JP2001519813A - Calcium soluble compounds - Google Patents

Abstract

  (57) [Summary] A novel arylalkylamino compound exhibiting calcium dissolving properties is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION                          Calcium soluble compounds                                Field of the invention   The present invention relates to a novel arylalkylamine calcium-soluble compound (calcilyt). ic compound), a pharmaceutical composition containing the compound and its calcium receptor For use as an antagonist.   In mammals, extracellular Ca²⁺Is under strict homeostatic regulation, clot formation, It controls various processes such as nerve and muscle excitability and moderate bone formation. Fine Extracellular Ca²⁺Inhibits the secretion of parathyroid hormone (PTH) from parathyroid cells Inhibits bone resorption by osteoclasts and stimulates secretion of calcitonin from C-cells I do. Calcium receptor protein causes certain differentiated cells to have extracellular Ca²⁺concentration Can respond to changes in   PTH is a major source of Ca in blood and extracellular fluids.²⁺Major endocrine factors controlling homeostasis I am a child. PTH acts on bone and kidney cells to produce Ca in the blood.²⁺Increase level Let it. This extracellular Ca²⁺Increases in negative feedback that suppress PTH secretion Acts as a signal. Extracellular Ca²⁺The interaction between PTH and PTH secretion is Ca²⁺ Form an important mechanism to specifically maintain homeostasis.   Extracellular Ca²⁺Acts directly on parathyroid cells to regulate PTH secretion. Extracellular C a²⁺The presence of a surface protein of parathyroid cells that detects changes in E. coli has been confirmed. See Brown et al., Nature 366: 574, 1993. Calcium in parathyroid cells This protein, a receptor, has extracellular Ca²⁺Acts as a receptor for Extracellular Ca²⁺Detects changes in the ion concentration of PTH and opens a functional cellular response and PTH secretion. Start.   Extracellular Ca²⁺Are reported in Nemeth et al., Cell Calcium 11: 319, 1990. Affect various cell functions. For example, extracellular Ca²⁺Are parafollicular cells (C -Cells) and parathyroid cells. Nemeth, Cell Calcium 1 See 1: 323, 1990. Extracellular Ca in osteoclasts²⁺The role of Has been studied. See Zaidi, Bioscience Reports 10: 493, 1990.   Extracellular Ca for calcium receptor molecule²⁺Compounds mimicking the action of It has been known. Calcium soluble substances (calcilytics) are calcium receptors -Inhibition of activity, thereby²⁺One or more evoked by Is a compound that can reduce the calcium receptor activity of Calciu Soluble substances are Ca²⁺Useful calcium modulators active at the receptor As a lead molecule when discovering, developing, designing, modifying and / or constructing It is for. Such a calcium-soluble substance has only one expression and / or secretion. Or more Ca²⁺One or more that is controlled or affected by activity at the receptor Other factors, for example, differences in polypeptides such as hormones, enzymes or growth factors. It is useful in treating various conditions characterized by constant levels. calcium Abnormal bone and mineral homeostasis as a disease or disorder targeted by soluble compounds Sex-related diseases.   The abnormal homeostasis of calcium is one or more of the following: serum calcium Abnormal increase or decrease in calcium; abnormal increase or decrease in calcium in urine Abnormal increase or decrease in bone calcium concentration (eg, by bone mineral density measurements) Abnormal absorption of dietary calcium; PTH and calcitonin, etc. And / or release of messengers affecting serum calcium levels Abnormal increase or decrease in blood flow; and messages affecting serum calcium levels It is characterized by abnormal changes in the response elicited by the sender.   That is, calcium receptor antagonists are abnormal bone or mineral Diseases associated with homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing Tact, osteoarthritis, rheumatoid arthritis, Paget's disease, malignant disease and fracture healing For pharmacotherapy of humoral hypercalcemia and osteoporosis associated with healing It provides the only way.                                