MXPA97005379A - Use of the 3,4-difenil-chromians for the manufacture of a pharmaceutical composition for treatment or profilaxis vasodilatad - Google Patents

Abstract

The present invention provides the novel use 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 vasodilated prophylaxis

Description

USE OF THE 3,4-DIFENIL-CHROMIANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR TREATMENT OR VASODILATOR PROFILAXIS FIELD OF THE INVENTION The present invention relates to the use of compounds of the general formula I for the vasodilator treatment of patients suffering from, for example, cerebral ischemia, angina pectoris or Raynaud's syndrome, and the 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 Vasodilator drugs are used in several conditions that involve tissue ischemia with the most important indication that is angina pectoris. Atherosclerosis is involved in most cases of angina. In recent years a number of studies have revealed important information regarding the effects of REF: 25038 estrogen on the cardiovascular system. Experiments on animals (Haarbo J. et al J. Clin. Invest. 1991; 87: 1294-1279) and epidemiological studies in humans (PEPI test, JAMA 1995; 273: 199-208) have shown that estrogens have antiatherogenic properties and it has been speculated that decreased cardiovascular morbidity and mortality, observed in women between 35 and 50 years compared to men, is due to an intact ovarian function with the production of estrogen. It has also been shown that estrogens have vasodilating properties, at least when administered in test systems in pharmacological doses. Estrogen and stimulation of the estrogen receptor can therefore have a double mechanism which can act synergistically on the pathological mechanisms involved in tissue ischemia. Recent studies (group riting for the PEPI test, JAMA 273: 199, 1955) confirm that oral estrogen taken alone or in combination with micronized progesterone or medroxyprogesterone acetate is associated with a beneficial effect on the risk of developing cardiovascular disease. However, it is also known that estrogen has adverse effects on the endometrium and perhaps on the breast tissue, by increasing the frequency of malignancies in these areas after prolonged treatment. Thus, there is a need for a new compound that has the beneficial vasodilatory effect of estrogen, but without introducing significant effects on the reproductive tissues. 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 lowers cholesterol, 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. An object of the present invention is to provide compounds that can be used effectively in the treatment or vasodilator prophylaxis of for example cerebral ischemia, angina pectoris or Raynaud's syndrome.

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 vasodilator prophylaxis of, for example, cerebral ischemia, angina pectoris or Raynaud's syndrome.

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- (linear pyrrol 1-yl) ethoxy) phenyl] -7-methoxy chroman) is a vasodilator drug effective against, for example, cerebral ischemia, angina pectoris or Raynaud's syndrome, among others in rats. Centroman is a racemic mixture. These animal models are generally recognized models for example of cerebral ischemia, angina pectoris or Raynaud's syndrome. These data thus indicate that the 3, 4-diarylchromans of the formula I are useful as therapeutic and preventive agents against, for example, cerebral ischemia, angina pectoris or Raynaud's syndrome. The above indications refer to mammals, including primates such as humans. Within the present invention, the compounds of the formula I as set forth in claim 1 are administered as vasodilating drugs against, for example, cerebral ischemia, angina pectoris or Raynaud's syndrome. Within the 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, tert-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-dialkylamine such as N, N-dimethylamine, N, N-diethylamine, N, N-dipropylamine and N, N-dibutylamine or a polymethyleneimine, 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 polymethylene:. 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, for example, d- or 1-enantiomers, can be used. Trans-d-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. 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. 18 (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. Optically active enantiomers d and 1 can be prepared as described by Salman et al., In US Patent Specification No. 4,447,622 (incorporated by reference herein) by the formation of an optically active acid salt which is subject to hydrolysis alkaline to produce the desired enantiomer. If R2 is different from R and R is different from R5, 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 similar. 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 as vasodilator drugs within the field of human and veterinary medicine, for example, in the treatment or prophylaxis of patients suffering from, for example, cerebral ischemia, angina of chest or Raynaud's syndrome. For use within the present invention, 3,4-diarylchromans of 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., Mac Publishing Co. , Easton, PA, 1990. Oral administration is preferred. In this way, 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 vasodilating effect against, for example, cerebral ischemia, angina pectoris or Raynaud's syndrome. Such amounts will depend, in part, on the particular condition to be treated, the age, weight and general health of the patient, and 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 d-3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-ethoxy-romane. 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 above description and in the following examples may, either separately and in any combination thereof, be the material for the inventor of the invention in various forms thereof.

EXAMPLE The effects of d-centchroman on arterial contractility were investigated in an in vi tro system using thoracic aorta rings from female Wistar rats. The rats were sacrificed and the thoracic aorta removed from the body and placed in a small organ bath in which it was possible to measure the contractility via a force transducer. Arterial contraction was induced by bathing the aorta ring in a solution containing 300 nM phenylephrine to which either increasing doses of vehicle (DMSO), estrogen or d-centcroman were added. The data revealed (table 1) that d-centchroman possessed the ability to dilate a precontracted aortic ring. D-centchroman was a potent vasodilator with an EC5o value of 13 μM, approximately 5 times as potent as estrogen. Subsequent experiments in which endothelial nitric oxide synthesis was blocked by the I-NAME showed a shift to the right of the dose-response curve with a factor of about 10. These data indicated that at least some of the relaxant effect of the -centcroman is dependent on the synthesis of NO (endothelium-derived relaxation factor, EDRF).

Table 1. Dose-response characteristics of the compounds Compound EC5o (μm)% Efficacy 17-ß-estradiol 60 57 d-centchroman 13 98 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 (19)

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