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  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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  • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
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  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
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  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
  • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

• the present invention relates to a novel arylalkylamine compound having an active action on Ca-sensitive receptor (CaSR) and useful as a pharmaceutical, and a process for producing the same.
• CaSR Ca-sensitive receptor
• Parathyroid hormone has a physiological function of inducing bone resorption and increasing blood calcium (Ca), and plays a role in maintaining blood Ca homeostasis. Is. When PTH secretion increases chronically, the calcium concentration in blood increases due to the continuous elution of Ca in bone strength, resulting in metabolic abnormalities. For this reason, secretion and synthesis of PTH are strictly controlled by signal transduction via a Ca-sensitive receptor (CaSR) that senses the concentration of extracellular force, ruthenium ion (Ca 2+ ).
• CaSR Ca-sensitive receptor
• Ca-sensitive receptor is one of the G protein-coupled receptors and is expressed on the surface of parathyroid cells. It is known that when a compound that activates the receptor (agonist) binds to the receptor, intracellular Ca 2+ concentration increases and PTH secretion from parathyroid cells is suppressed.
• Non-Patent Document 1 Brown et al., Nature, 366: 575-580, 1993;
• Non-Patent Document 2 Nemeth et al., Proc. Natl. Acad. Sci USA, 95: 4040-4045, 1998);
• Non-Patent Document 3 Brown, Annu. Rev. Nutr "20: 507-533, 2000;
• Non-Patent Document 4 Chattopadhyay, The International Journal of Biochemistry & Cell Biologic, 32: 789-804, 2000;
• Non-Patent Document 5 Coburn et al., Curr. Opin. Nephrol. Hypertens., 9: 123-132, 2000).
• Compounds that have an activating effect on CaSR that is, compounds that selectively act on CaSR and mimic the action of Ca2 +! / Are potent compounds with caldimimetics Called.
• a compound having an antagonistic action against CaSR that is, a compound that suppresses or inhibits the action of Ca2 + is also referred to as calcilytics.
• CaSR agost calcimimetics
• CaSR Ann The following reports have been made on the caldlytics.
• the present invention provides a novel arylalkylamine compound having an excellent Ca-sensitive receptor (CaSR) activity and a method for producing the same.
• CaSR Ca-sensitive receptor
• the ring portion of the heteroaryl represents a bicyclic heterocycle formed by condensation of a 5- to 6-membered monocyclic heterocycle containing 1 to 2 heteroatoms and a benzene ring.
• R 1 a cyclic hydrocarbon group which may have a substituent
• n represents an integer of 1 to 3.
• X Single bond hand, -CH --CO
• Y: — represents O or SO.
• R 2 represents phenyl or lower alkyl.
• R 3 R 4 each independently represents a hydrogen atom or lower alkyl.
• R 5 represents lower alkyl
• the ring part of the group represented by R 1 is not naphthyridine or a part thereof saturated.
• R 1 is naphthyl.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising as an active ingredient an arylalkylamine compound represented by the above general formula [I] or a pharmacologically acceptable salt thereof.
• a therapeutic or prophylactic method comprising administering to a patient an effective amount of the compound [I] or a pharmacologically acceptable salt thereof, and the compound [I] or a pharmacologically acceptable salt thereof as an active ingredient.
• a pharmaceutical composition comprising The present invention also relates to the compound [I] or a pharmacologically acceptable salt thereof, and a production method thereof.
• the target compound [I] of the present invention may have a plurality of optical isomers (for example, when n is 2 or 3 in the compound [I], the 3-position carbon atom of the nitrogen-containing ring structure moiety) ) O
• the present invention includes any of these isomers and also includes a mixture thereof.
• the lower alkyl, lower alkylthio, lower alkylsulfonyl group, lower alkoxy, and lower alkylamino linear or branched ones having 1 to 6 carbon atoms are mentioned, particularly those having 1 to 4 carbon atoms. Is mentioned.
• the lower alkanoyl and lower alkanoylamino include those having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms.
• the lower alkanol includes both lower alkyl CO 2 and lower cycloalkyl CO—.
• lower cycloalkyl and lower cycloalkenyl include those having 3 to 8 carbon atoms, especially 3 to 6 carbon atoms.
• Examples of the lower alkylene include linear or branched ones having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms.
• lower alkenyl and lower alkene examples include those having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms.
• examples of the halogen atom include fluorine, chlorine, bromine and iodine.
• examples of the amino group which may have a substituent include cyclic amino (1-pyrrolidyl, 1-piperidyl, 1-piperadil, 4 morpholinyl, etc.).
• the aryl moiety of the “aryl having a substituent may be monocyclic or bicyclic” represented by Ar A formula reel.
• heteroaryl portion of “having a substituent, but heteroaryl” represented by Ar includes 1 to 2 hetero atoms (selected from oxygen atom, sulfur atom and nitrogen atomic energy).
