CN1390213A - Aryloxy propanolamines for improving livestock production - Google Patents

Abstract

Disclosed is a compound represented by structural formula (I); R1 is a substituted or unsubstituted aryl group; R2 and R3 are independently -H, a C1-C4 straight chained or branched alkyl group; R4 and R5 are independently -H, a C1-C4 straight chained or branched alkyl group or, taken together with the nitrogen atom to which each is bonded, a non-aromatic heterocyclic ring; Ring A and Ring B are independently further substituted with zero, one or two substituents. Physiologically acceptable salts of structural formula shown above are also included. Also disclosed is a method promoting growth, efficiency of feed utilization and/or production of lean body mass in a livestock animal. The method comprises administering to the animal an effective amount of one or more compounds represented by the structural formula as shown or a physiologically acceptable salt thereof.

Description

Be used to improve the aryloxy propanol amine of tame livestock product

Background of invention

An important target is exploitation can increase quantity with the quality that improves meat of the meat that obtains from domestic animal a biologically active agent in the livestock industry.

＂ increases the food that obtains from domestic animal quantity ＂ is meant, refers in particular to, and promotes the domestic animal growth, increases the efficiency of feed utilization that is used to keep fowls and/or increases domestic animal lean meat output.The biologically active agent that can produce these effects is commonly called ＂ anabolic agent ＂.

＂ improves the food that obtains from domestic animal quality ＂ is meant, refers in particular to the quantity that reduces subcutaneous lipids in the meat when keeping intramuscular fat.Subcutaneous lipids is commonly referred to ＂ and repairs fatty ＂, may cause in the human body of edible a large amount of meat that the amount of cholesterol and/or triglyceride level raises, and its nutritive value is minimum, and may reduce the overall yield of meat.Therefore, people wish to reduce or eliminate this class fat from meat.On the other hand, intramuscular fat is commonly referred to ＂ streaky pork ＂, definitely helps to keep the fragrance of meat and the high-quality level of meat.Therefore, streaky pork is a kind of desirable quality.Suitably the biologically active agent of steatolysis can reduce subcutaneous lipids when keeping intramuscular fat.

It seems that some publication discloses arylprop alcamines, for example US5 013761 and WO97/10825 generally.But, needing a kind of biologically active agent, both anabolism was strong for it, again suitably steatolysis.Biologically active agent with these character can be used for domestic animal to improve the economic benefit of meat product by the productive rate (improving the finished product grade) that increases meat.Biologically active agent with these character can also increase the rentability of meat product by the meat of producing high-quality level, described high-quality level meat is because it is edible more healthy and can keep the fragrance of meat, so meat packer may approve that with the human consumer it has relative high price.

The invention summary

Have found that when having amide group on 2 that B encircles in the aryloxy propanol amine of being represented by structural formula (I), shown in hereinafter, can produce compound with strong anabolism performance.The anabolism of the corresponding regional isomer that has amide group on 4 is clearly low.For example, the minimizing percentage ratio that characterizes the serum urea nitrogen content (SUN) of anabolic action in the ox with the processing of 2-acid amides regional isomer is wanted big (referring to table 1 among the embodiment 17) compared with the minimizing percentage ratio of serum urea nitrogen content in the animal of handling with corresponding 4-acid amides regional isomer.In addition, the free fatty acid content (NEFA) that characterizes the steatolysis effect in the ox with the processing of 2-acid amides regional isomer is suitable, and the Niu Tongchang that handles with 4-acid amides regional isomer then demonstrates stronger increase (seeing table 1 among the embodiment 17).

In addition, have been found that when having amide group on 2 that B encircles in the aryloxy propanol amine of being represented by structural formula (I), shown in hereinafter, can obtain a kind of compound, raise the phase when feeding in 28 days male young chicken, particularly during 35-49 days of its lifetime, when feeding these chickens, can make the chicken weight increase significantly accelerate (referring to the table 4 of embodiment 20) with described compound.And, can observe a kind of trend, promptly fed and raise that feed conversion rate is improved in the phase at whole 28 days.At last, for the bird of treated mistake, with respect to reference examples, following carcass parameter also demonstrates significant increase: hot genetic ability for carcass weight; The band bone, the whole piece leg weight of belt leather; And the band bone, the brisket weight of belt leather (referring to the table 4 of embodiment 20).

Based on these results, the present invention openly improves the new compound and the novel method of livestock meat product.

One embodiment of the invention are the compounds by structural formula (I) expression:

With the acceptable salt of its physiology; Wherein

R1 is for replacing or unsubstituted aryl, but condition is that R1 is not replacement or unsubstituted carbazyl as-X-during for-CH-;

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, C1-C4 straight or branched alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic;

X is-N-or-CH-; With

Ring A and ring B also are not substituted independently or are replaced by one or two substituting group.

Another embodiment of the invention is the compound by structural formula (II) expression: With the acceptable salt of its physiology:

In structural formula (II), R1 is for replacing or unsubstituted aryl; R2-R5 and ring A-B are identical with above-described structural formula (I).

Another embodiment of the invention is the method that increases the quantity of the meat that obtains and improve meat quality from domestic animal.This method comprise give animal effective dose one or more by structural formula (I) or (II) expression compound or the acceptable salt of its physiology.

Compound of the present invention has strong anabolism performance and moderate steatolysis function.Therefore, these compounds can impose on domestic animal to increase the quantity of the meat that obtains from this animal.They also can improve the quality of meat by the amount that reduces subcutaneous lipids when keeping intramuscular fat.Therefore, compound of the present invention can be used for producing more substantial edible more healthy, keeps normal meat flavour simultaneously, promptly keeps the meat of streaky pork and high-quality level, and therefore can increase the rentability of meat product.Compound of the present invention is intended to be used to handle healthy animal.

The accompanying drawing summary

Fig. 1 illustrates the ox average daily gain curve of handling with the following method after 28 days: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 2 illustrates the feed conversion rate of handling ox after 28 days with the following method than curve: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 3 illustrates the hot genetic ability for carcass weight curve of handling ox after 28 days with the following method: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 4 illustrates the gauged twelfth rib bone fat thickness curve of handling ox after 28 days with the following method: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 5 illustrates the average flank eye muscle area curve of handling ox after 28 days with the following method: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 6 illustrates the carcass soft tissue of handling ox after 28 days with the following method and forms curve: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 7 illustrates the calculating finished product class curve of the beef of handling with the following method after 28 days: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Fig. 8 illustrates the structure score curve of handling the beef after 28 days with the following method: a) 0.0 milligram of compound 6 of per kilogram of body weight every day; 0.125 milligram of compound 6 of per kilogram of body weight every day; 0.250 milligram of compound 6 of per kilogram of body weight every day; With 0.5 milligram of compound 6 of per kilogram of body weight every day;

Detailed Description Of The Invention

It is a kind of by structural formula (I) or (II) compound of expression that the object of the invention is to provide. Also comprise the method that improves livestock products by giving one or more compounds of the present invention of domestic animal.

In a preferred embodiment, compound of the present invention is represented by structural formula (III):

R1 such as above structural formula (II) definition. Preferably, R1 (V), (VI), (VII) or (VIII) is represented by structural formula (IV):

Ring C-ring I is replacement or unsubstituted independently. Preferably, ring C-ring I is unsubstituted.

Aryl comprises the carbocyclic ring aromatic radical, phenyl for example, 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl, and heteroaryl, TMSIM N imidazole base for example, 2-imidazole radicals, 2-thienyl, 3-thienyl, the 2-furyl, 3-furyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, the 2-pyrimidine radicals, 4-pyrimidine radicals, 2-pyranose, 3-pyranose, 3-pyrazolyl, the 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.

Aryl also comprises the fused polycycle aromatic ring system that one of them carbocyclic ring aromatic ring or hetero-aromatic ring and one or more other hetero-aromatic ring condense. Example comprises 1-benzimidazoline base, 2-benzimidazoline base, 1-benzimidoyl thiazolinyl, 2-benzimidoyl thiazolinyl, 1-carbazyl, 2-carbazyl, the 3-carbazyl, 4-carbazyl, 3-indazolyl, the 4-indazolyl, 5-indazolyl, 6-indazolyl, 2-benzene thienyl, 3-benzothienyl, 2-benzofuranyl, the 3-benzofuranyl, 2-indyl, 3-indyl, the 2-quinolyl, 3-quinolyl, 2-[4-morpholinodithio base, 2-Ben Bing Evil azoles base, 2-benzimidazolyl, 2-quinolyl, the 3-quinolyl, 1-isoquinolyl, 3-quinolyl, 1-isoindolyl and 3-isoindolyl. As using in the present invention, term aryl comprises that also wherein one or more carbocyclic ring aromatic rings and/or hetero-aromatic ring are fused to the group on cycloalkyl or the non-aromatic heterocyclic.

Non-aromatic heterocyclic is to comprise one in ring, and two or three are selected from nitrogen, the heteroatomic non-aromatic carbocyclic ring that rock-steady structure can be provided of oxygen and sulphur. Described ring can be five, six, seven or octatomic ring. Example comprises the 2-tetrahydrofuran base, 3-tetrahydrofuran base, 2-tetrahydro-thienyl, 3-tetrahydro-thienyl, the 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholine generation, 3-thiomorpholine generation, 4-thiomorpholine generation, the 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, the 1-piperazinyl, 2-piperazinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl and 4-thiazolidinyl.

As using in the present invention, aliphatic group comprises C1-C20 complete saturated of straight chain, side chain or ring-type or comprises one, the alkyl of two or three unsaturated units.

The substituting group that is fit on aliphatic group, aromatic group (carbocyclic ring and heteroaryl), non-aromatic heterocyclic or the benzyl is those groups that significantly do not reduce the compou nd synthesis metabolism or change compound steatolysis effect. Example comprises :-OH, halogen (Br ,-Cl ,-I and-F) ,-OR ,-O-COR ,-CN ,-NO₂、-COOH、-NH ₂、-NHR、-NR ₂、-COOR、-COR、-CHO、-CONH ₂、 -CONHR、-CONR ₂,-SH ,-SR and-NH-C (=NH)-NH₂ R is C₁-C ₆Alkyl, benzyl or phenyl.

The non-aromatic heterocyclic that replaces can also have=O ,=S ,=NH or=NR is as substituting group, wherein R as above defines. The aliphatic series, the aromatics of replacement, the non-aromatic heterocyclic of replacement or the benzyl group of replacement that replace can contain one, two or three substituting groups.

