MXPA97005214A - Use of the 3,4-difenil-chromanos for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia or arterioesclerosis or for anti-treatment - Google Patents

Abstract

The present invention provides the use of novel compounds of the general formula (I) in which R1, R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); 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 hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia or anteriosclerosis or for the anticoagulant treatment

Description

Use of 3, 4-diphenyl-chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesteroleptia or arteriosclerosis or for anticoagulant treatment 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 hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia and prophylaxis thereof. The present invention also relates to the use of the compounds of the general formula I for the treatment of patients suffering from arteriosclerosis, including atherosclerosis and prophylaxis thereof, and also to the use of the compounds of the general formula I for the treatment of patients in need of a treatment or anticoagulant prophylaxis, for example, after a coronary thrombosis or postoperatively, for example, after surgery. The present invention also encompasses pharmaceutical compositions that REF: 25037 comprise these compounds and methods for using the compounds and their pharmaceutical compositions.

BACKGROUND OF THE INVENTION Ischemic heart disease (IHD), the relevant cardiovascular disease in relation to postmenopausal women, is mainly caused by atherosclerosis (Havel and Rapaport, N Eng J Med 1995/332: 1491-1498). Other frequent manifestations of atherosclerosis are cerebrovascular disease and intermittent claudication. An important risk factor for the development of atherosclerosis is a profile of atherogenic lipids, for example, hyperlipidemia with an increased level of LDL-cholesterol and a relatively low level of HDL-cholesterol. In epidemiological studies (Samsioe G. Int J Fertil, 1993; 38, suppl.1: 19-22) it has been indicated that estrogen therapy in postmenopausal women reduces coronary artery stenosis, thereby increasing the survival rate compared to an untreated population. An important factor in this effect on the coronary system is a reduction in serum lipids and a normalization of the relationship between LDL-cholesterol and HDL-cholesterol (Samsioe G. Int J Fertil 1994, 39 suppl 1: 43-49). An object of the present invention is to provide the compounds that can be used effectively in the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia. Data in men suggest that a reduction of 35% in LDL-cholesterol is required to achieve a 50% reduction in cardiovascular disease, for example, coronary atherosclerosis, with the proviso that LDL-cholesterol reduction is the only cause of cardioprotection. However, estrogen reduces LDL-cholesterols only by 5-10%. It is now believed that the effects of lipids represent only 25-40% of the reduction in the incidence of coronary heart disease after estrogen replacement therapy. A possible mechanism could be a direct effect on the vessel wall, improving blood flow and inhibiting independent atherogenic mechanisms on an effect on plasma lipids. Yet another objective of the present invention is to provide compounds that can be used effectively in the treatment or prophylaxis of arteriosclerosis including atherosclerosis. Coagulation and thrombosis are important mechanisms involved in the pathogenesis of atherosclerosis and its complications such as vascular occlusion and embolism. In addition, blood coagulation is important for the development of vascular restenosis after surgical intervention of blocked arteries. Restenosis occurs in approximately 35% of patients after 6 months. Current therapy such as heparin, low molecular weight heparin and aspirin or stents have failed to reduce the incidence of restenosis. New therapeutic possibilities that can inhibit a tendency for thrombosis after endothelial damage are therefore necessary. Yet another objective of the present invention is to provide compounds that can be used effectively in the treatment or prophylaxis of patients in need of anticoagulant treatment or prophylaxis, for example, after coronary thrombosis or after surgery. Recent studies (writing group for PEPI JAMA 273: 199, 1995) confirm that oral estrogen taken alone or in combination with micronized progesterone or medroxyprogesterone acetate, is associated with a beneficial effect where the risk of developing cardiovascular disease through of an improved effect on lipoprotein and fibrinogen profile. However, it is known that estrogen also has adverse effects on the endometrium and perhaps on breast tissue, due to the increased frequency of malignancies in these areas after prolonged treatment. Thus there is a need for new compounds that have beneficial effects on hyperlipopro einemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia or arteriesclerosis, including atherosclerosis or as an anticoagulant, but without introducing significant effects on the reproductive tissues. The centeromano is a non-steroidal compound that is 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. Endocrinal Acta (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.

Centro-Roman 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 agent for lowering cholesterol, expressed by a significant decrease in serum concentrations (S. D. Bain and collaborators J Min Bon Res 9 (1994), S 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.

BRIEF DESCRIPTION OF THE INVENTION It has surprisingly been found that the compounds of the general formula I as set out in claim 1 can be used in the prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, and it has also been surprisingly found that the compounds of the general formula I as set forth in claim 2 and 3 can be used in the treatment or prophylaxis of arteriosclerosis, including atherosclerosis, and that the compounds of the general formula I as set out in claim 4, can be used in the treatment or prophylaxis of patients in need of a treatment or anticoagulant prophylaxis, for example, after a coronary thrombosis or after surgery.

