JP2005518448A - Beta-3-adrenergic receptor agonist - Google Patents

Abstract

The present invention relates to β ₃ -adrenergic receptor agonists represented by the structural formula (I), pharmaceutical compositions thereof and methods for treating diseases, symptoms or disorders mediated by β ₃ -adrenergic receptors using such compounds. I will provide a.
[Chemical 1]

Description

(Field of Invention)
The present invention relates to β ₃ -adrenergic receptor agonists and their use in the treatment of diseases, symptoms and / or disorders mediated by β ₃ -adrenergic receptor agonists.

(Background of the Invention)
Disease (Authentic) Diabetes is a disease characterized by metabolic failure in the production and use of charcoal hydrate that results in failure to maintain adequate blood sugar levels. The consequences of these disorders include, among other things, elevated blood glucose or hyperglycemia. The focus of research related to the treatment of diabetes is on the means to normalize blood glucose levels before and after meals. Current treatments include external insulin administration, oral administration of medications and diet.

Two major types of diabetes are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM) is the result of an absolute deficiency of insulin, a hormone that regulates charcoal hydrate utilization. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often appears even at normal or elevated insulin levels and appears to be the result of the lack of ability of tissues to respond appropriately to insulin. Most patients with type 2 diabetes are also obese.
The compounds according to the invention effectively reduce blood glucose levels when administered orally to mammals suffering from hyperglycemia or diabetes.

  Obesity is a major health risk component leading to death and the development of type 2 diabetes, hypertension and dyslipidemia. In the United States, more than 50% of the adult population is overweight and nearly 25% of the population is considered obese. In the United States, diabetes incidence is increasing with a cumulative annual growth rate of 3%. Although the majority of diabetes occurs in the United States and Europe, the diabetes epidemic is also increasing in Japan. Furthermore, diabetes is a devastating disease that can impart confusion to an individual's mental health and self-management and can affect an individual's ability to engage in social interactions with others. Unfortunately, the exact etiology of diabetes is complex and poorly understood, and social concepts and assumptions related to diabetes have only a tendency to exacerbate the pathological effects of the disease. Although diabetes generally has a social impact, considerable efforts have been made to treat diabetes, but its long-term success in treatment and / or prevention remains difficult to understand.

The compounds, pharmaceutical compositions and combinations according to the invention reduce body weight or decrease body weight gain when administered to a mammal, including a human subject. The ability of the compounds to affect weight gain is due to the activation of β ₃ -adrenergic receptors that stimulate adipose tissue metabolism.

β-adrenergic drugs are generally classified into β ₁ , β ₂ and β ₃ receptor specific subtypes. Beta-receptor agonists promote adenyl cyclase activation. β ₁ -receptor activation causes an increase in heart rate, while β ₂ -receptor activation induces smooth muscle tissue relaxation that results in a decrease in blood pressure and the development of skeletal muscle tremor. Activation of β ₃ -receptors is known to stimulate lipolysis (eg, degradation of adipose tissue triglycerides to glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting fat mass loss. Yes. Accordingly, compounds that stimulate the β ₃ -receptor are useful as anti-obesity agents and can also be used to increase red meat content in meat animals. In addition, compounds that are β ₃ receptor agonists have hypoglycemic activity, but the exact mechanism of this action is currently unknown.

Until recently, β ₃ -adrenergic receptors were believed to predominate in adipose tissue, but at present, such β ₃ receptors are intestinal ( J. Clin. Invest. , 91, 344 (1993)) and brain ( Eur.
J. Pharm. , 219, 193 (1992)). β ₃ receptor stimulation has also been shown to induce relaxation of colon, trachea and bronchial smooth muscle. For example, Life
Science , 44, 1411 (1989), Br. J. Pharm. , 112, 55 (1994) and Br. J. Pharm. ,
110, 1311 (1993). Furthermore, stimulation of β ₃ receptors has also been found to induce relaxation of histamine-contracted guinea pig ileum. For example, J.
Pharm. Exp. Ther. , 260, 1, 192 (1992).

beta ₃ receptor is also expressed in human prostate (J. Clin. Invest., 91 , 344 (1993)). seems beta ₃ receptor stimulation smooth muscle has been shown to express the beta ₃ receptor, that is, from causing relaxation of intestinal smooth muscle, one of ordinary skill in the art also can predict relaxation of prostate smooth muscle It is. Accordingly, β ₃ agonists are useful for the treatment or prevention of prostate diseases.
US Pat. No. 5,977,124 discloses certain β ₃ adrenergic receptor agonists that can be used, inter alia, for the treatment of hypoglycemia and obesity.
US Pat. No. 5,776,983 discloses certain catecholamine compounds as β ₃ -agonists.

US Pat. No. 5,030,640 discloses certain α-heterocyclic ethanolaminoalkylindole compounds that can be used as growth promoters, bronchial relaxants, antidepressants and antiobesity agents. Yes.
US Pat. No. 5,019,578 discloses certain α-heterocyclic ethanolamine compounds that can be used as growth promoters.
U.S. Pat. No. 4,478,849 discloses pharmaceutical compositions containing certain ethanolamine derivatives and methods of using such compositions for the treatment of obesity and / or hyperglycemia. .

US Pat. No. 4,358,455 discloses certain heterocyclic compounds that can be used to treat glaucoma and cardiovascular diseases.
US Pat. No. 5,393,779 (EP516349B1) discloses certain 2-hydroxyphenethylamine compounds that can be used as anti-obesity and hypoglycemic agents and in related applications.
US Pat. No. 5,153,210 discloses certain heterocyclic compounds that can be used as anti-obesity agents and anti-hyperglycemic agents.

US Pat. No. 6,251,925 discloses biaryl compounds that can be used in the treatment of diseases that are sensitive to improvement by administration of atypical beta-adrenoceptor agonists.
US Publication No. 2002-0052392A1 (PCT Publication No. WO02 / 32897) is intended for the treatment of intestinal locomotor dysfunction, depression, prostate disease, lipid metabolism disorders and airway inflammatory disorders, and lean meat content of meat animals. Certain heterocyclic β ₃ -adrenergic agonists are disclosed that can be used to increase

(Summary of Invention)
The present invention relates to a β ₃ -adrenergic receptor agonist represented by the structural formula (I), a pharmaceutically acceptable salt thereof, a compound or a prodrug of the salt, or a solvate or water of the compound, the salt or the prodrug. Offer Japanese products:

Where
Ar is fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from phenyl, O, S or N, (C ₃ -C ₈ ) cycloalkyl A benzene ring fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N, or O, S or N Containing 1 to 3 heteroatoms selected from O, S or N fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from An aromatic or non-aromatic 5- or 6-membered heterocyclic ring (preferably Ar is phenyl or pyridyl, more preferably pyridyl);
R ¹ and R ² are each independently hydrogen, hydroxy, halogen, cyano, nitro, —NR ^1a R ^2a , —NR ^1a SO ₂ R ^2a , —OR ^1a , —SO ₂ R ^2a , —CF ₃ , (C ₃ -C ₈ ) cycloalkyl, phenyl, —NR ^1a COR ^2a , —COR ^2a , or (C ₁ -C ₆ ) alkyl, wherein the alkyl is selected from the group consisting of one or more hydroxy, nitro, halogen and cyano Wherein R ^1a and R ^2a are each independently hydrogen, (C ₃ -C ₈ ) cycloalkyl, phenyl (this phenyl is 1 to 3 halos, Optionally substituted by a substituent selected from (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy) or (C ₁ -C ₆ ) a Alkyl, wherein the alkyl is optionally substituted by a substituent selected from the group consisting of 1 to 3 hydroxy, fluoro, —CO ₂ H, phenyl and —NR ^1b R ^2b , wherein R ^1b And R ^2b are each independently hydrogen, amino, amino (C ₁ -C ₆ ) alkyl, aminoaryl, (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆ ) Optionally substituted by a substituent selected from the group consisting of alkoxy, fluoro, amino, (C ₁ -C ₆ ) alkylamino and acyl), (C ₃ -C ₈ ) cycloalkyl (this cycloalkyl is 1 pieces or more fluoro, _{alkyl, (C} 1 -C ₆₎ alkoxy, hydroxy, amino, aminoalkyl -, selected from the group consisting of acyl and amide Optionally substituted by a selected substituent), a 3-8 membered aromatic or non-aromatic heterocyclic ring, wherein the heterocyclic ring is one or more halogen, (C ₁ -C ₆ ) alkyl , (C ₁ -C ₆ ) optionally substituted by a substituent selected from the group consisting of alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide); or R ^1b and R ^2b are 3-8 membered aromatic or non-aromatic heterocyclic which may contain from 1 to 2 additional heteroatoms selected from O, S or N together with the nitrogen to which they are attached Forming a ring;
R ³ and R ⁴ are each independently hydrogen, or a substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl (wherein the alkyl is 1-3 hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Optionally substituted by);
R ⁵ may be substituted with a substituent selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl (wherein alkyl is 1-3 hydroxy, C ₁ -C ₆ ) alkoxy and fluoro. );
R ⁶ and R ⁷ are each independently a substituent selected from the group consisting of hydrogen, halogen or (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Optionally substituted by a group);
R ⁸ is —CONR ^1b R ^2b , —SOR ^1b , —SO ₂ R ^1b , —SO ₂ NR ^1b R ^2b , —NR ^1b SO ₂ R ^2b, or —CO ₂ R ^1b (preferably R ⁸ is -CONR ^1b R ^2b );
R ⁹ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) alkyl, where the alkyl is one or more fluoro, hydroxy and (C ₁ -C ₆ ) alkoxy. Optionally substituted by a substituent);
X is —O—, —NH—, —NR ^1a —, —CH ₂ —, —CH ₂ CH ₂ — or —CH ₂ O— (preferably X is —O—);
m is 0 or 1; and HET is an aromatic heterocyclic ring selected from the group consisting of imidazole, oxazole, pyrazole and thiazole (preferably HET is oxazole or pyrazole, more preferably Oxazole).

In a preferred embodiment, there is provided a compound of formula (IA), a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug. :

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and m are as defined above. In a preferred embodiment of the compound of formula (IA), Ar is pyridyl (more preferably 3-pyridyl); R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen; R ⁷ and R ⁹ each independently hydrogen, fluoro, or, _(C 1 -C ₆₎ is alkyl; ^{R 8} is ^-CONR 1b ^{R 2b (wherein, R 1b} and ^{R 2b} each independently the group consisting of hydrogen, (C ₃ -C ₆ ) cycloalkyl or (C ₁ -C ₆ ) alkyl (wherein the alkyl may be substituted by one or more fluoro); or R ^1b and R ^2b are the nitrogen to which they are attached and taken together form a non-aromatic heterocyclic ring one additional heteroatom may also be 4-6 membered and contain selected from O and N, more preferably, R ¹ And ^{R 2b} each independently selected from hydrogen or _(C 1 -C ₆₎ alkyl, and most ^preferably, each ^{R 1b} and ^{R 2b,} are independently selected from hydrogen or methyl); X is -O -And m is 1.

  Suitable compounds of the formula (IA) include the following compounds: 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl)- Ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-acetamide; 2- (4- {4- [2- (2 (R) -hydroxy-2-pyridine-3- Yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N-dimethyl-acetamide; N, N-diethyl-2- (4- {4- [2- (2 (R)- Hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -acetamide; 2- [4- (4- {2- [2- (6-chloro-pyridine-) 3-yl) -2 (R) -hydroxy-e Ruamino] -ethoxy} -phenyl) -oxazol-2-yl] -N-ethyl-N- (2,2,2-trifluoro-ethyl) -acetamide; 2- [4- (4- {2- [2 -(6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-diisopropyl-acetamide; 2- [4- (4- {2- [2- (6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl -Isobutyramide; 2- (4- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N-dimethyl-i 2- (4- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N- 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazole-2; -Yl] -N, N-dimethyl-propionamide; 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino]- Ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-butyramide; and 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridine-] 3-yl) -ethylamino] -eth Xy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-isobutyramide; a pharmaceutically acceptable salt thereof, a compound or prodrug of the salt, or a solvation of the compound, salt or prodrug Or hydrate.

  Further preferred compounds of formula (IA) include the following compounds: 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl)] -Ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-acetamide; 2- (4- {4- [2- (2 (R) -hydroxy-2-pyridine-3] -Yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N-dimethyl-acetamide; N, N-diethyl-2- (4- {4- [2- (2 (R)) -Hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -acetamide; 2- [4- (4- {2- [2 (R) -hydroxy-2] -(6-Methyl-pyridine-3- L) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-propionamide; 2- [4- (4- {2- [2 (R) -hydroxy-2-] (6-Methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-butyramide; and 2- [4- (4- {2- [ 2 (R) -Hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl] -N, N-dimethyl-isobutyramide; Or a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug.

In another preferred embodiment, a compound of formula (IA-1), a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydration of the compound, salt or prodrug Things are provided:

Where
R ¹ is hydrogen, hydroxy, halogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy (preferably R ¹ is hydrogen, halogen or (C ₁ -C ₆ ) alkyl) R ³ and R ⁴ are hydrogen; R ⁵ , R ⁶ , R ⁷ and R ⁹ are each independently hydrogen or (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more fluoro substituents); (Preferably R ⁵ , R ⁶ , R ⁷ and R ⁹ are all hydrogen); R ⁸ is —CONR ^1b R ^2b , where R ^1b and R ⁹ are optionally substituted by ^2b is independently _{hydrogen, (C} 3 -C ₆₎ cycloalkyl or _(C 1 -C ₆₎ alkyl (the alkyl may optionally be substituted by one or more fluoro), or ^{R 1a} and ^1b, together with the nitrogen to which they are attached, a non-aromatic heterocyclic ring O or one additional or 4-6 membered optionally containing a heteroatom selected from N (Preferably R ^1a and R ^1b are each independently hydrogen or (C ₁ -C ₆ ) alkyl, more preferably R ^1a and R ^1b are each independently hydrogen or methyl) X is —O—; and m is 1.

  The preferred compound is 2- [4- (4- {2- (2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino) -ethoxy} -phenyl) -oxazole-2 -Yl] -N, N-dimethyl-acetamide; and 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino]- Ethoxy} -phenyl) -oxazol-2-yl] -N-methyl-acetamide; or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or salt.

式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｘおよびｍは、上記定義のとおりである。 In yet another preferred embodiment, a compound of formula (IB), a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug Will be provided:

Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and m are as defined above.

In a preferred embodiment of the compounds of formula (IB), Ar is pyridyl (more preferably 3-pyridyl); R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen; R ⁷ and R ⁸ is each independently hydrogen, fluoro, or (C ₁ -C ₆ ) alkyl; R ⁸ is —CONR ^1b R ^2b (where R ^1b and R ^2b are each independently hydrogen, (C ₃ -C ₆ ) cycloalkyl or (C ₁ -C ₆ ) alkyl (wherein the alkyl may be substituted by one or more fluoro); or R ^1b and R ^2b are the nitrogen to which they are attached and O and taken together forms a non-aromatic heterocyclic ring one additional heteroatom may also be 4-6 membered and contain selected from N, more preferably, R ¹ And ^{R 2b} each independently selected from hydrogen or _(C 1 -C ₆₎ alkyl, most ^{preferably, R 1b} and ^{R 2b} each independently is independently selected from hydrogen or methyl); X is -O- and m is 1.

  Suitable compounds of the formula (IB) include the following compounds: 2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -Phenyl} -pyrazol-1-yl) -N, N-dimethyl-acetamide; N-ethyl-2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-) Ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -N-methyl-acetamide; 2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-) Ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -1-morpholin-4-yl-ethanone; 2- (3- {4- [2- (2 (R) -hydroxy-2-pyridine- 3-yl-ethylamino) -ethoxy] -fur Nyl} -pyrazol-1-yl) -1-pyrrolidin-1-yl-ethanone; and N-cyclopentyl-2- (3- {4- [2- (2 (R) -hydroxy-2-pyridine-3- Yl-ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -acetamide; a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or salt.

In another embodiment of the present invention there is provided a pharmaceutical composition comprising (1) a compound according to the present invention and (2) a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical composition can further contain additional agents. Suitable agents include apolipoprotein-B secretion / microsomal triglyceride transfer protein (apo-B / MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine resorption inhibitors (eg, sibutramine ( sibutramine), sympathomimetic drugs, cannabinoid receptor antagonists (e.g. rimonabant (SR-141, 716A)), dopamine agonists (e.g. bromocriptine), melanocyte stimulating hormone receptor analogues, 5HT2c Agonist, melanin-concentrating hormone antagonist, leptin (OB protein), leptin-related compound, leptin receptor agonist, galanin antagonist, Zease inhibitors (eg, tetrahydrolipstatin, ie orlistat), appetite suppressants (eg, bombesin agonists), neuropeptide-Y antagonists, thyroidomimetics, dehydroepiandrosterone or its Related compounds, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, serial neurotrophic factors (eg, Axokine (registered trade name)), human agouti (Agouti) -related protein (AGR) ), A ghrelin (ghrelin) receptor antagonist, antidiabetic agent selected from the group consisting of histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists.

In yet another embodiment of the invention, there is provided a method of treating a disease, symptom or disorder mediated by a β ₃ -adrenergic receptor agonist in an animal, which method comprises a therapeutically effective amount of a compound according to the invention (or pharmaceutical composition thereof). A) is administered to an animal in need of such treatment. Diseases, symptoms or disorders mediated by β ₃ -adrenergic receptor agonists in animals include weight loss (eg increased energy expenditure), obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenal inflammation , Crohn's disease, proctitis, asthma, intestinal locomotor disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, fatty liver, and respiratory inflammatory disorders Include. Accordingly, the compounds according to the invention can be used for the manufacture of a medicament for the treatment of diseases, conditions or disorders mediated by β ₃ -adrenergic receptor agonists.

