MXPA97002861A - Method to inhibit the conditions associated with bradicin - Google Patents

Abstract

A method for inhibiting a physiological condition associated with an excess of bradykinin, comprising administering to a human in need thereof, an effective amount of a compound having the formula (I), wherein R1 and R3 are independently hydrogen is disclosed , -CH3, (a) or (b), wherein Ar is optionally substituted phenyl, R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino, or a pharmaceutically acceptable salt or solvate thereof.

Description

METHOD TO INHIBIT THE CONDITIONS ASSOCIATED WITH BRADICININE BACKGROUND OF THE INVENTION Bradykinin is a nonapeptide that has the amino acid sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg hereinafter referred to as SEQ ID NO: 1, which belongs to a family of kinins that also includes the calidin or lysyl-bradykinin, which has the amino acid sequence Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg hereinafter referred to as SEQ ID NO: 2, and methionyl-lysyl-bradykinin, which has the amino acid sequence Met-Lys-Arg-Pro-Pro-Gly-Phe-SQr-P or-Phe-Arg from here - eji, ahead named as SEQ ID NO: 3. These kinins san. liberated from plasma precursors REF: 24602 (kininogens) by the action of plasma and tissue kallikreins, to regulate essential physiological functions. [For a review of the therapeutic perspectives of bradykinin receptor antagonists, see, J.N. Sharma, General Pharmacology 24: 267-274 (1993)]. Bradykinin is a mediator of pain, vascular permeability, inflammation, gastrointestinal function and smooth muscle tone in vascular tissue and other tissues. Bradykinin is one of the key mediators of the body's response to trauma and injury. Abnormally increased bradykinin released in response to noxious agents, tissue damage or lack of circulating kininases, can induce various pathological conditions ranging from rheumatoid arthritis to asthma. The receptors for bradykinin exist in the nervous system, in the epithelium, in smooth muscle and in fibroblasts. In each type of tissue, bradykinin triggers specific responses that include the release of neurotransmitters, the contraction of muscle, the secretion of fluids through the epithelia, and the stimulation of cell growth. The initial interaction for the biological response occurs at a bradykinin receptor site, on a cell. Bradykinin can activate neurons and produce the release of neurotransmitters. This can activate phospholipases C and A2, resulting in the production of a number of bioactive intermediates. The bradykinin receptors are the receptors coupled to protein G that activate phospholipase C or phospholipase A2, and increase the synthesis of inositol triphosphate, diacylglycerol, and arachidonic acid. Olsen et al., Journal of Biological Chemistry, 263: 18030-18035 (1988). G proteins are a family of membrane proteins that become activated only after the binding to guanosine triphosphate. Activated G proteins in turn activate an amplifying enzyme on the inner side of a membrane; the enzyme then converts the precursor molecules to second messengers. The bradykinin receptors have been classified as Bi and B2 based on the relative potencies of the agonists (kinins) and antagonists (kinin analogs) on various pharmaceutical preparations. R.J. Vavrek and J.M. Stewart, Peptides, 6: 161-164 (1985). The Bi receptors are generated de novo in the vascular smooth muscle during the incubation of the isolated tissue and during the antigen-induced arthritis. J. Bouthiller et al., British Journal of Pharology, 92: 257-264 (1987). There continues to be a need for the non-peptide antagonists of the bradykinin receptor. Pharmacological agents that contain portions of guanidine are known. See, for example, US Pat. Nos. 5,059,624 and 5,028,613. These two patents issued describe a series of pyrroloquinoline alkaloids isolated and purified from certain marine sponges. U.S. Patent No. 5,288,725 issued February 22, 1994, discloses a series of pyrroloquinoline-guanidine compounds useful as bradykinin receptor antagonists. U.S. Patent No. 5,212,182, issued May 18, 1993, describes a series of quinolinyl- and naphthalenylbenzamides and benzylamines, which are useful as bradykinin receptor antagonists which possess analgesic properties. U.S. Patent No. 5,216,165, issued June 1, 1993, discloses a series of N-substituted aminoquinolines, useful as analgesic agents through their properties as bradykinin receptor antagonists. There continues to be a need for effective and safe compounds that are useful as bradykinin receptor antagonists. The present invention provides a new series of such antagonists, which are administrable by a variety of routes, including orally as well as parenterally. This invention provides a method for the inhibition of a physiological disorder associated with an excess of bradykinin, which comprises the administration to a human in need thereof, of a therapeutically effective amount of a compound of Formula I (I) wherein R1 and R3 are independently hydrogen, 0 or II II -CH3, -C- (alkyl of 1 to 6 carbon atoms), or -C-Ar, wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and the 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 Formula I, are useful for the inhibition of a physiological condition associated with an excess of bradykinin. Therapeutic and prophylactic treatments provided by this invention are practiced by administering to a human in need thereof, a dose of a compound of the Formula a pharmaceutically acceptable salt or solvate thereof, which is effective to inhibit a physiological condition associated with an excess of bradykinin, or its symptoms. The term "inhibit" includes its generally accepted meaning which includes the prohibition, prevention, repression and reduction, arrest or reversal of progression, severity or a resulting symptom. As such, the present method includes therapeutic and / or prophylactic medical administration, as appropriate. Raloxifene is a preferred compound of this invention and this is the hydrochloride salt of a compound of Formula I, wherein R 1 and R 3 are hydrogen and R 2 is 1-piperidinyl. In general, at least one compound of the Formula I is formulated with common excipients, diluents, or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by intramuscular or intravenous routes. The compounds can be administered transdermally, and can be formulated as a sustained release dosage form and the like. The compounds used in the methods of the present invention may be manufactured according to established procedures, such as those described in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein. In general, the process begins with a benzo [bichtiofen having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The initial compound is protected, acylated, and deprotected to form the compounds of Formula I. Examples of the preparation of such compounds are given in US Pat. Nos. Discussed above. The term "optionally substituted phenyl" includes phenyl and phenyl substituted once or twice with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, chloro, fluoro, or tri (chloro or fluoro) ethyl) The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases, and include 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, hydrochloric, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric acids and the like. Salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts include in this manner acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, ethylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate. , butin-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, alato, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monoacid phosphate, diacid phosphate, metaphosphate , 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 -sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulphonates, tartrate, and the like. A preferred salt is the hydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formed by the reaction of a compound of Formula I with an equimolar or excess acid amount. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene. The salt normally precipitates from the solution within 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 salts include ammonium hydroxide and alkali metal and alkaline earth metal hydroxides, carbonates, as well as aliphatic amines 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. The pharmaceutically acceptable salts generally have improved solubility characteristics, as compared to the compound from which they are derived, and are thus often more suitable for 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 salicylic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; 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; adsorptive carriers such as kaolin and bentsnite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene 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 intramuscular, subcutaneous or intravenous routes. In addition, the compounds are well suited for formulation as a sustained release dosage form and the like. The formulations can be so constituted that they release the active ingredient only or preferably at a particular site of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices can be made, for example, from polymeric substances or waxes. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve the placement of a catheter for drug distribution within the host ventricular system to bypass the blood-brain barrier. An implantable distribution system of this type, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, issued April 30, 1991, which is incorporated by reference herein. . The particular dose of a compound of Formula I required to inhibit a physiological condition associated with an excess of bradykinin, or its symptoms, according to this invention, will depend on the severity of the condition, such as the route of administration, and the related factors that will be decided by the attending physician. In general, the accepted and effective daily doses will be from approximately 0.1 to approximately 1000 mg / day, and more typically from about 50 to about 200 mg / day. Such doses will be administered in a subject in need thereof, from one to about three times a day, or more frequently as necessary to effectively treat or prevent the disease or diseases or the symptom or symptoms. It is usually preferred to administer a compound of Formula I in the form of a salt by the addition of acid, as is customary in the administration of pharmaceutical products having a basic group, such as the piperidino ring. For these purposes the following oral dosage forms are available.

