WO1995020568A1 - Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker - Google Patents
Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker Download PDFInfo
- Publication number
- WO1995020568A1 WO1995020568A1 PCT/IE1995/000011 IE9500011W WO9520568A1 WO 1995020568 A1 WO1995020568 A1 WO 1995020568A1 IE 9500011 W IE9500011 W IE 9500011W WO 9520568 A1 WO9520568 A1 WO 9520568A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- blocker
- boc
- pharmaceutical product
- derivative
- aspirinate
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- 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
- A61P9/08—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
Definitions
- the invention relates to pharmaceutical products.
- ß Blocker refers to pharmacologically active ß Blocker compounds which relieve or act as prophylactic against cardiovascular disease including hypertension, angina pectoris (pain in the heart muscle), cardiac failure, or after a heart attack (post myocardial infarction).
- Beta-adrenoceptor blocking agents or antagonists are competitive inhibitors of catecholamines at beta-adrenergic receptor sites.
- the principal effect of beta blockers is to reduce cardiac activity by diminishing or preventing beta-adrenergic receptor stimulation.
- Beta blockers inhibit the secretion of renin and alter the sensitivity of the baroreceptor reflex, they also block the sympathetic drive to the heart. This reduces the chronotropic and inotropic responses during exercise and stress thus limiting oxygen requirements.
- the beta blockers are effective in reducing the severity and frequency of exertion angina (i.e. pain in the heart brought on by exercise) that is for angina pectoris.
- Beta blockers are also important in anti hypertensive therapy (lowering of blood pressure). This is thought to be achieved through the reduction of heart output, and in the inhibition of renin secretion and a change in the sensitivity of the baroreceptor reflex.
- Aspirin acetylsalicylic acid
- Aspirin has been widely used for many years as an analgesic/anti-pyretic and anti- inflammatory agent. As such, it is a most useful drug.
- Aspirin has a powerful anti-platelet effect. Platelets are microscopic particles within the blood that, under certain circumstances, can stick together to form a thrombus (clot). Aspirin prevents the sticking together of platelets and thus helps prevent the occurrence of heart attack or its complications.
- a pharmaceutical product comprising a salicylate of an esterifiable ß Blocker.
- salicylate refers to a salicylate or a salt, ester, derivative, complex thereof, or salts of the ester, derivative or complex having anti-platelet activity.
- the ß Blocker is directly esterifiable.
- the ß Blocker has an hydroxy group which is available for esterification.
- the product is formed by esterification of an esterifiable ß Blocker with acetylsalicylic acid.
- the ß Blocker is Atenolol.
- the invention further provides Atenolol-O-aspirinate and enantiomer(s) thereof.
- the ß blocker is Metoprolol.
- the invention also provides Metoprolol-O-Aspirinate.
- the ß blocker is Pindalol.
- the invention further provides Pindalol-O-Aspirinate.
- the invention also provides a process for preparing a pharmaceutical product of the invention by esterifying an esterifiable ⁇ blocker with acetylsalicylic acid.
- the process involves esterifying an esterifiable ⁇ blocker with salicylic acid.
- the process comprises the steps of :- protecting the secondary amine group in the ⁇ blocker; activating the carboxyl group in salicylic acid or derivative thereof; direct coupling of the activated carboxyl group of the salicylic acid or derivative thereof; and removing protecting groups from the secondary amine group in the ⁇ blocker.
- the secondary the secondary amine group in the ⁇ blocker is protected by forming an N-BOC derivative of the ⁇ blocker secondary amine and, after coupling, the N-BOC protecting group is removed.
- the N-BOC derivative of the ⁇ blocker is formed by reaction between the ß blocker secondary amine and di-t-butyl in t-BuOH/H 2 O to form the tert-butyloxycarbamide derivative.
- the N-BOC protecting group is removed using trifluoro-acetic acid to form the trifluoroacetate salt of the Aspirinate.
- the process includes the step of forming the ⁇ blocker Aspirinate base by extraction from a weakly alkaline medium.
- the process includes the steps of acidifying an alcoholic solution of the Aspirinate base in an acid to form a pharmaceutically acceptable salt.
