dissolved in a 1:1 mixture of concentrated hydrochloric acid and water, and cooled to 0°C. To this was added a solution of sodium nitrite (2.9 g) in water (5 ml), keeping the temperature below 5°C.
Stirred between 0 and ~0 5°C for 15 minutes. The diazonium mixture was then treated with a solution ofpotassium iodide (7.3 g) in water (10 ml), again keeping the temperature below 5°C. Stirred for 2 hours, whilst allowing to warm up to room temperature. Extracted into ethyl acetate (3x 150 ml), and the combined organics were washed with saturated sodium metabisulfite solution (3x 100 ml), dried over magneasium sulfate and filtered. The filtrate was is concentrated under reduced pressure, and the residue distilled with Kugekohr apparatus at 35-45°C (1.5 ton) to give the sub-title compound as a light brown oil (3.87 g).
MS (ESI) 234 (M-H)+
'NMR (DMSO-d6) 8.38(1H, d); 7.98(1H, dd); 6.75(1H, d).
b) 1-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanone zo A mixture of (t)-1-(biphenyl-4-yloxy)-but-3-en-2-of (1.0 g, Example la), acetonitrile (10 ml), triethylamine (4 ml), 3-iodo-6-methoxypyridine ( 1.1 g), tri-o-tolylphosphine (0.286 g) and palladium (II) acetate (0.105 g) were combined and heated in a sealed tube at 100°C for 2.5 hours. The reaction mixture was filtered through cotton wool and then concentrated under reduced pressure. The residue was purified by column chromatography zs over silica eluting with 1:3 ethyl acetate/isohexane to give the sub-title compound as a yellow gum, which crystallised on standing (0.550 g).
MS (APCI) 348 (M+H)+
'NMR (DMSO-d6) 8.01(1H, d); 7.62-7.55(SH, m); 7.43(2H, t); 7.30(1H, t);
6.95(2H, d); 6.75(1H, d); 4.87(2H, s); 3.80(3H, s); 2.90-2.82(2H, m); 2.81-2.75(2H, m).

c) (t}-1-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanol Sodium borohydride (0.06 g) was added to a stirred solution of I-(Biphenyl-4-yIoxy)-4-(3-(6-methoxy)pyridyl)-2-butanone (O.S3S g) in ethanol (20 ml) at 0°C.
Allowed to warm up to room temperature, and stirred for 2 hours. Concentrated under reduced pressure. The s residue was partitioned between water and dichloromethane (SOmI of each).
The organic phase was separated, and the aqueous extracted with dichloromethane (2xS0 ml).
The combined organics were washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resudue further purified by column chromatography eluting initially with 3:1 ethyl acetate/isohexane, then io 1:1, to give the title compound, after trituration under diethyl ether, as a colourless solid (0.230 g).
m.p. 101-I04°C
MS(APCI} 3S0 (M+H)+
'NMR (DMSO-d6) 8.01(1H, d); 7.63-7.SS(SH, m); 7.43(2H, t); 7.30(IH, t);
7.02(2H, is d); 6.75(1H, d); S.OS(1H, d}; 3.91(2H, d); 3.83-3.70(4H, m); 2.78-2.SS{2H, m); 1.88-1.7{2H, m).
Example 5 (~)-1-(Biphenyl-4-yloxy)-4-(6(1 H)-pyridone-3-yl)-2-butanol A solution of (t)-1-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanol (0.130g, zo Example 4) in ethanol (10 ml), was treated with concentrated hydrochloric acid (10 ml} for 6 hours. Cooled, and basified by the addition of sodium hydrogen carbonate.
The basic solution was extracted into ethyl acetate (3xS0 ml), combined, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was further purified by column chromatography over silica eluting with ethyl acetate, to give zs the title compound as a colourless solid (0.08 g).
m.p. I S7-I60 MS (APCI) 336(M+H)+
'NMR (DMSO-d6) 11.37(1H, br s); 7.63-7.SS(4H, m); 7.47-7.25(4H, m); 7.16(1H, d);
7.03(2H, d); 6.28(1H, d); 5.01(1H, d); 3.90(2H, d); 3.81-3.70(1H, m); 2.58-2.32(2H, m);
1.8-1.53(2H, m).

Example 6 1-(Biphenyl-4-yloxy)-4-[4-(3-fluoro)pyridylJ-2-butanol Prepared according to the method described in Example lb) from (t)-1-(biphenyl-s yloxy)but-3-en-2-of (2.15g, Example la), acetonitrile (12m1), triethylamine (4ml), 2-fluoro-4-iodopyridine (2g, J.Org.Chem., 1993, 58, 7832-7838), tri-o-tolylphosphine (O.SSg), and palladium (II) acetate (0.28g). After cooling the reaction mixture was filtered through Celite~ then concentrated under reduced pressure. The residue, which contained a mixture of (t)-1-(biphenyl-4-yloxy)-4-(4-(2-fluoro)pyridyl)but-3-en-2-of and 1-(biphenyl-,0 4-yloxy)-4-(4-(2-fluoro)pyridyl)-2-butanone, was purified by column chromatography over silica eluting with ethyl acetate : hexane (2:3) to give 1-(biphenyl-4-yloxy)-4-(4-(2-fluoro)pyridyl)-2-butanone as an oil (0.78g). This was dissolved in ethanol (lOm1) and sodium borohydride (0.1 g) was added. The reaction mixture was stirred overnight then concentrated under reduced pressure. The residue was purified by column chromatography is over silica eluting with ethyl acetate : hexane (1:4) to give the title compound as a white solid (0.27g).
mp 104-106°C
MS (APCI) 338 (M+H)+
'H NMR (DMSO-D6) 8.13(1H, d); 7.63-7.56(4H, m); 7.43(2H, t}; 7.33-7.24(2H, m);
zo 7.07-7.00(3H, m); 5.11 ( 1 H, d); 3.93(2H, d); 3.83-3.78( 1 H, m); 2.95-2.68(2H, m); 1.95-1.68(2H, m).
Example 7 1-(Biphenyl-4-yloxy)-4-[(3-methoxy}-4-pyridyl]-2-butanol zs Sodium methoxide in methanol (Sml, 25% w/v} was added to (t)-1-(biphenyl-4-yloxy)-4-(4-(2-fluoro)pyridyl)-2-butanol (0.22g, Example 6) and the mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and dichloromethane.
The organic 3o extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid. This was purified by column chromatography over silica eluting with ethyl acetate : hexane {1:3) then recrystallised from ether to give the title compound as a white solid (0.16g).

