MXPA97009542A - Modulation of cal calc - Google Patents

Abstract

The present invention relates to: A method for the modulation of calcium channels, increasing the density of calcium channels in vascular and cardiac tissue without changes in the inotropic or pressor response, comprises administering to a warm-blooded animal with need thereof, a pharmaceutically effective amount of a compound having the formula (I) wherein R1 and R3 are independently hydrogen, alkyl of 1-4 carbon atoms, -CO- (alkyl of 1-6 carbon atoms), or - CH2Ar, -CO-Ar, wherein Ar is phenyl or substituted phenyl: R2 is selected from the group consisting of pyrolidine, hexamethyleneimino, and piperidino: or a pharmaceutically acceptable salt thereof

Description

MODULATION OF CALCIUM CHANNELS This invention relates to the discovery that a group of 2-aryl-3-aroylbenzo [b] thiophenes are effective in the modulation of calcium channels, increasing the density of calcium channels in vascular and cardiac tissue, without changes in the inotropic or pressor response. The replacement of estrogen therapy is generally recognized as having beneficial effects on the cardiovascular system in postmenopausal women. See Knopt, O stet. Gynecol. , 72, 23s-30s (1988). In the postmenopausal woman, who receives estrogen; the proportion of cardiovascular mortality is reduced from approximately 30% to approximately 50%, and the proportion of cerebrovascular mortality is reduced by approximately 50%. See Stampfer et al. , N. Engl. J. Med., 325, 756-762 (1991). Through these beneficial cardiovascular effects alterations in the lipid profile may be involved, recent data suggest that estrogen may also have beneficial effects on the vascular response of atherosclerotic coronary arteries. See Gisclard et al. , J. Pharmacol. And Experimental Therapeutics, 244, 19-22 (1988); Williams et al., Circulation, 81, 1680-1687 (1990); Gangar et al. , Lancet, REF: 26291 388, 839-842 (1991); and Williams et al.r JACC, 20, 452-457 (1992). Both effects of endothelial-independent and endothelial-dependent estrogen have been described in vascular tissue. See Jiang et al., Br. J. Pharmacol. , 104, 1033-1037 (1991); Jiang et al., American Journal of Physiology, 32, H271-H275 (1992); Cheng and Gruetter, European Journal of Pharmacol., 215, 171-176 (1992); Mügge et al., Cardiovas. Res., 27, 1939-1942 (1993); Salas et al., European Journal of Pharmacol., 258, 47-55 (1994); Williams et al., Circulation, 81, 1680-1687 (1990); Cheng et al., Life Sciences, 10, 187-191 (1994); Gilligan et al., Circulation, 89, 2545-2551 (1994); and Reis et al., Circulation, 89, 52-60 (1994).

Several reports also suggest that the effects of estradiol vasodilation and / or its ability to decrease contractile responses can be mediated by the inhibition of input via voltage-dependent calcium channels. See Jiang et al., Br. J. Pharmacol., 104, 1033-1037 (1991); Jiang et. al., American Journal of Physiology, 32, H271-H275 (1992); Collins et al., Lancet, 341, 1264 (1993); Muck et al., Med. Sci. Res., 22, 19 (1994); and Salas et al., European Journal of Pharmacol., 258, 47-5 (1994). Others have postulated that estradiol can increase the cyclic content of AMP and cyclic GMP, or increase the ATP-sensitive potassium channels. See Mügge et al. , Cardiovas. Res. , 27, 1939-1942 (1993); Sudhir et al. , Am. Heart J., 129, 726-732. The 2-aryl-3-aroylbenzo [b] thiophene compounds that are employed in the methods of this invention were first developed by Jones and Suarez as anti-fertile agents. See U.S. Patent No. 4,133,814 (published January 9, 1979). These compounds are generally used to suppress the growth of mammary tumors. Jones later found that a group of these compounds are particularly used for anti-estrogen and antiandrogen therapy, especially in the treatment of prostate and breast tumors. See U.S. Patent 4, 418,068 (published November 29, 1983). One of these compounds, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidino-ethoxy) benzoyl] benzo [b] thiophene was studied clinicamento for the treatment of breast cancers. This compound is called raloxifene, formerly cheoxifen. This invention provides methods for the modulation of calcium channels, increasing the density of calcium channels in cardiac and vascular tissue without changes in the inotropic or pressor response, comprises administering to a warm-blooded animal in need thereof, an amount effective of a compound of the formula (I) wherein R1 and R3 are independently hydrogen. Alkyl of 1-4 carbon atoms, -CO- (C 1 -C 6 alkyl), -CH 2 Ar, or -CO-Ar, wherein Ar is phenyl or substituted phenyl. R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salt thereof. The present invention also provides the use of compounds of formula I, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the modulation of calcium channels in vascular and cardiac tissue.

