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United States Patent (19) [11] 3,968,111 Bach et al. (45) July 6, 1976 54 8,8-DISUBSTITUTED-6- 3,113,133 12/1963 Hofmann et al..w. 260/285.5 METHYLERGOLINES AND RELATED COMPOUNDS Primary Examiner-Alton D. Rollins 75) inventors: Nicholas J. Bach; Edmund C. Assistant Examiner-Mary Vaughn Kornfeld, both of Indianapolis, Ind. Attorney, Agent, or Firm-James L. Rowe, Everet F. 73) Assignee: Eli Lilly and Company, Indianapolis, Smith Ind. 22 Filed: Dec. 6, 1974 21 Appl. No.: 530,320 57 ABSTRACT 8,8-Disubstituted-6-methylergolines and 9-ergolenes, 52 U.S. Cl............................... 260/285.5; 424/261 prepared by alkylation of lysergic, isolysergic or their 51 int. C.’................ C07D 457/02; C07D 457/10 9,10-dihydro analogues, optionally followed by chemi 58) Field of Search.................................. 260/285.5 cal modification of an 8-substituent. 56 References Cited UNITED STATES PATENTS 9 Claims, No Drawings 2,86,074 1 1/1958 Kornfeld et al.................. 260/285.5 3,968, 111 1 2 1722 (1957) prepared the 8-methyl derivative of D-iso 8,8-DISUBSTITUTED-6-METHYLERGOLINES AND lysergic acid diethylamide, stating that they were, how RELATED COMPOUNDS ever, unable to obtain substitution at C8 using dihydro lysergic acid methyl ester and the alkylating agent used BACKGROUND OF THE INVENTION successfully with lysergic acid itself; to wit, methylio Compounds based on the ergoline ring system dide and potassium amide. These authors also prepared 8-ethyl-D-isolysergic acid diethylamide and the 1,8- dimethyl-D-isolysergic acid diethylamide. There is no mention in the literature of an 8,8-disubstituted-9-ergo O lene in which the substituents at 8 are other than amide groups and in which the 1-position is not substituted. 6-Methyl-8,8-disubstituted ergolines are not mentioned in the literature. 5 SUMMARY OF THE INVENTION This invention provides compounds of the formula R R 20 R. have a suprising variety of pharmaceutical activities. R For example, lysergic and isolysergic acid are 8-car -CH3 boxy-6-methyl-9-ergolenes. The amides of lysergic acid, many of which have valuable and unique pharma cologic properties, include the naturally occurring oxy 25 2. tocic alkaloids - ergocornine, ergokryptine, ergono N vine, ergocristine, ergosine, ergotamine, etc. - and synthetic oxytocics such as methergine, as well as the HN synthetic hallucinogen - lysergic acid diethylamide or LSD. The corresponding amides of 6-methyl-8-carbox 30 wherein R is alk, carbo(C-ca) alkoxy, Cl or Br; yergoline, known generically as dihydroergot alkaloids, R" is carboxyl, carbo(Cr-cs) alkoxy, or CH2, are oxytocic agents of lower potency and also lower wherein alk is (C-C)alkyl snf toxicity than the ergot alkaloids themselves. Recently, Z is H, OH, CN, OSO-alk, Y-phenyl, or Y-alk, it has been found by Clemens, Semonsky, Meites and wherein Y is S or O; and their various co-workers, that many ergot-related drugs 35 R'' and R' when taken singly are H; and, when have activity as prolactin inhibitors including ergocor taken together with the carbon atoms to which they nine, dihydroergocornine, 2-bromo-o-ergokryptine are attached, form a double bond. and d-6-methyl-8-cyanomethylergoline. References Also included within the scope of this invention are embodying some of the newer findings in this field of pharmaceutically-acceptable acid addition salts of ergoline pharmacology are the following: Nagasawa 40 compounds according to Formula 1 formed with a and Meites, Proc. Soc. Exp'tl. Biol. Med, 135, 469 non-toxic acid. These pharmaceutically-acceptable (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, salts include salts derived from inorganic acids such as: 1971); Heuson et al., Europ. J. Cancer, 353 (1970); hydrochloric acid, nitric acid, phosphoric acid, sulfuric Col. Czech, Chen. Commun., 33,577 (1968); Nature, acid, hydrobromic acid, hydriodic acid, nitrous acid, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 45 phosphorous acid and the like, as well as salts derived (1971); Mantle and Finn, id, 441; Semonsky and co from nontoxic organic acids such as aliphatic mono and workers, Col. Czech. Chen. Conn., 36, 2200 (1971); dicarboxylic acids, phenyl-substituted alkanoic acids, Schaar and Clemens, Endocr.,90, 285-8 (1972); Clem hydroxyalkanoic and alkandioic acids, aromatic acids, ens and Schaar, Proc. Soc. Exp. Biol. Med., 139, aliphatic and aromatic sulfonic acids, etc. Such phar 659-662 (1972) and Sweeney, Clemens, Kornfeld and 50 maceutically-acceptable salts thus include sulfate, Poore, 64th Annual Meeting, American Association pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phos Cancer Research, April, 1973. Recently issued patents phate, monohydrogenphosphate, dihydrogenphos in the field of erogoline derivatives or lysergic acid phate, metaphosphate, pyrophosphate, chloride, bro derivatives include the following: U.S. Pat. No. mide, iodide, fluoride, acetate, propionate, decanoate, 