IE46152B1 - Ergot peptide aklaloid derivatives - Google Patents

Abstract

ERGOT PEPTIDE ALKALOID DERIVATIVES Compounds of formula I, I wherein R1 is alkyl of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, R3 and R5 are, independently, hydrogen or methyl, R4 is hydrogen or alkyl of 1 to 4 carbon atoms, and R6 and R7 together form a single bond, or R6 and R7 are each hydrogen, R6 is methoxy, and R7 is hydrogen, are useful in the treatment of hypertension, angina pectoris, depressions, neuroses and psychoses.

Description

The present invention also provides a process for the production of a compound of formula I, which comprises a) reducing the 6' carbonyl group in a compound of wherein R^ to R? are as defined above, or b) condensing an acid addition salt of a compound of formula III, wherein R^ to Rg are as defined above, with a reactive acid derivative of a compound of formula IV, - 2 4 6152 wherein R, to R_ are as defined above. 7 Process a) may be effected in one step if desired, using reactive borane, e.g. diborane. The process may be effected in conventional manner for diborane reductions under mild conditions. Conveniently 5 to 15 moles of reactive borane are used per mole of a compound of formula XI. Tetrahydrofuran, diethyl ether or methylene chloride may be used as solvent. Suitable reaction temperatures may be from -20° to 20°C.

Process b) may be effected in conventional manner for condensations to produce analogous ergot cyclic peptide alkaloids.

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

Suitable reactive acid derivatives of a compound of formula IV include the acid chloride, the acid azide, and the mixed anhydride with sulphuric or trifluoroacetic acid. It is preferred to use the reactive acid derivative of a compound of formula IV arising out of the reaction of a connound of formula IV with dimethyl formamide or acetamide - 3 46132 and thionyl chloride, phosgene or oxalyl chloride. Preferably triethylamine or pyridine is present during the reaction. Suitable solvents include chloroform, methylene chloride, dimethyl formamide and acetonitrile.

Suitable reaction temperatures are from -30° to +20°C.

The starting materials are known or may be produced in conventional manner from known compounds.

Thus a compound of formula III may be prepared in known manner for the preparation of an aminocyclol from a compound of formula V; wherein R^ to R^ are as defined above.

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

A compound of formula V may be produced by reacting a compound of formula VI, C2H5OOC __ *.och2.c6h5 VI COCI wherein R^ is as defined above, with a compound of formula VII, VII HN CH. wherein R2 and R^ are as defined above, and hydrogenating the resultant product.

A compound of formula VII may be produced by reducing a compound of formula VIII, ΙΟ wherein R2 and R^ are as defined above, with lithium aluminium hydride.

Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation -δ46152 include hydrochloric and methane-sulphonic acids.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected.

The title compound of Example 2 forms no part of the · . present invention. It illustrates, however, the process of the invention and the preparation of the starting materials. 61 s a EXAMPLE 1; e^-desgxo-S^lO-dihydro^P^ergocryotine [process a)] 1.15 g of 9,10-dihydro-p-ergocryptine (2 mmols) are suspended and stirred at 0° in 25 ml of absolute tetra5 hydrofuran and then a freshly prepared solution of 20 mmols reactive borane (e.g. from NaBH^ and boron trifluoride etherate) in 35 nl of absolute tetrahydrofuran is added dropwise. After stirring for 4 hours at 0° the solution is cooled. The reaction mixture is carefully treated with 9 ml of 6N-hydrochloric acid, and then stirred for another 30 minutes at +60°, cooled, made alkaline with 30% sodium hydroxide, and then thoroughly extracted with methylene chloride. The methylene chloride extracts are chromatographed on aluminia (activity ΙΙ-III) to yield the title compound in free base form which is recrystallized from methylene chloride/ether. jn M.Pt. 159-160° ; [a]^ =-4 0 (c =0.5 DMP).

The title compound may also be prepared according to the process of Example 2.

