WO1991015464A1 - Amide ester acat inhibitors - Google Patents
Amide ester acat inhibitors Download PDFInfo
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- WO1991015464A1 WO1991015464A1 PCT/US1991/002441 US9102441W WO9115464A1 WO 1991015464 A1 WO1991015464 A1 WO 1991015464A1 US 9102441 W US9102441 W US 9102441W WO 9115464 A1 WO9115464 A1 WO 9115464A1
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- methylethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/32—Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- This invention relates to chemical compounds having pharmacological activity, to pharmaceutical compositions which include these compounds, and to a pharmaceutical method of treatment. More particularly, this invention concerns certain malonamide esters, compounds which inhibit the enzyme acylcoenzyme A: cholesterol acyltransferase (ACAT),
- This invention also describes novel intermediates useful in preparing the pharmaceutically active compounds of this invention.
- Deposits of cholesterol in the vascular system have been indicated as causative of a variety of patho- logical conditions including coronary heart disease.
- LDL cholesterol low density lipoprotein cholesterol
- HDL cholesterol high density lipoprotein cholesterol
- ACAT cholesterol acyltransferase
- the present invention provides a class of compounds which have acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitory activity and intermediates useful in preparing said compounds of the following general formula:
- ACAT cholesterol acyltransferase
- each of m and n is independently zero, one or two; wherein X is oxygen or sulfur;
- R 8 and R 9 are independently selected from hydrogen or an alkyl group having from one to six carbon atoms
- R 10 is phenyl, phenyl substituted with from one to three substituents selected from straight or branched alkyl having from one to six carbon atoirrs and which is straight or branched, straight or branched alkoxy having from one to six carbon atoms and which is straight or branched, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or -(CH 2 ) p NR 6 R 7 wherein p is zero or one and each of R 6 and R 7 is independently selected from hydrogen or an alkyl group having from one to four carbon atoms
- R 10 is a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member; or when R 8 is hydrogen each of R 9 and R 10 is independently selected from phenyl, phenyl substituted with from one to three
- alkyl has from one to
- bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member
- alkoxy having from one to six carbon atoms and which is straight or branched
- alkyl moiety has from one to four carbon atoms and is straight or branched, or -(CH 2 ) p NR 6 R 7 wherein p, R 6 , and R 7 have the meanings defined above;
- alkyl having from one to six carbon atoms and which is straight or branched
- alkoxy having from one to six carbon atoms and which is straight or branched
- hydroxy
- alkyl has from one to four carbon atoms and which is straight or branched
- heterocyclic group selected from pyrrolidono, piperidino, morpholino, or piperazino, each of which is unsubstituted or is
- ⁇ -hydroxyalkyl having from one to six carbon atoms
- alkyl having from one to six carbon atoms and which is straight or branched
- alkoxy having from one to six carbon atoms and which is straight or branched
- phenoxy
- alkyl has from one to four carbon atoms and which is straight or branched
- alkyl having from one to six carbon atoms and which is straight or branched; alkoxy having from one to six carbon atoms and which is straight or branched, hydroxy,
- alkyl has from one to four carbon atoms and is straight or branched, -(CH 2 ) p NR 6 R 7 wherein p, R 6 , and R 7 have the meanings defined above;
- R 8 and R 9 are independently selected from hydrogen or alkyl having from one to six carbon atoms, or when R 8 is hydrogen, R 9 can be the same as R 10 ; and R 10 is phenyl or phenyl substituted with from one to three substituents selected from straight or branched alkyl having from one to six carbon atoms, straight or branched alkoxy having from one to six carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro,
- alkyl has from one to four carbon atoms and is straight or branched, or
- bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member
- R 9 is hydrogen or alkyl having from one to six carbon atoms
- R 9 is hydrogen or alkyl having from one to six carbon atoms
- one of R 1 and R 2 is the group (c) the other of R 1 and R 2 is other than (b), (f), or (i);
- This invention also provides pharmaceutical compositions containing the compounds of Formula I and methods of treating hypercholesterolemia and atherosclerosis using the compounds of Formula I.
- the compounds of the present invention provide a novel class of amide esters which are ACAT inhibitors rendering them useful in treating hypercholesterolemia and atherosclerosis.
- six carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, and hexyl.
- 20 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-undecyl,
- Illustrative straight or branched hydrocarbon groups having from 1 to 20 carbon atoms and having from 1 to 3 double bonds are ethenyl, 2-propenyl,
- Straight or branched alkoxy groups having from 1 to 6 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, t-butoxy, and pentyloxy.
- a 5- or 6-membered monocyclic or fused bicyclic heterocycle is a monocyclic or fused bicyclic aromatic ring containing at least one to four hetero atoms in at least one ring, such as nitrogen, oxygen or sulfur or a combination thereof.
- a heterocyclic group includes, for example, thienyl, benzothienyl, furanyl, benzofuranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, isothiazolyl,
- heterocycle may be 2- or
- Preferred compounds of this invention are those wherein each of m and n is zero.
- Compounds wherein R 1 and R 2 are selected from phenyl or substituted phenyl and 2,6-disubstituted phenyl is particularly
- R 1 and R 2 are also preferred.
- Another preferred embodiment of the present invention is compounds wherein R 5 is phenyl or substituted phenyl, and 2,6- disubstituted phenyl is particularly preferred.
- hydrocarbon chain having from 1 to 20 carbon atoms and which is saturated or contains from one to
- the acid addition salts may be generated from the free base forms of the compounds by reaction of the latter with one equivalent of a suitable nontoxic, pharmaceutically acceptable acid, followed by
- the free base may be recovered from the acid addition salt by reaction of the salt with a water solution of the salt with a suitable base such as sodium carbonate.
- a suitable base such as sodium carbonate.
- Suitable acids for forming acid addition salts of the compounds of this invention include, but are not necessarily limited to acetic, benzoic, benzene- sulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric, and tartaric acids.
