CZ212397A3 - Use of 3,4-diphenylchromans for preparing pharmaceutical preparations for treating or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolaemia, hyperlipidaemia, hypercholesterolaemia, arteriosclerosis and reduction of blood sedimentation - Google Patents

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 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 hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment.

Description

, (57)

The present invention provides a novel use of a compound of formula (I) wherein R1. R 4 and R 5 are hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 2 and R 3 are hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for the preparation of a pharmaceutical composition for the treatment or prophylaxis of hyperlipioproteinaemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis and blood coagulation reduction, eg after coronary thrombosis or after surgery.

(AND)

CZ 2123-97 Aá

Use of 3,4-diphenylchromans for the preparation of pharmaceutical compositions for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis and reduction of blood clotting

Technical field

The present invention relates to the use of compounds of formula (1) for treating ·, γ, or prophylaxis of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, hypercholesterolaemia, arteriosclerosis and reduced blood clotting, e.g. after ^one and ^one coronary thrombosis or after surgery. The present invention also; includes a pharmaceutical composition comprising the compounds and methods of using the compounds and compositions.

Technical field

Ischemic heart disease (ICS) is a serious cardiovascular disease in postmenopausal women. It is primarily caused by atherosclerosis (Havel and Rapaport, N. Eng. J. Med. 1995, 332: 1491-1498). Another common manifestation of atherosclerosis is cerebrovascular disease and occasional lameness. Atherogenic lipids are an important risk factor in the development of atherosclerosis. An example of a related disease is hyperlipidemia with elevated LDL cholesterol and lowered HDL cholesterol. Epidemiological studies (Samsioe G., Int. J. fertil., 1993, 38, appendix 1: 19-23) have shown that estrogen therapy in postmenopausal women reduces coronary artery narrowing and increases life expectancy compared to the untreated population. An important factor in this effect on the coronary system is the reduction in serum lipids and normalization of the ratio between LDL and HDL cholesterol (Samsioe G., Int. J. fertil., 1994, 39, Appendix 1: 43-49).

One object of the present invention is to provide compounds that can be effectively used in the treatment and prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia and hypercholesterolemia.

Male data suggest that for a 50% reduction in cardiovascular disease, ie coronary atherosclerosis, a 35% reduction in LDL cholesterol is required, given the essence of lowering LDL cholesterol as heart protection. But estrogens lower cholesterol by only 5-10%. Therefore, lipids are now believed to reduce the impact of coronary heart disease in estrogen therapy by only 25-40%. A possible mechanism may be a direct effect on the vascular wall improving blood flow and inhibiting the dependence of atherogenic mechanisms on plasma lipid action.

It is a further object of the present invention to provide compounds that can be used effectively in the treatment and prophylaxis of atherosclerosis including atherosclerosis.

Blood coagulation and thrombosis are important mechanisms in the pathogenesis of atherosclerosis and its complications such as vascular occlusion and embolism. Furthermore, blood clotting is important for the development of vascular restenosis after surgical relief of clogged arteries. Restenosis occurs after 6 months in 35% of patients. Concomitant treatment with heparin, low molecular weight heparin aspirin, fails to reduce restenosis. Therefore, it is necessary to develop new therapies that can reduce thrombosis after endothelial damage.

It is another object of the present invention to provide compounds that can be used effectively in the need to reduce blood clotting, e.g., after coronary thrombosis or surgery.

Recent studies (JAMA 273: 199, 1995) confirm that oral administration of estrogen alone or a combination thereof with medroxyprogesterone acetate or microcontacted progesterone is associated with a user risk of developing cardiovascular disease due to increased action on lipoproteins and fibrinogen. However, estrogen is also known to have adverse effects on the uterine mucosa and breast tissue, increasing the risk of cancer of these tissues with long-term treatment.

Therefore, there is a need for new compounds for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis and reduction of blood coagulation, but without significant effect on reproductive tissues.

Centchroman is a non-steroidal compound for which antiestrogenic activity is known. In India it is used as an oral contraceptive - see. e.g., Saiman et al.

U.S. Pat. Patent Specification No. 4,447,622; Singh et al., AM Endocrinol. (Copenh) 126 (1992) 44-4-450; Grubb, Curr.Ooin. Obstet. Gynecol. and (1991), 491,495; Sankaran et al., Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). Centchroman is also a proven agent for the treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 (1989), 781 783).

Recently, racemic centchroman has been confirmed as a cholesterol lowering drug that greatly lowers serum concentrations (S.D. Bain et al., J. Min. Bon. Res. 9 (1994), 394).

U.S. Pat. U.S. Patent No. 5,280,040 discloses methods and pharmaceutical compositions for reducing bone loss using 3,4-diarychromans and pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that compounds of the general formula (1) according to claims 2, 3 and 4 can be used for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperliptdemia, hypercholesterolemia, arteriosclerosis and reduction of blood clotting eg after coronary thrombosis or surgery.

The present invention is based, in part, on the discovery that among other species in rabbits fed a cholesterol-containing diet, hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis and a reduction in blood coagulation, e.g. after coronary thrombosis or surgery diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman). These animal models are generally accepted models of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia and hypercholesterolemia. These data therefore demonstrate that the 3,4diarylchromans of formula (1) are effective in treating or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia in mammals including primates such as humans.

Further, the present invention is based on the discovery that a representative

3,4-diarychromans centchroman 3,4-trans-2,2-dimethyl-3-phenyl-4- [p-betapyrrolidonethoxy) phenyl] -7-methoxychroman is, among other species, in rabbits fed a cholesterol-containing diet, effective against direct vascular manifestations of arteriosclerosis, which proves that it is useful as a medicament for arteriosclerosis and / or arteriosclerosis. atherosclerosis in mammals including primates and humans.

The present invention is further based on the discovery that a representative

3,4-diarychromans centchroman 3,4-trans-2,2'-dimethyl-3-phenyl-4- [p-betapyrrolidonethoxy) phenyl] -7-methoxychroman is effective in the prevention and control of rats, among others. treatment to reduce blood clotting. These species are considered to be biological models of patients in which blood clotting needs to be reduced, for example after coronary thrombosis or after surgery. These data show that:

The 3.4-diarylchromans of formula 1 are useful for reducing blood clotting in mammals, resp. primates and humans in the treatment or prevention of, e.g., after coronary thrombosis or surgery.

The present invention relates to the treatment and prophylaxis of the diseases listed in the Lipid Research Clinics Program J.A.M.A. 251, 1984, 351-364 and J.A.M.A. 251, 1984, 365-374 and diseases which are apparent to those skilled in the art.

Within the scope of the present invention, the compounds of formula (I) according to any one of claims 1 to 4, wherein R 1, R 4 and R 5 are hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy) ; and R 2 and R 3 are hydrogen or lower alkyl. The term "lower alkyl" means a straight or branched chain alkyl radical containing 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, ethylbutyl, 2,3-dimethylbutyl. The term "lower alkoxy" means a straight or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, nhexyloxy, 2-ethylbutoxy 2,3-dimethylbutoxy. Halogen is chlorine, fluorine, bromine and iodine. The tertiary amine residue is Ν, Ν-dialkylamine such as Ν, Ν-dimethylamino, N, N-diethylamino, Ν, Ν-dipropylamino and Ν, Ν-dibutylamino or polymethyleneimine, e.g. piperidine, pyrrolidine, N-methylpiperazine or morpholine. The term "(tertiary amino) (lower alkoxy) means a lower alkoxy group substituted with a tertiary amino group. Preferred compounds have R 1 lower alkoxy; R 2 and R 3 lower alkyl, especially methyl; R4 is hydrogen; and R 5 (tertiary amino) (lower alkoxy) polymethyleneimine type. In a particularly preferred embodiment of the invention, R 1 is in the 7-position and is lower alkoxy, especially methoxy; R 2 and R 3 are both methyl, R 4 is hydrogen and R 5 is in the 4-position and is a (tertiary amino) (lower alkoxy) radical as a 2- (pyrrolidin-1-yl) ethoxy group. The invention includes all pharmaceutically acceptable salts of said compounds of formula (1).

The compounds of formula (1) are preferably used in the trans configuration. These compounds can be used as racemic mixtures or individual stereoisomers, e.g., the d- or 1-enantiomer. Trans-1-enantiomers are more preferred.

A particularly preferred compound for use in accordance with the present invention is the centchroman of formula (IV) according to claim 14.

Although only one enantiomer is indicated (the formula denotes the trans configuration of the 3 and 4-phenyl groups), the invention relates to both the d- and 1-enantiomers and to the racemic mixture.

3,4-Diarylchromans are prepared by known methods, e.g. Patent Speeification No. No. 3,340,276 to Carney et al. Patent Speeification No.

822 287 Bolger and Ray et al., J. Copper. Chem. 19 (1976), 276-279. The conversion of cis to the trans isomer by an organometallic catalyzed reaction is described in U.S. Pat. Patent Speeification No. The optically active d and I isomer can be prepared according to Saiman et al. U.S. Pat. Patent Speeification No. No. 4,476,722 by salt formation of an optically active acid which is subjected to basic hydrolysis to provide the desired enantiomer. When R2 is different from R3 and R4 is different from R5, the general formula (1) denotes 8 optical isomers.

In accordance with the present invention, the 3,4-diarylchromans of formula (1) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt containing both organic and inorganic acid salts. Examples of such salts are salts of organic acids such as formic, fumaric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, succinic, malonic, tartaric, citric, benzoic, salicylic. Suitable inorganic acid salts are inorganic acid salts such as hydrochloric, hydrobromic, sulfuric and phosphoric. Acid addition salts can be obtained directly as synthesis products.

Alternatively, the free base is dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The 3,4-diarylchromans of the general formula (1) and their salts can be used in human and veterinary medicine, eg for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis and reduced blood clotting, eg after coronary thrombosis or surgery. For use in accordance with the present invention, the 3,4-diarylchromans of formula (1) and pharmaceutically acceptable salts thereof are mixed with pharmaceutically acceptable carriers to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration in accordance with conventional methods. The compositions further comprise one or more fillers, diluents, emulsifiers, preservatives, buffers, excipients, and are in the form of a solution, powder, emulsion, suppository, liposome, transdermal patch, dermal implants, tablets. Those skilled in the art can adapt the compounds of the present invention, e.g., to Remington et Pharmaceutical Sciences, Gennaro, eds., Mack Publishing Co., Easton, PA, 1990.

Oral administration is preferred, therefore the compound of formula (1) is prepared in a form suitable for the method, i.e., tablets or capsules. Typically, a pharmaceutically acceptable salt of a compound of formula (1) is combined with a carrier and formed into tablets. A suitable carrier in this regard is starch, sugar, calcium phosphate, calcium stearate, magnesium stearate. Such compositions further comprise additives such as humectants, emulsifiers, preservatives, stabilizers, colorants.

Pharmaceutical compositions containing compounds of formula (1) may be administered one or more times per day or per week. An effective amount of such a composition is an amount that provides a clear clinical effect for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis, and a reduction in blood clotting, e.g., after coronary thrombosis or surgery. This amount depends on the particular situation, weight and general health of the patient and other factors known to those skilled in the art.

Pharmaceutical compositions containing the compounds of formula (1) may be administered once or more per day or per month. Alternatively, a controlled release amount of a dermal implant can be used to allow the release of the active compound for a period of up to several years. See. e.g., Sanders et al., J. Farm. Sci. 73 (1964), 1294-1297, 1984; U.S. Pat. Patent Specification No. 4,489,056; and U.S. Pat. Patent Specification No. 4,210,644

The following examples are illustrative, not limiting, of the invention.

Examples of suitable compounds are: centchroman as a racemic mixture, 1-centchroman and d-centchroman. Preferred is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-hydroxychroman. More preferred is 1- 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2 (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman.

Examples of pharmaceutically acceptable acid addition salts are salts of non-toxic inorganic or organic acids of hydrochloric, sulfuric, phosphoric, formic, fumaric, acetic, propionic, succinic, gluconic, milk lemon ascorbic, benzoic, embonic, methanesulfonic and malonic.

The present invention is further illustrated by the following non-limiting examples. The facts set forth in the foregoing description and in the following examples serve, individually or after combination, to practice the invention in various forms.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The effect of 1-centchroman on plasma cholesterol was investigated in rats and rabbits.

In the first study, 56 female Sprague-Dawley ovariectomy (OVX) rats were subjected to surgical siluration. The animals were administered the following (in groups of 8 rats):

1) comparison / carrier

2) OVX / carrier

3) OVX / ethynylestradiol 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

Doses were orally administered three times per week for 5 weeks. After the experiment, serum according to US Patent 5,407,955 was collected to determine cholesterol levels.

I-Centchroman had a significant effect on serum cholesterol at all dosages. Compared to the control group, it was significantly reduced - see FIG. Table 1.

Table 1 Effect of centchroman on cholesterol in rat serum

Administered preparation Serum Cholesterol (mmol / L) comparison / carrier 2.2 ± 0.3 OVX / carrier 2.9 ± 0.3 OVX / ethynylestradiol 0.2 mg / kg 1.9 ± 0.4 OVX / 1-centchroman 1 mg / kg 1.4 + 0.3 * OVX / 1-centchroman 5 mg / kg 1.5 ± 0.4 OVX / 1-centchroman 10 mg / kg 1.5 ± 0.2 OVX / 1-centchroman 25 mg / kg 1.2 ± 0.2 *

Values are given ± SD and * indicates a significant reduction in serum cholesterol compared to administration of OVX to ethynylestradiol (OVX rats); p <0.002.

Another study was conducted with l-centchroman to establish a clear dose-response relationship to serum cholesterol.

Again, 56 female rats were stimulated with surgery or surgery. the ovaries and rats were dosed as follows:

1) comparison / carrier

2) OVX / carrier

3) ethynylestradiol 0.2 mg / kg

4) OVX / i-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 1.0 mg / kg

Doses were orally administered three times per week for 5 weeks. After the experiment, serum was collected according to US Patent 5,407,955 to determine cholesterol levels. I-Centchroman had an effect on serum cholesterol with the dependence shown in Table 2.

Table 2 Effect of centchroman on cholesterol in rat serum

Administered preparation Serum Cholesterol (mmol / L) comparison / carrier 2.1 ± 0.3 OVX / carrier 2.7 ± 0.3 OVX / ethynylestradiol 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 *

Values are given ± SD and * indicates a significant decrease in serum cholesterol compared to vehicle administration to the comparator group; p <0.003.

Furthermore, the effect of l-centchroman on plasma lipids was investigated in rabbits fed a cholesterol diet. One week before the start of the test, 30 white New Zealand rabbits were removed under pentobarbital ovarian anesthesia. Three groups received subcutaneous administration: vehicle, 17-β-estradiol and 1-centchroman (7.5 mg / day). Doses were administered three times a week for four weeks. Serum cholesterol samples were then taken. As shown in Table 3, l-centchroman significantly decreased serum cholesterol compared to carrier and estrogen administration.

Table 3 Effect of centchroman on cholesterol in rat serum

Administered preparation Serum Cholesterol (mmol / L) OVX / carrier 11.0 ± 1.1 OVX / β-17 estradiol 50 pg / kg 3 times per week 7.5 ± 0.5 * OVX / 1-centchroman 7.5 mg / kg 3 times per week 8.2 ± 0.7 *

Values are given ± SEM and * indicates a significant reduction in serum cholesterol compared to the OVX vehicle administration group; p <0.05.

Example 2

The effect of l-centchroman on lipid accumulation in the aortic wall, ie the mechanism of atherosclerosis, was investigated in New Zealand white rabbits. One week before the start of the test, 45 adult white New Zealand rabbits were ovariectomized under pentobarbital anesthesia. In addition, 45 males were tested. Both males and females were divided into 3 groups of 15:

1) placebo

2) 17-β-estradiol 2.5 mg / kg / day

3) 1-centchroman 2.5 mg / kg / day

After 14 days, cholesterol was added to the diet. Every other day, total serum cholesterol was determined in the blood sample of each rabbit (Holm P. et al., Atherosklerosis 115: 191, 1995) and adjusted for the next day's cholesterol in the diet. sera were maintained at a constant level throughout the test, although some drugs are known to affect it, so that a direct effect of the treatment on the vessel wall can be detected, after three months of treatment, animals were sacrificed, aorta removed, and et al., Atherosklerosis 115: 191, 1995).

The results are shown in Table 4. It can be clearly seen that both estrogen and 1-centchroman in both the male and female significantly reduced the cholesterol content in the wall, which is independent of the serum cholesterol levels since this was maintained constant during the test. Therefore, it is apparent that l-centchroman acts directly on the vascular wall.

Table 4 Effect of l-centchroman on cholesterol in the inner layer of the vascular wall

Substance administered female (mmol / l) males (mmol / l) placebo 45 ± 9 27 ± 5 17-β-estradiol 8 ± 3 * 8 ± 2 * 1-centchroman 2.5 mg / kg 18 ± 5 * 13 ± 4 *

Values are given ± SEM and * indicates a significant decrease in cholesterol in the inner layer of the vascular wall compared to administration of piaceba; p <0.05.

Example 3

In vitro, 1-centchroman in platelet-rich plasma in rabbits has been shown to inhibit platelet activation factor (PAF) aggregation. The EC50 for this effect was 3 and 10 pg / ml. ADP-induced aggregation was unaffected.

Industrial applicability

It is an object of the present invention to provide compounds that can be effectively used for the treatment or prophylaxis of hyperlipoproteinemia, hypertriacylglycerolemia, hyperlipidemia, hypercholesterolemia, arteriosclerosis and reduction of blood clotting, e.g., after coronary thrombosis or after surgery. The present invention also includes a pharmaceutical composition comprising the compounds and methods of using the compounds and compositions.

Claims (27)

PATENT CLAIMS Use of a compound of formula (I) wherein R 1, R 4 and R 5 are hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 2 and R 3 are hydrogen or lower alkyl or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier for the preparation of a pharmaceutical composition for the treatment or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia, and hypercholesterolemia. . Use of a compound of formula (I) (I) wherein R 1, R 4 and R 5 are hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 2 and R 3 are hydrogen or lower alkyl or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier for the preparation of a pharmaceutical composition for the treatment or prophylaxis of atherosclerosis including atherosclerosis. Use according to claim 2 for the treatment or prophylaxis of atherosclerosis. Use of a compound of formula (I) wherein R 1, R 4 and R 5 are hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 2 and R 3 are hydrogen or lower alkyl or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier for the preparation of a pharmaceutical composition for the treatment or prophylaxis of patients in need of reduced blood coagulation following coronary thrombosis or surgery. Use according to any one of claims 1 to 4, wherein in the compound used R1 is a lower alkoxy group, R2 and R3 are lower alkyl groups, R4 is hydrogen and R5 is a tertiary amino lower alkoxy group. Use according to any one of claims 1 to 5, wherein R 1 is methoxy. Use according to any one of claims 1 to 6, wherein R 2 is a methyl group. Use according to any one of claims 1 to 7, wherein R 3 is a methyl group. Use according to any one of claims 1 to 8, wherein R 4 is hydrogen. Use according to any one of claims 1 to 9, wherein R 5 is a group of formula (II) o (ΙΟ The use of any one of claims 1 to 10, wherein said compound is a stereoisomer including an isolated d- or 1-enantiomer. Use according to any one of claims 1 to 11, wherein the compound is of formula (II0 R5 R1 (HO) wherein R1, R2, R3, R4 and R5 are as defined in any one of claims 1 to 11 The use of any one of claims 1 to 12, wherein said compound is an isolated 1-enantiomer. Use according to any one of claims 1 to 4, wherein said compound is centchroman 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman of formula (IV) (IV). The use of claim 14, wherein said compound is an isolated d- or enantiomer. The use of claim 14, wherein said compound is an isolated 1-enantiomer. Use according to any one of claims 1 to 16, wherein said composition is in a form suitable for oral administration. The use of any one of claims 1 to 17, wherein said compound is administered at a dose of 0.001 to 75, preferably 0.01 to 75, more preferably 0.01 to 50, most preferably 0.1 to 25 mg / kg patient weight per day. Use according to any one of claims 1 to 18, wherein said composition is administered one or more times per day or per week, The use of any one of claims 1, wherein said composition is in the form of a skin implant. A method of treating or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolemia, hyperlipidemia and hypercholesterolemia comprising administering to a patient a clinically effective amount of a compound of formula (I) according to claim 1 used according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. , hypertriacylglycerolemia, hyperlipidemia, and hypercholesterolemia. A method of treating and prophylaxis of atherosclerosis including atherosclerosis comprising administering to a patient a clinically effective amount of a compound of formula (I) according to claim 2 used according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in effective therapeutical or prophylactic amount. A method of treatment and prophylaxis for the need for reducing blood clotting comprising administering to a patient a clinically effective amount of a compound of formula (I) according to claim 4 used according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. coronary thrombosis or surgery. A method of treating or preventing hyperlipoproteinemia, hypertriacylglycerolemia, hyperlipidemia and hypercholesterolemia comprising administering to a patient in need of such treatment or prophylaxis a clinically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method of treating and preventing arteriosclerosis including atherosclerosis comprising administering to a patient in need of such treatment or prophylaxis a clinically effective amount of a compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof. A method of treatment and prophylaxis in patients after coronary thrombosis or surgery comprising administering to a patient in need of such treatment or prophylaxis a clinically effective amount of a compound of formula (I) or a pharmaceutical composition thereof according to any one of claims 1 to 25. 27. Any new part described herein or combinations thereof.