• hetero atoms selected from oxygen atom, sulfur atom and nitrogen atomic energy.
• Examples include bicyclic heterocyclic groups formed by condensation of a cyclic 5- to 6-membered heterocyclic ring with a benzene ring. Specifically, for example, benzo chale and the like can be mentioned.
• Examples of the substituent in "having a substituent, may be aryl" or “having a substituent, heteroaryl” represented by Ar include halogen, Cl, Br, etc. ), Hydroxy, halo-lower alkyl, lower alkyl, lower alkyl, lower alkoxy, lower alkylthio and the like.
• lower alkoxy groups (methoxy, ethoxy, etc.), lower alkyl (methyl, etc.) Etc. are suitable.
• the cyclic hydrocarbon group portion of the "optionally substituted cyclic hydrocarbon group" represented by R 1 may be, for example, partially or entirely saturated.
• monocyclic hydrocarbon groups having 3 to 7 carbon atoms such as phenol, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl, and carbon numbers such as indanyl, indur, naphthyl and tetrahydronaphthyl. Examples thereof include 9 to 11 bicyclic hydrocarbon groups.
• cyclic hydrocarbon groups monocyclic hydrocarbon groups such as phenyl and cyclohexyl, and bicyclic hydrocarbon groups such as indanyl and indur are preferred.
• monocyclic hydrocarbon groups are more preferred, especially phenol and cyclopropyl.
• the heterocyclic group portion of the "having a substituent, which may have a substituent" represented by R 1 includes a hetero atom selected from a nitrogen atom, an oxygen atom, and a sulfur nuclear atom.
• a saturated or unsaturated monocyclic or bicyclic heterocyclic ring containing at least one group is exemplified.
• Monocyclic one is a saturated or unsaturated 5- to 7-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms. Etc.
• the bicyclic ring is a heterocyclic ring formed by condensing two saturated or unsaturated two 5- to 7-membered rings, and selected from a nitrogen atom, an oxygen atom and a sulfur atom. And those containing other heterogenous atoms.
• monocyclic compounds include, for example, pyrrolidyl, imidazolidyl, pyrazolidinyl, oxolyl, thioral, pyrrolinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, and pyrazolyl.
• Bicyclic compounds include, for example, indoleyl, isoindoleyl, indolyl, indazolyl, isoindolyl, benzimidazolyl, benztriazolyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, benzocenyl, benzofuryl, thienopyri Zyl, thiazolopyridyl, pyropyridyl, pyropyrimidinyl, cyclopentapyrimidinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, phthalajuril, cinnolinyl, chloro, isochromal, benzothiazinyl, some or all of Bicyclic groups such as saturated cyclic groups and cyclic groups in which these heteroatoms (N or S) are acidified.
• indolyl benzimidazolyl, benztriazolyl, benzochel, quinolyl, phthalajur, benzothiazin and the like are suitable.
• heterocyclic group moiety of the “having a substituent, which may be substituted,” represented by R 1 among the monocyclic and bicyclic ones, monocyclic ones are more preferable. .
• substituent group Q1 As the substituent in the “cyclic hydrocarbon group which may have a substituent” or “heterocyclic group which may have a substituent” represented by R 1 , for example, Examples of the substituent group Q1 are as follows.
• Substituents may be lower alkyl
• Halogen, nitro-containing nitro, oxo, carboxy, hydroxy, lower alkoxy and halo, lower alkoxy, etc. may be optionally substituted with one or more selected groups.
• .Substituents may be lower alkoxy
• Halogen hydroxy; carboxy; aryl (such as phenol); lower cycloalkyl; lower alkoxy; mono- or di-lower alkylamino; lower alkanoylamino; substituted with oxo, etc.
• Nitrogen 5- to 6-membered heterocyclic group pyrrolidyl-, piberidinyl, morpholinyl, etc.); and; asil (lower alkanoyl, lower alkoxycarbonyl, carbamoyl, morpholino-carb, etc.); isotropic May be optionally substituted.
• Nitrogen 5- to 6-membered heterocyclic group pyrrolidyl-, piberidinyl, morpholinyl, etc.
• asil lower alkanoyl, lower alkoxycarbonyl, carbamoyl, morpholino-carb, etc.
• isotropic May be optionally substituted.
• Substituted ! may be aliphatic nitrogen-containing 5- to 6-membered heterocyclic group (piveridyl etc.)
• tetrahydroviral aliphatic nitrogen-containing 5- to 6-membered heterocyclic group
• R 1 has a substituent! /, But is a phenyl
• the substituent may be carboxy, halogen (F, C1, etc.), unsubstituted or substituted lower alkyl (carboxy Lower alkyl, halo lower alkyl, etc.), unsubstituted or substituted lower alkoxy (such as low-end lower alkoxy, etc.), asil (lower alkyl sulfone, strong rubamoyl, hydroxy lower alkyl strong rubamoyl, lower alkylamino sulfol, mono —Or di-lower alkylamino lower alkylamino sulfonyl, etc.), or an optionally substituted 5- to 6-membered monocyclic heterocyclic group (tetrazole or a partially saturated cyclic group), etc. Hope it is U.
