JPH0725854A - Condensed benzeneoxyacetic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a preventing and treating throm bosis, arteriosclerosis, ischemic heart disease, gastric ulcer, hypertension, etc., having PGI2 receptor agonist action. CONSTITUTION:A compound of formula I [group of formula II is group of formula III to formula VI (e is 3-5; f is 1-3; p and r are 1-4; q is 0-2; s is 0-3); A is group of formula VII to formula X (l) is 1-3; m is 1 or 2; R<4> is H, 1-4C alkyl, phenyl or 1-4C alkyl substituted with one or two hetero rings groups of 4- to 7-membered mono ring containing 1 or 2 phenyls or Ns; Y is O or S), etc.; R<1> is OH, 1-12C alkoxy, NR<2>R<3> (R<2> and R<3> are H, 1-4C alkyl or R<2>, R<3> and adjacent N form amino acid residue)], its nontoxic salt or its acid addition salt such as [2-(4-diphenylmethylpyrazol-2-yl)methyl-1,2,3,4,-tetrahydronaphthalen- 5-yloxy]acetic acid of formula XI.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a condensed benzeneoxyacetic acid derivative. More specifically, 1) General formula (I)

[0002]

[Chemical 44]

(Wherein all symbols have the same meanings as described below), a condensed benzeneoxyacetic acid derivative,
A non-toxic salt thereof and an acid addition salt thereof, 2) a method for producing them, and 3) a drug containing them as an active ingredient.

[0004]

BACKGROUND OF THE INVENTION Prostaglandin I ₂ (PGI ₂ )
Is a natural physiologically active substance having the following structure, which is produced from prostaglandin H ₂ (PGH ₂ ) in an in vivo metabolic pathway called arachidonic acid cascade.

[0005]

[Chemical formula 45]

[Nature, 263, 663 (1976), Prostaglandi
ns, 12 , 685 (1976), ibid, 12 , 915 (1976), ibid, 1
3 , 3 (1977) and Chemical and Engineering News, 1
See February 20, 17 (1976)] PGI ₂ has an extremely strong inhibitory effect on platelet aggregation.
It has been confirmed to have actions such as platelet aggregation dissociation, platelet adhesion inhibition, vasodilation, and gastric acid secretion inhibition. Therefore, PGI ₂ is considered to be useful for the treatment of thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcer, hypertension, etc. However, its application as a medicine is limited. Therefore, various PGI ₂ derivatives have been synthesized, and a lot of researches have been carried out for maintaining the duration of action and separating action. However, at present, satisfactory results have not been obtained. Therefore, recently, the above 2
In order to solve one problem, in view of PGI ₂ receptor level, research is being conducted to find out a PGI ₂ receptor agonist having a new type of skeleton, which is useful for treating or preventing the above-mentioned diseases.

[0007]

_2. Description of the Related Art Among the compounds having no PGI ₂ skeleton, it has been reported in the literature that the compounds described below are compounds that bind to PGI ₂ receptors and suppress platelet aggregation, that is, PGI ₂ receptor agonists.

[0008]

[Chemical formula 46]

[Brit. J. Pharmacol., 76 ; 423 (1982), ibid, 84 ; 595 (1985), ibid, 86 ; 643 (1985) and published patent publication 55-501098]

[0010]

[Chemical 47]

[Brit. J. Pharmacol., 76 ; 423 (1982), ibid, 84 ; 595 (1985), ibid, 86 ; 643 (1985) and published patent publication 55-501127]

[0012]

[Chemical 48]

[Brit. J. Pharmacol., 102; 251-266 (1991).
And West German Patent Publication No. 3,504,677]

[0014]

DISCLOSURE OF THE INVENTION That is, the present invention is: 1) General formula (I)

[0015]

[Chemical 49]

(Where

[Chemical 50]

[0017]

[Chemical 51]

[0018]

[Chemical 52]

[0019]

[Chemical 53]

[0020]

[Chemical 54]

A is

[Chemical 55]

[0022]

[Chemical 56]

[0023]

[Chemical 57]

[0024]

[Chemical 58]

[0025]

[Chemical 59]

[0026]

[Chemical 60]

[0027]

[Chemical formula 61]

[0028]

[Chemical formula 62]

[0029]

[Chemical formula 63]

[0030]

[Chemical 64]

[0031]

[Chemical 65]

[0032]

[Chemical formula 66]

[0033]

[Chemical formula 67]

[0034]

[Chemical 68]

[0035]

[Chemical 69]

R ¹ represents (i) a hydroxyl group, (ii) a C1-12 alkoxy group or (iii) NR ² R ³ ;

R ² and R ³ are each independently (i)
Hydrogen atom or (ii) represents a C1-4 alkyl group, or represents an amino acid residue together with an adjacent nitrogen atom,

R ⁴ independently contains (i) a hydrogen atom, (ii) a C1-4 alkyl group, (iii) a phenyl group, (iv) a phenyl group or 1 or 2 nitrogen atoms. Represents a C1-4 alkyl group substituted by 1 or 2 to 7-membered monocyclic heterocycle;
⁴ is a phenyl group, or a phenyl group or a nitrogen atom
Or when it represents a group containing a 4- to 7-membered monocyclic heterocycle containing two, the ring is a C1-4 alkyl group,
C1-4 alkoxy groups, halogen atoms, nitro groups or trihalomethyl groups may be substituted,

Y represents an oxygen atom or a sulfur atom,
e represents an integer of 3 to 5, f represents an integer of 1 to 3, l represents an integer of 1 to 3, m represents 1 or 2
Represents an integer of 1, p represents an integer of 1 to 4, and q represents
Zero or an integer of 1 or 2, r represents an integer of 1 to 4, and s represents zero or an integer of 1 to 3. However, (1) A

[0040]

[Chemical 70]

[0041]

[Chemical 71]

[0042]

[Chemical 72]

[0043]

[Chemical formula 73]

[0044]

[Chemical 74]

[0045]

[Chemical 75]

[0046]

[Chemical 76]

(Wherein all symbols have the same meanings as described above), or

[0048]

[Chemical 77]

(Wherein R ⁴ represents a hydrogen atom), q and s are not zero.
(2) A

[0050]

[Chemical 78]

[0051]

[Chemical 79]

[0052]

[Chemical 80]

[0053]

[Chemical 81]

[0054]

[Chemical formula 82]

[0055]

[Chemical 83]

[0056]

[Chemical 84]

[0057]

[Chemical 85]

[0058]

[Chemical 86]

[0059]

[Chemical 87]

[0060]

[Chemical 88]

(Wherein Y, l and m have the same meanings as described above) and when R ⁴ represents a C1-4 alkyl group substituted with a heterocycle, the heterocycle at that carbon atom only, and those that bind to an alkyl _{group, (3) - (CH 2} ) r - or = CH- (C
H ₂ ) _s- is bonded to either ring carbon atom a or b, and (4) A is

[0062]

[Chemical 89]

(Wherein R ⁴ has the same meaning as described above),

[0064]

[Chemical 90]

[0065]

[Chemical Formula 91]

Only take ) Condensed benzeneoxyacetic acid derivatives, their non-toxic salts and their acid addition salts, 2) their production method, and 3) pharmaceuticals containing them as active ingredients.

In the present invention, isomers include all of them unless otherwise specified. For example, an alkyl group, an alkoxy group, an alkylene group, an alkenyl group, and an alkenylene group include a straight-chain one and a branched-chain one.
Double bonds in alkenylene groups include those that are E, Z and EZ mixtures. Also included are isomers formed by the presence of asymmetric carbon atoms, such as when a branched chain alkyl group is present.

[0068]

[Comparison with Prior Art] The compounds of the present invention represented by the general formula (I) are novel compounds. It cannot be easily predicted that the compound having such a structure has a PGI ₂ receptor agonistic action.

[0069]

[Salt and Acid Addition Salt] The compound of the present invention represented by the general formula (I) can be converted into the corresponding salt and acid addition salt by a known method. Salts and acid addition salts are preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). , Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine,
Arginine, N-methyl-D-glucamine, etc.)

As the non-toxic acid addition salt, a hydrochloride salt,
Inorganic acid salts such as hydrobromide, sulfate, phosphate, nitrate or acetate, lactate, tartrate, oxalate, fumarate, maleate, citrate, benzoic acid Organic salts such as salts, methane sulfonates, ethane sulfonates, benzene sulfonates, toluene sulfonates, isethionates, glucuronates and gluconates can be mentioned. Preferred is the hydrochloride.

In the general formula (I), C represented by R ¹
1-12 alkoxy groups are methoxy, ethoxy,
Propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy,
Decyloxy, undecyloxy, dodecyloxy groups and isomer groups thereof. Further, in the groups represented by R ² , R ³ and R ⁴ , the C1-4 alkyl groups are methyl, ethyl, propyl, butyl groups and isomer groups thereof. In the group represented by R ⁴ in the general formula (I), as the 4- to 7-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, azole, azine (pyridine), azepine, diazole, diazine, Included are diazepine rings and rings that are partially or fully saturated.

In the group represented by R ⁴ , the phenyl group and the C1-4 alkyl group which is a substituent of the hetero ring are methyl, ethyl, propyl, butyl group and isomer groups thereof, The C1-4 alkoxy group is a methoxy group, an ethoxy group, a propoxy group, a butoxy group and an isomer group thereof, and the halogen atom in the halogen atom and the trihalomethyl group is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. .

