USE OF 3,4-DIPHENYL CHROMANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR VASODILATORY TREATMENT OR PROPHYLAXIS

Abstract: The present invention provides novel uses of compounds of general formula (I), wherein R1, R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary anmino)(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 vasodilatory treatment or prophylaxis.

Description: Use of 3.4-diphenyl chromans for the manufacture of a pharmaceutical composition for vasodilatorv treatment or prophylaxis FIELD OF THIS INVENTION The present invention relates to the use of compounds of the general formula I for the vasodilatory treatment of patients suffering from, e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome, and prophy¬ laxis hereof. The present invention also embraces pharmaceutical compo¬ sitions comprising these compounds and methods of using the com- pounds and their pharmaceutical compositions. BACKGROUND OF THIS INVENTION Vasodilator drugs are used in several conditions involving tissue ischemia with the most important indication being angina pectoris. Atherosclerosis is involved in most cases of angina pectoris. In recent years a number of studies have revealed important information about the effects of estro¬ gens on the cardiovascular system. Experiments in animals (Haarbo J et al. J Clin Invest 1991 ; 87:1294-1279) and epidemiologic studies in humans (PEPI trial, JAMA 1995; 273: 199-208) have demonstrated that estrogens possess antiatherogenic properties and it has been speculated that the decreased cardiovascular morbidity and mortality seen in women between 35 and 50 compared to men, is due to an intact ovarian func¬ tion with the production of estrogens. It has also been demonstrated that estrogens possess vasodilator properties, at least when admini¬ stered in test systems in pharmacological doses. Estrogens and estrogen receptor stimulation may therefore have a dual mechanism which may act synergistically on the pathologic mechanisms involved in tissue ischemia. Recent studies (Writing group for the PEPI trial, JAMA 273: 1 99, 1 955) confirm that oral estrogen taken alone or in combination with medroxy- progesterone acetate or micronized progesterone is associated with a beneficial effect on the risk of developing cardiovascular disease. How¬ ever, estrogen is also known to have adverse effects on endometrium and perhaps breast tissue by increasing the frequency of malignancies in these areas after prolonged treatment. Thus, there is a need for a new compound which has the beneficial vasodilatory effect of estrogen, but without introducing significant effects on the reproductive tissues. Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al., Acta Endocrinol. (Cooenh) 1 26 (1 992), 444 - 450; Grubb, Curr.Qpin.Ob- stet. Gvnecol. 3 ( 1 991 ), 491 - 495; Sankaran et al., Contraception 9 (1 974), 279 - 289; Indian Patent Specification No. 1 291 87). Centchro¬ man has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., int. J. Cancer 43 (1989), 781 - 783). Recently, centchroman as a racemate has been found potent as a cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J.Min.Bon.Res. 9 (1 994), 394) . U.S. patent 5,280,040 describes methods and pharmaceutical composi- tions for reducing bone loss using 3,4-diarylchromans and their pharma¬ ceutically acceptable salts. One object of the present invention is to provide compounds which can effectively be used in the vasodilatory treatment or prophylaxis of e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. BRIEF DESCRIPTION OF THIS INVENTION It has, surprisingly, been found that compounds of the general formula I as stated in Claim 1 can be used in the vasodilatory treatment or prophy¬ laxis of e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. DETAILED DESCRIPTION OF THIS INVENTION The present invention is based in part on the discovery that a representa¬ tive 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7-methoxychroman) is an effective vasodilatory drug against e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome, inter alia in rats. Centchroman is a racemic mix¬ ture. These animal models are generally recognized models of e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. These data thus indicate that the 3,4-diarylchromans of formula I are useful as therapeutic and preventive agents against e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. The above indications relate to mam¬ mals, including primates such as humans. Within the present invention, compounds of formula I as stated in Claim 1 are administered as vasodilatory drugs against e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. Within formula I, R , R 4 and R 5 are individually hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino)(lower alkoxy); and R 2 and R 3 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-propyl, 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- amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like. "Halogen" includes chloro, fluoro, bromo and iodo. The tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N- diethylamino, N,N-dipropylamino and N,N-dibutylamino or a polymethy- leneimine, e.g., piperidine, pyrrolidine, N-methylpiperazine or morpholine. Herein, the term "(tertiary aminoMlower alkoxy)" is a lower alkoxy group which is substituted by a tertiary amino group. Preferred compounds include those in which R 1 is lower alkoxy; R 2 and R 3 are lower alkyl, especially methyl; R 4 is hydrogen; and R° is (tertiary aminoMlower alkoxy) of the polymethyleneimine type. Within particularly preferred embodiments, R ' is in the 7-position and is lower alkoxy, particularly methoxy; each of R 2 and R 3 is methyl, R 4 is hydrogen, and R° is in the 4-position and is a (tertiary aminoMlower alkoxy) radical such as 2- (pyrrolidin-l -yl)ethoxy. To be included by this invention are all pharma¬ ceutically acceptable salts of the mentioned compounds of formula I. It is preferred to use the compounds of formula I in the transconfigura- tion. These compounds may be used as racemic mixtures, or the isolated stereoisomers, e.g. d- or I- enantiomers, may be used. The trans-d- enantiomers are more preferred. A particularly preferred compound for use within the present invention is centchroman consisting of l-centchroman and d-centchroman. Probably, l-centchroman has the formula IV 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., J.Med.Chem. 19 (1976), 276 - 279, the contents of which are incorpo¬ rated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrange¬ ment is disclosed in U.S. Patent Specification No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. If R 2 is different from R 3 and R 4 is different from R , the general formula I covers 8 optical isomers. Within the present invention, 3,4-diarylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of 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 salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. 3,4-diarylchromans of formula I and their salts are useful as vasodilatory drugs within the field of human and veterinary medicine, for example, in the treatment or prophylaxis of patients suffering from e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. For use within the present invention, 3,4-diarylchromans of formula I and their pharmaceuti¬ cally acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration according to conventional methods. Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, supposi¬ tories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One skilled in this art may formulate the com¬ pounds of formula I in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceuti¬ cal Sciences. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990. Oral administration is preferred. Thus, the active compound of 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 formula I is combined with a carrier and moulded into a tablet. Suit¬ able carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc. Pharmaceutical compositions containing a compound of formula I may be administered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount that provides a clinical¬ ly significant vasodilatory effect against e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art. The pharmaceutical compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implantation. Implants are formulated to provide release of active compound over the desired period of time, which can be up to several years. Controlled-release formulations are disclosed by, for example, Sanders et al., J.Pharm.Sci. 73 (1964), 1 294 - 1297, 1984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorporated herein by reference. Examples of preferred compounds of formula I are centchroman as a racemic mixture and as l-centchroman and d-centchroman. Furthermore, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- hydroxychroman is a preferred compound. A more preferred compound is d-3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)- 7-methoxychroman The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protec¬ tion. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof. EXAMPLE The effects of d-centchroman on arterial contractility was investigated in an in vitro system using thoracic aorta rings from female Wistar rats. The rats were killed and the thoracic aorta excised from the body and posi¬ tioned in a small organ bath in which it was possible to measure contrac¬ tility via a force transducer. Arterial contraction was induced by bathing the aorta ring in a solution containing 300 nM phenylephrine to which was added either increasing doses of vehicle (DMSO), estrogen or d- centchroman. The data revealed (table 1 ) that d-centchroman possessed the ability to dilate a precontracted aorta ring, d-centchroman was a potent vasodilator with an EC 50 value of 13 μM approximately 5 times as potent as estrogen. Subsequent experiments in which the endothelial nitric oxide synthesis was blocked by l-NAME showed a rightward shift of the dose-response curve with a factor of about 10. These data indicated that at least some of the relaxing effect of d-centchroman is dependent on the synthesis of NO (endothelium derived relaxing factor, EDRF). Table 1. Dose-response characteristics of compounds Compound EC 50 (μM) %Efficacy 17-β-estradiol 60 57 d-centchroman 13 98