• the “lower alkyl” represented by R 2 is preferably methyl or ethyl.
• the “lower alkyl” represented by R 3 and R 4 is preferably methyl or ethyl.
• the “lower alkyl” represented by R 5 is preferably methyl or ethyl.
• preferred compounds include the following partial structures: A compound having the general formula [I e]
• X is a single bond, CO or one (CH) — CO—.
• the compound group which is 2 m is mentioned. More preferable compounds include compounds in which n is 1 or 2, and is a single bond, —CO 2 or one (CH 2) 1 CO 2.
• Another example is a compound group in which n is 2 and X is a single bond. Furthermore, in any one of the above compound groups, a compound group in which Ar is an aryl optionally having a substituent is mentioned.
• any one of the above compound groups there may be mentioned a compound group in which Ar may have a phenyl group or a substituent which may have a substituent, and may be naphthyl.
• Ar may be optionally substituted with a group selected from halogen, hydroxy, sheared lower alkyl, lower alkyl, lower alkoxy, and lower alkylthio force.
• a group selected from halogen, hydroxy, sheared lower alkyl, lower alkyl, lower alkoxy, and lower alkylthio force is mentioned.
• Ar may be optionally substituted with a group selected from lower alkyl and lower alkoxy force, and there may be mentioned the compound group which is a group.
• any one of the above compound groups there is a compound group in which the ring portion of the group represented by R 1 is a cyclic hydrocarbon group or a monocyclic heterocyclic group.
• any one of the above compound groups a compound group which is (i) (ii) or (iii) below the cyclic group partial force of the group represented by R 1 can be mentioned.
• a heterocyclic ring formed by condensing two saturated or unsaturated 5- to 7-membered rings, and containing 1 to 6 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom Including bicyclic heterocyclic groups.
• any one of the above compound groups a compound group that is ⁇ ( ⁇ ) or (m) below the cyclic group partial force of the group represented by R 1 can be mentioned.
• the compound [I] of the present invention may be in a free form or a pharmaceutically acceptable salt form.
• Examples of pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, kenate, methane.
• examples thereof include organic acid salts such as sulfonate, benzenesulfonate, p-toluenesulfonate, and maleate.
• a salt with a base for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt
• the compound [I] or a salt thereof of the present invention includes an inner salt or an adduct thereof, a solvate or a hydrate thereof, and the like, and includes any deviations.
• the object compound [I] (especially compound [I e]) or a pharmacologically acceptable salt thereof of the present invention has an excellent CaSR activating action.
• the pharmaceutical composition comprising the target compound of the present invention as an active ingredient is a disease in which the pathological condition is expected to be improved by activating CaSR and / or suppressing PTH production (and / or decreasing the blood level of PTH via these).
• hyperparathyroidism primary hyperparathyroidism, secondary hyperparathyroidism, ectopic hyperparathyroidism, etc.
• Useful as an active ingredient Useful as an active ingredient.
• the object compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent activating effect on CaSR. In addition, it has high selectivity for CaSR.
• the target compound [I] of the present invention or a pharmacologically acceptable salt thereof suppresses the production of PTH through its activity against CaSR, and the blood level of PTH in vivo. It exhibits various medicinal effects, such as lowering blood levels. Therefore, the pharmaceutical composition containing the target compound [I] of the present invention or a pharmacologically acceptable salt thereof as an active ingredient can be used for the activity of CaSR.
• the pharmaceutical composition can also be used to suppress PTH production. It can also be used to lower the blood level of PTH in vivo.
• the pharmaceutical composition may be used for the treatment or prevention of a disease whose disease state is expected to be improved by inhibiting CaSR activity and / or suppressing PTH production (and / or decreasing the blood level of PTH mediated thereby). Can be used for
• Compounds having an active action on CaSR include, for example, WO93 / 04373, W094 / 18959, W095 / 11221, W096 / 12697, WO97 / 41090, W09 8/01417, WO03 / 99814 and WO03 / 99776. [It has been described!] It is known that anti-parathyroid function is enhanced through a decrease in blood PTH concentration.
• a pharmaceutical composition containing the target compound [I] of the present invention or a pharmacologically acceptable salt thereof as an active ingredient activates CaSR and / or suppresses PTH production (and / or these).
• diseases are expected to improve due to decreased blood levels of PTH (eg, hyperparathyroidism (primary hyperparathyroidism, secondary hyperparathyroidism and ectopic parathyroid gland)). It can be used for the treatment or prevention of hyperfunction etc.).
