CN1934104A - Compounds for the treatment of diseases - Google Patents
Compounds for the treatment of diseases Download PDFInfo
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- CN1934104A CN1934104A CN 200580009299 CN200580009299A CN1934104A CN 1934104 A CN1934104 A CN 1934104A CN 200580009299 CN200580009299 CN 200580009299 CN 200580009299 A CN200580009299 A CN 200580009299A CN 1934104 A CN1934104 A CN 1934104A
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- methyl
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Abstract
The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.
Description
Technical field
The present invention relates to the β2Ji Dongji of following general formula:
R wherein
1, R
2, n and Q
1Has following pointed meaning; And relate to the method for preparing this derivative, the purposes that comprises composition and this derivative of this derivative.
Background technology
Adrenoceptor is the member of the big super family of G protein coupled receptor.The adrenoceptor subfamily self is divided into α and β subfamily, and (β 1, β 2 and β 3 form the β subfamily by at least 3 kinds of receptor subtypes.These acceptors show different expression types in the tissue of mammiferous multiple systems and organ.Beta 2-adrenergic (β 2) acceptor is mainly expressed in smooth muscle cell (for example blood vessel, segmental bronchus, uterus or intestinal smooth muscle), yet (therefore beta 3 adrenoreceptor mainly expresses in fatty tissue, β 3 agonists might be applicable to treatment obesity and diabetes), and β1Shen Shangxiansunengshouti is mainly expressed (therefore, β 1 agonist mainly is used as the cardiac stimulation medicine) in heart tissue.
In the literature extensive review the physiopathology of airway disorders and treatment (bibliography can be referring to Bang Nisi (Barnes), P.J. chest (Chest), 1997,111:2, pp17S-26S; And cloth indigo plant (Bryan), people such as S.A., the expert on the research medicine advocates (Expert Opinionon investigational drugs), 2000,9:1 pp25-42), therefore, only comprises that in this article brief general introduction is to provide some background informations.
Glucocorticoids, anti-leukotrienes, theophylline, clo awns (cromones), cholilytic drug class and β2Ji Dongji constitute makes the medicament categories that is used for treating allergy and nonallergic airway disorders (such as asthma and chronic obstructive airway disease (COPD)) now.These treatment of diseases policies comprise fugitive and long-acting the suction β2Ji Dongji the two.β2Ji Dongji fugitive, that begin fast can make and be used for " rescue " bronchiectasis, yet long-acting form provides lasting alleviation and is used as supportive care.
The beta 2 adrenoreceptor that bronchiectasis is expressed on airway smooth muscle cells via excitement and mediating, it causes lax therefore bronchiectasis.Therefore, as functional antagonist, β2Ji Dongji can prevent and reverse the influence of (comprising leukotriene D (LTD4), vagusstoff, bradykinin, prostaglandin(PG), histamine and endothelin) of whole bronchoconstriction materials.Because beta 2 receptor is to be distributed in the respiratory tract so widely, so β2Ji Dongji can also influence the cell of other type that works in asthma.For example, report β2Ji Dongji and can stablize mastocyte.Suppress the release of bronchoconstriction material and may how to block principle for β2Ji Dongji by anaphylactogen, motion and the bronchoconstriction that freezing air brought out.Moreover β2Ji Dongji suppresses the cholinergic nerve transmission in the human airways, and it can cause the cholinergic reflectivity bronchoconstriction of attenuating.
Except air flue, also having established beta 2 adrenoreceptor also expresses in other organ and tissue, therefore, β2Ji Dongji (such as describing in the present invention those) can be used for treating other disease, such as (but being not limited to) neural system, premature labor, congestive heart failure exhaust, depressed, inflammatory and anaphylaxis dermatosis, psoriasis, hyperproliferative skin disease, glaucomatous those diseases; And to be used for the treatment of reducing stomach acidity be favourable illness, particularly stomach and peptide ulceration.
But, the purposes of many β2Ji Dongji is because its low selectivity, or exposes to the open air and mainly be restricted via the adverse side effect (vellication, tachycardia, palpitaition, fidgety) that drives that is used for mediating of the beta 2 adrenoreceptor of expressing air flue outside because of high general.Therefore, there is demand in the medicament of improveing in this class.
Therefore, still there is demand in the novel β2Ji Dongji with suitable pharmacological characteristic (for example, at effectiveness, selectivity, pharmacokinetics or acting duration).In this context, the present invention relates to novel β2Ji Dongji.
Summary of the invention
The present invention relates to the compound of general formula (1):
(CH wherein
2)
n-C (=O) Q
1Group or contraposition;
-R
1And R
2Be independently selected from H and C
1-C
4Alkyl;
-n is 0,1 or 2;
-Q
1For being selected from following group:
*-NR
8-Q
2-A or
*NR
8-Q
3,
Wherein
-p be 1 or 2 and q be 1 or 2;
-Q
2Be singly-bound or the optional C that replaces with OH
1-C
4Alkylidene group;
-R
8Be H or C
1-C
4Alkyl; And
-Q
3For choosing wantonly with NR
9R
10, OR
9Or the C of phenoxy group replacement
1-C
4Alkyl;
-A is selected from:
Zero C
3-C
10Cycloalkyl, this cycloalkyl is optional by one or more (being preferably 1,2,3 or 4) carbon atom bridge joint, and optional by a hydroxyl replacement;
05 to 6 element heterocycle groups (optional aromatic series), it comprises one or two heteroatomss that are selected from O, N or S, and it is chosen wantonly and is selected from C by one or two
1-C
4The substituting group of alkyl, benzyl and cyclopropyl methyl replaces; Or
Zero following groups
-R
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, C
1-C
4Alkyl, OR
9, SR
9, SOR
9, SCO
2R
9, halogen, CN, CF
3, OCF
3, SO
2NR
9R
10, COOR
9, CONR
9R
10, NR
9R
10, NHCOR
10With the optional phenyl that is replaced by OH;
-R
9And R
10Identical or different, and be selected from H or C
1-C
4Alkyl;
-R
11Be selected from H or OH; And
-R
12And R
13Identical or different, and be selected from H, optional with OR
9The C that replaces
1-C
4Alkyl, OR
9, C (=O) NH
2, C (=O) CH
3, N (CH
3) C (=O) CH
3, C (=O) OR
9, the optional phenyl that replaces with halogen, the optional pyridyl that replaces with CN, optional with C
1-C
4The di azoly that alkyl replaces; And
The tie point of-* representative and carbonyl;
Perhaps, if suitable, their pharmacy acceptable salts and/or its isomer, tautomer, solvate or isotopic variations.
The compound of formula (1) is the agonist of beta 2 receptor, and it is specially adapted to treat beta 2 mediated disease and/or symptom by demonstrating good effectiveness, particularly when via the inhalation route administration.
In this above-mentioned general formula (1), C
1-C
4Alkyl and C
1-C
4The alkylidene group representative contains the straight or branched group of 1,2,3 or 4 carbon atom.C
1-C
6Alkyl represent contains the straight or branched group of 1,2,3,4,5 or 6 carbon atom.If they carry substituting group or when occurring as the substituting group of other group, this also is suitable for, for example at O-(C
1-C
4) alkyl, S-(C
1-C
4) in the alkyl or the like.Suitable (C
1-C
4) example of alkyl has methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ...Suitable O-(C
1-C
4) example of alkyl has methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy ...
Wherein 2 carbon atoms or more a plurality of carbon atom are chosen the C by one or more carbon atom bridge joints wantonly
3-C
10Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, adamantyl, dicyclo [3.1.1] heptane, dicyclo [2.2.1] heptane, dicyclo [2.2.2] octane.Preferred cycloalkyl has cyclohexyl and adamantyl.
Non-limiting instance has morpholinyl, pyrrolidyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furyl, imidazolyl, isothiazolyl, thiazolyl, different azoles base, azoles base, pyridyl and pyrimidyl " to comprise one or two heteroatomic 5 to the 6 element heterocycle groups (optional aromatic series) that are selected from O, N or S ".
Preferably, this heterocyclic group comprises a nitrogen, two nitrogen or a nitrogen and a Sauerstoffatom.
Preferred aromatic series 5 to 6 element heterocycle groups are pyrazolyl and pyridyl.
Preferred non-aromatic 5 to 6 element heterocycle groups are morpholinyl, pyrrolidyl, piperidyl and piperazinyl.
At last, the halogen representative is selected from the halogen atom, particularly fluorine or chlorine of the group of being made up of fluorine, chlorine, bromine and iodine.
Hereinafter, the free linkage on phenyl, such as in following structure:
Meaning this phenyl can or contraposition be substituted.
The compound of formula (1):
Can use conventional program, such as utilizing following illustrated method to prepare, Q wherein
1, Q
2, R
1, R
2, A and n be as before to the definition (except as otherwise noted) of the compound of formula (1).
The amide derivatives of formula (1) can be by making the acid of formula (2):
With formula NHR
8-Q
2-A, NHR
8-Q
3Amine
Coupling and preparing.This coupling is usually in excessive this amine (as acid acceptor), with the coupler of routine (for example, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloric acid, N, N '-dicyclohexylcarbodiimide), choose wantonly under catalyzer (for example I-hydroxybenzotriazole hydrate or 1-hydroxyl-7-azepine benzotriazole) exists, and choose wantonly under tertiary amine base (for example N-methylmorpholine, triethylamine or diisopropyl ethyl amine) exists and carry out.This reaction can be carried out 1-24 hour under the temperature (room temperature) between 10 ℃ to 40 ℃ in suitable solvent (such as pyridine, dimethyl formamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), methylene dichloride or ethyl acetate).
Described amine can commerce be buied, and maybe can utilize the known ordinary method of those skilled in the art (coupling of for example reduction, oxidation, alkylation, transition metal mediation, protect, go protection or the like), from commercial material preparation of buying.
The acid of formula (2) can prepare from the ester of corresponding formula (4):
Wherein Ra is suitable acid protecting group, is preferably (C
1-C
4) alkyl, it comprises (but being not limited to) methyl and ethyl; Prepare acid according to any method well-known to those having ordinary skill in the art from ester, and do not change the remainder of this molecule.For example, this ester can be by handling with the aqueous solution of acid or alkali (for example hydrogenchloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), (for example choose wantonly in solvent or solvent mixture, water, 1,4-two alkane, tetrahydrofuran (THF)/water) exist down, under the temperature between 20 ℃ to 100 ℃, hydrolysis 1 to 40 hour.
The ester of formula (4) can be by the formula of removing (5) the phenol blocking group of compound prepare, wherein PG is defined as suitable phenol blocking group, is typically alkyl or alkoxyl group ether (for example, methyl, benzyl, methoxymethyl) and is preferably benzyl:
Be suitable for realizing that this de-protected reagent is described in T.W. Green Buddhist nun (Greene); blocking group in organic synthesis (Protective Groups in Organic Synthesis); in the textbook of (press between A. Willie-science (Wiley-Interscience Publication), 1981).In typical program, when PG represents benzyl, this can be by (for example using appropriate catalyst, palladium on palladium hydroxide or the activated carbon), in suitable solvent (such as ethanol or methyl alcohol), in the hydrogen environment, choose in elevated pressure (for example 60psi) down and between the temperature of room temperature to 60 ℃ hydrogenation 8-24 hour and realize wantonly.
Moreover, can appropriate catalyst (for example, palladium hydroxide) and ammonium formiate as hydrogen source, in suitable solvent (such as ethanol) and between the temperature of room temperature to 60 ℃, use transfer hydrogenation.
The ester of formula (5) can be by making formula (6) the bromide of amine (wherein Ra and n are as previously defined) and formula (7) react and prepare:
In typical program, with the amine of formula (6) and the bromide of formula (7), choose wantonly in solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, THF) exist down, choose wantonly in suitable alkali (for example triethylamine, diisopropyl ethyl amine, salt of wormwood) and exist down, between 60 ℃ to 120 ℃ temperature, reacted 12 to 48 hours.Then, can use appropriate reductant (such as sodium borohydride or diisobutylaluminium hydride) to reduce the intermediate keto-amine that is produced.
The bromide of formula (7) can be from the ketone of formula (19):
By preparing with suitable bromine source bromination.In typical program, this ketone is with bromizating agent (Et for example
4NBr
3), in suitable solvent (such as THF and methyl alcohol), under room temperature, handled about 24 hours.
The ketone of formula (19) can commerce be buied.
The amine of formula (6) (R wherein
1Be Me and R
2Be H) can be prepared as (R) or (S) enantiomorph from the corresponding protected amine of formula (8):
Wherein Ra and n are as previously defined; And Rb and Rc represent any suitable substituents; so that HNRbRc be Chiral Amine (for example; Rb can be hydrogen and Rc can be α-Jia Jibianji); condition is that the key between N and Rb and N and Rc can use the standard method of the nitrogen-protecting group group of splitting easily to split; so that the unhindered amina of formula (5) to be provided; described standard method is such as T.W. Green Buddhist nun, those that find in the textbook of the blocking group in organic synthesis (press between A. Willie-science, 1981).
The amine of formula (8) can be by making formula HNRbRc amine and the reactive ketone of formula (9) be prepared into single diastereomer:
Wherein Ra, Rb, Rc and n are as previously defined.
In typical program, the ketone of formula (9) and the reaction of the amine of formula HNRbRc produce chiral intermediate, and it can pass through appropriate reductant (for example, formula NaCNBH successively
3SODIUM CYANO BOROHYDRIDE or formula Na (OAc)
3The sodium triacetoxy borohydride of BH), chooses wantonly to exist down and choose wantonly and have reduction down,, be the mixture of diastereomer so that the amine of formula (8) to be provided in acid catalyst (for example acetate) in siccative (for example molecular sieve, sal epsom).This reaction in solvent (such as tetrahydrofuran (THF) or methylene dichloride), was carried out between 20 ℃ to 80 ℃ temperature 3 to 72 hours usually.Then, make the product that is produced convert hydrochloride to, and optional crystallization from suitable solvent or solvent mixture (for example Virahol, ethanol, methyl alcohol, Di Iso Propyl Ether or Di Iso Propyl Ether/methyl alcohol), so that (8) of single diastereomer form to be provided.
The ketone of formula (9) (wherein n=1) can be by preparing through the aryl halide of palladium mediated formula (10) and the coupling of enolate or enolate coordinator:
Wherein Ra as previously defined and Hal represent halogen atom, it comprises (but be not limited to) bromine and iodine.
In typical program, (it passes through with formula Bu with the aryl halide and the enolization tin of formula (10)
3The methanolizing tri-n-butyl tin of SnOMe is handled methylvinyl acetate and generation on the spot), in suitable palladium catalyst (acid chloride/formula Pd (OAc)
2/ P (O-Tol)
3The tri-o-tolyl phosphine) exist down, in non-polar solvent (for example toluene, benzene, hexane), react.Preferably, this is reflected between 80 ℃ to 110 ℃ temperature and carried out 6 to 16 hours.
The aryl halide of formula (10) can obtain by the respective acids of esterification formula (11):
Wherein Hal as previously defined; Prepare ester according to any method well-known to those having ordinary skill in the art from acid, and do not change the remainder of this molecule.
In typical program, with the acid of formula (11) and the alcoholic solvent of formula RaOH (wherein Ra is as previously defined), exist down in acid (such as hydrogenchloride), under the temperature (room temperature) between 10 ℃ to 40 ℃, reacted 8 to 16 hours.
The acid of formula (11) is commerical prod.
Can come the amine (R wherein of preparation formula (6) according to following scheme
1And R
2The two all is C
1-C
4Alkyl):
Scheme 1
R wherein
1, R
2And Ra as previously defined.
In typical program, use above-mentioned method, (the organo-metallic alkyl is such as R with " activated " alkyl to make the ester of formula (12)
2MgBr, R
2MgCl or R
2Li) reaction is to provide the corresponding tertiary alcohol of formula (13).
Then; with alkyl nitrile (for example acetonitrile, chloromethyl cyanide); have the tertiary alcohol of handling this formula (13) down in acid (for example sulfuric acid, acetate), so that shielded intermediate to be provided, its use successively the standard cracking method (such as in textbook, mentioned those) the nitrogen-protecting group group of splitting.Then, use and be described in the amino acid that method herein comes esterification to produce, so that the amine of formula (6) to be provided.
Perhaps, can come the amine (R wherein of preparation formula (6) according to following scheme
1And R
2The two all is C
1-C
4Alkyl and n=0):
Scheme 2
R wherein
1, R
2And Ra as previously defined.
In typical program, use above-mentioned method, (the organo-metallic alkyl is such as R with " activated " alkyl to make the ester of formula (14)
2MgBr, R
2MgCl or R
2Li) reaction is to provide the corresponding tertiary alcohol of formula (15).
Then; with alkyl nitrile (for example acetonitrile, chloromethyl cyanide); there is the tertiary alcohol of handling this formula (15) down in acid (for example sulfuric acid, acetate); so that shielded intermediate to be provided; its use successively the standard cracking method (such as in textbook, mentioned those) the nitrogen-protecting group group of splitting, so that bromo-amine (16) to be provided.
In the carbon monoxide environment, use RaOH (for example MeOH, EtOH) as solvent, under temperature (100 ℃) that raises and pressure (100psi), with suitable palladium catalyst (for example, [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II)) handle the bromo-amine (16) that is produced, so that the ester of formula (6) to be provided.
Can come the ketone (wherein n=2) of preparation formula (9) by the alkene of reduction-type (17):
In typical program, with palladium catalyst (for example, 10% palladium on the activated carbon), the olefin solution of the formula (17) in suitable solvent (for example methyl alcohol, ethanol, ethyl acetate), and in the hydrogen environment, stir, choose wantonly under elevated pressure (for example 60psi), between the temperature of room temperature to 60 ℃, handled 8-24 hour.
Can come the alkene of preparation formula (17) by coupling through the aryl halide of palladium mediated activated alkene and formula (18):
In typical program, with aryl halide (18) and vinyl ester (for example methyl acrylate), in suitable palladium catalyst (for example, formula Pd (PPh
3)
4Four (triphenyl phosphine) palladium (0), formula Pd (OAc)
2/ P (O-Tol)
3Acid chloride/tri-o-tolyl phosphine or formula dppfPdCl
2Chlorination (diphenylphosphino) ferrocenyl palladium) exist down, in suitable solvent (for example acetonitrile, N, dinethylformamide, toluene), choose wantonly in alkali (such as triethylamine) and exist down, between 40 ℃ to 110 ℃ temperature, coupling 8 to 24 hours.
The ketone of formula (18) is commerical prod.
Perhaps, the bromide that can be by making formula (7) and the amine of formula (20) react the compound of preparation formula (1);
R wherein
1, R
2, Q
1And n defines (except as otherwise noted) as the previous compound about formula (1).
In typical program, make the amine of formula (20) and the bromide of formula (7), choose wantonly in solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile) exist down, (for example choose wantonly in suitable alkali, triethylamine, diisopropyl ethyl amine, salt of wormwood) exist down, between 60 ℃ to 120 ℃ temperature, reacted 12 to 48 hours.Then, can use appropriate reductant (such as sodium borohydride or diisobutylaluminium hydride) to reduce the intermediate keto-amine that is produced.
Can mix the acid that suitable amine protecting group is rolled into a ball the formula (21) of P1 by making:
Amine coupling with following formula:
Come the acid amides of preparation formula (20).This coupling is usually in excessive this amine (as acid acceptor), with the coupler of routine (for example, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride or N, N '-dicyclohexylcarbodiimide), choose wantonly under catalyzer (for example I-hydroxybenzotriazole hydrate or 1-hydroxyl-7-azepine benzotriazole) exists, and choose wantonly under tertiary amine base (for example N-methylmorpholine, triethylamine or diisopropyl ethyl amine) exists and carry out.This reaction can between 10 ℃ to 40 ℃ temperature (room temperature), be carried out 1-24 hour in suitable solvent (such as pyridine, N, dinethylformamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), methylene dichloride or ethyl acetate).
This amine can commerce be buied, and maybe can utilize by the known ordinary method of those skilled in the art (coupling of for example reduction, oxidation, alkylation, transition metal mediation, protect, go protection or the like), from the material preparation that can commercially buy.
The acid that can come preparation formula (21) from the corresponding esters of formula (6).
Can from form preceding in acid or form after mix the acid that the ester (6) of the suitable P1 of amine protecting group group comes preparation formula (21), R wherein
1And R
2The two all is C
1-C
4Alkyl:
Wherein Ra is suitable acid protecting group, is preferably (C
1-C
4) alkyl, it comprises (but being not limited to) methyl and ethyl; According to preparing acid by any method well-known to those having ordinary skill in the art from ester, and do not change the remainder of this molecule.For example, this ester can be by the aqueous solution with acid or alkali (for example hydrogenchloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), (for example choose wantonly in solvent or solvent mixture, water, 1,4-two alkane, tetrahydrofuran (THF)/water) exist down, between 20 ℃ to 100 ℃ temperature, hydrolysis treatment 1 to 40 hour.
Can come the amine of preparation formula (6) according to following scheme, wherein R
1And R
2The two all is H:
Scheme 3
R wherein
1, R
2And Ra as previously defined.
In typical program, preferentially the acid with formula (22) is reduced into corresponding alcohol (23) under ester exists.This can also carry out with sodium borohydride or another kind of appropriate reductant subsequently originally by forming acylimidazole or blended acid anhydride.
Then, convert the primary alconol of this formula (23) to leavings group,, and replace with suitable amine nucleophile such as methanesulfonates, tosylate, bromide or iodide.Preferred nucleophile is an azides ion, and it can be reduced into primary amine via hydrogenation or triphenyl phosphine then.Another kind of nucleophile can comprise ammonia or alkylamine (such as benzylamine or allylamine), and the cracking alkyl is to provide this amine subsequently.
For some step of the method for above-mentioned preparation formula (1) compound in this article, the potential reaction functional group of reacting is not wanted in protection, and this blocking group of cracking subsequently may be essential.Under these circumstances, can use the blocking group of any compatibility.Particularly; can use such as by the T.W. Green Buddhist nun (blocking group in organic synthesis; A. press between Willie-science; 1981) or by P.J. bandit Xin Siji (Kocienski) (blocking group (ProtectingGroups); the turtledove lattice are examined Fu Leige (Georg Thieme Verlag), 1994) described those protections and go guard method.
For example, in aforesaid method, the bromine of formula (7) can be replaced by the bromine through protection of following formula:
This bromide can the racemize mode, uses reductive agent (such as sodium borohydride), prepares in suitable solvent (such as ethanol).Moreover this alcohol can be prepared as (R) or (S) enantiomorph according to abundant description method (tetrahedron fast soon (Tetrahedron Letters), 1994,35 (50), 9375) in the literature.
Then, can come the compound of acquisition formula (I) by the compound that removes to protect following formula:
Wherein the suitable pure blocking group of PG representative be typically silyl (such as TBDMS or TMS), and TBDMS is preferred.
This goes protection to carry out according to the method that is described in the standard textbook (such as " blocking group in organic synthesis " (press between A. Willie-science, 1981) of T.W. Green Buddhist nun).In typical program, in methanol aqueous solution, under about 45 ℃, handle the compound (wherein PG represents TBDMS) 18 to 42 hours of formula (24) with the normal Neutral ammonium fluoride of 10-18.It is the triethylamine trihydrofluoride of monovalent that another kind removes to protect reagent, in tetrahydrofuran (THF) or suitable solvent, and in room temperature following 12 hours.
Above-mentioned reaction and in preceding method the preparation of the raw material of employed novelty all be that routine and suitable reagent and its carry out or reaction conditions for preparing and the program that is used for separating the product of wanting, the reference precedent and the example and preparation will be known to one skilled in the art.
Similarly, can come purifying according to the multiple method of knowing (such as for example crystallization or chromatography)
The compound of formula (1) and the intermediate for preparing it.
Embodiment
In a preferred embodiment of the invention, Q
2Be singly-bound.
In a preferred embodiment of the invention, A is selected from morpholinyl, pyrrolidyl, piperidyl, piperazinyl or pyrazolyl, and it is optional by methyl substituted.
In a preferred embodiment of the invention, A is selected from optional by one or two C
1-C
4The pyrazolyl that alkyl replaces.
In a preferred embodiment of the invention, Q
1For
*-NR
8-Q
3
In a preferred embodiment of the invention, Q
1For being selected from following group:
In preferred embodiments, Q
1Be following groups:
R wherein
11And R
13Be H, and R
12For choosing wantonly with C
1-C
4Pyridyl or di azoly that alkyl replaces.
The compound of the formula (1) of group more preferably:
(CH wherein
2)
n-C (=O) Q
1Group or contraposition;
-R
1And R
2Be independently selected from H and C
1-C
4Alkyl;
-n is 0,1 or 2; And
-Q
1For being selected from following group:
And
*-NR
8-Q
2-A group, wherein p is 1 or 2, Q
2Be C
1-C
4Alkylidene group, R
8Be H or C
1-C
4Alkyl and A are pyridyl, C
3-C
10Cycloalkyl, this cycloalkyl is optional by 1,2,3 or 4 carbon atom (being preferably 1 or 2 carbon atom) bridge joint, THP trtrahydropyranyl, piperidyl, tetrahydro thiapyran base or following groups:
-R
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, C
1-C
4Alkyl, OR
9, SR
9, SOR
9, SO
2R
9, halogen, CN, CF
3, OCF
3, SO
2NR
9R
10, COOR
9, CONR
9R
10, NR
9R
10, NHCOR
10And the optional phenyl that replaces with OH;
-R
9And R
10Identical or different, and be selected from H or C
1-C
4Alkyl; And
The tie point of-* representative and carbonyl;
Perhaps, if suitable, their pharmacy acceptable salts and/or its isomer, tautomer, solvate or isotopic variations.
The compound that preferably comprises following substituent formula (1):
Preferably, Q
1For
*-NH-Q
2-A group, wherein A is cyclopropyl, cyclohexyl, suberyl or adamantyl.
More preferably, Q
1For
*-NH-Q
2-A group, wherein A is cyclohexyl or adamantyl.
Preferably, A is for choosing wantonly with OR
9The naphthyl that replaces.
Preferably, R
8Be H or CH
3More preferably, R
8Be H.
Preferably, Q
1For:
R wherein
3, R
4, R
5And R
6Be H.
Preferably, Q
1For
*-NH-Q
2-A group, wherein A is a following groups:
R wherein
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, C
1-C
4Alkyl, OR
9, SR
9, halogen, CN, CF
3, OCF
3, SO
2NR
9R
10, COOR
9, CONR
9R
10, NR
9R
10, NHCOR
10And the optional phenyl that replaces with OH, condition is R
3To R
7There are at least 2 to be H;
R wherein
9And R
10Identical or different, and be selected from H or C
1-C
4Alkyl.
More preferably, Q
1For
*-NH-Q
2-A group, wherein A is a following groups:
R wherein
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, CH
3, OCH
3, OCH
2-CH
3, SCH
3, halogen, CF
3, condition is R
3To R
7There are at least 2 to be H.
In the above-claimed cpd group, preferred especially following substituting group:
Q
2For-CH
2-,-(CH
2)
2-,-(CH
2)
3-,-CH (CH
3)-,-CH
2CH (CH
3)-or (CH (CH
3)
2)-, be preferred-CH
2-.
R
1Be H or C
1-C
4Alkyl and R
2Be C
1-C
4Alkyl.More preferably R
1Be H or CH
3And R
2Be CH
3
N is 1.
R
1Be H, R
2Be CH
3And n is 1.
