CZ2000618A3 - Method of reducing number of blood platelets - Google Patents

Abstract

A method of safely reducing platelet counts a person who involves the administration to a person in need an effective amount of a compound of Formula I wherein R 1 and R 3 are independently hydrogen, methyl or - CO (C1-C6 alkyl) or -COAr a group wherein Ar is an optionally substituted phenyl group; R 3 is selected from the group consisting of pyrrolidine, piperidine, and hexamethylenimino groups; or a pharmaceutically acceptable salt thereof a salt or solvate.

Description

A method for reducing the number of platelets

Technical field

The present invention provides methods for reducing platelet counts in humans, particularly postmenopausal women.

BACKGROUND OF THE INVENTION

Platelets are one of the major cell types found in blood and are essential for maintaining normal hemostasis. Platelets are derived from bone marrow stem cells and are usually found either in the bloodstream or sequestered in the spleen. The normal number of platelets in human blood is about 150,000 to 400,000 per ml; a condition where the platelet count falls substantially below this level is called thrombocytopenia, while an excess of platelet is called thrombocytosis or thrombocytemia.

The main function of the platelet is to control bleeding and blockage of any vessel rupture by forming a blood clot. The platelet functions not only as an integral structural element of the blood clot, but also responds to environmental conditions and responds by releasing a large number of mediators that affect surrounding cells and tissues. When a pathological situation occurs, for example, when the collagen fibers or the basement membrane are exposed, platelets adhere, aggregate and degranulate granules containing mediators such as ADP, smooth muscle mitogens, prostaglandins, thromboxanes, catecholamines, clotting factors and the like. These mediators not only trigger further platelet aggregation and blood clot formation, but also affect smooth muscle cells by causing them to contract and proliferate. In addition, these mediators affect other circulating cells such as lymphocytes and inflammatory cells, which can lead to biological consequences quite different from the formation of a blood clot. Many of these other consequences are pathological.

For hemostasis, it is necessary that sufficient platelets are available for the clotting process. Failure of the blood coagulation system is usually considered to be a very serious and life-threatening condition. In conditions where the platelet count falls below 100,000 per ml, there is cause for concern and this may indicate therapeutic intervention. Platelet counts below 40,000 are at the threshold of spontaneous bleeding and must be aggressively cured, usually by platelet infusions. Such a decrease in platelet count may occur in cancer patients treated with cytotoxic agents or radiation, in traumatological patients, particularly with burns, or in patients with immune system abnormalities (see, for example, "Harrison's Principles of Internal Medicine, 9th Ed., Chapter" 54, pp. 273-276, chapter 361, pp. 1555-1557, KJ Isselbacher et al., McGraw-Hill Book Co., NYC (1980) and references cited therein).

Paradoxically, however, the importance and necessity of platelets can often contribute to many, damaging conditions. For example, they are involved and are likely to cause inadequate thrombotic events such as arterial and vascular occlusion, leading to ischemic events and tissue damage. Inadequate activation of platelets can directly endanger life and there are numerous medicines available in medicine. * * · Β · · β · β · β · * Conditions that increase the risk of these activations, for example in patients suffering from atherosclerosis, patients recovering from surgery or trauma, patients recovering from angioplasty and the like. One proven way to reduce the risk of these inadequate activations is to reduce the total number of normal platelets in the circulation. In a recent clinical report it was shown that there is a direct correlation between platelet count and function and fatal coronary artery disease, ie patients with the highest platelet count and aggregability are most likely to be affected. Therefore, it seems logical that a platelet reducing agent should exert a positive effect on the prevention of coronary diseases (see E. Thaulow et al., "Blood Platelet Count and Function"). (2), 631-617 (1991) and L. Wilhelmsen, " Thrombocytes and Coronary Heart Disease, Circulation, 84 (2), 936-937 (1991)].

Although the beneficial effect of platelet reduction appears to be sufficient, it is critically important that platelet reduction does not cause thrombocytopenia. An ideal formulation could reduce platelet counts without reducing the respective blood clotting efficiency, for example, that platelet counts could remain within the normal range.

A recent clinical study has been conducted to demonstrate the reduction in platelet counts in women taking tamoxifen. However, tamoxifen is known for its major estrogen-agonist properties, especially in the uterus, and would therefore be less than an ideal product (see PM Mannucci et al., “Effects of Tamoxifen on Measurement of Haemostasis in Healthy Women, Arch. ^ dnf page 4 • 9 I

156, 1806-1810 (September 9, 1996)).

9999 98 99

9 9 9 9 9

9 9 9 9 9

SUMMARY OF THE INVENTION

The present invention provides methods for reducing the platelet count in a human comprising administering to a human in need thereof an effective amount of a compound of formula (I)

where

R ¹ and R ³ are each independently hydrogen, methyl or -CO (C 1 -C 6 alkyl), or -COAr group, wherein Ar is optionally substituted phenyl;

R ³ is selected from the group consisting of pyrrolidine, piperidine and hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof.

