WO2001004086A1 - Sulphamate compounds - Google Patents

Sulphamate compounds Download PDF

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Publication number
WO2001004086A1
WO2001004086A1 PCT/GB2000/002592 GB0002592W WO0104086A1 WO 2001004086 A1 WO2001004086 A1 WO 2001004086A1 GB 0002592 W GB0002592 W GB 0002592W WO 0104086 A1 WO0104086 A1 WO 0104086A1
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Prior art keywords
compound
alkyl
sulphamate
sulphatase
aryl
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PCT/GB2000/002592
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French (fr)
Inventor
Sabbir Ahmed
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Btg International Limited
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Priority to AU56984/00A priority Critical patent/AU5698400A/en
Publication of WO2001004086A1 publication Critical patent/WO2001004086A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids

Definitions

  • the present invention relates to members of a family of non-steroidal compounds which have been found to possess inhibitory activity against the enzyme oestrone sulphatase .
  • EI-STS oestrone sulphatase pathway
  • EIS to El the hydrolysis of oestrone sulphate (2) to oestrone (1) (EIS to El) (see Fig. 1)
  • AR inhibitors such as aminoglutethimide (AG) and 4-hydroxyandrostenedione 3 ' 4 ' 5 .
  • the oestrone sulphatase inhibitors are sulphamate esters, such as oestrone-3 -sulphamate (otherwise known as "EMATE”) .
  • EMATE (Compound 3: see Figure 1) is a potent EI-STS inhibitor and displays more than 99% inhibition of EI- STS activity in intact MCF-7 cells at 0. l ⁇ M concentration. EMATE also inhibits dehydroepiandrosterone sulphatase (DHEA-STS) , an enzyme that is believed to have a crucial role in regulating the biosynthesis of the oestrogenic steroid androstenediol 1 . Furthermore, there is now evidence to suggest that androstenediol 1 may be of even greater importance as a promoter of breast tumour growth 6 . Another known inhibitor is COUMATE (Compound 4: see Fig. 1) .
  • This present invention therefore seeks to provide compounds suitable for the inhibition of EI-STS and/or DHEA-STS.
  • Preferred compounds possess no, or a minimal, oestrogenic effect.
  • a non-steroidal sulphamate compound suitable for use as an inhibitor of oestrone sulphatase and/or dehydroepiandrosterone sulphatase wherein the compound has a ring structure wherein the ring mimics the A ring of oestrone.
  • the compound is of formula (A) :
  • R ⁇ -R 5 are independently selected from H, halo, alkyl, nitro, CN, aryl , OH, OR' (where R' is alkyl or aryl) , NR" 2 (where each R" is independently H, alkyl or aryl) and sulphamate groups, with the proviso that at least one of them is a sulphamate group;
  • X is selected from O, S, NH, NR' ' ' (where R' ' ' is alkyl or aryl)
  • R 6 is selected from H, alkyl, aryl, alkoxy, aryloxy and NR" 2 and/or is a compound of formula (A) wherein one of R ⁇ ⁇ R 5 is a sulphamate group and the others are selected so that the compound is a sulphamate ester of a phenol having a pK a in the range 7-9.
  • Alkyl groups may include unsaturation. They may be interrupted by heteroatoms e.g. O, N or S . Alkyl groups are preferably C ⁇ , more preferably C ⁇ g, especially C 1tician 6 .
  • Aryl' encompasses substituted aryl. Possible substituents include alkyl, halo, nitro and cyano . "Aryl ' encompasses heteroaryl . Aryl groups are preferably up to C 15 .
  • X is oxygen.
  • sulphamate as used herein includes an ester of sulphamic acid, or an ester of an N-substituted derivative of sulphamic acid, or a salt thereof.
  • the term includes functional groups of the formula: -O-S(O) (0)-N(R 7 ) (R 8 ) where R 7 and R 8 are independently selected from H, linear or branched alkyl which may be saturated or unsaturated and/or substituted or non- substituted, aryl, or any other suitable group.
  • R 7 and R 8 are H.
  • each of R 7 and R 8 is H.
  • a compound of the first aspect for use as a pharmaceutical product.
  • a compound of the first aspect for inhibiting oestrone sulphatase
  • a pharmaceutical composition comprising a compound according to the first aspect; and a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutically acceptable carrier for inhibiting oestrone sulphatase and/or dehydroepiandrosterone sulphatase, e.g.
  • oestrone sulphatase and/or dehydroepiandrosterone sulphatase activity e.g. endocrine-dependent cancers (particularly breast and prostate cancer) ; autoimmune diseases; and conditions affecting short and/or long term memory.
  • Compounds and compositions embodying the invention may be administered to individuals (human or non-human) .
  • Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient.
  • Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors .
  • a compound may be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.
  • compositions according to the present invention may comprise, in addition to the active ingredient, i.e. a compound of formula A, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient .
  • a pharmaceutically acceptable excipient e.g. a compound of formula A
  • Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient .
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. topical, subcutaneous, or intravenous.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such a gelatin.
  • the active ingredient will be in the form of a parenterally acceptable solution, usually aqueous, which is pyrogen- free and has suitable pH, isotonicity and stability.
  • Ri-R 5 is sulphamate and the others are independently selected from H, alkyl and haloalkyl .
  • R 3 is OS0 2 NH 2 or other sulphamate group.
  • the compound is any one of the compounds shown as Compounds 11-16 in Figure 2, particularly 4-0-sulfamoyl octaphenone or 4-O-sulfamoyl nonophenone, or a variant in which R ⁇ -R 5 include one or more electron withdrawing substituents, e.g. N0 2, CN or halo.
  • Preferred compounds of the present invention may have little or no oestrogenic activity, in particular, less than EMATE. They can therefore be deemed to be non-oestrogenic compounds.
  • non-oestrogenic compound as used herein means a compound exhibiting no or substantially reduced oestrogenic activity.
  • the present invention therefore provides non-steroidal compounds which have a reduced oestrogenic activity.
  • the non-steroidal compounds of the present invention act as EI-STS inhibitors.
  • the compounds may not be capable of being metabolised to compounds which display or induce hormonal activity.
  • the preferred compounds of the present invention are further advantageous in that the sulphamate compounds have an irreversible inhibitory effect.
  • Preferred compounds of the present invention are further advantageous in that they may also inhibit DHEA-STS.
  • the non-steroidal compounds are useful for the treatment of breast cancer .
  • the non-steroidal compounds are useful for the treatment of non-malignant conditions, such as the prevention of auto-immune diseases or the improvement of long or short term memory, particularly when pharmaceuticals may need to be administered from an early age.
  • a particularly preferred non-steroidal compound according to the present invention is 4-0-sulphamoyl nonophenone, or a derivative with a nitro or cyano substituent .
  • a highly preferred embodiment of the present invention therefore relates to pharmaceutical composition comprising 4-0-sulphamoyl nonophenone or a said derivative and a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention therefore relates to non-steroidal compounds which are suitable for use as sulphatase inhibitors.
  • 4-O-sulfamoyl nonaphenone together with 4-O-sulfamoyl octaphenone appear particularly active in vi tro .
  • 4-O-sulfamoyl nonaphenone together with 4-O-sulfamoyl octaphenone appear particularly active in vi tro .
  • 4-O-sulfamoyl nonophenone inhibited placental microsomal oestrone sulphatase by 76.4% at 5 ⁇ M with an IC 50 , of 0.86 ⁇ M.
  • 4-0-sulfamoyl octophenone also inhibited placental microsomal oestrone sulphatase by 80.1% at 5 ⁇ M with an IC 50 , of 1.16 ⁇ M. This inactivation was shown to be in a similar way to EMATE which inhibited placental microsomal oestrone sulphatase with an IC 50 , of 0.
  • the non-steroidal compounds of the present invention represent important compounds for the optimisation of non-steroidal sulphatase inhibition.
  • the compounds are also believed to have therapeutic uses other than for the treatment of endocrine-dependent cancers, such as the treatment of autoimmune diseases.
  • the compounds may also have uses in the increasing of short (and long) term memory .
  • Figure 1 shows the known structures of oestrone (1) , oestrone sulphate (2), EMATE (3) and COUMATE (4);
  • Figure 2 Shows the structures of 4-O-sulfamoyl benzaldehyde (11) , 4-O-sulfamoyl benzophenone (12) , 4-O-sulfamoyl acetophenone (13) , 4-O-sulfamoyl propiophenone (14) , 4-O-sulfamoyl octophenone (15) and 4-O-sulfamoyl nonophenone (16) ;
  • Figure 3 is a reaction scheme for the sulphamoylation of 4-hydroxy nonophenone.
  • Figure 4 a, b and c are dose-response curves showing plots of percentage inhibition versus Log [I] for the inhibition of placental microsomal oestrone sulphatase by compounds 13, 15 and 16 embodying the invention.
  • Aluminium chloride (2 moles equivalent) was added to a stirred solution of phenol in dichloromethane at 0°C under an atmosphere of nitrogen for 0.5 hours .
  • the appropriate acid chloride (1.1 moles equivalent) was then added dropwise, and the reaction allowed to warm up to ambient temperature overnight.
  • the slurry was then cautiously diluted with cool IM HCl (30ml) , and extracted into ether (3 x 30ml) .
  • the combined ether layers were extracted with 2M NaOH (3 x 30ml) .