• a method of administering an effective amount of the compound [I] of the present invention or a pharmacologically acceptable salt thereof to a patient, the compound [I] of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient The use for the manufacture of the pharmaceutical composition comprising is also applied for said purpose and is included in the present invention.
• the pharmacological effects of the compounds of the present invention are known methods (W097Z37967, WO93 / 04373, W094 / 18959, WO97 / 41090, Nemeth et al, Proc. Natl. Acad. Sci USA, 95: 4040—4045, 1998; Racke and Nemeth, J. Physiol., 468: 163-176, 1993; and Nemeth et al, J. Pharmacol. Exp. T. 308: 627-635, 2004), or an equivalent method.
• a method for assessing the action of a test compound using rat parathyroid cells can be suitably used.
• This method includes the following steps.
• thyroid cells are collected from rats and cultured primarily.
• preparation of cells is easier than in the conventional method using parathyroid cells of large animals (such as ushi).
• changes in PTH production can be observed under a moderate length of incubation, so the test can be performed stably and efficiently. A large number of test substances can be tested.
• the effect of lowering the PTH level in vivo can be detected by an in vivo test using a known animal model (such as a pathological model of hyperparathyroidism).
• a rat adenine model for example, a rat 5Z6 nephrectomy (nephrectomy) model, and the like can be applied. More specifically, for example, the methods described in Experimental Examples 3 and 4 below can be applied. it can.
• the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used as an active ingredient for pharmaceutical use, it is used together with an inert carrier according to the administration method, and a conventional pharmaceutical preparation (tablet Preparations, granules, capsules, powders, solutions, suspensions, emulsions, injections, drops, etc.).
• a conventional pharmaceutical preparation tablette Preparations, granules, capsules, powders, solutions, suspensions, emulsions, injections, drops, etc.
• strong carriers include binders (eg, gum arabic, gelatin, sorbit, polybulurpyrrolidone, etc.), excipients (lactose, sugar, corn starch, sorbit, etc.), lubricants that are acceptable in general medicine.
• disintegrants potato starch, etc.
• an injection or infusion it can be formulated using distilled water for injection, physiological saline, aqueous glucose solution, or the like.
• the method of administration when the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used for pharmaceutical purposes is not particularly limited, and a general oral or parenteral method (intravenous) Intramuscular, subcutaneous, transdermal, nasal, other transmucosal, enteral, etc.) can be applied.
• a general oral or parenteral method Intravenous
• Intramuscular, subcutaneous, transdermal, nasal, other transmucosal, enteral, etc. can be applied.
• the dose is effective enough to exhibit a medicinal effect depending on the potency characteristics of the compound as an active ingredient. What is necessary is just to set suitably in the range of quantity.
• the dose varies depending on the administration method, patient age, body weight, and condition.
• the general dose for example, 0.001 to 3 OOmgZkg per day is set to an appropriate amount.
• the target compound [I] of the present invention can be produced by the following [Method A], [Method B], [Method C], [Method D], [Method E], and [Method F]. It is not limited to these.
• X is a single bond.
• the compound shown can be produced, for example, as follows.
• a compound represented by the general formula [11] or a salt thereof is reacted with a compound represented by the general formula [12] to make the product a pharmacologically acceptable salt, if desired.
• Product [Ia] can be produced.
• a conventional reactive residue such as a halogen atom, a lower alkylsulfonyloxy group, and an arylsulfonyloxy group can be preferably used. Atoms are preferred.
• the salt of the compound [11] for example, a salt with an inorganic acid such as hydrochloride or sulfate can be used.
• the reaction in the method A can be carried out, for example, as in the following reaction Al and reaction A2. Monkey.
• reaction of compound [11] or a salt thereof and compound [12] can be carried out, for example, in a suitable solvent in the presence of a catalyst and a base.
• a palladium catalyst for example, palladium acetate, trisdibenzyldenacetone dipalladium, etc.
• a palladium catalyst for example, palladium acetate, trisdibenzyldenacetone dipalladium, etc.
• triphenylphosphine BINAP (2,2 and bis (di-phenylphosphino-l, l'-binaphthyl)), biphenyl-di-2-tert-butylphosphane, etc.
• a trivalent phosphorus compound or the like may be added.
• a divalent palladium catalyst without a ligand such as palladium acetate
• a trivalent phosphorus compound is added when a divalent palladium catalyst without a ligand (such as palladium acetate) is used as a catalyst.
• Examples of the base include cesium carbonate (Cs CO), sodium butoxide, alkali metal
• Amides lithium hexamethyl disilazide, potassium hexamethyl disilazide, sodium hexamethyl disilazide, etc. can be suitably used.
• This reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 120 ° C.
• the solvent may be any solvent that does not adversely influence the reaction, for example, tert-butanol, tetrahydrofuran, dioxane, toluene, 1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, diglyme, xylene, or a mixture thereof.
