CN101151262B - Substituted piperidines - Google Patents

Substituted piperidines Download PDF

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CN101151262B
CN101151262B CN2006800106014A CN200680010601A CN101151262B CN 101151262 B CN101151262 B CN 101151262B CN 2006800106014 A CN2006800106014 A CN 2006800106014A CN 200680010601 A CN200680010601 A CN 200680010601A CN 101151262 B CN101151262 B CN 101151262B
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alkyl
alkoxy
isosorbide
nitrae
phenyl
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CN101151262A (en
Inventor
P·赫罗尔德
R·马
V·特欣克
C·马蒂
S·施图茨
S·杰拉科维克
F·霍林杰
Z·D·康蒂蒂斯
J·L·卢丁顿
M·奎尔姆巴克
A·斯托贾诺维克
D·贝恩克
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Speedel Experimenta AG
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Speedel Experimenta AG
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Abstract

The present invention relates to SP-P2140 ATE-132- extractive, which is novel substituted piperidines of the general formulae (I) and (II) with the substituent definitions as explained in detail in the description. The compounds are suitable in particular as renin inhibitors and are highly effective.

Description

Substituted piperidines
Invention field
The present invention relates to new substituted piperidines, it is related to its preparation method, and be related to compound as medicine, especially as the purposes of renin inhibitor.
Background of invention
Piperidine derivative as medicine is disclosed in for example, in WO97/09311.However, particularly with the inhibitory action of feritin, in addition it is also necessary to highly effective active component.In this respect, the most concern is the improvement of pharmacokinetics performance.These performances are related to more preferable bioavilability, such as more preferable absorption, metabolic stability, solubility or lipophilicity.
Detailed description of the invention
This invention therefore provides logical formula (I) and the substituted piperidines of (II)：
Figure S2006800106014D00011
Wherein
R is C2-8- alkenyl, C1-8- alkyl, C2-8- alkynyl, C0-8- alkyl-carbonyl-amino-C1-8- alkyl, C3-8- cycloalkyl-C0-8- alkyl, C1-8- alkyl-sulfonyl base-C1-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional O-C1-8- alkylation carboxyl-C0-8- alkyl, optional N and/or N ' mono-, di--or three-C1-8- alkylation urea groups-C1-8- alkyl or Heterocyclylcarbonyl-C0-8- alkyl, each group preferably can be replaced by following groups：1-4 C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy carbonyl group-(N-C1-8- alkyl)-amino, C1-8- alkyl, C1-8- alkyl-carbonyl-(N-C1-8- alkyl)-amino, C1-8- alkyl-sulfanyl, C1-8- alkyl-sulfinyl；Aryl-C0-8- alkoxy, it is optionally by 1 or 2 aryl or C1-8- alkoxy base replaces；Aryl, it is optionally by 1 or 2 aryl or C1-8- alkoxy base replaces；Aryl-amino, cyano group, C3-8- cycloalkyloxy, halogen, heterocyclic radical-C0-8- alkyl, heterocyclic radical-C0-8- alkoxy, heterocyclic radical-C0-8- alkyl-amino, heterocyclic radical-carbonyl, hydroxyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylation carbamoyloxy group, optional N- is mono- or-the C of N, N- bis-1-8- alkylation sulfamoyl, optional N- is arylated or N- heterocyclic radicals-substituted carbamoyl, oxo, trifluoromethoxy or trifluoromethyl；
R1It is aryl or heterocyclic radical；
R2It is acenaphthenyl, cyclohexyl, diazine, furyl, imidazole radicals, naphthyl,
Figure 2006800106014_2
Di azoly,
Figure 2006800106014_3
Oxazolyl, phenyl, pyrazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, oxo pyridine base, tetrazole radical, thienyl, or triazolyl, each group can be replaced by following groups：1-3 C1-8- alkanoyloxy-C1-8- alkyl, C2-8- alkenyloxy group, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy carbonyl group, C1-8- alkoxycarbonyloxy-C1-8- alkyl, C1-8- alkyl, carboxyl-C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base-C1-8- alkoxy, C1-8- alkyl alkylthio base-C1-8- alkoxy -C1-8- alkyl, C1-8- alkyl alkylthio base-C1-8- alkyl, cyano group, cyano group-C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkoxy, C1-6- alkoxy -C0-6- alkyl-C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, halo-C1-8- alkyl, halogen, hydroxyl-C1-8- alkyl, hydroxyl, oxide, trifluoromethoxy or trifluoromethyl, or a C1-8- alkylenedioxy group, and/or by a L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent group；
L1, L2, L3, L4 and L5 are independently each key, C1-8- alkylidene, C2-8- alkenylene or C2-8- alkynylene, C3-8- cyclenes or non-existent；
T1, T2, T3 and T4 are independently each：
(a) key, or be not present, or one in following groups
(b)-CH(OH)-
(c)-CH(OR6)-
(d)-CH(NR5R6)-
(e)-CO-
(f)-CR7R8-
(g)-O- or-NR6-
(h)-S(O)0-2-
(i)-SO2NR6-
(j)-NR6SO2-
(k)-CONR6-
(l)-NR6CO-
(m)-O-CO-
(n)-CO-O-
(o)-O-CO-O-
(p)-O-CO-NR6-
(q)-N(R6)-CO-N(R6)-
(r)-N(R6)-CO-O-
(s) pyrrolidinylidene (pyrrolidinylene), piperidylidene (piperidinylene) or sub- piperazinyl (piperazinylene)
(t)-C(R11)(R12)-,
If key is from hetero atom, wherein it is connected to from (b)-(t) key in the saturation of adjacent group or aromatic carbon atom, and wherein at most there is two (b)-(f) groups, three (g)-(h) groups and-individual (i)-(t) groups；
R3It is hydrogen, hydroxyl, C1-8- alkoxy or C2-8- alkenyloxy group；
R4It is hydrogen, C2-8- alkenyl, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkyl, optional (N-C1-8- alkyl)-C1-8- alkoxy carbonyl group-amino-C1-8- alkoxy, optional (N-C1-8- alkyl)-C1-8- alkylcarbonyl-amino-C1-8- alkoxy, optionally (N- is mono- or-the C of N, N- bis-1-C8- alkyl)-amino-C1-8- alkoxy, benzyl, C3-8- cycloalkyl oxy, C3-8- cycloalkyl oxy-C1-8- alkoxy, heterocyclic radical-C0-8- alkoxy, heterocyclic radical epoxide-C1-8- alkoxy, hydroxyl, hydroxyl-C1-8- alkoxy -C1-8- alkoxy, hydroxyl-C1-8- alkyl, oxo or
R4a- Z1-X1- groups, wherein R4aIt is
(a)H-
(b)C1-8- alkyl-
(c)C2-8- alkenyl-
(d) hydroxyl-C1-8- alkyl-
(e) polyhydroxy-C1-8- alkyl-
(f)C1-8- alkyl-O-C1-8- alkyl-
(g) aryl-
(h) heterocyclic radical-
(i) aralkyl-
(j) Heterocyclylalkyl-
(k) aryloxyalkyl group-
(l) heterocyclyloxy alkyl-
(m)(R5, R6)N-(CH2)1-3-
(n)(R5, R6)N-
(o)C1-8- alkyl-S (O)0-2-
(p) aryl-S (O)0-2-
(q) heterocyclic radical-S (O)0-2-
(r)HO-SO3- or its salt
(S)H2N-C(NH)-NH-
(t)NC-
The carbon atom of key and adjacent group from (n)-(t) is connected, and if key is from hetero atom, the carbon atom is saturation；
Z1
(a) key, or be not present, or one in following groups
(b)-C1-8- alkylidene-
(c)-C2-8- alkenylene-
(d)-O- ,-N (R11)-,-S (O)0-2-
(e)-CO-
(f)-O-CO-
(g)-O-CO-O-
(h)-O-CO-N(R11)-
(i)-N(R11)-CO-O-
(j)-CO-N(R11)-
(k)-N(R11)-CO-
(l)-N(R11)-CO-N(R11)-
(m)-CH(OR9)-
The carbon atom of key and adjacent group from (d) and (f)-(m) is connected, and if key is from hetero atom, the carbon atom is saturation；
X1
(a) key, or be not present, or one in following groups
(b)-O-
(c)-N(R11)-
(d)-S(O)0-2-
(e)-(CH2)1-3-；
Or the R in formula (I)3And R4It is key together；
R5And R6It is hydrogen, C independently of one another1-8- alkyl, C2-8- alkenyl, aryl-C1-8- alkyl or acyl group, or with they combine nitrogen-atoms together be 5- or 6- circle heterocycles, the heterocycle can contain extra nitrogen, oxygen or sulphur atom or-SO- or SO2- group, and extra nitrogen-atoms can be optionally by C1-8- alkyl replaces；
R7And R8It is 3-7- yuan of rings together with the carbon atom that they are combined, the ring can contain one or two-O- or-S- atoms or-SO- or-SO2- group；
R9It is hydrogen, C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, acyl group or aralkyl；
R10It is carboxyalkyl, alkoxycarbonyl alkyl, alkyl or hydrogen；
R11It is hydrogen or C1-8- alkyl；
R12It is hydrogen or C1-8- alkyl；
Q is ethylidene or in the absence of (Formulas I), or ethylidene or methylene (Formula II)；
U is hydrogen, C1-8- alkyl, cyano group, optionally substituted C3-8- cycloalkyl, aryl or heterocyclic radical；
W is oxygen or sulphur；
X is key, oxygen or sulphur, or ＞ CH-R11, ＞ CHOR9,-O-CO-, ＞ CO, ＞ C=NOR10、-O-CHR11- or-O-CHR11-CO-NR9- group, and the saturated carbon atom or R of the key and Z group from oxygen or sulphur atom1Connection；
Z is C1-8- alkylidene, C2-8- alkenylene, hydroxyl-C1-8- alkylidene ,-O- ,-S- ,-O-alk- ,-S-alk- ,-alk-O- ,-alk-S- or-alk-NR9, wherein alk is C1-8- alkylidene；Wherein
If (a) Z is-O- or-S-, X is ＞ CH-R11, and R2Contain L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituents or R4It is non-hydrogen substituent as defined above；
If (b) Z is-O-alk- or-S-alk-, then X is ＞ CH-R11；With
If (c) X is key, then Z is C2-8- alkenylene ,-alk-O- or-alk-S-；
M is 0 or 1；
N is 0 or 1；
With its salt.
Can be the alkyl of straight or branched and the example of alkoxy base is C respectively1-8- alkyl and C1-8- alkoxy base, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, and methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec- butoxy and tert-butoxy, in addition C0- alcoxyl basis representation-O-.C1-8- alkylenedioxy group group is preferably methylenedioxy, ethylene epoxide and the epoxide of propylidene two.Can be the C of straight or branched1-8The example of-alkanoyl groups is acetyl group, propiono and bytyry.Cycloalkyl is the saturated cyclic with 3-12 carbon atom, i.e. cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two rings [2.2.1] heptyl, cyclooctyl, two rings [2.2.2] octyl group and adamantyl.Can be the C of straight or branched1-8- alkylidene group is the ethylidene for example, methylene, propylidene, 2- methyl propylenes, 2- methylbutylenes, 2- methyl but-2-enes, but-2-ene, butyl- 3- alkene, propyl- 2- alkene, four, five and hexa-methylene.Can be the C of straight or branched2-8- alkenylene group is such as ethenylidene and allylidene.Can be the C of straight or branched2-8- alkynylene group is such as ethynylene；Acyl group is alkanoyl groups, preferably C1-8- alkanoyl groups, or aroyl radicals such as benzoyl.Aryl represents the aryl of single or multiple ring, and it can be single or multiple substitution, such as phenyl, substituted phenyl, naphthyl, substituted naphthyl, tetralyl or substituted tetralyl.Substituent example on this aryl or heterocyclyl groups is C1-8- alkyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C2-6- alkenyls, C1-8- alkoxy, C1-8- alkyl sulphinyl, C1-8- alkyl carbonyl epoxide, hydroxyl, halogen, cyano group, carbamoyl, carboxyl and C1-8- alkylenedioxy group, and phenyl, phenoxy group, thiophenyl, phenyl-C1-8- alkyl or phenyl-C1-8- alkoxy, each optionally by following substitution：Halogen, C1-8- alkyl, C1-8- alkoxy or dihydroxy-C1-8- alkyl amino-carbonyl.The further example of substituent on aryl or heterocyclyl groups is oxo, C1-8- alkoxycarbonylphenyl, hydroxyl-C1-8- alkyl phenyl, benzyloxy, pyridylcarbonylamino-C1-8- alkyl, C2-6- alkenyloxy group, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkoxy, two-C1-8- alkyl amino, 2,3- dihydroxy propoxyl group, 2,3- dihydroxy propoxyl group C1-8- alkoxy, 2,3- dimethoxy propoxyl group, methoxybenzyl epoxide, hydroxybenzyloxy, phenethyl epoxide, methylene-dioxy benzyloxy, dioxolanyl-C1-8- alkoxy, cyclopropyl-C1-8- alkyl, cyclopropyl-C1-8- alkoxy, hydroxyl-C1-8- alkoxy, carbamoyl epoxide-C1-8- alkoxy, pyridinylamino formoxyl epoxide-C1-8- alkoxy, benzoyloxy-C1-8- alkoxy, picolyl epoxide, C1-8- alkoxy carbonyl group, C0-6- alkyl-carbonyl-amino, C0-6- alkyl-carbonyl-amino-C1-8- alkyl, C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, (N-C1-8- alkyl)-C0-6- alkyl-carbonyl-amino-C1-8- alkyl, (N-C1-8- alkyl)-C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, C3-8- cycloalkyl amino carbonyl-C1-8- alkyl, C3-8- cycloalkyl amino carbonyl-C1-8- alkoxy, C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkyl, hydroxyl-C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy-carbonyl amino-C1-8- alkyl, C1-8- alkoxycarbonyl amino-C1-8- alkoxy, C1-8- alkyl amino-carbonyl-amino-C1-8- alkyl, C1-8- alkyl amino-carbonyl-amino-C1-8- alkoxy, C1-8- alkyl amino-carbonyl-C1-8- alkyl, C1-8- alkyl amino-carbonyl-C1-8- alkoxy, C1-8- alkyl amino-carbonyl-C1-8- alkoxy -C1-8- alkyl, two-C1-8- alkyl-aminocarbonyl-C1-8- alkyl, two-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, C1-8- alkoxycarbonyloxy-C1-8- alkyl, C1-8- alkyl carbonyl epoxide-C1-8- alkyl, C1-8- alkyl carbonyl epoxide-C1-8- alkoxy, cyano group-C1-8- alkyl, cyano group-C1-8- alkoxy, 2- oxos
Figure 2006800106014_4
Oxazolidinyl-C1-8- alkyl, 2- oxos
Figure 2006800106014_5
Oxazolidinyl-C1-8- alkoxy, C1-8- alkoxy-carbonyl-C1-8- alkyl, C1-8- alkoxy carbonyl group-C1-8- alkoxy, C1-8- alkyl sulfonyl amino-C1-8- alkyl, C1-8- alkyl sulfonyl amino-C1-8- alkoxy, (N-C1-8- alkyl)-C1-8- alkyl sulfonyl amino-C1-8- alkyl, (N-C1-8- alkyl)-C1-8- alkyl sulfonyl amino-C1-8- alkoxy, amino-C1-8- alkyl, amino-C1-8- alkoxy, C1-8- alkyl amino-C1-8- alkyl, C1-8- alkyl amino-C1-8- alkoxy, two-C1-8- alkyl amino-C1-8- alkyl, two-C1-8- alkyl amino-C1-8- alkoxy, C1-8- alkyl sulphonyl-C1-8- alkyl, C1-8- alkyl sulphonyl-C1-8- alkoxy, carboxyl-C1-8- alkyl, carboxyl-C1-8- alkoxy, carboxyl-C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl-carbonyl, acyl group-C1-8- alkoxy -C1-8- alkyl, (N-C1-8- alkyl)-C1-8- alkoxycarbonyl amino, (N- hydroxyls)-C1-8- alkyl amino-carbonyl-C1-8- alkyl, (N- hydroxyls)-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, (N- hydroxyls) amino carbonyl-C1-8- alkyl, (N- hydroxyls) amino carbonyl-C1-8- alkoxy, C1-8- alkoxy amino carbonyl-C1-8- alkyl, C1-8- alkoxy-amino carbonyl-C1-8- alkoxy, (N-C1-8- alkoxy)-C1-8- alkyl amino-carbonyl-C1-8- alkyl, (N-C1-8- alkoxy)-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, (N- acyl groups)-C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl amino, C1-8- alkoxy -C1-8- alkyl-carbamoyl, (N-C1-8- alkyl)-C1-8- alkoxy -C1-8- alkyl-carbamoyl, C1-8- alkoxy -C1-8- alkyl-carbonyl, C1-8- alkoxy -C1-8- alkyl-carbonyl-amino, (N-C1-8- alkyl)-C1-8- alkoxy -C1-8- alkyl-carbonyl-amino, 1-C1-8- alkoxy -C1-8- alkyl imidazole -2- bases, 1-C1-8- alkoxy -C1-8- alkyl tetrazolium -5- bases, 5-C1-8- alkoxy -C1-8- alkyl-tetrazolium -1- bases, 2-C1-8- alkoxy -C1-8- alkyl -4- oxo-imidazol -1- bases, carbamoyl-C1-8- alkyl, carbamoyl-C1-8- alkoxy, C1-8- alkyl-carbamoyl, two-C1-8- alkyl-carbamoyl, C1-8- alkyl sulphonyl, C1-8- alkyl amidine (alkylamidinyl), acetyl group amidino groups (acetamidinyl)-C1-8- alkyl, O- methyl oximido (methyloximyl)-C1-8- alkyl, O, N- dimethylhydroxylaminos-C1-8- alkyl, C3-8- cycloalkyl-C1-8- alkanoyl, aryl-C1-8- alkanoyl, heterocyclic radical-C1-8- alkanoyl；And pyridine radicals, pyridine radicals epoxide, pyridinylthio, pridylamino, pyridine radicals-C1-8- alkyl, pyridine radicals-C1-8- alkoxy, pyrimidine radicals, pyrimidine radicals epoxide, pyrimidine-based sulfur-base, pyrimidinyl-amino, pyrimidine radicals-C1-8- alkyl, pyrimidine radicals-C1-8- alkoxy, thienyl, thienyl-C1-8- alkyl, thienyl-C1-8- alkoxy, furyl, furyl-C1-8- alkyl, furyl-C1-8- alkoxy, each optionally by following substitution：Halogen, C1-8- alkyl, C1-8- alkoxy or dihydroxy-C1-8- alkyl amino-carbonyl.
Term heterocycle basis representation saturation or the first particularly preferred 5 or 6 unit monocycle systems of undersaturated, 4-8, saturation or undersaturated, 7-12 are first, particularly preferred 9 or 10 membered bicyclic systems, and saturation or undersaturated, 7-12 membered tricyclic systems, in all cases, with N, O or S atom is included from 1 to 4 nitrogen and/or 1 or 2 sulphur or oxygen atom, and at least one ring, it is also possible that extra N, O or S atom, which is present in identical ring,.The group can be unsubstituted, or it is substituted one or more times, such as one or twice.It is also possible for there are many identical or different substituents.It is preferred that substituent be (in the case of unsaturated heterocycle base group) alkyl, hydroxyl, alkoxy, cyano group, oxide, nitrogen, halogen, and the substituent as defined in above aryl, or (in the case of saturated heterocyclyl group) alkyl and alkoxy.The example of heterocyclyl groups is pyridine radicals, thienyl, pyrazinyl, triazolyl, imidazole radicals, benzothiazolyl, furyl, pyranose, THP trtrahydropyranyl, azetidinyl, pyrimidine radicals, morpholinyl, quinazolyl, quinolyl, quinoxalinyl, isoquinolyl, tetrahydro-quinolinyl, tetrahydro isoquinolyl, benzo [b] thienyl, isobenzofuran-base, benzimidazolyl, 2- oxos benzo-imidazole radicals
Figure 2006800106014_6
Oxazolyl, thiazolyl, indyl, 2- oxo -1H- quinolyls, 2H- chromene bases, 2- oxo -2H- chromene bases, 1,1a, 2,7b- tetrahydrochysenes-cyclopropane simultaneously [c] chromene base, 2- oxos -1a, 7b- dihydro -1H- cyclopropane simultaneously [c] chromene base, pyrrole radicals, 2- oxo-dihydros benzo [d] [1,3]
Figure 2006800106014_7
Piperazine base, 4- oxo-dihydro imidazole radicals, 5- oxos -4H- [1,2,4] triazine radical, 3- oxo -4H- benzos [Isosorbide-5-Nitrae] thiazinyl, tetrahydroquinoxaline base, 1,1,3- trioxy- dihydro -2H-1 λ6- benzo [Isosorbide-5-Nitrae] thiazinyl, 1- oxo pyridine bases, dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_8
Piperazine base, 2- oxos tetrahydrochysene-benzo [e] [Isosorbide-5-Nitrae] diaza
Figure 2006800106014_9
Base, 2- oxo-dihydros benzo [e] [Isosorbide-5-Nitrae] diaza
Figure 2006800106014_10
Base, 1H- pyrrolopyrroles base (pyrrolizinyl), phthalazinyl, 1- oxo -3H- isobenzofuran-bases, 4- oxo -3H- thienos [2,3-d] pyrimidine radicals, 3- oxo -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_11
Piperazine base, [1,5] naphthyridines base (naphthyridyl), dihydro -2H- benzos [Isosorbide-5-Nitrae] thiazinyl, 1,1- dioxo dihydro -2H- benzos [Isosorbide-5-Nitrae] thiazinyl, 2- oxo -1H- pyridos [2,3-b] [Isosorbide-5-Nitrae]Piperazine base, dihydro -1H- pyridos [2,3-b] [Isosorbide-5-Nitrae]Piperazine base, 1H- pyrrolo-es [2,3-b] pyridine radicals, benzo [1,3] dioxolane base, benzo
Figure 2006800106014_14
Oxazolyl, 2- oxo benzos
Figure 2006800106014_15
Oxazolyl, 2- oxo -1,3- indolinyls, 2,3- indolinyls, 2- oxo-dihydro -1H- quinazolyls, indazolyl or benzofuranyl.The example of substituted heterocyclyl groups is nitrobenzene thiazole base, phenyltetrazole base, phenylDi azoly, Phenylpiperidine base, Phenylpiperazinyl, phenylpyrrole alkyl, thienyl
Figure 2006800106014_17
Di azoly, furylDi azoly, benzylDi azoly or phenyl
Figure 2006800106014_20
Oxazolyl.The example of substituted heterocyclyl groups is dioxolanyl, two
Figure 2006800106014_21
Alkyl, dithiolane base (dithiolanyl), dithian base, pyrrolidinyl, piperidyl, piperazinyl, 4- methyl-piperazinyl groups, morpholinyl, thiomorpholine base, 2- hydroxymethylpyrrol alkyl, 3- hydroxypyrrole alkyl, 3,4- dihydroxy-pyrrolidine alkyl, 4- hydroxy piperidine bases, 4- oxo-piperidine bases, 3,5- dimethylated morpholinyls, 4,4- dioxothiomorpholin bases, 4- oxo thiomorpholine bases, 2,6- dimethylated morpholinyls, THP trtrahydropyranyl, 2- oxoimidazolidinyls, 2- oxosOxazolidinyl, 2- oxo-piperidine bases, 2- oxo-pyrrolidine bases, 2- oxos-[1,3]
Figure 2006800106014_23
Piperazine base, 2- oxazepine cycloheptyl alkyl (oxoazepanyl), 2- oxo tetrahydro-pyrimidine bases etc..
In R1、R4aAnd R9In the case of, aryl, aroyl and heterocyclyl groups can be replaced by following groups in addition：Heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkoxy alkyl or heterocyclic radical, such as piperidinoalkyl, piperidino alkoxy, piperidino alkoxyalkyl, morpholine substituted alkyl, morpholino-alkoxy, morpholino alkoxyalkyl, Piperazino alkyl, Piperazino alkoxy, Piperazino alkoxyalkyl, [1,2,4]-triazol-1-yl alkyl, [1,2,4]-triazol-1-yl alkoxy, [1,2,4]-triazole-4-yl alkyl, [1,2,4]-triazole-4-yl alkoxy, [1,2,4]-
Figure 2006800106014_24
Diazole -5- base alkyl, [1,2,4] -
Figure 2006800106014_25
Diazole -5- base alkoxies, 3- methyl-[1,2,4] -
Figure 2006800106014_26
Diazole -5- base alkyl, 3- methyl-[1,2,4] -
Figure 2006800106014_27
Diazole -5- base alkoxies, 5- methyl-[1,2,4] -
Figure 2006800106014_28
Diazole -3- base alkyl, 5- methyl-[1,2,4] -Diazole -3- base alkoxies, tetrazolium -1- base alkyl, tetrazolium -1- base alkoxies, tetrazolium -2- base alkyl, tetrazolium -2- base alkoxies, tetrazolium -5- base alkyl, tetrazolium -5- base alkoxies, 5- methyl tetrazolium -1- base alkyl, 5- methyl tetrazolium -1- base alkoxies, thiazole-4-yl alkyl, thiazole-4-yl alkoxy
Figure 2006800106014_30
Azoles -4- base alkyl,
Figure 2006800106014_31
Azoles -4- base alkoxies; 2- oxo-pyrrolidine base alkyl; 2- oxo-pyrrolidine base alkoxies; imidazolylalkyl, imidazole radicals alkoxy, 2-methylimidazole base alkyl; 2- methyl-imidazolyl alkoxies; N methyl piperazine subbase alkyl, N methyl piperazine subbase alkoxy, N methyl piperazine subbase-alkoxyalkyl; and alkylaminoalkyl group; alkylaminoalkoxy, alkylaminoalkoxy alkyl, list and polyhydroxy alkyl;-alkoxy;-alkoxyalkyl and-alkyloxy-alkoxy, carbamoylalkyl epoxide, C1-8- alkoxy, amino-C1-8- alkoxy, hydroxyl-C1-8- alkoxy, dioxolanyl, twoAlkyl, dithiolane base, dithian base, pyrrolidinyl, piperidyl, piperazinyl, pyrrole radicals, 4- methyl piperazine bases, morpholinyl, thiomorpholine base, 2- hydroxy-methyl pyrrolidinyls, 3- hydroxypyrrole alkyl, 3,4- dihydroxy-pyrrolidine alkyl, 3- acetylamino methyls-pyrrolidinyl, 3-C1-8- alkoxy -C1-8- alkyl pyrrolidine base, 4- hydroxy piperidine bases, 4- oxo-piperidine bases, 3,5- dimethylated morpholinyls, 4,4- dioxothiomorpholin bases, 4- oxo thiomorpholine bases, 2,6- dimethylated morpholinyls, 2- oxoimidazolidinyls, 2- oxosOxazolidinyl, 2- oxo-pyrrolidine bases, 2- oxos [1,3]
Figure 2006800106014_34
Piperazine base, 2- oxo tetrahydro-pyrimidine bases etc., or by-O-CH2CH(OH)CH2NRx substituent groups, wherein NRx are single or two-C1-8- alkyl amino, piperidino, morpholino, Piperazino or N methyl piperazine subbase group.
By NR5R6The example of the 5- and 6- circle heterocycles of representative is pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholine base, 2- hydroxymethylpyrrol alkyl, 3- hydroxypyrrole alkyl, 3,4- dihydroxy-pyrrolidine alkyl, 4- hydroxy piperidine bases, 4- oxo-piperidine bases, 3,5- dimethylated morpholinyls, 4,4- dioxothiomorpholin bases, 4- oxo thiomorpholine bases, 2,6- dimethylated morpholinyls, 2- oxoimidazolidinyls, 2- oxos
Figure 2006800106014_35
Oxazolidinyl, 2- oxo-pyrrolidine bases, 2- oxos-[1,3]Piperazine base, 2- oxo tetrahydro-pyrimidinyls etc..By CR7R8The example of the 3-7 yuan of rings of representative is cyclopenta, cyclohexyl, suberyl, DOX base, 1,3- bis-Alkyl, 1,3- dithiolane base and 1,3- dithian base.
Term polyhydroxy alkyl represents the C that can be replaced by 2-6 hydroxyl1-7- alkyl, such as glyceryl, arabinose base (arabityl), sorb alcohol radical (sorbityl) etc..
Halogen or halo represent such as fluorine, chlorine or bromine, or by fluorine, chlorine or bromine be independent, multiple or abundant substituted group.
Salt is mainly workable for the pharmacy of formula (I) or formula (II) compound or nontoxic salts.Term " salt workable for pharmacy " include with inorganic or organic acid into salt, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, butanedioic acid, tartaric acid, methanesulfonic acid, p-methyl benzenesulfonic acid etc..
Salt with the compound for forming salt groups particularly acid-addition salts, with alkali into salt, or it is many formation salt groups in the presence of, be also sometimes salt-mixture or inner salt.
This salt can be formed for example by the formula (I) with acidic-group such as carboxyl or sulfo group or formula (II) compound, and it is such as its salt with suitable alkali, such as Ia derived from the periodic table of elements, Ib, the nontoxic metal salts of the metal of IIa and IIb races, such as alkali metal salt, particularly lithium, sodium or sylvite, alkali salt, such as magnesium or calcium salt, and zinc salt and ammonium salt, including those salt formed with organic amine, the list of such as optional hydroxyl-substituted, two-or trialkylamine, particularly single two-or three (low alkyl group) amine, or the salt with quaternary ammonium base formation, for example methyl-, ethyl-, diethyl-or triethylamine, it is single, two or three (2- hydroxyls (low alkyl group)) amine, for example ethanol-, diethanol-or triethanolamine, trihydroxymethylaminomethane or 2- hydroxy-tert-butylamines, N, N- bis- (low alkyl group)-N- (hydroxyl (low alkyl group)) amine, such as N,-N- the dimethyl-N -s of N- bis- (2- ethoxys) amine, or N- methyl-D-glucosamines, or quaternary ammonium hydroxide is for example hydroxylated tetrabutylammonium.Compound of formula I with base such as amino can form acid-addition salts, the salt for example formed with suitable following acid：Inorganic acid, such as halogen acids such as hydrochloric acid, hydrobromic acid, there is the sulfuric acid of one or two proton exchange, there is the phosphoric acid of one or more proton exchanges, such as orthophosphoric acid or metaphosphoric acid, there is the pyrophosphoric acid of one or more proton exchanges, or organic carboxyl acid, sulfonic acid or the sulfamic acid of phosphonic acids or N- substitution, such as acetic acid, propionic acid, hydroxyacetic acid, butanedioic acid, maleic acid, hydroxymaleic acid, citraconic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucosaccharic acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-ASA, 2- phenoxy benzoic acids, Aspirin, embelin (embonic acid), nicotinic acid, isonicotinic acid, and amino acid, a-amino acid as escribed above, and methanesulfonic acid, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, ethane -1, 2- disulfonic acid, benzene sulfonic acid, 4- toluene sulfonic acides, naphthalene-2-sulfonic acid, 2- or 3-phoshoglyceric acid, Robison ester, N- cyclohexylsulfamics (formation cyclamate) or other acidic organic compounds such as ascorbic acid.Formula (I) or formula (II) compound with acid and basic group can also form inner salt.
The salt obtained can be changed into other salt with per se known manner, for example, separate out with another sour suitable metal salt such as sodium, barium or silver salt processing in the undissolvable suitable solvent of inorganic salts and in thus being balanced from reaction and be changed into acid-addition salts, and be changed into basic salt by discharging re-forming for free acid and salt.