- the carboxyl group in salicylic acid or derivative thereof is activated by one or more of :- acid chloride formation; pentafluorothioester formation; or in situ formation of 2,6 dichlorobenzoyl anhydride.
- the ⁇ is coupled with acetylsalicylic acid derivative having an activated carboxyl group.
- the ⁇ blocker is coupled with a salicylic acid derivative having a protected hydroxy group.
- the hydroxy group is protected by benzyl ether formation.
- salicylic acid is converted into O-benzyloxy benzoic acid.
- the process also includes removing the salicylic acid hydroxy protection group after coupling.
- the protected salicylic acid hydroxy group is removed by hydrogenolysis.
- the salicylic acid derivative is acylated.
- the process comprises the steps of :- forming a protected salicylic acid hydroxy group; forming an N-BOC derivative of the ⁇ blocker secondary amine; coupling of the protected salicylic acid with the N-BOC ⁇ blocker; removing the protecting group from the salicylic acid hydroxy group; acylating the salicylic acid; and removing the N-BOC protecting group.
- the process comprises the steps of :- forming an N-BOC derivative of the ⁇ blocker secondary amine; direct coupling of the N-BOC derivative of the ⁇ blocker with acetylsalicylic acid ; removing the N-BOC protecting group .
- the process comprises the steps of forming acetylsalicoyl chloride; forming an N-BOC derivative of the ⁇ blocker secondary amine; direct coupling of the N-BOC ⁇ blocker with acetylsalicoyl chloride; and removing the N-BOC protecting group.
- the process preferably include the step, after removal of the protecting group, of forming the ⁇ blocker aspirinate base; and, optionally, forming pharmaceutically acceptable salts thereof by acidification of an alcoholic solution of the base using appropriate acids.
- the invention further provides a pharmaceutical product whenever prepared by a process of the invention.
- the invention also provides a pharmaceutical composition including a pharmaceutical product of the invention.
- the composition is preferably in the form of a tablet or capsule.
- ß Blockers and their salts, their enantiomers and their salts, derivatives (eg esters) and their salts are all 2-ethanolamine derivatives. More specifically they are compounds of the formula
- Atenolol is (RS)-4-(2-hydroxy-3-isopropyl-aminopropoxy)phenylacetamide-British Pharmacopoeia 1993 Volume I page 55.
- ARCH 2 CO 2.45 singlet ArOCOCH 3 : 6.9-8.25 aromatics. (8H)
- the Product of Example 1 may also be prepared by indirect esterification.
- acetylsalicylic acid In a 50ml round bottom flask equipped with a reflux condenser with drying tube attached, is placed 36g acetylsalicylic acid. Thionyl chloride 35.2gms is added gradually over 5 minutes. The mixture was heated under gentle reflux for 75 minutes and then cooled. The flask was then transferred to a rotary evaporator in a fume hood and the excess thionyl chloride removed under vacuum. The required acetylsalicyloyl chloride was identified by infra red (vCO 1784cm -1 ) and NMR(acetyl methyl 3H: 2.45 and aromatics 4H: 8.18 to 7.25).
- Atenolol 0.5gms, 3.75 mmol
- 25ml chloroform 25ml chloroform
- the acetylsalicyloyl chloride 5.5mls, 37.5 mmol
- the chloroform was evaporated in vacuo and the residue then taken up in ether.
- the ether was decolorised using charcoal, filtered and the solvent removed in vacuo.
- the residue was then dissolved in ethanol and the product recovered by precipitation using n-hexane as an oily semisolid.
- the product (25% yield) was characterised as Atenolol-O-aspirinate using FTIR and NMR as per appended spectra.
- esters may also be employed. Esterification of thiols to form esters may also be achieved by treating carboxylic acids such as acetylsalicylic acids, with agents such as:
- Trisalkylthioboranes Pelter et al J. Chem. Soc,
- Alkylchloroformate and triethylamine Kim and Kim, J. Org.
