CN101405260A - Amine derivatives - Google Patents
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- CN101405260A CN101405260A CNA2007800101481A CN200780010148A CN101405260A CN 101405260 A CN101405260 A CN 101405260A CN A2007800101481 A CNA2007800101481 A CN A2007800101481A CN 200780010148 A CN200780010148 A CN 200780010148A CN 101405260 A CN101405260 A CN 101405260A
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- phenyl
- ethyl
- hydroxyphenyl
- compound
- diisopropylaminoethyl
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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
The present invention relates to the compound of general formula (1):
Wherein A and B have implication as follows, and relate to method and the intermediate that is used to prepare this analog derivative, the purposes that contains composition and this analog derivative of this analog derivative.
β
22-adrenergic agonist components and cholinergic muscarine antagonist are for generally acknowledging the therapeutical agent that is used for the treatment of obstructive respiratory disease (such as COPD and asthma).The inhaling type β of current use
2Agonist comprise fugitive dose (such as salbutamol (salbutamol) (q.i.d.) and terbutaline (terbutaline) (t.i.d)) and sustained release drug ((b.i.d.)) such as Salmeterol (salmeterol) and formoterol (formoterol), and produce bronchiectasis via stimulating the adrenergic receptor on the tracheal smooth muscle.The inhaling type muscarine antagonist of clinical use comprise fugitive ipratropium bromide (ipratropium bromide) (q.i.d.), oxitropium bromide (oxitropiumbromide) (q.i.d) and long-acting tiotropium (tiotropium) (q.d.).The muscarine antagonist is by mainly producing bronchiectasis via the antagonism vagusstoff to the cholinergic state that is used for suppressing tracheae (cholinergic tone) of the muscarine acceptor that exists on the tracheal smooth muscle.Some open researchs show, for the obstructive pulmonary patient, compare inhaling type β with the patient of the medicament of the arbitrary single type of independent acceptance
2The combination medicine-feeding of agonist and inhaling type muscarine antagonist (no matter fugitive or long-acting) causes the more excellent improvement aspect pulmonary function, symptom and quality of the life measurement.Research so far once was subject to the combination research about single pharmacology medicament, yet the combination at two kinds of pharmacology of single intramolecularly will be for desired, this is because this combination can produce the enhancing bronchodilator effect that has with the similar therapeutic index of single medicament, or has the similar effect of higher therapeutic index.In addition, make up two kinds of pharmacology and in single molecule, will make and be combined into possibility, and then can provide triple therapy by single sucker with anti-inflammatory agent.
The present invention relates to the compound of general formula (1):
Wherein A is selected from:
Wherein * represents the tie point of A to the carbon atom that has hydroxyl;
And B is selected from:
1) * *-(CH
2)
2-(CH
2)
m-X
1-(CH
2)
n-* * *, wherein X
1Be O or S, m is 0 to 9 integer, and n is 0 to 9 integer, and n+m (comprises end points) between 4 to 9;
2) randomly through one or two C
1-C
4The C that alkyl replaces
6-C
12Alkylidene group;
3) group of following formula:
X wherein
2Be O or S, r is 2 to 7 integer, and s is 0 to 6 integer, and t is 0 to 6 integer, and s+t (comprises end points) between 1 to 6, and r+s+t (comprises end points) between 3 to 8; And
4) group of following formula:
* represents the tie point of B to adjacent NH group, and * * * represents the tie point of B to adjacent phenyl;
With and quaternary ammonium salt or, if when suitable, its pharmacy acceptable salt and/or its isomer, tautomer, solvate or isotopic variations.
The compound of formula (1) is beta 2-adrenergic receptor agonist and muscarine receptor antagonist, and it especially when using via inhalation route, is specially adapted to relate to the disease or the treatment of conditions of this receptoroid by showing splendid usefulness.
The compound of formula (1)
Can use ordinary method (such as by following exemplary methods) to prepare, wherein unless otherwise indicated, otherwise A and B were as before defining about formula (1) compound.
Formula (1) but the amine of sulfonamide derivatives through type (2):
The bromide of (wherein Ra represents hydrogen or suitable hydroxyl protecting group, is preferably benzyl) and formula (3):
The reaction of (wherein A defines about formula (1) compound as mentioned) and preparing.The preferred hydroxyl that uses suitable hydroxyl protecting group to protect A.Preferred hydroxyl protecting group is a benzyl.
In a typical method, randomly at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, propionitrile, acetonitrile) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus, sodium bicarbonate), in the bromide reaction of amine that under the temperature between 80 ℃ and 120 ℃, makes formula (2) and formula (3) 12 to 48 hours.Then can use the standard method that is used to excise the oxygen protecting group (to see teaching material T.W.Greene such as those; Protective Groups in Organic Synthesis; A.Wiley-Interscience Publication, the method in 1981) protecting group is removed.
The bromide of formula (3) can be according to the method preparation of WO2005/080324, US2005/222128, WO2004/032921, US2005/215590, WO2005/092861.
The amine of formula (2) can prepare from the protected amine of corresponding formula (4):
R wherein
bAnd R
cRepresent any suitable substituent; so that can use the standard method that is used to excise nitrogen-protecting group (to see teaching material T.W.Greene simply such as those; ProtectiveGroups in Organic Synthesis; A.Wiley-Interscience Publication, the method in 1981) makes N atom and R
bBetween key and N atom and R
cBetween bond rupture, to obtain the unhindered amina of formula (2).For example, R
bAnd R
cCan be selected from allyl group, benzyl, tertiary butyl carbaminate or be joined together to form phthalic imidine.R
bAnd R
cPreferably be tertiary butyl carbaminate or R
bBe H and R
cBe tertiary butyl carbaminate.
The amine of formula (4), wherein Ra is that benzyl and B are selected from (CH
2)
2-(CH
2)
m-X
1-(CH
2)
n(wherein n is 0, and m and X
1Define as compound about formula (1)) or the group of following formula:
(wherein t is 0 and r, s and X
2Define as compound about formula (1)),
But the compound of its through type (5):
(X wherein
3Be O or S) with the compound of formula (6):
(B wherein
1Be (CH
2)
2-(CH
2)
mOr following formula group:
In a typical method, at first use standard program (triphenyl phosphine/iodine for example; Triphenyl phosphine/carbon tetrabromide; Thionyl chloride; Methylsulfonyl chloride/triethylamine), exist down at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile) and to make the alkylol cpd of formula (6) be converted into halogenide (for example bromide, muriate, iodide) or sulfonate (for example mesylate).Then at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF)) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus, sodium bicarbonate), in the compound reaction that under the temperature between 60 ℃ and 120 ℃, makes this product and formula (5) 4 to 48 hours.
Perhaps, can in the presence of solvent or solvent mixture (for example toluene, acetonitrile, tetrahydrofuran (THF)),, last 2 to 4 hours under the temperature between 25 ℃ and 60 ℃, adopting Mitsunobu program (for example diethyl azodiformate/triphenyl phosphine).
The compound of formula (5) (X wherein
3Be O) can prepare from the aldehyde of formula (7):
In a typical method, in the presence of solvent or solvent mixture (for example methyl alcohol, water, acetonitrile), in the presence of acid (for example sulfuric acid), under the temperature between 25 ℃ and 60 ℃, using oxygenant (hydrogen peroxide for example; Metachloroperbenzoic acid) aldehyde (7) is handled, lasted 6 to 24 hours.
The aldehyde of formula (7) can be according to the method preparation of WO 2005/012227.
The compound of formula (5) (X wherein
3Be S) can prepare from the halogenide of formula (13):
In a typical method, at suitable palladium catalyst (formula Pd (OAc) for example
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, diisopropylethylamine, salt of wormwood, sodium bicarbonate), make this halogenide (13) and tri isopropyl silane thiol reactant.This reaction is preferable over carries out 4 to 16 hours under the temperature between 70 ℃ and 110 ℃.Then use and see teaching material T.W.Greene, Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, the method in 1981 is sloughed protecting group with product silyl thioesters.
The aromatic bromide of formula (13) can be according to the method preparation of WO 1994/11337.
The alkylol cpd of formula (6) can use from commercially available amine see teaching material T.W.Greene, Protective Groups in Organic Synthesis, A.Wiley-IntersciencePublication, the method preparation in 1981.
The amine of formula (4), wherein B is selected from:
-(CH
2)
2-(CH
2)
m-X
1-(CH
2)
n, X wherein
1Be O or S, m is 0 to 9 integer, and n is 3 to 9 integer, and n+m is between 4 to 9;
-randomly through one or two C
1-C
4The C that alkyl replaces
6-C
12Alkylidene group;
The group of-following formula:
X wherein
2Be O or S, r is 2 to 7 integer, and s is 0 to 6 integer, and t is 3 to 6 integer, and s+t is between 3 to 6, and r+s+t is between 5 to 8,
It can prepare from the amine of formula (8):
B wherein
2For-CH
2-(CH
2)
m-X
1-(CH
2)
N1, X wherein
1Be O or S, m is 0 to 9 integer, n
1Be 1 to 7 integer, and n
1+ m is between 2 to 7;
-randomly through one or two C
1-C
4The C that alkyl replaces
3-C
9Alkylidene group;
The group of-following formula:
X wherein
2Be O or S, r
1Be 1 to 6 integer, s is 0 to 6 integer, and t
1Be 1 to 4 integer, and s+t
1Between 1 to 4, and r
1+ s+t
1Between 2 to 5.
In a typical method,, use metal catalyst (palladium/carbon for example under the temperature between 20 ℃ and 90 ℃; Platinum oxide) in the presence of solvent (for example methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF)) with hydrogen source (ammonium formiate for example; Formic acid, hydrogen) amine of formula (8) is handled and hydrogenation 1 to 6 hour.
The amine of formula (8) can be by the reaction of the microcosmic salt of the aldehyde of formula as discussed previously (7) and formula (9) and is prepared:
In a typical method, with suitable alkali (for example sodium hydride, triethylamine, n-Butyl Lithium, two (trimethyl silane) amine) processing formula (9) microcosmic salt, then the aldehyde with formula (8) reacts in the presence of solvent or solvent mixture (for example toluene, tetrahydrofuran (THF), acetonitrile).This reaction is preferable over carries out 4 to 24 hours under the temperature between 50 ℃ and 110 ℃.
Microcosmic salt (9) can be by triphenylphosphine and formula (10) the prepared in reaction of bromide:
In a typical method, randomly in the presence of solvent or solvent mixture (for example toluene, tetrahydrofuran (THF), acetonitrile), make the bromide and the triphenylphosphine reaction of formula (10).This reaction is preferable over carries out 1 to 5 day under the temperature between 50 ℃ and 110 ℃.
The bromide of formula (10) can be by suitable amine or amine equivalent and formula (11) the reaction of dibromide form:
In a typical method, in the presence of solvent or solvent mixture (for example toluene, tetrahydrofuran (THF), acetonitrile) and appropriate base (for example sodium hydride, triethylamine, n-Butyl Lithium), make the dibromide of formula (11) and suitable amine or amine equivalent (for example phthalic imidine, imido grpup diamino acid two-tert-butyl ester) reaction.This reaction is preferable over carries out 4 to 24 hours under the temperature between 25 ℃ and 110 ℃.
The dibromide of formula (11) can be commercially available or can be from the glycol of formula (12):
Using standard method (for example triphenyl phosphine/carbon tetrabromide) to exist down at solvent or solvent mixture (for example methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile) forms.
The compound of formula (12) is commercially available or can uses commercially available material and standard method easily to prepare by those skilled in the art.
Perhaps, the amine of formula (4), wherein B is selected from:
-(CH
2)
2-(CH
2)
m-X
1-(CH
2)
n, X wherein
1Be O or S, m is 0 to 9 integer, and n is 3 to 9 integer, and n+m is between 4 to 9;
-randomly through one or two C
1-C
4The C that alkyl replaces
6-C
12Alkylidene group;
-or the group of following formula:
X wherein
2Be O or S, r is 2 to 7 integer, and s is 0 to 6 integer, and t is 3 to 6 integer, and s+t (comprises end points) between 3 to 6, and r+s+t (comprises end points) between 5 to 8,
But the bromide of its through type (13):
Alkene with formula (14):
(B wherein
2Reaction as hereinbefore defined) and preparing.
In a typical method, at suitable palladium catalyst (formula Pd (OAc) for example
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus), make the aryl halide of formula (13) and the olefine reaction of formula (14).This reaction is preferable over carries out 4 to 16 hours under the temperature between 70 ℃ and 110 ℃.
The aromatic bromide of formula (13) can be according to the method preparation of WO 1994/11337.
The amine of formula (14) can prepare from commercially available formula (15) halogenide:
Wherein X is Cl, Br or I.In a typical method, in the presence of solvent or solvent mixture (for example toluene, tetrahydrofuran (THF), acetonitrile) and appropriate base (for example sodium hydride, triethylamine, n-Butyl Lithium), make the halogenide of formula (15) and suitable amine or amine equivalent (for example phthalic imidine, imido grpup diamino acid two-tert-butyl ester) reaction.This reaction is preferable over carries out 4 to 24 hours under the temperature between 25 ℃ and 110 ℃.
Perhaps, if amine (14) has formula (16):
X wherein
2Be O or S, and t
2Be 1 to 4 integer, but the compound of its through type (17) then:
With commercially available formula (18) halogenide:
The reaction of (wherein X is Cl, Br or I) forms.
In a typical method, at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF)) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus, sodium hydride), in under the temperature between 0 ℃ and 80 ℃, the compound of formula (17) being handled, last 1 to 48 hour with halogenide (18).
The compound of formula (17) (X wherein
2Be O) can see teaching material T.W.Greene by commercially available 3-(2-amino-ethyl) phenol or the use of 4-(2-amino-ethyl) phenol, Protective Groups inOrganic Synthesis, A.Wiley-Interscience Publication, the method preparation in 1981.
The compound of formula (17) (X wherein
2Be S) can be by the halogenide of formula (17a):
(wherein X is Cl, Br or I) forms.
In a typical method, at suitable palladium catalyst (formula Pd (OAc) for example
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, diisopropylethylamine, salt of wormwood, sodium bicarbonate), make this halogenide (17a) and tri isopropyl silane thiol reactant.This reaction is preferable over carries out 4 to 16 hours under the temperature between 70 ℃ and 110 ℃.Then use and see teaching material T.W.Greene, Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, the method in 1981 is sloughed protecting group with product silyl thioesters.
The halogenide of formula (17a) can be from the halogenide of commercially available formula (17b):
Use sees teaching material T.W.Greene, Protective Groups in OrganicSynthesis, A.Wiley-Interscience Publication, the method preparation in 1981.
Perhaps, if amine (4) has formula (19):
But the then reaction of the compound of compound of its through type (17) and formula (20) and forming:
In a typical method, at first use standard program (triphenyl phosphine/iodine for example; Triphenyl phosphine/carbon tetrabromide; Thionyl chloride; Methylsulfonyl chloride/triethylamine), exist down at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile) and to make the compound of formula (20) be converted into halogenide (for example bromide, muriate, iodide) or sulfonate (for example mesylate).Then at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF)) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus), in the compound reaction that under the temperature between 60 ℃ and 120 ℃, makes this product and formula (17) 4 to 48 hours.
Perhaps, can in the presence of solvent or solvent mixture (for example toluene, acetonitrile, tetrahydrofuran (THF)),, last 2 to 4 hours under the temperature between 25 ℃ and 60 ℃, adopting Mitsunobu program (for example diethyl azodiformate/triphenyl phosphine).
The compound of formula (20) can be from the alkene of formula (21):
By and boron acidizing reagent (for example borine, 9-boron two ring [3.3.1] nonanes) in the presence of suitable solvent (for example tetrahydrofuran (THF)), formed in 4 to 24 hours under the temperature between 60 ℃ and 100 ℃, reacting.Then in suitable solvent or solvent mixture (for example water, methyl alcohol, tetrahydrofuran (THF)) and appropriate base (for example sodium hydroxide), use hydrogen peroxide oxidation.
The alkene of formula (21) can from aromatic bromide (13) by with suitable vinyl compound (vinyl tributyl stannane for example; The vinyl potassium tetrafluoroborate; 2,4,6-trivinyl boroxin pyridine mixture) reaction and forming.In a typical method, at suitable palladium catalyst (formula Pd (OAc) for example
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus), make aryl halide (13) and vinyl compound reaction.This reaction is preferable over carries out 4 to 16 hours under the temperature between 70 ℃ and 110 ℃.
Perhaps, the compound of formula (20) can be from the ester of formula (37):
By and reductive agent (for example lithium aluminum hydride, lithium borohydride) in the presence of suitable solvent (for example tetrahydrofuran (THF)), formed in 4 to 24 hours in reaction under the temperature between 0 ℃ and 100 ℃.
The ester of formula (37) can form by reacting under palladium catalysis with the tert.-butyl acetate negatively charged ion from the aromatic bromide of described formula (13) above.In a typical method, at suitable palladium catalyst (for example dibenzylidene acid chloride or formula Pd (OAc)
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus, hexamethyl two silica-based amido lithiums), make aryl halide (13) and ester anionic reactive.This reaction is preferable over carries out 4 to 16 hours under the temperature between 0 ℃ and 110 ℃.
Perhaps, the amine of formula (2) can be from the nitrile of corresponding formula (22):
(B wherein
2Prepare as hereinbefore defined).
In a typical method,, use metal catalyst or catalyst combination (palladium/carbon for example under the temperature between 20 ℃ and 90 ℃; Platinum oxide, Raney-
) in the presence of solvent (for example methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF)), with hydrogen source (for example ammonium formiate, formic acid, hydrogen) nitrile of formula (22) is handled and hydrogenation 1 to 6 hour.
The nitrile of formula (22) can prepare by the reaction of aromatic bromide (13) with the alkene of formula (23):
In a typical method, at suitable palladium catalyst (formula Pd (OAc) for example
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus), make the aryl halide of formula (13) and the olefine reaction of formula (14).This reaction is preferable over carries out 4 to 16 hours under the temperature between 70 ℃ and 110 ℃.
The alkene of formula (23) can be commercially available.
Perhaps, if alkene (23) has following formula (24):
X wherein
3Be O or S,
B
4Be CH
2-(CH
2)
m, wherein m is 0 to 9 integer, and B
5Be (CH
2)
N1, n wherein
1Be 1 to 7 integer, and n
1+ m (comprises end points) between 2 to 7, or
B
4Be the following formula group:
R wherein
1Be 1 to 6 integer, s is 0 to 6 integer, and B
5Be (CH
2)
T1Group, wherein t
1Be 1 to 4 integer, and s+t
1Between 1 to 4, (comprise end points), and r
1+ s+t
1Between 2 to 5, (comprise end points);
Then this formula (24) but the compound of compound through type (25):
Compound with formula (26):
In a typical method, at first use standard program (triphenyl phosphine/iodine for example; Triphenyl phosphine/carbon tetrabromide; Thionyl chloride; Methylsulfonyl chloride/triethylamine), exist one in the compound that makes formula (25) or (26) down to be converted into halogenide (for example bromide, muriate, iodide) or sulfonate (for example mesylate) at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile).Then at solvent or solvent mixture (for example water, dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF), methylene dichloride) exist down, in the presence of appropriate base (for example sodium hydroxide, potassium tert.-butoxide, sodium hydride), randomly in the presence of phase-transfer catalyst (for example tetraethyl-ammonium bromide), another person in the compound that makes this product and formula (25) or (26) under the temperature between 25 ℃ and 120 ℃ reacted 4 to 48 hours.
The compound of formula (25) and (26) is that commercially available many known programs of maybe can using easily prepare.
Perhaps, the amine of formula (2) can be from the nitrile of corresponding formula (32):
(B wherein
2Prepare as hereinbefore defined).
In a typical method,, use metal catalyst or catalyst combination (palladium/carbon for example under the temperature between 20 ℃ and 90 ℃; Platinum oxide, Raney-
) in the presence of solvent (for example methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF)), with hydrogen source (for example ammonium formiate, formic acid, hydrogen) nitrile of formula (32) is handled and hydrogenation 1 to 6 hour.
