WO2002053540A1 - Aspartate derivative of amlodipine as calcium channel antagonist - Google Patents
Aspartate derivative of amlodipine as calcium channel antagonist Download PDFInfo
- Publication number
- WO2002053540A1 WO2002053540A1 PCT/NL2001/000603 NL0100603W WO02053540A1 WO 2002053540 A1 WO2002053540 A1 WO 2002053540A1 NL 0100603 W NL0100603 W NL 0100603W WO 02053540 A1 WO02053540 A1 WO 02053540A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- amlodipine
- salt
- pharmaceutically acceptable
- Prior art date
Links
- OWGHROPUZICLBA-UHFFFAOYSA-N CCOC(C(C1c(cccc2)c2Cl)=C(COCCNC(CC(O)=O)C(O)=O)NC(C)=C1C(OC)=O)=O Chemical compound CCOC(C(C1c(cccc2)c2Cl)=C(COCCNC(CC(O)=O)C(O)=O)NC(C)=C1C(OC)=O)=O OWGHROPUZICLBA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/90—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having more than three double bonds between ring members or between ring members and non-ring members
-
- 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
-
- 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
- the present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
- the present invention relates to a novel derivative of Amlodipine.
- Calcium channel blockers (calcium antagonists) are useful in treating cardiac conditions including angina and/or hypertension.
- Dicarboxylate-dihydropyridine derivatives are generally known to possess calcium channel blocking activity.
- EP 089 167 and corresponding US 4,572,909 disclose a class of 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as being useful calcium channel blockers.
- These patents identify that one of the most preferred compounds is 2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6- methyl- 1 ,4-dihydropyridine.
- This compound, which is now commonly known as amlodipine has the following formula:
- Amlodipine exhibits good bioavailability and has a long half-life in the body. While a variety of acid addition salts are taught in these patents to be suitable, the maleate salt is identified as the most preferred acid addition salt. However, the commercial product of amlodipine (NORNASC by Pfizer) uses amlodipine besylate (benzene sulfonate) and not amlodipine maleate. Indeed, subsequent patents EP 244 944 and corresponding US 4,879,303 indicate that the besylate salt provides certain advantages over the known salts including good formulating properties. Apparently, amlodipine maleate suffered from tabletting and stability problems so as to cause a switch during development to the besylate salt. (See “Review of Original ⁇ DA" for ⁇ DA# 19-787 of 10.10.1990, obtainable from FDA under Freedom of Information Act ). The stability and tabletting issues/causes are not publicly disclosed in the information available from the FDA.
- the present invention relates to the discovery of a novel derivative of amlodipine, the use thereof, and methods of making the same. Specifically, the present invention provides a compound of the following formula (1):
- the compound of formula (1) is useful as a calcium channel blocker and thus further aspects of the invention relate to a pharmaceutical composition comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient as well as to a method of treating angina or hypertension by administering to a patient in need thereof an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof.
- the present invention can be used in combination with amlodipine as a pharmaceutically active ingredient composition.
- Fig. 1 shows an ⁇ -NMR of the compound produced in Example 1.
- Fig. 2 shows a C-NMR of the compound produced in Example 1.
- the compound of formula (1) can be described as N-(2- ⁇ [4-(2-chlorophenyl)- 3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-l,4-dihydro-2- pyridinyl]methoxy ⁇ ethyl)aspartic acid. It is understood that the compound represented by formula (1) may exist as the free acid form or as the corresponding zwitter ion form and that while both forms are included within the meaning of the structural formula, for simplicity sake, only the free acid form is shown.
- the compound of formula (1) can be in the form of a salt and is typically a pharmaceutically acceptable salt.
- Salts include those formed with a metal cation such as an alkali metal cation; those formed with ammonia or an amine compound including mono-, di-, or tri-alkylamine compounds and ring amine compounds; or with an acid. More specifically, metal salts include sodium, potassium and lithium salts of the compound of formula (1).
- Ammonia and amine salts include salts made with ammonium, methylamine, dimethylamine, triethylamine, pyridine, and amlodipine.