Can be preferred according to the following compounds of method preparation disclosed herein:
N-benzyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
N-cyclopropyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1R, 2S)-2-(methylol) cyclohexyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-morpholine-4-base propyl group) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(pyridine-2-ylmethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-morpholine-4-base ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-sec.-propyl ethanamide;
N-(4-benzyl chloride base)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[2-(dimethylamino) ethyl] ethanamide;
N-[2-(diethylamino) ethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-(dimethylamino) propyl group] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-amyl group ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-tetramethyleneimine-1-base ethyl) ethanamide;
N-(2, the 4-dichloro benzyl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
N-(3, the 4-dichloro benzyl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-methoxy-benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-hydroxyethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-propyl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-methoxy-propyl) ethanamide;
N-cyclobutyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1R)-and 1-(1-naphthyl) ethyl] ethanamide;
N-2,3-dihydro-1H-indenes-1-base-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[2-(1-methylpyrrolidin-2-yl) ethyl] ethanamide
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-luorobenzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-phenyl butyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-methoxy-benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-ethoxycarbonyl propyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3,4,5-trimethoxy benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[4-(trifluoromethyl) benzyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[2-(trifluoromethyl) benzyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3, the 5-dimethoxy-benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-phenoxy group ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 2-hydroxyl-1-methylethyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 1-(methylol)-2-methyl-propyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S, 2S)-1-(methylol)-2-methyl butyl] ethanamide;
N-[(1R)-1-benzyl-2-hydroxyethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1R)-and 1-(methylol) propyl group] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 1-(methylol)-2, the 2-dimethyl propyl] ethanamide;
N-[(1S)-2-cyclohexyl-1-(methylol) ethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-propoxy-ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-hydroxy-cyclohexyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-propoxy-propyl group) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-ethyl-N-(2-hydroxyethyl) ethanamide;
1-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl } piperidines-4-methane amide;
5-{2-[(2-{3-[2-(4-ethanoyl piperazine-1-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
5-{2-[(2-{3-[2-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
N-benzyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-methylacetamide;
5-(1-hydroxyl-2-{[2-(3-{2-[4-(2-hydroxyethyl) piperazine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
5-(2-{[2-(3-{2-[4-(4-chloro-phenyl-)-4-hydroxy piperidine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino }-the 1-hydroxyethyl) benzene-1, the 3-diphenol;
5-{2-[(1,1-dimethyl-2-{3-[2-(4-methylpiperazine-1-yl)-2-oxoethyl] phenyl } ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-methyl-N-(2-phenylethyl) ethanamide;
5-{2-[(1,1-dimethyl-2-{3-[2-oxo-2-(4-pyridine-2-base piperazine-1-yl) ethyl] phenyl } ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-(dimethylamino) propyl group]-the N-methylacetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-hydroxyethyl)-N-propyl acetamide;
N-[2-(diethylamino) ethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-methylacetamide;
5-{2-[(1,1-dimethyl-2-{3-[2-(4-methyl isophthalic acid, 4-Diazesuberane (diazepan)-1-yl)-2-oxoethyl] phenyl } ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
5-[2-(1,1-dimethyl-2-[3-(2-morpholine-4-base-2-oxoethyl) phenyl] and ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-methyl-N-[(1S)-the 1-phenylethyl] ethanamide;
5-[2-(1,1-dimethyl-2-[3-(2-oxo-2-piperidines-1-base ethyl) phenyl] and ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-diphenol;
5-(1-hydroxyl-2-{[2-(3-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
5-(1-hydroxyl-2-{[2-(3-{2-[(3R)-3-hydroxy piperidine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
5-{2-[(2-{3-[2-(4-ethanoyl-1,4-Diazesuberane-1-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
5-(1-hydroxyl-2-{[2-(3-{2-[4-(methylol) piperidines-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
N-(1-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl } tetramethyleneimine-3-yl)-the N-methylacetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-methoxy ethyl)-N-propyl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-ethyl-N-(2-methoxy ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-(dimethylamino)-2, the 2-dimethyl propyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-fluoro-5-(trifluoromethyl) benzyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 1-(methylol)-3-methyl butyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 2-hydroxyl-1-phenylethyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N, the N-diethyl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-1H-pyrazoles-5-yl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(5-methyl isophthalic acid H-pyrazole-3-yl) ethanamide;
N-(cyclohexyl methyl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
4-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl } piperazine-1-carboxylic acid, ethyl ester;
N-(5-chloropyridine-2-yl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(6-picoline-2-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-picoline-2-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-isoquinolyl-1 ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4,6-lutidine-2-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-methoxy-benzyl) ethanamide;
N-[{1S)-1-benzyl-2-hydroxyethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(1-ethyl-1H-pyrazoles-5-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(1,3-dimethyl-1H-pyrazoles-5-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-luorobenzyl) ethanamide;
1-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl }-the L-prolineamide;
5-{2-[(2-{3-[2-(the 5-amino-3-tertiary butyl-1H-pyrazol-1-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and the 1-phenylethyl] ethanamide;
5-{2-[(2-{3-[2-(1,4-two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
N-[2-(4-chloro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-diamantane-1-base-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide;
N-[2-(2-chloro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(2,3-dimethyl-phenyl)-ethyl]-benzamide;
N-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(4-methoxyl group-2,3-dimethyl-phenyl)-ethyl]-benzamide;
N-(3,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(3,4-two chloro-benzyls)-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-(4-chloro-benzyl)-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-diamantane-1-base-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-(4-chloro-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(4-trifluoro-methoxybenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-pyridine-2-ylmethyl-ethanamide;
N-(3,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-cyclohexyl methyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethyl ketone;
N-benzyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-methyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-hydroxyl-benzyl)-ethanamide;
N-(4-cyano group-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(3-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(cyclohexyl methyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-styroyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-chlorobenzene ethyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-phenyl styroyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4 '-hydroxyl-biphenyl-3-ylmethyl)-ethanamide;
N-suberyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-styroyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-methyl sulfane base-benzyl)-ethanamide;
N-(2,6-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-indane-2-base-ethanamide;
N-(2-chloro-6-luorobenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(4-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(2,5-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(3,5-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2,6-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-biphenyl-2-ylmethyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3-trifluoromethyl benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3, the 4-difluorobenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(2-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3, the 4-dimethyl benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3, the 4-dimethoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-kharophen]-methyl }-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-indane-1-base-ethanamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-chloro-phenyl)-ethyl]-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-naphthalene-1-ylmethyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-fluoro-5-trifluoromethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(3-benzyl chloride base)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methyl sulfane base-benzyl)-ethanamide;
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-kharophen]-methyl }-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-sulfamyl-benzyl)-ethanamide;
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-kharophen]-methyl }-benzoic acid methyl ester;
N-(1-benzyl-piperidin-4-yl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-the N-[2-styroyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(5-fluoro-2-methyl-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-trifluoromethyl-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-(2-naphthalene-1-base-ethyl)-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2,4,5-trimethylammonium-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2,3-dimethyl-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-hydroxyl-3-chloro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(4-chloro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-hydroxyl-5-chloro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methoxyl group-benzyl)-ethanamide
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-methoxyl group-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2,3-dimethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3,4-dimethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-chloro-6-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3-chloro-4-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-[2-(6-methoxyl group-naphthalene-2-yl)-ethyl]-ethanamide;
N-(2-benzyl chloride base)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) propionic acid amide;
N-(2, the 6-dichloro benzyl)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) propionic acid amide;
1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) third-1-ketone;
N-(2-chloro-4-luorobenzyl)-2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) ethanamide;
N-(4-bromobenzyl)-2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-(3, the 4-3,5-dimethylphenyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-N-(2, the 3-dimethyl benzyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-N-(4-luorobenzyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-1-(4-pyridine-2-base piperazine-1-yl) ethyl ketone; And
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-(2-phenyl propyl) ethanamide.
According to an aspect of the present invention, preferred (CH wherein usually
2)
n-C (=O) Q
1The compound of the formula (1) of position between group is positioned at.
The pharmacy acceptable salt of the compound of formula (1) comprises its sour addition and alkali salt.
Suitable acid salt can form from the acid that can form non-toxic salt.The example comprises acetate, adipate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, camsilate, Citrate trianion, cyclamate (cyclamate), ethanedisulphonate, ethyl sulfonate (esylate), formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, this salt of former times (hibenzate), hydrochloric acid/muriate, Hydrogen bromide/bromide, hydroiodic acid HI/iodide, hydrophosphate, isethionate, D-and L-lactic acid salt, malate, maleic acid salt, malonate, mesylate, Methylsulfate, the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, embonate, phosphoric acid salt/hydrogen, phosphate/phosphor acid dihydride salt, pyroglutamate, glucarate, stearate, succinate, tannate, D-and L-tartrate, 1-hydroxyl-2-naphthoate, tosylate and xinafoate.
Suitable alkali salt forms from the alkali that can form non-toxic salt.The example comprises aluminium, arginine, N, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, Methionin, magnesium, meglumine, thanomin, potassium, sodium, trometamol and zincum salts.
Also can form half salt of acid and alkali, for example, Hemisulphate and half calcium salt.
Summary about suitable salt, " medicine salt handbook: character, selection and use (Handbook of Pharmaceutical Salts:Properties; Selection; and Use) " (Willie-VCH referring to history many (Stahl) and nest Maas (Wermuth), Wen Han (Weinheim), Germany, 2002).
One or more that can utilize three kinds of methods come the pharmacy acceptable salt class of the compound of preparation formula (1):
(i) allow the compound of formula (1) and acid or the alkali reaction of wanting;
(ii) remove disacidify or alkali labile blocking group from the appropriate precursors of the compound of formula (1); Or use acid or the alkali wanted to make suitable cyclic precursor (for example, lactone or lactan) open loop; Or
(iii) by with suitable acid or alkali reaction or utilize suitable ion exchange column, convert a kind of salt of the compound of formula (1) to another kind of salt.
Whole three kinds of reaction typical cases carry out in solution.The salt that is produced is precipitable to be gone out and collects by filtering, and maybe can reclaim by evaporating solvent.Degree of ionization in the salt that is produced can be changed to almost unionization from complete ionization.
Compound of the present invention is solvation and through the two existence of solvation form not.Use term " solvate " to describe molecular complex herein, it comprises one or more pharmaceutically acceptable solvent molecules (for example, ethanol) of the amount of compound of the present invention and stoichiometric quantity.When this solvent is water, then use term " hydrate ".
Mixture within the scope of the present invention has such as inclusion compound, medicine-host's inclusion complex (itself and the aforementioned solvate of mentioning relatively, this medicine and host can stoichiometric quantity or the amount existence of calculated amount non-chemically).The mixture that this medicine is arranged that comprises equally, it comprises two kinds or more kinds of stoichiometric quantity or the organic and/or inorganic component of the amount of calculated amount non-chemically.The mixture that is produced can be through ionization, partial ionization or unionization.About the summary of this class mixture, referring to J.Pharm Sci, 64 (8), 1269-1288 (by Halley's Bloomsbury peace (Haleblian), in August, 1975).
In this article, all mentioning of compound to formula (I) comprise the solvate of its esters, solvate and mixture and its esters and mentioning of mixture.
Compound of the present invention comprises the compound of formula (1) as hereinbefore defined, comprise polymorph that they are whole and crystal practise shape, as defined its prodrug after in this article and isomer (comprising optics, geometry and tautomer isomer) and through the compound of the formula (1) of isotropic substance demarcation.
As noted, the compound of so-called formula (I) " prodrug " also within the scope of the invention.Therefore, they itself have seldom or there is no some derivative of compound of the formula (I) of pharmacological activity, when being administered into it in health or on the health time, being converted the compound that (for example, passing through hydrolytic rupture) becomes to have the active formula of wanting (I).This analog derivative refers to be called as " prodrug ".About using the further information of prodrug, can be at " prodrug is as the mediation system (Prodrugsas Novel Delivery Systems) of novelty; the 14th, ACS symposium series (ACSSymposium Series) " (T Xi Guqi (Higuchi) and W Shi Daila (Stella)); And " the bioreversible supporting agent in medicinal design (Bioreversible Carriers in DrugDesign) ", Pei Jiameng press (Pergamon Press), find in 1987 (sieve's ed.E.B interest (Roche), the U.S. medicine trade councils (American Pharmaceutical Association)).
Can be according to prodrug of the present invention for example by having can be used as the part of " prodrug moiety " by those skilled in the art is known with some, the suitable functional group that replaces in the compound that is present in formula (I) makes, as describing for example in " design of prodrug (Design of Prodrugs) " (Ai Ersiweier (Elsevier), 1985) by H. nation first (Bundgaard).
Some examples according to prodrug of the present invention comprise:
(i) when the compound of formula (1) comprise carboxylic functionality (COOH) time, its ester, for example, the hydrogen of the carboxylic functionality of the compound of its Chinese style (1) is by (C
1-C
8) alkyl metathetical compound;
(ii) when the compound of formula (1) comprise the carbinol-functional degree (OH) time, its ether, for example, the hydrogen of the carbinol-functional degree of the compound of its Chinese style (1) is by (C
1-C
6) alkanoyloxymethyl metathetical compound; And
(iii) the compound when formula (1) comprises uncle or secondary amino group functionality (NH
2Or-NHR, wherein during R ≠ H), its acid amides, for example, the example has one of amino functionality of compound of formula (1) or two hydrogen by (C
1-C
10) alkyloyl metathetical compound.
Can in the aforementioned bibliography of mentioning, find according to the further example of the displacement group of previous examples and the example of other prodrug type.
Moreover they itself can act as the prodrug of the compound of other formula (1) compound of some formula (1).
Also within the scope of the present invention be the meta-bolites of the compound of formula (1), that is, and the compound that behind this medicine of administration, in vivo forms.Some examples according to meta-bolites of the present invention comprise:
(i) when the compound of formula (1) comprises methyl, its hydroxymethyl derivative (CH
3→-CH
2OH):
(ii) when the compound of formula (1) comprises alkoxyl group, its hydroxy derivatives (OR →-OH);
(iii) when the compound of formula (1) comprises that uncle is amino, its secondary amino group derivative (NR
1R
2→-NHR
1Or-NHR
2);
(iv) when the compound of formula (1) comprises secondary amino group, its uncle's derivative (NHR
1→-NH
2);
(v) when the compound of formula (1) comprises phenyl moiety, its amphyl (Ph →-PhOH); And
(vi) when the compound of formula (1) comprises amide group, its carboxylic acid derivative (CONH
2→ COOH).
The compound that comprises the formula (I) of one or more unsymmetrical carbons can have two kinds or more kinds of steric isomer.When if the compound of formula (I) comprises thiazolinyl or alkenylene, has suitable/anti-(or Z/E) isomer how much.When if constitutional isomer can hinder change via low-yield resistance, the isomerism phenomenon (" tautomerism ") of tautomer then can take place.This can adopt the form of proton tautomerism in the compound of the formula (1) that comprises imino-for example, ketone group or oximido group, or is so-called valence tautomerism in the compound that comprises the aromatic series part.What followed is that the simplification compound can have the isomerism more than a type.
Also within the scope of the present invention be whole steric isomers, geometrical isomer and the tautomeric form of the compound of formula (I), it comprises having more than a kind of compound of isomr and one or more mixture thereof.What also comprise is wherein optically active sour addition of counter ion tool or alkali salt, for example, and d-lactic acid salt or l-Methionin; Or racemoid, for example dl-tartrate or dl-arginine.
Can utilize and separate suitable/trans isomer by the known routine techniques of those skilled in the art (for example, chromatography and fractional crystallization).
The routine techniques that is used for preparing/separate indivedual enantiomorphs comprises that to carry out chirality from the pure precursor of suitable optically-active synthetic; Or for example use chirality high pressure lipuid chromatography (HPLC) (HLPC) to resolve racemoid (or racemoid of salt or derivative).
Moreover this racemoid (or racemize precursor) can react with suitable activity of optically active compounds (for example, alcohol); Or comprise in the example of acidity or basic moiety at the compound of formula (I), with acid or alkali (such as tartrate or 1-phenyl ethyl amine) reaction.The non-enantiomer mixture that is produced can separate by chromatography and/or fractionation crystallization, and one or two of this diastereomer can be utilized and convert corresponding pure enantiomorph to by the known method of technician.
Can use chromatography (being typically HLPC), on asymmetric resin, use by hydrocarbon (being typically heptane or hexane), comprise the moving phase that the alkylamine (being typically 0.1% diethylamine) of 0 Virahol to volume 50% (being typically 2 to 20%) and 0 to 5 volume % is formed, obtain to be rich in the chipal compounds of the present invention (and chiral precurser) of enantiomeric form.Concentrated elutant can provide this mixture that is rich in.
Can utilize and come the aggregation of separation of stereoisomers by the known routine techniques of those skilled in the art, referring to E.L. for example according to " stereochemistry of organic compound (Stereochemistry of Organic Compounds) " (Willie of rel (Eliel), New York, 1994).
According to an aspect of the present invention, usually (R, R) steric isomer (R wherein of preferred following formula
1Be hydrogen, R
2Be C
1-C
4Alkyl (preferable methyl), n and Q
1As above-mentioned definition).
The present invention includes the whole pharmaceutically acceptable of formula (I) through isotope-labeled compound, wherein one or more atoms are had the same atoms number, but its nucleidic mass or total mass number and usually dominant nucleidic mass or the different atomic substitutions of total mass number in natural.
Be contained in the isotropic substance that isotropic substance example in the compound of the present invention comprises hydrogen in being appropriate to, such as
2H reaches
3H; Carbon, such as
11C,
13C reaches
14C; Chlorine, such as
36Cl; Fluorine, such as
18F; Iodine, such as
123I reaches
125I; Nitrogen, such as
13N reaches
15N; Oxygen, such as
15O,
17O reaches
18O; Phosphorus, such as
32P; And sulphur, such as
35S.
Formula (I) useful in medicine and/or matrix organization distribute research through isotope-labeled some compound (for example, mix radioisotopic those).For this purpose, in view of it mixes and existing test set easily, then the radio isotope tritium (promptly
3H) and carbon 14 (promptly
14C) particularly useful.
With heavier isotropic substance (such as deuterium, promptly
2H) replacement can obtain some treatment advantages, and it is owing to bigger metabolic stability, and for example therefore the dosage demand of in vivo transformation period of Zeng Jiaing or minimizing may be preferred in some cases.
With the emission positron isotropic substance (such as
11C,
18F,
15O reaches
13N) replace then applicable to checking matrix acceptor occupancy in positron tomoscan (PET) research.
Can utilizing usually by the known routine techniques of those skilled in the art of formula (I) through isotope-labeled compound, or utilize to be similar to and be described in those methods of following in embodiment and the preparation, use through suitable isotope-labeled reagent to replace the unlabelled reagent that uses in advance and prepare.
Pharmaceutically acceptable solvate according to the present invention comprises those that crystalline solvent wherein can replace through isotropic substance, for example D
2O, d
6-acetone, d
6-DMSO.
The compound of formula (1), their pharmacy acceptable salt classes and/or derivative form are useful pharmaceutically active compound, it is suitable be used for the treatment of and prevent many wherein relate to beta 2 receptor or wherein the excitement of acceptor can cause the disease of benefit, particularly allergy and nonallergic airway disorders, but it also can be used for treating other disease, such as (but be not limited to) neural disease, premature labor, congestive heart failure exhaust, depressed, inflammatory and anaphylaxis dermatosis, psoriasis, hyperproliferative skin disease, glaucomatous those; And be favourable illness, particularly stomach and peptide ulceration reducing stomach acidity.
The compound of the present invention that is intended to be used for pharmaceutical use can crystal or the administration of amorphous product.They can utilize such as precipitation, crystallization, lyophilize, spraying drying or evaporation drying method and obtain, and for example are the form of solid plug, powder or film.For this purpose can be used microwave or radio-frequency seasoning.
They can be individually dosed or with one or more other compound combination medicine-feedings of the present invention, or with one or more other medicines combination (or as being its any combination) administrations.As a rule, they will with one or more pharmaceutically acceptable vehicle bonded preparation administrations.Use term " vehicle " to describe any composition except compound of the present invention herein.The selection of vehicle will be depended on some factors to a great extent, such as special mode of administration, vehicle to solubleness and the influence of stability and the attribute of formulation.
Pharmaceutical composition that is appropriate to send compound of the present invention and preparation method thereof will be very tangible to one skilled in the art.Said composition and preparation method thereof can be for example at " Lei Shi medical science (Remington ' s Pharmaceutical sciences) ", finds in the 19th edition (mark publishing company (Mark Publishing Company), 1995).
Compound Orally-administrable of the present invention.Oral administration can comprise to be swallowed, so that allow this compound enter gi tract; Maybe can use oral cavity or sublingual administration, to allow this compound directly enter the blood flow from mouth.
The preparation that is appropriate to oral administration comprises solid preparation, such as tablet; The capsule that comprises particulate, liquid or powder; Lozenge (comprising liquid filling); Masticatory; Many-and nanoparticle; Gel; Sosoloid; Liposome; Film; Ovulum; Sprays and liquid preparation.
Liquid preparation comprises suspension, solution, syrup and elixir.This preparation also can use as stopping composition in soft or hard capsule, and its typical case comprises supporting agent (for example water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil) and one or more emulsifying agents and/or suspension agent.Liquid preparation also can for example prepare from sachet by reconstructing solid.
Compound of the present invention dissolving fast, quickly disintegrated formulation are used, advocate (Expert Opinion in Therapeutic Patents) such as the expert who is described in the treatment patent, 11 (6), those among the 981-986 (by beam (Liang) and old (Chen) (2001)).
Concerning Tabules, this medicine can account for 1 weight % to 80 weight % of formulation, more typical 5 weight % to the 60 weight % that account for formulation according to dosage.Except this medicine, tablet generally includes disintegrating agent.Hydroxypropylcellulose, starch, pregelatinized starch and sodiun alginate that the example of disintegrating agent comprises sodium starch glycolate, sodium carboxymethyl-cellulose, calcium carboxymethylcellulose salt, croscarmellose (croscarmellose) sodium, polyvinylpolypyrrolidone (crospovidone), polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, replaces through short-chain alkyl.As a rule, this disintegrating agent will account for 1 weight % to 25 weight % of formulation, preferably account for 5 weight % to 20 weight %.
The common cohesion matter of using tackiness agent to give tablet formulation.Suitable binder comprises Microcrystalline Cellulose, gelatin, carbohydrate, polyoxyethylene glycol, natural and synthetic gum, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and Vltra tears.Tablet also can comprise thinner, such as lactose (monohydrate, spray-dired monohydrate, anhydrous and analogue), N.F,USP MANNITOL, Xylitol, dextrose, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and dicalcium phosphate dihydrate.
Tablet also can be chosen wantonly and comprise tensio-active agent, such as sodium lauryl sulfate and Polysorbate 80; And glidant, such as silicon-dioxide and talcum.When existing, tensio-active agent can account for 0.2 weight % to 5 weight % of tablet; And glidant can account for 0.2 weight % to 1 weight % of tablet.
Tablet also comprises lubricant usually, such as the mixture of Magnesium Stearate, calcium stearate, Zinic stearas, FUMARIC ACID TECH GRADE stearate sodium and Magnesium Stearate and sodium lauryl sulfate.Lubricant accounts for 0.25 weight % to 10 weight % of tablet usually, preferably accounts for 0.5 weight % to 3 weight %.
Other possible composition comprises antioxidant, tinting material, seasonings, sanitas and taste screening agent.
Typical tablet comprise the highest about 80% medicine, about 10 weight % to the tackiness agent of about 90 weight %, about 0 weight % to the thinner of about 85 weight %, the lubricant of about 2 weight % to the disintegrating agent of about 10 weight % and about 0.25 weight % to about 10 weight %.
Tablet mixture can directly or by cylinder compress, to form tablet.In addition, the mixture of tablet mixture or part can be before film-making through moistening, drying or fusion granulating, fusion is condensed or push.Last preparation can comprise one or more layers and can be coated or dressing not; Itself in addition also can be by encapsulated.
((horse a little you (Marcel) is worn gram (Dekker) to tablet formulation to draw interest graceful (Lachman) by H. thunder Berman (Lieberman) and L. at " pharmaceutical dosage form: lozenge; the 1st (Pharmaceutical DosageForms:Tablets) ", New York, 1980) in discussion is arranged.
Consumable oral film human or for animals is typically soft water soluble or the expandable thin-film dosage form of water, its rapidly dissolvable or mucosal adhesive; And the typical case comprises the compound of formula (1), film forming polymkeric substance, tackiness agent, solvent, wetting Agent for Printing Inks, softening agent, stablizer or emulsifying agent, viscosity modifier and solvent.Some component of preparation can be finished more than a kind of function.
The compound of formula (1) can be water-soluble or water-fast.Water-soluble compound typical case accounts for 1 weight % to 80 weight % of solute, more typical 20 weight % to the 50 weight % that account for.More insoluble compound can account for the larger proportion of composition, typically accounts for the 88 weight % that are up to this solute.Moreover the compound of formula (1) can be multiparticulates globule form.
Film forming polymkeric substance can be selected from natural Polysaccharides, protein or synthetic hydro-colloid, with and typically at 0.01 to 99 weight %, more typically in the scope of 30 to 80 weight %, exist.
Other possible composition comprises antioxidant, tinting material, spices and smell toughener, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oils), wetting agent, swelling agent, anti-whipping agent, tensio-active agent and taste screening agent.
Membrane according to the invention typical case can prepare by the thin water-based film that evaporation drying has been applied on strippable supporting carrier or the paper.This can carry out in drying oven or passage (being typically the coating machine moisture eliminator of combination), maybe can or vacuumize by lyophilize and carry out.
The solid preparation that is used for oral administration can be formulated into the release that discharges immediately and/or change.The delivery formulations that changes comprises delays, continues, pulse, control, target and sequencing release.
The delivery formulations through suitable change that can be used for purpose of the present invention is described in U.S. Patent No. 6,106, in 864.The details of other suitable release tech (such as high-energy dispersion, infiltration and the particle through being coated with) can be in Buddhist horse people's such as (Verma) medical technology online (Pharmaceutical Technology On-line), 25 (2), find among the 1-14 (2001).Use chewing gum to realize then being described among the WO 00/35298 through the release of control.
Compound of the present invention also can be administered directly among blood flow, muscle or the internal.Suitable parenteral admin method comprises that intravenously, intra-arterial, intraperitoneal, sheath are interior, indoor, in the urethra, in the breastbone, encephalic, intramuscular and subcutaneous.The device that is appropriate to parenteral admin comprises pin (comprising micropin) syringe, needleless injector and infusion techn.
Parenteral formulation is typically the aqueous solution, and it can comprise vehicle, such as salt, carbohydrate and buffer reagent (preferred pH is 3 to 9); But concerning some was used, they can more suitably be formulated as aseptic non-aqueous solution or the dried forms for being used in combination with suitable vehicle (such as aseptic, apirogen water).
Can use and easily obtain preparation this parenteral formulation (for example, passing through freeze-drying) under sterile state by the known standard pharmaceutical technology of those skilled in the art.
Can use appropriate formulations technology (such as mixing the solubleness rising agent) to increase the solubleness of the compound of the formula (I) of use in the preparation of parenteral solution.
The release that the parenteral admin preparation can be formulated into immediately and/or change.The delivery formulations that changes comprises delays, continues, pulse, control, target and sequencing release.Therefore, compound of the present invention can be formulated into solid, semisolid or the thixotropic liquid that is used for the storage storehouse administration through implanting (release that it can provide this active compound to change).This examples of formulations comprises through the stent of medicine coating and poly-(dl-lactic acid-glycol) altogether acid (PGLA) microsphere.
But compound of the present invention also topical to skin or mucous membrane, that is, and skin or through percutaneous drug delivery.The exemplary formulations that is used for this purpose comprises gel, hydrogel, lotion, solution, emulsifiable paste, ointment, spraying powder, dressing, foam, film, transdermal patches, wafer, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Typical supporting agent comprises alcohol, water, mineral oil, whiteruss, white paraffin, glycerine, polyoxyethylene glycol and propylene glycol.Can mix penetration enhancer, for example can be referring to the J.Pharm Sci of Pfennig (Finnin) and the root that rubs (Morgan), 88 (10), 955-958 (in October, 1999).
The method of other topical comprise by electroporation, the saturating therapy of ion-conductance, sound wave penetrate method (phonophoresis), ultrasound penetrates method (sonophoresis) and micropin or needleless (for example, powder Jack spy (Powderject)
TM, biological Jack spy (Bioject)
TMOr the like) injected delivery.
The release that local administration preparation can be mixed with immediately and/or change.The delivery formulations that changes comprises delays, continues, pulse, control, target and sequencing release.
But compound of the present invention is also in the nose or pass through inhalation, typically with from the dry powder form of Diskus (separately, as mixture, for example with the drying composite of lactose, or be the blended component particles for example, mix with phosphatide (such as phosphatidylcholine)); Or be to hang oneself that (it can use or not use suitable propelling agent (such as 1 for the container, pump, atomizer, spraying gun (being preferably the spraying gun that uses electrical fluid mechanics (electrohydrodynamics) to produce the fine mist thing) of pressurization or sprinker, 1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-propane)) aerosol spray.Using in nose, this powder can comprise bioadhesive polymer, for example, and chitosan or cyclodextrin.
This container, pump, atomizer, spraying gun or sprinker through pressurization comprises solution or the suspension that contains compound of the present invention, its comprise ethanol for example, aqueous ethanolic solution or another kind ofly be appropriate to disperse, solubilising or prolong material that promoting agent discharges, as the propelling agent of solvent and optional tensio-active agent, such as three oleic acid sorbitan esters, oleic acid or lactic acid oligomer.
Before in being used in dry powder or suspension preparation, the pharmaceutical product micro mist is changed into the size (typical case is less than 5 microns) that is appropriate to suck transmission.This can realize by any suitable levigation method, such as spiral spray polishing, fluidised-bed spray polishing, treatment with supercritical fluid to form nanoparticle, high pressure homogenizing method or spray-drying process.
Being used in capsule (for example, making from gelatin or Vltra tears), blister and cartridge case in sucker or the insufflator can be formulated into and comprise compound of the present invention, suitable powder matrix (such as lactose or starch) and the powdered mixture of improvement in performance agent (such as l-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can be anhydrous or the monohydrate form, the preferred latter.Other suitable vehicle comprises dextran, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.
Can be used in and use the electrical fluid mechanics to produce the compound of the present invention that the each driving of suitable pharmaceutical solutions in the spraying gun of fine mist thing can comprise 1 microgram to 20 milligram, and it drives volume and can be changed to 100 microlitres from 1 microlitre.Typical formulation can comprise compound, propylene glycol, sterilized water, ethanol and the sodium-chlor of formula (I).Other can make the solvent that is used for replacing propylene glycol comprise glycerine and polyoxyethylene glycol.
Suitable seasonings (such as menthol and left-handed menthol) or sweeting agent (such as asccharin or soluble saccharin) can be added to and this invention is intended to be used to suck/those preparations of intranasal administration.
PGLA is for example used in the release that suction/intranasal administration preparation can be formulated into immediately and/or change.The delivery formulations that changes comprises delays, continues, pulse, control, target and sequencing release.
In the example of Foradil Aerolizer formoterol fumarate and aerosol, dose unit can be decided by the valve of carrying the amount through measuring.According to unit example of the present invention be arranged to give dosage or " one cigarette " through metering, it comprises the compound of 0.001 milligram to 10 milligrams formula (I).The dosage typical case of all day will be in 0.001 milligram to 40 milligrams scope, and it can the single dose administration or more generally spreads all over administration all day with separate doses.
The compound of formula (1) is appropriate to pass through inhalation especially.
But compound rectum of the present invention or vagina administration are for example with suppository, vaginal suppository or enema forms.Theobroma oil is traditional suppository base, can use different surrogates when still needing.
The release that the preparation of rectum/vagina administration can be formulated into immediately and/or change.The delivery formulations that changes comprises delays, continues, pulse, control, target and sequencing release.
Compound of the present invention also can be administered directly to eyes or ear, and canonical form is isoosmotic pressure, the micronization suspension in pH adjustment, Sterile Saline or the drops of solution.Other preparation that is appropriate to eyes and ear administration (for example comprises ointment, biodegradable; absorbable gel sponge, collagen) and biological nondegradable (for example siloxanes) implant, wafer, eyeglass and particulate or little bag system, such as big vesicle (niosomes) or liposome.Can be with polymkeric substance, such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer compound, for example, Vltra tears, Natvosol or methylcellulose gum or mixed polysaccharide polymkeric substance, for example, tying blue glue (gelan gum) mixes with sanitas (such as benzalkonium chloride).This preparation also can be carried by iontophoresis.
The release that eyes/the ear drug-delivery preparation can be formulated into immediately and/or change.The delivery formulations that changes comprises delays, continues, pulse, control, target or sequencing release.
Compound of the present invention can with soluble macromole entity, such as cyclodextrin and suitable derivative thereof or contain the polymkeric substance combination of polyoxyethylene glycol, so as to improve that their solubleness, dissolution rate, taste cover, bioavailability and/or stability, be used for any aforementioned mode of administration of mentioning.
For example, found that the drug-cyclodextrin mixture is useful to most formulation and route of administration usually.Can use inclusion and non-inclusion complex the two.Except with the direct complexing of medicine, cyclodextrin can be used as supplementary additive,, can be used as supporting agent, thinner or solubilizing agent that is.The most normal be used in these purposes have α-, β-and γ-Huan Hujing, the example can be found in international patent application No.WO 91/11172, WO 94/02518 and WO 98/55148.
Owing to want to give the combination of active compound, for example, purpose for special disease of treatment or symptom, in scope of the present invention, also comprise easily coming in conjunction with two kinds or more kinds of pharmaceutical composition wherein at least a comprising according to compound of the present invention with kit (kit) form that is appropriate to the co-administered said composition.
Therefore, kit of the present invention comprises two kinds or more kinds of independent pharmaceutical composition, the wherein at least a compound that comprises according to formula of the present invention (I); And be used for keeping respectively the device of said composition, such as the bottle of container, separation or the paper tinsel parcel of separating.The example of this kit is the blister of being familiar with that is used for package troche, capsule and analogue thereof.
Kit of the present invention is appropriate to give different formulations especially, and is for example, that parenteral uses, give the composition that independent composition or titration are separated from each other with different spacing of doses.In order to help to comply with, this kit typical case comprises the administration guidance and so-called memory aids can be provided.
In order to be administered to human patients, total dose range every day of compound of the present invention is typically 0.001 milligram to 5000 milligrams, and this decides according to mode of administration certainly.For example, intravenously dosage every day only needs 0.001 milligram to 40 milligrams.Every day, total dose can single or with the separate doses administration, and can be under doctor's judgement, dropped on outside the typical range that this paper provides.
These dosage are based on about 65 kilograms to the 70 kilograms human patients of mean body weight.The doctor can easily determine body weight to drop on this extraneous object (such as child and older's) dosage.
For fear of query, this paper mentions " treatment " comprises and mentions treatment, mitigation and prophylactic treatment.
According to another embodiment of the invention, the compound of formula (1) or its pharmacy acceptable salt class, derivative form or composition, can also be used as the combination that is administered to other medicine of patient with one or more desires altogether, so that obtain the treatment end-result that some are wanted especially, such as the relevant disease course of treatment physiopathology, comprise (but being not limited to): (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) disorganization, (v) sign and symptom (such as expiratory dyspnea, cough).This second and more kinds of other medicine also can be the β2Ji Dongji of knowing in the compound of formula (1) or its pharmacy acceptable salt, derivative form or composition or one or more this areas.More typically be, this second and more kinds of medicine will be selected from other medicine of different sorts.
As term " co-administered ", " giving altogether " of being used in this paper reach " with ... combination " and refer to the compound of formula (1) and one or more other medicines and be intended to mean and be meant really and comprise following:
When these components being mixed with together single formulation (its substantially identical time discharges these components to this patient), the compound of this formula (1) and the combination of medicine are administered to the patient who needs treatment simultaneously;
When these components are formulated into independent formulation (it is adopted by the substantially identical time point of this patient) apart from each other, the compound of this formula (1) and the combination of medicine are administered to the patient who needs treatment in fact simultaneously, so the substantially identical time point of these components is released into this patient;
When these components are formulated into independent formulation (it is adopted to have the mode read-around ratio in the tangible timed interval between each administration by this patient) apart from each other, the compound of this formula (1) and the combination of medicine are administered to the patient who needs treatment in succession, so the substantially different time point of these components is released into this patient; And
When these components are formulated into single formulation (its mode with control discharges these components) together, the compound of this formula (1) and the combination of medicine are administered to the patient who needs treatment in succession, so they can be by this patient in identical and/or different time points while, the continuous and/or ground administration that partly overlaps;
Wherein each part can be utilized identical or different administration.
The suitable example of other medicine that can use with the compound of formula (1) or its pharmacy acceptable salt, derivative form or combination of compositions comprises (but never being limited to):
(a) 5-lipoxidase (5-LO) inhibitor or 5-lipoxidase activation of protein (FLAP) antagonist;
(b) leukotriene antagonist (LTRA) comprises LTB
4, LTC
4, LTD
4And LTE
4Antagonist;
(c) histamine receptor antagonist comprises H1 and H3 antagonist;
(d) be used for the α of decongestant purposes
1-and α
2-3 adrenergic receptor agonists vasoconstriction parasympathomimetic agent;
(e) muscarinic M 3 receptors antagonist or anticholinergic;
(f) PDE inhibitor, for example PDE3, PDE4 and PDE5 inhibitor;
(g) theophylline;
(h) Sodium Cromoglicate;
(i) COX inhibitor, non-selective optionally COX-1 or the cox 2 inhibitor (NSAID) of reaching;
(j) the oral and glucocorticosteroid that sucks;
(k) the effective monoclonal antibody of anti-endogenous inflammatory entity;
(i) anti-tumor necrosis factor (medicament of anti-TNF-α);
(m) adhesion molecule inhibitor comprises the VLA-4 antagonist;
(n) kassinin kinin-B
1-and B
2-receptor antagonist;
(o) immunosuppressor;
(p) inhibitor of matrix metalloproteinase class (MMPs);
(q) tachykinin NK-1
1, NK
2And NK
3Receptor antagonist;
(R) elastase inhibitor;
(S) adenosine A 2a receptor stimulant;
(t) urokinase inhibitors;
(u) can act on compound on the Dopamine Receptors, for example the D2 agonist;
(the v) conditioning agent of NF κ beta pathway, for example IKK inhibitor;
(w) conditioning agent of cytokine signaling approach is such as p38MAP kinases or syk kinases or jak kinase inhibitor;
(x) can be categorized as the medicament of mucolytic agent or antitussive;
(y) microbiotic;
(z) hdac inhibitor; And
(aa) PI3 kinase inhibitor.
According to the present invention, the compound of preferred formula (1) and the combination of following material:
-H3 antagonist;
-muscarinic M 3 receptors antagonist;
-PDE4 inhibitor;
-glucocorticosteroid;
-adenosine A 2a receptor stimulant;
The conditioning agent of-cytokine signaling approach is such as p38MAP kinases or syk kinases; Or
-leukotriene antagonist (LTRA) comprises LTB
4, LTC
4, LTD
4And LTE
4Antagonist.
According to the present invention, the more preferably compound of formula (1) and the combination of following material:
-glucocorticosteroid, particularly have the inhaling type glucocorticosteroid of the systemic side effects of attenuating, comprise prednisone, prednisolone, flunisolide, Triamcinolone Acetonide, Viarox, budesonide, fluticasone propionate, ciclesonide and furoic acid momisone; Or
-muscarinic M 3 receptors antagonist or anticholinergic particularly comprise Ipratropium Bromured (ipratropium) salt, i.e. bromide; Thiophene tropine (tiotropium) salt, i.e. bromide; Oxitropine (oxitropium) salt, i.e. bromide; Pendant logical sequence Xiping (perenzepine) and telenzepine (telenzepine).
It should be understood that alleged treatment all comprises treatment, mitigation and prophylactic treatment herein.Ensuing explanation relates to the treatment of the compound that can use formula (1) and uses.
The compound of formula (1) has and the synergistic ability of beta 2 receptor, therefore has wide range of therapeutic applications scope (as further describing hereinafter), because the key player that beta 2 receptor is played the part of in whole mammiferous physiology.
Therefore, further aspect of the present invention relates to compound or its pharmacy acceptable salt, derivative form or the composition of the formula (1) that is used for the treatment of the disease, obstacle and the illness that relate to beta 2 receptor.More particularly, the invention still further relates to and be used for the treatment of compound or its pharmacy acceptable salt, derivative form or the composition that is selected from by the formula (1) of disease, obstacle and the illness of the following group of forming:
Which kind of type no matter, nosetiology or pathogenetic asthma particularly are selected from the asthma by the member of the following group of forming: atopic asthma, anallergic asthma, allergic asthma, the asthma of allergy segmental bronchus IgE mediation, bronchial asthma, the special property sent out asthma, true asthma, the intrinsic asthma that is caused by the pathologic, physiologic obstacle, by the extrinsic asthma that environmental factors caused, spy's property sent out asthma of the unknown or unknown cause, anallergic asthma, segmental bronchus inflammatory asthma, emphysematous asthma, exercise-induced asthma, bringing out property of anaphylactogen asthma, bringing out property of freezing air asthma, occupational asthma, by bacterium, fungi, protozoon or the infective asthma that virus infection caused, non-allergic asthma, the first property asthma of sending out, stridulating property baby comprehensive is levied and bronchiolitis;
Chronic or acute bronchoconstriction, chronic bronchitis, SAO and pulmonary emphysema;
No matter which kind of type, nosetiology or pathogenetic obstructive or airway inflammatory disease particularly are selected from chronic obstructive or airway inflammatory disease by the member of the following group of forming: acidophilia pneumonia, chronic obstructive pulmonary disease (COPD), comprise chronic bronchitis, pulmonary emphysema or relevant with COPD or incoherent dyspneic COPD, be characterized as irreversible COPD, carrying out property airway obstruction, the respiratory distress syndrome (ARDS) of growing up, treat the deterioration of caused airway hyperreactivity and the airway disorders relevant with pulmonary hypertension because of other medicines;
No matter which kind of type, nosetiology or pathogenetic bronchitis particularly are selected from the bronchitis by the member of the following group of forming: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus property or streptococcus bronchitis and vesicular bronchitis;
Acute lung injury;
No matter which kind of type, nosetiology or pathogenetic bronchiectasis particularly are selected from the bronchiectasis by the member of the following group of forming: cylindrical bronchiectasis, cystic bronchiectasis, spin hang down shape bronchiectasis, bronchiolectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
Still compound or its pharmacy acceptable salt, derivative form or composition that further aspect of the present invention also relates to formula (1) are used to make the purposes with the active medicine of β2Ji Dongji.Particularly, the present invention relates to the compound of formula (1) or the purposes that its pharmacy acceptable salt, derivative form or composition are used to make medicine, this medicine is used for the treatment of the disease and/or the symptom of β 2-mediation, disease of particularly listing above and/or symptom.
Therefore, the invention provides a kind of compound or its pharmacy acceptable salt, derivative form or the composition of the interesting formula with significant quantity (1) especially and treat the Mammals method of (comprising the mankind).More precisely, the invention provides a kind of interesting especially disease and/or symptom that is used for treating β 2-mediation in the Mammals (comprising the mankind), the disease of particularly listing above and/or the method for symptom, it compound, its pharmacy acceptable salt and/or derivative form that comprises the formula (1) with significant quantity is administered to this Mammals.
The following example is the preparation of the compound of Ming Dynasty style (1) for example:
Preparation 1
2,2 '-(1, the 3-phenylene) oxalic acid diethyl ester
With 2,2 '-(1, the 3-phenylene) oxalic acid (10.0 grams, 51 mmoles) is dissolved in the ethanol (100 milliliters), and dropwise handles this solution with catalytic ethanoyl chlorine (2.5 milliliters).Before cooling, under refluxing, stir this reaction mixture and reached under reduced pressure concentrated in 18 hours.Resistates is mixed in ethyl acetate (100 milliliters), and clean with sodium hydrogen carbonate solution (3 * 50 milliliters) and salt solution (3 * 50 milliliters).Dry organic phase and under reduced pressure concentrated on sal epsom.With the pentane grinding residues, to produce this title product, 11.8 grams.
1H NMR(CDCl
3，400MHz)δ1.31(6H，t)，3.65(4H，s)，4.20(4H，q)，7.24-7.36(4H，m)。
LRMS：m/z ES
+251[MH]
+
Preparation 2
[3-(2-oxyethyl group-2-oxoethyl) phenyl] acetate
With (4.9 milliliters of the hydrochloric acid of 12M, 58.8 mmole) dropwise handle the diester from preparation 1 (44.3 grams, 177 mmoles) in ethanol (24 milliliters) and two alkane (290 milliliters) with 2,2 '-(1, the 3-phenylene) solution of oxalic acid (59.2 grams, 308 mmoles).Before cooling, stir this reaction mixture and heating 18 hours under refluxing, and be concentrated into low volume.Dilute this reaction mixture and slurry that filtration was produced with toluene (125 milliliters).Concentrating filtrate under reduced pressure mixes resistates in water and neutralizes with sodium bicarbonate.Dilute this mixture and separate organic layer with ethyl acetate (200 milliliters), clean with sodium hydrogen carbonate solution (5 * 30 milliliters) and salt solution (50 milliliters).With the hydrochloric acid of 6M with bonded extract acidified aqueous solution to pH 3, and extract with ether (3 * 30 milliliters).Combined organic, dry and under reduced pressure concentrated on sal epsom.With the pentane grinding residues, title compound can be provided, be colorless solid 10.8 grams.
1H NMR(CD
3OD，400MHz)δ1.25(3H，t)，3.60(2H，m)，3.63(2H，m)，4.15(2H，q)，7.18-7.32(4H，m)
LRMS：m/z ES
+245[MNa]
+
Preparation 3
[3-(2-hydroxy-2-methyl-propyl group)-phenyl]-acetate
The solution of acid (6.85 grams, 32 mmoles) in Anaesthetie Ether (100 milliliters) of preparation 2 is cooled to 0 ℃, and with the solution-treated of 3M methylmagnesium-bromide in ether (23.5 milliliters, 70.0 mmoles).Reaction mixture is heated to room temperature gradually.After 2 hours, add saturated aqueous ammonium chloride solution (200 milliliters) and come stopped reaction.Separate organic phase and reach with salt solution (100 milliliters) cleaning, dry reaching under reduced pressure concentrates on sal epsom.Utilize column chromatography purifying on the silicon gel, with 60: 40 to 0: 100 pentane: the methylene dichloride wash-out, title compound can be provided, be water white oil, 6.23 grams.
1H NMR(CDCl
3，400MHz)δ1.22(6H，s)，2.75(2H，s)，3.63(2H，s)，7.12-7.30(4H，m)。
LRMS：m/z ES
+209[MH]
+
Preparation 4
3-[2-(2-chloro-kharophen)-2-methyl-propyl group]-phenyl }-acetate
With 2-chloromethyl cyanide (8.8 milliliters, 140 mmoles) be added in acetate (33 milliliters) from preparation 3 alcohol (16.0 grams, 70 mmoles) solution.The solution that is produced is cooled to 0 ℃, handles, and reaction mixture is heated to room temperature gradually with the vitriol oil (33 milliliters).After 4 hours, reaction mixture is poured into to reach on ice with solid sodium carbonate alkalizes.With ethyl acetate (2 * 500 milliliters) extraction solution, dry bonded organic extract and under reduced pressure concentrated so that title product to be provided, is colorless solid on sal epsom, 19.0 grams.
1H NMR(CDCl
3，400MHz)δ1.36(6H，s)，3.02(2H，s)，3.62(2H，s)，3.95(2H，s)，6.19(1H，br s)，7.06-7.31(4H，m)
LRMS：m/z ES
-282，284[M-H]
-
Preparation 5
[3-(2-amino-2-methyl propyl group) phenyl] methyl acetate
Under the nitrogen atmosphere, will be heated to from acid amides (5.1 grams, 18 mmoles), thiocarbamide (1.6 grams, 21 mmoles) and the solution of acetate (18 milliliters) in methyl alcohol (80 milliliters) of preparation 4 and reflux 16 hours.Cooling and filter this reaction mixture.Concentrating filtrate and resistates is dissolved in the methyl alcohol (150 milliliters) under reduced pressure.With saturated this solution of hydrogen chloride gas, be heated to then and refluxed 16 hours.Reduce solvent in a vacuum, and resistates is distributed between the aqueous sodium carbonate (200 milliliters) of ethyl acetate (200 milliliters) and 5%.Clean organic extract with saturated sodium-chlor (100 milliliters), dry and minimizing in a vacuum on sodium sulfate.Purifying resistates in strong Zeo-karb, with methyl alcohol then with the 2N ammonia wash-out in methyl alcohol, with eluted product.Concentrate elutant in a vacuum,, be yellow oil, 2.68 grams so that title compound to be provided.
1H NMR(CDCl
3，400MHz)δ1.14(6H，s)，2.68(2H，s)，3.62(2H，s)，3.69(3H，15s)，7.08-7.16(3H，m)，7.23-7.27(1H，m)。
LRMS：m/z ES
+236[MH]
+
Preparation 6
1-[3, two (benzyloxy) phenyl of 5-]-2-bromine ethyl ketone
At room temperature, at 1-[3, two (benzyloxy) phenyl of 5-] in the stirred solution of ethyl ketone (5 grams, 15.04 mmoles) in tetrahydrofuran (THF) (60 milliliters) and methyl alcohol (35 milliliters), be incorporated in the tetrabutylammonium tribromide (7.25 grams, 15.04 mmoles) in the tetrahydrofuran (THF) (20 milliliters).Stir this reaction mixture reached in a vacuum except that desolvating in 24 hours.Resistates is dissolved in the ethyl acetate (100 milliliters) and cleans with water (2 * 50 milliliters).Dry and concentrated bonded organic extract to obtain the compound of wanting of a certain amount of productive rate, is yellow oil on sal epsom.
1H NMR(400MHz，CDCl
3)δ4.38(2H，s)，5.05(4H，s)，6.81(1H，s)，7.10-7.25(2H，m)，7.30-7.42(10H，m)。
LRMS：m/z APCI
+413[MH
+]。
Preparation 7
3-[2-(2-[3, two (benzyloxy) phenyl of 5-]-the 2-hydroxyethyl } amino)-the 2-methyl-propyl] phenyl } methyl acetate
Under refluxing, calorify the stirred solution 24 hours of the compound (2.53 grams, 11.4 mmoles) of compound (4.7 grams, 11.4 mmoles), preparation 5 of the preparation 6 in the tetrahydrofuran (THF) (140 milliliters) and N-ethyl diisopropyl amine (2 milliliters, 11.4 mmoles).Reaction mixture is cooled to room temperature, adds sodium borohydride (647 milligrams, 17.10 mmoles), and at room temperature stirred this mixture 5 hours.Adding methyl alcohol (5 milliliters) comes stopped reaction to reach evaporating solvent in a vacuum.The orange oil of remnants is distributed between methylene dichloride (60 milliliters) and the saturated sodium hydrogen carbonate solution (40 milliliters).Separating these reaches mutually with methylene dichloride (3 * 40 milliliters) aqueous phase extracted.In conjunction with organic extract and concentrated in a vacuum.Utilize column chromatography purifying on the silicon gel, use methylene dichloride, use 95: 5: 0.5 methylene dichloride then: methyl alcohol: 0.88 ammonia is as eluent, the product that can obtain to want, 4.50 grams (70%).
1H NMR(400MHz，CD
3OD)δ1.01(6H，d)，2.61(4H，m)，3.58(2H，s)，3.62(3H，5s)，4.61-4.64(1H，dd)，5.03(4H，s)，6.54-6.55(1H，t)，6.63-6.64(2H，d)，7.00-7.01(1H，d)，7.08-7.10(2H，d)，7.16-7.20(1H，t)，7.25-7.28(2H，m)，7.31-7.34(4H，t)，7.38-7.40(4H，d)。
LRMS：m/z APCI
+554[MH
+]。
Preparation 8
[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] methyl acetate
Under refluxing, the mixture 24 hours of palladium hydroxide (900 milligrams) on the compound of the preparation 7 of heating in ethanol (80 milliliters) (4.50 grams, 8.13 mmoles), ammonium formiate (3.59 grams, 113.86 mmoles) and the carbon.Reaction mixture is cooled to room temperature, filters and clean with methyl alcohol (3 * 20 milliliters) by A Boxier (Arbocel) .Concentrating filtrate in a vacuum, it is the product of wanting that an orange oil can be provided, 2.64 grams (87%).
1H NMR(400MHz，CD
3OD)δ1.06(3H，s)，1.07(3H，s)，2.67-2.87(4H，m)，3.62(2H，s)，3.66(3H，s)，4.56-4.59(1H，q)，6.18-6.19(1H，t)，6.34(2H，d)，7.03-7.23(4H，m)。
LRMS：m/z APCI
+374[MH
+]。
Preparation 9
[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] acetate
The lithium hydroxide solution (21.2 milliliters, 21.2 mmoles) of 1M dropwise is added to the solution of compound (2.64 grams, 7.07 mmoles) in tetrahydrofuran (THF) (30 milliliters) of preparation 8, and stirred this reaction mixture 24 hours.The hydrochloric acid soln (21.2 milliliters, 21.2 mmoles) that adds 1M reaches to remove in a vacuum and desolvates.Allow crude product resistates and the methanol azeotropic that is obtained, be not further purified subsequently and use this product.
1H NMR(400MHz，DMSO-d
6)δ1.07(6H，s)，2.74-2.87(4H，m)，3.39(2H，s)，4.63-4.61(1H，d)，6.14-6.15(1H，t)，6.24-6.25(2H，d)，6.96-7.22(4H，m)。
LRMS：m/z APCI
+357[MH
+]。
Preparation 10
1-(3,5-couple-benzyloxy-phenyl)-2-bromo-ethanol
To be added to (R)-2-(phenylbenzene hydroxymethyl pyrrolidine) (1.48 grams, 5.80 mmoles) at the trimethylboroxin in the toluene (15 milliliters) (0.58 milliliter, 4.20 mmoles), and under nitrogen, stir this reaction 15 minutes.Utilize evaporation,, this liquor capacity is concentrated into 5 milliliters and the further toluene (10 milliliters) that adds at 1 normal atmosphere.Evaporate/redilution circulation 3 times, so that an orange solution (10 milliliters of the volumes of toluene) to be provided.Under-8 ℃, in nitrogen, this solution is added to the stirred solution of compound (5.00 grams, 12.2 mmoles) in tetrahydrofuran (THF) (72 milliliters) of preparation 6 by part.Utilize syringe pump, in 90 minutes, the solution of borine methyl thioether mixture (1.60 milliliters, 16.8 mmoles) in tetrahydrofuran (THF) (16 milliliters) added mixture so far, and with temperature maintenance at-8 ℃.In case add and to finish, in 45 minutes, utilize syringe pump to add methyl alcohol (16 milliliters), and with temperature maintenance at 0 ℃ and in 12 hours, reaction is heated to room temperature.Remove in a vacuum and desolvate so that a yellow oil to be provided, and add methyl alcohol (80 milliliters) and remove in a vacuum.Adding methyl alcohol (80 milliliters) reaches and removes in a vacuum, the yellow oil that is produced is dissolved in the methylene dichloride (500 milliliters), aqueous hydrochloric acid (96 milliliters), water (2 * 120 milliliters) with 1M clean, dry (sal epsom) reaches to remove in a vacuum and desolvates, so that title compound to be provided, be the creaminess solid, 4.73 grams.
1H NMR(400MHz，CD
3OD)δ3.52(1H，m)，3.62(1H，m)，4.82(1H，dd)，5.09(4H，s)，6.60(1H，m)，6.69(1H，s)，6.70(1H，s)，7.33(2H，m)，7.40(4H，m)，7.45(5H，m)。
LRMS:m/z electron spray(ES) 413,415[M+H
+].
Preparation 11
[1-(3,5-couple-benzyloxy-phenyl)-2-bromo-the oxyethyl group]-tertiary butyl-dimethyl-silane
Under 0 ℃, in nitrogen, with (3.40 milliliters of tertiary butyl dimethylsilane trifluoromethane sulfonic acid esters, 7.45 mmole) dropwise be added to compound (3.08 grams of preparation 10,7.45 mmole) with 2, the solution of 6-lutidine (1.75 milliliters, 15.0 mmoles) in methylene dichloride (74 milliliters).In 12 hours reaction is heated to room temperature, aqueous hydrochloric acid (2 * 24 milliliters), the water (2 * 32 milliliters) with 1M cleans then, and dry (sal epsom) reaches to remove in a vacuum and desolvates, so that yellow oil to be provided.This utilizes column chromatography purifying on the silicon gel, with the methylene dichloride wash-out, can provide title compound, is water white oil, 3.51 grams.