Preferred compounds of the present invention are [2- (imidazol-1-yl) methyl-2,3-dihydroinden-4-yloxy] acetic acid, [1- [2- (4-phenylmethylimidazol-1- Il) ethyl] -1,2,
3,4-Tetrahydronaphthalen-5-yloxy] acetic acid, [1- [3- (4-phenylmethylimidazole-
1-yl) -1-propenyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [1-
[2- (4-phenylmethylimidazol-1-yl)
Ethyl] -3,4-dihydronaphthalen-5-yloxy] acetic acid,

[1- [2- (4-phenylmethylimidazol-1-yl) ethylidene] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2-
(1-Diphenylmethylimidazol-2-yloxy) methyl-1,2,3,4-tetrahydronaphthalen-6-yloxy] acetic acid, [2- [3- (1-diphenylmethylimidazol-2-yloxy) -1- Propenyl] -1,2,3,4-tetrahydronaphthalene-5
-Yloxy] acetic acid, [2- (1-diphenylmethylimidazol-2-yloxy) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid,

[1- [2- (1-diphenylmethylimidazol-2-yloxy) ethylidene] -1,2,
3,4-Tetrahydronaphthalen-5-yloxy] acetic acid, [2- (4-diphenylmethylimidazole-2-
Ilthio) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- [3- (4-diphenylmethylimidazol-2-ylthio) -1-propenyl] -1,2,3,2 4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- (4-diphenylmethylimidazol-2-ylthio) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid,

[1- [2- (4-diphenylmethylimidazol-2-ylthio) ethylidene] -1,2,3
4-tetrahydronaphthalen-5-yloxy] acetic acid,
[2- [2- (2-oxo-4-diphenylmethylimidazol-1-yl) ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2-
[3- (2-oxo-4-diphenylmethylimidazol-1-yl) -1-propenyl] -1,2,3,4-
Tetrahydronaphthalen-5-yloxy] acetic acid,

[2- [2- (2-oxo-4-diphenylmethylimidazol-1-yl) ethyl] -3,4-
Dihydronaphthalen-5-yloxy] acetic acid, [1-
[2- (2-oxo-4-diphenylmethylimidazol-1-yl) ethylidene] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2-
(3,4,5-triphenylpyrazol-1-yl) methyl-benzocycloheptan-6-yloxy] acetic acid,
[2- [4-((3-chlorophenyl) phenylmethyl) pyrazol-2-yl] methyl-1,2,3,4-
Tetrahydronaphthalen-5-yloxy] acetic acid,

[2- [3- [4-((3-chlorophenyl) phenylmethyl) pyrazol-2-yl] -1-propenyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- [4-((3-chlorophenyl) phenylmethyl) pyrazol-2-yl] methyl-3,4-dihydronaphthalen-5-yloxy]
Acetic acid, [1- [2- [4-((3-chlorophenyl) phenylmethyl) pyrazol-2-yl] ethylidene]-
1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- [3-((4-diphenylmethyl))
-1,2,3-triazol-2-2-yl) -1-propenyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid,

[2-((4-diphenylmethyl) -1,
2,3-triazol-1-yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid, [1- [2
-((4-Diphenylmethyl) -1,2,3-triazol-3-yl) ethylidene] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2-
(1,2,4-oxadiazin-5-yl) methyl-
1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- [2- (1,2,4-oxadiazin-5-yl) -1-ethenyl] -1,2,3,4- Tetrahydronaphthalen-5-yloxy] acetic acid,

[2- (1,2,4-oxadiazine-5
-Yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid, [1- [2- (1,2,4-oxadiazin-5-yl) ethylidene] -1,2,3,4-tetrahydronaphthalene -5-yloxy] acetic acid, [2-
[3- (3-Phenyl-1,2,4-oxadiazol-5-yl) propyl] -2,3-dihydroindene-
4-yloxy] acetic acid, [2- [2- (oxazole-
2-yl) ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid,

[2- [2- (oxazol-2-yl)]
-1-Ethenyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- [2- (oxazol-2-yl) ethyl] -3,4-dihydronaphthalen-5-yloxy] Acetic acid, [1- [2- (oxazol-2-yl) ethylidene] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2-
[2- [4- (3-trifluoromethylphenyl) oxazol-2-yl] ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid,

[2- [2- [4- (3-trifluoromethylphenyl) oxazol-2-yl] -1-ethenyl] -1,2,3,4-tetrahydronaphthalene-5-
Iloxy] acetic acid, [2- [2- [4- (3-trifluoromethylphenyl) oxazol-2-yl] ethyl] -3,4-dihydronaphthalen-5-yloxy]
Acetic acid, [1- [2- [4- (3-trifluoromethylphenyl) oxazol-2-yl] ethylidene] -1,
2,3,4-Tetrahydronaphthalen-5-yloxy] acetic acid, [1- [2- (oxazol-4-yl) ethyl] -1,2,3,4-tetrahydronaphthalene-5
-Yloxy] acetic acid,

[1- [2- (2-((3-pyridyl) phenylmethyl) oxazol-4-yl) -1-ethenyl] -1,2,3,4-tetrahydronaphthalene-5-
Iloxy] acetic acid, [1- [2- (2-((3-pyridyl) phenylmethyl) oxazol-4-yl) ethyl] -3,4-dihydronaphthalen-5-yloxy]
Acetic acid, [1- [2- (2-((3-pyridyl) phenylmethyl) oxazol-4-yl) ethylidene] -1,
2,3,4-Tetrahydronaphthalen-5-yloxy] acetic acid, [1- [2- (3-nitrophenyl) oxazol-4-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] Acetic acid,

[1- [2- (2- (3-nitrophenyl) oxazol-4-yl) -1-ethenyl] -1,
2,3,4-Tetrahydronaphthalen-5-yloxy] acetic acid, [1- [2- (3-nitrophenyl) oxazol-4-yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid, [1 -[2- (2- (3-
Nitrophenyl) oxazol-4-yl) ethylidene] -1,2,3,4-tetrahydronaphthalene-5-
Iloxy] acetic acid, [2- (imidazol-4-yl)
Methyl-1,2,3,4-tetrahydronaphthalene-5
-Yloxy] acetic acid,

[2- (2- (imidazol-4-yl)
-1-Ethenyl) -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- (imidazol-4-yl) methyl-3,4-dihydronaphthalene-5
-Yloxy] acetic acid, [1- (2- (imidazole-4
-Yl) ethylidene) -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- [3- [4
-((1-imidazolyl) phenylmethyl) pyrazol-2-yl] -1-propenyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid,

[2- [4-((1-imidazolyl) phenylmethyl) pyrazol-2-yl] methyl-3,4-
Dihydronaphthalen-5-yloxy] acetic acid, [1-
[2- [4-((1-imidazolyl) phenylmethyl)
Pyrazol-2-yl] ethylidene] -1,2,3,4
-Tetrahydronaphthalen-5-yloxy] acetic acid,
[1- [3- (5-Diphenylmethyl-1,2,4-oxadiazol-3-yl) -1-propenyl] -1,
2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [1- [2- (5-diphenylmethyl-1,
2,4-oxadiazol-3-yl) ethyl] -3,
4-dihydronaphthalen-5-yloxy] acetic acid,

[1- [2- (5-diphenylmethyl-
1,2,4-oxadiazol-3-yl) ethylidene] -1,2,3,4-tetrahydronaphthalene-5-
Iloxy] acetic acid, [2- [2- (5-diphenylmethylisoxazol-3-yl) -1-ethenyl]-
1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, [2- (5-diphenylmethylisoxazol-3-yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid, [1- [2- (5-diphenylmethylisoxazol-3-yl) ethylidene]
-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid,

[2- [2- (3-diphenylmethylisoxazol-5-yl) -1-ethenyl] -1,2,
3,4-Tetrahydronaphthalen-5-yloxy] acetic acid, [2- (3-diphenylmethylisoxazole-
5-yl) methyl-3,4-tetrahydronaphthalene-
5-yloxy] acetic acid, [1- [2- (3-diphenylmethylisoxazol-5-yl) ethylidene]-
1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid, and the compounds described in the examples.

[Method for producing the compound of the present invention] (1) Of the compounds of the present invention represented by the general formula (I), the compound of the general formula (I-1)

[0090]

[Chemical Formula 92]

(In the formula, A ¹ has the same meaning as A. However, in the group represented by R ⁴ contained in A, a hetero ring which is a substituent of C1-4 alkyl groups is The compound of the present invention represented by the formula (1), which is bonded to an alkyl group only at a carbon atom, and other symbols have the same meanings as described above.
(A) General formula (III)

[0092]

[Chemical formula 93]

(Wherein R ^1a represents a methoxy group or an ethoxy group, and other symbols have the same meanings as described above), and a compound of the general formula (a) HA ^a (a) (wherein A is ^a is

[0094]

[Chemical 94]

[0095]

[Chemical 95]

[0096]

[Chemical 96]

[0097]

[Chemical 97]

[0098]

[Chemical 98]

[0099]

[Chemical 99]

[0100]

[Chemical 100]

(Wherein all symbols have the same meanings as described above). ) Or a compound represented by the general formula (III)

[0102]

[Chemical 101]

(Wherein all symbols have the same meanings as described above), the compound represented by the formula (V) is reacted with oxazole.

[0104]

[Chemical 102]

(Wherein all symbols have the same meanings as described above), or a cyclization reaction is carried out,
(D) General formula (VIII)

[0106]

[Chemical 103]

(Wherein R ^4a is (i) a C1-4 alkyl group, (ii) a phenyl group or (iii) a phenyl group or a 4-7 membered heterocycle containing one or two nitrogen atoms) A compound represented by the formula (b) BrCH ₂ COR ^1a (b), which represents a C1-4 alkyl group substituted by 1 or 2 and the other symbols have the same meanings as described above. (Wherein R ^1a has the same meaning as described above) or by reacting a compound represented by the formula (E)

[0108]

[Chemical 104]

(Wherein all symbols have the same meanings as described above), a compound represented by the general formula (b) BrCH ₂ COR ^1a (b) (wherein R ^1a has the same meaning as described above) .) Or by reacting (F) the general formula (XI)

[0110]

[Chemical 105]

(Wherein all symbols have the same meanings as described above) and the general formula (c) R ⁴ COCl (c) (wherein R ⁴ has the same meaning as described above). ) Or by reacting (G) the general formula (XII)

[0112]

[Chemical formula 106]

(Wherein all symbols have the same meanings as described above), and a compound of the general formula (d)

[0114]

[Chemical formula 107]

(Wherein R ⁴ has the same meaning as described above), or the compound of the general formula (H) is used.
(XIV)

[0116]

[Chemical 108]

(Wherein all symbols have the same meanings as described above)
(I) General formula (XVI)

[0118]

[Chemical 109]

(Wherein all symbols have the same meanings as described above) and a compound of the general formula (b) BrCH ₂ COR ^1a (b) (wherein R ^1a has the same meaning as described above). .) Or by reacting (J) the general formula (XIX)

[0120]

[Chemical 110]

(Wherein all symbols have the same meanings as described above), and the general formula (b) BrCH ₂ COR ^1a (b) (wherein R ^1a has the same meaning as described above). .) Or by reacting (K) the general formula (XX).

[0122]

[Chemical 111]

(Wherein all symbols have the same meanings as described above), and a compound of the general formula (b) BrCH ₂ COR ^1a (b) (wherein R ^1a has the same meaning as described above). .) Or by reacting (L) the general formula (Ia).

