IE41533B1

IE41533B1 - Thiomethyl ergolene derivatives

Info

Publication number: IE41533B1
Application number: IE542/75A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1974-03-14
Filing date: 1975-02-12
Publication date: 1980-01-30
Also published as: IE41533L; PH12966A; FI60865B; IL46809A0; NL7502807A; ES435538A1; IL46809A; SE420094B; DE2509471A1; FI750644A; JPS589111B2; DK141701B; AU7905775A; DK141701C; CA1071192A; MY8100331A; SE7502469L; HK8481A; GB1497681A; DK89375A

Abstract

1497681 6 - Methyl - 8 - mercaptomethylergolenes and ergolines SANDOZ Ltd 10 March 1975 [14 March 1974 23 July 1974] 9807/75 Heading C2 [Also in Division A5] Novel compounds of the Formula I wherein # is the group -CH = CH or and R is hydrogen; cyano; a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atom and having 1 to 3 heteroatoms, the first hetero atom being introgen, oxygen-or sulphur-and the second and third heteroatoms, if present, being nitrogen; or a 2- or 4-pyridyl monosubstituted by C 1-4 alkyl or alkoxy or chlorine, fluorine or bromine, with the proviso that when # is -CH=C< and the side chain in the 8 position has the #- configuration then R is other than 2-pyridyl, and acid addition salts thereof, may be prepared by reacting a compound of Formula II wherein X is a radical capable of being displaced by a thio group with a compound of the formula M5R wherein M is hydrogen or alkali metal or by reducing the -SCN group in a compound of the Formula I in which R is CN to -5N. 6 - Methyl - 8α - methanesulphonyloxymethyl ergoline-I is prepared by acrylation of 9,10- dihydro-isolysergol I with methane sulphonyl chloride. The compound I excluded by the proviso is the subject of Divisional Specification 1,497,682.

Description

The present invention relates to new heterocyclic compounds.

In accordance with the invention there are provided new compounds of formula I, R is hydrogen, cyano, a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atom and having 1, 2 or 3 hetero ring atoms, 1° the first hetero atom being nitrogen, oxygen or sulphur, and the second and third hetero atoms, if present, being nitrogen,or 2- or 4-pyridvl mcnosubstituted by lower alkyl oi 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carhon atoms or chlorine, fluorine or bromine.

When R is a heterocyclic radical, this is preferably fully unsaturated. P. has preferably two double bonds when five-membered. R has preferably three double bonds when six-membered. - 2 di S2S R has preferably one or two hetero atoms.

When R has one hetero atom this is conveniently pyridyl or thienyl. When R has two hetero atoms, this is conveniently oxazolyl, thiazolyl, imidazolyl or pyrlmidinyl. When R has three hetero atoms, this is conveniently 1,2,4-triazolyl, or 1,3,5-triazinyl.

The ring carbon atom through which R is attached is conveniently ortho or para to a ring hetero atom, e.g. 2-pyridyl or 4-pyridyl,2-thiazoyl, or l,2,4-triazol-3-yl.

When R is 2- or 4-pyridyl monosubstituted by lower alkyl, the alkyl substituent may, for example, contain especially 1 or 2 carbon atoms and preferably signifies methyl.

When R is 2- or 4-pyridyl moncsubstituted by lower alkoxy, the alkoxy substituent may, for example, contain especially 1 or 2 carbon atoms and preferably signifies methoxy.

When R is 2- or 4-pyridyl rcor.osubsti tuted by halogen, the halogen may denote ami especially chlorine.

The side chain in the 8 position of the ergolene moiety may be in the Jr or β-configuraticn.

Any carbon containing radical not particularly defined herein preferably has up to 10 carbon atoms.

Further, in accordance with the invention a compound of formula X may be obtained by a process comprising a) reacting II wherein y is as defined above, and X is an exchangeable radical capable of being displaced by a thio group with a compound of formula III, MS - R III wherein R is as defined above, and M is hydrogen or an alkali metal, or b) reducing the-SCN group to an -SH group in a compound of formula lb, wherein x y is as defined above, to produce a compound of formula Ia, wherein x y is as defined above.

Process variant a) may be effected in con5 ventional manner for nucleophilic substitution by a thio group, bearing in mind the other substituents present.

The radical X may, for example, signify halogen, such as chlorine or bromine, or a radical O-SO2_S^, wherein is lower alkyl or phenyl or tosyl It is preferred to use the correspond ing mesylate or tosylate as compound of formula II. 533 In general M in the compounds of formula III preferably denotes an alkali metal, especially when R is not basic, i.e. has no basic nitrogen atom.

