AU678979B2

AU678979B2 - Process for making phenylthiomethylpyridinylalkenoates

Info

Publication number: AU678979B2
Application number: AU46557/93A
Authority: AU
Inventors: Robert A Daines
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1992-06-30
Filing date: 1993-06-30
Publication date: 1997-06-19
Anticipated expiration: 2013-06-30
Also published as: AU4655793A; CN1095713A; NZ254473A; KR950702184A; WO1994000433A1; EP0649408A1; JP3181917B2; JPH07508283A; EP0649408A4; MX9303972A; TW247907B; CA2138955A1

Description

011 DATE 24/101/94 AOJP DATE 14/04/94 APPLN. ID 46557/93 JfJ11! 11111 li il PTNUMBER PCT/US93/06177 1111f111Iilfl AU9346557

INTER

(51) International Patent Classiflcation 5 C07D 213/65, 213/30, 213/32 1(11I) International Publication Number: Al J(43) International Publication Date:- WO 94/00433 6 January 1994 (06,01.94)

I

(21) International Application Number: (22) International Filing Date: Priority data: 07/906,951 3OJunc I 08!'025,200 2 MarchI 1 (60) Parent Applications or Grants (63) Related by Continuation us Filed on us Filed on PCT4 US93-'06177 30 June 1993 (30.06.93) 992 (30.06.92) 1993 (02.03.93) (72) Inventor-, and Inventor/Applicant tfiur VS onlo DAI NES, Robert, A.

IUSVUS]; 2587 Cold Spring Road, Lansdale, PA 19446

(US).

(74) Agents: KANAGY, James, M. et al.; SmithKline Becham Corporation, Corporate Intellectual Property, UW2220, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406.0939 (US).

(81) Designated States: AU, B8, BG, BR, BY, CA, CZ, Fl, HUJ, JP, KP, KR, KZ, LK, MG, MN, MW, NO, N, PL, RO, RU, SD, SK, UA, US, VN, European patent (AT, BE, CH., DE, DK, ES, FR, GB, OR, IE, IT, LUJ, MC. NL, PT, SE), QAPI patent (BF, BJ, CF. CG, CI, CM, GA, ON, ML, MR, NE, SN, TD, TG).

Published With international search report, 07!906,951 (CON) 30 June 1992 (30,06.92) 081025,200 (CON) 2 March 1993 (021.03.93) (71) Applicant (for all designated States e.veept USP: SMITH- KLINE BEECHAM CORPORATION IUS/USI; Corporate Intellectual Property, UW2210, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939

(US).

67 79_ (54) Title: PROCESS FOR MAKI NO PHENYLTi-IOM ETHYLPYRI DINYLALKENOATE-S NR)_ (R (57) Abstract This invention relates to a process of making a compound of formula where R 1 contains an aD-unsaturated carbonyl group and R, is hydrogen or nonhydrogen radicals wvhich do not have a functional group which interferes wvith the coupiing reaction, which process comprises coupling a thiolphenol or phenylalkylmercaptan wvith a chloromethylpyridine in the presence of DBU under an inert atmosphere. These compounds are leukotriene antagonists and as such can be used in treating various diseases associated with leukotrienes.

WO 94/00433 PCT/US93/061 Process for making phenylthiomethylpyridinylalkenoates.

Scone of the Invention The field of this invention is that of a process for making certain thioethers by coupling a chloromethyl pyridyl compound with thiophenols and related mercaptans. The products of this coupling, the thioethers and their related sulfoxides and sulfones are useful for treating diseases arising from or related to leukotrienes, particularly leukotriene B 4 As such there utility lies in antagonizing the affects ofleukotrienes.

Backeround of the Invention .0 A series of thioethers represented by the general formula 77 R, N

IN

ZN(CH2)

R

3 have been discovered to be useful in treating diseases involving the leukotriene cascade, particularly those diseases believed to be associated with or caused by the dihydroxyleukotrienes (leukotriene B 4 These thioethers can be found in certain publications, particularly PCT application serial number PCT/US91/03772. A method for preparing those novel therapeutic agents is disclosed therein along with a description of utility and the background of the family ofbioactive lipids known as the leukotrienes.