[0124]

[Chemical 112]

(Wherein all symbols have the same meanings as described above), the ester bond of the compound of formula (H) is hydrolyzed, or (M) the general formula (Ib)

[0126]

[Chemical 113]

(Wherein all symbols have the same meanings as described above), a compound of the general formula (f) R ^1b OH (f) (wherein R ^1b represents a C3-12 alkyl group) Represent)
Esterified with a compound represented by or (N) the general formula (Ib)

[0128]

[Chemical 114]

(Wherein all symbols have the same meanings as described above), a compound represented by the general formula (g) HNR ² R ³ (g) (wherein R ² and R ³ have the same meanings as described above) Represents.)
It can be produced by amidation using a compound represented by General formula (III), (V), (VIII), (I
(X), (XI), (XII), (XIV), (XVI), (XIX), (XX), (I
The compounds represented by a) and (Ib) can be produced by the method represented by the following reaction scheme. Formulas (a), (b), (c), (d), (f) and (g)
The compound represented by is known per se and is commercially available as a reagent, or can be produced from a commercially available reagent by a known method.

[0130]

[Chemical 115]

[0131]

[Chemical formula 116]

[0132]

[Chemical 117]

[0133]

[Chemical 118]

[0134]

[Chemical formula 119]

[0135]

[Chemical 120]

[0136]

[Chemical 121]

[0137]

[Chemical formula 122]

[0138]

[Chemical 123]

[0139]

[Chemical formula 124]

[0140]

[Chemical 125]

(In the reaction scheme, R ^4d is (i) hydrogen atom,
(ii) C1-4 alkyl group, (iii) phenyl group or (iv) phenyl group or a 4- to 7-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, 1 or 2 and / or
Or represents a C1~4 alkyl group substituted with one hydroxyl group, R ^4e, except that the hydroxyl group in R ^4d is behalf -OLi group represent the same meaning as R ^4d,

DMF stands for N, N-dimethylformamide, TEA stands for triethylamine, DHP stands for dihydropyran, THP stands for tetrahydropyran-2-yl group, DME stands for dimethoxyethane and TBAB stands for bromide. Represents tetra-n-butylammonium, and other symbols have the same meanings as described above. The compounds represented by the general formulas (j), (k) and (l) are known per se, and are commercially available as reagents, or can be produced from commercially available reagents by known methods. (2) Among the compounds of the present invention represented by the general formula (I), the general formula (I-2)

[0143]

[Chemical formula 126]

(In the formula, A ² is

[Chemical 127]

[0145]

[Chemical 128]

[0146]

[Chemical formula 129]

[0147]

[Chemical 130]

(In the formula, R ⁴ has the same meaning as described above.
However, the hetero ring, which is a substituent of C1-4 alkyl groups, is bonded to the alkyl group only at the nitrogen atom in the ring, and at least one of R4 is a hetero ring-substituted alkyl group. Other symbols have the same meanings as described above. ) Is represented. The compound of the present invention represented by
General formula (XIII)

[0149]

[Chemical 131]

(Where A ^b is

[Chemical 132]

[0151]

[Chemical 133]

[0152]

[Chemical 134]

[0153]

[Chemical 135]

(In the formula, R ^4b's independently of each other in (i)
A hydrogen atom, (ii) a C1-4 alkyl group, (iii) a phenyl group, (iv) a phenyl group or a ketone group, and a C1-4 alkyl group substituted by 1 or 2; ^{When 4b} represents a phenyl group or a phenyl group-containing group, the phenyl group may be substituted with C1 to 4 alkyl groups, C1 to 4 alkoxy groups, halogen atoms, nitro groups or trihalomethyl groups. age,

At least one of R ^4b is a C1-4 alkyl group substituted with a ketone group. ) And other symbols have the same meanings as described above. ) Is converted into a compound represented by (1) hydrolysis reaction, (2) reduction reaction,
(3) esterification reaction, optionally (4) mesylation reaction, and (5) formula R ^4c (i) (wherein R ^4c contains 1 or 2 nitrogen atoms 4 to 7).
Member heterocycles or their hydrohalides. ), A compound represented by the general formula (Ic)

[0156]

[Chemical 136]

(Wherein all symbols have the same meanings as described above), a compound represented by the general formula (Ia) or (Ib)
The compound of the general formula (I-1) can be produced by the same method as described in the above (L), (M) and (N) for producing the compound of the general formula (I-1) from the compound of (1). The compounds represented by the general formulas (XIII) and (Ic) can be produced by the method represented by the following reaction scheme.

[0158]

[Chemical 137]

(In the reaction scheme, all symbols have the same meanings as described above. In addition, general formula (h) and general formula (i)
The compound represented by is known per se or can be produced by a known method. )

In each reaction in the present specification, the reaction product is subjected to a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography or column chromatography. Alternatively, it can be purified by a method such as washing or recrystallization. Purification may be carried out for each reaction or after completion of some reactions. The starting material and each reagent in the present invention are known per se or can be produced by a known method. For example, the general formula (II) used as a starting material
Of the compounds represented by the formula

[0161]

[Chemical 138]

Of the compounds represented by the general formula (VI),

[0163]

[Chemical 139]

A compound represented by the formula (X):

[0165]

[Chemical 140]

Of the compounds represented by the general formula (XVII),

[0167]

[Chemical 141]

The method for producing the compound represented by the formula is described in Japanese Patent Application No. 3-130467. In addition, the general formula (VI)
Of the compounds represented by the formula

[0169]

[Chemical 142]

The production method of the compound represented by the formula is described in Japanese Patent Application No. 3-322612. Also, the general formula (XV)
The compound represented by is produced from the above general formula (VI) by a known method.

[0171]

[Pharmacological activity of the compound of the present invention] The fact that the compound of the present invention represented by the general formula (I) has a PGI ₂ receptor agonistic action was proved by the following experimental results. i) Human platelet membrane fraction PGI of ³ H-iloprost
Inhibition of binding to ₂ receptors

[Experimental Method] 15 mM magnesium chloride,
5 mM EDTA, 10 nM [ ³ H] -ilopro
A 50 mM Tris / hydrochloric acid buffer solution of pH 7.4 containing st was used as a reaction solution. Human platelet crude membrane fraction (0.3 mg) with or without addition of test compound to the reaction mixture (0.2 ml)
Protein) was added and incubated at 24 ° C. for 30 minutes. Next, the reaction solution was suction-filtered using a glass fiber filter to bind to the receptor [ ³ H] -ilopros.
[ ³ H] -iloprost not bound to t was separated, the radioactivity of the filter was measured, and [ ³ H] bound to [ ³ H]
-Iloprost amount was determined.

[ ³ H] -il specifically bound to the receptor
The amount of oprost was determined as the amount obtained by subtracting the nonspecific binding amount from the total binding amount. The non-specific binding amount was determined as the binding amount of [ ³ H] -iloprost when nonradioactive iloprost (10 μM) was added instead of the test compound. The inhibitory effect of the test compound was determined by the following formula. Inhibition rate (%) = 100− (B ₁ / B ₀ × 100) B ₁ : [ ³ H] -ilopr in the presence of test compound
Specific binding amount of ost B ₀ : [ ³ H] -ilop in the absence of test compound
Table 1 shows the results of the specific binding amount of rost.

[0174]

[Table 1]

Ii) Inhibitory action on human platelet aggregation [Experimental method] A plasma (Platelet RichPlasma) rich in 5 × 10 ⁵ / mm ³ platelets was prepared from human blood,
One minute after the addition of the test compound, ADP (4 μM) was added to measure the aggregation inhibitory effect. This measurement was performed using a multi-channel aggregometer, and the agglutination reaction was measured by the change in light transmittance of the aggregometer. The results are shown in Table 2.

[0176]

[Table 2]

[0177]

[Toxicity] The toxicity of the compound of the present invention is sufficiently low,
It was confirmed to be safe enough for use as a medicine.

[0178]

[Application to Pharmaceuticals] Since the compound of the present invention represented by the general formula (I) has a PGI ₂ receptor agonistic action, it can prevent thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcer, hypertension, etc. Or it is useful for treatment. In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, an acid addition salt or a hydrate thereof for the above purpose, it is usually systemically or locally in an oral or parenteral form. Administered in. The dose varies depending on age, symptoms, therapeutic effect, administration method, treatment time, etc., but is, for example, about 0.00 per 1 kg body weight per hour.
Dosages of 1 to about 100 mg are generally used, preferably in the range of about 0.1 to about 10 mg / kg body weight per hour.

Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases. When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like. Solid compositions for oral administration include tablets, pills,
Capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules.

Other compositions for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions and freeze-dried preparations. Other compositions for parenteral administration include external preparations such as external preparations, ointments, and coatings containing one or more active substances, and suppositories for rectal administration. And pessaries are included.

[0181]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in the parentheses shown in the chromatographic separation indicates the elution solvent or the developing solvent used, and the ratio represents the volume ratio. Unless otherwise specified, IR was measured by the KBr tablet method and N
MR is measured with deuterated chloroform.

Reference Example 1 Methyl (2-bromomethyl-1,2,3,4-tetrahydronaphthalen-5-yloxy) acetate

[Chemical 143]

Methyl (2-hydroxymethyl-1,
2,3,4-Tetrahydronaphthalen-5-yloxy) acetate (4.19g) in methylene chloride (80ml)
To the solution was added triphenylphosphine (6.61 g) and carbon tetrabromide (11.1 g) at room temperature with stirring. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give the title compound (4.58 g) having the following physical data.

IR (cm ^-1 ): 2927, 2849, 1762, 160
5, 1586, 1467, 1437, 1376, 1345,1283, 1206, 1120,
1003, 766, 710. Reference Example 2 2-benzyl-4-ethoxycarbonylpyrazole

[0185]

[Chemical 144]

Sodium hydride (content 63%, 652 m
A solution of 4-ethoxycarbonylpyrazole (2.00 g) in DMF (15 ml) was added to a suspension of g) in N, N-dimethylformamide (hereinafter abbreviated as DMF: 5.0 ml) at room temperature with stirring. The mixture was stirred at room temperature for 30 minutes, then benzyl bromide (2.04 ml) was added to the mixture. The mixture was stirred for 30 minutes and then quenched with water. The reaction mixture was extracted with a mixed solution of ethyl acetate-n-hexane. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purified in 1) and having the following physical data, the title compound (2.98
g) was obtained.

