DE2803543A1 - 6'-Deoxy-ergotamine analogues - with coronary and antihypertensive activity - Google Patents

Abstract

Ergotamine analogues of formula (I) and their acid-addn. salts are new: (where R1 is 1-4C alkyl; R2 is H, 1-4C alkyl or benzyl; R3 and R5 are H or Me; R4 is H or 1-4C alkyl; R6 and R7 are H or together form a bond, or R6 is MeO and R7 is H). (I) are useful for treating coronary disorders and as antihypertensives.

Description

Ergopeptide alkaloid derivatives, their use and

Manufacturing The invention relates to ergopeptide alkaloid derivatives.

The invention relates to new compounds of the formula I, where R1 is alkyl with 1 to 4 carbon atoms, R2 is hydrogen, alkyl has 1 to 4 carbon atoms or benzyl, R3 and R5 are each independently hydrogen or methyl, R4 is hydrogen or alkyl with 1 to 4 carbon atoms and R6 and R7 together form a single bond , or R6 and R7 are each hydrogen, or R6 is methoxy and R7 is hydrogen.

In formula I, R1 is, for example, methyl, ethyl or isopropyl. R2 usually denotes n- or iso-propyl, n-, iso- or sec-butyl or benzyl.

R3 and R5 usually both represent hydrogen.

R4 usually means methyl or iso-propyl. R6 and R7 mean preferably each hydrogen.

The present invention also encompasses processes for the preparation of a compound of the formula I by a) in a compound of the formula II, wherein R1 to R7 have the above meaning, reducing the 6'-carbonyl group, or by b) an acid addition salt of a compound of the formula III, wherein R1 to R3 have the above meaning with a reactive acid derivative of a compound of the formula IV, wherein R4 to R7 have the above meaning, condensed.

Process a) can, if desired, be carried out as a one-step process under Use of reactive borane, e.g.

Diborane. The method can be known per se Way for the reduction of diborane to be carried out under mild conditions. Per mole of a compound of the formula II, 5 to 15 mol reactive Borane used. Tetrahydrofuran, diethyl ether or methylene chloride can be used as Solvents are used. The reduction is preferably carried out at temperatures between about - 20 and + 20 ° C.

Process b) can be carried out analogously to known methods for the condensation for the production of analogous cyclic peptidergot alkaloids.

A suitable acid addition salt of a compound of formula III is the 2,5-naphthalene disulfonic acid salt.

As reactive, functional derivatives of a compound of the formula IV can be, for example, the acid chloride, the acid azide or the mixed anhydride with sulfuric acid or trifluoroacetic acid can be used. Used preferably one the addition 'roduct of a compound of formula IV with dimethylformamide or Acetamide and thionyl chloride, phosgene or oxalyl chloride. Preferably the reaction carried out in the presence of triethylamine or pyridine. Suitable solvents are e.g.

Chloroform, methylene chloride, dimethylformamide or acetonitrile.

The reaction can be carried out at temperatures between -30 to + 20 ° C will.

The starting products are known or can be prepared from known compounds by methods known per se. Thus, a compound of the formula III can be prepared according to the method for the preparation of an aminocyclole from a compound of the formula V, in which R1 to R3 have the above meaning, methods known per se are prepared.

For example, the corresponding acid can be formed first, then converted into the corresponding acid amide via the acid chloride1 which in turn is converted into the amine.

A compound of the formula V can be prepared by reacting a compound of the formula VI, wherein R1 has the above meaning with a compound of the formula VII, where R2 and R3 have the above meaning, and subsequent hydrogenation of the product formed.

A compound of the formula VII can be prepared by reducing a compound of the formula VIII, wherein R2 and R3 have the above meanings, with lithium aluminum hydride.

From the free bases of the compounds of formula I can be in known manner to produce acid addition salts and vice versa. Close suitable salts the hydrochloride and the methanesulfonate.

