CN1241994A - Substituted propionyl derivatives - Google Patents
Substituted propionyl derivatives Download PDFInfo
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- CN1241994A CN1241994A CN 97181034 CN97181034A CN1241994A CN 1241994 A CN1241994 A CN 1241994A CN 97181034 CN97181034 CN 97181034 CN 97181034 A CN97181034 A CN 97181034A CN 1241994 A CN1241994 A CN 1241994A
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- naphthyl
- formamyl
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- propionic acid
- pentyloxy
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Abstract
Q<1>-A<1>-Y<1> (1) Compounds represented by general formula (1) or salts thereof; and drugs containing the same as the active ingredient. Because of having potent squalene synthetase inhibitory effects, these compounds are useful as remedies or preventives for hypercholesterolemia, etc. In said formula, X<1> represents esterifiable carboxy, etc.; Y<1> represents a single bond, etc.; at least one of A<1>, A<2> and A<3> represents: -R<2>-a<1>-R<3>-a<2>}, wherein R<2> represents a divalent hydrocarbon group; R<3> represents a single bond etc.; a<1> and a<2> represent each a single bond, -S-, etc.; and } represents the bond to Q<1>, Q<2> or Q<3>; while the remainder(s) represent: -R<8>-a<3>-R<9>-a<4>}, wherein R<8> and R<9> represent each a single bond, etc.; a<3> and a<4> represent each a single bond, -S-, etc.; and } represents the bond to Q<1>, Q<2> or Q<3>; and at least one of Q<1>, Q<2> and Q<3> represents cyclic hydrocarbyl, etc., while the remainder(s) represent hydrogen, etc.
Description
The propionyl derivative that the present invention relates to replace; more particularly; the propionyl derivative that the present invention relates to replace, this derivative be based on having the squalene synthetase restraining effect, thereby can be used as treatment and prevention hypercholesterolemia, hyperlipoidemia or arteriosclerotic medicine.
In recent years, along with the increase that the westernization and the aging population of meals custom are taken advantage of a favourable situation, arteriosclerotic sickness rate is more and more higher, makes that also the cardiovascular and cerebrovascular diseases patient is increasing.Concerning the aging society of arriving, this class blood vessel kind disease has become serious social concern now.People recognize that extensively hypercholesterolemia is to cause arteriosclerotic primary hazard factor, and well-known be that the cholesterol depressant can be treated arteriosclerosis effectively.
At present, the cholesterol depressant mainly is hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, as lovastatin (US4231938), pravastatin (US4346227) and simvastatin (US4444784).
The HMG-CoA reductase enzyme is the rate-limiting enzyme in a kind of cholesterol biosynthesizing, and it is positioned at the relative upstream position of pathways metabolism.
Farnesylpyrophosphate is a kind of key metabolism intermediate, and it is to produce by latter stage the relative of pathways metabolism, through some steps farnesylpyrophosphate is changed into cholesterol again.The meta-bolites example that is transformed by farnesylpyrophosphate comprises non-sterols isoprene, as ubiquinone, dolichol and protoheme A.Non-sterols isoprene product has very important biological function, and for example, ubiquinone plays a key effect as the mitochondrial respiratory chain composition, and dolichol then is a long-chain alcohol involved in sugar albumen synthetic prerequisite.The restraining effect of HMG-CoA reductase enzyme says that in principle cholesterol not only capable of blocking is synthetic, and these essential elements capable of blocking is synthetic, thereby, just might bring side effect.So, the cholesterol depressant that the HMG-CoA reductase inhibitor is always not best.
In order to control cholesteric biosynthesizing and can not damage simultaneously biosynthesizing to biological essential element such as ubiquinone and dolichol, hope can suppress to compare with farnesylpyrophosphate the enzyme that is present in cholesterol biosynthetic pathway downstream.More particularly, post hope and suppress squalene synthetase.Described squalene synthetase has been controlled first committed step in the synthetic cholesteric approach, and responsible sterol is synthetic.Known compound as inhibitor for squalene synthetic enzyme comprises natural compounds at present, as zaragozic acids (" tetrahedron " (Tetrahedron)), 48 (47), 10221-10226 (1992)) and aqualestatins (" microbiotic magazine " (The Journalof Antibiotics), 45 (5) 639-647 (1992)); Also comprise the synthetic compound; as 4; 1-benzo oxygen azatropylidene derivative (EP 567026), the amino acid derivative (EP611749) and the α-phosphono sulfonic acid (" pharmaceutical chemistry magazine " (Journal ofMedicinal Chemistry), 39,661-664 (1996)) that replace.Yet, during these compound oral administration administrations, can't produce enough effects to cholesterol biosynthesizing and/or the cholesteric activity that suppresses that reduces in the blood.In addition, up to the present yet fail to illustrate the selectivity of these effects, thereby they also there is query as the application of medicine.
In order to treat and prevent hypercholesterolemia, hyperlipoidemia or arteriosclerosis, the inventor has furtherd investigate the restraining effect of squalene synthetase, and synthetic restraining effect of the shown cholesterol that goes out of squalene synthetase or blood cholesterol level reduction effect.Found that, can realize treatment and prevention hypercholesterolemia, hyperlipoidemia or arteriosclerotic purpose by the compound of following formula (1) expression, thereby finish the present invention.
Thereby, the invention provides a kind of propionyl derivative or its salt of the replacement by following formula (1) expression:
Wherein
X
1For can esterified carboxyl, tetrazolium-5-base, phosphonic acids or sulfonic acid group;
Y
1For singly-bound ,-O-or-N (R
1)-, wherein, R
1Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl;
A
1, A
2And A
3In at least a be the group of following formula (2) expression:
-R
2-a
1-R
3-a
2→ (2) wherein
R
2For replacing or bivalent hydrocarbon radical unsubstituted, that have 2-12 carbon atom R
3Be singly-bound, perhaps replace or bivalent hydrocarbon radical unsubstituted, that have 1-12 carbon atom a
1And a
2Be independently singly-bound ,-S-,-SO-,-SO
2-,-SO
2NH-,-O-,-N (R
4)-[wherein, R
4Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl] ,-CON (R
5)-[wherein, R
5Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl] ,-C (=O)-or Si (R
6) (R
7)-[wherein, R
6And R
7Independently for replacing or unsubstituted alkyl], → expression and Q
1, Q
2Or Q
3Key, A
1, A
2Or A
3In remaining one or both identical or different, each is the group of following formula (3) expression independently:
-R
8-a
3-R
9-a
4→ (3) wherein
R
8And R
9Be singly-bound independently, perhaps replace or bivalent hydrocarbon radical unsubstituted, that have 1-12 carbon atom a
3And a
4Be independently singly-bound ,-S-,-SO-,-SO
2-,-SO
2NH-,-O-,-N (R
10)-[wherein, R
10Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl] ,-CON (R
11)-[wherein, R
11Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl] ,-C (=O)-or Si (R
12) (R
13)-[wherein, R
12And R
13Independently for replacing or unsubstituted alkyl], → expression and Q
1, Q
2Or Q
3Key;
Q
1, Q
2Or Q
3In at least a for replacement or unsubstituted cyclic hydrocarbon radical or replacement or unsubstituted heterocyclic radical, Q
1, Q
2Or Q
3In remaining one or both be independently hydrogen atom, can esterified carboxyl, replacement or unsubstituted alkyl or replacement or unsubstituted heterocyclic.
The present invention also provides pharmaceutical composition, and it comprises propionyl derivative or its salt as above-mentioned formula (1) replacement of effective ingredient.
The present invention also provides pharmaceutical composition, and it comprises propionyl derivative or its salt and pharmaceutically acceptable carrier by the replacement of above-mentioned formula (1) expression.
The present invention also provides by the propionyl derivative of the replacement of above-mentioned formula (1) expression or its salt purposes as medicine.
The present invention also provides treatment hypercholesterolemia, hyperlipoidemia or arteriosclerotic method, comprises the propionyl derivative or its salt that give by the replacement of above-mentioned formula (1) expression.
In the formula (1) of the propionyl derivative that above-mentioned expression the present invention replaces, except that carboxyl, by X
1, Q
1, Q
2Or Q
3Expression and example that can esterified carboxyl comprise carbalkoxy, alkenyloxy carbonyl, alkanoyloxy carbalkoxy, alkyl oxy carbonyl oxygen carbalkoxy and formamyl oxygen base carbalkoxy.
The embodiment of carbalkoxy comprises C
1-7Carbalkoxy is as methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, the different third oxygen carbonyl, positive butoxy carbonyl, secondary butoxy carbonyl and tertbutyloxycarbonyl.The embodiment of alkenyloxy carbonyl comprises C
2-7The alkenyloxy carbonyl is as allyloxy carbonyl and 2-butylene oxygen base carbonyl.The example of alkanoyloxy carbalkoxy comprises (C
2-7Alkanoyloxy)-(C
1-7Carbalkoxy), as acetoxyl group methoxycarbonyl, 1-acetoxyl group ethoxycarbonyl, new pentane acyloxy methoxycarbonyl and 1-new pentane acyloxy ethoxycarbonyl.The example of alkyl oxy carbonyl oxygen carbalkoxy comprises (C
1-7Alkyl oxy carbonyl oxygen)-(C
1-7Carbalkoxy), as 1-(ethoxy carbonyl oxygen base) ethoxycarbonyl and 1-(cyclohexyl carbonyl oxygen base) ethoxycarbonyl.The embodiment of formamyl oxygen base carbalkoxy comprises formamyl oxygen base (C
1-7Carbalkoxy), as formamyl oxygen base methoxycarbonyl.In addition, the example that also can mention is (5-methyl-2-oxo-1,3-dioxole-4-yl) methoxycarbonyl.
Except that can esterified carboxyl, X
1Example comprise tetrazolium-5-base, phosphonyl group (PO
3H
2) and sulfonic acid group (SO
2H).Wherein, preferably can esterified carboxyl (COOR
14: wherein, R
14Ester residue for hydrogen atom or above-mentioned esterifying carboxyl group).Particularly preferred X
1Be carboxyl and carbalkoxy.
By R
1, R
4, R
5, R
6, R
7, R
10, R
11, R
12, R
13, Q
1, Q
2Or Q
3The replacement of expression or the example of unsubstituting hydrocarbyl comprise and replacing or unsubstituted, saturated or undersaturated alkyl, more particularly, be replacement or unsubstituted alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, aryl, aralkyl and aromatic yl alkenyl.
As alkyl, the C of preferred straight or branched
1-7Alkyl, the example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl butyl, 1-ethyl propyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-butyl, 2-ethyl-butyl, n-hexyl and n-heptyl, wherein, special preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and neo-pentyl.
As alkenyl, the C of preferred straight or branched
2-7Alkenyl, embodiment comprises: vinyl, allyl group, pseudoallyl, 1-propenyl, 2-methyl isophthalic acid-propenyl, 2-methyl-2-propenyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and 2-ethyl-1-butylene base, wherein, preferred especially allyl group, pseudoallyl and 3-methyl-2-butene base.
As alkynyl group, the C of preferred straight or branched
2-7Alkynyl group, the example comprises ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base, wherein, preferred especially ethynyl, 1-proyl and 2-propynyl.
As cycloalkyl, preferred C
3-7Cycloalkyl, preferred especially cyclopropyl, cyclobutyl and cyclopentyl.
As cycloalkenyl group, preferred C
3-7Cycloalkenyl group, preferred especially 2-cyclopentenes-1-base, 3-cyclopentenes-1-base, 2-tetrahydrobenzene-1-base and 3-tetrahydrobenzene-1-base.
The example of aryl comprises monocycle or fused polycycle C
6-18Aryl, as phenyl, naphthyl, anthryl and phenanthryl, preferred especially phenyl, 1-naphthyl and 2-naphthyl.
The example of aralkyl and aralkenyl comprises and is connected with C
1-7Alkyl and C
1-7The monocycle of alkenyl or fused polycycle C
7-18Aryl.Specific examples comprises benzyl, styroyl, the 3-phenyl propyl, the 4-phenyl butyl, the 5-phenylpentyl, 6-phenyl hexyl, 7-phenyl heptyl, the 1-menaphthyl, the 2-menaphthyl, 2-(1-naphthyl) ethyl, 2-(2-naphthyl) ethyl, 3-(1-naphthyl) propyl group, 3-(2-naphthyl) propyl group, 4-(1-naphthyl) butyl, 4-(2-naphthyl) butyl, 5-(1-naphthyl) amyl group, 5-(2-naphthyl) amyl group, 6-(1-naphthyl) hexyl, 6-(2-naphthyl) hexyl, 7-(1-naphthyl) heptyl, 7-(2-naphthyl) heptyl, 3-phenyl allyl group, 3-(1-naphthyl) allyl group and 3-(2-naphthyl) allyl group, preferred aralkyl, preferred especially benzyl, styroyl, the 3-phenyl propyl, the 2-naphthyl methyl, 2-(2-naphthyl) ethyl and 3-(2-naphthyl) propyl group.
The substituent example that above-mentioned alkyl can have comprises: hydroxyl, nitro, cyano group, halogen atom, amino, alkylamino, replacement or unsubstituted formamyl, alkanoyl, alkyl, alkoxyl group, can esterified carboxyl, aryl, aryloxy and aroyl, by optionally selecting 1-5 substituting group in the middle of their.Herein, the example of halogen atom comprises fluorine, chlorine, bromine and iodine atom.The example of alkylamino comprises one and dialkyl amido, more particularly, and one and two C
1-7Alkylamino is as methylamino-, ethylamino, third amino, isopropylamino, n-butyl amine base, dimethylamino, diethylin, ethylamino.The example that can have a substituent formamyl comprises can be by C
1-7The formamyl that alkyl and/or hydroxyl replace; as formamyl, N-methylamino formyl radical, N-ethylamino formyl radical, N-propyl group formamyl, N, N-formyl-dimethylamino, N-hydroxyl amino formyl radical, N-hydroxy-n-methylamino formyl radical and N-hydroxy-n-ethylamino formyl radical.The example of alkanoyl comprises C
1-7Alkyloyl is as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl and caproyl.The example of alkyl comprises C
1-7Alkyl is as methyl, ethyl, n-propyl, sec.-propyl and the tertiary butyl.The example of alkoxyl group is C
1-7Alkoxyl group is as methoxyl group, oxyethyl group, propoxy-, isopropoxy and tert.-butoxy.Example that can esterified carboxyl comprises: carboxyl, C
1-7Carbalkoxy is as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, different third oxygen carbonyl and the tertbutyloxycarbonyl.The example of aryl comprises phenyl and naphthyl.The example of aryloxy comprises phenoxy group and naphthyloxy, and the example of aroyl comprises benzoyl, toluyl and naphthoyl.
Have the replacement of 2-12 carbon atom or the example of unsubstituted bivalent hydrocarbon radical and comprise the alkylidene group of straight or branched, the alkylene group of straight or branched, the inferior alkynyl group and the arylidene of straight or branched, wherein, preferably have those of 2-10 carbon atom, especially preferably have those of 2-8 carbon atom, first-selection has those of 3-8 carbon atom.The example of the alkylidene group of straight or branched comprises ethylidene, trimethylene, propylidene, tetramethylene, butylidene, pentamethylene, hexa-methylene, heptamethylene, eight methylene radical, nine methylene radical, decamethylene, 11 methylene radical and ten dimethylenes.The example of straight or branched alkylene group comprises vinylidene, propenylidene, 1-crotonylidene, 2-crotonylidene and 1-inferior pentenyl.The example of the inferior alkynyl group of straight or branched comprises inferior proyl, 1-butynelene, 2-butynelene, the inferior pentynyl of 1-, the inferior pentynyl of 2-, the inferior hexin base of 1-, the inferior heptyne base of 1-and the inferior octyne base of 1-.The example of arylidene comprises phenylene.As these divalence C
2-12The substituting group of alkyl for example can be to exemplify by R above-mentioned
1, R
4, R
5, R
6, R
7, R
10, R
11, R
12Or R
13The similar substituting group of the alkyl of expression.
By R
3, R
8Or R
9The alkyl of expression, promptly having example 1-12 carbon atom, replacement or unsubstituted bivalent hydrocarbon radical comprises: the inferior alkynyl group and the arylidene of the alkylene group of straight or branched alkylidene group, straight or branched, straight or branched, wherein, preferably have those of 1-10 carbon atom, especially preferably have those of 1-8 carbon atom, first-selection has those of 3-8 carbon atom.The example of the alkylidene group of straight or branched comprises methylene radical, ethylidene, trimethylene, propylidene, tetramethylene, butylidene, pentamethylene, hexa-methylene, heptamethylene, eight methylene radical, nine methylene radical, decamethylene, 11 methylene radical and ten dimethylenes.The example of straight or branched alkylene group comprises vinylidene, propenylidene, 1-crotonylidene, 2-crotonylidene and 1-inferior pentenyl.The example of the inferior alkynyl group of straight or branched comprises inferior proyl, 1-butynelene, 2-butynelene, the inferior pentynyl of 1-, the inferior pentynyl of 2-, the inferior hexin base of 1-, the inferior heptyne base of 1-and the inferior octyne base of 1-.The example of arylidene comprises phenylene.As these divalence C
1-12The substituting group of alkyl for example can be to exemplify by R above-mentioned
1, R
4, R
5, R
6, R
7, R
10, R
11, R
12Or R
13The similar substituting group of the alkyl of expression.
