EP1292363A2 - Carboxyalkylether-acat inhibitor combinations - Google Patents
Carboxyalkylether-acat inhibitor combinationsInfo
- Publication number
- EP1292363A2 EP1292363A2 EP01937250A EP01937250A EP1292363A2 EP 1292363 A2 EP1292363 A2 EP 1292363A2 EP 01937250 A EP01937250 A EP 01937250A EP 01937250 A EP01937250 A EP 01937250A EP 1292363 A2 EP1292363 A2 EP 1292363A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- phenyl
- pharmaceutical composition
- acat inhibitor
- carbon atoms
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
-
- 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
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- 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
- A61P9/12—Antihypertensives
Definitions
- This invention relates to combinations of carboxyalkylether compounds with compounds which inhibit acyl-coenzyme A: cholesterol acyltransferase, and to a method for treating dyslipidemias employing such combinations.
- LDL low-density lipoprotein
- acyl-coenzyme A.cholesterol acyltransferase ACAT
- ACAT acyl-coenzyme A.cholesterol acyltransferase
- HDL-C high-density lipoproteins
- a drug which reduces the levels of atherogenic LDL-C and VLDL-C and elevates levels of protective HDL-C will produce a less atherogenic lipoprotein profile and thus a beneficial effect on atherosclerotic disease and its complications.
- This beneficial effect was demonstrated in man in the Helsinki Heart Study with the lipid regulator gemfibrozil which decreased LDL-C, increased HDL-C, and reduced the incidence of coronary artery disease (N. Eng. J. Med., 1987;317:1237-1245 and N. Eng. J.
- ACAT inhibitors Compounds which inhibit acyl-coenzyme A: cholesterol acyltransferase are known as ACAT inhibitors. Certain ACAT inhibitors and the methods for preparing them are taught in U.S. Patent Nos. 5,491,172 and 5,633,287, which are incorporated herein by reference. One such ACAT inhibitor currently undergoing clinical evaluation is avasimibe, also known as CI-1011 and PD-148515.
- U.S. Patent No. 5,648,387 discloses a group of compounds known as carboxyalkyiethers.
- the compounds are reported to be useful for treating dyslipidemias and atherosclerosis.
- the compounds alter various forms of lipoprotein cholesterol; for example, they elevate HDL-C and lower LDL-C, and are thus useful for treating patients with, or at risk of developing, ischemic syndromes. They are also reported to increase insulin sensitivity.
- One carboxyalkylether currently undergoing clinical evaluation is CI-1027.
- combination therapy with a carboxyalkylether and an ACAT inhibitor results in dramatic improvement in lipid control. Accordingly, such combinations are especially useful in treating dyslipidemias and associated complications such as ischemic syndromes, including heart attacks and related cardiovascular disorders.
- Carboxyalkyiethers are compounds characterized by having two alkyl groups linked through an oxygen atom, wherein the alkyl groups are substituted by a carboxy group or equivalent carboxy mimics.
- Typical carboxyalkyiethers are those described in U.S. Patent No. 5,648,387 (this and all other references cited are incorporated herein by reference); compounds of Formula 1
- n and m independently are integers from 2 to 9;
- R] independently are C2-C alkyl, CJ-CQ alkenyl, C2-C5 alkynyl, and Rj and R2 together with the carbon to which they are attached, and R3 and R4 together with the carbon to which they are attached, can complete a carbocyclic ring having from 3 to 6 carbons;
- Y and Y2 independently are COOH, CHO, tetrazole, and COOR5 where R5 is
- Preferred compounds to be employed in this invention have the above formula wherein n and m are the same integer, and wherein R ⁇ , R2, R3, and R4 each are alkyl.
- Y and Y2 independently are COOH or COOR5 where R 5 is alkyl.
- n and m are each an integer selected from 2, 3, 4, or 5, ideally 4 or 5.
- An especially preferred compound has the Formula III
- the combinations of this invention can also employ the pharmaceutically acceptable salts of the acids of the above formulas.
- the monocalcium salt of the compound of Formula III is now referred to as "CI-1027" and is currently being developed for clinical treatment of dyslipidemias, and is especially preferred according to this invention.