- the class of acids suitable for the formation of nontoxic, pharmaceutically acceptable salts is well known to practitioners of the pharmaceutical formulation arts. (See, for example, Stephen N. Berge, et al. J Pharm Sciences, 66:1-19 (1977).
- the compounds of the present invention may also exist in different stereoisomeric forms by virtue of the presence of one or more asymmetric centers in the compound.
- the present invention contemplates all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures.
- stereoisomers may be obtained, if desired by methods known in the art as, for example, the separation of stereoisomers in chiral chromatographic columns.
- 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.
- the compounds of the present invention are potent inhibitors of the enzyme acyl-CoA: cholesterol acyltransferase (ACAT), and are thus effective in
- the compounds of the present invention are thus useful in pharmaceutical formulations for the treatment of hypercholesterolemia or atherosclerosis.
- test assesses the ability of a test compound to inhibit the acylation of cholesterol by oleic acid by measuring the amount of radio labeled cholesterol oleate formed from radiolabeled oleic acid in a tissue preparation containing rabbit intestinal microsomes.
- IC 50 values i.e. the concentration of test compound required to inhibit the activity of the enzyme by 50%.
- the compounds may also be evaluated in an in vivo screen designated APCC whereby male Sprague-Dawley rats (200 to 225 g) are 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 is then replaced with the PCC diet with either 1% or 0.5% cholic acid.
- the rats consume this diet ad libitum during the night and are sacrificed at 8 AM to obtain blood samples for
- the compounds of Formula I 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 compound is mixed with the carrier having the necessary binding
- Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
- Suitable carriers are magnesium
- 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.
- cachets are also included.
- Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
- Liquid form preparations include solutions suitable for oral administration, or suspensions and 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 carboxymethyl cellulose, 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
- the unit dosage form can be a packaged preparation, the package 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 any of these packaged forms.
- an acid scavenger for example, triethylamine.
- the resulting diester (3) is then selectively hydrolyzed with sodium hydroxide or a similar base in a suitable organic solvent, and the carboxylic acid is generated with an acid wash such as hydrochloric acid.
- the resulting ester acid (4) is then reacted with the appropriate amine using any of the known coupling conditions, such as, dicyclocarbodiimide, carbonyldiimidazole, or by way of the acid chloride.
- the compounds of this invention may also be prepared as set forth in Chart II hereof.
- the amine (1) is reacted with an appropriate acid halide, e.g., the acid chloride (2) in an aprotic, nonpolar solvent such as ethyl acetate, tetrahydrofuran, diethyl ether or methylene chloride in the presence of a tertiary amine such as triethylamine, diisopropyl ethylamine or pyridine for about 1 to 24 hours at a temperature of from about 0° to 25°C to give the amide (3).
- the amide (3) is converted to the free acid (4) by
- a mild aqueous base e.g., sodium hydroxide in a lower alcohol such as methanol or ethanol at a temperature of from 25° to 80°C for from about 1 to 20 hours.
- the free acid can be converted to the amide ester (6) reaction with an appropriate alcohol or thioalcohol (5) and a carbodiimide such as dicyclohexylcarbodiimide in methylene chloride.
Abstract
Pharmaceutically useful compounds having acylcoenzyme A: cholesterol acyltransferase inhibitory activity having general formula (I) wherein each of m and n is zero, one or two; X is oxygen or sulfur and each of R1, R2, R3, R4, and R5 is hydrogen or a hydrocarbon substituent.
Description
AMIDE ESTER ACAT INHIBITORS
BACKGROUND OF THE INVENTION
This invention relates to chemical compounds having pharmacological activity, to pharmaceutical compositions which include these compounds, and to a pharmaceutical method of treatment. More particularly, this invention concerns certain malonamide esters, compounds which inhibit the enzyme acylcoenzyme A: cholesterol acyltransferase (ACAT),
pharmaceutical compositions containing these
compounds, and a method of treating hypercholesterolemia and atherosclerosis. This invention also describes novel intermediates useful in preparing the pharmaceutically active compounds of this invention.
In recent years the role which elevated blood plasma levels of cholesterol play 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 patho- logical 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 an exterior consisting primarily of phospholipids 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.
SUMMARY OF THE INVENTION
The present invention provides a class of compounds which have acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitory activity and intermediates useful in preparing said compounds of the following general formula:
wherein each of m and n is independently zero, one or two;
wherein X is oxygen or sulfur;
wherein each of R1 and R2 is independently
(a) hydrogen,
(b) the group
R10 is a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member; or when R8 is hydrogen each of R9 and R10 is independently selected from phenyl, phenyl substituted with from one to three
substituents selected from straight or branched alkyl having from one to six carbon atoms and which is straight or branched, straight or
branched alkoxy having from one to six carbon atoms and which is straight or branched, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or -(CH2)pNR6R7 wherein R6, R7, and p have the meanings defined above, or a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen, oxygen, or sulfur atoms in at least one ring member;
(c) the group
phenyl,
1- or 2-naphthyl,
phenyl or 1- or 2-naphthyl substituted with alkyl of from one to six carbon atoms and which is straight or branched,
alkoxy of from one to six carbon atoms and which is straight or branched,
hydroxy,
benzyloxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-NH-COCH3,
-CONH2,
-COOH,
-COOalkyl wherein alkyl has from one to
four carbon atoms and which is straight or branched,
-CH2COOH,
-CH2CONH2,
-(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above;
(d) a straight or branched hydrocarbon chain
having from 1 to 20 carbon atoms and which is saturated or contains from one to
