AU651988B2 - Derivatives of mupirocin - Google Patents

Description

OPI DATE 02/03/92 APPLN. ID 83104 91 I AOJP DATE 09/04/92 PCT NUMBER PCT/GB91/01285 INTERNATIinat Ij i IA I I'.IL. I-U .III ,4u1L I 11.. n an..oV. IREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/02518 C07D 405/14, 407/14, 409/14 C07D 413/14, 417/14 (43) International Publication Date: 20 February 1992 (20.02.92) A61K 31/35 (21) International Application Number: (22) International Filing Date: Priority data: 9016895.6 1 August 9105584.8 16 March 9107897.2 13 April PCT/GB91/01285 30 July 1991 (30.07.91) 1990 (01.08.90) 1991 (16.03.91) 1991 (13.04.91) (74) Agent: LOCKWOOD, Barbara, Ann; nithKline Beecham, Corporate Patents, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey KT18 5XQ (GB).

(81) Designated States: AT (European patent), AU, BE (European patent), CA, CH (European patent), DE (European patent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), SE (European patent), US.

Published With international search report.

(71) Applicant (for all designated States except US): BEECHAM GROUP PLC [GB/GB]; SB House, Great West Road, Brentford, Middlesex TW8 9BD (GB).

(72) Inventors; and Inventors/Applicants (for US only) HANNAN, Peter, Charles, Thomas [GB/GB]; SmithKline Beecham Pharmaceuticals, Brockham Park, Betchworth, Surrey RH3 7AJ O'HANLON, Peter, John [GB/GB]; SmithKline Beecham Pharmaceuticals, Brockham Park, Betchworth, surrey RH3 7AJ PEARSON, Neil, David [GB/GB]; SmithKline Beecham Pharmaceuticals, Brockham Park, Betchworth, Surrey RH3 7AJ (GB).

A'

c~ r S (54)Title: DERIVATIVES OF MUPIROCIN (57) Abstract The application discloses C-l heteroaryl ketone derivatives of monic and isomonic acids, their use in antibacterial and antimycoplasmal therapy, and processes for the preparation thereof.

;i WO 92/02518 PCT/GB91/01285 Derivatives of Mupirocin This invention relates to a novel class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine, and also to intermediates for use in the pr" "ration of such compounds.

Mupirocin, the compound of formula

H

3

C

exhibits good activity against Gram positive bacteria, H.influenzae, Leqionella and mycoplasma. It is marketed as a topical formulation by Beecham Group p.l.c. under the Trade Mark 'Bactroban'. Mupirocin (formerly known as pseudomonic acid) is rapidly hydrolysed in vivo to monic acid A, the compound of formula

CH

3

H

3

C

.OH

(B)

CH

3

O

which is inactive.

i I; WO 92/02518 PCT/GB9 2/01285 -2- Various proposals have been made to improve the metabolic stability of mupirocin with respect to enzymatic hydrolysis, by modifying of the C-1 ester functional group, including, for instance, C-1 heterocyclic derivatives (EP-A-0 087 953 and EP-A-0 123 578, Beecham Group) and C-1 amides (EP-A-0 001 914, Beecham Group). In addition, derivatives of monic acids A, B and C characterised in having a ketone functionality at C-l, including inter alia heterocyclic ketones in which the heterocyclic group is a 5- or 6membered ring containing a nitrogen, oxygen or sulphur atom are disclosed in EP-A-0 029 665 (Beecham Group). The examples provided are however mainly alkyl ketones, with no example of a heterocyclic ketone given.

More recently, Klein et al reported (in a poster presented at the Third Annual Chemical Congress of North America, Toronto, June 1988) the preparation of the C-1 fur-2-yl, pyrid-2-yl and N-methylimidazol-2-yl ketones. These are characterised by having the heteroaryl group linked to the ketone carbonyl group by a ring carbon atom which is adjacent to the heteroatom. The limited data provided on these derivatives data showed that these compounds were less active than the analogous butyl and phenyl ketones which in turn were less active than methyl pseudomonate. No results of in vivo activity were reported, the inference being that in vitro activity had not been sufficient to warrant in vivo investigation.

It has now been surprisingly found that with other types of heteroaryl ketone, enhanced antibacterial activity may be obtained. Improvements to in vitro activity and in vivo stability may be observed.

Accordingly, the present invention provides a compound of formula WO 92/02518 PCT/GB91 /01285 -3- OH R

HO

2T T

CH

3

R

H

3 C CH3 o (I)

OH

in which R 1 is hydrogen and R 2 is -COR 3 or

R

1 is COR 3 and R 2 is hydrogen, in which R denotes a heteroaryl group, and excluding the compounds in which R 3 comprises a fur-2-yl, pyrid-2-yl or imidazol-2-yl ring.

Suitably the heteroaryl group includes single and fused rings, each ring suitably comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems.

Examples of suitable rings for use in R 3 include, for example, fur-3-yl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiatriazolyl, pyrid-3-yl, pyrid-4-yl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

Preferred examples of rings for use in R 3 include thien-2-yl, thien-3-yl, fur-3-yl, pyrrol-3-yl, pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, WO 92/02518 PCT/GB91/01285 -4and quinolin-3-yl.

Preferably, when R 3 comprises a 5- or 6- membered heteroaryl ring having a nitrogen or oxygen heteroatom, R 3 is bonded to the ketone carbonyl group of -COR 3 by a ring carbon atom which is not adjacent to said ring heteroatom.

Advantageously said ring carbon atom is located P- to the ring heteroatom. Surprisingly however when R 3 comprises a thienyl group, good biological activity is observed with both thien-2-yl and thien-3-yl i.e. when thienyl is bonded to the carbonyl group via a ring carbon either a- or P- to the ring heteroatom.

Preferably in a ring in R 3 an acidic hydrogen arising from the presence in the ring of an NH moiety, for instance, when

R

3 is pyrazolyl, may be replaced by a substituent.

Preferably when the heteroaryl group of R 3 is substituted, the substitutent (other than fluorine) is located on a ring carbon which is not a- to a ring heteroatom.

When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.

When used herein, the term 'heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Suitably the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need only s WO 92/02518 PCT/GB91/01285 include one heterocyclic ring.

When used herein, the term 'halogen' refers to fluorine, chlorine, bromine or iodine.

Substituents for groups hereinbefore defined as being optionally substituted, for instance alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, include: halogen, cyano, azido, nitro, phthalimido, formyl, carboxy, carboxylate salts, sulpho, sulphonate salts, or oxo; amino, imino, hydrazino, hydrazono, ureido, guanidino, carbamoyl, or sulphonamido, in each of which groups a nitrogen may be further optio..ally substituted by one or two groups (which may be the same or different) selected from the groups listed in subparagraphs and hydroxy, oxyimino, hydroxyimoyl, benzohydroxyimoyl, or mercapto, in each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs and F a group R P wherein R P denotes aryl or heterocyclyl; a group R q wherein R q denotes (C 1 -6)alkyl, (C3- 7 )cycloalkyl, (C2- 6 )alkenyl, (C 3 8 )cycloalkenyl, or

(C

2 _6)alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in subparagraphs and and WO 92/02518 PCT/GB91 /01 295 groups RPCO-, RPOCO-, RqCQ_, R~qCQ_, RPSO-, RPSO 2 R3qS, an 0R3 2 wherein RP and Rq are as defined in subparagraphs and respectively.

Suitable substituents for an alkyl, cycloalkyl, alkenyl or alkynyl group include for example, halogen, cyano, azido, nitro, carboxy, (Cl..

6 )alkoxycarbonyl, carbamoyl, mono- or di-(C 1 6 )alkylcarbamoyl, suipho, sulphamoyl, mono- or di- (C 1 )2 Lupaol amino, mono- or l0 di-(Cl 1 6 )alkylamino, acylamino, ureido,

(C

1 6 alkoxycarbonylamino, 2,2, 2-trichioroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C 1 6)alkoxy, acyloxy, oxo, acyl, 2-thenoyl, (Cl 1 6 )alkylthio, (Cl..

6 )alkylsulphinyl, (Cl..

6 )alkylsulphonyl, hydroxyimino, (Cl.

6 )alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanidino, amidino, or iminoalkylamino.

Suitable substitvo r<;s for an aryl group include, for example, halogen, cyano, (Cl.

6 )alkyl, phenyl, (Cl..

6 )alkoxy, halo(CI-.

6 )alkyl, hydroxy, amino, mono- or di-(Cl..

6 )alkylamino, acylamino, nitro, carboxy,

(C

1 6 )alkoxycarbonyl, (Cl..

6 L-alkoxycarbonyl (Cl 1 6 )alkyl,

(C

1 6 )alkylcarbonyloxy, (Cl-.

6 )alkylthio, (Cl..

6 )alkylsulphinyl, (C 1 6 )alkylsulphonyl, sulphamoyl, mono- or 6 )alkylsulphamoyl, carbamoyl, and mono- or di- (C 1 6 alkylcarbamoyl.

Suitable substituents for a heteroaryl group include, for example, halogen, (Cl 1 6 )alkyl, (C 1 6 cycloalkyl, (C 6 )alkoxy, halo(C...

6 )alkyl, hydroxy, amino, mono- or di- (C 1 6 )alkylamino, carboxy, (Cl..

6 )alkoxycarbonyl, (Cl..

6 )alkoxycarbonyl(Cl..

6 )alkyl, aryl, oxo, non-aromatic heterocyclyl, (C 1 6 )alkylthio, (C 1 6 )alkylsulphinyl, or

(C

1 6 alkylsulphonyl.

WO 92/02518 PCT/GB91/01285 -7- Suitable substituents for a heterocyclyl group include, for example, halogen, (C1- 6 )alkyl, (C1- 6 )alkoxy, halo(C1_6)alkyl, hydroxy, amino, mono- or di-(C 1 -6)alkylamino, carboxy, (C 1 -6)alkoxycarbonyl,

(C

1 l 6 )alkoxycarbonyl(C 1 6 )alkyl, aryl or oxo.

A compound of formula of this invention incorporates a tri-substituted carbon-carbon double bond and may therefore exist as a E- (natural) or Z- (or iso) diastereoisomer. It is to be understood that both diastereoisomers of the compound of formula are included within the scope of this invention, as well as mixtures of the two diastereoisomers. If general it is found that greater activity is associated with the E-isomer of a particular compound of formula and it is therefore preferable to employ this isomer.

Accordingly, in a further aspect, the present invention provides compounds of formulae (Ia) (the E-isomer) and (Ib) (the Z-isomer):

OH

HO 3

H

3 C 0 CH 3 0 H0 (Ia)

OH

0 R"

OH

HO

CH3

H

3 C O CH 3 b o (Ib)

OH

in which R 3 is as hereinbefore defined.

WO 92/02518 PCT/GB91/01285 -8- Compounds of formula (Ia) may conveniently be named '(l-normon-2-yl)ketones'. Normonyl is the trivial name for the 3-[(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3epoxy-5-hydroxy-4-methylhexyl]-3,4-dihydroxytetrahydropyran-2-yl]-2-methylprop-l(E)-enyl radical, as shown in formula (II):

OH

HO

oCH3 HO

H

3 C .0 C H 3 OH

(II)

By analogy, compounds of formula (Ib) may conveniently be named' (l-norisomon-2-yl)ketones'.

It will be appreciated that in compounds of formula substituents of the heteroaryl group R 3 may contain one or more chiral centres. The present invention encompasses all such resultant isomeric possibilities.

Since the compounds of formula of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure are on a wt/wt basis). Impure preparations of the compounds of formula may be used for preparing the more pure forms 30 used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula Preferably, whenever possible, the compounds WO 92/02518 PCT/GB91/01285 -9of the present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise, or are recrystallised, from organic solvents.

solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases wa'Ler of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Examples of compounds within this invention include the following: (Fur-3-yl)-1-(normon-2-yl) ketone; (l-Methylpyrazol-4-yl)-1-(normon-2-yl) ketone; (4-Bromo-l-methyltriazol-5-yl)-1-(normon-2-yl) ketone; (2-Methoxypyrid-5-yl)-1-(normon-2-yl) ketone; Pyrid-3-yl-l-(normon-2-yl) ketone; (l-Methyltriazol-5-yl)-1-(normon-2-yl) ketone; (2-Methoxypyrimidin-5-yl)-1-(normon-2-yi) ketone; (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-yl) ketone; (2-Methylthiopyrid-5-yl)-1-(normon-2-yl) ketone; WO 92/02518 PCr/GB91 /01285 -l-(normon-2-yl) ketone; (Piperidin-1-y2.)pyrimidif-5-y1>1 -(normon-2-yl) ketone; (2-Dimethylaminopyrid-5-y-) (normon-2-yl) ketone; (1-Propylpyrazo2--4-yl) -2.-(normon-2-yl) ketone; (2-Acetylfur-4-yl) -2.-(norrnon-2-yl) ketonie; (Morpholin-4-yl)-pyrinidin-5-yl-]-l(normon-2-yl) ketone; (l-Methylpiperazin-4-yl) -pyrimidin-5-vl] -1-(normon-2-yl) ketone; 7-Dirnmethoxyquinolin-3-yl) (normon-2-yl) ketone; (1-Cyclohexylpyrazol-4-yl) -'2-(norrnon-2-yl) ketone; (Piperidin-2.-yl)pyridin-5-yl (normon-2-yl) ketone; (Thien-3-yl) -1-(norrnon-2-yl) ketone; (Thien-2-yl) -1-(norrnon-2-y.) ketone; (thien-2-yl) 1-2.-(normon-2-yl) ketone; (Methylmercapto) thiazol-5-yl) -1-(normon-2-yl) ketone; [2-(Piperidin-1-yl)thiazol-5-yl)-1-(normon-2-yl) ketone; -1-(norrnon-2-yl) ketone; NVO 92/02518 PCr/GB91/01285 (Hydroxymethyl)thien-5-yl]- 1 (normon-2-yl) ketone; (rormon-2-yl) ketone; (Pyrrol-3-yl) -1-(normon-2-yl) ketone;? [5-Bromo-(thien-2-yl) 1-1- (normon-2-yl) ketone; 12- (Methylsuiphinyl) thiazol-5-yl (normon-2-yl) ketone; (Dimethylarninoiminornethyl)thien-2-yl1-l- (normon-2-yl, ketone; [2-Dromo(py (normon-2-yl) ketone; (Pyrid-4-yl) -1-(normon-2-yl) ketone; (Piperidinyl)pyrimidin-5-yl)I--(norisomon-2-yl) ketone; (2-Dimethylaminopyrid-5-yl) -1-(norisomon-2-yl) ketone; and (Fur-3-yl) -2.-(norisomon-2-yl) ketone.

Compounds of the present invention may be prepared by methods known for the preparation of caj3-unsaturated ketoers. Sm fteepoesswl emr prpit than otesom. fteepoesswl emr prpit Suitably, compounds of formula may be prepared by a process which comprises treating the acid of formula (III): WO 92/02518 PCT/GB91/01 285 -12-

OZ

3 CH3 ZO CH2C CHCOOH

CH

3 H3C 0 (III) oz in w'h~ h Z, Z and Z 3 ae the same or different and each is hydrogen or a hydroxyl-protecting group, or an activated derivative thereof, with an organometallic reagent; and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Suitable organometallic reagents include: a Grignard reagent of the formula R 3 MgX in which R 3 is as defined with respect to formula and X represents chlorine, bromine or iodine, which reaction may optionally be carried out in .the presence of copper(I) iodide as catalyst; (ii) an organolithium reagent of formula R 3 Li in which R 3 is as defined with respect to formula (iii) an organomanganous reagent of the formula R 3 MnC1 in which R3 is as defined with respect to formula and (iv) an organocerium reagent R 3 Li-CeX 3 in which

R

3 is as defined with respect to formula and X represents chlorine, bromine or iodine.

WO 92/02518 PCT/GB91/01285 -13- The reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is dependent upon the specific requirements of the organometallic reagent. Preferably, the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran.

The reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at ambient temperature or below. The period for which the reaction is allowed to proceed depends upon the particular starting materials employed. The course of the reaction may be followed by conventional methods such as thin layer chromatography and the reaction may be terminated when an optimum quantity of product is present in the reaction mixture.

Compounds of formula (III) will be recognised by the skilled man as monic acid (E-isomer) or isomonic acid (Z-isomer), or hydroxyl protected derivatives thereof, as described in GB 1 587 058 (Beecham Group).

Suitable activated derivatives of the acid of formula (III) include thio-esters of formula (IV): 3 3 OZ CH3 Z CHCOS

H

3 C 0 0 I (IV) in which Z 1

Z

2 and Z 3 are as .iereinbefore defined and the moiety 1 M-'M-*l~rrCr- I. ~i WO 92/02518 rC i /GB9i/01285 -14represents a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted.

Preferred thio-esters are of formula (IVa):

OZ

3

CH

3 ZO 20

CH

2 C CHCOS CH3

N

H

3 C o (IVa)

OZ

in which Z 1

Z

2 and Z 3 are as hereinbefore defined.

A compound of formula (IVa) may be prepared by treating of a compound of formula (III) with 2,2'-dipyridyl disulphide in the presence of triphenylphosphine, by analogy with the method described by E.J, Corey and D.A Clark in Tetrahedron Letters, 1979, 31, 2875.

Other suitable activated derivatives of the acid of formula (III) include mixed anhydrides of the formula OZ 3 CH 3 Z CH2C== CHCOOCOOR

H

3 C C 0 M oz (V)

OZ

in which Z 1

Z

2 and Z3 are as hereinbefore defined, and R 4 is (C 1 6 )alkyl; WO 92/02518 PCT/GB9I/01285 and of the formula (VI): OZ3 CH3 z 20 5 6 C3 CH2C CHCOOPOR

R

H 3 O

OZ

1

(VI)

in which Z 1

Z

2 and Z 3 are as hereinbefore defined, and R and R 6 are the same or different and each denotes an aryl group, for instance phenyl, or a (C 1 _6)alkoxy group, for instance ethoxy.

A compound of formula may be obtained by treating a compound of formula (III) with for instance a suitable derivative of the formula R 3 0COCl using the method described by Crimmin M.J. et al., J.C.S. Perkin I, 1989, 2047.

A compound of formula (VI) may be obtained by treating a compound of formula (III) with CLPOR 5

R

6 using the method described by Baxter A.J.G. et al., Tetrahedron Letters, 1980, 21, 5071.

Further suitable activated derivatives of the acid of formula (III) include amides of the formula (VII): OZ3 CH 3 2 0 17 8 0Z O CHC--0 CHCONOR R

H

H

3 C 0 0

(VII)

r WO 92/02518 PCT/GB91/0128'5 -16in which Z 1

Z

2 and Z 3 are as hereinbefore defined, R 7 and

R

8 are the same or different, and each is (C 1 _6)alkyl, or the substituents R 7 and R 8 form a (C2_ 7 )alkylene chain; and of the formula (VIII):

OZ

3

CH

3 2 0 9 Z CH2C- CHCONOR R CH3 H 3C OZ (VIII) in which Z Z 2 and Z are as hereinbefore defined and R and R i0 together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring.

A preferred compound of formula (VII) is the N-methoxy- N-methylamide R 7 and R 8 is each methyl) as described in PCT/GB90/01932 (Beecham Group). The reaction of an N-methoxy-N-methylamide with an organolithium or a Grignard reagent to form a ketone is described by Nahm and Weinreb in Tetrahedron Letters, 1981, 3815.

A preferred amide of formula (VIII) is the imidazol-1-yl derivative. The reaction of an a,P-unsaturated acid or its imidazolyl derivative with a Grignard reagent is described in Chem. Ber., 1965, 95 1284.

30 Amides of formulae (VII) and (VIII) may suitably be obtained from monic acid or isomonic acid by treatment thereof with iso-butyl chloroformate in tetrahydrofuran, in the presence of triethylamine, at a temperature of from -5 to 20 0 C, for about 30 min, to form an intermediate mixed anhydride I ;A WO 92/02518 PCT/GB91/01285 -17- (monic/isomonic acid isobutyl carbonic anhydride). This intermediate may then be reacted with an amine HN(OR 7

)R

8 in dichloromethane at about 20 0 C for about 2h or an amine

HNR

9

R

10 .HC1 in the presence of triethylamine and p-dimethylaminopyridine, in THF, at about 20 0 C, to form the compound of formula (VII) in which Z 1

,Z

2 and Z 3 is each hydrogen (with R 3

,R

7

,R

8

R

9 and R 10 as hereinbefore defined). The hydroxyl groups thereof may be protected by treatment with a suitable hydroxyl protecting agent such as chlorotrimethylsilane, in a solvent such as THF in the presence of triethylamine and 4-dimethylamino pyridine as a catalyst.

Suitably a thio-ester of formula (IV) is treated with an organomanganous reagent of formula R 3 MnCl, as hereinbefore defined.

Suitably an amide of formula (VII) or (VIII) is treated with an organolithium reagent of formula R 3 Li as hereinbefore defined.

Preferably, a compound of formula is prepared by a process which comprises treating a compound of formula (VII) as hereinbefore defined, with an organolithium reagent of formula R 3 Li as hereinbefore defined.

Suitable organometallic reagents may be prepared according to conventional procedures.

30 Suitable organomanganous reagents of the formula R 3 MnCl may be conveniently preDared by addition of an organolithium reagent R 3 Li to a lution of manganous chloride and lithium chloride in dry THF, or a suspension of anhydrous manganous chloride in dry THF. An excess of R 3 MnCl is preferably employed. Alternatively, a Grignard reagent may be used in place of the organolithium reagent, to generate the UIL i. -7~ WO 92/02518 PCI'/GB91/01285 -18organomanganous reagent R 3 MnC1.

Other organomanganous reagents which may be used instead of

R

3 MnC1 include:

(R

3 3 MnLi or (R 3 3 MnMgX in which X is as hereinbefore defined, as described in Synthetic Communications, 1979, 9, 639; (ii) R 3 MnI in ether; as described in Synthetic Communications, 1979, I, 639; and (iii) R 3 MnBr in ether, as described in Tetrahedron Letters, 1976, 3155.

As in the case of R 3 MnC1, the above organomanganous reagents may be prepared in situ when required.

Organocerium reagents may be generated in situ by treating an organolithium compound of the formula R 3 Li, in which R 3 is as hereinbefore defined, with cerium (III) halide, by analogy with the procedure described by Imamoto et al; J.Chem. Soc., Chem. Commun, 1982, 1042.

Further processes for the preparation of compounds of formula are described in EP-A-0 029 665 (Beecham Group) and include treating an allylic alcohol of formula (IX): OZ 3 CH3

OZO

Z 0 CH3 U2C('-CHCHOHR 3 HC 0(IX)

OZ

iY WVO 92/02518 PCT/GB91/01285 -19in which R 3 Z, Z 2 and Z are as hereinbefore defined, with an oxidising agent which converts allylic alcohols into a,-unsaturated ketones, and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Suitable such oxidising agents include activated manganese dioxide, pyridinium dichromate and pyridinium chlorochromate.

Conveniently, the oxidation reaction is carried out in a non-polar organic solvent such as, for example, benzene or toluene.

Compounds of formula (IX) are novel and useful intermediates in the aforementioned process.

Accordingly, the invention further provides compounds of formula (IX) as hereinbefore defined.

An allylic alcohol of formula (IX) may be prepared by treatment of the corresponding aldehyde of formula 3 CH 3 z 20

CH

2 C CHCHO CH3

H

3 C 0O OZ 0(X) in which 1

Z

2 and Z 3 are as hereinbefore defined, with an organometallic reagent as hereinbefore defined, and thereafter, and if necessary, removing any hydroxyl-protecting groups.

1~ Ci WO 92/02518 PCT/GB91'/01285 An aldehyde of formula may be treated with a Grignard reagent of formula R 3 MgX or, more preferably, with an organocerium reagent R 3 Li-CeX 3 as hereinbefore defined.

