Derivatives heterocyclisation in the form of mixtures of isomers or of the individual isomers or their salts


(57) Abstract:

The object of the invention are derived heterocyclisation General formula (1)



A, B and D independently of one another denote hydrogen atoms or lower alkyl. Het denotes a heterocyclic residue of the formula:



R1means a hydrogen atom, R2- linear or branched alkyl containing 1-8 carbon atoms, which is substituted by the residue formula


or a residue of the formula


in the form of mixtures of isomers or of the individual isomers or their salts. table 2.

The invention relates to new chemical compounds with valuable properties, in particular to derive heterocyclyl-chromane General formula (1),

< / BR>

A,B and D are independent of each other and denote hydrogen atom, lower alkyl, Het heterocyclic residue formula

< / BR>

R1means a hydrogen atom and R2linear or branched alkyl with 1-8 carbon atoms, substituted by the residue formula

< / BR>

the remainder of the formula

in the form of mixtures of isomers or of the individual isomers or their salts.

In the framework of the present invention the preferred physiologically tolerated salts. new acids or sulphonic acids. Especially preferred, for example, salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultation, toluensulfonate, benzosulfimide, naphthalenedisulfonate, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Compounds according to the invention exist in stereoisomeric forms which represent a direct and inverse forms (enantiomers) or are not (diastereomers). The invention also concerns as antipodes and racemates, and mixtures of diastereomers. The racemates, as well as diastereomers, are separated in a known manner to separate stereoisomers.

Compounds according to the invention of General formula (1) can be obtained by ways of peers. For example, the compound of General formula (II)

< / BR>

A, B and D have the above meaning and Y represents hydroxy or a conventional useplease group, for example, tosylate, is subjected to the interaction with the compound of General formula (III)

H-Het (III),


Het has the above significance, in an inert will dissolve the current allocation of the target product in the form of mixtures of isomers or of the individual isomers or salts by known methods.

Compounds according to the invention can be used as active substances in medicinal products. Proposed by the present invention substances have particularly high medium to cerebral 5-hydroxy-tryptamine-receptor type 5-HT1. They also have a high medium to dopamine receptors D2type.

Compounds according to the invention have unexpectedly advantageous effect on the Central nervous system and can be used for therapeutic treatment of humans and animals.

Described in the present invention compounds are active substances for combating diseases which are characterized by impaired serotoninergicheskoi and dopaminergic system, particularly when the involution receptors, which have high affinity for 5-gidroksitriptaminu (type 5-HT1) and/or dopamine (type D2).

They are suitable in addition for the treatment of diseases of the Central nervous system, for example, state of fear, stress and depression caused by the Central nervous system of sexual dysfunction and sleep disorders, as well as for the regulation of pathological eating disorders, stimulants and drugs. They further year of Alzheimer's disease. They are also suitable for dealing with psychoses (e.g. schizophrenia, mania). In contrast to known doses they have a lower potential for side effects.

Further, these compounds are suitable for the modulation of the cardiovascular system. They contribute to the regulation of cerebral blood flow and therefore are an effective means to treat migraine headaches.

Also they are suitable for the prevention and combat the effects of cerebral infarction (stroke), such as cerebral hemorrhage, cerebral ischemia. In addition, the compounds can be used for the treatment of acute traumatic brain injury. Also the claimed compounds can be used for control of pain.

Affinity for 5-HT1-receptor

Below in an example of the high affinity of the compounds according to the invention to 5-hydroxytryptamine-receptor subtype 1. For these values it is 0 for data, which are obtained by studying the binding of the receptor membrane preparations from immunologi horns of the calf.

As a radioactively labeled ligand used here3H-serotonin.

connection example TOT(nmol/l)

13 3

15 2
3H-ipsapirone 5-HT1Areceptors in the membranes immunologi horns of the calf. It was found that the compounds according to the invention compete with radio-binding and inhibit it. The results of the tests are presented below.

connection example KT(nmol/l)

16 1,5

17 1,4

Experience with dopamine D2receptor

This experience is conducted in accordance with the following literary source: Imafuku I. (1978), Brain Research 402; 331-338.

This is measured by the binding of the selective D2-receptor-antagonist3H-sulpiride membranes from the striatum of rats. Compounds that bind to the dopamine D2receptors, inhibit, depending on the concentration of binding3H-sulpiride. From the curves of displacement gain values KT50and hence expect constant braking TOT. The results of the tests are presented below.

connection example TOT(nmol/l)

13 1,8

14 0,4

17 2,3

The active substance of the formula (1) may be contained in drugs at a concentration of from 0.1 to 99.5 weight. preferably from 0.5 to 95 weight. of the total mixture.

Along with the active substances of the formula (1) of the medicinal product may contain one who Zvezdnyi ways, for example, one or more of the target additives or carriers.