  • the combined aqueous layers were acidified to pH 2 with IM HCl, and extracted into ether (3 x 75ml) .
  • Methanoic acid (l.OOmL, 26.50mmol) was added drop wise to chlorosulfonyl isocyanate (2.31ml, 26.50mmol, dried over B 2 0 3 ) , under nitrogen at 0-4°C. After evolution of gas, anhydrous toluene (20ml) was added to dissolve the product, and the solution stirred for 1 hour .
  • the total assay volume was 1ml.
  • 3 H-estrone sulfate (25 ⁇ l, 20 ⁇ M/tube; 300 , OOOdpm/tube) and the inhibitors (25 ⁇ l in various concentrations) dissolved in ethanol were added to a 10ml assay tube, and the ethanol removed with a stream of nitrogen.
  • Tris-HCl buffer (0.05M, pH7.2 , 0.2ml) was added to each tube. Placental microsomes were. then diluted with Tris-HCl buffer (115 ⁇ g/ml) .
  • the microsomes and assay tubes were preincubated for 5min at 37°C in a shaking water bath prior to the addition of the microsomes (0.8ml) to the tubes.
  • toluene (4ml) was added to quench the assay, and the tubes placed in ice. The quenched samples were vortexed for 45 s and centrifuged (3000 rpm, 10 min) . 1ml of toluene was added to 5ml scintillation cocktail (TRITON-X) . The aliquots were counted for 3min. All samples were run in triplicate. Control samples with no inhibitor were incubated simultaneously. Blank samples were obtained by incubating with boiled microsomes.
  • Table I presents data for compounds 13, 14, 15, 16 of the invention and also for the known compounds EMATE and COUMATE.
  • Figs. 4a, b and c present the data for compounds 13, 15 and 16 graphically.
  • Table II Relationship of pK a and IC 50 for
  • pK a falls from a high value, the activity of the sulphamate rises to a maximum, and then begins to fall again.
  • the optimum pK a range is around 7-9, preferably 7-8 or 7.5-8.5.
  • Such a relationship also applies with the compounds of the invention such as those shown in Fig. 2.
  • a strongly electron-withdrawing substituent such as N0 2 or CN (particularly o or p_ to the sulphamate group) will produce a significant increase in activity.
  • Adding a second such substituent will generally not have a comparable effect, unless there is also a strongly electron donating substituent.

Abstract

Non-steroidal sulphamate compounds of formula (A), such as (B), which inhibit oestrone sulphatase and dehydroepiandrosterone sulphatase and are thus useful in treating sulphatase-associated conditions such as breast cancer.

Description

SULPHAMATE COMPOUNDS
Technical Field
The present invention relates to members of a family of non-steroidal compounds which have been found to possess inhibitory activity against the enzyme oestrone sulphatase .
Background Art Although plasma oestrogen concentrations are found to be similar in women with or without breast cancer, breast tumour levels of oestrone and oestradiol are significantly higher than in normal breast tissue or blood. Synthesis of oestrogens within tumours is thought to make an important contribution to these high levels of the female hormones. Oestrogens are suggested to be the major mitogens involved in promoting the growth of tumours in endocrine-dependent tissues, such as the breast and therefore specific inhibitors of oestrogen biosynthesis are of potential value for the treatment of endocrine-dependent tumours.
Recently, there has been considerable interest in the development of inhibitors of the cytochrome P-450 enzyme aromatase (AR) - a pathway which is responsible for the conversion of androgens into oestrogens, e.g. androstenedione to oestrone.
There is now evidence, however, that the oestrone sulphatase (EI-STS) pathway [the hydrolysis of oestrone sulphate (2) to oestrone (1) (EIS to El) (see Fig. 1)] is the major source of oestrogen in breast tumours1'2 as opposed to the AR pathway. This is supported by a modest reduction of plasma oestrogen concentration in postmenopausal women with breast cancer treated by AR inhibitors, such as aminoglutethimide (AG) and 4-hydroxyandrostenedione3'4'5.
The oestrone sulphatase inhibitors are sulphamate esters, such as oestrone-3 -sulphamate (otherwise known as "EMATE") .
EMATE (Compound 3: see Figure 1) is a potent EI-STS inhibitor and displays more than 99% inhibition of EI- STS activity in intact MCF-7 cells at 0. lμM concentration. EMATE also inhibits dehydroepiandrosterone sulphatase (DHEA-STS) , an enzyme that is believed to have a crucial role in regulating the biosynthesis of the oestrogenic steroid androstenediol1. Furthermore, there is now evidence to suggest that androstenediol1 may be of even greater importance as a promoter of breast tumour growth6. Another known inhibitor is COUMATE (Compound 4: see Fig. 1) .
