CN1173867A - Indolyl neuropeptide Y receptor antagonists - Google Patents
Indolyl neuropeptide Y receptor antagonists Download PDFInfo
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- CN1173867A CN1173867A CN96191324A CN96191324A CN1173867A CN 1173867 A CN1173867 A CN 1173867A CN 96191324 A CN96191324 A CN 96191324A CN 96191324 A CN96191324 A CN 96191324A CN 1173867 A CN1173867 A CN 1173867A
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Abstract
This invention provides a series of substituted indoles which are useful in treating or preventing a condition associated with an excess of neuropeptide Y. This invention also provides the novel substituted indoles as well as pharmaceutical formulations which comprise as an active ingredient one or more of these substituted indoles.
Description
Priority request
The application requires U.S. Provisional Application 60/003,150 and the U.S. Provisional Application 60/021,638 of registration on July 12nd, 1996 and English Patent 9523999.2 right of priority of registration on November 23 nineteen ninety-five of registration on September 1 nineteen ninety-five.
Background of the present invention
Neuropeptide tyrosine is to be present in the unify polypeptide of peripheral nervous system of central nervous system.In many nerves, this peptide and norepinephrine coexist, and work as neurotransmitter in essence or synergistically with one of norepinephrine.Though the fiber that contains neuropeptide tyrosine is in a large number arranged around the heart arter, around respiratory tract artery, intestines and stomach artery and genitourinary tract artery, has also found neuropeptide tyrosine.Neuropeptide tyrosine also is present in the release that brain influences blood pressure, dining and different hormones.The centre concentration change of neuropeptide tyrosine involves non compos mentis cause of disease always.
Nineteen eighty-two has been found neuropeptide tyrosine from the pig brain, separation has also been determined sequence, and this is the part for total screening scheme of finding carboxylic end amidation polypeptide, because neuropeptide tyrosine is isolating from nervous tissue, and two amino acid of carboxylic end and ammonia end all are tyrosine, so the called after neuropeptide tyrosine.Neuropeptide tyrosine is the member of pancreas peptide family, and has important sequence identity with pancreatic polypeptide and polypeptide YY.
Neuropeptide tyrosine and its other member of peptide family present tertiary structure, and this tertiary structure is by polyproline spiral and an amphipathic alpha-helix of N end, and the back that links to each other with β-corner produces a hairpin like ring, and it is folding that these refer to do pancreatic polypeptide (PP) sometimes.By these helix polies of hydrophobic interaction at one.Amidated C end is always stretched from hairpin loop.
Be accredited as the abundantest polypeptide of central nervous system after neuropeptide tyrosine is found, extensively be distributed in cortex, brain stem, hippocampus, hypotahlamus, tonsilla and thalamus with extending and be present in peripheral nerve, sympathetic nerve and the kidney pheochromocyte.
As if neuropeptide tyrosine satisfies the main standard that works as neurotransmitter, because it is stored in the cynapse particle, discharges when being subjected to electrical nerve stimulation, and acts on single-minded acceptor.Very clear, may in brain, neuropeptide tyrosine itself be exactly important courier, here neuropeptide tyrosine effectively suppresses the active of adenylate cyclase and reduces the increase of intracellular Ca2+ level.Maincenter injection neuropeptide tyrosine causes blood pressure, increases appetite, increases fat stores, improves blood sugar and Regular Insulin, reduces the locomotive organ activity, reduces body temperature, and catalepsy.
Neuropeptide tyrosine (and its related compound) acts on the membrane receptor that depends on amidino groups-nucleotide binding protein, is called G albumen-coupled receptor.G albumen is for only becoming activatory membranin family after in conjunction with black guanosine triphosphate ester.Activatory G albumen activates the amplification enzyme of film internal surface conversely; This kind of enzyme changes precursor molecule into second messenger then.
It seems that neuropeptide tyrosine interact with closely-related receptor family.According to the ability of the different fragments of other film of different tissues and receptors bind neuropeptide tyrosine and peptide PP family, these acceptors generally are divided into several hypotypes.Y
1The muscle Neuropeptide Y Receptors that receptor subtype is seemingly main.Y
2Receptor subtype appears on the vascular smooth muscle after also can node.Still unsegregated Y
3Receptor subtype seemingly is specific to neuropeptide tyrosine, does not combine with peptide YY.This receptor as if be present in the nephridial tissue, and other zone comprises medullary substance, heart, brain stem.(summary of neuropeptide tyrosine and Neuropeptide Y Receptors is for example seen: C.Wahlestedt and D.Reis,
Annual Review of Pharmacology and Toxicology, 33:309-352 (1993); D.Gehlert and P.Hipskind,
Current Pharmaceutical Design, 1:295-304 (1995)).
From with a large amount of clinical diseases and the excessive relevant angle of neuropeptide tyrosine, the exploitation neuropeptide Y receptor antagonist will control these clinical conditions.This receptoroid antagonist the earliest, for example the Patent Cooperation Traty PatentPublication WO 94/00486 that delivers in the Patent Cooperation Traty Patent Publication WO90/08223 that delivered on June 13rd, 1991 and on January 6th, 1994 is a polypeptide derivative.These antagonists are restricted as medicinal application owing to metabolic unstable.
The invention provides the effective non-peptide neuropeptide Y receptor antagonist of a class.Rely on their non-peptide nature, there be not the metabolism unsettled shortcoming of known polypeptide for the neuropeptide Y receptor antagonist on basis in compound of the present invention.
General introduction of the present invention
The present invention includes the method for treatment or prevention and the excessive diseases associated of neuropeptide tyrosine, this method comprises the compound of Formula I of taking significant quantity to the Mammals of this treatment of needs.
Wherein: R
bBe hydrogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
2-C
6Alkanoyl, trifluoromethyl, hydroxyl or halogen; R
1Be hydrogen, C
1-C
6Alkyl, or-(CH
2)
v-R
1a
Wherein v is 1 to 12, R
1aBe phenyl, naphthyl, hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, tryptolinyl, pyrrolidyl, quinuclidinyl or morpholinyl, any one base in phenyl, naphthyl, hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, tryptolinyl, pyrrolidyl, quinuclidinyl or the morpholinyl can be replaced by one or more residues, and these substituting groups are selected from C
1-C
6Alkyl, halogen, trifluoromethyl, benzyl, phenyl, two (C
1-C
6Alkyl) amino, C
1-C
6Alkylamino, C
2-C
6Alkanoyl, C
2-C
6Alkanoyloxy and C
3-C
8Cycloalkyl;
Described phenyl, benzyl or C
3-C
8Cycloalkyl is arbitrarily replaced by 1,2 or 3 substituting group, and these substituting groups are independently selected from C
1-C
6Alkyl, halogen or C
1-C
6Alkoxyl group; Or R
1aCan be by-(CH
2)
w-R
1bReplace, wherein w is 1 to 12, R
1bBe piperidyl, pyrimidyl, pyrrolidyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, two [two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group)] amino, two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group) amino, phenyl, C
3-C
8Cycloalkyl, pyrrolidyl, and kharophen,
Described phenyl or C
3-C
8Cycloalkyl is arbitrarily replaced by 1,2 or 3 substituting group, and these substituting groups are C independently
1-C
6Alkyl, halogen or C
1-C
6Alkoxyl group; A be a key ,-(CH
2)
mOr-C (O)-; A
1Be a key ,-NR
a-,-O-,-(CH
2)
m-or-S (O)
n-; Q is 0 to 6; P is 0 to 6; N is 0,1 or 2; M is 0 to 6; S is 0 to 6; R
aBe hydrogen, C
1-C
6Alkyl or C
2-C
6Chain acyl; D is a key, C
2-C
4Alkylene group (alkenylenyl) or-C (X) (Y)-,
Be hydroxyl one of among X and the Y wherein, another is a hydrogen, or X and Y the two all be hydrogen, or X and formation=O of Y, or=NOR
c
R
cBe hydrogen, benzyl, ethanoyl, benzoyl or C
1-C
6Alkyl; X
1And Y
1In one be hydroxyl, another is a hydrogen, or X
1And Y
1The two is hydrogen, or X
1And Y
1Formation=O or=NOR
d
R
dBe hydrogen or C
1-C
6Alkyl; R
2Be hydroxyl, C
1-C
6Alkyl, C
1-C
6The base of alkoxyl group, phenoxy group or following general formula
R wherein
4And R
5Independent separately is hydrogen, C
1-C
6Alkyl, phenyl or phenyl (C
1-C
6Alkylidene group)-, or R
2Be heterocyclic radical, these heterocyclic radicals are selected from hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidyl, quinuclidinyl or morpholinyl;
Any base in hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidyl, quinuclidinyl or the morpholinyl all can be replaced by one or more substituting groups, and these substituting groups are selected from C
1-C
6Alkyl, halogen, trifluoromethyl, benzyl, phenyl, two (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group)-, C
1-C
6Alkylamino (C
1-C
6Alkylidene group)-, C
2-C
6Chain acyl, amido, 2-glycyl, C
2-C
6Chain acyloxy, C
1-C
6Carbalkoxy-, C
1-C
6Alkylamino, C
3-C
8Cycloalkyl, piperidyl, pyrrolidyl, pyrimidyl, phenyl (C
1-C
6Alkylidene group)-, phenoxy group (C
1-C
6Alkylidene group)-, piperidyl (C
1-C
6Alkylidene group)-, pyrrolidyl (C
1-C
6Alkylidene group)-, pyrimidyl (C
1-C
6Alkylidene group)-, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, two [two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group)] amino, two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group) amino and kharophen,
Benzyl, phenyl, piperidyl, C
3-C
8Cycloalkyl, phenyl (C
1-C
6Alkylidene group)-, phenoxy group (C
1-C
6Alkylidene group)-, pyrrolidyl, piperidyl (C
1-C
6Alkylidene group)-, pyrrolidyl (C
1-C
6Alkylidene group)-, pyrimidyl (C
1-C
6Alkylidene group)-or pyrimidyl in any one base all can be replaced by one or more substituting groups, these substituting groups are selected from C
1-C
6Alkyl, halogen, trifluoromethyl, kharophen, C
2-C
6Chain acyl, C
2-C
7Chain acyloxy and C
1-C
6Alkoxyl group, or described piperidyl, pyrrolidyl, piperidyl (C
1-C
6Alkylidene group)-, pyrrolidyl (C
1-C
6Alkylidene group)-, pyrimidyl (C
1-C
6Alkylidene group)-or pyrimidyl on nitrogen can be replaced or R by amino protecting group
2Base for following general formula
R wherein
4a, R
5aAnd R
6aIndependent separately is hydrogen, C
1-C
6Alkyl, trifluoromethyl or C
1-C
6Alkoxyl group;
Or R
4aBe hydrogen, C
1-C
6Alkyl, trifluoromethyl or C
1-C
6Alkoxyl group, and R
5aAnd R
6aConstitute pyrrolidyl, piperidyl, hexamethyleneimino or heptamethylene imino-jointly with the nitrogen that is connected with them of nitrogen that links to each other with them;
Or R
4aBe oxygen, R
5aAnd R
6aThe nitrogen that is connected with them common formation pyrrolidyl, piperidyl, hexamethyleneimino or a heptamethylene imino-; R is phenyl, naphthyl, dihydro naphthyl, tetralyl, C
3-C
8Cycloalkyl, pyrazinyl, allyl group, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazyl, hexamethyleneimino, heptamethylene imino-, piperidyl, pyrrolidyl, quinuclidinyl or morpholinyl
Phenyl, naphthyl, dihydro naphthyl, tetralyl, C
3-C
8Any one base in cycloalkyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazyl, hexamethyleneimino, heptamethylene imino-, piperidyl, pyrrolidyl, quinuclidinyl or the morpholinyl all can be replaced by one or more substituting groups, and these substituting groups are selected from C
1-C
12Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, halogen, trifluoromethyl, amido, cyano group, benzyl, phenyl, two (C
1-C
12Alkyl) amino, C
2-C
6Chain acyl, C
2-C
6Chain acyloxy, C
1-C
6Alkylamino, oxazolyl, dihydro-oxazole base, piperidyl (C
1-C
12Alkoxyl group)-, piperidyl (C
1-C
12Alkoxyl group) (C
1-C
12Alkylidene group)-, piperidyl (C
1-C
12Alkylidene group)-, phenyl (C
1-C
12Alkoxyl group)-, phenyl (C
2-C
12Alkylidene group)-, C
3-C
8Cycloalkyl, piperidyl, pyrimidyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, general formula R
xR
yN-G-L (C
0-C
6Alkylidene group)-and kharophen,
R wherein
xAnd R
yIndependent separately is hydrogen, C
1-C
6Alkyl, phenyl, benzyl, piperidyl, pyrrolidyl, hexamethyleneimino, heptamethylene imino-, morpholinyl, piperazinyl or C
3-C
8Cycloalkyl,
Or R wherein
xR
yN is the ring that is selected from piperidyl, pyrrolidyl, hexamethyleneimino, heptamethylene imino-, azetidinyl, and these cyclic groups can be connected with G by any position of ring,
G is C
1-C
12Alkylidene group, C
2-C
12Alkenylene or C
2-C
12Alkynylene and
L be a key ,-O-,-S-,-S (O)-,-S (O)
2-or-NH-; Prerequisite is to work as A
1For-NR
a-,-O-or-S (O)
n-, A is-CH
2-time, R
1Be not hydrogen; Or take their salt of acceptable or solvate on the medicine of significant quantity.
The present invention also comprises the new compound of general formula I and the medicine composition that contains the compound of general formula I, and this prescription is made of jointly acceptable carrier, thinner or vehicle on the compound of general formula I and one or more medicines.
The detailed description of preferred embodiment
The present invention finds that the substituted indole compounds of group of those selections of general formula I has the Neuropeptide Y Receptors antagonistic action.
" C
1-C
6Alkoxyl group " the straight or branched alkyl chain that contains 1 to 6 carbon atom that links to each other with Sauerstoffatom of expression.Typical C
1-C
6Alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy or the like.Term " C
1-C
6Alkoxyl group " be included in " C in its range of definition
1-C
4Alkoxyl group " and " C
1-C
3Alkoxyl group ".
Such as used herein, term " C
1-C
12Alkyl " refer to contain 1 to 12 carbon atom straight or branched, univalent saturated aliphatic chain and include, but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl and hexyl.Term " C
1-C
12Alkyl " be included in the term " C in its range of definition
1-C
6Alkyl " and " C
1-C
4Alkyl ".
" C
2-C
7The chain acyloxy " represent that the straight or branched alkyl chain that contains 1 to 6 carbon atom is connected with Sauerstoffatom by this carbonyl with the continuous back of carbonyl again.Typical C
2-C
7The chain acyloxy comprises acetoxyl group, propionyloxy, different propionyloxy, butyryl acyloxy, uncle's butyryl acyloxy, penta acyloxy, hexylyloxy, 3-methylpent acyloxy or the like.
" C
3-C
8Cycloalkyl " refer to contain the saturated cyclic hydrocarbons structure of 3 to 8 carbon atoms.Typical C
3-C
8Cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl or the like.
" halogen " refers to chlorine, fluorine, bromine or iodine.
" C
1-C
10Alkylthio " refer to contain the straight or branched alkyl that links to each other with sulphur atom of 1 to 10 carbon atom.Typical C
1-C
10Alkylthio comprises methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio or the like.Term " C
1-C
10Alkylthio " be included in the term " C within its range of definition
1-C
6Alkylthio " and " C
1-C
3Alkylthio ".
" C
1-C
12Alkylidene group " refer to contain the straight or branched divalence saturated aliphatic chain of 1 to 12 carbon atom, and include but not limited to methylene radical, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, the inferior tertiary butyl, pentylidene, isopentylidene, hexylidene, octylene, octylene, the inferior decyl of 3-methyl.Term " C
1-C
6Alkylidene group " be included in term " C
1-C
12Alkylidene group " within.Term " C
0Alkylidene group " or any term that embodies this name all be meant key, for example " a C
0-C
6Alkylidene group " be meant a key or here the definition C
1-C
6Alkylidene group.
" C
1-C
10Alkylamino " refer to general formula
-NH (C
1-C
10Alkyl) base, the chain that wherein contains 1 to 10 carbon atom is connected on the amino.Typical C
1-C
4Alkylamino comprises methylamino-, ethylamino, third amino, isopropylamino, fourth amino, Zhong Ding amino or the like.
Term " C used herein
2-C
12Alkenyl " expression contains the univalent unsaturated fatty chain of straight or branched of 2 to 12 carbon atoms.Typical C
2-C
12Alkenyl comprises vinyl (also being Vinyl), 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 1-butylene base, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 2-propenyl, crotyl, pentenyl or the like.
" C used herein
2-C
12Alkynyl " expression contain at least a carbon carbon triple-linked contain 2 to 10 carbon atoms straight or branched, the undersaturated aliphatic chain of univalent.Typical C
2-C
12Alkynyl comprises ethynyl, 1-proyl, ethyl acetylene base, 1-hexin base, 2-propynyl, 2-butyne base, valerylene base or the like.
Term " C used herein
2-C
12Alkenylene " refer to contain the unsaturated fatty chain of divalence of the straight or branched of 2 to 12 carbon atoms.Typical C
2-C
12Alkenylene comprises-CH=CH-,-CH
2-CH=CH-,-CH
2-C (CH
3)=CH-CH
2-CH
2-or the like.
Term " C used herein
2-C
12Alkynylene " refer to contain the straight or branched divalence unsaturated fatty chain that at least one carbon carbon triple-linked contains 2 to 10 carbon atoms.Typical C
2-C
12Alkynylene comprises-C ≡ C-,-CH
2-C ≡ C ,-CH
2-C ≡ C-CH
2CH
2-or the like.
" C
3-C
8Cycloalkenyl group " contain the cyclic hydrocarbon structure that contains 3 to 8 carbon atoms of two keys in the representative ring at least.
" C
1-C
6Alkoxyl group " refer to the straight or branched alkyl that contains 1 to 6 carbon atom that is connected with Sauerstoffatom.Typical C
1-C
6Alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy or the like.Term " C
1-C
6Alkoxyl group " be included in the term " C in its range of definition
1-C
3Alkoxyl group ".
" C
2-C
6Chain acyl " refer to the straight or branched alkyl that contains 1 to 5 carbon atom that links to each other with a carbonyl.Typical C
2-C
6Chain acyl comprises ethanoyl, propionyl, different propionyl, butyryl radicals, uncle's butyryl radicals, pentanoyl, caproyl, 3-methylpent acyl group or the like.
" C
1-C
6Carbalkoxy " refer to the straight or branched alkoxyl group that contains 1 to 6 carbon atom that links to each other with a carbonyl.Typical C
1-C
6Carbalkoxy comprises methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl or the like.
The term that uses among the application " amino protecting group " refers to the substituting group on the amino, when other functional group reaction on the compound, is generally used for blocking or protection amino.The example of this class amino protecting group comprises formyl radical, trityl, phthalimide-based, the tribromo-acetyl base, chloracetyl, acetyl bromide, iodoacetyl, and the urethane type blocks base, carbobenzoxy-(Cbz) for example, 4-phenyl carbobenzoxy-(Cbz), 2-methyl carbobenzoxy-(Cbz), 4-methoxyl group benzyloxy carbonyl, 4-fluorine carbobenzoxy-(Cbz), 4-benzyloxycarbonylchloride base, 3-benzyloxycarbonylchloride base, 2-benzyloxycarbonylchloride base, 2,4-dichloro carbobenzoxy-(Cbz), the 4-bromo-benzyloxycarbonyl, the 3-bromo-benzyloxycarbonyl, 4-nitro carbobenzoxy-(Cbz), 4-cyano group carbobenzoxy-(Cbz), tertbutyloxycarbonyl, 1,1-hexichol second-1-base oxygen carbonyl, 1,1-two phenylpropyl alcohols-1-base oxygen carbonyl, 2-phenylpropyl alcohol-2-base oxygen carbonyl, 2-(p-methylphenyl)-third-2-base oxygen carbonyl, ring valeryl oxygen carbonyl, 1-methyl ring valeryl oxygen carbonyl, hexamethylene acyl-oxygen carbonyl, 1-methyl cyclohexane acyl-oxygen carbonyl, 2-methyl cyclohexane acyl-oxygen carbonyl, 2-(p-toluenesulfonyl) ethoxycarbonyl, 2-(methylsulfonyl) ethoxycarbonyl, 2-(triphenylphosphinyl) ethoxycarbonyl, fluorenes methoxycarbonyl (" FMOC "), 2-(trimethyl silicon based) ethoxycarbonyl, allyloxycarbonyl, 1-(trimethyl silicane ylmethyl) third-1-alkenyloxycarbonyl, 5-phenyl-isoxalyl methoxycarbonyl, 4-acetyloxy phenyl methanoyl carbonyl, 2,2, the 2-trichloro-ethoxycarbonyl, 2-ethynyl-2-third oxygen carbonyl, the cyclopropyl methoxycarbonyl, 4-(oxygen base in the last of the ten Heavenly stems) carbobenzoxy-(Cbz), isobornyl oxygen carbonyl, piperidino oxygen carbonyl or the like; Phenacyl alkylsulfonyl, 2-oil of mirbane sulfinyl, oxidation diphenylphosphine and similar amino protecting group.These amino protecting groups that use generally are not crucial; as long as it is stable and can optionally remove the not rest part of disturbing molecule at proper step that the amino of derivatize under the condition of reaction afterwards takes place in other position of intermediate molecule, comprise and do not disturb any other amino protecting group.Preferred amino protecting group is trityl, tertbutyloxycarbonyl (t-Boc, Boc or t-Boc), allyloxycarbonyl and carbobenzoxy-(Cbz).The further example E.Haslam of preferred above-mentioned base has description (J.G.W.McOmie in " Proteetive Groups in Organic Chemistry " chapter 2, ed., 1973) and T.W.Greene and P.G.M.Wuts, Protective Groups inOrgocnic Synthesis has description in the chapter 7 of (1991).
The term that uses in the application's book " carboxyl-protecting group " refers to the substituting group of carboxyl, is generally used for blocking or the protection carboxyl when other functional group of compound reacts.The example of this class carboxyl-protecting group comprises methyl; to nitrobenzyl; to methyl-benzyl; to methoxy-benzyl; 3; the 4-dimethoxy-benzyl; 2; the 4-dimethoxy-benzyl; 2; 4; 6-trimethoxy benzyl; 2; 4; the 6-trimethyl benzyl; the pentamethyl-benzyl; 3; the 4-Methylenedioxybenzyl; diphenyl-methyl; 4; 4 '-the dimethoxy diphenyl-methyl; 2; 2 '; 4; 4 '-the methoxyl group diphenyl-methyl; the tertiary butyl; tert-pentyl; trityl; 4-methoxy trityl; 4; 4 '-dimethoxytrityl; 4,4 ', 4 " trimethoxy trityls; 2-phenyl third-2-base; trimethyl silicon based; that tertiary butyl dimethyl is silica-based; phenacyl; 2; 2,2-three chloroethyls; 2-(two (normal-butyl) methyl is silica-based) ethyl; the tolysulfonyl ethyl; 4-nitrobenzyl sulphonyl ethyl; allyl group; cinnamyl; 1-(trimethyl silicane ylmethyl) third-1-alkene-3-base and similarly basic.Preferred carboxyl-protecting group is allyl group, benzyl and the tertiary butyl.See before the 5th chapter of works of T.W.Greene etc. of front, the 5th Zhanghe of E.Haslam works of face of the further example of these bases.
Term used herein " hydroxyl protecting group " refers to the substituting group of hydroxyl, is commonly used to block or the protection hydroxyl when other functional group reaction of compound.The example of this class hydroxyl protecting group comprises methoxyl methyl, benzyloxymethyl, methoxy (ethoxy) methyl, 2-(trimethyl silicon based) ethoxymethyl, first thiomethyl, 2,2-two chloro-1,1-two fluoro ethyls; THP trtrahydropyranyl, phenacyl, cyclopropyl methyl, allyl group, C
1-C
6Alkyl, 2,6-dimethyl benzyl, adjacent phenylbenzyl, 4-picolyl, dimethyl is silica-based, tertiary butyl dimethyl is silica-based, levulinic acid ester group, PIVALIC ACID CRUDE (25) ester group, phenylformic acid ester group, dimethyl methyl perester radical, dimethynitrosamine ester group, isopropylformic acid ester group, adamantoate and THP trtrahydropyranyl.The further example of these bases is seen T.W.Greene andP.G.M.Wuts, Protective Gronps in Organic Synttesis, the 3rd chapter of (1991).
Term used herein " leaving group " refer in the nucleophilicity substitution reaction since the nucleophilicity attack by carbon atom on substituted atomic radical.The term that uses in the presents " leaving group " includes but not limited to active base.
Term used herein " active base " refers to leaving group, when (a C=O) time-out, this leaving group more resemble and participate in acylation reaction rather than for example should the non-existent situation of base among the free carboxy acid with the carbonyl that is attached thereto.The active base of this class is very familiar to the professional, for example can be succimide oxygen.Phthalic imidine oxygen, benzotriazole oxygen, benzene sulfonyl oxygen, methylsulfonyl oxygen, tolylsulfonyl oxygen, azido-or-O-CO-(C
4-C
7Alkyl).
Compound of the present invention is the following indole derivatives that draws naming ﹠ numbering according to the strop of JACS.
Compound of the present invention can contain one or more asymmetric centers.Can occur with mixture and each enantiomer of racemic modification, enantiomer as the consequence of these chiral centres compound of the present invention, and occur with the mixture of making diastereomer and diastereomer.All asymmetric bodys, each isomer and their combination are all within the scope of the invention.
Normally used such in term used herein " R " and " S " and the organic chemistry, be the single-minded configuration that indicates chiral centre.Term " R " (rectus) refers to when (big, neutralization is little) order group meets the configuration of the chiral centre of clockwise relation by minimum group during towards front projection.Term " S " (sinister) refers to when (big, neutralization is little) order group meets the configuration of the chiral centre of inhour relation by minimum group during towards front projection.The order of group is that the ordination number (reducing order by ordination number) with them is arranged.103-120 page or leaf at Nomenclature of Organic Compaends:Principles and Practice (J.H, Fletcher, et al., eds., 1974) has a part tabulation that stereochemistry is discussed.
Except that (R)-(S) system, also can use the D-L system to specify absolute configuration in the presents, especially for the configuration of designated amino acid.With the Fischer projection formula when directed, No. 1 carbon potential that makes major key is in the top in this system.Prefix " D " is used for describing the absolute configuration that the functional group of (decisive) wherein is positioned at the isomer on chiral carbon right side, and " L " is meant that this functional group is positioned at the absolute configuration of the isomer in left side.
In order preferably to prepare a kind of optical isomer about its enantiomer, the technician can use in two routes.The technician can at first prepare the mixture of enantiomer, separates two kinds of enantiomers then.The common method that racemic modification (or mixture of enantiomer) is split into each enantiomer is to form salt by optically active acid or alkali and at first enantiomer is transformed into diastereomer.These diastereomers adopt differential solubleness, fractional crystallization, chromatogram or similar approach to separate then.J.Jseqeus et al., Enantiomers, Racemates, and Resolutions, (1991) are seen in the more careful description that enantiomeric mixture splits.
Except that above-mentioned outside the plan, the technician also can select the enantioselectivity scheme to prepare the compound of general formula I.The building-up reactions design that this scheme is used can remain on the chiral centre that exists in the raw material direction of hope.These reaction scheme usually generate wherein, and the title product more than 95% is the compound of the enantiomer of expectation.
Just as noted, the present invention includes acceptable salt on the medicine of compound of general formula I definition.Compound of the present invention can have sufficient acidic groups, basic group, or two class bases, thereby can generate acceptable salt on the medicine with a series of organic basess, mineral alkali, mineral acid and organic acid.
The term of these uses " acceptable salt on the medicine " is meant the salt of the compound of top general formula, and this salt pair biology is atoxic from seeing in essence.Acceptable salt is by acid of acceptable ore deposit or organic acid or organic bases on compound of the present invention and the medicine or mineral alkali prepared in reaction on the typical medicine.This class salt is called acid-adducting salt or adduct.
The acid that is generally used for forming acid-adducting salt is mineral acid, for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid or the like, and organic acid, for example tosic acid, methylsulfonic acid, oxalic acid, to bromo-benzene sulfonic acid, carbonic acid, Succinic Acid, citric acid, phenylformic acid, acetate or the like.The example of acceptable salt has vitriol on this class medicine, pyrosulphate, bisul-phate, sulphite, bisul-phite, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, methyl phosphate, pyrophosphate salt, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleic acid salt, 1,4-acetylenedicarboxylic acid salt, 1,6-hexyne dacid salt, benzoate, chloro-benzoate, tolyl acid salt, hydroxy benzoate, methoxybenzoic acid salt, adjacent benzene benzoate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, Citrate trianion, lactic acid salt, gamma hydroxybutyrate, gluconate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate or the like.The acceptable acid-adducting salt is and the salt of hydrochloric acid and the acid generation of Hydrogen bromide one class ore deposit and the salt that generates with maleic acid such as methylsulfonic acid one class organic acid on the preferred medicine.
The amine salt base also can comprise wherein and is connected with suitable organic group on the amino nitrogen, for example is connected with the quaternary ammonium salt of alkyl, thiazolinyl, alkynyl or aralkyl.
The alkali adduct comprises from mineral alkali deutero-salt, for example from ammonia, basic metal or alkaline-earth metal such as oxyhydroxide, carbonate or acid salt or the like deutero-salt.Comprise sodium hydroxide, potassium hydroxide, ammonium hydroxide, salt of wormwood, yellow soda ash, acid sodium carbonate, acid potassium carbonate, calcium hydroxide, lime carbonate or the like for the useful alkali of preparation salt of the present invention.Sylvite and sodium salt are preferred especially.
Will be appreciated that the counter ion that forms the part of any salt of the present invention is not crucial character usually, as long as salt is acceptable and as long as this counter ion is not contributed undesirable character to salt as a whole on the pharmacology as a whole.
The present invention further comprises acceptable solvate on the medicine of compound of general formula I.The compound of many general formula Is can combine with solvent, for example forms corresponding hydrate, methylate, ethylate and the second nitrile compound equal solvent thing of acceptable on the medicine with water, methyl alcohol, ethanol and acetonitrile.
The present invention also comprises acceptable prodrug on the medicine of compound of general formula I.Prodrug is meant through chemically modified and at its active medicine of site of action lifeless matter, can degrade or be modified into bioactive parent through a step or multistep or other physiological disposition.This prodrug should have the pharmacokinetic property different with parent, makes the easier mucous epithelium that strides across absorb, better salify or dissolving, or improved the stability (for example having increased plasma half-life) of system.
The chemically modified of this quasi-representative comprises:
1) easily by esterase or lipoidase cracked ester or amide derivatives;
2) can be by the polypeptide of exclusive or non-exclusive proteolytic enzyme understanding; Or
3) film by prodrug or modification prodrug is chosen in site of action cumulative derivative; Or any combination of 1 to 3 of talking about previously.The ordinary method of selection and the suitable prodrug derivant of preparation sees for example H.Bundgaard,
Design of Prodrugs(1985).
Preferred compound of the present invention is the compound of general formula I, wherein: a) R
bBe hydrogen, chlorine, fluorine, methyl, ethyl, hydroxyl or ethanoyl; B) R
1Be methyl, ethyl, or R
1aBe phenyl, piperidyl, pyrrolidyl, hexamethyleneimino, piperazinyl and v are 1 to 6; C) A
1Be a key ,-NH-,-N (CH
3)-,-S-or-O-; D) A is-CH
2-or-CH
2CH
2-; E) q is 0,1 or 2; F) p is 0,1 or 2; G) s is 0,1,2 or 3; H) D is a key ,-C (O)-,-CH (OH)-or-CH
2-; I) R
2Be general formula-NR
4R
5Or-N
+R
4aR
5aR
6aBase; J) R
4And R
5Be hydrogen, methyl, ethyl, benzyl or common and a formation of the nitrogen that is connected piperidyl, pyrrolidyl or hexamethyleneimino independently of one another; K) R
4a, R
5a, R
6aBe hydrogen, methyl, ethyl or R independently of one another
5aAnd R
6aForm piperidyl, pyrrolidyl or hexamethyleneimino with one in the nitrogen that is connected jointly; And l) R is phenyl, piperidyl, pyrrolidyl, hexamethyleneimino, heptamethylene imino-, naphthyl, thiazolyl, furyl, quinolyl, isoquinolyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl or quinuclidinyl; Or be acceptable salt or solvate on their medicine.
Preferable methods of the present invention is to use the method for the compound of general formula I, wherein a) R
bBe hydrogen, chlorine, fluorine, methyl, ethyl, hydroxyl or ethanoyl; B) R
1Be methyl, ethyl, or R
1aBe phenyl, piperidyl, pyrrolidyl, hexamethyleneimino, piperazinyl, and v is 1 to 6; C) A
1Be a key ,-NH-,-N (CH
3)-,-S-or-O-; D) A is-CH
2-or-CH
2CH
2-; E) q is 0,1 or 2; F) p is 0,1 or 2; G) s is 0,1,2 or 3; H) D is a key ,-C (O)-,-CH (OH)-or-CH
2-; I) R
2Be general formula-NR
4R
5Or-N
+R
4aR
5aR
6aBase; J) R
4And R
5Be hydrogen, methyl, ethyl, benzyl or common and a formation of the nitrogen that is connected piperidyl, pyrrolidyl or hexamethyleneimino independently of one another; K) R
4a, R
5a, R
6aBe hydrogen, methyl, ethyl independently of one another, or R
5aAnd R
6aForm piperidyl, pyrrolidyl or hexamethyleneimino with one in the nitrogen that is connected jointly; And l) R is phenyl, piperidyl, pyrrolidyl, hexamethyleneimino, heptamethylene imino-, naphthyl, thiazolyl, furyl, quinolyl, isoquinolyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl or quinuclidinyl; Or be acceptable salt or solvate on their medicine.
Particularly preferred compound of the present invention is the compound of general formula I, wherein a) R
bBe hydrogen, fluorine or methyl; B) R
1Be methyl, or R
1aBe piperidyl, pyrrolidyl, or hexamethyleneimino and v are 1,2 or 3; C) A
1Be a key ,-NH-,-S-or-O-; D) A is-CH
2-or-CH
2CH
2-; E) q is 0 or 1; F) p is 0 or 1; G) s is 0 or 1; H) D is a key, or-C (O)-; I) R
2Be general formula-NR
4R
5Base; J) R
4And R
5Be methyl independently of one another, or form piperidyl, piperazinyl or pyrrolidyl with one in the nitrogen that links to each other jointly; K) R is phenyl, naphthyl or the cyclohexyl that arbitrarily replaces; Or acceptable salt or solvate on their medicine.
The particularly preferred method and formulation of the present invention is to use the method and the reagent of the particularly preferred compound of the present invention.
Particularly preferred compound is the compound of general formula I, wherein: a) R
bBe hydrogen; B) R
1Be methyl, piperidyl (C
1-C
4Alkylidene group)-, or pyrrolidyl (C
1-C
4Alkylidene group)-; C) A
1Be a key or-O-; D) A is-CH
2-; D) q is 0; E) p is 0 or 1; F) s is 0 or 1; G) D is a key, or-C (O)-; H) R
2Be piperidyl or pyrrolidyl, they are by amino, two (C
1-C
6Alkyl) amino, (C
1-C
6Alkyl) amino, piperidyl or pyrrolidyl replace, or R
2Be phenyl, the piperazinyl that cyclohexyl or benzyl replace; And j) R is that substituting group is selected from C by the phenyl of 1 to 3 substituting group replacement
1-C
6Alkyl, trifluoromethyl and halogen; Perhaps acceptable salt or solvate on their medicine.
Particularly preferred method of the present invention and prescription are to use the method and the prescription of particularly preferred compound.