three double bonds;
(e) an alkyl group having from one to six carbon atoms wherein the terminal carbon is substituted with hydroxy or -NR6R7 wherein R6 and R7 have the meanings defined hereinabove;
(f) a 5- or 6-membered monocyclic or fused
bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member;
(g) phenyl or phenyl substituted with from one to three substituents selected from phenyl, alkyl having from one to six carbon atoms and which is straight or branched,
alkoxy having from one to six carbon atoms and which is straight or branched,
phenoxy,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or
-(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above;
(i) 1- or 2-naphthyl which is unsubstituted or substituted with from one to three substituents selected from
phenyl,
alkyl having from one to six carbon atoms and which is straight or branched, alkoxy having from one to six carbon atoms and which is straight or branched, hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from one to four carbon atoms and which is straight or branched,
-(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above; or
(j) NR1R2 taken together form a monocyclic
heterocyclic group selected from pyrrolidono, piperidino, morpholino, or piperazino, each of which is unsubstituted or is
substituted with one substituent selected from phenyl, straight or branched alkyl having from one to six carbon atoms or
ω-hydroxyalkyl having from one to six carbon atoms;
wherein each of R3 and R4 is independently
(a) hydrogen;
(b) a straight or branched alkyl group having from one to ten carbon atoms;
(c) a straight chain alkyl group having from one to ten carbon atoms wherein the terminal carbon atom is substituted with hydroxy or NR6R7 wherein R6 and R7 have the meanings defined above;
wherein R5 is
(a) hydrogen,
(b) phenyl which is unsubstituted or is
substituted with from one to three substituents selected from:
phenyl,
alkyl having from one to six carbon atoms and which is straight or branched, alkoxy having from one to six carbon atoms and which is straight or branched, phenoxy,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from one to four carbon atoms and which is straight or branched,
-(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above;
(c) 1- or 2-naphthyl which is unsubstituted or substituted with from one to three substituents selected from
phenyl,
alkyl having from one to six carbon atoms and which is straight or branched; alkoxy having from one to six carbon atoms and which is straight or branched,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl ,
-COOH,
-COOalkyl wherein alkyl has from one to four carbon atoms and is straight or branched, -(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above;
(d) the group
trifluoromethyl, -COOH, COOalkyl wherein alkyl has from one to four carbon atoms and is straight or branched, or
-(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above;
(e) the group
wherein q, r, s, and Ar' have the meanings defined above;
(f) a straight or branched hydrocarbon chain
having from 1 to 20 carbon atoms and which is saturated or contains from one to
three double bonds; or
(g) a 5- or 6- membered monocyclic or fused
bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member;
with the provisos that (1) when each R1 and R2 is the group (b) R9 is hydrogen or alkyl having from one to six carbon atoms, and (2) when one of R1 and R2 is the group (c) the other of R1 and R2 is other than (b), (f), or (i);
N-oxides thereof, or a pharmaceutically acceptable salt thereof.
This invention also provides pharmaceutical compositions containing the compounds of Formula I and methods of treating hypercholesterolemia and atherosclerosis using the compounds of Formula I.
DETAILED DESCRIPTION OF INVENTION The compounds of the present invention provide a novel class of amide esters which are ACAT inhibitors rendering them useful in treating hypercholesterolemia and atherosclerosis.
Illustrative examples of straight or branched alkyl groups having from one to four or one to
six carbon atoms includes methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, and hexyl.
Illustrative examples of straight or branched saturated hydrocarbon groups having from 1 to
20 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-undecyl,
n-dodecyl, n-hexadecyl, 2,2-dimethyldodecyl,
2-ethyltetradecyl, and n-octadecyl groups.
Illustrative straight or branched hydrocarbon groups having from 1 to 20 carbon atoms and having from 1 to 3 double bonds are ethenyl, 2-propenyl,
2-butenyl, 3-pentenyl, 2-octenyl, 5-nonenyl,
4-undecenyl, 5-hepadecenyl, 3-octadecenyl,
9-octadecenyl, 2, 2-dimethyl-11-eicosenyl,
9,12-octadecadienyl, and hexadecenyl.
Straight or branched alkoxy groups having from 1 to 6 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, t-butoxy, and pentyloxy.
A 5- or 6-membered monocyclic or fused bicyclic heterocycle is a monocyclic or fused bicyclic aromatic ring containing at least one to four hetero atoms in at least one ring, such as nitrogen, oxygen or sulfur or a combination thereof. Such a heterocyclic group includes, for example, thienyl, benzothienyl, furanyl, benzofuranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, isothiazolyl,
oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
imidazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, or N-oxides of a heterocycle containing a nitrogen atom.
More specifically, such heterocycle may be 2- or
3-thienyl; 2- or 3-furanyl; 2-, or 3-, or 4-pyridyl or -pyridyl-N-oxides; 2, 4, or 5-pyrimidinyl; 3- or
4-pyridazinyl; 2-pyrazinyl; 2- or 3-pyrrolyl; 3-, 4-, or 5-pyrazolyl, 3-, 4-, or 5-isoxazolyl; 3-, 4-, or 5- oxazolyl; 3-, 4-, or 5-isothiazolyl; 5-tetrazolyl; 3- or 5-(1,2,4-)triazolyl; 4- or 5-(1,2,3-)triazolyl; 2-,
4-, or 5-imidazolyl; 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 2-,' 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl; 2-, 4-, 5-, 6-, or 7- benzolthiazolyl; or 2-, 3-, 4-, 5-, 6-, or 7- benzothienyl.
Preferred compounds of this invention are those wherein each of m and n is zero. Compounds wherein R1 and R2 are selected from phenyl or substituted phenyl and 2,6-disubstituted phenyl is particularly
preferred. Compounds wherein one of R1 and R2 is hydrogen are also preferred. Another preferred embodiment of the present invention is compounds wherein R5 is phenyl or substituted phenyl, and 2,6- disubstituted phenyl is particularly preferred.
Compounds wherein R5 is a straight or branched
hydrocarbon chain having from 1 to 20 carbon atoms and which is saturated or contains from one to
three double bonds or wherein R5 is the group
are also preferred.
Pharmaceutically acceptable salts of the
compounds of Formula I are also included as a part of the present invention.
