USRE37721E1 - Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents - Google Patents
Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents Download PDFInfo
- Publication number
- USRE37721E1 USRE37721E1 US09/594,996 US59499600A USRE37721E US RE37721 E1 USRE37721 E1 US RE37721E1 US 59499600 A US59499600 A US 59499600A US RE37721 E USRE37721 E US RE37721E
- Authority
- US
- United States
- Prior art keywords
- azetidinone
- phenyl
- hydroxy
- compound
- methoxyphenyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased, expires
Links
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to hydroxy-substituted azetidinones useful as hypocholesterolemic agents in the treatment prevention of atherosclerosis, and to the combination of a hydroxy-substituted azetidinone of this invention and a cholesterol bioxynthesis inhibitor for the treatment and prevention of atherosclerosis.
- the invention also relates to a process for preparing hydroxy-substituted azetidinones.
- Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, cigar smoke and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk of CHD.
- Cholesteryl esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesteryl esters is also a key step in the intestinal absorption of dietary cholesterol. Thus, inhibition of cholesteryl ester formation and reduction of serum cholesterol is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesteryl esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.
- U.S. Pat. No. 4,983,597 discloses N-sulfonyl-2-azetidinones as anticholesterolemic agents and Ram, et al., in Indian J. Chem., Sect. B. 29B, 12 (1990), p. 1134-7, disclose ethyl 4-(2-oxoazetidin-4-yl)phenoxy-alkanoates as hypolipidemic agents.
- European Patent Publication 264,231 discloses 1-substituted-4-phenyl-3-(2-oxo-alkylidene)-2-azetidinones as blood platelet aggregation inhibitors.
- European Patent 199,630 and European Patent Application 337,549 disclose elastase inhibitory substituted azetidinones said to be useful treating inflammatory conditions resulting in tissue destruction which are associated with various disease states, e.g. atherosclerosis.
- WO93/102048 published Feb. 4, 1993, discloses substituted ⁇ -lactams useful as hypocholesterolemic agents.
- the regulation of whole-body cholesterol homeostasis in humans and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteinis.
- the liver is the major organ responsible for cholesterol biosynthesis and catabolism and for this reason, it is a prime determinant of plasma cholesterol levels.
- the liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation.
- VLDL very low density lipoproteins
- LDL low density lipoproteins
- LDL are the predominant cholesterol-carrying lipoproteins in the plasma and an increase in their concentration is correlated with increased atherosclerosis.
- VLDL hepatic lipoprotein
- HMG CoA reductase EC1.1.1.34
- HMG CoA reductase inhibitors EC1.1.1.34
- Combination therapy of an HMG CoA reductase inhibitor and a bile acid sequestrant has been demonstrated to be more effective in human hyperlipidemic patients than either agent in monotherapy (Illingworth, Drugs, 36 (Suppl. 3) (1988), p. 63-71).
- Novel hypocholesterolemic compounds of the present invention are represented by the formula I
- Ar 1 and Ar 2 are independently selected from the group consisting of aryl and R 4 -substituted aryl;
- Ar 3 is aryl or R 5 -substituted aryl
- X, Y and Z are independently selected from the group consisting of —CH 2 —, —CH(lower alkyl)— and —C(dilower alkyl)—;
- R and R 2 are independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9 and —O(CO)NR 6 R 7 ;
- R 1 and R 3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
- R 4 is 1-5 substituents independently selected from the group consisting of lower alkyl, —OR 6 , —O(CO)R 6 , R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-5 OR 6 , —O(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO)R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO) NR 7 R 8 , —NR 6 SO 2 R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , —(lower alkylene)COOR 6 , —CH ⁇ CH—COOR 6 , —CF 3 , —CN, —NO 2 and halogen;
- R 5 is 1-5 substituents independently selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 9 , —O(CH 2 ) 1-5 OR 6 , —O(CO)NR 6 R 7 , —NR 6 R 7 , —NR 6 (CO) R 7 , —NR 6 (CO)OR 9 , —NR 6 (CO)NR 7 R 8 , —NR 6 SO 2 R 9 , —COOR 6 , —CONR 6 R 7 , —COR 6 , —SO 2 NR 6 R 7 , S(O) 0-2 R 9 , —O(CH 2 ) 1-10 —COOR 6 , —O(CH 2 ) 1-10 CONR 6 R 7 , —(lower alkylene)COOR 6 and —CH ⁇ CH—COOR 6 ;
- R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
- R 9 is lower alkyl, aryl or aryl-substituted lower alkyl.
- R 4 is preferably 1-3 independently selected substituents, and R 5 is preferably 1-3 independently selected substituents.
- Ar 3 is preferably R 5 -substituted phenyl, especially (4-R 5 )-substituted phenyl.
- R 4 is preferably a halogen.
- R 4 is preferably halogen or —OR 6 and R 5 is preferably —OR 6 , wherein R 6 is lower alkyl or hydrogen.
- R 4 is preferably halogen or —OR 6 and R 5 is preferably —OR 6 , wherein R 6 is lower alkyl or hydrogen.
