OA13167A - Sulfamate benzothiophene derivatives as steroid sulfatase inhibitors. - Google Patents

Sulfamate benzothiophene derivatives as steroid sulfatase inhibitors. Download PDF

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OA13167A
OA13167A OA1200500321A OA1200500321A OA13167A OA 13167 A OA13167 A OA 13167A OA 1200500321 A OA1200500321 A OA 1200500321A OA 1200500321 A OA1200500321 A OA 1200500321A OA 13167 A OA13167 A OA 13167A
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methoxybenzothiophene
benzothiophene
dérivative
hydroxy
afford
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OA1200500321A
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Jean Lafay
Benoit Rondot
Denis Carniato
Paule Bonnet
Thierry Clerc
Jacqueline Shields
Igor Duc
Eric Duranti
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Theramex
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

013167
SULFAMATE BENZOTHIOPHENE DERIVATIVES AS STEROID SULFATASEINHIBITORS
Field of invention
The présent invention generally relates to steroid hormones, and morespecifically relates to novel sulfamate benzothiophene dérivatives which areinhibitors of the enzyme steroid sulfatase. The invention also relates topharmaceutical compositions containing these dérivatives, and to methods of usingthem.
Background of the invention
The enzyme steroid sulfatase (E.C. 3.1.6.2., STS) catalyses the hydrolysis ofestrone sulfate to estrone and of DHEA sulfate to DHEA (Dibbelt L, Biol. Chem,Hoppe-Seyler, 1991, 372, 173-185 and Stein C, J. Biol. Chem., 1989, 264, 13865-13872).
The steroid sulfatase pathway has been the focus of recent interest in thecontext of breast cancer, with regard to the local intra-tissue formation of estrogensfrom the abundant circulating pool of estrone sulfate (EiS) (Pasqualini JR, J. SteroidBiochem. Mol. Biol., 1999, 69, 287-292 and Purohit A, Mol. Cell. Endocrinol., 2001,171, 129-135).
Inhibition of this enzyme would prevent EiS to yield free estrone (Ei), whichin tum can be transformed into estradiol (E2) by enzymatic réduction. In addition tothe estrone sulfatase pathway, it is now believed that another potent estrogen,androstenediol (adiol) obtained from DHEA after hydrolysis of DHEA-S, could beanother important route, in the support of growth and development of hormonedépendent breast tumors.
The formation of estrogens in humans is schematically represented in figure 1.
In patients with hormone-dependent cancers, aromatase inhibitors arecurrently used to prevent estrogen synthesis. However, clinical trials showed arelative lack of efficacy for patients with estrogen receptors positive tumors(Castiglione-Gertsch M, Eur. J. Cancer, 1996, 32A, 393-395 and Jonat W, Eur. J.Cancer, 1996, 32A, 404-412). As an explanation, steroid sulfatase pathway could beanother important route for estrogen formation in breast tumors. 2 013167 EMATE (Ahmed S, Curr. Med. Chem., 2002, 9, 2, 263-273), estrone-3-sulfamate, is the historical standard steroid sulfatase inhibitor but with the majordrawback of being estrogenic because of its mechanism of inhibition: the sulfamatemoiety is cleaved during the process of enzyme inactivation, which releases Ei, not 5 from EiS but from EMATE itself (Ahmed S, J. Steroid Biochem. Mol. Biol., 2002,80, 429-440).
Estradiol
Other non steroid sulfamate compounds which release dérivatives without10 estrogenic properties are presented as acceptable drug candidates, in particular 6,6,7-COUMATE, a standard non-estrogenic sulfatase inhibitor from the literature (Purohit A, Cancer Res., 2000, 60, 3394-3396).
6,6,7 COUMATE 15 Accordingly, there is a need for steroid sulfatase inhibitors with the view of treatingin particular estrogen-dependent diseases.
Summary of the invention
An object of this invention is to provide sulfamate benzothiophenedérivatives which are potent steroid sulfatase inhibitors. 013167
Another object of this invention is to provide a pharmaceutical compositioncontaining, as active ingrédient, a sulfamate benzothiophene dérivative as mentionedabove.
Still a further object of this invention is to provide the use of a sulfamatebenzothiophene dérivative in the manufacture of a médicament for treating orpreventing various diseases and for managing reproductive functions in women, inmen as well as in female and male wild or domestic animais.
The sulfamate benzothiophene dérivatives of this invention can berepresented by the following general formula (I):
wherein: - Ri is hydrogen, a (Ci-Cgjalkyl, a (C2-Cô)alkene, a (C3-Cii)cycloalkyl or a (C3-Ci2)cycloalkene, wherein the cycloalkyl and cycloalkene are optionally mono- ordisubstituted with a (Ci-CzOalkyl; - R2 is hydrogen, a (CrC6)aIkyl or a (C3-Ci2)cycloalkyl; - R3 is hydrogen, a (Ci-Cô)alkoxy or a halogen; - mis 0, 1, 2; - n is 0,1,2; - when m is 0, Ri and R2 can also form together a group -(CH2)P- in which p is 3, 4or 5; - the dotted line indicates that the sulfamate group (OSCbCNFk)) is in position 5- or 6- of the benzothiophene ring.
Among the compounds of formula (I), those fulfilling at least one of the following conditions, are particularly preferred: 013167 - Ri is hydrogen, a (Ci-Cô) alkyl or a (C3-Ci2)cycloalkyl optionally mono- ordisubstituted with a (Ci-C4)alkyl, preferably Ri is a (C3-Cio)cycloalkyl optionallymono- or disubstituted with a (Ci-C^alkyl; -misOor 1; - R2 is hydrogen; - R3 is hydrogen; - n is 0 or 2; - the sulfamate group is in position 6- of the benzothiophene group.
In the description and appended daims, a (C1-C4) or (Ci-Cô)alkyl isunderstood as meaning a linear or branched saturated hydrocarbon chain having 1 to4 or, respectively, 1 to 6 carbon atoms. Such an alkyl radical is for example a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl radical. A (Ci-Cg)alkoxy is understood as meaning a group -OR in which R is a (Ci-Cô)alkyl as defined above. A (C3-Ci2)cycloalkyl is understood as meaning a saturated mono- or bicyclichydrocarbon having 3 to 12 carbon atoms. A (C3-Ci2)cycloalkyl radical is forexample a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl or adamantyl radical. A halogen is understood as meaning a chlorine, bromine, fluorine or iodine atom. A (C2-Cg)alkene is understood as meaning a linear or branched unsaturatedhydrocarbon chain having 2 to 6 carbon atoms. A (C2-Cg)alkene radical is forexample an ethylene or a propene, butene, pentene or hexene radical. A (C3-Ci2)cycloalkene is understood as meaning an unsaturated mono- orbicyclic hydrocarbon having 3 to 12 carbon atoms. A (C3-Ci2)cycloalkene radical isfor example a cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclooctene,cyclodecene or adamantene radical.
In view of their capability to inhibit steroid sulfatase, and thus to dry out other sources of endogenous estrogens as compared with aromatase inhibitors, the compounds of the présent invention can be used alone or in combination with one or several other sexual endocrine therapeutic agents such as antiestrogens, SERMs (Sélective Estrogen Receptor Modulators), antiaromatases, antiandrogens, lyase 5 013167 inhibitors, progestins or LH-RH agonists or antagonists, in the treatment orprévention of estrogen-dependent disorders or diseases. The compounds of theinvention can also be used for the control or management of estrogen-regulatedreproductive functions such as male or female fertility, pregnancy, abortion ordelivery in humans as well as in wild or domestic animal species, alone or incombination with one or several other therapeutic agents such as LH-RH agonists orantagonists, estroprogestative contraceptives, progestins, antiprogestins · orprostaglandins.
The breasts being sensitive targets of estrogen-stimulated prolifération and/ordifférentiation, the compounds of the invention can be used in the treatment orprévention of benign breast diseases in women, gynecomastia in men and in benignor malignant breast tumors with or without metastasis both in men and women or inmale or female domestic animais. The compounds of the invention can also be usedin the treatment or prévention of benign or malignant diseases of the utérus or theovary. In each case, the compounds of the invention can be used alone or incombination with one or several other sexual endocrine therapeutic agents such asthose mentioned above.
As the enzyme steroid sulfatase transforms DHEA sulfate into DHEA, aprecursôr of active androgens (testosterone and dihydrotestosterone), the compoundsof the invention can be used in the treatment or prévention of androgen-dependentdiseases such as androgénie alopecia (male pattern loss) (Hoffman R et al., J. Invest.Dermatol., 2001, 117, 1342-1348) or acné (Billich A et al., 1999, WO 9952890),benign or malignant diseases of the prostate or the testis (Reed MJ, Rev. Endocr.Relat. Cancer, 1993, 45, 51-62), alone or in combination with one or several othersexual endocrine therapeutic agents, such as antiandrogens, antiestrogens, SERMs,antiaromatase, progestins, lyase inhibitors or LH-RH agonists or antagonists.
Inhibitors of steroid sulfatase are also potentially involved in the treatment ofcognitive dysfunction, because they are able to enhance learning and spatial memoryin the rat (Johnson DA, Brain Res, 2000, 865, 286-290). DHEA sulfate as aneurosteroid affects a number of neurotransmitter Systems, including those involvingacétylcholine, glutamate, and GABA, resulting in increased neuronal excitability(Wolf OT, Brain Res. Rev, 1999, 30, 264-288). 6 013167
In addition, estrogens are involved in the régulation of the balance betweenThi and Th2 prédominant immune functions and may therefore be useful in thetreatment or prévention of gender-dependent auto-immune diseases such as lupus,multiple sclerosis, rheumatoid arthritis and the like (Daynes RA, J. Exp. Med, 1990,171, 979-996). Steroid sulfatase inhibition was shown to be protective in models ofcontact allergy and collagen-induçed arthritis in rodents (Suitters AJ, Immunology,1997,91,314-321).
Studies using 2-MeOEMATE hâve shown that steroid sulfatase inhibitorshâve potent estradiol-independent growth-inhibitory effect (MacCARTHY-MOOROGH L, Cancer Research, 2000, 60, 5441-5450). A decrease in tumorvolume was surprisingly observed with the compounds. of the invention, with lowtumor steroid sulfatase inhibition. In view of this, the compounds of the inventioncould lead to a decrease in cellular division because of the large interaction betweensuch new Chemical entities and the microtubular network within the cancerous cell,whatever the tissue, including breast, endometrium, uteri, prostate, testis ormetastasis generated from. The compounds of the invention could therefore be usefulin the treatment of non-estrogeno-dependent cancer.
Accordingly, it is another object of the invention to provide a method fortreating the above-mentioned diseases or disorders, in particular estrogen-dependentdiseases or disorders, i.e. estrogen-induced or estrogen-stimulated diseases ordisorders (GOLOB T, Bioorg. Med. Chem., 2002, 10, 3941-3953). The methodcomprises administering to a subject (human or animal) in need thereof atherapeutically effective amount of a compound of formula (I).
The pharmaceutical compositions containing the active ingredient(s) may bein a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous oroily suspensions, dispersible powders or granules, émulsions, hard or soft capsules,or syrups or élixirs. Compositions intended for oral use may be prepared according toany method known in the art for the manufacture of pharmaceutical compositionsand such compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically élégant and palatable préparations.Tablets contain the active ingredient(s) in admixture with non-toxic pharmaceutically 013187 acceptable excipients which are suitable for the manufacture of tablets. Theseexcipients may be for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid; binding agents, forexample starch, gelatin or acacia, and lubricating agents, for example, magnésiumstéarate, stearic acid or talc. The tablets may be uncoated or they may be coated byknown techniques to delay disintegration and absorption in the gastrointestinal tractand thereby provide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate may beemployed. The tablets may also be coated by the technique described in U.S. Patents4,256,108; 4,166,452 or 4,265,874 to form osmotic therapeutic tablets for controlrelease.
Formulations for oral use may- also be presented as hard gelatin capsuleswherein the active ingredient(s) is (are) mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsuleswherein the active ingredient(s) is (are) mixed with water or an oil medium, forexample peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active ingredient(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Such excipients aresuspending agents, for example sodium carboxymethylcellulose, methylcellulose,hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurringphosphatide, for example lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stéarate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxide withpartial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitolmonooleate, or condensation products of ethylene oxide with partial esters derivedfrom fatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or more preservatives,for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one 013167 or more flavoring agents, and one or more sweetening agents, such as sucrose,saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient(s) ina vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in aminerai oil such as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents suchas those mentioned above, and flavouring agents may be added to provide a palatableoral préparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for the préparation of an aqueoussuspension by the addition of water provide the active ingredient(s) in admixturewith a dispersing or wetting agent, suspending agent and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by thosealready mentioned above. Additional excipients, for example sweetening, flavouringand colouring agents, may also be présent. The pharmaceutical compositions of theinvention may also be in the form of an oil-in-water émulsion. The oily phase may bea vegetable oil, for example olive oil or arachis oil, or a minerai oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial estersderived from fatty acids and hexitol anhydrides, for example sorbitan monooleate,and condensation products of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The émulsions may also contain sweeteningand flavouring agents.
The pharmaceutical compositions of the invention may be in the form of astérile injectable aqueous or oleagenous suspension. This suspension may beformulated according to known methods using those suitable dispersing or wettingagents and suspending agents which hâve been mentioned above. The stérileinjectable préparation may also be a stérile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed,water, Ringer’s solution and isotonie sodium chloride solution can be mentioned. Inaddition, stérile, fixed oils are conventionally employed as a solvent or suspending 9 013167 medium. For this purpose any bland fixed oil may be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid find use in thepréparation of injectables.
The compounds of the invention can be used in the treatment of the above-5 indicated diseases or disorders at dosage levels of the order of from about 0.0001 mgto about 10 mg/kg of body weight per day, or altematively from about 0.01 mg to about 100 mg per patient per day.
The amount of active ingredient(s) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon the host treated 10 and the particular mode of administration.
It will be understood, however, that the spécifie dose level for any particularpatient will dépend upon a variety of factors including the âge, body weight, generalhealth, sex, diet, time of administration, route of administration, rate of excrétion,drug combination and the severity of the particular disease undergoing therapy. 15 The sulfamate benzothiophene dérivatives of formula (I) can be prepared according to the following general scheme 1. 10 013167
scheme 1
Ro
1
2
SH
013167 11
According to scheme 1 the 3-methoxythiophenol (1) is condensed with 2-bromo-l,l-diethoxyethane and the thio-compound intermediate (2) is cyclised withdifferent acids: polyphosphoric acid (Bioor. Med. Chem. Lett, 1999, 9, 759-64) ormethanesulfonic acid to afford the 6-methoxy-benzothiophene (3). This compoundcan also be prepared by reaction of a Lewis acid, trifluoroborane, with compound (2)using the conditions described by S. Graham (J. Med. Chem, 1989, 32, 2548-54).
The 6-methoxy-benzothiophene (3) is converted to the bromo dérivative (4)with N-bromosuccinimid and APTS using the conditions described by Y. Fort(Tetrahedron. 1994, 50, 11893-902). (4) is transformed into an organomagnesiumbromide, and then condensed with a ketone or an aldéhyde to afford themonosubstituted benzothiophene (5) using standard conditions.
The disubstituted benzothiophene (9) can be prepared by alkylation of themonosubstituted compound (5) using the conditions described by Kano. S(Heterocycles, 1982r 19, 6,1033-37).
The compounds where Ri and R2 form together a group -(CH2)P-, such as the 7-methoxy-l,2,3,4-tetrahydrodibenzothiophene (p = 4), can be prepared using theconditions described by Oliveira. M (Tetrahedron, 2002,58,1709-18).
Deprotection of the methoxybenzothiophene monosubstituted (5) ordisubstituted (9) with tribromoborane gave the hydroxy compounds (6) and (10)prepared using the conditions described by McOmie. J.F.W (Tetrahedron, 1968, 24,2289-92). These compounds were transformed into the corresponding sulfamates (7)and (11) by treatment with sodium hydride, with amidochlorosulfonic acid(Nussbaumer. P, J Med Chem, 2002, 45, 4310-20), or by reaction with sulfamoylchloride in dimethylacetamide (DMAc) (Makoto. O, Tetrahedron letters, 2000, 41,7047-51).
Oxidation of (7) and (11) by hydrogen peroxide in trifluoroacetic acid,following the conditions described by GRIVAS S. and RONNE E. (Acta ChemicaScandinavia, 1995, 49, 225-229), gave the final benzothiophenes (8) and (12).
The compounds of formula (I) where the sulfamate group is in position 5- of the benzothiophene ring can be prepared in the same way but starting from 4- methoxythiophenol. 013167 12
The following examples are intended to illustrate and not to limit the scope ofthe invention. PREPARATION OF THE 3-BROMO-6-METHOXYBENZOTHIOPHENE (4)EXAMPLE 1: 6-Methoxybenzothiophene (3)
Bromoacetaldehyde diethyl acetal (16.50 ml, 0.11 mol) was added dropwiseto a mixture of m-methoxybenzenethiol (1) (15 ml, 0.12 mol) and K2CO3 (16.60 g,0.12 mol) in acetone (150 ml) at room température. The reaction mixture was stirredfor 16 h and then filtered. The solid was washed with acetone, and the combinedfiltrâtes were concentrated under vacuum. The residue was diluted with water andextracted with Et2O. The organic phase was washed with 0.5 Μ KOH, water, andbrine, dried over Na2SO4, filtered, and concentrated under vacuum to give 27.40 g ofcompound (2) as a dark yellow oil. 'H-NMR (CDC13) : 1.18 (t, 6H), 3.13 (d, 2H), 3.43-3.73 (m, 4H), 3.77 (s, 3H), 4.67(t, 1 H), 6.60-7.27 (m, 4H). A solution of (2) (13.00 g, 0.051 mol) in CH2CI2 (100 ml) was addeddropwise to a solution of BF3.Et2O (6.70 ml, 0.054 mol) in CH2C12 (1000 ml) at roomtempérature under nitrogen atmosphère. After hydrolysis, the reaction mixture wasstirred until both phases became clear. The CH2C12 layer was separated, and theaqueous layer was extracted with CH2C12. The combined organic phases were driedover Na2SO4, filtered, and concentrated under vacuum to give 8.68 g of a 1:10mixture of 4 and 6-methoxybenzothiophene (3) as a dark brown oil. The crudeproduct was used without purification.
Major isomer (3) ’H-NMR (CDCI3) : 3.85 (s, 3H), 6.98 (dd, 1H), 7.23 (s, 2H),7.35 (d, 1H), 7.68 (d, 1 H). EXAMPLE 2: 3-Bromo-6-methoxybenzothiophene (4) N-bromosuccinimide (14.70 g, 82.59 mmol) and p-toluenesulfonic acid (2.70g, 15.68 mmol) were added to a solution of benzothiophene (3) (15.10 g, 92.07mmol) in 1,2-dichloroethane (300 ml). The mixture was maintained at 70°C for 35min, cooled in an ice bath, and the succinimide was removed by filtration. Thesolution was extracted with saturated sodium bicarbonate solution, dried overNa2SO4, filtered, and concentrated under vacuum to give 22.00 g as an oil.Crystallisation from pentane afforded a white solid (16.50 g, 74 %), mp 62°C. 013167 Ή-NMR (CDCls) : 3.85 (s, 3H), 6.9 (dd, 1H), 7.50 (m, 2H), 7.65 (d, 1H)PREPARATION OF MONOSUBSTITUED BENZOTHIOPHENE (5)EXAMPLE 3: 3-CyclohexyI-6-methoxybenzothiophene
To Mg (0.22 g, 9.05 mmol) under argon in Et2O (20 ml) was added dropwisea solution of bromide (4) (2.00 g, 8.23 mmol) in Et2O (20 ml). The mixture wasrefluxed for 2 h, a solution of cyclohexanone (1.00 ml, 9.87 mmol) in Et2O (5 ml)was added and the mixture was refluxed for 2 h. It was poured into iced water. Thesolution was extracted with ethyl acetate, dried over Na2SO4, filtered, andconcentrated under vacuum to give 8.00 g as an oil. Triturating from diisopropylether afforded 3-(l-hydroxycyclohexyl)-6-methoxybenzothiophene as a whitepowder (0.90 g, 65 %). Ή-NMR (DMSOd6) : 1.20-2.00 (m, 10H), 3.80 (s, 3H), 5.30 (s, 1H), 6.93 (dd, 1H), 7.10 (s,lH), 7.42 (d, 1H), 7.60 (d, 1H).
To 3-(l-hydroxycyclohexyl)-6-methoxybenzothiophene (0.30 g, 1.14 mmol)under argon in dichloromethane (10 ml) was added dropwise triethylsilane (0.22 ml,1.37 mmol). Then, the solution was stirred at 0°C, and trifluoroacetic acid (5.00 ml,67.31 mmol) was added. After 2 h at room température the mixture was poured intosaturated aqueous NaHCO3 and ice, extracted with ethyl acetate, dried over Na2SO4,filtered, and concentrated under vacuum to give 0.30 g as an oil (100%).Crystallisation from diisopropyl ether afforded a white crystal (0.20 g, 70 %).Ή-NMR (DMSOdô) : 1.00-2.20 (m, 11H), 2.72 (m, 1H), 3.75 (s, 3H), 6.93 (dd, 1H),7.01 (s, 1H), 7.43 (d, 1H), 7.58 (d, 1H).
Using the same procedure but replacing cyclohexanone by: - cyclopentanone - cycloheptanone - cyclooctanone - cyclodecanone - 4-methylcyclohexanone - 2-methylcyclohexanone - 2,2-dimethylcyclopentanone - 2-adamantanone - propanone 013167 14 - hexanone - cyclohexanecarboxaldehyde - cycloheptanecarboxaldehyde (prepared following J, G. Traynham et al,Tetrahedron, 7, 1959, 165-72), the following compounds were respectively obtained: EXAMPLE 4: 3-cyclopentyl-6-methoxybenzothiophene ’H-NMR (DMSOde): 1.40-2.20 (m, 8H), 2.72 (m, 1H), 3.80 (s, 3H), 6.94 (dd, 1H),7.13 (s, 1H), 7.45 (d, 1H), 7.64 (d, 1H). EXAMPLE 5: 3-cycIoheptyl-6-methoxybenzothiophene ‘H-NMR (DMSOd6): 1.40-2.20 (m, 12H), 3.05 (m, 1H), 3.80 (s, 3H), 6.90 (dd, 1H), 7.00 (s, 1H), 7.41 (d, 1H), 7.57 (d, 1H). EXAMPLE 6: 3-cyclooctyl-6-methoxybenzothiophene ^-NMR (DMSOde): 1.20-2.15 (m, 14H), 3.10 (m, 1H), 3.77 (s, 3H), 6.92 (dd, 1H),7.01 (s, 1H), 7.41 (d, 1H), 7.58 (d, 1H). EXAMPLE 7: 3-cyclodecyl-6-methoxybenzothiophene ^-NMR (DMSOd6): 1.20-2.15 (m, 18H), 3.12 (m, 1H), 3.75 (s, 3H), 6.92 (dd, 1H),7.01 (s, 1H), 7.40 (d, 1H), 7.55 (d, 1H). EXAMPLE 8: 3-(4-methylcyclohexyl)-6-methoxybenzothiophene ^-NMR (DMSOd6): 0.70-2.15 (m, 12H), 2.72 (m, 0.5H, diastereoisomer), 2.99 (m,0.5H, diastereoisomer), 3.76 (s, 3H), 6.92 (dd, 1H), 7.02 (s, 1H), 7.41 (d, 1H), 7.58(d, 1H). EXAMPLE 9: 3-(2-methylcyclohexyl)-6-methoxybenzothiophene ’H-NMR (DMSOde): 0.70-2.20 (m, 12H), 2.70 (m, 0.5H, diastereoisomer), 3.02 (m,0.5H, diastereoisomer), 3.75 (s, 3H), 6.92 (dd, 1H), 7.02 (s, 1H), 7.40 (d, 1H), 7.55(d, 1H). EXAMPLE 10: 3-(2,2-dimethylcyclopentyl)-6-methoxybenzothiophene‘H-NMR (DMSOdô): 0.70 (s, 3H), 1.10 (s, 3H), 1.45-2.20 (m, 6H), 2.93 (m, 1H), 3.78 (s, 3H), 7.02 (dd, 1H), 7.04 (s, 1H), 7.43 (d, 1H), 7.60 (d, 1H). EXAMPLE 11: 3-(2-adamantyl)-6-methoxybenzothiophene ’H-NMR (DMSOd6): 1.40-2.40 (m, 14H), 3.19 (br s, 1H), 3.79 (s, 3H), 6.92 (dd, 1H), 7.08 (s, 1H), 7.43 (d, 1H), 7.60 (d, 1H). EXAMPLE 12: 3-propyl-6-methoxybenzothiophene 013167 15 ^-NMR (DMSOdg): 0.95 (t, 3H), 1.68 (m, 2H), 2.78 (t, 2H), 3.79 (s, 3H), 6.92 (dd,1H), 7.00 (s, 1H), 7.43 (d, 1H), 7.58 (d, 1H). EXAMPLE 13: 3-hexyl-6-methoxybenzothiophene ’H-NMR (DMSOdô): 0.85 (t, 3H), 1.10-1.80 (m, 8H), 2.82 (t, 2H), 3.79 (s, 3H), 6.92(dd, 1H), 7.01 (s, 1H), 7.45 (d, 1H), 7.58 (d, 1H). EXAMPLE 14: 3-cyclohexylmethyl-6-methoxybenzothiophene ’H-NMR (DMSOdô): 0.75-1.85 (m, 11H), 2.70 (d, 2H), 3.80 (s, 3H), 6.92 (dd, 1H), 7.00 (s, 1H), 7.42 (d, 1H), 7.59 (d, 1H). EXAMPLE 15: 3-cycloheptylmethyI-6-methoxÿbenzothiophene ^-NMR (DMSOd6): 1.00-1.90 (m, 13H), 2.71 (d, 2H), 3.80 (s, 3H), 6.93 (dd, 1H),7.00 (s, 1H), 7.42 (d, 1H), 7.59 (d, 1H). PREPARATION OF MONOSUBSTITUTED BENZOTHIOPHENOL (6)EXAMPLE 16: 3-Cyclohexyl-benzothiophene-6-ol A solution of 3-cyclohexyl-6-methoxybenzothiophene (4.00 g, 16.0 mmol) in40 ml of dichloromethane is added at room température to a solution of borontribromide (24 ml, 24 mmol). After 2h at room température the mixture washydrolysed with saturated aqueous NaHCO3, extracted with dichloromethane, driedover Na2SO4, filtered, and concentrated in vacuum to give the alcohol (3.60 g as anoil, 97%). ’H-NMR (CDC13) : 1.10-2.10 (m, 10H), 2.80 (m, 1H), 6.78 (dd, 1H), 6.94 (s, 1H), 7.17 (d, 1H), 7.48 (d, 1H), 9.42 (s, 1H, OH).
Using the same procedure but replacing 3-cyclohexyl-6-methoxybenzothiophene by: - 3-cyclopentyl-6-methoxybenzothiophene - 3-cycloheptyl-6-methoxybenzothiophene - 3 -cyclooctyl-6-methoxybenzothiophene - 3-cyclodecyl-6-methoxybenzothiophene - 3-(4-methylcyclohexyl)-6-methoxybenzothiophene - 3-(2-methylcyclohexyl)-6-methoxybenzothiophene - 3-(2,2-dimethylcyclopentyl)-6-methoxybenzothiophene - 3-(2-adamantyl)-6-methoxybenzothiophene - 3-propyl-6-methoxybenzothiophene 013167 16 - 3-hexyl-6-methoxybenzothiophene - 3-cyclohexylmethyl-6-methoxybenzothiophene - 3-cycloheptylmethyl-6-methoxybenzothiophene,the following compounds were respectively obtained: EXAMPLE 17:3-cyciopentyl-benzothiophene-6-ol
mp 116°C 1 H-NMR (DMSOd6) : 1.45-2.20 (m, 8H), 3.25 (m, 1H), 6.78 (dd, 1H), 6.96 (s, 1H), 7.15 (d, 1H), 7.47 (d, 1H), 9,45 (s, 1H, OH).
EXAMPLE 18: 3-cycIoheptyl-benzothiophene-6-olmp 140°C ^-NMR (DMSOdé) : 1.35-2.15 (m, 12H), 3.00 (m, 1H), 6.79 (dd, 1H), 6.94 (s, 1H), 7.17 (d, 1H), 7.48 (d, 1H), 9,45 (s, 1H, OH).
EXAMPLE 19: 3-cyclooctyl-benzothiophene-6-olmp 100°C ’H-NMR (DMSOdô) : 1.35-2.10 (m, 14H), 3.07 (m, 1H), 6.78 (dd, 1H), 6.95 (s, 1H), 7.15 (d, 1H), 7.47 (d, 1H), 9,42 (s, 1H, OH).
EXAMPLE 20: 3-cycIodecyl-benzothiophene-6-oImp 108°C 1 H-NMR (DMSOd6) : 1.30-2.10 (m, 18H), 3.22 (m, 1H), 6.79 (dd, 1H), 6.99 (s, 1H), 7.15 (d, 1H), 7.48 (d, 1H), 9,42 (s, 1H, OH).
EXAMPLE 21: 3-(4-methylcyclohexyl)-benzothiophene-6-olmp 132°C ‘H-NMR (DMSOd6): 0.70-2.10 (m, 12H), 2.70 (m, 1H), 6.80 (dd, 1H), 6.92 (s, 1H), 7.15 (d, 1H), 7.48 (d, 1H), 9,42 (s, 1H, OH). EXAMPLE 22: 3-(2-methylcyclohexyI)-benzothiophene-6-ol
mp 125°C ^-NMR (DMSOdô): 0.60-2.20 (m, 12H), 3.05 (m, 1H), 6.80 (dd, 1H), 6.90 (s, 1H), 7.16 (d, 1H), 7.50 (d, 1H), 9,45 (s, 1H, OH). EXAMPLE 23: 3-(2,2-dimethyIcyclopentyl)-benzothiophene-6-ol
mp 90°C ’H-NMR (DMSOd6): 0.70 (s, 3H), 1.09 (s, 3H), 1.45-2.20 (m, 6H), 2.92 (dd, 1H), 6.80 (dd, 1H), 6.99 (s, 1H), 7.17 (d, 1H), 7.51 (d, 1H), 9.45 (s, 1H, OH). 013167 17 EXAMPLE 24: 3-(2-adamantyl)-benzothiophene-6-ol
mp 184°C 'H-NMR (DMSOdg): 1.40-2.40 (m, 14H), 3.16 (br s, 1H), 6.80 (dd, 1H), 7.00 (s,1H), 7.17 (d, 1H), 7.50 (d, 1H), 9,43 (s, 1H, OH).
EXAMPLE 25: 3-propyl-benzothiophene-6-olmp 56°C ’H-NMR (DMSOde): 0.97 (t, 3H), 1.68 (m, 2H), 2.79 (t, 2H), 6.80 (dd, 1H), 6.96 (s,1H), 7.17 (d, 1H), 7.50 (d, 1H), 9.46 (s, 1H, OH).
EXAMPLE 26: 3-hexyI-benzothiophene-6-olmp 68°C ’H-NMR (DMSOdi): 0.85 (t, 3H), 1.10-1.80 (m, 8H), 2.78 (t, 2H), 6.79 (dd, 1H),6.95 (s, 1H), 7.16 (d, 1H), 7.48 (d, 1H), 9.45 (s, 1H, OH).
EXAMPLE 27: 3-eycIohexylmethyI-benzothiophene-6-olmp 97°C ‘H-NMR (DMSOde): 0.75-1.80 (m, 11H), 2.68 (d, 2H), 6.78 (dd, 1H), 6.91 (s, 1H), 7.16 (d, 1H), 7.49 (d, 1H), 9.45 (s, 1H, OH).
EXAMPLE 28: 3-cycloheptylmethyl-benzothiophene-6-oImp 82°C ^-NMR (DMSOdô): 1.00-1.90 (m, 13H), 2.72 (d, 2H), 6.80 (dd, 1H), 6.92 (s, 1H), 7.18 (d, 1H), 7.49 (s, 1H), 9.48 (s, 1H, OH). PREPARATION OF SULFAMIC ACID MONOSUBSTITÜTEDBENZOTHIOPHENYL ESTER (7) EXAMPLE 29: Sulfamic acid, 3-cyclohexyl-benzothiophene-6-yl ester
Sodium hydride (0.60 g, 24.8 mmol) was carefully added to a solution of 3- cyclohexyl-benzothiophene-6-ol (3.60 g, 15.50 mmol) in dry DMF (36 ml) at 0°C.After being stirred for 30 min at room température and 30 min at 50°C, the mixturewas cooled (ice/water) and amidochlorosulfonic acid (4.45 g, 38.00 mmol) wasadded. After 3 h at room température the mixture was hydrolysed with saturatedaqueous NH4CI, extracted with ethyl acetate, dried over Na2SO4, filtered, andconcentrated under vacuum to give the crude product (4.80 g as oil). Flashchromatography on silica gel (toluene/l,4-dioxan: 8/2) yielded a limpid oil whichwas crystallised from éthanol to give the title product (0.50 g, 10%, mp 128°C). 18 013167 ‘H-NMR (CDC13) : 1.15-2.20 (m, 10H), 2.90 (m, 1H), 7.18 (s, 1H), 7.24 (dd, 1H),7.30 (d, 1H), 7.32 (s, 1H), 7.98 (s, 2H, NH2).
Using the same procedure but replacing 3-cyclohexylbenzothiophene-6-ol by: - 3 -cyclopentyl-benzothiophene-6-ol - 3-cycloheptyl-benzothiophene-6-ol - 3-cyclooctyl-benzothiophene-6-ol - 3-cyclodecyl-benzothiophene-6-ol - 3 -(4-methylcyclohexyl)-benzothiophene-6-ol - 3-(2-methylcyclohexyl)-benzothiophene-6-ol - 3-(2,2-dimethylcyclopentyl)-benzothiophene-6-ol - 3-(2-adamantyl)-benzothiophene-6-ol - 3-propyl-benzothiophene-6-ol - 3-hexyl-benzothiophene-6-ol - 3-cyclohexylmethyl-benzothiophene-6-ol - 3 -cycloheptylmethyl-benzothiophene-6-ol,the following compounds were respectively obtained:
EXAMPLE 30: Sulfamic acid, 3-cyclopentyl-benzothiophene-6-yl estermp 110°C ’H-NMR (DMSOd6) : 1.50-2.30 (m, 8H), 3.39 (m, 1H), 7.20 (s, 1H), 7.72 (dd, 1H), 7.78 (d, 1H), 7.95 (s, 2H, NH2). EXAMPLE 31: Sulfamic acid, 3-cycloheptyI-benzothiophene-6-yI ester
mp 132°C ’ll-NMR (DMSOdé): 1.35-2.20 (m, 12H), 3.12 (m, 1H), 7.19 (s, 1H), 7.24 (dd, 1H), 7.75 (d, 1H), 7.80 (d, 1H), 7.95 (s, 2H, NH2).
EXAMPLE 32: Sulfamic acid, 3-cyclooctyl-benzothiophene-6-yl estermp 126°C ^-NMR (DMSOd6) : 0.90-2.20 (m, 14H), 3.18 (m, 1H), 7.17 (s, 1H), 7.23 (dd, 1H), 7.76 (d, 1H), 7.80 (d, 1H), 7.95 (s, 2H, NH2). EXAMPLE 33: Sulfamic acid, 3-cycIodecyl-benzothiophene-6-yl ester
mp 98°C ‘H-NMR (DMSOde): 1.30-2.10 (m, 18H), 3.31 (m, 1H), 7.20 (s, 1H), 7.23 (dd, 1H), 7.76 (d, 1H), 7.79 (d, 1H), 7.96 (s, 2H, NH2). 19 013167
EXAMPLE 34: Sulfamic acid, 3-(4-methyIcyclohexyl)-benzothiophene-6-yl estermp 132°C ’H-NMR (DMSOd^): 0.75-2.15 (m, 12H), 2.55 (m, 1 H), 7.25 (s, 1H), 7.55 (dd, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.25 (s, 2H, NH2).
EXAMPLE 35: Sulfamic acid, 3-(2-methylcyclohexyl)-benzothiophene-6-yl estermpllO°C ’H-NMR (DMSOdé): 0.65-2.30 (m, 12H), 3.15 (m, 1H), 7.05-7.35 (m, 2H), 7.70-7.89 (m, 2H), 7.97 (s, 2H, NH2). EXAMPLE 36: Sulfamic acid, 3-(2,2-dimethyIcyclopentyl)-benzothiophene-6~yl ester
mp 72°C ’H-NMR (DMSOd6): 0.70 (s, 3H), 1.10 (s, 3H), 1.45-2.30 (m, 6H), 3.02 (dd, 1H),7.20 (s, 1H), 7.23 (dd, 1H), 7.78 (d, 1H), 7.80 (s, 1H), 7.96 (s, 2H, NH2).
EXAMPLE 37: Sulfamic acid, 3-(2-adamantyl)-benzothiophene-6-yl estermp 185°C ’H-NMR (DMSOdô): 1.50-2.40 (m, 12H), 3.37 (br s, 1H), 7.24 (m, 2H), 7.80 (d, 1H),7.82 (s, 1H), 7.97 (s, 2H, NH2). EXAMPLE 38: Sulfamic acid, 3-propyI-benzothiophene-6-yl ester
mp 112°C ’H-NMR (DMSOde): 0.96 (t, 3H), 1.70 (m, 2H), 2.88 (t, 2H), 7.19 (s, 1H), 7.24 (dd,1H), 7.78 (d, 1H), 7.80 (s, 1H), 7.97 (s, 2H, NH2).
EXAMPLE 39: Sulfamic acid, 3-hexyl-benzothiophene-6-yl esterMp 125°C ’H-NMR (DMSOde): 0.95 (t, 3H), 1.10-1.80 (m, 8H), 2.88 (t, 2H), 7.19 (s, 1H), 7.22(dd, 1H), 7.77 (d, 1H), 7.79 (s, 1H), 7.96 (s, 2H, NH2).
EXAMPLE 40: Sulfamic acid, 3-cyclohexylmethyl-benzothiophene-6-yl esterMpll5°C ’H-NMR (DMSOdô): 0.80-1.80 (m, 11H), 2.78 (d, 2H), 7.16 (s, 1H), 7.24 (dd, 1H), 7.77 (d, 1H), 7.79 (s, 1H), 7.97 (s, 2H, NH2). EXAMPLE 41: Sulfamic acid, 3-cycloheptylmethyl-benzotKiophene-6-yI ester
mp 90°C 20 013167 ’H-NMR (DMSOde): 1.00-2.00 (m, 13H), 2.82 (d, 2H), 7.18 (s, 1H), 7.22 (dd, 1H), 7.78 (d, 1H), 7.80 (s, 1H), 7.97 (s, 2H, NH2). PREPARATION OF MONO OR DI-OXIDIZED MONOSUBTITUTEDCOMPOUNDS (8) EXAMPLE 42: Sulfamic acid, 3-cyclohexyl-benzothiophenc-6-yl-l-oxide esterTo a solution of sulfamic acid, 3-cyclohexyl-benzothiophene-6-yl ester (1.00 g, 3.21 mmol) in dichloromethane (20 ml) and trifluoroacetic acid (5 ml) was added35% aqueous hydrogen peroxide (0.35 ml, 3.42 mmol, 1.05 équivalent). After 2 h at50°C the mixture was hydrolysed with saturated aqueous NaHCO3, extracted withdichloromethane, dried over Na2SC>4, filtered, and concentrated under vacuum togive the crude product. Flash chromatography on silica gel (toluene / 1,4-dioxan :6/4) yielded a limpid oil which was crystallised from éthanol to give the title product(0.25 g, 24%, mp 110°C). ^-NMR (DMSOdg) : 1.10-2.15 (m, 10H), 2.72 (m, 1H), 7.10 (s, 1H), 7.45 (dd, 1H),7.64 (d, 1H), 7.84 (d, 1H), 8.16 (s, 2H, NH2).
