DE3138233A1 - Neuropsychotropic pharmaceutical composition - Google Patents

Abstract

The invention relates to neuropsychotropic pharmaceutical compositions for the therapeutic treatment of humans and animals, which contain a polypeptide of the formula: <IMAGE> in which X is hydrogen, t-butyloxycarbonyl (Boc), Asp, Pyr-Glu, Pyr-Gl-Asp or Pyr-Asn-Asp, Y is Thr, Met, Leu, Nle or Val, and W is Met, Nle or Leu.

Description

Neuropsychotropic drug

The invention relates to a new application of an already known class of polypeptides.

In particular, the invention relates to a new application as a valuable medicament for the therapeutic treatment of neuropsychiatric disorders, especially schizophrenia and convulsive disorders in humans and animals with the aid of a polypeptide of the general formula: wherein X is selected from the group consisting of hydrogen, t-butyloxycarhonyl (Boc), Asp, Pyr-Glu, Pyr-Gln-Asp, Pyr-Asn-Asp; Y is selected from the group Thr, Met, Leu, Nle, Val, and W is selected from the group Met, Nle, Leu.

Asp, Pyr-Glu, Pyr-Gln-Asp, etc. are abbreviations corresponding to the Are known to those skilled in the art of polypeptide chemistry and which contain an amino acid, dipeptide and mean tripeptide residue.

These polypeptides are known in the literature, as are various ones Production process, e.g. on DE-PS 1 643 5G4, GB-PS 1 523 038, US-PS 3,705,140; U.S. Patents 3,723,406; 3,734,946 3,839,315.

Some of the polypeptides of structure (I) are not covered by the aforementioned patents, such as, for example, Phyllocaerulein and Asn2, Leu5-caerulein, which are described in the following documents: Phyllocaerulein "Structure and pharmacological actions of phyllocaerulein, a caerulein-like nonapeptide: its occurence in extracts of the skin of Phyllomedusa sauvagei and related phyllomedusa species", A. Anastasi, G. Bertaccini, JM Cei, G.de Caro, V. Erspamer and M. Impicciatore, Brit. J. Pharmacol. 37: 198-206 (1969); and "Synthesis of phyllocaerulein", L. Bernardi, G. Bosisio, R. de Castiglione and 0. Goffredo, Experientia 25, 7-8 (1969).

Asn2, Leu5-caerulein "Occurrence of Asn2; Leu5-caerulein in the skin of the African frog Hylambates maculatus", C. Montecucchi, G. Falconieri, Erspamer and J. Vissner, Experientia, 33, 1138-1139 (1977).

All of these polypeptides have cholecystokinin activity and function generally to the gastrointestinal tract.

One of the most intensively studied polypeptides of this class is caeruletid, a generic name for a decapeptide with the following structure: In the pending German patent application P 30 34 897.1, these polypeptides were described and claimed as valuable analgesic drugs.

Surprisingly, it has now been found and this is the main issue of the present application show that the polypeptides of structure (I) are effective and active antipsychotic and anticonvulsant agents in various experimental Represent situations. The title compounds have proven to be more active than haloperidol proven in the formation of catalepsy as well as in the weakening of methylphenidate-induced Stereotype behavior (Pedersen, V., and Christensen, AV., Acta pharmac. (Kbh.), 31, 488, 1972) when these compounds s.c. on mice at doses of 10 to 150 nmol / kg Body weight were administered (ntlol / kg is an abbreviation for 'tNanomol pro Kilograms).

The title compounds also performed significantly better than diazepan picrotoxin-induced ones Prevent convulsions in mice, with doses ranging from 50 to 1,200 nMol / kg s. c. were processed. However, they were not found to be effective against pentylenetetrazole-induced ones Seizures.

Other pharmacological characteristics which the title compounds contribute to Mice showed were: dose-dependent formation of eyelid paralysis (ptosis) (from 5 up to 500 nmol / kg s.c.), inhibition of rearing, i.e. a sedative activity (from 15 to 500 nAlol / kg s.c.) and extension of the hexobarbital Sleep time (from 40 to 500 nMol / Rg s.c.) The effects described above have strongly suggests potent neuropsychotropic activities, especially antipsychotic ones and anti-seizure activities, the mechanism of which is at least partially different differs from those as adopted for the mentioned standard drugs (IIökfelt, T. et al, Nature, London, 284, 515, 1980; Iversen, L.L., Nature, London, 285, 285, 1980).

To clinically evaluate the antipsychotic effects of this class of compounds To confirm, ceruletide was administered to patients suffering from hebephrenic or catatonic schizophrenia.