The acceptable salt of the physiology of compound disclosed by the invention comprises by structural formula (I), (II) and (III) compound of expression, also comprises the salt of the compound shown in the table 1. Salt can be formed by those compounds that contain acidic functionality and the alkali reaction that is fit to. This salt comprises and derives from such as the salt of the inorganic base of ammonium and alkali and alkaline earth metal ions hydroxide, carbonate, bicarbonate etc. and derive from alkaline organic amine, such as the salt of aliphatic series and aromatic amine, aliphatic diamine, hydroxyalkyl amine etc. Therefore, the alkali for the preparation of salt of the present invention comprises ammonium hydroxide, potash, sodium acid carbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, monoethanolamine etc.

Because amine segment, the salt of compound disclosed by the invention also can be by being prepared with the acid reaction that is fit to. The acid that is generally used for forming salt comprises inorganic acid, example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acid, such as p-methyl benzenesulfonic acid, pyrovinic acid, oxalic acid, to bromophenyl sulfonic acid, carbonic acid, butanedioic acid, citric acid, benzoic acid, acetic acid and relevant inorganic and organic acid. Therefore, the acceptable salt of this physiology comprises sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, the mono phosphoric acid ester hydrogen salt, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, enanthate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butine-1, the 4-diacid salt, 3-hexin-2, the 5-diacid salt, benzoate, chloro benzoate, the hydroxy benzenes hydrochlorate, methoxy benzoic acid salt, phthalate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, citrate, lactate, hippurate, beta-hydroxy-butanoic acid salt, glycolate, maleate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate etc. Preferred ammonium chloride, ammonium oxalate, ammonium acetate and 4-HBA ammonium salt. Particularly preferably be ammonium acetate and the 4-hydroxybenzoic acid ammonium salt of compound 6.

In the structural formula that the present invention describes, the key that chemical group or segment are connected to molecule or compound remainder represents with following symbol:

For example, in structural formula (IV)-(VIII), the phenyl ring of corresponding symbolic representation bicyclic system is connected to by structural formula (I), (II) or (III) key on 3 oxygen atoms of the molecule of expression.

The present invention includes the solvate and the acceptable salt of physiology thereof of structural formula I compound.Compound that the present invention is concrete or the acceptable salt of its physiology can form solvate with water or common organic solvent.This solvate is included in the scope of The compounds of this invention.

In addition, should be appreciated that, for structural formula I compound, may have diastereomer, and, depend on substituting group, also may there be other diastereomer.Compound of the present invention comprises the mixture of two or more diastereomers and steric isomer separately.

Should be appreciated that also some heterocycles may exist with tautomeric form.All these forms includes within the scope of the invention.

Domestic animal is the animal of feeding in order to produce food.Ruminant or ＂ ruminate and chew the ＂ animal, all are examples of domestic animal as milk cow, bull, heifer, lot bull, sheep, buffalo, wild ox, goat and antelope.Other example of domestic animal comprises pig and fowl (being poultry), as chicken, duck, turkey and goose.Other example of domestic animal also comprises fish, oyster and the Crustacean of aquaculture.Also comprise the adventive animal that is used to produce food, as crocodile, buffalo and ratite bird (as emu, rhea or ostrich).Method of the present invention is preferred for ruminating animal, as milk cow, heifer, bull and lot bull and fowl, as chicken, turkey and duck.

The ＂ significant quantity ＂ of The compounds of this invention is meant certain amount, and when giving the compound of this amount of domestic animal, the quantity of the meat that obtains from described animal and/or quality increase.

The quantity that increases gained meat refers to the animal of not handling to be compared, and can promote that the animal of handling has bigger increment.Perhaps, the quantity of increase gained meat refers to the formation that promotes lean meat.Promote lean meat to form and be meant that for example when comparing with the animal of not handling, the result who handles has higher muscle fat ratio.Perhaps, the quantity of increase gained meat refers to the raising food utilization efficiency.With respect to the animal of not handling, can be more for a long time when each quantitative food weight increase of handled animals consuming, we just say that feed utilisation is more effective.

The quality that improves meat refers to the carcass quality that improves described animal.Improve carcass quality and be meant, for example when keeping intramuscular fat (quality grade), form still less fatty tissue (subcutaneous lipids) and/or more lean meat (improving the finished product grade).Therefore improve carcass quality and can form edible healthy more meat usually, raise, also keep the fragrance of meat simultaneously as seldom causing triglyceride level and/or cholesterol level.

The moderate steatolysis agent ＂ of ＂ that the present invention uses mean can make non-esterified fatty acid content in the blood change into about 1-500, the preferred compound of about 1-300.

The significant quantity that gives animal will change with employed concrete the different of activeconstituents with pending concrete animal varieties to a certain extent, but every day, food ration add up to the about 1000ppm of about 0.2-(ppm: milligram compound/kilogram feed) usually.This consumption is about 0.002-50 milligram/kg body weight with the dosage that provides.A preferred embodiment has been used about 0.5-200ppm, more preferably from about 1-40ppm.For example, when animal, as described in implementing in ruminating animal or the pig during method, compound will be added in day feed rations with the amount of the about 1-100ppm of day feed rations.

Method of the present invention is preferably implemented by the The compounds of this invention that oral administration is bestowed the domestic animal significant quantity.Can use other route of administration, for example by (as by the nose internal sprayer) in the ovum, nose or subcutaneous, intramuscular or intravenous mode.But these approach are not too often to use.

Concerning the oral administration administration, compound of the present invention is preferably with the carrier that is fit to or be generally used for the mixing diluents of livestock industry.The animal-feed that contains The compounds of this invention is used as another embodiment of the invention.The carrier and the thinner that are generally used for feed comprise Semen Maydis powder, corn ear slag, soya-bean cake, alfalfa meal, rice husk, soybean mill slag, cottonseed oil-bound distemper, bone meal, Nian Gu, corn cob powder, wheat bran, lime stone, Lin Suanergai, sodium-chlor, urea, dry combustion method vinasse, VITAMIN and/or mineral intermixture, cane molasses or other liquid vehicle etc.This carrier promotes the uniform distribution of activeconstituents, and more generally content is about 20-98wt% of feed.

Though administration is bestowed the The compounds of this invention concerning oral administration, preferable methods is via feed rations every day, and this compound be directed into salt block and mineral substance is licked in the brick, and connects in tank preparation or the tap water for making things convenient for per os to ingest directly to add.In addition, for long-acting for a long time, compound also can be prepared with polymorphic material, wax etc., and as just giving animal to keep the activeconstituents of desirable every day of demand with pill or tablet.Compound also can be handled oral administration and/or through dermal administration by gavage.

To the administered parenterally method, compound of the present invention can mix with general carrier, as water, propylene glycol, polyoxyethylene glycol, N-Methyl pyrrolidone, glycerin methylal, Semen Maydis oil, sesame oil, calcium stearate, polymer materials etc.This preparation can be molded as ball, uses with injection or slowly-releasing hypodermic implant, the lasting form of ruminating equipment in transfer equipment or the nose.This administering mode can often use on demand to guarantee that suitable activeconstituents dosage is with the promotion rate of increase that obtains to want and the raising of lean meat and feed conversion rate.

The compounds of this invention can be prepared by disclosed method in people's such as Bell people's such as WO97/10825, Crowell WO98/09625, US5 808 080 and US6 046 227.These reference all are hereby incorporated by.The reaction process for preparing these compounds is presented among following the scheme I and II:

Scheme I

Scheme II

In scheme I and II, R1-R5, X and ring A-B are as mentioned above.

In scheme I and II, the amination of epoxide is known in the art to be carried out carrying out under the condition of this class reaction.For example, epoxide can with amine in the alcohol of room temperature under the reflux temperature of reaction mixture, preferably in ethanol, combine.For example, reaction usually people such as Atkins at Tetrahedron Letters, 27:2451 carries out under condition of describing in (1986), described document all is hereby incorporated by.The example that is used for the actual conditions of epoxide and amine reaction is seen embodiment 5.

The hydrolysis reaction of representing among the scheme II can carry out according to method well known in the art, uses for example Tripyrophosphoric acid, H ₂O ₂With the K in the methyl-sulphoxide ₂CO ₃, H ₂O ₂And ammonium hydroxide, H ₂O ₂And sodium hydroxide, the potassium hydroxide and the trimethyl carbinol or water and HCl.The example that is used for the actual conditions of nitrile hydrolysis is seen embodiment 6.

The preferred method of preparation table 1 compound 6 comprises uses the epoxide of being represented by following structural formula (a) by the amine amination of following structural formula (b) expression:

Wherein R6 is methyl or ethyl, uses aminoacyl amination COOR6 group to form compound 6 then.The example that is used for the actual conditions of synthetic compound 6 according to this method is seen embodiment 13-15.

Can exist scheme I and the noisy substituting group of II, condition is that they at first are converted into shielded form.The protecting group that is fit to it is known to the person skilled in the art that the radical protection ＂ in the ＂ organic synthesis that is disclosed in Green and Wuts, John Wiley and Sons, and in 1,991 one books, the document is hereby incorporated by.

The independent optically active isomer of The compounds of this invention can be prepared by method as mentioned above or by resolving racemic mixtures by its optically active precursor separately.Described fractionation can be implemented with chromatography or periodic crystallisation method subsequently by deriving with chiral reagent.Remove the optically pure basically isomer that chiral auxiliary(reagent) can obtain The compounds of this invention or its precursor by standard method.Can be about the more detailed data that splits from people's such as Jacques ＂ Enantiomers, Racemates, and Resolutions ＂, John Wiley ﹠amp; Sons, 1,981 one books obtain.

The compound that is used as starting raw material in The compounds of this invention synthetic is known, for non-commercially available compound, can synthesize at an easy rate by the general standard method of those of ordinary skills.

By following examples explanations the present invention, but this and do not mean that qualification to any way of the present invention.EXAMPLE Example 1:4-[(2S)-the epoxy ethyl methoxyl group]-preparation of 1H-indoles

At N ₂Under the protection, at room temperature with powder K ₂CO ₃(40 grams, 289mmol, 300 orders) join and contain H ₂In the methyl-sulphoxide (DMSO) (200 milliliters) of O (4 milliliters), stirred the mixture 30 minutes.(25.2 grams 189mmol) join (tepor is raised to 27 ℃) in this mixture, stir the mixture 10 minutes with the 4-oxyindole.Add (S) glycidyl nosylate (50.0 grams, 193mmol, 98.5%ee) (slight heat absorption).Slurries stirred 30 minutes at 20-25 ℃, stirred 23 hours at 25-27 ℃, finished up to reaction.With acetone (400 milliliters) diluted mixture thing, filter then.Filter cake also is concentrated to volume with it and is approximately 250 milliliters with acetone (400 milliliters) washing, merging filtrate under vacuum, keep temperature to be lower than 35 ℃.Under the ice-water bath, in about 2 hours, concentrated solution dropwise joined temperature and be in 15-20 ℃ the deionized water (650 milliliters).Under this temperature, product slurry was stirred 1 hour, stirred 30 minutes down at 5-10 ℃ then.The filtering separation solid washs it with cold deionized water (150 milliliters).Under vacuum, drying solid under 35 ℃ of temperature obtains 30.3 gram products.

