C-Linked pyrazole derivatives.

This invention relates to C-linked pyrazole derivatives, processes for their preparation and pharmaceutical compositions containing them.. According tc the invention we provide a compound of general formula (I):

<img file="AP254A_D0001.tif" />

or a physiologically acceptable salt, solvate (e.g. hydrate) or a metabolically labile ester thereof in which

R- represents a hydrogen atom or a group selected from C^.galkyl or C₂_galkenvl;

R*^- represents a hydrogen atom or a group selected from C-, _galkyi, Cj_₇cyc1oa 1ky 1, C3.₇cycloaIkyICj,₄aIky1, Cj.jalkenyl, fiuoroC’_&amp;alkyl, f 1 u0 r oC3 _.g a 1 ken y 1, phenyl, -(C^i^COR^ or -(CH₂)_kSO₂R⁵;

R^ represents a hydrogen atom or a group selected from C^.galkyl optionally substituted by a hydroxy or C^.galkoxy group, C₂_galkenyl, fluoroC₁_₆alkyl, -&lt;CH₂)_mR⁶, -(CH₂)_nCOR⁷ or

-(CH₂)_pNR⁸COR⁹;

R represents a group selected from -CO₂H, -NHSO₂CF3 or a C-linked tetrazolyl group;

R⁸ represents a group selected from Cj.galkyl, C₂_₆alkenyl, C^galkoxy or the group -NR^^R¹^;

R⁸ represents a phenoxy or benzyloxy group;

R⁷ represents a hydrogen atom or a group selected from hydroxy,

Ci_galkyl, C^_galkoxy, phenyl, phenoxy or the group -NR¹®R¹¹; o

R represents a hydrogen atom or a C^.galkyl group;

Q

R represents a hydrogen atom or a group selected from C|_galkyl, C|_galkoxy, phenyl, benzyl, phenoxy or the group -NR^R^;

iAD ORIGINAL ύβ)

CV3C6/C

R¹⁰ and R¹¹ which may be the same or different each independently represent a hydrogen atom or a Cj_₄alkyl group or -NR¹⁰R¹¹ forms a saturated heterocyclic ring which has 5 or 6 md may

<td colspan="2"> optionally contain</td><td> in the</td>

<td> k represents</td><td> zero</td><td> cr an .</td>

<td> 2, especially</td><td> zetz</td><td> or 1 ;</td>

<td> m represents</td><td> an in</td><td> teger :</td>

<td> r. represents</td><td> zero</td><td> or an :</td>

<td> 2, especially</td><td> 0 cr</td><td> 1; and</td>

^:rom 1 to 4, pre ferae esoeoial^v c represents an integer from 1 to 4, preferably 1 cr 2.

Where the compound of general formula (I) is optically active, said formula (I) is intended to cover all enantiomers, diastereoisomers and mixtures thereof including racemates. Where a compcund of the present invention contains one cr two double bonds, these may exist in the cis or trans configuration. Furthermore where such geometric isomers exist, formula (I) is intended to cover mixtures thereof.

The invention also includes within its scope the solvates, especially the hydrates, of compounds of general formula (1).

Within the above definition the term 'alkyl' cr 'aikexy' as a group or part of a group means that the group is straight or branched. The term 'alkenyl' as a group or part of a group means that the group is straight or branched and contains at least one carbon-carbon double bond. The term 'cycloalkyl' as a group or part of a group may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term 'fluoroC|_galkyl' or 'fluoroC&lt;a 1keny1' means an alkyl or alkenyl group in which one or more hydrogen atoms have been substituted by a fluorine atom, for example, -CH^CF^ or -CH’CHCF^.

Within the above definition when -NR¹®R¹¹ represents a saturated heterocyclic ring, this contains 5 or 6 ring members, one of which may be an oxygen atom. Suitable heterocyclic groups are a pyrrolidino, piperidino or morpholino group.

A preferred class of compounds of general formula (I) is that wherein the group R* is a C^_^alkyl (for example, ethyl, n-propyl or

<img file="AP254A_D0002.tif" />

AP Ο Ο Ο 2 5 4

<img file="AP254A_D0003.tif" />

Particularly preferred are those compounds wherein R² is an n-butyl, n-propyl, but-l-enyl or prop-l-enyl group.

Another preferred class of compounds of general formula (I) is that wherein the group R² is a fluoroC^.^alky1 group or the group (CK-)kSO2R⁵. Particularly preferred are those compounds wherein R²represents a fluoroCj_3aikyl group, especially -Cf^CF ₃, cr R³represents the group -NR²^rH (where Ρ^Αθ and R¹² each represent a Ci.^alkyl group), especially SC^NfCHg^·

A further preferred class of compound of general formula (I) is that wherein the group R is a group selected from Cj_galkyl, preferably C^.^alkyl, especially ethyl, isopropyl or isobutyl; Cg_₇cycloalkyl, preferably C₃_₃cycloalky1, especially cyclobutyl; Cg.-jcycloalkylCi.^alkyl, preferably C₃ _ ₅cyc loa Iky 1C₃ _ ₄alky 1, especially cyclopropyImethyl; or phenyl.

Another preferred class of compound of general formula (I) is that wherein the group R² is adjacent to the group R³ .

Yet another preferred class of compounds of general formula (I) is that wherein R is selected from a hydrogen atom or a group selected from C₃_galkyl, preferably C₃_₃alkyl, optionally substituted by hydroxy or C₃_₃alkoxy, especially methoxy; or

-(CH₂)_raR⁶, especially wherein R⁶ is a benzyloxy group; or 7 7 ~(CH₂)_nCOR , especially wherein R represents hydrogen, hydroxy or C₁_₃alkoxy, especially methoxy, and m is 1 or 2 and n is zero, 1 or 2, especially zero or 1. In particular, R³ may represent a hydrogen atom or a group selected from methyl, ethyl, propyl, butyl,-CH₂OH, -CHO, -CH₂OCH₃ or -CO₂H.

Another preferred class of compounds of general formula (I) is that wherein R³ is the group -(CH2)pNR⁸COR⁹, especially wherein R® represents' hydrogen or a C1_₃alkyl group and R® represents hydrogen or a C|_₃alkyl or C₃_₃alkoxy group.

Preferably, in the compounds of general formula (I), R⁴ may be the group -CO₂H, or a C-linked tetrazolyl group.

Particularly preferred compounds are:

4'- [ (3-butyl-5-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-1Hpyrazol-4-yl]methyl ]II,1’-biphenyl]-2-carboxylie acid;

4'-[[5-butyl-3-(methoxymethyl)-1-(2,2,2-t rifluoroethyl)-1Hpyrazol-4-yl]methyl J(1,1'-biphenyl]-2-carboxy lie acid;

bad original

CV3C6/C

5-[4' -{[3-butyl-5-(methoxymethyl)-1-(2,2,2-trifluoroethyl)-1Hpyrazol-4-yl]methyl][1,1'-biphenyl]-2-yl]-IH-tetrazole;

5- [4' {(S^^t^^S^ftfibltheJ^eethyl) -1- (2,2,2-trifluoroethyl) -1Hpvrazcl-4-yl]methyl][1,1'-biphenyl]-2-yl]-lH-tetrazcle;

4' - [ [5-butyl-l-[(dimethylamino) sulphonyl]-3-(methoxymethyl&gt; — 1H— pyrazol-4-yl]methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-; '3-butyl-l-[ (dime thvl amino) sulchor.vi ] -5 - (methoxymethyl) - IHpyrazol-4-yl]methyl][1,1'-biphenyl]-2-carbcxylic acid;

5-[4'-[[3-butyl-l-[(dimethylamino)sulphonyl]-5-(methoxymethyl)IH-pvrazol-4-yl[methyl][1,1'-biphenyl]-2-yl]-ΙΗ-tetrazole;

5-[4'-[[5-butyl-l-[(dimethylamino)sulphonyl]-3-(methoxymethyl)lH-pyrazol-4-yl]methyl][1,1'-biphenyl]-2-yl]-ΙΗ-tetrazole; and the physiologically acceptable salts, solvates and metabolically labile esters thereof.

Further particularly preferred compounds of the present invention include:

3-butyl-l-ethyl-4-[[ 2'- (ΙΗ-tetrazol-5-yl) [1,1'-biphenyl] - 4 yi[methyl]-IH-py razole-5-met hand;

3-butyl-l-(1-methylethyl)-4-[[ 2' -(lH-tetrazol-5-yl) [1, 1'biphenyl]-4-yl]methy1]-lH-pyrazole-5-methanol;

3-buty1-1-(2-methylpropyl)-4-[[ 2' -(lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-lH-pyrazole-5-methanol;

3-butyl-l-(2-cyclopropylmethyl)-4-[ [2' -(lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-lH-pyrazole-5-methanol;

3-butyl-l-cyclobutyl-4-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]4-vl ] methyl] -IH-py razole-5-met hand;

1,3-dibutyl-4-[ [2' - &lt;lH-tetrazol-5-yl) [1,1' -biphenyl]-4 yl]methyl]-lH-pyrazole-5-methanol;

l-ethyl-3-propyl-4-[(2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-pyrazole-5-methanol;

1-(1-methylethyl)-3-propyl-4-[[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-lH-pyrazole-5-methanol;

3-butyl-l-(1-met hylet hy1)-4-([ 2' -(lH-tetrazol-5-yl) [1, 1' biphenyl]-4-yl]methyl]-1H-pyrazole-5-carboxaldehyde;

3-butyl-l-(2-methylpropyl)-4-([ 2' - (lH-tetrazol-5-yl) [1, 1' biphenyl]-4-yl[methyl]-IH-pyrazole-5-ca rboxaldehyde;

3-butyl-l-(2-cyclopropylmethyl)-4-[12' -(lH-tetrazcl-5-yl) [1, 1' -

<img file="AP254A_D0004.tif" />

AP Ο Ο Ο 2 5 4

3-butyl-l-cyclobutyl-4-1(2'-(1H-tetrazol-5-y1) [1,1'-biphenyl) 4-yl]methyl]-ΙΗ-pyrazole-5-carboxaldehyde ;

1.3- dibutyl-4-[[2*-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yi jmethyl]-lH-pyrazcle-5-carboxaldehyde;

1-(1-nethylethyl)-3-propyl-4-[ [2'- (lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-iH-pyrazole-5-carbcxaldehyde;

3-but yl - - (I-mechylethy1&gt; - 4 - [ [2' - (lH-tetrazol-5-yl) [ 1, 1' biphenyl]-4-yljmethyl]-ΙΗ-pyrazole-5-carboxylic acid;

3-butyl-1-(2-methylpropy1)-4-[[2'- (lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-lH-pyrazole-5-carboxylic acid;

3-butyl-l-cyclobutyl-4-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl)4-yl]methyl]-lH-pyrazole-5-carboxylic acid;

3-butyl-4-[(2'-carboxy[1,1' -biphenyl]-4-yl)methyl]-1-ethyl-lHpyrazole-5-carboxylic acid;

3-butyI-l-propy1-4-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethy1]-ΙΗ-pyrazoIe-5-methanol;

l-ethvl-3-propyi-4-[(2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4vl]methyl]-lH-pyrazole-5-carboxaldehyde;

l-ethyl-3-prcpyl-4-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl[methyl]-lH-pyrazole-5-carboxyiic acid;

1- (1-methylethyl)-3-propyl-4-[[2'-(lH-tetrazol-5-yl) (1,1'biphenyl]-4-yl[methyl]-lH-pyrazole-5-carboxylic acid;

1.3- dibutyl-4-([2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-lH-pyrazole-5-carboxylic acid;

3-butvl-4-[(2'-carboxyfl, 1'-biphenyl]-4-yl)methyl]-l-(1 methylethyl)-lH-pyrazole-5-carboxylic acid;

3-buty1-1-ethyl-4 -[(2'-(lH-tetrazol-5-yl) [1,1'-biphenyl)-4yl]methyl]-lH-pyrazole-5-carboxaldehyde;

3-butyl-1-propyl-4-((2'-(lH-tetrazol-5-yl)(1,1'-biphenyl]-4yl]methyl]-IH-pyrazole-5-carboxaldehyde;

1- (2-me thyIpropyI)- 3-propyl-4-[(2'-(lH-tetrazol-5-yl) (1,1'biphenyl]-4-yl]methyl]-lH-pyrazole-5-carboxylic acid;

3-buty1-1-propyl-4-[(2'-(lH-tetrazol-5-yl)(1,1'-biphenyl] -4yl]methyl]-lH-pyrazcle-5-carboxylic acid;

3-butyI-l-ethyl-4-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl[methyl]-lH-pyrazole-5-carboxylic acid;

3-butyl-l-(2-eyeI opropy lmethyl)-4-[(2'-(lH-tetrazol-5-yl) [1,1' biphenyl]-4-yl]methyl]- lH-pyrazole-5-ca rboxy1ic acid;

[ 1,

<img file="AP254A_D0005.tif" />

3-butyi-l-ethyl-4-[[ 2' - (((trifluoromethy1) sulphonyl]amino] 1'-biphenyl]-4-yl]methyl]-lH-pyrazole-5-carboxylic acid;

l-ethyl-3-propyl-4-[[2'-[[(trifluoremethyl)sulphonyl]amino] 1'-biphenyl]-4-yl]methyl]-IH-pyra zole-5-carboxylic acid;

- [4' - [ [3-butyi-l-ethyl-5- (methoxymethyl) -lH-pyrazcl-4yl]methyl] [1,1' -biphenyl] - 2-yl] - IK-tetrazole ;

and the physiologically acceptable salts, solvates anc metabc1icaily laciie esters thereof.

In accordance with the first aspect of the present invention, there is also provided a compound of the general formula (I) above or a physiologically acceptable salt, solvate or metabolically labile ester thereof wherein

R* represents a Cj__galkyi group;

R⁴- represents a hydrogen atom or group selected from C1_galkyl, C2_7cycloalkyl, C-j.-jCyc loalky 1C2 _ 4 a iky 1, f luo r oCj _ g a Iky 1, phenyl, -(CH2)kCOR⁵ or -(CH2)_kSO₂R⁵;

R^ represents a group selected from C₂__gaikyi substituted by a hydroxy or C-^galkoxy group, -(CK₂)_mR^€ or - (CK₂ ) _r_CGR⁷ ;

R⁴ represents a group selected from -CO₂H, -NKSO₂CF-, or a C-lin.ked tetrazolyl group;

R ⁼ represents the group NR^R³·^;

R^ represents a benzyloxy group;

R⁷ represent a hydrogen atom or a hydroxy group;

R¹^ and R³·^3, each independently represent a hydrogen atom or a Ci_₄aikyl group;

k represents zero or an integer from 1 to 4;

m represents an integer from 1 to 4; and n represents zero or an integer from 1 to 4.

The' physiologically acceptable acid addition salts of the compounds of formula (I) may be derived from inorganic or organic acids. Examples of such salts include hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, methanesulphonates or trifluoroacetates.

The compounds may also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. dimethylammonium, triethyiammonium, 2 hydroxyethy1dimethy1 ammonium, piperaziniurn, N,N-dimethylCV306/C

AB ORIGINAL

AP Ο Ο 0 2 5 4 piper az inium, tetraalky lammonium, piper idinium, ethylenediammonium and choline).

It will be appreciated that, for pha^BU^eutical us·, the salts referred to above will be physiologically acceptable, but other salts may find use, for example, in the preparation of the compounds cf formula (I) and the physiologically acceptable salts thereof.

It will be further appreciated that the compounds cf general formula (I) may be chemically modified in the form of compounds which in vivo (for example, by enzymic attack) will provide the parent compounds of general formula (I) . Such prodrugs may be, for example, physiologically acceptable metabolically labile ester derivatives. These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I), with prior protection of any other reactive groups present in the molecule. Examples of such esters include lower alkyl esters (e.g. methyl or ethyl esters), alkenyl esters (e.g. vinyl or alkyl esters), alkynyl esters(e.g. ethynyl or propynyl esters), alkoxvalkyl esters, (e.g. methoxymethyl or 2-methoxyethyl esters), a lkylthioalkyl esters (e.g. methylthiomethyl esters) haioalkyl esters (e.g. 2-iodoethyl or 2,2,2,-1richloromethyl esters), alkancyloxyalkyi esters (e.g. acetoxymethyl, 1-acetoxyethyl or pivaloyloxymethyl esters), alkoxycarbonyloxyalkyl esters (e.g. 1ethoxycarbonyloxyethyl or 1-methoxycarbonyloxyethy1 esters), aroyloxyalkyl esters (e.g. benzoyloxymethyl or 1-benzoyloxyethyl esters), substituted or unsubstituted aralkyl esters (e.g. benzyl or 4-amidobenzyl esters), substituted or unsubstituted aminoethyl esters (e.g aminoalkyl or 2-N,N-dimethylaminoethy 1 esters) or hydroxyalkyl esters (e.g. 2-hydroxyethyl or 2, 3-dihydroxypropyl esters).

In addition to the above ester derivatives the present invention includes within its scope compounds of general formula (I) in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo into the parent compounds of general formula (I) .

According to a second aspect of the invention we provide a compound of general formula (I) or a physiologically acceptable

<img file="AP254A_D0006.tif" />

sale, solvate or metabolically labile ester thereof for use in therapy,

In particular, the compounds of the invention may be used in the treatment cr prophylaxis of hypertension. They are also potentially useful for the treatment cf cognitive disorders such as dementia (e.g. Alzheimer's disease) and other diseases such as renal failure, hyperaldcsteror.isrc, cardiac insufficiency, congestive heart failure, pcst-myocardia I infarction, cerebrovascular disorders, glaucoma and disorders of intracellular homeostasis.

According to a further aspect of the invention we provide a compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof for use in the treatment of the aforementioned diseases, especially hypertension.

According to another aspect of the invention we provide a compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof for the manufacture of a therapeutic agent for the treatment of the aforementioned diseases, especially hypertension.

According to a further aspect of the invention we provide a method of treating the aforementioned diseases, especially hypertension, which method comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof.