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- [p- (beta-pyrrolidinoethoxy) phenyl] -7-methoxy chroman) is effective as a hypolipoproteinemic, hypotriglyceridemic, hypolipidemic or hypocholesterolemic compound, among others in rabbits fed a diet containing cholesterol. These animal models are generally recognized models of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia. These data indicate that 3, 4-diarylchromans are useful as hypolipoproteinidemic, hypotriglyceridemic, hypolipidemic or hypocholesterolemic preventive and therapeutic agents in mammals, including primates such as humans. In addition, the present invention is based in part on the discovery of a representative 3, 4-diarylchroman, centroman (3, 4-trans-2,2-dimethyl-3-phenyl-4- [p- (beta- (pyrrolidinoethoxy ) phenyl] -7- ethoxy-roman) is also effective against the direct vascular effects of arteriosclerosis including atherosclerosis, among others in rabbits fed cholesterol-containing diet.These animal models are generally recognized models of arteriosclerosis, including atherosclerosis. These data thus indicate that all 3-diarylchromans are useful as therapeutic agents against arteriosclerosis, including atherosclerosis in mammals, including primates such as humans.The present invention is also based in part on the discovery that a 3, 4 - Representative Diarilchroman, centroman (3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxy-roman) has anticoagulant activities. or therapeutic when administered inter alia to rabbits. These animal models are recognized models of patients in need of anticoagulant treatment or prophylaxis, for example, after coronary thrombosis or after surgery. These data thus indicate that the 3, 4-diarylchromans of the formula I are useful as therapeutic or preventive agents for mammals, including primates such as humans, in need of a treatment or anticoagulant prophylaxis, for example, after coronary thrombosis. or after surgery. This invention is also related to the treatment or prophylaxis of disorders as defined in the Lipid Research Clinics Program. J.A.M.A. 251 (1984), 351-364 and J.A.M.A. 25 _: ^ (1984), 365-374 or that a person skilled in the art can consider as a subject for treatment or prophylaxis. Within the present invention, the compounds of the formula I are used for the indications as set forth in claims 1-4 of a patient. 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, 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-dialkylamine such as N, N-dimethylamine, N, N-diethylamine, N, N-dipropylamine and N, N-dibutylamine or a polymethylene nitrin, for example, piperidine, pyrrolidine, N- methylpiperazine or morpholine. In the present, the term "(tertiary arrimo) (lower alkoxy)" is a lower alkoxy group which is substituted by a tertiary amino group. Preferred compounds include those in which R: 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, R- is in the 7-position and is lower-alkoxy, particularly methoxy; each of R '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 centchroman having the formula IV as set forth in claim 14. Although only one enantiomer is shown, it will be understood that formula IV is used herein to designate the configuration trans of groups 3- and 4-phenyl and the enantiomers of d and 1, as well as the racemic mixture, are included. 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 isomer 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 attached to alkaline hydrolysis to produce the desired enantiomer. If R2 is different from R3 and R4 is different from R3, general formula I covers 8 optical isomers. Within the present invention, the 3,4-diarylchromans 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 salts of organic acids such as, formic acid, acetic acid, propionic acid, fumaric 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 and their salts are useful within the field of human and veterinary medicine, for example, in the treatment or prevention of patients suffering from, hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, or arteriosclerosis including atherosclerosis, or in need for treatment or anticoagulapte prophylaxis, for example, after a coronary thrombosis or after surgery. For use within the present invention, 3,4-diarylchromans and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, r.asal, rectal, subdermal or intradermal or transdermal administration, according to the 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 in an appropriate manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences, Gennaro, ed.,? Lack Publishing Co., Easton, PA, 1990 Oral administration is preferred. In this way, the active compound is prepared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound is combined with a carrier and molded into 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, and ulsificants, 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 such as hypolipoproteinemic, hypotriplyceridemic hypolipidemic or hypocholesterolemic agents, or a clinically significant effect against arteriosclerosis, including atherosclerosis, or provides a clinically meaningful effect to patients in need of treatment or anticoagulant prophylaxis, for example, after a coronary thrombosis or after surgery. 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. The following examples are offered by way of illustration, not limitation. Examples of the preferred compounds of formula I are centchroman as a racemic mixture and as 1-centcro-ano and d-cent-chroman. In addition, a preferred compound is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) f: enyl] -7-hydroxychroman. The most preferred compound is (1-3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxy chroman. examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, fumaric acid , gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulfonic acid and malonic acid The present invention is further illustrated by the following examples which, however, are not to be considered as limiting the scope The features described in the following description and in the following examples may, either separately and in any combination thereof, be the material for carrying out the invention and n various forms of it.