Using the same procedure but replacing the sulfamic acid, 3-cyclohexyl-benzothiophene-6-yl ester by: - Sulfamic acid, 3-cyclodecyl-benzothiophene-6-yl ester,the following compound was obtained:
EXAMPLE 43: Sulfamic acid, 3-cyclodecyl-benzothiophene-6-yl-l-oxide estermp 146°C ^-NMR (DMSOdô) : 1.35-2.10 (m, 18H), 3.12 (m, 1H), 7.15 (s, 1H), 7.45 (dd, 1H), 7.62 (d, 1H), 7.83 (d,lH), 8.15 (s, 2H, NH2).
Using the procedure of example 42 but with 2.2 équivalents of hydrogenperoxide, the following compound was obtained: EXAMPLE 44: Sulfamic acid, 3-cyclohexyl-benzothiophene-6-yl-l,l-dioxideester
mp 180°C ^-NMR (DMSOd6): 1.15-2.15 (m, 10H), 2.52 (m, 1H), 7.30 (s, 1H), 7.53 (dd, 1H), 7.63 (d, 1H), 7.71 (d, 1H), 8.25 (s, 2 H, NH2).
Using the same procedure but replacing the sulfamic acid, 3-cyclohexyl-benzothiopherte-6-yl ester by: 013167 21 - Sulfamic acid, 3-cycloheptyl-benzothiophene-6-yl ester - Sulfamic acid, 3-cyclooctyl-benzothiophene-6-yl ester - Sulfamic acid, 3-cyclodecyl-benzothiophene-ô-yl ester - Sulfamic acid, 3-(4-methylcyclohexyl)-benzothiophene-6-yl ester - Sulfamic acid, 3-(2-methylcyclohexyl)-benzothiophene-6-yl ester - Sulfamic acid, 3-(2,2-dimethylcyclopentyl)-benzothiophene-6-yl ester - Sulfamic acid, 3-(2-adamantyl)-benzothiophene-6-yl ester - Sulfamic acid, 3-propyl-benzothiophene-6-yl ester - Sulfamic acid, 3-hexyl-benzothiophene-6-yl ester - Sulfamic acid, 3-cyclohexylmethyl-benzothiophene-6-yl ester - Sulfamic acid, 3-cycloheptylmethyl-benzothiophene-6-yl ester,the following compounds were respectively obtained: EXAMPLE 45: Sulfamic acid, 3-cycloheptyl-benzothiophene-6-yl-l,l-dioxide ester
mp 137°C ’H-NMR (DMSOde): L35-2.15 (m, 12H), 2.75 (m, 1H), 7.32 (s, 1H), 7.52 (dd, 1H), 7.61 (d, 1H), 7.70 (d, 1H), 8.25 (s, 2H, NH2). EXAMPLE 46: Sulfamic acid, 3-cyclooctyl-benzothiophene-6-yl-l,l-dioxide ester
mp 122°C ’H-NMR (DMSOde): 1.35-2.10 (m, 14H), 2.81 (m, 1H), 7.32 (s, 1H), 7.52 (dd, 1H), 7.61 (d, 1H), 7.70 (d, 1H), 8.22 (s, 2 H, NH2). EXAMPLE 47: Sulfamic acid, 3-cyclodecyl-benzothiophene-6-yl-l,l-dioxide ester
mp 102°C ’H-NMR (DMSOde): 1.35-2.10 (m, 18H), 2.97 (m, 1H), 7.38 (s, 1H), 7.52 (dd, 1H),7.60 (d, 1H), 7.70 (d, 1H), 8.22 (s, 2 H, NH2). EXAMPLE 48: Sulfamic acid, 3-(4-methyIcyclohexyl)-benzothiophene-6-yl -1,1- dioxide ester
mp 170°C ’H-NMR (DMSOd6): 0.75-2.20 (m, 12H), 2.83 (m, 1H), 7.18 (s, 1H), 7.22 (dd, 1H), 7.78 (d, 1H), 7.80 (d, 1H), 7.95 (s, 2 H, NH2). 013167 22
EXAMPLE 49: Sulfamic acid, 3-(2-methyîcyclohexyl)-benzothiophene-6-yl -1,1-dioxide estermp 92°C lH-NMR (DMSOdô): 0.70-2.45 (m, 12H), 2.85 (m, 1H), 7.25 (s, 1H), 7.52 (m, 3H),8.25 (s, 2 H, NH2).
EXAMPLE 50: Sulfamic acid, 3-(2,2-dimethylcyclopentyl)-benzothiophene-6-yI-1,1-dioxide estermp 172°C 'H-NMR (DMSOd6): 0.90 (s, 3H), 1.16 (s, 3H), 1.50-2.15 (m, 6H), 2.66 (t, 1H), 7.49(s, 1H), 7.52 (dd, 1H), 7.61 (d, 1H), 7.70 (d, 1H), 8.24 (s, 2 H, NH2). EXAMPLE 51: Sulfamic acid, 3-(2-adamantyI)-benzothiophene-6-yl-l,l-dioxideester
mp 230°C ’H-NMR (DMSOde): 1.45-2.45 (m, 14H), 3.04 (br s, 1H), 7.38 (s, 1H), 7.53 (d, 1H),7.64 (d, 1H), 7.70 (d, 1H), 8.25 (s, 2 H, NH2).
EXAMPLE 52: Sulfamic acid, 3-propyl-benzothiophene-6-yl-l,l-dioxide estermp 159°C 'H-NMR (DMSOde): 0.99 (t, 3H), 1.70 (m, 2H), 2.49 (t, 2H), 7.29 (s, 1H), 7.52 (dd,1H), 7.63 (d, 1H), 7.73 (d, 1H), 8.50 (s, 2H, NH2). EXAMPLE 53: Sulfamic acid, 3-hexyl-benzothiophene-6-yl-l,l-dioxide ester
mp 98°C ’H-NMR (DMSOd6): 0.85 (t, 3H), 1.10-1.80 (m, 8H), 2.50 (t, 2H), 7.30 (s, 1H), 7.52(dd, 1H), 7.62 (d, 1H), 7.73 (d, 1H), 8.27 (s, 2H, NH2).
EXAMPLE 54: Sulfamic acid, 3-cycIohexylmethyl-benzothiophene-6-yl-l,l-dioxide estermp 132°C ^-NMR (DMSOd5): 0.80-1.95 (m, 11H), 2.40 (d, 2H), 7.30 (s, 1H), 7.53 (dd, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 8.25 (s, 2H, NH2).
EXAMPLE 55: Sulfamic acid, 3-cycloheptylmethyl-benzothiophene-6-yl-l,l-dioxide estermp 135°C 013167 23 Ή-NMR(DMSOdé): 1.00-2.15 (m, 13H), 2.45 (d, 2H), 7.29 (s, 1H), 7.53 (dd, 1H), 7.62 (d, 1H), 7.73 (d, 1H), 8.25 (s, 2H, NH2). PREPARATION OF DISUBSTITUTED 6-METHOXY-BENZOTHIOPHENE(9) EXAMPLE 56: 3-cycIoheptyI-6-methoxy-2-methyI-benzothiophene
To a solution of 3-cycloheptyl-6-methoxy-benzothiophene (2.00 g, 7.69 mmol) in dry THF (20 ml) at -70°C was added dropwise a 2.5 M solution of n-butyllithium in hexane (5 ml, 12.16 mmol). Then, the mixture was warmed to -30°Cduring 10 min and chilled at - 70°C for the addition of iodomethane (1.0 ml, 15.38mmol). The mixture was warmed to room température ovemight. It was hydrolysedwith saturated aqueous NH4CI, extracted with ethyl acetate, dried (NaaSO^, filteredand concentrated under vacuum to give 2.1 g of an oil. Flash chromatography onsilica gel (heptane / ethyl acetate : 1/1) yielded a limpid oil (1.50 g, 72 %) which wasused without further purification. Ή-NMR (DMSOd$): 1.35-2.15 (m, 12H), 2.29 (s, 3H), 3.00 (m, 1H), 3.80 (s, 3H),7.00 (s, 1 H), 7.04 (d, 1H), 7.49 (d, 1H).