- R 6 is lower alkyl or hydrogen.
- Especially preferred are compounds wherein each of Ar 1 and Ar 2 is 4-fluorophenyl and Ar 3 is 4-hydroxyphenyl or 4-methoxyphenyl.
- X, Y and Z are each preferably —CH 2 —.
- R 1 and R 3 are each preferably hydrogen.
- R and R 2 are preferably —OR 6 wherein R 6 is hydrogen, or a group readily metabolizable to a hydroxyl (such as —O(CO)R 6 , —O(CO)OR 9 and —OR 6 , especially —O(CO)NR 6 R 7 , defined above).
- the sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.
- Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2. Also preferred are compounds wherein p, q and n are each zero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, n and r are each zero, q is 1, p is 2, Z is —CH 2 and R is —OR 6 OR 6 , especially when R 6 is hydrogen. Also more preferred are compounds wherein p, q and n are each zero, r is 1, m is 2, X is —CH 2 — and R 2 is —OR 6 , especially when R 6 is hydrogen.
- Ar 1 is phenyl or R 4 -substituted phenyl
- Ar 2 is phenyl or R 4 -substituted phenyl
- Ar 3 is R 5 -substituted phenyl.
- Ar 1 is phenyl or R 4 -substituted phenyl
- Ar 2 is phenyl or R 4 -substituted phenyl
- Ar 3 is R 5 -substituted phenyl
- the sum of m, n, p, q and r is 2, 3 or 4, more especially 3.
- Ar 1 is phenyl or R 4 -substituted phenyl
- Ar 2 is phenyl or R 4 -substituted phenyl
- Ar 3 is R 5 -substituted phenyl
- m, n and r are each zero, q is 1 and p is 2, or wherein p, q and n are each zero, r is 1 and m is 2 or 3.
- This invention also relates to a method of lowering the serum cholesterol level in a mammal in need of such treatment comprising administering an effective amount of a compound of formula I. That is, the use of a compound of the present invention as an hypocholesterolemic agent is also claimed.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a serum cholesterol-lowering effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
- the present invention also relates to a method of reducing plasma cholesterol levels, and to a method of treating or preventing atherosclerosis, comprising administering to a mammal in need of such treatment an effective amount of a combination of a hydroxy-substituted azetidinone cholesterol absorption inhibitor of formula I and a cholesterol biosynthesis inhibitor. That is, the present invention relates to the use of a hydroxy-substituted azetidinone cholesterol absorption inhibitor of formula I for combined use with a cholesterol biosynthesis inhibitor (and, similarly, use of a cholesterol biosynthesis inhibitor for combined use with a hydroxy-substituted azetidinone cholesterol absorption inhibitor of formula I) to treat or prevent atherosclerosis or to reduce plasma cholesterol levels.
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of a hydroxy-substituted azetidinone cholesterol absorption inhibitor of formula I, a cholesterol biosynthesis inhibitor, and a pharmaceutically acceptable carrier.
- the invention relates to a kit comprising in one container an effective amount of a hydroxy-substituted azetidinone cholesterol absorption inhibitor of formula I in a pharmaceutically acceptable carrier, and in a separate container, an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier.
- the invention relates to a process for preparing certain compounds of formula I comprising the steps:
- R′ and R 2 ′ are R and R 2 , respectively, or are suitably protected hydroxy groups
- Ar 10 is Ar 1 , a suitably protected hydroxy substituted aryl or a suitably protected amino-substituted aryl; and the remaining variables are as defined above, provided that in lactone of formula B when n and r are each zero, p is 1-4;
- step (b) reacting the product of step (a) with an imine of the formula
- Ar 20 is Ar 2 , a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl
- Ar 30 is Ar 3 , a suitably protected hydroxy-substituted aryl or a suitably protected amino-substituted aryl
- lower alkyl means straight or branched alkyl chains of 1 to 6 carbon atoms.
- Aryl means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.
- Halogen refers to fluorine, chlorine, bromine or iodine atoms.
- R 6 , R 7 and R 8 are said to be independently selected from a group of substituents, means that R 6 , R 7 and R 8 are independently selected, but also that where an R 6 , R 6 or R 8 variable occurs more than once in a molecule, those occurrences are independently selected (e.g., if R is —OR 6 wherein R 6 is hydrogen, R 4 can be —OR 6 wherein R 6 is lower alkyl).
- Compounds of the invention have at least one asymmetric carbon atom and therefore all isomers, including enantiomers and diastereomers are contemplated as being part of this invention.
- the invention includes d and I l isomers in both pure form and in admixture including racemic mixtures.
- Isomers can be prepared using conventional techniques, either by reacting chiral starting materials or by separating isomers of a compound of formula I. Isomers may also include geometric isomers, e.g. when a double bond is present. All such geometric isomers are contemplated for this invention.
- Compounds of the invention with an amino group can form pharmaceutically acceptable salts with organic and inorganic acids.
- suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art.
- the salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
- the free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate.
- the free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base form for purposes of the invention.
- Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
- Cholesterol biosynthesis inhibitors for use in the combination of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin, and Cl-981; HMG CoA synthetase inhibitors, for example L-659,699 ((E,E)-11-[3′-R-(hydroxy-methyl)-4′-oxo-2′-R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example squalestatin 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanamine hydrochloride) and other cholesterol biosynthesis inhibitors
- a solubilizing agent such as hexamethylphosphoric triamide (HMPA) may optionally be added as a cosolvent.
- An imine of formula 11, wherein Ar 20 and Ar 30 are as defined above, is added, the reaction mixture is either warmed to room temperature or maintained at a suitable low temperature such as ⁇ 78° C. for the appropriate time, followed by quenching with a suitable acid such as 1N HCl.
- the product is isolated using conventional purification techniques.
- a protecting group as defined in Table 1 (below) is present on one or more of the optionally protected groups, an additional step comprising removal of the protecting group by conventional techniques is needed.
- Imines of formula II (Ar 30 —CH ⁇ N—Ar 20 ) can be prepared from aldehydes of the formula Ar 30 —CHO and amines of the formula Ar + —CHO and Ar 20 —NH 2 by procedures well known in the art.
- Aldehydes of formula Ar + Ar 30 —CHO and amines of formula Ar 20 —NH 2 are commercially available or can be prepared via known procedures.
- a strong base such as an alkyllithium (e.g., n-butyl-lithium),
- the reaction is carried out at about 0° C. to about ⁇ 85° C., preferably about ⁇ 78° C., over a period of about 5 to about 60 minutes, preferably about 30 minutes.
- 1-50% of solubilizing cosolvents may optionally be added, preferably about 10% HMPA.
- step (b) Add an imine of formula 11, wherein Ar 20 and Ar 30 are as defined above, to the product of step (a) over a period of 5 to 60 minutes, preferably 30 minutes, maintaining the reaction mixture at about 0° C. to about ⁇ 85° C., preferably about ⁇ 78° C., for 1 to 12 hours, preferably about 3 hours, or warming the reaction mixture over that time period at a rate of about 10° C. per hour to about 70° C. per hour, preferably about 30° C. per hour, to a temperature of about 20° C.
- treatment of the alcohol with an alkyl halide in the presence of a suitable base such as NaH will afford alkoxy-substituted compounds (i.e., R or R 2 is OR 6 , wherein R 6 is lower alkyl); treatment of the alcohol with an acylating agent such as acetylchloride will result in compounds wherein R or R 2 is —OC(O)R 6 ; treatment of the alcohol with phosgene followed by an alcohol of the formula HOR 9 affords compounds substituted with a —OC (O)OR 9 group; and treatment of the alcohol with phosgene followed by an amine of the formula HNR 6 R 7 affords compounds wherein R or R 2 is —OC(O)NR 6 R 7 .
- a suitable base such as NaH
- step c, d or e is isolated using conventional purification techniques such as extraction, crystallization or, preferably, silica gel 60 chromatography.
- purification techniques such as extraction, crystallization or, preferably, silica gel 60 chromatography.
- the resulting compound of formula Ic or Id is not racemic.
- lactones of formula IVa can be used to prepare compounds of formula Ig and Ih, provided that when n and r are each zero, p is 1-4:
- Lactones of formulae IV and IVa are known in the art or can be prepared by methods well known in the art. See, for example, U.S. Pat. No. 4,375,475 and J. Agric. Food Chem., 30 (5) (1982) p. 920-4.
- Azetidinones of formula V wherein Ar 20 and Ar 30 are as defined above, can be reacted to form compounds of formula Ie and If i.e., compounds of formula I wherein r is 1, R 2 is hydroxy, and p is zero) by treatment of azetidinone V with a strong base such as lithium iosoproptylcyclohexylamide isopropylcyclohexylamide in a suitable solvent such as THF in the presence or absent absence of HMPA at ⁇ 78° C., followed by the addition of an aldehyde or ketone of VI, wherein Ar 10 , X, Y, R′, R 1 , R 3 , m, n and q are as defined above. As in the case of Method A, protecting groups at Ar 10 , Ar 20 , Ar 30 , R′ and R 2′ are removed as necessary.
- DEAD is diethylazodicarboxylate and PPh 3 is triphenylphosphine.
- the reactants are stirred at room temperature overnight and the resultant formate ester is converted to the corresponding hydroxy compound with the desired stereochemistry.
- Compounds of formula Ia as defined above can also be prepared treatment of an imine of formula 11 , II, wherein Ar 20 and Ar 30 are as defined above, with an activated carboxylic acid derivative of formula VII as defined above in the presence of a tertiary amine base such as triethylamine, tributylamine or diethylisopropylamine in an inert solvent such as CH 2 Cl 2 .
- a tertiary amine base such as triethylamine, tributylamine or diethylisopropylamine in an inert solvent such as CH 2 Cl 2 .
- compound XII is dissolved in a suitable solvent, e.g., anhydrous CH 2 Cl 2 , and treated with a Lewis acid, e.g., TiCl 4 at about ⁇ 60° C. to 0° C., preferably at about ⁇ 25° C., under a dry, inert atmosphere, e.g., argon.