The compound of formula (I) and (II), includes their salt, can also be obtained in the form of hydrate, or include solvents used for crystallization.
For separating and purifying, the inappropriate salt of pharmacy can also be used.
Formula (I) and the compound of (II) also include wherein one or more atoms by its stabilization, those compounds that non radioactive isotope is substituted；For example hydrogen atom is substituted with deuterium.
Formula (I) or the compound of (II) can be prepared by similar to the preparation method disclosed in document.The method for optimizing for preparing optically pure formula (I) or (II) compound is comprised the steps of：Being built by following any of which needs the structure of multiple substituted piperidine scaffolds and its precursor：(i) chiral azepine-Diels-Alder reaction of imine derivative and diene is (referring to Chemistry-AEuropean Journal 2000,6 (13), 2435-2448 and references cited therein) [reaction scheme 1], or (ii) chiral amino acid derivative is condensed with Meldrum ' s acid, then cyclisation is (referring to Journal of Organic Chemistry 2004,69 (1), 130-141 and references cited therein) [reaction scheme 2].For former approach, the presence of the amine (such as triethylamine) of non-stoichiometry quantity is the deciding factor for obtaining high-optical-purity product.This amine component can both be present in the commercially available diene (for example originating from Aldrich Danishefsky ' s diene), can also be exogenous add.On the detailed content of the various change of specific preparation method, it can be obtained from embodiment.
Figure S2006800106014D00121
Scheme 1
Figure S2006800106014D00131
Scheme 2
Formula (I) or formula (II) compound have at least three asymmetric carbon atoms, and therefore can be optically pure diastereomer, non-enantiomer mixture, diastereomeric raceme, the form of the mixture of diastereomeric raceme or as mesomeric compound.The present invention includes all these forms.The mixture of non-enantiomer mixture, diastereomeric raceme or diastereomer raceme can be accustomed to the use of method and for example separated with column chromatography, thin-layer chromatography, HPLC etc..
Formula (I) or (II) compound can also be prepared in optically pure form.Being separated into enantiomer can be realized with method known per se, both can preferably with optically active acid such as (+)-or (-)-mandelic acid forming salt initial stage synthesis phase, diastereoisomeric salt separated by fractional crystallization, preferably diastereomer product can also be separated in the relatively late stage performed the derivatization with chiral auxiliary construction unit such as (+)-or (-)-camphor alkane acyl chlorides, with chromatogram and/or crystallization, then key is broken, chiral auxiliary is obtained.Pure diastereoisomeric salt and derivative can be analyzed with common spectrophotometric method, with the absolute configuration of the piperidines present in determination, and the X-ray spectrum on single-crystal structural is the method being particularly suitable.
In formula (I) or (II) compound, the configuration in single chiral center, which might have, selectively to be inverted.For example, the configuration of asymmetric carbon atom with nucleophilic displacement of fluorine base such as amino or hydroxyl, if appropriate, suitable nucleofugal leaving groups can be converted into the nucleophilic displacement of fluorine base of bonding and with introducing after the reagent reacting of original substituent, overturn by second nucleophilic substitution, or the configuration at the carbon atom with hydroxyl, can be according to similar to the method in european patent application EP-A-0 236 734, by aoxidizing and also overturning originally.It is also advantageous that carrying out reactive functionalized modification and its subsequent displacement of hydroxyl by the hydroxyl with configuration inversion.
Formula (I) or the compound of (II) also include those compounds (for example substituting hydrogen with deuterium) that wherein one or more atoms are stable by it, that non radioactive isotope is substituted.
The prodrug derivatives for the compound being described herein can be used in vivo, by chemistry or its derivative of physiology course release original chemical.Pro-drug can be changed into original chemical, for example, when reaching physiological ph, or pass through enzymatic conversion.Prodrug derivatives may, for example, be the ester of free appropriate carboxylic acid, S- the and O- acyl derivatives of mercaptan, alcohol or phenol, and acyl group is as defined herein.It is preferred that ester derivant workable for the pharmacy of original carboxylic acid can be converted into by solvolysis in physiological medium, such as lower alkyl esters, cycloalkyl ester, low-grade alkenyl ester, benzyl ester, for example rudimentary ω of single or dibasic lower alkyl esters-(amino, list or dialkyl amido, carboxyl, lower alkoxycarbonyl)-Arrcostab or for example rudimentary α-(alkanoyloxy, alkoxy carbonyl group or dialkyl amino carbonyl)-Arrcostab；It therefore, it can use valeryl epoxide-methyl esters and similar ester in a usual manner.
Due to the close relation between free cpds, prodrug derivatives and salt compound, some of present invention compound also includes its prodrug derivatives and salt form, and wherein these are possible and suitable.
Compound group mentioned below is not qualified as closure, and thinks that these compound groups of part can be changed mutually, or is omitted with the definition being given above, or with reasonable manner, for example, substitute usual definition by more specifically defining.According to conventional chemical principle, definition is effective, the conventional valence of such as atom.
It is preferred that the compounds of this invention be formula (IA) or those compounds of (IIA)
Figure S2006800106014D00141
Wherein R, R1、R2、R3、R4, each above formula (I) and (II) compound are defined freely by Q, W, X and Z, n and m.
Further preferred formula (I) or the compound of (II) or preferred formula (IA) or the compound of (IIA) are following compounds, wherein
R is C2-8- alkenyl, C1-8- alkyl, C2-8- alkynyl, C0-8- alkyl-carbonyl-amino-C1-8- alkyl, C3-8- cycloalkyl-C0-8- alkyl, C1-8- alkyl-sulfonyl base-C1-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional O-C1-8- alkylation carboxyl-C0-8- alkyl, optional N and/or N ' mono-, di--or three-C1-8- alkylation urea groups-C0-8- alkyl or Heterocyclylcarbonyl-C0-8- alkyl, each group can be preferably by following substitution：1-4 C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy carbonyl group-(N-C1-8- alkyl)-amino, C1-8- alkyl, C1-8- alkyl-carbonyl-(N-C1-8- alkyl)-amino, C1-8- alkyl-sulfanyl, C1-8- alkyl-sulfinyl, optionally by 1 or 2 aryl or C1-8Aryl-the C of-alkoxy base substitution0-8- alkoxy, optionally by 1 or 2 aryl or C1-8The aryl of-alkoxy base substitution, aryl-amino, cyano group, C3-8- cycloalkyloxy, halogen, heterocyclic radical-C0-8- alkyl, heterocyclic radical-C0-8- alkoxy, heterocyclic radical-C0-8- alkyl-amino, heterocyclic radical-carbonyl, hydroxyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylation carbamoyloxy group, optional N- is mono- or-the C of N, N- bis-1-8- alkylation sulfamoyl, optional N-C1-8- alkylation, N- is arylated or N- heterocyclic radicals-substituted carbamoyl, oxo, trifluoromethoxy or trifluoromethyl；
R1It is aryl or heterocyclic radical；
R2It is phenyl, cyclohexyl, tetrazole radical, naphthyl or acenaphthenyl, each group can be unsubstituted or substituted, preferably be replaced by following groups：1-3 C1-8Epoxide-C1-8- alkyl, C2-8- alkenyloxy group, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy carbonyl group, C1-8- alkoxycarbonyloxy-C1-8- alkyl, C1-8- alkyl, carboxyl-C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base-C1-8- alkoxy, C1-8- alkyl alkylthio base-C1-8- alkoxy -C1-8- alkyl, C1-8- alkyl alkylthio base-C1-8- alkyl, cyano group, cyano group-C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkoxy, C1-6- alkoxy -C0-6- alkyl-C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, halo-C1-8- alkyl, halogen, hydroxyl-C1-8- alkyl, hydroxyl, oxide, trifluoromethoxy or trifluoromethyl, or C1-8- alkylenedioxy group, and/or by L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent groups；
L1, L2, L3, L4 and L5 are independently each key, C1-8- alkylidene, C2-8- alkenylene or C2-8- alkynylene, C3-8- cyclenes or non-existent；
T1, T2, T3 and T4 are independently each：
(a) key, or be not present, or one in following groups
(b)-CH(OH)-
(c)-CH(OR6)-
(d)-CH(NR5R6)-
(e)-CO-
(f)-CR7R8-
(g)-O- or-NR6-
(h)-S(O)0-2-
(I)-SO2NR6-
(j)-NR6SO2-
(k)-CONR6-
(l)-NR6CO-
(m)-O-CO-
(n)-CO-O-
(o)-O-CO-O-
(p)-O-CO-NR6-
(q)-N(R6)-CO-N(R6)-
(r)-N(R6)-CO-O-
(s) pyrrolidinylidene, piperidylidene or sub- piperazinyl
(t)-C(R11)(R12)-,
If key is from hetero atom, wherein it is connected to from (b)-(t) key in the saturation of adjacent group or aromatic carbon atom, and wherein at most there is two (b)-(f) groups, three (g)-(h) groups and (i)-(t) group；
R3It is hydrogen, hydroxyl, C1-8- alkoxy or C2-8- alkenyloxy group；
R4It is hydrogen, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkyl, C1-8- alkyl, optional (N-C1-8- alkyl)-C1-8- alkoxy carbonyl group-amino-C1-8- alkoxy, optional (N-C1-8- alkyl)-C1-8- alkylcarbonyl-amino-C1-8- alkoxy, optionally (N- is mono- or-the C of N, N- bis-1-C8- alkyl)-amino-C1-8- alkoxy, C3-8- cycloalkyl oxy, C3-8- cycloalkyl oxy-C1-8- alkoxy, heterocyclic radical-C0-8- alkoxy, heterocyclic radical epoxide-C1-8- alkoxy, hydroxyl, oxo or hydroxyl-C1-8- alkoxy -C1-8- alkoxy；
R5And R6It is hydrogen, C independently of one another1-8- alkyl or acyl group, or with they combine nitrogen-atoms together be 5- or 6- circle heterocycles, the heterocycle can contain extra nitrogen, oxygen or sulphur atom；
R7And R8It is 3-7- yuan of rings together with the carbon atom that they are combined, the ring can contain one or two-O- or-S- atoms；
R9It is hydrogen, C1-8- alkyl, acyl group or aralkyl；
U is hydrogen, C1-8- alkyl, C3-8- cycloalkyl, cyano group, aryl or heterocyclic radical；
Q is ethylidene or in the absence of (formula (I)), and is ethylidene or methylene (formula (II))；
X is key, oxygen, sulphur or ＞ CHR11, ＞ CHOR9,-O-CO-, ＞ CO or-O-CH-R11-CO-NR9- group；
If R3It is hydrogen, W is oxygen or sulphur；
Z is C1-8- alkylidene or-alk-O-；
Wherein, if X is key, Z is-alk-O-；
N is 0 or 1；
M is 0 or 1；
With salt workable for its pharmacy.
The compound of the formula (I), (IA), (II) and (IIA) of (m is 0), and the non-existent formulas of wherein Q (I) and those compounds of (IA) are not present in further preferred wherein W.
It is preferred that R group be C1-8- alkyl, C0-8- alkyl-carbonyl-amino-C1-8- alkyl, C1-8- alkyl-sulfonyl base-C1-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional N and/or N ' mono-, di--or three C1-8- alkylation urea groups-C0-8- alkyl, heterocyclic radical-C0-8- alkyl, or Heterocyclylcarbonyl-C0-8- alkyl, each group can be substituted, and preferably be replaced by following groups：1-4 C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy carbonyl group-(N-C1-8- alkyl)-amino, C1-8- alkyl, C1-8- alkyl-carbonyl-(N-C1-8- alkyl)-amino, C1-8- alkyl-sulfanyl, optionally by 1 or 2 aryl or C1-8Aryl-the C of-alkoxy base substitution0-8- alkoxy, optionally by 1 or 2 aryl or C1-8The aryl of-alkoxy base substitution, cyano group, halogen, heterocyclic radical, heterocyclic radical-C0-8- alkyl-amino, heterocyclic radical-carbonyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylation carbamoyloxy group, hydroxyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine, trifluoromethoxy and trifluoromethyl.
It is preferred that R1Group is phenyl and the phenyl for being selected from following substituent group by 1-3：C1-8- alkyl, C1-8- alkoxy, halogen, hydroxyl, hydroxyl-C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkyl sulphinyl, carbamoyl, cyano group, trifluoromethyl, trifluoromethoxy, carboxyl, C1-8- alkoxy carbonyl group, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C0-6- alkyl-carbonyl-amino, C0-6- alkyl-carbonyl-amino-C1-8- alkyl, C0-6- alkyl-carbonylamino-C1-8- alkoxy, (N-C1-8- alkyl)-C0-6- alkyl-carbonyl-amino-C1-8- alkyl, (N-C1-8- alkyl)-C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, C3-8- cycloalkyl amino carbonyl-C1-8- alkyl, C3-8- cycloalkyl-carbonyl amino-C1-8- alkoxy, C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkyl, hydroxyl-C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxycarbonyl amino-C1-8- alkyl, C1-8- alkoxycarbonyl amino-C1-8- alkoxy, C1-8- alkyl amino-carbonyl-amino-C1-8- alkyl, C1-8- alkyl amino-carbonyl-amino-C1-8- alkoxy, C1-8- alkyl amino-carbonyl-C1-8- alkyl, C1-8- alkyl amino-carbonyl-C1-8- alkoxy, C1-8- alkylamino-carbonyl-C1-8- alkoxy -C1-8- alkyl, two-C1-8- alkyl amino-carbonyl-C1-8- alkyl, two-C1-8- alkylamino-carbonyl-C1-8- alkoxy, C1-8- alkyl carbonyl epoxide-C1-8- alkyl, C1-8- alkyl carbonyl epoxide-C1-8- alkoxy, cyano group-C1-8- alkyl, cyano group-C1-8- alkoxy, 2- oxos
Figure 2006800106014_38
Oxazolidinyl-C1-8- alkyl, 2- oxos
Figure 2006800106014_39
Oxazolidinyl-C1-8- alkoxy, C1-8- alkoxy carbonyl group-C1-8- alkyl, C1-8- alkoxy carbonyl group-C1-8- alkoxy, C1-8- alkyl sulfonyl amino-C1-8- alkyl, C1-8- alkyl sulfonyl amino-C1-8- alkoxy, (N-C1-8- alkyl)-C1-8- alkyl sulfonyl amino-C18- alkyl, (N-C1-8- alkyl)-C1-8- alkyl sulfonyl amino-C1-8- alkoxy, amino-C1-8- alkyl, amino-C1-8- alkoxy, C1-8- alkyl amino-C1-8- alkyl, C1-8- alkyl amino-C1-8- alkoxy, two-C1-8- alkyl amino-C1-8- alkyl, two-C1-8- alkyl amino-C1-8- alkoxy, C1-8- alkyl sulphonyl-C1-8- alkyl, C1-8- alkyl sulphonyl-C1-8- alkoxy, carboxyl-C1-8- alkyl, carboxyl-C1-8- alkoxy, carboxyl-C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl-carbonyl, acyl group-C1-8- alkoxy -C1-8- alkyl, (N-C1-8- alkyl)-C1-8- alkoxycarbonyl amino, (N- hydroxyls)-C1-8- alkyl amino-carbonyl-C1-8- alkyl, (N- hydroxyls)-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, (N- hydroxyls) amino carbonyl-C1-8- alkyl, (N- hydroxyls) amino carbonyl-C1-8- alkoxy, C1-8- alkoxy amino carbonyl-C1-8- alkyl, C1-8- alkoxy amino-carbonyl-C1-8- alkoxy, (N-C1-8- alkoxy)-C1-8- alkyl amino-carbonyl-C1-8- alkyl, (N-C1-8- alkoxy)-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, (N- acyl groups)-C1-8- alkoxy -C1-8- alkyl amino, C1-8- alkoxy -C1-8- alkyl-carbamoyl, (N-C1-8- alkyl)-C1-8- alkoxy -C1-8- alkyl-carbamoyl, C1-8- alkoxy -C1-8- alkyl-carbonyl, C1-8- alkoxy -C1-8- alkyl-carbonyl-amino, (N-C1-8- alkyl)-C1-8- alkoxy -C1-8- alkyl-carbonyl-amino, 1-C1-8- alkoxy -C1-8- alkyl imidazole -2- bases, 1-C1-8- alkoxy -C1-8- alkyl tetrazolium -5- bases, 5-C1-8- alkoxy -C1-8- alkyl-tetrazolium -1- bases, 2-C1-8- alkoxy -C1-8- alkyl -4- oxo-imidazole -1- bases, carbamoyl-C1-8- alkyl, carbamoyl-C1-8- alkoxy, C1-8- alkyl-carbamoyl, two-C1-8- alkyl-carbamoyl, C1-8- alkyl sulphonyl, piperidinoalkyl, piperidino alkoxy, piperidino alkoxyalkyl, morpholine substituted alkyl; morpholino alkoxy, morpholino alkoxy-alkyl, Piperazino alkyl, Piperazino alkoxy; Piperazino alkoxyalkyl, [1,2,4]-triazol-1-yl alkyl; [1,2,4]-triazol-1-yl alkoxy, [1; 2,4]-triazole-4-yl alkyl, [1,2; 4]-triazole-4-yl alkoxy, [1,2,4]-Diazole -5- base alkyl, [1,2,4] -
Figure 2006800106014_41
Diazole -5- base alkoxies, 3- methyl-[1,2,4] -Diazole -5- base alkyl, 3- methyl-[1,2,4] -
Figure 2006800106014_43
Diazole -5- base alkoxies, 5- methyl-[1,2,4] -
Figure 2006800106014_44
Diazole -3- base alkyl, 5- methyl-[1,2,4] -Diazole -3- base alkoxies, tetrazolium -1- base alkyl, tetrazolium -1- base alkoxies, tetrazolium -2- base alkyl, tetrazolium -2- base alkoxies, tetrazolium -5- base alkyl, tetrazolium -5- base alkoxies, 5- methyl tetrazolium -1- base alkyl, 5- methyl tetrazolium -1- base alkoxies, thiazole-4-yl alkyl, thiazole-4-yl alkoxy
Figure 2006800106014_46
Azoles -4- base alkyl,
Figure 2006800106014_47
Azoles -4- base alkoxies, 2- oxo-pyrrolidine base alkyl, 2- oxo-pyrrolidine base alkoxies, imidazolylalkyl, imidazole radicals alkoxy, 2-methylimidazole base alkyl, 2-methylimidazole base alkoxy, N- methyl-piperazino alkyl, N methyl piperazine subbase alkoxy, N methyl piperazine subbase alkoxyalkyl, pyrrolidinyl, piperidyl, piperazinyl, pyrrole radicals, 4- methyl piperazine bases, morpholinyl, thiomorpholine base, 2- hydroxy-methyl pyrrolidinyls, 3- hydroxypyrrole alkyl, 3,4- dihydroxy-pyrrolidine alkyl, 3- acetylamino methyls-pyrrolidinyl, 3-C1-8- alkoxy -C1-8- alkyl pyrrolidine base, 4- hydroxy piperidine bases, 4- oxo-piperidine bases, 3,5- dimethylated morpholinyls, 4,4- dioxothiomorpholin bases, 4- oxo thiomorpholine bases, 2,6- dimethylated morpholinyls, 2- oxoimidazolidinyls, 2- oxos
Figure 2006800106014_48
Oxazolidinyl, 2- oxo-pyrrolidine bases, 2- oxos [1,3]
Figure 2006800106014_49
Piperazine base and 2- oxo tetrahydro pyrimidine radicals.
Also, it is preferred that R1Group is benzofuranyl, benzimidazolyl, 4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_50
Piperazine base, benzo
Figure 2006800106014_51
Oxazolyl, 2- and 5- benzos [b] thienyl, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_52
Piperazine base, 1,3- indolinyl, 2,3- indolinyls, indazolyl, indyl, 1H- quinolyls, 2H- chromene bases, 1,1a, 2,7b- tetrahydrochysenes-cyclopropane simultaneously [c] chromene base, 1a, 7b- dihydro -1H- cyclopropane simultaneously [c] chromene base, 6- and 7- isoquinolyls, pyridine radicals, pyrimidine radicals, 6- and 7- quinazolyls, 6- and 7- quinolyls, 6- quinoxalinyls, 6- and 7- tetrahydro isoquinolyls, 6- and 7- tetrahydric quinoline groups, it is each selected from following substituent group by 1-3：Hydroxyl, oxo, oxide, halogen, cyano group, trifluoromethyl, trifluoromethoxy, carbamoyl, carboxyl, C1-8- alkyl, C1-8- alkoxy, hydroxyl-C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, two-C1-8- alkyl amino, 2,3- dihydroxy propoxyl group, 2,3- dihydroxy-propoxyl group C1-8- alkoxy, 2,3- dimethoxy propoxyl group, methoxybenzyl epoxide, hydroxybenzyloxy, phenethyl epoxide, methylene-dioxy benzyloxy, dioxolanyl-C1-8- alkoxy, cyclopropyl-C1-8- alkoxy, hydroxyl-C1-8- alkoxy, pyridinylamino formoxyl epoxide-C1-8- alkoxy, 3- morpholino -2- hydroxy propyloxy groups, benzyloxy-C1-8- alkoxy, picolyl epoxide, C1-8- alkoxy carbonyl group, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C0-6- alkyl-carbonyl-amino, C0-6- alkyl-carbonyl-amino-C1-8- alkyl, C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, (N-C1-8- alkyl)-C0-6- alkyl-carbonyl-amino-C1-8- alkyl, (N-C1-8- alkyl)-C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, C3-8- cycloalkyl amino carbonyl-C1-8- alkyl, C3-8- cycloalkyl amino carbonyl-C1-8- alkoxy, C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkyl, hydroxyl-C1-8- alkoxy -C1-8- alkyl, hydroxyl-C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxycarbonyl amino-C1-8- alkyl, C1-8- alkoxycarbonyl amino-C1-8- alkoxy, C1-8- alkyl-aminocarbonylamino-C1-8- alkyl, C1-8- alkyl amino-carbonyl-amino-C1-8- alkoxy, C1-8- alkylamino-carbonyl-C1-8- alkyl, C1-8- alkyl amino-carbonyl-C1-8- alkoxy, C1-8- alkyl amino-carbonyl-C1-8- alkoxy -C1-8- alkyl, two-C1-8- alkyl amino-carbonyl-C1-8- alkyl, two-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, C1-8- alkyl carbonyl epoxide-C1-8- alkyl, C1-8- alkyl carbonyl epoxide-C1-8- alkoxy, cyano group-C1-8- alkyl, cyano group-C1-8- alkoxy, 2- oxos
Figure 2006800106014_53
Oxazolidinyl-C1-8- alkyl, 2- oxos
Figure 2006800106014_54
Oxazolidinyl-C1-8- alkoxy, C1-8- alkoxy carbonyl group-C1-8- alkyl, C1-8- alkoxy carbonyl group-C1-8- alkoxy, C1-8- alkyl sulfonyl amino-C1-8- alkyl, C1-8- alkylsulfonyl-amino-C1-8- alkoxy, (N-C1-8- alkyl)-C1-8- alkyl sulfonyl amino-C1-8- alkyl, (N-C1-8- alkyl)-C1-8- alkyl-sulfonylamino-C1-8- alkoxy, amino-C1-8- alkyl, amino-C1-8- alkoxy, C1-8- alkyl amino-C1-8- alkyl, C1-8- alkyl amino-C1-8- alkoxy, two-C1-8- alkyl amino-C1-8- alkyl, two-C1-8- alkyl amino-C1-8- alkoxy, C1-8- alkyl sulphonyl-C1-8- alkyl, C1-8- alkyl sulphonyl-C1-8- alkoxy, carboxyl-C1-8- alkyl, carboxyl-C1-8- alkoxy, carboxyl-C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl-carbonyl, acyl group-C1-8- alkoxy -C1-8- alkyl, (N-C1-8- alkyl)-C1-8- alkoxycarbonyl amino, (N- hydroxyls)-C1-8- alkyl amino-carbonyl-C1-8- alkyl, (N- hydroxyls)-C1-8- alkyl amino-carbonyl-C1-8- alkoxy, (N- hydroxyls)-amino carbonyl-C1-8- alkyl, (N- hydroxyls) amino-carbonyl-C1-8- alkoxy, C1-8- alcoxyl amino-carbonyl-C1-8- alkyl, C1-8- alcoxyl amino-carbonyl-C1-8- alkoxy, (N-C1-8- alkoxy)-C1-8- alkyl amino-carbonyl-C1-8- alkyl, (N-C1-8- alkoxy)-C1-8- alkylamino-carbonyl-C1-8- alkoxy, (N- acyl groups)-C1-8- alkoxy -C1-8- alkyl amino, C1-8- alkoxy -C1-8- alkyl-carbamoyl, (N-C1-8- alkyl)-C1-8- alkoxy -C1-8- alkyl-carbamoyl, C1-8- alkoxy -C1-8- alkyl-carbonyl, C1-8- alkoxy -C1-8- alkyl-carbonyl-amino, (N-C1-8- alkyl)-C1-8- alkoxy -C1-8- alkyl-carbonyl-amino, 1-C1-8- alkoxy -C1-8- alkyl imidazole -2- bases, 1-C1-8- alkoxy -C1-8- alkyl tetrazolium -5- bases, 5-C1-8- alkoxy -C1-8- alkyl tetrazolium -1- bases, 2-C1-8- alkoxy -C1-8- alkyl -4- oxo-imidazole -1- bases, carbamoyl-C1-8- alkyl, carbamoyl-C1-8- alkoxy, C1-8- alkyl-carbamoyl, two-C1-8- alkyl-carbamoyl, C1-8- alkyl sulphonyl, piperidinoalkyl, piperidino alkoxy, piperidino alkoxyalkyl, morpholine substituted alkyl; morpholino alkoxy, morpholino alkoxyalkyl, Piperazino-alkyl, Piperazino alkoxy; Piperazino alkoxyalkyl, [1,2,4]-triazol-1-yl alkyl; [1,2,4]-triazol-1-yl alkoxy, [1; 2,4]-triazole-4-yl alkyl, [1,2; 4]-triazole-4-yl alkoxy, [1,2,4]-Diazole -5- base alkyl, [1,2,4] -
Figure 2006800106014_56
Diazole -5- base alkoxies, 3- methyl-[1,2,4] -
Figure 2006800106014_57
Diazole -5- base alkyl, 3- methyl-[1,2,4] -Diazole -5- base alkoxies, 5- methyl-[1,2,4] -
Figure 2006800106014_59
Diazole -3- base alkyl, 5- methyl-[1,2,4] -
Figure 2006800106014_60
Diazole -3- base alkoxies, tetrazolium -1- base alkyl, tetrazolium -1- base alkoxies, tetrazolium -2- base alkyl, tetrazolium -2- base alkoxies, tetrazolium -5- base alkyl, tetrazolium -5- base alkoxies, 5- methyl-tetrazole -1- base alkyl, 5- methyl tetrazolium -1- base alkoxies, thiazole-4-yl alkyl, thiazole-4-yl alkoxy
Figure 2006800106014_61
Azoles -4- base alkyl,
Figure 2006800106014_62
Azoles -4- base alkoxies, 2- oxo-pyrrolidine base alkyl, 2- oxo-pyrrolidine base alkoxies, imidazolylalkyl, imidazole radicals alkoxy, 2-methylimidazole base alkyl, 2-methylimidazole base alkoxy, N methyl piperazine subbase alkyl, N methyl piperazine subbase alkoxy, N methyl piperazine subbase alkoxyalkyl, pyrrolidinyl, piperidyl, piperazinyl, pyrrole radicals, 4- methyl piperazine bases, morpholinyl, thiomorpholine base, 2- hydroxymethylpyrrol alkyl, 3- hydroxypyrrole alkyl, 3,4- dihydroxy-pyrrolidine alkyl, 3- acetamidomethyl pyrrolidinyls, 3-C1-8- alkoxy -C1-8- alkyl pyrrolidine base, 4- hydroxy piperidine bases, 4- oxo-piperidine bases, 3,5- dimethylated morpholinyls, 4,4- dioxothiomorpholin bases, 4- oxo thiomorpholine bases, 2,6- dimethylated morpholinyls, 2- oxoimidazolidinyls, 2- oxos
Figure 2006800106014_63
Oxazolidinyl, 2- oxo-pyrrolidine bases, 2- oxos-[1,3]
Figure 2006800106014_64
Piperazine base and 2- oxo tetrahydro-pyrimidine bases.
Particularly preferred R1The example of group is phenyl, pyridine radicals, 3-C1-8- alkyl-indol base, benzofuranyl, 4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_65
Piperazine -3- ketone groups, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_66
Piperazine base, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] thiazinyls, 3,3- bis--C1-8- alkyl -1,3- Indolin-2-one base, 3,3- bis--C1-8- alkyl -1,3- indolinyl, indazolyl, indyl, 1H- quinolyls, 2H- chromene bases, 1,1a, 2,7b- tetrahydrochysenes-cyclopropane simultaneously [c] chromene base, 1a, 7b- dihydro -1H- cyclopropane simultaneously [c] chromene base, with spiral shell [cyclopropane -1,3 '] -2,3- dihydro -1H- indyls, it can be substituted as described above, especially be replaced by least one selected from following substituent：Halogen, oxide, oxo, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxycarbonyl amino-C1-8- alkoxy, C1-8- alkoxycarbonyl amino-C1-8- alkyl, C1-8- alkyl, C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, C0-6- alkyl-carbonyl-amino-C1-8- alkyl, N- acetyl group-C1-8- alkoxy -C1-8- alkyl amino, C1-8- alkanoyl acylamino- C1-8- alkyl, N-C1-8- alkyl-C1-8- alkanoyl acylamino- C1-8- alkyl, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, triazol-1-yl-C1-8- alkyl, tetrazolium -1- bases-C1-8- alkyl, tetrazolium -2- bases-C1-8- alkyl, tetrazolium -5- bases-C1-8- alkyl, C1-8- alkoxycarbonyl-C1-8- alkyl, pyrrolidone-base-C1-8- alkyl, imidazole radicals-C1-8- alkyl, cyano group-C1-8- alkyl, carboxyl-C1-8- alkyl, carboxyl-C1-8- alkoxy, C1-8- alkoxy carbonyl group-C0-6- alkyl, C1-8- alkylsulfonamido-C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl amide, C1-8- alkoxy -C1-8- alkanoyl acylamino--C1-8- alkyl, N- (C1-8- alkyl)-C1-8- alkoxy -C1-8- alkanol-amide base, N-C1-8- alkyl-carbamoyl-C1-8- alkyl, C3-8- cycloalkanoyl acylamino--C1-8- alkyl, C1-8- alkyl amino-carbonyl-amino-C1-8- alkyl, C1-8- alkanol-amide ylmethylpyrrolidine base, N- (C1-8- alkoxy -C1-8- alkyl) carbamoyl, N- (C1-8- alkoxy -C1-8- alkyl)-N- (C1-8- alkyl) carbamoyl, N- (C1-8- alkoxy -C1-8- alkyl) imidazoles -2- bases, hydroxyl-C1-8- alkyl, hydroxyl-C1-8- alkoxy, hydroxyl-C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy carbonyl acylamino--C1-8- alkyl, amino-C1-8- alkyl and C1-8- alkyl amino-C1-8- alkyl.
