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WO1997044314A1 - N-acyl sulfamic acid esters useful as hypocholesterolemic agents - Google Patents

N-acyl sulfamic acid esters useful as hypocholesterolemic agents 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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WO
WIPO (PCT)
Prior art keywords
phenyl
acetyl
diisopropyl
triisopropyl
sulfamic acid
Prior art date
Application number
PCT/US1997/006725
Other languages
French (fr)
Inventor
Helen Tsenwhei Lee
Joseph Armand Picard
William Howard Roark
Bruce David Roth
Drago Robert Sliskovic
Original Assignee
Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to US09/117,748 priority Critical patent/US6093744A/en
Priority to AU27388/97A priority patent/AU2738897A/en
Publication of WO1997044314A1 publication Critical patent/WO1997044314A1/en

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Classifications

    • 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

The instant invention is new compounds of formula (I), wherein R6 is -CN, -(CH¿2?)0-1-NR?7R8¿, -O-(CH¿2?)1-10-Z wherein Z is -NR?9R10, OR1¿, or CO¿2R?1, -OC(=O)R?11, -SR11¿, -SCN, -S(CH¿2?)1-10Z, -S(O)1-2R?12¿ wherein R12 is hydroxy, alkoxy, alkyl, (CH¿2?)1-10Z or NR?7R8¿, -C(=O)XR11, -CH2-R13 wherein R13 is (CH¿2?)0-5-Y-(CH2)0-5Z, or alkyl with from 1-3 double bonds, which alkyl is optionally substituted by one or more selected from -CN, NO2, halogen, OR?1, NR9R10¿, and CO¿2R?1; their use as cerebrovascular agents in diseases such as stroke, peripheral vascular disease, restenosis, and as agents for regulating plasma cholesterol concentrations, for treating hypercholesterolemia and atherosclerosis, and for lowering the serum or plasma level of Lp(a). A pharmaceutical composition is also claimed.

Description

N-ACYL SULFAMIC ACID ESTERS USEFUL AS HYPOCHOLESTEROLEMIC AGENTS
BACKGROUND OF INVENTION
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) .
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.
United States Patent Application 60/003,03 filed August 3, 1995, teaches other methods of using the compounds taught in Patent No. 5,491,172. Both of these are incorporated herein by reference. In recent years the role which elevated blood plasma levels of cholesterol plays in pathological conditions in man has received much attention. Deposits of cholesterol in the vascular system have been indicated as causative of a variety of pathological conditions including coronary heart disease .
Initially, studies of this problem were directed toward finding therapeutic agents which would be effective in lowering total serum cholesterol levels. It is now known that cholesterol is transported in the blood in the form of complex particles consisting of a core of cholesteryl esters plus triglycerides and a variety of types of protein which are recognized by specific receptors. For example, cholesterol is carried to the sites of deposit in blood vessels in the form of low density lipoprotein cholesterol (LDL cholesterol) and away from such sites of deposit by high density lipoprotein cholesterol (HDL cholesterol) . Following these discoveries, the search for therapeutic agents which control serum cholesterol turned to finding compounds which are more selective in their action; that is, agents which are effective in elevating the blood serum levels of HDL cholesterol and/or lowering the levels of LDL cholesterol. While such agents are effective in moderating the levels of serum cholesterol, they have little or no effect on controlling the initial absorption of dietary cholesterol in the body through the intestinal wall. In intestinal mucosal cells, dietary cholesterol is absorbed as free cholesterol which must be esterified by the action of the enzyme, acyl- CoA:cholesterol acyltransferase (ACAT) before it can be packaged into the chylomicrons which are then released into the blood stream. Thus, 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. SUMMARY OF THE INVENTION
The present invention is compounds of the formula
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof wherein:
R1 is hydrogen, alkyl, or alkoxy;
R to R~" are alkyl, alkoxy, or unsubstituted or substituted phenyl;
R is -CN-,
Figure imgf000005_0002
-O- (CH2) i-iθ-Z wherein Z is -NR9R10, OR 1 or
-OC(
Figure imgf000005_0003
-SR11, -SCN,
s hydroxy, alkoxy, alkyl,
Figure imgf000005_0004
-CH2-R13 wherein R13 is (CH2 ) 0-5"γ" (CH2) 0-52' 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,
NO- ,, halogen, OR1, NR9R10, and COoR1; wherein R 7 and RR are each independently selected from: -hydrogen, at least one of R 7 and RR is other than hydrogen,
- (CH2) ι_ιoz wnereln z is as defined above and R and R are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl, or
R
Figure imgf000006_0001
are taken together with the nitrogen to which they are attached to form a ring selected from:
- (CH2)2-0- (CH2)2, -(CH2)2-S- (CH2)2, - (CH2)2-CR14R15- (CH2) ι_2, and - (CH2)2-NR16- (CH2)2, wherein R14, R15, and R1 are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl ; -C(=Q)XR 11 wherein X is a bond or NH wherein Q is O or S, R x is hydrogen, alkyl, unsubstituted or substituted phenyl,
- (CH2) o-5"γ~ (CH2) 0-5Z wherein Z is as defined above and Y is phenyl or a bond;
-C(=0) -CR17R18Z; -C(=0)NHCR17R18Z wherein R17 and R18 are each independently hydrogen, alkyl, phenyl, substituted phenyl, or the side chain of a naturally occurring amino acid; 1 q 1 q
-S (O) i-2R wherein 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: - (CH2)2-0- (CH2)2-, - (CH2)2-S- (CH2)2-,
- (CH2) 2-CR14R15- (CH2) 1_2- ,
- (CH2) 2-NR ,1-L6Ό- (CH2) 2 ~ wherein R 14 R 15 and
R are as above. Preferred compounds of the invention 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; R6 is -NR R8 wherein R and R8 are each independently selected from: hydrogen, at least one of R 7 and RR° is not hydrogen,
-(CH2>1-10Z' -C(=Q)XR1:L, or
-S(0)1_2R19.
More preferred compounds are those of Formula I wherein
7
R is hydrogen and
R8 is -C(=0) CR17R18Z wherein Z is NH2 where one of R17 and R 1 R is the side chain of a naturally occurring amino acid and the other 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; R6 is NR7R8 wherein R7 and R8 taken together with the nitrogen to which they are attached to form a ring:
- (CH2) 2-0- (CH2)2 ~, -(CH2)2-S-(CH2)2-,
- (CH2) 2-CR14R15- (CH2) 2 ~ wherein R14 and R15 are each independently selected from hydrogen, alkyl, or phenyl, or
- {CH2)2-NR16- (CH2)2- wherein R16 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_2R19.
More preferred compounds are those of Formula I wherein
R is hydrogen or alkyl of from 1 to 4 carbons, o 5 Rώ to R are alkyl of from 1 to 4 carbons, and
R6 is -C(=0)XR1:L or -CH2R13.
Still other preferred compounds are those of
Formula I wherein: R1 is hydrogen or alkyl of from 1 to 4 carbon atoms; R 2 to R5 are alkyl of from 1 to 4 carbon atoms;
R6 is -0- (CH2) X-XQZ,
-0-C(=0)R1:L,
-SH, -SCN,
-S(CH2 ) 1_10 Z' or -S(0) ι_2R12 ■
Other preferred compounds are those of Formula I wherein R1 is hydrogen or alkyl of from 1 to 4 carbon atoms; to R5 are alkyl of from 1 to 4 carbon atoms;
Figure imgf000008_0001
Especially preferred are.
