COVER STORY
October 1, 2001
Volume 79, Number 40
CENEAR 79 40 pp. 79-97
ISSN 0009-2347
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CHIRAL PHARMACEUTICALS
Drug firms continue to develop chiral drugs as single enantiomers, to carry out racemic switches, and to use chirality to manage drug life cycles

STEPHEN C. STINSON
C&EN NORTHEAST NEWS BUREAU

Worldwide sales of chiral drugs in single-enantiomer dosage forms continued growing at a more than 13% annual rate to $133 billion in 2000, according to the consulting firm Technology Catalysts International, Falls Church, Va. At a future growth rate estimated by TCI, the figure could hit $200 billion in 2008. In a second growth trend, according to the firm, 40% of all dosage-form drug sales in 2000 were of single enantiomers. In 1999, the share was one-third.

IMAGE COURTESY OF TRIPOS
But as the role of chirality has become firmly established in the drug industry, that very success entails chances that the usual lenses for viewing growth will become distorted. In one dramatic development, for example, Bayer withdrew its Baycol brand of cerivastatin on Aug. 8.

That single-isomer inhibitor of -hydroxy--
methylglutarylcoenzyme A reductase for lowering serum cholesterol had caused a potentially fatal muscle-wasting side effect in some patients. The withdrawal prompted calls by European Union drug authorities for a reexamination of the safety of the whole "statin" class of drugs. The statins are unlikely to vanish en masse. But if they did, the disappearance of that $15 billion in annual sales would result in apparent zero growth or even a decline in chiral drug sales for that year.

A second development affecting the apparent market value of chiral drugs is the coming off patent of the compounds that pioneered the development of single enantiomers. Patents on the "pril" class of angiotensin-converting-enzyme (ACE) inhibitors for blood pressure control, such as captopril, enalapril, and lisinopril, have begun to expire. These expirations are leading to the introduction of generic versions at fractions of the innovators' prices, leading in turn to an apparent decrease in dollar value for this class. And not only has the patent on the chiral nonsteroidal anti-inflammatory naproxen expired, but the drug has been introduced over the counter at very low prices.

NEXT WEEK, at the Conference on Pharmaceutical Ingredients (CPhI) in London, attendees will see evidence of the actually quite prosperous climate for chirality in drugs. In this climate, drug companies continue to develop chiral drugs as single enantiomers, to use chirality as a tool for drug life-cycle management, and to redevelop racemic mixtures as single enantiomers, which is called a racemic switch.

In all these applications of chirality to research and business strategies, there are lively efforts at drug companies to devise and improve enantioselective processes. And at CPhI, fine chemicals companies will show off their latest enantioselective technology enabling them to sell single-enantiomer intermediates and catalyst ligands or to produce single-enantiomer compounds to special order.

Such companies as Synthon, Monmouth Junction, N.J., and Chiral Quest, State College, Pa., will exhibit enantioselective technology invented by the chemistry professors who founded them. And many other academic chemists also continue to devise enantioselective chemistry.

In the matter of racemic switches, drug companies like Forest Laboratories of New York City manage the life cycles of their own drugs by patenting the individual enantiomers and then switching the drugs as a means of prolonging total patent life. Chirotechnology companies like Celgene, Warren, N.J., and Sepracor, Marlborough, Mass., patent and carry out racemic switches of the drugs of other firms. They make money by licensing the patents back to the innovator firms, licensing to third parties, or marketing the enantiomers themselves.

Forest Labs licensed both the racemic antidepressant citalopram and active S isomer escitalopram from the drug firm H. Lundbeck of Copenhagen. Escitalopram is one of the advanced selective serotonin-reuptake inhibitors used to treat depression. The Food & Drug Administration approved sale of the racemate in July 1998. Forest filed a new-drug application (NDA) for the S isomer this March.

In August 2000, Forest licensed single-enantiomer dexloxiglumide for irritable bowel syndrome from the Italian drug firm Rotta. The compound is a selective cholecystokinin A receptor antagonist.

Names such as dexloxiglumide and escitalopram represent an ongoing problem for the authorities who assign generic names to drugs. Use of prefixes to denote chirality of compounds opens the door to alphabetized lists of drugs with long, confusing sequences beginning with the prefixes dex-, lev-, ar-, and es-. The situation is reminiscent of choosing the prefix cef- to name cephalosporin antibiotics.

