The rise and fall of the British Drug Houses, Ltd

ELSEVIER

The rise and fall of the British Drug Houses, Ltd Vladimir Petrow and Sir Frank Hartley Department o f Pathology, Duke University Medical Center, Durham, North Carolina, USA, and Rugby, England Yea, the first Morning of Creation wrote What the last day of reckoning shall read.

--E. Fitzgerald Steroid research at BDH began in earnest in 1946-1948, when Hartley and Petrow joined the company. With the need to find new progestational agents to replace ethisterone and progesterone, the company began work. They' were the first to discover the vital importance of 6-methylation in enhancing the hormonal effects of steroid hormones. Their progestational studies led them to work on antifertili~ agents and the development of ovulation inhibitors, the mini-pill, and preliminary studies on the postcoital pill. Their search for new steroids additionally resulted in synthesis for biological evaluation of new corticoids, anabolic agents, estrogens, and mineralocorticoids. In 1968 the company, then known as The BDH Group Ltd., was incorporated into the Glaxo Group and company research terminated. (Steroids 61:476-482, 1996)

Keywords: BDH; contraception; methylated and glucocorticoidal steroids

Introduction The British Drug Houses, Ltd., was formed in 1906 by Charles Alexander Hill by the amalgamation of six British pharmaceutical companies, of which the oldest had origins going back to 1714. It was a modest group, which only began its real expansion when Francis Carr joined the Company in the 1930s. Francis Carr achieved prominence in the British pharmaceutical industry and was chairman until his retirement in 1949. The company was one of the earliest producers of steroid hormones, for which it used dehydroepiandrosterone obtained from cholesterol. During the Second World War, Boots The Chemist, The British Drug Houses, Burroughs Wellcome, Glaxo, and May and Baker formed The Therapeutic Research Corporation (TRC) to speed up the search for new drugs and to collaborate with the US on penicillin research. Frank Hartley, who was manager at Organon at the time (and hence had steroid expertise) was appointed secretary of this important organization. Vladimir Petrow was Lecturer in Organic Chemistry at Queen Mary College, London. He had carried out postgraduate work in steroid chemistry under Charles Dote6, one of the doyens of steroid research, and had formed a friendship and research collaboration with Otto Rosenheim of The National Institute of Medical Re-

Address reprint requests to Dr. Vladimir Petrow, Department of Pathology, Duke University Medical Center, Box 3712, Durham, NC 27710, USA. Received February 22, 1996; accepted February 26, 1996. Steroids 61:476-482, 1996 © 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

search (see Jones ERH, 1992). As a result he had been invited to carry out steroid research for the government by the late Sir Robert Robinson. At the time, Queen Mary College had already transferred to King's College, Cambridge, for the duration of the war. Its principal, Major General Sir Frederick Maurice, refused to release Petrow for military service on the grounds that he was wanted for teaching duties at the college. At this point he was approached by Hartley to carry out part-time research for the TRC in addition to his teaching duties. Thus began an association and friendship that has lasted 55 years. In 1946 Hartley moved to BDH as research director, and in 1948 he invited Petrow to join the company as chief research chemist. Alan David was appointed chief pharmacologist. The company initiated a working relationship in 1957 with the Mead Johnson Company (MJ) of Evansville, Indiana, USA. In 1961 an agreement was made by which MJ could acquire 34% of the common stock of BDH. This option was exercised in 1962 when Mead Johnson obtained four seats on the BDH board and thus obtained a large measure of control over the company. The following year was marked by massive changes in top management. The managing director, G.F. Williams, was replaced by F.W. Griffin. The Wholesale Division underwent unprecedented expansion and shortly afterward joined forces with Glaxo to form a major wholesaling unit called Vestric. The following year the company became The BDH Group. This period was critical to the future of the company, as it laid the foundation for the relentless chain of events that led to its destruction. 0039-128X/96/$15.00 PII S0039-128X(96)00038-4

The rise and fall of the British Drug Houses, Ltd: Petrow and HaRley

Figure 1 Vladimir Petrow, 1995.

