DD209458A5 - METHOD FOR PRODUCING A NUTRITIONAL CORAL SUBSTITUTED BY AN ARYL GROUP AND ITS SAEURE ADDITION SALT - Google Patents

Abstract

The invention relates to a process for the preparation of ergot alkaloids for use as a medicament. The aim of the invention is to provide such ergot alkaloids which are suitable as psychogeriatrics. According to the invention in position 1 substituted by an aryl group ergot alkaloids, in particular compounds of formula I are prepared, wherein, for example: Ar is an aryl group; R and R are deep 2 hydrogen or methoxy u, a; Alkyl group having 1 to 3 carbon atoms in the form of the free base or a Saeureadditionssalzes.

Description

AP C07D / 248 035/3

O / O Π O C * ^ - Ί - 52 066 IS -C 4 Q U O ϋ O 30.6.83

Process for the preparation of ergot alkaloids Field of application of the invention

The invention relates to a process for the preparation of ergot alkaloids having valuable pharmacological properties. The compounds according to the invention are used as medicaments, for example for the treatment of senile dementia, for vigilance enhancement and for use as antidepressants, especially in elderly people.

Characteristic of the known technical solutions

Ergot alkaloids are known. However, no further details are known.

Object of the invention

The aim of the invention is the provision of new ergot alkaloids, which are particularly suitable as antidepressants, especially in the elderly and those for the treatment of senile dementia and Vigilanzerhöhung.

Explanation of the essence of the invention

The invention has for its object to find ergot alkaloids with the desired effect profile.

Erf indungsgemäß in position 1 by an aryl group substituted ergot alkaloids, in the form of the free bases -or-their. Acid addition salts prepared ·

-UUL 1983 * 101038

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These compounds, hereinafter referred to as compounds of the invention, include the 1-aryl derivatives of both naturally occurring or fermentally producible as well as synthetically accessible ergot alkaloids, - You can optionally carry the usual substituents in the chemistry of ergot alkaloids. Further, they may exist as isomers, e.g. B "as 8E and 8S isomers *

In particular, compounds of the formula I are included,

Ariflorin

Ar is an aryl group, H and B ^ are each hydrogen and E _{2 is} hydrogen or filethoxy or

S is hydrogen and E ^ and E ₂ together form a single bond or E and R * together form a single bond and E _{2 is} hydrogen or methoxy,

E is hydrogen, carboxy or a group (CEy _n -X, in which

η is 1 or 2 and

X is hydrogen, hydroxy, cyano, carboxy or YE ¹ , in which _. _.....

R * is an alkyl group having 1 to 4 carbon atoms, phenyl or pyridyl and

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Y is a sulfur or oxygen atom or a carbonyl

group, and E ^, an alkyl group having 1 to 3 carbon atoms,

where if B ^ for. (CH ₀ ) -OH, carboxy or (CH ₀ ) ^ - COOH

J C. LX. CH

is, the compound may also be in the form of a physiologically acceptable, hydrolyzable ester, in the form of the free bases or their acid addition salts.

E is hydrogen, E ^ may have the <C or the β configuration. The β configuration is preferred.

As compounds of the formula I z. B. may be mentioned, wherein

Ar is an aryl group,

E is hydrogen,

E ,. and Ep together form a simple bond or B ,. and E ₂ each is hydrogen, E-, is an ester -CH ₂ -E * ^ wherein

E * o is hydrogen, hydroxy, cyano, carboxy, alkoxy having 1 to 4 carbon atoms, alkoxymethyl or alkylthiomethyl having 2 to 5 carbon atoms, alkylcarbonyloxymethyl or alkylcarbonylmethyl each having 3 to 6 carbon atoms, and

E ^ is methyl.

The aryl radical Ar is an optionally mono- or polysubstituted, mono- or polynuclear, homo- or heteroaromatic Eest, where as substituents, z, B, halogen, hydroxy or acyloxy, alkyl, trifluoromethyl, alkoxy, aryl, Nitro, alkoxycarbonyl, acylamino or -alkylamino radicals come into question.

