JPH08239356A - Naphthyloxyacetic acid derivative and medicine containing the same as active ingredient - Google Patents

Abstract

PURPOSE: To obtain a naphthyloxyacetic acid derivative, having antagonistic actions, etc., on PGE2 and utilizable as a preventing agent, etc., for abortion. CONSTITUTION: This compound is represented by formula I [R<1> is H, a 1-4C alkyl, etc.; R<2> is a 1-6C alkyl, a 2-6C alkenyl, etc.; A is a single bond, a 1-6C alkylene, etc.; B is a group of the formula, NR<3> CO or CONR<3> (R<3> is H or a 1-4C alkyl)], e.g. [5-(2-diphenylmethylaminocarbonylethyl)naphthyl-1-oxy]acetic acid. The compound of formula I is obtained by carrying out the amidating reaction of a compound of formula II (R<1aa> is a 1-4C alkyl, etc.) with a compound of the formula, HOOC-R<2> .

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a naphthyloxyacetic acid derivative. More specifically, (1) general formula (I)

Embedded image (Wherein all symbols have the same meanings as described below), a naphthyloxyacetic acid derivative, a non-toxic salt thereof, a non-toxic acid addition salt thereof and hydrates thereof, (2) a method for producing them, And (3) prostaglandin E ₂ (hereinafter abbreviated as PGE ₂ ) containing them as an active ingredient.
Regarding antagonists or agonists.

[0002]

BACKGROUND OF THE INVENTION of PGE ₂ agonist (work働剤), including the so-called PGE ₂ itself, have been known many, PG
A compound (antagonist) that antagonizes E ₂ and inhibits the action of PGE ₂ is not known. PGE ₂ is known as a metabolite in the arachidonic acid cascade, and its actions include uterine contraction, pain-reducing action, promotion of gastrointestinal peristalsis,
It is known to have awakening action, gastric acid secretion inhibiting action, blood pressure lowering action, platelet aggregation inhibiting action and the like. It is expected to have the following actions by antagonizing these actions and acting.

Since antagonizing PGE ₂ means suppressing these effects, suppression of uterine contraction,
It may lead to analgesia, gastrointestinal motility suppression, and sleep-inducing action. Therefore, the PGE ₂ antagonist is useful as a miscarriage preventive agent, an analgesic agent, an antidiarrheal agent, and a hypnotic agent. Also, PGE
That agonizing the _2, it becomes to promote these effects, respectively, uterine contraction, hyperactivity of the digestive tract, gastric acid secretion inhibiting action, blood pressure lowering action, leading to platelet aggregation inhibiting action. Therefore, the PGE ₂ agonist is useful as an abortion agent, a laxative, an antiulcer agent, an antigastritis agent, a blood pressure lowering agent, and an antithrombotic agent.

JP-A-6-72978 (European publication 0542203)
A3) In the specification, compounds having the following structural formulas are disclosed.

That is, the general formula (A)

Embedded image

(Where

[Chemical 4]

A ^A is (i) -COW ^A , (ii) -NR ^4A
-Y ^A, or represents ^{(iii) -Z A -NR 4A -CONR} 2A R 3A, W A ^{is, (i) -NR 2A R 3A} , (ii) -NR 4A
-OR ^5A , (iii) -NR ^4A -NR ^2A R ^3A , or (iv)
It represents ^{-NR 4A -N = CR 2A R 3A} , Y A is, (i) -
^{CO-R 5A, (ii)} -CO-U A -NR 2A R 3A or,
(iii) represents a ^{-CS-U A -NR 2A R 3A} , the Z ^A, (i)
-CH = N-, or (ii) -CH ₂ -NR ^6A - it represents,

R ^1A represents a hydrogen atom or a C1-4 alkyl group, and R ^2A and R ^3A independently represent each other.
(i) hydrogen atom, (ii) phenyl group, (iii) benzoylphenyl group, (iv) 4-7 membered unsaturated monocyclic heterocyclic group containing one nitrogen atom as a hetero atom, or (v) hetero 1 to 4 arbitrarily selected from a 4- to 7-membered unsaturated monocyclic heterocycle containing one nitrogen atom as an atom and a phenyl ring
Represents a C1-4 alkyl group substituted by three ring system groups, R ^4A represents a hydrogen atom, a C1-6 alkyl group,
Or a phenyl group, R ^5A is (i) a phenyl group, (ii) a heteroatom containing one nitrogen atom;
7-membered unsaturated monocyclic heterocyclic group, or (iii) 1-3 ring optionally selected from 4- to 7-membered unsaturated monocyclic heterocycle containing one nitrogen atom as a heteroatom and phenyl ring represents C1~4 alkyl group substituted by a system group, R ^6A is hydrogen atom, an alkyl group or a phenyl group, a Cl to 6, U ^a represents a single bond or C1~4 alkylene group ,

Further, R ^2A , R ^3A , R ^4A , R ^5A and R ^6A
Represents a phenyl group or a phenyl-containing group, and R ^2A , R ^3A and R ^5A represent the heterocyclic group or the heterocyclic-containing group, the phenyl group and the heterocyclic group are a C1-4 alkyl group. , A C1-4 alkoxy group, a halogen atom, a nitro group or a trihalomethyl group may be substituted,

E represents an integer of 3 to 5, f represents an integer of 1 to 3, p represents zero or an integer of 1 to 4,
q represents zero or an integer of 1 or 2, r represents zero or an integer of 1 to 4, and s represents zero or an integer of 1 to 3.

[0011] However, (wherein, the R ^4A and Y ^A represents. As defined above) A ^A is (ii) -NR ^4A -Y ^A group when representing the can, q, r and s are not zero I shall. Also,

[0012]

Embedded image Is (iii) or (iv), the side chain-(CH ₂ ) _r
- or = CH- (CH _{2) s} - shall be attached to the carbon atom represented by a or b, respectively in the ring. There is a disclosure that the condensed benzeneoxyacetic acid derivative represented by the formula (1) binds to the PGI ₂ receptor and is useful as a pharmaceutical.

JP-A-6-72978 (European publication 0
The compound disclosed in Japanese Patent No. 542203A3) differs from the compound of the present invention in that the naphthalene ring as the basic structure is always partially saturated. The activity of this compound is also described as useful as a PGI ₂ antagonist or agonist. Those skilled in the art will appreciate that PGE ₂ and PG
Although I ₂ is in the same PG family, it is completely different in activity and action. Therefore, of course, PGE ₂
Compounds that antagonize or act on PGI ₂ and PGI ₂ have different activities and actions. Therefore, JP-A-6-72978
From the disclosure of the specification (European Publication 0542203A3),
It is not predictable that the compound of the present invention has a PGE ₂ antagonistic or agonistic action.

[0014]

DISCLOSURE OF THE INVENTION The present invention includes (1) general formula (I)

[0015]

[Chemical 6]

(Wherein R ¹ is (i) a hydrogen atom, (ii)
Alkyl C1 -4, (iii) expression (alkylene C1 -4) -COOR ¹⁰ (wherein, R ¹⁰ is a hydrogen atom or C1~
4 represents an alkyl group. Group represented by (), (iv) (C
1-4 alkylene) -OH group, (v) Formula (alkylene C1 -4) -CONR ⁴ R ⁵ (wherein, R ⁴ and R ^5,
Each independently represents a hydrogen atom or a C1-4 alkyl group. Groups represented by), (vi) expression (alkylene C1 -4) -CONR ⁶ - (alkylene C1 -4) -O
A group represented by H (in the formula, R ⁶ represents a hydrogen atom or a C1-4 alkyl group), (vii) a formula (C1-4 alkylene) -NR ⁴ R ⁵ (in the formula, R ⁴ and R ⁵ represents the same meaning as described above), (viii) (C1-4 alkylene) -cyano group, or (ix) (C1-4 alkylene) -tetrazolyl group,

A is a single bond, a C1-6 alkylene group,
Represents a C2-6 alkenylene group, a -S- (C1-6 alkylene) group or a -O- (C1-6 alkylene) group,

B represents a group represented by the formula NR ³ CO or CONR ³ (wherein R ³ represents a hydrogen atom or a C1-4 alkyl group),