The acid addition salts may be generated from the free base forms of the compounds by reaction of the latter with one equivalent of a suitable nontoxic, pharmaceutically acceptable acid, followed by
evaporation of the solvent employed for the reaction and recrystallization of the salt, if required. The free base may be recovered from the acid addition salt by reaction of the salt with a water solution of the salt with a suitable base such as sodium carbonate.
sodium bicarbonate, potassium carbonate, sodium hydroxide, and the like.
Suitable acids for forming acid addition salts of the compounds of this invention include, but are not necessarily limited to acetic, benzoic, benzene- sulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric, and tartaric acids. The class of acids suitable for the formation of nontoxic, pharmaceutically acceptable salts is well known to practitioners of the pharmaceutical formulation arts. (See, for example, Stephen N. Berge, et al. J Pharm Sciences, 66:1-19 (1977).
The compounds of the present invention may also exist in different stereoisomeric forms by virtue of the presence of one or more asymmetric centers in the compound. The present invention contemplates all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures.
Individual stereoisomers may be obtained, if desired by methods known in the art as, for example, the separation of stereoisomers in chiral chromatographic columns.
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.
As shown by the data presented below in Table 1, the compounds of the present invention are potent 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, F. J. and Salone, R. G., Biochemica et Biophysica 712: 557- 570 (1982). The test assesses the ability of a test compound to inhibit the acylation of cholesterol by oleic acid by measuring the amount of radio labeled cholesterol oleate formed from radiolabeled oleic acid in a tissue preparation containing rabbit intestinal microsomes.
The data appear in Table I where they are
expressed as IC50 values; i.e. the concentration of test compound required to inhibit the activity of the enzyme by 50%.
cholesterol analysis using standard procedures.
Statistical differences between mean cholesterol values for the same vehicle are determined using analysis of variance followed by Fisher's least significant test.
In therapeutic use as agents for treating
hypercholesterolemia or atherosclerosis, the compounds of Formula I 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 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 compound 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
carbonate, 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 are also included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions suitable for oral administration, or suspensions and 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 carboxymethyl cellulose, 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, the package 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 any of these packaged forms.
The compounds of general Formula I are prepared as shown in Charts I and II hereof wherein the various substituent groups R1, R2, R3, R4, R5, X, m, and n have the meanings defined in Formula I. In Chart I the requisite alcohol or thioalcohol (1) is reacted with an appropriate ester acid chloride compound (2) in an organic solvent such as dichloromethane. This
reaction is carried out between 0°C and room
temperature in the presence of an acid scavenger, for example, triethylamine. The resulting diester (3) is then selectively hydrolyzed with sodium hydroxide or a similar base in a suitable organic solvent, and the carboxylic acid is generated with an acid wash such as hydrochloric acid. The resulting ester acid (4) is then reacted with the appropriate amine using any of the known coupling conditions, such as, dicyclocarbodiimide, carbonyldiimidazole, or by way of the acid chloride.
The compounds of this invention may also be prepared as set forth in Chart II hereof. The amine (1) is reacted with an appropriate acid halide, e.g., the acid chloride (2) in an aprotic, nonpolar solvent such as ethyl acetate, tetrahydrofuran, diethyl ether or methylene chloride in the presence of a tertiary amine such as triethylamine, diisopropyl ethylamine or pyridine for about 1 to 24 hours at a temperature of from about 0° to 25°C to give the amide (3). The amide (3) is converted to the free acid (4) by
treatment with a mild aqueous base, e.g., sodium hydroxide in a lower alcohol such as methanol or ethanol at a temperature of from 25° to 80°C for from about 1 to 20 hours. The free acid can be converted to the amide ester (6) reaction with an appropriate
alcohol or thioalcohol (5) and a carbodiimide such as dicyclohexylcarbodiimide in methylene chloride.
The compounds of Formula I wherein R3 and R4 are other than hydrogen may be prepared from the
corresponding compounds wherein R and R are hydrogen by treatment with a mild base such as sodium hydride or sodium carbonate/dimethyl formamide and alkylating with an appropriate alkylhalide of the formula
R3-halide or R4-halide wherein R3 and R4 have the same meanings as in Formula I but are not hydrogen, and halide is e.g., chloride.
The following specific examples further
illustrate the invention.
EXAMPLE 1
3[[2 ,6-Bis(dimethylamino)phenyl]amino]-3- oxopropanoic acid, 2,6-bis (1-methylethyl)
phenyl ester
(a) To a methylene chloride solution of
2, 6-diisopropylphenol (29.6 g, 0.166 mol) and
triethylamine (46 mL, 0.33 mol) at -15°C under a nitrogen atmosphere was added ethyl malonyl chloride (29.6 g, 0.166 mol) dropwise with stirring. When the addition was complete the solution was allowed to warm to room temperature over 4 hours after which 50 mL IN HCl was added. The organic layer was separated, dried over magnesium sulfate, filtered, treated with
charcoal, filtered and concentrated in vacuo to give 3- (2, 6-bis (1-methylethyl)phenoxy)-3-oxopropionic acid, ethyl ester.
(b) The ethyl ester obtained in (a) above
(31.0 g, 0.11 mol) was dissolved in 250 mL tetrahydrofuran at 0°C with stirring. Sodium hydroxide (IN, 120 mL) was added, and the reaction mixture was stirred for 5 hours . At the 4th hour of stirring 100 mL of methanol was added. The solution was
concentrated in vacuo, and the residue was redissolved in water and was washed with ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate. The organic extract was washed with water and aqueous saturated sodium
chloride then dried over magnesium sulfate, filtered and concentrated in vacuo to give 3-[2,6-bis(1-methylethyl)phenoxy]-3-oxopropionic acid, m.p. 93-94°C.
(c) To a methylene chloride (30 mL) solution of the acid from (b) above (1 g, 0.00378 mol) and
2,6-bis-dimethylaminoaniline (0.68 g, 0.00378 mole) at 0°C under a nitrogen atmosphere was added
dicyclohexylcarbodiimide (0.82 g, 0.00397 mol) with stirring. The resulting suspension was stirred overnight, filtered and the filtrate concentrated in vacuo. The solid was recrystallized from ethyl acetate to give the title compound, m.p. 144-145°C.