Detailed description of the invention

The present invention relates to the discovery that a selected group of 2-arylbenzo [b] thiophenes (compounds of formula I) is suitable for reducing platelet counts.

spare side

The general terms used to describe the compounds described herein have their usual meanings. For example, "C 1 -C 6 alkyl" means straight or branched C 1 -C 6 aliphatic chains including methyl, ethyl, propyl, isopropyl, n-butyl, pentyl, hexyl and the like.

The term "substituted phenyl" means a phenyl group as such or having one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri ( chloro or fluoro) methyl groups. "C 1 -C 4 alkyl" means C 1 -C 4 alkyl bonded via an oxygen bridge such as methoxy, ethoxy, n-propoxy, isopropoxy and the like.

The term "pharmaceutically acceptable salt" refers to either acid or base addition salts known to be non-toxic and commonly used in the pharmaceutical literature. Commonly used acid addition salts are inorganic salts formed by the addition of sulfuric acid, nitric acid, hydrochloric acid; hydrobromic acid, phosphoric acid, phosphorous acid and the like; or organic salts formed by the addition of acetic acid, formic acid, benzoic acid, citric acid, methanesulfonic acid and the like. Commonly used base addition salts are those formed by alkali or alkaline earth metal hydroxides, ammonium hydroxide, alkylamines or aromatic amines and the like. Preferred salt according to the present

The invention is a hydrochloride salt.

The term "solvate" refers to a molecular complex of a compound of formula I with one or more solvent molecules. These solvent molecules will be those commonly reported in the pharmaceutical literature and which do not harm the recipient, for example, water, ethanol and the like.

The compounds of the present invention are derivatives of a centrally located carbon atom, such as the "-CO-" moiety of Formula I, such that the derivatives are methanones, for example, the compound A-CO-B would be called [A] [B] methanone. Other compounds of formula I are benzo [b] thiophene derivatives, which are named and numbered according to the American Chemical Society's circular index as follows:

Therefore, raloxifene hydrochloride, which is a preferred embodiment of the present invention, is a compound of formula I wherein R ¹ and R ³ are both hydrogen and R ² is a piperidyl ring such as its hydrochloride salt. Raloxifene hydrochloride is the term [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] -3-thienyl] [4- [2- (1-piperidyl) ethoxy] phenyl] methanone hydrochloride.

All compounds used in methods and «·

99 of the compositions of the present invention can be prepared by processes such as described in detail in U.S. Patent No. 4,133,814 and U.S. Patent No. 4,418,068, both of which are incorporated herein by reference. links. Generally, this process starts with a benzo [b] thiophene containing a 6-hydroxy group and a 2- (4-hydroxyphenyl) group. The starting compound is protected, alkylated, and deprotected to give compounds of Formula I. Compounds of Formula I, which are carboxylic acid esters, can be prepared by the methods described in U.S. Patent No. 5,393,763, incorporated herein by reference.

The compounds of formula I are members of a group of compounds formerly known as antiestrogens, but which have selective estrogen-agonist and antagonistic pharmacological effects. For example, the compounds of Formula I act as estrogen agonists in the treatment of the pathological consequences of menstrual discontinuation in women (see Draper et al. Int'1 Symp. On Osteoporosis (March 29, 1993); US Patent Nos. 5,393,763, U.S. Pat.

464,845 and 5,391,557). In addition, compounds of Formula I have been shown to inhibit angiogenesis, see U.S. Patent No. 5,610,166, which is incorporated herein by reference.

The term "effective amount" as used herein means an amount of a compound of the present invention that is capable of safely reducing the platelet count in a human, preferably a postmenopausal woman.

The term "platelet reduction, as used in the methods of the present invention, means reducing the number of circulating platelets without a level of thrombocytopenia (less than 100,000 per ml) that could potentially cause serious bleeding events.

By "pharmaceutically acceptable composition" is meant that the carrier, diluent, solvent, excipients and salts must be compatible with the active ingredient (a compound of Formula I) of the composition and must not be harmful to the recipients of such composition.

The pharmaceutical compositions may be prepared by methods known in the art. For example, the compounds of the present invention may be formulated with conventional excipients, diluents or carriers, and formed into tablets, capsules, and the like. Examples of excipients, diluents, and carriers that are suitable for such compositions include the following: fillers and extenders such as starch, sugars, mannitol, and siliceous derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants such as glycerol; disintegrants such as agar agar, calcium carbonate and sodium bicarbonate; dissolution control agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorbent carriers such as kaolin and bentonite; and lubricating agents such as talc, calcium stearate and magnesium stearate, and solid polyethylene glycols. The final pharmaceutical forms can be pills, tablets, powders, lozenges, syrups, aerosols, sachets, capsules, elixirs, suspensions, emulsions, ointments, suppositories, sterile injectable solutions or sterile packaged powders, depending on Of the type of excipient used.

