RU2093149C1 - Pharmaceutical composition used for treatment and prophylaxis of obesity-associated hypertension - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: composition has an active substance - thiazoline derivatives of the formula (I) given in description where: R^I,R²,R⁴,R⁵ - each is hydrogen or alkyl and R³ - hydrogen, aliphatic acyl, alkoxycarbonyl or arylcarbonyl, and their pharmaceutically acceptable salts and pharmaceutically acceptable carrier taken at the definite amounts. The synthesized compounds were used as drugs. EFFECT: improved method of synthesis, enhanced effectiveness of treatment. 6 cl, 2 tbl

Description

 The invention relates to a number of thiazolidine derivatives having antihypertensive activity, which are especially useful in the treatment and prevention of obesity-related hypertension.

 Hypertension (or high blood pressure) is a condition that can pose a threat to life or reduce the quality of life for those suffering from it. It has been firmly established that lowering blood pressure can significantly reduce the risk of illness and death. It has been convincingly shown that obesity is a factor that makes a significant contribution to the development of hypertension, and hypertension is much more often observed in obese patients than in people with normal body weight. It has also been shown that this type of hypertension can be a risk factor causing coronary artery disease.

 Hypertension associated with obesity is classified as primary hypertension. However, there are still many unsolved problems associated with the mechanism of hypertension. In particular, although it has been shown that various factors, such as an increased level of fluid in the body, the behavior of the sympathetic nervous system or the presence of hyperinsulinemia, may have some effect on the development of hypertension in obese patients, the relative importance of these and other factors has not been evaluated and there is no mechanism by which they exert their influence. It has recently been shown that obese people often exhibit increased insulin resistance, as well as hyperinsulinemia and lack of glucose tolerance. There are several reports that hyperinsulinemia and lack of glucose tolerance due to obesity may be important factors in the development of obesity-related hypertension (e.g., De Fronzo et al. J Clin Jnvest. 62, 204-213 (1978); Modan et al. J. Clin Jnvest. 75, 89-817 (1985); Reaven I Hoffman: Zancet, 2, 435-436 (1987); Ferramini et al. N. Engl. J. Med. 317, 350-357 (1987) )).

 Thus, attempts have been made to treat or alleviate the condition of obese hypertensive patients by improving insulin resistance and finding effective therapeutic agents for this purpose.

 We describe here a number of thiazolidine derivatives that can be used to treat and prevent hypertension associated with obesity. These thiazolidine derivatives are capable of not only reducing insulin resistance, but also improving glucose tolerance, they also exhibit antihypertensive activity.

где R¹, R², R⁴ и R⁵ одинаковы или различны и каждый означает атом водорода или алкильную группу, имеющую 1-6 атомов углерода;
R³ означает атом водорода, алифатическую ацильную группу, имеющую 1-7 атомов углерода, алкоксикарбонильную группу, имеющую 2-7 атомов углерода, арилкарбонильную группу, в которой арильная часть имеет от 6 до 14 кольцевых атомов углерода, незамещенных или замещенных по крайней мере одним из следующих заместителей: нитро-группы, амино-группы, алкиламино-группы, в которых алкильная часть имеет 1-4 атома углерода, диалкиламино-группы, в которых каждая алкильная часть имеет 1-4 атома углерода, алкокси-группы, имеющие 1-4 атома углерода, алкильные группы, имеющие 1-4 атома углерода, гидрокси-группы и атомы галогена; или их фармацевтически приемлемые соли.Thus, this invention describes a method and composition for the treatment and prevention of hypertension associated with obesity in mammals, and also in humans. The method involves administering effective amounts of an anti-hypertensive agent in which there is at least one thiazolidine derivative of formula I in combination with pharmacologically acceptable carriers or excipients

where R ¹ , R ² , R ⁴ and R ^{5 are the} same or different and each means a hydrogen atom or an alkyl group having 1-6 carbon atoms;
R ³ means a hydrogen atom, an aliphatic acyl group having 1-7 carbon atoms, an alkoxycarbonyl group having 2-7 carbon atoms, an arylcarbonyl group in which the aryl part has 6 to 14 ring carbon atoms unsubstituted or substituted by at least one of the following substituents: nitro groups, amino groups, alkylamino groups in which the alkyl part has 1-4 carbon atoms, dialkylamino groups in which each alkyl part has 1-4 carbon atoms, alkoxy groups having 1- 4 carbon atoms, alkyl groups having 1-4 carbon atoms, hydroxy groups and halogen atoms; or their pharmaceutically acceptable salts.