Although potency for the inhibition of EI-STS may have been attained in EMATE, it has been suggested that oestrone may be released during sulphatase inhibition7 and that EMATE and its analogues may possess oestrogenic activity8. Disclosure of Invention
This present invention therefore seeks to provide compounds suitable for the inhibition of EI-STS and/or DHEA-STS. Preferred compounds possess no, or a minimal, oestrogenic effect.
According to a first aspect of the present invention there is provided a non-steroidal sulphamate compound suitable for use as an inhibitor of oestrone sulphatase and/or dehydroepiandrosterone sulphatase wherein the compound has a ring structure wherein the ring mimics the A ring of oestrone.
Preferably the compound is of formula (A) :
Figure imgf000004_0001
wherein Rι-R5 are independently selected from H, halo, alkyl, nitro, CN, aryl , OH, OR' (where R' is alkyl or aryl) , NR"2 (where each R" is independently H, alkyl or aryl) and sulphamate groups, with the proviso that at least one of them is a sulphamate group; X is selected from O, S, NH, NR' ' ' (where R' ' ' is alkyl or aryl) , and R6 is selected from H, alkyl, aryl, alkoxy, aryloxy and NR"2 and/or is a compound of formula (A) wherein one of Rι~R5 is a sulphamate group and the others are selected so that the compound is a sulphamate ester of a phenol having a pKa in the range 7-9.
'Alkyl' encompasses branched, cyclic and straight chain alkyl. It includes substituted alkyl, e.g. aralkyl . Other possible substituents include halo, RCO (R=alkyl or H) and nitro. Alkyl groups may include unsaturation. They may be interrupted by heteroatoms e.g. O, N or S . Alkyl groups are preferably C^^, more preferably C^g, especially C1„6 .
'Aryl' encompasses substituted aryl. Possible substituents include alkyl, halo, nitro and cyano . "Aryl ' encompasses heteroaryl . Aryl groups are preferably up to C15.
Preferably X is oxygen. The -C(=X)-R6 sidechain is preferably an ester, amide or ketone moiety. The term "sulphamate" as used herein includes an ester of sulphamic acid, or an ester of an N-substituted derivative of sulphamic acid, or a salt thereof. Thus, the term includes functional groups of the formula: -O-S(O) (0)-N(R7) (R8) where R7 and R8 are independently selected from H, linear or branched alkyl which may be saturated or unsaturated and/or substituted or non- substituted, aryl, or any other suitable group.
Preferably, at least one of R7 and R8 is H. In a preferred embodiment, each of R7 and R8 is H. According to a second aspect of the present invention there is provided a compound of the first aspect for use as a pharmaceutical product. According to a third aspect of the present invention there is provided the use of a compound of the first aspect for inhibiting oestrone sulphatase
According to a fourth aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the first aspect; and a pharmaceutically acceptable carrier, excipient or diluent. (Such materials are well-known to those skilled in the art, and are too diverse to be stated here) . According to a fifth aspect of the present invention there is provided the use of a compound of the first aspect in the manufacture of a pharmaceutical product for inhibiting oestrone sulphatase and/or dehydroepiandrosterone sulphatase, e.g. for use in the treatment or prophylaxis of conditions associated with oestrone sulphatase and/or dehydroepiandrosterone sulphatase activity, e.g. endocrine-dependent cancers (particularly breast and prostate cancer) ; autoimmune diseases; and conditions affecting short and/or long term memory.
Compounds and compositions embodying the invention may be administered to individuals (human or non-human) . Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors . A compound may be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.
Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may comprise, in addition to the active ingredient, i.e. a compound of formula A, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient . The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. topical, subcutaneous, or intravenous.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such a gelatin. For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable solution, usually aqueous, which is pyrogen- free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required. Preferably one of Ri-R5 is sulphamate and the others are independently selected from H, alkyl and haloalkyl . Preferably R3 is OS02NH2 or other sulphamate group. Preferably the compound is any one of the compounds shown as Compounds 11-16 in Figure 2, particularly 4-0-sulfamoyl octaphenone or 4-O-sulfamoyl nonophenone, or a variant in which Rι-R5 include one or more electron withdrawing substituents, e.g. N02, CN or halo.
Preferred compounds of the present invention may have little or no oestrogenic activity, in particular, less than EMATE. They can therefore be deemed to be non-oestrogenic compounds.
The term "non-oestrogenic compound" as used herein means a compound exhibiting no or substantially reduced oestrogenic activity.
The present invention therefore provides non-steroidal compounds which have a reduced oestrogenic activity. In this regard, the non-steroidal compounds of the present invention act as EI-STS inhibitors.
Another advantage is that the compounds may not be capable of being metabolised to compounds which display or induce hormonal activity. The preferred compounds of the present invention are further advantageous in that the sulphamate compounds have an irreversible inhibitory effect.