1H NMR(400MHz，CD
3OD)δ-0.07(3H，s)，0.13(3H，s)，0.93(9H，s)，3.52(2H，m)，4.86(1H，dd)，5.10(4H，s)，6.60(1H，m)，6.65(1H，s)，6.66(1H，s)，7.33(2H，m)，7.40(4H，m)，7.45(4H，m)。
LRMS:m/z electron spray(ES) 549[M+Na
+].
Preparation 12
3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-2-methyl-propyl group }-benzoic acid methyl ester
The compound (2.54 grams, 4.80 mmoles) of preparation 11 is heated to 75 ℃ with the solution of compound (2.00 grams, 9.60 mmoles) in methylene dichloride (40 milliliters) for preparing 21, allows solvent evaporation fall.Under 75 ℃, the melt that heating is produced 4 days is cooled to room temperature with it then.Utilize column chromatography purifying resistates on the silicon gel, with 100: 0: 0 then with 95: 5: 0.5 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be yellow oil, 2.00 grams.
1H NMR(400MHz，CD
3OD)δ-0.18(3H，s)，-0.04(3H，s)，0.78(9H，s)，1.11(3H，s)，1.13(3H，s)，2.70(4H，m)，3.92(3H，s)，4.70(1H，dd)，5.12(4H，s)，6.60(1H，m)，6.62(1H，s)，6.63(1H，s)，7.32(2H，m)，7.38(6H，m)，7.45(4H，m)，7.92(2H，m)。
LRMS:m/z electron spray(ES) 654[M+H
+].
Preparation 13
3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-2-methyl-propyl group }-benzoic acid methyl ester
At room temperature, palladium hydroxide (340 milligrams) is added to the compound (1.97 grams, 3.00 mmoles) and the stirred solution of ammonium formiate (2.17 grams, 47.1 mmoles) in ethanol (31 milliliters) of preparation 12 by part.Under refluxing, heat this reaction 2 hours and allow it be cooled to room temperature.Should react by A Boxier and filter and concentrating filtrate in a vacuum, so that title compound to be provided, be the white foam shape, 1.41 grams.
1H NMR(400MHz，CD
3OD)δ-0.11(3H，s)，-0.00(3H，s)，0.81(9H，s)，1.13(3H，s)，1.15(3H，s)，2.70(4H，m)，3.96(3H，s)，4.63(1H，dd)，6.22(1H，m)，6.33(1H，s)，6.34(1H，s)，7.42(2H，m)，7.92(2H，m)。
LRMS:m/z electron spray(ES) 474[M+H
+], 496[Mna
+], 472[M-H
-].
Preparation 14
3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-2-methyl-propyl group }-phenylformic acid
At room temperature, the lithium hydroxide aqueous solution (9.00 milliliters, 9.00 mmoles) of 1M is added to the stirred solution of compound (1.39 grams, 2.93 mmoles) in tetrahydrofuran (THF) (30 milliliters) of preparation 13 by part.At room temperature stir this reaction 24 hours, and the aqueous hydrochloric acid (9.00 milliliters, 9.00 mmoles) that adds 1M by part.Remove in a vacuum and desolvate,, be brown foam-like material, 2.06 grams so that title compound to be provided.
1H NMR(400MHz，CD
3OD)δ-0.05(3H，s)，0.07(3H，s)，0.83(9H，s)，1.35(3H，s)，1.37(3H，s)，3.08(2H，m)，3.25(2H，m)，4.93(1H，m)，6.29(1H，m)，6.38(1H，s)，6.39(1H，s)，7.42(2H，m)，7.92(1H，m)，8.00(1H，m)。
LRMS:m/z electron spray(ES) 460[M+H
+].
Preparation 15
3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-2-methyl-propyl group }-N-[2-(4-chloro-phenyl)-ethyl]-benzamide
At room temperature, in nitrogen, with (967 milligrams of 4-chlorobenzene ethyl amine, 6.20 mmole), triethylamine is (1.00 milliliters, 7.20 mmole), hydroxybenzotriazole (567 milligrams, 4.20 mmoles) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (910 milligrams, 4.70 mmoles) are added to compound (2.06 grams of preparation 14,3.50 mmole) at N, the stirred solution in the dinethylformamide (35 milliliters).Stir this reaction reached in a vacuum except that desolvating in 12 hours, then, allow resistates and toluene (20 milliliters) azeotropic and utilize column chromatography purifying on the silicon gel, with 100: 0: 0 then with 95: 5: 0.5 then with 90: 10: 1 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, column chromatography again, with the ethyl acetate of 0: 100: 0 (changing to 80: 20: 5 when 10% step): pentane: 880 ammonia wash-outs, so that title compound to be provided, be the creaminess foam-like material, 773 milligrams.
1H NMR(400MHz，CD
3OD)δ-0.10(3H，s)，0.01(3H，s)，0.84(9H，s)，1.12(3H，25s)，1.14(3H，s)，2.74(4H，m)，3.94(2H，m)，3.62(2H，m)，4.66(1H，dd)，6.22(1H，m)，6.34(1H，s)，6.35(1H，s)，7.42(6H，m)，7.67(2H，m)。
LRMS:m/z electron spray(ES) 597[M+H
+].
Preparation 16
1-(3-bromophenyl)-2-methyl propan-2-ol)
Under 0 ℃, methylmagnesium-bromide (solution of 3M in Anaesthetie Ether, 51.6 milliliters, 155 mmoles) slowly is added to the solution of 1-(3-bromo-phenyl) third-2-ketone (15.0 grams, 70 mmoles) in anhydrous Anaesthetie Ether (200 milliliters).Allow the mixture of gained leave over 3 hours, be cooled to 0 ℃ then and reach slowly with saturated aqueous ammonium chloride solution stopped reaction.Clean organic phase and drying (sodium sulfate) with salt solution.Then, utilize column chromatography this yellow oil of purifying on the silicon gel, with the methylene dichloride of 90: 5: 5 (by volume): pentane: methanol-eluted fractions can obtain a light yellow oil (13.26 gram).
1H NMR(400MHz，CDCl
3)δ＝7.40(2H，m)，7.15(2H，m)，2.74(2H，s)，1.42(1H，bs)，1.22(6H，s)。
Preparation 17
N-[2-(3-bromophenyl)-1, the 1-dimethyl ethyl]-the 2-chlor(o)acetamide
At room temperature, chloromethyl cyanide (6.63 milliliters, 105 mmoles) is added to the stirred solution of 1-(3-bromophenyl)-2-methyl propan-2-ol (preparation 16) (12.0 grams, 52.0 mmoles) in acetate (25 milliliters).The solution that is produced is cooled to 0 ℃, adds the vitriol oil (25 milliliters) and temperature is remained on＜10 ℃.Leave over the solution that produced to stir 1 hour, then it is poured on ice and by adding solid carbonic acid potashization.With ethyl acetate (2 * 500 milliliters) extraction product, combined organic and Yi Shui (50 milliliters) clean, and dry (sodium sulfate) reaches to remove in a vacuum and desolvates, and can obtain title compound, are orange solids (16.08 gram).
1H NMR(400MHz，CDCl
3)δ＝7.39-7.32(1H，d)，7.26(1H，s)，7.1-7.13(1H，t)，7.08-7.03(1H，d)，6.17(1H，bs)，3.94(2H，s)，3.02(2H，s)，1.37(6H，s)。
C
12H
15The CHN calculated value (measured value) of BrClNO: C 47.32 (47.26), H4.96 (4.87), and N 4.60 (4.65).
LRMS (electron spray(ES)) m/z 306[M+H]
+
Preparation 18
2-(3-bromophenyl)-1, the 1-dimethylethyl amine
Will be at the N-[2-(3-bromophenyl)-1 in the ethanol (250 milliliters), 1-dimethyl ethyl]-2-chlor(o)acetamide (preparation 17) (32.0 grams, 105 mmoles), thiocarbamide (9.60 grams, 126 mmoles) and acetate (50 milliliters) solution is heated to reflux and spends the night.This reaction mixture is cooled to room temperature and filtration, in a vacuum concentrating filtrate and use aqueous sodium hydroxide solution (1M, 450 milliliters) alkalization.Clean the bonded organism with methylene dichloride (2 * 500 milliliters) extraction product and with salt solution (50 milliliters), dry (sodium sulfate) reaches to remove in a vacuum and desolvates, and can obtain title compound, is black oil (23 gram).
1H NMR(400MHz，CDCl
3)δ＝7.36-7.32(2H，m)，7.16-7.08(2H，m)，2.62(2H，s)，1.84(2H，bs)，1.12(6H，s)。
LRMS (electron spray(ES)) m/z 228[M+H]
+
Preparation 19
[2-(3-bromophenyl)-1,1-dimethyl ethyl] carboxylamine tertiary butyl ester
Handle 2-(3-bromophenyl)-1 with the tert-Butyl dicarbonate in methylene dichloride (50 milliliters) (5.26 gram, 24 mmoles), 1-dimethylethyl amine (preparation 18) (5.0 grams, 22 mmoles) and stirring 20 hours.Clean this reaction mixture with water (50 milliliters), dry (sodium sulfate) bonded organism reaches to remove in a vacuum and desolvates.Use cationic exchange column purification crude product material (methyl alcohol then is the ammonia of 2M in methyl alcohol), then utilize hurried column chromatography purifying on the silicon gel,, can obtain title compound, be brown oil (7.23 gram) with the methylene dichloride wash-out.
1H NMR(400MHz，CDCl
3)δ＝7.35(1H，d)，7.30(1H，s)，7.15-7.11(1H，t)，7.05(1H，d)，4.24(1H，bs)，2.97(2H，s)，1.50(9H，s)，1.27(6H，s)。
LRMS (electron spray(ES)) m/z 350[M+NH
4]
+
Preparation 20
3-(2-tert-butoxycarbonyl amino-2-methyl propyl group) benzoic acid methyl ester
In the carbon monoxide of 100psi, [2-(3-bromophenyl)-1 that will be in methyl alcohol (250 milliliters), the 1-dimethyl ethyl] carboxylamine tertiary butyl ester (preparation 19) (7.0 grams, 21 mmoles), [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II) (1.74 grams, 2.1 mmole) and triethylamine (5.94 milliliters, 43 mmoles) solution be heated to 100 ℃ 12 hours.Reaction mixture is reached concentrating filtrate in a vacuum by A Boxier filtration, utilize hurried column chromatography purifying on the silicon gel, methylene dichloride with 50: 50 (by volume): the pentane wash-out, can obtain title compound, be yellow solid (3.76 gram).
1H NMR(400MHz，CDCl
3)δ＝7.92-7.90(1H，m)，7.82(1H，s)，7.35-7.34(2H，m)，4.24(1H，bs)，3.90(3H，s)，3.05(2H，s)，1.48(9H，s)，1.26(6H，s)。
LRMS (electron spray(ES)) m/z 208[M+H-BOC]
+
Preparation 21
3-(2-amino-2-methyl propyl group) benzoic acid methyl ester
Under 0 ℃, with 3-(2-tert-butoxycarbonyl amino-2-methyl propyl group) benzoic acid methyl ester (preparation 20) (1.6 grams of trifluoroacetic acid (13.6 milliliters) processing in methylene dichloride (160 milliliters), 5.2 solution mmole), and leave over to be heated to room temperature above 2 hours.Except that desolvating and utilizing cation-exchange chromatography purified product (methyl alcohol then is the ammonia of 2M in methyl alcohol),, be amber oil (1.06 gram) in a vacuum to produce title compound.
1H NMR(400MHz，CDCl
3)δ＝7.90-7.88(1H，m)，7.84(1H，s)，7.36-7.35(2H，m)，3.90(3H，s)，2.71(2H，s)，1.67(2H，bs)，1.12(6H，s)。
LRMS (electron spray(ES)) m/z 208[M+H]
+
Preparation 22
3-[(2R)-the 2-aminopropyl] phenyl } methyl acetate
Will [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino }-propyl group)-phenyl]-methyl acetate hydrochloride (preparation 23) (7.69 grams, 22 mmoles) with ammonium formiate (6.94 grams, 110 mmoles) solution, (the Pd (OH) of palladium hydroxide on 20% activated carbon
2/ C, 2.00 grams) be heated to 75 ℃ under existing.After 90 minutes, this reaction mixture is cooled to room temperature, filter by A Boxier and reach concentrating filtrate in a vacuum.Be distributed in resistates between methylene dichloride (100 milliliters) and 880 ammonia (100 milliliters) and separate organic phase.With methylene dichloride (100 milliliters) aqueous phase extracted, and dry (sal epsom) bonded organic extract and minimizing in a vacuum, title compound can be provided, be water white oil (4.78 gram).
1H NMR(400MHz，CD
3OD)：δ＝7.27-7.23(1H，t)，7.13-7.09(3H，m)，3.67(3H，s)，3.63(2H，s)，3.12-3.05(1H，m)，2.67-2.57(2H，m)，1.06(3H，d)ppm。
LRMS (electron spray(ES)): m/z [M+H]
+208, [M+Na]
+230.
Preparation 23
[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino }-propyl group)-phenyl]-the methyl acetate hydrochloride
With [3-(2-oxopropyl) phenyl] methyl acetate (preparation 24) (8.50 grams, 41.2 mmole), (R)-Alpha-Methyl benzylamine is (4.8 milliliters, 37.2 sodium triacetoxy borohydride (11.6 grams mmole),, 56 mmoles) and (2.2 milliliters of acetate, 38 mmoles) solution in methylene dichloride (400 milliliters) at room temperature stirred 48 hours.End this reaction mixture by adding saturated sodium bicarbonate aqueous solution (200 milliliters), and stir it and stop up to effervesce.Separating organic phase reaches with methylene dichloride (100 milliliters) aqueous phase extracted.Dry (sal epsom) bonded organic extract and minimizing in a vacuum.Utilize hurried column chromatography purifying, with the methylene dichloride of 99: 1: 0.1 to 95: 5: 0.5 (by volume): methyl alcohol: the ammonia wash-out, 4: 1 non-enantiomer mixture (R, R is main) can be provided, be light yellow oil (8.71 gram).Handle with hydrogenchloride (40 milliliters, the solution of 1M in methyl alcohol, 40 mmoles), then, can provide title compound, be white crystalline solid (5.68 gram) for continuous three crystallizations (Di Iso Propyl Ether/methyl alcohol).
1H NMR(400MHz，CD
3OD)：δ＝7.52-7.48(5H，m)，7.28-7.25(1H，m)，7.18-7.16(1H，m)，7.02-6.99(2H，m)，4.59(1H，q)，3.62(2H，s)，3.30(3H，s)，3.30-3.25(1H，m)，3.26-3.15(1H，m)，2.66-2.60(1H，m)，1.68(3H，d)，1.18，(3H，d)ppm。
LRMS (electron spray(ES)): m/z[M+H]
+312, [M+Na]
+334.
Preparation 24
[3-(2-oxopropyl) phenyl] methyl acetate
Under 100 ℃, under nitrogen with (28.3 milliliters of methanolizing tributyl tins, 98 mmoles), preparation 25 (15.0 grams, 65 mmoles), methylvinyl acetate is (10.8 milliliters, 98 mmoles), acid chloride (II) is (750 milligrams, 3.30 mmole) and tri-o-tolyl phosphine (2.0 gram, 6.5 mmoles) be stirred in the toluene (75 milliliters) 5 hours together.After cooling, dilute this reaction and stirred 15 minutes with the potassium fluoride aqueous solution (90 milliliters) of ethyl acetate (150 milliliters) and 4M.Allow this mixture filter, separate organic phase and minimizing in a vacuum by A Boxier .Utilize hurried column chromatography purifying resistates on the silicon gel, with the Anaesthetie Ether of 0: 100 to 25: 75 (by volume): pentane changes over the solvent gradient elution of methylene dichloride, and title compound can be provided, and is light yellow oil (12.6 gram).
1H NMR(400MHz，CDCl
3)δ＝7.30(1H，t)，7.19(1H，d)，7.13-7.10(2H，m)，3.69(5H，s)，3.61(2H，s)，2.15(3H，s)ppm。
LRMS (electron spray(ES)): m/z[M+NH
4]
+224, [M+Na]
+229.
Preparation 25
(3-bromophenyl) methyl acetate
Under 0 ℃, in nitrogen, ethanoyl chlorine (0.7 milliliter, 9.3 mmoles) slowly is added to the solution of (3-bromo-phenyl)-acetate (20.0 gram, 93 mmoles) in methyl alcohol (500 milliliters), in 5 hours, should react and be heated to room temperature gradually.Remove in a vacuum and desolvate, the oil of remnants is dissolved in the methylene dichloride again, dry (sodium sulfate) and concentrate in a vacuum can provide title compound, is water white oil (20.6 gram).
1H NMR(400MHz，CDCl
3)：δ＝7.37-7.45(2H，m)，7.24-7.17(2H，m)，3.70(3H，s)，3.59(2H，s)ppm。
LRMS (electron spray(ES)): m/z[M+Na]
+253.
Preparation 26
[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino }-propyl group)-phenyl]-acetate
At room temperature, the lithium hydroxide aqueous solution (90 milliliters, 90 mmoles) of 1M is added to the stirred solution of compound (13.5 grams, 43.5 mmoles) in methyl alcohol (2000 milliliters) of preparation 23 by part.At room temperature stir this reaction 24 hours and pursued the aqueous hydrochloric acid (90 milliliters, 90 mmoles) that part adds 1M.Remove in a vacuum and desolvate, volume being reduced to 80 milliliters, and by shifting out the filtration white depositions, and clean with the ethanol (100 milliliters) of water (20 milliliters), 20% in water, drying can provide title compound, is white solid, 11.8 grams.
1H NMR(400MHz，CD
3OD)δ1.16(3H，d)，1.62(3H，d)，2.64(1H，m)，3.20(2H，m)，3.46(2H，s)，4.42(1H，q)，6.91(1H，d)，7.08(1H，s)，7.19(1H，s)，7.20(1H，m)，7.48(5H，m)。
LRMS:m/z electron spray(ES) 298[M+H
+], 296[M-H
-].
Preparation 27
N-diamantane-1-base-2-{3-[2-(1-phenyl-ethylamino)-propyl group]-phenyl }-ethanamide
At room temperature, in the stirred suspension of compound (297 milligrams, 1.00 mmoles) in methylene dichloride (4 milliliters) of preparation 26, add 1-adamantanamines (151 milligrams, 1.00 mmoles) and stirred this suspension 15 minutes.Be equal phase time in this reaction, add phosphofluoric acid 2-chloro-1,3-methylimidazole quinoline (278 milligrams, 1.00 mmoles) and stir this reaction 2 hours by part.Clean this reaction with water (5 milliliters), dry (sal epsom) reaches to remove in a vacuum and desolvates.Utilize column chromatography purifying resistates on the silicon gel, with 98: 2: 0.2 methylene dichloride of 95: 5: 0.5 then: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be weak yellow foam shape material, 325 milligrams.
1H NMR(400MHz，CD
3OD)δ0.89(3H，d)，1.36(3H，d)，1.75(6H，m)，1.98(6H，s)，2.04(6H，s)，2.40(1H，dd)，2.74(1H，m)，3.00(1H，dd)，3.36(2H，s)，4.00(1H，q)，6.90(1H，d)，6.98(1H，s)，7.08(1H，d)，7.19(1H，t)，7.22(1H，m)，7.38(4H，m)。
LRMS:m/z electron spray(ES) 431[M+H
+].
Preparation 28
N-diamantane-1-base-2-[3-(2-amino-propyl group)-phenyl]-ethanamide
(the Pd (OH) of palladium hydroxide on 20% activated carbon
2/ C, 2.00 restrain) exist down, the compound (17.6 grams, 36 mmoles) of preparation 27 and the solution of ammonium formiate (22.7 grams, 360 mmoles) are heated to 70 ℃.After 60 minutes, add other catalyzer (500 milligrams) and further heat this reaction 4 hours.This reaction mixture is cooled to room temperature, filters by A Boxier and reach concentrating filtrate in a vacuum.Resistates is distributed between 880 ammonia (150 milliliters) of methylene dichloride (300 milliliters) and 10% in water, separates organic phase, dry (sodium sulfate) and minimizing in a vacuum.Utilize column chromatography purifying resistates on the silicon gel, with 95: 5: 0.5 then with 90: 10: 1 methylene dichloride: methyl alcohol: 880 ammonia wash-outs so that title compound to be provided, are white solid, 10.8 grams.
1H NMR(400MHz，CD
3OD)δ1.09(3H，d)，1.68(6H，m)，2.00(6H，s)，2.03(3H，s)，2.64(2H，m)，3.14(1H，q)，3.40(2H，s)，7.14(4H，m)。
LRMS (electron spray(ES)): m/z[M+H]
+327.
Preparation 29
N-diamantane-1-base-2-(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-phenyl)-ethanamide
The compound (263 milligrams, 0.50 mmole) of preparation 11 is heated to 90 ℃ with the solution of compound (326 milligrams, 1.00 mmoles) in methylene dichloride (1 milliliter) for preparing 28.And solvent evaporated.The melt that heating is produced under 90 ℃ 1 day is cooled to room temperature with it then.Utilize column chromatography purifying resistates on the silicon gel, with 98: 2: 0.2 methylene dichloride: methyl alcohol; 880 ammonia wash-outs can provide title compound, are transparent oil, 168 milligrams.
1H NMR(400MHz，CD
3OD)δ-0.09(3H，s)，-0.02(3H，s)，0.82(9H，s)，1.03(3H，d)，1.66(6H，s)，1.99(6H，s)，2.02(3H，s)，2.59(1H，m)，2.65(2H，m)，2.85(2H，m)，3.37(2H，s)，4.86(1H，m)，5.06(4H，m)，6.54(3H，m)，7.00(14H，m)。
LRMS:m/z electron spray(ES) 773[M+H
+].
Preparation 30
N-diamantane-1-base-2-(3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino }-propyl group)-phenyl)-ethanamide
(the Pd (OH) of palladium hydroxide on 20% activated carbon
2/ C, 20 milligrams) exist down, the compound (160 milligrams, 0.21 mmole) of preparation 29 and the solution of ammonium formiate (150 milligrams, 2.10 mmoles) are heated to 70 ℃.After 3 hours, this reaction mixture is cooled to room temperature, filter by A Boxier and reach concentrating filtrate in a vacuum.Resistates is distributed between 880 ammonia (10 milliliters) of ethyl acetate (10 milliliters) and 10% in water, separates organic phase and drying.Organism so that methylene dichloride (2 * 50 milliliters) aqueous phase extracted and drying (sodium sulfate) merge reduces in a vacuum, and title compound can be provided, and is yellow foam-like material, 160 milligrams.
1H NMR(400MHz，CD
3OD)δ-0.16(3H，s)，0.01(3H，s)，0.84(9H，s)，1.03(3H，d)，1.69(6H，m)，2.01(9H，m)，2.60(3H，m)，2.91(2H，m)，3.39(2H，s)，4.60(1H，m)，6.13(1H，m)，6.20(2H，m)，6.98(1H，d)，7.05(1H，s)，7.07(1H，d)，7.18(1H，t)。
LRMS:m/z electron spray(ES) 593[M+H
+], 591[M-H]
-
Preparation 31
(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-2-methyl-propyl group }-phenyl)-the acetate methyl ester
Merge the compound (5.30 grams, 10.0 mmoles) of preparation 11 and the solution of the compound (4.42 grams, 20.0 mmoles) of preparation 5, and in nitrogen, be heated to 92 ℃.The melt that heating is produced under 92 ℃ 24 hours is cooled to room temperature with it then.Utilize column chromatography purifying resistates on the silicon gel, with 98: 2: 0.2 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be golden oil, 5.38 grams.
1H NMR(400MHz，CD
3OD)δ-0.20(3H，s)，-0.03(3H，s)，0.79(9H，s)，1.01-1.03(6H，d)，2.58-2.82(4H，m)，3.59(2H，s)，3.63(3H，s)，4.62-4.66(1H，m)，4.84(4H，s)，6.76(3H，s)，7.15-7.65(14H，m)。
LRMS:m/z electron spray(ES) 668[M+H
+].
Preparation 32
(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-2-methyl-propyl group }-phenyl)-acetate
At room temperature, in nitrogen, the lithium hydroxide aqueous solution (8.80 milliliters, 8.80 mmoles) of 1M is added to the stirred solution of compound (5.30 grams, 7.95 mmoles) in tetrahydrofuran (THF) (150 milliliters) of preparation 31 by part.At room temperature stir this reaction 24 hours and pursued the aqueous hydrochloric acid (8.80 milliliters, 8.80 mmoles) that part adds 1M.Remove most solvents in a vacuum, the mixture of gained is distributed between methylene dichloride (200 milliliters) and the water (200 milliliters).Clean organic layer with salt solution (50 milliliters), dry (sodium sulfate) reaches to remove in a vacuum and desolvates, and can obtain title compound, is colourless foam shape material (5.16 gram).
1H NMR(400MHz，CD
3OD)δ-0.17(3H，s)，0.02(3H，s)，0.82(9H，s)，1.26(6H，s)，2.84-2.96(2H，q)，3.18-3.19(2H，d)，3.53(2H，s)，4.87-4.92(1H，t)，5.10(4H，s)，6.60-6.63(3H，m)，7.03-7.43(14H，m)
LRMS:m/z electron spray(ES) 654[M+H
+].
Preparation 33
(3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-2-methyl-propyl group }-phenyl)-acetate
At room temperature, palladium hydroxide (500 milligrams) is added to the compound (5.10 grams, 7.81 mmoles) and the stirred solution of ammonium formiate (5.00 grams, 74.6 mmoles) in ethanol (250 milliliters) of preparation 32 by part.Heat this reaction 3 hours down at 70 ℃.Then, add other palladium hydroxide (250 milligrams) and 70 ℃ down heating this reacted other 1.5 hours, and in nitrogen, allow it be cooled to ambient temperature overnight.Should react by A Boxier filtration and reach concentrating filtrate in a vacuum.With water (50 milliliters) grinding residues and filtration, title compound can be provided, be white solid, 3.61 grams.
1H NMR(400MHz，CD
3OD)δ-0.07(3H，s)，0.03(3H，s)，0.83(9H，s)，1.34(6H，s)，2.90-2.97(2H，q)，3.18-3.19(2H，s)，3.50-3.58(2H，q)，4.85-4.95(1H，m)，6.12(1H，s)，6.35(2H，s)，7.03-7.35(4H，m)。
LRMS:m/z electron spray(ES) 474[M+H
+].
Preparation 34
2-(3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3,4-two chloro-benzyls)-ethanamide
At room temperature, in nitrogen, with 3, (53 milligrams of 4-dichloro benzyl amine, 0.301 mmole), hydroxybenzotriazole (39 milligrams, 0.289 mmole) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (57 milligrams, 0.297 mmole) are added to (142 milligrams of preparation 33 compounds, 0.300 mmole) at N, the stirred solution in the dinethylformamide (2 milliliters).Stir this reaction 18 hours and remove in a vacuum and desolvate, then resistates is distributed between methylene dichloride (50 milliliters) and the saturated sodium bicarbonate aqueous solution (50 milliliters).Dry (sodium sulfate) organic layer and remove in a vacuum and desolvate, and utilize column chromatography purifying on the silicon gel, with 95: 5: 0.5 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be the creaminess foam-like material, 125 milligrams.
1H NMR(400MHz，CD
3OD)δ-0.16(3H，s)，0.00(3H，s)，0.82(9H，s)，1.01-1.03(6H，d)，2.60-2.86(4H，m)，3.52(2H，s)，4.31(2H，s)，4.78-4.81(1H，m)，6.18(1H，s)，6.29(2H，s)，7.02-7.24(5H，m)，7.36-7.42(2H，m)。
LRMS:m/z electron spray(ES) 631[M+H
+].
Preparation 35
(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-phenyl)-the acetate methyl ester
The compound (5.00 grams, 9.45 mmoles) of preparation 11 is heated to 95 ℃ with the solution of compound (3.92 grams, 18.9 mmoles) in methylene dichloride (50 milliliters) for preparing 22, and solvent evaporated.The melt that heating is produced under 95 ℃ 24 hours is cooled to room temperature with it then.Add Anaesthetie Ether (50 milliliters) and stirred this mixture 5 minutes.Isolate the ether layer from this glue, extract this glue twice with Anaesthetie Ether (2 * 50 milliliters) then.Merging this ether extract reaches in a vacuum except that desolvating.Utilize column chromatography purifying resistates on the silicon gel, with 100: 0: 0 to 95: 5: 0.5 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be pale yellow glue, 4.50 grams.
