WO2010113860A1 - Biphenyl-cyclic amine compound - Google Patents

Abstract

Disclosed is a novel compound that has an antagonist action on a calcium receptor. Specifically disclosed is a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. (In the formula, the substituents are defined as follows: R¹, R^1', R² and R³ each represents a hydrogen atom or the like; Ar represents a phenyl group or the like; n represents 1 or the like; and m represents 1 or the like.)

Description

Biphenyl-cyclic amine compound

The present invention relates to a compound having a calcium-sensing receptor (CaSR, hereinafter simply referred to as a calcium receptor) antagonistic action.

Bone is known as a dynamic organ that constantly remodels and resorbs and remodels to maintain its own morphological changes and blood calcium levels. In normal bone, bone formation by osteoblasts and bone resorption by osteoclasts are in an equilibrium relationship, and the bone mass is kept constant. On the other hand, when the balance between bone formation and bone resorption is lost, bone metabolism abnormalities such as osteoporosis occur (Non-Patent Documents 1 and 2).

A number of systemic hormones and local cytokines have been reported as factors that regulate bone metabolism, and bone formation and maintenance are carried out by the joint action of these factors (Non-Patent Documents 3 and 4). . The development of osteoporosis is widely known as a change in bone tissue due to aging, but the mechanism of its onset is decreased secretion of sex hormones and receptor abnormalities, fluctuations in cytokine expression in bone, aging gene expression, osteoclast It is difficult to understand as a simple physiological phenomenon due to aging due to a variety of cells and osteoblast differentiation and dysfunction. Primary osteoporosis is roughly classified into postmenopausal osteoporosis due to decreased estrogen secretion and senile osteoporosis due to aging. In order to elucidate the onset mechanism and develop therapeutic agents, the mechanism of regulation of bone resorption and bone formation Progress in basic research is essential.

Osteoclasts are multinucleated cells derived from hematopoietic stem cells that release the chloride and hydrogen ions on the bone-adherent surface, thereby acidifying the gap between the cell-bone adhesive surface and being an acidic protease. Cathepsin K and the like are secreted (Non-patent Document 5). As a result, the degradation of bone matrix protein and calcium phosphate is induced, and calcium mobilization into the blood occurs.

Serum calcium concentration in normal mammals is strictly maintained at about 9-10 mg / dl (about 2.5 mM) (calcium homeostasis). Parathyroid hormone (PTH) is a hormone that plays a central role in maintaining calcium homeostasis, and PTH secretion from the parathyroid gland is immediately promoted when the blood Ca ²⁺ concentration decreases. The secreted PTH mobilizes Ca ²⁺ into the blood by promoting bone resorption in the bone and the blood in the kidney by promoting resorption of Ca ^{2+ in} the distal tubule. It has the function of increasing the medium Ca ²⁺ concentration.

PTH is known to increase bone mass when intermittently administered to humans and animals, and has already been clinically applied as a therapeutic agent for osteoporosis. In animal experiments, continuous administration of bovine PTH (1-84) to thyroid / parathyroidectomized rats promotes both cancellous bone formation and bone resorption in the femur and decreases net bone mass. Then, it is reported that bone resorption is not enhanced, only bone formation is enhanced, and bone mass is increased (Non-patent Document 6). In addition, when human PTH (1-34) was intermittently administered to the ovariectomized rats from the 4th week to 15 weeks after the operation, the bone formation was enhanced and the bone resorption was suppressed from the 5th week to the 10th week after the start of the administration. It was reported that the bone mass increased to about twice that of the sham operation group (Non-patent Document 7). This report suggests that PTH not only prevents bone loss in osteoporosis models, but also has an effect of restoring bone mass in animals where bone loss has already occurred prominently.

