TW200305414A - β 3 -Adrenergic receptor agonist salt, formulations, and uses thereof - Google Patents

Abstract

The present invention provides the tosylate salt of (R)-2-(2-(4-oxazol-4-yl-phenoxy)-ethylamino)-1-pyridin-3-yl-ethanol, the monohydrate of such salt, processes useful in the preparation of such salt and such monohydrate, pharmaceutical compositions comprising such salt, or such monohydrate, methods of treating β 3 -adrenergic receptor-mediated diseases, conditions, and disorders in a mammal using such salt, such monohydrate, or such pharmaceutical compositions; and methods of increasing the content of lean meat in edible animals using such salt, such monohydrate, or such pharmaceutical compositions.

Description

200305414 ⑴ 玖, loud description (the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiment and the simple description of the drawings) TECHNICAL FIELD The present invention provides a stone 3_adrenergic receptor agonist (R ) -2- (2- (4-g fluoren-4-yl-phenoxy) -ethylamino) -1-pyridin-3-ylethanol methanemate salt 'the monohydrate of the salt, A pharmaceutical composition comprising the salt or the monohydrate, its agonist is particularly useful for treating hypoglycemia and obesity, and increasing the meat content of food animals. Prior art Diabetes is characterized by metabolic defects in the manufacture and utilization of carbohydrates, making it impossible to maintain a proper amount of blood glucose. The consequences of these defects include, in particular, hyperglycemia or hypoglycemia. Research in the treatment of diabetes has focused on normalizing blood sugar levels quickly and after meals. Current treatments include exogenous Tengdaosu, oral medication and diet therapy. The main form of diabetes is known, and Type 1 diabetes or blood glucose-related diabetes (IDDM) is the result of an absolute lack of insulin (the hormone that regulates carbohydrate use). Type 2 diabetes or non-insulin-associated diabetic disease (NIDDM) is often caused by normal or even high levels of insulin, and the obvious consequence is that the tissue fails to respond properly to insulin. Most patients with type 2 diabetes also become overweight. The tosylate salt of the present invention, the monohydrate of the salt, and the pharmaceutical composition comprising the salt or the monohydrate can effectively reduce the glucose content in blood when orally administered to mammals with hypoglycemia or diabetes. . Obesity constitutes a major health risk, leading to death and accidents in type 2 diabetes, hypertension, and fat metabolism disorders. Adults Exceeding Views in the United States 200305414

(2) The ethnic group is overweight, and almost 25% of the ethnic group is considered overweight. The effect of obesity is to increase the cumulative age growth rate in the United States by three percentage points. Although the overweight is the most common in the United States and Europe, the prevalence of overweight has also increased in Japan. In addition, obesity is a very destructive disease, which will also cause great harm to personal mental health and self-esteem. Unfortunately, the causes of diabetes are complex and poorly understood, and the social stereotypes and self-righteous perceptions of diabetes exacerbate the psychological impact of diabetes. Due to the impact of obesity on the general society, great efforts have been made to treat diabetes. However, long-term treatment and / or prevention is still needed. When the tosylate salt of the present invention, the monohydrate of the salt, and the pharmaceutical composition including the salt or the monohydrate is administered to a mammal, it can also reduce body weight or increase body weight. The ability of the salt, or the monohydrate, or the composition to affect weight gain is due to activation of the yS3 -adrenergic receptor, which stimulates the metabolism of animal fat tissues. / 3-Adrenaline is generally divided into cold! , / 3 2 and / 5 3 receptor specific subtypes. / 5-Receptor agonist promotes the activation of nephrophylline,-Receptor activation includes increasing heart rate, but / 32-receptor activation relaxes smooth muscle tissue, lowers blood pressure, and causes skeletal muscles to begin to tremble . -Receptor activation is known to stimulate lipolysis (such as triglycerides of adipose tissue into glycerol and fatty acids) and metabolism rate (energy consumption), thus promoting fat mass loss. Accordingly, the stimulating / 33-receptor compound can therefore be used as an anti-obesity agent, and can further be used to increase the meat content of practical animals. In addition, compounds that are / 33-receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is currently unknown. 200305414

(3) To date, the stone 3-adrenoceptor is believed to be mainly located in adipose tissue, however, the cold 3-adrenoceptor is currently known to exist in the intestine (J. Clin · Invest ·, 91,344 (1993)) and Nao Shao (Eur · J. Pharm ·, 219, 193 (1992)). Stone 3-receptor stimulation has also been shown to relax smooth muscles in the colon, trachea, and bronchi. See, for example, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994), & Br. J. Pharmacol., 110, 1311 (1993), and Stimulation has also been found to relax ileum in guinea pigs that contract histamine. See, for example, J. Pharm. Exp. Ther ·, 260, 1,192 (1992) 0 / 53-receptors are also expressed in the human prostate (J · Clin · Invest ·, 91,344 (1993). Because of cold 3- Receptor stimulation results in smooth muscle that has been shown to exhibit cold 3-receptors, that is, smooth muscle in the intestine, so those skilled in the art can also expect to relax the smooth muscle of the prostate. Therefore, 'stone 3 β agonists can be used for treatment Or prevent prostate diseases. Co-assigned U.S. Patent No. 5,977,124 discloses specific / 5 3 -adrenergic receptor agonists particularly useful for treating hypoglycemia and obesity. U.S. Patent No. 5,776,983 discloses specific catechins Panamine acts as a stimulant. U.S. Patent No. 5,030,640 discloses specific U-heterocyclic ethanolamino alkyl oxindoles that can be used as growth promoters, bronchodilators, anti-sedatives, and anti-obesity agents. US Patent No. 5,019,578 discloses specific α-heterocyclic ethanolamines which can be used as growth promoters. US Patent No. 4,478,849 discloses 200305414 including specific ethanolamine derivatives.

