JP2003012616A - Calcium receptor antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound having a calcium receptor antagonism and a medicinal composition including the same, a calcium receptor antagonist and a remedy for therapy of diseases accompanying disorder of calcium homeostasis (osteoporosis, hypoparathyroidism, osteogenic sarcoma or the like). SOLUTION: This remedy is a compound expressed by formula (I) [R<1> is a (substituted) aryl group or the like; R<2> is a 1-6C (substituted) alkyl group or the like; R<3> is a 1-6C alkyl group or the like; R<4> is a 1-6C alkyl group or the like; R<5> and R<6> are each a 1-6C alkyl group or the like; R<7> is a (substituted) aryl group or the like; X<1> -X<3> are each a 1-6C alkylene group or the like; X<4> and X<5> are each a single bond or a methylene group or the like.], its salt or its solvate or its prodrug or the medicinal composition including the same, especially the calcium receptor antagonist and the remedy for osteoporosis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a compound having a calcium-sensing receptor (CaSR, hereinafter simply referred to as calcium receptor) antagonistic activity, and a pharmaceutical composition containing the compound, particularly The present invention relates to calcium receptor antagonists and therapeutic agents for osteoporosis, and intermediate compounds useful for synthesizing these compounds.

[0002]

2. Description of the Related Art Calcium receptors sense extracellular Ca ²⁺ concentration and increase intracellular Ca ²⁺ , thereby C
It functions to suppress the production of parathyroid hormone (PTH) related to the regulation of a ²⁺ metabolism and bone metabolism.

Serum calcium levels in normal mammals are
It is strictly maintained at about 9 to 10 mg / 100 ml (about 2.5 mM), which is called living body calcium homeostasis. When this value drops below 50%, it causes tetany, and conversely 50%.
A rise in% causes clouding of consciousness, which in any case is life threatening. The maintenance of this calcium homeostasis, as uptake organ duodenum Ca ^2+, as storage organs bone Ca ^2+, also kidney plays a role respectively as excretory organs of Ca ^2+. Furthermore, such regulation of Ca ²⁺ kinetics is performed by various hormones collectively referred to as “calcium-regulating hormone”. Representative hormones include active vitamin D [1α, 25 (OH) ₂ D ₃ ], P
TH, calcitonin, parathyroid hormone-related protein (Para
thyroid Hormone-Related Protein: PTH-related Pr
otein: PTHrP) and the like.

[0004] Bone not only plays a role as a supporting tissue of a living body and a moving organ, but also its constituent component, Ca ^2+.
Plays an important role as a storage organ. In order to perform such a function, bone tissue repeats its formation (bone formation) and resorption (bone resorption) for a lifetime. Osteogenic cells derived from mesenchymal cells play a major role in bone formation, and osteoclasts derived from hematopoietic cells play a major role in bone resorption. Osteogenesis is a mechanism that undergoes osteoid formation by osteogenic substances (bone matrix proteins such as type I collagen) produced by osteoblasts present on the osteogenic surface and subsequent calcification. On the other hand, in bone resorption, osteoclasts attach to the bone surface and Ca is intracellularized through acid secretion and ion transport.
²⁺ absorbs, by the absorbed Ca ²⁺ to discharge the bone marrow side, a mechanism for feeding the Ca ²⁺ in the blood. Bone defects absorbed by osteoclasts are repaired by osteoblastic bone formation. Such a series of phenomena is called bone remodeling. By the remodeling, old bone is replaced with new bone, the strength of the whole bone is maintained, and calcium homeostasis is maintained.

PTH is a hormone that plays a central role in maintaining calcium homeostasis. Blood Ca ²⁺
When the concentration decreases, the secretion of PTH from the parathyroid gland is immediately promoted, and it acts on osteoblasts in the bone (osteoblasts activate osteoclasts, produce bone organic degrading enzymes, etc.).
It promotes osteoclastic bone resorption and mobilizes Ca ²⁺ from the bone into the blood. In the kidney, PTH promotes Ca ²⁺ reabsorption in the distal tubule and in the proximal tubule.
25 (OH) vitamin D ₃ was activated, active vitamin D ₃ [l [alpha] having a function of promoting Ca ²⁺ absorption from the intestinal tract, 25
(OH) ₂ D ₃ ]. It also suppresses phosphorus reabsorption. As described above, PTH directly or indirectly causes blood Ca
It has the function of increasing the ²⁺ concentration.

On the other hand, when the blood Ca ²⁺ concentration rises, the calcium receptor senses it and immediately suppresses the secretion of PTH from the parathyroid gland, thereby decreasing the amount of Ca ²⁺ supplied to the blood. [Brown, EM, Homeostatic mechanisms regul
ating extracellular and intracellular calcium meta
bolism, in the parathyroids, p.19, (1994), Ravenpr
ess, New York]. Secretion of PTH is also suppressed by active vitamin D [1α, 25 (OH) ₂ D ₃ ].

Since PTH is a hormone that plays an important role in the regulation of Ca ²⁺ metabolism and the regulation of bone metabolism, attempts to apply it to the treatment of osteoporosis have been investigated. Tam in 1982
Et al. In bovine PTH (1-8) in thyroid / parathyroidectomized rats.
When 4) is continuously administered, both osteogenesis and bone resorption of the cancellous bone of the femur are increased and the net bone mass is decreased, but intermittent subcutaneous administration does not show the increase of bone resorption and only bone formation is increased.
We found that bone mass increased [Endocrinology, 110 , 5
06-512 (1982)]. Furthermore, Uzawa et al. Compared the effects of continuous administration and intermittent administration of PTH in the cancellous bones of young rat long bones and metaphysis. As a result, the continuous administration of PTH markedly increased the bone mass while observing abnormal findings such as thickening of the epiphyseal cartilage and fibrous osteomyelitis in the metaphyseal cancellous bone, which is greatly affected by endochondral ossification. Bone resorption was significantly enhanced in cancellous bone of the epiphysis, which had little effect, and bone mass was decreased with cortical bone coarsening [Bone, 16 , 477-484].
(1995)]. In addition, when PTH was intermittently administered, bone mass and trabecular width were significantly increased in both the epiphysis and metaphyseal cancellous bone without an increase in osteoclasts and a decrease in cortical bone. A report to that effect has also been made.

Furthermore, Scutt et al. Reported that, in chicken calvaria-derived osteoblasts, short-term (10 to 20 minutes) treatment of PTH promoted cell proliferation as compared to long-term (18 hours) treatment. [Calcif. Tissue Int., 55 , 208-21
5 (1994)]. Even from this, some of the effects of PTH on osteoblasts are transient, and the effect that these effects are expressed in an extremely short period of time is
It may be related to the difference in the action on bone tissue between continuous administration and intermittent administration of PTH in vivo.

In addition, Ishizuya et al. Investigated the effect of PTH on the differentiation of osteoblasts using an in vitro experimental system, and found that the effect of PTH was different depending on the treatment time. There is. When PTH was continuously applied to cultured rat calvaria-derived osteoblasts, they strongly suppressed osteoblast differentiation and almost completely suppressed in vitro osteogenesis, but for 48 hours. It has been reported that when PTH is allowed to act for the first 6 hours with 1 cycle as a cycle, osteoblast differentiation is significantly promoted and in vitro bone formation is promoted.

Further, it is considered that PTH not only prevents the bone loss in the osteoporosis model, but also has the bone mass restoring effect on the animals in which the bone loss has already been remarkable. Wronski et al. Intermittently administered human PTH (1-34) from the 4th week after the ovariectomy to the 15th week using 90-day-old SD rats in which the cancellous bone was obviously reduced 4 weeks after the ovariectomy. As a result, increased bone formation and suppressed bone resorption were observed from the 5th to 10th week after the start of administration, and it was shown that the bone mass was increased to about twice that of the sham operation group [Endocrinolo.
gy, 132 , 823-831 (1993)]. In addition, they report that in this experiment, estrogen and bisphosphonate prevented ovariectomized bone loss, but no increase in bone mass like PTH was observed. In addition, they analyzed the cortical bone of this experimental system in detail and found that PTH (1-34) intermittent administration showed osteogenesis promotion and increased bone mass on the periosteal and endosteal sides. It was also clarified that the increase in cancellous bone caused by erythrocyte was not accompanied by the decrease in cortical bone.
e, 15 , 51-58 (1994)].

[0011] Furthermore, Mosekilde et al.
-34) or human PTH (1-84) intermittently administered to the cancellous bone of rat vertebral body [Endocrinology, 129 , 421-4
28 (1991)] and cortical bone [J. Bone Miner. Res., 8 , 1097-11
01 (1993)] reported that not only the increase in bone mass but also the compressive strength and bending strength, which are indicators of bone quality, increased in a dose-dependent manner. As described above, PTH has a clear effect of increasing bone mass in experimental animals, but various studies have also been conducted on restrictive conditions that are expected in actual clinical application. Mizoguchi is a blood PT that is thought to be one of the causes of osteoporosis.
We examined whether or not the pharmacological effect of intermittent PTH administration was observed even when H was significantly elevated, and confirmed that an increase in bone mass occurs as usual [Nippon Bone Morphology, Vol. 5, 33-.
39 (1995)]. In addition, Takao et al. Investigated the administration interval of PTH, and in normal rats for 12 weeks,
It was reported that even once-a-week administration increases bone resorption with little increase in bone resorption, and increases bone mass in a dose-dependent manner [Nippon Bone Metabolism, Vol. 12 (Suppl.), S343 (1994)] It was suggested that the low-frequency administration, which is useful for clinical purposes, may be effective. The above results suggest that PTH may be a powerful and promising therapeutic drug for treatment of postmenopausal osteoporosis or post-ovariectomy osteoporosis, which can reduce the fracture rate as the bone mass increases.

From these results, it is clear that intermittent administration of PTH may be able to treat osteoporosis. However, in the case of PTH, injection has to be adopted as an administration means, and there is a problem that it is painful for many patients. On the other hand, the orally administrable drug capable of intermittently increasing the blood PTH concentration is the above-mentioned P
It is highly expected as a therapeutic drug for osteoporosis with a new mechanism of action different from TH and conventional calcitonin.

By the way, the calcium receptor is a G protein-coupled receptor which has been cloned as a molecule essential for the regulation of PTH secretion and which penetrates the cell membrane seven times. The human calcium receptor consists of 1078 amino acids and shows 93% amino acid homology with the bovine calcium receptor.
The human calcium receptor is composed of a large N-terminal extracellular region consisting of 612 amino acids, a transmembrane region consisting of 250 amino acids, and a C-terminal intracellular region consisting of 216 amino acids.

In addition to parathyroid gland, calcium receptor is expressed in kidney, thyroid C cells, brain and the like, and expression in bone marrow cells has been confirmed.

When the calcium receptor binds to a ligand such as Ca ²⁺ , it activates phospholipase C by coupling with G protein, resulting in the production of inositol triphosphate and the increase of intracellular Ca ²⁺ concentration. Secretion of PTH is suppressed [Nature, 366 , 575-580 (1993)].

As described above, a drug that inhibits the activation of calcium receptors, that is, a drug that antagonizes calcium receptors, releases the suppression of PTH secretion in parathyroid cells,
Promotes H secretion. Further, if the antagonistic action at this time is capable of non-sustainably and intermittently increasing the blood concentration of PTH, the antagonist can be expected to have the same effect as the intermittent administration of PTH, and the treatment of osteoporosis. It is considered that an extremely effective drug can be obtained.

As a CaSR antagonist, International Publication WO9
The compound represented by the following general formula is described in the specification of 9/51569.

[Chemical 8] [[Wherein Y₁Is a covalent bond, unsubstituted or C_1-4In alkyl
Substituted alkylene or alkeny having 4 or more carbon atoms
Len or O; Y₂Is unsubstituted or C_1-4Alkyl or
Is methylene substituted with haloalkyl; Y₃Is
Bonded or O, S, N-R^IVOr C_1-4Alkylene-O,
C_1-4Alkylene-S, C_1-4Alkylene-N-R^IVAnd
R; R₃And R_FourAre independently methyl or ethyl, or together
To form cyclopropyl; R_FiveIs aryl or
Fused aryl, dihydro or tetrahydro fused aryl
And these are unsubstituted or OH, halogen, C_1-4A
Rukiru, C_1-4Alkoxy, C _3-6Cycloalkyl, OS
O₂R^IV, CN, NO₂, OCF₃, CF₃, CH₂CF₃,
(CH₂)_nCO₂R^IV, And O- (CH₂)_nCO₂R^IVEmpty
Substituted with any substituent selected from the group
Where n is an integer from 0 to 3 and R^IVIs H, C _1-4Al
Kill and C_3-6Selected from the group consisting of cycloalkyl
R; or R_FiveIs heteroaryl or fused heteroaryl
Wherein the heterocycle includes N, O, S, and is aromatic
Group, dihydro, tetrahydro, unsubstituted or OH, OCH
₃, CH (CH₃)₂, Halogen, C_1-4Alkyl, C_1-4A
Lucoxy, C_3-6Cycloalkyl, OSO₂R^IV, CN,
NO₂, OCF₃, CF₃, CH₂CF₃, (CH₂)_nCO
₂H, (CH₂)_nCO₂R^IV, And O- (CH₂)_nCO₂R^IVOr
Substituted with any substituent selected from the group consisting of:
G is a covalent bond, CHR₆Or C-R₆And where R₆Is
H, OH or O (forming a ketone); R₇Is H, O
H or O-C_1-4Alkyl; R₈Is H or C_1-4A
Rukiru; or R₇And R₈Together form a ketone
A and B are independently a bond, CH₂, NH, O, S
And C = O, provided that A or B
This is CH₂And NH; or A and B are
Taken together are a bond; or CH = CH at the AB site
Or represents C≡C; X₁And X_FiveAre independently H, halogen,
CN, NO₂, C_1-4Alkyl, cycloalkyl, CH₂-
Aryl and CH₂-Selected from the group consisting of heteroaryl
Selected; however X₁Or X_FiveIs H; X₂,
X₃And X_FourIs H, halogen, OC_1-4Alkyl, O-a
Reel, O-heteroaryl, CH₂-Aryl, CH₂-
Heteroaryl, alkyl, C (O) aryl, C (O)
Teloaryl CH (OH) aryl, CH (OH) heteroa
Selected from the group consisting of reels and JK; J is a shared bond
, Alkylene having 5 or more carbon atoms, O-alkylene or
Is alkenylene, these are unsubstituted or C_1-4Alkyl,
OH, O (forming ketone), aryl, heteroaryl
And a substituent selected from the group consisting of NR'R "
Substituted, and R'and R "are independently H, alkyl, a
Reel, heteroaryl, C (O) alkyl, C (O) ant
And C (O) heteroaryl.
K; CO₂R^IV, OH, and CN
Is selected. ] And pharmaceutically acceptable thereof
Salts and their complexes. ]

In particular, the general formula in which Y ₃ is C _1-4 alkylene-O

[Chemical 9] Although the compound represented by is not described directly, it is suggested. However, in this case, “C _1-4 alkylene” means a straight chain, and the branching as in the present invention is neither described nor suggested.

International Publication WO99 / 51241 also describes a compound represented by the following general formula as a CaSR antagonist.

[Chemical 10] [[Wherein Y₁Is a covalent bond, unsubstituted or C_1-4Alkyl or
Is an alkylene or ar having 4 or more carbon atoms substituted with O.
Lukenylene; Y₂Is unsubstituted or C_1-4Alkyl young
Is methylene substituted with haloalkyl; Y₃Is
Covalent bond or O, S, N-R^IV, C_1-4Alkylene-O,
C_1-4Alkylene-S, and C_1-4Alkylene-N-R^IVOr
Selected from the group consisting of; R^IVIs H, C_1-4Alkyl, and
And C_3-6Selected from the group consisting of cycloalkyl; R₃Over
And R_FourIndependently, methyl or ethyl, or together
Forms cyclopropyl; R_FiveIs heteroaryl or condensed
Are heteroaryl; wherein the heterocycle is N, O,
Containing S, aromatic, dihydro, tetrahydro, unsubstituted or
Is OH, OCH₃, CH (CH₃)₂, Halogen, C_1-4Al
Kill, C_1-4Alkoxy, C_3-6Cycloalkyl, OSO
₂R^IV, CN, NO₂, OCF₃, CF₃, CH₂CF₃,
(CH₂)_nCO ₂H, (CH₂)_nCO₂R^IV, And O- (CH₂)
_nCO₂R^IVAny substituent selected from the group consisting of
Is substituted with; n is an integer from 0 to 3; G is a covalent bond
CHR₆Or C-R₆And where R₆Is H, OH or
Is O (forming a ketone); R₇Is H, OH, or O-
C_1-4Alkyl; R₈Is H or C_1-4In alkyl
R; or R₇And R₈Together form a ketone; A and
And B are independently a bond, CH₂, NH, O, S and C = O
Selected from the group consisting of, where either A or B is C
H₂And NH; or A and B together
Is a bond; or CH═CH or C≡C at the AB position
X is selected from the following sub-formulas (Ia) to (Ie):