Summary of the Invention   The present invention provides an arylalkylamine derivative represented by the following formula (I), , But not limited to, hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing Machine Osteoarthritis, rheumatoid arthritis, Paget's disease, malignant disease and fracture healing Humoral hypercalcemia associated with tactile and bone or mineral, including osteoporosis Its calcium receptor useful for treatment of various diseases associated with abnormal homeostasis of Lal There is provided use as an antagonist.   The compounds of the present invention can be used as compared to other calcium receptor antagonists. It shows increased stability while maintaining lucium receptor activity.   The present invention further provides a method for antagonizing calcium receptors in animals, including humans. A method comprising administering to an animal in need thereof an effective amount of a compound represented by the following formula (I): A method comprising administering a compound.                             Detailed description of the invention   The compound of the present invention has the following formula (I): [Where,   n is an integer from 0 to 3;   R₁Is R_ThreeAnd CH_TwoYR_ThreeSelected from the group consisting of_ThreeIs C_{1-1 Five} Aryl or C_1-20Alkyl, Y is CONH, COO, CONNHN Selected from the group consisting of HCO and CO;   R_TwoIs R_Three, CONHR_Three, H, OR_Three, X, N (R_Three)_Two, CON (R_Three)_Two, COR_Three And SR_ThreeSelected from the group consisting of_ThreeIs H, C_1-15Aryl Or C_1-20Alkyl] Selected from the compounds represented by   Preferably, n is 1 and R_TwoIs in beta position with respect to the N heteroatom . If n is 2, then R_TwoIs alpha or gamma relative to the N heteroatom It is in.   Preferably, R₁Is CH_TwoYR_ThreeIt is.   Preferably, Y is CONH or COO.   Preferably, R_TwoIs CONHR_ThreeIt is.   As used herein, the term "alkyl" refers to a bond connected by a single carbon-carbon bond. Optionally substituted having from 1 to 20 carbon atoms attached together Represents a hydrocarbon group which may be substituted. Alkyl hydrocarbon groups can be linear, branched or cyclic And may be saturated or unsaturated. Substituents are F, Cl, Br, I, N, S And O. Preferably, there are no more than three substituents. Even better Preferably, alkyl has 1-12 carbon atoms and is unsubstituted. Like Alternatively, the alkyl group is linear. Preferably, the alkyl group is saturated You.   As used herein, the term "aryl" refers to a small group having a conjugated pi-electron system. Optionally having at least one ring and containing up to two linked or fused ring systems Represents an aromatic group which may be more substituted. Aryl includes carbocyclic aryl And heteroaryl and biaryl groups, all of which are optionally It may be more substituted. The substituent is F, Cl, Br, I, N, S and O Selected from Preferably, the aryl is an optionally substituted Nyl or optionally substituted 2-naphthyl. Preferably Means that the aryl group is unsubstituted. Most preferred aryl groups are unsubstituted phenyl It is.   Preferred compounds useful in the present invention include the following compounds:   3-carbamoyl-1-((dodecylcarbamoyl) methyl) pyridinium chloride Do   4,4′-bifenacylene-bis (pyridinium bromide),   3- (dodecylcarbamoyl) -1-methylpyridinium bromide,   1-(((dodecyloxy) carbonyl) methyl) -3- (methylcarbamoyl) pyri Dinium chloride,   4-carbamoyl-1-((dodecyloxycarbonyl) methyl) pyridinium Lorido,   3-carbamoyl-1-((dodecyloxycarbonyl) methyl) pyridinium Lorido,   1-((decyloxycarbonyl) methyl) -3-carbamoyl-pyridinium Lorido,   1-((decyloxycarbonyl) methyl) -4-carbamoylpyridinium chloride Lido,   1-((decylcarbamoyl) methyl) -3-carbamoylpyridinium chloride ,   1-((dodecylcarbamoyl) methyl) -3- (phenylcarbamoyl) pyridini Umchloride,   1- (tetradecanoylhydrazinocarbonylmethyl) pyridinium chloride,   1-methyl-2- (decylcarbamoyl) pyridinium iodide,   2- (4- (4-dimethylamino) phenyl) -1,3-butadien-1-yl)- Ethylpyridinium perchlorate,   3-carbamoyl-1-undecylpyridinium bromide, and   1-((decylcarbamoyl) methyl) -4-carbamoylpyridinium chloride .   More preferred compounds useful in the present invention include the following compounds. Is:   3-carbamoyl-1-((dodecylcarbamoyl) methyl) pyridinium chloride Do   3- (dodecylcarbamoyl) -1-methylpyridinium bromide,   4-carbamoyl-1-((dodecyloxycarbonyl) methyl) pyridinium Lorido,   3-carbamoyl-1-((dodecyloxycarbonyl) methyl) pyridinium Lorido,   1-((decyloxycarbonyl) methyl) -3-carbamoyl-pyridinium Loride, and   1-((dodecylcarbamoyl) methyl) -3- (phenylcarbamoyl) pyridini Umchloride.   