MXPA97005697A - Methods to reduce your calcium levels - Google Patents

Abstract

The present invention relates to the use of a compound of the formula: wherein R 1 and R 3 are independently hydrogen, -CH 3, -C- (C 1 -C 6 alkyl), or -C-Ar, wherein Ar is substituted phenyl optionally, R2 is selected from the group consisting of pyrrolidine, hexamethylene imino and piperidino, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for reducing serum calcium levels in a human

Description

METHODS TO REDUCE SERUM CALCIUM LEVELS Field of the Invention The present invention relates to the provision of methods for inhibiting hypercalcemia and its effects, and in particular when it is caused by hyperparathyroidism or is related to some malignancy.

Background of the Invention Calcium is the most abundant and one of the most important minerals in the human body. Calcium is also an important cation in a wide variety of biological functions such as blood coagulation, maintenance of normal heartbeats and the onset of neuromuscular and metabolic activities. The skeletal system provides an important reservoir for blood calcium in these processes. More than 99 percent of the calcium in the body is present in the skeleton as hydroxyapatite. Several diseases and metabolic disorders can cause the serum calcium level to increase or decrease and consequently cause several biochemical and clinical Rsf.025042 abnormalities. Of the factors that control calcium and skeletal metabolism, two polypeptide hormones, parathyroid hormone and calcitonin, are considered to be the most important. Parathyroid hormone (PTH) is a peptide of 84 amino acids that acts to raise calcium in the blood and increase bone resorption. Calcitonin is a 32 amino acid polypeptide that acts to decrease bone resorption and decrease calcium in the blood. Calcitonin is produced in the thyroid gland and perhaps in extra thyroid sites and parathyroid hormone is produced in the parathyroid glands. The half-life of calcitonin and parathyroid hormone in the human body can be measured in minutes. Hypercalcemia is defined as an excessive amount of calcium in the blood. Hypercalcemia can occur as a result of numerous different clinical conditions, where high concentrations of free calcium ions are produced in the circulating blood. The causes of hypercalcemia may include, for example, hyperparathyroidism, cancer (with or without bone metastases), hypervitaminosis D, sarcoidosis, thyrotoxicosis, immobility, and renal failure, among others.