[Chemical 11] Where W is R₁, SO₂R₁, C (O) R₁, SO₂NR₁R
₁’、 C (O) NR₁R₁’、 C (O) OR₁, And SO₃R₁’
Selected from the group consisting of, where R₁And R₁’Is independent
Hydrogen, C_1-4Alkyl, C_3-6Cycloalkyl, C_2-5A
Lucenil, C_2-5Alkynyl, heterocycloalkyl,
Aryl and aryl C_1-4Selected from the group consisting of alkyl
Selected; or R₁And R₁’Join together and have 3 to 7 members
Form a heterocyclic ring which may be replaced;
The substituents are CN, aryl, CO₂R, CO₂NHR, OH,
OR, NH₂, Halo, CF₃, OCF₃And NO₂Consists of
Selected from any of the groups; R is C_1-4Alkyl, or
C_3-6Represents cycloalkyl; X₁Is CN, NO₂, C
l, F, Br, I, H, R ', OR', CF₃, OCF₃
And OSO₂Selected from the group consisting of R'where R '
Is C_1-4Alkyl or C_{3- 6}Represents cycloalkyl; X
₂, X₃And X_FourIndependently, CN, NO₂, Cl, F, B
r, I, H, R ", OR", CF₃, OCF₃And OSO
₂Selected from the group consisting of R ", where X₁Or X₃Throat
Raka is H, where R ″ is C_1-4Alkyl or halo
Alkyl; or X₁And X₂Together together Aryl
Or forming a heteroaryl ring, which may be substituted or unsubstituted
Wherein the heteroatoms are selected from N, S and O; and
And the substituents are halo and C_1-4Alkyl, OCF₃, CF₃, O
Me, CN, OSO₂R'and NO₂Select from the group consisting of
Yes; or X₃And X_FourAre independently C (O) R₁Represents; and
R₂Is hydrogen, C_1-4Alkyl, C_3-6Cycloalkyl, C
_2-5Alkenyl, C_2-5Alkynyl, heterocycloalkyn
Le, aryl and aryl C_1-4A group of alkyl
Selected; X₁"Is CN, NO₂, Cl, F, Br,
I, H, R, OR, CF₃, OCF₃And OSO₂From R
Is selected from the group consisting of_1-4Alkyl, or
C_3-6Represents cycloalkyl; X₂", X₃"And X_Four"Is
Independently CN, NO₂, Cl, F, Br, I, H,
R ', OR', CF₃, OCF₃And OSO₂From R ’
Selected from the group₁"Or X₃"Either is H
Where R'is C_1-4Alkyl or haloalkyl
Or X₁"And X₂Together with Aryl or
Forming a heteroaryl ring, which may be substituted or unsubstituted;
Where the heteroatoms are selected from N, S and O, and are substituted
Group is halo, C_1-4Alkyl, OCF₃, CF₃, OMe,
CN, OSO₂-C_{1 -Four}Alkyl, OSO₂-C_3-6Cycloa
Rukiru and NO₂Or is selected from the group consisting of:₃"And
And X_Four"Is independently C (O) R₁Represents; and R₁"And R₂”
Independently, hydrogen, C_1-4Alkyl, C_3-6Cycloalk
Le, C_2-5Alkenyl, C_2-5Alkynyl, heterocyclo
Selected from the group consisting of alkyl and aryl; or R
₁"And R₂"Although they are replaced together by 3 to 7 members
Form a good heterocyclic ring; the substituent is C
N, aryl, CO₂R ", CO₂NHR ", OH, O
R ", NH₂, Halo, CF₃, OCF₃And NO₂Consists of
Selected from any of the groups; where R ″ is C_1-4Archi
Or C_3-6Represents cycloalkyl; X₁"'Is CN,
NO₂, Cl, F, Br, I, H, R, OR, CF₃, O
CF₃And OSO₂Selected from the group consisting of R, where R
Is C_1-4Alkyl or C_3-6Represents cycloalkyl; X
₂"', X₃"" And X_Four“” Is independent, CN, NO₂, C
l, F, Br, I, H, R ', OR', CF₃, OCF₃
And OSO₂Selected from the group consisting of R'where X₁”’
Or X₃"" Is either H, where R'is C_1-4
Alkyl or haloalkyl; or X₁"'When
X₂"" Together form an aryl or heteroaryl ring
And are substituted or unsubstituted; wherein the heteroatom is
Selected from N, S and O, and the substituents are halo, C_1-4
Alkyl, OCF₃, CF₃, OMe, CN, OSO₂-C
_1-4Alkyl, OSO₂-C_3-6Cycloalkyl and NO₂
Or is selected from the group consisting of:₃"" And X_Four”’ Is German
Vertically C (O) R₁Represents; R₁"" And R₂"Is' independent,
Hydrogen, C_1-4Alkyl, C_3-6Cycloalkyl, C _2-5A
Lucenil, C_2-5Alkynyl, heterocycloalkyl and
Selected from the group consisting of₁"'as well as
R₂"" May together be substituted by 3 to 7 members
Form a heterocyclic ring; the substituents are CN,
Reel, CO₂R ", CO₂NHR ", OH, OR", N
H₂, Halo, CF₃, OCF₃And NO₂Selected from the group consisting of
Selected; where R "is C_1-4Alkyl or C_3-6Cyclo
Represents alkyl; D is H, CN, NO₂, Cl, F, B
r, I, R, OR, SR, CF₃, OCF₃And OSO₂
Selected from the group consisting of R, where R is C_1-4Archi
Le, C_3-6Cycloalkyl, or C_1-10Aryl or F
Represents teloaryl, the heteroatoms of which are N, S and O
Selected from the group consisting of halo and C_1-4Alkyl, OCF₃,
CF₃, OMe, CN, OSO₂-C_1-4Alkyl, OSO
₂-C_3-6Cycloalkyl and NO ₂Selected from the group consisting of
N is an integer of 1 or 2; each E is independently C or N
With the proviso that two or more E sites are not N;
Furthermore, when n is 2, each E is C; a and b are bonds
May be represented; R₁ ^IVIs (CH₂)_nCO₂R ', (CH₂)_n
CO₂H, (CH₂)_nCONR ’₂, (CH₂)_nCH₂O
R ', OR', SR ', CN, NO₂, Cl, F, B
R, I, H, CF₃, OCF₃, OSO₂R ', R'and
Selected from the group consisting of H, where R'is C _1-4Archi
Or C_3-6Cycloalkyl; or R₁ ^IVKeto
O that forms a ring, that is, YR₁ ^IVRepresents -C = O;
R₂ ^IVIs hydrogen, CN, NO₂, Cl, F, Br, I, H,
R ", OR", CF₃, OCF₃, And OSO₂From R ”
Is selected from the group consisting of_1-4Alkyl, or
Is C_3-6It is cycloalkyl. Y is C, CH, O, N
And S; but when Y is S, R₁ ^IVIs O or
Not represented; but when Y is O, R₁ ^IVIs expressed
No; X'is CH₂, NH, O and S. R₉Is O-a
Rukiru, O-CH₂-Aryl and O-aryl;
X₁"" Is CN, NO₂, Cl, F, Br, I, H, R,
OR, CF₃, OCF₃And OSO₂Selected from the group consisting of R
Where R is C_1-4Alkyl or C_3-6Cycloa
Represents Rukiru; X₂"", X₃"" And X_Four"" Is independent
, CN, NO₂, Cl, F, Br, I, H, R ', O
R ', CF₃, OCF₃And OSO₂From the group consisting of R '
Selected, but X ""₁Or X ""₃Is either H
Where R'is C_1-4Alkyl or haloalkyl
Or X₁"" And X₂"" Together with aryl or
Forming a heteroaryl ring, which may be substituted or unsubstituted;
Where the heteroatoms are selected from N, S and O, and are substituted
Group is halo, C_1-4Alkyl, OCF₃, CF₃, OMe,
CN, OSO₂-C_1-4Alkyl, OSO₂-C_3-6Cycloa
Rukiru and NO₂Or is selected from the group consisting of:₃""
And X_Four"" Is independently C (O) R₁Represents ] Is a compound
And pharmaceutically acceptable salts and complexes thereof. ]

Here again, the general formula in which Y ₃ is C _1-4 alkylene-O

[Chemical 12] Although the compound represented by is not described directly, it is suggested. However, in this case as well, "C _1-4 alkylene"
Means a straight chain, and the branching as in the present invention is neither described nor suggested.

In addition, International Publication WO98 / 45255 (European Application Publication 973730) also describes compounds represented by the following general formula as CaSR antagonists.

[Chemical 13] [In the formula, Y ₁ is an alkylene or alkenylene having 4 or more carbon atoms which is covalent bond, unsubstituted or substituted by C _1-4 alkyl; Y ₂ is unsubstituted or substituted by C _1-4 alkyl or CF ₃ Z is a covalent bond,
O, S, NH, N-C _1-4 alkyl, O (CH ₂ ) _n , (C
H ₂ ) _n O, NR "'C = O and C = ONR"', wherein R "'is C _1-4 alkyl,
And n are integers from 1 to 3, R ₃ and R ₄ are independently
Methyl or ethyl, or taken together to form cyclopropyl; R ₅ is phenyl or naphthyl, unsubstituted or OH, C _1-4 alkyl CH (CH ₃ ) ₂ , halo, halo C _1-4
Alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, O
SO ₂ R ^IV , CN, NO ₂ , OCF ₃ , CF ₃ and CH ₂ C
Substituted with one or more substituents selected from the group consisting of F ₃ , wherein R ^IV represents C _1-4 alkyl or C _3-6 cycloalkyl; G is a covalent bond or C—R ₆ And
Where R ₆ is H, OH or O (forms a carbonyl moiety)
R ₇ is H, OH, or O—C _1-4 alkyl; R ₈ is H or C _1-4 alkyl; or R ₇ and R ₈ together form a carbonyl moiety. The AB site is C
H ₂ CH ₂ , a covalent bond, —CH═CH— or —C≡C—; and X is a sub-formula (Ia), (Ib), (Ic), (Id) and
Selected from the group consisting of (Ie):

[Chemical 14] Here, for sub-expression (Ia): W is R₁, SO₂R₁, C
(O) R₁, SO₂NR₁R₁’、 C (O) NR₁R₁’、 C (O)
OR₁SO₃R₁’, Selected from the group consisting of₁
And R₁'Is independently hydrogen, C_1-4Alkyl, C_3-6Cyclo
Alkyl, C_2-5Alkenyl, C_2-5Alkynyl, hetero
Cycloalkyl aryl and aryl C_1-4Alkyl?
Selected from the group consisting of; or R₁And R₁Together
A 3 to 7 membered optionally substituted heterocyclic ring
Formed; its substituents are CN, aryl, CO₂R, CO₂
NHR, OH, OR, NH₂, Halo, CF₃, OCF₃Over
And NO₂Is selected from the group consisting of: R is C_1-4
Alkyl or C_3-6Represents cycloalkyl; X₁Is C
N, NO₂, Cl, F, Br, I, H, R ', OR',
CF₃, OCF₃And OSO₂Selected from the group consisting of R '
Where R'is C_1-4Alkyl or C_{3- 6}Cycloal
Represents a kill; X₂, X₃And X_FourIndependently, CN, NO₂,
Cl, F, Br, I, H, R ", OR", CF₃, OC
F₃And OSO₂Selected from the group consisting of R ", where
R "is C_{1 -Four}Alkyl or haloalkyl; or X₁
And X₂Together form an aryl or heteroaryl ring
Formed, substituted or unsubstituted; wherein the heteroatom is
Selected from N, S and O; and the substituents are halo, C_1-4
Alkyl, OCF₃, CF₃, OMe, CN, OSO
₂R'and NO₂Selected from any of the group consisting of;
Is X ₃And X_FourAre independently C (O) R₁Represents; however, haloal
When there are multiple substitutions of halo in a kill, halo represents F.
Shi; also X₁Or X₃Is hydrogen; and R₂Is
Hydrogen, C_1-4Alkyl, C_3-6Cycloalkyl, C_2-5A
Lucenil, C_2-5Alkynyl, heterocycloalkyl
Reel and aryl-C_1-4Select from the group consisting of alkyl
For sub formula (Ib): X₁"Is CN, NO₂, C
l, F, Br, I, H, R, OR, CF₃, OCF₃as well as
OSO₂Selected from the group consisting of R, where R is C_1-4A
Rukiru or C_3-6Represents cycloalkyl; X₂",
X₃"And X_Four"Is independent, CN, NO₂, Cl, F, B
r, I, H, R ', OR', CF₃, OCF₃And OSO
₂R'is selected from the group consisting of R'where R'is C_1-4Al
Kill or haloalkyl; with haloalkyl odor
And when there is multiple substitution of halo, halo represents F, or
X₁"And X₂"Together aryl or heteroaryl
Form a ring and are substituted or unsubstituted;
The child is selected from N, S and O, and the substituents are halo, C
_1-4Alkyl, OCF₃, CF₃, OMe, CN, OSO₂
-C_1-4Alkyl, OSO₂-C_3-6Cycloalkyl and N
O₂Or is selected from the group consisting of:₃"And X_Four"Is Germany
Vertically C (O) R₁Represents; however X₁"Or X₃Either
Is hydrogen; and R₁"And R₂"Is independently hydrogen, C
_1-4Alkyl, C_3-6Cycloalkyl, C_2-5Archeni
Le, C_2-5Alkynyl, heterocycloalkyl and ari
Selected from the group consisting of₁"And R₂"Is one
3-7 membered optionally substituted heterocycle
Forms a lick ring; hetero selected from O, S and N
Atoms may additionally be included; the substituents are CN, ar
CO,₂R ", CO₂NHR ", OH, OR", NH
₂, Halo, CF₃, OCF₃And NO₂Any of the group consisting of
Is selected; where R "is C_1-4Alkyl or C
_3-6Represents cycloalkyl; for sub-formula (Ic):
X₁"" Is CN, NO₂, Cl, F, Br, I, H, R,
OR, CF₃, OCF₃And OSO₂Selected from the group consisting of R
Where R is C_1-4Alkyl or C_3-6Cycloa
Represents Rukiru; X₂"', X₃"" And X_Four"'Is independent
, CN, NO₂, Cl, F, Br, I, H, R ', O
R ', CF₃, OCF₃And OSO₂From the group consisting of R '
Selected, where R'is C_1-4Alkyl or halo alk
Provided that there are multiple substitutions of halo in haloalkyl.
, Halo represents F; or X₁’’ And X₂"’ S together
To form an aryl or heteroaryl ring,
Or unsubstituted; where the heteroatoms are N, S and O
And the substituents are halo, C_1-4Alkyl, OC
F₃, CF₃, OMe, CN, OSO₂-C_1-4Alkyl,
OSO₂-C_3-6Cycloalkyl and NO₂From the group consisting of
Selected; or X₃"" And X_Four“” Is independently C (O) R₁
Represents; however X₁"" Or X₃Either "" is H
R; and R₁"" And R₂“Independently, hydrogen, C_1-4A
Rukiru, C_3-6Cycloalkyl, C _2-5Alkenyl, C
_2-5Alkynyl, heterocycloalkyl and aryl
Selected from the group consisting of; or R₁"" And R₂"'Is together
And may be substituted with 3 to 7 members, O, S and N
Het may optionally contain a heteroatom selected from
Forms a cyclic ring; the substituents are CN, aryl
Le, CO₂R ", CO₂NHR ", OH, OR", N
H₂, Halo, CF₃, OCF₃And NO₂Selected from the group consisting of
Selected; where R "is C_1-4Alkyl or C_3-6Cyclo
Represents alkyl; for sub-formula (Id): D is CN, NO
₂, Cl, F, Br, I, R, OR, SR, CF₃, OC
F₃And OSO₂Selected from the group consisting of R, where R is
C_1-4Alkyl, C_3-6Cycloalkyl, or C_1-10Ants
Or heteroaryl, the heteroatom of which is N,
Selected from S and O, the substituents are halo, C_1-4Archi
Le, OCF₃, CF₃, OMe, CN, OSO₂-C_1-4A
Rukiru, OSO₂-C_3-6Cycloalkyl and NO₂Empty
N is an integer of 1 or 2; each E is
Independently C or N, provided that two or more E sites are N
No further; however, when n is 2, each E is C;
a and b may represent a bond; R₁ ^IVIs (CH₂)_nCO₂
R ', (CH₂)_nCO₂H, (CH₂)_nCONR ’₂, (C
H₂)_nCH₂OR ', OR', SR ', CN, NO₂, C
l, F, Br, I, CF₃, OCF₃, OSO₂R ’,
R'and H are selected from the group consisting of; R'is C
_1-4Alkyl or C_3-6Cycloalkyl; or R
₁ ^IVIs O to form a ketone, ie YR₁ ^IVIs -C =
Represents O; R₂ ^IVIs hydrogen, CN, NO₂, Cl, F, B
r, I, H, R ", OR", CF₃, OCF₃, And OS
O₂Selected from the group consisting of R "; where R" is C_1-4A
Rukiru or C_3-6It is cycloalkyl. Y is C, C
Selected from H, O, N and S; provided that when Y is S, R₁
^IVIs O; and when Y is O, R₁ ^IVIs expressed
None; X'is CH₂, NH, O and S; and a bond
The site is the carbon atom marked 3; for sub-formula (Ie)
Te: X₁"" Is CN, NO₂, Cl, F, Br, I, H,
R ', OR', CF₃, OCF₃And OSO₂From R ’
R'is C_1-4Alkyl, or
C_3-6Represents cycloalkyl; X₂"", X₃""as well as
X_Four"" Is independent, CN, NO₂, Cl, F, Br, I,
H, R ", OR", CF₃, OCF₃And OSO₂R ”
Is selected from the group consisting of:_1-4Alkyl or
Is haloalkyl; or X₁"" And X₂"" Together
To form an aryl or heteroaryl ring which may be substituted or
Is unsubstituted; where the heteroatoms are N, S and O
And any substituents are halo, C_1-4Al
Kill, OCF₃, CF₃, OMe, CN, OSO₂R'and
And NO₂Or is selected from the group consisting of:₃""as well as
X_Four"" Is independently C (O) R₁Represents haloalkyl
And when there is multiple substitution of halo, halo represents F;
X₁"" Or X₃Either "" is hydrogen; and R₉
Is O-CH₂-Alkyl, O-CH₂-Aryl and O-Ali
It is ]

Further, Japanese Patent Publication No. 2001-501584 (International Publication WO97 / 37967, European Application Publication 901459, US Patent 602289)
No. 4) also describes a compound represented by the following general formula as a CaSR antagonist.