Most preferred of the present invention family is the compound of the general formula I of following general formula
Wherein:
D
1For-C (O)-or-CH
2-;
R
1Be methyl, piperidines-3-base-CH
2CH
2-, piperidines-3-base-CH
2CH
2CH
2-, piperidines-2-base-CH
2CH
2-, piperidines-2-base-CH
2CH
2CH
2-, tetramethyleneimine-3-base-CH
2CH
2-, tetramethyleneimine-3-base-CH
2CH
2CH
2-, piperidin-4-yl-CH
2CH
2-or piperidin-4-yl-CH
2CH
2CH
2-;
R
2Be piperidyl or pyrrolidyl, they are by amino, two (C
1-C
6Alkyl) amino, (C
1-C
6Alkyl) amino, piperidyl or pyrrolidyl replace, or R
2Piperazinyl for phenyl or cyclohexyl replacement;
R
*Be chlorine or bromine; With
R
*Be hydrogen or chlorine; Or acceptable salt or solvate on their medicine.
It also is most preferred using the method and the prescription of any compound in this most preferred family.
The compound of general formula I can be by the known method preparation of a series of documents.Prepare wherein R
1For the scheme of the compound of the general formula I of methyl is described in down by reaction formula 1.
Scheme 1
To the due evaluation of document, there are many methods to finish each step that following formula is described as the professional.This quasi-representative method is described by following general technology such as embodiment.Reduction
Reduction by 1-methyl-2-indole-carboxylic acid generates corresponding 2-methylol-1-skatole, can prepare the compound of many general formula Is.This reduzate can be by comprising the various kinds of document method preparation of catalytic hydrogenation.The most preferred method of finishing this reduction reaction is to use sodium borohydride, lithium borohydride, hydrogenation diisobutyl lithium, lithium triethylborohydride, borane-dimethyl sulphide complex compound to reflux in tetrahydrofuran (THF) and triethoxyl silane one class reductive agent.Another approach of this carboxylic acid of reducing is to use sodium, this method to be called the Bouveault-Blanc method in ethanol.Most preferred reductive agent is a lithium aluminium hydride in this reduction.Alkylation or arylation
Use standard technique aryl can be coupled on the top alcohol.For A wherein be-O-, p is 0, and R is those compounds of the general formula I of substituted-phenyl, and for example most preferred method comprises the phenol coupling of using Mitsunobu reagent.O.Mitsunobu，
et?al.，
Bulletin?of?the Chemical?Society?of?Japan，44：3427(1971)；O.Mitsunobu，
et?al.，
Journal?of?the?American?Chemical?Society，94：679(1972)。In this reaction, triphenylphosphine share one pot reaction with diethylazodicarboxylate (DEAD) pure pirouette is turned to corresponding alkoxyl group microcosmic salt, and this is useful alkylating reagent.
Though this linked reaction can be used the reactant and the reagent of various concentration, to use 1 to 2 equivalent indole-alcohol, triphenylphosphine and DEAD to be the best whenever measuring substituted phenol (ArOH).
This reaction also is preferably under the inert solvent existence to be carried out, and for example at toluene, benzene, is preferably in tetrahydrofuran (THF) and carries out.Temperature of reaction is about 0 ℃ to about 40 ℃, preferably reacts at ambient temperature, until the product generation of hope.Though the type reaction time at ambient temperature is 18 hours, can follow the tracks of reaction with the chromatographic technique of standard.
Another method of alcohol arylation is that use prepares alkoxide in advance and carries out the substitution reaction of aromatic fluoride nucleophilicity fragrance.At first in alcohol, add alkali, then add aromatic halides and finish reaction.Particularly preferred alkali is sodium hydride.Another preferred alkali is hexamethyl two silicon sodiumazide.Reaction is generally carried out in polar aprotic solvent, and for example at acetonitrile, N, dinethylformamide, N react in N-dimethyl benzene yl acetamide, methyl-sulphoxide or the hexamethyl phosphoric triamide.Alkylation
Adopt the serial of methods in the document can finish 1, the alkylation of 2-disubstituted indole.The preferred alkyl method of this substituted indole is the Mannich reaction.[summary of this reaction is seen Tramontini,
Synthesis, 703-775 (1973); House, MODERN SYNTHETIC REACTIONS, (2d, ed., 1972) at pages 654-660.]
In this reaction, formaldehyde (being other aldehyde sometimes) and HNR
4R
5Salt and the compound condensation that contains reactive hydrogen.If with primary amine (RNH
2), secondary amine (R
2NH) salt or acid amides (RCONH
2) replace ammonia to react, the product that obtains so respectively on nitrogen by R, R
2Replace with RCO.This reaction is generally carried out in lower alkyl alcohol, for example carries out in methyl alcohol or ethanol, or carries out in acid, for example carries out in acetate.
Prepare A wherein and be alkylidene group general formula I compound a kind of method at first oxidation alcohol generate corresponding aldehyde.
The oxygenant that this reaction is used is as pyridinium dichromate (PDC) or pyridinium chloro-chromate (PCC), for example carries out in the methylene dichloride at solvent.The aldehyde that generates reacts with substituted phosphonates in the presence of alkali then.
This Wittig type reaction causes generating the arylalkenyl thing.The alkali that uses in this reaction is preferably sodium hydride.This reacts generally generation (E) and (Z) mixture of type steric isomer.Then or by the above-described reductive agent of using, perhaps use standard technique to carry out catalytic hydrogenation two keys are reduced.This reacts preferred solvent and comprises ethylene dichloride.
Obtain 1, the 2-disubstituted indole mainly carries out 3 substitution reactions according to above-described Mannich chemistry then.
R wherein
1Be substituted alkylene ((CH
2)
v-R
1a) compound can be by the described preparation of later reaction formula II.
Reaction formula II 
Wherein Tr is a trityl.
Reaction formula II (continuing)
During with the oxidizer treatment of gentleness, for example in methyl alcohol, use hydrogen peroxide, in 0 ℃ and methylene dichloride, use m-chloro-benzoic acid peroxide (MCPBA) or in water-alcoholic solutions, use an alkali metal salt of Periodic acid, can make L wherein be converted into corresponding sulfoxide (SO-) compound for the derivative and the intermediate of the general formula I of the present invention of-S-.Use strong oxidizer, for example in acetate, use hydrogen peroxide or in methylene dichloride, use m-chloro-benzoic acid peroxide at 20 ℃ to 30 ℃, can be from sulfur-bearing or the corresponding sulfone (SO of sulfoxide compound preparation
2-).
Wherein the compound of the cyclosubstituted general formula I of benzo in the indoles can be according to a series of document currently known methods preparations.For example wherein 4 of the phenyl ring of indoles can be by the described preparation of reaction formula III of back by the compound of methyl substituted general formula I.
In the step a) below, use the Knoevenagel condensation, (reactant dehydration back) generates alkene.Though can use the reaction with same mole thing, make all usually that trinitride is excessive to react.
Ene product in step a) cyclisation then generates indole ring.Effectively cyclization method is that alkene is heated.The cyclisation process can be monitored with thin-layer chromatography.
The reaction formula III
Reaction formula III (continuing)
Reaction formula IV
Reaction formula IV (continuing)
Prepare wherein R
bTo see below reaction formula IV described for the another kind of method of the compound of the general formula I of hydrogen.
Prepare the necessary intermediate of compound of the present invention and other reagent or commodity, or document is known, perhaps can prepare by currently known methods.In addition, those skilled in the art it should be understood that as above-described and are not damaging the improvement that can finish the method for preparing the claim compound under the synthetic situation of these compounds.For example, can use other ester, protecting group, precursor, or directly on the benzo ring of indoles, introduce carboxyl (Kolbe-Schmitt reaction), or the like.Further can directly on the benzo ring, introduce R
bBase.For example, with iodobenzene, chlorine and pyridine reaction can import chlorine (Murakami,
Et al.,
Chem.Pharm.Bull., 19:1696 (1971)) or with the direct introducing chlorine (United States Patent (USP) 4,623,657, the full content of this patent document incorporated by reference in this application) of N-chlorosuccinimide and dimethyl formamide reaction.Except that above-described, other conversion, transformation and derivatize or description in the following embodiments, or be that the technician who knows document knows.
The following examples further describe compound of the present invention and their synthetic method.These embodiment are without any the intention that limits the scope of the invention, nor are interpreted as restricted intention.All experiments are all finished at drying nitrogen or argon gas direct draught.Only otherwise specialize, all solvents and reagent all are to buy from market and directly use.Anhydrous tetrahydro furan (THF) prepares through sodium Metal 99.5 distillation or the distillation of benzophenone radical sodium with preceding.
Proton magnetic resonance (PMR) (
1H NMR) spectrum GE QE-300 nuclear magnetic resonance spectrometer (at 300.15MHz), Bruker AM-500 nuclear magnetic resonance spectrometer (at 500MHz), or Bruker AC-200P nuclear magnetic resonance spectrometer (at 200MHz) or icotype mensuration.(only otherwise explain, term used herein " NMR " just is meant proton magnetic resonance (PMR).) fast atom bombardment mass spectroscopy(FABMS) (FAB) measures on VG ZAB-2SE mass spectrograph.Field desorption(FD) mass spectrum (EDMS) or measure at VG 70SE or on Varian MAT 731 mass spectrographs.
Optically-active is measured on Perkin-Elmer 241 polarimeters.Chromatographic separation is generally carried out on WatersPrep 500LC, only otherwise specialize, generally uses the specified linear gradient elution in back.
General with thin-layer chromatography (TLC) monitoring reaction terminal point.Chromatographic sheet is E.MerckKieselgel 60 F
254Plate, 5cm * 10cm, 0.25mm is thick.Use UV and chemical colour reaction to determine spot (thin plate being immersed cerous molybdate ammonium solution (75g ammonium molybdate, 4g cerous sulfate (IV) and 500ml 10% aqueous sulfuric acid)) then with the thin plate heating.Preparation type rotary thin layer chromatogram is used Harrison Model 7924A chromatographic instrument, uses Analtech silica gel G F flap.
Cation-exchange chromatography Dowex
50X8-100 ion exchange resin.Anion-exchange chromatography Bio-Rad AG
1-X8 anionite-exchange resin (the acetate type changes the hydrogen-oxygen template into).Flash chromatography is pressed Still,
Et al., Journal of Organic Chemistry, described the finishing of 43:2923 (1978).
Optically-active is reading under sodium-D-light (354nm).Carbon, hydrogen, nitrogen ultimate analysis are measured on ControlEquipment Corporation 440 Elemenial Analyzer, or university computational analysis center (pharmaceutical college, Madrid, Spain) finishes.Using opening glass tubule to measure on the Thomas Hoover capillary melting point apparatus or on the Buchi fusing point instrument, temperature is not proofreaied and correct.
The preparation scheme of the compound of the general formula I of describing among the following figure of method to the front provides explanation.The all method of back and the term among the embodiment " NMR ", " IR " and " UV " refer to proton magnetic resonance (PMR) spectrum, infrared spectra and UV spectrum respectively, and consistent with the title product of describing.
Preparation 1(3 ' R)-2-(piperidines-3-yl) ethyl acetate
(100g 0.606mol) is dissolved in the ethanol (1.8 liters), handles and at 60 ℃ 60 pounds/inch with 5% rhodium aluminum oxide (100g) with the 3-Pyridineacetic Acid ethyl ester
2Hydrogenation is spent the night under the hydrogen-pressure.The elimination catalyzer boils off solvent, obtains brown liquid (101.4g, 98%).Brown liquid is dissolved in ethyl acetate (600ml), use L-(+) amygdalic acid in warm ethyl acetate (600ml), to handle then.Refrigerator and cooled but 4 hours, collect solid, crystalline mother solution keeps treats that the back makes the usefulness of the another kind of enantiomer of preparation.The solid that obtains is used ethyl acetate (the 1.55-1.6 liter spends the night in envrionment temperature) again, and the title compound that obtains expecting is white needle-like crystals.Output 81.6g (41%).@589nm=+44.9 ° of optically-active (ethanol) ，; @365nm=+173.73 °, mp 118-119 ℃.
Preparation 2(3 ' S)-2-(piperidines-3-yl) ethyl acetate
Recrystallization mother liquor evaporate to dryness in the front preparation 1 obtains dark oil thing (100.3g).This oily matter is dissolved into cold salt of wormwood, and (52g is 0.377mol) and in water (250ml) solution, with ethyl acetate (5 * 150ml) extractions.Combining extraction liquid is used anhydrous magnesium sulfate drying.The pressure reducing and steaming solvent obtains black liquor (40.25g).Ethyl acetate (650mol) solution reaction of this black liquor and warm D-(-) amygdalic acid (36g), stirred overnight at room temperature.Twice usefulness ethyl acetate of the crystallization that obtains (being respectively 1.2 liters and 1.1 liters) recrystallization, the title product that obtains expecting is white, needle-shaped crystals.Output: 48.7g (24.9%).@589nm=-43.14 ° of optically-active (ethanol) ，; @365nm=-164.31 °, mp 115.5-117 ℃.
The chiral analysis method
Cold wet chemical (0.15g is dissolved in 10ml water) and the reaction of 0.3g mandelate, mixture ethyl acetate extraction (3 * 5ml).Combining extraction liquid, anhydrous magnesium sulfate drying, pressure reducing and steaming solvent.Residue dissolves in ether (10ml) and reacts with S-(-)-α-Jia Jibianji isocyanic ester (0.12ml).2.5 after hour, reaction mixture is handled with 1N hydrochloric acid (2ml).The cellophane goes out ether layer, successively with saturated aqueous common salt, saturated sodium bicarbonate aqueous solution and saturated common salt washing.The organic layer anhydrous sodium sulfate drying boils off solvent.Residue is at chirality OJ
TM(4.6 * 250mm) go up separation to performance liquid chromatographic column, and with 5% ethanol/hexane eluant solution, flow velocity is the 2.5ml/ branch.After the component collected be 1-(+) mandelate, the component of collecting earlier is d-(-) mandelate.The amount of mirror shadow body that contains it in two kinds of enantiomers of the HPLC analysis revealed of final crystalline product is all below 3%.
Preparation 3(the preparation of 3 ' R)-2-(N-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl acetate
Preparation make in 1 ((10.9g 34mmol) is dissolved in 50ml 12% aqueous sodium carbonate 3 ' R)-2-(piperidines-3-yl) ethyl acetate, the solution chloroform extraction that obtains.This extraction liquid drying boils off solvent.Residue is suspended in the ether, filters, evaporates, and gets free alkali (5.36g).Liquid is dissolved in ether (50ml) and drips ether (10ml) solution-treated of acid dimethyl dicarbonate butyl ester (7.9g).After stirring was spent the night, solution cooled off in ice bath, and dripped saturated aqueous citric acid solution (25ml) processing.The water layer extracted with diethyl ether.Merge organic layer, washing, saturated sodium bicarbonate solution is washed and saturated common salt washing, anhydrous magnesium sulfate drying.The pressure reducing and steaming solvent, the title product that obtains expecting is limpid liquid.NMR conforms to the structure of the title compound of expection.
Preparation 4(3 ' S)-2-(N-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl acetate
Preparation in 2 ((48.6g, 150mmol) (solution that obtains is with chloroform extraction (3 * 100ml) for 30g, 0.217mol) water (220ml) solution-treated with salt of wormwood for 3 ' S)-2-(piperidines-3-yl) ethyl acetate.The extraction liquid anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent.Residue mixes with ether (200ml), some suspended solidss of elimination.Boil off ether, obtain brown liquid (25g, theoretical amount is 25.7g).Residue is dissolved in ether (200ml) and cools off in ice bath, stirs to drip acid dimethyl dicarbonate butyl ester (31.8g, ether 0.146mol) (25ml) solution down inward.Remove ice bath, reaction mixture stirs and spends the night.Solution cools off in ice bath again, drips saturated aqueous citric acid solution (100ml) inward.Organic layer is washed with saturated common salt, and saturated sodium bicarbonate solution is washed, saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the title product that obtains expecting is limpid liquid (38.6g,＞99%).NMR conforms to the structure of the title compound of expectation.
Preparation 5The preparation of 3-(pyridin-3-yl) third-2-olefin(e) acid ethyl ester
The phosphino-ethyl acetate (98.6g, 0.44mol) with the solution of anhydrous tetrahydro furan (1200ml) with 60% sodium hydride (17.5g, 0.44mol) processing.Mixture stirring at room 2 hours is chilled to 0 ℃ then.(38.9g, 0.36mol), reaction mixture stirred 1-2 hour, rose to room temperature simultaneously to add the 3-pyridine aldehydes in this mixture.With thin-layer chromatography monitoring reaction process.
In reaction mixture, add water (1000ml).Organic layer ethyl acetate extraction (3 * 1000ml).Merge organic layer, wash with water (2 * 1000ml), and the saturated common salt washing (1 * 1000ml), use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains the title product that 62.5g (97%) expects.
Preparation 6(RS)-preparation of 3-(piperidines-3-yl) ethyl propionate
3-(pyridin-3-yl) third-2-olefin(e) acid ethyl ester (60g, handle with 5% rhodium aluminum oxide powder (17.2g) by ethanol 0.34mol) (600ml) solution.Mixture hydrogenation 5 hours in 60 ℃ of hydrogen that are placed on (55 pounds/square inch).Stop logical hydrogen, termination reaction, reaction mixture passes through CELITE
TMFilter.Residue is washed with hot ethanol.Filtrate concentrates, and with sudden strain of a muscle formula silica gel chromatography purifying, gets the title compound of 39.6g (63%) expectation.IR, NMR conform to the structure of the title compound of expectation.
Preparation 7(the preparation of 3 ' S)-3-(piperidines-3-yl) ethyl propionate mandelate
Amygdalic acid
(RS)-3-(piperidines-3-yl) ethyl propionate (52.0g, 281mmol) with the solution of hot ethyl acetate (300ml) be added to heat (R)-amygdalic acid solution (42.7g, 281mmol) in.Mixture filters, and limpid solution room temperature is placed and spent the night.From solution, leach newly-generated white crystalline salt.This crystallization is molten in the hot ethyl acetate (300ml), make to be chilled to room temperature, carry out recrystallization, this operation repeats once again, promptly carries out twice recrystallization.Final pure crystallizing and drying gets 33.1g (70%).NMR conforms to the structure of the title product of expectation with IR.Confirm the configuration of chiral centre with X ray.
Preparation 8(the preparation of 3 ' R)-3-(piperidines-3-yl) ethyl propionate mandelate
Amygdalic acid
Prepare title compound by the method for describing in the top preparation 7, just use S-(+) amygdalic acid to replace R-(-) amygdalic acid here.NMR conforms to the title product of description with IR.
Preparation 9(the preparation of 3 ' S)-3-(piperidines-3-yl) ethyl propionate
((33.1g 98mmol) handles with 30% wet chemical with the suspension of ethyl acetate (500ml) 3 ' S)-3-(piperidines-3-yl) ethyl propionate mandelate, reaches limpid until organic layer.In mixture impouring separating funnel, organic layer ethyl acetate extraction (3 * 300ml).Merge organic layer, washing (2 * 300ml), and the saturated common salt washing (1 * 300ml), anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the oily product yield that obtains is near 100%.NMR conforms to the title product structure of expectation with IR.
Preparation 10(the preparation of 3 ' R)-3-(piperidines-3-yl) ethyl propionate
By top preparation 9 described preparation title compounds, just use (3 ' R)-3-(piperidines-3-yl) ethyl propionate mandelate replacement (3 ' S)-3-(piperidines-3-yl) ethyl propionate mandelate here.NMR conforms to the title product structure of expectation with IR.
Preparation 11(the preparation of 3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate
(3 ' S)-3-(piperidines-3-yl) ethyl propionate (and 1 2.5g, 67.5mmol) and tetrahydrofuran (THF): water (2: 1,335: solution 168ml) with salt of wormwood (14g, 101mmol) and acid dimethyl dicarbonate butyl ester (17.7g 81mol) handles.Reaction mixture stirring at room 5 hours.Mixture is inclined in water (200ml) then.Organic layer ethyl acetate extraction (3 * 200ml).Merge organic layer, wash with water (2 * 200ml), and the saturated common salt washing (1 * 200ml), use anhydrous sodium sulfate drying then.Pressure reducing and steaming solvent, title product are used the flash chromatography purifying again.Output: 19.1g (99.2%).NMR conforms to the structure of the title product of expectation with IR.
Preparation 12(the preparation of 3 ' R)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate
According to top preparation 11 described preparation title product, just (3 ' R)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate replaces (3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate with waiting mole here.
Preparation 13(3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl alcohol
((17.1g, 60mol) solution with anhydrous ethyl acetate (600ml) is chilled to 0 ℃ to 3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate.Progressively add in the mixture hydrogenation lithium powder (2.5g, 65mmol).Mixture stirs also in 0 ℃ and slowly is warming up to room temperature, lasts 2 hours.Slowly add water (200ml) and 15% aqueous sodium hydroxide solution (50ml) termination reaction.(3 * 300ml) extract organic layer with ether.Merge organic layer, water (2 * 200ml) wash the saturated common salt washing (1 * 200ml), in the aqueous sodium persulfate drying.Removal of solvent under reduced pressure gets 13.2g (90%) title product.NMR conforms to the structure of the title product of expectation with IR.
Preparation 14(the preparation of 3 ' R)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl alcohol
The method of describing by top preparation 13 prepares title product, and just (3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate replaces (3 ' R)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethyl propionate with waiting mole here.
Preparation 15(3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl bromide
Toward the triphenylphosphine of ice-cold (0 ℃) (19.95g, 76mmol) with the solution of anhydrous methylene chloride (110ml) in dripping bromine, show light yellow until solution.Addend grain triphenylphosphine crystallization in the mixture bleaches color.Add in this mixture (3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl alcohol (13.2g, 54.4mmol), pyridine (8.0g, 76mmol) and the suspension of anhydrous methylene chloride (110ml).Reaction mixture stirs and was warming up to room temperature in 5 hours simultaneously.
Add water (200ml) termination reaction.Organic layer dichloromethane extraction (3 * 200ml).Merge organic layer, wash with water (2 * 200ml), and the saturated common salt washing (1 * 100ml), anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, the thick product of the glassy yellow that obtains get the title product of 11.6g (70%) expectation again through the flash chromatography purifying.NMR conforms to the structure of the title product of expectation with IR.
Preparation 16(the preparation of 3 ' R)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl bromide
According to top preparation 15 described preparation title product, just use (3 ' R)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl alcohol replacement (3 ' S)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl alcohol here.
Method APreparation 1-methyl-2-methylol-1H-indoles
Under argon shield in the 950ml tetrahydrofuran (THF) in addition lithium aluminum hydride (18.40g, 0.49mol).The mixture that obtains is placed on the ice bath.(84.92g 0.49mol) is dissolved in the 475ml anhydrous tetrahydro furan equal portions quantity 1-skatole-2-carboxylic acid, slowly is added in the lithium aluminum hydride mixture then, lasts about 40-45 minute.
Remove round-bottomed flask ice on every side, in the ice bath pot, add warm water rising temperature of reaction.Then with reaction mixture stirring at room 60-90 minute.Reaction process is monitored with thin-layer chromatography.
In case reaction is carried out fully just reaction vessel being put on the ice bath, then 20ml water slowly is added in the reaction mixture.Add 20ml 5N sodium hydroxide solution then in turn inward, add 60ml water then.Organic layer CELITE
TMFilter, use anhydrous sodium sulfate drying then.Organic solvent is removed in decompression, obtains white solid.
Then with white solid molten in the toluene reflux.Mixture is chilled to room temperature, is placed on refrigerator overnight then.Collect the canescence crystallization, wash with cold toluene, dry in vacuum oven then.Output 63.65g (81.4%).FDMS?161。Ultimate analysis C
10H
11NO: theoretical value: C, 74.51; H, 6.88; N, 8.69. measured value: C, 74.73; H, 6.90; N, the preparation of 8.76.1-methyl-2-(4-chlorobenzene oxygen methyl)-1H-indoles
The inflated with nitrogen and the sodium hydride of packing in 1 liter round-bottomed flask (9.28g, the mineral oil solution of 60% sodium hydride, 0.232mol) and N, dinethylformamide (211ml).Slowly add in this mixture 1-methyl-2-methylol-1H-indoles (34.0g, 0.211mol) with 100ml N, the solution of dinethylformamide.The heat release of application of sample process mild or moderate.About 3 hours of reaction mixture stirring at room.
(30.29g, 0.232mmol), the mixture that obtains is heated to 80 ℃ then, and keeps this temperature overnight to add 1-chloro-4-fluorobenzene in the top reaction mixture.This reaction process is followed the tracks of with thin-layer chromatography.Make the reaction mixture cooling.Reaction mixture is then in about 1 premium on currency of impouring, stir about 1 hour.The elimination solid washes with water.
The product benzene recrystallization of expectation, solvent removed in vacuo.
IR, NMR conform to the title product of expectation with UV.FDMS?271(M+)。Ultimate analysis C
16H
14ClNO: theoretical value: C, 70.72; H, 5.19; N, 5.15. measured value: C, 70.98; H, 5.18; N, the preparation of 5.37.1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(4-methyl piperidine-1-yl) Methyl-1H-indole (embodiment 14)
(0.109ml, 0.09g 0.92mmol) dissolve in the 210ml ethyl acetate, are added to then in the round-bottomed flask, and this round-bottomed flask is put into ice bath with the 4-methyl piperidine under nitrogen protection.Add concentrated hydrochloric acid (0.084ml), reaction mixture is removed ice bath.Add in this reaction mixture formaldehyde (0.304g, 1.01mmol), sodium acetate (0.113g, 1.38mmol) and 1-methyl-2-(4-chlorobenzene oxygen methyl)-1 H-indoles (0.250g, 0.92mmol).Obtain mixture then reflux spend the night.Reaction process is followed the tracks of with thin-layer chromatography.
Removal of solvent under reduced pressure.Solid dissolves in the methylene dichloride.Removal of solvent under reduced pressure.The product re-crystallizing in ethyl acetate of expectation.The product of expectation is used chromatogram purification again.NMR conforms to the structure of the title compound of being scheduled to.FDMS 382 ultimate analysis C
23H
27ClN
2O: theoretical value: C, 72.14; H, 7.11; N, 7.31. measured value: C, 72.33; H, 7.22; N, 7.47.
Method BThe preparation of 1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(2-(4-(piperidines-1-yl) piperidines-1-yl)-1,2-oxalyl group)-1H-indoles (embodiment 106)
Under the argon shield with 1-methyl-2-(4-chlorobenzene oxygen methyl)-(0.30g 1.10mmol) is dissolved in the 2.0ml tetrahydrofuran (THF) and the round-bottomed flask of packing into the 1H-indoles.Add in this solution oxalyl chloride (0.294g, 2.32mmol).About 45 minutes of mixture stirring at room.The pressure reducing and steaming solvent gets brownish black oily matter.
This brown oil dissolved in the 2.0ml anhydrous tetrahydro furan and adds 4-(piperidines-1-yl) piperidines that (1.07g is 6.38mmol) with the solution of about 10ml anhydrous tetrahydro furan.About 30 minutes of reaction mixture stirring at room.Reaction process is followed the tracks of with thin-layer chromatography.
The elimination solid, filtrate decompression boils off solvent.Residue dissolves in the methylene dichloride, washes with saturated sodium bicarbonate solution, uses the 1N hcl as extraction agent then 3 times.
Merge the back with the alkalization of 1N sodium hydroxide from the water layer that extracts above, use dichloromethane extraction then 3 times.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title product radial chromatography purifying of expectation.NMR conforms to the title compound structure of expection with IR.FDMS (M+) 493 ultimate analysis C
28H
32ClN
3O
3: theoretical value: C, 68.07; H, 6.53; N, 8.51. measured value: C, 67.97; H, 6.66; N, the preparation of 8.27.1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(4-(phenyl) piperazine-1-yl) Methyl-1H-indole (embodiment 20)
Under nitrogen protection, (0.149g 0.920mmol) dissolves in the 2.0ml ethylene dichloride with phenylpiperazine in round-bottomed flask.Reaction vessel is put into ice bath.(0.084ml, 1.01mmol), reaction vessel is removed ice bath to add concentrated hydrochloric acid.Add then Paraformaldehyde 96 (0.304g, 1.01mmol) and sodium acetate (0.113g, 0.920mmol), then add 1-methyl-2-(4-chlorobenzene oxygen methyl)-1H-indoles (0.250g, 0.920mmol).Reaction mixture is about 6 hours of reflux then.Follow the tracks of reaction with thin-layer chromatography.Reaction mixture is about 3 days of stirring at room then.
The pressure reducing and steaming solvent, residue distributes between ethyl acetate and 10% solution of potassium carbonate.Organic layer washes with water, then with the pickling of 1.0N salt.The sour water layer alkalizes with 10% solution of potassium carbonate.With organic component process anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.
The product re-crystallizing in ethyl acetate of expectation.NMR conforms to the title compound structure of expectation.FDMS 445 (M+) ultimate analysis C
27H
28ClN
3O: theoretical value: C, 72.71; H, 6.33; N, 9.42. measured value: C, 73.00; H, 6.41; N, 9.51.
Method C1The preparation of 1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(2-chloro-1,2-oxalyl)-1H-indoles
Under nitrogen protection in round-bottomed flask with 1-methyl-2-(4-chlorobenzene oxygen methyl)-(1.00g 3.68mmol) is dissolved in the 7.0ml ether to the 1H-indoles.Add in this solution oxalyl chloride (0.981g, 7.73mmol).Reaction mixture stirring at room 60 minutes.Reaction process is followed the tracks of with thin-layer chromatography.Incline and desolvate, crystallization is washed 5 times with cold diethyl ether.Merge solvent and leacheate, put refrigerator and cooled and froze 3 days.Collect crystallization, dry in vacuum oven, get the title product of 1.15g (86.3%) expectation.The preparation of 1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(2-(4-methyl piperidine-1-yl)-1,2-ethanedioyl)-1H-indoles (embodiment 102)
Under nitrogen protection round-bottomed flask is put into ice bath, (0.490ml, 0.411g 4.14mmol) dissolve in the 3.0ml anhydrous tetrahydro furan with the 4-methyl piperidine in this flask.Add in this reaction mixture 1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(2-chloro-1,2-ethanedioyl)-1H-indoles (0.500g, 1.39mmol), the mixture stirred overnight at room temperature that obtains.Reaction process is monitored with thin-layer chromatography.
The pressure reducing and steaming solvent, residue distributes between methylene dichloride and 1.0N sodium hydroxide.Organic layer is washed with 1.0N sulfuric acid, then washes with saturated common salt.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title product re-crystallizing in ethyl acetate of expectation.NMR conforms to the structure of the title compound of expection with IR.FDMS 425 (M+) ultimate analysis C
24H
25ClN
2O
3: theoretical value: C, 67.84; H, 5.93; N, 6.59. measured value: C, 68.04; H, 5.85; N, 6.74.
Method C22-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-1-[[4-(piperidines-1-yl) piperidines-1-yl] carbonyl] methyl]-1H-indoles (embodiment 77)
Under nitrogen protection, pack in the round-bottomed flask 1-methyl-2-(4-chlorobenzene oxygen methyl)-3-(2-(4-(piperidines-1-yl)-piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles (0.1414g, 0.282mmol) and the 2.8ml Denatured alcohol.Add in this mixture sodium borohydride (0.1064g, 1.69mmol).With the reaction-ure mixture stirred overnight at room temperature.Reaction process is monitored with thin-layer chromatography.
Boil off solvent, residue distributes between methylene dichloride and water.Water layer is washed 2 times with methylene dichloride.Merge organic layer, with saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product of expectation is further purified with chromatogram.NMR conforms to the title product structure of expection.FDMS 495 (M+) ultimate analysis C
28H
34ClN
3O
3: theoretical value: C, 67.80; H, 6.91; N, 8.47. measured value: C, 67.86; H, 6.90; N, 8.45.
Method DIndole-2-carboxylic methyl ester's preparation
(47.0g 292mmol) is dissolved in the 200ml methyl alcohol Indoline-2-carboxylic acid.In this solution, add the 6ml vitriol oil.Mixture heating up refluxes, and keeps refluxing about 16 hours.Reaction mixture is chilled to room temperature, and the elimination solid is washed with 200ml methyl alcohol then.Crystallization is dry in a vacuum, get the title product of 39.5g (77%) expectation, be white, needle-shaped crystals.The analytical data that obtains conforms to the structure of the title compound of expection.
1-(2-(1-trityl piperidin-4-yl) ethyl) indole-2-carboxylic methyl ester's preparation
(1.50g 8.56mmol) is dissolved in 8.6mlN, in the dinethylformamide with the indole-2-carboxylic methyl ester under argon shield.Solution is put into ice bath, and (0.377g, the mixture that 9.42mmol) obtains stirred on ice bath 20 minutes, made then to rise to room temperature to add sodium hydride.The reaction mixture stirring at room was so put into ice bath in 90 minutes again.
(4.53g 9.42mmol) dissolves in 15ml N, is added to behind the dinethylformamide in the top reaction mixture, and stirs about 3 days in ice bath by the preparation 15 iodo 2-that make (1-trityl piperidin-4-yl) ethane.Reaction mixture inclines in water, solid collected by filtration.Solid dissolves in methylene dichloride, anhydrous magnesium sulfate drying, and the pressure reducing and steaming solvent gets the title product of 4.98g (＞99%) expectation, is yellowish-white bubble gum.Analytical data conforms to the structure of expection.
1-(3-(1-trityl piperidines-3-yl) propyl group) indole-2-carboxylic methyl ester's preparation
(1.00g 5.71mmol) dissolves in 5.7mlN, in the dinethylformamide with the indole-2-carboxylic methyl ester under argon shield.This solution put in the ice bath cooling and add sodium hydride (0.251g, 60% solution, 6.28mmol).Mixture stirred in ice bath 20 minutes, was warming up to room temperature then.Reaction mixture stirring at room 60 minutes, and then put in the ice bath and cool off.
(3.11g 6.28mmol) dissolves in 8ml N, in the dinethylformamide, is added to then in the top reaction mixture, stirs in ice bath and spends the night with iodo 3-(1-trityl piperidines-3-yl) propane.Reaction mixture inclines in water, solid collected by filtration.Solid is dissolved in the methylene dichloride, wash with water, saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent gets the target product of 3.38g (＞99%) expectation.Analytical data conforms to the structure of the title compound of expection.
The preparation of 2-methylol-1-(2-(1-trityl piperidin-4-yl) ethyl)-1H-indoles
(0.325g 8.56mmol) dissolves in the 8.6ml anhydrous tetrahydro furan with lithium aluminium hydride under argon shield.Solution is put in the ice bath and is cooled off, and (4.68g is 8.52mmol) with the about solution of 10ml anhydrous tetrahydro furan to add 1-(2-(1-trityl piperidin-4-yl) ethyl) indole-2-carboxylic methyl ester inward.The mixture stirred overnight at room temperature.
In reaction mixture, add 0.35ml water carefully, then add 0.35ml 5.0N aqueous sodium hydroxide solution, add 1.0ml water then.The elimination solid, filtrate decompression concentrates, and removes and desolvates.Residue dissolves in methylene dichloride.The dichloromethane layer anhydrous magnesium sulfate drying that contains the product of expectation gets 3.96g (92.4%) bubble gum sample title product behind the pressure reducing and steaming solvent.
The analytical data that obtains conforms to the title compound structure of expection.
The preparation of 2-methylol-1-(3-(1-trityl piperidines-3-yl) propyl group)-1H-indoles
(3.38g 6.23mmol) is dissolved in the 3.1ml anhydrous tetrahydro furan indole-2-carboxylic methyl ester with 1-(3-(1-trityl piperidines-3-yl) propyl group) under argon shield.Then reaction vessel is put into ice bath, and the adding lithium aluminium hydride (0.236g, 6.23mmol).Reaction mixture stirred in ice bath about 10 minutes, then in stirred overnight at room temperature.Reaction process is followed the tracks of with thin-layer chromatography.
