KR830001244B1 - Process for preparing spiro-polycyclic imidazolidine dione derivatives - Google Patents

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Description

Process for preparing spiro-polycyclic imidazolidine dione derivatives

The present invention relates to a spiro-polycyclic imidazolidinedione derivative of the following formula (I) useful as a therapeutic agent for the treatment of chronic diabetes and a method for preparing a pharmaceutically toxic metal salt thereof.

In the above structural formula

A is naphth-α, β-0,

Atracene-α, β-0 of the following structural formula (IV), or

Substituted naphth-α, β0- with one or two identical substituents selected from methyl, chloro or bromine and Y is CH ₂ , S, SO, SO ₂ or 0

A and Y together represent naft-α, θ-0 of the following structural formula (V).

Many antidiabetic agents, such as sulfonyl urea, are effective in lowering blood sugar when administered orally, but are insufficient to suppress or alleviate chronic diabetes such as diabetic cataracts, neuropathy, retinopathy and kidney disease. According to US Pat. No. 3,821,383, aldose reductase inhibitors such as 1,3-dioxo-1H-benz [d, e] -isoquinoline-2 (3H) -acetic acid and derivatives thereof are useful in this field. Spiro-thienohydantoin derivatives are also aldose reductase inhibitors according to US Pat. No. 4,127,665. These compounds show the enzymatic reduction effect of aldoses such as glucose and galactose, compared to polyols such as sorbitol and glactitol, which can lead to retina and lens in cataracts caused by diabetes mellitus, and neuronal peripheral nerves and diabetes mellitus. Prevents or prevents accumulation of harmful polyols, which are harmful to kidneys.

When A is naphth-α, β-0, anthracene-α, β-0 or substituted naft-α, β-0, Y is bonded at the α or β position of A. This form of attachment determines whether ring A is syn or anti in relation to the hydantoin or imidazolidinedione ring. For example, when sulfur binds to the α position of naphth-α, β-0, it becomes the spiro-polycycloimidazolidinedione derivative B of the anti configuration, which is 2'-3'-dihydro-spiro [already It is named dazolidine-4,4 '-[4'H] -naphtho [1,2-b] thiopyran] -2,5-dione.

In addition, when sulfur is bonded at the β position, it is a derivative C of the syn sequence, which is 2 ', 3'-dihydro-spiro [imidazolidine-4,4'-[4'H] -naphtho [2,1- b] thiopyran] -2,5-dione.

When A and Y together are naft-α, θ-0, the resulting compound is a spiro-polycyclicimidazolidinedione derivative D which is a 2 ', 3'-dihydro-spiro [imidazolidine -4,1'-phenalene] -2,5-dione.

Preferred among the polycyclic imidazolidinedione derivatives of the present invention are compounds of formula (I) wherein A is naphth-α, β-0 and Y is CH ₂ , sulfur or oxygen and A is ε-methoxynaphth is a compound of formula (I) wherein -α, β-0 or δ-chloronaft-α, β-0 and Y is CH ₂ , sulfur or oxygen. Examples of particularly preferred compounds are as follows.

A is naphth-α, β-0, Y is sulfur and 2 ', 3'-dihydrospiro [imidazolidine-4,4' bonded to the β position of naphth-α, β-0 -[4'H'-naphtho [2,1-b] thiopyran] -2,5-dione.

2 ', 3'-dihydro-7' wherein A is ε-methoxynaphth-α, β-0, Y is oxygen and oxygen is bonded at the α-position of ε-methoxynaphth-α, β-0 -Methoxy-spiro [imidazolidine-4,4 '-[4H']-naphtho [1,2-b] pyran] -2,5-dione.

2 ', 3'-dihydro-spiro [imidazolidine-4,4' wherein A is naphth-α, β-0, Y is sulfur and sulfur is bonded at the α position of napht-α, β-0 -[4'H] -naphtho [1,2-b] thiopyran-2,5-dione.

2 ', 3'-dihydro-spiro [imidazolidine-4,1'-phenalene] -2,5-dione wherein A and Y together are naphth-α, θ-0.

2 ', 3'-dihydro-spiro [imidazolidine-4,4 wherein A is naphth-α, β-0, Y is oxygen and oxygen is bonded at the α position of napht-α, β-0 '-[4'H] -nipro [1,2-b] pyran] -2,5-dione.

6-chloro-4'H-2 ', 3' wherein A is δ-chloronaphth-α, β-0, Y is oxygen and oxygen is bonded at the α-position of δ-chloronaphth-α, β-0 -Dihydro-spiro [imidazolidine-4,4'-naphtho [1,2-b] pyran] -2,5-dione and A is naphtho-α, β-0 and Y is CH ₂ 1 ', 2', 3 ', 4'-tetrahydro-spiro [imidazolidine-4,1'-phenanthrene] -2, with CH ₂ bonded to the α position of naphth-α, β-0 5-dione.

