DE3843227A1 - Use of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole - Google Patents

Abstract

The compound 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole (racemate, (-)-enantiomer) and its acid addition salts bring about a reduction in the serum level of prolactin (PRL); they are therefore suitable for treatment of diseases in which the PRL is to be reduced.

Description

The invention relates to the use of the 2-amino-6-n-propolyamino-4,5,6,7-tetrahydrobenzthiazols (Racemate) and its (-) - enantiomer (SND 919) as well as their physiologically acceptable acid addition salts in lowering prolactin serum levels (PRL).

It is known from the compounds mentioned that they as drugs for the treatment of central nervous, neuropsychiatric disorders, in particular, schizophrenia, for the treatment of Parkinson's disease or Parkinson's disease and / or for the treatment of circulatory diseases, in particular hypertension, are suitable (EP-A 85116016.8).

As has now been found, the o. G. Connections too to lower the PRL.

To reduce the level of PRL in the blood can be the above compounds in the usual galenic preparations for oral, parenteral, incorporate rectal or transdermal application. The oral single dose in humans is usually between 25 μg and 500 μg, preferably between 50 μg and 300 μg; with multiple applications (eg 3 × daily), the daily doses can usually be between 50-1000 ug - preferably between 60-600 μg. Parenteral and rectal doses can in the same range as the oral ones Substance quantities are.

Compounds, in particular SND 919 and its salts can because of their PRL-lowering properties always be used when a reduction of the PRL level in the blood is indicated. This can especially in the following diseases  be therapeutically appropriate:

• 1.) pituitary tumors, suprasellar tumors (Craniopharyngioma), disruption of the pituitary Portal vessels,
• 2.) Propagation of PRL-producing cells (Pregnancy, hyperplasia, prolactinoma),
• 3.) When preponderating PRL secretion promoting factors about PIF (hypothyroidism),
• 4.) Cycle disorders:
  • - Amenorrhoea with or without galactorrhea
  • - Oligomenorrhoea
  • - PRL-related fertility disorders
  • - Corpus luteum insufficiency
  • - Premenstrual syndrome
  • - dysmenorrhea
  • - Anovulatory cycles
  • - Post-pill amenorrhea
• 5.) Mammary Cancer (Mamma-Ca)
• 6.) cervical dysplasia
• 7.) In the case of medication-induced blockade of DA receptors or inhibition of DA secretion:
  Combination of the compound with medicinal products associated with an increase in PRL (eg, phenothiazine or butyrophenone neuroleptics, antiemetics, eg metoclopramide).
• 8.) Lactation inhibition (primary and secondary weaning)  
• 9.) Puerperal mastitis
• 10.) PRL-related hypogonadism.

The active compounds which can be used according to the invention can also in combination with other drugs that are otherwise used for the indications listed under and 1.) to 10.) be used.

In animal experiments was the reduction of prolactin level examined in the blood on rats and monkeys.

In normal male (m) and female (f) rats, serum prolactin levels were determined after 14 weeks of oral administration of 0.5 mg / kg SND 919 hydrochloride per day. The blood was taken 2 hours after the last drug administration. The average values for n animals are given:

In another experiment, the active ingredient was i. v. administered. After 5 weeks of treatment with 0.2 mg / kg showed a reduction of 106.3 μg / l (average  of control animals) to 5.1 μg / L in the treated Animals (blood collection 2 hours after the last Treatment.

In rhesus monkeys, a reduction to 0.06 mg / kg was observed less than a quarter of that in the control animals achieved average value. The Treatment lasted 14 days, the blood collection took place again 2 hours after the last drug administration.

The experiments show that even after a long time Administration of the drug still a strong effect is achieved.

The compounds useful in the invention are relatively nontoxic. For SND 919 the oral LD₅₀ is in the mouse about 800 mg / kg, in the rat about 1700 mg / 7kg.

In humans, the favorable results of Animal experiments are confirmed.

Twelve healthy male subjects received 100 oral doses or 200 or 300 μg SND 919 hydrochloride. The average PRL decreased from 3 μg / L within 2 hours to 1.3 μ / l. Some subjects had one Proof no longer possible (the detection limit for Prolactin is 1 μg / l). In these cases was calculated with the value of 1 μg / l, so that the actual lowering of the PRL must be even greater. The recovery of the PRL was according to the dose different fast. At 100 μg, after approx. 8 hours the initial value is reached again at the higher doses became one more after 8 hours distinct effect observed.  

The following examples describe the preparation some pharmaceutical preparations.

example I Drag'ekern

Composition: 1 drag core contains: SND 919 × 2 HCl 50 μg lactose 38.45 mg corn starch 10.0 mg gelatin 1.0 mg magnesium stearate  0.5 mg 50.0 mg

production method

The mixture of the active substance with milk sugar and Corn starch is mixed with a 10% aqueous Gelatin solution granulated through sieve 1 mm, at 40 ° C dried and rubbed again through the above sieve. The granules obtained in this way are mixed with magnesium stearate mixed and pressed to drag cores. The production must be done in darkened rooms.

Core weight: 50 mg
Stamp: 5 mm, arched

The Drag'ekerne thus obtained become known Method coated with a sheath, which in the consists essentially of sugar and talc. The finished drag'es are made with the help of beeswax polished. Drag'e weight: 100 mg  

Beispliel II suppositories

1 suppository contains: SND 919 × 2 HCl | 100.0 μg Suppository mass (eg Witepsol W 45) 1690.0 mg

Production method:

The finely powdered substance is using a Immersion homogenizer in the molten and at 40 ° C cooled suppository mass stirred. The mass is added 35 ° C poured into slightly pre-cooled molds.

example III ampoules

1 ampoule contains: (±) -2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrobromide | 200 μg citric acid 7.0 mg Sodium phosphate sec. · 2 H₂O 3.0 mg pyrosulfite 1.0 mg Dest. Water ad 1.0 ml

production method

In boiled and cooled under CO₂ fumigation Water are successively the buffer substances, the Active substance and sodium pyrolsulfite dissolved. You fill with boiled water to the given volume and filtered pyrogen-free.  

Filling: in brown ampoules under protective fumigation
Sterilization: 20 minutes at 120 ° C.

The preparation and filling of the ampoule solution must be in darkened rooms are made.

Beispliel IV Drag'es with 1 mg SND 919 × 2 HCl

1 drag core contains: Active substance | 100 μg lactose 36.0 mg corn starch 12.4 mg gelatin 1.0 mg magnesium stearate  0.5 mg 50.0 mg

Production method:

Analogously to Example I. Core weight | 50 mg Stamp: 5 mm, arched Drag'egewicht: 100 mg

example V Gelatine capsules

1 capsule contains: Active substance usable according to the invention | 300 μg codeine phosphate 10.0 mg tartaric acid 3.0 mg corn starch  85.7 mg 100.0 mg

Production method:

The substances are mixed intensively and in Bottled opaque capsules of suitable size. Capsule filling: 100 mg

Claims (2)

1. Use of 2-amino-6-n-propylamino 4,5,6,7-tetrahydrobenzothiazole (racemate) and its (-) - enantiomer as well as its physiological compatible acid addition salts in the Treatment of diseases in which the Prolactin serum levels should be lowered. 2. Use of 2-amino-6-n-propylamino 4,5,6,7-tetrahydrobenzothiazole (racemate) and its (-) - enantiomer as well as its physiological compatible acid addition salts in the Production of drugs for the reduction of Prolactin.