It will be appreciated that the compounds of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof may advantageously be used in conjunction with one or more other therapeutic agents, such as for example diuretics and/or different antihypertensive agents such as β-blockers, calcium channel blockers or ACE inhibitors. It is to be understood that such combination therapy constitutes a further aspect of the present invention .

It will be further appreciated that reference herein to treatment extends to prophylaxis as well as to the treatment and relief of established symptoms.

Wnile it is possible that a compound of general formula (I) may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.

CV3C6. C

BAD ORIGINAL $

AP Ο Ο Ο 2 5 4

The compounds of general formula (I, and their physiologically acceptable salts, solvates and metabolically labile esters may be

<img file="AP254A_D0007.tif" />

<img file="AP254A_D0008.tif" />

•tion in any convenient way, and the invention also includes within its scope pharmaceutical compositions comprising at least cr.e compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile es;er thereof adapted for use in human cr veterinary medicine. Such compositions may be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Thus, the compounds according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fcr example mucilage of starch cr polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; dis integrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl o-hydroxybenzoates or sorbic acid. The compounds cr their salts or esters may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. For buccal administration the

CV306/C

BAD ORIGINAL composition may take the form of tablets or lozenges formulated in conventional manner.

It will be appreciated that both tabl^*y be manufactured in the form of sustained release formulations, such that they provide a controlled continuous release of the compounds according to the invention over a period of hours.

The compounds cf general formula (I) and their physiclogically acceptable salts, solvates and metabolically labile esters may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use cf a suitable propellant, s.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or other suitable gas. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

The pharmaceutical formulations according to the invention may also contain other active ingredients such as antimicrobial agents, cr preservatives.

It will be appreciated that the amount cf a compound cf general formula (I) required for use in treatment will vary not only with the particular compound selected but also with the route of

T3AD ORIGINAL

C73C6/C

<img file="AP254A_D0009.tif" />

AP Ο Ο Ο 2 5 A administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, when the compositions comprise dosage units, each unit will preferably contain O.lmg to 500mg, advantageously where the compounds are to be administered orally Img to 40Cmg of the active compound. The daily dosage as employed for adult human treatment will preferably range from O.lmg to 2g, most preferably from Img to lg which may be administered in 1 to 4 daily doses.

The compounds of the invention may be prepared by a number of processes as described below wherein the various groups are as defined for general formula (I) unless otherwise specified.

It will be appreciated by a person skilled in the art that where necessary, reactive or labile groups in the following processes may be protected in a conventional manner using, for example, one of the groups described in process (C) hereinafter.

Thus, according to a further aspect of the present invention we provide a process (A) for preparing the compounds of general formula (1) which comprises treating a compound of general formula (II)

<img file="AP254A_D0010.tif" />

(wherein R¹, R³ and R⁴ are as defined in general formula (I,) with a hydrazine of formula (III)

R²NHNH₂ (III) (wherein R is as defined in general formula (I)) followed by the removal of any protecting groups where present, as described hereinafter.

The reaction is preferably effected in a solvent such as an aqueous alcohol e.g. ethanol, an ether e.g tetrahydrofuran or dioxan, a substituted amide e.g dimethylformamide, acetonitrile or water at a temperature in the range of 0^cC to reflux and preferably at room temperature.

<img file="AP254A_D0011.tif" />

The intermediate diketones of formula (IX) are novel compounds and form a further aspect of the invention.

In another general process (B) a compound of general formula (I) may be obtained:by iatftconversior. of another compound of general formula (I). Thus for example, when R² represents a hydrogen atom, such a compound may be converted into a compound of o c general formula (I) wherein R⁴· represents a group - (Crf₂) xCOR^{0 cr}~ - ^H 2 ¹ k “ C £ ?·' by reaction with b - ( C H £ ) C C R ~ or b - ( C H 2 ) S C 2 R ⁵ , respectively (wherein b represents a leaving group, for example, a halogen atom such as a chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy, or ptcluenesulphonyloxy). The reaction is conveniently effected in a suitable solvent such as a substituted amide e.g dimethylformamide cr an ether e.g tetrahydrofuran in the presence of a base such as sodium hydride or sodium amide, at a temperature in the range ΟθΟ to reflux, and preferably at room temperature.

In an alternative example of process (B) a compound of general formula (I) wherein R is a hydrogen atom may be converted into a compound of general formula (I) wherein R represents a C₂_galkyl, C ΐ _ 7 cy c 1 0 a k I y I or C -3 _ 7 cy c 10 a 1 k y 1C . _ ₄ a 1 k v 1 group, cr a group - (CH21cr -(CH2)where k is 1 to 4, by reaction with a corresponding alkylating agent, for example, an alkvlhalide such as an alkyliodide. The reaction is conveniently effected in a suitable solvent such as a substituted amide e.g. dimethylformamide or an ether e.g. tetrahydrofuran in the presence of a base such as potassium carbonate or sodium hydride, at a temperature in the range of ΟθΟ to reflux, and preferably at room temperature.

It will also be appreciated that other substituents in a compound of general formula (I) may be modified by techniques well known in the art to produce alternative compounds of general formula (I) .

In another general process (C) a compound of general formula (I) may be obtained by deprotection of a protected intermediate of general formula (la)

<img file="AP254A_D0012.tif" />

BAD ORIGINAL

AP Ο Ο Ο 2 5 4

<img file="AP254A_D0013.tif" />

<img file="AP254A_D0014.tif" />

da) ί &gt; 3 4 (wherein R^A, R‘, R^J and R are as defined in general formula (I) except that at least c.ne reactive group is clocked by a protecting croup). The protecting groups may be any conventional protecting groups, for example as described in Protective Groups in Organic Synthesis by Theodora Greene (John Wiley and Sons Inc., 1981). Examples of carboxyl protecting groups include Cj_galkyl such as methyl or t-butyl, or C-_^Qaralkyl such as benzyl.

When R^ is a tetrazolyl group, this may be protected with, for example, the trityl group -C(phenyl)3, or a £-nitrobenzyl or 1ethoxyethyl group.

Deprotection to yield the compound of general formula (I) may be effected using conventional techniques. Thus, for example, aralkyl groups may be cleaved by hydrogenolysis in a suitable organic solvent such as an alcohol, e.g. ethanol, in the presence of a noble metal catalyst such as palladium or an oxide thereof on a support such as charcoal, and. conveniently at room temperature and pressure. Carboxyl protecting groups such as alkyl groups may be cleaved by hydrolysis using a base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) in a suitable solvent (e.g. an aqueous alcohol such as methanol or ethanol, at any suitable temperature up to reflux. Deprotection of the tetrazolyl group when protected with a trityl group may be effected by acid hydrolysis using trifluoroacetic acid, a sulphonic acid such as dl-10-camphor sulphonic acid, or a mineral acid such as hydrochloric acid in a suitable solvent such as methanol, ethanol, tetrahydrofuran or mixtures thereof conveniently at room temperature to reflux. Alternatively, when possible, deprotection of the tetrazolyl group can be effected by catalytic hydrogenation as previously described.

In another general process (D) a compound of general formula (I) in which the substituent R^ represents a C-linked tetrazolyl group, may also be prepared from a compound of general formula (IV)

BAD ORIGINAL ft

CV306/C (IV)

<img file="AP254A_D0015.tif" />

R

<img file="AP254A_D0016.tif" />

reaction wit r. a suitable azide such as sodium azide, ammonium azide (preferably prepared in situ from sodium azide and ammonium chloride), t r i a 1 ky 1 - (e . g . t r ie t hy 1) anunon ium azide (preferably prepared in situ from sodium azide and a trialkylamine (e.g. triethylamine)), a trialkylsilylazide (e.g. trimethylsilylazide) or an alkyl azide e.g. tributyl tin azide. The reaction is conveniently effected in a solvent such as xylene, an ether, for example, dimethoxyethane or tetrahydrofuran, or a substituted amide, for example, dimethylformamide, at an elevated temperature, such as the reflux temperature of the solvent, for between I and 10 days. Where the azide is tributyl tin azide the reaction may conveniently be effected in the absence of a solvent at a temperature between room temperature and ΙΘΟθΤ. Such a reaction leaves the tetrazolyl group protected with a tributyl tin group, which can readily be removed using aqueous base or acid. Where aqueous base is used to effect this deprotection, the compound may be treated with an aqueous acid to liberate the tetrazole.

Compounds of general formula (IV) may be prepared by processes analogous to those described herein commencing from a compound cf formula (XV) .

The Intermediate compounds of general formula (IV) are novel compounds and form a further aspect of the present invention.

In another general process (E) a compound of general formula (I) in which the substituent R⁴ represents -NHSCHCF^, may be prepared from a compound of general formula (V)

<img file="AP254A_D0017.tif" />

R (V)

<img file="AP254A_D0018.tif" />

CV306/C

BAD ORIGINAL $

AP Ο Ο Ο 2 5 4 (wherein R¹, R² and R³ are as defined in general formula (I)) by reaction with t r i f 1 u o r ome t h a nes, a nhy dr i de or trifluoromethylsulphonyl chloride, in a 3ulx»UISr^h&gt;ivent such as a haloger.ated hydrocarbon, e.g. dichloromethane or chlorform.

Compounds of general formula (V) may be prepared by processes analogous to those described herein commencing from a compound of formula (XVI) cr a nitro precursor thereof.

Alternatively, compounds of general formula (V) may be prepared by a Curtius rearrangement of a compound of formula (I) wherein R⁴is -CO2H (provided that this is the only carboxyl group in the molecule) using, for example, diphenylphosphorylazide in the presence cf a base such as triethylamine and in a solvent such as an alcohol (e.g. tert-butanol) to form a carbamate followed by deprotecticn of the amine in a conventional manner, for example by acid hydrolysis using hydrochloric acid in a solvent such as ethanol.

The intermediate compounds of general formula (V) and their acid addition salts are novel compounds and form a further aspect of the present invention.

In another general process (F) a compound of general formula (I) may be prepared by treating a compound of formula (VI) with a compound of formula (VII)

R*

<img file="AP254A_D0019.tif" />

(VI) (VII) (where one of R^A and R represents a halogen atom, for example, bromine or iodine, and the other represents the group -B(OH)2 ot an ester thereof, and R¹, R², R³ and R⁴ are as defined in general formula (I)).

The reaction may be effected in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0), in a suitable solvent such as an ether (e.g. 1,2-dimethoxyethane cr

CV306/C

BAD ORIGINAL fi tetrahydrofuran) or an aromatic hydrocarbon (e.g. benzene). The reaction is preferably carried out in the presence of a base such as an alkali or alkaline earth metal carbonate (e.g. sodium carbonate) at a suitable temperature up to reflux.

The intermediate compounds of formula (VI) are novel compounds anu term a further aspect cf the present invention.

In another general process (G) a compound cf general formula •1 z.-.ereir. R- represents the croup -sCH^^COR' where r. is zero and ? ti C₃_gaikcxy, may be prepared by reacting a biphenyl compound of formula (VIII)

<img file="AP254A_D0020.tif" />

(VIII) (wherein R⁴ is as defined in general formula (I) and L is a leaving group as defined above) with a compound of formula (IX)

<img file="AP254A_D0021.tif" />

Li (ix) ¹ + 7 a (••.herein R·¹ and R are as defined m general formula (I) and R ^a is a C-^alkcxy group) .

The reaction is conveniently effected at a temperature between -100°C and room temperature in a suitable solvent such as an ether, fcr example, tetrahvdrofuran, dimethoxyethane or diethyl ether.

In the processes (A),(B), (C) , (D), (E), (F) and (G) described above, the compounds of general formula (I) may be obtained in the form of -a salt, conveniently in the form of a physiologically acceptable salt. Where desired, such salts may be converted into the corresponding free acids or free bases using conventional methods .

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isoprcpanol.

IGINAL

CV3 rAP Ο Ο Ο 2 5 4

Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the coapmuyl&amp;gf £pneral formula (I), using conventional methods.

Thte

<img file="AP254A_D0022.tif" />

late compounds cf general formula (II) may be prepared from a compound cf formula (X)

CH, (X) (wherein R³ and R³ are as defined in general formula (I)) by condensation with a compound of formula (XI)

R⁴

<img file="AP254A_D0023.tif" />

(wherein R⁴ is defined in general formula (I) and L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy, or o-toluenesulphonyloxy). The reaction is preferably effected under basic conditions, for example, in the presence of sodium hydride, potassium carbonate or sodium methoxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or acetone, or a substituted amide e.g. dimethylformamide, at a temperature between 0³C and the reflux temperature of the solvent.

Compounds of formula (X) may be prepared by reaction of a compound of formula (XII) r¹coch₃

With a compound of formula (XIII) r³co₂ch₃ (XII) (XIII) preferably in the presence of a base such as sodium amide, sodium hydride or tetra-n-butyl ammonium fluoride. The reaction is conveniently effected in a solvent such as an ether e.g.

BAD ORIGINAL &amp;

CV306/C tetrahydrofuran dichloromethane temperature of the Compounds of compound of formul or dioxan, or a halogenated hydrocarbon e.g. at a temperature between 0®C and the reflux solvent. * formula (VIII) and (XI) may’be prepared from a a (XIV)

H.C

<img file="AP254A_D0024.tif" />

(XIV) using any suitable reagent well known in the art for converting the methyl group in formula (XIV) into the group -C^L (wherein L is as defined above). Thus for example, when L is a halogen atom, a compound of formula (XIV) can be converted into a compound cf formula (XI) using N-chloro amides, tert-butyl hypochlorite or Nbromcsuccinimide. Halogenation may be catalysed by light, thus the reaction mixture can be illuminated with a suitable artificial light source, and preferably in the presence of a free radical initiator such as azobisisobutyronitriie (AI3N) or dibe.nzovl peroxide. The reaction may be conveniently effected in a solvent such as a halogenated hydrocarbon, e.g. carbon tetrachloride at an elevated temperature such as the reflux temperature of the solvent.

Compounds of formula (XIV). in which R⁴ represents a C-linked tetrazolyl group may be prepared from a compound of formula (XV)

NC

<img file="AP254A_D0025.tif" />

using the reagents and conditions described in process (D).

Compounds of formula (XIV) in which R⁴ represents the group

-NHSO2CH3 may be prepared from a compound of formula (XVI)

H,C

<img file="AP254A_D0026.tif" />

(XVI) using the reagents and conditions described in process (E).

Compounds of f0rmul a (XIV) in which R⁴ represents -COOH or

-NHSC^CFj, and compounds cf formulae (XV) and (XVI), may be prepared by reaction of a compound cf formula (XVII)

CV306/C

BADORIGINAL ft

AP Ο Ο Ο 2 5 4 ί lift *

<img file="AP254A_D0027.tif" />

&gt;

(XVII) (wherein Ζ represents a bromine or iodine atom or the group -CSCoCF-j, and R^4a represents either -COOH, -NHSO2CF3, a nitrile or amino croup cr a group convertible thereto by standard methodology) with a corresponding 4-methvlbenzeneboronic acid derivative in the presence of a palladium (0) compound such as tetrakis(triphenylphosphine) palladium (0) in a solvent such as dimethoxyethane in the presence of a base such as sodium carbonate or thallium hydroxide. The reaction is conveniently effected at an elevated temperature, such as the reflux temperature of the solvent.

Compounds of formulae (VI) or (VII) where R¹^ or R¹^ represents -B(OH&gt;2 may be prepared from the corresponding halides by lithiation at low temperature followed by reaction with a suitable boronic acid ester (e.g. triisopropylborate) and subsequent hydrolysis with water or an acid (e.g. hydrochloric acid).

Alternatively, compounds of formula (VI) wherein represents Hal may be prepared by the reaction of a compound of formula (XVIII)

<img file="AP254A_D0028.tif" />

(XVIII) with a compound of formula (III) under the reaction conditions of general process (A) .

Compounds of formula (XVIII) may be prepared by reaction of a compound· of formula (XIX)

<img file="AP254A_D0029.tif" />

LCHj—. Λ—Hal (XIX) (wherein Hal is a bromine or iodine atom and L is a leaving group) with a compound of formula (X) under basic conditions, for example, in the presence of sodium hydride, potassium carbonate or sodium methoxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran, a ketene, e.g.

bad original 'V3C6/C acetone or a substituted amine e.g. dimethy1formamide, at a temperature between 0°C and the reflux temperature of the solvent.

Compoundsmay be prepared by lithiatior. cf a compound cf formula (XX) ccr⁷‘

<img file="AP254A_D0030.tif" />

(XX)

S'

The reaction may be effected using an alkyllithium compound, fcr example, tert-butyl lithium at a temperature between -100°C and room temperature, in a suitable solvent such as an ether, for example, tetrahydrofuran, dimethoxyethane or diethyl ether.

Compounds cf formula (XX) may be prepared by halogenation of a compound of formula (XXI)

<img file="AP254A_D0031.tif" />

using standard methodology described herein above.

Compounds of formula (XXI) may be prepared by the reaction of a

Ο T compound of formula (X) wherein R^J represents -(CH2&gt;_nCOR (where n is zero and R⁷ is C^.^alkoxy) with a compound of formula (III) using the method of general process (A) .

Intermediates of formulae (III), (VII), (VIII), (XII), (XIII), (XVI) and (XVII) are either known compounds or may be prepared by methods analogous tc those described herein or used for the preparation of the known compounds.

The following examples illustrate the invention. Temperatures are in ®C. Dried refers to drying using magnesium sulphate. Thin layer chromatography was carried out on silca, using one of the following solvent systems: A - ether: hexane, δ dichloromethane:ethanol: ammonia, C - ether :petroleum ether (40-60°), D - ethyl acetate: hexane , E - ethyl acetate :ethar,ol, F ether :acetic acid, G - ether:he xane:acetic acid, or H - ethyl

<img file="AP254A_D0032.tif" />

BAD ORIGINAL ft

AP Ο Ο Ο 2 5 4 acetate: acetic acid. The following abbreviations are used: DFC dry flash chromatography on silica gel (Merck 9385); THFtetrahydrofuran; DME - dimethoxyethane; AI BN azobisisobutyronitrile; DMF - N,N-dimethylformamide; TFA trifluoroacetic acid.