The nitrile of formula (32) can pass through the alkynes of aromatic bromide (13) and formula (33):
In a typical method, at suitable palladium catalyst (for example four (triphenyl phosphine) palladiums or formula Pd (OAc)
2/ { P (o-Tol)
3}
2Acid chloride/tri-o-tolyl phosphine) exist down, exist down in solvent or solvent mixture (for example toluene, acetonitrile, hexane), in the presence of alkali (for example triethylamine, piperidines, diisopropylethylamine, salt of wormwood, saleratus), make the aryl halide of formula (13) and the alkynes reaction of formula (33).This reaction is preferable over carries out 4 to 16 hours under the temperature between 70 ℃ and 110 ℃.
The alkynes of formula (33) can be commercially available.
Perhaps, if alkynes (33) has following formula (34):
X wherein
3Be O or S,
B
4Be CH
2-(CH
2)
m, wherein m is 0 to 9 integer, and B
5Be (CH
2)
N1, n wherein
1Be 1 to 7 integer, and n
1+ m (comprises end points) between 2 to 7, or
B
4Be the following formula group:
R wherein
1Be 1 to 6 integer, s is 0 to 6 integer, and B
5Be (CH
2)
T1Group, wherein t
1Be 1 to 4 integer, and s+t
1Between 1 to 4, (comprise end points), and r
1+ s+t
1Between 2 to 5, (comprise end points);
Then this formula (34) but the compound of compound through type (25):
Compound with formula (36):
In a typical method, at first use standard program (triphenyl phosphine/iodine for example; Triphenyl phosphine/carbon tetrabromide; Thionyl chloride; Methylsulfonyl chloride/triethylamine), exist one in the compound that makes formula (35) or (36) down to be converted into halogenide (for example bromide, muriate, iodide) or sulfonate (for example mesylate) at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile).Then at solvent or solvent mixture (for example water, dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF), methylene dichloride) exist down, exist down in appropriate base (for example sodium hydroxide, potassium tert.-butoxide, sodium hydride), randomly in the presence of phase-transfer catalyst (for example tetraethyl-ammonium bromide), another person in the compound that makes this product and formula (35) or (36) under the temperature between 25 ℃ and 120 ℃ reacted 4 to 48 hours.
The compound of formula (35) and (36) is commercially available or easily prepares according to the known method of crowd.
The compound of formula (1), wherein B is selected from (CH
2)
2-(CH
2)
m-X
1-(CH
2)
nThe group of (wherein n is 1) or following formula
(wherein t is 1), but the amine of its through type (27):
(X wherein
3, B
1And Ra as mentioned in institute define) and the reaction of the bromide of formula (3) and preparing.
In a typical method, randomly at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, propionitrile, acetonitrile) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, sodium bicarbonate), in the bromide reaction of amine that under the temperature between 80 ℃ and 120 ℃, makes formula (27) and formula (3) 12 to 48 hours.Then can use the standard method that is used to excise the oxygen protecting group (to see teaching material T.W.Greene such as those; Protective Groups in Organic Synthesis; A.Wiley-Interscience Publication, the method in 1981) protecting group is removed.
The amine of formula (27) can prepare from the protected amine of corresponding formula (28):
Wherein Rb and Rc are middle as mentioned defines.
Amine (28) can pass through alcohol (29):
Compound with formula (30):
In a typical method, at first use standard program (triphenyl phosphine/iodine for example; Triphenyl phosphine/carbon tetrabromide; Thionyl chloride; Methylsulfonyl chloride/triethylamine), exist down at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile) and to make the alcohol of formula (29) be converted into halogenide (for example bromide, muriate, iodide) or sulfonate (for example mesylate).Then at solvent or solvent mixture (for example water, dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF), methylene dichloride) exist down, exist down in appropriate base (for example sodium hydroxide, potassium tert.-butoxide, sodium hydride), randomly in the presence of phase-transfer catalyst (for example tetraethyl-ammonium bromide), in the compound reaction that under the temperature between 25 ℃ and 120 ℃, makes this product and formula (30) 4 to 48 hours.
The alcohol of formula (29) can be from the aldehyde preparation of formula (7).In a typical method,, in the presence of solvent (for example tetrahydrofuran (THF), methyl alcohol, toluene), use reductive agent (sodium borohydride for example under the temperature between 0 ℃ and 40 ℃; Lithium aluminum hydride) aldehyde (7) was handled 1 to 24 hour.
The compound of formula (30) can be from the alcohol of commercially available formula (31):
Use sees teaching material T.W.Greene, Protective Groups in OrganicSynthesis, A.Wiley-Interscience Publication, the method preparation in 1981.
Finally, if amine (4) has following formula (38):
But the compound of its through type (39) then:
Compound with formula (20):
Reaction and form.
Compound with following formula (39) can prepare according to the method described in the WO97/34905.
In a typical method, at first use standard program (triphenyl phosphine/iodine for example; Triphenyl phosphine/carbon tetrabromide; Thionyl chloride; Methylsulfonyl chloride/triethylamine), exist down at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), methylene dichloride, toluene, N, dinethylformamide, propionitrile, acetonitrile) and to make the compound of formula (20) be converted into halogenide (for example bromide, muriate, iodide) or sulfonate (for example mesylate).Then at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, acetonitrile, tetrahydrofuran (THF)) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus), in the compound reaction that under the temperature between 60 ℃ and 120 ℃, makes this product and formula (39) 4 to 48 hours.
Perhaps, can in the presence of solvent or solvent mixture (for example toluene, acetonitrile, tetrahydrofuran (THF)),, last 2 to 4 hours under the temperature between 25 ℃ and 60 ℃, adopting Mitsunobu program (for example diethyl azodiformate/triphenyl phosphine).
The quaternary ammonium salt of formula (1) compound comprises the compound of following formula:
R wherein
1Be selected from H, C
1-C
4Alkyl, benzyl or styroyl, and X-is suitable gegenion, such as acetate foundation, methylsulfonic acid foundation, former times naphthoic acid foundation, tartrate foundation, chlorion, bromide anion, iodide ion, sulphate groups, phosphoric acid foundation, nitric acid foundation, citric acid foundation, methylsulfonic acid foundation, the carboxylic acid foundation with 1 to 6 carbon atom, the dicarboxylic acid foundation with 2 to 6 carbon atoms, maleic acid foundation, FUMARIC ACID TECH GRADE foundation and phenylformic acid foundation.About other acceptable quaternary ammonium salt, referring to Int.J.Pharm, 33,201-217 (1986).X is preferably acetate foundation, FUMARIC ACID TECH GRADE foundation, methylsulfonic acid foundation, bromide anion, chlorion, sulphate groups, D-and L-tartrate foundation or former times naphthoic acid foundation (xinafoate).By at solvent or solvent mixture (for example dimethyl sulfoxide (DMSO), toluene, N, dinethylformamide, propionitrile, acetonitrile, methylene dichloride) exist down, randomly in the presence of appropriate base (for example triethylamine, diisopropylethylamine, salt of wormwood, saleratus), in compound that under the temperature between 60 ℃ and 120 ℃, makes formula (4) and alkylating agent R
1-X (R wherein
1Be C
1-C
4Alkyl, benzyl or styroyl, and X is suitable leaving group (preferred R
1-X group is a methyl iodide)) reacted 4 to 48 hours, can prepare this class quaternary ammonium salt.Then make the quaternary ammonium salt of gained formula (4) compound slough protecting group, and with as mentioned in formula (3) the bromide reaction that disclosed, to obtain the quaternary ammonium salt of this formula (1) compound.
For some steps in described formula (1) compounds process for production thereof above, have necessary protection and do not wish the potential reaction functional group that reacts, and therefore be necessary to make this class protecting group excision.In the case, can use any compatible protecting group.Particularly; can use such as those by T.W.GREENE (Protective Groups in OrganicSynthesis; A.Wiley-Interscience Publication; 1981) or P.J.Kocienski (Protecting groups; Georg Thieme Verlag, 1994) protection and the de-protected method of described method.
All above reaction and preparations about novel initial substance used in preceding method are conventional, and the program that is suitable for the reagent and the reaction conditions of its operation or preparation and is suitable for isolating the product of wanting is according to document precedent and the embodiment that is correlated with therewith and prepare and will be well known to those skilled in the art.
And formula (1) compound and the intermediate that is used for its preparation can carry out purifying according to the known method of various crowds, such as crystallization or chromatography.
The preferred definition of B is as shown in hereinafter.
According to an embodiment, when B for randomly through one or two C
1-C
4The C that alkyl replaces
6-C
12During alkylidene group, (CH
2)
8, (CH
2)
9And (CH
2)
10For preferably.
According to another embodiment, when B has formula * *-(CH
2)
2-(CH
2)
m-X
1-(CH
2)
nDuring-* * * ,-(CH
2)
6-O-(CH
2)
3,-(CH
2)
6-O-(CH
2)
4And-(CH
2)
7-O-is preferred.
According to another embodiment, when B has following formula:
Then following groups is preferred:
Position or contraposition between oxygen is preferably placed at.Oxygen is better to be positioned at contraposition.
According to another embodiment, when B has following formula:
The oxygen that then is positioned at contraposition is for preferred.
The quaternary ammonium salt of formula (1) compound also is preferred.Preferred quaternary ammonium salt is:
Wherein X be acetate foundation, FUMARIC ACID TECH GRADE foundation, methylsulfonic acid foundation, bromide anion, chlorion, sulphate groups, D-and L-tartrate foundation or former times the naphthoic acid foundation.
According to another embodiment of the present invention, the quaternary ammonium salt of following formula:
(wherein X is the Succinic Acid foundation) is also for preferred.
A is preferably the group of following formula:
A is more preferred from the group of following formula:
Particularly preferred compound according to the present invention is:
N-(5-{ (1R)-2-[(10-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } decyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
N-{5-[(1R)-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-(5-{ (1R)-2-[(7-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenoxy } heptyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino }-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide;
5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
5-[(1R)-the 1-{[hydroxyl }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] benzene-1, the 3-glycol;
N-{5-[(1R)-2-(2-[3-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(2-{3-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } ethyl) phenol;
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-glycol;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide;
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(2-{4-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } ethyl) phenol;
N-(5-{ (1R)-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
N-(5-{ (1R)-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(4-{4-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } butyl) phenol;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } the Toluidrin succinate; And
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl]-the 11-dimethyl ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone,
Or when suitable (if) its pharmacy acceptable salt and/or its isomer, tautomer, solvate or isotopic variations.
Optimizing compound according to the present invention is:
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino }-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide;
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } the Toluidrin succinate; And
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl]-the 11-dimethyl ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
Or when suitable (if) its pharmacy acceptable salt and/or its isomer, tautomer, solvate or isotopic variations.
The pharmacy acceptable salt and the quaternary ammonium salt thereof of formula (1) compound comprise its acid salt and alkali salt.
Suitable acid salt is formed by the acid that can form non-toxic salts.Example comprises acetate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, camsilate, Citrate trianion, ethanedisulphonate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, benzene is pricked salt (hibenzate), hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleic acid salt, malonate, mesylate, Methylsulfate, naphthoate, 1, the 5-napadisilate, the 2-naphthalenesulfonate, nicotinate (nicotinate), nitrate, Orotate, oxalate, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, the sucrose hydrochlorate, stearate, succinate, tartrate, tosylate and trifluoroacetate.
Suitable alkali salt is formed by the alkali that can form non-toxic salts.Example comprises aluminium salt, arginic acid salt, benzyl star salt, calcium salt, choline salt, diethyl amine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt, pure amine salt, sylvite, sodium salt, trometamol salt and zinc salt.
Also can form half salt of acid and alkali, for example Hemisulphate and half calcium salt.
To summary, referring to " Handbook ofPharmaceutical Salts:Properties, Selection, the and Use " (Wiley-VCH, Weinheim, Germany, 2002) of Stahl and Wermuth about acceptable acid addition salts.
The pharmacy acceptable salt of formula (1) compound and quaternary ammonium salt thereof can prepare by one or more method in following three kinds of methods:
(i) by making formula (1) compound and desired acid or alkali reaction;
(ii) remove acid sensitivity or the quick property of alkali protecting group, or, wherein use desired acid or alkali by with suitable ring-type presoma (for example lactone or lactan) open loop by suitable precursors from formula (1) compound; Or
(iii) by via making a kind of salt of formula (1) compound be converted into another kind of salt with the reaction of suitable acid or alkali or by means of the appropriate ions exchange column.
All three kinds of reactions are carried out in solution usually.Gained salt is precipitable to be separated out and collects by filtering, and maybe can reclaim by solvent evaporation.Degree of ionization in the gained salt can and change between the ionization hardly in complete ionization.
Compound of the present invention can non-solvent form and the existence of solvation form.Term " solvate " is used to describe a kind of molecular complex that comprises compound of the present invention and stoichiometric one or more pharmaceutically acceptable solvent molecule (for example ethanol) in this article.When this solvent adopts term " hydrate " during for water.
Comprise the mixture such as inclusion compound, medicine-host's inclusion complex in category of the present invention, wherein opposite with the aforementioned solvents compound, medicine and host exist with stoichiometry or non-stoichiometric amount.Also comprise and contain the medicinal composition that two or more can be the organic and/or inorganic component of stoichiometry or non-stoichiometric amount.The gained mixture can be ionization, partial ionization or non-ionizing.About the summary of this class mixture, referring to the J Pharm Sci of Haleblian, 64 (8), 1269-1288 (in August, 1975).
Hereinafter to all of formula (1) compound mention comprise to its salt, solvate and mixture with and the solvate of salt and mentioning of mixture.
Defined formula (1) compound during compound of the present invention comprises as mentioned comprises its all polymorphic forms and crystal habit, as the compound isotopically labelled of defined its prodrug and isomer (comprising optical isomer, geometrical isomer and tautomer) and formula (1) hereinafter.
As shown here, the what is called " prodrug " of formula (1) compound also belongs to category of the present invention.Therefore, itself may have some derivative of formula (1) compound of pharmacological activity hardly can be in being applied to body or during body surface, (for example) by hydrolytic scission be converted into have the active formula of wanting (1) compound.This analog derivative is called as " prodrug ".Further information about the prodrug purposes is found in ' Pro-drugs as Novel Delivery Systems ', the 14th volume, ACSSymposium Series (T.Higuchi and W.Stella) reaches ' BioreversibleCarriers in Drug Design ', Pergamon Press, in 1987 (E.B Roche compiles, American Pharmaceutical Association).
For example, can be by be known as " fore portion " (" Design of Prodrugs " (Elsevier of H.Bundgaard for example with those skilled in the art, 1985) described in) some part replace the appropriate functional group that is present in formula (1) compound, to make according to prodrug of the present invention.
Some examples according to prodrug of the present invention comprise:
(i) (contain under the situation of methyl) its hydroxymethyl derivative (CH at formula (1) compound
3→-CH
2OH);
(ii) (contain under the situation of alkoxyl group) at formula (1) compound its hydroxy derivatives (OR →-OH);
(iii) (contain under the situation of uncle's amino) its secondary amino group derivative (NR at formula (1) compound
1R
2→-NHR
1Or-NHR
2);
(iv) (contain under the situation of secondary amino group) its primary amino derivative (NHR at formula (1) compound
1→-NH
2);
(v) (contain under the situation of phenyl moiety) at formula (1) compound its amphyl (Ph →-PhOH); And
(vi) (contain under the situation of amide group) its carboxylic acid derivative (CONH at formula (1) compound
2→-COOH).
Be found in the aforementioned citing document according to other example of the displacement group of previous examples and the example of other prodrug type.
In addition, some compound of formula (1) self can serve as the prodrug of other formula (1) compound.
The metabolite that in category of the present invention, also comprises formula (1) compound, in case that is behind the drug administration promptly in the compound that in vivo forms.Some examples according to metabolite of the present invention comprise:
(i) (contain under the situation of secondary amino group) its primary amino derivative (NHR at formula (1) compound
1→-NH
2); And
(ii) (contain under the situation of phenyl moiety) at formula (1) compound its amphyl (Ph →-PhOH).
All steric isomers, geometrical isomer and the tautomeric form that comprise formula (1) compound in category of the present invention comprise the compound of showing multiple isomery type and the mixture of one or more this compounds.Also comprise that wherein gegenion is optically active acid salt or alkali salt, for example d-lactic acid salt or 1-lysine salt; Or racemoid, for example d1-tartrate or d1-arginic acid salt.
Suitable/trans isomer can separate by known techniques well-known to those skilled in the art (for example chromatography and Steppecd crystallization).
Preparation/isolating the known techniques that is used for indivedual enantiomers comprises from the pure presoma of suitable optical synthetic or use (for example) that chirality high pressure liquid chromatography (HPLC) method (HPLC) is resolved racemic modification (or racemic modification of salt or derivative) to chirality.
Perhaps, can make racemic modification (or racemize presoma) and suitable optical active compound (for example alcohol or contain acid or alkali under the situation of acidity or basic moiety at formula (1) compound, such as tartrate or 1-styroyl amine) reaction.The gained non-enantiomer mixture can separate by chromatography and/or Steppecd crystallization, and makes the one or both in the diastereomer be converted into corresponding pure enantiomer by method well-known to those skilled in the art.
(this mobile phase contains 0 to 50 volume %, is generally the Virahol of 2 to 20 volume % by the mobile phase be made up of hydrocarbon (being generally heptane or hexane) on asymmetric resin can to use chromatography (being generally HPLC), and the alkylamine of 0 to 5 volume %, be generally the diethylamine of 0.1 volume %) obtain to be the of the present invention of enantiomer enriched form to chipal compounds (and to chirality presoma).The concentrated enrichment mixture that obtains of elutriant.
The steric isomer agglomerated thing can separate by the known techniques known to those skilled in the art-referring to " Stereochemistry of Organic Compounds " (Wiley, New York, 1994) of (for example) E.L.Eliel.
The present invention includes all pharmaceutically acceptable compound isotopically labelleds of formula (1), wherein one or more atom is by having the same atoms ordinal number but atomic mass or total mass number are different from the atom of dominant atomic mass of occurring in nature or total mass number is replaced.
Be suitable for being included in the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, such as
2H reaches
3H; The isotropic substance of carbon, such as
11C,
13C reaches
14C; The isotropic substance of chlorine, such as
36Cl; The isotropic substance of fluorine, such as
18F; The isotropic substance of iodine, such as
123I reaches
125I; The isotropic substance of nitrogen, such as
13N reaches
15N; The isotropic substance of oxygen, such as
15O,
17O reaches
18O; The isotropic substance of phosphorus, such as
32P; And the isotropic substance of sulphur, such as
35S.
Some compound isotopically labelled of formula (1) (for example those wherein incorporate radioisotopic compound into) is applicable to medicine and/or matrix organization's distribution research.The radio isotope tritium (that is
3H) and carbon-14 (that is
14C) be easy to the property incorporated in view of it and be easy to detection property and be specially adapted to this purpose.
Use such as deuterium (that is
2H) higher isotope replaces can provide some treatment advantage, and it is produced by higher metabolic stability (for example, the in vivo transformation period of growth or the dosage of minimizing require), and therefore can be preferred in some cases.
With the positron emission isotropic substance (such as
11C,
18F,
15O reaches
13N) replace and can be used for positron emission tomography (PET) research, to be used to check the matrix receptor share.
Usually can reach the similar method of method described in " preparation " by known techniques well known by persons skilled in the art or by enclose with those " example ", use suitable isotope labeling reagent to replace the previous unmarked reagent that adopts to come the compound isotopically labelled of preparation formula (1).
Pharmaceutically acceptable solvate according to the present invention comprises those, and wherein the crystalline solvent can be through the solvate of isotropic substance replacement, for example D
2O, d
6-acetone, d
6-DMSO.
