JPS61277616A - Medicinal composition - 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 Field of Application] The present invention relates to a method for treating and/or preventing hyperglycemia and a composition used in this method.

[Conventional technology]

British patent application No. 2021100A is based on formula (4) (in which R
Each of "and R" may be the same or different and each represents a hydrogen or halogen atom or 1. represents an alkyl or alkoxy group containing ~4 carbon atoms.

X' is an oxygen or sulfur atom, an imino group, or 2 in an alkyl group.
represents an acylamino group or a methylene group containing ~4 carbon atoms, each of d and bo may be the same or different (1 represents the number of 1, 2 or 3, and d is 2 or 3)
and their physiologically acceptable acid addition salts. The compounds involved are described therein as having long-lasting antihypertensive activity.

European Patent No. 0072954 has a general formula [where R
” and R2a may be the same or different and are hydrogen or halogen, alkyl or alkoxy, each of which has 1 to 4 carbon atoms, R33 and R4
3 may be the same or different and are hydrogen or alkyl having 1 to 4 carbon atoms, and R'a,
R"+R" and R83 may be the same or different and are hydrogen or alkyl having 1 to 4 carbon atoms, or R63 and R6a together represent an ethylene group] Discloses the salts of the compounds Cloudy Soha [excluding 2-(N-aminoisoindolinyl)-imidacilline and 4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline].

Compounds of formula (B) are disclosed therein as having long-lasting hypertensive activity.

[Summary of the invention]

Compounds of formula (5), including those specifically disclosed in GB 202110OA, also have antihyperglycemic activity and are therefore useful for the treatment of hyperglycemia in mammals, including humans.
It has also been found that it may be used for prevention.

It has been found that the compound consisting of Bunmu Q3) has antihyperglycemic activity and may be used for the treatment and/or prevention of hyperglycemia in mammals including humans.

Accordingly, the present invention provides methods for treating and/or preventing hyperglycemia in humans or non-human mammals in need of such treatment and/or prevention in amounts that are effective and non-toxic to the mammal in need of such treatment and/or prevention. I) (In the formula, each of R1 and R2 may be the same or different and represents a hydrogen or halogen atom, or an alkyl or alkoxy group containing 1 to 4 carbon atoms, and X is an oxygen or sulfur atom, an imino group, represents an acylimino group or methylene group containing 2 to 4 carbon atoms in the acyl group, n and m each may be the same or different and represent a number of 1, 2 or 3, and p is 2 or or a pharmaceutically acceptable acid addition salt thereof; or [wherein R3 and Each of R4 is a hydrogen or halogen atom; or an alkyl or alkoxy group (any of the groups is 1
~4 carbon atoms); and either R3 or R4 must be hydrogen;
R' and R6 are the same or different and are either hydrogen or alkyl of 1 to 4 carbon atoms, and R? , Ha, RQ and RIO may be the same or different and are hydrogen or alkyl of 1 to 4 carbon atoms or R', R' and R'M
represents an alkyl group of 1 to 4 carbon atoms.

One preferred subgroup of compounds of formula (I) has the general formula (wherein R' + R" y n I In and p are of formula (I)
9 or a pharmaceutically acceptable acid addition salt thereof.

Another preferred subgroup of compounds of formula (Il) is the general formula (5)
R2 (wherein 1 and R2 are as defined in the formula (with respect to Il)).

One particularly preferred subgroup of compounds of formula (Il) are those represented by the general formula (■ in which R'' is hydrogen or chlorine) or a pharmaceutically acceptable acid addition salt thereof.

Preferably R'' is substituted in the ortho position on the phenyl ring to one of the -Cut moieties.

In a preferred embodiment, the compound of formula (1) is 4-chloro-
2-(2-imidazolin-2-ylamino)isoindoline or a pharmaceutically acceptable acid addition salt thereof.

In another preferred embodiment, the compound of formula (1) is 2-(2
-imidazolin-2-ylamino)isoindoline or a pharmaceutically acceptable acid addition salt thereof.

The present invention also provides a compound of formula (11) or formula (II) or a pharmaceutically acceptable acid addition salt thereof for use in the treatment and/or prevention of hyperglycemia.