An aldehyde of formula may be prepared by treatment of a amide of formula (VII), as hereinbefore defined, with a suitable reducing agent such as diisobutyl-aluminium hydride, and thereafter, and if necessary, removing any hydroxyl-protecting group. It is found that in practice, such treatment of the E-isomer of an amide of formula (VII) in which R 7 and R 8 is each methyl leads to a mixture of the E- and Z-isomers of the aldehyde of formula These isomers may be readily separated by conventional chromatography, thereby affording a convenient source of starting material for the subsequent preparation of Z-isomer compounds of formula Other suitable methods of preparation of an aldehyde of formula are described in EP-A-0 029 665 (Beecham Group).

A compound of formula may also be prepared by treating a ketone of formula (XI): 3 oz 2 ZO

CH

2

COCH

3 CH3

H

3 C 0 OZ

(XI)

in which Z 1

Z

2 and Z 3 are as hereinbefore defined, with a terminal alkyne of the formula (XII):

HC=C-R

3

(XII)

WO 92/02518 PCT/GB91/01285 -21in which R 3 is as hereinbefore defined, to form an intermediate which is treated with tris(triphenylsilyloxy)vanadate and triphenylsilanol, as described by H. Pauling in Helvetica, 1976, 59, 1233 and G.L. Olson, Helvetica, 1976, 59 567; and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Such a reaction may lack stereoselectively and accordingly may lead to the formation of both the E- and Z-isomers of the compound of formula which may then be readily separated by conventional separation procedures such as chromatography.

The preparation of a compound of formula (XI) is described in GB 1 587 060 (Beecham Group).

The skilled man will readily appreciated that the final obtention of either the E- or the Z-isomer of a compound of formula as required, may be conveniently effected by selecting, as starting material, a precusor containing a double bond which already has the desired E- or Z-stereochemistry. Alternatively processes may be used in which the double bond sterochemistry and, perhaps also the double bond itself, is generated during the course of the reaction. In addition, a compound of formula (Ib) may be converted into the corresponding compound of formula (Ia) or vice-versa by suitable isomerisation procedures, such as those described by Sonnet in Tetrahedron, 1980, 36, 55' and include photo-chemical and addition-elimination methods.

WO 92/02518 PCT/GB91/01285 -22- When used herein, the term 'hydroxyl protecting group' refers to any such group known in the art which may be removed without disruption of the remainder of the molecule.

Suitable hydroxyl-protecting groups include those described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981.

The hydroxyl groups of the compounds of formulae (III) to (XI) may be protected at any stage of the above processes, using conventional methods. The hydroxyl protecting group may be removed by methods known in the art, including enzymatic methods.

Particularly suitable hydroxyl protecting groups are silyl groups since these are readily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, of the formulae below:

L

3 SiY L 3 SiO-C=NSiL 3

L

2 SiY 2 L

L

3 SiNL 2 L3SiNHSiL 3

M:

3 Si-N "N

L

3 SiNHCOL

L

3 SiNHCONHSiL 3 BuMe2Si-N N LNHCONHSiL 3 BuMe2Si-O-SO2-CF 3 wherein Me denotes methyl and tBu denotes t-butyl, Y is halogen and each group L is independently selected from hydrogen, (C 1 -6)alkyl, (C 1 _6)alkoxy, aryl or aryl(C 1 -4)alkyl. A preferred silyating agent is trimethylsilyl chloride. Particularly suitable protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal.

I L- WO 92/02518 PCT/GB91/01285 -23- The glycol function of the compounds of formulae (III) to (XI) may be protected by forming a cyclic derivative using a compound of formula (XIII): 5R12

R

11 C OR 1 3

(XIII)

OR

14 wherein R 11 is hydrogen or (Cl_6)alkyl and each of R 12

R

13 and R 14 is (C 1 _6)alkyl. In the cyclic derivative Z 1 and Z 2 together are a moiety:

R

1 1

OR

1

\C

wherein R 1 5 is C 1 6 )alkyl.

Suitably R 11 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen. The groups R 12

R

13 and R 14 are suitably methyl, ethyl, n- or iso-propyl, or iso-, sec- or t-butyl; most suitably methyl.

Similarly the hydroxyl groups of a compound of formula (I) may be protected prior to conversion to a further compound of formu.la as described above.

S" In each case the hydroxyl protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K.

WO 92/0: 8 PCT/GB91 01283 -24- Luk and N.H. Rogers, in 'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I, 1979, 308.

This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.

The compositions may be formulated for administration by any route, and would depend on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice Oral liquid preparations may be in the form of, for example, i aqueous or oily suspensions, solutions, emulsions, syrups or 30 elixirs, or may be presented as a dry product for reconstitution 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 syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example 1; WO 92/02518 PCT/GB91/01285 lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl E-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, suc as 'Harry's Cosmeticology' 7th Ed., ed Wilkinson J.B. -nd Moore George Goodwin, London, 1982, and the British Pharmacopoeia.

Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability the composition can be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial. The drug can be sterilised by 30 exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.

For topical application to the ear, the drug may be made up into a suspension in a suitable liquid carrier, such as 1 1 WO 92/02518 PCT/GB91'/01285 -26water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.

For topical application to the eye, the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The dosage employed for compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg of the drug.

Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis, will generally contain a suspension of the drug in an oily vehicle.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the drug, depending on 'he method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg, of the drug. The dosage as employed for treating an adult human (of typical weight about 70 kg) will preferably range from 100 mg to 3 g, per day, for instance 30 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.

Alternatively, the drug may be administered to non-human animals as part of the total dietary intake. In this case the amount of drug employed may be less than 1% by weight of WO 92/02518 PCT/GB91/01285 -27the diet and in preferably no more than 0.5% by weight. The diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for admixture with the foodstuff. A suitable method of administration of the drug to a non-human animal is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 .Lg/ml, for example 5-200 .g/ml, is suitable.

The compounds of this invention are useful for the treatment of bacterial and myc-plasma-induced infections in non-human and human animals, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in human animals, mastitis in cattle, and respiratory infections in non-human animals such as pigs and cattle.

Accordingly in a further aspect, the present invention provides a method for treating the human or non-human animal which method comprises administering an effective amount of a compound of formula as hereinbefore defined, to a human or non-human animal in need of such therapy.

Alternatively, a pharmaceutical composition as hereinbefore described may be employed in the treatment.

In particular aspects of the treatment there are provided methods for treating bacterial infections of human or non-human animals, especially respiratory infections in human or non-human animals.

The compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus, for instance H.influenzae Ql; Branhamella,for instance WO 92/02518 PCT/GB91'/01285 -28- B.Catarrhalis 1502; Streptococci, for instance S.pyoqenes and S.pneumonia PU7; and Staphylococci, for instance S.aureus Oxford, and against mycoplasma. In addition, compounds of this invention are active against Staphylococci organisms such as S. aureus and S. epidermis which are resistant (including multiply-resistant) to other antibacterial agents, for instance, P-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides and lincosamides.

The compounds of this invention are also active against mycoplasma-induced infections, in particular infections caused by Mycoplasma fermentans, which has been implicated as a co-factor in the pathogenesis of AIDS.

Accordingly in a further aspect, the present invention provides a method of treating humans infected with M.

fermentans, in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula In a further aspect, the present invention provides a compound of formula for use in the manufacture of a medicament for antibacterial and/or antimycoplasmal therapy in human and non-human animals.

No adverse toxicological effects are expected from the administration of a compound of formula The following Examples illustrate the invention, but are not intended to limit the scope in any way.

WO~ 92/'02518 PCT/GB91/01285 -29- N-Methoxy-N-methyl-6,7,13-0-tris(trimethylsilyl)monamide N,O-Dimethyl hydroxylamine hydrochloride (1.95g, 20mmol) was dissolved in dichloromethane and aqueous sodium hydroxide (20ml:10ml, 2.5M). The aqueous layer was re-extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml). The organic layer was dried (MgSO 4 and added to monic acid isobutyl carbonic anhydride (10mmc i) After stirring at 20 0 C for lh the reaction mixture was diluted with dichloromethane and washed with saturated aqueous scium hydrogen carbonate and brine.

The combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgSO 4 and concentrated to give the amide, This was taken up in tetrahydrofuran (50ml) and treated with triethylamine (8.4ml, 60mmol) and chlorotrimethylsilane (6.3ml, 50mmol). After 10 minutes a catalytic amount of 4-N,N-dimethylaminopyridine was added.

After 2h at room temperature the reaction was diluted with diethyl ether, filtered, and the filtrate evaporated. The residue was taken up in hexane, refiltered, and washed with water and brine. After drying and evaporation the residue was taken up in hexane (20ml) and allowed to crystallise at 0-20 0 C, to give the required product as a colourless crystalline solid (3.0g, 50%) mp 78-79 0

C.

6,7,13-0-Tris(trimethylsilyl)monaldehyde Di-isobutylaluminium hydride (1.OM in hexane) (20.00ml, 20.00mmol) was added dropwise to a solution of Nmethoxy-N-methyl-6,7,13-0-tris(trimethylsilyl)monamide (l1.00g, 18.24mmol) in THF (150ml) cooled to -78 0 C whilst maintaining the temperature below -70 0 C. After 3h at -70 0

C,

WO 92/02518 PCT/GB91i01285 methanol (20ml) and saturated sodium sulphate solution were added. The precipitated solids were removed by filtration, the filtrate dried (MgSO 4 and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave initially the Z-isomer (Vide infra), followed by the E-isomer, the title compound, (4.90g, 50%) as a colourless oil; vmax (liquid film) 2960, 2900, 1675, 1250, 1120cm- 1 6

H

(CDC1 3 0.06-0.17 (27H, m, x SiCH 3 0.90 (3H, d, J 7.1Hz, 17-H 3 1.19 (3H, d, J 6.4Hz, 14-H 3 1.32-1.41 (1I, m, 12-H), 1.46-1.62 (2H, m, 9-Hz), 1.74-1.83 (1H, m, 2.10 (1H, dd, J 15.2 and 10.8Hz, 2.20 (3H, s, 15-H 3 2.56-2.73 (3H, m, 4, 10 and 11-H), 3.38 (1H, dd, J 9.1 and 3.53 (1H, d, J 11.0Hz, 16-H), 3.76-3.93 (4H, m, 5, 7, 13 and 16-H), 5.96 (1H, d, J 8.0Hz, 10.00 (1H, d, J 8.0Hz, m/z 544 (M 117 (100%).

6,7,13-0-Tris (trimethylsilyl)isomonaldehyde Di-isobutylaluminium hydride (1.OM in hexane) 40.00ml, 40.00mmol) was added dropwise to a solution of N-methoxy-Nmethyl-6,7,13-0-tris(trimethylsilyl)monamide (12.00g, 20.00mmol) in THF (150ml) cooled to -78 0 C whilst maintaining the temperature below -70 0 C. After 3h at -70 0 C, methanol and saturated sodium sulphate solution (50ml) were added. The precipitated solids were removed by filtration, the filtrate dried (MgSO 4 and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (2.03g, 19%) as a colourless oil; 5 H (CDC1 3 0.06-0.17 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.1Hz, 17-H 3 1.19 (3H, d, J 6.4Hz, 14-H 3 1.32-1.41 (1H, m, 12-H), 1.46-1.62 (2H, m, 9-H 2 1.74-1.83 (1H, m, 2.01 (3H, s, 15-H 3 2.53- 2.66 (4H, m, 4-H 2 10-H, 11-H), 3.39 (1H, d, J 8.6Hz, 16-H), 3.51 (1H, d, J 11.3Hz, 3.55-3.81 (4H, m, 5-H, 7-H, 13-H, 16-H), 5.93 (1H, d, J 8.1Hz, 9.91 (1H, d, J WO 92/02518 PCT/GB9J /01285 -31- 8.2Hz, m/z (NH 3 430 100%).

Example 1 (Fur-3-yl) -1-(norrnon-2-yl) ketorie a) (Fur-3-yl) 13-O-tris-trimethylsjlvnormon-2yl) ketone 3-Brornofuran (1.37g, 9.30mmol) in THF (2Oml) was added dropwise to n-butyllithiun (1.6M in hexane) (6.60m1, 10.22mmol) in TEF (l1rnl) whilst maintaining the temperature below -60 0 C. After 20rnins at -70 0

C

N-rnethoxy-N-methyl-6, 7, 13-0-tris (trimethylsilyl) monaimide (4.10g, 6.Blmmol) in THF (l0ml) was added dropwise whilst maintaining the temperature below -65 0 C. After lh at -70 0

C

and 1h at -60 0 C acetic acid (0.53m1) was added followed by water (lO0mi) Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure, and purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (3.67g, 88%) as a white foam; 8H (CDCl 3 0.09-0.17 (27H, mn, 9 x SiCH 3 0.89 (3H, d, J 7.0Hz, 17-H 3 1.19 (3H, d, J 6.3Hz, 14-H 3 21.36-1.41 (1H, m, 12-H), 1.55 (2H, br.s, 9-Hz), 1.77-1.86 2(1H, mn, 2.08 (1H, dd, J 14.6 and 10.5Hz, 2.24 (3H, s, 15-H 3 2.59 (1H, d, J 14.4Hz, 2.66-2.70 (2H, m 10 and 11-H), 3.39 (1H, dd, !1 9.0 and 2.4Hz, 3.55 (1H, d, J 11.4Hz, 16-H), 3.80-3.92 (4H, m, 5,7,13 and 16-H), 648 (1H, s, 6.79 (1H, d, I 1.3Hz, 51-H), 7.40 (1H, t, J 1.6Hz, 51-H), 7.99 (1H, s, 21-H); mhz (L.C.M.S.

therinospray) 628 (M 4 141 (Found: M+, 610.3154. C 30

H

54 0 2

S'

3 requires M, 610.3177).

WO 92/02518 WO 922518PU/GB9I001288 -32b) (Fur-3-Yl) (normon-2-yl) ketone The above ketone (0.26g, 0.43mxnol) and 4-dimethylaminopyridine dihydrochloride (6.6 x 10- 6 rol) in methanol (5mi) were stirred at room temperature for Saturated sodium hydrogen carbonate solution (10mi) then water (2Oml) were added. Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol in dichloromethane as eluent gave the title compound (0.122g, 73%) as a white foam; vmax (KBr) 3424, 2969, 2924, 1655, 1609 1156cm- 1 Xmax (EtOH) 258nm (e 11, 420) (CDCl 3 0.93 (3H, d, J 7.1Hz, 17-H 3 1.22 (3H, d, J 6.3Hz, 14-H 3 1.29-1.41 (1H, m, 12-H), 1.71-1.77 (2H, m, 9-Hz), 1.96-2.04 (1H, m, 2.27 (3H, s, 15-H 3 2.35 (1H, dd, J 14.6 and 9.0Hz, 2.64-2.73 (2H, in, 4 and 11-H), 2.78-2.83 (1H, m, 10-H), 3.51 (1H, dd, J 8.6 and 1.8Hz, 3.59 (1H, dd, J 11.5 and 1.8Hz, 16-H), 3.74-3.96 (4H, m, 5,7,13 and 16-H), 6.51 (1H, s, 6.80 (1H, d, J 1.8Hz, 41-H), 7.42 (1H, t, J 1.8Hz, 51-H), 8.01 (1H, s, 21H;8 (CDCl 3 12.7 20.1 20.8 (C-14), 31.6 39.7 42.8 43.3 55.6 61.3 65.4 68.9 70.4 71.4 75.1 109.0 123.2 129.6 125 144.1 (C21 or 147.0 (C21 or 156.7 185.7 M/z& 394 95 (Found: M, 394.2002. C 2 11 0 7 requires M, 394.1992).

Subsequent recrystallisation from ethyl acetate gave white micro-crystals (m.p.95-96 0 (Found: C, 62.5; H, 7.7.

C

21

H

30 0 7 1/2H 2 0 requires C, 62.5; H, WO 92/02518 PCIT/GB9I /01285 -33- Examole 2 (1-Methvlpyrazol-4-vl) -1-(normon-2-vl) ketone a) (1-Methylpyrazol,-4 v)-l-(6,7,13-0-tris--trimethylsilylnormon--2-vl) ketone 4-Bromo-l-methylpyrazole (0.97g, 6.Omxnol) in THF (10mi) was added to n-butyllithium (1.6M in hexane) (3.44m1, in THF (25ml) whilst maintaining the temperature at -70 to 0 C. After ten minutes at -70 0

C

N-methoxy--N-methyl-6, 7, 13-0-tris (trimethylsilyl) monamide (0.60g, lmxnol) in THF (l0mi) was added dropwise maintaining the temperature below -65 0 C. After l.5h at -70 0 C acetic acid (0.32ml) was added followed by water (J50m1) The solution was extracted with ethyl acetate, dried (MgSO 4 evaporated to dryness under reduced pressure and purified by flash chromatography using ethyl acetate/hexane as eluent to give the title compound (0.36g, 58%) as a white foam; 8H (CDCl 3 0.09-0.16 (27H, m, 9 x SiCH 3 0.90 (3H, d I 7.0Hz, 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.32-1.45 (1H, m, 12-H); 1.50-1.62 (2H, m, 9-H 2 1.77-1.86 (1H, m, 2.10 (1H, cid, J 14.6 and 10.6Hiz, 2.25 (3H, s, 3 2.60 (1H, d, J 14.6Hz, 2.63-2.72 (2H, m, and 11-H), 3.39 (1H, cid, J 8.9 and 2.4Hz, 3.55 (1H, di, J 11.3Hz, 16-H), 3.80-3.93 (4H, m, 5,7,13 and 16-H), 3.93 s, NCH 3 6.51 (1H, s, 7.87 (1H, s, 3' or 7.0(1H, s, or 51-H); m/z 62.4 117 (Found: M+ 1 624.3428. CH 5

NO

6 i requires M, WO 92/02518 PCTr/GB91 701285 -34b) (1-Methylpyrazol-4-yl) -1-(normon-2-yl) ketone The above ketone (0.35g, 0.56mnol) and 4-d,.imethylaminopyridine dihydrochioride (1.1mg) in methanol (7m1) were stirred at room temperature for 0.5h. Saturated sodium hydrogen carbonate solution (l0mi) and water (20m1) were added and the solution extracted with ethyl acetate.

Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane as eluent gave the title compound (0.16g, 70%) as a white foam; vmax (KBr) 3423, 2969, 2925, 1648, 1543, 1451, 1216, 1111cm- 1 %max (EtOH) 269.5nm (E 19, 180) 8H (CDCl 3 0. 94 (3H, d, J 7.0 Hz, 17-H 3 1.22 (3H, d, J 6.3Hz, 14-H 3 1.28-1.41 (1H, m, 12-H), 1.70-1.77 (2H, m, 9-Hz), 1.98-2.12 (1H, m, 2.26 O3H, s, 15-H 3 2.35 (1H, dd, J 14.5 and 8.8Hz, 4-H), 2.64-2.83 (3H, m, 4, 10 and 11-H), 3.48-3.51 (1H, m, 6-H), 3.58-3.63 (iR, m, 16-H), 3.75-3.96 (4H, m, 5,7,13 and 16-H), 3.93 (3H, s, NCR 3 6.54 (iH, s, 7.87 (1H, s, 3' or 7.90 (1H, s, 3' or 8-C (CDCl 3 12.8 (C-17), 20.1 20.8 31.7 39.3 (NCH 3 39.8 42.8 43.3 55.6 61.2 (C-11), 65.4 68.9 70.5 71.2 175.1 123.4 126.0 132.8 (C-31 or 51), 140.4 or 156.4 185.2 rn/. 408 (M, 109 (Found: 408.2264. C 21

H

32

N

2 0 6 requires M, 408.2260).

Example 3 -1-(normon-2-yl) ketone 4-Bromo-i-methyltriazole (0.97g, 6.Ommol) in THE' (l0mi) was added dropwise to n-butyllithium (1.6M in hexane) (3.44m1, 5.SMniol) in THF (25m1) cooled to -70 0 C, whilst maintaining the temperature above -60 0

C.

WO 92/02518 PCT/GB91/01285 N-methoxy-Nmethyl-6,7,13-0-tris(trimethylsilyl)monamide (0.60g, Immol) in THF (5ml) was added dropwise at -650C.

After 2h at -70 0 C and Ih at -50 0 C the solution was warmed to 0 C over lh and kept at that temperature for lh. Acetic acid (0.32ml) was added followed by saturated sodium hydrogen carbonate solution (10ml). Extraction with ethyl acetate (3 x 50ml), drying (MgS0 4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave impure (4-bromo-l-methyltriazol-5-yl)-1-(6,7,13-0-tris-trimethylsilyl-normon2-yl) ketone (0.085g). Further elution with 6% methanol in dichloromethane gave the required ketone (0.13g, The protected ketone was treated with 4-dimethylaminopyridine dihydrochloride (0.25mg) in methanol (3ml) at room temperature for 1.5h. Saturated sodium hydrogen carbonate solution (10ml) was added and the solution extracted with ethyl acetate. Drying (MgS0 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 6% methanol in dichloromethane as eluent gave the title compound (0.013g, 50%) as a white foam, giving an overall yield of 28%; vmax (KBr) 3423, 2968, 2923, 1656, 1607, 1439, 1287, 1111, 1083cm- 1 ax (EtOH) 278nm (em 14,128); 8H (CDC1 3 0.94 (3H, d, J 7.0Hz, 17-H 3 1.22 (3H, d, J 6.3Hz, 14-H 3 1.27-1.38 (1H, m, 12-H), 1.65-1.82 (2H, m, 9-H 2 2.02-2.10 (1H, m, 2.30 (3H, s, 15-H 3 2.42 (1H, dd, J 15.0 and 9.3Hz, 2.70 (1H, dd, J 6.2 and 2.6Hz, 11-H), 2.75-2.83 (2H, m, 4 and 10-H), 3.48-3.56 (1H, m, 3.60 (1H, d, l 10.0Hz, 16-H), 3.80-3.86 (3H, m, 5,7, and 13-H), 3.91 (1H, dd, J 11.8 and 2.8Hz, 16-H), 4A 4.27 (3H, s, N-CH 3 6.94 (1H, s, 8 C (CDC1 3 12.8 20.9 21.1 31.6 39.1 (NCH 3 39.8 42.8 43.6 55.6 61.3 65.5 68.9 70.4 71.4 (C-13), 74.8 122.6 123.2 134.0 162.8 180.0 m/z 489 (M 487 (M 43 (Found: M 487.1343. C 20

H

30

N

3 0 6 Br requires M, 487.1318).

II

WO 92/02518 PCT/GB91 01285 -36- Example 4 (2-Methoxypyrid-5-vl)-1-(normon-2-yl) ketone a) (2-Methoxypyrid-5-vl)-1-(6,7,13-0-tris-trimethylsilyl normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (3.27ml, 8.22mmol) was added dropwise to 5-bromo-2-methoxypyridine (0.99g, 5.72mmol) in THF (40ml) cooled to -85 0 C, maintaining the temperature below -80 0 C. After a further lh at -85 0 C, cerium trichloride (1.29g, 5.24mmol) was added and reaction mixture maintained at -80 0 C for lh. 6,7,13-0-Tris- (trimethylsilyl)monaldehyde in THF (10ml) was added dropwise at -80 0 C. After 1.5h at -85 0 C, acetic acid (0.30ml) then water (40ml) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the impure diastereomeric alcohols (1.77g, 78%) as a colourless oil.

Manganese dioxide (2.21g, 25.4mmol) and benzene (25ml) were added and the reaction mixture heated to reflux under Dean and Stark conditions for 0.5h. The solids were removed by filtration and washed with dioxane. The filtrates were combined and evaporated to dryness under reduced pressure.

Purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (1.25g, 71%) as a colourless oil; 8 H (CDC13) 0.10-0.16 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.0Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.33-1.44 (1H, m, 12-H), 1.53-1.64 (2H, m, 9-H 3 1.75-1.91 (IH, m, 2.14 (1H, dd, J 15.1 and 11.0Hz, 2.23 (3H, s, 15-H 3 3.40 (1H, dd, J 8.9 and 2.3Hz, 3.57 (1H, d, J 11.4Hz, 16-H), 3.81-4.00 (4H, m, 5,7,13 and 16-H), 4.00 (3H, s, OCH 3 6.74 (1H, s, 6.78 (1H, d, !J 8.8Hz, 8.15 (1H, dd, J 8.7 and 1.2Hz, 8.78 (1H, d, J 2.2Hz, 3-NOBA/Na) 674 (MNa 652 (M 136 (100%).

~L

W092/02518 PCT/G B91 /01285 -37b) j,,-Methoxvpvrid-5-vl)-l-(normon-2-vl) ketone The above ketone (0.30g, 0.46mmol) and 4-dimethylaminopyridinri dihydrochioride (4.0mg, 2.1 x 59 10- 5 mol) in methanol (4ml) were stirred at room temperature for lh. Saturated sodium hydrogen carbonate solution (Srnl) and water (20m1) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification as eluent gave the title compound (0.135g, 68%) as a white foam; Vmax (KBr) 3421, 2969, 2916, 1656, 1601, 1250cm- 1 ;Xa (EtOH) 287.5 (em 19, 290) 8H (CDCl 3 0. 94 (3H, d, J 7.1lHz, 17-H 3 1 1.22 (3H, d, J 6.3Hz, 14-H 3 1.29-1.42 (1H, m, 12-H), 1.72-1.75 (2H, m, 9-Hz), 1.96-2.10 (111, m, 2.23 (3H, s, 15-H 3 2.39 (1H, dd, J 14.7 and 9.0Hz, 2.68-2.85 (3H, m, 4, and 11-H), 3.49-3.53 (1H, m, 3.60 (1H, dd, J 11.8 and 2.0Hz, 16-H), 3.76-4.00 (4H, mn, 5,7,13 and 16-H), 4.00 O3H, s, OCH 3 6.75 (1H, s, 6.79 (1H, di, J 8.6Hz, 31-H), 8.15 (1H, dd, 1 8.6 and 2.4Hz, 41-H), 8.77 (11H, d, J 2.3Hz, 61-H1); 5C )CD 3 0D) 17.3 20.3 20.4 33.0 41.7 43.6 44.3 54.6 (OCH 3 56.8 61.2 66.4 70.0 70.6 71.6 (C-i1 76.3 111.8 123.0 129.9 150.0 159.3 167. 8 190.7 M/zK thioglycerol) 458 /kMi, 36 (100%).

Example Pyrid-3-yl-l- (normon-2-yl) ketone a) Pyrid-3-yl-1-' ,..7-13-0-tris-trimethysilnornoi-2- Yi) ketone 3-Bromopyridine (0.275g, 1.74mmol) in THF (3zn1) was added dropwise to n-butyllithium (1.6M in hexane) (i.09m1, WO 92/02518 PCT/GB91'/01285 -38- 1.74mmol) at -70 0 C. After ten minutes 6,7,13-0-tris(trimethylsilyl)monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added dropwise maintaining the temperature below -65 0 C. After 2h at -65 0 C the solution was warmed to -30 0 C over 0.5h. Acetic acid (0.10ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane as eluent gave impure diastereomeric alcohols (0.39g, The alcohols (0.37g, 0.59mmol) and manganese dioxide (0.60g, 6.9mmol) in benzene (10ml) were heated to reflux under Dean and Stark conditions for 2h.

The solids were removed by filtration and washed with dioxane. Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.254g, 65%) as a colourless oil; vmax (liquid film) 2960, 2900, 1660, 1610, 1580, 1245cm- 1 5H (CDCl 3 0.10-0.16 (27H, m, 9 x SiCH 3 0.89 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H 3 1.36-1.46 (IH, m, 12-H), 1.52-1.62 (2H, m, 9-H 2 1.77-1.86 (1H, m, 2.16 (1H, dd, J 14.9 and 10.9Hz, 2.26 (3H, s, 15-H 3 2.64-2.71 (3H, m, 4,10 and 11-H), 3.39 (1H, dd, J 9.0 and 2.3Hz, 6-H), 3.56 (1H, d, J 11.3Hz, 16-H), 3.80-3.99 (4H, m, 5,7,13, and 16-H), 6.80 (1H, s, 7.39 (1H, dd, J 7.8 and 4.9Hz, 8.1 (1H, dt, J 7.8 and 1.9Hz, 8.72 (1H, dd, J 4.8 and 1.5Hz, 9.21 (1H, d, J 1.6Hz, 2'-H)1 m/z 671 (M 117 (Found: M 661.3351.

C31H55NO6Si3 requires M, 661.3357).

b) Pyrid-3-yl-l-(normon-2-yl) ketone The above ketone (0.233g, 0.375mmol) and 4-dimethylamdiopyridine dihydrochloride (13.5mg, 6.9 x 10-5mmol) in methanol (5ml) were stirred at room temperature L~ -Z _i c WO 92/02518 PCTr/GB91/01285 -39for 4h. Saturated sodium hydrogen carbonate solution (l0mi) and water (l0mi) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and pur'fication by flash chromatography using 8% methanol in dichloromethane as eluent gave the title compound (0.10g, 66%) as a white foam; Vmax (KBr) 3423, 2969, 2933, 1659r 1608, 1419, 1254, 1111, 1049cm- 1 Imax (EtOH) 271nm (em 14,100); 8H (CD 3 OD) 0.95 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, di, !I 6.4Hz, 14-H 3 1.33-1.43 (1H, m, 12-H), 1.71 (2H, t, J 6.6Hz, 9-H 2 1.91-2.04 (1H, m, 2.26 (3H, s, 15-H 3 2.39 (1H, dd, J 14.3 and 10.6Hz, 2.69-2.82 (3H, m, 4,10 and 11-H), 3.41 (1H, dd, J and 2.9Hz, 3.61 (1H, d, J 11.7Hz, 16-H), 6.92 (1H, s, 7.57 (1H, cid, J 8.0 and 5.0Hz, 51-H), 8.33-8.37 (1H, m, 8.70 (1H, dd, J 4.9 and 1.7Hz, 9.07 (1H, cd, J 1.5Hz, 8C (CD 3 0D) 12.3 20.4 20.6 332.1 41.9 43.8 44.6 56.9 61.3 66.5 70.1 70.7 71.7 76.4 122.8 125.3 (C-51), 136.2 137.5 150.1 (C-21 or 153.2 (C-2' or 161.6 190.9 M/z 405 QjMi1 106 (round: 405.22-11. C 22

H

31 N0 6 requires M, 405.2230).

Example 6 -1-(normon-2-yl) ketone a) (1-Methvltriazol-5-vl)-1-(6,7,13-0-tris-trimethylsilvlnormon-2-vl) ketone 11-Butyllithium (1.6M in hexane) (1.88m1, 3.Ommol) was added dropwise to a solution of 1-methyltriazole (0.25g, 3.Ommol) in THF (l0mi) maintaining the temperature below -600C.

After 1h at -65 0 C cerium trichioride 14g, 3.Ommol) was added. After a further ih at -65 0

C

WO 92/02518 PCT/GB91/0128'5 N-methoxy-N-methyl-6,7,13-0-tris(trimethylsilyl)monamide (0.60g, Immol) in THF (5ml) was added dropwise maintaining the temperature below -60 0 C. After 2h at -65 0 C the solution was allowed to warm to 0 C over lh. Acetic acid (0.16ml) was added followed by water (50ml) and ethyl acetate The organic layer was separated, dried (MgSO 4 and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave the required ketone (0.19g, 31%) as a colourless oil; 5H (CDC1 3 0.11-0.18 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.1Hz, 17-H 3 1.21 (3H, d, J 6.4Hz, 14-H 3 1.35-1.43 (1H, m, 12-H), 1.52-1.63 (2H, m, 9-H2), 1.76-1.88 (1H, m, 2.15 (1H, dd, J 10.7 and 14.7Hz, 2.31 (3H, s, 3 2.64-2.73 (3H, m, 4,10 and 11-H), 3.40 (1H, dd, J 9.1 and 2.3Hz, 3.58 (1H, d, J 11.4Hz, 16-H), 3.82-3.95 (4H, m, 5,7,13 and 16-H), 4.34 (3H, s, NCH3), 6.61 (1H, s, 8.11 (1H, s, m/z 625 (M 117 (Found: M 625.342). C 2 9

H

5 5 N30 6 Si 3 requires M, 625.3399).

b) (l-Methyltriazol-5-yl)-1-(normon-2-yl) ketone The above ketone (0.18g, 0.288mmol) and 4-dimethylaminopyridine dihydrochloride (l.0mg, 5.1 x 10-6mmol) in methanol (7ml) were stirred at room temperature for ten minutes. Saturated sodium hydrogen carbonate solution (10ml) was added and the solution extracted with ethyl acetate (3 x 30ml). Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the required compound (0.080g, 68%) as a white foam; vmax (KBr) 3427, 2967, 2927, 1660, 1610, 1111, 1051cm- 1 ax (EtOH) 273.5nm (Cm 16,800); 8H (CDC1 3 0.94 (3H, d, J 7.1Hz, 17-H 3 1.23 (3H, d, J 6.3Hz, 14-H 3 1.27-1.41 (1H, m, 12-H), 1.71-1.81 (2H, m, 9-H 2 1.97-2.10 (1H, m, 2.32 (3H, s, 15-H 3 2.38 (IH, dd, J 9.2 and 14.8Hz, 2.69-2.83 (3H, m, 4,10 and 11-H), 3.49 (IH, WVO 92/02518 PCf/GB91 /01285 -41dd, J 8. 9 and 2. 9Hz, 6-H) 3. 63 (1H, d, J 11. 5Hz, 16-H) 3.73-4.00 (4H, mn, 5,7,13 and 16-H), 4.34 (3H, s, NCH- 3 6.64 (1H, s, 8.13 (1H, s, 8C (CD 3 OD) 12.2 (C-17), 20.3 20.4 32.9 28.3 (NCH 3 41.8 43.6 44.5 56.8 61.1 (C-l1), 66.3 69.9 70.6 71.5 76.3 123.7 137.1 137.4 163.4 181.2 m/zj 409 (Z 224 (Found: M 409.2207. C 20

H

31

N

3 0 6 requires M4, 409.2213).

Example 7 (rorion-2-yl) ketone a) (2-Methoxypyrimidin-5-yl) -1-(6,7,13-0-tristrinethylsilvlnorinon-2-vl) ketone 11-Butyllithiun (1.6M in hexane) (1.09m1, 1.74mnol) was added dropwise to 5-bromo-2-methoxypyrimidine (0.33g, 1.74mnol) in THF (l0mi) maintaining the temperature below -85 0 C. After 1h at -85 0 C cerium trichloride (0.43g, 1.74inmol) was added.

After lh at -90 0 C, 6,7,13-O-tris(triinethylsilyl)inonaldehyde (0-63g, 1.l6mmol) in THF (5in1) was added dropwise maintaining the temperature below -85 0 C. After 3h at -85 0

C

acetic acid (0.l0i) then water (20m1) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and J purific ation by flash chromatography using hexane/ethyl (0.56g, 74%) as a pale yellow oil. Mangan-,se dioxide (0-93g, 10,7inmol) and benzene (10m1) were added and the mixture heated to reflux under Dean and Stark conditions for The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromat~cgraphy using hexane/ethyl acetate as eluent WO 92/02518 PCr/GB9I001285 -42gave the title compound (0.29g, 52%) as a colourless oil; 8H (CDCl 3 0.11-0.17 (27H, mn, 9 x SiCH 3 0.91 (3H, d, J 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.31-1.46 (1H, in, 12-H), 1.52-1.64 (2H, in, 9-H 2 1.77-1.90 (1H, in, 2.13 (1H, dd, J 14.7 and 9.7Hz, 2.27 (3H, s, 15-H 3 2.64-2.72 (3H, mn, 4,10 and 11-H), 3.40 (1H, dd, J 9.0 and 2.1Hz, 3.58 (1H, d, J 11.3Hz, 16-H), 3.81-4.00 (4H,in 5,7,13 and 16-H), 4.09 (3H, s, OCH 3 6.70 (1H, s, 2-H), 9.05 (2H, s, 3' and 51-H); Mn/& 652 (Me, 73 (Found: M+ 1 652.3396. C 31

H

56

N

2

O

7 Si 3 requires M, 652.3395).

b) (2-methoxvpvriinidin-5-yl) -1-(norinon-2-yl) ketone The above ketone (0.27g, 0.414mnol) and 4-diinethylaininopyridine dihydrochloride (6.0mg, 0.O3nrol) in methanol (4in1) were stirred at room temperature for Saturated sodium hydrogen carbonate solution (l1inl) and water (20in1) were added and the solution extracted with ethyl acetatq. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloroinethane as eluent gave the title compound (0.155g,~ 86%) as a white foam; Vinax (KBr) 3380, 2922, 1661, 1610, 1588, 1248cm- 1 *a (EtOH) 296.Snn (em 21,465); 8H (CD 3 OD) 0.94 (3H, d, .1 7.1Hz, 17-H 3 1.19 (3H, d, !I 6.5Hz, 14-H 3 1.36-1.44 (1H, mn, 12-H), 1.67-1.73 (2H, in, 9-H 2 1.89-2.04 (1H, mn, 2.25 (2H, s, 15-H 3 2.25 (3H, s, 15-H 3 2.38 (lH, dd, J 14.3 and 8.4Hz, 4-H), 2.68-2.83 (OH, mn, 4,10 and~ 11-H), 3.40 (1H, dd, J 9.0 and 3.0Hz, 3.60 (1H, d, J 10.7Hz, 16-H), 3.73-3.92 (4H, in, 5,7,13 and 16-H), 4.08 (3H, s, OCH 3 6.86 (1H, s, 2-H), 9. 09 (2H, s, 4' and 61 5C (CD 3 OD) 12. 2 20.3 20.4 32.9 41.7 43.6 44.5 56.1 (OCH 3 56.8 61.2 66.4 70.0 70.6 71.6 76.3 122.3 127.9 161.4 161.6 167.8 WO 92/02518 WO 9202518PC1'/GB91 /01285 -43- (C-21) 188. 3 m/z I. 436 137 (100%); (Found: M+ 436.2213. C 22

H

32

N

2 0 7 requires M, 436.2210).

Example 8 -1-(norrnon-2-yl) ketone a) (2-Dimethylaminopyrimidin-5-yl)-l-(6,7, 13-0tristrimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09m1, 1.74mmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine in THF (l0mi) whilst maintaining the temperature below -85 0 C. After lh at 0 C cerium trichloride (0.43g, 1.74mmol) was added. After 1s a further 1h at -90 0

C

6,7,13-0-tris(trimethylsilyl)monaldehyde (0.63g, 1.l6mmol) in THF (3m1) was added dropwise whilst maintaining the temperature below -85 0 C. After 2.5h at -90 0 C acetic acid (0.l0ml) then water (l0mi) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the diastereomeric alcohols (0.21, 27%) as a colourless oil. Manganese dioxide (0.43g, 4.95mnol) and benzene (5m1) were added and the mixture heated to reflux under Dean and i Stark conditions for 0.5h. The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure. Purification TI 11by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.083g, 40%) as a pale yellow oil; 5H (CDCl 3 0.11-0.16 (27H, 9 x SiCH 3 0.90 OH1-, d, J1 7.1Hz, 12-H 3 1.20 (3H, d, 6.3Hz, 14-H3), 1.26-1.44(1H1, m, 12-H), 1.62-1.73 (2H, m, 9-H12), 1.79-1.84 (1H1, m, 2.12 (1H, dd, J 15.0 and 10.9Hz, 2.21 (3H, s, 15-H 3 2. 60-2.71 (3H, m, 4, 10 and 11-H) 3.27 6H, s, N(CH 3 2 3.389 (1Hf dd, J1 9.0 and 2.4Hz, 3.56 (1H1, 13-H, 16-H), 5.93 (1H, d, ~J 8.1Hz, 9.91 (18, CL, J WO 92/02518 -4-PCT/GB9I001 285" d, J 11.2Hz, 16-H), 3.80-3.96 (4H, mn, 5, 7, 13 and 16-H) 6. 63 (1H, s, 8.87 (28, s, 4' and 61 m/z; 6. 64 150 (Found: 665.3713. C 32

H

59

N

3

O

6 Si 3 requires M, 665.3712).

Ai b) (2-Dimethylaminopyrinidin-5-yl) -1-(normon-2-ylj ketone The above ketone (0.08g, 0.l2mnol) and 4-direthylaminopyrimidine dihydrochloride (1.5mg, 7.7 x umol) in methanol (5mi) were stirred at room temperature for 1.5h. Saturated sodium hydrogen carbonate solution and water (l0mi) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.0416g, 77%) as a white foam; vmax (KBr) 3430, 2924, 1651, 1593, 1559, 1266cm- 1 kmax (EtOH) (316nm (em 21,615) and 260nin (em 7,864);

(CD

3 OD) 0.94 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.4Hz, 14-H3), 1.37-1.45 (1H, m, 12-H), 1.62-1.79 (28, m, 9-H2), 1.93-2.03 (1H, m, 2.19 (38, s, 15-83), 2.35 (18, dd, J 14.8 and 10.0Hz, 2.71-2.84 (38, mn, 4,10 and 11-H), 3.25 [68, s, N(CH 3 )jJ, 3.41 (1H, dd, J1 8.9 and 3.0Hz, 6-H), 3.60 (1H, d, J 11.5Hz, 16-H), 3.76-3.92 (48, in, 5,7,13 and 6.74 (18, s, 8.83 (28, s, 4' and 61-H),

(CD

3 oD) 12.3 20.3 (C-14 and C-i5), 33.0 3.6 [N(C8H 3 2 J, 41.7 43.7 44.2 56.9 (C-0),61.3 66.4 70.0 70.0 70.7 71.6 76.3 121.9 122.7 158.6 160.1 163.5 189.5 in/z 449 150 (Found: 449.2534.

C

23

H

35

N

3 0 6 requires M, 449.2526).

WVO 92/02518 PCr/GB9I /01285 Exmpe 9 V (2-Methylthiopyrid-5--vl) (normon-2-yl) ketone a) (2-Methylthiopyrid-5-vl) 13-0-tris-tri.methylsilvlnornon-2-Yl ketone n-Butyllithium (1.6M in hexane) (3.27ml, 5.22mmol) was added dropwise to 5-bromo-2-methylthiopyridine (1.06g, 5.22mnol) in THF (45ml) at -85 0 C. After 1h at -85 0 C cerium trichioride (l.29g, 5.22mmol) was added and after a further lh at -85 0 C 6,7,13-O-tris(trimethylsilyl)monaldehyde (1.89g, 3.47mmol) in TEF (7m1) was added dropwise whilst maintaining the temperature below -85 0 C. After lh at -85 0 C acetic acic (0.30m1) and water (50m1) were added sequentially and the solution extracted with ethyl acetate. Drying (MgS0 4 and purification by flash chromatography using hexane/ethyl acetate as eluent gave the impure diastereome:ic alcohols (1.53g, 66%) as a colourless oil. Manganese dioxide (2.46g, 28.3niol) and benzene (20m1) were added and the mixture heated to reflux uinder Dean and Stark conditions for 0.5h. The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (1.03, 68%) as a colourless oil; 8H (CDCl 3 0.11-0.17 (27H, m, 9 x SiCH 3 0.91 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, d, I 6.3Hz, 14-H 3 1.35-1.43 (1H, m, 12-H) 1. 62-1. -9 (2H, m, 9- 2 ,1.75-1.85 (1H, m, 2.14 (1H, dd, J1 15.0 and 11.0Hz, 2.24 (3H, s, 15-H 3 2.60 (3H, s, SCH 3 2.60-, (3H, m, 4,10 and 11-H), 3.40 (1H, dd, J 9.0 and 2.4Hz, 3.58 (1H, d, !I 11.4Hz, 16-H), 3.80-3.95 (4H, m, 5,7,13 and 16-H), 6.75 (1H, s, 7.23 (1H, d, J 8.3Hz, 31-H), 8.02 (1H, dd, !1 8.4 and 2.2Hz, 41 8. 97 (1H, d, !1 1. 7Hz, m/z 667 (11 117 (Found: 667.3223. C 32

H

57

NO

6 Sj 3 requires M4, 667.3214).

WO 92/02518 PCT/GB9f/01 295 -46b) (2-Methylthiopyrid-5-yl)-l- (normon-2-vl) ketone The above ketone (1.02g, 1.53mmol) and 4-dimethylaminopyrimidine dihydrochioride (13. 6mg, 0 .O7mmol) in methanol (5ml) were stirred at room temperature for 1h.

Saturated sodium hydrogen carbonate solution (10m1) and water (20m1) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol in dichloromethane as eluent gave the title compound (0.55g, 80%) as a white foam; Vmax (K~r) 3426, 2924, 1654, 1580, 1114cm- 1 X-max (EtOH) 318.4nm (E 22,080) and 284.Onm Em 9, 628) 5H (CD 3 OD) 0 .94 (3H, d, I 7.0Hz, 17-H 3 1.19 (3H, d, J 6.4Hz, 14-H 3 1.33-1.47 (1H, m, 12-H), 1.68-1.73 (2H, m, 8-H 2 1.90-2.05 (1H, m, 2.23 (3H, s, 15-H 3 2.37 (1H, dd, J 14.3 and 9.6Hz, 2.59 O3H, s, SCHI- 3 2.69-2.83 (3H, m, 4,10 and 11-H), 3.41 (1H, dd, J 9.0 and 3.0Hz, 3.60 (1H, d, J 11.3Hz, 16-H), 3.74-3.93 (4H, m, 5,7,13 and 16-H), 6.87 (1H, s, 7.36 (1H, d, J 8.4Hz, 31-H), 8.10 (1H, dd, J 8.4 and 2.3Hz, 41-H), 8.93 (1H, d, J 17Hz, 5 C (CD 3 OD) 12.3 13.5 (SCH 3 20.4 20.5 33.0 41.8 43.7 44.3 56.9 61.3 66.4 70.0 70.7 71.6 (C-13), 76.4 121.8 122.9 131.6 136.6 150.6 160.3 166.6 99.6 z 451 152 (Found: M+ 451.2033.

C

23

H

33 N0 6 S requires M, 451.2029).

Example -1-(normon-2-yl-)-ketone m-Chloroperoxybenzoic acid (0.050g, 0.242mmo1) was added to the ketone of example 9 (0.10g, O.22mmol) in dichioromethane (3m1) and saturated sodium hydrogen solution (2m1) After 2h at room temperature water (lOml) was added WO 92/02518 PCU/GB91 /01285 -47and the solution extracted with ethyl acetate. Drying (MgS0 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol in dichioromethane as eluent gave the title compound (0.0369g, 36%) as a white foam; Vmax (KBr) 3419, 2968, 1661, 1609, 1573, 1242, 1041cm- 1 XLmax (EtOH) 281.5nm (E 14,857) and 237nm (em 7,863); 8H CD 3 OD) 0.94 (3H, 7.6Hz, 17-H 3 1.19 (3H, d, J 6.4Hz, 14-H 3 1.37-1.45 (1H, m, 12-H), 1.67-1.73 (2H, m, 9-H 2 1.93-2.02 (1H, mn, .27 (3H, two s, 15-CH 3 2.41 (1H, dd, J 4.3 and 9.6Hz, 2.71 (iH, dd, J 7.5 and 2.7Hz, 11-H), 2.80-2.84 (2H, mn, 4 and 2.90 and 2.91 (3H, two s, SOCH 3 3.42 (1H, dd, J and 3.0Hz, 3.61 (1H, d, J 11.5Hz, 16-H), 3.75-3.93 (4H, mn, 5,7,13 and 16-H), 6.94 (1H, s, 8.06 (1H, dd, J 8.2 and 6.7Hz, 31-H), 8.54 (1H, dd, J 8.2 and 2.1Hz, 41-H), 9.13 (1H, d, J 2.1Hz, 61-H); 8C (CD 3 OD) 12.3 70.3 20.6 33.0 41.1 (SCH 3 41.6 43.7 44.6 56.7 61.2 66.4 70.0 70.7 71.6 76.3 120.3 122.7 136.0 139.1 150.8 162.5 (C-3)f 169.5 190.0 in/z (F.A.B.

thioglycerol) 468 (IIH+, 24%) 126 (100%).