(S) - [5-tert-Butoxycarbonylammo-5- (3,5- dιιsopropyl-4- { [(2,4, 6-tnisopropyl-phenyl) - acetyl] sulfamoyloxy} -phenylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester;
(S) - [ (2, 4 , 6-Tnisopropyl-phenyl ) -acetyl] -sulfamic acid 4- (2, 6-dιammo-hexanoylamιno) -2,6-diisopropyl- phenyl ester dihydrochloride;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- (2-t-butoxycarbonylamιno-acetylammo) -2,6- dnsopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amιno-acetylammo) -2, 6-dιιsopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- (2-t-butoxycarbonylamιno-4-methylsulfanyl- butyrylammo) -2 , 6-diisopropyl-phenyl ester,
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amιno-4-methylsulfanyl-butyrylammo) -
2, 6-dnsopropyl-phenyl ester trifluoroacetate; 3- [3- (3 , 5-Diisopropyl-4- { [(2,4, 6-triisopropyl- phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
3- [3- (3 , 5-Diisopropyl-4- { [(2,4, 6-triisopropyl- phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [2-amino-3- (lH-indol-3-yl) -propionylamino] -2,6- diisopropyl-phenyl ester; [ (2 ,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- (5-amino-pentanoylamino) -2, 6-diisopropyl-phenyl ester trifluoroacetate (1 : 1) (salt) ;
(D) - [ (2, 4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-propionylamino) -2 , 6-diisopropyl-phenyl ester trifluoroacetate (1 : 1) (salt) ;
(L) - [ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-2-methyl-propionylamino) -2 , 6-diisopropyl- phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2 , 6-diisopropyl-phenyl ester; [ (2, 4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-amino-propoxy) -2, 6-diisopropyl-phenyl ester hydrochloride salt;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4-thiocyanato-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-cyano-2, 6-diisopropyl-phenyl ester; [ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [ (2-amino-acetylamino) -methyl] -2,6-diisopropyl-phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-formyl-2, 6-diisopropyl-phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-cyano-vinyl) -2, 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (benzylamino-methyl) -2 , 6-diisopropyl-phenyl ester mono hydrochloride;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4- (4-methyl-piperazin-l-ylmethyl) - phenyl ester, dihydrochloride;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-carbamoyl-2, 6-diisopropyl-phenyl ester;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-hydroxymethyl-2, 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-acetylamino-2, 6-diisopropyl-phenyl ester; [ (2,4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- (2-hydroxy-ethylamino) -2 , 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [bis- (2-hydroxy-ethyl) -amino] -2 , 6-diisopropyl-phenyl ester; [ (2, 4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- [3- (2 , 6-diisopropyl-phenyl) -ureido] -2 , 6-diisopropyl- phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4- (3-phenyl-ureido] -phenyl ester; [ (2, 4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
2, 6-diisopropyl-4- (3-phenyl-thioureido] -phenyl ester;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4- (thiophene-2-sulfonylamino) -phenyl ester; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5- dimethylamino-naphthalene-1-sulfonylamino) - 2, 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4-methanesulfonylamino-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2 , 6-diisopropyl-4-sulfamoyl-phenyl ester;
6- (3 , 5-Diisopropyl-4- { [(2,4, 6-triisopropyl-phenyl- acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester; and
6- (3 , 5-Diisopropyl-4- { [(2,4, 6-triisopropyl-phenyl- acetyl] sulfamoyloxy} -phenyl) -hexanoic acid.
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.
Pharmaceutical compositions containing one or more of the compounds are also part of this invention.
Novel intermediates are also part of the invention.
DETAILED DESCRIPTION
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. -lo¬ in Formula I above, 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
6 carbons, alkoxy, halogen, nitro, cyano, carboxylic acids and alkyl esters, amino, and hydroxyl.
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.
Pharmaceutically acceptable salts of the compounds of Formula I are also included as a part of the present invention.
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, ιl_. Pharm. Sci . ,
1977;66:1-19.
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.
Further, 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. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
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
30 mg/kg) by incorporating it into oatmeal cream pies (Little Debbie Snack Cakes, McKee Foods, Collegedale, Tennessee) . Tang breakfast beverage crystals (Kraft General Foods, Inc., White Plains, New York) , and additional cream filling is also added to individual servings. Most animals consume the drug-containing treat immediately since they are without food during the night. They are not given their daily meal until they have consumed the treat. Mean plasma cholesterol (top line) and Lp(a) (bottom line) values are calculated (all values in mg/dL) .
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. In therapeutic use as agents for treating 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. As shown by the data presented below in Table 1, 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. The compounds of the present invention are thus useful in pharmaceutical formulations for the treatment of hypercholesterolemia or atherosclerosis.
The ability of representative compounds of the present invention to inhibit ACAT was measured using an in vitro test more fully described in Field FJ,
Salone RG, Riochemioa ef Biophysica 1982;712:557-570. 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.
The data appear in Table 1 where they are expressed in IC50 values; i.e., the concentration of test compound required to inhibit the activity of the enzyme by 50%. TABLE 1. In Vitro Biological Data
Example LAI (μM)
2 >50 3 18
4 48
6 750
7 49
8 >50 9 24
10
11 >50
12 >50
13 >50 14 >50
15 >50
16 >50
17 29
18 >50 19 >50
20 43.2
21 44.6
22 22.8
23 50 24 43.8
25 38.5
26 30
27 43
28 43.8 29 33
30 20.3
31 37.4
32 31.1
33 10.6 34 45
35 50
36 19
37 >50 In one in vivo screen designated APCC, male Sprague-Dawley rats (200 to 225 g) were randomly divided into treatment groups and dosed at 4 PM with either vehicle (CMC/Tween) or suspensions of compounds in vehicle. The normal chow diet was then replaced with a high fat, high cholesterol diet (designated PCC) containing 0.5% cholic acid. The rats consumed this diet ad libitum during the night and were sacrificed at 8 AM to obtain blood samples for cholesterol analysis using standard procedures. Statistical differences between mean cholesterol values for the same vehicle were determined using analysis of variance followed by Fisher's least significant test. The results of this trial for representative compounds of the present invention appear in Table 2.
TABLE 2
APCC % Change in
Compound of
Plasma TC (dose Example in mg/kg)
1 +7 (1)
2 -60 (10)
3 -40 (30)
4 -65 (10)
6 -72 (10)
7 -30 (30)
8 -15 (10)
9 -25 (10)
10 -15 (10)
11 -19 (10)
12 -74 (10)
13 -8 (10)
14 -11 (10)
15 -26 (10)
16 -47 (10)
17 -46 (10)
18 -38 (10)
19 -16 (10) TABLE 2
APCC % Change m
Compound of
Plasma TC (dose Example in mg/kg)
20 -44 (10)
21 -35 (10)
22 -18 (10)
23 5 10)
24 -5 (10)
25 -54 (10)
26 -44 (10)
27 -
28 -48 (10)
29 -3 (10)
30 -30 (10)
31 -21 (10)
32 -60 (10)
33 -61 (10)
34 -13 (10)
35 - --
36 -17 (10)
37 -47 (10)
In therapeutic use as agents for treating hypercholesterolemia or atherosclerosis, 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.
For preparing the pharmaceutical compositions from the compounds of this invention, 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. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, 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.
The term "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. In a similar manner 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.
Preferably, the pharmaceutical preparation is in unit dosage form. In such 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.