At room temperature, to above thick product (30.3 grams, CH 171mmol) ₂Cl ₂Adding silica gel 62 in (100 milliliters) solution (1.6 grams, 0.05%wt/wt), N ₂Protection is stirred slurries 1 hour down.Mixture is by vacuum filtration then, filter cake CH ₂Cl ₂(20 milliliters) rinsing.Under the room temperature, in 1 hour, in filtrate, dropwise add heptane (500 milliliters) with the precipitation product.The gained slurries at room temperature stirred 30 minutes, and then stirred 30 minutes down in 0-5 ℃.Filtering mixt, and with cold heptane (150 milliliters) rinsing, vacuum-drying under 35 ℃/5 Torr again obtains 26.5 gram products (yield 79%), fusing point 72.4-74.0 ℃, then with its curing and fusion again under 79.8-81.3 ℃.The preparation of embodiment 2:4-(2-methyl-2-nitro propyl group) phenol

Under room temperature, mechanical stirring condition, to 2-nitropropane (260 milliliters, 2.90 moles), (65.0 grams, (29.6 restrain 4-hydroxybenzyl alcohol, 264mmol) to add potassium tert.-butoxide in diglyme 524mmol) (260 milliliters) solution.Temperature of reaction is elevated to 39 ℃ from 25 ℃ during the adding.The reacting by heating mixture stirred 6 hours down to reflux state and in about 137 ℃, remove water (28 milliliters of the distillate cumulative volumes of formation with the Dean-Stark water trap, the 7mL water), behind the cool to room temperature, in reaction solution, add deionized water (325 milliliters) and ethyl acetate (520 milliliters).Separate each phase, with deionized water (2 * 325 milliliters) washing organic phase.Obtain 181.2 gram oil by rotatory evaporator concentrated organic phase under 78 ℃, this oil is dissolved in methyl alcohol (65 milliliters) to be used for next step reaction.By ¹H NMR analyzes, and the concentration of gained solution is 56.3wt% (yield 99.6%).

The preparation of embodiment 3:4-(2-amino-2-methyl propyl group) phenol acetate

To N ₂4-(2-methyl-2-nitro propyl group) phenol of the degassing (45.0 grams, the Pd/C of adding 5% in methyl alcohol 230mmol) (450 milliliters) solution (catalyzer of the water-wet of 13.5 grams 50% is counted 15wt% with dry catalyst).With hydrogen mixture is pressurized to 35-40psi, and under vigorous agitation, is heated 60 ℃.When reaction is finished (about 6 hours), mixture is cooled to room temperature, removes by filter catalyzer by the mobile flocculating aids of Hy-modestly.With 50 ℃ methyl alcohol (135 milliliters) washing leaching cake, merging filtrate, and by rotary evaporation with its be concentrated to net weight about 120 the gram.With ethyl acetate (500 milliliters) dilution concentrated solution, in 30 minutes, in gained solution, add acetate (14.2 grams, ethyl acetate 235mmol) (250 milliliters) solution.The gained slurries at room temperature stirred 2 hours.Filter slurries, with ethyl acetate (2 * 100 milliliters) washing solid.Product vacuum-drying under 65 ℃/5Torr obtained the white crystalline solid of 46.5 grams (89.6%), fusing point 209-215.9 ℃ in 24 hours.Embodiment 4:2-[4-(2-amino-2-methyl propyl group) phenoxy group]-preparation of 3-itrile group pyridine

Mechanical stirrer is being housed, is having in the three-necked flask of the Dean-Stark water trap of condenser and thermopair, putting into 4-(2-amino-2-methyl propylphenol acetate (50.78 grams, 0.23 mole), 2-chlorine nicotine nitrile (32.8 grams, 0.24 mole) and K ₂CO ₃Powder (77.7 grams, 0.56 mole).In this solid, add N, N-dimethyl acetimide (609 milliliters) and octane-iso (pure isooctane, 122 milliliters).Add octane-iso in the Dean-Stark water trap, use N ₂System is purged.Under violent stirring, system is heated to then and refluxes and keep refluxing 1 hour.In 1 hour, olivaceous reaction mixture is cooled to 30 ℃ then, mixture is filtered with filter paper.With DMAC (250 milliliters) washing leaching cake, under the family expenses vacuum condition, filtrate was carried out stripping 1.5 hours under 80 ℃, obtain thick bottle-green oil.This oil is handled in methylene dichloride (580 milliliters) and is washed with deionized water (1160 milliliters).Separate each layer, organic layer washs with more water (250 milliliters).Organic layer mixes with water (1 liter) then, with 25 milliliters of dense HCl with its pH regulator to being approximately 1.Separate each layer, water/gas producing formation washs with methylene dichloride (250 milliliters).Water mixes with methylene dichloride (1 liter) then, and with 5N NaOH with its pH regulator to 12-13.Separate each layer, organic layer Na ₂SO ₄Drying is filtered and stripping, obtains brown solid product (53 grams, 88%, analyze＞99% with HPLC, the HPLC condition: the SB-C18 post, the permanent solvent mixture of 40/60 acetonitrile, 0.1% trifluoroacetic acid aqueous solution, the product retention time is 3.3 minutes).Get 20 gram products, carry out recrystallization, obtain being used for the sample of analysis and characterization with toluene (60 milliliters) and heptane (200 milliliters), fusing point 91.0-94.5 ℃, C ₁₆H ₁₇N ₃₀Calculated value: C, 71.89; H, 6.41; N, 15.72.Ultimate analysis value: C, 71.20; H, 6.38; N, 15.61.Embodiment 5:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-3-pyridine nitrile, the preparation of hydrochloride

In three neck round-bottomed flasks of condenser, nitrogen inlet, mechanical stirrer and thermopair are housed, put into 4-[(2S)-the oxyethane ylmethoxy]-1H-indoles (8.5 grams, 44.9mmol, 98.5%ee), 2-[4-(2-amino-2-methyl propyl group)-phenoxy group]-3-itrile group pyridine (21.01 grams, 78.6mmol) and Virahol (255 milliliters).N ₂Protection was reacted reflux (78 ℃) 17 hours down.Then with the solution cool to room temperature and stirred 1 hour.The refrigerative mixture filters by Hy-Flo flocculating aids (16.5 gram), and filter cake washs with Virahol (43 milliliters).Under 50 ℃, under the condition of perfect vacuum filtrate is concentrated to net weight 55 and restrains.Add ethyl acetate (85 milliliters) in strong solution, gained solution is concentrated to net weight 52 grams under the same conditions.Concentrated solution imports in the ethyl acetate (230 milliliters) then, adds 2.5wt%/vol NaCl solution (150ml).The vigorous stirring biphasic system, and with Glacial acetic acid with its pH regulator to 7.2.Separate each phase, with 2.5% salt solution (2 * 50 milliliters) extracted organic phase.Use NaOH/NaCl solution (50 milliliters, 0.89 gram NaOH) and water (50 milliliters) washing organic phase successively.

The formation of salt: under above-mentioned condition, organic phase is concentrated to net weight 40 and restrains.Enriched material dilutes with ethyl acetate, and the azeotropic stripping obtains 44.9 gram drying solution.Then solution is divided into three parts, 1/3rd solution concentration to 14 gram (about 6.83 gram free alkalis).Consider the residual solvent in the product enriched material, in enriched material, add the ethyl acetate (40 milliliters) of q.s and ethanol (18.7 milliliters) so that in the solution ratio of ethanol and ethyl acetate be 1/3.5, dilution factor be 12.3 milliliters/restrain product.Solution is refluxed and with ethyl acetate (the about 30.7 milliliters) solution of 0.5N HCl with pH regulator to 3.5.Now, the ratio of ethanol and ethyl acetate is approximately 1/4.3 in the solution, and dilution factor is approximately 14.5 milliliters/gram product.With the solution cool to room temperature and stirred 15 hours, this moment solution cool off in ice bath and 0 ℃ of stirring 3 hours.Filter slurries then, with cold 1: 4 ethanol/ethyl acetate (10 milliliters) washing crystal.Product is in vacuum, and 50 ℃ of following dried overnight obtain the white crystalline solid of 5.5 grams (75%), fusing point 188.8-191.0 ℃.C ₂₇H ₂₉ClN ₄O ₃Calculated value: C, 65.78; H, 5.93; Cl, 7.19; N, 11.36.Ultimate analysis value: C, 65.59; H, 6.12; Cl, 7.25; N, 11.36.

Vigorous stirring contains the biphasic system of MTBE (80mL), and the pH regulator of the acidic aqueous water extract that above processing is obtained with 1N NaOH solution is to 12-13.Separate each layer, organic extract liquid Na ₂SO ₄Drying is filtered and the concentrated solid, yield 80-90% of obtaining.Embodiment 6: by (S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-3-pyridine nitrile hydrochloride prepares free alkali compound 6

In three neck round-bottomed flasks of nitrogen inlet, mechanical stirrer and thermopair are housed, put into (S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-3-pyridine nitrile hydrochloride (10 grams, 20.3mmol) and DMSO (70 milliliters).Reaction is at room temperature stirred 30 minutes to guarantee dissolving fully.Solution is placed cooling bath, and in 10 minutes, add 2.2N NaOH (10 milliliters 22mmol), keep temperature to be lower than 35 ℃.Stir after 30 minutes, in 40 minutes, add 30%H with seven five equilibriums ₂O ₂The aqueous solution (2.71 milliliters) keeps temperature to be lower than 35 ℃ simultaneously.Afterreaction was finished in 30 minutes.In 15 minutes, in reaction mixture, divide 4 parts to add Na ₂SO ₃The aqueous solution (1.60 gram, 12.7mmol is dissolved in the solution that forms in 35 ml waters), keep temperature of reaction to be lower than 35 ℃ simultaneously.After 15 minutes, check is less than superoxide in the thick solution.Add ethyl acetate (75 milliliters), solution stirring 30 minutes.Add ethyl acetate (100 milliliters) and H in addition ₂O (100 milliliters), and separate each phase.Organic phase H ₂O (100 milliliters) washs.Merge water, it is stripped, gained organic phase and original organic part merging with ethyl acetate (100 milliliters).Part solution (10%) keeps the thick free alkali as compound 6, obtains compound 6 by removing to desolvate.By the EFI ionization massspectrum compound 6 is analyzed; Molecular ion peak is 475.0 (molecular weight of calculating is 474.56).