[Chemical 15] [Wherein R ₁ is aryl, long chain alk, and cyclo a
R ₂ is selected from the group consisting of lk; R ₂ is lower alk, cycloalk, alkoxy, H, OH, ═O, C (O) OH,
C (O) O-lower alk, C (O) NH-lower alk, C (O)
N (lower alk) ₂ , SH, S-lower alk, NH ₂ , NH-
Selected from the group consisting of lower alk and N (lower alk) ₂ ; R ₃ and R ₄ are each independently lower alk or, in combination, cyclopropyl; R ₅ is methyl, ethyl , Isopropyl, methoxy, Cl, F,
Optionally substituted naphthyl having 1 to 4 substituents independently selected from the group consisting of Br and lower haloalkoxy, or lower alkyl, methoxy, Cl, F, Br, and A substituted phenyl having 1 to 4 substituents having at least one substituent in the meta or para position, selected from the group consisting of lower haloalkoxy, provided that the substituted phenyl has 2 to 3 substituents. It may also have additional substituents; R ₆ , if present, is hydrogen, lower alkyl or lower alkenyl and R ₂ is
When O, R ₆ is absent; Y ₁ is a covalent bond, alkylene or alkenylene; Y ₂ is alkylene; Y ₃ is alkylene; and Z is a covalent bond,
Selected from the group consisting of O, S, NH, N-lower alk, alkylene, alkenylene, and alkynylene, provided that when Z is O, S, NH, or N-lower alkyl, Y ₁ is Not a covalent bond; further provided that Y ₁ and Z together may be a covalent bond; further provided that R ₁ is not 6-CN-2-pyridyl;
Further provided that when R ₅ is 3,4-dimethoxy-phenyl, R ₁ is CH 3 (CH 2) 5 O-phenyl; 2-cyclopentyl-phenyl; 2-Cl-phenyl; 2-CN-phenyl; 2- ( 3-furanyl) phenyl; or not 4- (1,2-benzisothiazole); further provided that when R ₅ is 4-methoxy-phenyl, R ₁ is 2-cyclopentyl-phenyl; 2-CH 3- Phenyl; 2-benzyl-phenyl; 3-CH3, 4-CH3SO2-phenyl; not 4- (1,2-benzisothiazole); provided that R ₁ is 4-Cl-phenyl, R ₁ is , 2-CH3-phenyl; 5-iso-propyl-phenyl; 2-CH3-phenyl; 4-
CH3-phenyl; phenyl; 2-Cl-phenyl; 4-Cl-phenyl; 2-methoxy; 4-CH3CHCH-phenyl; 3,4CH3-phenyl; 2,4CH3-phenyl; 2,3CH3-phenyl; 2-iso- Propyl; 5-CH3-phenyl; pyridyl; 1-imidazole; or not 4- (1,2-benzisothiazole); and further provided that R ₅ is 3,5-dimethyl, 4-methoxy-phenyl In case R ₁ is not 4-CH 3, 6-CN-2-pyridyl, or thiophenecarboxamide. ] And pharmaceutically acceptable salts and complexes thereof, which have an IC ₅₀ ≦ 10 μM in a calcium receptor inhibitor assay. ]

Further, Maxine Gowen et al., A compound called NPS-2143 having a CaSR antagonistic action.

[Chemical 16] Was orally administered to OVX rats, and its blood concentration and bone density were measured to examine the effect of the NPS-2143 on bone formation, and the results are reported [J. Cl.
in. Invest., 105, 1595-1604 (2000)].

According to it, NPS-2143 has PTH
Although it significantly promotes the release of broth, it has no direct effect on osteoblasts and osteoclasts in vitro,
As a result, there was neither bone loss nor bone increase. As one of the causes, it has been pointed out that NPS-2143 has a too long half-life in blood. That is, OV
When rat PTH (1-34) was administered to X rats at a dose of 5 μg / kg, the blood PTH concentration peaked at about 175 pg / ml after 30 minutes and returned to the original state after 2 hours. Against NPS-2143 100
When administered at a dose of μmol / kg, the PTH concentration in the blood continued to rise even after reaching a blood PTH concentration of approximately 115 pg / ml after 30 minutes, and the concentration was approximately 140 pg / ml even after 4 hours. [J. Clin. Inves
t., 105, 1595-1604 (2000), p. 1598, FIG. 3].

At this time, the blood concentration of NPS-2143 itself remained elevated to 100 ng / ml or more even after 8 hours from the administration, and became undetectable below 10 ng / ml after 24 hours. there were.

The above reference by Maxine Gowen et al. Is as if a calcium receptor antagonist with a blood half-life is too long.
The result is similar to that of continuous administration of TH,
It also shows that we cannot expect an increase in bone mass.

[0027]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound having a calcium receptor antagonistic action. The present invention also relates to diseases associated with abnormal calcium homeostasis containing the compound, namely osteoporosis, hypoparathyroidism, osteosarcoma, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget's disease. It is an object of the present invention to provide an orally administrable and intermittently administrable pharmaceutical composition, which is effective as a therapeutic agent for humoral hypercalcemia, autosomal dominant hypocalcemia, etc., especially as an osteoporosis therapeutic agent.
Another object of the present invention is to provide a synthetic intermediate for a compound having a calcium receptor antagonistic action.

[0028]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that a compound represented by the following general formula [I] has an excellent calcium receptor antagonistic action. In addition, the present invention has been completed by discovering that oral administration and intermittent administration are possible. All of the conventionally known calcium receptor antagonists continuously increase the blood PTH concentration, and therefore, a sufficient bone formation promoting action could not be expected. On the other hand, the compound represented by the following general formula is surprisingly capable of non-sustainably and intermittently increasing the blood PTH level, and is highly practically used as an excellent therapeutic drug for osteoporosis. It can be expected.

In the compound represented by the following general formula according to the present invention, the carbon atom adjacent to the oxygen atom has R ¹ and R ² as substituents.
Has, ie

[Chemical 17] It is characterized by having the structure of. As is clear from the test examples below,

[Chemical 18] The compound of the present invention having the structure of not only has an excellent calcium receptor antagonistic action,

[Chemical 19] PT, which is non-persistent and transient compared to the conventional compounds of the structure
It has an action of promoting H secretion. Therefore, it is considered that the administration of the compound of the present invention produces the same effect as the intermittent administration of PTH and is extremely effective for the treatment of osteoporosis.

The present invention is a compound represented by the following general formula:
The present invention relates to a calcium receptor antagonist containing the compound as an active ingredient, a therapeutic agent for osteoporosis, and an intermediate compound useful for synthesizing these compounds. More specifically, it is as shown in the following (1) to (18).

(1) General formula [I]

[Chemical 20] [In the formula, R¹Is an aryl group or a heteroaryl group
The reel group and the heteroaryl group are halogen atom, C_1-6
Alkyl group, halo C_1-6Alkyl group, hydroxy C _1-6A
Rukiru group, C_1-6Alkoxy C_1-6Alkyl group, hydroxyl group,
C_1-6Alkoxy group, halo C_1-6Alkoxy group, mercap
G group, C_1-6Alkylthio group, C_1-6Alkyl sulfani
Lu group, C_1-6Alkylsulfonyl group, aminosulfonyl
Base, C_1-6Alkylsulfamoyl group, di-C_1-6Alkyl
Sulfamoyl group, carboxy group, (C_1-6Arcoki
Si) Carbonyl group, C_1-7Acyl group, carbamoyl group,
(C_1-6Alkyl) carbamoyl group, di (C_1-6Archi
) Carbamoyl group, cyano group, nitro group, amino group,
C_1-6Alkylamino group, di-C_1-6Alkylamino group, C
_{1- 7}Acylamino group, C_1-3An alkylenedioxy group,

[Chemical 21] (Where R^AIs (C_1-6Alkoxy) carbonyl group or
Represents a carboxy group, R ^BIs a hydrogen atom or C_1-6Alkyl
Represents a group. Substituted with 1 to 3 substituents selected from
You may } Is represented; R²Is C_1-6Alkyl group (the C
_1-6Alkyl group is halogen atom, hydroxyl group, C_1-6Arcoki
Si group, carboxy group, amino group, C_1-6Alkylamino
Group, di-C_1-6Selected from alkylamino and oxo groups
It may be substituted with 1 to 3 substituents. ), C_3-7
Cycloalkyl group, C_2-6Alkenyl group, C_2-6Alkini
Group, aralkyl group, carboxy group, (C_1-6Arcoki
Si) represents a carbonyl group or a cyano group; R³Is hydrogen
Child, C_1-6Alkyl group, hydroxyl group, C_1-6Alkoxy group,
Lucapto group, C_1-6Alkylthio group, carboxy group,
(C_1-6Alkoxy) carbonyl group, (C_1-6Alkyl)
Carbamoyl group, di (C_1-6Alkyl) carbamoyl
Group, amino group, C_1-6Alkylamino group or di-C_1-6Al
Represents a kylamino group; R^FourIs a hydrogen atom, C_1-6Alkyl group
Or C_2-6Represents an alkenyl group or R³And R ^FourTogether
Represents an oxo group; R^Five, R⁶Are each C_1-6A
Represents an alkyl group or R^FiveAnd R⁶Together those
Represents a cyclopropyl group together with the carbon atom to which it is attached; R
⁷Is an aryl group or a heteroaryl group (the aryl group and
And heteroaryl groups are halogen atoms, C_1-6Alkyl
Group, halo C_1-6Alkyl group, hydroxy C_1-6Alkyl
Base, C_3-7Cycloalkyl group, hydroxyl group, C_1-6Alkoxy
Group, halo C_1-6Alkoxy group, carboxy group, (C_1-6A
Lucoxy) carbonyl group, nitro group, cyano group, C_1-6
Alkylsulfonyloxy group, carbamoyl group and C
_1-31 to 3 units selected from alkylenedioxy groups
It may be substituted with a substituent. } Is shown; X¹Is a single bond, C
_1-6Alkylene or C_2-6Alkynylene (the C_1-6Archi
Ren and C_2-6Alkynylene is C_1-6Alkyl group or oki
It may be substituted with a so-group. ); X²Is C_1-6Archi
Ren (the C_1-6Alkylene is C_1-6Alkyl group or halo C
_1-6It may be substituted with an alkyl group. ); X³Is simply
Bond or C_1-6Alkylene (the C_1-6Alkylene is a hydroxyl group
Alternatively, it may be substituted with an oxo group. ); X^Fouras well as
X^FiveTogether form a single bond, methylene, NH, oxygen source
Child, sulfur atom, C = O, -CH₂NH-, -CH₂O-,
-CH₂S-, -CH₂CO-, -NHCH₂-, -OC
H₂-, -SCH₂-, -COCH₂-, -CH = CH-
Alternatively, it represents -C≡C-. ] The compound shown by
Or a solvate thereof or a prodrug thereof.

(2) General formula [I-2]

[Chemical formula 22] Wherein, R ^11, R ¹² are the same or different and each is a hydrogen atom, a halogen atom, C _1-4 alkyl group, hydroxy C _1-6
An alkyl group, a C _1-6 alkoxy, a C _1-6 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a cyano group or a nitro group, or R ¹¹ and R ¹² together form a C _1-3 alkylenedi Represents an oxy group, R ²¹ represents a C _1-4 alkyl group (the alkyl group may be substituted with a C _1-4 alkoxy group),
_{Represents a} C _3-5 cycloalkyl group, a C _2-4 alkenyl group or an aralkyl group, and represents R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² ,
X ³ , X ⁴ and X ⁵ each have the same meaning as in claim 1. ] The compound shown by these, its salt, its solvate, or its prodrug.

(3) General formula [I-3]

[Chemical formula 23] (Here, R ⁷¹ and R ⁷² are the same or different and each independently represent a hydrogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group, or they are taken together to form —CH═CH—CH═CH— or C _1-3 represents an alkylenedioxy group, R ¹¹ ,
R ¹² and R ²¹ have the same meanings as in claim 2. )
Or a salt thereof, a solvate thereof, or a prodrug thereof.

(4) R ¹¹ and R ¹² are the same or different and each is a hydrogen atom, a chlorine atom, a methyl group, a hydroxymethyl group, a hydroxyl group, a methoxy group, a cyano group or a nitro group, or R ¹¹ and R 12 The compound according to (3) above, wherein ¹² together is a methylenedioxy group, and R ²¹ is an optionally branched C _1-4 alkyl group or C _3-5 cycloalkyl group, a salt thereof, or A solvate or a prodrug thereof.

(5) The compound, salt or solvate or prodrug thereof according to (4) above, wherein R ²¹ is a methyl group, an ethyl group, a cyclopropyl group or a cyclobutyl group.

(6) R ¹¹ is a hydrogen atom, R ¹² is a methyl group, a methoxy group or a hydroxymethyl group, or R ¹¹ and R ¹² together are a methylenedioxy group, and R ²¹ The compound according to (5) above, wherein is a methyl group or a cyclopropyl group, a salt thereof, a solvate thereof, or a prodrug thereof.

(7) The compound according to the above (6), wherein R ²¹ is a cyclopropyl group, a salt thereof, a solvate thereof, or a prodrug thereof.

(8) R ⁷¹ and R ⁷² are —CH═CH—CH
The compound according to (7) above, wherein ═CH—, a salt thereof, a solvate thereof, or a prodrug thereof.

(9) The above (7), wherein R ⁷¹ and R ⁷² are groups selected from a C _1-4 alkyl group and a C _1-4 alkoxy group.
The compound, salt or solvate thereof, or prodrug thereof according to 1.

(10) (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino]-
3-[(cyclopropyl) (2-methoxyphenyl) methoxypropan-2-ol, (2R) -1- [1,1
-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-methylphenyl) methoxypropan-2-ol, (2R) -1-
[1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (phenyl)
Methoxy] propan-2-ol, (2R) -1-
[1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) ethoxy] propan-2-ol, (2R) -1- [1,
1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methylphenyl) ethoxy]
Propan-2-ol, (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino]-
3- [1- (2-methoxyphenyl) propoxy] propan-2-ol, (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3-
[1- (2-cyanophenyl) ethoxy] propane-2
-Ol, (2R) -1- [1,1-dimethyl-2-
(Naphthalen-2-yl) ethylamino] -3- [1-
(3-Methoxyphenyl) ethoxy] propan-2-ol, (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (3-
Methylphenyl) ethoxy] propan-2-ol and (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-hydroxymethylphenyl ) A compound according to the above (1) selected from methoxypropan-2-ol, a salt thereof, a solvate thereof, or a prodrug thereof.

(11) A pharmaceutical composition comprising the compound according to any one of (1) to (10) above, a salt thereof, a solvate thereof or a prodrug thereof as an active ingredient.

(12) A calcium receptor antagonist comprising the compound according to any one of (1) to (10) above, a salt thereof, a solvate thereof or a prodrug thereof as an active ingredient.

(13) A therapeutic agent for osteoporosis, which comprises as an active ingredient the compound, the salt thereof, the solvate thereof, or the prodrug thereof described in any one of the above (1) to (10).

(14) General formula [II]

[Chemical formula 24] [In the formula, R ¹¹ 'is a halogen atom, a C _1-4 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, tert-butyl. It represents a dimethylsilyloxymethyl group, a cyano group or a nitro group. ] The compound shown by these, its salt, or its solvate.

(15) In the general formula [II], R ¹¹ 'is a C _1-4 alkyl group, a hydroxy C _1-6 alkyl group or C
_1-4 The compound according to (14) above, which is an alkoxy group, or a salt or solvate thereof.

(16) General formula [III]

[Chemical 25] [Wherein R ¹¹ ″ is a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, a hydroxyl group, C
_{1-4 represents an} alkoxy group, a tert-butyldimethylsilyloxymethyl group, a cyano group or a nitro group. ] The compound shown by these, its salt, or its solvate.

(17) In the general formula [III],
The compound according to (16) above, wherein R ¹¹ ″ is a C _1-4 alkoxy group, a salt thereof, or a solvate thereof.

(18) General formula [IV]

[Chemical formula 26] [In the formula, R ⁸ represents a carboxy group, a nitro group, a tert-butoxycarbonylamino group or a benzyloxycarbonylamino group. ] The compound shown by these, its salt, or its solvate.

The definitions of terms used in the present specification are as follows. The "aryl group" means a carbon number of 6 to 12
Aromatic hydrocarbon groups, which may be partially saturated. Examples thereof include a phenyl group, a biphenyl group, an indenyl group, naphthyl group, etc., preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group.
These aryl groups may be substituted with the substituents described below.
Further, the position of the bond of these aryl groups and the position of the substituent in the case of having a substituent are not particularly limited as long as they are chemically acceptable.

The "heteroaryl group" means 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom.
It represents a 5-membered to 6-membered unsaturated ring contained in an individual ring, and includes a condensed ring with a benzene ring or another heterocycle. Examples of these heteroaryl groups include, for example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, triazolyl group, indolyl group, benzofuryl group, benzothienyl group. , A benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a pyridyl group, a pyrimidinyl group, a quinolyl group or an isoquinolyl group. Preferred are a benzofuryl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a pyridyl group and a quinolyl group. These heteroaryl groups may be substituted with the substituents described below. Further, the position of the bond of the heteroaryl group and the position of the substituent when it has a substituent are not particularly limited as long as they are chemically acceptable.

The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and particularly preferably a chlorine atom.

The "C _1-6 alkyl group" is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group. Group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a tert-pentyl group, a hexyl group and the like, and preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group. And a C _1-4 alkyl group selected from a tert-butyl group.

The "halo C _1-6 alkyl group" means the above "C
_The " _1-6 alkyl group" represents a haloalkyl group in which one or more halogen atoms are substituted, and the substitution position is not particularly limited as long as it is chemically permissible. Examples of the “halo C _1-6 alkyl group” include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group,
Bromomethyl group, dibromomethyl group, tribromomethyl group, iodomethyl group, diiodomethyl group, triiodomethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2- Chloroethyl group, 2,2-dichloroethyl group, 2,2,2-
Trichloroethyl group, 2-bromoethyl group, 2,2-dibromoethyl group, 2,2,2-tribromoethyl group, 3
-Chloropropyl group or 4-chlorobutyl group and the like can be mentioned, preferably trifluoromethyl group and 2,2,2-
It is a halo C _1-2 alkyl group selected from a trichloroethyl group.