 The compounds of formula I used in this invention are known and described, for example, in Cocai Japanese Patent Application No. Sho 60-51189, US Patent No. 514-369 4572912 and European Patent No. 139421; they can be obtained as described in previous patents. The activity of some of these compounds is described in Fujiwara et al. Diabets vol. 37 (1988), pp. 1549-1558 and Joshioka et al. I. Med Chem. 32 (1989), pp. 421-428.

 The compound designated as CS-045 in these works is a compound that can be used in this invention.

In the compounds of formula I, when R ¹ is an alkyl group, it may be linear or branched alkyl having from 1 to 6 carbon atoms, preferably 1-5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl. Of these, we prefer an alkyl group having 1-4 carbon atoms, most preferably methyl.

When R ² and R ^{5 are} an alkyl group, they can be the same or different and each can be a linear or branched alkyl group having 1-6 carbon atoms, preferably 1-5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl , isobutyl or pentyl. Of these, we prefer alkyl groups having 1 to 3 carbon atoms, most preferably methyl.

R ³ means aliphatic acyl, it can be a linear or branched acyl group having 1-7 carbon atoms, preferably an alkanoyl group having 1-7 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl or heptanoyl . Of these, we prefer those acyl groups, especially alkanoyl groups that have 1-4 carbon atoms, the most preferred acetyl group.

R ³ means aromatic acyl, it is an arylcarbonyl group in which the aryl part has 6-10 carbon atoms, preferably 6-10, most preferably 6 or 10 carbon atoms, and is substituted or unsubstituted. So the whole acyl group has 7-15, preferably 7-11, most preferably 7 and 11 carbon atoms. If the group is substituted, then the number of substituents is in principle limited only by the number of substitution positions, for example 5 in phenyl or 7 in naphthyl, however, 1-5 substituents are preferred, 1-3 are most preferred. Examples of such substituents include:
nitro, amino, and hydroxy groups;
alkylamino groups in which the alkyl part has 1-4 carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino and isobutylamino groups;
dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms and two alkyl parts can be the same or different, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, methylethylamino, methylpropylamino, methylbutylamino, ethylpropylamino ;
alkoxy groups having 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups;
halogen atoms such as fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine;
alkyl groups having 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl.

 Examples of such substituted or unsubstituted groups are benzoyl, 4-nitrobenzoyl, 3-fluorobenzoyl, 2-chlorobenzoyl, 3,4-dichlorobenzoyl, 4-aminobenzoyl, 3-dimethylaminobenzoyl 2-methoxybenzoyl, 3,5-di-t-butyl-4- hydroxybenzoyl and 1-naphthoyl. Of these, we prefer an unsubstituted aromatic acyl group having 7-11 carbon atoms, benzoyl is most preferred.

When R ³ means an alkoxycarbonyl group, it can be a linear or branched alkoxycarbonyl group having 2-7 carbon atoms, i.e. 1-6 carbon atoms in the alkoxy part, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec β-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl and hexyloxycarbonyl. Of these, we prefer an alkoxycarbonyl group having 2-4 carbon atoms, ethoxycarbonyl most preferred.

When R ^{4 is} an alkyl group, it can be linear and branched alkyl which has 1-6, preferably 1-5, carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl. Of these, we prefer those alkyls which have 1-4 carbon atoms, more preferably methyl t-butyl, most preferably methyl.

 The compounds of this invention can form salts. There is practically no restriction on the nature of these salts, however, if their therapeutic use is intended as in this invention, they should be pharmacologically acceptable. If they are used for non-therapeutic purposes, for example, as intermediates for the preparation of other possibly more active compounds, even this restriction is removed. The compounds of this invention contain an acid group in the thiazolidinedione moiety and can give salts with bases. Examples of such salts include salts with alkali metals such as sodium, potassium or lithium, salts with alkaline earth metals such as calcium or barium, salts with other metals such as magnesium, salts with organic bases such as dicyclohexylamine, and salts with basic amino acids such as lysine and arginine. Also, if the compounds of this invention contain basic groups in the molecule, they can give onium salts with acids. Examples of such salts include salts with mineral, especially hydrohalic acids (such as hydrofluoric, hydrochloric, hydrobromic and hydroiodic acids), nitric acid, carbonic acid, sulfuric or phosphoric acid, salts with lower alkyl sulfonic acids such as methanesulfonic, trifluoromethanesulfonic or salts with arylsulfonic acids such as benzenesulfonic or p-toluenesulfonic acids, salts with organic carboxylic acids such as acetic, fumaric, tartaric, sorrel Single, maleic, malic, succinic, or citric acid, salts with amino acids such as glutamic and aspartic acids.