This invention relates to a process for making these compounds and other compounds of a similar nature where a chloromethylpridine is coupled with a thiophenol or benzylic mercaptan.

Summary of the Invention This invention covers a method for making a compound of formula I (R)n--f N" -_s-cH2)'

R

where R 1 contains an ca,-unsaturated carbonyl group and the designation (R)n indicates hydrogen or one or more non-hydrogen radicals capable of al WO 94/00433 PCT/US93/06177 being covalently bonded on the pyridyl and phenyl rings and m is 0 which method comprises coupling a chloromethylpyridine of formula II with a thiol of formula III in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under an inert gas at a temperature between about ambient and 1000 C for a period sufficient to effect the coupling.

HS(CH

2 )m 1% N I (R)n Cl Formula II Formula i where R 1 is defined above and (R)n is hydrogen or one or more radicals which can be substituted on either the pyridyl or phenyl ring and m is 0 General Embodiments The following definitions are used in describing this invention.

An ap-unsaturated carbonyl group is illustrated by -CH=CH-C(=O)or The undefined carbonyl function valence can be a carboncarbon bond, a carbon-heteroatom bond wherein the heteroatom is oxygen, nitrogen, sulfur or the like, including phosphorus. This invention is intended to cover all the enventualities where a thiol of the type illustrated is reacted with a pyridyl derivative which has an ac,-unsaturated carbonyl system at the 2-position which can undergo a Michael addition reaction with the thiol.

The (R)n designation is used here to indicate that one or more groups may be present on either the pyridyl ring or the phenyl ring. This invention also includes the case where each of these R groups is hydrogen.

It is expected that any number and combination of substituents may be present on either ring. The only limitation envisioned is that the one of these groups must not interfere with the coupling reaction to a degree as to render the reaction impractical, ie, it does not occur at all, the yield is vanishing small, the wrong product is obtained in an undesirable amount.

It should be understood that a given group may be in protected form, for example a carboxylate function may be present in the form of an ester, the acid being regenerated by hydrolytic, catalytic or enzymatic means once the coupling reaction is completed. The invention is that of the use of DBU to affect the coupling of the chloro and the thiol to achieve the thioether and is to be viewed as only so limited.

~31~ 1 WO 94/00433 PCT/US93/06177 As for other terms, "aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase "lower alkyl" means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O-.

"Acyl-lower alkyl" refers to the group (O)C-lower alkyl where the carbonyl carbon is counted as one of the carbons of the 1 to 6 carbons noted under the definition of lower alkyl. "Halo" refers to and means fluoro, chloro, bromo or iodo. The phenyl ring may be substituted with one or more of these radicals. Multiple substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl pattern.

Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention.

If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are irtended to be covered herein.

Compounds with a chiral center may be administered as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.

The compound 1,8-diazabicyclo[5.4.0)undec-7-ene (DBU) is available from Aldrich. To effect the coupling, the thiol or mercaptan is dissolved in a dry polar solvent like acetonitrile to which is added about an equivalent of the chloromethylpyridine adduct to be coupled. Then between 2 to equivalents of DBU as measured against the thiol or mercaptan are added.

About 3 equivalents of DBU are preferred. Dry conditions are maintained throughout the course of setting up and running the reaction. An inert atmosphere is used, preferably argon. The reaction is stirred at between about ambient temperature and 1000 C for several hours. The reaction can be made go in a useful manner by heating the stirred reactants for 2 to 4 hours unaer an argon gas at a temperature of about 50° C. Thereafter the reaction is cooled and the product, the thioether, is recovered and purified by conventional means.