The present invention provides enzymatic reduction of aldose in vivo. Methods of treating diabetic patients to inhibit harmful and to prevent or alleviate complications of diabetes such as cataracts, kidney disease, neuropathy and retinopathy. This treatment proceeds by administering an effective amount of the compound of formula (I) in the patient. In addition, an effective amount of a pharmaceutically acceptable carrier and a spiro-polycyclic imidazolidinedione derivative of the formula (I) is administered to inhibit the harmful effects of enzymatic reduction of aldose and to prevent cataracts, neuropathy, nephropathy or retinopathy. It can prevent or alleviate the complications of diabetes.

The polycyclimidazolidinedione derivatives of the present invention are readily prepared from ketones of the following formula (II).

In the above structural formula

A and Y are as described above.

For example, imidazolidinedione derivative B is prepared from a ketone of the formula

Imidazolidinedione derivative D is prepared from a ketone of the formula

Imidazolidinedione derivatives are prepared by condensing a ketone of formula (II) with an alkylimetal cyanide such as sodium cyanide or potassium cyanide and ammonium carbonate. The reaction is usually carried out in the presence of an inert polar organic solvent which can be intermixed with the reactants and reagents and preferred solvents include lower alkylene glycols such as cyclic ethers such as dioxane and tetrahydrofuran, lower alkylene glycols such as ethylene glycol and trimethylene glycol, methanol, ethanol And lower alkanols mixed with water such as isopropanol and N, N-di (lower alkyl) lower alkanoamides such as N, N-dimethyl formamide, N, N-diethylformamide and N, N-dimethyl acetamide, and the like. There is this.

In general, the reaction is carried out at 50 to 150 ° C., preferably at 90 ° to 130 ° C. for 2 hours to 4 days (related to temperature). The amount of reactants and reagents used in the reaction should be at least stoichiometric, but it is preferable to use an excess of alkali metal cyanide and ammonium carbonate compared to the starting material ketone to obtain the best yield. After the reaction is completed, the desired product can be easily separated by conventional methods. For example, the reaction mixture is diluted with water, the resulting aqueous solution is cooled to room temperature and acidified to give the desired spiro-polycycle.

Ketones of the formula (II) as starting materials can be readily obtained or prepared by known methods. Representative preparation methods include 4- (1- or 2-naphthyl or anthracenyl) butyric acid, 3- (1 or 2-naphthoxy or naphthylthio) propionic acid or monocyclic compounds of naphthyl, naphthoxy or naphthylthio compounds Or a cyclodelone, 4H-2,3-dihydropyran-4-one or 4H-2,3-dihydrothiopyran, by reacting a di-substituted form (where the substituents are as described above) with a Friedel-Crafts ring closure reaction. -4-one to form work. In this case, the acid may be a condensed naphthalene or anthracene compound with butyrolactone or a condensed naphthol or thionaphthol with acrylonitrile under basic conditions, thereby producing 3- (1- or 2-naphthoxy or naphthylthio) propionitrile. Obtained by hydrolysis.

For example, 5-chloro naphth-1-thiol is condensed with acrylonitrile in the presence of a base such as benzyltriethylammonium hydroxide and hydrolyzed in the presence of an acid or base to yield 3- (5-chloronaphthyl-1- Thio) propionic acid is obtained. The Friedel-Crafts reaction is carried out in the presence of an acid using a reagent such as polyphosphoric acid, in which polyphosphoric acid associates a piece of propionic acid with a naphthyl ring to form 7-chloro-4H-2 ', 3-dihydro-naphtho [2,1 -b] thiopyran-4-one.

Pharmaceutically toxic metal salts can be readily prepared from conventional compounds of formula (I) by conventional methods. That is, the spiro-polycyclic imidazolidinedione derivatives are treated with aqueous solutions of pharmaceutically toxic metal hydroxides or other metal bases and the resulting solution is preferably evaporated under reduced pressure to obtain salts. Alternatively, a lower alkanol solution of spiro-polycyclicimidazolidinedione derivatives is mixed with an alkoxide of a desired metal and the alkoxyl solvent is evaporated to form a pharmaceutically toxic metal hydroxide, base and alkoxide. Acidity

The spiro-imidazolidinedione derivatives of the present invention are useful as aldose reductase inhibitors and are effective in preventing and treating complications of chronic diabetes such as cataracts, retinopathy, kidney disease and neuropathy. The compound is administered to the subject by conventional methods of administration, such as oral, intravenous, intramuscular, subcutaneous, topical, eye drop, and intraperitoneal administration. Generally, the compound is administered at 1 to 250 mg / kg body weight per day. It depends on the condition of the patient and the competence of the attending physician.

