IE56282B1 - S isomer of betaxolol,its preparation and its application in therapy - Google Patents
S isomer of betaxolol,its preparation and its application in therapyInfo
- Publication number
- IE56282B1 IE56282B1 IE2716/83A IE271683A IE56282B1 IE 56282 B1 IE56282 B1 IE 56282B1 IE 2716/83 A IE2716/83 A IE 2716/83A IE 271683 A IE271683 A IE 271683A IE 56282 B1 IE56282 B1 IE 56282B1
- Authority
- IE
- Ireland
- Prior art keywords
- betaxolol
- acid addition
- pharmaceutically
- preparation
- addition salts
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229960004324 betaxolol Drugs 0.000 title description 7
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 title description 6
- 238000002560 therapeutic procedure Methods 0.000 title description 2
- NWIUTZDMDHAVTP-KRWDZBQOSA-N (S)-betaxolol Chemical compound C1=CC(OC[C@@H](O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-KRWDZBQOSA-N 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 3
- WNEQFDSWDCYKOE-UHFFFAOYSA-N 4-[2-(cyclopropylmethoxy)ethyl]phenol Chemical compound C1=CC(O)=CC=C1CCOCC1CC1 WNEQFDSWDCYKOE-UHFFFAOYSA-N 0.000 claims abstract 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 11
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 210000004165 myocardium Anatomy 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229960004771 levobetaxolol Drugs 0.000 claims 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 11
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 10
- 229960001317 isoprenaline Drugs 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 210000002837 heart atrium Anatomy 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000003943 catecholamines Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002688 maleic acid derivatives Chemical class 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 206010003130 Arrhythmia supraventricular Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000002057 chronotropic effect Effects 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- -1 methanesulphonates Chemical compound 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001245789 Goodea atripinnis Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- QZVCTJOXCFMACW-UHFFFAOYSA-N Phenoxybenzamine Chemical compound C=1C=CC=CC=1CN(CCCl)C(C)COC1=CC=CC=C1 QZVCTJOXCFMACW-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- ZCDNRPPFBQDQHR-SSYATKPKSA-N Syrosingopine Chemical compound C1=C(OC)C(OC(=O)OCC)=C(OC)C=C1C(=O)O[C@H]1[C@H](OC)[C@@H](C(=O)OC)[C@H]2C[C@@H]3C(NC=4C5=CC=C(OC)C=4)=C5CCN3C[C@H]2C1 ZCDNRPPFBQDQHR-SSYATKPKSA-N 0.000 description 1
- HNOAXSVPMXZKBT-ABLWVSNPSA-N [(2s)-2-phenyl-3-propan-2-yl-1,3-oxazolidin-5-yl]methanol Chemical compound CC(C)N1CC(CO)O[C@H]1C1=CC=CC=C1 HNOAXSVPMXZKBT-ABLWVSNPSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003418 phenoxybenzamine Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229950006534 syrosingopine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
(S)(-) Betaxolol of the formula: and its pharmaceutically-acceptable acid addition salts, are new compounds which are, in particular, useful for the treatment of cardiovascular diseases and glaucoma. (S)(-) Betaxolol can be prepared by reacting 4-(2-cyclopropylmethoxyethyl)phenol with the tosyl derivative of (S)-2-phenyl-5-hydroxymethyl-3- isopropyloxazolidine.
Description
The present invention relates to the S isomer of betaxolol, its preparation and its application in therapy, e.g. pharmaceutical compositions containing it.
The compound of the invention is the (S)(-) isomer of betaxolol corresponding to the formula: and its pharmaceutically-acceptable acid addition salts· The compound of the invention is prepared, according to a feature of the invention, by the process 10 which comprises reacting 4-(2-cyclopropylroethoxyethyl )phenol with the (S)-oxazolidine of the formula: II ffl20SO2C6Hi(CH3 ? r \ - 2 in an organic solvent, such as dimethylformamide, in the presence of a base such as sodium hydroxide, potassium hydroxide or, preferably, sodium hydride. <9 k-(2-Cyclopropylmethoxyethyl)-phenol can be 5 prepared in the manner described in Patent Specification * No. 43645.
Pharmaceutically-acceptable acid addition salts of the S isomer of betaxolol, e.g. methanesulphonates, mandelates, fumarates, oxalates, maleates, malonates, citrates, hydrochlorides, hydrobromides and hydroiodides, may be obtained by methods known per se. for example by treatment of the isomer base with the appropriate acid in a solvent medium, e.g· an alkanol or ether, or mixtures thereof· By the term 'methods known per se* as used in this specification is meant methods heretofore used or described in the literature.