Example 11 r2- (Piperidin-l-yl)pyriinidin-B-Yil -1-(norion-2-yl) ketone a) f2-(Piperidin-1-vl)-pyrimidin-5-yll-l--(6,7, 13-0tris-triinethylsilvlnorinon-2-yl) ketone n1-Butyllithiun (1.6M in hexane) (1.78m1, 2.B5nunol) was added dropwise to 5-bromo-2- (piperidin-l-yl)pyrimidine (0.67g, 2.76inmol) in THF (25m1) maintaining the temperature below -900C. After lh at -900C cerium trichloride (0.68g, 2.76inmol) was added and after a further 2h at -900C and lh WO 92/02518 PCT/GB91 0128- -48at -75 0 C acetic acid (0.16ml) and water (40ml) were added.

The solution was extracted with ethyl acetate, the combined extracts dried (MgSO 4 and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave the diastereomeric alcohols (0.71g, The alcohols (0.54g, 0.76mmol) and manganese dioxide (0.89g, 10.2mmol) in benzene were heated to reflux under Dean and Stark conditions for Ih. The solids were removed by filtration, washed with dioxane, and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.45g, 83%) as a colourless oil; 6

H

(CDCl 3 0.11-0.17 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 17-H3), 1.20 (3H, d, J 6.3Hz, 14-H 3 1.31-1.44 (1H, m, 12-H), 1.51-1.91 (9H, m, 8-H, 9-H2, 2 x 3"-H 2 and 4'-H2), 2.11 (1H, dd, J 5.0 and 11.0Hz, 2.21 (3H, s, 15-H 3 2.59-2.71 (3H, m, 4,10 and 11-H), 3.41 (IH, d, J 11.4Hz, 16-H), 3.80-4.03 (8H, m, 5,7,13 and 16-H, and 2 x 2"-H2), 8.77 (1H, s, 4" and m/z 705 (M 190 (100%).

b) [2-(Piperidin-1-yl)-pyrimidin-5-yll--(normon)2-vl) ketone The above ketone (0.44g, 0.62mmol) and 4-dimethylaminopyridine (8.0mg, 4.1 x 10- 5 mol) in methanol were stirred at room temperature for 1.5h. Saturated sodium hydrogen carbonate solution (20ml) and water were added and the solution extracted with ethyl acetate.

Drying (MgS04), evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane as eluent gave the title compound (0.250g, 83%) as a white foam; Vmax (KBr) 3427, 2933, 1653, 1591, 1527, 1249cm- 1 max (EtOH) 322nm (Em 25,545), 259.5 (Em 8,466) and 236nm (em 6,751); 8

H

0.94 (3H, d, I 7.1Hz, 17-H3), 1.20 (3H, d, J 6.4Hz, 14-H 3 1.37-1.45 (1H, m, 12-H), 1.57-1.67 (8H, m, 9-H 2 2 x I i~ 487n1318). C2OIH 3

ON

3 068r requires M, %v6O 92/02518 PCT/GB91/01285 -49- 311-H2 and 4-H 2 1.94-2.02 (1H, m, 2.19 (3H, s, 14-H 3 2.35 (1H, dd, J, 14.3 and 9.5Hz, 2.70-2.76 (2H, m, 4 and 11-H), 2.80-2.84 (1H, m, 10-H), 3.40 (1H, dd, J and 3.0Hz, 11-H), 2.80-2.84 (1H, m, 10-H), 3.40 (1H, dd, J 9.0 and 3.0Hz, 3.61 (1H, d, J 11.4Hz, 16-H), 3.76-3.92 (8H, m, 5,7,13 and 16-H, and 2 x 211-H 2 6.73 (1H, s, 2-H), 8.81 (2H, s, and 8 C (CD 3 OD) 12.1 20.3 20.3 20.3 25.6 26.9 (C-311), 33.0 41.7 43.6 44.2 l0 46. 1 56. 8 61.2 (C-1i) 1;6. 4 (C-16) 70. 0 70.6 71.6 76.3 121.9 122.7 158.4(C-3), 160.3 162.6 189.3 mf/z 489 (M 190 (Found: M 489.2837. C 26

H

39

N

3 0 6 requires M, 489.2839).

Example 12 -1-(normon-2-yl) ketone a) (2-Dimethlyaminopvrid-5-1) 13-0-tristrimethylsilylnormon-2-yl) ketone n-Butyllit ium (1.6M in hexa..) (i.09ml, i.76mmol) was added dropwise to 5-bromo-2-dimethylaminopyridine (0.35g, 1.74mmol) in THF (25m1) at -900C. After 1h at -85 0 C cerium trichloride (0.43g, 1.74mmol) was added. After ih at -85 0

C

6,7,13-O-tris(trimethylsilyl)monaldehyde (0.63g, 1.i6mnol) in THF (5mi) was added whilst maintaining the temperature below -850C. After 2h at -850C and lh at -750C acetic acid (0.i0m1) then water (20m1) were added and the solution extract~.J with ethyl acetate. Drying (MgSO 4 evaporation to dryness and reduced pressure and purification by flash chromatography using ethyl acetate/hexane as eluent gave the diastereomeric alcohols (0.48g, 62%) as a pale yellow foam. Manganese dioxide (0-60g, 6.9Ommol) and (MNa+, 37%) 652 136 (100%).

WO 92/02518 PCT/GB900128 benzene (l0mi) were added and the mixture heated to reflux under Dean and Stark conditions for 3Omins. The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure.

Purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.36g, as a white foam; 5H (CDCl 3 0.10-0.16 (27H, m, 9 x SiCH 3 0.91 (3H, d, I 9.0Hz, 17-H 3 1.20 (3H, d,.2 6.3Hz, 14-H 3 1.33-1.46 (1H, m, 12-H), 1.53-1.62 (2H, m, 9-H 2 1.79-1.90 (1H, m, 2.11-2.19 (1H, m, 2.19 (3H, s, 15-H 3 2.59-2.71 (3H, m, 4,10 and 11-H), 3.18 (6H, s, N(CH 3 2 3.40 (1H, d, I 9.0Hz, 3.57 (1H, d, !I 11.4Hz, 16-H), 3.80-3.96 (4H, m, 5,7,13 and 16-H), 6.51 (1H, d, J 6.70 (1H, s, 8.05 (1H, dd, !Z 9.0 and 2.1Hz, 41-H), 8.80 (1H, d, J1 2.0Hz, 61-H); M/.j 649

(M!-CH

3 141 (100%).

b) -(-imethylaninopyrid-5-yl) -1-(normon-2-yl) ketone The above ketone (0.35g, 0.53mmol) and 4-dimethylaminopyridine dihydrochloride (0 .030g, 0 in methanol (l0ml) were stirred at room temperature for 8h and at 0 0 C for 16h. Saturated sodium hydrogen carbonate solution (l0mi) and water (20m1) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash q chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.196g, 83%) as a pale yellow foam; vma (KBr) 3428, 2967, 2922, 1648, 1603, 1396, 1266cm- 1 X max (EtOH) 340nm (cm 24,050); 8 H (CD 3 OD) 0.94 1.33-1.47 (1H, mn, 12-HI), 1.68-1.74 (2H, m, 9-H 2 1.92-2.03 (1H, in, 2.16 (3H, so 15-H 3 2.34 dd, !1 14.4 and 9.6Hz, 2.69-2.85 (3H, in, 4,10 and 11-H), 3.17 [6H, s

N(CH

3 2 J, 3.41 (1H, dd, !1 9.0 and 3.0Hz, 6-H) 3. 62 (1H, d, J 11.4Hz, 16-H), 3.74-3.93 (4H, m, 5,7,13 and 16-H), 6.69 (iH, d, !j 9MHz, 31 6.78 (1H, s, 2-H) 8.04 (1H, dd, 9.2 and 2.4Hz, 8.71 (1H, d, J 2.3Hz, 61-11); 8C WO092/02518 PCI'/GB9I /01285 -51-

(CD

3 OD) 12.2 20.2 20.3 33.0 38.4 [N(CZH 3 2 1, 41.6 43.7 44.0 56.8 51.2 66.4 70.0 70.6 71 6 76.3 106.6 123.3 124.1 138.2 151.5 156.7 161.8 1.91.2 m/zj 448 (Me, 149 (100%); (Found: 448.2585. C 24

H

36

N

2 0 6 requires M, 448.2573).

1Example 13 (1-Propyvlpvrazol-4-vl) -1-(normon-2-yl) ketone a) 4-Sromo-l-propylpyrazole Bromine (1.42m1, 27.3mmol) in glacial acetic acid (3.Sml) was added dropwise to 1-propylpyrazole (3.0g, 27.3mnol) and sodium acetate (371g, 27.3mmol) in glacial acetic acid (l0mi) and water (25ml) After lh at room temperature -Ie solution was extracted with ethyl acetate, the extracts dried (MgSO 4 and evaporated to dryness under reduced pressure. Distillation at reduced pressure gave the title compound (4.00g, 77%) 86-90 0 C ca.l0mm. Hg) as a colourless liquid; 8 H (CDCl 3 0.91 (3H, t, J 7.3Hz, CH 3 .1.07 (2H, sextet, J 7.3Hz, CH 2

CH

2

CH

3 4.06 (2H, t, I 7.3Hz,

CH

2

CH

2

CH

3 7.40 (1H, s, 3 or 17.45 (1H, s, 3 or 8c (CDCl 3 11.0 (CH 3 23.6 (CH 2

CH

2 54.5 (CH 2

CH

2

CH

3 92.6 129.1 (C-3 or 139.6 (C-3 or Mf/z 190 (MeI 188 161 (Found: 187.9943.

C

6

H

9

N

2 Br requires M, 187.9949).

'I WO 92/02518 PCU/GB91/0128 -52b) (1-Propylp2yrazol-4-).) 13-tris-O-trimethylsilylnbrmon- 2 -Vl) ketone 4-Bromo-1-propylpyrazole (0.57g, 3.O0mnol) in TEF (5mi) was added dropwise to n-butyllithium (1.6M in hexane) (1.88mmol, 3.O0mnol) in THF (20m1) at -70 0 C. Added a further 40mins at -70 0 C N-methoxy-li-methy1 6,7,13-O5tris.- (trimethylsilyl)monamide (0.60g, 1.O0mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -60 0 C. After 4h at -70 0 C acetic acid (0.l1rnl) was added and the products poured into water (50m1) The solution was extracted with ethyl acetate, dried (MgSO 4 and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.57g, 88%) as a white foam; (CDCI-;) 0.10-0.16 (27H, m, 9 x SiCH3), 0.89-0.95 (6H, m, CqH 2

CH

2

CH

3 and 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.35-1.42 (1H, m, 12-H), 1.53-1.62 (2H, m, 9-H 2 1.74-1.97 (3H, m, 8-H and 21'-H 2 2.10 (1H, dd, 1 14.6 and 10.6Hz, 2.25 (3H, s, 15-H 3 2.63-2.72 (3H, m, 4,10 and 11-H), 3.40 (1H, dd, J 8.9 and 2.3Hz, 3.56 (1H, d, J 11.4Hz, 16-H), 3.80-3.94 (4H, m, 5,7,13 and 16-H), 4.09 (2H, t, !I 11'-H 2 6.52 (1H, s, 7.89 (1H, s, 3' or 7.92 (1H, s, 3' or ;M/z 3-NOBA/Na) 675 (Mgia 100%), 653 58%) C) (1-Propylpyrazol-4-yl) -1-(normon-2-yl) ketone The above ketone (0.56g, 0.86mmol) and 4-dimethylaminopyridine dihydrochioride (2.2mg, 11.3 x 6 mol) in methanol (14m1) were stirred at room temperature for 30mins. Saturated sodium hydrogen carbonate solution was added and the solution extracted with ethyl acetate.

Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 9% methanol in dichloromethane as eluent gave the title WO 92/02518 PCr/GB91 /01285 -53compound (0.32g, 86%) as a white foam; vmax (KBr) 3422, 2969, 2933, 2877, 1647, 1606, 1540, 1224, 1270, 1109, 1048cm- 1 Xmax (EtQH) 270.5nm (em 20,137); 81 (CD.-0D) 0.90 (3H, t, J 7.3Hz, 3''-H 3 0.94 (3H, di, J 7.3Hz, 17-H3), 1.19 (3H, di, J 6.3Hz, 14-H 3 1.34-1.47 (1H, m, 12-H), 1.70 (1H, t, J 6.5Hz, 17-H 2 1.81-1.96 (3H, m, 2'-H 2 and 2.24 (3H, s, 15-H 3 2.31 (1H, dci, J 14.2 and 9.6Hz, 2.69-2.84 (3H, m, 4,10 and 11-H), 3.39 (1H, dd, J 9.0 and 3.58 (1H, ci, J 11.4Hz, 16-H), 3.76-3.92 (4H, m, 5,7,13 and 16-H), 4.14 (3H, t, J 7.0Hz, 1''-H 2 6.66 (1H-, s, 17.96 (1H, s, 3' or 18.23 (1H, s, 31 or

(CD

3 OD) 11.1 (CH 2

CH

2

C!H

3 12.2 20.1 20.3 24.3 (CH 2

CH

2

CH

3 32.9 41.7 43.6 44.3 54.7 (CqH 2

CH

2

CH

3 56.8 61.1 66.3 70.0 70.6 71.6 76.3 124.4 126.5 133.9 or 141.1 or 158.7 187.0 m/z& ,436 (M 4, 137 (100%) (Found: 4 36.257 1.

0 23

H

3

N

2 0 6 requires M, 436.2!:4 Example 14 (2-Acetylfur-4-yl) -1-(normon-2-yl) ketone a 4-Bromo-2- (l-triethy lsilyloxyethen-l-vl)furan Triethylamine (2.94g, 4.06m1, 29.2mmol) and triethylsilyl trifluoromethanesuiphonate (5.76g, 4. 93m1, 1. B3mmol) were added sequentially to 2-acetyi-4,Sdibromofuran (3.93g, 14.6mmol) in THF (1O0mi) cooled to 000. After 2h, water was added and the solution extracted with ethyl acetate. Drying (MgSO 4 and evaporation to dryness under reduced pressure gave the crude silylenol ether (5.61g, 100%) as a pale yellow liquid. n-Butyllithium (1.6M in hexane) (9.12ml, 14.Emmol) was added dropwise to the crude silylenol ether/ (5.61g, 14.Ommol) in THF (40m1) whilst maintaining the WO 92/02518 PCT/GB91 /'iI285 -54temperature below -60 0 C. After 40mins, at -70 0 C the products were poured into a pH 7 buffer solution.

Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using dichloromethane/hexane (10:1) as eluent gave the title compound (2.20g, as a pale yellow liquid; vmax (liquid film) 2960, 2918, 2880, 1555, 1310, 1150, 1010, 925cm- 1 8H (CDCl 3 0.69-0.79 (61i, m, 3 x CH 2

CH

3 0.97-1.04 (9H, m, 3 x CH 2

CH

3 4.39 (1H, d, J 1.8Hz, olefinic 4.86 (1H, d, J 1.8Hz, olefinic 6.45 (1H, s, 7.33 (1H, s, 8C (CDC1 3 4.7 (CH 2 6.8 (CgH 3 90.4 100.9 109.9 140.3 146.9 (C-2 or 152.9 (C-2 or M/z NH 3 305 (M4H+ 303 (MH+ 1190 (100%).

b) r2-(l-Triethvlsilyloxvethen-l-vl) fur-4-yvll- 1- 13-O-tris-trimethylsilyliormon-2-yl) ketone The above bromofuran (0.50g, l.E5mmol) in THF (3m1) was added dropwise to n-butyllithium (1.6M in hexane) (l.03m1, at -700C. After a further 40mins. at -70 0

C

N-methoxy-N-methyl-6, 7, 13-0-tris (trimethylsilyl)mon~mide (0.60g, 1.O0mnol) in THF (5m1) was added dropwise. After 4h at -65 0 C acetic acid (0.l0ml) then water (30m1) were added.

Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure, and purification by flash chromatography using hexane/ethyl acetate (10:1) as eluent gave the title compound (0.13g, 17%) as a colourless oil; 8H (CDCl 3 0.10-0.16 (27H, m, 9 x SiCH 3 0.75 (6H, q, j 7.8Hz, 3 x CH 2

CH

3 0.90 (3H, d, !I 7.1Hz, 17-H3), 1.00 (9H, t, 7.8Hz, 3 x CH 3 1.20 (3H, d, j 6.3Hz, 14-H 3 1.33-1.43 (1H, m, 12-H), 1.62-1.72 (2H, m, 9-H 2 1.77-1.88 (1H, m, 2.09 (1H, dd, J 10.6 and 14.5Hz, 2.25 (2H, s, 3 2.60 (1H, d, j 14.5Hz, 2.62-2.71 (2H, m, and 11-H) 3.39 (1H, dd, J 8. 9 and 2.3Hz, 6-H) 3.55 (1H, d, J 11.4Hz, 16-H), 3.80-3.93 (4H, m, 5,7,13 and 16-H), 4.42 chromatography using hexane/ethyl acetate as eluent If, WO 92/02518 PCT/GB91/01285 (1H, d, J 1.5Hz, olefinic 4.89 (1H, d, J 1.5Hz, olefinic 6.47 (1H, s, 6.78 (1H, s, 7.90 (1H, s, c) (2-Acetvlfur-4-yl)-1-(normon-2-yl) ketone The above ketone (0.13g, 0.17mmol) and 4-dimethylaminopyridine dihydrochloride (0.50g, 2.5 x 6 mol) in methanol (4ml) were stirred at room temperature for 20min. Saturated sodium hydrogen carbonate solution was added and the solution extracted with ethyl acetate. The combined extracts were dried (MgSO 4 and evaporated to dryness under reduced pressure. THF (52ml) was added and the resulting solution treated with '.tra-n-butyl-ammonium fluoride trihydrate (0.054g, 0.17mmol) at 0°C. After at 0°C water (50ml) was added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 9% methanol in dichloromethane as eluent gave the title compound (0.031g, 42%) as a white foam; Vmax (KBr) 3447, 2967, 2924, 1683, 1659, 1609, 1572, 1250cm- 1 %max (EtOH) 277.5nm 17,260); 8H(CD 3 0D) 0.94 (3H, d, J 7.1Hz, 17-H 3 1.19 (3H, d, J 6.4Hz, 14-H 3 1.36-1.45 (1H, m, 12-H), 1.68-1.75 (2H, m, 9-H 2 1.92-2.01 (1H, m, 2.26 (3H, s, 15-H 3 2.34 (1H, dd, J 14.3 and 9.5Hz, 2.50 (3H, s, COCH 3 2.70-2.76 (2H, m, 4 and 11-H), 2.80-2.83 (1H, m, 10-H), 3.39 (1H, dd, J 9.0 and 3.59 (1H, d, J 11.1Hz, 16-H), 3.75-3.85 (2H, m, 13 and 16-H), 3.87-4.00 (2H, m, 5 and 6.70 (1H, s, ii 7.61 (1H, s, 8.46 (1H, s, 5 C

(CD

3 0D) 12.3 20.4 (C-15 and 14), 26.2 (COCH 3 33.0 41.6 43.8 44.5 56.9 61.3 66.5 70.1 70.7 71.7 (C-13), 76.4 117.0 123.8 132.3 151.8 154.6 161.0 186.0, 188.7; m/z 436 (M 47 (Found: M 436.2088.

C

2 3

H

3 2 0 8 requires M, 436.2097).

-1 I i WO 92/02518 PCT/GB91 0128 -56- Example [2-(Morpholin-4-yl)-pyrimidin-5-yl]-l(normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2-morpholinopyrimidine (0.43g, 1.74mmol) in THF (20ml) whilst maintaining the temperature at -80 to 0 C. After lh at -85 0 C cerium (III) chloride (0.43g, 1.74mmol) was added. After a further lh at -85 0

C

6,7,13-0-tris(trimethylsilyl)- monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -80 0 C. After 3h at -85 0 C acetic acid (0.96ml) then water (50ml) were added. Extraction with ethyl acetate, drying (MgSO 4 and evaporation to dryness under reduced pressure gave the crude alcohol which was dissolved in benzene (20ml) and treated with manganese dioxide (300g, 34.5mmol) under Dean and Stark conditions for Filtration, washing of the filtered solids with dioxane and evaporation to dryness under reduced pressure gave, after flash chromatography using hexane/ethyl acetate as eluent, the protected ketone (0.46g, 56%).

Methanol (10ml) and 4-dimethylaminopyridine dihydrochloride 0.04mmol) were added and the resulting solution stirred at room temperature for 30mins. Saturated sodium hydrogen carbonate solution (10ml) was added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol in dichloromethane as eluent gave the title compound (0.26g, 84%) as a white foam; Vmax (KBr) 3433, 2966, 2921, 1864, 1653, 1591, 1525, 1448, 1246, 1114cm- 1 %max (EtOH) 315nm (em 23,209), 264nm (Em 7,962) and 231nm (Em 5,693); 8

H

(CD

3 0D) 0.95 (3H, d, J 7.0Hz, 17-H 3 1.20 (3H, d, 2 6.3Hz, 14-H 3 1.34-1.47 (1H, m, 12-H), 1.70 (2H, t, 6.2Hz, 9-H 2 1.92-2.01 (1H, m, 2.20 (3H, s, 15-H 3 2.34 (IH, dd, J 14.4 and 9.5Hz, 2.70-2.84 (3H, m, 4,10 and 11-H), 3.40 (1H, dd, J 9.0 and 3.0Hz, 3.60 (1H, d, J 11.,6Hz, 16-H), 3.72-3.95 (12H, m, 5,7,13 and 16-H, 2 x d-- WO 92/02518 PCr/GB91 /01285 -57- 2"1-2and 2 x 3''1-H 2 6.76 (1H, s, 8 .87 (2H, s, 4' and 6' 5c (CD 3 OD) 12. 2 17) 2 0. 3 (C-15) 20.3 41.7 43.6 44.2 45.5 56.8 61.2 66.4 67.6 70.0 70.6 71.6 -76.3 122.6 122.8 158.9 160.2 163.0 189.2 m/z~ 491 192 (Found: 491.2632,

C

25

H

37

N

3 0 7 requires M, 491.2632).

Example 16 2- (l-Methvlpiperazin-4-,')-pvrimidin-5-vll-l- (norrnon2-yl) ketone a) 5-Brorno-2- (l-methylpiperazin-4-vl)pvrimidine N1-Methylpiperazine (0.5g, 5.6Bmmol) and 5-bromo-2chioropyrimidine (1.00g, 5.l7mmol) in methanol (25m1) were heated to reflux for 1h. The products were neutralised with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and recrystallisation from aqueous methanol gave the title compound (0.76g, 86%) as white crystals (mp.68-9 0 1fN; vma (KBr) 2955, 2926, 1579, 1528, 1491, 1449, 1360, -308, 1760cm- 1 5H8 D1)23 3,s

NCH

3 2.45 (4H, t, J 5.1Hz, 2 x 2''-H 2 3.80 (4H, t, J.