Preferred products of this reaction are those compounds of formula WO 94/00433 PCr/US93/06177 'NO~~S-(H2M 94043R2TLS3l 7

RR

Formula IA or an N-oxide, or a pharmaceutically acceptable salt, where m is 0 R is C 1 to 020-alliphatic, unsubstitutecr or substituted phenyl-Cl to where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C 1 to C 2 0 -aliphatic-O-, or R is unsubstituted or substituted phenyl-Cl to C10-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; RI is -(CH 2 )xCH=CHCORyP or -(CH 2 )xCH=CHCHO, where x is 0 2 and Ryis -OH or an ester thereof or NH 2 or a substituted amide derivative thereof;

R

2 is H, lower alkoxy, halo, -ON, -(0H2)nR4 where n is 0 5, lower alkyl, or OF 3

R

3 is H, lower alkoxy, halo, lower alkyl, OF 3 -CN, -(CH2)nR4 where n is 0

R

4 is tetrazol-5-yl or 00R 5 and

R

5 is lower alkoxy, CH 3

(CH

2 0 6 00 or phenyl(OH2)0~.3CO.

The more preferred products are those where R is substituted phenyl-C 2 to 08 alkoxy, particularly the unsubstituted-phenyl(OH).8-Ogroup, or the p-fluoro- or p-methoxyphenyl(OH)2..3-O- group, or 0H 3

(CH

2 7 9 m is 0 5, most preferably 0, 1, or 2; RI is H0 2 0- OH=OH-, or H0 2

C-CH

2

CH

2 or a salt, ester or amide derivative thereof.

Another sub-group of preferred products are those where R 2 and R 3 are both hydrogen, both halo, both methyl, or both methoxy. Another preferred set of compounds are those where R 2 is 00R 5 and R 3 is hydrogen. The 2,6dichioro is a preferred product. Specific preferred products are: (E)-methyl 3-[3-[4-,(4-methoxyphenyl)butyloxy-6-X2,6dicblorophenylthio)methyl-2-pyridinyl]-2-propenoate, cE)-methyl 3-[3-[4-(4methoxyphenyl)butyloxyJ-6-[phenylthiomethyl]- 2-pyridinyUl-2-propenoate.

WO 94/00433 PCT/US93/06177 (E)-methyl 3-[3-[2-(4-methoxyphenyl)ethyloxy]-6-[(2,6dichlorophenylthio)-methyl]-2-pyridinyl]-2-propenoate, (E)-methyl 3-[3-[2-(4-fluorophenyl)ethyloxy]-6-[(2,6dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate, or (E)-methyl 3-[3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-carbomethoxybenzylthio)methyl]-2-pyridinyl]-2-propenoate.

Synthesis Several methods, variations on the same process, have been used for preparing these compounds. In general, the approach taken was to first make the intermediates needed to make the R group, then to prepare the phenyl intermediate needed for forming the core structure of formula I; the pyridyl intermediate was then prepared and reacted with the phenyl intermediate to form the core structure. Salts, free acids, amides, alternative esters and the like were then prepared.

As noted, the first step was to make the intermediates needed for forming those R groups where the intermediates were not available commercially. This chemistry is illustrated for the case of the substituted phenyl-C 1 to C 1 0 -aliphatic-O- groups. The same or similar chemistry has been disclosed in published patent applications, for example PCT international application numbers PCT/US91/03772, PCT/US91/03940, and PCT/US91/03399. The chemistries set out in those documents can be used in place of or in conjunction with those given here to prepare the R groups of formula I.

Usually the substituted chloromethylpyridine is prepared next, as opposed to the thiol intermediate, but this is not critical to the practice of the invention. Making the substituted 6-chloromethylpyridyl intermediate can begin with the starting compound and the chemistry disclosed in the PCT application PCT/US91/03772 and the other PCT cases cited above.

The chemistry set out in the '03772 case can be used to convert the starting material, 2,6-lutidine-a 2 ,3-diol, to, for example, the 2-(E-2carboxymethylethenyl)-3-[4-(4-methoxyphenyl)batyloxy]-6chloromethylpyridine. This is illustrated in Scheme I given below. Novel chemistry, both conditions and the reagent DBU, are then used to couple the thiophenol with the chloromethyl substituted pyridine in order to make the basic structure of formula I. Base, or acid, can then be used to hydrolyze any ester group, if so desired. A free acid can be obtained from the salt by acidifying a solution of the salt. Esters and amides can be prepared using standard reaction conditions and reagents. Tetrazoles are I I I WO 94/00433 PCT/US93/06177 prepared from the corresponding acid halide, the acid chloride, by literature methods.