The compound of formula (1), its pharmacy acceptable salt and/or derivative form are quite valuable medicinal activity compound, it is applicable to treatment and prevents numerous deficiency disorders (wherein the short effect effect of beta 2 receptor and the antagonistic action of muscarine can cause benefit), especially is supersensitivity and nonallergic tracheal disease.
The The compounds of this invention that expection is used for medicinal use can be used as the form of crystallization or amorphous product and uses.For example, it can be by obtaining such as the method for precipitation, crystallization, lyophilize, spraying drying or the evaporation drying form as solid plug, powder or film.Can use microwave or radio-frequency seasoning for this purpose.
It can be used separately, or with one or more other compound of the present invention or with one or more other medicines form of its any combination (or as) combined administration.Generally speaking, it will be as using with the form of one or more pharmaceutically acceptable vehicle bonded preparation.Term " vehicle " is used to describe any composition except that compound of the present invention in this article.The selection of vehicle will be to a great extent on deciding such as following factor: specific administration pattern, vehicle are to the influence and the formulation characteristic of solubleness and stability.
The pharmaceutical composition and preparation method thereof that is suitable for the transmission of The compounds of this invention will be easy to be understood by those skilled in the art.For example, this based composition and preparation method thereof is found in ' Remington ' s Pharmaceutical Sciences ', in the 19th edition (Mack PublishingCompany, 1995).
Compound of the present invention can be oral.Swallow oral comprising, so that make compound enter gi tract, maybe can adopt orally administering or sublingual administration, and compound is directly entered in the blood flow from mouth.
Be applicable to that oral preparation comprises the solid preparation such as tablet, the capsule that contains particulate, liquid or powder, lozenge (comprising the topping up type), masticatory, multiple particulate and nanoparticle, gel, solid solution, liposome, film, ovum, sprays and liquid preparation.
Liquid preparation comprises suspension, solution, syrup and elixir.This class preparation can be used as the weighting agent in soft or the hard capsules, and comprises supporting agent (for example water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil) and one or more emulsifying agent and/or suspension agent usually.Liquid preparation also can prepare from anther sac by solid composite (for example).
The compounds of this invention can also dissolve fast, the form of quickly disintegrated formulation is used, such as those at the Expert of Liang and Chen Opinion in Therapeutic Patents, 11 (6), 981-986, the compound described in (2001).
For Tabules, to decide on dosage, medicine can account for 1 to 80 weight % of formulation, more generally accounts for 5 to 60 weight % of formulation.Except that medicine, tablet contains disintegrating agent usually.Hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate that the example of disintegrating agent comprises sodium starch glycollate, Xylo-Mucine, calcium carboxymethylcellulose, cross-linked carboxymethyl cellulose sodium, cross-linked pvp, polyethylene Pyrrolizidine ketone, methylcellulose gum, Microcrystalline Cellulose, replaces through low-carbon alkyl.Generally speaking, disintegrating agent will account for 1 to 25 weight % of formulation, be preferably 5 to 20 weight %.
Usually use tackiness agent to give the tablet formulation tackiness.Proper adhesive comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural gum and synthetical glue, polyethylene Pyrrolizidine ketone, pregelatinized Starch, hydroxypropylcellulose and Vltra tears.Tablet also can contain thinner, such as lactose (monohydrate, spray-dried monohydrate, anhydride and fellow thereof), N.F,USP MANNITOL, Xylitol, dextrose, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and two hypophosphite monohydrate hydrogen dicalcium.
Tablet also can randomly comprise tensio-active agent (such as Sodium Lauryl Sulphate BP/USP and poly-sorbitol ester 80) and glidant (such as silicon-dioxide and talcum powder).When existing, tensio-active agent can account for 0.2 to 5 weight % of tablet, and glidant can account for 0.2 to 1 weight % of tablet.
Tablet also contains lubricant usually, such as the mixture of Magnesium Stearate, calcium stearate, Zinic stearas, stearyl FUMARIC ACID TECH GRADE sodium and Magnesium Stearate and Sodium Lauryl Sulphate BP/USP.Lubricant accounts for 0.25 to 10 weight % of tablet usually, is preferably 0.5 to 3 weight %.
Other may comprise antioxidant, tinting material, perfume compound, sanitas and odor mask by composition.
Exemplary tablet contains medicine up to about 80%, about 10 tackiness agents to about 90 weight %, about 0 thinner to about 85 weight %, about 2 to about 10 weight % disintegrating agent and about 0.25 lubricant to about 10 weight %.
The tablet adulterant directly can be compressed or compress to form tablet by cylinder.Perhaps, tablet adulterant or part adulterant can be before tableted through wet granulation, dry type granulation or fusion granulation, fusion is condensed or push.Final preparation can comprise one or more layer and can be through coating or uncoated; Itself in addition can seal through capsule.
At the Pharmaceutical of H.Lieberman and L.Lachman Dosage Forms:Tablets, the 1st volume is discussed the allotment of tablet in (Marcel Dekker, New York, 1980).
Be used for the oral film of consuming of the mankind or veterinary purpose and be generally flexible water-soluble or water-swellable thin-film dosage form, its rapidly dissolvable or be the mucous membrane tackyness, and comprise formula (1) compound, film-forming polymer, tackiness agent, solvent, wetting Agent for Printing Inks, softening agent, stablizer or emulsifying agent, viscosity modification agent and solvent usually.Some components of this allotment can be carried out more than one function.
Formula (1) compound can be water miscible or insoluble.Water-soluble cpds comprises usually from 1 weight % to 80 weight %, is more typically the solute of 20 weight % to 50 weight %.The compound that solvability is lower can comprise the larger proportion of said composition, reaches the solute of 88 weight % usually.Perhaps, formula (1) compound can be the form of multiple particulate pearl.
Film-forming polymer can be selected from natural polysaccharide, protein or synthetic water colloid, and usually with the scope of in 0.01 to 99 weight %, the scope that is more typically 30 to 80 weight % exists.
Other may comprise antioxidant, tinting material, perfume compound and flavor potentiator, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oil), tenderizer, swelling agent, defoamer, tensio-active agent and odor mask by composition.
Membrane according to the invention will be usually by coating dry preparation of water-based thin film evaporation on peelable backing upholder or the paper.This can finish in drying oven or dry channel (being generally built-up type coating machine moisture eliminator), or finishes by lyophilize or vacuum-drying.
Can be allocated as release type and/or modification release type immediately with being used for oral solid preparation.Modify the release type preparation and comprise that delay discharges, continues release, pulse release, sustained release, target discharges and the programming delivery formulations.
At United States Patent (USP) the 6th, 106, the modification release type preparation of having described to be applicable to purpose of the present invention in No. 864.Be found in people's such as Verma Pharmaceutical Technology On-line about the detailed content of other suitable release tech (such as high energy dispersion and infiltration and coated particle), 25 (2), 1-14 is in (2001).The purposes of the chewing ingot be used to reach sustained release is described in WO 00/35298.
Also compound of the present invention can be applied directly in blood flow, muscle or the intracorporeal organ.The method that is applicable to administered parenterally comprises administration in administration in administration in intravenous administration, intra-arterial administration, intraperitoneal administration, intrathecal drug delivery, the ventricle, the urethra, the breastbone, encephalic administration, intramuscular administration and subcutaneous administration.The device that is applicable to administered parenterally comprises pin (comprising micropin) syringe, needleless injector and inculcates technology.
Stomach external form preparation is generally the aqueous solution, it can contain the vehicle such as salt, carbohydrate and buffer reagent (being preferably the pH value from 3 to 9), but for some application, the dried forms that it can be allocated as aseptic non-aqueous solution preferablyly or treat to be used in combination with suitable mediator (such as aseptic pyrogen-free matter water).
For example, prepare stomach external form preparation by lyophilize under aseptic condition, this can use standard medicine technology well-known to those skilled in the art easily to finish.
The solubleness that is used to prepare formula (1) compound of stomach external form solution can improve by using suitable blending technology (such as incorporating solubilizing agent into).
The preparation that is used for administered parenterally can be allocated as release type and/or modification release type immediately.Modify the release type preparation and comprise that delay discharges, continues release, pulse release, sustained release, target discharges and the programming delivery formulations.Therefore, compound of the present invention can be allocated as solid, semisolid or thixotropy liquid, to come administration as the form of implanted medicine storage tank, this can provide the modification of active compound to discharge.The example of this class allotment comprises through the intravascular stent of medicine coating and poly-(d1-lactic-co-glycolic acid) multipolymer (PGLA) microsphere.
Also but topical application is to skin or mucous membrane for compound of the present invention, that is epidermis is used or applied dermally.The exemplary formulations that is used for this purpose comprises gel, hydrogel, lotion, solution, emulsifiable paste, ointment, pulvis, dressing, foam, film, skin patch, wafer, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Typical case's supporting agent comprises ethanol, water, mineral oil, liquid vaseline, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.Can incorporate penetration enhancer-into referring to the J Pharm Sci of (for example) Finnin and Morgan, 88 (10), 955-958 (in October, 1999).
Other local administration method comprises by electroporation transmission, iontherapy, phonophoresis, phonophoresis method and micropin or needleless (Powderject for example
TM, Bioject
TMDeng) injection.
The preparation that is used for topical can be allocated as release type and/or modification release type immediately.Modify the release type preparation and comprise that delay discharges, continues release, pulse release, sustained release, target discharges and the programming delivery formulations.
Compound of the present invention also can be usually with the form of dry powder (individually, as mixture, for example with lactose in dried adulterant; Or, for example mix with phosphatide such as phosphatidylcholine as the mixed composition particle) from Diskus; Or as aerosol spray from using or not using suitable propelling agent (such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-propane) pressurizing vessel, pump, injector, spraying gun (being preferably the spraying gun that utilizes electrohydrodynamics to produce mist) or atomizer and intranasal administration or use by suction.For using in the nose, powder can comprise the bioadhesion agent, for example chitosan or cyclodextrin.
Pressurizing vessel, pump, injector, spraying gun or atomizer contain the solution or the suspension of The compounds of this invention, its including (for example) ethanol, aqueous ethanolic solution be used for dispersion, the solubilising of active substance or the suitable alternative reagent of releasing after the sentence expires, as the propelling agent of solvent and optional tensio-active agent, such as sorbitan trioleate, oleic acid or lactic acid oligomer.
Be used for the allotment of dry powder or suspension before, pharmaceutical product be micronized to be suitable for the size (usually less than 5 microns) transmitted by suction.This can reach by any suitable breaking method, such as spiral spray grind, fluidised-bed spray grinds, in order to form treatment with supercritical fluid, high pressure homogenizing or the spraying drying of nano particle.
The capsule (for example being made by gelatin or Vltra tears), vesicatory and the cartridge case that are used for sucker or insufflator can be through allotment with the powdered mixture that contains The compounds of this invention, suitable powder matrix (such as lactose or starch) and usefulness modification agents (such as 1-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can be anhydride or is the monohydrate form, is preferably the latter.Other appropriate excipients comprises dextran, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.
The each actuating of appropriate solution preparation of the spraying gun that is used to utilize electrohydrodynamics to produce mist can contain the The compounds of this invention of 1 μ g to 20mg, and activates volume and can change between 1 μ l to 100 μ l.Exemplary formulations can comprise formula (1) compound, propylene glycol, sterilized water, ethanol and sodium-chlor.The substituting solvent that can replace propylene glycol to use comprises glycerine and polyoxyethylene glycol.
Suitable fragrance (such as menthol and left menthol (levomenthol)) or sweeting agent (such as asccharin or soluble saccharin) can be added into those expections and be used for sucking/preparation of the present invention of intranasal administration.
Can use (for example) PGLA will be used to suck/preparation of intranasal administration is allocated as immediately release type and/or modifies release type.Modify the release type preparation and comprise that delay discharges, continues release, pulse release, sustained release, target discharges and the programming delivery formulations.
Under Diskus and aerocolloidal situation, determine dose unit by the valve that transmits the amount of measuring.Usually unit according to the present invention is configured to use dosage or " winding-up amount (puff) " of the metering of formula (1) compound that contains 0.001mg to 10mg.Total dose will be in the scope of 0.001mg to 40mg usually every day, and it can single dose, or be more typically with the fractionated dose whole day and use.
Formula (1) compound is particularly suitable for by sucking administration.
Compound of the present invention can (for example) be used with the form per rectum of suppository, hysterophore or enema or transvaginal is used.Theobroma oil is traditional suppository base, but if can use various surrogates suitably the time.
The preparation that is used for per rectum/transvaginal administration can be allocated as release type and/or modification release type immediately.Modify the release type preparation and comprise that delay discharges, continues release, pulse release, sustained release, target discharges and the programming delivery formulations.
Compound of the present invention also can be usually with open in waiting, micronization suspension in the stroke-physiological saline solution of pH through adjusting or the form of solution drops be applied directly to eyes or ear.Other preparation that is suitable for eye and ear administration comprises ointment, biodegradable (for example can absorb gel sponge, collagen protein) and biological non-degradable type (for example silicone) implant, wafer, lens and particulate or cryptomere system, such as nonionic surfactant vesicle (niosome) or liposome.Polymkeric substance (such as cross linked polyacrylate, polyvinyl alcohol, glass acid, cellulosic polymer (for example Vltra tears, Natvosol or methylcellulose gum) or different first polysaccharide polymkeric substance (for example colloid jelly)) can be incorporated into sanitas (such as Zephiran chloride).This class preparation also can be by the iontherapy transmission.
Can will be used for through eye/be allocated as immediately release type and/or modify release type through the preparation of ear administration.Modify the release type preparation and comprise that delay discharges, continues release, pulse release, sustained release, target discharges or the programming delivery formulations.
Can be with compound of the present invention and solvable giant molecule entity (such as cyclodextrin and suitable derivative thereof or contain the polymkeric substance of polyoxyethylene glycol) combination, so that improve its solubleness that is used for above-mentioned any mode of administration, dissolution rate, taste masking, biological usability and/or stability.
For example, find that the drug-cyclodextrin mixture is applicable to most formulations and route of administration usually.Inclusion complex and non-inclusion complex all can use.As with the alternative method of the direct misfit of medicine, cyclodextrin can be used as supplementary additive, that is as supporting agent, thinner or solubilizing agent.For these purposes, the most normal use alpha-cylodextrin, beta-cyclodextrin and γ-Huan Hujing, the example are found among No. 98/55148, No. 91/11172, international application WO, No. 94/02518, WO and the WO.
Because (for example) is for the purpose of treatment special disease or illness, can use the combination of active compound, therefore can suit with two or more pharmaceutical composition (wherein at least a contain with good grounds compound of the present invention) be suitable for composition altogether the cover group form of administration made up, this belongs to category of the present invention.
Therefore, cover group of the present invention comprises two or more independent pharmaceutical composition (wherein at least one contains with good grounds formula of the present invention (1) compound) and is used for keeping independently the member (such as container, separating bottle or separating foil encapsulation) of this based composition.One example of this kind cover group is the common blister pack that is used for the encapsulation of tablet, capsule and analogue thereof.
Cover group of the present invention is particularly suitable for using different dosage form (for example parenteral), is suitable for using the independent groups compound at interval with various dose, or is suitable for the independent groups compound is relative to each other carried out titration.For helping conformability, this cover group comprises the indication about administration usually, and may possess so-called " memory aids " arranged.
For the administration for human patients, total dose every day of The compounds of this invention is in the scope of 0.001mg to 5000mg usually, and certainly, this decides on mode of administration.For example, the intravenously per daily dose may only need 0.001mg to 40mg.Every day total dose can single dose or fractionated dose use, and, may exceed given typical range herein according to doctor's judgement.
This class dosage is based on the general human person under inspection with about 65kg to 70kg body weight.The doctor will be easy to determine that body weight exceeds the person under inspection of this scope (such as baby and old man's) dosage.
For avoiding doubt, this paper comprises curative therapy, palliative therapy and preventative-therapeutic mentioning mentioning of " treatment ".
According to another embodiment of the present invention, formula (1) compound or its pharmacy acceptable salt, derivative form or composition also can be used in combination to be applied to the patient altogether with one or more additional therapeutic agent, thereby obtain some desired especially treatment net result, such as the treatment of the diseases related process of pathologic, physiologic, this class disease include, but is not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) disorganization, (v) such as asthma, the cough symptom and symptom.Second and other additional therapeutic agent also can be formula (1) compound or its pharmacy acceptable salt, derivative form or composition, or one or more β2Ji Dongji, muscarine antagonist or be known in the art the active compound that has as β2Ji Dongji and muscarine antagonist.More generally, second and other therapeutical agent will be selected from different types of therapeutical agent.
As used herein, the term relevant with formula (1) compound and one or more other therapeutical agent " administration altogether ", " using altogether " reach " combination " and are intended to mean and refer to and comprise following meanings:
So combination of formula (1) compound and therapeutical agent is applied to the patient who needs treatment simultaneously, and when allocating this class component together to single formulation, this formulation side by side discharges this class component substantially to this patient,
So combination of formula (1) compound and therapeutical agent side by side is applied to the patient who needs treatment substantially, when allocating this class component apart from each other to separate dosage forms, side by side take this class formulation substantially by this patient, make this class component side by side be released into this patient substantially by this
So combination of formula (1) compound and therapeutical agent one after the other is applied to the patient who needs treatment, when allocating this class component apart from each other to separate dosage forms, between each time administration, take this class formulation continuously by this patient, make this class component when the different substantially time, be released into this patient by this with the remarkable timed interval; And
So combination of formula (1) compound and therapeutical agent one after the other is applied to the patient who needs treatment, when allocating this class component together to single formulation, this formulation discharges this class component in a controlled manner, make by this this class component side by side, continuously and/or crossover ground when identical and/or different time, be applied to this patient
Wherein each several part can be used by identical approach or different approaches.
The suitable example of other therapeutical agent that can use with formula (1) compound or its pharmacy acceptable salt, derivative form or combination of compositions comprises (but never being limited to):
(a) 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activated protein (FLAP) antagonist;
(b) leukotriene antagonist (LTRA), it comprises LTB
4, LTC
4, LTD
4And LTE
4Antagonist;
(c) histamine receptor antagonists, it comprises H1 and H3 antagonist;
(d) be used to the α of congested purposes
1-and α
2-adrenoceptor agonists vasoconstriction parasympathomimetic agent;
(e) PDE inhibitor, for example PDE3, PDE4 and PDE5 inhibitor;
(f) theophylline (theophylline);
(g) Sodium Cromoglicate (sodium cromoglycate);
(h) COX inhibitor, non-selective and selective COX-2-1 or cox 2 inhibitor (NSAID);
(i) prostaglandin receptor antagonist and PGSI;
(j) oral type and inhaled glucocorticoid;
(k) agonist that dissociates (DAGR) of adrenal cortical hormone receptor;
(l) has active monoclonal antibody for endogenous inflammatory entity;
(m) anti-tumor necrosis factor (reagent of anti-TNF-α);
(n) adhesion molecule inhibitor comprises the VLA-4 antagonist;
(o) kassinin kinin-B
1-and B
2-receptor antagonist;
(p) immunosuppressor comprises the inhibitor of IgE approach and ciclosporin;
(q) inhibitor of matrix metalloproteinase (MMP);
(r) tachykinin NK-1
1, NK
2And NK
3Receptor antagonist;
(s) proteinase inhibitor is such as elastase inhibitor;
(t) adenosine A 2a receptor stimulant and A2b antagonist;
(u) urokinase inhibitors;
(the v) compound that Dopamine Receptors is worked is such as the D2 agonist;
(w) conditioning agent of NF κ beta pathway is such as the IKK inhibitor;
(x) cytokine signaling pathway modulators is such as p38MAP kinases, PI3 kinases, jak kinase, syk kinases, EGFR or MK-2;
(y) can classify as the reagent of mucolytic or anti-cough agent;
(z) strengthen sucking the reagent of corticosteroid reaction;
(aa) migrate the effective microbiotic of microorganism and the antiviral agent of respiratory tract for meeting;
(bb) hdac inhibitor;
(cc) CXCR2 antagonist;
(dd) integrin antagonists;
(ee) chemokine;
(ff) epithelium sodium channel (ENaC) blocker or epithelium sodium channel (ENaC) inhibitor;
(gg) P2Y2 agonist and other nucleotide receptor agonist;
(hh) thromboxane inhibitor;
(ii) nicotinic acid reaches
(jj) adhesion factor comprises VLAM, ICAM and ELAM.