5.1Hz, 2 x 3''-H 2 8.28 (2H, s, 4 and SC (CDCl 3 43.9

(N-CH

3 46.2, 54.8, 105.7(q), 157.8, 159.9(q); M/ 258 (Mf' 256 13%) 70 (100%).

~fr WO 92/02518 Pc1'/GB91/0128 -58b) 12-(1-Methvlpiperazin-4.-yl)-pyrimidin-5-vll-l- 13-O-tris-trimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2- (1-methylpiperazin-4-yl)pyrimidine (0.44g, 1.74mnol) in THF (2Oml) at -85 0 C. After lh at 0 C, cerium trichloride (0.43g, 1.74mnmol) was added and the solution kept at -85 0 C for a further lh. 6,7,13-tris(trimethylsilyl)monaldehyde (0.63g, 1.l6mxnol) in THF (5mi) was added dropwise whilst maintaining the temperature below -80 0 C and after 3h at -85 0 C acetic acid (0.l0ml) then water (50m1) were added. Extraction with ethyl acetate, drying (MgSO 4 and evaporation to dryness under reduced pressure gave the crude alcohols which were dissolve~d in benzene (20m1) and treated with manganese dioxide (3.00g, 34.5rnrol) under Dean and Stark conditions for 30mins. Filtration, washing of the filtered solids with dioxane, evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/ hexane as eluent gave the title compound (0.33g, as a pale yellow oil; 5H (CDCl 3 0.10-0.16 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.3Hz, 17-H 3 1.19 (3H, d, J 6.3Hz, 14-H 3 1.34-1.41 (1H, mn, 1.50-1.58 (2H, m, 9-H 2 1.74-1.86 (1H, mn, 2.01 (1H, dd, J 14.9 and 11.0Hz, 2.21 (3H, s, 15-H 3 2.36 (3H, s, N-CH 3 2.43-2.52 (4H, m, 2 x 2''-H 2 2.59-2.71 (3H,m, 4,10 and 11-H), 3.38 (1H, dd, J 9.0 and 2.5Hz, 3.56 (1H, d, J 11.3Hz, 16-H), 3.79-4.03 (8H, in, 5,7,13, 16-H and 2 x 31'-H 2 6.62 (1H, s, 18.85 (2H, s, 720 117 (Found: M+ 720.4126. C 35 H1 64

N

4

O

6 Si 3 requires M, 720.4134).

WO 92/02518 WO 9202518PC1'/GB9J /01285 -59- Example 17 (5,7-Dirnethoxyq,.inolin-3-yl) 1-1- (norrnon-2-yl) ketone a) 3-Bromo-5, 7-dimethoxycruinoline Bromine (4.00g, 1.28ml, 25.Ommol) was added dropwise to a-bromoacrolein (3.38g, 25.Ommol) in acetic acid (60m1) at 5-10 0 C. After 20mins. 3,5-dimethoxyaniline (3.83g, 25.Omnol) was added and the solution heated to reflux for 1h. Evaporation to low volume under reduced pressure, addition of water, extraction with dichioromethane, evaporation to dryness under reduced pressure and purification by flash chromatography using dichioromethane as eluent gave the title compound (0.45g, as a pale yellow solid; Vmax (KBr) 2960, 1625, 1582, 1451, 1416, 1352, 1332, 1269, 1219, 1208, 1157, 1110cm- 1 8H (CDCl 3 3.93 (3H, s, OCH 3 3.96 (3H, s, OCH 3 6.53 (1H, d, J 7.2Hz, 6 or 6.97 (1H, d, J 7.2Hz, 6 or 8.56 (1H, d, J 2.0-Hz, 8.79 (1H, d, J 2.0Hz, 5C- (CDCl 3 55.6

(OCH

3 55.8 (OCH 3 99.0, 99.6, 113.9(q), 117.7(q), 132.4, 148.5(q), 151.7, 155.1, 161.5(q); mn/z 269 (M 267 (M100%); (Found: M 266.9896. C 11

H

1

O

0 2 rreues, 266.9895).

b) [2-(5,7-Dimethoxyqu~inolin-3-yl)1-1-(_6,7,13-0tris-trimethylsilylnormon-2-vl) ketone n-Butyllithium (1.6M in hexane) (1-05m1, 1.E8mmol) was added dropwise to the above quinoline in THE' (20m1) whilst maintaining the temperature below -85 0 C. After 'h at 0 C cerium (III) chloride (0.40g, 1.65miol) was added and after a further lh at -85 0 C acetic acid (0.l0ml) then water (20m1) were added. Extraction with ethyl acetate, drying (Na,S0 4 and evaporation to dryness under reduced pressure gave the crude alcohols. Manganese dioxide (3.00g, WO 92/02518 PCTI/GB91/01285 34.5mmol) and benzene (25ml) were added to the crude alcohols and the mixture was heated to reflux under Dean and Stark conditions for lh. Filtration, washing the filtered solids with dioxane, evaporation of the combined filtrates to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.35g, 41%) as a pale yellow foam; 8 H (CDC1 3 0.lOg, 0.20 (27H, m, 9 x SiCH 3 0.91 (3H, d, J 7.2Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 4-H 3 1.36-1.43 (1H, I0 m, 12-H), 1.52-1.64 (2H, m, 9-H 2 1.80-1.90 (1H, m, 8-H), 2.21 (1H, dd, J 15.0 and 11.0Hz, 2.28 (3H, s, 15-H 3 2.67-2.73 (3H, m, 4,10 and 11-H), 3.44 (1H, dd, J 9.0 and 2.3Hz, 3.01 (1H, d, J 11.4Hz, 16-H), 3.82-4.00 (4H, m, 5,7,13 and 16-H), 3.97 (3H, s, OCH3), 4.01 (3H, s, OCH3), 6.55 (1H, d, J 2.0Hz, 6' or 6.98 7.09 (1H, d, J 2.0Hz, 6' or 9.01 (1H, d, J 2.0Hz, 4-H), 9.34 (1H, d, J 2.0Hz, m/z 731 (M 73 (Found: M 731.3710. C 37

H

6 N08Si 3 requires M, 731.3705).

c) (5,7-Dimethoxvcuinolin-3-yl) 1-1- (normon-2-yl) ketone The above ketone (0.35g, 0.48mmol) and 4-dimethylaminopyridine dihydrochloride (0.028g, 0.14mmol) in methanol (10ml) were stirred at room temperature for 7h.

Saturated sodium hydrogen carbonate solution was added and the solution extracted into ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 7% methanol in dichloromethane as eluent gave the title compound (0.19g, 76%) as a white solid (mp.150-51 0 C (MeOH)]; vmax (KBr) 3423, 2967, 2927, 1653, 1617, 1453, 1431, 1414, 1282, 1251, 1151, 1108, 1045cm- 1 Xmax (EtOH) 344.5nm (Em 9,909) and 279.5nm (Em 29,1985); 5 H (CD 3 0D) 0.94 (3H, d, J 7.1Hz, 17-H 3 1.19 (3H, d, !I 6.3Hz, 14-H 3 1.33-1.47 (IH, m, 12-H), 1.73 (2H, t, J 6'Hz, 9-H 2 1.96-2.04 (1H, m, 2.26 (3H, s, 3 2.42 (1H, dd, 14.4 and 9.6Hz, 2.71 (IH, dd, i WO 92/02518 PCT/GB91 /01285 J 8.6 and 2.4Hz, 11-H), 2.78-2.85 (2H, m, 10 and 3.44 (1H, dd, J 9.0 and 3.0Hz, 3.66 (lH, d, J 11.6Hz, 16-H), 3.72-3.93 (4H1, mn, 5,7,13 and 16-H), 3.97 (3H, OCH 3 4.04 (3H, s, OCH 3 6.70 (1H, d, J 2.0Hz, 6' or 6.99 J 2.0Hz, 6' or 7.00 (1H, s, 8.99 (1H1, d, J 9.20 (1H, d, J 2.0Hz, 8C (CD 3 OD), 12.3 20.3 21.5 32.0 41.9 43.7 44.4 56.3 56.7 (OCH 3 56.9

(OCH

3 61.2 66.5 70.1 70.7 71.7 76.4 99.8 or 100.0 or 116.4 (quat.), 122.8 129.6 (quat.), 132.9 150.8 152.1 (quat.), 158.3 160.1, (quat.), 165.4 (quat.), 190.6 rn/z 515 (Mi, 216 (Found: 515.2514. C 28

H

37 N0 8 requires M, 515.2519).

Example 18 (1.-Cyclohexylpyrazol-4-yl) -1-(normon-2-vl) ketone a) 4-Broino-1-cycloh-exylpyrazole Bromine (0.49m1, 9.4oiniol) in acetic acid (3m1) was added dropwise to sodium acetate (1.28g, 9.4Omnol) and 1-cyclohexylpyrazole (1.41g, 9.4oinzol) in acetic acid (25in1) at room temperature. After 4h at room temperature the solution was evaporated to low volume and then basified with amnmonium hydroxide solution. Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure and recrystallisation from hexane gave the title compound (1.48g, 66%) as white needles (mp.55-56 0 v max (KBr) 2938, 2855, 1652, 1448, 1381, 950cm- 1 8H (CDCl 3 1.14-1.50 (3H1, in, cyclohexyl), 1.56-1.80 (3H, in, cyclohexyl), 1.84-1.95 (2H1, in, cyclohexyl), 2.08-2.19 (2H1, mn, cyclohexyl), 4.08 (111, tt, J 3.9 and 11.6Hz, 7.42 (1H1, s, 3 or 7.44 (1H, s, 3 or 8C (CDCl 3 25.3 and 33.4 61.9 82.3 126.7 WO 92/02518 WO 9202518PCI'/GB91/01285 -62- (C-3 or C-5) 137.-0 (C-3 or C-5) M/ z (Me, 8 22 8 (M+ 147 (Found: 228.0264. C 9

H

1 3

N

2 Br requires M, 228.0262).

b) (1-Cyclohexylpyrazol-4-yl)-l-(6,7,13-tris-0-trimethylsilylnornon-2-yl) ketone The above bromopyrazole (0.92g, 4.Ommol) in TEF (5m1) dropwise was added to n-butyllithium (1.6M in hexane) (2.5m1, 4.Omnol) in THF (25m1) maintaining the temperature below -70 0 C. After lh at -70 0 C N-methoxy-Nmethyl-6, 7, 13-0-tris (trimethylsilyl)monamide (1.20g, 2.Omnol) in THF (5m1) was added dropwise whilst maintaining the temperature below -70 0 C. After 3h at -70 0 C acetic acid (0.13m1) was added and the products poured into water.

Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compund (0.99g, 74%) as a colourless oil; 8H (CDCl 3 0.10-0.16 (27H, m, 9 x SiCH 3 0.90 (3H, d, !I 7.1Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.30-1.95 (14H, 8 x cyclohexyl, 9-H 2 8 and 12-H), 2.10-2.23 (3H, m, 4-H and 2 x cyclohexyl), 2.25 (3H, s, 15-H 3 2.60 (1H, d, J 14.5Hz, 2.65-2.73 (2H, m, 10 and 11-H), 3.40 (1H, dd, J 2.4 and 8.9Hz, 3.55 (1H, d, 2 11.4Hz, 16-H), 3.80-3.94 (4H, m, 5,7,13 and 16-H), 4.10 (1H, tt, J 3.9 and 11.6Hz, 11-H), 6.52 (1H, s, 7.91 (1H, s, 3' or 51-H), 7.94 (1H, s, 3' or rn/z 692 117 (100%); (Found: M+ 692.4072. C 35 fl 64

N

2

O

6 Si 3 requires M, 692.4072).

C) -(1-Cvclohexvlpyrazol-4-yl)--(normon-2--vl) ketone The above protected ketone (0.98g, 1.42mmol) and 4-dimethylaminopyridine dihydrochioride (4.0mg, 2.0 x 10- 5 mo1) in methanol (25m1) were stirred at room temperature for 30mmn. Saturated sodium hydrogen carbonate solution was WO 92/02518 PCT/GB9I /01285 -63added and the resulting solution extracted with ethyl acetate. Drying (MgSO 4 evaporption to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichioromethane as eluent gave the title compound (0.61g, as a white foam; Vmax (KBr) 3421, 2931, 2859, 1648, 1604, 1535, 1227cm- 1 %ma (EtOH) 280.5nm (E-m 19, 644) 8H (CD 3 OD) 0. 94 (3H, d, J 7.1lHz, 17-H 3 1.1-19 (3H, d, J 6.4Hz, 14-H 3 1.32-2.13 (14H, m, 10 x cyclohexyl, 9-H 2 7 and 12-H), .24 (3H, s, 15-H 3 2.32 (1H, dd, J 9.6 and 14.2Hz, 2.69-2.84 (3H, m, 4,10 and 11-H), 3.39 (1H, dd, J 9.0 and 3.0Hz, 16-H), 3.58 (1H, d, I 11.4Hz, 16-H), 3.73-3.91 (4H, mn, 5,7,13 and 16-H), 4.18 (1H, tt, J 3.6 and 11.5Hz, 6.67 (1H, s, 7.94 (1H, s, 3' or 8.26 (1H, s, 3' or 8 C (CD 3 OD) 12.3 (C-17), 20.4 20.7 (C-14) 26.3 (C-31 and 33.0 (C-9'J 34.3 41.8 43.7 44.4 56.7 61.2 62.9 66.4 70.1 70.7 71.7 76.4 124.6 126.4 131.7 or 140.7 (C-31 or 158.7 187.1 rn/z 476 (M 177 (Found: Mi+, 476.2899. C 24

H

40

N

2 0 6 requires M4, 476.2886).

Example 19 (Piperidin-1-vl)pvridin-5-vil-l- (normon-2-vl) ketone a) 5-Bromo-2- (piperidin-1-yl) pyridine Bromine (8.16g, 2.62m1, 51.9mnmol) in acetic acid (20m1) was added dropwise to 2-(piperidin-1-yl)pyridine (8.41g, 51.9mmoi) and sodium acetate (6.94g, 51.9mmol) (1O0mi) at room temperature. After 2 days at room temperature the solution was evaporated to low volume, water (50m1) added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl WO 92/02518 PC1'/GB9I/0128n- -64acetate as eluent gave the title compound (7.50g, as a pale yellow liquid; 8H (CDCl 3 1.55-1.71 (6H, mn, piperazinyl-H), 6.53 (1H, d, j 9.2Hz, 7.47 (1H, dd, J 9.3 and 2.5Hz, 8.16 (1H, d, I 2.5Hz, 8 C (CDC1 3 24.5 25.3 46.2 106.4 108.3 139.4 148.3 158.0 M/hz 242 (Mi, 240 (Me, 84 (Found: 240.0261.

C

10

H

13

N

2 Br requires M, 240.0262).

b) [2-(PiperidiimlI-yl)pyridin-5-y11-l-(6,7, 13-0tris-triinethylsilyinormon-2-yl) ketone N-Butyllithium (1.6M in hexane) (1.96m1, 3.14mmol) was added dropwise to the above brcimopyridine (0.76g, 3.l4nrol) in TI-F (25m1) whilst maintaining the temperature at -80 to -85 0

C.

After lh at -85 0 C cerium (III) chloride (0.77g, 3.l4mnol) was added and the solution kept at -85 0 C for a further lh.

6 ,7,13-0-tris(triinethylsilyl)monaldehyde (1.14g, 2.O9mnol) in THF (l0ml) was added dropwise maintaining the temperature below -80 0 C and after 3h at -85 0 C acetic acid (0.18m1) then water (50mi) were added. Extraction with ethyl acetate, drying (MgSO 4 and evaporation to dryness under reduced pressure gave the crude alcohols which were dissolved in benzene (30m1) and treated with manganese dioxide (6.00g, 69mxnol) under Dean and Stark conditions for Filtration, washing of the filtered solids with dioxane, evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane as eluent gave the title compound (0.87g, 59%) as a yellow oil;- 8 H1 (CDCl 3 0.10-0.15 (27H, m, 9 X SiCH 3 0.90 (3H, d, I 7.0Hz, 17-H 3 1.19 (3H, d, !I 6.2Hz, 14-H 3 1.42-1.49 (1H, in, 12-H), 1.52-1.90 (9H, in, 9-Hz, 8-H, and 511-H 2 2.08 (1H, mn, dd, !1 15.0 and 10.9Hz, 2.18 (3H, s, 15-H 3 2.58-2.70 (3H, mn, 4,10 and 11-H),1 3.39 (1H, ddf J 8. 9 and 3. 1Hz, 6-H),t 3.55 (1H, d, !I 11.6Hz, 16-H), 3.63-3.74 (4H, in, and 61H) WO 92/02518 -6-PCT/GB9I /01285 3. 79-3. 95 (14H, mn, 5, 7, 13 and 1 6-H) 6. 60 (1H, d, J 31 6. 68 (1H, s, 8.01 (1H, dd, J 9.0 and 2.2Hz, 41-H), 8.77 (1H, d, J 2.2Hz, g!hz 704 (M 189 (Found: 704.4087. C 36

H

64

N

2

O

6 Si 3 requires M, 704.4072).

C) (Pip2eridin-1-yl)pyridin-5-yll-l- (norrnon-2-yl) ketone The above protected ketone (0.86g, 1.2lmmol) was treated with hydrochloric acid (0.4M) (10.8m1) in THF (27m1) at room temperature for 2mins.

Saturated sodium hydrogen carbonate solution was added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 9% methanol in dichloroinethane as eluent gave the titlecoinpound (0.50g, 84%) as a pale yellow foam; Vinax (KBr) 3420, 2931, 2857, 1734, 1595, 1.242cm- 1 ;Xa (EtOH) 344nin (Sm 24,430); 8H

(CD

3 OD) 0.95 (3H, J 7 2 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.34-1.47 1.63-1.80 (8H, mn, 9, 411 and 511-H 2 1.90-2.01 (1H, mn, 2.16 (3H, s, 3 2.33 (1H, dd, J 14.4 and 9.6Hz, 2.69-2.85 (3H, mn, 4, 10 and 11-H), 3.41 (1H, dd, J 8.9 and 3.0Hz, 6-H), 361 (1H, d, !I 11.5Hz, 3.69-3.73 (4H, mn, and (1,dJI9.2Hz, and1 (1H, dd, 1 9.2 and 2.4Hz, 41-H), 8.69 (1H, d, !I 2.4Hz, S~(CD 3 O)1.

20.2 20.3 25.6 (C-411), 26.7 (C-3 33.0 41.6 43.7 44.0 47.0 56.6 61.2 66.4 70.0 70.6 (C-7)e 71.6 76.4 107.0 (C-31), 123.4 124.3 138.5 151.8 156.7 161.5 191.0 M/z& 488 (Mit 18%), 189 (100%).

WO 92/02518 PCT/GB91/01285 -66- Example (Thien-3-vl)-1-(normon-2-yl)ketone 3-Bromothiophene in THF (10ml) was added dropwise to n-butyl lithium (1.6M in hexano) in THF (20ml) as -70 0 C over minutes. After a further 20 min at -70 0 C N-methoxy-Nmethyl-6,7,13-0-tris(trimethylsilyl)monamide (1.20g, 2.00mmol) in THF (10ml) was added dropwise whilst maintaining the temperature below -65 0 C. After 1.5h at 0 C acetic acid (0.23ml) then water were added and the aqueous phase extracted with ethyl acetate. Drying (Na 2

SO

4 and evaporation to dryness under reduced pressure gave the crude protected ketone which was dissolved in methanol (25ml) and 4-dimethylaminopyridine dihydrochloride 0.026mmol) was added. After stirring at room temperature for 30 min, saturated sodium hydrogen carbonate solution was added and the solution extraction with ethyl acetate.

Drying (Na 2

SO

4 evaporation to dryness under reduced pressure and purification by flash chromatography using 7% methanol in dichloromethane as eluent gave the title compound (0.68g, 84%) as a white foam; vmax (KBr) 3465, 3308, 2968, 2920, 2888, 1657, 1598, 1246cm- 1 max (EtOH) 267nm (Em 11,960); 5 H (CD30D) 0.94 (3H, d, J 7.1Hz, 17-H 3 1.19 (3H, d, J 6.3Hz, 14-H 3 1.33-1.47 (1H, m, 12-H), 1.68- 1.73 (2H, m, 9-H 2 1.92-2.02 (1H, m, 2.23 (3H, s,

H

3 2.35 (1H, dd, J 9.5 and 14.3Hz, 2.69-2.84 (3H, m, 4, 10 and 11-H), 3.40 (1H, dd, J 9.0 and 3.0Hz, 3.59 (1H, d, J 11.5Hz, 16-H), 3.73-3.92 (4H, m, 5, 7, 13 and 16- 6.85 (1H, s, 7.44 (1H, dd, J 5.0 and 2.7Hz, 7.55 (1H, dd, J 5.0 and 1.3Hz, 8.26 (1H, dd, J 2.7 and 1.3Hz, 5C(CD 3 0D) 12.2(C-17), 20.2 20.3 32.9 41.7 43.6 44.3 56.8 61.2 66.3 70.0 71.6 (C- 13), 76.4, 124.0 127.5, 128.0, 133.3, 145.3 (C- 187.2 m/z 410 (M 178 (Found: M, 410.1760. C 2 1

H

30 0 6 S requires M 410.1763).

WO 92/02518 PCT/GB9I /01285 -67- Example 21 (Thien-2-yl) -1-(normon-2-yl) ketone a) -(Thien-2-yl) 13-0-tris-trirnethylsilyl- (normon-2-yl) ketone; n-Butyl lithium (1.6M in hexane) (1.00m1, l.6Ommol) was added dropwise to 2-bromothiophehe (0.24g, 1.5mxnol) in THF (4m1) whilst maintaining the temperature below -65*C. After mins at -70 0 C, N-methoxy-Ni-methyl-6,7,13-0-tris- (trimethylsilyl)monamide (0.60g, 1.O0mmol) in THF (15m1) was added dropwise whilst maintaining the temperature below After 15 mins at -70'C, acetic acid (0.14g) was added followed by water (20m1) Extraction witi-, diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure, and purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave the title compound (0.25g, 33%) as a white foam; 8H (CDCl 3 0.09-0.17 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.0Hz, 17-H 3 1.20 (3H, d, !I 6.3Hz, 14-H 3 1.30-1.41 (1H, m, 12-H), 1.56 (2H, br.s, 9-H 2 1.73-1.83 (1h, in, 2.10 (1H, dd, J2 14.6 and 10.6Hz, 2.24 (311, s, 15-H 3 2.59 (1H, d, J 14.6Hz, 4- ",2.70-2.74 (2H, mt 10 and 11-H), 3.41 (1H, dd, J 8.9 and Z'.4Hz, 3.56 (1H, d, J 11.3Hz, 16-H), 3.78-3.95 (4H, m, 5,7,13 and 16-H), 6.70 (1H, s, 7.10 (1H, t, J 3.7Hz 41-H), 7.60 (1H, dd, J4.2 and 0.9Hz, 7.69 (1H, dd, J 2.7 and 0MHz, b) '(Thien-2-yl) -1-(normon-2-yl) ketone The above ketone (0.23g, 0.38mmol) and hydrochloric acid (0.4H) (3.Qml, 1.2 x 10 3 mo1) in THF (15m1) were stirred at room temperature for 2 min. Saturated sodium hydrogen carbonate solution (7.5m1) was then added. Extraction with diethyl. ether, drying (MgSO 4 evaporation to dryness under B3 027 !2 9 Scplwirnbor 1992 -68reduced Pressure and purification by flash chromatography using 0-6% methanol in dichioromethane as eluent gave the title compound (0.112g, 71%) as a white foam; Vmax (KBr) 3440, 2970, 2926, 1639, 1602, 1246, 1184cmf 1 X max (EtOH) 296nm (F 14,044); 8H (CDCl 3 0.93 (3H, d, J 7.1Hz, 17-H 3 1.22 (3H, d, J 6.3Hz, 14-H 3 1.29-1.41 (1H, m, 12-H), 1.71- 1.77 (2H, m, 9-H 2 1.96-2.04 (1H, m, 2.30 (3H, s,

H

3 2.35 (1H, dd, J 1.6 and 9.0Hz, 2.59-2.73 (2H, m 4 and 11-H), 2.78-2.84 (1H, m, 10-H), 3.48 (lH, dd, J 8.9 and 2.0Hz, 3.59 (1H, dd, 1 11.3 and 1.8Hz, 16-H), 3.74-3.98 (4H, m, 5,7,13 and 16-H), 6.76 (1H, s, 7.10 (1H, t, J 3.7Hz, 41-H), 7.60 (1H, dd, 1 4.2 and 0.9Hz, 3'- 7.69 (1H, dd, 1 2.7 and 0.8Hz, 5C (CDCl 3 12.6.