The present invention concerns the discovery that a select group of 2-aryl-3-aroylbenzo [b] thiophenes (benzo [b] thiophenes), the compounds of formula I are effective in the modulation of calcium channels, increasing the density of the calcium channels in the vascular and cardiac tissue, without changes in the inotropic or pressor response. Therefore, the present invention provides methods for the modulation of cardiac channels in vascular and cardiac tissue. One aspect of the invention is a method for treating cardiac disorders including but not limited to variant angina, strained angina, unstable angina, ischemia-reperfusional damage to the myocardium, and arrhythmias. Another aspect is a method to treat cerebral vascular disorders, including but not limited to cerebral vasospasm due to arterial rupture, bumps, headaches, migraines. Another aspect is a method to treat kidney disorders by increasing the actual evacuation due to an increase in the flow of renal blood, used for the slow renal deterioration. Another aspect is a method to treat gastrointestinal disorders, including but not limited to diarrhea-related conditions, such as IBS and IBD, predominant diarrhea. Therapeutic treatments provided by this invention are practiced by administering to a warm-blooded animal in need thereof, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In the above formula, the term "Ci-Cg alkyl" represents a straight, cyclic or branched alkyl chain having from one to six carbon atoms. Typical Ci-Cß alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , and the like. The term "Ci-Cß alkyl" represents a straight or branched alkyl chain having one to four carbon atoms. Typical C1-C4 alkylo groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl and t-butyl. The term "Ar" represents groups such as phenyl and substituted phenyl. The term "substituted phenyl", as used herein, represents a phenyl group substituted with one or more parts selected from the group consisting of halogen, hydroxy, cyano, nitro, C-C4 alkyl, C1-C4 alkoxy, acetyl, formyl, trichloromethyl, or trifluoromethyl. Examples of a substituted phenyl group include 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro -4-fluorophenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-propylphenyl , 4-n-butylphenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4 , 6-trifluorophenyl, 2-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3,5-bis (trifluoromethyl) phenyl), 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl-4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitrophenyl, 2,4-dinitrophenyl, and the like. The term "C 1 -C 4 alkoxy" represents groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like. The term "halogen" represents fluoro, chloro, bromo and iodo. The term "pharmaceutically effective amount" is used herein to represent an amount of the compound of formula I that is capable of increasing the density of calcium channels in vascular and cardiac tissue. The particular dose of the compound of formula I would of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition treated, and similar considerations. The term "modulation", as used herein, represents an increase in the density of calcium channels in vascular and cardiac tissue, with no change in the inotropic or pressor response. The term "warm-blooded animal," as used here, includes humans; associated animals, such as dogs and cats; and domestic animals, such as horses, cows, sheep, pigs, goats and chicks. Preferably, the warm-blooded animal is a human or an associated animal. More preferably, the warm-blooded animal is a human. While all compounds of formula I are employed for the modulation of calcium channels in vascular and cardiac tissue, certain compounds are preferred. Preferably, R 1 and R 3 are independently hydrogen, C 1 -C 4 alkyl, -CO- (C 1 -C 6 alkyl), or benzyl, and R 2 is piperidino or pyrrolidino. Representative compounds of this preferred group include 6-hydroxy-2- (4-hydroxyphenyl) -3- [4 - '(2-pyrrolidinoethoxy) benzoyl] benzo [b] -thiophene, 6-methoxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene, 6-acetoxy-2- (4-acetoxy-phenyl) -3- [4- (2-pyrrolidinoethoxy) benzoyl] benzo [b] -thiophene, and -benzoyloxy- 2- (4-benzyloxyphenyl) -3- [4- (2-piperidino-ethoxy) benzoyl] benzo [b] -thiophene. More preferably, R1 and R3 are independently hydrogen or C4-C4 alkyl, and R2 is piperidino or pyrrolidino. More preferred representative compounds of this group include 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-pyrrolidino-ethoxy) benzoyl] benzo [b] thiophene, 6-hydroxy-2- (4- hydroxy-phenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] -thiophene, 6-methoxy-2- (4-methoxyphenyl) -3- [4- (2-pyrrolidinoethoxy) benzoyl] benzo [ b] -thiophene, and 6-methoxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] -thiophene. More preferably, R1 and R3 are hydrogen and R2 are piperidino. This most preferred compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] -thiophene. The compounds of formula I used in the methods of the present invention can be made in accordance with 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 herein by reference.