In reaction mixture, add 0.24ml water, then add 0.24ml 0.5N sodium hydroxide, add 0.72ml water again.Residue dissolves in methylene dichloride.Contain the dichloromethane layer anhydrous sodium sulfate drying of expecting product, removal of solvent under reduced pressure gets 2.89g (90.1%) bubble gum sample title product.The analytical data that obtains conforms to the structure of the title compound of expection.
The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-(1-trityl piperidin-4-yl) ethyl)-1H-indoles
(2-(1-trityl piperidin-4-yl) ethyl)-(3.91g 7.81mmol) is dissolved in about 10ml N, in the dinethylformamide to the 1H-indoles with 2-methylol-1-under argon shield.The solution that generates is put in the ice bath, add sodium hydride (0.468g, 11.71mmol), about 30 minutes of mixture stirring at room.(8.59mmol), the mixture room temperature lucifuge that obtains stirred about 4 days for 0.915ml, 1.12g to add 1-chloro-4-fluorobenzene in the reaction mixture.
In the reaction mixture impouring frozen water, solid collected by filtration.After the washing, solid is dry in vacuum oven.The product re-crystallizing in ethyl acetate of expection is washed with cold ethyl acetate, and output is 2.62g (54.9%).The analytical data that obtains conforms to the structure of the title compound of expection.
The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(1-trityl piperidines-3-yl) propyl group)-1H-indoles
(3-(1-trityl piperidines-3-yl) propyl group)-(2.89g 5.61mmol) dissolves in about 11.2ml N, in the dinethylformamide to the 1H-indoles with 2-methylol-1-under argon shield.The solution that generates is put in the ice bath then, add sodium hydride (0.247g, 60% suspension in mineral oil, 6.18mmol), mixture stirring at room 60 minutes.Add in this reaction mixture 1-chloro-4-fluorobenzene (0.658ml, 0.807g, 6.18mmol), the mixture stirred overnight at room temperature.Reaction mixture is heated to 80 ℃, is incubated about 8 hours.Reaction mixture is chilled to room temperature, and in stirred overnight at room temperature.Add other 1/2 equivalent sodium hydride again, reaction mixture is again in stirred overnight at room temperature.Add other 1/2 equivalent 1-chloro-4-fluorobenzene again, reaction mixture is heated to 80 ℃.
In reaction mixture impouring frozen water, between methylene dichloride and saturated aqueous common salt, distribute then.Water layer dichloromethane extraction 2 times.Merge organic layer, with saturated common salt washing, anhydrous sodium sulfate drying.The product of expectation is used chromatogram purification again, gets 1.0g (29%) title product.The analytical data that obtains conforms to the structure of the title compound of expection.
The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-(piperidin-4-yl) ethyl)-1H-indoles (embodiment 137)
Dou 2-under argon shield ((4-chlorophenoxy) methyl)-1-(2-(1-trityl piperidin-4-yl) ethyl)-1H-indoles dissolves in the 7.0ml methylene dichloride.Solution is put in the ice bath and is added formic acid (0.3383g).Reaction mixture is known in the ice bath and to be stirred about 5 hours.The reaction process chromatogram tracking.
Reaction mixture distributes between methylene dichloride and 1.0N sodium hydroxide.Water layer dichloromethane extraction 2 times.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent must steep foaming material.The product of expectation is used chromatogram purification again, gets 0.1864g (68.7%) product.NMR conforms to the structure of the title compound of expection.FDMS 368 (M+) ultimate analysis C
22H
25ClN
2O: theoretical value: C, 71.63; H, 6.83; N, 7.59. measured value: C, 71.66; H, 6.86; N, 7.87.
The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-1H-indoles (embodiment 139)
Prepare title compound according to the method for preparing 2-((4-chlorophenoxy) methyl)-1-(2-(piperidin-4-yl) ethyl)-1H-indoles, just use here and wait mole 2-((4-chlorophenoxy) methyl)-1-(3-(1-trityl piperidines-3-yl) propyl group)-1H-indoles to replace 2-((4-chlorophenoxy) methyl)-1-(2-(1-trityl piperidin-4-yl) ethyl)-1H-indoles.
NMR conforms to the structure of the title compound of expection.Chromatographic process confirms that product is highly purified simplification compound.
Method E
The preparation of 3-bromo-2-((4-chlorophenoxy) methyl)-1-(3-(1-trityl piperidines-3-yl) propyl group)-1H-indoles
(3-(1-trityl piperidines-3-yl) propyl group)-(0.992g 1.59mmol) is dissolved in the 4.0ml anhydrous tetrahydro furan 1H-indoles with 2-((4-chlorophenoxy) methyl)-1-in round-bottomed flask under argon shield.Reaction vessel is put into ice bath, slowly adds the solution of N-bromo-succinimide (0.282g, 1.587mmol, new recrystallization) and 4.0ml tetrahydrofuran (THF).Reaction mixture stirred in ice bath about 3 hours.
The reaction mixture impouring contains in the water of 2.5g sodium sulfate, water layer dichloromethane extraction 2 times.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent gets the compound of 0.26g (23%) expectation.Boil off the solvent in the mother liquor, residue ethyl acetate and hexane recrystallization, the product of the 0.65g that gets back (58%) expectation.The analytical data that obtains conforms to the structure of the title compound of expection.
(RS)-and 2-((4-chlorophenoxy) methyl)-1-(3-(1-trityl piperidines-3-yl) propyl group)-3-[[4-(piperidines-1-yl) piperidines-1-yl] ethanoyl]-preparation of 1H-indoles
Under argon shield, (3-(1-trityl piperidines-3-yl) propyl group)-(0.225g 0.319mmol) is dissolved in the anhydrous tetrahydro furan 1H-indoles with 3-bromo-2-((4-chlorophenoxy) methyl)-1-in round-bottomed flask.Reaction vessel is put in the dry ice/acetone batch.In this solution, drip tert-butyl lithium (0.64mmol) solution.Reaction mixture stirred in dry ice/acetone batch 35 minutes.
Add in the reaction mixture be dissolved in the 2.0ml tetrahydrofuran (THF) Weinreb acid amides N-methyl-N-methoxyl group-(4-(piperidines-1-yl) piperidines-1-yl) (0.0903g 0.335mmol), cools off in dry ice/acetone batch ethanamide.Reaction mixture stirred about 2 hours, then in the impouring saturated aqueous ammonium chloride.Water layer dichloromethane extraction 2 times merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product of expectation is used chromatogram again.Analytical data conforms to the structure of the title compound of expection.
(RS)-and 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-[[4-(piperidines-1-yl) piperidines-1-yl] ethanoyl]-preparation of 1H-indoles (embodiment 70)
Under argon shield with (RS)-2-((4-chlorophenoxy) methyl)-1-(3-(1-trityl piperidines-3-yl) propyl group)-3-[[4-(piperidines-1-yl) piperidines-1-yl] ethanoyl]-(0.0162g 0.0194mmol) dissolves in the 0.2ml methylene dichloride 1H-indoles.Reaction vessel is inserted in the ice bath, slowly add formic acid (0.073ml, 0.194mmol).Reaction mixture stirred on ice bath about 1 hour.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture and then stirring at room 2 hours, and then add 5.0 equivalent formic acid, stirring at room.
Reaction mixture distributes between 1.0N sodium hydroxide and methylene dichloride.Water layer dichloromethane extraction 2 times.Merge organic, anhydrous sodium sulfate drying.Evaporation removes and desolvates.NMR conforms to the structure of expected compound.High resolution mass spectrum (M+1) for C
35H
48ClN
4O
2:
Theoretical value: 591.3476
Measured value: 591.3476
Method FThe preparation (embodiment 47) of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2 (piperidines-1-yl) ethyl)-1H-indoles
(1-(piperidines-1-yl)-1,2-ethanedioyl)-(0.203g 0.493mmol) dissolves in the 2.0ml anhydrous tetrahydro furan to 1H-indoles (embodiment 100) with 2-((4-chlorophenoxy) methyl)-1-methyl-3-in round-bottomed flask under argon shield.Add lithium aluminium hydride (3.0ml, the tetrahydrofuran solution of 1.0M).About 4 hours of reaction mixture reflux.Reaction process is followed the tracks of with thin-layer chromatography.
Reaction mixture is chilled to room temperature, adds 1: 1 tetrahydrofuran (THF) of 10ml: methanol solution.In this mixture, add the saturated Rochelle ' of 5ml s salts solution.The pressure reducing and steaming solvent.
Residue distributes between methylene dichloride and saturated Rochelle ' s salts solution.Organic layer water and saturated common salt washing.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.
The product of expectation is used chromatogram purification again, gets 0.1112g (56.9%).NMR conforms to the structure of the title compound of expection.FDMS 398 (M+) ultimate analysis C
23H
27ClN
2O
2: theoretical value: C, 69.25; H, 6.82; N, 7.02. measured value: C, 69.51; H, 6.86; N, 6.81.
Method GThe preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(4-methyl piperidine-1-yl) ethyl)-1H-indoles (embodiment 48) and 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-methyl piperidine-1-yl) ethyl)-1H-indoles (embodiment 33)
(0.305g 0.824mmol) packs in the round-bottomed flask with 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-(piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles (embodiment 100) under nitrogen protection.(the THF solution of 4.12ml 1.0M borine, 4.12mmol), mixture stirred about 30 minutes slowly to add borine-tetrahydrofuran complex inward.Follow the tracks of reaction with thin-layer chromatography.Reaction mixture stirred 1 hour altogether, quenched with methyl alcohol then.
In reaction mixture, add ethanol, yellow soda ash and cesium fluoride, mixture heating up refluxes and spends the night.Reaction-ure mixture distributes between 10% yellow soda ash methylene dichloride.Water layer uses dichloromethane extraction more than 2 times.The organic layer that merges is used anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The product of expectation is used the radial chromatography purifying again.Obtain 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-methyl piperidine-1-yl) ethyl)-1H-indoles (embodiment 33).NMR conforms to the structure of the title product of expection.FDMS 396 (M+) ultimate analysis C
24H
29ClN
2O: theoretical value: C, 72.62; H, 7.36; N, 7.06. measured value: C, 72.40; H, 7.35; N, 7.25.2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(4-methyl piperidine-1-yl) ethyl)-1H-indoles (embodiment 48) NMR conforms to the structure of the title compound of expection.FDMS 412 (M+) ultimate analysis C
24H
29ClN
2O
2: theoretical value: C, 69.80; H, 7.08; N, 6.78. measured value: C, 70.02; H, 7.13; N, 7.00.
2-((2, the 4-dichlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(N-methyl-N-(1-methyl piperidine-4-yl) amino) ethyl)-1H-indoles (embodiment 54) and 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(N-methyl-N-(1-methyl piperidine-4-yl) amino) ethyl)-1H-indoles (embodiment 38)
Under nitrogen protection with 2-((2; the 4-dichlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-N-(1-methyl piperidine-4-yl) amino)-1; the 2-ethanedioyl)-(0.3349g 0.686mmol) puts into round-bottomed flask to the 1H-indoles, then this round-bottomed flask is put into ice bath.(4.11ml, the tetrahydrofuran solution of 1.0M borine 4.11mmol), are removed ice bath slowly to add borine-tetrahydrofuran complex.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture stirred about 1 hour, added 1: 1 tetrahydrofuran (THF) of 0.33ml then: methanol solution.Hydro-oxidation sodium (1.74ml 5.0N solution), mixture heating up reflux and spend the night.
Water layer extracts more than 2 times with tetrahydrofuran (THF).Merge organic layer, with saturated common salt washing 2 times, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The product of expectation is used the radial chromatography purifying again.Obtain 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(N-methyl-N-(1-methyl piperidine-4-yl) amino) ethyl)-1H-indoles (embodiment 38).NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 459 (M+) ultimate analysis C
25H
31Cl
2N
3O: theoretical value: C, 65.21; H, 6.79; N, 9.13. measured value: C, 65.07; H, 6.85; N, 9.06. get 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(1-hydroxyl-2-(N-methyl-N-(1-methyl piperidine-4-yl) amino) ethyl)-1H-indoles (embodiment 54) NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 475 (M+) ultimate analysis C
25H
31Cl
2N
3O
2: theoretical value: C, 63.02; H, 6.55; N, 8.82. measured value: C, 63.43; H, 6.88; N, 8.92.
The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((3-dimethylamino-propyl) amino) ethyl)-1 H-indoles (embodiment 30) and 2-((4-chlorophenoxy) methyl)-1-methyl-3-(((3-(dimethylamino) propyl group amino) carbonyl) methyl)-1H-indoles (embodiment 76)
2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(3-(dimethylamino) third amino)-1 of past round-bottomed flask under nitrogen protection; the 2-ethanedioyl)-1H-indoles (0.529g; 1.24mmol) in add borine-tetrahydrofuran (THF) (7.42ml, 1.0MTHF solution, 7.42mmol).About 1 hour of reaction mixture stirring at room.Follow the tracks of reaction process with thin-layer chromatography.Add 1: 1 tetrahydrofuran (THF): the methanol solution termination reaction.
Boil off solvent, residue dissolve in ethanol (8ml), yellow soda ash (2.62g, 24.72mmol) and cesium fluoride (2.88g is in mixture 18.94mmol).The reaction mixture reflux, and keep reflux temperature to spend the night.
Reaction mixture distributes between methylene dichloride and 10% sodium bisulfate.Water layer extracts 2 times with dichloromethane solution.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The product of expectation is used chromatogram purification again.
Get 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((3-dimethylamino-propyl) amino) ethyl)-1H-indoles (embodiment 30), NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 399 (M+) ultimate analysis C
23H
30ClN
3O: theoretical value: C, 69.07; H, 7.56; N, 10.51. measured value: C, 69.23; H, 7.79; N, 10.52.
2-((4-chlorophenoxy) methyl)-1-methyl-3-(((3-(dimethylamino) propyl group amino) carbonyl) methyl)-1H-indoles (embodiment 76), NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS413 (M+) ultimate analysis C
23H
28ClN
3O
2: theoretical value: C, 66.74; H, 6.82; N, 10.15. measured value: C, 66.89; H, 6.96; N, 10.11.
Method HThe preparation of 3-bromo-2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole
Under argon shield in the round-bottomed flask with 2-((4-chlorophenoxy) methyl)-(5.0g 18.40mmol) is dissolved in the 46ml tetrahydrofuran (THF) to the 1-Methyl-1H-indole.The solution that adds N-bromo-succinimide (3.28g, 18.4mmol, new recrystallization) and 46ml tetrahydrofuran (THF) in this solution.Reaction mixture stirred on ice bath about 3.5 hours, then the about 500ml of reaction mixture impouring was contained in the water of 5.0g sodium sulfate.
Water layer dichloromethane extraction 2 times.Merge organic layer, wash with saturated sodium bicarbonate solution earlier, the back is washed with saturated common salt.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.
The product re-crystallizing in ethyl acetate of expectation.Output: 5.36g (83.1%).The analytical data that obtains conforms to the result of the title compound of expection.
2-((4-chlorophenoxy) methyl)-1-methyl-3-[[2-(1-trityl piperidin-4-yl) ethyl] carbonyl]-preparation of 1H-indoles
Under argon shield, in round-bottomed flask with 3-bromo-2-((4-chlorophenoxy) methyl)-(0.500g 1.426mmol) is dissolved in the 3.0ml tetrahydrofuran (THF) to the 1-Methyl-1H-indole.Reaction vessel is placed in the dry ice/acetone batch.Add in this solution tert-butyl lithium (1.68ml, 2.85mmol) and the Weinreb acid amides, N-methyl-N-methoxyl group-(2-(1-trityl piperidin-4-yl) ethyl) ethanamide (0.631g, solution 1.426mmol).The mixture that obtains stirred on dry ice/acetone batch about 30 minutes, stirred 30 minutes on methyl alcohol/the dry ice bath then.Follow the tracks of reaction process with thin-layer chromatography.
Reaction mixture inclines in saturated ammonium chloride solution.Water layer dichloromethane extraction 2 times, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product of expectation is used chromatogram purification, re-crystallizing in ethyl acetate then again.The analytical data that obtains conforms to the structure of the title compound of expection.
2-((4-chlorophenoxy) methyl)-1-methyl-3-[[2-(piperidin-4-yl) ethyl] carbonyl]-preparation (embodiment 67) of 1H-indoles
Under argon shield, with 2-((4-chlorophenoxy) methyl)-1-methyl-3-[[2-(1-trityl piperidin-4-yl) ethyl] carbonyl]-(0.2723g 0.417mmol) is dissolved in the 2.1ml methylene dichloride 1H-indoles.Add in this solution formic acid (0.079ml, 0.096g, 2.084mmol), about 2.5 hours of mixture stirring at room.Reaction process is followed the tracks of with thin-layer chromatography.
Reaction mixture distributes between methylene dichloride and 1.0N sodium hydroxide.Water layer is inferior with dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, the title product that obtains expecting.NMR conforms to the structure of the title compound of expection.FDMS 411 (M+) ultimate analysis C
24H
27ClN
2O
2: theoretical value: C, 70.15; H, 6.62; N, 6.82. measured value: C, 69.87; H, 6.54; N, 6.79.
Method IThe preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-carboxyl-1H-indoles
Under argon shield with 2-((4-chlorophenoxy) methyl)-(0.500g 1.426mmol) is dissolved in the 1 4.3ml anhydrous tetrahydro furan 1-methyl-3-carboxyl-1H-indoles.Reaction vessel is put in the dry ice/acetone batch.Drip in this solution tert-butyl lithium (1.72ml, the pentane solution of 1.7M, 2.92mmol).The mixture that obtains stirred on dry ice/acetone batch about 15 minutes.In reaction mixture, lead to about 10 minutes carbonic acid gas, reaction mixture restir 10 minutes.Reaction vessel is placed in methyl alcohol/the dry ice bath, leads to about 10 minutes carbonic acid gas again in reaction mixture.
Reaction-ure mixture is warming up to room temperature, inclines then to having added in the 1.0N hydrochloric acid of about 50g dry ice to 100ml.The mixture that obtains stirred about 30 minutes.Solid collected by filtration.The product of expectation grinds with methylene dichloride.Output: 0.37g (82%) ultimate analysis C
17H
14ClNO
3: theoretical value: C, 64.67; H, 4.47; N, 4.44. measured value: C, 64.84; H, 4.60; N, 4.54.2-((4-chlorophenoxy) methyl)-1-methyl-3-[[N, two (3-dimethylamino-propyl) amino of N-] carbonyl]-preparation (embodiment 58) of 1H-indoles
Under argon shield with 2-((4-chlorophenoxy) methyl)-(0.100g 0.317mmol) is dissolved in 3.2ml N, in the dinethylformamide to 1-methyl-3-carboxyl-1H-indoles.In this solution, add N, N-two (3-dimethylamino-propyl) amine (0.074ml, 0.0623g, 0.332mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.091g, 0.475mmol) and the oxybenzene benzotriazole (0.0642g, 0.475mmol).The mixture heating up that obtains 6 hours, stirred overnight at room temperature then.Reaction process is followed the tracks of with thin-layer chromatography.
Reaction mixture distributes between methylene dichloride and water.Water layer dichloromethane extraction 2 times.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The product of expectation is used the radial chromatography purifying again.NMR conforms to the structure of the title compound of expection.FDMS 483 (M-1) FABMS 485 (M+1) ultimate analysis C
27H
37ClN
4O
2: theoretical value: C, 66.86; H, 7.69; N, 11.55. measured value: C, 66.91; H, 7.54; N, 11.69.
Method J2-((4-chlorophenoxy) methyl)-1-methyl-3-[[2-[1-[3-(1-trityl piperidines-3-yl) propyl group] piperidin-4-yl]] ethyl] carbonyl]-preparation (embodiment 69B) of 1H-indoles
Under nitrogen protection with 2-((4-chlorophenoxy) methyl)-1-methyl-3-[[(piperidin-4-yl) ethyl] carbonyl]-1H-indoles (0.091g; 0.222mmol), iodo 3-(1-trityl piperidines-3-yl) propane (0.110g; 0.2224mmol); salt of wormwood (0.0450g; 0.3255mmol) and the anhydrous N of 1.ml, dinethylformamide is packed in the 10ml round-bottomed flask.Mixture stirs and spends the night, then in the impouring frozen water.Solid collected by filtration is also used cold wash.Solid is dissolved in the methylene dichloride, use anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The product of expectation is used chromatogram purification again.Output: 0.1166g (67.3%).FDMS 779 (M+2) ultimate analysis C
51H
56ClN
3O
2: theoretical value: C, 78.69; H, 7.25; N, 5.40. measured value: C, 78.92; H, 7.41; N, 5.27.2-((4-chlorophenoxy) methyl)-1-methyl-3-[[2-[1-[3-(piperidines-3-yl) propyl group] piperidin-4-yl]] ethyl] carbonyl]-preparation (embodiment 69C) of 1H-indoles
Under nitrogen protection; in round-bottomed flask with 2-((4-chlorophenoxy) methyl)-1-methyl-3-[[2-[1-[3-(1-trityl piperidines-3-yl) propyl group] piperidin-4-yl]] ethyl] carbonyl]-(0.1006g 0.1292mmol) is dissolved in the 0.6ml methylene dichloride 1H-indoles.Add in this solution formic acid (0.0244ml, 0.0297g, 0.646mmol).The mixture room temperature lucifuge stirred for several that obtains hour.Reaction process is followed the tracks of with thin-layer chromatography.
Reaction mixture distributes between methylene dichloride and 1.0N sodium hydroxide.Water layer dichloromethane extraction 2 times.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product of expectation is used the radial chromatography purifying again.NMR (CDCl
3) conform to the structure of the title product of expecting.FDMS 536 (M+1) ultimate analysis C
32H
42ClN
3O
2: theoretical value: C, 71.69; H, 7.90; N, 7.84. measured value: C, 71.45; H, 7.85; N, 7.61.
Method KThe preparation (embodiment 236) of 2-((4-chlorophenoxy) methyl)-1-methyl-3-formyl radical-1H-indoles
Under nitrogen protection, with the anhydrous N of 0.63ml, dinethylformamide is packed in the round-bottomed flask.Reaction vessel is put in-20 ℃ the outer bath, add carefully then phosphorus oxychloride (0.187ml, 0.310g, 2.02mmol).Reaction mixture stirred on ice bath about 20 minutes, add then 2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole (0.50g, 1.84mmol) with 3.4ml N, the solution of dinethylformamide.About 90 minutes of the mixture stirring at room that obtains.Reaction mixture be heated in the oil bath 55 ℃ and under this temperature the insulation about 1 hour.Make reaction mixture be chilled to room temperature, incline in water then.Hydro-oxidation sodium (10ml, 5.0N solution) and reflux.Reaction mixture is put cold, solid collected by filtration.NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 299 (M+) ultimate analysis C
17H
14ClNO
2: theoretical value: C, 68.12; H, 4.71; N, 4.67. measured value: C, 67.90; H, 4.66; N, the preparation (embodiment 55) of 4.76.2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(1-hydroxyl-2-(methoxycarbonyl) ethyl)-1H-indoles
The round-bottomed flask of under nitrogen protection, the 6.7ml anhydrous tetrahydro furan being packed into.(1.401mmol), reaction vessel is put into ice bath for 0.196ml, 0.1417g with Diisopropylamine in bottle.(1.401mmol), reaction mixture stirred in ice bath about 15 minutes for 0.88ml, the hexane solution of 1.6M slowly to add n-Butyl Lithium in this mixture.Reaction mixture places dry ice/acetone batch, adds methyl acetate, and stirs 15 minutes in dry ice/acetone batch.Raw material aldehyde is dissolved in the total amount 7.0ml tetrahydrofuran (THF), and the solution that obtains is added in the reaction flask, and reaction mixture restir 1 hour on dry ice/acetone batch is placed on then in the ice bath and stirred about 30 minutes.In the reaction mixture impouring ammonium chloride solution (32g and 100ml ice are made into).The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product of expectation is used the radial chromatography purifying again.NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 373 (M+) ultimate analysis C
20H
20ClNO
4: theoretical value: C, 64.26; H, 5.39; N, 3.75. measured value: C, 64.55; H, 5.23; N, 3.79.3-{2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl } preparation of third-2-olefin(e) acid
Under nitrogen protection with the preparation (embodiment 55) of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(1-hydroxyl-2-(methoxycarbonyl) ethyl)-1H-indoles (0.149g, 0.398mmol) and the 6.11ml anhydrous tetrahydro furan be added in the round-bottomed flask.In this solution, add 1.22ml 2.0N lithium hydroxide solution, about 2 hours of the mixture stirring at room that obtains.The pressure reducing and steaming solvent, residue distributes between methylene dichloride and water.Water layer dichloromethane extraction 2 times.Merge organic layer, use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure.The title product of expectation is ground with ether.Analytical data conforms to the structure of expected compound.
2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-[[4-(dimethylamino) piperidines-1-yl) carbonyl] vinyl]-preparation (embodiment 44) of 1H-indoles
Under nitrogen protection, dimethylamino piperidine is dissolved in the 3.0ml methylene dichloride.In this solution, add 3-{2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl } third-2-olefin(e) acid (0.050g, 0.146mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.0356g, 0.278mmol).The mixture stirred overnight at room temperature.
Reaction mixture distributes between saturated sodium bicarbonate solution and dichloromethane solution.Water layer is used dichloromethane extraction 2 times with the alkalization of 1.0N sodium hydroxide.Merge organic layer, with the pickling of 1.0N salt, then with saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The target product of expectation is used the radial chromatography purifying again.NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum for C
26H
30ClN
3O
2:
Theoretical value: 452.2105
Measured value: 452.2099
Method LThe preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(methoxycarbonyl) ethyl)-1H-indoles
In round-bottomed flask, pack into 10% active palladium/carbon (0.150g), 20ml N, and dinethylformamide and 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(methoxycarbonyl) vinyl)-1H-indoles (1.44g, 4.22mmol).Reaction vessel is placed after 2 hours under hydrogen.Reaction mixture passes through CELITE
TMLayer distributes between water and methylene dichloride then.Water layer dichloromethane extraction 2 times.Merge organic layer, wash with water, saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The product of expectation is used chromatogram purification again.
3-{2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl } preparation of propionic acid
Under nitrogen protection, (2-(methoxycarbonyl) ethyl)-(0.275g 0.771mmol) dissolves in the 8ml anhydrous tetrahydro furan 1H-indoles with 2-((4-chlorophenoxy) methyl)-1-methyl-3-in round-bottomed flask.In this solution, add 4.0ml 2.0N lithium hydroxide solution.The reaction mixture stirred overnight at room temperature.Reaction process is followed the tracks of with thin-layer chromatography.
The pressure reducing and steaming solvent, residue distributes between methylene dichloride and 5% citric acid.Water layer dichloromethane extraction 2 times.Merge organic layer, with saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the title product that must expect.Output: 0.2984g (＞99%).
2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-[[4-(dimethylamino) piperidines-1-yl) carbonyl] ethyl]-preparation (embodiment 43) of 1H-indoles
Under nitrogen protection with 3-{2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl (0.286g 0.832mmol) is dissolved in the 6ml anhydrous tetrahydro furan propionic acid.Add 1,1 in this solution '-N,N'-carbonyldiimidazole (0.141g, 0.874mmol), about 2 hours of mixture stirring at room.The reaction mixture process is followed the tracks of with thin-layer chromatography.Reaction mixture is heated to 65 ℃, and 65 ℃ of insulations 35 minutes.(0.11g is 0.874mmol) with the about solution of 3.6ml tetrahydrofuran (THF) to add dimethylamino piperidine in this reaction mixture.This mixture stirs and spends the night.
Reaction mixture is heated to 60 ℃, and about 30 minutes of 60 ℃ of insulations.The pressure reducing and steaming solvent, residue distributes between methylene dichloride and water.Water layer is used dichloromethane extraction again.Merge organic layer, wash with water 2 times.The saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product chromatogram repurity of expectation.NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 453 (M+) ultimate analysis C
26H
32ClN
3O
2: theoretical value: C, 68.78; H, 7.10; N, 9.26. measured value: C, 68.74; H, 7.04; N, 9.38.
Method MThe preparation (embodiment 41) of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(3-(4-(N, N-dimethylamino) piperidines-1-yl) propyl group)-1H-indoles
Under nitrogen protection, with 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-[[4-(dimethylamino) piperidines-1-yl) carbonyl] ethyl]-1H-indoles (0.194g, 0.428mmol) round-bottomed flask of packing into.Flask is put in the ice bath, and adding borane-tetrahydrofuran complex (1.71ml, the THF solution of 1.0M, 1.71mmol).Reaction mixture shifts out ice bath, about 90 minutes of stirring at room.Reaction process is followed the tracks of with thin-layer chromatography.Add 1: 1 tetrahydrofuran (THF): methanol solution (0.20ml altogether) then adds 2.0ml 5.0N sodium hydroxide.
The mixture that obtains refluxes and spends the night.Boil off solvent, residue distributes between water and methylene dichloride.Organic layer is washed with saturated common salt, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 440 (M+1) ultimate analysis C
26H
34ClN
3O: theoretical value: C, 70.97; H, 7.79; N, 9.55. measured value: C, 70.73; H, 7.65; N, 9.44.
Method N2-((4-chlorophenoxy) methyl)-1-methyl-3-(3-(piperidines-3-yl) propyl group)-1H-indoles (embodiment 42) and 1, the preparation of 2-dimethyl-3-(3-(piperidines-3-yl) propyl group)-1H-indoles (embodiment 237)
Under nitrogen protection; with 2-((4-chlorophenoxy) methyl)-1-methyl-3-(3-(piperidines-3-yl) propionyl)-1H-indoles (0.0737g; 0.1793mmol) be dissolved in the 1.8ml dioxane, adding borane-dimethyl sulphide complex compound (0.108ml, 1.07mmol).The mixture stirred overnight at room temperature.Reaction process is followed the tracks of with thin-layer chromatography.Add 1: 1 tetrahydrofuran (THF): water mixed solvent (0.3ml) and 1.5ml 5.0N sodium hydroxide.Reaction mixture is heated to 85 ℃ and 85 ℃ of incubated overnight, rises to 225 ℃ then fast.
The pressure reducing and steaming solvent, residue distributes between methylene dichloride and 1.0N sodium hydroxide.Organic layer is washed with saturated common salt, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title product of expectation is used chromatogram purification again.The structure of the analytical data that obtains and the title compound of expection match (embodiment 42 and 237 that sees below).2, the preparation of 4-two chloro-1-acetylenylbenzenes
Under nitrogen protection, in the 500ml round-bottomed flask with 2,4-two chloroiodobenzones (3ml, 22.1mmol), triethylamine (6.16ml, 44.2mmol) and (trimethyl silicon based) acetylene (3.21ml, 22.1mmol) (6.16ml 44.2mmol) mixes with acetonitrile.In mixture, lead to 10 minutes nitrogen.Add in this mixture two (triphenylphosphine) palladiums (II) of chlorination (775mg, 1.10mmol) and the inferior ketone of iodate (105mg, 0.552mmol), mixture refluxed 4 hours.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture is chilled to envrionment temperature, and evaporation obtains the oily product.
Residue dissolves in methyl alcohol (50ml) and tetrahydrofuran (THF) (150ml), add solid salt of wormwood (30.54g, 0.221mol).Mixture stirred 19 hours in envrionment temperature.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture distributes between 1M salt of wormwood and ethyl acetate.Water layer is stripped 2 times with ethyl acetate.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent gets the title product of 2.6g expectation.NMR conforms to the structure of the title compound of expection.2, the preparation of 4-two chloro-1-(2-bromine ethene-1-yl) benzene
Under nitrogen protection, (tetrahydrofuran solution of 1M, 4.8ml 4.82mmol) are chilled to 0 ℃ with the borane tetrahydrofuran complex in the 100ml round-bottomed flask.Methyl-prop-(1.02ml, 9.65mmol), mixture slowly is warming up to envrionment temperature to 2-alkene, and stirs at ambient temperature 1 hour to drip 2-in this complex compound.Reaction mixture with hexamethylphosphoramide (5ml), tetrahydrofuran (THF) (5ml), cupric bromide (2.15g, 9.65mmol) and venus crystals (3.85g 19.3mmol) dilutes, then add water (86 μ l, 4.82mol).The mixture that obtains stirred 6 hours in envrionment temperature.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture dilutes with saturated aqueous common salt, uses extracted with diethyl ether 2 times.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.Residue is used the liquid chromatography purifying again.Output: 426mg.NMR conforms to the structure of the title compound of expection.The preparation of 4-hydroxy-n-sec.-propyl butylamine
Toward the 4-amino butanol (2.0mg, 22.4mmol) with the solution of 110ml ethylene dichloride in add acetone (3.3ml, 44.8mmol), acetate (5 equivalent) and acetoxyl group sodium borohydride (11.9g, 56.09mmol).This muddy mixture stirred about 18 hours at ambient temperature.Use the saturated sodium bicarbonate solution termination reaction.Hydro-oxidation sodium (1M) transfers pH to about 10.The water layer mixture extraction of Virahol and methylene dichloride (1: 3).Merge organic layer, anhydrous sodium sulfate drying filters, concentrates.The intermediate of expectation to the ball distillation purifying, obtains the limpid oil of 1.4g with ball., with 3: 1 toluene: the butanols aqueous layer extracted, can reclaim product.The preparation of N-(tertbutyloxycarbonyl)-4-hydroxy-n-sec.-propyl butylamine
4-hydroxy-n-sec.-propyl butylamine (3.0g, 22.8mmol) and dioxane: water: 1N sodium hydroxide (91ml: 28ml: the solution that mixed solvent 28ml) is made into and two (tertbutyloxycarbonyl) ether (4.98g, 22.8mmol) reaction.Muddy reaction mixture stirred 5 hours.The reaction mixture dichloromethane extraction.The organic phase drying is filtered, is concentrated.The title product of expectation is used high-efficient liquid phase chromatogram purification again, gets 2.6g (49%) colorless oil.The preparation of 2-fluoro-5-chlorobenzaldehyde
(5.79ml 41.3mmol) Yu in the 5ml tetrahydrofuran (THF) is mixed with diisopropylamino lithium at Diisopropylamine.Mixture is chilled to-78 ℃, keeps temperature not rise to when handling and exceed 64 ℃ with n-Butyl Lithium.Suspension stirred after 45 minutes, added remaining tetrahydrofuran (THF) (70ml), drip then the 4-chlorofluorobenzene (4.0ml, 37.6mmol).After 45 minutes, drip N, dinethylformamide.Reaction mixture restir 10 minutes is used acetate (6ml) termination reaction then, adds water (100ml) again.Cold mixt is transferred in the separating funnel, used dichloromethane extraction 2 times.Merge organic layer, anhydrous sodium sulfate drying filters.Removal of solvent under reduced pressure.Residue is used high-efficient liquid phase chromatogram purification again, gets the 4.00g white solid, mp 41-43 ℃.The preparation of 2-fluoro-5-xylyl alcohol
(1.80g, 12.3mmol) with 3: 1 tetrahydrofuran (THF)s: (0.93g 24.6mmol) reacts the solution of methyl alcohol (82ml altogether) 2-fluoro-5-tolyl aldehyde with sodium borohydride in 0 ℃.Reaction mixture slowly rises to envrionment temperature, stirs about 3 hours.The water termination reaction changes separating funnel over to, uses dichloromethane extraction.The organic layer anhydrous magnesium sulfate drying filters concentrating under reduced pressure.Residue is used high-efficient liquid phase chromatogram purification again, gets the limpid oily product of 1.3g (76%).The preparation of 2-fluoro-5-chlorobenzyl alcohol
Method according to the top 2-of preparation fluoro-5-xylyl alcohol prepares the title intermediate, here with waiting mole 2-fluoro-5-chlorobenzaldehyde to replace 2-fluoro-5-tolyl aldehyde.Output: 2.16g (86%) is limpid oily matter.The preparation of 2-fluoro-5-chlorine bromobenzyl
2-fluoro-5-chlorobenzyl chloride (1.28g, 7.97mmol) with the solution of ether (26ml) and triphenylphosphine (2.72g 10.36mmol) reacts, then add carbon tetrabromide (3.44g, 10.36mmol).The suspension that obtains stirred 3.5 hours, filtered, and washed with ether.Filtrate concentrates, and removes triphenyl by silica filler.Residue liquid chromatography purifying gets the 2.0g title compound, is limpid oil.The preparation of 4-(2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine
N-(tertbutyloxycarbonyl)-4-hydroxy-n-sec.-propyl butylamine (539mg, 2.33mmol) with the solution of tetrahydrofuran (THF) (11ml) in-40 ℃ with potassium tert.-butoxide (tetrahydrofuran solution of 1M, 2.54ml, 2.54mmol).After 40 minutes, suspension is chilled to-78 ℃, and (400mg is 2.12mmol) with the solution-treated of tetrahydrofuran (THF) (4ml) with 2-fluorine bromobenzyl.Reaction mixture slowly rises to room temperature, stirs about 5 hours.Reaction mixture dilutes with methylene dichloride, washes with 1M salt of wormwood, washes with saturated common salt.The organic layer anhydrous sodium sulfate drying filters, concentrates.Thick oily matter liquid chromatography purifying gets 555mg (77%) title intermediate, is limpid oil.The preparation of 4-(2-fluoro-5-chlorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine
The method for preparing 4-(2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine according to the front prepares the title intermediate, just uses here and waits mole 2-fluoro-5-chlorine bromobenzyl to replace 2-fluorine bromobenzyl.Output: 237mg (35%).The preparation of 4-(2-fluorine benzyloxy)-N-(sec.-propyl) butylamine
4-(2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine adopts the standard technique deprotection, the intermediate of preparation expectation.4-(2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine is mixed with 4: 1 mixtures of methylene dichloride and trifluoroacetic acid.Reaction process is followed the tracks of with thin-layer chromatography.The preparation of 4-(5-chloro-2-fluorine benzyloxy)-N-(sec.-propyl) butylamine
According to the top intermediate for preparing the method preparation expectation of 4-(2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine, just use here and wait mole 4-(5-chloro-2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine to replace 4-(2-fluorine benzyloxy)-N-(tertbutyloxycarbonyl)-N-(sec.-propyl) butylamine.Output: 138mg (98%).The preparation of 3-(5-bromo-2-fluorine benzyloxy)-1-(1-(tertbutyloxycarbonyl) piperidines-2-yl) propane
(800mg 3.29mmol) dissolves in tetrahydrofuran (THF) (17ml) to 3-(1-(tertbutyloxycarbonyl) piperidines-2-yl) propyl alcohol, is chilled to-40 ℃, and (tetrahydrofuran solution of 1M, 3.62ml 3.62mmol) handle with potassium tert.-butoxide.The mixture that obtains is chilled to-78 ℃ then in about 35 minutes of-40 ℃ of stirrings.(881mg is 3.29mmol) with the solution of tetrahydrofuran (THF) (5ml) to add 5-bromo-2-fluorine bromobenzyl then in this mixture.The yellow reaction mixture that obtains slowly is warming up to 0 ℃, and stirs about 4 hours.Reaction mixture dilutes with methylene dichloride, washes with the 1M potassium bicarbonate solution, washes with saturated common salt.The organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure.Thick oily matter high-efficient liquid phase chromatogram purification obtains 707mg (50%) title intermediate, is limpid oily matter.Ultimate analysis C
20H
29BrFNO
3: theoretical value: C, 55.82; H, 6.79; N, 3.25. measured value: C, 55.54; H, 6.88; N, 3.34.