GENERAL SYNTHETIC METHODS
Some intermediates for compounds of the present invention are readily obtainable using the methods set forth in Lee, et al . , United States Patent
No. 5,491,172. Thus, as shown in Scheme 1, a 4-nitro- phenol (I) is reacted with N-chlorosulfonyl isocyanate at elevated temperatures, and quenched with water to give the 4-nitro sulfamate (II) . This is then coupled with the phenyl acetic acid analog (III) using standard coupling techniques (e.g., DCC, CDI , acid chloride, and mixed anhydride) to give the compound (IV) . Simple reduction of the nitro group (Raney Nickel/hydrogen) gives the amino compound (V) which can be functionalized to give the compounds of the present invention. For example, alkylating with an activated alkyl group X- (CH2) nNR9R10 (where X is halo, triflate, or other similar leaving groups known to those skilled in the art, and n, R 7, and RR have the meanings defined in the scope of Formula I) gives a compound (VI) of the present invention. Similarly, reacting the amino compound (V) with an activated acyl group L-C(0)R
(where L is a group that activates carboxylic acid coupling reactions such as halo, imidazole, mixed anhydride, and R has the meaning defined in the scope of Formula I) gives an amide compound (VII) of the present invention. The amino compound (V) can also be reacted with activated sulfonyl compounds (LS (0) 2R 12 wherein R 12 has the meaning defined in the scope of Formula I) to give sulfonamides (VIII) and with di-alkyl compounds (X(CH2) 2Z (CH2) 2X 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) .
Synthesis of the corresponding oxygen analogs is shown in Scheme 2. A protected dihydroquinone (X)
(where 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) is treated with 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. For example, alkylating with an activated alkyl group X- (CH2) nNR9R10 (where X, n, R9, and R have the meanings defined in the scope of this patent) gives an ether compound (XIV) of the present invention. Similarly, reacting the hydroxy compound (XIII) with an activated acyl group L-C(0)R11 (where L is a group that activates carboxylic acid coupling reactions such as halo, imidazole, or mixed anhydride) gives an ester compound (XV) of the present invention. One method to obtain the sulfur analogs of the present invention is shown in Scheme 3. 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. For example, alkylating with an activated alkyl group X- (CH2) nNR9R10 (where X 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) gives a thioether compound (XX) of the present invention. Oxidation of the thioether (XX) gives the sulfoxide (XXI, m = 1) or sulfone (XXI, m = 2) . 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 (HNR9R10) to give a sulfonamide (VXXIV) .
Scheme 1
VIII
Scheme 2
Figure imgf000024_0001
Scheme 3
Figure imgf000025_0001
Synthesis of 2.6-b.i s (1-methylethyl ) -4-ni trophanyl wnl famat.e
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.
Synthesis of r t ?. , 4 , 6-Tri i sopropyl -phenyl ) -acptyl ] - sulfamic acid 2 r 6-di i sopropyl -4-ni frn-phpnyl estpr
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. The reaction was washed with 1 M HCI, dried over MgSO , filtered, and concentrated to give an oily solid. Recrystallization from hexanes gave 2.37 g (87%) of the title compound as a white solid; mp 85-89°C.
Synthesis nf [ f2 , 4 , 6-Tri i sopropy] -phenyl) -acety] 1 - sulfamic acid 4-ami nn-2 , 6-di i πnpropyl -pheny]—ester 22.0 g of [ (2, 4 , 6-Triisopropyl-phenyl) -acetyl] - sulfamic acid 2, 6-diisopropyl-4-nitro-phenyl ester and 6 g of Raney nickel were mixed in 110 mL tetrahydrofuran under 50 psi of hydrogen. After 21 hours, the reaction was filtered and concentrated to give an orange oil which was dissolved in ethyl acetate, filtered through a pad of silica, and concentrated to give an oily solid. Recrystallization from 5% diethyl ether/hexanes gave 18.60 g (89%) of the title compound as a cream colored solid; mp 153-155°C.
Synthesis of 2 r 6-Ri s (1 -methyl ethyl ) -4-cyannphpnyl ■sulfamate
Step (a) 2 ,6-Bifid -methylethyl ) -4- ( N- (1 - methylethyl ) carhoxami de) phenol 4-Cyanophenol (40.0 g, 336 mmol) was added in portions to a mixture of isopropanol (103 mL, 1.34 mol) and 80% sulfuric acid (300 mL) at 70°C. Heated for 20 hours then cooled to room temperature and quenched with ice. The resulting suspension was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and concentrated to give a green oil. Chromatography on silica gel (30% ethyl acetate/hexanes) gave 46.0 g of 2 , 6-bis (1-methylethyl) - 4- (N- (1-methylethyl) carboxamide)phenol as a white solid; mp 165-167°C.
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. 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 1.20 g of the title compound as an off-white solid.
_ Synthesis of 2.6-Ri s (1 -methylethyl ) -4 -formylphenyl πu] famate
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.
Synthesis of 3 , 5-Di isopropyl -4 - { f (2.4.6 -1ri i sopropyl - phenyl) -acetyl ] sul famoyloyy} -hen7:oi c acid mpthyl ester
Step (a) 3.5-RisM -methylethyl ) -4-
(sul famoyloxy) benzoi c acid methyl est.pr
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. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 3.58 g of the title compound as an off-white solid. Step (b) 3 , 5-Di i soprnpyl -4- { f (2.4 , 6-triisopropyl- phenyl ) -acetyl ] sul famoyl oxy} -benzoi c aci d methyl ester
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. 3 , 5-Bis (1-methylethyl) -4- (sulfamoyloxy) benzoic acid methyl ester (3.48 g, 11.6 mmol) and triethylamine (4.0 mL) were added and the resulting mixture was stirred for 2 hours. Washed with 1 M HCI, dried the organic layer over magnesium sulfate, filtered, and concentrated to give an off- white foam. Recrystallized (hexanes) to give 5.21 g of the title compound as a white solid; mp 144-146°C.
Synthesis of 6- f3 f 5-Di i soprnpyl -4-sulfamoyl oxy-phenyl ) - hexanoic aciH ethyl ester
Step (a) 6- (4-Hydroxy-3 , 5-di i soprnpyl -phenyl ) -6-nxn- hexannio acid ethyl estfir
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 . Step (b) 6- (4-Hydroxy-3 , 5-di i soprnpyl -phenyl ) -hexanni r acid ethyl ester Boron trifluoride diethyl etherate (4.8 mL, 39 mmol) was added to a mixture of 6- (4-hydroxy-3 , 5- diisopropyl-phenyl) -6-oxo-hexanoic acid ethyl ester (13.19 g, 39.4 mmol) and ethanedithiol (3.5 mL, 39.3 mmol) in dichloromethane (100 mL) , and the resulting deep red mixture was stirred overnight at room temperature. An additional amount of boron trifluoride diethyl etherate (1.2 mL, 10 mmol) was added, and the reaction mixture was stirred an additional 4 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, and the organic solution was dried over magnesium sulfate, filtered, and concentrated to an orange oil. The oil was chromatographed on silica gel (70-230 mesh) using 19:1, then 9:1, then 83:17 hexanes/ethyl acetate, v/v, as eluant . A mixture of this dithioketal (3.65 g, 8.9 mmol) , Raney nickel (41 g of a slurry in water) , and ethanol (250 mL) is heated to 50°C for 2.5 hours under nitrogen. No starting material remained by tic. The ethanol was decanted from the nickel and the nickel washed and decanted twice with ethanol . The combined ethanol solutions were passed through celite, the ethanol evaporated, and the residue chromatographed on silica gel (70 230 mesh) using 4:1, hexanes/ethyl acetate as eluant. The product was obtained as a yellow oil in two portions, 2.95 g. CI Mass Spectrum: [M + H+] + = 320.