Claims: CLAIMS It The use of compounds of the general formula I wherein R , R 4 and R° are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R 2 and R 3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma¬ ceutically acceptable carrier for the manufacture of a pharmaceutical composition showing a vasodilatory effect. 2i The use according to claim 1 for the treatment or prophylaxis of cerebral ischaemia. 3j. The use according to claim 1 for the treatment or prophylaxis of angina pectoris. 4Λ The use according to claim 1 for the treatment or prophylaxis of Raynard's syndrome. ϊ The use according to anyone of claims 1 -4 wherein said com¬ pound has the general formula III: wherein R 1 , R 2 , R 3 , R 4 and R 5 each has the meaning stated in Claim 1 . €L . The use according to any one of the preceding claims 1 -5 wherein R 1 is lower alkoxy, preferably methoxy. i The use according to any one of the preceding claims wherein R 2 is lower alkyl, preferably methyl. S J , The use according to any one of the preceding claims wherein R 3 is lower alkyl, preferably methyl. S The use according to any one of the preceding claims wherein R 4 is hydrogen. 10. The use according to any one of the preceding claims wherein R^ is (tertiary aminoMlower alkoxy), preferably 2-(pyrrolidin-1 -yl)ethoxy. 1 1 . The use according to any one of the preceding claims wherein said compound is a stereoisomer, e.g. an isolated d- or l-enantiomer. 12. The use according to anyone of the preceding claims wherein said compound is an isolated d-enantiomer. 13. The use according to any one of the preceding claims 1 -4 wherein said compound is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl]-7-methoxychroman. 14. The use according to the preceding claim wherein said compound is an isolated d- or l-enantiomer of 3,4-trans-2,2-dimethyl-3-phenyl-4-[4- (2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman. 15. The use according to claim 14 wherein said compound is d-3,4- trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- methoxychroman. 16. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration. 17. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.001 to 75, preferably in a range from 0.01 to 75, more preferably in the range from about 0.01 to 50, and especially in the range from about 0.1 to 25, mg/kg patient per day. 18. The use according to any one of the preceding claims wherein said composition is administered one or more times per day or week. 19. The use according to any one of the preceding claims wherein said composition is in the form of a dermal implant. 20. Method for the vasodilatory treatment and prophylaxis of e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome, comprising administering to a patient a clinically effective amount of compounds of formula I stated to be used in any one of the preceding use claims, or a pharmaceutically acceptable salt thereof. 21 . A vasodilatory method of treating or preventing e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome, which method comprises administering a clinically effective amount of a compound of formula I or a salt thereof and pharmaceutically acceptable compositions containing such a compound, to a patient in need of such a treatment. 22. Any novel feature or combination of features described herein.

Inventors: GULDHAMMER BIRGITTE HJORT, KORSGAARD NIELS, SHALMI MICHAEL, WEIS JAN ULRIK, GULDHAMMER, BIRGITTE, HJORT, KORSGAARD, NIELS, SHALMI, MICHAEL, WEIS, JAN, ULRIK
Applicants: GULDHAMMER BIRGITTE HJORT, KORSGAARD NIELS, NOVONORDISK AS, SHALMI MICHAEL, WEIS JAN ULRIK, GULDHAMMER, BIRGITTE, HJORT, KORSGAARD, NIELS, NOVO NORDISK A/S, SHALMI, MICHAEL, WEIS, JAN, ULRIK
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, C07D311