JP2008189549A - Carboxylic acid derivative or its salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound which can be used as a therapeutic agent for diseases in which an EP1 receptor is involved, particularly lower urinary tract diseases such as pollakiuria or urinary urgency and incontinence associated with overactive bladder, cystitis, interstitial cystitis and prostatitis. <P>SOLUTION: It has been found that a carboxylic acid derivative having a bicyclic heterocyclic group comprising condensed benzene rings or its salt has a potent EP1 receptor-antagonistic effect. The carboxylic acid derivative or its salt can be used as a therapeutic agent for diseases in which an EP1 receptor is involved, particularly a lower urinary tract diseases such as pollakiuria or urinary urgency and incontinence associated with overactive bladder, cystitis, interstitial cystitis and prostatitis. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a carboxylic acid derivative useful as a therapeutic agent for drugs, particularly lower urinary tract diseases, pain, cancer and the like.

  Overactive bladder is a pathological condition complaining of urgency regardless of incontinence, and is usually accompanied by frequent urination and nocturia (Non-Patent Document 1). Currently, anticholinergic drugs are mainly used for the treatment, and some treatment results are shown. However, on the other hand, side effects such as dry mouth, constipation, and blurred vision are also known, and there is a risk of urinary retention, which has been reported to be difficult to use for patients with prostatic hypertrophy and the elderly. There are also known patients who do not show efficacy with anticholinergic treatment. Based on the above, there are great expectations for drugs with a new mechanism for overactive bladder.

Prostaglandin E ₂ (PGE ₂ ) is an in-vivo active substance with arachidonic acid as a precursor, and it passes through four subtypes, EP1, EP2, EP3 and EP4, which are G protein-coupled receptors. It is known to be involved in functional regulation.
That intravesical instillation of PGE ₂ is causing a strong urinary urgency and bladder volume reduction in humans (Non-Patent Document 2), and intravesical instillation of PGE ₂ is known to reduce the bladder capacity of a rat (Non-Patent Reference 3) suggests that PGE ₂ may affect lower urinary tract function. In recent years, it has been reported that administration of EP1 receptor antagonists to spinal cord injury model rats is useful for improving urinary function (Non-patent Document 4), and EP1 receptor antagonists are frequently associated with overactive bladder. It is thought to be useful as a therapeutic agent for lower urinary tract diseases such as urinary urgency, urinary incontinence, cystitis, interstitial cystitis, prostatitis.

In addition, since EP1 receptor antagonists have different mechanisms of action, they can be effective for patients who are not effective with anticholinergic treatment, and can be expected to avoid side effects peculiar to anticholinergic drugs. The effect can be expected even for patients who do not show efficacy with choline treatment. In addition, this drug can be expected to improve the subjective symptoms by acting on sensory nerves. Furthermore, it has been reported to show a pathological condition improving effect without reducing the urination efficiency of rats with spinal cord injury (Non-Patent Document 5),
It can be expected to be safely administered to patients with benign prostatic hyperplasia and the elderly.

In addition, it is widely known that PGE ₂ is locally produced with inflammation and tissue damage and enhances the inflammatory response and is also involved in pain and fever. In recent years, EP1 receptor antagonists have shown efficacy in various pain model animals such as inflammatory pain (Non-patent document 6), postoperative pain (Non-patent document 7), and neuropathic pain (Non-patent document 8). The clinical effect of EP1 receptor antagonist administration for acetic acid-induced visceral pain has also been reported (Non-patent Document 9).

  Furthermore, EP1 receptor antagonists are known to have an inhibitory effect on colonic mucosal abnormal crypts and intestinal polyp formation (Patent Document 1). EP1 receptor antagonists are colon cancer, bladder cancer, prostate cancer, etc. It is thought that it is useful as a therapeutic agent.

（式中BはC5〜１５の炭素環、または１個または２個の酸素、硫黄または窒素原子を有する５〜７員複素環を示す。他の記号は当該公報参照。）
しかしながら、式（A）の化合物のB環部分としては本発明化合物の特徴であるベンゼン環が縮合した二環式へテロ環の開示はない。 As EP1 receptor antagonists, compounds shown in the following Patent Documents 2 to 4 have been reported.
Patent Document 2 discloses a compound represented by the formula (A).

(In the formula, B represents a C5-15 carbocyclic ring, or a 5- to 7-membered heterocyclic ring having one or two oxygen, sulfur or nitrogen atoms. For other symbols, refer to this publication.)
However, there is no disclosure of a bicyclic heterocycle having a benzene ring condensed, which is a feature of the compound of the present invention, as the B ring portion of the compound of the formula (A).

（式中、R³及びR⁴は(1)メチルおよびメチル、(2)メチルおよびクロロ、(3)クロロおよびメチル、(4)トリフルオロメチルおよび水素の組み合わせ、またはR³およびR⁴が結合している炭素原子と一体となって(5)シクロペンテンまたは(6)ベンゼン環を示す。他の記号は当該公報参照。）
しかしながら、式（B）の化合物においてR³およびR⁴がベンゼン環と一体となって形成する二環式環としては、本発明化合物の特徴である二環式ヘテロ環の開示はない。 Patent Document 3 discloses a compound represented by the formula (B).

(Where R ³ and R ⁴ are (1) methyl and methyl, (2) methyl and chloro, (3) chloro and methyl, (4) a combination of trifluoromethyl and hydrogen, or R ³ and R ⁴ are bonded. (5) Cyclopentene or (6) benzene ring together with the carbon atom being attached.
However, there is no disclosure of a bicyclic heterocycle that is a feature of the compound of the present invention as the bicyclic ring formed by R ³ and R ⁴ together with the benzene ring in the compound of the formula (B).

（式中の記号は当該公報参照。）
式（C）の化合物のAr²で実際に合成されているのは置換フェニルのみであり本発明化合物の特徴であるベンゼン環が縮合した二環式ヘテロ環の実施例はない。 Patent Document 4 discloses a compound represented by the formula (C) including a wide range of compounds.

(See the official gazette for symbols in the formula.)
It is only substituted phenyl that is actually synthesized with Ar ² of the compound of formula (C), and there is no example of a bicyclic heterocycle having a condensed benzene ring, which is a feature of the compound of the present invention.

