KR790000927B1 - Process for preparing new heterocyclic compound - Google Patents

Abstract

Heterocyclic compds(I; XY = -CH=C< or -CH2-CH<, R = pentagonal or hexagonal unsatd. heterocyclic group which form the ring with C and 1-3 hetro atom, H, cyano; X = displaceable group with thio group; M = H or alkalimetal) was prepd. by treating II with III, or by reduction of the -SH group to a -SCN group.

Description

Method for preparing heterocyclic compound

The present invention relates to a method for preparing a new heterocyclic compound of formula (I) having a dopaminergic central stimulating action.

here,

R is a 5-6 angular unsaturated heterocyclic group which is ringed together with hydrogen, cyano, carbon atom and 1, 2 or 3 heteroatoms, the first heteroatom being nitrogen, oxygen or sulfur and the second or third complex And, if present, a 2- or 4-pyridyl group monosubstituted with nitrogen or lower alkyl, lower alkoxy or halogen.

When R is a heterocyclic group, it is preferably sufficiently unsaturated.

When R is a pentagonal ring, it is preferable to have two double bonds.

When R is a hexagonal ring, it is preferable to have three double bonds.

It is preferable that R has 1-2 heteroatoms.

When R has one heteroatom, it is pyridyl or chienyl.

When R has two heteroatoms it is oxazolyl, thiazolyl, imidazolyl or pyrimidinyl.

When R has three heteroatoms it is 1, 2, 4-triazolyl, or 1, 3, 5-triazinyl.

The carbon atom to which R is bonded to form a ring is ortho or para relative to cyclic heteroatoms such as 2-pyridyl or 4-pyridyl, 2-thiazolyl or 1, 2, 4-triazol-3-yl.

When R is 2- or 4-pyridyl monosubstituted by lower alkyl, the alkyl substituent contains, for example, 1-4, in particular 1-2 carbon atoms, preferably methyl.

When R is a 2- or 4-pyridyl monosubstituted by lower alkoxy, the aryloxy substituent contains, for example, 1-4, in particular 1-2 carbon atoms, preferably methoxy.

When R is 2- or 4-pyridyl substituted by halogen, halogen is fluorine, cancelled, in particular chlorine.

The side chain at the 8 position of ergolene is at the α- or β-position. The carbon-containing group not particularly defined herein preferably has up to 10 carbon atoms.

Referring to the production method of the present invention in detail.

A) reacting a compound of formula (II) with a compound of formula (III)

B) A method of preparing the compound of formula (Ib), wherein the compound of formula (Ia) is obtained by reducing the -SCH group in the compound of formula (Ib) to the group -SH.

및 R은 전술한 바와 같으며 X는 치오기로 치환될 수 있는기,

And R is as described above and X is a group which may be substituted with

M is hydrogen or an alkali metal.

A) The method is carried out according to the nucleophilic substitution reaction by cheo when other substituents are present.

X is, for example, halogen such as chlorine or cancellation, or O-SO ₂ -R _{1 where} R ₁ is lower alkyl, phenyl or substituted phenyl.

It is preferable to use the corresponding mesylate or tosylate as the structural formula (II) compound.

In general, M in the compound of formula III is preferably an alkali metal, especially when it is not this basic nitrogen atom.

The reaction is usually carried out in a solvent. In particular, it is suitable to use an inert, neutral, polar solvent, that is, an amide of an organic carboxylic acid such as dimethylformamide, or hexamethylphosphoric acid triamide or acetonitrile, optionally mixed with a small amount of water.

The reaction is preferably carried out at a temperature of about 50 ° to 100 ° C.

The reaction is usually carried out in the absence of oxygen, ie in a stream of nitrogen.

It is convenient to use an excess of about 2-10 moles of the structural formula (III) compound relative to each mole of the structural formula (II) compound.

Reduction of the compound Ib to the compound Ia is carried out in the same way as the reduction of the similar cyanate compound to the mercapto compound in the presence of other substituents. However, preference is given to using lithium aluminum hydride. In the present invention, in particular, ether such as tetrahydrofuran is used as the solvent. It is effective to carry out the reaction for reducing lithium aluminum hydride at room temperature.

The compound of formula (I) thus obtained can be purified for a known method.