Preferred compounds of the present invention are further advantageous in that they may also inhibit DHEA-STS.
Thus, in a preferred embodiment, the non-steroidal compounds are useful for the treatment of breast cancer . In addition, the non-steroidal compounds are useful for the treatment of non-malignant conditions, such as the prevention of auto-immune diseases or the improvement of long or short term memory, particularly when pharmaceuticals may need to be administered from an early age.
A particularly preferred non-steroidal compound according to the present invention is 4-0-sulphamoyl nonophenone, or a derivative with a nitro or cyano substituent . A highly preferred embodiment of the present invention therefore relates to pharmaceutical composition comprising 4-0-sulphamoyl nonophenone or a said derivative and a pharmaceutically acceptable carrier, excipient or diluent.
The present invention therefore relates to non-steroidal compounds which are suitable for use as sulphatase inhibitors.
Of the preferred compounds, 4-O-sulfamoyl nonaphenone together with 4-O-sulfamoyl octaphenone appear particularly active in vi tro . In this regard,
4-O-sulfamoyl nonophenone inhibited placental microsomal oestrone sulphatase by 76.4% at 5μM with an IC50, of 0.86μM. 4-0-sulfamoyl octophenone also inhibited placental microsomal oestrone sulphatase by 80.1% at 5μM with an IC50, of 1.16μM. This inactivation was shown to be in a similar way to EMATE which inhibited placental microsomal oestrone sulphatase with an IC50, of 0. llμM The non-steroidal compounds of the present invention, in particular the preferred nitrated and non-nitrated sulphamates, represent important compounds for the optimisation of non-steroidal sulphatase inhibition. The compounds are also believed to have therapeutic uses other than for the treatment of endocrine-dependent cancers, such as the treatment of autoimmune diseases. The compounds may also have uses in the increasing of short (and long) term memory . Aspects of the present invention will now be described further by way of example with reference to the accompanying drawings .
Brief Description of Drawings
Figure 1 shows the known structures of oestrone (1) , oestrone sulphate (2), EMATE (3) and COUMATE (4);
Figure 2 Shows the structures of 4-O-sulfamoyl benzaldehyde (11) , 4-O-sulfamoyl benzophenone (12) , 4-O-sulfamoyl acetophenone (13) , 4-O-sulfamoyl propiophenone (14) , 4-O-sulfamoyl octophenone (15) and 4-O-sulfamoyl nonophenone (16) ;
Figure 3 is a reaction scheme for the sulphamoylation of 4-hydroxy nonophenone; and
Figure 4 a, b and c are dose-response curves showing plots of percentage inhibition versus Log [I] for the inhibition of placental microsomal oestrone sulphatase by compounds 13, 15 and 16 embodying the invention.
Modes for Carrying Out the Invention
EXAMPLES
General Procedure for the Synthesis of hydroxyalkylphenones
Aluminium chloride (2 moles equivalent) was added to a stirred solution of phenol in dichloromethane at 0°C under an atmosphere of nitrogen for 0.5 hours . The appropriate acid chloride (1.1 moles equivalent) was then added dropwise, and the reaction allowed to warm up to ambient temperature overnight. The slurry was then cautiously diluted with cool IM HCl (30ml) , and extracted into ether (3 x 30ml) . The combined ether layers were extracted with 2M NaOH (3 x 30ml) . The combined aqueous layers were acidified to pH 2 with IM HCl, and extracted into ether (3 x 75ml) . The organic layers were combined and washed with saturated NaHC03 (3 x 20ml) , and water (2 x 50ml) . The organic layer was dried (MgS04) , filtered, and concentrated in vacuo to give residues which were either crystallised in hexane, or columned (50 ether: 50 petroleum spirits 60-40°C) to give the required hydroxylalkylphenones .
Amino sulfonyl chloride ( 4) :
Methanoic acid (l.OOmL, 26.50mmol) was added drop wise to chlorosulfonyl isocyanate (2.31ml, 26.50mmol, dried over B203) , under nitrogen at 0-4°C. After evolution of gas, anhydrous toluene (20ml) was added to dissolve the product, and the solution stirred for 1 hour .