(4) a pharmaceutical composition, and a method for using the composition to treat obesity and hypoglycemia. U.S. Patent No. 4,358,455 discloses a specific heterocyclic compound having the structural formula Het-CHOH-CH2-NH-aralkyl, which is useful for treating glaucoma and cardiovascular diseases. European Patent Application Publication No. 0 516 349 (published on November 2, 1992) discloses a specific 2-merylphenethylamine with anti-obesity, hypoglycemia, and related uses. U.S. Patent No. 5,153,210 discloses a specific heterocyclic compound of the formula RO-X-CHCOH ^ CI ^ NiR1) -C (R) (R)-(CH2) nYA-R4-R5, which can be used as an anti-obesity agent and Antihyperglycemic agent. PCT International Patent Application Publication No. WO 99/65877 (published on November 23, 1999) discloses heterocyclic compounds having the following structural formula

Kidney compounds are used to treat a disease that can be easily improved by administering an atypical adrenaline receptor agonist. The same and strong US Provisional Application No. 60 / 242,274 (applied on October 20, 2000 and is hereby incorporated by reference) discloses the adrenergic receptor agonist of structural formula, 200305414 (5 )

R

OH

(I) its stereoisomers and prodrugs, and compounds, stereoisomers and prodrugs

A pharmaceutical composition comprising the aforementioned (R) -2- (2- (4-_oxazol-4-yl-phenoxy) -ethylamino) -1-eodo-3-yl-ethanol. The present invention provides a (R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1-exo-1: Yodo-3-yl · ethanol Acid salt, the monohydrate of the salt; method for preparing the salt and the monohydrate; a pharmaceutical composition including the salt or the monohydrate; using the salt, or the monohydrate, or the pharmaceutical composition A method of treating mammalian 3-adrenergic receptor-regulated diseases, symptoms and disorders; and a method of using the salt, the monohydrate or the pharmaceutical composition to increase the meat content of food animals.

SUMMARY OF THE INVENTION The present invention provides a mesylate salt of (R) -2- (2- (4- · pyrazol-4 · yl · phenoxy) -ethylamino) -1 -pyridine-3 -yl-ethanol The monohydrate of the salt; a method for preparing the salt and the monohydrate; a pharmaceutical composition including the salt or the monohydrate; using the salt, or the monohydrate, or the pharmaceutical composition to treat breastfeeding Animal / 3 3-Adrenergic receptor-modulated diseases, symptoms and disorders; and methods of using the salt, the monohydrate or the pharmaceutical composition to increase the meat content of food animals. Embodiment -10- 200305414

⑹

The present invention provides (R) -2- (2- (4-humazol-4-yl-phenoxy) -ethylamino) _ 1 -pyridine-3-yl · ethanol mesylate; the A salt monohydrate; a method for preparing the salt and the monohydrate; a pharmaceutical composition comprising the salt or the monohydrate; using the salt, or the monohydrate, or the pharmaceutical composition to treat mammalian cold 3-Adrenergic receptor-regulated methods, diseases, symptoms and disorders. The mesylate, the monohydrate, and the pharmaceutical composition are still useful for increasing the meat content of food animals, that is, ungulates, such as cattle, pigs, and poultry. As for the "therapeutically effective amount" used in this description and the scope of the attached patent application, it means (R) -2- (2-) that can alleviate, ameliorate, or avoid or delay the onset of one or more symptoms of a particular disease, symptom, or disorder. (4-Pyrazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol mesylate, or a monohydrate of the salt, or including the salt or the Monohydrate pharmaceutical composition. The term π mammal 'is intended to include animals such as dogs, cats, cows, sheep, horses, and humans. Preferred mammals include humans and include males and females

Sexual ethnic group. The term "pharmaceutically acceptable" means that the substance or composition is compatible with the other ingredients included in the pharmaceutical formulation and / or the chemical and / or toxicity of the mammal being treated. The term 'treatment' includes prevention, that is, prevention and remission treatment. Compound (R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1 · pyridin-3-yl-ethanol may be as described in the aforementioned U.S. Provisional Application No. 60 / Preparations are disclosed in 242,274. In addition, (R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1 -pyridine-3-yl-ethanol can also be prepared as listed below. Chemical-11-200305414 hafnium compound, a pharmaceutically acceptable salt thereof, or a hydrated salt of a pharmaceutically acceptable salt, the method comprises the steps of:

(a) Reduction of an α-bromoketone derivative of the following structural formula or an acid addition salt thereof.

(R) -bromoalcohol derivatives of the following structural formula ΟΗ

Β "(b) Protect the (R) -bromoalcohol derivative of step (a) to form a 0-protected derivative of the following structural formula

(c) The __protected derivative of step (b) is aminated with the following structural formula: • 12- 200305414 ⑻

HET

O-Protected Derivatives

N; and (d) deprotect the O-protected derivative of step (c) to form a compound of the following structure

Where: ΕΕ is selected from heterocyclic groups containing pyrazolyl, pyrazolyl, and thiazolyl; and P is selected from -SiR ^ W, -CH2Ph, -CH2 (p-CH3OPh), -CH (OCH2CH3) CH3 And O-protecting group of the group consisting of [j]: wherein R1, R2, and R3 are each independently a (Cm) alkyl group or a phenyl group. Preferably, P is -SiR ^ F ^ R3, and HET is selected from the group consisting of 2-pyrazolyl and 4-azolazole -13-200305414

Heterocyclic groups of the group consisting of sulfonyl, 3-p-pyridyl, 4-p-pyridyl, 2-p-sedyl and 4-p-sedyl. The best method is that P represents -SiRiR ^ R3, where R1 and R2 are both CH3, and R3 is -C (CH3) 3. The stereospecific reduction step (indicated by step (a) above) is preferably a fungus reducing agent. In general, fungal and / or microliter reducing agents used in stereospecific biological transfer of medical and pharmaceutical intermediates are known. See, for example, R.N. Patel, Advanced Applications in Biology, 43, 91-140 (1997). In particular, stereospecific reductions of α-haloketones having various microliters are generally known. See, for example, RN Patel et al., JAOCS, 75 (11), 1473-1482 (1998), which discloses Agrobacterium tumefaciens ATCC 15955, Alcaligenes eutrophus ATCC 17697, and Arthrobacter ( Arthrobacter petroleophagus) ATCC 21494, Debaryomyces hansenii ATCC 66354, Mycobacterium sp. ATCC 29676, Rhodococcus rhodochorous ATCC 14347, Hansenula anomala SC 13833, abnormal Hanson Use of yeast (H. anomala) ATCC 16142, H. saturnus SC 13829, and Spingomonas paucimobilis SC 16113 in the stereoreduction of α-bromoketone. The fungal reducing agent used in the reducing step (a) of the present invention preferably includes Absidia cylindrospora ATCC 22751 (American Type Culture Collection, Rockville, MD). The aforementioned reduction step provides the corresponding (R) -bromoalcohol in a high corresponding selectivity yield (i.e.,> 90% enantiomeric excess). Preferably, the (R) -bromoalcohol formed in the stereospecific reduction step (a) is then isolated to become a free test or an acid addition salt thereof. Stereospecific reduction of the (R) -bromoalcohol product formed in step (a) followed by 0--14-200305414

(ίο) Protection. Synthetic methods for protecting alcohol functional groups are well known to those skilled in the art, and may include, for example, the functionalization of an alcohol functional group into its dream group, ether or vinegar derivative. Although the conventional 0-protecting group compatible with the reaction conditions used in the subsequent synthetic steps can be used in the method of the present invention, the (R) -bromohydrin product of step (a) is

