NO750748L - - Google Patents

Description

Procedure for manufacturing new ones

heterocyclic compounds.

The present invention relates to a method for the production of new heterocyclic compounds of formula I

in which i£~*~ Y means the grouping -CH=C^ or -Cf^-^H and R stands for hydrogen, the cyano group, for a 5- or 6-membered unsaturated heterocyclic residue bonded over a carbon atom containing a maximum of 3 heteroatoms of the series nitrogen, oxygen or sulfur and of which no more than 1 heteroatom constitutes oxygen or sulphur,^or stands for a lower alkyl, lower alkoxy or halogen monosubstituted 2- or 4-pyridyl residue and acid addition salts thereof.

If R constitutes the first defined heterocyclic residue, this means if it contains a heteroatom, e.g. a thienyl or pyridyl residue, if it contains two heteroatoms, e.g. an oxazolyl, thiazolyl, imidazolyl or pyrimidinyl residue, and if it contains three heteroatoms e.g. 1,2,4,-triazol-3-yl or 1,3,5-triazin-2-yl residue.

If the heterocyclic radical contains only one heteroatom, a pyridyl radical is preferred, especially the 2-pyridyl and 4-pyridyl radicals.

If R stands for with lower alkyl monosubstituted 2- or 4-pyridyl, the alkyl substituent contains e.g. 1 to 4, especially 1 or 2 carbon atoms and preferably stands for methyl.

If R stands for lower alkoxy monosubstituted 2- or 4-pyridyl, the alkoxy substituent contains e.g. 1 to 4,

especially 1 or 2 carbon atoms and preferably stands for methoxy.

If R stands for one of the heterocyclic residues defined above, this residue preferably contains 1 or 2 heteroatoms. If the heterocyclic residue R is 5-membered, it preferably contains 2 double bonds, and if it is 6-membered, it preferably contains 3 double bonds.

If R stands for with halogen monosubstituted 2- or 4-pyridyl, the halogen can mean fluorine, bromine and especially chlorine.

The peculiarity of the method according to the invention for the production of the compounds of formula I and their acid addition salts is that

a) a compound of formula II

where x~<*>"~y has the above meaning and X stands for an exchangeable

residue, is reacted with a compound of formula III

in which R has the above meaning and M stands for hydrogen or an alkali metal, or b) for the preparation of a compound of formula Ia in

wherein x~*"y has the above meaning, a compound is reduced

with formula Ib

where x~*~~ y has the above meaning

and the thus obtained compounds of formula I are recovered as bases or in the form of acid addition salts.

The reaction between the compounds of formula II and the compounds of formula III can take place analogously to methods known for the preparation of similar compounds.

The remainder X stands for e.g. for halogen, such as chlorine or bromine, or for

a residue O-SC^-R-^ in which R^ means lower alkyl or optionally substituted phenyl. The corresponding mesylate or tosylate is preferably used as a compound with formula II.

Usually M in the compounds of formula II preferably stands for an alkali metal, especially when R is not basic.

The reaction is suitably carried out in a solvent. Particularly suitable under the reaction conditions are inert, aprotic, polar solvents, e.g. amides of organic carboxylic acids. such as dimethylformamide but also hexamethylphosphoric acid trisamide or acetonitrile, possibly in mixture with a small amount of water.

One prefers to work at an elevated temperature, e.g. between approximately 50 and 100°C.

The reaction is suitably carried out under the exclusion of oxygen, e.g. under nitrogen atmosphere.

An excess of the compound of formula III is advantageously used, e.g. 2 to 10 mol of compound of formula III per mol of compound of formula II.

The reduction of the compounds of formula Ib to the compounds of formula Ia can take place analogously to the methods known for the reduction of similar rhodanide compounds to mercapto compounds

(see Methoden derOrganischen Chemie, volume IX, pages 16, 17; 4th edition (1955)). However, it is preferably carried out using lithium aluminum hydride. Ethers such as tetrahydrofuran are then used as solvents.

The reduction with lithium aluminum hydride can be carried out at room temperature.

The preparation of the reaction mixtures obtained in accordance with the above methods and the purification of the thus obtained compounds of formula I can take place according to methods known per se.

The compounds of formula I can be present in free form or in the form of their addition salts with acids. From the free bases, acid addition salts can be prepared in a known manner and vice versa.

The starting compounds of formula II with X=chloro/O-mesyl or O-tosyl residue are known.

The compounds of formula II with X=bromine can be obtained, e.g. by reacting a compound of formula IV

wherein x~<*>""y has the above meaning, with phosphorus oxybromide.

To the extent that the production of the output connections does not

is described, these are known or can be produced according to per se known methods or analogously to those described here or analogously to methods known per se.