The 6-methylated steroid hormones In 1946 the useful lives of ethisterone and, to a lesser extent, progesterone were coming to an end. Norethindrone (19norethisterone) j was discovered by the Syntex group in 1951 and norethynodre 2 by the Searle group in 1953. The company was therefore interested in the discovery of new and more potent progestational agents. In 1954 Burstein et al. 3 found that hydrocortisone was metabolized by the guinea pig and by humans to 6[3hydroxy-hydrocortisone. Using this observation as a clue, Petrow conceived the idea of preventing metabolic deactivation of hormones and increasing their hormonal potency by methylation at C6. The results exceeded all expectations. 6-Methylation of both progesterone and ethisterone gave products of greatly increased potency, leading the company to mount a major effort to develop new routes to 6-methylated steroids (cf. Ref. 4), and to the discovery of megestrol (I), melengestrol OIL and dimethisterone (III), thereby opening the door to a search for a new oral contraceptive.

Megestrol acetate (I) Burn et al.5 had prepared 6c~-methylprogesterone in 1957. With the discovery by the Upjohn groups 6 that 17a-acetoxyprogesterone was orally active, the company prepared 6oL-methyl-17o~-acetoxyprogesterone.7 Unbeknown to them, six other research groups had the same idea. Priority fell

Figure 2 Sir Frank Hartley.

to the Upjohn Company, which synthesized medroxypro gesterone acetate by the ketal route in 19568 (see Ref. 4). The discovery of megestrol acetate (MA) was purely fortuitous. David had already shown that the 6[3-analog of medroxyprogesterone acetate was virtually without biological activity. 6-Dehydroprogesterone was a much weaker progestational agent than the parent steroid. The 6-methyl group in megestrol acetate is orientated away from the biologically favorable a-position toward the biologically unfavorable [3-position. Ergo the product was unlikely to be of any value. In spite of this prediction, Ellis et al. 9 synthesized megestrol acetate, which was found by David et al. m to be the most potent antiovulatory agent yet discovered. Four other groups subsequently reported its independent synthesis. 4 The role of androgens and estrogens as causative agents for benign prostatic hypertrophy (BPH) had been recognized by Huggins and Clark. ~1 David's studies had shown that MA had both antiandrogenic and antiestrogenic activity. 1° The MJ group had demonstrated that MA decreased the size of the male dog's prostate. Its beneficial effect on human BPH was established by Lebech and Nordentoft. 12 The value of megestrol acetate in breast cancer was realized through collaboration with Mead Johnson, ~3.14 which issued the drug as Megace in 1976. To return to the main theme: The company rapidly developed an oral contraceptive preparation based upon