Insoluble by products were removed by filtration. Removal of toluene under vacuum (<30°C) gave (4) as a yellow/orange solid, m.p. 33-38°C (expected 40°C Appel &
Berger) ; Rf = 0.93 compared to chlorosulfonyl isocyanate
Rf= 0.15 [DCM] . 4-O-Sulfamoyl benzene (5) :
NaH (80% dispersion in mineral oil, 0. 12g, 4.00mmol) was added to a stirred solution of phenol (0.30g, 3.19mmol) in DMF (20ml) under nitrogen at 0°C. After evolution of hydrogen had ceased, aminosulfonyl chloride in toluene (10ml, ~10mmol) was added in one portion and the reaction allowed to stir overnight. The reaction was then quenched in NaHC03 (50ml) , extracted into DCM (2 x 50ml) , washed (3 x 30ml water) and dried (MgS04) . Removal of the solvent under vacuum yielded a yellow oil, which was run through a column to give (5) (0.14g, 25.4%) as a pure white solid m.p. 77.6-81.2°C. Rf= 0.32 [diethyl ether / petroleum ether 40-60°C (6: 4)]. v (max. (Film) cm" 3421.1 and 3307.8 (NH) , 1367.5 and 1177.2 (S=0) . 300MHz δH (CDC13) 7.43-7.25 (5H2 m, ArH) , 5.24 (2H, s, NH2) . δc (CDCI3) 150.024, 129.923,
127.306, 122.142. MS (M+) calculated mass 173.014665, actual mass 173.015633.
4-O-Sulfamoyl benzophenone (12)
Compound (12) was synthesized following the same procedures as for compound (5) except that NaH (80% dispersion in mineral oil, O.lOg, 3.33mmol) was added to a stirred solution of 4-hydroxybenzophenone (0.48g, 2.42mmol) in DMF (10ml). Aminosulfonyl chloride in toluene (10ml, ~10mmol) was added after 30min. Removal of the solvent under vacuum yielded an orange oil, which was run through a column to give (12) (0.24g 35.8%) as a pure, white solid m.p. 139.5-142.4°C. Rf= 0.34 [ethyl acetate / petroleum ether 40-60°C (3.5 : 6.5 )] . v(max) (Film) cm"1 : 3336.7cm"1 (NH) , 1631.4cm"1 (C=0) , 1378.0 and 1178.5 (S=0) . 300MHz δH (CDCI3) 7.89-7.4;3 (9H, m, ArH) , 5.12 (2H, s, NH2 ) . MS m/z 277 (M+) , 121 (base peak) .
4-O-Sulfamoyl acetophenone (13) . Compound (13) was synthesized following the same procedures as for compound (5) except that NaH (80% dispersion in mineral oil, 0.18g, 6.00mmol) was added to a stirred solution of 4-hydroxyacetophenone (0.50g, 3.66mmol) in DMF (10ml). Aminosulfonyl chloride in toluene (10ml, ~10mmol) was added after 30 minutes.
Removal of the solvent under vacuum yielded an orange oil, which was run through a column to give (13) (0.05g, 6.3%) as a pure white solid Rf= 0.21 [ethyl acetate / petroleum ether 40-60°C (3.5 : 6.5)]. v(max) (Film) cm"1 : 3388.2cm"1 (NH) , 1664.2cm"1 (C=0) ,
1377.8 and 1177.0cm"1 (S=0) . 300MHz δH (CDC13) 8.04-8.01 (2H, dd, J = 9Hz, ArH), 7.44-7.41 (2H, dd, J = 9Hz, ArH), 5.10 (2H, s, NH2) , 2.62 (3H, s, H3C-).
4-O-Sulfamoyl propiophenone (14)
Compound (14) was synthesized following the same procedures as for compound (5) except that NaH (80% dispersion in mineral oil, 0.18g, 6.00mmol) was added to a stirred solution of 4-hydroxypropiophenone (0.50g 3.33mmol) in DMF (10ml) . Aminosulfonyl chloride in toluene (10ml, ~10mmol) was added after 30 min. Removal of the solvent under vacuum yielded an orange oil, which was run through a column to give (14) (0.09g, 11.8%) as a pure white solid m.p. 105.8-106.7°C. Rf= 0.30 [ethyl acetate / petroleum ether 40-60°C (3.5 : 6.5)]. v(max) (Film) cm"1 : 3388.6cm"1 (NH) , 1677.0cm"1 (C=0) , 1370.2 and 1181.2cm"1 (S=0) . 300MHz δH (CDC13) 8.03-8.00
(2H, dd, J = 9Hz, ArH), 7.42-7.40 (2H, dd, J = 9Hz, ArH), 5.14 (2H, s, NH2) , 3.03-2.96 (2H, q, J=7Hz, CH2CH3) 1.25-1.20 (3H, t, J= 7Hz, CH2CH3) .