The "hydroxy C _1-6 alkyl group" means a hydroxyalkyl group in which a hydroxyl group is substituted on the above "C _1-6 alkyl group", and the substitution position is not particularly limited as long as it is chemically permissible. It is not something that will be done. "Hydroxy C
Examples of the " _1-6 alkyl group" include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group and a 2-hydroxy-1 group.
-Methylethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 3-hydroxy-2-methylpropyl group, 2-hydroxy-1,1-dimethylethyl group , 5-hydroxypentyl group, 6-hydroxyhexyl group and the like, and preferably a hydroxy C _1-4 alkyl group selected from a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group and a 4-hydroxybutyl group. Is.

The "C _1-6 alkoxy group" is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and includes, for example, methoxy group, ethoxy group, propoxy group and iso-group. A propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group, a tert-pentyloxy group, a hexyloxy group and the like can be mentioned, and preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group. A C _1-4 alkoxy group selected from the group.

[0056] The "C _1-6 alkoxy C _1-6 alkyl group" is alkoxyalkyl group wherein the above "C _1-6 alkoxy group" is substituted with the "C _1-6 alkyl group", the substituent positions Is not particularly limited as long as it is chemically acceptable. Examples of the “C _1-6 alkoxy C _1-6 alkyl group” include methoxymethyl group, ethoxymethyl group, propoxymethyl group, butoxymethyl group, pentyloxymethyl group, hexyloxymethyl group, 1-methoxyethyl group, 1 -Ethoxyethyl group, 2-methoxyethyl group, 2
-Ethoxyethyl group, 1-methoxypropyl group, 1-ethoxypropyl group, 2-methoxypropyl group, 2-ethoxypropyl group, 3-methoxypropyl group, 3-ethoxypropyl group, 2-methoxy-1-methylethyl group 1
-Methoxybutyl group, 1-ethoxybutyl group, 2-methoxybutyl group, 2-ethoxybutyl group, 3-methoxybutyl group, 3-ethoxybutyl group, 4-methoxybutyl group, 4-ethoxybutyl group, 3-methoxy A 2-methylpropyl group, a 2-methoxy-1,1-dimethylethyl group, a 2-ethoxy-1,1-dimethylethyl group, a 5-methoxypentyl group, a 6-methoxyhexyl group and the like can be mentioned, preferably methoxy. It is a C _1-4 alkoxy C _1-4 alkyl group selected from a methyl group, an ethoxymethyl group, a propoxymethyl group, a butoxymethyl group, a 2-methoxyethyl group, a 3-methoxypropyl group and a 4-methoxybutyl group.

The "halo C _1-6 alkoxy group" refers to a haloalkoxy group in which one or more halogen atoms are substituted on the above "C _1-6 alkoxy group", and the substitution position is chemically permissible. If not, there is no particular limitation. Examples of the “halo C _1-6 alkoxy group” include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a chloromethoxy group, a dichloromethoxy group,
Trichloromethoxy group, bromomethoxy group, dibromomethoxy group, tribromomethoxy group, iodomethoxy group,
Diiodomethoxy group, triiodomethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 2,
2,2-trifluoroethoxy group, 2-chloroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trichloroethoxy group, 2-bromoethoxy group, 2,2-dibromoethoxy group, 2,2 , 2-tribromoethoxy group,
3-chloropropoxy group or 4-chlorobutoxy group and the like can be mentioned, preferably trifluoromethoxy group and 2,
Halo C _1-2 selected from 2,2-trichloroethoxy group
It is an alkoxy group.

The "C _1-6 alkylthio group" has 1 carbon atom.
To 6 and preferably 1 to 4 linear or branched alkylthio groups, for example, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, tert-butylthio group, pentylthio group, ter
and a t-pentylthio group, a hexylthio group and the like,
Preferably methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group or tert-
It is a C _1-4 alkylthio group selected from a butylthio group.

The "C _1-6 alkylsulfanyl group" means
Represents a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms, for example, methylsulfanyl group, ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl group, butylsulfanyl group, tert-butylsulfanyl group, pentylsulfanyl group, tert
-Pentylsulfanyl group, hexylsulfanyl group and the like, preferably methylsulfanyl group having 1 to 4 carbon atoms, ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl group, butylsulfanyl group or tert-butylsulfanyl group.

The "C _1-6 alkylsulfonyl group" means a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group. , A butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, a tert-pentylsulfonyl group, a hexylsulfonyl group and the like, and preferably a methylsulfonyl group having 1 to 4 carbon atoms, an ethylsulfonyl group, a propylsulfonyl group, isopropyl. A sulfonyl group, a butylsulfonyl group or a tert-butylsulfonyl group.

The "C _1-6 alkylsulfamoyl group" means a sulfamoyl group mono-substituted by the above-mentioned "C _1-6 alkyl group", for example, methylsulfamoyl group,
Ethylsulfamoyl group, propylsulfamoyl group,
Isopropylsulfamoyl group, butylsulfamoyl group, tert-butylsulfamoyl group, pentylsulfamoyl group, tert-pentylsulfamoyl group, hexylsulfamoyl group or the like, preferably having 1 to 4 carbon atoms Methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, butylsulfamoyl group or ter
It is a t-butylsulfamoyl group.

The "di C _1-6 alkylsulfamoyl group" means a disubstituted sulfamoyl group with the above-mentioned "C _1-6 alkyl group", for example, dimethylsulfamoyl group, diethylsulfamoyl group. , Dipropylsulfamoyl group, diisopropylsulfamoyl group, dibutylsulfamoyl group, diisobutylsulfamoyl group, di-
tert-butylsulfamoyl group, dipentylsulfamoyl group, ethylmethylsulfamoyl group, methylpropylsulfamoyl group, butylmethylsulfamoyl group, ethylpropylsulfamoyl group or ethylbutylsulfamoyl group, etc. is there. Preferred is a dimethylsulfamoyl group, a diethylsulfamoyl group or a dipropylsulfamoyl group.

[0063] The "(C _1-6 alkoxy) carbonyl group", alkoxycarbonyl group C _1-6 alkoxy portion is indicated by the "C _1-6 alkoxy group" include a methoxycarbonyl group, an ethoxycarbonyl group , A propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group or a hexyloxycarbonyl group. Preferred is a (C _1-4 alkoxy) carbonyl group selected from a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group or a tert-butoxycarbonyl group.

The "C _1-7 acyl group" means 1 to 7 carbon atoms.
Represents a single alkanoyl group or aroyl group, and examples thereof include a formyl group, an acetyl group, a propionyl group, a butyryl group, a pivaloyl group and a benzoyl group. It is preferably a formyl group, an acetyl group, a pivaloyl group or a benzoyl group.

The "(C _1-6 alkyl) carbamoyl group" refers to an alkylcarbamoyl group in which the C _1-6 alkyl group shown in the above "C _1-6 alkyl group" is substituted with a carbamoyl group, for example, methylcarbamoyl. Group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, tert-butylcarbamoyl group, pentylcarbamoyl group, tert-pentylcarbamoyl group or hexylcarbamoyl group, and the like, preferably methylcarbamoyl group, ethylcarbamoyl group group, a propylcarbamoyl group, isopropylcarbamoyl group, and a butylcarbamoyl group, or tert- butylcarbamoyl group (C _1-4 alkyl) carbamoyl group.

“Di (C _1-6 alkyl) carbamoyl group”
Represents a dialkylcarbamoyl group in which the above-mentioned “C _1-6 alkyl group” is disubstituted with a carbamoyl group, and the kind of the alkyl group may be different. For example, dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoyl group, di-tert-butylcarbamoyl group, dipentylcarbamoyl group, di-tert-pentylcarbamoyl group, dihexylcarbamoyl group, methylethylcarbamoyl group. , A methylpropylcarbamoyl group, a methylbutylcarbamoyl group, an ethylpropylcarbamoyl group, an ethylbutylcarbamoyl group and the like, and preferably a dimethylcarbamoyl group, a diethylcarbamoyl group,
It is a di (C _1-4 alkyl) carbamoyl group selected from a dipropylcarbamoyl group, a dibutylcarbamoyl group or a di-tert-butylcarbamoyl group.

The "C _1-6 alkylamino group" means an alkylamino group in which the above "C _1-6 alkyl group" is substituted with an amino group, and examples thereof include methylamino group, ethylamino group, propylamino group and isopropyl group. Amino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, isopentylamino group, te
An rt-pentylamino group, a hexylamino group or the like can be mentioned, preferably a C ₁ selected from a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group and a tert-butylamino group. _{-4 is} an alkylamino group.

The "di C _1-6 alkylamino group" represents a dialkylamino group obtained by substituting the above-mentioned "C _1-6 alkyl group" for an amino group, and the kind of the alkyl group may be different. For example, dimethylamino group, ethylmethylamino group,
Diethylamino group, methylpropylamino group, ethylpropylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group,
A di-tert-butylamino group, a dipentylamino group,
A diisopentylamino group, a di-tert-pentylamino group, a dihexylamino group and the like can be mentioned, and preferably a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group or a di- It is a di C _1-4 alkylamino group selected from a tert-butylamino group.

The "C _1-7 acylamino group" means the above "C
_1-7 acyl group "represents a substituted amino group, for example, an alkanoylamino group such as formylamino group, acetylamino group, propionylamino group, butyrylamino group or pivaloylamino group; or 1 to 3 substituents on the aryl group. An aroylamino group such as a benzoylamino group which may have Preferred is formylamino group, acetylamino group, pivaloylamino group or benzoylamino group.

The "C _3-7 cycloalkyl group" represents a cyclic alkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. , Preferably a C _3-5 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, more preferably a cyclopropyl group or a cyclobutyl group, and particularly preferably a cyclopropyl group.

The "C _2-6 alkenyl group" refers to an alkenyl group having 2 to 6 carbon atoms, for example, vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group, 3- Examples thereof include a butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group and a 5-hexenyl group, and a C _2-4 alkenyl group such as a vinyl group or an allyl group is preferable.

The "C _2-6 alkynyl group" represents an alkynyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms,
For example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group or 5 -Hexynyl group and the like, and preferably a C _2-4 alkynyl group selected from an ethynyl group, a 1-propynyl group or a 2-propynyl group.

The "aralkyl group" means an arylalkyl group in which the above "aryl group" is substituted with the above "C _1-6 alkyl group", and the substitution position is not particularly limited as long as it is chemically permissible. Not something. "Aralkyl group"
Examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, a 6-phenylhexyl group, a 1-naphthylmethyl group and a 2-naphthylmethyl group. Preferably the "aryl" moiety is phenyl and "alkyl"
A part is a phenyl C _1-2 alkyl group selected from a benzyl group and a phenethyl group, in which part is methyl or ethyl.

The "C _1-6 alkylsulfonyloxy group" is an alkylsulfonyloxy group in which the C _1-6 alkyl portion is the above-mentioned "C _1-6 alkyl group", and examples thereof include methylsulfonyloxy group and ethylsulfonyl group. Oxy group, propylsulfonyloxy group, isopropylsulfonyloxy group, butylsulfonyloxy group, isobutylsulfonyloxy group, tert-butylsulfonyloxy group, pentylsulfonyloxy group, isopentylsulfonyloxy group, tert-pentylsulfonyloxy group or hexylsulfonyl group And an oxy group, preferably a methylsulfonyloxy group, an ethylsulfonyloxy group, a propylsulfonyloxy group, an isopropylsulfonyloxy group, a butylsulfonyloxy group, an isobutylsulfonyloxy group or te. a C _1-4 alkylsulfonyloxy group selected from t- butylsulfonyl group.

The "C _1-3 alkylenedioxy group" represents a methylenedioxy group, an ethylenedioxy group or a propylenedioxy group, preferably a methylenedioxy group or an ethylenedioxy group, particularly preferably It is a methylenedioxy group.

"C _1-6 alkylene" represents alkylene having 1 to 6 carbon atoms, for example, methylene, ethylene,
Examples thereof include propylene, butylene, pentylene, hexylene and the like. Preferred is C _1-4 alkylene selected from methylene, ethylene or propylene.

"C _2-6 alkynylene" represents alkynylene having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms,
For example, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene. , 4-hexenylene, 5-hexenylene and the like. Preferred is C _2-3 alkynylene selected from vinylene, 1-propenylene or 2-propenylene.

The aryl group and heteroaryl group of the present invention include a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group and a C _1-6 alkoxy C group.
_1-6 alkyl group, hydroxyl group, C _1-6 alkoxy group, halo C
_1-6 alkoxy group, mercapto group, C _1-6 alkylthio group, C _1-6 alkylsulfanyl group, C _1-6 alkylsulfonyl group, aminosulfonyl group, C _1-6 alkylsulfamoyl group, diC _{1- 6} alkylsulfamoyl group, carboxy group, (C _1-6 alkoxy) carbonyl group, C _1-7 acyl group, carbamoyl group, (C _1-6 alkyl) carbamoyl group, di (C _1-6 alkyl) carbamoyl group , Cyano group, nitro group, amino group, C _1-6 alkylamino group, di C _1-6 alkylamino group, C _1-7 acylamino group, C _1-3
An alkylenedioxy group,

[Chemical 27] (Where R^AIs (C_1-6Alkoxy) carbonyl group or
Represents a carboxy group, R ^BIs a hydrogen atom or C_1-6Alkyl
Represents a group. Substituted with 1 to 3 substituents selected from
You may

The "salt" of the compound means an inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate, glycolate,
Organic acids such as lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate Addition salts; include, but are not limited to, amino acid addition salts such as aspartate or glutamate. Preferred "salt"
Is a hydrochloride or a fumarate, particularly preferably a fumarate.

The present invention includes solvates,
Here, the "solvate" of the compound means that the compound of the present invention is water in a solid state or solution such as crystal or amorphous,
It means one bonded to a solvent molecule such as alcohol by a relatively weak bond such as van der Waals force, electrostatic interaction, hydrogen bond, charge transfer bond, or coordinate bond. In some cases, the solvent may be incorporated in a solid state such as a water-containing material or an alcohol-containing material. The "solvate" of the compound is preferably a hydrate.

The "prodrug" of a compound has a group capable of being chemically or metabolically decomposed, and shows a pharmaceutically active substance by hydrolysis or solvolysis or by decomposition under physiological conditions. It is a derivative of the compound of the present invention.

General formulas [I] and [I-2] according to the present invention
And the compound represented by [I-3] may have various isomers such as optical isomers, stereoisomers, geometric isomers and tautomers. The scope of the present invention includes all these isomers and mixtures thereof.

[0083]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound represented by the general formula [I] according to the present invention, R ¹ is preferably an aryl group, more preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group. . When R ¹ is an aryl group, the substituent is preferably a halogen atom, C
_1-4 alkyl group, a hydroxy C _1-6 alkyl group, C _1-6 alkoxy C _1-6 alkyl group, hydroxyl group, C _1-4 alkoxy group, a cyano group, a nitro group or a C _1-3 alkylenedioxy group Yes, more preferably chlorine atom, methyl group, hydroxymethyl group, hydroxy group, methoxy group, cyano group, nitro group or methylenedioxy group, particularly preferably methyl group, hydroxymethyl group, methoxy group or methylenedioxy group. Is.

When R ¹ is a heteroaryl group, it is preferably selected from a thienyl group, a furyl group, a pyridyl group and a thiazolyl group, and when R ¹ is a heteroaryl group, the substituent is preferably C _1-6 alkyl. A group or a halogen atom, particularly preferably a methyl group or a bromine atom.

[0085] Preferably the substituted may be branched optionally C _1-4 alkyl group as R ^2, C _{3- 5} cycloalkyl group, C _2-4 alkenyl group, an aralkyl group, C _1-4 The substituent of the alkyl group is preferably a C _1-4 alkoxy group. R ²
Is more preferably a methyl group, an ethyl group, a cyclopropyl group or a cyclobutyl group, still more preferably a methyl group or a cyclopropyl group, and particularly preferably a cyclopropyl group.

R³Is preferably a hydroxyl group and R^FourWhen
And preferably a hydrogen atom. R ^FiveAnd R⁶As preferred
Each is a methyl group. R⁷Preferably as
Aryl group, more preferably phenyl group or naphth
It is a chill group. R⁷The substituent of is preferably C_1-6Al
Kill group, C_1-6Alkoxy group, hydroxyl group or C_1-3Arche
And a C group, more preferably C_1-4Alkyl
Base, C_1-4Alkoxy group or C_1-3Alkylenedioxy group
And more preferably C_1-4Alkyl group or C_1-4A
Rucoxy group, particularly preferably methyl group or methoxy group.
It is Shi group. R⁷Is preferably a naphthyl group, 4-me
Toxy-3-methylphenyl group or 3,4-methylenedi group
Oxyphenyl group, particularly preferably naphthyl group or
Is a 4-methoxy-3-methylphenyl group. X¹When
And preferably C_1-6Alkylene, particularly preferred
Is methylene. X²Is preferably methylene
It X³Is preferably methylene. X^FourAnd X^Five
Is preferably a single bond.

R ¹¹ is preferably a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a hydroxy C _1-6 alkyl group,
C _1-6 alkoxy is a C _1-6 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a cyano group or a nitro group, more preferably a hydrogen atom, a chlorine atom, a methyl group, a hydroxymethyl group, a hydroxyl group, a methoxy group, A cyano group or a nitro group, particularly preferably a hydrogen atom.

R ¹² is preferably a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a hydroxy C _1-6 alkyl group,
C _1-6 alkoxy is a C _1-6 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a cyano group or a nitro group, more preferably a chlorine atom, a methyl group, a hydroxymethyl group, a hydroxyl group,
It is a methoxy group, a cyano group or a nitro group, and particularly preferably a methyl group, a hydroxymethyl group or a methoxy group.

R ²¹ is preferably a methyl group, an ethyl group, a cyclopropyl group or a cyclobutyl group, more preferably a methyl group or a cyclopropyl group, and particularly preferably a cyclopropyl group.

[0090]

[Chemical 28] The three-dimensional arrangement of

[Chemical 29] Is preferred.

