(S)-Timolol maleate

(S)-Timolol maleate Basic information
Product Name:(S)-Timolol maleate
Synonyms:S[-]-1-[T-BUTYLAMINO]-3-(4-MORPHOLINO-1,2,5-THIADIAZOL-3-YL)OXY]-2-PROPANOL MALEATE SALT;(S)-1-[(1,1-DIMETHYLETHYL)AMINO]-3-[[4-(4-MORPHOLINYL)-1,2,5-THIADIAZOL-3-YL]OXY]-2-PROPANOL MALEATE;(s)-1-((1,1-dimethylethyl)amino)-3-((4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl)oxy)-2-propanol (z)-2-butenedioate (1:1);(-)-1-(tert-butylamino)-3-((4-morpholino-1,2,5-thiadiazol-3-yl)oxy)-2-propan;(s)-timololhydrogenmaleate;1-(tert-butylamino)-3-((4-morpholino-1,2,5-thiadiazol-3-yl)oxy)-2-propano(;betime;l-timololmaleate
CAS:26921-17-5
MF:C17H28N4O7S
MW:432.49
EINECS:248-111-5
Product Categories:BLOCADREN;Active Pharmaceutical Ingredients;Adrenoceptor;26921-17-5
Mol File:26921-17-5.mol
(S)-Timolol maleate Structure
(S)-Timolol maleate Chemical Properties
Melting point 202-203 °C(lit.)
alpha 24405 -12.0° (c = 5 in 1N HCl); D25 -4.2°
storage temp. 2-8°C
solubility H2O: soluble
form powder
color white to off-white
optical activity[α]25/D -5.4°, c = 4.9 in 1 M HCl(lit.)
Merck 14,9444
InChIKeyWLRMANUAADYWEA-NWASOUNVSA-N
CAS DataBase Reference26921-17-5(CAS DataBase Reference)
Safety Information
Hazard Codes Xn,Xi
Risk Statements 22-63-36/37/38
Safety Statements 36-37/39-26
WGK Germany 3
RTECS UA8475000
HS Code 29349990
MSDS Information
ProviderLanguage
SigmaAldrich English
(S)-Timolol maleate Usage And Synthesis
DescriptionTimolol is a non-selective β-adrenergic receptor antagonist with log Kd values of -8.27, -9.86, and -6.8 for binding to human β1-, β2-, and β3-adrenoceptors, respectively. It has been reported that only the (S) enantiomer contributes to the β-blocking effects of racemic timolol, but the weakly active (R) isomer maintains a beneficial effect on intraocular pressure without the undesirable side-effect of bronchial constriction caused by non-selective action of (S)-timolol on β1 and β2 receptors. Timolol has been use alone and in fixed combinations with either prostaglandin analogs or carbonic anhydrase inhibitors to reduce intraocular pressure in research models of ocular hypertension and glaucoma.
Chemical PropertiesWhite Solid
OriginatorBlocadren,MSD,UK,1974
UsesAnti hypertensive, Anti-glaucoma
UsesAntihypertensive; antiarrhythmic (class II); antianginal; antiglaucoma agent.
Usesbetaadrenergic blocker
DefinitionChEBI: The maleic acid salt of the active (S)-enantiomer of timolol, comprising equimolar amounts of (S)-timolol and maleic acid.
Manufacturing ProcessStep A: Preparation of 3-tert-Butylamino-2-Oxopropanol - To an aqueous solution of tert-butylamine (1 mol) at ambient temperature, there is added slowly and with vigorous stirring 2 mols bromoacetol. The reaction mixture is allowed to stand at ambient temperature for about 5 hours whereupon it is made basic by the addition of sodium hydroxide.
The reaction mixture then is extracted with ether, the excess amine is removed from the ethereal solution under reduced pressure and the ether then removed by evaporation to give 3-tert-butylamino-2-oxopropanol. Step B: A solution of the 3-tert-butylamino-2-oxopropanol in a mixture of pyridine hydrochloride and pyridine is treated with p-toluenesulfonylchloride. The mixture is stirred for 1/2 hour at 25° to 30°C and then poured into cold water. The solution is treated with potassium carbonate and the pyridine evaporated in vacuo at a temperature between 55° and 60°C. The aqueous residue is treated with potassium carbonate and the mixture extracted with methylene chloride. Evaporation of the dried extract provides 1- toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane.
Step C: Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Oxopropoxy)- 1,2,5-Thiadiazole - The 1-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane, prepared as described in Step B, (11 mols) is added to 0.80 N methanolic sodium methoxide (15 ml) at 0°C. The mixture is stirred for 15 minutes at 0° to 5°C, treated with 3-morpholino-4-hydroxy-1,2,5-thiadiazole (4.29 grams) and then refluxed for 16 hours. The solvent is evaporated in vacuo and the residue is treated with excess potassium carbonate to provide 3-morpholino- 4-(3-butylamino-2-oxopropoxy)-1,2,5-thiadiazole.
Step D: Chemical Reduction Preparation of 3-Morpholino-4-(3-tert_x0002_Butylamino-2-Hydroxypropoxy)-1,2,5-Thiadiazole - The 3-morpholino-4-(3- tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3- tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride).
Alternative Step D: Reduction with a Reductate - Sucrose (1 kg) is dissolved in water (9 liters) in a 20-liter bottle equipped with a gas trap. Baker's yeast (Saccharomyces cerevisiae, 1 kg) is made into a paste with water (1 liter) and added to the sucrose solution with stirring. After lively evolution of gas begins (within 1 to 3 hours), 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)- 1,2,5-thiadiazole hydrogen maleate [1.35 mols, prepared by reaction of the 3- morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole with an equimolar quantity of maleic acid in tetrahydrofuran]. The mixture is allowed to stand until fermentation subsides, after which the bottle is kept in a 32°C incubator until all fermentation has ended (in approximately 1 to 3 days). The yeast is filtered off with addition of diatomaceous earth and the filtrate is evaporated to dryness to give S-3-morpholino-4β-tert-butylamino-2- hydroxypropoxy)-1,2,5-thiadiazole, MP 195° to 198°C (as hydrogen maleate), according to US Patent 3,619,370.
Step E: The base may be converted to the maleate by maleic acid




