CA1105007A - Ergot peptide alkaloid derivatives - Google Patents

Abstract

ERGOT PEPTIDE ALKALOID DERIVATIVES

Abstract of the Disclosure 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 relates to ergot peptide alkaloid derivatives.
The present invention provides compounds of formula I, Rc ~ ~ O ~ ~ CU2 ~N-R4 R3 R2 ~:

R5-N `:
; `
wherein Rl is alkyl of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, R3 and R5 arev independently, hydrogen or methyl, R~ is hydrogen or alkyl of 1 to 4 carbon atoms, , : and :. :
: R6 and R7 together form a single bond, or 20 ~ R6 and R7 are each hydrogen, or R6 is methoxy and R7 is hydrogen, and pharmaceutically . :
acceptable acid addition salts thereof.
In formuLa I, Rl is for example methyl, ethyl or ~isopropyl. R2 is convenLently n- or iso-propyl, n-, iso-or sec.~butyl or benzyl ~R3 and R5 conveniently are both :;' " `
~ ' :.': :;
3 0:

,~

''5~7 100-~58 hydrogen. R~ is conveniently methyl or iso-propyl. R6 and R7 are preferably each hydrogen.
The present invention also provides a process for the production of a compourlcl of formula I, which comprises S a) reducing the 6' carbonyl group in a compound of `-formula II, r~

., . wherein Rl t-o R7 are as defined above, or ~) condensing an acid addition salt of a compound of `:
formula III, __ H2N~ ~ o ~ eN ~
I III
~ R3~`R2 wherein Rl to R3 are as defined above, wlt-h ~ reactive acid derivative of a compo~md of formula IV, ~ ~ 2 -.
': ' COOE~
7 ~ -~
R6~ ¦ H
N-~
IV

Il wherein R4 to ~ are as def~d above; and where desired~ convert~lg -~e re~tant product into a ph ~ aceutically acceptable salt thereof.
~'rvcess a) mav be er~ec'ed in one step process if desired,using reactive borane, e~g. diborane. The process may be effected in conventional manner for diborane reductions under mild conditions. Con~enientl~ ~ to 15 moles of reactive borane are used per mole of a compound or for~nulaI~ Tetrahydrofurant diethyl ether or methylene chloride may be used as solvent~ Suitable reaction ~ :-temperatures may be from 20 to 20C.
~ 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 ~ormula III is the ~,5-naphthalene-disulphonic acid salt.
L5 ~ Suitable reactive acid derivatlves of a compound of formula IV include the acid chloride, the acid azide, and th~. mixed anhydride with sulphuric or trifluoroacetic acid, It is preferred to use the addition product of a :
compound of for~ula IV with dimethyl formamide or acetamide .. , f' '' ' : : : , :. : , : ' 100-~658 and thionyl chloride, phosgene or oxalyl chloride.
Pxeferably triethylamine or pyridine is present during the reaction. Sui~able solvents include chloroform, methylene chloride, dimethyl formamide and acetonitrileO
Suitable reaction temperatures are from -30 to ~20C.
The star-l^ing 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 ror the p.~paration of an aminocyclol from a compound of formula V;

C2H50oc~-o~ V
- N ~ H2 wherein Rl to R3 are as defined above.
For example the corresponding acid may first be formed and then converted via the acid chloride into the lS corresponding acid amide, which in turn i5 coll~erted into ~he amine.
A compound of ormula V may be produced by reacting a compouncl of formula VI, . .

: .

.
.
,.
.~ ' , ~ :
; .

- . ~ : -.... .. - . ,, . - . ~ . : ~ . ..

¢~
100-~6 Rl ~ OCH ~C H

- 2 5C ", 2 6 5 VI

COCl ~here.in R is as defined ~bove, with a compo~nd of formula VII, ' .
r--~ N / .
I VII
HN ~ CH2 ~3 R2 .
wherei.n R2 and R3 are as defined above, ~nd hydrogerlating the resultant product.
5A compound of formula VII may be produced by reducing a compound of formula VIII, ~ ~J
VIII
IIN I
, ~0 R `R

wherein R~ ~ld R3 are as defined ahove, with lithium aluminium hydride.
Free base forms of the compounds of ~ormu].a I may ~ 10be converted into acid a~dition salt forms in conventional - manner ~ld vice versa. Suitable acids for sal~ forma~ivn :

:
, 100-~658 include hydrochloric and methane~sul.phonic acids~
In the following Examples all tenl.peratures are in degrees Centigrade and are uncorrected~

, . .

~; /

/
, , .. . _ ..... _ .

;
, ., .
.. : . .
... . . . . ... .... .. . . ~ .

~ 7 100~65 EXAMPLE 1: 5~-desoxo~9110 dihydro~~-er~ocrY~tine ____ ___~_ _____~ ________ ____,__ _ [process a)3 1.15 g of 9,10 dihydro ~-ergocryptine (2 mmols) are suspended and stirred at 0 in 25 ml of absolute tetxa-hydrofuran and then a freshly prepared solution of 20 INmols ~ reactive borane (e.g. from NaBH4 and boron trifluorid~
- ethexate) in 35 ml of absolute tetrahydrofuran is added dxopwise. After stirring for 4 hours at 0 the solution is cooled. The reaction mixture is carefuily treated with 9 ml of 6N-hydrochloric acid, and t~len stirred for another 30 minutes at +60, ~ooled, made alkaline with 30% sodiwn hydroxide, and then thorou~hly extractecl with methylene chloxide. The methylene chloride extracts are chromatographed on alurninia (activity II~III) to yield the title compound in free base form which is recrystalli~ed from methylene chloride/ether.
M.Pt~ lS~-160 ; [~]D = ~4 (c = 0.5 DMF).
The kitle compound may also be prepared accordin~ ~o the process of Exarlple 2.

EX~MPLE ~ methyl-6'-desoxo-9110-dihydr~r~oclist_ne ; [process b)l ~ solution of 1.1~1 ml ~17.L4 mmols) of oxalyl chloride in 15 ml of absolute acetonitrile is added ;
~ dr~pwise to 150 ml of absolute dimethyl ormamide a-t -15.

. , ' . .
~ 7 ~~

, .
.

~ : , ..... ~,, 5j~
1C~0~ 5 8 4.87 g (17.14 mmols) of dry l-methyl-9,10-dihydrolysergic acid are then added, and a grey de~osit precipitates fro~l the reaction mixture. After stirring for 30 minutes at 0, the n~ixture is cooled and treated with 37.5 ml of absolute pyridine, and then 5.14 g of (2R,5S,lOaS,~ObS)-2-amino-2 isopropyl-3-oxo-5-benzyl-lOb~hydro~-perhy~rooxazolor3,2-a~--pyrrolo[2,1-cJpyrazine.2,5-naphthalene-disulphonic acid (about 8.5 immols) are added, The mix~ure is stirred ~igorously for 2 hours, and then the temperature is lQ allowed to increase slowly from -10 to 0. The mixture - is then cooled a~ain and diluted with 40 ml of citrate-buffer (pH = 4), and then made alkaline ~ith 2N soda ~olution. After extraction with chloroform containing a small amount of ethanol, the extract is dried and evapora~ed~
15 The crude product is chromatographed on silicagel, to gi~-e the title compound in free base form on elution with 4~
methanol in methylene chlvride, ~hich is rec~stallised from acetone.
i M.Pt. 183 - 185; [a~D ~ ~77~ (c = 1, pyridine).
~0 The title compound may also be prepared by the process of Example 1.
The 2-amino-2-isopropyl-3 oxo-5-benzyl-lOb-hydroxy-perhydrooxazolo~3,2-a]pyrrolo[2,1-c] pyrazine . 2, 5-naphthalene-.isulphonic acid is obtalned as follows:-, ,.~ , ' :

: :

.

~ '7 loQ-465~

a) ~2s~asj-2~ e~nz~ erhxd-o-8-oxo-~?vrrolor2~ yr~zlne 36.4 g (960 mmols) o~ lithi~m aluminium hydride are suspended in 1~ 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 tetrahydrofuran is aclded dropwise over 45 minutes. After stirring for 18 hours at -10l the reaction mixture is diluted carefully at this temperature with 350 ml of ethyl acetate and then 350 ml of water. The resultant mlxture i5 filtered~
~epeated extraction of the ilter cake with boiliny methylene chloride is effected to obtain more procluct.
The combined organic phases and filtrate are dried ~ith sodium sulphate and evaporated. The pure title compound in free base form crystallises directly from methylene chloride/ether in bright heige crystals;
M.Pt. of 135 - 140; [~]20 ~ _3.5o (c = 1 in ethanol).

h) ~2RL5SLlOaSl]ObSL_~carh~ 2-iso~ro~ 3 oxo~5-benzvl-l~b_hxdroxy-~erhxdro-oxazolo~3l2-al~yrro~o[
b)i) fi7.8 g (207 mmols) of (2S,7aS)-2-benzyl-perhydro 8 oxo-pyrrolo[2,1-c)pyrazlne in 160 ml of absol~lte dioxane are treat:ed with 74.4 g (249 l~nols) of 9~ ) isopropyl-benz~loxy-malonic acid mono-ethyl estex mono-acid chloride and 34~9 g (2~0 mmols) of ~. ` ' .

:-: :

~ '7 100-~65~

N-ethyldiisopropylamine~ ~he mixture is stirred for 1 hour at +70. ~ter dilution with 1 litre of ether t the mixt~re is shaken twice with saturated sodi.um bicarbon~t~ soluti~n and dried over sod~um sulphate.
After evaporation of the solvent, 138 g of a brownish oil con~aining (2S,7~S) ~(2'S- 2-ben2.yloxy-2l-isopropyl-O-ethylmalononyl)-2-benzyl perhydro-8-oxo pyrrolo[2rl c]-pyraz.ine are obtained.
b)ii) This oil is dissolved in 105 litres of ethanol and is hydrogenated at 60 after addition of 60 ~ of palladium-active carbon (10~ w/~ Pd~, wherein, after 14 hours, about 6.5 litres of hydrogen are absorbed Aft.er filtration and evaporation o~ the filtra~e, the title compound is recrystalli~ed from isopropyl ether, as yellowish prisms with a M.Pt.
of g9 - 100; [~DO = ~57 7 (c - 0.65 in CHC13).

c) ~2R 5S lOaS lObS~-2 carboxy-2-iso~ro~vl-3-oxo-5-benz~l-~ _.L~
lOb-hydrox~-~erhvdro-oxazolor3L2-al~yrrolo~2~l-clp~razine _ _ _ _ _ _ _ _ _ _ _ _ . ~ _ _ _ _ _ _ _ _ . _ ~ .. . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ 39-3 g t97.8 mmols) of (2R,5s,loas~lo}~s)-2-carbethoxy-2--isopropyl-3-oxo-5-benzyl-lOb-hydroxy-perhydro-oxazolo-13,2-a]pyrrolo[2,1-c]pyrazine are dissolved in 245 ml o methanol and 245 ml of ~ N sodium hydroxide. The . mixt~lre is:stirred for 3 hours at room temperature, adjusted at 0 to a p~I of 405 with 2 N hydrochloric acid~

~- 1 0 ~

.

5~`7 loow465g and ~hen extt^acted repeatedly witll ethyl acetate.
-After drying the organic extract and evapor~ting the solvent at below +30, the ~itle compound crystallises . aft~er dilution wiih ether. M,Pt. 126 - 12~ ~decomp).~ter drying for 5 hours at 30 in a hi~h vacuum, the crystals contain ~ 1~2 ~lol water per mole of title compound.

d) (2R15SllOaSllObS)~2~amino-2-iso~ro~yl-3-oxo-5-benzyl-lOb-hydrox~-perhydro-oxazolo{3,2-al~vrxolo~ cl-?___.__ ____ ___.__ __ ______ ________ ___.________ _ ~yrazirle.2,5-na~hthalene d~sulEhonic acid .
di) A solution of 3 . 84 ml (45 mrnols) of oxalyl chloride in 15 ml of abso~ute acetonitrile is added in dxops ovex 10 minutes to a stirred mixture of 4~33 ml ~56.3 mmols) of ahsolute dime~hyl formamide and 30 ml of absolute acetonitrile which is cooled to -15~. The mixture is stlrred for a further 10 minutes. After dilution of ~he mixture with 45 ml of absolute ethex, 11.25 g , .
t30 mmols) o (2R~5S,lOaS,lObS)-2-carboxy-2-isopropyl~

3-oxo-5 benzyl~lOb hydroxy~perhydro~oxazolo~3,2~a]-p~rrolo[2,1-c]~razine.l/2 H20 ~re quickly added.
clear solution is produced, which is stixred for another 10 minutes at -10 thexeby producin~ the acid chloride.

dii) ~ solutlon of 20 g of sodium azide in 100 ml of watex, dilutecl with 300 ml of methylene chloride r iS added tu ~; .
the acld chloride solution ~

- 11 ~

: :
, .
: :

~5~ 7 ~00~658 and the 2-phase mlxture is shaken vigorously ~r ~1 minutes. Then, 150 ml of ice~cold t satura~ed sodiw~
bicarbonate solution are added. The org2nic phase is separated and dried well over sodium sulphate. After evapoxation of the solvent at below 30, a solution of 7.78 g 127 mmols) of 2~5 naphthalene disulphonic acid in 200 ml of dimethoxyethane and 20 ml of aceto-nitxile 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 ~he 2,5-naphthalene disulphonate salt~

diii) 6.35 g (~ 9mmo]s~ of the salt are heated for l hour to 80 in the presence of ~20 ml of dimethoYyethane which contains 0.l66 ml of water. The title compound ~ obtained with constant scraping, as a brownishr ; semi-~rystalline poT,~der~ which may be used directly ; aftex cooling, fi ltering and dryin~ at room temperature irl a high vacuum.

The following compounds of foxmula I may also be ~btained in analo~ous manner to that described in Example l or 2~

EXA~IPI.E 3- 6'-desoxo-~ lO^dih~dro~a-er~ocryptine M.Pt. l8~ - 185; [a]20 = ~1~ (c = 0.3 in dimethyl ormamide)~.

- 12 ~- ' ' ;

' :

:
.

~ 0~-~658 EXA~lPLE 4: 6'-desoxo~9,lO-d~hydroer~ocorn~ne M.Pt. 166 ~ 167(decomp); ~a]D ~ 18.5 (c - 0.66 in dimethyl ~ormamide~t EXA~PLE 5: 6'-de~.o~o-~10-d~h~dro~-er~osine M.Pt. 194 - 196 (sintering from 185~; [a]D - -18 (c - 0c3 in dimethyl o~mamide3.

~X~lPLE 60 6-nor-6_isor,,~ 6~_deSX_911__din~d---j er~otamine M.Pt. lB6 _ lgOo; [~20 _ -63 (c = 0.3 in dimethyl formamide).

~XA~IPL~ 7: 6'-desoxo-er~otamine ____________ ..____._ M.Pt. 176 - 180; [cx]20 ~ ~17 (c = 0.35 in di~ethyl ~oxmamide).

LY~MPLE 8: 6l-deso~o-er~ocristlne ~Y~MPL~ 9: 6'-deso~o-~-~erc~ocryPtine --_ _ _ _ EXAMPLE 10: 6'-desoxo-cx-er~ocry~tine __,_ _ _ ~ _-- -- -- ,, , . :

, ' ;' :~
' . .

100~4 65 I~XAMPLE llo 6~ so~o~9~ hyf~oex~focristin~

M.Pt. 208 - 209 ~decomp. ); [a] ~ G -75 (c -- 0 . 8 , pyridi ~e) .

EXP~MPLE 12: 6--deso~o~3l~lo-d-hydr~of~rgotamine M~Pt. 165 - 168 (decompO~; Ea]~ = 78 ~c = 1I pyridine).

: ~ 14 -- -' '' ,~ :

~ 100-4658 The compo~ds of ~orn;ula I exhibit pharmacolo~ical activity. In particular, the compounds of ~ormula I exhibit coronary therapeutic activity as indicated by a coronary dilation and vasodilation in the "open chest cat" test at an e~l~ective dose of from akout 0.03 to c~bout 1 mg/kg i~v.
The compounds are therefore indicated for use as coronary tllnrapewtic agents, e.g. for the treatment of angina pectoris,.
The compounds also exhibit anti~hypertensive activity as indicated by a blood pressure lowering in the above-mentioned open cllest cat test.
The compounds are thereore indicated for us,e as anti-hypertensives.
An indicated daily dose is from about 10 to about 300 mg, conveniently administered in divided doses 2 to ~
' times a day in unit dosage form containing from about 2 mg '~ to about 150 mg or in sustained release ~orm.
The Example 1 compound is the preferred compound.
... . .. ..

,;; , .......... i , .
;, The compounds may be admirlistered in pharma-ceutically acceptnble acid adaition salt for,m. 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 ~ aii~ defined : ~ .

'.

-, ~5~7 100-~65~

above in association with a pharmaceutical carrier or diluent. Such composition may be formulated in conventional m~nner so as to be for example a solution or a ~ablet.
In a group o compounds Rl is methyl, ethyl or isoprop~1, R2 is H, CH3, C2~5, n- or iso-C3H7, n-, iso-or sec.-butyl or benzyl, R4 is ~, CH3, C2H5, n or iso C3H7 or n-, i50- 01- sec.~butyl, and either R6 and R7 are each hydrogen or together fonn a bond.

~ `
:
:

.:
.
. I

Claims (6)

WHAT WE CLAIM IS:

1. A process for the production of a compound 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, or R6 is methoxy, and R7 is hydrogen, or a pharmaceutically acceptable acid addition salt thereof which comprises a) reducing the 6' carbonyl group in a compound of for-mula II, II

wherein R1 to R7 are as defined above, or b) condensing an acid addition salt of a compound of formula III, III

wherein R1 to R3 are as defined above, with a reactive acid derivative of a compound of formula IV, wherein R4 to R7 are as defined above, and where desired,converting the resultant product into a pharmaceutically acceptable acid addition salt thereof.

2. A process according to claim 1 (process a) wherein the compound of formula II is reduced by diborane.

3. A process according to claim 1 effected according to process b).

4. A compound of formula I as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, when-ever produced by a process according to claim 1, 2 or 3 or an obvious chemical equivalent thereof.

5. A process according to claim 1, wherein R1 is isopropyl, R2 is sec-butyl, R3 is hydrogen, R4 is methyl and R5, R6 and R7 are each hydrogen.

6. 6'-desoxo-9,10-dihydro-.beta.-ergocryptine or a pharmaceuti-cally acceptable acid addition salt thereof whenever pro-duced by a process according to claim5 or an obvious chemical equivalent thereof.