Many of the manifestations of hypercalcemia are not specific as to the dependent cause. Extreme hypercalcemia leads to coma and death. Neurological manifestations in less severe cases may include confusion, lethargy, weakness, and hyporeflexia. Hypercalcemia can be detected by shortening the T interval on the electrocardiogram. Arrhythmias are rare, but bradycardia and first-degree heart block have been reported. Acute hypercalcemia may be associated with significant hypertension. Gastrointestinal manifestations include constipation and anorexia; in severe cases, nausea and vomiting may occur. Acute pancreatitis has been reported in association with hypercalcemia of several causes. Hypercalcemia interferes with the action of antidiuretic hormone, which leads to polyuria and polydipsia. The reversible reduction in renal function associated with significant hypercalcemia is secretion and action. The active metabolite of vitamin D, 1,25 (OH) 2D (dihydroxLcolecalciferol), suppresses both the secretion and synthesis of PTH. The reduction in 1,25 (OH) 2D is a major factor contributing to an increased PTH secretion in renal failure. The present treatments for hypercalcemia include vigorous intravenous hydration with diuresis to purge calcium from a patient's body. In addition, glucocorticoids are also occasionally used in conjunction with such intravenous hydration with diuresis to purge calcium from a patient's body. Other methods which have been used to treat hypercalcemia include administering Mithramycin (a chemotherapeutic agent directly toxic to tumor cells and which can reduce plasma calcium levels), administer calcitonin (a hormone of the thyroid gland which can inhibit bone resorption and thereby decrease plasma calcium levels), Etidronate (a chemical compound which binds to calcium phosphate surfaces and inhibits crystalline resorption) of the bones) and administer phosphate. The results of treatment with each of the methods described above are relatively brief, and as a consequence, hypercalcemia easily returns after each of the treatments described above is interrupted. This invention provides methods for reducing serum calcium levels comprising administering to a human being in need thereof an effective amount of a compound of formula I (I) wherein R1 and R3 are independently hydrogen or 0 II II not, -CH3, -C- (C? -C6 alkyl), or -C-Ar, where Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof. The present invention relates to the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of the formula I, are useful for reducing the serum calcium level. Such an invention also provides methods for inhibiting hypercalcemia and its effects, and in particular when it is caused by hyperparathyroidism or is related to some malignancy. The methods of use provided by this invention are preactivated by administering to a human being in need thereof, a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, which is effective in reducing calcium levels. of the serum. The term "inhibit" includes its generally accepted meaning, which includes prohibiting, preventing, restricting and slowing down, stopping or reversing. As such, the present method includes both therapeutic and / or prophylactic administration, when appropriate. The term "serum calcium level" as used herein, means the level of calcium ions found in the plasma of human patients, and includes calcium which is bound to proteins and is non-diffusible, as well as calcium which is diffusible and exists in a free ionized form as well as in a complex form. A suitable method for determining plasma levels of calcium is described by Connerty, H.V. and Briggs, A.R., American Journal of Clinical Pathology, Vol. 45, p. 290 (1986). Raloxifene, a compound of this invention wherein the same is the hydrochloride salt of a compound of formula 1, R1 and R3 are hydrogen and R2 is 1- i -peridinyl, is a nuclear regulatory molecule. Raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an antiestrogen and which blocked the ability of estrogen to activate estrogen-dependent breast cancers and of the tissue of the uterus. Actually, raloxifene blocks the action of estrogen in some cells; however, in other cell types, raloxifene activates the same genes as estrogen and exhibits the same pharmacology, for example, osteoporosis, hyperlipidemia. As a result, raloxifene has been referred to as an antiestrogen with mixed agonist-antagonist properties. The only profile which exhibits raloxifene and differs from that of estrogen is now thought to be due to the single activation and / or deletion of various functions of the gene by the raloxifene-estrogen receptor complex as the opposite of activation and / or deletion of the genes by the estrogen complex-estrogen receptor complex. Therefore, although raloxifene and estrogen use and compete for the same receptor, the pharmacological consequence of gene regulation of the two is not easily predicted and is unique to each. In general, the compound is formulated with common excipients, diluents or vehicles, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered intramuscularly or intravenously. The compounds can be administered transdermally, and can be formulated as sustained release dosage forms and the like. The compounds used in the methods of the present invention can be made according to established procedures, such as those described in U.S. Pat. Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated for reference herein. In general, the process starts with a benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydrophenyl) group. The starting compound is protected, acylated, and deprotected to form the compounds of formula I. Examples of the preparation of such compounds are provided in U.S. Pat. described above. Substituted phenyl optionally includes phenyl and phenyl substituted once or twice with alkyl with Ci-Ce, C 1 -C 4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro) methyl. The compounds used in the methods of this invention form pharmaceutically acceptable basic and acid addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are frequently used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like acids. Salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkane and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic acids, can also be used. Such pharmaceutically acceptable salts thus include acetate, phenyl acetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β- hydroxybutyrate, butyn-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monoacid phosphate, diacid phosphate, mephosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, methanesulfonate, naphthalene-1-sulfatonate, naphthalene-2-sulfonate, p-toluenesulfonate, xi lensulfonate, tartarate and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of Formula I with an equimolar or excess amount of the acid. The reagents are generally combined in a mutual solvent such as diethyl ether or benzene. The salt is usually precipitated out of the solution in the course of about one hour to 10 days and can be isolated by filtration or the solvent can be removed by conventional means. The bases commonly used for the formation of the salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Bases especially useful in the preparation of the addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine. Pharmaceutically acceptable salts generally have improved solubility characteristics compared to the compound from which they are derived, and therefore are frequently more receptive to the formulation as liquids or emulsions. The pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate, adsorbent carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyether glycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example by the intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited for formulation as sustained release dosage forms and the like. The formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, shells, and protective matrices can be made, for example, of polymeric substances or waxes. The particular dosage and regimen of a compound of the formula I required for lower levels of serum calcium according to this invention will depend on the severity of the condition, the route of administration, and the related factors that will be decided by the attending physician. provide attention. In general, the accepted and effective daily doses will be from about 0.1 to about 1000 mg / day, and more typically from about 50 to about 600 mg / day, with a preferred range of 200 to 600 mg / day. Such dosages will be administered to a subject in need thereof from about one to about three times a day, or more frequently when necessary, and for a period of time sufficient to effectively reduce the calcium level of the patient's serum. . It is usually preferred to administer a compound of the formula I in the form of an acid addition salt, as is customary in the administration of pharmaceutical substances bearing a basic group, such as the piperidino ring. It is also advantageous to administer such compound orally. For such purposes, the following oral dosage forms are available.