Compounds of formula I, i.e. in the compounds with formula I in free form or in the form of addition salts with physiologically tolerable acids, exhibit interesting pharmacodynamic properties in animal experiments. They can be used as medicine.

Thus, these compounds have central dopaminergic stimulating properties and in animal experiments antagonize the catalepsy caused by reserpine. These pharmacodynamic properties make the use of the compound of formula I possible in the treatment of parkinson's disease, of conditions secondary to cerebral ischaemia, such as e.g. in cases of stroke as well as extrapyramidal side effects of e.g. neuroleptics.

The central dopaminergic stimulating properties can be ascertained e.g. in rats, in which a unilateral degeneration of the nigro-neostriatal dopamine pathway was produced by means of a 6-hydroxy-dopamine injection into the substantia nigra (method according to U. Ungerstedt, Acta physiol.scand., Suppl. 367 69- 93 (1971)). The thus "denervated" dopamine receptors show, on stimulation with dopaminergic substances, an increased sensitivity which can be recognized by the rats performing turning movements in the direction of the non "denervated" side. These appear after administration of the compounds of formula I in doses of approximately 0.3. to about 3 mg/kg s.c.

respectively about 5 mg/kg to about 10 mg/kg p.o.

The central-dopaminergic stimulating properties of the compounds

with formula I is enhanced by phosphodiesterase inhibitors, especially by compounds that inhibit phosphodiesterase action in the brain.

Suitable phosphodiesterase inhibitors are especially methylxanthines such as caffeine or theophylline, but also derivatives of 4-amino-lH-pyrazolo(3,4-b)-pyridine-5-carboxylic acid esters such as l-ethyl-4-(isopropylidenehydrazion)-lH-pyrazolo (3,4-b)pyridine-5-carboxylic acid ethyl ester, l-ethyl-4-hydrazino-1H-pyrazolo(3,4-b)pyridine-5-carboxylic acid ethyl ester and l-ethyl-4-butylamino-l -ethyl-1H-pyrazolo(3,4-b)pyridine-5-carboxylic acid ethyl ester, 4-(3,4-dimethoxybenzyl)-2-imidazolidones and analogous compounds thereof such as 4-(3-butoxy-4-methoxybenzyl)-2 -imidazolidinone, weak tranquilizers (Minor Tranquillizérs), e.g. The 1,4-benzodiazepine series such as 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide and 7-chloro-1,3-dihydro-1-methyl-5-phenyl- 2H-1,4-benzodiazepine-2-one, tricyclic antidepressants such as 4-(3-(5H-dibenz(b,f)azepin-5-yl)propyl)-1-piperazine-ethanol, phenothiazines such as 4-p_ (2-(trifluoromethyl)phenothiazine-10-ylJpropylj-1-piperazine- ethanol and 2-chloro-10-(3-dimethylaminopropyl)-phenothiazine, 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimidino(5,4 -d) pyrimidine,

and papaverine. As an example of advantageous pharmaceutical preparations, mention is made of preparations containing a compound of formula I and a phosphodiesterase inhibitor, as these in the form of the aforementioned preparations or by combined but separate administration can be used for the treatment of Parkinson's disease, of conditions secondary to cerebral ischaemia and of extrapyramidal side effects of e.g. neuroleptics. This potentiating effect can e.g. is detected by means of the above-mentioned experimental device, if the rats for the supply of about 1 mg/kg to about 5 mg/kg p.o. of a compound that can be prepared by the method according to the invention with a phosphodiesterase inhibitor is pretreated with e.g. about 5 to about 25 mg/kg i.p. of a methylxanthine such as caffeine, and manifests itself in an overaditi<y>increase in the turning movements.

The antagonistic effect of the compounds of formula I in relation to the catalepsy induced by reserpine (5 mg/kg i.p., 17 hours fbr/supply of a substance that can be prepared by the method according to the invention) in mice is shown at doses of approximately 0, 3 to about 3 mg/kg s.c.

For the above applications, the dose used naturally varies according to the substance used, the method of administration and the desired treatment. When using a compound of formula I as the sole active ingredient, satisfactory results are usually obtained with daily doses of about 0.02 to about 2 mg per kg body weight. If necessary, the supply can take place in several, e.g. in 2, 3, 4 or 5 partial doses daily or also as a retard form. For larger mammals, the daily dose is in the range from about 1 to about 100 mg of the substance. Suitable dosage forms for e.g. oral applications usually contain about 0.20 to 100 mg of active substance.