EXAMPLE 1 The effects of 1-centchroman on plasma cholesterol have been investigated in rats and rabbits. In the first study, sham surgery or ovarectomy (OVX) was performed on 56 female Sprague Dawley rats and the animals were assigned to the following treatments (8 rats per group): 1) simulated / vehicle; 2) OVX / vehicle, 3) OVX / ethinylestradiol 0.2 mg / kg; 4) OVX / 1-centchroman 1 mg / kg; 5) OVX / 1-centchroman 5 mg / kg; 6) OVX / 1- centchroman 10 mg / kg; 7) OVX / 1-centchroman 25 mg / kg. The doses were administered three times a week for 5 weeks by oral priming. At the conclusion of the experiment, the serum was collected for the determination of cholesterol level (US Pat. No. 5, 407, 955). 1-centchroman had a marked effect on serum cholesterol at all doses and reduced cholesterol level even below the level of sham-operated animals (Table 1).

Table 1. Effect of 1-centchroman on serum cholesterol in rats Serum cholesterol treatment (mmol / 1) Simulated / vehicle 2.2 ± 0.3 OVX / vehicle 2.9 ± 0.3 OVX / ethinylestradiol 0.2 mg / kg 1.9 ± 0.4 OVX / 1-centchroman 1 mg / kg 1.4 ± 0.3 * OVX / centchroman 5 mg / kg 1 5 ± 0.4 OVX / centchroman 10 mg / kg 0.5 ± 0.2 OVX / centchroman 25 mg / kg 1.2 ± 0.2 * The values are the means ± SD. * indicates significant reduction in serum cholesterol compared to OVX rats treated with ethinylestradiol; p < 0.002.

In order to show a clear dose response effect on serum cholesterol, an additional study was performed with 1-centchroman.

Again, a simulated surgery or ovarectomy was performed on 56 female rats and the rats were assigned to the following treatments: 1) simulated / vehicle; 2) OVX / vehicle, 3) OVX / ethinylestradiol 0.2 mg / kg; 4) OVX / 1-centchroman 0.05 mg / kg; 5) OVX / 1-centchroman 0.1 mg / kg; 6) OVX / 1-centchroman 0.5 mg / kg; 7) OVX / 1-centchroman 1 mg / kg. The doses were administered three times a week for 5 weeks by oral priming. At the conclusion of the experiment, serum was collected for the determination of cholesterol level (US Pat. No. 5,407,955). In this experiment, serum cholesterol was reduced in a dose-dependent manner (table 2).

Table 2. Effect of 1-centchroman on serum cholesterol in rats Treatment Serum cholesterol (mmol / 1) Simulated / vehicle 2.1 ± 0.3 OVX / vehicle 2.7 ± 0.3 OVX / ethinylestradiol 0.2 mg / kg 1.6 ± 0.4 OVX / 1-centchroman 0.05 mg / kg 2.4 ± 0.4 OVX / 1-centchroman 0.1 mg / kg 2.3 ± 0.3 OVX / 1- centchroman 0.5 mg / kg 1.7 ± 0.3 * OVX / 1-centchroman 1.0 mg / kg 1.5 ± 0.4 * OVX / centchroman 25 mg / kg 1.5 ± 0.4 * Values are the means ± SD. * indicates significant reduction of serum cholesterol compared to sham / vehicle treated animals; p < 0.003.

The effects of 1-centchroman on plasma lipids were also investigated in rabbits fed cholesterol. One week before the experiment was started, 30 sexually mature New Zealand white rabbits were ovariectomized during pentobarbital anesthesia. After the recovery, subcutaneous treatment was started in three groups. Vehicle 17-ß-estradiol or 1-centchroman 7.5 mg / kg. The doses were administered three times a week for 4 weeks. At the end of the experiment, plasma samples were taken for the analysis of serum cholesterol. Cone is shown in Table 3, 1-centchroman was recovered in serum cholesterol and significantly compared to the level and animals treated with vehicle and animals treated with estrogen.

Table 3. Effect of 1-centchroman on serum cholesterol in ovariectomized rabbits Treatment Serum cholesterol (mmol / 1) OVX / vehicle 11.0 ± 1.1 OVX / 17-ß-estradiol 50 μg / kg 3x / week 7.5 ± 0.5 * OVX / 1 -centcroman 7.5 mg / kg 3x / week 8.2 ± 0.7 * The values are the mean ± SEM. * indicates significant reduction of serum cholesterol compared to animals treated with OVX / vehicle; p < 0.05.

EXAMPLE 2 The effects of 1-centchroman on the accumulation of lipids in the aortic wall were investigated, for example, a central mechanism in the atherogenic process in New Zealand white rabbits. A week before the experiment was started, the ovaries were removed from 45 New Zealand white female rabbits, primers were tested during anesthesia with pentobarbital.

