KR19980701382A - Use of 3,4-diphenylchroman for the preparation of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, or atherosclerosis or for the treatment of anticoagulants - Google Patents

Abstract

The present invention is formulated 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 atherosclerosis or for the treatment of anticoagulants. Novel use of the compound of I or a pharmaceutically acceptable salt thereof is provided.

Formula I

Wherein R 1, R 4 and R 5 are each hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); R2 and R3 are each hydrogen or lower alkyl.

Description

Use of 3,4-diphenylchroman for the preparation of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, or atherosclerosis or for the treatment of anticoagulants

Ischemic heart disease (IHD), a related cardiovascular disease for postmenopausal women, is mainly due to atherosclerosis (Havel and Rapaport, N Eng J Med 1995; 332: 1491-1498). Another common manifestation of atherosclerosis is cerebrovascular disease and intermittent claudication. An important risk factor for developing atherosclerosis is the profile of lipids that cause atherosclerosis, namely hyperlipidemia, with an increase in LDL-cholesterol and a relatively decrease in HDL-cholesterol. In epidemiological studies (Samsioe G. Int J Fertil, 1993; 38, suppl. 1: 19-23), estrogen therapy in postmenopausal women reduces coronary artery stenosis and thereby survival rates compared to those who have not been treated. It is pointed out that it increases. An important factor in this effect on the coronary artery system is the reduction of serum fat and normalization of the relationship between LDL-cholesterol and HDL-cholesterol (Samsioe G. Int J Fertil 1994; 39, suppl. 1: 43-49).

One object of the present invention is to provide a compound that can be effectively used for the treatment or prevention of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia.

If LDL-cholesterol reduction is the only cause of cardioprotection, human data suggest a 35% reduction in LDL-cholesterol is required to achieve a 50% reduction in cardiovascular disease, ie atherosclerosis. However, estrogen reduces LDL-cholesterol by only 5-10%. Therefore, it is currently believed that the lipid effect is the cause for only a 25-40% reduction in the incidence of coronary heart disease following estrogen replacement therapy. One possible mechanism could be a direct effect on blood vessel walls that enhances blood flow and interferes with the causative mechanism of atherosclerosis, independent of its effect on plasma fat.

Another object of the present invention is to provide a compound that can be effectively used for the treatment or prevention of atherosclerosis, including atherosclerosis.

Coagulation and thrombosis are important mechanisms associated with the onset of atherosclerosis and its complications such as vascular occlusion and embolism. Moreover, blood coagulation is important for the development of vascular restenosis following surgical adjustment of blocked arteries. Restenosis occurs in about 35% of patients after 6 months. Current therapeutics such as heparin, small molecule heparin and aspirin or stents have failed to reduce the incidence of restenosis. Therefore, there is a need for new therapeutic means that can suppress the tendency to thrombosis after endothelial cell damage.

It is yet another object of the present invention to provide compounds which can be effectively used for the treatment and prevention of patients in need of anticoagulant treatment and prevention, for example following coronary thrombosis or after surgery.

A recent study (Writing group for the PEPI trial, JAMA 273: 199, 1995), which alone or in combination with hydroxyprogesterone acetate or undifferentiated progesterone, develops oral estrogens through improved effects on lipoproteins and fibrinogen profiles. It has been found to be associated with a useful effect on the risk of cardiovascular disease. However, estrogen is also known to have an adverse effect on the endometrium and possibly chest tissues by increasing the frequency of malignancy at this site after prolonged treatment.

Therefore, there is a need for new compounds that have a beneficial effect on or as an anticoagulant against atherosclerosis, including hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, or atherosclerosis, without causing significant effects on the reproductive tissues. have.

Centcroman is a nonsteroidal compound known to have antiestrogens activity. It is used as an oral contraceptive in India (see, eg, US Pat. No. 4,447,622 to Salman et al .; Singh et al., Acta Endocrinal ( Copenh ) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991) , 491-495; Sankaran et al., Contraception 9 (1974), 279-289; see Indian 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, only centroc as a racemate has been found to be effective as a drug for lowering cholesterol levels, which is expressed as a significant decrease in serum concentrations (SD Bain et al., J Min Bon Res 9 (1994), S 394).