- a tertiary amine base such as TMEDA is added and the mixture stirred at about ⁇ 60° C. to 0° C., preferably at about ⁇ 25° C. to ⁇ 15° C., for a period of about 1 h.
- An imine of formula Ar 30 CH ⁇ NAr 20 is added neat or optionally as a solution in a suitable solvent, e.g. anhydrous CH 2 Cl 2 , over a period of about 5 min, and the reaction is stirred vigorously at about ⁇ 60° C. to 0° C., preferably at about ⁇ 25° C. to ⁇ 15° C., for about 3 to 6 h, preferably about 4 h or until the reaction is complete by TLC.
- An acid e.g. acetic acid, is added to reaction at the reaction temperature and the mixture is allowed to warm to room temperature slowly with stirring for about 1-3 hours, preferably about 2 hours.
- the compound of formula XII is isolated by extraction with a suitable solvent, e.g. CH 2 Cl 2 , then purified by crystallization or silica gel chromatography.
- the product is treated with a strong non-nucleophilic base, such as sodium or lithium bistrimethylsilylamide at about ⁇ 78° C. to 100° C.
- a strong non-nucleophilic base such as sodium or lithium bistrimethylsilylamide
- the mixture is poured into aqueous tartaric acid and the product isolated from the organic layer.
- protecting groups at Ar 10 , Ar 20 , Ar 30 , R′ and R 2′ are removed as necessary.
- This process including the preparation of the starting material of formula XII, is also described in greater detail in WO93/02048.
- Compound of formula Ig′ and Ih′ i.e., compounds of formula I wherein R is OH
- R 2 ′ is a protected hydroxy group as defined above
- the remaining variables are as defined above
- an imine of formula 11 II and a carboxylic acid derivative of formula XIV wherein the variables are as defined above, according to Method D, followed by oxidation of the resultant halide of formula XV by treatment with an oxidizing agent such as trimethylamine oxide, CrO 3 or ozone in a solvent such as DMSO.
- the resultant aldehyde or ketone of formula XVI is then reacted with an aryl organometallic reagent (e.g., Ar 10 X m MgBr, Ar 10 X m Li, Ar 10 X m MgCl or Ar 10 X m CeCl 2 ) to obtain a compound of formula Ig′ or Ih′.
- an aryl organometallic reagent e.g., Ar 10 X m MgBr, Ar 10 X m Li, Ar 10 X m MgCl or Ar 10 X m CeCl 2
- the Ar 10 , Ar 20 , Ar 30 and R 2′ substituents can be converted to the desired Ar 1 , Ar 2 , Ar 3 and R 2 substituents by procedures well known in the art.
- Compounds of formula Ii having a hydroxy substituent on the side chain adjacent to the Ar 1 group can be prepared by heating a compound of formula XVII, prepared by Method D, above, wherein the variables are as defined above, for about 1-6 hours at about 60° C. to 100° C. with a halogenating agent such as N-bromosuccinimide (NBS) in a suitable solvent such as CCl 4 in the presence of an initiating agent such as benzoyl peroxide.
- a halogenating agent such as N-bromosuccinimide (NBS)
- N-bromosuccinimide (NBS) N-bromosuccinimide
- Compounds of formula Ij are prepared from compound XIX in 2 steps.
- a compound of formula XIX wherein the variables are as defined above, is dissolved in a suitable anhydrous solvent, e.g. THF, at about ⁇ 20° C. to about 22° C., preferably at about 0° C. under a dry inert atmosphere, e.g. argon and adding a transition metal source, e.g. tetrakis(triphenylphosphine)-palladium or palladium acetate/triphenyl phosphine.
- a suitable anhydrous solvent e.g. THF
- a dry inert atmosphere e.g. argon
- a transition metal source e.g. tetrakis(triphenylphosphine)-palladium or palladium acetate/triphenyl phosphine.
- An organometallic of formula Ar 10 -Xm m -Met wherein in Ar 10 , X and m are as defined above and Met is, for example, ZnCl or B(OH) 2 , is added to the reaction mixture at about ⁇ 20° C. to about 22° C., preferably at about 0° C., the reaction mixture is stirred for about 15 min to 4 h, preferably about 1 h, and is then allowed to warm to about 22° C. Addition of dilute acid, e.g. 1N HCl, followed by extraction with a suitable organic solvent, e.g. ethyl acetate (EtOAc), produces compound XX.
- a suitable organic solvent e.g. ethyl acetate (EtOAc)
- the ketone of-formula XX is dissolved in a suitable solvent e.g. CH 3 OH, a hydrogenation catalyst is added, e.g. Pd on carbon, and the mixture is exposed to H 2 gas under a pressure of about 14 psi to 100 psi, preferably about 60 psi for about 1 to 24 h, preferably, about 16 h.
- the hydrogenation catalyst is removed by filtration and the solvent is removed in vacuo to produce a compound Ij as a mixture of alcohol diastereomers which can be separated by conventional means.