To achieve the desired results have been preferable to introduce one or more compounds of the formula (1) in General in amounts of from 0.01 to 100 mg/kg, preferably 1 mg/kg to 50 mg/kg of body weight every 24 hours, optionally in the form of several individual doses. However, it may be preferable deviations from these quantities, namely depending on the body weight of the patient, from his individual relationship to the drug, the type and severity of the disease, the type of drug and type of application, the time and interval of administration of the drug.

The following examples explain the invention.

Given the values of Rfhave been received, unless nothing else, thin-layer chromatography on silica gel (aluminum plate, silica gel 60 f 254, company E. Merck). Visual detection of spots occurred in UV-light and/or by spraying with 1% solution of potassium permanganate.

Flash chromatography was performed on silica gel 60, 0,040 0,064 mm, firm E. Merck.

Elution with a gradient of solvents means that starting with a clean, non-polar components of the solvent mixture, primitivearray).

All products of the solvent is kept at the final pressure of about 0.1 Torr. Salt was left at this pressure overnight over potassium hydroxide and/or pjatiokisi phosphorus.

The following examples illustrate how to obtain the original compounds.

Example 1. 8-methoxy-chroman-2-carboxylic acid-(4-etoxycarbonyl)-piperidin

< / BR>
9.0 g (40 mmol) of acid chloride 8-methoxy-chroman-2-carboxylic acid is added in several portions to 6.3 g of ethyl ether piperidine-4-carboxylic acid (40 mmol) and 0.1 g of 4-dimethylaminopyridine in 20 ml of anhydrous pyridine. After incubation for 40 h at room temperature, poured on ice. Released after 30 min, the solid is washed with water and dried in a desiccator.

Yield: 6.2 g (45%).

This substance is then used without further purification.

Example 2. 2-hydroxymethyl-8-methoxy-chroman.

< / BR>
59.0 g (0.25 mol) of ethyl ester 8-methoxy-chroman-2-carboxylic acid in 525 ml of anhydrous tetrahydrofuran was added dropwise within 1 h under stirring at 20oC to a suspension of 9.5 g (0.25 mol) of sociallyengaged in 525 ml of anhydrous diethyl ether. The mixture is stirred over night and then when cooled sequentially who headed the remainder of twice recrystallized from a mixture of dichloromethane/petroleum ether.

Output: 38.0 g (87%)

So pl. 57-58oC.

Example 3. (2R)-2-hydroxymethyl-chroman.

< / BR>
To a solution of 22.1 g (0,124 mol) (2R)-chroman-2-carboxylic acid (purity isomer= 98,3% ) in 210 ml of anhydrous tetrahydrofuran in an argon atmosphere was added dropwise within 30 minutes at an internal temperature of 0oC 164 ml of 1 M solution of borane in tetrahydrofuran. Stop cooling and the mixture continued to be stirred for 4 hours While the internal temperature rises to 34oC. finally added dropwise 46 ml of a mixture of tetrahydrofuran/water (1:1) under cooling with ice. After addition of 40.7 g of anhydrous potassium carbonate and strong mixing a solution of tetrahydrofuran decanted and concentrated in a water jet vacuum pump. Direct distillation gives 18,8 g colorless 2R-hydroxymethylpropane with so Kip. 77-78oC/0,15 mbar. The purity of the isomer > 99%

Example 4. (2S)-2-hydroxymethyl-chroman.

< / BR>
Similar to the recipe of example 2 obtain the target compound of (2S)-2-chroman-2-carboxylic acid.

The purity of the isomer > 99%

So Kip.79-81oC/0,15 mbar.

Example 5. (2R)-2-tosyloxy-chroman.

< / BR>
To 12.8 g (0,078 mol) (2R)-2-hydroxymethylpropane (example 2) in 50 ml of anhydrous pyridine with stirring and ohlazhdeniya in ice-cold water and extracted with diethyl ether. The ether phase is washed twice with 5% ice hydrochloric acid and then washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated in a water jet vacuum pump. Get 22,4 g homogeneous ether 4-toluenesulfonic acid 2R-2-hydroxymethylpropane.

Rf0.6 (toluene/acetic ether 3:1), oil.

So pl. 62-65oC (petroleum ether/diclomelan);

[]d-51,1 (C=1, chloroform).

Example 6.(2S)-2-tosyloxy-chroman.

< / BR>
Similar to the recipe of example 4 to obtain the target compound of example 3.

Rf=0.6 (toluene/acetic ether 3:1), oil.

Example 7. 8-methoxy-2-tosyloxy-chroman.

< / BR>
So pl. 115-117oC (from dichloromethane).

Example 8. 2-phthalimidomethyl-8-methoxy-chroman.