4-O-Sulfamoyl octanophenone ( 15)
Compound (15) was synthesized following the same procedures as for compound (5) except that NaH (60% dispersion in mineral oil, O.lOg, 2.50 mmol) was added to a stirred solution of 4-hydroxyoctanophenone (0.50g 2.27mmol) in DMF (10ml). Aminosulfonyl chloride in toluene (10ml, ~10mmol) was added after 30 min. Removal of the solvent under vacuum yielded an orange oil, which was run through a column to give (15) (0.25g 36.8%) as a pure white solid m.p. 105-107°C. Rf= 0.46 [ether / petroleum ether 40-60°C (7 : 3)]. v (max . i [ Film) cm 3389 . 1cm"1 (NH) , 1681 . 8cm"1 ( C=0)
1377 . 5 and 1181 . 1cm"1 ( S=0) . 300MHz δH ( CDC13 ) 8 . 02 - 7 . 98 (2H, dd, J = 9Hz, ArH) , 7.42-7.39 (2H, dd, J = 9Hz, ArH) ,, 5.22 (2H, s, NH2) , 2.96-2.91 (2H, t, J=7Hz, COCH2CH2) , 1.75-1.67 (2H, m, J = 7Hz, COCH2CH2CH2) , 1.40-1.29 (8H, m, COCH2CH2 [CH2] 4CH3 0.90-0.86 (3H, t, J = 7Hz, CH3) .
4-O-Sulfamoyl nonanophenone (16)
Compound (16) was synthesized following the same procedures as for compound (5) except that NaH (60% dispersion in mineral oil, 0.18g, 4.50mmol) was added to a stirred solution of 4-hydroxynonanophenone (l.Og, 4.27mmol) in DMF (10ml) . Aminosulfonyl chloride in toluene (10ml, ~10mmol) was added after 30 min. Removal of the solvent under vacuum yielded a clear oil, which was run through a column to give (16) (0.29g 21.7%) as a pure white solid m.p. 102-104°C. Rf = 0.57 [ether / petroleum ether 40-60°C (7 : 3)]. v (max. ) (Film) cm"1 : 3389.0 and 3289.0cm"1 (NH) ,
1682.3cm"1 (C=0) , 1377.9 and 1181.8cm"1 (S=0) . 300MHz δH (CDC13) 8.02- 7.99 (2H, dd, 1 = 9Hz, ArH) , 7.42- 7.39 (2H, dd, J = 9Hz, ArH) , 5.17 (2H, s, NH2) , 2.96-2.91 (2H, t, l = 7Hz, COCH2CH2) , 1.74-1.69 (2H, m, J = 7Hz, COCH2CH2CH2) , 1.40-1.29 (10H, m, COCH2CH2 [CH2] CH3 0.90-0.86 (3H, t, J = 7Hz, CH3) . MS m/z313 (M+) , 121 (base peak)
In vitro biological testing
The total assay volume was 1ml. 3H-estrone sulfate (25μl, 20μM/tube; 300 , OOOdpm/tube) and the inhibitors (25μl in various concentrations) dissolved in ethanol were added to a 10ml assay tube, and the ethanol removed with a stream of nitrogen. Tris-HCl buffer (0.05M, pH7.2 , 0.2ml) was added to each tube. Placental microsomes were. then diluted with Tris-HCl buffer (115μg/ml) . The microsomes and assay tubes were preincubated for 5min at 37°C in a shaking water bath prior to the addition of the microsomes (0.8ml) to the tubes. After 20 min incubation (at 37°C) , toluene (4ml) was added to quench the assay, and the tubes placed in ice. The quenched samples were vortexed for 45 s and centrifuged (3000 rpm, 10 min) . 1ml of toluene was added to 5ml scintillation cocktail (TRITON-X) . The aliquots were counted for 3min. All samples were run in triplicate. Control samples with no inhibitor were incubated simultaneously. Blank samples were obtained by incubating with boiled microsomes.
Table I presents data for compounds 13, 14, 15, 16 of the invention and also for the known compounds EMATE and COUMATE. Figs. 4a, b and c present the data for compounds 13, 15 and 16 graphically.
Table I: Assay Results
Figure imgf000017_0001
Figure imgf000018_0001
We have also prepared a series of simple model compounds of formula Y-Ph-0. SO, .NH2 by treating the corresponding phenols Y-Ph-OH with H2NS02Cl and base (NaH or K2C03) in toluene and have measured (i) the pKa values of the phenols; and (b) the IC50 values of the sulphamates, using the assay described above. The results are presented in Table II below. These show the relationship between pKa of the phenol and inhibitory activity of the sulphamate which also holds good for the compounds of the present invention.
Table II: Relationship of pKa and IC50 for
Y-Ph-OS02NH2
Figure imgf000018_0002
Figure imgf000019_0001
As the pKa falls from a high value, the activity of the sulphamate rises to a maximum, and then begins to fall again. The optimum pKa range is around 7-9, preferably 7-8 or 7.5-8.5. Such a relationship also applies with the compounds of the invention such as those shown in Fig. 2. Thus it will generally be the case that inclusion of a strongly electron-withdrawing substituent such as N02 or CN (particularly o or p_ to the sulphamate group) will produce a significant increase in activity. Adding a second such substituent will generally not have a comparable effect, unless there is also a strongly electron donating substituent.