20.7 20.7 31.5 39.6 42.7 43.3 55.6 61.2 65.4 16), 68.8 70.3 71.2 74.9 121.8 128.0, 131.3, 133.2 (C31, C41 and C51) 146.6 (C21), 157.6 183.7 m/z 410 111 (Found: 410.1768. C 21

H

30 0 6 S requires M, 410.1763).

Example 22 (thien-2-yl) -1-(normon-2-yl) ketone a) 5-Methoxy-(thien-2-Yl)-l-(6,7, 13-0-tris-trimethyl silylnormon-2-yl) ketone utyl lithium (1.6M in hexane) (l.O0ml, l.E0mmol) was added dropwise to diisolpropylamine (0.18g, 1.7Bmmol) in THF (4m1) whilst maintaining the temperature at 02000. After mins at -200C, 2-methoxythiophene (0.17g, i.S0mmol) was added dropwise whilst maintaining the temperature below After 15 mins at -700C, cerous chloride (0.3700, i.50mmol) was added whilst maintaining the temperature below -650C. After a further 45 mins at -700C, N-methoxy- ,~N-methyl-6,7,l3-O-tris-(trimethylsilyl)monamide (0.60g, United KcmP Iont Office SU TITES T N ~POCT I; nai A!,,p.Ica tIt0 WO 92/02518 PCT/GB91/01285 -69- 1.00mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -65 0 C. After 1.25h at -70 0 C acetic acid (0.14g) was added foll..wed by water (20ml). Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave the title compound (0.08g, 13%) as a white foam; 6

H

0.09-0.17 (27H, m, 9 x SiCH 3 0.91 (3H, d, J 7.0Hz, 17-H 3 1.19 (3H, d, J 6.3Hz, 14-H 3 1.33-1.41 (1H, m, 12-H), 1.70 (2H, br.s, 9-H 2 1.80-1.88 (1H, m, 2.08 (1H, dd, J 14.6 and 10.7Hz, 2.18 (3H, s, 15-H 3 2.59 (1H, d, J 13.9, and 2.68-2.80 (2H, r, 10 and 11-H), 3.41 (1H, dd, J 12.0 and 3.0Hz, 3.59 (1H, d, J 11.3, 16-H), 3.80-3.92 (4H, m, 5,7,13 and 16H), 3.95 (3H, s, OCH 3 6.72 (1H, s, 6.34 (1H, d, J 4.3Hz, 7.58 (1H, d, J 4.3Hz, b) (5-Methoxythien-2-vl)-1-(normon-2-yl)ketone The above ketone (0.08g, 0.13mmol) and hydrochloric acid (0.4M) (3ml, 1.2 x 10- 3 mol) in THF (15ml) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate s-lution (7.5ml) was added. Extraction with diethyl ether drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 0-6% methanol in dichloromethane as eluent gave the J title compound (0.040g, 69%) as a white foam; vmax (KBr) 3426, 2970, 2887, 1638, 1598, 1242, 1051cm- 1 ax (EtOH) 333nm (em 14,424); 6H (CDC1 3 0.93 (3H, d, 7.1Hz, 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.35-1.47 (1H, m, 12-H), 1.67- 1.75 (2H, m, 9-H 2 1.92-2.03 (1H, m, 2.20 (3H, s,

H

3 2.35 (1H, dd, j 13.5 and 9.5Hz, 2.64-2.73 (2H, m, 4 and 11-H), 2.78-2.83 (1H, m, 10-H), 3.41 (1H, dd, J 1,2.0 and 3.0Hz, 3.59 (1H, dd, J 10.7 and 1.8Hz, 16-H), 3.74-3.95 (4H, m, 5,7,13 and 16-H), 3.97 (3H, s, OCH 3 6.77 (1H, s, 6.35 (1H, d, J 4.3Hz, 7.62 (1H, d, PC&B3 1 /01285 2 9 Sep'.emDer 1991 B3027 4.3Hz, 8 C (CDC13), 12.2 20.0 20.3 (C- 14), 33.0 41.7 43.7 44.2 56.9 60.9 (OCH 3 61.2 66.4 69.9 70.7 71.6 76.4 107.0 121.9 (C- 133.9 134.1 157.5 175.9 185.2 m/z 440 (M 141 (Found: 440.1871. C 22

H

32 0 7 S requires M, 440.1869).

Example 23 [2-(Methylmercapto)thiazol-5-yl]-1-(normon-2-yl)ketone Tetrabutylammonium hydroxide (1.OM in methanol) (5.00ml, and iodomethane (0.739, 5.0mmol) were add dropwise to 2-mercaptothiazole (0.59g, 5.0mmol) in THF (5ml) at room' temperature. After 1.5h and evaporation to dryness under reduced pressure, the reaction mixture was triturated with hexane and diethyl ether taking the solid up in dichlormethane. The combined extracts were dried (MgSO 4 evaporated to dryness under reduced pressure and purified by flash chromatography using diethyl ether in hexane (0.25%) as eluent to give 2-methylmercaptothiazole (0.23g, 34%).

n-Butyl lithium (1.6M in hexane) (0.60ml, 1.00mmol) was added dropwise to 2-methylmercaptothiazole (0.13g, 1.00mmol) in THF (5ml) whilst maintaining the temperature below After 30 mins at -70oC, N-methoxy- N-methyl-6,7,13-0-tris(trimethyylsily)monamide (0.6g, 1.00mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -650C. After 1.5h at -70°C, acetic acid (0,14g) was added followed by water (20ml). Extraction with diethyl ether, drying (MgSo 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in hexane as eluent gave the trimethylsilyl protected title compound (0.48g, 72%) as a white foam. This was then stirred with hydrochloric acid (0.4M) (3ml, 1.2 x 10-3mol) in THF Uniled m Office i PCT SUBST,.TE Sh..ET WO 92/02518 PCT/GB91/01285 -71at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was added. Extraction with diethyl ether drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (0.231g, 70%) as a white foam; Vmax (KBr) 3428, 2970, 2879, 1642, 1605, 1255, 1047 cm_1, ?max (EtOH) 330nm (Em 22,251); 6H (CDC13) 0.93 (3H, d, J 7.1Hz, 17-H 3 1.22 (3H, d, J 6.4Hz, 14-H 3 1.31.-1.45 (1H, m, 12-H), 1.65- 1.75 (2H, m, 9-H 2 1.90-2.04 (1H, m, 2.27 (3H, s,

H

3 2.35 (1H, dd, J 11.8 and 9.5Hz, 2.67-2.85 (6H, m, 4, 10 and 11-H), 2.75 (3H, s, SCH 3 3.41 (1H, dd, J 9.0 and 3.59 (1H, dd, J 10.9 and 1.8Hz, 16-H), 3.74- 3.96 (4H, m, 5,7,13 and 16-H), 6.67 (1H, s, 8.31 (1H, s, 6C (CDC13), 12.2 16.7 (S-CH 3 20.3 (C- 20.4 33.0 41.8 43.7 44.4 56.9 61.2 66.4 69.9 70.7 71.6 76.4 122.3 143.1 (C- 147.3 161.0 171.5 183.5 m/z 457 (M 457.1595. C 2 1

H

3 1 N0 6

S

2 requires M, 457.1593).

Example 24 2-(Piperidin-l-yl)thiazol-5-yll-1-(normon-2-yl) ketone a) 2-(Piperidin-1-vl)thiazole Chloroacetaldehyde (45% w/w in water) (0.92g, 5.25mmol) in ethanol (22ml) was added dropwise over 10 minutes to 1piperidinethiocarboxamide (0.91g, 6.3mmol) in ethanol (llml). After refluxing for 2h, iced water (55ml) was added, followed by dropwise addition of ammonia (18M) until the reaction mixture was found to be basic. Extraction with diethyl ether, evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane as eluent gave the title compound WO 92/02518 PCTr/GB9I/01285 -72- (0 .4 3g, 4 8H (CDCl 3 1. 67 (6H, mn, b-H 4 and c-H 2 3 .4 8 (4H, m, a-H 4 6.52. (1H, d, J 3. 6Hz, 5' H) 7. 19 (1H, d, J 3.6Hz, b r2- (Piperidin-l-yl)thiazol-5-yl-l-(normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.5ml, 2.4Omnol) was added dropwise to 2-piperidin-1-yl thiazole (0.40g, 2.4rnxol) in THF (7rnl) whilst maintaining the temperature below -65 0

C.

After lh at -70 0 C N-methoxy-l--methyl-6,7,13-O-tris(trimethylsilyl)monamide (0.98g, 1.6Ommol) in TEF (Bml) was added dropwise, maintaining the temperature below -65 0

C.

After 1.5h at -70 0 C acetic acid (0.22g) was aided, followed 1s by water (25m1) Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and partial purification by flash chromatography using ethyl acetate/hexare (15-50%) as eluent gave [2-(piperidin-1ketone (0.251.g) as a light brown foam. The above impure ketone (0.251g, <0.3mmol) and hydrochloric acid (0.4Mi) (8m1, 3.2. x 2.0-3mol) in THF (24m1) were stirred at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (12m1) was added. Extraction with diethyl ether, drying (MgS0 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichioromethane as eluent gave the title compound (0.107g, 13%) as a cream foam; 'uma (KBr) 3423, U4 2937, 2861, 1640, 1594, 12523, lO5lcnf 1 Xmax (EtOH) 356nrn (em 24, 935) 81j (CD 3 OD) 0. 93 (3H, d, 1 7.1IHz, 17-H 3 1.22 (3H, d, J1 6.4Hz, 14-H1 3 1.34-1.46 (1H, m, 12-H), 1.63-l./2 (8H, m, 9-H 2 b-H 4 and c-H 2 1.90-2.04 (1H, m, 2.20 (3H, s, 15-H 3 2.31 (1H, dd, J 14.3 and 9.5Hz, 2.67- 2.85 (3H, m, 4, 10, and 11-H), 3.40 (1H, dd, J 8.9 and 3.0Hz, 3.54-3.66 (5H, m, 16-H and a-H 4 3.73-3.92 M4, mn, 5,7,13 and 16-H), 6.67 (1H, s, 7.94 (1H, s, 41-H); 8C (CDCl 3 12.3 20.1 20.3 (C-14), 24.9 26.2 33.0 41.8 43.8 (C-12), WVO 92/02518 PCT/G B9 1/01285 -73- 44.2 50. 8 56. 9 61.3 (C-l1) 66. 4 (C-16) 70. 0 70. 0 71. 6 (C-13) 76. 4 122.4 131.7 148.7 156.9 176.5 184.4 m/z 494 195 (100%); (Found: 494.2470. C 25

H

38

N

2 0 4 S requires M, 494.2451).

Example -1-(normc, -2-vl) ketone a) (Isothiazol-5-yl)-l-(6,7,13-0-tris-trimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.O0ml, 1.60mnol) was added dropwise to isothiazole (0.12g, 1.5minol) in THF (4m1) whilst maintaining the temperature below -65 0 C. After i5mins at 0 C, 6,7,13-O-tris(trimethylsilyl)monaldehyde (0.54g, 1.Ommol) in THF (4m1) was added dropwise, maintaining the temperature beiow -65 0 C. After 30mins. at -70 0 C acetic acid (0.10g) was added, followed by water (20m1) Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane as eluent gave the diastereomeric alcohols (0.36g, 38%) as a yellow oil; 8H (CDCl 3 0.09-0.17 (27H, mn, 9 x SiCH 3 0.90 (3H, d, I 17-H 3 1.20 (3H, d, J6.3Hz, 14-H 3 1.30-1.41 (2H, m, 8 and 12-H), 1.56 (2H, m,9-H 2 1.80 (4H, m, 15-H 3 and OH), 1.96-2.05 (1H, dd, J 14.0 and 2.8Hz, 2.49 (1H, d, !I 16.7Hz, 2.63-2.73 (2H, mn, 10 and 11-H), 3.39 (1H, dd, J 8.7 and 2.1Hz, 3.56 (1H, d, J 11.4Hz, 16-H), 3.73- 3.93 (4H, m, 5,7,13 and 16-H), 5.54 (1H, d, J1 3.5Hz, 2-H), 5.85 (1H, d, !I 8.5Hz, 7.6 (1H, s, 41-H), 8.38 (IH, s, 31-H) Manganese dioxide (1.00g, 3wt equivalents) and benzene (15mi) were added to the above alcohols (0.36g, 0.S7inmol) and the reaction mixture heated to reflux under WO 92/02518 PCT/GB91/01285 -74- Dean and Stark conditions for 30mins. The solids were removed by filtration and washed with dioxane. The filtrates were combined and evaporated to dryness under reduced pressure. Purification by flash chromatography using ethyl acetate/hexane as eluent gave the title compound (0.02g, as a white foam; 8H (CDC1 3 0.09-0.19 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.0Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.33-1.43 (1H, m, 12-H), 1.59 (1H, m, 8-H), 1.78-1.85 (2H, m, 9-H 2 2.10 (1H, dd, J 14.6 and 10.2Hz, 2.30 (3H, s, 15-H 3 2.59-2.71 (3H, m, 4,10 and 11-H), 3.40 (1H, dd, J 9.0 and 2.4Hz, OH), 3.56 (1H, d, J 11.3Hz, 16-H), 3.77-3.95 (4H, m, 5,7,13 and 16-H), 6.66 (1H, s, 7.65 (1H, d, J 1.7Hz, 18.56 (1H, d, J 1.7Hz, b) (Isothiazol-5-vl)-1-(normon-2-yl) ketone The above ketone (18.3mg, 0.03mmol) and hydrochloric acid (0.4M) (1.5ml, 0.5mmol) in THF (7.5ml) were stirred at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (3.75ml) was then added. Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (1l.0mg, 92%) as a white foam; 8 H (CD 3 0D) 0.93 (3H, d, J 7.1Hz, 17-H 3 1.19 (3H, d, 2 6.4Hz, 14-H 3 1.35-1.45 (1H, m, 12-H), 1.64-1.74 (2H, m, 9-H2), 1.91-2.01 (1H, m, 2.30 (3H, s, 15-H 3 2.35 (1H, dd, J 14.3 and 9.6Hz, 2.70 (1H, dd, J 7.6 and 2.2Hz, 2.80 (2H, m, 10 and 11-H), 3.40 (1H, dd, J 12.1 and 3.1Hz, 3.60 (1H, d, J 11.2Hz, 16-H), 3.73-3.95 (4H, m, 5,7,13 and 16-H), 6.83 (1H, s, 7.84 (1H, d, J 1.8Hz, 8.60 (1H, d, J 1.7Hz, WO 92/02518 PCT/GB91/01285 Examole 26 [2-(Hydroxvmethvl)thien-5-vl]-l-(normon-2-vl) ketone Bromine (0.51ml, 10mmol) was added dropwise to 2-thiophene methanol (1.14g, 10mmol) in acetic acid (30ml). After stirring for 30mins. with efficient cooling, water was added. Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave (0.547g, 2.8mmol,. 28%) as a brown oil; 6 H (CDC13) 1.70 (1H, s, OH), 4.75 (2H, s, CH 2 6.76 (1H, d, J 3.8Hz, 6.90 (1H, d, J 3.8Hz, This was taken up in diethyl ether (10ml) and treated with triethylamine (0.8ml, 5.6mmol) and chlorotrimethylsilane (0.5ml, 4.2mmol). After 10mins. a catalytic amount of 4-N,N-dimethylaminopyridine was added.

After 45mins. at room temperature the reaction was diluted with diethyl ether, filtered and the filtrate evaporated.

The residue was taken up in hexane and refiltered.

Evaporation of the filtrate gave the required protected alcohol (0.63g, 2.37mmol, 85%) as a brown oil; Omax (CHC1 3 2960, 2937, 2865, 1607, 1460, 1450, 1382, 1258, 1175, 1072, 873, 851cm 1 n-Butyllithium (1.6M in hexane) 2.37mmol) was added dropwise to this material in THF whilst maintaining the temperature below -65 0 C. After at -70 0 C, N-methoxy-N-methyl-6,7,13-0-tris(trimethylsilyl)monamide (0.95g, 1.58mmol) in THF (8ml) was added dropwise, maintaining the temperature below -65 0 C. After 1.5h at -70 0

C

acetic acid (0.21g) was added, followed by water Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and partial purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave tetra-trimethylsilyl-protected ketone as a brown oil (0.277g, 0.36riAol, The above impure material and hydrochloric acid (0.4M) (4.75ml, 1.9mmol) in THF (24ml) were stirred at room temperature for 2mins. Saturated sodium WO 92/02518 WO 9202518PCT/GB91/01285 -76hydrogen carbonate solution (12m1) was added. Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (97.6mg, 58%) as a white foam; o 0 max 3421, 2969, 2877, 1639, 1602, 1257, 1049cm 1 Xmitax (EtOH) 306.5nm (e 661;~ (CD 3 OD) 0.94 (3H, d, J 7.0Hz, 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.35- 1.45 (1H, mn, 12-H), 1.64-1.73 (2H, m, 9-H 2 1.90-1.98 (1H, 2.22 (3H, s, 15-H 3 2.31 (1H, dd, J 14.4 and 9.6Hz, 2.67-2.84 (3H, in, 4,10 and 11-H), 3.39 (lH, dd, J 9.0 and 3.1Hz, 3.60 (1H, d, J 10.7Hz, 16-H), 3.74- 3.94 (4H, mn, 5,7,13 and 16-H), 6.82 (1H, s, 7.06 (1H, d, J 3.8Hz, 7.72 (1H, d, J 3.8Hz, 41-H); 5 C (CD 3

OD),

12.5 20.5 20.6 33.2 42.0 44.0 44.6 57.1 60.6 (C-CH- 2 61.5 66.7 70.2 71.0 71.9 (C-13)f 76.6 122.0 126.7 or 133.4 or 147.0 (C-21 or 158.3 (C-21 or 159.7 185.7 rn/z 441 (kli, 141 (100%); (Found: M+,1 440.1841. C 22

H

32 0 7 S requires M, 440.1869).

Examr~1e 27 (2-Foriylthien-5-yl)-l-(no mon-2-YI) ketone (2-(Hydroxyinethyl)thien-5-yl]-1-(6,7,13-0-tristrinethylsilylnormon-2-yl) ketone was obtained as one of the major products from the reaction of N-inethoxy-li-methyl- 6,7, 13-0-tris (trimethylsilyl)inonamide and trimethylsilylprotected 2-bromo-5-inethylhydroxythiophene (see Example 26).

Manganese dioxide (1.40g, 3 weight equivalents) and TI-F (40m1) were added to this impure material (1.02g, approx. Immol) and the reaction mixture stirred at room WO 92/02518 WO 9202518PCT/GB91/01285 -77temperature for 2.75h. The solids were removed by filtration and washed with TEF. The filtrates were combined and evaporated to dryness under reduced pressure. Partial purification by flash chromatography using ethyl acetate/hexane as eluent gave (2-formyl 13-O-tris-trimethylsilylnormon-2-yl) ketone (93.8mg, 14%) as a colourless foam. The above impure ketone (46.6mg, 0.O7lrnxol) and hydrochloric acid (0.4M) (3m1, 1.2mmol) in THF (15m1) were stirred at room temperature for 2mins.

Saturated sodium hydrogen carbonate solution (7.5m1) was added. Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (200mg, 64%) as a colourless foam; oma (KBr) 3446, 2969, 2924, 1673, 1645, 1605, 1245, 1207, 1050cm- 1 .ymax (CH 3 CN) (em 19, 275) 8H (CD 3 OD) 0. 94 (3Me d, J 7 .1Hz, 17-H 3 1.20 (3H, d, 2 6.4Hz, 14-H 3 1.31-1.47 (1H, m, 12-H), 1.65-1.75 (2H, m, 9-H2), 1.90-2.04 (1H1, m, 2.20 (3-hemiacetal-H, S, 15-H 3 2.28 (3-aldehyde-H, s, 15-H 3 2.31-2.43 (1H, dd, J 14.3 and 9.6Hz, 2.64-2.71 (1HI dd, J 7.6 and 2.2Hz, 2.75-2.84 (2H, m, 10 and 11-H), 3.41 (1H, dd, J and 3.1Hz, 3.62 (1H, d, !I 11.6Hz, 16-H), 3.73-3.92 (4H, m, 5,7,13 and 16-H), 5.71 (1-hemiacetal-H, s, CH(OD) (OCD 3 6.84 (1-hemiacetal-H, s, 6.90 (1aldehyde-H, s, 17.13 (1-hemiacetal-H, di, !I 3.9Hz, 31-H), 7.70 (1-hemiacetal-H, d, I 3.9Hz, 41-H), 7.90 (2aldehyde-H, m, 3' and 41-H), 9.94 (1-aldehyde-H, s, CHO); m/z 438 139 (Found: 438.76

C

22

H

30 0 7 S requires Mt 438.1712).

WO 92/02518 PCT/GB9I/ 01285' -78- Example 28 (Piperidin-l-vl)pvrimidin-5-vll-l- (normon-2-yl) ketone a) (Piperidin-l-yl) -pyrimidin--5-vll1-1-(6,7,13-0tristrimethylsillnormon-2-Vl) ketone n-Butyllithium (1.6M in hexane).(3.4'7ml, 5.53mmol) was added dropwise to 5-brorno-2- (piperidin-l-yl)pyrimidine (1.34g, 5.53mnol) in TI-F (B0ml) maintaining the temperature below 0 C. After 1h at -85 0 C cerium trichloride (1.36g, 5.53mnol) was added. After lh at -85 0 C N-methoxy-NI-met~iyl- 6,7,13-0-tris(trimethylsilyl)monamide (3.60g, 6.Q0mmol) in THF (20m1) was added dropwise whilst maintaining the temperature below -85 0 C. After 3h at -85 0 C acetic acid (O.32m1) was added followed by water (200m1). Extraction with ethyl acetate, drying (Na 2

SO

4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexarie/ethyl acetate as eluent gave the title compound (1.00g, 48%) as a colourless oil; (all spectroscopic details were identical to those of Example la).

2- (Piperidin-l-yl) -pvrimidin-5-vl (normon-2-vl) ketone As for Example llb using the above ketone (0.99g) giving the title compound (0.51g, 74%) as a pale yellow foam; (all spectroscopic data were identical to those of Example llb).

WO 92/02518 PCT/GB91/01285 -79- Example 29 (normon-2-yl) ketone a) (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-vl) ketone n-Butyllithium (1.6M in hexane) (2.81ml, 4.50mmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine (0.91g, 4.50mmol) in THF (30ml) at -85 0 C. After lh at -850C cerium trichloride (1.68g, 4.50mmol) was adCdd. After lh at -75 0

C

N-methoxy-N-methyl-6,7,13-0-tris(trimethylsilyl)monamide (1.36g, 2.25mmol) in THF (10ml) was added dropwise at -85 0

C.