1- Methcxv-2,4-octandione

2- Hexanone (96.8g) was added dropwise over 15min under nitrogen to a stirred suspension of sodium amide (37.7g) in dry ether (1 litre) at room temperature. The mixture was stirred for 12min, a solution of methyl methoxyacetate &lt;50.3g) in dry ether (150ml) was added dropwise over 20min, and the mixture was heated under reflux for 2h. The mixture was cooled, poured into ice and 2N hydrochloric acid (600ml) and the aqueous layer extracted with ether (4x 300ml). The organic layers were washed with 8% sodium bicarbonate solution and brine, dried and evaporated to give an orange liquid (102g). Purification by DFC, eluting with System A (5:95) gave a yellow Iiquid (3 6g) .

T.l.c. (System A 5:95) Rf 0.1.

Intermediate 2

1,1-Dimethylethyl 4'-bromomethylbiphenvl-3-carboxylate (a) 1,1-Dimethylethyl 2-bromobenzoate

A solution of o-bromobenzoic acid (lg), N,N'-dicyclohexy1 carbodiimide (1.129g), t-butanol (405mg) and 4-dimethylaminopyridine (61mg) in dry ether (20ml) was stirred at room temperature for 18h. The resulting precipitate was filtered off and the filtrate evaporated to give a colourless solid which was triturated under petroleum ether (40-60θ) (20ml) and filtered. The filtrate was evaporated to give a pale yellow oil (0.994g). b.p. 80-84®/0.35 mmHg .

(b) 1,1-Dimethylethyl 4'-methvlbiphenyl-2-carbcxvlate

A mixture of Intermediate 2a (2.0g) 4-methylbenzeneboronic acid (1 . 17g), tetrakis(triphenylphosphine) palladium (0) (269mg) and sodium carbonate solution (1M; 21ml) in DME (80ml) was heated under reflux for 18h. The solvent was evaporated and the residue

C7306/C

---BADOffiGINAL d partitioned between ether (3x 50ml) and sodium carbonate (2N; 100ml) and the combined organic extracts were washed with brine (2x 100ml) and dried. The solvent was evaporated to give a pale yellow oil which was purified by shcrt-path column chromatography on silica gel (Merck 7729; 40g) . Elution with System C (1:40) gave a colourless, mobile oil (1.88g) .

T.l.c (System C 1:40) Rf 0.3.

(c) 1,1-Elmethylethyl 4'-bromomethylbiphenyl-2-carboxylate

A mixture of Intermediate 2b (1.825g), N-bromosuccinimide (1.21g) and dibenzoyl peroxide (130mg) in carbon tetrachloride (30ml) was heated under reflux for 18h. The solvent was evaporated in vacuo and the residue partitioned between ether (3x 50mi) and sodium bisulphite solution (50ml). The combined organic extracts were dried and the solvent evaporated to give a yellow oil which was purified by short-path column chromatogrpahy on silica gel (Merck 7729; 60g). Elution with System C (1:50) gave a colourless crystalline solid (1.15g).

T.l.c (System C 1:50) Rf 0.25.

Intermediate 3

2- (4-3romomethyl(phenyl))-2'-(trishenvImethyl)tetrazol-1-vl benzene (a) 2-(4-Methvlphenyl)benzonitrile

To a solution of o_-b r o m o b e η z ο n i t r i 1 e (40g) and 4methylbenzeneboronic acid (33g) in DME (2 litres) was added tetrakis (triphenylphosphine) palladium (0, (7.58g) and then sodium carbonate (1M, 592ml). The mixture was stirred vigorously and heated at reflux for 18 hours. The solvent was removed in vacuo and the dark residue partitioned between ether (800ml) and sodium carbonate (1M, 800ml); the aqueous phase was extracted with ether (3x 400ml). The combined organic phases were dried and concentrated in vacuo to afford an orange oil which was crystallised from System C (1:3) using activated charcoal as a decolourising agent to afford a white solid (33.0a).

T.l.c. System A (1:9) Rf 0.30 (c) 2 - (4-Methylphenvl)-IH-tetrazol-l-vl benzene

BAD ORIGINAL ft

CV306/C

AP Ο Ο Ο 2 5 4

A mixture of Intermediate 3a (7g) and tributyl tin azide (24g) was heated at 160θ(3. Further amounts of Intermediate 3a were added after 2h (4g) and a further 1.5h (2g) ( thin continued for another I.5h. The cooled reaction with ether (200ml) and extracted with aqueous sodium hydroxide solution (2M;50mi). The aqueous mixture was poured into cold concentrated HC1 (50ml) ar.d the white solid filtered and air-dried. This solid was crystallised from toluene (200ml) to give the title compound as cream microcrystals (10.2g).

T.l.c. ether Rf. 040 (c) 2-(4-Methylphenyl)-2'-(triphenvlmethyl)tetrazol-l-yl benzene

To a suspension of Intermediate 3b (12.2g) in dry dichloromethane (100ml) was added triethyiamine (12.8ml). Trityl chloride (14.6g) was added followed by N,N-dimethylaminopyridine (251mg) and the resultant solution was stirred at room temperature for 16h. The reaction mixture was partitioned between water (200ml) and dichlorcmethane (200ml). The separated organic phase was washed with water (200ml), dried and concentrated in vacuo to give the title compound as a cream-coloured solid (21.2g) .

T.l.c. System A (1:1) Rf 0.55 (d) 2-(4-Bromomethyl(phenyl))-2'-(triphenvlmethyl)tetrazol-l-yl benzene

To a solution of Intermediate 3c (21. lg) in carbon tetrachloride (600ml) was added N-bromosuccinimide (8.3g), and the mixture heated almost to reflux. Dibenzoyl peroxide (854mg) was added and the mixture heated at reflux for 3.5h. Further dibenzoyl peroxide (800mg) was added and the reaction mixture heated at reflux for a further 60h. Further N-bromosuccinimide (4.2g) and dibenzoyl peroxide (854mg) were added and the mixture heated at reflux in the presence of a 200W lamp for 3h. The cooled mixture was filtered and the filtrate washed with water (2x150ml), dried and concentrated in vacuo to afford the title compound as a cream glassy solid (23g). T.l.c (ethyl acetate:petroleura ether 1:1) Rf 0.90.

Intermediate 4

<img file="AP254A_D0033.tif" />

CV306/C

1, 1-Dimethylethyl 4'-[2-(methoxyacetvl) -3-oxoheptanyl] [1,1’ — biphenyl]-2-carbcxylate

Intermediate 1 (13.4g) was heated under reflux with Intermediate 2 (30.Og) and anhydrous potassium carbonate (10.8g) in acetone (390ml) with stirring under nitrogen for 6h. The solvent was evaporated and the residue partitioned between water (30Cml) and ether (3x 20Cml); the organic extracts were washed with brine, dried and evaporated to give an orange oil (39.5g). Purification by 2FC eluting with System A (1:4) gave the title compound as a pale vellow oil (25c). T.l.c. System A (1:3) Rf 0.1.

Intermediate 5 l-Methoxv-3-[ (2'-[2 — &lt;tr iphenvlmeth v1)-2H-tetrazcl-5-vl] [1, 1' biphenvl]-4-vl]methyl]-2, 4-octandione

Sodium hydride (80% dispersion in oil, 200mg) was added to a stirred solution of Intermediate 1 (0.96g) in dry THF (20ml) at room temperature under nitrogen, and stirring was continued at room temperature for 40min. A solution of Intermediate 3 (2.C8g) in THF (5ml, was added, and the mixture was heated under reflux for 22h. The mixture w 3 s poured into water (50ml) and extracted with ether (3x 40ml); tne organic layers were washed with brine, dried and evaporated to give a dark yellow oil (2.38g) . Purification by DFC eluting with System A (20:80 to 50:50) gave the title compound as pale yellow oil (0.8g).

T.l.c. (System A 40:60) Rf 0.2.

Intermediate 6

1, 1-Dimethylethvl 4' - [[3-butyl-5-(methoxvmethvl)-lH-Pvrazol-4-yl] methyl] [1,1' -bipher.vl]-2-carboxvlate

Intermediate 4 (0.5g) was stirred at room temperature with hydrazine hydrate (85%, 0.086ml) in absolute ethanol (15ml) under nitrogen for 16n. The solvent was evaporated to give a colourless oil (375mg). Purification by OFC eluting with System 3 (98:2:0.2) gave a colourless oil (325mg).

T.l.c. System C (50:50), Rf 0.2.

I n t e r me d i a t e 7

V3C6/C

BAD ORIGINAL A

AP Ο Ο 0 2 5 4 (a) 1,1-Dimethylethy1 4*-[[5-butyl-3-(methoxymethyl)-1-phenyl-lHpyrazol-4-yI] methyl] 11,1'-biphenyl)-2-carboxyiate; and (b) 1.1-Di^nethvlethvl 4'-[[3-butvl-5- (methoxvmethyl)-1-phenyl-lHpvrazol 1,1*-biphenyl]-2-carboxvlate

Intermediate 4 (l.Og) was stirred with phenylhydrazine (0.224ml) in ethanol (absolute, 20ml&gt; at room temperature under nitrogen for 16h and heated under reflux for 24h. The solvent was evaporated to give an orange oil (1.22g). Purification by DFC eluting with System A (20:90 - 30:70) gave:

(a, Intermediate 7a as a pale yellow oil (229mg),

T.l.c. (System C 50:50) Rf 0.4, and (b) Intermediate 7b as a pale yellow oil (256mg),

T.l.c. (System C 50:50) Rf 0.75.

Intermediate 8 (a ) 1,1-Dimethylethyl 4'-(f3-butvl-5-(methcxvmethvl)-2-(2,2,2trlfluoroethyl) -2H-pvrazol-4-vl]methyl] [1, 1' -bichenvl]-2carboxvlate; and (b) 1, 1-Dimethylethvl 4'-[f5-butvl-3-(methcxvmethvl)-1-(2,2,2trifluoroethyl)-lH-svrazol-4-yl]methvl][1,1' -bichenvl]-2-carboxvlate

Intermediate 4 (0.5g) was stirred at room temperature under nitrogen with 2,2,2-trifluoroethylhydrazine (70% in water, 0.204ml) in ethanol (10ml, for 24h. The solvent was evaporated and the residue (0.7g) purified by DFC eluting with System A (10:90 - 50:50, to give:

(a) Intermediate 8a as a pale yellow oil (180mg),

T.l.c (System A 50:50) Rf 0.55; and (b) Intermediate 8b as a colourless oil (239mg),

T.l.c. .(System A 50:50) Rf 0.25.

Intermediate 9

5-[4*-[(3-Butyl-5 - (methoxymethyl)-lH-pyrazol-4-yl)]methylj f 1,1'biphenyl]-2-yl]-2- (triphenylmethyl)-2H-tetrazole

Intermediate 5 (150mg) was stirred at room temperature under nitrogen with hydrazine hydrate (80% hydrazine hydrate; 0.028ml) in absolute ethanol (3ml) for 3 days. The solvent was evaporated and the residue purified by DFC, eluting with ether to give the title compound as a colourless gum (78mg).

,D ORIGINAL ft

CV306/C

T.l.c. (ether) Rf 0.2.

<img file="AP254A_D0034.tif" />

Intermediate 10 (a) 5 - '4'-[[3-Butvl-5-(methoxymethvl)-1-(2,2,2-trifluoroethyl)-IHcvra zol-4-yl ] methvl] [1,1' -biphenvl ]—2 — yl]-2 - (t r ipheny lmethy 1) -2.Htet ratole,- and (b) 5-]4'-i;5-3utvl-3-fmethoxymethvl)-1-(2 ,2,2-t ri flucroethvlI -1Hcvrazol-4-vl]methvl] [1,1' -biphenyl ]-2-vl]-2- (t riphenylmethyl) -2.-:tet razole

Intermediate 5 (O.SOSg) was stirred at room temperature with 2,2,2trifluoroethylhydrazine (70% solution in water, 0.304ml) in ethanol for 21h. The solvent was evaporated and the residue purified by DFC eluting with System A (10:90 to 60:40) to give:

(a) Intermediate 10a, T.l.c (System A 50:50) Rf 0.35; and (b) Intermediate 10b, T.l.c. (System A 50:50) Rf 0.2.

Intermediate 11 ( a ) 1,1'-Dimethvlethvl 4'-[[1-(2-aminc-2-oxoethvl)-5-butvl-3( methoxymethvl) -lH-ovrazol-4-vl]methyl] [ 1, 1' - bio her, vl] - 2 oarbcxvlate; and (z) I,1'-Dimethvlethvl 4'-[[1-(2-amino-2-oxoethvl)-3-butvl-5(methoxymethyl)-lH-pyrazol-4-yI]methyl][1,1'-biphenvl]-2-carboxylate

Sodium hydride (52mg) was added to a stirred solution of Intermediate 6 (0.5g) in dry DMF (5ml), and stirring was continued at room temperature under nitrogen for 1.5h. Chloroacetamide (122mg) was added and stirring was continued at room temperature for 3h. The mixture was partitioned between water (30ml) and ethyl acetate (3x 20ml); the organic extracts were washed with 50:50 brine:water (3x30ml), dried and evaporated to give a pale yellow gum (658mg) . Purification by DFC, eluting with System D (50:50) followed by ethyl acetate, and System E (95:5) gave:

(a) Intermediate 11a as a colourless oil (291mg),

T.l.c. (ethyl acetate) Rf 0.15; and (b) Intermediate lib as a pale yellow gum (277mg),

T.l.c (ethyl acetate) Rf 0.3.

Intermediate 12 (a ) 1,1*-Dimethvlethvl 4'-[]5-butyl-3-(methoxymethvl) -1-met hy1-1HCV300/C

BAD ORIGINAL ft

ΑΡ θ Ο η 2 5 4 pyrazol-4-yljmethvl][1,1'biphenyl]-2-carboxylate; and (b) 1,1'-Dimethylethy1 4' -[13-butvl-5-(methoxymethyl)-1-methyl-lHpvrazol-4-yl]methyl][1,1'-biphenvl]-2-carboxylate * f ·£ί - ^C-—-— —- ---—————¹f A mixture of Intermediate 6 (l.Og), methyl iodide (330mg) and potassium carbonate (320mg) in DMF (30ml) was stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried and evaporated to give a colourless oil. This was chromatographed on silica gel eluting with System A (20:80 -&gt; 80:20) followed by ether to give:

(a) Intermediate 12a as a colourless oil (124mg),

T.l.c (System F 99:1) Rf 0.3; and (ic) Intermediate 12b as a colourless oil (330mg), ^L T.l.c (System A 50:50) Rf 0.50.

Intermediate 13 (a) 1,I-Dlmethylethyl 4' -[[5-butvl-l-((dimethvlamino)sulphonyl]-3( methoxymethvl)-IH-pvrazol-4-vl]methvl]-j1, 1'-biphenyl]-2ca rboxvlate; and (b) 1,1-Dimethylethvl 4' - [(3-butvI-l-[(dimethvlamino)sulphonvl]-5(methoxvmethvl)-lH-oyrazol-4-yl]methvl] [ 1, I' -biphenvl]-2-carboxylate

Sodium hydride (52mg; 80% dispersion in oil) was added to a stirred solution of Intermediate 6 (0.5g) in dry DMF (5ml) at room temperature under nitrogen. After stirring for 0.5h, N,Ndimethylsulphamoyl chloride (0.185ml) was added at 0θ and stirring was continued at 0θ for 2h. The mixture was partitioned between water (30ml) and ethyl acetate (3x 20ml); the organic layers were washed with 50:50 brine:water (3x 30ml) and brine (30ml), dried and evaporated to give a pale yellow oil &lt;0.76g). Purification by DFC eluting with System A (20:80 to 40:60) gave:

(a) Intermediate 13a as a colourless oil (296mg),

T.l.c. (System A 50:50) Rf 0.3; and (b) Intermediate 13b as a colourless oil (231mg),

T.l.c. (System A 50:50) Rf 0.45.

Intermediate 14 (^a) 5 ~[4'- ( [3-Butyl-l-ethvl-5-(methoxymethvl) -lH-pyrazol-4-

<img file="AP254A_D0035.tif" />

(b) 5 - [4' - [ [5-5utvl-l-ethyl-3-(methoxymet hyl)-lH-pycazol-4yl]methy][1,1' -biphenyl]-2-yl]-2-(triphenylmethyi)-2H-tetrazole

A solution_;Afejqtjecntdiat· 9 (1.26g) in dry DMF (5ml) was added dropwise to a suspension of sodium hydride (60% in oil, 116mg) in dry DMF (5ml). The resulting pale yellow solution was stirred at room temperature for 0.5h, then a solution of the ethyl iodide (O.lcmi) in dry DMF (Iml) was added dropwise. The mixture was stirred at room temperature for 2h, then partitioned between water (20ml) and ethyl acetate ( 3 x 20ml). The combined organic extracts were washed with brine/water 1:1 (3x 50ml) and dried. The solvent was evaporated to give a pale yellow foam (1.283g) which was purified by shcrt-path column chromatography on silica gel (Merck 7729) eluting with System C (1:1-2:1) to give:

(a) Intermediate 14a as a pale yellow gum (569mg)

n.m.r. (CDClg, 250 MHz) 5 0.85 (3H,t), 1.2-1.6 (4H, m) , 1.40 (3.H, t), 2.45 (2H, t), 3.20 &lt;3H, s) , 3.70 &lt;2H, s) , 4.12 (2H, q) , 4.20 (2H, s), 6.90-7.50 (TH, m), 7.85-7.9 (IH); and (b) Intermediate 14b (654mg)

n.m.r. (CDCi₃, 250 MHz) 6 0.85 &lt;3.4, t&gt;, 1.2-1.35 (4H, m) , 1.41 (3H, t), 2.40 (2H, t) , 3.33 (3H, s), 3.72 (2H, S) 4.05 (2H, q), 4.23 (2H, S), 6.90-7.50 (7H, m) , 7.85-7.9 (IH).