In general, the processes start with 6-hydroxy-2- (4-hydroxyphenyl) benzo [b] -thiophene. This initial compound is protected, acylated to C-3 with a 4- (2-aminoethoxy) benzoyl group, and optionally deprotected from the compounds of formula I: Examples of the preparation of such compounds are provided in the US Patents discussed above . The compound used in the methods of this invention from pharmaceutically acceptable acid, where R1 and / or R3 are hydrogen, the base addition salts with a wide variety of organic and inorganic acids and bases include, the physiologically acceptable salts which they are frequently used in pharmaceutical chemistry. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic, mono and dicarboxylic acids, substituted phenyl alkanoic acids, hydroxyalkane and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts also include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate and β-hydroxybutyrate, butyraldehyde. 1,4-dioate, hexane-1,6-dioate, caprate, caprylate, chlorine, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, decanoate, hippurate, lactate, malate, maleate, hydroxyaleate, mandate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen 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-toluenesulf Onate, xylenesulfonate, tartrate and the like. The most 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 an organic solvent such as methanol, diethyl ether or benzene. The salt is usually precipitated in the solution in about one hour to 10 days and can be isolated by filtration, or the solvent can be removed completely 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, primary amines. secondary and tertiary, and aliphatic diamines. The bases used especially in the preparation of the addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine. These salts are generally prepared by reacting a compound of formula I, wherein R1 and / or R3 are hydrogen, with one of the above bases in an organic solvent, such as methanol, diethyl ether or benzene. The salts are isolated as described in the previous paragraph. These pharmaceutically acceptable salts generally have increased solubility characteristics compared to the compound from which they are derived, moreover they are frequently more readily available for formulation as liquids or emulsions.

The compounds of formula I are preferably formulated prior to administration such as in pharmaceutical formulations comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient. These pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In the making of these compositions, the active ingredient would usually be mixed with a carrier, diluted by a carrier, or included within a carrier which may be in the form of a capsule, perfumed sack, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material in which it acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, perfumed bags, capsules, elixiris, suspensions, emulsions, solutions, syrups, sprays, ointments or ointments, for example up to 10% by weight of the active compound, capsules of soft and rigid gelatins, dermal patches, suppositories, sterile injectable solutions, and sterile bagged powders. Some examples of suitable carriers, excipients and diluents include lactose dextrose sucrose, sorbitol, mannitol, starch, gum, acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyvinylpyrrolidone links, cellulose or derivatives thereof, suspensions, water, methylcellulose, hydroxybenzoates of methyl and propyl, talc, esium stearate and mineral oil. The formulations may additionally include lubricating agents, suspending agents, disintegrating agents, preservatives, sweetening agents, or flavoring agents. The compositions of the invention can also be formulated to provide rapidly, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. The required dosage of a compound of formula I for the modulation of calcium channels in vascular and cardiac tissue, in accordance with this invention, will depend on the severity of the condition of the route of administration and the factors reported, which will be decided by professional attention. Generally, the daily dose will be from about 0.1 to about 1000 mg / day, and more typically from about 10 to about 100 mg / day. Such dosages will be administered to a subject in need thereof one to three times each day, or more frequently as needed to effectively treat the condition or symptom. It is usually preferred to administer a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceutical modes of a basic group, such as the piperidino group. For such purposes are available The following oral dosage forms are.

In the following formulations "the active ingredient" suggests a compound of formula I.

Formulation 1: Gelatin capsules Solid gelatin capsules are prepared using the following: Ingredient Amount (mg / capsule) Active ingredient 0.1 - 1000 Starch NF 0 - 650 Powder from starch 0 - 650 350 centistokes of liquid silicone 0 - 15 The ingredients are mixed, passed through a U.S. sieve. No. 45 mesh, and filled into solid gelatin capsules.