R very particularly preferably1The example of group is phenyl, pyridine radicals, or bicyclic heterocyclic radical, including with phenyl-ring from 1 to 3 nitrogen and/or 1 sulphur or the 5-6 members saturation of oxygen atom or undersaturated heterocycle cyclization, such as 4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_67
Piperazine -3- ketone -6- bases, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_68
Piperazine -6- bases, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] thiazine -6- bases, 2,2- dimethyl -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_69
Piperazine -6- bases, 2,2- dimethyl -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_70
Piperazine -3- ketone -6- bases, 4,4- dimethyl-Isosorbide-5-Nitrae-dihydrobenzo [d] [1,3]
Figure 2006800106014_71
Piperazine -2- ketone -8- bases, 3, 3- dimethyl -1, 3- Indolin-2-one -6- bases, 3, 3- dimethyl -1, 3- Indolin-2-one -7- bases, 3, 3- dimethyl -1, 3- indoline -6- bases, 3- methyl indol -6- bases, 1- methyl-indazol -5- bases, 3, 4- dihydro -1H- quinoline-2-one -7- bases, 4, 4- dimethyl -3, 4- dihydro -1H- quinoline-2-one -8- bases, 1H- quinolyls, 2H- chromene bases, 1, 1a, 2, 7b- tetrahydrochysenes-cyclopropane simultaneously [c] chromene base, 1a, 7b- dihydro -1H- cyclopropane simultaneously [c] chromene base, with spiral shell [cyclopropane -1, 3 '] -2, H- indoles -6- the bases of 3- dihydros -1, it can be substituted as described above, especially by least-individual replace selected from following substituent：C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxycarbonyl amino-C1-8- alkoxy, C1-8- alkoxycarbonyl amino-C1-8- alkyl, C1-8- alkyl, C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, C0-6- alkyl-carbonyl-amino-C1-8- alkyl, halogen, oxide, triazol-1-yl-C1-8- alkyl, and oxo, it is preferable that wherein in R1In the case of being bicyclic heterocyclic radical, phenyl-ring of bicyclic system is bonded with Z, or if n is 0, is bonded with X, and at least non-phenyl-ring is substituted as described.
It is preferred that R2Group is phenyl and by following substituted phenyl：Halogen, hydroxyl, cyano group, trifluoromethoxy, trifluoromethyl, C2-8- alkenyloxy group, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base-C1-8- alkyl, C1-8- alkyl alkylthio base-C1-8- alkoxy, C1-8- alkyl alkylthio base-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl sulfanyl-C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkoxy, heterocyclic radical-C0-6- alkoxy, heterocyclic radical-C0-6- alkoxy -C1-8- alkyl, halo C1-8- alkyl, hydroxyl-C1-8- alkyl, cyano group-C1-8- alkyl, carboxyl-C1-8- alkyl, C1-8- alkyl carbonyl epoxide-C1-8- alkyl, C1-8- alkoxycarbonyloxy-C1-8- alkyl, C1-8- alkoxy carbonyl group or C1-8- alkylenedioxy group.
Also, it is preferred that R2Group is that, by the phenyl and halogenophenyl of L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent groups, wherein L1 and L2 preferably there is no or C1-8- alkylidene, and L3 is not present and U is hydrogen, C1-8- alkyl, C3-8- cycloalkyl, Phenylpiperidine base, Phenylpiperazinyl, phenylpyrrole alkyl, phenyl, be each by following substituted phenyl or phenylpyrrole alkyl,：C1-8- alkyl, C1-8- alkoxy, C1-8- alkylthio group, C1-8- alkyl sulphinyl, C1-8- alkylenedioxy group, halogen, benzoyl-C1-8- alkyl, halogen-C1-8- alkyl, C1-8- alkanoyloxy or hydroxyl, or naphthyl, pyridine radicals, thienyl, pyrazinyl, triazolyl, imidazole radicals, phenyl
Figure 2006800106014_72
Di azoly, thienyl
Figure 2006800106014_73
Di azoly, furylDi azoly, phenyl
Figure 2006800106014_75
Oxazolyl, benzothiazolyl, furyl, pyrimidine radicals, nitrobenzene thiazole base, phenyltetrazole base, piperidyl, THP trtrahydropyranyl, morpholinyl or indyl.
In group T1-T4, preferably (a)-(c), (e)-(h), (k)-(n) and (r)-(t) definition.
Particularly preferred R2The example of group is unsubstituted phenyl and each by following substituted phenyl and halogenophenyl：C2-8- alkenyloxy group, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl-amino-C1-8- alkyl, C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base-C1-8- alkyl, C1-8- alkyl alkylthio base-C1-8- alkoxy, C1-8- alkyl alkylthio base-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl sulfanyl-C1-8- alkyl, C1-8- alkyl sulphonyl-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C1-6- alkoxy -C0-6- alkyl-C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C1-8- alkyl amino-C1-8- alkyl, halogen, heterocyclic radical-C0-6- alkoxy, heterocyclic radical-C0-6- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl amino-C1-8- alkyl, N- (halogenophenyl) pyrrolidinyl epoxide, N- (halogenophenyl) pyrrolidinyl epoxide-C1-8- alkyl, C1-8- alkoxy benzyloxy-C1-8- alkoxy, C1-8- alkoxy benzene epoxide-C1-8- alkoxy, C1-8- alkoxy benzene epoxide-C1-8- alkyl, C1-8- alkoxyl phenyl-C1-8- alkoxy -C1-8- alkoxy, halobenzyloxy-C1-8- alkoxy, halogenated phenoxy-C1-8- alkoxy, halogenated phenoxy-C1-8- alkoxy -C1-8- alkyl, halogenated phenoxy-C1-8- alkyl, halogenophenyl-C1-8- alkoxy -C1-8- alkoxy or C1-8- alkyl benzyl epoxide-C1-8- alkoxy.
R very particularly preferably2The example of group is each by following substituted phenyl and halogenophenyl：C2-8- alkenyloxy group, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl-amino-C1-8- alkyl, C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base-C1-8- alkyl, C1-8- alkyl alkylthio base-C1-8- alkoxy, C1-8- alkyl alkylthio base-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl sulfanyl-C1-8- alkyl, C1-8- alkyl sulphonyl-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C1-6- alkoxy -C0-6- alkyl-C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C1-8- alkyl-amino-C1-8- alkyl, halogen, heterocyclic radical-C0-6- alkoxy, heterocyclic radical-C0-6- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl amino-C1-8- alkyl, N- (halogenophenyl) pyrrolidinyl epoxide, N- (halogenophenyl) pyrrolidinyl epoxide-C1-8- alkyl, C1-8- alkoxy benzyloxy-C1-8- alkoxy, C1-8- alkoxy benzene epoxide-C1-8- alkoxy, C1-8- alkoxy-phenoxy group-C1-8- alkyl, C1-8- alkoxyl phenyl-C1-8- alkoxy -C1-8- alkoxy, halobenzyloxy-C1-8- alkoxy, halogenated phenoxy-C1-8- alkoxy, halogenated phenoxy-C1-8- alkoxy -C1-8- alkyl, halogenated phenoxy-C1-8- alkyl, halogenophenyl-C1-8- alkoxy -C1-8- alkoxy or C1-8- alkyl benzyloxy-C1-8- alkoxy.
R equally very particularly preferably2Group is each that wherein at least one substituent is relative to the R for being connected to remaining molecule according to substituted phenyl and halogenophenyl defined above2Key contraposition.Relative to the R for being connected to remaining molecule2Key contraposition, R2Upper preferred substituents are fluorine, ethyl, propyl group, butyl, isobutyl group, amyl group, methyl-sulfanyl, 2- methoxy ethyl sulfanyls, 3- methoxy-propyl sulfanyls, 4- methoxybutyl sulfanyls, 4- methoxyl group -3- methyl-butvl sulfanyls, allyloxy, methoxyl group, ethyoxyl, propoxyl group, 4- methoxybutoxies, 3- methoxy-propoxyls, 2- methoxy ethoxies, 3- cyclopropyl epoxide propoxyl group, (2- methoxyl groups-cyclopropyl) methoxy, (2- methoxies-cyclopropyl) methoxy, 3- methylsulfanyl propoxyl group, methoxy, 2- methoxvethoxvmethvls, 3- methoxy propoxy methyl, 2- methyl -3- methylsulfanyls-propoxy methyl, Cvclopropvlmethoxvmethvl, ethoxyl methyl, 2- methoxy ethyls, 3- methoxyl group -2- methyl-propoxy methyl, 2- methylsulfanyl ethoxyl methyls, methylsulfanyl methyl, 2- methoxy ethyl sulfanylmethyls, 3- methoxy-propyls sulfanylmethyl and cyclopropyl sulfanylmethyl.
It is preferred that the example of X group be oxygen, methylene ,-O-CH2- CO-NH- ,-O-CH2-CO-N(CH3)-and-O-CH (CH3)-CO-NH-。
Particularly preferred X is key, methylene and oxygen.
Particularly preferred Z group is alkylidene ,-(CH2)1-2- O- and-CH (CH3)-；
Wherein, if X is key, Z is-(CH2)1-2-O-。
Formula (I) or the compound of (II) or preferred formula (IA) or the compound of (IIA) very particularly preferably is following compounds, wherein
R is C1-8- alkyl, C0-8- alkyl-carbonyl-amino-C1-8- alkyl, C1-8- alkyl-sulfonyl base-C1-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional N and/or N ' mono-, di--or three C1-8- alkylation urea groups-C0-8- alkyl, heterocyclic radical-C0-8- alkyl, or Heterocyclylcarbonyl-C0-8- alkyl, each group can be substituted, preferably by following substitution：1-4 C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy carbonyl group-(N-C1-8- alkyl)-amino, C1-8- alkyl, C1-8- alkyl-carbonyl-(N-C1-8- alkyl)-amino, C1-8- alkyl-sulfanyl, optionally by 1 or 2 aryl or C1-8Aryl-the C of-alkoxy base substitution0-8- alkoxy, optionally by 1 or 2 aryl or C1-8The aryl of-alkoxy base substitution, cyano group, halogen, heterocyclic radical, heterocyclic radical-C0-8- alkyl-amino, heterocyclic radical-carbonyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylation carbamoyloxy group, hydroxyl, optional N- is mono- or-the C of N, N- bis-1-8- alkylated amine, trifluoromethoxy or trifluoromethyl；
R1It is phenyl, pyridine radicals, 4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_76
Piperazine -3- ketone -6- bases, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_77
Piperazine -6- bases, 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] thiazine -6- bases, 2,2- dimethyl -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_78
Piperazine -6- bases, 2,2- dimethyl -4H- benzos [Isosorbide-5-Nitrae]Piperazine -3- ketone -6- bases, 4,4- dimethyl-Isosorbide-5-Nitrae-dihydrobenzo [d] [1,3]Piperazine -2- ketone -8- bases, 3, 3- dimethyl -1, 3- Indolin-2-one -6- bases, 3, 3- dimethyl -1, 3- Indolin-2-one -7- bases, 3, 3- dimethyl -1, 3- indoline -6- bases, 3- methyl indol -6- bases, 1- methyl-indazol -5- bases, 3, 4- dihydro -1H- quinoline-2-one -7- bases, 4, 4- dimethyl -3, 4- dihydro -1H- quinoline-2-one -8- bases, 1H- quinolyls, 2H- chromene bases, 1, 1a, 2, 7b- tetrahydrochysenes-cyclopropane simultaneously [c] chromene base, 1a, 7b- dihydro -1H- cyclopropane simultaneously [c] chromene base, or spiral shell [cyclopropane -1, 3 '] -2, 3- dihydro -1H- indoles -6- bases, it can be substituted as described above, especially replaced by least one selected from following substituent：C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxycarbonyl amino-C1-8- alkoxy, C1-8- alkoxycarbonyl amino-C1-8- alkyl, C1-8- alkyl, C0-6- alkyl-carbonyl-amino-C1-8- alkoxy, C0-6- alkyl-carbonyl-amino-C1-8- alkyl, halogen, oxide, triazol-1-yl-C1-8- alkyl, or oxo；
R2It is each by following substituted phenyl or halogenophenyl：C2-8- alkenyloxy group, C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy -C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl-amino-C1-8- alkyl, C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base, C1-8- alkyl alkylthio base-C1-8- alkyl, C1-8- alkyl alkylthio base-C1-8- alkoxy, C1-8- alkyl alkylthio base-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl sulfanyl-C1-8- alkyl, C1-8- alkyl sulphonyl-C1-8- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C0-6- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkoxy, C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C1-6- alkoxy -C0-6- alkyl-C3-8- cycloalkyl-C0-6- alkoxy -C1-8- alkyl, C3-8- cycloalkyl-C1-8- alkyl amino-C1-8- alkyl, halogen, heterocyclic radical-C0-6- alkoxy, heterocyclic radical-C0-6- alkoxy -C1-8- alkyl, C1-8- alkoxy -C1-8- alkyl amino-C1-8- alkyl, N- (halogenophenyl) pyrrolidinyl epoxide, N- (halogenophenyl) pyrrolidinyl epoxide-C1-8- alkyl, C1-8- alkoxy benzyloxy-C1-8- alkoxy, C1-8- alkoxy benzene epoxide-C1-8- alkoxy, C1-8- alkoxy benzene epoxide-C1-8- alkyl, C1-8- alkoxyl phenyl-C1-8- alkoxy -C1-8- alkoxy, halobenzyloxy-C1-8- alkoxy, halogenated phenoxy-C1-8- alkoxy, halogenated phenoxy-C1-8- alkoxy -C1-8- alkyl, halogenated phenoxy-C1-8- alkyl, halogenophenyl-C1-8- alkoxy -C1-8- alkoxy or C1-8- alkyl-benzyloxy-C1-8- alkoxy, wherein at least one substituent is relative to the R for being connected to remaining molecule2Key contraposition.Relative to the R for being connected to remaining molecule2Key contraposition R2On preferred substituents be fluorine, ethyl, propyl group, butyl, isobutyl group, amyl group, methylsulfanyl, 2- methoxy ethyl sulfanyls, 3- methoxy-propyl sulfanyls, 4- methoxybutyl sulfanyls, 4- methoxyl group -3- methyl-butvl sulfanyls, allyloxy, methoxyl group, ethyoxyl, propoxyl group, 4- methoxybutoxies, 3- methoxy propoxies, 2- methoxy ethoxies, 3- cyclopropyl epoxide propoxyl group, (2- methoxyl groups-cyclopropyl) methoxy, (2- methoxies-cyclopropyl) methoxy, 3- methylsulfanyls-propoxyl group, methoxy, 2- methoxvethoxvmethvls, 3- methoxy propoxy methyl, 2- methyl -3- methylsulfanyls-propoxy methyl, Cvclopropvlmethoxvmethvl, ethoxyl methyl, 2- methoxy ethyls, 3- methoxyl group -2- methyl-propoxy methyl, 2- methylsulfanyl ethoxyl methyls, methylsulfanyl methyl, 2- methoxy ethyl sulfanylmethyls, 3- methoxy-propyls sulfanylmethyl and cyclopropyl sulfanylmethyl；
R3It is hydrogen；
R4It is hydrogen；
Q is not present；
X is key, methylene or oxygen；
Z is alkylidene ,-(CH2)1-2- O- and-CH (CH3)-；
Wherein, if X is key, Z is-(CH2)1-2-O-。
M=0 and
N=1.
Formula (I) and (II) or preferred formula (IA) or the compound of (IIA) and salt workable for their pharmacy are inhibited for natural enzyme renin.The latter causes the cracking of proangiotensin there from kidney enters blood, forms decapeptide angiotensin I, and then decapeptide angiotensin I is decomposed into octapeptide Angiotensin II in lung, kidney and other organs.Angiotensin II can directly be improved blood pressure by arterial contraction and improve blood pressure indirectly by discharging suppression from the hormone aldosterone of adrenal gland release sodium ion, and it is relevant with the rise of extracellular fluid volume.This rise is Angiotensin II in itself or in the heptapeptide Angiotensin II I formed by it as cleavage product exercising result.The inhibitor of the enzymatic activity of feritin can cause the formation of angiotensin I to reduce, and therefore form the Angiotensin II of lesser amt.The concentration of the reduction of this active peptide hormone, is the immediate cause of the hypotensive activity of renin inhibitor.
A test method for detecting renin inhibitor effect is to utilize in vitro test, wherein determining the reduction of the formation of the angiotensin I in different system (human plasma, pure human renin and synthesis or natural enzyme renin matrix).A used in vitro test is according to Nussberger et al. (1987) J.Cardiovascular Pharmacol., volume 9,39-44 pages of an in vitro test.The experiment determines the formation of the angiotensin I in human plasma.The amount of formed angiotensin I is determined in subsequent radiommunoassay.Within the system, by adding these materials of various concentrations, test inhibitor is for the had effect of angiotensin I formation.IC50Value refers to can be by the concentration of the specific inhibitor of the formation reduction by 50% of angiotensin I.The compound of the present invention shows inhibitory action, Cmin about 10 in system in vitro-3To about 10-10mol/l。
In order to illustrate the present invention, the compound of embodiment 10,12,21,33,40,53 and 120 suppresses the formation of angiotensin I, with about 10-5To about 10-7IC in the range of mol/l50Value.
In the animal that salt exhausts, renin inhibitor causes blood pressure to reduce.The feritin of people is different from the feritin of other species.In order to test the inhibitor of human renin, using primate (marmoset, Callithrixjacchus), because human renin and primate feritin are substantially homologous in the active region that enzyme is urged.A used in vivo studies is as follows：Tested with test compound in the other normotensive marmoset of two individual characteies, marmoset has about 350 grams of body weight, its be it is conscious, can be freely movable and in their normal cage.Using conduit, blood pressure and heart rate are determined in descending aorta, and carry out radioactivity record.Combining for 1 week for furosemide (the chloro- 2- of 5- (amino-sulfonyl) -4- [(2- furyl methyls) amino] benzoic acid) (5 mg/kg) is injected with independent intramuscular by low-salt diet, the interior originality release of feritin is stimulated.Furosemide is injected after 16 hours, substances are directly administered in femoral artery or are administered to by the method for feeding suspension or solution in stomach using injection-tube, their influences for blood pressure and heart rate are evaluated.In described in vivo studies, the compounds of this invention can be effectively reduced blood pressure, the mg/kg i.v. of dosage about 0.003 to about 0.3 and the mg/kg p.o of dosage about 0.3 to about 30.
Formula (I) or (II) or preferred formula (IA) or the compound of (IIA) and salt workable for their pharmacy may be used as medicine, such as with pharmaceutical dosage forms.Pharmaceutical preparation can be given with following form：Enteral, for example orally, such as tablet, coated tablet, sugar coated tablet, hard and soft gelatine capsule, solution, emulsion or form of suspension, nose is given, the form of such as nose spray, rectal administration, such as suppository form, or it is transdermal give, the form of such as ointment or paster.Can also parenteral give, such as intramuscular or intravenous, such as parenteral solution form.
In order to prepare tablet, coated tablet, sugar coated tablet and hard gelatin capsule, formula (I) or (II) or preferred formula (IA) or (IIA) compound can be processed together with the inorganic or organic excipients of pharmaceutical inert.Used this excipient, such as excipient of tablet, coated tablet and hard gelatin capsule, can be lactose, cornstarch or derivatives thereof, talcum powder, stearic acid or its salt etc..
Appropriate excipients for Perle are such as vegetable oil, paraffin, fat, semisolid and liquid polyol etc..
Appropriate excipients for preparing solution and syrup are such as water, polyalcohol, sucrose, inverted sugar, glucose, etc..
Appropriate excipients for parenteral solution are such as water, alcohol, polyalcohol, glycerine, vegetable oil, bile acid, lecithin, etc..
Appropriate excipients for suppository are for example natural or hardening oils, paraffin, fat, semisolid or liquid polyol etc..
Pharmaceutical preparation can also comprise additionally in preservative, solubilizer, viscosity increase material, stabilizer, wetting agent, emulsifying agent, sweetener, colorant, flavor enhancement, salt, buffer solution, coating or the antioxidant for changing osmotic pressure.They can also include other valuable materials for the treatment of.
Invention further provides formula (I) or (II) or preferred formula (IA) or the compound of (IIA) and salt workable for its pharmacy, the purposes in the mammal particularly heart failure of the mankind and glaucoma, miocardial infarction, kidney failure and ISR is treated or prevented.
Formula (I) or (II) or preferred formula (IA) or the compound of (IIA) and salt workable for its pharmacy, can also give, such as α and beta blocker such as phentolamine in the combination of the medicament with one or more with Cardiovascular, phenoxybenzamine, prazosin, Terazosin, tolazine, atenolol, metoprolol, Nadolol, propranolol, timolol, carteolol etc.；Vasodilator such as hydralazine, minoxidil, diazoxiide, nitroprusside, Flosequinan etc.；Calcium antagonist such as Amrinone, Bencyclane, diltiazem, Fendiline, flunarizine, nicardipine, Nimodipine, perhexilene, Verapamil, Gallopamil, nifedipine etc.；Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe such as Cilazapril, captopril, enalapril, lisinopril etc.；Potassium agents such as Pinacidil；Antiserotonin agent such as Ketanserin (Ketanserin)；Thromboxane-synthetase inhibitors；Neutral endopeptidase inhibitor (nep inhibitor)；Angiotensin-ii antagonist；And diuretics such as hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, Indacrinone, metolazone, spirolactone, triamterene, chlorthalidone etc.；Sympathicolytic such as ethyldopa, clonidine, guanabenz, reserpine；And it is suitable for treating other medicaments of vascular hypertension, heart failure or vascular diseases in the human and animal relevant with diabetes or for example acute or chronic kidney failure of nephrosis.This combination is can be used alone, or including being permitted to use in multi-component preparation.
The material that the other materials that can be used in the combination with formula (I) or (II) or preferred formula (IA) or (IIA) compound are classifications (i) on WO02/40007 page 1 to be illustrated to the compound (and preferably and wherein entering-walk the embodiment listed) of (ix) and page 20 and 21 of WO03/027091.
Dosage can be very big with amplitude of variation, and needs to be suitable for individual instances under each individual condition certainly.Generally, for oral, the daily dose of each about 3 milligrams to about 3 grams of adult's (70 kilograms), preferably from about 10 milligrams to about 1 gram, e.g., from about 300 milligrams, be preferably divided into 1-3 it is individually dosed be it is suitable, its can such as specification it is equal, but if it is considered to properly, the upper limit illustrated can also be exceeded；Typically, the age according to children and body weight, they can receive relatively low dosage.
Embodiment
The present invention has been illustrated in the following example.All temperature report that pressure is reported with millibar with Celsius temperature.Unless otherwise indicated, reaction is carried out at room temperature.Abbreviation " Rf=xx (A) " refers to obtain Rf values xx for example in solvent system A.Be mutually related solvent ratio always to report by volume parts.The chemical name of final product and intermediate is obtained by means of program AutoNom2000 (Automatic Nomenclature).
HPLC gradients, at Hypersil BDS C-18 (5 μm)；Post：On 4 × 125mm：
90% water*/ 10% acetonitrile*To 0% water*/ 100% acetonitrile*,+2.5 minutes 5 minutes (1.5 ml/min)；*：Contain 0.1% trifluoroacetic acid
Use following abbreviation：
Rf：In thin-layer chromatography, since starting point, the ratio of material displacement and eluent distance
Rt：Retention time (minute) of the material in HPLC
m.p.：Fusing point (temperature)
Conventional method A (N-Tos- deprotections)
At room temperature, 0.44mmol sodium dihydrogen phosphates and 0.90mmol sodium amalgams (10%Na) are added into 0.09mmol " tosyl acid amides " 10 ml methanol agitating solutions.Stirring reaction mixture 2-18 hours, is diluted with water, and extracted with ethyl acetate.Organic phase is merged, salt water washing is used, and dried with sodium sulphate.Be concentrated under reduced pressure solvent, and crude residue is passed through into flash chromatography (SiO260F) purify, obtain title compound.
Conventional method B：(deprotection of N- p-methoxyphenyls)
At 0 DEG C, 5.0 milliliters of aqueous solution of 1.43mol ceric ammonium nitrate are added into the agitating solution of 0.5mmol " P-nethoxyaniline " 10 milliliters of acetonitrile/waters (1: 1).Stir mixture 30 minutes, then add 1.0 grams of sodium sulfites.Behind extra 30 minutes, reactant mixture is diluted with water, and is extracted with t-butyl methyl ether.Organic phase is dried, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained.
Conventional method C：(BH3- reduction)
2-4mmol monoboranes tetrahydrofuran (1M, in tetrahydrofuran) is added into 1mmol " lactams " 3 milliliters of tetrahydrofuran agitating solutions, and is heated to 50 DEG C, holding 2-8 hours.Reactant mixture is quenched by adding 10 ml methanols, and is concentrated under reduced pressure.Utilize flash chromatography (SiO260F), title compound is obtained by residue.
Conventional method D：(acid amides-formation)
At room temperature, 5.0mmol triethylamines and the sour cyclic anhydride [68957-94-8] (50%, in ethyl acetate) of the propyl-phosphines of 1.0mmol tri- are added into 1.0mmol " acid " and 1.0mmol " amine " 20 milliliters of dichloromethane agitating solutions.Reactant mixture is stirred 1-3 hours, with dchloromethane, with 1N hydrochloric acid and salt water washing.Organic phase is merged, dried with sodium sulphate, and solvent under reduced pressure is concentrated.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained.
Conventional method E：(hydrogenation)
At 15-20 DEG C, 100-200 milligrams of Pd/C10% are added into 1mmol " matrix " 15 milliliters of tetrahydrofuran agitating solutions, and reactant mixture is hydrogenated.Reactant mixture is filtered and is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained.
Conventional method F：(Mesylation)
At 0 DEG C, 5mmol triethylamines and 2mmol mesyl chlorides are added into 1mmol " alcohol " 10 milliliters of dichloromethane agitating solutions.Reactant mixture is stirred 1 hour, with dchloromethane, with 1N salt acid elutions, dried with sodium sulphate.Be concentrated under reduced pressure solvent, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound, or just can directly be used in next step without further purifying.
Embodiment 1
{ (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_81
Piperazine -6- ylmethoxies]-piperidin-2-yl }-methanol
At 0 DEG C, to 0.10 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters 10 milliliters of tetrahydrofuran agitating solutions in add 17.0 milligrams of lithium aluminium hydrides.Stirring reaction mixture 1 hour, is diluted with t-butyl methyl ether at this temperature, and is quenched by adding 2.0 milliliters of saturated aqueous sodium sulfates.Mixture is warmed to room temperature, filters and is dried with sodium sulphate.Be concentrated under reduced pressure solvent, and crude residue is passed through into flash chromatography (SiO260F) purify, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,-oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] Piperazine -6- ylmethoxies]-piperidines -2- Carboxylic acid, ethyl ester
According to conventional method B, 0.3 gram of (2S, 4R, 5R)-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_84
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters, obtain title compound as yellow oil.Rf=0.15 (the concentrated ammonia liquors of methylene chloride-methanol -25%.200∶10∶1)；Rt=3.53.
b)(2S, 4R, 5R)-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_85
Piperazine -6- ylmethoxies]-piperidines - 2- carboxylic acid, ethyl esters
At -30 DEG C, to 5.20 grams of (2S, 4R, 5R) -5- hydroxyls-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) piperidines -2- carboxylic acid, ethyl esters and 5.62 gram 2,2,2- tri- chloro- acetimide acid 4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_86
1.1 milliliters of trifluoromethanesulfonic acids are added in 150 milliliters of dichloromethane agitating solutions of piperazine -6- ylmethyl esters.Stirring reaction mixture 1 hour, was then warming up to 0 DEG C in 2 hours at this temperature.Mixture is quenched by adding 2N sodium hydroxides, is extracted, is dried with sodium sulphate with dichloromethane, and be concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rf=0.15 (EtOAc- heptane 1: 1)；Rt=4.73.
c)(2S, 4R, 5R) -5- hydroxyls-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) piperidines -2- carboxylic acid second Ester
At room temperature, 56 milliliters of borine-tetrahydrofuran (1M) solution are added into 400 milliliters of tetrahydrofuran agitating solutions of 19.5 grams of Tetrahydro-pyridine -2- carboxylic acid, ethyl esters of (S)-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) -1,2,3,6-.Reactant mixture is heated to 40 DEG C, kept for 2-6 hours, room temperature is cooled to, 50 milliliters of 2N sodium hydroxide solutions is added and 100 milliliter of 30% hydrogenperoxide steam generator is quenched.Organic phase is separated, is dried, is concentrated under reduced pressure with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow solid is obtained.Rf=0.33 (EtOAc- heptane 1: 1)；Rt=3.58.
d)(S) Tetrahydro-pyridine -2- carboxylic acid second of-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) -1,2,3,6- Ester
To 38.0 grams of (S) -1- (4- methoxyl groups-phenyl) -4- trifyl Oxy-1s; 2; 100 milliliters of ethanol, 160 milliliters of 2N sodium carbonate liquors and 2.22 grams of tetrakis triphenylphosphine palladiums are added in 3,6- tetrahydropyridine -2- carboxylic acid, ethyl esters, 18.1 grams of 4- methoxyphenyl-boronic acids, 300 milliliters of dimethoxy-ethane suspension of 6.45 grams lithium chlorides.Reactant mixture is heated to 75 DEG C, kept for 3-6 hours, and is cooled to room temperature, overnight.Reactant mixture is filtered, and filter cake is re-dissolved in dichloromethane and water.Suspension is filtered again, be concentrated under reduced pressure organic phase, obtain title compound as colourless solid.Rf=0.25 (EtOAc- heptane 1: 4)；Rt=5.00.
e)(S) -1- (4- methoxyl groups-phenyl) -4- trifyl Oxy-1s, 2,3,6- tetra- Pyridinium hydroxide -2- carboxylic acid, ethyl esters
At -78 DEG C, to 0.94 gram of (S) -1- (4- methoxyl groups-phenyl) -4- oxo -1,2,3,3.7 milliliters of L-selectride (0.5M are added in 20 milliliters of tetrahydrofuran agitating solutions of 4- Tetrahydro-pyridine -2- carboxylic acid, ethyl esters [690224-49-8], Aldrich 17,849-7).Stir the mixture 1 hour, add 8 milliliters of tetrahydrofuran solutions of 1.18 grams of N- phenyl trifluoromethanesulfonates methylsulfonimides (Fluka 78175), and mixture is warming up to room temperature, overnight.Be concentrated under reduced pressure reactant mixture, and residue is purified by flash chromatography (aluminum oxide, Fluka 06290), obtains title compound brown solid.Rf=0.2 (EtOAc- heptane 1: 9)；Rt=5.14.
f)2,2,2- tri- chloro- acetimide acid 4- (3- methoxy-propvls) -3- oxos -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_87
Piperazine -6- ylmethyl esters
At 0 DEG C, to 8.50 grams of 6- methylols -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_88
1.28 grams of sodium hydrides are added in 200 milliliters of ether agitating solutions of piperazine -3- ketone.Stir the mixture 1 hour, be concentrated under reduced pressure into dry, obtain brown oil, it can directly be used without being further purified in next step.Rf=0.5 (EtOAc- heptane 1: 1).
g)6- methylols -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_89
Piperazine -3- ketone
By 1.79 grams of 6- methylol -4H- benzos [Isosorbide-5-Nitrae]Piperazine -3- ketone, 2.20 milliliters of 1- chlorine 3- methoxy propanes, 150 milliliters of acetonitrile stirred suspensions of 10 grams of potassium fluoride/aluminum oxide and 0.033 gram of KI are heated at reflux 72 hours.Reactant mixture is cooled to room temperature, filter and be concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained.Rf=0.60 (methylene chloride-methanol 9: 1)；Rt=2.74.
h)6- methylol -4H- benzos [Isosorbide-5-Nitrae] Piperazine -3- ketone
At -40 DEG C, to 6.9 grams of 3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_92
88.9 milliliters of diisobutyl aluminium hydrides (1.5M, in toluene) are added in 230 milliliters of tetrahydrofuran compounds of piperazine -6- carboxylate methyl esters [604756-32-3].The reactant mixture is stirred at -40 DEG C to -20 DEG C 1.5 hours, poured into 150 milliliters of 2N hydrochloric acid.Organic phase is separated, salt water washing is used, is dried with sodium sulphate, is concentrated under reduced pressure.With ethanol by residue crystallized, title compound beige solid is obtained.Rf=0.16 (EtOAc- heptane 2: 1)；Rt=2.23, m.p.：186-187℃.