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Ar is preferably an optionally substituted phenyl group, in particular an unsubstituted phenyl group

group. The phenyl group may, for. By hydroxy, alkyl,

or alkoxy (each having 1 to 4 carbon atoms) or tri-fluoromethyl monosubstituted or mono- or disubstituted by fluorine, chlorine or bromine.

B ,. and B ^ suitably form a simple bond. ·

Preferably, B ~ is a group CH ₂ -X. X is, for example, a hydroxyl, cyano or carboxy group, in particular a hydroxy group ·

As compounds of the formula I in the form of physiologically acceptable hydrolyzable esters, it is possible to mention, for example, those compounds of the formula I in which B 1 is an ester

COOE ¹ or

(CH ₂ ) J ₁ -COOE ¹ ,

wherein E is alkyl having 1 to 12 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or pyridyl, or represents an optionally monosubstituted in the phenyl ring by alkyl having 1 to 4 carbon atoms or mono- or disubstituted by chlorine, bromine or iodine, or by alkoxy with 1 to 4 carbon atoms mono-, di- or trisubstituted phenyl or phenylalkyl (having 7 to 12 carbon atoms) rest.

E ₂ ^ is preferably methyl »

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Of particular interest is the compound of Example 1 below.

According to the present invention, the compounds according to the invention are obtained by arylating a corresponding ergot alkaloid unsubstituted in position 1 or a precursor of such a compound in position 1. The reaction is preferably carried out by reaction with a compound of the formula II

X ₁ II

in which Ar has the above meaning and X 1 represents chlorine, bromine or iodine,

In particular, the compounds of the formula I and their esters and salts as defined above are obtained by reacting compounds of the formula III or their precursors,

wherein E, R *, Ep, Ε., and E ^ have the above meaning, or, if E ₃ (CH ₂ ) -QH, carboxy or (CH ₂ ) _n -COOH, also physiologically acceptable hydrolyzable esters of such compounds, or whose precursors are arylated in the position .1. The reaction is preferably carried out by reaction with compounds of the formula II.

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The process according to the invention can be carried out in a manner known per se under the conditions of an Ullmann reaction.

The catalyst used is preferably copper powder.

The reaction may be carried out either without a solvent or will be z · pyridine, Ghinolin ", toluene, ITitrobenzol, Dimethylsulfosid or ^{dimethylformamide.:}

When using non-acid-binding solvents, a. For example, potassium carbonate may be added.

The reaction temperatures are generally between 80 ⁰ G * and 200 ⁰ C.

The reaction is preferably carried out under inert gas such as nitrogen or argon.

The starting compounds of the formula III and the -hydroxyatable esters of the compounds of the formula III in which R 1 is (GH ₂ ) -OH, carboxy or (CH ₂ ) J ₂₁ -COOH can also be used in the form of a precursor, h »in the form of a compound which can be converted into the starting compound in a manner known per se. After the reaction with the compound of the formula II, the product obtained can be converted into a compound of the formula I by methods known per se.

The free bases can be converted into acid addition salts and vice versa. Suitable acids for salt formation. B, the hydrofluoric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid.

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The starting compounds of the formulas II and III are known or can be prepared by processes known per se ·;

The compounds of the formula I and their acid addition salts have hitherto not been described in the literature. They have interesting pharmacological properties in animal experiments and can therefore be used as medicaments.

In particular, these substances affect the metabolism of biogenic amines such as serotonin, dopamine, and adrenal in different regions of the batten-brain.

In both the cortex and hippocampus, the new substances cause s.c. at 10 mg / kg. a reduction of 5-hydroxy-indoleacetic acid (5-ΗΙΔΑ) »

In the striatum, they cause an increase of the two dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAG and HVA) at 50 mg / kg s.c.

In the hypothalamus and in the PonsAfeclulla segment, the noradrenal in-metol is eluted from 4-hydrox-3-methoxyphenyl ethylene glycol (MHPG-SO 2) at 50 mg / kg s, c. greatly increased ".