Well protected to 0-silyl ether derivatives. The preferred 0-silanization step (indicated by step (b) above) can be performed according to standard methods known to those skilled in the art. The preferred O-silanization is generally carried out by treating (R) -bromoalcohol with a suitable substituted silicon sintering agent. The crushing agent may include, for example, a silyl derivative of R ^ I ^ RSSi-X, where X includes a suitable leaving group. Preferably, the silylating agent includes a reaction agent of azole RiR2R3Si-X, wherein X is a leaving group selected from the group consisting of autogen (such as chlorine or bromine), cyano, imidazolyl, trifluoromethanesulfonate and the like . However, other silylating agents that can be used in the method of the present invention are also known to those skilled in the art. Preferred R1, R2 and R3 in the definition of the protected alcohol group -OSiR ^ R2! ^ Are independently (Cn) alkyl or phenyl. The most preferred is a 0-silyl ether derivative, in which both R1 and R2 are -CH3, and R3 is -C (CH3) 3. In general, the 0-silylation is achieved by bringing the alcohol to be protected and the silylating agent in a suitable organic base (eg Or a heterocyclic amine such as imidazole or azidobicyclo [5.4.0] undec-7-ene (DBU)) is condensed in a halogenated hydrocarbon solvent (such as dichloromethane). Alternatively, polar, aprotic solvents such as dimethylformamide or dimethylsulfoxide can be used. For the 0-silanization reaction of the present invention, dimethylformamide is preferred. Generally, the silylation is carried out by stirring the reactants for a long time (iso and overnight) at or near room temperature. However, the silanization is also -15- 200305414

It can be performed at an appropriate higher or lower ambient temperature. For a detailed discussion of the preferred method of protecting alcohol groups, including the use of a second calcining agent, see, for example, TW Greene et al., Protective Groups for Organic Synthesis, John Wiley & Sons, New York, NY (1991) This reference is hereby incorporated by reference. The 0-protected derivative formed in step (b) is then condensed with an amine of the following structural formula in step (c)

Get the product of the following structural formula

The above-mentioned condensation step (c) can be carried out under standard reaction conditions known to those skilled in the art. Preferably, the protected (R) -bromoalcohols and amines are in a suitable organic base (for example, alkylamines such as triethylamine, N, N-diisopropylethylamine (Hunig, s.)). Condensation in a polar aprotic solvent such as dimethyl acer. The condensation is carried out under Awen, preferably in the general range of about 40 ° C to about 120 ° C. The better groups-SiR1, R2R, and the better r1, R2, and R are independent. (Cl.6) alkyl or phenyl. The best method is a method in which R1 and R2 are both -CH3 'and R3 is -c (ch3) 3. -16- 200305414

(12) The amine compound used in the above step (c) can be prepared according to the method listed in the compound of the following structural formula or its acid addition salt.

HET The method includes the steps of: (a ') functionalizing a compound of the following structural formula

HO

HET to obtain compounds of the following structural formula

Ph

HET

; And (bf) defunctionalizing the compound formed in step (a ') to obtain a compound of the following structural formula

H2N

HE Ding -17- (13) 200305414

Among them: the hetero group of 4-oxazolyl and the 3_ group of hetero are such that the following structure HET is selected from the group consisting of oxazolyl, pyrazolyl, and oxazolyl. Preferably, HET represents a cyclic group selected from the group consisting of 2-airolyl, pyrazolyl, 4-pyrazolyl, 2-pyrazolyl and 'oxazolyl. 、,, ′ Ear energy-based step (as shown in the above step (a,)) in the formula I age-based compounds functionalized

HO

HET

Ester

PhN vr 〇. Lamp het phenol compound (can be prepared according to the method in the literature, soil% or can be prepared according to the synthetic procedures disclosed below) is most convenient.

PhCH2OCONHCH2CH2-Y (where γ includes the slave w < leaving group) is converted to T-energy. Groups and groups consisting of leaving bases (p-toluene transverse acid salts), formic acid salts (... two by toluate, chlorine, or moth), and the like are listed. Generally speaking ::: A, such as, Kuang Youwei formate, so the salt is leaving group. The generalization of the general formula PhCH2〇CONHCH2CH2-Y (where γ is methanesulfonic acid dish) can be as C.A. Townsend et al., Tetrahedron, 47, 2591 -18- 200305414

(14) (1991) < The functionalization of a phenolic compound is preferably in a polar, aprotic solvent such as dimethylsulfene, in the presence of an inorganic base such as potassium carbonate. Next. The functionalization is generally performed at a high temperature (usually at about 4 (rc to about 120 C). The urethane derivative formed in the above functionalization step (.0) is then defunctionalized in step 00. To obtain compounds of the following structural formula

het: the urethane product formed in step U,) knows that the defunctionalization can be performed according to the φ: method. For example, the urethane can be used with a suitable metal, vehicle (such as nickel salt or its complex) Palladium salts or their complexes or platinum or their complexes) are defunctionalized by catalytic hydrogenation. Age cups + and ^ are good. Depolarization is performed in polar, protic solvents (such as methanol), using formic acid and formic acid, and left + catalyst (preferably palladium / activated carbon) in the presence of ". 仃The defunctionalization is carried out at a temperature of 1 ° C (preferably the reflux temperature of the solvent used). The amine product thus formed in step (b) is better than the basic formula 1 π i and then leaves early, forming a free radical. _ Or in the form of addition salt. So that the traditional technique for early separation of Taigu mushrooms is freely used by those who know this technique. Similarly, the acidity of amine products; A total of organic acids (such as butane-, inspection # ,, tartaric acid, acetic acid, bismuth, maleic acid, methanesulfonic acid, or p-toluenesulfonic acid conjugated inorganic acids (such as hydrochloric acid, hydrogen acid, sulfuric acid Or: r Free base preparation. As previously disclosed above, the content of "U" is as early as 4 and its purity can be inert inert solvents (such as lack of separation of materials and pressure) (such as the salt will make it inactive. 200305414 (15) in a non-solvent, or a solvent that forms a salt precipitate upon subsequent addition of a non-solvent) Satisfactory achievement. The deprotection step (referred to as step (d) above) can be performed by standard methods known to those skilled in the art. The better -O-SiWf ^ R3 derivative formed in step (c) is preferred by using It is deprotected by reaction with a suitable alkylammonium fluoride (such as tetrabutylammonium fluoride). The deprotection can be carried out in an aprotic solvent (such as tetrahydrofluoran) at ambient temperature. A detailed discussion of ether deprotection methods can be found in, for example, TW Greene, et al., Supra, and is hereby incorporated by reference. The deprotected product of step (d) is preferably isolated and converted to the free base form or if required It can become a form of pharmaceutical acceptable salt or the form of the pharmaceutical acceptable salt. Isolation can be performed according to established methods. Similarly, the pharmaceutical acceptable salt can also be performed according to known methods, such as co-treatment with organic acids Free bases, such as succinic acid, tartaric acid, acetic acid, citric acid, maleic acid, methanesulfonic acid, or p-toluenesulfonic acid, etc. In addition, common inorganic acids such as hydrochloric acid, hydrobromic acid, Sulfuric acid or nitric acid, etc. Best The toluene sulfonate (ie, p-toluene sulfonate, which is abbreviated as TsOH in the scope of this description and the appended patents) of the deprotected product formed in step (d). To assist product isolation and improve purity The salt is formed in a solvent that is better re-reactive inert (such as a non-solvent that causes the salt to precipitate when the salt is formed) or better in a solvent that will precipitate the formed salt when the non-solvent is subsequently added. It should be further understood that the pharmaceutically acceptable salt can be formed into its hydrate form, and the hydrate form is included in the scope of the present invention. The hydrate of the pharmaceutically acceptable salt can be prepared by conventional techniques, for example, from a single solution-20-200305414 ( 16) Agents sublimate and crystallize hydrates, form hydrates by evaporation from a two-phase mixture, vapor diffusion, heat treatment, etc. A detailed discussion of the preparation of pharmaceutically acceptable salt hydrates is found, for example, in J. Keith Guillory, Polymorphism in Pharmaceutical Solids, Chapter 5, "Polymorphism, Hydrate, Solvate, and Amorphous Solid Formation ”, Pp. 183-219, Marcel Dekkei *, Inc. (1999). According to the practice of the present invention, the preferred one is (R) -2- (2- (4--pyrazol-4-yl-benzene-benzene). Oxy) -ethylamino) -1-pyridin-3-yl-ethanol toluate monohydrate. One object of the present invention is to provide (R) -2- (2- (4-oxazole) 4-yl-phenoxy) · ethylamino) -1 -pyridin-3-yl-ethanol tosylate, the salt is represented by the following structural formula