Step (c) 6- f3 , 5-Di i soprnpyl -4-sul famoyloxy-phenyl ) - hexannic acid ethyl ester Sodium hydride (0.257 g, 6.4 mmol) was added to 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. The reaction mixture was cooled to zero degrees and sulfamoyl chloride (1.18 g, 10.3 mmol) was added over ~3 minutes. The reaction mixture was stirred 1.5 hours at zero degrees and was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture is diluted with diethyl ether (300 mL) and water (100 mL) . The organic layer is washed with water (3 x 100 mL) , brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The oil is chromatographed on silica gel using 4:1 hexanes/ethyl acetate as eluant. The title compound is obtained as a light yellow oil, 1.29 g. CI Mass Spectrum: [M + H+] + = 400.
EXAMPLE 1
Synthesis of (S) - [5-tert -Rutnxycarbnnyl amirιo-5- (3,5- di i sopropyl -4- { [(2,4, 6-tri i snprnpyl -phenyl ) -acetyl 1 - sul famnyl nxy} -phenyl carhamoyl ) -pentyl 1 -carhami c aci d tert-butyl ester
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. The reaction was filtered, concentrated, and chromatographed on silica gel to give an oily solid. Recrystallization from 5% diethyl ether/hexanes gave 1.61 g (66%) of the title compound as a white solid; mp 167-171°C. EXAMPLE 2
Synthesis of (S) - T (2.4 r 6-Tri i soprnpyl -phenyl ) -acetyl ] - sulfamic acid 4- ( 2 , fi-di aminn-hexannyl ami no) -2 , 6- di i snpropyl -phenyl ester dihydrochloride HCI (g) was bubbled through a solution of
(S) - [5-tert-butoxycarbonylamino-5- (3 , 5-diisopropyl-4- { [(2,4, 6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} - phenylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester (1.08 g, 1.3 mmol) in 150 mL methanol for 30 minutes. The reaction was concentrated, and the resulting foam was triturated with 5% dichloromethane/hexanes to give 0.88 g (96%) of the title compound as a tan solid; mp 172-179°C.
EXAMPLE 3
Synthesis of r f3 , 5-Di i snpropyl -4-{ [(2.4,6-trii soprnpyl - phenyl ) -acetyl 1 sul famnyl nxy} -phenyl carbamoyl ) -methyl ] - rarhamic acid tert-butyl—esf.fir
When in the procedure of Example 1, bis-N,N'- (t-butoxycarbonyl) - (S) -lysine is replaced with N-(t- butoxycarbonyl) -glycine, the title compound is obtained; mp 177-188°C.
EXAMPLE 4 Synthesis nf r f2, 4 , 6-Tr-i i soprnpyl -phenyl ) -acetyl 1 - sulfamic acid 4- (2-aminn-acetyl ami no) -2.6-di i snpropyl - phenyl ester
When in the procedure of Example 1, bis-N,N'-
(t-butoxycarbonyl) - (S) -lysine is replaced with N- (9-fluorenylmethyoxycarbonyl) -glycine, and the crude product is stirred in 20% piperidine/N,N-dimethyl- formamide for 0.5 hours and purified by chromatography, the title compound is obtained. EXAMPLE 5
Synthesis of [ (2,4, 6-Triisopropyl -phenyl) -acetyl] - sulfamic acid 4- ( 2-t-bntnxycarhnnyl amino-4- methyl sul fanyl -butyryl amino) - 2 , 6-di isopropyl -phenyl ester When in the procedure of Example 1, bis-N,N'-
(t-butoxycarbonyl) - (S) -lysine is replaced with N- (t- butoxycarbonyl) -methionine, the title compound is obtained.
EXAMPLE 6
Synthesis nf [ ( 2, 4 f 6-Tri i snprnpyl -phenyl ) - acetyl 1 -sul famic acid 4- ( 2-amino-4-methyl sul fanyl - butyryl amino) -2 , 6-di isopropyl -phenyl ester tri flunrnacetate (2 , 4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4- (2-t-butoxycarbonylamino-4-methylsulfanyl- butyrylamino) -2, 6-diisopropyl-phenyl ester (0.2 g, 0.3 mmol) was dissolved in 30 mL 50% trifluroacetic acid/dichloromethane and stirred for 15 minutes. The title compound was isolated as an off-white solid.
EXAMPLE 7 Synthesis nf 3- T3- (3 , 5-Di i soprnpyl -4- { T (2 , 4.6- triisopropyl -phenyl) -acetyll sul famoyl oxy} -phenyl ) - ureidn] -propionic acid ethyl ester
Ethyl 3-isocyanatopropionate (0.29 g, 2.0 mmol) was added to a solution of [ (2,4, 6-triisopropyl- phenyl) -acetyl] -sulfamic acid 4-amino-2, 6-diisopropyl- phenyl ester (1.0 g, 1.9 mmol) in 50 mL dichloromethane under a dry air atmosphere. Stirred for 6 hours, concentrated in vacuo, and triturated the residue with 5% ethyl acetate in hexanes to give 1.04 g of the title compound as an off-white solid, mp 182-185°C. EXAMPLE 8 Synthesis of 3- T3- (3.5-Di i snpr-npy! -4- { r (2 , 4.6- tri i snpropyl-phenyl ) -acetyl ] sul famoyloxy} -phenyl ) - ureidnl -propinni c acid 3- [3- (3 , 5-Disopropyl-4- { [(2,4, 6-triisopropyl- phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester (0.54 g, 0.84 mmol) was suspended in 50 mL of 70% ethanol and 1.7 mL of 1M NaOH was added. The resulting mixture was stirred overnight, washed with diethyl ether, acidified with concentrated HCI, and extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered, and concentrated to leave an oily solid which was triturated with 50% ethyl acetate in hexanes to give the title compound as a white solid, mp 179-181°C.
EXAMPLE 9
Synthesis Qf r (2 f 4 , 6-Tri i sopropyl -phenyl ) -acetyl ] - sulfamic acid 4- r2-amino-3- (1 H-i ndol -3-yl ) - prnpinnyl aminol-2f6-dii snprnpyl -phenyl ester
When in the procedure of Example 1, bis-N,N'-(t- butoxycarbonyl) - (S) -lysine is replaced with N-(9- fluorenylmethyoxycarbonyl) -tryptophan, and the crude product is stirred in 20% piperidine/N,N- dimethylformamide for 0.5 hours and purified by chromatography, the title compound is obtained.
EXAMPLE 10 Synthesis nf [(2 , 4 , 6-Tri i snprnpyl -phenyl ) -acetyl 1 - sulfamic acid 4- (5-amino-pentanoyl amino) -2.6- di i sopropyl -phenyl ester tri f1uoroacetate (1 : 1) (salt)
When in the procedure of Example 1, bis-N,N'- (t-butoxycarbonyl) - (S) -lysine is replaced with N- (t-butoxycarbonyl) -5-aminopentanoic acid, and the t-butoxycarbonyl protecting group is removed by stirring for 15 minutes in a 50% trifluoroacetic acid solution in dichloromethane, the title compound is obtained.