The ingredients are mixed, passed through a U.S. sieve. No. 45 mesh, and filled into solid gelatin capsules. Examples of specific formulations of raloxifene capsules that have been made include those shown below: Formulation 2: Raloxifene Capsules Ingredient Quantity (mg / capsule) Raloxifene 1 Starch NF 112 Powder from starch 225. 3 350 centistokes of liquid silicone 1.7 Formulation 3: Raloxifene Capsules Ingredient Quantity (mg / capsule) Raloxifene 5 Starch NF 108 Powder from starch 22 i5. 3 350 centistoques of liquid silicone 1.7 Formulation 4: Capsules of Raloxifene Ingredient Quantity (mg / capsule) Raloxifene 10 Starch NF 103 Powder from starch 225.3 350 centistokes of liquid silicone 1. 7 Formulation 5: Raloxifene Capsules Ingredient Quantity (mg / capsule) Raloxifene 50 Starch NF 150 Powder from starch 397 350 centistokes of liquid silicone 3. 0 The specific formulations above can be changed in complicity with the reasonable variations provided. A tablet formulation is prepared using the ingredients below: Formulation 6: Tablets Ingredient Quantity (mg / capsule) Active Ingredient 0.1 - 1000 Microcrystalline cellulose 0 - 650 Silicon dioxide, gas 0 - 650 Stearate acid 0 - 15 The components are mixed and compressed to form tablets. Alternatively, each of the tablets contains 0.1-1000 mg of the active ingredient being made as follows: Formulation 7: Tablets Ingredient Quantity (mg / capsule) Active Ingredient 0.1 - 1000 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (10% as a solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch and cellulose, is passed through a U.S. No. 45 mesh and mixed completely. The solution of the polyvinylpyrrolidone is mixed with the resulting powders which are then passed through a U.S. No. 14. The granules thus produced are dried at 50 ° -60 ° C and passed through a US No. 18 mesh screen. Sodium carboxymethyl starch, magnesium stearate, and talc are previously passed through a US sieve No. 60 mesh and then added to the granules, which after mixing, are compressed in a tablet machine to obtain the tablets. Each of the suspensions containing 0.1-1000 mg of the active ingredient per 5 ml of doses are made as follows: Formulation 8: Suspensions Ingredient Quantity (mg / capsule) Active ingredient 0. 1 - 1000 mg Sodium carboxymethylcellulose 50 mg Suspension 1.25 mg Benzoic acid solution 0.10 mL Flavor c.v. Colorant c.v. purified water 5 mL The active ingredient is passed through a U.S. No. 45 mesh and mixed with the sodium carboxymethyl cellulose and the suspension to form a toothpaste. The solution of benzoic acid, flavoring and coloring are diluted with a little water and added, with stirring. Then add enough water to produce the required volume. Illustrative compounds that can be used in the methods of the present invention are shown in Table 1. Table 1 Compound No. Rl R3 R2 De -c (0) - © -F piperidino base -c (0) -®-F piperidino HCl 3 - . 3 -? U - | piperidino base -C (O) - ^ 4 piperidino HCl 5 - C (0) CH2CH2CH3 piperidino base 6 - C (0) CH2CH2CH3 piperidino HCl 7 - C (0) C (CH3) 3 piperidino base 8 - C (0) C (CH3) 3 piperidino HCl 9 C (0) CH2C (CH3) 3 piperidino base Table 1 (Continued) Compound No. Rl and R3 R2 Of 10 C (0) CH2C (CH3) 3 piperidino HCl n -C (0) - -CH, piperidinc HCl 12 piperidino base 13 H piperidino base 14 H piperidino HCl 15 H pyrrolidino base 16 H pyrrolidino HCl 17 H hexa ethyleneimino HCl 18 CH3 piperidino HCl The utility of the compounds of formula I is illustrated by the positive impact they have on at least one of the experiments described below.

Materials and Methods A selection and dosage of rats was essentially as described by Sato et al. Sato et al. , J. Bone and Mineral Research, 9, 715-724 (1994).