Another object of the present invention is to provide (R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol toluenesulfonic acid The monohydrate of the salt is represented by the following structural formula

-21-200305414

(17) Yet another object of the present invention is to provide (R) -2- (2- (4-humazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl- Tosylate of ethanol or a monohydrate of the salt, and a pharmaceutical composition of a pharmaceutically acceptable carrier or diluent. Yet another object of the present invention is to provide a method for treating mammalian / 53-adrenoceptor-regulated diseases, symptoms or disorders, comprising administering a therapeutically effective amount of (R) -2- (2) to a mammal in need of such treatment. -(4-oxazol-4-yl-phenoxy) · ethylamino) -1-pyridin-3-yl-ethanol tosylate or a monohydrate of the salt; or include the salt or the Monohydrate pharmaceutical composition. Better, / 5 3-Adrenergic receptor-regulated diseases, symptoms or disorders are selected from the group consisting of obesity, diabetes, allergic bowel complications, enteritis, esophagitis, duodenitis, Crohn's disease, proctitis, asthma, end-movement Disorders, ulcers, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, metabolic disorders, and airway inflammation. The best is a method for treating a disease, symptom, or disorder in which the cold 3-adrenergic receptor modulates is selected from the group consisting of obesity, diabetes, urinary incontinence, and polar bowel complications. (R) -2- (2- (4-Pyrazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol, benzenebenzenesulfonate or a salt of the salt Hydrates, and pharmaceutical compositions including the salts or the monohydrates can also be used to increase the meat content of food animals (ie, ungulates such as cattle, pigs, etc., and poultry). Therefore, the present invention also provides a method for increasing the refined meat content of food animals, which comprises administering an increased amount of (R) -2- (2- (4-oxazol-4-yl-phenoxy) · ethyl to food animals. Methylamino) -1 -pyridin-3-yl-ethanol tosylate, or a monohydrate of the salt, and a pharmaceutical composition including the salt or the monohydrate. -22- 200305414

(18) Toluenesulfonic acid salt of (R) -2- (2- (4-pyrazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol or the salt The monohydrate, and the pharmaceutical composition including the salt or the monohydrate may be administered to a patient at a dose of about 0.01 to about 1,000 mg per day. For an average adult weighing about 70 kg, a dosage range of about 0.01 mg to about 300 mg per day is generally sufficient. However, depending on the age and weight of the subject to be treated, the route of administration, etc., the general dosage range will need to be changed. The determination of the dosage range and optimal dosage for special patients is well known to those skilled in the art and is beneficial to this disclosure. According to the method of the present invention, (R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol tosylate Or a monohydrate of the salt, and a pharmaceutical composition comprising the salt or the monohydrate is administered to a mammal in need of the treatment, and is preferably a pharmaceutical composition including a pharmaceutically acceptable carrier or diluent form. Accordingly, the tosylate or the monohydrate may be used orally, rectally, transdermally, parenterally (eg, intravenously, arterially or subcutaneously), intracerebrally, intravaginally, intraperitoneally, bladder Intra-, topical (eg powder, ointment or drops), intra-buccal or intra-nasal dosage forms. Compositions suitable for parenteral injection may include pharmaceutically acceptable sterile or non-aqueous solutions, dispersions, suspensions or emulsions, and disinfecting powders which can be reconstituted into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (polyethylene glycol, polypropylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) And injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining a desired particle size in the dispersion, and by using a surfactant. -23- 200305414

(19) These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Preventing microbial contamination of these compositions can be achieved with various fungicides and fungicides, such as parabens Acid esters, chlorobutanol, phenol, ascorbic acid, etc. It may also require isotonic agents, such as sugar, sodium chloride, and the like. Prolonged absorption pharmaceutical compositions for injection can be achieved using agents that delay absorption, such as aluminum monostearate and gelatin. Solid dosage forms for oral administration include capsules, lozenges, powders and granules. In the solid dosage form, the tosylate salt of the present invention or the monohydrate of the salt is combined with at least one inert conventional pharmaceutical excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) a filler or Elongating agents; (b) binding agents (such as carboxymethyl cellulose, alginates, gelatin, polyvinylacetrolidone, sucrose, acacia, etc.); (c) wetting agents (such as glycerol, etc.); (D) disintegrating agents (such as rock cauliflower, calcium carbonate, tapioca or cassava starch, algin, certain mismatched silicates, sodium carbonate, etc.); (e) solution retarders (such as chain Alkanes, etc.); (f) absorption accelerators (for example, quaternary amine compounds, etc.); (g) wetting agents (for example, tetradecyl alcohol, glycerol monostearate, etc.); (h) absorbents (for example, , Kaolin, bentonite, etc.); and / or (i) lubricants (eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc.) are premixed. In the case of capsules or tablets, the dosage form may also include buffering agents. Solid compositions of a similar type can also be used as fillers in soft or hard-filled gelatin capsules using such excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as lozenges, coated tablets, capsules and granules can be prepared by coating or shelling, such as enteric coating and others known in the art. It may also contain specific -24- 200305414