When the compound of the present invention is used as a pharmaceutical, the compound itself (free form), a salt of the compound, a solvate of the compound or a prodrug form of the compound can be used, and the preferred form is the free form or the compound. Or a solvate of the compound, and particularly preferably a salt of the compound.

Next, the method for producing the compound represented by the general formula [I] according to the present invention will be specifically described. However, it goes without saying that the present invention is not limited to these manufacturing methods. When constructing the compound of the present invention, the order of construction may be appropriately selected from a site that is easy to perform. In addition, in each step, when there is a reactive functional group, it may be appropriately protected and deprotected, and reagents other than the exemplified reagents can be appropriately used in order to accelerate the progress of the reaction. All the compounds obtained in each step can be isolated and purified by a conventional method, but in some cases, the compound can proceed to the next step without isolation and purification.

[Chemical 30] (X represents a halogen atom, L ¹ and L ² are each a leaving group such as a halogen atom or a 3-nitrobenzenesulfonyloxy group, a p-toluenesulfonyloxy group, a benzenesulfonyloxy group, a p-bromobenzenesulfonyloxy group, Represents a sulfonyloxy group such as a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, R ³ 'represents an oxygen atom or a sulfur atom, and each of the other symbols has the same meaning as described above.)

Step 1 The aldehyde compound (4) is reacted with the Grignard reagent (5) in diethyl ether, tetrahydrofuran, 1,4-dioxane or the like or a mixed solvent thereof at −80 ° C. to room temperature to give the compound (6 ) Is obtained. The Grignard reagent may be prepared by a known method.
Alternatively, the ketone compound (4 ′) is treated with diethyl ether, tetrahydrofuran, 1,4-dioxane, isopropanol or the like or a mixed solvent thereof at −10 ° C. to room temperature to obtain lithium aluminum hydride, sodium borohydride, lithium borohydride, etc. The compound (6) can also be obtained by carrying out a reduction reaction with the reducing agent. Further, in this case, asymmetric reduction using an asymmetric reducing agent such as B-chlorodiisopinocampheylborane or dichloro [(S)-
(-)-2,2'-bis (diphenylphosphino)-
It is also possible to carry out an asymmetric hydrogenation reaction using a ruthenium complex such as 1,1′-binaphthyl] ruthenium (II).

Second Step The compound (6) obtained in the first step is treated with N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixed solvent thereof such as sodium hydride, sodium hydroxide, potassium hydroxide and carbonic acid. Compound (7) at a temperature of 0 ° C to room temperature in the presence of a base such as sodium, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine. Compound (8) is obtained by reacting. In this case, L ¹ may be a leaving group which is more reactive than L ² . When R ³ is a hydroxyl group or a mercapto group, R ⁴ is a hydrogen atom, and X ² is a methylene group, a compound (7 ′) may be used instead of the compound (7). Good. In this case, alkylammonium hydrogensulfate such as tetrabutylammonium hydrogensulfate can be added. A stereoselective reaction can be performed depending on the selection of a reagent and a leaving group to be used.

Third step The compound (8) obtained in the second step is treated with sodium hydride in N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixed solvent thereof.
Sodium hydroxide, potassium hydroxide, sodium carbonate,
By reacting the compound (9) in the presence of a base such as potassium carbonate at 0 ° C. to room temperature, the compound represented by the general formula [I] can be obtained. In addition, the compound (8 ′) and the compound (9) are treated with methanol, ethanol, n-propanol,
By reacting at room temperature to reflux temperature in isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene or the like or a mixed solvent thereof,
In the compound represented by the general formula [I], R ³ is a hydroxyl group or a mercapto group, R ⁴ is a hydrogen atom, and X ²
A compound in which is a methylene group is obtained. In this case, it is preferable to add alkali perchlorate such as lithium perchlorate.

When the acid addition salt of the compound represented by the general formula [I] is desired, a known method can be used. For example, a compound represented by the general formula [I] is converted into water, methanol,
Ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform or the like or a mixed solvent thereof is dissolved, and the above-mentioned solvent in which the desired acid is dissolved is dissolved. In addition, the precipitated crystals may be collected by filtration or concentrated under reduced pressure.

When the acid addition salt of the compound represented by the general formula [I] is used as a free form, the acid addition salt of the general formula [I] is converted into sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, By partitioning in a two-layer system of an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide and a solvent such as ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, methyl ethyl ketone or toluene, the general formula [ The free form of the compound represented by I] is obtained.

The compound (4 ') can be prepared by the following method.

[Chemical 31] (Each symbol has the same meaning as described above.)

Step 4 Compound (10) was added to dichloromethane, chloroform, 1,
Compound (11) is obtained by reacting N, O-dimethylhydroxylamine or a salt thereof in a solvent such as 2-dichloroethane, tetrahydrofuran or 1,4-dioxane in the presence of a base such as triethylamine or N, N-diisopropylethylamine. Is obtained.

Step 5 The compound (11) obtained in the Step 4 and the Grignard reagent (5) are treated with diethyl ether, tetrahydrofuran, 1,
-80 in 4-dioxane or the like or a mixed solvent thereof
The compound (4 ′) is obtained by reacting at ℃ to room temperature.

The following method can be used for the preparation of compound (9).

[Chemical 32] (Rh represents a carboxylic acid protecting group such as a benzyl group and a tert-butyl group, and each of the other symbols has the same meaning as described above.)

Step 6 The compound (12) is reacted with the compound (13) in a solvent such as tetrahydrofuran or n-hexane in the presence of a base such as n-butyllithium and hexamethylphosphoramide to give a compound (14). can get.

Step 7 This step is a step for obtaining the compound (15) from the compound (14) obtained in the step 6 by Curtius rearrangement. Compound (14) in water, acetone, methyl ethyl ketone or the like or a mixed solvent thereof, triethylamine, N, N
Reacting with an alkyl halide carbonate such as ethyl chlorocarbonate in the presence of a base such as diisopropylethylamine.
Then, the compound obtained by reacting sodium azide is rearranged under heating and then reacted with an alcohol represented by Rh-OH to obtain compound (15).

Eighth step This step is a step of preparing the compound (15) obtained in the seventh step with --CO
This is a step of deprotecting ₂ Rh, and a method usually used for deprotecting the protecting group may be performed. For example, when Rh is a benzyl group, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,
Compound (9) is obtained by hydrogenation reaction using a catalyst such as palladium carbon, palladium black, palladium hydroxide carbon, Raney nickel in a solvent such as 4-dioxane. Further, for example, when Rh is a tert-butyl group, water, methanol, ethanol, n-propanol,
Compound (9) is obtained by reacting with an acid such as hydrogen chloride, sulfuric acid, hydrogen bromide in isopropanol, tetrahydrofuran, 1,4-dioxane, acetic acid or the like or a mixed solvent thereof.

In addition, among the compounds (9), -X ³ -X ⁴ -X
^When a compound (9 ′) in which ⁵ -is methylene is desired,
The following method may be performed.

[Chemical 33] (Each symbol has the same meaning as described above.)

Step 9 Compound (18) is obtained by reacting compound (17) with compound (16) in a solvent such as tetrahydrofuran or n-hexane in the presence of a base such as n-butyllithium.

Step 10 The compound (18) obtained in Step 9 is reacted with acetonitrile and acetic acid by adding sulfuric acid to give the compound (1
9) is obtained.

Eleventh step The compound (19) obtained in the tenth step is treated with hydrogen chloride or sulfuric acid in water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetic acid or a mixed solvent thereof. Compound (9 ′) is obtained by reacting with an acid such as hydrogen bromide under heating. In addition, the compound (19) is water,
Methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane,
The compound (9 ′) can also be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a solvent such as ethylene glycol under heating.

The compound (9 ') can also be produced by the following method.

[Chemical 34] (Each symbol has the same meaning as described above.)

Step 12 Compound (21) is treated with tetraalkylammonium halide such as tetrabutylammonium fluoride and trialkylhalogenation such as tert-butyldimethylchlorosilane in a solvent such as tetrahydrofuran, N, N-dimethylformamide and dimethylsulfoxide. When reacted with the compound (20) in the presence of silane, the compound (22) is obtained.

Thirteenth Step The compound (22) obtained in the twelfth step is treated with thionyl chloride,
Compound (23) can be obtained by halogenation using a halogenating agent such as oxalyl chloride. In this reaction, the halogenating agent itself used may be used as a solvent, or a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran or 1,4-dioxane may be used.

Step 14 The compound (23) obtained in Step 13 is treated with a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or 1,4-dioxane in palladium carbon, palladium black or palladium hydroxide carbon. When the hydrogenation reaction is carried out in the presence of the catalyst of compound (24)
Is obtained. In this reaction, it is preferable to apply a slight pressure.

Fifteenth step The compound (24) obtained in the fourteenth step is subjected to hydrogenation reaction in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or 1,4-dioxane using a catalyst such as Raney nickel. By carrying out, the compound (9 ′) is obtained. In this reaction,
It is preferable to apply a slight pressure.

The thus-obtained compound represented by the general formula [I] according to the present invention has an excellent calcium receptor antagonistic action. The compound of the present invention is used for osteoporosis, hypoparathyroidism, osteosarcoma, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, liquid hypercalcemia, autosomal dominant hypocalcemia, etc. When used as a therapeutic agent, it is usually administered systemically or locally, orally or parenterally.

Although the dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., it is usually in the range of 0.01 mg to 10 g per adult and is orally or parenterally administered once to several times a day. To be done.

When the compound of the present invention is made into a solid composition for oral administration, it may be in the form of tablets, pills, powders, granules and the like. In such solid compositions, the one or more active substances are at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol,
It is mixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylhydrin, magnesium aluminometasilicate, anhydrous silicic acid powder or the like. Further, the composition may be mixed with an additive other than the diluent according to a conventional method.

In the case of preparing tablets or pills, it may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, if necessary, or with two or more layers. You may. Further, it may be a capsule of a substance such as gelatin or ethyl cellulose.

When the composition is a liquid composition for oral administration, it may be in the form of a pharmaceutically acceptable emulsion, solubilizer, suspension, syrup or elixir. Examples of the diluent to be used include purified water, ethanol, vegetable oil or emulsifier. In addition to the diluent, the composition may be mixed with an auxiliary agent such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent or a preservative.

When preparing an injection for parenteral administration,
Sterile aqueous or non-aqueous solutions, solubilizers, suspensions or emulsifiers are used. Examples of the aqueous solution, solubilizer, and suspension include distilled water for injection, physiological saline cyclodextrin and its derivatives, organic amines such as triethanolamine, diethanolamine, monoethanolamine, and triethylamine, or an inorganic alkaline solution. Etc.

In the case of preparing a water-soluble solution, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol may be used. Further, as the solubilizer, for example, polyoxyethylene hydrogenated castor oil, a surfactant (mixed micelle formation) such as sucrose fatty acid ester, or lecithin or hydrogenated lecithin (liposome formation) is used. It is also possible to prepare an emulsion preparation comprising a non-water-soluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol or the like.

Other compositions for parenteral administration include external preparations containing one or more active substances and prepared by a method known per se, coating agents such as ointments, suppositories or pessaries. Etc.

[0122]

EXAMPLES The compound represented by the general formula [I] and the method for producing the same according to the present invention will be specifically described by the following examples. However, it goes without saying that the present invention is not limited to these examples.

Example 1 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-methoxyphenyl) methoxy] propane-2
-All step 1 (cyclopropyl) (2-methoxyphenyl) methanol

[Chemical 35] Magnesium (10.7 g) was suspended in tetrahydrofuran (80 ml), and iodine (5 mg) was added. Bromocyclopropane (32.0 ml) was added dropwise thereto over 1.5 hours, and then 1.5
Heated to reflux for hours. Tetrahydrofuran was added to this to give a 1M cyclopropylmagnesium bromide-tetrahydrofuran solution. Then o-anisaldehyde (8.1
7 g) was dissolved in tetrahydrofuran (150 ml), and 1M cyclopropylmagnesium bromide-tetrahydrofuran solution (9
(0 ml) was added dropwise under ice cooling over 50 minutes, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was ice-cooled and saturated aqueous ammonium chloride solution was added.
(9 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give the title compound.
(6.13g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.41 (1H, d, J = 7.8Hz),
7.19 (1H, dt, J = 1.6, 7.7Hz), 6.92 (2H, t, J = 7.2Hz), 4.88
(1H, d, J = 4.8Hz), 4.55 (1H, t, J = 5.5Hz), 3.76 (3H, s), 1.
09-1.00 (1H, m), 0.33-0.25 (4H, m). MS (ESI, m / z) 161 (M + HH ₂ O) ⁺ .

Step 2 (R) -2-[(cyclopropyl) (2-methoxyphenyl) methoxymethyl] oxirane

[Chemical 36] (Cyclopropyl) (2-methoxyphenyl) methanol (3.57 g) obtained in Step 1 was dissolved in N, N-dimethylformamide (50 ml), and sodium hydride (960 mg, 60%) was added.
(Oiliness) was added and stirred for 3 minutes. Then, (R) -glycidyl 3-nitrobenzenesulfonate (6.22 g) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 88: 1).
Purification in 2) gave the title compound (1.10 g).

Step 3 2-Methyl-1- (naphthalen-2-yl) -2-nitropropanol

[Chemical 37] Tetrabutylammonium fluoride trihydrate (2.41
Tetrahydrofuran (20 ml) was added to g), and the mixture was ice-cooled. Under an atmosphere of argon, 2-nitropropane (2.7 ml), 2-naphthaldehyde (3.12 g) and triethylamine (2.8 ml) were added. Furthermore, tert-butyldimethylchlorosilane (4.5
A solution of 1 g) in tetrahydrofuran (20 ml) was added, and the mixture was stirred for 40 minutes while returning from ice cooling to room temperature. The insoluble material was filtered off, and the filtrate was a diethyl ether-n-hexane = 1: 3 solution (500 m
l) and washed twice with water (40 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue
Crystallization from -hexane gave the title compound (3.78g).

Step 4 2- (1-chloro-2-methyl-2-nitropropyl)
Naphthalene

[Chemical 38] 2-Methyl-1- (naphthalene-2-obtained in step 3)
Thionyl chloride (3.1 ml) was added to (yl) -2-nitropropanol (1.23 g), the mixture was heated under reflux for 1 hr, and then stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 93: 7). Purified. Further recrystallize with a solution of n-hexane: ethyl acetate = 4: 1 to give the title compound (776m
g) was obtained.

Step 5 2- (2-methyl-2-nitropropyl) naphthalene

[Chemical Formula 39] 2- (1-chloro-2-methyl-2-obtained in step 4
Nitropropyl) naphthalene (200 mg) in methanol (5 ml)
And ethyl acetate (5 ml), 10% palladium carbon (20 mg) was added, and hydrogenation reaction was carried out at 3 atm for 2 hours. The reaction solution was filtered through Celite, and silica gel column chromatography (n-hexane: ethyl acetate = 95: 5).
The title compound (139 mg) was obtained by purification. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.85-7.76 (3H, m), 7.58
(1H, s), 7.50-7.44 (2H, m), 7.22 (1H, dd, J = 1.7, 8.4Hz),
3.37 (2H, s), 1.69 (6H, s). MS (APCI, m / z) 183 (M + H-NO ₂ ) ⁺ .

Step 6 [2-Methyl-1- (naphthalen-2-yl) propan-2-yl] amine

[Chemical 40] Raney nickel W2 (200 mg) was suspended in ethanol (10 ml), and 2- (2-methyl-2-nitropropyl) naphthalene (134 mg) obtained in step 5 was added to the suspension at 3.5 atm.
The hydrogenation reaction was carried out for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate to give the title compound (70 mg).

Step 7 2-Methyl-1- (naphthalen-2-yl) -2-propanol

[Chemical 41] 2-Methylnaphthalene (7.11 g) was added to tetrahydrofuran (10
0 ml), cooled to −69 ° C., 1.6 M n-
Butyllithium-tetrahydrofuran solution (34 ml) was added dropwise. Then, acetone (4.41 ml) in tetrahydrofuran
(4.41 ml) solution was added dropwise, and the mixture was stirred for 12 hours while returning to room temperature. A saturated ammonium chloride solution (6 ml) was added dropwise to the reaction solution, which was then poured into water (200 ml) and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 1).
Purification in 5) gave the title compound (3.80 g).

Step 8 N- [2-Methyl-1- (naphthalen-2-yl) propan-2-yl] acetamide

[Chemical 42] 2-Methyl-1- (naphthalene-2-obtained in step 7
Yl) -2-propanol (500 mg) in acetonitrile (0.
5 ml) and acetic acid (0.5 ml) were added sequentially, and after cooling with ice, sulfuric acid (0.5 m
l) was added dropwise. After stirring for 20 minutes under ice cooling, the mixture was poured into a 1N aqueous sodium hydroxide solution and extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-n-hexane to give the title compound (303 mg).

Step 9 [2-Methyl-1- (naphthalen-2-yl) propan-2-yl] amine

[Chemical 43] N- [2-methyl-1- (naphthalen-2-yl) propan-2-yl] acetamide obtained in Step 8 (26 mg)
To the mixture was added 6N hydrochloric acid (2 ml), and the mixture was heated under reflux for 5 hours. The reaction solution was poured into water, made basic with a 4N sodium hydroxide aqueous solution, and then extracted with diethyl ether. The organic layer was washed with water, dried over potassium carbonate, and concentrated under reduced pressure to give the title compound (19 mg).