- a ketone of formula XX is dissolved in a suitable solvent, e.g. THF, at about ⁇ 40° C. to about 22° C., preferably at about 0° C., and a suitable reducing agent such as NaBH 4 , a substituted borohydride (e.g., [cbz-proline] 3 BHNa) or a borane is adlded, optionally in the presence of a suitable chiral promotor present either in catalytic or stoichiometric amounts, e.g., chiral borane of structures:
- the reaction is conducted at about 22 ° C., and the solvent and excess reagents are removed in vacuo.
- the compound XXI is reacted with a chiral auxiliary such as ( S )- 4 - phenyl - 2 - oxazolidinone according to the following procedure; a chiral auxiliary is treated with a strong base such as an alkyllithium, a metal hydride or a tertiary amine base such as triethylamine, in a suitable anhydrous organic solvent, e.g., dry THF, under a dry, inert atmosphere, e.g.
- argon at about ⁇ 85 ° C., to 22 ° C., preferably about 0 ° C., for about 10 min to 60 min, preferably about 30 minutes.
- the resulting anion is reacted, without isolation, with compound XXI in a suitable anhydrous organic solvent, e.g. dry THF, under a dry, inert atmosphere, e.g. argon at about ⁇ 85 ° C. to about 22 ° C., preferably 0 ° C., for about 30 min to 60 min, preferably 30 min.
- the reaction is warmed to about 22 ° C. and continued for 1 to 12 h, preferably 6 h. Water is added and compound XXII is isolated by extraction and purified by crystallization.
- Azetidinone ring closure can be accomplished by alternative procedures.
- a compound of formula XXIII is treated with a strong non-nucleophilic base, such as sodium or lithium-bistrimethylsilylamide, in a suitable inert organic solvent, e.g. CH 2 Cl 2 , at about ⁇ 78° C. to about 10° C., preferably about 0° C.
- a suitable inert organic solvent e.g. CH 2 Cl 2
- the mixture is stirred for about 1 to 2 hours while gradually warming to about 22° C.
- Compound XXIV is isolated by conventional extraction with CH 2 Cl 2 .
- a compound of formula XXIII is first treated with mild silylating agent, e.g.
- N,O-bis(trimethylsilyl)acetamide at about 0° C. to about 100° C., preferably about 40° C. for about 10 min to 60 min, preferably 30 min, then treated with a fluoride anion source, e.g. tetrabutylammonium fluoride (TBAF), at about 0° C. to about 100° C., preferably 40° C., and allowed to stir for about 0.5 to about 4 hours, preferably about 2 hours.
- TBAF tetrabutylammonium fluoride
- the compound of formula XXIV is hydrolysed by a suitable base, e.g. LiOH, in a suitable solvent, e.g. 66% CH 3 OH/water at about 0° C. to about 50° C., preferably 22° C., for about 1 to 4 hours, preferably 2 hours, then extracted with a suitable solvent, e.g. EtOAc.
- a suitable solvent e.g. EtOAc.
- the resulting acid is converted to the acid chloride as described above by treatment with a chlorination agent, e.g. oxalyl chloride, to afford compound
- a compound of formula XXV which can be prepared by Method D, above, is treated with an oxidizing agent such as SeO 2 , phenylselenic anhydride or CrO 3 in a suitable solvent such as dioxane at about 22° to 100° C. for about 0.5 to 12 hours. After the starting material is consumed as determined by TLC, or 12 hours, the reaction is cooled to about 22° C. and the product XXVI is isolated by extraction.
- an oxidizing agent such as SeO 2 , phenylselenic anhydride or CrO 3
- a suitable solvent such as dioxane
- an allylic alcohol of formula XXVI is dissolved in a suitable solvent, e.g., EtOAc, a hydrogenation catalyst added, e.g., Pd on carbon, and the mixture is exposed to H 2 gas under a pressure of about 14 psi to 60 psi for about 1 to 12 hours.
- the hydrogenation catalyst is removed in vacuo to obtain a compound of formula Ik.
- Alcohols of formula Im and In i.e., compounds of formula I where r is 1, R 2 is —OH, R 3 is hydrogen and p is 0
- ketones of formula XXVII in three steps comprising bromination, reduction and debromination. Since the stereochemistry of the major isomers of alcohols XXIXa and XXIXb are different, one can selectively prepare either diastereomeric alcohol.
- a ketone of formula XXVII which can be prepared by oxidation of the corresponding hydroxy compound by well known methods, is halogenated, for example by treatment in an inert solvent, e.g., THF, with NaH followed by N-bromosuccinimide, to obtain a mixture of 3-bromo-ketone compounds XXVIII (a and b).
- an inert solvent e.g., THF
- Compounds 15 XXVIIIa and XXVIIIb are then separately reduced to the corresponding alcohols, for example by treatment with magnesium trifluoroacetate (Mg(TFA) 2 ) and t-butylamine borane (t-Bu—NH 2 —BH 3 ) in an inert solvent such as THF at a temperature of about ⁇ 78° C. to 0° C.