- ACAT acyl-coenzyme A:cholesterol acyltransferase
- X and Y are selected from oxygen, sulfur, and (CR'R") n , wherein n is an integer of from 1 to 4 and R' and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, phenyl, optionally substituted or R' and R" together form a spirocycloalkyl or a carbonyl; with the proviso at least one of the X and Y is (CR'R") n and with the further proviso when X and Y are both (CR'R") n , and R' and R" are hydrogen and n is 1, Ri and R2 are aryl;
- R is hydrogen, a straight or branched alkyl of from 1 to 8 carbon atoms or benzyl; R ⁇ and R2 are each independently selected from
- alkyl has from 1 to 4 carbon atoms and is straight or branched, -(CH2)pNR3R4 wherein p is 0 or 1, and each of R3 and R4 is selected from hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms;
- alkyl has from 1 to 4 carbon atoms and is straight or branched, -(CH2)pNR3R4 wherein p, R3, and R4 have the meanings defined above;
- the ACAT inhibitor for use in the novel method may be selected from any effective compound, especially compounds of Formula IV above, especially sulfamic acid, [[2,4,6-tris(methylethyl)-phenyl]acetyl]-, 2,6-bis[( 1 -methylethyl)phenyl ester; 2,6-bis( 1 -methylethyl)phenyl- [[2,6-bis(l -methylethyl)-phenyl]sulfonyl]carbamate monosodium salt; N-(2,6-di-isopropyl-phenyl)-2-phenyl-malonamic acid dodecyl ester; N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- acetamide; 2,2-dimethyl-N- [2,4,6-trimethoxyphenyl)-docecanamide; and
- the dosage of each agent will vary depending upon the severity of the disease, the frequency of administration, the particular agents and combinations utilized, and other factors routinely considered by an attending medical practitioner.
- the carboxyalkylether normally will be administered at a daily dose of from about 0.25 mg to about 1500 mg, typically about 150 mg to about 1000 mg.
- a typical dosage for CI-1027, for example, will be about 150 to about 900 mg per day.
- the ACAT inhibitor will normally be administered at doses from about 50 mg to about 1500 mg per day, and more typically from about 100 mg to about 600 mg per day.
- a preferred ACAT inhibitor is CI-1011, and it will be employed at doses from about 50 mg to about 750 mg per day.
- the invention provides compositions of a carboxyalkylether and an ACAT inhibitor, and a method of treating dyslipidemia and controlling ischemic syndromes comprising administering to a patient in need of treatment an effective amount of a carboxyalkylether and an effective amount of an ACAT inhibitor.
- the amounts to be used are those that are effective for achieving an improvement in ischemic syndromes and/or dyslipidemias.
- the compositions will contain about one to about 1000 parts by weight of carboxyalkylether, and about 1000 to about one part by weight ACAT inhibitor.
- a typical composition of CI-1027 and CI-1011 will contain about 500 mg of CI-1027 and about 500 mg of CI-1011.
- 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 encapsulating material.
- Liquid form preparations include solutions, suspensions, or emulsions suitable for oral administration.
- Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
- Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceutical formulation art.
- the pharmaceutical preparation is in unit dosage form. In such form, the preparation is divided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of these packaged forms.
- the dosage forms are well within the skill of a physician who will be familiar with such factors as time of day and other pertinent considerations.
- any ACAT inhibitor can be used in combination with any carboxyalkylether.
- a preferred ACAT inhibitor is CI-1011.
- ACAT inhibitors are 2,6-bis-(l-methylethyl)-phenyl[[2,6-bis(l- methylethyl) phenoxy] -sulfonylj-carbamate monosodium salt; and similar compounds are disclosed in U.S. Patent No. 5,245,068; N-(2,6-diisopropyl- phenyl)-2-phenyl-malonamic acid dodecyl ester; and similar compounds are disclosed in U.S. States Patent No.
- CI-1027 and the combination of both compounds was assessed in a rabbit cuff model of atherosclerosis.
- the assay was carried out according to the following protocol.
- a chronic mechanical injury is created by placing a sterile, flexible polyethylene or silicone cuff around the left carotid artery of adult rabbits.
- the insult can be further enhanced by the inclusion of inflammatory agents, cytoldnes, or oxidative stress products dispersed in pluronic gel that would be encased by the collar.
- the periarterial sheath will be approximately 1 cm in length with a 1.8 mm inside diameter, and 3 mm outside diameter.
- the collars are biologically inert and will not obstruct blood flow.
- the progression study can include an acclimation period to the atherogenic diet for 1 to 2 weeks prior to surgical manipulation.
- the rabbits will be allocated according to their plasma total cholesterol levels.
- Drug treatment would commence at the time of surgery and would continue for 3 weeks. In the regression study, the surgery would be concurrent with cholesterol feeding. Lesions would develop for an additional 3 weeks.
- the animals will then be allocated into treatment groups based on their plasma total cholesterol levels. Afterwards, drug treatment would follow for the final 3 weeks. All compounds to be evaluated will be administered as an admixture to the cholesterol diet. Results are summarized in Table 1 below.
- Control 126 ⁇ 9.6 49 ⁇ 2.3 5 ⁇ 0.2 9.4 + 0.5 33 ⁇ 2.4 2.3 ⁇ 0.2
- TG Triglyceride
- Cholesterol Total cholesterol
- VLDL Very low-density cholesterol
- LDL Low-density cholesterol
- HDL High-density cholesterol
- HDL/VLDL+LDL HDL divided by the sum of VLDL and LDL.
