DD154897A1 - PROCESS FOR THE PREPARATION OF 8-SUBSTITUTED ERGOLINES - Google Patents

Abstract

The invention is important for the medicine and the pharmaceutical industry. The aim is to achieve an improvement of known therapeutic options or an expansion to new indications by partially synthetic modification of ergoline. The invention is therefore based on the object to synthesize ergoline derivatives of the general formula III. According to the invention, compounds of the general formula I are reacted with isatosyl anhydrides of the general formula III to give compounds of the general formula IIIa, the cyclization of which with orthoformic acid triethyl ester, ethoxymethylenemalononitrile or ethoxymethylenecenoic acid ethyl ester yields the corresponding compounds of the general formula IIIb. The preparation of compounds of general formula IIIa is carried out under Erwaermen in an anhydrous organic solvent. The cyclization is carried out under Erwaermen. The compounds of general formula III prepared by the process according to the invention have antiparkinson effect.

Description

22 5629

Process for the preparation of 8-substituted ergolines

The invention "relates to a process for the preparation of 8-substituted ergolines of general formula III.

Application Field of the fin-making

In addition to the more than 50 previously known naturally occurring ergot alkaloids, some of which are of great importance in medicine (for example ergotamine, ergocornine, ergokryptine, ergocristine, ergosine), there are numerous partially synthetic ergoline derivatives, of which various are pharmaceutical active ingredients Find. For example, D ~ 6-methyl-8-cyanomethylergoline acts as a nidation inhibitor, N- (D-6-methylisoergolenyl) -N. N, N'-diethylurea is a serotonin antagonist, and 2-bromoergocryptine is called prolactin Inhibitor used.

Also, 3,4-dihydro-4-oxoohinazoline show a variety of pharmacological effects. Thus compounds with antiphlogistic, analgesic and antipyretic effects or antibacterial, antiviral and anticonvulsant effects have been synthesized and introduced into therapy, such as, for example, For example, 2-methyl-3- (o-tolyl) -3,4-dihydro-4-oxoquinazoline * (methaqualone, dormutil) due to its hypnotic action. ·

Despite the variety of therapeutic uses for ergot alkaloids, the further partial synthetic derivatization of ergoline is sought in order to improve

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The invention is therefore of significance for the medical and pharmaceutical industries.

Characteristic of the known technical solutions

Isatoic anhydride reacts with nucleophiles, e.g. B. with aliphatic or aromatic amines, to 2-aminobenzamides (see, inter alia, RP STAIGER and BC WAGNER, J. org. Chem. IJi, 1427 (1953)), which with triethyl orthoformate, Ethoxymethylenmalonsäuredinitril or Ethoxymethylencyanessigsäureethylester to 3,4-dihydro- Cyclization of 4-oxoquinazolines (see, for example, BE NAGAHARA, K. TAICAGI and T. UEDA, Chem. Pharmacol. Bull. / Tokyo / 24, 1310 (1976)). In the reaction of aliphatic diamines with isatoic anhydride N, N'-bis - ^ - aminobenzoyl) -polymethylendiami- ne _s with triethyl orthoformate 3,3 '- »Polymethylenbis- (3,4-dihydr0-4-oxoquinazolines) provide (p JOHNE, M. SUSSE and B. JUNG, Pharmacy 33, 821 (1978)).

However, ergoline derivatives of general formula III are not yet known.

It is the object of the invention to achieve an improvement of known therapeutic possibilities or the development of new indications by partial synthetic modification of ergoline derivatives.

Rfindung Principle of the E.

The object of the invention is to synthesize 8-substituted ergolines of general formula III.

According to the invention, compounds of general formula I are reacted with isatoic anhydrides of general formula II to give compounds of general formula IIIa, whose

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Cyclization with triethyl orthoformate, ethoxymethylenemalononitrile or ethyl ethoxymethylenecyneacetate gives compounds of the general formula IHb. In the formulas E is optionally substituted 2-aminobenaoyl or optionally substituted 3,4-dihydro-4-oxoquinazolin-3-yl, R is alkyl (chain length C- ₁ -C.),

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R and R independently of one another preferably represent hydrogen, halogen or nitro. The compounds of the general formula IIIa are prepared by heating, preferably under reflux conditions, in an anhydrous organic solvent. The cyclization is carried out by heating for several hours, preferably under reflux conditions.

The compounds of the general formula III prepared by the process according to the invention are novel and have antiparkinson effect.

From Guide e g sh o ispiele

Example 1:

160 mg (0.98 mmol) of isatoic anhydride and 250 mg (0.98 mmol) of 9,10-dihydrolysergamine are refluxed in 30 ml of anhydrous ethanol for 1 hour. After concentration in vacuo, column chromatography on silica gel with chloroform as eluent to which increasing amounts of methanol are added yields 182 mg (50 $) of D-6-methyl-8- (2-aminobenzoyl) -arainomethylergoline-I.

IR (KBr, cm ^-1 ): 1450, 1528, 1587, 1613, 1628; MS (m / z): 374 (M ⁺ ), 255, 237, 225, 211, 197, 182, 167, 154, 144.

Example 2:

Analogously to Example 1, D-6-methyl-8- (2-amino-5-chlorobenzoyl) -aminomethyl-ergoline-I is obtained:

IR (KBr, cm ^-1 ): 1445, 1530, 1583, 1615, 1630;

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MS (m / z): 408 (M ⁺ ), 327, 297, 281, 269, 255, 237, 225, 197, 182, 167, 154, 144.

Example 3? ...

The cyclization of D-6-methyl-8- (2-amino-d-benzoyl) -aminomethyl-ergoline-I is carried out with triethyl orthoformate by heating for five hours at reflux. Concentration in vacuo and column chromatography on Sephadex IH-20 using clay chloroform / n-hexane 1: 1 as eluent gives 70 mg (37 #) of D-6-methyl-8- (3,4-dihydro-4-oxoquinoline-3 -yl) methyl-ergoline-I.

IE (CHCl ₃ , cm ^-1 ): 1610, 1630, 1675;

MS (m / z); 384 (M ⁺ ), 237, 223, 209, 195, 186, 182, 167, 154, 146, 120.

Examples 4 "to 6:

On an analogous basis, for example, the following ergolinohinazolines are obtained:

D-6-methyl-8- (6 ~ chloro-3,4-dihydro ~ 4-oxoquinazolin-3-yl) -methylergolin-I

IR (KBr, cm ^-1 ): 1605, 1680;

MS (m / z): 418 (M ⁺ ), 237, 223, 207, 195, 182, 167, 154, 144.

D-6-methyl-8- (6,8-diochloro-3,4-dihydro-4-oxo-quinazolin-3-yl) -methylergoline-I IR (Nujol, cm ^-1 ): 16.05, 1675;

MS (m / z): 452 (M ⁺ ), 265, 254, 237 ', 223, 207, 195, 182, 167, 154, 144.

D-6-methyl-8- (6-nitro-3,4-dihydro-4-oxoquinazolin-3-yl) methyl-ergoline-I

IR (KBr, cm " ¹ ): 1345, 1607, 1686;

MS (m / z): 429 (M ⁺ ), 399, 237, 223, 195, 167, 154, 144.

Claims (3)

2 2 562 9 ** Erf indung; sanspruch 1. A process for the preparation of 8-substituted ergolines of the general formula III, characterized in that compounds of the general formula I with isatoic anhydrides of the general formula II with heating in an anhydrous organic solvent to compounds' of the general formula IIIa and optionally subsequently under several hours Heating with triethyl orthoformate, Ethoxymethylenmalonsäuredinitril or Ethoxymethylencyanessigsäureethylester be cyolisiert to the corresponding compounds of the general formula IHb, wherein in the formulas R for optionally substituted 2-aminobenzoyl or optionally substituted 3,4-bihydro-4-oxoquinazolin-3 ~ yl, R * ¹ for Alkyl ( ^C 1 "* ^c l) ¹ ^ ^{R 1} ^ ^R independently represent hydrogen, halogen or nitro. 2. The method according to item 1, characterized in that the compounds of the general formula IHa are prepared under reflux conditions. 3. The method according to item 1, characterized in that the cyclization to compounds of general formula IHb is carried out with triethyl orthoformate with heating, in particular under reflux conditions. For this 1 page formulas 22 5 62 ZX O = O ZX ZX ZX ι-, γ-τ j ι · η η, it, /> ί \ . «it» )