WO1993022275A1 - Substituted 1,1,2-triphenylbutenes and their use in the treatment and diagnosis of cancer - Google Patents
Substituted 1,1,2-triphenylbutenes and their use in the treatment and diagnosis of cancer Download PDFInfo
- Publication number
- WO1993022275A1 WO1993022275A1 PCT/GB1993/000889 GB9300889W WO9322275A1 WO 1993022275 A1 WO1993022275 A1 WO 1993022275A1 GB 9300889 W GB9300889 W GB 9300889W WO 9322275 A1 WO9322275 A1 WO 9322275A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compounds according
- compounds
- oestrogen
- phenyl
- represent
- Prior art date
Links
- 0 *Oc1ccccc1 Chemical compound *Oc1ccccc1 0.000 description 3
- OFJWFSNDPCAWDK-UHFFFAOYSA-N CCC(C(O)=O)c1ccccc1 Chemical compound CCC(C(O)=O)c1ccccc1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
Definitions
- 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.
- I represents a 3- or 4- iodo substituent and R 1 and R 2 , which may be the same or different, represent C 1-3 alkyl groups or R 1 represents a hydrogen atom and R 2 a C 1-3 alkyl group and R 1 and R 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.
- R 1 and R 2 represent methyl groups or R 1 and R 2 together with the said nitrogen atom, represent a pyrrol idino 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 "Idoxifene” respectively.
- n is an integer of from 3 to 10
- I represents a 3- or 4-iodo substituent and R 1 and R 2 , which may be the same or different, represent C 1-3 alkyl groups or R 1 represents a hydrogen atom and R 2 a C 1-3 alkyl group or R 1 and R 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.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (2) in association with a pharmaceutically effective diluent or carrier.
- R 1 and R 2 are both alkyl groups, most preferably methyl or ethyl, or NR 1 R 2 is pyrrol idino.
- 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 organometallic 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 water and thereby provide the ethylenic double bond required.
- the preferred reagent for the preparation of the organometallic iodobenzene species is n-butyl lithium. Alternatively the magnesium Grignard reagent can be used.
- the dehydration is preferably carried out by heating the alcohol in a strong acid such as concentrated hydrochloric acid.
- a mixture of isomers is normally produced, of which the desired one is that in which the ethyl group and the Caminoalkoxy)phenyl group are trans.
- the starting ketone contains the 4-( ⁇ -chloroalkoxy)phenyl group.
- the dehydration to the olefin yields the ( ⁇ -chloroalkoxy)phenyl intermediate.
- the isomers can often be separated by crystallisation, which is very convenient, and the desired isomer appropriately aminated by reaction with the alkylamine required.
- the amination can be carried out in any manner known in the synthesis of tamoxifen, for example heating the chloroethoxy intermediate with the amine, such as methylamine or pyrrolidine, in a sealed vessel.
- the starting ketone already contains the 4-( ⁇ -aminoalkoxy)phenyl group and therefore the whole reaction can be carried out "direct” in one step (since the tertiary alcohol need not be isolated).
- the isomer separation is then carried out on the end product.
- the acid addition salts can be prepared in any manner analogous to those of tamoxifen, at any appropriate stage of the overall synthesis after formation of the tertiary alcohol. Usually they will be prepared as the final stage or by conversion of the final compounds. Examples of such salts are the hydrochloride, sulphate, phosphate, acetate and citrate. In the "direct" method of preparation, an acid addition salt is formed under the acidic dehydration conditions used. This will ordinarily be neutralised with, say, sodium hydroxide. The isomers can then be separated either as the free bases or, after adding a approximately stoichiometric proportion of acid, as acid addition salts.
- the compounds of formula (2) can be formulated in the same or a similar way to tamoxifen and administered similarly and in about the same dose. Preferably they are formulated as tablets.
- the compounds of formula (2) include those wherein the iodine atoms in some or all of the molecules of a given sample have a radioisotopic (a radioactive or "hot") iodine atom.
- a radioisotopic iodine atom Predominantly useful such atoms are 125 I which emits low energy electrons having a short, sub-cellular range and 131 I and 123 I which emit gamma rays.
- the 125 I isotopic iodine is useful in the therapy of tumour cells containing oestrogen receptors.
- the 123 I and 131 I isotopes, of which 131 I is preferred, are gamma emitters and therefore usable for imaging of oestrogen receptor-carrying tumour cells.
- the content of radioisotopic iodine in the iodotamoxife ⁇ formulation should be adjusted to conform to conventional radiotherapy and imaging practice.
- radioisotopes of iodine have a short half-life, for 131 I 8 days, for 125 I 60 days, and for 123 I 13 hours. It is therefore necessary to prepare the radioisotopic compounds of the invention only shortly before the expected time of use.
- the radioisotopic iodotamoxifen derivatives can be prepared by a process comprising reacting a compound of formula (4)
- n, R 1 and R 2 are as defined in connection with formula (2) and Y represents a 3- or 4- substituent, whether an atom or a group, capable of being cleaved from its benzene ring (including within this definition a non-radioisotopic iodine atom), with a reagent capable of effecting such cleavage and with a source of radioisotopic iodine (which can be added as molecular iodine or iodide ions according to the cleavage-effecting reagent used and other reaction conditions).
