JP2009057282A - Carboxylic acid derivative or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound usable as a therapeutic agent for diseases associated with an EP1 receptor, particularly diseases in the lower urinary tract such as pollakiuria-urinary urgency or incontinence of urine accompanied by the overactive bladder, cystitis, interstitial cystitis or prostatitis. <P>SOLUTION: It is confirmed that a carboxylic acid derivative characterized by having a sulfonamide structure and a methyl group substituted with a heterocycle as a substituent on an N atom of the sulfonamide in the chemical structure or a salt thereof has potent antagonistic actions on the EP1 receptor. Since the compound has the good antagonistic actions on the EP1 receptor, the compound is useful as the therapeutic agent for the diseases associated with the EP1 receptor, particularly the diseases in the lower urinary tract such as the pollakiuria-urinary urgency or incontinence of urine accompanied by the overactive bladder, cystitis, interstitial cystitis or prostatitis. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  INDUSTRIAL APPLICABILITY The present invention is useful as a therapeutic agent for pharmaceuticals, particularly urinary frequency / urinary urgency associated with overactive bladder, urinary incontinence, cystitis, interstitial cystitis, lower urinary tract diseases such as prostatitis, pain, cancer, etc. It relates to a carboxylic acid derivative.

  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 expected to avoid side effects peculiar to anticholinergic drugs, and can also be expected to be effective for patients who do not show efficacy with anticholinergic treatment. In addition, this drug acts on sensory nerves and can be expected to have a stronger effect of improving subjective symptoms. Furthermore, it has been reported that a pathological condition improving effect is exhibited without lowering the urination efficiency of rats with spinal cord injury (Non-patent Document 5), and it can be expected that it can 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Ｒ⁴は水素、Ｃ1〜8アルキル、Ｃ2〜8アルケニル、Ｃ2〜8アルキニル、１個または２個のCOOZ⁸、CONZ⁹Z¹⁰、OZ⁸、Ｃ1〜4アルコキシからなる群から選ばれる基によって置換されたＣ1〜６アルキル、Ｃ3〜７シクロアルキル、フェニルまたはＣ3〜７シクロアルキルで置換されたＣ1〜４アルキル、Ｃ2〜４アルケニル、Ｃ2〜４アルキニルを示す。他の記号は当該公報参照。）
しかしながら、式（Ａ）の化合物のＲ⁴として、本発明化合物の特徴である置換されていてもよいヘテロ環基で置換された低級アルキレンの開示はない。 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).

Wherein R ⁴ is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, 1 or 2 COOZ ⁸ , CONZ ⁹ Z ¹⁰ , OZ ⁸ , C 1-4 alkoxy. C1-6 alkyl substituted by a group, C3-7 cycloalkyl, phenyl or C1-4 alkyl substituted by C3-7 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl. reference.)
However, there is no disclosure of lower alkylene substituted with an optionally substituted heterocyclic group, which is a feature of the compound of the present invention, as R ⁴ of the compound of formula (A).

（式中、Ｒ⁵はイソプロピル、イソブチル、２−メチル−２−プロペニル、シクロプロピルメチル、メチル、エチル、プロピル、２−プロペニルまたは２−ヒドロキシ−２−メチルプロピルを示す。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Ｒ⁵として、本発明化合物の特徴である置換されていてもよいヘテロ環基で置換された低級アルキレンの開示はない。 Patent Document 3 discloses a compound represented by the formula (B).

(In the formula, R ⁵ represents isopropyl, isobutyl, 2-methyl-2-propenyl, cyclopropylmethyl, methyl, ethyl, propyl, 2-propenyl or 2-hydroxy-2-methylpropyl. reference.)
However, there is no disclosure of lower alkylene substituted with an optionally substituted heterocyclic group, which is a feature of the compound of the present invention, as R ⁵ in the compound of formula (B).

（式中の記号は当該公報参照。） Patent Document 4 discloses a compound represented by the formula (C) including a wide range of compounds, but a cyclic group such as phenyl which may be substituted as X and monocyclic heteroaryl which may be substituted. The chemical structure is different from the compound of the present invention in that it does not have a structure.

(See the official gazette for symbols in the formula.)

“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 incontinence, urinary incontinence, cystitis, interstitial cystitis, and prostatitis associated with the overactive bladder as described above are effective and safe. However, there is an urgent need to provide a therapeutic agent for lower urinary tract disease that is excellent in effectiveness and safety.