1H NMR(400MHz，CD
3OD)δ-0.20(3H，s)，-0.05(3H，s)，0.81(9H，s)，1.01-1.03(3H，d)，2.60(3H，m)，2.86(2H，m)，3.55(2H，s)，3.63(3H，s)，4.66(1H，m)，4.85(4H，m)，6.70(3H，m)，6.73(1H，m)，6.98(2H，m)，7.06(1H，m)，7.17(1H，m)，7.10(2H，m)，7.11-7.22(7H，m)。
LRMS:m/z electron spray(ES) 654[M+H
+].
Preparation 36
3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-2-methyl-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide
At room temperature, in nitrogen, with (95 milligrams of 2-fluorophenyl ethylamines, 0.680 mmole), hydroxybenzotriazole is (100 milligrams, 0.740 mmole), triethylamine (0.10 milliliter, 0.720 mmole) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (79 milligrams, 0.410 mmole) are added to (151 milligrams of preparation 14 compounds, 0.330 mmole) at N, the stirred solution in the dinethylformamide (1 milliliter).Stir this reaction reached in a vacuum except that desolvating in 18 hours, utilize column chromatography purifying on the silicon gel, with 100: 0: 0 to 95: 5: 0.5 to 90: 10: 1 methylene dichloride: methyl alcohol: 880 ammonia wash-outs can provide title compound, be the creaminess foam-like material, 132 milligrams.
1H NMR(400MHz，CD
3OD)δ-0.16(3H，s)，-0.02(3H，s)，0.78(9H，s)，1.12(6H，d)，2.65-2.95(6H，m)，3.61(2H，s)，4.64(1H，s)，6.18(1H，s)，6.29(2H，s)，6.93(1H，m)，7.02(1H，m)，7.06(1H，m)，7.20-7.39(3H，m)，7.64(2H，m)。
LRMS:m/z electron spray(ES) 581[M+H
+].
Use preparation 36 disclosed methods, prepare 37 to 43 with suitable amine from preparing 14 compound:
Preparation 44
(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-phenyl)-acetate
At room temperature, the lithium hydroxide aqueous solution (16.0 milliliters, 16.0 mmoles) of 1M is added to the stirred solution of compound (4.75 grams, 7.26 mmoles) in tetrahydrofuran (THF) (20 milliliters) of preparation 35 by part.At room temperature stir this reaction 24 hours, the aqueous hydrochloric acid that adds 1M arrives 1-2 up to pH.With methylene dichloride (1 * 200 milliliter, 2 * 50 milliliters then) extraction, clean the organic layer that merges with salt solution (20 milliliters), dry (sal epsom) reaches to remove in a vacuum and desolvates, and the title compound hydrochloride can be provided, and is the canescence foam-like material, 4.80 grams.
1H NMR(400MHz，CD
3OD)δ-0.12(3H，s)，0.06(3H，s)，0.86(9H，s)，1.23(3H，d)，2.77(1H，m)，3.03(1H，m)，3.23(1H，m)，3.45-3.60(3H，m)，5.01(1H，m)，5.10(4H，s)，6.64(2H，m)，6.68(1H，m)，7.10(1H，m)，7.15(1H，s)，7.23(1H，m)，7.27-7.43(11H，m)。
LRMS：m/z APCI 640[M+H
+]。
Preparation 45
(3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-propyl group }-phenyl)-acetate
At room temperature, palladium hydroxide (350 milligrams) is added to the compound (3.50 grams, 5.48 mmoles) and the stirred solution of ammonium formiate (1.80 grams, 39.1 mmoles) in ethanol (250 milliliters) of preparation 44 by part.This reaction of heating is 45 minutes under refluxing, and it is cooled to room temperature.Should react by A Boxier and filter and concentrating filtrate in a vacuum, title compound can be provided, be faint yellow solid, 2.30 grams.
1H NMR(400MHz，CD
3OD)δ-0.06(3H，s)，0.06(3H，s)，0.86(9H，s)，1.25(3H，d)，2.81(1H，m)，2.96(1H，m)，3.15(1H，m)，3.25(1H，m)，3.43-3.55(3H，m)，4.89(1H，m)，6.24(1H，m)，6.33(2H，m)，7.06(1H，m)，7.17(1H，s)，7.19-7.28(2H，m)。
LRMS：m/z APCI 460[M+H
+]。
Can use the method preparation 46 to 48,55 to 65 and 73 to 76 of preparation 34 from preparing 33 and suitable amine.These compounds have following general formula:
Be listed in the following table.
Can use the method preparation 49 to 54,66 to 72 and 77 to 87 of preparation 34 from preparing 45 and suitable amine.These compounds have following general formula:
Be listed in the following table.
Preparation 88
3-[(2R)-the 2-aminopropyl] phenyl } methyl acetate
(the Pd (OH) of palladium hydroxide on 20% activated carbon
2/ C, 1.36 gram) exist down, will [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino }-propyl group)-phenyl]-methyl acetate (preparation 89) (13.65 grams, 40.9 mmoles) is heated to backflow with the solution of ammonium formiate (12.9 grams, 204 mmoles) in ethanol (200 milliliters).After 3 hours, this reaction mixture is cooled to room temperature, filter by A Boxier and reach concentrating filtrate in a vacuum.Be distributed in resistates between methylene dichloride (200 milliliters) and 880 ammonia (100 milliliters) and separate organic phase.With other methylene dichloride (3 * 100 milliliters) aqueous phase extracted, clean the organic extract that merges with salt solution (100 milliliters), dry (sodium sulfate) and minimizing in a vacuum can provide title compound (8.48 gram), are light yellow oil.
1H NMR(400MHz，CDCl
3)：δ＝7.90-7.87(2H，m)，7.38-7.34(2H，m)，3.90(3H，s)，3.26-3.17(1H，m)，2.78-2.73(1H，dd)，2.64-2.59(1H，dd)，1.14-1.12(3H，d)ppm。
LRMS (electron spray(ES)): m/z[M+H]
+194.
Preparation 89
[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino }-propyl group)-phenyl]-the methyl acetate hydrochloride
At room temperature, stir [3-(2-oxopropyl) phenyl] methyl acetate (preparation 90) (45.3 grams, 236 mmoles), (R)-Alpha-Methyl benzylamine is (27.6 milliliters, 214 mmoles), sodium triacetoxy borohydride (68.1 grams, 321 mmoles) and the solution of acetate (14.7 milliliters, 257 mmoles) in methylene dichloride (1500 milliliters) 18 hours.Add saturated sodium bicarbonate aqueous solution (600 milliliters) and end this reaction mixture, and allow its stirring stop up to effervesce.Separating organic phase reaches with other methylene dichloride (2 * 100 milliliters) aqueous phase extracted.With the organic extract that salt solution (100 milliliters) cleaning merges, dry (sodium sulfate) filters and minimizing in a vacuum by diatomite (celite).This oil is dissolved in the methyl alcohol (200 milliliters), handles and minimizing in a vacuum, 4: 1 non-enantiomer mixture (R, R are main) can be provided, be the canescence hydrochloride with the hydrogenchloride (300 milliliters) of 1M in methyl alcohol.Continuous quadratic crystallization (Di Iso Propyl Ether/methyl alcohol) can provide title compound (27.3 gram), is colourless crystalline solid.
1H NMR(400MHz，CD
3OD)：δ＝7.92-7.90(1H，d)，7.75(1H，s)，7.55-7.49(5H，m)，7.45-7.42(1H，dd)，7.35-7.33(1H，d)，4.68-4.63(1H，q)，3.90(3H，s)，3.43-3.38(1H，dd)，3.25-3.19(1H，m)，2.71-2.65(1H，dd)，1.71-1.69(3H，d)，1.17-1.16，(3H，d)ppm。
Preparation 90
[3-(2-oxopropyl) phenyl] methyl acetate
Under 100 ℃, in nitrogen, with (80.3 milliliters of methanolizing tributyl tins, 279 mmoles), 3-methyl-bromobenzoate (53.5 grams, 249 mmoles), methylvinyl acetate is (39.4 milliliters, 358 mmoles), acid chloride (II) (2.6 gram, 11.6 mmoles) and tri-o-tolyl phosphine (7.1 grams, 23.2 mmoles) are stirred in the toluene (350 milliliters) 18 hours together.After cooling, handle this reaction and stirred 2 hours with the potassium fluoride aqueous solution (560 milliliters) of 4M.With the mixture of other toluene (200 milliliters) dilution gained and by diatomite filtration, wash this filter pad with ethyl acetate.Separate organic phase, dry (sodium sulfate) and minimizing in a vacuum.Utilize hurried column chromatography purifying resistates on the silicon gel, with change to 20: 80 at 10: 90 ethyl acetate of (by volume): the pentane wash-out, title compound (45.3 gram) can be provided, be orange oil.
1H NMR(400MHz，CDCl
3)：δ＝7.95-7.93(1H，d)，7.87(1H，s)，7.43-7.37(2H，m)，3.91(3H，s)，3.75(2H，s)，2.18(3H，s)ppm。
LRMS (electron spray(ES)): m/z[M+Na]
+215, [M-H]
-191.
Preparation 91
3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-benzoic acid methyl ester
Compound (5.23 grams, the 27.0 mmoles) solution that the compound (7.10 restrain 13.5 mmoles) of preparation 11 is added to the preparation 88 in methylene dichloride (50 milliliters) reaches to remove in a vacuum and desolvates.Heat this mixture 12 hours down and be cooled to room temperature at 95 ℃.Add Anaesthetie Ether (150 milliliters) and stir this reaction 1 hour, white depositions that produces by removing by filter and evaporation filtrate are to provide a yellow oil.Utilize column chromatography purifying resistates on the silicon gel, with 100: 0: 0 methylene dichloride of 95: 5: 0.5 then: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be yellow oil, 4.30 grams.
1H NMR(400MHz，CD
3OD)δ-0.23(3H，s)，-0.06(3H，s)，0.78(9H，s)，1.06(3H，d)，2.57(1H，m)，2.66(2H，m)，2.88(2H，m)，3.83(3H，s)，4.64(1H，m)，4.85(4H，s)，6.46(2H，s)，6.49(1H，m)，7.32(12H，m)，7.78(1H，s)，7.82(1H，m)。
LRMS：m/z APCI 640[M+H
+]。
Preparation 92
3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-the benzoate hydrochlorate
Be stirred in the compound (5.35 grams, 8.37 mmoles) of the preparation 91 in the tetrahydrofuran (THF) (20 milliliters), add the lithium hydroxide aqueous solution (18.4 milliliters, 18.4 mmoles) of 1M by part.Stir this reaction 12 hours, heated 12 hours down at 40 ℃ then.Add (36.8 milliliters of other 1M lithium hydroxide aqueous solutions by part, 36.8 mmole) and tetrahydrofuran (THF) (100 milliliters), and, cool off this reaction and add the lithium hydroxide aqueous solution (36.8 milliliters, 36.8 mmoles) of other 1M 40 ℃ of down these reactions of heating 12 hours.Heat this reaction 5 hours down and be cooled to room temperature at 60 ℃, under reduced pressure remove tetrahydrofuran (THF) and add two alkane (50 milliliters).Heat this reaction 1 hour down at 60 ℃, be cooled to room temperature and reach in a vacuum except that desolvating.Resistates is acidified to pH 1 and with methylene dichloride with the aqueous hydrochloric acid of 1M: methyl alcohol (97: 3; V/v; 3 * 150 milliliters) extraction, clean the organism that merges with salt solution (30 milliliters), dry (sal epsom) reaches to remove in a vacuum and desolvates, and title compound can be provided, and is yellow foam-like material, 5.00 grams.
1H NMR(400MHz，CD
3OD)δ-0.13(3H，s)，0.07(3H，s)，0.86(9H，s)，1.24(3H，d)，2.83(1H，m)，3.19(1H，m)，3.30(2H，m)，3.59(1H，m)，5.05(1H，m)，5.11(4H，s)，6.64(3H，m)，7.30(10H，m)，7.47(2H，m)，7.92(1H，s)，7.97(1H，m)。
LRMS：m/z APCI 626[M+H
+]。
Preparation 93
3-{2-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-(3,5-dihydroxyl-phenyl)-ethylamino]-propyl group }-phenylformic acid
The compound (4.97 grams, 7.95 mmoles) of preparation 92 is dissolved in ethanol (300 milliliters) and the ammonium formiate (2.75 grams, 60 mmoles), and adds palladium hydroxide (500 milligrams) by part.This reaction of heating is 1 hour under refluxing, and is cooled to room temperature, filters and cleans with methyl alcohol (500 milliliters) by A Boxier .Concentrating filtrate so that title compound to be provided, is pale solid 3.60 grams in a vacuum.
1H NMR(400MHz，CD
3OD)δ-0.06(3H，s)，0.05(3H，s)，0.86(9H，s)，1.23(3H，d)，2.83(1H，m)，3.12(2H，m)，3.25(1H，m)，3.51(1H，m)，4.90(1H，m)，6.24(1H，m)，6.35(2H，s)，7.27(2H，m)，7.83(1H，m)，7.88(1H，m)。
LRMS：m/z APCI 446[M+H
+]。
Can use the method preparation 100 to 104 and 115 to 124 of preparation 34 from preparing 33 and suitable amine.These compounds have following general formula:
Be listed in the following table.
Can use the method preparation 96 to 99 of preparation 34 from preparing 45 and suitable amine.These compounds have following general formula:
Be listed in the following table.
Can use the method preparation 94,95 and 105 to 114 of preparation 34 from preparing 93 and suitable amine.These compounds have following general formula:
Be listed in the following table.
Preparation 125
2-(4-methoxyl group-2,3-dimethyl-phenyl)-ethamine
At room temperature, in the hydrogen of 60psi, be stirred in the mixture 18 hours of (4-methoxyl group-2,3-dimethyl-phenyl)-acetonitrile (200 milligrams, 1.14 mmoles) and blue Buddhist nun (Raney) nickel (50 milligrams) in the methanol ammonia (10 milliliters) of 2M.TLC analyzes and demonstrates not is that whole raw materials consumes all, so adds the blue Buddhist nun nickel (50 milligrams) in the methanol ammonia (10 milliliters) of 2M in addition.In the hydrogen of 60psi, under room temperature, stirred this reaction mixture extra 18 hours, filter by A Boxier then.Concentrating filtrate and utilize column chromatography purifying resistates on the silicon gel in a vacuum, with 100: 0: 0 to 90: 10: 1 methylene dichloride: methyl alcohol: 0.88 ammonia wash-out, can obtain title product, be the light brown solid, 233 milligrams.
1H NMR(400MHz，CDCl
3)δ6.96(1H，d)，6.66(1H，d)，3.80(3H，s)，2.96-2.84(2H，m)，2.81-2.73(2H，m)，2.22(3H，s)，2.17(3H，s)，1.63(2H，s)ppm
LRMS APCI m/z180[M+H]
+
Preparation 126
2-(2,3-dimethyl-phenyl)-ethamine
In the hydrogen of 50psi, be stirred in 2 in the methanol ammonia (5 milliliters) of 2M, 3-3,5-dimethylphenyl acetonitrile (J.Org Chem, 51 (26), 5157-60; 1986) mixture of (190 milligrams, 1.31 mmoles) and blue Buddhist nun nickel (100 milligrams) is 4 days.Then, this mixture is filtered and concentrates in a vacuum by A Boxier ,, be solid, 130 milligrams to obtain title compound.
1H NMR(400MHz，CDCl
3)δ7.02-6.94(3H，m)，2.26-2.13(10H，m)ppm
LRMS ESI m/z 150[M+H]
+
Preparation 127
2-(2-chloro-4-fluoro-phenyl)-ethamine
With sodium borohydride (1.73 grams, 45.51 mmoles) be added to 2-chloro-4-fluorophenyl acetonitrile (1.04 grams, 6.15 mmoles) and the solution of cobalt chloride (II) hexahydrate (2.18 grams, 9.22 mmoles) in methyl alcohol (30 milliliters) in batches, at room temperature stirred this mixture 3 hours.Then, allow this suspension filter, concentrate in a vacuum and resistates is distributed between the hydrochloric acid (40 milliliters) and methylene dichloride (40 milliliters) of 1M by diatomite .Water phase separated alkalizes to pH 11 and extracts with methylene dichloride (2 * 40 milliliters) with the ammonia solution of 1M.Clean the organic solution that merges with salt solution (30 milliliters), dry and concentrated in a vacuum on sal epsom.Utilize column chromatography purifying resistates on the silicon gel, with 100: 0: 0 to 98: 2: 0.2 methylene dichloride: methyl alcohol: 0.88 ammonia wash-out, can obtain title compound, be yellow oil, 350 milligrams.
1H NMR(400MHz，CDCl
3)δ：7.30(1H，dd)，7.17(1H，dd)，6.99(1H，m)，2.86(4H，m)ppm
LRMS APCI m/z 174[M+H]
+
Preparation 128
2-(5-chloro-2-methoxyl group-phenyl)-ethamine
Chlorine trimethyl silane (2 milliliters, 16 mmoles) dropwise is added to lithium borohydride (2M in tetrahydrofuran (THF), 4 milliliters, 8 mmoles).Then, under 0 ℃, be added in 2-methoxyl group-5-chloro-phenyl-acetonitrile (312 milligrams, the 4 mmoles) solution in the tetrahydrofuran (THF) (2 milliliters), and stirred this mixture 24 hours, be heated to room temperature simultaneously.Then, dilute this mixture and concentrated in a vacuum with methyl alcohol (20 milliliters).Resistates is mixed in the potassium hydroxide solution (20 milliliters) in 20%, with methylene dichloride (3 * 20 milliliters) extraction and on sal epsom the dry organic solution that merges and concentrating in a vacuum.Utilize column chromatography, use Ai Suolute (Isolute) SCX-2 tube to come the purifying resistates, then with the ammonia wash-out of 1M in methyl alcohol, can provide an oily resistates with methyl alcohol.Grind this oil with Anaesthetie Ether, can obtain title compound, 485 milligrams.
1H NMR(400MHz，CDCl
3)δ7.11-7.00(2H，m)，6.75-6.65(1H，m)，3.72(3H，s)，2.90-2.80(2H，m)，2.70-2.60(2H，m)ppm
Preparation 129
2-(5-chloro-2-hydroxyl-phenyl)-ethamine
Preparation 128 amine (66 milligrams, 0.36 mmole) is dissolved in 48% the HBr aqueous solution, 80 ℃ of following heated and stirred 12 hours.This reaction is cooled to room temperature to be reached in a vacuum except that desolvating, so that a brown glue to be provided.Be dissolved in this in methyl alcohol (5 milliliters) and utilize the ion-exchange column purification,, be brown glue, 26 milligrams so that this title compound to be provided.
1H NMR(400MHz，CDCl
3)δ：2.70(2H，t)，2.90(2H，t)，6.70(1H，d)，6.98(1H，m)，7.02(1H，s)ppm
LRMS APCI m/z 172[M+H]
+
Preparation 130
2-(5-fluoro-2-methyl-phenyl)-ethamine
Use the method and the suitable nitrile of preparation 128 to prepare this compound.
1H NMR(400MHz，CDCl
3)δ：7.07(1H，m)，6.83(2H，m)，2.97(2H，t)，2.78(2H，m)，2.27(3H，s)ppm
LRMS APCI m/z 154[M+H]
+
Preparation 131
(3-iodine benzyl) t-butyl carbamate
With (3.1 milliliters of triethylamines, 22 mmoles) and tert-Butyl dicarbonate (4.40 the gram, 20 mmoles) handle 3-iodine benzyl amine hydrochlorate (4.95 grams, 18.4 the suspension in methylene dichloride (100 milliliters) mmole), the solution that is produced is left at room temperature, in the nitrogen atmosphere, stirred 1.5 hours.Hydrochloric acid (30 milliliters), water (30 milliliters) with 2M clean this reaction mixture, and dry (sodium sulfate), and remove in a vacuum and desolvate, title compound can be provided, be colorless solid (6.43 gram).
1H NMR(400MHz，CDCl
3)δ1.46(s，9H)，4.21-4.30(m，2H)，4.79-4.89(bs，1H)，7.06(dd，1H)，7.25(d，1H)，7.60(d，1H)，7.63(s，1H)ppm。
MS (electron spray(ES)) m/z 332[M-H]
-, 356[M+Na]
+
Preparation 132
[(4 '-xenol-3-yl) methyl] t-butyl carbamate
Handle from the iodide that prepare 131 (0.75 gram with the aqueous sodium carbonate (4 milliliters) of 2M, 2.25 4-hydroxy phenyl boric acid (0.62 gram mmole),, 4.50 mmole), chlorination 1,1 '-two (diphenylphosphino) ferrocenyl palladium (II) (0.11 gram, 0.14 mmole) at N, the solution in the dinethylformamide (14 milliliters); Under 80 ℃, the mixture 16 hours of heating gained in the nitrogen atmosphere.Under reduced pressure remove and desolvate, utilize column chromatography purifying resistates on the silicon gel, with 1: 3 ethyl acetate: the pentane wash-out, title compound can be provided, be rose pink crystalline solid (0.73 gram).
1H NMR(400MHz，CDCl
3)δ1.47(s，9H)，4.33-4.41(m)，4.87-4.94(bs，1H)，6.89(d，2H)，7.21(d，1H)，7.37(dd，1H)，7.43-7.45(m，4H)ppm。
MS (electron spray(ES)) m/z 298[M-H]
-, 322[M+Na]
+
Preparation 133
3 '-(amino methyl) biphenyl-4-phenates hydrochlorate
Handle from preparation 132 phenol (0.73 gram, 2.43 mmoles) with the HCl (6 milliliters, 24.3 mmoles) of 4M in two alkane, and at room temperature stirred the solution that produced 3 hours.Remove in a vacuum and desolvate,, be colorless solid so that title compound to be provided.
1H NMR(400MHz，CD
3OD)δ4.17(s，2H)，6.87(d，2H)，7.34(d，1H)，7.45-7.50(m，3H)，7.61(d，1H)，7.65(s，1H)ppm。
MS (electron spray(ES)) m/z 198[M-H]
-, 200[M+H]
+
Preparation 134
2-(3-chloro-2-hydroxyl-phenyl)-ethamine
According to the program preparation that is described among the DE 1959898.
Preparation 135
Methyl-3-[(2R)-the 2-aminopropyl] phenyl] propionic ester
According to being used in preparation 22 program, use methyl-[3-((2R)-2-{[(1R)-1-phenylethyl] amino } propyl group) phenyl] propionate salts hydrochlorate (preparation 136) prepares, and so that title compound to be provided, is brown oil.
1H NMR(400MHz，CD
3OD)：δ＝7.21-7.17(1H，t)，7.03-7.01(3H，m)，3.61(3H，s)，3.11-3.03(1H，m)，2.91-2.87(2H，t)，2.64-2.54(4H，m)，1.07-1.05(3H，d)ppm。
LRMS (electron spray(ES)): m/z[M+H]
+222.
Preparation 136
[3-((2R)-2-{[(1R)-1-phenylethyl] amino } propyl group) phenyl] the methyl propionate hydrochloride
According to the program preparation that is used in preparation 23, use methyl-3-[3-(2-oxopropyl) phenyl] propionic ester (preparation 137), so that title compound to be provided, be white crystalline solid.
1H NMR(400MHz，CD
3OD)：δ＝7.54-7.47(5H，m)，7.23-7.19(1H，t)，7.12-7.10(1H，d)，6.92-6.91(2H，d)，4.64-4.59(1H，q)，3.61(3H，s)，3.34-3.29(1H，m)，3.20-3.12(1H，m)，2.89-2.85(2H，t)，2.62-2.56(3H，m)，1.71-1.69(3H，d)，1.18-1.16(3H，d)ppm。
LRMS (electron spray(ES)): m/z[M+H]
+326.
Preparation 137
Methyl-3-[3-(2-oxopropyl) phenyl] propionic ester
In the hydrogen environment (60psi), under room temperature, stir (2E)-3-[3-(2-oxopropyl) phenyl] methyl acrylate (5.00 grams, preparation 138) and the suspension of 10% palladium/carbon (500 milligrams) in ethanol (50 milliliters) 16 hours.See through A Boxier and filter out catalyzer and concentrating filtrate in a vacuum,, be light yellow oil, be not further purified and use it so that title compound to be provided.
1H NMR(400MHz，CD
3OD)：δ＝7.27-7.23(1H，q)，7.11-7.09(1H，d)，7.05-7.04(2H，d)，3.66(5H，s)，2.96-2.92(2H，t)，2.64-2.60(2H，t)，2.14(3H，s)ppm。
LRMS (electron spray(ES)): m/z[M+Na]
+243, [M-H]
-219.
Preparation 138
(2E)-and 3-[3-(2-oxopropyl) phenyl] methyl acrylate
In the nitrogen atmosphere, will be at (50.0 grams of the 3-bromophenyl acetone in the acetonitrile (900 milliliters), 235 mmoles), methyl acrylate (40.4 grams, 469 mmoles), acid chloride (II) (7.9 grams, 35.2 mmole), tri-o-tolyl phosphine (21.4 grams, 70.4 mmoles) is heated to backflow 16 hours with the solution of triethylamine (82 milliliters).This reaction mixture is cooled to room temperature to be reached in a vacuum except that desolvating.Utilize hurried column chromatography purifying, with change to 70: 30 at 90: 10 pentane of (by volume): eluent ethyl acetate, title compound can be provided, be orange oil (54.3 gram).
1H NMR(400MHz，CD
3OD)：δ＝7.66-7.62(1H，d)，7.41-7.39(1H，d)，7.34-7.31(2H，t)，7.20-7.18(1H，d)，6.43-6.39(1H，d)，3.77(3H，s)，3.70(2H，s)，2.15(3H，s)ppm。
LRMS (electron spray(ES)): m/z[M+Na]
+241, [M-H]
-217.
Preparation 139
3-(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-phenyl)-the propionic acid methyl ester
In methylene dichloride (50 milliliters), merge the bromide (3.46 grams, 6.56 mmoles) of preparation 11 and the amine (2.90 grams, 13.1 mmoles) of preparation 135, and remove in a vacuum and desolvate.Heat the oil 12 hours that is produced down and be cooled to room temperature at 90 ℃, stirred this orange oil 5 minutes in ether (200 milliliters), carefully inclining the layer of ether.Orange oil and the ether (2 * 200 milliliters) of remnants are stirred other secondary, and the combined ether layer reaches to remove in a vacuum and desolvates.The orange oil of utilizing hurried column chromatography purifying to be produced, with 100: 0: 0 methylene dichloride of 96: 4: 0.4 then: methyl alcohol: the ammonia wash-out, title compound can be provided, be golden oil (3.40 gram).
1H NMR(400MHz，CD
3OD)δ-0.20(3H，s)，-0.05(3H，s)，0.82(9H，s)，1.03(3H，d)，2.52-2.65(5H，m)，2.79-2.94(4H，m)，3.60(3H，s)，4.66(1H，m)，5.04(4H，m)，6.49(2H，s)，6.53(1H，m)，6.89-6.96(2H，m)，6.99(1H，m)，7.15(1H，m)，7.23-7.44(10H，m)；
LRMS APCI m/z 668[M+H]
+
Preparation 140
3-(3-{2-[2-(3,5-couple-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-phenyl)-the propionic salt hydrochlorate
Handle the ester (3.40 grams, 5.10 mmoles) of the preparation 139 in tetrahydrofuran (THF) (15 milliliters) with lithium hydroxide (1M, 11.2 milliliters, 11.21 mmoles).Add two alkane (50 milliliters) and water (10 milliliters), and stirred the solution that produced 20 hours.This solution is acidified to pH 1 and extracts with hydrochloric acid (1N) with methylene dichloride (3 * 150 milliliters).With salt solution (50 milliliters) cleaning organic matter and drying (sal epsom).Filtration and evaporating solvent are to leave over a white foam shape material (3.5 grams, 91%)
1H NMR(400MHz，CD
3OD)δ-0.13(3H，s)，0.06(3H，s)，0.86(9H，s)，1.03(3H，d)，2.58(2H，t)，2.75(1H，m)，2.88(2H，t)，3.06(1H，m)，3.23(1H，m)，3.34(1H，m)，3.55(1H，m)，5.04-5.16(5H，m)，6.66(3H，m)，7.06(1H，m)，7.12(1H，s)，7.18(1H，m)，7.23-7.47(11H，m)；LRMS APCI m/z 655[M+H]
+
Preparation 141
3-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino] propyl group } phenyl) propionic acid
According to the program that is used in preparation 13, (3-{2-[2-(3 to use 3-, 5-is two-benzyloxy-phenyl)-2-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethylamino]-propyl group }-phenyl)-propionic salt hydrochlorate (preparation 140) prepares, and so that title compound to be provided, is yellow solid.