The preparation of 3-(5-bromo-2-fluorine benzyloxy)-1-(piperidines-2-yl) propane
(590mg 1.37mmol) is dissolved in methylene dichloride (11ml), is chilled to 0 ℃, handles with the 3ml trifluoroacetic acid with 3-(5-bromo-2-fluorine benzyloxy)-1-(1-(tertbutyloxycarbonyl) piperidines-2-yl) propane.Reaction mixture is warming up to envrionment temperature, restir 10 minutes then in 0 ℃ of stirring 20 minutes.Reaction mixture dilutes with methylene dichloride, quenches with saturated sodium bicarbonate solution.Transfer pH to about 10 with 1N sodium hydroxide.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying filters, and concentrates.Output: 420mg (93%).The not purified direct use of the intermediate that obtains.The preparation of 2-fluoro-5-bromine bromobenzyl
2-fluoro-5-bromobenzyl alcohol (20.0g, 97.5mmol) with the solution of ether (325ml) with triphenylphosphine (33.3g 127mmol) handles, then add carbon tetrabromide (42.1g, 127mmol).Mixture stirred about 4 hours at ambient temperature.Remove precipitation, wash with ether.The title product of expectation is distilled (150 ℃, 5mmHg (interior pressure)) purifying with bubble to bubble again.Output: 24.36g (93%) is white low melting point solid.The preparation of 4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-alkynol
2-fluoro-5-bromine bromobenzyl (15.6g, 58.1mmol) and N, dinethylformamide (290ml) is added to 1,4-dihydroxyl-2-butyne (20.0g, 232mmol) and sodium hydride (15.6g, 60% solution, 58.1mmol) in, last 35 minutes.The mixture that obtains stirred 4.5 hours in envrionment temperature.Reaction 1: 1: 1 saturated aqueous common salt of 100ml: water: 1M salt of wormwood mixing solutions quenches.Water layer dichloromethane extraction (3 * 300ml).The title product of expectation is used chromatogram purification again, gets 8.90g (56%).The preparation of 4-(2-fluoro-5-bromo-benzyloxy-) butanols
1,4-dihydroxyl butane (4.0ml, 45.13mmol) and N, (solution of dinethylformamide (62ml) 49.63mmol) is handled, and stirs about 50 minutes in envrionment temperature with sodium hydride by 1.98g, 60% solution.The mixture that obtains is chilled to 0 ℃, and (3.0g 11.28mmol) handles with 2-fluoro-5-bromine bromobenzyl.Reaction mixture stirred 4 hours at ambient temperature.The reaction water quenching.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate of expectation is used high-efficient liquid phase chromatogram purification again.Output: 1.8g (58%) is limpid oily matter.λ
max＝271nm。Ultimate analysis C
11H
14BrFO
2: theoretical value: C, 47.67; H, 5.09; Br, 28.83. measured value: C, 47.37; H, 5.15; Br, 28.55.N-(tertbutyloxycarbonyl)-4-(2-fluoro-5-bromo-benzyloxy-)-3, the preparation of 3-dimethyl butylamine
Stir 4-(t-butoxycarbonyl amino)-2 down, (1.5g, (tetrahydrofuran solution of 1M, 7.59ml 7.59mmol) handle 2-dimethyl butyrate-1-alcohol 6.90mmol) to use potassium tert.-butoxide with the solution of tetrahydrofuran (THF) (49ml) down at-45 ℃.The negative ion that generates stirred 30 minutes at-45 ℃, was chilled to-78 ℃ then, and (1.85g, tetrahydrofuran solution 6.90mmol) is handled with 2-fluoro-5-bromine bromobenzyl.The yellow mixture that obtains slowly is warming up to envrionment temperature, stirs about 18 hours.Muddy reaction mixture dilutes with methylene dichloride, washes with the 1M solution of potassium carbonate then.The organic layer anhydrous sodium sulfate drying filters removal of solvent under reduced pressure.Residue is used the preparative high performance liquid chromatography purifying again, gets 1.45g (52%) title intermediate, is colorless oil.
N-(tertbutyloxycarbonyl)-4-(2-fluoro-5-bromo-benzyloxy-)-2, the preparation of 2-dimethyl butylamine
Stir down, 4-(t-butoxycarbonyl amino)-3, (1.0g, 4.60mmol) (tetrahydrofuran solution of 1M, 5.06ml 5.06mmol) handle 3-dimethyl butyrate-1-alcohol with potassium tert.-butoxide in-45 ℃ with the solution of tetrahydrofuran (THF) (33ml).The negative ion that obtains was stirred about 30 minutes in-45 ℃, be chilled to then-78 ℃ and with 2-fluoro-5-bromine bromobenzyl (1.23g, tetrahydrofuran solution 4.60mmol) is handled.The yellow mixture that obtains slowly is warming up to 0 ℃, stirs about 4 hours.Muddy reaction mixture is washed with 1M salt of wormwood with methylene dichloride (100ml) dilution.The organic layer anhydrous sodium sulfate drying filters the pressure reducing and steaming solvent.Residue preparative high performance liquid chromatography purifying gets 1.38g (74%) title intermediate, is colorless oil.
The preparation of 2-((tertbutyloxycarbonyl) amino)-5-(2-fluoro-5-bromo-benzyloxy-)-2-methylpentane
Stir down, 4-(t-butoxycarbonyl amino)-4, (1.11g, (tetrahydrofuran solution of 1M, 5.62ml 5.62mmol) handle tetrahydrofuran (THF) 5.11mmol) (49ml) solution 4-dimethyl butyrate-1-alcohol with potassium tert.-butoxide down in-45 ℃.The negative ion that obtains stirred 30 minutes at-45 ℃, was chilled to-78 ℃ then, and (1.23g, tetrahydrofuran solution 4.60mmol) is handled with 2-fluoro-5-bromine bromobenzyl.The yellow mixture that obtains slowly is warming up to 0 ℃, stirs about 4 hours.Reaction mixture dilutes with methylene dichloride (100ml), and (20ml) washes with 1M salt of wormwood.The organic layer anhydrous sodium sulfate drying filters the pressure reducing and steaming solvent.Residue is used the preparative high performance liquid chromatography purifying again, gets 1.53g (74%) title intermediate, is colorless oil.
The preparation of trans-4-(t-butoxycarbonyl amino) hexalin
Toward trans-4-Trans-4-Amino Cyclohexanol (5.00g, 33.0mmol) with the solution of dioxane (132ml), water (41ml) and 1N sodium hydroxide (41ml) in add uncle's fourth oxygen acid anhydride (t-butoxgcarbouyl anhydride) (14.4g, 66mmol).Muddy solution stirring is spent the night.Reaction mixture is acidified to pH3.0 with the sodium pyrosulfate solid.The mixture that obtains dichloromethane extraction 2 times.Merge organic layer, use anhydrous sodium sulfate drying, concentrating under reduced pressure.The title intermediate and the hexane/ethyl acetate recrystallization of expectation get 6.5g (92%) title intermediate.MS 216.24 ultimate analysis C
11H
21NO
3: theoretical value: C, 61.37; H, 9.83; N, 6.50. measured value: C, 61.16; H, 9.54; N, 6.39. is trans-preparation of { 4-(butoxy carbonyl amino)-1-(2-fluoro-5-bromo-benzyloxy-] } hexanaphthene
Trans-{ 4-(butoxy carbonyl amino) } hexalin (550mg, 2.32mmol) solution with anhydrous tetrahydro furan (16.6ml) is chilled to-40 ℃, and (tetrahydrofuran solution of 1M, 2.55ml 2.55mmol) handle with potassium tert.-butoxide.Muddy yellow reaction mixture stirred about 30 minutes, was chilled to-78 ℃, and (622mg 2.32mmol) handles with 2-fluoro-5-bromine bromobenzyl.The yellow mixture that obtains progressively is warming up to 0 ℃, stirs about 2 hours.Reaction mixture dilutes with methylene dichloride, washes with saturated sodium bicarbonate solution.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The residue high-efficient liquid phase chromatogram purification gets the title intermediate of 558mg (62%) expectation, is white solid.Ultimate analysis C
18H
25BrFNO
3: theoretical value: C, 53.74; H, 6.26; N, 3.48. measured value: C, 53.87; H, 6.16; N, 3.11.
3, the preparation of 3-dimethyl-1-(tertbutyloxycarbonyl) pyrrolidin-2-one
According to F.Scheinmann and A.V.Stachulski,
Journal of Chemical Research, the intermediate of the method preparation expectation of describing among the 1993:414 (1993).(8.63g, tetrahydrofuran (THF) 43.3mmol) (48ml) solution is chilled to-78 ℃ to 3-methyl isophthalic acid-(tertbutyloxycarbonyl) pyridine alkane-2-ketone.This solution NaN[Si (CH
3)
2]
2(56.3ml 56.3mmol) handles, and stirs after about 50 minutes with methyl iodide (8.1ml, 130mmol) quenching.Reaction mixture slowly is warming up to envrionment temperature, continues to stir about 1 hour.Reaction mixture is washed (40ml) with ethyl acetate (100ml) and saturated common salt.The organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure.Collecting precipitation is used the flash chromatography purifying again, gets 8.49g (92%) title intermediate, is semisolid.NMR conforms to the structure of title compound.
4-(t-butoxycarbonyl amino)-2, the preparation of 2-dimethyl butyrate alcohol
3, (3.35g, (1.79g 47.1mmol) handles 3-dimethyl-1-(tertbutyloxycarbonyl) pyridine alkane-2-ketone 15.7mmol) to use sodium borohydride with the solution of dehydrated alcohol under nitrogen protection.The mixture that obtains stirred about 24 hours in envrionment temperature.Reaction process is followed the tracks of with thin-layer chromatography.The reaction mixture concentrating under reduced pressure.Residue dissolves in ethyl acetate, washes with sodium hydrogen carbonate solution.Water layer is with the ethyl acetate secondary of stripping.The organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue is used chromatogram purification again, gets 3.17g (93%) title intermediate, is limpid oily matter.mp?75.5-76.5℃。
The preparation of 4-(2-fluoro-5-bromo-benzyloxy-)-1-methoxy butyl-2-alkynes
4-(2-fluoro-5-bromo-benzyloxy-)-Ding-2-alkynyl alcohol (1.07g, 3.92mmol) solution with tetrahydrofuran (THF) (26ml) is chilled to-40 ℃, and (431ml, 1M tetrahydrofuran solution 4.31mmol) are handled with potassium tert.-butoxide.The dark orange solution stirring that obtains 30 minutes is chilled to-78 ℃, and (0.49ml 7.84mmol) handles with methyl iodide.Reaction is warming up to 0 ℃, stirs 1.5 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title intermediate of expectation is used high-efficient liquid phase chromatogram purification again, gets 790mg (70%) title intermediate, is limpid oily matter.
The preparation of bromo 4-(2-fluoro-5-bromo-benzyloxy-)-Ding-2-alkynes
4-(2-fluoro-5-bromo-benzyloxy-)-Ding-2-alkynol (8.9g, 32.6mmol) with the solution of ether (109ml) with triphenylphosphine (11.1g, 42.4mmol) and carbon tetrabromide (14.1g, 42.4mmol) processing.Muddy solution stirred about 14 hours at ambient temperature.The elimination precipitation, filtrate concentrates.The title intermediate flash chromatography purifying of expectation.Output 9.83g (90%) is limpid oily matter.
Ultimate analysis conforms to the structure of the title compound of expection with NMR.
The preparation of N-methyl-4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-ynamine
Aminomethane (89ml, the tetrahydrofuran solution of 2M, 178mmol) be added to bromo 4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-alkynes (6.0g, 17.8mmol) with the solution of tetrahydrofuran (THF) (89ml) in.Muddy reaction mixture stirred about 15 minutes, and thin-layer chromatography indication raw material this moment exhausts.Removal of solvent under reduced pressure.Residue dissolves in the methylene dichloride, washes with 1M salt of wormwood.Water layer dichloromethane extraction 2 times.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The oily matter that obtains flash chromatography purifying gets 4.24g (83%) title intermediate, is yellow oil.NMR conforms to the structure of the title compound of expectation.
The preparation of N-benzyl-4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-ynamine
With benzylamine (0.98ml, 8.93mmol) solution be added to bromo 4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-alkynes (300mg, 0.893mmol) with the solution of tetrahydrofuran (THF) (4.5ml) in.Muddy reaction mixture stirred about 20 hours, and thin-layer chromatography shows that this moment, raw material exhausted.Removal of solvent under reduced pressure.Residue dissolves in methylene dichloride, washes with 1M salt of wormwood.(2 * 15ml) strip water layer with methylene dichloride.Merge organic layer, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure.The oily matter that obtains flash chromatography purifying gets 200mg (62%) title intermediate.
The preparation of N-sec.-propyl-4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-ynamine
Isopropylamine solution (0.25ml, 2.9mmol) be added to bromo 4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-alkynes (97mg, 0.29mmol) with the solution of tetrahydrofuran (THF) (1.4ml) in.Muddy reaction mixture stirred about 20 hours.Thin-layer chromatography shows that this moment, raw material exhausted.The pressure reducing and steaming solvent.Residue dissolves in methylene dichloride, washes with 1 M salt of wormwood.(2 * 5ml) strip water layer with methylene dichloride.The organic layer that merges, anhydrous sodium sulfate drying.Solvent is steamed in decompression.The oily matter that obtains flash chromatography repurity gets 78mg (86%) title intermediate.NMR conforms to the structure of the title compound of expection.The preparation of N-cyclopropyl-4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-ynamine
Cyclopropylamine solution (1.10ml, 15.8mmol) be added to bromo 4-(2-fluoro-5-bromo-benzyloxy-) fourth-2-alkynes (530mg, 1.58mmol) with the solution of tetrahydrofuran (THF) (8ml) in.Muddy reaction mixture stirred about 30 minutes.Reaction mixture is chilled to 0 ℃, keep 0 ℃ about 4 hours, thin-layer chromatography show this moment raw material exhaust.Reaction mixture dilutes with methylene dichloride (50ml), and (10ml) washes with 1M salt of wormwood.The organic layer anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The oily matter that obtains is used the preparative high performance liquid chromatography purifying again, gets 362mg (73%) title intermediate, is limpid oily matter.
4,5-dihydro-2-(preparation of 2-fluoro-5-bromophenyl) oxazole
(956mg, (0.35ml 4.75mmol) handles dichloromethane solution 3.65mmol) N-(2-hydroxyethyl)-5-bromo-2-fluorobenzamide with sulfur oxychloride.Reaction mixture stirs in envrionment temperature, and reaction process is followed the tracks of with thin-layer chromatography.Stir after 1 hour, raw material disappears.Reaction mixture dilutes with methylene dichloride, adds water and 1N sodium hydroxide and quenches.The organic layer anhydrous sodium sulfate drying.Be condensed into white solid.This solid is dissolved in 80% acetonitrile solution (25ml), adds excessive salt of wormwood.The mixture that obtains stirred about 72 hours at ambient temperature, and reflux 30 hours is as top aftertreatment.The title product of expectation is used the liquid chromatography purifying again, and output is 260mg, yellow oil.
N, the preparation of N-dimethyl-2-fluoro-5-brombenzamide
(680mg, 3.10mmol) (0.35ml 4.04mmol) handles 2-fluoro-5-bromo-benzoic acid, adds 4 N then, dinethylformamide with oxalyl chloride with the solution of methylene dichloride (20ml).The clear solution that obtains stirred about 3 hours.Removal of solvent under reduced pressure, residue are dissolved in the methylene dichloride, and (4.6ml 8.9mmol) handles with dimethylamine.Continue to stir 18 hours.Reaction mixture dilutes with methylene dichloride, washes with saturated sodium bicarbonate solution, washes with saturated common salt.The organic layer anhydrous sodium sulfate drying, removal of solvent under reduced pressure.The title product of expectation is used the liquid chromatography purifying again.Output: 632mg (83%) is limpid oily matter.
The preparation of 1-methoxyl group-4-(2-fluoro-5-bromo-benzyloxy-) butane
4-(2-fluoro-5-bromo-benzyloxy-) butanols (897mg, 3.24mmol) solution with tetrahydrofuran (THF) (22ml) is chilled to-40 ℃, and (3.56ml, the tetrahydrofuran solution of 1M 3.56mmol) are handled to use potassium tert.-butoxide then.The orange solution stirring that obtains 30 minutes is chilled to-78 ℃, and (0.40ml 6.48mmol) handles with methyl iodide.Reaction is warming up to 0 ℃, stirs 1.5 hours.Reaction mixture distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title intermediate of expectation is used high-efficient liquid phase chromatogram purification again, gets the limpid oily matter of 687mg (73%).FDMS is 291.99.
The preparation of bromo 4-(2-fluoro-5-bromo-benzyloxy-) butane
4-(2-fluoro-5-bromo-benzyloxy-) butanols (7.03g, 26.3mmol) with the solution of ether (88ml) with triphenylphosphine (8.97g, 34.2mmol) and carbon tetrabromide (11.3g, 34.2mmol) processing.Muddy reaction mixture stirred about 30 hours at ambient temperature.The filtering precipitation, filtrate concentrates.The title intermediate of expectation is by bubble distillation filtrate purifying.Output is 8.68g (86%), is limpid oily matter.Ultimate analysis conforms to the structure of the title compound of expection with NMR.
N, the preparation of N-dimethyl-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
Toward 4-(2-fluoro-5-bromo-benzyloxy-) butyl bromide (1.2g, 3.53mmol) with the solution of tetrahydrofuran (THF) (18ml) in add diethylamine (17.6ml, 35.3mmol).The mixture that obtains stirred about 18 hours at ambient temperature.Reaction mixture dilutes with methylene dichloride, washes with saturated sodium bicarbonate solution.Water layer is stripped with dichloromethane solution.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate of expectation is used high-efficient liquid phase chromatogram purification again.Output: 842mg (79%) is light yellow oil.
The preparation of N-ethyl-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
(500mg, 1.47mmol) (242mg 1.6mmol) handles 4-(2-fluoro-5-bromo-benzyloxy-) butyl bromide with sodium iodide with the solution of acetone (7.3ml).The mixture that obtains stirs at ambient temperature.1.5 after hour, the elimination Sodium Bromide, filtrate concentrates.Residue ethylamine solution (11ml, 22.0mmol) processing of tetrahydrofuran (THF).The mixture that obtains stirred about 17 hours at ambient temperature.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture dilutes with methylene dichloride, washes the saturated common salt washing with the 25mM phosphoric acid buffer.The organic layer anhydrous sodium sulfate drying, removal of solvent under reduced pressure.The title intermediate of expectation is used the radial chromatography purifying again.Output: 337mg (75%) is yellow oil.NMR conforms to the structure of the title compound of expection.
The preparation of N-sec.-propyl-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
(1.2g, (484mg 3.2mmol) handles tetrahydrofuran (THF) 3.53mmol) (18ml) solution 4-(2-fluoro-5-bromo-benzyloxy-) butyl bromide with sodium iodide.The mixture that obtains stirs at ambient temperature.After 15 hours, the elimination Sodium Bromide, filtrate concentrates.(3.01ml, handle by tetrahydrofuran solution 35.2mmol) with isobutylamine for residue.Reaction process is followed the tracks of with thin-layer chromatography.The mixture that obtains stirs about 18 hours at ambient temperature, and then adds 10 equivalent Isopropylamines driving reaction.Reaction mixture dilutes with methylene dichloride, washes the saturated common salt washing with the 25mM phosphate buffered saline buffer.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title intermediate of expectation is used the liquid chromatography purifying again.Output: 517mg (46%) is yellow oil.Ultimate analysis C
14H
21BrFNO: theoretical value: C, 52.84; H, 6.65; N, 4.40. measured value: C, 52.87; H, 6.77; N, 4.64.
The preparation of N-(tertiary butyl)-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
(400mg, (242mg 1.6mmol) handles tetrahydrofuran (THF) 1.18mmol) (6ml) solution 4-(2-fluoro-5-bromo-benzyloxy-) butyl bromide with sodium iodide.Mixture stirs at ambient temperature.1.5 after hour, the elimination Sodium Bromide, filtrate concentrates.(1.24ml, handle by tetrahydrofuran solution 11.8mmol) with TERTIARY BUTYL AMINE for residue.Reaction process is followed the tracks of with thin-layer chromatography.The mixture that obtains stirred about 19 hours at ambient temperature.Reaction mixture dilutes with methylene dichloride, with saturated sodium bicarbonate solution wash, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title intermediate of expectation is used the radial chromatography purifying again.Output: 261mg (66%) is yellow oil.The title compound structure of NMR expection conforms to.
The preparation of 1-(piperidines-1-yl)-4-(2-fluoro-5-bromo-benzyloxy-) butane
(520mg, 1.53mmol) (1.5ml 15.3mmol) handles 4-(2-fluoro-5-bromo-benzyloxy-) butyl bromide with piperidines with the solution of tetrahydrofuran (THF) (8ml).Reaction mixture stirred about 24 hours.Reaction mixture dilutes with methylene dichloride, washes with saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title of expectation is used the radial chromatography purifying again.Output: 399mg (76%).
The preparation of 1-(morpholine-4-yl)-4-(2-fluoro-5-bromo-benzyloxy-) butane
(550mg, 1.62mol) (1.4ml 16.2mmol) handles 4-(2-fluoro-5-bromo-benzyloxy-) butyl bromide with morpholine with the solution of tetrahydrofuran (THF) (8ml).Reaction mixture stirred about 72 hours.Reaction mixture dilutes with methylene dichloride then, washes with saturated sodium bicarbonate solution.The organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent.The title intermediate of expectation is used the radial chromatography purifying again.Output: 446mg (79%) is limpid oily matter.
The preparation of 1-(2-fluoro-5-bromo-benzyloxy-)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propane
In the 10ml round-bottomed flask, under the nitrogen protection, (180mg 0.588mmol) is dissolved in N, in the dinethylformamide (1.5ml) with bromo 3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propane.(176mg, 1.18mmol), the mixture that obtains stirred 10 minutes to add sodium iodide under the envrionment temperature.(121mg 0.588mmol) handles reaction mixture, transfers to 0.5ml N as solution, in the dinethylformamide with 2-fluoro-5-bromobenzyl alcohol.Add in this mixture sodium hydride (60%, 35mg, 0.882mmol), the mixture that obtains stirred 3 hours at ambient temperature.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M solution of potassium carbonate and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The environment title product of expectation is used the liquid chromatography purifying again.Output: 0.115g.MS (M+) 430 ultimate analysis C
20H
29BrFNO
3: theoretical value: C, 55.82; H, 6.79; N, 3.26. measured value: C, 55.70; H, 6.59; N, 3.04.
The preparation of 1-(2-fluoro-5-bromo-benzyloxy-)-3-(piperidines-3-yl) propane
In the 100ml round-bottomed flask, 1-(2-fluoro-5-bromo-benzyloxy-)-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propane (0.395g) is dissolved in the methylene dichloride (42ml), after solution is chilled to 0 ℃, slowly drip trifluoroacetic acid (0.8ml) inward.Mixture stirred 30 minutes for 0 ℃, stirred at ambient temperature 30 minutes again.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M solution of potassium carbonate and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate of expectation is used the liquid chromatography purifying again.Output: 210mg is glassy yellow oily matter.Ultimate analysis C
16H
21BrFNO: theoretical value: C, 54.54; H, 6.41; N, 4.24. measured value: C, 54.32; H, 6.41 N, 4.34.
The preparation of 2-fluoro-5-bromine bromobenzyl
In the 250ml round-bottomed flask, under nitrogen protection, (5.85g 28.5mmol) is dissolved in the ether (1 25ml) with 2-fluoro-5-bromobenzyl alcohol.Add in this solution triphenylphosphine (9.73g, 37.1mmol) and carbon tetrabromide (12.30g, 37.1mmol).The mixture that obtains stirred about 3 hours at ambient temperature.There is thin-layer chromatography to follow the tracks of reaction process.Reaction mixture is about 19 hours of restir at ambient temperature.Reaction mixture filters, and washes with cold diethyl ether.Evaporate to dryness filtrate gets glassy yellow oily matter.This oily matter recycle silicon glue chromatogram purification is used the hexane wash-out.The component purifying that directly volatilizees of expectation, the title intermediate of 5.8g expectation.Slowly crystallization in the put procedure.Ultimate analysis C
7H
6Br
2F: theoretical value: C, 31.39; H, 1.88. measured value: C, 31.18; H, 1.91.
N, the preparation of N-dimethyl-3-(2-fluoro-5-bromo-benzyloxy-) propylamine
In the 10ml round-bottomed flask, under nitrogen protection, (245mg 0.914mmol) is dissolved in N, in the dinethylformamide (2.0ml) with 2-fluoro-5-bromine bromobenzyl.(137mg, 0.914mmol), the mixture that obtains stirred 30 minutes in envrionment temperature to add sodium iodide in this solution.In another 10ml flask, under nitrogen protection, (0.162ml 1.37mmol) is dissolved in N, in the dinethylformamide (2.0ml) with 3-(N, N-dimethylamino) propyl alcohol.Add in the propanol solution sodium hydride (60%, 62mg, 1.55mmol).Stir after 30 minutes, add the solution of bromobenzyl, sodium iodide in the mixture of this propyl alcohol.Some foams appear but dispersion rapidly.The mixture that obtains stirred 2 hours at ambient temperature.There is thin-layer chromatography to follow the tracks of reaction process.Reaction mixture distributes between M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The intermediate of expectation is used the liquid chromatography purifying again, gets 182mg (69%) title intermediate.NMR, IR conform to the structure of the title intermediate of expection with MS.Ultimate analysis C
12H
17BrFNO: theoretical value: C, 49.67; H, 5.91; N, 4.83. measured value: C, 49.46; H, 5.92; N, 4.99.
The preparation of 2-(2-fluoro-5-bromo-benzyloxy-)-1-methyl ethyl ether
In the 10ml flask, under nitrogen protection, (0.125ml 1.60mmol) is dissolved in N, in the dinethylformamide (2ml) with 2-methyl cellosolve.The adding sodium hydride (60%, 72mg, 1.81mmol), mixture stirred about 30 minutes at ambient temperature.Add in this reaction mixture 2-fluoro-5-bromine bromobenzyl (285mg, 1.06mmol) and N, the solution of dinethylformamide (2ml).The mixture that obtains stirred 2 hours at ambient temperature.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M solution of potassium carbonate and ether.Water layer is stripped with ether.Merge organic layer, with saturated common salt washing 7 times, anhydrous sodium sulfate drying, pressure reducing and steaming solvent.The not purified direct use of this title intermediate.Output: 165mg.
The preparation of 2-(2-fluoro-5-bromo-benzyloxy-)-(N, N-dimethyl) ethamine
In the 50ml flask, under nitrogen protection, (1.319g 4.92mmol) is dissolved in N, in the dinethylformamide (16ml) with 2-(N, N-dimethylamino) ethanol.The adding sodium hydride (60%, 335mg, 8.37mmol), mixture stirred about 20 minutes at ambient temperature.Add in this reaction mixture 2-fluoro-5-bromine bromobenzyl (1.319g, 4.92mmol) and N, the solution of dinethylformamide (3ml).The mixture that obtains stirred 2 hours at ambient temperature.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M solution of potassium carbonate and ether.Water layer is stripped with ether.Merge organic layer, with saturated common salt washing 7 times, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is not purified, directly uses.Output 1.023g (75%).
N, the preparation of N-dimethyl-2-fluoro-5-bretylium
In the 50ml flask, under nitrogen protection, (1.264g 4.72mmol) is dissolved in the methyl alcohol (10ml) with 2-fluoro-5-bromine bromobenzyl.(14.2mmol) with the solution of methyl alcohol (5ml), the mixture that obtains stirred about 2 hours at ambient temperature for the aqueous solution of 8M, 1.77ml to add dimethylamine.Follow the tracks of reaction process with thin-layer chromatography.Boil off methyl alcohol.Residue distributes between 1M wet chemical and ether.Water layer is stripped with ether.Merge organic layer, with saturated common salt washing 7 times, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The not purified direct use of title intermediate.Output: 0.987g.
The preparation of 2-(2-fluoro-5-bromo-benzyloxy-)-(N-methyl) ethamine
In the 50ml flask, under nitrogen protection, (317mg 1.15mmol) dissolves in ethylene dichloride (3.5ml) with 2-(2-fluoro-5-bromo-benzyloxy-)-(N, N-dimethyl) ethamine.This solution is chilled to 0 ℃, add ACECl (0.50ml, 4.59mmol).The mixture that obtains is warming up to envrionment temperature, and reflux is about 3 hours then.Follow the tracks of reaction process with thin-layer chromatography.Add methyl alcohol in reaction mixture, the mixture that obtains stirred under envrionment temperature about 3 days.Reaction mixture reflux 30 minutes.The pressure reducing and steaming solvent.Residue dissolves in the methyl alcohol, reflux 30 minutes, pressure reducing and steaming solvent.The not purified direct use of this title intermediate.Output: 210mg.
The preparation of N-methyl-2-fluoro-5-bretylium
In the 25ml flask, under nitrogen protection, (755mg 2.82mmol) is dissolved in the methyl alcohol (10ml) with 2-fluoro-5-bromine bromobenzyl.(0.99ml, 14.1mmol), mixture stirred about 3 hours at ambient temperature to add methylamine.Follow the tracks of reaction process with thin-layer chromatography.Boil off solution.Residue distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is used the liquid chromatography purifying again.Output: 0.435g.NMR conforms to the structure of the title compound of expection.
The preparation of N-methyl-3-(2-fluoro-5-bromo-benzyloxy-) propylamine
In the flask of 15ml, under nitrogen protection, with N, (351mg 1.21mmol) is dissolved in ethylene dichloride (3.5ml) to N-dimethyl-3-(2-fluoro-5-bromo-benzyloxy-) propylamine.(0.78mg, 7.26mmol), the mixture heating up that obtains refluxed 18 hours to add ACECl in this solution.Reaction mixture is chilled to envrionment temperature, the pressure reducing and steaming solvent.Residue dissolves in methyl alcohol, refluxes 1.5 hours.This methanol solution distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is used the liquid chromatography purifying again.NMR conforms to the structure of the title intermediate of expection.
Preparation
N, the preparation of N-dimethyl-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
In the flask of 50ml, under nitrogen protection, (967mg 3.61mmol) is dissolved in N, in the dinethylformamide (3.5ml) with 2-fluoro-5-bromine bromobenzyl.Add in this solution sodium hydride (60%, 245mg, 6.14mmol), the mixture that obtains stirred 10 minutes.(633mg, 5.41mmol), the mixture that obtains stirred 6 hours to add 4-(N, N-dimethylamino) butanols in the reaction mixture.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M potash water and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.Title intermediate liquid chromatography purifying.Output: 260mg (24%).NMR conforms to the structure of the title compound of expection.
The preparation of preparation N-methyl-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
In the 10ml flask, under nitrogen protection, with N, (215mg 0.707mmol) is dissolved in the ethylene dichloride (2.0ml) N-dimethyl-4-(2-fluoro-5-bromo-benzyloxy-) butylamine.(0.305ml, 2.83mmol), the mixture heating up that obtains refluxes to add ACECl in this solution.Reaction mixture refluxed 4 hours.Follow the tracks of reaction process with thin-layer chromatography.Mixture refluxed 16 hours again.The pressure reducing and steaming solvent, residue dissolves in the methyl alcohol.This methanol solution refluxed 1.5 hours, boiled off solvent.Residue distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is used the liquid chromatography purifying again.Output: 108mg.NMR conforms to the structure of the title compound of expection.