- Mg(TFA) 2 magnesium trifluoroacetate
- t-Bu—NH 2 —BH 3 t-butylamine borane
- the resultant alcohols XXIX are dehalogenated by treatment with tris(trimethylsilyl)silane ((TMS) 3 SiH) in a solvent such as toluene in the presence of a radical initiator such as 2,2′-azobisisobutyronitrile (AIBN) to obtain a mixture of isomers Im and In which can be separated into individual enantiomers by conventional means, e.g., HPLC.
- a radical initiator such as 2,2′-azobisisobutyronitrile (AIBN)
- Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction.
- Table 1 shows some typical protecting groups:
- compounds of this invention lower serum lipid levels, in particular serum cholesterol levels.
- Compounds of this invention have been found to inhibit the intestinal absorption of cholesterol and to significantly reduce the formation of liver cholesteryl esters in animal models.
- compounds of this invention are hypocholesterolemic agents by virtue of their ability to inhibit the intestinal absorption and/or esterification of cholesterol; they are, therefore, useful in the treatment and prevention of atherosclerosis in mammals, in particular in humans.
- Hamsters are separated into groups of six and given a controlled cholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) for seven days. Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral gavage of 0.2 mL of corn oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are anesthetized by intramuscular (IM) injection of ketamine and sacrificed by decapitation. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver excised for tissue lipid analysis.
- IM intramuscular
- Lipid analysis is conducted as per published procedures (Schnitzer-Polokoff, R., et al. Comp. Biochem. Physiol., 99A, 4 (1991), p. 665-670) and data is reported as percent reduction of lipid versus control.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
- the compounds of formula I can be administered in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution.
- the formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques.
- Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
- the daily hypocholesteremic dose of a compound of formula I is about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 mg/kg.
- the dosage level is therefore from about 5 mg to about 1000 mg of drug per day, given in a single dose of 2-4 divided doses.
- the exact dose is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
- the typical daily dose of the cholesterol biosynthesis inhibitor is 0.1 to 80 mg/kg of mammalian weight per day administered in single or divided dosages, usually once or twice a day; for example, for HMG CoA reductase inhibitors, about 10 to about 40 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 10 to 80 mg per day, and for the other cholesterol biosynthesis inhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 1 mg to about 200 mg per day.
- the exact dose of any component of the combination to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
- the number of doses of each component given per day may not necessarily be the same, e.g. where one component may have a greater duration of activity, and will therefore need to be administered less frequently.
- kits are contemplated wherein two separate units are combined: a cholesterol biosynthesis inhibitor pharmaceutical composition and a hydroxy substituted azetidinone cholesterol absorption inhibitor pharmaceutical composition.
- the kit will preferably include directions for the administration of the separate components.
- the kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals.
- LDA lithium diisopropylamide
- Step 1 To a refluxing solution of of 4-methoxyberizylidene anisidine (10.0 g, 41.5 mmol) and tributylamine (20.8 ml, 87 mmol) in toluene (100 ml), add 5-bromovaleroyl chloride (8.5 g, 43, mmol) in toluene (20 ml) dropwise over 2 h. Stir the reaction mixture at 80° C. for 12 h, cool to room temperature, wash 3 ⁇ with 1 N HCl, 1 ⁇ with water and dry the organic layer over MgSO 4 .
- Step 2 To a solution of the product of step 1 (5.1 g, 12.6 mmol) in (CH 3 ) 2 SO (20 ml), add (CH 3 ) 3 N(O) (2.39 g, 31.9 mmol). Heat the mixture at 60° C. for 3 h, cool to room temperature, dilute with EtOAc, and wash 3 ⁇ with water. Combine the aqueous fractions and extract with EtOAc. Combine the organic fractions and concentrate.
- Step 3 To a solution of the product of step 2 (0.7134 0.734 g, 2.2 mmol) in THF (4 ml) at 0° C., add phenylmagnesium bromide (2.4 ml, 2.4 mmol, 1.0 M in THF) over 0.25 h. After 1 h at 0° C., add water (5 ml), separate the layers, wash the organic layer 1 ⁇ with 1N HCl, dry with MgSO 4 and concentrate to an oil. Purify by silica gel chromatography, eluting with EtOAc:hexane (2:1) to obtain 0.372 g of the title compound (mix of diastereomers) as an oil. CI (M + H) 418.
- Step 1 To a solution of 1,4-(S)-bis(4-methoxyphenyl)-3-(3(R)-phenylpropyl)-2-azetidinone (5.04 g, 0.013 mole) in CCl 4 (20 ml) at 80° C., add NBS (2.76 g, 0.0155 mole) and benzoyl peroxide (0.24 g, 1.0 mmole) in three equal portions over 1 h.
- TLC 4:1 hexane:EtOAc
- Cool the reaction to 22° C. add NaHSO 4 , separate the layers and wash the organic layer 3 ⁇ with water. Concentrate the organic layer to obtain the crude product.