EXAMPLE 11 Synthesis nf (Ω) - \ ( 2 r 4 , 6-Tri i sopropyl -phenyl ) -acetyl 1 - sulfamic acid 4- (2-ami nn-prnpinnyl ami nn) -2 , 6- di i soprnpyl -phenyl ester tri fluoroacetate (1 : 1 ) (salt)
When in the procedure of Example 1, bis-N,N'~(t- butoxycarbonyl) - (S) -lysine is replaced with N- (t- butoxycarbonyl) - (D) -alanine, and the t-butoxycarbonyl protecting group is removed by stirring for 15 minutes in a 50% trifluoroacetic acid solution in dichloromethane, the title compound is obtained.
EXAMPLE 12
Synthesis of (T,) - \ ( 2. , 4 , 6-Tri i sopropyl -phenyl ) -acetyl ] - sulfamic acid 4- (2-ami no-propiαnylammo) -2 r 6- di i soprnpyl -phenyl ester
When in the procedure of Example 1, bιs-N,N'- (t-butoxycarbonyl) - (S) -lysine is replaced with
N- (9-fluorenylmethyoxycarbonyl) - (L) -alanine, and the crude product is stirred in 20% piperidme/ N,N-dimethylformamide for 0.5 hours and purified by chromatography, the title compound is obtained.
EXAMPLE 13 Synthesis of f ( 2 , 4 , 6-Tri i snprnpyl -phenyl ) -acetyl ] - sulfamic acid 4- (2-ami no-2-methyl -propi nnyl ami nn) - 2 , 6- diisopropyl -phenyJ ester When in the procedure of Example 1, bis-N,N'-
(t-butoxycarbonyl)- (S) -lysine is replaced with N- (9-fluorenylmethyoxycarbonyl) - (alpha-methyl) alanine, and the crude product is stirred in 20% piperidme/ N,N-dιmethylformamide for 0.5 hours and purified by chromatography, the title compound is obtained. EXAMPLE 14 Synthesis of [ ( 2 , 4 , 6-Tri i sopropyl -phenyl ) -acetyl ] - sulfamic acid 4- (3-dimethylamino-propoxy) -2 r 6- di i snprnpyl -phenyl ester Step (a) 2 r 6-Ri s (1 -methylethyl ) -1.4 -di hydmqui nnηp A solution of potassium persulfate (30.33 g, 112 mmol) in 250 mL water was added dropwise over 1 hour to a solution of 2, 6-bis (1-methylethyl) phenol (20.0 g, 112 mmol) in 250 mL 10% aqueous sodium hydroxide at 0°C. The resulting dark mixture was warmed to room temperature and stirred overnight. Neutralized to pH 7.0 with concentrated HCl and washed with diethyl ether. The aqueous layer was acidified with additional concentrated HCl and heated on a steam bath for 0.5 hour. Cooled to room temperature and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 10.5 g of 2 , 6-bis (1-methylethyl) - 1, 4-dihydroquinone as a dark oil which solidified upon standing.
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. The reaction was washed with 1M HCl, and the organic layer was dried over magnesium sulfate, filtered, and concentrated to give 20.24 g of 4- (tert-butyl-dimethyl-silanyloxy) - 2 , 6-diisopropyl-phenol as an orange oil. Step (c) 4- (tert-butyl -dimethyl-si 1anyl nxy) - 2 , 6- di i snprnpylphenyl sul famate
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 (2f 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. The resulting solution was stirred for 6 hours and then concentrated in vacuo. The residue was redissolved in 150 mL dichloromethane. 4- (Tert-butyl-dimethyl- silanyloxy) -2, 6-diisopropylphenyl sulfamate (8.36 g, 21.6 mmol) and triethylamine (7.5 mL, 54 mmol) were added, and the resulting mixture was stirred overnight. Washed with 1M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give 9.86 g of [ (2,4, 6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (tert-butyl-dimethyl-silanyloxy) -2,6- diisopropyl-phenyl ester. 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. Stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Trituration with hexanes gave 7.24 g of [ (2,4, 6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-hydroxy-2, 6-diisopropyl-phenyl ester as a white solid; mp 182-183°C.
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
Solid sodium hydride (0.16 g, 4 mmol) was added to a solution of [ (2,4 , 6-triisopropyl-phenyl) -acetyl] - sulfamic acid 4-hydroxy-2, 6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) in 50 mL of N,N-dimethylformamide. The resulting mixture was stirred for 1 hour before a mixture of triethylamine (1.08 mL, 7.8 mmol) and 3-dimethylaminopropylchloride hydrochloride (1.22 g, 3.9 mmol) in 75 mL tetrahydrofuran was added dropwise. The resulting mixture was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between saturated citric acid and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Trituration with a small amount of diethyl ether gave 0.36 g of [(2, 4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2 , 6-diisopropyl-phenyl ester as a white foam.
EXAMPLE 15 synthesis nf [ ( 2 ,4 , 6-Tri i sopropyl-phenyl) -aπef.yl ] - sulfamic acid 4- (3-dimethylamino-propoxy) -2 , 6- di i snprnpyl -phenyl ester hydrnchl nride salt
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2, 6-diisopropyl-phenyl ester (0.2 g) was suspended in 50 mL of diethyl ether and HCl (g) was bubbled through the solution for 15 minutes. The solution was concentrated in vacuo to give [(2,4, 6-triisopropyl-phenyl) -acetyl] -sulfamic acid-4- (3-dimethylamino-propoxy) -2 , 6-diisopropyl-phenyl ester hydrochloride salt as a white foam.
EXAMPLE 16 Synthesis nf [ (2 , 4 , fi-Tri i sopropyl -phenyl ) -acetyl ] - sulfamic acid 4- (3-amino-propoxy) -2 , 6-di i sopropyl - phenyl ester hydrochloride salt
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 λ -sul famic acid 4- (3-amino-propoxy) -2 , 6-di i soprnpyl - phenyl ester hydrochloride salt
HCl (g) was bubbled through a solution of [(2,4,6- triisopropyl-phenyl) -acetyl] -sulfamic acid 4-(3-tert- butoxycarbonylamino-propoxy) -2, 6-diisopropyl-phenyl ester in 150 mL methanol for 15 minutes. Concentrated in vacuo and triturated the residue with 50% diethyl ether in hexanes to give [ (2, 4 , 6-trnsopropyl-phenyl) - acetyl] -sulfamic acid 4- (3-amino-propoxy) -2 , 6- diisopropyl-phenyl ester hydrochloride salt as an off- white solid.
EXAMPLE 17
Synthes i s of f ( ? , 4 , 6 -Tri i sopropyl -phenyl ) - a cetyl 1 - sulfamic acid 2 , 6-di i soprnpyl-4-thiocyanato-phenyl ester
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-triιsopropylphenyl 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. The residue was redissolved in 150 mL dichloromethane. Sulfamic acid 2 , 6-diisopropyl- 4-thiocyanato-phenyl ester (1.70 g, 5.8 mmol) and triethylamine (2.0 mL) were added, and the resulting mixture was stirred for 2 hours. Washed with 1M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give 2.24 g of [(2,4,6- triisopropyl-phenyl) -acetyl] -sulfamic acid
2, 6-diisopropyl-4-thiocyanato-phenyl ester as a white solid; mp 164-165°C.
EXAMPLE 18 Synthesis nf [ ( 2 ,4 f 6-Tri i snprnpyl -phenyl ) -acetyl 1 - sulfamic acid 4-cyann- 2 , 6-di i snpropyl -phenyl—P.St.er Oxalyl chloride (0.48 mL, 5.5 mmol) was added dropwise to a solution of 2, 4 , 6-triisopropylphenyl acetic acid (1.21 g, 4.6 mmol) in 100 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. 2, 6-Bis (1-methylethyl) -4- cyanophenyl sulfamate (1.30 g, 4.6 mmol) and triethylamine (1.6 mL) were added, and the resulting mixture was stirred for 6 hours. Washed with 1 M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/ hexanes) gave 1.11 g of the title compound as a white solid; mp 79-84°C.