Step 10 2,2-Dimethyl-3- (naphthalen-2-yl) propionic acid

[Chemical 44] Diisopropylamine (576 ml) in tetrahydrofuran (3.
5L) solution was cooled to -68 ° C and 2. under argon atmosphere.
A 6M n-butyllithium-n-hexane solution (1.5 L) was slowly added. Next, a solution of isobutyric acid (181 ml) in hexamethylphosphoramide (340 ml) was added dropwise, and the mixture was stirred at room temperature for 3 days.
Stir for 0 minutes. After cooling with ice, a solution of 2-bromomethylnaphthalene (392 g) in tetrahydrofuran (1 L) was added dropwise, and the mixture was stirred at room temperature for 1 day. The reaction solution was ice-cooled, and 6N hydrochloric acid (665 m
l) was added and the organic layer and the aqueous layer were separated. The organic layer was separated and concentrated under reduced pressure to give a residue. On the other hand, ethyl acetate and water were added to the aqueous layer to separate the layers. The organic layer and the residue were combined and washed with water three times. Sodium hydroxide (8
A solution of 0 g) in water (600 ml) was added, and the mixture was extracted, and further extracted with 4N aqueous sodium hydroxide solution (200 ml) three times. The aqueous layer was washed with ethyl acetate, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (177.5g). ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.88-7.80 (3H, m), 7.6
6 (1H, s), 7.51-7.44 (2H, m), 7.33 (1H, dd, J = 8.4, 1.6H
z), 2.96 (2H, s), 1.13 (6H, s). MS (FAB, m / z) 228 (M) ⁺ .

Step 11 N- [2-Methyl-1- (naphthalen-2-yl) propan-2-yl] -benzyloxycarboxamide

[Chemical formula 45] 2,2-Dimethyl-3- (naphthalen-2-yl) propionic acid (205.4 g) obtained in Step 10 was dissolved in water (173 ml), triethylamine (131 ml) and acetone (800 ml), and the mixture was cooled with ice. Ethyl chlorocarbonate (101.5 ml) in acetone (40
0 ml) solution was added. Then sodium azide (73.1 g)
Of water (400 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water (1.5 L) and toluene (1.2 L) were added to the reaction solution, and the organic layer and the aqueous layer were separated. The organic layer was washed twice with water, three times with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was heated to 100 ° C under an argon atmosphere for 4 hours, and further stirred at 100 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and benzyl alcohol (500 m
l) was added and the mixture was stirred at 105 ° C for 1 day. The reaction mixture was concentrated under reduced pressure, ethyl acetate and n-hexane were added to the obtained residue, and the mixture was treated with activated carbon. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give the title compound (24
0.5g) was obtained. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 8.83-7.78 (1H, m), 7.71-
7.66 (2H, m), 7.45-7.36 (7H, m), 7.22 (1H, dd, J = 1.6, 8.4
Hz), 5.13 (2H, s), 4.54 (1H, br s), 3.15 (2H, s), 1.34 (6
H, s) .MS (FAB, m / z) 334 (M + H) ⁺ .

Step 12 [2-Methyl-1- (naphthalen-2-yl) propan-2-yl] amine

[Chemical formula 46] Palladium hydroxide carbon (19.7 g) was suspended in methanol (500 ml), and N- [2-methyl-1-
A solution of (naphthalen-2-yl) propan-2-yl] -benzyloxycarboxamide (237.6 g) in methanol (2 L) was added, and hydrogenation reaction was carried out at room temperature overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to give a solution, and concentrated hydrochloric acid (70 ml) was added to this to obtain crystals. The obtained crystals were suspended in water, 4N aqueous sodium hydroxide solution (350 ml) was added, and the mixture was extracted with ethyl acetate. Ethyl acetate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (138 g) as crystals.

Step 13 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-methoxyphenyl) methoxypropane-2-
All

[Chemical 47] (R) -2-[(cyclopropyl) obtained in Step 2
(2-Methoxyphenyl) methoxymethyl] oxirane
(703 mg) is dissolved in ethanol (12 ml), and the steps 6 and 9 are performed.
Alternatively, [2-methyl-1- (naphthalen-2-yl) propan-2-yl] amine (120 ml) obtained in Step 12 was added and stirred at 60 ° C. for 20 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 97: 3),
The title compound (954 mg) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.90-7.70 (3H, m), 7.6
7 (1H, s), 7.50-7.20 (5H, m) 7.00-6.90 (2H, m), 4.62 (1H,
br s), 4.29 (1H, d, J = 7.0Hz), 3.77 (3H, s), 3.70-3.50 (1
H, m), 3.30-3.10 (2H, m), 2.80-2.50 (4H, m), 1.50-0.85
(8H, m), 0.50-0.20 (4H, m). MS (APCI, m / z) 433 (M + H) ⁺ .

Example 2 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-methylphenyl) methoxy] propane-2 −
All steps 1 (Cyclopropyl) (2-methylphenyl) methanol

[Chemical 48] The title compound (5.36 g) was obtained in the same manner as in Step 1 of Example 1. However, o-tolualdehyde (4.81 g) was used instead of o-anisaldehyde. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.43 (1H, d, J = 7.2Hz),
7.18-7.10 (3H, m), 4.95 (1H, d, J = 4.8Hz), 4.36 (1H, dd, J =
4.4, 6.5Hz), 2.31 (3H, s), 1.20-1.07 (1H, m), 0.47-0.20
(4H, m) .MS (APCI, m / z) 145 (M + HH ₂ O) ⁺ .

Step 2 (R) -2-[(cyclopropyl) (2-methylphenyl) methoxymethyl] oxirane

[Chemical 49] The title compound (1.53 g) was obtained in the same manner as in Step 2 of Example 1 from (cyclopropyl) (2-methylphenyl) methanol (3.25 g) obtained in Step 1.

Step 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-methylphenyl) methoxy] propane-2-
All

[Chemical 50] (R) -2-[(cyclopropyl) obtained in Step 2
(2-Methylphenyl) methoxymethyl] oxirane (6
From 55 mg), the title compound (849 mg) was obtained in the same manner as in Step 13 of Example 1. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.90-7.70 (3H, m), 7.6
7 (1H, s), 7.50-7.25 (4H, m) 7.20-7.10 (3H, m), 4.65 (1H,
br s), 4.06 (1H, d, J = 7.4Hz), 3.70-3.50 (1H, m), 3.30-
3.10 (2H, m), 2.80-2.50 (4H, m), 2.31 (3H, s), 1.50-0.80
(8H, m), 0.60-0.10 (4H, m). MS (APCI, m / z) 417 (M + H) ⁺ .

Example 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (phenyl) methoxy] propan-2-ol step 1 (R) -2-[(cyclopropyl) (phenyl) methoxymethyl] oxirane

[Chemical 51] From α-cyclopropylbenzyl alcohol (740 mg),
The title compound (296 mg) was obtained in the same manner as in Step 2 of Example 1.

Step 2 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (phenyl) methoxy] propan-2-ol

[Chemical 52] (R) -2-[(cyclopropyl) obtained in Step 1
From (phenyl) methoxymethyl] oxirane (204 mg) in the same manner as in Step 13 of Example 1 the title compound (334 m
g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.90-7.70 (3H, m), 7.6
7 (1H, s), 7.50-7.20 (8H, m) 4.65 (1H, br s), 3.80-3.50
(2H, m), 3.30-3.10 (2H, m), 2.80-2.50 (4H, m), 1.50-0.8
0 (8H, m), 0.60-0.10 (4H, m). MS (APCI, m / z) 403 (M + H) ⁺ .

Example 4 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) ethoxy] propan-2-ol Step 1 1- (2-methoxyphenyl) ethanol

[Chemical 53] Lithium aluminum hydride (1.52 g) was suspended in tetrahydrofuran (100 ml), 2'-methoxyacetophenone (2.76 ml) was added under ice cooling, and the mixture was stirred for 30 minutes. Water (1.5 ml), 15% aqueous sodium hydroxide solution (1.5 ml),
Water (4.5 ml) was added sequentially. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (3.05g).

Step 2 (R) -2- [1- (2-methoxyphenyl) ethoxymethyl] oxirane

[Chemical 54] The title compound (123 mg) was obtained from 1- (2-methoxyphenyl) ethanol (837 mg) obtained in Step 1 in the same manner as in Step 2 of Example 1.

Step 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) ethoxy] propan-2-ol

[Chemical 55] The title compound (148 mg) was obtained in the same manner as in Step 13 of Example 1 from (R) -2- [1- (2-methoxyphenyl) ethoxymethyl] oxirane (115 mg) obtained in Step 2. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.85-7.70 (3H, m), 7.6
1 (1H, s), 7.50-7.20 (5H, m), 7.00-6.80 (2H, m), 4.88 (1
H, q, J = 6.4Hz), 3.85-3.75 (4H, m), 3.45-3.35 (2H, m), 2.
85-2.60 (4H, m), 1.40-1.37 (3H, m), 1.10-1.08 (6H, m). MS (APCI, m / z) 408 (M + H) ⁺ .

Example 5 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) ethoxy] propan-2-ol Hydrochloride

[Chemical 56] (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3-obtained in Example 4
[1- (2-methoxyphenyl) ethoxy] propane-
2-ol (141 mg) was dissolved in diethyl ether (5 ml),
A 4N hydrogen chloride-ethyl acetate solution was added. The reaction mixture was concentrated under reduced pressure, diethyl ether (5 ml) was added, and the mixture was concentrated under reduced pressure to give the title compound (154 mg). ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 8.91 (1H, br s), 8.54
(1H, br s), 7.95-7.86 (3H, m), 7.67 (1H, s), 7.55-7.45
(2H, m), 7.40-7.20 (3H, m), 7.02-6.93 (2H, m), 5.66-5.6
1 (1H, m), 4.90-4.80 (1H, m), 4.05-3.95 (1H, m), 3.80 (3
H, s), 3.40-3.10 (5H, m), 3.05-2.85 (1H, m), 1.32 (3H, d,
J = 6.4Hz), 1.09 (6H, s) .MS (APCI, m / z) 408 (M + H-HCl) ⁺ .

Example 6 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methylphenyl) ethoxy] propan-2-ol Step 1 1- (2-methylphenyl) ethanol

[Chemical 57] The title compound (755 mg) was obtained from 2′-methylacetophenone (2.68 g) in the same manner as in Step 1 of Example 4.

Step 2 (R) -2- [1- (2-methylphenyl) ethoxymethyl] oxirane

[Chemical 58] The title compound (123 mg) was obtained from 1- (2-methylphenyl) ethanol (749 mg) obtained in Step 1 in the same manner as in Step 2 of Example 1.

Step 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methylphenyl) ethoxy] propan-2-ol

[Chemical 59] The title compound (345 mg) was obtained from (R) -2- [1- (2-methylphenyl) ethoxymethyl] oxirane (192 mg) obtained in Step 2 in the same manner as in Step 13 of Example 1. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.85-7.70 (3H, m), 7.60
(1H, s), 7.50-7.10 (7H, m), 4.75-4.65 (1H, m), 3.80-3.7
0 (1H, m), 3.40-3.30 (2H, m), 2.90-2.60 (4H, m), 2.31 (3H,
s), 1.39 (3H, d, J = 6.4Hz), 1.10-1.07 (6H, m). MS (APCI, m / z) 392 (M + H) ⁺ .

Example 7 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methylphenyl) ethoxy] propan-2-ol Hydrochloride

[Chemical 60] (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3-obtained in Example 6
[1- (2-methylphenyl) ethoxy] propane-2
The title compound (337 mg) was obtained from -ol (339 mg) in the same manner as in Example 5. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 8.97 (1H, br s), 8.56
(1H, br s), 7.95-7.85 (3H, m), 7.77 (1H, s), 7.75-7.65
(2H, m), 7.40-7.32 (2H, m), 7.25-7.12 (3H, m), 5.66-5.6
1 (1H, m), 4.73 (1H, q, J = 6.3Hz), 4.10-3.95 (1H, br s),
3.40-3.10 (5H, m), 3.05-2.90 (1H, m), 2.31 (3H, s), 1.34
(3H, d, J = 6.6Hz), 1.27 (3H, s), 1.26 (3H, s). MS (APCI, m / z) 392 (M + H-HCl) ⁺ .

Example 8 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) propoxy] propan-2-ol Step 1 1- (2-methoxyphenyl) propanol

[Chemical formula 61] o-anisaldehyde (2.72 g) was added to tetrahydrofuran (50
0.93M ethylmagnesium bromide-tetrahydrofuran solution (31.3 ml) was added dropwise over 10 minutes under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution (40 ml) and water (40 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate,
The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (3.15 g).

Step 2 (R) -2- [1- (2-methoxyphenyl) propoxymethyl] oxirane

[Chemical formula 62] The title compound (264 mg) was obtained from 1- (2-methoxyphenyl) propanol (831 mg) obtained in Step 1 in the same manner as in Step 2 of Example 1.

Step 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) propoxy] propan-2-ol

[Chemical formula 63] From (R) -2- [1- (2-methoxyphenyl) propoxymethyl] oxirane (264 mg) obtained in Step 2,
The title compound (403 mg) was obtained in the same manner as in Step 13 of Example 1. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.85-7.70 (3H, m), 7.61
(1H, s), 7.50-7.20 (5H, m), 7.00-6.90 (1H, m), 6.85-6.7
5 (1H, m), 4.67 (1H, t, J = 6.3Hz), 3.85-3.70 (4H, m), 3.42
-3.27 (2H, m), 2.90-2.65 (6H, m), 1.15-1.05 (6H, m), 0.9
1 (3H, t, J = 7.4Hz). MS (APCI, m / z) 422 (M + H) ⁺ .

Examples 9 to 20 In the same manner as in Examples 1 to 8, compounds of Examples 9 to 20 were obtained. These are shown in Table 1 and Table 2.

[Table 1]

[0153]

[Table 2]

Example 21 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R) -1-
(2-Methoxyphenyl) ethoxy] propan-2-ol Step 1 (R) -1- (2-methoxyphenyl) ethanol

[Chemical 64] (+)-B-chlorodiisopinocampheylborane (10.
To a solution of 5 g) in tetrahydrofuran (50 ml) was added dropwise 2'-methoxyacetophenone (10.5 g) at -25 ° C. −
After stirring at 25 ° C. for 1 hour, the reaction solution was concentrated under reduced pressure. Diethyl ether (100 ml) and diethanolamine in the residue
(18.1 g) was added and the mixture was stirred at room temperature for 2 hours, then the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and then distilled under reduced pressure (bp 74
The title compound (8.00 g) was obtained after purification at -77 ° C / 1 mmHg).

Step 2 (R) -2-[(1R) -1- (2-methoxyphenyl) ethoxymethyl] oxirane

[Chemical 65] The title compound (930 mg) was obtained in the same manner as in Step 2 of Example 1 from (R) -1- (2-methoxyphenyl) ethanol (1.52 g) obtained in Step 1.

Step 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R) -1-
(2-Methoxyphenyl) ethoxy] propan-2-ol

[Chemical formula 66] (R) -2-[(1R) -1- (2-
Methoxyphenyl) ethoxymethyl] oxirane (417m
From g), in the same manner as in Step 13 of Example 1, the title compound (7
70 mg) was obtained. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.85-7.70 (3H, m), 7.61
(1H, s), 7.50-7.20 (5H, m), 7.00-6.80 (2H, m), 4.88 (1H,
q, J = 6.5Hz), 3.85-3.75 (4H, m), 3.38 (2H, d, J = 5.1Hz),
2.90-2.60 (4H, m), 1.38 (3H, d, J = 6.6Hz), 1.10 (3H, s),
1.07 (3H, s). MS (APCI, m / z) 408 (M + H) ⁺ .

Example 22 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R) -1-
(2-Methoxyphenyl) ethoxy] propan-2-ol hydrochloride

[Chemical formula 67] Obtained in Example 21 in the same manner as in Example 5 (2R)
From -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R) -1- (2-methoxyphenyl) ethoxy] propan-2-ol,
The title compound (810 g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 8.94 (1H, br s), 8.56
(1H, br s), 7.95-7.85 (3H, m), 7.77 (1H, s), 7.57-7.45
(2H, m), 7.42-7.20 (3H, m), 7.05-6.95 (2H, m), 5.61 (1H,
d, J = 4.8Hz), 4.84 (1H, q, J = 6.3Hz), 4.10-3.95 (1H, m),
3.80 (3H, s), 3.40-3.10 (5H, m), 3.00-2.85 (1H, m), 1.32
(3H, d, J = 6.3Hz), 1.26 (6H, s) .MS (APCI, m / z) 408 (M + H-HCl) ⁺ .

Example 23 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) (2-methylphenyl) methoxy ] Propan-2-ol Step 1 N-Methoxy-2, N-dimethylbenzamide

[Chemical 68] o-Toluyl acid chloride (3.09 g), triethylamine (5.
58 ml) in dichloromethane (150 ml) was added with N, O-dimethylhydroxylamine hydrochloride (3.90 g) under ice cooling,
The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.58g).

Step 2 Cyclopropyl 2-methylphenyl ketone

[Chemical 69] In a solution of N-methoxy-2, N-dimethylbenzamide (3.55 g) obtained in Step 1 in tetrahydrofuran (40 ml),
A 1 M cyclopropylmagnesium bromide-tetrahydrofuran solution (29.7 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 12 hours. 4N hydrogen chloride-ethyl acetate solution (10 ml) in the reaction solution
Was added and concentrated under reduced pressure. Dilute the residue with ethyl acetate and
It was washed successively with N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (1.05g).

Step 3 (R)-(Cyclopropyl) (2-methylphenyl) methanol

[Chemical 70] Dichloro [(S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl] ruthenium (II) (851 mg), (1S, 2S)-(−)-1,2 -Diphenylethylenediamine (191 mg), potassium-ter
To a suspension of t-butoxide (270 mg) in isopropanol (90 ml), the cyclopropyl 2-methylphenyl ketone (9.61 g) obtained in Step 2 was added, and hydrogenation under medium pressure (3.0 kgf / cm ² ) was performed at room temperature for 60 hours. )did. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (6.92 g). ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.43 (1H, d, J = 6.8Hz),
7.18-7.09 (3H, m), 4.97 (1H, d, J = 4.6Hz), 4.36 (1H, dd, J =
4.6, 6.4Hz), 2.30 (3H, s), 1.17-1.07 (1H, m), 0.41-0.24
(4H, m) .MS (APCI, m / z) 145 (M + HH ₂ O) ⁺ .