 The compounds of this invention contain an asymmetric carbon atom in the 2nd position of the chroman ring and can thus produce stereomers. Although they are all represented by a single molecular formula, this invention involves the use of both individual isolated stereometers and mixtures thereof, including racemates. If a stereospecific synthesis technique is used or optically active compounds are taken as the starting materials, individual isomers can be obtained directly, on the other hand, if a mixture of isomers is obtained, individual isomers can be obtained using a suitable separation technique or the mixture can be used without separation.

A preferred class of compounds of this invention are those compounds of formula I and their salts in which:
R ¹ means an alkyl group having 1-4 carbon atoms,
R ² means a hydrogen atom or an alkyl group having 1-3 carbon atoms,
R ³ means a hydrogen atom, an aliphatic acyl having 1-4 carbon atoms, an unsubstituted aromatic acyl having 7 or 11 carbon atoms or alkoxycarbonyl having from 2 to 4 carbon atoms.

R ⁴ means an alkyl group having 1-4 carbon atoms.

R ⁵ means a hydrogen atom or alkyl having 1-3 carbon atoms.

A more preferred class of compounds in which the compounds of formula I and their salts are those in which:
R ¹ means alkyl having 1-4 carbon atoms;
R ² means a hydrogen atom or alkyl having 1-3 carbon atoms;
R ³ means a hydrogen atom or acetyl, benzoyl or ethoxycarbonyl;
R ⁴ means alkyl having 1-4 carbon atoms;
R ⁵ means a hydrogen atom or alkyl having 1-3 carbon atoms.

Most preferred is the class of compounds of this invention in which the compounds of formula I and their salts are those in which:
R ¹ means a methyl group;
R ² means a hydrogen atom or a methyl group;
R ³ means a hydrogen atom or an acetyl or ethoxycarbonyl group;
R ⁴ means a methyl or t-butyl group;
R ⁵ means a hydrogen atom or a methyl group.

Specific examples of the thiazolidine derivatives of the present invention are those compounds of formula 1, R ¹ , R ² , R ³ , R ⁴ and R ⁵ which are defined in table. 1. The following abbreviations are used in this table:
Ac acetyl
i-bu isobutyl
t-Bu t-butyl
Butr butyryl
Boz benzoyl
Et ethyl
Etc ethoxycarbonyl
Me methyl
Pentyl pentyl
Of the above compounds, compounds N 1, 4, 5, 6, 8, and 10 are preferred. Compounds N are more preferred:
1.5- / 4 - / - 6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy / benzyl / thiazolidin-2,4-dione
2. 5- / 4 - / - 7-t-butyl-6-hydroxy-2-methylchroman-2-yl-methoxy / benzyl / thiazolidin-2,4-dione.

 10. 5- / 4 - / - 6-ethoxycarbonyloxy-2,5,7,8-tetramethylchroman-2-yl-methoxy / benzyl / thiazolidin-2,4-dione as well as their pharmacologically acceptable salts.

Of these, compounds N 1 and its pharmacologically acceptable salts are most preferred.
The compounds of this invention may be administered in various well-known forms depending on the disorder to be treated, the condition of the patient. For example, if a compound is to be administered orally, it is included in tablets, capsules, granules, powders and syrups, or for parenteral administration, it may be presented in the form of injections (intravenous, intramuscular or subcutaneous), droplet formulations or suppositories. These formulations can be prepared in the usual way and, if desired, the active ingredient can be mixed with any suitable additive, such as a liquid medium, a binder, a disintegrant, a lubricant, a modifier, a solubilizer, an emulsifier or a coating agent. Although the dosage will depend on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the medication, adult patients can usually be given a daily dose of 50 to 5000 mg of the compound in a single or divided dosage.

 The following examples show the biological activity of the compounds of this invention and the following formulations that illustrate the preparation of pharmaceutical compositions suitable for use in the treatment and prevention of hypertension. In these examples, the compounds of this invention are used as a mixture of stereoisomers prepared as described in US Pat. No. 4,572,913 without separation. The compounds of this invention are indicated by the numbers given to them in the above list.

 Example 1. Antihypertensive effect in hypertension associated with obesity.

 The antihypertensive effect of these compounds in hypertension associated with obesity was determined using the standard method.