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Review megestrol acetate-ethinyl estradiol (Volidan). In 1960 Williams, managing director of the company, was having dinner with the managing director of the Fisons Company. During the meal the Fison's managing director mentioned, in passing, that Fisons planned a hostile takeover of the company. The research staff, to put it mildly, was devastated by this news. Fortunately at the critical phase of the takeover, when Fison's offer was put to the shareholders, Hartley appeared on British television to announce the discovery of the first British oral contraceptive. The battle was won. The shareholders threw out the Fisons offer. Volidan was saved and was issued by the company in 1963. Clinical studies on Volidan had demonstrated 100% effectiveness, which was naturally included in the claims for the product. It was therefore a major shock to the company when an Australian user reported an unwanted pregnancy. Hartley immediately dispatched David to Australia to investigate this report. The company meanwhile withdrew all unsold supplies from the market. David's investigations showed that the woman in question had taken her Volidan pills regularly, but had suffered a traumatic shock, which had brought on ovulation. Study of hospital records over the years additionally confirmed the ovulation-inducing effect of a severe shock, which, in this particular case, was able to override the ovulation-inhibiting effect of the steroid. Voltdan labeling was naturally brought into line with this new observation. After the issue of Volidan, Petrow became a key lecturer on the pill in England, Europe, New Zealand, Australia, and the Far East. The visit to India was particularly memorable. At the time India was undergoing some political unrest. He was in Bombay to deliver a lecture when a riot started in the morning. In the afternoon a very frightened lecturer and his Indian host went by car through largely empty streets to the lecture hall. Only about a dozen guests were present of the 125 who had been invited. The lecture was delivered, after which the lecturer asked if there were any questions. Only one question was asked: "Dr. Petrow, where did you get your tie?" Being a perfect gentleman, the lecturer took off his tie and presented it to the questioner with the company's compliments. The journey back to the hotel was uneventful. The next morning he was told that a young employee of the hotel, whom he knew, had been caught in the riot, a bucket of gasoline had been thrown over him and set alight, and he had been burned to death. Hartley had mentioned in his television appearance that he believed the cost of the daily dose of oral contraceptive would be in the region of one halfpenny per day. It was now up to the research department to make this a reality. The company consequently made a detailed study of alternative routes to MA (see Ref. 4). D.N. Kirk, who was a senior section head in the research department, played a key role in developing a commercial process to MA. Kirk applied the Vilsmeier reaction to the enol ether of 17-acetoxyprogesterone and prepared the 6-methylene derivative (IV) in excellent yield] 4 This steroid was then readily isomerized to megestrol acetate (cf. Ref. 4 for details). The Vilsmeier reaction proved to be an extremely important route to new and exciting steroids 1 and is still, after 31 years, providing novel steroidal drugs (cf. Ref. 15).

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Melengestrol acetate (II) After its success with MA, the group turned its attention to 16-methylprogestins. The 16a- and 1613-methyl- derivatives of 17a-acetoxyprogesterone 24'25 had little biological interest. 17a-Acetoxy- 16-methylenepregn-4-ene-3,20-dione 26 and its 6a-methyl derivative, 27 in contrast, were potent progestagens. 28 When the last steroid was converted into the 4,6-diene, melengestrol acetate (II) (MGA) 29 was obtained. David and his colleagues found MGA to be marginally more potent than MA and to possess some glucocorticoid activity. His contraceptive work was expanding, and in 1963 he brought H.J.E. Cox into the department. Cox came from G.D. Searle & Co and had considerable experience in the contraceptive field. Their studies with various clinicians showed that MGA (II) was an excellent oral contraceptive, both in admixture with ethinyl estradiol and as a mini-pill in its own right. In addition, G.C. Liggins showed a therapeutic effect upon endometrial carcinoma. 3° Petrow subsequently expanded its antitumorigenic potential. 31 MGA was discovered independently by the Upjohn group. 32

Dimethisterone (III) Parallel with studies leading to MA, Adams et al. 34 were studying the 6-methylation of ethisterone. As the a-isomer proved to be approximately 6.5 times as potent as its parent in the Clauberg assay (David et al.), 35'36 a systematic study of to-alkylated ethisterone derivatives was initiated, leading to the preparation of the propynyl derivative (dimethisterone, secrosterone) (III),37 which was 12 times more potent than ethisterone. This was the first time the propynyl group had been introduced into a steroid. It has since been employed in such steroids as Ru-486. In common with other progestagens, dimethisterone proved to be effective against endometrial hyperplasia. Budd Wentz of MJ carried out studies on its value in primary uterine cancer and found it to be remarkably effective. 38 Dimethisterone was issued by the company as a progestational agent in 1958. 39 In collaboration with Mead Johnson, the company tested the hitherto unproved concept of sequential estrogenprogestagen contraception, 4°'4~ using dimethisterone as the progestagen. This joint effort proved successful and in 1965 resulted in release of the first sequential oral contraceptive in the United States by MJ (Oracon) and in Canada by BDH (Secrovin).