Also in November 2000, Forest licensed the calcium channel blocker lercanidipine to treat high blood pressure from Recordati of Milan, Italy. The activity of the compound is in the S isomer, with the R isomer reported as having only 1% of its racemate's activity.

Organic chemistry professor Roger A. Sheldon of Delft University of Technology in the Netherlands has commented on such situations. Sheldon advises that an enantiomer that appears to have 1% of the pharmacological activity of the other may actually have no activity at all. The seeming minute activity in tests might come from very small amounts of the active enantiomer in the test samples of the inactive one, he suggests.

Among the companies that are doing racemic switches of the drugs of other firms is Celgene, which has patented (R,R)-methylphenidate as the active enantiomer of the Ritalin brand of Novartis Pharmaceuticals, East Hanover, N.J. Novartis' original 1950 patent on the racemic methylphenidate compound has long expired. The drug is used to treat attention deficit disorder or hyperkinetic child syndrome. Novartis has taken a license on Celgene's patent, which will enable the company to compete with the controlled-release pills of racemic methylphenidate marketed by Alza Pharmaceuticals , Mountain View, Calif., and with the mix of racemic and d-amphetamine marketed by Shire US, Florence, Ky.

In switching the drugs of other companies, the firms doing the switching often find themselves in a game of "chicken" with the innovator. Thus Novartis only recently licensed the Celgene patent. Meanwhile, Celgene announced results of preliminary clinical testing on its own part in October 1997. And the company licensed Canadian rights to Biovail, Mississauga, Ontario, in June 1998. The agreement with Novartis finally came in April 2000.

Sepracor is in various phases of developing racemic switches of 10 drugs of other companies. The company also develops metabolites, whether chiral or not, of other companies' drugs. Metabolites are often superior to the original drugs because the metabolites do not compete with other compounds for the isozymes of the cytochrome P450 metabolic system and so do not interact with other drugs.

PERHAPS Sepracor's greatest success to date has been (R)-albuterol, whose assigned generic name is levalbuterol. The compound is a 2 adrenergic agonist aerosol inhalant for the treatment of asthmatic bronchospasm.

The discoverer of racemic albuterol was a subsidiary of Glaxo Wellcome in Uxbridge, U.K., which markets the drug in the U.S. under the trade name Ventolin. Glaxo Wellcome--now part of GlaxoSmithKline--licensed Schering Corp. to market it in the U.S. under the trade name Proventil. Neither firm licensed Sepracor's levalbuterol, and Sepracor itself got FDA approval in 1999.

Sepracor has hired 200 salespeople to inform general practitioners, allergists, and pulmonary specialists about the drug. Sepracor has licensed Abbott Laboratories, North Chicago, to market the drug to pediatricians. The company has an additional pediatric formulation in the approval process.

In a related development, Sepracor began Phase III studies of (R,R)-formoterol this year as a long-acting 2 adrenergic agonist inhalant for once-daily use against asthma, emphysema, and chronic obstructive pulmonary disease. Phase III studies use large numbers of patients to determine efficacy and long-term safety and are the last step before filing an NDA. The compound has two asymmetric atoms, and Novartis obtained FDA approval to market one diastereomeric racemic mixture in the U.S. last February.

Another Sepracor-sponsored drug is (S)-zopiclone, now named espopiclone, for insomnia. The original discoverer of racemic zopiclone was Rhône-Poulenc, now a part of Aventis, which markets the drug in many countries but never has done so in the U.S. Sepracor is finishing Phase III clinical studies on the single-enantiomer compound; the next step will be filing of an NDA with FDA.

YET ANOTHER Sepracor compound is the (S)-enantiomer of a zopiclone metabolite that is missing a methyl group that appears on zopiclone's piperidine ring. The company has assigned the compound code number, SEP-174559, and is beginning clinical studies for the treatment of anxiety.

In addition, Sepracor has a slow-release formulation of (S)-oxybutynin in Phase III studies for urinary incontinence. The racemate is marketed by Alza. Sepracor representatives say the combination of the single enantiomer with slow-release action may give more constant blood levels of the drug at lower oral doses, avoiding such side effects as dry mouth.

Another Sepracor candidate for urinary tract problems is (S)-doxasosin for benign hyperplasia (excessive growth) of the prostate gland. The compound is an a1 adrenergic blocking agent that relaxes the smooth muscle of the gland and prevents it from constricting and blocking flow from the bladder. Pfizer markets the racemate. Sepracor has the single enantiomer in Phase I, which is a small-scale study in healthy volunteers.