- Y is chloro, bromo, non-radioisotopic iodo or amino.
- Compounds of formula (4) can be prepared by methods analogous to those described in our said prior patent.
- Examples 1-5 describe the preparation of compounds of the invention.
- Example 6 describes tests relevant to their utility. "Ether” is diethyl ether.
- tamoxifen itself is designated as the Z geometric isomer
- the analogues prepared in these examples although having the analogous sterochemistry in which the ethyl group and the nitrogen-containing side-chain are trans with respect to the central double bond, are designed as E.
- the 4-(2-chloroethoxy)ketone is prepared by the usual method. Reaction thereof with 3-iodophenyl lithium gives the alcohol (not shown) which is dehydrated to give a mixture of E + Z isomers of the olefin. Reaction with sodium methoxide in DMF followed by treatment with toluenesulfonic acid in refluxing ethanol gives the phenolic compound as a mixture of E + Z isomers. Then phase-transfer reaction with octafluorotoluene gives the perfluorotolyl compound which allows separation of the isomers by chromatography or crystallization.
- Deprotection is accomplished by treatment with sodium methoxide in DMF and phase transfer reaction of the resulting phenolic compound with an ⁇ , ⁇ -dichloroalkane (here ClC 4 H 8 Cl) gives the chloroalkoxy compound (here, 4-chlorobutoxy). Reaction with pyrrolidine or dimethylamine in the usual fashion provides the desired title compounds.
- cAMP-PDE cyclic AMP phosphodiesterase
- calmodulin cyclic AMP phosphodiesterase
- cytotoxicity against the MCF-7 human breast cancer cell line was determined.
- the test methods used were those described by M.G. Rowlands et al., Biochemical Pharmacology 40, 283-289 (1990).
- results include figures for tamoxifen, 4-iodotamoxifen and its pyrrolidino analogue, Idoxifene. It will be seen that in the cAMP-PDE test that the inhibiting concentration required is reduced in the compounds of formula (2) compared with the corresponding prior art compounds. The MCF-7 cytotoxicity data also shows a lowering of the concentration required compared with the prior art compounds.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU42673/93A AU674146B2 (en) | 1992-05-01 | 1993-04-29 | Substituted 1,1,2-triphenylbutenes and their use in the treatment and diagnosis of cancer |
EP93911884A EP0638064B1 (en) | 1992-05-01 | 1993-04-29 | Substituted 1,1,2-triphenylbutenes and their use in the treatment and diagnosis of cancer |
US08/331,582 US5589500A (en) | 1992-05-01 | 1993-04-29 | Substituted 1,1,2-triphenylbutenes and their use in the treatment of cancer |
DE69313106T DE69313106T2 (en) | 1992-05-01 | 1993-04-29 | SUBSTITUTED 1,1,2, -TRIPHENYLBUTENES AND THEIR USE FOR TREATING AND DIAGNOSIS OF CANCER |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929209509A GB9209509D0 (en) | 1992-05-01 | 1992-05-01 | Substituted 1,1,2-triphenylbutenes |
GB9209509.0 | 1992-05-01 | ||
GB9303982.4 | 1993-02-26 | ||
GB939303982A GB9303982D0 (en) | 1993-02-26 | 1993-02-26 | Substituted 1,1,2 triphenylbutenes |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993022275A1 true WO1993022275A1 (en) | 1993-11-11 |
Family
ID=26300810
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1993/000889 WO1993022275A1 (en) | 1992-05-01 | 1993-04-29 | Substituted 1,1,2-triphenylbutenes and their use in the treatment and diagnosis of cancer |
Country Status (9)
Country | Link |
---|---|
US (1) | US5589500A (en) |
EP (1) | EP0638064B1 (en) |
JP (1) | JP3153554B2 (en) |
AT (1) | ATE156803T1 (en) |
AU (1) | AU674146B2 (en) |
CA (1) | CA2134772A1 (en) |
DE (1) | DE69313106T2 (en) |
ES (1) | ES2107030T3 (en) |
WO (1) | WO1993022275A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2262798A (en) * | 1991-12-24 | 1993-06-30 | British Aerospace | An aircraft cargo container |
DE4311870C2 (en) * | 1993-04-10 | 1998-07-30 | Altramed Holdings Ltd | Use of an anti-oestrigen for the therapy and prophylaxis of dementia diseases |
US6084117A (en) * | 1999-11-22 | 2000-07-04 | Albemarle Corporation | Production of silated haloarenes by selective silylation of polyhaloarenes |
US6599921B2 (en) | 2001-02-22 | 2003-07-29 | Nanodesign, Inc. | Non-steroidal estrogen receptor ligands |
US7196119B2 (en) | 2003-10-21 | 2007-03-27 | The Regents Of The University Of California | Development of new selective estrogen receptor modulators |