PTH preparation is an osteoporosis therapeutic agent that has been confirmed to have a remarkable fracture rate-reducing effect in clinical trials for postmenopausal osteoporosis patients, but has a disadvantage because it is a biological preparation. That is, injection must be adopted as an administration means, and the problem remains that it is painful for many patients. Therefore, the development of an orally administrable drug that can intermittently increase the PTH concentration in the blood is awaited.
The calcium receptor is a G protein-coupled receptor mainly expressed in parathyroid cells, and regulates PTH secretion by sensing blood Ca ²⁺ concentration (Non-patent Document 8). The human calcium receptor is composed of 1078 amino acids and has been reported to be expressed in kidney, thyroid C cells, brain and bone marrow cells in addition to the parathyroid gland. When the calcium receptor binds to the ligand Ca ^2+, it couples with the G protein and activates phospholipase C, leading to production of inositol triphosphate and an increase in intracellular Ca ²⁺ concentration, and as a result, the secretion of PTH is suppressed. (Non-Patent Document 9). Therefore, a drug that inhibits activation of the calcium receptor, that is, a drug that antagonizes the calcium receptor is expected to promote PTH secretion from parathyroid cells and increase the blood PTH concentration in vivo. At that time, if the increase in blood PTH concentration is not continuous but transient, it is considered that the effect of increasing bone mass can be expected in the same manner as intermittent administration of PTH.
On the other hand, as a compound having a cyclic amine structure, the compound described in Patent Document 1 is known, but the compound of the present invention having both a biphenyl group and a cyclic amine group in the same structure is not known.

WO2004 / 106295 (US 2004259860)

It is an object to provide a novel low molecular weight compound that exhibits a calcium receptor antagonistic action and is highly safe and can be administered orally.

As a result of intensive research aimed at developing a therapeutic agent having a calcium receptor antagonistic activity, the present inventors have found a novel biphenyl-cyclic amine compound that is highly safe and can be administered orally, and completed the present invention.

The biphenyl-cyclic amine compound of the present invention is a compound having a calcium receptor antagonistic action. By “having calcium receptor antagonism” is meant reducing one or more calcium receptor activities induced by extracellular Ca ²⁺ .

That is, the present invention
(1)
A compound having the general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein each substituent is defined as follows.
R ¹ : hydrogen atom, hydroxyl group, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or C7-C11 aralkyloxy group R ^{1 ′} : hydrogen atom, hydroxyl group, halogen atom, C1- C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or C7-C11 aralkyloxy group (or R ¹ and R ^{1 ′} together are a C1-C3 alkylene group)
R ² : hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or halogeno C1-C6 alkoxy group R ³ : hydrogen atom, nitro group, halogen atom, C1-C6 alkyl Group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or halogeno C1-C6 alkoxy group Ar: halogen atom, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group, halogeno C1 A C4-C10 aryl group optionally substituted with a group selected from the group consisting of a -C3 alkylenedioxy group and a halogeno C1-C6 alkoxy group n: 0, 1 or 2
m: 0, 1, 2, or 3]
The present invention preferably has the following aspects.
(2)
The compound or pharmacologically acceptable salt thereof according to (1), wherein R ¹ and R ^{1 ′} are a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom, a methoxy group or a benzyloxy group.
(3)
The compound according to (1) or (2) or a pharmacologically acceptable salt thereof, wherein R ² is a hydrogen atom.
(4)
R ³ is a hydrogen atom, a nitro group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group, the compound according to any one selected from (1) to (3) or a pharmacologically thereof Acceptable salt.
(5)
6. The compound according to any one of (1) to (4), wherein Ar is a phenyl group optionally substituted with a group selected from a methyl group, a fluorine atom and a chlorine atom, or a pharmacological thereof Top acceptable salt.
(6)
6. The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (5), wherein n is 0 or 1.
(7)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein m is 0, 1, or 2.
(8)
The compound according to (1) or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) is a compound selected from the following compound group.

(9)
The compound according to any one of (1) to (8) or a pharmacologically acceptable salt thereof for use as a calcium receptor antagonist.
(10)
(1) A pharmaceutical composition comprising as an active ingredient the compound described in any one of (8) or a pharmacologically acceptable salt thereof.
(11)
The pharmaceutical composition according to (10) for use as a calcium receptor antagonist.
(12)
The pharmaceutical composition according to (10) for use in treating or preventing a disease associated with abnormal bone or mineral homeostasis.
(13)
Diseases associated with abnormal bone or mineral homeostasis include hypoparathyroidism; osteosarcoma; periodontal disease; fracture healing; osteoarthritis; rheumatoid arthritis; Paget's disease; The pharmaceutical composition according to (12), which is accompanied by humoral hypercalcemia; or; osteoporosis.
(14)
The pharmaceutical composition according to (12), wherein the disease associated with abnormal bone or mineral homeostasis is osteoporosis.
(15)
A method for improving bone metabolism, comprising administering an effective amount of the pharmaceutical composition described in (10) to a mammal.
(16)
A method for preventing or treating osteoporosis, comprising administering an effective amount of the pharmaceutical composition described in (10) to a mammal.