EXAMPLE 19 Synthesis nf [( 2 f 4 , 6-Tri i sopropyl -phenyl ) -acetyl ] - sulfamic acid 4- f (2-amino-acetyl amino) -methyl 1 -2 , 6- di i snprnpyl -phenyl ester
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
When in the procedure of Example 1, bis-N,N'-(t- butoxycarbonyl) - (S) -lysine is replaced with N-(9- fluorenylmethyoxycarbonyl) -glycine, [(2,4,6- triisopropyl-phenyl) -acetyl] -sulfamic acid 4-amino-2,6- diisopropyl-phenyl ester is replaced by [(2,4,6- triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (aminomethylene) -2, 6-diisopropyl-phenyl ester, and the crude product is stirred in 20% piperidine/N,N- dimethylformamide for 0.5 hours followed by trituration with hexanes, the title compound is obtained; mp 193-195°C.
EXAMPLE 20 Synthesis of [ ( 2 , 4 , 6-Tri i sopropyl -phenyl ) -acetyl 1 - sulfamic acid 4-formyl -2.6-di i sopropyl -phenyl—ester When in the procedure of Example 8, 2, 6-Bis (1- methylethyl) -4-cyanophenyl sulfamate is replaced with 2, 6-bis (1-methylethyl) -4-formylphenyl sulfamate, the title compound is obtained; mp 71-76°C. EXAMPLE 21 Synthesis of [ (2 , 4 , 6-Tri i sopropyl -phenyl) -acetyl 1 - sulfamic acid 4-(2-cyano-vinyl) -2 , 6-diisopropyl -phenyl ester Diethylcyanomethyl phosphonate (1.49 mL, 9.2 mmol) was added dropwise to a suspension of sodium hydride (0.37 g, 9.2 mmol) in 20 mL tetrahydrofuran at 0°C. After 15 minutes, the reaction was cooled to -78°C and a solution of [ (2,4 , 6-triisopropyl-phenyl) -acetyl] - sulfamic acid 4-formyl-2 , 6-diisopropyl-phenyl ester
(2.32 g, 4.4 mmol) in 75 mL tetrahydrofuran was added dropwise. The reaction was allowed to warm to room temperature overnight and then concentrated in vacuo and partitioned the residue between 1 M HCl and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.16 g of the title compound as a white solid; mp 157-160°C.
EXAMPLE 22
Synthesis of f (2 , 4 , 6-Triisopropyl -phenyl ) -acetyl ] - sulfamic acid 4- (benzylami nn-methyl ) -2 , 6-di i sopropyl - phenyl ester mono hydrochloride [ (2, 4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4-formyl-2, 6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) , benzylamine (0.21 mL, 1.9 mmol) , and sodium triacetoxyborohydride (0.56 g, 2.6 mmol) were mixed in 100 mL of dichloromethane under a dry air atmosphere for 16 hours. Quenched by adding saturated sodium bicarbonate (50 mL) . The resulting white solid was collected by filtration and resuspended in diethyl ether. HCl gas was bubbled through for 30 minutes, and the resulting solution was concentrated in vacuo to give the title compound as a white solid; mp 179-183°C. EXAMPLE 23 Synthesis of [ (2 , 4 , 6-Tri i snprnpyl -phenyl ) -acetyl ] - sulfamic acid 2 , 6-di i snprnpyl -4- (4-methyl -piperaτ:in-1 - ylmethyl ) -phenyl ester, dihydrochloride When in the procedure of Example 22, benzylamine is replaced with 1-methyl piperazine, the title compound is obtained; mp 166-172°C.
EXAMPLE 24 Synthesis of [ (2,4 , 6-Triisopropyl-phenyl ) -acetyl ] - sulfamic acid 4-carbamnyl -2, 6-di i snprnpyl -phenyl ester
3 , 5-Diisopropyl-4- { [(2,4,6-triisopropyl-phenyl) - acetyl] sulfamoyloxy} -benzoic acid methyl ester (3.13 g, 5.6 mmol) was dissolved in a 3:1 methanol/1 M. NaOH solution and stirred for 16 hours, concentrated in vacuo, and partitioned the residue between water and diethyl ether. The aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate to give 2.85 g of the carboxylic acid as an off-white solid. 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. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.17 g of the title compound as a white foam. EXAMPLE 25 synthesis nf [(2,4, 6-Triisopropyl-phenyl) -acetyl] - sulfamic acid 4-hydroxymethyl -2 r 6-di i sopropyl -phenyl ester 3.9 mL of a 1 M solution of diisobutyl aluminum hydride in dichloromethane was added to a solution of 3 , 5-Diisopropyl-4- { [(2,4, 6-triisopropyl-phenyl) - acetyl] sulfamoyloxy} -benzoic acid methyl ester (1.0 g, 1.8 mmol) in 125 mL dichloromethane at -78°C. After 3 hours, the reaction was' warmed to room temperature and then quenched with a saturated aqueous sodium sulfate solution. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give a white foam. Triturated with 10% diethyl ether/hexanes to give 0.29 g of the title compound as a white solid; mp 163-168°C.
EXAMPLE 26 Synthesis nf [(2,4, 6-Tri i sopropyl -phenyl ) -acetyl ] - sulfamic acid 4-acetyl ami nn-2 , 6-di i snpropyl -phenyl ester
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-amino-2, 6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) was mixed with 0.54 mL (3.8 mmol) of triethyl amine in 50 mL of tetrahydrofuran at room temperature. Acetyl chloride (0.14 mL, 1.9 mmol) was added, and the resulting suspension was stirred overnight. Concentrated in vacuo and partitioned the oily residue between 1 M HCl and dichloromethane . Dried the organic layer over magnesium sulfate, filtered, and concentrated to give an orange foam. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.56 g of the title compound as a white solid; mp 203-205°C. EXAMPLE 27
Synthes i s of f ( 2 , 4 , 6 - Tri i snpropyl -phenyl ) - a cetyl 1 - su l f ami c acid 4 - ( 2 - hydroxy- ethyl ami no ) - 2. , 6 - d i i soprnpyl - phenyl ester [ (2,4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid
4-amino-2, 6-diisopropyl-phenyl ester (1.0 g, 1.9 mmol) was suspended in 50 mL of 1:1 glacial acetic acid/water and a stream of ethylene oxide was bubbled in for 15 minutes. The reaction mixture was sealed and allowed to stir overnight. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. Dried the organic layer over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.07 g of the title compound as a tan solid; mp 149-152°C.
EXAMPLE 28
Synthesis nf [(2 , 4 , 6-Tri i snpropyl -phenyl ) -acetyl ] - sulfamic acid 4- fbi s- ( 2-hydrnxy-ethyl ) -aminnl - 2 , 6- di i snprnpyl -phenyl ester
When in the procedure of Example 27, glacial acetic acid is used instead of a glacial acetic acid/water mixture and it is heated to 50°C in a sealed tube for 15 hours, the title compound is obtained; mp 143-146°C.