- ester 5 To a solution of salicylic acid 1 (75 mg, 0.54 mmol) in MeOH-H 2 O (30 ml, 10:1) was added aqueous Cs 2 CO 3 until the pH of the solution was slightly alkaline (Ph 7.5-8.0). The solvent was then evaporated on a rotary evaporator to leave an oil, to which toluene (30 ml) was added. Evaporation of the solvent on the rotary evaporator left a white solid of the caesium salt, which was dissolved in DMF (15 ml). To this solution was added benzyl chloride (0.14 g, 1.1 mmol, 2.0 eq).
- the aqueous phase was extracted and to it was added a dilute aqueous HCl (1 M, 100 ml) and ether (100 ml).
- the organic layer was isolated and the aqueous layer extracted with ether ( 2 ⁇ 50 ml).
- the combined organic extracts were washed with water, dried with MgSO 4 and filtered.
- ⁇ C (selected peaks only) 19.0 (2 ⁇ C, CH(CH 3 ) 2 , 21.4 (1 ⁇ C, CH 3 CO-O), 42.2 (1C, PhCH 2 CONH 2 ) , 55.0 and 70.1 (2 ⁇ C, CHCH 2 NCH(CH 3 ) 2 , 67.7 and 71.9 (2C, -NCH 2 -CHCH 2 OAr), 115 and 132 (2 ⁇ C, benzeneacetamide CH resonances), 124, 128, 134, and 136 (4 ⁇ C, Aspirin aromatic CH resonances), 122, 130, 152 and 157 (4 ⁇ C, Quaternary aromatic carbons), 157, 164 and 172 (3 ⁇ C, COO, COO and CONH 2 ).
- Fig. 12 1 H nmr Atenolol aspirinate
- Atenolol Aspirinate Trifluoroacetate (0.2g) was dissolved in 5 ml of methanol and treated with 10% aqueous NaHCO 3
- Atenolol aspirinate was dissolved in 5% methanolic HCl and stirred for 30 min. The solvent was evaporated to yield the hydrochloric salt.
- Atenolol aspirinare Treatment of Atenolol aspirinare with 0.5 equivalents of fumaric or tartaric acid in methanol yielded the corresponding fumarate and tartrate salts on evaporation of the solvent.
- Salicylic acid (1) was dissolved in methanol/water (10:1), treated with 1 molar equivalent of K 2 CO 3 and stirred at room temperature for 1 hour.
- the di-ionic salt 2 obtained by evaporation of the solvent, was treated with two molar equivalents of benzyl bromide in DMF and heated to 60°C for four hours. After workup and silica-gel chromatography the desired product, dibenzyl salicylate 3, was obtained in 61% yield in addition to benzyl salicylate (30%).
- Dibenzyl salicylate 3 (0.3g) was dissolved in 10 ml of a THF/methanol/water solution (2:1:1) and an equal volume of 2M NaOH was added. The solution was refluxed for 15 min. until the starting material had disappeared as evidenced by TLC. The solution was poured onto 100 ml water and extracted with 3 ⁇ 30 ml ether. The aqueous fraction was acidified to pH 3-4 with 2M HCl. The acidic solution was extracted with 3 ⁇ 30 ml ether and the combined organic fractions were dried (Na 2 SO 4 ) and evaporated to yield the title compound, O-benzyloxy benzoic acid 4 as a solid. Synthesis of N-BOC Metoprolol 5
- Metoprolol (1.0) was dissolved in 5 ml of t-BuOH/H 2 O (10:1) and di-t-butyl dicarbonate (0.82g) in 5 ml of t-BuOH/H2O (10:1) was added. The solution was stirred for 20 hours and then poured onto 100 ml water. The solution was extracted with 3 x 30ml of petroleum-ether (b.p. 40-60C). The combined organic fractions were dried (Na 2 SO 4 ) and concentrated. Flash column chromatography using 3:1 petroleum-ether: ether gave the title compound as a viscous liquid.
- O-Benzyloxy benzoic acid 4 (0.11g) and 4-dimethylamino pyridine (0.24g) 2343 dissolved in 20ml of dry toluene.
- the solution was heated to reflux and 2,6-dichlorobenzoyl chloride (0.10g) was added. After 10 min. under reflux N- BOC Metoprolol (0.18g) in 5 ml dry toluene was added and reflux was continued for a further 30 min.