The compounds according to the invention can be administered in combination with at least one of the agents described below. Suitable drugs include antidiabetic drugs (described above).
A combination therapy consists of (a) a single pharmaceutical composition containing a compound according to the invention, at least one additional agent and a pharmaceutically acceptable excipient, diluent or carrier, or (b) (I) a first pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable excipient, diluent or carrier, and (ii) at least one additional agent as described above and a pharmaceutically acceptable Can be administered as two separate pharmaceutical compositions, including a second composition containing an excipient, diluent, or carrier. The pharmaceutical compositions can be administered simultaneously or sequentially in any order.

In yet another aspect of the invention, a pharmaceutical kit is provided for use by a consumer to treat a disease, condition or disorder mediated by a β ₃ -adrenergic receptor agonist in an animal. The kit comprises: a) a suitable dosage form containing a compound according to the invention; and b) instructions describing how to use the dosage form to treat diseases linked to β ₃ -adrenergic receptor intervention. Is included.

In yet another embodiment of the invention, the pharmaceutical kit comprises a first dosage form comprising a) (i) a compound according to the invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b ) (I) a second dosage form containing the additional agent and (ii) a pharmaceutically acceptable carrier, excipient or diluent; and (c) a container.
In yet another aspect of the invention, an intermediate compound having the formula (Ia) is provided.

式中、
Ｒ^１は水素またはアミノ保護基であり；
Ｒ^５は水素、（Ｃ_１−Ｃ_６）アルキル（このアルキルは１〜３個のヒドロキシ、Ｃ_１−Ｃ_６）アルコキシ、およびフルオロからなる群から選択される置換基により置換されていてもよい）であり；および
Ｒ^８は−ＣＯＮＲ^１ｂＲ^２ｂ、−ＳＯＲ^１ｂ、−ＳＯ_２Ｒ^１ｂ、−ＳＯ_２ＮＲ^１ｂＲ^２ｂ−、−ＮＲ^１ｂＳＯ_２Ｒ^２ｂ、または−ＣＯ_２Ｒ^１ｂであり；ここでＲ^１ｂおよびＲ^２ｂはそれぞれ独立し、水素、アミノ、アミノ（Ｃ_１−Ｃ_６）アルキル、アミノアリール、（Ｃ_１−Ｃ_６）アルキル（このアルキルは１個以上のヒドロキシ、（Ｃ_１−Ｃ_６）アルコキシ、フルオロ、アミノ、（Ｃ_１−Ｃ_６）アルキルアミノ、およびアシルからなる群から選択される置換基により置換されていてもよい）、（Ｃ_３−Ｃ_８）シクロアルキル（このシクロアルキルは１個以上のフルオロ、アルキル、（Ｃ_１−Ｃ_６）アルコキシ、ヒドロキシ、アミノ、アミノアルキル−、アシル、およびアミドからなる群から選択される置換基により置換されていてもよい）、３〜８員の芳香族または非芳香族複素環式環（この複素環式環は１個以上のハロゲン、（Ｃ_１−Ｃ_６）アルキル、（Ｃ_１−Ｃ_６）アルコキシ、ヒドロキシ、アミノ、アミノアルキル−、アシル、およびアミドからなる群から選択される置換基により置換されていてもよい）であり；もしくはＲ^１ｂおよびＲ^２ｂは、これらが結合する窒素と一緒になって、Ｏ、ＳまたはＮから選択される１〜２個の追加のヘテロ原子を含有していてもよい３〜８員の芳香族または非芳香族複素環式環を形成している。

Where
R ¹ is hydrogen or an amino protecting group;
R ⁵ may be substituted with a substituent selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl (wherein alkyl is 1-3 hydroxy, C ₁ -C ₆ ) alkoxy, and fluoro. And R ⁸ is —CONR ^1b R ^2b , —SOR ^1b , —SO ₂ R ^1b , —SO ₂ NR ^1b R ^2b —, —NR ^1b SO ₂ R ^2b , or —CO ₂ R ^1b ; Wherein R ^1b and R ^2b are each independently hydrogen, amino, amino (C ₁ -C ₆ ) alkyl, aminoaryl, (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆₎ alkoxy, fluoro, _amino, optionally substituted with substituents selected from the group consisting of _(C 1 -C ₆₎ alkylamino, and acyl), (C ₃ -C ₈ ) cycloalkyl (wherein the cycloalkyl is one or more fluoro, alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide substituents selected from the group consisting of 3-8 membered aromatic or non-aromatic heterocyclic ring, which is optionally substituted by one or more halogens, (C ₁ -C ₆ ) alkyl, (C _1- C ₆ ) optionally substituted by a substituent selected from the group consisting of alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide; or R ^1b and R ^2b are the nitrogen to which they are attached. Together with a 3-8 membered aromatic or non-aromatic heterocyclic ring optionally containing 1-2 additional heteroatoms selected from O, S or N Forms.

Definitions As used herein, the term “alkyl” refers to a hydrocarbon group of the general formula C _n H _{2n + 1} . The alkane group can be linear or branched. For example, the term “(C ₁ -C ₆ ) alkyl” refers to a monovalent linear or branched aliphatic group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, i -Propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl Etc.). Unless stated otherwise, the alkane group can be unsubstituted or substituted by one or more substituents selected from the group of substituents listed in the “substituted” definition below. (Generally 1-3 substituents except for halogen substituents such as perchloro or perfluoroalkyl). By way of example, “halo-substituted alkyl” represents an alkyl group substituted with one or more halogen atoms (eg, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, etc.). Similarly, the alkyl portion of alkoxy, alkylamino, dialkylamino and alkylthio groups has the same definition as above.

  The term “cycloalkyl” refers to a non-aromatic ring that is fully hydrogenated and can exist as a monocyclic, bicyclic or spiro-fused ring. By way of example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl and the like. Generally, a cycloalkyl ring is a 3-8 membered ring. Unless stated otherwise, a cycloalkyl may be substituted (typically by one or more substituents selected from the group of substituents listed in the definition of “substituted” below) 1 to 3 substituents). A cycloalkyl group can be attached to a chemical entity or moiety by any one carbon atom in the carbocyclic ring system. Cycloalkyl fused to a benzene ring means a group such as indanyl.

  The term “non-aromatic heterocyclic ring” (also referred to as “heterocycle”) is partially or fully hydrogenated and exists as a monocyclic, bicyclic or spiro-fused ring. Represents a non-aromatic ring capable of Partially saturated or fully saturated heterocyclic rings are epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, Includes groups such as piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide. In general, a heterocycle is a 3-8 membered ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen. Unless otherwise stated, this non-aromatic heterocyclic group is a substituent selected from the group of one or more substituents listed in the definition of “substituted” below (typically , 1 to 3 substituents) may be optionally substituted. Heterocyclic rings fused to aryl groups include 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl, 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, etc. Includes groups. The heterocyclic ring can be attached to the chemical entity or moiety by any one carbon atom in the carbocyclic ring system.

The term “aryl” refers to a ring system containing one ring (eg, phenyl) or fused ring systems (eg, naphthalene, anthracene, phenanthrene, etc.). Unless stated otherwise, an aryl group is unsubstituted or substituted with one or more substituents selected from the group of substituents listed in the definition of “substituted” below (preferably 3 May be substituted with up to a number of substituents). Substituted aryl groups include aromatic molecular chains (eg, biphenyl, terphenyl, phenylnaphthalyl, etc.). The aryl group can be attached to the chemical entity or moiety by any one carbon atom in the aromatic ring system. Suitable aryl substituents are halogen (F, Cl, Br or I, preferably F or Cl), (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄₎ alkyl _(e.g., CH 2 F, CHF ₂ and CF _3), and cyano. Aryl groups fused to cycloalkyl groups include groups such as indanyl. Similarly, the aryl portion of aroyl or aroyloxy (ie, (aryl) -C (O) -O-) has the same definition as above.

The term “aromatic heterocyclic ring” or “heteroaryl” refers to an aromatic molecule that contains at least one heteroatom (eg, oxygen, sulfur, nitrogen, or combinations thereof) within an aromatic ring system. (E.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, oxadiazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, Oxazolyl).
The heteroaromatic molecule can consist of a single ring system or a fused ring system. Exemplary monocyclic heteroaryls are 5-6 membered rings containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and exemplary fused heteroaryl ring systems are 1-4. A 9-10 membered ring containing a heteroatom selected from oxygen, sulfur and nitrogen. Unless stated otherwise, a heteroaryl group is unsubstituted or substituted by one or more substituents selected from the group of substituents listed in the definition of “substituted” below. (Preferably no more than 3 substituents). A heteroaryl group can be attached to a chemical entity or moiety by any one atom in the aromatic ring system (eg, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, Imidazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl or pyrid-6-yl). Similarly, the heteroaryl portion (ie, heteroaromatic molecule) of heteroaroyl (ie, (heteroaryl) -C (O) —O—) has the same meaning as described above.

The term “acyl” refers to alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl and heteroaryl substituted by a carbonyl group. By way of example, acyl is (C ₁ -C ₆ ) alkanoyl (eg, formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C ₃ -C ₆ ) cycloalkylcarbonyl (eg, cyclo Propylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (eg, pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.) ), Aroyl (eg benzoyl) and heteroaroyl (eg thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl, 1H-pyro) Encompasses-2-carbonyl, 1H-pyrroyl-3-carbonyl, benzo [b] thiophenyl-2-carbonyl, etc.) group, such as. Furthermore, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portions of the acyl group can each be any one of the groups described by the above definitions. Unless stated otherwise, an acyl group is unsubstituted or substituted with one or more substituents selected from the group of substituents listed in the definition of “substituted” below. (Preferably 1 to 3 substituents).

The term “substituted” can anticipate and take into account one or more substituents common in the art. However, it is generally understood by those skilled in the art that these substituents should be selected so as not to adversely affect the pharmacological properties of the compound or interfere with its pharmaceutical use. It is. It will also be apparent to those skilled in the art that certain substituents may have inherent instabilities and therefore do not form part of the present invention. For any of the groups defined above, suitable substituents are (C ₁ -C ₆ ) alkyl, partially or fully saturated (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl. , Aryl, heteroaryl, partially saturated or fully saturated 3- to 6-membered heterocycle, halo (eg, chloro, bromo, iodo and fluoro), cyano, hydroxy, (C ₁ -C ₆ ) alkoxy, aryloxy, Sulfhydryl (mercapto), (C ₁ -C ₆ ) alkylthio, arylthio, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, quaternary ammonium salt, amino (C ₁ -C ₆ ) alkoxy, aminocarboxy rate (i.e., -NH-C (O) -O- (C 1 -C 6) _{alkyl), N- (C 1 -C 6} ) alkylamino-carbonitrile Shireto, hydroxy _(C 1 -C ₆₎ alkylamino, amino _(C 1 -C ₆₎ alkylthio, cyanoamino, formamide, acylamino (e.g., acetamido and benzamido), _N-(C 1 -C ₆₎ alkyl - acylamino (e.g. , N- methylacetamide), _{nitro, (C} 1 -C ₆₎ carbamyl, keto (oxy), _{acyl, (C} 1 -C ₆₎ alkoxycarbonyl, _{aryloxycarbonyl, (C} 1 -C ₆₎ carboxy, glycolyl, include glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thio _(C 1 -C ₆₎ carbonyl, thio _(C 1 -C ₆₎ carboxy, and combinations thereof. In the case of a substituted combination, for example, in the case of “substituted aryl (C ₁ -C ₆ ) alkyl”, either the aryl group or the alkyl group may be substituted, or both the aryl group and the alkyl group are both It may be substituted by one or more substituents (typically 1 to 3 substituents, except in the case of perhalo substitution). Aryl-substituted carbocyclic or heterocyclic groups can be fused rings (eg, indanyl, dihydrobenzofuranyl, dihydroindolyl, etc.). A cycloalkyl-substituted carbocycle or heterocycle can be a spiro-fused ring.

The term “solvate” denotes a molecular complex of a compound according to the invention with one or more solvent molecules. Such solvent molecules are conventional in pharmaceutical technology and are known to be non-toxic to recipients, such as water, ethanol and the like. The term “hydrate” refers to the complex where the solvent molecule is water.
"Protecting group" or "Pg" represents a substituent commonly used to block or protect a particular functional group but react with another functional group in the compound. By way of example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects an amino functional group present in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, “hydroxy-protecting group” means a substituent of a hydroxy group that blocks or protects a hydroxy functional group. Suitable protecting groups include acetyl and silyl. “Carboxy-protecting group” refers to a substituent of a carboxy group that blocks or protects a carboxy functional group. Conventional carboxy - protecting _{group, -CH 2 CH 2 SO 2 Ph} , cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p- toluenesulfonyl) ethyl, 2- (p-nitro Phenylphenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, reference can be made to Protective Groups in Organic Synthesis by TW Greene, John Wiley & Sons, New York, 1991.

The expression “therapeutically effective amount” includes (i) treating or preventing a particular disease, condition or disorder, (ii) attenuating, reducing or reducing one or more symptoms of a particular disease, condition or disorder. By (iii) is meant the amount of a compound according to the present invention that eliminates or prevents or delays the onset of one or more symptoms of a particular disease, symptom or disorder described herein.
The term “animal” refers to humans (male and female), companion animals (eg, dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species. “Edible animals” means cows, pigs, sheep and poultry.

The expression “pharmaceutically acceptable” indicates that the substance or composition is chemically and / or toxicologically compatible with another component of the composition and the animal treated therein.
"Beta ₃ - adrenergic receptor-mediated" or - the expression "beta _3-mediated adrenergic receptor", beta ₃ - represents the activation or deactivation of the adrenergic receptor. As an example, a β ₃ -adrenergic receptor ligand can act as an agonist, as a partial agonist, as an inverse agonist, as an antagonist, as a partial antagonist.

The term “agonist” refers to both full and partial agonists.
The terms “treating”, “treat” and “treatment” encompass both protective, ie prophylactic and palliative treatment.
The term “compound according to the invention” means (unless otherwise stated) the compounds of the formulas (I), (IA), (IA-1) and (IB), the pharmaceutically acceptable compounds of this compound. Salts, and / or prodrugs, and hydrates or solvates of the compounds, salts and / or prodrugs, and all stereoisomers (including diastereomers and enantiomers), tautomers and Represents an isotope-labeled compound.

(Detailed explanation)
The present invention provides compounds and compositions that are useful in the treatment of diseases, conditions and / or disorders mediated by β ₃ -adrenergic receptor agonists.
The compounds according to the invention can be synthesized by synthetic routes including methods similar to those well known in the chemical arts in view of the description contained herein. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) Or can be readily manufactured using methods well known to those skilled in the art (for example, Louis F. Fleser & Mary Fleser, Reagents for Organic Synthesis ,
v. 1-19, Wiley. New York (1967-1999), or Beilsteins Handbuch der organischen
Chemie , 4, Aufl.ed. Springer-Verlag, Berlin (including addendum) (which is also produced by the method generally described in the Beilstein online database).

  For illustrative purposes, the following reaction scheme shows the basic route for the synthesis of the compounds according to the invention as well as key intermediates. For a more detailed description of each reaction step, the following examples can be referred to. It will be apparent to those skilled in the art that alternative synthetic routes can be used to synthesize the compounds according to the invention. Certain starting materials and reactants are shown in this scheme and described below, but can be easily replaced with other starting materials and reactants to provide various derivatives and / or reaction conditions. be able to. In addition, many of the compounds prepared by the methods described below can be modified in light of this description using conventional chemistry well known to those skilled in the art.

In the preparation of the compounds according to the invention it may be necessary to protect remote functional groups of the intermediate (for example primary or secondary amines). The need for such protection will vary depending on the type of remote functional group and the conditions of the manufacturing process. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see Protective Groups in Organic Synthesis by TW Greene, Jojn.
See Wiley & Sons, New York, 1991. Scheme 1 illustrates one means for preparing the compounds according to the invention when HET is oxazole.

  In Scheme 1 above, α-bromoketone (1a) is condensed and cyclized with a correspondingly substituted amide to produce oxazole (1b). This fused cyclization is typically performed at elevated temperatures in polar protic or aprotic solvents such as dimethylformamide or N-methylpyrrolidone. The starting material α-bromoketone (1a) can be prepared by a conventional method, for example, according to the method described in the following Scheme 2 relating to the conversion of the protected acetophenone derivative (2b) to α-bromoketone (2c). The intermediate oxazole (1b) is then demethylated, preferably with methanesulfonic acid / methionine under standard conditions, to produce phenol (1c) and then non-existing in the presence of a weak base (eg potassium carbonate). Functionalize with methanesulfonic acid 2-phenoxycarbonylamino-ethyl ester in a protic solvent such as dimethyl sulfoxide to give the protected amine (1d). This protected amine (1d) is then deprotected, preferably by catalytic hydrogenation in a polar protic solvent, to give amine (1e). Amine (1e) is coupled with a substituted oxirane derivative (Q) to give an oxazole derivative (compound according to the invention in which HET is oxazole). Oxirane intermediates can be prepared by methods well known to those skilled in the art, for example, US Pat. Nos. 5,541,197; 5,561,142; 5,705,515; and 6,037,362. Can be produced according to the methods described in, and are incorporated herein by reference. Certain oxirane derivatives are also commercially available.