Additional chiral metabolites from Sepracor are those of both (R)- and (S)-sibutramine. Knoll Pharmaceutical, Mount Olive, N.J., markets racemic sibutramine, which inhibits reuptake of the neurotransmitters norepinephrine, serotonin, and dopamine at nerve synapses to treat obesity. Sepracor is carrying out Phase I studies of the R metabolite for treatment of depression and attention deficit disorder, and of the S metabolite for treatment of erectile and ejaculatory dysfunction.

As clinical studies progress, the company will need an economical process to make each enantiomer in large amounts. Sepracor chemist Dhileepkumar Krishnamurthy came to the American Chemical Society national meeting in Chicago in August to report progress toward that goal. In one approach, process chemists improved the synthesis of racemic demethylsibutramine as well as its resolution with (R)-mandelic acid. They further enhanced the enantiomeric excess (ee) of the S metabolite by crystallization with (S)-mandelic acid.

Though this resolution route could be scaled up, Krishnamurthy said that a short asymmetric synthesis would be most economical. The company has access to large amounts of the Schiff base of methylamine with 1-(4-chlorophenyl)cyclobutanecarboxaldehyde. Sepracor workers tried addition of isobutyllithium to that, mediated by an enantiomeric bis(oxazoline) ligand. The yield was 95%, but there was only a 40% ee. Crystallization with mandelic acid drove the ee beyond 99%.

Sepracor is in partnership with drug company UCB of Brussels to develop (S)-cetirizine for allergic rhinitis (hay fever); Pfizer markets the racemate. UCB got approval to market the S isomer in Germany, with Sepracor retaining U.S. rights. Thus, in April, Sepracor started getting royalties from UCB, and they will increase as approvals come elsewhere in the European Union.

Yet another Sepracor partnership is with Janssen Pharmaceutica Products, Titusville, N.J., to develop ticalopride, which is the generic name of a 3S,4R-substituted piperidine metabolite of cisapride. Janssen marketed racemic cisapride to improve gastric motility in diabetes patients. It withdrew the drug in July 2000 because of adverse interaction with other drugs that compete for the 3A4 isozyme of the cytochrome P450 metabolic complex. The current aim is treatment of gastroesophageal reflux disorder (heartburn). Phase II trials of ticalopride were suspended in April of this year pending analysis of a small number of adverse events.

Sepracor has begun preliminary work with several other single-enantiomer compounds that may lead to partnerships or to Sepracor's own marketing of resulting drugs. These agents include (S)-amlodipine, a calcium channel blocker for high blood pressure, whose racemate is marketed by Novartis and Pfizer; and (R)-ondansetron, a serotonin blocker to prevent nausea and vomiting during cancer chemotherapy, whose racemate is marketed by GlaxoSmithKline.

PROCESS CHEMISTS like Sepracor's Krishnamurthy hone enantioselective processes to switch the racemates of innovators' drugs, and process chemists at the pioneer companies develop methods to produce single-isomer forms of their own drugs. Process chemist Zhiguo Jake Song of Merck Research Laboratories, Rahway, N.J., described such a process to make a Merck compound at the ACS meeting in Chicago.

The compound is an antagonist specific to the endothelin receptor ETA. Endothelins are polypeptides that constrict blood vessels. Inhibiting their receptors might prevent endothelins' mediation of high blood pressure and failure of the heart and kidney.

The Merck compound features a cyclopentanopyridine with benzofuran and anisole nuclei attached. Song reported that the process uses coupling reactions of a bromoanisole and a bromobenzopyran, mediated by a chiral auxiliary, to attach the two components stereospecifically to a substituted pyridine. The sequence ends with the closure of the cyclopentano ring. The process is noteworthy for being applicable to a variety of compounds by changing the substitution patterns on the pyridine, benzopyran, and/or anisole systems.

A Merck solution to a more general problem involves syntheses of single-enantiomer terminal epoxides. Process chemist Steven A. Weissman and coworkers generate these from 1,2-diols, which are available by Sharpless dihydroxylations of terminal olefins [Org. Lett., 3, 2513 (2001)]. The Rahway workers treat a series of phenethane-1,2-diols, made from corresponding styrenes, with tricyclohexylphosphine and diisopropyl azodicarboxylate. Under these conditions, which are analogous to Mitsonobu esterifications of acids and alcohols, diols with electron-withdrawing groups such as trifluoromethyl give high yields and high enantiomeric excesses.