Briefly, virgin female rats (6 months old) were ovariectomized (Ovex), divided into 3 groups of 6, designated as follows: ovex; estradiol ethinyl (EE2, 0.1 mg / kg / day p.o); and ralaoxifene (compound 14, 1.0 § mg / kg / day p.o) A fourth group of apparently (apparent) operated females served as a second control. Doses of EE2 and 14 were selected for comparable effects on spine density parameters (Sato et al.); incidentally they produced effects IQ similarly significant (P, 0.05 vs ovex) in total low cholesterol (36 + 2 and 38 + 4 mg / dl, EE2 and 14, respectively vs, 85 + 7 and 87 + 7 mg / dl, ovex and apparent, respectively) . Ovex and apparent rats were administered from a vehicle (100 μg / g body weight of II hydroxypropyl-S-cyclodextrin 20%) The animals were dosed for 35 days and slaughtered for excess C02. Hearts and aortas were carefully dissected, rapidly cooled and stored at -70 ° C the membranes were not prepared immediately. l? The microsomal membrane vesicles were isolated from hearts or orta and cut 3-4 g from each of the groups, as previously described. Jones et al. , J. Biol. Chem., 254, 530-535 (197). The preparations were stored in 0.25 M sucrose / 30 i§ mM histidine at -70 ° C. Ligature studies using increased concentrations of calcium channel binders [3H] PN200-110 (0.1-4.0 nM) were made in glass tubes of 12x75 mm (total volume 500 μl) at 23 ° C for 2 hours using 100 ( heart) or 200 (aorta) μg of protein per tube. The tests were determined by rapid filtration on Whatman GF / C filter paper. The control (and wash) control was 50 mM tris / HCl (pH 7.3), 1 mM EDTA and 12 mM MgCl2. No specific ligature was defined as permanent ligature in the presence of 1 μM of nifedipine. The radioligant binding affinity and receptor density were determined from the isothermal unsaturation data using the LUNDON'-1 non-linear regression analysis program. Lundeen and Gordon, in Receptor Binding in Drug Research, 31-49, 1986. Cardiovascular hemodynamic parameters in response to BAY 8644 k were determined in rat marrows in each of the four groups (apparent, ovex EE2, and 14) as it is described by Hayes and Bowling with the following modifications: the drug was administered through the femoral vein; and a direct measurement of left ventricular systolic blood pressure was obtained by teaching a small piped section of PE 90 attached to a pressure transducer directly in the left ventricle. Hayes and Bowling, J. Pharmacol. And Exp. Ther. , 241, 861-869 (1987). Blood pressure, systolic and diastolic blood pressure, rat heart, left ventricular systolic pressure and right ventricle dP / dt were obtained.

RESULTS The effects of EE2 and 14 on ligations of Ca + 2 channels ([3H] PN-200-110) in cardiac and aortic tissues, and in hemodynamic responses in vivo to BAY 8644 k were determined and compared by the controls of ovex and apparent. While sites of high density dihydropyridine (Bmax) ligations in cardiac and aortic tissues were significantly increased in rats treated with EE2 and 14 compared to ovex rats, the affinities of the ligatures (Kd) were not significantly different between the groups in each one of the cardiac or aortic tissues.

Cardiac Chloride Group (3H) PN2O0-IOO aortic V'O-05 goes ovßc treatment mg / dL BtMxífi8l? Dg) Kd (pM) Bp-ax dinolAng) Kd (pM) ovex (n = 5-7) 85 + 7 296 + 51 200 + 19 61 + 15 1.0 + 0.3 s am (n = 4-6) 87 + 7 385 + 76 188 + 32 46 + 14 2.5 + 0.6 EE2 (n-5-7) 36 + 2 * 525 + 65 * 204 + 21 133 + 26 * 2.5 + 0.6 Ralx (n = 4-5) 38 + 4 * 535 + 80 * 171 + 18 124 + 18 * 1.3 + 0.6 Due to the increase in contractile Ca2 + Bmax channels in vivo, the rat heart and pressor responses to BAY 8644 K in rats treated with EE2 was not increased compared with that of the ovex and apparent controls. Furthermore, the density made of the Ca2 + channels did not result in a more sensitive response to the calcium channel agonist.

It is noted that in relation to this date, the best method known by the Solilicitante to carry out the aforementioned invention, is that which is clear from the objects to which it refers. Having described the invention as above, property is claimed as contained in the following

Claims (8)

CLAIMS:

1. A method for the modulation of calcium channels in vascular and cardiac tissue, characterized in that they comprise administering to a warm-blooded animal in need thereof, a pharmaceutically effective amount of a compound having the formula : D wherein R1 and R3 are independently hydrogen, C1-C4 alkyl, -CO- (C6-C6 alkyl), or -CH2Ar, -CO-Ar, wherein Ar is phenyl or substituted phenyl. R2 is selected from the group consisting of pyrolidine, hexamethyleneimino and piperidino; or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein R1 and 3 are independently hydrogen, C4-C4 alkyl, -CO- (C6-C6 alkyl), or benzyl; and R2 is piperidino or pyrrolidino.

3. The use according to claim 2, wherein R1 and R3 are independently hydrogen or C1-C4 alkyl, and R2 is piperidino or pyrolidino.

4. The use according to claim 3, wherein R? and R3 gon hydrogen and R2 is piperidino or pyrrolidino.

5. The use according to claim 4, wherein R2 is piperidino.

6. The use according to claim 5, wherein said pharmaceutically acceptable salt is the hydrochloride salt.

7. The use according to claim 4, wherein R2 is pyrrolidino.

8. The use according to claim 7, wherein said pharmaceutically acceptable salt is the hydrochloride salt.