The compound of the present invention or a pharmacologically acceptable salt thereof acts as a calcium receptor antagonist, thereby causing diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease It is useful for the treatment or prevention of humoral hypercalcemia and osteoporosis associated with fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, malignancy and fracture healing.

The present invention will be described below.
The compound having the general formula (I) is preferably a compound having the following combinations as substituents.
R ¹ and R ^{1 ′} are a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom, a methoxy group or a benzyloxy group,
R ² is a hydrogen atom,
R ³ is a hydrogen atom, a nitro group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group,
Ar is a phenyl group which may be substituted with a group selected from a methyl group, a fluorine atom and a chlorine atom;
n is 0 or 1, and m is 0, 1, or 2.
More preferable examples of the compound having the general formula (I) include the compounds described in Examples.

The “halogen atom” is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
The “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, or a t-butyl group. More preferably, it is a methyl group.
The “C1-C6 alkoxy group” is a group in which an oxygen atom is bonded to the C1-C6 alkyl group, preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a t-butoxy group. More preferably, it is a methoxy group.
The “halogeno C1-C6 alkyl group” is a group obtained by substituting a halogen atom for the C1-C6 alkyl group. For example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, Examples thereof include a trifluoroethyl group, and a trifluoromethyl group is preferable.
The “halogeno C1-C6 alkoxy group” is a group obtained by substituting a halogen atom for the C1-C6 alkoxy group. For example, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a fluoroethoxy group, a difluoroethoxy group, Examples thereof include a trifluoroethoxy group, and a trifluoromethoxy group is preferable.
The “C4-C10 aryl group” is a cyclic aromatic group having 4 to 10 carbon atoms, for example, an aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl, naphthyl (preferably, Phenyl group), furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, Aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, benzothienyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl A fused aromatic group such as noryl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl (preferably a furyl, thienyl, pyrrolyl or benzothienyl group, more preferably furyl, Thienyl or benzothienyl group).
The “C7-C11 aralkyloxy group” is a group obtained by substituting a methylene group for the C4-C10 aryl group, and is preferably a benzyl group, for example.
The “C1-C3 alkylene group” is a methylene group, an ethylene group or a propylene group.
The “halogeno C1-C3 alkylenedioxy group” is a C 1-3 alkylenedioxy group substituted with a halogen atom, and includes, for example, a difluoromethylenedioxy group.
“Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.

The “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
The pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt. Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates, and aspartates, and alkali metal salts are preferred.
The pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.

The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization. The present invention also includes such various hydrates, solvates and polymorphic compounds.

The light compounds of the present invention, salts thereof or solvates thereof may be isomers such as cis isomers and trans isomers, tautomers or optical isomers such as d isomers and l isomers, depending on the type and combination of substituents. The compounds of the present invention include all isomers, stereoisomers and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. Is. A mixture of these isomers can be separated by a known resolution means.
The compound of the present invention also includes a label, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioisotope (for example, ³ H, ¹⁴ C, ³⁵ S, etc.).

The present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention. A pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions. Drug-forming groups are described in Prog. Med., Volume 5, pages 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of. As the prodrug, more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated). Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert- In the case where a hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like. In addition, when a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation, or methylamidated compounds, etc.).

(Production method)
The compound of the present invention can be produced by applying various known synthesis methods using characteristics based on the basic skeleton or the type of substituent. Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases.
Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of the protecting group include Protective Groups in Organic Synthesis (3rd edition, 1999) by TW Greene and PG Wuts. May be appropriately selected depending on these reaction conditions. According to such a method, after carrying out the reaction by introducing the substituent, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
Further, a prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
The production method of the compound of the present invention is described below. However, the manufacturing method is not limited to the following method.