WO2015138340A1 (en) * | 2014-03-11 | 2015-09-17 | Repros Therapeutics Inc. | Clomiphene synthesis using a single solvent |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0260066B1 (en) * | 1986-09-11 | 1990-05-09 | National Research Development Corporation | Tamoxifen derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0677507B1 (en) * | 1993-10-25 | 1998-04-08 | Taiho Pharmaceutical Company Limited | Process for producing acid-addition salt of z-isomer of triphenylethylene compound |
-
1993
- 1993-04-29 JP JP51907293A patent/JP3153554B2/en not_active Expired - Fee Related
- 1993-04-29 AT AT93911884T patent/ATE156803T1/en not_active IP Right Cessation
- 1993-04-29 EP EP93911884A patent/EP0638064B1/en not_active Expired - Lifetime
- 1993-04-29 US US08/331,582 patent/US5589500A/en not_active Expired - Fee Related
- 1993-04-29 CA CA002134772A patent/CA2134772A1/en not_active Abandoned
- 1993-04-29 WO PCT/GB1993/000889 patent/WO1993022275A1/en active IP Right Grant
- 1993-04-29 DE DE69313106T patent/DE69313106T2/en not_active Expired - Fee Related
- 1993-04-29 ES ES93911884T patent/ES2107030T3/en not_active Expired - Lifetime
- 1993-04-29 AU AU42673/93A patent/AU674146B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0260066B1 (en) * | 1986-09-11 | 1990-05-09 | National Research Development Corporation | Tamoxifen derivatives |
Also Published As
Publication number | Publication date |
---|---|
EP0638064A1 (en) | 1995-02-15 |
CA2134772A1 (en) | 1993-11-11 |
AU4267393A (en) | 1993-11-29 |
US5589500A (en) | 1996-12-31 |
DE69313106T2 (en) | 1998-01-22 |
ES2107030T3 (en) | 1997-11-16 |
EP0638064B1 (en) | 1997-08-13 |
JP3153554B2 (en) | 2001-04-09 |
DE69313106D1 (en) | 1997-09-18 |
AU674146B2 (en) | 1996-12-12 |
ATE156803T1 (en) | 1997-08-15 |
JPH07506357A (en) | 1995-07-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4839155A (en) | Iodotamoxifen derivatives and use for estrogen receptor-positive breast cancer detection and therapy | |
EP0099148B1 (en) | Piperazine derivatives, processes for their preparation and pharmaceutical preparations containing them | |
US6706734B2 (en) | Arylpiperidinol and arylpiperidine derivatives and pharmaceuticals containing the same | |
US9340489B2 (en) | Process for the preparation of deuterated compounds containing N-alkyl groups | |
DK171748B1 (en) | Stable solvent adducts, process for their preparation, drug containing the adducts and use of the adducts | |
HU193536B (en) | Process for the production of new hydroxy-alkane- and alkene-tetrahydrofuran- and tetrahydropyran-derivatives | |
JPH0579654B2 (en) | ||
RU2404169C2 (en) | Method for synthesis of delmopinol and derivatives thereof | |
Hardcastle et al. | Rationally designed analogs of tamoxifen with improved calmodulin antagonism | |
EP0638064B1 (en) | Substituted 1,1,2-triphenylbutenes and their use in the treatment and diagnosis of cancer | |
FI78459B (en) | FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA DIALKYLAMINOALKOXIBENSYLALCOOL DERIVAT. | |
GB2266530A (en) | Substituted 1,1,2-triphenylbutenes. | |
IL147668A (en) | Process for the preparation of venlafaxin | |
Edwards et al. | 1-Alkylamino-3-(2-thiazolyloxy)-2-propanols. Novel class of mixed myocardial. beta.-stimulants/. beta.-blockers | |
US4465834A (en) | Anticholinergic drugs | |
JPH0419973B2 (en) | ||
EP0004107B1 (en) | 3-azabicyclo(3.1.0)hexane derivatives, a process for their preparation, biologically active compositions containing them and herbicidal method using them | |
CA1298832C (en) | 3-phenyl-1-propanones, process of preparing thereof and method of treating arrhythmias | |
JPS6123178B2 (en) | ||
WO2006106432A2 (en) | 4-arylpiperidine derivatives and use thereof for preparing a medicament for the treatment of cns disorders | |
JP2601661B2 (en) | New alkylenediamine derivatives and glutamate blockers | |
Vidal | Reaction of ethylene dibromide with triethylamine and the restoring action of some alkanebis (triethylammonium) ions upon sodium-deficient nerve fibers | |
US3127407A (en) | Certain 1-(chlorophenyl)-2-tertiary amino alkanes | |
Citerio et al. | 1, 2-diaryl-4-amino-4, 5-dihydro-5, 5-disubstituted imidazoles: behaviour in acidic medium | |
TWI294414B (en) | Amino alcohol derivatives as amadorase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2134772 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1993911884 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08331582 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1993911884 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1993911884 Country of ref document: EP |