Embodiment 2
(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_93
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters
According to conventional method B, 0.1 gram of (2S, 4R, 5R)-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_94
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters (coming from embodiment 1b).Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained.
Embodiment 3
(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_95
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid (biphenyl -3 - ylmethyl)-acid amides
According to conventional method E; use 0.05 gram of (2S, 4R, 5R) -2- [(biphenyl -3- ylmethyls)-carbamoyl] -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_96
Piperazine -6- ylmethoxies] piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- [(biphenyl -3- ylmethyls)-carbamoyl] -4- (4- methoxies Base-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_97
Piperazine -6- ylmethoxies] piperidines -1- carboxylic acid benzyl esters
According to conventional method D, 0.07 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters and 3- phenylbenzyls amine reaction, obtain title compound as colourless solid.Rf=0.15 (EtOAc- heptane 1: 1)；Rt=5.62.
b)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_99
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- Benzyl ester
At 0 DEG C, to 1.5 grams of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters (coming from embodiment 2) 60 ml methanols-solution of tetrahydrofuran-water 1: 1: 1 in add 2.85 milliliter of 1 N lithium hydroxide solution.Continue to stir extra 2 hours at room temperature, then add 40 milliliters of ethyl acetate, 20 milliliters of saturated aqueous sodium carbonates and 0.42 milliliter of benzyl chloroformate.Reactant mixture is stirred 1 hour, diluted with ethyl acetate, organic phase is dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as yellow oil.Rf=0.13 (EtOAc)；Rt=4.77.
Embodiment 4
{ (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_101
Piperazine -6- ylmethoxies]-piperidin-2-yl }-(3- phenyl - pyrrolidin-1-yl)-ketone
According to conventional method E, 0.08 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_102
Piperazine -6- ylmethoxies] -2- (3- phenyl-pyrrolidin -1- carbonyls)-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_103
Piperazine -6- ylmethoxies] -2- (3- phenyl-pyrrolidins - 1- carbonyls)-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, 0.10 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_104
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (derive from embodiment 3b) and 3- Phenylpyrrolidines react, and obtains title compound as colourless solid.Rf=0.15 (EtOAc- heptane 1: 1)；Rt=5.47.
Embodiment 5
(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_105
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid methylamides
According to conventional method E, 0.06 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_106
Piperazine -6- ylmethoxies]-Methvlcarbamovl-piperidine -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_107
Piperazine -6- ylmethoxies] -2- methylcarbamoyls - Piperidines -1- carboxylic acid benzyl esters
According to conventional method D, 0.05 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 3b) and methylamine hydrochloride, obtain title compound as yellow oil.Rf=0.50 (methylene chloride-methanol 9: 1)；Rt=4.52.
Embodiment 6
(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_109
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid amides
According to conventional method E, 0.06 gram of (2S, 4R, 5R) -2- carbamoyls -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] is used
Figure 2006800106014_110
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- carbamoyls -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_111
Piperazine -6- ylmethoxies]-piperidines - 1- carboxylic acid benzyl esters
To 0.51 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_112
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 3b) 1 milliliter of dichloromethane solution in add 1.2 milliliters of triethylamines and 0.79 milliliter of chloro-carbonic acid isopropyl esters.Reactant mixture is stirred 10 minutes, 2 milliliters of concentrated ammonia liquors (25%) are then added.After extra 10 minutes, dchloromethane reactant mixture is used, with 0.5N salt acid elutions, organic phase is dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.50 (methylene chloride-methanol 9: 1)；Rt=4.50.
Embodiment 7
(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_113
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acids
According to-as method E, use 0.05 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_114
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 3b), obtain title compound.
Embodiment 8
(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_115
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid dimethyl amines
According to conventional method E, 28.0 milligrams of (2S, 4R, 5R) -2- formyl-dimethylaminos -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_116
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- formyl-dimethylaminos -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_117
Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
It is similar to embodiment 6a, 50.0 milligrams of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_118
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 3b) and dimethylamine react, and obtains title compound as yellow oil.Rf=0.04 (methylene chloride-methanol 98: 2)；Rt=4.85.
Embodiment 9
2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_119
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N- first Base-N- quinoline -2- vlmethvl-acetamides
According to conventional method E, 50.0 milligrams of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_120
Piperazine -6- ylmethoxies] -2- [(Methyl-quinoline -2- ylmethyl-aminos formoxyl)-methyl]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_121
Piperazine -6- ylmethoxies] -2- [(Methyl-quinoline -2- Ylmethyl-amino formoxyl)-methyl]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, 42.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_122
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester and Methyl-quinoline -2- ylmethyls-amine [136727-11-2], obtain title compound as yellow oil.Rf=0.50 (methylene chloride-methanol 10: 1)；Rt=4.69.
b)(2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_123
Piperazine -6- ylmethoxies]-piperidines -1 - carboxylic acid benzyl ester
At -15 DEG C, to 45 milligrams of (2S, 4R, 5R) -2- (2- diazoes-acetyl group) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_124
Piperazine -6- ylmethoxies] 0.027 milliliter of triethylamine and 8.0 milligrams of silver trifluoroacetates are added in -10 milliliters of tetrahydrofurans of piperidines -1- carboxylic acid benzyl esters and the solution of 1 milliliter of water.Reactant mixture is warmed to room temperature, 2 hours is further stirred for, is diluted, dried with sodium sulphate with t-butyl methyl ether.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound brown oil.Rf=0.25 (EtOAc)；Rt=4.82.
c)(2S, 4R, 5R) -2- (2- diazoes-acetyl group) -4- (4- methoxyl groups-phenyl) -5 - [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_125
Piperazine -6- base methoxies Base]-piperidines -1- carboxylic acid benzyl esters
At -15 DEG C, to 0.1 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_126
Piperazine -6- ylmethoxies]-piperidines -1,2- carboxylic acid 1- benzyl esters (coming from embodiment 3b) 10 milliliters of tetrahydrofuran solutions in add 0.023 milliliter of triethylamine and 0.014 milliliter of ethyl chloroformate.Reactant mixture is warming up to 0 DEG C, stir 30 minutes at this temperature, be cooled to -10 DEG C, then add the diethyl ether solution (1.5%) of 20 milliliters of diazomethanes.Reactant mixture is warming up to ambient temperature overnight, diluted with t-butyl methyl ether, organic phase is washed with saturated sodium bicarbonate aqueous solution, dried with sodium sulphate, is concentrated under reduced pressure, flash chromatography (SiO2After 60F), title compound as yellow oil is obtained.Rf=0.16 (EtOAc- heptane 1: 1)；Rt=5.12.
Embodiment 10
2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] Piperazine -6- ylmethoxies]-piperidin-2-yl }-N- first Base-acetamide
According to-as method E, use 52.0 milligrams of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_128
Piperazine -6- ylmethoxies] -2- methylcarbamoylmethyls-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_129
Piperazine -6- ylmethoxies] -2- methylcarbamoyl first Base-piperidines -1- carboxylic acid benzyl esters
It is similar to embodiment 6a, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_130
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) and methylamine react, and obtains title compound as yellow oil.Rf=0.35 (methylene chloride-methanol 9: 1)；Rt=4.57.
Embodiment 11
2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_131
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N, N- Dimethyl-acetamide
According to conventional method E, 68.0 milligrams of (2S, 4R, 5R) -2- Dimethylcarbamoylmethyls -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_132
Piperazine -6- ylmethoxies }-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- Dimethylcarbamoylmethyls -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_133
Piperazine -6- Ji Jia Epoxide]-piperidines -1- carboxylic acid benzyl esters
It is similar to embodiment 6a, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (derive from embodiment 9b) reacts with dimethylamine, obtains title compound as yellow oil.Rf=0.40 (methylene chloride-methanol 9: 1)；Rt=4.82.
Embodiment 12
N- benzyls -2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [1,4]
Figure 2006800106014_135
Piperazine -6- ylmethoxies]-piperidines -2 - yl }-acetamide
According to conventional method E; use 50.0 milligrams of (2S, 4R, 5R) -2- (carbamovl-methyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_136
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- (carbamovl-methyl) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_137
Piperazine -6- bases Methoxyl group]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_138
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) and benzylamine react, and obtains title compound as yellow oil.Rf=0.50 (methylene chloride-methanol 9: 1)；Rt=5.17.
Embodiment 13
N- benzyls -2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_139
Piperazine -6- ylmethoxies]-piperidines -2 - yl }-N- methyl acetamides
According to conventional method E; use 50.0 milligrams of (2S, 4R, 5R) -2- [(Benzyl-methyl-amino formoxyl)-methyl] -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_140
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- [(Benzyl-methyl-amino formoxyl)-methyl] -4- (4- methoxies Base-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_141
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) and benzylmethylamine react, and obtains title compound as yellow oil.Rf=0.11 (EtOAc- heptane 1: 1)；Rt=5.47.
Embodiment 14
N- [1H- indol-3-yls methyl) -2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_143
Piperazine -6- bases Methoxyl group]-piperidin-2-yl }-N- methyl acetamides
According to conventional method E; use 50.0 milligrams of (2S; 4R; 5R) -2- { [(1H- indol-3-yls methyl)-methyl-cabanaoyl]-methyl } -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_144
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- [(1H- indol-3-yls methyl)-methyl-cabanaoyl] - Methyl } -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- bis- Hydrogen -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_145
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) and (1H- indol-3-yls methyl)-methyl-amine [36284-95-4] reacts, and obtains title compound as colourless oil.Rf=0.20 (EtOAc- heptane 2: 1)；Rt=5.23.
Embodiment 15
2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_147
Piperazine -6- ylmethoxies]-piperidin-2-yl }-ethanol
According to conventional method E, 70.0 milligrams of (2S, 4R, 5R) -2- (2- hydroxy-ethyls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_148
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- (2- hydroxy-ethyls) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
At 50 DEG C, to 0.10 gram of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_150
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) 8.0 milliliters of tetrahydrofuran solutions in add 0.31 milliliter of borine tetrahydrofuran (1M) solution.The reactant mixture is stirred 2 hours at this temperature, room temperature is cooled to, and adds methanol and be quenched.Be concentrated under reduced pressure mixture, and the residue of acquisition is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.50 (EtOAc- heptane 5: 1)；Rt=4.95.
Embodiment 16
2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_151
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N- first Base-N- (1- methyl isophthalic acids H- benzimidazolyl-2 radicals-ylmethyl)-acetamide
According to conventional method E, 45.0 milligrams (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -2- { [methyl-(1- methyl isophthalic acids H- benzimidazolyl-2 radicals-ylmethyl)-carbamoyl]-methyl }-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_153
Piperazine -6- ylmethoxies] -2- { [methyl-(1- methyl - 1H- benzimidazolyl-2 radicals-ylmethyl)-carbamoyl]-methyl }-piperidines -1- carboxylic acids Benzyl ester
According to conventional method D, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) and methyl-(1- methyl isophthalic acids H benzimidazolyl-2 radicals-ylmethyl)-amine [137898-62-5] reacts, and obtains title compound as yellow oil.Rf=0.65 (methylene chloride-methanol 9: 1)；Rt=4.59.
Embodiment 17
2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_155
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N- quinolines Quinoline -2- vlmethvl-acetamides
According to conventional method E, 64.0 milligrams of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -2- [(Methyl-quinoline -2- ylmethyl-aminos formoxyl)-methyl]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_157
Piperazine -6- ylmethoxies] -2- [(Methyl-quinoline -2- Ylmethyl-amino formoxyl)-methyl]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, make 50.0 milligrams of (2S, 4R, 5R) -2- carboxymethyls 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_158
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 9b) and Methyl-quinoline -2- ylmethyls amine [5760-20-3] reacts, and obtains title compound as yellow solid.Rf=0.25 (methylene chloride-methanol 9: 1)；Rt=4.52.
Embodiment 18
6- [(3R, 4R, 6S) -6- (2- methox-etlayls) -4- (4- methoxyl groups-phenyl)-piperidines - 3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_159
Piperazine
According to conventional method E, 47.0 milligrams of (2S, 4R, 5R) -2- (2- methox-etlayls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_160
Piperazine -6- ylmethoxies)-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S, 4R, 5R) -2- (2- methox-etlayls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_161
Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
At room temperature, to 0.10 gram of (2S, 4R, 5R) -2- (2- mesyloxies-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_162
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters 2.0 milliliters of DMF solution in add 0.060 milliliter of 5M sodium methoxide methanol solution.Reactant mixture is stirred 5 hours, diluted with t-butyl methyl ether, with 1N salt acid elutions, organic phase is dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound light brown oil.Rf=0.25 (EtOAc- heptane 1: 1)；Rt=5.47.
b)(2S, 4R, 5R) -2- (2- mesyloxies-ethyl) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_163
Piperazine -6- Ji Jia Epoxide]-piperidines -1- carboxylic acid benzyl esters
According to conventional method F, 0.35 gram of (2S, 4R, 5R) -2- (2- hydroxy-ethyls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] is used
Figure 2006800106014_164
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 15a), obtain title compound light brown oil.Rf=0.15 (methylene chloride-methanol 10: 1)；Rt=5.16.
Embodiment 19
3- (2R 4R 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_165
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N- first Base-propionamide
According to conventional method E, 70.0 milligrams of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -2- (2- methylcarbamoyl-ethyls)-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_167
Piperazine -6- ylmethoxies] -2- (2- methylcarbamoyls Base-ethyl)-piperidines -1- carboxylic acid benzyl esters
It is similar to embodiment 6a, make 80.0 milligrams of (2R, 4R, 5R) -2- (2- CARBOXY-ETHYLs) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester and methylamine react, and obtains title compound as yellow oil.Rf=0.35 (methylene chloride-methanol 9: 1)；Rt=4.69.
b)(2R, 4R, 5R) -2- (2- CARBOXY-ETHYLs) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_169
Piperazine -6- ylmethoxies - piperidines -1- carboxylic acid benzyl esters
By 0.90 gram of (2R, 4R, 5R) -2- (2- Cyano-ethyls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_170
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters 20 milliliters of ethanol and 20 milliliters of 2N sodium hydroxide agitating solutions be heated to 85 DEG C overnight.Reactant mixture is cooled to room temperature, be acidified by adding 1N hydrochloric acid solutions, and extracted with ethyl acetate.Organic phase is separated, is dried, is concentrated under reduced pressure with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless oil is obtained.Rf=0.50 (methylene chloride-methanol 10: 1)；Rt=4.85.
c)(2R, 4R, 5R) -2- (2- Cyano-ethyls) -4- (4- methoxyl groups-phenyl) -5 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_171
Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
To 0.90 gram of (2S, 4R, 5R) -2- (2- mesyloxies-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_172
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 18b) 10 milliliters of dimethyl sulfoxide agitating solutions in add 0.25 gram of Cymag, and the mixture is heated to 50 DEG C, kept for 4 hours.Reactant mixture is diluted with water, extracted with ethyl acetate, is dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless oil is obtained.Rf=0.30 (EtOAc- heptane 1: 1)；Rt=5.20.
Embodiment 20
3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_173
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N- benzene Base-propionamide
According to conventional method E, 0.11 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_174
Piperazine -6- ylmethoxies] -2- (2- carbaniloyls-ethyl)-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_175
Piperazine -6- ylmethoxies] -2- (2- carbaniloyls - Ethyl)-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, 0.10 gram of (2R, 4R, 5R) -2- (2- CARBOXY-ETHYLs) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_176
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 19b) and aniline reaction, obtain title compound as colourless oil.Rf=0.50 (methylene chloride-methanol 10: 1)；Rt=5.40.
Embodiment 21
N- (2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_177
Piperazine -6- ylmethoxies]-piperidin-2-yl } - Ethyl)-benzamide
According to conventional method E, use 50.0 milligrams of (2S, 4R, 5R) -2- (2- benzamidos-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2S 4R 5R) -2- (2- benzamidos-ethyl) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_179
Piperazine-E- Ji Jia Epoxide]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, make 50.0 milligrams of (2S, 4R, 5R) -2- (2- amino-ethyls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_180
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester and benzoic acid, flash chromatography (SiO2After 60F), title compound as colourless oil is obtained.Rf=0.50 (methylene chloride-methanol 10: 1)；Rt=5.33.
b)(2S 4R 5R) -2- (2- amino-ethyls) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
To 70.0 milligrams of (2S, 4R, 5R) -2- (2- azidos-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_182
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters 4.0 milliliters of tetrahydrofurans and 0.4 milliliter of aqueous solution in add 30 milligrams of triphenyl phasphines.Reactant mixture is stirred 2 days at room temperature, is concentrated under reduced pressure, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.05 (methylene chloride-methanol 10: 1)；Rt=4.27.
c)(2S, 4R, 5R) -2- (2- azidos-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_183
Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
To 98.0 milligrams of (2S, 4R, 5R) -2- (2- mesyloxies-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_184
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 18b) DMF solution in add 94 milligrams of sodium azide, and obtained mixture is stirred at room temperature 24 hours.Reactant mixture is diluted with water, extracted with t-butyl methyl ether, is dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless oil is obtained.Rf=0.47 (EtOAc- heptane 1: 1)；Rt=5.65.
Embodiment 22
3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_185
Piperazine -6- ylmethoxies]-piperidin-2-yl }-N, N- Dimethvl-propionamide
According to conventional method E; use 75 milligrams of (2R, 4R, 5R) -2- (2- formyl-dimethylaminos-ethyl) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_186
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2R, 4R, 5R) -2- (2- formyl-dimethylaminos-ethyl) -4- (4- methoxyl groups - Phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_187
Piperazine -6 - ylmethoxy]-piperidines -1- carboxylic acid benzyl esters
It is similar to embodiment 6a, make 80.0 milligrams of (2R, 4R, 5R) -2- (2- CARBOXY-ETHYLs) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 19b) and dimethylamine react, and obtains title compound as yellow oil.Rf=0.35 (methylene chloride-methanol 9: 1)；Rt=4.93.
Embodiment 23
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- (3- phenoxy-propyls)-piperidines - 3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dioxy -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_189
Piperazine
According to conventional method E, 90.0 milligrams of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -2- (3- phenoxy-propyls)-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_191
Piperazine -6- ylmethoxies] -2- (3- phenoxy-propyls) - piperidines -1- carboxylic acid benzyl esters
At room temperature, to 120 milligrams of (2R, 4R, 5R) -2- (3- hydroxyl-propyls) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters 8 milliliters of tetrahydrofuran agitating solutions in add 36.5 milligrams of triphenylphosphines and 0.052 milliliter of diisopropyl azodicarboxylate.Reactant mixture is stirred 1 hour, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless oil is obtained.Rf=0.30 (EtOAc- heptane 1: 2)；Rt=6.06.
b)(2R, 4R, 5R) -2- (3- hydroxyl-propyls) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_193
Piperazine -6- ylmethoxies] - piperidines -1- carboxylic acid benzyl esters
It is similar to embodiment 15a, use 0.2 gram of (2R, 4R, 5R) -2- (2- CARBOXY-ETHYLs) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_194
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acids benzyl ester (coming from embodiment 19b), obtain title compound as colourless oil.Rf=0.50 (EtOAc-heptane 5: 1)；Rt=4.91.
Embodiment 24
6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- (3- phenyl-propoxies methyl) - Piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzene And [Isosorbide-5-Nitrae]
Figure 2006800106014_195
Piperazine
According to conventional method A; use 128 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- (3- phenyl-propoxies methyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- (3- phenyl-propoxy first Base) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_197
Piperazine
At room temperature, to 158 milligrams of [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_198
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methanol 8 milliliters of DMF solution in add 104 milligrams of sodium hydrides, the bromo- 3- phenylpropyl alcohols alkane of 0.048 milliliter of 1- and 193 milligrams of iodate 4-butyl amines.Reactant mixture is stirred overnight, is diluted with water, is extracted with t-butyl methyl ether, organic phase is dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.30 (EtOAc- heptane 1: 2)；Rt=6.11.
b)[(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_199
Piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-methanol
It is similar to Example 1, make 0.45 gram of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidines -2- carboxylic acid, ethyl esters and lithium aluminium hydride react, and obtains title compound as yellow oil.Rf=0.3 (EtOAc- heptane 2: 1)；Rt=4.82.
c)(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_201
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) - piperidines -2- carboxylic acid, ethyl esters
At 0 DEG C, to 1.51 grams of (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_202
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters (coming from embodiment 1a) 25 milliliters of dichloromethane solutions in add 1.97 milliliters of triethylamines, 3.5 milligrams of 4-dimethylaminopyridines and 0.57 gram of 4- toluene sulfochloride.Reactant mixture is warmed to room temperature overnight, with water and 1N hydrochloric acids, organic phase is separated, is dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.50 (EtOAc- heptane 1: 1)；Rt=5.44.
Embodiment 24b another synthetic method：
[(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [, 4]
Figure 2006800106014_203
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) - Piperidin-2-yl]-methanol
At room temperature; to 17.09 grams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_204
The tetrahydrofuran solution of 42 milliliters of 1N tetrabutylammoniums is added in 200 milliliters of tetrahydrofuran agitating solutions of piperazine.Reactant mixture is stirred at room temperature 2 hours, is diluted with water, extracted with t-butyl methyl ether.The organic phase of merging is dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Crude product 60F) is purified, the limpid yellow oil of title compound is obtained.Rf=0.30 (EtOAc- heptane 2: 1)；Rt=4.82.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) - 6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_205
Piperazine
According to conventional method C; use 19.0 grams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]After piperazine -3- ketone, flash chromatography, the golden yellow oil of title compound is obtained.Rf=0.50 (EtOAc- heptane 1: 2)；Rt=6.44.
b)6- [(3R, 4R, 6S) -4- (] 4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) - 6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_207
Piperazine -3- ketone
At room temperature; to 22.65 grams of (3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- tri isopropyl silane base epoxide methyl-pi -3- alcohol, 11.6 grams of 6- bromomethyls -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_208
1.63 grams of sodium hydrides are added in 200 milliliters of DMF agitating solutions of piperazine -3- ketone and 16.56 grams of iodate 4-butyl amines.Reactant mixture is stirred at room temperature 2 hours, pours into frozen water, extracted with t-butyl methyl ether.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Crude product 60F) is purified, the limpid yellow oil of title compound is obtained.Rf=0.50 (EtOAc- heptane 1: 1)；Rt=6.74.
c)(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- Tri isopropyl silane base epoxide methyl-pi -3- alcohol
At room temperature; to 19.3 grams of (3R; 4R; 10.9 grams of imidazoles and 6.79 grams of tri isopropyl chlorosilanes 6S) are added in 400 milliliters of DMF agitating solutions of -6- methylols -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidin-3-ol.Stir the reactant mixture to stay overnight, use 1N hydrochloric acids, extracted with t-butyl methyl ether.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Crude product 60F) is purified, title compound light yellow oil is obtained.Rf=0.60 (EtOAc- heptane 1: 1)；Rt=6.39.
d)(3R, 4R, 6S) -6- methylols -4- (4- methoxyl groups-phenyl) -1- (toluene -4- Sulfonyl)-piperidin-3-ol
At room temperature; to 108.1 grams of [(S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -1; 2; 3,6- Tetrahydro-pyridine -2- bases]-methanol 1000 milliliters of tetrahydrofuran agitating solutions in add 504 milliliters of borine-tetrahydrofuran (1M) solution.Reactant mixture is heated to 40 DEG C, kept for 2-6 hours, room temperature is cooled to, 150 milliliters of 2N sodium hydroxide solutions is added and 150 milliliter of 30% hydrogenperoxide steam generator is quenched.Organic phase is separated, is dried, is concentrated under reduced pressure with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound white solid is obtained.Rf=0.19 (EtOAc- heptane 1: 1)；Rt=3.67.
e)[(S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -1,2,3,6- tetra- Hydrogen-pyridine -2- bases]-methanol
At 0 DEG C, 57.7 grams of paratoluensulfonyl chlorides are added into 72.0 grams of [Tetrahydro-pyridine -2- bases of (S) -4- (4- methoxyl groups-phenyl) -1,2,3,6-] 1.51 ethyl acetate of-methanol and 1.51 2N aqueous sodium carbonates.Stir the reactant mixture to stay overnight, extracted with ethyl acetate, the organic phase merged is dried with sodium sulphate, is concentrated under reduced pressure.Crude product can be used without further purification in next step.Rf=0.1 (EtOAc- heptane 1: 1)；Rt=4.20.
f)[Tetrahydro-pyridine -2- bases of (S) -4- (4- methoxyl groups-phenyl) -1,2,3,6-]-methanol
At 70 DEG C, 43 grams of (S) -4- (4- methoxyl groups-phenyl) -6- oxos -1,2,11 tetrahydrofuran solutions of 3,6- Tetrahydro-pyridine -2- carboxylic acid benzyl esters are added into 11 tetrahydrofuran stirred suspensions of 10.9 grams of lithium aluminium hydride reductions.Reactant mixture is further stirred for 3-4 hours at this temperature, 0 DEG C is cooled to, 12.4 milliliters of water, 12.4 milliliters of 2N sodium hydroxides and 37 milliliters of water is slowly added to and is quenched.Mixture is filtered, be concentrated under reduced pressure filtrate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound white solid is obtained.Rf=0.17 (concentrated ammonia liquor of methylene chloride-methanol -25% 90: 10: 1)；Rt=2.55.
g)(S) -4- (4- methoxyl groups-phenyl) -6- oxos -1,2,3,6- Tetrahydro-pyridine -2- Carboxylic acid benzyl ester
At room temperature, to 15 milliliters of Isosorbide-5-Nitraes two of 1.8 grams of (S) -4- (4- methoxyl groups-phenyl) -6- oxo -3,6- dihydro -2H- pyridine -1,2- dicarboxylic acids 2- benzyl ester 1- tertiary butyl esters
Figure 2006800106014_209
1.2 milliliters of 4N hydrochloric acid/Isosorbide-5-Nitraes two are added in alkane solution
Figure 2006800106014_210
Alkane.Stirring reaction mixture 1 hour, is concentrated under reduced pressure, and obtains title compound pale solid.Rf=0.1 (EtOAc- heptane 1: 1)；Rt=3.94.
h)(S) -4- (4- methoxyl groups-phenyl) -6- oxo -3,6- dihydro -2H- pyridines - 1,2- dicarboxylic acids 2- benzyl ester 1- tertiary butyl esters
In argon atmosphere, to 2.75 grams of 6- oxos -4- (toluene -4- sulfonyloxies) -3,6- dihydro -2H- pyridines -1,1.4 grams of 4- methoxyphenyl-boronic acids, 3.15 grams of potassium phosphates, 0.12 gram of ' ic ' cl ' hexyl-(2 ' are added in 18 milliliters of tetrahydrofuran solutions of 2- dicarboxylic acids 2- benzyl ester 1- tertiary butyl esters, 4 ', 6 '-triisopropyl-biphenyl -2- bases)-phosphine (X-PHOS) and 22 milligrams of acid chlorides.Reactant mixture is heated to 80 DEG C, is kept for 2 hours, is cooled to room temperature, is diluted with ethyl acetate, organic phase is washed with water, dried with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown solid is obtained.Rf=0.35 (EtOAc- heptane 1: 2)；Rt=4.95.
i)(S) -6- oxos -4- (toluene -4- sulfonyloxies) -3,6- dihydro -2H- pyridines - 1,2- dicarboxylic acids 2- benzyl ester 1- tertiary butyl esters
It is similar to embodiment 24c, 9.43 grams of (2S) -4,6- dioxo-piperidin -1,2- dicarboxylic acids 2- benzyl ester 1- tertiary butyl esters [176436-10-5] is reacted with paratoluensulfonyl chloride, obtain title compound as yellow oil.Rf=0.64 (EtOAc- heptane 1: 1)；Rt=5.20.
j)6- bromomethyls -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_211
Piperazine -3- ketone
At room temperature, to 74.0 grams of 6- methylols -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_212
58 milliliters of trimethylammonium bromide silane are added in 600 milliliters of chloroformic solutions of piperazine -3- ketone (coming from embodiment 1g).Reactant mixture is stirred 30 minutes, and is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound pale solid is obtained.Rf=0.46 (EtOAc- heptane 1: 1)；Rt=4.03.
Embodiment 25
N- (2- { (2R 4R 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_213
Piperazine -6- ylmethoxies]-piperidin-2-yl } - Ethyl)-acetamide
According to conventional method A, 50 milligrams of N- { 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_214
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl }-acetamide, obtain title compound.
Prepare initiation material as follows：
a)N- { 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_215
Piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl]-ethyl }-acetamide
To 131 milligrams of 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_216
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethamine 3 milliliters of dichloromethane solutions in add 0.124 milliliter of triethylamine and 0.015 milliliter of chloroacetic chloride.Reactant mixture is stirred at room temperature 30 minutes, and diluted with dichloromethane and water.Each phase is separated, organic phase is dried with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rt=4.67.
b)2- [(2R 4R 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_217
Piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-ethamine
To 189 milligrams of 6- [(3R; 4R; 6R) -6- (2- azidos-ethyl) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]3.2 milligrams of 10%Pd/C are added in 20 ml methanol agitating solutions of piperazine, and at room temperature hydrogenate reactant mixture 1.5 hours.Reactant mixture is filtered, and is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rt=4.30.
c)6- [(3R, 4R, 6R) -6- (2- azidos-ethyl) -4- (4- methoxyl groups-phenyl) - 1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_219
Piperazine
It is similar to embodiment 21c, make 235 milligrams of methanesulfonic acid 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_220
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl ester and reaction of sodium azide, obtain title compound as yellow oil.Rf=0.46 (EtOAc- heptane 1: 1)；Rt=5.53.
d)Methanesulfonic acid 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_221
Piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl]-ethyl ester
According to conventional method F, 200 milligrams of 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol synthesis, obtain title compound as yellow oil.Rf=0.20 (EtOAc- heptane 1: 1)；Rt=5.12.
e)2- [(2R 4R5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_223
Piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-ethanol
It is similar to embodiment 15a, by 0.75 gram of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_224
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] reduction of-acetic acid, obtain title compound as colourless foams.Rf=0.1 (EtOAc- heptane 1: 1)；Rt=4.83.
f)[(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] Piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-acetic acid
It is similar to embodiment 19b, use 0.5 gram of [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetonitrile, obtain title compound green foam body.Rf=0.33 (EtOAc- heptane 5: 1)；Rt=4.76.
g)[(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_227
Piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-acetonitrile
It is similar to embodiment 19c, use 0.5 gram of (2S, 4R, 5R)-methanesulfonic acid 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_228
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester, obtain title compound.Rf=0.26 (EtOAc- heptane 1: 1)；Rt=5.20.
h)(2S, 4R, 5R)-methanesulfonic acid 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_229
Piperazine -6- ylmethoxies] -1- (toluene -4- Sulfonyl)-piperidin-2-yl methyl ester
According to conventional method F, 225 milligrams of [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methanol (coming from embodiment 24b), obtain title compound.Rf=0.45 (EtOAc- heptane 1: 1)；Rt=5.15.
