JPWO2004106283A1 - Aminoalcohol derivatives, pharmaceutical compositions containing them, and uses thereof - Google Patents

Abstract

General formula (I) having strong stimulating action and high selectivity for human β3-adrenergic receptor: wherein R1 and R2 are independently hydrogen, halogen, lower alkyl, etc .; R3 is hydrogen R4 represents hydrogen, lower alkyl, aryl, aralkyl or heteroaralkyl, or R3 and R4 together form-(CH2) m-; R5 represents hydrogen, lower alkyl, or lower alkyl or aralkyl; , Aryl, aralkyl or heteroaralkyl; R6 is hydroxyl, lower alkoxy, aralkyloxy or —N (R7) (R8); A1 is a bond or lower alkylene; X is a bond or oxygen atom; n Or an pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and To provide those applications.

Description

The present invention relates to a novel aminoalcohol derivative having β ₃ -adrenergic receptor stimulating action, a pharmaceutical composition containing the same, and uses thereof.

〔式中、Ｒ^ＡおよびＲ^Ｂは、それぞれ水素または水酸基を表し；Ｒ^ＣおよびＲ^Ｄは、それぞれ水素または低級アルキル基を表し；Ｒ^Ｅは、水素、ハロゲン、低級アルキルまたは低級アルコキシ基を表し；Ｒ^Ｆは、アシルアミノ基、低級アルコキシカルボニルアミノ基、アモイル基またはウレイド基を表し；ａは、０〜４の整数を表し；Ｚ^２は、結合、酸素、硫黄またはイミノを表す〕で表される化合物を開示しているが（例えば、特許文献１参照）、ヒトβ_３−アドレナリン受容体刺激作用については何ら記載されていない。
１．Ｂｅｒｋｏｗｉｔｚ ＤＥ．ら，「Ｅｕｒ．Ｊ．Ｐｈａｒｍａｃｏｌ．」，１９９５年，２８９巻，ｐ．２２３−２２８ There are three subtypes of sympathetic β-adrenergic receptors, classified as β ₁ , β _2, and β ₃ , which are distributed in specific in vivo tissues, each with a unique function It is known.
β ₁ -adrenergic receptors are mainly present in the heart, and stimulation via the receptors causes an increase in heart rate and an increase in cardiac contractility. β ₂ -adrenergic receptors are mainly present in vascular, bronchial and uterine smooth muscles, and stimulation through the receptors leads to vascular and bronchial dilation and suppression of uterine contraction, respectively. Many β ₁ -adrenergic receptor stimulants and β ₂ -adrenergic receptor stimulants have been developed so far and are used in medicine as cardiotonic agents, bronchodilators and urgency / premature birth prevention agents.
On the other hand, β ₃ -adrenergic receptors are known to be present in adipocytes, brain, gallbladder, prostate, bladder, intestinal tract and the like (for example, Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Non-patent document 4), stimulation through the receptor, fat degradation action, heat production promotion action, hypoglycemic action; antihyperlipidemic action (triglyceride lowering action, cholesterol lowering action, HDL-cholesterol raising action) It has been reported that antidepressant action; bladder relaxation action; suppression of intestinal motility, etc. (see, for example, Non-Patent Document 2, Non-Patent Document 5, Non-Patent Document 6, and Non-Patent Document 7) . Accordingly, β ₃ -adrenergic receptor agonists are used for the treatment or prevention of obesity, diabetes, hyperlipidemia, depression, diseases derived from hyperbiliary motility, dysuria, or diseases derived from increased gastrointestinal function. It is considered useful as an agent.
Currently, research and development of β ₃ -adrenergic receptor agonists are actively conducted mainly on anti-obesity / diabetic drugs, but many of them are heart rate increase, muscle tremor, hypokalemia, etc. The β ₁ receptor and / or the β ₂ receptor have an effect derived from stimulation, and there was a problem in terms of side effects. Also, recently, the beta ₃ receptor is confirmed that there is species differences, conventionally, be a compound beta ₃ receptor stimulating effect in rodents, such as rats have been confirmed, a weak stimulatory effect in humans However, it has been reported that only this is allowed (see Non-Patent Document 8, for example). From this point of view, the human beta ₃ - has a strong stimulatory effect against adrenergic receptor, beta ₁ receptor and beta ₂ receptors with less side effects novel beta ₃ derived from stimulation of - adrenergic receptor Drug development is desired.
Cox D.C. A. Have the following general formula, which increases myocardial contractility and is useful as a treatment for congestive heart failure:

Wherein, R ^A and R ^B each represent hydrogen or a hydroxyl group; R ^C and R ^D, each represent hydrogen or a lower alkyl group; R ^E represents hydrogen, halogen, lower alkyl or lower alkoxy group R ^F represents an acylamino group, a lower alkoxycarbonylamino group, an amoyl group or a ureido group; a represents an integer of 0 to 4; Z ² represents a bond, oxygen, sulfur or imino] (For example, refer to Patent Document 1), however, there is no description on the action of stimulating human β ₃ -adrenergic receptors.
1. Berkowitz DE. Et al., “Eur. J. Pharmacol.”, 1995, 289, p. 223-228

2. Howe R. "Drugs of the Future", 1993, 18, 6, p. 529-549
3. Ponti FD. Et al., “Pharmacology”, 1995, 51, p. 288-297
4). Rodriguez M.M. Et al., “Brain Res. Mol. Brain Res.”, 1995, 29, 2, p. 369-375
5). Simiand J.M. Et al., “Eur. J. Pharm.”, 1992, 219, p. 193-201
6). Igawa Y. et al. Et al., “The Journal of Japanese Urological Association”, 1997, Volume 88, No. 2, p. 183
7). Igawa Y. et al. Et al., “Neurourol. Urodyn.”, 1997, Vol. 16, No. 5, p. 363-365
8). Furutani Y. et al. "Endocrinology / Diabetics", 2001, Vol. 12, No. 4, p. 416-422
1. British Patent Application No. 1301134

〔式中、
Ｒ^１およびＲ^２は、それぞれ独立して、水素原子、ハロゲン原子、低級アルキル基、ハロ低級アルキル基、ヒドロキシ低級アルキル基、シクロアルキル基、ヘテロシクロアルキル基、低級アルコキシ基、水酸基、ジ低級アルキルアミノ基、環状アミノ基、ジ低級アルキルアミノ低級アルキル基、アリール基、アリールオキシ基、アラルキルオキシ基、ヘテロアリール基、シアノ基、低級アシル基、低級アルキルスルファニル基または低級アルキルスルホニル基であり；
Ｒ^３は、水素原子、低級アルキル基またはアラルキル基であり；
Ｒ^４は、水素原子、低級アルキル基、アリール基、アラルキル基またはヘテロアラルキル基を表すか、あるいはＲ^３とＲ^４が、一緒になって−（ＣＨ_２）_ｍ−を形成し；
Ｒ^５は、水素原子、低級アルキル基、アリール基、アラルキル基またはヘテロアラルキル基であり；
Ｒ^６は、水酸基、低級アルコキシ基、アラルキルオキシ基、または−Ｎ（Ｒ^７）（Ｒ^８）であり；
Ｒ^７およびＲ^８は、それぞれ独立して、水素原子、低級アルキル基、カルボキシ低級アルキル基または低級アルコキシカルボニル低級アルキル基を表すか、あるいはＲ^７およびＲ^８が、結合している窒素原子と一緒になって環状アミンを形成し；
Ａ^１は、結合または低級アルキレン基であり；
Ｘは、結合または酸素原子であり；
ｍは、３〜５の整数であり；
ｎは、２〜５の整数である〕
で表される化合物またはそのプロドラッグ、あるいはそれらの薬理学的に許容される塩に関する。
また別の局面において、本発明は、前記一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩を有効成分として含有する医薬組成物に関する。
さらに別の局面において、本発明は、前記一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩を含有する肥満症、糖尿病、高脂血症、うつ病、排尿障害、胆石および胆道運動亢進に由来する疾患、または消化管機能亢進に由来する疾患の治療または予防剤に関する。
さらに別の局面において、本発明は、前記一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩と、β_３−アドレナリン受容体作動薬以外の抗肥満薬、抗糖尿病剤、抗高脂血症用剤および排尿障害治療薬から選択される少なくとも１種とを組み合わせてなる医薬に関する。
さらに別の局面において、本発明は、肥満症、糖尿病、高脂血症、うつ病、排尿障害、胆石および胆道運動亢進に由来する疾患、または消化管機能亢進に由来する疾患の治療または予防剤を製造するための前記一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩の使用に関する。
さらに別の局面において、本発明は、肥満症、糖尿病、高脂血症、うつ病、排尿障害、胆石および胆道運動亢進に由来する疾患、または消化管機能亢進に由来する疾患の治療または予防方法に関し、該方法は、前記一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩の有効量を投与する工程を包含する。
前記一般式（Ｉ）で表される化合物において、下記の用語は、特に断らない限り、以下の意味を有する。
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を表し、好適にはフッ素原子または塩素原子であり、さらに好適には塩素原子である。
「低級アルキル基」とは、直鎖または分岐鎖状の炭素数１〜６のアルキル基を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ−ペンチル基、１−メチルブチル基、２−メチルブチル基、１，２−ジメチルプロピル基、ヘキシル基、イソヘキシル基などが挙げられる。Ｒ^１、Ｒ^２およびＲ^３における低級アルキル基は、好適には炭素数１〜４のアルキル基であり、さらに好適にはメチル基である。Ｒ^４およびＲ^５における低級アルキル基は、好適には炭素数１〜４のアルキル基であり、さらに好適にはメチル基、イソプロピル基またはイソブチル基である。
「ハロ低級アルキル基」とは、１〜３個の同種または異種のハロゲン原子で置換された低級アルキル基を意味し、例えば、トリフルオロメチル基、２−クロロエチル基、２−フルオロエチル基、２，２，２−トリフルオロエチル基、２，２，２−トリクロロエチル基などが挙げられる。
「ヒドロキシ低級アルキル基」とは、水酸基で置換された低級アルキル基を意味し、例えば、ヒドロキシメチル基、２−ヒドロキシエチル基、１−ヒドロキシエチル基、３−ヒドロキシプロピル基、４−ヒドロキシブチル基などが挙げられる。
「シクロアルキル基」とは、炭素数３〜７の飽和環状炭化水素基を意味し、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基が挙げられる。
「ヘテロシクロアルキル基」とは、環内に酸素原子および硫黄原子から選択されるヘテロ原子を含有する４〜７員の飽和複素環基を意味し、例えば、テトラヒドロフリル基、テトラヒドロチエニル基、テトラヒドロピラニル基などが挙げられる。
「低級アルコキシ基」とは、直鎖または分岐鎖状の炭素数１〜６のアルコキシ基を意味し、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基などが挙げられる。
「ジ低級アルキルアミノ基」とは、低級アルキル基で二置換されたアミノ基を意味し、例えば、ジメチルアミノ基、ジエチルアミノ基などが挙げられる。
「ジ低級アルキルアミノ低級アルキル基」とは、ジ低級アルキルアミノ基で置換された低級アルキル基を意味し、例えば、ジメチルアミノメチル基などが挙げられる。
「環状アミンまたは環状アミノ基」とは、環内に酸素原子を含んでもよい５〜７員の飽和環状アミノ基を意味し、例えば、ピロリジル基、ピペリジル基、モルホリニル基などが挙げられる。
「低級アシル基」とは、（低級アルキル）−Ｃ（Ｏ）−で表される基を意味し、例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基、バレリル基、イソバレリル基などが挙げられる。
「低級アルキルスルファニル基」とは、（低級アルキル）−Ｓ−で表される基を意味し、例えば、メチルスルファニル基、エチルスルファニル基、プロピルスルファニル基、イソプロピルスルファニル基、ブチルスルファニル基、ペンチルスルファニル基、ヘキシルスルファニル基などが挙げられる。
「低級アルキルスルホニル基」とは、（低級アルキル）−ＳＯ_２−で表される基を意味し、例えば、メタンスルホニル基、エタンスルホニル基、プロパンスルホニル基、ブタンスルホニル基、ペンタンスルホニル基、ヘキサンスルホニル基などが挙げられる。
「カルボキシ低級アルキル基」とは、カルボキシ基で置換された低級アルキル基を意味し、例えば、カルボキシメチル基、１−カルボキシエチル基、２−カルボキシエチル基、３−カルボキシプロピル基、４−カルボキシブチル基などが挙げられる。
「低級アルコキシカルボニル基」とは、（低級アルコキシ）−Ｃ（Ｏ）−で表される基を意味し、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、ｓｅｃ−ブトキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル基、ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基などが挙げられ、好適にはメトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、またはブトキシカルボニル基である。
「低級アルコキシカルボニル低級アルキル基」とは、低級アルコキシカルボニル基で置換された低級アルキル基を意味し、例えば、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、イソプロポキシカルボニルメチル基、ブトキシカルボニルメチル基、２−（エトキシカルボニル）エチル基、１−（エトキシカルボニル）エチル基、３−（エトキシカルボニル）プロピル基、４−（エトキシカルボニル）ブチル基などが挙げられ、好適にはメトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、イソプロポキシカルボニルメチル基、またはブトキシカルボニルメチル基である。
「アリール基」とは、非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基、水酸基、カルボキシ基および低級アルコキシカルボニル基から独立して選択される１〜３個の基で置換される、炭素数６〜１４の芳香族炭化水素基を意味し、例えば、フェニル基、２−フルオロフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、２−クロロフェニル基、３，５−ジクロロフェニル基、４−メチルフェニル基、４−トリフルオロメチルフェニル基、２−メトキシフェニル基、４−メトキシフェニル基、４−ヒドロキシフェニル基、４−カルボキシフェニル基、４−メトキシカルボニルフェニル基、ナフチル基、アントリル基、フェナントリル基などが挙げられる。
「アリールオキシ基」とは、（アリール）−Ｏ−で表される基を意味し、例えば、フェノキシ基、２−フルオロフェノキシ基、３−フルオロフェノキシ基、４−フルオロフェノキシ基、２−クロロフェノキシ基、４−クロロフェノキシ基、３，５−ジクロロフェノキシ基、４−メチルフェノキシ基、４−トリフルオロメチルフェノキシ基、２−メトキシフェノキシ基、４−メトキシフェノキシ基、２−ヒドロキシフェノキシ基、４−カルボキシフェノキシ基、４−メトキシカルボニルフェノキシ基、ナフチルオキシ基、アントリルオキシ基、フェナントリルオキシ基などが挙げられる。
「アラルキル基」とは、アリール基で置換された低級アルキル基を意味し、例えば、ベンジル基、フェネチル基、３−フェニルプロピル基、２−フルオロベンジル基、３−フルオロベンジル基、４−フルオロベンジル基、２−クロロベンジル基、３，５−ジクロロベンジル基、４−メチルベンジル基、４−トリフルオロメチルベンジル基、２−メトキシベンジル基、４−ヒドロキシベンジル基、４−カルボキシベンジル基、４−メトキシカルボニルベンジル基などが挙げられ、好適にはベンジル基である。
「アラルキルオキシ基」とは、アリール基で置換された低級アルコキシ基を意味し、例えば、ベンジルオキシ基、フェネチルオキシ基、３−フェニルプロピルオキシ基、２−フルオロベンジルオキシ基、３−フルオロベンジルオキシ基、４−フルオロベンジルオキシ基、２−クロロベンジルオキシ基、３，５−ジクロロベンジルオキシ基、４−メチルベンジルオキシ基、４−トリフルオロメチルベンジルオキシ基、２−メトキシベンジルオキシ基、２−ヒドロキシベンジルオキシ基、４−カルボキシベンジルオキシ基、４−メトキシカルボニルベンジルオキシ基などが挙げられる。
「ヘテロアリール基」とは、窒素原子、酸素原子および硫黄原子からなる群から独立して選択される１〜４個のヘテロ原子を含有する５または６員の芳香族複素環基を意味し、但し、これらの環は、隣接する酸素原子および／または硫黄原子を含まない。ヘテロアリール基の具体例として、例えば、ピロリル基、フラニル基、チエニル基、イミダゾリル基、ピラゾリル基、１，２，４−トリアゾリル基、オキサゾリル基、イソキサゾリル基、テトラゾリル基、ピリジル基、ピラジニル基、ピリミジル基などが挙げられる。これらの芳香族複素環基の全ての位置異性体が考えられる（例えば、２−ピリジル基、３−ピリジル基、４−ピリジル基など）。またこれらの芳香族複素環は、必要に応じてハロゲン原子、低級アルキル基、低級アルコキシ基、水酸基、カルボキシ基、および低級アルコキシカルボニル基からなる群から独立して選択される１〜３個の基で置換することができる。
「ヘテロアラルキル基」とは、ヘテロアリール基で置換された低級アルキル基を意味し、例えば、２−ピリジルメチル基、３−ピリジルメチル基、４−ピリジルメチル基などが挙げられる。
「低級アルキレン基」とは、直鎖または分岐鎖状の炭素数１〜４の２価の飽和炭化水素鎖を意味し、例えば、−ＣＨ_２−、−ＣＨ_２ＣＨ_２−、−ＣＨ（ＣＨ_３）−、−ＣＨ_２ＣＨ_２ＣＨ_２−、−ＣＨ（ＣＨ_３）ＣＨ_２−、−ＣＨ_２ＣＨ（ＣＨ_３）−、−Ｃ（ＣＨ_３）_２−、−ＣＨ（ＣＨ_２ＣＨ_３）−、−ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２−などの基が挙げられる。
本発明の前記一般式（Ｉ）で表される化合物において１つまたはそれ以上の不斉炭素原子が存在する場合、本発明は各々の不斉炭素原子がＲ配置の化合物、Ｓ配置の化合物、およびそれらの任意の組み合せの化合物のいずれも包含する。またそれらのラセミ化合物、ラセミ混合物、単一のエナンチオマー、ジアステレオマー混合物が本発明の範囲に含まれる。本発明の前記一般式（Ｉ）で表される化合物において幾何学異性が存在する場合、本発明はその幾何学異性体のいずれも包含する。さらに本発明の前記一般式（Ｉ）で表される化合物には、水和物やエタノール等の医薬品として許容される溶媒との溶媒和物も含まれる。
本発明の前記一般式（Ｉ）で表される化合物は、塩の形態で存在することができる。このような塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸などの鉱酸との付加塩、ギ酸、酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、グルタミン酸、アスパラギン酸等の有機酸との付加塩、ナトリウム塩、カリウム塩、カルシウム塩等の無機塩基との塩、トリエチルアミン、ピペリジン、モルホリン、リジン等の有機塩基との塩を挙げることができる。
本発明において「プロドラッグ」とは、生体内において前記一般式（Ｉ）に変換される化合物を意味し、このようなプロドラッグはまた本発明の範囲内である。プロドラッグの様々な形態が当該分野において周知である。
例えば、本発明の前記一般式（Ｉ）で表される化合物がカルボキシ基を有する場合、プロドラッグとして、当該カルボキシ基の水素原子と、以下のような基：低級アルキル基（例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｔｅｒｔ−ブチル基など）；低級アシルオキシメチル基（例えば、ピバロイルオキシメチル基など）；１−（低級アシルオキシ）エチル基（例えば、１−（ピバロイルオキシ）エチル基など）；低級アルコキシカルボニルオキシメチル基（例えば、ｔｅｒｔ−ブトキシカルボニルオキシメチル基など）；１−（低級アルコキシカルボニルオキシ）エチル基（例えば、１−（ｔｅｒｔ−ブトキシカルボニルオキシ）エチル基など）；または３−フタリジル基との置換により形成されるエステルが挙げられる。
また本発明の前記一般式（Ｉ）で表される化合物が水酸基を有する場合、プロドラッグとして、当該水酸基の水素原子と、以下のような基：低級アシル基（例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基など）；低級アルコキシカルボニル基（例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル基など）；スクシノイル基；低級アシルオキシメチル基（例えば、ピバロイルオキシメチル基など）；１−（低級アシルオキシ）エチル基（例えば、１−（ピバロイルオキシ）エチル基など）；または低級アルコキシカルボニルオキシメチル基（例えば、ｔｅｒｔ−ブトキシカルボニルオキシメチル基など）との置換により形成される化合物が挙げられる。
また本発明の前記一般式（Ｉ）で表される化合物が、−ＮＨまたは−ＮＨ_２のようなアミノ基を有する場合、プロドラッグとして、当該アミノ基の水素原子と、以下のような基：低級アシル基（例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基など）；または低級アルコキシカルボニル基（例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル基など）との置換により形成される化合物が挙げられる。
これらのプロドラッグ化合物は、自体公知の方法、例えば、Ｔ．Ｗ．ＧｒｅｅｎおよびＰ．Ｇ．Ｈ．Ｗｕｔｓ，「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」第３版、およびそこに記載された参考文献に従って、一般式（Ｉ）で表される化合物から製造することができる。
上記一般式（Ｉ）で表される化合物において、
Ｒ^１およびＲ^２は、それぞれ独立して、水素原子、ハロゲン原子または低級アルキル基であり、さらに好適には水素原子、ハロゲン原子またはＣ_１−４アルキル基であり、なおさらに好適には水素原子、塩素原子またはメチル基であり；
Ｒ^３は、好適には水素原子であり；
Ｒ^４は、好適には水素原子、低級アルキル基またはアラルキル基であり；
Ｒ^５は、好適には水素原子または低級アルキル基であり；
Ｒ^６は、好適には水酸基または低級アルコキシ基であり；
Ｘは、一つの局面では酸素原子であり、また別の局面では結合であり、
Ｘが結合である場合、ｎは、好適には２または３であり、さらに好適には２であり、
Ｘが酸素原子である場合、ｎは、好適には２または３であり、さらに好適には２である。
一般式（Ｉ）で表される化合物の好ましい実施態様は、
Ｘが、結合である化合物またはその薬理学的に許容される塩である。
一般式（Ｉ）で表される化合物のさらに好ましい実施態様は、
Ｘが、結合であり、
ｎが、２である化合物またはその薬理学的に許容される塩である。
一般式（Ｉ）で表される化合物のなおさらに好ましい実施態様は、
Ｒ^１およびＲ^２が、それぞれ独立して、水素原子、ハロゲン原子または低級アルキル基であり、好ましくはＲ^１が水素原子であり、Ｒ^２がハロゲン原子であり、
Ｘが、結合であり、
ｎが、２である化合物またはその薬理学的に許容される塩である。
一般式（Ｉ）で表される化合物のなおさらに好ましい実施態様は、
Ｒ^１およびＲ^２が、それぞれ独立して、水素原子、ハロゲン原子または低級アルキル基であり、好ましくはＲ^１が水素原子であり、Ｒ^２がハロゲン原子であり、
Ｒ^３が、水素原子であり、
Ｒ^４が、水素原子、低級アルキル基またはアラルキル基であり、
Ｒ^５が、水素原子または低級アルキル基であり、
Ｒ^６が、水酸基または低級アルコキシ基であり、
Ａ^１が、結合であり、
Ｘが、結合であり、
ｎが、２である化合物またはその薬理学的に許容される塩である。
本発明の好ましい化合物の具体例は、以下からなる群から選択される化合物またはその薬理学的に許容される塩である：
（Ｓ）−２−（３−クロロ−４−｛２−［（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチルアミノ］エチル｝ベンゾイルアミノ）−３−フェニルプロピオン酸；
（Ｓ）−２−（４−｛２−［（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチルアミノ］エチル｝ベンゾイルアミノ）−３−フェニルプロピオン酸；および
（Ｓ）−２−（４−｛２−［（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチルアミノ］エチル｝ベンゾイルアミノ）−４−メチルペンタン酸。
本発明の一般式（Ｉ）で表される化合物は、スキーム１または２に示す方法により製造することができる。

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｘ、ｎおよびＡ^１は前記と同義であり、Ｙ^１は塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基などの脱離基を表し、Ｐ^１は水素原子またはベンジル基を表す）
工程１−１
アミノアルコール誘導体（Ｘ）とアルキル化剤（ＸＩ）とを、不活性溶媒（例えば、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリルなど）中、塩基（例えば、Ｎ，Ｎ−ジイソプロピルエチルアミン、トリエチルアミン、ジイソプロピルアミンなど）の存在下または非存在下に縮合させることにより、一般式（Ｉａ）で表される化合物が得られる。
ＣＯＲ^６がカルボン酸エステル基である化合物（Ｉａ）は、必要に応じて、適切な溶媒（例えば、エタノールなど）中、アルカリ水溶液を用いて加水分解することにより対応するカルボン酸へ変換することができる。またＣＯＲ^６がカルボキシ基である化合物（Ｉａ）は、不活性溶媒（例えば、テトラヒドロフラン、塩化メチレン、Ｎ，Ｎ−ジメチルホルムアミドなど）中、縮合剤（例えば、ジフェニルホスホリルアジド、シアノリン酸ジエチル、１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド塩酸塩など）の存在下にＮＨＲ^７Ｒ^８で表されるアミンと反応させることにより、対応するカルボン酸アミドへ変換することができる。
工程１−２
Ｐ^１がベンジル基である化合物（Ｉａ）は、不活性溶媒（例えば、エタノール、Ｎ，Ｎ−ジメチルホルムアミドなど）中、金属触媒（例えば、パラジウム炭素、酸化白金など）の存在下、水素雰囲気下にベンジル基を除去することにより、化合物（Ｉ）へ変換することができる。

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｘ、ｎ、Ａ^１およびＰ^１は前記と同義である）
工程２−１および２−２
アミノアルコール誘導体（Ｘ）とアルデヒド誘導体（ＸＩＩ）とを、適切な溶媒中、還元剤の存在下に縮合させることにより、化合物（Ｉａ）が得られる。この還元アミノ化反応に使用できる溶媒としては、例えば、テトラヒドロフラン、１，４−ジオキサンなどのエーテル類、塩化メチレンなどのハロゲン化炭素類、酢酸などの有機カルボン酸類、トルエンなどの炭化水素類、メタノール、エタノール類などのアルコール類、アセトニトリルなどが挙げられ、必要に応じて、これらの溶媒を２種以上組み合わせて使用することができる。還元剤としては、例えば、ＮａＢＨ_４、ＮａＢＨ_３ＣＮ、ＮａＢＨ（ＯＡｃ）_３などの水素化ホウ素アルカリ金属類、ＢＨ_３・ピリジン、ＢＨ_３・Ｎ，Ｎ−ジエチルアニリンなどのボラン類などが挙げられる。また本反応は、必要に応じて酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸、硫酸、塩酸などの酸を添加して行うことができる。また本反応は、上記還元剤を使用する代わりに、触媒量の金属触媒（例えば、５〜１０％パラジウムカーボン、ラネーニッケル、酸化白金、パラジウムブラック、１０％白金カーボン（硫黄被毒）など）の存在下に水素雰囲気下で行うことができる。本還元アミノ化反応は、化合物（ＸＩＩ）中の置換基の種類に応じて適切な還元条件を選択して行われる。
Ｐ^１がベンジル基である化合物（Ｉａ）は、工程１−２と同様にして脱ベンジル化することにより、化合物（Ｉ）へ変換することができる。
スキーム１において用いられるアルキル化剤（ＸＩ）は、スキーム３に示す方法により製造することができる。

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｘ、ｎ、Ａ^１およびＹ^１は前記と同義であり、Ｙ^２は塩素原子、臭素原子または水酸基を表す）
工程３−１
化合物（ＸＩＩＩ）とアミノ酸誘導体（ＸＩＶ）とを、不活性溶媒（例えば、テトラヒドロフラン、塩化メチレン、Ｎ，Ｎ−ジメチルホルムアミドなど）中、縮合剤の存在下に反応させることにより、アミド誘導体（ＸＩａ）が得られる。このアミド化反応に使用できる縮合剤としては、例えば、ジフェニルホスホリルアジド、シアノリン酸ジエチル、１，３−ジシクロヘキシルカルボジイミド、１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド塩酸塩、ベンゾトリアゾール−１−イルオキシトリス（ジメチルアミノ）ホスホニウムヘキサフルオロホスフェートなどが挙げられる。また本反応は、必要に応じて、Ｎ−ヒドロキシスクシンイミド、１−ヒドロキシベンゾトリアゾールなどの活性化剤を添加して行うことができる。
またこのアミド誘導体（ＸＩａ）は、化合物（ＸＩＩＩ）を、常法に基づき活性エステル（例えば、４−ニトロフェニルエステル、２，５−ジオキサピロリジンエステルなど）に変換した後、アミノ酸誘導体（ＸＩＶ）と縮合させることによっても得ることができる。
工程３−２
Ｙ^２が水酸基である化合物（ＸＩａ）は、不活性溶媒（例えば、塩化メチレン、クロロホルムなど）中、ハロゲン化試薬、または塩基（例えば、Ｎ，Ｎ−ジイソプロピルエチルアミンなど）の存在下にスルホニルハライドと反応させることにより、一般式（ＸＩ）で表される化合物へ変換することができる。このようなハロゲン化試薬としては、例えば、塩化チオニル、三臭化リン、トリフェニルホスフィン／四臭化炭素などが挙げられる。スルホニルクロリドとしては、例えば、メタンスルホニルクロリド、ｐ−トルエンスルホニルクロリドなどが挙げられる。
スキーム２において用いられるアルデヒド誘導体（ＸＩＩ）は、スキーム４に示す方法により製造することができる。

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｘ、ｎおよびＡ^１は前記と同義である）
工程４−１
アルコール誘導体（ＸＩｂ）を、不活性溶媒（例えば、塩化メチレンなど）中、適切な酸化剤を用いて酸化することによりアルデヒド誘導体（ＸＩＩ）が得られる。このような酸化剤としては、例えば、オキサリルクロリド／ジメチルスルホキシド、または１，１，１−トリアセトキシ−１，１−ジヒドロ−１，２−ベンズヨードキソール−３（１Ｈ）−オンなどが挙げられる。
スキーム３において用いられる安息香酸誘導体（ＸＩＩＩ）は、市販の試薬を使用するか、または常法に従って合成することができる。例えば、化合物（ＸＩＩＩａ）は、スキーム５に示す方法により製造することができる。

（式中、Ｒ^１、Ｒ^２、Ｘおよびｎは前記と同義であり、Ｙ^３はヨウ素原子またはトリフルオロメタンスルホニルオキシ基を表し、Ｒ^２０は低級アルキル基を表す）
工程５−１
化合物（ＸＶ）を、不活性溶媒中、ホスフィン配位子、パラジウム触媒および塩基の存在下に、一酸化炭素およびＲ^２０ＯＨと反応させることにより化合物（ＸＶＩ）が得られる。本反応に使用できる溶媒としては、例えば、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシドなどが挙げられる。ホスフィン配位子としては、例えば、トリフェニルホスフィン、１，３−ビス（ジフェニルホスフィノ）プロパンなどが挙げられる。パラジウム触媒としては、例えば、酢酸パラジウムなどが挙げられる。塩基としては、例えば、トリエチルアミンなどが挙げられる。
工程５−２
化合物（ＸＶＩ）を、適切な溶媒（例えば、エタノールなど）中、アルカリ水溶液を用いて加水分解することにより、安息香酸誘導体（ＸＩＩＩａ）が得られる。
スキーム１および２において用いられるアミノアルコール誘導体（Ｘｂ）は、スキーム６に示す方法により製造することができる。

（式中、Ｂｎはベンジル基を表す）
工程６−１および６−２
アミノアルコール誘導体（Ｘａ）を、トリフルオロ酢酸エチルを用いてトリフルオロ化すると化合物（ＸＶＩＩ）が得られる。この化合物（ＸＶＩＩ）のフェノール性水酸基を、不活性溶媒（例えば、Ｎ，Ｎ−ジメチルホルムアミドなど）中、塩基（例えば、炭酸カリウムなど）の存在下に、ベンジルハライド（例えば、ベンジルクロリドなど）と反応させるとＯ−ベンジル誘導体が得られる。続いてこのＯ−ベンジル誘導体を、常法により、アルカリ水溶液を用いて加水分解することにより化合物（Ｘｂ）が得られる。
アミノアルコール誘導体（Ｘａ）は、市販のエナンチオマー混合物を常法に従って光学分割するか、文献記載の方法（例えば、「Ｊ．Ｍｅｄ．Ｃｈｅｍ．」１９７７年，２０巻７号，ｐ．９７８−９８１）に従って合成することができる。
上記に示したスキームは、本発明の化合物またはその製造中間体を製造するための方法のいくつかの例示であり、当業者には容易に理解され得るようにこれらのスキームの様々な改変が可能である。
本発明の一般式（Ｉ）で表される化合物、および当該化合物を製造するために使用される中間体は、必要に応じて、当該分野の当業者には周知の単離・精製手段である溶媒抽出、結晶化、再結晶、クロマトグラフィー、分取高速液体クロマトグラフィーなどの操作を行うことにより、単離・精製することができる。
このようにして製造される本発明の化合物は、脂肪の分解作用および／または熱産生促進作用を有するので肥満症の治療または予防剤として有用である。また、本発明の化合物は、必要に応じて、β_３−アドレナリン受容体作動薬以外の抗肥満薬と組み合わせて使用することができる。このような抗肥満薬としては、例えば、食欲抑制剤が挙げられる。当該食欲抑制剤としては、例えば、モノアミン再取り込み阻害剤、セロトニン作動薬、ドーパミン作動薬、ニューロペプチドＹアンタゴニスト、レプチン、またはＣＣＫ−Ａ（コレシストキニン−Ａ）アゴニストが挙げられる。本発明の化合物と組み合わせて使用されるモノアミン再取り込み阻害剤としては、例えば、シブトラミン、ミルナシプラン、デュロキセチンおよびベンラファキシンなどが挙げられる。本発明の化合物と組み合わせて使用されるセロトニン作動薬としては、例えば、フェンフルラミンおよびデキスフェンフルラミンなどが挙げられる。本発明の化合物と組み合わせて使用されるドーパミン作動薬は、例えば、ブロモクリプチンなどである。本発明の化合物と組み合わせて使用されるニューロペプチドＹアンタゴニストとしては、例えば、ＣＰ−６７１９０６−０１およびＪ−１１５８１４などが挙げられる。本発明の化合物と組み合わせて使用されるレプチンとしては、例えば、ヒト遺伝子組換え型レプチンなどが挙げられる。本発明の化合物と組み合わせて使用されるＣＣＫ−Ａアゴニストとしては、例えば、ＧＷ−７１７８およびＳＲ−１４６１３１などが挙げられる。
また、本発明の化合物は、血糖降下作用を有し、さらにはインスリン抵抗性改善作用を有するので糖尿病、特にＩＩ型糖尿病、および糖尿病に起因する疾患の治療または予防剤として有用である。また、本発明の化合物は、必要に応じて、β_３−アドレナリン受容体作動薬以外の抗糖尿病薬と組み合わせて使用することができる。このような抗糖尿病薬としては、例えば、α−グリコシダーゼ阻害剤、インスリン感受性増強剤、インスリン製剤、インスリン分泌促進剤、ビグアナイド、グルカゴン様ペプチド−１、ＤＰＰＩＶ阻害剤、およびＳＧＬＴ阻害剤が挙げられる。本発明の化合物と組み合わせて使用されるα−グリコシダーゼ阻害剤の具体例としては、例えば、アカルボース、ミグリトールおよびボグリボースなどが挙げられる。本発明の化合物と組み合わせて使用されるインスリン感受性増強剤の具体例としては、例えば、ピオグリタゾン、ロジグリタゾン、エングリタゾン、ダルグリタゾン、イサグリタゾン、ＭＣＣ−５５５、ＧＩ−２６２５７０、およびＪＴＴ−５０１などが挙げられる。本発明の化合物と組み合わせて使用されるインスリン製剤としては、例えば、遺伝子工学的に合成されたヒトインスリン、およびウシ、ブタの膵臓から抽出されたインスリンなどが挙げられる。本発明の化合物と組み合わせて使用されるインスリン分泌促進剤の具体例としては、例えば、トルブタミド、クロルプロパミド、トラザミド、アセトヘキサミド、グリベンクラミド、グリピシドおよびグリクラシドなどのスルホニルウレア剤、ならびにミチグリニド（ＫＡＤ−１２２９）、ナテグリニド（ＡＹ−４１６６）およびグリメピリド（Ｈｏｅ４９０）などが挙げられる。本発明の化合物と組み合わせて使用されるビグアナイドの具体例としては、例えば、フェンホルミン、メトホルミンおよびブトホルミンなどが挙げられる。本発明の化合物と組み合わせて使用されるグルカゴン様ペプチド−１（ＧＬＰ−１）としては、例えば、ＧＬＰ−１（１−３６）アミド、ＧＬＰ−１（７−３６）アミドおよびＧＬＰ−１（７−３７）などが挙げられる。本発明の化合物と組み合わせて使用されるＤＰＰＩＶ（ｄｉｐｅｐｔｉｄｙｌ ｐｅｐｔｉｄａｓｅ ＩＶ）阻害剤の具体例としては、例えば、Ｐ−３２／９８、およびＮＶＰ−ＤＰＰ−７２８などが挙げられる。本発明の化合物と組み合わせて使用されるＳＧＬＴ（Ｎａ−ｄｅｐｅｎｄｅｎｔ ｇｌｕｃｏｓｅ ｃｏｔｒａｎｓｐｏｒｔｅｒ）阻害剤としては、例えば、ＷＯ０１／１６１４７、ＷＯ０１／６８６６０、ＷＯ０１／２７１２８、ＷＯ０１／７４８３４、ＷＯ０１／７４８３５、ＷＯ０２／２８８７２、ＷＯ０２／４４１９２、ＷＯ０２／５３５７３、ＷＯ０２／６４６０６、ＷＯ０２／６８４３９、ＷＯ０２／６８４４０、ＷＯ０２／９８８９３、ＥＰ８５０９４８、ＪＰ１２／０８００４１、ＪＰ１１／２１２４３、ＪＰ０９／１８８６２５に開示されたＳＧＬＴ阻害剤が挙げられる。
また、本発明の化合物は、血清トリグリセリド低下作用および／またはコレステロール低下作用を有するので高脂血症の治療または予防剤として有用である。本発明の化合物は、必要に応じて、β_３−アドレナリン受容体作動薬以外の抗高脂血症用剤と組み合わせて使用することができる。このような抗高脂血症用剤としては、例えば、ＨＭＧ−ＣｏＡ還元酵素阻害剤、陰イオン交換樹脂、フィブレート剤、ＭＴＰ阻害剤、ＣＥＴＰ阻害剤およびＡＣＡＴ阻害剤が挙げられる。また、本発明の化合物と組み合わせて使用されるＨＭＧ−ＣｏＡ還元酵素阻害剤の具体例としては、例えば、プラバスタチン、シンバスタチン、フルバスタチン、アトロバスタチン、セリバスタチンおよびニスバスタチンなどが挙げられる。本発明の化合物と組み合わせて使用される陰イオン交換樹脂の具体例としては、例えば、コレスチラミンおよびコレスチポールなどが挙げられる。本発明の化合物と組み合わせて使用されるフィブレート剤の具体例としては、例えば、ベザフィブラート、フェノフィブラート、ゲムフィブロジル、シンフィブラート、シプロフィブラートおよびクリノフィブラートなどが挙げられる。本発明の化合物と組み合わせて使用されるＭＴＰ（ｍｉｃｒｏｓｏｍａｌ ｔｒｉｇｌｙｃｅｒｉｄｅ ｔｒａｎｓｆｅｒ ｐｒｏｔｅｉｎ）阻害剤としては、例えば、ＢＭＳ−２０１０３８、ＢＭＳ−２１２１２２、およびＲ−１０３７５７などが挙げられる。本発明の化合物と組み合わせて使用されるＣＥＴＰ（ｃｈｏｌｅｓｔｅｒｙｌ ｅｓｔｅｒ ｔｒａｎｓｆｅｒ ｐｒｏｔｅｉｎ）阻害剤の具体例としては、例えば、ＣＥＴｉ−１、ＪＴＴ−７０５、およびＣＰ−５２９４１４などが挙げられる。本発明の化合物と組み合わせて使用されるＡＣＡＴ（ａｃｙｌ−ＣｏＡ：ｃｈｏｌｅｓｔｅｒｏｌ Ｏ−ａｃｙｌ ｔｒａｎｓｆｅｒａｓｅ）阻害剤の具体例としては、例えば、アバシミベ（ＣＩ−１０１１）、およびエフルシミベ（Ｆ−１２５１１）などが挙げられる。
また、本発明の化合物は、脳におけるβ_３−アドレナリン受容体の刺激により抗うつ作用を示すのでうつ病の治療または予防剤として有用である。
また、本発明の化合物は、膀胱排尿筋を弛緩させ、膀胱用量を増加させる作用を有するので排尿障害（例えば、神経性頻尿症、神経因性膀胱機能障害、夜間頻尿症、不安定膀胱、膀胱痙攣、慢性膀胱炎、慢性前立腺炎、前立腺肥大などにおける頻尿症、尿失禁など）の治療または予防剤として有用である。また、本発明の化合物は、必要に応じて、β_３−アドレナリン受容体作動薬以外の排尿障害治療薬と組み合わせて使用することができる。このような排尿障害治療薬としては、例えば、抗コリン剤、α_１−アドレナリン受容体アンタゴニスト、ＮＫ_１アンタゴニストおよびカリウムチャネルオープナーが挙げられる。本発明の化合物と組み合わせて使用される抗コリン剤の具体例としては、例えば、オキシブチニン、プロピベリン、トルテリジンなどが挙げられる。本発明の化合物と組み合わせて使用されるα_１−アドレナリン受容体アンタゴニストの具体例としては、例えば、タムスロシン、ウラピジル、ナフトピジルおよびシロドシン（ＫＭＤ−３２１３）などが挙げられる。本発明の化合物と組み合わせて使用されるＮＫ_１（Ｎｅｕｒｏｋｉｎｉｎ １）アンタゴニストの具体例としては、例えば、ＴＡＫ−６３７などが挙げられる。本発明の化合物と組み合わせて使用されるカリウムチャネルオープナーの具体例としては、例えば、ＫＷ−７１５８などが挙げられる。
また、本発明の化合物は、腸管運動の抑制作用を有するので消化管機能亢進に由来する疾患（例えば、食道アカラシア、胃炎、胆嚢炎、膵炎、腹膜炎、感染性腸炎、潰瘍性大腸炎、クローン病、過敏性腸症候群、大腸憩室炎、単純性下痢など）の治療または予防剤として有用である。
本発明の前記一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩を有効成分として含有する医薬組成物は、用法に応じ種々の剤型のものが使用される。このような剤型としては例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤、軟膏剤、坐剤、貼付剤などを挙げることができ、経口または非経口的に投与される。
これらの医薬組成物は、その剤型に応じ製剤学的に公知の手法により、適切な賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤などの医薬品添加物と適宜混合または希釈・溶解することにより調剤することができる。
一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩の投与量は患者の年齢、性別、体重、疾患および治療の程度等により適宜決定されるが、経口投与の場合成人１日当たり約０．０１ｍｇ〜約１００ｍｇの範囲で、非経口投与の場合は、成人１日当たり約０．００３ｍｇ〜約３０ｍｇの範囲で、一回または数回に分けて適宜投与することができる。
本発明の一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩と、β_３−アドレナリン受容体作動薬以外の抗肥満薬、抗糖尿病剤、抗高脂血症用剤および排尿障害治療薬から選択される少なくとも１種とを組み合わせてなる医薬は、これらの有効成分を一緒に含有する製剤、またはこれらの有効成分の各々を別々に製剤化した製剤として投与することができる。別々に製剤化した場合、それらの製剤を別々にまたは同時に投与することができる。また、別々に製剤化した場合、それらの製剤を使用時に希釈剤などを用いて混合し、同時に投与することができる。
本発明の一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩と、β_３−アドレナリン受容体作動薬以外の抗肥満薬、抗糖尿病剤、抗高脂血症用剤および排尿障害治療薬から選択される少なくとも１種とを組み合わせてなる医薬において、薬剤の投与量は、患者の年齢、性別、および体重、症状、投与時間、剤形、投与方法、薬剤の組み合わせなどにより、適宜選択することができる。
本発明の一般式（Ｉ）で表される化合物は、ヒトβ_３−アドレナリン受容体に対して強力な刺激作用を有する。さらに本発明の化合物は、β_３−アドレナリン受容体刺激作用に比べて軽微なβ_１−および／またはβ_２−アドレナリン受容体刺激作用しか示さないので、肥満症、糖尿病、高脂血症、うつ病、排尿障害、胆石および胆道運動亢進に由来する疾患、または消化管機能亢進に由来する疾患の治療または予防剤として好適である。We have human β ₃ A strong stimulatory action on adrenergic receptors, preferably β ₁ − And / or β ₂ -As a result of extensive research on novel compounds with reduced adrenergic receptor stimulating action, aminoalcohol derivatives represented by the general formula (I) are surprisingly ₁ − And / or β ₂ -Stronger human beta compared to adrenergic receptors ₃ -It has been found that it has an adrenergic receptor stimulating action, and the present invention has been completed.
That is, the present invention relates to the general formula (I):

[Where,
R ¹ And R ² Are each independently a hydrogen atom, halogen atom, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cycloalkyl group, heterocycloalkyl group, lower alkoxy group, hydroxyl group, di-lower alkylamino group, cyclic amino Group, di-lower alkylamino lower alkyl group, aryl group, aryloxy group, aralkyloxy group, heteroaryl group, cyano group, lower acyl group, lower alkylsulfanyl group or lower alkylsulfonyl group;
R ³ Is a hydrogen atom, a lower alkyl group or an aralkyl group;
R ⁴ Represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a heteroaralkyl group, or R ³ And R ⁴ Together,-(CH ₂ ) _m -Forming;
R ⁵ Is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R ⁶ Is a hydroxyl group, a lower alkoxy group, an aralkyloxy group, or —N (R ⁷ ) (R ⁸ );
R ⁷ And R ⁸ Each independently represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, or R ⁷ And R ⁸ Together with the nitrogen atom to form a cyclic amine;
A ¹ Is a bond or a lower alkylene group;
X is a bond or an oxygen atom;
m is an integer from 3 to 5;
n is an integer of 2 to 5]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
In still another aspect, the present invention relates to obesity, diabetes, hyperlipidemia, depression, dysuria, which contains the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, The present invention relates to a therapeutic or prophylactic agent for diseases caused by gallstones and biliary hyperactivity, or diseases caused by enhanced gastrointestinal function.
In still another aspect, the present invention provides a compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof, ₃ -It relates to a pharmaceutical comprising a combination of at least one selected from an anti-obesity agent other than an adrenergic receptor agonist, an anti-diabetic agent, an anti-hyperlipidemic agent and a dysuria drug.
In yet another aspect, the present invention provides a therapeutic or preventive agent for obesity, diabetes, hyperlipidemia, depression, dysuria, diseases derived from gallstones and hyperbiliary motility, or diseases derived from increased gastrointestinal function. The use of the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof for the production of
In still another aspect, the present invention provides a method for treating or preventing obesity, diabetes, hyperlipidemia, depression, dysuria, diseases derived from gallstones and hyperbiliary motility, or diseases derived from increased gastrointestinal function. The method includes a step of administering an effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
In the compound represented by the general formula (I), the following terms have the following meanings unless otherwise specified.
The “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
The “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl. Group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like. R ¹ , R ² And R ³ The lower alkyl group in is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group. R ⁴ And R ⁵ The lower alkyl group in is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group, an isopropyl group or an isobutyl group.
“Halo lower alkyl group” means a lower alkyl group substituted with 1 to 3 of the same or different halogen atoms, such as a trifluoromethyl group, 2-chloroethyl group, 2-fluoroethyl group, 2 , 2,2-trifluoroethyl group, 2,2,2-trichloroethyl group and the like.
“Hydroxy lower alkyl group” means a lower alkyl group substituted with a hydroxyl group, for example, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group. Etc.
The “cycloalkyl group” means a saturated cyclic hydrocarbon group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
The “heterocycloalkyl group” means a 4 to 7-membered saturated heterocyclic group containing a hetero atom selected from an oxygen atom and a sulfur atom in the ring, and includes, for example, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydro group. A pyranyl group etc. are mentioned.
The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec- Examples include butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
The “di-lower alkylamino group” means an amino group disubstituted with a lower alkyl group, and examples thereof include a dimethylamino group and a diethylamino group.
The “di-lower alkylamino lower alkyl group” means a lower alkyl group substituted with a di-lower alkylamino group, and examples thereof include a dimethylaminomethyl group.
The “cyclic amine or cyclic amino group” means a 5- to 7-membered saturated cyclic amino group that may contain an oxygen atom in the ring, and examples thereof include a pyrrolidyl group, a piperidyl group, and a morpholinyl group.
"Lower acyl group" means a group represented by (lower alkyl) -C (O)-, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, isovaleryl group, etc. Is mentioned.
"Lower alkylsulfanyl group" means a group represented by (lower alkyl) -S-, for example, methylsulfanyl group, ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl group, butylsulfanyl group, pentylsulfanyl group And a hexylsulfanyl group.
The “lower alkylsulfonyl group” means (lower alkyl) -SO ₂ -Means a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, a hexanesulfonyl group, and the like.
“Carboxy lower alkyl group” means a lower alkyl group substituted with a carboxy group, for example, carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group. Groups and the like.
"Lower alkoxycarbonyl group" means a group represented by (lower alkoxy) -C (O)-, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group , Isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, etc., preferably methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group Or a butoxycarbonyl group.
“Lower alkoxycarbonyl lower alkyl group” means a lower alkyl group substituted by a lower alkoxycarbonyl group, and includes, for example, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, an isopropoxycarbonylmethyl group, a butoxy group. Examples include carbonylmethyl group, 2- (ethoxycarbonyl) ethyl group, 1- (ethoxycarbonyl) ethyl group, 3- (ethoxycarbonyl) propyl group, 4- (ethoxycarbonyl) butyl group, and preferably methoxycarbonylmethyl. A ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, an isopropoxycarbonylmethyl group, or a butoxycarbonylmethyl group.
The “aryl group” is unsubstituted or independently selected from the group consisting of: a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a hydroxyl group, a carboxy group, and a lower alkoxycarbonyl group. Means an aromatic hydrocarbon group having 6 to 14 carbon atoms, which is substituted with a group of, for example, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group 3,5-dichlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-hydroxyphenyl group, 4-carboxyphenyl group, 4-methoxycarbonyl A phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, etc. are mentioned.
“Aryloxy group” means a group represented by (aryl) -O—, for example, phenoxy group, 2-fluorophenoxy group, 3-fluorophenoxy group, 4-fluorophenoxy group, 2-chlorophenoxy group. Group, 4-chlorophenoxy group, 3,5-dichlorophenoxy group, 4-methylphenoxy group, 4-trifluoromethylphenoxy group, 2-methoxyphenoxy group, 4-methoxyphenoxy group, 2-hydroxyphenoxy group, 4- Carboxyphenoxy group, 4-methoxycarbonylphenoxy group, naphthyloxy group, anthryloxy group, phenanthryloxy group and the like can be mentioned.
The “aralkyl group” means a lower alkyl group substituted with an aryl group, such as benzyl group, phenethyl group, 3-phenylpropyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group. Group, 2-chlorobenzyl group, 3,5-dichlorobenzyl group, 4-methylbenzyl group, 4-trifluoromethylbenzyl group, 2-methoxybenzyl group, 4-hydroxybenzyl group, 4-carboxybenzyl group, 4- A methoxycarbonyl benzyl group etc. are mentioned, A benzyl group is preferred.
The “aralkyloxy group” means a lower alkoxy group substituted with an aryl group. For example, benzyloxy group, phenethyloxy group, 3-phenylpropyloxy group, 2-fluorobenzyloxy group, 3-fluorobenzyloxy group Group, 4-fluorobenzyloxy group, 2-chlorobenzyloxy group, 3,5-dichlorobenzyloxy group, 4-methylbenzyloxy group, 4-trifluoromethylbenzyloxy group, 2-methoxybenzyloxy group, 2- A hydroxybenzyloxy group, 4-carboxybenzyloxy group, 4-methoxycarbonylbenzyloxy group and the like can be mentioned.
“Heteroaryl group” means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms; However, these rings do not contain an adjacent oxygen atom and / or sulfur atom. Specific examples of heteroaryl groups include, for example, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidyl Groups and the like. All positional isomers of these aromatic heterocyclic groups are conceivable (for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.). These aromatic heterocycles are optionally selected from 1 to 3 groups independently selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups, hydroxyl groups, carboxy groups, and lower alkoxycarbonyl groups. Can be substituted.
The “heteroaralkyl group” means a lower alkyl group substituted with a heteroaryl group, and examples thereof include a 2-pyridylmethyl group, a 3-pyridylmethyl group, and a 4-pyridylmethyl group.
The “lower alkylene group” means a linear or branched divalent saturated hydrocarbon chain having 1 to 4 carbon atoms, for example, —CH ₂ -, -CH ₂ CH ₂ -, -CH (CH ₃ )-, -CH ₂ CH ₂ CH ₂ -, -CH (CH ₃ ) CH ₂ -, -CH ₂ CH (CH ₃ )-, -C (CH ₃ ) ₂ -, -CH (CH ₂ CH ₃ )-, -CH ₂ CH ₂ CH ₂ CH ₂ Groups such as-.
When one or more asymmetric carbon atoms are present in the compound represented by the general formula (I) of the present invention, the present invention is a compound in which each asymmetric carbon atom is R configuration, S configuration compound, And any combination of these compounds. Also included within the scope of the present invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures. When geometric isomerism exists in the compound represented by the general formula (I) of the present invention, the present invention includes any of the geometric isomers. Furthermore, the compound represented by the general formula (I) of the present invention includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
The compound represented by the general formula (I) of the present invention can exist in the form of a salt. Such salts include addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfone Acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, addition salts with organic acids, sodium salts, Examples thereof include salts with inorganic bases such as potassium salts and calcium salts, and salts with organic bases such as triethylamine, piperidine, morpholine and lysine.
In the present invention, the “prodrug” means a compound that is converted into the general formula (I) in vivo, and such a prodrug is also within the scope of the present invention. Various forms of prodrugs are well known in the art.
For example, when the compound represented by the general formula (I) of the present invention has a carboxy group, as a prodrug, a hydrogen atom of the carboxy group and the following group: a lower alkyl group (for example, a methyl group, Ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, etc.); lower acyloxymethyl group (for example, pivaloyloxymethyl group); 1- (lower acyloxy) ethyl group (for example, 1- (pivaloyloxy) A lower alkoxycarbonyloxymethyl group (eg, tert-butoxycarbonyloxymethyl group); 1- (lower alkoxycarbonyloxy) ethyl group (eg, 1- (tert-butoxycarbonyloxy) ethyl group) Or an ester formed by substitution with a 3-phthalidyl group It is below.
When the compound represented by the general formula (I) of the present invention has a hydroxyl group, as a prodrug, a hydrogen atom of the hydroxyl group and the following group: lower acyl group (for example, acetyl group, propionyl group, Butyryl group, isobutyryl group, pivaloyl group, etc.); lower alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, etc.); succinoyl group; lower acyloxymethyl group (Eg, pivaloyloxymethyl group); 1- (lower acyloxy) ethyl group (eg, 1- (pivaloyloxy) ethyl group); or lower alkoxycarbonyloxymethyl group (eg, tert-butoxycarbonyloxymethyl group) Etc.) Compounds formed by the like.
The compound represented by the general formula (I) of the present invention is -NH or -NH. ₂ When having an amino group such as, as a prodrug, the hydrogen atom of the amino group and the following group: lower acyl group (for example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, etc.); Or the compound formed by substitution with a lower alkoxycarbonyl group (For example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group etc.) is mentioned.
These prodrug compounds are obtained by a method known per se, for example, T.W. W. Green and P.M. G. H. According to Wuts, “Protective Groups in Organic Synthesis”, 3rd edition, and references described therein, it can be produced from a compound represented by the general formula (I).
In the compound represented by the general formula (I),
R ¹ And R ² Are each independently a hydrogen atom, a halogen atom or a lower alkyl group, more preferably a hydrogen atom, a halogen atom or C _1-4 An alkyl group, still more preferably a hydrogen atom, a chlorine atom or a methyl group;
R ³ Is preferably a hydrogen atom;
R ⁴ Is preferably a hydrogen atom, a lower alkyl group or an aralkyl group;
R ⁵ Is preferably a hydrogen atom or a lower alkyl group;
R ⁶ Is preferably a hydroxyl group or a lower alkoxy group;
X is an oxygen atom in one aspect and a bond in another aspect;
When X is a bond, n is preferably 2 or 3, more preferably 2,
When X is an oxygen atom, n is preferably 2 or 3, and more preferably 2.
A preferred embodiment of the compound represented by formula (I) is:
X is a bond or a pharmacologically acceptable salt thereof.
A further preferred embodiment of the compound represented by formula (I) is:
X is a bond,
A compound in which n is 2, or a pharmacologically acceptable salt thereof.
Still further preferred embodiments of the compounds represented by general formula (I) are:
R ¹ And R ² Each independently represents a hydrogen atom, a halogen atom or a lower alkyl group, preferably R ¹ Is a hydrogen atom and R ² Is a halogen atom,
X is a bond,
A compound in which n is 2, or a pharmacologically acceptable salt thereof.
Still further preferred embodiments of the compounds represented by general formula (I) are:
R ¹ And R ² Each independently represents a hydrogen atom, a halogen atom or a lower alkyl group, preferably R ¹ Is a hydrogen atom and R ² Is a halogen atom,
R ³ Is a hydrogen atom,
R ⁴ Is a hydrogen atom, a lower alkyl group or an aralkyl group,
R ⁵ Is a hydrogen atom or a lower alkyl group,
R ⁶ Is a hydroxyl group or a lower alkoxy group,
A ¹ Is a bond,
X is a bond,
A compound in which n is 2, or a pharmacologically acceptable salt thereof.
Specific examples of preferred compounds of the invention are compounds selected from the group consisting of the following or pharmaceutically acceptable salts thereof:
(S) -2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3- Phenylpropionic acid;
(S) -2- (4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3-phenylpropionic acid; and
(S) -2- (4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -4-methylpentanoic acid.
The compound represented by the general formula (I) of the present invention can be produced by the method shown in Scheme 1 or 2.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, n and A ¹ Is as defined above, Y ¹ Represents a leaving group such as chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group, P ¹ Represents a hydrogen atom or a benzyl group)
Step 1-1
Aminoalcohol derivative (X) and alkylating agent (XI) are mixed with a base (eg, N, N-diisopropylethylamine, triethylamine, diisopropylamine, etc.) in an inert solvent (eg, N, N-dimethylformamide, acetonitrile, etc.). The compound represented by the general formula (Ia) is obtained by condensation in the presence or absence of ().
COR ⁶ Compound (Ia) in which is a carboxylic acid ester group can be converted to the corresponding carboxylic acid by hydrolysis using an aqueous alkaline solution in an appropriate solvent (for example, ethanol, etc.) as necessary. COR ⁶ Compound (Ia) in which is a carboxy group can be obtained by using a condensing agent (for example, diphenylphosphoryl azide, diethyl cyanophosphate, 1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride etc.) in the presence of NHR ⁷ R ⁸ Can be converted to the corresponding carboxylic acid amides.
Step 1-2
P ¹ Compound (Ia) in which is a benzyl group is obtained by reacting benzyl in an inert solvent (eg, ethanol, N, N-dimethylformamide, etc.) in the presence of a metal catalyst (eg, palladium carbon, platinum oxide, etc.) in a hydrogen atmosphere. By removing the group, it can be converted to the compound (I).

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, n, A ¹ And P ¹ Is as defined above)
Steps 2-1 and 2-2
Compound (Ia) is obtained by condensing amino alcohol derivative (X) and aldehyde derivative (XII) in the presence of a reducing agent in an appropriate solvent. Examples of the solvent that can be used in this reductive amination reaction include ethers such as tetrahydrofuran and 1,4-dioxane, halogenated carbons such as methylene chloride, organic carboxylic acids such as acetic acid, hydrocarbons such as toluene, methanol, and the like. , Alcohols such as ethanol, acetonitrile, and the like, and two or more of these solvents can be used in combination as necessary. Examples of the reducing agent include NaBH. ₄ , NaBH ₃ CN, NaBH (OAc) ₃ Alkali metal borohydrides such as BH ₃ ・ Pyridine, BH ₃ -Boranes such as N, N-diethylaniline are exemplified. Moreover, this reaction can be performed by adding acids, such as an acetic acid, p-toluenesulfonic acid, methanesulfonic acid, a sulfuric acid, hydrochloric acid, as needed. In this reaction, instead of using the reducing agent, a catalytic amount of a metal catalyst (for example, 5 to 10% palladium carbon, Raney nickel, platinum oxide, palladium black, 10% platinum carbon (sulfur poisoning), etc.) is present. Under hydrogen atmosphere can be performed. This reductive amination reaction is carried out by selecting appropriate reducing conditions according to the type of substituent in compound (XII).
P ¹ Compound (Ia) in which is a benzyl group can be converted to Compound (I) by debenzylation in the same manner as in Step 1-2.
The alkylating agent (XI) used in Scheme 1 can be produced by the method shown in Scheme 3.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, n, A ¹ And Y ¹ Is as defined above, Y ² Represents a chlorine atom, a bromine atom or a hydroxyl group)
Step 3-1
By reacting compound (XIII) with amino acid derivative (XIV) in an inert solvent (eg, tetrahydrofuran, methylene chloride, N, N-dimethylformamide, etc.) in the presence of a condensing agent, amide derivative (XIa) Is obtained. Examples of condensing agents that can be used in this amidation reaction include diphenylphosphoryl azide, diethyl cyanophosphate, 1,3-dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, benzotriazole Examples include -1-yloxytris (dimethylamino) phosphonium hexafluorophosphate. Moreover, this reaction can be performed by adding activators, such as N-hydroxysuccinimide and 1-hydroxybenzotriazole, as needed.
The amide derivative (XIa) is obtained by converting the compound (XIII) into an active ester (for example, 4-nitrophenyl ester, 2,5-dioxapyrrolidine ester, etc.) based on a conventional method, and then converting the amino acid derivative (XIV) It can also be obtained by condensation.
Step 3-2
Y ² Compound (XIa) in which is a hydroxyl group is reacted with a sulfonyl halide in an inert solvent (eg, methylene chloride, chloroform, etc.) in the presence of a halogenating reagent or a base (eg, N, N-diisopropylethylamine, etc.). Thus, the compound can be converted into a compound represented by the general formula (XI). Examples of such a halogenating reagent include thionyl chloride, phosphorus tribromide, triphenylphosphine / carbon tetrabromide, and the like. Examples of the sulfonyl chloride include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.
The aldehyde derivative (XII) used in Scheme 2 can be produced by the method shown in Scheme 4.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, n and A ¹ Is as defined above)
Step 4-1
The aldehyde derivative (XII) is obtained by oxidizing the alcohol derivative (XIb) in an inert solvent (for example, methylene chloride, etc.) using an appropriate oxidizing agent. Examples of such an oxidizing agent include oxalyl chloride / dimethyl sulfoxide or 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one. It is done.
The benzoic acid derivative (XIII) used in Scheme 3 can be synthesized using a commercially available reagent or according to a conventional method. For example, compound (XIIIa) can be produced by the method shown in Scheme 5.

(Wherein R ¹ , R ² , X and n are as defined above, and Y ³ Represents an iodine atom or a trifluoromethanesulfonyloxy group, R ²⁰ Represents a lower alkyl group)
Step 5-1
Compound (XV) is reacted with carbon monoxide and R in the presence of a phosphine ligand, a palladium catalyst and a base in an inert solvent. ²⁰ Compound (XVI) is obtained by reacting with OH. Examples of the solvent that can be used in this reaction include N, N-dimethylformamide, dimethyl sulfoxide and the like. Examples of the phosphine ligand include triphenylphosphine and 1,3-bis (diphenylphosphino) propane. Examples of the palladium catalyst include palladium acetate. Examples of the base include triethylamine.
Step 5-2
The benzoic acid derivative (XIIIa) is obtained by hydrolyzing the compound (XVI) in an appropriate solvent (for example, ethanol) using an aqueous alkaline solution.
The amino alcohol derivative (Xb) used in Schemes 1 and 2 can be produced by the method shown in Scheme 6.

(In the formula, Bn represents a benzyl group)
Steps 6-1 and 6-2
The aminoalcohol derivative (Xa) is trifluorinated with ethyl trifluoroacetate to give compound (XVII). The phenolic hydroxyl group of this compound (XVII) is combined with a benzyl halide (eg, benzyl chloride) in the presence of a base (eg, potassium carbonate) in an inert solvent (eg, N, N-dimethylformamide). When reacted, an O-benzyl derivative is obtained. Subsequently, the O-benzyl derivative is hydrolyzed using an aqueous alkaline solution by a conventional method to obtain compound (Xb).
The aminoalcohol derivative (Xa) can be obtained by optical resolution of a commercially available mixture of enantiomers according to a conventional method or a method described in the literature (for example, “J. Med. Chem.” 1977, Vol. 20, No. 7, p. 978-981). Can be synthesized according to
The schemes shown above are several examples of methods for preparing the compounds of the present invention or their intermediates, and various modifications of these schemes are possible as will be readily understood by those skilled in the art. It is.
The compound represented by the general formula (I) of the present invention and the intermediate used for producing the compound are isolation / purification means well known to those skilled in the art, if necessary. Isolation and purification can be performed by performing operations such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography and the like.
The compound of the present invention thus produced is useful as a therapeutic or prophylactic agent for obesity because it has an action of decomposing fat and / or promoting heat production. In addition, the compound of the present invention can be added as necessary. ₃ -Can be used in combination with anti-obesity drugs other than adrenergic receptor agonists. Examples of such anti-obesity agents include appetite suppressants. Examples of the appetite suppressant include a monoamine reuptake inhibitor, a serotonin agonist, a dopamine agonist, a neuropeptide Y antagonist, leptin, or a CCK-A (cholecystokinin-A) agonist. Examples of monoamine reuptake inhibitors used in combination with the compounds of the present invention include sibutramine, milnacipran, duloxetine and venlafaxine. Examples of serotonin agonists used in combination with the compounds of the present invention include fenfluramine and dexfenfluramine. An example of a dopamine agonist used in combination with a compound of the present invention is bromocriptine. Examples of the neuropeptide Y antagonist used in combination with the compound of the present invention include CP-671906-01 and J-115814. Examples of leptin used in combination with the compound of the present invention include human genetically modified leptin. Examples of the CCK-A agonist used in combination with the compound of the present invention include GW-7178 and SR-146131.
In addition, since the compound of the present invention has a hypoglycemic action and further has an insulin resistance improving action, it is useful as a therapeutic or preventive agent for diabetes, particularly type II diabetes, and diseases caused by diabetes. In addition, the compound of the present invention can be added as necessary. ₃ -Can be used in combination with anti-diabetic drugs other than adrenergic receptor agonists. Examples of such antidiabetic agents include α-glycosidase inhibitors, insulin sensitivity enhancers, insulin preparations, insulin secretagogues, biguanides, glucagon-like peptide-1, DPPIV inhibitors, and SGLT inhibitors. Specific examples of the α-glycosidase inhibitor used in combination with the compound of the present invention include acarbose, miglitol and voglibose. Specific examples of the insulin sensitivity enhancer used in combination with the compound of the present invention include, for example, pioglitazone, rosiglitazone, englitazone, darglitazone, isaglitazone, MCC-555, GI-262570, and JTT-501. It is done. Examples of the insulin preparation used in combination with the compound of the present invention include human insulin synthesized by genetic engineering and insulin extracted from bovine and porcine pancreas. Specific examples of the insulin secretagogue used in combination with the compound of the present invention include, for example, sulfonylureas such as tolbutamide, chlorpropamide, tolazamide, acetohexamide, glibenclamide, glipidoside and glicacside, and mitiglinide (KAD-1229). ), Nateglinide (AY-4166) and glimepiride (Hoe490). Specific examples of biguanides used in combination with the compounds of the present invention include phenformin, metformin, butformin and the like. Examples of glucagon-like peptide-1 (GLP-1) used in combination with the compound of the present invention include GLP-1 (1-36) amide, GLP-1 (7-36) amide and GLP-1 (7 -37). Specific examples of the DPPIV (dipeptidyl peptidase IV) inhibitor used in combination with the compound of the present invention include P-32 / 98 and NVP-DPP-728. SGLT (Na-dependent glucose transporter) inhibitors used in combination with the compounds of the present invention include, for example, WO01 / 16147, WO01 / 68660, WO01 / 27128, WO01 / 74834, WO01 / 74835, WO02 / 28872, WO02 / 44192, WO02 / 53573, WO02 / 64606, WO02 / 68439, WO02 / 68440, WO02 / 98893, EP850948, JP12 / 080041, JP111 / 21243, JP09 / 188625, and the like.
In addition, since the compound of the present invention has a serum triglyceride lowering action and / or a cholesterol lowering action, it is useful as a therapeutic or preventive agent for hyperlipidemia. The compounds of the present invention can be optionally synthesized according to β ₃ -It can be used in combination with antihyperlipidemic agents other than adrenergic receptor agonists. Examples of such antihyperlipidemic agents include HMG-CoA reductase inhibitors, anion exchange resins, fibrates, MTP inhibitors, CETP inhibitors, and ACAT inhibitors. Specific examples of the HMG-CoA reductase inhibitor used in combination with the compound of the present invention include pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and nisvastatin. Specific examples of the anion exchange resin used in combination with the compound of the present invention include cholestyramine and colestipol. Specific examples of the fibrate used in combination with the compound of the present invention include bezafibrate, fenofibrate, gemfibrozil, simfibrate, ciprofibrate and clinofibrate. Examples of the MTP (micro triglyceride transfer protein) inhibitor used in combination with the compound of the present invention include BMS-201038, BMS-212122, and R-103757. Specific examples of CETP (cholesteryl ester transfer protein) inhibitors used in combination with the compounds of the present invention include CETi-1, JTT-705, and CP-529414. Specific examples of ACAT (acyl-CoA) inhibitors used in combination with the compounds of the present invention include, for example, abashimibe (CI-1011) and efurushimibe (F-12511). .
The compounds of the present invention are also ₃ -It is useful as an agent for treating or preventing depression because it exhibits an antidepressant action upon stimulation of an adrenergic receptor.
In addition, since the compound of the present invention has the action of relaxing the bladder detrusor and increasing the bladder dose, dysuria (for example, neurogenic urination, neurogenic bladder dysfunction, nocturia, unstable bladder) , Bladder spasm, chronic cystitis, chronic prostatitis, frequent urination in prostatic hypertrophy, urinary incontinence, etc.). In addition, the compound of the present invention can be added as necessary. ₃ -It can be used in combination with urination disorder drugs other than adrenergic receptor agonists. Examples of such dysuria drugs include anticholinergic agents, α ₁ An adrenergic receptor antagonist, NK ₁ Antagonists and potassium channel openers are included. Specific examples of the anticholinergic agent used in combination with the compound of the present invention include oxybutynin, propiverine, tolteridine and the like. Α used in combination with a compound of the invention ₁ -Specific examples of adrenergic receptor antagonists include, for example, tamsulosin, urapidil, naphthopidyl and silodosin (KMD-3213). NK used in combination with compounds of the present invention ₁ Specific examples of (Neurokin 1) antagonist include, for example, TAK-637. Specific examples of the potassium channel opener used in combination with the compound of the present invention include, for example, KW-7158.
In addition, since the compound of the present invention has an action of suppressing intestinal motility, diseases derived from hypergastrointestinal function (for example, esophageal achalasia, gastritis, cholecystitis, pancreatitis, peritonitis, infectious enteritis, ulcerative colitis, Crohn's disease , Irritable bowel syndrome, colonic diverticulitis, simple diarrhea, etc.).
The pharmaceutical composition containing the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used in various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches and the like, orally or parenterally. Administered.
These pharmaceutical compositions are prepared according to pharmacologically known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives. It can be prepared by mixing or diluting / dissolving appropriately with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.
The dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, degree of treatment, etc. of the patient. In the case of parenteral administration in the range of about 0.01 mg to about 100 mg per day, it can be appropriately administered in one or several divided doses in the range of about 0.003 mg to about 30 mg per adult day.
A compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, and β ₃ -A pharmaceutical comprising a combination of at least one selected from an anti-obesity agent other than an adrenergic receptor agonist, an anti-diabetic agent, an anti-hyperlipidemic agent, and a dysuria drug, combines these active ingredients together The contained formulation or each of these active ingredients can be administered as a separately formulated formulation. When formulated separately, the formulations can be administered separately or simultaneously. Moreover, when it formulates separately, those formulations can be mixed using a diluent etc. at the time of use, and can be administered simultaneously.
A compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, and β ₃ -In a medicament comprising a combination of at least one selected from anti-obesity drugs other than adrenergic receptor agonists, anti-diabetic agents, anti-hyperlipidemic agents, and dysuria drugs, The age, sex, and body weight, symptoms, administration time, dosage form, administration method, drug combination, and the like can be appropriately selected.
The compound represented by the general formula (I) of the present invention is human β ₃ -Has a strong stimulating effect on adrenergic receptors. Furthermore, the compounds of the present invention are ₃ -Minor β compared to adrenergic receptor stimulation ₁ − And / or β ₂ -Treatment or prevention of diseases resulting from obesity, diabetes, hyperlipidemia, depression, dysuria, gallstones and increased biliary motility, or diseases resulting from hypergastrointestinal function because they only show adrenergic receptor stimulation Suitable as an agent.

The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to these contents.
Reference example 1
3-chloro-4- (2-hydroxyethyl) benzoic acid 3-chloro-4- (2-hydroxyethyl) phenyl trifluoromethanesulfonate (1.0 g), palladium acetate (0.0368 g), 1,3-bis A mixture of (diphenylphosphino) propane (0.0677 g) and triethylamine (1.014 ml) in methanol (10 ml) / dimethyl sulfoxide (15 ml) was stirred overnight at 80 ° C. in a carbon monoxide atmosphere. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain methyl 3-chloro-4- (2-hydroxyethyl) benzoate (0.7 g).
Subsequently, methyl 3-chloro-4- (2-hydroxyethyl) benzoate (0.7 g) in a mixture of water (2 mL) / 1,4-dioxane (5 mL) was mixed with lithium hydroxide monohydrate (1. 368 g) was added and stirred overnight. 2 mol / L hydrochloric acid (5 mL) was added and the reaction mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the resulting residue, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.584 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.10 (2H, t, J = 6.5 Hz), 3.95 (2H, dt, J = 1.5, 6.5 Hz), 7.41 (1H , D, J = 8.0 Hz), 7.93 (1H, d, J = 8.0 Hz), 8.10 (1H, s)
Reference example 2
(S) -2- [3-Chloro-4- (2-hydroxyethyl) benzoylamino] -3-phenylpropionic acid methyl 3-chloro-4- (2-hydroxyethyl) benzoic acid (0.25 g), 1 N-N-dimethylformamide (2 ml) mixed with ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.263 g) and 1-hydroxybenzotriazole (0.202 g) was mixed with L-phenylalanine methyl ester. Hydrochloric acid salt (0.296 g) was added and stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.41 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.05 (2H, t, J = 6.6 Hz), 3.22 (1H, dd, J = 5.4, 13.9 Hz), 3.29 (1H , Dd, J = 5.8, 13.9 Hz), 3.78 (3H, s), 3.91 (2H, t, J = 6.6 Hz), 5.02-5.10 (1 H, m) 6.51 (1H, d, J = 7.4 Hz), 7.05-7.85 (8H, m)
Reference example 3
The following compounds were obtained in the same manner as in Reference Example 2 using the corresponding benzoic acid derivatives and amino acid esters.
(S) -2- [3-Chloro-4- (2-hydroxyethyl) benzoylamino] -3-pyridin-3-ylpropionate ethyl
¹ H-NMR (CD ₃ OD) δ ppm: 1.24 (3H, t, J = 7.1 Hz), 3.01 (2H, t, J = 7.0 Hz), 3.15 (1H, dd, J = 9.6, 14.1 Hz), 3.35 (1H, dd, J = 5.7, 14.1 Hz), 3.78 (2H, t, J = 7.0 Hz), 4.20 (2H) , Q, J = 7.1 Hz), 4.86 (1H, dd, J = 5.7, 9.6 Hz), 7.37 (1H, dd, J = 5.0, 8.0 Hz), 7. 41 (1H, d, J = 8.0 Hz), 7.61 (1H, dd, J = 1.8, 8.0 Hz), 7.75-7.80 (2H, m), 8.39 (1H , Dd, J = 1.5, 5.0 Hz), 8.42-8.45 (1H, m)
Ethyl 2- [3-chloro-4- (2-hydroxyethyl) benzoylamino] -2-methylpropionate
¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (3H, t, J = 7.2 Hz), 1.68 (6H, s), 3.05 (2H, t, J = 6.6 Hz), 3.90 (2H, t, J = 6.6 Hz), 4.25 (2H, q, J = 7.2 Hz), 6.82 (1H, br s), 7.34 (1H, d, J = 8.0 Hz), 7.58 (1H, dd, J = 1.3, 8.0 Hz), 7.78 (1H, d, J = 1.3 Hz)
[4- (2-Bromoethyl) benzoylamino] acetic acid benzyl ester
¹ H-NMR (CDCl ₃ ) δ ppm: 3.19 (2H, t, J = 7.3 Hz), 3.56 (2H, t, J = 7.3 Hz), 4.25 (2H, d, J = 5.1 Hz), 5.21 (2H, s), 6.75-6.85 (1 H, m), 7.26 (2H, d, J = 8.2 Hz), 7.30-7.40. (5H, m), 7.76 (2H, d, J = 8.2 Hz)
(S) -2- [4- (2-Bromoethyl) benzoylamino] -3-phenylpropionic acid benzyl
¹ H-NMR (CDCl ₃ ) δ ppm: 3.20-3.35 (4H, m), 3.59 (2H, t, J = 7.3 Hz), 5.10-5.30 (3H, m ), 6.55 (1H, d, J = 7.3 Hz), 7.00-7.10 (2H, m), 7.20-7.45 (10H, m), 7.69 (2H, d) , J = 8.2Hz)
(S) -2- [4- (2-Bromoethyl) benzoylamino] -4-methylpentanoic acid benzyl
¹ H-NMR (CDCl ₃ ) δ ppm: 0.90-1.00 (6H, m), 1.60-1.80 (3H, m), 3.18 (2H, t, J = 7.2 Hz) ), 3.55 (2H, t, J = 7.2 Hz), 4.85-4.95 (1H, m), 5.19 (2H, d, J = 4.1 Hz), 6.71 (1H) , D, J = 8.2 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.25-7.40 (5H, m), 7.74 (2H, d, J = 8. 2Hz)
Reference example 4
(S) -2- [3-Chloro-4- (2-methanesulfonyloxyethyl) benzoylamino] -3-phenylpropionate methyl (S) -2- [3-chloro-4- (2-hydroxyethyl) Methylenesulfonyl chloride (0.092 mL) was added to a solution of methyl benzoylamino] -3-phenylpropionate (0.41 g) and triethylamine (0.191 mL) in methylene chloride (10 mL), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.499 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.92 (3H, s), 3.17-3.34 (4H, m), 3.78 (3H, s), 4.46 (2H, t, J = 6.7 Hz), 5.06 (1H, dt, J = 7.5, 5.5 Hz), 6.51 (1H, d, J = 7.4 Hz), 7.10-7.15 (2H) , M), 7.23-8.10 (6H, m)
Reference Example 5
The following compounds were obtained in the same manner as in Reference Example 4 using the corresponding phenethyl alcohol derivatives.
(S) -2- [3-Chloro-4- (2-methanesulfonyloxyethyl) benzoylamino] -3-pyridin-3-ylpropionate ethyl
¹ H-NMR (CDCl ₃ ) δ ppm: 1.30 (3H, t, J = 7.3 Hz), 2.93 (3H, s), 3.20-3.30 (3H, m), 3. 36 (1H, dd, J = 5.9, 14.3 Hz), 4.25 (2H, q, J = 7.3 Hz), 4.46 (2H, t, J = 6.7 Hz), 5.04 (1H, dd, J = 5.8, 7.2 Hz), 6.80 (1H, d, J = 7.1 Hz), 7.31 (1H, dd, J = 4.9, 7.7 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.55-7.63 (2H, m), 7.81 (1H, d, J = 1.8 Hz), 8.46 (1H, d , J = 1.8 Hz), 8.50-8.55 (1H, m)
Ethyl 2- [3-chloro-4- (2-methanesulfonyloxyethyl) benzoylamino] -2-methylpropionate
¹ H-NMR (CDCl ₃ ) δ ppm: 1.30 (3H, t, J = 7.1 Hz), 1.69 (6H, s), 2.92 (3H, s), 3.24 (2H, t, J = 6.6 Hz), 4.25 (2H, q, J = 7.1 Hz), 4.46 (2H, t, J = 6.6 Hz), 6.84 (1H, br s), 7 .36 (1H, d, J = 8.0 Hz), 7.62 (1H, dd, J = 1.9, 8.0 Hz), 7.82 (1H, d, J = 1.9 Hz)
Reference Example 6
(4- {2-[(1S, 2R) -2- (4-benzyloxyphenyl) -2-hydroxy-1-methylethylamino] ethyl} benzoylamino) benzyl acetate (1R, 2S) -2-amino- N, N-dimethylformamide (3 ml) mixture of 1- (4-benzyloxyphenyl) propan-1-ol (0.0653 g) and [4- (2-bromoethyl) benzoylamino] acetic acid benzyl (0.0954 g) Was added diisopropylamine (0.053 ml), and the mixture was stirred at 70 ° C. for 20 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 15/1) to obtain the title compound (0.0548 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 0.86 (3H, d, J = 6.6 Hz), 2.75-2.95 (4H, m), 2.95-3.05 (1H, m ), 4.18 (2H, dd, J = 1.9, 5.0 Hz), 4.62 (1H, d, J = 4.4 Hz), 5.03 (2H, s), 5.19 (2H) , S), 6.80 (1H, t, J = 5.4 Hz) 6.91 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 7. 20 (2H, d, J = 8.5 Hz), 7.25-7.45 (10H, m), 7.70 (2H, d, J = 8.2 Hz)
Reference Example 7
The following compounds were obtained in the same manner as in Reference Example 6 using the corresponding phenethyl bromide derivatives.
(S) -2- (4- {2-[(1S, 2R) -2- (4-benzyloxyphenyl) -2-hydroxy-1-methylethylamino] ethyl} benzoylamino) -3-phenylpropionic acid Benzyl
¹ H-NMR (CDCl ₃ ) δ ppm: 0.86 (3H, d, J = 6.3 Hz), 2.80-3.10 (6H, m), 3.15-3.30 (2H, m ), 4.72 (1H, d, J = 3.8 Hz), 5.03 (2H, m), 5.05-5.25 (2H, m), 6.65 (1H, d, J = 7) .6 Hz), 6.91 (2H, d, J = 8.9 Hz), 7.00-7.05 (2H, m), 7.15-7.45 (17H, m), 7.64 (2H) , D, J = 8.2 Hz)
(S) -2- (4- {2-[(1S, 2R) -2- (4-benzyloxyphenyl) -2-hydroxy-1-methylethylamino] ethyl} benzoylamino) -4-methylpentanoic acid Benzyl
¹ H-NMR (CDCl ₃ ) δ ppm: 0.86 (3H, d, J = 6.3 Hz), 0.90-1.00 (9H, m), 1.60-1.80 (3H, m ), 2.95-3.15 (5H, m), 4.85-4.95 (2H, m), 5.03 (2H, s), 5.15-5.25 (2H, m), 6.66 (1H, d, J = 8.2 Hz), 6.91 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 7.25 (2H , D, J = 8.2 Hz), 7.30-7.45 (10H, m), 7.72 (2H, d, J = 8.2 Hz)

(4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) acetic acid (Compound 1)
(4- {2-[(1S, 2R) -2- (4-Benzyloxyphenyl) -2-hydroxy-1-methylethylamino] ethyl} benzoylamino) acetic acid benzyl (0.0548 g) and 10% palladium carbon (0.025 g) of tetrahydrofuran (1 mL) was stirred for 5 hours under a hydrogen atmosphere at room temperature. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (0.0236 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.87 (3H, d, J = 6.3 Hz), 2.70-3.00 (5H, m), 3.76 (2H, d, J = 5.4 Hz), 4.55-4.65 (1 H, m), 6.68 (2 H, d, J = 8.2 Hz), 7.06 (2 H, d, J = 8.2 Hz), 7 .23 (2H, d, J = 7.9 Hz), 7.74 (2H, d, J = 7.9 Hz), 8.34 (1H, br)

The following compounds were obtained in the same manner as in Example 1 using the corresponding dibenzyl derivatives.
(S) -2- (4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3-phenylpropionic acid ( Compound 2)
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.94 (3H, d, J = 6.3 Hz), 2.90-3.45 (7H, m), 4.55-4.65 (1H M), 4.97 (1H, br), 6.75 (2H, d, J = 8.5 Hz), 7.10-7.20 (3H, m), 7.20-7.40 (6H). M), 7.77 (2H, d, J = 8.2 Hz), 8.59 (1H, d, J = 7.9 Hz), 9.36 (1H, br)
(S) -2- (4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -4 methylpentanoic acid (compound 3)
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.85-0.90 (6H, m), 0.92 (3H, d, J = 6.6 Hz), 1.55-1.80 (3H M), 2.80-3.15 (5H, m), 4.35-4.45 (1H, m), 4.75-4.85 (1H, m), 6.72 (2H, d). , J = 8.5 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8. 2 Hz), 7.95 (1 H, s), 8.38 (1 H, d, J = 7.6 Hz), 9.33 (1 H, br)

(S) -2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3- Phenylpropionic acid (compound 4)
Process 1
(S) -2- [3-Chloro-4- (2-methanesulfonyloxyethyl) benzoylamino] -3-phenylpropionate methyl (0.499 g) and 4-((1R, 2S) -2-amino- N, N-Diisopropylethylamine (0.296 mL) was added to a solution of 1-hydroxypropyl) phenol (0.284 g) in N, N-dimethylformamide (10 mL), and the mixture was stirred at 80 ° C. overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified with an SCX ion exchange column conditioned with tetrahydrofuran (1 g made by Argonaute, washing solvent: tetrahydrofuran, elution solvent: 2 mol / L ammonia methanol solution), ( S) -2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3-phenylpropi Methyl onate was obtained.
Process 2
(S) -2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} obtained in Step 1 Methyl benzoylamino) -3-phenylpropionate was dissolved in 1,4-dioxane (5 mL), 2 mol / L aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature overnight. 2 mol / L hydrochloric acid (1 mL) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to reverse-phase preparative column chromatography (CAPEELL PAK C18 ODS, manufactured by Shiseido Co., Ltd., 5 μm, 120 mm, 20 × 50 mm, linear gradient, 0.1% aqueous formic acid / acetonitrile = 90 / 10-60 / 40). And purified under reduced pressure to obtain the title compound (0.035 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.95 (3H, d, J = 6.5 Hz), 2.95-3.55 (7H, m), 4.43-4.50 (1H M), 4.92-4.95 (1H, m), 6.76 (2H, d, J = 8.6 Hz), 7.10-7.30 (7H, m), 7.43 (1H) , D, J = 8.0 Hz), 7.67 (1H, dd, J = 1.7, 8.0 Hz), 7.81 (1H, d, J = 1.7 Hz), 8.25-8. 30 (2H, m)
MS (ESI, m / z): 497 (M + H) ⁺

^１）；１０^−１０Ｍから２×１０^−４Ｍまでの全ての濃度において内活性が５０％以下を示した。
このように本発明の化合物は、ヒトβ_３−アドレナリン受容体に対して強力な刺激作用を示した。また本発明の化合物は、β_３−アドレナリン受容体刺激作用に比べて軽微なβ_１−およびβ_２−アドレナリン受容体刺激作用しか持たないことが示された。The following compounds were obtained in substantially the same manner as in Example 3 using the corresponding methanesulfonyl derivatives.
(S) -2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3- Pyridin-3-ylpropionic acid (Compound 5)
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.90 (3H, d, J = 6.6 Hz), 2.95-3.30 (9H, m), 4.48-4.58 (1H M), 4.85-4.90 (1H, m), 6.73 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.25. (1H, dd, J = 4.8, 7.8 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.65-7.70 (2H, m), 7.83 (1H, d, J = 1.7 Hz), 8.36 (1H, dd, J = 1.7, 4.8 Hz), 8.45 (1H, d, J = 1.8 Hz), 8.55 (1H, d , J = 7.8Hz)
MS (ESI, m / z): 498 (M + H) ⁺
2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -2-methylpropionic acid ( Compound 6)
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.87 (3H, d, J = 6.6 Hz), 1.45 (6H, s), 2.90-3.00 (5H, m), 4.66 (1H, d, J = 3.6 Hz), 6.70 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.40 (1H , D, J = 8.1 Hz), 7.70 (1H, dd, J = 1.6, 8.1 Hz), 7.86 (1H, d, J = 1.6 Hz), 8.53 (1H, s)
Test example 1
1. Measurement of human β-adrenergic receptor agonist activity Measurement of human β ₃ -adrenoceptor agonist activity A test compound was dissolved in 50% dimethyl sulfoxide to 10 ⁻² M, and further 1 × 10 5 with D-PBS (−) (Gibco-BRL: LIFE TECHNOLOGIES). A 10-fold dilution series with ^-3 M as the highest dose was prepared and used as a sample for activity measurement. SK-N-MC cells (American Type Culture Collection, 1 × 10 ³ cells / mL) were placed in a 96-well plate in a volume of 100 μL and cultured for about 24 hours. 40 μL of D-PBS (−) and 20 μL of CGP-201712A (Funakoshi, 3 × 10 ⁻⁶ mol / L D-PBS (−) solution) were added and reacted for 20 minutes. Thereafter, 20 μL of 3-isobutyl-1-methylxanthine (SIGMA, 1 × 10 ⁻² mol / L D-PBS (−) solution) and 20 μL of the sample were added and incubated at 37 ° C. under 5% CO ₂ for 30 minutes. . The cAMP concentration accumulated in the cells was reacted with cAMP-Screen (Applied Biosystems) and detected with Microplate Luminometer TR717 (Applied Biosystems). The maximum reaction of isoproterenol, which is a positive control, was taken as 100%, and the concentration of the test compound that gave 50% of the reaction was calculated as the EC ₅₀ value. The ratio of the maximum response of each test compound to the maximum response of isoproterenol was calculated as internal activity (IA). Isoproterenol was similarly tested as a control. The results are shown in Table 1.
2. Measurement of human β ₁ -and β ₂ -adrenergic receptor agonist activity 1) Preparation of human β ₁ -and β ₂ -adrenergic receptor expression plasmid vector (1) Human β ₁ -adrenergic receptor Accession No. in GenBank / EMBL database . Based on the DNA base information registered as J03019, both ends of the region including the full length of the human β ₁ -adrenergic receptor were amplified. The amplified DNA fragment was inserted into a cloning vector and then amplified in E. coli. The cloned plasmid was incorporated into a protein expression vector pCI-neo (manufactured by Promega), the plasmid DNA was extracted and purified, and used for the preparation of the following expression cells.
(2) Human β ₂ -adrenergic receptor Accession No. in GenBank / EMBL database. Based on the base information registered as M15169, a primer having a restriction enzyme recognition site added at the 5 ′ end was designed, and PCR was performed using human bladder-derived cDNA as a template to obtain a clone. The clone was incorporated into pGEM-Tvector and amplified with Escherichia coli as a plasmid, followed by purification, and the sequence was determined using 310 Genetic Analyzer (manufactured by ABI) over the entire length of the inserted sequence and before and after. The cloned DNA fragment was not different from the base information registered in the GenBank / EMBL database.
2) Preparation of human β ₁ -and β ₂ -adrenergic receptor expressing cells (1) Preparation of human β ₁ -adrenergic receptor expressing cells DMEM medium (Gibco-BRL: 10% fetal calf serum (Sanko Junyaku)) LIFE cells (manufactured by TECHNOLOGIES) and suspended in ⁴ × 10 ⁴ CHO cells were transfected with 320 ng of the expression plasmid obtained in the previous section using Lipofectamine 2000 (Invitrogen). The cells were dispensed in a 96-well plate at 5 × 10 ⁴ cells / 100 μL per well. After culturing at 37 ° C. under 5% CO ₂ for 24 hours, it was used for measurement.
(2) Preparation of human β ₂ -adrenergic receptor-expressing cells For 5 × 10 ⁴ CHO cells suspended in DMEM medium containing 10% fetal calf serum, 80 ng of the expression plasmid obtained in the previous section was used with Lipofectamine2000. Transfected. The cells were dispensed in a 96-well plate at 5 × 10 ⁴ cells / 100 μL per well. After culturing at 37 ° C. under 5% CO ₂ for 24 hours, it was used for measurement.
3) Measurement of human β ₁ -and β ₂ -adrenergic receptor agonist activity The test compound was dissolved in 50% dimethyl sulfoxide to 10 ⁻² M, and further 2 × 10 ⁻⁴ M was added with D-PBS (−). A 10-fold dilution series with the highest dose was prepared and used as a sample for activity measurement. After removing the culture medium of CHO cells of the previous section and washing twice with 200 μL per well using D-PBS (−), 50 μL of 1 mM 3-isobutyl-1-methylxanthine (SIGMA) was added at room temperature. Then, the sample was added in an amount of 50 μL, and incubated at 37 ° C. and 5% CO ₂ for 30 minutes. The cAMP concentration accumulated in the cells was reacted with cAMP-Screen and detected with Microplate Luminometer TR717. The maximum reaction of isoproterenol, which is a positive control, was taken as 100%, and the concentration of the test compound that gave 50% of the reaction was calculated as the EC ₅₀ value. The ratio of the maximum response of each test compound to the maximum response of isoproterenol was calculated as internal activity (IA). Isoproterenol was similarly tested as a control. The results are shown in Table 1.

¹⁾ ; The internal activity was 50% or less at all concentrations from 10 ⁻¹⁰ M to 2 × 10 ⁻⁴ M.
Thus, the compound of the present invention showed a strong stimulating action on the human β ₃ -adrenergic receptor. Further, it was shown that the compound of the present invention has a slight β ₁ -and β ₂ -adrenergic receptor stimulating action as compared with the β ₃ -adrenergic receptor stimulating action.

Since the compound represented by the general formula (I) of the present invention has a strong stimulating action on human β ₃ -adrenergic receptor, obesity, diabetes, hyperlipidemia, depression, dysuria, gallstones In addition, it is suitable as a therapeutic or prophylactic agent for diseases caused by increased biliary motility or diseases caused by enhanced gastrointestinal function.

Claims (11)

Formula (I):

[Where,
R ¹ and R ² are each independently a hydrogen atom, halogen atom, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cycloalkyl group, heterocycloalkyl group, lower alkoxy group, hydroxyl group, di-lower alkyl An amino group, cyclic amino group, di-lower alkylamino lower alkyl group, aryl group, aryloxy group, aralkyloxy group, heteroaryl group, cyano group, lower acyl group, lower alkylsulfanyl group or lower alkylsulfonyl group;
R ³ is a hydrogen atom, a lower alkyl group or an aralkyl group;
R ⁴ represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a heteroaralkyl group, or R ³ and R ⁴ together form — (CH ₂ ) _m —;
R ⁵ is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R ⁶ is a hydroxyl group, a lower alkoxy group, an aralkyloxy group, or —N (R ⁷ ) (R ⁸ );
R ⁷ and R ⁸ each independently represent a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which R ⁷ and R ⁸ are bonded. To form a cyclic amine;
A ¹ is a bond or a lower alkylene group;
X is a bond or an oxygen atom;
m is an integer from 3 to 5;
n is an integer of 2 to 5]
Or a prodrug thereof, or a pharmacologically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a bond. The compound according to claim 2, wherein n is 2, or a pharmaceutically acceptable salt thereof. The compound or pharmacologically acceptable salt thereof according to claim 3, wherein R ¹ and R ² are each independently a hydrogen atom, a halogen atom or a lower alkyl group. R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom, a lower alkyl group or an aralkyl group,
R ⁵ is a hydrogen atom or a lower alkyl group,
R ⁶ is a hydroxyl group or a lower alkoxy group,
The compound or pharmacologically acceptable salt thereof according to claim 4, wherein A ¹ is a bond. The group consisting of:
(S) -2- (3-Chloro-4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3- Phenylpropionic acid;
(S) -2- (4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -3-phenylpropionic acid; And (S) -2- (4- {2-[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl} benzoylamino) -4-methylpentanoic acid ,
The compound of Claim 1 selected from these, or its pharmacologically acceptable salt. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient. Obesity, diabetes, hyperlipidemia, depression, dysuria, gallstones and biliary tracts containing the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient A therapeutic or prophylactic agent for a disease caused by increased exercise or a disease caused by increased gastrointestinal function. The compound according to any one of claims 1 to 6, or a pharmacologically acceptable salt thereof, and an antiobesity agent other than a β ₃ -adrenergic receptor agonist, an antidiabetic agent, and an antihyperlipidemic agent A pharmaceutical comprising a combination of at least one selected from an agent and a therapeutic drug for dysuria. Claims 1 to 1 for producing a therapeutic or preventive agent for obesity, diabetes, hyperlipidemia, depression, dysuria, diseases derived from gallstones and increased biliary motility, or diseases derived from hypergastrointestinal function. Use of the compound according to any one of 6 or a pharmaceutically acceptable salt thereof. A method for treating or preventing obesity, diabetes, hyperlipidemia, depression, dysuria, diseases resulting from gallstones and increased biliary motility, or diseases resulting from increased gastrointestinal function, said method comprising claim 1 A method comprising administering an effective amount of the compound according to any one of -6 to pharmacologically acceptable salt thereof.