  As described above, EP1 receptor antagonists can be expected to be highly safe therapeutic agents for lower urinary tract diseases 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。
Ｒ¹及びＲ²：同一又は互いに異なって、Ｈ、ハロゲン、低級アルキル、ハロゲノ低級アルキル、-ＯＨ、-Ｏ-低級アルキル、或いは、Ｒ¹及びＲ²が結合している炭素原子と一体となって（１）シクロペンテン、（２）シクロヘキセン、（３）シクロへプテン、（４）シクロオクテン、又は（５）ベンゼン環を形成してもよく、
Ｒ³：-ＯＨ、又は-Ｏ-低級アルキル、
Ａ：置換されていてもよいフェニル、又は置換されていてもよい単環式ヘテロアリール、
Ｂ：置換されていてもよいヘテロ環基、
Ｃ：置換されていてもよいフェニル、又は置換されていてもよい単環式ヘテロアリール、
Ｘ：低級アルキレン、低級アルケニレン、-Ｏ-低級アルキレン-*、
又は-低級アルキレン-Ｏ-*、
Ｙ：単結合、低級アルキレン、低級アルケニレン、又は*-Ｏ-低級アルキレン、
Ｚ：低級アルキレン、
ただし、Ｘ及びＹにおける*はＣ環への結合を示す。以下同様。） That is, the present invention relates to a carboxylic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.
R ¹ and R ² are the same or different from each other and are combined with H, halogen, lower alkyl, halogeno lower alkyl, —OH, —O-lower alkyl, or the carbon atom to which R ¹ and R ² are bonded. (1) cyclopentene, (2) cyclohexene, (3) cycloheptene, (4) cyclooctene, or (5) a benzene ring may be formed,
R ³ : —OH or —O-lower alkyl,
A: phenyl which may be substituted, or monocyclic heteroaryl which may be substituted,
B: an optionally substituted heterocyclic group,
C: optionally substituted phenyl, or optionally substituted monocyclic heteroaryl,
X: lower alkylene, lower alkenylene, -O-lower alkylene- *,
Or -lower alkylene-O- *,
Y: single bond, lower alkylene, lower alkenylene, or * -O-lower alkylene,
Z: lower alkylene,
However, * in X and Y represents a bond to the C ring. The same applies below. )

  Since the compound of the present invention has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urination / urinary urgency associated with overactive bladder and urinary incontinence, cystitis, interstitial cystitis, It is useful as a therapeutic agent for lower urinary tract diseases such as prostatitis.

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. Preferably it is a C1-C3 thing, More preferably, they are methyl and ethyl.
The “lower alkylene” means a divalent group formed by removing one hydrogen at any position of C _1-6 alkyl. Specific examples include methylene, ethylene, methylmethylene, dimethylmethylene, propylene and the like. Preferred are methylene, ethylene and propylene, and more preferred are methylene and ethylene.
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.

  “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.

  “Monocyclic heteroaryl” is a monocyclic 5- or 6-membered aromatic ring group containing 1 to 3 heteroatoms selected from O, S and N, and the ring atom S or N is oxidized. Oxides and dioxides may be formed. Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl and the like. Pyridyl, furyl, thienyl and thiazolyl are preferable.

“Heterocyclic group” means a saturated, unsaturated or partially unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from O, S and N; A 14-membered bicyclic heterocyclic group means a 11-20 membered tricyclic heterocyclic group. 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 heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furyl, dihydrofuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, oxetanyl, Examples include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like. Specific examples of the bicyclic heterocyclic group include indolyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl and the like. Specific examples of the tricyclic heterocyclic group include carbazolyl and acridinyl.
The “heterocyclic group” is preferably pyridyl, pyridazinyl, pyrazinyl, furyl, thienyl, thiazolyl, oxazolyl, oxadiazolyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, indolyl, benzofuranyl, benzothienyl, more preferably pyridyl, pyrazinyl , Thiazolyl, oxadiazolyl, oxetanyl, tetrahydrofuranyl.