The reaction is conveniently effected in a solvent. Specially suitable are inert, aprotic, polar solvents, e.g. amides of organic carboxylic acids, such as dimethyl formamide, or alternatively hexamethylphosphoric acid triamide or acetonitrile, optionally admixed with a small portion of water.

The reaction is preferably effected at an elevated temperature, e.g. between about 50 and 100°C.

The reaction is conveniently effected in the absence of oxygen, e.g. in an atmosphere of nitrogen.

It is convenient to use an excess of the compound of formula III, e.g. about 2 to 10 mols of the compound of formula III, for each mol of the compound of formula II.

The reduction of compounds of formula lb to compounds of formula la may be effected in a manner analogous to known methods for the reduction of similar cyanate compounds to mercapto compounds, bearing in mind the other substituents present. However, it is preferably effected with lithium aluminium hydride. In this case an ether, such as tetrahydrofuran, is especially used as solvent. - 6 The reduction with lithium aluminium hydride may be effected at room temperature.

The working up of the reaction mixture obtained in accordance with the above processes and 5 the purification of the so obtained compounds of formula I may be effected iri accordance with known methods.

The compounds of formula I may be present in free form or in the form of acid addition salts thereof. Acid addition salt forms may be produced from the free bases in known manner and vice vers ?. A suitable acid for salt formation is tartaric or fumaric acid.

The starting materials of formula II wherein 15 X is chlorine, 0-mesyl or O-tosyl, are known.

Compounds of formula II wherein X is bromine, may, for example, be obtained by reaction wherein x y is as defined above, 20 with phosphorus oxybromide.

Insofar as the production of the starting materials is not described, these are known or maybe produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.

The compounds of formula I exhibit pharmacological activity. In particular they exhibit central dopaminergic stimulant activity as indicated by, for example, induction of turning in rats lesioned with 6-hydroxvdopamj.ne in the Substantia nigra method of U. Unger.-:tcdt, ^Acta physiol.scand., Suppl. 367, 69-93 (1971) j, and additionally by an antagonism of reserpine induced catalepsy in mice, the reserp.ine being administered j.p. at 5 mg/kg animal body weight about 17 hours before the test substance and the catalepsy being considered antagonised if the mice can walk off a horizontal twine covered pole in a coordinated manner.

The compounds are therefore indicated for use as anti-Parkinson agents. For this use an indicated daily dose is from about 1 to about 100 mg, conveniently administered in divided doses 2 to 5 times a day in unit dosage form containing from about 0.2 to about 50 mg, or in sustained release form. - 0 41533 The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

Such compositions may be made in conventional manner to he in the form of, for example, a solution or a tablet.

Additionally the central dopaminergic stimulant activity of a compound of formula I is synergistically potentiated when administered concomitantly with an inhibitor cf phosphodiesterase activity , as indicated by a superadditive increase in turning movements in the above-indicated test when a compound of formula I is administered after administration of an inhibitor of phosphodiesterase activity such as caffeine.

Therefore combinations of a compound of formula I and an inhibitor of phosphodiesterase activity are further especially indicated for use as anti-Parkinson agents. An indicated daily dose of a - 9 41533 compound of formula I is from about 0.5 to about 50 mg and an indicated ratio of formula I compound to phosphodiesterase inhibitor is from about 10:1 to about 1:5000, preferably 2:1 to 1:1000, e.g. 1:50 to 1:1, e.g. 1:5 to 1:1, 1:25 or 1:10 to 1:50.

Suitable phosphodiesterase inhibitors are especially thosawhich inhibit phosphodiesterase activity in the brain, e.g. methyl xanthines such as caffeine or theophylline, but also may be chosen from derivatives of 4-amino-lH-pyrazolo[3,4-b]pyridine-5-carboxyclic acid esters, such as l-ethyl-4-(isopropylidene-hydrazino)-1Kpyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pvridine-5carboxylic acid ethyl ester and l-ethyl-4-butylamino15 l-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4-(3,4-dimethoxybenzyl)-2-iroidazolidinone and analogues thereof, such as 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, minor tranquilizers, e.g. of the 1,4-benzodiazepine series, such as 7-chloro20 2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide and 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4benzodiazepin-2-one, tricyclic antidepressants, such as 4-[3-(5K-dibenz[b,f]azepin-5-yl)propyl]-1-piperazine ethanol, phenothiazines such as 4-(3-[2-(trifluoro25 methyl)phenothiazin-10-yi]propyl)-1-piperazine ethanol - 10 41533 and 2-chloro-10-(3-dimethylaminopropyl)phenothiazine, 2,6-bis-(diethanolamino)-4,8-dipiperidino-pyrimidino[5,4-d]pyrimidine · and papaverine· The present invention also provides a pharmaceutical package containing as active agents a compound of formula I and an inhibitor of phosphodiesterase activity, the active agents being admixed or kept separate until required for concomitant administration .