Step 4 (R) -2-[(1R)-(cyclopropyl) (2-methylphenyl) methoxymethyl] oxirane

[Chemical 71] The title compound (1.80 g) was obtained in the same manner as in Step 2 of Example 1 from (R)-(cyclopropyl) (2-methylphenyl) methanol (3.24 g) obtained in Step 3.

Step 5 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) (2-methylphenyl) methoxy] Propan-2-ol

[Chemical 72] The title compound (1.17) was obtained in the same manner as in Step 13 of Example 1 from (R) -2-[(1R)-(cyclopropyl) (2-methylphenyl) methoxymethyl] oxirane (655 mg) obtained in Step 4. g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.90-7.70 (3H, m), 7.6
6 (1H, s), 7.50-7.25 (4H, m) 7.20-7.10 (3H, m), 4.64 (1H,
br s), 4.06 (1H, d, J = 7.4Hz), 3.70-3.50 (1H, m), 3.30-
3.10 (2H, m), 2.80-2.50 (4H, m), 2.31 (3H, s), 1.50-0.85
(2H, m), 0.60-0.10 (4H, m). MS (APCI, m / z) 417 (M + H) ⁺ .

Example 24 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) (2-methoxyphenyl) methoxy ] Propan-2-ol Step 1 2, N-dimethoxy-N-methylbenzamide

[Chemical formula 73] Example 2 from 2-methoxybenzoic acid chloride (3.41 g)
The title compound (3.56 g) was obtained in the same manner as in Step 1 of 3.

Step 2 Cyclopropyl 2-methoxyphenyl ketone

[Chemical 74] The title compound (2.27 g) was obtained from 2, N-dimethoxy-N-methylbenzamide (3.55 g) obtained in Step 1 in the same manner as in Step 2 of Example 23. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.59 (1H, dd, J = 7.5, 1.7H
z), 7.48-7.42 (1H, m), 7.02-6.97 (2H, m), 3.91 (3H, s),
2.77-2.68 (1H, m), 1.25-1.20 (2H, m), 1.01-0.95 (1H, m). MS (ESI, m / z) 177 (M + H) ⁺ .

Step 3 (R)-(Cyclopropyl) (2-methoxyphenyl)
methanol

[Chemical 75] The title compound (3.55 g) was obtained from cyclopropyl 2-methoxyphenyl ketone (3.52 g) obtained in Step 2 in the same manner as in Step 3 of Example 23. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.40 (1H, dd, J = 1.6, 7.5H
z), 7.26 (1H, dt, J = 1.7, 7.8Hz), 7.00-6.89 (2H, m), 4.2
0 (1H, br d, J = 8.4Hz), 3.87 (3H, s), 2.83 (1H, brs), 1.42
-1.30 (1H, m), 0.70-0.61 (1H, m), 0.57-0.44 (2H, m), 0.3
7-0.27 (1H, m) .MS (ESI, m / z) 161 (M + HH ₂ O) ⁺ .

Step 4 (R) -2-[(1R)-(cyclopropyl) (2-methoxyphenyl) methoxymethyl] oxirane

[Chemical 76] The title compound (840 mg) was obtained in the same manner as in Step 2 of Example 1 from (R)-(cyclopropyl) (2-methoxyphenyl) methanol (1.78 g) obtained in Step 3.

Step 5 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) (2-methoxyphenyl) methoxy] Propan-2-ol

[Chemical 77] From (R) -2-[(1R)-(cyclopropyl) (2-methoxyphenyl) methoxymethyl] oxirane (586 mg) obtained in Step 4, the title compound (970 mg) was prepared in the same manner as in Step 13 of Example 1. ) Got. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.83-7.70 (3H, m), 7.61
(1H, s), 7.50-7.37 (3H, m), 7.35-7.20 (2H, m), 7.00-6.8
2 (2H, m), 4.28 (1H, d, J = 7.8Hz), 3.83-3.70 (4H, m), 3.42
-3.30 (2H, m), 2.90-2.60 (4H, m), 1.25-1.10 (7H, m), 0.6
0-0.50 (1H, m), 0.45-0.30 (3H, m). MS (APCI, m / z) 434 (M + H) ⁺ .

Example 25 to Example 56 Example 25 to Example 56 are carried out in the same manner as Example 1 to 24.
Was obtained. These are shown in Tables 3 to 7.

[0169]

[Table 3]

[0170]

[Table 4]

[0171]

[Table 5]

[0172]

[Table 6]

[0173]

[Table 7]

Example 57 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-hydroxymethylphenyl) methoxy] propane- 2-ol process 1 2-bromo-1-tert-butyldimethylsilyloxymethylbenzene

[Chemical 78] 2-Bromobenzyl alcohol (25.0 g) was dissolved in N, N-dimethylformamide (150 ml), and imidazole (20.
0 g) and tert-butyldimethylchlorosilane (22.2 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (40.9 g).

Step 2 (Cyclopropyl) (2-tert-butyldimethylsilyloxymethylphenyl) methanol

[Chemical 79] Magnesium (2.20 g) was suspended in tetrahydrofuran (4 ml), and iodine (2 mg) was added. 2-Bromo-1-tert-butyldimethylsilyloxymethylbenzene (24.0 g) obtained in step 1 was dissolved in tetrahydrofuran (10 ml).
The solution was added dropwise over 30 minutes and then heated under reflux for 1 hour.
Tetrahydrofuran is added to this and 1M 2-ter
A t-butyldimethylsilyloxymethylphenyl magnesium bromide-tetrahydrofuran solution was prepared. Next, sicle propane carboxaldehyde (2.80 g) was dissolved in tetrahydrofuran (120 ml), and 1M 2-tert
A -butyldimethylsilyloxymethylphenyl magnesium bromide-tetrahydrofuran solution (80 ml) was added dropwise over 50 minutes under ice cooling, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous ammonium chloride solution (8 ml) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by further drying over anhydrous magnesium sulfate and concentrating under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5) to obtain the title compound (8.20 g). ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.53-7.34 (2H, m), 7.2
5-7.20 (2H, m), 4.91 (1H, d, J = 4.6Hz), 4.81 (2H, s), 4.31
(1H, dd, J = 4.7, 6.5Hz), 1.20-1.10 (1H, m), 0.91 (9H, s),
0.47-0.23 (4H, m), 0.10 (3H, s), 0.08 (3H, s). MS (APCI, m / z) 275 (M + HH ₂ O) ⁺ .

Step 3 (R) -2-[(cyclopropyl) (2-tert-butyldimethylsilyloxymethylphenyl) methoxymethyl] oxirane

[Chemical 80] (Cyclopropyl) [2- (tert) obtained in Step 2
The title compound (1.04 g) was obtained from -butyldimethylsilyloxymethyl) phenyl] methanol (2.11 g) in the same manner as in Step 2 of Example 1.

Step 4 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) Phenyl] methoxy] propan-2-ol

[Chemical 81] (R) -2-[(cyclopropyl) obtained in Step 3
[2- (tert-Butyldimethylsilyloxymethyl) phenyl] methoxymethyl] oxirane (546 mg) was used, and the title compound (345 m) was obtained in the same manner as in Step 13 of Example 1.
g) was obtained.

Step 5 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (2-hydroxymethylphenyl) methoxy] propane-2 -All

[Chemical formula 82] (2R) -1- [1,1-dimethyl-obtained in step 4
2- (Naphthalen-2-yl) ethylamino] -3-
[(Cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methoxy] propan-2-ol (365 mg) was dissolved in tetrahydrofuran (4 ml), and tetrabutylammonium fluoride-1M was added under ice cooling.
Tetrahydrofuran solution (0.73 ml) was added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution (1 m
l) was added, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 98:
Purification in 2) gave the title compound (221 mg). ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.90-7.70 (3H, m), 7.6
7 (1H, s), 7.50-7.20 (7H, m), 5.13 (1H, brs), 4.90-4.40
(3H, m), 4.20-4.05 (1H, m), 3.70-3.50 (1H, m), 3.30-3.1
0 (2H, m), 2.80-2.50 (4H, m), 1.40-0.85 (7H, m), 0.60-0.
10 (4H, m). MS (APCI, m / z) 434 (M + H) ⁺ .

Example 58 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) [2- (hydroxymethyl)] Phenyl] methoxy] propan-2-ol hemifumarate Step 1 2-tert-butyldimethylsilyloxymethyl-N
-Methoxy-N-methylbenzamide

[Chemical 83] N, O-dimethylhydroxylamine hydrochloride (58.5 g) and aluminum chloride (40.0 g) were sequentially added to a solution of phthalide (26.8 g) in methylene chloride (600 ml) under ice cooling, and then triethylamine (139 ml) was added for 40 minutes. Was added dropwise and stirred at room temperature for 12 hours. The reaction solution was poured into diluted hydrochloric acid, and the organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2-hydroxymethyl-N-methoxy-N-.
Methylbenzamide was obtained. The obtained 2-hydroxymethyl-N-methoxy-N-methylbenzamide was added to N, N
-Dissolved in dimethylformamide (300 ml), imidazole (9.53 g), tert-butyldimethylchlorosilane (2
1.1 g) was added and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3). The title compound (42.0 g) was obtained.

Step 2 (Cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methanone

[Chemical 84] 2-tert-butyldimethylsilyloxymethyl-N-methoxy-N-methylbenzamide obtained in step 1
The title compound (18.4 g) was obtained from (21.7 g) in the same manner as in Step 2 of Example 23. ¹ H-NMR (300MHz, δppm, CDCl ₃ ) 7.88 (1H, dd, J = 1.1, 7.7H
z), 7.78 (1H, d, J = 7.3Hz), 7.53 (1H, dt, J = 1.2, 7.6Hz),
7.35 (1H, t, J = 7.2Hz), 4.97 (2H, s), 2.57-2.48 (1H, m),
1.24-1.20 (2H, m), 1.06-1.01 (2H, m), 0.95 (9H, s), 0.11
(6H, s).

Step 3 (R)-(Cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methanol

[Chemical 85] Dichloro [(S) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] [(S) -1,1'-
Obtained in Step 2 in a suspension of bis (p-methoxyphenyl) -2-isopropylethane-1,2-diamine] ruthenium (II) (111 mg) and potassium-tert-butoxide (44.9 mg) in isopropanol (100 ml). The resulting (cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methanone (5.81 g) was added, and the mixture was cooled to 36 at room temperature.
Hydrogen was added under pressure (5.0 kgf / cm ² ) for an hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound.
(5.82g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.49-7.46 (1H, m), 7.3
9-7.37 (1H, m), 7.25-7.22 (2H, m), 4.99 (1H, br s), 4.81
(2H, s), 4.32 (1H, d, J = 6.3Hz), 1,32-1.09 (1H, m), 0.91
(9H, s), 0.49-0.22 (4H, m), 0.10 (3H, s), 0.08 (3H, s). MS (ESI, m / z) 275 (M + HH ₂ O) ⁺ .

Step 4 (R) -2-[(1R)-(cyclopropyl) [2-
(Tert-Butyldimethylsilyloxymethyl) phenyl] methoxymethyl] oxirane

[Chemical 86] (R)-(cyclopropyl) [2- obtained in Step 3
The title compound (2.52 g) was obtained from (tert-butyldimethylsilyloxymethyl) phenyl] methanol (2.92 g) in the same manner as in Step 2 of Example 1.

Step 5 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) [2- (tert-butyldimethyl) Silyloxymethyl) phenyl] methoxypropan-2-ol

[Chemical 87] (R) -2-[(1R)-(cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methoxymethyl] oxirane (1.2) obtained in Step 4
2g) in the same manner as in Step 3 of Example 1 to give the title compound (1.
79 g) was obtained.

Step 6 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) [2- (hydroxymethyl) phenyl ] Methoxypropan-2-ol

[Chemical 88] (2R) -1- [1,1-dimethyl-obtained in step 5
2- (Naphthalen-2-yl) ethylamino] -3-
The title compound (710 mg) was obtained from [(1R)-(cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methoxypropan-2-ol (1.70 g) in the same manner as in Step 5 of Example 57. Got

Step 7 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1R)-(cyclopropyl) [2- (hydroxymethyl) phenyl ] Methoxy] propan-2-ol hemifumarate

[Chemical 89] (2R) -1- [1,1-dimethyl-obtained in step 6
2- (Naphthalen-2-yl) ethylamino] -3-
[(1R)-(Cyclopropyl) [2- (hydroxymethyl) phenyl] methoxy] propan-2-ol (700
mg) was dissolved in methanol (15 ml), fumaric acid (94 mg) was added, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound (720 mg). ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.95-7.85 (3H, m), 7.7
3 (1H, s), 7.55-7.20 (7H, m), 6.51 (1H, s), 4.63 (1H, d, J =
13.2Hz), 4.56 (1H, d, J = 13.2Hz), 4.13 (1H, d, J = 7.5Hz),
3.90-3.80 (1H, brs), 3.40-3.15 (2H, m), 3.05-2.95 (3H,
m), 2.80-2.65 (1H, m), 1.20-1.00 (7H, m), 0.60-0.20 (4
H (m) .MS (ESI, m / z) 434 (M + H-1 / 2C ₄ H ₄ O ₄ ) ⁺ .

Example 59 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1S)-(cyclopropyl) [2- (hydroxymethyl)] Phenyl] methoxy] propan-2-ol hemifumarate Step 1 (S)-(cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methanol

[Chemical 90] Dichloro [(R) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] [(R) -1,1'-
Bis (p-methoxyphenyl) -2-isopropylethane-1,2-diamine] ruthenium (II) (111 mg), potassium-tert-butoxide (44.9 mg) in isopropanol (100 ml) suspension in Example 58. (Cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methanone obtained in 2 (5.81 g) was added,
Medium-pressure hydrogenation (5.0 kgf / cm ² ) was performed at room temperature for 36 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5),
The title compound (5.50 g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.49-7.46 (1H, m), 7.4
0-7.37 (1H, m), 7.22-7.20 (2H, m), 4.99 (1H, d, J = 4.2Hz),
4.81 (2H, s), 4.31 (1H, dd, J = 4.5, 6.6Hz), 1.20-1.09 (1
H, m), 0.91 (9H, s), 0.47-0.21 (4H, m), 0.10 (3H, s), 0.0
8 (3H, s) .MS (ESI, m / z) 275 (M + HH ₂ O) ⁺ .

Step 2 (R) -2-[(1S)-(cyclopropyl) [2-
(Tert-Butyldimethylsilyloxymethyl) phenyl] methoxymethyl] oxirane

[Chemical Formula 91] (S)-(cyclopropyl) [2- obtained in Step 1
The title compound (2.62 g) was obtained from (tert-butyldimethylsilyloxymethyl) phenyl] methanol (2.92 g) in the same manner as in Step 2 of Example 1.

Step 3 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1S)-(cyclopropyl) [2- (tert-butyldimethyl) Silyloxymethyl) phenyl] methoxy] propan-2-ol

[Chemical Formula 92] (R) -2-[(1S)-(cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methoxymethyl] oxirane obtained in Step 2 (1.2
2g) in the same manner as in Step 3 of Example 1 to give the title compound (1.
80g) was obtained.

Step 4 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1S)-(cyclopropyl) [2- (hydroxymethyl) phenyl ] Methoxy] propan-2-ol

[Chemical formula 93] (2R) -1- [1,1-dimethyl-obtained in step 3
2- (Naphthalen-2-yl) ethylamino] -3-
The title compound (1.26) was prepared from [(1S)-(cyclopropyl) [2- (tert-butyldimethylsilyloxymethyl) phenyl] methoxy] propan-2-ol (1.70 g) in the same manner as in Step 5 of Example 57. g) was obtained.

Step 5 (2R) -1- [1,1-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(1S)-(cyclopropyl) [2- (hydroxymethyl) phenyl ] Methoxy] propan-2-ol hemifumarate

[Chemical 94] (2R) -1- [1,1-dimethyl-obtained in step 4
2- (Naphthalen-2-yl) ethylamino] -3-
[(1S)-(Cyclopropyl) [2- (hydroxymethyl) phenyl] methoxy] propan-2-ol (1.2
5g) in the same manner as in Step 7 of Example 58.
(1.33g) was obtained. ¹ H-NMR (300MHz, δppm, DMSO-d ₆ ) 7.90-7.80 (3H, m), 7.7
1 (1H, s), 7.50-7.20 (7H, m), 6.48 (1H, s), 4.63 (1H, d, J =
13.2Hz), 4.56 (1H, d, J = 13.2Hz), 4.12 (1H, d, J = 7.8Hz),
3.80-3.70 (1H, brs), 3.35-3.15 (2H, m), 2.95-2.85 (3H,
m), 2.80-2.65 (1H, m), 1.20-1.00 (7H, m), 0.60-0.20 (4
H (m) .MS (ESI, m / z) 434 (M + H-1 / 2C ₄ H ₄ O ₄ ) ⁺ .

Example 60 to Example 160 Example 60 to Example 16 were carried out in the same manner as Example 1 to 59.
0 compound was obtained. These are shown in Tables 8 to 23.

[Table 8]

[0192]

[Table 9]

[0193]

[Table 10]

[0194]

[Table 11]

[0195]

[Table 12]

[0196]

[Table 13]

[0197]

[Table 14]

[0198]

[Table 15]

[0199]

[Table 16]

[0200]

[Table 17]

[0201]

[Table 18]

[0202]

[Table 19]

[0203]

[Table 20]

[0204]

[Table 21]

[0205]

[Table 22]

[0206]

[Table 23]

Test Example Next, the biological activity of the compound of the present invention was tested. Test Example 1 Evaluation of Calcium Receptor Antagonism Using Reporter Gene A rat adrenal-derived cell line into which a luciferase cDNA and a human calcium receptor cDNA were introduced and transformed was used, and a medium (0.5% dialyzed horse serum and The cells were cultured overnight in F12 medium containing 0.25% dialyzed fetal bovine serum. The next day, the test compound group contained 0.01-100 mM test compound.
A dimethyl sulfoxide solution containing 100-fold diluted with a medium was added in an amount of 10 μl per well. To the control group, 10 μl of 50 mM calcium chloride-containing medium was added per well so that the final concentration of calcium in the medium was 5 mM. Only the medium was added to the blank group. After culturing for 4 hours, a luciferase substrate (Picagene LT-2.0, Toyo Ink) was added, and the luciferase activity was measured with a photoluminometer. The inhibition rate (%) was calculated from the obtained measured values by the following formula.