The most preferred compound useful in the present invention is 3-carbamoyl-1-((dode Silcarbamoyl) methyl) pyridinium chloride.   The compounds of the present invention may be formulated as pharmaceutically acceptable salts and complexes thereof. Can be. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered.   Pharmaceutically acceptable salts include sulfate, hydrochloride, fumarate, maleate, Phosphate, sulfamate, acetate, citrate, lactate, tartrate, methane Sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfate Acids containing folate, cyclohexyl sulfamate and quinate And addition salts. Pharmaceutically acceptable salts include hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid , Sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfone Acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclo Can be obtained from acids such as hexylsulfamic acid, fumaric acid and quinic acid .   Pharmaceutically acceptable salts also include acidic agents such as carboxylic acids or phenols. If functional groups are present, benzathine, chloroprocaine, choline, diethanol Min, ethylenediamine, meglumine, procaine, aluminum, calcium , Lithium, magnesium, potassium, sodium, ammonium, alkyl Base addition salts such as those containing a min and zinc are included.   The present invention is represented by formula (I) above, which can be prepared using standard techniques. Compounds are provided. The overall method of making the preferred compounds described herein is Can be performed as described in this section. The following examples are 3 shows the synthesis of a constant compound. Using the protocol described herein as a model, Other compounds of the invention can be readily prepared by those skilled in the art.   All reagents and solvents were obtained from commercial sources. Starting materials (eg, amines and And epoxides) were synthesized using standard techniques and procedures.   The general procedure used to synthesize many of the compounds of the present invention is as follows: Is:   The preparation of the compounds described herein may be according to previously published methods, or , According to the method described below. Produce the preferred compounds described herein The overall method for doing so can be done as described in this section it can. The following examples illustrate the synthesis of certain compounds. As a model here Using the protocol described, one of ordinary skill in the art can convert another compound of formula (I). Content It can be easily manufactured.   All reagents and solvents were obtained from commercial sources. Starting materials are prepared using standard techniques and techniques. And the procedure is followed.   The general procedure used to synthesize many of the compounds is described in Scheme 1 below. Performed as described. Substituted pyridines (eg, nicotinamide, 1 mm Mol) and excess alkylating agent (eg, N-dodecyl-2-chloroacetoacetate). Amide, 2 mmol) in nitromethane or a similar solvent (2 mL) is 90-1. Stir at 00 ° C. for 24 hours. Typically, the pyridinium salt is precipitated from solution upon cooling. And collect the corresponding salt.                                Scheme 1 a. BrR₁, NO_TwoCH_Three, 90-100 ° C, 24 hours   With the appropriate manipulation and protection of all chemical functional groups, the above methods and experimental sections Of the remaining compound of formula (I) Perform synthesis.   A compound of formula (I) or a pharmaceutical thereof for the treatment of humans and other mammals In order to use acceptable salts, pharmaceutical groups usually follow standard pharmaceutical practices. Formulated as a product.   The calcium-soluble compound is intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical Administration can be by various routes, including (transdermal) or transmucosal administration. About systemic administration In addition, transdermal administration is preferred. For oral administration, for example, the compound can be in a capsule Preparations, tablets and liquid preparations such as syrups, elixirs and concentrated drops And the like can be formulated into conventional oral administration forms.   