- the method of treating dyslipidemia and ischemic syndromes employing a combination of a carboxyalkylether and an ACAT inhibitor also will be established in a long-term controlled clinical evaluation.
- the study will determine the efficacy and safety of the ACAT inhibitor alone and in combination with the carboxyalkylether for the treatment of dyslipidemias and ischemic syndromes. This study will target the segment of the population at risk for developing a heart attack.
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US21005600P | 2000-06-07 | 2000-06-07 | |
US210056P | 2000-06-07 | ||
PCT/US2001/014804 WO2001093845A2 (en) | 2000-06-07 | 2001-05-08 | Carboxyalkylether-acat inhibitor combinations |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1292363A2 true EP1292363A2 (en) | 2003-03-19 |
Family
ID=22781424
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01937250A Withdrawn EP1292363A2 (en) | 2000-06-07 | 2001-05-08 | Carboxyalkylether-acat inhibitor combinations |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1292363A2 (en) |
JP (1) | JP2003535125A (en) |
AR (1) | AR034255A1 (en) |
AU (1) | AU2001263003A1 (en) |
BR (1) | BR0111428A (en) |
CA (1) | CA2413906A1 (en) |
GT (1) | GT200100106A (en) |
MX (1) | MXPA02010762A (en) |
PA (1) | PA8518601A1 (en) |
PE (1) | PE20020265A1 (en) |
SV (1) | SV2002000466A (en) |
TN (1) | TNSN01085A1 (en) |
UY (1) | UY26752A1 (en) |
WO (1) | WO2001093845A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7387236B2 (en) | 2001-10-09 | 2008-06-17 | Delaware Capital Formation, Inc. | Dispensing of currency |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100592842B1 (en) * | 1998-01-28 | 2006-06-26 | 워너-램버트 캄파니 엘엘씨 | Method for Treating Alzheimer's Disease |
-
2001
- 2001-05-08 WO PCT/US2001/014804 patent/WO2001093845A2/en active Application Filing
- 2001-05-08 AU AU2001263003A patent/AU2001263003A1/en not_active Abandoned
- 2001-05-08 MX MXPA02010762A patent/MXPA02010762A/en not_active Application Discontinuation
- 2001-05-08 EP EP01937250A patent/EP1292363A2/en not_active Withdrawn
- 2001-05-08 JP JP2002501418A patent/JP2003535125A/en active Pending
- 2001-05-08 CA CA002413906A patent/CA2413906A1/en not_active Abandoned
- 2001-05-08 BR BR0111428-0A patent/BR0111428A/en not_active IP Right Cessation
- 2001-05-24 SV SV2001000466A patent/SV2002000466A/en not_active Application Discontinuation
- 2001-06-05 GT GT200100106A patent/GT200100106A/en unknown
- 2001-06-05 PE PE2001000517A patent/PE20020265A1/en not_active Application Discontinuation
- 2001-06-05 PA PA20018518601A patent/PA8518601A1/en unknown
- 2001-06-05 UY UY26752A patent/UY26752A1/en not_active Application Discontinuation
- 2001-06-05 TN TNTNSN01085A patent/TNSN01085A1/en unknown
- 2001-06-06 AR ARP010102688A patent/AR034255A1/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0193845A2 * |
Also Published As
Publication number | Publication date |
---|---|
MXPA02010762A (en) | 2003-03-10 |
JP2003535125A (en) | 2003-11-25 |
AU2001263003A1 (en) | 2001-12-17 |
PE20020265A1 (en) | 2002-04-19 |
GT200100106A (en) | 2002-05-20 |
WO2001093845A2 (en) | 2001-12-13 |
WO2001093845A3 (en) | 2002-10-10 |
BR0111428A (en) | 2003-06-10 |
PA8518601A1 (en) | 2002-07-30 |
UY26752A1 (en) | 2001-07-31 |
CA2413906A1 (en) | 2001-12-13 |
TNSN01085A1 (en) | 2005-11-10 |
SV2002000466A (en) | 2002-04-03 |
AR034255A1 (en) | 2004-02-18 |
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Legal Events
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Extension state: AL LT LV MK RO SI |
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17P | Request for examination filed |
Effective date: 20030410 |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: ZOBEL, DONNA,LEE Inventor name: AUERBACH, BRUCE JEFFREY |
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17Q | First examination report despatched |
Effective date: 20041020 |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: WARNER-LAMBERT COMPANY LLC |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: WARNER-LAMBERT COMPANY LLC |
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Effective date: 20041020 |
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Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 20071005 |