26839-75-8

Usage

Uses

Used in Ophthalmology:
Timolol is used as a treatment for glaucoma, specifically for both chronic open-angle glaucoma and closed-angle glaucoma. It is administered in the form of eye drops, which help to decrease intraocular pressure, thus reducing the risk of optic nerve damage and vision loss.
Used in Cardiology:
Timolol is used as a β-adrenergic blocker for the treatment of raised blood pressure. It helps to lower the heart rate and reduce the force of heart contractions, which in turn decreases the oxygen demand of the heart and blood vessels.
Used in Angina Treatment:
Timolol is used to treat angina, which is chest pain caused by an inadequate supply of oxygen to the heart muscle. By reducing the heart's oxygen demand, Timolol helps to alleviate the pain and prevent further damage to the heart.
Used in Heart Rhythm Disturbances:
Timolol is also used to treat some disturbances of heart rhythm, as it can help to regulate the electrical activity of the heart and maintain a normal heart rate.
Used in Migraine Prevention:
Timolol is used to prevent migraine headaches, as it can help to reduce the frequency and severity of these headaches by stabilizing blood pressure and reducing the effects of catecholamines.
Used in Pharmaceutical Industry (Betimol Sanofi Winthrop):
Timolol is marketed under the brand name Betimol by Sanofi Winthrop, a pharmaceutical company. It is available in various forms, such as tablets and eye drops, to cater to the different medical applications mentioned above.

Originator

Blocadren,MSD,UK,1974

Manufacturing Process

Step 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 Function

Antiarrhythmic, Antiglaucoma

Contact allergens

Timolol was implicated in allergic contact dermatitis due to beta-blocker agents in eyedrops.

Metabolism

Timolol (Timoptic) is almost completely absorbed from the gastrointestinal tract. Peak plasma levels occur 2 to 4 hours after oral administration; the plasma halflife of timolol is approximately 5.5 hours.The extensive tissue distribution of timolol into lung, liver, and kidney is similar to that of other -blockers. Approximately 70% of the drug is excreted in the urine within 24 hours, mostly as highly polar unconjugated metabolites. Only 6% of an administered dose is recovered in the feces. Although timolol is approved for the topical treatment of elevated intraocular pressure, there is limited information about its pharmacokinetics following administration by this route.The drug apparently can reach the systemic circulation after intraocular instillation, but plasma levels are only about 7% of those achieved in the aqueous humor.

InChI:InChI=1/C13H24N4O3S/c1-13(2,3)14-8-10(18)9-20-12-11(15-21-16-12)17-4-6-19-7-5-17/h10,14,18H,4-9H2,1-3H3/t10-/m0/s1

Upstream product

• 30165-97-0 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole 
• 45720-12-5 tert-butyl({[(2S)-oxiran-2-yl]methyl})amine 
• 30165-96-9 3-Morpholino-4-chloro-1,2,5-thiadiazole 
• 194861-99-9 ((2Ξ,5S)-3-tert-butyl-2-phenyl-oxazolidin-5-yl)-methanol 
• 58827-68-2 4-{4-[(2R/S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine 
• 75-64-9 tert-butylamine 
• 69500-53-4 4-{4-[(2S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine 
• 29023-48-1 timolol 
• 26921-17-5 timolol maleate 
• 30315-46-9 (S)-1-tert-butylamino-2,3-dihydroxypropane 
• 295776-81-7 (S)-3-[4-(N-morpholino)-1,2,5-thiadiazolyloxy]propane-1,2-diol 
• 935528-00-0 (2R)-1-chloro-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol 
• 85665-60-7 (R,S)-5-(hydroxymethyl)-3-tert-butyloxazolidin-2-one 
• 507-19-7 t-butyl bromide 

Downstream Products

• 30165-97-0 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole 
• 26921-17-5 timolol maleate 
• 1167426-99-4 C₂₃H₃₃N₅O₉S 
• 1167426-97-2 C₂₃H₃₃N₅O₉S 
• 1167426-95-0 C₂₄H₃₅N₅O₉S 
• 1167426-93-8 C₂₄H₃₅N₅O₉S 
• 1167426-91-6 C₂₄H₃₄N₆O₁₂S 
• 1167426-87-0 C₂₃H₃₃N₅O₉S 
• 1167426-85-8 C₂₂H₃₁N₅O₈S 
• 1167426-83-6 C₂₂H₃₁N₅O₈S 
• 1215295-18-3 1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)propan-2-yl 4-(3-thioxo-3H-1,2-dithiol-4-yl)benzoate 
• 1058180-07-6 C₂₀H₃₈N₄O₆S 

Relevant academic research and scientific papers

Biocatalytic asymmetric synthesis of (S)- and (R)-Timolol

A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro-1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.

Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines

An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (±)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively.

An improved process of separation of R- and S-timolol

Diastereomeric timolol tartrates 4 are obtained in a one-pot synthesis from the racemic base 2 and optically active O,O-diacetyl- or O,O,- dibenzoyltartaric anhydrides 3, as only one of the diastereomers precipitates from acetone solution. Acidic hydrolysis as the corresponding 4 leads to timolol in high yield and optical purity.

New approach to nonracemic 1-alkylamino-3-aryloxypropan-2-ols belonging to β-blockers via cyclic sulfites

Nonracemic β-blockers, viz., (S)-propranolol and (S)-timolol, were prepared from (S)-glycidol in three steps consisting in the reaction with SOCl2 followed by the reaction of the resulting (4S)-4-chloromethyl-2-oxo-1,3,2-dioxathiolanes with the corresponding phenol and the final cleavage of (4R)-aryloxymethyl sulfites under the action of amines in DMF.

COMPOSITIONS AND METHODS FOR THE TREATMENT OF PAIN AND DEPENDANCE DISORDERS

Provided herein are (e.g., controlled release) compositions for the treatment of acute or chronic diseases or disorders. Described herein are processable opioid conjugates. Also described herein are compositions and methods for the treatment of central nervous system (CNS) diseases or disorders including chronic pain (e.g., cancer pain), acute pain, opioid addiction, alcohol addiction, alcohol dependence, opioid-induced constipation, and narcotic depression. Said compositions and methods comprise opioid agonists and/or opioid antagonists, which demonstrate CNS activity and/or other desirable activities. Injection of said compositions subcutaneously or intraspinally provides therapeutic benefit to individuals suffering from CNS diseases or disorders

DRUGS AND COMPOSITIONS FOR THE TREATMENT OF OCULAR DISORDERS

The present invention provides new prodrugs of therapeutically active compounds, including oligomeric prodrugs, and compositions to treat medical disorders, for example glaucoma, a disorder or abnormality related to an increase in intraocular pressure (IOP), a disorder requiring neuroprotection, age-related macular degeneration, or diabetic retinopathy.

PHOSPHATE-FREE PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF GLAUCOMA

The invention relates to a phosphate-free pharmaceutical composition which comprises at least one FP prostanoid receptor agonist and/or at least one prostamide receptor agonist and also citrate salts and/or citric acid.

Chiral separations of some β-adrenergic agonists and antagonists on AmyCoat column by HPLC

Sixteen β-adrenergic antagonists namely acebutalol, alprenolol, atenolol, bisoprolol, bopindolol, bufurolol, carazolol, celiprolol, indenolol, metaprolol, nebivolol, oxprenolol, practolol, propranolol, tertalol, and timolol, and two β-adrenergic agonists namely cimeterol and clenbuterol were resolved on AmyCoat (150 x 46 mm, 3 μm size of silica particle) by using (85:15:0.1, v/v/v), (90:10:0.1, v/v/v), and (95:05:0.1, v/v/v) combinations of η-heptane, ethanol, and diethylamine solvents, respectively. The flow rates used were 0.5, 1.0, 2.0, and 3.0 ml/min with detection at 225 nm. The values of capacity, separation, and resolution factors ranged from 0.38 to 19.70, 1.08-2.33, and 1.0 and 4.50, respectively. The maximum and minimum resolutions were achieved for celiprolol and bufurolol, respectively. The chiral recognition mechanisms were also discussed. The values of validation parameters were calculated.

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

ANTIHYPERTENSIVE THERAPY

A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.