Intermediate 15 (a) 5 - [ 4' - [ [3-Butyl-l-l (dimethylamino)sulphonovl]-5(methoxymethyl)-lH-pyrazol-4-vl]methvl] [1,1'-biphenyl]-2-yl]-2(triphenylmethyl)-2K-tetrazole; and (b) 5-[4'-[[5-Butyl-l-[(dimethylamino)suIphonoyl]-3(methoxvmethyl)-lH-pyrazol-4-yl]methyl][1,l'-biphenvl]-2-vl]-2(triphenvimethyl)-2H-tetrazole

Sodium hydride (60% in oil; 93mg) was added portionwise to a solution of Intermediate 9 (l.Og) in dry DMF (10ml) at room temperature under nitrogen. The resulting pale yellow suspension was stirred at room temperature for O.Sh, cooled to 0°C then a solution of dimethylsuiphamoyl chloride (222mg) in dry DMF (0.5ml) was added dropwise. The resulting mixture was stirred at room temperature for 2h, then partitioned between ethyl acetate (3 x 20ml) and water (20ml) . The combined organic extracts were washed with brine/water (1:1) (3 x 20ml) and dried. The solvent was —-BAOORtGtNALI

CV3C6/C

AP Ο Ο Ο 2 5 4 evaporated to give a pale yellow foam (1.27g), which was purified by short-path column chromatography on silica gel (Merck 7729) eluting with System A (1:2) to give:

<td> (a)</td><td> Intermediate 15a</td><td> as</td><td> a</td><td> colourless</td><td> foam</td><td> (462mg)</td>

<td> T.l.c</td><td> . (System C 1:1)</td><td> Rf</td><td> 0</td><td> .4; and</td><td></td><td></td>

<td> (b)</td><td> Intermediate 15b</td><td> as</td><td> a</td><td> colourless</td><td> foam</td><td> (615mg)</td>

T.l.c (System C 1:1) Rf 0.35.

Intermediate 16

Phenylmethoxv-2,4-octandione

2-Hexanone (26.7g) was added dropwise over 5 min at room temperature to a stirred suspension of sodium amide (10.4g) in dry ether (290ml) under nitrogen. The reaction mixture was stirred for 13min and a solution of methyl phenylmethoxyacetate (24.Og) in dry ether (40ml) was added dropwise ever 12min. The mixture was then heated at reflux for 3h, cooled, and then poured into ice (400g) and 2N HC1 (200ml). The aqueous phase was extracted with ether (2 x 350ml) and the combined etheral solution washed with 8% sodium bicarbonate solution (2 x 250ml), water (200ml) and brine (200ml), then dried and evaporated to leave a yellow liquid (35.8g). This was purified by column chromatography on silica gel eluting with System A (2:98) to give the title compound as a yellow oil (10.95g)

T.l.c. (System C 1:9) Rf. 0.50

Intermediate 17

1-[(Phenylmethoxy)methyl]-3-([2' -[2-(triphenylmethyl)-2H-tetrazol-5yl ] [ 1,1'-biphenyl]-4-yl]methyl]-2, 4-octandione

To a suspension of sodium hydride (60% in oil; 820mg) in THF (63ml) at 0°C was added a solution of Intermediate 16 (4g) in THF (6.5ml^. dropwise over 35min. The reaction mixture was stirred at room temperature for 40min prior to the addition of Intermediate 3 (6.38g) in THF (21ml) over 15 min. The resultant reaction mixture was heated at reflux for 17h. The reaction mixture was concentrated in vacuo and the residue partitioned between water (80ml) and ether (3x80ml). The combined organic layers were dried and concentrated in vacuo and then purified by column chromatography on silica gel eluting with System C (1:8) to afford the title compound (3.0g) as a white solid.

C73C6/C

<img file="AP254A_D0036.tif" />

BAD ORIGINAL

T.l.c (System C 1:3) Rf 0.28

Intermediate 18

- '4' - i [3-3utvl-5-j (phenvlmethoxv)methyl]-lH-ovrazol-4vl'methvl] ] 1,1'- biphenyl]-2-y1]-2-(triphenylmethyl)-2H-tetrazole

Hycrazine hydrate (55%; 0.85ml) was added to a solution of

I n t e r me i i a t e 1^ (l?.17g) in ethanol (100ml) containing c rc.nl creme thane (20ml) . The mixture was stirred at room temperature for 2 days. The solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel eluting with System C (4:1) and increasing the polarity to neat ether, to give the title compound as a colourless foam (7.67g),

T.l.c (ether) Rf 0.5.

Intermediate 19

Phenvlmethoxv-2,4-heptandione

From 2-heptanone and methyl pher.y lmetnoxyacetate according to the method of Intermediate 16.

T.l.c. System A (1:10) Rf 0.39

Intermediate 20

1-ί (Phenvlmethoxv)methvl]-3-[[2'- [2-(triphenvlmethvl)-2H-tetrazol-5vl] jl, 1' -biphenyl]-4-yl]methyl]-2,4-heptandione

From Intermediate 19 according to the method of Intermediate 17. T.l.c. System A (1:4) Rf 0.20

Intermediate 21

5-[ 4 ' - f [3-Propvl-5 - [ (phenylmethoxy)methyl]-lH-pyrazol-4vl]methvl] [1,1'-biphenyl]—2—yl]—2—(t riphenylmethyl)-2H-tetrazole

From Intermediate 20 according to the method of Intermediate 18. T.l.c. System A (5:1) Rf 0.25

Intermediate 22 (a) 5-[4'-[[3-Buty1-1-ethyl-5-[(phenylmethoxy)methyl]-lH-pyrazol-4yl]methvl](1,1'-biphenyl]-2-yl]-2-(triDhenvlmethvl)-2H-tetrazoIe;

and (b) 5 -[4'-[jS-Buty1-1-ethy1-3-[(phenylmethoxy) methyl]-lH-pvrazol- 4 vllmethyl][l,l^,-biphenyi]-2-yl]-2-(triphenylmethvl)-2H-tetrazole

BADOBIGWAf'

CV306/C

AP Ο Ο Ο 2 5 4

A solution of Intermediate 18 (3.0g) in dry DMF (15ml) was added dropwise to a suspension of sodium hydride (60% dispersion in oil; 254mg), in dry DMF (15ml) at 0* under^nAt jgogen. Th· mixture was stirred at 5-10’ for 15mins, then a solution of ethyl iodide (660mg) in dry IMF (1ml) was added dropwise. The mixture was allowed to warm to room temperature over lh. The mixture was partitioned between water (50ml) and ethyl acetate (3x25ml) and the combined organic extracts washed with brine/water 1:1 (2x50ml) and dried.

The solvent was evaporated to give a pale yellow gum (3.19g) which was purified by column chromatography on silica gel eluting with System A (1:2-1:1) to give the title compound:

(a) Example 22a as a colourless foam (1.33g),

T.l.c System A (1:2) Rf 0.2; and (b) Example 22b as a colourless foam (1.60g),

T.l.c. System A (1:2) Rf 0.5.

Similarly prepared from Intermediate 18 and the appropriate alkyl halide w-re:Intermedlates 23a and b (aι 5-[4'-[ί 3-3u~vl-l-(1-methvlethvl)-5-[(phenvlmethoxy)methyl]-1Hpyra zol-4-vi]methyl][1,1'-biphenvl]-2-yl]-2-(triphenylmethyl)-2Htetrazole

T.l.c. System A (1:2) Rf 0.45 (b) 5-[4*-[[5-Butyl-l-(1-methylethyl)-3-[(phenvlmethoxy)methyl]-1Hpvrazol-4-yl]methyl][1,1' -biphenyl]-2-yl]-2-(triphenylmethyl)-2Htet razole

T.l.c. System A (1:2) Rf 0.35

Intermediates 24a and b (a) 5-[4'-[[3-Butyl-l-(2-methylpropyl)-5-[(phenylmethoxv)methyl]-1Hpvrazol-4-yl]methyl] [l,l'-biphenyl]-2-yl]-2 - (triphenylmethyl)-2Htet razole

T.l.c. System A (2:3) Rf 0.3 (b, 5-[4'- [[5-9utyl-l-(2-methvlpropyl)-3-[(phenylmethoxy)methyl]-1Hcv race 1-4-vl]methyl] [1,1'-binhenvl]-2-yl]-2-(triphenylmethyl)-2Htetrazc.e

T.l.c. System. A (1 :2) Rf 0.2 5

ORIGINAL

Intermediates 25a and b (a) 5-[4 * - [[3-Butyl-1-(2-eye 1oprcpylmethy1)-5-[ (phenylmethoxy) methvl] -lH-oyrazol-4-yl)methyl] [ 1, 1' -biphenyl]-2-yl]-2(t ripher.ylmethyl) -2H-tetrazole

T.l.c. System A (2:3) Rf 0.45 ( b) 5 - ί 4 ' - ί ’ 5-5utvl-l - (2-cvclcprccvl methvl) - 3- f (cr.er.ylnethoxy) methvl]-Di- cvrazol-4-yl]methvl]Γ 1 ,l^,-biphenvl]-2-yl]-2(triphenvImethyl)-2H-tetrazole

T.l.c. System A (2:3) Rf 0.42

Intermediates 26a and b (^a) 5-[4'-[[3-Butyl-l-cycIobutyl-5-[(phenylmethoxy)methyl]-1Hpvrazol-4-yl]rr.ethyl][l_fl'-biphenvl]-2-yl]-2- (triphenyImethyl) -2Htet ra zole

T.l.c. System A (1:1) Rf 0.71 (b) 5-[4'- [;5-3utyl-I-cvclobutvl-3-[(phenylmethoxy)methvl]-lHcvrazol-4-vl]methvl] [1, l'-biphenvl]-2-ylj-2-(t riphenvlmethvl) -2HC c ζ Γ a 2 O i 6

T.l.c. System A (1:1) Rf 0.68

Intermediates 27a and b (a) 5-[4' -[[3-Sutyl-l-methyl-5-[(phenylmethoxy)methyl]-lH-pyrazol-4vlImethyl] [1,1*-biphenyl]-2-yl]-2-(tripheny Imethyl)-2H-tetrazole

T.l.c. System A (4:1) Rf 0.44 (b) 5-[4'-[[5-Butyl-l-methyl-3-[(phenylmethoxy)methyl]-lH-pvrazol-4v1]methvl] [1,1*-biphenyl]-2-yl]-2-(t riphenyImethyl)-2H-tetrazole

T.l.c. System A (4:1) Rf 0.34

Intermediates 28a and b (a) 5-[4' -[[3-Butyl-l-propyl-5-[(phenylmethoxy)methyl]-lH-pvrazol-4vl]methvl] [1,1' -biphenyl]-2-vl]-2-(triphenyImethyl)-2H-tetrazole

T.l.c. System A (2:1) Rf 0.60 (b) 5-[4' -[[5-Butyl-1-propyl-3-[(phenylmethcxy) methyl]-lH-pyrazol-4vlmethyl][1,1'-biphenyl]-2-yl]-2-(t riphenylmethy1)-2H-tetrazcle

T.l.c. System A (2:1) Rf 0.44

Intermediates 29a and b

TV3C6/C —BXDORIGINAL ft

AP Ο Ο Ο 2 5 4 (a ) 5-[4*- [[1,3-Dibutvl-5-ί(phenyImethoxy)methyl]-lH-pyrazol-4yl3methyl] [1,1*-biphenyl]-2-yl]-2-(triphenylmethyl)-2H-tetrazole

T.l.c. Sy&lt;t·»G (¢0:30:1) Rf 0.80 vljmethyl](1,1'-biohenvl]-2-yl]-2-(triphenylmethyl)-2H-tetrazole

T.l.c. System G (60:30:1) Rf 0.66

Similarly prepared from Intermediate 21 and the appropriate alkyl halide were:Intermediates 30a and b (a) 5- [4'-[[l-Ethyl-3-propyl-S-[(phenylmethoxy)methyl]-lH-pyrazol-4yl] methyl][1,1'-biohenvl]-2-yl]-2-(triphenylmethyl)-2K-tetrazole

T.l.c. System A (3:1) Rf 0.75 (b) 5-[4'-f[l-Ethyl-5-propvl-3-[(phenylmethoxy)methyl]-lH-pvrazol-4vl]methyl][1,1'-biohenvl]-2-yl]-2-(triphenylmethyl)-2H-tetrazole

T.l.c. System A (3:1) Rf 0.60

Intermediates 31a and b (a) 5- [ 4' - [ [1- (1-Methvlethyl) -3-propvl-5-[ (Pher.v Ime thoxy) methyl 3-1Hpvrazol-4-vl]methyl] (1,1'-biphenyl 3-2-vl]-2-(triphenylmethyl)-2Htetrazole

T.l.c. System A (1:1) Rf 0.50 (b) 5- [4*-[[1-(1-Methylethyl)-5-propyl-3-((phenylmethoxy)methyl]-1Hpyrazol-4-yl]methyl][1,1'-biphenyl]-2-yl]-2-(triphenylmethyl)-2Htetrazole

T.l.c. System A (1:1) Rf 0.36

Intermediate 32

Phenylmethoxy-2,4-hexandione

2-Butanone (47.65ml) was added dropwise over lOmin to a mechanically stirred suspension of sodium amide (95%; 20.78g) dry ether (600ml) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 15min. A solution of methyl phenylmethoxyacetate (48.Og) in dry ether (50ml) was added dropwise over 13min at room temperature under nitrogen, and the reaction progressed according to the method of Intermediate 16, to give the title compound as a yellow oil (23.35g)

<img file="AP254A_D0037.tif" />

CV306/C

T.l.c. System A (1:10) Rf 0.15.

Intermediate 33 ,

- [ (Phenvlmethoxv)methyl] - 3- ί [ 2 - [ 2 - (t r iphlfiffiroetl·: yl) -2H-tetrazol-5vlj [1,1'-biphenyl)-4-vl]methyl]-2,4-hexandione

From Intermediate 32 according to the method of Intermediate 20. T.l.c. System A (1:4) Rf 3.30.

Intermediate 34

- [ 4 ' - j ]3-Sthvl-5- I (phenylmethoxy)methyl] -IH-pvr a zol-4 vl]methvl] .'1,1' -blchenvl]-2-vl]-2- (triphenylmethyl) -2H-tetrazole

From Intermediate 33 according to the method of Intermediate 21. T.l.c. System A (6:1) Rf 0.21.

Intermediates 35a and b (a ) 5 -[4'-f[l,3-Dlethvl-5-[(phenylmethoxy)methyl]-lH-pvrazol-4vl]methvl] ] 1, 1' -biohenvl]-2-yl]-2-(triphenylmethyl)-2H-tetrazole;

and (b) 5-4'-[[1,5-Diethvl-3-((Phenvlmethoxv)methvl]-lH-cvrazol-4vlj methvl] blchenvl] -2-vl] - 2- (trIphenvlmethvl) -2H-tetrazole

<td> From Intermedia</td><td colspan="2"> te 3 4 acc</td><td colspan="2"> crdi.ng to</td>

<td> gave :</td><td></td><td></td><td></td><td></td>

<td> (a) Intermediate</td><td> 35a</td><td> as a</td><td> yellow</td><td> gum</td>

<td> T.l.c. System A</td><td> (3:1)</td><td> Rf 0</td><td> . 60</td><td></td>

<td> (b) Intermediate</td><td> 35b</td><td> as a</td><td> yellow</td><td> gum</td>

<td> T.l.c. System A</td><td> (3:1)</td><td> Rf .</td><td> 0.40.</td><td></td>

the method of Intermediate 22 (l.iBg) (1.40g)

Intermediate 36

1,1-Dimethylethyl 4'-[3-cxo-2-(phenoxvacetyl)heptanvl] [1,1' biphenyl]-2-carboxvlate

From Intermediate 16 and Intermediate 2 according to the method of Intermediate 17.

T.l.c. System A (1:5) Rf 0.25.

Intermediate 37

1, 1-Dimethylethvl 4' - [[3-butyl-5-[(phenylmethcxy)methyl]-In-pvrazol4-vl]methyl] !1, 1'-biphenyl]-2-carboxvlate

From Intermediate 36 according to the method of Intermediate 18.

CV3C6/C

BAD ORIGINAL

AP 0 0 0 2 5 4

T.l.c. System A (3:2) Rf 0.15.

Intermediate 38a and b ( a ) 1,1-Dimethylethyl 4 ' - [ [3-butvl-l-ethyl-5- [ (phenylmethoxy) methyl]-lH-pyrazol-4-vljmethvl][1,1' -biphenyl]-2-carboxylate; and (b) 1,1-Dimethylethyl 4'-[[5-butyl-l-ethyl-5-[(phenyimethoxy) methyl]-IH-pvra zol-4-vl]methvl][1,1' -biphenyl]-2-carboxvlate

From Intermediate 37 anc ethyl iodide according to the method of

Intermediate 22.

Intermediate 38a: T.l.c. System A (1:1) Rf 0.35

Intermediate 38b: T.l.c. System A (1:1) Rf 0.2.

Intermediate 39a and b ( a ) 1, 1-Dimethylethyl 4'-[ [3-butyl-l-(1-methylethyl)- 5 [(phenylmethoxy)methyl]-lH-pyrazol-4-yl]methyl][1,l'-biphenyl]-2carboxvlate; and &lt; b) 1&gt; 1-Dimethvlethvl 4*- [ [5-butyl-l- (1-methvlethyl) - 3 [(phenylmethoxy)methvl]-lH-pyrazol-4-yl]methyl][ 1,1' -biphenyl]-2ca rboxylate

From Intermediate 37 and isopropyl iodide according to the method of Intermediate 22.