• a solvent can be appropriately used.
• reaction of compound [11] or a salt thereof and compound [12] can be carried out, for example, in a suitable solvent in the presence of a base.
• strong bases include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium butoxide, and sodium trioxide.
• An alkali metal alkoxide such as ummethoxide) or an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.
• inorganic bases for example, alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium butoxide, and sodium trioxide.
• An alkali metal alkoxide such as ummethoxide
• an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.
• This reaction suitably proceeds at 20 to 200 ° C, particularly 70 to 140 ° C.
• Solvents include acetonitrile, methanol, ethanol, isopropyl alcohol, n-propyl alcohol, tert-butanol, acetone, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, jetyl ether, dioxane, ethyl acetate, toluene, methylene chloride. , Dichloroethane, black mouth form, ⁇ , ⁇ -dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, diglyme, xylene or These mixed solvents can be used as appropriate.
• a thing can be manufactured as follows, for example.
• reaction of compound [11] or a salt thereof and compound [13] can be carried out in a suitable solvent in the presence of a reducing agent.
• sodium triacetoxyborohydride sodium borohydride, sodium cyanoborohydride and the like can be suitably used.
• an organic acid such as acetic acid or propionic acid may be added.
• This reaction proceeds suitably at 0 to 60 ° C, particularly 20 to 40 ° C.
• the solvent may be any solvent that does not adversely affect the reaction.
• Tan, xylene, or a mixed solvent thereof can be used as appropriate, and among these, methylene chloride can be preferably used.
• X 1 is -CO-,-(CH) -CO-, -CH (R 2 ) -CO-,
• X is —CO —— (CH 2) —CO—, —CH (R 2 ) —
• the compound represented by the general formula [I_c] which is —N (R 5 ) —CO— can be produced, for example, as follows.
• the product is converted into a pharmacologically acceptable salt.
• the target compound [Ic] can be produced.
• reaction of compound [11] or a salt thereof and compound [14a] can be carried out in a suitable solvent in the presence of a base.
• an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.
• an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.
• This reaction suitably proceeds at ⁇ 20 50 ° C., particularly 10 30 ° C.
• Any solvent may be used as long as it does not adversely affect the reaction.
• Tetrahydrofuran, jetyl ether, dioxane, ethyl acetate, toluene, methyl chloride, dichloroethane, chloroform, 1,2-dimethoxyethane, xylene, or a mixed solvent thereof can be used as appropriate.
• reaction of compound [11] or a salt thereof and compound [14b] is carried out in an appropriate solvent in the presence of a condensing agent, and optionally in the presence or absence of an additive and Z or a base. It can be done.
• Condensation agents include: O benzotriazole 1-yl N, N, ⁇ ', ⁇ '-tetramethyl carboxy-hexafluorophosphate, DCC (dicyclohexylcarbodiimide), ED C (l ethyl — (3— (3-dimethylaminopropyl) carbodiimide), chloroformate esters (eg, ethyl chloroformate, isobutyl chloroformate), carbodiimidazole, and the like can be suitably used.
• additives such as 1-hydroxybenzotriazole and 1-hydroxysuccinimide and a base can be added together with the condensing agent.
• strong bases include organic bases (eg, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.), alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), etc. Can be suitably used. This reaction suitably proceeds at 0 to 100 ° C, particularly 20 to 50 ° C.
• any solvent that does not adversely influence the reaction may be used.
• ⁇ , ⁇ -dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, xylene, or a mixed solvent thereof can be used as appropriate.
• the compound represented by the general formula [Id] wherein X is —NH—CO— can be produced, for example, as follows.
• a compound represented by the general formula [11] or a salt thereof is reacted with a compound represented by the general formula [15] to make the product a pharmacologically acceptable salt as desired.
• An object [Id] can be manufactured.
• reaction of compound [11] or a salt thereof and compound [15] can be carried out in a suitable solvent in the presence or absence of a base.
• strong bases include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium butoxide, sodium hydroxide, potassium hydroxide and potassium hydroxide). Hydroxy-alkali metal such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc. It is out.
• alkali metal hydrides such as sodium hydride
• alkali metal carbonates such as sodium carbonate and potassium carbonate
• alkali metal alkoxides such as sodium butoxide, sodium hydroxide, potassium hydroxide and potassium hydroxide
• Hydroxy-alkali metal such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc. It is out.
• This reaction suitably proceeds at 0 to 60 ° C, particularly 10 to 30 ° C.
• any solvent that does not adversely influence the reaction may be used.
• ⁇ , ⁇ -dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, xylene, or a mixed solvent thereof can be used as appropriate.
• the target compound [a] can also be produced, for example, as follows.