This compound, alone or in the form of a pharmaceutical formulation using a pharmaceutically toxic carrier such as an inert solid diluent, an aqueous solution or various non-toxic organic solvents, in the form of a dosage form such as gelatin capsules, tablets, powders, troches, syrups, injections and the like Administered. Such formulations include water, ethanol, gelatin, lactose, starch, vegetable oil, petroleum jelly, gums, glycols, talc, benzyl alcohol and known carriers. If necessary, the pharmaceutical preparation may contain adjuvants such as preservatives, wetting agents, stabilizers, lubricants, absorbents, buffers and isotonic agents.

The effectiveness of the spiro-polycyclicimidazolidinedione of the present invention in treating chronic diabetes complications can be measured by the following standard biological and pharmaceutical tests.

1) Determination of the ability to inhibit enzymatic activity of free aldose reductase

2) Determination of the ability to reduce or inhibit the accumulation of sorbitol in the sciatic nerve of drug-induced (ie diabetic) rats.

3) Measurement of ability to reverse sorbitol levels already elevated in sciatic nerve and lens of rats with chronic diabetes mellitus induced by sciatic nerve and drugs

4) Measurement of the ability to prevent or inhibit the formation of galactitol in the lens of mice with acute galactoseemia.

5) Determination of the ability to delay cataract formation and reduce the opacity of the lens of mice (severe) with chronic galactoseemia

The present invention describes the preparation of spiro-polycyclicimidazolidinedione derivatives and their biological activities through the above tests (1) and (2). However, this does not limit the scope of the present invention.

Common recipe

The spiro-polycyclicimidazolidinedione derivatives to be described in Table 1 below are synthesized from ketones of formula (II) by the following method.

(g ketone 5/2 to 3 g potassium cyanide, 2 to 10 g ammonium carbonate, 10 to 25 ml ethanol and 0 to 25 ml water are heated in a steel bomb to a temperature of 100 to 130 ° C. for 15 to 75 hours. The reaction mixture is cooled, diluted with the same volume of 1N aqueous potassium hydroxide and washed four times with ether.

Neutralize with cooled aqueous layer 12N hydrochloric acid and extract the neutralized solution four times with 100-200 ml of ethyl acetate. The combined organic layers are extracted again with saturated brine. The organic layer is dehydrated with a reagent such as magnesium sulfate, filtered and the solvent is removed in vacuo and the residue is recrystallized from a suitable organic solvent. Examples of the prepared compounds and their properties are described in Table 1 below.

TABLE 1

Examples of Spiro-polycyclicimidazolidinedione Derivatives and Their Physical Properties

Aldose Reductase Inhibitory Activity

The spiro-polycyclic imidazolidine dione derivatives prepared in the above examples were prepared by the method of US Pat. No. 3,821,383 based on the method of Hayman et al, Journal of Biological Chamistry 240, 877 (1965). Test for the ability to reduce or inhibit activity. The material used is a reductase obtained from bovine lens, which is partially purified. Drugs are tested at 10 ^-4 molar concentrations, optionally at lower concentrations, and the results are expressed as percentage inhibition against enzymatic activity.

* This number is the average of 2 to 3 experiments.

Suppression of Sorbitol Accumulation

The accumulation of sorbitol in the sciatic nerve of rats streptozotocinized (ie, diabetic) with the spiro-polycyclic imidazolidinedione derivatives prepared in the above examples was described in US Pat. No. 3,821,383. Test to inhibit.

In this study, sorbitol accumulation in the sciatic nerve is measured 27 hours after diabetes induction. The compound is administered orally at 4,8 and 24 hours after streptozotocin administration. The results obtained with this method were% inhibition by this compound compared to the absence of the present compound (ie, untreated animals with sorbitol levels typically between about 50 and 100 mM / g tissue and up to 400 mM / g tissue within 27 hours of the test period). To be displayed.

* Example 5 showed 58% inhibition by administering 5.0 mg / kg, and Example 8 showed 28% inhibition by administering 5.0 mg / kg.

Claims (1)

The ketone of the following formula (II) is condensed with at least stoichiometric amounts of alkali metal cyanide and ammonium carbonate at 50 to 150 ° C. for 2 to 96 hours in an inert, polar organic solvent. A method for producing a spiropolycyclic imidazolidinedione derivative.

In the above structural formula A is naphth-α, β-0,

Anthracene-α, β-0 of the following structural formula (IV),

Or substituted naft-α, β-0 having one or two identical substituents selected from methyl, chloro or bromo and Y is CH ₂ , S, SO, SO ₂ or 0 or A and Y together are (V) shows naft-α and θ-0.