“Neurourology and Urodynamics” (UK), 2002, Vol. 21, pp.167-78 "Urological Research" (USA), 1990, Vol. 18, No. 5, p.349-52 "The Journal of Urology" (USA), June 1995, Volume 153, No. 6, p. 2034-8 “The Journal of Japanese Urological Association”, February 2001, Vol. 92, No. 2, p. 304 "Proceedings of the 89th Annual Meeting of the Japanese Urological Association", Kobe, 2001, MP-305 "Anesthesiology", (USA), November 2002, Vol. 97, No. 5, p.1254-62 "Anesthesia and Analgesia" (USA), December 2002, Volume 95, No. 6, p.1708-12 "Anesthesia and Analgesia" (USA), October 2001, volume 93, number 4, pages 1012-7 “Gastroenterology”, January 2003, Vol. 124, No. 1, p.18-25 International Publication No. 00/69465 Pamphlet International Publication No. 98/27053 Pamphlet International Publication No. 02/72564 Pamphlet International Publication No. 00/20371 Pamphlet

  As described above, therapeutic agents for lower urinary tract diseases such as urinary frequency, urinary urgency, urinary incontinence, cystitis, interstitial cystitis, and prostatitis associated with existing overactive bladder are effective and safe. There is an urgent need to provide a therapeutic agent for lower urinary tract disease that is not satisfactory and has excellent efficacy and safety.

  As described above, the EP1 receptor antagonist can be expected to be a highly safe therapeutic agent for lower urinary tract disease with few side effects such as dry mouth and urinary retention. Accordingly, the present inventors have intensively studied compounds having EP1 receptor antagonistic activity for the purpose of providing novel compounds useful for the treatment of lower urinary tract diseases and the like. As a result, it was found that a novel carboxylic acid derivative represented by the following general formula (I) has a strong EP1 receptor antagonistic action, and the present invention was completed.

[式中の記号は以下の意味を示す。
Ａ環：置換されていてもよい５乃至８員へテロ環。
Ｂ環：シクロアルキル、アリールまたはヘテロ環。
R¹:置換されていてもよい低級アルキル。
R²:C_1-12アルキル、シクロアルキル、アリール、ヘテロ環基、低級アルキレン−シクロアルキル、低級アルキレン-アリールまたは低級アルキレン-ヘテロ環基。
ただし、R²におけるC_1-12アルキル、シクロアルキル、アリール及びヘテロ環基は置換されていてもよい。
R³:-OR⁰または-NR⁵R^5a。
R⁰、R⁰⁰：それぞれ独立して、-Hまたは低級アルキル。
R⁵、R^5a：それぞれ独立して、-R⁰、低級アルキレン-NR⁰R⁰⁰、低級アルキレン-CO₂R⁰、シクロアルキル、アリール、ヘテロ環基、低級アルキレン-シクロアルキル、低級アルキレン-アリール、低級アルキレン-ヘテロ環基。
ただし、R⁵、R^5aにおけるシクロアルキル、アリール及びヘテロ環基は置換されていてもよい。
R⁴：それぞれ独立して、ハロゲン、低級アルキル、ハロゲノ低級アルキル、シアノ、ニトロ、-OR⁰、-O-ハロゲノ低級アルキル、-C(O)R⁰、-NR⁰C(O)R⁰⁰。
m:0、１または２。
ただし、mが2である場合、2つのR⁴は同一または互いに異なっていてもよい。
Ｊ：低級アルキレン、低級アルケニレン、-O-低級アルキレン-*、低級アルキレン-O-*、-O-低級アルケニレン-*、低級アルケニレン-O-*、-C(O)NR⁰-*または-NR⁰C(O)-*。
X:単結合、低級アルキレン、低級アルケニレン、*-O-低級アルキレン、*-O-低級アルケニレン、*-NR⁰-低級アルキレン、*-S(O)_n-低級アルキレンまたは*-S(O)_n-低級アルケニレン。
ただし、JとXにおける*はB環への結合を示す。
n：０、１または２。
L:単結合、-C(O)-または-S(O)₂-。以下同様。]
That is, the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

[The symbols in the formula have the following meanings.
Ring A: 5- to 8-membered hetero ring which may be substituted.
Ring B: cycloalkyl, aryl or heterocycle.
R ¹ : optionally substituted lower alkyl.
R ² : C _1-12 alkyl, cycloalkyl, aryl, heterocyclic group, lower alkylene-cycloalkyl, lower alkylene-aryl or lower alkylene-heterocyclic group.
However, the C _1-12 alkyl, cycloalkyl, aryl and heterocyclic groups in R ² may be substituted.
R ³ : -OR ⁰ or -NR ⁵ R ^5a .
R ⁰ , R ⁰⁰ : each independently -H or lower alkyl.
R ⁵ , R ^5a : each independently -R ⁰ , lower alkylene-NR ⁰ R ⁰⁰ , lower alkylene-CO ₂ R ⁰ , cycloalkyl, aryl, heterocyclic group, lower alkylene-cycloalkyl, lower alkylene-aryl , Lower alkylene-heterocyclic group.
However, the cycloalkyl, aryl and heterocyclic groups in R ⁵ and R ^5a may be substituted.
R ⁴ : each independently halogen, lower alkyl, halogeno lower alkyl, cyano, nitro, —OR ⁰ , —O-halogeno lower alkyl, —C (O) R ⁰ , —NR ⁰ C (O) R ⁰⁰ .
m: 0, 1 or 2.
However, when m is 2, two R ^{4 s} may be the same or different from each other.
J: Lower alkylene, lower alkenylene, -O-lower alkylene- *, lower alkylene-O- *, -O-lower alkenylene- *, lower alkenylene-O- *, -C (O) NR ^0- * or -NR ⁰ C (O)-*.
X: single bond, lower alkylene, lower alkenylene, * -O-lower alkylene, * -O-lower alkenylene, * -NR ⁰ -lower alkylene, * -S (O) _n -lower alkylene or * -S (O) _n -Lower alkenylene.
However, * in J and X indicates a bond to the B ring.
n: 0, 1 or 2.
L: Single bond, —C (O) — or —S (O) ₂ —. The same applies below. ]