Formulations In the following formulations, "active ingredient" means a compound of Formula I.

Formulation I: Gelatin capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0.1 - 1000 Starch, NF 0 - 650 Flowable starch powder 0 - 650 Silicone fluid at 350 centistokes 0 - 15 The ingredients are mixed, passed through a No. 45 mesh American sieve, and filled into hard gelatin capsules. Examples of raloxifene-specific capsule formulations that have been made include those shown below: Formulation 2: Raloxifene capsule Ing-rediente Quantity (mg / capsule) Raloxifene 1 Starch, NF 112 Flueble starch powder 225.3 Silicone fluid at 350 centistokes 1.7 Formulation 3: Raloxifene capsule Ing-re < iie-nt - Quantity (mg / capsule) Raloxifene 5 Starch, NF 108 Flueble starch powder 225.3 Silicone fluid at 350 centistokes 1.7 Formulation 4: Raloxifene Capsule Ingredient Quantity (mg / capsule) Raloxifene 10 Starch, NF 103 Flueble starch powder 225.3 Silicone fluid at 350 centistokes 1.7 Formulation 5: Raloxifene Capsule Ingredient Quantity (mg / capsule) Raloxifene 50 Starch, NF 150 Flueble starch powder 397 Silicone fluid at 350 centistokes 3-0 The specific formulations above can be changed in compliance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients: Formulation 6: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.1 1000 Microcrystalline cellulose 0 650 Silicon dioxide, smoked 0 650 Stearic acid 0 15 The components are mixed and compressed to form tablets. Alternatively, the tablets each containing 0.1-1000 mg of Active ingredient are constituted as follows: Formulation 7: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.1 1000 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% solution in water) 4 Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch and cellulose are passed through a No. 45 mesh American sieve and They blend perfectly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a No. 14 mesh North American sieve. The granules thus prepared are dried at 50 ° -60 ° C and passed through a No. 18 mesh North American sieve. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh American sieve, are then added to the granules, which after mixing, they are compressed in a tablet forming machine to produce them. The solutions each containing 0.1 -1000 mg of active ingredient per 5 ml of dose, are prepared as follows: Formulation 8: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.1 1000 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Taste q. v.