- Suitable acid salts include inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, acetic, propionic, maleic, fumaric, tartaric, benzoic, methane sulfonic, and benzene sulfonic acid. Salts can also be formed with ambivalent compounds such as aminoacids, e.g. glycine or alanine.
- the salt of the compound of formula (1) can be a mono-salt, a di-salt, or a mixed salt.
- Preferred salts include salts made with a pharmaceutically acceptable acid, especially maleic acid.
- the compound of formula (1) and its salts are normally solid at room temperature and can be crystalline or amorphous.
- the crystalline forms include anhydrate forms, hydrated forms and solvate forms.
- the compound may be isolated and thus of relatively high purity, typically greater than 50 wt % pure, preferably greater than 75 weight % pure, more preferably greater than 90 weight % pure. However, relatively impure forms are also included as are dissolved forms.
- the compound of formula (1) can be made by reacting amlodipine or a salt thereof with maleic acid. The reaction is illustrated below.
- the formation reaction of the compound of formula (1) can be carried out by bringing amlodipine free base or a salt thereof and maleic acid into intimate contact with each other.
- amlodipine and maleic acid under mild conditions, such as good conditions for acid addition salt formation, can result in low conversion rates and very low yields; e.g. no formation, due to short contact times.
- the reaction is essentially a Michael addition and is thus advanced by using conditions of higher pH, higher temperature, and longer reaction or contact time.
- the reaction is preferably carried out in a melt phase or in a solution.
- a "melt phase" means that amlodipine is melted at least momentarily while in the presence of maleic acid.
- the temperature is preferably at least 60°C, more preferably at least 80°C, and typically within the range of 85°C to 110°C.
- solvents suitable for the addition reaction are polar aprotic solvents, for example N,N-dimethylformamide, alcohols such as ethanol and isopropanol, esters such as ethyl acetate, and hydrocarbons such as toluene.
- the amlodipine and maleic acid are normally combined in approximately stoichiometric ratios, namely 0.9:1 to 1:0.9.
- a convenient method to carry out the reaction is to melt amlodipine maleate.
- amlodipine free base and amlodipine maleate can be combined in a solvent or dry mixed and melted, etc., to carry out the reaction.
- amlodipine such as in the case where a mixture of amlodipine and a compound of formula (1) is desired.
- a large molar excess of amlodipine to maleic acid may be used, e.g. up to 50:1, more typically up to 20:1, and generally 2: 1 to 10:1 of amlodipine to maleic acid on a molar basis to form the desired mixture.
- Amlodipine free base may be prepared according to the procedures generally outlined in patent No U.S. 4,572,909. Another useful synthesis scheme for making amlodipine or salts thereof in good yields and purity via a phthalimidoamlodipine intermediate is described in commonly-owned provisional application serial No. 60/258,613, filed December 29, 2000, the entire contents of which are incorporated herein by reference, and in commonly-owned co-pending U.S. patent application serial No. 09/809,351, filed on March 16, 2001 and entitled "Process for Making Amlodipine, Derivatives Thereof, and Precursors Therefor," the entire contents of which are incorporated herein by reference. Maleic acid is commercially available.
- the compound (1) may be isolated from the reaction medium by conventional methods such as evaporation, precipitation, or by extraction and crystallisation.
- the compound of formula (1) can be purified by recrystallization from a solution or hot slurry, for example at reflux temperature in an appropriate solvent, e.g., an ester such as ethyl acetate, an alcohol such as ethanol, propan-2-ol or butan-2- ol, or a ketone such as acetone.
- the enantiomers may be separated by crystallization or chromatography, optionally in the form of a salt, for example as salt with an optically active base or acid by methods generally known in the art.
- Other salts of compound (1) may be formed by reaction with an equivalent amount of a base, such as for example sodium hydroxide to form a sodium or di- sodium salt of the compound of formula (1).
- the compound of formula (1) and its pharmaceutically acceptable salts are useful calcium channel blockers and thus can be used to treat any cardiac condition that would be benefited by administration of a calcium channel blocker.
- the calcium channel blocking activity of the compound of the invention is useful calcium channel blockers and thus can be used to treat any cardiac condition that would be benefited by administration of a calcium channel blocker.