Intermediate 39a: T.l.c. System A (1:2) Rf 0.3

Intermediate 39b: T.l.c. System A (1:2) Rf 0.2.

Intermediate 40

1, 1-Dimethylethy1 4'-[[3-butyl-l-ethyl-S-[(hydroxymethyl)-lHpyrazol-4-vl]methyl](1,1'-biphenyl]-2-carboxylate

From Intermediate 38a according to the method of Example 26.

T.l.c. ethyl acetate: hexane (1:1) Rf. 0.4.

Intermediate 41

1,1-Dimethylethyl 4*-[[3-butyl-5-(hydroxymethyl)-1-(1-methylethvl) lH-pyrazol-4-vljmethyl][1,1'-biphenyl]-2-carboxylate

From Intermediate 39a according to the method of Example 26.

T.l.c. System A (1:1) Rf. 0.25.

Intermediate 42

CV306/C

BAD ORIGINAL fl

1,1-Dimethylethyl 4' - [[3-buty1-1-ethy1- 5-formy1 - 1H-pyrazo1- 4 vl]methyl3 [1,1*-biphenyl]-2-carboxylate

From Intermediate 40 according to the method of Example 42.

T.l.c. System (1:1) Rf 0.7.

Intermediate 43

1, 1-Dimethvlethvl 4' - [ f 3 - bu t v1- 5 -f o rmy1-1- ( 1-me t h vIe t h v 1) -1Hpyra zo1-4-vl]methyl 3 31,1'-biphenylj-2-ca rbcxvlate

From Intermediate 41 according to the method of Example 42.

T.l.c. System A (1:1) Rf. 0.7.

Intermediate 44

3-3utvl-4-[[2'-[(1,l-dimethvlethoxylcarbonvl] [1,1'-biohenyl]-4 yl]methyl]-l-ethyl-lH-oyrazole-5-carboxvlic acid

From Intermediate 42 according to the method of Example 50.

T.l.c. ether: hexane : acetic acid (50:50:1) Rf. 0.6

Intermediates 45a and b (a) 5-[4'-[[1-(2-Methyloropvl)-3-oropyl-5-[(ohenvlmethoxy)metnvl]lK-ovrazol-4-yl]methvl] (1,1' -ciphenvl]-2-v!3-2-(tr ocher, y Imethyl)-2Htetrazole; and (b) 5-[4*-[[1-(2-Methylpropvl)-5-orooyl-3-[(ohenvlmethoxy)methyl]lH-pyra2ol-4-yl]methyl][1,1'-biphenyl]-2-vl]-2-(triphenyImethyl)-2Htetrazole

From Intermediate 21 and 2-methylpropyl iodide according to the method of Intermediate 22.

Intermediate 45a: T.l.c. System A (1:1) Rf 0.27

Intermediate 45b: T.l.c. System A (1:1) Rf 0.19

Intermediate 46

3-SutvI-4-[[2'-(1,1-dimethylethoxy)carbonyl][1,1'-biphenyl]-4vl]methyl]-l-(1-methylethyl)-lH-pyrazole-5-carboxylie acid

From Intermediate 43 according to the method of Example 50.

T.l.c. System G (20:20:1) Rf 0.65

Example I ' - [3-3utvl-5 - (methoxy methvl) - l.H-pyrazol-4-vl3 methvl] [ 1, 1' pjphenvl]-2-carboxylic acid t r i1 uoroacetate (1:1) salt

CV3C6/C

BAD ORIGINAL ft

AP Ο Ο Ο 2 5 4

A solution of Intermediate 6 (320mg) in dry dichloromethane (30ml) was treated with TFA (1ml) and the reaction stirred at room temperature for 5h . The volatiles were removed in vacuo and the residue triturated with ether to give the title compound (I62mg) as a white solid.

T.l.c. (System C 50:50), Rf 0.05.

Assay Round: C,60.7; .4,5.7; N,5.5.

^C25^H26^N2^C3-^CF3^CO2^H requires C,61.0; .4,5.5; N,5.7%.

Example 2

4' - [ 15-Butyl-3- (methcxvmethyl) -1-phenyl-ΙΗ-pyrazol-4-yl]methyl] [1,1'

-biphenyl]-2-carboxvlic acid

A solution of Intermediate 7a in TFA (3ml) was stirred at 20θ for 90min. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (15ml). The organic layer was extracted with sodium bicarbonate solution (8%; 3x 30ml). The combined extracts were acidified to pH«l with dilute hydrochloric acid and then extracted with dichloromethane (3x 30ml). The combined extracts were washed with brine (30ml), dried and concentrated in vacuo to yield a the title compound as a pale brown solid (157mg). m.p. S5-91°C

T.l.c. (System 3 50:8:1) Rf 0.44.

Example 3

4' - [ [ 3-Butvl-5- (methoxymethyl) -1-pheny1-lH-pyrazol-4vllmethyl] (1,1*biphenyl]-2-carboxylic acid

Intermediate 7b (256mg) was stirred at room temperature with TFA (1ml) in dry dichloromethane (5ml) overnight. The solvent was evaporated to give a brown oil (280mg). Purification by DFC eluting with System G gave the title compound as a pale yellow gum (95mg) . T.l.c. (System G 50:50:1) Rf 0.4

Analysis Found: C,76.6; H,6.9; N,5.7 .

^29^30^2^3 ires C, 7 6,6; H,6.65 14,6.2%

Example 4

4'-[j 3-Buty1-5-(methoxymethyl) -1-(2,2,2-trifluoroethvl)-IH-pyrazol

-4-vl]methvl][1,1'-biphenyl]-2-carboxylic acid

BAD ORIGINAL fi

CV306/C

Intermediate Sa (ISCmg) was dissolved in 96^ formic acid (4ml) and tr.e solution allowed tc stand at room temperature cvernicht (16h) The excess formic acid was evaporated and tr.e residue acectrcped with toluene (2 3ml) tc cive a cc lour less cum (ITSmc). p··.-- « ·' _ e.ut inc wit;

(50:03:1) cave tne tit.

as a : es 0,65.2: H, 5 . 9; N,6.1 * .

4'- ' ' 5-3utyl-3- (m.e the :·:€ thvl) - 2- (2,2,2-trifluorcethv1) - IH-cvr a cc 2

Intermediate St was treated according to the method c give tr.e title compound as a odourless cum (39ng) . T.i.c (System F 99:1) Rf 0.75.

Ar.s*ys:s Sounc: C, c 5 . 5 ; H, c . 2 ; N, 5.9 .

- ~ ς ό - - F £ N -&gt; a -3 r ecu ires C, 6 5.2 ; H, 5 . 9; N, c . 1 % .

le 4 t o

u.xamo.e o ; met r. c xvmet..'.·. ; - -.-.-cv:a zc i- -.- v_a met r.v.

.e

Intermediate 9 (40mg) was treated with 2N hydrochloric acid (1ml) in THF (5ml) at room temperature and the mixture was stirred at room temperature fcr 7h. The mixture was partitioned between ethyl acetate (15ml) and dilute aqueous sodium hydroxide (2ml of 2N in 15ml of water) . The aqueous layer was neutralized with excess saturated aqueous ammonium chloride (10ml) and ex:

:ed with et hvl acetate (3x 10ml). The latter organic layers were washed trine, dried and evaporated tc cive the title compound as a 1 /* with cclcurless cum (dmc) . n . m . r . ( C T C1 ₃ , 2 5 0 MHz) δ ,

2.45 (2 H , t) , 3.2 (3 H, s), (EH, m.) , 3.3 (2H, broad s).

(System. H 99:1) Rf C.3.

0.35 (3H, t), 1.15-1.55 (4K, m),

3.77 (2 H, S) , 4.14 (2 H, s) , 7.C-2.C

4'-j(3-3utvI-5-&lt;methcxvmethvl)-1-(2,2,2-trlfIucrmethyl)-1Hcvrazc.-4-v. me ethyl j ( 1, 1' -blohenvl j -2 -yl) - IH-tet razde

27225/T

BAD ORIGINAL

A

AP Ο Ο Ο 2 5 4 dl-10-Camphor sulphonic acid (20mg) was added to a stirred solution of Intermediate 10a (103mg) in THF (10ml) and methanol (3ml), and ΐ i stirring was continued at room temperature for 16h. The solvent was evaporated to give a pale yellow oil, which was purified by DFC eluting with System G to give the title compound as a white solid (39mg). m.p. 45-51°C T.l.c. (System F 99:1) Rf 0.5.

Example 8

5- [ 4'~ 1 [ 5-Buty1-3-(methoxvmethyl)-1-(2,2,2-trifluoroethyl)-1Hpvrazol-4-yl]methyl][1,1'-biphenyl]-2-yl]-lH-tetrazole dl-10-Camphor sulphonic acid (40mg) was added to a stirred solution of Intermediate 10b (203mg) in THF (20ml) and methanol (6ml), and stirring was continued at room temperature for 20h. The solvent was evaporated to give a pale yellow oil. Purification by DFC eluting with System G (50:50:1 to 100:0:1) gave a colourless oil (129mg) which was dissolved in chloroform (10ml). n-Heptane was added, and the solvents evaporated to give the title compound as a white foam (iOlmg) m.p. 48-50θ.

T.l.c. (System F 99:1) Rf 0.4.

Example 9

4'-[[1-(2-Amino-2-oxoethyl)-5-butvl-3-(methoxymethyl)-lH-pyrazol-4ylImethyl][1,1'-biphenyl]-2-carboxylic acid

Intermediate 11a was treated according to the method of Example 4 to give the title compound as a white solid (170mg), m.p. 204-206⁸, T.l.c. (System H 98:2) Rf 0.15 .

Example 10

4*-[[1-(2-Amino-2-oxoethvl)-3-butyl-5-(methoxymethyl)-IH-pyrazol-4vl]methyl](1,1'-biphenyl]-2-carboxvlic acid

Intermediate lib was treated according to the method of Example 4 to give the title compound as a white solid (126mg), m.p. 179-180⁸T.l.c (System H 98:2) Rf 0.3.

Example 11

4'-[(5-Butyl-3-(methoxymethyl)-l-methyl-lH-pyrazoI-4-vl] methyl] [1,1'

-biphenyl]-2-carboxylic acid

<img file="AP254A_D0038.tif" />

A solution cf Intermediate 12a (114mg) in dry TKF (5ml) was treated with TFA (1ml) at room temperature, and stirring was continued at t frh # -to°^m temperature for 19h. The solvent was evaporated to give a pale ί ¥'4'ΐ ci ' yeluow ctu, w.--._en was azectroped w:tn η-heptane tc give a vellow oil. Purification cy 2F2 eluting System F &lt;'9E:2) gave a pale orange ::1 illOmg), which was azeotropec Kith n-hepta.ne tc give the title

-. ' - ' [ 3 - E u t v 1 - 5 - i m e t h c x ·.· m e t h v 1 ) - 1 - m e c h v 1 - 1 P - c · r a z c 1 - 4 nethv.

rtflucrcacetate ifluorcacetic acid (1ml) was added tc a sti :ermediate 12 b (310mg) in dry DXF (13mi) at root . 'λ 3 5 CCfl cZ Z c. * ’&gt;2 r€ ^£ZZ iccraoed tc cive a cale vellow cil :47C'no).

ed solution cf r. temperature, and

The solvent was •ectar.e (2 Omi) was . s was (- £ 3 me

Example 13

4'- [ [5-Buty1-1- (dlmethvlamlno)sulchcnvl]-3-(methoxymethyli-1Kcvrazcl-4-vljmethvlj [ 1,1'-biphenyl]-2-carbcxylio acid

Intermediate 13a (22lmg) was dissolved in S6% formic acid (4ml) and the solution allowed to stand at room temperature for ch. The excess formic acid was evaporated and the residue azectrccec twice with toluene (2x I 5ml) to give a colourless gum ( 2 50mg). Purification by DFC eluting with System A (50:50) and System G (50::0:1) gave the title compound as a colourless gum (l£?mg). T.l.c. (System F 99:1) Rf 0.7

Analysis Found: C,61.5; H,6.4; N,8.'.

Tc jh. - NjCc S requires C, ό 1.8 ; H, 6 . 4 ; N, 8 . 6 5 % .

Example 14 * - 3 ~3t y 1 ~ 1 ~ (di.net,hy 1ar~. 1 r&gt;c.) su 1 chcr.y l· ' - 5 ~ r_ts.yr\£ζ hy 1) — _ H ~ cy ra1- 4-y l·' zr.ethy 1. ] ' 1, ? icr.eny 1 - -2 -ca rtc ///1 ic ac i·^

BAD ORIGINAL d

AP Ο Ο Ο 2 5 4

Intermediate 13b was treated according to the method of example 13 to give the title compound as a white foam (lllmg).

T.l.c. (System F 99:1) Rf 0.8.

Analysis Found: C,62.0; H,6.5; N,8.4.

^C25^H31^N3°5^S requires C,61.8; H,6.4; N,8.65%.

example

- [ 4' - [ [3-3utvl-i-ethyl-5-(methoxvmethvl) -lH-pyrazol-4vl]methyl](1,1' -biphenyl]-2-yl]-ΙΗ-tetrazole

Concentrated HCl (0.4ml) was added dropwise to a solution of Intermediate 14a (0.542g) in methanol (10ml) containing THF (2ml). The mixture was stirred at room temperature under nitrogen for lh, then basified to pH 10 with sodium hydroxide solution (2N; 3ml). The solvent was concentrated in vacuo and the residue diluted with water (20ml). The mixture was extracted with ether (3 x 20ml), then the aqueous phase acidified to pH 1 with HCl (2N; 4ml). The resulting opaque solution was extracted with ethyl acetate (3 x 30ml) and the combined ethyl acetate fractions washed with brine (1 x 30ml) and dried. The solvent was evaporated in vacuo to give a colourless foam (0.34g) which was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (4060°) (2:1) to give the title compound as a colourless foam (304mg) n.m.r. (MeOD, 250 MHz) δ 0.85 (3H, t), 1.2-1.5 (6H, m), 2.45 (2H, t), 3.25 (3H, s), 3.80 (2H, 3), 4.13 (2H, q), 4.38 (2H, s), 7.04 (4H, dd), 7.5-7.68 (4H, m).

T.l.c. (ether/petroleum ether/acetic acid 50:20:0.2) Rf 0.2.

Similarly prepared:

Example 16

5-[ 4 ' - ( [5-Butyl-l-ethyl-3- (me t ho xymethvl)-lH-pyrazol-4yl]methyl][1, 1'-biphenyl]-2-yl-lH-tetrazole as a colourless foam (373mg).

<td> n.m.r. (MeOD, 250 MHz) δ 0.85 (3H, t), 1.3-1.4</td><td> (6H,</td><td> m), 2.55</td><td> (2H,</td>

<td> t), 3.25 (3H, s), 3.80 (2H, s), 4.05 (2H, q) ,</td><td> 4.28</td><td> (2H, s),</td><td> 7.05</td>

<td> &lt;4H, q) , 7.5-7.68 (4H, m) .</td><td></td><td></td><td></td>

T.l.c (ether/petroleum ether/acetic acid 50:20:0.2) Rf 0.15.

CV306/C

BAD ORIGINAL ft

From the dropwise addition of concentrated HCI (0.4mi) to a solution of Intermediate 14b (634mg) in methanol (IOmi) and THF (2ml).

LXar.c.e 1 ~ ( 4' - ' ; 3 - But v 1 -1 - ' 'dlmet hvlamine ) su Ic non o vl j - 5 - (r.e: hoxvmet h vi t -1 - as a ,1 .

n.m.r. id^-CXSC, 252 XHc) δ 0.60 (3.4, t), 1.8-1.3 (2H,m), 2.42 (2H, t), 2.9C (cH, s) 3.23 (3H, s), ¢2.-:, s), 7.:-7.: (44, cd j , '.40-7.0S (4:-:, m). T.l.c (ethyl acetate; =f 2 . ~ .

From the dreowise addition of concentrated HCi (2 cf intermediate 15a (43Cm.c; in methanol (12ml) an

2.4,m), 1.37 8 3 (2 Η, s), .1) to a sol

Hr (2ml).

— x a m c . e -8

<img file="AP254A_D0039.tif" />

dd) , ~.4 8 -7.i5 (44, m ’ .

T.l.c (ethyl acetate) Rf 2.~.

From the dropwise addition of concentrated HC1 (0.5ml) to a solution of Intermediate 15b (579mc) in methanol (10ml) and THF (2ml).

Example 19 (a) 5 - ! 4 ' - ? [3-5utvl-5-[ fphenvlmethcxy)methyl.--l-(2,2,2t r1fluoroet hv1) -IH-pvra zo1-4-ν1j methvlj (1, 1' -biohenvl] -2 - vl - IH tetracele; and (b) 5 - ( 4' - ' [5-3utvl-3- [ (phenvimethexv)methvl] -1- (2, 2, 2trlfluoroethyl) -lH-pvraccl-4-vl'methvl.¹ ' 1, 1' -biphenyl] - 2- vl; -1H ;et race j.e

A solution of Intermediate 17 (2.6g) and 2,2,2-trifluoroethylhydrazine (70% in water, 5 8 4 m g ) in ethanol (75 ml) and dichicrcnethane (25ir.i) was heated at reflux for 3h at which point a furt.ner quantity of 2,2,2-t r i f luc rcet by Ihycr a z ine &lt;320mg) was added and the resultant solution heated at reflux for 16h. Concentrated HCi (Iml) «as added to the cooled reaction mixture and the resultant

<img file="AP254A_D0040.tif" />

BAD ORIGINAL

AP Ο Ο Ο 2 5 4 solution stirred at room temperature for 4h. The reaction mixture was then adjusted to pH 10 (5N NaOH aq) and the solvents removed in t i_'| % ir. '* S' ' vacuo. The residue was partitioned betweenand ether (3 x 100ml) and the aqueous phase was acidified to pH 5 (2N HC1 aq, and extracted into ethyl acetate (3 x 100ml). The combined organic extracts were dried, concentrated in vacuo and purified by column cr. r : m. atcgraphy cm silica gel eluting with petroleum ether :etherrmethanol:acetic acid (66:34:1:1) to afford:

(a) Example 19a as a white solid (930mg),

T.l.c (petroleum ether:ether:methanol:acetic acid 66: 34:1 : 1) Rf. 0.5 n.m.r. (CDC1₃, 250MHz) 6 0.85 (3H, t), 1.28 &lt;2H, sex), 1.51 (2H, pent), 2.48 (2H, t) 3.8 (2H, s), 4.46 (4H, 2 x S), 4.68 (2K, q), 7.2-7.6 (12H,m), 8.1 (1H, d); and (b) Example 19b as a white solid (892 mg,.