Corticoids Early in 1951 the BDH group began the conversion of desoxycholic acid into the 12o~-hydroxy analog of hydrocortisone (V), which, it was hoped, would show antiphlogistic activityh Standard reactions were employed to prepare this steroid. 2 Unfortunately it proved to be without corticoidlike biological properties 43 This led to the novel concept that biologically active compounds possessed specific (~) and nonspecific (v) pharmacodynamical groups. The molecule of a biologically active compound was pictured as

The rise and fall of the British Drug Houses, Ltd: Petrow and Hartley being partly embedded in the receptor system, the ~-groups lying within the system and the v-groups resting upon its surface. Any changes in the ~-groups altered the delicate spatial relationship between the active compound and its receptor center, making juxtaposition impossible, with consequent loss of activity. Limited changes in the surface v-groups were compatible with retention of activity. Such changes, however, could lead to biologically inactive structures that bound firmly to the receptor system, thus blocking the approach of active molecules, (i.e., acting as antihormones). Steroid (V) was therefore tested for anticortisone properties and was found to show some activity.43 At this point hecogenin became available, and an attempt was made to convert it into the 12-oxo-analog of cortisone, but without s u c c e s s . 44-46 Hecogenin was readily transformed into 21acetoxy-17a-hydroxy-allo-pregnane-3,12,20-trione, but attempts to introduce a 4,5-unsaturated linkage proved unsuccessful. It was ultimately made from hecogenin. 44-46 The hecogenin route was used to prepare the 12[3-hydroxy analog of hydrocortisone.47 Unfortunately, none of these steroids had biological utility. Employing 3,3,20,20-bisethylenedioxy-5a,6c~-epoxypregnan-1113,17~,21-triol as starting material, the group prepared 6a-methylhydrocortisone (VI). 48 In 1953 the group began studies on the preparation of 16a-hydroxy "compound S" and 16a-hydroxycortisone. No methods were available at the time for building the 16a,17a-dihydroxyketol side chain. Potassium permanganate and osmic acid were selected as oxidants. Osmic acid proved unsatisfactory, as it yielded not only the required 16c~,17c~-glycol but an equal quantity of a D-homo rearrangement product. 49 In contrast, addition of potassium permanganate in aqueous acetone to the steroid dissolved in acetone containing a small quantity of acetic acid led to the desired glycol in excellent yield. 5° Thus 21-acetoxypregna4,16-diene-3,20-dione was readily converted into the 16ahydroxy derivative of "compound S," and 21-acetoxypregna-4,16-diene-3,11,20-trione into 16a-hydroxycortisone acetate (VII). 5~ The last compound was without significant antiphlogistic activity. Oxidation of 6c~-methylpregna-4,16diene-3,20-dione with potassium permanganate likewise furnished the l 6a, l 7a-glycol, which was converted into the isopropylidenedioxy-derivative52 and thence into the 1-dehydro-derivative (VIII). The last two steroids were found by David and colleagues to approach hydrocortisone in antiinflammatory potency.

2,3-Dichloro-5,6-dicyanobenzoquinone The late Prof. E.A. Braude of Imperial College, London, kindly gave Petrow a sample of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) 53 for study of its effects upon steroids. DDQ proved to be a reagent of great value to the steroid chemist. Not only did it smoothly convert 4-en-3ones and 4,6-dien-3-ones into their 1-dehydro-derivatives (XX), 54 but it oxidized steroidal allylic alcohols to the M3-unsaturated ketones at room temperature in excellent yield. 55 It has since found wide usage.

17[3-Hydroxy-17ol-alkynyl derivatives of androstane and estrane The dimethisterone program was extended to new structural derivatives of androstane and estrane for study as antifertility agents. 17a-Chloroethynyl-derivatives (IX) were prepared by treating the 17-one in liquid ammonia with lithium chloroacetylide prepared in situ from transdichloroethylene.56 17~-Chloroethynyl-3,17[3-dimethoxyestra-l,3,5(10)-triene (IX) proved to be an exceptionally active estrogen. 17c~-Bromoethynyl-, 17c~-iodoethynyl-, 17a-trifluoropropynyl-, 17c~-vinyl-, and 17c~-trifluorovinylstructural types (XX) were also prepared for biological study. 57 Steroidal ethynyl amines (X) were made by the Mannich reaction on the corresponding ethynyl derivatives. 58 Unfortunately, neither the amines nor their quaternary salts proved to be of any interest.