Embodiment 26
6- [(3R, 4R, 6S) -6- benzyloxymethyls -4- (4- methoxyl groups-phenyl)-piperidines -3- Base epoxide methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_231
Piperazine
According to conventional method A; use 74 milligrams of 6- [(3R; 4R; 6S) -6- benzyloxymethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_232
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -6- benzyloxymethyls -4- (4- methoxyl groups-phenyl) -1- (first Benzene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_233
Piperazine
It is similar to embodiment 24a, make 80 milligrams of [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_234
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methanol (coming from embodiment 24b) and benzyl bromine reaction, flash chromatography (SiO2After 60F), title compound as white oil is obtained.Rf=0.38 (EtOAc- heptane 1: 1)；Rt=5.91.
Embodiment 27
6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- Phenoxymethyl-piperidines -3- Base epoxide methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_235
Piperazine
According to conventional method A; use 72.0 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- phenoxymethyls -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_236
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- phenoxymethyl -1- (first Benzene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 76.0 milligrams of (2S, 4R, 5R)-methanesulfonic acid 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_238
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester (coming from embodiment 25h) 2 milliliters of DMF agitating solutions in add 9.0 milligrams of sodium hydrides and 42.0 milligrams of phenol.Reactant mixture is warming up to 90 DEG C, is kept for 3 hours, is cooled to room temperature, is diluted with water, and extracted with t-butyl methyl ether.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.28 (EtOAc- heptane 1: 2)；Rt=5.90.
Embodiment 28
6- [(3R, 4R, 6S) -6- (3- methoxy-phenoxymethyls) -4- (4- methoxyl groups-phenyl) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 9.6 milligrams of 6- [((3R; 4R; 6S) -6- (3- methoxy-phenoxymethyls) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -6- (3- methoxy-phenoxymethyls) -4- (4- methoxyl groups - Phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 27a, make 54 milligrams of (2S, 4R, 5R)-methanesulfonic acid 4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_242
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester (coming from embodiment 25h) and 3- metoxyphenols react, and obtains title compound as yellow oil.Rf=0.24 (EtOAc- heptane 1: 2)；Rt=5.82.
Embodiment 29
(R, S) -1- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -propyl- 2- alcohol (non-enantiomer mixture)
According to conventional method A, 54 milligrams (R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- alcohol (non-enantiomer mixture), obtain the non-enantiomer mixture of title compound.
Prepare initiation material as follows：
a)(R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -propyl- 2- alcohol (non-enantiomer mixture)
At room temperature, to 0.5 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_246
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone 8.0 milliliters of tetrahydrofuran agitating solutions in add 1.5 milliliters of 1M borine tetrahydrofuran complex solutions.Reactant mixture is stirred 3 hours, is quenched, is concentrated under reduced pressure with 60 ml methanols.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.53 (EtOAc- heptane 5: 1)；Rt=4.95 and 5.06.
b)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -propyl- 2- ketone
At 0 DEG C, to 0.79 gram of N- methoxyl groups -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_248
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides 10 milliliters of tetrahydrofuran agitating solutions in add 1.3 milliliters of 3M methyl-magnesium-bromides tetrahydrofuran solution.Stirring reaction mixture 1 hour, is diluted with 1 N aqueous potassium hydrogen sulfates, is extracted with t-butyl methyl ether.Merge organic phase, dried with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.20 (EtOAc- heptane 1: 1)；Rt=5.14.
c)N- methoxyl groups -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides
According to conventional method D, make 0.79 gram of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_250
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid (coming from embodiment 25f) and N, O- dimethyl hydroxylamine hydrochloride react, and obtains title compound as colourless foams.Rf=0.44 (EtOAc- heptane 5: 1)；Rt=5.00.
Embodiment 30
6- [((3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R, S) -2- methoxyl groups-the third Base)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H - benzo [Isosorbide-5-Nitrae]  piperazines (non-enantiomer mixture)
According to conventional method A; use 77.0 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((R; S) -2- methoxy-propvls) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R, S) -2- methoxyl groups - Propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines (non-enantiomer mixture)
At 0 DEG C, to 87 milligrams of (R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_254
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- alcohol (non-enantiomer mixture) (coming from embodiment 29a) 2.0 milliliters of DMF solution in add 59 milligrams of sodium hydrides and 0.110 milliliter of iodomethane.Stir the reactant mixture 1 hour, use 1N hydrochloric acids, extracted with t-butyl methyl ether.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.30 (EtOAc- heptane 1: 1)；Rt=5.50.
Embodiment 31
(R, S) -3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2- methyl-propanenitriles (non-enantiomer mixture)
According to conventional method A, 72.0 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_256
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-propanenitriles (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -2- methyl-propanenitriles (non-enantiomer mixture)
It is similar to embodiment 19c, use 249 milligrams of methanesulfonic acid (R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_258
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (non-enantiomer mixture), obtain title compound pale red oil.Rf=0.25 (EtOAc- heptane 1: 1)；Rt=5.25.
b)Methanesulfonic acid (R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl] (diastereomer is mixed -1- methyl-ethyl ester Thing)
According to conventional method F, 210 milligrams of (R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_260
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- alcohol (non-enantiomer mixture) (coming from embodiment 29a), obtain title compound as yellow oil.Rf=0.27 (EtOAc- heptane 1: 1)；Rt=5.23.
Embodiment 32
6- [(3R, 4R, 6R) -6- (2- benzyloxy-ethyls) -4- (4- methoxyl groups-phenyl)-piperidines - 3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 66 milligrams of 6- [(3R; 4R; 6R) -6- (2- benzyloxy-ethyls) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -6- (2- benzyloxy-ethyls) -4- (4- methoxyl groups-phenyl) - 1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 24a, make 80 milligrams of 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_264
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol (derive from embodiment 25e) and benzyl bromine reaction, obtain title compound as yellow oil.Rf=0.3 (EtOAc- heptane 1: 2)；Rt=5.85.
Embodiment 33
N- (2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] piperazine -6- ylmethoxies]-piperidin-2-yl } - Ethyl)-N- methyl acetamides
According to conventional method A, 72 milligrams of N- { 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_266
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl }-N- methyl acetamides, obtain title compound.
Prepare initiation material as follows：
a)N- (2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl]-ethyl }-N- methyl acetamides
At 0 DEG C, to 82 milligrams of N- { 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_268
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl-acetamide (coming from embodiment 25a) 2.0 milliliters of DMF solution in add 59 milligrams of sodium hydrides and 0.110 milliliter of iodomethane.Stir the reactant mixture 1 hour, use 1N hydrochloric acids, extracted with t-butyl methyl ether.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.49 (methylene chloride-methanol 10: 1)；Rt=4.83.
Embodiment 34
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- methoxy-propvls) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 61 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- methoxy-propvls) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_270
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- methoxyl groups-the third Base) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to embodiment 30a, 63 milligrams of 1- [4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_272
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- (R) -2- alcohol (diastereomer 1), obtain title compound as yellow oil.Rt=5.58.
b)(R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -propyl- 2- alcohol (diastereomer 1) and
(S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -propyl- 2- alcohol (diastereomer 2)
It is similar to embodiment 29a, use 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_275
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone (coming from embodiment 29b), obtain title compound.Utilize flash chromatography (SiO260F), diastereomer is separated.
Diastereomer 1：Yellow oil；Rf=0.18 (EtOAc- heptane 1: 1)；Rt=5.10.
Diastereomer 2：Yellow oil；Rf=0.09 (EtOAc- heptane 1: 1)；Rt=4.98.
Embodiment 35
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- methoxy-propvls) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- methoxy-propvls) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_277
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- methoxyl groups-the third Base) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 30a, use 1- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_279
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- (S) -2- alcohol (diastereomer 2) (coming from embodiment 34b), obtain title compound as yellow oil.Rt=5.54.
Embodiment 36
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- methylsulfanyls-the third Base)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H - benzo [Isosorbide-5-Nitrae]  piperazines (diastereomer 1)
To 92 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- methylsulfanyls-propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]100 milligrams of naphthalenes and 20 milligrams of sodium are added in 2.0 milliliters of dimethoxyethane solutions of piperazine (diastereomer 1).By ultrasonically treated 10 minutes of reactant mixture, it is diluted with water, and extracted with dichloromethane.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- methylsulfanyls - propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 103 milligrams of methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_283
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester 2.0 milliliters of DMF solution in add 19.5 milligrams of sodium methyl mercaptides, and by obtained mixture be heated to 70 DEG C overnight.Reactant mixture is cooled to room temperature, is diluted with water, and is extracted with dichloromethane.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound orange oil is obtained.Rf=0.53 (EtOAc- heptane 5: 1)；Rt=5.81.
b)Methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester
According to conventional method F, 0.58 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_285
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- (S) -2- alcohol (diastereomer 2) (coming from embodiment 34b), obtain title compound brown oil.Rf=0.53 (EtOAc- heptane 5: 1)；Rt=5.28.
Embodiment 37
N- ((R) -2- { (2R 4R 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - yl } -1- methyl-ethyls)-acetamide
According to conventional method A, 70 milligrams of N- { (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_287
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-acetamide, obtain title compound.
Prepare initiation material as follows：
a)N- { (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-acetamide
According to conventional method D, make 80 milligrams of (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines and acetic acid reaction, obtain title compound brown oil.Rf=0.17 (EtOAc- heptane 5: 1)；Rt=4.67.
b)(R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -1- methyl ethylamines
It is similar to embodiment 21b; by 90 milligrams of 6- [(3R; 4R; 6R) -6- ((R) -2- azidos-propyl group) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine is reduced, and obtains title compound black oil.Rf=0.17 (EtOAc- heptane 5: 1)；Rt=4.42.
c)6- [(3R, 4R, 6R) -6- ((R) -2- azidos-propyl group) -4- (4- methoxyl groups-benzene Base) -1- (toluene -4- sulfonyls))-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar with embodiment 21c, use 150 milligrams of methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (diastereomer 2) (coming from embodiment 36b), obtain title compound green oil.Rf=0.24 (EtOAc- heptane 1: 2)；Rt=5.76.
Embodiment 38
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- methylsulfanyls-the third Base)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H - benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 48 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- methylsulfanyls-propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_295
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- methylsulfanyls - propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 36a, use 108 milligrams of methanesulfonic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_297
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester, obtain title compound orange oil.Rf=0.53 (EtOAc- heptane 5: 1)；Rt=5.80.
b)Methanesulfonic acid (R) -2- ((2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester
It is similar to embodiment 36b, use 0.36 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_299
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-Piperidin-2-yl] -propyl- (R) -2- alcohol (diastereomer 1) (coming from embodiment 34b), obtain title compound brown oil.
Rf=0.53 (EtOAc- heptane 5: 1)；Rt=5.28.
Embodiment 39
6- [(3R, 4R, 6R) -6- ((R) -2- Ethylsulfanyls-propyl group) -4- (4- methoxyl groups-benzene Base)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H - benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 60 milligrams of 6- [(3R; 4R; 6R) -6- (6- (R) -2- Ethylsulfanyls-propyl group) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -6- ((R) -2- Ethylsulfanyls-propyl group) -4- (4- methoxyl groups - phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 36a, make 90 milligrams of methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_303
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1 methyl-ethyl ester (coming from embodiment 36a) and ethyl mercaptan sodium reacts, and obtains the faint yellow oil of title compound.Rf=0.50 (EtOAc- heptane 1: 1)；Rt=5.96.
Embodiment 40
((R) -2- (2R, AR, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 1- methyl-ethyls)-dimethyl-amines
According to conventional method A, 58 milligrams of { (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_305
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-dimethyl-amines, obtain title compound.
Prepare initiation material as follows：
a){ (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-dimethyl-amines
To 40 milligrams of (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines (coming from embodiment 37b) 1 milliliter of tetrahydrofuran solution in add O.065 milliliter formic acid and O.065 milliliter formalin (37%); and obtained reactant mixture is heated to 80 DEG C, kept for 1 hour.Ethyl acetate diluted reaction mixture is used, is washed with saturated sodium bicarbonate, and by organic phase separation of merging, is dried with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rf=0.20 (EtOAc- heptane 1: 1)；Rt=4.58.
Embodiment 41
N- ((R) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - yl } -1- methyl-ethyls) -2,2- dimethvl-propionamides
According to conventional method A, 8.O milligrams of N- { (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_309
Piperazine -6- ylmethoxies]-l- (toluene -4- sulfonyls)-piperidin-2-yl]-l- methyl-ethyls } -2,2- dimethvl-propionamides, obtain title compound.
Prepare initiation material as follows：
a)N- { (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls } -2,2- dimethyl-the third Acid amides
At room temperature, to 50 milligrams of (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines (coming from embodiment 37b) 5.0 milliliters of dichloromethane solutions in add 0.057 milliliter of DIPEA and 0.010 milliliter of pivalyl chloride.Stirring reaction mixture is stayed overnight, and is concentrated under reduced pressure, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless foams.Rf=0.50 (EtOAc- heptane 5: 1)；Rt=5.26.
Embodiment 42
6- [(3R 4R 6R) -6- ((R) -2- imidazoles -1- bases-propyl group) -4- (4- methoxyl groups - Phenyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros - 2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 18 milligrams of 6- [(3R; 4R; 6R) -6- ((R) -2- imidazoles -1- bases-propyl group) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -6- ((R) -2- imidazoles -1- bases-propyl group) -4- (4- methoxies Base-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 50 milligrams of methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_315
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (diastereomer 2) (coming from embodiment 36b) 0.2 milliliter of N- crassitude solution in add 48 milligrams of imidazoles, and by reactant mixture 70 DEG C heat 3 days.Be concentrated under reduced pressure reactant mixture, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.40 (methylene chloride-methanol 10: 1)；Rt=4.58.
Embodiment 43
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R, S) -2- pyrrolidines -1- Base-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- bis- Hydrogen -2H- benzo [Isosorbide-5-Nitrae]  piperazines (non-enantiomer mixture)
According to conventional method A; use 130 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((R; S) -2- pyrrolidin-1-yls-propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_317
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R, S) -2- pyrrolidines - 1- bases-propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 100 milligrams of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_319
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone (coming from embodiment 29b) 5 milliliters of ethanol solutions in add 0.026 milliliter of pyrrolidines, 0.009 milliliter of acetic acid and 31 milligrams of sodium cyanoborohydrides.Stirring reaction mixture is stayed overnight, and with dchloromethane, is washed with 1N sodium hydrate aqueous solutions.Organic phase is merged, dried with sodium sulphate, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless oil is obtained.Rf=0.50 (methylene chloride-methanol 2: 1)；Rt=4.67.
According to the method described by embodiment 43, following compounds are prepared in a similar way：Embodiment：
58 6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R, S) -2- morpholines -4 - base-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
59 Diethyl-((R, S) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl } -1- methyl-ethyls)-amine
63 Isobutyl group-((R, S) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl } -1- methyl-ethyls)-methyl-amine
Embodiment 44
Isopropyl-(2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- Base }-ethyl)-amine
According to conventional method A, 110 milligrams of isopropyls-{ 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_324
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl }-amine, obtain title compound.
Prepare initiation material as follows：
a) Isopropyl-(2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl]-ethyl }-amine
To 100 milligrams of 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_326
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethamine 3 milliliters of ethanol solutions in add 0.006 milliliter of acetone, 0.009 milliliter of acetic acid and 0.032 gram of sodium cyanoborohydride.Reactant mixture is stirred at room temperature overnight, diluted with t-butyl methyl ether, is washed with 1N sodium hydroxides, and organic phase is merged, is dried with sodium sulphate.The muddy yellow oil of crude product is obtained, it may be used for next step without further purifying.Rf=0.23 (EtOAc- heptane 2: 1)；Rt=4.59.
b)2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-ethamine
To 1.9 grams of [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_328
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetonitrile (coming from embodiment 25g) 30 milliliters of tetrahydrofuran solutions in add 11.0 milliliters of 1M borine tetrahydrofuran solutions.Reactant mixture is stirred overnight, is quenched with methanol, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.09 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 10: 1)；Rt=4.32.
Embodiment 45
N- (2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - Ethyl) -2- (ttetrahydro-pyran -4- bases)-isobutyramide
According to conventional method A, 160 milligrams of N- { 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl } -2- (ttetrahydro-pyran -4- bases)-isobutyramide, obtain title compound.
Prepare initiation material as follows：
a)N- (2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl]-ethyl } -2- (ttetrahydro-pyran -4- bases)-isobutyryl Amine
According to conventional method D, make 100 milligrams of 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_332
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethamine (coming from embodiment 44b) and 2- methyl -2- (ttetrahydro-pyran -4- bases)-propionic acid [16386-97-3] react, and obtains title compound as yellow oil.Rf=0.40 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 20: 1)；Rt=3.87.
Embodiment 46
6- [(3R, 4R, 6R) -6- ((S) -2- imidazoles -1- bases-propyl group) -4- (4- methoxyl groups - Phenyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4 dihydros - 2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A, use 40 milligrams of 6- [(3R, 4R, 6R) -6- ((S) -2- imidazoles -1- bases-propyl group) -4- (4- methoxyl groups-phenyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_334
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)(3R, 4R, 6R) -6-（（S)-imidazoles -1- bases-propyl group) -4- (4- methoxyl groups-phenyl) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 42a, make methanesulfonic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_336
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (coming from embodiment 38b) and imidazoles react, and obtains title compound as colourless oil.Rf=0.22 (methylene chloride-methanol 10: 1)；Rt=4.60.
Embodiment 47
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R) -2- [1,2,4] triazoles -1 - base-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 100 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- ((R) -2- [1; 2; 4] triazol-1-yl-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_338
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) - 6- ((R) -2- [1,2,4] triazol-1-yl-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 0.126 gram 1,2, the N of 4- triazoles (triazaole) sodium salt, 0.1 gram of methanesulfonic acid (S) -2- [(2R is added in dinethylformamide solution, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_340
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (diastereomer 2) (coming from embodiment 36b), and obtained mixture is stirred at room temperature 2 days.Reactant mixture is diluted with water, extracted with ethyl acetate, organic phase is separated, is dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.50 (EtOAc- heptane 5: 1)；Rt=4.76.
Embodiment 48
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- [1,2,4] triazoles -1 - base-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- ((S) -2- [1; 2; 4] triazol-1-yl-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_342
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) - 6- ((S) -2- [1,2,4] triazol-1-yl-propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 47a, use methanesulfonic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_344
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (coming from embodiment 38b), obtain title compound as colourless oil.Rf=0.13 (EtOAc- heptane 5: 1)；Rt=4.84.
Embodiment 49
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLEs -5 - yl)-propyl group]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 26.0 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLE -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_346
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLEs - 5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 0.12 gram of (R) -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_348
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-propanenitriles and 0.0043 gram of dibutyl tin oxide 4.0 milliliters of toluene agitating solutions in add 0.44 milliliter of trimethylsilyl azide.Reactant mixture is heated to 125 DEG C overnight, is concentrated under reduced pressure, and pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rf=0.7 (methylene chloride-methanol 9: 1)；Rt=4.71
b)(R) -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -2- methyl-propanenitriles
It is similar to embodiment 31, use methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_350
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (diastereomer 2) (coming from embodiment 36b), obtain title compound brown oil.Rf=0.58 (EtOAc- heptane 2: 1)；Rt=5.18.
Embodiment 50
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -2- (1H-TETRAZOLE -5- Base)-propyl group]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- bis- Hydrogen -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 0.096 gram of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -2- (1H-TETRAZOLE -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_352
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -2- (1H-TETRAZOLEs - 5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 49, use 0.1 gram of (S) -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_354
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-propanenitriles, obtain title compound brown oil.Rf=0.7 (methylene chloride-methanol 9: 1)；Rt=4.71
b)(S) -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -2- methyl-propanenitriles
It is similar to embodiment 31, use methanesulfonic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_356
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (coming from embodiment 38b), obtain title compound brown oil.Rf=0.58 (EtOAc- heptane 2: 1)；Rt=5.18.
Embodiment 51
1- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2- first Base -propyl- 2- alcohol
According to conventional method A, 0.095 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol, obtain title compound.
Prepare initiation material as follows：
a)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol
At 0 DEG C, 0.34 milliliter of methyl magnesium bromide solution (3M, in ether) is added to 0.17 gram of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_360
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methyl acetate 3 milliliters of tetrahydrofuran solutions in.It is quenched with 1N aqueous potassium hydrogen sulfates after 3 hours, reactant mixture is post-processed, and is extracted (3X) with t-butyl methyl ether.By the organic layer of merging salt water washing, dried with sodium sulphate, and be concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, the muddy yellow oil of title compound is obtained.Rf=0.12 (EtOAc- heptane 1: 1)；Rt=5.11.
b)[(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-methyl acetate
At 0 DEG C, the ethereal solution (0.2M) of 4 milliliters of diazomethanes is added dropwise to 0.12 gram of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid (coming from embodiment 25f) 2 ml methanol solution in.It is quenched with solid magnesium sulfate after 3.5 hours, reactant mixture is post-processed, to decompose any excessive diazomethane, is filtered and be concentrated under reduced pressure, obtain crude title compound light yellow solid, it can just be used without further purifying in next step.Rf=0.78 (EtOAc)；Rt=5.26.
Embodiment 52
(S) -1- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 3- methyl-butyl- 2- alcohol
According to conventional method A, 0.058 gram of (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (diastereomer 1), obtain title compound.
Prepare initiation material as follows：
a)(S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (diastereomer 1) and (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (diastereomer 2)
It is similar to embodiment 34b, by 0.16 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_367
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-there is provided title compound for the reduction of butyl- 2- ketone.
Diastereomer 1：Colorless oil；Rf=0.26 (EtOAc- heptane 1: 1)；Rt=5.40.
Diastereomer 2：Colorless oil；Rf=0.19 (EtOAc- heptane 1: 1)；Rt=5.50.
b)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -3- methyl-butyl- 2- ketone
At room temperature, by 0.19 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_369
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-butyl- 3- alkene -2- ketone and 0.044 gram of 10%Pd/C mixture hydrogenates 30 minutes in 5 milliliters of ethanol.Reactant mixture is clarified by filtering, concentrates, obtains crude title compound shallow brown oil, it can just be used without further purifying in next step.Rf=0.30 (EtOAc- heptane 1: 1)；Rt=5.54.
c)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -3- methyl-butyl- 3- alkene -2- ketone
It is similar to embodiment 29b, make 0.20 gram of N- methoxyl groups -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_371
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides (coming from embodiment 29c) and isopropenyl magnesium bromide (0.5M; in tetrahydrofuran) reaction; crude title compound yellowish-brown oil is obtained, it can just be used without further purifying in next step.Rf=0.22 (EtOAc- heptane 1: 1)；Rt=5.49.
Embodiment 53
(R) -1- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 3- methyl-butyl- 2- alcohol
According to conventional method A, 0.024 gram of (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (diastereomer 2) (coming from embodiment 52a), obtain title compound.
Embodiment 54
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- pyrazol-1-yls - Propyl group)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros - 2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 100 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- pyrazol-1-yls-propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- pyrazoles -1- Base-propyl group) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 42a, make methanesulfonic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_377
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] sodium salt of -1- methyl-ethyl ester (coming from embodiment 38b) and pyrazoles reacts, and obtains title compound as colourless solid.Rf=0.62 (EtOAc)；Rt=5.07.
Embodiment 55
6- { (3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (5- methyl-tetrazoles - 2- bases)-propyl group]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 62 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (5- methyl-tetrazole -2- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_379
Piperazine (region isomer 1), obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (5- methyl - Tetrazolium -2- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine (region isomers 1) and
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (5- methyl - Tetrazolium -1- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine (region isomers 2)
It is similar to embodiment 42a, make methanesulfonic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] sodium salt of -1- methyl-ethyl ester (diastereomer 2) (coming from embodiment 36b) and 5- methyl tetrazoliums reacts; the mixture of the region isomer comprising title compound is obtained, then passes through flash chromatography (SiO260F) separated region isomers.
Region isomer 1：Colorless oil；Rf=0.25 (EtOAc- heptane 1: 1)；Rt=5.07.
Region isomer 2：Crystalline solid；Rf=0.08 (EtOAc- heptane 1: 1)；Rt=4.92.
Embodiment 56
6- { (3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (5- methyl-tetrazoles - 1- bases)-propyl group]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 44 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (5- methyl-tetrazole -1- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_384
Piperazine (region isomer 2) (coming from embodiment 55a), obtains title compound.
Embodiment 57
6- [(3R, 4R, 6R) -6- [2- (2- Mehtoxy-ethoxies) -2- methyI-oropvDs] -4- (4- methoxyl groups-phenyl)-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 64.2 milligrams of 6- [(3R; 4R; 6R) -6- [2- (2- Mehtoxy-ethoxies) -2- methyI-oropvDs] -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound as yellow oil.Rf=0.28 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 20: 1)；Rt=4.56.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -6- [2- (2- Mehtoxy-ethoxies) -2- methyI-oropvDs] - 4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 100 milligrams of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol 0.7 milliliter of tetrahydrofuran solution in add 35 milligrams of sodium hydrides (55% dispersion, in oil).Stir the reactant mixture 30 minutes, then add 47 μ 12- chloroethyl methyl ethers and 10 milligrams of iodate 4-butyl amines.Mixture is stirred 5 hours at 70 DEG C.During this time, repeat (5x) and add sodium hydride and 2- chloroethyl methyl ethers.By mixture with 2 milliliters of water process, and (2x) is extracted with 50 milliliters of ethyl acetate.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.13 (EtOAc- heptane 1: 1)；Rt=5.58.
b)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol
At 0 DEG C, to 700 milligrams of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_390
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methyl acetate 10 milliliters of tetrahydrofuran solutions in add 1.43 milliliters of methyl-magnesium-bromides (3M solution, in ether).After reactant mixture is handled 2.5 hours with 1N aqueous potassium hydrogen sulfates, (2x) is extracted with 60 milliliters of ethyl acetate.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, is evaporated under reduced pressure, obtains title compound as white foams.Rf=0.10 (EtOAc- heptane 1: 1)；Rt=5.11.
c)[(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-methyl acetate
At 0 DEG C, to 2.03 grams of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_392
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid (coming from embodiment 25f) 50 ml methanol solution in add 0.1M diazomethanes ethereal solution, until to methyl esters conversion complete untill.Reactant mixture is handled with magnesium sulfate, to remove excessive diazomethane.Solid is filtered to remove, be concentrated under reduced pressure organic layer.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.24 (EtOAc- heptane 1: 1)；Rt=5.24.
Embodiment 60：
Dimethyl-amino formic acid 2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- bases } -1,1- dimethyl-ethyl ester
According to conventional method A, 35 milligrams of dimethyl-amino formic acid 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_394
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl-ethyl ester, obtain title compound.
Prepare initiation material as follows：
a) Dimethyl-amino formic acid 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl-ethyl ester
To 120 milligrams of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_396
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol (coming from embodiment 57b) 0.5 milliliter of tetrahydrofuran solution in add 80 milligrams of hydrofinings (35% dispersion, in oil).Stir the reactant mixture 1 hour, then add 163 μ l formyl-dimethylamino chlorine.Mixture is stirred at room temperature 18 hours.By mixture with 2 milliliters of water process, and (2x) is extracted with 50 milliliters of ethyl acetate.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow solid is obtained.Rf=0.45 (EtOAc- heptane 2: 1)；Rt=5.59.
The method described according to embodiment 60, prepares following compounds in a similar way：
Embodiment：
70 Dimethyl-amino formic acid (S) -1-（2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide]-piperidin-2-yl methyl }-propyl diester
From (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_398
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol (diastereomer 2) (coming from embodiment 64d) start prepare.
71 Dimethyl-amino formic acid (R) -1- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide]-piperidin-2-yl methyl }-propyl diester
From (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_400
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol (diastereomer 1) (coming from embodiment 64d) start prepare.
86 Dimethyl-amino formic acid (S) -1- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide]-piperidin-2-yl methyl } -2- methyl-propyl esters
From (S) -1 [((2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_402
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (diastereomer 1) (coming from embodiment 52a) start prepare.
87 Dimethyl-amino formic acid (R) -1- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) - 5- [4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia of 4- (3- methoxy-propvls) -3 Epoxide]-piperidin-2-yl methyl } -2- methyl-propyl esters
From (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_404
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (diastereomer 2) (coming from embodiment 52a) start prepare.
Embodiment 61
1- ((R, S) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine -2 - yl } -1- methyl-ethyls)-pyrrolidin-2-one
According to conventional method A, 0.035 gram of 1- { (R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-pyrrolidin-2-one, obtain title compound.
Prepare initiation material as follows：
a)1- { { (R, S) -2- [(2R 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-pyrrolidin-2-one
According to conventional method D, 0.116 gram of 4- { (R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines base }-butyric acid, obtain title compound as yellow oil.Rf=0.23 (methylene chloride-methanol 9: 1)；Rt=4.90.
b)4- { (R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethylaminos }-butyric acid
Similar to embodiment 43a, 0.100 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone (coming from embodiment 29b) and the reaction of 0.164 gram of 4-Aminobutanoicacid, obtain title compound as yellow " pastel ".Rf=0.02 (methanol)；Rt=4.40.
The method described according to embodiment 61, prepares following compounds in a similar way：
Embodiment：
62 1- ((R or S) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- bases } -1- methyl-ethyls)-pyrrolidin-2-one
Embodiment 64
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLEs -5 - yl)-butyl]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 184 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLE -5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_413
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLEs - 5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 49a, use (R) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_415
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyronitrile, obtain title compound as yellow oil.Rf=0.25 (methylene chloride-methanol 10: 1)；Rt=4.76.
b)(R) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl methyl]-butyronitrile
It is similar to embodiment 19c, in the presence of 274 milligrams of tetrabutyl ammonium cyanides, use 363 milligrams of methanesulfonic acid (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propyl diester, obtain title compound as colourless oil.Rf=0.35 (EtOAc- heptane 1: 1)；Rt=5.26.
c)Methanesulfonic acid (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propyl diester
According to conventional method F, 100 milligrams of (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol (diastereomer 2), obtain title compound brown oil.Rt=5.22.
d)(R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl]-butyl- 2- alcohol (diastereomer 1) and
(S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -55- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl]-butyl- 2- alcohol (diastereomer 2)
It is similar to embodiment 29a, use 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_422
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone, obtain title compound.Utilize flash chromatography (SiO260F), diastereomer is separated.
Diastereomer 1：Colorless oil；Rf=0.60 (EtOAc- heptane 5: 1)；Rt=5.11；
Diastereomer 2：Colorless oil；Rf=0.50 (EtOAc- heptane 1: 1)；Rt=5.01；
e)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-butyl- 2- ketone
It is similar to embodiment 29b, in the presence of ethyl-magnesium-bromide, use 1.0 grams of N- methoxyl groups -2- [4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_424
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides (coming from embodiment 29c), flash chromatography (SiO2Title compound as colourless oil is obtained after 60F).Rf=0.20 (EtOAc- heptane 1: 1)；Rt=5.13.
The method described according to embodiment 64, prepares following compounds in a similar way：
Embodiment：
91 6- { (3R, 4R, 6S) -4- (4- fluoro-phenyls) -6- [(R) -2- (1H-TETRAZOLEs -5 - yl)-butyl]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
Embodiment 65
N- ethyls -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - yl } -2,2- dimethvl-propionamides
According to conventional method A, 100 milligrams of N- ethyls -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethvl-propionamides, obtain title compound.
Prepare initiation material as follows：
a)N- ethyls -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethvl-propionamides
According to conventional method D, 150 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_429
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids and 1.0 grams of ethamine, obtain title compound brown oil.Rf=0.13 (EtOAc- heptane 1: 1)；Rt=5.14.
b)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- Dimethyl-propionic acids
To 8.62 grams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_431
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acid methyl esters 20 milliliters of tetrahydrofurans and 50 milliliters of ethanol solutions in add 60 milliliter of 20% sodium hydroxide solution.Reactant mixture is stirred 4 hours at 65 DEG C.Organic solvent is evaporated under reduced pressure, is acidified remaining solution with 6M aqueous hydrochloric acid solutions, untill pH value 2.(3x) mixture is extracted with 200 milliliters of ethyl acetate.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless foams are obtained.Rf=0.27 (EtOAc- heptane 3: 1)；Rt=5.10.
c)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- Dimethyl-propionic acid methyl esters
At -78 DEG C, 100 milliliters of 0.5M lithium diisopropylamide solution are added into 28 milliliters of tetrahydrofuran solutions of 5.75 milliliters of methyl isobutyrates, and stir at -78 DEG C the reactant mixture 30 minutes.Then 17.74 milliliters of hexamethyl phosphoramides are added at -78 DEG C, and further stirs the mixture 30 minutes.Then at -78 DEG C; by 8.66 grams of 6- [(3R; 4R; 6S) -6- bromomethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]28 milliliters of tetrahydrofuran solutions of piperazine are added dropwise in " enolate ", and stir the solution 30 minutes.Reactant mixture is warming up to -12 DEG C, and extra stirring 40 minutes at this temperature.The solution is quenched with 1M aqueous hydrochloric acid solutions, and (3x) is extracted with 200 milliliters of ethyl acetate.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless foams are obtained.Rf=0.29 (EtOAc- heptane 1: 1)；Rt=5.65.
d)6- [(3R, 4R, 6S) -6- bromomethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4 - sulfonyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- bis- Hydrogen -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 11.18 grams of methanesulfonic acid (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_435
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester (coming from embodiment 25h) 40 milliliters of dimethyl formamide solutions in add 13.78 grams of lithium bromides, and stir at 65 DEG C the reactant mixture 14 hours.Reactant mixture is warmed to room temperature, 50 milliliters of water are added.(3x) mixture is extracted with 300 milliliters of t-butyl methyl ethers.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless foams are obtained.Rf=0.39 (EtOAc- heptane 1: 1)；Rt=5.68.
Embodiment 66
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -2- (1H-TETRAZOLE -5- Base)-butyl]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- bis- Hydrogen -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 34 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -2- (1H-TETRAZOLE -5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -2- (1H-TETRAZOLEs - 5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 49a, use (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_439
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyronitrile, obtain title compound as yellow oil.Rf=0.22 (methylene chloride-methanol 10: 1)；Rt=4.77.
b)(S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl methyl]-butyronitrile
It is similar to embodiment 19c, in the presence of 93 milligrams of cyaniding tetrabutylammoniums, use 123 milligrams of methanesulfonic acid (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_441
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propyl diester, obtain title compound as colourless oil.
Rf=0.32 (EtOAc- heptane 1: 1)；Rt=5.28.
c)Methanesulfonic acid (R) -1- [(2R 4R5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propyl diester
According to conventional method F, 100 milligrams of (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_443
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol (diastereomer 1) (coming from embodiment 64d), obtain title compound brown oil.Rt=5.38.
The method described according to embodiment 66, prepares following compounds in a similar way：
Embodiment：
89 6- { (3R, 4R, 6S) -4- (4- fluoro-phenyls) -6- [(S) -2- (1H-TETRAZOLE -5- Base)-butyl]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- bis- Hydrogen -2H- benzos [Isosorbide-5-Nitrae]  piperazines
Embodiment 67
Dimethyl-amino formic acid (R) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl } -1- methyl-ethyl ester
According to conventional method A, use 112 milligrams of dimethyl-amino formic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_446
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester, obtain title compound.
Prepare initiation material as follows：
a)Dimethyl-amino formic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5 - [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- base methoxies Base] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (diastereomer 1)
At room temperature, to 100 milligrams of (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- alcohol (diastereomer 1) (coming from embodiment 34b) 10 milliliters of tetrahydrofuran solutions in add 35 milligrams of hydrofinings and 0.14 milliliter of N, N- formyl-dimethylamino chlorine.Extra one hour of stirring reaction mixture, it is diluted with water, is extracted with t-butyl methyl ether.The organic phase of merging is dried and is concentrated under reduced pressure, crude title compound is obtained.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.37 (EtOAc- heptane 2: 1)；Rt=5.44.
Embodiment 68
Dimethyl-amino formic acid (S) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl } -1 methyl-ethyl ester
According to conventional method A, use 100 milligrams of dimethyl-amino formic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_450
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester, obtain title compound.
Prepare initiation material as follows：
a)Dimethyl-amino formic acid (S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5 - [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- base methoxies Base] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester
At room temperature, to 100 milligrams of (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_452
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- alcohol (diastereomer 2) (coming from embodiment 34b) 10 milliliters of tetrahydrofuran solutions in add 34 milligrams of hydrofinings and 0.14 milliliter of N, N- formyl-dimethylamino chlorine.Extra one hour of stirring reaction mixture, it is diluted with water, is extracted with t-butyl methyl ether.The organic phase of merging is dried and is concentrated under reduced pressure, crude title compound is obtained.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.41 (EtOAc- heptane 2: 1)；Rt=5.47.
Embodiment 69
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -3- methyl -2- (1H- Tetrazolium -5- bases)-butyl]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines (diastereomer 1)
According to conventional method A; use 100 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -3- methyl -2- (1H-TETRAZOLE -5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine (diastereomer 1), obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(S) -3- methyl -2- (1H-TETRAZOLE -5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base oxygen Ylmethyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 49a, use (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_456
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] -3- methyl-butanenitriles, obtain the oil of title compound slightly brown.Rf=0.20 (EtOAc- heptane 1: 1)；Rt=4.86.
b)(S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl methyl] -3- methyl-butanenitriles
It is similar to embodiment 19c, in the presence of 275 milligrams of cyaniding tetrabutylammonium/acetonitriles, use 370 milligrams of methanesulfonic acid (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_458
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] -2- methyl-propyl esters, obtain title compound as yellow oil.Rf=0.30 (EtOAc- heptane 1: 1)；Rt=5.38.
c)  Methanesulfonic acid (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] -2- methyl-propyl esters
According to conventional method F, 400 milligrams of (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -]-(toluene -4- sulfonyls)-piperidin-2-yl] -3- methyl-butyl- 2- alcohol (coming from embodiment 53), obtain title compound as colourless oil.Rf=0.29 (EtOAc- heptane 1: 1)；Rt=5.34.
Embodiment 72
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl-propionic acid
According to conventional method A, 100 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_462
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b), obtain title compound.
Embodiment 73
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R)-[1,2,4] triazol-1-yls - butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros - 2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 46 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- ((R) -2- [1; 2; 4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_464
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) - 6- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 55a, by 90 milligrams of methanesulfonic acid (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_466
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] sodium salt of-propyl diester (coming from embodiment 64c) and 116 milligrams of 1,2,4-triazoles is stirred overnight in 1 milliliter of DMF, at 40 DEG C.Reactant mixture is diluted with water, extracted with ethyl acetate.Organic phase is merged, dries, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.20 (EtOAc- heptane 2: 1)；Rt=4.85.
The method described according to embodiment 73, prepares following compounds in a similar way：
Embodiment：
88 6- [(3R, 4R, 6R) -4- (4- fluoro-phenyls) -6- ((R) -2- [1,2,4] triazoles -1 - base-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
75 6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((S) -2- [1,2,4] triazoles - 1- bases-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
From methanesulfonic acid (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_469
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propyl diester (coming from embodiment 66c) start prepare.
The method described according to embodiment 75, prepares following compounds in a similar way：
Embodiment：
94 6- [(3R, 4R, 6R) -4- (4- fluoro-phenyls) -6- ((S) -2- [1,2,4] triazoles -1 - base-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
Embodiment 74
(R, S) -3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2- rnethyl-propanoic acids (mixture of diastereomer)
According to conventional method A, 150 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_472
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- rnethyl-propanoic acids, after flash chromatography, obtain title compound as yellow oil.Rf=0.07 (concentrated ammonia liquor of methylene chloride-methanol -25% 100: 20: 1)；Rt=3.66 and 3.77.
Prepare initiation material as follows：
a)(R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -2- rnethyl-propanoic acids (non-enantiomer mixture)
By 1.1 grams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_474
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-propanenitriles (non-enantiomer mixture) (coming from embodiment 31a) 20 milliliters of ethanol and 2N sodium hydroxide agitating solutions be heated to 80 DEG C, kept for 2 days.After hydrolysis is completed, add 2N hydrochloric acid and be acidified reactant mixture, and extracted with dichloromethane.Organic phase is merged, dries, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.20 (EtOAc- heptane 2: 1)；Rt=4.85.
Embodiment 76
(R, S) -3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - methyl-N- (ttetrahydro-pyran -4- bases)-propionamide (non-enantiomer mixture)
According to conventional method A, 104 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_476
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-N- (ttetrahydro-pyran -4- bases)-propionamide (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -2- methyl-N- (ttetrahydro-pyran -4- bases) - Propionamide (non-enantiomer mixture)
According to conventional method D, 85 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_478
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- rnethyl-propanoic acids (mixture of diastereomer) (coming from embodiment 74a) and 14 milligrams of 4- amido tetrahydrofurans, flash chromatography (SiO2After 60F), title compound as yellow oil is obtained.Rf=0.23 (EtOAc- heptane 2: 1)；Rt=4.91.
Embodiment 77
(R, S) -3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2- methyl-N- [(S) -1- (tetrahydro-furan -2- bases)-methyl]-propionamide is (non-right Reflect the mixture of body)
According to conventional method A, 100 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_480
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-N- [(S) -1- (tetrahydro-furan -2- bases)-methyl]-propionamide (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -2- methyl-N- [(S) -1- (tetrahydro-furans -2 - yl)-methyl]-propionamide (non-enantiomer mixture)
According to conventional method D, 100 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_482
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- rnethyl-propanoic acids (non-enantiomer mixture) (coming from embodiment 74a) and 16 milligrams of (S)-tetrahydrofurfuryl amines, flash chromatography (SiO2After 60F), title compound as yellow oil is obtained.Rf=0.22 and 0.19 (EtOAc- heptane 4: 1)；Rt=5.06.
Embodiment 78
(R, S)-N- (2- carbamoyl -2- methyI-oropvDs) -3- { (2R, 4R, 5R) -4- (4 - methoxyl group-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2- methyl-malonamic (diastereomers Mixture)
According to conventional method A; use 93 milligrams of (R; S)-N- (2- carbamoyl -2- methyI-oropvDs) -3- [(2R; 4R; 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_484
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-malonamics (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S)-N- (2- carbamoyl -2- methyI-oropvDs) -3- [(2R, 4R, 5R) -4 - (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] - 2- methyl-malonamics (non-enantiomer mixture)
According to conventional method D, 100 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_486
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- rnethyl-propanoic acids (non-enantiomer mixture) (coming from embodiment 74a) and 19 milligrams of 3- amino -2; 2- dimethvl-propionamides, obtain title compound as yellow oil.Rf=0.16 (EtOAc)；Rt=4.62.
Embodiment 79
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl-N-[(S) -1- (tetrahydro-furan -2- bases)-methyl]-propionamide
According to conventional method A, 97 milligrams of 3- [(2S, 5R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_488
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl-N -s [(S) -1- (tetrahydro-furan -2- bases)-methyl]-propionamide, obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- dimethyl-N -s [(S) -1- (tetrahydro-furan -2- Base)-methyl]-propionamide
According to conventional method D, 110 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_490
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b) and 20 milligrams of (S)-tetrahydrofurfuryl amines, obtain title compound as yellow oil.Rf=0.35 (EtOAc- heptane 8: 1)；Rt=5.12.
The method described according to embodiment 79, prepares following compounds in a similar way：
Embodiment：
80 3- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2,2- dimethyl-N -s (ttetrahydro-pyran -4- bases)-propionamide
85 3- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2,2- dimethyl -1- morpholines -4- bases -propyl- 1- ketone
132 N- (2- dimethylarnino-ethyls) -3- (2S, 4R, 5R) -4- (4- methoxyl groups - Phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy]-piperidin-2-yl } -2,2- dimethvl-propionamides
133 N- (3- dimethylammo-propyls) -3- (2S, 4R, 5R) -4- (4- methoxyl groups - Phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy]-piperidin-2-yl } -2,2- dimethvl-propionamides
Embodiment 81
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl-propionitrile
According to conventional method A (at 0 DEG C), 100 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_496
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl-propionitrile, obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- dimethyl-treasure's nitrile
By 500 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_498
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2; 5 milliliters of tetrahydrofuran suspension of 2- Dimethyl-propionic acids (coming from embodiment 65b), 111.2 milligrams of ammonium chlorides and 0.7 milliliter of triethylamine are cooled to -10 DEG C, and 1.21 milliliters of T3P are added dropwise
Figure 2006800106014_499
Solution (50%, in ethyl acetate).Reactant mixture is warmed to room temperature, and stirred 8 hours.Obtained suspension is stirred 2 days at 70 DEG C.During this time, 111.2 milligrams of ammonium chlorides of addition, 0.7 milliliter of triethylamine and 1.21 milliliters of T3P are repeated twice
Figure 2006800106014_500
Solution (50%, in ethyl acetate).Reactant mixture is quenched by adding 5 milliliters of water, (3x) is extracted with 50 milliliters of ethyl acetate.By the organic layer of merging salt water washing, and dried with sodium sulphate.Organic layer is filtered, is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless foams are obtained.Rf=0.12 (EtOAc- heptane 1: 2)；Rt=5.42.
Embodiment 82
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [2- methyl -2- (1H-TETRAZOLEs - 5- bases)-propyl group]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 45.7 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [2- methyl -2- (1H-TETRAZOLE -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxide methyl 4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [2- methyl -2- (1H- Tetrazolium -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 140 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_504
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2; 0.55 milliliter of trimethylsilyl azide and 5.3 milligrams of dibutyl tin oxides are added in 3 milliliters of toluene solutions of 2- dimethyl-propionitrile (coming from embodiment 81a), and the mixture is flowed back 24 hours.During this time, 0.55 milliliter of trimethylsilyl azide of addition and 5.3 milligrams of dibutyl tin oxides are repeated twice.Reactant mixture is warming up to room temperature, and hydrolyzed with 2 milliliters of 1N aqueous hydrochloric acid solutions.(3x) mixture is extracted with 50 milliliters of dichloroethanes, and by the organic layer of merging salt water washing, is dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.15 (EtOAc- heptane 3: 1)；Rt=4.87.
Embodiment 83
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [2- (1H-TETRAZOLE -5- bases) - ethyl]-piperidines -3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- dihydros - 2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 150 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [2- (1H-TETRAZOLE -5- bases)-ethyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_506
Piperazine, obtains title compound.Prepare initiation material as follows：
a)6- [(3R 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [2- (1H-TETRAZOLE -5- Base)-ethyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 49a, use 200 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_508
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionitrile, obtain the sticky yellow oil of title compound.Rf=0.10 (EtOAc- heptane 4: 1)；Rt=4.71.
b)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-propionitrile
It is similar to embodiment 19c, use 2.75 grams of methanesulfonic acid 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_510
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl ester (coming from embodiment 25d), obtain title compound as colourless oil.
Embodiment 84
(R, S) -3- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [14]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2- methyl isophthalic acids-morpholine -4- bases -propyl- 1- ketone (non-enantiomer mixture)
According to conventional method A, 108 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_512
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl isophthalic acids-morpholine -4- bases -propyl- 1- ketone (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -2- methyl isophthalic acids-morpholine -4- bases -propyl- 1- ketone (non-enantiomer mixture)
According to conventional method D, 100 milligrams of (R, S) -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_514
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- rnethyl-propanoic acids (non-enantiomer mixture) (coming from embodiment 74a) and 14 milligrams of morpholines, obtain title compound as yellow oil.Rf=0.23 (EtOAc- heptane 4: 1)；Rt=5.01 and 5.08.
Embodiment 90
6- { (3R 4R 6S) -4- [4- (3- methoxy-propoxyls)-phenyl] -6- [(R) -2- (1H-TETRAZOLE -5- bases)-propyl group]-piperidines -3- base epoxides methyl } -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 50 milligrams of 6- [(3R; 4R; 6S) -4- [4- (3- methoxy-propoxyls)-phenyl] -6- [(R) -2- (1H-TETRAZOLE -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_516
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- [4- (3- methoxy-propoxyls)-phenyl] -6- [(R) -2 - (1H-TETRAZOLE -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- bases Epoxide methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 180 milligrams of 4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_518
Piperazine -6- ylmethoxies] -2- [(R) -2- (1 H- tetrazolium -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidin-4-yl]-phenol and 104 milligrams of 3- methoxy-propyl chlorine DMF agitating solution in add 147 milligrams of cesium carbonates.Suspension is heated to 60 DEG C overnight, is diluted with water, and extracted with ethyl acetate.Organic phase is merged, dries and is concentrated under reduced pressure, obtain crude title compound.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rf=0.40 (EtOAc- heptane 5: 1)；Rt=4.81.
b)4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzene And [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -2- [(R) -2- (1H-TETRAZOLE -5- bases)-propyl group] - 1- (toluene -4- sulfonyls)-piperidin-4-yl]-phenol
To 200 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLE -5- bases)-propyl group] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_520
470 milligrams of ethyl mercaptan sodium are added in the DMF agitating solution of piperazine (coming from embodiment 49a), and obtained suspension is heated to 130 DEG C overnight.Reactant mixture is diluted with 1N hydrochloric acid solutions, and extracted with ethyl acetate.Organic phase is merged, dries and is concentrated under reduced pressure, obtain crude title compound.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rf=0.40 (EtOAc- heptane 5: 1)；Rt=4.81.
Embodiment 92
1- (2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 1,1- dimethyl-ethyI) -3- (ttetrahydro-pyran -4- bases)-urea
According to conventional method A, 138.7 milligrams of 1- { 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl-ethyIs } -3- (ttetrahydro-pyran -4- bases)-urea, obtain title compound as white foams.Rf=0.15 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 10: 1)；Rt=3.79.
Prepare initiation material as follows：
a)1- (2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -1,1- dimethyl-ethyIs } -3- (ttetrahydro-pyrans -4 - yl)-urea
To 150 milligrams of 6- [(3R; 4R; 6S) -6- (2- isocyanide acyl -2- methyI-oropvDs) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_524
228 milligrams of 4- amino-ttetrahydro-pyrans are added in 1 milliliter of tetrahydrofuran solution of piperazine, and the mixture is stirred at room temperature 2 hours.Solvent is evaporated under reduced pressure, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.31 (EtOAc- heptane 7: 1)；Rt=4.91.
b)6- [(3R, 4R, 6S) -6- (2- isocyanides root closes base 2- methyI-oropvDs) -4- (4- first Epoxide-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
At 0 DEG C, to 290.2 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_526
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2; 80 μ l ethyl chloroformates are added in 4 milliliters of tetrahydrofuran solutions of 2- Dimethyl-propionic acids (coming from embodiment 65b) and 0.14 milliliter of triethylamine, and the mixture is stirred 1 hour at 0 DEG C.Then, 2 milliliters of aqueous solution of 523 milligrams of sodium azide are added dropwise, and reactant mixture is further stirred 45 minutes at 0 DEG C.Mixture is warming up to room temperature, and diluted with 2 milliliters of water.(3x) mixture is extracted with 50 milliliters of ethyl acetate, and (2x) is washed with water in the organic layer of merging, is dried with sodium sulphate.Organic layer is filtered, and is evaporated under reduced pressure.Pass through flash chromatography (SiO260F, EtOAc- heptane 1: residue 1) is purified, corresponding acyl azide colorless oil is obtained.Residue is re-dissolved in 2 milliliters of toluene, and is heated to 115 DEG C, holding 1 hour.Toluene is evaporated under reduced pressure, crude title compound brown oil is obtained.Rt=5.77.
The method described according to embodiment 92, prepares following compounds in a similar way：
Embodiment：
93 3- (2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- Base } -1,1- dimethyl-ethyIs) -1,1- dimethyl-urea
99 Morpholine -4- carboxylic acids (2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - Piperidin-2-yl } -1,1- dimethyl-ethyIs)-acid amides
Embodiment 95
6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- phenylmethylsulfonyl methyl-pis - 3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method C, 60 milligrams of 6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- phenyl-mesylmethyl-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_530
Piperazine -3- ketone, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- phenylmethylsulfonyls methyl - Piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]  piperazines - 3- ketone
According to conventional method A; use 157 milligrams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- phenyl-mesylmethyl -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_532
Piperazine -3- ketone, obtains title compound as white foams.Rf=0.28 (methylene chloride-methanol 20: 1)；Rt=3.77.
b)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- phenyl-mesylmethyl - 1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups-the third Base) -4H- benzos [Isosorbide-5-Nitrae]  piperazine -3- ketone
To 160 milligrams of 6- [(3R; 4R; 6S) -6- Benzylsulfanyls methyl -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_534
128 milligrams of chloro- benzylhydroperoxide of 3- are added in the chloroformic solution of piperazine -3- ketone, and obtained mixture is stirred at room temperature 1 hour.With 0.5M sodium hydrate aqueous solutions (40 milliliters) diluted reaction mixture, extracted with t-butyl methyl ether.Organic phase is separated, is dried, is concentrated under reduced pressure with sodium sulphate.Pass through flash chromatography (SiO2Residue 60F) is purified, white foam is obtained.Rf=0.33 (EtOAc- heptane 2: 1)；Rt=5.07.
c)6- [(3R, 4R, 6S) -6- Benzylsulfanyl methyl -4- (4- methoxyl groups-phenyl] -1 - (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) - 4H- benzos [Isosorbide-5-Nitrae]  piperazine -3- ketone
0.070 milliliter of benzyl mercaptan is added into 8 milliliters of DMFs stirring mixture of 28 milligrams of sodium hydrides.After 15 minutes, 200 milligrams of methanesulfonic acid (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are addedPiperazine -6- ylmethoxies]-piperidin-2-yl methyl ester, and the reactant mixture is stirred at room temperature 3 hours.By reactant mixture (50 milliliters) dilutions of 1M sodium bicarbonate aqueous solutions, extracted with t-butyl methyl ether, separate organic phase, and dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.27 (EtOAc- heptane 1: 1)；Rt=5.75.
d)Methanesulfonic acid (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3- oxos -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- ylmethyl esters
According to conventional method F, 5 grams of 6- [(3R, 4R, 6S) -6- methylols -4- (4- methoxyl groups-phenyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_538
Piperazine -3- ketone, obtains title compound as white foams.Rf=0.27 (EtOAc- heptane 2: 1)；Rt=4.81.
e)6- [(3R, 4R, 6S) -6- methylols -4- (4- methoxyl groups-phenyl)-piperidines -3- Base epoxide methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]  piperazine -3- ketone
At 5 DEG C; to 14.8 grams of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_540
The tetrahydrofuran solution that 34.6 milliliters of 1N are fluorinated 4-butyl amine is added in 200 milliliters of tetrahydrofuran agitating solutions of piperazine -3- ketone (coming from embodiment 24b-b).Reactant mixture is stirred at room temperature 2 hours, is diluted with water, extracted with t-butyl methyl ether.By the organic phase of merging salt water washing, dried with sodium sulphate, and be concentrated under reduced pressure.Pass through flash chromatography (SiO2Crude product 60F) is purified, title compound as white foams are obtained.Rf=0.20 (EtOAc- heptane 2: 1)；Rt=4.54.
The method described according to embodiment 95, prepares following compounds in a similar way：
Embodiment：
96 6- [(3R, 4R, 6S) -6- mesylmethyls -4- (4- methoxyl groups-phenyl)-piperidines - 3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
97 6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- (2- methyl-propans -2 - sulfonvlmethvl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
Embodiment 98
((R) -2- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 1- methyl-ethyls)-pyridine -2- bases-amine
According to conventional method A, 73 milligrams of ((R) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_544
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-pyridine -2- bases-amine, obtain title compound.
Prepare initiation material as follows：
a){ (R) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls }-pyridine -2- bases-amine
In argon atmosphere, by 96 milligrams of (R) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_546
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines (coming from embodiment 37b), 21 milligrams of sodium tert-butoxides, 0.022 milliliter of chloro- pyridine of 2- and 1.0 milliliters of toluene are placed in " schlenk test tubes ".2.7 milligrams of acid chlorides (II), 0.4 milliliter of toluene solution of 5.1 milligrams of 1,3- bis- (diphenylphosphino) propane are added into the mixture.Reactant mixture is stirred 2 days at 70 DEG C.By (25 milliliters) dilutions of water of obtained mixture, extracted with t-butyl methyl ether, separate organic phase, and dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as yellow oil.Rf=0.09 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 10: 1)；Rt=4.62.
Embodiment 100
6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- ((2- methyl -2H - tetrazolium -5- bases))-butyl]-piperidines -3- base epoxides methyl } -4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 0.099 gram of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- ((2- methyl -2H- tetrazolium -5- bases) or (1- methyl isophthalic acid H- tetrazolium -5- bases))-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine (region isomer 1), obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- ((2- methyl - 2H- tetrazolium -5- bases))-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base oxygen Ylmethyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines (region Isomers 1) and
6- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- ((1- methyl - 1H-TETRAZOLE -5- bases)))-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- bases Epoxide methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines (area Domain isomers 2)
At 0 DEG C, freshly prepd diazomethane/diethyl ether solution (is come from into Diazald
Figure 2006800106014_551
) it is added dropwise to 0.201 gram of 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- (1H-TETRAZOLE -5- bases)-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_552
In 8 ml methanol solution of piperazine (coming from embodiment 64a).After 2.5 hours, solid magnesium sulfate, to decompose any excessive diazomethane, then concentrated reaction mixture are added.Obtained residue is suspended in dichloromethane, filters and concentrates again.Pass through flash chromatography (SiO2Residue 60F) is purified, the region isomer that title compound and its N- methylate is obtained.
Diastereomer 1, region isomer 1：Brown oil；Rf=0.19 (EtOAc- heptane 2: 1)；Rt=5.19.
Diastereomer 1, region isomer 2：Yellow oil；Rf=0.26 (EtOAc- heptane 2: 1)；Rt=5.38.
The method described according to embodiment 100, prepares following compounds in a similar way：
Embodiment：
101 6- { (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- ((1- methyl - 1H-TETRAZOLE -5- bases) or (2- methyl -2H- tetrazolium -5- bases))-butyl]-piperidines - 3- base epoxides methyl } -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
From 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- [(R) -2- ((1- methyl isophthalic acid H- tetrazolium -5- bases) or (2- methyl -2H- tetrazolium -5- bases))-butyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_554
Piperazine (region isomer 2) (coming from embodiment 100a) starts to prepare.
Embodiment 102
3- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl-N-(1- methyl-pi -4- bases)-propionamide
According to conventional method A, 100 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl-N -s (1- methyl-pi -4- bases)-propionamide, obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- dimethyl-N -s (1- methyl-pi -4- bases)-the third Acid amides
According to conventional method D, 196 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_558
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b) and 37 milligrams of 1- methyl-pi -4- base amine, obtain title compound as colourless oil.Rf=0.24 (methylene chloride-methanol 10: 1)；Rt=4.47.
Embodiment 103
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl-N-piperidin-4-yl-propionamide
According to conventional method A, 90 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_560
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl-N -s piperidin-4-yl-propionamide, obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- dimethyl-N -s piperidin-4-yl-propionamide
According to conventional method E, 160 milligrams of 4- { 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl-propanoylamino }-piperidines -1- carboxylic acid benzyl esters, obtain title compound as yellow oil.Rf=0.50 (methylene chloride-methanol 5: 1)；Rt=4.55.
b)4- { 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -2,2- dimethyl-propanoylamino }-piperidines -1- carboxylics Sour benzyl ester
According to conventional method D, 224 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b) and 87 milligrams of 4- amino-piperadine -1- carboxylic acid benzyl esters, obtain title compound as colourless oil.Rf=0.18 (EtOAc- heptane 1: 1)；Rt=5.53.
Embodiment 104
(S or R) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- Base } -1- (2H- tetrazolium -5- bases)-ethanol
According to conventional method A, 230 milligrams of (S or R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_566
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- (2H- tetrazolium -5- bases)-ethanol, obtain title compound.
Prepare initiation material as follows：
a)(S or R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl] -1- (2H- tetrazolium -5- bases)-ethanol
It is similar to embodiment 49a, use 1.0 grams of (R, S) -2- hydroxyls -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_568
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionitrile (non-enantiomer mixture), pass through flash chromatography (SiO260F) after separation diastereomer, title compound as colourless foams are obtained.Rf=0.15 (EtOAc- heptane 1: 1)；Rt=4.54.
b)(R, S) -2- hydroxyls -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionitrile (non-enantiomer mixture)
At room temperature, to 3.7 grams of [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_570
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetaldehyde 50 milliliters of dichloromethane agitating solutions in add 3.03 grams of trimethylsilyl cyanides and 1.36 grams of zinc bromides.Reactant mixture is stirred overnight, is diluted with two chloro- methane and water, separates organic phase and drying.Be concentrated under reduced pressure organic phase, and then residue is dissolved in 25 ml methanols, then adds 2.5 grams of potassium fluorides.Reactant mixture is stirred 2 hours, is concentrated under reduced pressure, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as yellow oil.Rf=0.25 (EtOAc- heptane 1: 1)；Rt=4.93.
c)[(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-acetaldehyde
At 0 DEG C, to 4.29 grams of 2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_572
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol (coming from embodiment 25e) 6.0 milliliters of dimethyl sulfoxides and 30 milliliters of dichloromethane agitating solutions in add 4.80 milliliters of triethylamines and 3.60 grams of pyridine. sulfur trioxide compounds.Extra stirring reaction mixture 3 hours, are then warming up to room temperature, are diluted with water at this temperature, add 1N potassium hydrogen sulfate solutions and are acidified, then use extracted by ether.Organic phase is dried, is concentrated under reduced pressure, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as colourless oil.Rf=0.21 (EtOAc- heptane 1: 1)；Rt=4.82.
Embodiment 105
(R, S) -2- (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 1 (S, R)-(2H- tetrazolium -5- bases)-ethanol (non-enantiomer mixture)
According to conventional method A, 950 milligrams of (R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_574
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- (2H- tetrazolium -5- bases)-ethanol (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -1- (2H- tetrazolium -5- bases)-ethanol (diastereomeric Body mixture)
It is similar to embodiment 49a, use 1.0 grams of 2- hydroxyls -3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_576
Piperazine -6- ylmethoxies] -1 (S, R)-(toluene -4- sulfonyls)-piperidin-2-yl]-propionitrile (non-enantiomer mixture) (coming from embodiment 104b), flash chromatography (SiO2After 60F), the brown oil of the non-enantiomer mixture of title compound is obtained.Rf=0.10 (EtOAc- heptane 1: 1)；Rt=4.54.
Embodiment 106
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl -1- (4- thyl-piperazin -1- bases) -propyl- 1- ketone
It is similar to embodiment 102, make 1- methyl piperazines and 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_578
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2; 2- Dimethyl-propionic acids (coming from embodiment 65b) react; obtain 3- [(2S; 4R; 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl -1- (4- thyl-piperazin -1- bases) -propyl- 1- ketone, it is then deprotected according to conventional method A, title compound is obtained.
Embodiment 107
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2- Dimethyl -1- piperazines -1- bases -propyl- 1- ketone
It is similar to embodiment 102, make piperazine and 3- [(2S, 4R, 5R) -4- (4- ethyoxyls-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_581
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2; 2- Dimethyl-propionic acids (coming from embodiment 65b) react; obtain 3- [(2S; 4R; 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_582
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl -1- piperazines -1- bases -propyl- 1- ketone, it is then deprotected according to conventional method A, title compound is obtained.
Embodiment 108
((S) -2- (2S 4R5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 1- methyl-ethyls)-(1H-TETRAZOLE -5- bases)-amine
According to conventional method A, 159 milligrams of N- { (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_584
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls } -4- methyl-N- (1H-TETRAZOLE -5- bases)-benzsulfamide, obtain title compound.
Prepare initiation material as follows：
a)N- { (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls } -4- methyl-N- (1H - tetrazolium -5- bases)-benzsulfamide
It is similar to method 49a, use 435 milligrams of N- { (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_586
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls } -4- methyl-N- (cyano group)-benzsulfamide, obtain title compound as yellow oil.Rf=0.17 (concentrated ammonia liquor=100 of methylene chloride-methanol -25%: 10: 1)；Rt=5.37.
b)N- { (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyls } -4- methyl-N- (cyanogen Base)-benzsulfamide
At room temperature, to 399 milligrams of (S) -2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines 5 milliliters of dichloromethane agitating solutions in add 0.12 milliliter of triethylamine and 66 milligrams of cyanogen bromides.Stir the reactant mixture 2 hours, then add 0.32 milliliter of triethylamine, 178 milligrams of 4- toluene sulfochlorides and 7 milligrams of 4-N- dimethyl aminopyridines.Reactant mixture is heated to 50 DEG C, is kept for 4 hours, is then washed with 1N hydrochloric acid solutions, and extracted with dichloromethane.Organic phase is merged, dries, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.16 (EtOAc- heptane 1: 1)；Rt=5.71.
c)(S) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl] -1- methyl ethylamines
It is similar to embodiment 37b; by 1.52 grams of 6- [(3R; 4R; 6R) -6- ((S) -2- azidos-propyl group) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_590
Piperazine is reduced, and obtains title compound as colourless oil.Rf=0.45 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 20: 1)；Rt=4.41.
d)6- [(3R, 4R, 6R) -6- ((S) -2- azidos-propyl group) -4- (4- methoxyl groups-benzene Base) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 37c, use 150 milligrams of methanesulfonic acid (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_592
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl-ethyl ester (coming from the 8b of embodiment 3), obtain title compound green oil.Rf=0.33 (EtOAc- heptane 1: 1)；Rt=5.71.
The method described according to embodiment 108, prepares following compounds in a similar way：
Embodiment：
109 ((R) -2- { (3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - yl } -1- methyl-ethyls)-(1H-TETRAZOLE -5- bases)-amine
From (R) -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_594
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1- methyl ethylamines (coming from embodiment 37b) start prepare.
Embodiment 110
(R, S) -1- methoxyl groups -3- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - Piperidin-2-yl } -2- methyl -propyl- 2- alcohol (non-enantiomer mixture)
According to conventional method A, 200 milligrams of (R, S) -1- methoxyl groups -3- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_596
Piperazine -6- ylmethoxies]-piperidin-2-yl } -2- methyl -propyl- 2- alcohol (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -1- methoxyl groups -3- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl } -2- methyl -propyl- 2- alcohol (non-enantiomer mixture)
To 1.0 grams of (R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_598
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone (coming from embodiment 29b) 15 ml methanol agitating solutions in add 360 milligrams of oxidation trimethyl-sulfonium iodides (trimethyl-sulfoxonium iodide) and 273 milligrams of sodium hydroxides; and reactant mixture is heated to 70 DEG C, kept for 1 day.Reactant mixture is concentrated under reduced pressure, and residue is received in water and dichloromethane.Organic phase is dried, and is concentrated under reduced pressure, crude title compound is obtained.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.39 (EtOAc- heptane 1: 1)；Rt=5.09.
Embodiment 111
(R, S) -4- methoxyl groups -1- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - Piperidin-2-yl } -2- methyl-butyl- 2- alcohol (non-enantiomer mixture)
According to conventional method A, 65 milligrams of (R, S) -4- methoxyl groups -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_600
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-butyl- 2- alcohol (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -4- methoxyl groups -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-butyl- 2- alcohol (diastereomeric Body mixture)
It is similar to embodiment 29b, make 4- methoxyl groups -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_602
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone and methyl bromide reactive magnesium, obtain title compound as yellow oil.Rf=0.22 (EtOAc- heptane 1: 1)；Rt=5.12.
b)4- methoxyl groups -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone
To 0.5 gram of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_604
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 3- alkene -2- ketone 1.5 ml methanol agitating solutions in add 38 milligram 2; 8; the sec-butyls -2 of 9- tri-; 5; 8; tetra- azepine -1- phosphas of 9- two ring [3.3.3] hendecane, and the reactant mixture is heated to 35 DEG C, kept for 1 day.Reactant mixture is diluted with 1N hydrochloric acid solutions, and extracted with ethyl acetate.Organic phase is merged, dries and is concentrated under reduced pressure, obtain crude title compound.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.25 (EtOAc- heptane 2: 3)；Rt=5.16.
c)1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-butyl- 3- alkene -2- ketone
It is similar to embodiment 29b, use N- methoxyl groups -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_606
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides (coming from embodiment 29c) and vinyl magnesium bromide, obtain title compound as yellow oil.Rf=0.50 (EtOAc- heptane 1: 1)；Rt=5.23.
Embodiment 112
(R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- Sulfonyl)-piperidin-2-yl] -2- methyl -3- [1,2,4] triazol-1-yl -propyl- 2- alcohol (non-enantiomer mixture)
According to conventional method A, 200 milligrams of (R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_608
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -3- [1,2,4] triazol-1-yl -propyl- 2- alcohol (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(R, S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3, 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl] -2- methyl -3- [1,2,4] triazol-1-yl -propyl- 2- alcohol (non-enantiomer mixture)
To 200 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- ((R; S) -2- methyl-oxiranyl methyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_610
310 milligram 1 of addition in 2.0 milliliters of DMF agitating solutions of piperazine (non-enantiomer mixture), the sodium salt of 2,4- triazoles, and reactant mixture is heated to 40 DEG C overnight.Reactant mixture is diluted with water, extracted with ethyl acetate.Organic phase is merged, dries and is concentrated under reduced pressure, obtain crude title compound.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.15 (EtOAc- heptane 1: 1)；Rt=4.61.
b)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- ((R, S) -2- methyl-oxygen Heterocycle hydroxypropyl methyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines (non-enantiomer mixture)
At room temperature, 56 milligrams of sodium hydrides are added into 5.0 milliliters of dimethyl sulfoxide agitating solutions of 331 milligrams of oxidation trimethyl sulfonium iodides, then add 912 milligrams of 1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_612
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone (coming from embodiment 29b).Stir the reactant mixture 3 hours, use 1N hydrochloric acids, extracted with t-butyl methyl ether.Organic phase is dried and is concentrated under reduced pressure, crude title compound is obtained.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.19 (EtOAc- heptane 1: 1)；Rt=5.29.
Embodiment 113
(3- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2 - Dimethyl-propyl)-(ttetrahydro-pyran -4- bases)-amine
According to conventional method A, 182 milligrams of { 3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_614
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propyls }-(ttetrahydro-pyran -4- bases)-amine, obtain title compound.
Prepare initiation material as follows：
a){ 3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- Dimethyl-propyls }-(ttetrahydro-pyran -4- bases) - Amine
It is similar to embodiment 43a, use 430 milligrams of 3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_616
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl-propionic aldehyde and 79 milligrams of 4- amino tetrahydro pyrans, obtain title compound as yellow oil.Rf=0.05 (EtOAc- heptane 1: 1)；Rt=4.65.
b)3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- dimethyl-propionic aldehyde
It is similar to embodiment 104c, use 390 milligrams of 3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_618
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethyl -propyl- 1- alcohol, obtain title compound as yellow oil.Rt=5.50.
c)3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2- dimethyl -propyl- 1- alcohol
According to conventional method C, 500 milligrams of 3- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_620
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b), obtain title compound as yellow foams.Rf=0.20 (EtOAc- heptane 1: 2)；Rt=5.26.
Embodiment 114
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- (2- morpholines -4- bases-ethyl) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 400 milligrams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- (2- morpholines -4- bases-ethyl) -1- (methyl -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propyls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_622
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- (2- morpholines -4- bases-second Base) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 43a, use 400 milligrams of [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetaldehyde and 112 milligrams of morpholines, obtain title compound as colourless oil.
Rf=0.20 (EtOAc- heptane 1: 1)；Rt=4.44.
b)[(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-acetaldehyde
It is similar to embodiment 104c, use 800 milligrams of 2- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol (coming from embodiment 25e), obtain title compound as colourless oil.Rf=0.30 (EtOAc- heptane 1: 2)；Rt=4.98.
Embodiment 115
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2,2, N - trimethyl-propionamide
According to conventional method A, 170 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2, N- trimethyls-propionamide
According to conventional method D, 150 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_630
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b) and methylamine, obtain title compound brown oil.Rf=0.18 (EtOAc- heptane 5: 1)；Rt=4.97.
The method described according to embodiment 115, prepares following compounds in a similar way：
144N- ethyls -3- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines - 2- bases } -2,2- dimethvl-propionamides
Embodiment 116
N- (2- methox-etlayls) -3- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl } -2,2- dimethvl-propionamides
According to conventional method A, use 180 milligrams of N- (2- methox-etlayls) -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_633
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethvl-propionamides, obtain title compound.
Prepare initiation material as follows：
a)N- (2- methox-etlayls) -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- dimethvl-propionamides
According to conventional method D, 150 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b) and 2- methoxy ethyl amine, obtain title compound brown oil.Rf=0.18 (EtOAc- heptane 5: 1)；Rt=5.05.
Embodiment 117
(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -34 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid (biphenyl -3 - ylmethyl)-acid amides
According to conventional method E; use (2R, 4R, 5R)-(2- [biphenyl -3- ylmethyls)-carbamoyl] -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_637
Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters, obtain title compound.
Prepare initiation material as follows：
a)(2R, 4R 5R) -2- [(biphenyl -3- ylmethyls)-carbamoyl] -4- (4- methoxies Base-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  Piperazine -6- ylmethoxies]-piperidines -1- carboxylic acid benzyl esters
According to conventional method D, 445 milligrams of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_639
Piperazine -6- ylmethoxies]-piperidines -1,2- dicarboxylic acids 1- benzyl esters and 128 milligrams of 3- phenylbenzyl amine, obtain title compound as colourless foams.Rf=0.23 (EtOAc- heptane 1: 1)；Rt=5.62.
b)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -1,2- dicarboxylic acids 1 - benzyl ester
By 0.370 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] 18 ml methanols-solution of tetrahydrofuran-water 1: 1: 1 of-piperidines -1,2- dicarboxylic acids 1- benzyl ester 2- ethyl esters is cooled to 0 DEG C.Lithium hydroxide (0.050 gram) is added, and mixture is warming up to room temperature, is stirred 16 hours at this temperature.Mixture is acidified with 1M hydrochloric acid, and extracted (2x) with dichloromethane.The organic phase of merging is dried with sodium sulphate, filters, is concentrated under reduced pressure.Pass through flash chromatography (SiO260F) there is provided product light red wax for purifying residue.Rf=0.25 (EtOAc- heptane-acetic acid 20: 10: 1)；Rt=4.95.
c)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [14]  piperazine -6- ylmethoxies]-piperidines -1,2- dicarboxylic acids 1 - benzyl ester 2- ethyl esters
According to conventional method C, from 0.403 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]
Figure 2006800106014_643
Piperazine -6- ylmethoxies]-piperidines -1,2- dicarboxylic acids 1- benzyl ester 2- ethyl esters start, and obtain title compound light yellow oil.Rf=0.25 (EtOAc- heptane 1: 1)；Rt=5.55.
d)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3- oxos -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -1,2- Dicarboxylic acids 1- benzyl ester 2- ethyl esters
The method described according to embodiment 119a, starts from 1.150 grams of (2S, 4R, 5R) -5- hydroxyls -4- (4- methoxyl groups-phenyl)-piperidines -1,2- dicarboxylic acids 1- benzyl ester 2- ethyl esters, prepares title compound.Utilize flash chromatography (SiO260F), formed diastereomer is separated.Diastereomer yellow waxy thing required for obtaining.Rf=0.10 (EtOAc- heptane 1: 1), Rt=5.34
e)(2S, 4R, 5R) -5- hydroxyls -4- (4- methoxyl groups-phenyl)-piperidines -1,2- dicarboxylic acids 1- benzyl ester 2- ethyl esters
At 0 DEG C, by 1.2 grams of (2S, 4R, 5R) mixture of -5- hydroxyls -4- (4- methoxyl groups-phenyl)-piperidines -2- carboxylic acid, ethyl esters in 40 milliliters of ethyl acetate, 20 milliliters of saturated aqueous sodium carbonates and 0.42 milliliter of benzyl chloroformate is stirred 1 hour, diluted with ethyl acetate, and organic phase is dried with sodium sulphate.Be concentrated under reduced pressure organic phase, and residue is passed through into flash chromatography (SiO260F) purify, obtain title compound as yellow oil.Rf=0.3 (EtOAc- heptane 1: 1)；Rt=4.34.
f)(2S, 4R, 5R) -5- hydroxyls -4- (4- methoxyl groups-phenyl)-piperidines -2- carboxylic acid second Ester
Conventionally B, uses (2S, 4R, 5R) -5- hydroxyls-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl)-piperidines -2- carboxylic acid, ethyl esters (deriving from embodiment 1C), obtains title compound.Rf=0.1 (methylene chloride-methanol 20: 1)；Rt=2.66.
Embodiment 118
{ (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl }-((R, S) -3 - phenyl-pyrrolidin -1- bases)-ketone (non-enantiomer mixture)
According to conventional method E, 330 milligrams of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_646
Piperazine -6- ylmethoxies] -2- ((R, S) -3- phenyl-pyrrolidin -1- carbonyls)-piperidines -1- carboxylic acids benzyl ester (non-enantiomer mixture), obtain title compound.
Prepare initiation material as follows：
a)(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -2- ((R, S) -3- phenyl - Pyrrolidines -1- carbonyls)-piperidines -1- carboxylic acids benzyl ester (non-enantiomer mixture)
According to conventional method D, 445 milligrams of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies]-piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 117b) and 135 milligrams of racemic 3- Phenylpyrrolidines, obtain title compound as colourless foams.Rf=0.10 (EtOAc- heptane 1: 1)；Rt=5.58.
Embodiment 119
(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- Oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- carboxylic acids Ethyl ester
According to conventional method B, from (2R, 4R, 5R)-Isosorbide-5-Nitrae-two -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_650
Piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid, ethyl esters start, and prepare title compound.
Prepare initiation material as follows：
a)(2R, 4R, 5R)-Isosorbide-5-Nitrae-two -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3- oxos -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - Piperidines -2- carboxylic acid, ethyl esters
By 1.000 grams of (2S, 4R, 5R) -5- hydroxyls-Isosorbide-5-Nitrae-two (4- methoxyl groups-phenyl)-piperidines -2- carboxylic acid, ethyl esters and 0.783 gram of 6- bromomethyls -4- (3- methoxy-propvl -4H- benzo [Isosorbide-5-Nitrae]
Figure 2006800106014_652
The dry DMF solution of 15 milliliters of piperazine -3- ketone is cooled to -20 DEG C.0.100 gram of sodium hydride (60% dispersion, in oil) is added, and reactant mixture was warming up to room temperature with 8 hours.By adding the quenching reaction of 1M aqueous hydrochloric acid solutions.The solid of precipitation is separated by filtration, and passes through flash chromatography (SiO260F) it is further purified.Rf=0.29 (EtOAc- heptane 1: 1)；Rt=5.20.
b)6- bromomethyls -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]  piperazine -3- ketone
With 10 minutes, bromine trimethylsilane (11.7 milliliters) is added dropwise to 15.0 grams of 6- methylols -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_654
In 150 milliliters of chloroformic solutions of piperazine -3- ketone (coming from embodiment 1h).Reaction solution is stood to 30 minutes at room temperature, is then concentrated under reduced pressure.Pass through flash chromatography (SiO260F) there is provided title compound gray solid for purifying residue.Rf=0.55 (EtOAc- heptane 1: 1)；Rt=4.09.
Embodiment 120
(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl }-methanol
According to embodiment 1, from 0.126 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]
Figure 2006800106014_656
Piperazine -6- ylmethoxies] beginning of-piperidines -2- carboxylic acid, ethyl esters (coming from embodiment 119), prepare title compound.
Embodiment 121
(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzene And [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- carboxylic acids
According to conventional method E, from 0.035 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_658
Piperazine -6- ylmethoxies] beginning of-piperidines -1,2- dicarboxylic acids benzyl ester (coming from embodiment 117b), prepare title compound.
Embodiment 122
(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4-3- methoxy-propvls) -3,4- Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid dimethylamides
According to embodiment 8, from 0.051 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_660
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 117b) beginning, prepare title compound.
Embodiment 123
(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4-3- methoxy-propvls) - Dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2- carboxylic acid methylamides
According to embodiment 5, from 0.051 gram of (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_662
Piperazine -6- ylmethoxies] piperidines -1,2- dicarboxylic acids 1- benzyl esters (coming from embodiment 117b) beginning, prepare title compound.
Embodiment 124
3- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } - 2,2, N, N- tetramethyl-propionamide
According to conventional method A, 170 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N, N- tetramethyls-propionamide, obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2,2, N, N- tetramethyls-propionamide
According to conventional method D, 150 milligrams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_666
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids (coming from embodiment 65b) and dimethylamine, obtain title compound brown oil.Rf=0.45 (EtOAc- heptane 1: 1)；Rt=5.27.
The method described according to embodiment 124, prepares following compounds in a similar way：
132N- (2- dimethylarnino-ethyls) -3- (2S, 4R, 5R) -4- (4- methoxyl groups - Phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy]-piperidin-2-yl } -2,2- dimethvl-propionamides
133N- (3- dimethylammo-propyls) -3- (2S, 4R, 5R) -4- (4- methoxyl groups - Phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy]-piperidin-2-yl } -2,2- dimethvl-propionamides
Embodiment 125
4- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2- first Base-butyl- 2- alcohol
According to conventional method A, 327 milligrams of 4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_670
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl-butyl- 2- alcohol, obtain title compound.
Prepare initiation material as follows：
a)4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2- methyl-butyl- 2- alcohol
It is similar to embodiment 29b, use 200 milligrams of 4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_672
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone and 0.5 milliliter of methyl-magnesium-bromide (1N solution, in tetrahydrofuran), obtain the cream-coloured oil of title compound.Rf=0.12 (EtOAc- heptane 1: 1)；Rt=5.14.
b)4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-butyl- 2- ketone
It is similar to embodiment 29b, use 1.68 grams of N- methoxyl groups -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_674
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl-malonamics and 4.3 milliliters of methyl-magnesium-bromides (1N solution, in tetrahydrofuran), obtain title compound as colourless oil.Rf=0.23 (EtOAc- heptane 1: 1)；Rt=5.25.
c)N- methoxyl groups -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl-malonamics
According to conventional method D, 1.65 grams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionic acid and 271 milligrams of N, O- hydrochloride base azanol, obtain the cream-coloured oil of title compound.Rf=0.18 (EtOAc- heptane 2: 1)；Rt=5.09.
d)3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-propionic acid
It is similar to method 74a, use 1.62 grams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_678
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionitrile (coming from embodiment 81a), obtain title compound brown oil.Rf=0.25 (EtOAc)；Rt=4.85.
Embodiment 126
6- [(3R, 4R, 6S) -6- (3 (R, S)-methoxy-but) -4- (4- methoxyl groups-phenyl) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines (non-enantiomer mixture)
According to conventional method A; use 210 milligrams of 6- [(3R; 4R; 6S) -6- (3- methoxy-buts) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_680
Piperazine (non-enantiomer mixture), obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -6- (3- methoxy-buts) -4- (4- methoxyl groups-phenyl) - 1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines (non-enantiomer mixture)
It is similar to embodiment 30a, use 550 milligrams of 4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol (non-enantiomer mixture), obtain title compound as yellow oil.Rf=0.30 (EtOAc- heptane 1: 1)；Rt=5.60.
b)4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-butyl- 2- alcohol (non-enantiomer mixture)
It is similar to method 29a, use 800 milligrams of 4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_684
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone and 3.0 milliliters of borine-tetrahydrofuran compounds (1N, in tetrahydrofuran), obtain title compound as yellow oil.Rf=0.22 (EtOAc- heptane 2: 1)；Rt=5.00.
c)4- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-butyl- 2- ketone
It is similar to embodiment 29b, in the presence of methyl-magnesium-bromide, use 1.68 grams of N- methoxyl group -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_686
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl-malonamics, flash chromatography (SiO2After 60F), title compound as colourless oil is obtained.Rf=0.23 (EtOAc- heptane 1: 1)；Rt=5.25.
d)N- methoxyl groups -3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl-malonamics
According to conventional method D, make 1.65 grams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_688
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionic acid and N, O- dimethyl hydroxylamine hydrochloride react, and obtains title compound gray oil.Rf=0.18 (EtOAc- heptane 5: 1)；Rt=5.09.
e)3- [(2S, 4R 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl]-propionic acid
It is similar to embodiment 19b, use 1.62 grams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_690
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionitrile (coming from embodiment 83b), obtain title compound brown oil.Rf=0.25 (EtOAc)；Rt=4.85.
Embodiment 127
3- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines - 2- yls } -2,2, N- trimethyls-propionamide
According to conventional method A, 290 milligrams of 3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide
According to conventional method D, 250 milligrams of 3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_694
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids, obtain title compound as yellow oil.Rf=0.05 (EtOAc- heptane 1: 1)；Rt=5.10.
b)3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids
It is similar to embodiment 72b, use 806 milligrams of 3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_696
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acid 3- methoxy-propvl esters, obtain title compound as yellow oil.Rf=0.17 (EtOAc- heptane 1: 1)；Rt=5.25.
c)3-[（2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls -)-piperidin-2-yl] -2,2- Dimethyl-propionic acid 3- methoxyl groups - propyl diester
To 702 milligrams of 3- [(2S, 4R, 5R) -4- (4- hydroxy-phenies) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_698
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,1.34 grams of cesium carbonates and 890 milligrams of 3- methoxy-propyl chlorides are added in 5 milliliters of DMF agitating solutions of 2 Dimethyl-propionic acids.Reactant mixture is heated to 50 DEG C overnight, 1N hydrochloric acids are used, and extracted with ethyl acetate.The organic phase of merging is dried and is concentrated under reduced pressure, crude title compound is obtained.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rt=5.86.
d)3- [(2S, 4R, 5R) -4- (4- hydroxy-phenies) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl] -2,2- Dimethyl-propionic acids
To 1.1 grams of 3- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_700
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2; 10 milliliters of N of 2 Dimethyl-propionic acids (coming from embodiment 65b); 1.35 grams of ethyl mercaptan sodium are added in dinethylformamide agitating solution; and reactant mixture is heated to 95 DEG C, kept for 2 days.Reactant mixture is diluted with 1N hydrochloric acid solutions, extracted with t-butyl methyl ether.Organic phase is merged, dries and is concentrated under reduced pressure, obtain crude title compound.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as colourless oil is obtained.Rf=0.10 (EtOAc- heptane 1: 1)；Rt=4.67.
Embodiment 128
1- (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl } -2- first Base -propyl- 2- alcohol
According to conventional method A, 153 milligrams of 1- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_702
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol, obtain title compound.
Prepare initiation material as follows：
a)1- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol
It is similar to embodiment 29b, use 1.56 grams of 1- [4- (4- methoxyl groups-phenyl) -5- [(2S, 4R, 5R) -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_704
Piperazine -6- ylmethoxies) -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2- ketone, obtain title compound as yellow oil.Rf=0.18 (EtOAc- heptane 1: 1)；Rt=5.14.
b)1- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphurs Acyl group)-piperidin-2-yl] -propyl- 2- ketone
It is similar to embodiment 104c, use 3.2 grams of 1- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_706
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -propyl- 2 (R, S) -ol (non-enantiomer mixture), obtain title compound as yellow oil.
Rf=0.14 (EtOAc- heptane 1: 1).
c)1- [(2S, 4R, 5R) -4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) - piperidin-2-yl] -propyl- 2 (R, S) -ol (non-enantiomer mixture)
It is similar to embodiment 29b, use 4.0 grams of [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_708
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetaldehyde, obtain title compound as yellow oil.Rf=0.53 (EtOAc- heptane 5: 1)；Rt=5.05.
d)[(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-acetaldehyde
At -30 DEG C, to 8.30 grams (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_710
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetonitrile 80 milliliters of dichloromethane agitating solutions in add 18.7 milliliters of diisobutyl aluminium hydride (1.0M, in dichloromethane) solution.During 5 hours, reactant mixture is warming up to -5 DEG C, -30 DEG C are then cooled to again overnight.Dchloromethane reactant mixture is used, 50 milliliters of 1N tartaric acid solutions is added and 50 milliliters of 1N Rochelles (Rochelles) salting liquids is quenched.Mixture is filtered, is concentrated under reduced pressure, and passes through flash chromatography (SiO2Residue 60F) is purified, title compound brown oil is obtained.Rf=0.29 (EtOAc- heptane 1: 1)；Rt=5.14.
e)[(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl]-acetonitrile
It is similar to embodiment 19c, use 0.5 gram of methanesulfonic acid (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_712
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester (coming from embodiment 25h), obtain title compound.Rf=0.26 (EtOAc- heptane 1: 1)；Rt=5.20.
Embodiment 129
6- [(3R, 4R, 6S) -6- [2- (2- Mehtoxy-ethoxies) -2- methyI-oropvDs] -4- (4- methoxyl groups-phenyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) - 3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 100 milligrams of 6- [(3R; 4R; 6S) -6- [2- (2- Mehtoxy-ethoxies) -2- methyI-oropvDs] -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_714
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -6- [2- (2- Mehtoxy-ethoxies) -2- methyI-oropvDs] - 4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 30a, use 350 milligrams of 1- [(3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_716
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol (coming from embodiment 128a) and 774 milligrams of 2- chloroethyl methyl ethers, obtain title compound as yellow oil.Rf=0.26 (EtOAc- heptane 1: 1)；Rt=5.69.
Embodiment 130
Diyl-carbamic acid 2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines - 2- bases } -1,1- dimethyl-ethyl ester
According to conventional method A, 100 milligrams of dimethyl-amino formic acid 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_718
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl-ethyl ester, obtain title compound.
Prepare initiation material as follows：
a)Dimethyl-amino formic acid 2- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl-ethyl ester
It is similar to embodiment 30a, in the presence of 137 milligrams of hydrofinings, use 335 milligrams of 1- [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol (coming from embodiment 128a) and 0.5 gram of N, N- formyl-dimethylamino chlorine, obtain title compound as yellow oil.Rt=5.62.
Embodiment 131
3- { (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- bases } -2,2, N- trimethyls-the third Acid amides
According to conventional method A, 6.60 grams of 3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide obtain title compound.
Prepare initiation material as follows：
a)3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide
According to conventional method D, 7.00 grams of 3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_724
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids, obtain title compound as yellow oil.Rf=0.13 (EtOAc- heptane 5: 1)；Rt=4.85.
b)3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids
The method described according to embodiment 65b-d; use 11.92 grams of 6- [(3R; 4R; 6S) -6- bromomethyls -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_726
Piperazine, obtains title compound as yellow oil.Rf=0.25 (EtOAc)；Rt=5.01.
c)6- [(3R, 4R, 6S) -6- bromomethyls -4- [4- (2- Methoxy-ethoxymethyls) - Phenyl] -1- (methyl -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to embodiment 65d, 13.81 grams of methanesulfonic acid (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_728
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester, obtain title compound as yellow oil.Rf=0.34 (EtOAc- heptane 2: 1)；Rt=5.55.
d)Methanesulfonic acid (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester
According to conventional method F, 14.34 grams of [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methanol, obtain title compound brown oil.Rf=0.22 (EtOAc- heptane 4: 1)；Rt=5.02.
e)[(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl]-methanol
According to embodiment 24b; use 18.14 grams of 6- [(3R; 4R; 6S) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -1- (toluene -4- sulfonyls) -6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_732
Piperazine, obtains title compound as yellow oil.Rf=0.13 (EtOAc- heptane 3: 1)；Rt=4.76.
f)6- [(3R, 4R, 6S) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -1- (first Benzene -4- sulfonyls) -6- tri isopropyl silane base epoxide methyl-pi -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to embodiment 57a, 25.83 grams of { 4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_734
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- tri isopropyl silane base epoxide methyl-pi -4- bases]-phenyl }-methanol, obtain title compound as yellow oil.Rf=0.31 (EtOAc- heptane 1: 1)；Rt=6.65.
g){ 4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzene And [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- tri isopropyl silanes Base epoxide methyl-pi -4- bases]-phenyl }-methanol
According to conventional method C, 30.35 grams of 4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_736
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- tri isopropyl silanes bases epoxide-methyl-pi -4- bases]-benzoic acid, obtain title compound as yellow oil.Rf=0.19 (EtOAc- heptane 1: 1)；Rt=6.03.
h)4- [(2S, 4R, 5R) -5- [4- dihydros of 4- (3- methoxy-propvls) -3- oxos -3 - 2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- three Isopropyl silanyloxymethyl-piperidin-4-yl]-benzoic acid
According to embodiment 65b, 33.15 grams of 4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- tri isopropyl silane base epoxide methyl-pi -4- bases]-methyl benzoate, obtain title compound as white foams.Rf=0.20 (EtOAc- heptane 1: 1)；Rt=6.30.
i)4- [(2S, 4R, 5R) -5- [4- (3- methoxy-propvls) -3- oxo -3,4- dihydros - 2H- bases simultaneously [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- three Isopropyl silanyloxymethyl-piperidin-4-yl]-methyl benzoate
According to embodiment 24b (or b); use 33.24 grams of 4- [(2S; 4R, 5R) -5- hydroxyls -1- (toluene -4- sulfonyls) -2- tri isopropyl silane base epoxide methyl-pi -4- bases]-methyl benzoate, obtain title compound as yellow oil.Rf=0.43 (EtOAc- heptane 1: 1)；Rt=6.79.
j)4- [(2S, 4R, 5R) -5- hydroxyls -1- (toluene -4- sulfonyls) -2- triisopropyl silicon Alkyl oxy methyl-pi -4- bases]-methyl benzoate
According to embodiment 24b (or c), using 24.19 grams of 4- [(2S, 4R, 5R) -5- hydroxyl -2- methylols -1- (toluene -4- sulfonyls)-piperidin-4-yl]-methyl benzoate, title compound as yellow oil is obtained.Rf=0.45 (EtOAc- heptane 1: 1)；Rt=6.46.
k)4- [(2S, 4R, 5R) -5- hydroxyl -2- methylols -1- (toluene -4- sulfonyls) - Piperidin-4-yl]-methyl benzoate
To 6 grams of Trifluoro-methanesulfonic acid 4- [(2S; 4R; 5R) -5- hydroxyls -2- methylols -1- (toluene -4- sulfonyls)-piperidin-4-yl]-phenyl ester 42 milliliters of N; the triethylamine of 3.1 milliliters of addition in dinethylformamide and 32 ml methanol solution; 245 milligrams of acid chlorides (II) and 454 milligrams of 1,3- bis- (diphenylphosphino) propane.Reactant mixture is added in autoclave, applies the carbon monoxide pressure of 70 bars, is subsequently heated to 70 DEG C.Under those reaction conditions, reactant mixture is kept for 5 hours, be then concentrated under reduced pressure mixture.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound dark yellow oil is obtained.Rf=0.38 (EtOAc- heptane 1: 1)；Rt=3.75.