Remaining organic extract liquid that merges is by being concentrated to net weight 18-20 gram at 50 ℃ of rotary evaporations.Residue is dissolved in ethyl acetate and the ethanol, makes that ethyl acetate/alcoholic acid ratio is 7: 1, and the concentration of free alkali is 8 milliliters/gram.Measure the percentage composition of water by Karl Fischer titration.Maximum water content during the crystal maximum output should be between 1.0-2.0%w/w.Solution is heated to backflow back adding Glacial acetic acid, and (1.10 grams 18.3mmol), occur planting brilliant in the solution.The slurries cool to room temperature also stirs and spends the night.0 ℃ of cooling after 2 hours, filtering product, filter cake is with the washing of ethyl acetate/ethanol (20 milliliters) of 7: 1, solid air drying 1 hour.Product spends the night 70 ℃ of vacuum-dryings, obtains 7.4 gram white crystalline solid products (purity 96%, yield 86%), fusing point 137 (contraction), 143.1-153.2 ℃.C ₂₇H ₃₀N ₄O ₄-C ₂H ₄O ₂Calculated value: C, 65.15; H, 6.41; N, 10.48; Ultimate analysis value: C, 65.55; H, 6.37; N, 10.88.Embodiment 7: the preparation of the salt of compound 6 Hydrochloride

Reflux down, to compound 6 free alkalis (2.0 grams, add in ethanolic soln 4.2mmol) HCl ethanolic soln (7.04 milliliters 0.6M solution, 4.22mmol).Add triethylamine or HCl as required, modestly with its pH regulator to 3.0.Kind of a crystalline substance appears in solution, and makes its cool to room temperature, stirs this moment and spends the night.Slurries be cooled to 0 ℃ 2 hours, filter, filtrate is with 3 milliliters cold washing with alcohol.White solid vacuum-drying under 50 ℃/5Torr is spent the night, and obtains 1.90 gram white solids (yield 88%), fusing point 207.0-211.0 ℃.C ₂₇H ₃₀N ₄O ₄The calculated value of-HCl: C, 63.46; H, 6.11; N, 10.96.Ultimate analysis value: C, 63.00; H, 6.19; N, 11.04. Acetate

Reflux down, to compound 6 free alkalis (2.0 grams, add in ethyl acetate 4.2mmol) (14.0 milliliters) solution acetate (278 milligrams, ethanolic soln 4.6mmol) (2.0 milliliters).Kind of a crystalline substance appears in solution, and cool to room temperature and stirring are spent the night at leisure.Slurries filter 0 ℃ of cooling 2 hours, and filtrate is washed with 7: 1 cold ethyl acetate/ethanol (4 milliliters).White solid vacuum-drying under 70 ℃/5Torr is spent the night, and obtains 1.94 gram white solids (yield 86%), fusing point 148.7-154.2 ℃.C ₂₇H ₃₀N ₄O ₄-C ₂H ₄O ₂Calculated value: C, 65.15; H, 6.41; N, 10.48.Ultimate analysis value: C, 65.72; H, 6.30; N, 11.06.

The X-ray powder diffraction of other various compounds with similar methods preparation shows that it is a crystalline solid. The 4-hydroxy benzoate

(12.53 grams, hot ethanol 90.7mmol) (171 milliliters) solution join the free alkali of backflow, and (42.8 grams, in ethyl acetate 90.2mmol) (343 milliliters) solution, gained solution refluxed 15 minutes with the 4-hydroxy-benzoic acid.Solution dewaters through decant, isolates a small amount of undissolved residue and kind of a crystalline substance occurs.Solution is cool to room temperature and stir and to spend the night at leisure.Slurries be cooled to 0 ℃ 2 hours.Cross filter solid, with 2: 1 cold ethyl acetate/ethanol it is washed, vacuum-drying is spent the night under 70 ℃/5Torr, obtains 45.4 gram white solids (yield 82%), and fusing point 148.3-150.5, this solid solidify and 159-186.9 ℃ of fusion again.Wet cake and dried solid X-ray powder diffraction show that all it is an xln. The hydrochlorate

To the free alkali of backheat (250 milligrams, add in methyl alcohol 0.53mmol) (2.5 milliliters) solution heat oxalic acid (37.8 milligrams, methyl alcohol 0.42mmol) (2.5 milliliters) solution.Vlil 1 hour.Solution is cool to room temperature and stir and to spend the night at leisure.Slurries be cooled to 0 ℃ 2 hours.Filter out solid, with the cold methanol washing, dried overnight under 70 ℃/5Torr obtains 194 milligrams of white solids (65%), 214.9 ℃ of fusing points.Wet cake and dried solid X-ray powder diffraction show that all it is an xln.Embodiment 8:2-[4-(2-amino-2-methyl propyl group) phenoxy group]-3-pyridine carboxylic acid ethyl ester synthetic

(55.18 grams 244.9mmol) join among the KOH of 5.05N (97.2mmol, 2.0 equivalents) 4-(2-amino-2-methyl propyl group) phenol.Mixture heating up to 50 ℃ obtains uniform yellow solution.(10.7 grams, 122mmol), mixture heating up is to reflux (about 100 ℃) to add chlorobenzene (1104 milliliters) and N,N-dimethylacetamide.Via Dean-Stark water trap azeotropic removal of water.In the time of about 125 ℃, begin to form solid.When the still temperature reached 132 ℃, water was removed, and reaction mixture is a kind of thick slurries (needing mechanical stirring) that still can stir.Remove the Dean-Stark water trap, remove 100 milliliters of other chlorobenzenes.In slurries, add dry chlorobenzene (50 milliliters), add 2-chlorine apellagrin ethyl ester (50.0 grams, chlorobenzene 269mmol) (50 milliliters) solution subsequently.The heating slurries are finished (about 24 hours) up to reaction under refluxing.Reaction is carried out in the process, and slurries are thinning and become cream-coloured.Behind the cool to room temperature, in mixture, add entry (385 milliliters) and 1N NaOH (25 milliliters, 0.1 equivalent), separate each phase.Water (285 milliliters) washing organic phase, solution concentration is used for next step reaction to net weight 700 grams (HPLC detects, effect 9.83%, yield 89%).Embodiment 9:2-[4-(2-amino-2-methyl propyl group) phenoxy group]-3-pyridine carboxylic acid ethyl ester, the preparation of acetate

2-[4-(2-amino-2-first propyl group) phenoxy group]-(10.3 grams 32.8mmol) are dissolved in ethyl acetate (52 milliliters) and the heptane (41 milliliters) 3-pyridine carboxylic acid ethyl ester, and solution is heated to reflux state.(1.97 grams, 38.8mmol), kind of crystalline substance, a cool to room temperature at leisure appear in solution to add acetate.After at room temperature 30 minutes, slurries are cooled to 0 ℃ and stirred 1.5 hours.Filtering product with 1: 1 cold ethyl acetate/heptane (20 milliliters) washing, 50 ℃ of following vacuum-dryings 18 hours, obtains 10.29 gram products (purity 97%, yield 81%), fusing point 122.9-124.5 ℃.Embodiment 10:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-3-pyridine carboxylic acid ethyl ester, and the preparation of 4-hydroxy benzoate

4-[(2S)-the oxyethane ylmethoxy]-1H-indoles (9.00 grams, 47.6mmol) join 2-[4-(2-amino-2-methyl propyl group)-phenoxy group]-the 3-pyridine carboxylic acid ethyl ester (chlorobenzene solution of the 10.1%w/w of 162.8 grams, 52.3mmol) solution in, gained vlil 37 hours.When epoxide ran out of, solution was cooled to 80 ℃, the 4-hydroxy-benzoic acid that disposable adding is 50 ℃ (6.57 grams, 2B-3 ethanol 47.6mmol) (34 gram) solution.At 70 ℃, uniformly solution occur kind brilliant, and cool to room temperature at leisure under agitation.0 ℃ was stirred down after 1 hour, filtered slurries, with chlorobenzene (3 * 50 milliliters) washing, and 70 ℃ of vacuum-dryings 18 hours, obtained 20.82 gram white solid products (yield 68%), fusing point 172.4-175 ℃.C ₂₉H ₃₃N ₃O ₅-C ₇H ₆O ₃Calculated value: C, 67.38; H, 6.12; N, 6.54; Ultimate analysis value: C, 67.18; H, 6.07; N, 6.77.Embodiment 11:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-the 3-pyridine carboxylic acid, the preparation of ethyl ester

Stir down, should inscribe a compound (17.1 restrain, 4-hydroxy benzoate 26.6mmol) join methyl tertiary butyl ether (200 milliliters, MTBE) with the mixture of 1N NaOH (7 5 milliliters) in.When all initial solids had all dissolved, residue was easy on a small quantity by filtering the deep green solid that (Whatman 1# paper) is removed.With salt solution (2 * 30 milliliters) washing organic phase, and use anhydrous MgSO ₄Dry.Remove by filter siccative.Following with methyl alcohol exchange MTBE solvent, by the rotary evaporation concentrated solution, again residue is dissolved in the methyl alcohol, and then concentrates.Repeat this method, make residue be dissolved in anhydrous methanol and be directly used in subsequent reaction.Embodiment 12:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-the 3-picolinamide, the preparation of acetate

(S)-2-[4-2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-3-pyridine carboxylic acid ethyl ester (13.2 grams, methyl alcohol 26.1mmol) (66 milliliters) solution impouring pressurization and replace with 25 pounds of/square inch (psig) ammonias in 3 times the container.Then, the pressure in the container is adjusted to 50psig with ammonia, and described yellow solution stirred 18 hours at 24 ℃.Up to flask in remaining 25 except that desolvating with ammonia by rotary evaporation restrains.Add ethanol (100 milliliters 2B-3), are removed by rotary evaporation once more and desolvate up to residue 26 grams.Alcoholic acid adds and evaporation repeats more than 3 times to be ethanol with solvent replacing and to remove ammonia.After last the evaporation, take by weighing the interior material of flask 25.0 grams and restrain free alkalis and 12.5 gram ethanol as 12.5 of theory.Add ethyl acetate (87.7 milliliters) and H ₂O (1.0 milliliters) is heated to backflow with solution.(1.73 grams, 28.8mmol), kind of a crystalline substance appears in solution to add acetate.After 1 hour, no longer white mixture is heated.24 ℃ stir 1 hour after, collect white solid and with 7: 1 ethyl acetate by vacuum filtration: ethanol (20 milliliters) washed twice, and with 7: 1 ethyl acetate: ethanol 10 (milliliter) washs 1 time.Vacuum-drying is spent the night under 50 ℃/5Torr, obtains 11.6 gram white solids (purity 96.9%, yield 97%), fusing point 157-158 ℃.C ₂₇H ₃₀N ₄O ₄Calculated value: C, 65.15; H, 6.41; N, 10.48.Ultimate analysis value: C, 65.01; H, 6.28; N, 10.26.Embodiment 13:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-the 3-pyridine carboxylic acid, ethyl ester, and the preparation of 4-hydroxy benzoate