When using preparations containing a compound of formula I and a phosphodiesterase inhibitor, or when using the individual components in a combination therapy, the dosage also depends on the nature of the substance used, the method of administration and the individual needs of the patient. When treated with compounds of formula I in combination with a phosphodiesterase inhibitor, satisfactory results are usually obtained using daily doses of about 0.01 mg/kg to about 1 mg/kg of a compound of formula I combined with about 0. 5 to about 10 mg/kg of a phosphodiesterase inhibitor. For larger mammals, the daily dose ranges from about 0.5 to about 50 mg of a compound of formula I in combination with about. 25 to about 500 mg of a phosphodiesterase inhibitor. Here, too, the daily dose can be administered in several, e.g. 2, 3, 4 or 5 partial doses. The single doses then contain e.g. about 0.1 to about 50 mg

of a compound of formula I in combination with about 5 to 500 mg of a phosphodiesterase inhibitor. The quantity ratio between compound of formula I and phosphodiesterase inhibitor is usually between 1:10 and 1:50.

The compounds of formula I in which x~~~y stands for -CH=C^, show particularly interesting central dopaminergic stimulating properties.

R preferably means 2-pyridyl or the cyano group.

The compounds of formula I can be administered in the form of pharmaceutical preparations. E.g. the pharmaceutical preparations can be used in the form of tablets, powders, granules, capsules, syrups and elixirs for oral administration, as well as in the form of solutions, dispersions and emulsions for parenteral administration.

The production of these pharmaceutical preparations can take place in a manner known per se using common excipients.

A special form of production of the medical preparations

are, as mentioned, those containing a compound of formula I and a phosphodiesterase inhibitor. For. preparation of the latter preparations, a compound of formula I and a phosphodiesterase inhibitor are mixed. This mixture can then be brought into a dosage form suitable for therapeutic purposes using methods known per se.

The following examples illustrate the invention in more detail.

All temperature indications are in degrees Celsius.

Example 1: 6-methyl-8B-rhodanomethylerqoleneD'

4.5 g (13.5 m mol) of 6-methyl-1-8|3-methanesulfonyloxymethylergolene is heated with 4.5 g of fea. 46 m mol) of potassium rhodanide in a mixture of 45 ml of hexamethylphosphoric acid trisamide and 3 ml of water under nitrogen strbm at 80°C for 20 hours. For processing, the reaction mixture is poured into 450 ml of 0.5 N sodium hydroxide solution and filtered.

The dry residue is dissolved hot in methylene chloride/ether mixtures and treated with activated charcoal. The filtrate is evaporated and the compound mentioned in the title is obtained by crystallization from ethanol in pale pink prisms with a melting point of 186 - 188°C.

Hydrogen fumarate: from methylene chloride/ethanol,

melting point 182 - 184°C; (a)^° 55°

(c = 0.5, dimethylformamide.)

Example 2: 6-methyl 1 - 8( 3-mercaptomety 1 erqolene.

Analogous to example 1, 4.5 g (approx. 60 m mol) of sodium hydrogen sulphide are used. H20. After rapid work-up to avoid disulfide formation, the crystalline compound mentioned in the title is obtained from methylene chloride/isopropanol. Cleavage point approx. 200°C, (ct)^° = + 86° (c = 0.5, dimethylformamide).

Analogously to example I, the following compounds of formula I are obtained using corresponding starting compounds with formulas II and III.

Example 3: 6-methyl-83-(2-pyridyl-thiomethyl)-ergolene.

Melting point 200 - 201°C (decomposition).

Tartrate: Melting point 195 - 196°C; (cc)£° = 26° (c = 1,dimethylsulfoxide).

(using 2-mercaptopyridine as compound of formula III).

Example 4: 6-methyl-83-(2-pyridyl-thiomethyl\-erqoline).

Melting point 191 - ;195°C; (cc)£° = -113° (c = 1, pyridine)

Example 5: 6-methyl-8(3-(4-pyridyl-thiomethyl)-erqolene.

Melting point 191 - 194°C; (a)^° = + 52.5° (c = 1, dimethyl sulfoxide)

Example 6; 6-methyl-83-(2-thiazolyl-thiomethyl)-erqoleR.

Melting point 192 - 195°C (decomposition); (a)^° = + 58.2° (c = 1, dimethyl sulfoxide)

Example 7: 6-methyl-8(3-rhodanomethylerqoline-I.

Melting point 189 - 193°C; (a)^° = -58° (c = 1, dimethyl sulfoxide)

Example 8: 6-methyl-8g-rhodanomethyl-erqolin-I.

Melting point 185 - 188°C.

Example 9: 6-methyl-83-(2-thienyl-thiomethyl)erqolene.

Example IQ; 6- methyl- 83-(2- oxazolyl-thiomethyl) erqolene.

Example 11: 6-methyl-83-(2-imidazolyl-thiomethyl)erqolene.

Example 12: 6-methyl-83-(2-pyrimidinylthiomethyl)erqolene.

Example 13: 6-methy. 1- 83- ( 3 - ( 1, 2, 4- triazolyl) thiomethyl) erqolene.

Example 14: 6-methyl-8(3-(2-(1,3,5-triazinyl)thiomethyl)erqolene.