T.l.c (petroleum ether:ether:methanol:acetic acid 66:34:1:1)

Rf 0.22

n.m.r. (CDCI3, 250MHz) δ 0.9 (3H, t), 1.3 - 1.5 (4H,m), 2.62 (2H, t), 3.86 (2H, s), 4.40 (2H, s), 4.42 (2H, s), 4.62 (2H, q) , 7.0 -7.6 (!2H,m), 8.12 (1H, dd).

Example 20

- ! 4 ' - ! [3-Butyl-l-(2,2,2-trifluoroethyl)-lH-pyrazol-4yl]methvl][1,1' -biphenyl]-2-yl]-lH-tetrazole-5-methanol

A suspension of palladium on charcoal (10%, 32mg) in ethanol (5ml) was pre-treated with hydrogen and then a solution of the product of Example 19a (170mg) in ethanol (3ml) was added and the resultant mixture was stirred vigorously under an atmosphere of hydrogen for 16h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. This crude product was purified by column chromatography on silica gel eluting with chloroform/methanol (20:1) to afford the title compound (90mg) as a white solid.

n.m.r. (CDC1₃, 400MHz) δ 0.90 (3H, t), 1.25 (2H, sex), 1.52 (2H, pent), 2.52 &lt;2H, t, 3.0-4.0 (2H, br,, 3.82 (2H, s), 4.52 (2H, s) , 4.76 (2H, dd), 6.9-7.6 (7H,m), 8.18 (lH,d).

I.r. (CHC1₃, cm^-1 3464 (s) . 2873 (m) , 1717 (w) 1390 (m) .

Similarly prepared:CV3C6/C

<img file="AP254A_D0041.tif" />

BAD ORIGINAL

<img file="AP254A_D0042.tif" />

·, Η

<img file="AP254A_D0043.tif" />

7.1.; (petroleum ether: ether:methancl:acetίο acid 50:51:3:3) Rf C . 15 room a solution tf the product of Example 19c ,-. 5 lot! in ethar.tl

h.m.r. ϋ—ΕΜΕΰ, 35 2MHz) 0 . SC (3H,t), 1.20 (4H,m), 2.50 (2)-),-), 3.51 :2.-.,s;, 4.31 (ΣΗ,ε), 5.00 (2H,dc), 7.00 (2)-),d), 7.12(2.-),0), 7.5-'.7 ί 4H,m).

Ξx3 7101β 2 2

- Ξ u t v 1 - 4 - ’ (2'-(lH-tetrszol-5-vl) ' 1, 1' - o 1 o h e r. v 1 j - 4 - v 1 ] me t h v 1 ] -1 (2,2,2-trifluoroethyl)-lK-pvrazcle-5-carbcxaldehvde let ra-r.-pr opylanmcniun perruthenate (2mg) was added to a mixture of one product cf Example 20 (2 6.5mg), 4-methyImcrpholine N-oxide iTOmg) and powdered 4A molecular sieves (132mg) ir. a mixture of cry di o.tl oromethar.e (2ml! and dry acetonitrile i2.nl) at room temperat-re -d e r nitrogen. The resultant .mixture was stirred at room er. the s:.ve residue was purified oy shcrt-patr. column cr. r oma t ogr achy on silica gel eluting with ether,''petroleum ether/aoetio acid &lt;73 :35:1) to give the title compound as a pale purple foam (18mg)

n.m.r. (CDCI^; 250 MHz) δ 0.9 (2H,m), 2.53 (2H, t), 4.15 (2H, 3.15 (IH, d), 9.8 5 (IK, s) . T.l.c. (ether/acetic acid 100:1) (3H, t), 1.3-1.4 (2H,m), 1.5-1.6

s), 5.18 (2H, q), 7.18-7.65 (7H,m),

Rf. 0.35

Similarly prepared:Example 23

5-5utvl-4~] ' 2 * -(lH-tetrazcl-5-vl) ( 1, I'-biphenyl]- 4 -y1]methvl]-!&lt; 2, 2,2-t rif1uoroethvl) -lH-pvrazcle-3-carbcxaldehyde as a white solid (20.6mg).

7.1.0. (petroleum ether:ether: metha no 1: acecic acid 2 5:2 5:1 : 1) Rf

n.m.r. (33C1_;, 250MKzl, 0.76 (3H , t) , 1.1-1.2 (4H,m), 2.45(2H, t) , 2 . 91 (2H, s) , 4.50 &lt;2H, a), 6.8-7.3 (7H,m), 3.0 (lH,d),9.75 (lH,s).

<img file="AP254A_D0044.tif" />

BAD ORIGINAL

AP Ο Ο Ο 2 5 4

<img file="AP254A_D0045.tif" />

From the addition of tetra-n-propylammonium perruthenoate (4mg) to a stirred mixture of the product of Example 21 (104mg), Nme t h ylmorphc31 &lt;&gt;wg) and freshly powdered 4A molecular selves (1 .lg) (2.5ml).

n dry dlchloromethane (2.5ml) and dry acetonitrile

Examde 2 4

3-3utyl-4-[!2*-(lH-tetrazol-5-yl) [1, 1' - biphenyl]-4-yl]methyl]-1(2,2,2-trifluoroethvl)-IH-pvrazole-5-carboxylie acid

A solution of sodium chlorite (325mg; 80%) and sodium dihydrogen phosphate (325mg) in water (3ml) was added to a solution of the product cf Example 22 (16Smg), 2-methyi-2-butene &lt;2.14ml;2M in THF), tert-butanol (4ml) in THF (3ml) at room temperature and the mixture stirred for 15 min under nitrogen. The solvent was evaporated and the residue was partitioned between water (10ml) and ethyl acetate (3 x 10ml). The combined organic extracts were dried and evaporated to give a pale purple foam (242mg). The crude material was purified by short-path column chromatography on silica gel eluting with ether/petroleum ether/acetic acid (50:50:1) to give the title compound as a colourless foam (9img).

T.l.c (ether/petroleum ether/acetic acid 50:50:1) Rf 0.2.

n.m.r. (MeOD; 250 MHz) 8 0.88 (3H, t), 1.1-1.5 (4H,m), 2.49 &lt;2H, t,, 4.15 (2H, s), 5.25 (2H, q) 7.05 (4H, dd), 7.50-7.70 (4H,ra).

Similarly prepared:Example 25

5-Butyl-4-[ (2^,-(lH-tetrazol-5-yl) [1,1' - biphenyl]-4-yl]methyl]-1(2,2,2-trifluoroethvl)-lH-pyrazole-3-carboxvlic acid as a white solid (44mg).

T.l.c. (ether : petroleum ether : ethanol:acetic acid, 25:25:1:1) Rf 0.12.

n.m.r. (dg-DMSO,400MHz) δ 0.81 (3H, t), 1.24 (4H, br),2.62 &lt;2H, t), 4.05 (2H, s), 5.12 (2H,q), 6.98 (4H, dd) , 7.3-7.6 (4H, m) .

From a solution of sodium chlorite (17lmg; 80%) and sodium dihydrogen phosphate (171mg, in water (1.5ml, added to a stirred solution of the product of Example 23 (88.5mg), 2-methyibut-2-ene (2M in THF, 1.13ml), tert-butanol (2ml) and THF (1.6,mi).

CV306/C (AD ORIGINAL ft

<img file="AP254A_D0046.tif" />

' r.ydrcgenc lysed over palladium, catalyst , 1 . -. g, ci tr. activated catalyst iCv.-2.4g) and glaccal acetic acid (1 ml; was added and tne mixture hydrcgenolysed fcr a further 12h. A further portion cf palladium, catalyst &lt;5%;0.4g) was added with concentrated HCl (lm.1) ar.d the mixture hycrcgenclysed fcr a further 12h. Che catalyst was filtered off and the filtrate evaporated in vacu: tc give a pale yellow foam w.tich was purified by column chromatography cn silica gel eluting with System F (100:1) . Che combined fractions were evaporated and azectroped with heptane tc give the title .ccm.ocuno as a colourless foam (2.54g)

C.l.c. System. F (111:1) Rf 0.2.

n.m.r. δ (251 MHz; 22C1-;) 1.S2 (2H,0), 1.15 — 2.22 :c.H, t -rr.) , 1.45 ¹2h, m) , 2.42(2--,0), 2. *s -2:-:,s), 2.55 )2.-:, c;, 4. 4: 2-:,s), 7.1 .2.-:, (12.-:,

d)

Similarly prepared:Example 27

3-5utvl-l-(1-methylethyl)-4-([2' -(IH-tetraz

-4-vl ] methvl] -IH-Pvraccle-t-metr.anol

m.p. 107-113°C

T.l.c. ether:acetic acid (100:1) Rf C.5

From Intermediate 23a.

){1,1'-biphenylj

5-3utv1-1-(1-methylethvl)-4-:&gt;2'-(1.H- retrace 1-5-v2) )1, 1'-biphenylj

-4-vl ] methyl] -l.H-pvr azole-3 -methanol

m.p. eC-54°C

T.l.c. drchlorcmethane:ether :acetic acid (7 5:2 5:1! .- f 0.1

From :ntemediate 2 It.

BAD ORIGINAL ft

AP Ο Ο Ο 2 5 4

<img file="AP254A_D0047.tif" />

Example 29

3-Buty1-1-(2-methylpropyl) -4-[[2*-(1H-tetrazol-5-yl) [1,1'-biphenyl]

-4-yl3methyl]-IH-pyrazole-5-methanol

m.p. 86-89°C

T.l.c. dichlorcmethane .-methanol (10:1) Rf 0.45

From Intermediate 24a.

Example 30

3-3utyld-12-cyclopropylmethyl)-4-[ [2'-(ΙΗ-tetrazol-5-yl) [1,1*biohenyl]-4-yl]methvl3-lH-pyrazole-5-methanol

m.p. 87-98°C

T.l.c. dichloromethane:methanol (10:1) Rf 0.5

From Intermediate 25a.

Example 31

S-autvl-l-ethvl^-I^'-dH-tetrazol-S-vl) [l_&gt;l^,-biphenvl]-4yl3 methyl]-lH-pyrazole-3-methancl

m. p. 1C3-1C9°C

T.l.c. dichlorcmethane:methanol (10:1) Rf 0.5

From Intermediate 22b.

Example 32

3-Butvl-1-cyciobutyl-4-[ [ 2' - (1H-tetrazol-5-yl) [1,1*-biphenyl3-4 vl] methyl]-lH-pyrazole-5-methanol

T.l.c. System F (95:5) Rf 0.47

n. m.r (250MHz; CDC1₃) δ 0.65 (3H,t), 0.95-2.70 (12H,m), 3.58 (2H,s), 4.28 (2H,s), 4.71 (lH,pent), 6.80-7.55 (8H,m).

From Intermediate 26a.

Example 33

5-Butyl-l-cyclobutyl-4-[[2'-(lH-tetrazol-5-yl)[1,1*-biphenyl] -4yl3 methylj-lH-pyrazole-5-methanol

m.p. 85-90°C

T.l.c. dichloromethane:ether:acetic:acid (70:10:1) Rf 0.16

From Intermediate 26b.

<img file="AP254A_D0048.tif" />

;-- = otvl-l-methvl-4-;!2^,-(lH-tetrazol-5-vl),^rl,l^,-blpher.vll-4vl]methyl]-IH-pyrazole-5-methanol .*

..¾

m. p ane:methancl:aoetio aoio (200: 15:1) Rf 0.12 cvr = z:1a-3-methanol ar.e:methar.cl (9:1) Rf C.6C

Frcx fntermeaiace t/c.

£&gt;:arrcle 3 c l_z ;-3:cuty1- 4 - [ [ &lt;-' - (IH-^etrazcl-5-yl) ' 1, 1' - b i c In e r y 1' - 4 - v _ ‘ ~.e i h v 1 ] - - ^vrs2C&gt;e~: -r.e·; r. a r. c«.

zaiic acic l, ;-Ilbotyl-4-F]2^,-(lH-tetrazoi-5-vl);i,l'-prphenvi;-4-yl]methvl·1H-pyrazole-3-methanol

m. p. 56-58^cC

T.l.c. System G (60:30:1) Rf 0.17 “rom Intermediate 29b.

£ y a rrc a 3 S l-Ethvi-3-propyl-4-[ [2'-(lH-tetrazol-5-yl) ί1, 1'-bipheny1]- 4 yl] methvl] -lH-cyrazcle-5-methanol

m.p. 77-82^2

T.l.c. dichlorcmethane:methanol (10:1, Rf 0.34

From Intermediate 30a.

Example 39

1-Ethy 1-5-cropv 1-4-[ ?2'-(lH-tetra

<img file="AP254A_D0049.tif" />

BAD ORIGINAL

AP Ο Ο Ο 2 5 4

T.l.c. dichloromethane:methanol (10:1) Rf 0.45

From Intermediate 30b.

Example 40

1-(1-Methvlethvl)-3-proPvl-4-[[2'-(lH-tetrazol-5-vl)[1,1'-biphenvl]

-4-vlJmethyl]-lH-pvrazole-5-methanol

m.p. 59-91°C

T.l.c. dichloromethane .-methanol (10:1) Rf 0.55

From Intermediate 3la.

Example 41

1-(1-Methylethyl)-5-propvl-4-[[2' - (lH-tetrazol-5-vl) [1,1'-biphenyl]

-4-vljmethyl]-IH-pyrazcle-3-methanol

m. p. 86-90°C

T.l.c. dichloromethane:methanol (10:1) Rf 0.80

From Intermediate 31b.

Example 42

3-3utyl-l-ethvl-4-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]- 4 vl'methyl]-lH-ovrazole-5-carbcxaldehyde letra-n-propylammonium perruthenate (TPAP,22mg) was added to a mixture of the product of Example 26 (531mg), 4-methyl morpholine-Noxide (224mg) and powdered 4A molecular sieves (6.3g) in a mixture of dry dichloromethane (15ml) and acetonitrile (15ml) at room temperature under nitrogen. The mixture was stirred for lh at room temperature. Further portions of TPAP (27mg), and 4-methyl morpholine-N-oxide (224mg) were added and the mixture stirred at room temperature for 15 mins. The solvent was evaporated and the residue purified by column chromatography on silica gel eluting with dichloromethane/ether/acetic acid (75:25:1) to give the title compound as a pale purple foam (221mg).

T.l.c. dichloromethane/ether/acetic acid (75:25:1) Rf 0.6

n. m.r (250MHz; CDCI3) δ 0.90 &lt;3H,t), 1.25-1.45 (5H, t+m) 1.55 (2H, m) , 2.55 (2H,t), 4.11 (2H,s), 4.49 (2H,q),7.15 (lH,dd), 7.51-7.63 (2H,2xddd), 8.15 (lH,dd), 9.85 (1H,S).

Similarly prepared:CV306/C

BAD ORIGINAL

C.

Example 4 3

3- 5utvl-l- (1 -tnethvlethyl) -4-f f2'-(lK-tetrazol-5-yl) il, l'-bipher.vll4- vl] re~-7.vI]-lK-pvrarele-3-carbexaldehvce . . c . ci chi or one t ar.e:etr.er:acetrc acre (75:23:1) Rf 0 . ~ 5

r..m..r. (250’KHr, CSCl^J δ 0.9 (3H,t) , 1.30 (4 K, m.) , 1.50 (64,d), 2.60 &lt;2.-_zc), 4.10 (24,s', 5.30(IH, sept), 7.20 (4K,A'=S'), 7.4 (14,rr.d), 7.53--.65 (2 Ή ,m' , :.23 (1H, c r . d i , 9.55 (1H,s) : r 2. 2 .te C r CC -.CC 2 2 r Χ.ά.Τ,0-6 - , .

E:-:ar.P.6 4 4

5- 2ut v1 -1 - ! 1-methvleth vl)-4-f ' 2 * -(IK-tetrazcl-c-vl) '1 1'-bic---’¹ 4-vl ] methyl ] -1.4-pyraz;le-3-carbcxaldehyde

m.p. 14c-146^cC

T.l.c. hr chlcrcmet ha.-.e :ether :acetrc acre (73 : 25:1) Rf C.5

Ertm the product of Example 28.

<img file="AP254A_D0050.tif" />

( 2K, ~'i , 2.15 (IH, sept ; , 2.57 ( 2H, e ) , 4.13 (2 K, s) , 4.27 (2.4, d) , 7.12 (4H, A'B3'&gt;, 7.4 -,1.4,00), 7.52-7.62 (2H, m) , 8.20 (1.4,dc), 9.85 (IK,s) .

From the produce cf Example 29.

Example 46

2-3utvl-l- (2-cvclccropylmethvl)-4-[[ 2'-(lK-eeerazcI-5-vl) [ 1, 1'biphenyl]-4-vl;methyl]-lH-pyrazcle-5-carboxaldehvde

m.p. 38-00°C

T.l.c. crchloromethane : ether :aoeeic acid (75:25:1) Rf 0.65

From the product ce Example 30.

Example 47

3-3utyl-l-cvcIobuf.^,l-4-f[2'-(lH-tetrazoI-5-vl) ] 1, 1 v 1 ] met hvl ] - 1K - pvr a r e 1 e- 5 - oa rboxa Ideh ·,·de

T.l.c. System. E (93:3) Rf 0.63

1? (CK2r₃) 1 677cm-BAD ORIGINAL fi

AP Ο Ο Ο 2 5 4

From the product of Example 32.