The usefulness of the compound (I) of the present invention was confirmed by the following test.
(1) Measurement of receptor antagonistic activity using EP1 receptor-expressing cells HEK293 cells (American Type Culture Collection) stably expressing rat EP1 were tested on the day before the experiment. Dispense into 96-well poly-D-lysine-coated plates (trade name: Biocoat PDL96W Black / Clear, Nippon Becton Dickinson) at 2 ° C ⁴ cells / well, 37 ° C, 5 The cells are cultured overnight in a medium containing 10% fetal bovine serum (FBS) (trade name: DMEM, Invitrogen) under% carbon dioxide (CO ₂ ). Washing medium containing loading buffer (fluorescent labeling reagent (trade name: Fluo3-AM, Dojindo), 4 μM: Hank's balanced salt solution (HBSS), 20 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl ] Plate washer (trade name) with ethanesulfonic acid (HEPES) -sodium hydroxide (NaOH), 2.5 mM probenecid, 0.1% bovine serum albumin (BSA), left at room temperature for 3 hours, and then set with washing solution : ELx405, BIO-TEK Instruments Inc.). A compound previously dissolved and diluted with a washing solution is added and set in an intracellular calcium (Ca) concentration measurement system (trade name: FLIPR, Molecular Devices). After 5 minutes, PGE ₂ is added to a final concentration of 100 nM, and the change in intracellular Ca concentration is measured. The difference between the maximum value and the minimum value of intracellular Ca concentration change was calculated and stored as measurement data. The concentration that inhibits 50% was calculated as the IC ₅₀ value, assuming that 0% was obtained when 100 nM PGE _{2 was} added and the response when buffer was added was 100%.
The results are shown in Table 1 below. Ex represents an example compound number described later.

(2) Receptor binding experiments using EP1 receptor-expressing cells Rat EP1 receptor is expressed after introducing a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) and a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) at the N-terminus Subcloning into a vector (trade name: pCEP4, Invitrogen) was performed. This rat EP1 expression vector was transfected into HEK293EBNA cells (American Type Culture Collection) using a transfection reagent (trade name: Fugene-6, Roche Diagnostics) Then, the cells were cultured for 2 days in a medium containing 10% FBS (trade name: DMEM, Invitrogen) at 37 ° C. and 5% CO ₂ . The cultured cells were collected, treated with a cell lysate (20 mM Tris (hydroxymethyl) aminomethane (Tris) buffer pH 7.5, 5 mM ethylenediaminetetraacetic acid (EDTA)), and ultracentrifuged (23,000 rpm, The membrane preparation was roughly adjusted by 25 minutes × 2 times).
Reaction solution (150 μl, composition: 10 mM 2- (N-morpholino) ethanesulfonic acid (MES) / potassium hydroxide (KOH) pH 6.0, 1 mM EDTA containing the prepared membrane preparation (15 μg) and ³ H-PGE ₂ , 10 mM magnesium chloride (MgCl ₂ ), 0.02% 3-[(3-colamidopropyl) dimethylammonio] propanesulfonic acid (CHAPS)) was incubated for 1 hour at room temperature. The reaction is stopped with ice-cold buffer, and ³ H-PGE ₂ bound by suction filtration under reduced pressure is trapped on a glass filter (trade name: Unifilter-96, GF / B, PerkinElmer) and bound radioactivity Were measured with a microplate scintillation counter (trade name: Topcount, Packard) using a micro scintillation (trade name: Microcinch 20, PerkinElmer).
The dissociation constant (Kd) and maximum binding (Bmax) values were determined from the Scatchard plot ("Annals of the New York Academy of Science"). (USA), 1949, vol. 51, p.660). Non-specific binding was determined as binding in the presence of unlabeled PGE ₂ in excess (2.5 [mu] M). The ³ H-PGE ₂ binding inhibitory action of the compound of the present invention was measured by adding 2.5 nM of ³ H-PGE ₂ and the compound of the present invention.
The inhibition constant Ki (nM) for each compound was determined by the following formula:
Ki = IC ₅₀ / (1 + ([C] / Kd))
In the formula, [C] represents the ³ H-PGE ₂ concentration used in the reaction system.
The results are shown in Table 2 below.

(3) Action of the compound on acetic acid-induced frequent urination rats The anti- frequent urination action of the compound was examined using a disease state model. It is known that intravesical treatment of acetic acid in rats causes damage to the bladder mucosa and activates nociceptive afferent nerves ("The Journal of Neuroscience", (USA) ) December 1992, Vol. 12, No. 12, p.4878-89). Since frequent urination is induced by intravesical treatment with acetic acid, it is possible to evaluate the efficacy of these symptoms.
Wistar male rats (Charles River) having a body weight of 200 to 450 g were used for the experiment. Under anesthesia with pentobarbital (50 mg / kg, ip), a midline incision was made in the abdomen to expose the bladder, and residual urine in the bladder was removed with a syringe equipped with a 27G needle. Thereafter, 0.5-0.7 mL of 1% acetic acid solution was injected into the bladder and closed. The experiment was conducted two days later. Rats were placed in a metabolic cage and acclimated for 1 hour, then the test drug was administered, and urine weight change was continuously measured for 6 hours immediately after that. The effective bladder capacity was calculated by dividing the total urination volume by the total number of urinations. As a result, the effective bladder capacity decreased in the acetic acid intravesical treatment group compared with the sham operation group, and a frequent urination state was exhibited. On the other hand, the compound of the present invention improved the frequent urination state well.
From the results of the above tests (1) to (3), it was confirmed that the compound of the present invention has a strong antagonistic action on EP1 and satisfactorily improves the frequent urination state.

Hereinafter, the present invention will be described in detail.
In the present specification, the term “lower” means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms unless otherwise specified.

“Lower alkyl” means C _1-6 alkyl. Specific examples include methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like. Methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl and tert-butyl are preferred.
“Lower alkenyl” means C _2-6 alkenyl. The double bond may be in any position and may have a plurality of double bonds. Specific examples include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl and the like. Preferred are ethenyl, 1-propenyl and 2-propenyl.
“Lower alkylene” means a divalent group formed by removing one hydrogen from any position of C _1-6 alkyl. Specific examples include methylene, ethylene, methylmethylene, dimethylmethylene, propylene and the like. Ethylene and propylene are preferable.
The “lower alkenylene” means a divalent group formed by removing one hydrogen at any position of C _2-6 alkenyl. Specific examples include vinylene, propenylene, 1-butenylene, 2-butenylene and the like. Vinylene is preferred.

“Cycloalkyl” means a C _3-15 non-aromatic hydrocarbon ring, which may form a bridged ring or a spiro ring, or may have a partially unsaturated bond. . Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclooctanedienyl, adamantyl and norbornyl. Preferred is cyclobutyl, cyclopentyl or cyclohexyl.

  “Halogen” means a halogen atom. Specific examples include fluoro, chloro, bromo and iodo. Preferred is fluoro or chloro.

  The “halogeno lower alkyl” means a group in which one or more arbitrary hydrogen atoms of the “lower alkyl” are the same or different from each other and substituted with the “halogen”. Specific examples include trifluoromethyl and pentafluoroethyl. Preferably, it is trifluoromethyl.

