5143-94-2

Upstream product

• 186581-53-3 diazomethane 
• 6838-23-9 6-methyl-ergoline-8α-carboxylic acid 
• 35470-52-1 (5R,8S,10S)-8-methoxycarbonyl-6-methylergoline 
• 3006-19-7 9,10-dihydrolysergic acid methyl ester 
• 5878-43-3 9,10-dihydrolysergic acid 
• 67-56-1 methanol 
• 82-58-6 D-lysergic acid 
• 6190-39-2 dihydroergotamine mesylate 
• 25447-66-9 Dihydroergocryptine 
• 30341-92-5 rac-5α-ergoline-8β-carboxylic acid methyl ester 
• 30341-92-5 #rac-5α-ergoline-8α-carboxylic acid methyl ester 
• 82-58-6 (+/-)-lysergic acid 
• 30341-92-5 #rac-ergoline-8β-carboxylic acid methyl ester 
• 4224-69-5 methyl 2-(bromomethyl)propenoate 

Downstream Products

• 51153-15-2 (6-methyl-ergolin-8α-yl)-methanol 
• 41564-31-2 (5R,8S,10R)-8-hydrazinocarbonyl-6-methylergolin 
• 6838-23-9 6-methyl-ergoline-8α-carboxylic acid 
• 5878-43-3 9,10-dihydrolysergic acid 
• 18051-16-6 9,10-dihydrolysergol 
• 30341-92-5 methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate 
• 30341-94-7 6-nor-6-n-ethyl-9,10-dihydrolysergic acid methyl ester 
• 58752-31-1 6-methyl-8β-tosyloxymethyl-ergoline 
• 63719-21-1 D-6-propyl-8β-hydroxymethylergoline 
• 63719-09-5 6-nor-6-n-propyl-9,10-dihydrolysergic acid methyl ester 
• 105579-43-9 1-(6-Methylergolin-8β-ylmethyl)imidazole 
• 105579-45-1 (5R,8R,10R)-6-methyl-8-(1-pyrazolylmethyl)ergoline 
• 162070-34-0 (6aR,9R,10aR)-5-Chloro-9-imidazol-1-ylmethyl-7-methyl-4,6,6a,7,8,9,10,10a-octahydro-indolo[4,3-fg]quinoline 

Relevant academic research and scientific papers

Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs

Abstract The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels-Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4+2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches.

ERGOLINE DERIVATIVES AS DOPAMINE RECEPTOR MODULATORS

The invention provides compounds of formula (I) wherein R1-R4 have any of the values defined in the specification, and salts thereof. The compounds are useful as dopamine receptor modulators for the treatment of diseases where modulation of dopamine receptors is implicated (e.g. sexual dysfunction, prolactinoma, Parkinson's disease, and Cushings disease).

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

For the use of analytics, European pharmacopoeial impurities A, B, C, and D of cabergoline were synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two approaches, different in length and stereochemical outcome. A longer, indirect approach was realized through otherwise problematic oxidations of the 9,10-dihidrolysergol derivative, to the corresponding aldehyde and carboxylic acid. This was achieved by the use of activated DMSO and a Pinnick oxidation sequence. All four synthesized impurities are used as analytical standards in cabergoline manufacturing processes.

Synthesis of novel analogs of cabergoline: Improving cardiovascular safety by removing 5-HT2B receptor agonism

The dopamine agonist cabergoline has been used to treat prolactinomas, Parkinson's disease, Cushing's disease, and sexual dysfunction. However, its clinical use was severely curtailed when it was found that patients taking cabergoline had an increased risk of developing cardiac-valve regurgitation. This potentially life-threatening condition has been associated with drugs, such as cabergoline, that are 5-HT2B receptor agonists. We prepared analogs of cabergoline and have identified several that have limited or no agonism at the 5-HT2B receptor.

Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst1 receptor

Non-peptidic compounds containing the octahydro-indolo[4,3-fg]quinoline (ergoline) structural element have been optimized into derivatives with high affinity (pKd r sst1 > 9) and selectivity (>1000-fold for h sst1 over h sst2-h sst5) for the somatostatin sst1 receptor. In functional assays, these ergolines act as antagonists at human recombinant sst1 receptors. Pharmacokinetic studies in rodents reveal good oral bioavailability and brain penetration for some of these compounds.