By Q
1, Q
2Or Q
3The replacement of expression or the embodiment of unsubstituted cyclic hydrocarbon radical comprise have 6-18 carbon atom, saturated or undersaturated monocycle or fused polycycle alkyl, as phenyl, naphthyl, anthryl, phenanthryl, indanyl and indenyl.If these groups have multiple constitutional isomer, then the present invention also comprises these isomer.Wherein, the present invention preferably adopts phenyl, 1-naphthyl, 2-naphthyl, 5-indanyl etc.As the substituting group of these aryl, for example can be to exemplify by R to above-mentioned
1, R
4, R
5, R
6, R
7, R
10, R
11, R
12Or R
13The similar substituting group of the alkyl of expression.
By Q
1, Q
2Or Q
3The replacement of expression or the example of unsubstituted heterocyclic comprise aromatic heterocyclic radical and non-aromatic heterocycle.The example of aromatic heterocyclic radical comprises aromatic monocyclic heterocyclic radical and aromatic condensed heterocyclic radical.The specific examples of aromatic monocyclic heterocyclic radical comprises furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, piperazinyl and triazinyl, wherein, preferred furyl, thienyl and tetrazyl.
The example of aromatic condensed heterocyclic radical comprises: benzofuryl, isobenzofuran-base, benzo [b] thienyl, indyl, pseudoindoyl, the 1H-indazolyl, benzimidazolyl-benzoxazolyl, 1,2-benzoisoxazole base, benzothiazolyl, 1, the different benzothiazolyl of 2-, 1H-benzotriazole base, imidazopyridyl, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, the β-Ka Lin base, the gamma-carbolines base, acridyl phenoxazinyl, phenothiazinyl, phenazinyl, thianthrenyl, phenanthridinyl, phenanthroline base and indolizine base, wherein, preferred benzofuryl, benzo [b] thienyl benzoxazolyl and benzothiazolyl.
Term " non-aromatic heterocycle " is meant that at least two hydrogen atoms add to the above-mentioned saturated or unsaturated heterocycle base that exemplifies on the aromatic heterocyclic radical herein, the example comprises tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, THP trtrahydropyranyl, piperidyl, morpholinyl, piperazinyl, 2, the 3-dihydro benzo furyl, indolinyl, 4,5,6,7-tetrahydro indole base, 4,5,6,7-tetrahydrochysene indazole base, 3,4-dihydro-2H-benzopyranyl, the 2H-benzopyranyl, 1,2-dihydroquinoline base, 1,2,3, the 4-tetrahydric quinoline group, 1,2,3, the 4-tetrahydro isoquinolyl, 1,2-dihydro-isoquinoline base, 1,3-benzo dioxolyl and 1,4-benzo dioxane base, wherein, preferred 2, the 3-dihydro benzo furyl, 3,4-dihydro-2H-benzopyranyl, the 2H-benzopyranyl, 1,2-dihydroquinoline base and 1,3-benzo dioxolyl.
The substituent example of these heterocyclic groups comprises hydroxyl, halogen atom, alkyl, alkoxyl group and phenyl, therefrom optionally selects 1-5 substituting group.Among the present invention, halogen atom, alkyl and alkoxyl group are similar to those that exemplify previously.
As previously mentioned, A
1, A
2And A
3In at least a be group by formula (2) expression, A
1, A
2And A
3In all the other one or both identical or different, be group by formula (3) expression.Wherein, preferred A
1, A
2And A
3In one or both be group by formula (2a) expression:
R
2-a
1→ (2a) wherein, R
2, a
1With → have an identical as previously mentioned definition, and, remaining A
1, A
2And A
3Identical or different, be group by following formula (3a) expression:
-R
8-a
3-R
9-a
4→ (3a) wherein, R
8, R
9, a
3, a
4With → have an identical as previously mentioned definition.Occasionally, formula (2a) is meant wherein R
3And a
2Represent single bonded formula (2) simultaneously.
In formula (1) compound, preferred following compound: wherein, X
1Expression can esterified carboxyl (COOR
14), A
1Expression-R
2-a
1→, A
2Expression-R
8a-a
3a-R
9a-a
4a→, A
3Expression-R
8b-a
3b-R
9b-a
4b→, that is, and by the compound of following formula (1A) expression:
Wherein, R
14Expression hydrogen atom or ester residue,
R
8aAnd R
8bIdentical or different, have independently with to R
8Define identical definition,
a
3aAnd a
3bIdentical or different, have independently with to a
3Define identical definition,
R
9aAnd R
9bIdentical or different, have independently with to R
9Define identical definition,
a
4aAnd a
4bIdentical or different, have independently with to a
4Define identical definition,
Q
1aFor replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic,
Q
2aAnd Q
3aIn one be hydrogen atom or can esterified carboxyl, another perhaps replaces or unsubstituted heterocyclic for replacing or unsubstituted cyclic hydrocarbon radical; With
Y
1, a
1And R
2Identical with aforementioned definitions.
The compound of formula (1), wherein X
1Expression can esterified carboxyl (COOR
15), A
1The expression singly-bound (under the situation of formula (3), R
8, a
3, R
9And a
4The expression singly-bound), Q
1Expression hydrogen atom or replacement or unsubstituted alkyl (R
16), A
2Expression R
2-a
1→, promptly by the compound of following formula (1B) expression:
Wherein
R
15Be hydrogen atom or ester residue, R
16Be hydrogen atom, perhaps replace or unsubstituted alkyl,
Q
2bAnd Q
3bIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic and
Y
1, R
2, R
8, R
9, a
1, a
3And a
4Identical with aforementioned definitions.
Between formula (1A) and compound (1B), preferred formula (1A) compound.
More preferably in formula (1A), Q
1aAnd Q
2aIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic Q
3aBe hydrogen atom or can esterified carboxyl.
Preferably in formula (1A), group Y
1For singly-bound or-(NR
1)-, wherein, R
1Identical with aforementioned definitions.More preferably group Y
1For-(NR
1)-, wherein, first-selected R
1Be hydrogen atom or alkyl.
Preferably in formula (1A), group-R
8a-a
3a-R
9a-expression has the replacement or the unsubstituted bivalent hydrocarbon radical of 1-12 carbon atom, more preferably has the bivalent hydrocarbon radical of 3-8 carbon atom, and first-selection has the alkylidene group of 3-8 carbon atom.
Preferably in formula (1A), group-R
8b-a
3b-R
9b-a
4b→ expression singly-bound or have the replacement or the unsubstituted bivalent hydrocarbon radical of 1-12 carbon atom, more preferably singly-bound or have the bivalent hydrocarbon radical (alkylidene group that more preferably has 1-3 carbon atom) of 1-3 carbon atom, first-selected singly-bound or methylene radical.
Preferably in formula (1A), group a
1For singly-bound or-(NR
4)-, wherein, R
4Identical with aforementioned definitions, and-(NR
4)-in more preferably-NH-.
Preferably in formula (1A), group a
4aFor singly-bound or-(NR
10)-, wherein, R
10Identical with aforementioned definitions, and-(NR
10)-in more preferably-NH-.
Briefly, more preferably following formula (1A) compound, wherein, R
14Be hydrogen atom or ester residue,
Q
1aAnd Q
2aIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic,
Q
3aBe hydrogen atom or can esterified carboxyl,
a
1For singly-bound or-(NR
4)-, wherein, R
4It is identical with aforementioned definitions,
R
2Be replacement or unsubstituted bivalent hydrocarbon radical with 2-12 carbon atom,
Y
1For-(NR
1)-, wherein, R
1It is identical with aforementioned definitions,
Group-R
8a-a
3a-R
9a-be to replace or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom,
a
4aFor singly-bound or-(NR
10)-, wherein, R
10It is identical with aforementioned definitions,
R
8bHave with to R
8Define identical definition,
a
3bHave with to a
3Define identical definition,
R
9bHave with to R
9Define identical definition,
a
4bHave with to a
4Define identical definition.
More preferably following formula (1A) compound, wherein, R
14Be hydrogen atom or ester residue,
Q
1aAnd Q
2aIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic,
Q
3aBe hydrogen atom or can esterified carboxyl,
a
1For singly-bound or-(NR
4)-, wherein, R
4It is identical with aforementioned definitions,
R
2Be replacement or unsubstituted bivalent hydrocarbon radical with 2-12 carbon atom,
Y
1For-(NR
1)-, wherein, R
1It is identical with aforementioned definitions,
Group-R
8a-a
3a-R
9a-be to replace or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom,
a
4aFor singly-bound or-(NR
10)-, wherein, R
10It is identical with aforementioned definitions,
Group-R
8b-a
3b-R
9b-a
4bBe singly-bound, replacement or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom.
Example by the salt of the compound of formula (1) expression comprises pharmacologically acceptable salt, as metal-salt, for example sodium salt, sylvite, calcium salt and magnesium salts, ammonium salt, and organic amine salt, for example front three amine salt, triethylamine salt, dicyclohexyl amine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt and tert-butylamine salt.
The present invention can have steric isomer by the compound of formula (1) expression, as optically active isomer, diastereomer or geometrical isomer.These steric isomers and its mixture all are included within the scope of the invention.
The compound or its salt of formula (1) can hydrate or the existence of all kinds of SOLVENTS thing.They are also contained within the scope of the present invention.
In the compound of the present invention (1), following compound and its steric isomer preferred embodiment for mentioning especially.
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-new pentane acyloxy methoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
3-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
3-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] ethyl propionate
2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid new pentane acyloxy methyl esters
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[4-(2-naphthyloxy) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-[4-(2-naphthyl) butyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[4-(2-naphthyl amino) butyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(2-hydroxyl-oxethyl)-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
3-(2-hydroxyl-oxethyl)-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
2-hydroxyl-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-hydroxyl-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] methyl propionate
2-hydroxyl-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid new pentane acyloxy methyl esters
2-carboxyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid new pentane acyloxy methyl esters
2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-oxyethyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[4-(2-naphthyloxy) butoxy] propionic acid
2-(2-oxopropoxy)-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyloxy) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-[3-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-(3, the 4-dichloro benzyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-(N-neo-pentyl formamyl)-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-hydroxy-n-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-10-(2-naphthyl)-3-[5-(2-naphthyl) pentyloxy]-4-oxo capric acid
2-carboxyl methoxyl group-3-[N-(7-phenyl heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(2-naphthyl) pentyloxy]-3-[N-[3-(3-Phenoxyphenyl) propyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2-naphthyl) pentyloxy]-3-[N-[5-(4-Phenoxyphenyl) propyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[7-(2-naphthyl) oxygen base in heptan] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[7-(2-naphthyl) oxygen base in heptan] ethyl propionate
2-(2-hydroxyl-oxethyl)-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(2-oxopropoxy)-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[4-(2-naphthyloxy) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-propyl group-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-isobutyl--N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-benzyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-[N-[5-(2-naphthyl) amyl group] formamyl] methoxyl group-3-[5-(2-naphthyl) pentyloxy] succsinic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-phenyl pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[7-phenyl oxygen in heptan base] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-chloro-phenyl-) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-phenyl-) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-chloro-phenyl-) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(4-chloro-phenyl-) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2,4 dichloro benzene base) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(4-aminomethyl phenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-p-methoxy-phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(4-trifluoromethyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(4-tert-butyl-phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-fluorophenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-ethoxycarbonyl methoxyl group-3-[5-(4-fluorophenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-cyano-phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-carboxyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-aminophenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(4-nitrophenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3-chloro-4-aminomethyl phenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-chloro-3-aminomethyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-fluoro-4-aminomethyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-fluoro-3-aminomethyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-chloro-3-fluorophenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(Z)-5-(4-aminomethyl phenyl)-4-pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(E)-5-(4-aminomethyl phenyl)-4-pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4-ethylphenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-[4-(2-propyl group) phenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-[4-(2-methyl isophthalic acid-propyl group) phenyl] pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-[4-(3-methyl isophthalic acid-butyl) phenyl] pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(Z)-5-(3, the 4-3,5-dimethylphenyl)-4-amylene oxygen base]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(E)-5-(3, the 4-3,5-dimethylphenyl)-4-amylene oxygen base]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3, the 4-3,5-dimethylphenyl) hexyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(Z)-6-(3, the 4-3,5-dimethylphenyl)-5-hexenyl]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(E)-6-(3, the 4-3,5-dimethylphenyl)-5-hexene thiazolinyl]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[7-(3, the 4-3,5-dimethylphenyl) oxygen base in heptan]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(Z)-7-(3, the 4-3,5-dimethylphenyl)-6-heptene oxygen base]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[(E)-7-(3, the 4-3,5-dimethylphenyl)-6-heptene oxygen base]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(4-chloro-phenyl-) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(4-aminomethyl phenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(4-fluorophenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3, the 4-dichlorophenyl) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(4-chloro-phenyl-) hexyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[6-(4-aminomethyl phenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[6-(4-fluorophenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3, the 4-3,5-dimethylphenyl) hexyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3, the 4-dichlorophenyl) hexyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3-chloro-4-aminomethyl phenyl) hexyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(4-chloro-phenyl-) heptyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[7-(4-aminomethyl phenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[7-(4-fluorophenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3, the 4-3,5-dimethylphenyl) heptyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3, the 4-dichlorophenyl) heptyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3-chloro-4-aminomethyl phenyl) heptyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[4-(3, the 4-dimethyl phenoxy) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(4-chloro-phenyl-) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(4-aminomethyl phenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(4-fluorophenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3, the 4-dichlorophenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(4-chloro-phenyl-) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(4-aminomethyl phenyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(4-fluorophenyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3, the 4-3,5-dimethylphenyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3, the 4-dichlorophenyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3-chloro-4-aminomethyl phenyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(4-chloro-phenyl-) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(4-aminomethyl phenyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(4-fluorophenyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3, the 4-3,5-dimethylphenyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3, the 4-dichlorophenyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3-chloro-4-aminomethyl phenyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(2-naphthyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(2-naphthyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[6-(2-naphthyl) hexyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(2-naphthyl) hexyl] formamyl]-3-[6-(2-naphthyl) hexyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(2-naphthyl) heptyl] formamyl]-3-[6-(2-naphthyl) hexyloxy] propionic acid
2-carboxyl methoxyl group-3-[7-(2-naphthyl) oxygen base in heptan]-3-[N-[6-(2-naphthyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(2-naphthyl) heptyl] formamyl]-3-[7-(2-naphthyl) oxygen base in heptan] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(1-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(1,3-benzo dioxole-5-yl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-benzoxazolyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(2-benzoxazolyl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(2-benzoxazolyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-[4-morpholinodithio base) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-benzofuryl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(2-benzofuryl) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(2-benzofuryl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(1,3-benzo dioxole-5-yl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(1,3-benzo dioxole-5-yl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2-benzoxazolyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-ethoxycarbonyl methoxyl group-3-[5-(2-benzoxazolyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2-[4-morpholinodithio base) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-ethoxycarbonyl methoxyl group-3-[5-(2-[4-morpholinodithio base) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-ethoxycarbonyl methoxyl group-3-[5-(2-benzoxazolyl) pentyloxy]-3-[N-[5-(1,3-benzo dioxole-5-yl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2-benzimidazolyl-) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(5-chloro-2-benzoxazolyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2-imidazo [4,5-b] pyridyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(1,4-benzo dioxane-6-yl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-[2-(2-propyl group)-4-oxazolyl] pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-[2-phenyl-4-oxazolyl] pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(5-benzofuryl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(5-benzothiazolyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(5-benzo [b] thienyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(2,3-dihydro-5-benzo [b] thienyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(6-imidazo [1,5-a] pyridyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(7-imidazo [1,2-a] pyridyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(6-quinoxalinyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(6-quinolyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3-furyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(3-thienyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(3-pyrryl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(4,5-dimethyl-2-thiazolyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4,5-dimethyl-2-oxazolyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(5-benzoxazolyl oxygen base) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(7-quinolyl oxygen base) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(7-isoquinolyl oxygen base) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(4,5-dimethyl pyrimidine-2-yl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(4-pyridyl) pentyloxy] propionic acid
2-carbamyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N, N-formyl-dimethylamino) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-morpholino carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy]-2-(Piperazino methoxyl group) propionic acid
2-(4-methylpiperazine subbase) carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-methoxycarbonyl methylamino formyl radical) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-[N-(2-methoxy ethyl) formamyl] methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-diazanyl carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-hydroxyl amino formyl radical) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-methoxyl group formamyl) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-methoxyl group-N-methylamino formyl radical) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(morpholinyl-2-oxopropoxy)-3-[4-(2-naphthyloxy) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-[(2S-methoxycarbonyl pyrrolidino) carbonyl] methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-ethylamino formyl radical oxygen base)-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-benzyloxy formamyl) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(2-isoxazole alkyl subbase) carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-hydroxy-n-methylamino formyl radical) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(N-methoxyl group formamyl) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-sulfonyloxy methyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2,3-dihydroxyl propoxy--3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-[N-(anti--the 4-hydroxy-cyclohexyl) formamyl] methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-[N-(methyl sulphonyl) formamyl] methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-[N-(aminomethyl phenyl alkylsulfonyl) formamyl] methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy]-2-[N-(sulfamyl) formamyl oxygen base] propionic acid
3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-2-[2-morpholino oxyethyl group)-3-[5-(2-naphthyl) pentyloxy] propionic acid
3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy]-2-(pyridine subbase carbonyl methoxyl group) propionic acid
3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy]-2-(N-tert.-butoxy formamyl) methoxypropionic acid
2-[N-(4-dimethylamino phenyl) formamyl] methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-acetoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-(2-hydroxyl-3-morpholino propoxy-)-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[4-(2-naphthyloxy) butoxy] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[6-(3, the 4-3,5-dimethylphenyl) hexyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[7-(3, the 4-3,5-dimethylphenyl) oxygen base in heptan]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-acetoxy-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-hydroxyl-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-acetoxy-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-acetoxy-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-methyl-N-methoxyl group formamyl) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-methoxyl group formamyl) methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-methoxyl group formamyl) methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-(N-benzyloxy formamyl) methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-(N-benzyloxy formamyl) methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-(2, the 5-Dimethoxyphenyl) carbonyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(2-p-methoxy-phenyl) carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(2-furyl) carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(2-thiazolyl) carbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-methoxymethoxy-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-(2-hydroxy phenyl) formamyl) methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-(4-hydroxy phenyl) formamyl) methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[N-[5-(1,3-benzo dioxole-5-yl) amyl group] formamyl]-2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
3-[N-[5-(1,3-benzo dioxole-5-yl) amyl group]-N-methylamino formyl radical]-2-ethoxycarbonyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
3-[N-[5-(1,3-benzo dioxole-5-yl) amyl group]-N-methylamino formyl radical]-2-ethoxycarbonyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl]-the 2-third oxygen carbonyl methoxypropionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[6-(3, the 4-3,5-dimethylphenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[7-(3, the 4-3,5-dimethylphenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[7-(3-chloro-4-aminomethyl phenyl) oxygen base in heptan]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[7-(3, the 4-dichlorophenyl) oxygen base in heptan]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Though still there are many unknown parts for the arteriosclerotic cause of disease,, it is believed that the LDL that oxidation induces low-density lipoprotein (LDL) to be transformed into oxidation is a major reason.Particularly, the LDL of oxidation is absorbed by scavenger cell in the blood vessel endothelium, yet, because excessively picked-up will be gathered a large amount of cholesterol esters in the scavenger cell, and finally become foam, cause blood vessel endothelium to break.This is considered to the arteriosclerotic starting stage.Reach the output of control LDL except the control cholesterol is synthetic, the positive inhibition of the LDL oxidation (degraded) that oxidation-resistance material such as free-radical scavengers carry out also is to suppress the powerful measure that arteriosclerosis takes place, generations such as described free-radical scavengers may command active oxygen, and described active oxygen for example becomes and carries out the reason that sequestering action carries out oxidation by iron ion etc.Consider that from the angle of validity and security the image angle squalene synthetase inhibitor is the same, reduce cholesteric content and can not damage antioxidant in the organism such as the biosynthesizing of ubiquinone or dolichol is very important.Thereby, have the inhibiting compound expection of synthetic restraining effect of squalene and antioxygenation LDL oxidation (degeneration) simultaneously and have higher effectiveness.