Using the precursors prepared as per the noted PCT applications or which have been purchased from a commercial source, and the steps outlined in Scheme I, can be used to prepare compounds of formula I.

HCI

DBU

MeO 2

I

p-MeOC 6 H4(CH 4 aq LiOH U 0 2 C N u oaC^^

N"

A general description of the conditions and reagents which can be used for converting the diol to the 6-(chloromethyl)pyridine compound can be found in PCT application number PCT/US91/03772. That description of the generalized case for each step is incorporated herein by reference along with the specific chemistry set out in the Examples of that application.

A number of thiophenols and thioalkylphenyl compounds useful for making the right hand portion of formula I can be purchased from o 1 31131 WO 94/00433 PCT/US93/061 77 commercial sources. A list, not intended to be exhaustive, is as follows: 2,6-dimethylthiophenol,2-chloro-6-fluorobenzyl mercaptan, and 2,4-difluorobenzyl thiol. Other thiols can be made by published chemistry; that chemistry involves converting a haloalkylphenyl (the bromo form is preferred) compound to the corresponding mercaptan by treating the bromo compound with thiourea followed by base hydrolysis.

Alternatively the thiophenols can be prepared by thermal rearrangement of the corresponding thiocarbamate followed by hydrolysis.

Coupling the thiol with the chioromethylpyridyl compound using a novel method which employs 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and an appropriate solvent, for example CH 3 CN. Moisture is excluded from the system and an inert gas is used, for example argon. A slightly elevated temperature is preferred, one that is about 500 C or so; the co, -ing reaction is complete in about 3 hours.

Once the core structure is prepared any ester can be hydrolyzed with acid or base, base is preferred, or that acid can be converted to another ester, an amide or another salt.

Suecific Embodiments The following examples are given to illustrate how to make and use the compounds of this invention. These Examples are just that, examples, and are not intended to circumscribe or otherwise limit the scope of this invention. Reference is made to the claims for defining what is rese'-ed to the inventors.

BxZ=p 1 (E)-Lithium 3-[3-r4-4-methoMnhenvl)hbvl-6-r(2.6di chlorophenvlthio)methvfl-2-pvridinvll-2-propenoate 2A (E)-Methvl 3-r3-r4-(4-metho~henv1)butvlou~b6-(2,A 1 enylthi )mthl-2:ridinl-2-roep oat 2,6- Dichlorothiophenol (53mg, 0.297xnmol, Aldrich) was dissolved in dry MeCN (0.6OmL) and treated with 2-(E-2-carboxymethylethenyl)-3-14-(4methoxyphenyl)butyloxy)-6-chloromethylpyridine hydrochloride (115mg, 0.27Ommol) and 1,8-diazabicyclo[5A4.0]undec-7-ene (DBU, 0. 142mL, O.949mmol). The reaction was stirred under an atmosphere of argon at T0 for 3h. The reaction solution was diluted with EtOAc and washed with H120 and brine and dried (MgSO4). Purification by flash column chromatography (silica, EtOAc: 011202: hexane, 10: 15: 75) gave a colorless waxy solid: 1 H NMR (250MM, CDCl 3 8 7.94 Kd J=15.7Hz, 1H1, 1 6- 4-9'7;17-49 7.

vinyl), 7.31 J=7.6Hz, 211, aryl), 7.13 (mn, 4H, aryl, pyridy'.), 7.11 toU, J=B.4Hz, 111, pyridyl), 6.8G J=8.7Yiz, 211, phenyl), 6.69 Cd, J=15.7Hz, 111, vinyl), 4.14 2H, CH 2 3.97 J=6.lHz, 211, CH 2 3.80 3H1, OMe), 3.78 311, methyl ester), 2.63 J=7.2Hz, 2H1, benzylic), 1.81 Cm, 411,