Formulations In the formulations that follow, "Active ingredient" means a compound of formula I.

Formulation 1: Gelatin capsules Hard gelatin capsules are prepared using the following ingredients: Ingredient Quantity (mg / capsule) Active Ingredient 0.1 - 1000 Starch, NF 0 - 650 Powder able to flow, from Starch 0 - 650 Silicone fluid from 350 centistokes 0 - 15 The ingredients are combined, passed through a U.S. No. 45 mesh, and filled into hard gelatin capsules. Examples of specific raloxifene capsule formulations that have been made include those shown below: Formulation 2: Raloxifene capsule Ingredient Quantity (mg / capsule) Raloxifene 1 Starch, NF 112 Powder capable of flowing, of starch 225.3 Silicone fluid of 350 centistokes 1.7 Formulation 3: Raloxifene capsule Ingredient Quantity (mg / capsule) Raloxifene 5 Starch, NF 108 Powder capable of flow, of starch 225.3 Formulation 3 (Continued) 350 centistokes silicone fluid 1.7 Formulation 4: Raloxifene capsule Ingredient Quantity (mg / capsule) Raloxifene 10 Starch, NF 103 Powder capable of flowing, of starch 225.3 Silicone fluid of 350 centistokes 1.7 Formulation 5: Raloxifene capsule Ingredient Quantity (mg / capsule) Raloxifene 50 Starch, NF 150 Powder capable of flowing, of starch 397 Silicone fluid of 350 centistokes 3.0 The specific formulations above can be changed according to the reasonable variations provided. A tablet formulation is prepared using the ingredients below: Formulation 6: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.1 - 1000 Cellulose, microcrystalline 0 - 650 Silicon dio, steaming 0 - 650 Stearic acid 0 - 15 The components are combined and compressed to form tablets. Alternatively, the tablets each containing 0.1-1000 mg of the active ingredient are composed as follows: Formulation 7: Tablets Ingredient Quantity (mg / tablet; Active ingredient 0.1 - 1000 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Carboxymethyl cellulose sodium 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch, and cellulose are made to pass through a U.S. No. 45 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders which are then passed through a U.S. of mesh No. 14. The granules are dried at 50 ° -60 ° C and passed through a U.S. No. 18 mesh. Sodium carboxymethyl cellulose, starch, magnesium stearate, and talc, previously passed through a U.S. sieve. No. 60, are then added to the granules which, after mixing, are compressed on a tabletting machine, to produce the tablets. The suspensions each containing 0.1-1000 mg of medication per dose of 5 ml, are made as follows: Formulation 8: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.1 - 1000 mg Carboxymethyl cellulose sodium 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Condimento c.v. Color c.v. Purified water up to 5 mi The medicament is passed through a U.S. No. 45 and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, the seasoning, and the color are diluted with some of the water and are added, with agitation. Sufficient water is added to produce the required volume.

PROOF PROCEDURE In Study 1, two hundred and fifty-one (251) healthy postmenopausal women are assigned to one of four groups: Group 1 - Raloxifene HC1, 200 mg / day; Group 2 - Raloxifene HC1, 600 mg / day; Group 3 - Premarin, 0.625 mg / day; or Group 4 - Placebo.

In Study 2, 167 healthy postmenopausal women are randomly assigned to one of four groups: Group 1 - Placebo; Group 2 - Raloxifene HC1, 200 mg / day; Group 3 - Raloxifene HC1, 50 mg / day; or Group 4 - Raloxifene HC1, 10 mg / day. The administration period for the Studies is 8 weeks. For both Studies, clinical laboratory safety evaluations include a CBC evaluation of the serum and chemical panel at the baseline (week 0), and at each return visit (weeks 2, 4, and 8). After it is completed, the Study data is analyzed statistically.

The utility of the compounds of the invention is demonstrated by the impact they have on serum calcium levels when used in the previous studies.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

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

Claims (5)

CLAIMS FOR MEXICO

1. The use of a compound of the formula

(I) where R1 and R3 are independently hydrogen // not, -CH3, -C- (alkyl with C? -C6), or -C-Ar, where Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidine, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for reducing serum calcium levels in a human. 2. The use according to claim 1, wherein the compound is the hydrochloride salt of the same.

3. The use according to claim 1, wherein the compound is or its hydrochloride salt.

4. The use according to claim 1, wherein the human being suffers from hypercalcemia.

5. The use according to claim 4, wherein the hypercalcemia is caused by hyperparathyroidism or is related to a malignancy.