In another aspect, the invention also provides the use of a compound of formula (I) or formula ([I) or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment and/or prevention of hyperglycemia. provide.

In another embodiment of the present invention, a compound of the formula (fil) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier thereof is used for the treatment and/or prevention of hyperglycemia. Pharmaceutical compositions for use are provided.

Compounds of the formula (Il) are disclosed in British Patent No.
may be manufactured using methods well known to those skilled in the art as disclosed in No.

Compounds of formula ([[) are e.g. E p , T O0729
54 using methods well known to those skilled in the art.

Suitable pharmaceutically acceptable acid addition salts of compounds of formulas (Il and (II)) and methods for preparing these salts are disclosed in British Patents No. ?2021100A and EP0072954, respectively.
Disclosed in the issue.

Administration to mammals may be by oral or parenteral administration.

Preferably, the compound of formula (■) or formula (7) or a pharmaceutically acceptable acid addition salt (hereinafter referred to as "drug") is in the form of a unit dosage composition, e.g. a unit dosage oral or parenteral composition. This unit dose will usually consist of 0.1 to 550,119 units of ``drug'', rather than 0.1 to 1000 units.

Such compositions can be disintegrated by mixing and suitably made for oral or parenteral administration and as such in tablets, capsules, oral solutions, powders, granules, troches, reproducible powders, injections and perfusions. may be in the form of a solution or suspension. Orally administrable compositions, especially shaped oral compositions, are preferred. This is because they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in unit doses and may contain conventional additives such as binders, fillers, diluents,
Contains tableting aids, lubricants, disintegrants, colorants, flavors and wetting agents. The tablets may be coated by methods well known to those skilled in the art.

Preferred fillers for use are cellulose, mannitol,
Contains lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone, and starch derivatives such as starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

These solid oral compositions may be manufactured by conventional methods such as mixing, filling, tabletting, etc. Repeated mixing operations may be used to distribute the active ingredient throughout these compositions using large amounts of filler.

Such operations are of course well known to those skilled in the art.

Oral solutions may be presented, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as a dry product which can be redissolved with water or other suitable vehicle before use. Such solutions may contain conventional additives such as suspending agents such as sorbisol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents such as lecithin.

Sorbitan monooleate or gum arabic; non-aqueous media (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives such as methyl or propyl p-hydroxy It may also contain benzoate or sorbic acid and, if desired, conventional flavoring or coloring agents.

Oral formulations also include conventional sustained release formulations such as tablets or granules with enteric coatings.

Liquid unit dosage forms containing the drug and sterile vehicle are prepared for parenteral administration. Depending on the vehicle and concentration, the drug may be suspended or dissolved.

Parenteral solutions usually dissolve the ``drug'' in a vehicle and
It is manufactured by sterilizing and sealing the vials or ampoules before filling them.

Advantageously, auxiliary agents such as local anesthetics, preservatives and buffers are also dissolved in the vehicle. To increase stability, the composition can be filled into vials and frozen where the water is removed under vacuum.

Parenteral suspensions are manufactured in substantially the same manner, except that
The drug is suspended in a vehicle instead of being dissolved and is sterilized by exposure to ethylene oxide before being suspended in a sterilizing medium. Advantageously, a surfactant or wetting agent is included in the composition to aid in uniform distribution of the Drug.

To treat hyperglycemic animals, especially dogs, the total daily dose for an adult of 70 to 9 years is approximately 0.
02 s my/kg to 2 s m9/K For example 0.
It will be administered orally, usually once or twice a day, from 19/17 to 20/20 to 9/20.

〔effect〕

The following pharmacological data illustrate the activity of the Drug in tests indicating its potential use in the treatment of hyperglycemia.

Pharmacological data A, diabetic mice, midday blood glucose concentration 5-6 weeks old C57B1/KSJ diabetes (db/db)
Five female mice were placed in each two cages and fed with powdered oxoid rat and mouse feed for one week. Midday blood glucose concentrations were then determined for all mice. Animals were subsequently fed powdered feed or the same feed containing the test compound. After 7 days, midday blood glucose was determined again in all mice.