Color q. v.

Purified water up to 5 mi The Active ingredient is passed through a No. 45 mesh North American sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with agitation. Sufficient water is then added to produce the required volume. The biological activity of the compounds of the present invention was evaluated using an initial screening test which rapidly and accurately measured the binding of the tested compound to the known sites of the bradykinin receptor. Trials useful for the evaluation of bradykinin receptor antagonists are well known in the art. See, for example, U.S. Patent Nos. 5,162,497, issued November 10, 1992; 5,212,182, issued May 18, 1993; 5,216,165, issued June 1, 1993; and 5,288,725, issued February 22, 1994, all of which are incorporated by reference herein. See also, Ransom et al., Biochemical Pharmacology, 43: 1823 (1992).

Bradykinin Linkage Assay in Guinea Pigs Guinea pigs were humanely sacrificed and the intestines were removed. These intestines were washed thoroughly with 0.9% saline solution, dried and weighed. The tissues were homogenized in at least four volumes of 50 mM Tris buffer, pH 7.7, and centrifuged at 15,000 g for approximately thirty minutes. The centrifugation buttons were then washed three times by successive suspensions in 50 mM Tris, pH 7.7, followed by centrifugation. The final buttons were resuspended in a sufficient volume of 50 mM Tris, pH 7.7, to provide a concentration of 1 g of tissue wet weight per 4 ml of buffer. These samples were stored frozen at -80 ° C. For the binding assay, 190-195 μl of the assay buffer [50 mM Tris, pH 7.4, 1, 10 m-phenanthroline, and 10 μM Plummer inhibitor] were mixed with 200 μl of tissue homogenate, and 5-10 μl of the test sample, the additions occurring in the order mentioned. This test mixture was then mixed perfectly. Non-specific binding was determined in the presence of unlabeled 1 μM bradykinin. To this test cocktail, 100 μl was added (1 nM) bradykinin labeled with 3H. The binding reaction was then incubated for approximately 90 minutes at room temperature, and then filtered through GF / B glass fiber filters, the filters having been prewetted for at least one hour in 0.3% polyethylenimine. The filters were washed with 50 mM cold Tris, pH 7.7 (3 x 3 ml) and then counted in a scintillation counter. Many of the compounds prepared above showed significant activity as bradykinin receptor antagonists. Since the compounds of Formula I are effective antagonists of the bradykinin receptor, these compounds are of value in the treatment of a wide variety of clinical conditions, which are characterized by the presence of an excess of bradykinin. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of bradykinin, which method comprises administering, to a mammal in nof such treatment, an effective amount of a compound of the Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term "physiological disorder associated with an excess of bradykinin" encompasses those disorders associated with inappropriate stimulation of bradykinin receptors, notwithstanding the effective amount of bradykinin present at the site. These physiological disorders can include disorders such as rhinitis, asthma, irritable bowel syndrome, ulcerative colitis, pain or nociception, inflammation, periodontitis, rheumatoid arthritis, and osteomyelitis. It is also known that bradykinins have important roles in circulation homeostasis and bradykinin receptor antagonists can therefore be useful in regulating blood pressure and in treating or preventing hypertension or hypotension. Bradykinin receptor antagonists are also useful in the treatment or prevention of endotoxic shock, which results from an interaction of the endotoxin produced from bacterial cell walls, with cells of the reticuloendothelial system.

It is noted that in relation to this date, the best method known to 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 (8)

1. A method for inhibiting a physiological condition associated with an excess of bradykinin, which comprises administering to a human in need thereof, an effective amount of a compound of the formula characterized in that R1 and R3 are independently hydrogen, O O ?? p -CH 3, -C- (alkyl of 1 to 6 carbon atoms), or -C-Ar, wherein Ar is optionally substituted phenyl; R 'is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salt or solvate thereof.

2. The method according to claim 1, characterized in that the compound is the hydrochloride salt thereof,

3. The method according to claim 1, characterized in that the administration is prophylactic.

4. The method according to claim 1, characterized in that the compound is or its hydrochloride salt.

5. A method according to claim 1, characterized in that the condition associated with an excess of bradykinin is pain and nociception.

6. A method according to claim 1, characterized in that the condition associated with an excess of bradykinin is inflammation.

7. A method according to claim 1, characterized in that the condition associated with an excess of bradykinin is rhinitis.

8. A method according to claim 1, characterized in that the condition associated with an excess of bradykinin is asthma.