  Alternatively, compounds according to the present invention in which HET is oxazole can be prepared according to the method outlined in Scheme 2 below.

As outlined in Scheme 2 above, 4-hydroxyacetophenone is condensed with protected N- (2-hydroxyethyl) -carbamate to produce the protected acetophenone derivative (2a). This condensation can be carried out according to methods well known to those skilled in the art. Preferably, this condensation is performed by a Mitsunobu reaction. This reaction is typically performed in the presence of a dehydrating agent such as a stoichiometric amount of a diazocarboxyl compound such as 1,1 ′-(azodicarbonyl) -dipiperidine (ADDP) and a phosphine such as triphenylphosphine. Perform with stirring at room temperature (or at an elevated temperature if necessary). This condensation reaction can be carried out in any reaction-inert solvent (eg, tetrahydrofuran, dimethylformamide, hydrocarbon, or halogenated hydrocarbon solvent). This protected acetophenone derivative (2a) is then α-brominated to give α-bromoketone (2b). This bromination is carried out according to a conventional method, preferably by reaction of (2a) with tetrabutylammonium tribromide (TBA Br ₃ ). Compound (2b) is condensed and cyclized with an appropriately substituted amide to give protected oxazole (1d). This (1d) is then deprotected to give the amine (1e). Such deprotection can be achieved using conventional deprotection methods. As an example, when Pg is a benzyl group, the benzyl group is separated by treatment with methanesulfonic acid or by treatment with various other deprotecting agents using standard conditions well known to those skilled in the art. be able to. Preferably, this deprotection is carried out by hydrogenolysis in an inert solvent in the presence of a suitable metal catalyst (eg palladium on carbon). Amine (1e) is then coupled with a correspondingly substituted oxirane derivative (Q) to give a compound according to the invention in which HET is oxazole.

  Compounds according to the invention in which HET is a pyrazole group can be prepared by synthetic routes outlined in Schemes 3 and 4 below.

  In Scheme 3 above, the protected amine (2b) is heated with N, N-dimethylformamide diethyl acetal to give the protected amine (3a). Preferably, the reaction of this protected amine (2b) with N, N-dimethylformamide diethyl acetal simply neatly combines both reagents together and the resulting mixture is generally about extended over an extended period of time. This is accomplished by heating for 24 hours to about 48 hours. The resulting product is then precipitated by the addition of a nonpolar solvent (eg, hexane). Subsequent condensation cyclization of (3a) with hydrazine hydrate preferably combines the reactants together in a polar protic solvent (eg, ethanol) and then the mixture is heated for about 12 hours to about 24 hours. Is achieved. The resulting pyrazole (3b) is then N-alkylated with ethyl bromoacetate, preferably in the presence of a base (eg, sodium ethoxide) in a polar protic solvent (eg, ethanol) to give acetate (3c). Basic saponification of (3c), preferably saponification with lithium hydroxide in tetrahydrofuran to produce acid (3d), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) And reaction with a correspondingly substituted amine in the presence of 1-hydroxybenzotriazole (HOBT) to give the amide (3e). As described in Scheme 2 above, deprotection of (3e) followed by coupling with a substituted oxirane derivative (Q) provides a compound according to the invention in which HET is pyrazole.

  Alternatively, compounds according to the present invention in which HET is pyrazole can be prepared according to the method outlined in Scheme 4 below.

  In Scheme 4 above, a commercially available pyrazole-anisole derivative (4a) is N-alkylated with ethyl bromoacetate to produce acetate (4b), then a base (eg, in aqueous tetrahydrofuran) (eg, aqueous tetrahydrofuran). Saponification with sodium hydroxide) to give the acid (4c). The acid (4c) is preferably reacted in the presence of benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoride (PyBop), preferably in an inert solvent (eg 1,2-dichloroethane). The amide (4d) is prepared by reacting with a substituted amine. As described above in Scheme 1, the amide (4d) is demethylated and the resulting phenol (4e) is then protected by condensation with methanesulfonic acid 2-phenoxycarbonylamino-ethyl ester. Amine (3e) is obtained. (3e) is preferably catalytically deprotected with palladium on carbon in a protic solvent (eg ethanol) and the resulting amine (3f) is then coupled with the correspondingly substituted epoxide (Q). To obtain a compound according to the invention in which HET is pyrazole.

In the above reaction scheme, the described oxazole and pyrazole residues contain substituents that are limited to the R ⁸ group. A method for preparing other heterocyclic congeners containing R ⁷ and / or R ⁹ groups is outlined in Scheme 5 below. The methylene linking group sandwiched between HET and the R ⁸ group of the intermediate compound (5a) shown in Scheme 5 is replaced by at least one acidic hydrogen atom (replaced, and R ⁷ and / or R ⁹ One skilled in the art will appreciate that it contains (which may be substituted). In the compound (5a), Pg represents a conventional O-protecting group (for example, methyl, benzyl, tetrahydropyranyl, etc.), and HET is as defined above. Preferably HET represents an oxazole, pyrazole, or triazole heterocyclic group. When HET is imidazole, the NH functional group of such residues must be appropriately protected using the conventional protection scheme.

In Scheme 5 above, the active methylene group of compound (5a) is deprotonated with a suitable base, and the resulting anion (one or more) is then removed with a leaving group (eg, R ⁷ -L- R ⁹ -L-, wherein R ⁷ and R ⁹ are as defined above, except that R ⁷ and R ⁹ are not hydrogen or halogen). To produce the functionalized and protected phenol derivative (5b). Suitable leaving groups include halogen (preferably bromo or iodo), triflate and the like. This deprotonation is usually performed using a strong base (eg, lithium diisopropylamide, sodium hydride, lithium carbonate, lithium bis (trimethylsilyl) amide, etc.) in a reaction inert solvent (eg, tetrahydrofuran or ether). Preferably, this deprotonation is performed using lithium bis (trimethylsilyl) amide in tetrahydrofuran. The exact stoichiometric amount of base used and R ⁷ -L- and / or R ⁹ -L- dictates whether compound (5b) is further functionalized to yield compound (5c). Although the preparation of compound (5c) is shown in Scheme 5 as another reaction sequence involving a different intermediate (5b), when R ⁷ and R ⁹ are the same, compound (5c) is generally It is generated by the one-pot method. For a more detailed description of the deprotonation and functionalization reaction sequence shown in Scheme 5, reference can be made to the preparation of Intermediate 1-3a in the Example section below.

The protected phenol derivative (5b) and / or (5c) can then be deprotected according to routine methods well known to those skilled in the art including the above methods. Functionalization followed by coupling with a substituted oxirane derivative (Q) according to the methods described above in Schemes 1-4 gives the compounds according to the invention.
An example of a coupling reaction between an oxirane derivative (Q) and a correspondingly substituted amine can be found in Example 1A-1 in the Examples section below. Alternatively, a compound according to the invention can be prepared by dehalogenation of a coupled compound according to the invention in which Ar in the molecule is a 2-chloro substituted pyridine derivative, an example of which is given in the examples section below. Illustrated in 1A-2.

  Conventional isolation and / or purification methods known to those skilled in the art can be used for the isolation of the compounds according to the invention and the various intermediates associated therewith. Such techniques are well known to those skilled in the art, for example all types of chromatography (high pressure liquid chromatography (HPLC), column chromatography using conventional adsorbents such as silica gel and thin layer chromatography). Recrystallization and fractional extraction techniques can be included.

The compounds according to the invention can be isolated and used as such or in the form of their pharmaceutically acceptable salts, solvates and / or hydrates. The term “salt” refers to the inorganic and organic salts of the compounds according to the invention. These salts can be prepared in situ during the final isolation and purification of the compound or are produced by reacting the compound, N-oxide or prodrug separately with a suitable organic or inorganic acid. It can be produced by isolating the salt. Typical salts are hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitate, pamoate, malonate, stear Rate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzenesulfonate, tosylate, formate, titrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate, glucoheptonate, lactate Includes bionate, lauryl sulfonate, and the like. These include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and non-limiting ammonium, tetramethylammonium, tetraethyl Amine cations such as ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine can be included, for example, see J. Pharm. Sci. , 66, 1-19 (1977) by Berge et al.

The term “prodrug” means a compound that is transformed in vivo to yield a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. This conversion can occur by various mechanisms such as hydrolysis in the blood. For an explanation of the use of prodrugs, see “Pro-drugs as Novel Delivery System”, ACS by T. Higuchi and W. Stella.
Edited by Symposium Series Vol. 14 and Bioreversible Carriers in Drug Design, Edward B. Roche, American
Provided in Pharmaceutical Association and Pergamon Press, 1987.

As an example, when the compound according to the invention contains a carboxylic acid functional group, the hydrogen atom of this acid group is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, carbon atoms 4-9 1- (alkanoyloxy) ethyl having 1 to 5 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 4 to 7 carbon atoms 1- (alkoxycarbonyloxy) ethyl having 1 to 5, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl, 3-phthalidyl, 4-crotonlac having 4 to 10 carbon atoms Cycloalkenyl, gamma - butyrolactone-4-yl, di _{-N, N- (C 1 -C 2} ) alkylamino _(C 2 -C ₃₎ alkyl (e.g., beta-dimethylaminoethyl) carbamoyl - _(C 1 -C ₂ ) by replacing with groups such as alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl and piperidino-, pyrrolidino- or morpholino (C ₂ -C ₃ ) alkyl Includes the resulting ester.

Similarly, when the compound according to the invention contains an alcohol functional group, the prodrug may be replaced with a hydrogen atom of the alcohol group, (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy. ) Ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl is independent and naturally acidic L- amino _{acids, P (O) (OH)} 2, P (O) (O (C 1 -C 6) _{alkyl) 2} or glycosyl (charcoal It can be generated by replacing by groups such as groups) resulting from the separation of the hydroxy group of the hemiacetal of hydrates.

When the compound according to the invention contains an amino-functional group, the prodrug is a hydrogen atom of the amine group, R-carbonyl, RO-carbonyl, NRR′-carbonyl (wherein R and R ′ are independent, C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R-carbonyl is natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl), —C (OH) C (O) OY ′ (where Y ′ is H, (C ₁ -C ₆ ) alkyl or benzyl), —C (OY ₀ ) Y ₁ (where Y ₀ is (C ₁ -C ₆ ) alkyl, and Y ₁ is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₆ ) alkyl or mono-N- or di-N, N- (C ₁ -C _{6) alkylaminoalkyl), - C (Y 2)} Y 3 ( wherein, _{Y 2} is H or methyl, and _{Y 3} is mono -N- or di -N, N- _{(C 1} -C ₆₎ alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl) can be generated by replacing by groups such as.

  The compounds according to the invention can contain asymmetric carbon atoms and can therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds according to the invention, as well as mixtures thereof, including racemic mixtures, are intended to form part of the invention. Furthermore, the present invention encompasses all geometric and positional isomers. By way of example, when a compound according to the invention has a double bond or a fused ring, both cis- and trans- forms and mixtures are included within the scope of the invention. Single regioisomers and regioisomer mixtures produced by N-oxidation of the pyrimidine and pyrazine rings are also within the scope of the present invention.

  Diastereomeric mixtures can be separated into their respective diastereomers on the basis of their physicochemical properties by methods well known to those skilled in the art, for example, chromatography and / or fractional crystallization. Enantiomers convert an enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (eg, a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and then separating each diastereomer. Separation can be achieved by conversion (eg, hydrolysis) to the corresponding pure enantiomer. Also, some of the compounds according to the invention may be atrop isomers (eg substituted biaryls) and are considered part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

The compounds according to the invention can exist as unsolvated as well as in the form of solvates with pharmaceutically acceptable solvents such as water, both unsolvated and solvated forms of the present invention. Is included.
The compounds according to the invention can also exist in different tautomeric forms, all such forms being included within the scope of the invention. By way of example, all tautomers of imidazole and pyrazole molecules are encompassed by the present invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are encompassed by the present invention.

The present invention is also identical to the compounds described herein, but one or more atoms are replaced by an atom having an atomic mass or mass number that differs from the atomic mass or mass number normally found in nature. Which are labeled with the same isotope. Examples of isotopes that can be inserted into the compounds according to the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine isotopes, for example ² H, ³ H, ¹³ C, ¹⁴ C, respectively. , ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ³⁶ Cl.

Compounds labeled with certain isotopes according to the present invention (eg, compounds labeled with ³ H and ¹⁴ C) are useful for compound and / or substrate tissue distribution analysis. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detection. In addition, replacement with heavier isotopes such as double hydrogen (ie ² H) has greater metabolic stability (eg, increased in vivo half-life or reduced dosing requirements). Can provide certain therapeutic benefits and may therefore be preferred in certain circumstances. Compounds labeled with isotopes according to the present invention are generally labeled with isotopes instead of non-isotopically labeled reagents, following methods similar to those described in the schemes and / or examples below. It can be produced by using a reactant.

The compounds according to the invention are useful for the treatment of diseases, conditions and / or disorders mediated by β ₃ adrenergic receptor agonists, so another aspect of the invention is therefore a therapeutically effective amount of a compound according to the invention and pharmaceutically In pharmaceutical compositions containing acceptable excipients, diluents or carriers.
A typical formulation is prepared by mixing a compound according to the invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art, such as charcoal hydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, Includes water. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound according to the present invention is being applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for administration to mammals (GRAS). In general, safe solvents are non-toxic solvents such as water and other water-soluble or water-miscible non-toxic solvents. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (eg, PEG 400, PEG 300), and the like, and mixtures thereof. The composition also includes one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glazes, processing aids. Known additives or pharmaceutical preparations (ie, pharmaceuticals) that impart an elegant aspect to agents, colorants, sweeteners, flavors, flavoring agents, and other pharmaceuticals (ie, compounds according to the invention or pharmaceutical compositions thereof) ) In the production of).

  The formulations can be manufactured using conventional dissolution and mixing methods. By way of example, a bulk drug substance (ie a compound according to the invention or a stabilized form of the compound (for example a complex with a cyclodextrin derivative or other complexing agent)) with one or more of the above-mentioned shaping Dissolve in a suitable solvent in the presence of the agent. The compounds according to the present invention are typically formulated into pharmaceutical dosage forms that provide easily controllable pharmaceutical dosage forms and that give elegant and easy-to-handle products to patients.

  The pharmaceutical composition (or formulation) for application can be packaged in various ways depending on the method used for the pharmaceutical administration. In general, distribution articles include containers in which a pharmaceutical composition is placed in a suitable form. Suitable containers are well known to those skilled in the art and include bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container also includes an anti-tamper assembly that prevents intimate access to the package contents. In addition, the container has a label therein indicating the contents of the container. This label can also include appropriate notices.

The present invention further provides a method for the treatment of diseases, conditions and / or disorders mediated by β ₃ -adrenergic receptor agonists in animals, which method comprises a therapeutically effective amount of a compound according to the invention or a therapeutically effective amount of the invention. Or a pharmaceutical composition containing a pharmaceutically acceptable excipient, diluent or carrier to an animal in need of such treatment.

beta ₃ - Study of the adrenergic receptor agonists, the following diseases, disorders and / or symptoms beta ₃ - showed that adrenergic receptor agonist mediated: (increased e.g., energy consumption) weight loss, obesity, Diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenal inflammation, Crohn's disease, proctitis, asthma, intestinal locomotor disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression , Prostate disease, dyslipidemia, fatty liver, and airway inflammatory disorders.
Accordingly, the compounds according to the invention described herein are useful for the treatment of diseases, symptoms and / or disorders mediated by β ₃ -adrenergic receptor agonists. Consequently, the compounds according to the present invention (including compositions and methods used therein) can be used for the manufacture of a medicament for therapeutic use as described herein.

  The compounds according to the invention can be administered to a patient at dosage levels in the range of about 0.7 mg to about 7,000 mg per day. For normal human adults having a body weight of about 70 kg, doses in the range of about 0.01 mg to about 100 mg / kg are typically sufficient. However, some variation in this general dosage range may be necessary depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered, and the like. Determination of the dose range and optimal dose for a particular patient is well within the ability of those skilled in the art to benefit from this description. It should be noted that the compounds according to the invention can be used in sustained release, controlled release and delayed release formulations, which forms are also well known to those skilled in the art.

  The compounds according to the present invention can also be used in combination with other agents for treating the diseases, symptoms and / or disorders described herein. Accordingly, there is also provided a method of treatment comprising administering a compound according to the invention in combination with another type of agent. Suitable agents that can be used in combination with the compounds according to the invention are apolipoprotein-B secretion / microsomal triglyceride transfer protein (apo-B / MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reabsorption inhibitors (eg, sibutramine), sympathomimetics, cannabinoid receptor antagonists (eg, rimonabant (SR-141, 716A)), dopamine agonists (eg, , Bromocriptine), melanocyte-stimulating hormone receptor analog, 5HT2c agonist, melanin-concentrating hormone antagonist, leptin (O Protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (eg, tetrahydrolipstatin, ie orlistat), appetite suppressants (eg, bombesin agonists), Neuropeptide-Y antagonists, thyrometic drugs, dehydroepiandrosterone or related compounds, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, serial neurones A tropic factor (eg, Regeneron Pharma) Axokine (registered trade name), human agouti-related protein (AGRP), ghrelin receptor, available from cementals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinati, OH Including antidiabetic agents such as histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists. Other types of anti-diabetic agents, including the preferred agents listed below, are well known or will be readily apparent to those skilled in the art from this description.

