KR900001912B1 - Tetrahydrobenzochiazoles and the preparation and use thereof - Google Patents

Abstract

Tetrahydobenzothiazoles of formula (I) and their acid addn. salts are prepared. In (I), R1=H, F, Cl, Me, Et, OH or CF3; R2=H, Cl, Me or methoxy; R3=H or NH2; R4=H, Me or Et; R5=R6=H, C1-4 alkyl, phenyl- substd. C1-3 alkyl or allyl; n=1,2 or 3. (I) are useful for treating Parkinson's disease or Parkinsonism.

Description

[Name of invention]

Tetrahydrobenzothiazole, preparation method and use thereof

Detailed description of the invention

The present invention relates to novel tetrahydrobenzothiazole derivatives, their preparation and their use as medicaments in conventional formulations.

It has been found that the compounds of the general formula (I) and acid addition salts thereof can be used as medicaments.

Wherein n is 1,2 or 3; R ₁ is hydrogen, fluorine, chlorine, bromine, CH ₃ , C ₂ H ₅ , OCH _3, OC ₂ H _5, OH or CF ₃ ; R ₂ is hydrogen, chlorine, CH _3, OCH _3, OC ₂ H ₅ or OH; R ₃ is hydrogen or NH ₂ ; R ₄ is hydrogen, CH ₃ or C ₂ H ₅ ; R ₅ and R ₆ are hydrogen, C _1-4 -alkyl, phenyl-substituted C _1-3 alkyl, allyl or propargyl.

In the context of the above definition, R ₁ to R ₆ may be the same or different and may be or contain branched or unbranched hydrocarbon radicals.

Preferably R ₁ is hydrogen, OCH ₃ , OH, chlorine, bromine, CH ₃ or C ₂ H ₅ , R ₂ is hydrogen, OCH ₃ or chlorine, R ₄ is hydrogen or CH ₃ , R ₅ is hydrogen , C _1-3 alkyl, allyl or phenethyl and R ₆ is hydrogen, C _1-3 alkyl or allyl. Particular emphasis is given to compounds in which R ₁ is OCH ₃ or OH, R ₂ , R ₃ and R ₄ are hydrogen and R ₅ and R ₆ are hydrogen or C _1-3 alkyl.

It is preferred if the index n is 2 or 3, especially 2.

Where at least one of the radicals R ₁ to R ₄ is not hydrogen, it is preferred to be substituted at the 4-position, while further substituents which may be present are preferably at the 3-position.

Typical radicals of the general formula (II) below are, for example, 4-methoxyphenyl, 4-chlorophenyl, 4-hydroxyphenyl, 3,4-dimethoxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-methylphenyl and 3,5-dichloro-4-aminophenyl.

The novel compounds may exist as racemates or pure enantiomers, as well as as specific mixtures of specific proportions of enantiomers.

Generally, one of the racemate enantiomers is more active than the other.

The novel compounds can be prepared by the following methods known per se.

1. A method for reductive amination of a compound of formula (III) using a compound of formula (IV) and a reducing agent.

Wherein n, R ₁ to R ₆ are the same as defined above.

Reducing agents that can be used are hydrogen and hydrogenation catalysts, for example complexes such as Raney nickel, platinum or palladium, or sodium borohydride. Suitable reaction media are polar organic solvents which are inert under the reaction conditions, for example lower aliphatic alcohols such as methanol or ethanol. The reaction is preferably carried out with gentle cooling (e.g., when NaBH ₄ is used as the reducing agent), and when hydrogen / catalyst is used as the reducing agent in some cases, it is preferable to proceed with the reaction under warming under pressure. .

2. In order to prepare compounds of general formula (I) containing phenolic OH groups, suitable ethers such as, for example, methyl ethers can also be subjected to conventional ether decomposition using, for example, boron bromide. Suitable solvents are, for example, halogenated hydrocarbons such as methylene chloride or ethylene chloride.

The reaction is carried out at room temperature for convenience.

3. In order to prepare compounds of formula (I) in which the radicals R ₅ or R ₆ are not all hydrogen, a suitable compound in which R ₆ is hydrogen may be reacted with a compound of formula (V).

Wherein R ' ₆ is the same as R ₆ but not hydrogen and X is a group that can be removed when introducing R' ₆ into an amino group, for example a halogen atom.

If the starting materials are not known, they may be prepared by conventional methods.

Compounds of formula (III) are, for example, acyl chloride of formula (IV), preferably 6-oxo-2-aminotetrahydrobenzo, in the presence of a tertiary aliphatic amine such as triethylamine in an inert organic solvent. It can manufacture by reacting with thiazole under heating.

Wherein n, R ₁ , R ₂ and R ₃ are the same as defined above.

The final product of formula (I), initially obtained as a base, can be converted to acid addition salts by conventional methods, and the acid addition salts obtained initially can be converted to salts of bases or other acids.