After 3h at -85 0 C acetic acid (0.26ml) then water were added. Extraction with ethyl acetate, drying (Na 2

SO

4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the impure protected ketone (1.13g, 76%) as a colourless oil. This oil was dissolved in THF (57ml) and hydrochloric acid (0.4N) (11.3ml) and the solution stirred at room temperature for 2mins. then saturated sodium hydrogen carbonate solution (12ml) was added. Extraction with ethyl acetate, drying (Na 2

SO

4 evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.56g, 74%) as a white foam; (all spectroscopic data were identical to those of Example 8b) c L Examole (normon-2-vl) -ketone a) (2-Dimethylamiino-pvrid-5-Yl 6,7. 13-0tris-trimethylsilyl normon-2-yl) ketone n -Butyllith-ium (1.6M in hexane) (6.25ml, 10.00mnol) was added dropwise to 5-bromo-2-dimethvlaminopyridine (2.01g, 10.O0mrnol) in THF (80mi) at -85 0 C. After 2,h atL -85 0 C cerium trichioride (2.47g, 10.O0ramol) was added. After lh at -85 0

C

N-methoxy-N-methyl-6, 7, 13-O-tris '(trimethylsilyl) monamide (3.00g, 4.97mnol) in THF (20ml) was added dropwise at -85 0

C.

After 3h at -8500 acetic acid (0.57ml) then water (100mi) were added. Extraction with ethyl acetate, drying, (Na 2

SO

4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acet-ate as eluent gave the title compound (2.69g, 66%) as a pale yellow oil; (all spectroscopic data were identical to those of Example 12a) b) (2-Dimethylamino;Vwrid-5-yl) (normon-2-yl) ketone The above ketone (2.69g, 3.3Ommol) in TI-F (190m1) was treated with hydrochloric acid (0.4N) (37.5m1) at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (40m1) was a.dded and the solution extracted with V ethyl z!etic. Drying (Na SO 4 evaporation to dryness under *2 4) reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (1.65g, 91%) as a pale yellow foam; (all spectroscopic data were identical to those of Example 12b).

WO 92/02518 'WO 9202518PCF/GB9I /01285 Example 31 (Pyrrol-3-l) (norinon-2-yl) ketone a) (1-Triisopropylsilylpyrrol-3-vl)-l-(6,7,13-0tristrirnethylsilylnormon-2-yl) ketone t-Butyllithiun (1.7M in pentane) (6.57inl, 10.52mmuol) was added dropwise to 3-bromo-1-triisopropylsilylpyrrole (1.54g, 5.26inmol) in THF (25m1) at -78oC. After lh at -78 0

C

N-methoxy-Ni-methyl-6, 17, 13-0-tris (trimethylsilyl)nonainide (1.80g, 3.O0mmol) in THF (l0mi) was added dropwise at After 3h at -75 0 C acetic acid (0.36m1) then water (G6ini) were added. Extraction with ethyl acetate, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (1.42g, 62%) as a colourless oil; 5H (CD 3 OE 0.10-0.18 \(27H, in, 9 x SiCH 3 0.90 (3H, d, J 7.1Hz, 17-H 3 1.10 [18H, in, 3 x CH(CH 3 2 1.20 (3H, d, 'J 6.3Hz, 14-H 3 1.37-1.70 [6H, m, 12-H, 9-H 2 and 3 x CH(CH 3 1.75-1.90 (1H, in, 8-H), 2.09 (1H, dd, J 14.6 and 9.2Hz, 2.23 (3H, s, 15-H 3 2.59 (1H, d, J 14.6Hz, 2.63-2.71 (2H, mn, 10 and 11-H), 3.41 (1H, dd, J 8.9 and 2.4Hz, 3.54 (1H, d, J 11.3Hz, 16-H), 3.80-3.94 (4H, in, 5,7,13 and 16-H), 6.59 (1H, s, 6.70-6.75 (2H, in, 2 x pyrrole-H), 7.37-7.40 (1H, in, pyrrole-H); in/z 765 (j 73 (Found: M 765.4687. C 39

H

75 9NO 6 Si 4 requires M, 765.4672).

(Pyrrol *Y1)-1-(nornon-2-yl) ketone T~e above ketone (0.47g, 0.61;nmol) in T. (19in1) was treated W.',th hydrochloric acid (0.4N) (3.70n1) at room temperature for 2inins. Saturated sodium hydrogen carbonate solution was added, the solution extracted with ethyl acetate, the WO 92/02518 PC1'/GB91 01 28' -82combined organic fractions dried (MgSO 4 and evaporated to dryness under reduced pressure to g,;ve the crude N-protected pyrrol-3-yl ketone. THE '(10ml) and tetrabutylanmo-LUin fluor'.de trihydrate (0.21g, 0.67mmol) were added and the solution stirred at room temperature for l0mins. Evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichioroinethane as eluent gave the title compound (0.22g, 92%) as a white foam; Umnax (KBr) 3400, 2968, 2931, 1643, 1595, 1501cmn 1 Xmax (EtOH) 293nin (shoulder) (em 7,630) and 259.5 (e-m 12,597); (CDCl 3 0.94 (3H, d, J 7.0Hz, 17-H 3 1.22 (3H, d, J 6.3Hz, 14-H 3 1.33-1.50 (1H, mn, 12-H), 1.65-1.78 (2H, mn, 9-H 2 1.93-2.06 (1H, m, 2.21 (3H, s, 15-H 3 2.31 (1H, dd, J 14.6 and 9.3Hz, 2.67-2.85 (3H, in, 4,10 and 11-H), 3.41 (1H, dd, J 9.0 and 3.0Hz, 3.60 (1H, d, J 11.4Hz, 16-H), 3.75-3.94 (4H, in, 5,7,13 and 16-H), 6.62-6.65 (2H, in, 2-H and pyrrole-H), 6.72-6.78 (1H, mn, pyrrole-H), 7.44-7.48 (1H, mn, pyrrole-H), 10.65 (1H, br.s, 5C (CDCl 3

/CD

3

OD)

12.,5 19.8 20.5 31.6 39.7 42.6 42.8 55.8 60.9 (C-li), 65.3 68.5 70.3 70.9 75.1 108.4 119.6 (C-21 or 123.9 124.2 or 51), 127.2 153.6 188.2 m/z 393 94 (Found: M4k 393.2166.

C

21

H

31 N0 6 requires M, 393.2151).

Example 32 (thien-2-yl) -1-(normon-2-yl) ketone '1 a) 5-Bromo- (thien-2-Vl) 7,13-O-tris-triinethvlsilylnorinon-2-vl) ketone 1-Butyllithiun (1.6M in hexane) (5.O0rnl, 8.O0rmmol) was added dropwise to 2-brornothiophene (1.22g, 7.S0rnmol) in THF (20m1) WO 92/02518 PCT/GB91/01285 -83whilst maintaining the temperature below -65 0 C. After mins. at -70 0 C N-methoxy-N-methyl-6,7,13-0tris(trimethylsilyl)monamide (3.00g, 5.00mmol) in THF was added dropwise maintaining the temperature below -650C.

After 30 mins. at 70 0 C, acetic acid (0.70g) was added followed by water (100ml). Extraction with diethyl ether, drying (MgS04), evaporation to dryness under reduced pressure and purification by flash chromatography using diethyl ether in hexane as eluent gave the title compound (0.11g, as the minor product (white foam). [See example 21 for major product]; 8H (CDC1 3 0.06-0.17 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.34-1.45 (1H, m, 12-H), 1.60 (2H, br.s, 9-H 2 1.75-1.85 (1H, m, 2.10 (1H, dd, J 15.4 and 11.2Hz, 2.28 (3H, s, 15-H 3 2.58-2.75 (3H, m, 10,11 and 3.39 (1H, dd, J 9.0 and 2.4Hz, 3.56 (1H, d, J 11.4Hz, 16-H), 3.77-3.95 (4H, m, 5,17,13 and 16-H), 6.63 (1H, s, 7.06 (1H, d, J 4.0,iz, 7.42 (1H, d, J 4.1Hz, b) 5-Bromo-(thien-2-yl)-1-(normon-2-yl)ketone The above ketone (0.llg, 0.16mmol) and hydrochloric acid (0.4M) (3.0ml, 1.2 x 10-3mol) in THF (15ml) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was then added. Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane as eluent gave the title compound (0.05g, 58%) as a white foam; Xmax (EtOH) 308nm (em 26,220); 8 H (CD 3 OD) 0.95 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.35-1.45 (1H, m, 12-H), 1.70 (2H, br.s, 9-H 2 1.90-2.02 (1H, m, 2.25 (3H, s, 3 2.33 (1H, dd, J 14.3 and 9.6Hz, 2.70 (1H, dd, J 7.5 and 2.1Hz, 2.75-2.85 (2H, m, 10 and 11-H), 3.38 (1H, dd, J 9.1 and 3.0Hz, 3.60 (1H, d, J 11.5Hz, WO 92/02518 PCT/GB91/1285 -84- 16-H), 3.76-3.93 (3H, m, 5,7,13 and 16-H), 6.78 (1H, s, 7.21 (1H, d, J 4.0Hz, 7.61 (1H, d, J 4.1Hz, m/z 489 (MH 111 (Found: M 488.0825. C 2 1

H

2 9 06SBr requires M, 488.0868).

Example 33 [2-(Methylsulphinvl)thiazol-5-yl]-1-(normon-2-yl)ketone Saturated aqueous sodium hydrogen carbonate solution (1.40ml) was added to [2-(methylmercapto)thiazol-5-yl]-1- (normon-2-yl) ketone (0.05g, 0.10mmol) in dichloromethane (2.75ml) at room temperature. After cooling to 0 0 C, mchloroperoxybenzoic acid (0.03g, 0.15mmol) was added. After 2.5h at 0°C, dichloromethane (20ml) was added. The aqueous layer was evaporated to dryness under reduced pressure and triturated exhaustively with ethyl acetate and diethyl ether. Evaporation to dryness under reduced pressure of the combined organic layers and purification by flash chromatography using methanol in dichloromethane as eluent, gave the title compound (0.02g, Xmax (EtOH) 298nm (em 23,440); 8H (CD 3 OD) 0.95 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, d, J 6.5Hz, 14-H 3 1.35-1.46 (1H, m, 12-H), 1.67- 1.75 (2H, br.s, 9-H 2 1.90-2.02 (1H, m, 2.29 (3H, s, 15-H 3 2.39 (1H, dd, J 14.2 and 9.6Hz, 2.70 (1H, d, J 7.6Hz, 2.76-2.84 (2H, m, 10 and 11-H), 3.06 (3H, s,

SOCH

3 3.40 (1H, dd, J 8.9 and 3.0Hz, 3.60 (1H, d, J 11.5Hz, 16-H), 3.72-3.92 (4H, m, 5,7,13 and 16-H), 6.85 (1H, s, 8.57 (1H, s, m/z 474 (MH 91 (100%).

I i; WO 92 /02518 PCT/GB91 /01285 Example 34 (Dimethylaminoiminomethyl) thien-2-yll -1-(norrnon-2-yl) ketone a) r5-(Dimethvlaminoiminomethyl)thien-2-yll-l-(6,7,13- O-tris-trimethylsilylnormon-2-vl) ketone 1,1,N,N-Dimethylhydrazine (0.42g, 7.O0mnol) was added to bromo 2-thiophene carboxaldehyde (0.88g, 5.O0mmol) in ethanol (25m1) at room temperature. After 2h and evaporation to dryness under reduced pressure, the reaction mixture was purified by flash chromatography using diethyl ether in hexane as eluent to give aminoiminomethyl thiophene (0.67g, 58%) n-Butyllithium (1.6M in hexane) (1.Oml, 1.50mmol) was added dropwise to 2thiophene 37g, 1. 6Ommol) in THF (5m1) whilst maintaining the temperature below -85 0

C.

After 10 mins. at -90 0 C N-met .oxy-li-methyl-6,7,13-Otris(trimethylsilyl)monamide (0.6g, 1.O0mmol) in THF (5m1) was added dropwise whilst maintaining the temperature below 0 C. After 1.75h, allowing the temperature to increase to -635 0 C, acetic acid (0.13g) was added, followed by water (15m1) Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in hexane (10-30%) as eluent gave the title compound (0.13g, 18%) as a colourless oil; 8H (CDCl 3 0.09-0.18 (27H, m, 9 x SiCH 3 0.90 (3H, d, I 7.1Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.30-1.42 (1 H, m, 12--H) 1. 56 (2 H, b r.s, 9 -H 2 1.78-1.88 (1H, m, 2.13 di, J 14.6 and 1. 2.28 (3H, s, 15-H3), 2.59-2.72 (3H, m, 10,J.I %nd 4-H), 3.04 (6H, s, N(CH 3 2 1, 3.40 (1H, dd, !1 8.9 and 2.3Hz, 6-H), 3.55 (1H, d, J 11.4Hz, 16-H), 3.78-3.95 (4H, m, 5,7,13 and 1 6-H)I, 6. 70 (1H, s, 7.03 (1H, d, I 3.9Hz, 3' or 7.57 (2H, d, J 3.9Hz, 3' or 41-H and CH=N).

WO 92/02518 Pc[/GB9I/0128 -86b) (Dimethylaminoiminomethyl)thien-2-yll-l- (normon- 2-yl) ketone The above ketone (0.13g, 0.l8mnol) and hydrochloric acid (0.4M) (3.Oml, 1.2 x lO- 3 mol) in THF (15m1) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5m1) was then added. Extraction with diethyl ether, drying (MgSO 4 evaporation to drynes under reduced pressure and purification by flash chromatography using methanol in dichloromethane as eluent gave the title compound (73.4mg, 85%) as a yellow foam; 'umax (KBr) 3427, 2965, 2924, 2327, 1637, 1598, 1448, 1257, 1050cm 1 X.max (EtOH) 399nm (em 20, 871); ,8H (CD 3 OD) 0. 93 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.35-1.44 (1H, m, 12-H), 1.68-1.75 (3H, br.s, 9-H 2 1.94-2.02 (1H, m, 2.24 (3H, s, 15-H 3 2.31 (1H, dd, J 14.5 and 2.69-2.84 (3H, m, 10,11 and 3.00 [6H, s,

N(CH

3 2 1, 3.41 (1H, dd, J 8.8 and 3.2Hz, 3.60 (1H, d, J 10.8Hz, 16-H), 3.74-3.93 (4H, m, 5,7,13 and 16-H), 6.81 (1H, s, 7.02 (1H, D, J 4.1Hz, 3' or 7.36 (1H, s, CH=N), 7.66 (1H, D, J 4.0Hz, 3' or 41-H); mj/z 480 181 (Found: 480.2265. C 24

H

36

N

2 0 6

S

requires M, 480.2294).

Example 2-Bromo- (pyrid-5-yl) -1-(normon-2-vl) ketone a) 2-Bromo-(pyrid-5-yl)-1- (6,7,13-0-tris-trimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (3.75m1, 6.O0immol) was added dropwise to 2,5 dibromopyridine (1.42g, 6.Ommol) in THF ____~Llli WO 92/02518 PCT/GB91/01285 -87- (16ml) whilst maintaining the temperature below -85 0 C. After mins. at -90 0 C N-methoxy-N-methyl-6,7,13-0tris(trimethylsilyl)monamide (1.82g, 3.00mmol) in THF (20"1) was added dropwise maintaining the temperature below -85 0

C.

After 30 mins. allowing the temperature to increase to 0 C, acetic acid (0.56g) was added, followed by water Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in hexane (10-30%) as eluent gave the title compound (0.92g, 44%) as a white foam; 6H (CDC1 3 0.09-0.17 (27H, m, 9 x SiCH 3 0.90 (3H, d, J 7.0Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.30-1.43 (1H, m, 12-H), 1.58 (2H, br.s, 9-H 2 1.76-1.86 (1H, m, 2.13 (1H, dd, J 14.7 and 10.6Hz, 2.23 s, 15-H3), 2.60-2.72 (3H, m, 4,10 and 11-H), 3.39 (1H, dd, J 9.0 and 2.4Hz, 3.57 (1H, d, J 11.3Hz, 16-H), 3.76-3.95 (4H, m, 5,7,13 and 16-H), 6.70 (1H, s, 7.57 (1H, d, J 8.3Hz, 8.07 (1H, dd, J 8.3 and 8.90 (1H, d, J 2.3Hz, b) 2-Bromo-(pyrid-5-yl)-1-(normon-2-yl)ketone The above ketone (0.47g, 0.70mmol) and hydrochloric acid (0.4M) (6.0ml, 2.4 x 10-3mol) in THf (30ml) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (15ml) was then added. Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane as eluent gave the title compound (0.322g, 94%) as a white foam; umax (KBr) 3433, 2924, 1657, 1607, 1087cm- 1 max (EtOH) 280.5nm (Em 19,001); 8H (CD 3 0D) 0.93 (3H, d, J 7.1Hz, 17-H3), 1.21 (3H, d, 3 6.4Hz, 14-H 3 1.34-1.47 (1H, m, 12-H), 1.66-1.76 (2H, m, 9-H2), 1.91-2.03 (1H, m, 2.24 (3H, s, 15-H3), 2.38 (1H, dd, J 14.2 and 9.6Hz, 2.70 (1H, dd, J 7.6 and 2.2Hz, 2.73-2.83 (2H, m, 10 and 11-H), 3.40 (1H, dd, J 9.0 and 3.0Hz, 3.60 (1H, d, J 11.1Hz, 16-H), WO 92/02518 PCU/GB91 /0128:^) -88- 3. 73-3. 93 (4H, mn, 5, 7, 13 and 1 6-H) 6. 88 (1H1, s, 2-H) 7. 73 (1H, d, J 8. 3Hz, 3' 8. 18 (1H, dd, 1 8. 3 and 2. 4' 8. 86 (1H, di, J 2. 3Hz, 6' 8C (CD 3 OD) 12. 3 17) 2 0. 3 15) 2 0. 5 14) 3 3. 0 9) 4 1. 9 4 3. 8 12) 4 4. 6 4) 5 6. 9 1) 61. 2 (C-il) 6 6. 4 16) 7 0. 0 6) 7 0. 7 7) 7 1 .6 13) 7 6. 3 5) 12 2. 6 2) 12 9. 6 31) 135. 2 13 9. 6 14 6. 6 151. 1 (C-61) 162. 1 190. 0 la (E.I1.) 484 225%) 43 (100%) Example 36 (Pyrid-4-yl) -1-(norinon-2-y1) ket one a) (Pyrid-4-yl) -1-(6,7,13-O-tris-trimethylsilyl-normoi- 2-vl) ketone Sodium hydrogen carbonate was added to 4-bromopyridine hydrochloride (0.58g, 3.O0inmol) in water (5mi) until pH >7.

Extraction with diethyl ether, drying (MgSO 4 and evaporation to dryness under reduced pressure gave 4bromopyridine (0.28g, 59%) as a colourless oil. This material (0.28g, i.77mnol) in THF (2mb) was added dropwise to n-butyllithium (1.6M in hexane) (1.l0ml, 1.76mnol) in THF (2mb) whilst mnaintaining the temperature below -65 0 C. After mins. at -70 0 C N-methoxy-H-methyl-6,7,13-Otris(trimethylsilyl)monamide (0.60g, i.O0mnol) in TEF (3mb) was added dropwise maintaining the temperature below -65 0

C.

ywter (2 t-0mb) acetrcacion with4g diethydehr A0ftle 45 wis.at -70mC aEtcacidn withg wasthadedhr drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using diethyl ether in hexane as eluent gave the title compound (0.04g, 4%6) as a colourless oil; (CDCl 3 0.09-0.17 (27H, m, 9 x SiCH- 3 0.90 (3H, d, J1 7.1Hz, 17-H 3 1.20 (3H, d, !I 6.4Hz, 14-H 3 1.37-1.47 Uli, m, 12-H), 1.70 (2H, br.s, WO 92/02518 WO 9202518PCT/GB91/01285 89- 9-H 2 1. 92-2. 02 (1H, mn, 8-H) 2. 10 (1H, dd, 1 14. 3 and 9. 5Hz, 4 2. 28 (3H, s, 15 -H 3 2. 66 (1H, d, J 7. 6Hz, 2.73-2.81 (2H, m, 2.0 and 11-H), 3.41 (1H, dd, J and 3. 1Hz, 6-H) 3.59 (1H, d, J 11. 6Hz, 16-H) 3. 75-3. (4H, m, 5,7,13 and 16-H), 6.89 (1H, s, 7.85 (2H, dd, J 4.6 and 1.6Hz, 2' and 61-H), 8.72 (2H, dd, J 4.5 and 3' and b) (Pyrid-4-Vl) -1-(normon-2-yl) ketone The above ketone (0.04g, 0.O7mrnol) and hydrochloric acid (0.4M) (3.Oml, 1.2 x 10- 3 mo1) in THF (i5mi) were stirred at room temperature for 2 mins. SaturatedI sodium hydrogen carbonate solution (7.5m1) was then added. Extraction with diethyl ether, drying (MgSO 4 evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane as eluent gave the title comp nd (0.02g, 59%) as a white foam; 1 umax (KBr) 3415, 297C 2887, 1662, 1610, 1412, 1243, 1056cm- 1 %max (EtOH) 272nm (em 22,752); 8H (CD 3 OD) 0.93 (3H1, d, J 7.1Hz, 17-H 3 1.20 (3H, d, J 6.4Hz, 14-H 3 1.39-1.48 (1H, m, 12-H), 1.68-1.74 (2H, m, 9-H 2 1.96-2.03 (1H, m, 2.29 (3H, s, 15-H 3 2.40 (1H, dd, J 14.3 and 9.5Hz, 2.71 (1H, dd, J 7.6 and 2.2Hz, 2.77 (2H, mn, 10 and 11-H), 3.41 (1H, dd, J 9.0 and 3.1Hz, 3.60 (1H, d, 11 11.6Hz, 16-H), 95 (4H, in, 5,7,13 anid 16-H), 6.93 s, 7.85 (2H, dd, J 4.6 and 1.6Hz, 2' and 8.73 (2H, dd, J 4.6 and 1.6Hz, 3' and m/z 405 17%), 106 (Found: 405.2150. C 22 H3 1 N0 6 requires M, 405. 2151.

PCT/01 1 0128 !2 9 Septemrber 1992 B3027 Example 37 (Piperidinyl)pyrimidin-5-ylJ- (l-norisomon-2-yl) ketone a) (2-Piperidinyl)pyrimidin-5-yl]-l-(6,7,13-O-tristrimethy isilyl-norisomon-2- vi) ketone n-Butyllithium (1.6M in hexane) (1.09m1, 1.74mmol) was added dropwise to 5-bromo-2-piperidinylpyrimidine 42g, l.74mmol) in THF (10mi) at -70 0 C. After 45 mins. at -70 0

C

cerium (III) chloride (0.43g, 1.74mmol) was added at -70 0

C.

After 1 hour at -70oC 6,7,13-O-tris(trimethylsilyl)isomonaldehyde (0.63g, 1.l6mmol) in THF (5m1) was added dropwise maintaining the temperature below -65 0 C. After 2 hours at -70 0 C acetic acid (0.lml) and water (20m1) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 and evaporating to dryness under reduced pressure gave the impure diastereomeric alcohols. The alcohols and manganese (IV) oxide (1.64g, 18.9mmol) in benzene (40m1) were heated to reflux under Dean and Stark conditions for 3 hours. The solids were removed by filtration and washed with dioxane and dichioromethane. Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the title compound (0.52g, 63%) as a yellow oil;

(CD

3 OD) 0.05-0.16 (27H, m, 9 x SiGH 3 0.90 (3H, d, J 17-H 3 1.19 d, J 6.3Hz, 14-H 3 1.15-1.40 (1H, m, 12-H), 1.45-1.90 (9H, m, 9-H2, 8-H and 6 x piperidinyl-H), 2.05 (3H, s, 15-H 3 2.69-2.74 (2H, m, 10-H, 11-H), 2.76- 2.89 (2H, m, 4-H 2 3.45-3.51 (2H, m, 6-H, 16-H), 3.81-3.93 (8H, m, 5-H, 7-H, 13-H, 16-H and 4 x piperidinyl-H), 6.68 (1H, s, 8.82 (2H, s, 31-H, m/zj 705. 1 73 [Found: 705.4010. C 3 5

H

6 3

N

3

O

6 Si 3 requires M, 705.4025).

0 t .nLci~~o ~etOfc I' r l-St MUMIT ITF r--T WO 92/02518 PCT/GB91 /01285 -91b) -[(2-Piperidinyl)pyrimidin-5-yll-l- (norisomon-2-yl) ketone Hydrochloric acid (0.4N) (4.2ml) was added to the above ketone (0.52g, 0.l4mnol) in THF (22m1) at room temperature.