The concentration of glucose in midday blood samples taken at the end of each treatment period was the mean (rrIM) S,D
, as shown below. Comparative values for animals fed only powdered oxoid diet are also shown.

B, obese mice, oral glucose tolerance test C57B
1/6 oblob male mice were housed 6 per cage and fed powdered oxoid rat and mouse chow for at least one week.

Mice were then fed powder chow alone or chow containing the test compound for 8 days. After 88 oral glucose loading (3,
All mice were fed for 5 hours before being fed 9/9). Blood samples for glucose analysis were taken at 0.45, 90 and 135 minutes after glucose administration. The results are shown below as a percentage decrease in the area under the blood sugar curve when compared to the control group. Six mice were used for each treatment.

C, Adrenergic exacerbation in mice Glucose tolerance A C++LP female mouse weighing about 25 g was treated with water (10g/g/9g).
) or fasted for 24 hours before receiving the test compound orally. After 30 minutes, glucose (1,97 units) and epinephrine (300 μE/kli) were injected subcutaneously. Blood sample for glucose analysis 0,3 after glucose administration
Successive samples were taken from the tail of each mouse at 0, 60, 90 and 120 minutes and the results obtained are shown below as % reduction in area under the blood glucose curve. Test compound-treated groups were compared to water-administered control groups in seven separate experiments.

Six mice were used in each treatment group.

Indoline Toxicological Data No harmful toxicological effects were observed in all of the above-mentioned experiments.

Claims (7)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 may be the same or different and each represents a hydrogen or halogen atom or 1 to 4 carbon atoms X represents an oxygen or sulfur atom, an imino group, an acylimino group or methylene group containing 2 to 4 carbon atoms in the acyl group, and each of n and m may be the same or different. often represents the number 1, 2 or 3, and p represents the number 2 or 3, and when the part ▲ is a mathematical formula, chemical formula, table, etc. ▼ is present in the formula (I), R^1 or R Either ＾2 must represent hydrogen) or a pharmaceutically acceptable acid addition salt thereof; or formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [R＾3 in the formula and each of R^4 is either a hydrogen or halogen atom; or an alkyl or alkoxy group (any of which groups may have 1 to 4 carbon atoms); and R^3 or R Any of ^4 must be hydrogen; R^5 and R^6 are the same or different and are either hydrogen or alkyl of 1 to 4 carbon atoms, and R ^7, R^8, R^9 and R^1^0
may be the same or different and are either hydrogen or alkyl of 1 to 4 carbon atoms or R^7 and R^8 together represent an ethylene group, and R When ^7 and R^8 represent an ethylene group, R^5
, R^6, R^9 and R^1^0 are 1~
or a pharmaceutically acceptable acid addition salt thereof; and a pharmaceutically acceptable carrier therefor, for use in the treatment and/or prevention of hyperglycemia. . (2) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R^1, R^2, n, m, and p are as specified for formula (I)) The composition according to claim (1), comprising a compound or a pharmaceutically acceptable acid addition salt thereof. (3) Compound of general formula (IV) ▲Mathematical formula, chemical formula, table, etc.▼(IV) (in the formula, R^1 and R^2 are as defined for formula (I)) or its pharmaceutically acceptable compound The composition according to claim (1) or (2), which comprises an acid addition salt that can be used as an acid addition salt. (4) General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^1^1 is hydrogen or chlorine) Consisting of a compound or a pharmaceutically acceptable acid addition salt thereof A composition according to any one of claims (1) to (3). (5) 4-chloro-2-(2-imidazolin-2-ylamino)isoindoline; 2-(2-imidazoline-2
-ylamino)isoindoline; 2-(2-oxazolin-2-ylamino)isoindoline; and 2-(2-
The composition according to claim (1), comprising a compound selected from the group consisting of imidazolin-2-ylamino)-1,2,3,4-tetrahydroisoquinoline; or a pharmaceutically acceptable acid addition salt thereof. . (6) The composition according to claim (1), comprising 4-chloro-2-(2-imidazolin-2-ylamino)isoindoline or a pharmaceutically acceptable acid addition salt thereof. (7) The composition according to claim (1), comprising 2-(2-imidazolin-2-ylamino)-isoindoline or a pharmaceutically acceptable acid addition salt thereof.