“Aryl” means a monocyclic to tricyclic C _6-14 aromatic hydrocarbon ring, and specific examples include phenyl, naphthyl and the like. Preferred is phenyl. Further, the C _5-8 cycloalkyl ring may be condensed, and for example, indanyl or tetrahydronaphthyl may be formed.

  “Heterocycle” means a saturated, unsaturated or partially unsaturated 3 to 8 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from O, S and N, 8 to 14 members Bicyclic heterocycle means 11-20 membered tricyclic heterocycle. The ring atom S or N may be oxidized to form an oxide or dioxide, or a bridged ring or spiro ring may be formed. Specific examples of the monocyclic heterocycle include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, dihydrofuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl and the like. Specific examples of the bicyclic heterocycle include indolyl, benzofuranyl, dihydrobenzfuranyl, benzothienyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl and the like. Specific examples of the tricyclic heterocycle include carbazolyl and acridinyl. Preferable examples include pyridyl, furyl, dihydrofuryl, thienyl, thiazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, benzofuranyl, dihydrobenzfuranyl, benzothienyl and the like.

  The term “which may be substituted” means “not substituted” or “substituted with 1 to 5 substituents which are the same or different”.

In the present specification, the permissible substituent of the word “which may be substituted” may be any substituent as long as it is a commonly used substituent in the technical field. In addition, each group may have one or more substituents which are the same or different.
The substituent in the “optionally substituted 5- to 8-membered heterocycle” of the A ring is preferably halogen, lower alkyl, halogeno lower alkyl, —OR ⁰ or —O-halogeno lower alkyl.
The substituent in the “optionally substituted lower alkyl” of R ¹ is preferably a group selected from the following G group.
Group G: halogen, —OR ⁰ , —O-halogeno lower alkyl, —O—SiR ⁰ R ⁰⁰ (aryl), oxo, —NR ⁰ R ⁰⁰ , —C (O) R ⁰ , —CO ₂ R ⁰ , — NR ⁰ C (O) R ⁰⁰ , —C (O) NR ⁰ R ⁰⁰ , cycloalkyl, aryl and heterocyclic groups. However, the cycloalkyl, aryl and heterocyclic groups in Group G may be substituted with halogen, lower alkyl, halogeno lower alkyl, —OR ⁰ or —O-halogeno lower alkyl.
As the substituent in “C _1-12 alkyl” which may be substituted in R ² , halogen, —OR ⁰ , —NR ⁰ R ⁰⁰ , —CO ₂ R ⁰ or —C (O) NR ⁰ R ^{00 are} preferable. It is.
As the substituent in “cycloalkyl”, “aryl” and “heterocyclic group” which may each be substituted in R ² , a group selected from the following group P is preferable.
Group P: a group selected from the group consisting of halogen, —OR ⁰ , —O—SiR ⁰ R ⁰⁰ (aryl), —NR ⁰ R ⁰⁰ , —CO ₂ R ⁰ and —C (O) NR ⁰ R ⁰⁰ Optionally substituted lower alkyl, halogen, cyano, nitro, -OR ⁰ , -O-halogeno lower alkyl, -C (O) R ⁰ , -CO ₂ R ⁰ , -NR ⁰ C (O) R ⁰⁰ , -C (O) NR ⁰ R ⁰⁰ .
R ⁵ , R ^5a are each preferably a substituent in the optionally substituted “cycloalkyl”, “aryl” and “heterocyclic group”, preferably halogen, lower alkyl, halogeno lower alkyl, —OR ⁰ or —O— Halogeno lower alkyl.

Preferred embodiments in the present invention are shown below.
The ring A is preferably furan or dihydrofuran, and together with the condensed benzene ring, forms benzofuran and dihydrobenzofuran, respectively.
Benzene is preferable as the B ring.
R ¹ is preferably lower alkyl which may be substituted, and more preferably isobutyl.
R ² is preferably an optionally substituted aryl or heterocyclic group.
R ³ is preferably —OH.
X is preferably a single bond.
J is preferably —O-lower alkylene- *, more preferably —O-methylene- *.
L is preferably —S (O) ₂ —.

The compound of the present invention may have a geometric isomer or a tautomer depending on the kind of the substituent, but the present invention includes a mixture of these isomers or a mixture thereof.
Further, the compound of the present invention may have an asymmetric carbon atom, and optical isomers such as (R) isomer and (S) isomer based on this may exist. The present invention includes all of these optical isomers and isolated ones.

Furthermore, the compound of the present invention includes pharmacologically acceptable prodrugs. A pharmacologically acceptable prodrug is a compound having a group that can be converted to NH ₂ , OH, CO ₂ H, etc. of the present invention by solvolysis or under physiological conditions. Prodrug-forming groups include “Progress in Medicine”, Life Science Medica, 1985, Volume 5, p.2157-2161 and “Pharmaceutical Development (Volume 7) Molecule The group described in “Design”, Yodogawa Shoten, 1990, p.163-198.

The compound of the present invention may form a salt with a base depending on the type of acid addition salt or substituent. Such salts are pharmaceutically acceptable salts, specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid. , Oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, acid addition salts with organic acids such as aspartic acid, glutamic acid, sodium, Examples thereof include inorganic bases such as potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salts.
Furthermore, the present invention also includes various hydrates and solvates of the compound (I) and salts thereof and crystalline polymorphic substances.

(Production method)
The compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with an appropriate protective group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There is a case. Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups, and examples of their protecting groups include Protective Groups in Organic Synthesis by TW Greene and PGM Wuts. (Protective Groups in Organic Synthesis) ”, (USA), 3rd edition, John Wiley & Sons, 1999. It may be appropriately selected and used accordingly. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary or converting it to a desired group.

（式中、Lvは脱離基を意味する。R^1a及びR^2aは後述する還元的アミノ化反応によりそれぞれR¹及びR²に変換される基を示す。） Hereinafter, representative production methods of the compound of the present invention will be described.
(Production method 1)

(In the formula, Lv represents a leaving group. R ^1a and R ^2a represent groups that are converted into R ¹ and R ² , respectively, by reductive amination reaction described later.)

First Step The first step is a step for producing the compound (V) from the compound (II) by alkylation.
(1) First step-1
This step is a step for producing compound (V) by reductive alkylation of compound (II) and carbonyl compound (III). For the reaction, for example, the method described in “Chemical Experiment Course (Vol. 20) Organic Synthesis 2” edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, p. Specifically, in the absence of solvent or halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, diethyl ether, tetrahydrofuran (THF), reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride in solvents inert to reactions such as ethers such as dioxane, alcohols such as methanol and ethanol, and acetic acid. It is preferably carried out under cooling and at room temperature to under reflux. Depending on the compound, it may be advantageous to carry out the reaction in the presence of a mineral acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, an acid such as an organic acid such as formic acid or acetic acid, or a Lewis acid such as titanium tetrachloride. Further, for example, palladium-carbon, Raney nickel, platinum or the like is used as a catalyst, and the above-mentioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, N, N in a hydrogen atmosphere of normal pressure to pressure. -Dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile, acetic acid and the like can be carried out at room temperature or under reflux with heating. Depending on the compound, it may be advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid, etc.) to facilitate the reaction.
(2) First step-2
This step is a step for producing compound (V) by alkylating compound (II) with compound (IV) having a leaving group. The leaving group represented by Lv may be any leaving group commonly used in nucleophilic substitution reactions, such as halogens such as chloro and bromo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like. Sulfonyl such as sulfonyloxy, lower alkylsulfonyl, arylsulfonyl and the like are preferably used. For the alkylation reaction in this step, alkylation which can be usually used by those skilled in the art can be adopted. For example, in the absence of a solvent, or the above-mentioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, dimethyl sulfoxide (DMSO), acetonitrile and other inert solvents, or The reaction can be carried out in a solvent such as alcohols at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) Performing in the presence of sodium oxide, potassium hydroxide, sodium hydride, tert-butoxypotassium, etc.) may be advantageous for allowing the reaction to proceed smoothly.

Second step-1
This step is a step for producing the present compound (Ia) in which L is —S (O) ₂ — by sulfonylating the compound (V) with the compound (VI). As the leaving group for Lv, halogen such as chloro and bromo is preferably used. For the reaction, for example, the sulfonylation conditions described in the above-mentioned “Protective Groups in Organic Synthesis” can be applied. Specifically, the reaction can be carried out in a solvent such as tetrahydrofuran, methylene chloride, acetonitrile or the like, if necessary in the presence of a base such as triethylamine or pyridine, under cooling to heating under reflux.

Second step-2
This step is a step for producing the compound (Ib) of the present invention in which L is —C (O) — by acylating the compound (V) with a carboxylic acid (VII) or a reactive derivative thereof. Reactive derivatives include acid halides (acid chloride, acid bromide, etc.), acid anhydrides (ethyl chlorocarbonate, benzyl chlorocarbonate, phenyl chlorocarbonate, p-toluenesulfonic acid, isovaleric acid, etc.) Acid anhydrides or symmetrical acid anhydrides), active esters (phenols optionally substituted with electron-withdrawing groups such as nitro groups or fluorine atoms, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HONSu), etc. Ester), lower alkyl esters, acid azides and the like. These reactive derivatives can be produced by conventional methods. The reaction is carried out using equimolar amounts of the carboxylic acid compound (VII) or its reactive derivative and the compound (V), or an excess of one, and aromatic hydrocarbons, halogenated hydrocarbons, ethers, DMF, DMA, NMP. In a solvent inert to the reaction such as ethyl acetate or acetonitrile, the reaction can be carried out under cooling to heating. Depending on the type of reactive derivative, the reaction may be facilitated by the reaction in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.). In some cases, it may be advantageous to proceed. Pyridine can also serve as a solvent.
When using free carboxylic acids, condensing agents (N, N'-dicyclohexylcarbodiimide (DCC), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (WSC), 1,1'-carbonylbis Imidazole (CDI), N, N'-disuccinimidyl carbonate, Bop reagent (Aldrich, USA), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro Nitrotetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), diphenyl phosphate azide (DPPA), Phosphorous oxychloride, phosphorous trichloride, triphenylphosphine / N-bromosuccinimide, etc.), and in some cases, it is preferable to use an additive (for example, HONSu, HOBt etc.).

Second step-3
This step is a step for producing the compound (Ic) of the present invention in which L is a single bond by alkylating the compound (V) with the compound (VIII) or the compound (IX). The alkylation in this step can be performed in the same manner as the alkylation in the first step.

(Manufacturing method 2)

1st process This process is a process of manufacturing a compound (X) from a compound (II) by sulfonylation, acylation, or alkylation. The sulfonylation, acylation, and alkylation can be carried out in the same manner as in the second step-1 to the second step-3 of production method 1, respectively.

Second Step This step is a step for producing the present compound (I) from the compound (X) by alkylation. The alkylation reaction in this step can be produced in the same manner as in the first step-2 of production method 1. In addition, the compound (IV) in which Lv is —OH can be used in a solvent such as tetrahydrofuran and methylene chloride in the presence of triphenylphosphine and diethyl azodicarboxylate under cooling to room temperature.

（式中、Rは低級アルキルを示す。） (Manufacturing method 3)

(In the formula, R represents lower alkyl.)

First Step This step is a step for producing the present compound (Ie) in which R ³ is —OH from the present compound (Id) in which R ³ is —OR by hydrolysis. The hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in the above-mentioned “Protective Groups in Organic Synthesis”.

Second Step This step is a step for producing the present compound (If) in which R ³ is —NR ⁵ R ^5a from the present compound (Ie) in which R ³ is —OH by amidation. The amidation reaction in this step can be performed in the same manner as in the second step-2 of production method 1.

The starting compound used for the production of the compound (I) of the present invention can be produced, for example, using the following method, a known method, or a modified method thereof.
(Raw material synthesis 1)

First Step This step is a step for producing compound (XIII) by nitration of compound (XII). Nitration can be produced by a method that can be generally employed by those skilled in the art. For example, concentrated nitric acid can be used as a nitrating agent in a solvent such as acetic acid or concentrated sulfuric acid.

Second Step This step is a step for producing the compound (II) by reducing the nitro compound (XIII). For the reduction reaction of nitro in this step, a reduction reaction of a nitro group which can be usually employed by those skilled in the art can be used. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride, and a hydrogenation reaction using palladium-carbon or the like as a catalyst.

（式中、J¹及びJ²はJに変換しうる基を示す。） (Raw material synthesis 2)

(In the formula, J ¹ and J ² represent groups that can be converted to J.)