TLC (ethyl acetate: n-hexane = 1: 1)
3): Rf = 0.27; IR (cm ⁻¹ ): 3122, 2973, 1714, 1555, 1457, 137
3, 1350, 1307, 1224, 1192, 1115, 1027, 988, 881, 77
1, 706, 621. Reference Example 3 1-benzyl-4-diphenylhydroxymethylpyrazole

[0188]

[Chemical 145]

Phenylmagnesium bromide (61.9 m) was added to a solution of the compound (2.85 g) produced in Reference Example 2 in tetrahydrofuran (THF, 30 ml) at 0 ° C. with stirring.
mol) was added. After stirring the mixture at room temperature for 1 hour,
The reaction was stopped with ice and an aqueous solution of ammonium chloride. The reaction mixture was extracted with a mixed solution of ethyl acetate-n-hexane (1: 2). The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane =
2: 5) and the title compound (1.
31 g) was obtained.

TLC (ethyl acetate: n-hexane = 1: 1)
1): Rf = 0.48; IR (cm ⁻¹ ): 3242, 3062, 3030, 2929, 1601, 155
3, 1495, 1449, 1387,1332, 1160, 1030, 1001, 879, 8
08, 757, 729, 700, 529. Reference Example 4 4-diphenylmethylpyrazole

[0191]

[Chemical 146]

A small piece of metallic sodium was added to liquid ammonia (30 ml) at −78 ° C., and then a solution of the compound (1.3 g) prepared in Reference Example 3 in THF (10 ml) was added.
The mixture was stirred at −70 ° C. initially, increasing the temperature to −25 ° C. for 3 hours. Add ammonium chloride (1.
The reaction was stopped by adding 5 g). The temperature of the reaction mixture was raised to room temperature and excess ammonia was removed. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1 → 1: 0),
The title compound was obtained having the following physical data.

TLC (ethyl acetate: n-hexane = 1: 1)
1): Rf = 0.40; IR (cm ^-1 ): 3120, 3024, 2946, 1601, 1490, 145
1, 1391, 1362, 1144, 1078, 1052, 1032, 1007, 953, 8
79, 824, 750, 734, 699, 763, 636, 506, 476. Reference Example 5 1,1-diphenyl-2-amino-hydroxyiminoethane

[0194]

[Chemical 147]

Diphenylacetonitrile (7.0 g), hydroxylamine hydrochloride (3.03 g) and sodium acetate were added to a mixture of ethanol and water (5: 1) (150 ml). The mixture was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, the mixture was triturated, filtered, and the compound collected by filtration was dried to give the title compound (2.5 g) having the following physical data.

NMR: δ 7.40 to 7.00 (10H, m), 5.55 (2
H, brs), 4.88 (1H, s), 4.57 (1H, brs); IR (cm ^-1 ): 3481, 3371, 3196, 1668, 1575, 149
2, 1452, 1359, 1084, 1030, 959, 933, 863, 725, 704,
633. Reference Example 6 Methyl [1- [2- (1-amino-2,2-diphenylethylidene) aminooxycarbonylethyl] -1,
2,3,4-Tetrahydronaphthalen-5-yloxy] acetate

[0197]

[Chemical 148]

3- (5-methoxycarbonylmethoxy-
1,2,3,4-tetrahydronaphthalen-2-yl)
Propionic acid (300 mg) oxalic chloride (5.
The (0 ml) suspension was refluxed for 1 hour with stirring. The temperature of the reaction mixture was lowered to room temperature and concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml). The solution
1,1-diphenyl-2-amino-produced in Reference Example 5
2-Hydroxyiminoethane (279 mg) and triethylamine (0.29 ml) were added dropwise to a methylene chloride (3.0 ml) solution under ice cooling. After the dropping was completed, the solution was stirred at room temperature for 1 hour. Dilute the reaction mixture with ethyl acetate,
The mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2) to give the title compound (447 mg) having the following physical data.

MS (m / z): 501 (M ⁺¹ ); IR (cm ^-1 ): 3493, 3370, 2944, 1737, 1617, 158
1, 1494, 1456, 1367, 1338, 1274, 1164, 1130, 1081,
1003, 872, 783, 702, 640. Reference Example 7 2-Carboxymethyl-5-hydroxy-1,2,3,3
4-tetrahydronaphthalene

[0200]

[Chemical 149]

2-methoxycarbonylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0
A mixture of g) and pyridine hydrochloride (40 g) was stirred at 190 ° C. for 2 hours. The reaction mixture was cooled and dissolved in water. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue containing the title compound having the following physical data. The obtained residue was used for the next reaction without purification.

NMR: δ 8.38 (1H, brs), 6.92 (1H, t, J =
8Hz), 6.64 (1H, d, J = 8Hz), 6.57 (1H, d, J = 8Hz), 2.98 to 2.
78 (2H, m), 2.67 ~ 1.91 (7H, m), 1.54 ~ 1.30 (1H, m). Reference Example 8 2-methoxycarbonylmethyl-5-hydroxy-1,
2,3,4-tetrahydronaphthalene

[0203]

[Chemical 150]

Thionyl chloride (5.0 ml) was added to -20
It was added dropwise to methanol (18 ml) at ℃. The mixture was stirred at -20 ° C for 30 minutes. A solution of the residue produced in Reference Example 7 in methanol (10 ml) was added to the mixture by -20.
Added at ° C. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound (3.52 g) having the following physical data.

TLC (n-hexane: ethyl acetate = 3:
1): Rf = 0.22; IR (cm ⁻¹ ): 3425, 2925, 1713, 1587, 1466, 143
9, 1336, 1279, 1159, 1088, 1070, 1010, 772, 713. Reference Example 9 2-Methoxycarbonylmethyl-5- (tetrahydropyran-2-yl) oxy-1,2,3,4-tetrahydronaphthalene

[0206]

[Chemical 151]

A mixture of the compound (1.25 g) prepared in Reference Example 8, dihydropyran (0.68 ml), a small amount of p-toluenesulfonate of pyridine and methylene chloride (10 ml) was stirred at room temperature for 3 days. Triethylamine (0.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 6: 1) to give the title compound (1.72 g) having the following physical data.

IR (cm ^-1 ): 2943, 1738, 1586, 146
4, 1438, 1356, 1283, 1251, 1202,1158, 1124, 1076,
1024, 955, 918, 873, 820, 770, 736. Reference Example 10 [5- (tetrahydropyran-2-yl) oxy-1,
2,3,4-Tetrahydronaphthalen-2-yl] acetic acid

[0209]

[Chemical 152]

A solution of the compound (1.72 g) prepared in Reference Example 9 in dimethoxyethane (15 ml) was stirred at 0 ° C.
At 2N sodium hydroxide (5.6 ml) was added. The solution was stirred overnight at room temperature. The reaction mixture was mixed with 2N hydrochloric acid (5.
The mixture was neutralized with 6 ml) and extracted with ethyl acetate. The extract was washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of n-hexane-ethyl acetate to obtain the title compound (1.27 g) having the following physical properties.

Melting point: 104-109 ° C; MS: 290 (M ⁺ ), 256, 234. Reference Example 11 2-Diphenylmethylcarbonylmethoxycarbonylmethyl-5- (tetrahydropyran-2-yl) oxy-
1,2,3,4-tetrahydronaphthalene

[0212]

[Chemical 153]

The compound prepared in Reference Example 10 (290 m
To a solution of g) in ethanol (2 ml) was added 1N aqueous sodium hydroxide solution (1 ml). The solution was concentrated under reduced pressure to obtain the sodium salt of the compound produced in Reference Example 10. Its sodium salt, tetra-n-butylammonium bromide (32 mg) and 3-bromo-1,1
A solution of -diphenyl-2-propanone (578 mg) in toluene (5.0 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ether.
The extract was washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (n-hexane: ethyl acetate = 5:
Purified in 1), the title compound (447) having the following physical data was obtained.
mg) was obtained.

TLC (n-hexane: ethyl acetate = 3:
1): Rf = 0.45; IR (cm ⁻¹ ): 3029, 2938, 1735, 1585, 1499, 146
4, 1412, 1358, 1251, 1202, 1155, 1123, 1078, 1024,
955, 918, 900, 873, 820, 771, 747, 703. Reference Example 12 2- (4-diphenylmethyloxazol-2-yl)
Methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene

[0215]

[Chemical 154]

The compound prepared in Reference Example 11 (386 m
g), ammonium acetate (298 mg) and acetic acid (2.0 m
l) was refluxed for 2.5 hours. The reaction mixture was diluted with ether. The mixture was washed with aqueous potassium carbonate solution, water, and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4),
The title compound (147 mg) having the following physical data was obtained.

TLC (ethyl acetate: n-hexane = 1: 1)
2): Rf = 0.45; IR (cm ⁻¹ ): 3061, 3028, 2924, 2362, 1736, 158
7, 1571, 1495, 1465, 1453, 1435, 1338, 1307, 1247,
1202, 1156, 1123, 1099, 1032, 995, 956, 904, 836,
770, 749, 701, 507. Reference Example 13 (5-tert-butylcarbonyloxy-1,2,3,4
-Tetrahydronaphthalen-2-yl) acetic acid

[0218]

[Chemical 155]

The compound prepared in Reference Example 7 (600 m
g) To a mixture of 2N aqueous sodium hydroxide solution (2.91 ml) and dioxane (3.0 ml) was added pivaloyl chloride (0.39 ml) with stirring at 0 ° C. The mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Wash the extract with saline,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to obtain the title compound (408 mg) having the following physical properties.

TLC (methanol: chloroform = 1:
9): Rf = 0.43; IR (cm ⁻¹ ): 2975, 2932, 1751, 1708, 1582, 148
2, 1461, 1413, 1368,1282, 1236, 1125, 1032, 941, 7
67, 712. Reference Example 14 2-Bromomethylcarbonylmethyl-5-tert-butylcarbonyloxy-1,2,3,4-tetrahydronaphthalene

[0221]

[Chemical 156]

The compound prepared in Reference Example 13 (390 m
Oxalyl chloride (4.0 ml) was added to a mixture of g) and a small amount of DMF at room temperature with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove excess oxalic acid chloride and the residue was diluted with ether. This solution was added to a solution of diazomethane in ether (20 ml) at 0 ° C. The mixture was diluted at 0 ° C for 2 hours. Hydrogen bromide gas (produced from tetralin and bromine) was bubbled through the reaction mixture at 0 ° C. for 20 minutes. Water was added to the reaction mixture and the organic layer was separated. Water organic layer,
Then, the extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (42
4 mg) was obtained.

