WO1997044314A1 - Esters d'acide sulfamique n-acyle utilises en qualites d'agents hypocholesterolemiques - Google Patents

Esters d'acide sulfamique n-acyle utilises en qualites d'agents hypocholesterolemiques Download PDF

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Publication number
WO1997044314A1
WO1997044314A1 PCT/US1997/006725 US9706725W WO9744314A1 WO 1997044314 A1 WO1997044314 A1 WO 1997044314A1 US 9706725 W US9706725 W US 9706725W WO 9744314 A1 WO9744314 A1 WO 9744314A1
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Prior art keywords
phenyl
acetyl
diisopropyl
triisopropyl
sulfamic acid
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PCT/US1997/006725
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English (en)
Inventor
Helen Tsenwhei Lee
Joseph Armand Picard
William Howard Roark
Bruce David Roth
Drago Robert Sliskovic
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Warner-Lambert Company
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Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU27388/97A priority Critical patent/AU2738897A/en
Priority to US09/117,748 priority patent/US6093744A/en
Publication of WO1997044314A1 publication Critical patent/WO1997044314A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

  • This invention relates to chemical compounds having pharmacological activity, to pharmaceutical compositions which include these compounds, and to pharmaceutical methods of treatment using the compounds. More particularly, this invention concerns certain N-acyl sulfamic acid esters with improved physical properties which inhibit the enzyme and acyl- coenzyme A:cholesterol acyltransferase (ACAT) .
  • ACAT acyl- coenzyme A:cholesterol acyltransferase
  • the compounds of the instant invention show increased chemical stability over those of United States Patent No. 5,245,068.
  • the compounds of the instant invention show improved physical properties (such as aqueous solubility, decreased lipophilicity, and improved dissolution rates) over those disclosed in United States Patent No. 5,491,172.
  • acyl- CoA:cholesterol acyltransferase ACAT
  • therapeutic agents which effectively inhibit the action of ACAT prevent the intestinal absorption of dietary cholesterol into the blood stream or the reabsorption of cholesterol which has been previously released into the intestine through the body's own regulatory action.
  • the present invention relates to methods of using the novel compounds to lower plasma cholesterol and/or lipoprotein(a) , Lp(a) , and more particularly to methods and agents to lower their plasma concentrations to achieve therapeutic benefit.
  • the present invention is compounds of the formula
  • R 1 is hydrogen, alkyl, or alkoxy
  • R to R ⁇ " are alkyl, alkoxy, or unsubstituted or substituted phenyl
  • R is -CN-
  • R 13 is ( CH 2 ) 0-5" ⁇ " (CH 2 ) 0-5 2 ' or alkyl of from 1 to 20 carbons with from 1-3 double bonds, which alkyl is optionally substituted by one or more moieties selected from -CN,
  • R 7 and RR are each independently selected from: -hydrogen, at least one of R 7 and RR is other than hydrogen,
  • R and R are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl, or
  • R are taken together with the nitrogen to which they are attached to form a ring selected from:
  • R 17 and R 18 are each independently hydrogen, alkyl, phenyl, substituted phenyl, or the side chain of a naturally occurring amino acid; 1 q 1 q
  • R is alkyl, unsubstituted or substituted phenyl, naphthyl, or a heteroaromatic ring, or NR R or
  • R 7 and RR are taken together with the nitrogen to which they are attached to form a ring: - (CH 2 ) 2 -0- (CH 2 ) 2 -, - (CH 2 ) 2 -S- (CH 2 ) 2 -,
  • R is hydrogen or alkyl of from 1 to 4 carbon atoms; R ⁇ to R are each alkyl of from 1 to 4 carbon atoms; R 6 is -NR R 8 wherein R and R 8 are each independently selected from: hydrogen, at least one of R 7 and RR° is not hydrogen,
  • R is hydrogen
  • Other preferred compounds are those of Formula I wherein:
  • R is hydrogen or alkyl of from 1 to 4 carbon atoms; R ⁇ to R are each alkyl of from 1 to 4 carbon atoms; R 6 is NR 7 R 8 wherein R 7 and R 8 taken together with the nitrogen to which they are attached to form a ring:
  • R 14 and R 15 are each independently selected from hydrogen, alkyl, or phenyl, or
  • R 16 is hydrogen, alkyl, or phenyl. Still other perferred compounds are those of Formula I wherein: R is hydrogen or alkyl of from 1 to 4 carbon atoms;