The compounds of formula (I) prepared according to the process of the present invention are in free form or in their acid addition salts. Acid addition salt forms are prepared from free bases according to known methods. Suitable acids for salt preparation are tartaric acid and fumaric acid.

The starting material of formula II wherein X is chlorine, 0-mesyl or 0-tosyl is a known compound.

Compounds of formula II wherein X is cancelled are prepared by reacting compounds of formula IV with phosphorus oxybromide.

The compounds of formula (I) prepared according to the method of the present invention have a pharmacological action. In particular, when injured substantia nigra rats were injected with 6-hydroxy dopamine, 17 mg prior to administration of the test substance, 5 mg of reserpin per kg of the mice were intraperitoneally administered. If mice were able to walk and fall while covering the same two sticks horizontally, they could be found to have dopaminergic central stimulation by antagonism of reserpin-induced sclerosis, such as measuring that stiffness was significantly antagonized.

Therefore, the compounds of formula (I) are used as anti-Parkinson's agents. When used for this purpose, the daily dosage is about 1-100 mg and is administered 2-5 times a day in the form of a single formulation containing about 0.2-50 mg.

Formula (I) compounds are administered in the form of pharmaceutically acceptable acid salts. Such acid salt form has the same mechanism of action as the free base form and can be easily prepared by known methods.

The compounds of formula (I) may be administered in a pharmaceutical or tablet form by mixing with a pharmaceutical carrier or diluent.

In addition, the dopaminergic central stimulation of the structural formula (I) is synergistically increased after administration of the compound of the structural formula (I) after administration of an inhibitor of caffeine-like phosphodiesterase action.

Therefore, it is particularly effective as an anti-Parkinson's agent when the compound of formula (I) and an inhibitor of phosphodiesterase action are administered together.

The daily dose of the compound of formula (I) is about 0.5-50 mg and the ratio of the compound of formula (I) to the phosphodiesterase inhibitor is about 10: 1 to 1: 5,000, preferably 2: 1 to 1: 1,000 That is, 1:50 to 1: 1, 1: 5 to 1: 1, 1:25 or 1:10 to 1:50.

Suitable phosphodiesterase inhibitors are substances that inhibit phosphodiesterase action, particularly in the brain, such as methylxanthine, such as caffeine or theophylline, and also 1-ethyl-4- (isopuropylidene-hydrazino) -1H. -Pyrazolo [3, 4-b] pyridine-5-carboxylic acid ethyl ester, 1-ethyl-4-hydrazino-1H-pyrazolo [3, 4-b] pyridine-5-carboxylic acid ethyl ester and 1-ethyl 4-amino-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid ester such as 4-butylamino-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid ethyl ester Derivatives of 4- (3,4-dimethoxybenzyl) -2-imidazolidinone and its analogs, such as 4- (3-butoxy-4-methoxybenzyl) -2-imidazolidinone, 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 1, 4-benzodiazepine-based minor Tranquila Low, tricyclic antidepressants such as 4- [3- (5H-dibenzo [b, f] azepin-5-yl) furophyll] -1-piperazine ethanol, 4- {3- [2- (trifluoro Rhomethyl) phenoxyazine-10-yl] furophil} -1-piperazin ethanol and phenoxyazines such as 2-chloro-10- (3-dimethylaminofurophyll) phenoxyazine, 2, 6-bis- ( Diethanolamino) -4, 8-dipiperidino-pyrimidino [5, 4-d] pyrimidine and papaverine.

The two active ingredients described above may be pressed together to form pharmaceutical compositions in the form of oral administration tablets, powders, granules, capsules, syrups, elixirs, as well as parenteral administration formulations, dispersants and emulsions.

The composition of the structural formula (I) compound and the phosphodiesterase inhibitor is administered 2-5 times a day in the form of a single agent.

Such compositions contain about 0.1 to 25 mg of the compound of formula (I) and an appropriate amount of phosphodiesterase inhibitor in the aforementioned ranges.

인 구조식(Ⅰ) 화합물은 특히 흥미있는 도파민성 중추자극작용을 가지고 있다. R은 바람직하게는 2-피리딜 또는 시아노기 이다.

Phosphorus (I) compounds have a particularly interesting dopaminergic central stimulus. R is preferably 2-pyridyl or cyano group.

R is hydrogen, cyano or a heterocycle as described above.

And R is cyano, 4-pyridyl, or 2-thiazolyl.