Using the same procedure but replacing iodomethane by: - bromobutane, the following compound was obtained: EXAMPLE 57: 3-cycloheptyl-6-methoxy-2-butyl-benzothiophene Ή-NMR (DMSOd6): 0.90 (t, 3H), 1.10-2.20 (m, 16H), 2.75 (t, 2H), 3.04 (m, 1H),3.80 (s, 3H), 7.00 (s, 1 H), 7.05 (d, 1H), 7.51 (d, 1H). EXAMPLE 58: 7-methoxy-l,2,3,4-tetrahydro-dibenzothiophene
This compound was prepared using the conditions described by Oliveira. M(Tetrahedron, 2002, 58, 1709-18). Ή-NMR (CDCI3): 1.92 (m, 4H), 2.72 (m, 2H), 2.83 (m, 2H), 3.89 (s, 3H), 6.97 (dd,1 H), 7.30 (d, 1H), 7.47 (d, 1H). PREPARATION OF DISUBSTITUTED BENZOTHIOPHENE-OL (10)
Following the procedure used for the monosubstituted compounds, butreplacing 3-cyclohexyl-6-methoxy-benzothiophene by: - 3 -cycloheptyl-2-methyl-6-methoxy-benzothiophene - 3-cycloheptyl-6-methoxy-2-butyl-benzothiophene 013167 24 - 7-methoxy-l,2,3,4-tetrahydro-dibenzothiophene,the following compounds were respectively obtained:
EXAMPLE 59: 3-cycloheptyl-2-methyl-benzothiophene-6-oImp 96°C ’H-NMR (DMSOdg): 1.30-2.15 (m, 12H), 2.44 (s, 3H), 3.01 (m, 1H), 6.87 (d, 1H),6.97 (s, 1H), 7.34 (d, 1H), 9.31 (s, 1H, OH). EXAMPLE 60: 3-cycIoheptyI-2-butyl-benzothiophene-6-oIlimpid oil JH-NMR (DMSOdg): 0.92 (t, 3H), 1.15-2.20 (m, 16H), 2.80 (t, 2H\ 3.02 (m, 1H),6.85 (d, 1H), 6.95 (s, 1H), 7.32 (d, 1H), 9.22 (s, 1H, OH).
EXAMPLE 61: l,2,3,4-tetrahydro-dibenzothiophene-7-olmp 116°C ’H-NMR (CDC13): 1.90 (m, 4H), 2.68 (m, 2H), 2.79 (m, 2H), 4.98 (br s, 1H, OH),6.88 (dd, 1 H), 7.20 (d, 1H), 7.42 (d, 1H). PREPARATION OF SULFAMIC ACID DISUBSTITUTEDBENZOTHIOPHENYL ESTER (11)
Following thr procedure used for the monosubstituted compounds butreplacing 3-cyclohexyl-benzothiophene-6-ol by: - 3 -cycloheptyl-2-methyl-benzothiophene-6-ol - 3-cycloheptyl-2-butyl-benzothiophene-6-ol - 1 ,2,3,4-tetrahydro-dibenzothiophene-7-ol,the following compounds were respectively obtained:
EXAMPLE 62: Sujfamic acid, 3-cycloheptyl-2-methyl-benzothiophene-6-yl estermp 107°C ^-NMR (DMSOdg): 1.40-2.20 (m, 12H), 2.46 (s, 3H), 3.14 (m, 1H), 7.20 (s, 1H),7.30 (dd, 1H), 7.60 (d, 1H), 8.00 (s, 2H, NH2). EXAMPLE 63: Sulfamic acid, 3-cycloheptyi-2-butyl-benzothiophene-6-yl esterlimpid oil !H-NMR (DMSOdg): 0.91 (t, 3H), 1.15-2.20 (m, 16H), 2.77 (t, 2H), 3.11 (m, 1H),7.15 (s, 1H), 7.32 (d, 1H), 7.59 (d, 1H), 8.04 (s, 2H, NH2).
EXAMPLE 64: Sulfamic acid, l,2,3,4-tetrahydro-dibenzothiophene-7-yl estermp 165°C 013167 25 ^-NMR (DMSOde): 1.87 (m, 4H), 2.70 (m, 2H), 2.82 (m, 2H), 7.28 (dd, 1 H), 7.66(d, 1H), 7.72 (d, 1H). PREPARATION OF DIOXIDIZED DISUBTITUTED COMPOUNDS (12)
Following the procedure used for the monosubstituted compounds butreplacing the suif amie acid, 3-cycloheptyl-benzothiophene-6-ol ester by: - Sulfamic acid, 3-cycloheptyl-2-methyl-benzothiophene-6-ol ester - Sulfamic acid, 3-cycloheptyl-2-butyl-benzothiophene-6-ol ester - Sulfamic acid, l,2,3,4-tetrahydro-dibenzothiophene-7-ol ester,the following compounds were respectively obtained:
EXAMPLE 65: Sulfamic acid, 3-cycIoheptyI-2-methyl-benzothiophene-6-yl-l,l-dioxide estermp 90QC ’H-NMR (DMSOd6): 1.30-2.20 (m, 12H), 2.48 (s, 3H), 2.76 (m, 1H), 7.28 (s, 1H),7.41 (d, 1H), 7.52 (d, 1H), 8.27 (s, 2H, NH2). EXAMPLE 66: Sulfamic acid, 3-cycloheptyl-2-butyl-benzothiophene-6-yl-l,l-dioxide esterlimpid oil ^-NMR (DMSOd6): 0.91 (t, 3H), 1.15-2.15 (m, 16H), 2.75 (m, 1H), 2.90 (t, 2H),7.25 (s, 1H), 7.40 (d, 1H), 7.56 (d, 1H), 8.31 (s, 2H, N%). EXAMPLE 67: Sulfamic acid, l,2,3,4-tetrahydro-dibenzothiophene-7-yl-l,l-dioxide ester
mp 229°C 'H-NMR (DMSO6): 1.78 (m, 4H), 2.30-2.70 (m, 4H), 7.54 (dd, 1 H), 7.61 (d, 1H),7.74 (d, 1H).
BIOLOGICAL TEST RESULTS
INHIBITION OF STEROID SULFATASE IN VITRO
Estrone sulfate (EiS) is a major circulating plasma estrogen that is convertedby the steroid sulfatase enzyme into estrone (EQ, which in tum can be transformedinto estradiol (E2) by enzymatic réduction. Steroid sulfatase activity is présent inmost tissues (utérus, liver, breast, etc..) and is significantly higher in malignant thanin normal breast tissue. The close association of estrogens with the promotion of the 013167 26 growth and development of breast cancer has long been recognized, therefore steroidsulfatase appears as a potential target to inhibit in situ formation of estrogens.
Potent inhibitors of this enzyme, containing a sulfamate moiety which isbelieved to be involved in the irréversible inhibition of steroid sulfatase, hâve beensynthesized. To date the most active compound is EMATE, estrone-3-sulfamate, butits estrogenic activity has rendered this compound unsuitable for use in the treatmentof hormone-dependent-tumors. Numerous structurally diversified inhibitors ofsteroid sulfatase hâve been reported among which, 6,6,7-COUMATE emerged as astandard non-steroidal inhibitor lacking estrogenic properties.
In vitro results
Two in vitro models on whole cells were used. The JEG-3 cell line, derivedfrom a human placental choriocarcinoma, is spontaneously very rich in humanestrone sulfatase and therefore, a useful practical biological system to screen in a 96-well microplate format a large number of compounds and evaluate putative steroidsulfatase inhibitors in vitro. Despite a lower content in steroid sulfatase activity, theMCF-7 cells constitute another suitable model to test steroid sulfatase inhibitors onhuman breast adenocarcinoma cells. Moreover, these cells were used in the in vivomodel of hormono-dependent induced xenografts.
Estrone sulfatase assay bn cells
Whole-cell assays were performed as originally described by Duncan et al.(Cancer Res., 1993, 53: 298-303) on intact MCF-7 cell monolayers. Assays werecarried out with cells in logarithmic growth phase, on 96-well (JEG-3) or 24-well(MCF-7) microplates. Twenty-four hours (JEG-3) or 72 h (MCF-7) before studies,cells were seeded in decomplemented fêtai calf sérum (dFCS) supplementedmedium. Then, the seeding medium was removed and the cells were rinsed with PBSto eliminate any trace of dFCS. Then, 3H-EjS was added, foliowed by testcompounds ranging from 10'12 M to 10'5 M. After 4 h (JEG-3) or 20 h (MCF-7) oftreatment, the medium was transferred into either 96-deep-well microplates (JEG-3)or plastic tubes (MCF-7) and centrifuged at 200 x g for 10 min to pellet cells beforetoluene extraction. A fraction of medium was used for toluene extraction in order toseparate conjugated substrate and non-conjugated products. The radioactivity in thetoluene phase was measured by liquid scintillation counting (LSC). Finally, estrone 27 013167 sulfatase activity was expressed in pmoles of 3H-Et + 3H-E2 formed per 4 or 20 hoursand per pg DNA and estrone sulfatase inhibition in percentage of control activitywithout inhibitor. A non linear fit analysis (GraphPad Prism Software) of %inhibition vs. inhibitor concentrations allowed for the détermination of 50 %inhibitory concentration (IC50): the lowest IC50 corresponds to the most potentinhibitors (Table 1).
Table 1: Inhibition of estrone sulfatase on whole-cell assays JEG-3 cells MCF-7 cells Compounds IC50(nM)±S.E.M. n IC50 (nM) ± S.E.M. n EMATE 3.2 ±0.2 4 0.06 ± 0.01 18 6,6,7-COUMATE 4.5 ±0.6 37 0.33 ± 0.06 24 Ex 30 78.8 ±39.8 5 Ex 31 101.8 ±58.0 5 Ex 32 433.7 ±94.8 5 Ex 33 743.8 ±139.6 5 Ex 34 317.7 ±42.9 5 Ex 35 146.8 ± 16.3 4 Ex 36 128.5 ± 14.2 4 Ex 37 92.4 ± 15.6 5 Ex 42 7.0 ±1.2 5 0.16 ±0.03 4 Ex 44 10.9 ±2.6 5 0.24 ± 0.05 4 Ex 47 52.1 ±4.4 5 0.08 ±0.01 4 Ex 48 7.6 ±1.3 5 0.09 ±0.02 4 Ex 49 2.6 ± 0.4 4 Ex 50 2.5 ±0.5 4 013167 28
Ex 52 24.7 ± 5.0 5 Ex 53 12.5 ±3.3 5 Ex 54 10.0 ±1.2 4 0.10 ±0.03 4 Ex 55 ' 7.7 ±0.4 4 0.05 ±0.01 6 Ex 64 565.8 ± 129.6 5 Ex 65 31.7 ±9.9 4
Among the tested compounds, Ex 42, Ex 44, Ex 48, Ex 49, Ex 50, Ex 54 andEx 55 showed a strong inhibition (IC50 of about 10 nM) of human estrone sulfataseactivity in JEG-3 cells. These compounds were checked for residual estrogenic 5 activity in vivo in the classical uterotrophic assay after 3-day administration by oralroute in prepubescent female rats. INHIBITION OF STEROID SULFATASE IN VIVOResidual estrogenic activity in vivo
Prepubescent female rats were orally treated at 1 mg/rat/day for 3 days. On 10 the day foliowing the last treatment, uteri were removed and wet weight wererecorded.