EXAMPLE 2
3-[(2,6-Dimethylphenyl)amino]-3-oxopropionic acid,
2,6-bis(1-methylethyl)phenyl ester
To a methylene chloride (30 mL) solution of
3-[2,6-bis(1-methylethyl)phenoxy]-3-oxopropionic acid (1 g, 0.00378 mol) and 2, 6-dimethylaniline (0.46 mL, 0.00378 mol) with stirring under a nitrogen atmosphere was added dicyclohexylcarbodiimide (0.00397 mol) at 0°C. The resulting suspension was stirred overnight at room temperature and filtered. The filtrate was concentrated in vacuo, and the resulting solid was recrystallized from ethyl acetate to give the title compound, m.p. 160-162°C.
EXAMPLE 3
3-[[2 ,6-Bis(1-methylethyl)phenyl]amino]-3-oxopropionic acid, diphenylmethyl ester
(a) To a mixture of 43.30 g (0.24 mole) of 2,6- diisopropylaniline and excess triethylamine in 400 mL of ethyl acetate was added dropwise 36.7 g (0.24 mole) of ethyl malonylchloride (technical) at 0°C, more ethyl acetate was added as the reaction mixture became a slurry. The reaction mixture was stirred for 1 hour at 0°C then allowed to sit at room temperature for 30 minutes. The resulting white precipitate was filtered off, concentrated on a rotary evaporator leaving an oil which crystallized. Hexane was added to the crystalline material and the solid collected by filtration to give 3-[[2,6-bis(1-methyl-ethyl)- phenyl]amino]-3-oxopropionic acid ethyl ester.
(b) To 4.6 g (0.016 mole) of the ethyl ester obtained above in 50 mL MeOH was added 17 mL 1M NaOH at room temperature, after which water was added until the solution became cloudy. The solution was allowed to sit at room temperature for 2 hours then
concentrated on a rotary evaporator, diluted with HO and EtOAc and made acidic with IN HCl. Brine was added and the layers were separated, the organic layer was washed with brine, dried over MgSO, filtered, and stripped to a white flaky solid. The solid was recrystallized from hexane to give 3-[[2,6-bis (1- methyl)phenyl]amino]-3-oxopropionic acid.
(c) To a solution of methylene chloride (30 mL) of 3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxo- propionic acid (1 g, 0.00379 mol) and diphenylmethanol (0.7 g, 0.00379 mol) at 0°C under an atmosphere of nitrogen was added dicyclohexylcarbodiimide
(0.00397 mol). The resulting suspension was stirred overnight at room temperature and filtered. The filtrate was concentrated in vacuo, and the solid was
recrystallized from ethylacetate-hexane to give the title compound, m.p. 141-143°C.
EXAMPLE 4
3-[[2,6-Bis(1-methylethyl)phenyl]amino]-3-oxopropionic acid, 1,1':3',1"-terphen-2'-yl ester
To a methylene chloride (30 mL) solution of
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropionic acid (1 g, 0.00379 mol) and 2, 6-diphenylphenol
(0.94 g, 0.0037.9 mol) at 0°C under an atmosphere of nitrogen was added dicyclohexylcarbodiimide
(0.00397 mol). The resulting suspension was stirred overnight at room temperature and filtered. The filtrate was concentrated in vacuo, and the solid was recrystallized from ethyl acetate-hexane to give the title compound, m.p. 151-153°C.
EXAMPLE 5
3-[[2,6-Bis(1-methylethyl)phenyl]amino]-3-oxopropionic acid, 2,6-bis(1-methylethyl)phenyl ester
To a solution of 3-[[2,6-bis(1-methylethyl)- phenyl]amino]-3-oxopropionic acid (1.5 g, 0.0057 mol) and 2, 6-diisopropylphenol (1.02 g, 0.0057 mol) in dichloromethane (50 mL) at 0°C under an atmosphere of nitrogen dicyclohexylcarbodiimide was added in one portion. The solution was allowed to warm to room temperature, stirred for 16 hours, then concentrated to dryness. The residue was slurried in diethyl ether, filtered and evaporated to give a yellow oil which was triturated with hexane to give the title compound as a white solid, m.p. 126-127°C.
Following the general procedure of Examples 1 and
2 only using an appropriate amount of the aniline listed in the following Table 2 the respective products listed in Table 2 were obtained.
Following the general procedures of Example 3, 4, and 5 only using an appropriate amount of the alcohol listed below the respective products listed in Table 3 were obtained.
3-[Bis(phenylmethyl)amino]-3-oxopropanoic acid, 2,6- bis(1-methylethyl)phenyl ester
When in the general procedure of Example 2 an appropriate amount of dibenzylamine was substituted for 2, 6-bis-dimethylaniline, the title compound was obtained 1H NMR (CDCl3), 6 7.41-7.16 (m, 13H), 4.70 (s, 2H), 4.55 (s, 2H), 3.84 (s, 2H), 2.99 (m, 2H), 1.18 (d, 12H). EXAMPLE 17
3-[(Diphenylmethyl)amino]-3-oxopropanoic acid, 2,6- bis(1-methylethyl)phenyl ester
When in the general procedure of Example 2 an appropriate amount of diphenylmethylamine was
substituted for 2,6-bis-dimethylaniline, the title compound was obtained, m.p. 142-144°C.
EXAMPLE 18
3-[[2 ,6-Bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, dodecyl ester
When in the general procedure of Example 3 an appropriate amount of dodecanol was substituted for benzhydrol, the title compound was obtained,
m.p. 55-57°C.
EXAMPLE 19
(±) 3-[[2,6-Bis(1-methylethyl)phenyl]amino]-3-oxo- propanoic acid, 1-methyltridecyl ester
When in the general procedure of Example 3 an appropriate amount of 1-methyltridecanol was
substituted for benzhydrol, the title compound was obtained, m.p. 41-44°C.