- the compound of formula (1) and its pharmaceutically acceptable salts can be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need thereof.
- the specific form of angina is not particularly limited and specifically includes chronic stable angina pectoris and vasospastic angina (Prinzmetal's angina).
- the compound can be administered by any suitable route including orally or parenterally.
- the "patients" intended to be treated include human and non-human animals especially non-human mammals.
- a further aspect of the invention is a pharmaceutical composition for treating or preventing hypertension or angina that comprises an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
- Excipients include any inert or non-active material used in making a pharmaceutical dosage form.
- tablet excipients include, but are not limited to, calcium phosphate, cellulose, starch or lactose.
- Capsules such as those made of gelatin, may contain or carry the compound of formula (1) or a pharmaceutically acceptable salt thereof alone or in admixture with other excipients.
- Liquid dosage forms are also included such as oral liquids in the form of liquors or suspensions, as well as injectable solutions.
- the pharmaceutical composition may be formulated for transdermal administration in the form of a patch. All of the above-described pharmaceutical compositions may optionally contain one or more of each of the following excipients: carriers, diluents, colorants, flavoring agents, lubricants, solubilizing agents, disintegrants, binders and preservatives.
- the pharmaceutical composition is normally provided in a unit dose.
- a unit dose is typically administered once or twice daily, more typically once daily.
- the unit dose (one patch) is generally applied at least once a month, more commonly at least once a bi-week, and typically once a week.
- An effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof in a unit dose for treating or preventing hypertension or angina is generally within the range of 0.1 to 100 mg, typically 1 to 100, more typically 1 to 50 mg, and normally 1 to 20 mg.
- the pharmaceutical composition typically contains about 1, 2.5, 5.0, or 10 mg of the compound of formula (1) or a pharmaceutically acceptable salt thereof.
- the pharmaceutically active ingredient composition comprises (a) 100 parts by weight of amlodipine or a pharmaceutically acceptable salt thereof and (b) about 0.1 to about 1000 parts by weight, usually 0.5 to 500 parts by weight, more typically 2 to 100 parts by weight of a compound of formula (1) or a pharmaceutically acceptable salt thereof.
- the amlodipine is preferably in the form of an acid addition salt, especially the maleate salt.
- the compound of formula (1) is preferably the free base or an acid addition salt, especially the maleate salt.
- the blend may be obtained directly by controlling the reaction conditions and duration in forming the compound of formula (1); e.g by using elevated temperatures, prolonged contact, proper ratios of maleic acid to amlodipine, etc.
- the pharmaceutically active ingredient composition can be formed by blending the amlodipine compound with the compound of formula (1) (or their respective salt forms, etc.) in the desired ratio.
- the pharmaceutically active ingredient composition can be used in like manner as the compound of formula (1) to form a pharmaceutical composition for treating hypertension or angina.
- a pharmaceutical composition comprises an effective amount of the pharmaceutically active ingredient composition and a pharmaceutically acceptable excipient as previously described.
- the unit dose contains between 0.1 and 100 mg, typically 1 to 100, more typically 1 to 50 mg such as 1 to 20 mg and specifically the solid oral dosage forms (tablets, capsules, etc.) typically contain 1, 2.5, 5.0, or 10 mg of the pharmaceutically active ingredient composition.
- the stated amounts refer to the weight corresponding to the sum of the free base of the amlodipine and the compound of formula (1).
- the pharmaceutically active ingredient composition per se or in the form of a pharmaceutical composition can be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need thereof.
- the tablets can be made by dry granulation/direct compression or by a classical wet granulation method.
- capsules can be made by blending the ingredients and filling the capsule.
- a suitable pharmaceutical composition for the above-described pharmaceutically active ingredient composition, having good stability can be obtained by selecting the excipients so as to have a pH of less than 7.0, when measured as a 20 wt % aqueous slurry, as is more fully described in commonly-owned co-pending U.S. patent application serial No. 09/809,346, filed on March 16, 2001, and entitled "Pharmaceutical Compositions Comprising Amlodipine Maleate,” the entire contents of which are incorporated herein by reference.