[Wherein, R ¹ , R ^{1 ′} , Ar, n are as defined above, and PG represents an amino-protecting group. ]

The first step is a condensation reaction of carboxylic acid and hydroxyamine, and is a step of producing compound (2) from compound (1). The second step is a step of producing a compound (3) which is a ketone by reacting a compound (2) with a Grignard reagent. The third step is a step of obtaining compound (4) by reducing compound (3).
The first to third steps are carried out according to the method described in Zhou et al., Heteroatom Chemistry 2003, 14, 603-606.
Steps 4 to 6 are steps for producing compound (7) from compound (4). The Barton-McCombie Reaction of the fourth step and the fifth step is described in Mulzer et al. J. Org. Chem. 1986, 51, 5294-5299. The sixth step is performed by deprotecting the protecting group according to the method described in Protective Groups in Organic Synthesis (3rd edition, 1999).
Compound (7) can also be synthesized by the following route.

[Wherein, R ¹ , R ^{1 ′} , Ar, n, and PG have the same meaning as described above, and Ph represents a phenyl group. ]
The seventh step is a step of producing compound (8) by phosphorylating compound (1). The eighth step is a step of producing the compound (3) by using a Grignard reagent as in the second step.
The ninth step is a step of producing the compound (6) by reducing the ketone of the compound (3), and the tenth step is similar to the above-mentioned sixth step, in which Protective Groups in Organic Synthesis (3rd edition, 1999) by deprotecting the protecting group.
The seventh to tenth steps are the reaction examples described in page 16 of WO 2004/106295 and Yang et al. Bioorg. Med. Chem. Lett. 2005, 15, 1225-1228.

[Wherein R ² represents the same meaning as described above, and L ¹ and L ² represent a leaving group for the substitution reaction. ]

The eleventh step is a step of producing compound (10) using compound (9), which is a substituted benzoic acid, and N, O-dimethylhydroxylamine hydrochloride, which is described in Kunishima et al. Of Tetrahedron 1999, 55, 13159-13170.
The twelfth step can be performed in the same manner as the second step described above, and is a step of producing the compound (11) from the compound (10). Further, in step 13, compound (11) is reduced to give compound (12), and then in step 14, compound (12) and compound (13) are reacted to produce compound (14). .
The 12th to 14th steps are performed according to the reaction example described on page 40 of WO02 / 14259. More specifically, the twelfth step is performed according to the eighth step and step 23 of Example 23 described on page 49 of WO02 / 14259. The thirteenth step is performed according to Example 21, step 1 described on page 66 of WO02 / 14259. The 14th step is carried out in accordance with Example 1 Step 2 described on page 50 of WO02 / 14259.

[Wherein R ¹ , R ^{1 ′} , R ² , R ³ , Ar, m, n, and L ¹ have the same meaning as described above. Y ¹ represents a leaving group on the phenyl group. ]
The fifteenth to nineteenth steps can be carried out according to the reaction example described on page 77 of WO2004 / 094362.
The fifteenth step is a step for producing the compound (16) by protecting the carboxy group of the compound (15) with a protecting group R ⁴ , according to Example 1-1, step 2 described on page 99 of WO2004 / 094362. Do.
The sixteenth step is a step of producing compound (17) by reacting compound (16) with boric acid ester, and is produced according to Example 1-1, step 3 described on page 100 of WO2004 / 094362.
The seventeenth step is a step of producing compound (18) by coupling compound (17) and compound (14), and is produced according to Example 1-1, step 3 described on page 100 of WO2004 / 094362. .
The 18th step is a step of producing the compound (19) by reacting the epoxide portion of the compound (18) with the amine of the compound (7). In Example 1-1 described in page 103 of WO2004 / 094362, Manufacture accordingly.
The nineteenth step is a step of producing the compound (20) by hydrolyzing the ester moiety of the compound (19), which is produced according to Example 1-1, step 9 described on page 103 of WO2004 / 094362.

The compound of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
Further, when the compound having the general formula (I) of the present invention or the intermediate of production has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography. References for a method for resolving optical isomers from racemates include “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by J. Jacques et al.

When the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.

The pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.

The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. The preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.

The dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, body weight, type of drug to be administered in combination, dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), or once or several times a day, orally or parenterally, in the equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.

Furthermore, in the pharmaceutical composition of the present invention, other active ingredients can be used in combination as necessary, as long as the effects of the present invention are not impaired.
The present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof.
Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.

Formulation Example 1 (Powder)
The powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender.
Formulation Example 2 (granule)
After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
Formulation Example 3 (tablet)
A compound is prepared by mixing 5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender and then tableting with a tablet machine.