  • R to R are each alkyl of from 1 to 4 ;
  • R f is NR7RR wherein one of R7 and RR is hydrogen and the other is S(0) 1 _ 2 R 19 .
  • R is hydrogen or alkyl of from 1 to 4 carbons, o 5 R ⁇ to R are alkyl of from 1 to 4 carbons, and
  • Still other preferred compounds are those of
  • R 1 is hydrogen or alkyl of from 1 to 4 carbon atoms
  • R 2 to R5 are alkyl of from 1 to 4 carbon atoms
  • R 6 is -0- (CH 2 ) X-X Q Z,
  • R 1 is hydrogen or alkyl of from 1 to 4 carbon atoms; to R5 are alkyl of from 1 to 4 carbon atoms;
  • the compounds of the invention are useful in treating cerebrovascular diseases such as stroke, peripheral vascular diseases, and restenosis. They are useful in lowering serum or plasma levels of Lp(a) . They are agents for regulating plasma cholesterol concentrations. The compounds are useful in treating hypercholesteremia and atherosclerosis.
  • compositions containing one or more of the compounds are also part of this invention.
  • Novel intermediates are also part of the invention.
  • the compounds of the present invention provide a novel class of N-acyl sulfamic acid esters (or thioesters) , N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) which are ACAT inhibitors, rendering them useful in pharmaceutical treatments.
  • the advantage of the instant invention is the improved physical properties which provide compounds suitable as pharmaceuticals.
  • illustrative examples of straight or branched carbon chains having from 1 to 10 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, and n-octyl.
  • Alkoxy means straight or branched groups having from 1 to 6 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, Jc-butoxy, and pentyloxy.
  • the natural (essential) amino acids are: valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, alanine, aginine, aspartic acid, cysteine, glutamic acid, glycine, histidine, proline, serine, tyrosine, asparagine, and glutamine.
  • Preferred natural amino acids are: valine, leucine, isoleucine, threonine, lysine, alanine, glycine, serine, asparagine, and glutamine.
  • Phenyl, naphthyl, and heteroaromatic rings are unsubstituted or substituted by from 1 to 5 substituents selected from alkyl of from 1 to
  • Heteroaromatic rings are, for example, 2-, 3-, or 4-pyridinyl; 2-, 4-, or 5-pyrimidinyl ; 2- or 3-thienyl; isoquinolines, quinolines, pyrroles, indoles, and thiazoles .
  • Preferred substituents are halogen, for example, fluoro and chloro, methoxy, and amino.
  • the base salts may be generated from compounds of Formula I by reaction of the latter with one equivalent of a suitable nontoxic, pharmaceutically acceptable base followed by evaporation of the solvent employed for the reaction and recrystallization of the salt, if required.
  • the compounds of Formula I may be recovered from the base salt by reaction of the salt with an aqueous solution of a suitable acid such as hydrobromic, hydrochloric, or acetic acid.
  • Suitable bases for forming base salts of the compounds of this invention include amines such as triethylamine or dibutylamine, or alkali metal bases and alkaline earth metal bases.
  • Preferred alkali metal hydroxides and alkaline earth metal hydroxides as salt formers are the hydroxides of lithium, sodium, potassium, magnesium, or calcium.
  • the class of bases suitable for the formation of nontoxic, pharmaceutically acceptable salts is well known to practitioners of the pharmaceutical formulation arts. See, for example, Berge SN, et al, ⁇ l_. Pharm. Sci . ,
  • Suitable acids for forming acid salts of the compounds of this invention containing a basic group include, but are not necessarily limited to acetic, benzoic, benzenesulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric, and tartaric acids.
  • the acid addition salts are formed by procedures well known in the art.
  • the compounds of the present invention may also exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compound.
  • the present invention contemplates all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures.
  • the compounds of this invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • Lp(a) The ability of the compounds of the present invention to lower Lp(a) is evaluated in the following procedure .
  • Nine male cynomolgus monkeys (Macaca fascicularis, 4-5 kg) are maintained on a standard monkey chow diet (containing less than 5% fat and only trace amounts of cholesterol) .