Compound of the present invention comprises having the compound that squalene synthetase suppresses active and anti-oxidant activity simultaneously.Following compound and its steric isomer are the typical compound with above-mentioned two kinds of effects.
2-carboxyl methoxyl group-3-[N-[5-(3,5-dimethyl-4-hydroxy phenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[7-(3,5-dimethyl-4-hydroxy phenyl) heptyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(3,5-dimethyl-4-hydroxy phenyl) pentyloxy] propionic acid
2-ethoxycarbonyl methoxyl group-3-[N-[5-(3,5-dimethyl-4-hydroxy phenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3, the 5-di-tert-butyl-hydroxy phenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3,4-dihydro-6-hydroxyl-2,5,7,8-tetramethyl--2H-1-cumarone-2-yl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) pentyloxy] formamyl]-3-[4-(2-naphthyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) pentyloxy] formamyl]-3-[4-(3,4,5-trimethoxyphenyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) pentyloxy] formamyl]-3-[4-(1,2-dihydro-2,2,4-trimethylquinoline-6-oxygen base) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-[4-(3,4,5-trimethoxyphenyl amino) butyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[4-(3,5-Dimethoxyphenyl amino) butyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group]-3-[4-(3,5-Dimethoxyphenyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[4-(3-p-methoxy-phenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(4-p-methoxy-phenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(2,4-3,5-dimethylphenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3,4-Dimethoxyphenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(1,3-benzo dioxole-5-base is amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[4-(2,4,6-trimethylphenyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[4-(6-benzothiazolyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(5-indanyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(4-chloro-3-aminomethyl phenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(4-aminomethyl phenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(4-chloro-phenyl-) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(4-fluorophenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(3-chloro-4-aminomethyl phenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[6-(4-aminomethyl phenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[6-(4-chloro-phenyl-) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[6-(4-fluorophenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[6-(3, the 4-3,5-dimethylphenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[6-(3-chloro-4-aminomethyl phenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[6-(2-naphthyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[7-(4-aminomethyl phenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[7-(4-chloro-phenyl-) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[7-(4-fluorophenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[7-(3, the 4-3,5-dimethylphenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[7-(3-chloro-4-aminomethyl phenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[7-(2-naphthyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl amino) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl amino) pentyloxy]-3-[N-[6-(2-naphthyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl amino) pentyloxy]-3-[N-[7-(2-naphthyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl amino) pentyloxy]-3-[N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl amino) pentyloxy]-3-[N-[6-(3, the 4-3,5-dimethylphenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl amino) pentyloxy]-3-[N-[7-(3, the 4-3,5-dimethylphenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3-chloro-4-aminomethyl phenyl amino) hexyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3-chloro-4-aminomethyl phenyl amino) hexyloxy]-3-[N-[6-(2-naphthyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3-chloro-4-aminomethyl phenyl amino) hexyloxy]-3-[N-[7-(2-naphthyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3-chloro-4-aminomethyl phenyl amino) hexyloxy]-3-[N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3-chloro-4-aminomethyl phenyl amino) hexyloxy]-3-[N-[6-(3, the 4-3,5-dimethylphenyl) hexyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[6-(3-chloro-4-aminomethyl phenyl amino) hexyloxy]-3-[N-[7-(3, the 4-3,5-dimethylphenyl) heptyl] formamyl] propionic acid
2-carboxyl methoxyl group-3-[3-[N-(4-dimethylaminophenyl) formamyl] propoxy-]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[3-[N-(4-dimethylaminophenyl) formamyl] propoxy-]-3-[N-[5-(3, the 4-3,5-dimethylphenyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(2-naphthyl) amyl group]-N-propyl group formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-(5-indanyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-ethoxycarbonyl methoxyl group-3-[4-(5-indanyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-[N-(3-chloro-4-aminomethyl phenyl)-N-methylamino] butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-[N-(3-chloro-4-aminomethyl phenyl)-N-(phenyl methyl) amino] butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[4-[N-(3-chloro-4-aminomethyl phenyl amino] butoxy]-3-[N-[5-(3, the 4-dichlorophenyl) amyl group] formamyl] propionic acid
3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-hydroxyl-3-[4-(5-indanyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[N-[4-(3,4-3,5-dimethylphenyl amino) butyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3-chloro-4-aminomethyl phenyl amino) hexyl] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[4-(3-chloro-4-aminomethyl phenyl amino) butyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxypropionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxypropionic acid
2-carboxyl methoxyl group-3-[N-[6-(3-chloro-4-aminomethyl phenyl amino) hexyl] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[6-(3-chloro-4-aminomethyl phenyl amino) hexyl]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxypropionic acid
2-carboxyl methoxyl group-3-[5-(3,4-3,5-dimethylphenyl amino) pentyloxy]-3-[N-[5-(5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2 hydroxy propanoic acid
3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2 hydroxy propanoic acid
3-[5-(3,4-3,5-dimethylphenyl amino) pentyloxy]-2-hydroxyl-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[4-(3, the 4-3,5-dimethylphenyl) butoxy] propionic acid
2-carboxyl methoxyl group-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[4-(5-indanyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[4-(5-indanyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[4-(5-indanyl amino) butoxy]-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-2 hydroxy propanoic acid
3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-2 hydroxy propanoic acid
3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-hydroxyl-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-2 hydroxy propanoic acid
3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-2 hydroxy propanoic acid
3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-2-hydroxyl-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-2-hydroxyl-3-[4-(5-indanyl amino) butoxy] propionic acid
3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-2-hydroxyl-3-[4-(5-indanyl amino) butoxy] propionic acid
2-hydroxyl-3-[4-(5-indanyl amino) butoxy]-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[4-(4-aminomethyl phenyl amino) butoxy] propionic acid
2-carboxyl methoxyl group-3-[4-(4-p-methoxy-phenyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
3-[4-(1,3-benzo dioxole-5-base is amino) butoxy]-2-carboxyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3,4-Dimethoxyphenyl amino) pentyloxy]-3-[N-methyl-N-[5-(4-aminomethyl phenyl amino) amyl group] formamyl] propionic acid
2-carboxyl methoxyl group-3-[5-(3,4-Dimethoxyphenyl amino) pentyloxy]-3-[N-[5-(4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical] propionic acid
2-carboxyl methoxyl group-3-[5-(3,4-Dimethoxyphenyl amino) pentyloxy]-3-[N-[5-(1,3-benzo dioxole-5-base is amino) amyl group]-N-methylamino formyl radical] propionic acid
Compound of the present invention (1) can be for example by method A as described below, method B or method C preparation.[method A]
Be used for the method for preparation by the compound (1-1) of formula (1) expression, in the compound (1-1), X
1Expression can esterified carboxyl, Y
1Expression-O-or N (R
1)-:
Wherein, R
17Expression hydrogen atom or ester residue, Y
1aExpression-O-or N (R
1)-, Q
1, Q
2, Q
3, A
1, A
2, A
3And R
1Has foregoing definition.
Above-claimed cpd (1-1) can be according to following reaction scheme (A-1) preparation, for example adopts compound (2) [" organic chemistry magazine " (Journal of Organic Chmistry, 50,3462 (1985)] etc.[reaction scheme (A-1)]
Wherein, R
18, R
20And R
21Represent the ester residue independently, R
19Expression is used for the protecting group of hydroxyl, Q
1ARepresent that its functional group can protected Q
1, Q
2ARepresent that its functional group can protected Q
2, Q
3ARepresent that its functional group can protected Q
3, LG represents leavings group, A
1, A
2, A
3, Y
1aAnd R
13Has foregoing definition.
In above-mentioned reaction scheme, by R
18, R
20And R
21The embodiment of ester residue of expression comprises alkyl, allyl group and aralkyl (as benzyl, nitrobenzyl, to methoxy-benzyl and diphenyl methyl).The example that is used for the protecting group of hydroxyl comprises benzyl, nitrobenzyl, to methoxy-benzyl, diphenyl methyl, trityl group, methoxymethyl, benzyloxymethyl, t-butyldimethylsilyl and t-butyldiphenylsilyl.The example of leavings group comprises halogen atom and sulfonyloxy, as mesyloxy and tolysulfonyl oxygen base.Q
1, Q
2Or Q
3The example of protecting group of functional group comprise the protecting group that is used for hydroxyl or carboxyl, as alkyl, allyl alkene, aralkyl, methoxymethyl, THP trtrahydropyranyl, trityl group, t-butyldimethylsilyl, t-butyldiphenylsilyl and 2-trimethyl silyl ethyl; With the protecting group that is used for amino or alkylamino, as acyl group, carbalkoxy and aralkoxycarbonyl.
In inert solvent, carry out in the presence of alkali by compound (2) and compound (3) preparation compound (4) or by the reaction process that compound (9) and compound (10) prepare compound (11), and, be 1 mole or excessive (preferred 1-2 mole) formula (3) or formula (10) compound and 1 mole of raw material (2) or (9) reaction.The example of inert solvent comprises ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide and methyl-sulphoxide and its mixture.The example of alkali comprises hydrogenant basic metal such as sodium hydride, lithium hydride and potassium hydride KH; Alkali metal ammonia compound such as lithamide, di-isopropyl lithamide, two trimethyl silyl lithamide, lithium alkylide such as lithium methide, butyllithium, tert-butyl lithium; With the metal alkylide alcoholate, as sodium methylate, sodium ethylate and potassium tert.-butoxide.In raw material, the consumption of alkali is generally 1 mole or excessive, preferred 1-3 mole.Temperature of reaction is generally-100 ℃ to the boiling point that is used for reacting solvent, preferred-78 ℃ to 80 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 20 minutes to 24 hours.
Reaction process by compound (4) preparation compound (5) is carried out in the presence of inert solvent (methylene dichloride, tetrahydrofuran (THF) etc.) and acid, and described acid for example is hydrochloric acid, acetate, trifluoroacetic acid or tosic acid.
Hydrolytic process as the compound (6) of lactone for example is in solvent such as tetrahydrofuran (THF) or ethanol, finish by the aqueous solution effect of itself and alkali metal hydroxide or carbonate, described alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, alkali-metal carbonate such as yellow soda ash or salt of wormwood.
Method for oxidation as the compound (7) of primary alconol; the method that promptly prepares corresponding carboxylic acid is to adopt Jones reagent (Organic Synthesis, IV, 310; 1973) carry out, oxygenant and compound (7) are reacted in the presence of the nitroxyl derivative.Be used for for example can adopting clorox, sodium bromite, Losantin etc. as oxygenant by the method that in the presence of the nitroxyl derivative, prepares corresponding carboxylic acid with the oxygenant effect; and at nitroxyl derivative such as 4-benzoyloxy 2; 2; 6,6-tetramethyl-piperidyl-1-oxygen base free radical carries out under existing.In raw material, the add-on of nitroxyl derivative is 0.5-3 mole %, preferred 1 mole of %.As solvent, can adopt solvent mixture, as acetonitrile and sodium bicarbonate aqueous solution to the solvent of reactionlessness.Temperature of reaction is generally-78 ℃ of zeolites to the solvent that is used to react, preferred-20 ℃ to 50 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 30 minutes to 24 hours.
Thereby the oxidation primary alconol prepares another method of corresponding carboxylic acid, according to Swern method for oxidation (Journal of Organic Chemistry, 43,2480,1978), adopt oxalyl chloride and methyl-sulphoxide, primary alconol is changed into corresponding aldehyde, again according to Dess-Martinperiodinane (Journal of Organic Chemistry, 48,4155,1983) carry out oxidation, perhaps adopt four n-propyls to cross the ruthenic acid ammonium and 4-methylmorpholine-4-oxide compound etc. carries out oxidation (Synthesis, 639,1994), after this, in the presence of Textone etc., carry out oxidation again and change into corresponding carboxylic acid.
The method for preparing compound (14) by compound (12) and compound (13) is compound (13) and the condensing agent reaction that makes 1 mole of raw material (12) and 1 mole or excessive (preferred 1-2 mole) in inert solvent.If necessary, above-mentioned reaction can be carried out in the presence of alkali, described alkali is as being triethylamine or 4-Dimethylamino pyridine, and then, also can add the N-oxy-compound, as I-hydroxybenzotriazole, N-hydroxyl succinic diamide or N-hydroxyphthalimide or oxybenzene compound such as 4-nitrophenols, 2,2, 4-dinitrophenol, 2,4,5-Trichlorophenol or pentachlorophenol are as reaction accelerator.The example of inert solvent comprises methylene dichloride, chloroform, ethylene dichloride, ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide, acetonitrile, acetoneand ethyl acetate and its mixture.The example of condensing agent comprises N, N '-dicyclohexyl carbodiimide and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride.1 mole raw material (12) adopts 1 mole or excessive condensing agent usually, preferred 1-3 mole.Temperature of reaction be generally for-100 ℃ to the boiling point that is used for reacting solvent, preferred-78 ℃ to 80 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 30 minutes to 24 hours.