- amlodipine aspartate of formula (1) is as a reference standard or reference marker for evaluating the purity of amlodipine maleate and pharmaceutical compositions comprising amlodipine maleate as is more fully described in commonly-owned U.S. patent application serial No. 09/809,347, filed on March 16, 2001, and entitled "Reference Standard For Determining The Purity or Stability of Amlodipine Maleate and Processes Therefor," the entire contents of which are incorporated herein by reference.
- the following Examples illustrate the invention.
- the H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated dimethylsulfoxide at 400 MHz. It is represented on Fig.1.
- Example 2 A mixture of amlodipine maleate and the compound of formula (1)
- compositions containing the compound of Formula (1)
- amlodipine aspartate is sieved through a 500 ⁇ m screen.
- the calcium hydrogenphosphate anhydrous, magnesium oxide, microcrystalline cellulose, sodium starch glycollate and magnesium stearate are sieved through a 850 ⁇ m screen.
- the amlodipine aspartate, magnesium oxide and about 30 % of the amount of microcrystalline cellulose (MCC) are mixed in a free fall mixer for 10 minutes at about 25 rpm.
- MCC calcium hydrogenphopsphate anhydrous and sodium starch glycollate
- the remaining amount of MCC, calcium hydrogenphopsphate anhydrous and sodium starch glycollate are added and the blend is mixed for 15 minutes at about 25 rpm.
- Magnesium stearate is added and the powder blend is mixed for another 5 minutes at about 25 rpm.
- compositions containing the compound of Formula (1)
- the Amlodipine aspartate is sieved through a 500 ⁇ m screen.
- the calcium hydrogenphosphate anhydrous, magnesium oxide, microcrystalline cellulose, sodium starch glycollate and magnesium stearate are sieved through a 850 ⁇ m screen.
- Amlodipine aspartate, microcrystalline cellulose, calcium hydrogenphopsphate anhydrous and sodium starch glycollate are transferred into a free fall mixer and the blend is mixed for 15 minutes at about 25 rpm.
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002433191A CA2433191A1 (en) | 2000-12-29 | 2001-08-15 | Aspartate derivative of amlodipine as calcium channel antagonist |
BR0116553-4A BR0116553A (en) | 2000-12-29 | 2001-08-15 | Compound, pharmaceutical composition for treating angina or hypertension, process, process for treating or preventing angina or hypertension, composition of pharmaceutically active ingredients, pharmaceutical composition for treatment or prevention of angina or hypertension and process for treating or preventing angina or hypertension |
MXPA03005886A MXPA03005886A (en) | 2000-12-29 | 2001-08-15 | Aspartate derivative of amlodipine as calcium channel antagonist. |
GB0131064A GB2372036B (en) | 2000-12-29 | 2001-08-15 | Aspartate derivative of amlodipine |
EP01974985A EP1309558A1 (en) | 2000-12-29 | 2001-08-15 | Aspartate derivative of amlodipine as calcium channel antagonist |
IE20011105A IES20011105A2 (en) | 2000-12-29 | 2001-12-21 | Aspartate derivative of amlodipine |
HU0105456A HUP0105456A3 (en) | 2000-12-29 | 2001-12-27 | Aspartate derivative of amlodipine, process for producing it and pharmaceutical composition containing it |
CA002366391A CA2366391C (en) | 2000-12-29 | 2001-12-28 | Aspartate derivative of amlodipine |
GR20010100602A GR1004124B (en) | 2000-12-29 | 2001-12-28 | Aspartate derivative of amlodipine |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25860200P | 2000-12-29 | 2000-12-29 | |
