JP2010254641A - Azole carboxamide compound or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent acting based on an excellent action of inhibiting a trkA receptor and used for treating and/or preventing frequent urination, urinary urgency, and urinary incontinence involved in various lower urinary tract diseases including overactive bladder, various lower-urinary-tract-pain-accompanying lower urinary tract diseases such as interstitial cystitis and chronic prostatitis, and various pain-accompanying diseases. <P>SOLUTION: The present invention has been accomplished as the result of the confirmation that a new azole carboxamide compound in which a thiazole ring or an oxazole ring is bonded to a benzene ring, a pyridine ring, a pyrazole ring, or a like ring through a carboxamide or a salt thereof has potent trkA receptor inhibition activity and of the finding that it has possibility of acting as a highly effective and highly safe agent for treating and/or preventing frequent urination, urinary urgency, and urinary incontinence involved in various lower urinary tract diseases, various lower-urinary-tract-pain-accompanying diseases such as interstitial cystitis and chronic prostatitis, and various pain-accompanying diseases. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention is effective for pharmaceutical compositions, particularly pharmaceutical compositions for treating various urinary urinary tract diseases including overactive bladder, urinary urgency, urinary incontinence, lower urinary tract pain, and various diseases associated with pain. The present invention relates to an azolecarboxamide compound useful as a component.

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.
Nerve growth factor (NGF) is one of the humoral factors collectively called neurotrophic factor, and plays an important role in the generation, differentiation and maintenance of neurons in vivo. . NGF receptors are known as high affinity trkA receptor (receptor tyrosine kinase) and low affinity p75 receptor. Although p75 has been reported to bind to all neurotrophic factors and participate in apoptosis during neuronal development, its role has not been fully elucidated. NGF and trkA receptor knockout mice are known to exhibit similar phenotypes (Non-patent Document 1), and the physiological effects of NGF are thought to be expressed mainly via trkA receptors.

  It is known that patients with overactive bladder or interstitial cystitis have elevated NGF levels in the bladder (Non-Patent Document 2), and intravesical infusion of NGF reduces rat bladder capacity, It has been reported that NGF inhibition improves micturition function in pollakiuria model rats (Non-patent Document 3). In addition, since there is a report (Non-Patent Document 4) that NGF inhibition improved frequent urination and urinary incontinence in patients with interstitial cystitis, trkA receptor inhibitors are overactive bladder, interstitial cystitis, It is considered useful as a therapeutic agent for lower urinary tract diseases such as prostatitis.

In addition, since the mechanism of action of trkA receptor inhibitors is different, it can be expected to avoid side effects peculiar to anticholinergic drugs, and can 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 micturition pressure of the frequent urine model rat (Non-patent Document 5), and it can be expected that it can be safely administered to patients with benign prostatic hyperplasia and the elderly.
It is known that administration of NGF to humans and rats induces pain and lack of pain sensation in trkA receptor knockout mice. NGF is thought to be strongly involved in the development of pain in vivo. ing. NGF inhibition has been shown to be effective in model animals such as neuropathic pain and inflammatory pain such as the sciatic nerve injury-induced pain model (Non-patent document 6) and knee joint injury-induced pain model (Non-patent document 7). The receptor inhibitor is considered to be useful as a therapeutic agent for various pains such as lower urinary tract disease accompanied by lower urinary tract pain and osteoarthritis.

  Examples of such compounds include indolocarbazole derivatives (Non-patent Document 8), pyrrolocarbazole derivatives (Patent Document 1), pyrazolone derivatives (Patent Document 2), oxindole derivatives (Patent Documents 3 and 4), azaoxindole. Derivatives (Patent Document 5), pyrazolyl fused ring compounds (Patent Document 6), pyrazole derivatives (Patent Documents 7 and 8), tricyclic derivatives (Patent Document 9), ALE-0540 (Patent Document 10), benzo [de] An isoquinoline derivative (Patent Document 11), a benzo [lmn] phenanthroline derivative (Patent Document 12), and a pyrrolotriazine derivative (Patent Document 13) are known.

（式中の記号の意味は当該公報を参照。） Further, although an azolecarboxamide compound represented by the formula (A) is disclosed in Patent Document 14 as a trkA receptor inhibitor, a monocyclic or bicyclic alicyclic nitrogen-containing heterocycle which may be substituted with Q. The structure is different from the compound of the present invention in that it has a cyclic group.

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

International publication pamphlet WO01 / 14380 International publication pamphlet WO01 / 32653 International Publication Pamphlet WO02 / 20479 International publication pamphlet WO02 / 20513 International publication pamphlet WO03 / 027111 JP2003-231687 International Publication Pamphlet WO2005 / 049033 International Publication Pamphlet WO2005 / 103010 International publication pamphlet WO2005 / 076695 International publication pamphlet WO01 / 78698 International pamphlet WO2007 / 030939 International Publication Pamphlet WO2007 / 030934 International Publication Pamphlet WO2007 / 061882 International Publication Pamphlet WO2007 / 123269 “Reviews in the Neurosciences” (UK), 1997, Volume 8, pages 13-27 "British Journal of Urology" (UK), 1997, 79, p.572-7 “Neuroscience” (USA), 1997, Vol. 78, No. 2, p.449-59 "Proceedings of the 99th Annual Meeting of the American Urological Association", San Francisco, 2004, # 363 "The Journal of Urology" (USA), 2005, 173, p.1016-21 "Pain", (USA), 1999, Vol. 81, p.245-55 "Pain", (USA), 2005, 116, p.8-16 “Cancer Research”, 1999, Vol. 59, p.2395-2401

  As described above, the therapeutic agents for various lower urinary tract diseases accompanied by lower urinary tract pain such as interstitial cystitis and chronic prostatitis such as frequent urination, urgency, urinary incontinence associated with existing overactive bladder are effective. However, there is nothing satisfactory in terms of safety and the like, and there is an urgent need to provide a therapeutic agent for lower urinary tract diseases that is excellent in effectiveness and safety.

（式中の記号は以下の意味を有する。
Ｘ：Ｓ又はＯ、
Ｒ¹：

Ｒ^1a：Ｈ、−ＯＨ、−Ｏ−低級アルキル又は−Ｏ−シクロアルキル、
Ｒ^1b：Ｆ又は−Ｏ−低級アルキル、
Ｒ^1c：Ｈ又は低級アルキル、
Ｒ^1d：−Ｏ−低級アルキルで置換されてもよい低級アルキル、
Ｒ²：Ｈ、（Ｆ若しくは−Ｏ−低級アルキル）で置換されてもよい低級アルキル、３−テトラヒドロフリル又は４−テトラヒドロピラニル、
Ａ：

Ｒ³：Ｒ^3A又は−ＣＨ₂−Ｒ^3B、
Ｒ^3A：−ＣＯ₂Ｍｅ又は下記環基、

Ｒ⁰⁰：低級アルキル、
Ｒ^3B：−ＯＨ、−Ｏ−低級アルキル又は下記群から選択される環基、

Ｒ⁰：Ｈ又は低級アルキル、
ｍ：１又は２、
Ｒ^a：Ｈ、Ｆ、フェニル又は−低級アルキレン−Ｏ−低級アルキル、
Ｒ^b：Ｈ又はＦ、
Ｒ⁴: −Ｏ−低級アルキルで置換されてもよい低級アルキル。）
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。 As described above, the trkA receptor inhibitor is expected to be a highly safe therapeutic agent for lower urinary tract disease with few side effects such as dry mouth and urinary retention. Therefore, the present inventors have intensively studied compounds having trkA receptor inhibitory 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 the azolecarboxamide compound represented by the following formula (I) has a potent trkA receptor inhibitory action, and the present invention was completed.
That is, this invention relates to the pharmaceutical composition containing the compound or its salt of a formula (I), or its salt, and an excipient | filler, and an excipient | filler.