Particularly suitable are antidiabetic drugs selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. Preferably, the compounds and combination therapies according to the present invention are administered in combination with exercise and a thoughtful diet.
Representative anti-diabetic agents used in the combinations, pharmaceutical compositions and methods of the present invention can be prepared using methods known to those skilled in the art, for example sibutramine is described in US Pat. No. 4,929,629. Bromocriptine can be prepared as described in US Pat. Nos. 3,752,814 and 3,752,888; and orlistat is described in US Pat. 274,143; 5,420,305; 5,540,917; and 5,643,874. All of the above cited US patents are incorporated herein by reference.

Another class of drugs that can be useful are antihypertensive drugs; antidepressants; insulin and insulin analogs (eg, LysPro insulin); GLP-1 (7-37) (insulinotropin) ( Ensulinotropin) and _{GLP-1 (7-36) -NH 2} ; sulfonylureas and analogs compounds; chlorpropamide, glibenclamide (glibenclamide), tolbutamide, tolazamide (tolazamide), acetohexamide, glipizide (Glypizide) (registered trade name ), Glimepiride, repaglinide, meglitinide; biguanides: metformin, buformin (bu ormin); α2-antagonists and imidazoline compounds; midaglizole, isaglidele, idazoxan, efaloxan, flupaloxan; other insulin secretagogues, linogliride 6 Glitazones: Actos (registered trade name) (pioglitazone), englitazone, troglitazone, Avandia 3R (registered trade name 49); Agents: chromoxil, etomoki Emoxir, α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MD45-L, 45; Agonists: BRL35135, BRL37344, RO16-8714, ICID7114, CL316,243; Phosphodiesterase inhibitors: L-386,398; Lipid lowering drugs: benfluorex: fenfluamine; vanadate and vanadium complexes (e.g. , Naglivan (registered trade name)) and peroxovanadium complexes; amylin (a ilin) antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogues; antilipolytic agents: nicotinic acid, acipimox, WAG994, pramlintide (Symlin (registered trade name)), AC2993, nateglinide, aldose reductase inhibitors (eg, zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, sodium-hydrogen exchange type 1 (NHE-1) and / or cholesterol biosynthesis Synthesis inhibitors or cholesterol absorption inhibitors, in particular HMG-CoA synthase inhibitors, or HMG-CoA reda Synthase or synthase gene expression inhibitor, comprising CETP inhibitors, bile acid chelating agents, fibrates (fibrate), ACAT inhibitors, sectioning Allen synthetase inhibitors, antioxidants or niacin (niacin). The compounds according to the invention can also be administered in combination with naturally occurring compounds that have an action to lower plasma cholesterol levels. Such naturally produced compounds are commonly referred to as nutraceuticals and include, for example, leek extract, Hoodia plant extract and niacin.

  The dose of this additional agent also depends on the condition of the subject being treated, the degree of treatment desired, the nature and type of current therapy, if any, and the frequency of treatment, and the nature of the desired effect. Depends on many factors, including In general, the dosage range of anti-diabetic drugs is about 0.001 mg to about 100 mg / kg body weight of each subject per day, preferably about 0.1 mg to about 10 mg / kg body weight of each subject per day. However, some variation in this general dosage range may also be necessary depending on the age and weight of the subject being treated, the intended route of administration, the particular antidiabetic agent being administered, and the like. The dose range and optimal dose for a particular patient is well within the scope of those skilled in the art who have benefited from this description.

  In accordance with the method of the present invention, a compound according to the present invention or a combination of a compound according to the present invention and at least one additional agent is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition. In a combination aspect of the invention, the compound according to the invention and the at least one additional agent can be administered separately or as a pharmaceutical composition containing both. It is generally preferred that such administration be oral. However, parenteral or transdermal administration may be appropriate if the subject being treated cannot be swallowed, or otherwise oral administration is harmful or undesirable.

  In accordance with the method of the present invention, when a combination of a compound according to the present invention and at least one additional agent is administered together, such administration can be performed sequentially or simultaneously at a convenient point in time. The simultaneous method is generally preferred. When administered sequentially, the compound according to the invention and the additional agent can be administered in any order. It is generally preferred that such administration be oral. It is particularly preferred that such administration be oral and simultaneous. When the compound according to the invention and the additional agent are administered sequentially, each administration can be by the same method or by different methods.

  In accordance with the present invention, a compound according to the present invention or a combination of a compound according to the present invention and at least one additional agent (referred to herein as a “combination”) is administered in the form of a pharmaceutical composition. It is preferable. Thus, the compounds or combinations according to the present invention may be used separately or together in any conventional oral, rectal, transdermal, parenteral (eg intravenous, intramuscular or subcutaneous), intrathecal, intravaginal, It can be administered intraperitoneally, intracapsularly, topically (eg, powder, ointment or drops), or buccal, or as a nasal dosage form.

  Compositions suitable for parenteral injection are generally sterile pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders which are reconstituted in sterile injectable solutions or dispersions Is included. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles are water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (eg olive oil) and injectable Includes organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, in the case of dispersion, by the control of the required particle size and by the use of surfactants.

  These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial contamination of the composition can be accomplished using various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical compositions can be brought about by the use of auxiliaries which can delay the absorption, for example, aluminum monostearate and gelatin.

  Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the compound or combination according to the invention comprises at least one conventional inert pharmaceutical excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler. Or bulking agents (eg starch, lactose, sucrose, mannitol, silicic acid, etc.); (b) binders (eg carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia etc.); (D) disintegrating agents (eg, agar, calcium carbonate, potato or tapioca starch, arginic acid, certain complexes, silicates, calcium carbonate, etc.); (e) dissolution retardants (eg, Paraffin etc.); (f) Absorption enhancers (eg quaternary ammoniumation) (G) wetting agents (eg, cetyl alcohol, glycerol monostearate, etc.); (h) adsorbents (eg, kaolin, bentonite, etc.); and / or (i) lubricants (eg, talc, calcium stearate). , Magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, etc.). In the case of capsules and tablets, these dosage forms can also contain buffering agents.

Similar forms of solid compositions can also be used as fillers in soft or hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.
Solid dosage forms such as tablets, capsules and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can also contain opacifiers and can be compositions such that they release the compounds according to the invention and / or additional agents in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The medicament can also be in micro-encapsulated form using one or more of the above excipients, if desired.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds or combinations according to the invention, the liquid dosage forms are inert diluents customary in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example, cottonseed oil, plant oil that bears fruit under the ground, corn germ oil, olive oil, sesame oil, etc.), glycerol, tetrahydrofurfuryl alcohol , Polyethylene glycol and sorbitan fatty acid esters, or a mixture of these substances.

Besides such inert diluents, the composition can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming substances.
Suspensions are in addition to the compounds or combinations according to the invention plus suspending agents such as ethoxylated isostearyl alcohol, polyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or these It may further contain a mixture of substances.

Rectal or vaginal administration compositions preferably include suppositories, which are compounds or combinations according to the invention that are suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycols or normal solids at room temperature Can be prepared by mixing with a suppository wax that is liquid at body temperature and therefore melts in the rectum or vagina, thereby releasing the active ingredient (s).
Dosage forms for topical administration of a compound according to the invention and a combination of a compound according to the invention and an antidiabetic can include ointments, powders, sprays and inhalants. The medicament is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be encompassed within the scope of the present invention.

In the following section, examples of formulations and dosage forms useful for animals other than humans are described. Administration of a compound according to the invention or a combination of a compound according to the invention and an antidiabetic agent can be carried out orally or parenterally (for example by injection).
An amount of a compound according to the invention or a combination of a compound according to the invention and an antidiabetic is administered so that an effective amount is received. In general, the daily dosage administered orally to an animal is about 0.01 to about 1,000 mg / kg body weight, preferably about 0.01 to about 300 mg / kg body weight.
Preferably, the compound (or combination) according to the present invention can be placed in drinking water so that a therapeutic dose of the compound is ingested during the daily water supply. The compound can be directly metered into the drinking water, preferably in the form of a liquid, a water-soluble concentrate (eg, an aqueous solution of a water-soluble salt).

  Preferably, the compounds (or combinations) according to the invention can also be added directly to the feed as it is or in the form of animal feed supplements called premixes or concentrates. Premixes or concentrates of the compounds in the carrier are more routinely used to include such agents in the feed. Suitable carriers are optionally liquid or solid, such as water, various foods (eg, alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal meal) , And mineral mixes (eg, those commonly used in poultry feed). A particularly effective carrier is each animal feed itself; that is, a small portion of such a feed. The carrier promotes a uniform distribution of the compound in the finished feed formulated with the premix. Preferably, the compound is fully incorporated into the premix and then into the feed. In this regard, the compound can be dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil, etc., or in a volatile organic solvent, and then mixed with a carrier. The amount of compound in the finished feed can be adjusted by combining an appropriate proportion of the premix with the feed to obtain the desired compound level, so the proportion of compound in the concentrate can vary widely Is obvious.

  High titer concentrates can be formulated by feed manufacturers with soy oil meal and other protein-rich carriers such as the above meals to produce a concentrated supplement, which is suitable for direct feed supply to animals. In such a case, the animal is allowed to eat a normal diet. Alternatively, such concentrated supplements can be added directly to the feed to produce a nutritionally balanced finished feed containing therapeutically effective levels of a compound according to the present invention. These mixtures are thoroughly blended by standard methods such as a V-shaped blender to ensure homogeneity.

The use of supplements as a surface decoration for feed also helps to ensure a uniform compound distribution across the surface of the decorated feed.
Drinking water and feeds effective to increase red meat deposition and improve the ratio of lean meat to fat are generally sufficient to provide about 10 ⁻³ to about 500 ppm of compound in the feed or water. Produced by mixing an amount of a compound according to the invention with an animal sample.
Suitable pharmaceutical-containing pig, cow, sheep and goat feeds generally contain from about 1 g to about 400 g of a compound (or combination) according to the invention per tonne of feed, and the optimum amount for these animals is usually about 50 g. ~ About 300g / ton of feed.

Suitable poultry and domestic animal feeds usually contain from about 1 to about 400 g, preferably from about 10 g to about 400 g of a compound (or combination) according to the invention per ton of feed.
When administered parenterally to animals, the compounds (or combinations) according to the invention are prepared in the form of pastes or pellets and are used in animal heads where an increase in the distribution of red meat and an improvement in the ratio of red meat to fat is sought. Transplant under part or ear skin.
In general, parenteral administration includes injection of a compound (or combination) according to the present invention in an amount sufficient to provide about 0.01 to about 20 mg / kg of body weight / day of the medicament to the animal. Suitable doses for poultry, pigs, cows, sheep, goats and domestic pets range from about 0.05 to about 10 mg / kg body weight / day of pharmaceutical.

The pasty composition can be prepared by dispersing the medicament in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil and the like.
Pellets containing an effective amount of a compound, pharmaceutical composition or combination according to the present invention can be prepared by mixing a compound or combination according to the present invention with a diluent such as carbowax, camba wax, etc. For example, magnesium stearate or calcium stearate can be added to improve pellet formation.

It will be appreciated that more than one pellet can be administered to an animal to obtain a desirable dosage level that results in an increased distribution of red meat and an improved ratio of red meat to fat. is there. Furthermore, transplantation can also be performed periodically during the animal treatment period to maintain an appropriate pharmaceutical level for the animal body.
The present invention has several advantageous veterinary characteristics. For pet animals owners or veterinarians who wish to increase lean meat and / or reduce unwanted fat from pet animals, the present invention provides a means by which this can be accomplished. For poultry and pig growers, the method of the present invention provides animals with lean meat that dominate higher selling prices from the meat industry.

  Embodiments of the invention are illustrated by the following examples. However, it will be understood by those skilled in the art that other variations are known or apparent from the disclosure herein, so that aspects of the invention are not limited to the specific details of these examples. Should.

Preparation of key intermediates Preparation of intermediate [4- (4-methoxy-phenyl) -oxazol-2-yl] -acetic acid methyl ester (I-1a):

p-Methoxybromoacetophenone (3.0 g, 13 mmol) and methyl malonate monoamide (23 g, 196 mmol) were combined together in a round bottom flask and then heated to about 130 ° C. for 90 minutes. The reaction mixture was then allowed to cool to room temperature and the resulting orange solid was partitioned between ethyl acetate and water, then extracted with ethyl acetate. The organic extract was collected, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting crude solid was purified by column chromatography (5% ethyl acetate / hexane-10% ethyl acetate / hexane) to give 2.5 g (77% yield) of the title compound ( I-1a ) as a white solid Got as. LRMS ([M + H] ⁺ ): 248.3.

Preparation of intermediate [4-methoxy-phenyl] -oxazol-2-yl] -acetic acid (I-1b):

To a round bottom flask containing [4- (4-methoxy-phenyl) -oxazol - 2-yl] -acetic acid methyl ester I-1a (2.4 g, 9.7 mmol) was added 97 ml each of tetrahydrofuran, methanol and 1N NaOH. Were sequentially added. The resulting solution is stirred at room temperature for about 3 hours, then concentrated and volatiles are removed under reduced pressure. The resulting mixture was partitioned between water and ethyl acetate and the pH of the aqueous layer was adjusted to about 3 with concentrated HCl. The aqueous layer was then extracted with ethyl acetate and the collected organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was recrystallized from ethyl acetate to give the title compound ( I-1b ) as a white solid (1.5 g, 66% yield).

Preparation of intermediate 2- [4- (4-methoxy-phenyl) -oxazol-2-yl] -1-pyrrolidin-1-yl-ethanone (I-1c):

In a round bottom flask, [4- (4-methoxy-phenyl) -oxazol - 2-yl] -acetic acid I-1b (500 mg, 2.14 mmol) was added pyrrolidine (228 mg, 3.21 mmol), EDC in 21 ml dichloromethane. (615 mg, 3.21 mmol) and hydroxybenzotriazole (433 mg, 3.21 mmol) were combined. The resulting mixture was stirred overnight and then concentrated in vacuo to reduce the reaction volume to approximately 1/3 and then added directly onto a chromatographic silica gel column (50% EtOAc / hexanes). The product ( I-1c ) was obtained as a white solid (670 mg, 109% yield). LRMS ([M + H] ⁺ ): 287.2.

Preparation of intermediate 2- [4- (hydroxy-phenyl) -oxazol-2-yl] -1-pyrrolidin-1-yl-ethanone (I-1d):

2- [4- (4-Methoxy-phenyl) -oxazol - 2-yl] -1-pyrrolidin-1-yl-ethanone I-1c (670 mg, 2.34 mmol) was added to D, in methanesulfonic acid (10 ml). Combined with L-methionine (489 mg, 3.28 mmol) and the resulting mixture was heated at 60 ° C. for about 24 hours. The reaction mixture was allowed to cool to room temperature and then slowly added to stirred saturated aqueous sodium carbonate and ethyl acetate. The pH was adjusted to about 9 and the phases were separated. The aqueous phase was extracted with ethyl acetate and the collected organic layers were washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crystalline solid was suspended in a small amount of ethyl acetate and then collected by vacuum filtration to give 480 mg (75% yield) of the desired title product ( I-1d ). LRMS ([M + H] ⁺ ): 273.2.

Preparation of intermediate (2- {4- [2- (2-oxo-2-pyrrolidin-1-ylethyl) -oxazol-4-yl] -phenoxy} -ethyl) -carbamic acid benzyl ester (I-1e)

In a round bottom flask, 2- [4- (4-hydroxy-phenyl) -oxazol-2-yl] -1-pyrrolidin-1-yl-ethanone I-1d (474 mg, 1.74 mmol) was added to dimethyl sulfoxide (6 ml). ) And then potassium carbonate (powder, 722 mg, 5.22 mmol) was added in one portion. To this mixture was added methanesulfonic acid 2-benzyloxycarbonylamino-ethyl ester (952 mg, 3.48 mmol) and the resulting heterogeneous solution was heated to 70 ° C. for about 18 hours. The completion of the reaction was determined by thin layer chromatography, then allowed to cool to room temperature and then poured into 50 ml of water and then 50 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The collected organic extracts were washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give a dark yellow oil. The crude material was purified by column chromatography (2% methanol / dichloromethane) to give the desired title product I-1e (529 mg, 68% yield). LRMS ([M + H] ⁺ ): 450.1.

Preparation of intermediate (2- {4- [4- (2-amino-ethoxy) -phenyl] -oxazol-2-yl} -1-pyrrolidin-1-yl-ethanone (I-1f):

In a bottle for hydrogenation, (2- {4- [2- (2-oxo-2-pyrrolidin-1-ylethyl) -oxazol-4-yl] -phenoxy} -ethyl) -carbamic acid benzyl ester I-1e ( 529 mg, 1.18 mmol) was dissolved in methanol (30 ml) and then 10% Pd / C (30 wt%, 160 mg) was added in one portion. The mixture was hydrogenated under 45 psi hydrogen pressure over about 2 hours and the completion of the reaction was determined by thin layer chromatography. The mixture was then filtered through a pad of diatomaceous earth and then rinsed with methanol to separate the catalyst. The filtrate was concentrated in vacuo to give the desired product I-1f (370 mg, 100% yield) as a white solid. LRMS ([M + H] ⁺ ): 316.2.