Example 15: 6-methyl-83-(2-(4-methylpyridyl)thiomethyl)erqolene.

Example 16: 6-methyl-83-(2-(4-methoxypyridyl)thiomethyl)erqolene.

Example 17: 6-methyl-8(3-(4-(2-chloropyridyl)thiomethyl)erqolene.

Example 18: 6-methyl-8(3-mercaptomethyl-1-erqol) (method b).

Into a suspension of 15.1 g (0.4 m mol) of lithium aluminum hydride in 800 ml of absolute tetrahydrofuran under nitrogen, 11.8 g (40 m mol) of 6-methyl-8(3-rhodanomethyl-9-ergolene) are introduced in portions at room temperature and it is stirred for a further 1 hour at this temperature. For work-up, it is carefully split with water under good cooling and incorporated into 500 ml of 5% aqueous tartaric acid solution. It is then made alkaline with pot ash solution and the aqueous phase is quickly extracted with ethylene chloride containing 10% methanol. After filtration over sodium sulphate and distillation of the solvent, the compound mentioned in the title remains: cleavage approx. 200°C, (a)^° = + 86° (c = 0.5, dimethylformamide)

Example 19: 6-methyl-8g-methanesulfonyloxynethyl-erqolin-I.

(output connection for example 8).

A stirred suspension of 2.56 g (10 m mol) of 9,10-dihydro-isolysergol I (heiv. 32, 1947 (1949)) in 15 ml of abs. pyridine and 25 ml abs. Acetonitrile is added at +10°C dropwise with a solution of 1.95 ml (25 m mol) methanesulfonyl chloride in 5 ml abs. acetonitrile and stirred further for 1 hour at room temperature. For processing, cool to 0°C, dilute with methanol until a clear solution has formed and, after alkaline adjustment, extract between 2N-ammonia/methylene chloride. After distillation and evaporation of the combined organic phases, 6-methyl-8a-methanesulfonyl-oxymethyl-ergoline-I crystallizes from ethanol.

Melting point 139 - 141°C (ct)^° = -54.6° (c = 1, dimethylformamide).

Example 20: Preparation of a solid pharmaceutical preparation.

a) lvtmg of a compound of formula I is mixed with lactose and optionally with 25 mg of a phosphodiesterase inhibitor. The mixture

granulate with water, 0.5% sodium alginate or 1% gelatin solution.

The dry granules are pressed in the presence of some tartaric acid, approx

5% talc, about 5% corn starch and about 0.1% magnesium stearate for tablets.

In this way, e.g. tablets with the following composition:

b) Capsules

The capsules can contain only the active ingredient or the active substances.

One obtains e.g. using known methods the following capsules.

Example 21: Preparation of a liquid pharmaceutical preparation.

A liquid preparation, e.g. a suspension suitable for oral administration, contains a compound of formula I or a compound of formula I and a phosphodiesterase inhibitor together with an inert, pharmaceutically acceptable liquid diluent or carrier. Thus, the preparation can also further contain additives, e.g. sweeteners, flavoring ingredients, coloring agents, stabilizers, etc.

When using known methods, e.g. the following oral suspensions:

(q.s.) = suitable quantity

Preferred compounds of formula I for use in the examples

20 and 21 are 6H-methyl-8|3-rhodanomethylergolene and 6-methyl-8-(2-pyridyl-thiomethyl)-ergolene.

Preferred phosphodiesterase inhibitors for use in

examples 20 and 21 are theophylline and caffeine.

Claims (3)

1. Process for the preparation of compounds of formula I where x y means the grouping's -CH=C^ or -CH9 -CH and R stands for hydrogen, the cyano group, for a 5- to 6-membered unsaturated heterocyclic residue bonded over a carbon atom that contains a maximum of 3 heteroatoms of the series nitrogen, oxygen or sulfur and of which at least 1 heteroatom is oxygen or sulphur, or represents a monosubstituted 2- or 4-pyridyl residue with lower alkyl, lower alkoxy or halogen and acid addition salts thereof, characterized by ata) a compound of formula II wherein x~"~y has the above-mentioned meaning and X stands for an exchangeable residue, is reacted with a compound of formula III MS-R III in which R has the above meaning and M stands for hydrogen or an alkali metal, orb) for the preparation of a compound of formula Ia wherein x~^~y has the above-mentioned meaning, a compound of formula Ib is reduced where x y has the above meaning and the thus obtained compounds of formula I are recovered in the form of bases or in the form of acid addition salts. 2. Procedure as stated in claim 1, characterized in that 6-methyl-8(3-rhodanomethyl-ergolene is produced. 3. Procedure as stated in claim.l, characterized in that 6-methyl-8(3-(2-pyridyl-thiomethyl)-ergolene is produced.