R ² is (i) a C1-6 alkyl group, (i
i) C2-6 alkenyl group, (iii) phenyl group, C4
~ 7 cycloalkyl group, naphthyl group and nitrogen atom 1
A C1-6 alkyl group substituted with 1 to 3 substituents arbitrarily selected from a 4 to 7 membered heterocyclic group containing
(iv) C2 substituted with 1 to 3 substituents arbitrarily selected from a phenyl group, a C4-7 cycloalkyl group, a naphthyl group and a 4-7 membered heterocyclic group containing one nitrogen atom. ~ 6 alkenyl group, (v) formula NR ⁷ R ⁸ (wherein R
⁷ and R ⁸ independently represent a phenyl group, a C4-7 cycloalkyl group, a naphthyl group or a 4-7 membered heterocyclic group containing one nitrogen atom. ), Or (vi) a group represented by the formula (C1-6 alkylene) -NR ⁷ R ⁸ (in the formula, R ⁷ and R ⁸ have the same meanings as described above). However, the ring in R ² has 1 to 3 rings,
It may be substituted with a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom, a nitro group or a trifluoromethyl group. ) A naphthyloxyacetic acid derivative, a non-toxic salt thereof, a non-toxic acid addition salt thereof and a hydrate thereof,

(2) A method for producing them, and (3) A PGE ₂ antagonist or agonist containing them as an active ingredient.

In the general formula (I), R ¹ , R ³ , R ⁴ , R ⁵ and R
The C1~4 alkyl group ⁶ and R ¹⁰ in the alkyl group and R ² C1~4 represented by means methyl, ethyl, propyl, butyl and isomeric groups thereof. In the general formula (I), the C1-4 alkoxy group in R ² means methoxy, ethoxy, propoxy, butoxy and their isomer groups. In the general formula (I), C1 to in R ¹
The alkylene group of 4 means methylene, ethylene, trimethylene, tetramethylene and isomer groups thereof. In formula (I), A and the C1-6 alkylene group in A mean methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomer groups thereof. In the general formula (I), the C2-6 alkenylene group represented by A means one having 1 to 3 double bonds in the above alkylene group, and examples thereof include vinylene, propenylene, butenylene, pentenylene, and hexenylene. Groups and the like.

In the general formula (I), the C1-6 alkyl group represented by R ² is methyl, ethyl, propyl, butyl,
It means pentyl, hexyl and their isomeric groups. In the formula (I), represented by R ² or in R ² C2-6
The alkenyl group means a group containing 1 to 3 double bonds in the above alkyl group, and examples thereof include vinyl, propenyl, butenyl, pentenyl, and hexenyl groups. In the general formula (I), the C4-7 cycloalkyl group in R ² means a cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. In the general formula (I),
The 4- to 7-membered heterocycle containing one nitrogen atom in R ² may be saturated or unsaturated, and examples thereof include azeto, pyrrole, pyrroline, pyrrolidine, pyridine,
Pyridrin, pyridridine, piperidine, azepine, azoline, azolidine and the like can be mentioned. In the general formula (I),
The halogen atom in R ² means chlorine, bromine, fluorine or iodine.

A preferred group of R ² is a group having no 4- to 7-membered heterocycle containing one nitrogen atom in the group, specifically, (i) C1-6 alkyl. Base,
(ii) a C2-6 alkenyl group, (iii-a) a phenyl group, a C4-7 cycloalkyl group and a C1-6 alkyl group substituted with 1 to 3 substituents selected from a naphthyl group, (iv-a) C2-6 alkenyl group substituted with 1 to 3 substituents selected from phenyl group, C4-7 cycloalkyl group and naphthyl group, (va) Formula NR ^7a
R ^8a (wherein R ^7a and R ^8a are independently a phenyl group,
It represents a C4-7 cycloalkyl group or a naphthyl group. Group or (vi-a) formula (alkylene Cl to 6) -NR ^7a R ^8a (wherein, in represented by), R ^7a and R ^8a is a group represented by the representative.) As defined above .

Another preferred group of R ² is a group having, as an essential substituent, a 4- to 7-membered heterocyclic group containing 1 nitrogen atom in the group. (i
ii-b) 4- to 7-membered heterocyclic group 1 containing one nitrogen atom
As an essential substituent and other substituents selected from a phenyl group, a C4-7 cycloalkyl group, a naphthyl group, and a 4- to 7-membered heterocyclic group containing one nitrogen atom. A C1-6 alkyl group having no or one or two substituents, (iv-b) one 4- to 7-membered heterocyclic group containing one nitrogen atom as an essential substituent And a substituent other than that, a phenyl group,
C2 having no or one or two substituents selected from a C4-7 cycloalkyl group, a naphthyl group and a 4- to 7-membered heterocyclic group containing one nitrogen atom.
~ 6 alkenyl group, (vb) formula NR ^7b R ^8b (wherein R
^{One of 7b} and R ^8b contains one nitrogen atom 4
~ 7-membered heterocyclic group, the other is a phenyl group, C
It represents a 4 to 7 cycloalkyl group, a naphthyl group or a 4 to 7 membered heterocyclic group containing one nitrogen atom. ) Or a (vi-b) formula (C1-6 alkylene)
—NR ^7b R ^8b (in the formula, R ^7b and R ^8b have the same meanings as described above).

In the compounds of the present invention, all isomers are included unless otherwise specified. For example, alkyl groups, alkylene groups and alkenylene groups include straight-chain and branched ones, and the double bond in the alkenylene group includes those which 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.

[0026]

[Salt, acid addition salt and hydrate] The compound represented by the general formula (I) can be converted into the corresponding salt or 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,
Examples thereof include salts of triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.). . Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, oxalate, fumarate, Organic acid salts such as maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate Can be mentioned. In addition, the compound represented by the general formula (I), a salt thereof or an acid addition salt thereof can be converted into a hydrate by a known method.

Among the compounds represented by the general formula (I), particularly preferred compounds are the compounds shown in Examples and the compounds shown in Tables 1 to 49 below.

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

[0033]

[Table 6]

[0034]

[Table 7]

[0035]

[Table 8]

[0036]

[Table 9]

[0037]

[Table 10]

[0038]

[Table 11]

[0039]

[Table 12]

[0040]

[Table 13]

[0041]

[Table 14]

[0042]

[Table 15]

[0043]

[Table 16]

[0044]

[Table 17]

[0045]

[Table 18]

[0046]

[Table 19]

[0047]

[Table 20]

[0048]

[Table 21]

[0049]

[Table 22]

[0050]

[Table 23]

[0051]

[Table 24]

[0052]

[Table 25]

[0053]

[Table 26]

[0054]

[Table 27]

[0055]

[Table 28]

[0056]

[Table 29]

[0057]

[Table 30]

[0058]

[Table 31]

[0059]

[Table 32]

[0060]

[Table 33]

[0061]

[Table 34]

[0062]

[Table 35]

[0063]

[Table 36]

[0064]

[Table 37]

[0065]

[Table 38]

[0066]

[Table 39]

[0067]

[Table 40]

[0068]

[Table 41]

[0069]

[Table 42]

[0070]

[Table 43]

[0071]

[Table 44]

[0072]

[Table 45]

[0073]

[Table 46]

[0074]

[Table 47]

[0075]

[Table 48]

[0076]

[Table 49]

[0077]

[Table 50]

[0078]

[Table 51]

[0079]

[Table 52]

[0080]

[Table 53]

[0081]

[Table 54]

[0082]

[Table 55]

[0083]

[Table 56]

[0084]

[Table 57]

[0085]

[Table 58]

[0086]

[Table 59]

[0087]

[Table 60]

[0088]

[Table 61]

[0089]

[Table 62]

[0090]

[Table 63]

[0091]

[Table 64]

[0092]

[Table 65]

[0093]

[Table 66]

[0094]

[Table 67]

[0095]

[Table 68]

[0096]

[Table 69]

[0097]

[Table 70]

[0098]

[Table 71]

[0099]

[Table 72]

[0100]

[Table 73]

[0101]

[Table 74]

[0102]

[Table 75]

[0103]

[Table 76]

[0104]

[Table 77]

[0105]

[Table 78]

[0106]

[Table 79]

[0107]

[Table 80]

[0108]