3.704,233, U.S. Pat. No. 3,709,891, U.S. Pat. No. 55 caprylate, acrylate, formate, isobutyrate, caprate, hep 3,585,201, U.S. Pat. No. 3,666,762, U.S. Pat. No. tanoate, propiolate, oxalate, malonate, succinate, su 3,586,683, U.S. Pat. No. 3,717,640, and U.S. Pat. No. berate, sebacate, fumarate, maleate, mandelate, 3,592,816. - butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlo Only a few 8,8-disubstituted ergolines have been robenzoate, methylbenzoate, dinitrobenzoate, hydrox prepared. A majority of these compounds also have a 60 ybenzoate, methoxybenzoate, phthalate, terephthalate, substituent on the indole nitrogen thus yielding a 1,8,8- benzenesulfonates, toluenesulfonate, chlorobenzene tri-substituted derivative. For example, Baker et al. sulfonate, xylenesulfonate, phenylacetate, phenylpro publishing in Molecular Pharmacology, 9, 23 (1973) pionate, phenylbutyrate, citrate, lactate, 3-hydroxybu reported 1,8-dimethyl-D-lysergic acid p-bromanilide. tyrate, glycolate, malate, tartrate, methanesulfonate, This compound showed no hallucinogenic activity un 65 propanesulfonate, naphthalene-1-sulfonate, naphtha like D-lysergic acid p-bromanilide. The same com lene-2-sulfonate and the like salts. pound is mentioned in Science, 178, 614 (1972). In the above formula, (C-C)alkyl includes the Troxler and Hofmann, Helvetica Chemica Acta, 40, groups methyl, ethyl, propyl, and isopropyl. The term 3,968,111 3 4 (C-C3)alkoxy thus includes the terms methoxy, eth oxy, and propoxy and the term carbo(C-C)alkoxy includes the terms carbomethoxy, carboethoxy, carbo COO at R (CH2) -- propoxy and carboisopropoxy. In the above formula, when R'' and R'' are hydrogen, the compound is de R nominated an ergoline, but when R'' and R', when taken together with a carbon atom to which they are attached, form a double bond, the compound is denom -CH2 inated a 9-ergolene. The following compounds exem plify the scope of our invention: O D-6-methyl-8o-ethyl-8cy-carbomethoxyergoline sul fate D-6-methyl-8o-isopropyl-8ps-chloroergoline phos phate D-8o-isopropyl lysergic acid 15 D-8a-ethyl lysergic acid D-8o-ethyl dihydrolysergic acid D-83-methylisolysergic acid A strong non-hydrolytic base such as sodium amide, D-6-methyl-86-ethyl-8o-carbo-n-propoxy-9-ergo potassium amide, lithium tetramethylpiperidide, potas lene maleate 20 sium diisopropyl amide and the like are used to replace D-6-methyl-86-hydroxymethyl-8a-ethyl-9-ergolene the hydrogen at Cs to form an anion, which anion then succinate reacts with the alkylating agent R' (CH).X. Com D-6-methyl-8g-cyanomethyl-8o-carboethoxy-9- pounds according to formula I above in which R is ergolene carboxyl are prepared by hydrolyzing the correspond D-6-methyl-8o-cyanomethyl-8p-n-propylergoline 25 ing carbo (C-C) alkoxy compound. Compounds in hydrochloride which R' is CHZ wherein Z is hydroxyl are prepared D-6-methyl-86-mesyloxymethyl-8-a-bromoergoline by lithium aluminum hydride reduction of the corre tartrate sponding ester grouping. Compounds in which Z is D-6-methyl-8o-methoxymethyl-8g-carboethoxyer cyanide are prepared by first forming the mesylate goline citrate 30 ester of the hydroxymethyl derivative (compounds D-6-methyl-8g-ethoxymethyl-8o-carboisopropoxy wherein R' is CHZ and Z is OH) and then replacing 9-ergolene lactate the mesylate radical with cyanide by use of sodium D-6-methyl-8-a-phenoxymethyl-8g-carbomethoxyer cyanide. Compounds in which Z is Y-phenyl or Y-alk goline methane sulfonate D-6-methyl-86-phenoxymethyl-8o-carboethoxy-9- 35 are prepared in similar fashion by reacting the mesylate ergolene ester with phenol or phenylmercaptan, a lower alkanol D-8a-phenylmercaptomethyl lysergic acid or a lower alkylmercaptan. Finally, compounds in D-8a-methylmercaptomethyl lysergic acid toluene which R is Cl or Br and R' is carboCC-C)alkoxy are sulfonate prepared by reacting the alkali metal salt of a lysergic, D-86-n-propylmercaptomethyl isolysergic acid, 40 dihydrolysergic or isolysergic acid corresponding and the like. The compounds of this invention are white thereto with p-toluenesulfonylchloride, p-toluenesul crystalline solids, as are their acid addition salts formed fonylbromide or other acyl chloride or bromide. In this with non-toxic acids. Compounds in which one of R or reaction, suprisingly, the ester group does not replace R" is carbo(C-C)alkoxy, are prepared by alkylating the anion but the halogen atom. 45 It will be apparent to those skilled in the art from the an ester of lysergic or isolysergic acid or of dihydroly above general directions that individual combinations sergic or dihydroisolysergic acid with an alkylating of substituents for RandR' can be achieved by altering agent of the formula R' (CH),X wherein R' is the order in which reactions are carried out involving a CH, CN-CH or carbo(C-C)alkoxy group after the initial reaction with the alkylating agent, R'(CH).X. 50 This invention is further, illustrated by the following C-O-alk, specific examples.