(For the quantitative determination of the above biochemical parameters, see F · Karoum et al ·, Europ · J * Pharmacol 44, 311 - 318 (1977) \ BHC Westrink et al., Europ · J. Pharmacol., 42, 179-190 (1977) and HE Bürki et al., Psychopharmacology j> 2, 227-237 (1978)).

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Furthermore, the new substances on the sleep / wake cycle in the cat, with 3 to 10 mg / kg p.o ·, reduce the duration of paradoxical sleep without affecting classic sleep and prolonging the wakefulness.

In addition, the new substances on the Ungerstedt Eatte (method according to U, Ungerstedt, Acta physiol · scand · Suppl. 282 »69-93 (1971)) cause rotations contralateral to the nigrostriatal lesions, with doses of 1 to 3 mg / kg i. p ·

In the above-mentioned experiments, 8β-hydroxymethyl-6-methyl-1-phenyl-9,10-didehydroergoline has been distinguished by a particularly interesting profile of action. On the sleep / wake cycle in the cat, eg B, this compound reduced by about 30 % after 3 mg / kg ρ · the duration of paradoxical sleep .

Due to the in vivo biochemical studies on the serotonin and norepinephrine metabolism and the results on the Ungerstedt model, the new substances can be used as antidepressants, especially in older people.

Due to the biochemical in vivo studies on the serotonin, dopamine and horadrenaline metabolism and the results on the Ungerstedt model and on the sleep / wake cycle in the cat, the new substances for the treatment of senile dementia, especially in the suitable for early stage · Based on the results on sleep / h-cyclic-us-in the cat, the substances can also be used for the enhancement of vigilance.

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In addition, due to the biochemical in vivo studies in the rat on the dopamine metabolism, they are suitable as ueuroleptica.

The invention also relates to pharmaceutical compositions containing the compounds of the invention, for their preparation, the auxiliaries and carriers commonly used in pharmacy can be used.

Furthermore, the invention relates to the use of the new Subst zeh as pharmaceuticals, for example in the therapeutic treatment, for example, for the treatment of senile dementia in the early stage or as antidepressants or vigilanzerhöhende Mit

embodiment

In the following examples, which explain the invention in more detail, all temperatures are given in degrees Celsius and are uncorrected.

example 1

8β-Hydroxymethyl-6-methyl-1-phenyl-9,10-didehydroergoline

(1-phenyl-lysergol)

5.7 S copper powder and 3.3 g of potassium carbonate are placed in a sulphonation flask and then treated with a solution of 5 »t S lysergol in 60 ml of dimethylformamide and 4.5 JBl iodobenzene. The copper-brown suspension is stirred for 5 hours at 170 ⁰ G under nitrogen · After cooling, the brown mixture is diluted with methylene chloride and filtered through Hyflo. The filtrate is extracted three times with 2N sodium carbonate solution. The combined organic phases are washed with water.

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see, treated with charcoal, dried over sodium sulfate and evaporated. This gives 5.5 g of crude product which crystallized from ether / petroleum ether. After two Umkristal lisieren of methylene chloride / Hesan obtained white crystals of the mp ·: 133 - 136 ⁰ J / V7r ° = + 19, ί ° Cc = 0.74 in chloroform) ·

Hydrogen maleate: mp: 199 - 201 ° (dec.); Ü ^ J ^ - + 88.0 ° (c = 0.7 in dimethylformamide).

The following compounds can be prepared analogously to the method described in Example 1:

Example 2

8SS-hydroxymethyl-6-methyl-1-phenyl-ergoline

(1-phenyl-9,10-dihydrolysergol)

Mp .: 200 - 202 °; Γ <* 3ψ = -93.5 ° (α = 0.73 in chloroform).