EXAMPLE 29 Synthesis of [(2,4, 6-Tri i sopropyl -phenyl ) -acetyl 1 - sulfamic acid 4- T3- (2 , 6-di i soprnpyl-phenyl) -ureidn] -
2f 6-di i soprnpyl -phenyl ester
When in the procedure of Example 7, ethyl 3-isocyanatopropionate is replaced with
2, 6-diisopropylphenyl isocyanate, the title compound is obtained; mp 133-135°C. EXAMPLE 30 Synthesis nf [ (2, 4 , 6-Tri i snprnpyl -phenyl.) -acetyl 1 - sulfamic acid 2 , 6-di i sopropyl -4- (3-phenyl-ureidol - phenyl ester When in the procedure of Example 7, ethyl
3-isocyanatopropionate is replaced with phenyl isocyanate, the title compound is obtained; mp 185-187°C.
EXAMPLE 31
Synthesis of [(2,4, 6-Tri,isopropyl -phenyl) -acetyl ] - sulfamic acid 2 , 6-di i sopropyl -4- (3-phenyl -thinurei dn] - phenyl ester
When in the procedure of Example 7, ethyl 3-isocyanatopropionate is replaced with phenyl isothiocyanate, the title compound is obtained; mp 173-175°C.
EXAMPLE 32 Synthesis nf [(2 , 4 , 6-Tri i snprnpyl -phenyl ) -acetyl 1 - sulfamic acid 2,6 di i snprnpyl -4- (thiophene-2- sul fonylamino) -phenyl ester
When in the procedure of Example 26, acetyl chloride is replaced with thiophene-2-yl sulfonyl chloride, the title compound is obtained.
EXAMPLE 33 Synthesis nf [( 2 , 4 , 6-Tri i snprnpyl -phenyl ) -acetyl ] - sulfamic acid 4- (5 dimethyl amino-naphtha1ene-1 - sul fonyl aminn) -2, 6-di i snprnpyl -phenyl ester
When in the procedure of Example 26, acetyl chloride is replaced with dansyl chloride, the title compound is obtained; mp 103-105°C. EXAMPLE 34 Synthesis nf f (2 ,4 , 6-Tri i snprnpyl -phenyl ) -acetyl 1 - sulfamic acid 2,6 di i snprnpyl -4methanesu1 fnnyl ami no- pheny] ester When in the procedure of Example 26, acetyl chloride is replaced with methanesulfonyl chloride, the title compound is obtained; mp 164-166°C.
EXAMPLE 35 Synthesis of [(2,4, 6-Trii sopropyl-phenyl ) -acetyl 1 - sulfamic acid 2,6 di i soprnpyl -4-sul famoyl -phenyl ester Sodium nitrite (0.78 g, 11.3 mmol) in 1.25 mL H20 was added to a solution of [ (2 , 4 , 6-triisopropyl- phenyl) -acetyl] -sulfamic acid 4-amino-2 , 6 diisopropyl- phenyl ester (3.875 g, 7.5 mmol) in 10 mL AcOH and
1.75 mL concentrated HCl. The diazotized solution was stirred for 1/2 hour before pouring into a saturated solution of SO2 containing 0.25 g of CUCI2 in 20 mL AcOH and 20 mL benzene. After stirring overnight, the solution was poured onto ice water and precipitated [(2,4, 6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4-sulfonyl chloride-phenyl ester which was collected by filtration, total weight 3.8 g, (84%) . Ammonia gas was bubbled through a solution of [ (2,4, 6-triisopropyl phenyl) -acetyl] -sulfamic acid
2, 6-diisopropyl-4-sulfonyl chloride-phenyl ester (1 g, 1.7 mmol) in 10 mL THF. The precipitate was collected and purified by column chromatography (1:1 = EtOAc/Hexane) , white powder obtained weight 0.5 g; mp 164-166°C. EXAMPLE 36 Synthesis nf 6- (3.5-Di i soprnpyl -4- { \ ( 2 .4.6- tri i soprnpyl -phenyl -acetyl 1 sul famoyloxy} -phenyl ) - hexanoic acid ethyl ester When in the procedure of Example 18, 2, 6-bis (1- methylethyl) -4-cyanophenyl sulfamate is replaced with 6- (3, 5-Diisopropyl-4-sulfamoyloxy-phenyl) -hexanoic acid ethyl ester, the title compound is obtained as a white solid from hexanes, 0.1441 g. Atmospheric pressure CI Mass Spectrum: [M + H+] + = 644.4.
EXAMPLE 37 Synthesis nf 6- (3.5-ni i soprnpyl -4- { \ ( 2 .4 , 6- tri i sopropyl -phenyl -acetyl 1 sul famoyl nxy} -phenyl ) - hexanoic acid
6- (3 , 5-Diisopropyl-4-{ [(2,4, 6-triisopropyl-phenyl- acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester (1.52 g, 2.36 mmol) is taken up in methanol (20 mL) and IN sodium hydroxide solution is added, and the mixture is stirred at room temperature. Water is added to the reaction mixture as the reaction proceeds. The reaction mixture is stirred overnight at room temperature and then concentrated to remove methanol. The resulting mixture is partitioned between ethyl acetate and citric acid solution (10% aqueous, 100 mL) . 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,
0.992 g.
Atmospheric pressure CI Mass Spectrum: [M - H] = 614.4.

Claims

CLAIMS aim:
A compound of formula
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof wherein:
R1 is hydrogen, alkyl, or alkoxy; R 2 to R5 are alkyl, alkoxy, or unsubstituted or substituted phenyl;
R6 is -CN,
- (CH2)0_1-NR7R8,
-O- (CH2) ι-ιθ"z wherein Z is -NR9R10, OR1, or
-OC(
Figure imgf000050_0002
-SR11,
-SCN,
Figure imgf000050_0003
herein R12 is hydroxy, alkoxy, alkyl, (CH2) i-ioz or NR7R8,
-C(=0)XR1:L,
-CH2-R13 wherein R13 is (CH2 ) 0-5"γ" <CH2) 0-5Z' or alkyl of from 1 to 20 carbons with from 1-3 double bonds, which alkyl is optionally substituted by one or more selected from -CN, N02, halogen, OR1,
NR9R10, and C02R1; wherein R 7 and R8 are each independently selected from: -hydrogen, at least one of R7 and RR° is other than hydrogen,
- (CH2) i-ioz wherein Z is as above and R9 and
R are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl, or R and R are taken together with the nitrogen to which they are attached to form a ring selected from:
- (CH2)2-0- (CH2)2,
- (CH2)2-S- (CH2)2, - (CH2) 2-CR14R15- (CH2) χ_2, and
- (CH2) 2-NR16- (CH2) 2 ' wherein
R14, R15, and R16 are each independently selected from hydrogen, alkyl, and unsubstituted or substituted phenyl;
-C(=Q)XR wherein X is a bond or NH wherein
Q is O or S, R 11 is hydrogen, alkyl, unsubstituted or substituted phenyl,
- (CH2) Q_5-Y- (CH2) 0--5Z wherein Z is as defined above and Y is phenyl or a bond;
-C(=0)CR17R18Z; -C(=0)NRCR17R18Z wherein R17 and R18 are each independently hydrogen, alkyl, phenyl, substituted phenyl, or the side chain of a naturally occurring amino acid;
-S(0)ι_2R19 wherein R19 is alkyl, unsubstituted or substituted phenyl, naphthyl, or a heteroaromatic ring, or
NR9R10 or R7 and RR are taken together with the nitrogen to which they are attached to form a ring:
- (CH2)2-0- (CH2)2-, - (CH2)2-S- (CH2)2-, - (CH2) 2-CR14R15- (CH2) !-2- , - (CH2)2-NR16- (CH2)2- wherein R14, R15, and R are as above.