(20) A nebulizing agent, and the composition capable of releasing the active compound or compounds in a delayed manner. Examples of such compositions that can be used are polymeric substances and rhenium. The tosylate salt of the present invention or the monohydrate of the salt may also be added in the form of microcapsules, and may also have one or more of the above-mentioned excipients if appropriate. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and licorice. In addition to tosylate or the monohydrate of the salt, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, dissolving agents and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, acetic acid Ethyl ester, ethyl alcohol, ethyl benzoate, propylene glycol, 1,3-butanediol, dimethyl formate, oil (especially cotton seed oil, peanut oil, corn oil, castor oil, sesame oil, etc.), glycerol, Tetrahydrofluorenyl alcohol, fatty acid esters of polyethylene glycol and sorbitan, or mixtures of these. In addition to the inert diluent, the composition may also include adjuvants such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavoring agents, and fragrances. Suspensions (in addition to the tosylate or the monohydrate of the salt) may also include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylated sorbitol and sorbitan esters, microcrystalline fibers Vegetarian, aluminum hydroxide, bentonite, stone cauliflower, and teragacons, or a mixture of these substances. Compositions for rectal or vaginal administration preferably include suppositories, which can be obtained by combining the tosylate salt of the present invention or a monohydrate of the salt with a suitable non-irritating excipient or carrier such as cocoa butter, poly Ethylene glycol is either solid at normal room temperature but liquid at body temperature, and therefore can be melted in the rectum or vagina, so a suppository wax that releases the salt or the monohydrate is prepared by mixing. Topical dosage forms may include ointments, powders, sprays and inhalants. -25- 200305414

(21) The tosylate salt or the monohydrate of the salt of the present invention may be pre-mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservative, buffer or propellant which may also be required. The scope of the invention also includes ophthalmic formulations, eye ointments, powders and solutions. The following sections describe formulations, dosage forms, etc. for non-human animals. To the animal, (R)-(2- (4-pyrazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol tosylate or the salt of The administration of the monohydrate can be performed orally or parenterally (for example by injection). (R)-(2- (4-Pyrazol-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol tosylate or the monohydrate of the salt The dosage is such that an effective dose is acceptable. Generally, the daily dosage for oral administration to animals is about 0.01 to about 1,000 mg / kg body weight, preferably about 0.01 to about 300 mg / kg body weight. Conveniently, the tosylate or the monohydrate of the salt can be carried with drinking water so that the therapeutic dose of the compound can be supplied daily with water. The salt can be measured directly in drinking water and is preferably a liquid, water-soluble concentrate (e.g. a salt solution in water). Conveniently, the tosylate salt or the monohydrate of the salt of the present invention can also be added directly to the feed or in the form of animal feed supplements, also known as premixes or concentrates. Carriers of salt-containing premixes or concentrates are more commonly used in the salts of feeds. Suitable carriers are liquid or solid, such as water, various meals, such as alfalfa meal, soybean meal, cottonseed oil meal, flaxseed oil meal, corn ear meal and corn meal, molasses, urea, bone meal, and mixtures of inorganic substances, such as Used in poultry feed. The most effective carrier is -26- 200305414 for individual animals.

(22) Feed; that is, a small portion of the feed. The vehicle assists the uniform distribution of the tosylate or the monohydrate of the salt in the final feed blended with the premix. It is important that the salt or the hydrate is fully incorporated in the premix and then in the feed. Therefore, the salt or the monohydrate may be dispersed or dissolved in a suitable oily carrier such as soybean oil, corn oil, cotton seed oil, etc., or a volatile organic solvent, and then blended with the carrier. It should be understood that the proportion of the salt or the monohydrate in the concentrate can be widely varied, as the amount in the final feed can be obtained by blending a suitable proportion of the premix with the feed to obtain the required amount of the salt or The monohydrate. High potency concentrates can be blended with protein carriers such as the above-mentioned soybean oil meals and other meal meals by feed manufacturers to make concentrated supplements suitable for direct feeding into animals. In this example, the animals were allowed to eat normally. In addition, the concentrated supplement can be directly added to the feed to obtain nutritional balance, and the final feed contains a therapeutically effective amount of the tosylate salt of the present invention or a monohydrate of the salt. The mixture is thoroughly mixed using standard procedures, such as a double-helix shell blend, to ensure uniformity. If a supplement is used as an additive on a feed, it can also help ensure that the toluate or monohydrate of the salt is dispersed evenly over the desired feed. Drinking water and feed that are effective for increasing the storage of refined meat and increasing the ratio of refined meat to fat are generally made by (R)-(2- (4-oxazol-4-yl-phenoxy) -ethylamine) -1 -Pyridine · 3-yl-ethanol is mixed with a sufficient amount of animal feed to obtain the salt or the monohydrate in the feed or water at about 10-3 to about 500 ppm. The medicated pig, cattle, sheep, and goat feeds generally contain about -27- 200305414 (23) 1 to about 400 grams of tosylate or monohydrate of the salt per ton of feed. The optimum amount of these animals is usually About 50 to about 300 grams per ton of feed. The preferred poultry and pet feed usually contains from about 1 to about 400 grams per ton of feed, and preferably from about 10 to about 400 grams of tosylate or a monohydrate of the salt. For parenteral administration to animals, the tosylate salt or the monohydrate of the salt of the present invention can be prepared in the form of a paste or tablet, and is usually administered by infusion, and is usually on the skin of the animal's head and ears Submerged to increase lean meat deposition and improve lean meat to fat ratio. Generally, parenteral administration involves injecting a sufficient amount of the tosylate salt of the present invention or a monohydrate of the salt, so that the animal obtains a drug of about 0.01 to about 20 mg / kg body weight per day. The preferred dose range for poultry, pigs, cattle, sheep, goats and pets is from about 0.05 to about 10 mg / kg body weight per day. The paste formulation can be prepared by dispersing tosylate or a monohydrate of the salt in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil and the like. A tablet containing an effective amount of the tosylate salt of the present invention or the monohydrate of the salt can be premixed by diluting the salt or the monohydrate with a diluent such as a carbon wax, carbamate, and the like, and a lubricant can be added Such as magnesium stearate or calcium stearate to improve the tabletting process. Of course, it is necessary to understand that more than one kind of tablets can be administered to animals in order to achieve the required dose which can increase the deposition of refined meat and improve the required ratio of refined meat to fat. Furthermore, it can be infused periodically during animal treatment to maintain an appropriate amount of drug in the animal. -28- 200305414