The compounds of the invention exemplified above (Table I) are simpler compounds than EMATE and COUMATE but have comparable inhibitory activities, without side effects due to oestrogenic activity. Inclusion of electron withdrawing substituents will further enhance the desirable properties. REFERENCES
1. Santer, S. J. , Feil, P. D. and Santen, R. J. , J. Clin. Endocrinol. Metab., 1984, 59, 29-33.
2. Yamamoto, T., Kitawaki, J. , Urabe, M. , Honjo, H. ,
Tamura, T. , Noguchi , T., Okada, H., Sasaki, H., Tada, A., Terashima, Y., Nakamura, J. and Yoshihama, M., J. Steroid Biochem. Mol . Biol . , 1993, 44, 463-468.
3. Santen, R. J. , Santer, S. J. , Davis, B., Veldhuis, J., Samojilik, E. and Ruby, E., J. Clin. Endocrinol. Metab., 1978, 47, 1257-1265.
4. Reed, M. J. , Lai, L. C, Owen, A. M. , Singh, A., Coldham, N. G. , Purhoit, A., ghilichik, M. W. , Shaikh, N. A., James, V. H. T. , Cancer Res., 1990, 50, 193-196.
5. Ruder, H. J. , Loraiux, D. L. and Lipsett, M. B., J. Clin. Investig., 1972, 51, 1020-1023.
6. Dauvois, S. and Labri, F., Breast Cancer Res. Treat., 1989, 13, 61-69.
7. Purhoit, A., Williams, G. J. , Howarth, N. M. , Potter, B. V. L., Williams, G. J. and Reed, M. J. , J. Steroid Biochem. Mol. Biol., 1994, 50, 101-104. 8. Elgar, W., Schwarz, S., Hedden, A., Reddersen, G. and Schneider, B., J. Steroid Biochem. Mol. Biol., 1995, 55, 395-403.

Claims

1. A compound of formula (A) or a salt thereof
Figure imgf000022_0001
wherein R1-R5 are independently selected from H, halo, alkyl, nitro, CN, aryl, OH, OR' (where R' is alkyl or aryl) , NR"2 (where each R" is independently H, alkyl or aryl) and sulphamate groups, with the proviso that at least one of them is a sulphamate group; X is selected from O, S, NH, NR ' ' ' where R' ' ' is alkyl or aryl) , and R6 is selected from H, alkyl, aryl, alkoxy, aryloxy and NR"2
2. A compound according to claim 1 wherein the groups Rx-R5 and R6-C(=X)- are selected so as to have an overall electron-withdrawing effect on the benzene ring to which they are attached.
3. A compound according to claim 1 or claim 2 which is a sulphamate of a phenol having a pKa in the range 7-9.
4. A compound of formula (A) or a salt thereof
Figure imgf000023_0001
wherein X and R6 are as defined in claim 1, and one of Rx- R5 is a sulphamate group and the others are selected so that the compound is a sulphamate ester of a phenol having a pKa in the range 7-9.
5. A compound according to any preceding claim wherein R3 is a sulphamate group.
6. A compound according to claim 5 wherein three of R,, R2, R4 and R5 are H and the fourth is selected from H and electron withdrawing groups .
7. A compound according to any preceding claim wherein X is O.
8. A compound according to any preceding claim wherein R6 is H or a hydrocarbyl group selected from C,_8 alkyl and phenyl .
9. A method of preparing a compound according to any preceding claim comprising reacting a phenol with a sulphamoylating agent to convert it into a sulphamoyl benzene .
10. A pharmaceutical composition comprising a compound of any of claims 1-8.
11. Use of a compound of any of claims 1-8 in the manufacture of a composition for use in the treatment or prophylaxis of a condition associated with a sulphatase.
12. Use according to claim 11 wherein the sulphatase is oestrone sulphatase and/or dehydroepiandrosterone sulphatase .
13. Use according to claim 11 or 12 wherein the condition is an endocrine-dependent cancer.
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US6677325B2 (en) 1991-08-28 2004-01-13 Sterix Ltd. Steroid sulphatase inhibitors
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US6903084B2 (en) 1991-08-29 2005-06-07 Sterix Limited Steroid sulphatase inhibitors
US7098199B2 (en) 1991-08-29 2006-08-29 Sterix Limited Steroid sulphatase inhibitors
US7335650B2 (en) 2000-01-14 2008-02-26 Sterix Limited Composition
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US8093265B2 (en) 2007-03-09 2012-01-10 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US9603848B2 (en) 2007-06-08 2017-03-28 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
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