The compounds of the formula I in free form or in the form of physiologically acceptable ones Acid addition salts with acids are distinguished by interesting pharmacological Properties from; they can be used as remedies.

Thus, the compounds according to the invention can be used in the treatment of Find coronary diseases and as antihypertensive drugs. The invention relates to also remedies that contain a compound of formula I in free form or in the form of their contain physiologically compatible addition salts with acids. These remedies For example, a solution or a tablet can according to methods known per se, be prepared using the usual auxiliaries and carriers.

The following examples illustrate the invention.

Temperatures are given in degrees Celsius and are uncorrected.

Example 1: 6'-Deoxo-9,10-dihydro-p-ergocryptine (method a) 1.15 g of 9,10-dihydro-p-ergocryptin (2 mblol) are in 25 ml of abs. Tetrahydrofuran (THF) suspended and with stirring at 0 ° dropwise with a freshly prepared solution of 20 ntrol BH3 in 35 ml abs. THF (e.g. from NaBH4 and boron trifluoride etherate) added.

After stirring for 4 hours at 0 °, the mixture is strongly cooled and decomposed Carefully pour the reaction mixture into 9 ml of 6N hydrochloric acid. Then stir for another 30 Minutes at + 60 °, after cooling with 30 percent.

Sodium hydroxide made alkaline and extracted the reaction mixture thoroughly with methylene chloride. After chromatography of the methylene chloride extracts on 100 g of alox the activity level 2 to 3 can be the title compound from methylene chloride / ether crystallize in the form of the free base.

M.p. 159-160 °; [α] D20 = -4 ° (c = 0.5 in dimethylformamide).

The title compound can also be made according to that Procedure of Example 2 below.

Example 2: 1-methyl-6'-deoxo-9, 10-dihydroergocristine (method b) 150 ml abs. Dimethylformamide (DMF) are cooled to -15 ° with stirring and dropwise with an inert solution of 1.14 ml (17.14 mol) of oxalyl chloride in 15 ml of abs. Acetonitrile added. Then 4.87 g (17.14 mol) of dry 1-methyl-9,10-dihydro-lysergic acid are carried a, whereby Uhter temporary solution precipitates a gray precipitate. After 30 Stirring at 0 ° for minutes, the mixture is diluted with 37.5 ml of abs while cooling vigorously. Pyridine and carries 5.14 g (2R, 5S, 10aS, 10bS-) 2-amino-2-isopropyl-3-oxo-5-benzyl-OB-hydroxy-perhydrooxazolo [3, 2-a] pyrrolo [2, l-cJ pyrazine.2,5-naphthalene disulfonic acid (approx. 8.5 m mol) a, stir vigorously for 2 hours and let the temperature slowly from -10 to 0 ° rise. For work-up, 40 ml of citrate buffer is added to pH with strong cooling = 4 diluted and made alkaline with 2N soda solution. After extraction with chloroform, which contains some% ethanol, drying and evaporating the extract, becomes the crude product chromatographed on 500 g of silica gel, the title compound with 4% methanol is eluted in methylene chloride and crystallized from acetone.

M.p. 183-185%; [aJ 20 = -77 ° (c-1, pyridine).

D The title compound can also be used analogously to that described in Example 1 Process are produced.

The 2-amino-2-isopropyl-3-oXo-5-benzyl-lOb-hydroxy-perhydrooxazolot3,2-a] required as starting material] pyrrolof2,1-c] pyrazine.2,5-naphthalene disulphonic acid is obtained in the following way: a) (2S, 7aS) -2-Benzyl-perhydro-8-oxo-pyrrolo [2,1-c) pyrazine Suspend under nitrogen 36.4 g (960 m mol) of lithium aluminum hydride in 1.3 liters of abs. Tetrahydrofuran and a solution of 117.2 g (480 m mol) of L-Phe-L-pro-lactam is added dropwise over a period of 45 minutes in 1.4 liter abs. Tetrahydrofuran too. After stirring at -10 ° for 18 hours, at this temperature in turn carefully with 350 ml of ethyl acetate and 350 ml of water diluted. The reaction pulp is filtered, with the reaction product still adhering subsequently extracted by repeated extraction of the filter cake with boiling methylene chloride will. The combined organic phases are dried with sodium sulfate and evaporated. The pure title compound crystallizes directly from methylene chloride / ether in light beige crystals with a melting point of 135-140 °; t «] D = - 3.5 ° (c = 1 in ethanol).

b) (2R, 5S, 10aS, 10bS) 2-carbethoxy-2-isopropyl-3-oxo-5-benzyl-10b-hydroxy-erhydro-oxazolo [3,2-a] pyrrolo [2,1-c] pyrazine 47.8 g (207 m mol) (2S, 7aS) -2-benzyl-perhydro-8-oxo-pyrrolo [2,1-c] pyrazine in 160 ml abs. Dioxane are mixed with 74.4 g (249 m mol) of S (+) - isopropylbenzyloxymalonic acid ethyl ester chloride and 34.9 g (270 m mol) of N-ethyldiisopropylamine and mixed for 1 hour at + 70 ° touched. After dilution with 1 liter of ether, it is saturated twice with Sodium bicarbonate solution shaken and dried over sodium sulfate. After evaporation of the solvent 138 g of a brownish oil containing (2S, 7aS) - (2'S-2'-benzyloxy-2'-isopropyl-O-ethylmalononyl) -2-benzyl-perhydro-8-oxo-pyrrolo [2, I-c-pyrazine, obtained, dissolved in 1.5 liters of ethanol and stored at 60 ° after moving is hydrogenated with 60 g of palladium-activated carbon (10% Pd), after 14 hours about Absorb 6.5 liters of hydrogen.

After filtration and evaporation of the filtrate, the title compound crystallizes after taking up in isopropyl ether in yellowish prisms with a melting point of 99-100 °; [α] D20 = - 57.7 ° (c = 0.65 in CHCl3).

c) (2R, 5S, 10aS, 10dS) 2-carboxy-2-isopropyl-2R, 5S, 2aS, 10bS) 2-carboxy-2-isopropyl-3-oxo-5-benzyl-10b-hydroxy-hydro-oxazolot3 , 2-a] yrrolo [2,1-c] pyrazine 39.3 g (97.8 m mol) (2R, 5S, 10aS, 10bS) 2-carbethoxy-2-isopropyl-3-oxo-5-benzyl-10b-hydroxy-perhydrooxazolof3, 2-a] pyrrolo r 2,1-c] pyrazine are dissolved in 245 ml of methanol and 245 ml of 2N sodium hydroxide and stirred for 3 hours at room temperature.

For work-up, the pH is adjusted to 4.5 at 0 ° using 2N hydrochloric acid and extracted repeatedly with ethyl acetate. After drying the organic extract and evaporation of the solvent below +30, the title compound crystallizes after dilution with ether. M.p. 126-128 ° (dec.). It contains after 5 hours Drying at 30 ° in a high vacuum -1/2 mol of water of crystallization.