Similarly the following compounds were prepared:
(Z)-3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 9-octadecenyl ester, 1H NMR (CDCl3) 5 8.6 ppm (bs, 1H), 7.0-7.4 (m, 3H), 5.4 (tr, 2H), 4.2 (tr, 2H), 3.5 (s, 2H), 3.1 (m, 2H), 1.0-2.0 (m, 33H). 3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, octyl ester, m.p. 69-72°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, decyl ester, m.p. 58-60°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, tetradecyl ester, m.p. 62-65°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxo-l,1- dimethylethyl ester, m.p. 165-168°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1-cyclopropyl-l-methylethyl ester,
mp. 115-117°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1,1-dimethylbutyl ester, m.p. 106-107°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, undecyl ester, 1H NMR (CDCl3) δ 8.6 ppm (bs, 1H) , 7.1-7.3 (m, 3H), 3.5 (s, 2H), 3.1 (m, 2H),
0.9-1.5 (m, 23H).
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, hexadecyl ester, m.p. 64-65°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, octadecyl ester, m.p. 74-76°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1,1-dimethyltridecyl ester, m.p. 81-83°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1-methylundecyl ester; 1H NMR (CDCl3) 8 8.6 ppm (bs, 1H), 7.1-7.3 (m, 3H), 5.0 (m, 1H), 3.6 (s, 2H), 3.1 (m, 2H), 0.9-1.4 (m, 21H).
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, methylpentadecyl ester, 1H NMR (CDCl3) δ 8.6 ppm (6s, 1H), 7.1-7.3 (m, 3H), 5.0 (m, 1H), 3.5 (s, 2H), 3.05 (m, 2H), 0.9-1.3 (m, 29H).
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1,1-dimethylpentyl ester, m.p. 107-109°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-2,2-dimethyl- 3-oxopropanoic acid, ethyl ester, 176-178 °C; 3-[(2,4-difluorophenyl)amino]-3-oxopropanoic acid, 1-methyltridecyl ester, m.p. 47-49°C;
3-[(2,4,6-trimethyoxyphenyl)amino]-3-oxopropanoic acid, 1-methyltridecyl ester, m.p. 68-71°C;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-2,2- dimethylpropanoic acid, 1-methyltridecyl ester, 1H NMR (CDCl3) δ 7.8 (bs, 1H), 7.0-7.4 (m, 3H), 5.0 (m, H), 3.05 (m, 2H), 1.7 (s, 3H), 1.6 (s, 6H), 0.9-1.4 (m, 25H).
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1-methylhexyl ester, m.p. 102-104 °C; and
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxopropanoic acid, 1-methylnonyl ester, m.p. 94-96°C.
Claims
1. A compound of the formula
wherein X is oxygen or sulfur;
wherein each of R and R is independently
(a) hydrogen,
(b) the group
6-membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member; or when R8 is hydrogen each of R9 and R10 is independently selected from phenyl, phenyl substituted with from one to three substituents selected from straight or branched alkyl having from one to six carbon atoms, straight or branched alkoxy having from one to six carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or
-(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined above, or a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member;
(c) the group
1- or 2-naphthyl,
phenyl or 1- or 2-naphthyl substituted with an alkyl group of from one to six carbon atoms and which is straight or branched, an alkoxy group of from one to six carbon atoms and which is straight or branched, hydroxy,
benzyloxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-NH-COCH3,
-CONH2,
-COOH,
-COOalkyl wherein alkyl has from one to
four carbon atoms,
-CH2COOH,
-CH2CONH2,
-(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined above;
(d) a straight or branched hydrocarbon chain
having from 1 to 20 carbon atoms and which is saturated or contains from one to
three double bonds;
(e) an alkyl group having from one to six carbon atoms wherein the terminal carbon is
substituted with hydroxy or -(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined hereinabove;
(f) a 5- or 6-membered monocyclic or fused
bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member;
(g) phenyl or phenyl substituted with from one to three substituents selected from
phenyl,
an alkyl group having from one to six carbon atoms and which is straight or branched, an alkoxy group having from one to six carbon atoms and which is straight or branched, phenoxy,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or
-(CH2)pNR6R7 wherein p, and R7 have the meanings defined above;
(i) 1- or 2-naphthyl which is unsubstituted or substituted with from one to three substituents selected from
phenyl,
an alkyl group having from one to six carbon atoms and which is straight or branched, an alkoxy group having from one to six carbon atoms and which is straight or branched, hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from one to four carbon atoms and is straight or
branched,
-(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined above; or
(j) NR1R2 taken together form a monocyclic
heterocyclic group selected from pyrrolidino, piperidino, morpholino, or piperazino, each of which is unsubstituted or is substituted with one substituent selected from phenyl, a straight or branched alkyl group having from one to six carbon atoms or ω-hydroxyalkyl having from one to six carbon atoms.
wherein each of R3 and R4 is independently
(a) hydrogen;
(b) a straight or branched alkyl group having from one to ten carbon atoms;
(c) a straight chain alkyl group having from one to ten carbon atoms wherein the terminal carbon atom is substituted with hydroxy or -(CH2)pNR6R7 wherein R6 and R7 have the meanings defined above; wherein R5 is
(a) hydrogen,
(b) phenyl which is unsubstituted or is
substituted with from one to three substituents selected from:
phenyl,
alkyl group having from one to six carbon atoms and which is straight or branched, alkoxy group having from one to six carbon atoms and which is straight or branched,
phenoxy,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from one to four carbon atoms and is straight or branched, -(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined above;
(c) 1- or 2-naphthyl which is unsubstituted or substituted with from one to three substituents selected from
phenyl,
an alkyl group having from one to six carbon atoms and which is straight or branched;
an alkoxy group having from one to six carbon atoms and which is straight or branched, hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from one to four carbons atoms and is straight or
branched
-(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined above;
(d) the group
COOH, COOalkyl wherein alkyl has from one to four carbon atoms, or
-(CH2)pNR6R7 wherein R6 and R7 have the meanings defined above;
(e) the group
(f) a straight or branched hydrocarbon chain
having from 1 to 20 carbon atoms and which is saturated or contains from one to
three double bonds; or
(g) a 5- or 6-membered monocyclic or fused
bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member;
with the provisos that (1) when each of R1 and R2 is the group (b) Rg is hydrogen or alkyl having from one to six carbon atoms and (2) when one of
R1 and R2 is the group (c) the other of R1 and R2 is other than (b), (f), or (i);
N-oxides, or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein one of R and R is hydrogen.
