ZA200509286B - Carboxylic compound and medicine comprising the same - Google Patents

Description

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.

SPECIFICATION oY

Carboxylic compound and medicine comprising the same

Technical Field

The present invention relates to a carboxylic compound which exerts potent hypoglycemic action, plasma insulin decreasing action, and triglyceride decreasing action, and enables preventive and/or therapeutic treatment of diseases such as diabetes, complications of diabetes, hyperlipemia, and atherosclerosis, without causing weight gain or obesity. The present invention also relates to a medicine comprising the compound.

Background Art

Diabetes, which is a metabolic disorder caused by plural factors, is roughly classified into Type I diabetes caused by failure of insulin secretion and Type II diabetes resulting from decline of insulin sensitivity in peripheral tissues. A rapid increase of Type II diabetes has been recognized in recent years, attributable to environmental factors such as obesity and hyperphagia as background factors.

Diabetes prevalence rate in the world is estimated to be 5%.

Insulin and sulfonylurea agents are frequently used for medicinal treatments of diabetes. However, insulin and sulfonylurea agents induce hypoglycemia as a side effect and sulfonylurea agents also induce secondary pancreatic failure because of exhaustion of pancreas. Biguanide agents improve the insulin sensitivity and slightly normalize hyperglycemia, however, the agents have possibility to induce lactic acidosis. A thiazolidinedione type therapeutic medicine for diabetes, which has been recently developed, has an improving effect on insulin resistance in periphery (Expert Opinion on Investigational Drugs, 9, pp1347-1361, 2000), and is considered to achieve suitable blood glucose control without causing hypoglycemia. However, the medicine is reported to have side effects such as serious hepatic disorder. Therefore, a non-thiazolidinedione type medicine for improving insulin resistance is desired.

As a non-thiazolidinedione type compound, 2,2-dichloroalkanecarboxylic acid compound is known to lower a blood glucose level in a diabetes-model animal,

vd and also exhibit decreasing actions of plasma insulin and plasma triglycerides (European Journal of Medicinal Chemistry, 33, pp775-787, 1998).

Hyperinsulinemia suggests the presence of insulin resistance, and hyperlipemia, as a dysfunction of lipid metabolism with diabetes, is considered to be a risk factor of atherosclerosis. Therefore, improvements of the above symptoms are important for preventive and/or therapeutic treatment of diabetes and complications of diabetes.

For example, the following Compound A exert anti-diabetes actions in various animal models (Compound 3e described in Eur. J. Med. Chem., 33, pp.775-787, 1998; Metabolism, 48, pp 34-40, 1999), and effectiveness thereof is considered to be superior to that of thiazolidinedione type compounds. Compound A has no PPAR y activating action which is the mode of action of thiazolidinedione type compounds (Archives of Toxicology, 73, pp440-450, 1999). Therefore,

Compound A has an apparently different action from that of thiazolidinedione type compounds, and is expected to achieve reduction of side effects.

Compound A

Cl 0

OH ci Ci

Disclosure of the Invention

In order to achieve effective treatment of diabetes and complications of diabetes, a compound is desired which has higher activity or has equal or higher activity at a lower dose to easily control a blood glucose level and to avoid drug interactions under combination with other agents, as well as to reduce or eliminate side effects.

From the forgoing point of view, a compound which is more potent than

Compound A or has the same level of activity at a lower dose as compared with

Compound A is expected to be useful for preventive and/or therapeutic treatment of diabetes and complications of diabetes, and moreover, hyperlipemia and atherosclerosis.

The inventors of the present invention made researches to find a more active compound. As a result, the inventors found that a carboxylic compound ro represented by the following general formula (1) has a potent hypoglycemic action and is useful as a medicine for preventive and/or therapeutic treatment of diabetes, complications of diabetes, hyperlipemia, atherosclerosis and others, without causing weight gain or obesity. The present invention was achieved on the basis of the above findings.

The present invention thus provides a compound represented by the following general formula (1):

Cl

Cl. Cl (CH2)m (CHy)n ~COLH [wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents -CH(OR)- (wherein R represents hydrogen atom or a protective group of hydroxyl group) or -C(=0)-], a salt thereof, or an ester thereof.

The present invention also provides a medicine which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the aforementioned general formula (1) [wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents -CH(OR)- (wherein R represents hydrogen atom or a protective group of hydroxyl group) or -C(=0)-], a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof.

The aforementioned medicine can be used as a medicine for preventive and/or therapeutic treatment of a disease selected from the group consisting of hyperlipemia, atherosclerosis, diabetes, complications of diabetes, inflammation, and cardiopathy. The medicine is preferably provided as a pharmaceutical composition comprising the aforementioned substance as an active ingredient and a pharmaceutically acceptable carrier.