  • the diet is available daily from 9 AM until 2 PM.
  • These animals transport approximately equal amounts of cholesterol in HDL (47%) and LDL (51%) and have low triglycerides compared to humans (approximately 50 mg/dL) .
  • Five weekly blood samples are taken from anesthetized, restrained animals, and then the animals were dosed with the desired compound daily before meals (for 3 weeks at
  • the average baseline values for cholesterol and Lp(a) are calculated. Using these values, the percentage decreases for cholesterol and Lp(a) are known. It is important to note that every animal demonstrates a decrease in cholesterol and Lp(a) . The decrease in total cholesterol is due primarily to a decrease in LDL-cholesterol .
  • the compounds of the present invention are thus useful in pharmaceutical formulations for the treatment of stroke, peripheral vascular disease, and restenosis.
  • the compounds of Formula I or pharmaceutically acceptable salts thereof are administered to the patient at dosage levels of from 250 to 3000 mg per day. For a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 5 to 40 mg/kg of body weight per day.
  • the specific dosages employed, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
  • the compounds of the present invention are inhibitors of the enzyme acyl-CoA: cholesterol acyltransferase (ACAT) , and are thus effective in inhibiting the esterification and transport of cholesterol across the intestinal cell wall.
  • ACAT cholesterol acyltransferase
  • the compounds of the present invention are thus useful in pharmaceutical formulations for the treatment of hypercholesterolemia or atherosclerosis.
  • the test assesses the ability of a test compound to inhibit the acylation of cholesterol by oleic acid by measuring the amount of radiolabeled cholesterol oleate formed from radiolabeled oleic acid in a tissue preparation containing rat liver microsomes.
  • Plasma TC (dose Example in mg/kg)
  • Plasma TC (dose Example in mg/kg)
  • the compounds of Formula I or pharmaceutically acceptable salts thereof are administered to the patient at dosage levels of from 250 to 3000 mg per day. For a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 5 to 40 mg/kg of body weight per day.
  • the specific dosages employed, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, and cachets.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient .
  • Suitable carriers are magnesium dicarbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets or transdermal systems are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions, suspensions, or emulsions suitable for oral administration.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of these packaged forms.
  • amide compound (VII) of the present invention gives an amide compound (VII) of the present invention.
  • the amino compound (V) can also be reacted with activated sulfonyl compounds (LS (0) 2 R 12 wherein R 12 has the meaning defined in the scope of Formula I) to give sulfonamides (VIII) and with di-alkyl compounds (X(CH 2 ) 2 Z (CH 2 ) 2 X wherein Z is 0, S, NR, or CRR and X is halo, triflate, or other similar leaving groups known to those skilled in the art) to give the cyclic compounds (IX) .
  • the protecting group can be any of the groups known to those skilled in the art, such as silyl ethers, benzyl ethers, alkyl ethers, and acyl groups
  • N-chlorosulfonyl isocyanate at elevated temperatures, and quenched with water to give the sulfamate (XI) .
  • This is then coupled with the phenyl acetic acid analog (III) using standard coupling techniques (e.g., DCC, CDI, acid chloride, or mixed anhydride,) to give the compound (XII) .
  • Deprotection of the hydroxyl group gives the hydroxy compound (XIII) which can be functionalized to give the compounds of the present invention.
  • a 4-thiocyanato phenol (XVI) is reacted with N-chlorosulfonyl isocyanate at elevated temperatures, and quenched with water to give the sulfamate (XVII) .
  • This is then coupled with the phenyl acetic acid analog (III) using standard coupling techniques (e.g., DCC, CDI, acid chloride, or mixed anhydride) to give the thiocyanato compound of the present invention (XVIII) .
  • Hydrolysis of the thiocyanato group gives the thiol (XIX) which can be functionalized to give the compounds of the present invention.
  • alkylating with an activated alkyl group X- (CH 2 ) n NR 9 R 10 gives a thioether compound (XX) of the present invention.