3. A compound of Claim 2 wherein each of m and n is zero or one.
4. A compound of Claim 3 wherein m and n are zero.
5. A compound of Claim 4 wherein each of R3 and R4 is hydrogen or a straight or branched alkyl group having from one to ten carbon atoms.
6. A compound of Claim 5 wherein each of R3 and R4 is hydrogen or a straight or branched alkyl group having from one to four carbon atoms.
7. A compound of Claim 4 wherein R5 is phenyl which is unsubstituted or is substituted with from one to three substituents selected from;
phenyl,
alkyl group having from one to six carbon atoms and which is straight or branched,
alkoxy having from one to six carbon atoms and which is straight or branched,
phenoxy,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from one to
four carbon atoms and is straight or branched,
-(CH2)pNR6R7 wherein p is zero or one and each of R5 and R6 is independently selected from hydrogen or an alkyl group having from one to four carbon atoms.
8. A compound of Claim 7 wherein R5 is phenyl substituted with from one to three substituents.
9. A compound of Claim 8 wherein R5 is phenyl
substituted with two substituents on the 2- and 6-positions.
10. A compound of Claim 9 wherein the substituents are an alkyl group having from one to six carbon atoms and which is straight or branched.
11. A compound of Claim 10 wherein the substituents are 1-methylethyl groups.
12. A compound of Claim 11 which is 3[[2,6-bis-
(dimethylamino)phenyl]amino]-3-oxopropanoic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-[[2,6-dimethylphenyl)amino]-3-oxopropionic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropionic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-[(2,6-difluorophenyl)amino]-3-oxopropanoic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-[(2,4-difluorophenyl)amino]-3-oxopropanoic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-oxo-3-[(2,4,6-trifluorophenyl)amino]propanoic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-oxo-3-[(2,4,6-trichlorophenyl)amino]propanoic acid, 2,6-bis(1-methylethyl)phenyl ester,
3-oxo-3-(phenylamino)propanoic acid, 2,6-bis(1- methylethyl)phenyl ester,
3-oxo-3[(2,4,6-trimethoxyphenyl)amino]propanoic acid, 2,6-bis(1-methylethyl)phenyl ester
3-[bis(phenylmethyl)amino]-3-oxopropanoic acid, 2,6-bis(1-methylethyl)phenyl ester, or 3-[(diphenylmethyl)amino]-3-oxopropanoic acid, 2,6-bis(1-methylethyl) phenyl ester.
13. A compound of Claim 9 which is 3-[[2,6-bis(1- methylethyl)phenyl]amino]-3-oxopropanoic acid,
2,6-dimethylphenyl ester
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 2,6-dimethoxylphenyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxo- propionic acid, 1,1':3',1"-terphen-2'-yl ester;
(Z)-3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 9-octadecenyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, octyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, decyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, tetradecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3-oxo-
1,1-dimethylethyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1-cyclopropyl-1-methylethyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1,1-dimethylbutyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, undecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, hexadecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, octadecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1,1-dimethyltridecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1-methylundecyl ester; 3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, methyIpentadecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1,1-dimethylpentyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-2,2- dimethyl-3-oxopropanoic acid, ethyl ester;
3-[(2,4-difluorophenyl)amino]-3-oxopropanoic acid, 1-methyltridecyl ester;
3-[(2,4,6-trimethyoxyphenyl)amino]-3-oxopropanoic acid, 1-methyltridecyl ester;
3-[[2,6-bis(1-methylethyl)phenyl]amino]-2,2- dimethylpropanoic acid, 1-methyltridecyl ester; 3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1-methylhexyl ester; and 3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1-methylnonyl ester.
14. A compound of Claim 4 wherein R5 is a straight or branched hydrocarbon chain having from 1 to
20 carbon atoms and which is saturated or contains from one to three double bonds.
15. A compound of Claim 14 wherein the hydrocarbon chain is saturated.
16. A compound of Claim 15 which is 3-[[2,6-bis(1- methylethyl)phenyl]amino]-3-oxopropanoic acid, dodecyl ester or
(±)-3-[[2,6-bis(1-methylethyl)phenyl]amino]-3- oxopropanoic acid, 1-methyltridecyl ester.
17. A compound of Claim 5 wherein R is the group
substituents selected from straight or branched alkyl having from one to six carbon atoms, straight or branched alkoxy having from one to six carbon atoms, phenoxy, hydroxy, fluorine chlorine, bromine, nitro, trifluoromethyl, -COOH,
-COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched or -(CH2)pNR6R7, or wherein p is zero or one and each of R6 and R7 is independently selected from hydrogen or an alkyl group having from one to four carbon atoms or R10 is a 5- or 6-membered monocyclic or fused bicyclic heterocycle
containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member; or when R8 is hydrogen each of R9 and R10 is
independently selected from phenyl, phenyl substituted with from one to three substituents selected from straight or branched alkyl having from one to six carbon atoms, straight or
branched alkoxy having from one to six carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein the alkyl moiety has from one to
four carbon atoms, or -(CH2)pNR6R7 wherein p, R6 and R7 have the meanings defined above, or a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least one to
four nitrogen, oxygen, or sulfur atoms in at least one ring member.