- Step 2 Dissolve the crude product of Step 1 in CH 2 Cl 2 (30 ml) and add 40% n-BuNOC(O)CF 3 in water (30 ml). Reflux the biphasic reaction for 24 h, cool, separate the layers and wash the organic layer 6 ⁇ with water. Concentrate the organic layer to dryness and immediately redissolve the residue in ethanol saturated with NH 3 (10 ml). After 1 h, concentrate the reaction mixture and partially purify by silica gel chromatography. Further purify by HPLC to obtain a 1:1 mixture of compounds 4A and 4B. The mixture can be further purified on a Chiracel OD column to obtain 4A and 4B separately as characterized above.
- Step 1) To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH 2 Cl 2 (20 ml), add 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 ml, 0.61 mol) and cool the reaction to 0° C. Add methyl-4-(chloroformyl)butyrate (50 9 g , 0.3 mol) as a solution in CH 2 Cl 2 (375 ml) dropwise over 1 h, and allow the reaction to warm to 22° C. After 17 h, add water and H 2 SO 4 (2N, 100 ml), separate the layers, and wash the organic layer sequentially with NaOH (10%). NaCI (sat'd) and water. Dry the organic layer over MgSO 4 and concentrate to obtain a semicrystalline product.
- 4-dimethylaminopyridine 2.5 g, 0.02 mol
- triethylamine 84.7 ml, 0.61
- Step 2 To a solution of TiCl 4 (18.2 ml, 0.165 mol) in CH 2 Cl 2 (600 ml) at 0° C., add titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min, add the product of Step 1 (49.0 9, 0.17 mol) as a solution in CH 2 Cl 2 (100 ml). After 5 min., add diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) and stir at 0° C. for 1 h, cool the reaction mixture to ⁇ 20° C., and add 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) as a solid.
- DIPEA diisopropylethylamine
- Step 3 To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 ml) at 50° C., add N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3 mmol). After 0.5 h, add solid TBAF (0.39 g, 1.5 mmol) and stir the reaction at 50° C. for an additional 3 h. Cool the reaction mixture to 22° C., add CH 3 OH (10 ml), wash the reaction mixture with HCl (1N), NaHCO 3 (1N) and NaCI (sat'd), and dry the organic layer over MgSO 4 .
- BSA N,O-bis(trimethylsilyl)acetamide
- Step 4) To a solution of the product of Step 3 (0.94 g, 2.2 mmol) and CH 3 OH (3 ml), add water (1 ml) and LiOH.H 2 O (102 mg, 2.4 mmole). Stir the reaction at 22° C. for 1 h and add additional LiOH.H 2 O (54 mg, 1.3 mmole). After a total of 2 h, add HCl (1N) and EtOAc, separate the layers, dry the organic layer and concentrate in vacuo. To a solution of resultant product (0.91 g, 2.2 mmol) in CH 2 Cl 2 at 22° C., add ClCOCOCl (0.29 ml, 3.3 mmol) and stir for 16 h. Remove the solvent in vacuo.
- Step 5 To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide 5 (1M in THF, 4.4 ml, 4.4 mmol) and ZnCl 2 (0.6 g, 4.4 mmol) at 4° C., add tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) and the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). Stir the reaction for 1 h at 0° C. and then for 0.5 h at 22° C. Add HCl (1N, 5 ml) and extract with EtOAc.
- Step 6) To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), add (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole (120 mg, 0.43 mmol) and cool the mixture to ⁇ 20° C. After 5 min, add borohydride-dimethylsulfide complex (2M in THF: 0.85 ml, 1.7 mmol) dropwise over 0.5 h.
- 2M in THF 0.85 ml, 1.7 mmol
- Step 6′ (Alternative): To a solution of the product of Step 5 (0.14 g, 0.3 mmol) in ethanol (2 ml), add 10% Pd/C (0.03 g) and stir the reaction under a pressure (60 psi) of H 2 gas for 16 h. Filter the reaction mixture and concentrate the solvent to afford a 1:1 mixture of compounds 6A and 6B.
- Example 4A To a solution of the product of Example 4A (90 mg, 0.2 mmol) in CH 2 Cl 2 , add acetyl chloride (80 mg, 1.0 mmol) and pyridine (8 mg, 0.1 mmol) and stir at room temperature for 1 h. Add water, separate the layers and isolate the corresponding acetoxy compound, 8A. In a similar manner, treat the products of Examples 4B, 6B and 6A to obtain the following compounds 8B, 8° C. and 8D, respectively:
- compositions comprising a cholesterol biosynthesis inhibitor are well known in the art. It is contemplated that where the two active ingredients are administered as a single composition, the dosage forms disclosed above for substituted azetidinone compounds may readily be modified using the knowledge of one skilled in the art.