[Table 81]

[0109]

[Table 82]

[0110]

[Table 83]

[0111]

[Table 84]

[0112]

[Table 85]

[0113]

[Table 86]

[0114]

[Table 87]

[0115]

[Table 88]

[0116]

[Table 89]

[0117]

[Table 90]

[0118]

[Table 91]

[0119]

[Table 92]

[0120]

[Table 93]

[0121]

[Table 94]

[0122]

[Table 95]

[0123]

[Table 96]

[0124]

[Table 97]

[0125]

[Table 98]

[0126]

[Production Method] Of the compounds represented by the general formula (I), R
¹ (wherein, R ¹⁰ is. To the same meanings as defined above) alkyl or (alkylene C1 -4) -COOR ¹⁰ in C1 -4 represents a group represented by, B is the formula NR ³ CO
(In the formula, R ³ has the same meaning as described above.) A group represented by the general formula (Ia)

[0127]

[Chemical 7]

(Wherein R ^1a is a C1-4 alkyl group or formula (C1-4 alkylene) -COOR ¹⁰ (wherein R ^1a is
¹⁰ has the same meaning as described above. ) And other symbols have the same meanings as described above. ) Is a compound represented by the general formula (II)

[0129]

Embedded image

(In the formula, R ^1aa is a C1-4 alkyl group or a group represented by formula (C1-4 alkylene) -COOR ^10a (in the formula, R ^10a represents a C1-4 alkyl group). And other symbols have the same meanings as described above), and a compound of the general formula (III)

Embedded image A compound represented by HOOC-R ² (III) (wherein R ² has the same meaning as described above) is subjected to an amidation reaction and, if necessary, a hydrolysis reaction under alkaline conditions. It can be manufactured.

The reaction of reacting an acid with an amine to form an amide bond is known, and for example, (1) a method using an acid halide, (2) a method using a mixed acid anhydride,
(3) Condensing agent (1- (3-dimethylaminopropyl)
Examples thereof include a method using -3-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC) and the like.

The following is a detailed description of these methods.
(1) A method using an acid halide is, for example, a carboxylic acid in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran (THF) or the like) or without a solvent, and an acid halide (oxalyl chloride, thionyl chloride or the like). The resulting acid halide is reacted with -20 ° C to reflux temperature in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) and the amine and an inert organic solvent (chloroform, methylene chloride, diethyl ether). Ether, THF, etc.)
The reaction is carried out at 0 to 40 ° C in the medium.

(2) A method using a mixed acid anhydride is, for example, a carboxylic acid in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.) or without a solvent, and a tertiary amine (pyridine, triethylamine, Dimethylaniline, dimethylaminopyridine, etc.),
It is carried out by reacting with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at 0 to 40 ° C.

(3) In the method using a condensing agent such as EDC and DCC, for example, a carboxylic acid and an amine are mixed with an inert organic solvent (chloroform, methylene chloride, diethyl ether,
THF or the like or without a solvent, a tertiary amine (pyridine,
EDC, DC in the presence or absence of (triethylamine, dimethylaniline, dimethylaminopyridine, etc.)
It is carried out by reacting with C or the like at 0 to 40 ° C.

It is desirable that the reactions (1), (2) and (3) are all carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

Hydrolysis under alkaline conditions is known and, for example, in an organic solvent miscible with water (methanol, ethanol, dimethoxyethane or a mixed solvent thereof), alkali (eg sodium hydroxide, hydroxide) is used. It is carried out at a temperature of 0 to 50 ° C. using an aqueous solution of potassium or the like).

Of the compounds represented by the general formula (I), R
(Wherein, R ¹⁰ represents. As defined above) ¹ is an alkyl group or the formula (C1 -4 alkylene) of C1 -4 -COOR ¹⁰ represents a group represented by, B is the formula CONR ³ (wherein , R ³ has the same meaning as described above.) Is a group represented by the general formula (Ib)

[Chemical 10] (In the formula, all symbols have the same meanings as described above.) Are represented by the general formula (IV)

[Chemical 11] (Wherein all symbols have the same meanings as described above) and the compound represented by the general formula (V)

Embedded image A compound represented by R ³ HN—R ² (V) (wherein all symbols have the same meanings as described above) is subjected to an amidation reaction, and if necessary, subjected to a hydrolysis reaction under alkaline conditions. It can be manufactured by attaching to.

The amidation reaction and the hydrolysis reaction under alkaline conditions are carried out by the method described above.

The compounds represented by the general formulas (II) and (IV) can be produced according to the following reaction schemes (A) and (B). In the reaction process formulas (A) and (B), R ^3a represents a C1-4 alkyl group, and R ²⁰
Represents a t-butoxycarbonyl group (boc) or a benzyloxycarbonyl group (cbz), R ³⁰ represents a benzyl group or a t-butyl group, X ¹ and X ² each independently represent a halogen atom, and The symbols have the same meanings as described above.

[0140]

[Chemical 13]

[0141]

Embedded image

In the general formula (I), R ¹ is a group represented by the formula (C1-4 alkylene) -COOR ¹⁰ , a (C1-4 alkylene) -OH group, a formula (C1-4 alkylene) -C
ONR ⁴ R ⁵ group, formula (C1-4 alkylene)
A group represented by —CONR ⁶ — (C1-4 alkylene) —OH, a group represented by formula (C1-4 alkylene) —NR ⁴ R ⁵ , a (C1-4 alkylene) -cyano group, or (C1 ~ 4 alkylene) -tetrazolyl group (wherein the symbols have the same meanings as described above), the general formula (Ic).

[0143]

[Chemical 15]

(Wherein R ^1c is a group represented by the formula (C1-4 alkylene) -COOR ¹⁰ , a (C1-4 alkylene) -OH group, a formula (C1-4 alkylene) -CONR
⁴ R ⁵ is a group represented by formula (C1-4 alkylene) -CO
NR ^6- (C 1-4 alkylene) -OH group, group (C 1-4 alkylene) -NR ⁴ R ⁵ group, (C 1-4 alkylene) -cyano group, or (C
1 to 4 alkylene) -tetrazolyl group, and other symbols have the same meanings as described above. ) Is a compound represented by the general formula (Id):

Embedded image (Wherein all symbols have the same meanings as described above) and the general formula

Embedded image X ³ -R ^1ca (wherein, X ³ represents a halogen atom, R ^1ca the formula (C
Groups represented by 1-4 alkylene) -COOR ^10a, wherein (groups represented by C1 -4 alkylene) -OR ^30a, a group represented by the formula (alkylene C1~4) -CONR ⁴ R ^5a, formula ( alkylene of C1~4) -CONR ⁶ - (C1
To alkylene) -OR ^30a , a group represented by the formula (C1
~ 4 alkylene) -NR ⁴ R ^5a group, (C1
To 4 alkylene) - cyano group or a group represented by the formula (alkylene C1 -4), - in the group represented by tetrazolyl -R ^30a (wherein, R ^5a is an alkyl group of C1 -4, cbz group or b
oc group, R ^30a is a tetrahydropyranyl group, c
represents a bz group or a boc group. ) Is represented. It can be produced by reacting a compound represented by the formula (1) and subjecting it to a hydrolysis reaction under alkaline conditions or removing a protecting group, if necessary.

The O-alkylation reaction is known, and, for example, in an organic solvent miscible with water (acetone, THF, methylene chloride, etc.) in the presence of a base (potassium carbonate, etc.), 0-50.
It is carried out at a temperature of ° C. Hydrolysis under alkaline conditions
The procedure is similar to that described above. Removal of the protecting group
It is carried out by a known method. For example, the removal of the cbz group is performed in a hydrogen atmosphere in an organic solvent (methanol, ethanol, THF, etc.) using a catalyst (palladium-carbon, palladium, nickel, etc.) at a temperature of 0 to 50 ° C. The tetrahydropyranyl group and the boc group can be removed by using an organic acid (acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, etc.) or an organic solvent (methanol, ethanol, THF, dioxane, etc.) or a water-miscible organic solvent. 0-using inorganic acid (hydrochloric acid, hydrobromic acid, etc.)
It is carried out at a temperature of 90 ° C.

In the compound of the general formula (Ic), wherein R ^1c is a (C1-4 alkylene) -tetrazolyl group, in the general formula (Ic), R ^1c is a (C1-4 alkylene) -cyano group. It can also be produced by reacting a compound with sodium azide in an organic solvent (dihydrofuran (DHF) or the like) in the presence of ammonium chloride.

In the general formula (I), R ¹ is a hydrogen atom.

Embedded image (In the formula, all symbols have the same meanings as described above.) Are represented by the general formula (XIII).

[Chemical 19] (In the formula, R ⁴⁰ represents a C1-4 alkyl group or a benzyl group, and other symbols have the same meanings as described above.)
It can be produced by subjecting a compound represented by to a reduction reaction or a dealkylation reaction.

The reduction reaction is known, and, for example, in a hydrogen atmosphere, an organic solvent (methanol, ethanol, THF, etc.) is used.
In the presence of a reducing catalyst (palladium-carbon, palladium, nickel, etc.) at a temperature of 0 to 50 ° C. The dealkylation reaction is known, and for example, using BBr ₃ in an inert organic solvent (methylene chloride, chloroform, etc.),
It is carried out at a temperature of 0 to 50 ° C.

The compound represented by the general formula (XIII) can be produced according to the following reaction process formula (C).

[0150]

Embedded image

Further, R ¹ is a group represented by the formula (C 1-3 alkylene) -CH ₂ OH, a group represented by the formula (C 1-3 alkylene) -CH ₂ NH ₂ , a group represented by the formula (C 1-4). Alkylene) -CONR ⁴ R ⁵ and a group of the formula (C1
To 4 alkylene) -CONR ⁶ - (the compound represented by the group represented by the C1~4 alkylene) -OH from the general formula (Ie) (Ih), the following reaction process formula (D)
Can be manufactured according to.

[0152]

[Chemical 21]

In each reaction in the present specification, the reaction product is 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,
Alternatively, it can be purified by a method such as column chromatography, washing, recrystallization and the like. Purification may be carried out for each reaction or after completion of some reactions.

[0154]

[Starting materials and reagents] The starting materials and reagents used in the present invention are known per se or can be produced by known methods.

[0155]

[Pharmacological activity] The compound represented by the general formula (I) is PGE
It is useful as a PGE ₂ antagonist or PGE ₂ agonist because it binds to ₂ receptors and antagonizes or acts on its action. For example, in a laboratory experiment, the pharmacological activity of the compound of the present invention was confirmed by the PGE ₂ binding inhibitory effect of the cell line expressing the mouse receptor.

Prostanoid receptor subtype expression
Receptor binding experiment using cells Method of Sugimoto et al. [J. Biol. Chem., 267 ,
6463-6466 (1992)], CHO cells expressing a prostanoid receptor subtype (mouse EP _3α ) were prepared and used as a membrane preparation. Prepared membrane fraction (0.5 m
g / ml), a reaction solution containing ³ H-PGE ₂ (200 ml)
Were incubated for 1 hour at room temperature. The reaction was stopped with ice-cold buffer (3 ml) and suction filtered under reduced pressure to bind.
³ H-PGE ₂ was trapped in a glass filter (GF / B), and the bound radioactivity was measured with a liquid scintillator.
Kd and Bmax values were obtained from Scatchard plots [An
n. NYAcad. Sci., 51 , 660 (1949)]. Non-specific binding was determined as binding in the presence of excess (2.5 nM) unlabeled PGE ₂ . ³ by the compound represented by the general formula (I)
To measure the H-PGE ₂ binding inhibitory effect, ³ H-PGE ₂ was measured 2.
5 nM, 1 mM of the compound of the general formula (I) was added thereto. The following buffer was used for all reactions. Buffer: 10 mM potassium phosphate (pH 6.0),
1 mM EDTA, 10 mM MgCl ₂ , 0.1 MN
aCl

The dissociation constant Ki of each compound was determined by the following formula. Ki = IC ₅₀ / (1 + ([C] / Kd)) The results are shown in Table 50.

[0158]

[Table 99]

[0159]

[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.

[0160]

[Application to Pharmaceuticals] The compound represented by the general formula (I), its non-toxic salt, its non-toxic acid addition salt and their hydrates bind to the PGE ₂ receptor and antagonize its action. Since it exhibits an action that acts on or acts, it is useful as a PGE ₂ antagonist or PGE ₂ agonist. Antagonism of PGE ₂ leads to the effects of uterine contraction suppression, analgesia, gastrointestinal motility suppression, and insomnia, as described above. Therefore, the PGE ₂ antagonist is useful as a miscarriage preventive agent, an analgesic agent, an antidiarrheal agent, and a hypnotic agent. Further, the action on PGE ₂ leads to uterine contraction, gastrointestinal hyperactivity, gastric acid secretion inhibitory action, blood pressure lowering action, and platelet aggregation inhibitory action, as described above. Therefore, the PGE ₂ agonist is useful as an abortion agent, a laxative, an antiulcer agent, an antigastritis agent, a blood pressure lowering agent, and an antithrombotic agent. In order to use the compound represented by the general formula (I), a non-toxic salt thereof, a non-toxic acid addition salt thereof or a hydrate thereof for the above-mentioned purpose, usually, systemically or locally, orally or It is administered orally.

The dose depends on age, body weight, symptoms, therapeutic effect,
Depending on the administration method, treatment time, etc., it is usually orally administered once per adult in the range of 1 μg to 100 mg once to several times a day, or 0.1 μg per adult per administration. To 10 mg once to several times a day by parenteral administration (preferably intravenous administration), or 1 hour to 24 hours a day by continuous intravenous administration. 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 necessary 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. In such solid compositions, the one or more active substances comprises at least one inert diluent such as lactose, mannitol, mannitol,
It is admixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate. According to a conventional method, the composition contains an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a solubilizing agent such as glutamic acid or aspartic acid. May be included. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylcellulose phthalate, or may be coated with two or more layers. . Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such a liquid composition, one or more active substances are contained in a generally used inert diluent (eg, purified water, ethanol).
The composition may contain, in addition to an inert diluent, a wetting agent, an auxiliary agent such as a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative. Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se. This composition contains, in addition to an inert diluent, a stabilizer such as sodium bisulfite and a stabilizer that imparts isotonicity, an isotonic agent such as sodium chloride, sodium citrate or citric acid. May be. The manufacturing method of the spray agent is, for example, U.S. Patent Nos. 2,868,691 and 3,095,3.
No. 55 is described in detail.

The injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Such a composition may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers and solubilizing agents (eg glutamic acid, aspartic acid). These are sterilized by filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterilized or sterile distilled water for injection or other solvent before use. Other compositions for parenteral administration include external liquid preparations, ointments, liniments, suppositories for rectal administration and vaginal administration which include one or more active substances and are prescribed by a conventional method. Includes pessaries and the like.

[0165]

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. In addition, the solvent in the parentheses shown at the place of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. Unless otherwise noted, NMR is based on heavy dimethyl sulfoxide (D
It is measured by MSO-d ₆₎ solution.

Reference Example 1 [5- (2-t-Butoxycarbonylethyl) naphthyl-1-oxy] acetic acid methyl ester

[Chemical formula 22]

5- (2-t-Butoxycarbonylethyl) naphth-1-ol (700 mg), methyl bromoacetate (0.29 ml), potassium carbonate (442 mg)
And a mixture of acetone (8 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (819 mg) having the following physical data. TLC: Rf 0.34 (ethyl acetate: n-hexane = 1: 1
3); Melting point: 78-79 ° C.

Reference Example 2 [5- (2-Carboxyethyl) naphthyl-1-oxy] acetic acid methyl ester

[Chemical formula 23]

Compound synthesized in Reference Example 1 (605 mg)
Trifluoroacetic acid (1 ml) was added to a dichloromethane (5 ml) solution of the above at room temperature and stirred for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the title compound (50
6 mg) was obtained. Melting point: 183-185 [deg.] C.

Example 1 [5- (2-Diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid methyl ester

[Chemical formula 24]

Compound synthesized in Reference Example 2 (327 m
g), benzhydrylamine (250 mg) and 1-
4-Dimethylaminopyridine (14 mg) was added at room temperature to a solution of ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) (261 mg) in dichloromethane (20 ml), and the mixture was stirred at the same temperature for 3 days.
Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated under reduced pressure to give the title compound having the following physical data.

TLC: Rf 0.34 (ethyl acetate: benzene = 1: 4); NMR (CDCl ₃ ): δ 8.31 (1H, m), 7.77 (1H, d), 7.45-6.
98 (13H, m), 6.71 (1H, d), 6.21 (1H, d), 5.87 (1H, d), 4.82
(2H, s), 3.82 (3H, s), 3.43 (2H, t), 2.67 (2H, t).

Example 1 (a) 1-methoxy-5- (2-diphenylmethylaminocarbonylethyl) naphthalene

[Chemical 25]

By the same operation as in Example 1, the title compound having the following physical data was obtained. TLC: Rf 0.35 (n-hexane: ethyl acetate = 2:
1); NMR (CDCl ₃ ): δ 8.20 (1H, m), 7.61 (1H, d), 7.47-7.
18 (9H, m), 7.11-6.97 (4H, m), 6.82 (1H, d), 6.21 (1H, d),
5.88 (1H, d), 4.00 (3H, s), 3.43 (2H, d), 2.67 (2H, d).

Example 2 [5- (2-Diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid

[Chemical formula 26]

1N was added to a mixed solution of the compound synthesized in Example 1 in dimethothietane-methanol (2: 1, 10 ml).
Aqueous sodium hydroxide solution (2 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. Hydrochloric acid and water were added to the reaction solution, and the resulting precipitate was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to give the title compound (4
68 mg) was obtained.

TLC: Rf 0.08 (methanol: methylene chloride = 1: 9); NMR: δ 8.78 (1H, d), 8.13 (1H, m), 7.67 (1H, d), 7.
50-7.10 (13H, m), 6.88 (1H, d), 6.12 (1H, d), 4.87 (2H,
s), 3.28 (2H, t), 2.62 (2H, t).

Examples 2 (a) to 2 (o) By the same operation as in Reference Examples 1 and 2 and Examples 1 and 2,
Each compound having the following physical property values was obtained.

Example 2 (a) [5- [2- (3,3-diphenylcarbazoyl) ethyl] naphthyl-1-oxy] acetic acid

[Chemical 27]

TLC: Rf 0.08 (methanol: methylene chloride = 1: 9); NMR: δ 10.32 (1H, s), 8.04 (1H, dd), 7.56 (1H, d),
7.40-6.6 (14H, m), 4.73 (2H, s), 3.32 (2H, t), 2.48 (2H,
t).

Example 2 (b) [5- (diphenylmethylaminocarbonylmethoxy)]
Naphthyl-1-oxy] acetic acid

[Chemical 28]

TLC: Rf 0.51 (methanol: methylene chloride = 1: 4); NMR: δ 9.09 (1H, d), 7.82 (2H, d), 7.5-7.2 (12H,
m), 6.92 (1H, d), 6.91 (1H, d), 6.21 (1H, d), 4.85 (2H,
s), 4.83 (2H, s), 3.35 (1H, br).

Example 2 (c) [5-[(3,3-diphenylcarbazoyl) methoxy] naphthyl-1-oxy] acetic acid

[Chemical 29]

TLC: Rf 0.46 (methanol: methylene chloride = 1: 4); NMR: δ 10.96 (1H, s), 7.98 (1H, d), 7.86 (1H, d),
7.44 (1H, t), 7.42 (1H, t), 7.28 (4H, t), 7.12 (4H, d), 7.1
-6.9 (4H, m), 4.90 (2H, s), 4.87 (2H, s), 3.34 (1H, br).

Example 2 (d) [5- (diphenylmethylaminocarbonylmethyl) naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.35 (methanol: chloroform = 3: 7); NMR: δ 13.00 (1H, brs), 9.17 (1H, d), 8.17 (1H, d)
d), 7.70 (1H, d), 7.50-7.17 (13H, m), 6.87 (1H, d), 6.12
(1H, d), 4.86 (2H, s), 4.02 (2H, s).

Example 2 (e) [5- (diphenylmethylaminocarbonyl) naphthyl-1-oxy] acetic acid

[Chemical 31]

TLC: Rf 0.19 (methanol: methylene chloride = 1: 5); NMR (CDCl ₃ + CD ₃ OD): δ 8.40 (1H, d), 8.29 (1H, s),
7.87 (1H, d), 7.53 (1H, d), 7.48-7.20 (11H, m), 6.82 (1H,
d), 6.50 (1H, s), 4.80 (2H, s).

Example 2 (f) [6- (diphenylmethylaminocarbonylmethyl) naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.30 (methanol: methylene chloride = 1: 4); NMR: δ 9.10 (1H, d), 8.13 (1H, d), 7.72 (1H, s), 7.
52-7.17 (13H, m), 6.82 (1H, dd), 6.13 (1H, d), 4.86 (2H,
s), 3.73 (2H, s).

Example 2 (g) [6- (phenylmethylaminocarbonylmethyl) naphthyl-1-oxy] acetic acid

[Chemical 33]

TLC: Rf 0.23 (methanol: methylene chloride = 1: 4); NMR: δ 8.61 (1H, t), 8.15 (1H, d), 7.73 (1H, s), 7.
50-7.13 (8H, m), 6.84 (1H, d), 4.87 (2H, s), 4.30 (2H, d),
3.67 (2H, s).

Example 2 (h) [5- (2-phenylmethylaminocarbonylethyl)]
Naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.28 (methanol: chloroform = 3: 7); NMR (DMSO-d ₆ + CDCl ₃ ): δ 8.27-8.12 (2H, m), 7.69
(1H, d), 7.48-7.10 (8H, m), 6.79 (1H, d), 4.79 (2H, s),
4.30 (2H, d), 3.35 (2H, t), 2.60 (2H, t).

Example 2 (i) [5- (diphenylmethylaminocarbonyl) naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.15 (methanol: methylene chloride = 1: 5); NMR (CDCl ₃ + CD ₃ OD): δ 8.49 (1H, d), 7.78 (1H, d),
7.65 (1H, d), 7.53-7.20 (12H, m), 6.79 (1H, d), 6.54 (1H,
s), 4.79 (2H, s).

Example 2 (j) [6- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.30 (methanol: chloroform = 3: 7); NMR: δ 8.77 (1H, d), 8.13 (1H, d), 7.66 (1H, s), 7.
43-7.06 (13H, m), 6.83 (1H, m), 6.09 (1H, d), 4.90 (2H,
s), 3.03 (2H, t), 2.64 (2H, t).

Example 2 (k) [5- [2-((1R) -1-phenylethyl) aminocarbonylethyl] naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.21 (chloroform: methanol = 20: 1); NMR: δ 13.18-12.92 (1H, br), 8.30 (1H, d), 8.18 (1
H, d), 7.63 (1H, d), 7.40-7.18 (8H, m), 6.89 (1H, d), 5.0
0-4.89 (1H, m), 4.88 (2H, s), 3.31-3.22 (2H, m), 2.52-2.
49 (2H, m), 1.31 (3H, d).

Example 2 (l) [5- [2-((1S) -1-phenylethyl) aminocarbonylethyl] naphthyl-1-oxy] acetic acid

[Chemical 38]

TLC: Rf 0.21 (chloroform: methanol = 20: 1); NMR: δ 13.18-12.92 (1H, br), 8.30 (1H, d), 8.18 (1
H, d), 7.63 (1H, d), 7.40-7.18 (8H, m), 6.89 (1H, d), 5.0
0-4.89 (1H, m), 4.88 (2H, s), 3.31-3.22 (2H, m), 2.52-2.
49 (2H, m), 1.31 (3H, d).

Example 2 (m) [5- [2- [1-phenyl-1- (3-pyridyl) methyl] aminocarbonylethyl] naphthyl-1-oxy] acetic acid

[Chemical Formula 39]

TLC: Rf 0.22 (chloroform: methanol = 20: 1); NMR: δ 8.82 (1H, d), 8.17 (1H, d), 7.61 (1H, d), 7.
40-7.18 (13H, m), 6.75 (1H, d), 6.14 (1H, d), 4.34 (2H,
s), 2.59 (2H, t), 2.50-2.49 (2H, m).