The preparation of preparation chloro 5-(2-fluoro-5-bromo-benzyloxy-) pentane
In the 50ml flask, under nitrogen protection, (2.139g 10.4mmol) dissolves in N, in the dinethylformamide (25ml) with 2-fluoro-5-bromobenzyl alcohol.Add in this solution sodium hydride (60%, 625mg, 15.6mmol), the mixture that obtains stirred 20 minutes.Add bromo 5-chloropentane in this reaction mixture, the mixture that obtains stirred 2 hours in envrionment temperature.Follow the tracks of reaction process with thin-layer chromatography.(3.127g, 20.9mmol), reaction mixture stirred 3 hours at ambient temperature to add sodium iodide.Reaction mixture dilutes with ether, with saturated common salt washing 7 times.The pressure reducing and steaming solvent.Title intermediate recycle silicon glue purification.Output: 1.82g (56%).NMR conforms to the structure of the title compound of expection.
Preparation N, the preparation of N-dimethyl-5-(2-fluoro-5-bromo-benzyloxy-) amylamine
In a pipe that can seal, under nitrogen protection, (0.380g 1.23mmol) is dissolved in N, in the dinethylformamide (5ml) with chloro 5-(2-fluoro-5-bromo-benzyloxy-) pentane.(55mg, 0.368mmol), the mixture that obtains is chilled to-78 ℃ and adds dimethylamine (condensation under anhydrous condition in advance) in this reaction mixture and with channel closure to add sodium iodide in this solution.Mixture is warming up to 85 ℃, stirs 8 hours.Mixture is chilled to envrionment temperature, restir 12 hours.In this mixture, lead to 15 minutes nitrogen so that remove excessive dimethylamine with the form of bubbling.Reaction mixture distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying, removal of solvent under reduced pressure.The silica gel repurity of title intermediate.
Preparation
The preparation of N-methyl-5-(2-fluoro-5-bromo-benzyloxy-) amylamine
In the flask of 25ml, under nitrogen protection, with N, (696mg 1.87mmol) is dissolved in methylene dichloride (6.0ml) to N-dimethyl-5-(2-fluoro-5-bromo-benzyloxy-) amylamine.(0.305ml, 2.83mmol), the mixture heating up that obtains refluxed 20 hours to add ACECl in this solution.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture refluxed 16 hours again.The pressure reducing and steaming solvent, residue distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is used the liquid chromatography purifying again.Output: 248mg.NMR conforms to the structure of the title intermediate of expection.Ultimate analysis C
13H
19BrFNO: theoretical value: C, 51.33; H, 6.30; N, 4.60. measured value: C, 51.06; H, 6.12; N, 4.49.
The preparation of preparation 1-(2-fluoro-5-bromo-benzyloxy-) hexane
In the flask of 100ml, under nitrogen protection, (1.44ml 11.5mmol) is dissolved in N, dinethylformamide (35ml) with n-hexyl alcohol.Add in this solution sodium hydride (60%, 521mg, 13.0mmol), the mixture that obtains stirred 10 minutes.(2.054,7.67mmol), the mixture that obtains stirred 6 hours at ambient temperature to add 2-fluoro-5-bromine bromobenzyl in the reaction mixture.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M wet chemical/saturated aqueous common salt (1: 1) and ether.Organic layer is washed 6 times with saturated common salt.The organic layer anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is used the liquid chromatography purifying again.Output: 1.32g.NMR conforms to the structure of the title intermediate of expection.
The preparation of preparation 1-(tertbutyloxycarbonyl)-3-(2-(2-fluoro-5-bromo-benzyloxy-) ethyl) piperidines
In the round-bottomed flask of 25ml, (1.011g 3.46mmol) is dissolved in N, dinethylformamide (9ml) with bromo 2-(1-(tertbutyloxycarbonyl) piperidines-3-yl) ethane.(1.037g, 6.92mmol), the mixture that obtains stirred under envrionment temperature 10 minutes to add sodium iodide.Add then 2-fluoro-5-bromobenzyl alcohol (0.852g, 4.15mmol) and sodium hydride (60%, 208mg, 5.19mmol), the mixture that obtains begins to spume and heat release.Solution cooling and solid after 30 minutes.Add 3ml N, the dinethylformamide material is a muddy, stirs 3 hours.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between saturated aqueous common salt and ether.Organic layer is used anhydrous sodium sulphate sodium sulfate with saturated common salt washing 6 times.The title product of expectation is used the liquid chromatography purifying again.Output: 0.540g.NMR conforms to the structure of the title compound of expection.
The preparation of preparation 3-(2-(2-fluoro-5-bromo-benzyloxy-) ethyl) piperidines
Under nitrogen protection, in 1 ml round-bottomed flask, 1-(tertbutyloxycarbonyl)-3-(2-(2-fluoro-5-bromo-benzyloxy-) ethyl) piperidines (0.495g) is dissolved in methylene dichloride (4ml).Solution is chilled to 0 ℃, slowly drips trifluoroacetic acid (1ml) inward.The mixture that obtains stirred 30 minutes at ambient temperature.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The residue that obtains directly uses.Output: 240mg.NMR conforms to the structure of the title compound of expection.
The preparation of preparation 1-methylol-2-(2-(2-fluoro-5-bromo-benzyloxy-) methyl) cyclopropane
In the round-bottomed flask of 100ml, with 1, (398mg 3.90mmol) is dissolved in N to 2-two (methylol) cyclopropane, in the dinethylformamide (15ml).Add sodium hydride (60%, 171mg, 4.29mmol), the mixture that obtains stirred 15 minutes at 0 ℃, stirred at ambient temperature then 15 minutes.Reaction soln is chilled to 0 ℃, adds 2-fluoro-5-bromine bromobenzyl (348mg, N 1.30mmol), the solution of dinethylformamide.The mixture that obtains stirred 1.5 hours for 0 ℃, stirred at ambient temperature 30 minutes, followed the tracks of reaction process with thin-layer chromatography.Reaction mixture is used anhydrous sodium sulfate drying then saturated common salt washing 7 times.The title product of expectation is used the liquid chromatography purifying again.Output: 0.240g (21%).NMR conforms to the structure of the title compound of expection.
The preparation of preparation 1-brooethyl-2-(2-(2-fluoro-5-bromo-benzyloxy-) methyl) cyclopropane
In the flask of 50ml, under nitrogen protection, (420mg 1.45mmol) is dissolved in the ether (10ml) cyclopropane with 1-methylol-2-(2-(2-fluoro-5-bromo-benzyloxy-) methyl).Reaction mixture with triphenylphosphine (495mg, 1.89mmol) and carbon tetrabromide (626mg, 1.89mmol) processing, stirred at ambient temperature 17 hours.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture is handled with 0.19g triphenylphosphine and 0.241g carbon tetrabromide again.Restir is after 4 hours at ambient temperature, the pressure reducing and steaming solvent.Residue gets the title intermediate with the liquid chromatography purifying again.Output: 0.389g (76%) is limpid oily matter.
The preparation of preparation 1-((N-methylamino-) methyl)-2-(2-(2-fluoro-5-bromo-benzyloxy-) methyl) cyclopropane
Under nitrogen protection, in the 100ml flask, (344mg 0.977mmol) is dissolved in anhydrous tetrahydro furan (5ml) to cyclopropane with 1-brooethyl-2-(2-(2-fluoro-5-bromo-benzyloxy-) methyl).(tetrahydrofuran solution of 2M, 1.9ml 3.91mmol) handle reaction mixture with methylamine.The mixture that obtains stirs at ambient temperature and adds methylamine (2ml) after 1 hour again.The mixture heating up that obtains refluxed 4 hours.Follow the tracks of the reactant process with thin-layer chromatography.Reaction mixture distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The title intermediate is used the liquid chromatography purifying again.Output: 0.131g (44%) is glassy yellow oily matter.NMR conforms to the title intermediate structure of expection.
The preparation of preparation cis 4-(2-fluoro-5-bromo-benzyloxy-) but-2-ene-1-alcohol
Under nitrogen protection, in the 500ml flask, with 1, (6.13ml 74.5mmol) dissolves in N to 4-dihydroxyl but-2-ene, dinethylformamide (150ml).The adding sodium hydride (60%, 2.98g, 74.5mmol), the mixture that obtains stirred 30 minutes at ambient temperature.Reaction mixture is chilled to 0 ℃, and dropping 2-fluoro-bromine bromobenzyl (3.99g, 149mmol).The mixture that obtains is warming up to envrionment temperature, stirs 4 hours.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic phase, anhydrous sodium sulfate drying.The title intermediate and the liquid chromatography purifying of expectation.Output: 2.145g (61%) is limpid oily matter.NMR conforms to the title intermediate structure of expectation with MS.
The preparation of preparation cis 4-(2-fluoro-5-bromo-benzyloxy-) but-2-ene base bromine
Under nitrogen protection, in the 100ml round-bottomed flask, (2.145g 7.80mmol) is dissolved in ether to but-2-ene-1-alcohol with 4-(2-fluoro-5-bromo-benzyloxy-).Add earlier in the reaction mixture triphenylphosphine (2.66g, 10.1mmol), after add carbon tetrabromide (3.36g, 10.1mmol).The mixture that obtains stirred 6 hours at ambient temperature, and the adularescent precipitation generates in the stirring process.Follow the tracks of reaction process with thin-layer chromatography.Reacting liquid filtering gets thick oily matter after the filtrate evaporation.The title intermediate of expectation is used the liquid chromatography purifying again.Output: 2.16g (83%).NMR conforms to the structure of the title compound of expection with MS.
The preparation of preparation cis N-methyl-4-(2-fluoro-5-bromo-benzyloxy-) but-2-ene base amine
In the 250ml flask, (1.968g 5.89mmol) is dissolved in anhydrous tetrahydro furan (40ml) with 4-(2-fluoro-5-bromo-benzyloxy-) but-2-ene base bromine.(29.5ml, 5.89mmol), the mixture that obtains stirred 5 hours at ambient temperature once to add methylamine in this solution.Follow the tracks of reaction process with thin-layer chromatography.Pressure reducing and steaming solvent, residue dissolve in the 1M wet chemical, use dichloromethane extraction 2 times.Merge organic layer, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the title intermediate of expectation is used the liquid chromatography purifying again.Output: 1.199g (70%).NMR conforms to the structure of the title intermediate of expection with MS.
The preparation of preparation N-(tertbutyloxycarbonyl)-4-(2-fluoro-5-bromo-benzyloxy-) butylamine
Under the nitrogen protection, in the 25ml flask, 4-(t-butoxycarbonyl amino) butanols is dissolved in tetrahydrofuran (THF) (15ml).The solution that obtains is chilled to-40 ℃, slowly add potassium tert.-butoxide (tetrahydrofuran solution of 1M, 2.14ml, 2.14mmol).The mixture that obtains stirred 30 minutes in-40 ℃.(521mg is 1.94mmol) with the solution of tetrahydrofuran (THF) (3.5ml) to drip 2-fluoro-5-bromine bromobenzyl in this reaction mixture.The mixture that obtains slowly is warming up to 0 ℃, and stirs 2 hours at 0 ℃.Follow the tracks of reaction process with thin-layer chromatography.Reaction mixture distributes between 1M wet chemical and methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The intermediate of expectation is used the liquid chromatography purifying again.Output: 335mg (46%) is yellow oil.Ultimate analysis C
16H
23BrFNO
3: theoretical value: C, 51.07; H, 6.16; N, 3.72. measured value: C, 51.18; H, 6.18; N, 3.80.
The preparation of preparation 4-(2-fluoro-5-bromo-benzyloxy-) butylamine
Under nitrogen protection, in the 250ml flask, N-(tertbutyloxycarbonyl)-4-(2-fluoro-5-bromo-benzyloxy-) butylamine (3.5g) is dissolved in the methylene dichloride (60ml).In this solution, add trifluoroacetic acid (15ml) down at 0 ℃.The mixture that obtains stirred 30 minutes at 0 ℃, stirred at ambient temperature 15 minutes.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture distributes between 1M wet chemical methylene dichloride.The water layer dichloromethane extraction.Merge organic layer, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent.The intermediate of expectation is used the liquid chromatography purifying again.Output: 1.82g.NMR conforms to the structure of the title intermediate of expectation.
The preparation of preparation 4-Methyl-1H-indole-2-carboxylic acid
Under argon shield, (0.91g 6.96mmol) is dissolved in 1 2ml tetrahydrofuran (THF) with the 4-skatole.The solution that obtains cools off in dry ice/acetone batch.(7.17mmol), the mixture that obtains stirred 50 minutes for the hexane solution of 1.6M, 4.48ml to add n-Butyl Lithium in this solution carefully.Bubbling can 20 minutes carbonic acid gas in the 26ml tetrahydrofuran (THF) in dry ice/acetone batch.Cold carbonic acid gas/tetrahydrofuran (THF) sleeve pipe imports in the organolithium solution.Can carbonic acid gas in the reaction mixture, the mixture that obtains stirred on dry ice/acetone batch 30 minutes.Reaction mixture is stirring at room 10 minutes then, and continuing simultaneously can carbonic acid gas.Stop the energy carbonic acid gas, reaction mixture stirring at room 90 minutes.
The pressure reducing and steaming solvent adds argon gas in reaction vessel, use the drip washing of 5ml tetrahydrofuran (THF) then.The pressure reducing and steaming solvent.Brown solid keeps in Dark Place in 4 ℃ under argon shield and spends the night.
Residue is dissolved in the 12ml temperature tetrahydrofuran (THF), and the solution that obtains cools off in dry ice/acetone batch.(pentane solution of 1.7M, 4.22ml 7.17mmol), last 15 minutes to add tert-butyl lithium solution carefully in this solution.The mixture that obtains stirred on dry ice/acetone batch about 70 minutes.In another container, toward using logical carbonic acid gas in the dry ice/acetone batch refrigerative 26ml tetrahydrofuran (THF).Carbonic acid gas/tetrahydrofuran solution is added in the organolithium solution through conduit.In reaction mixture, directly lead to 5 minutes carbonic acid gas again.Reaction mixture stirred on dry ice/acetone batch 1 hour, led to carbonic acid gas half an hour then in reaction mixture.In reaction mixture, add 1ml water, reaction mixture stirring at room 7 hours.
Reaction mixture inclines in saturated aqueous ammonium chloride, uses extracted with diethyl ether 2 times.Merge organic layer, removal of solvent under reduced pressure, the water recrystallization gets the intermediate of 0.17g expectation.Water layer adds 5% sulfuric acid acidation, stirring at room 1 hour.Filter collection solid, the title intermediate of 0.48g expectation again.NMR conforms to the structure of the title intermediate of expection.
The preparation of preparation 4-Methyl-1H-indole-2-carboxylate methyl ester
Under argon shield, (0.64g 3.65mmol) is dissolved in 20ml methyl alcohol with 4-Methyl-1H-indole-2-carboxylic acid.Add the vitriol oil (0.5ml), the mixture heating up that obtains refluxes and spends the night.Follow the tracks of reaction process with thin-layer chromatography.Some solvents of pressure reducing and steaming leach the crystallization that obtains.Solid is dissolved in ether, wash 2 times, with saturated common salt washing 1 time with saturated sodium bicarbonate solution.The organic layer anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent.Output: 0.38g (55.1%).
The preparation of preparation 2-(4-chlorobenzene oxygen methyl)-3-(2-acetyl bromide)-1H-indoles
Under nitrogen protection with bromoacetyl bromide (1.31ml, 0.015mol) be added to muddy 2-(4-chlorobenzene oxygen methyl)-1H-indoles (0.81g, 0.003mol) and Quilonum Retard (2.22g, 0.03mol) with ether (37.5ml) mixture in.The mixture heating up to 55 that obtains ℃, reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture distributes between ethanol and sodium hydrogen carbonate solution.Organic layer washes with water, and anhydrous sodium sulfate drying is used in the saturated common salt washing then.The pressure reducing and steaming solvent.Output: 1.34g.NMR conforms to the title compound structure of expection.
The preparation of preparation 2-(4-chlorobenzene oxygen methyl)-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
Toward 2-(4-chlorobenzene oxygen methyl)-3-(2-acetyl bromide)-1H-indoles (3mmol).Quilonum Retard (0.47g, 6mmol) with the muddy mixture of tetrahydrofuran (THF) (10ml) in add 4-(piperidines-1-yl) piperidines (1.01g, 6mmol).About 2.5 hours of the mixture stirring at room that obtains.Reaction process is followed the tracks of with thin-layer chromatography.Reaction mixture 1N hcl as extraction agent 2 times.The acid extraction liquid ethyl acetate extraction that merges with the yellow soda ash alkalization, is used ethyl acetate extraction 2 times then.Dichloromethane extraction 2 times.Merge organic layer, the pressure reducing and steaming solvent.With the crystalline product that obtains the 0.46g expectation after the ether grinding.
NMR, IR conform to the structure of the title compound of expection with UV.
High resolution FABMS C
28H
35ClN
3O
2:
Theoretical value: 480.2418
Measured value: 480.2411
FDMS?479(M+)
mp?144-145℃
The following examples are mainly pressed the route and the described preparation of method of front.In the following embodiments, only otherwise explain, NMR just conforms to the structure of the title compound of expecting.
Embodiment 1The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(amino) Methyl-1H-indole
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 300 (M+) ultimate analysis C
17H
17ClN
2O:
Theoretical value: C, 67.88; H, 5.70; N, 9.31.
Measured value: C, 67.64; H, 5.86; N, 9.24.
Embodiment 22-((4-chlorophenoxy) methyl)-1-methyl-3-((N, N-dimethylamino) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 328 (M+) ultimate analysis C
19H
21ClN
2O:
Theoretical value: C, 69.40; H, 6.44; N, 8.52.
Measured value: C, 69.18; H, 6.73; N, 8.54.
Embodiment 3The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N, N-diethylin) methyl)-1H-indole hydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 356 (M+) ultimate analysis C
21H
25ClN
2O
2HCl:
Theoretical value: C, 64.12; H, 6.66; N, 7.12.
Measured value: C, 64.30; H, 6.69; N, 7.18.
Embodiment 42-((4-chlorophenoxy) methyl)-1-methyl-3-((N, N, N-trimethylammonium ammonium) methyl)-1H-indoles iodide
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 343 (M+) ultimate analysis C
20H
24ClN
2OI:
Theoretical value: C, 51.03; H, 5.14; N, 5.95.
Measured value: C, 50.80; H, 4.93; N, 6.00.
Embodiment 5The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((benzyl amino) methyl)-1H-indole hydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 390 (M+) ultimate analysis C
24H
23ClN
2OHCl:
Theoretical value: C, 67.45; H, 5.66; N, 6.56.
Measured value: C, 67.63; H, 5.70; N, 6.60.
Embodiment 6The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-styroyl amino) methyl)-1H-indole hydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 404 (M+) ultimate analysis C
25H
25ClN
2OHCl:
Theoretical value: C, 68.03; H, 5.94; N, 6.35.
Measured value: C, 68.27; H, 5.99; N, 6.60.
Embodiment 7The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N-methyl-N-butyl amino) methyl)-1H-indoles
NMR (CD
3Cl) structure with the title compound of expecting conforms to.IR conforms to the structure of the title compound of expection.FDMS 370 (M+) ultimate analysis C
22H
27ClN
2O:
Theoretical value: C, 71.24; H, 7.34; N, 7.55.
Measured value: C, 71.19; H, 7.48; N, 7.39.
Embodiment 8The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N-methyl-N-benzylamino) methyl)-1H-indole hydrochloride
NMR, IR conform to the structure of the title compound of expection with UV.FDMS 404 (M+) ultimate analysis C
25H
25ClN
2OHCl:
Theoretical value: C, 68.03; H, 5.94; N, 6.35.
Measured value: C, 68.30; H, 5.92; N, 6.45.
Embodiment 9The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N-methyl-N-(3-N ', N '-dimethylamino-propyl) amino) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 400 (M+1) ultimate analysis C
23H
30ClN
3O:
Theoretical value: C, 69.07; H, 7.56; N, 10.51.
Measured value: C, 69.33; H, 7.34; N, 10.41.
Embodiment 10The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N-methyl-N-(3-(N ', N '-dimethylamino)-2,2-dimethyl propyl) amino) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 414 (M+1) ultimate analysis C
24H
32ClN
3O:
Theoretical value: C, 69.93; H, 7.79; N, 10.15.
Measured value: C, 69.67; H, 7.78; N, 10.17.
Embodiment 11The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((tetramethyleneimine-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 354 (M+) ultimate analysis C
21H
23ClN
2OHCl:
Theoretical value: C, 64.45; H, 6.18; N, 7.16.
Measured value: C, 64.66; H, 6.33; N, 7.03.
Embodiment 12The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, IR conform to the structure of the title compound of expection with UV.FDMS 368 (M+) ultimate analysis C
22H
25ClN
2OHCl:
Theoretical value: C, 65.19; H, 6.46; N, 6.91.
Measured value: C, 65.46; H, 6.52; N, 7.16.
Embodiment 13The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((3-methyl piperidine-1-yl) methyl)-1H-indoles
NMR (DOMS) conforms to the structure of the title compound of expection.FDMS 382 (M+) ultimate analysis C
23H
27ClN
2O:
Theoretical value: C, 72.14; H, 7.11; N, 7.32.
Measured value: C, 72.38; H, 7.22; N, 7.36.
Embodiment 14The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-methyl piperidine-1-yl) methyl)-1H-indoles
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 382 (M+) ultimate analysis C
23H
27ClN
2O:
Theoretical value: C, 72.14; H, 7.11; N, 7.32.
Measured value: C, 72.33; H, 7.22; N, 7.47.
Embodiment 15The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-(N, N-dimethylamino) piperidines-1-yl) methyl)-1H-indoles
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 411 (M+) ultimate analysis C
24H
30ClN
3O:
Theoretical value: C, 69.97; H, 7.34; N, 10.20.
Measured value: C, 69.74; H, 7.38; N, 10.13.
Embodiment 16The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-(piperidines-1-yl) piperidines-1-yl) methyl)-1H-indoles
FDMS 451 (M+) ultimate analysis C
27H
34ClN
3O:
Theoretical value: C, 71.74; H, 7.58; N, 9.30.
Measured value: C, 71.55; H, 7.44; N, 9.14.
Embodiment 17The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-acetamido-4-Phenylpiperidine-1-yl) methyl)-1H-indoles
FDMS 501 (M+) ultimate analysis C
30H
32ClN
3O
2:
Theoretical value: C, 71.77; H, 6.43; N, 8.37.
Measured value: C, 71.79; H, 6.61; N, 8.52.
Embodiment 18The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-methylpiperazine-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 383 (M+) ultimate analysis C
22H
26ClN
3O:
Theoretical value: C, 68.83; H, 6.83; N, 10.95.
Measured value: C, 68.80; H, 6.71; N, 10.95.
Embodiment 19The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-sec.-propyl piperazine-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 411 (M+) ultimate analysis C
24H
30ClN
3O:
Theoretical value: C, 69.97; H, 7.34; N, 10.20.
Measured value: C, 69.97; H, 7.36; N, 10.02.
Embodiment 20The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-phenylpiperazine-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FDMS 445 (M+) ultimate analysis C
27H
28ClN
3O:
Theoretical value: C, 72.71; H, 6.33; N, 9.42.
Measured value: C, 73.00; H, 6.41; N, 9.51.
Embodiment 21The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-benzyl diethylenediamine-1-yl) methyl)-1H-indole hydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 459 (M+) high resolution mass spectrum (FAB+) C
28H
31ClN
3O:
Theoretical value: 460.2155.
Measured value: 460.2145.
Embodiment 22The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-cyclohexyl piperazine-1-yl) methyl)-1H-indoles
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 451 (M+) ultimate analysis C
27H
34ClN
3O:
Theoretical value: C, 71.74; H, 7.58; N, 9.30.
Measured value: C, 71.48; H, 7.53; N, 9.26.
Embodiment 23The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(((4-pyrimidine-2-base) piperazine-1-yl) methyl)-1H-indoles
NMR (CD3Cl) conforms to the structure of the title compound of expection.FDMS 447 (M+) ultimate analysis C
25H
26ClN
5O:
Theoretical value: C, 67.03; H, 5.85; N, 15.63.
Measured value: C, 67.05; H, 5.93; N, 15.64.
Embodiment 24The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((morpholine-4-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FDMS 370 (M+) ultimate analysis C
21H
23ClN
2O
2:
Theoretical value: C, 68.01; H, 6.25; N, 7.55.
Measured value: C, 67.84; H, 6.65; N, 7.25.
Embodiment 25The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((tryptolin-2-yl) methyl)-1H-indoles
NMR (CD
3Cl) structure with the title compound of expecting conforms to.FDMS 455 (M+) ultimate analysis C
28H
26ClN
3O:
Theoretical value: C, 73.75; H, 5.75; N, 9.21.
Measured value: C, 73.99; H, 6.00; N, 9.03.
Embodiment 262-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(N-(1-methyl piperidine-4-yl)-N-methylamino-) methyl)-preparation of 1H-indoles dihydrochloride-hydrate
NMR conforms to the structure of the title compound of expection.Mp 196-197 ℃ FDMS 446 (M+) ultimate analysis C
24H
29Cl
2N
3O2HClH
2O:
Theoretical value: C, 53.64; H, 6.19; N, 7.82.
Measured value: C, 53.66; H, 5.92; N, 8.10.
Embodiment 27The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((4-(N, N-dimethylamino) piperidines-1-yl) methyl)-1H-indoles
NMR, IR conform to the structure of the title compound of expection with UV.Mp 105-106 ℃ FDMS 445 (M+) ultimate analysis C
24H
29Cl
2N
3O:
Theoretical value: C, 64.57; H, 6.55; N, 9.41.
Measured value: C, 64.27; H, 6.48; N, 9.49.
Embodiment 28The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((4-(piperidines-1-yl) piperidines-1-yl) methyl)-1H-indoles
NMR, IR conform to the structure of the title compound of expection with UV.106-107 ℃ of ultimate analysis C of FDMS 485 (M+) mp
27H
33Cl
2N
3O:
Theoretical value: C, 66.66; H, 6.84; N, 8.64.
Measured value: C, 66.92; H, 7.04; N, 8.74.
Embodiment 29The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-aminoethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 314 (M+) ultimate analysis (FAB) C
18H
20ClN
2O:
Theoretical value: 315.1264.
Measured value: 315.1246.
Embodiment 30The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((3-dimethylaminopropyl) amino) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 399 (M+) ultimate analysis C
23H
30ClN
3O:
Theoretical value: C, 69.07; H, 7.56; N, 10.51.
Measured value: C, 69.23; H, 7.79; N, 10.52.
Embodiment 31The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-N-(3-methylamino-propyl group) amino) ethyl)-1H-indoles dihydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 413 (M+) high resolution FAB-MS C24H33ClN3O:
Theoretical value: 414.2312.
Measured value: 414.2312.
Embodiment 32The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(piperidines-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 382 (M+) ultimate analysis C
23H
27ClN
2O:
Theoretical value: C, 72.14; H, 7.11; N, 7.32.
Measured value: C, 72.40; H, 7.26; N, 7.37.
Embodiment 33The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-methyl piperidine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 396 (M+) ultimate analysis C
24H
29ClN
2O:
Theoretical value: C, 72.62; H, 7.36; N, 7.06.
Measured value: C, 72.40; H, 7.35; N, 7.25.
Embodiment 34The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-benzyl piepridine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 472 (M+) ultimate analysis C
30H
33ClN
2O:
Theoretical value: C, 76.17; H, 7.03; N, 5.92.
Measured value: C, 76.37; H, 7.15; N, 5.85.
Embodiment 35The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(N, N-dimethylamino) piperidines-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution FAB-MS C
25H
33ClN
3O:
Theoretical value: 426.2312.
Measured value: 426.2297.
Embodiment 36The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) ethyl)-1H-indoles
FDMS 465 (M+) ultimate analysis C
28H
36ClN
3O:
Theoretical value: C, 72.16; H, 7.79; N, 9.02.
Measured value: C, 72.09; H, 7.69; N, 9.09.
Embodiment 37The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-cyclohexyl piperazine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 465 (M+) ultimate analysis C
28H
36ClN
3O:
Theoretical value: C, 72.16; H, 7.79; N, 9.02.
Measured value: C, 72.00; H, 7.88; N, 9.05.
Embodiment 382-((2,4 dichloro benzene oxygen base) the methyl)-1-methyl-3-(preparation of 2-(N-methyl-N-(1-methyl piperidine-4-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 459 (M+) ultimate analysis C
25H
31Cl
2N
3O:
Theoretical value: C, 65.21; H, 6.79; N, 9.13.
Measured value: C, 65.07; H, 6.85; N, 9.06.
Embodiment 39The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(4-(N, N-dimethylamino) piperidines-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
25H
32Cl
2N
3O:
Theoretical value: 460.1922.
Measured value: 460.1890.
Embodiment 40The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
28H
36Cl
2N
3O:
Theoretical value: 500.2235.
Measured value: 500.2215.
Embodiment 41The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(3-(4-(N, N-dimethylamino) piperidines-1-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 440 (M+) ultimate analysis C
26H
34ClN
3O:
Theoretical value: C, 70.97; H, 7.79; N, 9.55.
Measured value: C, 70.73; H, 7.65; N, 9.44.
Embodiment 42(RS)-preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(3-(piperidines-3-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
24H
30ClN
2O:
Theoretical value: 397.2047.
Measured value: 397.2055.
Embodiment 43The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((4-(dimethylamino) piperidines-1-yl) carbonyl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 453 (M+) ultimate analysis C
26H
32ClN
3O
2:
Theoretical value: C, 68.78; H, 7.10; N, 9.26.
Measured value: C, 68.74; H, 7.04; N, 9.38.
Embodiment 44The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((4-(dimethylamino) piperidines-1-yl) carbonyl) vinyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution FAB-MS C
26H
31ClN
3O
2:
Theoretical value: 452.2105.
Measured value: 452.2099.
Embodiment 46The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-((3-kharophen) tetramethyleneimine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 442 (M+) high resolution FAB-MS (M+1) C
24H
29ClN
3O
3:
Theoretical value: 442.1897.
Measured value: 442.1878.
Embodiment 47The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(piperidines-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 398 (M+) ultimate analysis C
23H
27ClN
2O
2:
Theoretical value: C, 69.25; H, 6.82; N, 7.02.
Measured value: C, 69.51; H, 6.86; N, 6.81.
Embodiment 48The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(4-methyl piperidine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 412 (M+) ultimate analysis C
24H
29ClN
2O
2:
Theoretical value: C, 69.80; H, 7.08; N, 6.78.
Measured value: C, 70.02; H, 7.13; N, 7.00.
Embodiment 49The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(4-benzyl piepridine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 488 (M+) ultimate analysis C
30H
33ClN
2O
2:
Theoretical value: C, 73.67; H, 6.80; N, 5.73.
Measured value: C, 73.52; H, 6.87; N, 5.58.
Embodiment 50The preparation of 2-((4-chlorophenoxy) methyl)-3-(1-hydroxyl-2-(4-dimethylamino piperidine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 442 (M+) ultimate analysis C
25H
32ClN
3O
2:
Theoretical value: C, 67.94; H, 7.30; N, 9.51.
Measured value: C, 67.73; H, 7.52; N, 9.75.
Embodiment 51The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(4-(piperidines-1-yl) piperidines-1-yl) ethyl)-1H-indoles dihydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 481 (M+1) ultimate analysis C
28H
35ClN
3O
22HCl
Theoretical value: C, 60.71; H, 6.73; N, 7.59; Cl, 19.20.
Measured value: C, 60.86; H, 6.90; N, 7.53; Cl, 19.19.
Embodiment 52The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(4-cyclohexyl piperazine-1-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 482 (M+1) ultimate analysis C
28H
36ClN
3O
2:
Theoretical value: C, 69.76; H, 7.53; N, 8.72.
Measured value: C, 70.06; H, 7.61; N, 8.46.
Embodiment 53The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-3-(piperidin-4-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS412 (M+) confirms that with chromatographic process this simplification compound has high purity.Ultimate analysis C
24H
29ClN
2O
2:
Theoretical value: C, 69.80; H, 7.08; N, 6.78
Measured value: C, 68.18; H, 7.87; N, 6.58
Embodiment 54The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(1-hydroxyl-2-(N-methyl-N-(1-methyl piperidine-4-yl) amino) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 475 (M+) ultimate analysis C
25H
31Cl
2N
3O
2:
Theoretical value: C, 63.02; H, 6.55; N, 8.82.
Measured value: C, 63.43; H, 6.88; N, 8.92.
Embodiment 55The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-2-(methoxycarbonyl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 373 (M+) ultimate analysis C
20H
20ClNO
4:
Theoretical value: C, 64.26; H, 5.39; N, 3.75.
Measured value: C, 64.55; H, 5.23; N, 3.79
Embodiment 56The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-carboxyl-1H-indoles
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 315 (M+) ultimate analysis C
17H
14ClNO
3:
Theoretical value: C, 64.67; H, 4.47; N, 4.44.
Measured value: C, 64.84; H, 4.60; N, 4.54.
Embodiment 57The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((3-dimethylamino-2,3-dimethyl propyl amino) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FAB 426 (M-1) ultimate analysis C
24H
30ClN
3O
2:
Theoretical value: C, 67.36; H, 7.07; N, 9.82.
Measured value: C, 67.58; H, 6.79; N, 9.64.
Embodiment 58The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N, two (3-dimethylaminopropyl) amino of N-) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 483 (M-1) FABMS 485 (M+1) ultimate analysis C
27H
37ClN
4O
2:
Theoretical value: C, 66.86; H, 7.69; N, 11.55.
Measured value: C, 66.91; H, 7.54; N, 11.69.
Embodiment 59The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N-methyl-N-(1-methyl piperidine-4-yl) amino) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 427 (M+2) ultimate analysis C
24H
28ClN
3O
2:
Theoretical value: C, 67.67; H, 6.63; N, 9.86.
Measured value: C, 67.38; H, 6.90; N, 9.94.
Embodiment 60The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-(piperidines-1-yl) piperidines-1-yl) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 465 (M+) ultimate analysis C
27H
32ClN
3O
2:
Theoretical value: C, 69.59; H, 6.92; N, 9.02.
Measured value: C, 69.47; H, 7.00; N, 9.22.
Embodiment 61(RS)-preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((piperidines-3-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 396 (M+) ultimate analysis C
23H
25ClN
2O
2:
Theoretical value: C, 69.60; H, 6.35; N, 7.06.
Measured value: C, 69.71; H, 6.28; N, 7.20.
Embodiment 62The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((1-trityl piperidin-4-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 638 (M+) ultimate analysis C
42H
39ClN
2O
2:
Theoretical value: C, 78.92; H, 6.15; N, 4.38.
Measured value: C, 78.73; H, 6.15; N, 4.25.
Embodiment 63The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((piperidin-4-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 397 (M+1) ultimate analysis C
23H
25ClN
2O
2:
Theoretical value: C, 69.60; H, 6.35; N, 7.06.
Measured value: C, 69.34; H, 6.43; N, 6.86.
Embodiment 64The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles dihydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 479 (M+) ultimate analysis C
28H
34ClN
3O
22HCl:
Theoretical value: C, 60.82; H, 6.56; N, 7.60.
Measured value: C, 60.67; H, 6.70; N, 7.38.
Embodiment 65The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-(piperidines-3-yl) ethyl) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 411 (M+1) ultimate analysis C
24H
27ClN
2O
2:
Theoretical value: C, 70.15; H, 6.67; N, 6.82.
Measured value: C, 70.38; H, 6.39; N, 7.02.
Embodiment 66The preparation of 2-((4-chlorobenzene chloro) methyl)-1-methyl-3-((2-(1-trityl piperidin-4-yl) ethyl) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.C
43H
41ClN
2O
2FDMS?652(M
+)。Chromatogram proof product is highly purified simplification compound.