Example 48 . * Ujb|.||*g₄ .,, l, 3-Dlbutyl-4- [ '2' - (lH-tetrazol-5-vl) [1, l^f-olwi&lt;WWb^»&lt;-Vl1n&gt;ethvl] lH-pyrazcle-5-carboxaldehyde

m. p.50-53°C

T.l.c. dichloromethane:ether:acetic acid (75:25:1) Rf 0.71

From the product of Example 36.

Example 49

1-(1-Methylethyl)-3-propyl-4-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]4-vl] met hyl] -lH-pyrazole-5-carboxaldehyde

m.p. 48-50°C

T.l.c. dichloromethane:ether:acetic acid (80:20:1) Rf 0.73

From the product of Example 40.

Example 50

3-Butvl-l-ethv1-4-( [2'-(lH-tetrazol-5-yl) (l,l'-biphenyl]-4vl]methyl]-IH-oyrazole-5-carboxylic acid

A solution of sodium chlorite (80%;0.44g) and sodium dihydrogen phosphate (0.44g) in water (5ml) was added to a mixture of the product of Example 27 (203mg), 2-methyl-2-butene (2M,0.62ml) and tbutanol (4ml) in THF (10ml) at room temperature. The mixture was stirred vigorously for 20 mins. The mixture was partitioned between ethyl acetate (3x15ml, and water (15ml). The combined organic extracts were dried. The solvent was evaporated to give a colourless foam (0.2g) which was purified by column chromatography on silica gel eluting with System G (50:50:1) to give the title compound as a colourless solid (60mg).

T.l.c. System G (50:50:1) Rf 0.25;

Assay Found: C,66.8; H,6.0; N,19.4;

^C24^H26^N6°2 requires: C,67.0; H,6.1; N,19.5%

Similarly prepared:Examole 51

3- Butvl-l-(l-methvlethyl)-4-[[2' -(lH-tetrazol-5-yl) (1,1*-biphenyl]4- yl]methyl]-lH-oyrazole-5-carboxylic acid

CV3C6/C

AD ORIGINAL

<img file="AP254A_D0051.tif" />

m.p. iO-il'C

T.l.c. dichioromethane .-ether :acetic acid (120:10:1) Rf 0.2

<img file="AP254A_D0052.tif" />

1.-.c. ci ο.-.. ζ σ me t ca ne : e t ne : : a cet id acid (15:25:1) Rf 0.25 From ode product cf Examcle 44.

ζ,ϊ.εο-.ο-?

3-5 -1 v1-1 - (2 -methylcrcovl) - 4- ( [2' - (IH-t etraccl-5-vl

4-vl'.methyl; -lH-pyrazole-5-carbcxviic acid

<img file="AP254A_D0053.tif" />

cr:

^ethane: ether : acet ic acid (15 of Example 45.

0.5 .envl· · “ :arocxvlie acre

T.l.c. dienicromethane: ether: acetic acid (115:10:1) Rf 0.15

From the product of Example 47.

Examcle5 5

-ί 4' '3-Eutvl-5-!met hexymethvl) -l-phenvI-lH-pvrazcl-4-.-1} methyl' ; 1,1' -biphenvlj-2 -vl]-1H-tet ra zcIe ? c.eny Ihycra z ine and Intermediate 5 were reacted according to the method cf Intermediate 18 to give the title comp;und as a pale vellcw foam.

T.l.c. ether:petrcleum ether:acetic acid ( 100:100:1) Rf. 0.2

n.m.r. (25CMHz, CH3OD) δ 0.68 (3H,t), 1.30 (2H,m), 1.48 (2H,m), 2.52 (2H,t), 3.28 (3H,s), 3.92 (2H,s), 4.30 (2H,s), 7.1 (4H,dd), 7.4-1.7 ( 9H,m) .

E &gt;: a mp i e 5 6

BAD ORIGINAL

AP Ο Ο Ο 2 5 4

1,3-Diethyl-4- [ [2*-(lH-tetrazol-5-yl) (1,1' -biphenyl] - 4-yl ]methyl ] lH-pyrazole-S-methanol

From according to the method of Example 26.

T.l.c. diehJOTbSevMini:methanol (10:1) Rf 0.56 IR (Nujol mull) 3350 t 1494 cm^-1.

Example 57 l, 5-Drethvl-4- [ [2' - (lH-tet razol-5-yl) :'l, 1'-biphenyl] -4-yl]methvl]ΙΗ-pyrazole-3-methanol

From Intermediate 35b according to the method of Example 26.

T.l.c. dichloromethane:methanol (10:1) Rf 0.36 IR (Nujol mull) 3317 &amp; 1494 cm¹.

Example 58

3-3utvl-4 - ( (2' -car boxv ¢1, 1' -biPhenvl j^-ypmethvll-l-ethvl-lHcvrazole-5-carboxvlic acid

From Intermediate 44 according to the method of Example 4.

m. p. 190-192°C

T.l.c. ether : hexane : acetic acid (50:50:1) Rf 0.35

Example 59

3-3utvl-l-propvl-4-[[2'-(lH-tetrazol-5-yl)[1,l'-biphenyl]-4yl]methyl]-lH-pyrazole-5-methanol

From Intermediate 28a according to the method of Example 26. m.p. 79-82°C.

T.l.c. dichloromethane:methanol (10:1) Rf 0.45

Example 60 l-Ethyl-3-propyl-4-[[2'-(lH-tetrazol-5-yl)[1,l'-biphenyl]-4vl Imethyl]-lH-pvrazole-5-carboxaIdehyde

From the product of Example 38 according to the method of Example 42 .

m.p. 48-50°C.

T.l.c. dichloromethane:ether:acetic acid (80:20:1) Rf 0.73.

Example 61 l-£thyl-3-propyl-4-1[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4vl]methyl]-lH-pyrazole-5-carboxylic acid

<img file="AP254A_D0054.tif" />

From the product of Example 60 according tc the method cf Example

C. fl ::8-ΐΣ3°ς&gt; 3»j| chiercmetnancether:acetic acid (63 :21 :1) Rf 0.45

<img file="AP254A_D0055.tif" />

rrom the product cf Example 49 according to the method cf Exsmcle

T.l.c. dichlorcmethane: ether :acetic acid (90:13:1) Rf 0.62.

<img file="AP254A_D0056.tif" />

cf

E x:

a to the method cf Examcle

3-5utv 1-4- [ ( 2 ' -c a r b o x v ί1, 1'-biphenvl]-4-vI)methyl]-1-(1 methvlethyl)-lH-pvrazcle-5-carbcxyIic acid

From the product of Intermediate 46 accorcir.c to the method of Example 4. m.p. 213-215°C.

T.l.c. System G (20:20:1) Rf 0.44 an

Na

The compounds of the invent giotensin II antagonism. Aortic sf : a 1a n d white rabbits and p r e pa .-.tract icns in response to cumuiat: e potencies of test antagonists a ilities to displace the angiote.os socr.se C'jrve. The r^echod used is t 1 . Acad, 5 c i . , 7 4(12) , pp5725-29 ion are tested in vitro for mips are obtained from male New red for recording isometric ive addition cf angiotensin II. re assessed by measuring their in II cumulative concentration that of Ackerly et al., Prop . (1977) with the exception that

<img file="AP254A_D0057.tif" />

bAD ORIGINAL

1· --·4

ΑΡ Ο 0 0 2 5 4 the final composition of the physiological salt solution is as given below in Table 1:

TABLE 1

Ingredient

Amount (mM)

Na K ⁺Mg

Ca

Cl

HPC

SC

42HCOglucose indomethacin ascorbic acid

143.4

5.9

0.6

1.3

124.5

1.2

0.6

25.0

11.1

0.005

0.1

The tissues are initially challenged with K⁺ (80mM) and then washed at 3, 5, 10 and 15 minutes after the response to Κ⁺ has plateaued. After a further 45 minutes an angiotensin II cumulative response curve is constructed (O.lnM to Ο.ΙμΜ in 10-fold increments) and the tissues are washed as before. A second, third and fourth angiotensin II cumulative response curve (O.lnM to Ο.ΙμΜ in 3-fold increments) is then constructed at hourly intervals (15 minutes washing after each curve followed by 45 minutes equilibration). The compounds of the invention (30μΜ) are tested for angiotensin II antagonism by application 45 minutes before construction of the fourth angiotensin II curve. The third and fourth angiotensin II curves are expressed graphically and a concentration ratio (CR) is calculated by dividing the angiotensin II EC^q value obtained in the presence of the test antagonist (i.e. fourth curve) by the angiotensin II EC^q value obtained in the absence of the test antagonist (i.e. third curve,.

The potency of the test antagonist is expressed as a pKb which is calculated from the equation :

V306/C

BAD ORIGINAL ft

<img file="AP254A_D0058.tif" />

ρκ fCompounds of the inventton will desirably exhibit a pKb in the range between 5 and 12. T.tus we have found that the compounds cf the invention inherit the action of t he hormone angiotensin 21 and are tnereftre useful tn. the treatment cf conditions in which it is desiratle tc inhibit angictenstn II activity. In particular, the compounds cf Examples are active in the above test.

There is thus provides as a further aspect cf the inventtcn a

<img file="AP254A_D0059.tif" />

acceptable salt, solvate or metabo1ically labile ester thereof for the manufacture cf a therapeutic agent for the treatment of conditions associated with excessive cr unregulated angiotensin II activity.

There is also provided tn a further cr alternative aspect of the invention a method for the treatment cf conditions associated with excessive or unregulated angiotensin II activity in a mammal including man comprising administration cf ar. effective amount tc a mammal in need cf such treatment a compound cf general formula (I) or a p.nys i clog tea 1 ly acceptable salt, solvate cr metabc1ical ly labile ester thereof.

The following examples illustrate pharmaceutical formulations according to the invention. Tne term, active ingredient is used herein to represent a compound cf f:rm_la (I) .

BAD ORIGINAL ft

AP Ο Ο η 2 5 4

Pharmaceutical Example 1

Oral Tablet A

Active Ingredient 700mg Sodium starch giycollate lOmg Microcrystalline cellulose 50mg Magnesium stearate 4mg

Sieve the active ingredient and microcrystalline cellulose through a 40 mesh screen and blend in a appropriate blender. Sieve the sodium starch giycollate and magnesium stearate through a 60 mesh screen, add to the powder blend and blend until homogeneous. Compress with appropriate punches in an automatic tablet press. The tablets may be coated with a thin polymer coat applied by the film coating techniques well known to those skilled in the art. Pigments may be incorporated in the film coat.

Pharmaceutical Example 2

Oral Tablet B

Active Ingredient 500mg

Lactose lOOmg

Maize Starch 50mg

Polyvinyl pyrrolidone 3mg

Sodium starch giycollate lOmg

Magnesium stearate 4mg

Tablet Weight 667mg

Sieve the active ingredient, lactose and maize starch through a 40 mesh screen and blend the powders in a suitable blender. Make an aqueous solution of the polyvinyl pyrrolidone (5 - 10% w/v,. Add this solution to the blended powders and mix until granulated; pass the granulate through a 12 mesh screen and dry the granules in a suitable oven or fluid bed dryer. Sieve the remaining components through a 60 mesh screen and blend them with the dried granules. Compress, using appropriate punches, on an automatic tablet press.

<img file="AP254A_D0060.tif" />

CV306/C

BAD ORIGINAL :8

The tablets may be coated with a thin polymer coat applied by film coating techniques well known to those skilled in art. Pigments may be incorporated in the film coat .

Pharmaceutical example 3

Active tr. crecier. t Ir.2

Lactose 2 4m.g

Sler.d active ingredient, particle sice reduced to a very fine particle size (weight mean diameter ca. turn) with the lactose in a suitable powder blender and fill the powder blender into No. 3 hard gelatin capsules.

The contents cf the cartridges may be administered using a

'.-.’a ter fcr injections 3. P. to 1GG.CC

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability ar.d,'or tc facilitate solution of the active ingredient using dilute acid or alkali cr by the addition cf suitable buffer salts. Antioxidants and metal chelating salts may also be included.

The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one cf the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere cf nitrogen.

BAD ORIGINAL Ά

AP Ο Ο Ο 2 5 4

The present invention is further illustrated by the following Examples: Ir.te ( a ) rmediates 47a and b

<img file="AP254A_D0061.tif" />

5-14' - [ (1- ( 2 , 2-Pimethylprooyl) - 3- propyl-5ar.v ime the xy) methyl]- lH-pvrazol-4-yl] me thyl] [1, 1' -biphenyl ] - 2·/1 -1 - (t rioher.vlmethvl) -2H-tetrazole; and ¹ ° ^] 5 - { A ’ - [ [1-(2, 2-Dimethylpropyl) -5-propyl-3f (or.env Imet hoxv) methyl] -IH-pyrazol-4-yl]methyl ] [1,1' -biphenyl] -2-yl2-(triohenvlmethyl)-2H-tetrazole

From Intermediate 21 and 2,2-dimethyipropyl iodide according to the method cf Intermediate 22.

Intermediate 47a: T.l.c. System A (1:2) Rf 0.29

Intermediate 47b: T.l.c. System A (1:2) Rf 0.21

Intermediates 45a and b (a ) 5 - f 4' - [ [ 3-Butvl-5-methoxymethyl-1- (prop-2-enyl) -lH-pyrazol-4vl]methvl] {1,1'-biphenyl]-2-vl]-2-(t riphenvlmethyl)-2H-tetrazole;

and (b) 5 -[4'-Γ;5-Butyl-3-methexvmethvl-1-(prop-2-enyl)-ΙΗ-pyrazol-4 vljmethvl](1,1'-biphenyl]-2-vl]-2-(triphenylroethyl)-2H-tetrazole

A solution of Intermediate 9 (2.5g) in DMF (10ml) was added dropwise to a suspension of sodium hydride (60% dispersion in oil, 0.22g) in DMF (5ml) at Q’C under nitrogen. 3-Bromopropene (0.46g) was added to the stirred mixture and stirring continued at room temperature for 3 hours. The solvent was removed in vacuo and the residue purified by column chromatography eluting with System A (4:3) to give the title compound:

<td> (a) Intermediate</td><td> 48a</td><td> as a white</td><td> foam</td><td> (860mg),</td>

<td> T.l.c. System A</td><td> (2:1)</td><td> Rf 0.50</td><td></td><td></td>

<td> (b) Intermediate</td><td> 48b</td><td> as a white</td><td> foam</td><td> (lOlmg),</td>

<td> T.l.c. System A</td><td> (2:1)</td><td> Rf 0.25</td><td></td><td></td>

inc-grinediates 49a and b &lt;a ) 1,1-Dimethvlethvl 4'-[[3-butvl-1-methvl-5-[(phenvImethoxv) methvli-lH-pvrazol-4-yl)methvl][1,1'-biphenyl]-2-carboxylate; and (b) 1, 1-DimethvIethyl 4'-[[5-butyl-l-methyl-3-[ (phenylmethoxy) methyl]-lH-pvrazol-4-vl]methyl][1,1'-biphenyl)-2-carboxylate

CV306/C

BAD ORIGINAL ft

From Intermediate Intermediate 22. Intermediate 45a:

Intermediate 4 5b:

and methyl

System A

Svs tern A tde according to the method of

<img file="AP254A_D0062.tif" />

cyrace 1-4-vl) methvl) '1,1' -biohen.·.·I; -2-care;xvlate

From Intermediate 45a according tc the method of Example 26. T.l.c. Svstem I (1:1; ?.f 0.1

Intermediate 51

1, i-Timet η v 1 e t h v 1 4' - \ 3-butv 1 -5 -f ; r mv 1-1-methvl-lH-cvrazo 1 -4-

<img file="AP254A_D0063.tif" />

r - n .

<img file="AP254A_D0064.tif" />

<img file="AP254A_D0065.tif" />

Intermediate 53

- f 2 * -Nitro [ 1, 1' -richervl] - 4- vl) methyl] -1- (phenvlmethoxy) - 2, 4 heot andlcne

From Intermediate 15 and 4'-(bromcmethyl)-2-nitro-i,1'-biphenyl according to the method of Intermediate 17.

T.l.c. System, A (1:1) ?.f 0.6

Σ r. t 6 Γτπβόί 3 . β 5 4

3-[ ί 2'-Ν11 r : ί 1, 1'- b i c h e η V1 ]-4-vl)methvl]-1- (phenvlmethoxy) -2 , 4octandlcne

From Intermediate 16 and 4'-(bromcmethyl)-2-mtro-1,1'-bipheny1 according to the metr.cd of Intermediate 17.

T.l.c. Svstem. A (1 : 5 ) Ft 2.4

BADORIGINAL ft

AP Ο Ο Ο 2 5 4

4-j (2'-Nitro[1,1*-biphenyl]-4-yl) methyl] -5-[(phenylmethoxy)methyl]3-propyl-lH-pyrazole

From Intermediate 53 and hydrazine hydrate according to the method • W ' j 4 !

cf Intermediate 18. ^; - T.l.c. System B (300:8:1, Rf 0.28

Intermediate 56 c -5Litvl-4- j (2' -nitro [ 1, 1 * -biphenvl j - 4-yl) methvl] -5 - [ (phenylmethoxy) methyl]-IH-pvrazole

Frcm Intermediate 54 and hydrazine hydrate according to the method of Intermediate 18.