Example 2 (n) [5- [2- (N-diphenylmethyl-N-ethylaminocarbonyl) ethyl] naphthyl-1-oxy] acetic acid

[Chemical 40]

TLC: Rf 0.28 (chloroform: methanol = 20: 1); NMR: δ 8.12-7.99 (2H, m), 7.39-7.06 (8H, m), 6.99
-6.95 (4H, m), 6.85-6.59 (2H, m), 4.45 (2H, s), 3.94-3.3
8 (4H, m), 2.81-2.59 (2H, m), 0.46-0.18 (3H, m).

Example 2 (o) [5- [2- (diphenylmethylaminocarbonyl) vinyl] naphthyl-1-oxy] acetic acid

Embedded image

TLC: Rf 0.50 (chloroform: methanol: acetic acid = 93: 5: 2); NMR: δ 9.15 (1H, d), 8.32 (1H, d), 8.23 (1H, d), 7.
81 (1H, d), 7.76 (1H, d), 7.57 (1H, dd), 7.50 (1H, dd), 7.4
0-7.20 (10H, m), 6.96 (1H, d), 6.92 (1H, d), 6.32 (1H, d),
4.89 (2H, s).

Example 3 2- [5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] ethanol

Embedded image

Compound synthesized in Example 1 (750 mg)
Of sodium borohydride (125 mg) was added to the methanol-THF (10 ml + 6 ml) solution of
It was stirred for 2 hours. After the reaction was completed, 1N hydrochloric acid was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (600 mg) having the following physical data.

TLC: Rf 0.40 (ethanol: methylene chloride = 3: 7); NMR (CDCl ₃ ): δ 8.21 (1H, m), 7.65 (1H, d, J = 8Hz),
7.45-7.17 (9H, m), 7.13-6.98 (4H, m), 6.85 (1H, d, J = 8H
z), 6.22 (1H, d, J = 8Hz), 5.86 (1H, d, J = 8Hz), 4.28 (2H, t,
J = 4Hz), 4.12 (2H, m), 3.45 (2H, t, J = 7Hz), 2.68 (2H, t, J =
7Hz), 2.14 (1H, t, J = 7Hz).

Example 4 [5- (2-Diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid amide

[Chemical 43]

Concentrated aqueous ammonia (0.2 ml) was added to the THF solution (1 ml) of the compound (75 mg) synthesized in Example 1, and the mixture was stirred at room temperature for 10 hours. The reaction solution was diluted with methylene chloride, washed with 1N hydrochloric acid and saturated saline, dried,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound having the following physical data.

TLC: Rf 0.46 (chloroform: methanol = 9: 1); NMR: δ 8.79 (1H, d, J = 9Hz), 8.28 (1H, m), 7.69 (1H,
d, J = 9Hz), 7.64-7.14 (15H, m), 6.90 (1H, d, J = 7Hz), 6.13
(1H, d, J = 9Hz), 4.62 (2H, s), 3.32 (2H, m), 2.63 (2H, t, J =
8Hz).

Example 4 (a) N, N-Dimethyl- [5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid amide

[Chemical 44]

By the same operation as in Example 4, the title compound having the following physical data was obtained. TLC: Rf 0.58 (chloroform: methanol = 9:
1); NMR (CDCl ₃ ): δ 8.22 (1H, m), 7.64 (1H, d, J = 8Hz),
7.43-7.16 (9H, m), 7.12-7.00 (4H, m), 6.83 (1H, d, J = 8H
z), 6.22 (1H, d, J = 8Hz), 6.08 (1H, d, J = 8Hz), 4.83 (2H,
s), 3.42 (2H, t, J = 8Hz), 3.12 (3H, s), 2.97 (3H, s), 2.66
(2H, t, J = 8Hz).

Example 4 (b) N- (2-hydroxyethyl)-[5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid amide

Embedded image

By the same procedure as in Example 4, the title compound having the following physical data was obtained. TLC: Rf 0.44 (chloroform: methanol = 9:
1); NMR (CDCl ₃ ): δ 8.14 (1H, m), 7.72 (1H, d, J = 9Hz),
7.50-7.34 (3H, m), 7.34-7.18 (6H, m), 7.14-6.98 (5H, m),
6.82 (1H, d, J = 7Hz), 6.22 (1H, d, J = 8Hz), 5.89 (1H, d, J = 8
Hz), 4.71 (2H, s), 3.77 (2H, m), 3.56 (2H, t, J = 5Hz), 3.4
6 (2H, t, J = 8Hz), 2.69 (2H, t, J = 8Hz), 2.24 (1H, t, J = 5H
z).

Example 5 2- [5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] ethylamine

Embedded image

To a solution of the compound (51 mg) synthesized in Example 3 in pyridine (1 ml) was added tosyl chloride (30 m).
g) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and concentrated under reduced pressure. Sodium azide (16 mg) was added to a dimethylformamide (DMF) solution of the residue (65 mg), and the mixture was heated under reflux for 4 hours. After cooling, the reaction solution was diluted with water and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated under reduced pressure. Palladium-carbon (10 mg; 10%) was added to a solution of the residue (48 mg) in methanol (2 ml), and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (31
mg).

TLC: Rf 0.28 (chloroform: methanol = 7: 3); NMR (CDCl ₃ ): δ 8.20 (1H, m), 7.62 (1H, d, J = 8Hz),
7.43-6.97 (13H, m), 6.81 (1H, d, J = 8Hz), 6.21 (1H, d, J = 8H
z), 6.01 (1H, d, J = 8Hz), 4.14 (2H, t, J = 5Hz), 3.45 (2H, t,
J = 7Hz), 3.19 (2H, t, J = 5Hz), 2.67 (2H, t, J = 7Hz), 1.50 (2
H, s).

Reference Example 3 1-Benzyloxy-5- [2- (diphenylmethylcarbonylamino) ethyl] naphthalene

[Chemical 47]

Dimethylaminopyridine (0.01 g) and 1-benzyloxy-5- (2-aminoethyl) naphthalene (0.196 g) were added to a solution of diphenylacetic acid (0.171 g) in methylene chloride (10 ml) at room temperature. After 10 minutes, EDC.HCl (0.154 g) was added to this solution and stirred at room temperature overnight. After the reaction was completed, water and methylene chloride were added. The organic layer was saturated aqueous ammonium chloride solution, water,
The extract was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.172 g) having the following physical data. TLC: Rf 0.42 (ethyl acetate: n-hexane = 1: 1
2).

Example 6 5- [2- (diphenylmethylcarbonylamino) ethyl] naphth-1-ol

Embedded image

In a hydrogen atmosphere at room temperature, the compound (0.168 g) synthesized in Reference Example 3 and palladium-carbon (0.1 g; 10)
%) And methanol (20 ml) was vigorously stirred for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (0.13 g) having the following physical data. TLC: Rf 0.26 (ethyl acetate: n-hexane = 1: 1
2).

Example 7 [5- [2- (Diphenylmethylcarbonylamino) ethyl] naphthyl-1-oxy] acetic acid methyl ester

[Chemical 49]

A solution of the compound (0.128 g) synthesized in Example 6 in acetone (15 ml) was added with potassium carbonate (0.056 g).
And methyl bromoacetate (0.062g) were added at room temperature. The reaction solution was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from a mixed solvent of ethyl acetate-hexane to give the title compound (0.073 g) having the following physical data. TLC: Rf 0.48 (ethyl acetate: benzene = 1: 1
5).

Example 8 [5- [2- (Diphenylmethylcarbonylamino) ethyl] naphthyl-1-oxy] acetic acid

Embedded image

The title compound (0.05 g) having the following physical data was obtained in the same manner as in Example 2 using the compound (0.067 g) synthesized in Example 7. TLC: Rf 0.22 (methanol: methylene chloride = 1: 1
5); NMR (CDCl ₃ + CD ₃ OD): δ 8.26 (1H, d), 7.65 (1H, d),
7.40-7.00 (13H, m), 6.75 (1H, d), 6.27-6.10 (1H, m), 4.8
5 (1H, s), 4.80 (2H, s), 3.80-3.40 (2H, m), 3.22 (2H, t).