Embodiment 67The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-(piperidin-4-yl) ethyl) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 411 (M+1) ultimate analysis: C
24H
27ClN
2O
2
Theoretical value: C, 70.15; H, 6.62; N, 6.82
Measured value: C, 69.87; H, 6.54; N, 6.79
Embodiment 68The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-(1-(3-((1-trityl piperidin-4-yl) propyl group) piperidin-4-yl)) ethyl) carbonyl)-1H-indoles
FDMS 779 (M+2) ultimate analysis C
51H
56ClN
3O:
Theoretical value: C, 78.69; H, 7.25; N, 5.40.
Measured value: C, 78.90; H, 7.34; N, 5.60.
Embodiment 69A2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-(1-(3-(piperidin-4-yl) propyl group) piperidin-4-yl)) ethyl) carbonyl)-preparation of 1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS?536(M+)
High resolution FAB (M+1) C
32H
43ClN
3O
2:
Theoretical value: 536.3044.
Measured value: 536.3044.
Embodiment 69B2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-(1-(3-(1-trityl piperidines-3-yl) propyl group) piperidin-4-yl)) ethyl) carbonyl)-preparation of 1H-indoles
FDMS 779 (M+2) ultimate analysis C
51H
56ClN
3O
2:
Theoretical value: C, 78.69; H, 7.25; N, 5.40.
Measured value: C, 78.92; H, 7.41; N, 5.27.
Embodiment 69CThe preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((2-(1-(3-(piperidines-3-yl) propyl group) piperidin-4-yl) ethyl) carbonyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 536 (M+2) ultimate analysis C
32H
42ClN
3O
2:
Theoretical value: C, 71.69; H, 7.90; N, 7.84.
Measured value: C, 71.45; H, 7.85; N, 7.61.
Embodiment 70(RS)-preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-((4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution FAB-MS (M+) C
35H
48ClN
4O
2:
Theoretical value: 591.3466.
Measured value: 591.3476.
Embodiment 70A(S)-preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-((4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FABMS 591.3476 (M+) ultimate analysis C
35H
47ClN
4O
2:
Theoretical value: C, 71.10; H, 8.01; N, 9.48.
Measured value: C, 70.82; H, 8.14; N, 9.23.
Embodiment 70B(R)-preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-((4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
35H
48ClN
4O
2:
Theoretical value: 591.3466
Measured value: 591.3458
Embodiment 71The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidin-4-yl) propyl group)-3-((4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.Ultimate analysis C
35H
48ClN
4O
2:
Theoretical value: 591.3466.
Measured value: 591.3464.
Embodiment 72(RS)-preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-(3-(piperidines-3-yl) propionyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
31H
41ClN
3O
2:
Theoretical value: 522.2887.
Measured value: 522.2905.
Embodiment 73The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidin-4-yl) propyl group)-3-(3-(piperidines-3-yl) propionyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
31H
41ClN
3O
2(M+1):
Theoretical value: 522.2887.
Measured value: 522.2910.
Embodiment 74The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-(3-(piperidin-4-yl) propionyl)-1H-indoles
IR and NMR (CDCl
3) conform to the structure of the title compound of expecting.FABMS 522 (M+1) ultimate analysis C
31H
40ClN
3O
2:
Theoretical value: C, 71.31; H, 7.72; N, 8.05.
Measured value: C, 71.04; H, 7.89; N, 7.78.
Embodiment 75The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidin-4-yl) propyl group)-3-(3-(piperidin-4-yl) propionyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 522 (M+1) ultimate analysis C
31H
40ClN
3O
2:
Theoretical value: C, 71.31; H, 7.72; N, 8.05.
Analytical value: C, 71.10; H, 7.66; N, 7.97.
Embodiment 76The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(((3-(dimethylamino) propyl group amino) carbonyl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 413 (M+) ultimate analysis C
23H
28ClN
3O
2:
Theoretical value: C, 66.74; H, 6.82; N, 10.15.
Analytical value: C, 66.89; H, 6.96; N, 10.11.
Embodiment 77The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(1-hydroxyl-1-((4-(piperidines-1-yl) piperidines-1-yl) carbonyl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 495 (M+) ultimate analysis C
28H
34ClN
3O
3:
Theoretical value: C, 67.80; H, 6.91; N, 8.47.
Analytical value: C, 67.86; H, 6.90; N, 8.45.
Embodiment 78The preparation of 2-(1-methyl-2-((4-chlorophenoxy) methyl) indol-3-yl) oxoethanoic acid
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 343 (M+) ultimate analysis C
18H
14ClNO
4:
Theoretical value: C, 62.89; H, 4.11; N, 4.07.
Analytical value: C, 63.15; H, 4.37; N, 3.92.
Embodiment 79The preparation of 2-(1-methyl-2-((4-chlorophenoxy) methyl) indol-3-yl) glyoxalic acid methylester
NMR (CDCl
3) conform to the structure of the title compound of expection with IR.High resolution FAB (M+1) C
19H
17ClNO
4:
Theoretical value: 358.0846.
Analytical value: 358.0818.
Embodiment 80The preparation of 2-(1-methyl-2-((4-chlorophenoxy) methyl) indol-3-yl) oxoethanoic acid phenyl ester
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 419 (M+) ultimate analysis C
24H
18ClNO
4:
Theoretical value: C, 68.66; H, 4.32; N, 3.34.
Analytical value: C, 68.90; H, 4.49; N, 3.33.
Embodiment 81The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-amino-1,2-ethanedioyl)-1H-indoles
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 342 (M+) ultimate analysis C
18H
15ClN
2O
3:
Theoretical value: C, 63.07; H, 4.41; N, 8.17.
Measured value: C, 63.36; H, 4.50; N, 8.18.
Embodiment 822-(4-chlorophenoxy) methyl)-preparation of 1-methyl-3-(2-methylamino--1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 357 (M+1) ultimate analysis C
19H
17ClN
2O
3:
Theoretical value: C, 63.96; H, 4.80; N, 7.85.
Measured value: C, 63.97; H, 4.83; N, 7.82.
Embodiment 83The preparation of 2-(1-methyl-2-((4-chlorophenoxy) methyl) indol-3-yl) oxoethanoic acid 3-dimethylamino propyl ester
NMR (CDCl
3) conform to the structure of the title compound of expecting.C
23H
25ClN
2O
4：FAB?429(M+)。With chromatographic process proof product is highly purified simplification compound.
Embodiment 84The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(2-(dimethylamino) ethylamino)-1,2-ethanedioyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.IR conforms to the structure of the title compound of expection.FDMS 413 (M+) ultimate analysis C
22H
24ClN
3O
3HCl:
Theoretical value: C, 58.67; H, 5.59; N, 9.33.
Measured value: C, 58.38; H, 5.82; N, 9.48.
Embodiment 85The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(3-(dimethylamino) propyl group amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution FAB-MS (M+1) C
23H
27ClN
3O
3:
Theoretical value: 428.1741.
Measured value: 428.1738.
Embodiment 862-((4-chlorophenoxy) methyl)-1-methyl-3-(preparation of 2-(3-amino propyl amino-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 399 (M+) ultimate analysis C
21H
22ClN
3O
3:
Theoretical value: C, 63.08; H, 5.55; N, 10.51.
Measured value: C, 69.53; H, 6.18; N, the 11.70. chromatographic process confirms that this product is highly purified simplification compound.
Embodiment 87The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(3-(t-butoxycarbonyl amino) propyl group amino)-1,2 ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.175-176 ℃ of ultimate analysis C of FDMS 499 (M+) mp
26H
30ClN
3O
5:
Theoretical value: C, 62.46; H, 6.05; N, 8.40.
Measured value: C, 62.19; H, 6.08; N, 8.27.
Embodiment 88The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(2,2-dimethyl-3-(dimethylamino) propyl group amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 455 (M+) ultimate analysis C
25H
30ClN
3O
3:
Theoretical value: C, 65.85; H, 6.63; N, 9.22.
Measured value: C, 65.62; H, 6.76; N, 9.12.
Embodiment 89The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(6-(dimethylamino) hexyl amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the structure of the title compound of expection.High resolving power FAB-MS (M+1) C
27H
33ClN
3O
3:
Theoretical value: 470.2210
Measured value: 470.2196
Embodiment 90The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-2-(dimethylamino) ethylamino)-1,2-ethanedioyl)-1H-indoles
NMR, UV conforms to the structure of the title compound of expection with IR.142-143 ℃ of FDMS 427 (M+) .mp. ultimate analysis C
23H
26ClN
3O
3:
Theoretical value: C, 64.56; H, 6.12; N, 9.82.
Measured value: C, 64.82; H, 6.32; N, 9.89.
Embodiment 91The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-3-(dimethylamino) propyl group amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR learns structure with the title compound of expection and conforms to.High resolving power FAB-MS (M+1) C
24H
29ClN
30
3:
Theoretical value: 442.1897
Measured value: 442.1904
Embodiment 92The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-3-(dimethylamino) propyl group amino)-1,2-ethanedioyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR learns structure with the title compound of expection and conforms to.High resolving power FAB-MS (M+1) C
24H
29ClN
3O
3:
Theoretical value: 442.1897.
Measured value: 442.1895.
Embodiment 93The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(two (3-(dimethylamino) propyl group) amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 512 (M+) ultimate analysis C
28H
37ClN
4O
3:
Theoretical value: C, 65.55; H, 7.27; N, 10.92.
Measured value: C, 65.85; H, 7.46; N, 11.04.
Embodiment 94The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-benzyl-3-(dimethylamino) propyl group amino)-1,2-ethanedioyl)-1H-indoles
NMR, UV conforms to the structure of the title compound of expection with IR.FDMS 517 (M+) ultimate analysis C
30H
32ClN
3O
3:
Theoretical value: C, 69.55; H, 6.23; N, 8.11.
Measured value: C, 69.82; H, 6.31; N, 8.13.
Embodiment 95The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-3-(1-(tertbutyloxycarbonyl) piperidines-3-yl) propyl group amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 581 (M+) ultimate analysis C
32H
40ClN
3O
5:
Theoretical value: C, 66.02; H, 6.93; N, 7.22.
Measured value: C, 65.91; H, 7.14; N, 7.08.
Embodiment 962-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(1-methyl piperidine-3-yl) amino)-1,2-ethanedioyl)-preparation of 1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the structure of the title compound of expection.FDMS 439 (M+) ultimate analysis C
24H
26ClN
3O
3:
Theoretical value: C, 65.52; H, 5.96; N, 9.55.
Measured value: C, 65.80; H, 5.96; N, 9.56.
Embodiment 97The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-(1-methylpyrrolidin-3-yl) amino)-1,2-ethanedioyl)-1H-indoles
NMR, UV conforms to the structure of the title compound of expection with IR.FDMS 439 (M+) ultimate analysis C
24H
26ClN
3O
3:
Theoretical value: C, 65.52; H, 5.96; N, 9.55.
Measured value: C, 65.54; H, 6.03; N, 9.69.
Embodiment 98The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(N-methyl-(1-methyl piperidine-3-yl) amino)-1,2-ethanedioyl)-1H-indoles
IR conforms to the structure of the title compound of expection.FDMS 453 (M+) ultimate analysis C
25H
28ClN
3O
3:
Theoretical value: C, 66.14; H, 6.22; N, 9.26.
Measured value: C, 65.86; H, 6.17; N, 9.29.
Embodiment 99The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((quinoline rather encircles-the 3-yl) amino)-1,2-ethanedioyl)-1H-indoles
NMR, UV conforms to the structure of the title compound of expection with IR.204-205 ℃ of FDMS 451 (M+) .mp. ultimate analysis C
25H
26ClN
3O
3:
Theoretical value: C, 66.44; H, 5.80; N, 9.30.
Measured value: C, 66.37; H, 5.88; N, 9.37.
Embodiment 100The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 410 (M+) ultimate analysis C
23H
23ClN
2O
3:
Theoretical value: C, 67.22; H, 5.64; N, 6.82.
Measured value: C, 67.50; H, 5.81; N, 6.63.
Embodiment 1012-((4-chlorophenoxy) the methyl)-1-methyl-3-(preparation of 2-(2-(dimethylaminomethyl) cyclohexyl amino-1,2-ethanedioyl)-1H-indole hydrochloride
NMR (DMSO) conforms to the structure of the title compound of expection.FDMS 481 (M+) ultimate analysis C
27H
32ClN
3O
3HCl:
Theoretical value: C, 62.55; H, 6.42; N, 8.10.
Measured value: C, 62.56; H, 6.44; N, 8.06.
Embodiment 102The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-methyl piperidine-1-yl) 1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the structure of the title compound of expection.FDMS 424 (M+) ultimate analysis C
24H
25ClN
2O
3:
Theoretical value: C, 67.84; H, 5.93; N, 6.59.
Measured value: C, 68.04; H, 5.85; N, 6.74.
Embodiment 103The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-benzyl piepridine-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the structure of the title compound of expection.FDMS 500 (M+) ultimate analysis C
30H
29ClN
2O
3:
Theoretical value: C, 71.92; H, 5.83; N, 5.59.
Measured value: C, 71.69; H, 5.74; N, 5.38.
Embodiment 104The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-aminocarboxyl piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR, UV conforms to the structure of the title compound of expection with IR.220-221 ℃ of ultimate analysis C of FDMS 453 (M+) fusing point
24H
24ClN
3O
4:
Theoretical value: C, 63.50; H, 5.33; N, 9.26.
Measured value: C, 63.45; H, 5.50; N, 9.18.
Embodiment 105The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-dimethylamino phenylpiperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolving power FAB MS (M+1) C
25H
29ClN
3O
3:
Theoretical value: 454.1897.
Measured value: 454.1882.
Embodiment 106The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expection with IR.FDMS 493 (M+) ultimate analysis C
28H
32ClN
3O
3:
Theoretical value: C, 68.07; H, 6.53; N, 8.51.
Measured value: C, 67.97; H, 6.66; N, 8.27.
Embodiment 107The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(3-aminocarboxyl piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conforms to the structure of the title compound of expection with UV.229-230 ℃ of ultimate analysis C of FDMS 453 (M+) mp
24H
24ClN
3O
4:
Theoretical value: C, 63.50; H, 5.33; N, 9.26.
Measured value: C, 63.53; H, 5.44; N, 9.04.
Embodiment 108The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(piperazine-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.Fusing point: 168-169 ℃ of ultimate analysis C of FDMS 411 (M+)
22H
22ClN
3O
3:
Theoretical value: C, 64.15; H, 5.38; N, 10.20.
Measured value: C, 63.95; H, 5.36; N, 10.08.
Embodiment 109The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-sec.-propyl piperazine-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 453 (M+) ultimate analysis C
25H
28ClN
3O
3:
Theoretical value: C, 66.15; H, 6.22; N, 9.26.
Measured value: C, 65.94; H, 6.48; N, 8.97.
Embodiment 110The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(tertbutyloxycarbonyl) piperazine-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conforms to the structure of the title compound of expection with UV.Fusing point: 200-201 ℃ of ultimate analysis C of FDMS 511 (M+)
27H
30ClN
3O
5:
Theoretical value: C, 63.34; H, 5.91; N, 8.21.
Measured value: C, 63.10; H, 5.80; N, 7.98.
Embodiment 111The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-cyclohexyl piperazine-1-yl)-1,2-ethanedioyl)-1 H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the structure of the title compound of expection.FDMS 493 (M+) ultimate analysis C
28H
32ClN
3O
3:
Theoretical value: C, 68.07; H, 6.53; N, 8.50.
Measured value: C, 67.81; H, 6.60; N, 8.24.
Embodiment 112The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(2-dimethyl aminoethyl) piperazine-1-yl)-1,2-ethanedioyl)-1H-indoles dihydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the title compound institute structure of expection.FDMS 482 (M+) ultimate analysis C
26H
31ClN
4O
32HCl:
Theoretical value: C, 56.17; H, 5.98; N, 10.07.
Measured value: C, 56.47; H, 6.07; N, 10.05.
Embodiment 113The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(3-glycyl tetramethyleneimine-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
IR conforms to the structure of the title compound of expection.FDMS 453 (M+) ultimate analysis C
24H
24ClN
3O
4:
Theoretical value: C, 63.50; H, 5.33; N, 9.26.
Measured value: C, 63.75; H, 5.37; N, 9.21.
Embodiment 114The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(N-methyl-3-(dimethylamino) propyl group amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.
UV conforms to the structure of the title compound of expection.FDMS 475 (M+) ultimate analysis C
24H
27Cl
2N
3O
3:
Theoretical value: C, 60.51; H, 5.71; N, 8.82.
Measured value: C, 60.69; H, 5.80; N, 8.77.
Embodiment 115The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(N-methyl (1-methyl piperidine-4-yl) amino)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.C
25H
27ClN
3O
3: FDMS 487 (M+) chromatographic process proves that this product is highly purified simplification compound.
Embodiment 116The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(4-(N, N-dimethylamino) piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.UV conforms to the structure of the title compound of expection.FDMS 487,489 (M+) ultimate analysis C
25H
27Cl
2N
3O
3:
Theoretical value: C, 61.48; H, 5.57; N, 8.60.
Measured value: C, 61.75; H, 5.63; N, 8.59.
Embodiment 117The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-((4-piperidines-1-yl) piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 527,529 (M+) ultimate analysis C
28H
31Cl
2N
3O
3:
Theoretical value: C, 63.64; H, 5.91; N, 7.95.
Measured value: C, 63.82; H, 6.08; N, 7.85.
Embodiment 118The preparation of 2-((2-cyano group-4-bromine phenoxy group) methyl)-1-methyl-3-(2-(N-methyl-(3-dimethylaminopropyl) amino)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 511,513 (M+) ultimate analysis C
25H
27BrN
4O
30.5H
2O:
Theoretical value: C, 57.70; H, 5.42; N, 10.75.
Measured value: C, 57.56; H, 5.36; N, 10.60. high resolution mass spectrum C
25H
28BrN
4O
3:
Theoretical value: 511.1332.
Measured value: 511.1345.
Embodiment 119The preparation of 2-((2-cyano group-4-bromine phenoxy group) methyl)-1-methyl-3-(2-(N-methyl-(1-methyl piperidine-4-yl) amino)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 522,524 (M+) ultimate analysis C
26H
27BrN
4O
3:
Theoretical value: C, 59.66; H, 5.20; N, 10.70.
Measured value: C, 59.38; H, 5.24; N, 10.49.
Embodiment 120The preparation of 2-((2-cyano group-4-bromine phenoxy group) methyl)-1-methyl-3-(2-(4-dimethylamino piperidine-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 522,524 (M+) ultimate analysis C
26H
27BrN
4O
30.5H
2O:
Theoretical value: C, 58.65; H, 5.30; N, 10.52.
Measured value: C, 58.61; H, 5.21; N, 10.42. high resolution mass spectrum C
26H
28BrN
4O
3:
Theoretical value: 523.1345.
Measured value: 523.1365.
Embodiment 121The preparation of 2-((2-cyano group-4-bromine phenoxy group) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 563,565 (M+) ultimate analysis C
29H
31BrN
4O
3:
Theoretical value: C, 61.81; H, 5.54; N, 9.94.
Measured value: C, 61.56; H, 5.62; N, 9.91.
Embodiment 122The preparation of 2-((4-chlorophenoxy) methyl)-1-ethyl-3-(2-(4-dimethylamino phenylpiperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 467 ultimate analysis C
26H
30ClN
3O
3:
Theoretical value: C, 66.73; H, 6.46; N, 8.98.
Measured value: C, 66.88; H, 6.57; N, 8.90.
Embodiment 123The preparation of 2-((4-chlorophenoxy) methyl)-1-ethyl-3-(2-(N-methyl-(1-methyl piperidine-4-yl) amino)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 467 ultimate analysis C
26H
30ClN
3O
3:
Theoretical value: C, 66.73; H, 6.46; N, 8.98.
Measured value: C, 66.90; H, 6.70; N, 9.03.
Embodiment 124The preparation of 2-((4-chlorophenoxy) methyl)-1-benzyl-3-(2-(4-dimethylamino phenylpiperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 529 ultimate analysis C
31H
32ClN
3O
3:
Theoretical value: C, 70.24; H, 6.08; N, 7.93.
Measured value: C, 70.26; H, 6.18; N, 7.73.
Embodiment 125The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-piperidines-1-base-ethyl)-3-(2-(4-(piperidines-1-yl) piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution FAB-MS C
34H
44ClN
4O
5:
Theoretical value: 591.3102.
Measured value: 591.3100.
Embodiment 126The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-(piperidines-1-base-methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.Chromatographic process proves that this product is highly purified simplification compound.
Embodiment 127The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(1-methyl piperidine-3-yl) propyl group)-3-(piperidines-1-base-methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.Chromatographic process proves that this product is highly purified simplification compound.
Embodiment 128The preparation of 2-((4-chlorophenoxy) methyl)-1-ethyl-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with UV.Fusing point: 115-116 ℃ of ultimate analysis C of FDMS 425 (M+)
25H
32ClN
3O:
Theoretical value: C, 70.49; H, 7.57; N, 9.86.
Measured value: C, 70.70; H, 7.67; N, 9.80.
Embodiment 129The preparation of 2-((4-chlorophenoxy) methyl)-1-benzyl-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with UV.127-128 ℃ of ultimate analysis C of FDMS 488 (M+) fusing point
30H
34ClN
3O:
Theoretical value: C, 73.83; H, 7.02; N, 8.61.
Measured value: C, 73.77; H, 7.21; N, 8.66.
Embodiment 130The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-(piperidines-1-yl) ethyl)-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution FAB-MS for C
30H
42ClN
4O:
Theoretical value: 509.3047.
Measured value: 509.3018.
Embodiment 131The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-1-yl) propyl group)-3-((4-dimethylamino phenylpiperidines-1-yl)-methyl)-1H-indoles tri hydrochloride
NMR conforms to the structure of the title compound of expection with UV.240-242 ℃ of ultimate analysis C of FDMS 523 (M+1) fusing point
31H
43ClN
4O3HCl:
Theoretical value: C, 58.86; H, 7.33; N, 8.86.
Measured value: C, 58.66; H, 7.09; N, 8.77.
Embodiment 132The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.C
31H
43ClN
4O:FDMS 522 (M+) apportioning method proves that this product is highly purified simplification compound.
Embodiment 133The preparation of 2-((4-chlorophenoxy) methyl)-1-ethyl-3-((4-(piperidines-1-yl) piperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with UV.130-131 ℃ of ultimate analysis C of FDMS 465 (M+) fusing point
28H
36ClN
3O:
Theoretical value: C, 72.16; H, 7.79; N, 9.02.
Measured value: C, 72.12; H, 7.78; N, 8.86.
Embodiment 134The preparation of 2-((4-chlorophenoxy) methyl)-1-benzyl-3-((4-(piperidines-1-yl) piperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with UV.153-154 ℃ of ultimate analysis C of FDMS 527 (M+) fusing point
33H
38ClN
3O:
Theoretical value: C, 75.05; H, 7.25; N, 7.96.
Measured value: C, 75.25; H, 7.40; N, 8.08.
Embodiment 132The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-(piperidines-1-yl) ethyl)-3-((4-(piperidines-1-yl) piperidines-1-yl) methyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.102-103 ℃ of ultimate analysis C of FDMS 548 (M+) fusing point
33H
45ClN
4O:
Theoretical value: C, 72.17; H, 8.26; N, 10.20.
Measured value: C, 72.12; H, 8.31; N, 10.17.
Embodiment 136The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-(piperidines-1-yl) ethyl)-1H-indoles
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 368 (M+) FAB 369 (M+1) ultimate analysis C
22H
25ClN
2O:
Theoretical value: C, 71.63; H, 6.83; N, 7.59.
Measured value: C, 71.93; H, 7.28; N, the 7.22. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 137The preparation of 2-((4-chlorophenoxy) methyl)-1-(2-(piperidin-4-yl) ethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 368 (M+) ultimate analysis C
22H
25ClN
2O:
Theoretical value: C, 71.63; H, 6.83; N, 7.59
Measured value: C, 71.66; H, 6.86; N, 7.87.
Embodiment 138The preparation of 2-((thiophenyl) methyl)-1-(3-(piperidines-3-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 364 (M+) ultimate analysis C
23H
28N
2S:
Theoretical value: C, 75.78; H, 7.75; N, 7.69.
Measured value: C, 75.70; H, 7.73; N, 7.86.
Embodiment 139The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidines-3-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.Chromatographic process proves that this product is highly purified simplification compound.
Embodiment 140The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(methyl piperidine-3-yl) propyl group)-1H-indoles
The structure of the title compound of NMR and UV conforms to.Fusing point 97-98 ℃ of ultimate analysis C
24H
29ClN
2O:
Theoretical value: C, 72.62; H, 7.36; N, 7.06.
Measured value: C, 72.59; H, 7.48; N, 7.14.
Embodiment 141The preparation of 2-((4-chlorophenoxy) methyl)-1-(3-(piperidin-4-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.C
23H
27ClN
2O:FDMS 382 (M+) chromatographic process proves that this product is highly purified simplification compound.
Embodiment 142The preparation of 2-(2-(4-chloro-phenyl-) ethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 366 (M+) ultimate analysis C
23H
27ClN
2HCl:
Theoretical value: C, 68.48; H, 7.00; N, 6.94.
Measured value: C, 68.26; H, 6.87; N, 6.75.
Embodiment 143The preparation of 2-((4-chloro-phenyl-amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.169 ℃ of ultimate analysis C of FDMS 367 (M+) fusing point
22H
26ClN
3:
Theoretical value: C, 71.82; H, 7.12; N, 11.42.
Measured value: C, 71.60; H, 7.05; N, 11.46.
Embodiment 146The preparation of 2-((2,4 dichloro benzene base amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.147-148 ℃ of ultimate analysis C of FDMS 401,403 (M+) fusing point
22H
25Cl
2N
3:
Theoretical value: C, 65.67; H, 6.26; N, 10.44.
Measured value: C, 65.48; H, 6.30; N, 10.59.
Embodiment 147The preparation of 2-((4-chloro-phenyl-amino) methyl)-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.135 ℃ of ultimate analysis C of FDMS 353,354 (M+) fusing point
21H
24ClN
3:
Theoretical value: C, 71.27; H, 6.84; N, 11.87.
Measured value: C, 71.90; H, 7.17; N, 12.02.
Embodiment 148The preparation of 2-((2,4 dichloro benzene base amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.147-148 ℃ of ultimate analysis C of FDMS 401 (M+) fusing point
22H
25Cl
2N
3:
Theoretical value: C, 65.47; H, 6.26; N, 10.44.
Measured value: C, 65.48; H, 6.30; N, 10.59.
Embodiment 149The preparation of 2-((cyclohexyl amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.162-164 ℃ of ultimate analysis C of FDMS 339 (M+) fusing point
22H
33N
3:
Theoretical value: C, 77.83; H, 9.80; N, 12.38.
Measured value: C, 75.98; H, 9.11; N, 12.67. high resolution FAB-MS C
22H
34N
3:
Theoretical value: 340.2753.
Measured value: 340.2770.
Embodiment 150The preparation of 2-((cyclohexyl methyl amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles dihydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.159-161 ℃ of ultimate analysis C of FDMS 354,390 (M+) fusing point
23H
35N
32HCl:
Theoretical value: C, 64.78; H, 8.75; N, 9.85.
Measured value: C, 64.62; H, 8.82; N, 9.65.
Embodiment 151The preparation of 2-((naphthalene-2-base is amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.144 ℃ of ultimate analysis C of FDMS 383 (M+) fusing point
26H
29N
3:
Theoretical value: C, 81.42; H, 7.62; N, 10.96.
Measured value: C, 81.26; H, 7.49; N, 10.89.
Embodiment 152The preparation of 2-((N-ethanoyl-N-(cyclohexyl methyl) amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 395 (M+) ultimate analysis C
25H
37N
3OHCl:
Theoretical value: C, 69.50; H, 8.87; N, 9.73.
Measured value: C, 68.87; H, 9.29; N, 9.30. high resolution FAB-MS C
25H
38N
3O:
Theoretical value: 396.3015.
Measured value: 396.3020.
Embodiment 153The preparation of 2-((N-ethanoyl-N-(benzyl) amino) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.148-150 ℃ of ultimate analysis C of FDMS 389 (M+) fusing point
25H
31N
3OHCl:
Theoretical value: C, 70.49; H, 7.57; N, 9.86.
Measured value: C, 70.21; H, 7.40; N, 9.73.
Embodiment 154The preparation of 2-(((3-chloro-phenyl-) amino) carbonyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.137-138 ℃ of ultimate analysis C of FDMS 381,383 (M+) mp
22H
24ClN
3O:
Theoretical value: C, 69.19; H, 6.33; N, 11.00.
Measured value: C, 69.39; H, 6.39; N, 11.20.
Embodiment 155The preparation of 2-(((2,4 dichloro benzene base) amino) carbonyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.180-182 ℃ of ultimate analysis C of FDMS 417 (M+) fusing point
22H
23Cl
2N
3O:
Theoretical value: C, 63.47; H, 5.57; N, 10.09.
Measured value: C, 63.27; H, 5.65; N, 10.18.
Embodiment 156The preparation of 2-(((cyclohexyl) amino) carbonyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.180 ℃ of high resolution FAB-MS of FDMS 353 (M+) fusing point C
22H
32N
3O:
Theoretical value: 354.2545.
Measured value: 354.2543.
Embodiment 157The preparation of 2-(((cyclohexyl methyl) amino) carbonyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.126 ℃ of ultimate analysis C of fusing point
23H
33N
3O:
Theoretical value: C, 75.16; H, 9.05; N, 11.43.
Measured value: C, 75.09; H, 9.03; N, 11.25.
Embodiment 158The preparation of 2-(((naphthalene-2-yl) amino) carbonyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.187 ℃ of ultimate analysis C of FDMS 397 (M+) fusing point
26H
27N
3O:
Theoretical value: C, 78.56; H, 6.85; N, 10.57.
Measured value: C, 78.84; H, 7.02; N, 10.78.
Embodiment 159The preparation of 2-(phenoxymethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.225 ℃ of ultimate analysis C of FDMS 334 (M+) mp
22H
26N
2OHCl:
Theoretical value: C, 71.32; H, 7.34; N, 7.55.
Measured value: C, 71.45; H, 7.44; N, 7.79.
Embodiment 160The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.214 ℃ of ultimate analysis C of FDMS 368 (M+) fusing point
22H
25ClN
2OHCl:
Theoretical value: C, 65.32; H, 6.46; N, 6.91.
Measured value: C, 65.46; H, 6.52; N, 7.16.
Embodiment 161The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 368 (M+) ultimate analysis C
22H
25ClN
2O:
Theoretical value: C, 71.63; H, 6.83; N, 7.59.
Measured value: C, 68.39; H, 6.55; N, 6.16.
Embodiment 162The preparation of 2-((3-chlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.222 ℃ of ultimate analysis C of FDMS 368 (M+) fusing point
22H
25ClN
2OHCl:
Theoretical value: C, 65.19; H, 6.46; N, 6.91.
Measured value: C, 65.15; H, 6.55; N, 6.95.
Embodiment 163The preparation of 2-((2-chlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 369 (M+) ultimate analysis C
22H
25ClN
2OHCl:
Theoretical value: C, 65.19; H, 6.46; N, 6.91.
Measured value: C, 65.48; H, 6.65; N, 6.98.
Embodiment 164The preparation of 2-((4-fluorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 352 (M+) ultimate analysis C
22H
25FN
2OHCl:
Theoretical value: C, 67.94; H, 6.74; N, 7.20.
Measured value: C, 67.74; H, 6.77; N, 7.16.
Embodiment 165The preparation of 2-((3-fluorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 352 (M+) ultimate analysis C
22H
25FN
2OHCl:
Theoretical value: C, 67.94; H, 6.74; N, 7.20.
Measured value: C, 65.85; H, 6.51; N, the 6.68. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 166The preparation of 2-((2-fluorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 352 (M+) ultimate analysis C
22H
25FN
2OHCl:
Theoretical value: C, 67.94; H, 6.74; N, 7.20.
Measured value: C, 67.67; H, 6.63; N, 7.40.
Embodiment 167The preparation of 2-((4-4-trifluoromethylphenopendant) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
23H
25F
3N
2OHCl:
Theoretical value: C, 62.94; H, 5.97; N, 6.38.
Measured value: C, 63.51; H, 6.05; N, the 6.41. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 168The preparation of 2-((3-4-trifluoromethylphenopendant) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
23H
25F
3N
2OHCl:
Theoretical value: C, 62.94; H, 5.97; N, 6.38.
Measured value: C, 64.11; H, 6.07; N, the 6.42. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 169The preparation of 2-((2-4-trifluoromethylphenopendant) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
23H
25F
3N
2OHCl:
Theoretical value: C, 62.94; H, 5.97; N, 6.38.
Measured value: C, 62.89; H, 6.02; N, 6.37.
Embodiment 170The preparation of 2-((4-ethanoyl phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 376 (M+) ultimate analysis C
24H
28N
2OHCl:
Theoretical value: C, 69.80; H, 7.08; N, 6.78.
Measured value: C, 69.69; H, 7.27; N, 6.72.
Embodiment 171The preparation of 2-((3-ethanoyl phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 376 (M+) ultimate analysis C
24H
28N
2O
2HCl:
Theoretical value: C, 69.80; H, 7.08; N, 6.78.
Measured value: C, 69.91; H, 7.18; N, 6.81.
Embodiment 172The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with UV.FDMS 402 (M+) ultimate analysis C
22H
24Cl
2N
2O:
Theoretical value: C, 60.26; H, 5.75; N, 6.39.
Measured value: C, 61.61; H, 5.69; N, the 6.34. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 173The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
22H
24Cl
2N
2OHCl:
Theoretical value: C, 60.08; H, 5.73; N, 6.37.
Measured value: C, 60.31; H, 6.00; N, 6.62.
Embodiment 174The preparation of 2-((3, the 5-dichlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
22H
24Cl
2N
2OHCl:
Theoretical value: C, 60.08; H, 5.73; N, 6.37.
Measured value: C, 58.13; H, 5.25; N, the 5.99. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 175The preparation of 2-((2, the 5-dichlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
22H
24Cl
2N
2O:
Theoretical value: C, 65.51; H, 6.00; N, 6.95.
Measured value: C, 65.71; H, 6.00; N, 6.93.
Embodiment 176The hydrochloride preparation of 2-((2, the 6-dichlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
22H
24Cl
2N
2OHCl:
Theoretical value: C, 60.08; H, 5.73; N, 6.37.
Measured value: C, 59.79; H, 5.43; N, 6.11.
Embodiment 177The preparation of 2-((3, the 4-dichlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
22H
24Cl
2N
2OHCl:
Theoretical value: C, 60.08; H, 5.73; N, 6.37.
Measured value: C, 59.82; H, 5.72; N, 6.21.
Embodiment 178The preparation of 2-((2, the 3-dichlorophenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 402 (M+) ultimate analysis C
24H
24Cl
2N
2O:
Theoretical value: C, 65.51; H, 6.00; N, 6.95.
Measured value: C, 65.23; H, 5.96; N, 6.82.
Embodiment 179The preparation of 2-((4-phenyl phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 410 (M+) ultimate analysis C
28H
30N
2O:
Theoretical value: C, 81.91; H, 7.36; N, 6.82.
Measured value: C, 80.96; H, 7.34; N, the 6.73. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 180The preparation of 2-((3-phenyl phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 410 (M+) ultimate analysis C
28H
30N
2OHCl:
Theoretical value: C, 75.23; H, 6.99; N, 6.27.
Measured value: C, 74.74; H, 7.10; N, the 6.23. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 181The preparation of 2-((2-phenyl phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 410 (M+) ultimate analysis C
28H
30N
2OHCl:
Theoretical value: C, 75.23; H, 6.99; N, 6.27.