The Example which follows illustrates the process of the invention· EXAMPLE 22.lg (0.1 mol) of (S)-2-phenyl-5-hydroxymethyl3-isopropyloxazolidine of the formula: ί * - 3 ('V-CeHs 111 B—j—A s s ch2oh (described by Baldwin et al.. J. Med. Chem· 1979, Vol· 22, No. 11) are dissolved in 37.5 al of pyridine, and 19.Og of tosyl chloride are added in portions, the temperature being kept at about 25°C· When the addition has ended, the reaction mixture is stirred for 2 hours at ambient tenperature and a solution of 13.8g of K2C03 in 75 ml of water is then added cautiously. The mixture is extracted 3 times with 100 ml of CH2C12, the organic phase is dried with MgSO^ and filtered, and the filtrate is evaporated at a temperature below 50°C, initially under a water pump vacuum and then under 0.1 non of mercury. This gives 33-9g of an oil, which is used in the crude state for the subsequent reaction.
A solution of 17.3g (0.09 mol) of 4-(2-cyclopropy lme thoxyethyl)-phenol in 50 ml of dimethylformamide (DMF) is added dropwise to a suspension of 4.8g (0.1 mol) of 50% NaH in 50 ml of DMF, and the mixture is stirred until the evolution of hydrogen has ceased. The mixture is cooled using a bath of iced water, and a solution of * - 4 33.9g of the previously obtained oil in 50 ml of DMF is added in portions; the mixture is then heated at 60-70°C for 2 hours· The mixture is left to stand overnight and heated again at a temperature of about 60°C for 4 hours.
The mixture is cooled, poured onto ice and extracted twice with diethyl ether. The ether phase is washed with water, dried over MgSO^ and filtered, and the filtrate is evaporated. The oil is taken up in water and the mixture is acidified with 50 ml of concentrated HCI, stirred for 1/2 hour at ambient temperature and then extracted twice with diethyl ether.
The aqueous phase is rendered alkaline with sodium hydroxide and extracted with diethyl ether. The ether phase is washed with water, dried over MgSO^ and filtered, and the filtrate is evaporated.
The residual oil is taken up in diethyl ether, a stoichiometric amount of maleic acid is added to this solution, and the maleate salt of the (S)(—) isomer of betaxolol crystallises slowly. The maleate melts at 96°C, [a]2J = -16.2° (C = 1.87 %; CH^H) (S)(-)-Betaxolol is prepared from its maleate I ? salt by alkalinisation with a dilute solution of sodium hydroxide. It is an oil; [a]2® =-0.5° (C = 3.56%, CH30H) - 5 The compound of the invention was subjected to pharmacological tests in the cardiovascular field and in the treatment of glaucoma· (1) Effect of (S) (-)-betaxolol maleate on the chronotropic * and inotropic responses of guinea-pig atrium to isoprenaline, after depletion of the catecholamines.
The method used is similar to that recommended by O'Donnell and Nhnstall (1979).
Guinea-pigs (Hartley), weighing 250 to 300g, are given a subcutaneous injection of syrosingopine (5.0 mg/kg) approximately 18 hours before the start of the experiment, in order to cause depletion of catecholamines in the peripheral tissue reserves. The guinea-pigs are sacrificed by dislocation of the cervix and the whole hearts are removed and placed in a Krebs solution, at ambient temperature (21°C), oxygenated with a mixture containing 95% of 02 and 5% of C02. The composition of the solution, in mM, is: NaCl 114.0; KC1 4.7; CaCl2 2.5; ΚΗ2Ρ0^ 1.2; MgSO^ 1.2; NaHCO^ 25.0; glucose 11.7. Ascorbic acid (1.1 raM) is added to the isoprenaline solutions in order to reduce the oxidation thereof. After the two atria have been separated, each is attached by its base to a hook fixed to a support. A wire is then attached to the apex of each atrium, and the atria are immersed in an isolated * organ bath containing 30 ml of Krebs solution at 37 C.
They are connected to a displacement force transducer * (Grass, model TFO3 C) by the wire attached to the apex, and are placed under a rest tension of 0.5g. The right atrium beats spontaneously whereas the left atrium is driven electrically hy a current consisting of 2 millisecond 5 pulses of about 30 V (supramaximum voltage) delivered 120 tiroes/minute. The atrial rhythm and the contractile force are recorded on a polygraph (Grass 79B).