(Test Example 1)
Evaluation of inhibitory activity against calcium-sensing receptor (CaSR) with an increase in intracellular calcium as an index Using CHO cells (CHO / hCaSR) transformed to stably express human calcium-sensing receptor (CaSR), CaSR antagonist activity was evaluated by using how much the increase in intracellular calcium induced by increasing the calcium concentration was suppressed by the test compound.
CHO / hCaSR prepared at 2 × 10 ⁵ cells / ml in F12 medium (Invitrogen) containing 10% fetal bovine serum was plated at 50 μl / well in a 384-well plate and cultured overnight in a CO ₂ incubator. . The culture supernatant was completely removed, and assay buffer (20 mM HEPES, 2.5 mM probenecid-containing HBSS (Ca and Mg-free), pH 7.4) containing Calcium 3 (manufactured by Molecular Devices), a fluorescent intracellular calcium indicator. 25 μl / well was added and allowed to stand in a CO ₂ incubator for 1 hour. Calcium 3 was prepared according to the protocol attached to FLIPR Calcium 3 Assay Kit (manufactured by Molecular Devices). After standing for 1 hour, 25 μl / well of a solution prepared by adjusting the test compound to a concentration of 2.1 to 20,000 nM (final concentration: 1.05 to 10,000 nM) in assay buffer was added and placed in a CO ₂ incubator. Let stand for 15 minutes. Next, 25 μl / well of CaCl ₂ solution prepared to an assay buffer of 8.1 nM (final concentration 2.7 nM) was added, and the induced intracellular Ca rise (fluorescence intensity) was measured with a fluorescence imaging plate reader (FLIPR , Manufactured by Molecular Device Co., Ltd.). From the obtained data, the difference between the fluorescence intensity before adding the CaCl ₂ solution and the maximum fluorescence intensity after adding the CaCl ₂ solution was calculated, and the 50% inhibitory concentration (IC ₅₀ ) of the test compound was calculated.

In this test, Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, The compounds shown in 25, 26, 27, 28, 29, 30, 32, 33, 34, 35, 36, 38, _40, 41, ₄₄ showed an inhibitory activity with an IC _{50 of} 1.1 μg / ml or less.

(Test Example 2)
Evaluation of PTH secretion-promoting action using rats 10-14 week-old female F344 rats (Nippon Charles River) fasted overnight were collected from the jugular vein under ether anesthesia to prepare pre-dose serum. Subsequently, the test compound was orally administered at a dose of 3 mg / 5 ml / kg using a solvent (0.5% methylcellulose aqueous solution containing 5% DMA). Blood was collected from the jugular vein under ether anesthesia 5, 15, 30, 60, 120, and 240 minutes after administration of the test compound. Serum PTH concentration was measured using a rat Intact PTH ELISA kit (manufactured by Immupics).

In this test, the compounds shown in Examples 1, 7, 8, 9, 13, 18, and 34 had a serum PTH concentration of 100 pg / ml or less at 0 minutes increased to 400 pg / ml or more after 15 to 30 minutes. After 240 minutes, it was lowered to 150 pg / ml or less.

Example 1
2 ′-[(1R) -1-({(2R) -3-[(2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl} oxy) ethyl ] -3-Methylbiphenyl-4-carboxylic acid

(1a) tert-butyl (2S) -2- (3-fluoro-4-methylbenzoyl) pyrrolidine-1-carboxylate tert-butyl (2S) -2- [methoxy (methyl) carbamoyl] pyrrolidine-under argon atmosphere To a solution of 1-carboxylate (2.35 g, 9.10 mmol) in tetrahydrofuran (10 mL) was added a 0.5 M tetrahydrofuran solution (20 mL, 10 mmol) of bromo (3-fluoro-4-methylphenyl) magnesium under ice cooling. It was dripped. After dropping, the mixture was stirred at room temperature for 16 hours, and a saturated aqueous citric acid solution (40 mL) was added. The obtained mixture was extracted with ethyl acetate (30 mL × 3), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 6/4) to obtain 1.35 g of the title compound (yield 48%) as a brown oil.

(1b) tert-butyl (2S) -2-[(3-fluoro-4-methylphenyl) (hydroxy) methyl] pyrrolidine-1-carboxylate tert-butyl obtained in Example 1 (1a) (2S) To a solution of -2- (3-fluoro-4-methylbenzoyl) pyrrolidine-1-carboxylate (1.35 g, 4.38 mmol) in methanol (5 mL) was added sodium borohydride (0.20 g, 5.23 mmol). After adding under ice cooling, the mixture was stirred at room temperature for 0.5 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. . The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 3/1) to obtain 1.30 g of the title compound (yield (96%) as an orange oil).