Therapeutic FunctionAntiarrhythmic, Antiglaucoma
Biological Activityβ 1 -adrenergic blocker.
Clinical UseBeta-adrenoceptor blocker:
Hypertension
Angina
Glaucoma
Migraine prophylaxis


Veterinary Drugs and TreatmentsTimolol maleate is used primarily to prevent the development of primary glaucoma in the contralateral eye of a dog which has developed primary glaucoma in one eye. It only reduces intraocular pressure 3 – 10 mmHg and, therefore is of minimal usefulness in patients requiring treatment of primary acute congestive glaucoma. Timolol’s mechanism of action: decreases cyclic-AMP synthesis in non-pigmented ciliary epithelium resulting in decreased aqueous humor production. It may also cause slight miosis in dogs and cats. Timolol maleate is rarely used alone but is combined with dorzolamide solution (Cosopt?). Caution is advised with use of Beta blocking agents in cats with concurrent asthma. As timolol maleate is now available in generic form, it is the primary Beta blocker agent now used.
Drug interactionsPotentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: NSAIDs antagonise hypotensive effect.
Anti-arrhythmics: increased risk of myocardial depression and bradycardia; increased risk of bradycardia, myocardial depression and AV block with amiodarone; increased risk of myocardial depression and bradycardia with flecainide.
Antidepressants: enhanced hypotensive effect with MAOIs.
Antihypertensives: enhanced hypotensive effect; increased risk of withdrawal hypertension with clonidine; increased risk of first dose hypotensive effect with post-synaptic alpha-blockers such as prazosin.
Antimalarials: increased risk of bradycardia with mefloquine.
Antipsychotics: enhanced hypotensive effect with phenothiazines.
Calcium-channel blockers: increased risk of bradycardia and AV block with diltiazem; hypotension and heart failure possible with nifedipine and nisoldipine; asystole, severe hypotension and heart failure with verapamil.
Cytotoxics: possible increased risk of bradycardia with crizotinib.
Diuretics: enhanced hypotensive effect.
Fingolimod: possibly increased risk of bradycardia.
Moxisylyte: possible severe postural hypotension.
Sympathomimetics: severe hypertension with adrenaline and noradrenaline and possibly with dobutamine; also response to adrenaline may be reduced.
MetabolismTimolol undergoes significant hepatic metabolism, but first pass metabolism is low. The metabolites are excreted in the urine with some unchanged timolol.
(S)-Timolol maleate Preparation Products And Raw materials
Raw materialstert-Butylamine-->Tosyl chloride-->Sodium borohydride-->Maleic acid
3-(ISOPROPYLAMINO)-1,2-PROPANEDIOL TIMOLOL MALEATE RACEMATE (R)-(+)-Timolol maleate,d-timolol maleate Moroxydine hydrochloride 4-MORPHOLIN-4-YL-1,2,5-THIADIAZOL-3-OL 3-Chloro-4-Mopholino-1,2,5-Thiadiazol (intermediate of timolol maleate) 2-(TERT-BUTYLAMINO)ETHANOL Sucrose benzoate ALTRENOGEST Cinepazide maleate Trimebutine maleate TIMOLOL MALEATE MM STANDARD 1,2,5-THIADIAZOL-3-OL AMINO ACIDS (R)-TIMOLOL MALEATE EPY(CRM STANDARD) TIMOLOL MALEATE USP STANDARD DI-TERT-BUTYL ETHER (S)-3-ISOPROPYLAMINO-1,2-PROPANEDIOL

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