Alternatively, injection (parenteral administration), for example, intramuscular injection, intravenous injection, intraperitoneal injection Shoots and subcutaneous injections may be used. For injection, the compounds of the invention can be used as a solution, Preferably physiologically compatible, such as saline, Hanks' solution or Ringer's solution Formulation in an aqueous buffer or solution. Furthermore, the compounds are formulated in solid form And may be redissolved or suspended immediately before use. Lyophilized form can also be prepared You.   Systemic administration can also be by transmucosal or transdermal means. Transmucosal Or, for transdermal administration, a penetrant appropriate to the barrier to be permeated is included in the formulation. Used. Such penetrants are generally known in the art, and include, for example, For membrane administration, bile salts and fusidic acid derivatives are included. In addition, washing Purifiers may be used to enhance penetration. For transmucosal administration, for example, nasal spray, direct It is performed with enteric or vaginal suppositories.   For topical administration, the compounds of the present invention are generally known in the art. As such, they can be formulated into ointments, salves, gels or creams.   The dosage of the various calcium-soluble compounds is determined by the compound IC₅₀, EC₅₀Of the compound Biological half-life, age, size and weight of the patient, and Can be determined by standard means taking into account factors such as the disease or disorder. these The significance of this factor and other possible factors is known to those skilled in the art.   Dosage will also depend on the route of administration and degree of oral bioavailability. For example For compounds with low oral bioavailability, higher doses should be administered. Must.   Preferably, the compositions are in unit dosage form. For oral use, for example Tablets or capsules, for nasal use, quantitative For transdermal applications, topical formulations or patches For transmucosal delivery applications, buccal patches may be administered Good. In each case, the dose is such that the patient may be given a single dose .   Each unit dose for oral administration is a compound of the formula (I) or a medicament thereof. Containing 0.01 to 500 mg / kg of the above acceptable salt, calculated as the free base It is suitable to contain 0.1 to 50 mg / kg. Parenteral, The daily dose for the nasal, oral inhalation, transmucosal or transdermal route is given by formula (I) Suitably it will contain from 0.01 mg to 100 mg / kg of the compound. Topical preparations The compound represented by the formula (I) is suitably contained in an amount of 0.01 to 5.0%. Yes The active ingredient is administered in a dose sufficient to exhibit the desired activity, as will be readily apparent to those skilled in the art. It may be administered 1 to 6 times, preferably once a day.   As used herein, "modulator" refers to an antagonist .   As used herein, "treatment" of a disease includes, but is not limited to, Disease prevention, delay and prevention (prophylaxis).   Diseases and disorders to be treated or prevented based on diseased cells include bone and bone. And mineral-related diseases or disorders; hypoparathyroidism; those of the central nervous system, such as If seizure, stroke, head injury, spinal cord injury, cardiac arrest or new Hypoxia-induced neuronal damage, as occurs in live distress, epilepsy, Alzha Neurodegenerative diseases such as Immer's disease, Huntington's disease and Parkinson's disease, dementia , Muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, Schizophrenia, neuroleptic malignant syndrome and Tourette syndrome; ADH secretion syndrome Disease associated with excessive water reabsorption by the kidneys, such as the group (SIADH), cirrhosis, Congestive heart failure and nephrosis; hypertension; cationic antibiotics (eg, amino Glycoside antibiotics) to prevent and / or reduce nephrotoxicity; diarrhea and spasticity Intestinal motility disorders such as the colon; GI ulcer disease; excessive calculosis such as sarcoidosis GI disease with asium absorption; autoimmune disease and organ transplant rejection; squamous cell carcinoma And pancreatitis.   In a preferred embodiment of the present invention, the compound of the present invention comprises a serum parathyroid hormone. Used to increase MON ("PTH") levels. Increase serum PTH levels Are hypoparathyroidism, osteosarcoma, periodontal disease, fractures, osteoarthritis, Such as rheumatism, Paget's disease, humoral hypercalcemia malignant disease and osteoporosis It can help treat the disease.   Compounds of Formula (I) Effective When Administered Orally and Their Pharmaceutically Acceptable Salt can be formulated as syrups, tablets, capsules and lozenges. You. A syrup preparation is generally a flavoring agent or a salt of the compound or salt. Has colorants, such as ethanol, peanut oil, olive oil, glycerin or water Consists of a suspension or solution in any liquid carrier. When the composition is in the form of a tablet, Any pharmaceutical carrier conventionally used for preparing solid formulations may be used . Examples of such carriers include magnesium stearate, clay, talc, gelatin. Gum, gum arabic, stearic acid, starch, lactose and sucrose I can do it. When the composition is in the form of a capsule, for example, a hard gelatin capsule Any conventional encapsulation is suitable, such as using the above carriers in a Puser shell. I have. When the composition is in the form of a soft gelatin shell capsule, for example, For the preparation of dispersions or suspensions of aqueous gums, celluloses, silicates or oils Any pharmaceutical carrier that is conventionally used may be used, and soft gelatin capsules may be used. Integrated into the shell.   Typical parenteral compositions optionally include, for example, polyethylene glycol, Parenterally acceptable such as ribyl pyrrolidone, lecithin, peanut oil or sesame oil Of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing an oil Or consist of a suspension.   Typical inhalation compositions include solutions, suspensions, which may be administered as a dry powder. Or emulsion form or dichlorodifluoromethane or trichlorofluorometa It is in the form of an aerosol using a conventional propellant such as an aerosol.   Typical suppository formulations include binders and / or lubricants, eg, , Gelatin, cocoa butter or other low melting vegetable waxes or fats or their Compounds of formula (I) which are effective in such administrations together with synthetic analogues of Or a pharmaceutically acceptable salt thereof.   Typical dermal and transdermal formulations include conventional aqueous or non-aqueous vehicles, e.g. Consist of, for example, creams, ointments, lotions or pastes, or , Pharmaceutical plasters, patches or membranes.   Preferably, the composition is administered in a unit dose such that the patient may administer a single dose. It is in the form of, for example, a tablet, capsule or metered dose aerosol.   Unacceptable toxicological effects are expected when administering the compounds of the present invention according to the present invention. I can't.   The biological activity of the compounds of formula (I) is shown by the following tests:   (I)Calcium receptor inhibitor assay   Calcium dissolving activity is determined by the expression of HE that stably expresses the human calcium receptor. Extracellular Ca in K293 4.0-7 cells²⁺Induced by intracellular Ca²⁺Increase IC of test compound for blocking loading₅₀Was measured. HEK293 4.0-7 cells were obtained from Rogers et al. Bone Miner. Res. 10Suppl. 1: Constructed in accordance with the description by S483, 1995 Was. Intracellular Ca²⁺The increase is due to extracellular Ca²⁺From 1 mM to 1.75 mM It was induced by: Intracellular Ca²⁺Is a fluorescent calcium indicator fluo- 3 was used.   The method is as follows:   1. 5% CO at 37 ° C. in a T-150 flask_Two: Selection medium under 95% air (Supplemented with 10% fetal calf serum and 200 ug / mL hygromycin B The cells were maintained in DMEM) and grown to 90% confluency.   2. The medium was decanted and the cell monolayer was maintained in phosphate buffered saline maintained at 37 ° C. (PBS) and washed twice. After the second wash, 0.02% EDTA 6 in PBS mL was added and incubated at 37 ° C. for 4 minutes. After incubation, The cells were dispersed by gentle stirring.   3. Cells from two or three flasks were pooled and pelleted (10 0xg). Resuspend the cell pellet in SPF-PCB + 10-15 mL and centrifuge The pellet was formed again by separation. This washing was performed twice.   Sulfate-free and phosphate-free parathyroid cell buffer (SPF-PCB) contains 20 mM Na- Hepes (pH 7.4), 126 mM NaCl, 5 mM KCl and 1 mM  MgCl_TwoIt contains. SPF-PCB was prepared and stored at 4 ° C. On use day, SPF-PCB was added with 1 mg / mL D-glucose and 1 mM CaCl_TwoSupplement with And divided into two fractions. One fraction contains bovine serum albumin ( BSA; fraction V, ICN) at 5 mg / mL (SPF-PCB) +). This buffer was used for washing, adding and maintaining the cells. No BSA hula The section was used for dilution of the cells in a cuvette for fluorometry.   