(The symbols in the formula have the following meanings.
X: S or O,
R ¹ :

R ^1a : H, —OH, —O-lower alkyl or —O-cycloalkyl,
R ^1b : F or —O-lower alkyl,
R ^1c : H or lower alkyl,
R ^1d : lower alkyl optionally substituted by —O-lower alkyl,
R ² : H, lower alkyl optionally substituted with (F or —O-lower alkyl), 3-tetrahydrofuryl or 4-tetrahydropyranyl,
A:

R ³ : R ^3A or —CH ₂ —R ^3B ,
R ^3A: -CO ₂ Me or the following cyclic groups,

R ⁰⁰ : lower alkyl,
R ^3B : —OH, —O-lower alkyl, or a cyclic group selected from the following group:

R ⁰ : H or lower alkyl,
m: 1 or 2,
R ^a : H, F, phenyl or -lower alkylene-O-lower alkyl,
R ^b : H or F,
R ⁴ : lower alkyl optionally substituted with —O-lower alkyl. )
Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.

The present invention also provides frequent urination, urgency, urinary incontinence, lower urinary tract pain, and various types of pain associated with various lower urinary tract diseases including overactive bladder containing a compound of formula (I) or a salt thereof. Pharmaceutical compositions for the treatment of diseases, i.e. frequent urination, urgency, urinary incontinence, lower urinary tract pain associated with various lower urinary tract diseases including overactive bladder containing a compound of formula (I) or a salt thereof, and The present invention relates to a therapeutic agent for various diseases accompanied by pain.
The present invention also provides a pharmaceutical composition for treating various urinary urinary tract diseases including overactive bladder, urinary urgency, urinary incontinence, lower urinary tract pain, and various diseases associated with pain. Use of a compound of the formula (I) or a salt thereof, and frequent urination and urinary urinary tract associated with various lower urinary tract diseases including overactive bladder comprising administering an effective amount of the compound of the formula (I) or a salt thereof The present invention relates to a method for treating urgency, urinary incontinence, lower urinary tract pain, and various diseases associated with pain.

  The compound of the formula (I) or a salt thereof has potent trkA receptor inhibitory activity in vitro and potent NGF inhibitory activity in vivo, frequent urination associated with various lower urinary tract diseases including overactive bladder, It can be used as a therapeutic and / or prophylactic agent for various lower urinary tract diseases accompanied by lower urinary tract pain such as interstitial cystitis and chronic prostatitis, and various diseases accompanied by pain, such as urinary urgency, urinary incontinence.

Hereinafter, the present invention will be described in detail.
In the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ) unless otherwise specified.
“Lower alkyl” means C _1-6 alkyl, for example, linear alkyl such as methyl, ethyl, n-propyl, n-butyl, etc., and branched such as isopropyl, isobutyl, tert-butyl, neopentyl, etc. Of alkyl. Another embodiment is C _1-4 alkyl, and yet another embodiment is methyl, ethyl, n-propyl or isopropyl. “Lower alkylene” is a divalent group formed by removing any hydrogen atom of C _1-6 alkyl. For example, methylene, ethylene, methylmethylene, ethylmethylene, methylethylene, dimethylmethylene, trimethylene, tetramethylene, Dimethylethylene, pentamethylene, 2,2-dimethyltrimethylene and the like. Another embodiment is C _1-3 alkylene, and yet another embodiment is methylene, ethylene, methylmethylene, methylethylene, dimethylmethylene or trimethylene.
“Cycloalkyl” is a C _3-10 saturated hydrocarbon ring group, which may have a bridge. Another embodiment is C _3-8 cycloalkyl, and yet another embodiment is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of the cycloalkyl having a bridge include bicyclo [2.2.1] heptyl, adamantyl and the like.

“Optionally substituted” means “unsubstituted” or “substituted with 1 to 5, preferably 1 or 2 substituents, the same or different” When substituted with a substituent, the substituents may be the same or different from each other, and may be substituted on the same atom. In the formula (I), when m is 2, two R ^{0 s} and two R ^{a s} may be the same or different from each other, and bonded to the same or different carbon atoms of the ring group to which they are bonded. May be.

である化合物。
（４）Ｒ¹が、３位が−ＯＨ、−Ｏ−低級アルキル及び−Ｏ−シクロアルキルからなる群から選択される１つの基で置換されてもよいアゼチジノである化合物。
（５）Ｒ¹が３−メトキシアゼチジノである化合物。
（６）Ｒ²が、（Ｆ若しくは−Ｏ−低級アルキル）で置換された低級アルキル、３−テトラヒドロフリル又は４−テトラヒドロピラニルである化合物。
（７）Ｒ²が、２−メトキシエチル、３−フルオロプロピル又は３−テトラヒドロフリルである化合物。
（８）Ａが下記である化合物。

（ここで、Ｒ³はＲ^3A又は−ＣＨ₂−Ｒ^3Bであり、Ｒ^3Aは−ＣＯ₂Ｍｅ又は環基；

であり、Ｒ⁰⁰はメチル又はエチルであり、Ｒ^3Bは−Ｏ−低級アルキル又は下記群から選択される環基；

であり、Ｒ⁰はＨ又はメチルであり、ｍは１又は２であり、Ｒ^aはＨ、Ｆ、フェニル又はメトキシメチルであり、Ｒ^bはＨ又はＦである。）
（９）Ａが下記である化合物。

（１０）上記（１）〜（９）に記載の基のうち、二以上の組み合わせである化合物。
上記（１０）における組み合わせの態様としては、例えば、上記（１）、（５）、（７）及び（９）の組み合わせである式（Ｉ−Ａ）の化合物が挙げられる。

（式中の記号は以下の意味を有する。
Ｒ⁵：下記群から選択される環基、

Ｒ⁶：２−メトキシエチル、３−フルオロプロピル又は３−テトラヒドロフリル。） Certain embodiments of the compound of formula (I) in the present invention are shown below.
(1) A compound wherein X is S.
(2) A compound in which X is O.
(3) R ¹ is a group;

A compound that is
(4) The compound wherein R ¹ is azetidino which may be substituted at the 3-position with one group selected from the group consisting of —OH, —O-lower alkyl and —O-cycloalkyl.
(5) The compound wherein R ¹ is 3-methoxyazetidino.
(6) The compound wherein R ² is lower alkyl, 3-tetrahydrofuryl or 4-tetrahydropyranyl substituted with (F or —O-lower alkyl).
(7) The compound wherein R ² is 2-methoxyethyl, 3-fluoropropyl or 3-tetrahydrofuryl.
(8) A compound in which A is the following.

(Where R ³ is R ^3A or —CH ₂ —R ^3B , and R ^3A is —CO ₂ Me or a cyclic group;

In and, R ⁰⁰ is methyl or ethyl, ring R ^3B is selected from -O- lower alkyl or the following group;

R ⁰ is H or methyl, m is 1 or 2, R ^a is H, F, phenyl or methoxymethyl, and R ^b is H or F. )
(9) A compound in which A is the following.

(10) A compound that is a combination of two or more of the groups described in (1) to (9) above.
Examples of the combination in (10) above include compounds of the formula (IA) which are combinations of the above (1), (5), (7) and (9).

(The symbols in the formula have the following meanings.
R ⁵ : a ring group selected from the following group,

R ⁶ : 2-methoxyethyl, 3-fluoropropyl or 3-tetrahydrofuryl. )

  In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof. In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  Furthermore, the present invention includes pharmaceutically acceptable prodrugs of the compound of formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

  The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there. 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 Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

  Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

(Production method)
The compound of the formula (I) and salts thereof can be produced by applying various known synthesis methods utilizing 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 replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is. Examples of such protecting groups include protecting groups described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by Greene and Wuts. What is necessary is just to select suitably according to reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
In addition, the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of formula (I). Can be manufactured. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.