  In the present specification, “optionally substituted phenyl”, “optionally substituted monocyclic heteroaryl” and “optionally substituted heterocyclic group” are described as monovalent groups for convenience. However, depending on the structure, it may be a divalent or higher polyvalent group. The present invention includes those structures. For example, a specific embodiment of the divalent group corresponds to one obtained by converting the above-mentioned ring group suffix to diyl according to the organic compound nomenclature. For example, a divalent group corresponding to a phenyl group that is a monovalent group is phenylene. The divalent group corresponding to the oxetanyl group which is a monovalent group is oxetanediyl. In this case, for example, those in the form of geminal substitution such as 3,3-oxetanediyl are also included.

  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 “optionally substituted phenyl” for A and C is preferably lower alkyl, halogen, halogeno lower alkyl, —OH, —O-lower alkyl.
Preferred examples of the substituent in the “optionally substituted heteroaryl” for A and C include lower alkyl, halogen, halogeno lower alkyl, and —O-lower alkyl.
Preferred examples of the substituent in the “optionally substituted heterocyclic group” for B include lower alkyl, halogen, halogeno lower alkyl, —OH, and —O-lower alkyl.

Preferred embodiments in the present invention are shown below.
A is preferably an optionally substituted thiazolyl, an optionally substituted furyl, or an optionally substituted phenyl. Here, as the substituent on A, the substituents described above are preferable.
B is preferably an optionally substituted oxetanyl, an optionally substituted tetrahydrofuranyl, or an optionally substituted pyridyl. Here, as the substituent on B, the substituents described above are preferable.
C is preferably phenylene which may be substituted, thiophene diyl which may be substituted, or pyridinediyl which may be substituted. Here, as the substituent on C, the substituents described above are preferable.
R ¹ and R ² are preferably a case where a cyclohexene ring is formed integrally with the carbon to which R ¹ and R ² are bonded.
R ³ is preferably —OH.
X is preferably —O-lower alkylene- *, more preferably —O-methylene- *.
Y is preferably a single bond.
Z is preferably methylene, methylmethylene or ethylene.
A particularly preferred embodiment of the present invention is a compound comprising a combination of each preferred group described above.

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 or the like 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.
Further, the present invention 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は脱離基を示し、その他の記号は前記と同じ意味を表す。） 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, and other symbols have the same meaning as described above.)

  This step is a step for producing the compound (I) of the present invention by alkylating the compound (II) with the compound (III) 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 solvent, or aromatic hydrocarbons such as benzene, toluene, xylene, esters such as ethyl acetate, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dichloromethane, 1,2-dichloroethane, chloroform Inactive for reactions such as halogenated hydrocarbons such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and acetonitrile The reaction can be carried out in a solvent or a solvent such as alcohols at room temperature to heating under reflux. 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.

  In addition, using a compound in which Lv is —OH in the formula (III), ethers such as THF, dioxane and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as toluene and benzene In solvents such as DMF, triphenylphosphine, tri-n-butylphosphine, tris (dimethylamino) phosphine, triphenylphosphite, diphenoxyphenylphosphine, diphenyl (2-pyridyl) phosphine, (4-dimethylamino) The reaction can also be carried out under cooling to room temperature in the presence of a phosphine such as diphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, dimethyl azodicarboxylate.

（式中、Rは低級アルキルを示し、その他の記号は前記と同じ意味を表す。） (Manufacturing method 2)

(In the formula, R represents lower alkyl, and other symbols have the same meaning as described above.)

This step is a step for producing the present compound (Ib) in which R ³ is —OH from the present compound (Ia) 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”.

（式中、Lvは脱離基を示し、その他の記号は前記と同じ意味を表す。） The raw material compound used for the production of the compound (I) of the present invention can be easily produced using, for example, the following method, a known method, or a modified method thereof.
(Raw material synthesis 1)

(In the formula, Lv represents a leaving group, and other symbols have the same meaning as described above.)

First Step This step is a step for producing compound (VI) by alkylating compound (IV) with compound (V) having a leaving group. The alkylation in this step can be performed in the same manner as in production method 1.

Second Step This step is a step for producing compound (VII) by nitration of compound (VI). 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.

Third Step This step is a step for producing compound (VIII) by reducing nitro compound (VII). The reduction reaction of the nitro group in this step can be a reduction reaction of a nitro group that can be usually employed by those skilled in the art. 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、Lvは脱離基を示し、その他の記号は前記と同じ意味を表す。） (Raw material synthesis 2)

(In the formula, Lv represents a leaving group, and other symbols have the same meaning as described above.)