mp 96-97°C
MS (APCI) 350 (M+H)+
'H NMR (DMSO-D6) 8.05(1H, d); 7.62-7.57(4H, m); 7.43(2H, t); 7.30(1H, t);
7.02(2H, dt); 6.87(1H, dd); 6.67(lH,s); 5.07(1H, d); 3.92(2H, d); 3.82-3.75(4H, m); 2.82-2.60(2H, m); 1.90-1.68(2H, m).
Example 8 1-(Biphenyl-4-yloxy)-4-(4-pyridin-2-one)-2-butanol (t)-1-(Biphenyl-4-yloxy)-4-(4-(2-methoxy)pyridyl}-2-butanol (0.138 Example 7) was to added to ethanol (1 Oml) and concentrated hydrochloric acid (2m1) then heated under reflex overnight. After cooling the reaction mixture was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography eluting with dichloromethane : methanol (95:5) then is recrystallised from methanol to give the title compound as a solid (0.043g).
mp 178-180°C
MS (APCI) 336 (M+H)*
'H NMR (DMSO-D6) 11.33(1H, br.s); 7.58(4H, dd); 7.43(2H, t); 7.32-7.25(2H, m);
7.02(2H, d); 6.14( 1 H, s); 6.07( 1 H,dd); 5.04( 1 H, d); 3.91 (2H, d); 3 .82-3.77( 1 H, m); 2.69 20 2.42(2H, m); 1.86-1.60(2H, m).
Example 9 1-[(Biphenyl-4-yloxy)]-4-(4-pyridazin-3-yl)-2-butanol n-Butyllithium (4.25m1, 2.SM solution in hexanes) was slowly added to a solution of is diisopropylamine (1.08g) in tetrahydrofuran (30m1) and stirred for 0.5 hour at 0°C. The reaction mixture was then cooled to -78°C (dry ice / acetone bath) before the slow addition of 3-methylpyridazine. A deep red colour was immediately produced. This was stirred for 0.5 hour then treated with a solution of 2-(biphenyl-4-ylmethyl)oxirane (2.Sg, J.MedChem., 1968, 11(6), 1139-44) in tetrahydrofuran (15m1). The reaction mixture was 3o allowed to reach room temperature overnight and poured into a saturated solution of ammonium chloride in water (100m1). The organic layer was removed and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with dichloromethane : methanol (95:5) and reverse phase HPLC eluting with a mixture of 0.1% w/v ammonium acetate and acetonitrile to give the title compound as a solid (0.114g).
mp I 11 °C
MS (APCI) 321 (M+H)+
'H NMR (DMSO-D6) 9.07(1H, t); 7.63-7.57(6H, m); 7.43(2H, dd); 7.33-7.29(1H, m);
7.05-7.01(2H, m); 5.10(1H, d); 3.96-3.80(3H, m); 3.20-2.92(2H, m); 2.12-1.80(2H, m).
~o Example 10 1-[(Biphenyl-4-yloxy)]-4-(pyridazin-4-yl)-2-butanol Prepared according to the method described in Example 9 from diisopropylamine (O.Sg), tetrahydofuran (35m1), n-butyllithium (2m1, 2.SM solution in hexanes), 4-methylpyridazine ,5 (O.Sg) and 2-(biphenyl-4-ylmethyl)oxirane (1.13g,.LMedChem., 1968, 11(6), 1139-44).
After work up, the crude material was purified by column chromatography over silica eluting with dichloromethane : ethanol (95:5) and reverse phase HPLC eluting with a mixture of 0.1 % w/v ammonium acetate and acetonitrile to give the title compound as a cream solid (0.25g).
2o mp 119-121 °C
MS (APCI) 321 (M+H)+
'H NMR (DMSO-D6) 9.17(1H, s); 9.08(1H, dd); 7.62-7.56(SH, m); 7.42(2H, t);
7.30(1H, t); 7.02(2H, d); S.I2(1H, d); 3.93(2H, d); 3.83-3.77(1H, m); 2.90-2.65(2H, m);
1.95-1.69(2H, m).
Example 11 1-((Biphenyl-4-yloxy)]-4-(pyrimidin-4-yl)-2-butanol Prepared according to the method described in Example 9 from diisopropylamine (1.08g), tetrahydofuran (60m1), n-butyllithium (4m1, 2.SM solution in hexanes), 4-so methylpyrimidine (I .Og) and 2-(biphenyl-4-ylmethyl)oxirane (2.3g), J.Med Chem., 1968, 11(6), 1139-44). After work up, the crude material was purified by column chromatography over silica eluting with dichloromethane : ethanol (95:5) and reverse phase HPLC eluting with a mixture of 0.1 % w/v ammonium acetate and acetonitrile to give the title compound as a white solid (O.IOg).
s mp 105-107°C
MS (APCI) 321 (M+H)+
'H NMR (DMSO-D6) 9.07(1H, s); 8.66(IH, d); 7.63-7.56(4H, m); 7.45-7.40(3H, m);
7.33-7.28(IH, m); 7.05-7.00(2H, m); 5.07(1H, d); 3.94(2H, d); 3.88-3.82(IH, m); 3.00-2.75(2H, m); 2.08-1.75(2H, m).
io Example 12 (~)-4-(2-(Hydroxymethyl)phenyl)-1-(2-thionaphthyl)-2-butanol a) (t)-2-(3,4-Epoxybutyl)benzyl alcohol is Solid m-chloroperoxybenzoic acid (50-60%, 2.1 g) and then potassium carbonate (1.5 g) were added to a solution of 2-(3-butenyl)benzyl alcohol (3.Sg; Tetrahedron Lett, 88), 29, 4799) in dichloromethane (100 ml) and the mixture stirred at room temperature for 5 days.
Water was added and the organic layer separated. The latter was then washed with saturated aqueous sodium sulphite, dried over anhydrous magnesium sulphate, filtered and Zo concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ether/hexane ( 1:1 ) to give the title compound as an oil (0.82 g).
IH NMR (CDCl3) 7.37(IH, d); 7.3-7.I5(3H, m); 4.73(2H, s); 3.0-2.7(4H, m); 2.55-2.45(1H, m); 2.05-1.6(3H, m).
is b) (t)-4-(2-(Hydroxymethyl)phenyl)-1-(2-naphthalenylthio)-2-butanol Solid 2-thionaphthalene (1.12 g) was added to a stirring mixture of sodium hydride (60%
dispersion in oil, 0.27 g) in tetrahydrofiwan (20 ml) at room temperature.
After 15 minutes this solution was added to a solution of (t)-2-(3,4-epoxybutyl}benzyl alcohol (0.82 g) in tetrahydrofuran (20 ml) followed by stirring for 15 minutes. Water (50 ml) was added and 3o the mixture extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ether/hexane (I:1) then ether/hexane (9:1) to give the title compound as a white solid (1.14 g).
mp 109-1 I 1 °C