The atria are left to stand in the isolated organ bath for 30 minutes. The mechanisms of neuronal and extraneuronal Ϊ0 capture of the catecholamines are then blocked by keeping the atria in contact with phenoxybenzamine (50 μΗ) for 30 minutes· After washing with Krebs solution, each preparation is sensitised hy adding isoprenaline (0.3 μΜ) 20 minutes before the first curve of concentration-effect of the 15 isoprenaline is plotted. The isoprenaline is added to the bath in cumulative increasing concentrations (semi-log interval)- The maximum changes in the contractile force and the heart rate which are caused by each dose are the values used for analysing the results.
Approximately 45 minutes after the first curve of concentration-response to the isoprenaline has been plotted, when the parameters studied have returned to their initial values, the preparations are immersed for 30 minutes in a r Krebs solution containing (S)(-)-betaxolol maleate (0.3 μΜ).
Each change in the atrial rhythm or the contractile force which is generated by the isoprenaline is expressed - 7 as a percentage of the response of the atrium to a aupramaximum dose of isoprenaline. A more detailed analysis of the results is only carried out if the second dose/effect curve is parallel to the control curve and if the mayyna of the two curves do not differ more than ± 20%.
The pA2 values are calculated according to van Rossum (1963)· The average pA^ values are compared by variance analysis· The differences between the averages are considered to be significant when t corresponds to p<0.05.
The pAj value of the compound of the invention is - 8.76 ±0.06 in respect of the chronotropic effects on the isoprenaline (spontaneously beating atrium), and - 8.78 + 0.12 in respect of the inotropic effects (electrically stimulated atrium) of the isoprenaline. (2) Effect of (S)(-,-betaxolol maleate on glaucoma.
Drops are prepared by dissolving a sufficient amount of the maleate salt of the compound of the invention in distilled water so as to give solutions containing 0.1%, 0.5%, 0.75% and 2% of compound· 2 drops of solution are a&ninistered to a normal rabbit eye and to an ocularly hypertensive rabbit eye. The intraocular pressure of the two rabbit eyes (normal and ocularly hypertensive) is reduced significantly and measured at intervals of 6 hours.
The S isomer of betaxolol and its pharmaceutically( acceptable salts can be used for the treatment of cardiovascular diseases and, in particular, for coronary - 8 complaints, complaints affecting the myocardium and disorders of the heart rate, and for the treatment of glaucoma· The invention consequently includes pharmaceutical 5 compositions containing (S)(-) betaxolol, or a pharmaceutically-acceptable. acid addition salt thereof, in combination with any excipient suitable for oral, rectal or parenteral administration.
Examples of suitable pharmaceutical forms are tablets, coated tablets, gelatine capsules, ordinary capsules, cachets, solutions and suspensions to be taken orally, suppositories and stabilised and/or buffered injectable solutions, prepared in advance or for immediate use.
The daily dosage can range from 5 to 50 mg of (S)(-) betaxolol.
For the treatment of glaucoma, the concentration of the eye solutions can range from 0.25 to 3% of (S)(«) betaxolol-
Claims (8)
1. (5)(-) Betaxolol of the formula: and its pharmaceutically-acceptable acid addition salts.
2. * (5)(-) Betaxolol maleate.
3. A process for the preparation of (5)(-) betaxolol which comprises reacting 4-(2-cyclopropylmethoxyethyl)phenol with the (S) oxazolidine of the formula: CH 2 OSO 2 C 6 H 4 CH in an organic solvent in the presence of a base.
4. A process according to claim 3 in which the organic solvent is dimethylformamide and the base is sodium hydride. i - 10
5. A process according to claim 3 or 4 followed by the step of converting (S)(-) betaxolol so obtained by a method known per se into a pharmaceutically-acceptable acid addition salt.
6. A process for the preparation of (S)(-) betaxolol, and pharmaceutically-acceptable acid addition salts thereof, substantially as hereinbefore described with especial reference to the foregoing Example.
7. Pharmaceutical compositions which comprise, 10 as active ingredient, (S)(-) betaxolol, or a pharmaceuticallyacceptable acid addition salt thereof, in association with a pharmacologically-acceptable excipient.