To the reaction of compound (7), introducing protecting group by compound (6), in esterification by compound (6) carboxylic acid and from compound (7) to the reaction of compound (8) to compound (7), and by compound (8) to compound (9) and by compound (11) to compound (12) with by compound (14) the leaving away of protecting group to the compound (1-1), difference according to protecting group or ester kind there are differences, but, can carry out according to the described method of following document: " ProtectiveGroups in Organic Synthesis ", the 2nd edition, T.W.Green, P.G.M.Wuts is by John ﹠amp; Sons publishes, and perhaps carry out according to similar method (1991).For example, the method for removing protecting group can adopt acid or alkali to be hydrolyzed, and carries out hydrogenation in the presence of palladium-Pd/carbon catalyst or Raney nickel, adopts the method for trifluoroacetic acid etc.
Compound (7) in reaction scheme (A-1) also can be synthetic according to following reaction scheme (A-2).Reaction scheme (A-2)
Wherein, R
22Expression is used for the protecting group of hydroxyl, LG, A
2, Q
2A, R
19, R
20And R
21Has foregoing definition.
Can transform (reduction) by compound (17) according to " Chemistry Letters; 1389-1392 (1984) " described method and become compound (18), particularly, in the presence of inert solvent such as tetrahydrofuran (THF), the sodium borohydride of borine-dimethyl thioether title complex and catalytic amount is acted on to compound (17).Preparation process except that above-mentioned steps can be carried out according to the described process of reaction scheme (A-1).
Compound (9) in reaction scheme (A-1) also can synthesize according to following reaction scheme (A-3): reaction scheme (A-3)
Wherein, LG, A
2, Q
2A, R
20And R
21Has definition as previously mentioned.
Process by compound (23) preparation compound (22) is to make 1 mole to excessive in inert solvent in the presence of Lewis acid, and the reductive agent of preferred 1-5 mole and 1 mole raw material (22) react.The example of inert solvent comprises tetrahydrofuran (THF), diox, benzene, toluene and N, dinethylformamide and its mixture.The example of Lewis acid comprises diethyl methoxyl group borine, and in the molar weight of raw material (22), its common consumption is 1 mole or excessive, preferred 1-3 mole.The example of reductive agent comprises the metal hydride title complex, as sodium borohydride, trimethoxy sodium borohydride and diisobutyl sodium hydride.Temperature of reaction be generally for-78 ℃ to the boiling point that is used for reacting solvent, preferred-50 ℃ to 50 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 1 hour to 24 hours.
Oxygenated compound (23) thus the process for preparing corresponding carboxylic acid intermediate can carry out in a conventional manner, particularly, in the liquid mixture of inert solvent and biphosphate sodium water solution, in the presence of the 2-methyl-2-butene, make 1 mole raw material (23) and the oxidant reaction of 1 mole or excessive (preferred 3-30 mole).The example of inert solvent comprises tetrahydrofuran (THF), diox, benzene, toluene, N, the dinethylformamide and the trimethyl carbinol and its mixture.The example of oxygenant is a Textone.Temperature of reaction be generally for-78 ℃ to the boiling point that is used for reacting solvent, preferred-20 ℃ to 50 ℃.Reaction times is generally 1 hour to 5 days, preferred 3 hours to 3 days.
Preparation process except that above-mentioned steps can be carried out according to the described method of reaction scheme (A-1).
Compound (1-1) also can adopt tartrate to synthesize as raw material according to following reaction scheme (A-4).Reaction scheme (A-4)
Wherein, R
17, R
20, R
21, LG, A
1, A
2, A
3, Q
1A, Q
2A, Q
3A, Q
1, Q
2, Q
3And Y
1aHas definition as previously mentioned.
In the reaction scheme (A-4), the reaction in each step can be carried out according to reaction scheme (A-1), (A-2) or method (A-3).Compound (14) can be according to the method described above by making the compound (13) and the mixture of compound (12) and compound (12a) carry out condensation, and purifying obtains by separating also in the compound (14a) by silica gel column chromatography then.
Similarly reaction can will be used for above-mentioned reaction scheme (A-1) to (A-4)
LG-A
2-Q
2A(3)，
LG-A
3-Q
3A(10) and
Q
1A-A
1-Y
1a-H (13) replaces
LG-A
2A-O-PG
2(101)，
LG-A
3A-O-PG
3(102) and
PG
1-O-A
1A-Y
1a-H (103) wherein, PG
1, PG
2And PG
3Expression is used for the protecting group of hydroxyl or ester residue independently, and other has identical as previously mentioned definition.Each intermediate by prepared in reaction can prepare the purpose compound by eliminating protecting group (PG) and carry out following reaction in the suitable step of reacting afterwards.For example, at reaction scheme (A
1) in intermediate (14) can pass through the described step of reaction scheme (A5-1) and introduce.Reaction scheme A5-1
Wherein, each symbol has definition as previously mentioned.
In above-mentioned reaction scheme, by PG
2The example of the protecting group that is used for hydroxyl of expression comprises benzyl, nitrobenzyl, to methoxy-benzyl, diphenyl methyl, trityl group, methoxymethyl, benzyloxymethyl, THP trtrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and 2-trimethyl silyl ethyl.
The method that is prepared compound (104) by compound (21) is in inert solvent, the diester (21) by 1 mole in the presence of alkali with 1 mole or excessive, the compound reaction of formula (101) expression of preferred 1-2 mole.The example of inert solvent comprises ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide and methyl-sulphoxide and its mixture.The example of alkali comprises hydrogenant basic metal such as sodium hydride, lithium hydride and potassium hydride KH; Alkali metal ammonia compound such as lithium amide, diisopropylaminoethyl lithium, two trimethyl silyl lithium amide, two trimethyl silyl sodium amides, two trimethyl silyl amination potassium, lithium alkylide such as lithium methide, butyllithium, tert-butyl lithium; With the metal alkylide alcoholate, as sodium methylate, sodium ethylate and potassium tert.-butoxide.In raw material (21), the consumption of alkali is generally 1 mole or excessive, preferred 1-3 mole.Temperature of reaction is generally-100 ℃ to the boiling point that is used for reacting solvent, preferred-78 ℃ to 80 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 20 minutes to 24 hours.
All can carry out by each step of compound (104) preparation compound (110) according to above-mentioned reaction scheme (A-1), (A-2) or method (A-3).
Below provide the method a-d that tool is stopped in the above-mentioned reaction scheme.
Shown in following reaction scheme (A5-2); method a for example method a-1 is: be used for by oxidising process alkylol cpd (110) being changed into corresponding ketone or formylation compound; carrying out Wittig reaction again makes formula (112) De phosphonium salts and compound (111) reacts in the presence of alkali; or phosphonate (ester) derivative of formula (113) and compound (111) are reacted in the presence of alkali, thereby make compound (111) form corresponding vinylidene derivative (14-1).Perhaps, sulfonamide derivatives (14-2) can react the compound (111) and the sulfonamide derivatives of formula (114) by (method a-2), adopts suitable reductive agent or catalytic reduction to react then and prepares.
Reaction scheme A5-2
Wherein, Z
1Expression chlorine, bromine or iodine atom, R
101And R
103Represent hydrogen atom or replacement or unsubstituted alkyl independently, R
102Expression replaces or unsubstituted alkyl, and all the other groups have identical as previously mentioned definition.
In above-mentioned reaction scheme, by R
101Or R
103The replacement or the unsubstituted alkyl and aforementioned of expression by R
1The group that exemplifies is similar, by R
102The replacement of expression or the example of unsubstituted alkyl comprise ethyl and 2,2, the 2-trifluoroethyl.
Prepare compound (110) by oxidizing reaction by compound (111) in a conventional manner, for example according to the Swern method for oxidation, adopt oxalyl chloride and methyl-sulphoxide, with Dess-Martinperiodinane or adopt four n-propyls to cross the ruthenic acid ammonium and 4-methylmorpholine-4-oxide compound carries out oxidation.
By compound (111) preparation compound (14-1), particularly, in inert solvent, 1 mole of tool is extremely excessive in the presence of alkali, the formula (112) of preferred 1-3 mole or (113) and 1 mole of carbonyl derivative (111) reaction in a conventional manner.The example of inert solvent comprises ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide and methyl-sulphoxide and its mixture.The example of alkali comprises hydrogenant basic metal such as sodium hydride, lithium hydride and potassium hydride KH; Alkali metal ammonia compound such as lithium amide, diisopropylaminoethyl lithium, two trimethyl silyl lithium amide, two trimethyl silyl sodium amide and two trimethyl silyl amination potassium; Lithium alkylide such as lithium methide, butyllithium, tert-butyl lithium; With the metal alkylide alcoholate, as sodium methylate, sodium ethylate, 2-methyl-2-butanols potassium and potassium tert.-butoxide.In 1 mole compound (112) or (113), the consumption of alkali is generally 1 mole or excessive, preferred 1-3 mole.Temperature of reaction is generally-100 ℃ to the boiling point that is used for reacting solvent, preferred-78 ℃ to 80 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 30 minutes to 24 hours.Preferably after alkali and compound (112) or (113) are preferentially mixed, reaction is begun by adding carbonyl derivative (111).
In inert solvent, make 1 mole or excessive, the sulfonamide derivatives of the formula (114) of preferred 1-2 mole and the reaction of 1 mole carbonyl derivative (111), in the presence of catalyzer such as palladium charcoal, carry out hydrogenation then, perhaps with 1 mole or excessive, the reductive agent such as the effect of hydrogenant metal complexes of preferred 1-3 mole are by compound (111) preparation compound (14-2).The example of inert solvent comprises glycol dimethyl ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide and N,N-dimethylacetamide; Alcohol is as methyl alcohol and ethanol and its mixture.The example of hydrogenant metal complexes comprises sodium borohydride, lithium borohydride and sodium cyanoborohydride.Temperature of reaction is generally-78 ℃ to the boiling point that is used for reacting solvent, preferred-78 ℃ to 80 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 30 minutes to 24 hours.
Method b is the method (method b-1) by so-called Mitsunobu prepared in reaction compound (14-3), even formula (115) compound, diethyl azodiformate (DEAD) and triphenyl phosphine (PPh3) and alkylol cpd (110) reaction are shown in following reaction scheme (A5-3).Perhaps, compound (14-4) can prepare like this: the dinitrobenzene sulfone amide derivative that makes formula (116) expression is with diethyl azodiformate and triphenyl phosphine and compound (110) reaction, then in the presence of alkali such as triethylamine with mercaptoethanol acid-respons (method b-2).Reaction scheme (A5-3)
Method b-1:
Wherein, each symbol has definition as hereinbefore.
By compound (110) preparation compound (14-3) is in inert solvent, makes 1 mole or excessive, compound, diethyl azodiformate and the triphenyl phosphine of the formula (115) of preferred 1-3 mole and the reaction of 1 mole alkylol cpd (110).The example of inert solvent comprises ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide and methyl-sulphoxide; With its mixture.Temperature of reaction is generally-78 ℃ to the boiling point that is used for reacting solvent, preferred-20 ℃ to 60 ℃.Reaction times is generally 5 minutes to 48 hours, preferred 30 minutes to 24 hours.
The first step by compound (110) preparation compound (14-4) is in inert solvent, makes 1 mole or excessive, compound, diethyl azodiformate and the triphenyl phosphine of the formula (116) of preferred 1-3 mole and the reaction of 1 mole alkylol cpd (110).The example of inert solvent comprises ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide and methyl-sulphoxide; With its mixture.Temperature of reaction is generally-78 ℃ to the boiling point that is used for reacting solvent, preferred-20 ℃ to 60 ℃.Reaction times is generally 5 minutes to 48 hours, preferred 30 minutes to 24 hours.Second step was in inert solvent, in the presence of alkali, made 1 mole or excessive, the mercaptoethanol acid of preferred 1-5 mole and 1 mole of intermediate reaction that obtains suddenly in previous step.The example of inert solvent comprises: methylene dichloride, ether, tetrahydrofuran (THF), diox, benzene, toluene and N, dinethylformamide and its mixture.The example of alkali comprises alkylamine, and as triethylamine, alkaline carbonate such as salt of wormwood and alkali-metal oxyhydroxide are as lithium hydroxide.In 1 mole of intermediate, the consumption of alkali is generally 1 mole to excessive, preferred 1-10 mole.Temperature of reaction is generally-78 ℃ to the boiling point that is used for reacting solvent, preferred-20 ℃ to 60 ℃.Reaction times is generally 5 minutes to 36 hours, preferred 10 minutes to 24 hours.
Method c for example (method c-1 or c-3) is a kind of like this compound (14-3) or method (14-5) of preparing: by make the hydroxyl activation of alkylol cpd (110) with suitable elimination group, thereby alkylol cpd (110) is changed into compound (117), the compound and the compound (117) of formula (115) or (118) are reacted, in the presence of alkali shown in following reaction scheme (A5-4).Perhaps, compound (14-4) can prepare like this: the dinitrobenzene sulfone amide derivative of formula (116) and compound (117) are reacted in the presence of alkali, react (method c-2) with mercaptoethanol acid then in the presence of alkali such as triethylamine.Reaction scheme (A5-4)
Wherein, LG2 has as described above the identical definition of LG (leavings group), and other has identical as previously mentioned definition.
Prepare compound (117) according to ordinary method by compound (110), particularly, carry out halogenating reaction, mesyloxy formation reaction, phenylsulfonyloxy formation reaction or the formation of tolysulfonyl oxygen base and react.The chlorination reaction that the example of halogenating reaction carries out with thionyl chloride, bromination reaction that carries out with boron tribromide or two bromo triphenyl phosphines and the iodination reaction of carrying out with sodium iodide and trimethylchlorosilane.Mesyloxy forms reaction, phenylsulfonyloxy forms reaction or tolysulfonyl oxygen base formation reaction is in the presence of alkali, makes the reaction of methylsulfonyl chloride, benzene methylsulfonyl chloride or Tosyl chloride and compound (117) respectively.
In inert solvent, in the presence of alkali, make 1 mole or excessive, the formula (115) of preferred 1-3 mole, the compound of (116) or (117) and 1 mole compound (117) reaction, thus prepare compound (14-3), (14-4) or (14-5) by compound (117).The example of inert solvent comprises ether, tetrahydrofuran (THF), diox, benzene, toluene, N, dinethylformamide, methyl-sulphoxide, methylene dichloride and acetonitrile and its mixture.The example of alkali comprises hydrogenant basic metal such as sodium hydride, lithium hydride and potassium hydride KH; Alkali metal ammonia compound such as lithium amide, diisopropylaminoethyl lithium, two trimethyl silyl lithium amide, two trimethyl silyl sodium amide and two trimethyl silyl amination potassium; Lithium alkylide such as lithium methide, butyllithium, tert-butyl lithium; The metal alkylide alcoholate is as sodium methylate, sodium ethylate and potassium tert.-butoxide and alkaline carbonate such as yellow soda ash and salt of wormwood.In 1 mole compound (115), (116) or (118), the consumption of alkali is generally 1 mole or excessive, preferred 1-3 mole.Temperature of reaction is generally-50 ℃ to the boiling point that is used for reacting solvent, preferred-20 ℃ to 80 ℃.Reaction times is generally 10 minutes to 48 hours, preferred 30 minutes to 24 hours.Second step of method c-2 can be similar to the mode in second step of method b-2 and carry out.
Following described method d.When protecting group PG2 is the ester residue in above-claimed cpd (109), represent by formula (119) by the compound (110) that deprotection obtains, and under other situation, compound (110) can change into compound (119) by oxidizing reaction.Method d for example is a kind of method that acts on this carboxylic acid cpd (119).Particularly, shown in reaction scheme (A5-5), method d is in the presence of condensing agent, makes the reaction of the compound of formula (115) or (114) and compound (119) and is used to prepare the method for ester derivative (14-6) or amide derivatives (14-7).Reaction scheme (A5-5)
Wherein, each symbol has identical as previously mentioned definition.
According to method shown in the above-mentioned reaction scheme (A-1) and or (14-7) by compound (119) preparation compound (14-6) by compound (110) preparation compound (119).
Except the described method of above-mentioned reaction scheme (A5-1), the method that adopts compound (101), (102) or (103) to prepare compound (14) will be described below.
For example, according to the described method of reaction scheme (A6), adopt compound (103) preparation compound (14).Particularly; compound (14) can prepare like this: make compound (103) and condensing agent and compound (11) prepared in reaction compound (120); then, make and remove the alkylol cpd (122) that obtains behind the protecting group PG1 by compound (120) and carry out any method among the method a-d.Perhaps, compound (122) can replace compound (103) carry out condensation preparing by the alcohol (121) that adopts the unprotect base.Reaction scheme (A6)
Wherein, PG1 has identical definition with PG2, and other symbol has identical as described above definition.
In above reaction scheme, all carry out according to the method in the above-mentioned reaction scheme by compound (11) to each preparation process of compound (14).
The method that is prepared compound (14) by compound (102) will be described in following reaction scheme (A7-1).Particularly, compound (102) reacts with compound (9), and it is changed into compound (123).Behind deprotection, carry out the condensation reaction with compound (13), thereby obtain compound (125).Make the alkylol cpd (126) that obtains behind compound (125) deprotection carry out any method among the method a-d, thereby obtain compound (14).Reaction scheme (A7-1)
Wherein, PG3 has identical definition with PG2, and other symbol has identical as previously mentioned definition.
In above reaction scheme, all carry out according to the method in the above-mentioned reaction scheme by compound (9) to each preparation process of compound (14).
What below show is that the another kind of above-mentioned reaction scheme (A7-1) prepares the method for compound (125).Particularly, compound (125) is preparation like this: the hydroxyl of compound (9) is protected with suitable protecting group, thereby obtained compound (127), remove the ester residue R of compound (127)
16, form corresponding carboxylic acid (128), carry out condensation with compound (13), obtain compound (129), remove protecting group R
15, introduce compound (102) then.Reaction scheme (A7-2)
Wherein, each symbol has identical as previously mentioned definition.
In above reaction scheme, all carry out according to the method in the above-mentioned reaction scheme by compound (9) to each preparation process of compound (125).[method B]
Be used to prepare the method for compound (1-2), in the compound (1-2), X
1For can esterified carboxyl in the formula (1), Y
1Be the singly-bound in the formula (1):
Wherein, R
17Expression hydrogen atom or ester residue, A
1, A
2, A
3, Q
1, Q
2And Q
3Has identical as previously mentioned definition.
Compound (1-2) for example can prepare according to following reaction scheme (B).
Wherein, LG
1The expression leavings group, as halogen atom or N-methyl-N-methoxyl group amino, M represents basic metal, MgBr, MgCl, ZnBr etc., LG, R
15, R
16, R
18, A
1, A
2, A
3, Q
1A, Q
2A, Q
3A, Q
1, Q
2And Q
3Has identical as previously mentioned definition.
Process by compound (27) preparation compound (29) for example can be carried out like this: compound (27) and activatory nucleophilic reagent (28) are reacted in inert solvent (tetrahydrofuran (THF) etc.) as an alkali metal salt (as lithium, sodium or sylvite) or Grignard reagent.Preparation process in other step can adopt with above-mentioned reaction scheme (A-1), (A-2), (A-3) and (A-4) similarly method carry out.[method C]
Be used to prepare the method for compound (1-3), in this compound, X
1Be the tetrazolium in the formula (1)-5-base: P90
Wherein, Y
1, A
1, A
2, A
3, Q
1, Q
2And Q
3Has identical as previously mentioned definition.
Compound (1-3) for example can prepare according to following reaction scheme (C).
Wherein, R
17, Y
1, A
1, A
2, A
3, Q
1, Q
2, Q
3, Q
1A, Q
2AAnd Q
3AHas identical as described above definition.
Process by compound (32) preparation compound (1-3) is, for example, the method that adopts by routine, with compound (32)-COOR
17After changing into the free carboxy acid or changing into the free carboxy acid, change into formamyl; The compound of trifluoroacetic anhydride and formation is reacted in the presence of thionyl chloride or alkali such as pyridine, convert it into corresponding nitrile compound (33); Then, make compound (33) carry out conventional tetrazolium and form reaction, for example at inert solvent such as N, in the dinethylformamide, Lewis acid as aluminum chloride, ammonium chloride or pyridinium chloride in the presence of, compound (33) and even sodium nitride are reacted.Deprotection reaction can above-mentioned reaction scheme (A-1) in similarly mode carry out.
In above-mentioned reaction scheme, the compound with required steric configuration can make as raw material by the compound that employing has a required steric configuration, for example, adopts L-(±)-tartrate, D-(-)-tartrate, mesotartaric acid etc.Then, can prepare any and have (2R, 3R), (2S, 3S), (2R, 3S) and (2S, 3R) compound of the formula of steric configuration (1).
The formula that is obtained (1) compound can be according to ordinary method, by changing into corresponding salt with reactions such as metal hydroxides, organic amines.
As later general can find out in an embodiment, The compounds of this invention (1) or its salt have excellent squalene synthetase restraining effect and the synthetic restraining effect of cholesterol, and has antioxygenation, thereby it can be used as treatment and prevention hypercholesterolemia, hyperlipoidemia or arteriosclerotic medicine.
When formula of the present invention (1) compound or its salt was used as medicine, although dosage is relevant with the illness of age, sex or individual patient, preferably the dosage of being grown up every day was 0.1mg to 1g, more preferably 0.5mg to 100mg.
Every day, dosage can single administration or 2-4 administration of branch.If necessary, every day, dosage can surpass above-mentioned scope.
To the administering mode of the medicine that contains compound (1) or its salt or formulation particular restriction not.With regard to the various compounding method of preparation that routine adopts, by adding the medicine of the suitable form of medication of pharmaceutical carrier preparation as required.
The example of oral preparations comprises: solid preparation, as tablet, pulvis, granule, pill and capsule, liquid preparation is as solution, syrup, elixir, suspension liquor and emulsion.
When drug administration by injection, the solution of compound (1) or its salt can be charged in the bottle, its lyophilize is become solid preparation, its before use reprovision become liquid preparation.Can add stablizer, sanitas, solubilizing agent etc. as required.The dose or the multidose of injection can be charged in the bottle.
The example of external preparation comprises liquid and solution, suspension, emulsion, ointment, gel, creme, lotion, aerosol, liniment, ointment, suppository, paste, inhalation and collyrium.
Solid preparation can comprise the pharmaceutically acceptable additive except that active compound, and said preparation can be selected required for example suitable weighting agent, supplement, tackiness agent, disintegrating agent, solubilising accelerator, wetting agent etc. and mix with it.
Embodiment
By following embodiment the present invention is described in more detail.Yet the present invention is not subjected to the restriction of these embodiment.Embodiment 1 (2R, 3R)-2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
(1) (2R, 3R)-3-carbobenzoxy-(Cbz)-3-hydroxyl-2-[5-(2-naphthyl)-pentenyl oxygen base] the propionic acid tert-butyl ester and (2R, 3R)-3-carbobenzoxy-(Cbz)-2-hydroxyl-3-[5-(2-naphthyl)-pentenyl oxygen base] the propionic acid tert-butyl ester
(60% oily dispersion liquid 1.60g) is suspended in N, in the dinethylformamide (120ml) with sodium hydride.Under the frozen water cooling, in the suspension that forms, add L-tartrate benzyl tertiary butyl ester (13.55g), subsequently, in about 10 minutes, be added dropwise to the N of 5-(2-naphthyl)-pentenyl iodine (10.9g), dinethylformamide (50ml) solution.After at room temperature stirring 2 hours, reaction mixture is poured in the mixture of frozen water (400ml) and saturated brine (200ml), extracted with ethyl acetate subsequently.Extraction liquid saturated brine washed twice, decompression steams solvent.Resistates (is used 10-20% ethyl acetate-hexane wash-out) several times with silica gel chromatography, thereby obtains the mixture (6.42g) of oily title compound.Mass (EI) m/Z:490 (M
+).
1H-NMR (CDCl
3) δ: 1.46,1.48 (total 9H, s each), 2.36-2.43 (2H, m), and 2.78-2.84 (2H, m), 3.06,3.13 (total 1H, d each, J=8.8/8.3Hz), 3.77,3.89 (total 1H, dd each, J=11.7,6.8/11.7,7.3Hz), 4.09,4.21 (total 1H, dd each, J=10.7,7.3/11.7,5.9Hz), 4.15,4.30 (total 1H, d each, J=2.4/2.4Hz), 4.48,4.59 (total1H, dd each, J=7.8,2.4/8.8,2.4Hz), 5.14,5.21,5.27 (total 2H, deach, J=12.2/12.2/12.2Hz), 5.31-5.38,5.51-5.75 (total 2H, meach), and 7.28-7.46 (8H, m), 7.58 (1H, s), 7.74-7.80 (3H, m). (2) (2R, 3R)-3-carbobenzoxy-(Cbz)-3-tertiary butyloxycarbonyl ylmethoxy-2-[5-(2-naphthyl)-pentenyl oxygen base] the propionic acid tert-butyl ester and (2R, 3R)-3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(2-naphthyl)-pentenyl oxygen base] the propionic acid tert-butyl ester
The mixture (1.97g) that (1) is obtained is dissolved in N, in the dinethylformamide (20ml).(60% oily dispersion liquid 0.19g), is added dropwise to the N of bromo-acetic acid tert-butyl (1.09g) again, dinethylformamide (3ml) solution to add sodium hydride in the solution that forms.After at room temperature stirring 2 hours, the mixture that forms is poured in the mixture of frozen water (100ml) frozen water and saturated brine, extracted with ethyl acetate.With extraction liquid saturated brine washed twice, use anhydrous sodium sulfate drying.Then, decompression steams solvent.Resistates is with silica gel chromatography (with 9% ethyl acetate-hexane wash-out), thereby obtains the mixture (1.22g) of oily title compound.
1H-NMR (CDCl
3) δ: 1.43,1.44,1.46, (1.48 total 18H, s each), 2.34-2.43 (4H, m), and 2.78-2.83 (4H, m), 3.79-3.84,3.87-3.92 (total 1H, meach), 4.01,4.13 (total 1H, d each, J=16.6/16.1Hz), 4.08-4.12,4.17-4.22 (total 1H, m each), 4.25,4.26 (total 1H, d each, J=16.1/16.6Hz), 4.25,4.42 (total1H, d each, J=2.9/2.9Hz), 4.48,4.71 (total 1H, deach, J=2.9/2.9Hz), 5.13, (5.25 total 1H, d eachJ=12.2/12.2Hz), 5.23,5.28 (total 1H, d each, J=12.2/12.2Hz), 5.35-5.45,5.53-5.74 (total 2H, m each), and 7.27-7.44 (8H, m), 7.57 (1H, s), and 7.74-7.80 (3H, m). (3) (2R, 3R)-3-carboxyl-3-tertiary butyloxycarbonyl ylmethoxy-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carboxyl-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
The mixture (0.75g) that obtains in (2) is dissolved in the mixing solutions of ethanol (8ml) and tetrahydrofuran (THF) (5ml).In the solution that forms, add 10% palladium-charcoal (0.1g), mixture was stirred 13.5 hours under nitrogen atmosphere.After removing by filter palladium-Pd/carbon catalyst, removal of solvent under reduced pressure from filtrate, thereby the mixture (0.56g) of acquisition oily title compound.Mass (FAB+) m/Z:539 (M+Na)
+.
1H-NMR (CDCl
3) δ: 1.43-1.52 (20H, m), 1.60-1.73 (4H; m), and 2.72-2.78 (2H, m); 3.40-3.47 (1H, m), 3.64-3.69; 3.74-3.79 (total 1H; meach), 4.02,4.03 (total 1H; d each; J=16.1/17.1Hz), 4.28-4.31,4.35-4.41 (total 3H; m each); 7.23-7.44 (3H, m), 7.57; 7.59 (total 1H; s each), and 7.74-7.79 (3H, m). (4) (2R; 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
The mixture (0.53g) that obtains in (3) is dissolved in the methylene dichloride (15ml), adds 5-(2-naphthyl) amylamine hydrochloride (0.275g) and 4-Dimethylamino pyridine (0.136g) again.Under the frozen water cooling, in the mixture that forms, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.257g).After at room temperature stirring 21 hours, decompression steams solvent.Resistates is dissolved in the ethyl acetate.The solution that forms is washed with 0.5N hydrochloric acid and saturated brine, use anhydrous sodium sulfate drying then.Resistates silica gel chromatography (with 25-30% ethyl acetate-hexane wash-out); thereby from eluting fraction faster, obtain buttery (2R, 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.22g).Mass(EI)m/Z：711(M
+).
1H-NMR(CDCl
3)δ：1.37-1.46(4H，m)，1.44(9H，s)，1.51(9H，s)，1.54-1.72(8H，m)，2.71-2.76(4H，m)，3.22-3.29(2H，m)，3.32-3.38(1H，m)，3.73-3.78(1H，m)，3.86(1H，d，J＝16.6Hz)，4.26(1H，d，J＝16.6Hz)，4.27(1H，d，J＝2.9Hz)，4.32(1H，d，J＝2.9Hz)，7.26-7.29(2H，m)，7.36-7.43(4H，m)，7.56(2H，s)，7.69-7.77(6H，m)，7.86(1H，dd，J＝5.8，5.3Hz).
In addition, from slower eluting fraction, obtain buttery (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.21g).Mass (EI) m/Z:711 (M
+).
1H-NMR (CDCl
3) δ: 1.34-1.44 (4H, m), 1.42 (9H, s); 1.48 (9H, s), 1.54-1.57 (4H, m); 1.64-1.73 (4H, m), 2.71-2.76 (4H, m); 3.28 (2H, dd, J=13.2,6.8Hz); 3.35-3.41 (1H, m), 3.42-3.47 (1H, m); 3.87 (1H, d, J=16.1Hz), 4.15 (1H; d, J=1.9Hz), 4.25 (1H, d; J=16.1Hz), 4.31 (1H, d, J=1.9Hz); 6.68 (1H, t, J=5.8Hz), 7.29 (2H; d, J=8.3Hz), 7.37-7.44 (4H; m), 7.57 (2H, s); 7.72-7.78 (6H, m). (5) (2R, 3R)-and 2-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
(2R with (4) acquisition; 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.21g) is dissolved in the methylene dichloride (2ml), adds trifluoroacetic acid (2ml) again under the frozen water cooling.After at room temperature stirring 2.5 hours, decompression steams solvent, thereby obtains oily title compound (0.17g).Mass (FAB+) m/Z:600 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26-1.33 (4H, m), 1.45-1.52 (4H, m); 1.59-1.67 (4H, m), 2.70 (4H, m); 3.17-3.27 (2H, m), 3.37-3.43 (1H, m); 3.46-3.51 (1H, m), 4.17 (1H, d; J=17.1Hz), 4.28 (1H, d, J=17.1Hz); 4.35 (1H, s), 4.31 (1H, s); 7.01 (1H, broad), 7.24 (2H, s); 7.35-7.41 (4H, m), 7.54 (2H; s), and 7.70-7.75 (6H, m); 10.27 (～3H, broad). embodiment 2 (2R, 3R)-3-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
With with the identical mode of embodiment 1-(5); by embodiment 1-(4) make (2R, 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.18g) preparation oily title compound (0.15g).Mass (FAB+) m/Z:600 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.25-1.38 (4H, m), 1.46-1.70 (8H, m); 2.66-2.72 (4H, m), 3.18-3.23 (2H, m); 3.32 (1H, dd, J=15.6,6.8Hz); 3.70 (1H, dd, J=15.6,6.8Hz); 4.16 (2H, s), 4.36 (1H, d; J=2.4Hz), 4.42 (1H, d; J=2.4Hz), and 7.22-7.26 (2H, m); 7.36-7.42 (4H, m), 7.52 (1H; s), 7.54 (1H, s); 7.67-7.76 (6H, m). embodiment 3 (2R, 3R)-3-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
(1) (2R, 3R)-3-carbobenzoxy-(Cbz)-2-ethoxycarbonyl methoxyl group-3-[5-(2-naphthyl)-2-pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carbobenzoxy-(Cbz)-3-ethoxycarbonyl methoxyl group-2-[5-(2-naphthyl)-2-pentyloxy] the propionic acid tert-butyl ester
With with the identical mode of embodiment 1-(2), just replace bromo-acetic acid tert-butyl by ethyl bromoacetate, (the 2R that makes by embodiment 1-(1), 3R)-3-carbobenzoxy-(Cbz)-2-hydroxyl-3-[5-(2-naphthyl)-2-pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carbobenzoxy-(Cbz)-3-hydroxyl-2-[5-(2-naphthyl)-2-pentyloxy] mixture (2.63g) of mixture (3.17g) preparation colorless oil title compound of the propionic acid tert-butyl ester.Mass (EI) m/Z:576 (M
+).
1H-NMR (CDCl
3) δ: 1.22-1.27 (3H, m), 1.46, (1.48 total 9H, s each), 2.36-2.43 (2H, m), and 2.78-2.83 (2H, m), 3.79-3.83,3.87-3.92 (total1H, dd each, J=11.7,6.8Hz), 4.08-4.27 (4.5H, m), 4.37,4.38 (total 1H, d each, J=16.6/16.6Hz), 4.43,4.48,4.69 (total 1.5H, d each, J=2.9/2.9/2.9Hz), 5.12,5.22,5.25,5.28 (total 2H, d each, J=12.2/12.2/11.2/11.2Hz), 5.34-5.42,5.53-5.74 (total 2H, meach), and 7.28-7.46 (3H, m), 7.57 (1H, s), 7.74-7.80 (3H, m). (2) (2R, 3R)-3-carboxyl-2-ethoxycarbonyl methoxyl group-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carboxyl-3-ethoxycarbonyl methoxyl group-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
With with the identical mode of embodiment 1-(3), handle the mixture (2.63g) that (1) obtains, thereby obtain the mixture (2.16g) of colorless oil title compound.Mass (EI) m/Z:488 (M
+).
1H-NMR (CDCl
3) δ: 1.25,1.29 (total 3H, t each; J=6.8/7.3Hz), and 1.36-1.50 (11H, m); 1.62-1.71 (4H, m), 2.72-2.78 (2H; m); 3.40-3.46 (1H, m), 3.64-3.81 (1H; m); 4.11-4.29 (4H, m), 4.35-4.48 (2H; m); 7.27-7.44 (3H, m), 7.57; 7.59 (total 1H; s each), and 7.73-7.79 (3H, m). (3) (2R; 3R)-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
With with the identical mode of embodiment 1-(4), handle the mixture (3.29g) that (2) obtain.Carry out silica gel column chromatography (33% ethyl acetate-hexane wash-out) purifying; from eluting fraction faster, obtain colorless oil (2R, 3R)-3-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.893g).Mass(EI)m/Z：683(M
+).
1H-NMR(CDCl
3)δ：1.26(3H，t，J＝6.3Hz)，1.35-1.5(4H，m)，1.51(9H，s)，1.5-1.85(8H，m)，2.7-2.9(4H，m)，3.2-3.45(3H，m)，3.7-3.85(1H，m)，3.99(1H，d，J＝16.6Hz)，4.12-4.25(2H，m)，4.3-4.5(3H，m)，7.2-7.3(2H，m)，7.34-7.46(4H，m)，7.57(2H，s)，7.65-7.82(6H，m).
In addition, from slower eluting fraction, obtain colorless oil (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (1.03g).Mass (EI) m/Z:683 (M
+).
1H-NMR (CDCl
3) δ: 1.21 (3H, t, J=6.8Hz), 1.28-1.43 (4H, m); 1.49 (9H, s), 1.52-1.63 (4H, m); 1.63-1.78 (4H, m), 2.70-2.80 (4H, m); 3.20-3.33 (2H, m), 3.33-3.50 (2H, m); 4.01 (1H, d, J=16.1Hz), 4.10-4.20 (3H; m), 4.34 (1H, d, J=2.0Hz); 4.35 (1H, d, J=16.1Hz), 6.65 (1H; t, J=5.9Hz), 7.28 (2H, d; J=8.3Hz), and 7.35-7.45 (4H, m), 7.57 (2H; s), 7.72-7.83 (6H, m). (4) (2R, 3R)-and 3-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
With with the identical mode of embodiment 1-(5); by (3) obtain (2R, 3R)-3-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.17g) makes colorless oil title compound (0.162g).Mass (FAB+) m/Z:628 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.25 (3H, t, J=7.3Hz), 1.34-1.46 (4H; m), and 1.54-1.78 (8H, m), 2.70-2.80 (4H; m), and 3.25-3.30 (2H, m), 3.45-3.55 (1H; m), and 3.67-3.76 (1H, m), 4.01 (1H; d, J=7.1Hz), 4.12-4.23 (2H, m); 4.3-4.4 (2H, m), 4.48 (1H, d; J=1.9Hz), and 7.25-7.31 (2H, m), 7.37-7.46 (4H; m), 7.56 (1H, s), 7.57 (1H; s), and 7.70-7.80 (6H, m), 7.96 (1H; t, J=5.9Hz). embodiment 4 (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
With with the identical mode of embodiment 1-(5); by embodiment 3-(3) make (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.18g) preparation colorless oil title compound (0.17g).Mass (FAB+) m/Z:628 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.27 (3H, t, J=7.3Hz), 1.30-1.41 (4H; m), and 1.47-1.62 (4H, m), 1.64-1.75 (4H; m), and 2.72-2.80 (4H, m), 3.25-3.30 (2H; m), and 3.42-3.52 (1H, m), 3.56-3.64 (1H; m), 4.10 (1H, d, J=17.5Hz); 4.24 (2H, q, J=7.3Hz), 4.32 (1H; d, J=17.5Hz), 4.38 (1H, d; J=1.9Hz), 4.55 (1H, d, J=1.9Hz); 6.85 (1H, t, J=5.9Hz); 7.26-7.32 (2H, m), 7.36-7.46 (4H; m), 7.57 (2H, s); 7.71-7.81 (6H, m). embodiment 5 (2R, 3R)-3-carboxyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] ethyl propionate
(1) (2R, 3R)-2-hydroxyl-3-ethoxycarbonyl-3-[5-(2-naphthyl)-2-pentyloxy] benzyl propionate and (2R, 3R)-3-hydroxyl-3-ethoxycarbonyl-2-[5-(2-naphthyl)-2-pentyloxy] benzyl propionate
With with the identical mode of embodiment 1-(1), just replace L-tartrate benzyl tertiary butyl ester, the mixture (1.88g) of preparation colorless oil title compound by L-tartrate benzyl ethyl ester (2.8g).Mass (EI) m/Z:462 (M
+).
1H-NMR (CDCl
3) δ: 1.24,1.29 (total 3H, t each, J=6.8/6.8Hz), 2.30-2.50 (2H, m), 2.75-2.90 (2H, m), 3.07 (total 1H, deach, J=9.3/8.3Hz), 3.78,3.89 (total 1H, ddeach, J=12.2,6.8/11.7,6.8Hz), 4.05-4.30 (2.5H, m), 4.32 (0.5H, d, J=2.4Hz), 4.57,4.61 (total 1H, ddeach, J=6.7,2.4/6.8,2.4Hz), 5.16,5.23 (total 1H, deach, J=12.2/12.2Hz), 5.24,5.26 (total 1H, deach, J=12.2/12.2Hz), 5.26-5.35,5.43-5.52,5.60-5.75 (total2H, m each), and 7.27-7.47 (8H, m), 7.58 (1H, s), 7.75-7.80 (3H, m). (2) (2R, 3R)-3-carbobenzoxy-(Cbz)-3-tertiary butyloxycarbonyl ylmethoxy-2-[5-(2-naphthyl)-2-pentyloxy] ethyl propionate and (2R, 3R)-3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(2-naphthyl)-2-pentyloxy] ethyl propionate
With with the identical mode of embodiment 1-(2), handle the mixture (1.88g) that (1) obtains, thereby obtain the mixture (0.837g) of colorless oil title compound.Mass (EI) m/Z:576 (M
+).
1H-NMR (CDCl
3) δ: 1.23,1.25 (total 3H, t each, J=7.3/7.3Hz), 1.43,1.44 (total 9H, s each), and 2.34-2.43 (2H, m), 2.75-2.83 (2H, m), 3.82,3.91 (total 1H, ddeach, J=11.7,7.3/11.7,6.8Hz), 4.03 (0.5H, d, J=17.1Hz), 4.09-4.28 (4.5H, m), 4.37,4.43 (total 1H, d each, J=3.4/3.4Hz), 4.57,4.63 (total 1H, d each, J=3.4/3.4Hz), 5.15,5.25 (total1H, d each, J=12.2/11.7Hz), 5.23,5.28 (total 1H, deach, J=12.2/11.7Hz), 5.35-5.42,5.48-5.56,5.63-5.74 (total2H, m each), and 7.27-7.37 (5H, m), 7.39-7.46 (3H, m), 7.58 (1H, s), 7.75-7.81 (3H, m). (3) (2R, 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-carboxyl-2-[5-(2-naphthyl) pentyloxy] ethyl propionate and (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-carboxyl-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
With with the identical mode of embodiment 1-(3), handle the mixture (0.837g) that (2) obtain, thereby obtain the mixture (0.709g) of colorless oil title compound.
1H-NMR (CDCl
3) δ: 1.24,1.30 (total 3H, t each; J=6.8/6.8Hz), and 1.35-1.50 (11H, m); 1.55-1.70 (4H, m), 2.72-2.77 (2H; m), and 3.34-3.48 (1H, m); 3.68-3.79 (1H, m), 4.02-4.07 (1H; m); 4.13-4.53 (5H, m), 7.28-7.32 (1H; m); 7.37-7.44 (2H, m), 7.57; 7.59 (total 1H; s each), and 7.73-7.78 (3H, m). (4) (2R; 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] ethyl propionate and (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
With with the identical mode of embodiment 1-(4), handle the mixture (0.709g) that (3) obtain.Carry out silica gel chromatography, from eluting fraction faster, obtain colorless oil (2R, 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] ethyl propionate (0.300g).Mass(FAB+)m/Z：684(M+H)
+.
1H-NMR(CDCl
3)δ：1.31(3H，t，J＝6.8Hz)，1.37-1.49(13H，m)，1.52-1.75(8H，m)，2.71-2.77(4H，m)，3.22-3.29(2H，m)，3.34-3.38(1H，m)，3.72-3.77(1H，m)，3.86(1H，d，J＝16.6Hz)，4.19(1H，d，J＝16.6Hz)，4.20-4.30(3H，m)，4.41(1H，d，J＝2.9Hz)，7.26-7.29(2H，m)，7.36-7.45(4H，m)，7.56(2H，s)，7.69-7.77(6H，m).
In addition, from slower eluting fraction, obtain colorless oil (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate (0.392g).Mass (FAB+) m/Z:684 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26 (3H, t, J=6.8Hz), 1.30-1.45 (13H; m), and 1.50-1.57 (4H, m), 1.64-1.75 (4H; m), and 2.71-2.76 (4H, m), 3.27 (2H; dd, J=13.2,6.8Hz), 3.31-3.37 (1H; m), and 3.43-3.49 (1H, m), 3.93 (1H; d, J=16.1Hz), 4.16-4.24 (4H, m); 4.46 (1H, d, J=2.4Hz), 6.69 (1H; t, J=5.9Hz), 7.29 (2H, d; J=8.3Hz), and 7.37-7.44 (4H, m), 7.57 (2H; s), 7.72-7.78 (6H, m). (5) (2R, 3R)-and 3-carboxyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] ethyl propionate
With with the identical mode of embodiment 1-(5); (the 2R that processing is obtained by (4); 3R)-and 3-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] ethyl propionate (0.210g), thus obtain colorless oil title compound (0.20g).Mass (FAB+) m/Z:628 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26 (3H, t, J=7.3Hz), 1.30-1.42 (4H, m); 1.47-1.70 (8H, m), 2.71 (4H, t; J=7.8Hz), 3.22 (2H, dd, J=13.5; 6.8Hz), 3.30-3.39 (1H, m), 3.71-3.76 (1H; m), 4.02 (1H, d, J=17.1Hz); 4.22 (2H, q, J=7.3Hz), 4.26 (1H; d, J=17.1Hz), 4.36 (2H, s); 7.22-7.28 (2H, m), 7.36-7.44 (4H, m); 7.54 (2H, s), 7.62 (1H, t; J=5.8Hz), 7.68-7.76 (6H, m). embodiment 6 (2R, 3R)-2-carboxyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
With the identical mode of embodiment 1-(5); (the 2R that processing is obtained by embodiment 5-(4); 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate (0.219g), thus obtain colorless oil title compound (0.221g).Mass (FAB+) m/Z:628 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.24 (3H, t, J=6.8Hz), 1.25-1.35 (4H; m), and 1.46-1.54 (4H, m), 1.62-1.71 (4H; m), and 2.70-2.75 (4H, m), 3.20-3.35 (3H; m), and 3.39-3.44 (1H, m), 4.14-4.23 (4H; m), 4.27 (1H, d, J=2.4Hz); 4.52 (1H, d, J=2.4Hz); 6.90 (1H, t, J=5.9Hz); 7.26-7.29 (2H, m), 7.36-7.44 (4H; m), 7.56 (2H, s); 7.71-7.78 (6H, m). embodiment 7 (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate
With embodiment 6 obtain (2R, 3R)-2-carboxyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] ethyl propionate (0.108g) and ethanol (1ml) is dissolved in the methylene dichloride (5ml).Under the frozen water cooling, in the solution that forms, add 4-Dimethylamino pyridine (0.025g) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.05g).Stir after 4 hours,, use anhydrous sodium sulfate drying with saturated brine washing reaction mixture.Decompression steams solvent then.Resistates silica gel column chromatography (50% ethyl acetate-hexane) purifying, thus colourless crystallization shape title compound (0.092g) obtained.[α]
D 27+ 35.7 ° of (c=0.95, CHCl
3) Mass (EI) m/Z:655 (M
+).
1H-NMR (CDCl
3) δ: 1.22 (3H, t, J=6.8Hz), 1.26 (3H; t, H=7.3Hz), 1.30-1.41 (4H, m); 1.50-1.57 (4H, m), 1.62-1.74 (4H, m); 2.71-2.76 (4H, m), 3.25-3.37 (3H, m); 3.43-3.49 (1H, m), 4.04 (1H, d; J=16.1Hz), and 4.12-4.23 (5H, m), 4.33 (1H; d, J=16.1Hz), 4.47 (1H; d, J=2.4Hz), 6.65 (1H; t, J=5.8Hz), 7.29 (2H; d, J=8.3Hz), 7.36-7.45 (4H; m), 7.57 (2H, s); 7.72-7.78 (6H, m). embodiment 8 (3R)-3-[(1R)-7-(2-naphthyl)-1-[N-[5-(2-naphthyl) amyl group] formamyl]-2-oxa--1-heptyl]-1, the 4-dioxane oneself-2-ketone
(1) (2R, 3R)-2-(2-hydroxyl-oxethyl)-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
In the mixture of tetrahydrofuran (THF) (5ml) and methyl alcohol (1ml), embodiment 3-(3) is obtained (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.217g) is dissolved in the mixture of tetrahydrofuran (THF) (5ml) and methyl alcohol (1ml).Under the frozen water cooling, in the solution that forms, add sodium borohydride, mixture was at room temperature stirred 2.5 hours.Add the dilute aqueous soln of hydrochloric acid, the mixture of formation extracts with ethyl acetate.After washing with water, extraction liquid with the saturated brine washing, is used anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates silica gel column chromatography (50% ethyl acetate-hexane) purifying, thus colorless oil title compound (0.145g) obtained.Mass (EI) m/Z:641 (M
+).
1H-NMR (CDCl
3) δ: 1.30-1.42 (4H, m), 1.45-1.55 (13H, m); 1.62-1.75 (4H, m), 2.74 (4H, t; J=7.3Hz), and 3.22-3.32 (2.5H, m), 3.39-3.49 (2H; m), and 3.60-3.65 (3H, broad), 3.71-3.74 (1H; m), 4.22 (1H, d, J=2.4Hz); 4.45 (1H, d, J=2.4Hz), 6.72 (1H; t, J=5.8Hz), 7.28 (2H; d, J=8.3Hz), 7.37-7.47 (4H; m), 7.57 (2H, s); 7.73-7.79 (6H, m). (2) (3R)-3-[(1R)-7-(2-naphthyl)-1-[N-[5-(2-naphthyl) amyl group] formamyl]-2-oxa--1-heptyl]-1, the 4-dioxane oneself-2-ketone
The hydroxyethyl compound (0.157g) that (1) is obtained is dissolved in the methylene dichloride (8ml).Under the frozen water cooling, in the solution that forms, add trifluoroacetic acid (8ml), mixture was at room temperature stirred 2 hours.Decompression steams solvent.Resistates silica gel column chromatography (50% ethyl acetate-hexane) purifying, thus colourless crystallization shape title compound (0.11g) obtained.Fusing point: 99-100 ℃
1H-NMR (CDCl
3) δ: 1.30-1.40 (4H, m), 1.50-1.58 (4H, m), 1.65-1.75 (4H, m), and 2.72-2.78 (4H, m), 3.24-3.30 (2H, m), 3.48 (2H, t, J=6.3Hz), 3.68 (1H, ddd, J=12.7,9.8,2.4Hz), 3.79-3.84 (1H, m), 4.22 (1H, dt, J=8.3,2.9Hz), 4.29-4.35 (3H, m), 4.78 (1H, d, J=2.0Hz), 6.58 (1H, broad), 7.27-7.32 (2H, m), 7.37-7.44 (4H, m), 7.57 (1H, s), 7.58 (1H, s), 7.72-7.78 (6H, m). to C
36H
41NO
5Ultimate analysis: calculated value: C, 76.16; H, 7.28; N, 2.43 measured values: C, 75.96; H, 7.10; N, 2.37 embodiment 9 (2R, 3R)-3-(2-hydroxyl-oxethyl)-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
(1) (2R, 3R)-3-(2-hydroxyl-oxethyl)-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
With the identical method of embodiment 8-(1); (the 2R that Processing Example 3-(3) obtains; 3R)-and 3-ethoxycarbonyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.189g), thus obtain colorless oil title compound (0.157g).