- the mixture was filtered through silica and the filtrate was evaporated yielding the title compound in quantitative yield.
- the -CH 2 OCH 3 methylene protons and the amino methylene protons give a multiplet at 3.4-3.65 ppm.
- the methoxy group gives a singlet at 3.34 ppm.
- the triplet at 2.81 ppm is assigned to the ArCH 2 .
- the acetate protons produce a singlet at 2.32 ppm.
- the t-butyl group shows up as a singlet at 1.47 ppm. The remaining doublet at 1.14 ppm is due to the isopropylamine methyl protons.
- N-BOC Metoprolol Aspirinate 8 (0.05g) was dissolved in 10 ml dry dichloromethane and trifluoroacetic acid (3ml) was added. The solution was stirred for 1 hour. The solvent was evaporated yielding the compound as a viscous liquid.
- the methine proton of the isopropylamine group and the -CH 2 OCH 3 methylene give rise to overlapping multiplets at 3.42 to 3.7 ppm.
- the doublet at 4.24 ppm is assigned to the ArOCH 2 - methylene hydrogens.
- the broad multiplet at 5.6 ppm is assigned to the ester methine proton.
- the metoprolol aromatic protons are present as two multiplets at 6.83 ppm and 7.12 ppm.
- the multiplet at 7.12 ppm also contains signals for one of the aspirinate protons.
- the three remaining multiplets 7.3 ppm, 7.59 ppm and 7.95 ppm are due to aspirinate protons.
- Metoprolol Aspirinate Preparation of Metoprolol Aspirinate and conversion to its hydrochloride, fumarate and tartrate salts.
- Metoprolol Aspirinate Trifluoroacetate (0.2g) was dissolved in 5 ml of methanol and treated with 10% aqueous NaHCO 3 (100 ml). The aqueous solution was extracted with 3 ⁇ 30 ml dichloromethane. The organic solution was dried (Na 2 SO 4 ) and evaporated yielding Metoprolol aspirinate.
- Metoprolol aspirinate was dissolved in 5% methanolic HCl and stirred for 30 min. The solvent was evaporated to yield the hydrochloric salt. Treatment of Metoprolol aspirinate with 0.5 equivalents of fumaric or tartaric acid in methanol yielded the corresponding fumarate and tartrate salts on evaporation of the solvent.
- Pindolol (1) (0.93g, 3.74mmol) was dissolved in 5ml of t-BuOH/H 2 O (10:1) and di-t-butyl dicarbonate (0.82g, 3.74mmol) in 5ml of t-BuOH/H 2 O (10:1) was added. The solution was stirred for 20 hours and then poured onto 100ml water. The solution was extracted with 3x30ml of petroleum-ether (b.p. 40-60C). The combined organic fractions were dried (Na 2 SO 4 ) and concentrated. Flash column chromatography using 3:1 petroleum-ether:ether gave the title compound as a viscous liquid.
- O-Benzyloxy benzoic acid (3) (0.11g) and 4-dimethylamino pyridine (0.24g) were dissolved in 20ml of dry toluene. The solution was heated to reflux and 2,6-dichlorobenzoyl chloride (0.10g) was added. After 10 minutes under reflux N-BOC Pindolol (0.18g, 0.48mmol) in 5ml dry toluene was added and reflux was continued for a further 30 minutes. The mixture was filtered through silica and the filtrate was evaporated yielding the title compound in quantitative yield.
- N-BOC Pindolol Aspirinate (6) (0.06g) was dissolved in 10ml dry dichloromethane and trifluoroacetic acid (3ml) was added. The solution was stirred for 1 hour. The solvent was evaporated yielding the title compound as a viscous liquid.
- Pindolol Aspirinate Trifluoroacetate (0.1g) was dissolved in 5ml of methanol and treated with 10% aqueous NaHCO 3 (100ml). The aqueous solution was extracted with 3 ⁇ 30ml dichloromethane. The organic solution was dried (Na 2 SO 4 ) and evaporated furnishing Pindolol aspirinate.