• a compound represented by the general formula [21] or a salt thereof is reacted with a compound represented by the general formula [22] to obtain a compound represented by the general formula [23]. This is subjected to an oxidation reaction to give a general formula The compound represented by [24] is obtained.
• the desired compound [Ia] can be produced by reacting the compound [24] with the compound represented by the general formula [25] or a salt thereof to make the product a pharmacologically acceptable salt if desired. .
• salts of the compounds [21] and [25] for example, salts with inorganic acids such as hydrochloride and sulfate can be used.
• reaction of compound [21] or a salt thereof and compound [22] can be carried out in a suitable solvent in the presence of a copper reagent.
• copper reagent copper acetate or the like can be suitably used.
• a base is added.
• a strong base for example, triethylamine, pyridine and the like can be preferably used.
• a dehydrating agent such as molecular sieve 4A may be added to the reaction system!
• This reaction suitably proceeds at 0 to 40 ° C, particularly 10 to 30 ° C.
• any solvent that does not adversely influence the reaction may be used.
• methylene chloride, dichloroethane, or a mixed solvent thereof can be appropriately used, and methylene chloride is particularly preferable.
• the oxidation reaction of compound [23] can be carried out by a conventional method, for example, in a suitable solvent in the presence of an oxidizing agent.
• oxidizing agent oxalyl chloride-dimethyl sulfoxide, sulfatrioxide pyridin complex and the like can be suitably used.
• This reaction suitably proceeds at 70 to 40 ° C, particularly at -70 to 20 ° C.
• the solvent may be any solvent that does not adversely affect the reaction.
• salt oxalyl monodimethyl sulfoxide methylene chloride or the like can be preferably used, and in the case of using a sulfatrioxide pyridine complex as an oxidizing agent, dimethyl sulfoxide can be preferably used.
• the target compound [I_b] can also be produced, for example, as follows.
• a compound represented by the general formula [21] or a salt thereof is reacted with the compound [13] to obtain a compound represented by the general formula [26]. This is subjected to an oxidation reaction to obtain a compound represented by the general formula [27].
• the desired compound [Ib] can be produced by reacting the compound [27] with the compound [25] or a salt thereof to produce a pharmacologically acceptable salt as desired.
• reaction of compound [21] or a salt thereof and compound [13] can be carried out in the same manner as the reaction of compound [11] and compound [13].
• the oxidation reaction of the compound [26] can be carried out in the same manner as the oxidation reaction of the compound [23].
• the reaction of the compound [27] with the compound [25] or a salt thereof can be carried out with the compound [24] and the compound [25]. It can carry out like the reaction with.
• Compound [11] which is a raw material compound in the above-mentioned method A, method B, method C and method D, can be produced by, for example, the following method.
• compound [31] is subjected to an oxidation reaction to obtain a compound represented by general formula [32]. This is reacted with the compound [25] or a salt thereof to obtain compound [33].
• Compound [11] can be produced from compound [33] by removing the amino-protecting group.
• the amino-protecting group represented by Q includes: t-butoxycarbonyl group, benzyloxycarbonyl group, trifluoroacetyl group, 9-fluoromethyloxycarboxyl group conventional amino group protection Any group can be suitably used.
• reaction of compound [31] with compound [25] or a salt thereof can be carried out in a suitable solvent in the presence of trifluoromethanesulfonic anhydride or the like and in the presence of a base.
• a base for example, an organic base such as diisopropylethylamine can be suitably used.
• This reaction suitably proceeds at 50 ° C to room temperature, particularly 20 ° C to room temperature.
• the solvent may be any solvent that does not adversely affect the reaction.
• Tylene, dichloroethane, black mouth form, 1,2-dimethoxyethane, xylene or a mixed solvent thereof can be appropriately used, and methylene chloride can be particularly preferably used.
• the oxidation reaction of compound [31] can be carried out in the same manner as the oxidation reaction of compound [23].
• the reaction of compound [32] with compound [25] or a salt thereof can be carried out by reacting compound [24] with compound [23].
• the reaction can be carried out in the same manner as in the reaction with [25].
• titanium tetraisopropoxide or the like can be used as a condensing agent, and sodium borohydride or the like can be used as a reducing agent.
• Removal of the compound [33] powerful amino group protecting group (Q) can be carried out by a conventional method, for example, by acid treatment, base treatment or catalytic reduction in a suitable solvent or without solvent.
• compound [33] and compound [11] have optical isomers having a chiral center at the 3-position carbon of the nitrogen-containing ring.
• optically active compound [33] and compound [11] can be produced from the diastereomeric mixture [33] as follows, for example.
• the compound [33] is reacted with phosgenes, and the resulting product (diastereomer mixture) is purified and separated by crystallization and / or column chromatography, if necessary, to give a general formula [ 34a] and an optically active compound represented by the general formula [34b] are obtained.