Other structural types Kirk and Petrow 59'6° successfully prepared 4-methylated steroids by condensing a 3-oxo-4-enic steroid with an organic thiol and formaldehyde in the presence of a tertiary amine catalyst and treating the resulting "Mannich" product with Raney nickel in acetone. The reaction was successfully extended to the preparation of 4,6-dimethyl steroids (XI). 61"62 By condensing 1 1-oxotigogenin with methyl mag6~ nesium iodide under forcing conditions, Kirk and Petrow obtained 1 lot-methyl-I l[3-hydroxytigogenin, from which the 1 1-methylene-derivative was obtained and converted by standard reactions into 1 1-methylenetestosterone (XII). The observation that 16~,17oL-methylenepregn-4-ene-3,20-dione 64 possessed progestational activity led to the synthesis of substituted derivatives (XIII) 65 thereof. A new method was developed for the preparation of 4-chloro testosterone ( X I V ) , 66 but priority for this anabolic agent fell to Sala and Baldratti. 67 Some methylated spiro-lactones (XV) were also prepared. 68 An extended series of pentacyclic structures was developed by condensing 16-hydroxymethylene- 17-ketones with methyl vinyl ketone. 69 Unfortunately, these structurally interesting types did not show anti-infammatory activity.

Additional antifertility studies The oral contraception era undoubtedly began in 1960, when the Food and Drug Administration approved the Searle product Enovid (Colton) 7° for ovulation inhibition. Work was therefore directed primarily to a search for ovulation inhibitors. That this was not the only contraceptive mechanism brought into play by progestins was proposed by Greenblatt. 7~ He suggested that contraception might be effectively prevented at doses lower than those required to inhibit ovulation by congealing cervical mucin, thus making it impenetrable to sperm. Moreover, certain 19-nor steroids could interrupt the postimplantation phase of pregnancy. It was therefore difficult to define the precise mechanism of action of antifertility steroids. The term "claudogen":2 was introduced to cover these antifertility effects. John Bennett was brought into the contraceptive group in 1963 and given responsibility to expand the antifertility screen to include

Steroids, 1996, vol. 61, August

479

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effects upon cervical mucin and upon the postimplantation phases of pregnancy. The cervical mucin assay was a particularly difficult assignment, as available assays were tedious and cumbersome. Bennett et al. 73 successfully developed a new rabbit assay and showed that MA (I) was particularly effective in inhibiting sperm migration through cervical mucin. Little did the research department realize at this time what was in store for them. The managing director had told Petrow that a high officer of Mead Johnson had mentioned that the U.S. company believed that "the bloom had gone from the pharmaceutical rose." The full significance of this

480 Steroids, 1996, vol. 61, August

comment was not recognized. Research proceeded without interruption. As the effect of megestrol acetate in women lasted some 24 h, Bennett, Cox, David, and Petrow developed the concept of using this steroid as a "pre-coital" pill. Clinical studies on the duration of the effects of MA on cervical mucin in women were carried out by Cox with very encouraging results. However, in late 1967, senior management was suddenly summoned to Griffin's office, where a grim-faced managing director shocked them with the news that, without any warning or prior consultation, Mead Johnson had sold its equity in the company to Glaxo. The meeting was told that Glaxo understandably wished to safe-

The rise and fall of the British Drug Houses, Ltd: Petrow and Hartley guard its investment in Vestric, but knew little about the rest of BDH. The future looked bleak. In 1968 these fears were realized. Glaxo took over BDH and dismantled the company. Research on the pre-coital pill had already been terminated before the work had been completed. Cox TM subsequently published experimental data confirming the validity of the "precoital concept." But this work was premature. The sexual revolution was still a decade away.

20.

21.

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23.

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