This test was conducted on male Zucker fatty rats aged 5 to 12 months. They were used in groups of 8. The blood pressure of each rat was determined. Rats were distributed in decreasing order of their blood pressure and were divided into two groups, the control and the one to which the medicine was administered. Within 3 weeks after the first injection of compound N 1, the blood pressure of each rat of the test group was measured once a week using the following method: the rat was heated for 5 min in a box previously heated to 40 ^o C. Then it was transferred to an acrylic box, where it was immobilized. Using a PE-30300 non-intrusive blood pressure measurement apparatus, a Narico Co product (Japan) measured the change in capacitance in the tail region and thus systolic blood pressure was determined. Heart rate (HR) was measured as a pulse for 4 s, multiplied by 15. The results are presented in table. 2 (the value in parentheses is heart rate,
As shown in the table. 2, Compound No. 1 exhibits an excellent antihypertensive effect in hypertension associated with obesity and does not lead to any changes in heart rate in our animal experiments.

 Example 2. Acute toxicity.

 Acute toxicity was determined by the standard method, 300 mg / kg was orally administered to each of 3 male ddY mice, animals were observed for 5 days, during this period all mice were alive.

 Similarly, compounds N 2, 3, 4 and 10 were administered orally. Acute toxicity values for all of these compounds exceed 300 mg / kg.

 Recipes

The powder is mixed from the following ingredients:
Compound N 1 100.0 mg
Lactose 168.3 mg
Corn Starch 70.0 mg
Magnesium Stearate 1.7 mg
The resulting mixture was passed through a 20 mesh sieve / Tyler standard / and 340 mg of the mixture was placed in a No. 2 capsule.

 As can be seen from the above tests, the compounds of this invention exhibit an excellent antihypertensive effect in hypertension associated with obesity without any changes in heart rate, moreover, they have low toxicity. As a result, they are useful in the prevention and treatment of obesity-related hypertension.

Claims (6)

1. A pharmaceutical composition for treating or preventing obesity-related hypertension, comprising an active substance and a pharmaceutically acceptable carrier or solvent, characterized in that the active substance contains a thiazolidine derivative or a salt thereof of the formula

where R ¹ , R ² , R ⁴ , R ⁵ a hydrogen atom or alkyl having 1 to 6 carbon atoms;
R ^{3 is} a hydrogen atom, an aliphatic acyl having 1 7 carbon atoms, an alkoxycarbonyl having 2 7 carbon atoms or an aryl carbonyl, in which the aryl part has 6 14 ring carbon atoms, unsubstituted or substituted by at least one of the following substituents — nitro groups, amino groups, alkylamino groups in which the alkyl part has 1 4 carbon atoms, dialkylamino groups in which each alkyl part has 1 4 carbon atoms, alkoxy groups having 1 4 carbon atoms, alkyl groups having 1 4 carbon atoms, hyd oxyl groups and halogen atoms in an amount of 50 to 5000 mg per unit dose. 2. The composition according to p. 1, characterized in that the active substance contains a compound of formula I or its salt, where R ^{3 is} a hydrogen atom or benzoyl, 4-nitrobenzoyl, 3-fluorobenzoyl, 2-chlorobenzoyl, 3,4-dichlorobenzoyl 4-aminobenzoyl, 3-dimethylaminobenzoyl, 2-methoxybenzoyl, 3,5-di-t-butyl-4-hydroxy-benzoyl or 1-naphthoyl. 3. The composition according to p. 1, characterized in that as the active substance contains a compound of formula I or its salt, where R ⁴ a hydrogen atom or methyl. 4. The composition according to p. 1, characterized in that the active substance contains a compound of formula I or its salt, where R ¹ alkyl having 1 to 4 carbon atoms, R ² hydrogen atom or alkyl having 1 3 carbon atoms, R ³ hydrogen atom, aliphatic acyl having 1 4 carbon atoms, unsubstituted aromatic acyl having 7 or 11 carbon atoms or alkoxycarbonyl having 2 4 carbon atoms, R ⁴ alkyl having 1 4 carbon atoms, R ⁵ hydrogen atom or alkyl having 1 3 carbon atoms. 5. The composition according to p. 1, characterized in that the active substance contains a compound of formula I or its salt, where R ^{1 is} methyl, R ² is a hydrogen atom or methyl, R ^{3 is} a hydrogen atom, acetyl or ethoxycarbonyl, R ^{4 is} methyl or t-butyl, R ^{5 is} a hydrogen atom or methyl.  6. The composition according to p. 1, characterized in that the active substance contains 5- [4- (7-t-butyl-6-hydroxy-2 methyl-chroman-2-yl-methoxy) benzyl] thiazolidin-2, 4-dionite, or a pharmaceutically acceptable salt thereof, or 5- [4- (6-ethoxycarbonyloxy-2,5,7,8 tetramethyl-chroman-2yl-methoxy) benzyl] thiazolidine-2,4-dione and a pharmaceutically acceptable salt thereof .

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