US60/258,602 | 2000-12-29 | ||
US80934901A | 2001-03-16 | 2001-03-16 | |
US09/809,349 | 2001-03-16 | ||
BE2001/0712A BE1014455A6 (en) | 2000-12-29 | 2001-11-05 | New amlodipine aspartate derivative useful for treatment and prevention of angina and hypertension |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002053540A1 true WO2002053540A1 (en) | 2002-07-11 |
Family
ID=29740328
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL2001/000603 WO2002053540A1 (en) | 2000-12-29 | 2001-08-15 | Aspartate derivative of amlodipine as calcium channel antagonist |
Country Status (14)
Country | Link |
---|---|
US (1) | US6479525B2 (en) |
EP (1) | EP1309558A1 (en) |
BE (1) | BE1014455A6 (en) |
BR (1) | BR0116553A (en) |
CA (2) | CA2433191A1 (en) |
CR (1) | CR7011A (en) |
DE (1) | DE20116170U1 (en) |
GB (1) | GB2372036B (en) |
GR (1) | GR1004124B (en) |
HU (1) | HUP0105456A3 (en) |
IE (1) | IES20011105A2 (en) |
MX (1) | MXPA03005886A (en) |
WO (1) | WO2002053540A1 (en) |
ZA (1) | ZA200110470B (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100756565B1 (en) * | 2000-04-11 | 2007-09-07 | 상꾜 가부시키가이샤 | Stabilized pharmaceutical compositions containing calcium channel blockers |
WO2002053542A1 (en) * | 2000-12-29 | 2002-07-11 | Pfizer Limited | Process for making amlodipine maleate |
MXPA03005882A (en) * | 2000-12-29 | 2005-04-19 | Pfizer Ltd | Amide derivative of amlodipine. |
WO2002053541A1 (en) * | 2000-12-29 | 2002-07-11 | Pfizer Limited | Amide derivative of amlodipine |
US6653481B2 (en) * | 2000-12-29 | 2003-11-25 | Synthon Bv | Process for making amlodipine |
KR100467669B1 (en) * | 2002-08-21 | 2005-01-24 | 씨제이 주식회사 | An organic acid salt of amlodipine |
TW200806648A (en) * | 2005-11-29 | 2008-02-01 | Sankyo Co | Acid addition salts of dihydropyridine derivatives |
TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
EP3960158A1 (en) | 2016-10-07 | 2022-03-02 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
US10799453B2 (en) | 2018-04-11 | 2020-10-13 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4572909A (en) * | 1982-03-11 | 1986-02-25 | Pfizer Inc. | 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents |
US4879303A (en) * | 1986-04-04 | 1989-11-07 | Pfizer Inc. | Pharmaceutically acceptable salts |
Family Cites Families (16)
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US4983740A (en) | 1986-08-04 | 1991-01-08 | Adir Et Compagnie | Process for 1,4-dihydropyridine compounds |
GB8710493D0 (en) | 1987-05-02 | 1987-06-03 | Pfizer Ltd | Dihydropyridines |
US5155120A (en) | 1991-01-14 | 1992-10-13 | Pfizer Inc | Method for treating congestive heart failure |
WO1993006082A1 (en) | 1991-09-13 | 1993-04-01 | Merck & Co., Inc. | Process for the preparation of 4-substituted-1,4-dihydropyridines |
US5389654A (en) | 1992-11-26 | 1995-02-14 | Lek, Tovarna, Farmacevtskih In Kemicnih . . . | 3-ethyl 5-methyl(±)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate |
HU221810B1 (en) | 1997-08-12 | 2003-01-28 | EGIS Gyógyszergyár Rt. | Process for producing amlopidine besylate and the intermediates |
ZA9810320B (en) | 1997-11-14 | 2000-05-11 | Gea Farmaceutisk Fabrik As | Process for the preparation of 1,4-dihydropyridines and novel compounds of use for such purpose. |
PL189666B1 (en) | 1998-04-09 | 2005-09-30 | Adamed Sp Z Oo | Method of obtaining amlopidine benzenosulphonate |
GB9812413D0 (en) | 1998-06-10 | 1998-08-05 | Glaxo Group Ltd | Compound and its use |