In the following examples all temperatures are in degrees Celsius.

Example 1

6-Methyl-8β-thiocyanomethyl ergolene (A) method)

4.5 g (13.5 mmol) of 6-methyl-8β-methanesulfonyloxymethylergolene in a mixture of 45 cc of hexamethylphosphoric acid triamide with 3 cc of water under 4.5 ° C. nitrogen stream Heated to about 46 mmol) potassium thiocyanate for 20 hours.

The reaction mixture was poured into 450 N 0.5 N sodium carbonate solution and filtered. The anhydrous residue is dissolved in the methylene chloride / ether mixture when hot and treated with activated carbon. The filtrate is concentrated and crystallized with ethanol to give the main product in the form of pinks and prisms having a melting point of 186-188 °.

Hydrogen fumarate: crystallized from methylene chloride / ethanol

=+55°(C=0.5, 디메틸포름아마이드).Melting point 182-184 °;

= + 55 ° (C = 0.5, dimethylformamide).

Example 2

6-Methyl-8β-MuraptomethylEergolene

4.5 g (about 60 mmol) of sodium hydrogen sulfide H ₂ O were treated in the same manner as in Example 1 and crystallized with methylene chloride / isofuropanol to obtain the crystalline main product.

=+86°(C=0.5, 디메틸포름아마이드).Decomposition point: about 200 °

= + 86 ° (C = 0.5, dimethylformamide).

The following compounds of formula (I) are prepared according to the method of Example 1 using the corresponding starting materials of formulas (II) and (III).

Example 3

6-Methyl-8β- (2-pyridyl-thiomethyl) -ergolene

Melting point 200-201 ° (decomposition)

=+26°(C=1, 디메틸설폭사이드).Tartrate: Melting point 195-196 °:

= + 26 ° (C = 1, dimethylsulfoxide).

(Use 2-mercapto pyridine as structural formula (III) compound)

Example 4

6-methyl-8β- (2-pyridyl-thiomethyl) ergoline

=-113°(C=1, 피리딘).Melting Point 191-195 °:

= -113 ° (C = 1, pyridine).

Example 5

6-methyl-8β- (4-pyridyl-thiomethyl) ergolene

=+52.5°(C=1, 디메틸설폭사이드).Melting Point 191-194 °:

= + 52.5 ° (C = 1, dimethylsulfoxide).

Example 6

6-Methyl-8β- (2-thiazolyl-thiomethyl) ergolene

=+58.2°(C=1, 디메틸설폭사이드).Melting Point 192-195 °:

= + 58.2 ° (C = 1, dimethylsulfoxide).

Example 7

6-Methyl-8β-thiocyanomethylergoline-I

=-58°(C=1, 디메틸설폭사이드).Melting Point 189-193 °:

= -58 ° (C = 1, dimethyl sulfoxide).

Example 8

6-Methyl-8β-thiocyanomethylergoline-I

Example 9

6-methyl-8β- (2-chienyl-thiomethyl) ergolene

Example 10

6-Methyl-8β- (2-oxazolyl-thiomethyl) ergolene

Example 11

6-Methyl-8β- (2-imidazolyl-thiomethyl) ergolene

Example 12

6-Methyl-8β- (2-pyrimidinyl-thiomethyl) ergolene

Example 13

6-methyl-8β- [3- (1, 2, 4-triazolyl) thiomethyl) ergolene

Example 14

6-methyl-8β- [2- (1,3,5-triazinyl) thiomethyl) ergolene

Example 15

6-methyl-8β- [2- (4-methylpyridyl) thiomethyl) ergolene

Example 16

6-methyl-8β- [2- (4-methoxypyridyl) thiomethyl) ergolene

Example 17

6-methyl-8β- [4- (2-chloropyridyl) thiomethyl) ergolene

Example 18

6-Methyl-8β-Mercapto Methyl Ergolene (Me) Method)

11.8 g (40 mmol) of 6-methyl-8β-thiocyanomethyl- in a suspension suspended by stirring 15.1 g (0.4 mmol) of lithium aluminum hydride in 800 kV anhydrous tetrahydrofuran in a nitrogen stream. 9-ergolene was added dropwise at room temperature and stirring continued for 1 hour at this temperature. Take care while cooling well and dissolve with water and add to 500 ml of 5% aqueous tin acid solution with stirring.

Potassium carbonate solution is added to the reaction mixture to make it alkaline and the aqueous layer is quickly extracted with methylene chloride containing 10% methanol. Dehydrate with sodium sulfate and distill the solvent to give the main product.

=+86°(C=0.5, 디메틸포름아마이드).Decomposition: about 200 °

= + 86 ° (C = 0.5, dimethylformamide).

Example 19

6-Methyl-8α-methanesulfonyloxymethyl ergoline-I

(Starting material of Example 8)

A solution of 2.56 g (10 mmol) of methane sulfonyl chloride in 5 cc of anhydrous acetonitrile was dissolved in 15 cc of anhydrous pyridine and 25 cc of anhydrous acetonitrile of 2.56 g (10 mmol) of 9,10-dihydro-isosoriser. Goal I. [Helv. 32, 1947 (1949) was added dropwise to the suspension suspension at + 10 ° and then stirred at room temperature for 1 hour. Cool to 0 ° and dilute with methanol until alkaline solution, alkalinize and shake with 2N-ammonia / methylene chloride. After dehydration and evaporation of the mixed organic layers, 6-methyl-8α-methanesulfonyloxymethyl-ergoline-I was dropped into crystals with ethanol.

=-54.6°(C=1, 디메틸포름아미드)Melting point 139-141 °,

= -54.6 ° (C = 1, dimethylformamide)

The following composition relates to a method for the preparation of a pharmaceutical formulation containing the compound of formula (I) obtained according to the method of the present invention as an active ingredient.

[Composition Example 1]

Preparation of Pharmaceutical Solid Formulations

A) 1 mg of the compound of formula (I) is mixed with lactose and optionally 25 mg of phosphodiesterase inhibitor.

The mixture is granulated with water, 0.5% sodium alginate or 1% gelatin solution. The dried granules are pressed and compressed in the presence of oxygen stannate, about 5% talc, about 5% corn starch and about 0.1% magnesium stearate.

According to this method, the tablet which consists of the following compositions can be obtained.

Structural Formula (I) Compound 1 mg 1 mg

Phosphodiesterase inhibitors-mg 25 mg

Lactose 85.9mg 60.9mg

Tartaric acid 3mg 3mg

Corn starch 5mg 5mg

Talc 5mg 5mg

Magnesium Stearate 0.1mg 0.1mg

100.0mg 100.0mg

1 tablet

B) capsules

Capsules may contain only active ingredients.

Obtain the next Capsul by the known method.

Structural Formula (I) Compound 5mg 5mg

Phosphodiesterase inhibitor 50 mg-mg

Diluent (e.g. kaolin)-295 mg

55mg 300mg

Capsule content

[Composition Example 2]

Preparation of Pharmaceutical Liquid Formulations

Liquid formulations, such as suspending agents suitable for oral administration, contain a compound of formula (I) and a phosphodiesterase inhibitor with an inert, pharmaceutically acceptable liquid solvent or carrier. Furthermore, it may contain other additives such as sweeteners, colorants, fragrances and stabilizers.

Using known methods, the following oral suspensions are obtained.

Structural Formula (I) Compound 1.0 mg 1 mg

Phosphodiesterase inhibitors-10

Vanilla Flavor Requirement

Required amount of colorant

Buffer Requirements Required

Water up to 5 water up to 5

Preferred compounds of formula (I) used in Composition Examples 20 and 21 are 6-methyl-8β-thiocyanomethyl ergolene and 6-methyl-8β- (2-pyridyl-thiomethyl) ergolene.

Preferred phosphodiesterase inhibitors used in Compositions 20 and 21 are theophylene and carfenin.

Claims (1)

Compound (II) is obtained by reacting a compound of formula (II) with a compound of formula (III) or reducing a -SCN group in a cast (Ib) compound with -SH to obtain a compound of formula (Ia). How to manufacture.

here

R is a 5-6 angular unsaturated heterocyclic group which is ringed together with hydrogen, cyano, carbon atom and 1, 2 or 3 heteroatoms, the first heteroatom being nitrogen, oxygen or sulfur and the second or third complex And, if present, a 2- or 4-pyridyl group monosubstituted with nitrogen or lower alkyl, lower alkoxy or halogen. X is a group which may be substituted with cheo. M is hydrogen or an alkali metal.