- Pindolol aspirinate was dissolved in 5% methanolic HCl and stirred for 30 minutes. The solvent was evaporated to yield the hydrochloride salt.
- the products of the invention are useful as in a single chemical entity a product which acts both as a ß blocker and also has anti-platelet activity as described above is provided.
- the products may be formulated in any suitable pharmaceutical compositions using conventional excipients or vehicles.
- the pharmaceutical composition will be provided in a form for oral administration, preferably in a capsule or tablet form. It will be appreciated that the composition may include a diuretic and potassium salts in a single tablet or capsule.
- the diuretic may be frusemide, amiloride, hydrochlorothiazide or a potassium sparing diuretic such as spironolactone or trimterene. It will also be appreciated that some of the ⁇ blocker aspirinates especially timilol aspirinate may be formulated as an eye drop, i.e. for topical application in the treatment of ocular hypertension and glaucoma.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU16708/95A AU1670895A (en) | 1994-01-28 | 1995-01-27 | Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker |
JP7519968A JPH09508378A (en) | 1994-01-28 | 1995-01-27 | Pharmaceutical product containing the esterifiable β-blocker salicylate |
GB9616298A GB2300636A (en) | 1994-01-28 | 1995-01-27 | Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker |
EP95908363A EP0750608A1 (en) | 1994-01-28 | 1995-01-27 | Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker |
MXPA/A/1996/003034A MXPA96003034A (en) | 1994-01-28 | 1996-07-26 | Pharmaceutical product that comprises a salicilatode a beta sterify blocker |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE940079 | 1994-01-28 | ||
IE940079 | 1994-01-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995020568A1 true WO1995020568A1 (en) | 1995-08-03 |
Family
ID=11040279
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IE1995/000011 WO1995020568A1 (en) | 1994-01-28 | 1995-01-27 | Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0750608A1 (en) |
JP (1) | JPH09508378A (en) |
AU (1) | AU1670895A (en) |
CA (1) | CA2182219A1 (en) |
GB (1) | GB2300636A (en) |
WO (1) | WO1995020568A1 (en) |
ZA (1) | ZA95704B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997005128A1 (en) * | 1995-07-27 | 1997-02-13 | Cal International Limited | Cardioactive aspirinates |
EP0794772A1 (en) * | 1994-12-09 | 1997-09-17 | The Regents Of The University Of California | A method for enhancing outflow of aqueous humor in treatment of glaucoma |
US6228873B1 (en) | 1994-12-09 | 2001-05-08 | The Regents Of The University Of California | Method for enhancing outflow of aqueous humor in treatment of glaucoma |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19743143A1 (en) * | 1997-09-30 | 1999-04-01 | Knoll Ag | Combination pharmaceutical preparations |
JP5092940B2 (en) * | 2008-07-01 | 2012-12-05 | 信越半導体株式会社 | Single crystal manufacturing apparatus and single crystal manufacturing method |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2635209A1 (en) * | 1975-08-15 | 1977-02-24 | Sandoz Ag | NEW 2-METHYLINDOLE DERIVATIVES, THEIR PRODUCTION AND USE |
WO1988007044A1 (en) * | 1987-03-17 | 1988-09-22 | Insite Vision, Inc. | Timolol derivatives |
EP0449426A1 (en) * | 1990-02-26 | 1991-10-02 | Byrne Rynne Holdings Limited | A pharmaceutical composition |
-
1995
- 1995-01-27 EP EP95908363A patent/EP0750608A1/en not_active Withdrawn
- 1995-01-27 GB GB9616298A patent/GB2300636A/en not_active Withdrawn
- 1995-01-27 JP JP7519968A patent/JPH09508378A/en active Pending
- 1995-01-27 AU AU16708/95A patent/AU1670895A/en not_active Abandoned
- 1995-01-27 WO PCT/IE1995/000011 patent/WO1995020568A1/en not_active Application Discontinuation
- 1995-01-27 CA CA002182219A patent/CA2182219A1/en not_active Abandoned
- 1995-01-30 ZA ZA95704A patent/ZA95704B/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2635209A1 (en) * | 1975-08-15 | 1977-02-24 | Sandoz Ag | NEW 2-METHYLINDOLE DERIVATIVES, THEIR PRODUCTION AND USE |