EXAMPLE 2: iTraSthZizSLgdesoxogg^lOgdihydro^rgjccrLstyTe. [process b)] A solution of 1.14 ml (17.14 mmols) of oxalyl chloride in 15 ml of absolute acetonitrile is added dropwise to 150 ml of absolute dimethyl forraamide at -15°. - 7 4.87 g (17.14 mmols) of dry l-methyl-9,10-dihydrolysergic acid are then added, and a grey deposit precipitates from the reaction mixture. After stirring for 30 minutes at 0°, the mixture is cooled and treated with 37.5 ml of absolute pyridine, and then 5.14 g of (2R,5S,10aS,10bS)-2-amino-2isopropyl-3-oxo-5-benzyl-10b-hydroxy-perhydrooxazolo[3,2-a]pyrrolo[2,1-c]pyrazine.2,5-naphthalene-disulphonic acid (about 8.5 mmols) are added, The mixture is stirred vigorously for 2 hours, and then the temperature is allowed to increase slowly from -10° to 0°. The mixture is then cooled again and diluted with 40 ml of citratebuffer (pH = 4), and then made alkaline with 2N soda solution. After extraction with chloroform containing a small amount of ethanol, the extract is dried and evaporated The crude product is chromatographed on silicagel, to give the title compound in free base form on elution with 4% methanol in methylene chloride, which is recrystallised from acetone.

JO M.Pt. 183° - 185°; [cc]^ = -77° (c = 1, pyridine).

The title compound may also be prepared by the process of Example 1.

The 2-amino-2-isopropyl-3-oxo-5benzyl-lOb~hydroxyperhydrooxazolo[3,2-a]pyrrolo[2,1-c]pyrazine.2,5-naphthalene· disulphonic acid is obtained as follows :8 46lsa a) J2Sj,7aS].-22benzyl22erhydro283OXO"nyrrolo_[2xl2c2gyrazine 36.4 g (960 mmols) of lithium aluminium hydride are suspended in 1.3 litres of absolute tetrahydrofuran in a nitrogen atmosphere, and a solution of 117.2 g (480 mmols) of L-Phe-L-Pro-lactam in 1.4 litres of absolute tetrahvdrofuran is added dropwise over 45 minutes. After stirring for 18 hours at -10°, the reaction mixture is diluted carefully at this temperature with 350 ml of ethyl acetate and then 350 ml of water. The resultant mixture is filtered.

Repeated extraction of the filter cake with boiling methylene chloride is effected to obtain more product.

The combined organic phases and filtrate are dried with sodium sulphate and evaporated. The pure title compound in free base form crystallises directly from methylene chloride/ether in bright beige crystals; M.Pt. of 135° - 140°; (α]θ - -3.5° (c = 1 in ethanol). b) 12Βχ5£χ122§χΙ2!ΐ5ΐΣ2Ίί2£^ίι.1ί?ίϊζΣ,2ΣΪ£2ΕΕ2Ε'ΖΐΣ2Σ2ς·2Σ§Σΐ22Ε2Ζ];Σ IQbghYBlSiiy^ESSBYHro-oxazolo D_,2-a2gv rrolo^^l^c^gyr azine b)i) 47.8 g (207 mmols) of (2S,7aS)-2-benzyl-perhydro-8oxo-pyrrolo[2,l~c]pyrazine in 160 ml of absolute dioxane are treated with 74.4 g (249 mmols) of S-(+)-isopropyl-benzyloxy-malonic acid mono-ethyl ester mono-acid chloride and 34.9 g (270 mmols) of - 9 4 615 2 N-ethyldiisopropylamine. The mixture is stirred for • 1 hour at +70°. After dilution with 1 litre of ether, the mixture is shaken twice with saturated sodium bicarbonate solution and dried over sodium sulphate.

After evaporation of the solvent, 138 g of a brownish oil containing (2S,7aS) -(2*S--2-benzyloxy-2'-isopropyl-0 ethylmalononyl)-2-benzyl-perhydro-8-oxo-pyrrolo[2,1-c]pyrazine are obtained. b) ii) This oil is dissolved in 1.5 litres of ethanol and is hydrogenated at 60° after addition of 60 g of palladium-active carbon (10% w/w Pd), wherein, after 14 hours, about 6.5 litres of hydrogen are absorbed. After filtration and evaporation of the filtrate, the title compound is recrystallized from isopropyl ether, as yellowish prisms with a M.Pt. of 99° - 100°; [a]20 = -57.7° (c = 0.65 in CHCl3). c) J^BxSS^lOaS^lObfU-2-carboxy-2;:i5oproDyl-320XO;;5;;benzylISk^hydroxy^perhydro^oxazoloD.^alpyrrolgJ^l^c] pyrazine 39.3 g (97.8 mmols) of (2R,5S,10aS,10bS)-2-carbethoxy-220 isopropyl-3-oxo-5-benzyl-10b-hydroxy~perhydro-oxaZolo[3,2-a]pyrrolo[2,1-c]pyrazine are dissolved in 245 ml of methanol and 245 ml of 2 N sodium hydroxide. The mixture is stirred for 3 hours at room temperature, adjusted at 0° to a pH of 4.5 with 2 N hydrochloric acid, - 10 46152 and then extracted repeatedly with ethyl acetate.

After drying the organic extract and evaporating the solvent at below +30°, the title compound crystallises after dilution with ether. M.Pt. 126° - 128° (decomp).After drying for 5 hours at 30° in a high vacuum, the crystals contain ~ 1/2 mol water per mole of title compound. 4) T^R^SS^lOaS^lObS)-S-amino^^^isogrODvl-S^oxo^S^benzyl; ISfeliiy^roxy-Derh^dro^oxazoloflj^-alpyrroloJ^l^c].di) A solution of 3.84 ml (45 mmols) of oxalyl chloride in 15 ml of absolute acetonitrile is added in drops over 10 minutes to a stirred mixture of 4.33 ml (56.3 mmols) of absolute dimethyl formamide and 30 ml of absolute acetonitrile which is cooled to -15°. The mixture is stirred for a further 10 minutes. After dilution of the mixture with 45 ml of absolute ether, 11,25 g (30 mmols) of (2R,5S,10aS,10bS)-2-carboxy-2-isopropyl" 3~oxo-5"benzyl-10b-hydroxy-perhydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine. 1/2 H20 are quickly added. A clear solution is produced, which is stirred for another 10 minutes at -10° thereby producing the acid chloride. dii) A solution of 20 g of sodium azide in 100 ml of water, diluted with 300 ml of methylene chloride, is added to the acid chloride solution-- 11 46152 and the 2-phase mixture is shaken vigorously for 4 minutes. Then, 150 ml of ice-cold, saturated sodium bicarbonate solution are added. The organic phase is separated and dried well over sodium sulphate. After evaporation of the solvent at below 30°, a solution of 7.78 g (27 mmols) of 2,5-naphthalene disulphonic acid in 200 ml of dimethoxyethane and 20 ml of acetonitrile is added. The mixture is then slowly concentrated in a vacuum. After dilution of the mixture with absolute ether, the acid azide is isolated as the 2,5-naphthalene disulphonate salt. diii) 6.35 g (~9mmols) of the salt are heated for 1 hour to 80° in the presence of 120 ml of dimethoxyethane which contains 0.166 ml of water. The title compound is obtained with constant scraping, as a brownish, semi-crystalline powder, which may be used directly after cooling, filtering and drying at room temperature in a high vacuum.

The following compounds may be obtained in analogous manner to that described in Example or 2. - .12 46152 EXAMPLE 7: 15 EXAMPLE 8: EXAMPLE 9,: EXAMPLE 3: 6lzflesoxo;9210-dihydroergocornine M.Pt. 166° - 167°(decomp); [ EXAMPLE 4: iilztfesoxo-ji.jlO^dihydro^ggergosine M.Pt. 194° - 196° (sintering from 185°) j [a]^ = -18° (c = 0.3 in dimethyl formamide).

EXAMPLE 5: 83S2EG^zi22£E22Ylz81z8esoxo;92102dihYdro2E22i2Si22 M.Pt. 186° - 190°; [a]* = "63° (c = 0.3 in dimethyl formamide).

EXAMPLE 6: i^-desoxo^ergotamine M.Pt. 176° - 180°; [a]20 = +17° (c = 0.35 in dimethyl §Lz2£S2ii2Z£l:222Ei2l:i2£ ®lzS25252Z£z2E222£Z2£i22 δ1ζ3£2222Ζ2Ζ2Ε22Ξ£ϊΕ£ί22 formamide).