Suitable acids are all inorganic or organic acids which, together with the bases according to the invention, give suitably stable salts.

Salts of physiologically acceptable acids such as hydrochloride, hydrobromide, sulfate, methanesulfonate, succinate, fumarate, maleate, citrate and formate and the like are used directly as medicaments.

The compounds according to the invention are generally produced as racemates because they have a chiral center, which in some cases, for example, tartaric acid, O, O-dibenzoyl tartaric acid, camphorsulfonic acid and α-methoxyphenyl Conventional optically active acids such as acetic acid can be used to separate enantiomers.

If optically active starting materials are used, for example in the case of preparation 2 or 3, enantiomers may be obtained directly.

The new compounds are particularly suitable as medicaments for the treatment of Parkinson's disease or Parkinson's syndrome. The compounds may also be used for prolactin inhibition and schizophrenia treatment.

According to the present invention, the compound exhibits a particularly preferred mode of action as follows.

The action lasts a long time (up to about 20 hours).

Vomiting does not occur in the therapeutic dose range.

Low adrenergic action is observed.

Compounds having this mode of action have never been described. The action can be demonstrated from monkeys (MPTP model).

[Measurement of Anti Parkinson's Syndrome and Anti Parkinson's Action]

The discovery of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) has made animal models of Parkinson's disease useful. [Reference: Langston et al., Science 219,979 (1983)]

The irreversible neurological clinical symptoms caused by MPTP in humans and monkeys are largely similar to those of idiopathic Parkinson's disease in its clinical, pathological, biochemical and pharmacological properties. Markey et al., Nature 311, 464 (1984). This similarity is due to MPTP's selective destruction of small groups of dopaminergic neurons in cerebral medulla, which are sometimes destroyed by naturally occurring Parkinson's degeneration. It is also discussed whether the cause of idiopathic Parkinson's disease is MPTP or a similar compound produced in an organism. Snyder, S.H. Nature 311, 514 (1984). Perhaps due to the specific metabolism of MPTP, the clinical characteristics of MPTP-Parkinson's symptoms can only be detected in monkeys other than humans. Therefore, the MPTP model realized in rhesus monkeys is well suited for testing the action of anti-Parkinson's drugs. MPTP (1 × 0.15 mg / kg intramuscularly daily for 3 days, suspended 3 days, intramuscularly administered 1 × 0.30 to 0.40 mg / kg daily for 3 days) is administered to the rhesus monkey. They have the following symptoms; The animals were inactive and could not eat water or food. They show normal body squats. Catalepsy sometimes occurs. Chills occur in the extremities, which are briefly interrupted by epilepsy convulsions when they show movement to the outside. It is generally impossible to generate voluntary movements of the buttocks and limbs even by the strongest and most painful stimuli.

After a few minutes of intramuscular administration of the compound according to the invention, the first voluntary movement takes place, and then the motor nerve becomes progressive and substantially normal. The animals can then eat food. They are self-supporting themselves within us, as well as with regard to alertness and servants, especially behavior. Temporary and slightly passive tremors and loss of stamina are recorded as sequelae.

In some cases, after about 20 hours, the action of the compound of the present invention may drop so that the Parkinson's symptoms described above occur again in the animals.

Re-administration of the compound substantially relieves or improves clinical and pathological symptoms. The advantageous action of the compound can thus be regenerated.

Conventional galenic formulations are prepared for the therapeutic administration of the novel compounds, such as tablets, tablets, suppositories, powders, suspensions and solutions. 0.1 to 10 mg, preferably 0.5 to 5 mg per kg body weight is the daily dose. It is administered in one or several divided doses.

Example of the manufacture of a medicament according to the invention (data is expressed in parts by weight):

(Skin tablets)

5.0 parts of active compound according to the invention

Lactose-Part 33.5

Corn starch 10.0 parts

Gelatin Part 1.0

0.5 part magnesium stearate

The active compound, lactose and corn starch of the powdered components are granulated with an aqueous solution of gelatin and then dried. The granules are mixed with magnesium stearate and compressed to produce 50 mg of the epidermal tablet nuclei, which are nucleated by known methods.

(Station)

10 parts active compound according to the invention

1690 parts of suppository substance (eg witepsol W45)

The finely divided material is uniformly dispersed in the molten suppository cooled to 40 ° C. using a homogenizer. 1.7 g of suppositories are molded from the mixture.

The following examples are intended to illustrate the invention in more detail.

