JPS5976085A - Improvement on organic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to novel heterocyclic compounds.

According to the present invention, the formula ■ R' (In the formula, R is hydrogen or alkyl having 2 to 6 carbon atoms) Provided are novel compounds and acid addition salts thereof.

Preferred compounds of the formula (1) in which R is alkyl having 2 to 6 carbon atoms include those in which R is 2 to 4. especially containing 2 or 3 carbon atoms or in particular α to the nitrogen atom to which R is attached
It is a compound that is branched in position.

R especially stands for Inglovir.

Furthermore, according to the invention, the compound of 2) is obtained by condensing a reactive functional derivative of an acid of the formula 1H', in which R is as defined above, with the compound of 2) in the form of a salt; and, if desired, by converting the resulting compound of formula I into its acid addition salt using known methods.

Compounds of formula I are peptide ergot alkaloids. The reaction of the present invention is an amide condensation reaction. The process of the invention is carried out analogously to known methods for producing structurally similar peptide alkaloids.

The reaction is carried out in an inert organic solvent or solvent mixture in the presence of an acid binder. The condensation is preferably carried out at temperatures between -30° and +20°C.

1.2 to 2.4 moles of the reactive derivative of the acid of formula (1) are advantageously used in salt form for each mole of the compound of formula (1).

One example of a suitable reactive derivative of an acid of formula (1) is an acid of formula (1) with a chlorinating agent and an N-di(lower)alkyl-substituted acid amide of an aliphatic carboxylic acid having 1 to 3 carbon atoms, such as It is an addition product resulting from reaction with dimethylformamide or dimethylacetamide.

For example, thionyl chloride, phosgene or oxalyl chloride can be used as chlorinating agents.

Examples of suitable inert solvents for use in the reaction include chlorinated aliphatic hydrocarbons such as chloroform and methylene chloride;
N-di(lower)alkyl-substituted acid amides of aliphatic carboxylic acids such as dimethylformamide or other organic solvents such as acetonitrile.

Tertiary organic bases, such as triethylamine, preferably pyridine, are advantageously used as condensing agents.

For the reaction of the addition product mentioned above, the formula ■
It is also possible to use other reactive derivatives of the acid, such as the acid chloride hydrochloride, the acid azide or the mixed anhydride of the acid of formula (2) with sulfuric acid or trifluoroacetic acid. However, 6-true 9,10-dihydrolysergic acid is preferably activated with trimethylformamide/oxolyl chloride.

The production of these reactive derivatives of acids of formula (1) can be carried out analogously to known methods using the corresponding acids.

Completion of the reaction and liberation are carried out according to known methods.

Acid addition salts are formed from the free base by known methods (5). and vice versa.

Among the compounds of formula n, 6-true 9,10-sohydrolysergic acid and 6-true 6-ethyl-9,10-dihydrolysergic acid are [He1v, chim, Acta 53
, 2197f (1970)), the novel compound of formula 11a has the formula
It can be obtained by hydrolyzing the compound of

H' (6) (wherein R' is as defined above, 9 and R1 is a group that can be separated by hydrolysis).

R1 represents, for example, lower alkyl such as methyl or ethyl.

Compounds of formula ia are pharmacologically active 6-true 6-R'-
Ergoline (where R' is as above), for example 6
-True 6- R'-9,10-dihydro-2'β-
It is a valuable intermediate for the preparation of methyl-5'α-pendyl-ergopetine compounds, where R' is as defined above.

Hydrolysis of the compound of formula (1) can be carried out in a manner similar to the known method for hydrolysis of lysergic acid esters.

The hydrolysis is advantageously carried out under alkaline conditions, for example by treating a solution of the compound of formula (1) in a water-miscible organic solvent or a solvent mixture with an alkali metal hydroxide, such as caustic soda solution.

Suitable solvents are, for example, ethers such as dioxane or tetrahydrofuran, or alcohols such as methanol. And suitable solvent mixtures include, for example, methanol/methylene chloride.

The reaction is carried out under mild conditions. When the reaction is carried out at room temperature, it lasts about 24 hours.

The compound of formula (1) can be obtained by alkylation of a compound of formula V/2 (wherein R1 is as defined above). For example, alkylation is He1v.

chim, Acta 53, 2197f (197
This may be carried out by a method similar to the known method described in 0). This document also describes a preferred demethylation process for the production of 6-norurisergic acid esters. The compound of formula (1) can be obtained by demethylation of the compound of (2) H' (wherein R1 is as defined above) in a similar manner.

Unless the preparation of the starting materials is specifically stated, they can be prepared by known methods or by methods analogous to known methods.

The compounds of formula I and their salts with physiologically acceptable acids exhibit interesting properties and are used as medicines.

For example, they exhibit long-term pressor effects in dorsal spinal cord cats caused by increased blood pressure. Because of this activity, these compounds are used as intravenous tonic agents for the treatment of orthostatic disorders, and dihydroel is also used in similar applications to tamins. The daily dose is approximately 1.5 to 15 m9. If necessary(9), this amount may be administered in two to four divided doses or in delayed form.