1)Trifluoro-methanesulfonic acid 4- [(2S, 4R, 5R) -5- hydroxyl -2- methylol -1- (toluene -4 - sulfonyl)-piperidin-4-yl]-phenyl ester
To 29.39 grams of (3R; 4R, 6S) -6- methylols -4- (4- hydroxy-phenies) -1- (toluene -4- sulfonyls)-piperidin-3-ol 170 milliliters of dichloromethane solutions in add 29.23 grams of N- phenyl trifluoromethanesulfonates-sulfonyl methane imines and 11.55 milliliters of triethylamines.Reactant mixture is stirred at room temperature 2 hours, is diluted with sodium bicarbonate solution, extracted with dichloromethane.Organic phase is merged, dries, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound white solid is obtained.Rf=0.27 (EtOAc- heptane 1: 1)；Rt=4.46.
m)(3R, 4R, 6S) -6- methylols -4- (4- hydroxy-phenies) -1- (toluene -4- sulphurs Acyl group)-piperidin-3-ol
According to embodiment 90b; use 25 grams of (3R; 4R, 6S) -6- methylols -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidin-3-ol (coming from embodiment 24b-c), obtain title compound as white foams.Rf=0.20 (EtOAc- heptane 2: 1)；Rt=3.22.
The method described according to embodiment 131, prepares following compounds in a similar way：
136N- ethyls -3- (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls) - Phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy]-piperidin-2-yl } -2,2- dimethvl-propionamidesMethylamine is replaced using ethamine.
137 3- { (2S, 4R, 5R) -4- (4- methoxymethyl-phenyls) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - yl } -2,2, N- trimethyls-propionamide
The bromo- 2- methoxyl groups-ethane of 1- is replaced using iodomethane.
138N- ((S) -2- hydroxyl-propyls) -3- { (2S, 4R, 5R) -4- (4- methoxies - phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines - 6- ylmethoxies]-piperidin-2-yl } -2,2- dimethvl-propionamides
The bromo- 2- methoxyl groups-ethane of 1- and (S) -1- amino -propyl- 2- alcohol [2799-17-9] is replaced to replace methylamine using iodomethane.
139N- ((R) -2- hydroxyl-propyls) -3- { (2S, 4R, 5R) -4- (4- methoxies - phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines - 6- ylmethoxies]-piperidin-2-yl } -2,2- dimethvl-propionamides
The bromo- 2- methoxyl groups-ethane of 1- and (R) -1- amino -propyl- 2- alcohol [2799-16-8] is replaced to replace methylamine using iodomethane.
140N- (2- methox-etlayls) -3- (2S, 4R, 5R) -4- (4- methoxies - Phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy]-piperidin-2-yl } -2,2- dimethvl-propionamides
The bromo- 2- methoxyl groups-ethane of 1- and 2- methoxy-ethylamines [199-87-3] is replaced to replace methylamine using iodomethane.
Embodiment 134
(R) -1- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl first Base }-propyl group)-methyl carbamate
According to conventional method D, { (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_746
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propyl group }-methyl carbamate, obtain title compound.
Prepare initiation material as follows：
a){ (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene - 4- sulfonyls)-piperidin-2-yl methyl]-propyl group }-methyl carbamate
At room temperature, to 403 milligrams of (R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_748
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propylamine 4 milliliters of dichloromethane solutions in add 0.4 milliliter of triethylamine and 0.145 milliliter of methylchloroformate.Stirring reaction mixture 3 hours, with dchloromethane, is washed with water, and separates organic phase, dries and is concentrated under reduced pressure, obtains crude product.Pass through flash chromatography (SiO2Crude product 60F) is purified, title compound as yellow oil is obtained.Rf=0.47 (EtOAc- heptane 1: 1)；Rt=5.23.
b)(R) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4 - sulfonyl)-piperidin-2-yl methyl]-propylamine
According to conventional method E; by 1.7 grams of 6- [(3R; 4R; 6R) -6- (R) -2- azidos-butyl) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_750
Piperazine is hydrogenated, flash chromatography (SiO2After 60F), title compound brown oil is obtained.Rf=0.14 (concentrated ammonia liquor of methylene chloride-methanol -25% 200: 10: 1)；Rt=4.52.
c)6- [(3R, 4R, 6R) -6- (R) -2- azidos-butyl) -4- (4- methoxyl groups-benzene Base) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 2.55 grams of methanesulfonic acid (S) -1- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_752
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-propyl diester (diastereomer 2) (coming from embodiment 64c) 5.0 milliliters of N; 1.81 grams of sodium azide are added in N dimethyl-formamide solution, and the mixture is heated to 80 DEG C overnight.Reactant mixture is diluted with water, extracted with t-butyl methyl ether.Merge organic phase, be concentrated under reduced pressure, obtain crude title compound, pass through flash chromatography (SiO260F) it is purified, obtains title compound as yellow oil.Rf=0.14 (EtOAc- heptane 1: 1)；Rt=4.52.
Embodiment 135
6- [(3R, 4R, 6S) -6- (2- methoxyl group -2- methyI-oropvDs) -4- (4- methoxyl groups - Phenyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros - 2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 100 milligrams of 6- [(3R; 4R; 6S) -6- (2- methoxyl group -2- methyI-oropvDs) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_754
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6S) -6- (2- methoxyl group -2- methyI-oropvDs) -4- (4- methoxyl groups - phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
To 60 milligrams of 1- [4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_756
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol (coming from embodiment 128) DMF solution in add 25 milligrams of sodium hydrides and 0.2 milliliter of iodomethane.The reactant mixture is stirred at room temperature 2 days, is acidified, is extracted with t-butyl methyl ether with 1N hydrochloric acid.Organic phase is merged, dries, is concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound as yellow oil is obtained.Rf=0.21 (EtOAc- heptane 1: 1)；Rt=5.70.
Embodiment 141
6- [(3R, 4R, 6R) -4- [4- (3- methoxy-propoxyls)-phenyl] -6- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxyl groups - Propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 300 milligrams of 6- [(3R; 4R; 6R) -4- [4- (3- methoxy-propoxyls)-phenyl] -1- (toluene -4- sulfonyls) -6- ((R) -2- [1; 2; 4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_758
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- [4- (3- methoxy-propoxyls)-phenyl] -1- (toluene - 4- sulfonyls) -6- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidines -3- bases Epoxide methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 127c, use 500 milligrams of 4- [(2R, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidin-4-yl]-phenol and the bromo- 2- methoxyl groups-ethane of 1-, obtain title compound as yellow oil.Rf=0.19 (EtOAc- heptane 1: 1)；Rt=5.08.
b)4- [(2R, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzene And [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidin-4-yl]-phenol
It is similar to embodiment 90b; use 1.8 grams of 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls) -6- ((R) -2- [1; 2; 4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_762
Piperazine (comes from embodiment 73a), obtains title compound as yellow oil.
Rf=0.21 (EtOAc- heptane 1: 1)；Rt=4.34.
Embodiment 142
6- [(3R, 4R, 6R) -4- (4- methoxymethyl-phenyls) -6- ((R) -2- [1,2,4] triazoles - 1- bases-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4 - dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 6- [(3R; 4R; 6R) -4- (4- methoxymethyl-phenyls) -1- (toluene -4- sulfonyls) -6- ((R) -2- [1; 2; 4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_764
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxymethyl-phenyls) -1- (toluene -4- sulphonyl Base) -6- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidines -3- base epoxides methyl] - 4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
It is similar to embodiment 131c, use { 4- [(2R, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_766
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- ((R) -2- [1; 2; 4] triazol-1-yl-butyl)-piperidin-4-yl]-phenyl }-methanol and iodomethane, title compound is obtained, is differentiated based on its Rf value.
b){ 4- [(2R, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzene And [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- ((R) -2- [1,2,4] triazol-1-yl-butyl)-piperidin-4-yl]-phenyl }-methanol
The method described according to embodiment 131d-g, uses 4- [(2R, 4R, 5R) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_768
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) -2- ((R) -2- [1; 2; 4] triazol-1-yl-butyl)-piperidin-4-yl]-phenol (coming from embodiment 141b), title compound is obtained, is differentiated based on its Rf value.
The method described according to embodiment 142, prepares following compounds in a similar way：
143 6- [(3R, 4R, 6R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -6- ((R) -2- [1,2,4] triazol-1-yl-butyl) piperidines -3- base epoxides methyl] -4- (3- Methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
Iodomethane is replaced using the bromo- 2- methoxyl groups-ethane of 1-.
Embodiment 145
Dimethyl-amino formic acid 2- { (2R, 4R, 5R) -4-R4- (3- methoxy-propoxyls)-benzeneBase] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines -6- Ylmethoxy]-piperidin-2-yl } -1,1- dimethyl-ethyl ester
According to conventional method A, use 0.44 gram of dimethyl-amino formic acid 2- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_771
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl-ethyl ester, obtain title compound.
Prepare initiation material as follows：
a)Dimethyl-amino formic acid 2- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls) - phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines - 6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -1,1- dimethyl - ethyl ester
According to embodiment 60a, 0.7 gram of 1- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_773
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol, obtain title compound as yellow oil.Rf=0.28 (EtOAc- heptane 1: 1)；Rt=5.70.
b)1- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxyl group-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl] -2- methyl -propyl- 2- alcohol
According to embodiment 51a, 1.05 grams of [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_775
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid 3- methoxy-propvl esters, obtain title compound as colourless oil.Rf=0.22 (EtOAc- heptane 1: 1)；Rt=5.24.
c)[(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl]-acetic acid 3- methoxy-propvl esters
The method described according to embodiment 90a-b (using the cesium carbonate and the 3- methoxy-propyls chlorine of 2.2 equivalents of 4 equivalents), use 1.17 [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_777
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methyl acetate (coming from embodiment 51b), obtain title compound as yellow oil.Rt=5.46.
Embodiment 146
(R) -2- { (2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl methyl }-N- methyl-butyramides
According to conventional method A, (R) -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_779
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides, title compound is obtained, is differentiated based on its Rf value.
Prepare initiation material as follows：
a)(R) -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides With
(S) -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- bases simultaneously [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides
According to conventional method D, 2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_782
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyric acid (non-enantiomer mixture) and methylamine (8M, in ethanol), title compound is obtained, is differentiated based on its Rf value.
b)(R, S) -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- bases Methoxyl group] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyric acid (diastereomer Mixture)
According to embodiment 19b, 2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_784
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyronitrile (non-enantiomer mixture), the title compound is obtained, is differentiated based on its Rf value.
c)2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyronitrile (non-enantiomer mixture)
The method described according to embodiment 64b-e, use N- methoxyl groups -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_786
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides (non-enantiomer mixture), title compound is obtained, is differentiated based on its Rf value.
d)N- methoxyl groups -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls) - Phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae]  piperazines -6 - ylmethoxy] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl-acetyl Amine
According to embodiment 29c, [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_788
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid, title compound is obtained, is differentiated based on its Rf value.
e)[(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid
The method described according to embodiment 19b-c, uses methanesulfonic acid (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_790
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl ester (coming from embodiment 131d), title compound is obtained, is differentiated based on its Rf value.
The method described according to embodiment 146, prepares following compounds in a similar way：
151(R) -2- { (2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- bases Methoxyl group]-piperidin-2-yl methyl }-N, N- dimethyl-butyramides
Methylamine is replaced using dimethylamine.
152(R) -2- { (2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- bases Methoxyl group]-piperidin-2-yl methyl }-butyramide
Embodiment 146a condition is replaced using embodiment 6a condition.
158(R) -2- { (2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5 - [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- base methoxies Base]-piperidin-2-yl methyl }-N- methyl-butyramides
From [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_794
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid (coming from embodiment 156f) beginning
168(R) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - ylmethyl }-N- methyl-butyramides
From N- methoxyl groups -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_796
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides (coming from embodiment 29c) beginning.
Embodiment 147
3- { (2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- bases } -2,2, N- trimethyls-propionamide
According to conventional method A, 3- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_798
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide obtain title compound, are differentiated based on its Rf value.
Prepare initiation material as follows：
a)3- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2, N- trimethyls-propionamide
According to conventional method D, methylamine (8M, in ethanol) and 3- [(2R are used, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_800
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids, title compound is obtained, is differentiated based on its Rf value.
b)3- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acids
According to embodiment 65b, 3- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_802
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acid methyl esters, title compound is obtained, is differentiated based on its Rf value.
c)3- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl] -2,2- Dimethyl-propionic acid methyl esters
At -78 DEG C, to 0.157mmol lithium diisopropylamides (0.5M, in THF) agitating solution in add 0.150mmol3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_804
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-methyl propionate (being dissolved in 0.3 milliliter of THF).At -78 DEG C, after stirring 30 minutes, 0.11mmol iodomethane is added, and reactant mixture is warming up to room temperature.Then at -78 DEG C, this solution is added in 0.157mmol lithium diisopropylamides (0.5M, in THF) solution again, extra stirring 30 minutes.At -78 DEG C, 0.11mmol iodomethane is added, and reactant mixture is warming up to room temperature.Reactant mixture is hydrolyzed with 0.5M HCI, extracted three times with t-butyl methyl ether.By the organic layer of merging salt water washing, dried with sodium sulphate, and removal of solvent under reduced pressure.Pass through flash chromatography (SiO2F60 title compound) is purified, and is differentiated based on its Rf value.
d)3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl]-methyl propionate
According to embodiment 51b, 3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_806
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) piperidin-2-yl]-propionic acid, title compound is obtained, is differentiated based on its Rf value.
e)3- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionic acid
The method described according to embodiment 19b-c, use methanesulfonic acid 2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_808
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl ester, title compound is obtained, is differentiated based on its Rf value.
f)Methanesulfonic acid 2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- bases Methoxyl group] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl ester
According to conventional method F, 2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol, title compound is obtained, is differentiated based on its Rf value.
g)2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls] -1- piperidin-2-yls]-ethanol
According to conventional method C, use [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls] -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls) piperidin-2-yl]-acetic acid (coming from embodiment 146e), title compound is obtained, is differentiated based on its Rf value.
The method described according to embodiment 147, prepares following compounds in a similar way：
148 3- { (2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- dihydro -2H- the bases of 4- (3- methoxy-propvls) -3 simultaneously [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies - piperidin-2-yl } -2,2, N, N- tetramethyls-propionamide
Methylamine is replaced using dimethylamine.
159 3- { (2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - Piperidin-2-yl } -2,2, N- trimethyls-propionamide
From 3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_815
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl)-propionic acid (coming from embodiment 156c) beginning
160 3- { (2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - Piperidin-2-yl } -2,2, N, N- tetramethyls-propionamide
From 3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_817
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionic acid (coming from embodiment 156c) starts, and replace methylamine using dimethylamine.
Embodiment 149
(S) -2- { (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl methyl }-N- methyl-butyramides
According to conventional method A, (S) -2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_819
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides, obtain title compound.
Prepare initiation material as follows：
a)(S) -2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5 - [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- base methoxies Base] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides
With
(R) -2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzene [Isosorbide-5-Nitrae]  piperazine -6- Ji Jia Epoxide] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] N- methyl-butyramides
According to conventional method D, 2- [(2R, 4R, 5R) -4- (4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_822
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyric acid (non-enantiomer mixture) and methylamine (8M, in ethanol), title compound is obtained, is differentiated based on its Rf value.
b)2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-butyric acid (non-enantiomer mixture)
According to embodiment 65b, 2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_824
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-methyl butyrate (non-enantiomer mixture), title compound is obtained, is differentiated based on its Rf value.
c)2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] (diastereomer is mixed-methyl butyrate Thing)
According to embodiment 65c (replacing methyl isobutyrate using methyl butyrate); use 6- [(3R; 4R; 6S) -6- bromomethyls -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_826
Piperazine (comes from embodiment 131c), obtains title compound, is differentiated based on its Rf value.
The method described according to embodiment 149, prepares following compounds in a similar way：
155(S) -2- { (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- bases Methoxyl group]-piperidin-2-yl methyl }-butyramide
Embodiment 149a condition is replaced using embodiment 6a condition.
162(S) -2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl methyl }-N- methyl-butyramides
From 2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_829
Piperazine -6- ylmethoxies]-piperidin-2-yl methyl }-butyric acid (non-enantiomer mixture) beginning.
Prepare initiation material as follows：
a)2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- ylmethyls }-butyric acid (non-enantiomer mixture)
According to embodiment 65b, 2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_831
Piperazine -6- ylmethoxies]-piperidin-2-yl methyl }-butyric acid 3- methoxy-propvls ester (non-enantiomer mixture), title compound is obtained, is differentiated based on its Rf value.
b)2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -55- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- ylmethyls }-butyric acid 3- methoxy-propvls ester (non-enantiomer mixture)
The method described according to embodiment 90a-b (using the cesium carbonate and the 3- methoxy-propyls chlorine of 2.2 equivalents of 4 equivalents), use 2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_833
Piperazine -6- ylmethoxies]-piperidin-2-yl methyl }-methyl butyrate (non-enantiomer mixture), title compound is obtained, is differentiated based on its Rf value.
c)2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxyl groups-the third Base) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidin-2-yl first Base }-methyl butyrate (non-enantiomer mixture)
According to embodiment 65c; use 6- [(3R, 4R, 6S) -6- bromomethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_835
Piperazine (coming from embodiment 65d) and methyl butyrate, obtain title compound, are differentiated based on its Rf value.
166(S) -2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - ylmethyl }-N- methyl-butyramides
From 6- [(3R; 4R; 6S) -6- bromomethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_837
Piperazine (coming from embodiment 65d) starts.
Embodiment 150
(R) -2- { (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-Ji Ji] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl methyl }-N- methyl-butyramides
According to conventional method A, (R) -2- [(2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_839
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides (coming from embodiment 149a), obtain title compound.
The method described according to embodiment 150 and 149, prepares following compounds in a similar way：
153(R) -2- { (2S, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] - 5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- bases Methoxyl group]-piperidin-2-yl methyl }-butyramide
Embodiment 159a condition is replaced using embodiment 6a condition.
163(R) -2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl methyl }-N- methyl-butyramides
From 2- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_842
Piperazine -6- ylmethoxies]-piperidin-2-yl methyl }-butyric acid (non-enantiomer mixture) (coming from embodiment 162a) beginning.
165(R) -2- { (2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - ylmethyl }-N- methyl-butyramides
From 6- [(3R; 4R; 6S) -6- bromomethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]Piperazine (coming from embodiment 65d) starts.
Embodiment 156
(S) -4- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperazine Pyridine -2- bases }-butyl- 2- alcohol
According to conventional method A, (S) -4- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_846
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol, title compound is obtained, is differentiated based on its Rf value.
Prepare initiation material as follows：
a)(R) -4- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol and
(S) -4- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4 - (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- alcohol
According to conventional method C, 4- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_849
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone, title compound is obtained, is differentiated based on its Rf value.
b)4- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl]-butyl- 2- ketone
The method described according to embodiment 29b-c, uses 3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_851
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-propionic acid, title compound is obtained, is differentiated based on its Rf value.
c)3- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl]-propionic acid
The method described according to embodiment 19b-c, uses methanesulfonic acid 2- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_853
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl ester, title compound is obtained, is differentiated based on its Rf value.
d)Methanesulfonic acid 2- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - 1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethyl ester
According to conventional method F, 2- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_855
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol, title compound is obtained, is differentiated based on its Rf value.
e)2- [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3 - methoxy-propvl) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1 - (toluene -4- sulfonyls)-piperidin-2-yl]-ethanol
According to conventional method C, [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are usedPiperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid, title compound is obtained, is differentiated based on its Rf value.
f)[(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (first Benzene -4- sulfonyls)-piperidin-2-yl]-acetic acid
According to embodiment 65b, [(2R, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae] are used
Figure 2006800106014_859
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-acetic acid 3- methoxy-propvls ester (coming from embodiment 145c), title compound is obtained, is differentiated based on its Rf value.
The method described according to embodiment 156, prepares following compounds in a similar way：
157(R) -4- { (2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl }-butyl- 2- alcohol
From (R) -4- [(2S, 4R, 5R) -4- [4- (3- methoxy-propoxyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_861
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl] beginning of-butyl- 2- alcohol (coming from embodiment 156a).
Embodiment 164
(S) -2- { (2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] - piperidin-2-yl methyl }-N- methyl-butyramides
According to conventional method A, use (S) -2- [(2R, 4R, 5R) -4- [4- (2- Methoxy-ethoxymethyls)-phenyl] -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_863
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl]-N- methyl-butyramides (coming from embodiment 146a), the title compound is obtained, is differentiated based on its Rf value.
The method described according to embodiment 164 and 146, prepares following compounds in a similar way：
167(S) -2- { (2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies]-piperidines -2 - ylmethyl }-N- methyl-butyramides
From N- methoxyl groups -2- [(2R, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_865
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl]-N- methyl acetamides (coming from embodiment 29c) beginning.
Embodiment 169
6- [(3R, 4R, 6R) -4- (4- methoxyl groups-benzene its) -6- (ttetrahydro-pyran -4- ylmethyls) - piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydros -2H- Benzo [Isosorbide-5-Nitrae]  piperazines
According to conventional method A; use 6- [(3R; 4R; 6R) -4- (4- methoxyl groups-phenyl) -6- (ttetrahydro-pyran -4- ylmethyls) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_867
Piperazine, obtains title compound.
Prepare initiation material as follows：
a)6- [(3R, 4R, 6R) -4- (4- methoxyl groups-phenyl) -6- (ttetrahydro-pyran -4- bases Methyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxies Base-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
According to conventional method E (using ethanol as solvent); use 6- [(3R; 4R; 6S) -4- (4- methoxyl groups-phenyl) -6- (ttetrahydro-pyran -4- ylidenylmethyls) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3; 4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_869
Piperazine, obtains title compound, is differentiated based on its Rf value.
b)[(ttetrahydro-pyran -4- is sub- by (3R, 4R, 6S) -4- (4- methoxyl groups-phenyl) -6- by 6- Ylmethyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- first Epoxide-propyl group) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]  piperazines
At 0 DEG C, by 2.3mmol [(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl) -5- [4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_871
Piperazine -6- ylmethoxies] -1- (toluene -4- sulfonyls)-piperidin-2-yl methyl] suspension of-triphenyl-phosphonium bromide phosphine and 7.5 milliliters of tetrahydrofurans handles with 3.2mmol n-BuLis (1.6M, in hexane).Reactant mixture is stirred at room temperature 1 hour, then handled with 2.5 milliliters of tetrahydrofuran solutions of ttetrahydro-pyran -4- ketone.Reactant mixture is stirred at room temperature 4 hours, is then poured in 1M ammonium chloride solutions, and extracted with t-butyl methyl ether.By the organic phase of merging salt water washing, dried with sodium sulphate, and be concentrated under reduced pressure.Pass through flash chromatography (SiO2Residue 60F) is purified, title compound is obtained, is differentiated based on its Rf value.
c)[(2S, 4R, 5R) -4- (4- methoxyl groups-phenyl] -5- [4- (3- methoxy-propvls) - 3,4- bis- Hydrogen -2H- benzos [Isosorbide-5-Nitrae]  piperazine -6- ylmethoxies] -1- (toluene -4- sulphonyl Base)-piperidin-2-yl methyl]-triphenyl-phosphonium bromide phosphine
By 3mmol6- [(3R; 4R; 6S) -6- bromomethyls -4- (4- methoxyl groups-phenyl) -1- (toluene -4- sulfonyls)-piperidines -3- base epoxides methyl] -4- (3- methoxy-propvls) -3,4- dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure 2006800106014_873
5 milliliters of acetonitrile solution 3.6mmol triphenylphosphines processing of piperazine (coming from embodiment 65d), and stirred 12 hours at 70 DEG C.Reactant mixture is cooled to room temperature, filter out solid, obtain title compound, differentiated based on its Rf value.
Figure S2006800106014D01581
Figure S2006800106014D01591
Figure S2006800106014D01601
Figure S2006800106014D01611
Figure S2006800106014D01621
Figure S2006800106014D01631
Figure S2006800106014D01641
Figure S2006800106014D01651
Figure S2006800106014D01661
Figure S2006800106014D01671
Figure S2006800106014D01681
Figure S2006800106014D01691
Figure S2006800106014D01701
Figure S2006800106014D01711
Figure S2006800106014D01721
Figure S2006800106014D01731
Figure S2006800106014D01741
Figure S2006800106014D01751
Figure S2006800106014D01761
Figure S2006800106014D01781
Figure S2006800106014D01791
Figure S2006800106014D01801
Figure S2006800106014D01811
Figure S2006800106014D01821
Figure S2006800106014D01841
Figure S2006800106014D01851
Figure S2006800106014D01861
Thin-film chromatography elution system：
A methylene chloride-methanol=10: 1
B  EtOAc
Concentrated ammonia liquor=200 of C methylene chloride-methanols -25%: 10: 1
Concentrated ammonia liquor=200 of D methylene chloride-methanols -25%: 20: 1
Dense acetic acid=150 of E methylene chloride-methanol-water-: 54: 10: 1
F methylene chloride-methanol=20: 1
G methylene chloride-methanol=5: 1
H methylene chloride-methanol=1: 1
I EtOAc- heptane=5: 1
Concentrated ammonia liquor=100 of J methylene chloride-methanols -25%: 10: 1
Concentrated ammonia liquor=10 of K methylene chloride-methanols -25%: 1: 0.1
L EtOAc- heptane=1: 1
M methylene chloride-methanol=9: 1
Concentrated ammonia liquor=40 of N methylene chloride-methanols -25%: 10: 1
O methylene chloride-methanols-dense acetic acid=100: 10: 1
Concentrated ammonia liquor=90 of P methylene chloride-methanols -25%: 10: 1
Q methylene chloride-methanols-dense acetic acid=100: 10: 2
R methylene chloride-methanol=30: 1
Concentrated ammonia liquor=600 of S methylene chloride-methanols -25%: 20: 1
Concentrated ammonia liquor=200 of T methylene chloride-methanols -25%: 5: 1
Concentrated ammonia liquor=5 of U methylene chloride-methanols -25%: 1: 0.1
V toluene-EtOAc- triethylamine=5: 3: 0.2
Concentrated ammonia liquor=200 of W methylene chloride-methanols -25%: 15: 1
Concentrated ammonia liquor=200 of X methylene chloride-methanols -25%: 40: 1

Claims (4)

1. the compound or its salt of formula (IA)：
Figure FSB00000384354300011
Wherein
R is C0-8- alkyl-carbonyl-amino-C1-8- alkyl, C1-8- alkyl-sulfonyl base-C0-8- alkyl, be not alkylated or N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, be not alkylated or O-C1-8- alkylation carboxyl-C0-8- alkyl, be not alkylated or N and/or N ' mono-, di-s-or three-C1-8- alkylation urea groups-C1-8- alkyl or Heterocyclylcarbonyl-C0-8- alkyl, or
R is C1-8- alkyl, C0-8- alkyl-carbonyl-amino-C1-8- alkyl, C1-8- alkyl-sulfonyl base-C0-8- alkyl, be not alkylated or N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, be not alkylated or O-C1-8- alkylation carboxyl-C0 -8- alkyl, be not alkylated or N and/or N ' mono-, di-s-or three-C1-8- alkylation urea groups-C0-8- alkyl or Heterocyclylcarbonyl-C0-8- alkyl, each group is by following substitution：C1-8- alkoxy -C1-8- alkoxy, C1-8- alkoxy carbonyl group-(N-C1-8- alkyl)-amino, C1 -8- alkyl, C1-8- alkyl-carbonyl-(N-C1-8- alkyl)-amino, C1-8- alkyl-sulfanyl, C1-8- alkyl-sulfinyl, it is unsubstituted or by 1 or 2 aryl or C1-8Aryl-the C of-alkoxy base substitution1-8- alkoxy, it is unsubstituted or by 1 or 2 aryl or C1-8The aryl of-alkoxy base substitution, aryl-amino, cyano group, halogen, heterocyclic radical-C0-8- alkyl, heterocyclic radical-C0-8- alkyl-amino, heterocyclic radical-carbonyl, be not alkylated or N- is mono- or-the C of N, N- bis-1-8- alkylated amine, be not alkylated or N- is mono- or-the C of N, N- bis-1-8- alkylated amine formoxyl-C0-8- alkyl, be not alkylated or N- is mono- or-the C of N, N- bis-1-8- alkylation carbamoyloxy group, non-arylation or N- arylations or unsubstituted or N- heterocyclic radicals-substituted carbamoyl, or oxo；
R1It is N- (3- methoxycarbonyl propyls) dihydro -2H- benzos [Isosorbide-5-Nitrae]
Figure FSB00000384354300012
Piperazine base；
R2It is phenyl, it is replaced by following radicals：Methoxyl group, fluorine, 3- methoxy-propoxyls, or
2- methoxvethoxvmethvls；
R3It is hydrogen；
R4It is hydrogen；
Z is CH2；
X is O；
Q is not present；
M is 0；
N is 1；
Or wherein one or more atoms are substituted by the non radioactive isotope of their stabilization.
2. a kind of pharmaceutical preparation, it includes formula (IA) compound of claim 1.
3. formula (IA) compound of claim 1 or the preparation of claim 2 are preparing the purposes in being used to treat or prevent the medicine of vascular hypertension, heart failure, glaucoma, miocardial infarction, kidney failure, ISR or apoplexy.
4. following intermediates：
6- bromomethyls -4- (3- methoxy-propvls) -4H- benzos [Isosorbide-5-Nitrae]
Figure FSB00000384354300021
Piperazine -3- ketone.
CN2006800106014A 2005-03-31 2006-03-30 Substituted piperidines Expired - Fee Related CN101151262B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1202152A (en) * 1995-09-07 1998-12-16 弗·哈夫曼-拉罗切有限公司 4-(oxyalkoxyphenyl)-3-oxy-piperidines for treating heart and kidney insufficiency
CN1349524A (en) * 1999-04-27 2002-05-15 弗·哈夫曼-拉罗切有限公司 Renin inhibitors
CN1349503A (en) * 1999-04-27 2002-05-15 弗·哈夫曼-拉罗切有限公司 Renin ihibitors
WO2004089903A1 (en) * 2003-04-10 2004-10-21 Warner-Lambert Company Llc Piperidine derivatives as renin inhibitors for the treatment of hypertension

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1202152A (en) * 1995-09-07 1998-12-16 弗·哈夫曼-拉罗切有限公司 4-(oxyalkoxyphenyl)-3-oxy-piperidines for treating heart and kidney insufficiency
CN1349524A (en) * 1999-04-27 2002-05-15 弗·哈夫曼-拉罗切有限公司 Renin inhibitors
CN1349503A (en) * 1999-04-27 2002-05-15 弗·哈夫曼-拉罗切有限公司 Renin ihibitors
WO2004089903A1 (en) * 2003-04-10 2004-10-21 Warner-Lambert Company Llc Piperidine derivatives as renin inhibitors for the treatment of hypertension

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Medicinal Chemistry Letters9.1999,91403-1408. *
Rolf Gtiller et al..PIPERIDINE-RENIN INHIBITORS COMPOUNDS WITHIMPROVED PHYSICOCHEMICAL PROPERTIES.Bioorganic & Medicinal Chemistry Letters9.1999,91403-1408.
Rolf Gtiller et al..PIPERIDINE-RENIN INHIBITORS COMPOUNDS WITHIMPROVED PHYSICOCHEMICAL PROPERTIES.Bioorganic &amp *

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