GB1590150A - Ergot peptide alkaloid derivative - Google Patents

Description

PATENT SPECIFICATION

Application No 9862/80 ( 22) Filed 31 Aug 1977 Divided out of No 1590149 Convention Application No 11287/76 Filed 6 Sept 1976 Convention Application No 11286/76 Filed 6 Sept 1976 in Switzerland (CH) ( 11) 1 590 150 ( 44) Complete Specification published 28 May 1981 ( 51) INT CL 3 C 07 D 519/02 A 61 K 31/48 ( 52) Index at acceptance C 2 C 1364 1369 213 214 247 250 252 255 25 Y 280 281 28 X 30 Y 342 34 Y 351 352 360 363 36 Y 604 623 62 X 672 802 80 Y AA KR ( 72) Inventors PETER STUTZ and PAUL STADLER ( 54) AN ERGOT PEPTIDE ALKALOID DERIVATIVE ( 71) We, SANDOZ LTD, of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare that invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-

The present invention relates to an ergot peptide alkaloid derivative.

The present invention provides the compound of formula I, CH 3 CH 3 Ss CH 1 OH R I CH 3 H -N which is 6 '-desoxo-9,10-dihydro-3-ergocryptine.

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 formula II, CH 3 CH 3 0 CH { OH I n H 10: 1 II H CII 3 H or b) condensing an acid addition salt of a compound of formula III, ( 21) ( 62) ( 31) ( 32) ( 31) ( 32) ( 33) k M " 4 mo m H CH 3 Ci 3 n 2 N _ _ J 3 3 CH OH CHCH H N N ll C O H 2 CIU 3 with a reactive acid derivative of a compound of formula IV, 0 o H C OH H H N-CH 3 IV H-N Process a) may be effected in one step if desired, using diborane The process may be effected in conventional manner for diborane reductions under mild 5 conditions Conveniently 5 to 15 moles of reactive borane are used per mole of a compound of formula II 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 10 A suitable acid addition salt of a compound of formula III is the 2,5naphthalene-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 15 compound of formula IV arising out of reacting a compound of formula IV with dimethyl formamide or acetamide 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 20 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 25 V, CH 3 CH 3 Cpsoc i C -Ci { ii H 1 CH 2 CH 3 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 30 1,590,150 A compound of formula V may be produced by reacting a compound of formula VI, CH 3 CH 3 3 X 3 CH CH 5 OX 052 CH V COCI 1 with a compound of formula VII, H N HCH 2 VII 5 H'Cil 2-CH CH 3 and hydrogenating the resultant product.

A compound of formula VII may be produced by reducing a compound of formula VIII, H c 11 K > f""CH 2 -CH 3 CH 3 with lithium aluminium hydride 10 The free base form of the compound of formula I may be converted into acid addition salt forms in conventional manner and vice versa Suitable acids for salt formation include hydrochloric and methane-sulphonic acids.

In the following examples all temperatures are in degrees Centigrade and are uncorrected 15 The compound of example 2 forms no part of the present invention It is present to illustrate an alternative preparation of the example 1 compound by process b).

EXAMPLE 1

6 '-desoxo-9,10-dihydro-p-ergocryptine lprocess a)l 20 1.15 g of 9,10-dihydro-/3-ergocryptmine ( 2 mmols) are suspended and stirred at 0 in 25 ml of absolute tetrahydrofuran and then a freshly prepared solution of 20 mmols reactive borane (e g from Na BH 4 and boron trifluoride etherate) in 35 ml 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 6 N 25 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 alumina (activity II-III) to yield the title compound in free base form which is recrystallized from methylene chloride/ether 30 M.Pt 159-160 , lalWO=-4 (c= 0 5 DMF).

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

EXAMPLE 2

1-methyl-6 '-desoxo-9,10-dihydroergocristine lprocess b)l 35 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 formamide at -15 .

1,590,150 4.87 g ( 17 14 mmols) of dry 1-methyl-9,10-dihydrolysergic acid are then added, and a grey deposit precipitates from the reaction mixture After stirring for 30 minutes at O C, the mixture is cooled and treated with 37 5 ml of absolute pyridine, and then 5 14 g of ( 2 R,5 S,0 I Oa S,l Ob S) 2 amino 2 isopropyl 3 oxo 5 benzyl O lb hydroxy perhydrooxazolol 3,2-al pyrrolol 2,1 -clpyrazine2,5 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 (p H= 4), and then made alkaline with 2 N soda solution After extraction with chloroform containing a small amount of ethanol, the extract is dried and 10 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.

M.Pt 183 0-185 , lal O =-77 (c=l, pyridine).

The 2 amino 2 isopropyl 3 oxo 5 benzyl 10 b hydroxy 15 perhydrooxazolol 3,2-alpyrrolol 2,1-clpyrazine 2,5 naphthalene disulnhonic acid is obtained as follows:a) ( 2 S,7 a S) 2 benzyl perhydro 8 oxo pyrrolol 2,1-clpyrazine 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 20 mmols) of L-Phe-L-Pro-lactam in 1 4 litres of absolute tetrahydrofuran 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 25 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 135-140 , lWlO=-3 5 (c=l in ethanol).

b) ( 2 R,5 S,I Oa S,I Ob S)2 carbethoxy 2 isopropyl 3 oxo 5 benzyl 30 l Ob hydroxy perhydro oxazolol 3,2-alpyrrolol 2,1-clpyrazine b)i) 47 8 g ( 207 mmols) of ( 2 S,7 a S)-2-benzyl-perhydro-8-oxo-pyrrolol 2,1clpyrazine in 160 ml of absolute dioxane are treated with 74 4 g ( 249 mmols) of S(+)-isopropyl-benzyloxymalonic acid mono-ethyl ester mono-acid chloride and 34 9 g ( 270 mmols) of N-ethyldiisopropyl-amine The mixture is stirred for I hour at 35 + 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 brownish oil containing ( 2 S,7 a S) ( 2 'S 2 'benzyloxy 2 ' isopropyl O ethylmalononyl) 2 benzyl perhydro 8 oxo pyrrolol 2,1cl pyrazine are obtained 40 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 , lal =-57 7 (c= 0 65 in CHCI 3) 45 c) ( 2 R,5 S,I Oa S,I Ob S)2carboxy 2 isopropyl 3 oxo 5 benzyl l Ob hydroxy perhydro oxazolol 3,2-alpyrrolol 2, 1-clpyrazine 39.3 g ( 97 8 mmols) of ( 2 R,5 S,1 Oa S,1 Ob S) 2 carbethoxy 2 isopropyl 3 oxo 5 benzyl l Ob hydroxy perhydro oxazolo l 3,2-alpyrrolol 2,1clpyrazine are dissolved in 245 ml of methanol and 245 ml of 2 N sodium hydroxide 50 The mixture is stirred for 3 hours at room temperature, adjusted at O to a p H of 4 5 with 2 N hydrochloride acid, 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 55 vacuum, the crystals contain ca 1/2 mol water per mole of title compound.

d) ( 2 R,5 S,1 Oa S,O 10 b S)2 amino 2 isopropyl 3 oxo 5 benzyl l Ob hydroxy perhydro oxazolol 3,2-alpyrrolol 2,1 -clpyrazine 2,5 naphthalene disulphonic acid di) A solution of 3 84 ml ( 45 mmols) of oxalyl chloride in 15 ml of absolute 60 acetonitrile is added in drops over 10 minutes to a stirred mixture of 4 33 ml ( 56 3 1,590,150 1,590,150 5 nmols) 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 ( 2 R,5 SJ Oa S,l Ob S) 2 carboxy 2 isopropyl 3 oxo 5 benzyl l Ob perhydro oxaholol 3,2alpyrrolol 2,1-clpyrazine 1/2 H 20 are quickly added A clear solution is produced, 5 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 and the 2phase 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 10 sodium sulphate After evaporation of the solvent at below 300, a solution of 7 78 g ( 27 mmols) of 2,5-naphthalene disulphonic acid in 200 ml of dimethoxyethane and 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 15 diii) 6 35 g (ca 9 mmols) of the salt are heated for 1 hour to 800 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 semicrystalline powder, which may be used directly after cooling, filtering and drying at room temperature in a high vacuum 20 The compound of formula I exhibits pharmacological activity In particular, the compound of formula I exhibits 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 compound is therefore indicated for use as a coronary therapeutic agent, 25 e.g for the treatment of angina pectoris.

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

The compound is therefore indicated for use as an anti-hypertensive.

An indicated daily dose is from about 10 to about 300 ing, conveniently 30 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 compound 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 35 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.

Claims (8)

WHAT WE CLAIM IS:-

1 The compound of formula 1 40 CH 3 CH CH H-N CH I which is 6 '-desoxo-9,10,-dihydro-p-ergocryptine.

2 The compound of claim 1 in acid addition salt form.

3 A process for the production of the compound of claim I which comprises reducing the 6 ' carbonyl group in the compound of formula II, 45 1,590,150 CH 3 0 H H 1 N-CH 3 H l ql /CI' 2CH 3 cll 3 H-N

4 A process for the production of the compound of claim I which comprises condensing an acid addition salt of the compound of formula III, CH 3 CH 3 CH OH H 2 lN'CH 2-CH 3 C H 13 with a reactive acid derivative of the compound of formula IV,

5 o H n H, H -CH 3 IV H'N H-N A process for the production of the compound of claim I substantially as hereinbefore described with reference to any one of the examples.

6 The compound of formula I whenever produced by the process of claim 3.

7 The compound of formula I whenever produced by the process of claim 4 or 10 5.

8 A pharmaceutical composition which comprises the compound of claim I or 6 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

B A YORKE & CO, 98, The Centre, Feltham, Middx.

Printed for Her Maiesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.