(1c) tert-butyl (2S) -2-{(3-fluoro-4-methylphenyl) [(1H-imidazol-1-ylcarbonothioyl) oxy] methyl} pyrrolidine-1-carboxylate Example 1 Tert-butyl (2S) -2-[(3-fluoro-4-methylphenyl) (hydroxy) methyl] pyrrolidine-1-carboxylate (1.30 g, 4.19 mmol) obtained in 1b), 1,1 '-Thiocarbonyldiimidazole (1.12 g, 6.28 mmol) and 4-di (methylamino) pyridine (0.05 g, 0.42 mmol) were dissolved in tetrahydrofuran (8.4 mL), and the mixture was stirred with heating under reflux for 16 hours. did. The reaction mixture was allowed to cool to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then decompressed. The solvent was distilled off under. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to obtain 0.83 g of the title compound (yield 47%) as a yellow wax.

(1d) tert-Butyl (2S) -2- (3-Fluoro-4-methylbenzyl) pyrrolidine-1-carboxylate tert-Butyl obtained in Example 1 (1c) (2S) -2-{(3 -Fluoro-4-methylphenyl) [(1H-imidazol-1-ylcarbonothioyl) oxy] methyl} pyrrolidine-1-carboxylate (0.83 g, 1.98 mmol), tributyltin hydride (1.73 g, 5.94 mmol) and 2,2′-azobis (isobutyronitrile) (0.07 g, 0.40 mmol) were dissolved in toluene (4 mL), and the mixture was stirred for 6 hours with heating under reflux. The reaction mixture was allowed to cool to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then under reduced pressure. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain 0.33 g of the title compound (yield 57%) as a colorless oil.

(1e) (2S) -2- (3-Fluoro-4-methylbenzyl) pyrrolidine tert-butyl (2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidine obtained in Example 1 (1d) To a solution of -1-carboxylate (0.95 g, 3.24 mmol) in methylene chloride (9 mL) was added trifluoroacetic acid (2.40 mL, 32.3 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the residue, and the mixture was extracted with methylene chloride (20 mL × 3). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. To give 0.44 g of the title compound (71% yield) as a yellow oil.

(1f) Methyl 2 ′-[(1R) -1-({(2R) -3-[(2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl } Oxy) ethyl] -3-methylbiphenyl-4-carboxylate Methyl 3-methyl-2 ′-{(1R) -1-[(2R) -oxiran-2-ylmethoxy] ethyl} biphenyl- described in WO2004 / 094362 4-carboxylate (1.19 g, 3.64 mmol), (2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidine (587 mg, 3.04 mmol) obtained in Example 1 (1e) and excess A mixture of lithium chlorate (194 mg, 1.82 mmol) in toluene (36 mL) was stirred at room temperature for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. . The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 952 mg of the title compound (61% yield) as a colorless oil.

(1g) 2 ′-[(1R) -1-({(2R) -3-[(2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl} Oxy) ethyl] -3-methylbiphenyl-4-carboxylic acid Methyl methyl obtained in Example 1 (1f) 2 ′-[(1R) -1-({(2R) -3-[(2S)- 2- (3-Fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl} oxy) ethyl] -3-methylbiphenyl-4-carboxylate (952 mg, 1.83 mmol) in tetrahydrofuran (10 mL) 2N-aqueous sodium hydroxide solution (5 mL, 2.50 mmol) was added to a mixed solution of methanol and methanol (10 mL), and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 920 mg of the title compound (yield 99%) as a white amorphous substance.

Example 2
3 ′-[(1R) -1-({(2R) -3-[(2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl} oxy) ethyl ] -3-Methylbiphenyl-4-carboxylic acid (2a) (2R) -2-{[(1R) -1- (3-bromophenyl) ethoxy] methyl} oxirane (1R) -1- (3-bromo Phenyl) ethanol (503 mg, 2.50 mmol), (2R) -oxiran-2-ylmethyl 3-nitrobenzenesulfonate (843 mg, 3.25 mmol) was dissolved in N, N-dimethylformamide (12.5 mL) Sodium chloride (142 mg, 3.25 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain 472 mg of the title compound (yield 73%) as a colorless oil.