< / BR>
By the interaction of the compounds according to example 2 with phthalimide in the presence of equimolar amounts of triphenylphosphine and diethyl ester of azodicarboxylic acid in tetrahydrofuran obtain the target product with a yield of 80% in the form of syrup, which is used directly on.

Rf=0,46 (toluene/ether acetic acid 3:1).

Example 9. Hydrochloride of 2-[(4-hydroxymethyl)-piperid is astora sodium bis-(2-methoxyethoxy)-dehydroalanine in toluene and stirred for 18 h at 50oC in argon. After dilution with toluene hydrolyzing a mixture of tetrahydrofuran/water (1:1). After filtration and flash chromatography of the filtrate (silica gel, gradient solvent mixture toluene/propanol 100:0 to 50: 50) to give the product as free base, 2.8 g (yield 64%), syrup.

After treatment with ethereal hydrochloric acid to obtain the hydrochloride, which is recrystallized from acetonitrile.

So pl. 107-112oC (after Perekrest. from acetonitrile).

IR (KBr): 3510, 3301 (W), 2945, 2548 (W), 1630 (s), 1583 (s), 1481.

Analogously to examples 1 and 9 receive connections, which are listed in the table. 1.

The following examples illustrate how to obtain the final product of formula (1).

Example 12. Hydrochloride of 2-(1H-2,3-dihydro-2-indol-2-yl)methyl-8-methoxy-chroman

< / BR>
To 2.5 g (68 mmol) of sociallyengaged in 80 ml of diethyl ether was added dropwise to 7.3 g (23 mmol) of the compound from example 8 in 50 ml of tetrahydrofuran. The mixture is heated 5 hours to the boil under reflux and then leave for 15 h at room temperature. Was added dropwise 10 ml of water in 30 ml of tetrahydrofuran, followed by 5 ml of 45% caustic soda. After filtration through silica gel and subsequent washing of the solids with a mixture of t the following flash chromatography (silica gel, gradient solvent mixture toluene/ether acetic acid 100:0 to 75:25) to obtain 6.2 g (93%) of the desired product as free base (syrup). From it by treatment with ethereal hydrochloric acid to obtain the hydrochloride.

So pl. 256-258oC (after Perekrest. from 2-propanol).

Rf=0,35 (silica gel, toluene/ether acetic acid 1:1).

MC (.from.): 295, 132 (100%), 105, 36.

Example 13. The oxalate hydrate 2-[4-(isoindole-1, 3-dione-2-yl)methyl-piperidine-1-yl]methyl-8-methoxypropane.

< / BR>
4.1 g (14 mmol) of the compound from example 9, 4.1 g (15 mmol) of triphenylphosphane and 2.3 g (15 mmol) of phthalimide dissolved in 6 ml of dry tetrahydrofuran. To this was added dropwise at room temperature 2.7 g of diethyl ester of azodicarboxylic acid in 10 ml of tetrahydrofuran. After aging for 10 days at room temperature, concentrated and the residue is treated with cyclohexane. Filtered nerastvorimaya substance and the filtrate concentrated in a rotary evaporator. Chromatography (silica gel, toluene/ether acetic acid 100:0 to 50:50) and re-chromatography (silica gel, dichloromethane/2-propanol 50:1 to 10: 1) gives the desired product in the form of oil (1,15 g). From it by treatment with ethereal hydrochloric acid precipitated kuchenny processing dihydrate of oxalic acid in alcohol solution oxalate recrystallization from 2-propanol obtained after cooling down to -36oC of 0.30 g of the target compound.

So pl.>70oC (decomp.)

Rf=0,3 (silica gel, dichloromethane/2-propanol 20:1).

Example 14. 1-(chroman-2-yl-methyl)-4-(2-oxo-1-benzimidazolyl)-piperidine

< / BR>
A mixture of 8.8 g (27.7 mmol) in ether (chroman-2R,S-yl-methyl)-4-toluenesulfonic acid, 2.1 g (20 mmol) of anhydrous sodium carbonate and 6.5 g (30 mmol) of 4-(2-oxo-1-benzimidazolinyl)-piperidine in 70 ml of anhydrous dimethylformamide is stirred for 6 h at 110oC and then poured onto ice (250 g). After extraction with ethyl acetate, washing the organic extract with water, drying over anhydrous sodium sulfate and evaporation of the organic phase in water-jet vacuum pump gain of 9.8 g almost homogeneous crystalline crude product, which for analysis twice recrystallized from a mixture of dichloromethane/petroleum ether.

So pl. 107-109oC (Kapil.)

Similar to the recipe of example 14 receive connection table.2.

Derivatives heterocyclisation General formula

< / BR>
where A, B and D are independently from each other hydrogen, lower alkyl;

Het heterocyclic residue of General formula

< / BR>

< / BR>
where R1hydrogen;

R2linear or branched al the e isomeric mixture or individual isomers, or their salts.


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