1H NMR(400MHz，CD
3OD)δ-0.06(3H，s)，0.08(3H，s)，0.86(9H，s)，1.22(3H，d)，2.54(2H，t)，2.74(1H，m)，2.90(2H，t)，3.15(1H，m)，3.26(1H，m)，3.45(1H，m)，4.90(1H，m)，6.26(1H，m)，6.35(2H，s)，7.02(1H，m)，7.08(1H，s)，7.16(1H，m)，7.24(1H，m)；LRMSAPCI m/z 474[M+H]
+
Preparation 142
3-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino] propyl group } phenyl)-N-(2-benzyl chloride base) propionic acid amide
According to the program that is used in preparation 34, use preparation 141,2-benzyl chloride base amine to reach with N,N-dimethylacetamide displacement N, dinethylformamide prepares.
1H NMR(400MHz，CD
3OD)δ-0.15(3H，s)，0.01(3H，s)，0.84(9H，s)，1.03(3H，d)，2.47-2.58(3H，m)，2.60-2.70(2H，m)，2.80-2.95(4H，m)，4.41(2H，m)，4.59(1H，m)，6.16(1H，m)，6.24(2H，s)，6.95(2H，m)，7.02-7.08(2H，m)，7.13-7.25(3H，m)，7.36(1H，m)；LRMS APCIm/z 598[M+H]
+
Preparation 143
3-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino] propyl group) phenyl)-N-(2, the 6-dichloro benzyl) propionic acid amide
According to the program that is used in preparation 34, use preparation 141,2,6-dichloro benzyl amine reaches with N,N-dimethylacetamide displacement N, and dinethylformamide prepares.
1H NMR(400MHz，CD
3OD)δ-0.15(3H，s)，0.00(3H，s)，0.85(9H，s)，1.03(3H，d)，2.44-2.57(3H，m)，2.60-2.68(2H，m)，2.80-2.90(4H，m)，4.55-4.65(3H，m)，6.16(1H，m)，6.24(2H，s)，6.91(1H，m)，6.94(1H，m)，7.01(1H，m)，7.12(1H，m)，7.26(1H，m)，7.37-7.41(2H，m)；LRMS APCI m/z 631[M+H]
+
Preparation 144
3-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3,5-dihydroxyl-phenyl) ethylamino] propyl group } phenyl)-1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-third-1-ketone
According to the program that is used in preparation 34, use preparation 141,1,2,3, the 4-tetrahydroisoquinoline reaches with N,N-dimethylacetamide displacement N, and dinethylformamide prepares.
1H NMR(400MHz，CD
3OD)δ-0.15(3H，s)，-0.01(3H，s)，0.85(9H，s)，0.99(3H，m)，2.42-2.64(3H，m)，2.68-2.96(8H，m)，3.63-3.76(2H，m)，4.55-4.67(3H，m)，6.16(1H，m)，6.23(2H，s)，6.81-7.21(8H，m)；LRMS APCI m/z 590[M+H]
+
Preparation 145
2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3,5-dihydroxyl-phenyl) ethylamino] propyl group } phenyl)-N-(2-chloro-4-luorobenzyl) ethanamide
According to the program that is used in preparation 142, use acid and 2-chloro-4-luorobenzyl amine to prepare from preparation 33.
1H NMR(400MHz，CD
3OD)δ-0.02(3H，d)，0.00(3H，s)，0.84(9H，s)，1.04(3H，d)，2.54-2.70(3H，m)，2.86-2.93(2H，m)，3.53(2H，s)，4.41(1H，s)，4.46(1H，s)，4.60-4.63(1H，m)，6.14-6.15(1H，m)，6.22(2H，d)，6.97-7.50(7H，m)，7.64-7.69(1H，m)；LRMS APCI m/z 601[M+H]
+
Preparation 146
N-(4-bromobenzyl)-2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino]-the 2-methyl-propyl } phenyl) ethanamide
According to the program that is used in preparation 34, use acid and 4-bromobenzyl amine to prepare from preparation 33.
1H NMR(400MHz，CD
3OD)δ-0.23(s，3H)，-0.04(s，3H)，0.82(s，9H)，1.07(d，6H)，2.63-2.77(m，3H)，2.84(t，1H)，3.56(s，2H)，4.31(s，2H)，4.57-4.63(m，1H)，6.18(t，1H)，6.36(s，2H)，7.08(t，2H)，7.12-7.18(m，3H)，7.21(t，1H)，7.42(d，2H)。；LRMS ESI m/z643[M+H]
+
Preparation 147
2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino]-the 2-methyl-propyl } phenyl)-N-(3, the 4-3,5-dimethylphenyl) ethanamide
According to the program that is used in preparation 34, use acid and 3 from preparation 33, the 4-xylidine prepares.
1H NMR(400MHz，CD
3OD)δ-0.17(s，3H)，-0.03(s，3H)，0.81(s，9H)，1.07(d，6H)，2.22(d，6H)，2.61-2.77(m，3H)，2.83(t，1H)，3.61(s，2H)，4.57-4.61(m，1H)，6.18(s，1H)，6.29(s，2H)，7.06(t，2H)，7.18(s，1H)，7.21-7.25(m，3H)，7.31(s，1H)；LRMS ESI m/z 643[M+H]
+
Preparation 148
2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino] propyl group } phenyl)-N-(2, the 3-dimethyl benzyl) ethanamide
According to the program that is used in preparation 34, use acid and 2 from preparation 45, the 3-dimethyl benzyl amine reaches with N,N-dimethylacetamide displacement N, and dinethylformamide prepares.
1H NMR(400MHz，CD
3OD)δ-0.17(3H，s)，-0.04(3H，s)，0.80(9H，s)，0.97(3H，d)，2.09(3H，s)，2.21，2.46-2.51(1H，dd)，2.56-2.65(2H，m)，2.76-2.84(2H，m)，3.45(2H，s)，4.32(2H，s)，4.53(1H，dd)，5.44(2H，s)，6.09(1H，t)，6.17(1H，1)，6.18(1H，s)，6.93-7.17(7H，m)；LRMS APCI m/z 578[M+H]
+
Preparation 149
2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino] propyl group } phenyl)-N-(4-luorobenzyl) ethanamide
According to the program that is used in preparation 34, use acid and 4-luorobenzyl amine to reach with N,N-dimethylacetamide displacement N from preparation 45, dinethylformamide prepares.
1H NMR(400MHz，CD
3OD)δ-0.17(3H，s)，-0.04(3H，s)，0.80(9H，s)，0.98(3H，d)，2.47(1H，dd)，2.55-2.64(H，m)，2.77-2.84(2H，m)，3.46(2H，s)，4.28(2H，s)，4.53(1H，dd)，6.09-6.11(1H，m)，6.17(1H，s)，6.18(1H，s)，6.91-7.02(4H，m)，7.05-7.08(1H，m)，7.13(1H，t)，7.17-7.23(2H，m)；LRMS APCI m/z 567[M+H]
+。
Preparation 150
2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino] propyl group } phenyl)-1-(4-pyridine-2-base-piperazine-1-yl) ethyl ketone
According to the program that is used in preparation 34, use acid and 1-pyridine-2-base piperazine to reach with N,N-dimethylacetamide displacement N from preparation 45, dinethylformamide prepares.
1H NMR(400MHz，CD
3OD)δ-0.12(3H，s)，0.00(3H，s)，0.80(9H，s)，1.12(3H，d)，2.66(1H，dd)，2.88-2.93(2H，m)，3.04-3.10(1H，m)，3.15(1H，dd)，3.32-3.43(4H，m)，3.60-3.66(4H，m)，3.73-3.79(2H，m)，4.81-4.85(1H，m)，6.18(1H，t)，6.25(1H，s)，6.26(1H，s)，6.60-6.63(1H，m)，6.72(1H，d)，7.04-7.07(2H，m)，7.12(1H，d)，7.23(1H，t)，7.46(1H，dt)，8.00(1H，d)；LRMS APCI m/z 606[M+H]
+。
Preparation 151
2-(3-{2-[2-(tertiary butyl dimethyl-silicon alcoxyl base)-2-(3, the 5-dihydroxyphenyl) ethylamino]-the 2-methyl-propyl } phenyl)-N-(2-phenyl propyl) ethanamide
From preparing 33 compound and suitable amine, use the method that is described in preparation 34 to prepare title compound, and be separated into the white foam shape.
1H NMR(400MHz，CD
3OD)δ-0.20(3H，s)，-0.07(3H，s)，0.74(9H，s)，1.02(3H，d)，1.09(3H，d)，2.62(1H，dd)，2.79(1H，dd)，2.88-2.97(2H，m)，3.04(1H，dd)，3.16-3.24(1H，m)，3.27-3.88(2H，m)，3.41(2H，s)，4.74(1H，dd)，6.19(1H，t)，6.27(1H，s)，6.28(1H，s)，7.01-7.07(2H，m)，7.13-7.27(4H，m)。
LRMS APCI m/z 578[M+H
+]。
Embodiment 1
N-benzyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide
At N, acid of the preparation 9 in the dinethylformamide (1 milliliter) (50 milligrams, 0.10 mmole) and (14 milligrams of benzylamines, 0.13 in solution mmole), be added in N, the phosphofluoric acid O-in the dinethylformamide (3 milliliters) (1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea (50 milligrams, 0.13 mmole), and stir this reaction 12 hours.Remove in a vacuum and desolvate, so that the crude product resistates to be provided.Utilize column chromatography to use 97.5: 2.5 on the silicon gel: 0.25-90: 10: 1 methylene dichloride: methyl alcohol: 0.88 ammonia purifying can provide the product of wanting, 17 milligrams (37%).
1H NMR(400MHz，CD
3OD)δ1.02(3H，s)，1.04(3H，s)，2.84-2.64(4H，m)，3.52(2H，s)，4.35(2H，s)，4.53-4.57(1H，q)，6.18(1H，s)，6.33(2H，s)，7.02-7.04(2H，d)，7.12-7.28(7H，m)。
LRMS：m/z APCI
+449[MH
+]。
Embodiment 2-11
Will be at N, the solution from preparation 9 acid (30 micromole) in the dinethylformamide (100 microlitre) is added at N the suitable amine (HNR in the dinethylformamide (100 microlitre)
AR
B) (30 micromole), and seal this reaction mixture and rock.Be added in N, the phosphofluoric acid O-benzotriazole-1-base-N in the dinethylformamide (200 microlitre), N, N ', N '-tetramethyl-urea (11.38 milligrams, 30 micromoles) solution seals this reaction mixture and rocks, and keeps at room temperature 4 days.Directly utilize HPLC to come this reaction mixture of purifying, use Fino Mannix (PHenomenex) Lu Na (Luna) C18 post (150 * 10 millimeters, 10 microns), detect, use following gradient system with flow velocity 8 ml/min and in 225 nanometers.
The diethylamine aqueous solution of A-0.05%
The B-acetonitrile
| Time (minute) | B％ |
| 0-0.2 | 5 |
| 0.2-8 | 5-95 |
| 8-9.6 | 95 |
Use Mannix Shandong, Fino to receive C18 (30 * 4.6 millimeters, 5 microns) post,, use the gradient that is described in following table to analyze every kind of product with flow velocity 2.5 ml/min.
A-5%6.5mM is at water: the ammonium acetate in the acetonitrile (95: 5)
The B-acetonitrile
| Time (minute) | B％ |
| 0 | 0 |
| 3 | 95 |
| 3.5 | 95 |
A=is as prepared 3-amino-5-ethyl-1H-pyrazoles as being described among the WO 03/048133
Embodiment 12
N-[2-(4-chloro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide
At room temperature, Neutral ammonium fluoride (1.08 grams, 29.2 mmoles) is added to the stirred solution of compound (1.56 grams, 2.61 mmoles) in methyl alcohol (25 milliliters) and water (18 milliliters) of preparation 15 with a part.This reaction be heated to 40 ℃ 48 hours, it is cooled to room temperature and removes in a vacuum and desolvate.Utilize column chromatography purifying resistates on the silicon gel, with 100: 0: 0 then with 95: 5: 0.5 then with 90: 10: 1 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be brown solid, 885 milligrams.
1H NMR(400MHz，CD
3OD)δ1.10(3H，s)，1.16(3H，s)，2.75(6H，m)，3.62(2H，m)，4.66(1H，dd)，6.23(1H，m)，6.40(1H，s)，6.41(1H，s)，7.33(6H，m)，7.67(2H，m)。
LRMS：m/z APCI 484[M+H
+]。
Embodiment 13
N-diamantane-1-base-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
At room temperature, Neutral ammonium fluoride (100 milligrams, 2.70 mmoles) is added to the stirred solution of compound (160 milligrams, 0.27 mmole) in methyl alcohol (2 milliliters) and water (1 milliliter) of preparation 30 with a part.With this reaction be heated to 40 ℃ 12 hours, it is cooled to room temperature and removes in a vacuum and desolvate.Utilize column chromatography purifying resistates on the silicon gel, with 93: 7: 0.7 methylene dichloride: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be the white foam shape, 78 milligrams.
1H NMR(400MHz，CD
3OD)δ1.07(3H，d)，1.68(6H，s)，2.01(9H，m)，2.60(4H，m)，2.91(1H，m)，3.40(2H，s)，4.50(1H，m)，6.13(1H，m)，6.23(2H，s)，6.99(1H，d)，7.08(1H，s)，7.10(1H，d)，7.18(1H，t)。
LRMS:m/z electron spray(ES) 479[M+H
+], 477[M-H]
-
Embodiment 14
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide
From preparing 36 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.11(3H，s)，1.15(3H，s)，2.74-2.82(2H，m)，2.90-3.00(4H，m)，3.62-3.66(2H，m)，4.61-4.66(1H，m)，6.23-6.24(1H，m)，6.39(1H，s)，6.40(1H，s)，6.94-6.98(1H，m)，7.03-7.07(1H，m)，7.10-7.12(1H，m)，7.29-7.43(3H，m)，7.65-7.69(2H，m)。
LRMS：m/z APCI 467[M+H
+]。
Embodiment 15
N-[2-(2-chloro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide
From preparing 37 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.10(3H，s)，1.15(3H，s)，2.76-2.84(2H，m)，2.88-2.96(2H，m)，3.10-3.14(2H，m)，3.66-3.70(2H，m)，4.61-4.64(1H，m)，6.22-6.24(1H，m)，6.39(1H，s)，6.40(1H，s)，7.21-7.28(2H，m)，7.35-7.42(4H，m)，7.66-7.69(2H，m)。
LRMS：m/z APCI 483[M+H
+]。
Embodiment 16
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(2,3-dimethyl-phenyl)-ethyl]-benzamide
From preparing 38 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.14(3H，s)，1.19(3H，s)，2.30(3H，s)，2.31(3H，s)，2.80-3.02(6H，m)，3.56-3.59(2H，m)，4.63-4.67(1H，m)，6.24-6.25(1H，m)，6.40(1H，s)，6.41(1H，s)，6.99-7.07(3H，m)，7.38-7.45(2H，m)，7.68-7.72(2H，m)。
LRMS：m/z APCI 477[M+H
+]。
Embodiment 17
N-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide
From preparing 39 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.09(3H，s)，1.15(3H，s)，2.75-2.83(2H，m)，2.88-2.96(2H，m)，3.08-3.11(2H，m)，3.64-3.68(2H，m)，4.61-4.64(1H，m)，6.22-6.23(1H，m)，6.39(1H，s)，6.40(1H，s)，7.01-7.06(1H，m)，7.21-7.24(1H，m)，7.35-7.42(3H，m)，7.65-7.68(2H，m)。
LRMS：m/z APCI 501[M+H
+]。
Embodiment 18
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-2-(4-methoxyl group-2,3-dimethyl-phenyl)-ethyl]-benzamide
From preparing 40 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.12(3H，s)，1.18(3H，s)，2.16(3H，s)，2.30(3H，s)，2.77-3.00(6H，m)，3.52-3.56(2H，m)，3.80(3H，s)，4.62-4.65(1H，m)，6.23-6.24(1H，m)，6.40(1H，s)，6.41(1H，s)，6.72-6.74(1H，d)，7.01-7.03(1H，d)，7.37-7.44(2H，m)，7.67(1H，s)，7.70-7.72(1H，m)。
LRMS：m/z APCI 507[M+H
+]。
Embodiment 19
N-(3,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 34 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.02(3H，s)，1.04(3H，s)，2.74(4H，m)，3.56(2H，s)，4.32(2H，s)，4.54(1H，m)，6.17(1H，s)，6.36(2H，s)，7.03(1H，d)，7.15(3H，m)，7.22(1H，t)，7.36(1H，d)，7.43(1H，d)。
LRMS:m/z electron spray(ES) 517[M+H
+].
Embodiment 20
N-(3,4-two chloro-benzyls)-3-(2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group)-benzamide
From preparing 41 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.16(3H，s)，1.20(3H，s)，2.83-3.01(4H，m)，4.59(2H，s)，4.64-4.67(1H，m)，6.23(1H，m)，6.38(1H，s)，6.39(1H，s)，7.31-7.34(1H，m)，7.41-7.55(4H，s)，7.76-7.80(2H，s)。
LRMS：m/z APCI 503[M+H
+]。
Embodiment 21
N-(4-chloro-benzyl)-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide
From preparing 42 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.10(3H，s)，1.15(3H，s)，2.76-2.82(2H，m)，2.90-2.96(2H，m)，4.59(2H，s)，4.60-4.63(1H，m)，6.23(1H，m)，6.37(1H，s)，6.38(1H，s)，7.34-7.45(6H，m)，7.74-7.77(2H，m)。
LRMS：m/z APCI 469[M+H
+]。
Embodiment 22
N-diamantane-1-base-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide
From preparing 43 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.27(3H，s)，1.28(3H，s)，1.79-1.81(6H，m)，2.14(3H，m)，2.21-2.22(6H，m)，2.95-3.09(4H，m)，4.71-4.74(1H，m)，6.26(1H，m)，6.42(1H，s)，6.42(1H，s)，7.40-7.46(2H，m)，7.65(1H，s)，7.68-7.70(1H，m)。
LRMS：m/z APCI 480[M+H
+]。
Embodiment 23
N-(4-chloro-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 46 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.01(3H，s)，1.04(3H，s)，2.74(4H，m)，3.53(2H，s)，4.34(2H，s)，4.54(1H，m)，6.18(1H，s)，6.34(2H，s)，7.03(1H，d)，7.11(1H，s)，7.20(6H，m)。
LRMS:m/z electron spray(ES) 483[M+H
+].
Embodiment 24
N-(4-trifluoro-methoxybenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 47 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.01(3H，s)，1.03(3H，s)，2.74(4H，m)，3.53(2H，s)，4.37(2H，s)，4.54(1H，m)，6.18(1H，s)，6.34(2H，s)，7.03(1H，d)，7.20(7H，m)。
LRMS:m/z electron spray(ES) 533[M+H
+].
Embodiment 25
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-pyridine-2-ylmethyl-ethanamide
From preparing 48 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.01(3H，s)，1.03(3H，s)，2.74(4H，m)，3.59(2H，s)，4.45(2H，s)，4.54(1H，m)，6.16(1H，s)，6.35(2H，s)，7.05(1H，d)，7.20(5H，m)，7.72(1H，t)，8.42(1H，d)。
LRMS:m/z electron spray(ES) 450[M+H
+].
Embodiment 26
N-(3,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 49 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.01(3H，d)，2.58(1H，m)，2.64(2H，m)，2.78(1H，m)，2.90(1H，m)，3.56(2H，s)，4.37(2H，s)，4.54(1H，m)，6.18(1H，s)，6.25(2H，s)，7.03(5H，m)，7.38(2H，m)。
LRMS:m/z electron spray(ES) 503[M+H
+].
Embodiment 27
N-(benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 50 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.57(1H，m)，2.68(2H，m)，2.81(1H，m)，2.90(1H，m)，3.53(2H，s)，4.35(2H，s)，4.52(1H，m)，6.16(1H，m)，6.25(2H，s)，7.01(1H，m)，7.08(1H，s)，7.13(1H，m)，7.20(6H，m)。
LRMS：m/z APCI 435[M+H
+]，433[M-H
-]。
Embodiment 28
N-cyclohexyl methyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 51 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be brown foam-like material.
1H NMR(400MHz，CD
3OD)δ0.88(2H，m)，1.06(3H，d)，1.18(3H，m)，1.42(1H，m)，1.68(5H，m)，2.58(1H，m)，2.70(2H，m)，2.81(1H，m)，2.92(1H，m)，2.99(2H，d)，3.46(2H，s)，4.53(1H，m)，6.15(1H，m)，6.25(2H，s)，7.00(1H，m)，7.08(2H，m)，7.19(1H，m)。
LRMS：m/z APCI 441[M+H
+]，439[M-H
-]。
Embodiment 29
1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethyl ketone
From preparing 52 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.00(3H，m)，2.57(7H，m)，3.70(1H，m)，3.80(3H，m)，4.50(1H，m)，4.68(2H，d)，6.16(1H，m)，6.26(2H，s)，7.01(7H，m)。
LRMS：m/z APCI 461[M+H
+]，459[M-H
-]。
Embodiment 30
N-benzyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-methyl-ethanamide
From preparing 53 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be brown foam-like material.
1H NMR(400MHz，CD
3OD)：1.05(3H，d)，2.62(3H，m)，2.88(5H，m)，3.78(2H，m)，4.50(1H，m)，4.58(2H，m)，6.16(1H，m)，6.26(2H，s)，7.01(2H，m)，7.07(2H，m)，7.20(5H，m)。
LRMS：m/z APCI 449[M+H
+]，447[M-H
-]。
Embodiment 31
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-hydroxyl-benzyl)-ethanamide
From preparing 54 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.56(1H，m)，2.68(2H，m)，2.81(2H，m)，3.52(2H，s)，4.34(2H，s)，4.53(1H，m)，6.16(1H，m)，6.25(2H，s)，6.76(2H，m)，7.00(1H，m)，7.08(4H，m)，7.18(1H，m)。
LRMS：m/z APCI 451[M+H
+]，449[M-H
-]。
Embodiment 32
N-(4-cyano group-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 55 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.13(3H，s)，1.15(3H，s)，2.85(4H，m)，3.61(2H，s)，4.47(2H，s)，4.62(1H，m)，6.23(1H，m)，6.38(2H，s)，7.11(1H，d)，7.21(2H，s)，7.28(1H，m)，7.42(2H，d)，7.67(2H，d)。
LRMS; M/z electron spray(ES) 474[M+H
+], 472[M-H
-].
Embodiment 33
N-(2,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 56 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.12(3H，s)，1.13(3H，s)，2.85(4H，m)，3.60(2H，s)，4.46(2H，s)，4.62(1H，m)，6.23(1H，m)，6.38(2H，s)，7.11(1H，d)，7.20(2H，m)，7.28(3H，m)，7.47(1H，s)。
LRMS:m/z electron spray(ES) 517[M+H
+], 515[M-H
-].
Embodiment 34
N-(benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
At room temperature, triethylamine trihydrofluoride (42 microlitres, 0.25 mmole) is added to the stirred solution of compound (130 milligrams, 0.23 mmole) in methyl alcohol (4 milliliters) of preparation 57 with a part.Stir this reaction 12 hours, use trifluoroacetic acid that pH is adjusted to pH 7 then.Remove in a vacuum and desolvate and utilize column chromatography purifying resistates on the silicon gel, with 95: 5: 0.5 methylene dichloride of 90: 10: 1 then: methyl alcohol: 880 ammonia wash-outs, title compound can be provided, be the white foam shape, 80 milligrams.
1H NMR(400MHz，CD
3OD)δ1.09(3H，s)，1.10(3H，s)，2.79(4H，m)，3.53(2H，s)，4.37(2H，s)，4.55(1H，m)，6.18(1H，t)，6.33(2H，s)，7.04(1H，d)，7.13(1H，s)，7.16(1H，d)，7.25(6H，m)。
LRMS:m/z electron spray(ES) 449[M+H
+].
Embodiment 35
N-(2-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 58 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3Od)δ1.06(3H，s)，1.08(3H，s)，2.70(3H，m)，2.83(1H，m)，3.57(2H，s)，4.43(2H，s)，4.56(1H，m)，6.18(1H，s)，6.34(2H，s)，7.04(1H，d)，7.18(6H，m)，7.17(1H，d)。
LRMS:m/z electron spray(ES) 483[M+H
+].
Embodiment 36
N-(3-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 59 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，s)，1.08(3H，s)，2.72(4H，m)，3.53(2H，s)，3.68(3H，s)，4.33(2H，s)，4.56(1H，m)，6.18(1H，m)，6.32(2H，s)，6.78(2H，m)，7.03(1H，d)，7.18(5H，m)。
LRMS:m/z electron spray(ES) 479[M+H
+].
Embodiment 37
N-(cyclohexyl methyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group)-phenyl)-ethanamide
From preparing 60 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ0.91(2H，m)，1.06(3H，s)，1.08(3H，s)，1.18(3H，m)，1.44(1H，m)，1.70(5H，m)，2.70(3H，m)，2.84(1H，m)，3.02(2H，d)，3.46(2H，s)，4.58(1H，m)，6.17(1H，t)，6.34(2H，s)，7.07(1H，d)，7.17(2H，d)，7.22(1H，t)。
LRMS：m/z APCI 455[M+H
+]。
Embodiment 38
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-styroyl-ethanamide
From preparing 61 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.07(3H，s)，1.08(3H，s)，2.73(6H，m)，3.42(2H，m)，3.47(2H，s)，4.55(1H，m)，6.17(1H，s)，6.33(2H，s)，7.15(8H，m)。
LRMS:m/z electron spray(ES) 463[M+H
+], 461[M-H
-].
Embodiment 39
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-chlorobenzene ethyl)-ethanamide
From preparing 62 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.07(3H，s)，1.08(3H，s)，2.73(6H，m)，3.43(2H，m)，3.42(2H，s)，4.55(1H，m)，6.17(1H，s)，6.36(2H，s)，7.08(5H，m)，7.21(3H，m)。
LRMS:m/z electron spray(ES) 497[M+H
+], 495[M-H
-].
Embodiment 40
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-phenyl styroyl)-ethanamide
From compound 63, use the method be described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.73(6H，m)，3.43(4H，m)，4.55(1H，m)，6.18(1H，m)，6.33(2H，s)，7.08(3H，m)，7.21(3H，m)，7.31(1H，t)，7.42(2H，m)，7.51(2H，d)，7.56(2H，d)。
LRMS:m/z electron spray(ES) 540[M+H
+].
Embodiment 41
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4 '-hydroxyl-biphenyl-3-ylmethyl)-ethanamide
From preparing 64 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.07(3H，s)，1.08(3H，s)，2.73(2H，m)，2.85(2H，m)，3.57(2H，s)，4.42(2H，s)，4.58(1H，m)，6.19(1H，m)，6.33(2H，s)，6.83(2H，d)，7.07(1H，d)，7.13(2H，d)，7.23(2H，m)，7.38(5H，m)。
LRMS:m/z electron spray(ES) 541[M+H
+], 539[M-H
-].
Embodiment 42
N-suberyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 65 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.07(3H，s)，1.08(3H，s)，1.58(10H，m)，1.86(2H，m)，2.73(4H，m)，3.44(2H，s)，3.80(1H，m)，4.58(1H，m)，6.18(1H，m)，6.32(2H，s)，7.05(1H，d)，7.15(2H，d)，7.23(1H，t)。
LRMS:m/z electron spray(ES) 455[M+H
+], 453[M-H
-].