Measured value: C, 74.03; H, 7.10; N, the 6.35. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 182The preparation of 2-((4-methylphenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 348 (M+) ultimate analysis C
23H
28N
2OHCl:
Theoretical value: C, 71.76; H, 7.59; N, 7.28.
Measured value: C, 70.88; H, 7.70; N, the 7.32. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 183The preparation of 2-((3-methylphenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 348 (M+) ultimate analysis C
23H
28N
2OHCl:
Theoretical value: C, 71.76; H, 7.59; N, 7.28.
Measured value: C, 72.41; H, 7.78; N, the 7.29. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 184The preparation of 2-((2-methylphenoxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 348 (M+) ultimate analysis C
23H
28N
2OHCl:
Theoretical value: C, 71.76; H, 7.59; N, 7.28.
Measured value: C, 71.71; H, 7.54; N, 7.21.
Embodiment 185The preparation of 2-((4-methoxyl group phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 364 (M+) ultimate analysis C
23H
28N
2O
2HCl:
Theoretical value: C, 68.90; H, 7.29; N, 6.99.
Measured value: C, 68.68; H, 7.30; N, 7.12.
Embodiment 186The preparation of 2-((3-methoxyl group phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 364 (M+) ultimate analysis C
23H
28N
2O
2HCl:
Theoretical value: C, 68.90; H, 7.29; N, 6.99.
Measured value: C, 69.13; H, 7.38; N, 6.83.
Embodiment 187The preparation of 2-((2-methoxyl group phenoxy group) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 364 (M+) ultimate analysis C
23H
28N
2O
2HCl:
Theoretical value: C, 68.90; H, 7.29; N, 6.99.
Measured value: C, 73.45; H, 7.94; N, the 6.92. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 188The preparation of 2-(2-hydroxyethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
Ultimate analysis C
16H
22N
2O:
Theoretical value: C, 74.38; H, 8.58; N, 10.84.
Measured value: C, 74.35; H, 8.78; N, 10.96.
Embodiment 189The preparation of 2-(2-methoxy ethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FDMS 272,273 (M+) ultimate analysis C
17H
24N
2O:
Theoretical value: C, 74.96; H, 8.88; N, 10.28.
Measured value: C, 73.31; H, 8.86; N, 9.97.
Embodiment 190The preparation of 2-(2-allyl group oxygen ethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 298 (M+) ultimate analysis C
19H
26N
2OHCl:
Theoretical value: C, 68.14; H, 8.13; N, 8.37
Measured value: C, 68.30; H, 8.14; N, 8.39.
Embodiment 191The preparation of 2-(benzyloxymethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.FDMS 384 (M+) ultimate analysis C
23H
28N
2OHCl:
Theoretical value: C, 71.76; H, 7.59; N, 7.28.
Measured value: C, 68.44; H, 7.04; N, the 6.36. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 192The preparation of 2-((3-chlorine benzyloxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR conforms to the structure of the title compound of expection.FDMS 382 (M+) ultimate analysis C
23H
27ClN
2OHCl:
Theoretical value: C, 72.14; H, 7.11; N, 7.32.
Measured value: C, 71.92; H, 7.22; N, 7.43.
Embodiment 193The preparation of 2-((2-chlorine benzyloxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.82-83 ℃ of ultimate analysis C of FDMS 382 (M+) fusing point
23H
27ClN
2O:
Theoretical value: C, 72.14; H, 7.11; N, 7.32.
Measured value: C, 71.87; H, 7.07; N, 7.36.
Embodiment 194The preparation of 2-((4-chlorine benzyloxy) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3), IR conforms to the structure of the title compound of expection with UV.FDMS 382 (M+) ultimate analysis C
23H
27ClN
2OHCl:
Theoretical value: C, 65.87; H, 6.73; N, 6.68
Measured value: C, 65.54; H, 6.59; N, 6.39.
Embodiment 195The preparation of 2-((naphthalene-1-base oxygen) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 384 (M+) ultimate analysis C
26H
28N
2OHCl:
Theoretical value: C, 74.18; H, 6.94; N, 6.65.
Measured value: C, 74.47; H, 7.05; N, 6.64.
Embodiment 196The preparation of 2-((naphthalene-2-base oxygen) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 384 (M+) ultimate analysis C
26H
28N
2OHCl:
Theoretical value: C, 74.18; H, 6.94; N, 6.65.
Measured value: C, 71.44; H, 6.93; N, the 6.67. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 197The preparation of 2-((thiazol-2-yl) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.Fusing point 175-176 ℃ FDMS 341 (M+) ultimate analysis C
19H
23N
3OS:
Theoretical value: C, 66.83; H, 6.79; N, 12.31.
Measured value: C, 66.64; H, 6.82; N, 12.03.
Embodiment 198The preparation of 2-((piperazine-2-yl) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.101 ℃ of ultimate analysis C of FDMS 336 (M+) mp
20H
24N
4O:
Theoretical value: C, 71.40; H, 7.19; N, 16.65.
Measured value: C, 71.44; H, 7.33; N, 16.43.
Embodiment 19The preparation of 92-((6-chloropyrazine-2-yl) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.94-96 ℃ of ultimate analysis C of FDMS 370 (M+) fusing point
20H
23ClN
4O:
Theoretical value: C, 64.77; H, 6.25; N, 15.11.
Measured value: C, 65.04; H, 6.45; N, 15.21.
Embodiment 200The preparation of 2-((pyrimidine-2-base) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.123-125 ℃ of ultimate analysis C of FDMS 337 (M+1) mp
20H
24N
4O:
Theoretical value: C, 71.40; H, 7.19; N, 16.65.
Measured value: C, 71.60; H, 7.43; N, 16.59.
Embodiment 201The preparation of 2-((quinoline-2-yl) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.113 ℃ of ultimate analysis C of FDMS 385 (M+1) fusing point
25H
27N
30:
Theoretical value: C, 77.89; H, 7.06; N, 10.90.
Measured value: C, 77.64; H, 7.00; N, 11.05.
Embodiment 202The preparation of 2-((6-chlorine pyridazine-2-yl) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.138-139 ℃ of ultimate analysis C of FDMS 371 (M+1) fusing point
20H
23ClN
4O:
Theoretical value: C, 64.77; H, 6.25; N, 15.11.
Measured value: C, 64.84; H, 6.28; N, 15.00.
Embodiment 203The preparation of 2-((5,6,7,8-naphthane-1-yl) methyl)-1-methyl-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FDMS 431 (M+) ultimate analysis C
28H
37N
3O:
Theoretical value: C, 77.92; H, 8.64; N, 9.74.
Measured value: C, 75.79; H, 8.74; N, 8.74.
Embodiment 204The preparation of 2-((5,6,7,8-naphthane-2-yl) methyl)-1-methyl-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles dihydrochloride hydrate
NMR conforms to the structure of the title compound of expection with UV.202 ℃ of ultimate analysis C of FDMS 431,432 (M+) mp
28H
37N
3O2HClH
2O:
Theoretical value: C, 64.36; H, 7.91; N, 8.04.
Measured value: C, 64.73; H, 7.50; N, 7.99.
Embodiment 205The preparation of 2-(phenyl thiomethyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 350 (M+1) ultimate analysis C
22H
26N
2SHCl:
Theoretical value: C, 68.28; H, 7.03; N, 7.24.
Measured value: C, 68.03; H, 7.00; N, 7.10.
Embodiment 206The preparation of 2-((4-chloro-phenyl-sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 384 (M+) ultimate analysis C
22H
25ClN
2SHCl:
Theoretical value: C, 62.70; H, 6.22; N, 6.65.
Measured value: C, 62.12; H, 6.42; N, the 6.22. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 207The preparation of 2-((3-chloro-phenyl-sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 384 (M+) ultimate analysis C
22H
25ClN
2SHCl:
Theoretical value: C, 62.70; H, 6.22; N, 6.65.
Measured value: C, 62.94; H, 6.23; N, 6.93.
Embodiment 208The preparation of 2-((2-chloro-phenyl-sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 384 (M+) ultimate analysis C
22H
25ClN
2SHCl:
Theoretical value: C, 62.70; H, 6.22; N, 6.65.
Measured value: C, 62.76; H, 6.20; N, 6.67.
Embodiment 209The preparation of 2-((2,4 dichloro benzene base sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 418 (M+) ultimate analysis C
22H
24Cl
2N
2SHCl:
Theoretical value: C, 57.96; H, 5.53; N, 6.15.
Measured value: C, 56.61; H, 5.70; N, the 6.05. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 210The preparation of 2-((2,5-dichlorophenyl sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 418,420 (M+1) ultimate analysis C
22H
24Cl
2N
2SHCl:
Theoretical value: C, 57.96; H, 5.53; N, 6.15.
Measured value: C, 57.87; H, 5.50; N, 5.99.
Embodiment 211The preparation of 2-((2,6-dichlorophenyl sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 417 (M+) ultimate analysis C
22H
24Cl
2N
2SHCl:
Theoretical value: C, 57.96; H, 5.53; N, 6.15.
Measured value: C, 58.16; H, 5.68; N, 6.33.
Embodiment 212The preparation of 2-((3,4-dichlorophenyl sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 418,420 (M+1) ultimate analysis C
22H
24Cl
2N
2SHCl:
Theoretical value: C, 57.96; H, 5.53; N, 6.15.
Measured value: C, 57.98; H, 5.54; N, 6.16.
Embodiment 213The preparation of 2-((cyclohexyl sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.FDMS 356 (M+) ultimate analysis C
22H
32N
2SHCl:
Theoretical value: C, 67.23; H, 8.46; N, 7.13.
Measured value: C, 66.28; H, 9.27; N, the 7.71. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 214The preparation of 2-((n-propyl sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.FDMS 316 (M+) ultimate analysis C
19H
28N
2SHCl:
Theoretical value: C, 64.65; H, 8.28; N, 7.94.
Measured value: C, 64.72; H, 8.03; N, 8.12.
Embodiment 215The preparation of 2-((dibenzylsulfide) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 365 (M+) ultimate analysis C
23H
28N
2SHCl:
Theoretical value: C, 68.89; H, 7.29; N, 6.99.
Measured value: C, 68.63; H, 7.52; N, 7.11.
Embodiment 216The preparation of 2-((2-ethylthio phenyl) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.C
24H
30N
2S:FDMS 379 (M+1) chromatographic process proves that this product is highly purified simplification compound.
Embodiment 127The preparation of 2-((naphthalene-2-base sulphur) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.FDMS 400 (M+) ultimate analysis C
26H
28N
2SHCl:
Theoretical value: C, 71.45; H, 6.69; N, 6.41.
Measured value: C, 69.59; H, 6.67; N, the 6.21. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 220The preparation of 2-phenyl-3-(piperidines-1-yl) Methyl-1H-indole
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 290 (M+) ultimate analysis C
20H
22N
2:
Theoretical value: C, 82.72; H, 7.64; N, 9.65.
Measured value: C, 82.97; H, 7.74; N, 9.81.
Embodiment 221The preparation of 2-methyl-2-phenyl-3-(piperidines-1-yl) Methyl-1H-indole
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 304,305 (M+1) ultimate analysis C
21H
24N
2:
Theoretical value: C, 82.85; H, 7.95; N, 9.20.
Measured value: C, 82.68; H, 7.92; N, 9.40.
Embodiment 222The 2-phenyl-(preparation of 1-methyl-3-(2-(piperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR (CDCl
3), UV conforms to the structure of the title compound of expection with IR.FDMS 346 (M+) ultimate analysis C
22H
22N
2O
2:
Theoretical value: C, 76.28; H, 6.40; N, 8.09.
Measured value: C, 76.09; H, 6.35; N, 8.09.
Embodiment 223The 2-phenyl-(preparation of 1-methyl-3-(2-(N-benzyl-N-3-(dimethylaminopropyl) amino)-1,2-ethanedioyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 453 (M+) ultimate analysis C
29H
31N
3O
2:
Theoretical value: C, 76.79; H; 6.89; N, 9.26.
Measured value: C, 77.06; H, 7.02; N, 9.45.
Embodiment 224The 2-phenyl-(preparation of 1-methyl-3-(2-(4-dimethylamino phenylpiperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 389 (M+) ultimate analysis C
24H
27N
3O
2:
Theoretical value: C, 74.01; H, 6.99; N, 10.79.
Measured value: C, 73.82; H, 6.98; N, 10.75.
Embodiment 225The preparation of 1-methyl-3-(2-(N-benzyl-N-3-(dimethylaminopropyl) amino)-1,2-ethanoyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 377 (M+) FAB 378 (M+1) ultimate analysis C
23H
27N
3O
2:
Theoretical value: C, 73.18; H, 7.21; N, 11.13.
Measured value: C, 70.74; H, 7.14; N, the 10.75. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 226The preparation of 1-methyl-3-(2-(4-dimethylamino phenylpiperidines-1-yl)-1,2-ethanedioyl)-1H-indoles
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 313 (M+1) ultimate analysis C
18H
23N
3O
2:
Theoretical value: C, 68.98; H, 7.40; N, 13.41.
Measured value: C, 68.97; H, 7.59; N, 13.43.
Embodiment 227The preparation of 5-chloro-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.Mp 177-179 ℃ of ultimate analysis C
22H
23Cl
3N
2OHCl:
Theoretical value: C, 55.72; H, 5.10; N, 5.91.
Measured value: C, 55.70; H, 5.21; N, 6.16.
Embodiment 228The preparation of 5-methoxyl group-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((piperidines-1-yl) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.119-121 ℃ of ultimate analysis C of FDMS 432 (M+) fusing point
23H
26Cl
2N
2O
2:
Theoretical value: C, 63.74; H, 6.05; N, 6.46.
Measured value: C, 63.70; H, 6.12; N, 6.46.
Embodiment 229The preparation of 5-chloro-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indole hydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.Ultimate analysis C
24H
28Cl
3N
3O2HCl:
Theoretical value: C, 52.05; H, 5.46; N, 7.59.
Measured value: C, 52.05; H, 5.41; N, 7.56.
Embodiment 230The preparation of 5-chloro-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(((4-piperidines-1-yl) piperidines-1-yl) methyl)-1H-indoles dihydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.Ultimate analysis C
27H
32Cl
3N
3O2HCl:
Theoretical value: C, 54.61; H, 5.77; N, 7.08.
Measured value: C, 51.53; H, 6.53; N, 7.57.
Embodiment 231The preparation of 5-bromo-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(piperidines-1-yl) ethyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with IR.Mp 158-160 ℃ of ultimate analysis C
23H
25BrCl
2N
2O:
Theoretical value: C, 55.67; H, 5.08; N, 5.64.
Measured value: C, 55.96; H, 5.28; N, 5.69.
Embodiment 232The preparation of 2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole
NMR, UV conform to the structure of the title compound of expection with IR.FDMS 271 (M+) ultimate analysis C
16H
14ClNO:
Theoretical value: C, 70.72; H, 5.19; N, 5.15.
Measured value: C, 70.52; H, 5.26; N, 5.28.
Embodiment 233The preparation of 2-((2,4 dichloro benzene oxygen base) methyl)-1-Methyl-1H-indole
IR, NMR conform to the structure of the title compound of expection with UV.FDMS 305 ultimate analysis C
16H
13Cl
2NO:
Theoretical value: C, 62.76; H, 4.28; N, 4.57.
Measured value: C, 63.37; H, 4.72; N, 4.37.
Embodiment 234The preparation of 2-((5,6,7,8-naphthane-1-base oxygen) methyl)-1-Methyl-1H-indole
NMR conforms to the structure of the title compound of expection.FDMS 292 (M+1) ultimate analysis C
20H
21NO:
Theoretical value: C, 82.44; H, 7.26; N, 4.81.
Measured value: C, 82.51; H, 7.28; N, 4.80.
Embodiment 235The preparation of 2-((5,6,7,8-naphthane-2-base oxygen) methyl)-1-Methyl-1H-indole
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 291 (M+) ultimate analysis C
20H
21NO:
Theoretical value: C, 82.44; H, 7.26; N, 4.81.
Measured value: C, 82.25; H, 6.98; N, 4.95.
Embodiment 236The preparation of 2-((4-chlorophenoxy) methyl)-3-formyl radical-1-Methyl-1H-indole
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 299 (M+) ultimate analysis C
17H
14ClNO
2:
Theoretical value: C, 68.12; H, 4.71; N, 4.67.
Measured value: C, 67.90; H, 4.93; N, 4.73.
Embodiment 237(RS)-1, the preparation of 2-dimethyl-3-(3-(piperidines-3-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolution mass spectrum C
18H
27N
2:
Theoretical value: 271.2174.
Measured value: 271.2176.
Embodiment 238The preparation of 1-methyl-2-((2-((piperidines-1-yl) methyl) phenoxy group) methyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 335 (M+) ultimate analysis: C
22H
26N
2O:
Theoretical value: C, 79.01; H, 7.84; N, 8.38.
Measured value: C, 78.78; H, 7.58; N, 8.56.
Embodiment 239The preparation of 1-methyl-3-(2-((4-chlorophenoxy) methyl) piperidines-1-ylmethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 368 (M+) ultimate analysis: C
22H
25ClN
2OHCl:
Theoretical value: C, 65.19; H, 6.46; N, 6.91.
Measured value: C, 64.93; H, 6.44; N, 6.78.
Embodiment 240The preparation of 1-methyl-3-(3-((4-chlorophenoxy) methyl) piperidines-1-ylmethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 368 (M+) ultimate analysis: C
22H
25ClN
2O:
Theoretical value: C, 71.63; H, 6.83; N, 7.59.
Measured value: C, 63.74; H, 6.54; N, 6.86.
Embodiment 241The preparation of 1-methyl-3-(2-(2-(4-chlorophenoxy) ethyl) piperidines-1-ylmethyl)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 382 (M+) ultimate analysis: C
23H
27ClN
2O:
Theoretical value: C, 65.87; H, 6.73; N, 6.68.
Measured value: C, 62.05; H, 6.36; N, 6.18.
Embodiment 243The preparation of 3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl)-ethyl propionate
NMR (CDCl
3) conform to the structure of the title compound of expecting.FDMS 371 (M+) chromatographic process proves that this product is highly purified simplification compound.
Embodiment 244(RS)-preparation of 2-amino-3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl) ethyl propionate
NMR conforms to the structure of the title compound of expection.FDMS 386. ultimate analysis C
21H
23ClN
2O
3:
Theoretical value: C, 65.20; H, 5.99; N, 7.24.
Measured value: C, 64.95; H, 5.95; N, 7.27.
Embodiment 245The preparation of 2-oximino-3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl) ethyl propionate
IR, NMR conforms to the structure of the title compound of expection with UV.FDMS?400(M+)。Mp165-166 ℃ of ultimate analysis C
21H
21ClN
2O
40.2H
2O:
Theoretical value: C, 62.36; H, 5.33; N, 6.93.
Measured value: C, 62.38; H, 5.38; N, 6.87.
Embodiment 246(RS)-preparation of 2-methoxyimino-3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl) methyl propionate
IR, NMR conforms to the structure of the title compound of expection with UV.Fusing point: 106-107 ℃ of ultimate analysis C of FDMS 414 (M+)
22H
23ClN
2O
4:
Theoretical value: C, 63.69; H, 5.59; N, 6.75.
Measured value: C, 63.95; H, 5.57; N, 7.01.
Embodiment 247The preparation of 2-benzyloxy imino--3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl) ethyl propionate
IR, NMR conforms to the structure of the title compound of expection with UV..mp96 ℃ of FDMS 490 (M+). ultimate analysis C
28H
27ClN
2O
4:
Theoretical value: C, 68.50; H, 5.54; N, 5.71.
Measured value: C, 68.78; H, 5.67; N, 5.64.
Embodiment 248The preparation of 2-acetoxyl group imino--3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl) ethyl propionate
IR, NMR conforms to the structure of the title compound of expection with UV.FDMS 442 (M+). fusing point 128-129 ℃. ultimate analysis C
23H
23ClN
2O
5:
Theoretical value: C, 62.37; H, 5.23; N, 6.32.
Measured value: C, 62.44; H, 5.40; N, 6.33.
Embodiment 2492-benzoyloxy imino--3-(2-((4-chlorophenoxy) methyl)-1-Methyl-1H-indole-3-yl) ethyl propionate
IR, NMR conforms to the structure of the title compound of expection with UV..mp146-147 ℃ of FDMS 504 (M+). ultimate analysis C
28H
25ClN
2O
5:
Theoretical value: C, 66.60; H, 4.99; N, 5.55.
Measured value: C, 66.88; H, 5.22; N, 5.80.
Embodiment 250The preparation of 2-((4-chlorophenoxy) methyl)-3-(4-hydroxyl-1-methyl piperidine-4-yl)-1-Methyl-1H-indole
IR, NMR conforms to the structure of the title compound of expection with UV.FDMS 384 (M+). ultimate analysis C
22H
25ClN
2O
2:
Theoretical value: C, 68.65; H, 6.55; N, 7.28.
Measured value: C, 69.46; H, 6.44; N, the 7.28. chromatographic process proves that this product is highly purified simplification compound.
Embodiment 251The preparation of 2-oxyimino-3-(1-methyl-2-phenyl-1H-indol-3-yl) ethyl propionate
NMR (CDCl
3) conform to the structure of the title compound of expecting.
UV conforms to the structure of the title compound of expection with IR.141-142 ℃ of FDMS 332 (M+) mp. ultimate analysis C19H18N2O3:
Theoretical value: C, 70.79; H, 5.62; N, 8.69.
Measured value: C, 70.64; H, 5.89; N, 8.58.
Embodiment 252The preparation of 2-oxyimino-3-(1H-indol-3-yl) ethyl propionate
IR, NMR conforms to the structure of the title compound of expection with UV.FDMS 246 (M+). 156 ℃ of fusing points. ultimate analysis C
13H
14N
2O
30.3H
2O:
Theoretical value: C, 62.04; H, 5.85; N, 11.13.
Measured value: C, 61.77; H, 5.55; N, 11.07.
Embodiment 253The preparation of 6-chloro-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(piperidines-1-yl) ethyl)-1H-indoles
IR conforms to the structure of the title compound of expection with NMR.FDMS 450 (M+). fusing point 116.5-118.5 ℃. ultimate analysis C
23H
25Cl
3N
2O:
Theoretical value: C, 61.14; H, 5.58; N, 6.20
Measured value: C, 61.43; H, 5.67; N, 6.26.
Embodiment 255The preparation of 7-chloro-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(2-(piperidines-1-yl) ethyl)-1H-indoles
IR conforms to the structure of the title compound of expection with NMR.Mp134-136 ℃. ultimate analysis C
23H
25Cl
3N
2O:
Theoretical value: C, 61.14; H, 5.58; N, 6.20.
Measured value: C, 61.39; H, 5.71; N, 6.47.
Embodiment 256The preparation of 4-methyl-2-((2,4 dichloro benzene oxygen base) methyl)-1-(3-(piperidines-3-yl) propyl group)-1H-indoles
NMR (CDCl
3) conform to the structure of the title compound of expecting.High resolving power FAB-MS (M+1) C
24H
30ClN
2O:
Theoretical value: 397.2047.
Measured value: 397.2041.
Embodiment 257The preparation of 5-chloro-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-((4-dimethylamino phenylpiperidines-1-yl) methyl)-1H-indoles dihydrochloride
Ultimate analysis C
24H
28Cl
3N
3O:
Theoretical value: C, 52.05; H, 5.46; N, 7.59.
Measured value: C, 52.05; H, 5.41; N, 7.56.
Embodiment 258The preparation of 7-methyl-2-((2,4 dichloro benzene oxygen base) methyl)-1-methyl-3-(3-(piperidines-1-yl) propyl group)-1H-indoles dihydrochloride
NMR (CDCl
3) conform to the structure of the title compound of expecting.Fusing point 129-131 ℃. ultimate analysis C
25H
30Cl
2N
2O:
Theoretical value: C, 67.41; H, 6.79; N, 6.29
Measured value: C, 67.34; H, 6.80; N, 6.05.
Embodiment 2591, the preparation of 2-dimethyl-3-((4-(piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
NMR, IR conforms to the structure of the title compound of expection with UV.FDMS 353 (M+) ultimate analysis C
22H
31N
3O:
Theoretical value: C, 74.75; H, 8.84; N, 11.89.
Measured value: C, 74.76; H, 8.96; N, 11.76.
Embodiment 2601, the preparation of 2-dimethyl-3-((4-(N, N-dimethylamino) piperidines-1-yl) ethanoyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.C
19H
27N
3O：FDMS?313(M+)。
Embodiment 261The preparation of 2-((4-chlorophenoxy) methyl)-3-(((4-cyclohexyl) piperazine-1-yl) ethanoyl)-1-Methyl-1H-indole
NMR conforms to the structure of the title compound of expection.C
28H
34N
3O
2：FDMS?480(M+)。
Embodiment 262The preparation of 2-((4-chlorophenoxy) methyl)-3-(((4-phenyl) piperazine-1-yl) ethanoyl)-1-Methyl-1H-indole
NMR conforms to the structure of the title compound of expection.C
28H
28ClN
3O
2：FDMS?474(M+)。
Embodiment 263The preparation of 2-((4-chlorophenoxy) methyl)-3-((4-(N, N-dimethylamino) piperidines-1-yl) ethanoyl)-1-Methyl-1H-indole
NMR, IR conforms to the structure of the title compound of expection with UV.FDMS 439 (M+) ultimate analysis C
25H
30ClN
3O
2:
Theoretical value: C, 68.25; H, 6.87; N, 9.55.
Measured value: C, 67.98; H, 6.81; N, 9.40.
Embodiment 264The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-((N-methyl-N-(3-N ', N '-dimethylaminopropyl) amino) ethanoyl)-1H-indoles
NMR conforms to the structure of the title compound of expection with IR.FDMS 428 (M+1) high resolving power FAB-MS C
24H
31ClN
3O
2:
Theoretical value: 428.2105.
Measured value: 428.2113.
Embodiment 265The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-((4-piperidines-1-yl) piperidines-1-yl) ethanoyl)-1H-indoles
NMR, IR conforms to the structure of the title compound of expection with UV.FDMS 479 (M
+ 1) high resolving power FAB-MS C
28H
35ClN
3O
2:
Calculated value: 480.2418.
Measured value: 480.2411.
Embodiment 266The preparation of 2-((4-chlorophenoxy) methyl)-3-(2-((4-piperidines-1-yl) piperidines-1-yl) ethanoyl)-1-(2-(N, N-lupetidine-4-yl) ethyl)-1H-indoles iodide
NMR conforms to the structure of the title compound of expection.Ultimate analysis C
36H
50ClIN
4O
2H
2O:
Theoretical value: C, 57.56; H, 6.90; N, 7.46.
Measured value: C, 57.85; H, 6.86; N, 7.04
Embodiment 267The preparation of 2-((4-chlorophenoxy) methyl)-1-((2-piperidin-4-yl) ethyl-3-(2-(4-piperidines-1-yl) piperidines-1-yl) acetyl-1-yl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FDMS 577 (M+1) ultimate analysis C
34H
45ClN
4O
2:
Theoretical value: C, 70.75; H, 7.86; N, 9.71
Measured value: C, 70.55; H, 7.87; N, 9.52
Embodiment 268The preparation of 2-((4-chlorophenoxy) methyl)-3-(2-(methylamino propyl-dimethyl amino) acetyl-1-yl)-1-((2-piperidines-3-yl) ethyl)-indoles
NMR conforms to the structure of the title compound of expection.FABMS 525 (M+1) high resolution mass spectrum C
30H
42N
4O
2Cl:
Theoretical value: 525.2996
Measured value: 525.3003
Embodiment 269The preparation of 2-((4-chlorophenoxy) methyl)-1-((2-piperidines-3-yl) ethyl)-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) acetyl-1-yl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FDMS (M+1) ultimate analysis C
34H
45N
4O
2Cl:
Theoretical value: C, 70.75; H, 7.86; N, 9.71
Measured value: C, 70.72; H, 7.83; N, 9.63
Embodiment 270The preparation of 2-((4-chlorophenoxy) methyl)-3-(2-(methylamino propyl-dimethyl amino) acetyl-1-yl)-1-((2-piperidin-4-yl) ethyl)-1H-indoles
NMR conforms to the structure of the title compound of expection.High resolution mass spectrum C
30H
42N
4O
4Cl (M+1):
Theoretical value: 525.2996
Measured value: 525.3013
Embodiment 271The preparation of S-2-((4-chlorophenoxy) methyl)-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) acetyl-1-yl)-1-((3-piperidines-3-yl) propyl group)-1H-indoles
NMR conforms to the structure of the title compound of expection.FABMS (M+1) ultimate analysis C
35H
47ClN
4O
2
Theoretical value: C, 71.10; H, 8.01; N, 9.48
Measured value: C, 70.82; H, 8.14; N, 9.23
Embodiment 272The preparation of R-2-((4-chlorophenoxy) methyl)-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) acetyl-1-yl)-1-((3-piperidines-3-yl) propyl group)-1H-indoles
NMR conforms to the structure of the title compound of expection.High resolution mass spectrum C
35H
48ClN
4O
2:
Theoretical value: 591.3466
Measured value: 591.3458
Embodiment 273The preparation of suitable/anti--2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) hexamethylene-1-yl) acetyl-1-yl)-1H-indoles
Suitable/trans isomer 1 conforms to the structure of the title compound of expection with 2 mixture NMR.FDMS 478 (M+1) ultimate analysis C
29H
35ClN
2O
2
Theoretical value: C, 72.71; H, 7.36; N, 5.85
Measured value: C, 72.65; H, 7.61; N, 5.95
Embodiment 274The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) hexamethylene-1-yl) acetyl-1-yl)-1H-indoles
Isomer 1NMR conforms to the structure of the title compound of expection.FDMS 478 (M+1) ultimate analysis C
29H
35ClN
2O
2
Theoretical value: C, 72.71; H, 7.36; N, 5.85
Measured value: C, 72.55; H, 7.52; N, 5.67
Embodiment 275The preparation of 2-((4-chlorophenoxy) methyl)-3-(2-(4-(piperidines-1-yl) hexamethylene-1-yl) acetyl-1-yl)-1-((2-piperidin-4-yl) ethyl)-1H-indoles
Isomer 1NMR conforms to the structure of the title compound of expection.FDMS 575 (M+) ultimate analysis C
35H
46ClN
3O
2
Theoretical value: C, 72.95; H, 8.05; N, 7.29
Measured value: C, 72.88; H, 8.23; N, 7.53
Embodiment 276The preparation of 2-((4-chlorophenoxy) methyl)-1-methyl-3-(2-(4-(piperidines-1-yl) hexamethylene-1-yl) acetyl-1-yl)-indoles
Isomer 2NMR conforms to the structure of the title compound of expection.FDMS 478 (M+) ultimate analysis C
29H
35ClN
2O
2
Theoretical value: C, 72.71; H, 7.36; N, 5.85
Measured value: C, 72.43; H, 7.42; N, 5.86
Embodiment 277The preparation of 2-((4-chlorophenoxy) methyl)-5-fluoro-1-methyl-3-(2-(4-(piperidines-1-yl) piperidines-1-yl) acetyl-1-yl)-1H-indoles
NMR conforms to the structure of the title compound of expection.FABMS 498 (M+1) ultimate analysis C
28H
33ClFN
3O
2
Theoretical value: C, 67.53; H, 6.68; N, 8.44
Measured value: C, 67.34; H, 6.59; N, 8.58
According to above-described method, the professional can prepare other compound of general formula I in essence.
Compound of the present invention be attached on the specificity acceptor of neuropeptide tyrosine and closely relevant neuropeptide (summary of Neuropeptide Y Receptors sees, D.Gehlert,
Life Sciences, 55:551-562 (1994); P.A, Hipskind and D.R.Gehlert,
Annual Reports in Medicinal Chemistry,31:1 (1996)).As if although pancreatic polypeptide has the receptor site of its feature, the acceptor of neuropeptide tyrosine and peptide YY has suitable overlapping.Many functions of neuropeptide (but not all function) can repeat with peptide YY.
The segmental affinity rate of 13-36 of neuropeptide tyrosine of goods that two kinds of receptor subtypes of neuropeptide tyrosine are to use sympathetic nervous system at first is for basis hypothesis.These are Neuropeptide Y Receptorss of preferably setting up, but have definite evidence explanation to also have other receptor subtype.Preferably set up neuropeptide tyrosine is replied acceptor is the Y-3 acceptor, but Y-3 is not the acceptor of peptide YY.Another acceptor of describing has recently been described bonded peptide YY and has been had high affinity rate, and neuropeptide tyrosine has low affinity rate.Though the natural pharmacology that the feed of neuropeptide tyrosine is replied is Y-1, reported other " feed acceptor ".Several acceptors have successfully been cloned at present.Following chapters and sections have been summarized utilizable information and their powerful effects in physiological function of known Neuropeptide Y Receptors hypotype.
The Y-1 acceptor
The Y-1 acceptor is the best acceptor of neuropeptide tyrosine setting.It is generally acknowledged that this receptor is postsynaptic receptor and can mediates the many known action of neuropeptide tyrosine in periphery.This receptor is described to C end fragment to neuropeptide tyrosine at first, and for example the segmental avidity of 13-36 is low, but does the time spent with the total length of neuropeptide tyrosine and peptide YY, and avidity equates.C.Wahlestedt，
et?al.，Regulatory Peptides，13：307-318(1986)；C.Wahlestedt，et?al.，NEURONALMESSENGERS?IN?VASCULAR?FUNCTION，231-241(Nobin，et?al.，eds.1987)。34 amino acid proline(Pro) (Pro
34) replace, the protein that obtains is that the Y-1 acceptor is exclusive.E.K.Pother，
et?al. European?
Journal?
of pharmacology，193：15-19(1991)。This instrument is used to establish the effect of Y-1 acceptor in a series of functions.This receptor is considered to mode and the adenylate cyclase coupling to suppress in pallium muscle smooth muscle cell and KS-N-MC cell.(see summary: B.J.Mcdermott,
Et al.,
Cardiovascular Research, 27:893-905 (1993)).This effect has been confirmed the effect of g protein coupled receptor by the Toxins, pertussis blocking-up.Moving of the sick intracellular calcium of Y-1 is receptor-mediated essence and blood pipe smooth muscle cell and people's red white corpuscle.
Clone's people Y-1 acceptor is the type that depends on the cell that acceptor is expressed therein in the inhibition coupling of phosphotidylinositol hydrolysis coupling or adenylate cyclase on earth.H.Herzog,
Et al., Proceedings of the National Academy of Sciences (USA),89:5794-5798 (1992). reported when the using-system goods are studied, the Y-1 acceptor or with the second messenger system coupling, or with the cell strain coupling of natural expression this receptor.D.Gehlert,
The same, 553.So, the Y-1 acceptor can not be uniquely with single second messenger's coupling be that the basis is distinguished.
The regulation and control of Y-1 acceptor (regulation and control of perhaps typical or atypical Y-1 acceptor) are believed can influence the multiple physiological condition, include, but is not limited to obesity or bulimia, the adult onset diabetes, anorexia nervosa, pheochromocytoma-inductive hypertension, subarachnoid hemorrhage, nervosa myopachynsis, hypertension, anxiety and anorexia nervosa.It is open on June 6th, 96/16542,1996 to see PCT PatentPublication WO, P135, and the reference of quoting from here.