MS (FAB) 338 (M)+
IH NMR (CDCl3) 7.85-7.65(4H, m); 7.55-7.4(3H, m); 7.3-7.1(4H, m); 4.73(1H, d);
4.63(1H, d); 3.75-3.65(1H, m); 3.2-2.75(SH,m); 2.39(1H, bs); 2.0-1.8(2H, m).
s Example 13 (t)-N-Methyl-Z-(4-(2-thionaphthyl)-3-hydroxybutyl)benzamide a) (~)-N-Methyl 2-(3,4-epoxybutyl)benzamide A solution of n-butyllithium (2.SM in hexanes, 27 ml) was added over I0 minutes with ~o stirnng to a solution of N-methyl 2-methylbenzamide (5.03 g) in tetrahydrofuran (100 mI) at 0°C. After a further 2 minutes allyl bromide (3.5 ml) was rapidly added and the temperature rose to 30°C. After 2 minutes saturated aqueous ammonium chloride (100 mI) was added and the mixture extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced is pressure. The residue was purified by column chromatography over silica eluting with acetone/dichloromethane (1:19) to give N-methyl 2-(3-hutenyl)benzamide, as a liquid (4.34 g).
Solid m-chloroperoxybenzoic acid (50-60%, 14.25 g) and then potassium carbonate (7.03 g) were added to a solution of N-methyl 2-(3-butenyl)benzamide (4.34 g) in Zo dichloromethane (200 ml) at 0°C. The mixture was then stirred at room temperature for 8 days. Water was added and the organic phase separated and washed with saturated aqueous sodium sulphite. The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with acetone/ dichloromethane (1:9) then zs acetone/dichloromethane (3:7) to give recovered N-methyl 2-(3-butenyl)benzamide (1.30 g) and the sub-title compound as a liquid (1.68 g).
IH NMR (CDCl3) 7.4-7.15(4H, m); 6.03(1H, bs); 3.0-2.95(6H, m); 2.73(1H, t);
2.5-2.4(1H, m); 2.0-I.7(2H, m).
3o b) (~)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzamide Prepared according to the method described in Example 12b) from 2-naphthalenethiol (2.01 g), sodium hydride (O.SOg, 60% dispersion in oil) and (t)-N-methyl 2-(3,4-epoxybutyl)benzamide (1.66 g) in tetrahydrofuran (40 ml) to give the title compound as an oil ( 1.43 g).
ss MS (EI) 365 (M)+

1H NMR (CDC13) 7.8-7.6(4H, m); 7.5-7.35(3H, m); 7.~5-7.2(3H, m); 7.14(1H, t);
5.97(1H, bs); 4.43(1H, d); 3.7-3.55(1H, m); 3.15-2.9(3H, m); 2.95(3H, d); 2.85-2.75(1H, m); 2.15-2.0(1H, m); 1.95-1.8(1H, m).
Example 14 (t)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzyiamine hydrochloride A solution of lithium aluminium hydride. (0.26 g) and (t)-N-methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzamide (0.50 g) in tetrahydrofuran (50 ml) was boiled for 24 hours and ~o then stirred at room temperature for 4 days. The reaction was quenched by careful, slow addition of water (0.5 ml) then aqueous sodium hydroxide (50%, 0.5 mI) then water (1.5 ml). The mixture was filtered and the residue washed with ethyl acetate.
The filtrate and the washings were combined, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography is over silica eluting with ethyl acetate then triethylamine/methanol (1:9) to give an oil (0.32 g). This material was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride. The salt so produced was purified by precipitating from ethanol by addition of ether to give a cream solid (0.17 g).
mp 158-160°C
zo MS {ESI) 352 (M+H-HCl)+
1H NMR (d6-DMSO) 9.35-9.15(2H, bs); 7.9-7.8(4H, m); 7.55-7.4(4H, m); 7.35-7.2(3H, m); 5.35-5.25(1H, m); 4.14(2H, s); 3.69(1H, s); 3.25-3.1(2H, m); 2.9-2.7(2H, m);
2.57(3H, s); 1.95-1.8(1H, m); 1.75-1.6(1H, m).
is Example 15 (~)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-hydroxybutyl)benzamide a) (t)-(2-(5,6,7,8-Tetrahydronaphthalenyl)oxymethyl)oxirane 5,6,7,8-Tetrahydro-2-naphthol (7.0 g), acetonitrile (300 ml), epichlorohydrin (20 ml) and 3o cesium carbonate ( 15.4 g) were combined in that order and then the mixture was boiled for 4 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was partitioned between ether (300 ml) and water (I00 ml), the organic extract dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting 3s with hexane/ether (4:I), to give the sub-title compound as a clear liquid (8.52 g).
MS (EI) 204 (M)+

WO 00/15614 PCTlSE99/01600 1H NMR (CDC13) 6.95(1H, d); 6.67(1H, d); 6.6(1H, d); 4.15(1H, dd); 3.95(1H, dd);
3.4-3.3(1H, m); 2.9(1H, t); 2.8-2.65(SH, m); 1.85-1.7(4H, m).
b) A solution of n-butyllithium (1.6M in hexanes, 17.5 ml) was added with stirring to a s solution ofN-methyl 2-methylbenzamide (2.04 g) in tetrahydrofuran (100 ml) at 0°C. After 2 minutes a solution of (t)-(2-(5,6,7,8-tetrahydronaphthalenyl)oxymethyl)oxirane (2.80 g) in tetrahydrofuran (15 ml) was rapidly added and the solution was allowed to room temperature. After 15 minutes saturated aqueous ammonium chloride ( 100 ml) was added.
The organic phase was separated and the aqueous phase extracted with ethyl acetate i o ( 100 ml}. The combined organic extracts were washed with brine ( 100 ml), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane then ether to give the title compound as an oil (4.17 g).
MS (ESI) 354 (M+H}+
is IH NMR (CDC13) 7.4-7.15(4H, m); 6.93(1H, d); 6.63(IH, dd); 6.57(IH, d);
6.13(1H, bs); 4.01(1H, d); 3.84(3H, d); 3.05-2.8(SH, m); 2.75-2.6(4H, m); 2.05-1.85(2H, m); I.85-1.75(4H, m).
Example 16 zo (f}-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyioxy))-3-hydroxybutyl)benzylamine Prepared according to the method described in Example 14 from (t)-2-(3-hydroxy-4-(2-(5,6,7,8-tetrahydronaphthalenyl)oxy)butyl)-N-methyl benzamide (2.50 g) and lithium aluminium hydride (1.25 g) in tetrahydrofuran (200 ml) to give the title compound as an oil zs (2.17 g).
MS (ESI) 340 (M+H)+
1H NMR (CDCl3) 7.3-7.25(2H, m); 7.25-7.1(2H, m}; 6.92(1H, d); 6.63(1H, dd);
6.75 (1H, d); 3.97(1H, d); 3.9-3.75(2H, ABX); 3.6-3.5(2H, m); 3.1-3.0(1H, m); 2.85-2.75(1H, m); 2.75-2.6(4H, m); 2.52(3H, s); 2.1-I.85(2H, m); 1.85-1.7(4H, m).
Example 17 (t}-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy)}-3-hydroxybutyl)benzyl alcohol a) (~)-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy)}-3-hydroxybutyl)benzoic acid 3s A solution ofn-butyllithium (1.6M in hexanes, 31 ml) was added to a solution of diisopropylamine (7 ml) in tetrahydrofuran (200 ml) at 0°C. After 5 minutes a solution of o-toluic acid (3.33 g) in tetrahydrofixran (200 ml) was slowly added. After a further 5 minutes a solution of (t)-(2-(5,6,7,8-tetrahydronaphthalenyl)oxymethyl)oxirane (5.00 g, Example 15a) in tetrahydrofuran (20 ml) was added rapidly. The ice bath cooling was removed and the reaction stirred at room temperature for 90 minutes. Dilute aqueous s hydrochloric acid (1M, 200 ml) was added and the layers separated. The aqueous phase was washed with ether (100 ml) and the combined organic phases concentrated under reduced pressure. The residue was dissolved in aqueous sodium hydroxide (1M, 200 ml) and the solution extracted with ether (2 x 100 ml). The aqueous phase was then neutralised with aqueous hydrochloric acid (2M, 100 ml), and extracted with ether (3 x 100 ml). The ~o latter extracts were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane then dichloromethane : ether (4:1 ) then dichloromethane ether (1:1) then ether to give the subtitle compound as a white solid (4.64 g).
mp 75-78°C
is MS (EI) 340 (1VI)+
1 H NMR (CDCl3 ) 8.04( 1 H, dd); 7.49( 1 H, td); 7.3 5-7.25 (2H, m); 6.94( 1 H, d);
6.66(IH, dd); 6.61(1H, d); 4.1-4.0(1H, m); 4.0-3.9(1H, m); 3.9-3.8(1H, m); 3.3-3.1(2H, m); 2.75-2.6(4H, m); 2.0-1.85(2H, m); 1.8-1.7(4H, m).
Zo b) (~)-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy))-3-hydroxybutyl)benzyl alcohol Solid (f)-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy))-3-hydroxybutyl)benzoic acid (1.01 g) was added to a solution of diborane (1.OM in tetrahydrofuran, 20 ml) and the solution stirred at room temperature for 3 hours. Water ( 10 ml) was added followed by brine ( 100 ml). The mixture was extracted with ethyl acetate (2 x I00 ml), the combined organic is extracts dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified twice by column chromatography over silica eluting with ether : hexane (4:1 ) (first column) and ether (second column) to give the title compound as a colourless solid (0.39 g).
mp 98-99°C
3o MS (EI) 326 (M)+
1H NMR (CDCl3) 7.35(1H, d); 7.3-7.15(3H, m); 6.95(1H, d); 6.64(1H, dd);
6.58(1H, d); 4.78(1H, ABX); 4.65(1H, ABX); 3.95-3.85(2H, m); 3.80(1H, dd); 3.0-2.85(3H, m);
2.75-2.65(4H, m); 2.62(1H, t); 1.90(2H, q); 1.80-1.75(4H, m).

Example 18 (1 S,2RS)-4'-(2-Hydroxy-1-methyl-4-thiazol-2-yI-butoxy)-biphenyl-3-carbonitrile.
a) (3S)- [3-(4-Bromo-phenoxy)-2-oxo-butyl]-phosphoric acid dimethyl ester s Diethylazodicarboxylate (8.54 ml) in dry tetrahydrofuran (2S ml) was added dropwise over 30 minutes to a stirred solution of triphenylphosphine (13.1 g), (R)-(+)-methyl lactate (S.2 g) and 4-bromophenol (8.65 g) in dry tetrahydrofuran (12S ml). The resulting solution was stirred at room temperature for I8 hours then concentrated under reduced pressure. A
mixture of isohexane : ether (9 : 1) (200 ml) was added to the residue and the mixture was ~o stirred at room temperature for 30 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane : dichloromethane ( 1:1 ) to give the sub-title compound as an oil (13.5 g) that was immediately taken onto the next step without analysis. A
solution of butyl lithium (2.S molar in hexanes, 35.2 ml) was added dropwise to a solution is of dimethylinethylphosphonate (12.4 g) in tetrahydrofuran (200 mI) at -70°C. The resulting solution was stirred for 10 minutes and then the compound from above (10.92 g) it tetrahydrofuran (20 ml) was added dropwise. The reaction was stirred for 30 minutes and was then poured into water (200 ml) and extracted into ethyl acetate (3x100 ml), the combined extracts were dried over anhydrous magnesium sulfate, filtered and zo concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate to afford the title compound as an oil.
MS (APCI) 351, 3S3 (M+H)+
'H NMR (CDCI,) 7.38 (2H, d); 6.80 (2H, d); 4.78 (1H, c~; 3.77 (3H, d); 3.73 (3H, d);
3.38-3.16 (2H, m); 1.52 (3H, d).
zs b) (4S)-4-(4-Bromo-phenoxy)-1-thiazol-2-yl-pent-1-en-3-one.
2-Formylthiazole (0.38 ml) in dry acetonitrile (15 ml) was added dropwise to a mixture of dried lithium chloride (0.85 g), diisopropylethylamine (1.OS ml) and (3S)-[3-(4-Bromophenoxy)-2-oxo-butyl)phosphonic acid dimethyl ester (1.41g)) in dry acetonitrile (SO ml) which had been stirred at room temperature fox 20 hours. The resulting mixture 3o was stirred at room temperature for 90 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a yellow oil (1.35 g).
MS(APCI)337.9(M+H]+
ss c) (42S,3RS)-4-(4-Bromophenoxy)-1-thiazol-2-yl-pent-I-en-3-ol.

Sodium borohydride (0.15 g) was added to a solution of cerium trichloride heptahydrate (1.49 g) and (4S)-4-(4-Bromophenoxy)-1-thiazol-2-yl-pent-1-en-3-one (1.35 g) in methanol at -20 °C. The solution was stirred at -20 °C for 30 minutes then allowed to warm to room temperature. The solution was concentrated in vacuo. The residue was s partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica eluting with ethyl acetate:isohexane (1:1) to give the sub-title compound as a yellow oil and as a 6:1 mixture of diastereomers (0.91 g).
MS(APCI) 342[M+H]+
io 'H1VMR(CDC13, majordiastereomer) 1.33(3H,d); 3.01(lH,d); 4.36-4..28(lH,m);
4.44-4.39(lH,m); 6.70-6.61(lH,m); 6.83(2H,d); 7.04-6.96(lH,m); 7.25(lH,t);
7.36(2H,d);
7.77( 1 H,d).
d) (4S,3RS)-4-(4-Bromophenoxy)-1-thiazol-2-yl-pentan-3-ol.
(4S,3RS)-4-(4-Bromophenoxy)-1-thiazol-2-yl-pent-1-en-3-of (0.66 g) was dissolved in ,s ethyl acetate (20 ml) and hydrogenated at 2 atmospheres using 5% rhodium on carbon (0.02 g) as catalyst. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give a grey liquid. The residue was purified by column chromatography over silica eluting with isohexane:ethyl acetate (2:1) to give the sub-title compound as a colourless oil and as a 6:1 mixture of diasteromers (0.35 g).
zo MS(APCI) 344 [M+H]+
'H1VMR (CDCI,, major diastereomer) 1.28(3H,d); 2.14-1.95(2H,m); 3.28-3.22(2H,m);
3.37(lH,d); 3.78-3.74(lH,m); 4.30-4.24(lH,m); 6.82-6.76(2H,m); 7.21(lH,d);
7.39-7.34(2H,m); 7.68(lH,d).
e) (1S,2RS)-4'-(2-Hydroxy-1-methyl-4-thiazol-2-yl-butoxy-biphenyl-3-carbonitrile zs A solution of (4S,3RS)-4-(4-Bromophenoxy)-1-thiazol-2-yl-pentan-3-of (0.35 g), 3-cyanobenzene boronic acid (0.30 g), aqueous sodium carbonate solution (2M, 1.18 ml) and tetrakis(triphenylphosphine)palladium (0) (0.02 g) in toluene (5 ml) and ethanol (2 ml) was refluxed for 4 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with 3o dichloromethane:methanol (19:1) to give the title compound as a yellow oil and as a 6:1 mixture of diastereomers (0.27 g).
MS(APCI) 365[M+H)+
'HrTMR(CDCI" major diasteromer) 1.36(3H,d); 2.18-2.01(2H,m); 3.30-3.25(2H,m);
3.42(lH,d); 3.83-3.79(lH,m); 4.42-4.36(lH,m); 7.00(2H,d); 7.22(lH,d); 7.68-ss 7.47(4H,m); 7.69( 1 H,d); 7.78-7.75( 1 H,m); 7.8I ( 1 H,s).

Example 19 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butylj-2-methoxy-phenol a) 1-(Biphenyl-4-yloxy)-3-chloro-propan-2-one To a stirred suspension of 4-phenylphenol (9.5 g) and caesium carbonate (21.25 g) in acetonitrile (80 ml) was added epichlorohydrin (20 ml} and the resulting mixture was stirred at reflux for 3 hours, cooled, filtered and concentrated. The residue was dissolved in tetrahydrofuran (200 ml) and treated with hydrochloric acid (~ molar, 1 ~ ml). The reaction was stirred for 15 minutes, poured into water (200 ml) and extracted into ethyl acetate (3 x 100 mI) and the combined organic ~o extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the residue in acetone (200 ml) was added, dropwise a solution of sodium dichromate in water in sulfuric acid [made by dissolving sodium dichromate ( 18.34 g} in water (53 ml) and cautiously adding concentrated sulfuric acid (20 ml)]. The reaction was stirred for 20 hours and then propan-2-of (20 ml) was added. The reaction was stirred for 1 hour and was then poured into water (1000 ml) and extracted into diethyl ether (3x300 ml) and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purif ed by chromatography on silica gel eluting with dichloromethane/hexane ( 1:1 ) to afford the sub-title compound (7.34 g).
MS (EI) 260/262 (M)' Zo 'H NMR (CDCI,) 7.56-7.52 (4H, m); 7.43 (2H, t); 7.32 (1H, t); 6.97 (2H, d);
4.82 (2H, s); 4.44 (2H, s).
b) [3-(Biphenyl-4-yloxy}-2-oxo-propyl]-triphenyl-phosphonium chloride 1-(Biphenyl-4-yloxy)-3-chloro-propan-2-one (7.34 g) was dissolved in acetonitrile (150 ml) and triphenylphosphine (8.88 g) added. The resulting mixture was stirred at reflux for 15 hours, cooled zs and the precipitate isolated by filtration to afford the sub-title compound as a solid that was used in the next reaction without fiuther purification ( 11.28 g).
MS (APCI) 497 (M-Cl)' c) 1-(Biphenyl-4-yloxy)-4-(4-hydroxy-3-methoxy-phenyl)-but-3-en-2-one (3-(Biphenyl-4-yloxy)-2-oxo-propyl]-triphenyl-phosphonium chloride (3.14 g) was partitioned so between dichloromethane (20 ml) and sodium hydroxide solution ( 1 molar, 10 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in anhydrous tetrahydrofitran (30 ml) and vanillin (0.76 g) added. The resulting solution was stirred at reflux for 20 hours and then a second aliquot of vanillin (1.57 g) was added and the reaction refluxed for a further 100 hours. The mixture was cooled, concentrated 3s under reduced pressure and the residue purified by chromatography on silica gel eluting with diethyl ether/hexane ( 1: i ) to afford the sub-title compound as a solid ( 1.9 g) m.p. 142-143°C
MS (APCI) 361.3 (M+H)' 'H NMR (CDC13) 7.73 (1H, d); 7.56-7.52 (4H, m); 7.41 (2H, t); 7.31 (1H, t);
7.17 (1H, dd); 7.08 ( I H, d); 7.01 (2H, d); 6.96 ( 1 H, d); 6.93 ( I H, d); 5.94 ( 1 H, s); 4.82 (2H, s);
s 3.94 (3H, s).
d) 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-2-methoxy-phenol 1-(Biphenyl-4-yloxy)-4-(4-hydroxy-3-methoxy-phenyl)-but-3-en-2-one (0.65 g) was dissolved in ethyl acetate (20 ml) and 10% palladium on carbon (0.050 g) added. The mixture was hydrogenated at 3 atmospheres until no further uptake of hydrogen was observed. The mixture was ~o filtered and concentrated and the residue was purified by chromatography on silica geI eluting with diethyl ether/hexane (3:2) to afford the title compound as a solid (0.056 g).
m.p. 74-76°C
MS (APCI, -ve) 363.4 (MH)' 'H NMR (CDCI,) 7.57-7.54 (4H, m); 7.53 (2H, t); 7.39 (1H, t); 6.98 (2H, d);
6.85 (1H, d);
~s 6.75 (1H, s), 6.75 (1H, d); 5.47 (1H, s); 4.08-4.00 (2H, m), 3.90-3.87 (1H, m); 3.88 (3H, s);
2.59-2.52 (2H, m); 2.32 (1H, d); 1.93-1.80 (2H, m).
Example 20 4-(4-(Biphenyl-4-yloxy)-3-hydroxy-butyl)-1-methyl-pyrrolidin-2-one a). 4-Hydroxymethyl-1-methyl-pyrolidin-2-one A solution of dimethyl itaconate (10 g) and methylamine (7.2 ml, 30% w/v in methanol) in methanol (100 ml) was stirred at room temperature for 3 days. The mixture was concentrated and the residue was dissolved in ethanol (200 ml), cooled to OoC
and sodium zs borohydride (4.8 g) was portionwise added. The reaction mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was dissolved in chloroform (100 ml) and heated at reflux for 30 minutes, cooled and dried over anhydrous magnesium sulfate, filtered and concentrated to afford the sub-title compound that was used without further purification (8.12 g) 3o MS (EI) 129 (M)"
'H NMR (CDCI,) 3.68-3.58 (2H, m); 3.49 (1H, dd); 3.25 (1H, dd); 2.84 (3H, s);
2.61-2.45 (2H, m); 2.40 ( 1 H, br), 2.20 ( 1 H, dd).
b) 4-[4-(Biphenyl-4-yloxy)-3-oxo-but-1-enyl]-1-methyl-pyrrolidin-2-one 3s 4-Hydroxymethyl-1-methyl-pyrolidin-2-one (0.516 g) was dissolved in dichloromethane (50 ml) and was added to a stirred suspension of Dess-Martin periodinane (2.65 g) and WO 00115614 PCTlSE99/01600 pyridine (0.3 ml) in dichloromethane (15 m1). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The filtrate was dissolved in tetrahydrofuran (20 ml) and filtered. To the filtrate was added the compound from example 19b (1.045 g) and the resulting solution was stirred at reflux for 20 hours, cooled and s concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate to afford the sub-title compound (0.305 g) as an oil.
MS (APCI) 336 (M+H)+
'H NMR (CDCI,) 7.55 (4H, d); 7.40 (2H, d); 7.31 (1H, dd); 7.01 (1H, dd); 6.95 (2H, d);
6.52 (1H, d); 4.73 (2H, s); 3.60-3.54 (1H, m); 3.25-3.20 (2H, m); 2.83 (3H, s); 2.63 (1H, a o dd); 2.34 ( 1 H, dd) c) 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-but-I-enylJ-1-methyl-pyrrolidin-2-one 4-[4-(Biphenyl-4-yloxy)-3-oxo-but-1-enylJ-1-methyl-pyrrolidin-2-one (0.30 g) was dissolved in methanol (5 ml) and cerium trichloride heptahydrate (0.33g) was added. The is suspension was cooled to 5°C and sodium borohydride (0.034 g) was added. The mixture was stirred for 15 minutes and was poured into water (20 ml) and was extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was columned on silica gel eluting with ethyl acetate to afford the sub-title compound (0.209 g) as a solid.
zo m.p.113-115°C
MS (APCI,) 338 (MH)+
'H NMR (CDCI,) 7.55-7.51 (4H, m); 7.41 (2H, t); 7.30 (1H, dd); 6.96 (2H, d);
5.90 (1H, dd); 5.67 ( 1 H, dd); 4.6-4.52 ( 1 H, m); 4.05 ( 1 H, dd); 3.90 ( 1 H, dd); 3 .52 ( 1 H, dt); 3.21 (1H, dt); 3.07 (1H, c~; 2.80 (3H, s); 2.60 (1H, dd); 2.45 (1H, t); 2.35-2.25 (1H, m).
2s d) 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-1-methyl-pyrrolidin-2-one 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-but-1-enylJ-I-methyl-pyrrolidin-2-one (0.15 g) was dissolved in ethyl acetate and was hydrogenated at 3 atmospheres pressure using 10%
palladium on carbon (0.020 g) as catalyst. The mixture was filtered and concentrated under 3o reduced pressure. The residue was purified by normal phase HPLC eluting with ethyl acetate to afford the title compound (0.082 g) as an oil.
MS (A.PCI,) 340.3 (MH)+
'H NMR (CDCI,) 7.57-7.52 (4H, m); 7.41 (2H, t); 7.30 (1H, dd); 6.97 (2H, d);
4.05-3.98 (2H, m); 3.88 (IH, t); 3.51 (1H, t); 3.06 (1H, dd); 2.71 (3H, s); 2.61-2.50 (1H, m); 2.49 3s 2.35 (IH, m); 2.35 (1H, t); 2.16-2.05 (IH, m); 1.80-1,67 {1H, m); 1.60-1.50 (3H, m).

Example 21 (t)-4-[4-(Biphenyl-4-yloxy~3-hydroxybutyl]-I-methyl-1H pyridin-Z-one (f)-1-(Biphenyl-4-yloxy)-4-(4-(2-fluoro)pyridyl)-2-butanol (0.25g, Example 6) was dissolved in dimethylformamide (3.Om1) and treated with methyl iodide (l.Om1).
The reaction mixture was heated under nitrogen at 100°C overnight. After cooling, the reaction mixture was partitioned between ether and water then 2M sodium hydroxide (Sml) was added. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with dichloromethane : methanol (97:3) to o give the title compound as a solid (0.12g).
mp 129°C
MS (APCI) 350 (M+H)+
'H NMR (DMSO-D6) 7.62-7.56(SH, m); 7.43(2H, t); 7.30(1H, t); 7.02(2H, d);
6.21(1H, s); 6.11(1H, dd); 5.04(1H, d); 3.91(2H, d); 3.84-3.76(1H, m);
3.36(3H, s); 2.65-,5 2.42(2H, m); 1.90-1.60(2H, m).
Pharmacological activity Superoxide assay zo 96-well plates contained 50 ml hIgGl in HBSS in each well from overnight incubation at 4 °C. To this 50 ml cytochrome c solution was added per well and 20 m1 compound or 1 (v/v) DMSO in HBSSg. The plate with additions was pre-warmed with the lid on at 37 °C
for 15 min by placing in a water-bath ensuring that no air-bubbles were trapped under the zs plate. The assay was started by addition of 200 000 neutrophils (37 °C) in 80 ml with a Biohit 8-channel pipettor and the plate incubated in a waterbath with Iid on at 37 °C for 60 min. At this point the reduction of cytochrome c was determined (A550- A468) in a spectramax plate reader. In each individual experiment incubations were in triplicate.
3o Hank's Balanced Salt Solution (HBSS) Hank's Balanced Salt Solution with gelatine 1 mg.ml-' (HBSSg) Cytochrome c solution: cytochrome c 400 ~,M , NaN3 8 mM in HBSSg Compounds exemplified herein inhibit superoxide production from neutrophils in the range 1 E-6 to 1 E-1 OM

Claims (12)

Claims
1. A compound of formula I:
wherein;
A is a phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R is halogen, nitro, C1-6 alkyl, C1-6 alkoxy, (CH2)p R3 where p is 0 to 3 and R3 is hydroxy, or NR4R5 where R4 and R5 are independently hydrogen or C1-6 alkyl or R is CONR4R5;
n is 0, 1,2 or 3;
X is O, S or CH2;
R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl or R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group;
Ar1 is biphenyl, naphthyl or tetrahydronaphthyl, each Ar1 group being optionally substituted by halo, nitro, C1-6 alkyl (optionally substituted by one or more fluorine atoms), CN, -Y-NR8C(O)NR9R10, -O-Y-C(O)NR9R10, -O-Y-C(S)NR9R10, -Y-C(O) NR9R10, -Y-C(S)NR9R10, -Y-SO2NR9R10, -Y-NR9R10, SO2NR9R10, C(O)NR9R10, C(S)NR9R10, C(O)R11, -OC(O)R11, -Y-OR11, -Y-CO2R11, SO2R13, N(R12)SO2R3, N(R12)C(O)R13 or N(R12)CO2R13 where:
Y is a bond, C1-6 alkylene or C1-6 alkenylene;
R9 and R10 are independently hydrogen or C1-6 alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur;
R8, R11, R12 and R13 are independently hydrogen or C1-10 alkyl (optionally substituted by one or more fluorine atoms);
or a salt or solvate thereof, ~ provided that when n is zero then A is not pyridyl or pyrimidinyl.
2. A compound according to claim 1 in which A is phenyl, pyridine, pyrimidine, thiazole or pyrrolidone.
3. A compound according to claim 1 or 2 in which n is 0 or 1.
4. A compound according to any one of claims 1 to 3 in which X is O.
5. A compound according to any one of claims 1 to 4 in which R is fluoro, nitro, methyl, methoxy, dimethylamino, (CH2)pR3 where p is 1 and R3 is hydroxy or NR4R5 where R4 is hydrogen and. R5 is methyl or C1-6 alkyl, or R is or R is CONR4R5 where R4 is hydrogen and R5 is methyl.
6. A compound according to any one of claims 1 to 5 in which R1 and R2 are both hydrogen.
7. A compound according to any one of claims 1 to 6 in which Ar1 is biphenyl, naphthyl or tetrahydronaphthyl each having one or two substituents as defined in claim 1.
8. A compound according to claim 1 which is;
(~)-1-(Biphenyl-4-yloxy)-4-(3-(2-fluoro)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(3-(2-methoxy)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(3-(6-fluoro)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanol, (~)-1-(Biphenyl-4-yloxy)-4-(6(1H)-pyridone-3-yl)-2-butanol, 1-(Biphenyl-4-yloxy)-4-[4-(3-fluoro)pyridyl]-2-butanol, 1-(Biphenyl-4-yloxy)-4-[(3-methoxy)-4-pyridyl]-2-butanol, 1-(Biphenyl-4-yloxy)-4-(4-pyridin-2-one)-2-butanol, 1-[(Biphenyl-4-yloxy)]-4-(4-pyridazin-3-yl)-2-butanol, 1-[(Biphenyl-4-yloxy)]-4-(pyridazin-4-yl)-2-butanol, 1-[(Biphenyl-4-yloxy)]-4-(pyrimidin-4-yl)-2-butanol, (~)-4-(2-(Hydroxymethyl)phenyl)-1-(2-thionaphthyl)-2-butanol, (~)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzamide, (~)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzylamine, (~)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-hydroxybutyl)benzamide, (~)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-hydroxybutyl)benzylamine, (~)-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy))-3-hydroxybutyl)benzyl alcohol, (1S,2RS)-4'-(2-Hydroxy-1-methyl-4-thiazol-2-yl-butoxy)-biphenyl-3-carbonitrile, 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-2-methoxy-phenol, 4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-1-methyl-pyrrolidin-2-one, (~)-4-[4-(Biphenyl-4-yloxy)-3-hydroxybutyl]-1-methyl-1H-pyridin-2-one, or salts or solvates thereof.
9. A compound of formula (IA):
wherein;
A is a phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R is halogen, nitro, C1-6 alkyl, C1-6 alkoxy, (CH2)p R3 where p is 0 to 3 and R3 is hydroxy, or NR4R5 where R4 and R5 are independently hydrogen or C1-6 alkyl or R is CONR4R5;
n is 0, 1, 2 or 3;
X is O, S or CH,;
R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl or R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group;
Ar1 is a fused bicyclic ring system optionally containing one or more heteroatoms, a fused tricyclic ring system optionally containing an oxygen atom, or Ar1 is a group R6-R7 where one of R6/R7 is a phenyl ring and the other is phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms, each Ar1 group being optionally substituted by halo, nitro, C1-6 alkyl (optionally substituted by one or more fluorine atoms), CN, -Y-NR8C(O)NR9R10, -O-Y-C(O)NR9R10, -O-Y-C(S)NR9R10, -Y-C(O) NR9R10, -Y-C(S)NR9R10, -Y-SO2NR9R10, -Y-NR9R10, SO2NR9R10, C(O)NR9R10, C(S)NR9R10, C(O)R11, - OC(O)R11 , -Y-OR1 -Y-CO2R11, SO2R13, N(R12)SO2R13, N(R12)C(O)R13 or N(R12)CO2R13 where:
Y is a bond, C1-6 alkylene or C2-6 alkenylene;
R9 and R10 are independently hydrogen or C1-6 alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur;

