MXPA97005378A - Use of the 3,4-difenil-chromians for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of the obesi - Google Patents

Abstract

The present invention provides the novel uses of the compounds of the general formula (I), wherein R1, R4 and R5 are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of obesity.

Description

USE OF THE 3,4-DIFENIL-CHROMIANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT O PROPHYLAXIS OF OBESITY FIELD OF THE INVENTION The present invention relates to the use of the compounds of the general formula I for the treatment of patients suffering from obesity and prophylaxis thereof. The present invention also encompasses pharmaceutical compositions comprising these compounds and methods for using the compounds and their pharmaceutical compositions.

BACKGROUND OF THE INVENTION Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension and diabetes. The incidence of obese people and therefore also of these diseases is increasing around the whole industrialized world. Except for exercise, diet and food restriction, there is currently no convincing pharmacological treatment to reduce body weight in an effective and acceptable manner. REF: 25033 However, due to its indirect but important effect as a risk factor in deadly and common diseases, it will be important to find treatment for obesity. The term obesity implies an excess of adipose tissue. In this context, obesity is better observed as any degree of excess of adiposity that imparts a risk to health. The limit between normal and obese individuals can only be approximate, but the risk to the. Health imparted by obesity is probably continuous with the increase in adiposity. The Framingham study shows that a 20% excess over desirable weight clearly imparts a health risk (Mann GV N. Engl. J. Med 291: 226, 1974). In the United States a consensus panel of the National Institutes of Health on obesity, agreed that a 20% increase in relative weight or a body mass index (BMI = body weight in kilograms divided by height in meters) Above the 85th percentile for young adults, it constitutes a health risk. By using these criteria, 20 to 30 percent of adult men and 30 to 40 percent of adult women in the United States are obese. (NIH, Ann Intern Med 103: 147, 1985).

Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the industrialized western world the prevalence of obesity has increased significantly in recent few decades. Due to the high prevalence of obesity and its consequences for health, its prevention and treatment should be a high public health priority. When the uptake of energy exceeds the expenditure, excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, for example there are two components for weight balance, and an abnormality on either side (intake or expense) can lead to obesity. The regulation of eating behavior is incompletely understood. To a certain degree the appetite is controlled by the discrete areas in the hypothalamus: a feeding center in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety center in the hippocampus: ventromedial poplar (VMH). positive signals from the feeding center that stimulate eating, and the satiety center modulates its process by sending inhibitory impulses to the feeding center.Several regulatory processes can influence these hypothalamic centers. activated by increases in plasma glucose and / or insulin following a meal.Gastric distension induced by food is another possible factor of inhibition.In addition, hypothalamic centers are sensitive to catecholamines, and beta-adrenergic stimulation inhibits the eating behavior. In the end, the cerebral cortex controls the behavior of eating, and the impulses from the feeding center to the cerebral cortex are only one input. The psychological, social and genetic factors also influence the intake of food. To date a variety of techniques are available to effect the initial weight loss. Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most patients eventually regain their weight. An effective means to establish and / or sustain weight loss is the greatest challenge in the treatment of obesity today.

Cent-chroman is a non-steroidal compound known to have antiestrogenic activity. This is in use in India as an oral contraceptive (see, for example, Salman et al., US Patent Specification No. 4,447,622; Singh et al., Acta Endocrinol. (Copenh) 126 (1992), 444-450; Grubb, Curr Opin. Obstet Gynecol. 3 (1991), 491-495; Sankaran et al., Contraception 9_ (1974), 279-289; Hindu Patent Specification No., 129187). Centcroman has also been investigated as an anticancer agent for the treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 (1989), 781-783). Recently, it has been found that centchroman as a racemate is potent as a pharmaceutical product that decreases co-sterol, expressed by a significant decrease in serum concentrations (SD Bain et al., J. Min. Bon. Res. 9 (1994 ), 394). U.S. Patent No. 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts. Thus, a need remains in the art today for compositions and methods that are useful in the treatment or prophylaxis of obesity.

An objective of the present invention is to provide compounds that can be used effectively in the treatment or prophylaxis of obesity.

BRIEF DESCRIPTION OF THE INVENTION It has surprisingly been found that the compounds of the general formula I as set forth in claim 1 can be used in the treatment or prophylaxis of obesity.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based in part on the discovery that a representative 3, 4-diarylchroman, centroman (3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin- 1-yl) ethoxy) phenyl] -7-methoxy chroman) is effective against obesity, among others in rabbits. Centroman is a racemic mixture. These animal models are generally recognized obesity models. These data thus indicate that the 3, 4-diarylchromans of formula I are useful as therapeutics against obesity in mammals, including primates such as humans.