TLC (n-hexane: ethyl acetate = 7:
1): Rf = 0.22; IR (cm ⁻¹ ): 2974, 2932, 1747, 1581, 1479, 146
0, 1397, 1364, 1280, 1236, 1127, 1032, 983, 898, 76
8, 711. Reference Example 15 2-diphenylmethylcarbonyloxymethylcarbonylmethyl-5-tert-butylcarbonyloxy-1,
2,3,4-tetrahydronaphthalene

[0224]

[Chemical 157]

Diphenylacetic acid sodium salt (1.67 mmo
l) and tetra-n-butylammonium bromide (32 m
g), a mixture of the compound (400 mg) prepared in Reference Example 14 and toluene (5.0 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ether. The extract was washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give the title compound (531 mg) having the following physical data.

TLC (n-hexane: ethyl acetate = 3:
1): Rf = 0.40; IR (cm ⁻¹ ): 3029, 2974, 2931, 1747, 1581, 149
6, 1460, 1397, 1370, 1279, 1235, 1186, 1126, 899, 7
67, 746, 702. Reference Example 16 2- (2-diphenylmethyloxazol-4-yl)
Methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene

[0227]

[Chemical 158]

Compound (190 mg) obtained in the same manner as in Reference Example 12 using the compound prepared in Reference Example 15.
With dimethoxyethane (3.0 ml) and methanol (0.5 ml).
ml). A 1N aqueous sodium hydroxide solution (1.5 ml) was added to the solution at 0 ° C. The solution was stirred at room temperature for 2 hours. The reaction mixture was 1N hydrochloric acid (1.5 ml)
After neutralizing with, the mixture was extracted with ether. The extract was washed with aqueous sodium hydrogen carbonate solution and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give the title compound (150 mg) having the following physical data.

TLC (n-hexane: ethyl acetate = 3:
1): Rf = 0.25; IR (cm ⁻¹ ): 3062, 3029, 2921, 2844, 1735, 158
7, 1557, 1495, 1464, 1338, 1275, 1202, 1158, 1091,
1032, 1004, 985, 846, 770, 751, 699, 640,585, 50
6. Reference Example 17 Methyl [2- (2-hydroxyimino-n-pentyl) -1,2,3,4-tetrahydronaphthalene-5-
Iloxy] acetate

[0230]

[Chemical 159]

Methyl [2- (2-oxo-n-pentyl) -1,2,3,4-tetrahydronaphthalene-2-
Iloxy] acetate (608 mg), hydroxyamine hydrochloride (290 mg), triethylamine (0.55 m
A mixture of l) and ethanol (5.0 ml) was stirred overnight at room temperature. The reaction mixture was charged with triethylamine (1.0 m
After 1) was added, the solvent was distilled off. The residue was dissolved in a diethyl ether-water mixture. The organic layer was separated, washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (540 mg) having the following physical data.

Melting point: 95.9 to 97 ° C .; TLC (n-hexane: ethyl acetate = 3: 1): Rf =
0.24; IR (cm ^-1 ): 3246, 2942, 1767, 1586, 1468, 143
6, 1347, 1311, 1276, 1200, 1195, 1127, 1003, 963, 9
48, 828, 766, 744, 709. Reference Example 18 Methyl [2- (3-bromo-2-oxopropyl)-
1,2,3,4-Tetrahydronaphthalen-5-yloxy] acetate

[0233]

[Chemical 160]

(5-methoxycarbonylmethoxy-1,
2,3,4-tetrahydronaphthalen-2-yl) acetic acid was used and operated in the same manner as in Reference Example 14 to obtain the title compound having the following physical properties.

Melting point: 77 to 78 ° C .; TLC (n-hexane: ethyl acetate = 4: 1): Rf =
0.25; IR (cm ^-1 ): 3010, 2944, 2920, 2905, 1763, 173
5, 1583, 1469, 1435, 1398, 1384, 1343, 1264, 1218,
1205, 1149, 1101, 1088, 1030, 966, 777, 745, 710,
608. Reference Example 19 Mixture of amidinodiphenylmethane (A) and amidinodiphenylhydroxymethane (B)

[0236]

[Chemical 161]

A mixture of diphenylacetonitrile (10 g) and ammonium thiocyanate (16 g) was heated to 180 ° C. for 5 hours. The reaction mixture was cooled and treated with hot water. The mixture was filtered, and the filtrate was treated with 5N aqueous sodium hydroxide solution. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Picric acid (1.5 g) and ethanol (50 ml) were added to the residue and dissolved. The solution was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a mixture of the title compounds having the following physical properties.

TLC (chloroform: methanol: acetic acid = 17: 2: 1): (A) Rf = 0.45, (B) Rf = 0.
38; NMR: δ 7.46 to 7.17 (10H, m), 4.94 (1H, s). Reference Example 20 Methyl [2- (4-benzoylpyrazol-2-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0239]

[Chemical 162]

The title invention of the present invention having the following physical data was obtained by operating in the same manner as in Reference Example 1 and Example 1 (however, 4-benzoylpyrazole was used in place of the compound prepared in Reference Example 4). The compound was obtained.

TLC (n-hexane: ethyl acetate = 1: 1
1): Rf = 0.43. Reference Example 21 Methyl [1- (2-cyanoethyl) -1,2,3,4
-Tetrahydronaphthalen-5-yloxy] acetate

[0242]

[Chemical formula 163]

A solution of potassium cyanide (1.16 g) and 18-crown-6 (236 mg) in acetonitrile (18 m
l) was stirred under an argon atmosphere for 15 minutes. Methyl [1- (2-bromoethyl) -1,2,3,3 was added to the mixture.
A mixture of 4-tetrahydronaphthalen-5-yloxy] acetate (2.92 g) and tributylphosphine (1.99 g) in acetonitrile (10 ml) was added. A solution of carbon tetrachloride (0.95 ml) in acetonitrile (10 ml) was added dropwise to the mixture under ice cooling. The mixture was stirred at room temperature overnight. Dilute the reaction mixture with diethyl ether, 1
It was washed with 0% citric acid. Carbon tetrachloride (10
ml) was added, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 9) to give the title compound (1.72 g) having the following physical data.

NMR: δ 7.05 (1H, t, J = 8Hz), 6.83 (1H,
d, J = 8Hz), 6.52 (1H, d, J = 8Hz), 2.90 to 2.60 (5H, m), 2.30
~ 1.50 (6H, m). Reference Example 22 Methyl [1- (3-amino-3-hydroxyimino)]
Propyl-1,2,3,4-tetrahydronaphthalene-
5-yloxy] acetate

[0245]

[Chemical 164]

The compound (1.01 g) produced in Reference Example 21,
Hydroxylamine hydrochloride (331 mg) and sodium acetate (391 mg) were added to ethanol-water (5: 1,30).
ml). The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the title compound (132 mg) having the following physical data.

MS (m / z): 306 (M ⁺⁺ 1). Reference Example 23 Methyl [1- [3- (diphenylmethylcarbonyloxyimino) -3-aminopropyl] -1,2,3,4
-Tetrahydronaphthalen-5-yloxy] acetate

[0248]

[Chemical 165]

A suspension of diphenylacetic acid (201 mg) in thionyl chloride (5 ml) was refluxed for 1 hour. The temperature of the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Triethylamine (0.27 ml) was added to a solution of the residue and the compound (132 mg) produced in Reference Example 22 in methylene chloride (5 ml), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with ether. Wash the extract with water and brine,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the title compound (67 mg) having the following physical data.

MS (m / z): 501 (M ⁺⁺ 1). Reference Example 24 2- (N-methoxy-N-methylcarbamoylmethyl)
-5-methoxy-1,2,3,4-tetrahydronaphthalene

[0251]

[Chemical 166]

2-carboxymethyl-5-methoxy-
Oxalic acid chloride (30 ml) was added to a solution of 1,2,3,4-tetrahydronaphthalene (10.1 g) in methylene chloride (20 ml) at 0 ° C. The mixture at room temperature for 45
Stir for minutes. The solvent of the reaction mixture was evaporated, and the residue was dissolved in methylene chloride (50 ml). This solution is
O-dimethylhydroxylamine hydrochloride (5.37 g),
Triethylamine (19.2 ml) and methylene chloride (1
50 ml) at 0 ° C. Mix the mixture at room temperature 3
Stir for 0 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give the title compound (10.88 g) having the following physical data.

MS (m / z): 263 (M ⁺ ). Reference Example 25 2- (5-hydroxy-5,5-diphenyl-2-oxo-3-pentynyl) -5-methoxy-1,2,3,4
-Tetrahydronaphthalene

[0254]

[Chemical 167]

1,1-diphenyl-2-propyne-1-
To a solution of all (2.15 g) in THF (20 ml), -70
N-Butyllithium (13 ml; 1.6 M / L hexane solution) was added dropwise at C. The mixture was stirred at the same temperature for 30 minutes. Boron trifluoride ethyl ether complex (2.7 ml) was added to the reaction mixture, and the mixture was stirred for 30 minutes. A THF (10 ml) solution of the compound (900 mg) produced in Reference Example 24 was added to the reaction mixture at -70 ° C, and the mixture was stirred for 1 hour. Ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to give the title compound (1.05 g) having the following physical data.

MS (m / z): 410 (M ⁺ ). Reference Example 26 2- (5-diphenylhydroxymethylisoxazol-3-yl) methyl-5-methoxy-1,2,3,4
-Tetrahydronaphthalene

[0257]

[Chemical 168]

The compound prepared in Reference Example 25 (820 m
g), hydroxylamine hydrochloride (1.50 g), pyridine (10 ml) and ethanol (10 ml) were stirred at 100 ° C. for 6 hours. After cooling, the solvent of the reaction mixture was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1),
The title compound (680 mg) having the following physical data was obtained.

MS (m / z): 425 (M ⁺ ). Reference Example 27 2- (5-diphenylmethylisoxazol-3-yl) methyl-5-methoxy-1,2,3,4-tetrahydronaphthalene

[0260]

[Chemical 169]

The compound prepared in Reference Example 26 (650 m
To a mixture of g) and toluchloroacetic acid (6 ml) was added a solution of triethylsilane (350 mg) in methylene chloride (2 ml) at 0 ° C. The mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off. A sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give the title compound (525 mg) having the following physical data.

MS (m / z): 409 (M ⁺ ). Reference Example 28 2- (5-diphenylmethylisoxazol-3-yl) methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene

[0263]

[Chemical 170]

The compound prepared in Reference Example 27 (470 m
Boron tribromide (0.34 ml) was added to a solution of g) in methylene chloride (6 ml) at 0 ° C. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give the title compound (328 mg) having the following physical data.