本工程は、化合物（２）又はその反応性誘導体と、化合物（１）又はその塩とを、常法によりアミド化することにより、式（Ｉ）の化合物を製造する工程である。
化合物（２）の反応性誘導体としては、メチルエステル、エチルエステル、tert-ブチルエステルなどの通常のエステル；酸クロリド、酸ブロミド等の酸ハライド；酸アジド；1-ヒドロキシベンゾトリアゾール、p-ニトロフェノールやN-ヒドロキシスクシンイミド等との活性エステル；対称型酸無水物；アルキル炭酸ハライド等のハロカルボン酸アルキルエステル、ピバロイルハライド、p-トルエンスルホン酸クロリド等との混合酸無水物；塩化ジフェニルホスホリル、N-メチルモルホリンとを反応させて得られるリン酸系混合酸無水物等の混合酸無水物等が挙げられる。
化合物（２）を遊離酸で反応させる場合、あるいは活性エステルを単離せずに反応させる場合等は当業者が通常用いうるアミド化を採用することができるが、1-ヒドロキシベンゾトリアゾール（HOBt）存在下、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（WSC・HCl）や、ジシクロヘキシルカルボジイミド（DCC）、カルボニルジイミダゾール（CDI）、ジフェニルホスホリルアジド（DPPA）、ジエチルホスホリルシアニド（DEPC）、O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウム ヘキサフルオロホスフェート（HATU）、N,N,N',N'-テトラメチルフルオロホルムアミジニウム ヘキサフルオロホスフェート（TFFH）等の縮合剤を作用させる方法、又はオキシ塩化リンをピリジン溶媒中で作用させる方法が好適に用いられる。 (First manufacturing method)

This step is a step for producing a compound of formula (I) by amidating compound (2) or a reactive derivative thereof with compound (1) or a salt thereof by a conventional method.
Examples of reactive derivatives of the compound (2) include ordinary esters such as methyl ester, ethyl ester and tert-butyl ester; acid halides such as acid chloride and acid bromide; acid azide; 1-hydroxybenzotriazole and p-nitrophenol. Active esters with N, N-hydroxysuccinimide, etc .; symmetrical acid anhydrides; halocarboxylic acid alkyl esters such as alkyl carbonate halides, mixed acid anhydrides with pivaloyl halide, p-toluenesulfonic acid chloride, etc .; diphenylphosphoryl chloride, Examples thereof include mixed acid anhydrides such as phosphoric acid mixed acid anhydrides obtained by reacting with N-methylmorpholine.
In the case of reacting compound (2) with a free acid, or in the case of reacting without isolating the active ester, amidation which can be usually used by those skilled in the art can be adopted, but 1-hydroxybenzotriazole (HOBt) is present. Below, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC / HCl), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide ( DEPC), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), N, N, N', N'-tetramethyl A method in which a condensing agent such as fluoroformamidinium hexafluorophosphate (TFFH) is allowed to act or a method in which phosphorus oxychloride is allowed to act in a pyridine solvent is preferably used.

In particular, in the present invention, the acid chloride method and the method of reacting in the presence of an active esterifying agent and a condensing agent are simple.
The reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as methylene chloride, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; ether, tetrahydrofuran (THF) Ethers such as ethyl acetate (EtOAc), etc .; Organics inert to reactions such as acetonitrile, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO) The reaction is carried out in a solvent under cooling, cooling to room temperature, or room temperature to heating.
In the reaction, the compound (1) is used in excess, or N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, In some cases, the reaction in the presence of a base such as lutidine is advantageous for allowing the reaction to proceed smoothly. Further, a salt composed of a weak base and a strong acid such as pyridine hydrochloride, pyridine p-toluenesulfonate, N, N-dimethylaniline hydrochloride may be used. Pyridine can also be used as a solvent.
In particular, the reaction is preferably carried out in the presence of a base such as triethylamine in a solvent such as THF or DMF.

（上記式中、Lv¹は脱離基を示し、好ましくはハロゲン、−ＳＭｅ、−ＳＯＭｅ、−ＳＯ₂Ｍｅ、−ＳＯ₃Ｈ又は−Ｏ−ＳＯ₂ＣＦ₃である。以下同様。）
本工程はチアゾール２位に脱離基を有する化合物（３）と１級又は２級アミン化合物（４）を反応させることにより、式（Ｉ）においてＸがＳである化合物（Ｉ−ａ）を製造する工程である。なお、化合物（３）は第１製法に準じて製造することができる。
本工程の求核置換反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、エステル類、メタノール、エタノール、イソプロパノール等のアルコール類、アセトニトリル、DMF、DMA、DMSO等の反応に不活性な有機溶媒中、トリエチルアミン、ジイソプロピルエチルアミン等の有機塩基、及び/又は炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素ナトリウム、水素化ナトリウム等の無機塩基存在下に行うことができる。なお、反応を加速させるために、4-(N,N-ジメチルアミノ)ピリジン等の触媒を加えてもよい。また、有機塩基及び/又は無機塩基に代えて、化合物(４)を過剰に用いてもよい。反応は用いる塩基によって異なるが、冷却乃至室温下、室温下乃至加熱下、室温下乃至還流下に行うことができる。 (Second manufacturing method)

(In the above formula, Lv ¹ represents a leaving group, preferably halogen, —SMe, —SOMe, —SO ₂ Me, —SO ₃ H or —O—SO ₂ CF _{3. The same} applies hereinafter.)
In this step, compound (Ia) in which X is S in formula (I) is obtained by reacting compound (3) having a leaving group at the 2-position of thiazole with primary or secondary amine compound (4). It is a manufacturing process. Compound (3) can be produced according to the first production method.
The nucleophilic substitution reaction in this step is inert to reactions such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols such as methanol, ethanol, isopropanol, acetonitrile, DMF, DMA, DMSO, etc. In an organic solvent in the presence of an organic base such as triethylamine and diisopropylethylamine and / or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride. In order to accelerate the reaction, a catalyst such as 4- (N, N-dimethylamino) pyridine may be added. In addition, in place of the organic base and / or inorganic base, the compound (4) may be used in excess. The reaction varies depending on the base used, but can be carried out under cooling to room temperature, from room temperature to heating, or from room temperature to reflux.

本工程は、化合物（５）と化合物（６）よりアミド化反応を行い、式（Ｉ）の化合物を製造する工程である。本工程のアミド化反応は第１製法に準じて行うことができる。 (3rd manufacturing method)

This step is a step for producing a compound of the formula (I) by carrying out an amidation reaction from the compound (5) and the compound (6). The amidation reaction in this step can be performed according to the first production method.

(4th manufacturing method)
Furthermore, the compounds having various functional groups represented by the formula (I) are known alkylation, acylation, substitution reaction, oxidation, reduction from the compounds obtained by the first production method, the second production method or the third production method. It can be produced by arbitrarily combining processes that can be usually employed by those skilled in the art, such as hydrolysis. This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction. Further, these steps that can be usually employed by those skilled in the art are not limited to the application to the compound of the formula (I), but can also be applied to the production intermediate.
A typical reaction is shown below.
(1) Amination Of the compounds of formula (I), compounds having secondary amines and tertiary amines are made from compounds having alkyl halides or organic sulfonate esters of alcohols as raw materials, and other primary amines and secondary amines. It can manufacture by making it react with the compound which has this. The reaction can be performed with reference to, for example, “Chemical Experiment Course (4th edition)” edited by The Chemical Society of Japan, Volume 20 (1992) (Maruzen).
(2) Reductive alkylation Among the compounds of formula (I), compounds having secondary amines and tertiary amines may be used in the presence of a reducing agent such as sodium borohydride or sodium triacetoxyborohydride, or in a hydrogen atmosphere. An alkyl group can be introduced by a reductive alkylation reaction with an aldehyde or a ketone using a compound having a primary amine or a secondary amine as a raw material under catalytic reduction conditions such as palladium on carbon. For example, the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th edition)”, Volume 20 (1992) (Maruzen) can be used.
(3) Reduction Among the compounds of formula (I), a compound having a primary alcohol can be produced by a reduction reaction of a compound having a corresponding carboxyl group or ester group. The reaction can be performed with reference to, for example, the method described in “Chemical Experiment Course (4th edition)” volume 26 (1992) (Maruzen) edited by the Chemical Society of Japan.

  The raw material compound used for the production of the compound of formula (I) is produced using, for example, the following method, the method described in the after-mentioned production examples, a known method, a method obvious to those skilled in the art, or a modified method thereof. Can do.