Studies on oxidation of ergot alkaloids: oxidation and desaturation of dihydrolysergol-stereochemical requirements

A new method for the oxidation of ergoline alcohols to aldehydes was found (TFFA-DMSO, -78 °C, then DIPEA). Structural features of ergolines required for successful C7-C8 double bond introduction via Polonovski-Potier reaction of respective 6-N-oxides were defined and experimentally confirmed: (i) the presence of electron-withdrawing group at C-8; (ii) trans-diaxial orientation of N6-O and C7-H bonds (both requirements are fulfilled for dihydrolyserg-17-al and its 2,4-dinitrophenyl hydrazone prepared in this work).

Synthesis and structure-activity relationships of new (5R,8R,10R)-ergoline derivatives with antihypertensive or dopaminergic activity

A series of new (5R,8R,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were tested in conscious spontaneously hypertensive rats and in rats with unilateral 6- hydroxydopamine-induced lesions of the substantia nigra. (5R,8R,10R)-6- Alkyl-8-ergolinemethanols, prepared from the corresponding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen atoms to afford the new ergolines. (5R,8R,10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-methylergoline (4s, maleate: BAM-1110) exhibited potent dopaminergic activity, about 18- fold greater than that of bromocriptine mesylate. (5R,8R,10R)-8-(1,2,4- Triazol-1-ylmethyl)-6-propylergoline (8b, fumarate: BAM-1602) showed extremely potent dopaminergic activity, being about 220 and 1.15 times more active than bromocriptine mesylate and pergolide mesylate, respectively. Several compounds exhibited potent antihypertensive activity. Structure- activity relationships for antihypertensive and dopaminergic activities are discussed.

Synthesis and structure-activity relationships of new (5R,8S,10R)-ergoline derivatives with antihypertensive of dopaminergic activity

A series of new (5R,8S,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were evaluated in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra, respectively. (5R,8S,10R)-6-Methyl-8-ergolinemethanols, prepared from the corresponding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen atoms to afford the new ergolines. (5R,8S,10R)-8-(1-Imidazolylmethyl)-6-methylergoline (5a, BAM-2101) and (5R,8S,10R)-2-bromo-6-methyl-8-(1,2,4-triazol-1-ylmethyl)ergoline (7c, BAM-2202) exhibited potent antihypertensive activities. The maximum falls of systolic blood presure after oral administration of 5a and 7c at 3 mg/kg were 95 and 132 mmHg, respectively, while those of cianergoline, bromocriptine mesylate, hydralazine, and nifedipine at the same dose were 40, 37, 47, and 49 mmHg, respectively. The durations of significant antihypertensive effects of these compounds except nifedipine were more than 7 h. None of the ergolines exhibited potent dopaminergic activity. Structure-activity relationships are discussed.

Diastereospecific formation of 6-N-oxide ergolines: A 1H NMR study of the configuration at nitrogen

The 6-N-oxides derivatives of a series of analogous ergoline/ene derivatives were prepared and their stereochemistry at nitrogen determined by 1H NMR analysis. The factors governing the outcome of the oxidation are discussed.

6-Methylergoline-8-carboxylic acid esters as serotonin antagonists: N1-substituent effects on 5HT2 receptor affinity

Three series of 6-methylergoline-8-carboxylic acid esters with various alkyl substituents in the N1-position were prepared and their 5HT2 receptor affinities measured. Some overlap occurred in the 5HT2 receptor affinities of the different ester series, indicating that both the ester side chain and the indole substituent influenced 5HT2 receptor affinity. While 5HT2 receptor affinity was affected by the structure of the ester side chain, the N1-substituent played a more crucial role in determining 5HT2 receptor affinity. When the ester side chain was held constant, maximal 5HT2 receptor affinity for that series of esteres was obtained when the N1-substituent was isopropyl. Smaller substituents in the N1-position resulted in reduced 5HT2 receptor affinity. Groups C4 or larger in the N1-position resulted in a further decline in 5HT2 receptor affinity. The importance of the N1-substituent in determining 5HT2 receptor affinity was further substantiated when several 2-methyl-3-ethyl-5-(dimethylamino)indoles with various N1-substituents were tested. Again, maximal 5HT2 receptor affinity was obtained when the N1-substituent was isopropyl.