The results are expressed as % of stimulation of utérus weight in comparisonwith Controls. 15 Table 2: residual estrogenic activity
Compound % stimulation Number of animais 6,6,7 COUMATE 3% 16 Ex 42 0% 8 Ex 44 0% 8 Ex 47 4% 8 Ex 48 3% 8 013167 29
Ex 49 8% 8 Ex 50 24% 8 Ex 54 6% 8 Ex 55 3% 8
Antiuterotrophic /Antisulfatase activity A short model, derived from Purohit’s method, was developed for the évaluation in vivo of nonestrogenic steroid sulfatase inhibitors. 5 Wistar female rats were ovariectomized and left to rest for 4 weeks. Prior to treatment, the absence of cyclicity was checked by vaginal smears.
Animais were supplemented with estrone sulfate (EiS) at 50 pg/kg/day s.c., alone or combined with oral administration of potential sulfatase inhibitors, at 1mg/kg/day for 4 days. The uteri were removed, freed' of adjacent tissue and wet 10 weighed.
The results are expressed as % of inhibition of the EiS induced stimulation.
Table 3: antiuterotrophic activity
Compound % inhibition Number of animais 6,6,7 COUMATE 86% 48 Ex 42 38% 8 Ex 44 70% 8 Ex 47 62% 8 Ex 48 60% 8 Ex 54 49% 8 Ex 55 81% 16 013167 30
Ex 55 was chosen as potential inhibitor of steroid sulfatase activity because of lack of estrogenicity and significant inhibition of EiS stimulated utérus weight.
These in vivo results were in good accordance with in vitro results obtained in JEG-3 and MCF-7 whole-cell assays. 5 Evaluation of the potency of Ex 55
The activity of Ex 55 on EiS stimulated utérus weight was evaluated inrelation to the standard inhibitor 6,6,7 COUMATE from 0.03 mg/kg/day to 1mg/kg/day p.o.
In this study, a last administration was performed 24 hours before the necropsy10 for EiS and E2 sérum levels assays. The uteri were removed, freed of adjacent tissue,wet weighed and immediately deep frozen until the détermination of sulfatase activity. • Inhibition of EjS stimulated utérus weight 15 Table 4
Dose mg/kg/day 6,6,7 COUMATE Ex 55 0.03 0% 0% 0.1 13% 0% 0.3 52% 36% 1 84% 72% • Measure of estrone sulfatase activity in the utérus
Estrone sulfatase activity was measured according to the method described byPurohit et al., with slight modifications. Briefly, uteri were thawed, weighed and 20 homogenized. Aliquots of the supematant were treated with dextran-coated charcoaland assayed for sulfatase. EiS activity was assessed after 30 min of incubation with 5nM of 3H-EiS and 20 μΜ of unlabelled EjS as substrate. Radioactivity was measuredby LSC.
Estrone sulfatase activity was expressed as pmol/h/mg protein and reported as 25 percentage of inhibition versus EiS. 013167 31
Table 5
Dose mg/kg/day 6,6,7 COUMATE Ex 55 0.03 36% 19% 0.1 78% 64% 0.3 96% 96% 1 97% 97% • Sérum estrogen levels
EiS and E2 levels were determined according to the supplier’s standard method5 (DSL,Webster,TX,USA).
Table 6: EjS levels (ng/ml)
Dose mg/kg/day 6,6,7 COUMATE Ex 55 0 6.3 ±0.3 0.03 24 ±3.1 17 ±2.5 0.1 26 ± 2.6 21 ±2.4 0.3 59 ± 6.4 69 ± 5.9 1 80 ± 5.7 83 ±2.5 013167 32
Table 7: E2 levels (pg/ml)
Dose mg/kg/day 6,6,7 COUMATE Ex 55 0 7.8 ±0.7 0.03 33 ±5.8 31 ±2.8 0.1 28 ± 2.5 28 ± 1.3 0.3 18± 1.1 22 ±1.2 1 16 ±1.5 15 ±0.9
Hormono-dependent induced xenografts 5 MCF-7 cells, derived from human breast adenocarcinoma, were injected subcutaneously in ovariectomized athymie nude mice supplemented with estronesulfate (pellets 0.5 mg/90 day release). Xenograft volumes were determined onceweekly. When tumor volumes reached a significant increase, 6,6,7 COUMATE andEx 55 were orally administered at O.lmg/kg/day for 6 weeks. 10 Xenografts were measured, removed, weighed, and deep frozen until the détermination of steroid sulfatase activity.
Table 8: Xenograft volume (mm3) Treatment Xenograft volume after 6 week treatment Control placebo 71 ±8.2 EiS pellet (0.5mg/90day release) 1816±337 EiS + 6,6,7 COUMATE O.lmg/kg/day 1854 ±243
EjS + Ex 55 O.lmg/kg/day 1488±233 33 013167 6,6,7 COUMATE did not inhibit the EiS induced stimulation after 6 weeks oraladministration at O.lmg/kg/day. By contrast 18% inhibition were obtained with Ex55 at the same dose level. 5 ' Table 9: Xenograft weight (mg)
Treatment Xenograft weight after 6 week treatment Control placebo 31+3.8 EiS pellet (0.5mg/90day release) 1350 ± 277 E^ + 6,6,7 COUMATE O.lmg/kg/day 1467 ±191 EiS + Ex 55 O.lmg/kg/day 877 ±185 6,6,7 COUMATE did not inhibit xenograft weight while 35% inhibition wereobtained with Ex 55. 10 Table 10: Xenograft steroid sulfatase activity (pmol/h/mg protein)
Treatment Sulfatase activity E)S pellet (0.5mg/90day release) 1653 ±101 E,S + 6,6,7 COUMATE O.lmg/kg/day 540 ± 54 EjS + Ex 55 O.lmg/kg/day 263 ± 17
The inhibition of intratumoral steroid sulfatase activity was higher with Ex 55(84%) than with 6,6,7 COUMATE (67%).

Claims (53)

  1. 013167 34 CLAIMS
    1. A compound of formula (la) or formula (Ib):
    (Ib) wherein: - Ri is hydrogen, a (Ci-C6)alkyl, a (C2-C6)alkene, a (C3-Ci2)cycloalkyl or a (C3-10 C12)cycloalkene wherein the cycloalkyl and the cycloalkene are optionally mono- or disubstituted with a (Ci-COalkyl; - R2 is hydrogen, - R'2 is a (Ci-C6)alkyl or a (C3-Ci2)cycloalkyl; - R3 is hydrogen, a (CrCe)alkoxy or a halogen; 15 - m is 0, 1, 2; - n is 0, 1, 2; - when m is 0, Ri and R2 can also form together a group -(CH2)P- in which p is 3, 4or 5; - the dotted line indicates that the sulfamate group is in position 5- or 6- of the20 benzothiophene ring. 013167 35
  2. 2. The compound according to claim 1, wherein Rj is hydrogen, a (Ci-Ce)alkyl,or a (C3-Ci2)cycloalkyl which is optionally mono- or disubstituted with a (Ci-C^alkyl.
  3. 3. The compound according to claim 2, wherein Ri is a (C3-Ci0)cycloalkyl whichis optionally mono- or disubstituted with a (Ci-C4)alkyl.
  4. 4. The compound according to one of daims 1 to 3, wherein m is 0 or 1.
  5. 5. The compound according to one of daims 1 to 4, wherein R3 is hydrogen.
  6. 6. The compound according to one of daims 1 to 5, wherein n is 0 or 2.
  7. 7. The compound according to one of daims 1 to 6, wherein the sulfamate group is in position 6- of the benzothiophene ring.
  8. 8. Sulfamate benzothiophene dérivative obtainable by the process comprisingthe steps of: 1) converting the 6-methoxy-benzothiophene (3): R. (3) in which R3 is hydrogen, a (C!-C6) alkoxy or a halogen or the corresponding 5-methoxy-benzothiophene to the corresponding monobromo dérivative withN-bromosuccinimide and APTS using standard conditions; 2) transforming said monobromo dérivative into an organomagnesiumbromide and then condensing it with a ketone or an aldéhyde selected fromthe group consisting of cyclopentanone, cyclohexanone, cycloheptanone,cyclooctanone, cyclodecanone, 4-methylcyclohexanone, 2-methylcyclohexanone, 2,2-dimethyl-cyclopentanone, 2-adamantanone,propanai, hexanal, cyclohexane-carboxaldehyde, cycloheptanecarboxaldehydeto afford the corresponding substituted methoxybenzothiophene usingstandard conditions; 013167 36 3) optionally alkylating the corresponding substituted methoxybenzothiopheneusing conventional conditions to afford the corresponding substitutedmethoxybenzothiophene bearing a (Ci-C6)alkyl or a (C3-Ci2)cycloalkyl; 4) deprotecting the substituted methoxybenzothiophene obtained in step 2)or in step 3) with tribromoborane under conventional conditions; 5) transforming the resulting hydroxy compound into the correspondingsulfamàte by treatment with sodium hydride, with amidochlorosulfonic acid orby reaction with sulfamoyl chloride in dimethylacetamide; and 6) optionally oxidating the resulting compound by hydrogen peroxide intrifluoroacetic acid using conventional conditions.