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  • Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds As a Basis of Their Therapeutic Application

    Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds As a Basis of Their Therapeutic Application

    CHAPTER I Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds as a Basis of Their Therapeutic Application B. BERDE and E. STURMER "Truth is rarely pure and never simple" OSCAR WILDE This chapter, rather unorthodox for a volume of the Handbook of Experimental Pharmacology, is not intended as a summary of the wealth of information accumu- lated in this book. It is an attempt at a compact synopsis to help those teaching pharmacology or writing a textbook of pharmacology not to overlook the essential chemical and biological basis of the therapeutically most important compounds and those of their activities which are believed to be relevant for their therapeutic effects. The present volume, entitled Ergot Alkaloids and Related Compounds, deals with chemical entities containing the tetracyclic ergolene- or ergoline-ring system. They can be obtained by extraction of different strains of the fungus cIaviceps- grown on rye or cultivated in fermentation tanks-or alternatively by partial or total synthesis. These compounds can be divided into four main structural groups: cIavine alkaloids, lysergic acids, simple lysergic acid-amides, and peptide alkaloids. One example of each type of molecule is given in Figure 1. The degree of oxidation is a criterion for further differentiation in the group of cIavine alkaloids, all of which are compounds of minor biological importance. The naturally occurring lysergic acids are divided into compounds with a double bond in the 8-9 position (8-ergolenes) and in the 9-10 position (9-ergolenes). All congeners are methylated in position (i. The two asymmetric carbon atoms in position 5 and 10 (in the case of 8-ergolenes) or 5 and 8 (in the case of Glavine-Alkaloids Lysergic Acid group Lysergic Acid Amides Peptide-Alkaloids of Alkaloids Examples: I'_ GOOH I"'" NH'GH3 b ~HN Elymoclavine D-Lysergic Acid Ergometrine Ergotamine Fig.
  • Biotechnology and Genetics of Ergot Alkaloids

    Biotechnology and Genetics of Ergot Alkaloids

    Appl Microbiol Biotechnol (2001) 57:593–605 DOI 10.1007/s002530100801 MINI-REVIEW P. Tudzynski · T. Correia · U. Keller Biotechnology and genetics of ergot alkaloids Received: 28 May 2001 / Received revision: 8 August 2001 / Accepted: 17 August 2001 / Published online: 20 October 2001 © Springer-Verlag 2001 Abstract Ergot alkaloids, i.e. ergoline-derived toxic me- tions in the therapy of human CNS disorders. Chemical- tabolites, are produced by a wide range of fungi, pre- ly the ergot alkaloids are 3,4-substituted indol deriva- dominantly by members of the grass-parasitizing family tives having a tetracyclic ergoline ring structure (Fig. 1). of the Clavicipitaceae. Naturally occurring alkaloids like Based on their complexity, they can be divided into two the D-lysergic acid amides, produced by the “ergot fun- families of compounds. In the D-lysergic acid deriva- gus” Claviceps purpurea, have been used as medicinal tives, a simple amino alcohol or a short peptide chain agents for a long time. The pharmacological effects of (e.g. ergotamine) is attached to the ergoline nucleus in the various ergot alkaloids and their derivatives are due amide linkage via a carboxy group in the 8-position. In to the structural similarity of the tetracyclic ring system the simpler clavine alkaloids (e.g. agroclavine) that car- to neurotransmitters such as noradrenaline, dopamine or boxy group is replaced by a methyl or hydroxymethyl to serotonin. In addition to “classical” indications, e.g. mi- which attachment of side groups such as in the amide- graine or blood pressure regulation, there is a wide spec- type alkaloids is not possible.