4-[(2S)-the epoxy ethyl methoxyl group]-1H-indoles (8.00 grams, 42.3mmol) join 2-[4-(2-amino-2-methyl propyl group)-phenoxy group]-3-pyridine carboxylic acid ethyl ester (14.4 grams, 46.5mmol) 2B-3 ethanol (80 milliliters) solution in, the gained vlil ran out of up to epoxide in 20 hours.Solution is cooled to 70-75 ℃, and (uniformly solution occurs kind brilliantly, and continues to stir 1 hour at 70-75 ℃ for 5.9 grams, 2B-3 ethanol 42.3mmol) (20 milliliters) solution once to add 70-75 ℃ 4-hydroxy-benzoic acid.Mixture is cooled to 26 ℃ and stirred 1 hour, is cooled to 5 ℃ of restir then 1 hour.By solid collected by filtration,,, obtain 21.8 gram white solid products (yield 80.4%), fusing point 174-176 ℃ 50 ℃ of vacuum-dryings 45 hours with 2B-3 ethanol (45 milliliters) washing.Embodiment 14:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-preparation of 3-pyridine carboxylic acid ethyl ester

Stir down, should inscribe a compound (40.0 restrain, 4-hydroxy benzoate 62.3mmol) join methyl tertiary butyl ether (350 milliliters, MTBE) and in the mixture of methyl alcohol (20 milliliters).Continue to stir and disperseed preferably up to solid in 90 minutes, add 1N sodium hydroxide (160 milliliters) and deionized water (40 milliliters) then.In case the solid dissolving then separates each layer, twice of the solution extraction of organic phase usefulness deionized water (120 milliliters) and sodium-chlor (8.0 gram).After being cooled to 0-5 ℃, filter with glassine paper, organic layer is concentrated to 80 milliliters under 40 ℃ and the 24-28 inch of mercury.Add methyl alcohol (160 milliliters) and volume is reduced to 80 milliliters once more.With methyl alcohol cumulative volume is adjusted to 240 milliliters, gained solution is directly used in subsequent reaction.Embodiment 15:(S)-2-[4-[2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-preparation of 3-picolinamide acetate

(S)-2-[4-2-[2-hydroxyl-3-(1H-indoles-4-base oxygen) propyl group amino]-the 2-methyl-propyl]-phenoxy group]-(31.4 grams, methyl alcohol 62.3mmol) (264 milliliters) solution pressurizes 3-pyridine carboxylic acid ethyl ester, and replaces 3 times with the 5psig ammonia.With ammonia the pressure in the container is adjusted to 5psig then, yellow solution stirred 22 hours at 40 ℃.Under 30-40 ℃ and 25 inches of mercury, volume is concentrated to 60 milliliters.Add methyl ethyl ketone (450 milliliters, MEK), under 40-50 ℃ and 25 inches of mercury, volume is reduced to 60 milliliters once more, add methylethylketone (200 milliliters) once more and volume reduced to 60 milliliters.At 15-20 ℃, with methylethylketone the cumulative volume of material is adjusted to 300 milliliters, filter with 20 microns sintered glass filter funnels, use the methylethylketone rinsing then, obtain cumulative volume and be 310 milliliters filtrate.Solution is heated to 65 ℃, at 65 ℃ of adding Glacial acetic acid (3.75 grams, methylethylketone 62.4mmol) (15 milliliters) solution.After kind of crystalline substance occurring, mixture stirred 90 minutes at 65 ℃, in 14 hours, stirs down it is cooled to 25 ℃ then.Mixture is cooled to 3 ℃ and stirred 1 hour.Collect slurries by filtering,,, obtain 30.3 gram white solid products (yield 90.9%), fusing point 156-158 ℃ 70 ℃ of vacuum-dryings 46 hours with methylethylketone (90 milliliters) washing.The preparation of embodiment 16:4-oxyindole and other R1-OH compound

Can be disclosed in J.Chem.Soc.1955:2412 (1955) and H.D.Porter and W.D.Peterson according to Davies and be disclosed in ＂ Organic Synthesis ＂, III accumulates volume, and 660 pages method prepares the 4-oxyindole.These reference all are hereby incorporated by.The actual conditions that is used to prepare the 4-oxyindole is as described below.A. prepare the 4-nitroindoline from 2-methyl-3-nitro aniline

Sodium Nitrite (20 grams, 0.29 mole) is dissolved in 50 ml waters.During near zero degree, all these solution join in the glacial acetic acid solution of 2-methyl-3-nitro aniline (20 grams, 0.13 mole) at once, with overhead stirrer vigorous stirring reaction solution.Precipitation appears when adding sodium nitrite solution immediately.Reaction is reached stir after the room temperature and spend the night.Leach precipitation and vacuum concentrated filtrate.Dark orange solids is suspended in the water, filters, and drying obtains 14-21 and restrains dark orange solids (yield 99%).B. prepare the 4-amino indole from the 4-nitroindoline

In the Parr hydrogenation vessel, heating is dissolved in ethanol (300ml) with 4-nitroindoline (12 gram) down.(palladium/carbon of 5% (12 gram) joins in the container.Reaction is pressurized to 50 PSI and shook 1 hour.TLC shows that product forms and significant loss.By the Celite filter reaction mixture.With methyl alcohol thorough washing catalyzer up to all products are all rinsed out.Concentrated filtrate obtains the lead solid, and it is dissolved in the ethyl acetate and through the silicon-dioxide liner and filters.Concentrated filtrate obtains filbert solid (9.6 grams, yield 97%).C. prepare the 4-oxyindole from the 4-amino indole

4-amino indole (9.6 grams, 0.072 mole) is dissolved in the 75 ml water solution that are contained in the gram of 7.2 in the reaction vessel vitriol oil.Be sealed to then in the stainless steel autoclave, be heated to 170 ℃ and spend the night.Reaction mixture comprises many black precipitates.With ethyl acetate with the water diluted reaction mixture and pack into and separate with distributing in the funnel.There is not water with the ethyl acetate extraction several times in water layer up to all products.Merge organic moiety, and use the salt water washing, use dried over mgso, filter, and be condensed into dun or black oil.By with it via the silicon-dioxide liner, with 50% ethyl acetate/hexane purifying mixture product, obtain white solid (3.3 gram, yield 33%).

The general method that utilizes the present invention to describe, those skilled in the art can prepare other R1-OH aryloxy compound and its salt similarly, compound 2,4 for example of the present invention and 8-13 (referring to

Embodiment 17, table 1).

Prepare compound 2,4 and 8 and it is analyzed by method as mentioned above by the EFI ionization massspectrum.The molecular ion peak of compound 2 is 476.0 (molecular weight of calculating is 475.55); Compound 4 is 508.0 (molecular weight of calculating is 507.61); Compound 8 is 492.24 (molecular weight of calculating is 492.01).Embodiment 17: use compound of the present invention in the injection of ox vena systemica

Using compound of the present invention at the ox body by intravenous injection can increase the serum non-esterified fatty acid and reduce serum urea.In this embodiment, be used for the Angus (angus) of this research/Angus hybridization calf, the starting weight of heifer and lot bull be about 282 pounds (128 kilograms) to 788 pounds (357.8 kilograms), it is ensphered in the hurdle 5 calves in every hurdle.At least 1 week tamed ox so that their adapt to the hurdle of institute's stable breeding before beginning one's study.

Calf quantity-unlimiting feeding every day raises twice, (approximately 6-15 pound (2.7-6.8 kilogram)/sky).During handling, in the morning, the feed time interleaving is raised to guarantee that all animals were all fed in about 1 hour before carrying out administration.In afternoon, ox feeds immediately after accepting the injection in afternoon and raises.

After gathering pre-treatment (T=0) blood sample on one's body from each animal, the morning 6:30 and afternoon 2:30 by jugular vein intravenous administration test compound, dosage is per kilogram 40ug.The application concentration of each test compound in treatment media is the 1.00-1.25 mg/ml, and treatment media is the mixture of Macrogol 200/water of 50/50.

Handle and gathered a blood sample (T+15min) in back 15 minutes.Calf gets back in separately the hurdle up to handle next time then, and handle next time greatly after 8 hours.Morning next day 6:30,24 hours blood sample (T+24h) after all calf acquisition process.Analyze the non-esterified fatty acid amount (NEFA) and the serum urea nitrogen content (SUN) of all blood samples.For each independent animal, relatively it handles the amount of back NEFA and SUN and the amount before the processing.The results are shown in table 1.

Table 1 structure Δ NEFA ^*Δ NEFA ^*Δ %SUN ^{* *}

15 minutes 24 hours 24 hours only is medium～0～0～0

Compound 6 40.7-1.44-47

Compound 7 134.1-4.2-9.7 * concerning each individuality, (T=0) compares with benchmark, the increase (micromoles per liter) (the NEFA value of NEFA value-T=0 of Δ NEFA=T+15min) of NEFA in animal blood when test compound is handled 15 minutes shown in using.This value is the mean value of five animals.* is concerning each individuality, and (T=0) compares with benchmark, the increase (micromoles per liter) (the NEFA value of NEFA value-T=0 of Δ NEFA=T+24h) of NEFA in animal blood when test compound is handled 24 hours shown in using.This value is the mean value of five animals.* * is concerning each individuality, and (T=0) compares with benchmark, SUN minimizing percentage ratio in animal blood when test compound is handled 24 hours shown in using.This value is the mean value of five animals. $\%\mathrm{\ΔSUN}=\frac{(T+24\mathrm{h\; SUN})-(T=0\mathrm{SUN})}{T=0\mathrm{SUN}}\×100\%$

From the variation of the amount of serum urea nitrogen shown in the table 1 as can be seen, after 3-acid amides regional isomer (compound 2,4, the 6 and 8) dispenser anabolic action 24 hours the time significantly greater than corresponding 5-carboxylic acid amides regional isomer (compound 1,3,5 and 7).Result by table 1 non-esterified fatty acid amount 15 minutes and 24 hours after dispenser as can be seen, compound 2,4,6 and 8 also have moderate steatolysis effect.