1st process This process is a process of manufacturing a compound (VII) by alkylating a compound (IX) using a compound (V). The alkylation in this step can be performed in the same manner as in production method 1.

Second Step This step is a step for producing compound (VIII) by reducing nitro compound (VII). The reduction of the nitro group in this step can be performed by the same method as in the third step of raw material synthesis 1.

（式中、Lvは脱離基を示し、その他の記号は前記と同じ意味を表す。） (Raw material synthesis 3)

(In the formula, Lv represents a leaving group, and other symbols have the same meaning as described above.)

This step is a step for producing compound (II) by sulfonylating compound (VIII) with compound (X). 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 without cooling or in a solvent such as tetrahydrofuran, methylene chloride, or acetonitrile, if necessary, in the presence of a base such as triethylamine or pyridine, under cooling to heating under reflux.

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.

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 EP1 receptor antagonistic action and that the frequent urination state is satisfactorily improved in animal experiments.

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, the composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, flavoring agents, 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 a composition 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) (If not specified, [M + H] ⁺ ); EN: ESI-MS (Neg) ([MH] ^- ); API: API-MS (Pos) (If not specified, [M + H] ^{+); FP: FAB-MS} (Pos) ( when it is no description ^{[M + H] +);} FN: FAB-MS (Neg) ( if it is no description ^{[MH] -); NMR1:} DMSO characteristic peaks in ¹ HNMR of -d in _{6 δ (ppm); NMR2:} δ characteristic peaks in ¹ HNMR in CDCl ₃ (ppm); Sal: the salt (No description is free form For example, when HCl is described, it indicates that the compound is a hydrochloride.)), Me: methyl, Et: ethyl, Ph: phenyl, Py: pyridyl, the number before the substituent is the substitution position Thus, for example, 3,5-diF-Ph represents 3,5-difluorophenyl), Syn: production method (numbers are examples of the number) In the same manner as the example compound having the symbol, it indicates that the compound was produced using the corresponding raw material.When R is preceded by the number, it corresponds to the reference compound having the number as a reference example number. It shows that it was manufactured using raw materials.)

Reference example 1
By reacting 5-hydroxyindane with ethyl 5- (bromomethyl) thiophene-2-carboxylic acid in dimethylformamide in the presence of potassium carbonate, ethyl 5-[(2,3-dihydro-1H-inden-5-yloxy ) Methyl] thiophene-2-carboxylic acid was prepared.
Reference example 2
Nitration of ethyl 5-[(2,3-dihydro-1H-inden-5-yloxy) methyl] thiophene-2-carboxylic acid in acetic acid using concentrated nitric acid gave ethyl 5-{[(6-nitro -2,3-Dihydro-1H-inden-5-yl) oxy] methyl} thiophene-2-carboxylic acid was prepared.
Reference example 3
2-Nitro-4- (trifluoromethyl) phenol is reacted with methyl 4- (bromomethyl) benzoic acid in the presence of potassium carbonate in dimethylformamide to give methyl 4-{[2-nitro-4- (trifluoro Methyl) phenyl] methyl} benzoic acid was prepared.

Reference example 4
Ethyl 5-{[(6-nitro-2,3-dihydro-1H-inden-5-yl) oxy] methyl} thiophene-2-carboxylic acid in acetic acid with reduced iron to reduce the nitro group, Ethyl 5-{[(6-amino-2,3-dihydro-1H-inden-5-yl) oxy] methyl} thiophene-2-carboxylic acid was prepared.
Reference Example 5
Methyl 6-{[(6-Amino-2,3-dihydro-1H-inden-5-yl) oxy] methyl} nicotinic acid reacts with 4-methyl-1,3-thiazole-2-sulfonyl chloride in pyridine Methyl 6-{[(6-{[(4-methyl-1,3-thiazol-2-yl) sulfonyl] amino} -2,3-dihydro-1H-inden-5-yl) oxy] Methyl} nicotinic acid was produced.

  In the same manner as in Reference Examples 1 to 5, the Reference Example compounds shown in Tables 3 to 7 below were produced using the corresponding raw materials. Tables 3 to 7 show the structures and physicochemical data of the reference example compounds.