8. · (8)(-) Betaxolol and pharmaceuticallyacceptable acid addition salts thereof for use as medicaments 15 and, more especially, for the treatment of cardiovascular diseases and, in particular, for coronary complaints, conplaints affecting the myocardium and disorders of the heart rate, and for the treatment of glaucoma.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8219506A FR2536390B1 (en) | 1982-11-22 | 1982-11-22 | ISOMERS OF BETAXOLOL, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE832716L IE832716L (en) | 1984-05-22 |
| IE56282B1 true IE56282B1 (en) | 1991-06-05 |
Family
ID=9279382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2716/83A IE56282B1 (en) | 1982-11-22 | 1983-11-21 | S isomer of betaxolol,its preparation and its application in therapy |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS59108745A (en) |
| AU (1) | AU559204B2 (en) |
| BE (1) | BE898277A (en) |
| CH (1) | CH658049A5 (en) |
| DE (1) | DE3341983A1 (en) |
| FR (1) | FR2536390B1 (en) |
| GB (1) | GB2130585B (en) |
| IE (1) | IE56282B1 (en) |
| IL (1) | IL70282A0 (en) |
| IT (1) | IT1169131B (en) |
| LU (1) | LU85099A1 (en) |
| NL (1) | NL8304000A (en) |
| ZA (1) | ZA838682B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8609190A1 (en) * | 1985-02-07 | 1986-07-16 | Pharma Investi S A | Housing belt. |
| US6258350B1 (en) | 1999-01-20 | 2001-07-10 | Alcon Manufacturing, Ltd. | Sustained release ophthalmic formulation |
| US7001615B1 (en) | 2001-12-07 | 2006-02-21 | Alcon, Inc. | Sustained release ophthalmic, otic and nasal suspension |
| US20100113606A1 (en) * | 2008-11-05 | 2010-05-06 | Auspex Pharmaceuticals, Inc. | Aminopropanol modulators of beta-1 adrenergic receptor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2330383A1 (en) * | 1975-11-06 | 1977-06-03 | Synthelabo | NEW PHENOL SUBSTITUTE ETHERS, THEIR SALTS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| US4294966A (en) * | 1978-07-28 | 1981-10-13 | Ciba-Geigy Corporation | Process for inverting the configuration in optically active compounds |
| US4342783A (en) * | 1980-06-30 | 1982-08-03 | Synthelabo | Anti-glaucoma agent |
-
1982
- 1982-11-22 FR FR8219506A patent/FR2536390B1/en not_active Expired
-
1983
- 1983-11-21 JP JP58220484A patent/JPS59108745A/en active Pending
- 1983-11-21 BE BE0/211909A patent/BE898277A/en not_active IP Right Cessation
- 1983-11-21 IL IL70282A patent/IL70282A0/en unknown
- 1983-11-21 CH CH6254/83A patent/CH658049A5/en not_active IP Right Cessation
- 1983-11-21 LU LU85099A patent/LU85099A1/en unknown
- 1983-11-21 ZA ZA838682A patent/ZA838682B/en unknown
- 1983-11-21 DE DE19833341983 patent/DE3341983A1/en not_active Ceased
- 1983-11-21 AU AU21558/83A patent/AU559204B2/en not_active Ceased
- 1983-11-21 NL NL8304000A patent/NL8304000A/en active Search and Examination
- 1983-11-21 IE IE2716/83A patent/IE56282B1/en not_active IP Right Cessation
- 1983-11-21 GB GB08331038A patent/GB2130585B/en not_active Expired
- 1983-11-21 IT IT23803/83A patent/IT1169131B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| BE898277A (en) | 1984-05-21 |
| GB2130585B (en) | 1985-12-04 |
| NL8304000A (en) | 1984-06-18 |
| IE832716L (en) | 1984-05-22 |
| CH658049A5 (en) | 1986-10-15 |
| DE3341983A1 (en) | 1984-05-24 |
| GB2130585A (en) | 1984-06-06 |
| AU2155883A (en) | 1984-05-31 |
| FR2536390A1 (en) | 1984-05-25 |
| LU85099A1 (en) | 1985-07-17 |
| FR2536390B1 (en) | 1986-03-21 |
| ZA838682B (en) | 1985-03-27 |
| IT8323803A0 (en) | 1983-11-21 |
| AU559204B2 (en) | 1987-02-26 |
| JPS59108745A (en) | 1984-06-23 |
| IT1169131B (en) | 1987-05-27 |
| GB8331038D0 (en) | 1983-12-29 |
| IL70282A0 (en) | 1984-02-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |