6-NOR-6-ISOPROPYL-9,10-DIHYDRO-2'.beta.-METHYL-(OU ETHYL)-5'.alpha.-ISOPROPLYERGOPEPTINE

6-NOR-6-ISOPROPYL-9,10-DIHYDRO-2'.beta.-METHYL OR ETHYL-5'.alpha.-ISOPROPYL-ERGOPEPTINE

Abrégé anglais

6-Nor-6-Isopropyl-9,10-Dihydro-2'.beta.-Methyl Or Ethyl-5'd-
Isopropyl-Ergopeptine

Abstract of the Disclosure

This invention provides new compounds of
formula I,
Image I

wherein R1 is alkyl of 2 to 5 carbon atoms, and
R2 is methyl or ethyl,

useful as anti-migraine agents.

Revendications

- 9 -
What is claimed is:


1. A process for the production of a compound
of formula I,

Image I

wherein R1 is alkyl of 2 to 5 carbon atoms, and
R2 is methyl or ethyl,
comprising condensing a reactive functional derivative of
an acid of formula II,

Image II

- 10 -

wherein R1 is as defined above,
with a compound of formula III,

Image III

wherein R2 is as defined above,
in pharmaceutically acceptable acid addition salt form.
2. A compound of formula I, as defined in
Claim 1, whenever produced by the process of Claim 1.
3. A process for the production of a compound
of formula I, as defined in Claim 1, wherein R1 is iso-
propyl and R2 is methyl, comprising condensing a reactive
functional derivative of an acid of formula II, as defined
in Claim 1, wherein R1 is isopropyl, with a compound of
formula III, as defined in Claim 1, wherein R2 is methyl.
4. 6-Nor-6-isopropyl-9,10-dihydro-2'.beta.-methyl-
5'.alpha.-isopropyl-ergopeptine whenever produced by the process
of Claim 3.
5. A process for the production of a compound


- 11 -

of formula I, as defined in Claim 1, wherein R1 is
isopropyl and R2 is ethyl, comprising condensing a
reactive functional derivative of an acid of formula
II, as defined in Claim 1, wherein R1 is isopropyl,
with a compound of formula III, as defined in Claim 1,
wherein R2 is ethyl.
6. 6-Nor-6-isopropyl-9,10-dihydro-2'.beta.-
ethyl-5'.alpha.-isopropyl-ergopeptine whenever produced
by the process of Claim 5,

Description

~05~285
..
: The pr~sent invention relates to new hetero~
cyclic compounds. ~ ;
In accordance with the inv2ntion there are
provided new compounds of formula I, ~ . ~

: ~2 ~ ~ :
H ~ CO-N}I~ ~ y N -;

l B ~
CH3 \CB



: 5 wherein Rl is alkyl of 2 to 5 carbon atoms~ and ;
R2 is methyl or ethyl.
' . .. . . ' . '.. :
. i . -,
. . ~ _ , ,
.~ :fi.... . ~

.: . '' ~''`'' ''
~: ~urther, in accordance with the invention
a compound o~ formula I may be obtained by a process
comprising conder.sing a reactive functional derivative ;~
of an acid of formula II, :~
COOI~ ~ ~




"

i,,~ ~ .
,' .'"1; ',
~,,~.". .. .
. ,

fSff7ff~si
- 2 - 100-4192



wherein Rl is as defined above, ~ -
with a compound of formula III,
. ,- ~`,

H2~ ~ ~ III

N~o
H~ ~C~

C ~3 \CH
; ~:
wherein R2 is as defined above,
in pharmaceutically acceptable acid addition salt form.

Rl preferably is branched, especially in the
position to the nitro~en atom to which it is bound. ,~
The reaction of the invention is a condensation ;~
~ :. -
reaction for amides. It may be carried out in a manner

; analogous to known methods.

- 10 The condensation i5 effected in an inert

~ ~organic solvent or solvent mixture in the presence of an
,.: ~ : :: . .
acid-bind1ng agent.

i~ ~ For example, the condensation may be Pffected
.. . . .
using as reactive functional derivative of an acid of ~ ~
. ~ :

formula II the addition product resulting from the
,, .-. :~
reaction of an acid of formula II with a chlorinating
agent and an N-di(lower)alkyl-substituted acid amide of
an aliphatic carboxylic acid of 1 to 3 carbon atoms~


:; `~"`,: :f

~-:, .




'. . ', . ., , ' . , :. i, , ..: ; : '

_ 3 ~ 7Z85 l00~4lg2 `~

~ such as dimethyl formamide or dimethyl acetamide. Other
. ~
reactive derivatives of an acid of formula II, which may

be produced in accordance with known methods, e.g. the ~ ;~
,: . .
acid chloride hydrochloride, the acid azide or mixed ~
: :: - :, .
5 anhydrides of an acid of formula II with sulphuric acid
or trifluoroacetic acid, may alternativel~ be used.
Suitable organic solvents are, for example,
chloroform, methylene chloride, acetonitrile or dimethyl
formamide, and suitable acid-binding agents are ~ ~ ;
tertiary organic bases, e.g. pyridine or homologues
thereof. Examples of chlorinating a~ents which may be
used are thionyl chloride, phosgene or oxalyl chloride.

, ~ . ,:. ~ ,
; The reaction may be effected at a temperature hetween

-30 ~nd 0C and at normal pressure ~ ;~

It is convenient to use 1.2 to 204 mols of an
. ~ . ~ . . .
acid of formula II for every mol of a compound of~
formula III in salt form. The preferred salt form of
.he compounds of formula III is the hydxochloride. The
course of the reaction is independent of the sequence
;~ 20 ~ o~ addition of the reagents.
The working up of the reaction mixture and
isolation of the compounds of formula I may be effected
in known manner.
Acid addltion salt forms may be obtalned in
known manner from the free bases and vice versa. ;~

A suitable acid is tartaric acid.


. , ;,

~''~`:
.

~ i7~8~ :
; - 4 - 100-~192



The compounds of formula II, required as
start.incr materials, are new and may be obtained ln
accordarlce with known methods. For example, a compound -
of formula IV, -~


COOCH3

Rl IV

N


wherein Rl is as defined above,
may be saponified under mild alkaline conditions, con-
, veniently by treatMent with caustic soda solutton in
I an organic solvent or solvent mixture, and ~ay then
be weakly acid~fied.
,~
The compounds of fo:rmula IV may be obtained
by aIk~lation oS 6-nor 9,10-dihydrolysergic acid
methyl ester.
; The compounds of formula III are ~nown. ;~
:. ..
.
In the following non-limitative EY.amples all
temperatures are indicated in degrees Centi~xade and are ;-~
i uncorrected. Insofar as the production of the starting
materials is not described, these are known or may be
produced in accordance with known processes or in a

manner analogous to kno~m processes.

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

;:
~,

, , . ,, .. .,.. , . ., ..................... :
", " , , ~
,. . . .

_ 5 _ lOS7Z85 100-419?.
:~ ' :,',' ,: '
; . ~
,.,'' ~'','~ ''
. ~ . . .
The name of the compounds of formula I is ;~
derived from the basic structure of formula V,
.. . ,:



~3 ~ ~ V



:; which is named ergopeptine or the sake of simpliclty.




I " - ~,




~,


:~ . -

. ;.

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

- 6 ~ '7~85 100-4192

EXAMPIE 1: 6-nor-6-iso~ropyl~9!lo-dihydro-2'~

5'~-isopropy1-erqo~e~tine
.. .
8.6 cc of o~alyl chloride dissolved in 20 cc of
acetonitrile are added dropwise, a~ -10 to -15, within
10 minutes to a solution of 300 cc of dimethyl formamide
and lSO cc of acetonitrile, and stirring is effected for a
further 10 minutes. 32 g of anhydrous 6-nor-6-isopropyl-

9,10-dihydrolysergic acid are then sprinkled into the -
solution at -20, and stirring is effected at -10 for -~
30 minutes. ~fter cooling to -20, 200 cc of pyridine and
16.3 g of (2R,SS,lOaS,lObS)-2-amino 2-methyl-5-isopropyl- ~
3,6-dioxo-lOb-hydroxy-octahydro-8H-oxazolo[3,2-a]pyrrolo- -
~ ,
[2,1-c]pyrazine hydrochloride are added, and stirring is
effected at 0 to 2 hours. Working up is effected by add~
ing 100 cc of a buffer solution pH = 4 and distributing the
reactlon mixture between methylene chloride and a 2N soda
; solution. The organic phases are washed twice with water, ;
dried with sodium sulphate and evaporated to dryness on a -~
rotary evaporator. After drying in a high vacuum, the
20 resulting crude base is dissolved in about 150 cc of etha- ~'
nol and the solution is seeded. The *itle compound has an
M.P. of 194 (decomp.)~ r~]D = -32.3 (c = 0.995 in meth- ~;
anol).

' '"''~ ~ .


: , '.. ~:,



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

;: ' , " ' "" ' ' ' ` ' "' , . ' . :

~7~8~ :~
_ 7 _ 1~0-4192

Produçtion_of the hydrogen tartrate form.
8.3 g of the ~ase (C31E341N505) are dissolved
in 120 cc of etha7l01 at about 50, and 2.22 g of
L-tartaric acid dissolved in about 10 cc of ethanol
are added. Aftex cooling to room temperature, the salt
crystallizes. The pr~cipitated salt is separat~d from
the mother liquor, is washed with a small amount of
ethanol and is then dxied in a high vacuum at 80.
M.P. 200 (decomp.), [a]D= -1~.4 (c = 1.0 in ethanol). ;~
The 6-nor-6-isopropyl-9,10-dihydrolysergic
acid, used as starting material, may, for example, ke -
obtained by alkylation of 6-nor-9,10~dihydrolyser~ic
acid methyl ester with isopropyl bromide and saponifio- ~ -~
ation of the resulting 6-nor-6-isopropyl-9,10-dihydro~
lysergic acid methyl ester (M.P. 194).
1 6-nor-6~isopropyl 9,10-dihydrolysergic acid -;
I has an M.P. of 290 (decomp.), ~20= -101 (c = 0.6
in methanol).

EXAMPLE 2: 6-nor-6-.isopropyl-9,10-dihydro-2'~
~; 20 ~ ~ et~yl-5'a-isopropyl-ergope~tine

. Production in a mannar analogous to that
described in Example 1. The title compound has an M.P.
of 176-I78 (decomp.), [a]20- -23 (c = 0.5 in ~`
methylene chloride.
.1 ,, .

,. . ~ ':



: ' . '
:
- :. : , : : ,. ~ : . :
.,,, , , . i ,~
. .

- 8 ~ ~S7~s 100-~192



The compounds exhibit pharmacological
activity. In particular, they exhibit vasoconstrictor
activity, as indicated by pressor activity indicated
in standard tests, e.g. in the pithed rat test
S ~Gillespie and Muir, Br.J.Pharmac. 30, 78-87 (1967)]
and in the Mellander-cat test [Angiologica 3, 77-99 --
(1966~ by an arterial vasotonic effect.

The compounds are therefore further indicated
for use as vasoconstrictor agents possibly for the
treatment of migraine. For this use an indicated
daily dose is from about 0.1 to about 3 mg, convenient~
ly administered in divided doses 2 to 4 times a day
in unit dosage foxm containing from about 0002 to
about 1.5 mg, or in sustained release form.

lS ~he compounds of formula I may be administered ;;
ln pharmaceutically acceptable acid additLon salt form. `~
The present 1nven~lon also`provides a pharmaceut~cal
compositlon comprlslng a compound of formula I, ln
free base form or in pharmaceutically acceptable
acid addition salt ~orm, in association with a
pharmaceutical carrier or diluent. Such compositions
may ~e formulated in conventional manner so as to
be, for example, a solution or a tablet. ;~;
... , , .. ~ .~:
In a pre~erred group of compounds Rl ~s
isopropyl and esp~cially R2 is methyl.



.. ,.. , :