  9. 9. Sulfamate benzothiophene dérivative with a melting point of 128 °Cobtainable by the process çomprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclohexanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  10. 10. Sulfamate benzothiophene dérivative with a melting point of 110 °Cobtainable by the process çomprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toiuenesulfonic acid; 013167 37 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclohexanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 1.05 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  11. 11. Sulfamate benzothiophene dérivative with a melting point of 98 °Cobtainable by: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclodecanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid. 013167 38
  12. 12. Sulfamate benzothiophene dérivative with a melting point of 146 °Cobtainable by: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclodecanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 1.05 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  13. 13. Sulfamate benzothiophene dérivative with a melting point of 180 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclohexanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted benzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 013167 39 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  14. 14. Sulfamate benzothiophene dérivative with a melting point of 132 °Cobtainable bÿ the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcycloheptanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  15. 15. Sulfamate benzothiophene dérivative with a melting point of 137 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcycloheptanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 013167 40 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  16. 16. Sulfamate benzothiophene dérivative with a melting point of 126 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclooctanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  17. 17. Sulfamate benzothiophene dérivative with a melting point of 122 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclooctanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 41 013167 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  18. 18. Sulfamate benzothiophene dérivative with a melting point of 102 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclodecanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  19. 19. Sulfamate benzothiophene dérivative with a melting point of 132 °Cobtainable by the process comprising the steps of: 013167 42 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbrorriide with Mg under argon in Et2O and then condensing it with4-methylcyclohexanone in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  20. 20. Sulfamate benzothiophene dérivative with a melting point of 170 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with 4-methylcyclohexanone in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane. 013167 43
  21. 21. Sulfamate benzothiophene dérivative with a melting point of 110 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with2-methylcyclohexanone in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon ίη dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  22. 22. Sulfamate benzothiophene dérivative with a melting point of 92 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with2-methylcyclohexanone in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 013167 44 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  23. 23. Sulfamate benzothiophene dérivative with a melting point of 72 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with2,2-dimethylcyclopentanone in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  24. 24. Sulfamate benzothiophene dérivative with a melting point of 172 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with2,2-dimethylcyclopentanone in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 013167 45 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein triflüoroacetic acid and dichloromethane.
  25. 25. Sulfamate benzothiophene dérivative with a melting point of 185 °Cobtainable by the process comprising the steps of: 1) convertihg the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with2-adamantanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  26. 26. Sulfamate benzothiophene dérivative with a melting point of 230 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuecinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with2-adamantanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 013167 46 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  27. 27. Sulfamate benzothiophene dérivative with a melting point of 112 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with propanai inEt2O to afford the corresponding hydroxy substituted methoxybenzothiopheneusing standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  28. 28. Sulfamate benzothiophene dérivative with a melting point of 159 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 013167 47 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with propanai inEt2O to afford the corresponding hydroxy substituted methoxybenzothiopheneusing standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  29. 29. Sulfamate benzothiophene dérivative with a melting point of 125 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with hexanal inEt2O to afford the corresponding hydroxy substituted methoxybenzothiopheneusing standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid. 013167 48
  30. 30. Sulfamate benzothiophene dérivative with a melting point of 98 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it with hexanal inEt2O to afford the corresponding hydroxy substituted methoxybenzothiopheneusing standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon irï dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  31. 31. Sulfamate benzothiophene dérivative with a melting point of 115 °Cobtainable by: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclohexanecarboxaldehyde in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted benzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3). insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 013167 49 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid;
  32. 32. Sulfamate benzothiophene dérivative with a melting point of 132 °Cobtainable by: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonob'romo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcyclohexanecarboxaldehyde in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted benzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  33. 33. Sulfamate benzothiophene dérivative with a melting point of 90 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcydoheptanecarboxaldehyde in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 013167 50 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  34. 34. Sulfamate benzothiophene dérivative with a melting point of 135 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcycloheptanecarboxaldehyde in Et2O to afford the corresponding hydroxysubstituted methoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 6) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  35. 35. Sulfamate benzothiophene dérivative with a melting point of 107 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcycloheptanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 013167 51 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) alkylating the corresponding substituted methoxybenzothiophene byadding iodomethane to a mixture of said monosubstitutedmethoxybenzothiophene in a solution of n-butyl lithium in hexane to affordthe corresponding methoxybenzothiophene; 5) adding the substituted methoxybenzothiophene obtained in step 4) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 6) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid.
  36. 36. Sulfamate benzothiophene dérivative with a melting point of 90 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcycloheptanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) alkylating the corresponding substituted methoxybenzothiophene byadding iodomethane to a mixture of said monosubstitutedmethoxybenzothiophene in a solution of n-butyl lithium in hexane to affordthe corresponding methoxybenzothiophene; 5) adding the substituted methoxybenzothiophene obtained in step 4) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 6) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 013167 52 7) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  37. 37. Sulfamate benzothiophene dérivative under the form of a limpid oilobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg Under argon in Et2O and then condensing it withcycloheptanone in Et2O to 'afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) alkylating the corresponding substituted methoxybenzothiophene byadding bromobutane to a mixture of said monosubstitutedmethoxybenzothiophene in a solution of n-butyl lithium in hexane to affordthe corresponding methoxybenzothiophene; 5) adding the substituted methoxybenzothiophene obtained in step 4) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 6) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride andamidochlorosulfonic acid.
  38. 38. Sulfamate benzothiophene dérivative under the form of a limpid oilobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcycloheptanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 013167 53 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) alkylating the corresponding substituted methoxybenzothiophene byadding bromobutane to a mixture of said monosubstitutedmethoxybenzothiophene in a solution of n-butyl lithium in hexane to affordthe corresponding methoxybenzothiophene; 5) adding the substituted methoxybenzothiophene obtained in step 4) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 6) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid; 7) oxidizing the resulting compound by 2.2 équivalents of hydrogen peroxidein trifluoroacetic acid and dichloromethane.
  39. 39. Sulfamate benzothiophene dérivative with a melting point of 110 °Cobtainable by the process comprising the steps of: 1) converting the 6-methoxy-benzothiophene (3) to the correspondingmonobromo dérivative with N-bromosuccinimide and p-toluenesulfonic acid; 2) transforming said monobromo dérivative into an organomagnesiumbromide with Mg under argon in Et2O and then condensing it withcydopentanone in Et2O to afford the corresponding hydroxy substitutedmethoxybenzothiophene using standard conditions; 3) treating said hydroxy substituted methoxybenzothiophene withtriethylsilane under argon in dichloromethane to afford the correspondingsubstituted methoxybenzothiophene; 4) adding the substituted methoxybenzothiophene obtained in step 3) insolution in dichloromethane to a solution of boron tribromide to afford thecorresponding hydroxy benzothiophene; 5) transforming said hydroxy compound into the corresponding sulfamate bytreatment with sodium hydride and amidochlorosulfonic acid. 013167 54
    wherein: - Ri is hydrogen; - R2 is hydrogen, a (Ci~C6)alkyI or a (C3-C12)cycloalkyl; - R3 is hydrogen, a (Ci-C6)alkoxy or a halogen; - m is 0; - n is 0, 1, 2; - the dotted line indicates that the sulfamate group is in position 5- or 6- of thebenzothiophene ring.
  40. 41. A compound of formula (I): O H2N-S— O
    (I) wherein: - Ri and R2 form together a group -(CH2)P- in which p is 3, 4 or 5; - R3 is hydrogen, a (Ci-C6)alkoxy or a halogen; - n is 0, 1, 2; 013767 55 - m is 0; - the dotted line indicates that the sulfamate group is in position 5- or 6- ofthe benzothiophene ring.
  41. 42. The compound according to daim 40 or 41, wherein R3 is hydrogen.
  42. 43. The compound according to any one of daims 40 to 42, wherein thesulfamate group is in position 6- of the benzothiophene ring.
  43. 44. The compound according to daim 41 which is the sulfamic acid, 1,2,3,4-tetrahydro-dibenzothiophene-7-yl ester
  44. 45. The compound according to daim 41 which is the sulfamic acid, 1,2,3,4-tetrahydro-dibenzothiophene-7-yl-l, 1-dioxide ester
  45. 46. A pharmaceutical composition comprising a compound according to one ofdaims 1 to 45, and a pharmaceutically acceptable carrier.
  46. 47. A compound according to one of daims 1 to 45 for use as a pharmaceutical.
  47. 48. The compound according to daim 47 for use as an inhibitor of steroidsulfatase.
  48. 49. Use of a compound according to one of daims 1 to 45 in the manufactureof a médicament for the treatment or prévention of estrogen-dependent disorders,wherein said compound is optionally combined with one or several sexual endocrinetherapeutic agents selected from the group consisting of antiestrogens, SERMs,antiaromatases, antiandrogens, lyase inhibitors, progestins and LK-RK agonists orantagonists.
  49. 50. Use of a compound according to one of daims 1 to 45 in the manufactureof a médicament for the control or management of reproductive functions, whereinsaid compound is optionally combined with one or several other therapeutic agents 013167 56 selected from the group consisting of LH-RH agonists or antagoniste,estroprogestative contraceptives, progestins, antiprogestins and prostaglandins.
  50. 51. Use of a compound according to one of daims 1 to 45 in the manufacture5 of a médicament for the treatment or prévention of benign or malignant diseases of the breast, the utérus or the ovary, wherein said compound is optionally combinedwith one or several sexual endocrine therapeutic agente selected from the groupconsisting of antiestrogens, SERMs, antiaromatases, antiandrogens, lyase inhibitors,progestins and LH-RH agoniste or antagoniste. 10
  51. 52. Use of a compound according to one of daims 1 to 45 in the manufactureof a médicament for the treatment or prévention of androgen-dependent diseases,benign or malignant diseases of the prostate or the testis, wherein said compoundis optionally combined with one or several sexual endocrine therapeutic agente 15 selected from the group consisting of antiandrogens, progestins, lyase inhibitors andLH-RH agoniste or antagoniste.
  52. 53. Use of a compound according to one of daims 1 to 45 in the manufactureof a médicament for the treatment or prévention of cognitive dysfunction. 20
  53. 54. Use of a compound according to one of daims 1 to 45 in the manufactureof a médicament for the treatment or prévention of immune fonctions.
OA1200500321A 2003-05-16 2003-05-16 Sulfamate benzothiophene derivatives as steroid sulfatase inhibitors. OA13167A (en)

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