1H-NMR (CDCl
3) δ: 1.32-1.41 (4H, m), 1.47-1.73 (17H, m); 2.13 (1H, broad), 2.70-2.76 (4H, m); 3.14-3.32 (3H, m), 3.44-3.56 (3H, m); 3.62-3.69 (1H, m), 3.76 (1H, dt; J=9.3,6.3Hz), 4.22 (1H, d; J=2.9Hz), 4.23 (1H, d, J=2.9Hz); 6.92 (1H, broad), 7.25-7.29 (2H, m); 7.37-7.44 (4H, m), 7.56 (1H; s), 7.57 (1H, s); 7.69-7.78 (6H, m). (2) (2R, 3R)-and 3-(2-hydroxyl-oxethyl)-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid
With with the identical mode of embodiment 8-(2); handle the hydroxyethyl compound (0.157g) that (1) obtains; thereby obtain (2R, 3R)-3-(2-hydroxyl-oxethyl)-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] propionic acid.
Mass spectrum (FAB+) m/z:586 (M+H)
+
The mixture that forms is dissolved in the ethanol (5ml), again to wherein adding 1N aqueous sodium hydroxide solution (0.25ml).Decompression steams solvent.In resistates, add ethanol again to be cured.The solid that filter to collect forms, thus obtain the amorphous solid shape (2R, 3R)-3-(2-hydroxyl-oxethyl)-3-N-[5-(2-naphthyl) amyl group] formamyl]-2-[5-(2-naphthyl) pentyloxy] Sodium Propionate (0.054g).
1H-NMR (CD
3OD) δ: 1.28-1.42 (4H, m), 1.47-1.75 (8H, m), 2.66-2.75 (4H, m), and 3.05-3.20 (2H, m), 3.40-3.75 (6H, m), 4.02 (1H, d, J=2.4Hz), 4.20 (1H, d, J=2.4Hz), 7.24-7.32 (2H, m), 7.32-7.42 (4H, m), 7.54 (1H, s), 7.55 (1H, s), 7.65-7.78 (6H, m). to C
36H
42NNaO
52H
2The ultimate analysis of O: calculated value: C, 67.17; H, 7.20; N, 2.18 measured values: C, 67.33; H, 7.00; N, 2.14 embodiment 10 (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
(1) (2R, 3R)-3-tertbutyloxycarbonyl-2-methoxymethoxy-3-[5-(2-naphthyl) pentyloxy] benzyl propionate
Methylene dichloride (25ml) is mixed with oxalyl chloride (1.2ml).After mixture being cooled to-78 ℃, in the mixture that forms, be added dropwise to methylene dichloride (12ml) solution of methyl-sulphoxide (1.6ml), mixture was stirred 10 minutes.Drip in reaction mixture that embodiment 4-(3) obtains (2R, 3S)-4-hydroxyl-3-methoxymethoxy-2-[5-(2-naphthyl) pentyloxy] methylene dichloride (15ml) solution of tert-butyl acetate (3.95g), stir mixture 70 minutes.After being added dropwise to triethylamine (6ml), reaction mixture is warming up to 0 ℃, under this temperature, stirred 15 minutes.In reaction mixture, add entry.The mixture dichloromethane extraction that forms is used anhydrous sodium sulfate drying.The decompression steam solvent, obtain oily (2R, 3R)-3-methoxymethoxy-2-[5-(2-naphthyl) pentyloxy]-the 4-ketobutyric acid tert-butyl ester.
With the compound of formation and the aqueous solution (5ml), the trimethyl carbinol (30ml) and the 2-methyl-2-butene of SODIUM PHOSPHATE, MONOBASIC (5g) (2N tetrahydrofuran solution, solution mixture mixing 15ml), stirring at room temperature.In 2 hours, in reaction mixture, add the aqueous solution (5ml) of Textone (5g) in batches.After extracted with diethyl ether, anhydrous sodium sulfate drying is used in extraction liquid water and saturated brine washing then.Decompression steams solvent, thus the acquisition oily (2R, 3R)-3-tertbutyloxycarbonyl-2-methoxymethoxy-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester.
With the compound dissolution that forms in N, among the N '-dimethyl formamide (15ml).In the mixture that forms, add triethylamine (3ml) and bromotoluene (1.6ml), mixture was at room temperature stirred 12 hours.The mixture that forms is diluted with ether, and anhydrous sodium sulfate drying is used in water and saturated brine washing.Decompression steams solvent, resistates silica gel column chromatography (ethyl acetate-hexane 1: 4) purifying, thus obtain oily title compound (3.15g).Mass (EI) m/Z:536 (M
+).
1H-NMR (CDCl
3) δ: 1.20-1.80 (6H, m), 1.47 (9H, s), 2.73 (2H, t, J=7.8Hz), 3.17 (1H, dt, J=8.8,6.8Hz), 3.35 (3H, s), 3.71 (1H, dt, J=8.8,6.4Hz), 4.21 (1H, d, J=3.4Hz), 4.64 (1H, d, J=3.4Hz), 4.68 (1H, d, J=6.8Hz), 4.77 (1H, d, J=6.8Hz), 5.11 (1H, d, J=12.2Hz), 5.20 (1H, d, J=12.2Hz), 7.22-7.37 (6H, m), and 7.39-7.43 (2H, m), 7.57 (1H, s), and 7.67-7.79 (3H, m). (2) (2R, 3R)-and 3-tertbutyloxycarbonyl-2-hydroxyl-3-[5-(2-naphthyl) pentyloxy] benzyl propionate
The benzyl ester compound (70.7mg) that (1) is obtained is dissolved in the methylene dichloride (1ml).In the solution that forms, add B-bromo catecholborane (30mg), mixture was at room temperature stirred 45 minutes.In reaction mixture, add entry.After with dichloromethane extraction, extraction liquid with 2N aqueous sodium hydroxide solution and saturated brine washing, is used anhydrous sodium sulfate drying successively.Decompression steams solvent then.Resistates silica gel column chromatography (ethyl acetate-hexane 1: 3) purifying, thus oily title compound (39mg) obtained.Mass (EI) m/Z:492 (M
+).
1H-NMR (CDCl
3) δ: 1.23-1.72 (6H, m), 1.48 (9H, s); 2.74 (2H, t, J=7.8Hz), 3.03 (1H; d, J=9.3Hz), 3.12 (1H, dt; J=8.8,6.8Hz), 3.69 (1H, dt; J=8.8,6.3Hz), 4.09 (1H, d; J=2.5Hz), 4.59 (1H, dd, J=9.3; 2.5Hz), 5.14 (1H, d, J=12.2Hz); 5.20 (1H, d, J=12.2Hz), 7.25-(8H; m), 7.58 (1H, s); 7.74-7.80 (3H, m). (3) (2R, 3R)-and 2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] benzyl propionate
The 2-oxy-compound (0.569g) that (2) are obtained is dissolved in N, in the dinethylformamide (5ml), add again sodium hydride (60% oily dispersion liquid, 0.06g).Dripping bromine ethyl acetate (0.2ml) in the mixture that forms at room temperature stirred the mixture of mixture 3 hours.The mixture that forms dilutes with ether, with saturated brine washing reaction mixture, uses anhydrous sodium sulfate drying.Decompression steams solvent then.Resistates is with silica gel column chromatography (ethyl acetate-hexane 1: 2) purifying, thus obtain buttery (2R, 3R)-3-tertbutyloxycarbonyl-2-ethoxycarbonyl methoxyl group-3-[5-(2-naphthyl) pentyloxy] benzyl propionate.Mass(EI)m/Z：578(M
+).
1H-NMR(CDCl
3)δ：1.20-1.71(6H，m)，1.23(3H，t，J＝7.3Hz)，1.48(9H，s)，3.18(1H，dt，J＝8.8，6.8Hz)，3.68(1H，dt，J＝8.8，6.8Hz)，4.14(2H，q，J＝3.4Hz)，4.20(1H，d，J＝3.4Hz)，4.20(1H，d，J＝3.4Hz)，4.25(1H，d，J＝16.6Hz)，4.38(1H，d，J＝16.6Hz)，4.69(1H，d，J＝3.4Hz)，5.13(1H，d，J＝12.2Hz)，5.19(1H，d，J＝12.2Hz)，7.27-7.35(6H，m)，7.35-7.50(2H，m)，7.58(1H，s)，7.73-7.79(3H，m).
With the compound dissolution that forms in methylene dichloride (6ml).In the solution that forms, add trifluoroacetic acid (1.5ml), mixture was at room temperature stirred 1.5 hours.Reaction mixture is evaporated to dried, thereby obtain buttery (2R, 3R)-3-carboxyl-2-ethoxycarbonyl methoxyl group-3-[5-(2-naphthyl) pentyloxy] benzyl propionate.
With the compound dissolution that forms in methylene dichloride (5ml).Add methyl [5-(2-naphthyl) pentyloxy] amine (0.30g) in the solution that forms, I-hydroxybenzotriazole (0.03g) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride at room temperature stirred mixture 24 hours again.Reaction mixture is diluted with ether, and water and saturated brine washing reaction mixture are used anhydrous sodium sulfate drying.Decompression steams solvent then.Resistates silica gel column chromatography (ethyl acetate-hexane 2: 3) purifying, thus oily title compound (0.456g) obtained.Mass (EI) m/Z:731 (M
+).
1H-NMR (rotational isomer mixture, CDCl
3) δ: 1.23 (3H, t, J=7.3Hz), 1.23-1.39 (4H; m), and 1.47-1.88 (8H, m), 2.65-2.79 (4H; m), 2.83,3.09 (total 3H, s each); 3.15-3.60 (4H, m), 4.07-4.19 (3H, m); 4.32-4.39 (1H, m), 4.48-4.55 (2H, m); 5.11 (1H, d, J=12.2Hz); 5.18 (1H, d, J=12.2Hz); 7.20-7.31 (7H, m), 7.33-7.44 (4H; m), and 7.51-7.57 (2H, m); 7.71-7.79 (6H, m). (4) (2R, 3R)-and 2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
The benzyl ester compound (0.40g) that (3) are obtained is dissolved in the mixture of ethanol (5ml) and tetrahydrofuran (THF) (5ml).In the solution that forms, add 10% palladium-charcoal (0.05g), under nitrogen atmosphere, mixture was at room temperature stirred 3 days.After removing by filter 10% palladium-charcoal, decompression steams solvent, thereby obtains oily title compound (0.10g).Mass (FAB+) m/Z:642 (M+H)
+.
1H-NMR (rotational isomer mixture, CDCl
3) δ: 1.26,1.27 (total 3H, teach, J=7.4Hz); 1.20-1.80 (13H, m), 2.70-2.85 (4H, m); 2.94,3.09 (total 3H, s each), 3.25-3.55 (5H; m), and 4.10-4.25 (2H, m), 4.32-4.34 (1H; m), 4.42,4.31 (1H; d each, J=5.8Hz), 4.66; 4.69 (1H, d each, J=5.8Hz); 7.20-7.30 (2H, m), 7.35-7.45 (4H; m), 7.55-7.60 (2H, broad s); 7.70-7.85 (6H, m). embodiment 11 (2R, 3R)-2-carboxyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid disodium
With embodiment 10-(4) obtain (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] benzyl propionate (0.19g) is dissolved in the ethanol (2ml).In the solution that forms, add the aqueous solution (0.58ml) of 1N sodium hydroxide, again mixture was stirred under room temperature 2 days.Decompression steams solvent, adds ether in resistates, thereby obtains amorphous powder title compound (0.096g).Mass (FAB+) m/Z:680 (M+Na)
+, 658 (M+H)
+.
1H-NMR (rotational isomer mixture, CD
3OD) δ: 1.24-1.42 (4H, m), 1.53-1.80 (8H, m), 2.72-2.77 (4H, m), 2.90,3.09 (total 3H, s each), and 3.10-3.50 (2H, m), 3.63,3.66 (total 1H, d each, J=14.1/14.1Hz), 3.87,3.91 (total 1H, s/d, J=1.5Hz), 4.16,4.17 (total 1H, deach, J=14.1/14.1Hz), 4.66,4.68 (total 1H, d/s, J=1.5Hz), 7.26-7.39 (6H, m), 7.56,7.59 (total 2H, s each), and 7.69-7.76 (6H, m). to C
37H
41NNa
2O
53H
2The ultimate analysis of O: calculated value: C, 62.43; H, 6.66; N, 1.97 measured values: C, 62.59; H, 6.59; N, 1.82 embodiment 12 (2R, 3R)-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
(1) (2R, 3R)-3-carboxyl-2-hydroxyl-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carboxyl-3-hydroxyl-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
(2R with embodiment 1-(1) acquisition, 3R)-3-carbobenzoxy-(Cbz)-3-hydroxyl-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carbobenzoxy-(Cbz)-2-hydroxyl-2-[5-(2-naphthyl) pentyloxy] mixture (1.45g) of the propionic acid tert-butyl ester is dissolved in the mixture of ethanol (20ml) and tetrahydrofuran (THF) (8ml).In the solution that forms, add 10% palladium-charcoal (0.2g), under nitrogen atmosphere, mixture was at room temperature stirred 31 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain oily (2R, 3R)-3-carboxyl-3-hydroxyl-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester and (2R, 3R)-3-carboxyl-2-hydroxyl-2-[5-(2-naphthyl) pentyloxy] mixture (1.20g) of the propionic acid tert-butyl ester.Mass (FAB+) m/Z:425 (M+Na)
+.
1H-NMR (CDCl
3) δ: 1.37-1.46 (2H, m), 1.48; (1.52 total 9H, s each), 1.61-1.73 (4H; m), 2.74 (2H, m); 3.33-3.40 (1H, m), 3.67-3.77 (1H; m), 4.19,4.23 (total 1H; d each, J=2.4/2.4Hz), 4.48; 4.55 (total 1H, d each, J=2.4/2.4Hz); 7.33-7.45 (3H, m), 7.58 (1H; s); 7.73-7.79 (3H, m). (2) (2R, 3R)-and 2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
Mixture (0.43g), methyl [5-(2-naphthyl) amyl group] formamyl that (1) is obtained] amine (0.268g) and 4-Dimethylamino pyridine (0.122g) be dissolved in the methylene dichloride (15ml); under the frozen water cooling, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.266g) again.After at room temperature stirring 16.5 hours, reaction mixture dilutes with methylene dichloride, adds 0.5N hydrochloric acid.Then, by the diatomite filtration mixture.Organic layer is told from filtrate,, used anhydrous sodium sulfate drying then with the saturated brine washing.Decompression steams solvent, resistates silica gel column chromatography (with 40% ethyl acetate-hexane wash-out) purifying, thus obtain oily title compound (0.106g).Mass (EI) m/Z:611 (M
+).
1H-NMR (rotational isomer mixture, CDCl
3) δ: 1.33-1.42 (4H, m), 1.44; (1.48 total 9H, s each), 1.54;-1.72 (8H, m), 2.72-2.75 (4H; m), 2.92,3.09 (total 3H; s each), and 3.24-3.58 (4H, m); 4.30-4.40 (2H, m), 7.28-7.30 (2H; m), and 7.38-7.44 (4H, m); 7.57 (1H, s), 7.58 (1H; s); 7.73-7.79 (6H, m). (3) (2R, 3R)-and 2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
Handle the tert-butyl ester compound (0.106g) that (2) obtain in the mode identical, thereby obtain oily title compound (0.10g) with embodiment 1-(5).
1H-NMR (rotational isomer mixture, CDCl
3) δ: 1.25-1.36 (4H, m), 1.55-1.75 (8H, m), 2.72-2.79 (4H, m), 2.95,3.04 (total 3H, s each), 3.32-3.40 (3H, m), and 3.50-3.55 (1H, m), 4.35,4.37 (total1H, seach), 4.61,4.63 (total 1H, d/s, J=2.4Hz), 7.28-7.30 (2H, m), 7.37-7.46 (4H, m), 7.57 (2H, s), 7.73-7.80 (6H, m).
The compound dissolution that forms in ethanol (3ml), is added the aqueous solution (0.17ml) of 1N sodium hydroxide again.The mixture that forms was at room temperature stirred 2 hours.Reaction mixture is evaporated to dried, thereby obtain the viscosity oily (2R, 3R)-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] Sodium Propionate (0.109g).Mass (FAB+) m/Z:600 (M+Na)
+, 578 (M+H)
+ 1H-NMR (rotational isomer mixture, CD
3OD) δ: 1.30-1.39 (4H, m), 1.55-1.73 (8H; m), and 2.71-2.74 (4H, m); 2.89,3.08 (total 3H, s each); 3.26-3.47,3.57-3.65 (total 4H, m each); 4.01,4.05 (total 1H, deach; J=2.0/2.0Hz), 4.60,4.65 (total 1H; d each, J=2.0/2.0Hz), 7.28-7.41 (6H; m), 7.57 (2H, broad s); 7.69-7.76 (6H; m). embodiment 13 (2R, 3R)-3-carboxyl methoxyl group-3-[N-(5-(3,5-dimethyl-4-hydroxy phenyl) amyl group) formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
(1) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(3,5-dimethyl-4-methoxymethoxy phenyl) amyl group] formamyl-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
With the identical mode of embodiment 1-(4), only be to use 5-(3,5-dimethyl-4-methoxymethoxy phenyl) I-hydroxybenzotriazole of amylamine and catalytic amount replaces 5-(2-naphthyl) amylamine hydrochloride and 4-Dimethylamino pyridine respectively, obtains oily title compound (0.20g).Mass (EI) m/Z:749 (M
+).