R8, R11, R12 and R13 are independently hydrogen or C1-10 alkyl (optionally substituted by one or more fluorine atoms);
or a pharmaceutically acceptable salt or solvate thereof for use as a therapeutic agent, ~ provided that when n is zero then A is not pyridyl.
10. Use as claimed in claim 9, wherein the disease is asthma or rhinitis.
11. A pharmaceutical composition comprising a compound of formula I or a salt or solvate thereof as defined in claim 9 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
12. A process for the preparation of compounds of formula I which comprises:
(a) reduction of a compound of formula (II):
wherein A, R, n, R1, R2, X and Ar1 is as defined in formula (I) or are protected derivatives thereof;
(b) for compounds of formula (I), wherein Ar1 is a group R6-R7, forming the R6-R7 bond by reaction of a compound of formula (III):
with a compound of formula (IV):

(IV) where A, R, n, R1, R2, R6, R7 and are as defined in formula (II), R16 is a hydroxy protecting group, and one of R17/R18 is triflate or halo and the other is B(OH)2 or ZnHal; or (c) for compounds of formula (I) where R1 and R2 are both hydrogen, reaction of a compound of formula (V):

where A, R and n are as defined in formula (II), with a compound of formula (VI):
MYAr1 (VI) where Y is O, S or CH2, M is Li, Na, K, Cs or MgHal where Hal is halogen and Ar2 is as defined in formula (I);
or with a compound of formula (VII):
HYAr1 (VII) where Y is as defined in formula (VI) in the presence of a base; or (d) for compounds of formula (I), where R1 and R2 are both hydrogen, and X
represents O
or S, reaction of a compound of formula (V) or (VI), as hereinbefore defined, with a suitably protected and activated derivative of a diol of formula (VIII):

where R, n and A are as defined in formula (II); or (e) preparation of compounds of formula (I) wherein X represents O, from a compound of formula (IX):

in which R, n, A, R1, R2, and R16 are as defined in process (b) by reaction with a compound of formula (VII) wherein Y represents O; or (f) reaction of a compound of formula (X):

in which A, R and n are as defined in formula (II) and Hal is halogen with a compound of formula (XI):

in which R1, R2, X and Ar1 are as defined in formula (II) in the presence of a suitable catalyst, or (g) preparation of compounds of formula (I) wherein X represents O, from a compound of formula (XII):

in which Ar1 is as defined in formula (II) with a compound of formula (XIII):

in which R and n are as defined in formula (II) and M is a metal, or (h) preparation of compounds of formula (I) wherein X represents O from a compound of formula (XIV):

in which Ar1 is as defined in formula (II) with a compound of formula (XV):

in which R and n are as defined in formula (II), followed by hydrogenation of the resulting product using a suitable catalyst and optionally thereafter process (a) to (h):
~ removing any protecting groups ~ converting a compound of formula (I) into a further compound of formula (I) ~ forming a pharmaceutically acceptable salt or solvate.
CA002341440A 1998-09-14 1999-09-13 Novel compounds Abandoned CA2341440A1 (en)

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PCT/SE1999/001600 WO2000015614A1 (en) 1998-09-14 1999-09-13 Novel compounds

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US6376524B1 (en) 2000-06-21 2002-04-23 Sunesis Pharmaceuticals, Inc. Triphenyl compounds as interleukin-4 antagonists
CN105085347B (en) * 2015-08-14 2016-09-14 天津小新医药科技有限公司 MENTHOL class P2Y12 receptor antagonist of one class nitrile group-containing and application thereof
CN105152996B (en) * 2015-08-14 2017-04-12 天津小新医药科技有限公司 L-menthol type P2Y12 receptor antagonists and application thereof
CN105111119B (en) * 2015-08-14 2017-04-12 天津小新医药科技有限公司 Halogenobenzene L-menthol P2Y12 receptor antagonists and application thereof
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US4379167A (en) * 1974-10-25 1983-04-05 A. H. Robins Company, Inc. 1-Aryloxy-4-amino-2-butanols and the pharmaceutical use thereof
US4609735A (en) * 1974-10-25 1986-09-02 A. H. Robins Company, Inc. Certain aryloxy-4-chloro-2-butanol intermediates
DE2507425A1 (en) * 1975-02-21 1976-09-02 Hoechst Ag ANALOGS OF PROSTANIC ACIDS AND THE PROCESS FOR THEIR PRODUCTION
JPS5931510B2 (en) * 1979-09-03 1984-08-02 東レ株式会社 5,6,7-trinor-4,8-inter-m-phenylene PGI↓2 derivative
WO1989012048A1 (en) * 1988-06-01 1989-12-14 Yoshitomi Pharmaceutical Industries, Ltd. Cis-2,6-diazabicyclo[3.3.0]octane derivatives and their medicinal use
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IL141504A0 (en) 2002-03-10
BR9913601A (en) 2001-05-22
NZ510071A (en) 2003-06-30
NO20011262D0 (en) 2001-03-13
NO20011262L (en) 2001-05-14
CN1318054A (en) 2001-10-17
AU6236799A (en) 2000-04-03
WO2000015614A1 (en) 2000-03-23
ZA200101759B (en) 2002-06-03
SE9803107D0 (en) 1998-09-14

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