JPS6036421A - Progressive senile idiot therapy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a new use of "minisomatostatin", particularly in the pharmaceutical field.

As used herein, the term "minisomatostatin" has a structure derived from that of somatostatin, a naturally occurring tetradecapeptide, and consists of a substantially smaller number of amino acid residues than somatostatin itself, and is either in its complete form or It is intended to include any known oligopeptide incorporating one or more partial peptide sequences contained in the derivatized form of the somatostatin molecule.

[Conventional technology]

Somatostatin itself is a compound of the following formula.

The essential drug group of somatostatin is the residue sequence - circle 1
c -Trp -Lys -Thr - [Barber et al., Nature
280, pp. 512-514 (1979) and 29
2, p. 5558 (1981)], the distinguishing characteristic of minisomatostatins is the presence of the -1-pharmaceutical group, either in intact or derivatized form.

Typical modifications of the pharmacophore made with minisomatostatin include, for example: replacement of the ring of ) -Phc7- to generate e.g. -Tyr7-, i > va411
Replacement of Thr10- by 1- (actually' 2 is
Replacement of β-0I-I group of -Thr- by methyl)
, iil) alkylation of the α-N-atom, e.g. methylation, iv) replacement of each residue by the corresponding I)-isomer, e.g. -(1)l-Trp8-+7) permutation, and in a few cases V) inversion of sequences. When such derivatizations are carried out, the structural relationship to the original pharmacophore is generally readily apparent.

In addition to the drug group, minisomatostatins also usually contain one or more lateral peptide units located on one or both sides of the drug group.

The uniqueness of the individual amino acid units present in such lateral units generally causes greater changes in minisomatostatin than the drug complex itself. That is, although generally one or more of the residues corresponding to -Phe6-1-Pl+c"-1'i'br12- and/or -5er18- are present, such lateral units are 3 and 14 (with or without the γS-residue; the above pair (γS-
When residues are present, they are joined to form a ring shape similar to that in somatostatin. Other bridging groups (typically polyalkylene bridging groups) are present to link the amino acid residues of the peptide sequence of the minisomatostatin molecule;
Additional or alternative ring shapes may be created, and the C- and N-termini of the peptide sequence of minisomatostatin may be directly linked to create a cyclic structure. Despite these changes, the pharmacodynamics of minisomatostatin is
It remains characteristic as before and shows minisomatostatin as a recognizable group.

[Disclosure of the invention]

According to this invention, surprisingly, minisomatostatin and especially the specific minisomatostatin SM described below
S and compounds II, III, IV and ■ are (
1) Presenile dementia, also known as Alzheimer's disease (A1.) (i.e., seen in patients aged 65 years); Dementia (SDAT)
It has been found to be useful in the treatment (treatment and prevention) of degenerative senile dementia, including senile dementia itself, also known as senile dementia.

Minisomatostatin suitable for use in this invention is disclosed in European Patent No. 29579 (U.S. Pat. No. 439,540).
No. 3 and Australian Patent Application No. 64688/80
and in particular those described in the Examples of the European Patent No.

The most preferred minisomatostatin for use in this invention is the compound represented by the formula (hereinafter abbreviated as SMS), the method of synthesis of which is described in the European patent mentioned above.

A second minisomatostatin suitable for use in this invention.
The group is of the type identified in Belgian patent no. Example 1-
20. Among this second group, minisomatostatin suitable for use in the present invention is a compound represented by the formula % (hereinafter abbreviated as compound II).

Another minisomatostatin i;t that can be used in this invention
It is expressed by the following formula.

[Haru tongue, Mekholism (Mctabolism) 2
731111Ii:il, 1:39 Sada <1978), Compound ■] [1-Lotupa Special 4. '1 Application No. 7810
No. 0994.9...Refer to Publication No. 1295, Compound IV
'l] [Pepper et al., Life Sciences (Li [c
5cicnccs) Vol. 34, 137], p.-1378 (1984) and European Patent Application No. 8210
See 6205.6 (Publication No. 7o 02 x), compound ■. This is cyclo-(N-Me-Ala-Tyr(I
))-Trp-Lys-Val-Pbc). ] (''1) All amino acid residues in the formula are shown according to the nomenclature and represent the L, -configuration unless otherwise specified.The residue -'Uhr-ol is the L-threoninol shown in the formula. -McAIa- indicates N-methylalanyl residue) [Effect] The usefulness of minisomatostatin according to the present invention, especially SMS and compounds II, lit, 1v and It can be shown by the standard gf-test model.

(1) Observational test in mice.

SMS to mice at doses of about 20 μg to about 2 my/K9, particularly about 50 μg to about 1.01 my/K9.
After subcutaneous administration of IJ, prolonged wakefulness and enhanced response to external stimuli were observed. Similar results were obtained with other minisomatostatins, 4.1j and compound 11, m, tv oyo: v + c p; with the same i) or with the same orc.