After 2 minutes at room temperature saturated sodium hydrogencarbonate solution (l0mi) was added and the solution was then extracted with ethyl acetate. Drying (MgSO 4 evaporating to dryness under reduced pressure and recrystallisation from methanol gave the title compound (0.27g, 75%) as white micro-needles u~max (KBr) 3471, 2969, 2921, 2866, 1655, 1591, 1527, 1250, 1215, 1017, 798, 748cm- 1 -max (EtOH) 327.5nm (e-m 24,607); 5H (CDCl 3

)I

0.95 (3H, d, J 7.0Hz, 17-H 3 1.21 (2H, d, J 6.3Hz, 14-H 3 1.24-1.33 (1H, m, 12-H), 1.54-1.82 (8H, m, 6 x piperidinyl-H and 9-H 2 2.00-2.06 (lH, m, 2.12 (3H, s, 15-H 3 2.40 (1H, br.s, 13-OH), 2.66 (1H, dd, J 8.1 and 2.2, 11-H), 2.69- 2.83 (3H, mi, 10-H, 4-H and 7-OH), 3.03 dd, J 13.5 and 4.4Hz, 3.50 (1H, ddd, J 3.1, 2.7 and 9.7Hz, 3.64 (1H, d, !I 11.5Hz, 16-H), 3.72-4.02 (8H, m, 5-H, 7-H, 13-H, 16-H and 4 x piperidinyl-H), 5.85 (1H, d, J 2.7Hz, 6-OH), 6.71. (1H, s, 8.83 (2H, s, 3' and 51-H); 5C (CDCl 3 12.7 20.7 24.7, 25.9, 27.7 31.9 36.9 39.0 42.9 45.3, 56.0 61.4 65.8 67.6 70.3 71.3 76.3 119.9, 122.2 158.7 159.7 161.6, 188.6 m/z 489 190 [Found: 489.2832. C 26

H

39

N

3 0 4 requires M,~ 489.2839].

WO 92/ "2518 WO 2,~Z18PC.B91/0128 -S Example 38 -2 2-Dimethylaminopy rid-S-il-l-(norisomon-2- vl) ketone a) 2-Dimethylaminopyrid-5-yl-l- 13-0-tristrimethylsil-;lnorisomon-2-yl) ketone n-Butyliithiun (1.6M in hexane) (1.l4ml, J..B2mmol) was added dropwise to 5-bromo-2-dimethylaminopyridine 37g, 1.B2mnol) in THF (l0mi) at -70 0 C. After 45 mins. at -70 0

C

cerium (III) chloride (0.45g, 1.B2mmoi) was adc-,J at -70 0

C.

After 1 hour at -70 3 C 6,7,13-O-tris(trimethylsiiyl)isomonaldehyde (0.50g, O.92mmol) in THF (5mi) was added dropwise maintaining the temperature below -65 0 C. After 2 hours at -70 0 C acetic acid (0.07m1) and water (20m1) were added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporating to dryness gave the impure diastereomeric alcohols. The alcohols and manganese (IV) oxide (3.28g, 37.8mmol) in benzene (25m1) were heated to reflux under Dean and Stark conditions for 1 hour. The solids were removed by filtration and washed with dioxane and dichioromethane. Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography us',ng ethyl acetate/hexane gave the title compound (0.26g, 43%) as a yellow oil; 5H (CD 3

OD)

0.10-0.15 (27H, m, 9 x SiCH 3 0.39 (3H, d, J 7.1Hz, 17-H 3 1.20 (3H, d, J 6.3Hz, 14-H 3 1.31-1.41 (1H, m, 12-H), 1.52- 1.65 (2H, m, 9-H 2 1.80-1.95 (1H, m, 2.04 (3H, s, 3 2.63-2.67 (2H, m, 10-H, 11-H), 2.76-2.85 (2H, m, 3.05-3.10 (1H, m, 3.18 [6H, s, N(CH 3 3.42- 3.51 (2H, m, 6-H, 16-H), 3.77-3.95 (4H, m, 5-H, 7-H, 13-H, 16-H), 6.50 (11-1, d, J 9.1Hz, 31-H), 6.68 (1H, s, 8.05 (1H, dd, !1 9.1 and 2.0Hz, 8.77 (1H, d, J m/z 664 175 (100%).

WO 92/02518 PCI/GB9I /01285 -93b) 2-Dimethylaminopyrid-5-yl-l- (norisomon-2-yl) ketone Hydrochloric acid (2.3ml) was added to the above ketone, (0.25g, 0.38mmol) in THF (12m1) at room temperature.

After 2 mins. at room temperature saturated sodium hydrogencarbonate solution (5m1) was added and the solution was then extracted with ethyl acetate. Drying (MgSO 4 evaporating to dryness under reduced pressure and purification by flash chromatography using 9% methanol in dichloromethane as eluent gave the title compound (0.122g, 72%) as a pale yellow foam; U~max (KBr) 3400, 2968, 2951, 1643, 1595, 1501, 1431, 1374, 1320, 1250, 1050, 811cm- 1 %max OH) 343.5nm (Em 25,214) 5H (CDCl 3 0.95 (3H, d, J 17-H 3 1.21 (3H, d, J 6.2Hz, 14-H 3 1.20-1.35 (1H, M, 12-H), 1.54-1.66 (1H, m, 1.73-1.86 (1H, m, 9-H), 1.98-2.06 (1H, m, 2.12 (3H, d, J 0.6Hz, 15-H 3 2.41 (1H, br.s, 13-OH), 2.63-2.73 (2H, m, 4-H and 11-H), 2.79 (1H, ddd, J 6.3, 5.8 and 2.2Hz, 10-H), 2.86 (1H, s, 7-OH), 3.02 (1H, dd, J 4.6 and 13.4Hz, 3.19 (6H, s, N(CH 3 2 1, 3.52 (1H, dd, J 3.1 and 9.7Hzj 3.64 (1H, d, J 11.5Hz, 16-H), 3.72-3.88 (2H, m, 13-H, 3.94 (1H, dd, J 2.4 and 11.5Hz, 161-H), 3.95-4.05 (1H, m, 6.10 (1H, s, 6-OH), 6.51 (1H, d, J9.1Hz, 31-H); 6.81 (1H, d, J 0.6Hz, 2-H), 8.02 (1H, dd, J9.1 and 2.3Hz, 41-H), 8.79 (1H, d, J 2.3Hz, 61-H); 5C (CDC1 3 12.8 (C-17, 20.7 27.6 31.9 36.9 38.2 (N(CH 3 2 39.0 43.0 56.1 61.6 65.9 67.4 70.4 73.4 76.3 105.3 122.4 123.1 137.5 151.3 157.0 160.7 190.1 mn/z 448 [Found: M+ 448.2571. C 24

H

36

N

2 0 6 requires M, 448.2573].

WO 92/02518 PCT/GB91/612851 -94- Example 39 Fur-3-yl-l-(norisomon-2-yl) ketone 3-Bromofuran (0.27g, 1.82mmol) in THF (2ml) was added dropwise to n-butyllithium (1.6M in hexane) (1.14g, 1.82mmol) at -70 0 C. After 60 mins. at -70 0 C 6,7,13-0tris(trimethylsilyl)isomonaldehyde (0.50g, 0.92mmol) in THF was added dropwise maintaining the temperature below -65 0 C. After lh at -70 0 C acetic acid (0.07ml) and water were added and the solution extracted with ethyl acetate. Drying (MgSO 4 and evaporating to dryness under reduced pressure gave the impure diastereomeric alcohols.

The alcohols and manganese (IV) oxide (3.28g, 37.8mmol) in benzene (30ml) were heated to reflux under Dean and Stark conditions for 2 hours. The solids were removed by filtration and washed with dioxane and dichloromethane.

Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent gave the crude protected title compound (0.10g, 18%) as a yellow oil.

Hydrochloric acid (0.4N) (1.0ml) was added to the above crude ketone in THF (5ml) at room temperature. After 2 mins.

saturated sodium hydrogencarbonate solution (5ml) was added and the solution extracted with ethyl acetate. Drying (MgSO 4 evaporating to dryness under reduced pressure and purification by flash chromatography using 7% methanol in dichloromethane as eluent gave the title compound (0.030g, 18%) as a colourless foam; vmax (KBr) 3431, 2972, 2926, 1652, 1605, 1300, 1156, 1043, 1873, 804, 739cm- 1 ax (EtOH) 269.5nm (em 9,565); 8 H (CDCl 3 0.95 (3H, d, J 17-H 3 1.21 (3H, d, J 6.3Hz, 14-H 3 1.23-1.38 (1H, m, 12-H), 1.55-1.85 (2H, m, 9-H 2 1.95-2.10 (1H, m, 2.11 (3H, s, 15-H 3 2.67 (1H, dd, JJ 2.1 and 8.1Hz, 11-H), 2.76- 2.85 (3H, m, 4-H, 7-OH and 10-H), 3.00 (1H, dd, J 4.5 and 13.5Hz, 3.48 (1H, dd, J 2.8 and 9.4Hz, 3.64 (1H, d, J 11.5Hz, 16-H), 3.72-3.88 (2H, m, 13-H, 3.93 (1H, dd, J 2.5 and 11.5Hz, 3.95-4.05 (1H, m, 5.42 added, the solution extracted with ethyl acetate, une WO 92/02518 PCT/GB91/01285 (1H, br.s, 6-OH), 6.58 (1H, s, 6.79 (1H, d, J 1.4Hz, furyl-H), 7.43-7.48 (1H, m, furyl-H), 8.07 (1H, s, furyl-H); m/z 394 (M 95 [Found: M 394.1994.

C2 1

H

30 0 7 requires M, 394.1992].

Biological Activity The Examples were tested for antibacterial activity against a range of bacterial strains important in human infections influenzae Q1; B. catarrhalis 1502; Strep. pyogenes CN 10; Streo. pneumoniae PU7 and Steph. aureus Oxford) in a conventional microbiological assay, using serial dilutions in nutrient agar with 5% chocolate horse blood. The MICs were determined after incubation for 18h at 370 values in the range 0.06 to 32 gg ml-1 were observed.

the range 0.06 to 32 pg ml were observed.

I

I^ iiii=iS-l~i 95a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

4a

I

0 ee o e "*l i 940427,p:\opr\db,83104.Spe,9

Claims (4)

1. A compound of formula 11 3 C CH 3 011 in which R 1 is hydrogen and R2is -COR 3 or Rl is -CaR 3 and R 2 is hydrogen, in which R 3 denotes a heteroaryl group, and excluding the compounds in which R 3 comprises a fur-2-yl, is pyrid-2-yl or imidazol-2-yl ring.

2. A compound as claimed in claim 1 of the formula (Ia): OH- CE 3 HO R 3 H 3 C 0 C 3 0 Oil in which R 3 is as defined in claim 1. (Ia) U> -4

3. A compound as claimed in claim 1 or claim 2 in which R 3 comprises a fur-3-yl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, oxazolyl, isoxazolyl, thiazolyl, 3o isothiazolyl, pyrazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiatriazolyl, pyrid-3-yl, pyrid-4-yl, guinoliiyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl ring. B3027/C

97- 4. A compound as claimed in claim 3 in which R 3 comprises a thien-2-yl, thien-3-yl, fur-3-yl, pyrrol-3-yl, isothiazol-5-yl, pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl or quinolin-3-yl ring. A compound as claimed in claim 1 or claim 2 in which R 3 comprises a 5- or 6- membered heteroaryl ring having a nitrogen or oxygen heteroatom, and in which R 3 is bonded to the ketone carbonyl group of -CaR 3 by a ring carbon atom which is not adjacent to said ring heteroatom. 6. A compound as claimed in claim 5 in which the ring carbon atom is located P3- to the ring heteroatom. 7. A compound selected from: (Fur-3-yl) -1-(normon-2-yl) ketone; (l-Methylpyrazol-4-yl)--1-(normon-2-yl) ketone; (4-Bromo-1-methyltriazol-5-yl) -1-(normon-2-yl) ketone; (2-Methoxypyrid-5-yl)-1-(normon-2-yl) ketone; Pyrid-3-yl-1- (rormon-2-yl) ketone; (1-Methyltriazol-5-yl)-l-(normon-2-yl) ketone; 30(2-Methoxypyrimidin-5-yl) -1-(normon-2-yl) ketone; -1-(normon-2-yl) ketone; B3027/C 98 Cnormon-2-yl) ketone; -1-(normon-2-yl) ketone; [2-(Piperidin-1-yl)pyrimidin-5-yl-.-(normon-2-yl) ketone; -1-(normon-2-yl) ketone; (1-Propylpyrazol-4-yl) -1-(norznon-2-yl) ketone; (2-Acetylffur-4-yl) (norrnon-2-yl) ketone; [2-(Morpho2.in-4-yl)-pyrimidin-5-yl]-1(normon-2-yl) ketone; [2-(1-Methylpiperazin-4-yl)-pyrimidin-5-yl)--(nornon-2-yl) ketone; (5,7-Dimethoxyquinolin-3-yl) ]-2.-(norinon-2-yl) ketone; (1-Cyclohexylpyrazol-4-yl) -1-(norrnon-2-yl) ketone; (Pipericlin-1-yl)pyriclin-5-yl)-1- (normori-2-yl) ketone; (Thien-3-yl) -1-(normon-2-yl) ketone; (Thien-2-yl)-1-(normon-2-yl) ketone; ~,(5-Meithoxy-(thien-2-yl) 2-1-(normon-2-yl) ketone; 2-(Methylmercapto)thiazol-5-yl)-2.-(normon-2-yl) ketone; [2-(Piperidin-1-yl)thiazol-5-yl]-l-(normon-2-yl) ketone; B3027/C -99- (normon-2-yl) ketone; [2-(HydroxymethyJ~thien-5-ylJ-l-(normon-2-yl) ketone; s (2-Formylthien-5-yl) -1-(normon-2-yl) ketone; (Pyrrol-3-yl) (normon-2-yl) ketone; (thien-2-yl) -1-(normon-2-yl) ketone; (Methylsulphinyl)thiazol-5-yl]-l- (normon-2-yl) ketone; (Dimethylarninoiminomethyl) thien-2-yl]1 (normon-2-yl) ketone; Booprd5-l11(omn--l eoe [2Bro(yrid--yl) (normon-2-yl) ketone; (Piperidinyl)pyrimidin-5-yl]-1-(norisomon-2-yl) ketone; -1-(norisomon-2-yl) ketone; and (Fur-3-yl) (norisomon-2-yl) ketone. 28. A process for preparing a compound of formula as defined in claim 1 which process comprises: Htreating an acid of formula (III): CCO 30 3 I 2I H3 C 0 3 c 0 ~5/~~U1 B3027/C 100 in which Z 1 Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl protecting group, or an activated derivative thereof, with an organometallic reagent; (ii) treating an allylic alcohol of formula (IX): OZ 3 CH 3 io-3 Z O CH2C== CHCHOHR 3 H 3 C 0 o (IX) OZI in which R 3 is as defined in claim 1 and, 2 1 Z 2 and Z 3 are as hereinbefore defined, with an oxidising agent which converts allylic alcohols ihto a,p-unsaturated ketones, or (iii) treating a ketone of formula (XI): 3 OZ 2 Z 0 CH 2 COCH3 SH3C O (XI) Sin which Z Z 2 and Z 3 are as hereinbefore defined, with a terminal alkyne of the formula (XII): HC-C-R 3 (XII) -101 in which R 3 is as hereinbefore defined, to form an intermediate which is treated with tris(triphenylsilyloxy)vanadate and triphenylsilanol; and thereafter, and if necessary, removing any hydroxyl protecting groups. 9. A compound of formula (IX) as defined in claim 8. A pharmaceutical or veterinary composition which comprises a compound as defined in any one of claims 1 to 7 together with a pharmaceutically or veterinarily acceptable carrier or excipient. 11. A method for the treatment of bacterial infections in non-human or human animals which comprises administering an effective amount of a compound as defined in any one of claims 1 to 7 to non-human or human animals in need thereof. 12. A method of treatment of mycoplasma-induced infections in non-human or human animals which comprises administering an effective amount of a compound of formula OH R HO CH 3 R 3 H 3 C 0 CH 3 i S* OH in which R 1 is hydrogen and R 2 -COR 3 or R 1 is -COR 3 and R 2 is hydrogen, in which R 3 is a heteroaryl group to non-human or human animals in need thereof. 13. A method as claimed in claim 12 for the treatment of a STT?, mycoplasma fermentans induced infection. 940428,p:\apcr\db,8314.spc,101 -102- 14. A method as claimed in claim 13 for the treatment of mycoplasma fermentans and HIV infections. The use of a compound as defined in any one of claims 1 to 7 for the manufacture of a medicament for antibacterial therapy in human and non-human animals. 16. Compounds of formula or processes for their preparation, substantially as hereinbefore described with reference to the Examples. DATED this 28th day of April, 1994 Beecham Group p.l.c. By Its Patent Attorneys DAVIES COLLISON CAVE i $i I .4 a i 9401Z7,p:\Oper\dab,831G4.sp, 102 ii i INTERNATIONAL SEARCH REPORT International Application No PCT/GB 91/01285 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC C 07 D 405/14, 407/14, 409/14, 413/14, 417/14, A 61 K 31/35 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols C 07 D Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in Fields Searched 8 III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 X US, A, 4312874 (NORMAN H. ROGERS ET AL.) 1-7,11, 26 January 1982, 12,16, see especially column 2, first paragraph 17,19, and examples 8-9 39-40, 42,44- 54 A 8-10,13- 15,18, 20-38, 41,43 A J. Med. Chem., vol. 32, January 1989, L.L. Klein 1 et al: "Synthesis and Activity of Nonhydrolyzable Pseudomonic Acid Analogues", pages 151-160, see compound 9 Special categories of cited documents: 10 T" later document published after the int.rnational filing date dA'o ontdninn ln the qeneral slate o th .t which is not or priority date and not in conflict with the application but A de nrcal state of the art whch s ot ted to understand the principle or theory underlying the cons ered to be of particular relevance invention earlier document but published on or after the International Sil tg da t ut publsh or ntentional document of particular relevance, the claimed invention cannot be considered novel or cannot be considered to document which may throw doubts on oriority claim(s) or involve an inventive step which Is cited to establish the publication dale of another d o p r e c. in i citation or other special reason (as specified) document of particular relevance, the claimed invention cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or docuent is combined with one or more other such docu- other means nents, such combination being obvious to a person skilled in the art. document published prior tothe International filing date but d t m o t s p later than the priority date claimed document member ofthe same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this international Search Report 6th November 1991 0 2 12. 91 International Searching Authority Signature of Authorized i r EUROPEAN PATENT OFFICE van der Drift Form PCT/ISA/210 (second sheet) (January International Application No. PCT/GB 91/01285 Ill. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) Category' Citation of Document, with indication, where appropriate, of the relevant passages Relevant to Claim No A DE, C2, 2726618 (BECCHAM GROUP LTD.) 1 29 December 1977, see page 3 A Chemical Congress of North America 3 Toronto 1988, 1 Third Chemical Congress of North America, (Abstracts of papers American chemical society), L.L. Klein et al: "Non-hydrolyzable analogs of pseudomonic acid see abstract MEDI 61. I s' I Form PCT/ISA/Z10 (extra sheet) (January 1985) International Application No. PCT/GB 91/01285 FURTHER INFORMATION CONTINUED FROM THE SECOND SWEET OESERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHAELE This International search report has not been established In respect of certain claims under Artcie 17(2 for the following reasons: .MClaim numnbrs 5 5 8 P because they relate to subject matter not required to be searhed by this Authority, namely: A method for treatment of the human or animal-body by therapy, see rule 39. 2QClaim numberA.-..Z.., because they relate to parts of the International applicaton thal do not comply with the prescribed require- mennte to such an extent that no meaningful International search can be carried out. specificaft The scope of clziims 1-3, 44-54, 59-61 is so broadly formulated that many compounds of a very wide range of structures are included. The search has thus been limited to the compounds considered to be most relevant. 3.E] Ctei nmayer,.......becaue tre awe depetdent clalmw and ers not erafted in a=ordar. With the se n d fl*d sartwoce of PCT RtMs 6.4(a). Vt.E OBSERVATIONS WHERE UNITY OF INVENTION 1S LACKING I This Interniational Searching Authority found multiple inventions in this international application as follows: 1,M As oit required additional searfch fees were timely paid by the applicant thia International search report cover a all searchable cillms of the International application. LM As only some of the required additional search fees wiera timely paid by the applicant, this international search report covers only thooa claims of the International application for which ye"s were paid, specifically clims: &]No required adiditionasarch ftees were timely paid by the applicant. Consequenly, this International search report Is restricted to the Invention first mentioned In the claims: It Is covered by claim numbers: 4QAs all searchable claims could be searched without effort justifying an additional fee, the Internationa Searching Authority did not Invite payment of any additional fee. Remark on Protest EThe additional search fees were accompanied by applicant's protest. Ho protest accomps.an'ed the Payment of additional "earch foe. Form PCTIISA12I0 (supplemental sheet (January 1ill) f ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/GB 91/01285 SA 50159 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 27/09/91 The European Patent office is in no way liable for theseparticulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date US-A- 4312874 26/01/82 AU-D- 6417080 14/05/81 EP-A-B- 0029665 03/06/81 JP-A- 56079685 30/06/81 DE-C2- 2726618 29/12/77 9 AT-B- AT-B- AU-D- CA-A- CA-A- CH-A- CH-A- CH-A- CH-A- DE-A-C- DE-C- FR-A-B- FR-A-B- JP-C- JP-C- JP-A- JP-A- JP-B- NL-A- NL-A- SE-B-C- SE-A- SE-A- SE-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- US-A- AT-B- 358734 363596 2611377 1099264 1101851 637952 637953 642653 642654 2726619 2760423 2355016 2355017 1515302 1515303 53002470 53002471 63060754 7706529 7706532 433214 7706877 7706878 8105936 4102901 4102904 4152337 4166863 4217447 4217448 4235784 4256762 4256879 4267316 4283411 4283412 4289779 4318856 4465689 353962 25/09/80 10/08/81 21/12/78 14/04/81 26/05/81 31/08/83 31/08/83 30/04/84 30/04/84 29/12/77 10/11/88 13/01/78 13/01/78 24/08/89 24/08/89 11/01/78 11/01/78 25/11/88 19/12/77 19/12/77 14/05/84 16/12/77 16/12/77 07/10/81 25/07/78 25/07/78 01/05/79 04/09/79 12/08/80 12/08/80 25/11/80 17/03/81 17/03/81 12/05/81 11/08/81 11/08/81 15/09/81 09/03/82 14/08/84 10/12/79 For more details about this anniex: see Official Journal of the European patent Office, No. 12/82 EPO FORM P0479 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/GB 91/01285 SA 50159 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 27/09/91 The European Patent office is in no way liable for theseparticulars which are merely given for the purpose of information. EPO FORM P0479