In addition, a group of 45 years and weight adjusted to male rabbits, is included in the experiment. Briefly, the oral recovery treatment was initiated. Males and females were treated in 3 groups (15 animals per group): 1) animals treated with placebo; 2) 17-ß-estradiol 2-5 mg / kg / day; 3) 1-centchroman, 2.5 mg / kg / day. After 14 days of treatment, cholesterol was added to the food. Every second day a blood sample was collected from each rabbit, and serum total cholesterol was determined (Holm P et al. Atherosclerosis 115: 191, 1995). Based on this measurement, the concentration of cholesterol in the diet was regulated in the following days until the next measurement. In that way, serum cholesterol was kept constant throughout the treatment period, even though some of the treatments are known to have effects on the plasma cholesterol level. The direct effect of the treatment on the wall of the vessels could be isolated. After 3 months of treatment the animals were sacrificed, the aorta artery of each animal was isolated and the cholesterol accumulated on the intima of the aorta was determined (Holm P et al. Atherosclerosis, 115: 191, 1995).

The results are shown in Table 4. It is clearly observed that estrogen and 1-centcroman in male and female rabbits have a significant reducing effect on the content of cholesterol in the intimate, which is independent of serum cholesterol, since this , has had constant throughout the experiment. The anti-atherosclerotic effect of 1-centchroman can therefore be partially due to a direct effect on the vascular wall.

Table 4. Effect of 1-centchroman and estrogen on the content of cholesterol in the intima Treatment cholesterol in intimate (mmol / 1) intimate cholesterol (mmol / 1) female male Placebo 45 ± 9 27 ± 5 17-ß-estradiol 8 ± 3 * 8 ± 2 * 1-centchroman 18 ± 5 * 13 ± 4 * 2. 5 mg / kg The values are the me ± SEM. * indicates significant reduction of col-sterol in the intima compared to animals treated with placebo; p < 0.05.

EXAMPLE 3 In vitro it has been shown that 1-centchroman in platelet-rich plasma in rabbits inhibited platelet aggregation and induced platelet activation factor (PAF). The EC50 for this effect was between 3 and 10 μg / ml. The aggregation induced by ADP was not affected.

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 intention.

Having described the invention as above, property is claimed as contained in the following:

Claims (20)

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 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 hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, with the proviso that the pertinent compounds and pharmaceutical compositions as defined, do not include the optical isomer d-centchroman.

2. The use of the compounds of the general formula I. characterized in that R ', R4 and R "are individually hydrogen, hydroxyl, halogen, tri fluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy), and R2 and R3 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 arteriosclerosis including atherosclerosis.

3. The use according to claim 2, characterized in that it is for the treatment or prophylaxis of atherosclerosis.

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 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 patients in need of a treatment or anticoagulant prophylaxis , for example, after a coronary thrombosis after surgery.

5. The use according to any of claims 1 to 4, characterized in that R1 in the compound used is lower alkoxy R2 and R3 are lower alkyl, R4 is hydrogen and R5 is (tertiary amino) (lower alkoxy).

6. The use according to any of claims 1 to 5, characterized in that R1 is methoxy.

7. The use according to any of claims 1 to 6, characterized in that R2 is methyl.

8. The use according to any of claims 1 to 7, characterized in that R3 is methyl.

9. The use according to any of claims 1 to 8, characterized in that R4 is hydrogen.

10. The use according to any of claims 1 to 9, characterized in that R5 is a group as set forth in the following formula II: (II) O • o

11. The use according to any of claims 1 to 10, characterized in that the compound is a stereoisomer, which includes an isolated d- or 1-enantiomer.

12. The use according to any of claims 1 to 11, characterized in that the compound has the general formula III as set forth below: III) wherein R, Rz, R3, R4 and R5 each have the meaning of conformance as set forth in any of the preceding claims.

13. The use according to any of the preceding claims, characterized in that the compound is an isolated 1-enantiomer.

14. The use according to any of claims 1 to 4, characterized in that the compound is cent-chroman 3, 4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidine-1-yl) ) ethoxy) phenyl] -7-methoxy chroman having the formula IV as set forth below:

15. The use according to claim 14, characterized in that the compound is an isolated d- or 1-enantiomer.

16. The use according to claim 14, characterized in that the compound is an isolated 1-anantiomer.

17. The use according to any of the preceding claims, characterized in that the composition is in a form suitable for oral administration.

18. 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 about 0.01 to 75, more preferably in the range of about 0.01 to 50, and especially in the range of approximately 0.1 to 25 mg / kg in patient per day.

19. The use according to any of the preceding claims, characterized in that the composition is administered one or more times per day or week.

20. The use according to any of the preceding claims, characterized in that the composition is in the form of a dermal implant.