NZ204661A - Certain 8 alpha-sulphamoylamino-6-n-propyl-ergolines - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £04661 2 04661 tiu'w—pjw. *u'uii»i r i.1—"l"' ' • ;Priority DuU{x): «?f; .7. •&>.&).#.* 19: fa Cor.-::[c:.c C^colfication Filed:AV.~2'. fl Publication u&'cs: ''.0. Jou;r-'l Nc: ...

I2&"7 |<ji NEW ZEALAND PATENTS ACT, 1953 Divided frcm No. 197810 No.: Date: jjciv; Under the provisions of RegUv lation 23^(1) the Specificat;?." bss been anta-dated to iBT .Initials COMPLETE SPECIFICATION ERGOLINE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM JC/We, SANDOZ LTD. , 35 Lichtstrasse, CH-4002 Basle, Switzerland; a Swiss Body Corporate hereby declare the invention for which K/ we pray that a patent may be granted to jiie/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) $ S 6 1 00 5440/I.II la ' ERGOLINE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM This invention relates to ergoline derivatives, their production and pharmaceutical compositions containing them.

The present invention provides compounds of formula I H NH-S02-N I N-R 1 H R.-N 4 wherein R^ is- n-propyl, R2 is hydrogen or alkyl(C-|_g)i is al k.yl (C-| __2) > an(^ R^ is hydrogen or methyl other than 8a-(N,N-die~ thylsulfamoylamino)-6-n-propylergoline.

None of the present compounds which have a n-propyl substituent in the 6-position of the ergoline nucleus have been specifically disclosed or suggested by the literature, and it has been found that they have a 204661 very interesting pharmacological profile, and are particularly well tolerated and potent, e.g. as indicated in the pharmacological tests mentioned hereinafter.

Preferably and R^ are identical and preferably they are methyl or ethyl , provided that and are not both ethyl when R^ is hydrogen.

The present invention also provides a process for the production of a compound of formula I as described above which includes the step of condensing an appropriate compound of formula II II or a precursor thereof with an appropriate conpound of formula III y-N in or a precursor .thereof 2 04S -3- 199-544©— vferein and are as defined above, is hydrogen, or n-propyl , Rg is hydrogen or aikyl(C^_^), and one of X and Y is SO^Z wherein Z is a leaving group, 5 and the other of X and y is hydrogen.

The reac±ion is preferably effected by reacting a ccnpound of formula II wherein X is hydrogen with a compound of formula IV z-sOj-ra^Rg iv lO wherein R^ and R^ and Z are as defined above.

The reaction may be effected in conventional manner for the production of analogous ccrnpounds. Z is preferably chlorine or bromine. Suitable solvents include7for example/appropriate chlorinated aliphatic hydrocarbons such as methylene chloride 15 or chloroform or appropriate cyclic or open chain ethers such as dioxane. Suitable reaction temperatures may be between about -10 and about 8C°C.

The ccsnpound of formula II and/or III may be used in ' the form of a precursor, e.g. in protected form and then depro-20 tected later. The protecting group may for example be attached to a nitrogen atcm and may for example be an amino — protecting group.

Naturally if R^ or R^ is hydrogen, then a subsequent alkylation is necessary to produce a conpound of formula I. 25 Besides the alkylation in position 1 or 6 of the ergoline nucleus, the sulfamoyl group may he easily alkylated. . " - 2 O 4 S 6 1 i©©—S-440 /444- Any desired further conversion, e.g. alkylation, may be effected in conventional manner. The type, amounts of alkylating agents used, and reaction conditions may naturally be chosen, if desired, along with temporary protection .of amine croups, to effect alkylation selectively in position 1, or 6 or effect mono or dialkylation in the sulfarrqyl group.

An alkylation in position 1 or 6 of the ergoline nucleus may be/for example/effected by reaction of the corresponding compound unsubstituted in position 1 or 6 with a compound of formula or respectively wherein is as defined above _ ! . — . and Z is a leaving group, e.g. halogen of atomic number 9 to 53 or an organic sulphonic acid radical e.g". tosyloxy.

The reaction is preferably effected in an inert organic solvent, conveniently at temperatures of between about 10 and about 100°C and suitably in the presence of a base. The alkylation in position 6 may alternatively be effected under reductive conditions, e.g. by catalytic hydrogenation under mild reaction conditions.