WO1988007044A1 (en) * | 1987-03-17 | 1988-09-22 | Insite Vision, Inc. | Timolol derivatives |
EP0449426A1 (en) * | 1990-02-26 | 1991-10-02 | Byrne Rynne Holdings Limited | A pharmaceutical composition |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0794772A1 (en) * | 1994-12-09 | 1997-09-17 | The Regents Of The University Of California | A method for enhancing outflow of aqueous humor in treatment of glaucoma |
EP0794772A4 (en) * | 1994-12-09 | 1999-06-02 | Univ California | A method for enhancing outflow of aqueous humor in treatment of glaucoma |
US6228873B1 (en) | 1994-12-09 | 2001-05-08 | The Regents Of The University Of California | Method for enhancing outflow of aqueous humor in treatment of glaucoma |
US6576219B2 (en) | 1994-12-09 | 2003-06-10 | The Regents Of The University Of California | Method for enhancing outflow of aqueous humor in treatment of glaucoma |
WO1997005128A1 (en) * | 1995-07-27 | 1997-02-13 | Cal International Limited | Cardioactive aspirinates |
Also Published As
Publication number | Publication date |
---|---|
CA2182219A1 (en) | 1995-08-03 |
MX9603034A (en) | 1998-05-31 |
GB9616298D0 (en) | 1996-09-11 |
EP0750608A1 (en) | 1997-01-02 |
JPH09508378A (en) | 1997-08-26 |
GB2300636A (en) | 1996-11-13 |
AU1670895A (en) | 1995-08-15 |
ZA95704B (en) | 1995-10-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4238506A (en) | Hypoglycaemically and hypolipidaemically active derivatives of phenyl-alkane-carboxylic acids | |
CA1180021A (en) | Substituted carbamoyloxy derivatives of phenylethanolamine | |
PL117997B1 (en) | Process for preparing novel,optically active phenethanoloamineslaminov | |
AU7893881A (en) | Method for treatment of prophylaxis of cardiac disorders | |
US9309215B2 (en) | Chiral intermediate, process for producing the same and its use in the manufacture of tolterodine, fesoterodine, or the active metabolite thereof | |
KR100258657B1 (en) | Pyrrolidinyl hydroxamic acid compounds and their production process | |
WO1987003584A1 (en) | Synthesis of optically active aryloxypropanolamines and arylethanolamines | |
WO1995020568A1 (en) | Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker | |
AU6774987A (en) | Synthesis of aryloxypropanolamines and arylethanolamines | |
AU546152B2 (en) | Compounds and method for treatment or prophylaxis of cardiac disorders | |
US5288898A (en) | N-methylphenylserine alkyl ester derivatives and uses thereof | |
IE950062A1 (en) | A pharmaceutical product | |
ZA200005589B (en) | 2-methylpropionic acid derivatives and medicinal compositions containing the same. | |
MXPA96003034A (en) | Pharmaceutical product that comprises a salicilatode a beta sterify blocker | |
US4252824A (en) | Amino-ethanol derivatives | |
US5310757A (en) | 3,3,5-trimethylcyclohexyl 2-methylpropionate derivatives, their method of preparation and therapeutic compositions in which they are present | |
US4873232A (en) | Novel use for carbamoyl benzoates | |
JPS6155496B2 (en) | ||
CH617173A5 (en) | ||
EP0218440A2 (en) | N-Methylphenylserine alkyl ester derivatives and uses thereof | |
JPH09249628A (en) | Derivatives of phenol | |
JPS637179B2 (en) | ||
EP0301834A2 (en) | Derivatives of benzoyloxyacetic acid, and preparation and formulations thereof for therapeutic use | |
JPS637180B2 (en) | ||
WO1993021163A1 (en) | Quinazolones having cardiovascular activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DE DK DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/1996/003034 Country of ref document: MX Ref document number: 2182219 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 1996 682662 Country of ref document: US Date of ref document: 19960729 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1995908363 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1995908363 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995908363 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: GB Free format text: 950127 A 9616298 |