According to the present invention, being combined as of formula (1) compound and following person is preferred:
-H3 antagonist,
-PDE4 inhibitor,
-oral type and inhaled glucocorticoid,
The agonist that dissociates (DAGR) of-adrenal cortical hormone receptor;
-adenosine A 2a receptor stimulant,
-cytokine signaling pathway modulators, such as p38, map kinase, PI3 kinases, jak kinase, syk kinases, EGFR or MK-2, or
-leukotriene antagonist (LTRA), it comprises LTB
4, LTC
4, LTD
4And LTE
4Antagonist.
According to the present invention, formula (1) compound and glucocorticosteroid be combined as better person, this glucocoricoid comprises prednisone (prednisone), prednisolone (prednisolone), flunisolide (flunisolide), Triamcinolone Acetonide (triamcinolone acetonide), beclomethasone dipropionate (beclomethasone dipropionate), budesonide (budesonide), FLUTICASONE PROPIONATE (fluticasone propionate), ciclesonide (ciclesonide), Mometasone Furoate (mometasone furoate) and Mometasone Furoate (mometasone furoate) monohydrate, and especially be the inhaling type glucocorticosteroid with systemic side effect of reduction.
Should be appreciated that this paper in all of treatment are mentioned and being comprised curative therapy, palliative therapy and preventative-therapeutic mentioning.
Formula (1) compound has the ability with beta 2 receptor and cholinergic muscarine acceptor interaction, and therefore because the vital role that beta 2 receptor and muscarine acceptor are risen in all mammiferous physiological functions, thereby formula (1) compound has extensive treatment and uses, and this is as further being described hereinafter.
Therefore, another aspect of the present invention relates to formula (1) compound or its pharmacy acceptable salt, derivative form or composition, and it is used for wherein relating to disease, deficiency disorder and the treatment of conditions of beta 2 receptor and/or muscarine acceptor.More specifically, the present invention also relates to formula (1) compound or its pharmacy acceptable salt, derivative form or composition, and it is used to be selected from the group's who is made up of following each person disease, deficiency disorder and treatment of conditions:
Any kind, the asthma of the cause of disease or pathology is especially for being selected from the asthma of a member among the group who is made up of following each person: atopic asthma, ergotropy asthma, allergic asthma, the asthma of atopy segmental bronchus IgE mediation, bronchial asthma, the special property sent out asthma (essentialasthma), true property asthma, the intrinsic asthma that causes by pathologic, physiologic imbalance, the extrinsic asthma that causes by environmental factors, spy's property sent out asthma that the cause of disease is unknown or not clear, ergotropy 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, the infective asthma that protozoon or virus infection cause, non-allergic asthma, initial stage asthma, stridulate baby comprehensive disease and bronchiolitis;
Chronic or acute bronchoconstriction, chronic bronchitis, tracheole block and pulmonary emphysema;
Any kind, the obstructive of the cause of disease or pathology or inflammatory tracheal disease are especially for being selected from the obstructive or the inflammatory tracheal disease of a member among the group who is made up of following each person: chronic eosinophilic pneumonia (chronic eosinophilic pneumonia), chronic obstructive pulmonary disease (COPD), comprise relevant with COPD or irrelevant chronic bronchitis, pulmonary emphysema or dyspneic COPD, be characterized as the COPD of irreversible carrying out property airway obstruction, adult respiratory distress syndrome (ARDS), over-reactive deterioration of tracheae and the tracheal disease relevant after the other medicines treatment with pulmonary hypertension;
Any kind, the bronchitis of the cause of disease or pathology is especially for being selected from the bronchitis of a member among the group who is made up of following each person: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis (arachidic bronchitis), catarrhal bronchitis (catarrhal bronchitis), croupous bronchitis (croupusbronchitis), dry bronchitis, infectious asthmatic bronchitis (infectiousasthmatic bronchitis), productive bronchitis (productive bronchitis), staphylococcus property or streptococcus bronchitis and vesicular bronchitis;
Acute lung injury;
The bronchiectasis of any kind, the cause of disease or pathology is especially for being selected from the bronchiectasis of a member among the group who is made up of following each person: cylindrical bronchiectasis, tumour shape bronchiectasis, spindle shape bronchiectasis, bronchiolectasis, cystic bronchiectasis (cysticbronchiectasis), dry bronchiectasis and follicular bronchiectasis (follicularbronchiectasis).
Another aspect of the present invention also relates to the purposes that formula (1) compound or its pharmacy acceptable salt, derivative form or composition are used to make the medicine with β2Ji Dongji activity and M3 antagonistic activity.Detailed speech, the present invention relates to the purposes that formula (1) compound or its pharmacy acceptable salt, derivative form or composition are used to make medicine, this medicine is used for the treatment of disease and/or the illness relevant with β 2 and M3 acceptor, especially is disease listed above and/or illness.
Therefore, the invention provides a kind of formula (1) compound of significant quantity or noticeable especially method that its pharmacy acceptable salt, derivative form or composition are treated Mammals (comprising the mankind) used.Clearer and more definite, the invention provides a kind of noticeable especially method that is used for the treatment of beta 2 mediated disease relevant with β 2 and M3 acceptor in the Mammals (comprising the mankind) and/or illness (especially being disease listed above and/or illness), its formula (1) compound, its pharmacy acceptable salt and/or derivative form that comprises with significant quantity is applied to this Mammals.
The preparation of the following example formula (1) compound:
Preparation 1
(9-bromo nonyl) imide carbonic acid two-tert-butyl ester
(60% dispersion liquid of 1.31g in oil, (6.50g is 30.0mmol) in N, in the solution in the dinethylformamide (5ml) 30.0mmol) to be added into imido grpup diamino acid two-tert-butyl ester through stirring once with sodium hydride under 0 ℃, nitrogen.Under 0 ℃, this reactant was stirred 5 minutes, and then at room temperature stirred 30 minutes.This reactant is cooled to 0 ℃, and dropwise adds 1,9-two bromononanes (8.60g, 30.0mmol), permission with this reactant temperature to room temperature and stirred 3 days.Add ether (50ml) and water (20ml) carefully, and organic phase is separated, wash water layer and will make up organic phase drying (sal epsom) with ether (50ml), and remove solvent in a vacuum to obtain clarified oil.Use ether by column chromatography: hexane (by volume 10/90) should the oil purifying via the silica gel wash-out, to obtain the title compound that 5.80g is colorless oil.
1H NMR(400MHz，CD
3OD)：δ＝1.30(10H，m)，1.50(20H，m)，1.83(2H，m)，3.42(2H，t)，3.58(2H，t)ppm。
Preparation 2
[10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } last of the ten Heavenly stems-9-alkene-1-yl] imide two carbonic acid two-tert-butyl ester
With (9-bromo nonyl) imide carbonic acid two-tert-butyl ester (preparation 1,1.80g, 4.26mmol) and triphenyl phosphine (2.00g 7.63mmol) is dissolved in the acetonitrile (40ml), and heating 48 hours under refluxing.This reactant is cooled to room temperature, and in a vacuum solvent is reduced to 8ml.With the heating 12 hours and make it be cooled to room temperature under refluxing of this reactant.Remove solvent in a vacuum, to obtain being gelationus intermediate microcosmic salt.(1.70g 2.48mmol) is dissolved in the tetrahydrofuran (THF) (15ml) and is cooled to-78 ℃ with this jelly under nitrogen atmosphere.(the 2.5M solution of 0.90ml in hexane is 2.25mmol) obtaining orange solution, then with its temperature to 0 ℃ and stirred 45 minutes dropwise to add n-Butyl Lithium.This reactant is cooled to-78 ℃, and dropwise adding 4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl aldehyde is (according to WO 2005/012227 preparation, 320mg, 0.75mmol) solution in tetrahydrofuran (THF) (5ml), and under-78 ℃, this reactant was stirred 10 minutes.This reactant temperature to room temperature and stir 12 hours, and then is poured on ethyl acetate (30ml) and the water (20ml).Organic phase is separated, dry (sal epsom) and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 90/10/1.0) via the silica gel wash-out with residue purified, to obtain the 140mg gelationus title compound that is white in color.
LRMS：m/z 755.7[M+H]
+。
Preparation 3
10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } last of the ten Heavenly stems-9-alkene-1-amine
Under room temperature, nitrogen atmosphere, hydrochloric acid (the 2M solution of 10.0ml in ether) is added into once [10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl through stirring } last of the ten Heavenly stems-9-alkene-1-yl] (the preparation 2 of imide two carbonic acid two-tert-butyl ester, 450mg is 0.59mmol) in the solution in methylene dichloride (5ml).This reactant was stirred 2 hours and remove solvent in a vacuum, resistates is dissolved in ethyl acetate (30ml) and the saturated sodium bicarbonate aqueous solution (20ml).Organic phase is separated water (10ml) washing, dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 90/10/1.0) with residue purified, are glass title compound to obtain 180mg via the silica gel wash-out.
LRMS：m/z 556[M+H]
+。
Preparation 4
N-{2-(benzyloxy)-5-[(1R)-2-{[10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } last of the ten Heavenly stems-9-alkene-1-yl] amino }-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin
Under 90 ℃ with 10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl the last of the ten Heavenly stems-9-alkene-1-amine (preparation 3,170mg, 0.33mmol) and N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] phenyl Toluidrin (prepares according to WO2005/080324,180mg 0.33mmol) heated 12 hours in methyl-sulphoxide (0.5ml).Add ethyl acetate (20ml) and water (10ml), and organic phase is separated, water (10ml) washing, dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 80/20/2.0) with residue purified, are glass title compound to obtain 90mg via the silica gel wash-out.
LRMS：m/z 989[M+H]
+。
Preparation 5
2-[4-(allyloxy) phenyl] and ethyl } t-butyl carbamate
At room temperature with bromopropylene (2.10ml, 24.8mmol) be added into salt of wormwood (4.40g once, 31.8mmol) reach [2-(4-hydroxyphenyl) ethyl] t-butyl carbamate (according to Journal of Organic Chemistry 1999,64,1074 preparations, 5.00g, 21.1mmol) in the suspension in acetonitrile (50ml).This reactant was stirred 12 hours and remove solvent in a vacuum.Add ether (50ml) and water (20ml), and organic phase is separated, water (20ml) washing, dry (sal epsom) and remove solvent in a vacuum is to obtain clarified oil.Use ethyl acetate by column chromatography: pentane (by volume 25/75) should the oil purifying via the silica gel wash-out, to obtain the 3.80g solid title compound that is white in color.
1H NMR(400MHz，CDCl
3)：δ＝1.42(9H，s)，2.78(2H，m)，3.37(2H，m)，4.58(3H，m)，5.28(1H，dd)，5.40(1H，dd)，6.10(1H，m)，6.84(2H，d)，7.10(2H，d)ppm。
Preparation 6
[2-(4-{[(2E)-3-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } third-2-alkene-1-yl] the oxygen base } phenyl) ethyl] t-butyl carbamate
Under 90 ℃, nitrogen atmosphere with (3R)-3-[2-(benzyloxy)-5-bromo phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine (prepares according to WO1994/11337,800mg, 1.66mmol), 2-[4-(allyloxy) phenyl] and ethyl } t-butyl carbamate (preparation 5,924mg, 3.33mmol), acid chloride (37mg, 0.16mmol), three (o-tolyl) phosphine (101mg, 0.33mmol) and diisopropylethylamine (435 μ l, 2.50mmol) in acetonitrile (10ml) heating 12 hours.This reactant is cooled to room temperature and be poured into ethyl acetate (30ml) and water (20ml) on.Organic phase is separated, with saturated sodium bicarbonate aqueous solution (20ml), water (20ml), bittern (20ml) washing, dry (sal epsom) and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 90/10/1.0) with residue purified, are glass title compound to obtain 475mg via the silica gel wash-out.
LRMS：m/z 677[M+H]
+。
Preparation 7
2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } t-butyl carbamate
With [2-(4-{[(2E)-3-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } third-2-alkene-1-yl] the oxygen base } phenyl) ethyl] t-butyl carbamate (preparation 6,475mg, 0.70mmol) be dissolved in the ethanol (20ml), and add 10% palladium/carbon (50mg).Under the hydrogen of 50psi, this reactant is heated to 40 ℃ and lasts 4 hours.This reactant is cooled to room temperature and via Arbocel
TMFilter, collect filtrate and remove solvent in a vacuum and be glass title compound to obtain 400mg.
LRMS：m/z 589[M+H]
+。
Preparation 8
4-{3-[4-(2-amino-ethyl) phenoxy group] propyl group }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] phenol
Will 2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } t-butyl carbamate (preparation 7,400mg, 0.68mmol) be dissolved in the methylene dichloride (15ml), and under 0 ℃ hydrochloric acid (the 2M solution of 10ml in ether) is being added in this solution through stirring.Remove solvent after 3 hours in a vacuum, and add ethyl acetate (20ml) and saturated sodium bicarbonate aqueous solution (10ml), and organic phase is separated.Use methylene dichloride: methyl alcohol (by volume 90: 10,2 * 20ml) washing waters, and, dry (sal epsom) and remove solvent in a vacuum with organic phase combination.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 80/20/2.0) with residue purified, are glass title compound to obtain 135mg via the silica gel wash-out.
LRMS：m/z 489[M+H]
+。
Preparation 9
N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino) ethyl] phenyl } Toluidrin
Under 90 ℃ with 4-{3-[4-(2-amino-ethyl) phenoxy group] propyl group-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenol (preparation 8,134mg, 0.27mmol) and N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] phenyl Toluidrin (prepares according to WO2005/080324,145mg 0.28mmol) heated 24 hours in methyl-sulphoxide (0.5ml).Add ethyl acetate (20ml) and water (10ml) and organic phase is separated.With ethyl acetate (20ml) washing water, and with bittern (10ml) washing combination organic phase, drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 80/20/2.0) with residue purified, are glass title compound to obtain 101mg via the silica gel wash-out.
LRMS：m/z 923[M+H]
+。
Preparation 10
N-{5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino) ethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino) ethyl] phenyl } Toluidrin (preparation 9,100mg, 0.11mmol) be dissolved in the ethanol (10ml), and add ammonium formiate (68mg, 1.07mmol) and 10% palladium hydroxide/carbon (20mg).90 ℃ down with the heating of the reactant through stirring 2 hours, be cooled to room temperature and via Arbocel
TMFilter, collect filtrate and remove solvent in a vacuum to obtain the title compound that 98mg is the yellow glass shape.
LRMS：m/z 833[M+H]
+。
Preparation 11
[2-(4-{[(3E)-4-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } fourth-3-alkene-1-yl] the oxygen base } phenyl) ethyl] t-butyl carbamate
With [2-(4-hydroxyphenyl) ethyl] t-butyl carbamate (according to Journal of OrganicChemistry 1999,64,1074 preparations, 1g, 4.2mmol) be dissolved in the dimethyl formamide (8ml), and interpolation salt of wormwood (698mg, 5.1mmol), then (0.51ml is 5.1mmol) and with this mixture heating up to 60 ℃ to add 4-bromo but-1-ene.At 5 hours postcooling to room temperature, then add another part salt of wormwood (698mg, 5.1mmol) and 4-bromo but-1-ene (0.51ml 5.1mmol), and reheats this mixture to 60 ℃.At 18 hours postcooling to room temperature, then add another part salt of wormwood (698mg, 5.1mmol) and 4-bromo but-1-ene (0.51ml 5.1mmol), and reheats this mixture to 60 ℃.At 5 hours other postcooling to room temperature, then add another part salt of wormwood (350mg, 2.5mmol) and 4-bromo but-1-ene (0.25ml 2.5mmol), and reheats this mixture to 60 ℃.Keep somewhere stirred overnight, then be cooled to room temperature, add water and use ethyl acetate extraction, dry (sal epsom) and remove solvent in a vacuum, by column chromatography use pentane: ethyl acetate (by volume 80/20) via the silica gel wash-out with residue purified.Repeat above reaction to obtain the 1.1g intermediate, it is dissolved in the acetonitrile (10ml), add (3R)-3-[2-(benzyloxy)-5-bromophenyl]-N, N-di-isopropyl-3-phenyl third-1-amine (prepares according to WO9411337,1.2g, 2.5mmol), three (2-aminomethyl phenyl) phosphine (760mg, 2.5mmol) and diisopropylethylamine (0.87ml, 4.99mmol), and use argon gas stream with this mixture degassing.(280mg is 1.25mmol) and with this mixture heating up to 90 ℃ to add palladium diacetate.After 5 hours, be cooled to room temperature and keep somewhere stirred overnight.With mixture via Arbocel
TMFilter, and remove solvent in a vacuum.Add water and use ethyl acetate extraction, organic layer is separated and dry (sal epsom), and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 96/4/0.4) via the silica gel wash-out with residue purified, to obtain the title compound that 1.45g is colourless jelly.
LRMS：m/z 691[M+H]
+。
Preparation 12
2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } t-butyl carbamate
With [2-(4-{[(3E)-4-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } fourth-3-alkene-1-yl] the oxygen base } phenyl) ethyl] t-butyl carbamate (preparation 11,725mg, 1.05mmol) be dissolved in the ethanol (10ml), add palladium hydroxide (20 weight % on carbon, 181mg, 0.25mmol), then add ammonium formiate (529mg, 8.39mmol), and be heated to 80 ℃ and last 5 minutes, then stirred 1 hour down at 75 ℃.This reactant is cooled to room temperature and with this mixture via Arbocel
TMFilter, and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 97/3/0.3 to 94/6/0.6) via the silica gel wash-out with residue purified, to obtain the 460mg foamy title compound that is white in color.
LRMS：m/z 603[M+H]
+。
Preparation 13
4-{4-[4-(2-amino-ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] the phenol dihydrochloride
Will 2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } t-butyl carbamate (preparation 12,450mg, 0.75mmol) be dissolved in the methylene dichloride (10ml), (2M is in ether to add hydrogenchloride, 6ml, 12mmol), add ethanol (1ml) then.After 3 days, remove solvent in a vacuum and be yellow foamed title compound to obtain 420mg.
LRMS:m/z 503[M (free alkali)+H]
+
Preparation 14
N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] phenyl } Toluidrin
With 4-{4-[4-(2-amino-ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] (the preparation 13 of phenol dihydrochloride, 420mg, 0.73mmol), N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (prepares according to WO2005/080324,375mg, 0.73mmol), sodium bicarbonate (245mg, 2.92mmol) and potassiumiodide (121mg, 0.73mmol) be added in the acetonitrile (15ml) and be heated to 90 ℃ and last 30 minutes, and at room temperature kept somewhere 48 hours, add water and use ethyl acetate extraction, dry (sal epsom) and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 97/3/0.3 to 92/8/0.8) via the silica gel wash-out with residue purified, to obtain the 207mg foamy title compound that is white in color.
LRMS：m/z 937[M+H]
+。
Preparation 15
N-{5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] phenyl } Toluidrin (preparation 14,200mg, 0.2mmol) and palladium hydroxide (20 weight % are on carbon, 50mg, 0.07mmol) be dissolved in the ethanol (5ml), then add ammonium formiate (74mg, 1.2mmol) and be heated to 80 ℃ and last 5 minutes, then stirred 1 hour down at 75 ℃.This reactant is cooled to room temperature and with mixture via Arbocel
TMFilter, and remove solvent in a vacuum to obtain the 190mg foamy title compound that is white in color.
LRMS：m/z 847[M+H]
+。
Preparation 16
4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenol
With 4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl aldehyde (prepares according to WO2005012227,1g, 2.32mmol) be dissolved in the methyl alcohol (40ml), add sulfuric acid (2M, 6ml), (30 weight % 2ml), and allow this reaction mixture of stirred overnight in water then to add hydrogen peroxide.Between water and ether, divide this mixture molten, organic layer is separated, wash with saturated sodium bisulfite solution, dry (sal epsom), filter and remove in a vacuum solvent, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 24/1/0.1 to 23/2/0.2) with residue purified, are light yellow foamy title compound to obtain 560mg via the silica gel wash-out.
LRMS：m/z 418[M+H]
+。
Preparation 17
(7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenoxy group } heptyl) imide two carbonic acid two-tert-butyl ester
With 4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] and phenol (preparation 16,150mg 0.36mmol) is dissolved in the dimethyl formamide (2ml), and (140mg 0.43mmol) and at room temperature stirred 30 minutes to add cesium carbonate.Add (the 7-bromo heptyl) t-butyl carbamate be dissolved in the dimethyl formamide (1ml) (according to J.Med.Chem., the 1994,137, the 2537th to 2551 pages of preparations, 170mg 0.43mmol), and is heated to 70 ℃.After 2.5 hours, add cesium carbonate (70mg, 0.22mmol), and behind other 10 minutes, add (7-bromo heptyl) t-butyl carbamate (70mg, 0.18mmol).After 1 hour, add cesium carbonate (20mg, 0.06mmol) and (7-bromo heptyl) t-butyl carbamate (35mg, 0.09mmol), and this mixture is cooled to room temperature after following 1 hour and stirred 3 days in 70 ℃, add water and salt solution subsequently, with this mixture of ethyl acetate extraction, dry (sal epsom), filter and remove in a vacuum solvent, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 95/5/0.5) with residue purified, are colourless gelationus title compound to obtain 220mg via the silica gel wash-out.
LRMS：m/z 731[M+H]
+。
Preparation 18
7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenoxy group } heptan-1-amine dihydrochloride
Will (7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenoxy group } heptyl) (the preparation 17 of imide two carbonic acid two-tert-butyl ester, 220mg, 0.30mmol) be dissolved in the methylene dichloride (6ml), then add hydrogenchloride (the 2M solution in ether, 6ml, 12mmol), and after 30 minutes, add ethanol (1ml) and keep somewhere and spend the night.Remove solvent in a vacuum and be light brown foamy title compound to obtain 190mg.
LRMS:m/z 531[M (free alkali)+H]
+
Preparation 19
N-{2-(benzyloxy)-5-[(1R)-2-[(7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenoxy group } heptyl) amino]-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin
With 7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenoxy group } heptan-(preparation 18 of 1-amine dihydrochloride, 190mg, 0.31mmol), N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (prepares according to WO2005/080324,161mg, 0.32mmol), sodium bicarbonate (106mg, 1.26mmol) and potassiumiodide (52mg, 0.32mmol) be added in the acetonitrile (5ml) and be heated to 90 ℃ and last 24 hours, then at room temperature keep somewhere and spend the night, add water and salt solution and use ethyl acetate extraction, dry (sal epsom) and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 92/8/0.8) with residue purified, are colourless gelationus title compound to obtain 100mg via the silica gel wash-out.
LRMS：m/z 965[M+H]
+。
Preparation 20
N-(5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(7-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenoxy } heptyl) amino] ethyl }-the 2-hydroxyphenyl) Toluidrin
With N-{2-(benzyloxy)-5-[(1R)-2-[(7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenoxy group } heptyl) amino]-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (preparation 19,96mg, 0.10mmol) and palladium hydroxide (20 weight % are on carbon, 25mg, 0.04mmol) be dissolved in the ethanol (3ml), then add ammonium formiate (69mg, 1.1mmol) and be heated to 80 ℃ and last 1 hour.This reactant is cooled to room temperature and with this mixture via Arbocel
TMFilter, and remove solvent in a vacuum.Resistates is dissolved in methylene dichloride (containing trace carbinol) and washes (to add salt solution to help separate) with water,, filter, and remove solvent in a vacuum to obtain the 68mg foamy title compound that is white in color with organic layer drying (sal epsom).
LRMS：m/z 785[M+H]
+。
Preparation 21
(3R)-and 3-[5-{2-[4-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine
With 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } ethanol (prepares according to WO9843942,390mg, 0.88mmol) be dissolved in the tetrahydrofuran (THF) (6ml), add triphenyl phosphine (344mg, 1.31mmol), then add (E)-diazene-1, (265mg 1.31mmol) and with this mixture stirred 20 minutes the 2-di-tert-butyl dicarboxylate.(according to the WO2004/020415 preparation, 311mg is 1.31mmol) and with this reactant stirred overnight then to add [2-(4-hydroxyphenyl) ethyl] t-butyl carbamate.(4M is in ether to add hydrogenchloride, 5ml) and keep somewhere to stir 3 days, then add hydrochloric acid (2M, 5ml) and after 1 hour wash this mixture,, use extracted with diethyl ether with the alkalization of 2N sodium hydroxide with ether, dry (sal epsom), filter and remove in a vacuum solvent, and use methylene dichloride: methyl alcohol by column chromatography: 880 ammonia (by volume 242/8/0.8 to 95/5/0.5) via the silica gel wash-out with residue purified, to obtain the title compound that 100mg is colorless oil.
LRMS：m/z 566[M+H]
+。
Preparation 22
N-{2-(benzyloxy)-5-[(1R)-2-(2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin
With (3R)-3-[5-{2-[4-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, (the preparation 21 of N-di-isopropyl-3-phenyl third-1-amine, 95mg, 0.17mmol), N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (WO2005/080324,86mg, 0.17mmol), sodium bicarbonate (42mg, 0.51mmol) and potassiumiodide (28mg, 0.17mmol) be added in the acetonitrile (2.5ml) and be heated to reflux and last 24 hours, then be cooled to room temperature and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 242/8/0.8 to 95/5/0.5) via the silica gel wash-out with residue purified, to obtain the 78mg foamy title compound that is white in color.
LRMS：m/z 999[M+H]
+。
Preparation 23
The own nitrile of 6-(fourth-3-alkene-1-base oxygen base)
With the own nitrile (1.19ml of 6-bromine, 9.00mmol) and 3-butene-1-alcohol (946 μ l, 11.0mmol) be added into potassium hydroxide through stirring (6.16g, 110mmol) and the bromination tetrabutylammonium (434mg is 1.35mmol) in the solution in water (6ml) and methylene dichloride (2ml).This reactant was at room temperature stirred 4 days, and then with ether (2 * 50ml) washings.To make up organic phase wash with water (3 * 30ml), dry (sal epsom) and remove solvent in a vacuum to obtain the title compound that 1.48g is colorless oil.
LRMS：m/z 168[M+H]
+。
Preparation 24
6-{[(3E)-and 4-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } fourth-3-alkene-1-yl] the oxygen base } own nitrile
With (3R)-3-[2-(benzyloxy)-5-bromophenyl]-N, N-di-isopropyl-3-phenyl third-1-amine (WO9411337,1.21g, 2.50mmol) be dissolved in the acetonitrile (8ml), and add 6-(fourth-3-alkene-1-base oxygen base) own nitrile (preparation 23,708mg, 4.20mmol), diisopropylethylamine (0.64ml, 3.75mmol), acid chloride (54mg, 0.25mmol) and three (o-tolyl) phosphine (145mg, 0.25mmol).Under 90 ℃, nitrogen atmosphere, will be somebody's turn to do reactant heating 12 hours, and be cooled to room temperature and remove solvent in a vacuum through stirring.Resistates is dissolved in the ethyl acetate (50ml) and with saturated sodium bicarbonate aqueous solution (50ml), bittern (50ml) washing dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/0.5) with residue purified, are buttery title compound to obtain 960mg via the silica gel wash-out.
LRMS：m/z 567[M+H]
+。
Preparation 25
6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) own nitrile
With 6-{[(3E)-4-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } fourth-3-alkene-1-yl] the oxygen base } (the preparation 24 of own nitrile, 935mg, 1.65mmol) be dissolved in the ethanol (20ml), and add ammonium formiate (1.90g, 30.0mmol) and 10% palladium hydroxide/carbon (190mg).Under refluxing with this reactant heating 1 hour, be cooled to room temperature and with this reactant via Arbocel
TMFilter, remove the filtrate solvent in a vacuum to obtain the title compound that 783mg is colorless oil.
LRMS：m/z 479[M+H]
+。
Preparation 26
The amino hexyl of 4-{4-[(6-) oxygen base] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] phenol
With 6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) (preparation 25,783mg 1.64mmol) are dissolved in the ethanol (20ml) and interpolation Buddhist nun Ruan (Raney) nickel (100mg) own nitrile.Under 40 ℃ and 60psi, make this reactant hydrogenation 18 hours, be cooled to room temperature and via Arbocel
TMFilter this reactant, and remove the filtrate solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 90/10/1.0) via the silica gel wash-out with residue purified, to obtain the 506mg title compound.
LRMS：m/z 481[M+H]
+。
Preparation 27
N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino } ethyl] phenyl } Toluidrin
Under 90 ℃ with the amino hexyl of 4-{4-[(6-) the oxygen base] butyl-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenol (preparation 26,153mg, 0.32mmol) and N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] phenyl Toluidrin (prepares according to WO2005/080324,155mg, 0.32mmol), potassiumiodide (10mg) and sodium bicarbonate (104mg, 1.23mmol) heating 24 hours in propionitrile (3ml).This reactant is cooled to room temperature, and removes solvent in a vacuum.Resistates is dissolved in the ethyl acetate (30ml), with saturated sodium bicarbonate aqueous solution (30ml), water (30ml), bittern (30ml) washing and drying (sal epsom).Remove solvent in a vacuum, and use methylene dichloride: methyl alcohol by column chromatography: 880 ammonia (by volume 85/15/1.5) via the silica gel wash-out with oily purifying, to obtain the title compound that 130mg is yellow oily.
LRMS (ES)：m/z 917[M+H]
+。
Preparation 28
N-{5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino } ethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino } ethyl] phenyl } Toluidrin (preparation 27,530mg, 0.55mmol) be dissolved in the ethanol, and add ammonium formiate (700mg, 10.9mmol) and 10% palladium hydroxide/carbon (100mg).With the heating 12 hours under refluxing of this reactant, be cooled to room temperature and further add ammonium formiate (600mg, 9.37mmol) and 10% palladium hydroxide/carbon (60mg).This reactant was heated 3 hours under refluxing, be cooled to room temperature and further add 10% palladium hydroxide/carbon (60mg).With the heating 3 hours under refluxing of this reactant, be cooled to room temperature and via Arbocel
TMFilter.Remove the filtrate solvent in a vacuum, and use methylene dichloride: methyl alcohol by column chromatography: 880 ammonia (by volume 80/20/2.0) via the silica gel wash-out with oily purifying, to obtain the title compound that 420mg is yellow oily.
LRMS (ES)：m/z 827[M+H]
+。
Preparation 29
N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] phenyl } methane amide
With N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methane amide (prepares according to US2005/215590,500mg, 1.1mmol), 4-{4-[4-(2-amino-ethyl) phenoxy group] butyl-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] the phenol dihydrochloride (preparation 13,745mg, 1.3mmol), sodium bicarbonate (550mg, 6.5mmol) and potassiumiodide (50mg, 0.30mmol) be added in the propionitrile (8ml), and be heated to 90 ℃ and indwelling stirred overnight.Then further add 4-{4-[4-(2-amino-ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] (preparation 13,50mg 0.087mmol) and under 90 ℃ further stir mixture 24 hours phenol.After the cooling, interpolation ethyl acetate and saturated sodium bicarbonate aqueous solution with the organic phase separation and with more saturated sodium bicarbonate aqueous solutions washings, then wash with bittern and follow drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 96/4/0.4 to 92/8/0.8) with residue purified, are buttery title compound to obtain 400mg via the silica gel wash-out.
LRMS：m/z 887[M+H]
+。
Preparation 30
N-{5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-the 2-hydroxyphenyl } methane amide
With N-{2-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] phenyl } methane amide (preparation 29,400mg, 0.45mmol), ammonium formiate (570mg, 9.0mmol) and 20% palladium hydroxide/carbon (60mg) in methyl alcohol (8ml), mix, and under 70 ℃, nitrogen, stirred 1 hour.Then further add ammonium formiate (500mg, 7.9mmol) and 20% palladium hydroxide/carbon (50mg) and further continue heating 1 hour down at 70 ℃.Then, collect filtrate and remove solvent in a vacuum this reaction mixture cooling and filtration.Resistates is dissolved in the methyl alcohol (8ml), and add ammonium formiate (500mg, 7.9mmol) and 20% palladium hydroxide/carbon (50mg) and under 70 ℃, nitrogen, stirring 1 hour.Then, collect filtrate and remove solvent in a vacuum reaction mixture cooling and filtration.Resistates is dissolved in ethyl acetate (25ml) and the saturated sodium bicarbonate aqueous solution (25ml).Organic phase separated and with bittern (15ml) washing drying (sal epsom) and remove solvent in a vacuum to obtain the title compound that 280mg is yellow solid.
LRMS：m/z 797[M+H]
+。
Preparation 31
8-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] quinoline-2 (1H)-ketone
With 8-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] quinoline-2 (1H)-ketone (prepares according to WO2005/092861,530mg, 1.1mmol), 4-{4-[4-(2-amino-ethyl) phenoxy group] butyl-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] the phenol dihydrochloride (preparation 13,650mg, 1.3mmol), sodium bicarbonate (550mg, 6.5mmol) and potassiumiodide (50mg, 0.30mmol) be added in the propionitrile (8ml), and be heated to 90 ℃ and indwelling stirred overnight.After cooling off, interpolation ethyl acetate and saturated sodium bicarbonate aqueous solution with the organic phase separation and with more saturated sodium bicarbonate aqueous solutions washings, then wash with bittern and follow drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 94/6/0.6) with residue purified, are buttery title compound to obtain 406mg via the silica gel wash-out.
LRMS：m/z 911[M+H]
+。
Preparation 32
5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-oxine-2 (1H)-ketone
With 8-(benzyloxy)-the 5-[(1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] (the preparation 31 of quinoline-2 (1H)-ketone, 406mg, 0.45mmol), ammonium formiate (560mg, 9.0mmol) and 20% palladium hydroxide/carbon (60mg) in methyl alcohol (8ml), mix, and under 70 ℃, nitrogen, stirred 1 hour.Then further add ammonium formiate (300mg, 4.8mmol) and 20% palladium hydroxide/carbon (30mg) and further continue heating 1 hour down at 70 ℃.Then, collect filtrate and remove solvent in a vacuum this reaction mixture cooling and filtration.Resistates is dissolved in the methyl alcohol (8ml), and add ammonium formiate (560mg, 8.9mmol) and 20% palladium hydroxide/carbon (60mg) and under 70 ℃, nitrogen, stirring 1 hour.Then, collect filtrate and remove solvent in a vacuum reaction mixture cooling and filtration.Resistates is dissolved in ethyl acetate (25ml) and the saturated sodium bicarbonate aqueous solution (25ml).Organic phase separated and with bittern (15ml) washing drying (sal epsom) and remove solvent in a vacuum to obtain the title compound that 305mg is yellow solid.
LRMS：m/z 821[M+H]
+。
Preparation 33
4-{4-[4-(2-{[(2R)-2-[3, two (benzyloxy) phenyl of 5-]-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] amino } ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] phenol
Will (1R)-1-[3, two (benzyloxy) phenyl of 5-]-2-bromo oxyethyl group } (tertiary butyl) dimethylsilane (prepares according to US2005/222128,570mg, 1.1mmol), 4-{4-[4-(2-amino-ethyl) phenoxy group] butyl-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] the phenol dihydrochloride (preparation 13,746mg, 1.3mmol), sodium bicarbonate (544mg, 6.48mmol) and potassiumiodide (50mg, 0.30mmol) be added in the propionitrile (8ml), and be heated to 90 ℃ and indwelling stirred overnight.After cooling off, interpolation ethyl acetate and saturated sodium bicarbonate aqueous solution with the organic phase separation and with more saturated sodium bicarbonate aqueous solutions washings, then wash with bittern and follow drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 94/6/0.6) via the silica gel wash-out with residue purified, to obtain the title compound that 720mg is yellow oily.
LRMS：m/z 950[M+H]
+。
Preparation 34
5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] benzene-1, the 3-glycol
With 4-{4-[4-(2-{[(2R)-2-[3, two (benzyloxy) phenyl of 5-]-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] amino } ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] phenol (preparation 33,720mg, 0.76mmol), ammonium formiate (960mg, 15.0mmol) and 20% palladium hydroxide/carbon (110mg) in methyl alcohol (8ml), mix, and under 70 ℃, nitrogen, stirred 1 hour.Then further add ammonium formiate (300mg, 4.75mmol) and 20% palladium hydroxide/carbon (30mg) and further continue heating 1 hour down at 70 ℃.Then, collect filtrate and remove solvent in a vacuum reaction mixture cooling and filtration.Resistates is dissolved in the methyl alcohol (8ml), and add ammonium formiate (900mg, 14mmol) and 20% palladium hydroxide/carbon (100mg) and under 70 ℃, nitrogen, stirring 1 hour.Then, collect filtrate and remove solvent in a vacuum reaction mixture cooling and filtration.Resistates is dissolved in ethyl acetate (25ml) and the saturated sodium bicarbonate aqueous solution (25ml).Organic phase separated and with bittern (15ml) washing drying (sal epsom) and remove solvent in a vacuum and be canescence foamy title compound to obtain 555mg.
LRMS：m/z 770[M+H]
+。
Preparation 35
[2-(3-hydroxyphenyl) ethyl] t-butyl carbamate
With 3-(2-amino-ethyl) phenates hydrochlorate (3g, 17.3mmol) and triethylamine (6.02ml 43.2mmol) is dissolved in the water (15ml), and adds 1,4-dioxane (45ml) and two carbonic acid, two-tert-butyl ester (4.52g, 1.20mmol).At room temperature mixture was stirred 2 days.(2M is in water then to add ether (100ml) and hydrogenchloride, 100ml), and wash with the organic phase separation and with saturated sodium bicarbonate aqueous solution (100ml), then with bittern (100ml) washing, then dry (sal epsom) and remove solvent in a vacuum and be the gelationus title compound of clarification to obtain 4.42g.
LRMS：m/z 260[M+Na]
+。
Preparation 36
Methylsulfonic acid 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } ethyl ester
With 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } ethanol (prepares according to WO1998/43942,1.0g, 2.25mmol) be dissolved in the methylene dichloride (20ml), and add N, the N-diisopropylethylamine (1.8ml, 10mmol).Then this solution is cooled to 0 ℃ and add methylsulfonyl chloride (0.42ml, 5.4mmol).After stirring 2 hours under 0 ℃, use methylene dichloride (20ml) dilution and water (50ml), bittern (50ml) to wash in this mixture, and follow dry (sal epsom) and remove solvent in a vacuum to obtain the title compound that 1.56g is yellow oily.
LRMS：m/z 524[M+H]
+。
Preparation 37
2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-phenyl } oxyethyl group) phenyl] ethyl } t-butyl carbamate
With (the preparation 35 of [2-(3-hydroxyphenyl) ethyl] t-butyl carbamate, 1.7g, 5.96mmol), salt of wormwood (1.65g, 11.9mmol), potassiumiodide (5.0g, 0.03mmol) and methylsulfonic acid 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl ethyl ester (preparation 36,1.56g, 2.98mmol) in dimethyl formamide (20ml), stir and 60 ℃ of following stirred overnight.After cooling, add water (250ml) and ether (250ml), organic phase is separated and water (100ml * 3), bittern (150ml) washing, then dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 90/10/1.0) with residue purified, are buttery title compound to obtain 1.3g via the silica gel wash-out.
LRMS：m/z 666[M+H]
+。
Preparation 38
(3R)-and 3-[5-{2-[3-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine
Will 2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-phenyl } oxyethyl group) phenyl] ethyl } t-butyl carbamate (preparation 37,1.3g, 2.0mmol) be dissolved in the methylene dichloride (5ml) and interpolation hydrochloric acid (4M is in dioxin (dioxin)).Under room temperature, nitrogen, mixture was stirred 3 hours.Remove solvent in a vacuum, and with resistates be dissolved in methylene dichloride (100ml) and aqueous sodium hydroxide solution (1M, 100ml) in, extract with aqueous phase separation and with methylene dichloride (100ml).To make up organic phase drying (sal epsom) and remove solvent in a vacuum, be the buttery title compound to obtain 880mg.
LRMS：m/z 565[M+H]
+。
Preparation 39
N-{2-(benzyloxy)-5-[(1R)-2-(2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin
With (3R)-3-[5-{2-[3-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, (the preparation 38 of N-di-isopropyl-3-phenyl third-1-amine, 340mg, 0.52mmol), potassiumiodide (86mg, 0.52mmol), sodium bicarbonate (175mg, 2.08mmol) and N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] phenyl Toluidrin (prepares according to WO2005/080324,270mg, 0.52mmol) be added in the propionitrile (5ml), and under 100 ℃, nitrogen stirred overnight.With mixture cooling and interpolation water (100ml) and ethyl acetate (100ml).Organic phase separated and with bittern (100ml) washing drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 85/15/1.5) with residue purified, are glass title compound to obtain 257mg via the silica gel wash-out.
LRMS：m/z 999[M+H]
+。
Preparation 40
2-(benzyloxy)-5-[(1R)-2-(2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methyl alcohol
Under 100 ℃, nitrogen with (3R)-3-[5-{2-[3-(2-amino-ethyl) phenoxy group] ethyl-2-(benzyloxy) phenyl]-N, (the preparation 38 of N-di-isopropyl-3-phenyl third-1-amine, 470mg, 0.72mmol), potassiumiodide (120mg, 0.72mmol), sodium bicarbonate (240mg, 2.9mmol) and { 2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl] phenyl methyl alcohol (prepares according to WO2004/032921,325mg 0.72mmol) stirred 24 hours in propionitrile.After being cooled to room temperature, add water (100ml) and ethyl acetate (100ml), organic phase is separated and with bittern (100ml) washing drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 85/15/1.5) via the silica gel wash-out with residue purified, to obtain the title compound that 450mg is the brown glass shape.
LRMS：m/z 935[M+H]
+。
Preparation 41
2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } t-butyl carbamate
[2-(4-hydroxyphenyl) ethyl] t-butyl carbamate (is prepared according to WO1998/43942,3.8g, 7.3mmol), salt of wormwood (2.6g, 8.0mmol), potassiumiodide (1.1g, 7.3mmol) and methylsulfonic acid 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl ethyl ester (preparation 36,1.56g, 2.98mmol) in toluene (20ml), stir and 120 ℃ of following stirred overnight.After cooling, add water (80ml) and ethyl acetate (80ml), with the organic phase separation and with saturated sodium bicarbonate aqueous solution (40ml), bittern (40ml) washing, follow dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 99/1/0.1 to 90/10/1.0) with residue purified, are buttery title compound to obtain 3.4g via the silica gel wash-out.
LRMS：m/z 666[M+H]
+。
Preparation 42
(3R)-and 3-[5-{2-[4-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine dihydrochloride
Will 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } t-butyl carbamate (preparation 41,3.4g, 5.1mmol) be dissolved in that (4M 26ml) handles in the dioxane (20ml) and with hydrochloric acid in dioxane.After at room temperature stirring 4 hours, remove solvent in a vacuum.With resistates from twice of methylene dichloride azeotropic to obtain being the title compound of brown solid, 3.
LRMS：m/z 565[M+H]
+。
Preparation 43
(3R)-and 3-[2-(benzyloxy)-5-{2-[4-(2-{[(2R)-2-[3, two (benzyloxy) phenyl of 5-]-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] amino } ethyl) phenoxy group] ethyl } phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine
With (3R)-3-[5-{2-[4-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, (the preparation 42 of N-di-isopropyl-3-phenyl third-1-amine dihydrochloride, 600mg, 0.94mmol), (1R)-1-[3, two (benzyloxy) phenyl of 5-]-2-bromo oxyethyl group } (tertiary butyl) dimethylsilane (prepares according to US2005/222128,500mg, 0.94mmol), potassiumiodide (160mg, 0.94mmol), sodium bicarbonate (480mg, 5.65mmol) be added in the propionitrile (10ml), and under 100 ℃, nitrogen stirred overnight.With mixture cooling and interpolation water (75ml) and ethyl acetate (75ml).Organic phase separated and with bittern (25ml) washing drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 99/1/0.1 to 90/10/1) with residue purified, are gelationus title compound to obtain 346mg via the silica gel wash-out.
LRMS：m/z 1012[M+H]
+。
Preparation 44
5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino) ethyl] benzene-1, the 3-glycol
With (3R)-3-[2-(benzyloxy)-5-{2-[4-(2-{[(2R)-2-[3, two (benzyloxy) phenyl of 5-]-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] amino } ethyl) phenoxy group] ethyl } phenyl]-N, (the preparation 43 of N-di-isopropyl-3-phenyl third-1-amine, 346mg, 0.30mmol) be dissolved in the methyl alcohol (30ml), and add ammonium formiate (380mg, 6.1mmol) and 20% palladium hydroxide/carbon (43mg).Then under 90 ℃, will heat 2 hours through reaction stirred.After being cooled to room temperature, mixture is filtered and removes in a vacuum solvent.Then resistates is dissolved in ethyl acetate (50ml) and the saturated sodium bicarbonate aqueous solution (50ml).Organic phase is separated,, follow dry (sal epsom) and remove solvent in a vacuum to obtain the title compound that 174mg is the yellow glass shape with the bittern washing.
LRMS：m/z 742[M+H]
+。
Preparation 45
N-{2-(benzyloxy)-5-[(1R)-2-(2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methane amide
With N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methane amide (prepares according to US2005/215590,440mg, 0.95mmol), (3R)-3-[5-{2-[4-(2-amino-ethyl) phenoxy group] ethyl-2-(benzyloxy) phenyl]-N, (the preparation 42 of N-di-isopropyl-3-phenyl third-1-amine dihydrochloride, 600mg, 0.94mmol), potassiumiodide (160mg, 0.94mmol), sodium bicarbonate (480mg, 5.65mmol) be added in the propionitrile (10ml), and under 100 ℃, nitrogen, stirred 24 hours.With mixture cooling and interpolation water (75ml) and ethyl acetate (75ml).Organic phase separated and with the bittern washing dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 99/1/0.1 to 90/10/1) with residue purified, are gelationus title compound to obtain 174mg via the silica gel wash-out.
LRMS：m/z 949[M+H]
+。
Preparation 46
N-{5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino) ethyl]-2 hydroxyphenyl } methane amide
With N-{2-(benzyloxy)-5-[(1R)-2-({ 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methane amide (preparation 45,174mg, 0.18mmol) be dissolved in the methyl alcohol (20ml), and add ammonium formiate (230mg, 3.7mmol) and 20% palladium hydroxide/carbon (26mg).Then under 90 ℃, will heat 2 hours through reaction stirred.After being cooled to room temperature, mixture is filtered and removes in a vacuum solvent.Then resistates is dissolved in ethyl acetate (50ml) and the saturated sodium bicarbonate aqueous solution (50ml).Organic phase is separated, follow dry (sal epsom) and remove solvent in a vacuum to obtain the title compound that 180mg is the yellow glass shape with the bittern washing.
LRMS：m/z 769[M+H]
+。
Preparation 47
8-(benzyloxy)-5-[(1R)-2-(2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] quinoline-2 (1H)-ketone
With (3R)-3-[5-{2-[4-(2-amino-ethyl) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, (the preparation 42 of N-di-isopropyl-3-phenyl third-1-amine dihydrochloride, 800mg, 1.25mmol), 8-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] quinoline-2 (1H)-ketone (prepares according to WO2005/092861,615mg, 1.25mmol), potassiumiodide (210mg, 1.25mmol), sodium bicarbonate (630mg, 7.5mmol) be added in the propionitrile (15ml), and under 100 ℃, nitrogen stirred overnight.With mixture cooling and interpolation water (100ml) and ethyl acetate (100ml).Organic phase is separated and water (100ml) washing, then with bittern (50ml) washing, dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 90/10/1) with residue purified, are gelationus title compound to obtain 297mg via the silica gel wash-out.
LRMS：m/z 973[M+H]
+。
Preparation 48
2-(benzyloxy)-5-[(1R)-2-(2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methyl alcohol
Will 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } t-butyl carbamate (preparation 41,830mg, 1.25mmol) (8ml is in 1 with hydrochloric acid, 4M solution in the 4-dioxane) handle and stirred overnight at room temperature, and remove solvent in a vacuum.Resistates be dissolved in the acetonitrile (8ml) and add { 2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl] phenyl } methyl alcohol (Sali patent, 560mg, 1.24mmol) and sodium bicarbonate (368mg, 4.34mmol).With mixture heating up to 85 ℃ and stirred overnight.Reactant is cooled to room temperature and adds ethyl acetate and water, wash with the water layer separation and with ethyl acetate, and will make up organic phase drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 92.5/7.5/1) with residue purified, are gelationus title compound to obtain 280mg via the silica gel wash-out.
LRMS：m/z 936[M+H]
+。
Preparation 49
4-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino) ethyl]-2-(methylol) phenol
Will 2-(benzyloxy)-5-[(1R)-2-(2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methyl alcohol (preparation 48,280mg, 0.30mmol) be dissolved in the ethanol (6ml), and (20 weight % are on carbon to add palladium hydroxide, 14mg, 0.02mmol).Under room temperature and 40psi, make this reactant hydrogenation 18 hours, be cooled to room temperature and with reactant via Celite
TMFilter, and remove the filtrate solvent in a vacuum and be gelationus title compound to obtain 235mg.
LRMS：m/z 756[M+H]
+。
Preparation 50
Suffering-7-alkene-1-base imide two carbonic acid two-tert-butyl ester
To the sodium hydride through stirring (60% dispersion liquid of 840mg in oil, 21.0mmol) in N, add once in the suspension in the dinethylformamide (40ml) imido grpup diamino acid two-tert-butyl ester (4.56g, 21.0mmol).After stirring 40 minutes, suffering-(3.50ml 21mmol) and at room temperature stirs mixture overnight 1-alkene to add the 8-bromo.Remove solvent in a vacuum and resistates is dissolved in water and the ethyl acetate.Organic layer is separated and wash with water, then with the bittern washing, dry (sal epsom) and remove solvent in a vacuum.Use ether by column chromatography: pentane (by volume 1/99 to 6/94) with residue purified, is clarification buttery title compound to obtain 5.51g via the silica gel wash-out.
Preparation 51
[(7E)-and 8-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } suffering-7-alkene-1-yl] imide two carbonic acid two-tert-butyl ester
With suffering-7-alkene-1-base imide two carbonic acid two-tert-butyl ester (preparation 50,649mg, 1.98mmol), (3R)-3-[2-(benzyloxy)-5-bromo phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine (prepares according to WO1994/11337,560mg, 1.16mmol), palladium diacetate (27mg, 0.12mmol), three (2-aminomethyl phenyl) phosphine (73mg, 0.24mmol) and N, N-diisopropylethylamine (0.304ml, 1.75mmol) be added in the acetonitrile (6ml), and with this mixture heating up to 90 ℃ and keep somewhere stirred overnight under nitrogen.With mixture cooling and interpolation saturated sodium bicarbonate aqueous solution and ethyl acetate.Organic phase separated and with saturated sodium bicarbonate aqueous solution, bittern washing drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 96/4/0.4) with residue purified, are buttery title compound to obtain 530mg via the silica gel wash-out.
LRMS：m/z 727[M+H]
+。
Preparation 52
(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) imide two carbonic acid two-tert-butyl ester
Will [(7E)-and 8-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } suffering-7-alkene-1-yl] (the preparation 51 of imide two carbonic acid two-tert-butyl ester, 530mg, 0.73mmol), (20 weight % are on carbon for palladium hydroxide, 100mg, 0.14mmol) and ammonium formiate (1.1g 17mmol) is dissolved in the ethanol (20ml) and is heated to 70 ℃ and lasts 3 hours.With reaction mixture cooling and filter, and remove solvent in a vacuum and be clarification buttery title compound to obtain 340mg.
LRMS：m/z 640[M+H]
+。
Preparation 53
4-(the amino octyl group of 8-)-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenol
With (8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) (the preparation 52 of imide two carbonic acid two-tert-butyl ester, 340mg, 0.53mmol) be dissolved in the methylene dichloride (5ml) and interpolation hydrochloric acid (the 2M solution of 5.0ml in ether), and at room temperature mixture overnight is stirred.Remove solvent in a vacuum and resistates is dissolved in the mixture of ethyl acetate and saturated sodium bicarbonate aqueous solution.Organic layer is separated, and dry (sal epsom) and remove solvent in a vacuum is to obtain the title compound that 170mg is yellow oily.
LRMS：m/z 439[M+H]
+。
Preparation 54
N-[2-(benzyloxy)-5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) amino] ethyl } phenyl] Toluidrin
Under 90 ℃ with 4-(8-amino octyl group)-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenol (preparation 53,170mg, 0.39mmol) and N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] phenyl Toluidrin (prepares according to WO2005/080324,191mg, 0.37mmol) heating in methyl-sulphoxide (0.5ml), spend the night.Add ethyl acetate and saturated sodium bicarbonate aqueous solution and organic phase is separated, with saturated sodium bicarbonate aqueous solution, bittern washing, dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 99/1/0.1 to 95/5/0.5) via the silica gel wash-out with residue purified, to obtain the title compound that 90mg is yellow oily.
LRMS：m/z 872[M+H]
+。
Preparation 55
N-(5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) amino] ethyl }-the 2-hydroxyphenyl) Toluidrin
With N-[2-(benzyloxy)-5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) amino] ethyl } phenyl] Toluidrin (preparation 54,90mg, 0.10mmol), ammonium formiate (130mg, 2.0mmol) and 20% palladium hydroxide/carbon (20mg) in ethanol (3ml), mix and be heated to 70 ℃, spend the night.Then with reaction mixture cooling and filtration.Collect filtrate and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 91/9/0.9) with residue purified, to obtain being gelationus title compound, are glass title compound to obtain 82mg via the silica gel wash-out.
LRMS：m/z 783[M+H]
+。
Preparation 56
2-[4-(penta-4-alkene-1-base oxygen base) phenyl] and ethyl } t-butyl carbamate
With [2-(4-hydroxyphenyl) ethyl] t-butyl carbamate (according to Journal of OrganicChemistry 1999,64,1074 preparations, 1.0g, 4.21mmol) be dissolved in the dimethyl formamide (8ml), and add salt of wormwood (1.2g, 8.4mmol), then (0.99ml 8.4mmol), and stirs this mixture overnight under 60 ℃ to add 5-bromo penta-1-alkene after 15 minutes.
After being cooled to room temperature, to add water and use extracted with diethyl ether, drying (sal epsom) and remove solvent in a vacuum is to obtain the 1.2g solid title compound that is white in color.
LRMS：m/z 328[M+Na]
+。
Preparation 57
[2-(4-{[(4E)-5-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } penta-4-alkene-1-yl] the oxygen base } phenyl) ethyl] t-butyl carbamate
Will 2-[4-(penta-4-alkene-1-base oxygen base) phenyl] and ethyl } t-butyl carbamate (preparation 56,1.2g, 3.9mmol), (3R)-3-[2-(benzyloxy)-5-bromo phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine (prepares according to WO9411337,1.9g, 3.9mmol), acid chloride (90mg, 0.4mmol), three (o-tolyl) phosphine (200mg, 0.8mmol) and diisopropylethylamine (1.0ml, 5.9mmol) in acetonitrile (12ml), mix, outgas with argon gas, and be heated to 90 ℃ and last 5 hours.This reactant is cooled to room temperature, via Arbocel
TMFilter and remove in a vacuum solvent.Resistates is dissolved in water and the ethyl acetate, organic phase is separated, dry (sal epsom) and remove solvent in a vacuum, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 95/5/0.5) via the silica gel wash-out with residue purified, to obtain the title compound that 2.5g is the weak yellow foam shape.
LRMS：m/z 705[M+H]
+。
Preparation 58
(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) t-butyl carbamate
With [2-(4-{[(4E)-5-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } penta-4-alkene-1-yl] the oxygen base } phenyl) ethyl] t-butyl carbamate (preparation 57,2.5g, 3.5mmol) be dissolved in the ethanol (50ml), and (20 weight % are on carbon to add palladium hydroxide, 600mg, 0.84mmol) and ammonium formiate (2.0mg, 30mmol), and 90 ℃ of following stirrings 1 hour.With the reactant cooling and via Arbocel
TMFilter and remove in a vacuum solvent.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/0.5 to 90/10/1) via the silica gel wash-out with residue purified, to obtain the 1.66g foamy title compound that is white in color.
LRMS：m/z 617[M+H]
+。
Preparation 59
4-{5-[4-(2-amino-ethyl) phenoxy group] amyl group }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] the phenol dihydrochloride
With (2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) t-butyl carbamate (preparation 58,1.66g, 2.69mmol) be dissolved in methylene dichloride (20ml) and the ethanol (3ml), and add hydrochloric acid (the 2M solution of 12ml in ether), and at room temperature mixture overnight is stirred.Remove solvent in a vacuum and resistates is dissolved in the methylene dichloride, and remove solvent once more in a vacuum and be yellow foamed title compound to obtain 1.6g.
LRMS：m/z 517[M+H]
+。
Preparation 60
N-[2-(benzyloxy)-5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) amino] ethyl } phenyl] Toluidrin
With 4-{5-[4-(2-amino-ethyl) phenoxy group] amyl group }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] (the preparation 59 of phenol dihydrochloride, 400mg, 0.68mmol) be dissolved in the water, and alkalize with saturated sodium bicarbonate aqueous solution, then use dichloromethane extraction.With organic phase drying (sal epsom) and remove solvent in a vacuum.Resistates be dissolved in the methyl-sulphoxide (0.3ml) and add N-{2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (prepares according to WO2005/080324,400mg, 0.8mmol), and under 80 ℃, in sealed vessel, heated 6 hours.After being cooled to room temperature, add water, use dichloromethane extraction, drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/0.5) via the silica gel wash-out with residue purified, to obtain the 370mg title compound.
LRMS：m/z 948[M+H]
+。
Preparation 61
N-(5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) amino] ethyl }-the 2-hydroxyphenyl) Toluidrin
With N-[2-(benzyloxy)-5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) amino] ethyl } phenyl] Toluidrin (preparation 60,350mg, 0.37mmol) be dissolved in the ethanol (10ml), and add ammonium formiate (1.0g, 16mmol) and 20% palladium hydroxide/carbon (250mg), and be heated to 90 ℃ and last 1 hour.Then with the reaction mixture cooling and via Arbocel
TMFilter, and remove solvent in a vacuum to obtain the title compound that 250mg is colorless oil.
LRMS：m/z 858[M+H]
+。
Preparation 62
4-{4-[4-(2-{[(2R)-2-[4-(benzyloxy)-3-(methylol) phenyl]-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] amino } ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] phenol
With 4-{4-[4-(2-amino-ethyl) phenoxy group] butyl }-2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] the phenol tertiary butyl 2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } (the preparation 13 of carbamate dihydrochloride, 1.30g, 2.26mmol) be dissolved in the mixture of saturated sodium bicarbonate aqueous solution and methylene dichloride.Organic layer is separated dry (sal epsom) and remove solvent in a vacuum.Resistates be dissolved in the acetonitrile (10ml) and add { 2-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl] phenyl } methyl alcohol (prepares according to WO2004/032921,1.02g, 2.26mmol), sodium bicarbonate (570mg, 6.78mmol), and be heated to 85 ℃ and stirred overnight.In vacuum, removing solvent after the cooling, and with resistates be dissolved in methylene dichloride (30ml) and water (2 * 20ml) washings, then with bittern (20ml) washing, dry (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/1 to 90/10/1) with residue purified, are gelationus title compound to obtain 388mg via the silica gel wash-out.
LRMS：m/z 874[M+H]
+。
Preparation 63
4-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-2-(methylol) phenol
With 4-{4-[4-(2-{[(2R)-2-[4-(benzyloxy)-3-(methylol) phenyl]-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] amino } ethyl) phenoxy group] butyl }-2-[(1R)-and 3-(diisopropylaminoethyl)-1-phenyl propyl] phenol (preparation 62,388mg, 0.44mmol) be dissolved in the ethanol (5ml), and add ammonium formiate (280mg, 4.44mmol) and 20% palladium hydroxide/carbon (58mg).Under 85 ℃, will heat 18 hours through reaction stirred.After being cooled to room temperature, (140mg 2.22mmol) and 20% palladium hydroxide/carbon (20mg), and stirs mixture 3 hours under 85 ℃ further to add ammonium formiate.Subsequently with the reaction mixture cooling and via Arbocel
TMFilter, collect filtrate and remove solvent in a vacuum and be glass title compound to obtain 311mg.
LRMS：m/z 784[M+H]
+。
Preparation 64
2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl]-1, the 1-dimethyl ethyl } t-butyl carbamate
With [2-(4-hydroxyphenyl)-1, the 1-dimethyl ethyl] t-butyl carbamate (prepares according to WO1997/34905,1.5g, 5.6mmol), cesium carbonate (2.9g, 9.0mmol), sodium iodide (670mg, 4.5mmol) and methylsulfonic acid 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl ethyl ester (preparation 36,2.4g, 4.5mmol) in toluene (18ml) in the mixing and 120 ℃ of following stirred overnight.After cooling, add water (100ml) and ethyl acetate (100ml), then extract with the water layer separation and with other ethyl acetate (100ml * 2).Then will make up organic phase drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/1), separate appropriate flow part and remove solvent in a vacuum residue purified via the silica gel wash-out.Resistates is dissolved in the ethyl acetate of minimum volume and adds pentane (100ml).Then with organic phase with the NaOH aqueous solution (1N, 150ml * 2) washing, then dry (sal epsom) and remove solvent in a vacuum and be the buttery title compound to obtain 1.72g.
LRMS：m/z 694[M+H]
+。
Preparation 65
(3R)-and 3-[5-{2-[4-(2-amino-2-methyl propyl group) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-N, N-di-isopropyl-3-phenyl third-1-amine dihydrochloride
(4M is in dioxane with hydrochloric acid, 15ml) handle 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-phenyl } oxyethyl group) phenyl]-the 11-dimethyl ethyl } t-butyl carbamate (preparation 64,1.72g, 2.48mmol).At room temperature in vacuum, remove solvent after the stirred overnight, to obtain the title compound that 1.60g is colourless foam.
LRMS：m/z 594[M+H]
+。
Preparation 66
8-(benzyloxy)-5-[(1R)-2-(2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl]-1, the 1-dimethyl ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] quinoline-2 (1H)-ketone
With (3R)-3-[5-{2-[4-(2-amino-2-methyl propyl group) phenoxy group] ethyl }-2-(benzyloxy) phenyl]-(preparation 65 of NN-di-isopropyl-3-phenyl third-1-amine dihydrochloride, 550mg, 0.83mmol), 8-(benzyloxy)-the 5-[(1R)-2-bromo-1-{[tertiary butyl (dimethyl) silyl] the oxygen base ethyl] quinoline-2 (1H)-ketone (prepares according to WO2005/092861,405mg, 0.83mmol) and sodium bicarbonate (244mg, 2.9mmol) be added in the acetonitrile (6ml), and under 90 ℃, nitrogen, stirred 20 hours.With mixture cooling and remove solvent in a vacuum.Then resistates is divided moltenly between water (40ml) and methylene dichloride (40ml), layer separated and with other methylene dichloride (40ml) aqueous layer extracted.To make up organic phase drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/0.5 to 80/20/2) with residue purified, are gelationus title compound to obtain 100mg via the silica gel wash-out.
LRMS：m/z 999[M-H]
-。
Preparation 67
5-[(1R)-and the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl]-1, the 1-dimethyl ethyl } amino) ethyl]-oxine-2 (1H)-ketone
With 8-(benzyloxy)-5-[(1R)-2-({ 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl]-1, the 1-dimethyl ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] (the preparation 66 of quinoline-2 (1H)-ketone, 370mg, 0.37mmol), ammonium formiate (234mg, 3.7mmol) and 20% palladium hydroxide/carbon (100mg) in ethanol (5ml), mix, and under nitrogen atmosphere, be heated to 85 ℃, spend the night.Then with the reaction mixture cooling and via Celite
TMFilter, and remove the filtrate solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 97.5/2.5/0.25 to 95/5/0.5) with residue purified, are gelationus title compound to obtain 160mg via the silica gel wash-out.
LRMS：m/z 821[M+H]
+。
Embodiment 1
N-(5-{ (1R)-2-[(10-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } decyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin
At room temperature (10% on carbon with palladium hydroxide, 20mg) be added into ammonium formiate (344mg through stirring, 5.46mmol) and N-{2-(benzyloxy)-5-[(1R)-2-{[10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl the last of the ten Heavenly stems-9-alkene-1-yl] amino }-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (preparation 4,90mg is 0.091mmol) in the solution in methyl alcohol (10ml).With the heating 1 hour under refluxing of this reactant, be cooled to room temperature and via Arbocel
TMFilter.Collect filtrate and remove solvent in a vacuum, with obtain as with the N-of the mixture that remains ammonium formiate (5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(10-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl decyl) amino] ethyl-the 2-hydroxyphenyl) Toluidrin.LRMS：m/z 811[M+H]
+。This mixture is dissolved in tetrahydrofuran (THF) (4ml) and the methyl alcohol (2ml), and at room temperature add once triethylamine trihydrofluoride (88 μ l, 0.54mmol).This reactant was stirred 12 hours and under reduced pressure remove solvent, be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 80/20/2.0) with residue purified, are glass title compound to obtain 35mg via the silica gel wash-out.
LRMS：m/z 697[M+H]
+。
Embodiment 2
N-{5-[(1R)-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino) ethyl]-the 2-hydroxyphenyl } Toluidrin (preparation 10,98mg, 0.11mmol) be dissolved in tetrahydrofuran (THF) (4ml) and the methyl alcohol (2ml), and at room temperature add once triethylamine trihydrofluoride (95 μ l, 0.58mmol).This reactant was stirred 24 hours and under reduced pressure remove solvent, be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent, to obtain pale solid.Be dissolved in this solid in the methyl alcohol (1ml) and use excessive diisopropyl ether to precipitate, collect this solid to obtain the 16mg solid title compound that is white in color by filtering.
LRMS：m/z 718[M+H]
+。
Embodiment 3
N-{5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-the 2-hydroxyphenyl } Toluidrin (preparation 15,190mg, 0.22mmol) be dissolved in the tetrahydrofuran (THF) (5ml), and dropwise add N, N-diethyl ethamine three hydrofluorides (0.2ml, 1mmol).At the mixture that adds tetrahydrofuran (THF) (5ml) and 880 ammonia (5ml) after 29 hours and after 15 minutes, add bittern, organic layer is separated, dry (sal epsom), filter, remove solvent in a vacuum and use methylene dichloride: methyl alcohol by column chromatography: 880 ammonia (by volume 98/2/0.2 to 92/8/0.8) via the silica gel wash-out with residue purified, to obtain the 90mg foamy title compound that is white in color.
LRMS：m/z 732[M+H]
+。
Embodiment 4
N-(5-{ (1R)-2-[(7-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenoxy } heptyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin
With N-(5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(7-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenoxy heptyl) amino] ethyl-the 2-hydroxyphenyl) Toluidrin (preparation 20,68mg, 0.087mmol) be dissolved in the tetrahydrofuran (THF) (3ml), and dropwise add N, N-diethyl ethamine three hydrofluorides (71 μ l, 0.43mmol).At the mixture that adds methyl alcohol (4ml) and 880 ammonia (8ml) after 18 hours and after 15 minutes, in vacuum, remove solvent.Be dissolved in resistates in the methylene dichloride and remove solvent once more in a vacuum, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 97/3/0.3 to 88/12/1.2) via the silica gel wash-out with residue purified, to obtain the 30mg solid title compound that is white in color.
LRMS：m/z 670[M+H]
+。
Embodiment 5
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{2-(benzyloxy)-5-[(1R)-2-({ 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (preparation 22,78mg, 0.078mmol) be dissolved in the ethanol (2ml), add ammonium formiate (200mg, 3.17mmol), be heated to backflow, (20 weight % are on carbon then to add palladium hydroxide, 50mg, 0.07mmol), and after 30 minutes, this reactant is cooled to room temperature and with mixture via Arbocel
TMFilter and remove in a vacuum solvent.Be dissolved in resistates in the tetrahydrofuran (THF) (2ml) and interpolation N, N-diethyl ethamine three hydrofluorides (59 μ l 0.37mmol) and subsequently add 1 methyl alcohol, and with this reaction mixture stirred overnight.Remove solvent in a vacuum and resistates is dissolved in methyl alcohol/880 ammonia of 1: 1, remove solvent in a vacuum and repeat this process 4 times.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 230/20/2 to 90/10/1) via the silica gel wash-out with residue purified, to obtain the 28mg solid title compound that is white in color.
LRMS：m/z 704[M+H]
+。
Embodiment 6
N-{5-[(1R)-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino }-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino } ethyl]-the 2-hydroxyphenyl } Toluidrin (preparation 28,420mg, 0.51mmol) be dissolved in the tetrahydrofuran (THF) (6ml) and add triethylamine trihydrofluoride (415 μ l, 2.55mmol).At room temperature this reactant was stirred 4 hours and remove solvent in a vacuum, be dissolved in resistates in methyl alcohol (1ml) and 880 ammonia (1ml) and remove solvent in a vacuum, be dissolved in resistates in methyl alcohol (1ml) and 880 ammonia (1ml) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 89/11/1.1) via the silica gel wash-out with gained oil purifying, to obtain the title compound that 26mg is yellow solid.
LRMS (ES)：m/z 712[M+H]
+。
Embodiment 7
N-{5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide
With N-{5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-2 hydroxyphenyl } methane amide (preparation 30,280mg, 0.35mmol) be dissolved in the tetrahydrofuran (THF) (5ml) and interpolation triethylamine trihydrofluoride (0.29ml, 1.8mmol), and at room temperature this mixture overnight is stirred.Then add tetrahydrofuran (THF) (6ml) and 880 ammonia (6ml), mixture was stirred 20 minutes, then, then, follow dry (sal epsom) and remove solvent in a vacuum with bittern (10ml) washing with the organic phase separation and with saturated sodium bicarbonate aqueous solution (10ml) washing.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 88/12/1.2) via the silica gel wash-out with residue purified, to obtain the title compound that 74mg is pale solid.
LRMS：m/z 683[M+H]
+。
Embodiment 8
5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone
With 5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-(preparation 32 of oxine-2 (1H)-ketone, 305mg, 0.37mmol) be dissolved in the tetrahydrofuran (THF) (5ml) and interpolation triethylamine trihydrofluoride (0.30ml, 1.9mmol), and at room temperature this mixture overnight is stirred.Then add tetrahydrofuran (THF) (6ml) and 880 ammonia (6ml), this mixture was stirred 20 minutes, then, then, follow dry (sal epsom) and remove solvent in a vacuum with bittern (10ml) washing with the organic phase separation and with saturated sodium bicarbonate aqueous solution (10ml) washing.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 88/12/1.2) via the silica gel wash-out with residue purified, to obtain the title compound that 99mg is yellow solid.
LRMS：m/z 707[M+H]
+。
Embodiment 9
5-[(1R)-the 1-{[hydroxyl }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] benzene-1, the 3-glycol
With 5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] benzene-1, (the preparation 34 of 3-glycol, 555mg, 0.72mmol) be dissolved in the tetrahydrofuran (THF) (8ml) and interpolation triethylamine trihydrofluoride (0.59ml, 3.6mmol), and at room temperature this mixture overnight is stirred.Then add tetrahydrofuran (THF) (6ml) and 880 ammonia (6ml), this mixture was stirred 20 minutes, then, then, follow dry (sal epsom) and remove solvent in a vacuum with bittern (10ml) washing with the organic phase separation and with saturated sodium bicarbonate aqueous solution (10ml) washing.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 88/12/1.2) via the silica gel wash-out with residue purified, to obtain the 54mg solid title compound that is white in color.
LRMS：m/z 655[M+H]
+。
Embodiment 10
N-{5-[(1R)-2-(2-[3-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin
With N-{2-(benzyloxy)-5-[(1R)-2-({ 2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } Toluidrin (preparation 39,257mg, 0.26mmol) be dissolved in the ethanol (20ml), and add ammonium formiate (325mg, 5.15mmol) and 20% palladium hydroxide/carbon (36mg).At 90 ℃ of following heating reactants through stirring, (325mg 5.15mmol) and 20% palladium hydroxide/carbon (36mg), and further stirs mixture 2 hours under 90 ℃ further to add ammonium formiate after 2 hours.After being cooled to room temperature, mixture is filtered and remove solvent in a vacuum, (325mg 5.15mmol) and 20% palladium hydroxide/carbon (36mg), and with this mixture heating up to 90 ℃, lasts 2 hours again then to add ethanol (20ml), ammonium formiate.After cooling, mixture is filtered and removes in a vacuum solvent.Resistates is dissolved in methyl alcohol (10ml) and the tetrahydrofuran (THF) (20ml), and the interpolation triethylamine trihydrofluoride (0.25ml, 1.5mmol).Mixture overnight is stirred, then remove solvent in a vacuum.Be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent.Repeat this process, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 99/1/0.1 to 80/20/2.0) via the silica gel wash-out with residue purified, to obtain (after in diisopropyl ether, grinding) 52mg solid title compound that is white in color.
LRMS：m/z 704[M+H]
+。
Embodiment 11
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(2-{3-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } ethyl) phenol
Descend to incite somebody to action at 90 ℃ 2-(benzyloxy)-5-[(1R)-2-(2-[3-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] phenyl } methyl alcohol (preparation 40,450mg, 0.48mmol), ammonium formiate (610mg, 9.6mmol) and 20% palladium hydroxide/carbon (68mg) in ethanol, stirred 30 minutes.Further add ammonium formiate (610mg, 9.6mmol) and 20% palladium hydroxide/carbon (70mg) and under 90 ℃, mixture further being stirred 30 minutes.Mixture is cooled to room temperature and stirred overnight, and (610mg 9.6mmol) and 20% palladium hydroxide/carbon (70mg), stirred 1 hour down at 90 ℃ subsequently then further to add ammonium formiate.After cooling, mixture is filtered and removes in a vacuum solvent.(0.47ml 2.9mmol) and at room temperature stirs mixture 3 days to add methyl alcohol (10ml), tetrahydrofuran (THF) (20ml) and triethylamine trihydrofluoride.Remove solvent in a vacuum and be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent.Repeat this process, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 99/1/0.1 to 80/20/2.0) via the silica gel wash-out with residue purified, to obtain (after grinding with diisopropyl ether) 95mg solid title compound that is white in color.
LRMS：m/z 641[M+H]
+。
Embodiment 12
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-glycol
With 5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino) ethyl] benzene-1, (the preparation 44 of 3-glycol, 174mg, 0.23mmol) be dissolved in methyl alcohol (5ml) and the tetrahydrofuran (THF) (10ml), and the interpolation triethylamine trihydrofluoride (0.23ml, 1.4mmol).Mixture overnight is stirred, and then remove solvent in a vacuum.Be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent.Repeat this process, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/0.5 to 80/20/2.0) with residue purified, are foamy title compound to obtain 83mg via the silica gel wash-out.
LRMS：m/z 627[M+H]
+。
Embodiment 13
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide
With N-{5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino) ethyl]-2 hydroxyphenyl } methane amide (preparation 46,180mg, 0.18mmol) be dissolved in methyl alcohol (5ml) and the tetrahydrofuran (THF) (10ml), and the interpolation triethylamine trihydrofluoride (0.18ml, 1.1mmol).Mixture overnight is stirred, and then remove solvent in a vacuum.Be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent.Repeat this process, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 80/20/2.0) with residue purified, are gelationus title compound to obtain 69mg via the silica gel wash-out.
LRMS：m/z 654[M+H]
+。
Embodiment 14
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone
With 8-(benzyloxy)-5-[(1R)-2-({ 2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl] phenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl] (the preparation 47 of quinoline-2 (1H)-ketone, 295mg, 0.30mmol) be dissolved in the methyl alcohol (30ml), and add ammonium formiate (380mg, 6.1mmol) and 20% palladium hydroxide/carbon (43mg).Then under 90 ℃, will heat 2 hours through reaction stirred.After being cooled to room temperature, mixture is filtered and removes in a vacuum solvent.Then resistates is dissolved in ethyl acetate (50ml) and the saturated sodium bicarbonate aqueous solution (50ml).Organic phase is separated,, follow dry (sal epsom) and remove solvent in a vacuum with the bittern washing.Then resistates is dissolved in methyl alcohol (10ml) and the tetrahydrofuran (THF) (20ml), and the interpolation triethylamine trihydrofluoride (0.30ml, 1.8mmol).Mixture overnight is stirred, and then remove solvent in a vacuum.Be dissolved in resistates in methyl alcohol (20ml) and 880 ammonia (2ml) and under reduced pressure remove solvent.Repeat this process, and use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 98/2/0.2 to 80/20/2.0) with residue purified, are yellow foamed title compound to obtain 137mg via the silica gel wash-out.
LRMS：m/z 678[M+H]
+。
Embodiment 15
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(2-{4-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } ethyl) phenol
With 4-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino) ethyl]-(preparation 49 of 2-(methylol) phenol, 235mg, 0.30mmol) be dissolved in methyl alcohol (2.9ml) and the water (1.4ml), and the interpolation Neutral ammonium fluoride (112mg, 3.0mmol).This reactant is heated to 40 ℃ and stirred overnight, is cooled to room temperature and then adds saturated sodium bicarbonate aqueous solution (20ml) and ethyl acetate (20).Extract with aqueous phase separation and with ethyl acetate, and will make up organic phase drying (sal epsom) and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 80/20/1.0) with residue purified, are glass title compound to obtain 55mg via the silica gel wash-out.
LRMS：m/z 641[M+H]
+。
Embodiment 16
N-(5-{ (1R)-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin
With N-(5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl octyl group) amino] ethyl-the 2-hydroxyphenyl) Toluidrin (preparation 55,74mg, 0.095mmol) be dissolved in the tetrahydrofuran (THF) (3ml), and at room temperature add once triethylamine trihydrofluoride (90 μ l, 0.54mmol).This reactant was stirred 12 hours and under reduced pressure remove solvent, be dissolved in resistates in methyl alcohol (10ml) and 880 ammonia (1ml) and under reduced pressure remove solvent.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 97/3/0.3 to 85/15/1.5) via the silica gel wash-out with residue purified, to obtain the title compound that 34mg is yellow solid.
LRMS：m/z 668[M+H]
+。
Embodiment 17
N-(5-{ (1R)-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin
With N-(5-{ (the 1R)-1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl amyl group) the oxygen base] phenyl ethyl) amino] ethyl-the 2-hydroxyphenyl) Toluidrin (preparation 61,250mg, 0.29mmol) be dissolved in tetrahydrofuran (THF) (10ml) and the methyl alcohol (0.5ml), and the interpolation triethylamine trihydrofluoride (1.0ml, 6.1mmol).This reactant was stirred 3 days and remove solvent in a vacuum.Be dissolved in resistates in 880 ammonia (1ml) and under reduced pressure remove solvent, repeat this process 3 times.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 95/5/0.5) via the silica gel wash-out with residue purified, to obtain the title compound that 100mg is the weak yellow foam shape.
LRMS：m/z 746[M+H]
+。
Embodiment 18
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(4-{4-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } butyl) phenol
With 4-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl]-(preparation 63 of 2-(methylol) phenol, 311mg, 0.356mmol) be dissolved in methyl alcohol (4ml) and the water (0.5ml), and the interpolation Neutral ammonium fluoride (132mg, 3.56mmol).This reactant is heated to 40 ℃ and stirred overnight.With reaction mixture cooling and remove solvent in a vacuum.Use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 100/0/0 to 90/10/1.0) with residue purified, are glass title compound to obtain 84mg via the silica gel wash-out.
LRMS：m/z 669[M+H]
+。
Embodiment 19
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } the Toluidrin succinate
With N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } (embodiment 5 for Toluidrin, 2000mg, 2.84mmol) be dissolved in the methyl alcohol (8ml), and at room temperature (336mg 2.84mmol) is added in this solution through stirring once with the Succinic Acid in water (2ml) and the methyl alcohol (2ml).Further add water and occur as jelly until salt, this jelly with the small-crystalline of previous isolating salt as crystal seed.Mixture kept somewhere spend the night and stirred to help crystallization every now and then.With solid filtering and dry in vacuum, to obtain the be white in color title compound of crystalline solid of 2336mg, fusing point is 148 to 150 ℃ after 5 days.
LRMS：m/z 704[M+H]
+。
Embodiment 20
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl]-1, the 1-dimethyl ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone
With 5-[(1R)-the 1-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl]-the 11-dimethyl ethyl } amino) ethyl]-(preparation 67 of oxine-2 (1H)-ketone, 160mg, 0.20mmol) be dissolved in methyl alcohol (20ml) and the water (10ml), and the interpolation Neutral ammonium fluoride (740mg, 3.6mmol).This reactant is heated to 40 ℃ and stirred 21 hours under nitrogen atmosphere.With reaction mixture cooling and remove solvent in a vacuum.Resistates is followed from the methylene dichloride azeotropic to obtain white solid from methylbenzene azeotropic, use methylene dichloride by column chromatography: methyl alcohol: 880 ammonia (by volume 90/10/1 to 80/20/2) with this white solid purifying, are glass title compound to obtain 19mg via the silica gel wash-out.
LRMS：m/z 707[M+H]
+。
Expressing hM
3The full cell β-Nei Xiananmei reporter-gene assays method of use is carried out the functional evaluation to antagonistic activity in the Chinese hamster ovary celI of acceptor.
Cell cultures
With recombinant expressed human muscarine M
3The CHO of acceptor (Chinese hamster ovary) cell NFAT_ β-Lac_Zeo plasmid transfection.Make cell have Glutamax-1, replenish 25mMHEPES (Life Technologies 32430-027), contain 10%FCS (foetal calf serum; SigmaF-7524), 1nM Sodium.alpha.-ketopropionate (Sigma S-8636), NEAA (non-essential amino acid; Invitrogen 11140-035) and among the DMEM of 200 μ g/ml Zeocin (Invitrogen R250-01) grow.
HM3 β-Lac measuring method
When cell reaches 80 to 90% fraction of coverage, use no enzyme cell dissociation buffer (Dissociation Solution) (Life technologies 13151-014) and this cell under 37 ℃ in containing 5%CO
2Atmosphere in together incubation collected this cell in 5 minutes, for mensuration.With separated cell harvesting in warm substratum and with the speed of 2000rpm centrifugal 10 minutes, at PBS (phosphate buffered saline (PBS); Life Technologies 14190-094) washing and as recentrifuge as described in just now in.Make this cell with 2 * 10
5The concentration of individual cell/ml is suspended in the substratum (composition as noted before) again.In each hole of 384 hole black transparent base plates (Greiner Bio One 781091-PFI), add 20 these cell suspending liquids of μ l.Used mensuration damping fluid is for replenishing the PBS of 0.05%Pluronic F-127 (Sigma 9003-11-6) and 2.5%DMSO.Use 80nM amine Carbamoylcholine (Aldrich N240-9) and this cell at 37 ℃/5%CO
2Incubation stimulated muscarine M in 4 hours together down
3Receptor signal, and when the incubation period end, use Tecan SpectraFluor+ plate reader (λ-excite 405nm launches 450nm and 503nm) to monitor.When incubation period began in 4 hours, test compounds is added in the mensuration thing, and the compound activity measurement is the concentration dependent restraining effect of amine Carbamoylcholine inducement signal.Draw and suppress curve and use 4 parameter S shape matches to generate IC
50Be worth, and use the K of amine Carbamoylcholine in Cheng-Prusoff correction and this mensuration
DValue is with IC
50Value is converted into the Ki value.
Expressing hB
2The plain enzyme reporter-gene assays of the full cell fluorescence of use method is carried out the functional evaluation to agonist usefulness and effect in the Chinese hamster ovary celI of acceptor.
Cell cultures
With recombinant expressed human suprarenin B
2The CHO of acceptor and luciferase reporter gene transfection (Chinese hamster ovary) cell is maintained in the substratum that is made of the F12:DMEM (Sigma D6421) that contains 10% foetal calf serum (FBS:SigmaF03921), 10 μ g/ml tetracyclines (Sigma N277698), 0.5mg/ml Geneticin G418 (Sigma G7034) and 2mM L-glutaminate (Sigma G7513).Under 37 ℃ in containing 5%CO
2Atmosphere in, this cell is kept under the aseptic condition.
The hB2 fluorescein is measured program
When cell reaches 80 to 90% fraction of coverage, use no enzyme cell dissociation buffer (Lifetechnologies 13151-014) and this cell under 37 ℃ in containing 5%CO
2Atmosphere in together incubation collected this cell in 5 minutes, for mensuration.With separated cell harvesting in warm substratum (composition mentioned above), and be suspended in again and measure in the medium (F12:DMEM (Sigma D6421) that contains 1% foetal calf serum (FBS:Sigma F03921), 10 μ g/ml tetracyclines (Sigma N277698), 0.5mg/ml Geneticin G418 (Sigma G7034) and 2mM L-glutaminate (Sigma G7513)), to obtain 1 * 10
6The viable cell concentrations of individual cell/ml.To in each hole of low volume 384 orifice plates (Greiner 788073) of tissue culture treated, adding 10 these suspension of μ l, and with this plate under 37 ℃ in containing 5%CO
2Atmosphere in incubation 2 hours.The test compounds of a series of concentration of preparation in the phosphate buffered saline (PBS) that contains 0.05%Pluronic-F127 (Sigma P2443) and 2.5%DMSO.The thing of 2 each test concentrations of μ l is added in suitable 384 plate holes, and is back to incubator, last 4 hours again.Steady-Glo reagent (the Steady-Glo luciferase is measured system (PromegaE2520)) with 4 μ l when the incubation period end is added into each hole, and in the Leadseeker plate reader (Amersham Bioscience) that uses the 660nm spectral filter this plate is carried out reading immediately.Draw concentration-response curve, and use 4 parameter S shape matches (it uses the internal data routine analyzer) to generate EC
50Value.In each mensuration, use Racemic isoproterenol as the reference standard.
According to assay method disclosed above embodiment 1 to 20 is tested, and obtains following result:
| The embodiment numbering | EC50-β2(nM) | Ki-M3(nM) |
| 1 | 0.88 | 3.4 |
| 2 | 0.32 | 1.1 |
| 3 | 0.14 | 1.4 |
| 4 | 1.3 | 0.28 |
| 5 | 0.2 | 0.3 |
| 6 | 0.19 | 2.4 |
| 7 | 0.049 | 2.1 |
| 8 | 0.035 | 0.31 |
| 9 | 4.8 | 1.1 |
| 10 | 0.26 | 1.10 |
| 11 | 2.2 | 1.5 |
| 12 | 13.8 | 0.26 |
| 13 | 0.078 | 0.38 |
| 14 | 0.054 | 0.76 |
| 15 | 0.25 | 0.060 |
| 16 | 1.3 | 2.0 |
| 17 | 0.57 | 3.0 |
| 18 | 0.22 | 0.77 |
| 19 | 0.2 | 0.3 |
| 20 | 0.028 | 0.39 |
Claims (27)
1. the compound of a general formula (1):
Wherein A is selected from:
Wherein * represents the tie point of A to the carbon atom that has hydroxyl;
And B is selected from:
1) * *-(CH
2)
2-(CH
2)
m-X
1-(CH
2)
n-* * *, wherein X
1Be O or S, m is 0 to 9 integer, and n is 0 to 9 integer, and n+m between comprise end points 4 to 9 between;
2) randomly use one or two C
1-C
4The C that alkyl replaces
6-C
12Alkylidene group;
3) group of following formula:
X wherein
2Be O or S, r is 2 to 7 integer, and s is 0 to 6 integer, and t is 0 to 6 integer, s+t between comprise end points 1 to 6 between, and r+s+t between comprise end points 3 to 8 between; With
4) group of following formula:
* represents the tie point of B to adjacent NH group, and * * * represents the tie point of B to adjacent phenyl;
With and quaternary ammonium salt or, if suitable, its pharmacy acceptable salt and/or its isomer, tautomer, solvate or isotopic variations.
2. according to the compound of claim 1, wherein B is C
6-C
12Alkylidene group.
3. according to the compound of claim 2, wherein B is selected from (CH
2)
8, (CH
2)
9Or (CH
2)
10
4. according to the compound of claim 1, wherein B is (CH
2)
2-(CH
2)
m-X
1-(CH
2)
n
5. according to the compound of claim 4, X wherein
1Be O.
6. according to the compound of claim 5, wherein B is selected from (CH
2)
6-O-(CH
2)
3, (CH
2)
6-O-(CH
2)
4(CH
2)
7-O-.
7. according to the compound of claim 1, wherein B is the group of following formula:
8. according to the compound of claim 7, X wherein
2Be O.
9. compound according to Claim 8, wherein B is selected from:
10. according to the compound of claim 9, wherein B is selected from:
11. according to the compound of claim 1, wherein B has following formula:
12. according to the compound of claim 11, wherein B has following formula:
13. according to each compound of claim 1 to 12, wherein A has following formula:
14. according to the compound of claim 1, it is selected from:
N-(5-{ (1R)-2-[(10-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } decyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
N-{5-[(1R)-2-(2-[4-(3-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } propoxy-) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-(5-{ (1R)-2-[(7-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenoxy } heptyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-{[6-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) hexyl] amino }-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
N-{5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide;
5-[(1R)-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
5-[(1R)-the 1-{[hydroxyl }-2-(2-[4-(4-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } butoxy) phenyl] ethyl } amino) ethyl] benzene-1, the 3-glycol;
N-{5-[(1R)-2-(2-[3-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } Toluidrin;
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(2-{3-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } ethyl) phenol;
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl] benzene-1, the 3-glycol;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } methane amide;
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(2-{4-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } ethyl) phenol;
N-(5-{ (1R)-2-[(8-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } octyl group) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
N-(5-{ (1R)-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } amyl group) the oxygen base] phenyl } ethyl) amino]-the 1-hydroxyethyl }-the 2-hydroxyphenyl) Toluidrin;
2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(4-{4-[2-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) ethyl] phenoxy group } butyl) phenol;
N-{5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl] ethyl } amino)-the 1-hydroxyethyl]-the 2-hydroxyphenyl } the Toluidrin succinate;
5-[(1R)-2-(2-[4-(2-{3-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-the 4-hydroxyphenyl } oxyethyl group) phenyl]-1, the 1-dimethyl ethyl } amino)-the 1-hydroxyethyl]-oxine-2 (1H)-ketone;
With and quaternary ammonium salt or if suitable, its pharmacy acceptable salt and/or its isomer, tautomer, solvate or isotopic variations.
15. according to the quaternary ammonium salt of the compound of claim 1, described quaternary ammonium salt has following formula:
Wherein X be acetate moiety, fumarate, methanesulfonate, bromide anion, chlorion, sulfate radical, D-and L-tartrate anion or former times the naphthoic acid foundation.
16. according to the quaternary ammonium salt of the compound of claim 1, described quaternary ammonium salt has following formula:
Wherein X is a succinic.
17. a pharmaceutical composition, its comprise significant quantity at least according to claim 1 to 16 each described formula (1) compound or its pharmacy acceptable salt or derivative form.
18. according to the pharmaceutical composition of claim 17, it further comprises one or more pharmaceutically acceptable vehicle and/or additive.
19. according to claim 1 to 16 each described formula (1) compound or its pharmacy acceptable salt, derivative form or composition, it is as medicine.
20. according to each described formula (1) compound or its pharmacy acceptable salt, derivative form or composition in the claim 1 to 16, it is used for the treatment of disease, deficiency disorder and the illness that wherein relates to β 2 and M3 acceptor.
21. according to claim 1 to 16 each described formula (1) compound or its pharmacy acceptable salt, derivative form or composition, it is used for the treatment of disease, deficiency disorder and the illness that is selected from following group:
● any kind, the asthma of the cause of disease or pathology is especially for being selected from the asthma of following a member: atopic asthma, ergotropy asthma, allergic asthma, the asthma of atopy segmental bronchus IgE mediation, bronchial asthma, the special property sent out asthma, true property asthma, the intrinsic asthma that causes by pathologic, physiologic imbalance, the extrinsic asthma that causes by environmental factors, spy's property sent out asthma that the cause of disease is unknown or not clear, ergotropy 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, the infective asthma that protozoon or virus infection cause, non-allergic asthma, initial stage asthma, stridulate baby comprehensive disease and bronchiolitis;
● chronic or acute bronchoconstriction, chronic bronchitis, tracheole obstruction and pulmonary emphysema;
● the obstructive of any kind, the cause of disease or pathology or inflammatory tracheal disease, especially for being selected from the obstructive or the inflammatory tracheal disease of following a member: chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), comprise relevant with COPD or irrelevant chronic bronchitis, pulmonary emphysema or dyspneic COPD, the COPD that is characterized by irreversible carrying out property airway obstruction, adult respiratory distress syndrome (ARDS), the over-reactive deterioration of tracheae after the other medicines treatment and the tracheal disease of being correlated with pulmonary hypertension;
The bronchitis of any kind, the cause of disease or pathology is especially for being selected from the bronchitis of following a member: 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;
● the bronchiectasis of any kind, the cause of disease or pathology, especially for being selected from the bronchiectasis of following a member: cylindrical bronchiectasis, tumour shape bronchiectasis, spindle shape bronchiectasis, bronchiolectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
22. according to the purposes of each described formula (1) compound of claim 1 to 16 or its pharmacy acceptable salt, derivative form or composition, it is used to make the medicine that has β2Ji Dongji activity and M3 antagonistic activity simultaneously.
23. according to the purposes of each described formula (1) compound of claim 1 to 16 or its pharmacy acceptable salt, solvate or composition, it is used to make and is used for the treatment of the medicine of disease, deficiency disorder and illness that is selected from according to the group described in the claim 21.
24. treatment comprises human mammiferous method, it comprise use significant quantity treat described Mammals according to formula (1) compound or its pharmacy acceptable salt, derivative form or the composition of claim 1 to 16 described in each.
25. according to the method for claim 24, wherein said disease, deficiency disorder and illness are selected from according to the group described in the claim 21.
26. according to claim 1 to 16 each compound and the combination of other therapeutical agent, described other therapeutical agent is selected from:
(a) 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activated protein (FLAP) antagonist;
(b) leukotriene antagonist (LTRA), it comprises LTB
4, LTC
4, LTD
4And LTE
4Antagonist;
(c) histamine receptor antagonists, it comprises H1 and H3 antagonist;
(d) be used to the α of congested purposes
1-and α
2-adrenoceptor agonists vasoconstriction parasympathomimetic agent;
(e) PDE inhibitor, for example PDE3, PDE4 and PDE5 inhibitor;
(f) theophylline;
(g) Sodium Cromoglicate;
(h) COX inhibitor, non-selective and selective COX-2-1 or cox 2 inhibitor (NSAID);
(i) prostaglandin receptor antagonist and PGSI;
(j) oral type and inhaled glucocorticoid;
(k) agonist that dissociates (DAGR) of adrenal cortical hormone receptor;
(l) has active monoclonal antibody for endogenous inflammatory entity;
(m) anti-tumor necrosis factor (reagent of anti-TNF-α);
(n) adhesion molecule inhibitor comprises the VLA-4 antagonist;
(o) kassinin kinin-B
1-and B
2-receptor antagonist;
(p) immunosuppressor comprises the inhibitor of IgE approach and ciclosporin;
(q) inhibitor of matrix metalloproteinase (MMP);
(r) tachykinin NK-1
1, NK
2And NK
3Receptor antagonist;
(s) proteinase inhibitor, for example elastase inhibitor;
(t) adenosine A 2a receptor stimulant and A2b antagonist;
(u) urokinase inhibitors;
(the v) compound that Dopamine Receptors is worked, for example D2 agonist;
(w) conditioning agent of NF κ beta pathway, for example IKK inhibitor;
(x) cytokine signaling pathway modulators, for example p38 map kinase, PI3 kinases, jak kinase, syk kinases, EGFR or MK-2;
(y) can classify as the reagent of mucolytic or anti-cough agent;
(z) strengthen sucking the reagent of corticosteroid reaction;
(aa) migrate the effective microbiotic of microorganism and the antiviral agent of respiratory tract for meeting;
(bb) hdac inhibitor;
(cc) CXCR2 antagonist;
(dd) integrin antagonists;
(ee) chemokine;
(ff) epithelium sodium channel (ENaC) blocker or epithelium sodium channel (ENaC) inhibitor;
(gg) P2Y2 agonist and other nucleotide receptor agonist;
(hh) thromboxane inhibitor;
(ii) nicotinic acid reaches
(jj) adhesion factor comprises VLAM, ICAM and ELAM.
27. the compound of following formula:
Wherein:
B as defined in claim 1,
Ra represents hydrogen or suitable hydroxyl protecting group,
Rb and Rc represent any suitable substituents, so that key between N and the Rb and the key between N and the Rc can easily be ruptured obtaining corresponding amine,
B
2Be selected from:
-CH
2-(CH
2)
m-X
1-(CH
2)
N1, X wherein
1Be O or S, m is 0 to 9 integer, n
1Be 1 to 7 integer, and n
1+ m between comprise end points 2 to 7 between;
-randomly use one or two C
1-C
4The C that alkyl replaces
3-C
9Alkylidene group; Or
The group of-following formula:
X wherein
2Be O or S, r
1Be 1 to 6 integer, s is 0 to 6 integer, and t
1Be 1 to 4 integer, and s+t
1Between comprise end points 1 to 4 between, and r
1+ s+t
1Between comprise end points 2 to 5 between.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78451906P | 2006-03-20 | 2006-03-20 | |
| US60/784,519 | 2006-03-20 | ||
| US60/803,745 | 2006-06-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101405260A true CN101405260A (en) | 2009-04-08 |
Family
ID=40538751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800101481A Pending CN101405260A (en) | 2006-03-20 | 2007-03-07 | Amine derivatives |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN101405260A (en) |
| HN (1) | HN2007009671A (en) |
| UA (1) | UA91115C2 (en) |
| ZA (1) | ZA200807679B (en) |
-
2007
- 2007-03-07 CN CNA2007800101481A patent/CN101405260A/en active Pending
- 2007-03-07 UA UAA200810439A patent/UA91115C2/en unknown
- 2007-03-19 HN HN2007009671A patent/HN2007009671A/en unknown
-
2008
- 2008-09-05 ZA ZA200807679A patent/ZA200807679B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HN2007009671A (en) | 2010-10-04 |
| ZA200807679B (en) | 2009-08-26 |
| UA91115C2 (en) | 2010-06-25 |
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