Example 9 5- (2-diphenylmethylaminocarbonylethyl)
Naft-1-ol

[Chemical 51]

The compound synthesized in Example 1 (a) (1.767
g) in methylene chloride (50 ml) at 0 ° C. with BBr
₃ (0.96 ml) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.62 g) having the following physical data.

TLC: Rf 0.20 (n-hexane: ethyl acetate = 2: 1); NMR: δ 10.07 (1H, s), 8.79 (1H, d), 8.05 (1H, m),
7.53 (1H, d), 7.40-7.16 (13H, m), 6.88 (1H, d), 6.14 (1H,
d), 3.38 (2H, d), 2.63 (2H, d).

Example 10 1-Cyanomethoxy-5- (2-diphenylmethylaminocarbonylethyl) naphthalene

Embedded image

By using the compound synthesized in Example 9 and following the same procedure as in Example 7, the title compound having the following physical data was obtained. TLC: Rf 0.30 (n-hexane: ethyl acetate = 7:
3); NMR (CDCl ₃ ): δ 8.12 (1H, t-like), 7.77 (1H, d), 7.
46 (1H, d), 7.41-7.38 (2H, m), 7.29-7.24 (6H, m), 7.07-
7.03 (4H, m), 6.93 (1H, d), 6.21 (1H, d), 5.92-5.79 (1H,
m), 4.97 (3H, s), 3.46 (2H, t), 2.68 (2H, t).

Example 11 1-Tetrazolylmethoxy-5- (2-diphenylmethylaminocarbonylethyl) naphthalene

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The compound synthesized in Example 10 (420 m
g) in DHF (2 ml) solution, sodium azide (7
2 mg) and ammonium chloride (59 mg) were added,
The mixture was stirred at 120 ° C for 12 hours. After adding water (2 ml) to the reaction solution, the pH was adjusted to 2 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with ice water and ether, dried under reduced pressure,
The title compound (391 mg) having the following physical data was obtained.

TLC: Rf 0.31 (chloroform: methanol = 20: 1); NMR: δ 8.67 (1H, d), 8.03 (1H, t-like), 7.58 (1H,
d), 7.37 (1H, d), 7.29-6.89 (13H, m), 6.00 (1H, d), 5.56
(3H, s), 3.17 (2H, t), 2.51 (3H, t).

Example 12 1-Methoxy-5- [2- [1-phenyl-1- (3-
Chlorophenyl) methyl] aminocarbonylethyl] naphthalene

[Chemical 54]

Using [1-phenyl-1- (3-chlorophenyl) methyl] amine in place of benzhydrylamine in Example 1, the same operation as in Example 1 was carried out to give the following physical properties. The compound was obtained. TLC: Rf 0.50 (n-hexane: ethyl acetate = 1: 1
1); NMR (CDCl ₃ ): δ 8.20 (1H, m), 7.62 (1H, d), 7.52-6.
80 (13H, m), 6.16 (1H, d), 5.80 (1H, d), 4.02 (3H, s), 3.45
(2H, t), 2.69 (2H, t).

Example 13 5- [2- [1-phenyl-1- (3-chlorophenyl) methyl] aminocarbonylethyl] naphth-1-ol

[Chemical 55]

The title compound having the following physical data was obtained in the same manner as in Example 9 by using the compound synthesized in Example 12. TLC: Rf 0.41 (n-hexane: ethyl acetate = 1: 1
1); NMR: δ 10.05 (1H, s), 8.82 (1H, d), 8.03 (1H, m),
7.52 (1H, d), 7.40-7.15 (12H, m), 6.88 (1H, d), 6.15 (1H,
d), 3.27 (2H, t), 2.63 (2H, t).

Example 14 1-Cyanomethoxy-5- [2- [1-phenyl-1-
(3-Chlorophenyl) methyl] aminocarbonylethyl] naphthalene

[Chemical 56]

The title compound having the following physical data was obtained in the same manner as in Example 7 by using the compound synthesized in Example 13. TLC: Rf 0.30 (ethyl acetate: benzene = 3: 1)
7); NMR (CDCl ₃ ): δ 8.13 (1H, m), 7.76 (1H, d, J = 8Hz),
7.52-6.86 (13H, m), 6.16 (1H, d, J = 8Hz), 5.90 (1H, d, J = 8H
z, NH), 4.97 (2H, s, -OCH ₂ ), 3.44 (2H, t, J = 7Hz), 2.67 (2
H, t, J = 7 Hz).

Example 15 [5- [2- [1-Phenyl-1- (3-chlorophenyl) methyl] aminocarbonylethyl] naphthyl-1-
Oxy] acetic acid methyl ester

[Chemical 57]

The title compound having the following physical data was obtained in the same manner as in Example 7 except that the compound synthesized in Example 13 was used. TLC: Rf 0.33 (ethyl acetate: benzene = 3: 1)
7); NMR (CDCl ₃ ): δ 8.27 (1H, m), 7.67 (1H, d, J = 8Hz),
7.50-6.87 (12H, m), 6.71 (1H, d, J = 8Hz), 6.16 (1H, d, J = 8H
z), 5.83 (1H, d, J = 8Hz, NH), 4.82 (2H, s, -OCH ₂ ), 3.83 (3
_{H, s, -OCH 3),} 3.44 (2H, t, J = 7Hz), 2.67 (2H, t, J = 7Hz).

Example 16 [5- [2- [1-Phenyl-1- (3-chlorophenyl) methyl] aminocarbonylethyl] naphthyl-1-
Oxy] acetic acid

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The title compound having the following physical data was obtained in the same manner as in Example 2 by using the compound synthesized in Example 15. TLC: Rf 0.18 (methanol: chloroform = 1:
4); NMR: δ 13.07 (1H, brs, COOH), 8.82 (1H, d, J = 8Hz, N
H), 8.13 (1H, m), 7.67 (1H, d, J = 8Hz), 7.50-7.11 (12H,
m), 6.87 (1H, d, J = 8Hz), 6.15 (1H, d, J = 8Hz), 4.86 (2H, s,
-OCH ₂ ), 3.30 (2H, t, J = 7Hz), 2.63 (2H, t, J = 7Hz).

[0248]

[Formulation example]

Formulation Example 1 The following components were admixed in a conventional method and punched out to give 100 tablets each containing 5 mg of active ingredient. -[5- (2-Diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid methyl ester (compound of Example 1) -500 mg-Carboxymethylcellulose calcium-200 mg-Magnesium stearate--100 mg-Microcrystals Cellulose: 9.2 g

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/40 A61K 31/40 31/41 31/41 31/44 AEL 31/44 AEL 31/55 31/55 C07C 243/32 C07C 243/32 255/13 255/13 323/40 323/40 323/62 323/62 C07D 205/10 9159-4C C07D 205/10 207/09 207/09 207/335 207 / 335 213/75 213/75 213/82 213/82 223/04 223/04 223/12 223/12 Z 257/04 257/04 B 401/12 257 401/12 257 // C07M 9:00

Claims (10)

