27848-84-6

Usage

Uses

Used in Pharmaceutical Industry:
Nicergoline is used as an antipsychotic drug for the treatment of age-dependent cognitive impairments, such as Alzheimer's disease and other types of dementia. It helps protect cultured neurons against β-amyloid toxicity, which is a key factor in the development of these cognitive disorders.
Nicergoline is also used as a neuroprotective agent, as it has been shown to protect against neuronal cell death induced by activated microglia and astrocytes. This protection is achieved through the inhibition of inflammatory mediators and the upregulation of neurotrophic factors by glial cells, which contribute to the overall health and function of the nervous system.

Originator

Sermion,Farmitalia,Italy,1974

Manufacturing Process

Preparation of 1-Methyl Lumilysergic Acid 8-Methyl Ester-10-Methyl Ether: Into a suspension of 10 grams of 1-methyl-lumilysergic acid in 600 cc of absolute methanol a stream of anhydrous hydrogen chloride is bubbled for 1.5 hours with strong cooling. The stream of hydrogen chloride is stopped and the mixture is allowed to stand for 30 minutes at 0°C, and is evaporated in vacuo to dryness. The residue is taken up with ice-cooled water made alkaline with concentrated ammonia and extracted with chloroform. The combined chloroform extracts are washed first with a 5% aqueous solution of sodium bicarbonate, then with water, and are thereafter dried over anhydrous sodium sulfate and finally evaporated in vacuo to dryness.Preparation of 1-Methyl Lumilysergol-10-Methyl Ether: To a boiling suspension of 2 grams of lithium aluminum hydride in 50 cc of anhydrous tetrahydrofuran, a solution of 1 gram of 1-methyl lumilysergic acid-8-methyl ester-10-methyl ether in 20 cc of anhydrous tetrahydrofuran is added dropwise and the resulting solution is refluxed for a further 2 hours. After cooling the resulting solution, aqueous tetrahydrofuran is added to destroy the excess reducing agent and the solution is filtered. Tetrahydrofuran is distilled off and the residue is recrystallized from acetone petroleum ether.Preparation of Nicergoline: To a solution of 1-methyl lumilysergol-10-methyl ether in pyridine, 5-bromonicotinyl chloride is used as an acylating agent at room temperature. The mixture is stirred for 1 hour. Water and methanol are added and the resulting mixture is stirred for 1 hour, extracted with chloroform, and washed in sequence with 1% aqueous caustic soda, 5% aqueous sodium bicarbonate solution, and water. The resulting solution is dried over anhydrous sodium sulfate and the solvent is distilled off. By recrystallization of the residue from acetone petroleum ether, nicergoline is obtained, melting at 136° to 138°C.

Therapeutic Function

Vasodilator

Biological Activity

α -adrenergic, vasodilator. Cognitive enhancer.

Pharmacology

Nicergoline is an ergot derivative that may protect against degeneration of cholinergic neurones (Giardino et al.,2002). Nicergoline has a broad spectrum of action (Winblad et al,2008): (1) as a1-adrenoceptor antagonist it induces vasodilatation and increases arterial blood flow; (2) it enhances cholinergic and catecholaminergic neurotransmission; (3) it inhibits platelet aggregation; (4) it promotes metabolic activity, resulting in increased oxygen and glucose utilization; and (5) it has neurotrophic and antioxidant properties. Nicergoline has been used for the treatment of various dementias, including AD and VaD (Fioravanti and Flicker, 2001). The therapeutic effects of nicergoline were evident by 2 months of treatment and were maintained for 6-12 months.

Safety Profile

Poison by intravenous route. Moderately toxic by ingestion and subcutaneous routes. An experimental teratogen. Other experimental reproductive effects. A vasodilator. When heated to decomposition it emits very toxic fumes of Brand NOx.

InChI:InChI=1/C24H26BrN3O3/c1-27-13-17-8-21-24(30-3,19-5-4-6-20(27)22(17)19)9-15(12-28(21)2)14-31-23(29)16-7-18(25)11-26-10-16/h4-7,10-11,13,15,21H,8-9,12,14H2,1-3H3/p+1/t15-,21-,24+/m1/s1

Upstream product

• 20826-04-4 5-bromo-3-pyridinecarboxylic acid 
• 35155-28-3 1-Methyl-10alpha-methoxy-9,10-dihydrolysergol 
• 29681-44-5 5-bromo-3-pyridine carboxylic acid methyl ester 
• 74-88-4 methyl iodide 
• 53375-83-0 10-methoxy-1,6-dimethyl-ergoline-8-carboxylic acid methyl ester 
• 23495-64-9 10α-methoxy-9,10-dihydrolysergic acid methylester 
• 5572-96-3 1-Methyllysergol 
• 602-85-7 lysergol 
• 39620-02-5 5-bromonicotinoyl chloride 

Downstream Products

• 20826-04-4 5-bromo-3-pyridinecarboxylic acid 
• 35155-28-3 1-Methyl-10alpha-methoxy-9,10-dihydrolysergol 

Relevant academic research and scientific papers

Synthesis method and application of nicergoline

The invention belongs to the field of medicine synthesis, and discloses a synthesis method and application of nicergoline. The synthesis method provided by the invention comprises the following steps: carrying out esterification reaction on a compound 1 and a compound 2 under the condition of catalysis by concentrated sulfuric acid, and carrying out methylation reaction in an alkaline environment through methyl iodide so as to obtain nicergoline after the reaction is finished. According to the synthesis method of nicergoline provided by the invention, process flow is simplified, requirements on the reaction environment is reduced, reaction yield is improved, and industrial production cost is saved; and the method is suitable for synthesizing nicergoline, and the synthesized nicergoline is used for preparing nicergoline for injection.

Nicergoline synthesis method

The invention belongs to the technical field of raw material medicine synthesis, and particularly relates to a nicergoline synthesis method, which comprises the following steps: (1) methylating nitrogen-hydrogen bonds in 10-methoxyl-methyl ergoate to obtain a; (2) reducing an ester group in a into a hydroxyl group to obtain b; and (3) acylating the hydroxyl in the b. The nicergoline synthesized by the synthesis method is high in purity, methyl ether impurities can be effectively avoided, reaction conditions are mild and controllable, industrial large-scale production of the nicergoline raw material medicine is facilitated, and the method plays a positive role in promoting improvement of the quality of the nicergoline raw material medicine and reducing side effects and risks of medication of patients.

Synthetic method of nicergoline

The invention discloses a synthetic method of nicergoline. The synthetic method comprises the following steps: (1) photocatalytic addition reaction; (2) purification of 10-methoxy-dihydroergosterol; (3) methylation reaction; (4) purification of 10-methoxy-1, 6-dimethane-8-carbinol-ergoline; (5) esterification reaction; and (6) purifying of the nicergoline. According to the Synthetic method of thenicergoline, the mild photocatalytic addition, methylation and esterification reactions in the reaction process are adopted, and the raw materials and reagents with high safety are selected, so that the whole synthesis process is safe and controllable, the post-processing process is simplified, and the product obtained by the reaction is high in yield, high in purity, good in quality and suitablefor industrial production.

Novel preparation method of nicergoline

The invention relates to a new preparation method of nicergoline. The method comprises the following steps: (1) adding an inorganic alkali into a polar aprotic solvent, and carrying out a methylationreaction on lysergol (II) and a methylation reagent to generate 1-methyl lysergol (III); (2) carrying out a light reaction on the 1-methyl lysergol (III) and methanol under the catalysis of concentrated sulfuric acid to prepare 1-methyl-10 alpha-methoxy dihydrolysergol (IV); and (3) in a polar aprotic organic solvent, carrying out a reaction on 5-bromonicotinic acid (V) and N,N'-carbonyl diimidazole by taking the N,N'-carbonyl diimidazole as a condensing agent to prepare a 5-bromo nicotinyl imidazole (VI) intermediate, and then carrying out a condensation reaction on the 5-bromo nicotinyl imidazole (VI) intermediate and the 1-methyl-10 alpha-methoxy dihydrolysergol (IV) to prepare nicergoline (I). Compared with the method in the prior art, the method of the invention does not require inertgas protection, is small in acid consumption, good in product quality, high in yield, easy in reaction byproduct recovery and utilization and suitable for industrial production.

Improved preparation method of nicergoline (by machine translation)

Compared the prior art,bromonicotinoyl chloride intermediate, is prepared-methoxyphenylglycinol :(1) by a reaction with an organic amine as, an acid-binding agent, to produce 10α -(2) methyl - 101010101010101010and X3B1,methoxyphenylglycinol, in a solvent, 10α - The final yield of the product can reach or above product to be 1 - suitable for large-scale ;(3) production, The, method 5 - comprises the following 5 - steps 5 - carrying out a methylation reaction 1 - with an organic, amine, as an organic amine as an acid,binding compound, in a solvent in a solvent and an inorganic base by an organic amine as an acid-binding agent in, an amide type non-protonic solvent to prepare 50% the . nylmyralyl chloride 99%, midst with an organic amine as an organic amine as an acid-binding agent. (by machine translation)

Synthetic method for nicergoline

The invention discloses a synthetic method for nicergoline. The synthetic method comprises the following steps: allowing lysergol and methanol to generate a methoxylation reaction, and carrying out purifying so as to obtain 10alpha-methoxyl-dihydrolysergol; allowing the 10alpha-methoxyl-dihydrolysergol and trimethylsulphoxonium iodide to generate a methylation reaction, and carrying out purifyingso as to obtain 1-methyl-10alpha-methoxyl-dihydrolysergol; and allowing the 1-methyl-10alpha-methoxyl-dihydrolysergol and 5-bromonicotinoyl chloride to generate an acylation reaction, and carrying outrefining so as to obtain the nicergoline. The synthetic method provided by the invention has the advantages of simple process, mild reaction conditions, easy operation, low toxicity of raw materials,high quality of a finished product, and facilitation of industrial popularization and application.

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.

Method for treating resistant hypertension

A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, 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.