A chiral auxiliary was also a solution to the problem of producing a compound at GlaxoSmithKline Pharmaceuticals, King of Prussia, Pa. The compound, which is called SB-219994 for now, is aimed at noninsulin-dependent diabetes. Persons with such diabetes still produce insulin, but their tissues become relatively insensitive to it. The new compound is an agonist of the so-called peroxisome proliferator-activated receptor . Activation of PPAR increases production of glucose-transporting proteins, which in turn raises the sensitivity of cells to insulin signals.

Research chemist Qiaogong Su told an audience at the Chicago ACS meeting that a key step was attaching 2,2,2-trifluoroethoxyacetic acid to an imidazolidinone chiral auxiliary and adding that amide stereospecifically to a substituted benzaldehyde. The addition was by a boron aldol reaction, but that method used costly, sensitive, and hazardous dibutylboron trifluoromethanesulfonate and triethylsilane. Su and his coworkers hit on the alternative of using lithium hexamethyldisilazide to generate an anion from the chiral acetyl derivative and using the anion to displace iodide from a benzyl iodide.

Just as process chemists at drug companies work to make their compounds with acceptable reagents, solvents, and catalysts, so fine chemicals companies continue to multiply their offerings of such compounds. The laboratory catalog firm Lancaster Synthesis, Morcombe, U.K., has new chiral compounds based on agreements with BASF and Charnwood Catalysis, Loughborough, U.K.

New to the company's catalog from BASF are 11 compounds from the ChiPros line of single-isomer amines and alcohols, such as (R)- and (S)-p-chloro--phenethylamine and (R)--chloro--phenethyl alcohol. There are nine resin-supported enantiomers from Charnwood, including (1S,2R)- and (1R,2S)-ephedrine.

Aldrich Chemical, Milwaukee, introduced 53 chiral compounds just in the four-week period ending Sept. 6. Among these were both isomers of propylene and styrene oxides, made according to the kinetic epoxide resolution technique invented by Harvard University organic and inorganic chemistry professor Eric N. Jacobsen and licensed for industrial-scale use to Rhodia ChiRex of Boston.

Eastman Chemical is coming to CPhI to announce a new class of amino phosphine asymmetric catalyst ligands. Named BoPhoz after their invention by senior research associate Neil W. Boaz, the compounds achieve enantiomeric excesses as high as those from competing catalysts. The Eastman compounds have the advantages of ease of preparation and scale-up and stability at room temperature in the open air.

Takasago International, Kanagawa, Japan, has also developed phosphine catalyst ligands that are in some ways superior to even its flagship BINAP [2,2'bis(diphenylphosphino)-1,1'-binaphthyl]. Called SegPhos, the ligands are a series of 5,5'-bis(diarylphosphino)-4,4'-bis(benzodioxolyls). Yoshinori Kawai, who is associate director of fine chemicals in the company's Rockleigh, N.J., office, tells C&EN that the aryl groups are phenyl, 3,5-dimethylphenyl, or 2,6-di-tert-butyl-4-anisyl. When chelated with ruthenium, the ligands outperform BINAP in asymmetric hydrogenation of hydroxyacetone to (R)-propylene glycol.

Whenever new catalyst ligands are invented or licensed by companies for industrial use, they are also often licensed to Strem Chemicals, Newburyport, Mass., for research use only. Among compounds new to the Strem catalog are the all-organic asymmetric imidazolidinone catalysts of organic chemistry professor David W. C. MacMillan of California Institute of Technology. These catalysts are noteworthy for not requiring possibly toxic transition metals for efficacy. Materia of Pasadena is the firm licensed for industrial use. Other new catalysts at Strem are the CATHy aminoindanol-rhodocene of Avecia and FerroTane of ChiroTech.

Fine chemicals companies also reach out in academic collaborations. For example, Karlheinz Drauz, vice president for research and development at Degussa Fine Chemicals, Hanau, Germany, has reported work with organic chemistry professor Detlef Heller at the University of Rostock, Germany, on a process to make -amino acids [J. Org. Chem., published Sept. 1 ASAP, http://pubs.acs.org/journals/joceah].

SUCH AMINO ACIDS have found use in making nonnatural peptides with pharmaceutical activity and resistance to hydrolysis. Similar chiral amino acids also serve as scaffolds for synthesizing combinatorial libraries of compounds by such companies as Ascot Fine Chemicals, Cambridge, U.K., in its ChiroTech Technologies division.