18. A compound of Claim 4 wherein one of R1 and R2 is the group
(a)
R10 is phenyl, phenyl substituted with from one to three substituents selected from straight or branched alkyl having from one to six carbon atoms, straight or branched alkoxy having from one to six carbon atoms, phenoxy, hydroxy, fluorine chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or - (CH2)pNR6R7 wherein p is zero or one and each of R6 and R7 is independently selected from hydrogen or an alkyl group having from one to four carbon atoms, or R10 is a 5- or 6- membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen, oxygen or sulfur atoms in at least one ring member; or when R8 is hydrogen each of R9 and R10 is independently selected from phenyl, phenyl substituted with from one to three substituents selected from straight or branched alkyl having from one to six carbon atoms, straight or branched alkoxy having from one to six carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or -(CH2)pNR6R7 wherein p, R6, and R7 have the meanings defined above, or a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least one to four nitrogen oxygen or sulfur atoms in at least one ring member;
(b) a straight or branched hydrocarbon chain
having from 1 to 20 carbon atoms and which is saturated or contains from one to
three double bonds; or
(c) phenyl or phenyl substituted with from one to three substituents selected from
phenyl,
an alkyl group having from one to six carbon atoms and which is straight or branched, an alkoxy group having from one to six carbon atoms and which is straight or branched, phenoxy,
hydroxy,
fluorine,
chlorine,
bromine,
nitro,
trifluoromethyl
-COOH,
-COOalkyl wherein the alkyl moiety has from one to four carbon atoms and is straight or branched, or -(CH2)pNR6R7 wherein p, R6, and
R7 have the meanings defined above.
19. A compound of Claim 18 wherein one of R1 and R2 is the group 
wherein t, w, R8, R9, and R10 have the meanings defined in Claim 18.
20. A compound of Claim 18 wherein one of R1 and R2 is a straight or branched hydrocarbon chain.
21. A compound of Claim 18 wherein one of R1 and R2 is phenyl or phenyl substituted with from one to three substituents.
22. A compound of Claim 18 wherein one or R1 and R2 is phenyl substituted with two substituents in the 2- and 6-positions.
23. A compound of Claim 22 wherein the substituents are an alkyl group having from one to six carbon atoms and which is straight or branched.
24. A compound of Claim 23 wherein the substituents are 1-methylethyl.
25. A pharmaceutical composition comprising a
compound of Claim 1 and a pharmaceutically acceptable carrier.
26. A method of treating atherosclerosis in a patient in need of treatment which comprises
administering to said patient an effective amount of a compound of Claim 1.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50831590A | 1990-04-11 | 1990-04-11 | |
| US508,315 | 1990-04-11 | ||
| US66781391A | 1991-03-15 | 1991-03-15 | |
| US667,813 | 1991-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1991015464A1 true WO1991015464A1 (en) | 1991-10-17 |
Family
ID=27056152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1991/002441 WO1991015464A1 (en) | 1990-04-11 | 1991-04-09 | Amide ester acat inhibitors |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7745991A (en) |
| PT (1) | PT97310A (en) |
| WO (1) | WO1991015464A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5420339A (en) * | 1993-11-22 | 1995-05-30 | Warner-Lambert Company | Alpha-aryl or heteroaryl-substituted amide ester ACAT inhibitors |
| EP1680409A2 (en) * | 2003-10-24 | 2006-07-19 | Auspex Pharmaceuticals, Inc. | Ph sensitive prodrugs of 2,6-diisopropylphenol |
| US7205440B2 (en) | 2001-12-19 | 2007-04-17 | Lanxess Deutschland Gmbh | Method of producing amines |
| US7589239B2 (en) | 2005-09-02 | 2009-09-15 | Auspex Pharmaceuticals | Therapeutic agents for the treatment of cancer, metabolic diseases and skin disorders |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5238908A (en) * | 1989-08-31 | 1993-08-24 | Rohm And Haas Company | Herbicidal glutaramic acids and derivatives |
| FR2673625B1 (en) * | 1991-03-08 | 1993-05-07 | Adir | NOVEL ACYLAMINOPHENOL DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
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-
1991
- 1991-04-09 AU AU77459/91A patent/AU7745991A/en not_active Abandoned
- 1991-04-09 WO PCT/US1991/002441 patent/WO1991015464A1/en not_active Application Discontinuation
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5420339A (en) * | 1993-11-22 | 1995-05-30 | Warner-Lambert Company | Alpha-aryl or heteroaryl-substituted amide ester ACAT inhibitors |
| WO1995014657A1 (en) * | 1993-11-22 | 1995-06-01 | Parke, Davis & Company | Alpha-aryl or heteroaryl-substituted amide ester acat inhibitors |
| US5502198A (en) * | 1993-11-22 | 1996-03-26 | Warner-Lambert Company | α-aryl or heteroaryl-substituted amide ester ACAT inhibitors |
| US7205440B2 (en) | 2001-12-19 | 2007-04-17 | Lanxess Deutschland Gmbh | Method of producing amines |
| EP1680409A2 (en) * | 2003-10-24 | 2006-07-19 | Auspex Pharmaceuticals, Inc. | Ph sensitive prodrugs of 2,6-diisopropylphenol |
| US7250412B2 (en) * | 2003-10-24 | 2007-07-31 | Auspex Pharmaceuticals, Inc. | PH sensitive prodrugs of 2,6-Diisopropylphenol |
| EP1680409A4 (en) * | 2003-10-24 | 2007-12-05 | Auspex Pharmaceuticals Inc | Ph sensitive prodrugs of 2,6-diisopropylphenol |
| US7691904B2 (en) | 2003-10-24 | 2010-04-06 | Auspex Pharmaceuticals, Inc | pH sensitive prodrugs of 2,6-diisopropylphenol |
| US7589239B2 (en) | 2005-09-02 | 2009-09-15 | Auspex Pharmaceuticals | Therapeutic agents for the treatment of cancer, metabolic diseases and skin disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| PT97310A (en) | 1992-01-31 |
| AU7745991A (en) | 1991-10-30 |
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