3006-19-7Relevant academic research and scientific papers
Synthesis of novel analogs of cabergoline: Improving cardiovascular safety by removing 5-HT2B receptor agonism
Dosa, Peter I.,Ward, Tim,Walters, Michael A.,Kim, Suck Won
, p. 254 - 258 (2013)
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.
Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs
Lee, Kiyoun,Poudel, Yam B.,Glinkerman, Christopher M.,Boger, Dale L.
, p. 5897 - 5905 (2015/08/03)
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
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Page/Page column 17; 18, (2014/06/11)
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
Wagger, Jernej,Pozes, Aljaz,Pozgan, Franc
, p. 23146 - 23156 (2013/11/19)
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.
Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst1 receptor
Troxler, Thomas,Enz, Albert,Hoyer, Daniel,Langenegger, Daniel,Neumann, Peter,Pfaeffli, Paul,Schoeffter, Philippe,Hurth, Konstanze
, p. 979 - 982 (2008/09/18)
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
Ga?ák, Radek,K?en, Vladimír,Sedmera, Petr,Passarella, Daniele,Novotná, Michaela,Danieli, Bruno
, p. 10466 - 10478 (2008/03/13)
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
Ohno,Adachi,Koumori,Mizukoshi,Nagasaka,Ichihara,Kato -
, p. 1463 - 1473 (2007/10/02)
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.
6-Methylergoline-8-carboxylic acid esters as serotonin antagonists: N1-substituent effects on 5HT2 receptor affinity
Marzoni,Garbrecht,Fludzinksi,Cohen
, p. 1823 - 1826 (2007/10/02)
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.
EPIMERIZATION OF ESTERS OF STEREOISOMERIC 8-ERGOLINECARBOXYLIC ACIDS ON CARBON C(8)
Benes, Jan,Cerny, Antonin,Miller, Vladimir,Kudrnac, Stanislav
, p. 1333 - 1340 (2007/10/02)
Esters of 8β-ergolinecarboxylic acids, I-XI, exposed to strong bases, such as lithium diisopropylamide, in polar aprotic solvents gave enolates, which were decomposed by suitable proton donors to a mixture of epimers.This contained, apart from the starting 8β-esters, the corresponding 8α-esters, Ia-IVa and VIa-XIa (65-80percent) and Va (about 16percent).Exposure of 8α-ester XIIa to these conditions produced epimerization on C(8) (about 54percent) and, to a small extent, isomerization on C(10), affording ester I(c. 1percent) and Ia (c. 5percent).