（上記式中、Ｒは低級アルキルを示す。以下同様。）
工程1
本工程は化合物（７）を加水分解して化合物（８）を製造する工程である。本工程の加水分解反応は、例えば前記の「Protective Groups in Organic Synthesis(第3版、1999年)」に記載の脱保護反応に準じて行うことができる。
工程２
本工程は化合物（８）をアミド化して化合物（１）を製造する工程である。本工程のアミド化反応は第１製法に準じて行うことができる。 (Raw material synthesis 1)

(In the above formula, R represents lower alkyl. The same shall apply hereinafter.)
Process 1
This step is a step of producing compound (8) by hydrolyzing compound (7). The hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in “Protective Groups in Organic Synthesis (3rd edition, 1999)”.
Process 2
In this step, compound (8) is amidated to produce compound (1). The amidation reaction in this step can be performed according to the first production method.

（上記式中、Ｌはカルボン酸の保護基を示す。以下同様。）
工程１
本工程は化合物（９）のチアゾール環２位にて置換反応を行い化合物（１０）を製造する工程である。本工程の置換反応は第２製法と同様の方法で行うことができる。
工程２
本工程はカルボン酸エステル（１０）を加水分解して化合物（２ａ）を製造する工程である。本工程の加水分解反応は原料合成１の工程１と同様の方法で行うことができる。 (Raw material synthesis 2)

(In the above formula, L represents a carboxylic acid protecting group. The same shall apply hereinafter.)
Process 1
This step is a step for producing a compound (10) by carrying out a substitution reaction at the 2-position of the thiazole ring of the compound (9). The substitution reaction in this step can be performed by the same method as in the second production method.
Process 2
This step is a step of producing the compound (2a) by hydrolyzing the carboxylic acid ester (10). The hydrolysis reaction in this step can be performed in the same manner as in step 1 of raw material synthesis 1.

工程１
本工程は、チオ尿素若しくは尿素（１１）に対し、ブロモピルビン酸エステル等に代表されるα-ハロケトンを作用させてチアゾール環若しくはオキサゾール環を構築する方法である。「Comprehensive Organic Chemistry」第４巻、Turchi編「Heterocyclic Compounds」第45巻又はPalmer編「Heterocyclic Compounds」第60巻 partAに記載された方法又はそれらに準じた方法を採用することができる。また、環化反応促進の為、無水トリフルオロ酢酸等の酸を添加するのが好ましい場合がある。
工程２
本工程は、カルボン酸エステル（１２）を加水分解してカルボン酸（２）を製造する工程である。本工程の加水分解反応は原料合成１の工程１と同様の方法で行うことができる。 (Raw material synthesis 3)

Process 1
This step is a method for constructing a thiazole ring or an oxazole ring by reacting thiourea or urea (11) with an α-haloketone represented by bromopyruvate or the like. The methods described in “Comprehensive Organic Chemistry”, Vol. 4, Turchi, “Heterocyclic Compounds”, Vol. 45, or Palmer, “Heterocyclic Compounds”, Vol. 60, part A can be employed. In addition, it may be preferable to add an acid such as trifluoroacetic anhydride to accelerate the cyclization reaction.
Process 2
This step is a step of producing the carboxylic acid (2) by hydrolyzing the carboxylic acid ester (12). The hydrolysis reaction in this step can be performed in the same manner as in step 1 of raw material synthesis 1.

工程１
本工程はニトロ化合物（１３）を還元して化合物（６）を製造する工程である。本工程のニトロ基の還元反応は当業者が通常採用しうるニトロ基の還元反応を用いることができる。例えば、還元鉄、塩化スズ等の還元剤を用いた還元反応や、パラジウム炭素、ロジウム炭素等を触媒とした水素添加反応が挙げられる。反応は、例えば日本化学会編「実験化学講座(第４版)」26巻（1992年）(丸善)に記載の方法を参考に実施できる。
工程２
本工程は、化合物（７）と化合物（２）よりアミド化反応を行い、化合物（１４）を製造する工程である。本工程のアミド化反応は第１製法に準じて行うことができる。
工程３
本工程は化合物（１４）を加水分解して化合物（５）を製造する工程である。本工程の加水分解反応は原料合成１の工程１と同様の方法で行うことができる。 (Raw material synthesis 4)

Process 1
This step is a step of producing the compound (6) by reducing the nitro compound (13). 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, rhodium carbon and the like as a catalyst. The reaction can be performed with reference to, for example, the method described in “Chemical Experiment Course (4th edition)” volume 26 (1992) (Maruzen) edited by the Chemical Society of Japan.
Process 2
This step is a step of producing a compound (14) by carrying out an amidation reaction from the compound (7) and the compound (2). The amidation reaction in this step can be performed according to the first production method.
Process 3
This step is a step of producing the compound (5) by hydrolyzing the compound (14). The hydrolysis reaction in this step can be performed in the same manner as in step 1 of raw material synthesis 1.

The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances. The salt of the compound of formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

The pharmacological activity of the compound of formula (I) was confirmed by the following test.
Test Example 1 Measurement experiment of trkA receptor inhibitory activity using nerve growth factor receptor (trkA receptor) expressing cells
The trkA receptor inhibitory activity was measured using an increase in ligand-dependent intracellular calcium concentration as an index. The HEK293 cells (American Type Culture Collection) stably expressing the human trkA receptor were transferred to 96 wells so that the concentration was 2 × 10 ⁴ cells / well the day before the experiment. -D- lysine - coated plate (trade name: Bio-coat PDL96W black / clear, Nippon Becton Dickinson) to dispensed, 37 ℃, with 5% carbon dioxide (CO ₂₎ below, 10% fetal bovine serum (FBS ) In a medium (trade name: DMEM, Invitrogen) containing Washing medium containing loading buffer (1.5 μM fluorescent labeling reagent (trade name: Fluo4-AM, Dojindo)): Hank's balanced salt solution (HBSS), 20 mM 2- [4- (2-hydroxyethyl) -1- [Piperazinyl] ethanesulfonic acid (HEPES) -sodium hydroxide (NaOH), 2.5 mM probenecid, 0.1% bovine serum albumin (BSA)) Name: 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, nerve growth factor (NGF, mouse-derived 2.5S, Allomone) corresponding to 80% stimulation of the maximum response is added (about 100-150 ng / ml as the final concentration), and the intracellular Ca concentration change 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 IC ₅₀ value was calculated as the concentration that inhibits 50%, assuming 0% when NGF was added and 100% when buffer was added. The results of some example compounds are shown in Table 1 below. In the table, Ex represents an Example compound number described later (the same applies hereinafter). As a result of this test, it was confirmed that the following representative compounds of the present invention have trkA receptor inhibitory action.

Test Example 2 Evaluation of Compound Inhibitory Activity on Rat NGF-Induced Vascular Permeability The in vivo NGF inhibitory activity of the compound was examined. Wistar female rats (Japan SLC) were forcibly orally administered with a compound (0.5% methylcellulose solution) 10 mg / 3 ml / kg or a solvent (0.5% methylcellulose solution) 3 ml / kg. 60 or 90 minutes after administration under physiological anesthesia, physiological saline or 1 μg / ml NGF (NGF, mouse-derived 2.5S, Allomone) was intradermally administered at 50 μl / site on the back and immediately afterwards 1% Evans Blue solution (dissolved in physiological saline) was administered at 3 ml / kg from the tail vein. Ten minutes after administration, the back skin was collected and shaken in formamide for 16 hours. After shaking, the absorbance of Evans blue extracted in formamide was measured with an absorptiometer (wavelength 620 nm), and the concentration was calculated by a calibration curve method. The value obtained by subtracting the Evans blue concentration at the saline administration site from the Evans blue concentration at the NGF administration site was defined as NGF-dependent action, and the inhibition rate of the compound group was calculated when the solvent administration group was 100%. The results are shown in Table 2 below. In the table, NT indicates that it has not been evaluated. In this test, it was confirmed that the following representative compounds of the present invention have an excellent inhibitory action on rat NGF-induced vascular permeability enhancement.

  As a result of the above test, it was confirmed that the compound of the formula (I) has a strong trkA receptor inhibitory activity in vitro and a strong NGF inhibitory activity in vivo. Therefore, it is clear that it shows an action for improving frequent urination and pain (see Patent Document 14), frequent urination associated with various lower urinary tract diseases including overactive bladder, urgency, urinary incontinence, and It can be used as a therapeutic and / or prophylactic agent for various lower urinary tract diseases accompanied by lower urinary tract pain such as interstitial cystitis and chronic prostatitis, and various diseases accompanied by pain such as osteoarthritis.

A pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is usually prepared using a pharmaceutical excipient, a drug-soluble carrier or the like that is usually used in the art. It can be prepared by the method used.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or 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 or suspending it in sterile water or a sterile solvent for injection before use.

  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. 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 administration, 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.

  In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

  Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is demonstrated as a manufacture example. In addition, the manufacturing method of the compound of Formula (I) is not limited only to the manufacturing method of the specific Example shown below, The compound of Formula (I) is a combination of these manufacturing methods, or those skilled in the art. It can also be produced by methods that are self-evident.

Moreover, the following abbreviations may be used in Examples, Production Examples, and Tables below.
Pre: Production example number, Ex: Example number, Str: Structural formula, Syn: Production method (In the examples / production examples, production number or example number produced in the same manner is shown. Here, P represents production. For example, E indicates an example, for example, indicates that the compound of Preparation Example 40 was prepared in the same manner as the compound of Preparation Example 1, and the compound of Example 7 was prepared in the same manner as the compound of Example 4. In addition, when a plurality of production methods are described, it indicates that the reaction was carried out in that order.), Dat: Physicochemical data (NMR1: ¹ H-NMR in DMSO-d6) [delta] (ppm) in, NMR2: δ in ¹ H-NMR in _{CDCl 3 (ppm), NMR3:} δ in ¹ H-NMR in _{CD 3 OD (ppm), MS} : mass spectrometry value), Sal: salt ( The compounds not mentioned mean free forms: Fum: fumarate, 1.5Fum: 1.5 fumarate, 2Fum: 2 fumarate), Me: methyl, Et: ethyl, nPr: n- Propyl, Ph: phenyl, Bn: benzyl, Boc: tert-butoxycarbonyl.

Production Example 1
To a mixture of 200 mg of methyl 5- (bromomethyl) -2-nitrobenzoate and 2 ml of DMF, 127 μl of morpholine was added and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and 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 = 80: 20-0: 100), and methyl 5- (morpholin-4-ylmethyl) -2-nitrobenzoate. 192 mg was produced.
Production Example 2
To a mixture of 190 mg of methyl 5- (morpholin-4-ylmethyl) -2-nitrobenzoate, 3.8 ml of methanol and 950 μl of water, 113 mg of iron and 18 mg of ammonium chloride were added and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. A saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated 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 (chloroform: methanol = 100: 0-40: 1) to obtain a solid. This was suspended in a mixed solvent of hexane-ethyl acetate (3: 1) and collected by filtration to produce 95 mg of methyl 2-amino-5- (morpholin-4-ylmethyl) benzoate.

Production Example 3
To a mixture of 2.02 g of 3-methoxyazetidine hydrochloride and 20 ml of DMA, 6.59 ml of triethylamine and 3.50 g of methyl 2-bromo-1,3-thiazole-4-carboxylate were added and heated at 100 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and 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 = 2: 1-1: 1) to give 2- (3-methoxyazetidin-1-yl) -1, 2.84 g of methyl 3-thiazole-4-carboxylate was produced.
Production Example 4
To a mixture of 2.83 g of methyl 2- (3-methoxyazetidin-1-yl) -1,3-thiazole-4-carboxylate, 30 ml of THF, and 30 ml of methanol, 37.1 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature. Stir for hours. The solvent was distilled off under reduced pressure, neutralized with 1M hydrochloric acid under ice cooling, and then the solvent was distilled off under reduced pressure. Ethanol was added to the residue, the precipitated salt was filtered off, and the filtrate was distilled off under reduced pressure to produce 2.60 g of 2- (3-methoxyazetidin-1-yl) -1,3-thiazole-4-carboxylic acid did.

Production Example 5
To a mixture of 2.85 g 2- (3-methoxyazetidin-1-yl) -1,3-thiazole-4-carboxylic acid and 20 ml DMF, 2.00 g methyl 2-amino-5- (morpholin-4-ylmethyl) benzoate , HOBt 1.72 g, WSC · HCl 2.45 g and triethylamine 2.23 ml were added, and the mixture was stirred at 50 ° C. for 4 days and at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 80 ml of water and 20 ml of saturated aqueous sodium hydrogen carbonate solution were added and stirred for 16 hours, and the precipitated solid was collected by filtration to give 2-({[2- (3-methoxyazetidine-1- 2.55 g of methyl) yl) -1,3-thiazol-4-yl] carbonyl} amino) -5- (morpholin-4-ylmethyl) benzoate was prepared.
Production Example 6
2-({[2- (3-methoxyazetidin-1-yl) -1,3-thiazol-4-yl] carbonyl} amino) -5- (morpholin-4-ylmethyl) benzoate 200 mg, THF 1 ml and To a mixture of 1 ml of methanol was added 493 μl of 4M aqueous sodium hydroxide solution, and the mixture was stirred at 50 ° C. for 13 hours. The reaction mixture was cooled to room temperature, 493 μl of 1M hydrochloric acid was added, and the precipitated solid was collected by filtration to give 2-({[2- (3-methoxyazetidin-1-yl) -1,3-thiazol-4- Ile] carbonyl} amino) -5- (morpholin-4-ylmethyl) benzoic acid 152 mg was prepared.
Production Example 7
2-({[2- (3-methoxyazetidin-1-yl) -1,3-thiazol-4-yl] carbonyl} amino) -5- (morpholin-4-ylmethyl) benzoate 100 mg and 1, To a mixture of 2 ml of 2-dichloroethane, 30 μl of ethyl chloroformate was added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, water was added, chloroform was added for extraction, and the organic layer was washed with saturated brine and 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 = 4: 1) to give 5- (chloromethyl) -2-({[2- (3-methoxyazetidine 60 mg of methyl -1-yl) -1,3-thiazol-4-yl] carbonyl} amino) benzoate was prepared.

Production Example 8
1.40 g of cesium carbonate and 5- (chloromethyl) -2-({[2- (3-methoxyazetidin-1-yl) -1 in a mixture of 305 mg and DMF 7 ml with 1,3,3-trimethylpiperazine dihydrochloride , 3-Thiazol-4-yl] carbonyl} amino) methyl benzoate (500 mg) was added, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-({[2- (3-methoxyazetidin-1-yl) -1,3-thiazol-4-yl] carbonyl} amino) -5-[(2,2, 615 mg of methyl 4-trimethylpiperazin-1-yl) methyl] benzoate was produced.
Production Example 9
To a mixture of methyl 4- (bromomethyl) -2-nitrobenzoate (4.00 g) and 1,2-dichloroethane (40 ml), ethanol (1.71 ml) and silver oxide (5.00 g) were added and stirred at room temperature for 16 hours, and morpholine (5 ml) was added for another 3 hours. Stir. 50 ml of ethanol was added to the reaction mixture and filtered through celite, and the filtrate was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then 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 = 20: 1-8: 1) to produce 880 mg of methyl 5- (ethoxymethyl) -2-nitrobenzoate. did.