(2b) Methyl 3-methyl-3 ′-{(1R) -1-[(2R) -oxiran-2-ylmethoxy] ethyl} biphenyl-4-carboxylate
Methyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (555 mg, 2.01 mmol) described in WO 2004/094362 in toluene-ethanol (1 (1,8 mL) in solution to the (2R) -2-{[(1R) -1- (3-bromophenyl) ethoxy] methyl} oxirane (470 mg, 1.83 mmol) obtained in Example 2 (2a) and A suspension of bis (diphenylphosphino) ferrocene palladium chloride (II) -dichloromethane complex (60 mg, 0.073 mmol) in ethanol (4 mL) was added, then 2M aqueous sodium carbonate solution (4 mL) was added, and the mixture was heated to reflux for 2 hours. The reaction solution was filtered through Celite, and the filtrate was washed with water (x1) and saturated brine (x1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/9) to obtain 474 mg of the title compound (yield 79%) as a colorless oil.

(2c) methyl 3 ′-[(1R) -1-({(2R) -3-[(2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl } Oxy) ethyl] -3-methylbiphenyl-4-carboxylate methyl 3-methyl-3 ′-{(1R) -1-[(2R) -oxiran-2-ylmethoxy obtained in Example 2 (2b) ] Ethyl} biphenyl-4-carboxylate was used in the same manner as in Example 1 (1f) to give the title compound (yield 80%) as a pale brown oil.

(2d) 3 ′-[(1R) -1-({(2R) -3-[(2S) -2- (3-fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl} Oxy) ethyl] -3-methylbiphenyl-4-carboxylic acid methyl 3 ′-[(1R) -1-({(2R) -3-[(2S) -2] obtained in Example 2 (2c) -(3-Fluoro-4-methylbenzyl) pyrrolidin-1-yl] -2-hydroxypropyl} oxy) ethyl] -3-methylbiphenyl-4-carboxylate was used as described in Example 1 (1 g). The reaction was carried out in the same manner as in the method to obtain the title compound (quantitative) as a pale yellow amorphous substance.

Example 3
2 ′-[(1R) -1-({(2R) -3-[(2R) -2- (3-fluoro-4-methylbenzyl) azetidin-1-yl] -2-hydroxypropyl} oxy) ethyl ] -3-Methylbiphenyl-4-carboxylic acid (3a) tert-butyl (2S) -2-[(3-fluoro-4-methylphenyl) carbonyl] azetidine-1-carboxylate Eur. J. et al. Med. Chem. 2000, 35, 979-988. Using the tert-butyl (2S) -2- [methoxy (methyl) carbamoyl] azetidine-1-carboxylate described, the reaction was carried out in the same manner as described in Example 1 (1a) and the title compound (87% ) Was obtained as a pale yellow oil.

(3b) tert-butyl (2S) -2-[(3-fluoro-4-methylphenyl) (hydroxy) methyl] azetidine-1-carboxylate
Using tert-butyl (2S) -2-[(3-fluoro-4-methylphenyl) carbonyl] azetidine-1-carboxylate obtained in Example 3 (3a), described in Example 1 (1b) In the same manner as described above, the title compound was converted to diastereomer A (yield 79%) and 223 mg of diastereomer B (yield 16%) to give colorless oils.
(3c) tert-butyl (2S) -2-{(3-fluoro-4-methylphenyl) [(1H-imidazol-1-ylcarbonothioyl) oxy] methyl} azetidine-1-carboxylate Example 3 Using tert-butyl (2S) -2-[(3-fluoro-4-methylphenyl) (hydroxy) methyl] azetidine-1-carboxylate (diastereomer A) obtained in 3b) The reaction was conducted in the same manner as described in (1c) to obtain the title compound (yield 92%) as a colorless amorphous substance.

(3d) tert-Butyl (2R) -2- (3-Fluoro-4-methylbenzyl) azetidine-1-carboxylate tert-Butyl obtained in Example 3 (3c) (2S) -2-{(3 -Fluoro-4-methylphenyl) [(1H-imidazol-1-ylcarbonothioyl) oxy] methyl} azetidine-1-carboxylate was reacted in the same manner as described in Example 1 (1d). The title compound (yield 86%) was obtained as a colorless oil.