Example 1
Methyl 4-{[(6-{[(4-methyl-1,3-thiazol-2-yl) sulfonyl] amino} -2,3-dihydro-1H-inden-5-yl) oxy] methyl} benzoic acid 2.00 g, (3-methyloxetane-3-yl) methanol 445 mg, and triphenylphosphine 2.29 g were dissolved in tetrahydrofuran 8.00 mL. Under ice-cooling, 3.97 mL of a 40% toluene solution of diethyl azodicarboxylate was added dropwise. And stirred at room temperature for 12 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and methyl 4-{[(6-{[(3-methyloxetane-3-yl ) Methyl] [(4-methyl-1,3-thiazol-2-yl) sulfonyl] amino} -2,3-dihydro-1H-inden-5-yl) oxy] methyl} benzoic acid 2.36 g was prepared.
Example 2
Methyl 4-{[(6-{[(4-methyl-1,3-thiazol-2-yl) sulfonyl] amino} -2,3-dihydro-1H-inden-5-yl) oxy] methyl} benzoic acid 459 mg was dissolved in 10.0 ml of DMF, and 198 mg of 5- (bromomethyl) tetrahydrofuran, 166 mg of potassium carbonate and 166 mg of potassium iodide were added thereto, and the mixture was stirred at 100 ° C. for 7 hours. The reaction mixture was concentrated under reduced pressure, water 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 sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and methyl 4-[({6-[[(4-methyl-1,3- 286 mg of thiazol-2-yl) sulfonyl] (tetrahydrofuran-2-ylmethyl) amino] -2,3-dihydro-1H-inden-5-yl} oxy) methyl] benzoic acid was obtained.

Example 3
Methyl 4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfonyl] (tetrahydrofuran-2-ylmethyl) amino] -2,3-dihydro-1H-inden-5-yl } Oxy) methyl] benzoic acid 260 mg was dissolved in tetrahydrofuran 5.00 ml and methanol 5.00 ml, 1M aqueous sodium hydroxide solution 2.00 ml was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture 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 manufactured by Isotute. Hexane and ethyl acetate were 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 hexane / ethyl acetate to give 4-[({6-[[(4-methyl-1,3-thiazol-2-yl) sulfonyl] (tetrahydrofuran-2-ylmethyl) amino]. 219 mg of -2,3-dihydro-1H-inden-5-yl} oxy) methyl] benzoic acid were obtained.
Example 4
Methyl 4-{[(6-{[(3-methyloxetan-3-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfonyl] amino} -2,3-dihydro-1H -Inden-5-yl) oxy] methyl} benzoic acid (1.64 g) was dissolved in 15.00 ml of methanol, and 3.10 ml of 1M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 30 minutes. The crude crystals obtained by concentrating the reaction solution under reduced pressure were recrystallized from ethanol / isopropyl ether to give 4-{[(6-{[(3-methyloxetane-3-yl) methyl] [(4-methyl-1 1,3-thiazol-2-yl) sulfonyl] amino} -2,3-dihydro-1H-inden-5-yl) oxy] methyl} sodium benzoate 1.7hydrate 1.51 g was obtained.

  In the same manner as in the above Examples 1 to 4, the Example compounds shown in Tables 8 to 16 below were produced using the corresponding raw materials. Tables 8 to 16 show the structures and physicochemical data of the example compounds.

  Tables 17 and 18 show the structures of other compounds 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, especially frequent urination / urinary urgency and 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 carboxylic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.
R ¹ and R ² are the same or different from each other and are combined with H, halogen, lower alkyl, halogeno lower alkyl, —OH, —O-lower alkyl, or the carbon atom to which R ¹ and R ² are bonded. (1) cyclopentene, (2) cyclohexene, (3) cycloheptene, (4) cyclooctene, or (5) a benzene ring may be formed,
R ³ : —OH or —O-lower alkyl,
A: phenyl which may be substituted, or monocyclic heteroaryl which may be substituted,
B: an optionally substituted heterocyclic group,
C: optionally substituted phenyl, or optionally substituted monocyclic heteroaryl,
X: lower alkylene, lower alkenylene, -O-lower alkylene- *,
Or -lower alkylene-O- *,
Y: single bond, lower alkylene, lower alkenylene, or * -O-lower alkylene,
Z: lower alkylene,
However, * in X and Y represents a bond to the C ring. )