Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-17
1996-12-31
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514648, 548570, 564324, C07C21718, C07D295088, A61K 31135, A61K 3140
Patent
active
055895000
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 93/00889 filed Apr. 29, 1993.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to substituted 1,1,2-triphenylbutenes which are structurally related to tamoxifen, a drug used in the treatment of oestrogen-dependent cancer, especially breast cancer, and their use for the same purpose.
2. Background of the Inventions
Researchers into anti-cancer drugs continually seek to improve on existing drugs, in particular to increase their efficacy. Many variations of the structure of tamoxifen have already been proposed. One such proposal is contained in our U.S. Pat. 4,839,155. (The European counterpart is EP-B 260 066). This patent claims 3- and 4-iodotamoxifen derivatives of formula (1): ##STR2## wherein I represents a 3- or 4-iodo substituent and R.sup.1 and R.sup.2, which may be the same or different, represent C.sub.1-3 alkyl groups or R.sup.1 represents a hydrogen atom and R.sup.2 a C.sub.1-3 alkyl group and R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, in the form of the free bases or their pharmaceutically acceptable acid addition salts. Preferably R.sup.1 and R.sup.2 represent methyl groups or R.sup.1 and R.sup.2 together with the said nitrogen atom, represent a pyrrolidino group. The most preferred such compounds have the iodine atom in the 4-position of the phenyl group and are termed "4-iodo tamoxifen" and "Idoxlfene" respectively.
SUMMARY OF THE INVENTION
It has now been found that extending the ethylene (--CH.sub.2 --CH.sub.2 --) part of the side-chain of such compounds confers on representative compounds benefits over tamoxifen, and even over 4-iodotamoxifen or Idoxifene, from which it can reasonably be concluded that they will be particularly valuable for treatment of oestrogen-dependent cancer, especially breast cancer.
Accordingly, the present invention provides compounds of the general formula (2) ##STR3## wherein n is an integer of from 3 to 10, I represents a 3- or 4-iodo substituent and R.sup.1 and R.sup.2, which may be the same or different, represent C.sub.1-3 alkyl groups or R.sup.1 represents a hydrogen atom and R.sup.2 a C.sub.1-3 alkyl group or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group and their pharmaceutically acceptable acid addition salts.
The invention also includes compounds of formula (2) for use in the treatment of said cancers, most particularly in humans.
Compounds of formula (2) in which the iodine atom is radioisotopic are included in the invention, as well as their use in treating the said cancers by radiotherapy or in diagnosing them, according to the isotope employed.
The invention further provides a pharmaceutical composition comprising a compound of formula (2) in association with a pharmaceutically effective diluent or carrier.
D. W. Robertson et al, J. Med. Chem. 25, 167-171 (1982) showed that the chain-extended, unsubstituted pyrrolidino tamoxifen of formula (3) ##STR4## wherein n=3, has a lower binding affinity for the oestrogen receptor, as measured in a rat uterine cytosol competitive binding assay, than pyrrolidino tamoxifen itself (n=2). Such evidence has dissuaded researchers from experimenting with chain extension of tamoxifen derivatives and points away from the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The 4-iodo derivatives are preferred to the 3-iodo. Preferably R.sup.1 and R.sup.2 are both alkyl groups, most preferably methyl or ethyl, or NR.sup.1 R.sup.2 is pyrrolidino. Preferably n is from 3 to 8, most preferably from 3 to 6.
The compounds of formula (2) and their salts can be prepared starting from ketones which are easily preparable analogues of known compounds. The ketone is reacted with an organometalltc reagent derived from 1,3- or 1,4-diiodobenzene and capable of addition to a ketone group, in a substantially anhydrous organic solvent, to form a tertiary alcohol which is then dehydrated to eliminate a molecule of
REFERENCES:
D. W. Robertson et al., "Antiestrogen Bascity--Activity Relationships . . . ", J. Med. Chem. 25, 167-171 (1982.
M. G. Rowlands et al., "Variation on the inhibitions of calmodulin dependent cyclic AMP phosphodiesterase . . . ", Biochemical Pharmacology 40, 283-289 (1990).
A. Bouhoute and G. Le Clercq, "Antagonistic effect of triphenylethylenic antiestrogens . . . ", Biochem. Biophys. Res. Comm. 184, 1432-1440 (May 15, 1992).
C.D.M.A. Van den Koeduk et al., "Comparative affinity of steroidal and non-steriodal antioestrogens . . . ", Biochem. Pharm. 43, 2511-2518 (1992).
R. McCague et al., "The iodine atom in 4-iodotamoxifen reduces the extent of metabolism . . . ", Brit. J. Cancern 62, 505 (1990).
B. P. Haynes et al., "Metabolism and pharmacokinetics of pyrrolidino-4-iodotamoxifen inthe rat", Breast Cancer Research and Treatment 19, 174 (1991).
M. G. Rowlands et al., "Idoxifene (pyrrolidino-4-iodotamoxifen)-a new antiestrogen . . . ", Annals of Oncology, 157, (1992).
S. K. Chander et al., "Pyrrolidino-4-iodotamoxifen and 4-iodotamoxifen, new analogues of the antioestrogen tamoxifen . . . " Annals of Oncology, 157, (1992).
S. Y. Loh et al., "The effect of calmodulin inhibitors on cisplatin-sensitive and -resistant human ovarian carcinoma cell lines", (abstract P173), Brit. J. Cancer. 67, 74 (1993).
R. McCague et al., "Metabolism of the 4-iodo derivatives of tamoxifen by isolated rat hepatocytes", Biochem, Pharmacol. 40, 2277-2283 (1990).
K. J. Edwards et al., "A molecular modelling study of the interactions between the antiestrogen drug tmoxifen and several derivatives . . . ", J. Med. Chem. 35, 2753-2761 (1990).
R. C. Coombes et al., "New endocrine agents for the treatment of breast cancer" Recent Results in Cancer Research, 127, 267-275, (1993).
Edwards Karen J.
Hardcastle Ian R.
Jarman Michael
Laughton Charles A.
Neidle Stephen
British Technology Group Limited
Gerstl Robert
LandOfFree
Substituted 1,1,2-triphenylbutenes and their use in the treatmen does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted 1,1,2-triphenylbutenes and their use in the treatmen, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 1,1,2-triphenylbutenes and their use in the treatmen will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1142462