In a clinical pilot study, which is still ongoing, were 6 patients treated, 4 male and 2 female, aged 18 to 32 years, which under Hebephrenic schizophrenia (2 people) and catatonic schizophrenia (4 people) suffered.

Ceruletid was administered by intramuscular injection at a dose of 20 ßg (micrograms) administered, so far, two administrations with a time interval carried out for 48 hours.

During the observation period of the one week treatment the researchers have an improvement in social activity and affect, one Increase in promotion and motivation and a decrease in the overall rating of the "Brief Psychiatric Comprehensive Rating Shell Observed.

On the basis of these preliminary attempts, the possibility appears given, ceruletide and its analogues for therapeutic neuropsychiatric disorders Application.

The polypeptide of structure (I) which comprises ceruletide can administered either to humans or to animals by a variety of dosage forms via the parenteral route.

The polypeptides of structure (I) can be used as water-soluble salts, generally as alkali salts, such as sodium or potassium salts, or as alkylamine salts, preferably administered as diethylamine salts.

The pharmaceutical or veterinary agents which contain any of the polypeptides of structure (I) and / or salts thereof can be carried out in a conventional manner are produced and contain conventional carriers and / or extenders or

Thinners for peptides and their salts.

When formulated as an injection, the polypeptides reside in the structure (I) and their salts preferably as a sterile powder, which with water or reconstituted with other suitable vehicles for injection shortly before use will.

For example, are used for intravenous or intramuscular injections sterile aqueous isotonic solutions are used, preferably aqueous isotonic Sodium chloride solutions.

The sterile powder is easily obtained by lyophilization; in this case the active ingredient is mixed with an inert carrier such as lactose, mixed.

Alternatively, compounds according to the invention can be used as solutions in aqueous vehicles are present, and they may contain agents for formulation, such as stabilizing agents.

The average doses for ceruletide were of 0.5 nanograms / kg Body weight (i.v.) up to 600 nanograms / kg body weight (intramuscular), depending on of the diseases to be treated.

Polypeptides which are encompassed by the general formula (I) and which are of particular importance and represent preferred embodiments for the treatment of neuropsychiatric disorders according to the invention are listed below: (Ceruletide) (X = Pyr-Gln-Asp, Y = Thr, W = Met); (X = Pyr-Gln-Asp, Y = Thr, W = Nle); (X = Pyr-Gln-Asp, Y = Val, W = Nle); (X = Asp, Y = Met, W = Met); (X = Boc, Y = Thr, W = Leu); (X = Boc, Y = Thr, W = Nle); (X = H, Y = Thr, W = Nle).

Claims (7)

Neuropsychotropic drug Patent claims 1. Neuropsychotropic drug for use in therapy in humans and animals, characterized in that it comprises a polypeptide of the following formula: wherein X is hydrogen, t-butyloxycarbonyl (Boc), Asp, Pyr-Glu, Pyr-Gln-Asp or Pyr-Asn-Asp, Y is Thr, Met, Leu, Nle or Val and W is Met, Nle or Leu represents. 2. Neuropsychotropic drug according to claim 1, characterized in that g It is not noted that the polypeptide is present in an effective amount for the treatment of humans and animals, which among neuropsychiatric Suffer from disorders such as convulsive disorders, schizo-affective disorders, depressive syndromes and neurotic syndrome. 3. Neuropsychotropic drug according to claim 2, characterized in that g It is not noted that it is a preparation to be administered parenterally represents. 4. Neuropsychotropic drug according to claim 3, characterized in that g It is not noted that the polypeptide is ceruletide or its salts. 5. Neuropsychotropic drug according to claims 1 to 3, it is noted that there is one or more of the named Polypeptides at a dose level of 0.1 ng / kg body weight (especially in Case of intravenous injection) up to 5000 ng / kg (especially in the case of intramuscular Injection) as a mixture with conventional ones suitable for parenteral administration Includes straps. 6. Neuropsychotropic drug according to claim 4, in one pharmaceutical form, it is not noted that it is Ceruletid at a dose level of 0.5 ng / kg body weight (especially in the case of intravenous Injection) to 600 ng / kg (especially in the case of intramuscular injection) im Contains mixture with conventional carriers suitable for parenteral administration. 7. Pharmaceutical agent with quantitative proportions according to Claim 6 for the treatment of neuropsychotropic disorders, in particular schizophrenia, in which ceruletide as diethylamine salt in aqueous solution, which sodium thio Contains malate as an antioxidant, present or with lactose as a supporting agent Agent is freeze-dried.