6-nor-6-isopropyl-9,10-dihydro-2
'β-Methyl-5'α-benzyl-ergopegutin has been found to be particularly effective for this use. The corresponding 6-true 6-ethyl and 6-true 6-propyl compounds also show good effects.

The compounds of formula (1) or their physiologically acceptable acid addition salts can be used as medicaments on their own or in the form of suitable formulations with pharmacologically inert excipients. The preparation of these preparations, such as tablets, is carried out analogously to known methods.

Furthermore, 6-true 9,10-dihydro-2'β-methyl-5'α-penzyl-ergohesothene H9,10-dihydro-2'β-methyl-5'α-penzol-erpeff
It is a valuable starting material for the preparation of 6-true 6-alkyl-9,10-dihydro-2'β-methyl-5'α-penno-ergopegutin compounds such as dihydroergotamine. This dihydroergotamine can be obtained, for example, by alkylation of the corresponding 6-nor compound as described for the alkylation of compound (10) of formula (1).

The name of the compound of formula (■) is derived from the basic structure of formula (■).

/ This structure is simply called Elk 0 pegtin.

In the following non-limiting examples all temperatures are given in degrees Celsius.

Lugobezotin (compound of formula 7) 7-k) 8.6 cc (100 mmol) of oxalyl chloride, dissolved in 20 cc of nitrile, -10
Dimethylformamide 300% within 1o min at -15°
cc and acetonitrile 150 cc solution,
Stir for an additional 10 minutes. 6-true 6-isoprobil-9
, 30.9 (100 mmol) of 10-dihydrolysergic anhydride are then poured in at -20° and stirred for 30 minutes at -10°. After cooling to -20°, 200 cc of pyridine and (2R, 5S, 10as, 10bs)-2-amino-2-methyl-5-benzo-3,6-thioxo-10b-hydroxy-octahydro-8■-oxazolo-( 3,2-a:) Add 29.41 (80 mmol) of pyrrolo[2,1-c]pyrazine hydrochloride and stir at Oo for 2 hours. The reaction is worked up by adding 100 cc of buffer solution pH=4 and partitioning the reaction mixture between methylene chloride and 2N caustic soda solution. The organic phase is washed twice with water, dried over sodium sulfate and evaporated to dryness on a rotary evaporator. After drying in a high vacuum, the resulting crude salt is dissolved in about 150 cc of ethanol and the solution is purified. The pure crystalline title compound obtained is M, P, 225° (decomposed),
[α]20=−40.5° (c=0.930 in methylene chloride).

Preparation of methanesulfonate Pure 6-true 6-ituderovir-9.10-dihydro-2'β-methyl-5'α-pendyl-ergoheftine 1719 is dissolved in acetone IJ and methanesulfonic acid 2.67j' Add. Crystallization occurs when concentrated to about the original volume.

When filtered and washed with acetone, M, P, 206-20
8° (decomposition), producing pure methanesulfonate with [α]2'=-23.5° (C-0.5 in methanol).

The following compounds of formula I are obtained in an analogous manner to Example 2 using the corresponding starting materials of formulas 1 and 2 in salt form.

(13) t<A'+ Monozohydrolysergic acid (compound of formula 11a) 34.6 g (0,111 mol) of 6-true 6-ytugroby-9,10-dihydrolysergic acid methyl ester was dissolved in methanol 6 Q Q cc and Methylene chloride 100cc
Add 100 cc of 2N caustic soda solution. −
After stirring overnight at room temperature, the organic solvent was removed on a rotary evaporator and the residue was diluted with 1 ml of water. Dilute it. The pH of the solution is adjusted to 5 with glacial acetic acid and the acid is obtained as a jelly-like ring. When heated to 806 ml, it becomes a transparent liquid, which is further cooled to yield an acid. Drying at 1300 in high vacuum gives the title anhydrous compound, M, P, 290° 20 knees (decomposed), [α)D 101° (C=0.6 in methanol).

The compounds of formula (1) shown in the table above are obtained by hydrolysis of the corresponding esters in a similar manner to Example 6.

Compound) 6-true 9,10-dihydrolysergic acid methyl ether (1
5) (14 Nostel 4011 (0,148 mol) dissolved in 400 cc of dimethylformamide, 139 cc (1,48 mol) of isopropyl bromide of anhydrous potassium carbonate of 611 was added, stirred for 48 hours, and heated to 80°. .

After work-up and purification of the reaction, the title compound crystallizes out as colorless crystals in ethanol, M, P, 194'.

[α] and'=-80,2° (C=0.582 in methanol).

(16+)

Claims (1)

[Claims] Formula ■ (wherein, R' is alkyl having 3 to 6 carbon atoms, R7
is a group that can be diseparated by hydrolysis), the method comprises alkylating a compound of formula V (wherein R1 is as described above).