(S)-(+)-4-[7-(2,2-Dimethyl-1-oxopro- poxy)-4-methyl-2-[4-[2-(1-piperidinyl)- ethoxy]phenyl]-2H-1-benzopyran-3-yl]- phenyl 2,2-Dimethylpropanoate (EM-800):  A Highly Potent, Specific, and Orally Active Nonsteroidal Antiestrogen

Abstract

Breast cancer is the most frequent cancer and the second cause of cancer death in women in North America. 1 Unfortunately, the available therapies show a low rate and an usually short duration of positive responses. 2 Since estrogens are known to play a predominant role in breast cancer development and growth, 2,3 a logical approach for the treatment of estrogen-sensitive breast cancer is the use of antiestrogens which block the interaction of estrogens with their specific receptor. Despite its well-demonstrated and important clinical benefits, Tamoxifen, the antiestrogen widely available for the treatment of breast cancer, possesses mixed agonist-antagonist activities, thus potentially limiting its efficacy as blocker of estrogen action. 4 The discovery and development of specific and potent antiestrogens has thus become an important scientific challenge.The first class of specific antiestrogens obtained were 7R-substituted estradiol derivatives, 2d,5 especially ICI 164,384, EM-139, and ICI 182,780 (Chart 1). However, the development of these compounds as drugs is problematic due to their limited oral bioavailability. We thus concentrated our efforts on the synthesis of nonsteroidal compounds having oral activity in order to overcome this difficulty. We report the synthesis of (S)-(+)-[4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl] 2,2-dimethylpropanoate [EM-800, (S)-1] and comparison of some biological properties of enantiomers (R)-1 and (S)-1 [or (R)-6 and (S)-6].Synthesis of chromene 6, the racemic precursor of EM-800 [(S)-1], is shown in Scheme 1. The first step was a Friedel-Crafts reaction using BF 3 ‚Et 2 O as catalyst and solvent. 6 Resorcinol was thus acylated with 4-hydroxyphenylacetic acid (2) to yield trihydroxydeoxybenzoin 3 at a 70% yield. The trihydroxydeoxybenzoin 3 was then protected with DHP, in the presence of TsOH as catalyst, to give the bis-THP ether 4 at a 69% yield. The Knoevenagel reaction of bis-THP ether 4 with 4-hydroxybenzaldehyde, in the presence of piperidine in refluxing benzene, gave a mixture of chromanones and chalcones at a 3:2 molar ratio. The crude intermediates were then alkylated with 1-(2-chloroethyl)piperidine monohydrochloride, in the presence of Cs 2 CO 3 in refluxing acetone-water, to yield the chromanones 5 at a 65% yield. 7 The chromanones 5 were then alkylated with methyllithium, in THF at -78°C to room temperature, to give tertiary alcohols. The crude alcohols were then dehydrated and deprotected in 90% aqueous acetic acid at 90°C to yield the desired chromene 6 (EM-343) at a 60% yield after chromatography. The chromene 6 was an amorphous solid with variable coloration (light pink to red) and contained relatively large amounts of residual solvents (5-10% by weight).The strategy used to obtain compound (S)-1 is a chiral separation of the racemic chromene 6 and then prodrug derivatization of the active enantiomer (S)-6 (EM-652). The chromene 6 was resolved using preparative HPLC and a Chiralpak AD column...

Intracrinology and The Skin

“…In addition, we have administered the combination of DHEA with the pure antiandrogen Flutamide [49, 50]or the pure antiestrogen EM-800 [51, 52, 53, 54, 55, 56]for 12 months in order to analyze the androgenic and/or estrogenic component(s) in the action of DHEA in rat skin [57]. …”

Synthesis of 14C‐labelled EM‐800 (SCH 57050) and EM‐652·HCl (SCH 57068·HCl, acolbifene), pure selective estrogen receptor modulators

“…However, we decided to use an alternative method which resolved the racemate 4 with (+)-CSA as previously described by us for the resolution of unlabelled ( AE )-EM-343. 7 To the best of our knowledge, this is the first report of chemical resolution of racemic radiolabelled amine by chiral acid. Initially, the ( AE )-EM-343 Á (+)-CSA salt was prepared by adding (+)-CSA to a solution of amine in methanol, then the isolated salt was recrystallized from a mixture of DMF-dichloromethane to give crystalline (+)-EM-652 Á (+)-CSA (34% yield, 95% diastereomeric excess (de)).…”

Advances in the Science of Estrogen Receptor Modulation

“…EM-652, 61, a metabolite of EM-800, 6 0 (containing pivaloyl esters of the phenolic groups), is a potent orally active antiestrogen and is in clinical trials for the trearment of estrogen sensitive breast and endometrial cancers. EM-652 is reported to exhibit a higher binding affinity than any of the known antiestrogens and possesses a 2.9 fold higher receptor affinity than estradiol [229][230][231]. EM 652 has a higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene, and hydroxytoremifene.…”