• the optically active compound can be similarly obtained by column separation of the resulting rubamate diastereomeric mixture formed by reacting the resulting carbamoyl chloride diastereomeric mixture with an alcohol (such as tert-butanol). Can be obtained.
• Compound [33a] or compound [33b] can also be prepared by removing the amino-protecting group to produce general formula [11a] or general formula [1 lb].
• the reaction with -trochlorochloroformate etc. can be carried out in a suitable solvent in the presence of a base.
• a strong base an organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylamine, dimethylaminopyridine, etc.) can be preferably used.
• This reaction suitably proceeds at 40 to 40 ° C, particularly 20 ° C to room temperature.
• the solvent may be any solvent that does not adversely affect the reaction.
• Tan, xylene or a mixed solvent thereof can be used as appropriate, and in particular, methylene chloride can be preferably used.
• This reaction suitably proceeds at room temperature to 120 ° C, particularly 70 to 100 ° C.
• any solvent that does not adversely affect the reaction may be used. Rum, ⁇ , ⁇ -dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, 1,2-dimethoxyethane, xylene or a mixed solvent thereof should be used as appropriate. You can.
• raw material compounds can be produced in the same manner as the known methods and the methods described in Z or Reference Examples below.
• the target compound [I] produced by the above production method may further include the method described in the Examples below, Z, or a known method.
• the structure can be converted into another target compound [I] by a combination thereof.
• the compound [I] of the present invention or its starting material compound produced as described above is isolated and purified as it is or as a salt thereof.
• the salt can be produced by subjecting it to a commonly used salt formation treatment. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.
• Table Al, Table A2, Table B, Table CD, Table EF, Table X, Table Y, and Reference Examples at the end show chemical structural formulas and physical property values of the compounds of Examples and Reference Examples.
• MS 'APCI represents a mass analysis value (atmospheric pressure chemical ionization mass spectrum).
• CaSR is a member of the G protein-coupled receptor (GPCR).
• GPCR G protein-coupled receptor
• PLC phospholipase C
• Gq G protein
• a cDNA fragment encoding human CaSR was obtained from a cDNA library derived from human kidney by PCR.
• cDNA fragments were appropriately connected to an expression vector to obtain a plasmid for expressing functional human CaSR in animal cells.
• this human CaSR expression plasmid contains neomycin (G418) after transfection into CHO cells together with Ga 16 expression plasmid (plasmid for expressing ⁇ -subunit (a 16) of G protein). To obtain a stable expression cell line.
• the resulting cell line stably expressed human CaSR and the ⁇ 16 subunit of the G protein.
• the change in intracellular calcium concentration when stimulated in the presence or absence of the test compound was measured as follows.
• the cells are collected with a cell scraper, and then added to Hepes buffer (10 mM Hepes (7.3), 10 mM glucose, 140 mM NaCl, 5 mM KC1, 2 mM CaCl, ImM MgCl) with 0.1% cremophor and 3 ⁇ m.
• Hepes buffer 10 mM Hepes (7.3), 10 mM glucose, 140 mM NaCl, 5 mM KC1, 2 mM CaCl, ImM MgCl
• the suspension was suspended in a solution to which M Fura-2 had been added, and reacted at 37 ° C for 1 hour under the conditions in which various concentrations of the test compound were added (or without the addition).
• the cells suspended in Hepes buffer are seeded on a plate (number of cells about 2 X 10 ° per well in a 96-well plate), and FDSS (Functional Drug Screening Sysytem; Hamamatsu Photonitas) is used. Then, by detecting the fluorescence intensity (Ratio of 340/380 nm), changes in intracellular force concentration were measured.
• concentration anti-J curve concentration / response curves, EC50 value, concentration of agony giving a half maximal response
• the treated product was passed through a cell strainer, and after removing the residue, the cells were collected. This was washed twice with ITS-containing DMEM / F-12 medium (low Ca) containing 5% FCS and suspended in the same medium. Parathyroid cells in the cell suspension were prepared to a cell density of about 5xl04 4 cells Zml. Seed this in a 96-well plate (200 lZwell), about 37 ° C in a CO incubator
• the ITS-containing DMEM / F-12 medium (low Ca) used above was prepared as follows. Ca-free DMEM (Dulbecco's modified Eagle's medium) (Gibco, catalog No. 21068-028) 500 ml and F-12 (F-12 nutrient mixture; G3 ⁇ 4co, catalog No. 11765-054) 500 ml, ITS (Insulin 5 ⁇ g / ml, transferrin 5 ⁇ g / ml, and selenium 5 ng / ml included? _? Kneading liquor (lTS + Premix; BD Biosciences, Catalog No. 35435) 10 ml was mixed with this. HEPES ( NACALAI TESQUE, catalog No.
• Rat parathyroid cells were pre-cultured as described in (1) above, the medium was changed, and cultured in a medium supplemented with the test compound and CaCl for 22 to 24 hours (96-well plate, 200 ⁇ 1 / well
• the cells were collected and removed by centrifugation, and then stored at -80 ° C.