Example 3

8β-cyanomethyl; yl-6-niethyl-1-phenyl-9 % 10-didehydro erol in

Mp: 164-167 °; / Γοζ7 ^ ° = ^ »? ° (0 = 0.63 in chloroform),

Example 4

1-phenyl-6-methyl-9,10-didehydro-ergoline 8ss-acetic acid

C1-phenyl-homo-lysergic acid)

M.p .: 270 ° (dec.).

^{δ2 06δ}

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Example 5

8-Ey & roxymethyl-6-methyl-1-phenyl ~ 8,9-didehydro-ergulin

(1-phenyl-elymoclavine)

M.p .: 140.- 143 ° C

= -118.0 ° (ο = 0.58 in chloroform

Example 6

ergoline

Mp .: 201 - 202 ° (decomp.); Chloroform) ·

= + 12.8 ⁰ Cc = 0.5 in

Example 7

9,10-didehydro-8ss-hydroxymethyl-6-methyl-1- (3,4-diohlor-

phenyl) -ergoline -

Mp .: 107 ° (dec.); formamide) ·

= -10.3 ° (o - 0.5 in dimethyl

Example 8

9,10-didehydro-8ss-hydroxymethyl-6-methyl-1- (4-methoxyphenyl)

ergoline

Mp: 160-161 ° (dec) j chloroform).

= + 41 * 5 ⁰ Cc = 0.7 in

Example 9

9,10-didehydro-8β-hydroxymethyl-6-methyl-1- (4-fluorophenyl)

ergoline

Mp .: 200-210 ° (decomp.); Dimethylformamide). -

- -5 »5? (c = 0.5 in

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Example 10

9,10-didehydro-8ss-hydroxymethyl-6-methyl-i- (2-methoxyphenyl) -

ergoline . ^.

M.p .: 155-157 (dec.) _} Ocj ^ = +18.2 ^u (c = 0.5 in dimethylformamide).

Example 11

9,10-didehydro-8ss hydrozymethyl-6-methyl-1- (2-fluorophenyl) -

ergolin '

Mp: 141-144 ° (dec.); C ° CJ ^ = + 13 ° (o = 0.5 in dimethylformamide)

Example 12

9,10-didehydro-8ss hydro2ymethyl-6-methyl-1- (4-methyl-

phenyD-ergoline

Mp .: 202 - 203 ° (dec.); C ⁰ G ^ = -1.2 ° (o = 0.5 in dimethylformamide)

Example 13

gilO-didehydro-eß ^ hydroxymethyl-e-methyl-iC ^ trifluoro- methylphenyl) -serolin

Mp .: 151 - 152 ° (Zers.); foCj ^ = -7.3 ° (o = 0.5 in dimethylformamide). -

Example 14

9,10-didehydro-8ss-hydroxymethyl-6-methyl-1- (3-ohlorphenyl)

ergoline . , .

Mp: 170-172 °; CoCJq ⁰ = -6.0 ° (c = 0.45 in dimethylformamide)

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Example I5

9,10-didehydro-β-hydroxymethyl-e-methyl-i - (3-methoxy)

phenyl) -ergo1in

M.p .: 160 - 162 ⁰ J C ⁰ CJ ^ = ~ ² » ⁸ ° (° = °> 5 in dimethylformamide)

Example 16

8SS-Acetosymethyl-9, IO äidehydro-6-methyl-i-phenyl-

ergolln hydrogen fumarate __

Mp .: 190 - 194 ° (Zers.) J / T ⁰ CJj? = + 9.0 ° (c = 0.5 in dimethylformamide).

Example I7

9,10-didehydro-6-methyl-8ss niootinoyloxymethyl-1-phenyl-

ergoline

Mp: 135-138 ° (dec.) I Ο ^ ΐψ = + 20.0 ° (c = 0.5 in dimethylformamide)

Example 18

9,10-didehydro-e-methyl-i-phenyl-SjB-trimethylacetoxymethyl

ergoline

mp .; 130-133 ° C i ⁰⁰ = ^{+ 1} J ^ ^ '° ° (g = 0.7 in dimethylformamide) ·

Example I9

9,10-Didehydro-6,8B-dimethyl-1-phenyl-ersolin-hydrochloride id

Mp: 282-285 ° (decomp.); / T ⁰ CJ ^ ⁰ = + ^ 09 ⁰ Co = 0.5 in dimethylformamide).