U.S. Patent 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchroman and its pharmaceutically acceptable salts.

The present invention relates to the use of a compound of formula (I) for the treatment and prevention of patients suffering from hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia. Moreover, the present invention relates to the use of a compound of formula (I) for the treatment and prevention of patients suffering from atherosclerosis, including atherosclerosis, and more particularly for the treatment of patients in need of anticoagulant treatment or prevention following surgery or coronary thrombosis. To the use of compounds of formula (I) for The present invention also includes a pharmaceutical composition consisting of the compound and a method of using the compound and the pharmaceutical composition.

Brief Description of the Invention

It has surprisingly been found that compounds of formula (I) as mentioned in claim 1 can be used for the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, and more surprisingly with those mentioned in claims 2 and 3 The same compounds of formula (I) can be used for the treatment or prevention of atherosclerosis, including atherosclerosis, and compounds of formula (I) as mentioned in claim 4 can be used in patients requiring treatment or prophylaxis of anticoagulants following for example coronary thrombosis or surgery. It has been found that it can be used for treatment or prevention.

Detailed description of the invention

The present invention is representative of 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [p- (beta-pyrrolidinoethoxy) phenyl]- 7-methoxychromen) is based in part on the discovery that, among other things, is effective as a compound of hypolipoproteinemia, hypotriglyceridemia, hypolipidemia or hypocholesterolemia in rabbits raised with food containing cholesterol. This animal model is generally recognized as a model of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia. Therefore, these data indicate that only 3,4-diarylchrom is useful as a therapeutic and prophylactic agent in hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia in mammals including primates such as humans.

Furthermore, the present invention is representative of 3,4-diarylchroman and centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [p- (beta-pyrrolidinoethoxy) phenyl] It is based in part on the finding that -7-methoxychromen) is, among other things, also effective against the direct vascular effects of atherosclerosis, including atherosclerosis, in rabbits fed with cholesterol-containing foods. These animal models are generally recognized as typical of atherosclerosis, including atherosclerosis. Therefore, these data indicate that only 3,4-diarylchrom is useful as a therapeutic agent for atherosclerosis including atherosclerosis in mammals including primates such as humans.

Furthermore, the present invention is representative of 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) (Ethoxy) phenyl] -7-methoxychroman) is based, among other things, on profound or therapeutic anticoagulant activity when administered to rats. These animal models are generally recognized as models of patients in need of anticoagulant treatment or prevention, such as following coronary thrombosis or surgery. These data therefore suggest that only 3,4-diarylchromes of formula I are useful as therapeutic and prophylactic agents in mammals, including primates such as coronary thrombosis or humans in need of anticoagulant treatment or prophylaxis following surgery.

The present invention is to be regarded as a subject for treatment or prevention by a disease as defined in the Lipid Research Clinics Program. JAMA 251 (1984), 351-364, and JAMA 251 (1984), 365-374. It relates to the treatment or prevention of what may be.

In the scope of the invention, the compounds of formula (I) are used for applications as mentioned in claims 1 to 4 in patients. In formula (I), R 1, R 4 and R 5 are each hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy) and R 2 and R 3 are each hydrogen or lower alkyl. As used herein, the term lower alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3 -Straight and branched chain alkyl radicals containing 1 to 6 carbon atoms, such as dimethylbutyl and the like. The term lower alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amylooxy, sec-amylooxy, n-hexyloxy, 2-ethylbutoxy And straight and branched chain alkoxy radicals containing 1 to 6 carbon atoms, such as 2,3-dimethylbutoxy and the like. The term halogen includes chloro, fluoro, bromo and iodo. Tertiary amino radicals are N, N-dialkylamines such as N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino and N, N-dibutylamino or piperidine, for example, Polymethyleneimines such as pyrrolidine, N-methylpiperazine or morpholine. The term (tertiary amino) (lower alkoxy) here is a lower alkoxy group substituted by a tertiary amino group. Preferred compounds are those in which R ¹ is lower alkoxy; R ² and R ³ are lower alkyl, in particular methyl; R ⁴ is hydrogen; And R ⁵ comprises a compound which is (tertiary amino) (lower alkoxy) in polymethyleneimine form. In a particularly preferred embodiment, R ¹ is at the 7-position and is lower alkoxy, especially methoxy; R ² and R ³ are each methyl; R ⁴ is hydrogen, R ⁵ is in the 4-position and is (tertiary amino) (lower alkoxy) such as 2- (pyrrolidin-1-yl) ethoxy. All pharmaceutically acceptable salts of the compounds of formula (I) mentioned are included in the present invention.