(compound 9-13) repeats above-described test with 2-acid amides regional isomer, and the result is as follows.Do not use 4-acid amides regional isomer in the test corresponding to compound 9-13.The results are shown in following table 2:

Table 2

Structure Δ NEFA ^*Δ NEFA ^*Δ %SUN ^{* *}

15 minutes 24 hours 24 hours

Can find based on the data that table 1 and 2 provides, when having amide group by 2 of B ring in the aryloxy propanol amine of structural formula (I) expression shown in above, can make compound have strong anabolism performance.The corresponding anabolism clearly low (table 1) that on 5, has the regional isomer of amide group.In addition, have found that, shown in above when having amide group on 3 of B ring in the aryloxy propanol amine of structural formula (I) expression, can make compound have moderate steatolysis performance.The regional isomer that the corresponding amide base is positioned on 5 then shows the steatolysis effect of more strengthening.Embodiment 18: the effect of compound 6 aspect muscle and lipid content

Find that in the research of 28 longicorns compound 6 can improve muscle content, reduces lipid content.32 Angus hybrid lot bulls are divided into heavy type (recombinating average initial body weight=1226 pounds (557 kilograms) most for 4) and light-duty (4 the lightest group, average initial body weight=1164 pounds (528 kilograms)) two groups by weight.The bull of castrating in every group divides 4 parts of processing (8/handle) with 6 influences for growth and carcass measurement of research oral administration compound, and feeding is butchered after 28 days immediately.Processing comprises a Comparative Examples (0.0 milligram of compound 6 per kilogram of body weight) and three other compounds 6 of level (LOW, 0.125 milligram of compound 6 per kilogram of body weight; MED, 0.250 milligram of compound 6 per kilogram of body weight; HIGH, 0.500 milligram of compound 6 per kilogram of body weight).Compound 6 mix with the ground corn as they every day feed fatten up feeding to give and castrate bull.The ground corn that bull accepts analog quantity of castrating of Comparative Examples adds material as fattening.Require to castrate bull before the feed of residual content and consume initial feed and fatten and add material issuing.Basal diet is commercially available feed (19.3%CP, DM yl).The all quantity-unlimiting supply of feed and water.Castrating bull encloses respectively in 12 feet * 48 feet the hurdle that independent feed bunk and automatic drinking bowl are housed.At the 28th day, will castrate that bull is weighed and in transport to the slaughterhouse butcher before blood sample collection and carry out carcass evaluation subsequently.

The live body performance perameter of the ox of handling with compound 6 is improved.LOW, MED and HIGH demonstrate the increase of the average daily gain (ADG, pound/sky) of 54%-73% compared with Comparative Examples, be respectively 6.31,7.07,6.74 and 4.08 pounds/day (2.86,3.21,3.06 and 1.85 kg/day) clearly; P＜0.0002; See Fig. 1.The dry-matter constant (P＞0.47) that day during the processing is taken in.Compare with Comparative Examples, LOW, MED, be improved (is respectively 4.36,4.19,4.18 and 7.04 to the efficiency of feed utilization of HIGH (every pound of weightening finish of pound feed); See Fig. 2).

Weightening finish in the carcass improves can pass through LOW, and MED obtains proof with HIGH with the Comparative Examples raising of specific heat genetic ability for carcass weight mutually (P＜0.0001), is respectively 848,855,854 and 781 pounds (384,388,388 and 355 kilograms) clearly (Fig. 3).After compound 6 processing, higher (F test: P=0.1138 that the percentage ratio of fattening also tends to; Handle: P＜0.05), the quadrature comparative descriptions has significant (P＜0.0043) low dosage steadily to respond when adding compound 6.The fat thickness at twelfth rib bone place does not have what difference (P＞0.78; Fig. 4), but LOW, and the area of longissimus muscle at the twelfth rib bone place of MED and HIGH increases 10.7-18.9% (P＜0.0068) with respect to Comparative Examples and (is respectively 13.5,14.3,14.5,12.2 in2s; Fig. 5).

Trunk is formed and is comprised % fat, % protein, and % moisture and % bone are used Hankins, O.G. and Howe, the equation that P.E.1946.US Department of Agriculture TechnicalBulletin No.926 pp.1-20 (Fig. 6) proposes calculates.In the processing of using any component, carcass composition does not have what difference (P＞0.12) statistically, but with the % fat of compound 6 processing than Comparative Examples less in number (about 1.2-2.7%).Yet, owing to use LOW, it is heavier that MED and HIGH handle the genetic ability for carcass weight that is observed, and therefore obviously (protein is respectively 115.8 than Comparative Examples bigger (P＜0.0036) for the yield that calculates or the pound (Fig. 6) of protein and moisture, 115.1,115.8,103.1 pound (52.6,52.3,52.6,46.8 kilograms); Moisture is respectively 389.2,384.7,393.4,34 5.3 pounds (176.7,174.7,178.6,156.8 kilograms)).

The meat scientist has carried out estimating and having measured the scoring of USDA (USDA) quality grade and streaky pork to carcass.USDA quality grade and streaky pork scoring all identical (P＞0.90) in the processing.Calculate finished product grade (YG) value (Fig. 7) from the measurement of necessary component.YG is the sign of retail stripping and slicing meat amount, and it is big more that the low more expression high value of value adapts to the meat amount.Compare with Comparative Examples, three YG with the example that compound 6 is handled trend towards lower (F test: P=0.0632; Handle: P＜0.09).Relatively the quadrature analysis of Comparative Examples, LOW, MED and HIGH shows along with compound 6 dosage increase the reduction of YG straight line, forms platform (P=0.0021 at last under MED and HIGH dosage; YG is respectively 3.14,2.76, and 2.51 and 2.46).The example of handling with compound 6 is with respect to Comparative Examples, and the structure scoring (Fig. 8) that is used for subjective tolerance muscle development degree is higher, and this carcass that shows that compound 6 handles is thicker than the muscle of Comparative Examples carcass, and muscle development is better.

Use several different measuring methods to measure the quality of longissimus dorsi muscle strip meat.Use Hunter a*, do not handle on the color and luster that b* and L* measure with not handling and do not have what difference (P＞.5), or kill the back and place the pH that measures after 14 days and also do not have what difference.The subjective colour of the longissimus dorsi muscle at after death about 24 hours twelfth rib bone places, texture and flintiness are measured and are also shown to handle and do not handle do not have what difference (F tests P＞0.07).

On 14 days meat, measured the Warner-Bratzler shearing force, (national cowboying NAB National Association 0f Broadcasters, " Standardized Warner-Bratzler Shear Force Proceduresfor Genetic Evaluation " (1994); Referring to people such as Wheeler, J.AnimalSci., 75,2423-2432, (1997)), it is a kind of ＂ flexibility ＂ predictor (value is low more, and is soft more) of machinery.Comparative Examples relatively, LOW, MED and HIGH, (F test: P=0.106) that the shear force of 14 days meat (be respectively 2.25,2.92,2.55 with 3.01 kilograms) has nothing different.The quadrature contrast of these 4 kinds of processing has shown that low dosage steadily responds (P=0.0294).Though it is higher on the shear force numeral of the meat of handling with compound 6 of castrating bull, but the shear force that observes is within 2.27-3.58 kilogram scope, people such as Boleman are at J.Anim.Sci.75:521-1524, think in 1997 that numerical value is ＂ softish ＂ at the meat of this scope, it is lower than need be considered to " tough and tensile " 5.90 kilograms.

In a word, compound 6 feedings are castrated bull efficiency of gain is improved, than the feed feeding of the same amount high 54-73% that increases weight.The carcass weightening finish is high more, shows that hot genetic ability for carcass weight is high more.Extra carcass weight mainly comes from the muscle development amount of increase.Streaky pork scoring, color and luster, pH and Warner-Bratzler shearing force by measuring 14 days strip meat of carcass as can be seen, the muscle development increasing amount all for the quality of meat without any tangible harmful effect.Embodiment 19: compound 6 is for the influence of weightening finish during last 14 days of young chicken vegetative period and food utilization efficiency

About 1500 Peterson-Hubbard, several huge male chickens are used for carrying out at random the whole group of design (Comparative Examples, 1PPM clenbuterol, 3PPM and 15PPM (milligram/kilogram feed) compound 6) of 4 kinds of processing.Testing installation comprises 36 hurdles, is divided equally into 6 groups.In the hurdle in processing is assigned randomly to every group.Each processing is made up of 6 hurdles, 10 chickens in every hurdle.

Several huge chickens come from Goshen, and the Pine Manor hatcher of In. at random is placed on about 40 chickens in one hurdle when receiving.When growing by 30 days, all chickens are all weighed, and select 15 the most close group interior average chicken.It is big up to 35 days to raise and train these chickens.That day of the 35th day, all remaining chickens were weighed once more, selected in every hurdle treatment stage that the chicken of mean value being used in 10 the most close group.In whole test, chicken is carried out quantity-unlimiting feeding feed and water.From the 1st day up to the 18th day, all chickens all feed the corn-soybean food of raising 23% crude protein.From the 18th day up to the 49th day, feed is changed into the corn-soybean food of 20% crude protein.Use 20% identical crude protein basal diet combination treatment feed.From the 35th day to the 49th day feed, use the processing feed.Calculate the feed intake in whole 14 days processing cycles.Finish that day (the 49th day) in test, chicken is weighed and is transported to Purdue University, West Lafayette, Indiana 47907, and U.S.A. meat laboratory was butchered in the 50th day and is carried out carcass measurement.Weigh hot trunk, fat pad and the internal organ of all animals.

Result of study is summarized in table 3.Data show, compare with clenbuterol, and compound 6 helps the increase of weightening finish during last 14 days of young chicken vegetative period and the raising of food utilization efficiency.Than Comparative Examples 3.17% weightening finish increase (P=0.0987) is arranged with 6 processing of 3PPM compound, handling with 15 PPM compounds 6 has 3.17% increase (P=0.0756) than Comparative Examples.The chicken that clenbuterol is handled demonstrates the increase (P=0.1430) than Comparative Examples high 2.38% in 14 days processing cycle.When treatment capacity was 3 PPM, compound 6 improved 2.50% (P=0.2936) with food utilization efficiency, when treatment capacity is 15 PPM, improved 3.00% (P=0.1957).The animal that clenbuterol is handled is compared with Comparative Examples, and food utilization efficiency improves 0.50% (P=0.7320).

The compound of high dosage test is carrying out the carcass evaluation proposition for the influence of weightening finish and food utilization efficiency by PurdueUniversity.For all processing, heat-obtaining trunk, internal organ and fat pad weight.The hot genetic ability for carcass weight of handling with test compound all has increase with respect to Comparative Examples.When handling with 3 PPM compounds 6 and 15 PPM compounds 6, hot genetic ability for carcass weight increases by 2.50% (P=0.0174) and 2.82% (P=0.0078) respectively.The hot genetic ability for carcass weight of handling with clenbuterol of example increases by 3.25% (P=0.0027).With respect to Comparative Examples, the example internal organ weight of handling with test compound all reduces.With the example that 3PPM compound 6 and 15PPM compound 6 are handled, internal organ weight reduces by 1.50% (P=0.3981) and 0.65% (P=0.7279) respectively.Clenbuterol makes internal organ weight reduce by 0.66% (P=0.7215).Can observe a kind of trend, that is, two kinds of processing all can increase fat pad weight.With the example that 3 PPM compounds 6 and 15PPM compound 6 are handled, fat pad weight increases by 9.68% (P=0.1069) and 4.09% (P=0.4814) respectively.

Table 3: growth performance and trunk characteristic

Handle	Dosage	Starting weight (kg)	Final weight (kg)	14 days total augment weights (kg)	Every hurdle feed is taken in (kg)	Feed conversion rate F/G
							Comparative Examples	??0PPM	??1.72	????2.98	????1.26	????25.16	????2.00
Clenbuterol	??1PPM	??1.73	????3.02	????1.29	????25.20	????1.99
							Compound 6	??3PPM	??1.72	????3.02	????1.30	????25.74	????1.95
Compound 6	??15PPM	??1.72	????3.02	????1.30	????25.25	????1.94

Handle	Dosage	The percentage ratio of fattening	Hot ketoboidies weight (g)	Internal organ weight (g)	Fat pad weight (g)
						Comparative Examples	??0PPM	????71.83	????2122.71	???287.36	????26.14
Clenbuterol	??1PPM	????72.77 **	????2191.64 **	???285.45	????26.86
						Compound 6	??3PPM	????72.43 *	????2175.69 *	???283.04	????28.67
Compound 6	??15PPM	????72.63 **	????2182.55 **	???285.49	????27.21

(60 chicken/processing), i.e. 6 hurdle/processing, 10 chicken/hurdles,

Peterson x Hubbard chicken

14 days processing cycles (35-49 days)

F/G is that every hurdle feed intake/total hurdle is heavy

20% crude protein ration

(* P＜0.05) and (* * P＜0.01) shows the difference embodiment 20 with Comparative Examples: compound 6 is for weightening finish during last 28 days of vegetative period of young chicken, food utilization efficiency and breast, the influence of whole piece leg weight

About 2500 Peterson-Hubbard, several huge male chickens are used for whole group of design carrying out 4 kinds of processing (Comparative Examples, 3PPM and 15PPM (milligram/kilogram feed) compound 6) at random.Testing installation comprises two classifications, and each comprises 30 hurdles.Hurdle in each classification is divided into 6 groups, one group on five hurdles.Processing is assigned randomly in every group.Each processing is made up of 12 hurdles, 10 chickens in every hurdle.

Several huge chickens come from Goshen, and the Pine Manor hatcher of IN. at random is placed on about 40 chickens in one hurdle when receiving.When growing by 16 days, all chickens are all weighed, and select the chicken of 15 the most close group interior mean value.It is big up to 21 days to raise and train these chickens.That day of the 21st day, all remaining chickens were weighed once more, selected in every hurdle treatment stage that the chicken of mean value being used in 10 the most close group.In whole test, all adopt to chicken and carry out quantity-unlimiting feeding feed and water.From the 1st day up to the 18th day, all chickens all feed the grain-soybean food of raising 23% crude protein.From the 18th day up to the 49th day, feed is changed into the corn-soybean food of 20% crude protein.Use 20% identical crude protein basal diet to be mixed with the processing feed.From the 21st day to the 49th day feed, use the processing feed.At the 35th day, take by weighing intermediate weight.Calculate the feed intake in whole 28 days processing cycles.Finish that day (the 49th day) in test, chicken is weighed and be transported to PurdueUniversity meat laboratory, butchered in the 50th day and carry out carcass measurement.To all animal heat-obtaining trunks; Fat pad; Internal organ; Band bone, belt leather chest; Whole piece leg weight with band bone, belt leather.

Result of study is summarized in table 4.The chicken of handling with 3PPM compound 6 increases weight during first 14 days processing cycles than Comparative Examples increase by 3.22% (P=0.0395).The chicken of handling with 15PPM increases by 1.08% (P=0.7600) in identical cycle internal ratio Comparative Examples.In the end during 14 days the processing, the chicken of handling with 3PPM and 15PPM compound 6 increases by 6.67% (P=0.0064) and 1.90% (P=0.5028) respectively.In whole 28 days processing cycles, the weightening finish of the chicken of handling with 3PPM and 15PPM compound 6 increases by 5.03% (P=0.0051) and 1.01% (P=0.5419) respectively.

When measuring with feed/weightening finish, the feed conversion rate of two kinds of processing in 28 days processing cycles all presents the trend of raising.With respect to Comparative Examples, present the raising of 6.85% (P=0.1426) and 4.57% (P=0.3594) with the example of 3PPM compound 6 and 6 processing of 15PPM compound.

The carcass evaluation of hot genetic ability for carcass weight has significant increase with respect to Comparative Examples.Demonstrate the increase of 6.50% (P=0.0001) and 2.90% (P=0.0434) respectively with the animal of 3PPM compound 6 and 6 processing of 15PPM compound.Peel fat pad (comprising stomach fat and gizzard fat) from every chicken, and weigh to measure of the influence of these compounds to adipose hyperplasia.The compound 6 of two kinds of dosage is all less than significantly influence.When comparing with Comparative Examples, each is handled and all shows the trend that reduces internal organ weight.When handling, reduce by 1.54% (P=0.4004) and 3.29% (P=0.0764) respectively with 3PPM compound 6 and 15PPM compound 6.

Weigh and be with the chest muscle of bone and belt leather.The compound 6 of low dosage demonstrates 4.00% increase (P=0.0227), and high dosage then demonstrates 1.06% increase (P=0.5351).When handling with compound 6, the band bone, the weight of the whole piece leg of belt leather also has the increase of highly significant (when promptly handling with 3PPM and 15PPM, to increase by 10.63% (P=0.0001 and 5.60% (P=0.0003)) respectively.

In a word, when feeding from 21-35 days of lifetime when raising, male young chicken oral administration is bestowed compound 6 can not increase weightening finish significantly.But during 35-49 days, the compound 6 of 3PPM can make weightening finish increase (P＜0.01) significantly.When hello the phase of raising was analyzed to whole 28 days, increasing also was significant (P＜0.01).Fed the trend that the food utilization efficiency of raising all processing in the phase also presents raising at whole 28 days.All dosage all can make hot genetic ability for carcass weight significantly increase (P＜0.05).Under two kinds of dosage, the weight (P＜0.01) of the increase band bone of compound 6 equal energy highly significants, the whole piece leg of belt leather.The compound 6 of 3PPM dosage just can significantly increase the weight (P＜0.05) of the breast of band bone, belt leather.

Table 4: growth performance and trunk characteristic

Handle	Dosage (PP M)	Starting weight (kg) 21 days	Middle heavy (kg) 35 days	Eventually heavy (kg) 49 days	Weightening finish (kg) (d21-35) in 1 during this time	Weightening finish (kg) (d35-49) in 2 during this time	Total augment weight (kg) (d21-49)	Hurdle feed intake (kg)	Feed conversion rate F/G
										Comparative Examples	????0	????0.69	????1.62	????2.68	????0.93	????1.05	????1.99	????39.98	????2.19
Compound 6	????3	????0.69	????1.66 *	????2.78 **	????0.96 *	????1.12 **	????2.09 **	????41.22	????2.04
										Compound 6	????15	????0.69	????1.63	????2.70	????0.94	????1.07	????2.01	????39.09	????2.09

Handle	Dosage (PPM)	The percentage ratio of fattening	Hot ketoboidies heavy (g)	Internal organ heavy (g)	Fat pad heavy (g)	Band bone, belt leather chest heavy (g)	Band bone, belt leather whole piece leg heavy (g)
								Comparative Examples	????0	????69.85	??1873.8 ??1	??269.97	??50.71	??594.28	??601.67
Compound 6	????3	????71.14 **	??1995.5 ??8 **	??265.82	??51.67	??618.03 *	??665.64 **
								Compound 6	????15	????71.16 **	??1928.1 ??7 *	??261.08	??49.16	??600.55	??635.36 **

(120 chicken/processing), i.e. 12 hurdle/processing, 10 chicken/hurdles, Peterson x Hubbard 28 days processing cycles of chicken (21-49 days) F/G is that every hurdle feed intake/total hurdle weighs 20% crude protein corn-soybean ration (* P＜0.05) and (* * P＜0.01) and shows with the following example of formulations of the difference of Comparative Examples and only be to illustrate the present invention that purpose does not lie in and limits scope of the present invention by any way.Certainly, " activeconstituents " means compound in structural formula I or acceptable salt of its physiology or solvate.Embodiment 21: the cooperation additive of chicken Composition Weight percentageActiveconstituents 25 ground corns 74 sodium-chlor 1

100 embodiment 22: ruminating animal cooperates additive Composition Weight percentageActiveconstituents 30 ground Semen Maydiss 60 alfalfa meals 10

100 embodiment 23: the cooperation additive of pig Composition Weight percentageActiveconstituents 10 ground corns 88 mineral oil 2

100

Above composition mixes with the flowable cooperation additive that obtains doing, and it can mix so that contain the activeconstituents of the 20ppm that has an appointment in the final feed in certain proportion with typical animal-feed.For example, cooperate additive can join in the following pig growth ration, be used for pig expediently per os take this activeconstituents.Composition weight percentage pound/ton ground Semen Maydis 76.70 1534 soybean-cake flours, solvent-extracted, 19.35 387 lime carbonate, 1.20 24 Lin Suanergais of peeling, feed grade 1.20 24 salt (sodium-chlor) 0.50 10 trace mineral cooperates additive, AN-031 0.10 2 pig VITAMIN cooperates additive, SW-032 0.65 13 vitamin A cooperates additive, 3M USP unit/pound 3 0.05 1 hydroxyl methionine(Met) analogues, 93% 0.20 4 selenium cooperates additive 0.005 1Amounting to 100.00 20001 per kilograms cooperates additive to comprise: 50 gram manganese, in manganous sulfate; 100 gram zinc are in zinc carbonate; 50 gram iron are in ferrous sulfate; 5 gram copper are in cupric oxide; 1.5 gram iodine, in potassiumiodide and the highest 150 grams, minimum 130 gram calcium are in lime carbonate.2 per kilograms cooperate additive to comprise: 77161 IU vitamin D2s; 2205 IU vitamin-Es; 411 mcg riboflavins; 1620 milligrams of pantothenic acid; 2205 milligrams of nicotinic acid; 4.4 milligram vitamin B12; 441 milligrams of vitamin Ks; 19180 milligrams of choline; 110 milligrams of folic acid; 165 milligrams of Vit B6s; 110 milligrams of VITMAIN B1; 22 milligrams of vitamin Hs.3 per kilograms cooperate additive to comprise: 6 613 800 IU vitamin A.4 per kilograms cooperate additive to comprise 200 milligrams of selenium, in Sodium Selenite.