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Example 20

9,10-Didebydro · -8β · laydΓoxyEle bhyl-6-pentyl-1-pentynyl-eΓsoline

hydrochloride

Smp.i 270-273 ° (aer-s.) Γ j = +68 ° $ ΐψ ⁰ Cc = 1.0 in dimethylformamide).

Example 21

9,10-dihydro-1-phenyl-lysic acid methyl ester     > '

Mp: 155-157 ⁰ J C <7 ^ ° = -91.8 ° (o = 0.55 in chloroform)

Example 22

1-phenyl-6-me-bhyl-iso 1 in

Mp: 242-243 ϊ C <7 ^ = -46.8 ^υ (ο = 0.77 in dimethylformamide).

Example 23

(2-pyridyl-i; hiomethyl) 9,10-didehydro-6-methyl-1-phenyl-8ß- -

ergoline

M.p .: 107-109 °; C ^ lJ ^ = '- 20.0 ⁰ Cc = 0.4 in chloroform).

Example 24

9,10-didehydro-8ss hydrosymethyl-ö-methyl-i- (3-hydroxyphenyl) -

ergoline

Smp.j 201-203 ° (decomp.); C <7 ^ ° = +1.0 ° (o = 0.5 in dimethylformamide).

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Example 25

9,10-didehydro-8β-hydro: xymethyl · _! ^ methyl · · -1- (4-- hydroxy-

phenyp-ergoline

Mp: 186-190 ° (decays); C ° <J ^ = +5.0 ° (o = 0.55 in dimethylformamide).

Example 26

8 fl -cyanomethyl-6-methyl-1-phenyl-ergo 1 in

Mp: 147 - 149 ⁰ JZ ~ «2.7p ° = -99.0 ° (o = 0.94 in chloroform).

Claims (3)

invention claim 16 - 1. A process for preparing a substituted in position 1 by an aryl group ergot alkaloids and its acid addition salts, characterized in that one arylates a corresponding unsubstatuted in position 1 ergot alkaloid or a precursor of such a compound in position 1. 2t method according to item 1, characterized in that the reaction by reaction with a compound of formula II Ar - II where Ar is an aryl group and X ,. Chlorine, bromine or iodine means carried out. 3. The method according to item 1, characterized in that compounds of formula I are prepared Ar-ϊΤ M worxn Ar is an aryl group, R and each represents hydrogen and R _{2 is} hydrogen together one or methoxy means or
R is hydrogen and R ₁ and form simple bond or
-R and. R_.zit £ amnien .-- a. form simple bond and R stands for hydrogen or methosy, -3.JÄN.1984-14O97I 62 066 13 248035 3 _ "_ R ₀ '. Hydrogen, carboxy or a group (CHp) ^ - Z bodoutet, wherein
η is 1 or 2 and X is hydrogen, hydroxy, cyano, carboxy or T-R, in which R is an alkyl group having 1 to 4 carbon atoms, phenyl or pyridyl, and Y represents a sulfur or oxygen atom or a carboxyl group, and R represents an alkyl group having 1 to 3 carbon atoms, when R _{3 is} (CHg) _n -QH, carboxy or (CHg) COOH, the compound may also be present in the form of a physiologically acceptable hydrolyzed arene ester, in the form of the free base or an acid addition salt, by adding compounds Formula III or its precursors « ^ren >"R' IX. wherein R, R ^, R ", R and R are as defined in point 2, or, if R _{3 is} (CHg) _n -OH, carboxy or (CH ^ -COOH, also physiologically compatible hydrolyzable Sster _; Such compounds, or their precursors in position 1 arylates. 4. The method according to item 3, characterized in that the reaction by reaction with compounds of formula II wherein Ar and X ₁ are defined as in point 2 is carried out. -3JAH1984-i4O97ffG