  • XX is halo, triflate, or other similar leaving groups known to those skilled in the art, and n, R , and R have the meanings defined in the scope of this patent.
  • the thiocyanato compound (XVIII) can also be oxidized to give the sulfonic acid compound (XXII) which can be further functionalized by coupling with an activated alkyl group (X alkyl) to give the sulfonate ester (XXIII) or an amine (HNR 9 R 10 ) to give a sulfonamide (VXXIV) .
  • N-Chlorosulfonyl isocyanate (7.2 mL, 82.6 mmol) was added slowly to a warm solution of 2, 6-bis (1- methylethyl) -4-nitrophenol (17.57 g, 78.7 mmol) in 400 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice . and extracted with 4 x 500 mL dichloromethane. The organic solution was dried over MgSO ⁇ , filtered, and concentrated to give a tan solid. Recrystallization from dichloromethane gave 14.18 g (60%) of the title compound as an off-white solid; mp 163-167°C.
  • Oxalyl chloride (0.52 mL, 5.9 mmol) was added dropwise to a solution of 2, 4 , 6-tris (1-methylethyl) - phenyl acetic acid in 150 mL toluene with four drops N,N-dimethylformamide added as a catalyst. The resulting solution was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was redissolved in 200 mL dichloromethane with 2,6-bis(l- methylethyl) -4-nitrophenyl sulfamate (1.50 g, 4.9 mmol) and excess (3 mL) triethylamine and stirred for 16 hours.
  • Step (b) 2 6-Ri s (1 -methyl ethyl ) -4-cyanophenyl sul famate N-Chlorosulfonyl isocyanate (3.5 mL, 39.9 mmol) was added slowly to a warm solution of 2,6-bis(l- methylethyl) -4- (N- (1-methylethyl) carboxamide)phenol (5.0 g, 19.0 mmol) in 300 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with ethyl acetate.
  • N-Chlorosulfonyl isocyanate (21.6 mL, 248 mmol) was added slowly to a warm solution of 3 , 5-diisopropyl- 4-hydroxy-benzaldehyde (24.4 g, 118 mmol) in 500 mL toluene.
  • the resulting solution was heated to reflux for 4 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with ethyl acetate .
  • the organic solution was dried over magnesium sulfate, filtered, and concentrated to give a tan solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 11.15 g of the title compound as an off-white solid.
  • N-Chlorosulfonyl isocyanate (2.12 mL, 24.3 mmol) was added slowly to a warm solution of 3 , 5-diisopropyl- 4-hydroxy-benzoic acid methyl ester (5.47 g, 23.1 mmol) in 300 mL toluene.
  • the resulting solution was heated to reflux for 6 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a tan solid.
  • Oxalyl chloride (1.12 mL, 12.8 mmol) was added dropwise to a solution of 2, 4 , 6-triisopropylphenyl acetic acid (3.05 g, 11.6 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo. The residue was re-dissolved in 150 mL dichloromethane.
  • Monomethyl adipate (61 g, 350 mmol) was treated with excess oxalyl chloride in tetrahydrofuran. The mixture was concentrated, and the resulting acid chloride was mixed with 2, 6-Diisopropyl phenol (57 g, 350 mmol) at 0°C.
  • Aluminum chloride (93 g, 700 mmol) and a catalytic amount of 1, 2-dichloroethane were added in portions, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1 M HCI and extracted with ethyl acetate. Concentrated in vacuo and chromatographed the residue to give the expected product .
  • Sodium hydride 0.257 g, 6.4 mmol
  • 6- (4-hydroxy-3 , 5-diisopropyl-phenyl) -hexanoic acid ethyl ester (1.46 g, 5.0 mmol) in dimethylformamide (20 mL) at 0°C over about 3 minutes.
  • the cooling bath was removed, and the mixture was stirred at room temperature for 10 minutes.
  • N,N-Dicyclohexylcarbodiimide (0.63 g, 3.0 mmol) was added to a solution of [ (2, 4 , 6-Triisopropyl- phenyl) -acetyl] -sulfamic acid 4-amino-2 , 6-diisopropyl- phenyl ester (1.5 g, 2.9 mmol) and bis-N,N'- (t- butoxycarbonyl) - (S) -lysine (1.1 g, 2.9 mmol) in 100 mL of dichloromethane at -15°C under an atmosphere of nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours.
  • Step (b) 4- ftert-butyl -dimethyl -sil anyloxy) -2 , 6- di i snprnpylphennl 2, 6-Bis (1-methylethyl) -1,4-dihydroquinone (21.32 g, 109 mmol) and tert-butyl-dimethyl-silyl chloride (18.2 g, 121 mmol) were mixed in 300 mL dichloromethane at room temperature. Triethylamine (18.4 mL, 133 mmol) was added, and the resulting mixture was stirred for 3 days.
  • N-Chlorosulfonyl isocyanate (3.43 mL, 39.4 mmol) was added to a warm solution of 4- (tert-butyl-dimethyl- __ silanyloxy) -2, 6-diisopropylphenol (11.59 g, 37.6 mmol) in 400 mL toluene.