T.l.c. System B (400:8:1) Rf 0.5

Intermediates 57a and b ( a ) l-EthyI-4-[ ( 2 '-nitro[1, 1' -biphenyl]-4-yl)methyl]- 5 [(phenylmethoxy)methvl]-3-propyl-lH-pyrazole; and ( s ) l-Ethvl-4-[ (2'- nitro [1, 1'-biphenyl]-4-yl)methyl]-3 ](phenvlmethcxy)methvl]-5-propyl-lH-pvrazoIe

Frcm Intermediate 55 and ethyl iodide according to the method of

<td> Intermediate</td><td> 22.</td><td></td><td></td><td></td><td></td><td></td>

<td> Intermediate</td><td> 57a:</td><td> T.l.c.</td><td> System A</td><td> (1:1)</td><td> Rf</td><td> 0.2</td>

<td> Intermediate</td><td> 57b:</td><td> T.l.c.</td><td> System A</td><td> (1:1)</td><td> Rf</td><td> 0.12</td>

<td> Intermediates</td><td> 58a</td><td> and b</td><td></td><td></td><td></td><td></td>

(a) 3-Butvl-l-ethvl-4-[(2'-nitro[1, 1' -biphenyl]-4-yl) methyl]-5[(phenvlmethoxv)methvl]-ΙΗ-pyrazole; and (b) 5-Butvl-l-ethvl-4-[(2'-nitro[1,1' -biphenyl]-4-yl)methyl]-3[(phenylmethoxy)methvl]-lH-pyrazole

From Intermediate 56 and ethyl iodide according to the method of

<td> Intermediate</td><td> 22.</td><td></td><td></td><td></td><td></td>

<td> Intermediate</td><td> 58a: T.l.c.</td><td> System A</td><td> (1:1)</td><td> Rf</td><td> 0.22</td>

<td> Intermediate</td><td> 58b: T.l.c.</td><td> System A</td><td> (1:1)</td><td> Rf</td><td> 0.11</td>

<td> Intermediate</td><td> 59</td><td></td><td></td><td></td><td></td>

' -[ [l-Ethyl-5-( (phenylmethoxy)methyl]-3-propyl-lH-pyrazol-4yl]methvl][1,1'-biphenyl]-2-amine

Titanium trichloride solution (IStw/v, 33ml) was added to a solution cf Intermediate 57a (1 . 5g) in acetone (30ml) and the resulting

CV3O6/C

BAD ORIGINAL A mixture stirred overnight. Further titanium trichloride solution (10ml) was added and the reaction warmed to 40’C for 16h. 2N Sodium carbonate was added and the mixture extracted with ci cr.iorcmethane (3x150ml) . The combined, cried, organic extracts were evaporated 1 n vact: and the residue purified by chromatography eluting with System A &lt;2:1) tc give the title compound as a yellow hcxy) r.eihy 1 - l· H-cvr a z c 1 - 4 2 -arr.ir.e =n. - (.

,e rrr.eciste r z - e z ’. 2 r. e s u 1 z η ο n a rm 0 e lution 0: Intermediate 5? (lg) and triethylamine (0.35ml) in dry :loromethane (20ml) at -70’C was treated dropwise with a solution of trifiic anhydride (0.46ml) in dichloromethane (5ml) and the resulting mixture stirred at -70’C for Ih. Water (10ml) was added and the reaction allowed to warm to room temperature. The aqueous layer was separated and the organic washed with 2N hydrochloric acid (1Imi). The dried organic solution was evaporated in vacuo and the residue purified by chromatography eluting with System B (300:8:1) tc give the title compound as a foam (O.S3g).

T.I.C. System 5 (100:8:1), Rf 0.31 ;r-v oreparec:. ntermenrate c.

oromethane-sulohonamide .l.C. System 3 (150: rem Intermediate 60.

Rf 0.15

BAD ORIGINAL A

AP Ο Ο Ο 2 5 4

Examples 65 to 71 inclusive were prepared according the method v A · of Example 2 6:Example 65

5-9utvl-l-(2-methylpropyl)-4-[[2*-(lH-tetrazol-5-yl)[1,1’-biphenyl]4 — V 1 ' ΓΓ:^Λ “ 1 H “C V * d 2 c' “ 2 ” u h 3 fl c 1

m.p. 65-66°C

T.l.c. dichloromethane:ether:acetic acid (75:25:1) Rf 0.15 From Intermediate 24b.

Example 66

5-Butvl-l-(2-eyelooropyImethyl)-4-([2'-(lH-tetrazol-S-yl·) (1,1'biphenvl]-4-yl]methvl]-lH-pyrazole-3-methanol

m.p. 70-75°C

T.l.c. dichloromethane:ether:acetic acid (75:25:1) Rf 0.15 From Intermediate 25b.

z.:-:amp^e 67

5-3utvl-l-propyl-4-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-lH-pyrazcle-3-methanol

m.p. 59-62°C

T.l.c. dichloromethane:methanol (10:1) Rf 0.41

From Intermediate 28b.

Example 68 l-(2-Methylpropyl)-3-propyl-4-[[2'-(lH-tetrazol-5-yl)(1,1'biphenyl]-4-vl]methyl]-lH-pyrazole-5-methanol

m.p. 104-108°C

T.l.c. dichloromethane:methanol (10:1) Rf 0.7

From Intermediate 45a.

Example 69

1- (2-Methyloropyl)-5-propyl-4-[ [2'-(lH-tetrazol-5-yl) [1, 1' blphenvl]-4-yl]methyl]-ΙΗ-pyrazole-3-methanol

m.p. 55-61 °C

T.l.c. dichloromethane:methanol (10:1, Rf 0.57

I': u&gt;m Intermediate 4 5b.

<img file="AP254A_D0066.tif" />

BAD ORIGINAL ft

1-··:,;-: -mettvlcr:t ν. · -3-propvl-4-; [2'- ( 1H-tet razcl-5-yl·) [1,1''.e r : acet.

:ic

I)

- '2,2 -0 2 me t h v 1 p r c ρ v 1)-5-prcpyl-4-j[2'-(lH-tetrazol-5-yl) [1, 1' b i cnenvl’ - 4 - vi ] methyl· ] -1H-cvra zcie-3-met har. c 1

<img file="AP254A_D0067.tif" />

T.l.c. dichlorornet han.e : ether: acet ic acid (90:10:11 Rf 0.28

From. Intermediate 4 7c.

Examples 2 tc 75 inclusive were prepared according to the ~e—cd cf Example ⁴2:T.l.c. dichIcremethane: ether :acetic acid (50:10:1) Rf 0.3

From the product of Example 34.

Example 73

-Ξ u t v 2 -1 -p r ο p v1- 4 - ; [2'-(lH-tetrazol-5-vl) [ 1, l'-blphenvl]-4vl]methyl]-IH-pvrazcLe-5-ca rboxaIdehvde

m.p. 48-50^cC

T.l.c. dichloromethane : ether :acetic acid (75:25:1) Rf 0.68

From the product of Example 59.

Example 74 l-;2-y.ethvlpropvl)-c-propyl-4-[[2'-(iH-tetrazol-5-yl)[l,l'h jphenvl]-4-vl;methvl]-1H-cvra zole-5-ca rbexaIdehvde

m.p. 54-56^cC

<img file="AP254A_D0068.tif" />

AP Ο Ο Ο 2 5 4

Example 75

1-(2 ,2-Dimethylpropyl)-3-propyl-4-[[2' -(lH-tetrazol-5-yl) (1,1*blcher.vl] -4-yl]methvl ] -lH-pvra2ole-5-carboxaIdehvde

m.p. 60-62°C

T.l.c. dichloromethane .-ether: acetic acid (90:10:1) Rf 0.46

From the product of Example 70.

Examples 76 to 80 inclusive were prepared according to the method of Example 50:Example 76

3-3utyl-l-(2-cyclopropylmethyl)-4-[ [Z'-dH-tetrazol-S-yl) [1, 1' biphenyl]-4-yl]methyl]-lH-pyrazole-5-carboxylic acid

m.p. 205-206°C

T.l.c. dic'nloromethane :ether:acetic acid (72:25:1) Rf 0.5

From the product of Example 46.

Example 77

3-3utvl-l-methyl-4-{?2^,-(lH-tetrazol-5-vl) [1,1'-biphenyl]- 4vl]methyl]-lH-pvrazole-5-carboxvlic acid

m.p. 118-122°C

T.l.c. dichloromethane:ether:acetic acid (90:10:1) Rf 0.23

From the product of Example 72.

Example 78

3-Butvl-l-propyl-4-[ [2'-(lH-tetrazol-5-yl) [1, l'-biphenyl)-4vl]methvl]-IH-oyrazole-5-carboxylie acid

m.p. 181-183°C

T.l.c. dichloromethane:ether:acetic acid (90:10:1) Rf 0.36

From the product of Example 73.

Example 79

1-(2-Methvlpropvl)-3-propvl-4-[ [2'-(lH-tetrazol-5-yl) II, 1* biphenyl]-4-vl]methvl]-ΙΗ-pyrazole-5-carboxylic acid

m.p. 138-140°C

T.l.c. dichloromet ha.ne : ether : acet ic acid (90:10:1) Rf 0.22

<img file="AP254A_D0069.tif" />

:-//-Zi.-ne-.ny:crcpvl)-3-procy:-4-[[2^,-(:H-tetrazol-5-vl);i,l^&lt;t m neo-.- / - 4-vl ] methyl] -lH-pyrazcle-5-carbcxylic acid

T.l.c. ci chi c r omethane: et he r : acet ic acid (95:5:1) P.f 0.3

<td> 5 - 4 ' - //-=utvl-3 - me the xvme th vl -1 - (1, 1 -dime thv let hvl) - IH-cv</td><td> razol-4-</td>

<td> vl;-eonvi; /, 1'-bichenvlj-2-vl]-IH-tetrazoie</td><td></td>

<td> .-. soi-tion of Intermediate 5 (Sc), 1, 1 -dimethylethyIh/.</td><td> .· d r a z i n e</td>

hycr;cnloride (55 9m.g) and triethyiamine (1.11ml) in ethanol (50m)

<td> was nested at 60’c for 6h after which time additional triet</td><td> hyfamine</td>

<td> //1ml· and 1, 1-dimethylethyihycrazine hydrochloride (1.9</td><td> 2g) were</td>

<td> 3 1 - j .. 3 - . 7.F ά.ΖΞΓ.Ζ .T. 1X ί 'J Γ 1 i Γ Γ 6 G 2 C 6 0 * C f C - 5 f 1 Γ'</td><td> tier 18h</td>

<td> anc tn.en at room, temperature for 24h. The solvents were re</td><td> moved in</td>

<td> vaouo anc toe reside ounfiec cv cc_umn o.nr omatocraDhv elut</td><td> mg with</td>

<td> ceorole.m eo.ner : eo.ner (2:1) initially followed by ethar.;</td><td> ; 1 . The</td>

<td> C Γ. C iζ Σ i ’ 2 1 6 · Γ. 2 Γ. C 1 i C € X t Γ 2 C t S W β Γ € f - Σ i.”, 6 Γ D‘J rifled C</td><td> · c o 1 u mn</td>

<td></td><td> ; e 1111 e</td>

<td> com.cour.d (46m.c) as a cream coloured foam.</td><td></td>

<td> m.p 58-50*2</td><td></td>

<td> Examcle ?2</td><td></td>

<td> 1, 5-T ibutvl-4- ' [2' - (lH-tetrazol-5-vl) [1, 1' -bicher.vl ] -4 - vl ·:</td><td> r.e t h v 1 ] -</td>

iH-cyrazcle-3-carbcxvlic acid

A solution of potassium permanganate (55mg) in water (3ml) was added to a stirred solution of the product cf Example 37 &lt;142mg) in acetone ί iml) at 50’C. The resulting mixture was stirred at 6 5 * C for 1 : hours. A further portion of potassium permanganate (55mg)

<td> was added and the mixture stirred for 3 hours.</td><td> Sodium</td>

<td> .metabisulphite (5% w/v, 15ml) was added and the aqueous pr</td><td> ;a$e was</td>

<td> extracted with ethyl acetate (3x30ml). The combined</td><td> organic</td>

tntoaots were dried and concentrated to yield a white foam wnich was pu r . i i e i by column chromatography, eluting with ether ci on heron.ethane (1:1) to yield the title compound as a white s tlid (7Cmg) .

GBAD ORIGINAL s

AP Ο Ο Ο 2 5 4

m.p. 1O0’C

Examcle 83

3-[4'- [ [3-Butvl-S . .¾

-methoxvmethy1-I-(prop-2-enyl) -ΙΗ-pyrazol-4vl]methyl][1,1'-biphenyl]-2-vl]-IH-tetrazole

A solution of Intermediate 48a (800mg), methanol (15ml) and ten cent rated hydrochloric acid (0.5 ml) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to pH9 (2N NaCO₃) and the solvent removed in vacuo. The residue was partitioned between water (20ml) and ether (3x20ml). The aqueous layer was then acidified to pH3 (2NHC1) and extracted into ethyl acetate (3x20ml). The ethyl acetate fractions were combined, dried and the solvent removed in vacuo to afford the title compound as a white foam (470mg). m.p. 39-41’C

T.l.c. ether Rf 0.40

Similarly prepared:Examcle 84

-'4' -f [5 -5u t vl- 3-ms t ho xvmet hv1-1-(proc-2-envl)-lH-ovrazol-4v I ] methvl] ^f 1, 1' -biohenyl] -2-vl] -Ι,.Η-tetrazole as a white foam (600mg).m.p. 37-40°C T.l.c. ether Rf 0.24

From a solution of Intermediate 48b (l.OOg), methanol (15ml) and concentrated hydrochloric acid (0.5ml).

Example 85

3-Butvl-4 - [ (2'carboxy[1,1'-biphenyl]-4-yl)methyl]-1-methyl-1Hpvrazole-5-carboxyIic acid

From Intermediate 52 according to the method of Example 4.

m.p. 168-170°C.

Analysis Found C,70.2; H,6.3; N,6.8;

^C23^H24^N2°4 requires C,70.4; H,6.2; N,7.1%

Example 86

N- f 4 ' - [ [1-Ethvl-5-(hydroxymethyl ) -3-propv1 -ΙΗ-pyra zol-4vl]methyl] [1,1'-biphenyl]-2-v1]t ri fluoromethanesuIphonamide

BAD ORIGINAL ft

A solution of Intermediate tl (C.89g) in absolute ethanol (25ml) and IN hydrochloric acid (0.7ml) was hydrogenated with 10% palladium on carbon catalyst (3.6ο_; for I'-’.-b. The |«S .filtered into a ficsk containing 2N sodium carbonate sofution (0.7ml) and the s i - v e n t removed ι η v acre . The residue was taker, up in u1 : ·. 1 o r at na ne :15ml, and washed with water (15ml) . The organic iXliC :iy pr&lt;

Exam.cle 87

-· · : v. -J [ 3 - 3 u t y 1 - 1 - e t h v 1 - 5 - (hydroxymethyl) - iH-pvrazo i - 4 -.-1; metnvi j [1,1' -bichenvl;-2-vl,'trif lucrcmethanesulphcnamlde

T.l.c System 3 (130:5:1) Rf 0.12

Analysis found C,3~.S; 3,6.1: Ν',8.2;

requires 1,35.2; .-.,5.; N’,8.5% yl] :1, 1'b iphenvl]-2-yl]t r1flucromethanesulphonamice

Tetra-n-propylammcnium perruther.ate (46mg) was added to a mixture of tne product of Example 8 6 ( 6 3 0mg), N-methylmorpho 1ine N-oxice

1.46c) and 4A molecular sieves (2.5g) in dichloromethane (10ml) and ur y acetonitrile (10mi) and the reaction left for 5min. The reaction was filtered, solvent removed in vacuo and the residue adsorbed, onto silica. The material was purified by chromatography eluting with System A (4:1) to give the title compound as a yellow gum (0.44c).

T.l.c. System A (4:1), Rf 0.64

I.r. (CKSr₅) 1679, 1597, 1366 cm¹.

Similarly prepared :Examsle b$

BAD ORIGINAL A

AP Ο Ο η 2 5 4

Ν - [ 4 ' - [ [ 3-Butν1-1-ethyl-5-formyl-lH-pyrazol-4-yl]methyl] (1, 1'biphenvl]-2-yl]trifluoromethanesulphonamide

T-l.c. 0.56

n.m.r. «*ϋάφ'*250MHz) ί 0.94 (3H,t), 1.44 &lt;3H,t), 1.62 (2H,m), 2.55 &lt;2H,t), 4.15 (2H,S), 4.54 (2H, quad), 7.25-7.45 (7H,m), 7.64 (lH,m),

9.9 (IH,s).

From the product of Example 87.

Examole 90

1-Ethyl-3-Propyl-4-[[2'-[[(trifluoromethyl) sulphonyl]amino]11,1^r — biohenvl]-4-vl]methvl]-lH-pvrazole-5-carboxvlic acid

A solution of sodium chlorite (0.4g) and sodium dihydrogen orthophosphate (2.56g) in water (5ml) was added to a solution of the product of Example 88 (430mg) and 2-methyl-2-butene (4.5ml, 2M solution in THF) in t-butancl (5ml) and THF (10ml) and the resulting mixture stirred for 3h. Solvent was removed in vacuo, the residue taken up in dichloromethane (10ml) and washed with water (10ml). 2N Sodium hydroxide (10ml) was added to the organic solution and the organic layer removed. 2N Hydrochloric acid (-11ml) was added to the aqueous phase which was then extracted with ethyl acetate (2x15ml). The dried organic extracts were evaporated in vacuo to give a yellow gummy solid which was recrystallised from System D (1:1) to give the title compound as a white solid (250mg) m.p. 6872’C.

T.l.c. System A (2:1), Rf 0.53

Similarly prepared:Example 91

3-5utvl-l-ethvl-4 - [ [2'-[[(trifluoromethvl) sulphonyl]amino][1,1'biphenvl-4-vl]methyl]-lH-pyrazole-5-carboxylic acid

T.l.c. System G (300:100:4) Rf 0.55

n.m.r. (CDC1₃, 250MHz) 6 0.87 (3H,t), 1.32 &lt;2H, m) , 1.44 (3H,t), 1.55 (2H,m), 2.56 (2H,t), 4.18 (2H,s), 4.58 (2H,q), 6.67 (lH,br.s), 7.17-7.3 (7H,m), 7.37 (lH,dt), 7.61 (lH,br.d).

From the product of Example 89.