ES2151850B1 (en) | 1998-10-26 | 2001-08-16 | Esteve Quimica Sa | INTERMEDIATE FOR THE SYNTHESIS OF AMLODIPINO FOR ITS OBTAINING AND CORRESPONDING USE. |
GB9827387D0 (en) | 1998-12-11 | 1999-02-03 | Smithkline Beecham Plc | Novel process |
GB9827431D0 (en) | 1998-12-11 | 1999-02-03 | Smithkline Beecham Plc | Novel compound |
GB2371862B (en) | 2000-12-29 | 2004-07-14 | Bioorg Bv | Reference standards for determining the purity or stability of amlodipine maleate and processes therefor |
AT5874U1 (en) * | 2000-12-29 | 2003-01-27 | Bioorg Bv | PHARMACEUTICAL PREPARATIONS CONTAINING AMLODIPINMALEAT |
WO2002053542A1 (en) * | 2000-12-29 | 2002-07-11 | Pfizer Limited | Process for making amlodipine maleate |
GB0114709D0 (en) | 2001-06-15 | 2001-08-08 | Pfizer Ltd | Stabilised formulations of amlodipine maleate |
-
2001
- 2001-08-15 MX MXPA03005886A patent/MXPA03005886A/en active IP Right Grant
- 2001-08-15 GB GB0131064A patent/GB2372036B/en not_active Expired - Fee Related
- 2001-08-15 CA CA002433191A patent/CA2433191A1/en not_active Abandoned
- 2001-08-15 WO PCT/NL2001/000603 patent/WO2002053540A1/en active Application Filing
- 2001-08-15 BR BR0116553-4A patent/BR0116553A/en not_active Application Discontinuation
- 2001-08-15 EP EP01974985A patent/EP1309558A1/en not_active Withdrawn
- 2001-08-27 US US09/938,817 patent/US6479525B2/en not_active Expired - Fee Related
- 2001-10-02 DE DE20116170U patent/DE20116170U1/en not_active Ceased
- 2001-11-05 BE BE2001/0712A patent/BE1014455A6/en not_active IP Right Cessation
- 2001-12-20 ZA ZA200110470A patent/ZA200110470B/en unknown
- 2001-12-21 IE IE20011105A patent/IES20011105A2/en not_active IP Right Cessation
- 2001-12-27 HU HU0105456A patent/HUP0105456A3/en unknown
- 2001-12-28 GR GR20010100602A patent/GR1004124B/en unknown
- 2001-12-28 CA CA002366391A patent/CA2366391C/en not_active Expired - Fee Related
-
2003
- 2003-06-26 CR CR7011A patent/CR7011A/en not_active Application Discontinuation
Patent Citations (2)
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US4572909A (en) * | 1982-03-11 | 1986-02-25 | Pfizer Inc. | 2-(Secondary aminoalkoxymethyl) dihydropyridine derivatives as anti-ischaemic and antihypertensive agents |
US4879303A (en) * | 1986-04-04 | 1989-11-07 | Pfizer Inc. | Pharmaceutically acceptable salts |
Non-Patent Citations (2)
Title |
---|
ARROWSMITH J E ET AL: "LONG-ACTING DIHYDROPYRIDINE CALCIUM ANTAGONISTS. 1. 2-ALKOXYMETHYL DERIVATIVES INCORPORATING BASIC SUBSTITUENTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 29, no. 9, 1986, pages 1696 - 1702, XP002070765, ISSN: 0022-2623 * |
See also references of EP1309558A1 * |
Also Published As
Publication number | Publication date |
---|---|
GB2372036B (en) | 2004-05-19 |
GR20010100602A (en) | 2002-10-09 |
GB2372036A (en) | 2002-08-14 |
DE20116170U1 (en) | 2002-04-04 |
GR1004124B (en) | 2003-01-24 |
CR7011A (en) | 2004-03-10 |
ZA200110470B (en) | 2002-07-11 |
HUP0105456A2 (en) | 2002-10-28 |
CA2366391C (en) | 2005-10-18 |
HUP0105456A3 (en) | 2004-01-28 |
GB0131064D0 (en) | 2002-02-13 |
BR0116553A (en) | 2004-02-03 |
US6479525B2 (en) | 2002-11-12 |
EP1309558A1 (en) | 2003-05-14 |
BE1014455A6 (en) | 2003-10-07 |
CA2433191A1 (en) | 2002-07-11 |
CA2366391A1 (en) | 2002-06-29 |
IES20011105A2 (en) | 2002-12-30 |
US20020128296A1 (en) | 2002-09-12 |
HU0105456D0 (en) | 2002-02-28 |
MXPA03005886A (en) | 2005-04-19 |
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