CH

2 CH2); analysis celcd. for 0 27

H

27 01 2 N0 4 S: 0, 60.90; H, 5.11; N, 2.63; found: C, 60.61; H, 5.01; N, 2.57; MS 532.0 Proceeding in a similar manner, but substituting for the intermediates listed in 1A and lB the appropriate chioromethylpyridifle and thiophenol or mercaptoalkylphenyl adducts, the following compounds can be prepared: cE)-methyl 3-[3-[8-(4-methoxyphenyl)octyloxy-6-C3carboinethoxybenzylthio)-muthyU.-2-pyridinyl)-2-propenoate, CE-znethyl 3-t3-(4-(4-methoxyphenyl)butyloxy-6-[phenylthioxnethyUl- 2-pyridinylj-2-propenoate, and (E)-methyl 3-[3-[4-(4-methoxyphenylbutyloxy.6-[(2,6-dicbl orophenylthio)meth 1l-2-pyridinyl]-2-propenotte.

0. ME-Lithium 3-r3-r4(4-methoxvhevla ~utlox-1r2.

dichlorohenyltho)methyj 3-pvrdinvllI-2-Rronenoate. CE>-Methyl 343-j .20~q (4-inethoxyphenyl)butyloxy-6-(2,6-dicblorophenylthio)nethyJ-2see pyridinylJ-2-propenoate (65mg, 0.122romol), was dissolved in TEIF %:and MeQH (0.50mL) and treated with 1.OM LiOH (O.25znL, 0.25mmol).

The eacionwasstired nde anargann atmos phere for 20h. The solvent was evaporated and the product purified by Reversed Phased MPLC CRI';18 -:-125 silica, H20-MeOH gradient). Lyophilization yielded a colorless amo .rphous solid: 1H NMR (250MHz, d 4 -MeOH) 857.68 J=15.711z, 111, vinyl), 7.37 Cd, J=7.6Hz, 2H1, aryl), 7.13 Cm, 411, aryl, pyridyl), 7.02 J=8.4Hz, 1H1, pyridyl), 6.82 J=15.7H1z, 111, viryl), 6.81 J=8.711z, 2H1, phenyl), 4.13 230 2H, CH 2 4.00 J=6.lHz, 2H, CH2-O), 3.75 3H, OMe), 2.62 Ct, e: 3 J=7.2Hz, 2H, benzylic), 1.80 Cm, 4H1, CH2CH2); analysis caled. for see 11 C 26 H24Cl 2

NO

4 SLi 15/81120: C, 55.96; H, 5.01; N, 2.51; found: C, 55.75; H, 4.58; N, 2.36; MS 518.0 CM+H, free acid).

Throughout this specification and the claims which fol low, unless the context requires 0 so 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.

-8-

Claims

1. A process for making a compound of formula IA Rr R, N R 71/ 1A R, or an N-oxide, or a pharmaceutically acceptable salt where R, contains an c~p-unsaturated carbonyl group; R is C 1 to C 2 q-aliphafic, unsubstituted or substituted phenyl-C, to C 10 -atiphatir where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C, to CO- 0 e..aliphatic-Q-, or R is unsubstituted or substituted phenyl-C, to C 1 -aliphatic-O- 0 0 ee.: 1.5 where slibstituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalornethyl, and halo; .0R 2 is H, lower alkoxy, halo, -CN, -(CH.I),R 4 where n is 0-5, lower alkyl, or CF 3 R 3 is H, lower alkoxy, halo, lower alkyl, CF,, -CN, or -(CH 2 ),R 4 where n is 8:06P. 4 is tetrazol-5-yl or COR3; 04: 20 R 5 is lower alkoxy, CH 3 (CH2)0J 6 CO or phenyl(CHD( 3 CO; and m is V. which process comprises coupling a chioromethylpyridine of formula HI with a thiol of formula I 1 H C2) C1 R 3 Formulia HI Formula H1I **see: 730 where R, R 1 R 2 R 3 and m are as defined above 4 1 1 1 4 0 in the presence of 2 to 5 equivalents of 1,8.dinzzbicylo[5.4.0]undec-7-cne (DBU) under an inert gas at a tcmperaturf: between ambient and 100T for a period sufficient to effect the coupling.

2 The process of claim I where about 3 equivalents of DBU is used and the reaction is carried out in acetonitrilc under argon at a temperature of about 50 0 C for 2 to 4 hours.