First Step This step is a step for producing compound (XVI) by condensing compound (XIV) and compound (XV). This step can be produced by amidation, alkylation or the like which can be usually employed by those skilled in the art depending on the structure of J. For example, the compound (XVI) in which J is —O-lower alkylene- * (where * represents a bond to the B ring), the compound (XIV) in which J ¹ is —OH, and J ² is —lower alkylene— It can be produced by alkylation using compound (XV) which is Lv (Lv represents a leaving group). The alkylation can be carried out in the same manner as in the first step-2 of production method 1.

The reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced by subjecting it to normal salt formation treatment.
Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by conventional methods utilizing physicochemical differences between isomers. For example, optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. Optical isomers can also be produced from appropriate optically active raw material compounds.

A preparation containing one or more of the compounds of the present invention or a salt thereof as an active ingredient is usually prepared using carriers, excipients, and other additives used for formulation.
Administration is oral by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral by injections such as intravenous injections, intramuscular injections, suppositories, transdermal agents, nasal agents or inhalants. Either form may be sufficient. The dosage is appropriately determined according to the individual case, taking into account the symptoms, age of the subject, sex, etc. In general, in the case of oral administration, it is about 0.001 mg / kg to 100 mg / kg per day for an adult. This is administered once, or divided into 2 to 4 times. In addition, when administered intravenously, it is usually administered once or multiple times per day in the range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of nasal administration, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of inhalation, it is usually administered once or several times a day in the range of 0.0001 mg / kg to 1 mg / kg per adult.

  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with magnesium aluminate acid. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert solvents such as purified water, ethanol, etc. . In addition to the inert solvent, this composition may contain solubilizers, wetting agents, auxiliary agents such as suspending agents, sweeteners, corrigents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
Transmucosal agents such as inhalants and nasal agents are used in the form of solids, liquids and semisolids, and can be produced according to conventionally known methods. For example, excipients such as lactose and starch, and pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administrations, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

  Hereinafter, production examples of the compound of the present invention will be given and the production method of the compound of the present invention will be specifically described. However, the present invention is not limited to these examples. In addition, the raw material compound of this invention compound also contains a novel compound, The manufacturing method of these compounds is demonstrated as a reference example.

The symbols in the reference examples and examples have the following meanings (the same applies hereinafter).
Rf: Reference number, Ex: Example number, No: Compound number, Structure: Structural formula, DATA: Physical data ((EI: EI-MS ([M] ⁺ ); EP: ESI-MS (Pos) ([M + H] ⁺ ); EN: ESI-MS (Neg) ([MH] ^- ); API: API-MS (Pos) ([M + H] ⁺ if not specified); FP: FAB -MS (Pos) (when it is no description ^{[M + H] +);} FN: FAB-MS (Neg) ( if it is no described ^{[MH] -); NMR1:} 1 in DMSO-d ₆ characteristic peaks at HNMR δ (ppm); NMR2: δ characteristic peaks in ¹ HNMR in CDCl ₃ (ppm); Sal: salt (No description indicates a free form, for example, HCl is described ), Me: methyl, Et: ethyl, cPr: cyclopropyl, iPr: isopropyl, nBu: normal butyl, cBu: cyclobutyl, iBu: isobutyl, cPen : Cyclopentyl, cHex: cyclohexyl, nOct: normal octyl, Ph: phenyl, Bn: Benzyl, Ac: acetyl, Py: pyridyl, furyl: furyl, thienyl: thienyl, TBDPS: tert-butyldiphenylsilyl, the number before the substituent indicates the substitution position, for example, 2,4-diF-Ph is 2 , 4-difluorophenyl), Syn: Production method (numbers indicate production using corresponding raw materials in the same manner as Example compounds having the numbers as Example numbers. ) Indicates that it was produced using the corresponding raw material in the same manner as the reference example compound having that number as a reference example number.

Reference example 1
A solution of 12.6 g of 2,3-dihydro-6-hydroxybenzofuran in acetic acid (90.0 ml) was cooled to 15 ° C., and 7.17 ml of concentrated nitric acid (69%) was added dropwise with stirring. After completion of dropping, the reaction solution was heated to 35 ° C. and stirred for 10 minutes. After adding water to the reaction solution, the mixture was concentrated under reduced pressure, and the precipitated crude product was collected by filtration. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 9.00 g of 5-nitro-2,3-dihydro-6-hydroxybenzofuran.

Reference example 2
To a mixture of 11.7 ml of concentrated nitric acid (69%) and 25.0 ml of acetic acid, a solution of 17.5 g of 1,3-benzodioxol-5-yl acetic acid (20.0 ml) was added dropwise under ice cooling. After stirring for 30 minutes under ice cooling, the reaction solution is poured into ice water, and the deposited precipitate is collected by filtration to obtain 19.7 g of 6-nitro-1,3-benzodioxol-5-yl acetic acid as a pale yellow solid. It was. 6-Nitro-1,3-benzodioxol-5-yl To a methanol solution (160 ml) of 4.50 g of acetic acid was added 80.0 ml of 3M hydrochloric acid, and the mixture was heated to reflux for 4.5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to about 100 ml. The precipitate deposited by ice cooling was collected by filtration and dried under reduced pressure to obtain 3.49 g of 6-nitro-5-hydroxy-1,3-benzodioxole.

Reference example 3
2,4-Dihydro-5-hydroxybenzofuran (4.04 g) was dissolved in DMF (50 ml), methyl 4- (bromomethyl) benzoic acid (7.47 g) and potassium carbonate (2.75 g) were added thereto, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 30: 1) to give methyl 4-[(2,3-dihydro-1-benzofuran-5-yloxy) methyl. ] 5.62 g of benzoic acid was obtained.

Reference example 4
Dissolve 3.00 g of 5-nitro-2,3-dihydro-1-benzofuran-6-ol in 30 ml of DMF, add 4.17 g of methyl 4- (bromomethyl) benzoic acid and 2.75 g of potassium carbonate, and add it at 60 ° C. Stir overnight. After cooling the reaction solution to room temperature, water and ethyl acetate were added, and the deposited precipitate was collected by filtration and dried under reduced pressure to give methyl 4-{[(5-nitro-2,3-dihydro-1-benzofuran-6. -Yl) oxy] methyl} benzoic acid 5.40 g was obtained.

Reference Example 5
1.00 g of methyl 4-[(2,3-dihydro-1-benzofuran-5-yloxy) methyl] benzoic acid was dissolved in 10 ml of acetic acid, and 0.245 ml of concentrated nitric acid (69%) was added dropwise with stirring. After completion of dropping, the mixture was stirred at room temperature for 10 minutes. The deposited precipitate was collected by filtration, washed with water, dried under reduced pressure, and methyl 4-{[(6-nitro-2,3-dihydro-1-benzofuran-5-yl) oxy] methyl} benzoic acid 1.16 g was obtained.