Alkylation on the sulfamoyl nitrogen may be effected in conventional manner for alkylation of amines. Naturally it is to be appreciated that when R^ or R^ in the starting material is hydrogen then these positions may be alkylated first.

The reaction is preferably effected with an alkyl halide in acetone, dimethylformamide or a chlorinated hydrocarbon in the presence of a base. If a mono-alkylation on the sulfamoylamino nitrogen atom is required (and if desired alkylation in positions 1 or 6 2 04:j -5- Jr0e-5440 /III of the ergoline nucleus) the alkyl halide is preferably used in at most equivalent amounts based on the ergoline starting material. If a dialkylation of the sul-famoylamino nitrogen is required then the alkyl halide is 5 preferably used in excess.

The compounds of formula I may be isolated and purified 111 conventional maimer.

Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional mariner and 10 vice versa. Suitable acids for salt formation include for example hydrochloric acid, sulphuric acid, maleic acid, fumaric acid and tartaric acid.

Compounds of formula II wherein X is SO2Z may be obtained by introducing the group SO^Z into the corresponding compounds 15 of formula II wherein X is hydrogen. When Z is chlorine this may be effected for example by reacting a compound of formula II wherein X is hydrogen with sulphuryl chloride, if necessary with temporary protection of the nitrogen atom in positions 1 or 6 of the ergoline nucleus when or ^ is hydrogen.

Sane of the compounds of formula II wherein X is hydrogen are new, for exanple, compounds of formula II wherein X is hydrogen, R^ is hydrogen or methyl and is hydrogen and compounds of formula II wherein X is hydrogen, R^ is methyl and R^ is n-propyl. All the compounds of formula II wherein X is hydrogen 25 may be produced in conventional manner from 8a-amino-6-irethyl-ergo-line. Thus the 8a-amino group may be protected by e.g. benzyloxy-carbonyl. The 6-irethy 1 group can then be replaced by a group R^ and the 1 position may be methylated.

Insofar as the production of any starting material is not 30 particularly described, these are known or may be produced in conventional manner .

In the following examples all temperatures are in degrees Centigrade and are uncorrected. 204661 EXAMPI. E 1 : 8a-(N N - d i" me t h y 1 s u 1 f arnoy 1 a in i no) ^6 -n -p ro [) v 1 e r a o ]_ i n s [alternative nomenclature N ,N-dimethyl -M '-(.6-propy1 ergo 1i n-8a-yl)su1famide] A solution of 2 ml (ca 26 rnM) dimethyl sul f ami nic acid chloride in 5 ml chloroform is added dropwise to a refluxing solution of 2.2 g (8.2 mM) 8a-amino-6-n-propv 1-ergol ins in 50 ml chloroform and 5 ml triethyl amine. The mixture is refluxed for 12 hours,and then cooled to room temperature. 10 ml of 2N sodium hydroxide are added and the mixture is stirred for 1 hour at room temperature. To worfc up,extraction is effected three times with methylene chloride/ propanol (9:1). The combined organic phases are dried with sodium sulphate,fi1tered and concentrated to yield the title compound.

The hydrochloride salt form is recrystal1ised from ethanol/ ?p methylene chloride (l:l).M.pt. from 220° (decomp.); [a^ -63° (c = 0.43 in etha no 1/water (1:1)].