3. The proccss of claim 1 or claim 2 wherein R, is -(CHiCH=CCRy, or (CI-lxCF=CHC11O, where x is 0-2 and Ry is -OH or an ester thereof or NH2 or a substituted amide derivative thereof.

4. The process of JAaimn 3 wherein the product is-, *Se methyl 3-(3-[4-(4-methoxyphenyl)butyloxyJ-6-((2, 6-dichlorophua,,ylthio)methyl]-2- 1 pyridinyll1- -propeno ate, ~methyl 3-[3-[4(4-methoxypheny1)butyloxyJ-6-(phenylthiomethyl]-2-pyridinyU)-2- propenoate, methyl 3-[3-[2-(4-xmTeffoxyphenyl)etlyloxy)-6-f(2,6-dichloro, 4enylthio)methyl]-2- pyridinyl]-2-propenoate, methyl 3 3 -L ',-(4-fluorophenyl)ethyloxyl-6-((2, 6-dichlorophenyltbio)rnethylj-2- pyridinyl]-2-propenoate, or e~g methyl 3-(3-(S.(4-methoxyplienyl)octyloxcy]-6-((3.carbomethoxybcnzylthio)methyl]- 2-pyridiuyl]-2-propeno ate, 25

5. A process according to claim I substantially as hereinbcfvbre described with reference to any one of the Examples. 30 DATED this 16th day of April 1997 SMITHKLMN BEECIAM CORPORATION By Davies Collison Cave Patent Attc' rucys for the Applicant RMTRNATIONAL SEARCH REPORT [;~aao o In m4orutl appliciWon No. CTIUS93/06177 A. CLASSIFICATION OF SUBJECT MATTER [PC(S) :O7D, 213165. 213130, 213132 US CL ;546W39, 546132. 546/01, 546/300 Accortuing to International Patent Classification (IPC) or to both national classification and [PC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classificntion symbols) U.S. :546/339, 546/32, 546/301, 5461300 Documenntation searched other thant minimum documentation to the extent that such documents ame included in the fields searched Electronic data base conrilted durig the international search (name of data base and, where practicable, search termis used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indiration, where app ropriate, of the relevant passages Relevant to claim No. X J. Org. Chem., Vol. 53, issued 1988, Trost et al., "Tetra-n- 1-3 butylammonlum Oxone. Oxidations under Anhydrous Conditions", pages 532-537, esp. pg. 535. See entire document. Further documents are listod in the continuation of Box C. [E see patent family annex. PW Spca goe"M at" "MONA dar Wa docowtwiPUK6Wad w 6walde h ndim Mks or irort* daw md ma hamcceflktwikdo ~qlorobug 4ad to 6Ue to be fM~t OfWu n riei~iorvoooimru h i'mi .6E tr.nhibd- X. dOCumm of pmn~tkiia lrce doe ckld kivutlio aw be 046t 00A~ pubvw cecc sw do6kcsfdow 4oos mmcrW od or mw baosWtaerd wn kylve moveue p Lv domm"wik Wey 6"o dhA" os Pnonhy CW3(I) or whkb Is wbes 668O~ do hkc s a &%Me. cill n bu to a oVdoPubub. dM o a 646Mt C of at ohe Y. doaa of punkmWe nkvince ckiwd ikvmon caud be aOeciaI wo (at upecdwd cowm tokov vtv Wpwmted-- .0 dooain ,efvmg to oral disckmu-, e zhA~ tu~oo otber oomWwlkoam or am other a" docatm .uch coa~oei mb bew vobvious to r pet uin doh sWt T. domnwpt oprno the beerusoW M4Jl date fWe thn 6w douamnmwAvkr ofdt wm pateg tuax*i Date of the actua completion of the internatoWa search Date of mailing of the ints national search report 16 AUGUST 1993 Nanm and mailing address of the ISA/US Atoie fie Commisaioar of Patents and TErdCIZIBs Box ParMRINETITN Washingioc, D.C. 20231 Facsimile No. NOT APPLICABLE TeleRhone No. (703) 308-1235 Form PCl'flSAI2IO (second shcet)(July 1992)* M