The object is asymmetric hydrogenation of methyl -acetaminocrotonate. The problem is that the substrate exists as both E and Z isomers. Past efforts have led to poor enantiomeric excesses owing to lack of enantioselectivity in the Z isomer. Drauz, Heller, and their coworkers find that success comes with use of a polar solvent such as methanol and low hydrogen pressures. They get 98% ee with pure E isomer, 88% with pure Z isomer, and 92% with a mixture used as prepared without separating.

In addition to advances by industrial chemists, sometimes in collaboration with academicians, university chemists are making progress in potentially commercial enantioselective technology on their own. Organic chemistry professor Samuel H. Gellman of the University of Wisconsin, Madison, has made his own contribution to synthesis of -amino acids [J. Org. Chem., 66, 5629 (2001)].

The desired products are 1S,2S and 1R,2R isomers of trans-2-aminocyclopentanecarboxylic acid. Such compounds are similar to the 3-aminocyclopentanecarboxylic acids used as scaffolds by ChiroTech. The Gellman route begins with ethyl 2-oxocyclopentanecarboxylate, readily available from Dieckmann condensation of diethyl adipate. Reductive amination of that compound with (S)--phenethylamine and sodium cyanoborohydride yields the 1S,2S amino ester, which is converted to the free acid by hydrolysis of the ester followed by hydrogenation to expel ethylbenzene. The 1R,2R isomer is accessible from the other isomer of the phenethylamine.

In what may be the most significant potential chiral chemical advance of the year, chemists in Kyoto, Japan, and Shanghai have made chiral compounds from allenes [Org. Lett., 3, 2615 (2001)]. Making allenes is so laborious and costly that their use in industry has seemed unlikely.

But organic chemistry professor Tamio Hayashi at the University of Kyoto has found a way to make one easily from chloroprene. Although it is a suspected human carcinogen, chloroprene is available cheaply in large amounts because of its use in making elastomers. Thus there is great potential for allenes and their downstream derivatives to become available in large numbers and amounts from firms that can handle chloroprene safely.

For example, reaction of chloroprene with dimethyl malonate, catalyzed by a palladium diphosphine chelate, gives dimethyl 3,4-pentadiene-1,1-dicarboxylate. And among many possibilities available to such a terminal allene, organic chemistry professor Shengming Ma at the Shanghai Institute of Organic Chemistry finds that reaction with iodobenzene, also catalyzed by a palladium phosphine, yields racemic dimethyl-2-(1-phenylethenyl)cyclopropane-1,1-dicarboxylate [Org. Lett., 2, 2495 (2000)]. It seems likely that further work will turn up asymmetric phosphine ligands that catalyze reaction of chloroprene all the way to chiral compounds in high enantiomeric excesses.

Organic chemistry professor Ben L. Feringa of Groningen University in the Netherlands has reported a rapid screening technique to estimate enantiomeric excesses of reaction mixtures [Angew. Chem. Int. Ed., 40, 3198 (2001)]. The screening is a visual scan of the color of reflected light from 96-well titer plates in which various catalyst candidates have effected an enantioselective reaction. Feringa's method makes use of the fact that the degree of helical twist of molecular ordering in nematic liquid crystals is affected by chiral dopants. He uses a commercially available mixture, called E7, from EM Industries, Darmstadt, Germany. He makes derivatives of the chiral compounds with other liquid-crystal-forming molecules to use in doping E7.

As attendees converge on London for CPhI, they will find that chirality has solidified its role in the worldwide drug industry. Most firms focus on single enantiomers to ensure smooth success in drug development. A few firms use chirality to choreograph patents and life cycles.

Indeed, so entrenched are single-isomer drugs that maturations and failures become magnified and distorted when viewed only through the lens of dollar value. Through all of this, process chemists at drug companies constantly devise processes for large-scale production of chiral compounds that have never existed before. And there is a constant crisscrossing of chemists between industrial and academic settings as they invent new enantioselective technologies and add to their offerings of single-isomer intermediates and ligands.