Reference Example 6
Methyl 4-{[(5-nitro-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 5.50 g was dissolved in 60 ml acetic acid and 15 ml water, and the temperature was raised to 60 ° C. 4.64 g of reduced iron was added and stirred at 60 ° C. for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, the solution was neutralized with sodium hydrogen carbonate, and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 4: 1) to give methyl 4-{[(5-amino-2,3-dihydro-1-benzofuran- 6.47 g of 6-yl) oxy] methyl} benzoic acid were obtained.

Reference Example 7
Methyl 4- {3-[(5-nitro-2,3-dihydro-1-benzofuran-6-yl) oxy] propyl} benzoic acid 507 mg was dissolved in methanol 10 ml and tetrahydrofuran 5 ml, and 10% w / w 232 mg of palladium carbon (containing 50% water) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and methyl 4- {3-[(5-amino-2,3-dihydro-1-benzofuran-6-yl) oxy ] Propyl} benzoic acid 412mg was obtained.

Reference Example 8
Methyl 4-{[(5-amino-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid (4.46 g) was dissolved in pyridine (60 ml), and 5-methylfuran-2-sulfonyl chloride was dissolved therein. 3.50 g was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 9: 1) to give methyl 4-{[(5-{[(5-methyl-2-furyl) sulfonyl. Amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 6.14 g was obtained.

Reference Example 9
Methyl 4-{[(5-{[(5-Methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 1.00 g in toluene 10 ml After dissolution, 512 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added thereto and stirred at 100 ° C. for 3 hours. The reaction solution was cooled to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1), and methyl 4-{[(5-{[(5-methyl-2 852 mg of -furyl) sulfonyl] amino} -1-benzofuran-6-yl) oxy] methyl} benzoic acid were obtained.

Reference Example 10
Methyl 4-{[(5-amino-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 3.49g was dissolved in 100ml dichloroethane, and 1.17ml isobutyraldehyde and triacetoxy hydrogenated 3.21 g of sodium boron was added and stirred overnight at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 5: 1) to give methyl 4-({[5- (isobutylamino) -2,3 -Dihydro-1-benzofuran-6-yl] oxy} methyl) benzoic acid 3.60g.

  In the same manner as in the above Reference Examples 1 to 10, the Reference Example compounds shown in Tables 3 to 12 below were produced using the corresponding raw materials. The structures and physicochemical data of the reference example compounds in Tables 3 to 12 are shown.

Example 1
Methyl 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 385 mg and methanol 5 ml Dissolved in 10 ml of tetrahydrofuran, 3 ml of 1M aqueous sodium hydroxide solution was added thereto and stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, 1M hydrochloric acid and chloroform were added to the resulting residue, and the organic layer was separated using a phase separate filter (Phase Separate-filter, manufactured by Isotute). Ethyl acetate was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration. The crude product obtained was recrystallized from ethyl acetate and 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl. ) Oxy] methyl} benzoic acid 294 mg was obtained.

Example 2
1.67 g of methyl 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid Dissolved in 60 ml of 4-dioxane and 60 ml of methanol, 40 ml of 1M sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate). The obtained crude product was dissolved in ethanol, 1M aqueous sodium hydroxide solution was added, and the mixture was concentrated under reduced pressure. The resulting crude crystals were recrystallized from water to give 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl). 3.25 g of sodium oxy] methyl} benzoate monohydrate was obtained.

Example 3
4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 220 mg dissolved in DMF 5 ml To this, 216 mg of ammonium carbonate, 104 mg of WSC · hydrochloride and 73 mg of HOBt were added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. Toluene was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration. The resulting crude product was recrystallized from ethanol to give 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6- Yl) oxy] methyl} benzamide 100 mg was obtained.

Example 4
Methyl 4-{[(5-{[(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 209 mg is dissolved in DMF 5 ml To this, 130 mg of isobutyl iodide and 459 mg of cesium carbonate were added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). The resulting crude product was recrystallized from ethanol to give methyl 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6. 140 mg of -yl) oxy] methyl} benzoic acid were obtained.

Example 5
Methyl 4-({[5- (isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) benzoic acid 380 mg is dissolved in dichloroethane 10 ml to give 5-methyl-2-furaldehyde 0.29 ml and sodium triacetoxyborohydride (750 mg) were added, and the mixture was stirred at room temperature overnight. A sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give methyl 4-{[(5- {isobutyl 478 mg of [(5-methyl-2-furyl) methyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid was obtained.

Example 6
Methyl 4-{[(5-{[(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 4.54 g in DMF 50 ml After dissolution, 3.77 g of isobutyl iodide and 9.97 g of cesium carbonate were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 19: 1), and methyl 4-{[(5- {isobutyl [(5-methyl-2-furyl) 4.68 g of sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid was obtained.

Example 7
Methyl 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} cinnamic acid 160 mg and nickel chloride ( II) 14 mg of hexahydrate was dissolved in 5 ml of methanol and 1 ml of tetrahydrofuran, and 28 mg of sodium borohydride was added thereto under ice cooling. After stirring at room temperature for 3 hours, 1M hydrochloric acid was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and methyl 3- (4-{[(5- {isobutyl [(5-methyl-2 155 mg of -furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} phenyl) propionic acid were obtained.

Example 8
Methyl 4-{[(5-{((2R) -3-{[tert-butyldiphenyl) silyl] oxy} -2-methylpropyl) [(5-methyl-2-furyl) sulfonyl] amino} -2, 453 mg of 3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid was dissolved in 6 ml of tetrahydrofuran, 0.9 ml of 1M tetrabutylammonium fluoride tetrahydrofuran solution was added thereto, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1), and methyl 4-{[(5-{[(2R) -3- 296 mg of hydroxy-2-methylpropyl] [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl l} benzoic acid was obtained.
Example 9
Methyl 4-({[5- (isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) benzoic acid 360 mg was dissolved in pyridine 10 ml, to which benzenesulfonyl chloride 231 mg was added, Stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (toluene: ethyl acetate = 3: 1) to give methyl 4-[({5- [isobutyl 477 mg of (phenylsulfonyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid was obtained.