Abstract
Description
TABLE 1 | |
Group to be | Group to be Protected and |
Protected | Protecting Group |
—COOH | —COOalkyl, —COObenzyl, —COOphenyl |
|
|
|
|
|
|
—NH2 |
|
—OH |
|
—OSi(CH3)3, or —OCH2phenyl | |
3A |
|
1H in CDCl3:7.32-7.18(m, 11H); 7.08-6.99 (m, 1H); 6.89(d, J = 9 Hz, 2H); 4.80(d, J = 2.4 Hz, 1H); 4.10-4.00(m, 1H); 3.79(s, 3H); 3.20-3.16(m, 1H); 2.90-2.67(m, 2H); 2.15-1.85(m, 3H) |
3B |
|
1H in CDCl3:7.35-7.10(m, 11H); 7.08-6.99 (m, 1H); 6.89(d, J = 9 Hz, 2H); 5.09(d, J = 2.4 Hz, 1H); 4.26-4.14(m, 1H); 3.79(s, 3H); 3.21-3.14(m, 1H); 2.89-2.57(m, 2H); 2.10-1.85(m, 3H) |
3C |
|
1H in CDCl3:7.30-7.00(m, 10H); 6.99 (d, J = 8 Hz, 2H); 6.83(d, J = 9 Hz, 2H); 5.12(d, J = 5.5 Hz, 1H); 3.82(s, 3H); 3.75-3.63(m, 1H); 3.52(dd, J = 9.5 Hz, 1H); 2.71-2.57(m, 1H); 2.49-2.33(m, 1H); 1.68-1.50(m, 1H); 1.47-1.31)m, 1H) |
Tablets |
No. | Ingredient | mg/tablet | mg/tablet |
1 | Active Compound | 100 | 500 |
2 | Lactose USP | 122 | 113 |
3 | Corn Starch, Food Grade, as a 10% | 30 | 40 |
paste in Purified Water | |||
4 | Corn Starch, Food Grade | 45 | 40 |
5 | Magnesium Stearate | 3 | 7 |
Total | 300 | 700 | |
Capsules |
No. | Ingredient | mg/tablet | mg/tablet |
1 | Active Compound | 100 | 500 |
2 | Lactose USP | 106 | 123 |
3 | Corn Starch, Food Grade | 40 | 70 |
4 | Magnesium Stearate NF | 4 | 7 |
Total | 250 | 700 | |
% Reduction |
Serum | Cholest. | Dose | |||
Ex. # | Cholest. | Esters | mg/kg | ||
1A | −23 | 0 | 50 | ||
1B | −15 | −39 | 50 | ||
1C | 14 | 0 | 50 | ||
2 | 0 | 0 | 50 | ||
3A | −31 | −69 | 50 | ||
3C | −60 | −92 | 50 | ||
3D | −17 | −61 | 10 | ||
3E | 0 | 0 | 10 | ||
3F | −29 | −77 | 10 | ||
3G | −16 | −38 | 10 | ||
3H | −41 | −86 | 10 | ||
3I | 0 | −22 | 10 | ||
3J | 0 | 0 | 3 | ||
3K | 0 | 0 | 10 | ||
3L | −15 | −21 | 10 | ||
3M | 0 | −22 | 10 | ||
4A | 0 | −54 | 5 | ||
4B | −37 | −89 | 8 | ||
4C | −12.5 | 0 | 3 | ||
4D | 9 | 0 | 7 | ||
4E | 0 | −46 | 3 | ||
4F | −29 | −95 | 3 | ||
5 | 0 | −64 | 10 | ||
6A | −59 | −95 | 1 | ||
6A-1 | −43 | −93 | 1 | ||
6B | −40 | −92 | 3 | ||
6C | 0 | −48 | 3 | ||
6D | −46 | −95 | 10 | ||
8A | 0 | −44 | 3 | ||
8B | −50 | −95 | 3 | ||
8C | −14 | −37 | 1 | ||
8D | −49 | −98 | 1 | ||
8E | −22 | −66 | 3 | ||
8F | −43 | −94 | 1 | ||
10 | −26 | −77 | 3 | ||
Claims (13)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/797,341 USRE42461E1 (en) | 1993-09-21 | 1994-09-14 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US09/594,996 USRE37721E1 (en) | 1993-09-21 | 2000-06-15 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10244093A | 1993-09-21 | 1993-09-21 | |
US08/257,593 US5631365A (en) | 1993-09-21 | 1994-06-09 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US08/617,751 US5767115A (en) | 1993-09-21 | 1996-03-18 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US09/594,996 USRE37721E1 (en) | 1993-09-21 | 2000-06-15 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
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US12/797,341 Reissue USRE42461E1 (en) | 1993-09-21 | 1994-09-14 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
Publications (1)
Publication Number | Publication Date |
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USRE37721E1 true USRE37721E1 (en) | 2002-05-28 |
Family
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US12/797,341 Expired - Lifetime USRE42461E1 (en) | 1993-09-21 | 1994-09-14 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US08/617,751 Expired - Lifetime US5767115A (en) | 1993-09-21 | 1996-03-18 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US08/953,825 Expired - Lifetime US5846966A (en) | 1993-09-21 | 1997-10-14 | Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors |
US09/594,996 Ceased USRE37721E1 (en) | 1993-09-21 | 2000-06-15 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
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US12/797,341 Expired - Lifetime USRE42461E1 (en) | 1993-09-21 | 1994-09-14 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US08/617,751 Expired - Lifetime US5767115A (en) | 1993-09-21 | 1996-03-18 | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
US08/953,825 Expired - Lifetime US5846966A (en) | 1993-09-21 | 1997-10-14 | Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors |
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