[Equation 1] From this, the concentration showing the 50% inhibition rate (IC ₅₀ ) was determined.

A compound in which R ²¹ is a hydrogen atom

[Chemical 95] For Comparative Example 1 as well, a test was conducted for reference. The results are shown in Tables 24 and 25.

Test Example 2 PTH secretion promoting action A 6-9 week-old male SD rat (Charles River Japan) fasted for 20 hours was treated with a test compound in a solvent (5% ethanol, 0.5% methylcellulose aqueous solution) for 30 m.
Oral doses of g / 5 ml / kg and 100 mg / 5 ml / kg. Control group only 5ml solvent
Orally administered at a dose of / kg. Immediately before administration of the test compound and 0.5, 1, 2, 4, 6 hours after administration, blood was collected from the tail vein and serum was collected. Serum PTH concentration was measured with a rat PTH (1-84) ELISA kit (Nippon Mediphysics). Before administration, 30 minutes after administration and administration 4
The results of PTH concentration in serum after the lapse of time are shown in Table 24 and 30.
Table 25 shows the results of the serum PTH concentration before administration, 30 minutes after administration, and 2 hours after administration in the mg / 5 ml / kg dose administration group. In addition, FIGS. 1, 2 and 3 show changes over time in the serum PTH concentration at a dose of 30 mg / kg in Example 22, Example 23 and Example 24. In addition, for reference, FIG. 4 shows a graph of FIG.
Shows the time course of serum PTH concentration at a dose of 30 mg / kg of NPS-2143.

[0210]

[Table 24]

[0211]

[Table 25]

Test Example 3 PTH Secretion-Promoting Action A test compound was used as a solvent (5%) in 4 to 6-week-old female Fischer rats (Charles River Japan) that had been fasted for 20 hours.
Oral administration was carried out at a dose of 30 mg / 5 ml / kg using ethanol and a 0.5% aqueous solution of methyl cellulose). In the control group, the solvent alone was orally administered at a dose of 5 ml / kg. Immediately before administration of the test compound and administration of 0.5,
One, two, and four hours later, blood was collected from the tail vein and serum was collected. Rat PTH (1-84) E
The measurement was performed using a LISA kit (Nippon Mediphysics).
Serum PTH before administration, 30 minutes after administration, and 4 hours after administration
The results of the concentration are shown in Table 26.

[0213]

[Table 26]

When the blood level of PTH is increased by inhibiting the action of calcium receptor to treat osteoporosis, it is considered that the compound used therefor must have at least the following properties. . The compounds have a sufficient antagonistic effect on calcium receptors. That is, the IC ₅₀ values of those compounds are sufficiently low. By the way, international publication WO99 /
No. 512124, “In general, compounds having a lower IC ₅₀ value in an assay for inhibitors of calcium receptors are better compounds. IC ₅₀ 's of ₅₀ μM and above.
Compounds with values are considered inactive. Preferred compounds have IC ₅₀ values of less than 10 [mu] M, more preferred compounds have an IC ₅₀ value of 1 [mu] M, most preferred compounds have IC ₅₀ values less than or equal 0.1 [mu] M. It is described as ". Administration of these compounds should sufficiently improve blood PTH concentration. The blood concentration over time when these compounds are administered is non-sustaining. Desirably, the PTH concentration before the administration is restored 3 or 4 hours after the administration of the compound.

From the above test results, it is clear that the compound of the present invention has the above-mentioned properties. As shown in Tables 24 and 25, the compounds of the present invention each have an IC ₅₀ value of 1 μM or less, and have a sufficient antagonistic action on calcium receptors. It can be said that all the compounds of the present invention are preferable compounds from the viewpoint of IC ₅₀ value. About; as shown in Tables 24 to 26 and FIGS. 1 to 3, 30 mg / kg after 30 minutes
In the administration group, 2.0-3.0 times as much as before administration, 100 mg / k
In the g-administered group, the PTH concentration in blood was 2.2 to 3.6 times that before administration, and it was confirmed that all the compounds of the present invention have an excellent PTH secretion-promoting action. On the other hand, as shown in Table 24 and FIG. 4, the compound of Comparative Example 1 had a PTH concentration in blood which was 1.3 times as high as 30 minutes after administration even at a dose of 100 mg / kg, and no excellent PTH secretion promoting action was observed.
It cannot be expected as a medicine. About; Table 24-Table 2
As shown in Fig. 6 and Figs.
Secretion peaks 30 minutes after administration, then rapidly decreases, and returns to blood PTH concentration before administration approximately 2 to 4 hours later. It is clear that the compound of the present invention is also excellent in this respect. On the other hand, NPS-shown in the literature
We also conducted a supplementary test on 2143 and found that NPS
It was confirmed that the PTH secretion promoting action of -2143 was also persistent (from FIG. 5).

[0216]

The compound of the general formula [I] according to the present invention has an excellent calcium receptor antagonistic action, as is clear from Test Example 1 above. Therefore, diseases associated with abnormal calcium homeostasis, namely osteoporosis, hypoparathyroidism, osteosarcoma, periodontal disease, bone fracture, osteoarthritis,
It is expected to be useful as a therapeutic drug for rheumatoid arthritis, Paget's disease, liquid hypercalcemia, autosomal dominant hypocalcemia and the like. Further, as is clear from Test Examples 2 and 3, the compound of the present invention has a transient action of promoting PTH secretion. Therefore, it is particularly useful as a therapeutic drug for osteoporosis.

[Brief description of drawings]

FIG. 1 is a graph showing the time course of serum PTH concentration after administration of Example 22 at 30 mg / kg to rats.

FIG. 2 is a view showing the time course of serum PTH concentration after administration of Example 23 at 30 mg / kg to rats.

FIG. 3 is a graph showing the time course of serum PTH concentration after administration of Example 24 at 30 mg / kg to rats.

FIG. 4 is a graph showing the time course of serum PTH concentration after administration of Comparative Example 1 to rats at 100 mg / kg.

FIG. 5 is a graph showing the time course of serum PTH concentration after administration of 30 mg / kg of NPS-2143 to rats.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/277 A61K 31/277 4C206 31/341 31/341 4H006 31/36 31/36 31/381 31 / 381 31/426 31/426 A61P 3/14 A61P 3/14 19/00 19/00 19/02 19/02 19/08 19/08 19/10 19/10 27/16 27/16 29/00 101 29 / 00 101 35/00 35/00 43/00 111 43/00 111 123 123 C07C 217/76 C07C 217/76 229/38 229/38 235/42 235/42 235/60 235/60 237/30 237 / 30 255/54 255/54 311/21 311/21 311/29 311/29 C07D 277/24 C07D 277/24 307/42 307/42 317/54 317/54 317/58 317/58 333/16 333 / 16 333/28 333/28 333/32 333/32 333/40 333/40 333/56 333/56 (72) Inventor Takashi Nakagawa 1-1 No. 1 Murasakicho, Takatsuki-shi, Osaka Japan Tobacco Inc. Pharmaceutical Synthesis F-term in the laboratory (see Remarks) 4C022 BA01 CA04 4C023 BA02 FA03 HA02 4C033 AD16 4C037 HA08 4C086 AA01 AA02 AA03 AA04 BA03 BA13 BB02 BC78 MA01 MA04 NA14 NA15 ZA67 ZA96 ZA97 ZB15 ZB26 ZC42 4C206 AA01 AA02 AA03 AA04 DA18 DB15 FA05 GA09 HA14 MA01 MA04 NA14 NA15 ZA67 ZA96 ZA97 ZB15 ZB26 ZC42 4H006 AA01 AA03 AB20 BJ20 BJ50 BM10 BM30 BM71 BM72 BM73 BN10 BN30 BP10 BP30 BU32

Claims (18)

[Claims] 1. A general formula [I] [Chemical 1] [In the formula, R¹Is an aryl group or a heteroaryl group
The reel group and the heteroaryl group are halogen atom, C_1-6
Alkyl group, halo C_1-6Alkyl group, hydroxy C _1-6A
Rukiru group, C_1-6Alkoxy C_1-6Alkyl group, hydroxyl group,
C_1-6Alkoxy group, halo C_1-6Alkoxy group, mercap
G group, C_1-6Alkylthio group, C_1-6Alkyl sulfani
Lu group, C_1-6Alkylsulfonyl group, aminosulfonyl
Base, C_1-6Alkylsulfamoyl group, di-C_1-6Alkyl
Sulfamoyl group, carboxy group, (C_1-6Arcoki
Si) Carbonyl group, C_1-7Acyl group, carbamoyl group,
(C_1-6Alkyl) carbamoyl group, di (C_1-6Archi
) Carbamoyl group, cyano group, nitro group, amino group,
C_1-6Alkylamino group, di-C_1-6Alkylamino group, C
_{1- 7}Acylamino group, C_1-3An alkylenedioxy group, [Chemical 2] (Where R^AIs (C_1-6Alkoxy) carbonyl group or
Represents a carboxy group, R ^BIs a hydrogen atom or C_1-6Alkyl
Represents a group. Substituted with 1 to 3 substituents selected from
You may } Is represented; R²Is C_1-6Alkyl group (the C
_1-6Alkyl group is halogen atom, hydroxyl group, C_1-6Arcoki
Si group, carboxy group, amino group, C_1-6Alkylamino
Group, di-C_1-6Selected from alkylamino and oxo groups
It may be substituted with 1 to 3 substituents. ), C_3-7
Cycloalkyl group, C_2-6Alkenyl group, C_2-6Alkini
Group, aralkyl group, carboxy group, (C_1-6Arcoki
Si) represents a carbonyl group or a cyano group; R³Is hydrogen
Child, C_1-6Alkyl group, hydroxyl group, C_1-6Alkoxy group,
Lucapto group, C_1-6Alkylthio group, carboxy group,
(C_1-6Alkoxy) carbonyl group, (C_1-6Alkyl)
Carbamoyl group, di (C_1-6Alkyl) carbamoyl
Group, amino group, C_1-6Alkylamino group or di-C_1-6Al
Represents a kylamino group; R^FourIs a hydrogen atom, C_1-6Alkyl group
Or C_2-6Represents an alkenyl group or R³And R ^FourTogether
Represents an oxo group; R^Five, R⁶Are each C_1-6A
Represents an alkyl group or R^FiveAnd R⁶Together those
Represents a cyclopropyl group together with the carbon atom to which it is attached; R
⁷Is an aryl group or a heteroaryl group (the aryl group and
And heteroaryl groups are halogen atoms, C_1-6Alkyl
Group, halo C_1-6Alkyl group, hydroxy C_1-6Alkyl
Base, C_3-7Cycloalkyl group, hydroxyl group, C_1-6Alkoxy
Group, halo C_1-6Alkoxy group, carboxy group, (C_1-6A
Lucoxy) carbonyl group, nitro group, cyano group, C_1-6
Alkylsulfonyloxy group, carbamoyl group and C
_1-31 to 3 units selected from alkylenedioxy groups
It may be substituted with a substituent. } Is shown; X¹Is a single bond, C
_1-6Alkylene or C_2-6Alkynylene (the C_1-6Archi
Ren and C_2-6Alkynylene is C_1-6Alkyl group or oki
It may be substituted with a so-group. ); X²Is C_1-6Archi
Ren (the C_1-6Alkylene is C_1-6Alkyl group or halo C
_1-6It may be substituted with an alkyl group. ); X³Is simply
Bond or C_1-6Alkylene (the C_1-6Alkylene is a hydroxyl group
Alternatively, it may be substituted with an oxo group. ); X^Fouras well as
X^FiveTogether form a single bond, methylene, NH, oxygen source
Child, sulfur atom, C = O, -CH₂NH-, -CH₂O-,
-CH₂S-, -CH₂CO-, -NHCH₂-, -OC
H₂-, -SCH₂-, -COCH₂-, -CH = CH-
Alternatively, it represents -C≡C-. ] The compound shown by
Or a solvate thereof or a prodrug thereof. 2. A compound represented by the general formula [I-2]: Wherein, R ^11, R ¹² are the same or different and each is a hydrogen atom, a halogen atom, C _1-4 alkyl group, hydroxy C _1-6
An alkyl group, a C _1-6 alkoxy, a C _1-6 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, a cyano group or a nitro group, or R ¹¹ and R ¹² together form a C _1-3 alkylenedi Represents an oxy group, R ²¹ represents a C _1-4 alkyl group (the alkyl group may be substituted with a C _1-4 alkoxy group),
_{Represents a} C _3-5 cycloalkyl group, a C _2-4 alkenyl group or an aralkyl group, and represents R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² ,
X ³ , X ⁴ and X ⁵ each have the same meaning as in claim 1. ] The compound shown by these, its salt, its solvate, or its prodrug. 3. A compound represented by the general formula [I-3]: (Here, R ⁷¹ and R ⁷² are the same or different and each independently represent a hydrogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group, or they are taken together to form —CH═CH—CH═CH— or C _1-3 represents an alkylenedioxy group, R ¹¹ ,
R ¹² and R ²¹ have the same meanings as in claim 2. )
The compound, salt or solvate or prodrug thereof according to claim 2, which is represented by 4. R¹¹, R¹²Are the same or different
Hydrogen atom, chlorine atom, methyl group, hydroxymethyl
Group, hydroxyl group, methoxy group, cyano group or nitro group
Yes or R¹¹And R¹²Together with methylene dioki
R group ^{twenty one}C may branch_1-4Alkyl group
Is C_3-5The compound according to claim 3, which is a cycloalkyl group.
Or its salt or its solvate or its prodrug
Gu. 5. The compound according to claim 4, wherein R ²¹ is a methyl group, an ethyl group, a cyclopropyl group or a cyclobutyl group, a salt thereof, a solvate thereof or a prodrug thereof. 6. R ¹¹ is a hydrogen atom and R ¹² is a methyl group, a methoxy group or a hydroxymethyl group,
Or a compound, a salt thereof, a solvate thereof, or a prodrug thereof according to claim 5, wherein R ¹¹ and R ¹² together are a methylenedioxy group, and R ²¹ is a methyl group or a cyclopropyl group. 7. The method according to claim 6, wherein R ²¹ is a cyclopropyl group.
The compound, salt or solvate thereof, or prodrug thereof according to 1. 8. R ⁷¹ and R ⁷² are —CH═CH—CH═CH.
The compound of claim 7, a salt thereof, a solvate thereof, or a prodrug thereof. 9. R ⁷¹ and R ⁷² are each a C _1-4 alkyl group or C _1-4.
The compound according to claim 7, which is a group selected from an alkoxy group, a salt thereof, a solvate thereof, or a prodrug thereof. 10. (2R) -1- [1,1-dimethyl-
2- (Naphthalen-2-yl) ethylamino] -3-
[(Cyclopropyl) (2-methoxyphenyl) methoxypropan-2-ol, (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino]]
-3-[(cyclopropyl) (2-methylphenyl) methoxypropan-2-ol, (2R) -1- [1,1
-Dimethyl-2- (naphthalen-2-yl) ethylamino] -3-[(cyclopropyl) (phenyl) methoxy] propan-2-ol, (2R) -1- [1,1-
Dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (2-methoxyphenyl) ethoxy]
Propan-2-ol, (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino]-
3- [1- (2-methylphenyl) ethoxy] propan-2-ol, (2R) -1- [1,1-dimethyl-2
-(Naphthalen-2-yl) ethylamino] -3- [1
-(2-Methoxyphenyl) propoxy] propane-2
-Ol, (2R) -1- [1,1-dimethyl-2-
(Naphthalen-2-yl) ethylamino] -3- [1-
(2-Cyanophenyl) ethoxy] propan-2-ol, (2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (3-methoxyphenyl) ) Ethoxy] propan-2-ol,
(2R) -1- [1,1-dimethyl-2- (naphthalen-2-yl) ethylamino] -3- [1- (3-methylphenyl) ethoxy] propan-2-ol and (2
R) -1- [1,1-dimethyl-2- (naphthalene-2
-Yl) ethylamino] -3-[(cyclopropyl)
(2-hydroxymethylphenyl) methoxypropane-
The compound according to claim 1, a salt thereof, a solvate thereof, or a prodrug thereof selected from 2-ol. 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, a salt thereof, a solvate thereof or a prodrug thereof as an active ingredient. 12. A calcium receptor antagonist comprising the compound according to any one of claims 1 to 10, a salt thereof, a solvate thereof, or a prodrug thereof as an active ingredient. 13. A therapeutic agent for osteoporosis, which comprises the compound according to any one of claims 1 to 10, a salt thereof, a solvate thereof, or a prodrug thereof as an active ingredient. 14. A compound represented by the general formula [II]: [In the formula, R ¹¹ 'is a halogen atom, a C _1-4 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, a hydroxyl group, a C _1-4 alkoxy group, tert-butyl. It represents a dimethylsilyloxymethyl group, a cyano group or a nitro group. ] The compound shown by these, its salt, or its solvate. 15. In the general formula [II], R ¹¹ ′ is C _1-4.
The compound according to claim 14, which is an alkyl group, a hydroxy C _1-6 alkyl group or a C _1-4 alkoxy group, a salt thereof or a solvate thereof. 16. A compound represented by the general formula [III]: [Wherein R ¹¹ ″ is a halogen atom, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, a hydroxyl group, C
_{1-4 represents an} alkoxy group, a tert-butyldimethylsilyloxymethyl group, a cyano group or a nitro group. ] The compound shown by these, its salt, or its solvate. 17. In the general formula [III], R ¹¹ ″ is C
The compound according to claim 16, which is a _1-4 alkoxy group, or a salt or solvate thereof. 18. A compound represented by the general formula [IV]: [In the formula, R ⁸ represents a carboxy group, a nitro group, a tert-butoxycarbonylamino group or a benzyloxycarbonylamino group. ] The compound shown by these, its salt, or its solvate.