It is contemplated that all the usual pharmaceutical compositions may be made to encompass the above-indicated two active agents, e.g. tablets, powders, granulates, capsules, sirups and elixirs for oral administration, as well as solutions, dispersions and emulsions for parenteral administration. It is also contemplated that these compositions may be made in conventional manner using conventional pharmaceutical carriers and diluents.

Accordingly the present invention also provides a process for the production of a pharmaceutical composition including the step of bringing a compound of formula I as one active agent into association with an inhibitor of phosphodiesterase activity as another active agent, the active agents being sufficiently pure for pharmaceutical acceptability. - 11 41533 It will be appreciated that combinations of a compound of formula I and a phosphodiesterase inhibitor may be conveniently administered in unit dosage form 2 to 5 times a day or in sustained release form. Such combinations may contain for example from about 0.1 to about 25 mg of a compound of formula I and the appropriate amount of phosphodiesterase inhibitor to give the indicated ratio range mentioned above.

The compounds of formula I wherein τ' 1° is -CH=C^ exhibit especially interesting central dopaminergic stimulating properties. R preferably signifies the 2-pyridyl or cyano group.

In one group cf compounds R is hydrogen, cyano or a heterocyclic as defined above. In another group of compounds R is cyano, 4-pyridyl or 2-thiazoyl.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade. - 1? 4153 3 EXAMPLE 1; 6-methyl-8p-thiocyanoniethvlerqolene [process variant a)1 4.5 g (13.5 millimols) of 6-methyl-8pmethanesulphonyloxymethylergolene are heated together with 4.5 g (approx. 46 millimols) of potassium thiocyanate in a mixture of 45 cc of hexamethylphosphoric acid triamide and 3 cc of water to 80° under a stream of nitrogen for 20 hours. Working Up is effected by pouring the reaction mixture into 450 cc of a 0.5 normal soda solution and filtering. The dry residue is dissolved whilst hot in a mixture of methylene chloride/ether and treated with active charcoal. The filtrate is concentrated and the title compound is obtained by crystallization from ethanol in the form of pink-tinged prisms having a M.P. of 186-188°.

Hydrogen fumarate; from methylene chloride/ethanol, M.P. 182-184°; [ct]2°= + 55° (c = 0.5, dimethyl formamide).

EXAMPLE 2; 6-methyl-8p-:nercaptcniethylerqolene 4.5 g (approx. 60 millimols) of sodium hydrogen sulphide ‘ H^O are used in a manner analogous to that described in Example 1. After working up - 13 4 3.533 rapidly, the crystalline title compound is obtained from methylene chloride/isopropanol; decomposition 2Π point approx. 200°, [al^ = +86° (c = 0.5, dimethyl formamide).

The following compounds of formula I are obtained in a manner analogous to that described in Example 1, using the corresponding starting materials of formulae II and III: EXAMPLE 3: 6-methyl-8p-(2-pyrid/l-thiomethyl)10 ergolene M.P. 200-201° (decomp.) Tartrate: M.P. 195-196°; [a]2°= + 26° (c = 1, dimethyl sulphoxide) (using 2-mercaptopyridine as compound cf 15 formula III).

EXAMPLE 4: 6-methyl-8n-(2-oyriayl-thiomethyl)ergoline- I M.P. 191-195°; [«] -113° (c = 1, pyridine).

EXAMPLE 5: 6-methyl-8β-(4-pyridyl-thiomethyl)20 ergolene M.P. 191-194°; [a] ^=+52.5° (c = 1, dimethyl sulphoxide) - 1), 41533 EXAMPLE 6: 6-methyl-8il- (2-thiazolyl-thiomethyl) ergolene M.P. 192-195° (deeomp.); [a] Q= + 58.2’ (c = 1, dimethyl , sulphoxide).

EXAMPLE 7: 6-methvl-8P-thiocvanomethylergoline-l M.P. 189-193°; [a] £= "58° (o = 1, dimethyl sulphoxide).

EXAMPLE 8: S-methyl-Sa-thioeyanomcthylergoline-I M.P. 185-188°.

EXAMPLE 9: 6-methyl-8p- (2-thienyl-thiomethyJ.) ergolene EXAMPLE 10: 6-tn-:thyl-8p-(2-oxazolvl-thiomethyl) ergolene EXAMPLE 11: 6-methyl-8P-(2-imidazolyl-thiomethyl)ergolene EXAMPLE 12: 6-methyl-8P-(2-ovrimidinyl-thiomethyl)ergolene EXAMPLE 13: 6-methyl-8p-[3-(1,2,4-triazolyl)thiomethylI ergolene EXAMPLE 14; 6-mothyJ.-8p-[2-(1,3,S-triazinyl)thiomethylI · ergolene EXAMPLE 15: EXAMPLE 16: EXAMPLE 17: -methyl-0(1-( 2-(4-methylpyridvl) thiomethyl] ergolene 6-methyl-8β-f 2-(4-methoxypyridyl)thiomethyl]ergolene 6-methvl-8p-[4-(2-chloropyridvl)thiomethyl]ergolene EXAMPLE 18: 6-methyl-8 β-mercaptomethylergolene tprocess b)] 11.8 g (40 millimols) of 6-methyl-8pthiocyanomethyl-9-ergolene are added portionwise at room temperature to a suspension stirred under nitrogen of 15.1 g (0.4 millimols) of lithium aluminium hydride in 800 cc of absolute tetrahydrofuran, and stirring is effected 'for one hour at this temperature. Working up is effected by carefully decomposing with water while cooling well and stirring into 500 cc of a 5 % aqueous tartaric acid solution. The reaction mixture is subsequently rendered alkaline with a potash solution and the aqueous phase is rapidly extracted w’ith methylene chloride containing 10 % of methanol. After drying over sodium sulphate and removing the solvent by distillation, the title compound is obtained. - 16 41533 Decomp. approx. 200°, [a] = +86° (c = 0.5, dimethyl formamide).

EXAMPLE 19; 6-methyl-8rc -methane sulphonyloxymethvlergoline-I (starting material for Example 8) A solution of 1.95 cc (25 millimols) of methanesulphonyl chloride in 5 cc of absolute acetonitrile is added dropwise at +10° to a stirred suspension of 2.56 g (10 millimols) of 9,10-dihydro-isolysergol I [Helv. 32, 1947 (1949)] in 15 cc of absolute pyridine and 25 cc of absolute acetonitrile, and stirring is effected at room temperature for one hour. Working up is effected by cooling to 0°, diluting with methanol until a clear solution is obtained, rendering alkaline and distributing between 2N ammonia/methylenc chloride. After drying and concentrating the combined organic phases by evaporation, 6-methyl-8a-methanesulphonyloxymethyl-ergoline-l crystallizes from ethanol.

M.P. 139-141°, [cc]2°= -54.6° (c = 1, dimethyl formamide). - 17 33 EXAMPLE 20: Production of,a solid pharmaceutical preparation a) 1 mg of a compound of formula I is mixed with lactose and optionally with 25 mg of a phosphodiesterase inhibitor. The mixture is granulated with water, 0.5 % sodium alginate or 1 % gelatin solution. The dry granulate is pressed into tablets in the presence of some tartaric acid, approx. 5 % of talc, about 5 % of maize starch and approx. 0.1 % of magnesium stearate.

In this manner it is possible to obtain, for example, tablets having the following composition: Compound of formula I 1 mg 1 mg Phosphodiesterase inhibitor - mg 25 mg Lactose 85.9 mg 60.9 mg Tartaric acid 3 mg 3 mg Maize starch 5 mg 5 mg Talc 5 mg 5 mg Magnesium stearate 0.1 mg 0.1 mg Tablet of 100.0 mg 100.0 mg b) Capsules The capsules may contain the active agent or agents alone. The following capsules may, for example, be obtained in accordance with known methods: - 18 41533 100-4146 Compound of formula I 5 mg Phosphodiesterase inhibitor 50 mg Diluent (e.g. kaolin) mg - mg 295 mg Capsule content of mg 300 mg EXAMPLE 21: Production of a liquid pharmaceutical preparation A liquid preparation, e.g. a suspension suitable for oral administration, may contain a compound of formula I and a phosphodiesterase inhibitor together with an inert, pharmaceutically tolerable liquid solvent or carrier material. It may further contain other additive;·, e.g. sweetening and colouring agents, flavourings and stabilizing agents.

The following oral suspension may, for example, be obtained using known methods: Compound of formula I 1.0 mg 1 mg Phosphodiesterase inhibitor - 10 Vanilla essence q.s. q.s. Colouring agent q.s. q.s. Buffer q.s. q.s. Water q.s. up q.s. up to 5 cc to 5 cc The preferred compounds of formula I for - 19 41533 100-4146 use in Examples 20 and 21 arc u-mothyl-Bp-thiocyanomethylergolene and 6-methyl-8p-(2-pyridyl-thiomethyl)ergolene.

The preferred phosphodiesterase inhibitors 5 for use in Examples 20 and. 21 are theophylline and caffeine.

Claims

1. I. A process for the production of a compound of formula I, wherein x y is the group -CK=C* or -Ct^-CH , and R is hydrogen, cyano, a 5- or 6-membered 5 unsaturated heterocyclic radical attached through a ring carbon atom and having 1, 2 or 3 hetero ring atoms, the first hetero atom being nitrogen, oxygen or sulphur, and the second and 10 third hetero atoms, if present, being nitrogen,or 2- or 4-pyridyl monosubstituted by lower alkyl of 1 to 4 carbon, atoms s lower alkoxy of 1 to 4 carbon atoms or chlorine, f luorine, or / roinine. - 21 41533 which comprises a) reacting a compound of formula II, wherein x y X is as defined above, and is an exchangeable radical capable of being displaced by a thio group with a compound of formula III, MS - R III wherein R is as defined above, and M is hydrogen or an alkali metal, or b) reducing the-9CN group to an -SH group in a compound of formula lb, wherein x y is as defined above, to produce a compound of formula Ia, wherein x y is as defined above.

2. «, A process for the production of a 5 compound of formula I, as stated in Claim 1, substantially as hereinbefore described with reference to any one of the Examples.

3. A compound of formula I, whenever produced by a process according to Claim 1 or 2. 10

4. A compound of formula I, as defined in Claim 1.

5. A compound of Claim 4, wherein x 'y’is - 23 41533 / -CH =

6. A compound of Claim 4 wherein R is H.

7. A compound of Claim 4 wherein R is CN

8. A compound of Claim 4 wherein R is a 5 5- or 6-membered heterocyclic radical.

9. A compound of Claim 4 wherein R is 2- or 4-pyridyl.

10. A compound of Claim 4 wherein R is cyano, 4-pyridyl or 2-thiazoyl. 10

11. A compound of Claim 4 wherein R is 1,2,4-triazol-3-yl.

12. The compound of Claim ί which is 6-methyl-8 0-thiocyanomethylergolene.

13. The compound of Claim 1- which is 15 6-methyl-80-mercaptomethylergolene.

14. The compound of Claim t which is 6-methy1-80-(2-pyridyl-thiomethyl)-ergoline - I.

15. The compound of Claim-t which is 6-methy1-8(3-(2-pyridyl-thiomethyl)-ergolene. 20

16. The compound of Claim 4 which is 6-methyl-80-(4-pyridyl-thiomethyl)-ergolene.

17. The compound of Claim t which is 6-methyl-80-(2-thiazolvl-thiomethyl)-ergolene.

18. The compound of Claim 4 which is 25 6-methyl-8B-thiocyanomethylergoline-I. -2k415SS

19. The compound of Claim 4- which is ' 6-methyl-8ra-thiocyanomethylergoline-I.

20. The compound of Claim 4· which is 6-methyl-8ii- (2-thienyl—thiomethyl) ergolene. 5

21. , The compound of Claim 4- which is 6-methyl-8p-(2-oxazolyl-thiomethyl) ergolene.

22. » The compound of Claim which is 6-methyl-80-(2-imidazolyl-thiomethyl)-ergolene.

23. The compound of Claim t which is 10 6-methyl-8ct-(2-pyrimidinyl-thiomethyl)-ergolene.

24. The compound of Claim 4 which is 6-methyl-Sp-[3-(1,2,4-triazolyl)thiomethyl]-ergolene.

25. The compound of Claim 4 which is 5- methy 1-88-/2--(1,3,5-triazinyl)thiomethyl]-ergolene. 15

26. The compound of Claim 4 which is 6- methyl-8p-[2-(4-methylpyridyl)thiomethyl]-ergolene.

27. The compound of Claim 4- which is 6-methyl—88-[2-(4-methoxypyridyl)thiomethyl]-ergolene

28. The compound of Claim 4 which is 20 5-methyl-88- [4- (2-chlorcpyridyl) thioitiethyl]ergolene.

29. A compound according to any one of Claims 3 to 28 in free base form.

30. A compound according to any one of Claims 3 to 28 in acid addition salt form. - 2? 41533

31. A pharmaceutical composition comprising a compound according to any one of Claims 3 to 28 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical 5 carrier or diluent.

32. A pharmaceutical composition according to Claim 31, incorporating additionally a phosphodiesterase inhibitor.