Production Example 10
To a solution of 2-amino-5- (methoxycarbonyl) benzoic acid 12.4 g in DMF (60 ml), add WSC / HCl 12.20 g, HOBt 8.60 g, triethylamine 8.87 ml and 2-methoxyethylamine 5.49 ml, and stir at room temperature for 70 hours. did. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and 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 = 1: 11-1: 3) to give 4-amino-3-[(2-methoxyethyl) carbamoyl] benzoate. 10.4 g of methyl acid was produced.
Production Example 11
To a mixture of (3S) -3- (methoxymethyl) morpholine hydrochloride 2.50 g, toluene 40 ml and THF 20 ml were added triethylamine 2.50 ml and benzoyl isothiocyanate 2.02 ml and stirred at room temperature for 5 hours. The solvent was distilled off 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 anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to produce 3.74 g of N-{[(3S) -3- (methoxymethyl) morpholin-4-yl] carbonothioyl} benzamide.
Production Example 12
To a mixture of N-{[(3S) -3- (methoxymethyl) morpholin-4-yl] carbonothioyl} benzamide 3.73g and ethanol 40ml, add 9.8M methylamine / methanol solution 40ml and stir at room temperature for 14 hours did. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to produce 2.81 g of (3S) -3- (methoxymethyl) morpholine-4-carbothioamide. .

Production Example 13
1.75 ml of ethyl α-bromopyruvate was added dropwise to a mixture of 2.80 g of (3S) -3- (methoxymethyl) morpholine-4-carbothioamide and 60 ml of ethanol, and the mixture was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was stirred for 15 minutes and extracted with ethyl acetate. The organic layer was washed with saturated brine and 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 = 8: 1-2: 1) to give 2-[(3S) -3- (methoxymethyl) morpholine-4 3.09 g of ethyl -yl] -1,3-thiazole-4-carboxylate was produced.
Production Example 14
To a mixture of 1.00 g of methyl 4-nitro-1H-pyrazole-3-carboxylate benzoate and 30 ml of DMF were added 2.42 g of potassium carbonate and 0.61 ml of 2-bromoethyl methyl ether, and the mixture was stirred at room temperature for 5 hours. After adding water to the reaction mixture, the organic solvent was distilled off under reduced pressure and extracted with chloroform. The organic layer was washed with 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 (chloroform: methanol = 99: 1-90: 10), and 1- (2-methoxyethyl) -4-nitro-1H-pyrazole- 1.17 g of methyl 3-carboxylate was produced.
Production Example 15
1- (2-methoxyethyl) -4-nitro-1H-pyrazole-3-carboxylate 1.17 g of methanol 40 ml solution was added with 10% palladium carbon 117 mg under argon atmosphere, and then at room temperature under hydrogen atmosphere at room temperature. Stir for hours. The reaction mixture was purged with argon, and the catalyst was filtered off through Celite filtration. The filtrate was distilled off under reduced pressure to produce 782 mg of methyl 4-amino-1- (2-methoxyethyl) -1H-pyrazole-3-carboxylate. .

Production Example 16
To a mixture of 4.5 g of methyl 5-bromo-2-nitrobenzoate and 45 ml of toluene, add 5.54 ml of tributylvinyltin, 1.16 g of tri-o-tolylphosphine and 1.58 g of tris (dibenzylideneacetone) dipalladium, and add 100 ° C. For 2 hours. The reaction mixture was cooled to room temperature, 50 ml of diethyl ether, 5.03 g of potassium fluoride and 1 ml of water were added and stirred for 30 minutes, followed by Celite filtration, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-10: 1) to produce 4.54 g of methyl 2-nitro-5-vinylbenzoate.
Production Example 17
To a mixture of 2.5 g of methyl 2-nitro-5-vinylbenzoate and 75 ml of methylene chloride, 5.55 g of m-chloroperbenzoic acid was added and stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated 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 (hexane: ethyl acetate = 100: 0-2: 1) to give 1.55 g of methyl 2-nitro-5-oxiran-2-ylbenzoate Manufactured.
Production Example 18
To a mixture of 250 mg of methyl 2-nitro-5-oxiran-2-ylbenzoate and 3 ml of methanol, 269 μl of 2- (methylamino) ethanol was added and stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with a chloroform-methanol mixed solvent (5: 1). The organic layer was washed with saturated 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 (chloroform: methanol = 100: 0-10: 1) to give 5- {1-hydroxy-2-[(2-hydroxyethyl) ( 324 mg of methyl) amino] ethyl} -2-nitrobenzoate were prepared.

Production Example 19
To a mixture of 320 mg of methyl 5- {1-hydroxy-2-[(2-hydroxyethyl) (methyl) amino] ethyl} -2-nitrobenzoate, 395 mg of triphenylphosphine and 6.4 ml of THF, After dropwise addition of 731 μl of diethyl dicarboxylate / toluene solution, the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 0-10: 1) to give 5- (4-methylmorpholin-2-yl) -2-nitrobenzoic acid. 880 mg of methyl acid were produced.
Production Example 20
N- {2-[(2-methoxyethyl) carbamoyl] -4- (morpholin-4-ylmethyl) phenyl} -2-[(3S) -3-methoxypyrrolidin-1-yl] -1,3-thiazole- To a mixture of 2.92 g of 4-carboxamide and 75 ml of 1,2-dichloroethane, 949 μl of 1-chloroethyl chloroformate was added and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 99: 1-97: 3) and purified by N- {4- (chloromethyl) -2-[(2-methoxyethyl ) Carbamoyl] phenyl} -2-[(3S) -3-methoxypyrrolidin-1-yl] -1,3-thiazole-4-carboxamide 1.44 g was prepared.

Production Example 21
45.0 g of trimethylsilyl isocyanate was added to a solution of 32.5 g of (S)-(−)-3-pyrrolidinol in THF (500 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. After adding 40 ml of methanol to the reaction mixture and stirring at room temperature for further 30 minutes, the solvent was distilled off under reduced pressure to produce 48.55 g of (3S) -3-hydroxypyrrolidine-1-carboxamide.
Production Example 22
95.8 g of ethyl bromopyruvate was added to a solution of 48.6 g of (3S) -3-hydroxypyrrolidine-1-carboxamide in ethanol (500 ml), and the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, water was added and the mixture was washed with ethyl acetate, the organic layer was combined with the aqueous layer washed with 1M hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate solution, Extracted with ethyl acetate and chloroform. Each organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to produce 76.7 g of ethyl 2-[(3S) -3-hydroxypyrrolidin-1-yl] -1,3-oxazol-4-carboxylate.
Production Example 23
To a solution of 500 mg of ethyl 2-[(3S) -3-hydroxypyrrolidin-1-yl] -1,3-oxazole-4-carboxylate in DMF (5.1 ml) was added 125 mg of sodium hydride under ice cooling. And stirred at room temperature for 15 minutes. The reaction mixture was ice-cooled, 0.17 ml of methyl iodide was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. 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 (hexane: ethyl acetate = 20: 1-12: 1) to give 2-[(3S) -3-methoxypyrrolidin-1-yl] 324 mg of ethyl 1,3-oxazole-4-carboxylate was produced.

Production Example 24
(2S) -4- {3-[(2-methoxyethyl) carbamoyl] -4-[({2-[(3S) -3-methoxypyrrolidin-1-yl] -1,3-thiazol-4-yl } Carbonyl) amino] benzyl} -2-methylpiperazine-1-carboxylate tert-Butyl 270mg in 1,4-dioxane (6ml) solution with 4M hydrogen chloride / 1,4-dioxane solution in 1ml and room temperature for 4 days Stir. The solvent was distilled off under reduced pressure to give N- (2-[(2-methoxyethyl) carbamoyl] -4-{[(3S) -3-methoxypiperazin-1-yl] methyl} phenyl) -2-[(3S) 265 mg of 3-methoxypyrrolidin-1-yl] -1,3-thiazole-4-carboxamide trihydrochloride was prepared.
Production Example 25
To a mixture of 10.0 g of methyl 2-{[(2-bromo-1,3-thiazol-4-yl) carbonyl] amino} -5- (morpholin-4-ylmethyl) benzoate and 50 ml of DMF, 10.4 g of 3-thiazole-4-carboxylic acid, 9.00 g of WSC · HCl and 9.00 g of HOBt were added, and the mixture was stirred at room temperature for 5 days. To the reaction mixture, 300 ml of water and 200 ml of a saturated aqueous sodium hydrogen carbonate solution were added and stirred for 30 minutes, and insoluble matter was collected by filtration. To this was added 100 ml of ethanol, dissolved by heating and then cooled, and the precipitated solid was collected by filtration to give 2-{[(2-bromo-1,3-thiazol-4-yl) carbonyl] amino} -5- (morpholine- 13.2 g of methyl 4-ylmethyl) benzoate was produced.

Production Example 26
To a mixture of methyl 2-{[(2-bromo-1,3-thiazol-4-yl) carbonyl] amino} -5- (morpholin-4-ylmethyl) benzoate, 13.2 g of methanol, 100 ml of methanol and 250 ml of THF, 90 ml of an aqueous sodium solution was added and stirred at room temperature for 14 hours. The reaction mixture was neutralized by adding 90 ml of 1 M hydrochloric acid, and the precipitated solid was collected by filtration to give 2-{[(2-bromo-1,3-thiazol-4-yl) carbonyl] amino} -5- (morpholine. 10.9 g of -4-ylmethyl) benzoic acid was produced.
Production Example 27
2-{[(2-bromo-1,3-thiazol-4-yl) carbonyl] amino} -5- (morpholin-4-ylmethyl) benzoic acid in a mixture of 10.9 g of DMF and 220 ml of DMF, 6.00 g of WSC · HCl, HOBt 4.80 g and 2-methoxyethylamine 3.48 g were added and stirred at room temperature for 19 hours. To the reaction mixture, 600 ml of water and 600 ml of a saturated aqueous sodium hydrogen carbonate solution were added and stirred for 1 hour, and insoluble matter was collected by filtration. To this was added 200 ml of ethanol, dissolved by heating, cooled, and the precipitated solid was collected by filtration to give 2-bromo-N- {2-[(2-methoxyethyl) carbamoyl] -4- (morpholin-4-ylmethyl) phenyl } -1,3-thiazole-4-carboxamide 7.32 g was prepared.
Production Example 28
To a mixture of 2.61 g of tert-butyl 3-hydroxyazetidine-1-carboxylate and 39 ml of n-butyl vinyl ether was added 34 mg of palladium (II) acetate, 50 mg of 4,7-diphenyl-1,10-phenanthroline and 0.21 ml of triethylamine. And stirred at 75 ° C. for 7 days. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give 3- (vinyloxy) azetidine-1-carboxylic acid. 2.00 g of tert-butyl was produced.

Production Example 29
Under an argon atmosphere, a mixture of 10 ml of methylene chloride and 20 ml of 1.0M diethylzinc / hexane solution was ice-cooled, 1.54 ml of methylene chloride (10 ml) solution of trifluoroacetic acid was added dropwise, and the mixture was stirred for 30 minutes under ice-cooling. Next, 1.61 ml of methylene chloride (10 ml) in diiodomethane was added dropwise and stirred for 30 minutes, and then a solution of tert-butyl 3- (vinyloxy) azetidine-1-carboxylate 1.99 g in methylene chloride (30 ml) was added dropwise at room temperature. Stir for 15 hours. Next, 4.87 ml of triethylamine and 2.62 g of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, followed by extraction with chloroform. 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 (hexane: ethyl acetate = 19: 1-10: 1) to give tert-butyl 3- (cyclopropyloxy) azetidine-1-carboxylate. 406 mg was produced.
Production Example 30
After adding 1.5 ml of 4M hydrogen chloride / 1,4-dioxane solution to 1,4-dioxane (5 ml) solution of 400 mg tert-butyl 3- (cyclopropyloxy) azetidine-1-carboxylate and stirring at room temperature for 15 hours Then, 5 ml of ethanol was added and stirred for 2 hours. The solvent was distilled off under reduced pressure to produce 280 mg of 3- (cyclopropyloxy) azetidine hydrochloride.
Production Example 31
2-amino-5-{[(2S) -2-methylmorpholin-4-yl] methyl} methyl benzoate 300 mg in methanol (5 ml) solution was added 3.4 ml of 1M aqueous sodium hydroxide solution at 50 ° C. Stir for hours. The reaction mixture was cooled to room temperature, an equivalent amount of 1M hydrochloric acid was added, and then the solvent was distilled off under reduced pressure to give 2-amino-5-{[(2S) -2-methylmorpholin-4-yl] methyl} benzoic acid Was obtained as a mixture with sodium chloride. To this, 5 ml of DMF was added, 283 mg of WSC · HCl, 199 mg of HOBt and 149 mg of tetrahydro-2H-pyran-4-amine were added and stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 97: 3-92: 8) to give 2-amino-5-{[(2S) -2-methylmorpholine- 427 mg of 4-yl] methyl} -N- (tetrahydro-2H-pyran-4-yl) benzamide were prepared.

Production Example 32
To a mixture of 5 g of methyl 5-bromo-2-nitrobenzoate and 75 ml of acetonitrile, add 5.14 g of ethyl N- (diphenylmethylene) glycine, 7.97 g of potassium carbonate and 620 mg of tetra-n-butylammonium bromide, and heat for 15 hours. Refluxed. The reaction mixture was cooled to room temperature, the solid was filtered off, and the filtrate was evaporated under reduced pressure. Diethyl ether was added to the residue, the precipitated solid was filtered off, 50 ml of 1M hydrochloric acid was added to the filtrate, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was transferred to a separatory funnel and washed with diethyl ether. The aqueous layer was made weak alkaline by adding a saturated aqueous sodium hydrogen carbonate solution and extracted with 150 ml of methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, 8.39 g of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 5 hr and at 40 ° C. for 1 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 0-30: 1) to give 5- {1-[(tert-butoxycarbonyl) amino] -2- 1.68 g of methyl ethoxy-2-oxoethyl} -2-nitrobenzoate was produced.
Production Example 33
To a mixture of methyl 1.80 g of 5- {1-[(tert-butoxycarbonyl) amino] -2-ethoxy-2-oxoethyl} -2-nitrobenzoate, 54 ml of THF and 9 ml of methanol, 267 mg of sodium borohydride was added, Stir at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred for a while and extracted with chloroform. The organic layer was washed with saturated brine and 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 = 100: 0-1: 1) to give 5- {1-[(tert-butoxycarbonyl) amino] -2 1.44 g of methyl -hydroxyethyl} -2-nitrobenzoate were produced.

Production Example 34
To 418 mg of methyl 5- {1-[(tert-butoxycarbonyl) amino] -2-hydroxyethyl} -2-nitrobenzoate was added 4.18 ml of 4M hydrogen chloride / ethyl acetate solution, and the mixture was stirred at room temperature for 1.5 hours. To the residue obtained by distilling off the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with a chloroform-methanol mixed solvent (5: 1), and the organic layer was washed with saturated brine and then with anhydrous sodium sulfate. Dried. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 0-20: 1) to give 5- (1-amino-2-hydroxyethyl) -2-nitrobenzoic acid. 150 mg of methyl acid was produced.
Production Example 35
To a mixture of 150 mg of methyl 5- (1-amino-2-hydroxyethyl) -2-nitrobenzoate and 1.5 ml of methylene chloride was added 94 mg of benzyloxyacetaldehyde, 358 μl of acetic acid and 159 mg of sodium triacetoxyborohydride at room temperature. Stir for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0-20: 1) to give 5- (1-{[2- (benzyloxy) ethyl] amino}- 140 mg of methyl 2-hydroxyethyl) -2-nitrobenzoate was produced.

Production Example 36
To a mixture of 1.27 g of methyl 5- (1-{[2- (benzyloxy) ethyl] amino} -2-hydroxyethyl) -2-nitrobenzoate and 25 ml of methylene chloride, 4.95 g of 37% aqueous formaldehyde, 2.13 ml of acetic acid and 791 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 40 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated 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 (chloroform: methanol = 100: 0-30: 1) to give 5- (1-{[2- (benzyloxy) ethyl] (methyl 694 mg of methyl} amino} -2-hydroxyethyl) -2-nitrobenzoate were prepared.
Production Example 37
Under an argon atmosphere, a mixture of methyl 5- (1-{[2- (benzyloxy) ethyl] (methyl) amino} -2-hydroxyethyl) -2-nitrobenzoate (690 mg) and methylene chloride (28 ml) was added with pentamethylbenzene 1.31. After adding g and cooling to -78 ° C, 1.04 trichloroborane / n-heptane solution (4.44 ml) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. 1 ml of methanol was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 15 minutes. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 0-10: 1) to give 5- {2-hydroxy-1-[(2-hydroxyethyl) ( 421 mg of methyl) amino] ethyl} -2-nitrobenzoate were prepared.