The particular dosage of a compound of Formula I required to safely reduce the platelet count of the present invention will depend on the particular symptom and its severity. Balance sheets such as dose, route of administration, and frequency of dosing are most conveniently made by the attending physician. In general, recognized and effective dosages for oral and parenteral administration will be from 10 to 800 mg, more usually between 20 and 100 mg. A particularly suitable dose is 60 mg per day by the oral route, especially in a postmenopausal woman. These doses will be administered to the patient in need of treatment one to three times a day, or as often as necessary to effectively and safely reduce the platelet count.

DETAILED DESCRIPTION OF THE INVENTION

The means that follow are given by way of illustration and are not intended to be limiting in any way. The total amount of active ingredients in these compositions comprises from 0.1 to 99.9% by weight of the composition. The term "active ingredient" refers to a compound of formula I, preferably raloxifene hydrochloride.

Composition 1: Gelatin capsules

Component Amount Active ingredient (mg / capsule) 50 to 600 Starch NF 0 to 500 Starch as free-flowing powder 0 to 500 Silicone fluid 0 to 15

350 · 10 ~ ⁶ m ² 'N ^_ • 0 000 0000 0000 000 00 0 00 00

The ingredients are mixed, sieved through a 0.300 mm sieve and filled into hard gelatin capsules.

Composition 2: Tablets

Ingredient Amount (mg / tablet)

Active ingredient 50 to 600

Starch 10 to 50

Microcrystalline cellulose 10 to 20

Polyvinylpyrrolidone 5 (as a 10% solution in water)

Sodium carboxymethylcellulose 5

Magnesium stearate

Talc 1 to 5

The active ingredient, starch and cellulose are mixed, sieved through a sieve for a particle size of 0.300 mm and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then sieved through a sieve for a particle size of 1.168 mm. The granules thus prepared are dried at 50 to 60 ° C and sieved through a sieve for a particle size of 0.912 mm. Sodium carboxymethylcellulose, magnesium stearate and talc, previously sieved through a 0.246 mm sieve, are added to the above granules, added to the above granules and mixed thoroughly.

The resulting material is compressed in a tabletting machine to obtain tablets.

Composition 3: Aerosol

Component% by weight

Active ingredient

0.50 «« 00000 00 00

00 ·· 90 0 * 000

0 00 000 000

000 00 00 00 0 0 000 000

0090 · 4 0 00 0 00 00

Ethanol 29.50

Propellant (Propellant 22, chlorodifluoromethane 70.00)

Total 100.00

The active ingredient is mixed with ethanol, and the mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filler. The required amount is then filled into a stainless steel vessel and diluted with the remaining propellant. The vessel is then equipped with valve units.

Composition 4: Suspension

Each suspension contains 100 mg of compound of formula I per 5 ml dose.

Component

Active ingredient

Sodium carboxymethylcellulose Syrup

0.1 M benzoic acid solution

Flavoring

Dye

Purified water to:

Weight 100 mg 50 mg 1.25 ml 0.10 ml 5 ml as needed

The compound of the formula I is sieved through a sieve for a particle size of 0.300 mm and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Benzoic acid solution, flavoring and coloring agent dissolved in water are added, and the mixture is stirred vigorously. Additional water was added to achieve the desired volume of the mixtures.

Determination of 4 to 4

4 4 · 4 4 9

4 4 4 4 4 4

4,444 4 4 4 · «

2043 healthy postmenopausal women are selected. These patients were randomly assigned to a control group of 584 patients and the following three test groups: 288 patients receiving 30 mg per day of raloxifene hydrochloride; 584 patients receiving 60 mg of raloxifene hydrochloride per day; and 590 patients receiving 120 or 150 mg per day of raloxifene hydrochloride. Patients in the control group receive oral placebo daily. The clinical study lasts two years. As part of the overall patient examination, various clinical tests are performed on an interval and different parameters are measured. Periodically measured parameters include platelet count.

Comparison of baseline platelet count with endpoints demonstrates a 7 to 9% reduction in circulating platelet counts in patients in the test group. There were no unusual bleeding episodes compared to the control group, and platelet counts never drop below 100,000 per ml.

Claims (4)

PATET Claims What is claimed is: 1. A method of reducing platelet count in a human, comprising administering to a human in need thereof an effective amount of a compound of Formula I: OR ³ and ₂ ch ₂ r ² where R ¹ and R ³ are each independently hydrogen, methyl or -CO (C 1 -C 6 alkyl) or -COAr, wherein Ar is optionally substituted phenyl; R ³ is selected from the group consisting of pyrrolidine, piperidine and hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof. 2. The process of claim 1 wherein said compound is [2- (4-hydroxyphenyl) -6-hydroxybenzo [b] -3-thienyl] [4- [2- (1-piperidyl) ethoxy] phenyl] methanone hydrochloride. Φ * ·· * · φφ ·· Φ Φ · I · · · 1 φφ φφ 3. The method of claim 1 wherein said human is a postmenopausal woman. 4. The method of claim 3, wherein the compound is administered in an amount of 60 mg per day by the oral route.