Embodiment 43
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-styroyl-ethanamide
From preparing 66 compound, the method for use is described in embodiment 12 and prepares title compound and separation, is the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.78(7H，m)，3.40(4H，m)，4.52(1H，m)，6.13(1H，m)，6.24(2H，s)，7.08(9H，m)。
LRMS：m/z APCI 447[M-H
-]。
Embodiment 44
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-methyl sulfane base-benzyl)-ethanamide
From preparing 67 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.44(3H，s)，2.56(1H，m)，2.75(4H，m)，3.53(2H，s)，4.44(2H，s)，4.52(1H，m)，6.13(1H，m)，6.24(2H，s)，7.10(8H，m)。
Embodiment 45
N-(2,6-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 68 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.54(1H，m)，2.78(5H，m)，3.48(2H，s)，4.52(1H，m)，4.66(2H，s)，6.15(1H，m)，6.25(2H，s)，7.00(1H，m)，7.08(2H，m)，7.18(1H，m)，7.27(1H，m)，7.38(2H，m)。
LRMS：m/z APCI 503[M+H
+]。
Embodiment 46
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-indane-2-base-ethanamide
From preparing 69 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.58(1H，m)，2.78(6H，m)，3.22(2H，m)，3.45(2H，s)，4.56(2H，m)，6.15(1H，m)，6.25(2H，s)，7.00(8H，m)。
LRMS：m/z APCI 461[M+H
+]。
Embodiment 47
N-(2-chloro-6-luorobenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 70 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.54(1H，m)，2.71(2H，m)，2.83(2H，m)，3.48(2H，s)，4.57(3H，m)，6.15(1H，s)，6.25(2H，s)，7.27(7H，m)。
LRMS：m/z APCI 487[M+H
+]，485[M-H
-]。
Embodiment 49
N-(4-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 72 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)：1.05(3H，d)，2.58(1H，m)，2.71(2H，m)，2.83(1H，m)，2.90(1H，m)，3.48(2H，s)，4.38(2H，s)，4.57(1H，m)，6.16(1H，s)，6.25(2H，s)，7.02(1H，d)，7.09(1H，s)，7.11(1H，m)，7.20(3H，m)，7.28(2H，m)。
LRMS：m/z APCI 469[M+H
+]，467[M-H
-]。
Embodiment 50
N-(2,5-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 73 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.12(3H，s)，1.13(3H，s)，2.85(4H，m)，3.62(2H，s)，4.46(2H，s)，4.62(1H，m)，6.23(1H，m)，6.38(2H，s)，7.20(6H，m)，7.39(1H，d)。
LRMS:m/z electron spray(ES) 517[M+H
+], 515[M-H
-].
Embodiment 51
N-(3,5-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 74 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.11(3H，s)，1.13(3H，s)，2.85(4H，m)，3.59(2H，s)，4.37(2H，s)，4.62(1H，m)，6.23(1H，m)，6.38(2H，s)，7.01(1H，m)，7.12(1H，m)，7.17(3H，m)，7.28(1H，d)，7.32(1H，m)。
LRMS:m/z electron spray(ES) 517[M+H
+], 515[M-H
-].
Embodiment 52
N-(2,6-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 75 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.10(3H，s)，1.11(3H，s)，2.82(4H，m)，3.54(2H，s)，4.60(1H，m)，4.71(2H，s)，6.22(1H，m)，6.38(2H，s)，7.07(1H，m)，7.18(2H，m)，7.26(1H，m)，7.31(1H，m)，7.43(1H，s)，7.45(1H，m)。
LRMS:m/z electron spray(ES) 520[M+H
+], 518[M-H
-].
Embodiment 53
N-biphenyl-2-ylmethyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 76 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.14(3H，s)，1.15(3H，s)，2.82(2H，m)，2.93(2H，m)，3.52(2H，s)，4.32(2H，s)，4.62(1H，m)，6.23(1H，m)，6.38(2H，s)，7.11(13H，m)。
LRMS:m/z electron spray(ES) 527[M+H
+], 525[M-H
-].
Embodiment 54
N-(2-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 77 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.56(1H，m)，2.80(4H，m)，3.55(2H，s)，4.45(2H，s)，4.52(1H，m)，6.14(1H，m)，6.25(2H，s)，7.19(8H，m)。
LRMS：m/z APCI 469[M+H
+]。
Embodiment 55
N-(3-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 78 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.60(5H，m)，3.51(2H，s)，3.69(3H，s)，4.32(2H，s)，4.51(1H，m)，6.15(1H，m)，6.25(2H，s)，6.75(3H，m)，7.02(1H，m)，7.21(4H，m)。
LRMS：m/z APCI 465[M+H
+]。
Embodiment 56
N-(3-trifluoromethyl benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 79 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.57(1H，m)，2.66(2H，m)，2.80(1H，m)，2.90(1H，m)，3.55(2H，s)，4.43(2H，s)，4.51(1H，m)，6.16(1H，m)，6.25(2H，s)，7.03(1H，m)，7.07(1H，s)，7.14(1H，m)，7.21(1H，m)，7.47(2H，m)，7.53(2H，m)。
LRMS：m/z APCI 503[M+H
+]，501[M-H
-]。
Embodiment 57
N-(3, the 4-difluorobenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 80 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.58(1H，m)，2.66(2H，m)，2.80(1H，m)，2.90(1H，m)，3.53(2H，s)，4.30(2H，s)，4.52(1H，m)，6.16(1H，m)，6.24(2H，s)，7.01(2H，m)，7.15(5H，m)。
LRMS：m/z APCI 471[M+H
+]，469[M-H
-]。
Embodiment 58
N-(2-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 81 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.57(1H，m)，2.68(2H，m)，2.80(1H，m)，2.87(1H，m)，3.53(2H，s)，3.78(3H，s)，4.35(2H，s)，4.52(1H，m)，6.16(1H，m)，6.23(2H，s)，6.84(1H，m)，6.91(1H，m)，7.01(1H，m)，7.07(1H，s)，7.15(2H，m)，7.21(2H，m)。
LRMS：m/z APCI 465[M+H
+]，463[M-H
-]。
Embodiment 59
N-(3, the 4-dimethyl benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 82 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.04(3H，d)，2.19(3H，s)，2.19(3H，s)，2.57(1H，m)，2.66(2H，m)，2.78(1H，m)，2.88(1H，m)，3.49(2H，s)，4.26(2H，s)，4.49(1H，m)，6.16(1H，m)，6.24(2H，s)，6.93(1H，m)，6.97(1H，s)，7.01(2H，m)，7.06(1H，s)，7.13(1H，m)，7.19(1H，m)。
LRMS：m/z APCI 463[M+H
+]，461[M-H
-]。
Embodiment 60
N-(3, the 4-dimethoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 83 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.04(3H，d)，2.57(1H，m)，2.66(2H，m)，2.79(1H，m)，2.88(1H，m)，3.50(2H，s)，3.72(3H，s)，3.78(3H，s)，4.28(2H，s)，4.50(1H，m)，6.16(1H，m)，6.24(2H，s)，6.78(2H，m)，6.85(1H，m)，7.01(1H，m)，7.07(1H，s)，7.14(1H，m)，7.19(1H，m)。
LRMS：m/z APCI 495[M+H
+]，493[M-H
-]。
Embodiment 61:
N-(2-ethoxy benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 84 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.04(3H，d)，1.35(3H，t)，2.57(1H，m)，2.68(2H，m)，2.80(1H，m)，2.88(1H，m)，3.53(2H，s)，4.00(2H，q)，4.36(2H，s)，4.50(1H，m)，6.15(1H，m)，6.25(2H，s)，6.83(1H，m)，6.88(1H，m)，7.01(1H，m)，7.07(1H，s)，7.15(2H，m)，7.19(2H，m)。
LRMS：m/z APCI 479[M+H
+]，477[M-H
-]。
Embodiment 62
N-[2-(2-chloro-phenyl)-ethyl]-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide
From preparing 85 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3Od)δ1.06(3H，d)，2.58(1H，m)，2.67(2H，m)，2.81(1H，m)，2.88(3H，m)，3.43(4H，m)，4.53(1H，m)，6.16(1H，m)，6.24(2H，s)，7.04(3H，m)，7.20(6H，m)。
LRMS：m/z APCI 483[M+H
+]，481[M-H
-]。
Embodiment 63
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-kharophen]-methyl }-benzamide
From preparing 86 compound, use the method that is described in embodiment 12 to prepare title compound and be separated into the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，d)，2.57(1H，m)，2.68(2H，m)，2.80(1H，m)，2.87(1H，m)，3.58(2H，s)，4.38(2H，s)，4.51(1H，m)，6.17(1H，m)，6.25(2H，s)，7.01(1H，d)，7.07(2H，m)，7.20(1H，m)，7.29(2H，d)，7.80(2H，d)。
LRMS：m/z APCI 478[M+H
+]，476[M-H
-]。
Embodiment 64
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-indane-1-base-ethanamide
From preparing 87 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the light brown foam-like material.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，1.81(1H，m)，2.46(1H，m)，2.57(1H，m)，2.72(2H，m)，2.87(4H，m)，3.52(2H，m)，4.53(1H，m)，5.36(1H，m)，6.16(1H，m)，6.25(2H，s)，7.01(1H，m)，7.14(7H，m)。
LRMS：m/z APCI 461[M+H
+]，459[M-H
-]。
Embodiment 65
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide
From preparing 94 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.80(7H，m)，3.59(2H，m)，4.55(1H，m)，6.15(1H，m)，6.26(2H，s)，7.01(3H，m)，7.30(3H，m)，7.58(2H，m)。
LRMS：m/z APCI 453[M+H
+]。
Embodiment 66
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-chloro-phenyl)-ethyl]-benzamide
From preparing 95 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.81(5H，m)，3.07(2H，t)，3.63(2H，t)，4.53(1H，m)，6.15(1H，m)，6.26(2H，s)，7.20(6H，m)，7.55(2H，m)。
LRMS：m/z APCI 469[M+H
+]。
Embodiment 67
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-naphthalene-1-ylmethyl-ethanamide
From preparing 96 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)：0.98(3H，d)，2.47(1H，m)，2.54(2H，m)，2.78(2H，m)，3.54(2H，s)，4.51(1H，m)，4.80(2H，s)，6.17(1H，s)，6.25(2H，s)，6.98(2H，m)，7.07(2H，m)，7.40(4H，m)，7.78(1H，d)，7.84(1H，d)，7.90(1H，d)。
LRMS：m/z APCI 485[M+H
+]，483[M-H
-]。
Embodiment 68
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-fluoro-5-trifluoromethyl-benzyl)-ethanamide
From preparing 97 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.03(3H，d)，2.47(1H，m)，2.63(2H，m)，2.78(1H，m)，2.89(1H，m)，3.54(2H，s)，4.46(2H，s)，4.58(1H，m)，6.17(1H，s)，6.22(2H，s)，7.01(1H，d)，7.08(2H，m)，7.20(2H，m)，7.58(2H，m)。
LRMS：m/z APCI 521[M+H
+]，519[M-H
-]。
Embodiment 69
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(3-benzyl chloride base)-ethanamide
From preparing 98 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.03(3H，d)，2.58(1H，m)，2.63(2H，m)，2.78(1H，m)，2.85(1H，m)，3.57(2H，s)，4.38(2H，s)，4.52(1H，m)，6.17(1H，s)，6.26(2H，s)，7.01(1H，d)，7.08(1H，s)，7.20(6H，m)。
LRMS：m/z APCI 469[M+H
+]，467[M-H
-]。
Embodiment 70
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-ethanamide
From preparing 99 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.03(3H，d)，2.58(1H，m)，2.63(2H，m)，2.78(1H，m)，2.89(1H，m)，3.52(2H，s)，4.38(2H，s)，4.52(1H，m)，6.17(1H，s)，6.26(2H，s)，7.03(1H，d)，7.08(2H，m)，7.20(2H，m)，7.51(2H，m)。
LRMS：m/z APCI 521[M+H
+]，519[M-H
-]。
Embodiment 71
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methyl sulfane base-benzyl)-ethanamide
From preparing 100 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.11(3H，s)，1.12(3H，s)，2.48(3H，s)，2.85(4H，m)，3.59(2H，s)，4.47(2H，s)，4.61(1H，m)，6.23(1H，m)，6.38(2H，s)，7.07(2H，m)，7.26(6H，m)。
LRMS:m/z electron spray(ES) 497[M+H
+], 494[M-H
-].
Embodiment 72
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-kharophen]-methyl }-benzamide
From preparing 101 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)：1.11(3H，s)，1.12(3H，s)，2.85(4H，m)，3.60(2H，s)，4.46(2H，s)，4.61(1H，m)，6.23(1H，m)，6.38(2H，s)，7.10(1H，d)，7.22(2H，m)，7.28(1H，m)，7.34(2H，d)，7.82(2H，d)。
LRMS:m/z electron spray(ES) 493[M+H
+], 491[M-H
-].
Embodiment 73
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-sulfamyl-benzyl)-ethanamide
From preparing 102 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.12(3H，s)，1.13(3H，s)，2.85(4H，m)，3.60(2H，s)，4.47(2H，s)，4.61(1H，m)，6.23(1H，m)，6.38(2H，s)，7.10(1H，d)，7.22(2H，m)，7.28(1H，m)，7.40(2H，d)，7.84(2H，d)。
LRMS:m/z electron spray(ES) 529[M+H
+], 527[M-H
-]
Embodiment 74
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-kharophen]-methyl }-benzoic acid methyl ester
From preparing 103 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.08(3H，s)，1.10(3H，s)，2.85(4H，m)，3.60(2H，s)，3.92(3H，s)，4.47(2H，s)，4.61(1H，m)，6.22(1H，m)，6.38(2H，s)，7.09(1H，d)，7.20(2H，m)，7.28(1H，m)，7.37(2H，d)，7.95(2H，d)。
LRMS:m/z electron spray(ES) 508[M+H
+], 506[M-H
-].
Embodiment 75
N-(1-benzyl-piperidin-4-yl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide
From preparing 104 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be white solid.
1H NMR(400MHz，CD
3OD)δ1.12(3H，s)，1.13(3H，s)，1.55(2H，m)，1.87(2H，m)，2.15(2H，m)，2.80(6H，m)，3.50(2H，s)，3.55(2H，s)，3.68(1H，m)，4.61(1H，m)，6.22(1H，m)，6.37(2H，s)，7.08(1H，d)，7.18(2H，m)，7.26(2H，m)，7.35(2H，s)，7.36(2H，s)。
LRMS:m/z electron spray(ES) 533[M+H
+], 531[M-H
-].
Embodiment 76
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-the N-[2-styroyl]-benzamide
From preparing 105 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.62(1H，m)，2.75(1H，m)，2.80(2H，m)，2.94(3H，m)，3.58(2H，t)，4.56(1H，m)，6.16(1H，m)，6.27(2H，s)，7.18(1H，m)，7.26(6H，m)，7.57(1H，s)，7.59(1H，m)。
LRMS：m/z APCI 435[M+H
+]，433[M-H
-]。
Embodiment 77
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(5-fluoro-2-methyl-phenyl)-ethyl]-benzamide
From preparing 106 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.33(3H，s)，2.62(1H，m)，2.76(1H，m)，2.80(2H，m)，2.94(3H，m)，3.58(2H，t)，4.55(1H，m)，6.17(1H，m)，6.26(2H，s)，6.82(1H，m)，6.93(1H，m)，7.12(1H，m)，7.35(2H，m)，7.57(1H，s)，7.61(1H，m)。
LRMS：m/z APCI 467[M+H
+]，465[M-H
-]。
Embodiment 78
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-trifluoromethyl-phenyl)-ethyl]-benzamide
From preparing 107 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.62(1H，m)，2.75(1H，m)，2.82(2H，m)，2.98(1H，m)，3.12(2H，t)，3.62(2H，t)，4.56(1H，m)，6.17(1H，m)，6.26(2H，s)，7.35(3H，m)，7.50(2H，m)，7.61(3H，m)。
LRMS：m/z APCI 503[M+H
+]，501[M-H
-]。
Embodiment 79
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-(2-naphthalene-1-base-ethyl)-benzamide
From preparing 108 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.60(1H，m)，2.75(3H，m)，2.96(1H，m)，3.40(2H，t)，3.70(2H，t)，4.57(1H，m)，6.17(1H，m)，6.28(2H，s)，7.35(5H，m)，7.48(3H，m)，7.59(1H，m)，7.75(1H，m)，7.84(1H，m)，8.23(1H，m)。
LRMS：m/z APCI 485[M+H
+]，483[M-H
-]。
Embodiment 80
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2,4,5-trimethylammonium-phenyl)-ethyl]-benzamide
From preparing 109 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.17(3H，s)，2.17(6H，s)，2.27(3H，s)，2.62(1H，m)，2.75(1H，m)，2.81(4H，m)，2.98(1H，m)，3.50(2H，t)，4.55(1H，m)，6.17(1H，m)，6.26(2H，s)，6.88(1H，s)，6.91(1H，s)，7.35(2H，m)，7.38(1H，s)，7.40(1H，m)。
LRMS：m/z APCI 477[M+H
+]，475[M-H
-]。
Embodiment 81
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2,3-dimethyl-phenyl)-ethyl]-benzamide
From preparing 110 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.26(3H，s)，2.26(3H，s)，2.62(1H，m)，2.75(1H，m)，2.81(2H，m)，2.95(3H，m)，3.54(2H，t)，4.56(1H，m)，6.17(1H，m)，6.26(2H，s)，6.98(3H，m)，7.35(2H，m)，7.38(1H，s)，7.41(1H，m)。
LRMS：m/z APCI 463[M+H
+]，461[M-H
-]。
Embodiment 82
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-hydroxyl-3-chloro-phenyl)-ethyl]-benzamide
From preparing 111 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.62(1H，m)，2.75(1H，m)，2.81(2H，m)，2.95(3H，m)，3.60(2H，t)，4.56(1H，m)，6.17(1H，m)，6.26(2H，s)，6.74(1H，m)，7.06(1H，m)，7.17(1H，m)，7.35(2H，m)，7.57(1H，s)，7.60(1H，m)。
LRMS：m/z APCI 485[M+H
+]，483[M-H
-]。
Embodiment 83
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(4-chloro-phenyl)-ethyl]-benzamide
From preparing 112 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.62(1H，m)，2.75(1H，m)，2.81(2H，m)，2.95(3H，m)，3.58(2H，t)，4.56(1H，m)，6.17(1H，m)，6.26(2H，s)，7.30(6H，m)，7.58(2H，m)。
LRMS：m/z APCI 469[M+H
+]，467[M-H
-]。
Embodiment 84
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-hydroxyl-5-chloro-phenyl)-ethyl]-benzamide
From preparing 113 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.06(3H，d)，2.63(1H，m)，2.77(1H，m)，2.86(4H，m)，3.00(1H，m)，3.58(2H，t)，4.57(1H，m)，6.17(1H，m)，6.26(2H，s)，6.78(1H，m)，7.00(1H，m)，7.09(1H，m)，7.30(2H，m)，7.57(1H，s)，7.59(1H，m)。
LRMS：m/z APCI 485[M+H
+]，483[M-H
-]。
Embodiment 85
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-benzamide
From preparing 114 compound, use the method that is described in embodiment 12 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.62(1H，m)，2.75(1H，m)，2.83(2H，m)，3.00(1H，m)，3.05(2H，t)，3.62(2H，t)，4.56(1H，m)，6.17(1H，m)，6.26(2H，s)，6.99(1H，m)，7.19(1H，m)，7.35(3H，m)，7.60(2H，m)。
LRMS：m/z APCI 487[M+H
+]，485[M-H
-]。
Embodiment 86
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methyl-benzyl)-ethanamide
From preparing 115 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.22(3H，s)，2.73(3H，m)，2.83(1H，m)，3.56(2H，s)，4.37(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，7.04(1H，d)，7.10(6H，m)，7.21(1H，t)。
LRMS:m/z electron spray(ES) 465[M+H
+], 462[M-H
-].
Embodiment 87
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3-methyl-benzyl)-ethanamide
From preparing 116 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.23(3H，s)，2.73(3H，m)，2.83(1H，m)，3.56(2H，s)，4.31(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，7.04(4H，m)，7.15(3H，m)，7.21(1H，t)。
LRMS:m/z electron spray(ES) 465[M+H
+], 462[M-H
-].
Embodiment 88
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-methyl-benzyl)-ethanamide
From preparing 117 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.27(3H，s)，2.73(3H，m)，2.83(1H，m)，3.56(2H，s)，4.28(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，7.04(1H，d)，7.10(5H，m)，7.17(1H，d)，7.22(1H，m)。
LRMS:m/z electron spray(ES) 465[M+H
+], 462[M-H
-].
Embodiment 89
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methoxyl group-benzyl)-ethanamide
From preparing 118 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.68(2H，t)，2.77(1H，m)，2.83(1H，m)，3.56(2H，s)，3.79(3H，s)，4.37(2H，s)，4.55(1H，m)，6.18(1H，m)，6.37(2H，s)，6.82(1H，m)，6.92(1H，d)，7.03(1H，d)，7.12(3H，m)，7.22(2H，m)。
LRMS:m/z electron spray(ES) 480[M+H
+], 478[M-H
-].
Embodiment 90
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-methoxyl group-benzyl)-ethanamide
From preparing 119 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.68(3H，m)，2.83(1H，m)，3.56(2H，s)，3.77(3H，s)，4.27(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，6.92(2H，d)，7.04(2H，d)，7.17(4H，m)，7.21(1H，m)。
LRMS:m/z electron spray(ES) 481[M+H
+], 478[M-H
-].
Embodiment 91
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2,3-dimethyl-benzyl)-ethanamide
From preparing 120 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.15(3H，s)，2.24(3H，s)，2.68(3H，m)，2.83(1H，m)，3.53(2H，s)，4.37(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，7.02(1H，d)，7.08(3H，m)，7.11(1H，m)，7.17(1H，d)，7.21(1H，m)。
LRMS:m/z electron spray(ES) 478[M+H
+], 476[M-H
-].
Embodiment 92
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3,4-dimethyl-benzyl)-ethanamide
From preparing 121 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.19(3H，s)，2.19(3H，s)，2.68(3H，m)，2.83(1H，m)，3.54(2H，s)，4.27(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，6.96(1H，d)，6.97(1H，s)，7.06(2H，m)，7.11(1H，m)，7.18(1H，m)，7.21(1H，m)。
LRMS:m/z electron spray(ES) 477[M+H
+], 475[M-H
-].
Embodiment 93
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-chloro-6-methyl-benzyl)-ethanamide
From preparing 122 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.37(3H，s)，2.68(3H，m)，2.83(1H，m)，3.47(2H，s)，4.53(2H，s)，4.55(1H，m)，6.18(1H，m)，6.36(2H，s)，7.04(1H，d)，7.09(1H，m)，7.18(4H，m)，7.21(1H，m)。
LRMS:m/z electron spray(ES) 497[M+H
+].
Embodiment 94
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3-chloro-4-methyl-benzyl)-ethanamide
From preparing 123 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.04(3H，s)，1.05(3H，s)，2.31(3H，s)，2.68(3H，m)，2.83(1H，m)，3.56(2H，s)，4.28(2H，s)，4.53(1H，m)，6.18(1H，m)，6.36(2H，s)，7.04(1H，d)，7.11(1H，s)，7.18(1H，m)，7.21(4H，m)。
LRMS:m/z electron spray(ES) 497[M+H
+].
Embodiment 95
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-[2-(6-methoxynaphthalene-2-yl) ethyl] ethanamide
From preparing 124 compound, use the method that is described in embodiment 34 to prepare title compound and separation, be the white foam shape.
1H NMR(400MHz，CD
3OD)δ1.07(3H，s)，1.07(3H，s)，2.63(2H，m)，2.81(2H，m)，3.44(2H，s)，3.51(2H，m)，3.64(2H，s)，3.87(3H，s)，4.58(1H，m)，6.18(1H，m)，6.36(2H，s)，7.04(6H，m)，7.24(1H，d)，7.47(1H，s)，7.63(2H，m)。
LRMS:m/z electron spray(ES) 543[M+H
+].
Embodiment 96:
N-(2-benzyl chloride base)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) propionic acid amide
According to the program that is used in embodiment 12, use preparation 142 to prepare.
1H NMR(400MHz，CD
3OD)1.04(3H，d)，2.50-2.72(3H，m)，2.65-2.75(2H，m)，2.76-2.85(1H，m)，2.86-2.95(3H，m)，4.40(2H，s)，4.53(1H，m)，6.16(1H，m)，6.26(2H，s)，6.94-7.08(4H，m)，7.13-7.24(3H，m)，7.35(1H，m)；LRMS APCI m/z 483[M+H]
+
Embodiment 97
N-(2, the 6-dichloro benzyl)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) propionic acid amide
According to the program that is used in embodiment 12, use preparation 143 to prepare.
1H NMR(400MHz，CD
3OD)δ1.04(3H，d)，2.42-2.58(3H，m)，2.62-2.75(2H，m)，2.76-2.95(4H，m)，4.53(1H，m)，4.62(2H，s)，6.16(1H，m)，6.25(2H，s)，6.92(1H，m)，6.96(1H，s)，7.01(1H，m)，7.13(1H，t)，7.26(1H，t)，7.38(2H，m)；
LRMS APCI m/z 517[M+H]
+
Embodiment 98
1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) third-1-ketone
According to the program that is used in embodiment 12, use preparation 144 to prepare.
1H NMR(400MHz，CD
3OD)δ1.03(3H，d)，2.65-2.95(11H，m)，3.62-3.75(2H，m)，4.46-4.68(3H，m)，6.16(1H，m)，6.24(2H，s)，6.84-7.19(8H，m)；LRMS APCI m/z 475[M+H]
+
Embodiment 99
N-(2-chloro-4-luorobenzyl)-2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) ethanamide
From preparing 145 compound, use the method that is described in embodiment 34 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ1.00(3H，d)，2.60-2.65(1H，m)，2.64-2.68(2H，m)，2.83-2.93(1H，m)，3.48(2H，s)，4.86(2H，s)，4.47-4.50(1H，m)，6.11(1H，s)，6.21(2H，m)，6.99-7.83(7H，m)。
LRMS：m/z APCI 687[M+H
+]。
Embodiment 100
N-(4-bromobenzyl)-2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl) ethanamide
From preparing 146 compound, use the method that is described in embodiment 34 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ1.07(d，6H)，2.63-2.78(m，3H)，2.84(t，1H)，3.57(s，2H)，4.31(s，2H)，4.53-4.57(m，1H)，6.18(s，1H)，6.37(s，2H)，7.05(d，1H)，7.16(t，4H)，7.22(t，1H)，7.42(d，2H)；LRMS APCI m/z 529[M+H]
+。
Embodiment 101
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-(3, the 4-3,5-dimethylphenyl) ethanamide
From preparing 147 compound, use the method that is described in embodiment 34 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ1.05(d，6H)，2.22(d，6H)，2.66-2.78(m，3H)，2.83(t，1H)，3.62(s，2H)，4.56-4.59(m，1H)，6.18(s，1H)，6.32(s，2H)，7.04(t，2H)，7.18-7.24(m，4H)，7.31(s，1H)；LRMS APCI m/z 463[M+H]
+。
Embodiment 102
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-N-(2, the 3-dimethyl benzyl) ethanamide
From preparing 148 compound, use the method that is described in embodiment 12 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ0.99(3H，s)，2.20(3H，s)，2.48(1H，dd)，2.61-2.67(2H，m)，2.72(1H，dd)，2.80(1H，dt)，3.45(2H，s)，4.31(2H，s)，4.44(1H，dd)，6.09(1H，t)，6.19(1H，s)，6.20(1H，s)，6.92-7.17(7H，m)；LRMS APCI m/z 462[M+H]
+。
Embodiment 103
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-N-(4-luorobenzyl) ethanamide
From preparing 149 compound, use the method that is described in embodiment 12 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ0.99(3H，d)，2.49(1H，dd)，2.60-2.66(2H，m)，2.74(1H，dd)，2.82-2.89(1H，m)，3.46(2H，s)，4.27(2H，s)，4.46(1H，dd)，6.12(1H，t)，6.21(1H，s)，6.22(1H，s)，6.91-6.98(3H，m)，7.02-7.07(2H，m)，7.03-7.21(3H，m)；LRMS APCIm/z 451[M+H]
+。
Embodiment 104
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-1-(4-pyridine-2-base piperazine-1-yl) ethyl ketone
From preparing 150 compound, use the method that is described in embodiment 12 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ1.05(3H，d)，2.59(1H，dd)，2.78-2.93(3H，m)，3.08-3.15(1H，m)，3.31(2H，t)，3.41(2H，t)，3.59(2H，t)，3.66(2H，t)，3.77(2H，s)，4.55(1H，dd)，6.13(1H，t)，6.25(1H，s)，6.26(1H，s)，6.62-6.65(1H，m)，6.73(1H，d)，7.02-7.11(3H，m)，7.20(1H，t)，7.48(1H，dt)，8.01(1H，bd)；LRMS APCI m/z 491[M+H]
+。
Embodiment 105
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-(2-phenyl propyl) ethanamide
From preparing 151 compound, use the method that is described in embodiment 12 to prepare title compound.
1H NMR(400MHz，CD
3OD)δ0.92(3H，d)，1.06(3H，d)，2.40(1H，dd)，2.53-2.59(2H，m)，2.66(1H，dd)，2.74-2.83(2H，m)，3.14-3.24(2H，m)，3.27(2H，s)，4.38(1H，dd)，6.02(1H，t)，6.13(1H，s)，6.13(1H，s)，6.83-6.90(2H，m)，6.98-7.07(4H，m)，7.08-7.13(2H，m)；LRMSAPCI m/z 463[M+H]
+。
The ability that the compound of formula (1) is therefore regulated smooth muscle loosening as potent property β2Ji Dongji can be measured the effect of the electrical field stimulation contraction of guinea-pig tracheal strip by measuring the beta-2 adrenergic receptor stimulation.
Guinea pig trachea
Utilize CO
2Suffocate and put to death male, Tang Jin hartley (Dunkin-Hartley) cavy (475-525 gram), and from femoral artery bloodletting and separation tracheae.Obtain four prepared products from every animal, begin to dissect under the larynx and take out the tracheae of 2.5 cm long immediately.Open this tracheae piece by cut cartilage with respect to tracheal muscle muscle, cut the square section then, 3-4 cartilage ring width.Use was this up and down cotton thread of zona cartilaginea, the rectangular prepared product that is produced was suspended among 5 milliliters the organ trough.The atenolol USP 23 (A7655 of Sigma) of the guanethidine (G8520 of Sigma) of the indomethacin that comprises 3 μ M (I7378 of Sigma (Sigma)), 10 μ M and 10 μ M in the improved Ke Liebaishi logical sequence rank of nobility (Krebs Ringer) damping fluid (K0507 of Sigma), make described rectangular balance, do not tighten 20 minutes, before the initial tension force that applies 1 gram, heat down and supply 95%O at 37 ℃
2/ 5%CO
2Gas.Tighten (to 1 gram) again with 15 minutes interval at them and during twice, allow the further balance 30-45 of this prepared product minute.Via writing down and monitor tension change with data gathering system banded standard equal proportion transmodulator (isometric transducers) (Pfizer (Pfizer) custom design).Behind equalization of strain, use following parameters to make this tissue accept electrical field stimulation (EFS): conduction in per 2 minutes 10 seconds, pulse width 0.1 microsecond, 10 hertz reach only peak voltage (25 volts), run through experiment length continuously.The EFS of the back neuroganglion choline nerve in tracheae causes the single-phase contraction of unstriated muscle, and record is twitched highly.Whole experimental session continues perfused organ's groove by the above-mentioned Ke Liebaishi logical sequence rank of nobility damping fluid of peristaltic pump system (flow rate pump 7.5 ml/min), except when when adding according to β of the present invention-2 agonist; Then, the time of injecting this groove in accumulation stops this pump, and starts once more after arriving maximum reaction and continue the period of washing out.
The experimental program of assessment effectiveness and effect
With the EFS balance after, stop peristaltic pump, with these prepared products of Racemic isoproterenol (I5627 of Sigma) " perfusion " of single dose 300nM, set up maximum reaction just to suppress shrinkable EFS reaction.Then, wash 40 fens clock times of Racemic isoproterenol off.After perfusion and washing out recovery, the semilog increment of working concentration, by cumulative, be added to this groove in a large number, whole tissues are carried out typical curve (Racemic isoproterenol curve 1) to Racemic isoproterenol.Employed concentration range is 1
E-9To 1
e/ 3
E-6M.At the last place of Racemic isoproterenol curve,, cleaned these prepared products once more 40 minutes at beginning Racemic isoproterenol (as internal contrast) or according to second time of β of the present invention-2 agonist before the curve.Per-cent with the EFS reaction suppresses to represent the reaction of β-2 agonist.By this inhibition being expressed as in curve 1 percentage that suppresses by the maximum that Racemic isoproterenol the brought out data of stdn β-2 agonist recently.EC according to β of the present invention-2 agonist
50Value refers to half the required compound concentration that produces maximum effect.Then, (the EC that the data representation of β-2 agonist according to the present invention can be served as reasons
50β-2 agonist)/(EC
50The effectiveness with respect to Racemic isoproterenol of ratio definition Racemic isoproterenol).
The confirmation of the functionally active of β-2 mediation
Use such scheme to come β-2 agonist activity of confirmatory test compound; But, before the curve that makes up according to β of the present invention-2 agonist, cultivate described prepared product (minimum 45 minutes) in advance with the ICI 118551 of 300nM (optionally β 2 antagonists, it causes the situation of the effect of β-2 mediation in the skew to the right of this test compound dose response curve).
According to another replacement scheme, also can be by measuring the half (EC that produces maximum effect for beta 2 receptor
50) required compound concentration according to the present invention comes the agonist of beta 2 receptor of the compound of measurement formula (1) to render a service.
The compound thing
In 4%DMSO, 10mM/100%DMSO (dimethyl sulfoxide (DMSO)) stock solution of compound is diluted to needed top dosage.Use this top dosage to come 10 half-log curves of construction, all in 4% DMSO.(Sigma is I-5627) as standard in each experiment and to the use of the control wells on every block of plate Racemic isoproterenol.Data are expressed as the reaction of % Racemic isoproterenol.
Cell cultures
Detain this (Dulbeccos) MEM/NUT MIX F12 (jeep button (Gibco) at Da Erbei, 21331-020), CHO (Chinese hamster ovary) cell of recombinant expressed human beta 2-adrenergic receptor of growing (is finished card people such as (Kobilka), PNAS 84:46-50,1987 from the bandit; And Bu Weier people such as (Bouvier), Mol Pharmacol 33:133-1391988CHOh β 2), above-mentioned culture medium supplemented 10% foetal calf serum (Sigma, F4135, lot number 90K8404Exp09/04), the glutamine (Sigma of 2mM, G7513), the Geneticin of 500 mcg/ml (Sigma, G7034) and the tetracycline of 10 mcg/ml (Sigma, P8833).The sowing cell is to provide about 90% converge that is used for testing.
Test method
The every dosage compound in 25 microlitres/hole is transferred to the rapid plate of cAMP-(Flashplate) , and (NEN, SMP004b), the DMSO with 1% contrasts as maximum as the Racemic isoproterenol of basis contrast and 100nM.This dilutes with 1: 2 by adding the PBS in 25 microlitres/hole.With the cell trypsinized (0.25% Sigma, T4049), with PBS (the jeep button, 14040-174) clean and resuspending in stimulate damping fluid (NEN, SMP004b) in, to provide 1 * 10
6Cells/ml CHOhB2.Compound with 50 microlitres/hole came culturing cell 1 hour.Then, comprise 0.18 μ Ci/ milliliter by adding 100 microlitres/hole
125(NEN, (NEN SMP004b) comes dissolved cell to detection damping fluid NEX-130) to I-cAMP, and other 2 hours of culture plate at room temperature.Use Tuo Pukang (Topcount) NXT (Bock (Packard)) quantitatively to be bonded to rapid plate 's
125The amount of I-cAMP, normal counting efficiency 1 minute.The dose response data are expressed as % Racemic isoproterenol activity, and use four parameter S shape matches to come match.
Therefore find, go out to be lower than the β 2 cAMP EC of 30nM in the compound exhibits according to formula of the present invention (1) of embodiment 1 to 105 illustrated
50
Claims (17)
1. the compound of general formula (1):
(CH wherein
2)
n-C (=O) Q
1Group is in a position or contraposition;
-R
1And R
2Be independently selected from H and C
1-C
4Alkyl;
-n be 0,1 or 2 and
-Q
1For being selected from following group:
Wherein
-p be 1 or 2 and q be 1 or 2;
-Q
2Be singly-bound or the optional C that replaces with OH
1-C
4Alkylidene group;
-R
8Be H or C
1-C
4Alkyl and
-Q
3For choosing wantonly with NR
9R
10, OR
9Or the C of phenoxy group replacement
1-C
6Alkyl;
-A is selected from:
Zero C
3-C
10Cycloalkyl, this cycloalkyl can be chosen wantonly by one or more carbon atom bridge joints, and optional by a hydroxyl replacement;
05 to 6 element heterocycle groups, optional is aromatic series, and it comprises one or two heteroatomss that are selected from O, N or S, and it is chosen wantonly and is selected from C by one or two
1-C
4The substituting group of alkyl, benzyl and cyclopropyl methyl replaces; Or
Zero following groups
Quinolyl or isoquinolyl;
-R
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, C
1-C
4Alkyl, OR
9, SR
9, SOR
9, SO
2R
9, halogen, CN, CF
3, OCF
3, SO
2NR
9R
10, COOR
9, CONR
9R
10, NR
9R
10, NHCOR
10And the optional phenyl that replaces with OH;
-R
9And R
10Identical or different, and be selected from H or C
1-C
4Alkyl;
-R
11Be selected from H or OH, and
-R
12And R
13Identical or different, and be selected from H, optional with OR
9The C that replaces
1-C
4Alkyl, OR
9, C (=O) NH
2, C (=O) CH
3, N (CH
3) C (=O) CH
3, C (=O) OR
9, the optional phenyl that replaces with halogen, the optional pyridyl that replaces with CN, optional with C
1-C
4The di azoly that alkyl replaces; And
The tie point of-* representative and carbonyl;
Perhaps, if suitable, their pharmacy acceptable salts and/or its isomer, tautomer, solvate or isotopic variations.
2. according to the compound of the general formula (1) of claim 1, (CH wherein
2)
n-C (=O) Q
1Group is in a position or contraposition;
-R
1And R
2Be independently selected from H and C
1-C
4Alkyl;
-n is 0,1 or 2;
-Q
1For being selected from following group:
And *-NR
8-Q
2-A group, wherein p is 1 or 2, Q
2Be C
1-C
4Alkylidene group, R
8Be H or C
1-C
4Alkyl, and A is pyridyl, C
3-C
10Cycloalkyl, this cycloalkyl is optional by 1,2,3 or 4 carbon atom bridge joint, THP trtrahydropyranyl, piperidyl, tetrahydro thiapyran base or following groups:
-R
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, C
1-C
4Alkyl, OR
9, SR
9, SOR
9, SO
2R
9, halogen, CN, CF
3, OCF
3, SO
2NR
9R
10, COOR
9, CONR
9R
10, NR
9R
10, NHCOR
10And the optional phenyl that replaces with OH;
-R
9And R
10Identical or different, and be selected from H or C
1-C
4Alkyl, and the tie point of * representative and carbonyl;
Perhaps, if suitable, their pharmacy acceptable salts and/or its isomer, tautomer, solvate or isotopic variations.
3. according to the compound of claim 1 or 2, Q wherein
1Be *-NH-Q
2-A group, wherein A is cyclohexyl or adamantyl.
4. according to the compound of claim 1 or 2, wherein A is for choosing wantonly with OR
9The naphthyl that replaces.
5. according to the compound of claim 2, Q wherein
1Be *-NH-Q
2-A group, wherein A is a following groups:
R wherein
3, R
4, R
5, R
6And R
7Identical or different, and be selected from H, C
1-C
4Alkyl, OR
9, SR
9, halogen, CN, CF
3, OCF
3, SO
2NR
9R
10, COOR
9, CONR
9R
10, NR
9R
10, NHCOR
10And the optional phenyl that replaces with OH, condition is R
3To R
7There are at least 2 to be H;
R wherein
9And R
10Identical or different, and be selected from H or C
1-C
4Alkyl.
6. according to each compound of claim 1 to 5, wherein Q
2For-CH
2-,-(CH
2)
2-,-(CH
2)
3-,-CH (CH
3)-,-CH
2CH (CH
3)-or C (CH
3)
2-.
7. according to the compound of claim 1 or 2, Q wherein
1For
R wherein
3, R
4, R
5And R
6Be H.
8. according to each compound of claim 1 to 7, wherein R
1Be H or CH
3And R
2Be CH
3
9. according to each compound of claim 1 to 8, wherein n is 0 or 1.
10. according to each (R, R) steric isomer of compound of claim 1 to 9.
11. according to each compound of claim 1 to 10, wherein (CH
2)
n-C (=O) Q
1Group is in a position.
12. according to the compound of claim 1, it can be selected from the group of being made up of following:
N-benzyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
N-cyclopropyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1R, 2S)-2-(methylol) cyclohexyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-morpholine-4-base propyl group) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(pyridine-2-ylmethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-morpholine-4-base ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-sec.-propyl ethanamide;
N-(4-benzyl chloride base)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[2-(dimethylamino) ethyl] ethanamide;
N-[2-(diethylamino) ethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-(dimethylamino) propyl group] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-amyl group ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-tetramethyleneimine-1-base ethyl) ethanamide;
N-(2, the 4-dichloro benzyl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
N-(3, the 4-dichloro benzyl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-methoxy-benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-hydroxyethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-propyl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-methoxy-propyl) ethanamide;
N-cyclobutyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1R)-and 1-(1-naphthyl) ethyl] ethanamide;
N-2,3-dihydro-1H-indenes-1-base-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[2-(1-methylpyrrolidin-2-yl) ethyl] ethanamide
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-luorobenzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-phenyl butyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-methoxy-benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-ethoxycarbonyl propyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3,4,5-trimethoxy benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[4-(trifluoromethyl) benzyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[2-(trifluoromethyl) benzyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3, the 5-dimethoxy-benzyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-phenoxy group ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 2-hydroxyl-1-methylethyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 1-(methylol)-2-methyl-propyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S, 2S)-1-(methylol)-2-methyl butyl] ethanamide;
N-[(1R)-1-benzyl-2-hydroxyethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1R)-and 1-(methylol) propyl group] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 1-(methylol)-2, the 2-dimethyl propyl] ethanamide;
N-[(1S)-2-cyclohexyl-1-(methylol) ethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-propoxy-ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4-hydroxy-cyclohexyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-propoxy-propyl group) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-ethyl-N-(2-hydroxyethyl) ethanamide;
1-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl } piperidines-4-methane amide;
5-{2-[(2-{3-[2-(4-ethanoyl piperazine-1-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
5-{2-[(2-{3-[2-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
N-benzyl-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-methylacetamide;
5-(1-hydroxyl-2-{[2-(3-{2-[4-(2-hydroxyethyl) piperazine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
5-(2-{[2-(3-{2-[4-(4-chloro-phenyl-)-4-hydroxy piperidine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino }-the 1-hydroxyethyl) benzene-1, the 3-diphenol;
5-{2-[(1,1-dimethyl-2-{3-[2-(4-methylpiperazine-1-yl)-2-oxoethyl] phenyl } ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-methyl-N-(2-phenylethyl) ethanamide;
5-{2-[(1,1-dimethyl-2-{3-[2-oxo-2-(4-pyridine-2-base piperazine-1-yl) ethyl] phenyl } ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-(dimethylamino) propyl group]-the N-methylacetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-hydroxyethyl)-N-propyl acetamide;
N-[2-(diethylamino) ethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-methylacetamide;
5-{2-[(1,1-dimethyl-2-{3-[2-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-oxoethyl] phenyl } ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
5-[2-(1,1-dimethyl-2-[3-(2-morpholine-4-base-2-oxoethyl) phenyl] and ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-the N-methyl-N-[(1S)-the 1-phenylethyl] ethanamide;
5-[2-(1,1-dimethyl-2-[3-(2-oxo-2-piperidines-1-base ethyl) phenyl] and ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-diphenol;
5-(1-hydroxyl-2-{[2-(3-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
5-(1-hydroxyl-2-{[2-(3-{2-[(3R)-3-hydroxy piperidine-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
5-{2-[(2-{3-[2-(4-ethanoyl-1,4-Diazesuberane-1-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
5-(1-hydroxyl-2-{[2-(3-{2-[4-(methylol) piperidines-1-yl]-the 2-oxoethyl } phenyl)-1, the 1-dimethyl ethyl] amino } ethyl) benzene-1, the 3-diphenol;
N-(1-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl } tetramethyleneimine-3-yl)-the N-methylacetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-methoxy ethyl)-N-propyl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-ethyl-N-(2-methoxy ethyl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-(dimethylamino)-2, the 2-dimethyl propyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[3-fluoro-5-(trifluoromethyl) benzyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 1-(methylol)-3-methyl butyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and 2-hydroxyl-1-phenylethyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N, the N-diethyl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-1H-pyrazoles-5-yl acetamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(5-methyl isophthalic acid H-pyrazole-3-yl) ethanamide;
N-(cyclohexyl methyl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
4-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl } piperazine-1-carboxylic acid, ethyl ester;
N-(5-chloropyridine-2-yl)-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(6-picoline-2-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-picoline-2-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-isoquinolyl-1 ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(4,6-lutidine-2-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(2-methoxy-benzyl) ethanamide;
N-[(1S)-1-benzyl-2-hydroxyethyl]-2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(1-ethyl-1H-pyrazoles-5-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(1,3-dimethyl-1H-pyrazoles-5-yl) ethanamide;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-(3-luorobenzyl) ethanamide;
1-{[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl] ethanoyl }-the L-prolineamide;
5-{2-[(2-{3-[2-(the 5-amino-3-tertiary butyl-1H-pyrazol-1-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
2-[3-(2-{[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethyl] amino }-the 2-methyl-propyl) phenyl]-N-[(1S)-and the 1-phenylethyl] ethanamide;
5-{2-[(2-{3-[2-(1,4-two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-yl)-2-oxoethyl] phenyl }-1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl } benzene-1, the 3-diphenol;
N-[2-(4-chloro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-diamantane-1-base-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide;
N-[2-(2-chloro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(2,3-dimethyl-phenyl)-ethyl]-benzamide;
N-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-N-[2-(4-methoxyl group-2,3-dimethyl-phenyl)-ethyl]-benzamide;
N-(3,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(3,4-two chloro-benzyls)-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-(4-chloro-benzyl)-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-diamantane-1-base-3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-benzamide;
N-(4-chloro-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(4-trifluoro-methoxybenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-pyridine-2-ylmethyl-ethanamide;
N-(3,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-cyclohexyl methyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethyl ketone;
N-benzyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-methyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-hydroxyl-benzyl)-ethanamide;
N-(4-cyano group-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2,4-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(3-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(cyclohexyl methyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-styroyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-chlorobenzene ethyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-phenyl styroyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4 '-hydroxyl-biphenyl-3-ylmethyl)-ethanamide;
N-suberyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-styroyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-methyl sulfane base-benzyl)-ethanamide;
N-(2,6-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-indane-2-base-ethanamide;
N-(2-chloro-6-luorobenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(4-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(2,5-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(3,5-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2,6-two chloro-benzyls)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-biphenyl-2-ylmethyl-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
N-(2-benzyl chloride base)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3-trifluoromethyl benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3, the 4-difluorobenzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(2-methoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3, the 4-dimethyl benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
N-(3, the 4-dimethoxy-benzyl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-ethanamide;
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-kharophen]-methyl }-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-indane-1-base-ethanamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(3-fluoro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-chloro-phenyl)-ethyl]-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-naphthalene-1-ylmethyl-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(2-fluoro-5-trifluoromethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(3-benzyl chloride base)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methyl sulfane base-benzyl)-ethanamide;
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-kharophen]-methyl }-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-sulfamyl-benzyl)-ethanamide;
4-{[2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-kharophen]-methyl }-benzoic acid methyl ester;
N-(1-benzyl-piperidin-4-yl)-2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-ethanamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-the N-[2-styroyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(5-fluoro-2-methyl-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-trifluoromethyl-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-(2-naphthalene-1-base-ethyl)-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2,4,5-trimethylammonium-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2,3-dimethyl-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-hydroxyl-3-chloro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(4-chloro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-hydroxyl-5-chloro-phenyl)-ethyl]-benzamide;
3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-propyl group }-N-[2-(2-chloro-4-fluoro-phenyl)-ethyl]-benzamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-methoxyl group-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(4-methoxyl group-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2,3-dimethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3,4-dimethyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(2-chloro-6-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-(3-chloro-4-methyl-benzyl)-ethanamide;
2-(3-{2-[2-(3,5-dihydroxyl-phenyl)-2-hydroxyl-ethylamino]-2-methyl-propyl group }-phenyl)-N-[2-(6-methoxyl group-naphthalene-2-yl)-ethyl]-ethanamide;
N-(2-benzyl chloride base)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) propionic acid amide;
N-(2, the 6-dichloro benzyl)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) propionic acid amide;
1-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-3-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) third-1-ketone;
N-(2-chloro-4-luorobenzyl)-2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl) ethanamide;
N-(4-bromobenzyl)-2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-(3, the 4-3,5-dimethylphenyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-N-(2, the 3-dimethyl benzyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-N-(4-luorobenzyl) ethanamide;
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino] propyl group } phenyl)-1-(4-pyridine-2-base piperazine-1-yl) ethyl ketone; And,
2-(3-{2-[2-(3, the 5-dihydroxyphenyl)-2-hydroxyethylamino]-the 2-methyl-propyl } phenyl)-N-(2-phenyl propyl) ethanamide.
13. a pharmaceutical composition, its comprise significant quantity at least according to formula (1) compound or its pharmacy acceptable salt or the derivative form of claim 1 to 12 described in each.
14. as medicament according to formula (1) compound or its pharmacy acceptable salt, derivative form or the composition of claim 1 to 12 described in each.
15. according to each formula (1) compound or its pharmacy acceptable salt, solvate or the composition purposes that is used to make medicine of claim 1 to 12, this medicine is used for the treatment of the medicine that is selected from by disease, obstacle and the illness of the following group of forming:
Which kind of type no matter, nosetiology or pathogenetic asthma particularly are selected from the asthma by the following group of forming: atopic asthma, anallergic asthma, allergic asthma, the asthma of allergy segmental bronchus IgE mediation, bronchial asthma, the special property sent out asthma, true asthma, the intrinsic asthma that is caused by the pathologic, physiologic obstacle, by the extrinsic asthma that environmental factors caused, spy's property sent out asthma of the unknown or unknown cause, anallergic asthma, bronchitis asthma, emphysematous asthma, the asthma of exercise induced, the asthma that anaphylactogen brings out, the asthma that freezing air brings out, occupational asthma, by bacterium, fungi, protozoon or the infective asthma that virus infection caused, non-allergic asthma, the first property asthma of sending out, stridulating property baby comprehensive is levied and bronchiolitis;
Chronic or acute bronchoconstriction, chronic bronchitis, SAO and pulmonary emphysema;
No matter which kind of type, nosetiology or pathogenetic obstructive or airway inflammatory disease particularly are selected from obstructive or airway inflammatory disease by the member of the following group of forming: chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), comprise chronic bronchitis, pulmonary emphysema or relevant with COPD or incoherent dyspneic COPD, be characterized as irreversible COPD, the obstruction of the air passage of carrying out property, the respiratory distress syndrome (ARDS) of growing up, the deterioration of the airway hyperreactivity that caused because of the other medicines treatment and the airway disorders relevant with pulmonary hypertension;
No matter which kind of type, nosetiology or pathogenetic bronchitis particularly are selected from the bronchitis by the member of the following group of forming: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus property or streptococcus bronchitis and vesicular bronchitis;
Acute lung injury;
No matter which kind of type, nosetiology or pathogenetic bronchiectasis particularly are selected from the bronchiectasis by the member of the following group of forming: cylindrical bronchiectasis, cystic bronchiectasis, spin hang down shape bronchiectasis, bronchiolectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
16. comprise human mammiferous method with the β2Ji Dongji treatment, it comprise with significant quantity as formula (1) compound of claim 1 to 12 described in each, or with the described Mammals of its pharmacy acceptable salt, derivative form or combination treatment.
17. according to claim 1 to 15 each compound be selected from the combination of other following therapeutical agent:
(a) 5-lipoxidase (5-LO) inhibitor or 5-lipoxidase activation of protein (FLAP) antagonist;
(b) leukotriene antagonist (LTRA) comprises LTB
4, LTC
4, LTD
4And LTE
4Antagonist;
(c) histamine receptor antagonist comprises H1 and H3 antagonist;
(d) be used for the α of decongestant purposes
1-and α
2-adrenoceptor agonists vasoconstriction parasympathomimetic agent;
(e) muscarinic M 3 receptors antagonist or anticholinergic;
(f) PDE inhibitor, for example PDE3, PDE4 and PDE5 inhibitor;
(g) theophylline;
(h) Sodium Cromoglicate;
(i) COX inhibitor, non-selective optionally COX-1 or the cox 2 inhibitor (NSAID) of reaching;
(j) the oral and glucocorticosteroid that sucks is such as DAGR (agonist that dissociates of corticoid acceptor);
(k) the effective monoclonal antibody of anti-endogenous inflammatory entity;
(l) anti-tumor necrosis factor (medicament of anti-TNF-α);
(m) adhesion molecule inhibitor comprises the VLA-4 antagonist;
(n) kassinin kinin-B
1-and B
2-receptor antagonist;
(o) immunosuppressor;
(p) inhibitor of matrix metalloproteinase class (MMPs);
(q) tachykinin NK-1
1, NK
2And NK
3Receptor antagonist;
(r) elastase inhibitor;
(s) adenosine A 2a receptor stimulant;
(t) urokinase inhibitors;
(u) act on compound on the Dopamine Receptors, for example the D2 agonist;
(the v) conditioning agent of NF κ beta pathway, for example IKK inhibitor;
(w) conditioning agent of cytokine signaling approach is such as p38MAP kinases, syk kinases or jak kinase inhibitor;
(x) can be categorized as the medicament of mucolytic agent or antitussive;
(y) microbiotic.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04290769 | 2004-03-23 | ||
| EP04290769.1 | 2004-03-23 | ||
| US60/591,789 | 2004-07-27 | ||
| GB0420867.4 | 2004-09-21 | ||
| US60/625,505 | 2004-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1934104A true CN1934104A (en) | 2007-03-21 |
Family
ID=34931010
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580009299 Pending CN1934104A (en) | 2004-03-23 | 2005-03-10 | Compounds for the treatment of diseases |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1934104A (en) |
| GT (1) | GT200500059A (en) |
| TN (1) | TNSN06302A1 (en) |
| ZA (1) | ZA200606780B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083839A (en) * | 2008-02-06 | 2011-06-01 | 阿斯利康(瑞典)有限公司 | Compounds |
| CN109305920A (en) * | 2017-07-27 | 2019-02-05 | 海南利能康泰制药有限公司 | A kind of preparation method of high-purity injection stage bricalin |
-
2005
- 2005-03-10 CN CN 200580009299 patent/CN1934104A/en active Pending
- 2005-03-21 GT GT200500059A patent/GT200500059A/en unknown
-
2006
- 2006-08-15 ZA ZA200606780A patent/ZA200606780B/en unknown
- 2006-09-22 TN TNP2006000302A patent/TNSN06302A1/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083839A (en) * | 2008-02-06 | 2011-06-01 | 阿斯利康(瑞典)有限公司 | Compounds |
| CN102083839B (en) * | 2008-02-06 | 2014-03-26 | 阿斯利康(瑞典)有限公司 | Compounds |
| CN109305920A (en) * | 2017-07-27 | 2019-02-05 | 海南利能康泰制药有限公司 | A kind of preparation method of high-purity injection stage bricalin |
Also Published As
| Publication number | Publication date |
|---|---|
| GT200500059A (en) | 2005-10-24 |
| ZA200606780B (en) | 2008-08-27 |
| TNSN06302A1 (en) | 2007-12-03 |
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