(24) The invention has many advantageous veterinary properties. For pet owners or veterinarians who wish to increase their lean meat and / or remove unnecessary fat from their pets, the present invention provides a achievable method. For owners of poultry and cattle, the method of the present invention can be used to obtain a larger number of refined meat animals which are more expensive in the meat industry. Examples The present invention is illustrated by the following examples. However, it should be understood that the present invention is not limited to the details of these examples, and changes made by those skilled in the art after reading this disclosure will become known and apparent. Preparation of intermediates Interstitial (R) -2-bromo-ΐ-pyridine-3--3--ethanol Π-n plastic mouth · ΟΗ

2-Bromo-1-pyridin-3.yl-ethanone hydrobromide (GB Davies et al., Aust J. Chem., 42, 1735 (1989)) and Botrytis cinerea grown in Fernbach flasks ( Absidia cylindrospora) ATCC 22751 cultures, or yeast cultures containing medium A (40 g / l wheat solids and 20 g / l glucose adjusted to pH 4.85 before pressure cooker). Each containing 500 ml of medium A

Fernbach bottle (8) was filled with 5 ml of Absidia cylindrospora ATCC 22751 sowing and culturing. S. cylindrospora seed cultures were prepared in two 300-liter conical flasks each containing 40¾ liters of Medium A. These seeded cultures were poured into the robe teeth of A. cylindrospora, and were dropped at 29 C for about 24 hours. After stirring at about 29 ° C for about 4 hours, 2 ml of 2-bromo-p-pyridine-3--29-200305414

(25) A 20 g / l aqueous solution of methyl ethyl ketone hydrobromide was added to each Fernbach bottle culture bacteria. The bottle was stirred for about another 5 hours, then the contents of the bottle were combined and the solids were removed by centrifugation. The culture of Absidia cylindrospora ATCC 22751 was allowed to grow in yeast containing 8 liters of medium A. The yeasts were each infused into a single culture of A. cylindrospora grown in a Fembach bottle containing 400 ml of Medium A. Fernbach flask culture bacteria was added to 1.8 ml of A. cylindrospora ATCC 22751 gown teeth, and stirred (200 rpm) at about 29 ° C for about 40 hours. After about 24 hours, the two yeast cultures were treated with 2-bromo-1.pyridin-3-yl-ethanone hydrobromide aqueous solution (30 g / l) to obtain an additional 8 g of 2-bromo- 1-pyridin-3-yl-ethanone hydrobromide, and 16 g of 2-bromo-1-pyridin-3-yl-ethanone hydrobromide was obtained in another yeast. 8 g of 2-bromo-1 -pyridin-3-yl-ethanone hydrobromide was obtained from the yeast culture about 24 hours after the substrate was added, but other yeasts were obtained about 5 hours after the substrate was added. The contents of the second yeast culture were also centrifuged to remove solid matter. The upper phases of the eight Fernbach flask cultures and the two yeast cultures were combined, filtered through filter paper, and passed through 737 grams of XAD-16 'resin (Rohm &Haas; Philadelphia, PA). Then dissolve with a mixture of methanol and water (1 liter of 10% methanol, 1 liter of 20% methanol, 1 liter of 30% methanol, 1 liter of 50% methanol, 3 X 1 liter of 80% methanol, and 1 liter of 100% methanol) and collect Fractions. These fractions were analyzed by HPLC on a 4.6X150 mm Kromasil® C4 column (Phenomenex; Torrance, CA) with 10 mM ammonium acetate: acetonitrile (76.5: 23.5, v / v) at 1.0 ml / min. The fractions containing the desired product (10% methanol-80% methyl-30-200305414 (26) alcohol) were collected, the solvent was removed by concentration, and extraction was performed with ethyl acetate. The ethyl acetate extracts were combined, concentrated to about 600 ml, dehydrated with magnesium sulfate and filtered. The material was divided into many parts, and then in a silicone box (1.2 x 7.5 cm and 4 x 15 cm, Biotage; Charlottesville, VA), with a mixture of ethyl acetate and hexane (ethyl acetate: hexane containing 0.1% acetic acid) : Acetic acid; 60: 40: 0.1; v / v / v) flash chromatography purification. The fractions containing the desired product were concentrated to obtain 1.93 g (9.6%) of the title compound as a pale yellow oil. a d = -16.4. (C = 0.53, methyl alcohol). The product was analyzed by palm HPLC on a 4.6X250 mm Chir ale el® 0D column (Chiral Technologies; Exton, PA) with hexane: isopropanol (9: 1, v / v) and 1.5 ml / min. The enantiomeric excess was determined to be 91.2%. -1HNMR (400 mHz, d6-DMSO): δ 8.55 (d, 1H, J = 2 · 1 Ηζ), 8.44 (dd, 1H, J = 1.7, 4 · 6 Hz), 7.75 (dd, 1H, J = 2.5, 4.2 Hz), 7.33 (m, 1H), 5.93 (d, 1H, J = 4.6 Hz), 4.85 (m, 1H), 3.60 (ddd, 2H, J = 5.0, 10.4, 14.9 Hz ). GC-MS (m / z,%): 201/203 (M +, 10), 108 (100) ° _Intermediate (R) _3 dibromo_ 丨 tert-butyl-dimethyl-silane Ethylpyridine (II-2):

) 3 L2 at room temperature in 20 ml of anhydrous N, N-dimethylbenzene containing 54 g (7.61 mmol) of (R) -2-bromo-1-pyridin-3-yl-ethanol 1-1 To the stirred solution of methylformamide was added 1.55 g (22.83 mmol) of imidazole, followed by 172 g (114 mmol-31-200305414).

(27) Ear) Third butyldimethylsilyl chloride. The mixture was stirred at room temperature for about 18 hours, and then 1.55 g (22.83 mmol) of imidazole and 1.72 g (11.4 mmol) of third butyldimethylsilyl chloride were added, and the mixture was allowed to stand at Stir for about 24 hours at room temperature. The mixture was poured into 200 ml of water and extracted with ethyl acetate (2 x 2000 ml). The organic extracts were combined, washed sequentially with water (1 × 40 ml), brine (1 × 40 ml), dehydrated with magnesium sulfate and concentrated in vacuo to obtain an oil. Chromatography on silica gel with ethyl acetate: hexane (2: 3, v / v) gave 1.41 g (58% yield) of the desired title compound as a clear oil, ^ 0 = -51.5 ^ 0 = 0.60, chloroform). The products were analyzed by palm HPLC on a 4.6X250 mm Chiralcel (R) OD column (Chiral Technologies; Exton, PA) with tig ·· isopropanol (7: 3, v / v) and 1.0 mL / min. The enantiomeric excess was determined to be 91.3%. 'HNMR (400 mHz, CDC13): δ 8.58 (s, 1Η) 5 8.55 (m5 1Η) 5 7.70 (d, 1Η), 7.30 (m, 1Η), 4.90 (m, 1Η), 3.46 (ddd, 2Η, J = 1, 2, 7.1, 8 · 3 (Ηζ), 0.87 (s, 9H), 0.11 (s, 3H). MS (m / z,%): 316/318 (M +, 100). Preparation of Intermediate f 2-(4-Hemazole-4 -yl-benzyl) -ethyl 1-aminocarbamate (II-3)