+21 Increased uptake of tertiary 14C-thioxycurcose into the brain JJtl.

So: J o 7 [J, Ccrcl]ral 131o
od Flow and〜1rLal)o1is… 1
Volume 7-36 (1981)], Zahaki', 4'< [
Brain Rcsearch 233 pages 347 (1
982)] and Macrotuho et al. [J, Ccrcbr
al 131ood; IINI Mctal]
About 20a! /Kq or about 2 m
y/K9, especially about 50/II! i' AC9 not (-5 approx. 1, □ my/K90:)=teS
After administering MS, 1 in the limbic system appears in specific areas of the brain, ribs, etc.
Increased uptake of 4C-deoxy/glucose was observed.

Similar results or other minisomatostatins, especially Compound I
I, III, IV and ■ obtained with the same dose or the same oak dose.

Also, minisomatostatin according to the present invention, especially S M
The usefulness of compounds 1], 111.1■ and V is that they exhibit endocrine dysfunction similar to that seen in patients with A I)/Sl) Δ′1゛ characteristic of patients with At)/Sl)Δ′1゛. Animals with a range of central nervous system (CNS) activity disorders, including impaired attention and behavior and cognitive and/or learning functions, such as impaired glucose metabolic control (particularly rat with islet cell tumor)
and in a model using cysteamine-treated rats. Improvements in CNS activity in such animals range from about 20μ7 to about 2m9/9, especially about 50μ! or about 1. , Om! J/K9 stimulant is observed when SMS is administered subcutaneously or intravenously.

Improvements in CNS activity are also observed with other minisomatostatins, particularly compounds It, III, 1v and ■, at the same dose or on the same order of mm.

Minisomatosfucin according to the invention, especially SMS as well as compound 11. The activities of III, 1■ and ■ are also confirmed, for example, by the clinical tests described below.

Study A, Effect of SMS in the presence or absence of co-administered glucose.

1') Moderate to severe AI according to the parameters described in SM-III (Diagnostic and Statistical Manual of Mental Disorders, Third Edition)
and ♂) except for patients with severe cardiovascular disease, hypotension (systolic pressure (120), severe endocrine disease, severe liver disease, renal failure and/or malabsorption symptomsffl)
The study was conducted using a test group consisting of 0 patients.

The study began with E Ii G and psychometrics at time zero. The patient was then given a placebo, glucose, S
MS or SMS+glucose was administered as below and E F, G and psychometric measurements were taken at 60, 120 and 1
Repeated after 80 minutes.

Psychometric measures include:

1) Choice association test [Buschke, "Choice association for the analysis of the mind and learning J J, Verbal Lcarnin"
gand Verbal Bclaviour 12
9543-550 (1973)] 11) Interpretation ability measurement [Muramoto et al.
Page 503 (1973) 111) Memory for Geometric Figures (Benton Modified Visual Retention Test) The test dose was administered as follows.

1v) For patients receiving Placepo, 100.0 mg of saline over 4 hours starting at time zero. An injection of nl was administered, plus oral placebo administration.

■) For patients receiving glucose, add a loading dose of 10 to 100 (e.g. 50 or 7
5) Glucose was administered 1-1 g.

yi) For patients receiving only SMS, saline and S
MS (Example described later) O, l ”? / ml solution 1
rnl was administered, plus oral placebo administration.

For patients receiving viDsMs+glucose, the loading dose of glucose in V) was administered orally in place of the placebo in the treatment of vi).

Additionally, the following parameters were monitored.

Hematology: R, 13, C,, II B, II C']
-, W, B, C, white blood cell percentage, sedimentation rate, blood glucose urine: albumin, glucose serum: alkaline phosphatase, S-ΔIaL, 5-A
5a L, 5-GTlS-bilirubin, 5--r4
, S-1' 3, S-1' S It, Creatinine"1, patients receiving SMS or SMS+glucose had better EEG results and mental health during the study than patients receiving placebo or glucose alone. Measurement results showed a significant improvement in symptoms.

Similar results were observed with other minisomatosfucins, especially compound 1.
1.111.1 ■ and ■ were obtained with the same G' or doses of the same order.

Test 1～. Long term test.

The long-term test is similar to test A in Section 1, AI)/S1)
Using 10 or more AT patients,
Test drugs were administered for 1 to 4 weeks.

SMS is administered to each patient at a daily dose of 0.01 to 0.2 mg, such as 0.01, 0.05 or 0.1 m'j
was administered subcutaneously or by infusion according to the general method described in Study A. Test patients were also given oral administration of curcose at IO to 100, for example 50 or 75 IO.
! A loading dose of i'/day was administered in addition to SMS.

Control groups received subcutaneous injections or infusions of placebo with or without concomitant oral administration of glucose.

The psychometric measurements of the test patients were as follows:
) or 1ill, the Plutchik Behavior Rating Scale, and the Unihiller Intelligence Test.