The compounds of formula I exhibit pharmacological activity. In particular, the compounds of formula I exhibit coronary therapeutic activity as indicated by a coronary dilation and vasodilation in the open chest cat test at an effective dose of from about 0.03 to about 1 mg/kg i.v.

The compounds are therefore indicated for use as coronary therapeutic agents, e.g. for the treatment of angina pectoris.

The compounds also exhibit anti-hypertensive 10 activity as indicated by a blood pressure lowering in the above-mentioned open chest cat test.

The compounds are therefore indicated for use as anti-hypertensives.

An indicated daily dose is from about 10 to about 15 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 2 mg to about 150 mg or in sustained release form.

The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms have the same order of activity as the free base forms. The present invention provides a pharmaceutical composition comprising a compound of formula I as defined above in association with a pharmaceutical carrier or diluent. Such composition may be formulated in conventional manner so as to be for example a solution or a tablet.

In the following claims we make no claim to the following 5 compounds: 6'-desoxo-9, 10-dihydroergotamine; 6'-desoxO"9,10-dihydro-lmethylergotami ne; 6'-desoxo-9,10-dihvdroergocri sti ne; 6'-desoxo9,10-dihydro-1-methylergocristine; and 6'-desoxo-9, 10-dihydro-aergocryptine, and methods for their production.

Claims (5)

1. A process for the production of a compound of formula I, wherein R^ is alkyl of 1 to 4 carbon atoms, R 2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, R 3 30 R 5 aEe » independently, hydrogen or methyl, R^ is hydrogen or alkyl of 1 to 4 carbon atoms, and Rg and R? together form a single bond, or Rg and R? are each hydrogen or R, is methoxy, and o R? .is hydrogen, which comprises _ 16 ΙΟ a) reducing the 6’ carbonyl group in a compound of II wherein R^ to are as defined above, or b) condensing an acid addition salt of a compound of formula III, III wherein Rg to Rg are as defined above, with a reactive acid derivative of a compound of t formula IV -Π46152 wherein R^ to R? are as defined above.

2. A process for the production of a compound of formula I, as stated in Claim 1, substantially as herein5 before described with reference to any one of the Examples 1 to 10.

3. A compound of formula I, whenever produced by a process according to Claim 1 or 2.

4. A compound of formula I, as defined in Claim 1 as defined in claim 1, 10 5. a compound of formula 1/ wherein R^ is methyl, ethyl or isopropyl, R 2 is H, CH^, C 2 H,., n- or iso-C^H^ or R a and Rg are as defined in claim 1 η-, iso- or sec-butyl,or benzyl,and R^ is H, Clly C 2 Hg, n- or iso-C^H? or η-, iso- or sec-butyl, and either Rg and R? are each hydrogen, or together form a bond. 15 6. A compound of Claim 4, which is 6'-desoxo-9, 10-dihydro-β -ergocryptine. 7. A compound of Claim 4, which is 1-methyl~6'-desoxo-9, 10-dihydroergocristine. 8. -A compound of Claim 4, which is 6'-desoxo-9,10 i n dihydroergocornine. - 18 46152 9. A compound of Claim 4, which is 6' -desoxo-9, 10-dihydro - β -ergosine. 10. A compound of Claim 4, which is e-nor-e-isopropyl -6'-desoxo-9, 10-di hydroergotami ne. 5 11. A compound of Claim 4, which is 6' - desoxo ergotamine. 12. A compound of Claim 4, which is 6'-desoxoergocristine. 13. A compound of Claim 4, which is 6'-desoxo -610 ergocryptine. 14. A compound of Claim 4, which is 6'-desoxo -aergocryptine. 15. A compound of any one of Claims 5 to 12 in free base form. 15 16. A compound of any one of Claims 5 to 12 in acid addition salt form. 17. A pharmaceutical composition comprising a compound of any one of Claims 5 to 12 in free base form or in pharmaceutically acceptable acid addition salt form in association 20 with a pharmaceutical carrier or diluent. -19 46152 18. A compound of any one of claims 3,4,13 and 14 in free base form, 19. A compound of any one of claims 3,4,13 and 14 in acid addition salt form.

5. 20. A pharmaceutical compound comprising a compound of any one of claims 3,4,13 and 14 in free base form or pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. Dated this 5th day of September 1977. BY:>ffiMKINS & CO.,