Example 10
16.5 g of tert-butyl (2-furylmethoxy) diphenylsilane was dissolved in 100 ml of dichloroethane, 27.3 g of SO ₃ -pyridine complex was added thereto, and the mixture was stirred at 80 ° C. for 6 days. After cooling to room temperature, 1 ml of DMF and 25.3 ml of oxalyl chloride were added to the reaction solution and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 5-({[tert-butyl (diphenyl) silyl] oxy} methyl) furan-2. 10.9 g of sulfonyl chloride was obtained.
300 mg of methyl 4-({[5- (isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) benzoic acid was dissolved in 8 ml of pyridine, and 5-({[tert- 1.84 g of butyl (diphenyl) silyl] oxy} methyl) furan-2-sulfonyl chloride was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and methyl 4-[({5-[{[5-({[tert-butyl ( 537 mg of diphenyl) silyl] oxy} methyl) -2-furyl] sulfonyl} (isobutyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid was obtained.

Example 11
Methyl 4-[({5-[{[5-({[tert-butyl (diphenyl) silyl] oxy} methyl) -2-furyl] sulfonyl} (isobutyl) amino] -2,3-dihydro-1-benzofuran -6-yl} oxy) methyl] benzoic acid (537 mg) was dissolved in tetrahydrofuran (10 ml), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (1.42 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give methyl 4-[({5-[{[5- (hydroxymethyl) -2- Furyl] sulfonyl} (isobutyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid 334 mg was obtained.

Example 12
Methyl 4-{[(5-amino-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 450mg is dissolved in dichloroethane 7ml and acetic acid 3.5ml, and 2-acetylpyridine 0.18ml And 413 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 5 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. Methyl 4-[({5-[(1-pyridin-2-ylethyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid obtained by distilling off the solvent under reduced pressure The crude acid was dissolved in 15 ml of pyridine, and 406 mg of 5-methylfuran-2-sulfonyl chloride was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give methyl 4-[({5-[[ 547 mg of (5-methyl-2-furyl) sulfonyl] (1-pyridin-2-ylethyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid was obtained.

Example 13
Methyl 4-{[(5-{[(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 300 mg dissolved in pyridine 4 ml To this was added 196 mg of propylene oxide, and the mixture was stirred overnight at 100 ° C. in a sealed tube. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with 1M hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 4: 1), and methyl 4-{[(5-{(2-hydroxypropyl) [(5-methyl 2-Furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 333 mg was obtained.

Example 14
Methyl 4-{[(5-{(2-hydroxypropyl) [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxypropyl} benzoic acid 433 mg Was dissolved in 4 ml of DMF, 165 mg of sodium hydride (55%) and 0.82 ml of methyl iodide were added thereto, and the mixture was stirred in a sealed tube at 80 ° C. for 2 days. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene: ethyl acetate = 3: 1) to give methyl 4-{[(5- { 281 mg of (2-methoxypropyl) [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid was obtained.

Example 15
Methyl 4-{[(5-{[(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 222 mg is dissolved in tetrahydrofuran 5 ml To this, 53 mg of 2- (dimethylamino) ethanol, 262 mg of triphenylphosphine and 0.458 ml of diethyl azocarboxylate (40% toluene solution) were added and stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-chloroform: methanol = 100: 1) to give methyl 4-{[(5-{[2- 188 mg of (dimethylamino) ethyl] [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid was obtained.

Example 16
Methyl 4-({[5- (isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) benzoic acid 250 mg was dissolved in dichloroethane 10 ml, to which triethylamine 0.29 ml and benzoyl chloride 231 mg And stirred at room temperature overnight. A sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 3: 1) to give methyl 4-[({ 318 mg of 5- [benzoyl (isobutyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid was obtained.

  In the same manner as in the above Examples 1 to 16, Example compounds shown in Tables 13 to 41 described below were produced using the corresponding raw materials. Tables 13 to 41 show the structures and physicochemical data of the example compounds.

  Table 42 shows the structure of another compound of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in the Examples and methods obvious to those skilled in the art, or variations thereof.

  The compound of the present invention is excellent in EP1 receptor antagonistic activity, and diseases involving EP1 receptor, particularly frequent urination / urinary urgency or urinary incontinence associated with overactive bladder, cystitis, interstitial cystitis, prostatitis It is useful as a therapeutic agent for lower urinary tract diseases such as.

  The numerical heading <223> in the sequence listing below describes the “Artificial Sequence”. Specifically, the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing is an artificially synthesized signal peptide sequence. Further, the amino acid sequence represented by the sequence number 2 in the sequence listing is an artificially synthesized FLAG sequence.

Claims (1)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[The symbols in the formula have the following meanings.
Ring A: 5- to 8-membered hetero ring which may be substituted.
Ring B: cycloalkyl, aryl or heterocycle.
R ¹ : optionally substituted lower alkyl.
R ² : C _1-12 alkyl, cycloalkyl, aryl, heterocyclic group, lower alkylene-cycloalkyl, lower alkylene-aryl or lower alkylene-heterocyclic group.
However, the C _1-12 alkyl, cycloalkyl, aryl and heterocyclic groups in R ² may be substituted.
R ³ : -OR ⁰ or -NR ⁵ R ^5a .
R ⁰ , R ⁰⁰ : each independently -H or lower alkyl.
R ⁵ , R ^5a : each independently -R ⁰ , lower alkylene-NR ⁰ R ⁰⁰ , lower alkylene-CO ₂ R ⁰ , cycloalkyl, aryl, heterocyclic group, lower alkylene-cycloalkyl, lower alkylene-aryl , Lower alkylene-heterocyclic group.
However, the cycloalkyl, aryl and heterocyclic groups in R ⁵ and R ^5a may be substituted.
R ⁴ : each independently halogen, lower alkyl, halogeno lower alkyl, cyano, nitro, —OR ⁰ , —O-halogeno lower alkyl, —C (O) R ⁰ , —NR ⁰ C (O) R ⁰⁰ .
m: 0, 1 or 2.
However, when m is 2, two R ^{4 s} may be the same or different from each other.
J: Lower alkylene, lower alkenylene, -O-lower alkylene- *, lower alkylene-O- *, -O-lower alkenylene- *, lower alkenylene-O- *, -C (O) NR ^0- * or -NR ⁰ C (O)-*.
X: single bond, lower alkylene, lower alkenylene, * -O-lower alkylene, * -O-lower alkenylene, * -NR ⁰ -lower alkylene, * -S (O) _n -lower alkylene or * -S (O) _n -Lower alkenylene.
However, * in J and X represents a bond to the B ring.
n: 0, 1 or 2.
L: Single bond, —C (O) — or —S (O) ₂ —. ]