Embodiment 24: lamb feed ingredient percentage pound/ton yellow maize 61.00 1220.0 maize cob 20.00 400.0 dehydrated alfalfa grass meals 5.40 108.0 soybean-cake flours 8.00 160.0 urea; Feed grade 0.50 10.0 molasses, sugarcane 3.00 60.0 Dicalcium Phosphates 0.43 8.6 salt 0.30 6.0 calcium carbonate 0.14 2.3 trace mineral cooperates additive¹0.03 0.6 vitamin A+D ³Cooperate additive ²0.10 2.0 vitamin-Es cooperate additive ³0.10 2.0 activeconstituentss 1.00 20.0

100.00 2000.01 trace minerals cooperate additive to comprise: 2.5% manganese, in manganese oxide, 0.07% iodine, in potassiumiodide, 0.3% cobalt, in cobaltous carbonate, 0.5% bronze medal is in cupric oxide and 20.0% zinc, in zinc sulfate.2 every pound of vitamin A and D ₃Cooperate additive to comprise 2 000 000 USP unit vitamin A and 225750 USP unit vitamins Ds ₃3 every pound of vitamin-Es cooperate additive to comprise, 20 000 IU vitamin-Es. embodiment 25: young chicken fattening ration ingredient percetage by weight yellow maize 66.40 1328.00 animals that pound/ton grinds-vegetable fat 1.53 30.60 corn flour, (60%) 4.00 80.00 soya-bean cake, (48%) 19.19 383.80 fish meal-catfish 2.50 50.00 Dicalcium Phosphates 1.01 34.20 feather meals-moisture 2.50 50.00 calcium carbonate that grind, 0.83 16.60 salt, 0.30 6.00 vitamin cooperates additive¹0.50 10.00 trace minerals cooperate additive ²0.10 2.00 hydroxyl methionine(Met) analogues, 0.15 3.00 lysine hydrochloride 0.29 5.80

100.00 the VITAMIN of 2000.01 per kilogram complete feeds cooperates additive to comprise 3000 IU vitamin A, 900 ICU Vitamin D3 500,000 I.U/GMs, 40 milligrams of vitamin-Es, 0.7 the milligram vitamin K, 1000 milligrams of choline, 70 milligrams of nicotinic acid, 4 milligrams of pantothenic acid, 4 mcg riboflavins, 100 microgram vitamin B12,100 microgram vitamin Hs and 125 milligrams of Santoflexs.The trace mineral of 2 per kilogram complete feeds cooperates additive to provide 75 milligrams of manganese, 50 milligrams of zinc, 25 milligrams of iron and 1 milligram of iodine.Equivalence

Only use conventional test, it will be recognized by those skilled in the art the many equivalence that maybe can determine with specific embodiments of the present invention described herein.This equivalence is included in the following claim.

Claims (43)

1. compound of representing by following structural:

With the acceptable salt of its physiology, wherein:

R1 is for replacing or unsubstituted aryl;

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic; With

Ring A and ring B also are not substituted independently or are replaced by one or two substituting group.

2. the compound of claim 1, wherein compound is represented by following structural formula:

3. the compound of claim 2, wherein the R1 representative is selected from the group of following structural formula:

Wherein, ring C-ring I is replacement or unsubstituted independently.

4. compound of representing by following structural:

With the acceptable salt of its physiology, wherein the R1 representative is selected from following structural formula:

5. compound of representing by following structural:

With the acceptable salt of its physiology:

6. the ammonium chloride of claim 5 compound, ammonium oxalate, ammonium acetate or 4-hydroxy-benzoic acid ammonium salt.

7. compound of representing by following structural: With the acceptable salt of its physiology, wherein:

R1 is replacement or unsubstituted aryl,

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as nonaromatic heterocycle;

X is-CH-or-N-; With

Ring A and ring B also are not substituted independently, or replace with one or two substituting group,

Condition is that R1 replaces or unsubstituted carbazyl as X during for-CH-.

8. one kind promotes livestock animals to grow, improve the method for food utilization efficiency and/or lean meat production, comprises one or more compounds of being represented by following structural that give animal effective dose: With the acceptable salt of its physiology, wherein:

R1 is for replacing or unsubstituted aryl;

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic;

X is-CH-or-N-; With

Ring A and ring B are also independent not to be substituted, or is replaced by one or two substituting group,

Condition is that R1 replaces or unsubstituted carbazyl as X during for-CH-.

9. one kind promotes livestock animals to grow, improve the method for efficiency of feed utilization and/or lean meat production, comprises one or more compounds of being represented by following structural that give animal effective dose:

With the acceptable salt of its physiology, wherein:

R1 is replacement or unsubstituted aryl,

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic; With

Ring A and ring B also are not substituted independently or are replaced by one or two substituting group.

10. the method for claim 9, wherein said animal is a ruminating animal.

11. the method for claim 10, wherein said ruminating animal is a cow, bull, heifer or castrate bull.

12. the method for claim 9, wherein said animal is a poultry.

13. the method for claim 12, wherein said poultry is a chicken, turkey or duck.

14. a method that promotes the livestock animals growth, improves efficiency of feed utilization and/or lean meat production comprises a kind of compound of being represented by following structural that gives animal effective dose: With the acceptable salt of its physiology, wherein the R1 representative is selected from the group of following structural formula:

15. the method for claim 14, wherein said animal is a ruminating animal.

16. the method for claim 15, wherein said ruminating animal is a cow, bull, heifer or castrate bull.

17. the method for claim 14, wherein said animal is a poultry.

18. the method for claim 17, wherein said poultry is a chicken, turkey or duck.

19. a method that promotes the livestock animals growth, improves efficiency of feed utilization and/or lean meat production comprises a kind of compound of being represented by following structural that gives animal effective dose: With the acceptable salt of its physiology.

20. the method for claim 19, wherein said animal is a ruminating animal.

21. the method for claim 20, wherein said ruminating animal is a cow, bull, heifer or castrate bull.

22. the method for claim 21 comprises the ammonium chloride of using described compound, ammonium oxalate, ammonium acetate or 4-hydroxy-benzoic acid ammonium salt.

23. the method for claim 19, wherein said animal is a poultry.

24. the method for claim 23, wherein said poultry is a chicken, turkey or duck.

25. the method for claim 24 comprises the ammonium chloride of using described compound, ammonium oxalate, ammonium acetate or 4-hydroxy-benzoic acid ammonium salt.

26. the quantity of the meat that an increase obtains from livestock animals or improve the method for quality of the meat that obtains from livestock animals comprises one or more compounds of being represented by following structural that give animal effective dose:

With the acceptable salt of its physiology, wherein:

R1 is replacement or unsubstituted aryl,

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic; With

Ring A and ring B also are not substituted independently or are replaced by one or two substituting group.

27. the quantity of the meat that an increase obtains from livestock animals or improve the method for quality of the meat that obtains from livestock animals comprises one or more compounds of being represented by following structural that give animal effective dose:

With the acceptable salt of its physiology, wherein the R1 representative is selected from the group by following structural formula:

With

28. the quantity of the meat that an increase obtains from livestock animals or improve the method for quality of the meat that obtains from livestock animals comprises one or more compounds of being represented by following structural that give animal effective dose:

With the acceptable salt of its physiology.

29. the method for claim 28 comprises the ammonium chloride of using described compound, ammonium oxalate, ammonium acetate or 4-hydroxy-benzoic acid ammonium salt.

30. the quantity of the meat that an increase obtains from livestock animals or improve the method for quality of the meat that obtains from livestock animals comprises one or more compounds of being represented by following structural that give animal effective dose:

With the acceptable salt of its physiology, wherein:

R1 is replacement or unsubstituted aryl,

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic;

X is-CH-or-N-; With

Ring A and ring B also are not substituted independently, or are replaced by one or two substituting group,

Condition is when X is CH-, and R1 replaces or unsubstituted carbazyl.

31. a pharmaceutical composition, its comprise acceptable carrier on the pharmacology or thinner and by the compound of following structural formula (II) expression as activeconstituents:

With the acceptable salt of its physiology, wherein:

R1 is replacement or unsubstituted aryl,

R2 and R3 are hydrogen independently, C1-C4 straight or branched alkyl;

R4 and R5 are hydrogen independently, straight key of C1-C4 or key alkyl, or with the nitrogen-atoms that links to each other with it as non-aromatic heterocyclic; With

Ring A and ring B also are not substituted independently or are replaced by one or two substituting group.

32. be essentially the compound of any one chemical formula (II) of embodiments described herein 1 to 20.

33. a pharmaceutical composition comprises as the claim 1 to 7 of activeconstituents desired compound and physiologically acceptable diluent or carrier in any one.

34. any one desired compound of claim 1 to 7 is as the purposes of anabolic agent.

35. any one desired compound of claim 1 to 7 is as the purposes of moderate steatolysis agent.

36. the compound of chemical formula (II) of definition or the acceptable salt of its physiology are used to increase the quantity of the meat that obtains from domestic animal or improve purposes aspect the medicament of the interior quality that obtains from domestic animal in manufacturing in the claim 1.

37. a method for preparing any one desired compound in the claim 1 to 7 comprises and uses the epoxide of being represented by following structural (a) by the amine amination of following structural (b) expression,

Wherein, R1, R2, R3, R4, R5, X, A and B are as defined in claim 1; Wherein, can form the acceptable salt of its physiology if desired.

38. a method for preparing any one desired compound in the claim 1 to 7 comprises:

(a) use the epoxide of representing by following structural (A) by the amine amination of following structural (B) expression;

(b) hydrolysis cyano group is to form amide group;

Wherein, R1, R2, R3, X, A and B are as defined in claim 1;

Wherein, can form the acceptable salt of its physiology if desired.

39. a method for preparing any one desired compound in the claim 1 to 7 comprises:

(a) use the epoxide of representing by following structural (A) by the amine amination of following structural (B) expression;

Wherein R6 is methyl or ethyl; With

(b) with ammonia amidation COOR6 base;

Wherein, R2, R3, A and B as defined in claim 1, R6 is methyl or ethyl;

Wherein, can form the acceptable salt of its physiology if desired.

40. an animal-feed cooperates additive, it contains compound in structural formula I as defined in claim 1, or acceptable salt of its physiology or solvate, and a kind of suitable carrier.

41. the animal-feed of claim 40 cooperates additive, wherein compound in structural formula I as defined in claim 1 is compound 6 or acceptable salt of its physiology or solvate.

42. an animal feedstuff compositions, it comprises compound in structural formula I as defined in claim 1, or acceptable salt of its physiology or solvate, and a kind of suitable carrier.

43. the animal feedstuff compositions of claim 42, wherein said compound in structural formula I as defined in claim 1 are compound 6 or acceptable salt of its physiology or solvate.

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