The ergoline starting material may be obtained as follows:- a ) 8a_^benz vloxy car bony 1 amino^S^methylergoline .5 ml (75 mM) carbobenzyloxychloride sre added to a suspension of 18 g (74.7 mM) 8a-anii no-6-methyl ergol i ne in 1000 ml chloroform, 150 ml isopropanol and 37 ml 2N (74 mM) sodium hydroxide at room temperature.The mixture is stirred for 2 hours at room temperature.After separation of the organic phase,this is dried,fi1tered and concentrated.The resultant crude product is filtered through silicagel with methylene ch1 oride/methano1 (99:1) giving the heading compound as a foam. b) 8a-benzyloxycarbonylami.no-6;;cyancerao]_ine A solution cf 29.5 g (79 mM) of 8a-benzyloxycarbonylamino-6-methyler-goline obtained from step a) and 25 g (236 mM) cyanogen-bromide in 600 ml chloroform is stirred for 65 hours at room temperature and finally concentrated on a rotary evaporator to give the heading compound which is dried in a hich vacuum. 204661 ■7 c) Sa-benzvloxycarbonvlaminoergoline 18 g (46.5 mM) of 8a-benzylaxycarbonyianrLno-6-cyancergoline obtained frcra step b) in 100 ml acetic acid are added to a suspension of 40 g zinc in ICO ml acetic acid. 40 ml water are 5 added and the mixture is heated at 100° for 10 hours. To work up, the mixture is filtered through a filtering aid such as Hyflo and concentrated in a rotary evaporator. The residue is partitioned bet.veen potassium bicarbonate aqueous solution and methylene chloride/isopropanol (9:1). The organic phase is 10 dried over sodium sulphate, filtered and concentrated to give the heading compound in crude form. d) 8o-han zylcxycar bonvl amino-□ -n-pronvlergoline A suspension of 17.5 g (ca 46 mM) of 8a-benzyloxycarbenyl-aminoergolir.e obtained fran step c) , 13.5 g potassium carbonate 15 and 6 ml (62 rrM) n-propyl iodide in 300 inl dimethylforiramicle is stirred for 18 hours at rocm temperature. The mixture is filtered and concentrated in a rotary evaporator. The residue is treated with methylene chloride and shaken with water. The organic phase is dried over sodium sulphate, filtered and concentrated 20 to give the crude heading conpound. e) 'Sa-amino-6-n-orooylergoline 12g (ca 30 r:M) of •" 8 cx-ben zyloxvc arbony lamino -6-n-propylergoline obtained frcm step d) and 1.5 g palladium in charcoal (10% by weight) in 500 ml ethanol are hydrogenated at normal pressure until hydrogen 25 uptake ceases. The mixture is filtered and concentrated. This resultant heading canpound is crystallised frcm methanol.

In analogous manner to that described in Example 1 the following compounds of formula I are obtained by reacting the appropriate conpound of formula II and a compound of formula IV, wherein X is K and Y is C1S02:~ 204661 -8- VQfl^MO/ril EXAMPLE-2 : 1 ;§a~{N_, N^d i me th.yl su 1 f am oy Teaming)-63 n- Er2pyl§rs2li!i® ?n Hydrochloride salt:M.pt. from 220° (decomp); [a3D = -60° Cc = 0.445 in ethano1/water (1:1)].

EXAMPLE 3: §«:{N , N -di ethyl ?u If amoyl amfno^-^1 ethyl ;6-n-2r22Yl§!I92ll!]® on Hydrochloride salt. M.pt. from 180° (decomp); [a]p - 31.5° [c = 0.96 in pyridine].

EXAMPLE 4 : N:™ethylsul famoyl ami no^e^n^gropyl ergol ine Free base: 103-107° 204661 -9- lGQ-544Q-^H~i~ The compounds of formula I exhibit pharmacological activity. In particular, they exhibit prolactin secretion 5 inhibition activity as indicated by an inhibition of the implantation of fertilized eggs in the uterus on day 5 after insemination of female rats on administration of frcm about 0.001 to about 0.1 irg/kg s.c. of the compounds [according to the principles of Experienta 34_, 1330 (1978)] .

The compounds are therefore furthermore indicated for use as prolactin secretion inhibition agents, e.g. for the treatment of endocrinological indications associated with prolactin secretion An indicated daily dosage is in the range frcm about 0.1 15 to about 1 mg conveniently given in divided doses 2 to 4 times a day in unit dosage form containing frcm about -J). 0 3 mg to about 0.5 rng of the compounds, or in sustained release form.

Additionally the compounds of formula I exhibit dopaminer-20 gic activity as indicated by an induction of contralateral turning in rats with a unilateral 6-hydraxydoparaine-induced degeneration at doses of about 0.05 to about 2 mg/kg i.p. [According to the principles of U.Ungerstedt, Act.physiol. Scand.Suppl.367, 69-93,(1971)].

The compounds are therefore additionally indicated for use as anti-parkinson agents.

An indicated daily dosage for this indication is in the range frcm about 0.5 to about 10 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form 30 contaiiiing frcm about 0.15 mg to about 5 mg of the ccmpounds or in sustained release form. 2046 -10- -ffcOD 5440—/HI Moreover, the carpounds of formula I exhibit antidepressant activity as indicated in animal tests, e.g. an antagonism of reserpine-induced catalepsy and ptosis is observed at doses of frcm about 0.01 to about 0.1 rag/kg s.c.

The compounds are therefore furthermore indicated for use as anti-depressant agents.

As indicated daily dosage for this indication is in the range frcm about 1 to about 10 mg; conveniently given in divided doses 2 to 4 times a day or in unit dosage form 10 containing frcm about 0.5 mg to about 5 mg of the compounds, or in sustained release form.

The invention also includes compounds for use in the 15 above-mentioned indications, i.e. prolactin secretion inhibition, Morbus Parkinson and depression.

The ccmpounds may be administered in the form of a pharmaceutical Iv acceptable acid addition salt. Such salt forms have the same order of activity as the free base forms. 20 The present invention accordingly provides a conpound of formula I in free base form or in pharmaceutically acceptable acid additicn salt form in association with a pharmaceutical carrier or diluent. Such canpositions may be formulated in conventional manner so as to be, for exanple, a solution or a 25 tablet.

In a group of compounds is n-propyl and R^ is methyl. 2.046 61

Claims (16)

WHAT WE CLAIM IS:

1. A process for the production of a ccrnpound of formula I H. NH-S00-N^ 2 N-R, wherein is n-propyl, R2 is hydrogen or alkylt is alkyl (C-^_3) , and R^ is hydrogen or ma thy 1, other than 8a- (N , N -diet hy 1 -sulfainoylaniino)-6-n-propylergoline which includes the step of condensing an appropriate compound of formula II tJH-X N-R, II 10 or a precursor thereof, with an appropriate compound of formula III Y-N '*2 «» *6 HI -12- 204661 or a precursor thereof, wherein and R^, are as defined above, and Rg is hydrogen, or n-propyl, Rg is hydrogen or alkyl(C-j > and one of X arid Y is SO^Z wherein Z is a leaving group and the other of X and Y is hydrogen.

2. A process as claimed in claim 1 wherein at least one of P^, R^,, Rg and is hydrogen and the resultant compound is appropriately alkylated to produce a com- 10 pound of formula I.

3. A process for the production of a compound of claim 1 substantially as hereinbefore described with reference to any one of the Examples.

4. A compound of claim 1 whenever produced by a process 15 of claim 1, 2 or 3.

5. A compound of formula I as defined in claim 1.

6. A compound of claim 5 wherein R-j is n-propyl and R^ is methyl.

7. A compound of claim 5 which is 1-me thy!-8a-(H,N-di-20 methylsulfamoylamino)-6-n-propylergoli ne.

8. A compound of claim 5 which is 8a-(.N ,N-dijnethyl sul -famoylamino)-6-n-propylergoline.

9. A compound of claim 5 which is 8a-( N,N-diethylsulfamoyl amino)-1 -methy 1 - 6- n-propylergoli no. 25

10. A compound of claim 5 which is 8a-(N-methylsulfa-moylamino)-6-n-propylergoline. 204661 - 13 -

11. A compound of any one of claims 4 to 10 in acid addition salt form.

12. A compound of any one of claims 4 to 10 in free base form or in pharmaceutically acceptable acid addition salt form in a form suitable for use as a prolactin secretion inhibitor.

13. A compound of any one of claims 4 to 10 in free base form or in pharmaceutically acceptable acid addition salt form in a form suitable for use as an anti-parkinson agent.

14. A compound of any one of claims 4 to 10 in free base form or in pharmaceutically acceptable acid addition salt form in a form suitable for use as an anti-depressant agent.

15. A pharmaceutical composition which comprises a compound of any one of claims 4 to 10 in free base form or in pharmaceutical1y acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

16. The compound of formula II as defined in claim 1 wherein X is hydrogen, is methyl, and is n-propyl. DATE# THIS /5 OAY OF G<dr>hzr A. J. PARK A SON « 9-<p JZ-> re* AGENTS FOR THE APPLICANTS