Preparation of intermediate benzyl- [2- (4-acetyl-phenoxy) -ethyl] -carbamate (I-2a):

In a round bottom flask equipped with a mechanical stirrer, 4-hydroxyacetophenone I-2a (5.00 g, 36.7 mmol) was dissolved in toluene (122 ml) and then triphenylphosphine (14.4 g, 55.1 mmol). ) And benzyl N- (2-hydroxyethyl) carbamate (10.8 g, 55.1 mmol) were added. The reaction mixture was allowed to cool to about 0 ° C. and then 1,1 ′-(azodicarbonyl) dipiperidine (13.9 g, 55.1 mmol) was added in one portion. The mixture was allowed to warm to room temperature and then after stirring for about 10 minutes, an additional 122 ml of toluene and 122 ml of tetrahydrofuran were added to the dark orange solution. The mixture was stirred for about 24 hours and then the solid was filtered off. The filtrate was concentrated under reduced pressure, and the resulting solid was purified by column chromatography (hexane to 2: 1 hexane / ethyl acetate) to give 9.68 g (yield 84%) of the desired product ( I-2a ). Obtained as a white solid. LRMS ([M + H] ⁺ ): 312.2

Preparation of intermediate benzyl- [2- (4-bromoacetylphenoxy) -ethyl] -carbamate (I-2b) :

Benzyl [2- (4-acetyl-phenoxy) -ethyl] -carbamate I-2a (10.2 g, 32.5 mmol) was dissolved in dichloromethane (100 ml) and methanol (50 ml) and then tetrabutylammonium tribromide ( 15.7 g, 32.5 mmol) was added in one portion. The reaction mixture was stirred for about 16 hours and then allowed to cool with water. The aqueous phase was extracted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium bisulfite. The collected organic extracts are dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, and the resulting crude material is purified by column chromatography (hexane to 2: 1 hexane / ethyl acetate) and colorless to solidify upon standing. An oil I-2b was obtained (11.5 g, 90% yield).

Preparation of intermediate {4- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -oxazol-2-yl} -acetic acid methyl ester (I-2c) :

Methoxymalonamide (10.6 g, 90.6 mmol) and benzyl [2- (4-bromoacetyl-phenoxy) -ethyl] -carbamate I-2b (2.37 g, 6.04 mmol) were combined together in a round bottom flask. Combined and then heated to 130 ° C. for about 90 minutes. The reaction mixture was allowed to cool to room temperature and the resulting orange solid was partitioned between ethyl acetate and water, then extracted with ethyl acetate. The collected organic extracts were washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude solid was purified by column chromatography (30% hexane / ethyl acetate to 50% hexane / ethyl acetate) to give 1.29 g (50% yield) of the title product as a white solid ( I-2c ).

Preparation of intermediate {4- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -oxazol-2-yl} -acetic acid (I-2d) :

In a round bottom flask containing {4- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -oxazol-2-yl} -acetic acid methyl ester I-2c (1.29 g, 3.00 mmol), Tetrahydrofuran, methanol and 1N NaOH were sequentially added in an amount of 10 ml. The resulting solution was stirred at room temperature for about 5 minutes, then quenched with 1N HCl and then extracted with ethyl acetate. The collected organic layers were washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting yellow solid ( I-2d ) was determined to be pure by ¹ H NMR and was used directly in the subsequent reaction (1.20 g, 100% yield).

Preparation of intermediate [2- (4- {2-[(diisopropylcarbamoyl) -methyl] -oxazol-4-yl} -phenoxy) -ethyl-carbamic acid benzyl ester (I-2e) :

In a round bottom flask, {4- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -oxazol - 2-yl} -acetic acid I-2d (350 mg, 0.883 mmol) was added to 1,2-dichloroethane. (4.4 ml), diisopropylamine (160 μl, 1.15 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) (598 mg, 1.15 mmol) and diisopropylethylamine (230 μl, 1. 32 mmol). The resulting mixture was stirred overnight, concentrated under reduced pressure to reduce the reaction volume to approximately 1/3, and then added directly onto a chromatographic silica gel column (50% hexane / ethyl acetate). This product was obtained as a white solid I-2e (219 mg, 52% yield). LRMS ([M + H] ⁺ ): 480.2.

Preparation of intermediate 2- [4- (4-methoxy-phenyl) -oxazol-2-yl] -hexanoic acid N, N-dimethylamide (I-3a) :

To a stirred solution of 300 mg (1.15 mmol) of 2- [4- (4-methoxy-phenyl) -oxazol-2-yl] -N, N-dimethyl-acetamide in 4 ml of tetrahydrofuran at 0 ° C. under nitrogen atmosphere. 1.15 ml of 1.0M tetrahydrofuran solution of lithium bis (trimethylsilyl) amide was added and the resulting solution was stirred for 30 minutes. To this solution was added 0.13 μl (1.15 mmol) of 1-iodobutane and the reaction mixture was allowed to warm to room temperature and stirred overnight. After cooling to 0 ° C., water was added and then the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate and the collected organic layers were dried over sodium sulfate and then concentrated under reduced pressure. The resulting material is purified by column chromatography using 2% acetone / dichloromethane to 5% acetone / dichloromethane as gradient eluent to give the desired title product I-3a (212 mg, 58% yield) as a solid. Obtained. LRMS ([M + H] ⁺ ): 317.5.

Preparation of intermediate {2- [4- (3-dimethylamino-acryloyl) -phenoxy] -ethyl} -carbamic acid benzyl ester (I-4a):

Benzyl [2- (4-acetyl-phenoxy) -ethyl] -carbamate (28.3 g, 90.3 mmol) and N, N-dimethylformamide diethyl acetal (62 ml, 361 mmol) were combined together in a round bottom flask and then Heated at 70 ° C. for about 28 hours. The reaction mixture was then allowed to cool to room temperature and left overnight, then 25 ml of hexane was added to the heterogeneous reaction mixture. The resulting slurry was filtered, and then the solid was dried under reduced pressure to obtain 30.11 g (81.7 mmol, yield 90%) of mustard yellow powder ( I-4a ). LRMS ([M + H] ⁺ ): 369.3.

Preparation of intermediate {2- [4- (1H-pyrazol-3-yl) -phenoxy] -ethyl} -carbamic acid benzyl ester (I-4b):

In a round bottom flask, {2- [4- (3-dimethylamino-acryloxy) -phenoxy] -ethyl} -carbamic acid benzyl ester I-4a (12.85 g, 34.87 mmol) was added in ethanol (70 ml). And then hydrazine hydrate (3.38 ml, 69.76 mmol) was added dropwise via a syringe. The reaction flask was equipped with a reflux condenser and then heated at 80 ° C. for about 18 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid was suspended in a small amount of ethanol and then filtered under reduced pressure. This solid was dried under reduced pressure to obtain colorless solid I-4b (6.55 g). The filtrate was concentrated and then resuspended in ethanol to give solid I-4b as a second crop (2.27 g, overall yield 75%). LRMS ([M + H] ⁺ ): 338.3.

Preparation of intermediate {3- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -pyrazol-1-yl} -acetic acid ethyl ester (I-4c):

In a 500 ml round bottom flask was added {2- [4- (1H-pyrazol-3-yl) -phenoxy] -ethyl} -carbamic acid benzyl ester I-4b (8.39 g, 24.87 mmol) and ethanol (80 ml). I was charged. Sodium ethoxide (27.9 ml of a 21 wt% solution in ethanol, 74.6 mmol) was added dropwise via an addition funnel over about 5 minutes, followed by addition of bromoacetic acid ethyl ester (5.51 ml, 49.73 mmol). . The resulting mixture was stirred for about 15 hours and then sedated to neutral pH by the addition of concentrated HCl. Volatiles were removed under reduced pressure and then 500 ml of diethyl ether was added to produce a slurry. The solid was separated by vacuum filtration and 10.6 g of the resulting brown solid was discarded. The ethereal filtrate was then concentrated and the resulting oil (8.1 g) was purified by column chromatography (40% hexane / ethyl acetate) to yield 3.06 g of the desired title product I-4c ( 7.22 mmol, 29% yield). LRMS ([M + H] ⁺ ): 424.3.

Preparation of intermediate {3- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -pyrazol-1-yl} -acetic acid (I-4d):

In a round bottom flask, {3- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -pyrazol - 1-yl} -acetic acid ethyl ester I-4c (1.19 g, 2.81 mmol) was added to tetrahydrofuran. (9.0 ml). Methanol (9 ml) and 1N LiOH (9 ml) were added sequentially and the mixture was stirred for about 10 minutes. The reaction was brought to pH 3 with 3N HCl and then diluted with water and dichloromethane. The aqueous phase was extracted with dichloromethane and the collected organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure. The resulting crude material (1.17 g) was triturated with ether and then decanted to yield 936 mg (84% yield) of the desired product ( I-4d ). LRMS ([M + H] ⁺ ): 396.3.

Preparation of intermediate {2- [4- (1-cyclopentylcarbamoylmethyl-1H-pyrazol-3-yl) -phenoxy] -ethyl} -carbamic acid benzyl ester (I-4e):

In a round bottom flask, {3- [4- (2-benzyloxycarbonylamino-ethoxy) -phenyl] -pyrazol - 1-yl} -acetic acid I-4d (244 mg, 0.617 mmol) and diisopropylethylamine (322 μl, 1 .85 mmol) was dissolved in dichloromethane (6 ml). To this solution was added EDC.HCl (178 mg, 0.926 mmol) followed by hydroxybenzotriazole hydrate (125 mg, 0.926 mmol) and cyclopentylamine (122 μl, 1.23 mmol). The reaction mixture was stirred for about 48 hours and then diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate and the collected organic layers were dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (1.5% methanol / dichloromethane) to give 290 mg (102% yield) of the desired product ( I-4e ). LRMS ([M + H] ⁺ ): 463.4.

Preparation of intermediate 2- {3- [4- (2-amino-ethoxy) -phenyl] -pyrazol-1-yl} -N-cyclopentyl-acetamide (I-4f):

In a nitrogen purged round bottom flask, {2- [4- (1-cyclopentylcarbamoylmethyl-1H-pyrazol-3-yl) -phenoxy] -ethyl} -carbamic acid benzyl ester I-4e (285 mg, 0.616 mmol) Was dissolved in methanol (6.1 ml). To this solution was added 10% Pd / C (100 mg, 30 wt%) and formic acid (2.46 ml, 95 mmol) and the reaction mixture was stirred overnight. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated. The resulting material was then dissolved in water, the pH was adjusted to 12 with 5N NaOH, and the aqueous phase was extracted with ethyl acetate. The collected organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure. The resulting product I-4f (173 mg, 85% yield) was carried directly to the subsequent reaction. LRMS ([M + H] ⁺ ): 329.4.

Preparation of intermediate 3-dimethylamino-1- (4-methoxy-phenyl) -prop-2-en-1-one (I-5a):

p-Methoxyacetophenone (4.50 g, 30.0 mmol) and N, N-dimethylformamide diethyl acetal (25.7 ml, 150 mmol) were combined together in a round bottom flask and then heated at 130 ° C. for about 18 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Diethyl ether (30 ml) was added to the reaction mixture, and the resulting solid (2.59 g) was collected by vacuum filtration. The filtrate was concentrated to dryness and then resuspended in diethyl ether to produce a solid as a second crop. This solid was collected by filtration (1.38 g). The collected solid I-5a (3.97 g, 65% yield) was carried directly to the subsequent process.

Preparation of intermediate [5- (4-methoxy-phenyl) -pyrazol-1-yl] -acetic acid ethyl ester (I-5b):

Ethyl hydrazinoacetate hydrochloride (1.91 g, 12.3 mmol) and 3-dimethylamino-1- (4-methoxy-phenyl) -prop-2-en-1-one I-5a (2.53 g, 12. 3 mmol) was dissolved in ethanol (40 ml). To this solution was added potassium carbonate (1.70 g, 12.3 mmol) and the resulting mixture was heated to 80 ° C. for about 16 hours. The reaction was allowed to cool to room temperature and then concentrated under reduced pressure. This crude paste was suspended in water (50 ml) and then its pH was adjusted to 9. The aqueous mixture was extracted with ethyl acetate and the collected organic extracts were washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. This product was then purified by column chromatography (hexane to 35% ethyl acetate / hexane) to give 2.61 g (81% yield) of the desired product ( I-5b ). LRMS ([M + H] ⁺ ): 261.3.

Preparation of intermediate [5- (4-methoxy-phenyl) -pyrazol-1-yl] -acetic acid (I-5c):

[5- (4-Methoxy-phenyl) -pyrazol-1-yl] -acetic acid ethyl ester I-5b (2.50 g, 9.60 mmol) was dissolved in tetrahydrofuran (30 ml) and methanol (30 ml). To this mixture was added LiOH (902 mg, 38.4 mmol) and water (30 ml). The mixture was stirred for about 15 minutes and then partitioned between ethyl acetate and water. The pH was adjusted to 3, then the aqueous phase was extracted with ethyl acetate. The organic extracts were collected, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give the title compound ( I-5c ) as a colorless solid (2.08 g, 93% yield). LRMS ([M + H] ⁺ ): 233.3.

Preparation of intermediate 2- [5- (4-methoxy-phenyl) -pyrazol-1-yl] -1-pyrrolidin-1-yl-ethanone (I-5d):

[5- (4-Methoxy-phenyl) -pyrazol-1-yl] -acetic acid I-5c was dissolved in dichloromethane (9.5 ml) in a round bottom flask. To this solution, EDC.HCl (817 mg, 4.26 mmol), diisopropylethylamine (1.48 ml, 8.52 mmol), hydroxybenzotriazole hydrate (576 mg, 4.26 mmol) and pyrrolidine (475 μl, 5.68 mmol) were sequentially added. Added. The reaction mixture was stirred for about 2 days, then diluted with dichloromethane and then sedated with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane and the organic phase was collected, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude material was purified by column chromatography (3% methanol / dichloromethane) to give 475 mg (59% yield) of the desired product ( I-5d ). LRMS ([M + H] ⁺ ): 286.3.

Preparation of intermediate 2- [5- (4-hydroxy-phenyl) -pyrazol-1-yl] -1-pyrrolidin-1-yl-ethanone (I-5e):

In a round bottom flask, 2- [5- (4-methoxy-phenyl) -pyrazol-1-yl] -1-pyrrolidin-1-yl-ethanone I-5d (440 mg, 1.54 mmol) was added to methanesulfonic acid ( Combined with D, L-methionine (345 mg, 2.31 mmol) in 6.2 ml) and the resulting mixture was heated to 70 ° C. for about 22 hours. The reaction was then allowed to cool to room temperature and then slowly added to stirred saturated aqueous sodium carbonate and ethyl acetate. The pH was adjusted to 9 and then the phases were separated. The aqueous phase was extracted with ethyl acetate and the organic phase was collected, washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting crude material was purified by column chromatography (dichloromethane to 3% methanol / dichloromethane) to give 280 mg (1.03 mmol, 67% yield) of the desired product ( I-5e ) as a colorless solid. . LRMS ([M + H] ⁺ ): 272.2.

Intermediate (2- {4- [2- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2H-pyrazol-3-yl] -phenoxy} -ethyl-carbamic acid benzyl ester (I-5f) Manufacturing of:

In a round bottom flask, 2- [5- (4-hydroxy-phenyl) -pyrazol - 1-yl] -1-pyrrolidin-1-yl-ethanone I-5e (273 mg, 1.00 mmol) was added to dimethyl sulfoxide (2 ml). ) And then potassium carbonate (powder, 415 mg, 3.00 mmol) was added in one portion. To this mixture was added methanesulfonic acid 2-benzyloxycarbonylamino-ethyl ester (547 mg, 2.00 mmol) and the resulting heterogeneous solution was heated to 70 ° C. for about 18 hours. The completion of the reaction was judged by thin layer chromatography, then allowed to cool to room temperature and then poured into 20 ml of water. This aqueous phase was extracted three times with dichloromethane and the organic extracts were collected, washed with brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give a dark yellow oil. The crude material was purified by column chromatography (2% methanol / dichloromethane) to give the desired product I-5f (390 mg, 87% yield). LRMS ([M + H] ⁺ ): 449.4.

Preparation of intermediate 2- {5- [4- (2-amino-ethoxy) -phenyl] -pyrazol-1-yl} -1-pyrrolidin-1-yl-ethanone (I-5 g):

In a nitrogen purged round bottom flask, (2- {4- [2- (2-oxo-2-pyrrolidin-1-ethyl) -2H-pyrazol-3-yl] -phenoxy} -ethyl) -carbamic acid benzyl ester I-5f (390 mg, 0.870 mmol) was dissolved in methanol (8.70 ml). To this solution was added 10% Pd / C (150 mg, 30 wt%) and formic acid (3.48 ml, 133 mmol) and the reaction was stirred overnight. The reaction mixture was then filtered through a pad of diatomaceous earth and the filtrate was concentrated. The resulting material was then dissolved in water, then its pH was adjusted to 12 with 5N NaOH and the aqueous phase was extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The resulting product I-5 g (225 mg, 72% yield) was carried directly to the subsequent reaction. LRMS ([M + H] ⁺ ): 315.4.

Example 1 illustrates the preparation of a compound according to the invention where Ar is a pyridyl group.
Example 1
2- [4- (4- {2- [2- (6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- Production of pyrrolidin-1-yl-ethanone (1-1A):

In a round bottom flask, (R) -2-chloro-5-oxiranyl-pyridine (123 mg, 0.79 mmol) and 2- {4- [4- (2-amino-ethoxy) -phenyl] -oxazol-2-yl } -1-Pyrrolidin-1-yl-ethanone I-1f (370 mg, 1.18 mmol) was dissolved in 20 ml of ethanol and the mixture was heated to 80 ° C. for about 16 hours. The solution was then concentrated in vacuo to an oil and the crude material was purified by column chromatography (dichloromethane to 10% methanol / dichloromethane) to afford 200 mg (54% yield) of the title product as a white solid. Obtained. LRMS ([M + H] ⁺ ): 471.3. ¹ H NMR: (400 MHZ, CD ₃ OD): δ 1.91 (m, 2H), 1.99 (m, 2H), 2.85 (m, 2H), 3.03 (m, 2H), 3 .45 (m, 2H), 3.61 (m, 2H), 3.95 (s, 2H), 4.10 (m, 2H), 4.84 (m, 1H), 6.97 (d, 2H, J = 8.8 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.83 (dd, 1H, J = 2) .8, 8.4 Hz), 8.10 (s, 1 H), 8.37 (d, 1 H, J = 2.8 Hz).

2- (4- {4- [2- (2 (R) -Hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -1-pyrrolidine-1- Production of il-ethanone (1-1B):

In a round bottom flask purged with nitrogen, (R) -2- [4- (4- {2- [2- (6-chloro-pyridin-3-yl) -2-hydroxy-ethylamino] -ethoxy} -phenyl ) -Oxazol-2-yl] -pyrrolidin-1-yl-ethanone 1-1A (200 mg, 0.42 mmol) was dissolved in methanol (15 ml). 10% Pd / C (160 mg, 80 wt%) and ammonium formate (321 mg, 5.1 mmol) were then added sequentially. The reaction mixture was stirred overnight and then filtered through a pad of diatomaceous earth and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated and the resulting white solid was taken up in ethyl acetate and saturated aqueous sodium carbonate and then extracted. The organic extract was washed with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give a crude solid. This product was suspended in diethyl ether and then isolated by vacuum filtration to give crystalline solid 1-1B (110 mg, 59% yield). This material was then converted to the corresponding hydrochloride salt. Analytical data for the HCl salt: LRMS ([M + H] ⁺ ): 437.4. ¹ H NMR: (400 MHZ, CD ₃ OD): δ 1.91 (m, 2H), 2.02 (m, 2H), 3.37-3.29 (m, 2H), 3.45 (m, 2H), 3.54-3.63 (m, 5H), 3.97 (s, 2H), 4.37 (t, 2H, J = 4.8 Hz), 5.38 (dd, 1H, J = 3.2, 10.4 Hz), 7.07 (dd, 2H, J = 2.8, 9.6 Hz), 7.69 (dd, 2H, J = 1.8, 6.4 Hz), 8.14 (M, 2H), 8.75 (m, 1H), 8.86 (d, 1H, J = 6.0 Hz), 8.99 (m, 1H).

2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- Production of N, N-dimethyl-acetamide (1-1C):

In a round bottom flask, (R) -2-methyl-5-oxiranyl-pyridine (4.4 g, 0.015 mol) and 2- {4- [4- (2-amino-ethoxy) -phenyl] -oxazole-2 -Il} -N, N-dimethyl-acetamide (2.3 g, 0.017 mol) was dissolved in 16 ml of ethanol and the mixture was heated to 60 ° C. for about 16 hours. After about 1 hour, a precipitate started to form. The reaction mixture was then allowed to cool to room temperature and then diluted with ethyl acetate. The resulting mixture was stirred for 1 hour and the solid was then separated by filtration and then washed with ethyl acetate. These solids were then resuspended in ethyl acetate and then heated to 70 ° C. to give a pale yellow solution. The solution was then allowed to cool slowly and the resulting solid was isolated to give 1.9 g (29%) of the title product as a pale pink solid. LRMS ([M + H] ⁺ ): 425.0. ¹ H NMR: (400 MHZ, CD ₃ OD): δ 8.42 (d, J = 2.49, 1H), 8.12 (s, 1H), 7.76 (dd, 1H), 7.67 ( dt, 2H), 7.29 (d, J = 8.3, 1H), 6.99 (dt, 2H), 4.87 (t, J = 6.23, 1H), 4.16 (m, 2H), 4.03 (s, 2H), 3.16 (s, 3H), 3.12 (m, 2H), 2.98 (s, 3H), 2.93 (d, J = 6.64) , 2H), 2.52 (s, 3H).

Table 1 below lists compounds prepared using the general methods described above for the preparation of compounds 1-1A , 1-1B and 1-1C and using the corresponding starting materials.

Example 2 illustrates the preparation of a compound according to the invention where Ar is a phenyl group.
(Example 2)
N- {5- [2- (2- {4- [2- (2-azetidin-1-yl-2-oxo-ethyl) -oxazol-4-yl] -phenoxy} -ethylamino) -1 (R ) -Hydroxy-ethyl] -2-chloro-phenyl} -methanesulfonamide hydrochloride (2-1A):

In a round bottom flask, (R) -N- (2-chloro-5-oxiranyl-phenyl) -methanesulfonamide (18 mg, 0.073 mmol) and 2- {4- [4- (2-amino-ethoxy)- [Phenyl] -oxazol-2-yl} -1-azetidin-1-yl-ethanone (33 mg, 0.11 mmol) was dissolved in 0.7 ml of ethanol and the mixture was heated to 80 ° C. for 12 hours. The solution was then concentrated in vacuo to an oil and the crude product was purified by column chromatography (2% methanol / dichloromethane to 7% methanol / dichloromethane) to yield 16 mg (40% yield) of the coupled product. Obtained as a white solid. This material is dissolved in dichloromethane and ethyl acetate (1: 1) and this solution is dissolved in 1N in ether.
HCl 0.06 ml was added to give the HCl salt. The solution was concentrated to give the title compound as a yellow solid. LRMS ([M + H] ⁺ ): 349.1. ¹ H NMR: (400 MHZ, CD ₃ OD): δ 2.33 (m, 2H), 2.98 (s, 3H), 3.19 (m, 1H), 3.28 (s, 2H), 3 .33 (m, 1H), 3.54 (m, 2H), 4.04 (m, 2H), 4.33 (m, 4H), 5.02 (m, 1H), 7.05 (d, 2H, J = 8.8 Hz), 7.31 (m, 1H), 7.50 (d, 1H, J = 8.4 Hz), 7.64 (d, 1H, J = 1.6 Hz), 7. 69 (d, 2H, J = 8.4 Hz), 8.13 (s, 1H).

Table 2 below lists compounds having the above general structure prepared using the above general methods for the preparation of compound 2-1A and the corresponding starting materials.

Example 3 illustrates the preparation of a compound according to the invention where HET is pyrazole.
(Example 3)
2- [3- (4- {2- [2- (6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -pyrazol-1-yl]- Production of 1-pyrrolidin-1-yl-ethanone (3-1A):

In a round bottom flask, (R) -2-chloro-5-oxiranyl-pyridine (23 mg, 0.15 mmol) and 2- {4- [1- (2-amino-ethoxy) -phenyl] -pyrazol-1-yl } -1-Pyrrolidin-1-yl-ethanone I-4f (71 mg, 0.23 mmol) was dissolved in 1.5 ml of ethanol and the mixture was heated to 80 ° C. for about 16 hours. The solution was then concentrated in vacuo to an oil and the crude material was purified by column chromatography (dichloromethane to 11% methanol / dichloromethane) to yield 45 mg (63% yield) of the title product as a white solid. Obtained.
LRMS ([M + H] ⁺ ): 470.0. ¹ H NMR: (400 MHZ, CD ₃ OD): δ 1.91 (m, 2H), 2.03 (m, 2H), 2.88 (m, 2H), 3.05 (m, 2H), 3 .46 (t, 2H, J = 6.8 Hz), 3.59 (t, 2H, J = 6.7 Hz), 4.12 (m, 2H), 4.86 (m, 1H), 5.04 (S, 2H), 6.59 (d, 1H, J = 4.5 Hz), 6.96 (d, 2H, J = 8.0 Hz), 7.43 (d, 1H, J = 8.4 Hz) 7.62 (d, 1H, J = 2.8 Hz), 7.69 (d, 2H, J = 8.0 Hz), 7.85 (dd, 1H, J = 2.5, 8.3 Hz), 8.35 (d, 1H, J = 2.2 Hz).

Table 3 below lists the compounds prepared using the above general method for the preparation of compound 3-1A , using the corresponding starting materials.

Biological Assays The usefulness of the compounds according to the invention in carrying out the methods of the invention can be assessed by their activity in at least one of the methods described in detail below.
Assay 1
beta ₁ and beta ₂ in vitro beta ₃ receptor activity and selectivity over adrenergic receptor over the body beta ₃ receptor selectivity beta ₁ and beta ₂ adrenergic receptors, Chinese (Chinese) cyclic adenosine monophosphate in hamster ovary cells It can be measured by measuring (cAMP) accumulation.

Chinese hamster ovary cells specifically transfected with cDNAs related to human β ₁ , β ₂ or β ₃ adrenergic receptors were obtained from the American Type Culture Catalog of Cell Line and Hybridomas, 7th.
Edition, 1992, p 36, containing 10% fetal bovine serum, 500 mg / ml geneticin 100 U / ml penicillin, 100 mg / ml streptomycin and 250 ng / ml fungizone according to the method described in ATCC CCL61 CHO-K1 Grow densely in Ham's F12 medium. Compounds were prepared as 25mM stock solutions in DMSO (0.1% DMSO final concentration), diluted in Ham's F12 medium and then with ^{10 -5} M isobutylmethylxanthine to inhibit phosphodiesterase activity, 10 ^- added to cells at ¹⁰ to 10 ^-5 M.

The medium and cells are then incubated for 60 minutes at 37 ° C. At the end of this incubation period, the medium is aspirated and the cells are lysed with 0.01 N HCl. The cell content of this cAMP is measured by radioimmunoassay (RIA) using a kit from New England Nuclear (Burlington, Mass.). There is a correlation between the cellular content of cAMP and the antagonism of β ₁ , β ₂ or β ₃ adrenergic receptors. The non-selective full β-adrenergic agonist isoproterenol is included as a positive control at 10 ⁻⁵ M.

An ED ₅₀ value range of 13 μM to 155 μM was found for the compounds listed in Examples 1, 2 and 3 (Example 1-1A to Example 3-1K). As a specific example, the compound of Example 3-1H had an ED ₅₀ of 88 μM. Example 3-1H was selected for illustrative purposes only and does not imply that the compound of Example 3-1H is a suitable compound.

Assay 2
Many G protein coupled receptors (GPDRs) exhibit at least two agonist affinity states. High affinity agonists that bind to GPDRs require receptor binding or coupling with GDP-linked heterotrimeric G protein complexes. In general, a low affinity agonist binding site indicates an unbound receptor state. A high affinity agonist binding site can be converted to a low affinity site by the addition of GTP or an analog thereof. In the absence of an agonist, G protein has a high affinity for GTP. In the presence of an agonist, G protein has a high affinity for GDP. Thus, when an agonist and GTP are added to the receptor / G protein complex, GTP is replaced by GDP and the receptor is separated from the G protein. Two affinity states for agonists can be detected with radioligand competitive binding assays. Two sites are generally found for agonists for a significant number of GPCRs and can be calculated using commercially available software. The high-affinity site (K _iH ) corresponds to the G-protein binding site, and in the case of β ₃ -adrenergic receptor, has a sufficient correlation with the functional value ED ₅₀ involved in stimulating cAMP accumulation.

To identify compounds that weaken the binding of [ ¹²⁵ I] cyanopindolol (ICYP) to the β ₃ adrenergic receptor, the following radioligand binding assay can be used.

Radioligand binding assay
ICYP beta ₃ adrenergic receptor competitive binding assay ^[125 I] specific activity of ICYP is 2000 Ci / mmole. ICYP undergoes catastrophic decay upon radiolysis. Thus, this specific activity always remains at 2000 Ci / mmole, but the concentration decreases over time. The final concentration of ICPY is 250 pM. Therefore, it is necessary to make 2.5nM (10x) raw material. [ ¹²⁵ I] ICYP can be obtained from New England Nuclear, Boston, MA.

It is possible to test the compounds of up to four by competition curves of the competitor 96 well Homat 13. An example involving one compound is outlined below.
(Compound 1)
A 1,2-10
B 1,2-9.3
C 1,2-9
D 1,2-8.3
E 1, 2-8
F 1,2-7.3
G 1,2-7
H 1,2-6.3
A 3,4-6
B 3,4-5
C 3,4 -4
D 3,4 Pindolol E 3,4 General

The following compounds start with F3,4. Two sets of total and non-specific binding are added to the plate. Wells E3,4 and G7,8 are involved in total cpm binding. Wells D3,4 and H7,8 are for measuring non-specific binding involving 100 μM pindolol.
Order of addition to each well : 20 μl of buffer for the “total” well; 20 μl of 1 mM pindolol for the pindolol well; 20 μl concentration of each compound for the corresponding well; 20 μl of 2.5 nM ICYP for all wells; and 15 μg / 160 μl of membrane diluted to 160 μl.

Method 1. Setup assay for Packard 96 well unifilter (Unifilter) with GF / C filter (Packard; Meriden, CT) using 96 well microtiter plates.
2. Incubate for 90-120 minutes with agitation at room temperature.
3. Inhalation of the sample into the processing head using a Packard cell collector (Packard; Meriden, CT). Use of a pre-adsorption (0.3% PEI) filter.
4). 4 washes with cold wash buffer.
5. Dry plate and add 25 μl of Microscint (ICN manufacturer: Costa Mesa, Calif.) To each well.
6). Weigh sample with Wallac beta plate reader (Wallac; Turku, Finland).

Binding buffer : 50 mM Hepes / 10 mM MgCl ₂ , pH 7.4 (prepared from 10 × stock solution) and 0.2% BSA (fraction V).
Protease inhibitors (prepared from 100 × stock solution): 100 μg / ml bacitracin; 100 μg / ml benzamidine; 5 μg / ml aprotin; and 5 μg / ml leupeptin.
Washing buffer : 50 nM Hepes / 10 mM MgCl ₂ , pH 7.4, ice-cooled (prepared from 10 × stock solution).

Assay 3
Oxygen consumption As is well known to those skilled in the art, during an increase in energy consumption, animals generally consume an increased amount of oxygen. In addition, metabolic fuels such as glucose and fatty acids are oxidized to CO ₂ and H ₂ O with fouling generation of heat. This effect is commonly referred to in the art as heat production. Thus, the measurement of oxygen consumption in animals, including humans and companion animals, is an indirect measurement of heat production and should be routinely used by those skilled in the art for such energy consumption measurements in animals, such as humans. Can do.
The ability of the compounds of formula (I), their stereoisomers and prodrugs, and the pharmaceutically acceptable salts of this compound, stereoisomers and prodrugs to produce an exothermic response is described by male Sprague-Dawley (Sprague -Dawley) Rats (Charles River, Wilmington, MA) can be used and demonstrated according to the following method.

  Total animal oxygen consumption can be measured using an open circuit, indirect calorimeter [Oxymax (registered trade name) Columbia Instruments, Columbia, OH]. Prior to each test, the gas detector is calibrated with gaseous nitrogen and a gas mixture (0.5% carbon dioxide, 20.5% oxygen, 79% nitrogen; Abco Industrial Supplies, Waterford, CT). Male Sprague-Dawley rats (weighing 300-380 g) are placed in a closed room (43 x 43 x 10 cm) with calorimeter and this room is mounted on an activity tracker. The flow rate of air through this room is set to 1.6-1.7 l / ml. The calorimeter measures the oxygen consumption based on the flow rate of air passing through this room and the difference in oxygen content at the inlet and outlet. This activity tracker has 15 infrared rays spaced 1 inch apart in each axis; if two consecutive rays are broken, it records the movement activity (no repeated interruptions of the same ray are registered) ), And record the result as a count value. Basal oxygen consumption and locomotor activity are measured every 10 minutes for 2.5-3 hours. At the end of this basal period, the room is opened and the test compound (prepared in 0.01-20 mg / kg, water, 0.5% methylcellulose, or other suitable vehicle) or an equal amount of vehicle is administered by oral gavage. Administer by administration. Oxygen consumption and locomotor activity are measured every 10 minutes for an additional 2-6 hours after administration. The percent change in oxygen consumption is calculated by averaging the post-dose values and then dividing by the basal oxygen consumption (average of dose before administration excluding the first hour). If the mobile activity exceeds a value of 100, the oxygen consumption value obtained during the elapsed time is excluded from the calculation. Thus, these numbers represent the percent change in resting oxygen consumption.

Assay 4
Hypoglycemic activity The compounds according to the invention can be tested for hypoglycemic activity according to the following method and, as an aid, can be used to determine doses relative to different test compounds and standards.

Five to eight week old C57BL / 6J-ob / ob mice (Jackson Laboratory, Bar Harbor, ME) are placed in one cage for every five animals at an ambient temperature of 66 ° C. under standard animal care practices. . After an acclimatization period of 1 week, the animals are weighed and then 25 microliters of blood is collected from the eye blood before any treatment is performed. The blood sample is immediately diluted 1: 5 with 2% sodium heparin containing saline in a tube kept in ice. The blood sample is centrifuged for 2 minutes, red blood cells are separated, and the supernatant is analyzed for glucose concentration using a clinical autoanalyzer (Abbott Spectrum (registered trade name) CCx; Abbott Laboratories, Abbott Park, IL). analyse. The animals are then regrouped into groups of 5 animals per cage so that the group average glucose values are similar. Mice are then followed by positive controls (US Pat. No. 4,467,902) such as test compound (0.01-20 mg / kg), englitazone or ciglitazone (50 mg / kg po); Chem. Pharm. Bull., 32 , 4460-4465 (1984)) or vehicle by Sohda et al., Once or twice daily for 5 days. All compounds are administered by oral gavage in vehicles consisting of 0.5% weight / volume methylcellulose or other suitable vehicle. On the fifth day, the animals are weighed again and blood (by ocular route) is measured for blood glucose levels as described above. Plasma glucose is then calculated from the equation.