Preference is given to using transarrayed compounds of formula (I). These compounds may be used as racemic mixtures, or separate stereoisomers such as d- or l-enantiomers may be used. More preferred are the trans-enantiomers.

Particularly preferred compounds for use in the present invention are the centchroms of formula IV as mentioned in claim 14.

Although only one enantiomer is shown, Formula IV is used herein to denote the trans configuration of 3- and 4-phenyl groups, and it is to be understood that both the d- and l-enantiomers as well as the racemic mixture are included. will be.

3,4-Diarylchroman is described in Carney's US Patent Specification No., incorporated herein by reference. 3,340,276, Bolger, US Pat. 3,822,287 and Ray et al ., Prepared according to known methods such as those disclosed in J Med Chem 19 (1976), 276-279. Conversion of cis isomers to transarrays by organometallic base-catalyzed potential reactions is described in US Pat. 3,822,287. Optically active d- and l-enantiomers form an optically active acid salt and alkali hydrolyze it to produce the desired enantiomer. 4,447,622 (incorporated herein by reference). Formula R includes eight optical isomers when R ² is different from R ³ and R ⁴ is different from R ⁵ .

In the present invention, only 3,4-diarylchrom can be prepared in the form of pharmaceutically acceptable salts, in particular in the form of acid addition salts including salts of organic and inorganic 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 salts such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. This acid addition salt can be obtained as a direct product of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent including a suitable acid and the salts may be separated by evaporation of the solvent or other separation of the salt and the solvent.

3,4-Diarylchromans and salts thereof include those suffering from atherosclerosis, including hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, or atherosclerosis, or for example following coronary thrombosis or surgery. It is useful as human and veterinary medicine in the treatment or prevention of patients in need of anticoagulant treatment or prevention. In the use of the present invention, 3,4-diarylchroman and its pharmaceutically acceptable salts are prepared according to conventional methods for providing a medicament for parenteral, oral, nasal, rectal, subcutaneous or intradermal, or transdermal administration. It is formulated with a pharmaceutically acceptable carrier. Formulations may include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, and the like, and may be provided in the form of liquids, powders, emulsions, suppositories, liposomes, transdermal preparations, sustained release skin grafts, tablets, and the like. have. One skilled in the art can formulate the compounds according to appropriate manners and accepted applications as disclosed in Remington's Pharmaceutical Sciences , Gennaro, ed., Mack Publishing Co., Easton, PA, 1990.

Oral administration is preferred. Thus, the active compounds are prepared in a form suitable for oral administration such as tablets or capsules. Typically, pharmaceutically acceptable salts of the compounds are combined with the carrier and shaped into tablets. Suitable carriers in this regard include starch, sugar, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions further comprise one or more auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers, colorants and the like.

Pharmaceutical compositions containing a compound of formula (I) are administered at least once per day or week. Effective amounts of such pharmaceutical compositions provide clinically significant effects as hypolipoproteinemia, hypotriglyceridemia, hypolipidemia or hypocholesterolemia drugs, or clinically significant effects on atherosclerosis, including atherosclerosis, It is an amount that provides a clinically significant effect to a patient in need of anticoagulant treatment or prevention, such as following coronary thrombosis or after surgery. Such amount depends in part on the particular condition to be treated, the age, weight and general state of health of the patient, and other factors apparent to those skilled in the art.