The Y-2 acceptor
As the Y-1 acceptor, this receptor hypotype is at first described with the muscle preparation.On pharmacology, can distinguish Y-2 acceptor and Y-1 acceptor to the avidity of neuropeptide tyrosine C-end fragment by showing.Though neuropeptide tyrosine 3-36 fragment and peptide YY provide improved affinity rate and selectivity, but the most normal use neuropeptide tyrosine (13-36) is distinguished this receptor.Y.Dumont，
et?al.，
Society?for?Neuroscience?Abstracts，19：726(1993)。As the Y-1 acceptor, the inhibition coupling of this receptor and adenylate cyclase.Though it is can Toxins, pertussis insensitive in some goods.Find that the Y-2 acceptor is by optionally suppressing N-type calcium by reducing the level of intracellular calcium in the cynapse.As the Y-1 acceptor, the Y-2 acceptor can show the different coupling with the second messenger.Believe that the Y-2 acceptor is relevant with the regulation and control of hypertension, epileptic seizures and nervosa myopachynsis.It is open on June 6th, 96/16542,1996 to see PCT Patent PublicationWO, P135, and the reference of quoting from here.
All find the Y-2 acceptor in a series of brains zone, comprised hippocampus, the black substance outside, blood brain, following blood brain and brain stem.In periphery, for example at sympathetic nerve, parasympathetic nerve and sensory nerve have been found the Y-2 acceptor in peripheral nervous system.In all these tissues, the attenuating that the receptor-mediated neurotransmitter of Y-2 discharges.Use the clone technology of expressing to clone the Y-2 acceptor.See P.M.Rose,
Et al.,
Journal of Biological Chemistry, 270:22661 (1995); C.Gerald,
Et al.,
Journal of Biological Chemistry, 270:26758 (1995); D.R.Gehlert,
Et al.,
Molecular Pharmacology, 49:224 (1996).
The Y-3 acceptor
This receptor has high affinity rate and peptide YY is had low affinity rate neuropeptide tyrosine.Though neuropeptide tyrosine is an agonist in full force and effect to this receptor group, peptide YY poor effect.This pharmacological property is used to define this receptor.Use electrophysiological technique to determine have a kind of acceptor to have and the similar pharmacology of Y-3 acceptor in the CA3 zone of hippocampus.This receptor can strengthen these nerves the excitability of N-methyl-D-aspartate ester (NMDA) is replied.F.P.Monnet，
et al.European?Journal?of?Pharmacology，182：207-208(1990)。This receptor is believed regulation and control hypertension.It is open on June 6th, 96/16542,1996 to see PCT Patent Publication WO, P135, and the reference of quoting from here.
In the rat brain stem, established the existence of this receptor in the independent nucleus bundle (nucleus tractus solitarius) best.Use neuropeptide tyrosine to produce dose-dependent blood pressure reduces and decreased heart rate in this zone.Can also there be the significant contribution from Y-1 and Y-2 acceptor in this zone of brain.Neuropeptide tyrosine also suppresses the release from medulliadrenal catecholamine of acetylcholine-induced, and this effect may realize by the Y-3 acceptor.C.Wahlestedf，
et?al.，Life?Sciences，50：PL7-PL14(1992)。
The preferred acceptor of peptide YY
Described the 4th kind of acceptor, this receptor has shown peptide YY than the preferred property of the appropriateness of neuropeptide tyrosine.This receptor at first is described in the small intestine of rat, and it is high 5～10 times to the affinity rate of the affinity rate comparison neuropeptide tyrosine of peptide YY.Y.M.Laburthe，
et?al，Endocrinology，118：1910-1917(1986)。In lipocyte and renal proximal tubule cell strain, found acceptor afterwards.Mode and the adenylic acid (AMP) hexamethylene enzyme coupling of this receptor to suppress, and to the Toxins, pertussis sensitivity.
In small intestine, this receptor convection cell and electrolytical secretion produce powerful restraining effect.This receptor is positioned the glandular tube cell, believes the secretion that the small intestine oxide compound takes place here.The mechanism that the preferred acceptor of peptide YY in lipocyte relies on by cyclic monophosphate (cAMP) mediates the reduction of steatolysis.
" feed acceptor "
One of central action of the neuropeptide tyrosine of Fa Xianing is to increase feed the earliest, and this effect is that the blood brain is observed after giving neuropeptide tyrosine under rat.When neuropeptide tyrosine is filled into down perifornical when zone of blood brain, this reply the most powerful.B.G.Stanley，
et?al.，Brain
Research，604：304-317(1993)。Although this pharmacology of replying and Y-1 acceptor are similar, the 2-36 fragment of neuropeptide tyrosine is obvious strong more a lot of than neuropeptide tyrosine.In addition, though Intraventricular neuropeptide tyrosine (2-36) fragment stimulates feed fully, do not resemble and reduce body temperature the total length neuropeptide tyrosine.See Y.F.B.Jolicoeur,,
Et al.,
Brain Research Bulletin, 26:309-311 (1991).Two parts of disclosed recently patents have been described the clone and the expression of Y-5 acceptor, it is believed that Here it is " feed acceptor " to see Patent Cooperation Treaty PublicationWO 96/16542, published June 6,1996; And Australian Patent PublicationAU956467 A0, published November 30,1995.
Use accurate rapidly mensuration test compound and known Neuropeptide Y Receptors position to divide bonded primary screen choosing method to estimate the biological activity of The compounds of this invention.To estimating the useful detection method of neuropeptide Y receptor antagonist is that this document is known.See United States Patents5 for example, 284,839, issued February 8,1994, which is herein incorporated byreference.
See also, M.W.Walker,
Et al.,
Journal of Neurosciences, 8:2438-2446 (1988).
Neuropeptide tyrosine is in conjunction with detection
The major programme of descriptions such as the top M.W.Walker of use has been estimated the binding ability of compound of the present invention and neuropeptide tyrosine.In detecting, this uses the SK-N-MC cell strain.This cell strain is from Sloane-kettering Memorial Hospital, New York.Dulbecco ' s Minimal Essential the substratum (DMEM) that these cells are strengthened with 5% foetal calf serum in the T-150 flask is cultivated.Manual by scraping and becoming ball that cell is taken out from flask and in-70 ℃ of preservations.
With glass spoon slurry device ball resuspending with taking-up in the buffered soln of the 25mM HEPES (pH7.4) that contains 2.5mM calcium chloride, 1mM magnesium chloride and 2g/L bacitracin.At 0.1nM
125I-peptide YY (2200ci/mmol) and the proteic final volume of 0.2-0.4mg are about 2 hours of D incubated at room in the medium of 200 μ l.
The radioactivity amount that still keeps being attached to this tissue after hatching in the presence of the 1 μ M neuropeptide tyrosine is defined as the non-exclusive combination.The compound that in the mixtures incubated of some tests, does not contain various concentration.
In 96-well formula grabber, stop rapidly hatching with the glass funnel that in 0.3% poly-ethylidene imido, soaked in advance.Funnel uses 5ml 50mM tris buffer (pH7.4) in 4 ℃ of washings and dry rapidly in 60 ℃.The radioactivity that is retained on the funnel handled and counts then by this funnel with the fusion diamante.Obtain the result with various software package analyses.Coumassie protein assay reagent with standard is measured protein concentration, makes standard with bovine serum albumin.
The chemical compound lot for preparing previously shows clear and definite neuropeptide Y receptor antagonist activity (Ki=10 μ M to 0.1nM).Because the compound of general formula I is effective antagonist of Neuropeptide Y Receptors, so these compounds are valuable in the excessive disease widely that exists for feature with neuropeptide tyrosine in treatment.Like this, the invention provides the method for the excessive relevant disorder of treatment or prevention and neuropeptide tyrosine, this method comprises to the Mammals of the described treatment of needs takes acceptable salt, solvate or prodrug on the compound of general formula I of significant quantity or their pharmacology.Term " with the excessive relevant disorder of neuropeptide tyrosine " comprises those imbalances relevant with the unsuitable excitement of Neuropeptide Y Receptors, no matter the actual amount of the neuropeptide tyrosine that those positions exist.
Those disorders comprise:
Imbalance or the disease relevant with heart, blood vessel or renal system, for example vasospasm, heart failure, shock, cardiac hypertrophy, elevation of blood pressure, stenocardia, myocardial infarction, sudden cardiac death, congestive heart failure, heart disorder, external cause vascular disease, and renal dysfunction, for example the fluidic unusual or renal failure of mobile, mass transfer that do not match;
With the active relevant state that raises of parasympathetic nerve, for example among the coronary artery surgery operation and afterwards and the operating state of gi tract.
Disease of brain and the illness relevant with central nervous system, for example cerebral embolism, nerve degeneration, epilepsy, apoplexy, with apoplexy, brain spasm and hemorrhage, depressed, anxiety, schizophrenia, dementia, the epileptic seizures state relevant with epilepsy;
The state relevant with pain or nociception;
With gi tract abnormal motion and secretion diseases associated, for example multi-form intestinal obstruction, the urinary incontinence and Crohn ' s disease;
Drink and eat not normally, for example obesity, apocleisis, voracity and metabolism are not normal;
With sexual dysfunction and reproduction imbalance diseases associated;
State or imbalance with inflammation-related;
Respiratory tract disease, for example asthma and state and the bronchostenosis relevant with asthma; With
Discharge unusual diseases associated with hormone, for example discharge unusual diseases associated with leutinizing hormone, tethelin, Regular Insulin and prolactin.
Compound of Formula I is usually with the form administration of pharmaceutical composition.These compounds can be by comprising various administrations such as oral administration, rectal administration, transdermal administration, subcutaneous administration, intravenous injection, intramuscular administration and intranasal administration.The two is all effective as injectable and oral compositions for these compounds.These compositions are according to the preparation of the currently known methods in the pharmacy literature and comprise at least a active compound.
The present invention also comprises the method that makes pharmaceutical composition, and the compound that this pharmaceutical composition contains as the general formula I of active ingredient combines with acceptable carrier on the medicine.When making composition of the present invention, normally activeconstituents is mixed with excipient, with the excipient dilution or be wrapped in the carrier that can place within capsule, sachet, paper or other container.When excipient when the thinner, excipient can be solid, semisolid or liquid material, they are as excipient, carrier or the medium of active ingredient.So, composition can be a tablet, pill, pulvis, lozenge, sachet agent, cachet, elixir, suspension agent, emulsifying agent, solution, syrup, aerosol (with solid form or in liquid medium) contains the ointment up to 10% weight active compound, soft or hard gelatine capsule, suppository, aseptic injectable solution and aseptic packaging powder.
In when prescription preparation, with the powder that is necessary active compound is worn into the granularity that suits before other composition combine.If the insoluble in fact words of active compound are worn into the following powder of 200 orders usually.If active compound is water-soluble in fact, can come the normal regulating granularity to make active compound by mill be uniform distribution in essence in prescription, and granularity is about 40 orders.
The example of some excipient comprises lactose, glucose, sucrose, Sorbitol Powder, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, water, syrup and methylcellulose gum.Prescription also comprises in addition: lubricant, talcum powder for example, Magnesium Stearate and mineral oil; Heat preserving agent; Emulsifying agent and suspension agent; Sanitas, for example methyl hydroxybenzoate and nipasol; Sweeting agent; And perfume compound.Composition of the present invention can be according to document currently known methods prescription, so that agent shape quick, lasting or slow release of active compounds is provided after patient takes medicine.
The composition screening formulation becomes unit dose shape, and each dosage contains about 5mg to about 100mg, the more frequent extremely approximately 30mg activeconstituents of about 10mg that contains.Term " unit dose shape " is meant physically discontinuous unit, this unit is suitable for as people or other mammiferous unitary dose, each unit contains the active substance according to the amount of pre-determining that produces desired therapeutic effect calculating, and this active substance combines with the medicinal excipient that suits.
This active compound is effective in wide dosage range.For example normal about 0.5mg to the 30mg/kg body weight of per daily dose scope.Treatment is during the grownup, and the preferred dosage scope is arranged especially is about 1mg to about 15mg/kg body weight/day, once or part vic.But be to be understood that, actual dosage should be determined by the doctor, promptly by the doctor according to relevant environment, comprise the state of being treated, route of administration, the actual compound of taking selected, age, body weight and each patient's the situation of replying decides as the seriousness of patient symptom, thus top dosage range without any meaning from any angle limits scope of the present invention.In some cases, dosage level is lower than the lower limit of the dosage range of saying previously may be more suitable, and in other cases, use bigger dosage also can not cause any deleterious side effect, and this class heavy dose at first is divided into several less dosage, and whole day is taken.
Be the preparation solids composition, for example tablet mixes main activeconstituents with medicinal excipient, makes the solid-state pre-prescription composition that forms the uniform mixture that contains The compounds of this invention.When mentioning these pre-prescription compositions and be even thing, mean to be evenly dispersed in the composition activeconstituents is whole, so that can being divided at any time again, said composition equates effective unit dosage, for example tablet, pill and capsule.The unit dosage that contains about 0.1mg to 500mg activeconstituents of the present invention of type above being divided into then, is described the pre-prescription of this solid.
Tablet of the present invention or pill can dressings, make the agent shape that obtains that long lasting benefit can be provided.Agent or outer agent component in for example tablet or pill can contain, the latter seals the former.These two kinds of components can be separated by casing, and the effect of casing is the disintegration that stops under one's belt, in allowing component complete by and enter duodenum or slowly discharge.A series of materials can be used as this class casing or dressing, and this class material comprises the mixture of the material of a series of poly carboxylic acid and poly carboxylic acid and shellac, hexadecanol and cellulose acetate one class.
New blend of the present invention mixes wherein so that liquid dosage form oral or injection comprises the aqueous solution, suitable syrupus aromaticus, water-based or oily suspensions, contains edible oil, for example contains the fragrant emulsion of cotton seed oil, sesame oil, Oleum Cocois or peanut oil, and elixir and similar medicinal excipient.
Suck or blow out composition and comprise acceptable solution and suspension on the medicine, water-based or organic solvent, or their mixture and pulvis.The liquid or solid composition can contain acceptable excipient on the previously described appropriate drug.For reaching the effect of part or system, composition is the administration by oral or nasal respiration preferably.Composition on preferred medicine in the acceptable solvent can use inert gas atomizer.The solution of atomizing can directly be breathed from spraying gun or atomizing facility or intermittent positive pressure breathing (IPPB) machine, and atomising devices can be connected on face shield, the account shape thing.Solution, suspension agent or dust composition can pass through apparatus preferred oral or nose administration, and this apparatus is with suitable mode release formulation.
Following Example is described can pharmaceutical composition of the present invention.
Formulation 1
Preparation contains the hard gelatine capsule of following component:
Component
Amount (mg/ capsule)
Active ingredient 30.0
Starch 305.0
Magnesium Stearate 5.0
The amount that top component is mixed by 340mg is filled in the hard gelatine capsule.
Formulation 2
Prepare tablet with following component:
Component
Amount (mg/ sheet)
Active ingredient 25.0
Microcrystalline Cellulose 200.0
Colloidal silica 10.0
Stearic acid 5.0
These group punching presses are in blocks, every heavy 240mg.
Formulation 3
The dry powder doses of the imbedibility of preparation contains following component
Component
Weight %
Active ingredient 5
Lactose 95
Activated mixture mixes with lactose, and mixture is added to for sucking in the dry powder that uses.
Formulation 4
Every tablet preparation that contains the 30mg active ingredient is as follows:
Component
Amount (mg/ sheet)
Active ingredient 30.0mg
Starch 45.0mg
Microcrystalline Cellulose 35.0mg
Polyvinylpyrrolidone 4.0mg
(aqueous solution with 10% uses)
Sodium starch glycolate 4.5mg
Magnesium Stearate 0.5mg
Talcum powder 1.0mg
Total amount 120mg
Activeconstituents, starch and Mierocrystalline cellulose are crossed 20 purpose U.S. sieves, and thoroughly mix.The solution of polyvinylpyrrolidone and the powder mixes of sieving are crossed 16 purpose U.S. sieves then.The particle that makes like this is 50 to 60 ℃ of dryings and cross 16 purpose U.S. sieves.Sodium starch glycolate, Magnesium Stearate and talcum powder are crossed 30 mesh sieves in advance, are added to then in the particle, mix after the tabletting machine compressing tablet every heavy 120mg.
Formulation 5
The capsule that contains the 40mg medicine is prepared as follows:
Component
Amount (mg/ capsule)
Active ingredient 40.0mg
Starch 109.0mg
Magnesium Stearate
1.0mg
Total amount 150.0mg
Activeconstituents, Mierocrystalline cellulose, starch and Magnesium Stearate mix, cross 20 order U.S. sieves, are filled in the hard gelatine capsule by the 150mg amount.
Formulation 6
The suppository that contains the 25mg activeconstituents is prepared as follows:
Component
Amount
Active ingredient 25.0mg
Saturated fatty acid glyceride 2000mg
Activeconstituents is crossed 60 order U.S. sieves, is suspended in advance as required in the low-grade fever fused saturated fatty acid glyceride.Mixture impouring capacity is in the suppository mold of 2.0g, cooling.
Formulation 7
The suspension agent that contains the 50mg medicine in every 5ml dosage is prepared as follows:
Composition
Amount
Activeconstituents 50.0mg
Xanthan glue 4.0mg
Xylo-Mucine (11%) 50.0mg
Microcrystalline Cellulose (89%)
Sucrose 1.75mg
Sodium Benzoate 10.0mg
Perfume compound and tinting material q.v.
Pure water adds to 5ml
Medicine, sucrose such as Xanthan glue mix, and cross 10 order U.S. sieves, then with the aqueous solution of previously prepared Microcrystalline Cellulose and Xylo-Mucine.Sodium Benzoate, perfume compound and tinting material dilute with suitable quantity of water, under agitation are added in the top mixture.The water that adds capacity makes the volume that reaches needs.
Formulation 8
The capsule that contains the 15mg medicine is prepared as follows:
Composition
(mg/ capsule)
Activeconstituents 15.0mg
Starch 407.0mg
Magnesium Stearate
3.0mg
Total amount 425.0mg
Activeconstituents, Mierocrystalline cellulose, starch and Magnesium Stearate mix, cross 20 order U.S. sieves, are filled in the hard gelatine capsule by the 425mg amount.
Formulation 9
Intravenous formulation is prepared as follows:
Composition
Amount
Activeconstituents 250.0mg
Isotonic saline solution 1000ml
Formulation 10
Topical preparation is prepared as follows:
Composition
Amount
Activeconstituents 1-10g
Emulsifying wax 30g
Whiteruss 20g
The white soft wax adds to 100g
White soft wax heating and melting.Add whiteruss and emulsifying wax, stir and make dissolving.Add activeconstituents, continue to stir until homodisperse.The mixture cooling curing.
Formulation 11
The sublingual lozenge or the buccal tablets that contain the 10mg activeconstituents are prepared as follows:
Composition
Amount (every)
Activeconstituents 10.0mg
Glycerine 210.5mg
Water 143.0mg
Trisodium Citrate 4.5mg
Polyvinyl alcohol 26.5mg
Polyvinylpyrrolidone
15.5mg
Total amount 410.0mg
Glycerine, water, Trisodium Citrate, polyvinyl alcohol and polyvinylpyrrolidone mix to one by continuously stirring and keep temperature in about 90 ℃.When the superpolymer pass into solution, solution is cooled to about 50 to 55 ℃, sneak into drug slow.Homogeneous mixture inclines to the model of being made by inert material, and the thickness that contains medicine with generation is about 2 to 4mm diffusion matrix.This diffusion matrix is cut into the slice, thin piece with appropriate size then.
The another kind of screening formulation that uses in the method for the present invention is to use transdermal release form (" plaster ").The plaster of this class Transdermal absorption can be in order to the mode of manipulated variable with the continuous or discontinuous diffusion of compound of the present invention.The making of the plaster of transdermal release medicament and use to document known.For example seeing, U.S.Patent registered document incorporated by reference here on June 11st, 5,023,252,1991.This class plaster can discharge continuously according to medicament, and pulse release or discharge is on request made.
Usually expectation maybe must be with pharmaceutical composition or is directly or indirectly guided in the brain.Directly technology generally includes the drug release conduit is inserted host's the ventricles of the brain so that pass through hemato encephalic barrier.A kind of so implantable delivery systme is used for biotic factor is transported to the health region of anatomy, sees U.S.5011472, registration on April 30th, 1991, document incorporated by reference here.
Indirection techniques usually is preferred, generally comprises hydrophilic medicament is converted into fat-soluble medicine or prodrug, so that make the composition of prescription that pro-drug is provided.Block the hydroxyl on the medicine, carbonyl, vitriol and one-level amido can reach the latentiation purpose, and it is bigger fat-soluble and can see through hemato encephalic barrier that medicine is had.The another kind of method that can strengthen hydrophilic medicament release is the intra-arterial perfusion hypertonic solution of breakdown hemato encephalic barrier immediately.
Claims (15)
1. the compound of following general formula:
Wherein:
R
bBe hydrogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
2-C
6Chain acyl, trifluoromethyl, hydroxyl or halogen;
R
1Be hydrogen, C
1-C
6Alkyl, or-(CH
2)
v-R
1a
Wherein v is 1 to 12, R
1aBe phenyl, naphthyl, hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, tryptolinyl, pyrrolidyl, quinuclidinyl or morpholinyl, any phenyl wherein, naphthyl, hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, tryptolinyl, pyrrolidyl, quinuclidinyl or morpholinyl can be replaced by one or more substituting groups, and these substituting groups are selected from C
1-C
6Alkyl, halogen, trifluoromethyl, benzyl, phenyl, two (C
1-C
6Alkyl) amino, C
1-C
6Alkylamino, C
2-C
6Chain acyl, C
2-C
6Chain acyloxy and C
3-C
8Cycloalkyl;
Described phenyl, benzyl or C
3-C
8Arbitrarily by 1,2 or 3 substituting groups replacements, these substituting groups are independently selected from C to cycloalkyl
1-C
6Alkyl, halogen or C
1-C
6Alkoxyl group;
Or R
1aCan be by-(CH
2)
w-R
1bReplace, wherein w is 1 to 12, R
1bBe piperidyl, pyrimidyl, pyrrolidyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, two [two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group)] amino, two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group) amino, phenyl, C
3-C
8Cycloalkyl, pyrrolidyl, and kharophen,
Described phenyl or C
3-C
8Cycloalkyl is arbitrarily by 1, and 2 or 3 substituting groups replace, and these substituting groups are C independently
1-C
6Alkyl, halogen or C
1-C
6Alkoxyl group; A be a key ,-(CH
2)
mOr-C (O)-; A
1Be a key ,-NR
a-,-O-,-(CH
2)
m-or-S (O)
n-; Q is 0 to 6; P is 0 to 6; N is 0,1 or 2; M is 0 to 6; S is 0 to 6; R
aBe hydrogen, C
1-C
6Alkyl or C
2-C
6Chain acyl; D is a key, C
2-C
4Alkenylene or-C (X) (Y)-,
Wherein among X and the Y is a hydroxyl, and another is a hydrogen, or X and Y the two be hydrogen, or X and Y form=O jointly, or=NOR
c
R
cBe hydrogen, benzyl, ethanoyl, benzoyl or C
1-C
6Alkyl; X
1And Y
1In one be hydroxyl, another is a hydrogen, or X
1And Y
1The two is hydrogen, or X
1And Y
1Common formation=O or=NOR
d
R
dBe hydrogen or C
1-C
6Alkyl; R
2Be hydroxyl, C
1-C
6Alkyl, C
1-C
6The base of alkoxyl group, phenoxy group or following general formula
R wherein
4And R
5Independent separately is hydrogen, C
1-C
6Alkyl, phenyl or phenyl (C
1-C
6Alkylidene group)-, or R
2Be heterocyclic radical, these heterocyclic radicals are selected from hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidyl, quinuclidinyl or morpholinyl;
Wherein any hexamethyleneimino, piperazinyl, heptamethylene imino-, imidazolinyl, piperidyl, 2-tryptolinyl, pyrrolidyl, quinuclidinyl or morpholinyl can be replaced by one or more substituting groups, and these substituting groups are selected from C
1-C
6Alkyl, halogen, trifluoromethyl, benzyl, phenyl, two (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group)-, C
1-C
6Alkylamino (C
1-C
6Alkylidene group)-, C
2-C
6Chain acyl, amido, 2-glycyl, C
2-C
6Chain acyloxy, C
1-C
6Carbalkoxy, C
1-C
6Alkylamino, C
3-C
8Cycloalkyl, piperidyl, pyrrolidyl, pyrimidyl, phenyl (C
1-C
6Alkylidene group)-, phenoxy group (C
1-C
6Alkylidene group)-, piperidyl (C
1-C
6Alkylidene group)-, pyrrolidyl (C
1-C
6Alkylidene group)-, pyrimidyl (C
1-C
6Alkylidene group)-, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio, two [two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group)] amino, two (C
1-C
6Alkyl) amino (C
1-C
6Alkylidene group) amino and kharophen,
Any one benzyl wherein, phenyl, piperidyl, C
3-C
8Cycloalkyl, phenyl (C
1-C
6Alkylidene group)-, phenoxy group (C
1-C
6Alkylidene group)-, pyrrolidyl, piperidyl (C
1-C
6Alkylidene group)-, pyrrolidyl (C
1-C
6Alkylidene group)-, pyrimidyl (C
1-C
6Alkylidene group)-or pyrimidyl can be replaced by one or more substituting groups, these substituting groups are selected from C
1-C
6Alkyl, halogen, trifluoromethyl, kharophen, C
2-C
6Chain acyl, C
2-C
7Chain acyloxy and C
1-C
6Alkoxyl group, or described piperidyl, pyrrolidyl, piperidyl (C
1-C
6Alkylidene group)-, pyrrolidyl (C
1-C
6Alkylidene group)-, pyrimidyl (C
1-C
6Alkylidene group)-or pyrimidyl on nitrogen-atoms can be replaced or R by amino protecting group
2Base for following general formula
R wherein
4a, R
5aAnd R
6aIndependent separately is hydrogen, C
1-C
6Alkyl, trifluoromethyl or C
1-C
6Alkoxyl group;
Or R
4aBe hydrogen, C
1-C
6Alkyl, trifluoromethyl or C
1-C
6Alkoxyl group, and R
5aAnd R
6aThe nitrogen that links to each other with them forms pyrrolidyl, piperidyl, hexamethyleneimino or heptamethylene imino-jointly;
Or R
4aBe oxygen, R
5aAnd R
6aForm pyrrolidyl, piperidyl, hexamethyleneimino or heptamethylene imino-jointly with the nitrogen that links to each other with them; R is phenyl, naphthyl, dihydro naphthyl, tetralyl, C
3-C
8Cycloalkyl, pyrazinyl, allyl group, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazyl, hexamethyleneimino, heptamethylene imino-, piperidyl, pyrrolidyl, quinuclidinyl or morpholinyl
Any phenyl wherein, naphthyl, dihydro naphthyl, tetralyl, C
3-C
8Cycloalkyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazyl, hexamethyleneimino, heptamethylene imino-, piperidyl, pyrrolidyl, quinuclidinyl, or morpholinyl can replace by one or more substituting groups, and these substituting groups are selected from C
1-C
12Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, halogen, trifluoromethyl, amido, cyano group, benzyl, phenyl, two (C
1-C
12Alkyl) amino, C
2-C
6Chain acyl, C
2-C
6Chain acyloxy, C
1-C
6Alkylamino, oxazolyl, dihydro-oxazole base, piperidyl (C
1-C
12Alkoxyl group)-, piperidyl (C
1-C
12Alkoxyl group) (C
1-C
6Alkylidene group)-, piperidyl (C
1-C
12Alkylidene group)-, phenyl (C
1-C
12Alkoxyl group)-, phenyl (C
2-C
12Alkylidene group)-, C
3-C
8Cycloalkyl, piperidyl, pyrimidyl, C
1-C
6Alkoxyl group, C
1-C
12Alkylthio, general formula R
xR
yN-G-L-(C
0-C
6Alkylidene group)-base and kharophen,
R wherein
xAnd R
yIndependent separately is hydrogen, C
1-C
6Alkyl, phenyl, benzyl, piperidyl, pyrrolidyl, hexamethyleneimino, heptamethylene imino-, morpholinyl, piperazinyl or C
3-C
8Cycloalkyl,
Perhaps R wherein
xR
yN is the ring that is selected from piperidyl, pyrrolidyl, hexamethyleneimino, heptamethylene imino-, azetidinyl, and this ring can link to each other with G by any suitable position,
G is C
1-C
12Alkylidene group, C
2-C
12Alkenylene or C
2-C
12Alkynylene, and
L be a key ,-O-,-S-,-S (O)-,-S (O)
2-or-NH-; Prerequisite is to work as A
1For-NR
a-,-O-or-S (O)
n-with A be-CH
2-time, R
1Be not hydrogen; Or the last acceptable salt or the solvate of their medicine.
2. the compound of claim 1, wherein R
1Be hydrogen or methyl, or R
1aBe piperidyl, pyrrolidyl, piperazinyl or quinuclidinyl, or acceptable salt or solvate on their medicine.
3. the compound of claim 2, wherein R
1aBe acceptable salt or solvate on piperidines-3-base, piperidines-2-base, tetramethyleneimine-3-base, tetramethyleneimine-2-base, piperidines-1-base, piperidin-4-yl, tetramethyleneimine-1-base or tetramethyleneimine-4-base, phenyl or their medicine.
4. the compound of claim 3, wherein A
1Be a key or-O-, or acceptable salt or solvate on their medicine.
5. the compound of claim 4, wherein-(CH
2)
q-D-(CH
2)
s-be a key, methylene radical, ethylidene or-C (O)-, or acceptable salt or solvate on their medicine.
6. the compound of claim 5, wherein X
1And Y
1The two is acceptable salt or solvate on hydrogen or their medicine.
7. the compound of claim 6, wherein R
2Amino, two (C serve as reasons
1-C
6Alkyl) amino, C
1-C
6The piperidyl that alkylamino or piperidyl replace, or R
2Amino, two (C serve as reasons
1-C
6Alkyl) amino, C
1-C
6The pyrrolidyl that alkylamino or pyrrolidyl replace, or R
2Be the piperazinyl that replaces by phenyl or cyclohexyl, or acceptable salt or solvate on their medicine.
8. the compound of claim 7, wherein-A-A
1-(CH
2)
p-be-CH
2-O-,-CH
2-NH-, or-CH
2-S-, or acceptable salt or solvate on their medicine.
9. the compound of claim 8, wherein R is naphthyl, phenyl, piperidyl, pyrrolidyl or cyclohexyl, or acceptable salt or solvate on their medicine.
10. the compound of claim 9, wherein R is 4 and 2 arbitrarily independent phenyl that replaced by halogen, or acceptable salt or solvate on their medicine.
11. a pharmaceutical preparation comprises wherein that each compound is an activeconstituents in the claim 1 to 10, acceptable carrier, thinner or vehicle combine on this activeconstituents and one or more medicines.
12. the compound of each of claim 1 to 10 is used for the treatment of and neuropeptide tyrosine or the excessive relevant illness of related peptides.
13. the method for treatment and the excessive relevant illness of neuropeptide tyrosine, this method comprise that the Mammals for the treatment of to needs takes arbitrary compound of the claim 1 to 10 of significant quantity.
14. the purposes of arbitrary compound of claim 1 to 10 in the medicine of the excessive relevant illness of preparation treatment and neuropeptide tyrosine.
15. be suitable for treating the formula of medicine with the excessive relevant illness of neuropeptide tyrosine, comprise arbitrary compound of claim 1 to 10 in this prescription.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US315095P | 1995-09-01 | 1995-09-01 | |
| US60/003,150 | 1995-09-01 | ||
| GB9523999.2 | 1995-11-23 | ||
| GBGB9523999.2A GB9523999D0 (en) | 1995-11-23 | 1995-11-23 | Indolyl neuropeptide y receptor antagonists |
| US2163896P | 1996-07-12 | 1996-07-12 | |
| US08/021,638 | 1996-07-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1173867A true CN1173867A (en) | 1998-02-18 |
Family
ID=27267993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96191324A Pending CN1173867A (en) | 1995-09-01 | 1996-08-30 | Indolyl neuropeptide Y receptor antagonists |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0789688A4 (en) |
| CN (1) | CN1173867A (en) |
| AU (1) | AU717422B2 (en) |
| BR (1) | BR9606619A (en) |
| CA (1) | CA2203912A1 (en) |
| CZ (1) | CZ132897A3 (en) |
| HU (1) | HUP9701714A3 (en) |
| IL (1) | IL120724A0 (en) |
| MX (1) | MX9703186A (en) |
| NO (1) | NO308296B1 (en) |
| NZ (1) | NZ318228A (en) |
| PL (1) | PL320010A1 (en) |
| TR (1) | TR199700334T1 (en) |
| WO (1) | WO1997009308A1 (en) |
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| CN111377821A (en) * | 2018-12-28 | 2020-07-07 | 南京艾德凯腾生物医药有限责任公司 | Method for synthesizing 4-isopropylamino-1-butanol |
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| IL115613A0 (en) * | 1994-10-20 | 1996-01-19 | Lilly Co Eli | Bicyclic neuropeptide y receptor antagonists |
-
1996
- 1996-08-30 CA CA002203912A patent/CA2203912A1/en not_active Abandoned
- 1996-08-30 MX MX9703186A patent/MX9703186A/en unknown
- 1996-08-30 EP EP96930691A patent/EP0789688A4/en not_active Withdrawn
- 1996-08-30 CN CN96191324A patent/CN1173867A/en active Pending
- 1996-08-30 BR BR9606619A patent/BR9606619A/en unknown
- 1996-08-30 NZ NZ318228A patent/NZ318228A/en unknown
- 1996-08-30 WO PCT/US1996/014163 patent/WO1997009308A1/en not_active Application Discontinuation
- 1996-08-30 IL IL12072496A patent/IL120724A0/en unknown
- 1996-08-30 PL PL96320010A patent/PL320010A1/en unknown
- 1996-08-30 HU HU9701714A patent/HUP9701714A3/en unknown
- 1996-08-30 CZ CZ971328A patent/CZ132897A3/en unknown
- 1996-08-30 AU AU69650/96A patent/AU717422B2/en not_active Ceased
- 1996-08-30 TR TR97/00334T patent/TR199700334T1/en unknown
-
1997
- 1997-04-30 NO NO972016A patent/NO308296B1/en not_active IP Right Cessation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016161826A1 (en) * | 2015-02-13 | 2016-10-13 | 上海适济生物科技有限公司 | Method for preparing 4-isopropylamino-1-butanol |
| US10144701B2 (en) | 2015-02-13 | 2018-12-04 | Seasons Biotechnology (Taizhou) Co., Ltd. | Method for preparing 4-isopropylamino-1-butanol |
| US10428012B2 (en) | 2015-02-13 | 2019-10-01 | Seasons Biotechnology Co., Ltd. | Method of preparation of 4-isopropylamino-1-butanol |
| CN105949135A (en) * | 2016-05-10 | 2016-09-21 | 湖南欧亚生物有限公司 | Synthetic method of selexipag |
| CN111377821A (en) * | 2018-12-28 | 2020-07-07 | 南京艾德凯腾生物医药有限责任公司 | Method for synthesizing 4-isopropylamino-1-butanol |
Also Published As
| Publication number | Publication date |
|---|---|
| AU717422B2 (en) | 2000-03-23 |
| TR199700334T1 (en) | 1997-08-21 |
| IL120724A0 (en) | 1997-08-14 |
| CZ132897A3 (en) | 1997-11-12 |
| NZ318228A (en) | 1999-07-29 |
| PL320010A1 (en) | 1997-09-01 |
| AU6965096A (en) | 1997-03-27 |
| HUP9701714A2 (en) | 1999-06-28 |
| NO972016D0 (en) | 1997-04-30 |
| NO308296B1 (en) | 2000-08-28 |
| HUP9701714A3 (en) | 2000-03-28 |
| CA2203912A1 (en) | 1997-03-13 |
| EP0789688A1 (en) | 1997-08-20 |
| NO972016L (en) | 1997-06-17 |
| BR9606619A (en) | 1997-12-23 |
| MX9703186A (en) | 1997-07-31 |
| WO1997009308A1 (en) | 1997-03-13 |
| EP0789688A4 (en) | 1997-11-19 |
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