Example 1

2- (4-methoxypropionyl) amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole)

a) Preparation of racemates

15.1 g (0.09 mol) of 6-oxo-2-amino-tetrahydrobenzothiazole and 20.5 g (0.1 mol) of 4-methoxyphenylpropionyl chloride were refluxed in 450 ml of tetrahydrofuran and 0.1 mol of triethylamine for 2 hours. After making, pour into ice and extract using ethyl acetate. After drying, 2- (4-methoxyphenylpropionyl) amino-6-oxotetrahydrobenzothiazole (17.5 g) was concentrated to crystallize, dissolved in methanol and no further purification in autoclave with propylamine. Reductively amination (Raney nickel, 5 bar, 60 ° C.). After the catalyst is suctioned off by filtration, the solvent is distilled off. The residue is crystallized from iso-propyl ether.

Yield: 12.5 g (63% of theory)

Base: melting point 105-106 ° C. (recrystallized from ethyl acetate)

Dihydrochloride: Melting Point 259-261 ° C

b) segmentation of racemates

(0.025몰)을, 200ml의 물 중 상기 a)에 의해 수득된 생성물(9.3g, 0.025몰)의 현탁액에 가한다. 그 혼합물을 15분 동안 환류시킨 후 여과시킨다. 하루 후 침전하는 무색 결정들을 흡인 여과시킨다. 이L(-(+)-타타르산 염을 물 75ml로 5회 재결정화시킨다. 유리된 염기의 광회전[α]_D ²⁰=-45.5℃(C=1, CH₃OH)라는 값은 더 재결정화를 해도 변화하지 않는다.L-(+)-tartaric acid [Aldrich:

(0.025 mol) is added to a suspension of the product (9.3 g, 0.025 mol) obtained by a) above in 200 ml of water. The mixture is refluxed for 15 minutes and then filtered. The colorless crystals that settle out after one day are suction filtered. The L (-(+)-tartaric acid salt is recrystallized five times with 75 ml of water.The optical rotation of the free base [α] _D ²⁰ = -45.5 ° C. (C = 1, CH ₃ OH) is further recrystallized. It doesn't change when you get angry.

The base is liberated using concentrated ammonia from the pure L-(+)-tartaric acid salt and then extracted with ethyl acetate. After washing and drying (magnesium sulfate), the solvent is removed in vacuo. Etheric hydrochloric acid is used to determine the dihydrochloride of (-)-ethanethiomer.

Yield: 0.9, melting point 261 to 262 ° C

[a] _D ² ° = -41.1 ° (C = 1, CH ₃ OH)

Example 2

2- (4-hydroxyphenylpropionyl) amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole

9.6 g (0.026 mole) of the compound obtained in Example 1 was dissolved in 300 ml of methylene chloride and then stirred with 90 ml of boron tribromide at 15 ° C. for 3 hours. Water is added to the reaction mixture and then made alkaline using concentrated ammonia. The organic phase is extracted with methylene chloride, dried and concentrated. Dihydrobromide of the title compound is obtained from the residue using ethanol hydrobromic acid.

Yield: 4.95 g (49% of theory) Melting Point 228-229 ° C

[Examples 3 to 37]

Claims (8)

Tetrahydrobenzothiazole of general formula (I) and its acid addition salt.

Wherein n is 1,2 or 3; R ₁ is hydrogen, fluorine, chlorine, bromine, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , OH or CF ₃ ; R ₂ is hydrogen, chlorine, CH ₃ , OCH ₃ , OC ₂ H ₅ or OH; R ₃ is hydrogen or NH ₂ ; R ₄ is hydrogen, CH ₃ or C ₂ H ₅ ; R ₅ and R ₆ are hydrogen, C _1-4 alkyl, phenyl-substituted C _1-3 alkyl, allyl or propargyl. The compound of claim 1, wherein R ₁ is hydrogen, OCH ₃ , OH, chlorine, bromine, CH ₃ or C ₂ H ₅ , R ₂ is hydrogen, OCH ₃ or chlorine, R ₃ is hydrogen or NH ₂ , R ₄ is hydrogen or CH ₃ , R ₅ is hydrogen, C _1-3 alkyl, allyl or phenethyl, R ₆ is hydrogen, C _1-3 alkyl or allyl, and n is the same as defined in claim 1. The compound of claim 1, wherein R ₁ is OCH ₃ or OH, R ₂ , R ₃ and R ₄ are hydrogen, R ₅ and R ₆ are hydrogen or C _1-3 alkyl, and n is as defined in claim 1. Same compound. The compound of claim 1, wherein n is 2 or 3. 5. The compound of any one of claims 1-3, wherein n is 2. 5. 2- (4-methoxyphenylpropionyl) amino-6-n-propylamino-4, 5, 6, 7-tetra, in racemic or active enantiomer form, respectively present as free base or acid addition salt Hydro benzothiazole. Use of a compound according to claim 1 for treating Parkinson's disease or Parkinson's syndrome. A process for preparing a compound of formula (I) according to claim 1, characterized in that the compound of formula (III) is reacted with a compound of formula (IV) under conditions of a reductive amination reaction.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and n are the same as defined in claim 1.