d) (2R, 5S, 10aS, 10bS) 2-amino-2-isopropyl-3-oxo-5-benzyl-10b-hydroxy-perhydro-oxazolof3,2-a3pyrrolo [2,1-c] pydrazine.2,5-naphthalene disulfonic acid In a stirred, cooled to -15 ° Mixture of 4.33 ml (56.3 m mol) of abs. Dimethylformamide and 30 ml of abs. Acetonitrile a solution of 3.84 ml (45 mol) of oxalyl chloride is added dropwise within 10 minutes 15 ml abs. Acetonitrile is added and the mixture is stirred for a further 10 minutes. After diluting with 45 ml abs. Ether becomes 11.25 g (30 m mol) (2R, 5S, 10aS, 10bS) Z-carboxy-2-isopropyl-3-oxo-5-benzyl-lOb-hydroxy-perhydro-oxazolof3,2-b] pyrrolo [2,1-c] pyrazin.1 / 2 H2O entered rapidly, with a clear solution containing the acid chloride is formed, which is stirred for a further 10 minutes at -100. Then layered one with a solution of 20 g of sodium azide in 100 ml of water, diluted with 300 ml Methylene chloride and shake the 2-phase mixture vigorously for 4 minutes. Then you add 150 ml of ice-cold, saturated sodium bicarbonate solution are added, the organic separates Phase off and dry well over sodium sulfate. After concentrating the solvent below 30 ° with a solution of 7.78 g (27 mol) of 2,5-naphthalene disulfonic acid in 200 ml of dimethoxyethane and 20 ml of acetonitrile are added and the mixture is slowly concentrated in vacuo. After diluting with abs. Aether is the acid azide as a salt in the form of a beige Powder isolated. 6.35 g (^ 9 m mol) of the dried powder are mixed with 120 ml Dimethoxyethane containing 0.166 ml of water, 1 hour at 80 ° heated, with a brownish color with constant scratching. semi-crystalline powder obtained after cooling, filtering and drying at room temperature in a high vacuum can be used directly for condensation.

The following compounds of the formula I can be prepared analogously to that in the examples 1 or 2 described processes are prepared: Example 3: 6'-Deoxo-9,10-dihydro-a-ergocryptin M.p. 182-185 0; [aJ DO = + 14 ° (c = 0.3 in dimethylformamide).

Example 4: 6'-Deoxo-9,10-dihydroergocornine m.p. 166-167 ° (dec.); [al 20 = -18.5 ° (c = 0.66 in D dimethylformamide).

Example 5: 6'-Deoxo-9,10-dihydro-B-ergosine m.p. 194 - 196 ° (sinter of 185 °); [α] D20 = -18 ° (c = 0.3 in dimethylformamide).

Example 6: 6-nor-6-isopropyl-6-deoxo-9, 10-dihydroergotamine mp. 186-190 °; [α] D20 = -63 ° (c = 0.3 in dimethylformamide).

Example 7: 6'-Deoxo-ergotamine mp 176-180 °; [α] D20 = + 17 ° (c = 0.35 in dimethylformamide).

Example 8: 6'-Deoxo-ergocristin Example 9: 6'-Deoxo-p-ergocryptin Example 10: 6'-Deoxo-a-ergocryptine Example 11: 6'-Deoxo-9,10-dihydroergocristine 20 m.p. 208-209 ° (dec.); [α] D20 = -750 (c = 0.8, pyridine).

Example 12: 6'-Deoxo-9,10-dihydroergotamine m.p. 165-168 0 (dec.); [a] DO = -780 (c = 1, pyridine).

Claims (3)

Claims: 1. Compounds of the formula I, where R1 is alkyl with 1 to 4 carbon atoms, R2 is hydrogen, alkyl with 1 to 4 carbon atoms or benzyl, R3 and R5 are each independently hydrogen or methyl, R4 is hydrogen or alkyl with 1 to 4 carbon atoms, and R6 and R7 together are a single bond form, or R6 and R7 each represent hydrogen, or R6 represent methoxy, and R7 represent hydrogen, and their acid addition salts. 2. Process for the preparation of compounds of the formula I, in which R1 to R7 have the above meaning, and their acid addition salts, characterized in that a) the 6'-carbonyl group in a compound of the formula II, wherein P1 to R7 have the above meaning, or that b) an acid addition salt of a compound of the formula III, wherein R1 to R3 have the above meaning with a reactive acid derivative of a compound of the formula IV, in which R4 to R7 have the above meaning, condensed and the compounds of the formula I thus obtained are obtained in the form of bases or of acid addition salts. 3. Medicinal products containing a compound of the formula I in which R1 to R7 have the meaning given in claim 1, in free form or in form of a physiologically acceptable acid addition salt with an acid.