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Chiral Components
Sales of enantiomeric intermediates and single-enantiomer drugs are up

ENANTIOMERIC
INTERMEDIATES
BULK
ENANTIOMERIC DRUGS
$ MILLIONS 1999 2000 2005 1999 2000 2005
Anti-inflammatory/analgesics $150 $156 $168 $200 $223 $241
Antiviral 794 830 1,643 983 1,180 2,054
Cancer 892 1,073 1,297 1,783 2,146 2,593
Cardiovascular 1,133 2,281 3,269 1,889 3,802 5,449
Central nervous system 1,038 1,142 1,821 1,483 1,632 2,602
Dermatology 82 85 106 164 170 212
Gastrointestinal 251 331 649 413 567 1,082
Ophthalmic 238 284 401 340 405 573
Respiratory 576 656 914 1,151 1,511 2,287
Other 140 170 356 315 426 891
TOTAL $5,294 $7,008 $10,624 $8,721 $12,062 $17,984
SOURCE: Technology Catalysts International

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Going Up
Worldwide chiral drug sales increased 13% last year

ALL DRUGS SINGLE-ENANTIOMER DRUGS
$ MILLIONS 1999 2000 1999 2000 2005
Analgesics $21,500 $23,000 $1,173 $1,291 $1,395
Antibiotic/antifungals 29,300 31,700 24,918 26,140 29,747
Antiviral 17,700 19,100 6,717 8,820 12,201
Cancer 13,700 15,600 8,891 10,690 13,605
Cardiovascular 42,700 46,600 24,895 27,650 34,627
Central nervous system 47,700 53,900 8,439 9,094 14,700
Dermatology 17,900 18,400 16,202 1,272 1,540
Gastrointestinal 43,900 47,200 1,970 4,033 6,590
Hematology 16,500 15,400 7,405 8,879 11,295
Hormone/endocrinology 20,000 22,000 14,510 15,384 19,790
Ophthalmics 7,100 7,400 1,270 2,265 2,705
Respiratory 36,500 40,500 5,696 6,615 9,620
Vaccines 6,500 7,300 2,503 3,349 4,320
Other 39,000 41,900 6,248 7,032 9,730
TOTAL $360,000 $390,000 $117,763 $132,514 $171,865
NOTE: Figures are for dosage formulations. SOURCE: Technology Catalysts International

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MEETINGS
Expositions, Symposia Highlight Chiral Chemistry

Oct. 11–12, Chiral Europe 2001. London. Contact Scientific Update, Wyvern Cottage, High St., Mayfield, East Sussex TN20 6AE, U.K.; phone 44 14 3587 3062, fax 44 14 3587 2734, e-mail: sciup@scientificupdate.co.uk.

Nov. 12–14, ChiraSource. Philadelphia. Contact Catalyst Group, P.O. Box 637, Spring House, PA 19477; phone (215) 628-4447, fax (215) 628-2267, e-mail: cnf@catalystgrp.com

Nov. 19–20, Fine Chemicals Conference 2001. London. Contact Folio Consultants, Braeside, High St., Oxshott, Surrey KT22 OJP, U.K.; phone 44 13 7284 1010, fax 44 13 7284 1012, e-mail: Paulfolio@aol.com.

Feb. 26–March 1, 2002, Informex. New Orleans. Contact Synthetic Organic Chemical Manufacturers Assoc.,1850 M St., N.W., Washington, DC 20036; phone (202) 721-4100, fax (202) 296-8120, e-mail: diane.mcmahon@socma.com.

April 28–30, 2002, Chiral Asia 2002. Hong Kong. Contact Scientific Update.

June 26–27, 2002, ChemSpec Europe. Basel, Switzerland. Exposition: Contact DMG World Media, 2 Queensway, Redhill, Surrey RH1 1QS, U.K.; phone 44 17 3785 5523, fax 44 17 3785 5474, e-mail: sallyembling@uk.dmgworldmedia.com. Symposium: Contact British Assoc. for Chemical Specialities, Gate House, White Cross, Lancaster LA1 4XQ, U.K.; phone 44 15 2484 9606, fax 44 15 2484 9194, e-mail: enquiries@bacsnet.org.

Oct. 1–3, 2002, Conference on Pharmaceutical Ingredients. Paris. For both the expo and symposia, contact CMP Information, P.O. Box 200, 3600 AE Maarssen, the Netherlands; phone 31 346 559 444, fax 31 346 573 811, e-mail: cphi@cmpinformatio.com.

Oct. 14–15, 2002, Chiral USA 2002. Boston. Contact Scientific Update.

Oct. 16–17, 2002, Outsource 2002. Boston. Contact Scientific Update.

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