A compound according to Claim 1 wherein
R is3 hhyyddrroogen or alkyl of from 1 to 4 carbon atoms; R" 2- to >
Figure imgf000052_0001
aarre each alkyl of from 1 to 4 carbon atoms;
R6 is -NR7R8 wherein R7 and R8 are each independently selected from: hydrogen, at least one of R 7 and R8° is not hydrogen, -(CH2)1_10Z,
-C(=Q)XR1:I, or -S(0)1_2R19.
3. A compound according to Claim 2 wherein: η
R is hydrogen and
R8 is -C(=0)CR17R18Z wherein Z is NH2^ wherein one of R 17 or R1xR is the side chain of a naturally occurring ammo acid and the other is hydrogen.
4. A compound according to Claim 2 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
R6 is NR R wherein one of R is hydrogen and the R8 is S(O) !_2R19. 5. A compound according to Claim 1 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;
R6 is NR7R8 wherein R7 and R8 taken together with the nitrogen to which they are attached to form a ring:
- (CH2)2-0- (CH2)2-, - (CH2)2-S- (CH2)2-,
- (CH2)2-CR14R15- (CH2) 2- wherein R14 and R 15 are each independently selected from hydrogen, alkyl, or phenyl, or
- (CH2)2-NR16- (CH2)2- wherein R16 is hydrogen, alkyl, or phenyl.
A compound according to Claim 1 wherein:
R is hydrogen or alkyl of from 1 to 4 carbons, R 2 to R5 an alkyl of from 1 to 4 carbons, and
R6 is -C(=0)XRn or -CH2-R13.
A compound according to Claim 1 wherein:
R is hydrogen or alkyl of from 1 to 4 carbon atoms; R 2 to R5 are alkyl of from 1 to 4 carbon atoms;
R6 is -0- (CH2)1_10Z,
-0-C(=0)Ri:L,
-SH,
-SCN,
-S(CH2) χ_10Z, or
-S(0)1_2R 12 8. A compound according to Claim 6 wherein:
R is hydrogen or alkyl of from 1 to 4 carbon atoms; to R5 are alkyl of from 1 to 4 carbon atoms; Rβ is 0(CH2) 1_10NR9R10.
9. A compound according to Claim 1 and selected from:
(S) - [5-tert-Butoxycarbonylamino-5- (3,5- diisopropyl-4- { [(2,4, 6-triisopropyl-phenyl) - acetyl] sulfamoyloxy} -phenylcarbamoyl) -pentyl] - carbamic acid tert-butyl ester;
(S) - [ (2,4, 6-Triisopropyl-phenyl) -acetyl] - sulfamic acid 4- (2, 6-diamino-hexanoylamino) -2 , 6- diisopropyl-phenyl ester dihydrochloride;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-t-butoxycarbonylamino-acetylamino) -2, 6- diisopropyl-phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-acetylamino) -2,6-diisopropyl¬ phenyl ester; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-t-butoxycarbonylamino-4-methylsulfanyl- butyrylamino) -2 , 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-4-methylsulfanyl-butyrylamino) - 2, 6-diisopropyl-phenyl ester trifluoroacetate,•
3- [3- (3, 5-Diisopropyl-4-{ [ (2,4,6- triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) - ureido] -propionic acid ethyl ester;
3- [3- (3, 5-Diisopropyl-4-{ [ (2,4,6- triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) - ureido] -propionic acid;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [2-amino-3- (lH-indol-3-yl) -propionylamino] - 2, 6-diisopropyl-phenyl ester; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-amino-pentanoylamino) -2 , 6-diisopropyl- phenyl ester trifluoroacetate (1 : 1) (salt) ;
(D) - [ (2,4, 6-Triisopropyl-phenyl) -acetyl] - sulfamic acid 4- (2-amino-propionylamino) -2, 6- diisopropyl-phenyl ester trifluoroacetate (1 :1)
(salt) ;
(L) -[(2,4, 6-Triisopropyl-phenyl) -acetyl] - sulfamic acid 4- (2-amino-propionylamino) -2 , 6- diisopropyl-phenyl ester; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-2-methyl-propionylamino) -2,6- diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2, 6-diisopropyl- phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl¬ phenyl ester hydrochloride salt;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-amino-propoxy) -2, 6-diisopropyl-phenyl ester hydrochloride salt;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2 , 6-diisopropyl-4-thiocyanato-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-cyano-2, 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [ (2-amino-acetylamino) -methyl] -2,6- diisopropyl-phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-formyl-2, 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-cyano-vinyl) -2, 6-diisopropyl-phenyl ester; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (benzylamino-methyl) -2, 6-diisopropyl-phenyl ester mono hydrochloride;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4- (4-methyl-piperazin-l- ylmethyl) -phenyl ester, dihydrochloride; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-carbamoyl-2, 6-diisopropyl-phenyl ester;
[ (2,4 , 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-hydroxymethyl-2, 6-diisopropyl-phenyl ester; [{2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-acetylamino-2 , 6-diisopropyl-phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-hydroxy-ethylamino) -2 , 6-diisopropyl- phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [bis- (2-hydroxy-ethyl) -ammo] -2, 6- diisopropyl-phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (2, 6-diisopropyl-phenyl) -ureido] -2,6- diisopropyl-phenyl ester; [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2 , 6-diisopropyl-4- (3-phenyl-ureido] -phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4- (3-phenyl-thioureido] - phenyl ester;
[ (2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2 , 6-diisopropyl-4- (thiophene-2-sulfonyl- amino) -phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5- dimethylamino-naphthalene-1- sulfonylamino) -2, 6-diisopropyl-phenyl ester;
[(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4-methanesulfonylamino-phenyl ester; 100 [(2,4, 6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2, 6-diisopropyl-4-sulfamoyl-phenyl ester;
6- (3, 5-Diisopropyl-4-{ [(2,4, 6-triisopropyl- phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester; and
105 6- (3, 5-Diisopropyl-4-{ [ (2,4, 6-triisopropyl- phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
11. A method of treating hypercholesterolemia comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound of Claim 1.
12. A method of treating atherosclerosis comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound of Claim 1.
13. A method of regulating plasma cholesterol concentrations comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to
5 Claim 1.
14. A method for lowering the serum or plasma level of Lp(a) in a mammal in need of said treatment, comprising administering to said mammal an amount effective for lowering the serum or plasma level
5 of said Lp(a) of a compound according to Claim 1. 15. A method of treating peripheral vascular disease comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to Claim 1.
16. A method of treating restenosis comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to Claim 1.
PCT/US1997/006725 1996-05-17 1997-04-21 N-acyl sulfamic acid esters useful as hypocholesterolemic agents WO1997044314A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004086A1 (en) * 1999-07-09 2001-01-18 Btg International Limited Sulphamate compounds
EP1236468A1 (en) * 2001-02-12 2002-09-04 Warner-Lambert Company Sulfonylaminocarbonyl derivatives for the treatment of nuclear factor-kappa B mediated diseases and disorders

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 (en) * 1999-07-09 2001-01-18 Btg International Limited Sulphamate compounds
EP1236468A1 (en) * 2001-02-12 2002-09-04 Warner-Lambert Company Sulfonylaminocarbonyl derivatives for the treatment of nuclear factor-kappa B mediated diseases and disorders

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ZA974231B (en) 1997-12-11

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