From another aspect, the present invention provides a use of a substance selected from the group consisting of a compound represented by the aforementioned general formula (1) [wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents -CH(OR)- (wherein R represents hydrogen atom or a protective group of hydroxyl group) or -C(=0)-], a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof for the manufacture of the aforementioned medicine, and a method for preventive and/or therapeutic treatment ro AL of a disease selected from the group consisting of hyperlipemia, atherosclerosis, diabetes, complications of diabetes, inflammation, and cardiopathy which comprises the step of administering to a mammal including human an effective amount for preventive and/or therapeutic treatment of a substance selected from the group consisting of a compound represented by the aforementioned general formula (1) [wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents -CH(OR)- (wherein R represents hydrogen atom or a protective group of hydroxyl group) or -C(=0)-], a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof.

Best Mode for Carrying out the Invention

As the salt of the compound represented by the general formula (1), examples include salts of alkali metals such as sodium salt and potassium salt; salts of alkaline earth metals such as calcium salt and magnesium salt; organic base salts such as ammonium salt and trialkylamine salt; mineral acid salts such as hydrochloride and sulfate; organic acid salts such as acetate. Among these examples, physiologically acceptable salts are preferred.

The physiologically acceptable ester of the compound represented by the general formula (1) is an ester formed from the carboxyl group of the compound represented by the general formula (1), and preferred to be an ester that increase an absorption rate from intestinal canal in oral administration and is susceptible to hydrolysis after being absorbed in vivo. Examples include an alkyl ester (the alkyl group may be linear, branched, cyclic, or combinations thereof, for example the alkyl group has 1 to 20 carbon atoms, the alkyl group may contain a hetero atom such as oxygen atom and nitrogen atom on the alkyl chain and/or one or more unsaturated bond, and may have one or more optional substituents on the alkyl chain) and an aryl ester. More specifically, examples include ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-0xo0-1,3-dioxolen-4-yl) methyl ester, cyclohexyloxycarbonylethyl ester. However, the esters are not limited to these examples. Further, the physiologically acceptable amides of the compound represented by the general formula (1) may be used. An example includes methyl amide.

¥ - t

In the general formula (1), W represents -CH(OR)- (wherein R represents hydrogen atom or a protective group of hydroxyl group) or -C(=0)-. As a protective group of hydroxy group represented by R, a protective group which is synthetically useful (for such a protective group, "Protective Groups in Organic Synthesis," edited by P. G. M. Wuts and T. W. Greene, the 3rd edition, John Wiley & Sons, Inc. (1999) can be referred to), and further a protective group may be used which increase absorption rate of the protected compound from intestinal canal and is susceptible to deprotection in vivo to give the compound wherein R is hydrogen atom. The compound which has a protective group of the latter class is useful when the compound is used as a prodrug depending on variety of purposes. As the protective group, examples include acetyl group, palmitoyl group, propanoyl group, pivaloyl group, succinyl group, fumaryl group, alanyl group, and dimethylaminomethylcarbonyl group, however the protective group is not limited to these examples.

In the general formula (1), symbol m represents an integer of 0 to 4, symbol n represents an integer of 5 to 9, and m+n is preferable in a range of 8 to 10, more preferably 9. Symbol m is preferably an integer of 1 to 3, more preferably 1 or 2.

Symbol n is preferably an integer of 6 to 9, more preferably 7 or 8.

The compound represented by general formula (1), a salt thereof, or an ester thereof may exist as a solvate which includes typically a hydrate, and any solvate falls within the scope of the present invention. Further, the compound represented by general formula (1) has one asymmetric carbon when R is hydrogen atom, and the compound of the present invention (hereinafter when “the compound of the present invention” is referred to, the term encompasses the compound represented by general formula (1) and an ester thereof) may have another one or more asymmetric carbons depending on the type of R or the ester. Stereoisomers in a pure form such as optical isomer and diastereoisomers based on one or more asymmetric carbons and any mixtures of stereoisomers such as racemates fall within the scope of the present invention.

Among the compounds of the present invention, preferable examples include 2,2-dichloro-12-(4-chlorophenyl)-10-hydroxydodecanoic acid, 2,2-dichloro-12-(4-chlorophenyl)-11-hydroxydodecanoic acid and a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof.

’ -

The compound of the present invention can be prepared, for example, by the method described in the following preparation route 1 or 4. The compound of the present invention wherein m is 0 can also be prepared by the method described in the preparation route 2. Further, the compound of the present invention wherein m 1s 1 can also be prepared by the method described in the preparation route 3. (In the following scheme, each of m and n represents the same meaning as that mentioned above, R! represents a protective group of hydroxy group, R2 represents an alkyl group, an aryl group, or an allyl group, and each of X and Y represents a halogen atom.) <Preparation route 1>

Cc Cl H

Ci ox Kons! LO

M I) {am

CL or! “C1 R' ol gl a ron oo xv)

Vv)

TO ag TO 3a (CH2)m (CHy)y CO3R? (CH2)m (CH,), COzH (VD (VID)

Step 1:

Aldehyde compound (II) is dissolved in an inert solvent such as tetrahydrofuran (THF), dioxane, ether, or dimethoxyethane. The solution is added with an inert solvent solution of Grignard reagent (I) prepared from a corresponding halide under atmosphere of an inert gas and stirred under cooling or at room temperature for 30 minutes to several hours. Compound (III) can thus be prepared.