4. Pellet was added to 2.2 uM fluo-3 (Molecular Probes (Molecular Probes)), resuspend in SPF-PCB + 10 mL, room temperature For 35 minutes.   5. After the incubation period, cells were pelleted by centrifugation. Get The pellet was washed with SPF-PCB +. After this washing, cells were washed with SPF-PC Cells 1-2 × 10 in B +⁶Resuspended at a concentration of pcs / mL.   6. To record the fluorescent signal, 300 uL of the cell suspension was added to 1 mM CaC l_TwoAnd 1.2 mL of SPF buffer containing 1 mg / mL D-glucose Diluted. Fluorescence was measured at 37 ° C. using a spectrofluorimeter with constant stirring. Excitation and emission wavelengths were measured at 485 nm and 535 nm, respectively. Fluorescent Add digitonin (5 mg / mL in ethanol) , F_maxAnd Tris-EGTA (2.5 M Tris-Base, 0.3 M E GTA), the apparent F_minWas measured. Intracellular calcium concentration The degree is given by the following equation:               Intracellular calcium = (F-F_min/ F_max) × Kd (Where Kd = 400 nM) Was calculated.   7. To measure the potential calcium lytic activity of test compounds, extracellular Ca²⁺ The cells were allowed to grow for 90 seconds before increasing the concentration of the test compound from 1 mM to 2 mM. Or vehicle for controls). Calcium solubility The compound is extracellular Ca in a concentration dependent manner.²⁺Induced by intracellular Ca²⁺Of concentration Detected by its ability to block the increase.   Generally, IC in calcium receptor inhibitor assays₅₀Those with low values Is a more preferred compound. IC₅₀Compounds exceeding 50 uM are unacceptable. Considered active. Preferred compounds are IC₅₀Is a compound having a concentration of 10 uM or less. More preferred compounds are IC₅₀Is 1 uM, and the most preferred compound is I C₅₀Is 0.1 uM or less.   (II ) Calcium receptor binding assay   Stable transfection with human parathyroid calcium receptor ("HuPCaR") The resulting HEK293 4.0-7 cells were plated in T180 tissue culture flasks. Called up. 1 uM leupeptin, 0.04 uM pepstatin and 1 m Polytron homogeneous in the presence of a protease inhibitor cocktail containing M PMSF Membrane by plasma dosing or glass douncing Get. Aliquoted membranes were flash frozen and stored at -80 ° C.^ThreeH-labeled compound Radiolabeled to a specific activity of 81 Ci / mmol, aliquoted, Stored in liquid nitrogen for qualification.   A typical reaction mixture contains 0.1% gelatin and 10% in a 0.5 mL reaction volume. 2 nM in homogenization buffer containing% EtOH^ThreeH compound ((R, R) -N-4 ′ -Methoxy-t-3-3'-methyl-1'-ethylphenyl-1- (1-naphthyl) Ethylamine), 4-10 ug of film. 12 x 75 polyethylene in ice water bath Incubate in tube. Test sample 25 in 100% EtOH for each tube uL is added, then 400 uL of cold incubation buffer and 100 20 nM in% EtOH^ThreeAdd 25 uL of H-compound. incubation 50 u of 80-200 ug / mL HEK293 4.0-7 membrane diluted in buffer The binding reaction is started by the addition of L and incubated at 4 ° C. for 30 minutes. Washing The buffer is 50 mM Tris-HCl containing 0.1% PEI. Non-specific Binding was determined by the addition of a 100-fold excess of unlabeled cognate ligand, Generally, 30% of the total binding. Brandel Harvestor Reaction by rapid filtration over 1% PEI pretreated GF / C filters using To stop. Place the filter in the scintillation fluid and The radioactivity is measured by counting.   The following examples illustrate specific examples of the present invention and are not intended to be limiting. Absent.                                 Example 1 2- (decylcarbamoyl) -1-methylpyridinium iodide:   a) N-decylpicolinamide:   Picolinic acid (1.0 g, 8.1 mmol), decylamine (1.28 g, 8.1) Mmol), HOBT. H_TwoO (1.31 g, 9.7 mmol), diisopropyl Ethylamine (2.10 g, 16.2 mmol) and EDC (2.89 g, 9. (7 mmol) in dry acetonitrile (15 mL) at room temperature for 14 h did. The mixture is concentrated and H_TwoDissolved in O and extracted three times with ethyl acetate. Matching NaHCO saturated organic extract_Three, Washed with brine, MgSO_Four, Filtered, Concentration gave a light brown oil (2.00 g, 94%). b) 2- (N-decylcarboxyamidyl) -1-methylpyridinium iodide Do :   N-decylpicolinamide (0.41 g, 1.5 mmol) and methyl iodide (1.02 g, 7.8 mmol) in anhydrous p-dioxane (5 mL). Refluxed for 12 hours. The mixture was cooled and concentrated to