1ζ3 contains 290.0 grams (1.80 ¾ mole) of 4-0 spit-4-yl-fluorene (Η · Jones et al., 1. Med · Chem ·, 21, 1110 (1978)), 737.7 grams (2.70 mole ) Methanesulfonic acid 2- -32- 200305414

(28) The mixture of decyloxycarbonylamino-ethyl and 746.0 g (5.40 ¾ mole) of stearic acid but 4.6 liters of anhydrous dimethylsulfine was stirred and heated to about 8 ° C. Add another 500 ml of dimethyl sulfide, and stir vigorously at about 80 ° C for about two hours. The resulting mixture was cooled to about 50 c 'and poured into about 1 liter of sand-ice ice water' for about one hour. Then it was filtered. The moist filter cake was washed with water (2 X 1 liter), and then partially dried in a vacuum for about two hours. The wet solid was poured into a round-bottomed flask, 6 liters of methanol 'was added and the mixture was warmed to about 60 ° C, and 3 liters of water was added. The heating source was removed, and the mixture was stirred for about 8 hours, followed by filtration. The filter cake was washed with 1: 1 methanol / water (v / v; 2 × 500 ml), and then dried under vacuum at about 40 ° C. for about 18 hours to obtain the title compound (389.5 g, 64% yield) as a beige powder. rate). Mizuki Tozaki-Methoxyethylamine (Preparation of ID:

1-4 Stir at room temperature containing 234.0 g (0.692 mole) of [2- (4-pyrazol_4-yl-phenoxy) -ethyl] -carbamic acid benzyl ester 1-3, 295.1 ml ( 3.097 Mo earrings hexadiene and 93.60 grams of 10% Pd / C (50% water wet) 5.6 liters of methanol to stir the mixture for about 2 2 hours. The mixture was pulverized alga (1 3 X 3 cm ), Then the filter cake was washed with 12 liters of 100 ·· 1 v / v methanol / triethylamine. The filtrate was evaporated in vacuo and the remaining solid was added to 250 ml of toluene. The mixture was stirred at room temperature for about 30 minutes. An additional 2.5 liters of hexane was added over about 5 to 10 minutes, and the resulting slurry was stirred for about one hour. 33-200305414 (29) The mixture was filtered, followed by 1: 1 toluene / hexane (3 x 100 ml) The mixture was washed with the filter cake, and the solid was dried in a vacuum at about 50 ° C for about 18 hours. The title compound was obtained as a white powder (115 g, 81.5% yield). Intermediate-tert-butyl Of dimethyl-dimethylsilylamino group V2 · pyridin-3-yl · ethyl)-(2- (4-oxazol-4-yl-benzylethylamine Π-5):

Contains 1.24 g (3.91 mmol) (R) -3- (2-bromo-1- (third butyl-dimethyl-silyl) -ethyl) -pyridine 1-2, 1.6 g (7.83 mmol) Mol) 2- (4-Pyrazol-4-yl-phenoxy) -ethylamine 1-4 and 1-4 ml (7.83 mmol) diisopropylethylamine in 20 ml of anhydrous dimethyl sulfinate The stirred mixture was heated at about 90 ° C for about 18 hours. The mixture was poured into 400 ml of water and extracted with ethyl acetate (2 X 400 ml). The organic extracts were combined, washed sequentially with water (2 X 100 ml) and brine (1 X 100 ml), dehydrated with magnesium sulfate and concentrated in vacuo to obtain an oil. Chromatography on silica gel with methanol: dichloromethane (1:19, v / v) gave 963 mg (56% yield) of the title compound as an amber oil, (^ 0 = -45.70 (0 = 0.49 , Chloroform) ^ NMR (400 mHz, CDC13): δ 8.56 (d5 1Η? J = 2.1 Hz), 8.50 (dd? 1H, J = 1.7, 5.0 Hz), 7.90 (d, 1H, J = 0.8 Hz) , 7.84 (d, 1H, J = 0.8 Hz), 7.65 (m, 3H), 7.26 (m, 2H), 6.90 (m, 2H), 4.85 (dd, 1H, J = 3.7, -34- 200305414 (30 )

8 · 3 Ηζ), 4.07 (m, 2H), 3.01 (dd, 2H,] = 4 pills 6 2 Ηζ), 2.88 (dd, 2H, J = 8.3, 12.0 Hz), 2.76 (dd, 2H, B 37, u 6 Hz), 0sS (s, 9H), 0.06 (s, 3H). MS (m / z,%): 441 (M ++ 1, 100).

3-yl_ethyl.ol Π-6)

At room temperature, containing 646 mg (ΐ · 47 亳 mol) (R) of "2-Third-Butyl-Dimethylsalanyloxy) -2-p Biyodo_3_yl · ethyl ) (2_ (4 · ^ Jun-4-yl-benzyloxy) -ethyl) -amine 1-5 in 5 ml of anhydrous tetrahydrofuran sample solution was added 2.2 ml (2.20 mmol) containing 1. ] y [Tetrabutylamine fluoride tetraquat squeaked. The mixture was stirred at room temperature overnight, poured into 1,000 milliliters of water 'and extracted with ethyl acetate (2 X 100 ml). The organic extracts were combined , Washed sequentially with water (1 X 20 ml) and brine (1 X 20 ml), dehydrated with tritium sulfate and concentrated in vacuo to obtain a solid. On a silicone gel with methanol: difluoromethane * (1 · 9 'ν / ν) dissolution chromatography to obtain a solid. Dissolve in 10 ml of ethyl acetate; hexane (1 · 1 ν / ν) was dispersed to obtain 250 mg (5 2% yield) of a white solid standard transfer port. Mp · 98-100t :, a D = -31.6 ° (c = 0.58, chloroform). The product was placed on a 4 · 6 X 5 cm Chiralpak AS ⑧ column (Chiral Technologies; Exton 'PA) with acetonitrile. ·· Methanol (95 ·· 5, v / v) and 1.0 · L / min dissolve- 35- 200305414