Within the present invention, the compounds of the formula I as set forth in claim 1 are used against obese patients. Within formula I, R1, R4 and R5 are individually hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R2 and R3 are individually hydrogen or a lower alkyl. As used herein, the term "lower alkyl" includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-prolyl, isopropyl, n-butyl, ter- butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "lower alkoxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec. -amiloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like. "Halogen" includes chlorine, fluorine, bromine and iodine. The tertiary amino radical can be an N, N-dialkyla ine such as N, N-dimethylamine, N, N-diethylamine, N, -dipropylamine and N, N-dibutylamine or a polymethyleneiin, eg, piperidine, pyrrolidine, N -methylpiperazine or morpholine. In the present, the term "(tertiary amino) (lower alkoxy)" is a lower alkoxy group which is substituted by a tertiary amino group. Preferred compounds include those in which R1 is lower alkoxy; R2 and R3 are lower alkyl, especially methyl; R4 is hydrogen; and R5 is (tertiary amino) (lower alkoxy) of the polymethyleneimine type. Within the particularly preferred embodiments, R1 is in the 7-position and is lower-alkoxy, particularly methoxy; each of R2 and R3 is methyl, R4 is hydrogen, and R5 is in the 4-position and is a radical (tertiary amino) (lower alkoxy) such as 2- (pyrrolidin-1-yl) ethoxy. To be included by this invention are all pharmaceutically acceptable salts of the aforementioned compounds of the formula I. It is preferred to use the compounds of the formula I in the trans configuration. These compounds can be used as racemic mixtures, or the isolated stereoisomers can be used, for example, d- or 1-enantiomers. Trans-1-enantiomers are more preferred. A particularly preferred compound for use within the present invention is cent-chroman consisting of 1-centchroman and d-centchroman. Probably, 1-centchroman has the formula IV. (IV) the 3, 4-diarylchromans are prepared according to known methods, such as those described in US Patent Specification No. 3,340,276 to Carney et al., US Patent Specification No. 3, 822,287 to Bolger, and Ray et al. , J. Med. Chem. 19 (1976), 276-279, the contents of which are incorporated by reference herein. The conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is described in US Patent Specification No. 3,822,287. The optically active d and 1 enantiomers can be prepared as described by Salman et al., US Patent Specification No. 4,447,622 (incorporated by reference herein) by the formation of an optically active acid salt which is subjected to alkaline hydrolysis for produce the desired enantiome ^ c. Yes R? is different from R3 and R4 is different from R, general formula I covers 8 optical isomers. Within the present invention, the 3,4-diarylchromans of the formula I can be prepared in the form of pharmaceutically acceptable salts, especially of acid addition salts, including the salts of organic acids and mineral acids. Examples of such salts include organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid. , salicylic acid and the like. Suitable inorganic acid addition salts include the salts of hydrochloric, hydrobromic, sulfuric and phosphoric acids, and the like. The acid addition salts can be obtained as the direct products of the synthesis of the compound. In an alternative, the free base can be dissolved in an appropriate solvent containing the appropriate acid, and the salt isolated by evaporation of the solvent or otherwise the salt and the solvent are separated.

The 3, 4-diarylchromans of the formula I and their salts are useful in the field of human and veterinary medicine, for example, in the treatment or prophylaxis of patients suffering from obesity. For use within the present invention, the 3,4-diarylchromans of the formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal administration or transdermal, according to conventional methods. The formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and can be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release dermal implants, tablets, etc. One of skill in this art can formulate the compounds of formula I in an appropriate manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., Easton, PA, 1990. Oral administration is preferred. Thus, the active compound of the formula I is prepared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound of the formula I is combined with a carrier and molded in the form of a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate, and the like. Such compositions may also include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives, etc. Pharmaceutical compositions containing a compound of the formula I can be administered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against obesity. Such amounts will depend, in part, of the particular condition to be treated, of the age, weight and general health of the patient, and of other factors evident to those skilled in the art. Pharmaceutical compositions containing a compound of formula I can be administered in unit dosage form one or more times per day or week. In the alternative, these may be provided as controlled release formulations appropriate for the dermal implant. The implants are formulated to provide the release of the active compound over the desired period of time, which may be up to several years. Controlled release formulations are described, for example, in Sanders et al., J. Pharm. Sci. 73 (1964), 1294-1297, 1984; US Patent Specification No. 4,489,056; and US Patent Specification No. 4,210,644, which are incorporated by reference herein. Examples of preferred compounds of formula I are centchroman as a racemic mixture and as 1-centchroman and d-centchroman. In addition, a preferred compound is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-hydroxychroman.

A more preferred compound is 1-3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxy chroman. The present invention is further illustrated by the following examples which, however, are not to be considered as limiting the scope of protection. The features described in the foregoing description and in the following examples may, either separately and in any combination thereof. be the material for carrying out the invention in various forms of the same.