Over time, patients receiving SMS or SMS+glucose compared to patients receiving placebo or glucose alone.
showed significant improvement. In particular cases of patients receiving SMS (with or without glucose administration), evidence of increased environmental awareness, ease of contact, etc. was observed.

Similar results were obtained with other minisomatostatins, particularly compounds 11, III, IV and ■, at the same or the same alternating doses.

Once, the present invention provides a method for the treatment of progressive senile ij:1i (e.g. AI or SI) A T) in a subject in need of treatment, comprising administering to the subject an effective h1 of minisomatostatin. It provides:

As mentioned above, according to the invention, minisomatostatin (e.g. 5M5) can be administered alone as a single drug or in combination with other suitable drugs, e.g. curcose. can. For example,
According to the results of the study No. 1, co-administration with glucose can be used in the treatment of progressive senile +5', +i dementia in general or in patients with abnormally low serum glucose levels, for example, in combination with JLl. It was found that the effect of administered minisomatostatin was enhanced or blood clotting.

According to another aspect, the present invention provides a method for treating progressive senile dementia in a subject in need of treatment (eg, A 1. ) or SL) AT)
This provides a treatment method for

When administering minisomatostatin with curcose,
The administration of minisomatostatin and curcose is the same as 117.
They may be administered simultaneously, substantially simultaneously, or may be administered separately, for example, by multiple administrations, such as 12 doses of minisomatostatin and 1 dose of curucose 11.

The dose of minisomatostatin used according to this invention is:
This will, of course, vary depending on the method of administration, the particular minisomatostatin used, the patient's condition and the desired treatment.

Generally, SMS provides a daily dose of about 1.0 to about 0.001, preferably about 0.005 (:'t''+0.05) to about 021'1 g/eye, preferably parenterally. JlIQi administered once a day or twice a day in divided doses, or in the form of a sustained-release preparation, may result in severe results (1). Suitable for parenteral administration. Your form is
5MS about 00005 to 1, preferably about 0.002
5 (particularly 0.025) to about 0.2 m'j mixed with a suitable diluent or carrier.

Other minisomatostatins, especially compounds II1. llI,
1v and 5X are at the same or similar levels, depending on their relative activity compared to, for example, S l't45.

When the treatment is carried out in combination with glucose, it is suitable that curcose is administered orally. ) j1/varies depending on metabolism. Generally, a suitable daily dose of crucose for use in this invention is JO to 100 S/, for example 10
to 757.4jj and 15 to 507 autographs.

z) Minitsuma 1 Hescutin needs to have sufficient +iiJ capacity during the treatment sequence at the desired dose.

El, SMS, which is a constant minisomatostatin, is 4”f
The river used in this invention: 1: is well accepted. (), 02.0.8 and O” 3.2 mV/9/eye: Primary long-term (repeated dose) toxicity of SMS administered intravenously to pegle dogs over 4 weeks at 1 leBel. In experiments, the non-toxic effective level is 0.2 mg/K9/
S
In the second experiment in which the drug was administered intraperitoneally, the non-11T effective level was 4m! ? It was decided that the date would be 9/.

The minisomatostatin used in this invention can be administered in free form, in pharmaceutically acceptable salt form, or in 314 form. Such salt or complex forms are known and exhibit the same order of activity and tolerability as the free forms. These can be manufactured by conventional methods. Therefore, minisomatostatin referred to in this specification, for example, SMS
and Compounds II, Ill, IV, ■ shall include, in addition to the free base form, pharmaceutically acceptable salt forms and 311-isomer forms.

Minisomatostatin can be administered in the form of a pharmaceutical composition comprising minisomatostatin mixed with a pharmaceutically acceptable carrier or bulking agent. They are preferably formulated in a dosage form suitable for injection, eg for parenteral administration.

A suitable side shape for injection may be, for example, according to the example below.
It can be manufactured by the standard method.

〔Example〕

Example 1 Using the following ingredients, the active ingredient (SMS) was 0.025
．． Aqueous solutions consisting of 0.05, 0.1 and 0.5 nrq/ml were prepared.

Solutions for injection are prepared by standard methods, sterile filtered and CO
Ampules were filled under sterile conditions in 2 gases.

Claims (7)

[Claims] (1) A stimulant consisting of an effective amount of minisomatostatin.
Senile v:11 treatment agent. (2) The agent according to claim 1, wherein minisomatostatin is SMS represented by the formula. (3) The agent according to claim 1.h;2, wherein minisomatostatin is a compound II represented by the formula %. (4) The agent according to claim 1, which is minisomatostatin or a compound Ut represented by the formula. (5) The agent according to claim 1, wherein minisomatostatin is a compound IV represented by the formula. (6) The agent according to claim 1, wherein minisomatostatin is a compound V represented by the formula. (7) The agent according to claim 1, wherein minisomatostatin is administered together with glucose.