Plasma glucose (mg / dl) = sample value × 5 × 1.67 = 8.35 × sample value where 5 is the dilution factor and 1.67 is the plasma hematocrit adjustment (assuming hematocrit is 40% To do).
Animals administered vehicle maintain hyperglycemic glucose levels that are substantially unchanged (eg, 300 mg / dl), while positive control animals have reduced glucose levels (eg, 130 mg / dl). . The glucose lowering activity of the test compound is expressed in terms of% glucose normalization. As an example, glucose levels that are identical to the positive control are expressed as 100%.

Assay 5
β ₁ and β ₂ Receptor Selectivity The in vivo selectivity of β ₁ and β ₂ receptors is the heart rate collected in awake and catheterized rats (male Sprague-Dawley rats, body weight 300-400 g), It can be measured by measuring blood pressure and plasma potassium concentration. To implant the catheter, rats are anesthetized with pentobarbital (50-60 mg / kg ip) and a PE50 tube is inserted into the left carotid artery. The catheter is implanted subcutaneously and removed behind the neck, filled with a solution of polyvinylpyrrolidone in heparinized saline, the frame sealed, and then taped. The experiment is carried out over 7 days after surgery. On the first day of the experiment, the catheter tape is removed and then flushed with saline. After at least 30 minutes, basal values of heart rate and blood pressure are measured by attaching a pressure transducer to the sphygmomanometer, and the results are recorded on a Grass Model 7 polygraph (Grass Medical Instrument, Quincy, Mass.) And a basal blood sample Is obtained from an arterial catheter. After obtaining basal values, the test compound or vehicle was administered by oral gavage and blood pressure (measure of beta ₁ activity) (beta ₂ activity measure) and heart rate measurements, 15 min, 30 min, 45 Min and 60 min time points were collected, and potassium measurements (β ₂ ) of blood samples were obtained at 30 and 60 min time points. As a positive control, non-selective β-agonists can be tested at a dose range of 0.001-1 mg / kg (sc injection in saline medium). Plasma potassium is measured by flame spectrophotometry. To measure the change, the basal value is subtracted from the mean value after administration.

Assay 6
Reduction of intestinal motility The compounds of formula (I) have the effect of reducing intestinal motility and are therefore various gastrointestinal disorders such as irritable bowel syndrome, peptic ulceration, esophagitis, gastritis, duodenum Inflammation [including those induced by Helicobacter pylon], intestinal ulceration (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis), and gastrointestinal ulceration Useful as an adjunct in the treatment of It has been suggested that automotility due to non-spinning smooth muscle contraction is mediated by activity at the β ₃ adrenergic receptor. The availability as an agonist specific for β ₃ with little activity on β ₁ and β ₂ receptors, pharmacologically regulates intestinal motility without the accompanying effects on the cardiovascular system. Would help control.

The in vivo activity of the compound represented by the formula (I) involved in the treatment or prevention of intestinal automotility disorder can be measured according to the following method. Male Sprague-Dawley (CD) rats (175-225 g) fasted for 18 hours were given p.p. test compound or vehicle (distilled water) in an amount of 0.01-20 mg / kg. o. Administer. At 30 minutes after test compound administration, rats were orally dosed with 0.25 ml of a sodium chromate solution in 0.9% saline containing approximately 20,000 cpm ⁵¹ Cr (specific activity 350 mCi / mg Cr). To do. After 20 minutes, the rats are sacrificed and the gastroomental omentum, pylorus and ileocecal joint are then ligated to separate the stomach and small intestine. The small intestine is divided into equal lengths, and the stomach and each length of the small intestine are analyzed for radioactivity using a gamma counter. For each rat, the gastric void fraction can then be measured by comparing the amount of intestinal radioactivity to intestine + total radioactivity. In addition, the geometric center of the distribution of radioactive markers is used as a measure of the overall migration rate through the stomach and intestine. This geometric center is calculated by summing the product of the ⁵¹ Cr fraction in each section and the number of sections: geometric center = S (( ⁵¹ Cr fraction / section) × (number of sections)). In these calculations, the stomach is considered to have a segment number of 0 and 10 intestinal segments are numbered 1-10. Thus, a geometric center of 0.0 indicates that the full load of ⁵¹ Cr remains in the stomach. Data from two experiments are collected and statistical evaluation is performed using Dunnett's multiple comparison test.

Alternatively, 8 groups of fasted male Sprague-Dawley (CD) rats (175-225 g) are anesthetized with methoxyflurane. Make a small incision in the abdomen and ligate the pylorus. Immediately following ligation, a solution or medium of test compound (distilled water) is injected proximal to the duodenum. The dose of test compound used should be 0.01-20 mg / kg body weight. The ligature is then closed and the rat is allowed to recover from anesthesia. At 2 hours after ligation, rats are sacrificed and gastric fluid is collected and clarified by centrifugation. The total amount of secretion is determined by weight and the acidity is measured by titrating with 0.1N sodium hydroxide to pH 7.0 using an automatic titrator. Data from two experiments is then collected. Rats from groups treated with the antisecretory histamine H ₂ -receptor antagonist cimetidine 10 mg / kg can be included as positive controls. Statistical evaluation can be performed using the Student's t-test.

  In vitro activity related to relaxation of contracted ileum from isolated guinea pig ileum is measured according to the following method. A fresh isolated section of guinea pig ileum (about 1.5 cm long) is placed in a tissue bath containing Tyrode's physiological salt solution at about 30 ° C. and oxygen: carbon dioxide (95%: 5%) is added. Pass continuously. The tissue is then equilibrated for 60-90 minutes under 4.0 gm tension to obtain a stable baseline. Histamine is then added to the bath in an accumulation manner with concentrations ranging from 1 nM to 10 mM. The maximum tension generated after each addition of histamine is recorded with a Glass Physiograph (Grass Medical Instruments, Quincy, Mass.). The tissue is then washed with several different solutions of tilodo, the basal tension is readjusted to 4.0 gm, and a stable baseline is again obtained. Each tissue is then exposed to one concentration of test compound (1 nM to 10 mM) or vehicle, and after a 30 minute equilibration period, the histamine dose response curve is then repeated. Results from multiple experiments are normalized to the maximum response of the control tissue (0-100%) and graphed as the maximum percent tension versus log histamine concentration in the presence and absence of test compound.

Assay 7
Protective against gastric ulcers Female Sprague-Dawley rats (Charlies River, Wilmington, Mass.) Weighing 70-120 g are not fed food (excluding water). The food is then accessible for 90 minutes. A single dose of test compound is then p. o. Administered (0.01-20 mg / kg at a dose of 1 ml / 100 g) followed by subcutaneous injection of indomethacin (Sigma Chemical Co., St. Louis, MO) (60 mg / kg, 1 ml / 100 g body weight) . Control rats receive a subcutaneous injection of indomethacin as a β-adrenerceptor agonist and administration of vehicle (0.5% methylcellulose in distilled water). The animal is then given continuous access to food, but no water. The animals are then sacrificed by cervical amputation at 6 hours after indomethacin administration. The stomach is then removed and incised along the Great Bay and then lavaged in 0.9% saline. Assess gastric damage by an observer who is unaware of the regimen. A transparent plastic grid divided into 1 mm ² sections is placed over the sinus and the area of microscopic damage is assessed in mm ² as the total area of visible lesions. This number is expressed as a percentage of the total sinus area.

Assay 8
Antidepressant active Male CD1 mice weighing 20-25 g and Sprague-Dawley rats weighing 200-250 g are obtained from Charles River, Wilmington, Mass. A test compound represented by the formula (I) is dissolved in water. These compounds are administered in a volume of 10 ml / kg for mice and in a volume of 2 ml / kg for rats. Control animals receive medium. A positive test result for the following parameters indicates antidepressant activity.

(1) Antagonism of hypothermia induced by reserpine Mice are anesthetized with reserpine (dissolved in 1% citric acid, 2.5 mg / kg, ip). Their rectal temperature is measured after 3.5 hours. The mice are then divided into different groups so that each group has the same mean rectal temperature. After 0.5 hours (ie, 4 hours after reserpine administration) mice are given vehicle or test compound. After 90 minutes, rectal temperature is re-measured (ie, 5 hours 30 minutes after reserpine administration). (The Value of the Reserpine Test in Psychopharmacology, Arzneim,
Forsch., 33 , 1173 (1983)).

(2) Antagonism of abnormal hypothermia induced by apomorphine Mice are placed in their respective cages 0.5 hours later and their rectal temperature is recorded. Animals are allocated and the same mean rectal temperature is obtained for each group. Apomorphine (16 mg / kg sc) is administered 30 minutes after test compound or vehicle administration. Rectal temperature is then remeasured 30 minutes after apomorphine treatment (Puech et al. Antagonism of Hypothermia and Behavioral Response to
Apomorphine; A Simple, Rapid, and Discriminating Test for Screening
Anti-Depressants and Neuroleptics, Psychopharmacology, 75 , 84 (1981)).

(3) Effect on learned helpless behavior ( Giral et al.) Reversal of Helpless Behavior in Rats by Putative 5-HT _1A
Performed as described in Agonist, Biol. Psychiat., 23, 237 (1988). An electric shock is applied to the foot of a male albino spragule-dawley rat placed in a chamber (20 × 10 × 10) with a wall and cover made of Plexiglas (registered trade name). This floor is formed from a stainless steel grid (1.5 cm mesh). A constant current shock is applied to the grid floor as 60 random scrambled and unavoidable shocks (15 seconds duration, 0.8 mA, 60 + 15 seconds each). Control rats are then placed in the same chamber but with no shock. All pre-conditional trials are performed between 9 am and 11 am on the first day. The avoidance training is in an automatic two-way shuttle box (60 x 21 x 30 cm) with a wall made of Plexiglas (registered trade name) and a floor of stainless steel bars present at intervals of 1.0 cm to prevent climbing and escaping. After the unavoidable shock, start at 48 hours (3rd day). Each shuttle box is divided into two equally sized chambers with gates that allow access to adjacent areas through a 7x7 cm spacing. The shuttle box period is 3 consecutive days (3rd, 4th and 5th days). Each animal is placed in this shuttle box, accustomed to the environment over 5 minutes (only at the start of the first), and then 30 trials. The interval between trials is 30 seconds. A light signal used as a conditioned stimulus is provided for the first 3 seconds of each trial. During this “conditioned stimulus only” period, the rat can cross into a separate room in the box through the gate, thereby allowing shock avoidance. If an avoidance response does not occur, there can be a period of conditioned stimulation + foot-shock (0.8 mA). This conditioned stimulus + crossing to another room through the gate during the shock period is referred to as an escape response. The absence of an escape response during a conditioned stimulus + shock period lasting 3 seconds is considered an escape failure.

  Rats (n = 10 / group) are randomly treated according to one of the following methods: a control sample that is not shocked and given medium alone, or an unavoidable shock, depending on the medium or test compound. Laboratory animals treated daily. Animals are treated orally for 5 consecutive days, ie 6 hours after shock pretreatment on day 1 and then twice daily, half the dose in the morning (30 minutes before the shuttle box period) and the dose in the afternoon Half (except day 5) is administered. Statistical analysis is performed using a two-way analysis of deviation values (subject x start) and then based on the mean number of escape failures by Dunnett test.

Assay 9
Bronchial relaxation and seriality mobility
The in vitro activity of compounds of formula (I) for the treatment of airway inflammatory disorders such as asthma and obstructive pulmonary disease can be measured by measuring guinea pig bronchial ring relaxation according to the following method.
Guinea pig bronchial rings were obtained from either sex-tricolored guinea pig (250-350 g) anesthetized with urethane (1.25 g / kg) and supplied with 95% oxygen: 5% carbon dioxide gas. Suspend in (Krebs) solution at 37 ° C. under an initial tension of 2.0 g. After equilibration for about 1 hour, these guinea pig bronchial rings are contracted with acetylcholine (10 ⁻³ M) and relaxed with theophylline (10 ⁻³ M), then they are washed with Krebs solution every 15 minutes. Allow to equilibrate for an additional 60 minutes.

The change in tension is measured isometrically with a strain gauge and an amplifier and shown on the recorder. The composition of the Krebs solution is (mM) and is NaCl 118.0, FCl 5.4, CaCl ₂ 2.5, KHPO ₄ 1.2, MgSO ₄ 1.2, NAHCO ₃ 25.0 and glucose 11.7. .
To test the effect of a test compound on dormant tension, the cumulative concentration is added by adding the test compound (10 ⁻⁹ to 10 ⁻⁵ M) every 10 to 20 minutes until a state of low fluctuation is reached. -Obtain a response curve. The relaxation effect of the test compound is expressed as a percentage of the maximum relaxation induced by theophylline (3 × 10 ⁻³ M).

Assay 10
Prostate disease Male ventral prostate of male Sprague-Dawley rats (300-400 g) anesthetized with diethyl ether are rapidly excised and placed in oxygenated Krebs solution. Remove the attached fat and connective tissue while keeping at room temperature in this buffer. The prostate is then warmed to 37 ° C. and suspended in a 10 ml organ bath containing Krebs solution, then 95% oxygen and 5 Vent a mixture of% carbon dioxide. The composition of the Krebs solution was NaCl 118.4 mM, KCl 4.7 mM, MgSO ₄ 1.2 mM, CaCl ₂ 2.5 mM, dextrose 11.1 mM, NAHCO ₃ 25.0 mM, distilled and dissolved in demineralized water. And KH ₂ PO ₄ 1.2 mM. The tissue is coupled to an isometric force-displacement transducer and isometric contraction is recorded under a 0.5 g load tension. After equilibration for 1-2 hours, the test compound is added. Sub-maximal contraction is first triggered by repeated concentrations of 1 × 10 ⁻⁵ M phenylephedrine until a constant response is obtained. Control and test compound-treatment experiments are performed on different specimens. Determine concentration-response curves for accumulated concentrations of phenylephedrine or acetylcholine (10 ⁻⁹ to 10 ⁻⁴ M). In the case of a test compound, a concentration-response curve for phenylephedrine or acetylcholine is measured in the presence of the compound.

  The in vitro activity of the compounds of formula (I) can also be measured for specific effects in the human prostate as described below.

Prostate tissue samples are obtained from patients with BPH symptoms who have undergone open prostatectomy. The isolated human prostate tissue is cut into 5-8 pieces (each piece: 3 mm wide, 3 mm thick and 15 mm long). These fragments are placed vertically in an organ bath containing 20 ml of Krebs solution having the following composition: (mM): NaCl 112, KCl 5.9, MgCl ₂ 1.2, CaCl ₂ 2, NAHCO ₃ 25, NaHPO ₄ 1.2 and glucose 11.5. The medium is maintained at 37 ° C. and pH 7.4 and equilibrated with a gas mixture consisting of 95% oxygen and 5% carbon dioxide. A resting tension of 0.5 g is applied and the response is then isometrically recorded by a force-displacement transducer. Prior to the start of the experiment, the sample is allowed to equilibrate for 90 minutes.

Concentration-response curves for phenylephedrine or acetylcholine (10 ⁻⁹ to 10 ⁻⁴ M) are determined by adding the test compound directly to the bath medium in an accumulating manner. In the case of a test compound, the prostate fragment is incubated for 30 minutes in the presence of the compound (1 or 10 μM), then phenylephedrine or acetylcholine is added to the medium in an accumulation manner, and a concentration-response curve in the presence of the test compound is obtained. obtain.

Assay 11
Effect on Triglyceride Levels and Abnormal Lipidemia The compound of formula (I) decreases triglyceride and cholesterol levels and increases high density lipoprotein levels. Thus, these compounds can be used in the fight against disease states where such a decrease (and increase) is considered beneficial. That is, the compounds of formula (I) are not only atherosclerotic, such as coronary, cerebrovascular and peripheral arteriosclerosis, cardiovascular diseases and related symptoms, but also hypertriglyceridemia, hypercholesterolemia and It can be used to treat low HDL (high density lipoprotein) level conditions.

  The activity of the compound represented by formula (I) against dyslipidemia can be measured according to the following method. C57BL / 6 Job / ob mice (male, body weight 30-40 g, Jackson Lab, Bar Harbor, ME) housed in an environmentally controlled room at a rate of 5 mice / cage, test compounds (0. 01-20 mg / kg, n = 15 / group) or medium (0.5% weight / volume methylcellulose / distilled water, water or other suitable medium) by oral gavage once or twice daily for 3 weeks, Administer. At the end of the experiment, i.e. 24 hours after the last compound administration, sacrifice is made by decapitation and then blood is collected. Plasma concentrations of free fatty acids and triglycerides are measured using an automated clinical analyzer (Abbott Spectrum® CCx; Abbott Park, IL).

Assay 12
Reduction of body fat The activity of the compound according to the present invention relating to the reduction of body fat can be measured according to the following method. C57BL / 6 Job / ob mice (male, body weight 30-40 g, Jackson Lab, Bar Harbor, ME) are placed in an environmentally controlled room with free access to food (pellet mouse food) and water. House at the rate of 5 mice / 檻. Test compound or vehicle (0.5% weight / volume methylcellulose / distilled water, water or other suitable vehicle) is administered by oral gavage once or twice daily for 3 weeks (0.01-20 mg / kg) N = 15 / group). Each mouse is weighed daily and the food intake per cage is measured by measuring the weight of the amount of food left in the box without the lid. At the end of the experiment, ie 24 hours after the last compound administration, mice are weighed and then sacrificed by cervical amputation. The testicular fat mass is removed from each mouse and weighed.
Using absolute body weight and fat mass weight, the fat to body weight ratio is measured for each mouse.
A reduction in fat mass weight suggests a reduction in total body fat.

Claims (15)

A compound of formula (I), a pharmaceutically acceptable salt thereof, a compound or a prodrug of a salt, or a solvate or hydrate of a compound, salt or prodrug:

[Where:
Ar is fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from phenyl, O, S or N, (C ₃ -C ₈ ) cycloalkyl A benzene ring fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N, or O, S or N Containing 1 to 3 heteroatoms selected from O, S or N fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from An aromatic or non-aromatic 5- or 6-membered heterocyclic ring;
R ¹ and R ² are each independently hydrogen, hydroxy, halogen, cyano, nitro, —NR ^1a R ^2a , —NR ^1a SO ₂ R ^2a , —OR ^1a , —SO ₂ R ^2a , —CF ₃ , (C ₃ -C ₈ ) cycloalkyl, phenyl, —NR ^1a COR ^2a , —COR ^2a , or (C ₁ -C ₆ ) alkyl, wherein the alkyl is selected from the group consisting of one or more hydroxy, nitro, halogen and cyano Wherein R ^1a and R ^2a are each independently hydrogen, (C ₃ -C ₈ ) cycloalkyl, phenyl (this phenyl is 1 to 3 halos, _(C 1 -C ₆₎ alkyl and _(C 1 -C ₆₎ may be substituted by a substituent selected from the group consisting of alkoxy) or _{(C 1} C ₆₎ alkyl (the alkyl is 1 to 3 hydroxy, fluoro, may be substituted by a substituent selected from the group consisting of _-CO 2 H, phenyl and ^-NR 1b ^{R 2b),} wherein R ^1b and R ^2b are each independently hydrogen, amino, amino (C ₁ -C ₆ ) alkyl, aminoaryl, (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C _1- C ₆ ) alkoxy, fluoro, amino, (C ₁ -C ₆ ) optionally substituted by a substituent selected from the group consisting of alkylamino and acyl), (C ₃ -C ₈ ) cycloalkyl (this cyclo Alkyl consists of one or more fluoro, alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl and amide. A 3- to 8-membered aromatic or non-aromatic heterocyclic ring (which is substituted with one or more halogens, (C _1- C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl, and optionally substituted by a substituent selected from the group consisting of amides; or R ^1b and R ^2b may contain from 1 to 2 additional heteroatoms selected from O, S or N together with the nitrogen to which they are attached, 3-8 membered aromatic or non-aromatic Forming a heterocyclic ring of
R ³ and R ⁴ are each independently hydrogen, or a substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl (wherein the alkyl is 1-3 hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Optionally substituted by);
R ⁵ is hydrogen, (C ₁ -C ₆ ) alkyl (this alkyl is optionally substituted by a substituent selected from the group consisting of _{1 to} 3 hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) );
R ⁶ and R ⁷ are each independently a hydrogen, halogen or (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆ ) alkoxy or fluoro substituted) Optionally substituted by a group);
R ⁸ is —CONR ^1b R ^2b , —SOR ^1b , —SO ₂ R ^1b , —SO ₂ NR ^1b R ^2b , —NR ^1b SO ₂ R ^2b, or —CO ₂ R ^1b ;
R ⁹ is selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) alkyl, where the alkyl is one or more fluoro, hydroxy and (C ₁ -C ₆ ) alkoxy. Optionally substituted by a substituent);
X is —O—, —NH—, —NR ^1a —, —CH ₂ —, —CH ₂ CH ₂ — or —CH ₂ O—;
m is 0 or 1; and HET is an aromatic heterocyclic ring selected from the group consisting of imidazole, oxazole, pyrazole and thiazole. ] The compound of claim 1, having the formula (IA), a pharmaceutically acceptable salt thereof, a compound or a prodrug of a salt, or a solvate or hydrate of a compound, a salt or a prodrug:

[Where:
Ar is fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from phenyl, O, S or N, (C ₃ -C ₈ ) cycloalkyl A benzene ring fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N, or O, S or N Containing 1 to 3 heteroatoms selected from O, S or N fused to an aromatic or non-aromatic 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from An aromatic or non-aromatic 5- or 6-membered heterocyclic ring;
R ¹ and R ² are each independently hydrogen, hydroxy, halogen, cyano, nitro, —NR ^1a R ^2a , —NR ^1a SO ₂ R ^2a , —OR ^1a , —SO ₂ R ^2a , —CF ₃ , (C ₃ -C ₈ ) cycloalkyl, phenyl, —NR ^1a COR ^2a , —COR ^2a , or (C ₁ -C ₆ ) alkyl, wherein the alkyl is selected from the group consisting of one or more hydroxy, nitro, halogen and cyano Wherein R ^1a and R ^2a are each independently hydrogen, (C ₃ -C ₈ ) cycloalkyl, phenyl (this phenyl is 1 to 3 halos, (Optionally substituted with a substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy), or (C ₁ -C ₆₎ alkyl (the alkyl is 1 to 3 hydroxy, fluoro, it may be substituted by a substituent selected from the group consisting of _-CO 2 H, phenyl and ^-NR 1b ^{R 2b),} Wherein R ^1b and R ^2b are each independently hydrogen, amino, amino (C ₁ -C ₆ ) alkyl, aminoaryl, (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆₎ alkoxy, fluoro, _{amino, (C} 1 -C ₆₎ may be substituted by a substituent selected from the group consisting of alkylamino and _{acyl), (C} 3 -C ₈₎ cycloalkyl (this Cycloalkyl is from one or more of fluoro, alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl and amide. Optionally substituted with a substituent selected from the group consisting of 3 to 8 membered aromatic or non-aromatic heterocyclic ring, wherein the heterocyclic ring is one or more halogens, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) optionally substituted by a substituent selected from the group consisting of alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide); or R ^1b and R ^2b , together with the nitrogen to which they are attached, may contain 1 to 2 additional heteroatoms selected from O, S or N, 3-8 membered aromatic or non-aromatic Forming a heterocyclic ring;
R ³ and R ⁴ are each independently hydrogen, or a substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl (wherein the alkyl is 1-3 hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Optionally substituted by);
R ⁵ is hydrogen, (C ₁ -C ₆ ) alkyl (this alkyl is optionally substituted by a substituent selected from the group consisting of _{1 to} 3 hydroxy, C ₁ -C ₆ ) alkoxy and fluoro) Is;
R ⁶ and R ⁷ are each independently a hydrogen, halogen or (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆ ) alkoxy or fluoro substituted) Optionally substituted by a group);
R ⁸ is —CONR ^1b R ^2b , —SOR ^1b , —SO ₂ R ^1b , —SO ₂ NR ^1b R ^2b , —NR ^1b SO ₂ R ^2b, or —CO ₂ R ^1b ;
R ⁹ is selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) alkyl, where the alkyl is one or more fluoro, hydroxy and (C ₁ -C ₆ ) alkoxy. Optionally substituted by a substituent);
X is —O—, —NH—, —NR ^1a —, —CH ₂ —, —CH ₂ CH ₂ — or —CH ₂ O—; and m is 0 or 1. ] The compound according to claim 2, having the formula (IA-1), a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug:

[Where:
R ¹ is hydrogen, hydroxy, halogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy;
R ³ and R ⁴ are hydrogen;
R ⁵ , R ⁶ , R ⁷ and R ⁹ are each independently hydrogen or (C ₁ -C ₆ ) alkyl, where the alkyl may be substituted with one or more fluoro substituents;
R ⁸ is —CONR ^1b R ^2b , where R ^1b and R ^2b are each independently hydrogen, (C ₃ -C ₆ ) cycloalkyl, or (C ₁ -C ₆ ) alkyl (one alkyl R ^1b and R ^2b may contain an additional heteroatom selected from O or N together with the nitrogen to which they are attached. Forming a 4-6 membered non-aromatic heterocyclic ring which may be
X is —O—; and m is 1. ] The compound of claim 1, having the formula (IB), a pharmaceutically acceptable salt thereof, a prodrug of this compound or salt, or a solvate or hydrate of this compound, salt or prodrug:

[Where:
Ar is condensed phenyl, O, aromatic or non-aromatic heterocyclic ring of 5 or 6 membered containing 1 to 4 heteroatoms selected from S or N, the (C 3 _{-C 8)} cycloalkyl Benzene ring fused to a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N, or O, S or N Contains 1 to 3 heteroatoms selected from O, S or N fused to a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from A 5- or 6-membered aromatic or non-aromatic heterocyclic ring;
R ¹ and R ² are each independently hydrogen, hydroxy, halogen, cyano, nitro, —NR ^1a R ^2a , —NR ^1a SO ₂ R ^2a , —OR ^1a , —SO ₂ R ^2a , —CF ₃ , (C ₃ -C ₈ ) cycloalkyl, phenyl, —NR ^1a COR ^2a , —COR ^2a , or (C ₁ -C ₆ ) alkyl, wherein the alkyl is selected from the group consisting of one or more hydroxy, nitro, halogen and cyano Wherein R ^1a and R ^2a are each independently hydrogen, (C ₃ -C ₈ ) cycloalkyl, phenyl (this phenyl is 1 to 3 halos, (Optionally substituted with a substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy), or (C ₁ -C ₆₎ alkyl (the alkyl is 1 to 3 hydroxy, fluoro, it may be substituted by a substituent selected from the group consisting of _-CO 2 H, phenyl and ^-NR 1b ^{R 2b),} Wherein R ^1b and R ^2b are each independently hydrogen, amino, amino (C ₁ -C ₆ ) alkyl, aminoaryl, (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆₎ alkoxy, fluoro, _{amino, (C} 1 -C ₆₎ alkylamino, and may be substituted by a substituent selected from the group consisting of _{acyl), (C} 3 -C ₈₎ cycloalkyl ( The cycloalkyl is one or more of fluoro, alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide Optionally substituted with a substituent selected from the group consisting of: 3 to 8 membered aromatic or non-aromatic heterocyclic ring, wherein the heterocyclic ring is one or more halogens, (C _1- C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl, and optionally substituted by a substituent selected from the group consisting of amides; or R ^1b and R ^2b together with the nitrogen to which they are attached may contain 1 to 2 additional heteroatoms selected from O, S or N 3-8 membered aromatic or non-aromatic Forming a heterocyclic ring;
R ³ and R ⁴ are each independently hydrogen, or a substituent selected from the group consisting of (C ₁ -C ₆ ) alkyl (wherein the alkyl is 1-3 hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Optionally substituted by);
R ⁵ is hydrogen or (C ₁ -C ₆ ) alkyl (wherein this alkyl is substituted by a substituent selected from the group consisting of _{1 to} 3 hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Good);
R ⁶ and R ⁷ are each independently a substituent selected from the group consisting of hydrogen, halogen or (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆ ) alkoxy and fluoro) Optionally substituted by a group);
R ⁸ is —CONR ^1b R ^2b , —SOR ^1b , —SO ₂ R ^1b , —SO ₂ NR ^1b R ^2b , —NR ^1b SO ₂ R ^2b , or —CO ₂ R ^1b ;
R ⁹ is selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) alkyl, where the alkyl is one or more fluoro, hydroxy and (C ₁ -C ₆ ) alkoxy. Optionally substituted by a substituent);
X is —O—, —NH—, —NR ^1a —, —CH ₂ —, —CH ₂ CH ₂ — or —CH ₂ O—; and m is 0 or 1. ] R ¹ is hydrogen, halogen or (C ₁ -C ₆ ) alkyl;
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁹ are hydrogen;
R ⁸ is —CONR ^1b R ^2b , wherein R ^1b and R ^2b are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
X is —O—; and m is 1. The compound according to claim 1, 2, 3 or 4, a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or the compound, salt Or a solvate or hydrate of a prodrug. 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- N, N-dimethyl-acetamide;
2- (4- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N-dimethyl- Acetamide;
N, N-diethyl-2- (4- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl)- Acetamide;
2- [4- (4- {2- [2- (6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- N-ethyl-N- (2,2,2-trifluoro-ethyl) -acetamide;
2- [4- (4- {2- [2- (6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- N, N-diisopropyl-acetamide;
2- [4- (4- {2- [2- (6-Chloro-pyridin-3-yl) -2 (R) -hydroxy-ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- N, N-dimethyl-isobutyramide;
2- (4- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N-dimethyl- Isobutyramide;
2- (4- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -oxazol-2-yl) -N, N-dimethyl- Butyramide;
2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- N, N-dimethyl-propionamide;
2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- N, N-dimethyl-butyramide; and 2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl; ) -Oxazol-2-yl] -N, N-dimethyl-isobutyramide;
2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -N, N-dimethyl- Acetamide;
N-ethyl-2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -N- Methyl-acetamide;
2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -1-morpholine-4- Il-ethanone;
2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -pyrazol-1-yl) -1-pyrrolidine-1- Yl-ethanone; and N-cyclopentyl-2- (3- {4- [2- (2 (R) -hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy] -phenyl} -pyrazole-1- Yl) -acetamide;
The compound of claim 1, selected from the group consisting of: a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, and a solvate or water of the compound, the salt or the prodrug Japanese products.   2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- The compound according to claim 1, which is N, N-dimethyl-acetamide; or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or salt.   2- [4- (4- {2- [2 (R) -hydroxy-2- (6-methyl-pyridin-3-yl) -ethylamino] -ethoxy} -phenyl) -oxazol-2-yl]- The compound according to claim 1, which is N-methyl-acetamide, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or salt.   A pharmaceutical composition comprising (1) a compound according to any one of the preceding claims; and (2) a pharmaceutically acceptable excipient, diluent or carrier.   The pharmaceutical composition according to claim 9, further comprising an additional agent.   The additional agent is apolipoprotein-B secretion / microsomal triglyceride transfer protein inhibitor, MCR-4 agonist, cholecystokinin-A agonist, monoamine reabsorption inhibitor, sympathomimetic agent, cannabinoid receptor antagonist, dopamine agonist, melanin Cell-stimulating hormone receptor analog, 5HT2c agonist, melanin-concentrating hormone antagonist, leptin, leptin analog, leptin receptor agonist, galanin antagonist, lipase inhibitor, appetite suppressant, neuropeptide-Y antagonist, thyroid-like drug, dehydroepi Androsterone or related compounds, glucocorticoid receptor agonist or antagonist, orexin receptor antagonist, glucago 6. A peptide-like 1 receptor agonist, a serial neurotrophic factor, a human agouti-related protein, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist. The pharmaceutical composition according to 10. A method of treating a disease, symptom or disorder mediated by a β ₃ -adrenergic receptor agonist in an animal, comprising a therapeutically effective amount of the compound of claim 1, 2, 3, 4, 5, 6, 7 or 8. Administering a pharmaceutically acceptable salt, compound or prodrug of the salt, or a solvate or hydrate of the compound, salt or prodrug to an animal in need of such treatment. The said treatment method. Diseases, symptoms or disorders mediated by β ₃ -adrenergic agonists in animals are weight loss, obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenal inflammation, Crohn's disease, proctitis, asthma, Claims selected from the group consisting of intestinal locomotor dysfunction, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, fatty liver, and airway inflammatory disorders 12. The method according to 12. Beta ₃ in animals - adrenergic disease receptor antagonist mediated, in the manufacture of a medicament for treating a condition or disorder, the compounds according to claim 7 or 8, the Use of a pharmaceutically acceptable salt, compound or prodrug of a salt, or a solvate or hydrate of a compound, salt or prodrug. Intermediate compounds having formula (Ia):

[Where:
R ¹ is hydrogen or an amino protecting group;
R ⁵ may be substituted with a substituent selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl (wherein this alkyl is 1-3 hydroxy, (C ₁ -C ₆ ) alkoxy, and fluoro) And R ⁸ is —CONR ^1b R ^2b , —SOR ^1b , —SO ₂ R ^1b , —SO ₂ NR ^1b R ^2b , —NR ^1b SO ₂ R ^2b , or —CO ₂ R ^1b ; Wherein R ^1b and R ^2b are each independently hydrogen, amino, amino (C ₁ -C ₆ ) alkyl, aminoaryl, (C ₁ -C ₆ ) alkyl (wherein the alkyl is one or more hydroxy, (C ₁ -C ₆₎ alkoxy, fluoro, _amino, optionally substituted with substituents selected from the group consisting of _(C 1 -C ₆₎ alkylamino, and acyl), (C ₃ -C ₈ ) cycloalkyl (wherein the cycloalkyl is one or more fluoro, alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide substituents selected from the group consisting of 3-8 membered aromatic or non-aromatic heterocyclic ring, which is optionally substituted by one or more halogens, (C ₁ -C ₆ ) alkyl, (C _1- C ₆ ) optionally substituted by a substituent selected from the group consisting of alkoxy, hydroxy, amino, aminoalkyl-, acyl, and amide; or R ^1b and R ^2b are the nitrogen to which they are attached. Together with a 3-8 membered aromatic or non-aromatic heterocyclic ring optionally containing 1-2 additional heteroatoms selected from O, S or N Forms. ]