EXAMPLES Test 1 The effects of 1-centchroman on weight gain in rabbits have been investigated in rabbits fed cholesterol. Thirty New Zealand white female rabbits, sexually mature in the weight range of 3000 to 3550 grams, were obtained bodily). The animals were housed in 35 x 45 cm cages, one in each cage, with access to water ad libitum. The ambient temperature was maintained at 18 ± C.5 ° C with a minimum relative humidity of 40%. One week before the medical treatment was started, the animals were removed their ovaries bilaterally during pentobarbital anesthesia. After the recovery and a recovery period of one week, the subcutaneous treatment was started in three groups: Vehicle, 17-ß-estradiol (0.5 mg / kg or 1-centchroman 7.5 mg / kg). Doses will be administered three times week for 4 weeks throughout the experiment the animals were subjected to food restriction by being offered only 100 g of feed each day.All the rabbits ate all their food each day.In the beginning, once a week during the period of At the end of the experiment, the rabbits were weighed and the gain in weight throughout the whole period was determined As shown in Table 1, 1-centchroman significantly reduced weight gain compared to animals treated with vehicle and at the level of animals treated with estrogen.

Table 1. Weight gain in rabbits treated with food and drug, constants Treatment Gain in Weight (grams) Placebo 255 ± 20 Estrogen 246 ± 34 1-Centchroman 38 ± 28 * The values are the mean ± SEM. * indicates significant reduction in weight gain compared to animals treated with placebo; p less than 0.001.

In addition to the demonstrated benefits of the compound used in the methods of the present invention, no harmful toxicological effects were observed.

Test 2 Twenty-eight genetically obese male mice (ob / ob mice) were obtained from Mollegaards Breeding Center, Ll. Skensved, Denmark. The animals were housed in hanging metal cages in groups of 3 or 4 per cage, and had ad libitum access to food and water for a week of acclimatization. The ambient temperature is maintained at 21 ± 0.5 ° C with a relative humidity of 40%. The photoperiod in the room is 12 hours of light and 12 hours of darkness. After a one-week acclimation period, dosing with the test compounds was started. The amount of the compound administered is 0.001 to 100 mg / day and the administration period is 1 month. The compound is administered by isotonic injections intraperitoneally twice a week. Food consumption is measured daily and animals are weighed twice a week during the treatment period.

Test 3 The same procedure is used as in Trial 2, except that the administration period is 3 months.

Test 4 The same procedure is used as in Trial 2, except that the administration period is 6 months.

Test 5 Between 3 and 20 obese women (according to the criteria mentioned above) are administered a compound of the present invention. The amount of the compound administered is 0.1 to 1000 mg / day, and the treatment period is 6 months. The women were observed during the administration period, and up to 3 months after the discontinuation of the administration, for the effects on their obesity.

Test 6 The same procedure is used as in Exhibit 5, except that the administration period is 1 year.

Test 7 The same procedure is used as in Test 5, except that between 3 and 20 obese males are used.

Test 8 The same procedure is used as in Test 7, except that the administration period is 1 year.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (16)

1. The use of the compounds of the general formula I characterized in that R ", R4 and R are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy), and R 'and R' are individually hydrogen or lower alkyl, or as a salt pharmaceutically acceptable thereof, in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of obesity.
2. 2. The use according to claim 1, characterized in that the compound has the general formula III: wherein R ', R', R3, R4 and R5 each have the meaning in accordance with claim 1.
3. 3. The use according to claim 1 or 2, characterized in that R1 is lower alkoxy, preferably methoxy.
4. 4. The use according to any of the preceding claims, characterized in that R2 is lower alkyl, preferably methyl.
5. 5. The use according to any of the preceding claims, characterized in that R3 is lower alkyl, preferably methyl.
6. 6. The use according to any of the preceding claims, characterized in that R "is hydrogen.
7. 7. The use according to any of the preceding claims, characterized in that R5 is (tertiary amino) (lower alkoxy), preferably 2- (pyrrolidin-1-yl) ethoxy.
8. 8. The use according to any of the preceding claims, characterized in that the compound is a stereoisomer, for example an isolated d- or 1-enantiomer.
9. 9. The use according to any of the preceding claims, characterized in that the compound is an isolated d-enantiomer.
10. 10. The use according to claim 1, characterized in that the compound is 3,4-trans-2,2-dimethy1-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] - 7-methoxy chroman.
11. 11. The use according to the preceding claim, characterized in that the compound is an isolated d- or 1-enantiomer of 3,4-trans-2,2-dimethyl-3-pheny1-4- [4- (2- (pyrrolidin- 1-yl) ethoxy) phenyl] -7-methoxy chroman.
12. 12. The use according to claim 11, characterized in that the compound is 1-3, 4-trans-2, 2-dimeti1-3-pheny1-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl ] -7-methoxychroman.
13. 13. The use according to any of the preceding claims, characterized in that the composition is in a form suitable for oral administration.
14. 14. The use according to any of the preceding claims, characterized in that the compound is administered as a dose in a range of about 0.001 to 75, preferably in a range of 0.01 to 75, more preferably in a range of 0.01 to 50, and especially in the range of about 0.1 to 25, mg / kg of the patient per day.
15. 15. The use according to any of the preceding claims, characterized in that the composition is administered one or more times per day or week.
16. 16. The use according to any of the preceding claims, characterized in that the composition is in the form of a dermal implant.