Pharmaceutical compositions containing a compound of formula (I) may be administered in unit dosage form one or more times per week. Alternatively, it may be provided as a sustained release formulation suitable for skin grafts. The graft is formulated to provide release of the active compound over a desired period of time, which can be several years. Sustained release preparations are described, for example, in J Pharm Sci 73 (1964), 1294-1297, 1984, US Pat. 4,489,056 and US patent specification no. 4,210,644.

The following examples are provided by way of illustration and not of limitation.

Examples of preferred compounds of formula (I) are the racemic mixtures and the centchroms as d-deckman and l-deckman. Moreover, 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-hydroxychrome only is preferred to be. More preferred compounds are trans-l-Centroman (l-3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) Phenyl] -7-methoxychromen).

Examples of pharmaceutically acceptable acid addition salts are inorganic acids such as non-toxic acids, hydrochloric acid, sulfuric acid, phosphoric acid or 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 Salts with organic acids such as malonic acid.

The invention is further illustrated by the following examples, which are not to be construed as limiting the scope of protection. The features already disclosed in the foregoing description and in the following embodiments, independently and in any combination thereof, are elements for realizing the invention in various forms.

Example 1

The effect of l-Seccroman on plasma cholesterol was investigated in rats and rabbits.

A first Sham Surgery or ovariectomy (OVX) was performed on 56 female Sprague-Dawley rats and the animals were classified according to the following treatments (8 rats per group):

1) Sham / excipient; 2) OVX / excipients; 3) 0.2 mg / kg OVX / ethynylestradiol;

4) OVX / l-Seccroman 1 mg / kg; 5) OVX / l-Seccromann 5 mg / kg;

6) OVX / l-Seccroman 10 mg / kg; 7) OVX / l-Seccroman 25 mg / kg.

This dose was administered orally three times per week for 5 weeks. At the end of the experiment, serum was collected for determination of cholesterol levels (US Pat. No. 5,407,955).

1-Centromann showed a significant effect on serum cholesterol at all doses and even reduced cholesterol levels below the levels of the simulated animals.

Effect of l-Seccroman on Serum Cholesterol in Rats Processing method Serum cholesterol (mmol / l) sham / excipient 2.2 ± 0.3 OVX / Excipients 2.9 ± 0.3 OVX / ethynyl estradiol 0.2 mg / kg 1.9 ± 0.4 OVX / l-Seccroman 1 mg / kg 1.4 ± 0.3 ^* OVX / l-Seccromann 5 mg / kg 1.5 ± 0.4 OVX / l-Seccroman 10 mg / kg 1.5 ± 0.2 OVX / l-Seccroman 25 mg / kg 1.2 ± 0.2 ^* These values are mean ± SD. * Shows a marked decrease in serum cholesterol compared to OVX mice treated with ethynyl estradiol; p <0.002.

Further studies were conducted with l-Centro alone to elucidate the clear dose-response effect on serum cholesterol.

Again mock surgery or ovarian resection was performed on 56 rats, and the rats were classified according to the following treatments:

1) Sham / excipient; 2) OVX / excipients; 3) 0.2 mg / kg OVX / ethynylestradiol;

4) 0.05 mg / kg OVX / l-Seccroman; 5) OVX / l-Seccromann 0.1 mg / kg;

6) OVX / l-Seccromann 0.5 mg / kg; 7) 1 mg / kg OVX / l-Seccroman.

Doses were administered orally three times per week for 5 weeks. At the end of the experiment, serum was collected for determination of cholesterol levels (US Pat. No. 5,407,955). In this experiment serum cholesterol was reduced in a dose-dependent manner (Table 2).

L-Seccroman's Effect on Serum Cholesterol in Rats Processing method Serum cholesterol (mmol / l) sham / excipient 2.1 ± 0.3 OVX / Excipients 2.7 ± 0.3 OVX / ethynyl estradiol 0.2 mg / kg 1.6 ± 0.4 OVX / l-Seccromann 0.05 mg / kg 2.4 ± 0.4 OVX / l-Seccroman 0.1 mg / kg 2.3 ± 0.3 OVX / l-Seccromann 0.5 mg / kg 1.7 ± 0.3 ^* OVX / l-Seccromann 1.0 mg / kg 1.5 ± 0.4 ^* These values are mean ± SD. * Shows a significant reduction in serum cholesterol compared to sham / excipient treated animals; p <0.003.