  • the resulting solution was heated to reflux for 6 hours and then cooled to room temperature and stirred overnight.
  • the reaction was concentrated in vacuo, and the residue was quenched with ice water and extracted with dichloromethane.
  • the organic layer was dried over magnesium sulfate, filtered, and concentrated to give an orange oil. Chromatography on silica gel gave 6.06 g of 4- (tert-butyl-dimethyl-silanyloxy) -2,6- diisopropylphenyl sulfamate as an orange oil .
  • Step (d) r (2 f 4 , 6-Tri i sopropyl-phenyl. ) -acetyl 1 -sul fami c acid 4- (tert-butyl -dimethyl -si 1 anyl nxy) -2 r 6- di i snpropyl -phenyl ester
  • Oxalyl chloride (2.45 mL, 28 mmol) was added dropwise to a solution of 2, 4 , 6-triisopropylphenyl acetic acid (5.66 g, 21.6 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst.
  • Step (e) [ ( 2 , 4 , 6-Tri i snprnpyl -phenyl ) -acetyl 1 -snl fami r- acid 4-hydroxy-2, 6 dii.snprnpyl -phenyl ester
  • a solution of 15 mL concentrated HF in 150 mL acetonitrile was added dropwise to a solution of [ (2, 4 , 6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (tert-butyl-dimethyl-silanyloxy) -2, 6-diisopropyl- phenyl ester (9.71 g, 15.4 mmol) in 400 mL acetonitrile at room temperature under a nitrogen atmosphere.
  • Step (f) [ 1 2 , 4 , 6-Tri isopropyl-phenyl ) -acetyl 1 -sul fami r ar-i d 4- (3 -dimethyl amino-prnpoxy) -2,6- di i sopropyl -phenyl ester
  • Step (a) r (2.4 , 6-Tri i snpropyl. -phenyl ) -acetyl 1 -sul fami r acid 4- (3-tert-butoxycarbonyl aminn-prnpnxy) - 2 , 6-di i snprnpyl -phenyl ester
  • This compound was prepared in the same manner as Example 14, except that 3-tert-butoxycarbonylamino- propyl alcohol was used in place of the triethylamine and 3-dimethylaminopropylchloride hydrochloride mixture.
  • Step (b) [ (2,4 t 6-Trii sopropyl-phenyl) -acetyl ⁇ -sul famic acid 4- (3-amino-propoxy) -2 , 6-di i soprnpyl - phenyl ester hydrochloride salt
  • Step (a) Sulfamic acid 2 , 6-di isopropyl -4-thi ncyanatn- phenyl ester N-Chlorosulfonyl isocyanate (1.02 mL, 11.7 mmol) was added to a warm solution of 2, 6-diisopropyl-4- thiocyanato-phenol (2.5 g, 10.6 mmol) m 150 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and stirred overnight. The reaction was concentrated in vacuo and the residue was quenched with ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1.75 g of sulfamic acid 2 , 6-diisopropyl-4-thiocyanato-phenyl ester as a white solid.
  • Step (b) [ ( 2 , 4 , 6-Tri i sopropyl -phenyl ) -acetyl 1 -snl fami ⁇ - ar-i d 2 , 6-di i sopropyl -4 -thi ocyanato-phenyl ester
  • Oxalyl chloride (0.6 mL, 6.9 mmol) was added dropwise to a solution of 2, 4 , 6-tri ⁇ sopropylphenyl acetic acid (1.52 g, 5.8 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo.
  • Step (a) [(2,4, 6-Tri i snpropyl -phenyl ) -acetyl 1 -sul fami r acid 4- faminomethylene) -2 , 6-di i sopropyl - phenyl ester [ (2,4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
  • 4-cyano-2, 6-diisopropyl-phenyl ester (5.15 g, 9.8 mmol) was dissolved in 100 mL of methanolic ammonia and 2.0 g of Raney-nickel was added. The resulting mixture was stirred under 50 psi of hydrogen at room temperature for 20 hours. Filtered and concentrated the residue to give a dark solid. Suspended in diethyl ether and acidified with HCl gas. Concentrated in vacuo and neutralized the residue with saturated aqueous sodium bicarbonate. The resulting white suspension was used without further purification.
  • Step (b) r ( 2.4.6-Tri i sopropyl -phenyl ) -acetyl 1 -snl fami r- aoi d 4- [ (2-amino-acetyl amino) -methyl 1 -2.6- rii isopropyl-pheny] ester
  • Oxalyl chloride (0.16 mL, 1.8 mmol) was added dropwise to a suspension of the carboxylic acid (0.9 g, 1.65 mmol) in 50 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred for 2 hours, and then concentrated in vacuo. The residue was re-dissolved in 30 mL of methanolic ammonia, and the resulting mixture was stirred overnight. Concentrated in vacuo and partitioned between 1 M HCl and ethyl acetate. Dried the organic layer over magnesium sulfate, filtered, and concentrated to give a white solid.
  • the layers are separated, the organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil.
  • the oil is chromatographed on silica gel (70-230 mesh) using hexanes/ethyl acetate, 1:1, v/v.
  • the product is obtained as a white solid from hexanes