• PTH (1-84) in the culture supernatant was measured by ELISA to obtain a PTH production value.
• the measurement of H (1-84) was carried out using a measurement kit (Rat Intact PTH ELISA kit; Immutopics, catalog No. 60-2500).
• PTH production value From the measured value (PTH production value), the PTH production inhibition rate of the test compound was calculated.
• PTH production inhibition rate of the test compound was calculated.
• PTH during culture in 1.15 mM CaCl-containing medium (no test compound added) is used.
• the production value (A) is the maximum production value, and it is cultured in a 2.15 mM CaCl-containing medium (no test compound added)
• the PTH production value (B) at the time was set as the minimum production, and the inhibition rate was calculated from the following formula.
• PTH production inhibition rate (%) ⁇ (A)-(1.15 mM CaCl and various concentrations of test compound
• the inhibition rate is 0%, and if it is the same as the minimum production level, the inhibition rate is 100%.
• IC values were determined from the inhibition rate of PTH production in the presence of various concentrations of test compounds.
• IC values are calculated using concentration response curve plotting software (Graphpad PRISM 3.0; Graphpad S
• a rat adenine model was used as an animal model of hyperparathyroidism, and its effect on blood PTH levels (blood PTH lowering effect) was examined by the following in vivo tests.
• the diet is a normal diet (CRF1) force adenine diet (0.75% adenine-containing high phosphorus low calcium diet (CaO. 5%, Pil. 2%); 2 weeks later, blood (250 1) was collected from each individual under ether anesthesia as heparinized blood from the jugular vein. The test was performed using a G (0.50 ⁇ 25 mm) needle, and the blood was compressed and stopped after blood collection. The collected blood was centrifuged at 120 OOrpm for 3 minutes, and the supernatant was collected as a plasma sample.
• PTH (PTH (1-84)) in the collected plasma was measured by ELISA.
• test substance On the next day, prior to administration of the test compound, the test substance was orally administered after pre-collecting blood (400 ⁇ l). After 1, 4 and 24 hours after administration, 400 1 blood was collected, and the plasma obtained by centrifugation was stored at -80 ° C (or -20 ° C).
• Plasma PTH was measured for stored samples.
• the rat 5Z6 nephrectomy model was used as an animal model of hyperparathyroidism, and the effect on blood PTH level (blood PTH lowering effect) was investigated by the following in vivo tests.
• test compound was orally administered once a day for 2 weeks, and blood was collected twice a week before administration of the test compound.
• PTH, Ca, P and BUN concentrations were measured on each collected blood sample.
• these compounds were subjected to an in vivo test using a rat adenine model in the same manner as in Experimental Example 4, and as a result, these compounds were compared with a control group to which the test compound was not administered in oral administration. It showed an effect of lowering medium PTH level.
• Example 1.001 By treating in the same manner as in Example 1.001, the compounds shown in Table Al below and Examples 1.002 to 1.081 were obtained.
• Example 1.082 By treating in the same manner as in Example 1.082, the compound shown in Table Al below and Example 1.083 was used. Got.
• Example 1.020 4-[(S) 3 [(R) -l- (naphthalene-1-yl) ethylamino] pyrrolidine 1-yl] benzoic acid tert butyl ester (see below) A2, the compound of Example 1.020) was obtained.
• Example 3.018 (1) In the same manner as in Example 2.016, 1 [(3) — (6-Chloropyrimidine-4-yl) pyridine lysine 3-yl]-(R) -1— (Naphthalene-1-yl ) Ethylamine (free form of the compound of Example 2.012 shown in Table below) was obtained.
• Example 5.001 By treating in the same manner as in Example 5.001, the compounds shown in Table C below and Examples 5.002 to 5.016 were obtained.
• Example 6.002 The compound of the postscript Table C and Example 6.002 was obtained by processing like the said Example 6.001.
• Example 1.082 By treating in the same manner as in Example 1.082, the compounds of Table X below and Examples 10.001 to 10.007 were obtained.
• Example 3.001 4 [(S) -3 [(R) — 1 (Naphthalene 1 yl) ethynoleamino] pyrrolidine 1 — yl] benzoic acid hydrochloride 150 mg, (1) —alanine methyl ester Add 1 [3 (dimethylaminopropyl)] 3 ethylcarbodiimide hydrochloride 163 mg, 1-hydroxybenzotriazole 115 mg, triethylamine 125 1 to 58 ml of DMF in 5 ml of DMF, and stir the reaction at room temperature for 1 day did. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and then separated.
• (R) 3 [black carbocyclic [(R) -1- (naphthalene-1-yl) ethyl] amino] pyrrolidine-1 carboxylic acid tert-butyl ester 15.58 g

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