[Claims] 1. A compound of the general formula (I) (In the formula, R ¹ is (i) hydrogen atom, (ii) C1-4 alkyl group, (iii) formula (C1-4 alkylene) -COOR ¹⁰ (In the formula, R ¹⁰ is a hydrogen atom or C 1-4) a group represented by represents.) 4 alkyl, (iv) (C1 -4 alkylene) -OH group, ⁴ R ⁵ (wherein (v) formula (alkylene C1 -4) -CONR, R ⁴ and R ⁵ are each independently a group represented by) represents a hydrogen atom or a C1 -4 alkyl group, (vi) expression (alkylene C1~4) -CONR ⁶ -. (C
1-4 alkylene) -OH (in the formula, R ⁶ represents a hydrogen atom or a C 1-4 alkyl group), (vii) formula (C 1-4 alkylene) -NR ⁴ R ⁵ ( In the formula,
R ⁴ and R ⁵ have the same meanings as described above. ), (Viii) (C1-4 alkylene) -cyano group, or (ix) (C1-4 alkylene) -tetrazolyl group, A represents a single bond, C1-6 alkylene group, alkenylene group C2-6, -S- represents a group or -O- (alkylene Cl to 6) group (alkylene of Cl to 6), B is wherein NR ³ CO or CONR ³ (wherein, R ³ is A hydrogen atom or a C1-4 alkyl group), R ² is (i) a C1-6 alkyl group, (ii) a C2-6 alkenyl group, (iii) a phenyl group, A C1-6 alkyl group substituted with 1 to 3 substituents arbitrarily selected from a C4-7 cycloalkyl group, a naphthyl group and a 4-7 membered heterocyclic group containing one nitrogen atom, (iv) Phenyl group, C4-7 cycloalkyl group, naphthyl group and 1-3 C2~6 alkenyl group which is substituted with a substituent one finely nitrogen atoms from 4-7 membered heterocyclic group containing a chosen arbitrarily, (v) formula NR ⁷ R ⁸ (wherein Wherein R ⁷ and R ⁸ independently represent a phenyl group, a C4-7 cycloalkyl group, a naphthyl group or a 4-7 membered heterocyclic group containing one nitrogen atom). Or (vi) Formula (C1-6 alkylene) —NR ⁷ R ⁸ (wherein
R ⁷ and R ⁸ have the same meaning as described above. ) Represents a group represented by. However, the ring in R ² is 1 to 3 rings of C1.
It may be substituted with an alkyl group of -4, a C1-4 alkoxy group, a halogen atom, a nitro group or a trifluoromethyl group. ) A naphthyloxyacetic acid derivative, a non-toxic salt thereof, a non-toxic acid addition salt thereof or a hydrate thereof. 2. The compound according to claim 1, wherein R ¹ is a group represented by the formula (iii) (C1-4 alkylene) -COOR ¹⁰ . 3. R ¹ is (i) hydrogen atom, (ii) C1-4 alkyl group, (iv) (C1-4 alkylene) -OH group, (v) formula (C1-4 alkylene) A group represented by —CONR ⁴ R ⁵ , (vi) formula (C1-4 alkylene) —CONR ⁶ — (C
Groups represented by 1-4 alkylene) -OH, (vii) expression (alkylene C1 -4) -NR ⁴ group represented by R ^5, (viii) (alkylene C1 -4) - cyano group, or, ( ix) The compound according to claim 1, which is a (C1-4 alkylene) -tetrazolyl group. 4. R ² is selected from (i) a C1-6 alkyl group, (ii) a C2-6 alkenyl group, (iii-a) phenyl group, a C4-7 cycloalkyl group and a naphthyl group. Substituted with 1 to 3 substituents selected from C1 to C6 alkyl group substituted with 1 to 3 substituents, (iv-a) phenyl group, C4 to 7 cycloalkyl group and naphthyl group C2-6 alkenyl group, (va) formula NR
^7a R ^8a (in the formula, R ^7a and R ^8a independently represent a phenyl group, a C4-7 cycloalkyl group or a naphthyl group), or a (vi-a) formula (C1-6 Alkylene) -NR ^7a R ^8a (wherein R ^7a and R ^8a are
It has the same meaning as above. The compound of Claim 2 or 3 which is a group shown by these. 5. R ³ has one (iii-b) one 4- to 7-membered heterocyclic group containing one nitrogen atom as an essential substituent, and other substituents include a phenyl group, A C1-6 alkyl having no or one or two substituents selected from a C4-7 cycloalkyl group, a naphthyl group and a 4- to 7-membered heterocyclic group containing one nitrogen atom. Group, (iv-b) having one 4- to 7-membered heterocyclic group containing one nitrogen atom as an essential substituent, and other substituents include a phenyl group and a C4-7 cycloalkyl group. , A naphthyl group and a C2-6 alkenyl group having no or one or two substituents selected from a 4- to 7-membered heterocyclic group containing one nitrogen atom, (v-
b) Formula NR ^7b R ^8b (wherein one of R ^7b and R ^8b represents a 4 to 7 membered heterocyclic group containing one nitrogen atom, the other represents a phenyl group, a C 4-7 cycloalkyl group). An alkyl group, a naphthyl group or a 4- to 7-membered heterocyclic group containing one nitrogen atom)), or (vi-b)
Formula (alkylene C1~6) -NR ^7b R ^8b (wherein, R
^7b and R ^8b have the same meanings as described above. The compound of Claim 2 or 3 which is a group shown by these. 6. The compound is [5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid, [5- [2- (3,3-diphenylcarbazoyl)].
Ethyl] naphthyl-1-oxy] acetic acid, [5- (diphenylmethylaminocarbonylmethoxy) naphthyl-1-
Oxy] acetic acid, [5-[(3,3-diphenylcarbazoyl) methoxy] naphthyl-1-oxy] acetic acid, [5-
(Diphenylmethylaminocarbonylmethyl) naphthyl-1-oxy] acetic acid, [5- (diphenylmethylaminocarbonyl) naphthyl-1-oxy] acetic acid, [6- (diphenylmethylaminocarbonylmethyl) naphthyl-1
-Oxy] acetic acid, [6- (phenylmethylaminocarbonylmethyl) naphthyl-1-oxy] acetic acid, [5- (2
-Phenylmethylaminocarbonylethyl) naphthyl-
1-oxy] acetic acid, [5- (diphenylmethylaminocarbonyl) naphthyl-1-oxy] acetic acid, [6- (2-
Diphenylmethylaminocarbonylethyl) naphthyl-
1-oxy] acetic acid, [5- [2-((1R) -1-phenylethyl) aminocarbonylethyl] naphthyl-1-
Oxy] acetic acid, [5- [2-((1S) -1-phenylethyl) aminocarbonylethyl] naphthyl-1-oxy] acetic acid, [5- [2- (N-diphenylmethyl-N-
Ethylaminocarbonyl) ethyl] naphthyl-1-oxy] acetic acid, [5- [2- (diphenylmethylaminocarbonyl) vinyl] naphthyl-1-oxy] acetic acid, [5-
[2- (diphenylmethylcarbonylamino) ethyl]
Naphthyl-1-oxy] acetic acid or [5- [2- [1-
The compound according to claim 4, which is phenyl-1- (3-chlorophenyl) methyl] aminocarbonylethyl] naphthyl-1-oxy] acetic acid or a methyl ester thereof. 7. The compound according to claim 5, which is [5- [2- [1-phenyl-1- (3-pyridyl) methyl] aminocarbonylethyl] naphthyl-1-oxy] acetic acid or a methyl ester thereof. Compound of. 8. The compound is 1-methoxy-5- (2-diphenylmethylaminocarbonylethyl) naphthalene,
2- [5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] ethanol, [5- (2
-Diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid amide, N, N-dimethyl- [5-
(2-Diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid amide, N- (2-hydroxyethyl)-[5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] acetic acid amide, 2-
[5- (2-diphenylmethylaminocarbonylethyl) naphthyl-1-oxy] ethylamine, 5- [2-
(Diphenylmethylcarbonylamino) ethyl] naphth-1-ol, 5- (2-diphenylmethylaminocarbonylethyl) naphth-1-ol, 1-cyanomethoxy-5- (2-diphenylmethylaminocarbonylethyl) naphthalene, 1 -Tetrazolylmethoxy-5- (2
-Diphenylmethylaminocarbonylethyl) naphthalene, 1-methoxy-5- [2- [1-phenyl-1-
(3-chlorophenyl) methyl] aminocarbonylethyl] naphthalene, 5- [2- [1-phenyl-1- (3
-Chlorophenyl) methyl] aminocarbonylethyl]
Naphtho-1-ol or 1-cyanomethoxy-5
The compound according to claim 3, which is [2- [1-phenyl-1- (3-chlorophenyl) methyl] aminocarbonylethyl] naphthalene. 9. A pharmaceutical composition containing a naphthyloxyacetic acid derivative represented by the general formula (I) according to claim 1, a non-toxic salt thereof, a non-toxic acid addition salt thereof or a hydrate thereof as an active ingredient. . 10. Prevention of miscarriage containing a naphthyloxyacetic acid derivative represented by the general formula (I) according to claim 1, a non-toxic salt thereof, a non-toxic acid addition salt thereof or a hydrate thereof as an active ingredient. Agents, analgesics, antidiarrheals, insomnia, abortions, laxatives, antiulcers, antigastritis agents, antihypertensive agents or antithrombotic agents.