MS (m / z): 395 (M ⁺ ). Reference Example 29 2- (3,3-dibromo-2-propenyl) -3-methoxy-1,2,3,4-tetrahydronaphthalene

[0266]

[Chemical 171]

Carbon tetrabromide (19.5 g) in methylene chloride (5
0 ml) solution at 0 ° C with triphenylphosphine (30.8
g) was added and stirred for 10 minutes. A solution of 2-formylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.09 g; produced by the method described in Japanese Patent Application No. 3-130467) in methylene chloride (25 ml) was added to the mixture. Was added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes.
Hexane was gradually added to the reaction mixture, and the precipitated triphenylphosphine oxide was filtered. The filtrate was washed with water and brine and dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 24: 1) to give the title compound (6.42 g) having the following physical data.

MS (m / z): 362, 360, 358
(M ⁺ ). Reference Example 30 2- (2-propynyl) -5-methoxy-1,2,3,3
4-tetrahydronaphthalene

[0269]

[Chemical 172]

N-Butyllithium (23.7 ml; 1.6 M / L hexane solution) was added dropwise to a THF (70 ml) solution of the compound (6.20 g) produced in Reference Example 29 at -70 ° C. The mixture was stirred at -70 ° C for 30 minutes. Water and ammonium chloride were added to the reaction mixture at the same temperature and the temperature was raised to room temperature. The mixture was mixed with hexane-ethyl acetate (6:
Extracted in 1). The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 24: 1) to give the title compound (3.40 g) having the following physical data.

MS (m / z): 200 (M ⁺ ). Reference Example 31 2- (5,5-diphenyl-4-oxo-2-pentynyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene

[0272]

[Chemical 173]

Ethyl magnesium bromide (5.7 m
1; 3.0 M / L ether solution) and THF (40 m
l) to the mixture prepared in Reference Example 30 (3.0
A solution of g) in THF (20 ml) was added dropwise over 10 minutes. The mixture was stirred at room temperature for 2 hours. Diphenylacetaldehyde (2.94 g) in THF (10
ml) solution was added. The mixture was stirred for another 2 hours. Ammonium chloride was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the residue in ether (50 ml) was added at room temperature to manganese dioxide (2.
7 g) was added. The mixture was stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to give the title compound (2.41 g) having the following physical data.

MS (m / z): 394 (M ⁺ ). Reference Example 32 2- (3-diphenylmethylisoxazol-5-yl) methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene

[0275]

[Chemical 174]

The title compound having the following physical data was obtained in the same manner as in Reference Example 26 and Reference Example 28 using the compound prepared in Reference Example 31.

MS (m / z): 395 (M ⁺ ). Reference Example 33 2- (4-imino-2-hydroxy-5-diphenyl-
2-Pentenyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene

[0278]

[Chemical 175]

Using the compound prepared in Reference Example 31 and operating in the same manner as in Reference Example 26 (600 m
A mixture of g), Raney nickel (300 mg) and ethanol (5 ml) was stirred under a hydrogen stream overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:
Purification with benzene = 7: 93) gave the title compound (325 mg) having the following physical data.

MS (m / z): 411 (M ⁺ ). Reference Example 34 2- (3-diphenylmethylisothiazol-5-yl) methyl-5-methoxy-1,2,3,4-tetrahydronaphthalene

[0281]

[Chemical 176]

The compound prepared in Reference Example 33 (255 m
g), p-chloranil (153 mg), phosphorus pentasulfide (413 mg) and toluene (4 ml) were added to a mixture of 3
Reflux for 0 minutes. After cooling the reaction mixture, benzene was added. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 1) to give the title compound (128 mg) having the following physical data.

MS (m / z): 425 (M ⁺ ). Reference Example 35 2- (3-diphenylmethylisothiazol-5-yl) methyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene

[0284]

[Chemical 177]

The title compound (90 mg) having the following physical data was obtained by the same procedures as in Reference Example 7 using the compound prepared in Reference Example 34.

MS (m / z): 411 (M ⁺ ). Example 1 Methyl [2- (4-diphenylmethylpyrazole-2
-Yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0287]

[Chemical 178]

Sodium hydride (content 60%, 68 m
A DMF (2.0 ml) solution of the compound (190 mg) produced in Reference Example 4 was added to a suspension of g) in DMF (2.0 ml) at room temperature with stirring. After stirring the mixture for 30 minutes at room temperature, the compound prepared in Reference Example 1 (280 mg)
Of DMF (2.0 ml) was added. The mixture was stirred for 30 minutes and then quenched with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate-n-hexane (1: 2). The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 2) to give the title compound of the present invention (90 m) having the following physical data.
g) was obtained.

TLC (n-hexane: ethyl acetate = 2:
1): Rf = 0.36; IR (cm ⁻¹ ): 3061, 3027, 2928, 1762, 1741, 160
2, 1586, 1494, 1466,1374, 1346, 1207, 1120, 1031,
1018, 992, 918, 849, 764, 702. Example 2 [2- (4-diphenylmethylpyrazol-2-yl)
Methyl-1,2,3,4-tetrahydronaphthalene-5
-Yloxy] acetic acid

[0290]

[Chemical 179]

The compound (78 mg) produced in Example 1 was dissolved in a mixed solution of THF (2.0 ml) and methanol (2.0 ml). A 1N aqueous sodium hydroxide solution (0.5 ml) was added to the solution at room temperature with stirring. The solution was stirred at room temperature for 1 hour. The reaction mixture was added with 2N hydrochloric acid (0.
It was neutralized with 25 ml) and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of n-hexane-ethyl acetate to obtain the title compound of the present invention (62 mg) having the following physical data.

TLC (chloroform: methanol = 1)
7: 3): Rf = 0.31; NMR: δ 7.37 to 7.14 (1H, m), 7.02 (1H, t, J = 8.0Hz),
6.98 (1H, s), 6.67 (1H, d, J = 8.0Hz), 6.56 (1H, d, J = 8.0H
z), 5.35 (1H, s), 4.62 (2H, s), 4.50 (1H, br, s), 4.15 ~
3.93 (2H, m), 3.05 ~ 2.85 (1H, m), 2.71 ~ 2.10 (4H, m), 1.
93 to 1.75 (1H, m), 1.45 to 1.20 (1H, m). Examples 2 (a) to 2 (l) The same operation as in Example 1 was performed (however, the compound (a) shown in the following Table 3 was used in place of the compound produced in Reference Example 4).
Using the obtained compound, operating in the same manner as in Example 2,
The compounds of the present invention shown in Table 3 below were obtained.

[0293]

[Table 3]

[0294]

[Table 4]

[0295]

[Table 5]

[0296]

[Table 6]

[0297]

[Table 7]

[0298]

[Table 8]

Example 3 Methyl [2- [2- (4,5-diphenylimidazol-1-yl) ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0300]

[Chemical 180]

Methyl (2-hydroxymethyl-1,
Reference example 1 using methyl [2- (2-hydroxyethyl) -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate instead of 2,3,4-tetrahydronaphthalen-5-yloxy) acetate. Using the compound obtained by the same procedure as in Example 1, the same procedure as in Example 1 was carried out (however, 4,5-diphenylimidazole was used in place of the compound prepared in Reference Example 4), and the following compound was obtained. The title compound of the present invention having physical properties was obtained.

NMR: δ 7.64 (1H, s), 7.60 to 7.10 (10
H, m), 7.02 (1H, t, J = 7Hz), 6.62 (1H, d, J = 7Hz), 6.48 (1H,
d, J = 7Hz), 4.62 (2H, s), 3.92 (2H, t, J = 6Hz), 3.78 (3H,
s), 3.00 ~ 2.10 (5H, m), 1.95 ~ 1.50 (3H, m), 1.25 (1H,
m); IR (cm ^-1 ): 3434, 2925, 1761, 1603, 1585, 150
7, 1466, 1441, 1373,1245, 1207, 1118, 1022, 954, 9
18, 773, 721, 700, 654. Example 4 [2- [2- (4,5-diphenylimidazole-1-
Iyl) ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0303]

[Chemical 181]

The title compound of the present invention having the following physical data was obtained by repeating the procedure of Example 2 using the compound prepared in Example 3.

Melting point: 197 ° C .; TLC (methylene chloride: methanol = 9: 1): Rf =
0.16; IR (cm ^-1 ): 3453, 2922, 1734, 1585, 1551, 146
7, 1441, 1244, 1113, 767, 697. Examples 4 (a) to 4 (f) The compounds (a) shown in the following Table 4 were used instead of 4,5-diphenylimidazole, and the compounds obtained by the same procedure as in Example 3 were used. The procedure of Example 2 was repeated to obtain the compounds of the present invention shown in Table 4 below.

[0306]

[Table 9]

[0307]

[Table 10]

[0308]

[Table 11]

Example 5 Methyl [1- [2- (4,5-diphenylimidazol-1-yl) ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0310]

[Chemical 182]

Methyl [2- (2-hydroxyethyl)]
Using methyl [1- (2-hydroxyethyl) -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate instead of -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate The procedure of Example 3 was repeated to give the title compound of the present invention having the following physical data.

IR (cm ^-1 ): 3066, 2932, 2861, 236
1, 1761, 1676, 1603, 1581, 1506,1463, 1442, 1371,
1339, 1244, 1210, 1121, 1073, 1022, 954, 918, 849,
775, 755, 721, 699; MS: 466 (M ⁺ ). Example 6 [1- [2- (4,5-diphenylimidazole-1-
Iyl) ethyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0313]

[Chemical 183]

The title compound of the present invention having the following physical data was obtained by operating in the same manner as in Example 2 using the compound prepared in Example 5.

TLC (methylene chloride: methanol = 1
0: 1): Rf = 0.17; IR (cm ^-1 ): 3449, 3058, 2932, 2862, 1736, 160
3, 1581, 1508, 1463,1444, 1339, 1230, 1115, 1075,
920, 885, 775, 722, 700. Examples 6 (a) to 6 (c) Using compounds (a) shown in the following Table 5 in place of 4,5-diphenylimidazole and using the compound obtained by the same procedure as in Example 3, it was carried out. In the same manner as in Example 2, the compounds of the present invention shown in Table 5 below were obtained.

[0316]

[Table 12]

[0317]

[Table 13]

Example 7 Methyl [1- [2- (3-diphenylmethyl-1,
2,4-oxadiazol-5-yl) ethyl] -1,
2,3,4-Tetrahydronaphthalen-5-yl] oxy] acetate

[0319]

[Chemical 184]

Compound prepared in Reference Example 6 (400 mg)
A toluene (20 ml) suspension of was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound of the present invention (305) having the following physical data.
mg) was obtained.

MS (m / z): 482 (M ⁺ ), 423, 31
5, 273, 263, 250, 167; IR (cm ^-1 ): 3029, 2935, 1762, 1739, 1581, 149
6, 1464, 1374, 1210,1121, 1080, 1033, 846, 777, 70
2. Example 8 [1- [2- (3-Diphenylmethyl-1,2,4-oxadiazol-5-yl) ethyl] -1,2,3,4
-Tetrahydronaphthalen-5-yloxy] acetic acid

[0322]

[Chemical 185]

The title compound of the present invention having the following physical data was obtained by repeating the procedure of Example 2 using the compound prepared in Example 7.

TLC (methanol: methylene chloride = 1:
9): Rf = 0.11; IR (cm ^-1 ): 2935, 1748, 1708, 1578, 1496, 146
5, 1429, 1377, 1240, 1123, 1032, 923, 782, 747, 72
2, 702, 634, 587. Examples 8 (a) and (b) Instead of the compound prepared in Reference Example 6, methyl [2-
((1-Amino-2,2-diphenylethylidene) aminooxycarbonylmethyl) -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate, or the compound prepared in Reference Example 23 was used. By operating in the same manner as in Example 7 and Example 8, the compounds of the present invention shown in Table 6 below were obtained.

[0325]

[Table 14]

Example 9 Methyl [2- (4-diphenylmethyloxazole-
2-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0327]

[Chemical 186]

The compound prepared in Reference Example 12 (132 m
g) and potassium carbonate (93 mg) in acetone (2.0 m
l) Bromoacetic acid methyl ester (0.063 ml) was added to the suspension at room temperature with stirring. The mixture was stirred at 40 ° C. for 4 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give the title compound of the present invention (145 m
g) was obtained.

TLC (ethyl acetate: n-hexane = 1: 1)
3): Rf = 0.28; IR (cm ⁻¹ ): 3027, 2926, 1762, 1585, 1495, 146
6, 1452, 1437, 1345,1282, 1207, 1156, 1120, 1099,
1032, 997, 839, 767, 750, 702. Example 10 [2- (4-Diphenylmethyloxazol-2-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0330]

[Chemical 187]

The title compound of the present invention having the following physical data was obtained by operating in the same manner as in Example 2 by using the compound prepared in Example 9.

Melting point: 129.5 to 131.5 ° C .; TLC (methanol: chloroform = 3: 17): Rf
= 0.24; IR (cm ^-1 ): 3029, 2923, 1748, 1585, 1570, 149
5, 1467, 1453, 1433, 1307, 1243, 1212, 1120, 1032,
984, 913, 764, 730, 700. Example 11 Methyl [2- (2-diphenylmethyloxazole-
4-yl] methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0333]

[Chemical 188]

The title compound of the present invention having the following physical data was obtained by operating in the same manner as in Example 9 using the compound prepared in Reference Example 16.

Melting point: 91 to 93 ° C .; TLC (n-hexane: ethyl acetate = 3: 1): Rf =
0.32; IR (cm ^-1 ): 3100, 3028, 2933, 1756, 1601, 158
5, 1566, 1495, 1463, 1378, 1345, 1275, 1202, 1168,
1117, 1086, 1031, 987, 955, 770, 757, 742,718, 70
1, 538. Example 12 [2- (2-Diphenylmethyloxazol-4-yl] methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0336]

[Chemical 189]

By using the compound prepared in Example 11 and operating in the same manner as in Example 2, the title compound of the present invention having the following physical data was obtained.

Melting point: 158 to 159.5 ° C .; TLC (chloroform: methanol = 9: 1): Rf =
0.19; IR (cm ^-1 ): 3414, 3062, 2925, 1756, 1603, 158
5, 1557, 1495, 1467, 1451, 1435, 1345, 1118, 968, 7
65, 736, 720, 698, 648, 585.

Example 12 (a) [2- (2-((3-pyridyl) phenylmethyl) oxazol-4-yl] methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0340]

[Chemical 190]

Using the same operation as in Reference Example 15 (however,
(3-Pyridyl) phenylacetic acid sodium salt was used instead of diphenylacetic acid sodium salt. ) The obtained compound was used as Reference Example 16 and Example 11 → Example 12;
The title compound of the present invention having the following physical data was obtained in the same manner.

NMR: δ 8.52-8.30 (2H, m), 7.78-7.
64 (1H, m), 7.41 ~ 7.15 (7H, m), 7.00 (1H, t, J = 8Hz), 6.68
(1H, d, J = 8Hz), 6.57 (1H, d, J = 8Hz), 5.72 (1H, s), 4.61 (2
H, s), 3.04 to 1.90 (8H, m), 1.53 to 1.33 (1H, m). Example 13 Methyl [2- (2-diphenylmethyl-5-ethyloxazol-4-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0343]

[Chemical 191]

The compound prepared in Reference Example 17 was added to diphenylacetyl chloride (6 mmol) under ice cooling. The mixture was stirred at 100 ° C. overnight. The reaction mixture was cooled and then poured into water. The mixture was extracted with ethyl acetate. The extract was washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) and further purified by silica gel column chromatography (benzene: ethyl acetate = 97: 3) to give the title compound having the following physical properties. The compound of the present invention (93 m
g) was obtained.

TLC (benzene: ethyl acetate = 19:
1): Rf = 0.29; IR (cm ⁻¹ ): 3063, 3029, 2926, 1763, 1603, 158
5, 1566, 1455, 1437, 1377, 1283, 1206, 1121, 1032,
854, 767, 748, 702. Example 14 [2- (2-Diphenylmethyl-5-ethyloxazol-4-yl] methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0346]

[Chemical 192]

The title compound of the present invention having the following physical data was obtained by operating in the same manner as in Example 2 using the compound prepared in Example 13.

Melting point: 150.5 to 151.5 ° C .; TLC (chloroform: methanol = 9: 1): Rf =
0.27; IR (cm ^-1 ): 3030, 2974, 2932, 2504, 1907, 171
8, 1585, 1562, 1495,1343, 1249, 1211, 1155, 1113,
1032, 767, 747, 727, 701, 633, 586. Example 15 Methyl [2- (2-diphenylmethylimidazole-
4-yl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0349]

[Chemical formula 193]

The mixture prepared in Reference Example 18 (350 m
g) and the compound prepared in Reference Example 19 (450 mg)
Was refluxed for 18 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was dried over water, brine and anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n
Purification with -hexane: ethyl acetate = 1: 1) gave the title compound of the present invention (181 mg) having the following physical data.

TLC (ethyl acetate: n-hexane = 1: 1)
1): 0.23; IR (cm ^-1 ): 3026, 2925, 2362, 1762, 1585, 149
5, 1466, 1455, 1438, 1208, 1120, 766, 701, 589. Example 16 [2- (2-Diphenylmethylimidazol-4-yl] methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0352]

[Chemical 194]

The title compound of the present invention having the following physical data was obtained by operating in the same manner as in Example 2 using the compound prepared in Example 15.

Melting point: 170 ° C .; TLC (chloroform: methanol: acetic acid = 17: 2:
1): Rf = 0.25; IR (cm ^-1 ): 3424, 3030, 2922, 1955, 1641, 158
6, 1496, 1411, 1329,1237, 1106, 1081, 1005, 768, 7
00, 587. Example 17 Octyl [2- (4-diphenylmethylpyrazole-
2-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate

[0355]

[Chemical 195]

The carboxylic acid prepared in Example 2 (0.453
g) was dissolved in oxalic acid chloride (3 ml). The solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove excess oxalic acid chloride. The residue was dissolved in pyridine (2 ml) and n-octyl alcohol (156 mg) was added to the solution. Mix the mixture at room temperature 1
Stir for hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1),
The title compound of the present invention (0.48 g) having the following physical data was obtained.

MS: m / z 565 (M ⁺ +1); TLC (n-hexane: ethyl acetate = 3: 1): Rf =
0.33. Example 18 [2- (4-Diphenylmethylpyrazol-2-yl)
Methyl-1,2,3,4-tetrahydronaphthalene-5
-Yloxy] acetamide

[0358]

[Chemical 196]

The carboxylic acid prepared in Example 2 (452 m
g) was dissolved in oxalic acid chloride (2.0 ml).
The solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove excess oxalic acid chloride. The residue was dissolved in methylene chloride (5.0 ml). 0 of the solution
After cooling to 0 ° C., ammonia gas was blown into the mixture to make it cloudy. The mixture was stirred at room temperature for 30 minutes, the insoluble material was filtered off, the filtrate was concentrated and purified by silica gel column chromatography (methanol: methylene chloride = 1: 4) to give the title compound having the following physical data. The compound of the present invention (420 m
g) was obtained.

TLC (methylene chloride: methanol = 4:
1): Rf = 0.22; MS: m / z 451 (M ⁺ ). Example 19 [2- (4-Diphenylmethylpyrazol-2-yl)
Methyl-1,2,3,4-tetrahydronaphthalene-5
-Iloxy] acetic acid and glycine amide

[0361]

[Chemical 197]

The carboxylic acid prepared in Example 2 (452 m
g), glycine-tert-butyl ester hydrochloride, 2-chloro-1-methylpyridinium iodide (307 m
g) and triethylamine (0.42 ml) were dissolved in methylene chloride (5.0 ml). The solution was stirred at room temperature for 4 hours and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain a condensate. The obtained condensate was dissolved in methylene chloride (3.0 ml), trifluoroacetic acid (3.0 ml) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The residue was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 1).
Purification in 9) gave the title compound of the present invention (403 mg) having the following physical data.

TLC (methylene chloride: methanol = 9:
1): Rf = 0.21; MS: m / z 509 (M ⁺ ). Example 20 [1- [3- (4-Diphenylmethylpyrazole-1-
And yl) propyl] -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0364]

[Chemical 198]

Methyl (2-hydroxymethyl-1,
Reference example 1 using methyl [1- (3-hydroxypropyl) -1,2,3,4-tetrahydronaphthalen-5-yloxy] acetate instead of 2,3,4-tetrahydronaphthalen-5-yloxy] acetate ,
The title compound of the present invention having the following physical data was obtained in the same manner as in Example 1 and Example 2.

TLC (chloroform: methanol = 4:
1): Rf = 0.30; IR (cm ⁻¹ ): 3027, 2932, 2862, 1736, 1602, 158
2, 1494, 1464, 1374, 1340, 1216, 1118, 1080, 1015,
874, 752, 702.

Example 21 [2- [3- (4-((3-pyridyl) phenylmethyl) pyrazol-2-yl) -1-propenyl] -1,
2,3,4-Tetrahydronaphthalen-5-yloxy] acetic acid

[0368]

[Chemical formula 199]

Methyl (2-hydroxymethyl-1,
Using methyl (2- (3-hydroxy-1-propenyl) -1,2,3,4-tetrahydronaphthalen-5-yloxy) acetate instead of 2,3,4-tetrahydronaphthalen-5-yloxy) acetate ,
Using the compound obtained in the same manner as in Reference Example 1 and 4-((3-pyridyl) phenylmethyl) pyrazole instead of the compound produced in Reference Example 4, the same procedure as in Example 1 and Example 2 was performed. The title compound of the present invention having the following physical data was obtained.

NMR: δ 8.55 (1H, s), 8.43 (1H, d, J = 4H
z), 7.62 (1H, d, J = 7Hz), 7.37 ~ 7.00 (10H, m), 6.69 (1H,
d, J = 8Hz), 6.62 (1H, d, J = 8Hz), 6.32 ~ 6.21 (2H, m), 5.4
0 (1H, s), 4.88 (2H, d, J = 6Hz), 4.59 (1H, s), 3.02 ~ 1.85
(6H, m), 1.56 to 1.40 (1H, m).

Example 22 [2- (4- (Diphenylmethyl) pyrazol-2-yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid

[0372]

[Chemical 200]

Methyl (2-hydroxymethyl-1,
2,3,4-tetrahydronaphthalen-5-yloxy) acetate instead of methyl (2-hydroxymethyl-3,4-dihydronaphthalen-5-yloxy)
Example 1 was conducted using the compound obtained in the same manner as in Reference Example 1 using acetate and the compound produced in Reference Example 4.
Then, the title compound of the present invention having the following physical data was obtained in the same manner as in Example 2.

NMR: δ 8.00 (1H, brs), 7.37 to 7.12 (1
1H, m), 7.06 (1H, s), 7.04 (1H, t, J = 8Hz), 6.66 (1H, d, J = 8
Hz), 6.62 (1H, d, J = 8Hz), 6.18 (1H, s), 5.35 (1H, s), 4.7
8 (2H, s), 4.58 (2H, s), 2.84 (2H, t, J = 8Hz), 2.13 (2H, d, J
= 8Hz).

Example 22 (a) [2- (4-((3-pyridyl) phenylmethyl) pyrazol-2-yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid

[0376]

[Chemical 201]

Instead of the compound prepared in Reference Example 4, 4-
Using ((3-pyridyl) phenylmethyl) pyrazole and the same procedure as in Example 22, the title compound of the present invention having the following physical data was obtained.

NMR: δ 8.52 (2H, m), 7.60 (1H, m), 7.
4 to 7.0 (10H, m), 6.69 (2H, d, J = 8Hz), 6.23 (1H, s), 5.40
(1H, s), 4.80 (2H, s), 4.60 (2H, s), 2.89 (2H, t, J = 9Hz),
2.14 (2H, t, J = 9Hz). Example 23 [1- (2- (4-((3-pyridyl) phenylmethyl) pyrazol-2-yl) ethylidene) -1,2,
3,4-Tetrahydronaphthalen-5-yloxy] acetic acid

[0379]

[Chemical 202]

Methyl (2-hydroxymethyl-1,
Reference example using methyl (1- (2-hydroxyethylidene) -1,2,3,4-tetrahydronaphthalen-5-yloxy) acetate instead of 2,3,4-tetrahydronaphthalen-5-yloxy) acetate Using the compound obtained in the same manner as in Example 1 and 4-((3-pyridyl) phenylmethyl) pyrazole in place of the compound prepared in Reference Example 4 and operating in the same manner as in Example 1 and Example 2. The title compound of the present invention having the following physical data was obtained.

NMR: δ 8.65-8.42 (2H, m), 7.73-7.
65 (1H, d, J = 7Hz), 7.40 ~ 6.96 (11H, m), 6.62 (1H, d, J = 8H
z), 6.12 (1H, t, J = 5Hz), 5.43 (1H, s), 4.82 (2H, d, J = 5H
z), 4.61 (2H, s), 3.05 (2H, t, J = 6Hz), 2.43 (2H, t, J = 6H
z), 1.82 to 1.68 (2H, m). Example 24 [2- (4-((1-imidazolyl) phenylmethyl)
Pyrazol-2-yl) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0382]

[Chemical 203]

1) Compound (48) prepared in Reference Example 20
To a solution of 0 mg) in THF-methanol (2: 1, 4 ml) was added 1N sodium hydroxide solution (2.0 ml) at room temperature with stirring. The solution was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 1N hydrochloric acid (2.0 ml) and then extracted with ethyl acetate. Wash the extract with saline,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

2) The residue was dissolved in methanol (4 ml), cooled to 0 ° C. and sodium borohydride (1
00 mg) was added. The mixed solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. After acidifying the residue with 1N hydrochloric acid,
It was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

3) The residue was dissolved in ethyl acetate-methanol (9: 1, 3 ml) and cooled to 0 ° C. An ethanol solution of diazomethane was excessively added to the mixed solution. The reaction solution was left at room temperature for 10 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 2).

4) The obtained compound (280 mg), imidazole hydrobromide (700 mg), molecular sieves 4A (1 g) and DMF (3 ml) were added to the mixture (11 mg).
The mixture was stirred at 0 ° C for 5 hours. The reaction mixture was cooled to room temperature, diluted with hexane-ethyl acetate (1: 1), washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol: chloroform = 1: 99 →
2: 98 → 3: 97).

5) The title compound of the present invention having the following physical data was obtained by treating the thus obtained compound in the same manner as in Example 2.

NMR: δ 8.10 to 7.60 (2H, m), 7.42 to 7.
06 (8H, m), 6.99 (1H, t, J = 8Hz), 6.92 (1H, s), 6.70 ~ 6.50
(2H, m), 6.45 (1H, s), 4.57 (2H, s), 4.15 ~ 3.90 (2H, m),
3.05 ~ 2.85 (1H, m), 2.74 ~ 2.18 (4H, m), 1.93 ~ 1.74 (1H,
m), 1.46 to 1.20 (1H, m). Example 25 [2- (5-diphenylmethylisoxazole-3-
Il) methyl-1,2,3,4-tetrahydronaphthalen-5-yloxy] acetic acid

[0389]

[Chemical 204]

The title compound of the present invention having the following physical data was obtained by treating the compound produced in Reference Example 28 in the same manner as in Example 9 and Example 10.

NMR: δ 7.40 to 7.02 (11H, m), 7.00 (1
H, t, J = 8Hz), 6.72 (1H, dJ = 8Hz), 6.60 (1H, d, J = 8Hz), 5.
60 (1H, s), 5.43 (1H, s), 4.53 (2H, s), 3.06 ~ 2.85 (1H,
m), 2.76-2.10 (4H, m), 1.95 ~ 1.75 (1H, m), 1.45-1.20
(1H, m). Examples 25 (a) and (b) By using the compounds produced in Reference Example 32 and Reference Example 35 instead of the compound produced in Reference Example 28, the same operation as in Example 25 was carried out, and the results are shown in Table 7 below. The compound of the present invention was obtained.

[0390]

[Table 15]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 249/04 502 7329-4C 249/06 502 7329-4C 261/08 263/32 271/06 275 / 02 401/06 231 403/06 231 413 413/06 213 // A61K 31/41 ABX 9454-4C 31/415 ACB 9454-4C AEL 9454-4C 31/42 ABS 9454-4C 31/425 ABU 9454-4C 31 / 44 ACL 9454-4C (C07D 401/06 213: 36 231: 12) (C07D 403/06 231: 12 233: 61) (C07D 413/06 213: 36 263: 32)

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, [Chemical 3] [Chemical 4] [Chemical 5] [Chemical 6] A is [Chemical 8] [Chemical 9] [Chemical 10] [Chemical 11] [Chemical 12] [Chemical 13] [Chemical 14] [Chemical 15] [Chemical 16] [Chemical 17] [Chemical 18] [Chemical 19] [Chemical 20] [Chemical 21] R ¹ represents (i) a hydroxyl group, (ii) a C1-12 alkoxy group or (iii) NR ² R ³ , and R ² and R ³ are each independently (i) a hydrogen atom or (ii) C 1 ~ 4 alkyl groups or, together with adjacent nitrogen atoms, represents an amino acid residue, R ⁴ is each independently (i) a hydrogen atom, (ii) a C 1-4 alkyl group (Iii) a phenyl group, (iv) a phenyl group or a C1-4 alkyl group substituted by 1 or 2 4- to 7-membered monocyclic heterocycles containing 1 or 2 nitrogen atoms, Further, when R ⁴ represents a phenyl group, or a group containing a phenyl group or a 4- to 7-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the ring is a C1-4 alkyl group, C1
To 4 alkoxy groups, halogen atoms, nitro groups or trihalomethyl groups may be substituted, Y represents an oxygen atom or a sulfur atom, e represents an integer of 3 to 5, and f represents , 1 represents an integer of 1 to 3, l represents an integer of 1 to 3, m represents an integer of 1 or 2, p represents an integer of 1 to 4, and q represents zero or 1 or 2 Represents an integer of 1, r represents an integer of 1 to 4, and s represents zero or an integer of 1 to 3. However,
(1) A is [Chemical formula 23] [Chemical formula 24] [Chemical 25] [Chemical formula 26] [Chemical 27] [Chemical 28] (In the formula, all symbols have the same meanings as described above.),
Or (Wherein R ⁴ represents a hydrogen atom), q and s are not zero, and (2) A is [Chemical 31] [Chemical 32] [Chemical 33] [Chemical 34] [Chemical 35] [Chemical 36] [Chemical 37] [Chemical 38] [Chemical Formula 39] [Chemical 40] (In the formula, Y, l and m have the same meanings as described above.)
And R ⁴ represents a C1-4 alkyl group substituted with a heterocycle, the heterocycle shall be bonded to the alkyl group only at that carbon atom, and (3)-
(CH ₂ ) _r − or = CH— (CH ₂ ) _s — is bonded to either ring carbon atom a or b, and (4) A is (Wherein R ⁴ has the same meaning as described above), [Chemical 43] Take only. ), A condensed benzeneoxyacetic acid derivative, a non-toxic salt thereof, or an acid addition salt thereof.