Step 2:

This is to protect the hydroxy group of Compound (III) with a suitable protective group such as acetyl group or methoxymethyl group. As to type of the protective group and condition for introducing the protective group, for example, "Protective Groups in Organic Synthesis," edited by P. G. M. Wuts and T. W. Greene,

’ r the 3rd edition, (1999) John Wiley & Sons, Inc. can be referred to.

Step 3:

This step can be performed by dissolving Compound (IV) and an ester of dichloroacetic acid in a solvent such as THF, dioxane, 1,2-dimethoxyethane, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), adding a base such as sodium alkoxide, sodium hydride, or lithium diisopropylamide (LDA) to the solution under atmosphere of an inert gas, and stirring at room temperature or under heating for one hour to 24 hours.

Step 4:

This step is to deprotect the protected hydroxy group of Compound (V). As to condition for deprotection of the hydroxy group, "Protective Groups in Organic

Synthesis," P. G. M. Wuts and T. W. Greene, the 3rd edition, (1999) John Wiley &

Sons, Inc. can be referred to. In some compounds, the deprotection can be achieved in the following step 5 simultaneously, and for those compounds, this step 4 can be omitted.

Step 5

Compound (VI) is dissolved in a solvent such as methanol, ethanol, THF, dioxane, or 1,2-dimethoxyethane. The solution is added with a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, stirred under cooling or under heating for from one hour to 24 hours, and added with an acid such as hydrochloric acid so as to be acidic. The desired compound can thus be prepared. <Preparation route 2>

1 bt

Hz WE! Hz pa

JO CoH — (yen 0,R?

Ci Cl (VII) (IX)

X pe H opp _ (ow ORZ yee CO,R?

Ci Cl xX) (x1) — (CHz)n CO2H

Cl (XI

Step 1:

Compound (IX) can be prepared by an esterification of Compound (VIII) according to an ordinary method. The esterification method is not particularly limited, and may be any appropriate method such as active esterification method, a mixed acid anhydride method, or a condensation method which are generally used.

Step 2:

Compound (IX) is dissolved in a solvent such as carbon tetrachloride, cyclohexane, or benzene. The solution is added with a halogenating agent such as

N-bromosuccinimide, stirred at room temperature or under heating for one hour to 24 hours. Compound (X) can thus be obtained. For promotion of the reaction, a radical initiator such as dibenzoyl peroxide or azobisisobutyronitrile can be added to the reaction mixture.

Step 3:

Compound (X) is dissolved in water or a mixed solvent of water and organic solvent such as acetone, THF, and DMF. The solution is added with a silver salt such as silver nitrate or silver perchlorate, or a base such as sodium hydrogen carbonate, and stirred under cooling or under heating for one hour to 24 hours.

Compound (XI) can thus be obtained.

Step 4:

This step can be achieved by the same method as that of the step 5 of the

’ t preparation route 1. <Preparation route 3>

RSE: cl Cl ag Cl Cl

Torin cou —_— og co (XII) Xv)

Cl cl

Te oe TR ep _— (CHy)y COR® ——— g (CHg)n, ~CO2R? (XV) (Xvi)

ROLE

— Hy (CH3)y, COzH (XVID)

Step 1:

Compound (XIII), without a solvent or being dissolved in a solvent such as toluene, acetone, or DMSO, is added with an acid such as sulfuric acid, phosphoric acid, oxalic acid, or p-toluenesulfonic acid and stirred under cooling or under heating for one hour to 24 hours. Compound (XIV) can thus be obtained.

Step 2:

Compound (XIV) is dissolved in a solvent such as chloroform, methylene chloride, or diethyl ether. The solution or a mixed solution of the solution and aqueous sodium hydrogencarbonate solution is added with a peracid such as perbenzoic acid, 3-chloro perbenzoic acid, or trifluoroperacetic acid and stirred under cooling or under heating for one hour to 24 hours. Compound (XV) can thus be obtained.

Step 3:

Compound (XV) is dissolved in a solvent such as THF, ethyl acetate, alcohols, or acetic acid. The solution is added with a catalyst such as palladium on carbon or

Raney nickel and stirred at atmospheric pressure or positive pressure under hydrogen atmosphere, and under cooling or under heating for one hour to 24 hours,

Compound (XVI) can thus be obtained.

Claims (4)

What is claimed is:

1. A compound selected from the group consisting of 2,2-dichloro-12-(4-chlorophenyl)-10-hydroxydodecanoic acid and 2,2-dichloro-12-(4-chlorophenyl)-11-hydroxydodecanoic acid, a salt thereof, or an ester thereof.

2. A medicine which comprises as an active ingredient a substance selected from 2,2-dichloro-12-(4-chlorophenyl)-10-hydroxydodecanoic acid and 2,2-dichloro-12-(4-chlorophenyl)-11-hydroxydodecanoic acid, a salt thereof, or an ester thereof.

3. The medicine according to claim 2 for preventive and/or therapeutic treatment of a disease selected from the group consisting of hyperlipemia, atherosclerosis, diabetes, complications of diabetes, inflammation, and cardiopathy.

4. The medicine according to claim 2 or 3 in a form of a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier. 33 Amended sheet: 21 November 200¢