(31) Enantiomeric excess > 99.9% determined by palm HPLC analysis. ^ NMR (400 mHz, d6-DMSO): δ 8.52 (d, 1Η5 J = 2.1 Hz), 8.47 (d5 1H, J = 0.8, 5.0 Hz), 8.41 (dd, 1H, J = 1.7, 4.6 Hz), 8.38 (d, 1H, J = 0.8 Hz), 7.70 (m, 3H), 7.30 (m, 1H), 6.96 (ddd, 2H, J = 2.5, 4.6, 9.5 Hz), 5.47 (d, 1H, J = 3.7 Hz), 4.67 (d, 1H), 4.02 (m, 2H), 2.89 (t, 2H, J = 5.4 Hz), 2.72 (d, 2H, J = 6.2 Hz). MS (m / z,%) : 326 (M ++ 1, 100). Analysis: Calculated for C18H19N303: C, 66.45; H, 5.89; N, 12.91. Found: C, 66.22; H, 5.92; N, 12.83. Example 1 Preparation of ((R) -2- (2- (4-oxazol-4-yl-benzyl) -ethylamino) -1-pyridin-3-yl-ethanol) p-methanesulfonate :

At room temperature, containing 197 mg (0.61 mmol) of (R) -2- (2- (4-Hemazol-4-yl-phenoxy) -ethylamino) -1-pyridine-3 To 2 ml of a methanol-based ethanol solution of 1-6 ethanol was added 118 mg (0.61 mmol) of p-toluene transverse acid monohydrate. The mixture was stirred at room temperature for about 30 minutes, and then 4 ml of isopropyl ether was added low. The resulting precipitate was stirred for another 15 minutes, filtered, washed with 4 ml of isopropyl ether: methanol (3: 1, v / v) and dried to obtain 225 mg (74% yield) of the title compound as a white solid . m.p. 155.5 ° C, a D = -36- 200305414

(32) -16.9 ° (c = 0.49, methanol). The product was determined on a 4 · 6 mm X 5 cm Chiralpak AS® column (Chiral Technologies; Exton, PA) using acetonitrile: methanol (95: 5, v / v) and 1.0 ml / min dissolution. Enantiomeric excess > 99.9%. WNMR (400 mHz, d6-DMSO): δ 8.85 (s, br, 2H), 8.59 (d5 1H, J = 1.7 Hz), 8.51 (m, 2H), 8.40 (d, 1H, J = 0.8 Hz ), 7.80 (ddd, 1H, J = 1.7, 3.7, 7.9 Hz), 7.72 (ddd, 2H, J = 2.9, 4.6, 9.6 Hz), 7.43 (m, 3H), 7.04 (m, 4H), 6.30 ( d, 1H, J = 4.2 Hz), 5.01 (dd, br, 1H, J = 3.3, 7.1 Hz), 4.28 (d, br, 2H, J = 5.5 Hz), 3.31 (d, br, 1H, J = 12.5 Hz), 3.16 (t, br, J = 11.2 Hz), 2.25 (s, 3H); MS (m / z,%): 326 (M ++ 1, 100). Analysis: C25H27N3S06i Calculated value · C, 60.35; H, 5.47; N, 8_45 · Measured value: C, 60.26; H, 5.48; N, 8.38. Example 2 ((R) -2- (2- (4-slogan succin-4-yl-phenoxyethyl monthanyl) -1-koubito-3-yl-ethanol) p-toluenesulfonic acid Preparation of salt monohydrate:

30 mg of ((R) -2-〇2- (4-humazol-4-yl-phenoxy) -ethylamino) -1 -pyridin-3-yl-ethanol) p-toluene of Example 1 The sulfonate is ground to a particle size of less than about 10 microns. As for the formula with humidity, and it is left for about 14 days at 100% relative humidity, the anhydrous p-toluenesulfonate is completely converted into a monohydrate (its- 37- 200305414

(33) Confirmed by near-infrared spectroscopy. Analysis: Calculated values for C25H29N3S07: C, 58.2; H, 5.7; N, 8.1; S, 6.2. Found: C, 58.5; Η, 5.6; N, 8.1; S, 6.6. -38-

Claims (1)

200305414 Scope of patent application 1. One kind of ((R) -2- (2- (4 ^ azol-4-yl-phenoxy) -ethylamino) -1-pyridine-3 -yl-ethanol) P-Toluenesulfonate. 2. — ((R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1 · pyridin-3-yl-ethanol) p-toluenesulfonic acid Salt monohydrate. 3. A pharmaceutical composition comprising a therapeutically effective amount of ((R) -2- (2- (4-purazol-4-yl-phenoxy) -ethylamino) -1-pyridine-3 -Yl-ethanol) p-toluenesulfonate or ((R) -2- (2- (4-indazol-4-yl-phenoxy) -ethylamino) -1 -pyridine-3 -yl -Ethanol) p-toluenesulfonate monohydrate; and a pharmaceutically acceptable carrier or diluent. 4. A method of treating a disease, symptom or disorder that modulates a 3-adrenergic receptor, comprising administering to a mammal in need of the treatment a therapeutically effective amount of ((R) -2- (2- (4- 噚) Azole-4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol) p-toluenesulfonate; ((R) -2- (2- (4-humidazole- 4-yl-phenoxy) -ethylamino) -1-pyridin-3-yl-ethanol) p-toluenesulfonate monohydrate; or the steps of the pharmaceutical composition as described in claim 3 . 5. A method for increasing the content of refined meat in a food animal, the method comprising administering to the food animal an increased amount of ((R) -2- (2- (4-oxazol-4-yl-phenoxy)- Ethylamino) -1 -pyridine-3 -yl-ethanol) p-toluenesulfonate; ((R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethyl Amine) -1-pyridine-3-yl-ethanol) p-toluenesulfonate monohydrate; or a pharmaceutical composition such as item 3 of the scope of patent application. 6. —Species ((R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1-pyridine 200305414 -3-yl-ethanol) p-toluenesulfonate; or ((R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1-pyridine- 3-yl-ethanol) p-toluenesulfonate monohydrate is used for the manufacture of drugs for treating / S3-adrenoceptor-regulated diseases, symptoms or disorders. 7. —Species ((R) -2- (2- (4-azazol-4-yl-phenoxy) · ethylamino) -1-pyridin-3-yl-ethanol) p-toluenesulfonic acid Salt; or ((R) -2- (2- (4-oxazol-4-yl-phenoxy) -ethylamino) -1 -pyridine-3-yl-ethanol) p-toluenesulfonate The use of monohydrate is used in the manufacture of medicine for the content of edible animal meat. -2- 200305414 Lu, (1), the designated representative of this case is: 笫 __ 图 (二), the element representative symbols of this representative diagram are simply explained: 柒, if there is a chemical formula in this case, please disclose the one that can best show the characteristics of the invention Chemical formula: