WO1999048497A1

WO1999048497A1 - USE OF 3,4-DIPHENYLCHROMANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR LOWERING PLASMA LEVELS OF Lp(a) IN A HUMAN OR SUB-HUMAN PRIMATE

Info

Publication number: WO1999048497A1
Application number: PCT/DK1999/000139
Authority: WO
Inventors: Birgitte Hjort Guldhammer; Niels Korsgaard
Original assignee: Novo Nordisk A/S
Priority date: 1998-03-20
Filing date: 1999-03-17
Publication date: 1999-09-30
Also published as: AU3023999A

Abstract

The present invention relates to the use of 3,4-diphenylchromans for the manufacture of a pharmaceutical composition for lowering plasma levels of Lp(a) in a human or sub-human primate.

Description

1

Use of 3,4-diphenylchromans for the manufacture of a pharmaceutical composition for lowering plasma levels of Lp(a) in a human or sub-human primate

FIELD OF THIS INVENTION

The present invention relates to the use of compounds of the general formula I for lowering plasma levels of Lp(a) or for inhibiting generation of apo(a) in a human. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions. Moreover, the present in- vention relates to the use of compounds of the general formula I for prevention or treatment of premature occlusive arterial disease, stroke, coronary artery disease, diabetic vasculo- pathies, arteriosclerosis, atherosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

BACKGROUND OF THIS INVENTION

Lipoprotein a (Lp(a)) is a unique lipoprotein which is made up of an LDL-like particle containing cholesterol, phospholipids and apolipoprotein B100 (apoBIOO) to which is covalently linked apolipoprotein (a), apo(a), the glycoprotein that is the specific marker of Lp(a). Lp(a) is found in the plasma of only humans, some primates and the European hedgehog. All components of the Lp(a) particle are synthesized in the liver. Currently, it is not established whether the assemply and maturation of Lp(a) occur within or outsite the hepatocyte itself, or both. Furthermore, the major routes of plasma clearance of Lp(a) remain unknown. Contrary to LDL, which is catabolized chiefly by the LDL receptor, the metabolic fate of Lp(a) appears to be to a large extent independent of this receptor.

Although it is generally true that Lp(a) levels remain fairly constant throughout life it appears that some individuals undergo a weak acute-phase response of plasma Lp(a) in reponse to e.g. myocardial infarction and major surgery. More consistently, however, it has been noted that treatment with estrogen, progesterone and other sex hormones depresses plasma Lp(a) levels by roughly 50% (Soma MR et al. Arch Intern Med 153:1462-1468, 1993). This is consistent with reports that plasma Lp(a) levels increase after menopause (Jenner JL et al. Circulation 87:1135-1141 , 1993). The normal function of Lp(a) is still mostly unknown. Individuals with complete or near abscence of Lp(a) suffer no apparent ill effects. However, in patients with an elevated level of Lp(a) it is considered to be an independent risk factor for premature occlusive arterial di- seases, such as atherosclerosis, coronary artery disease, myocardial infarction, cerebral infarction (stroke), peripheral artery disease including diabetic vasculopathies, restenosis following balloon angioplasty and stenosis of bypass grafts.

If one concurs with the notion that the cardiovascular pathogenecity of Lp(a) is related to its high plasma levels. Then lowering them should represent a desirable therapeutic goal. Dietary and/or physical fitness programs commonly used in the treatment of dyslipoproteinemic states have little effect on plasma Lp(a) levels. In general this is also true for pharmacological agents such as HMG-CoA reductase inhibitors and fibrates. An exception is niacin, which, in dosages of 3 to 4 g daily, has been shown to decrease the plasma levels of Lp(a) by about 30%. However, this experience is not universal and may depend on pretreatment plasma Lp(a) levels, apo(a) phenotype, dosage and length of treatment. Because of the potential side effects of high dosages of niacin, the risk benefit relationships must be carefully evaluated with particular reference to impaired liver function, glucose intolerance, hyperuri- cemia and dermatological changes. Several reports have shown that hormones and particu- lar estrogens may lower significantly plasma Lp(a); however, their safety in a sustained treatment program remains to be established.

We have now discovered that certain compounds are effective in inhibiting the generation of apo(a) and are effective in lowering plasma levels of Lp(a) in a human, and are therefore useful in treating or preventing disease-states which are alleviated by inhibiting the generation of apo(a) or by lowering the plasma levels of Lp(a).

The 3,4-diphenylchroman of formula I

CH₃- 0

( I )

and pharmaceutically acceptable salts thereof are well known in the art, see e.g. U.S. Patent No. 5,280,040. This patent describes the preparation of these compounds, as well as their use for reducing bone loss. The preparation of pharmaceutical compositions thereof is also described. These compounds are also known to be effective in the treatment of a variety of other medical indications e.g. as described in WO 96/21442, WO 96/21443, WO 96/21444, WO 96/22091 , WO 96/22092 and WO 96/22093. 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2- pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman encompassed by the above formula I, also known as 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 No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 2S (1992), 444 - 450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491 - 495; Sankaran et al-, Contraception 9 (1974), 279 - 289; Indian Patent Specification No. 129187). Centchroman 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 as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min Bon Res 9 (1994), S 394). WO 97/25036 describes methods of treatment or prophylaxis of atrophy of skin and/or mucous membranes by administering 3,4- diarylchromans. US Patent No. 5,451 ,603 describes methods for the treatment of dermatitis by administering 3,4-diarylchromans. 4 SUMMARY

The 3,4-diphenylchroman of formula I, and in particular levormeloxifene, may be administered to humans and sub-human primates, in particular humans, for lowering plasma levels of Lp(a) or for inhibiting generation of apo(a). Thus, the 3,4-diphenylchroman of formula I can be used for preventing or treating premature occlusive arterial disease, as well as preventing or treating stroke, coronary heart disease, coronary artery disease, diabetic vascuiopathy, arteriosclerosis, atherosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

DESCRIPTION OF THIS INVENTION

This invention provides the use of a 3,4-diphenylchroman of formula I

( i )

and in particular ( - ) - 3R.4R - trans- 7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane (in the following referred to as levormeloxifene), or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for lowering plasma levels of Lp(a) in a human or for inhibiting generation of apo(a) in a human.

The present invention also relates to the use of a 3,4-diphenylchroman of formula I CH₃- O

( I )

or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease-state which is alleviated by reducing plasma levels of Lp(a) in a human or inhibiting generation of apo(a) in a human.

In another aspect the present invention is directed to a method of inhibiting generation of apo(a) in vitro or in vivo by administering a 3,4-diphenylchroman of formula I as defined above.

Moreover, the present invention relates to a method of lowering plasma levels of Lp(a) in a human or inhibiting generation of apo(a) in a human, comprising administering to said human an effective amount of a 3,4-diphenylchroman of formula I

or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention relates to a method for treating a human having a disease-state which is alleviated by lowering plasma levels of Lp(a) or inhibiting generation of 6 apo(a), comprising administering to said human a therapeutically effective amount of a 3,4- diphenylchroman of formula I

( i )

or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention the disease-state is premature occlusive arterial disease. In the present specification "premature occlusive arterial disease" is intended to comprise those disease-states, which are characterized by the closure of an artery or the progress of closing an artery, and which a) develop earlier in life than normal and b) are associated with high levels of Lp(a) in the plasma; and includes, La., stroke, coronary artery disease, atherosclerosis, arteriosclerosis, myocardial infarction, restenosis, peripheral artery disease and bypass graft stenosis.

In other embodiments of the present invention the disease-state is stroke, coronary heart disease, coronary artery disease, diabetic vasculopathy, atherosclerosis, arteriosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

It is preferred to use the compounds of formula I in the trans configuration. The I- enantiomeric forms are preferred over racemic mixtures. Preferred 3,4-diphenylchromans of formula I for use in accordance with the present invention comprises centchroman as a racemic mixture, i.e. (+/-)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane, and most preferred is the l-form, i.e. levormeloxifene. Particularly preferred salts of levormeloxifene is levormeloxifene hydrogen fumarate or levormeloxifene hydrogen maleate, levormeloxifene hydrogen fumarate is most preferred. 7 The term "treating" or "treatment" as used herein cover the treatment of a disease-state in a human or sub-human primate (male or female), which disease-state is alleviated by the reduction of plasma levels of Lp(a) or the inhibition of the generation of apo(a); and include i) preventing the disease-state from occuring in a human or sub-human primate, in particular, when such human or sub-human primate is predisposed to the disease-state but has not yet been diagnosed as having it; ii) inhibiting the disease-state, i.e., arresting its development; or iii) relieving the disease-state, i.e., causing regression of the disease-state.

To be included by this invention are all pharmaceutically acceptable salts of the mentioned 3,4-diphenylchromans of formula I.

The 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent No. 3,340,276 to Carney et al., U.S. Patent No. 3,822,287 to Bolger, the contents of which are incorporated herein by reference; and in Ray et aj., J Med Chem 19 (1976), 276 - 279. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Patent No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman et al- in U.S. Patent 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. The resolvation of ( +/- ) - 3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Patent No. 4,447,622 incorporated herein by reference. Example 1 of U.S. Patent No. 4,447,622 describes the preparation of the minus enantiomer, shown by formula II :

CH₃-0

(ll) 8 (In this specification, the compound of formula II is referred to as levormeloxifene.) Within the present invention, 3,4-diphenylchromans 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 with non-toxic organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyru- vic acid, oxalic acid, succinic acid, gluconic acid, malic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, embonic acid, methanesulphonic acid and malonic acid. Suitable inorganic acid-addition salts include salts with non-toxic acids such as 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.

A preferred pharmaceutically acceptable salt of 3,4-diphenylchromans of formula I is the fu- marate salt, particularly preferred is levormeloxifene hydrogen fumarate.

Another preferred pharmaceutically acceptable salt of 3,4-diphenylchromans of formula I is the maleate salt, particularly preferred is levormeloxifene hydrogen maleate.

3,4-diphenylchromans of formula I and their pharmaceutically acceptable salts are useful within human and veterinary medicine for preventing or treating conditions associated with high plasma levels of Lp(a) or generation of apo(a). These 3,4-diphenylchromans of formula I may be used, for example, in patients suffering from coronary heart disease, coronary artery disease, stroke, diabetic vasculopathy, atherosclerosis, arteriosclerosis, myocardial in- farction, restenosis, peripheral artery disease or bypass graft stenosis.

For use within the present invention, 3,4-diphenylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transder- mal 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, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One skilled in this art may formulate the 3,4-diphenylchromans of formula I in an appropriate manner, and in accordance with 9 accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gen- naro, ed., Mack Publishing Co., Easton, PA, 1990.

Oral administration is preferred. Thus, the active 3,4-diphenylchroman of formula I is pre- pared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the 3,4-diphenylchroman of formula I is combined with a carrier and moulded into a tablet. Suitable carriers in this regard include starch, sugars, di- calcium 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 3,4-diphenylchroman of formula I may be administered one or more times per day or week. An effective amount of such a 3,4- diphenylchroman of formula I is the amount required to lower the plasma levels of Lp(a) or to inhibit the generation of apo(a), according to this invention. A therapeutically effective amount of a 3,4-diphenylchroman of formula I is the amount which, when administered to a human in need thereof, is sufficient to effect treatment (as defined above) for disease-states alleviated by the reduction of plasma levels of Lp(a) or by the inhibition of the generation of apo(a). Such amount will depend, in part, on the particular disease-state and its severity, age, weight, and general health of the patient, and other factors evident to those skilled in the art, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. A typical daily dose will contain a nontoxic dosage range of from about 0.0001 to about 75 mg/kg patient per day of a 3,4-diphenylchroman of formula I, in particular levormeloxifene. A suitable dose of a 3,4-diphenylchroman of formula I, such as levormeloxifene, is e.g. from 0.1 to 2.5 mg per day to a patient.

The pharmaceutical compositions containing a 3,4-diphenylchroman 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. Im- plants 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 (1964L 1294 - 1297, 1984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which U.S. Patents are incorporated herein by reference. 10

The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. 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.

EXAMPLES

The ability of the 3,4-diphenylchromans of formula I, and in particular levormeloxifene, to lower plasma levels of Lp(a) or inhibit generation of apo(a) in a human will be determined by testing the efficacy of the compounds in vivo in women.

Five to fifty women are selected for the clinical study. The women are post-menopausal, i.e. having ceased menstruating for between 6 and 12 month prior to the initiation of the study. At the entrance into the study plasma Lp(a) together with a generallipid profile will be determined. Women are categorized according to their plasma Lp(a) levels. The women included should be in good general health. The study has a placebo control group, i.e. the women are divided into two groups, one of which receives the active agent of this invention and the other recieves the placebo. Women in the test group receive between 0.1-500 mg of the ac- tive agent per day by the oral route. They continue this therapy for 6-36 months. Accurate records are kept as to the plasma Lp(a) levels in both groups and at the end of the study these result are compared. The results are compared both between members of each group and also the results for each patient are compared to the plasma Lp(a) levels for each patient before the study began. Activity of the test result is illustrated by a reduction of plasma Lp(a) in the patients taking the test drug.

Claims

11CLAIMS

1. Use of a 3,4-diphenylchroman of formula I

( i )

or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for lowering plasma levels of Lp(a) in a human.

2. Use of a 3,4-diphenylchroman of formula I

( i )

or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for inhibiting generation of apo(a) in a human.

3. Use of a 3,4-diphenylchroman of formula I 12

( I )

or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease-state which is alleviated by reducing plasma levels of Lp(a) in a human.

4. The use according to claim 3 wherein said disease-state is premature occlusive arterial disease.

5. The use according to claim 3 wherein said disease-state is stroke, coronary heart disease, coronary artery disease, diabetic vasculopathy, arteriosclerosis, atherosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

6. Use of a 3,4-diphenylchroman of formula I

( I ) 13 or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease-state which is alleviated by inhibiting generation of apo(a) in a human.

7. The use according to claim 6 wherein said disease-state is premature occlusive arterial disease.

8. The use according to claim 6 wherein said disease-state is stroke, coronary heart disease, coronary artery disease, diabetic vasculopathy, atherosclerosis, arteriosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

9. The use according to any one of the preceding claims, wherein said 3,4-diphenylchroman of formula I is levormeloxifene.

10. The use according to any one of the preceding claims, wherein said 3,4- diphenylchroman of formula I is levormeloxifene hydrogen fumarate or levormeloxifene hydrogen maleate.

11. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.

12. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.0001 to 75 mg/kg patient per day.

13. The use according to any one of the preceding claims wherein said composition is administered one or more times per day or week.

14. The use according to any one of the claims 1-10 wherein said composition is in the form of a dermal implant.

15. A method of lowering plasma levels of Lp(a) in a human, comprising administering to said human an effective amount of a 3,4-diphenylchroman of formula I 14

or a pharmaceutically acceptable salt thereof.

16. A method of inhibiting generation of apo(a) in a human, comprising administering to said human an effective amount of a 3,4-diphenylchroman of formula I

( i )

or a pharmaceutically acceptable salt thereof.

17. A method for treating a human having a disease-state which is alleviated by reducing plasma levels of Lp(a), comprising administering to said human a therapeutically effective amount of a 3,4-diphenylchroman of formula I 15

CH₃- O

or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17 wherein said disease-state is premature occlusive arterial disease.

19. The method according to claim 17 wherein said disease-state is stroke, coronary heart disease, coronary artery disease, diabetic vasculopathy, atherosclerosis, arteriosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

20. A method for treating a human having a disease-state which is alleviated by inhibiting generation of apo(a), comprising administering to said human a therapeutically effective amount of a 3,4-diphenylchroman of formula I

( I )

or a pharmaceutically acceptable salt thereof. 16

21. The method according to claim 20 wherein said disease-state is premature occlusive arterial disease.

22. The method according to claim 20 wherein said disease-state is stroke, coronary heart disease, coronary artery disease, diabetic vasculopathy, atherosclerosis, arteriosclerosis, myocardial infarction, restenosis, peripheral artery disease or bypass graft stenosis.

23. The method according to any one of the preceding method claims, wherein said 3,4- diphenylchroman of formula I is levormeloxifene.

24. The method according to any one of the preceding method claims, wherein said 3,4- diphenylchroman of formula I is levormeloxifene hydrogen fumarate or levormeloxifene hydrogen maleate.

25. The method according to any one of the preceding method claims wherein said composition is in a form suitable for oral administration.

26. The method according to any one of the preceding method claims wherein said 3,4- diphenylchroman of formula I is administered as a dose in a range from about 0.0001 to 75 mg/kg patient per day.

27. The method according to any one of the preceding method claims wherein said composition is administered one or more times per day or week.

28. The method according to any one of the claims 15-24 wherein said composition is in the form of a dermal implant.