(3e) (2R) -2- (3-Fluoro-4-methylbenzyl) azetidine
Using the tert-butyl (2R) -2- (3-fluoro-4-methylbenzyl) azetidine-1-carboxylate obtained in Example 3 (3d) and the method described in Example 1 (1e) The reaction was conducted in the same manner to obtain the title compound (yield 93%) as a light brown solid.

(3f) Methyl 2 ′-[(1R) -1-({(2R) -3-[(2R) -2- (3-fluoro-4-methylbenzyl) azetidin-1-yl] -2-hydroxypropyl } Oxy) ethyl] -3-methylbiphenyl-4-carboxylate Example 1 (2R) -2- (3-fluoro-4-methylbenzyl) azetidine obtained in Example 3 (3e) The reaction was carried out in the same manner as described in 1f) to obtain the title compound (yield 28%) as a colorless oil.

(3g) 2 ′-[(1R) -1-({(2R) -3-[(2R) -2- (3-fluoro-4-methylbenzyl) azetidin-1-yl] -2-hydroxypropyl} Oxy) ethyl] -3-methylbiphenyl-4-carboxylic acid methyl 2 ′-[(1R) -1-({(2R) -3-[(2R) -2] obtained in Example 3 (3f) -(3-Fluoro-4-methylbenzyl) azetidin-1-yl] -2-hydroxypropyl} oxy) ethyl] -3-methylbiphenyl-4-carboxylate was described in Example 1 (1 g). Reaction was performed in the same manner as in the method to obtain the title compound (yield 89%) as a pale white solid.

The compound of Example 4-45 was produced according to the production method described in Example 1-3. The physicochemical data of the example compounds are shown below.

Claims (16)

1. A compound having the general formula (I) or a pharmacologically acceptable salt thereof.
   

   

   
   [Wherein each substituent is defined as follows.
   R ¹ : hydrogen atom, hydroxyl group, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or C7-C11 aralkyloxy group R ^{1 ′} : hydrogen atom, hydroxyl group, halogen atom, C1- C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or C7-C11 aralkyloxy group (or R ¹ and R ^{1 ′} together are a C1-C3 alkylene group)
   R ² : hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or halogeno C1-C6 alkoxy group R ³ : hydrogen atom, nitro group, halogen atom, C1-C6 alkyl Group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group or halogeno C1-C6 alkoxy group Ar: halogen atom, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkyl group, halogeno C1 A C4-C10 aryl group optionally substituted with a group selected from the group consisting of a -C3 alkylenedioxy group and a halogeno C1-C6 alkoxy group n: 0, 1 or 2
   m: 0, 1, 2, or 3]
2. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ and R ^{1 '} are a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom, a methoxy group or a benzyloxy group.
3. The compound or pharmacologically acceptable salt thereof according to claim 1 or ² , wherein R ² is a hydrogen atom.
4. R ³ is a hydrogen atom, a nitro group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group, or the pharmacologically acceptable compound thereof according to any one of claims 1 to 3 selected from Salt.
5. The compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof, wherein Ar is a phenyl group optionally substituted with a group selected from a methyl group, a fluorine atom and a chlorine atom. Salt.
6. 6. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 5, wherein n is 0 or 1.
7. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein m is 0, 1, or 2.
8. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) is a compound selected from the following group of compounds.
   

   

   

   

   

   
9. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 8, which is used as a calcium receptor antagonist.
10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient.
11. The pharmaceutical composition according to claim 10 for use as a calcium receptor antagonist.
12. 11. A pharmaceutical composition according to claim 10 for use in treating or preventing a disease associated with abnormal bone or mineral homeostasis.
13. Diseases associated with abnormal bone or mineral homeostasis include hypoparathyroidism; osteosarcoma; periodontal disease; fracture healing; osteoarthritis; rheumatoid arthritis; Paget's disease; The pharmaceutical composition according to claim 12, which is accompanied by humoral hypercalcemia; or; osteoporosis.
14. The pharmaceutical composition according to claim 12, wherein the disease associated with abnormal bone or mineral homeostasis is osteoporosis.
15. A method for improving bone metabolism, comprising administering an effective amount of the pharmaceutical composition according to claim 10 to a mammal.
16. A method for preventing or treating osteoporosis, comprising administering an effective amount of the pharmaceutical composition according to claim 10 to a mammal.