dryness. Residue in acetone / acetone Trituration with ter gave a white solid (0.11 g, 17%). Example 2 3-carbamoyl-1-[(dodecylcarbamoyl) methyl] pyridinium chloride Do a) N-dodecyl-2-chloroacetamide   n-decylamine (13.93 g, 88.5426 mmol) and triethyl Luamine (8.96 g, 88.5426 mmol) in dry THF (100 mL) Chloroacetyl chloride (10.0 g, 88.5426 mmol ) Was added dropwise. After stirring for 1 hour at 0 ° C., the mixture is_TwoQuenched by O, Et Extracted three times with OAc. The organic extract was washed with brine and dried over MgSO_FourAnd let it dry Filtration and concentration gave a pale brown solid which was triturated in pentane to give A whitish solid was obtained (15.52 g, 75%). b) 3-carbamoyl-1-[(dodecylcarbamoyl) methyl] pyridinium Lorido   Nicotinamide (0.77 g, 6.3 mmol) and N-dodecyl-2-c Loroacetamide (2.9 g, 12.6 mmol) in nitromethane (15 mL) The medium mixture was refluxed for 24 hours. The mixture was cooled and the resulting solid was filtered, Trituration in ton / EtOAc gave a pale yellow solid (0.83 g, 37%).   Pharmaceutical formulations incorporating the compounds of the invention may be prepared in various forms and using various excipients. Can be prepared. Examples of such formulations are set forth below.                                 Example 3 Inhalation formulation   A compound of the formula (I) (1 mg to 100 mg) was added from a quantitative inhaler to eazo. And administer the desired amount of drug for use.                                 Example 4 Tablet formulation Tablet / ingredient Per tablet   1. Active ingredient       (Compound represented by formula (I)) 40 mg   2. 20mg corn starch   3. Alginate 20mg   4. Sodium alginate 20mg   5. 1.3 mg of magnesium stearate   LockPreparation method of drug formulation   Blend components 1, 2, 3 and 4 in a suitable mixer / blender. each With careful mixing after addition, pour enough water into the blend to Change to wet granules by dripping until they have a sea. The wet mass was 8 me Into granules through a vibrating granulator using a brush (2.38 mm) screen . The wet granules are then dried in a 140 ° F (60 ° C) oven to a dry state. I do. Component No. 5. Smooth the granules using a suitable tableting machine. Compress with                                 Example 5 Parenteral formulation   Compounds of formula (I) in polyethylene glycol in an appropriate amount while heating Is dissolved to prepare a pharmaceutical composition for parenteral administration. This solution is then Dilute (to 100 ml) with distilled water for injection. The solution was then reduced to 0.22 micron Sterilize by filtering through a membrane filter and seal in a sterile container.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 101 A61P 29/00 101 35/00 35/00 43/00 111 43/00 111 (72) Inventor Lago, Amparo M. United States 19403 Poundview Drive 701, Audubon, PA 1972 Nguyen, Thomas T. United States 19406 Crossfield Road, King of Prussia, PA 19406

Claims (1)

[Claims] 1. A method of antagonizing a calcium receptor which comprises administering to a patient in need thereof an effective amount of formula (I): Wherein n is an integer from 0 to 3; R ₁ is R ₃ or CH ₂ YR ₃ , wherein R ₃ is C _1-15 aryl or C _1-20 alkyl; Y is selected from the group consisting of CONH, COO, CONHNHCO and CO ₂ ; R ₂ is R ₃ , CONHR ₃ , H, OR ₃ , X, N (R ₃ ) ₂ , CON (R ₃ ) ₂ , COR ₃ And SR ₃ , wherein R ₃ is H, C _1-15 aryl or C _1-20 alkyl] or a pharmaceutically acceptable salt thereof. How to be. 2. The method of claim 1, wherein n is 1. 3. _3. The method according to claim 2, wherein R3 is unsubstituted phenyl or _C1-12 straight-chain unsubstituted saturated alkyl. 4. 4. The method according to claim 3, wherein Y is CONH or COO. 5. The method of claim 4, wherein R ₃ is methyl. 6. The method of claim 2 wherein R ₁ is CH ₂ YR _3. 7. A method of treating a disease or disorder characterized by abnormal bone or mineral homeostasis, comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1. 8. 8. The bone or mineral disease or disorder is selected from the group consisting of osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemic malignancy and osteoporosis. The described method. 9. 9. The method according to claim 8, wherein the bone or mineral disease or disorder is osteoporosis. 10. A method of increasing serum parathyroid gland levels comprising administering to a patient in need of treatment an effective amount of a compound of claim 1.