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Abstract

La présente invention concerne de nouveaux composés correspondant à la formule générale (I) où R6 représente l'un des éléments suivants: -CN; -(CH¿2?)0-1-NR?7R8¿; -O-(CH¿2?)1-10-Z dans lequel Z représente -NR?9R10, OR1¿ ou CO¿2R?1; -OC(=O)R?11; -SR11¿; -SNC; -S(CH¿2?)1-10Z; -S(O)1-2R?12¿ dans lequel R12 représente hydroxy, alcoxy, alkyle, (CH¿2?)1-10Z ou NR?7R8¿; -C(=O)XR11; -CH2-R13 dans lequel R13 représente (CH¿2?)0-5-Y-(CH2)0-5Z ou un alkyle possédant de 1 à 3 liaisons doubles, étant entendu que cet alkyle peut être éventuellement substitué par un ou plusieurs éléments choisis dans le groupe -CN, NO2, halogène, OR?1, NR9R10¿ et CO¿2R?1. Cette invention concerne également l'utilisation de ces composés en qualité d'agents cérébrovasculaires dans des maladies comme les attaques, les maladies vasculaires périphériques et la resténose. Ces composés peuvent également être utilisés en qualité d'agents de régulation des concentrations de cholestérol dans le plasma, dans le traitement de l'hypercholestérolémie et de l'athérosclérose, ainsi que dans la réduction du niveau de Lp(a) dans le sérum ou le plasma. Cette invention concerne en outre une composition pharmaceutique.
PCT/US1997/006725 1996-05-17 1997-04-21 Esters d'acide sulfamique n-acyle utilises en qualites d'agents hypocholesterolemiques WO1997044314A1 (fr)

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US09/117,748 US6093744A (en) 1997-04-21 1997-04-21 N-acyl sulfamic acid esters useful as hypocholesterolemic agents

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US60/017,882 1996-05-17

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004086A1 (fr) * 1999-07-09 2001-01-18 Btg International Limited Composes de sulphamate
EP1236468A1 (fr) * 2001-02-12 2002-09-04 Warner-Lambert Company Des derivés de sulfonylaminocarbonyle utiles dans le traitement des maladies médiées par le facteur nucleaire kappa B

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5491172A (en) * 1993-05-14 1996-02-13 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5491172A (en) * 1993-05-14 1996-02-13 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004086A1 (fr) * 1999-07-09 2001-01-18 Btg International Limited Composes de sulphamate
EP1236468A1 (fr) * 2001-02-12 2002-09-04 Warner-Lambert Company Des derivés de sulfonylaminocarbonyle utiles dans le traitement des maladies médiées par le facteur nucleaire kappa B

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AU2738897A (en) 1997-12-09

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