  In the same manner as in Production Examples 1 to 37, the compounds of Production Examples 40 to 158 shown in the tables below were produced. The compounds of Production Examples 38 and 39 were produced in the same manner as in Example 1 described later. The structures, production methods and physicochemical data of the production example compounds are shown in Tables 3 to 21.

Example 1
2-({[2- (3-methoxyazetidin-1-yl) -1,3-thiazol-4-yl] carbonyl} amino) -5- (morpholin-4-ylmethyl) benzoic acid 110 mg and DMF 2 ml WSC · HCl 59 mg, HOBt 41 mg, triethylamine 107 μl and (2R) -2-methoxypropan-1-amine hydrochloride 96 mg were added at room temperature, and the mixture was stirred at room temperature for 17 hours and then stirred at 50 ° C. for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 99: 1-30: 1). This was suspended in 1 ml of ethanol, 17 mg of fumaric acid was added, and after stirring, the solid was collected by filtration, and 2- (3-methoxyazetidin-1-yl) -N- [2-{[(2R) -2- 66 mg of methoxypropyl] carbamoyl} -4- (morpholin-4-ylmethyl) phenyl] -1,3-thiazole-4-carboxamide fumarate was prepared.

Example 2
To a mixture of 1.00 g of 2- (3-methoxyazetidin-1-yl) -1,3-thiazole-4-carboxylic acid and 11 ml of 1,2-dichloroethane was added 3 μl of DMF and 1.11 ml of oxalyl dichloride under ice cooling, The mixture was stirred for 1 hour under ice cooling. After the reaction mixture was concentrated under reduced pressure, 6 ml of pyridine and 6 ml of methylene chloride were added to the residue, and 892 mg of methyl 4-amino-3-[(2-methoxyethyl) carbamoyl] benzoate and 44 mg of 4- (N, N-dimethylamino) pyridine were added. And stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with chloroform, washed with saturated 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 (chloroform: methanol = 99: 1-30: 1) to give 4-({[2- (3-methoxyazetidin-1-yl 1.17 g of methyl) -1,3-thiazol-4-yl] carbamoyl} amino) -3-[(2-methoxyethyl) carbamoyl] benzoate was prepared.
Example 3
4-({[2- (3-methoxyazetidin-1-yl) -1,3-thiazol-4-yl] carbonyl} amino) -3-[(2-methoxyethyl) carbamoyl] methyl benzoate 200 mg To the THF (3 ml) solution was added 20 mg of lithium borohydride under ice cooling, and the mixture was stirred at room temperature for 3 days. 1M Hydrochloric acid was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 40: 1). This was suspended in ether, and the powder was collected by filtration and dried to give N- {4- (hydroxymethyl) -2-[(2-methoxyethyl) carbamoyl] phenyl} -2- (3-methoxyazetidine-1 40 mg of -yl) -1,3-thiazole-4-carboxamide was prepared.

Example 4
N- {4- (Chloromethyl) -2-[(2-methoxyethyl) carbamoyl] phenyl} -2-[(3S) -3-methoxypyrrolidin-1-yl] -1,3-thiazole-4-carboxamide To a mixture of 200 mg and 2 ml of DMF, 67 mg of (8aR) -octahydropyrrolo [1,2-a] pyrazine and 216 mg of cesium carbonate were added and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 0-10: 1). This was suspended in 2 ml of ethanol, 102 mg of fumaric acid was added, and after stirring, the solid was collected by filtration, and N- {4-[(8aR) -hexahydropyrrolo [1,2-a] pyrazine-2 (1H)- 165 mg of ylmethyl] -2-[(2-methoxyethyl) carbamoyl] phenyl} -2-[(3S) -3-methoxypyrrolidin-1-yl] -1,3-thiazole-4-carboxamide 2 fumarate Manufactured.
Example 5
N- (2-[(2-methoxyethyl) carbamoyl] -4-{[(3S) -3-methylpiperazin-1-yl] methyl} phenyl) -2-[(3S) -3-methoxypyrrolidine-1 -Il] -1,3-thiazole-4-carboxamide hydrochloride To a mixture of 265 mg and 1,2-dichloroethane 7 ml, 177 μl of triethylamine, 242 μl of acetic acid and 200 mg of 37% aqueous formaldehyde were added and stirred at room temperature for 30 minutes. 269 mg of sodium acetoxyborohydride was added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 99: 1-95: 5). 94 mg of this product was dissolved in 1 ml of ethanol, 43 mg of fumaric acid was added and stirred at room temperature, and the precipitated solid was collected by filtration and dried to give N- (4-{[(3S) -3,4dimethylpiperazine-1- Yl] methyl} -2-[(2-methoxyethyl) carbamoyl] phenyl) -2-[(3S) -3-methoxypyrrolidin-1-yl] -1,3-thiazole-4-carboxamide fumarate 100 mg Manufactured.

Example 6
2-Bromo-N- {2-[(2-methoxyethyl) carbamoyl] -4- (morpholin-4-ylmethyl) phenyl} -1,3-thiazole-4-carboxamide in a mixture of 200 mg and DMA 2 ml, N-ethyl 200 μl of ethanamine was added and stirred at 100 ° C. for 20 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 99: 1). This was dissolved in 1 ml of ethanol, and after stirring, the precipitated solid was collected by filtration, and 2- (diethylamino) -N- {2-[(2-methoxyethyl) carbamoyl] -4- (morpholin-4-ylmethyl) phenyl } -1,3-thiazole-4-carboxamide 89 mg was prepared.

  In the same manner as in Examples 1 to 6, the compounds of Examples 7 to 90 shown in the table below were produced. The structures of Example compounds are shown in Tables 22 to 34, and the production methods and physicochemical data are shown in Tables 35 to 39, respectively.

  The compound of the formula (I) or a salt thereof has potent trkA receptor inhibitory activity in vitro and potent NGF inhibitory activity in vivo, frequent urination associated with various lower urinary tract diseases including overactive bladder, It can be used as a therapeutic and / or prophylactic agent for various lower urinary tract diseases accompanied by lower urinary tract pain such as interstitial cystitis and chronic prostatitis, and various diseases accompanied by pain, such as urinary urgency, urinary incontinence.

Claims (3)

A compound of formula (I) or a salt thereof.

(The symbols in the formula have the following meanings.
X: S or O,
R ¹ :

R ^1a : H, —OH, —O-lower alkyl or —O-cycloalkyl,
R ^1b : F or —O-lower alkyl,
R ^1c : H or lower alkyl,
R ^1d : lower alkyl optionally substituted by —O-lower alkyl,
R ² : H, lower alkyl optionally substituted with (F or —O-lower alkyl), 3-tetrahydrofuryl or 4-tetrahydropyranyl,
A:

R ³ : R ^3A or —CH ₂ —R ^3B ,
R ^3A : —CO ₂ Me or the following ring group,

R ⁰⁰ : lower alkyl,
R ^3B : —OH, —O-lower alkyl, or a cyclic group selected from the following group:

R ⁰ : H or lower alkyl,
m: 1 or 2,
R ^a : H, F, phenyl or -lower alkylene-O-lower alkyl,
R ^b : H or F,
R ⁴ : lower alkyl optionally substituted with —O-lower alkyl. ) The compound or a salt thereof according to claim ¹ , wherein R ¹ is azetidino optionally substituted with one group selected from the group consisting of -OH, -O-lower alkyl and -O-cycloalkyl at the 3-position. A compound of the formula (IA) or a salt thereof.

(The symbols in the formula have the following meanings.
R ⁵ : a ring group selected from the following group,

R ⁶ : 2-methoxyethyl, 3-fluoropropyl or 3-tetrahydrofuryl. )