The effect of l-Secroman on plasma fat was also examined in rabbits bred with cholesterol. One week before the start of the experiment, 30 sexually mature New Zealand white rabbits performed ovarian reconstruction during pentobarbital anesthesia. After recovery, subcutaneous treatment was started in three groups: 7.5 mg / kg of excipient, 17-β-estradiol or l-secron only. This dose was administered three times per week for four weeks. At the end of the experiment plasma samples were taken for analysis of serum cholesterol. As shown in Table 3, l-Secroman significantly reduced serum cholesterol compared to animals treated with excipients or estrogens.

Effect of l-Seccroman on Serum Cholesterol in Ovariectomized Rabbits Processing method Serum cholesterol (mmol / l) OVX / Excipients 11.0 ± 1.1 OVX / 17-β-estradiol 50μg / kg 3x / week 7.5 ± 0.5 ^* OVX / l-Seccromann 7.5 mg / kg 3x / week 8.2 ± 0.7 ^* These values are mean ± SEM. * Shows a significant reduction in serum cholesterol compared to OVX / excipient treated animals; p <0.05.

Example 2

The effect of l-Centromann on fat accumulation in the aortic wall, ie the main mechanism of the process of causing atherosclerosis, was investigated in New Zealand white rabbits. One week before the start of the experiment, 45 sexually mature New Zealand white rabbits were underwent ovarian reconstruction during pentobarbital anesthesia. In addition, 45 male rabbits of equal age and weight were included in the experiment. Oral treatment was started after recovery. Male and female were treated in three groups (15 animals per group):

1) placebo treated animals; 2) 17-β-estradiol 2.5 mg / kg / day; 3) l-Centro only, 2.5 mg / kg / day.

After 14 days of treatment, cholesterol was added to the food. Blood samples were taken from each rabbit every second day and total serum cholesterol was measured (Holm P et al. Atherosclerosis, 115: 191, 1995). Based on this measurement, the cholesterol concentration in the food was adjusted the next day until the next measurement. Although some of the treatments have been known to affect plasma cholesterol levels, in this way serum cholesterol concentrations were kept constant for the duration of the treatment. The direct effects of treatment on the vessel wall could be isolated. After three months of treatment, the animals were sacrificed, the artery of each animal was isolated, and the cholesterol accumulated in the endometrium of the aorta was measured (Holm P et al. Atherosclerosis, 115: 191, 1995).

The results are shown in Table 4. It can be clearly seen that both estrogen and l-Seccroman have a significant reduction in the arterial cholesterol content independent of serum cholesterol because serum cholesterol remained constant during the experiments in female and male rabbits. Therefore, the anti-atherosclerotic effect of l-Secroman may be due in part to the direct vascular wall effect.

Effect of l-Secroman and Estrogen on Endothelial Cholesterol Content Treatment method Endothelial Cholesterol (mmol / l) Female Intimal cholesterol (mmol / l) male Placebo 45 ± 9 27 ± 5 17-β-estradiol 8 ± 3 ^* 8 ± 2 ^* l-Seccromann 2.5 mg / kg 18 ± 5 ^* 13 ± 4 ^* Values are mean ± SEM. * Shows a significant reduction in endometrial cholesterol in comparison to placebo treated animals; p0.05.

Example 3

In vitro, l-Secroman proved to inhibit platelet aggregation induced by platelet activating factor (PAF) in rabbits with platelet rich serum. EC 50 for this effect was between 3 and 10 μg / ml. Aggregation induced by ADP was not affected.

Claims (27)

Preparation of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, provided that the related compounds and pharmaceutical compositions defined below do not contain only the optical isomer d-sentcro. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for: Wherein R 1, R 4 and R 5 are each hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); R2 and R3 are each hydrogen or lower alkyl. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for preparing a pharmaceutical composition for the treatment or prevention of atherosclerosis, including atherosclerosis. Formula I Wherein R 1, R 4 and R 5 are each hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); R2 and R3 are each hydrogen or lower alkyl. Use according to claim 2, for the treatment or prevention of atherosclerosis. Of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for preparing a pharmaceutical composition for the treatment or prevention of, for example, a patient in need of anticoagulant treatment or prevention after coronary thrombosis or surgery use. Formula I Wherein R 1, R 4 and R 5 are each hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); R2 and R3 are each hydrogen or lower alkyl. 5. The compound according to claim 1, wherein R 1 of the compound used is lower alkoxy, R 2 and R 3 are lower alkyl, R 4 is hydrogen, and R 5 is tertiary amino lower alkoxy. use. 6. Use according to any one of claims 1 to 5, wherein R &lt; 1 &gt; is methoxy. 7. Use according to any one of claims 1 to 6, wherein R2 is methyl. 8. Use according to any one of the preceding claims, wherein R3 is methyl. The use according to any one of claims 1 to 8, wherein R4 is hydrogen. Use according to any of the preceding claims, wherein R 5 is a group as mentioned in formula (II) below. Use according to any of the preceding claims, characterized in that the compound is a stereoisomer comprising separated d- or l-enantiomers. Use according to any of the preceding claims, characterized in that the compound has the formula (III) as mentioned below. Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as mentioned in any of the preceding claims. Use according to any of the preceding claims, characterized in that the compound is an isolated l-enantiomer. The method according to any one of claims 1 to 4, wherein the compound has a centromene 3,4-trans-2,2-dimethyl-3-phenyl-4- [4 having the formula IV as mentioned below. -(2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman. 15. Use according to claim 14, wherein the compound is an isolated d- or l-enantiomer. 15. Use according to claim 14, wherein the compound is an isolated l-enantiomer. Use according to any one of the preceding claims, wherein the composition is in a form suitable for oral administration. The method of claim 1, wherein the compound is in the range of about 0.001-75 mg, preferably in the range of about 0.01-75 mg, more preferably in the range of about 0.01-50 mg, in particular about 0.1- per kg patient per day. Use characterized in that it is administered in the range of 25 mg. Use according to any of the preceding claims, characterized in that the composition is administered at least once per day or week. Use according to any one of the preceding claims, characterized in that the composition is in the form of a skin graft. A clinically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 referred to for use in any of the above claims for use is hypolipoproteinemia, hypotriglyceridemia, hypolipidemia Or a hypocholesterolemia agent, which is administered to a patient in an amount sufficient to treat or prevent the hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia. A clinically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 2 referred to for use in any of the above claims for use may be used for the treatment or prevention of atherosclerosis, including atherosclerosis. A method for treating and preventing atherosclerosis, including atherosclerosis, which is administered to a patient in a sufficient amount. A clinically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 4 referred to for use in any one of the above claims for use, such as for example after coronary thrombosis or after surgery A method of treating and preventing anticoagulants in a patient, comprising administering to the patient in an amount sufficient to treat or prevent the coagulated patient. In patients in need of the treatment or prevention of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia, or hypercholesterolemia, the compounds of formula (I) or salts thereof according to the preceding claims and the pharmaceutically acceptable compositions thereof A method of treating or preventing hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia, or hypercholesterolemia, comprising administering an effective amount. Atherosclerosis comprising administering to a patient in need of treatment or prevention of atherosclerosis, including atherosclerosis, a clinically effective amount of a compound of formula (I) or a salt thereof and a pharmaceutically acceptable composition according to the preceding claims A method of treating or preventing atherosclerosis, including sclerosis. For patients in need of anticoagulant treatment or prophylaxis, such as following coronary thrombosis or surgical operation, a clinically acceptable formulation of a compound of formula I or a salt thereof and a pharmaceutically acceptable composition containing such a compound according to the preceding claims A method of treating or preventing anticoagulants, for example following coronary thrombosis or after surgery, which comprises administering an effective amount. Any novel feature or combination of features described herein.