1H-NMR (CDCl
3) δ: 1.31-1.70 (12H, m), 1.43 (9H, s), 1.49 (9H; s), 2.25 (6H, s), 2.46 (2H, t; J=7.8Hz), 2.75 (2H, t, J=7.3Hz), 3.25 (2H; q, J=6.8Hz), 3.39-3.55 (2H, m), 3.60 (3H; s), 3.88 (1H, d, J=15.6Hz), 4.17 (1H; d, J=2.5Hz), 4.25 (1H, d, J=15.6Hz); 4.32 (1H, d, J=2.5Hz), 4.92 (2H, s); 6.70 (1H, t, J=6.0Hz), 6.79 (2H, s); 7.29 (1H, dd, J=8.9,1.0Hz), 7.41 (2H; dt, J=8.9,1.0Hz), 7.57 (1H, s); 7.75 (2H, d, J=8.3Hz), 7.79 (1H; d, J=8.3Hz). (2) (2R, 3R)-and 2-carboxyl methoxyl group-3-[N-[5-(3,5-dimethyl-4-hydroxy phenyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] propionic acid
Handle above-mentioned di tert butyl carbonate compound (0.20g) in the mode identical with embodiment 1-(5).Then, resistates is carried out purifying with high performance liquid chromatography (" Sensyu Pak ODS-5251-SH " is with 65: 35 (V/V) wash-outs of acetonitrile-0.1% trifluoroacetic acid), thereby obtain oily title compound (0.055g).Mass (FAB+) m/Z:594 (M+H).
1H-NMR (CDCl
3) δ: 1.23-1.69 (12H, m), 2.18 (6H, s), 2.42 (2H; t, J=7.3Hz), 2.73 (2H, t; J=7.3Hz), 3.23 (2H, q, J=6.4Hz); 3.47-3.58 (2H, m), 4.10 (1H, d; J=17.6Hz), 4.24 (1H, d, J=17.6Hz); 4.35 (1H, s), 4.55 (1H, s); 6.72 (2H, s), 6.95 (1H, t; J=5.6Hz), 7.28 (1H, d, J=8.3Hz); 7.40 (2H, dt, J=6.8,1.0Hz); 7.57 (1H, s), 7.73 (1H, d; J=8.3Hz), 7.74 (1H, d, J=8.3Hz); 7.76 (1H, d, J=8.3Hz). embodiment 14 (2R, 3R)-2-[N-[5-(2-naphthyl) amyl group] formamyl] methoxyl group-3-[5-(2-naphthyl) pentyloxy] succsinic acid
(1) (2R, 3R)-2-hydroxyl-3-[5-(2-naphthyl)-2-amylene oxygen base] ethyl succinate
(1.60g) is suspended in N with 60% sodium hydride, in the dinethylformamide (120ml).Under the frozen water cooling, add the N of L-diethyl tartrate (8.25g) in the suspension that forms, dinethylformamide (10ml) solution is again in about 7 minutes, be added dropwise to the N of 5-(2-naphthyl)-pentenyl iodine (9.0g), dinethylformamide (40ml) solution.After at room temperature stirring 1 hour, reaction mixture is poured in the mixture of frozen water (500ml) and saturated brine (200ml).With the mixture ethyl acetate extraction that forms.Extraction liquid saturated brine washed twice is used anhydrous sodium sulfate drying then.Decompression steams solvent, and resistates obtains oily title compound (6.51g) with silica gel chromatography (with 25-30% ethyl acetate-hexane wash-out).Mass (EI) m/Z:400 (M
+).
1H-NMR (CDCl
3) δ: 1.26 (3H, t, J=7.4Hz), 1.31 (3H, t, J=7.3Hz), 2.42-2.47 (2H, m), 2.80-2.87 (2H, m), 3.06 (1H, d, J=8.3Hz), 3.89 (1H, dd, J=11.7,7.3Hz), 4.20-4.31 (6H, m), 4.55 (1H, dd, J=8.8,2.4Hz), 5.46-5.53 (1H, m), and 5.69-5.77 (1H, m), 7.31 (1H, dd, J=8.3,1.5Hz), 7.40-7.47 (2H, m), 7.59 (1H, s), 7.76-7.81 (3H, m). (2) (2R, 3R)-and 2-hydroxyl-3-[5-(2-naphthyl) pentyloxy] ethyl succinate
3-[5-(2-naphthyl)-2-pentyloxy that (1) is obtained] compound (7.7g) is dissolved in the ethyl acetate (80ml).In the solution that forms, add 10% palladium-charcoal (0.8g), under nitrogen atmosphere, mixture was at room temperature stirred 17.5 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain oily title compound (6.75g).Mass (EI) m/Z:402 (M
+).
1H-NMR (CDCl
3) δ: 1.23-1.49 (8H, m), 1.55-1.74 (4H, m), 2.76 (2H, t, J=6.8Hz), 3.06 (1H, d, J=7.8Hz), 3.26-3.31 (1H, m), 3.75-3.81 (1H, m), 4.17-4.32 (5H, m), 4.57 (1H, m), 7.31 (1H, dd, J=8.3,1.5Hz), 7.38-7.46 (2H, m), 7.59 (1H, s), and 7.74-7.80 (3H, m). (3) (2R, 3R)-and 2-hydroxyl-3-[5-(2-naphthyl) pentyloxy] succsinic acid
3-[5-(2-naphthyl)-2-pentyloxy that (2) are obtained] compound (5.70g) is dissolved in the ethanol (60ml), to wherein being added dropwise to 2N aqueous sodium hydroxide solution (18ml).After at room temperature stirring 1.25 hours, in reaction mixture, add the first alcohol and water, the dissolving insoluble substance.Add ion exchange resin (" DOWEX
TX50W-X4, H
+Type ") make the solution acidifying of formation.Filtrate and washing lotion are merged, carry out concentrating under reduced pressure then.In resistates, add toluene and make its powdered precipitation, thereby obtain light yellow crystalloid title compound (4.33g).Mass (FAB+) m/Z:347 (M+H)
+.
1H-NMR (CD
3OD) δ: 1.42-1.49 (2H, m), 1.59-1.75 (4H, m), 2.77 (2H, t, J=7.3Hz), 3.32-3.38 (1H, m), and 3.74-3.79 (1H, m), 4.31 (1H, d, J=2.4Hz), 4.54 (1H, d, J=2.4Hz), and 7.32-7.41 (3H, m), 7.61 (1H, s), and 7.73-7.78 (3H, m). to C
19H
22O
6Ultimate analysis: calculated value: C, 65.89; H, 6.40 measured values: C, 65.54; H, 6.34 (4) (2R, 3R)-2-hydroxyl-3-[5-(2-naphthyl) pentyloxy] Dibenzyl succinate
The succinic acid compound (3.0g) that (3) are obtained is dissolved in N, in the dinethylformamide (30ml).Under the frozen water cooling, in the solution that forms, add triethylamine (3.05ml), be added dropwise to bromotoluene (2.6ml) again.After at room temperature stirring 21 hours, add triethylamine (1.2ml) and bromotoluene (0.5ml) again, the mixture that forms was stirred 19 hours.Reaction mixture is poured in the dilute hydrochloric acid, extracted with ethyl acetate.Extraction liquid washs with saturated brine, uses anhydrous sodium sulfate drying.Decompression steams solvent, resistates silica gel chromatography (with 30% ethyl acetate-hexane) wash-out, thus obtain oily title compound (3.19g).Mass (FAB+) m/Z:527 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.23-1.36 (2H, m), 1.46-1.53 (2H, m), 1.60-1.68 (2H, m), 2.72 (2H, t, J=7.3Hz), 3.08 (1H, d, J=8.8Hz), 3.10-3.16 (1H, m), 3.65-3.70 (1H, m), 4.26 (1H, d, J=2.0Hz), 4.64 (1H, dd, J=8.8,2.4Hz), 5.14 (1H, d, J=12.2Hz), 5.19 (1H, d, J=12.2Hz), 5.20 (1H, d, J=12.2Hz), 5.23 (1H, d, J=12.2Hz), 7.26-7.34 (11H, m), and 7.37-7.45 (2H, m), 7.57 (1H, s), and 7.76-7.80 (3H, m). (5) (2R, 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(2-naphthyl) pentyloxy] Dibenzyl succinate
With with the identical mode of embodiment 1-(2), handle the dibenzyl ester compound (2.08g) that obtains in (4), thereby obtain oily title compound (0.88g).Mass (FAB+) m/Z:641 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.25-1.38 (2H, m), 1.42 (9H, s), 1.49-1.68 (4H, m), 2.71 (2H, t, J=7.8Hz), and 3.15-3.21 (1H, m), 3.64-3.69 (1H, m), 4.04 (1H, d, J=16.6Hz), 4.24 (1H, d, J=16.6Hz), 4.37 (1H, d, J=2.9Hz), 4.63 (1H, d, J=2.9Hz), 5.10 (1H, d, J=12.2Hz), 5.17 (1H, d, J=12.2Hz), 5.20 (1H, d, J=12.2Hz), 5.25 (1H, d, J=12.2Hz), and 7.26-7.35 (9H, m), 7.37-7.44 (4H, m), 7.56 (1H, s), 7.73-7.79 (3H, m). (6) (2R, 3R)-and 2-carboxyl methoxyl group-3-[5-(2-naphthyl) pentyloxy] Dibenzyl succinate
With with the identical mode of embodiment 1-(5), handle the 2-tertbutyloxycarbonyl methoxylation compound (0.88g) that obtains in (5), thereby obtain oily title compound (0.87g).Mass (FAB+) m/Z:585 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.22-1.35 (2H, m), 1.45-1.54 (2H, m); 1.60-1.68 (2H, m), 2.72 (2H, t; J=7.3Hz), and 3.14-3.20 (1H, m), 3.66-3.72 (1H; m), 4.09 (1H, d, J=16.6Hz); 4.11 (1H, d, J=16.6Hz), 4.36 (1H; d, J=3.4Hz), 4.49 (1H, d; J=3.4Hz), 5.11 (1H, d, J=11.7Hz); 5.14 (1H, d, J=12.2Hz), 5.18 (1H; d, J=12.2Hz), 5.24 (1H, d; J=11.7Hz), and 7.25-7.33 (11H, m), 7.38-7.45 (2H; m), 7.57 (1H, s); 7.74-7.79 (3H, m). (7) (2R, 3R)-and 2-[N-[5-(2-naphthyl) amyl group] formamyl] methoxyl group-3-[5-(2-naphthyl) pentyloxy] Dibenzyl succinate
With with the identical mode of embodiment 1-(4), handle the 2-carboxyl methoxylation compound (0.465g) that obtains in (6), thereby obtain oily title compound (0.40g).Mass (FAB+) m/Z:780 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.23-1.40 (2H, m), 1.46-1.57 (4H, m), 1.63-1.73 (4H; m), and 2.69-2.7 6 (4H, m), 3.14-3.22 (3H, m); 3.66-3.72 (1H, m), 3.86 (1H, d; J=15.1Hz), 4.08 (1H, d, J=15.1Hz); 4.35 (1H, d, J=3.4Hz), 4.38 (1H; d, J=3.4Hz), 5.09 (1H, d; J=12.2Hz), 5.12 (1H, d, J=12.2Hz); 5.15 (1H, d, J=12.2Hz), 5.20 (1H; d, J=12.2Hz), 6.99 (1H, t; J=5.4Hz), and 7.26-7.34 (12H, m), 7.37-7.44 (4H; m), 7.56 (1H, s), 7.58 (1H; s), and 7.72-7.78 (6H, m). (8) (2R, 3R)-and 2-[N-[5-(2-naphthyl) amyl group] formamyl] methoxyl group-3-[5-(2-naphthyl) pentyloxy] succsinic acid
The 2-formamyl methoxylation compound (0.39g) that obtains in (7) is dissolved in ethanol (5ml) and the tetrahydrofuran (THF) (1ml).In the solution that forms, add 10% palladium-charcoal (0.08g), under nitrogen atmosphere, mixture was at room temperature stirred 18.5 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain oily title compound (0.274g).Mass(FAB+)m/Z：622(M+Na)
+，600(M+H)
+.
1H-NMR(CDCl
3)δ：1.31-1.39(4H，m)，1.48-1.55(2H，m)，1.57-1.70(6H，m)，2.68-2.73(4H，m)，3.19-3.24(2H，m)，3.38-3.43(1H，m)，3.68-3.74(1H，m)，4.14(1H，d，J＝16.1Hz)，4.20(1H，d，J＝16.1Hz)，4.36(1H，d，J＝2.9Hz)，4.39(1H，d，J＝2.9Hz)，5.01(～4H，broad)，7.25-7.28(2H，m)，7.35-7.43(4H，m)，7.55(2H，s)，7.70-7.77(6H，m).
The compound (0.256g) that forms is dissolved in the ethanol (5ml).In the solution that forms, add 2N aqueous sodium hydroxide solution (0.43ml), mixture was stirred 30 minutes.The decompression steam solvent, resistates forms powder precipitation with ethanol, thus obtain pulverous (2R, 3R)-2-[N-[5-(2-naphthyl) amyl group] formamyl] methoxyl group-3-[5-(2-naphthyl) pentyloxy] disodium succinate (0.095g).Mass (FAB+) m/Z:666 (M+Na)
+, 644 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.37-1.45 (4H, m), 1.57-1.78 (8H, m), 2.75-2.80 (4H, m), and 3.19-3.23 (2H, m), 3.3-3.34 (1H, m), 3.68-3.74 (1H, m), 3.90 (1H, d, J=16.1Hz), 4.17 (1H, d, J=2.4Hz), 4.18 (1H, d, J=16.1Hz), 4.19 (1H, d, J=2.4Hz), 7.31-7.43 (6H, m), 7.61 (2H, s), 7.72-7.78 (6H, m). to C
36H
39NNa
2O
7H
2The ultimate analysis of O: calculated value: C, 65.34; H, 6.24; N, 2.12 measured values: C, 64.92; H, 6.24; N, and 2.03 embodiment 15 (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-carboxyl-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
(1) (2R, 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-hydroxyl-2-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
Method A) dicarboxylic acid compound (2.0g) that embodiment 14 (3) is obtained is dissolved in the methylene dichloride (30ml).Add the O-tertiary butyl-N in the solution that forms, N '-di-isopropyl isourea (5.8g) at room temperature stirred mixture 2 days.The filtering insoluble substance, concentrating under reduced pressure filtrate.Resistates is dissolved in the ethyl acetate.The solution that forms is used anhydrous sodium sulfate drying with 1N hydrochloric acid and saturated brine washing.Resistates silica gel chromatography (with 15% ethyl acetate-hexane wash-out), thus colorless oil title compound (1.1g) obtained.Mass (FAB+) m/Z:459 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.38-1.50 (2H, m), 1.48 (9H, s), 1.50 (9H, s), 1.60-1.74 (4H, m), 2.75 (2H, t, J=7.8Hz), 3.01 (1H, d, J=8.3Hz), 3.29 (1H, dt, J=8.8,6.8Hz), 3.74 (1H, dt, J=8.8,6.8Hz), 4.07 (1H, d, J=2.4Hz), 4.44 (1H, dd, J=8.3,2.4Hz), 7.31 (1H, dd, J=8.3,1.5Hz), 7.38-7.45 (2H, m), 7.58 (1H, s), 7.74-7.80 (3H, m). method b) (60% oily dispersion liquid 9.12g) is suspended in N, in the dinethylformamide (600ml) with sodium hydride, under the frozen water cooling, be added dropwise to the N of L-(+)-tartrate di tert butyl carbonate (59.8g), dinethylformamide (100ml) solution again.After 5 minutes, be added dropwise to 5-(2-naphthyl)-pentenyl iodide (61.2g), the mixture that forms was at room temperature stirred 2 hours.Under agitation, reaction mixture is poured in frozen water (1000ml) and the ethyl acetate (1000ml).In the mixture that forms, add saturated brine to isolate organic layer.Organic layer washs with saturated brine, uses anhydrous sodium sulfate drying.Decompression steams solvent.Resistates is with silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus obtain light yellow oily (2R, 3R)-the basic oxygen base of 3-tertbutyloxycarbonyl-3-hydroxyl-2-[5-(2-naphthyl) penta-2-alkene-1-] the propionic acid tert-butyl ester (44.7g).
1H-NMR(CDCl
3)δ：1.47(9H，s)，1.50(9H，s)，2.41-2.47(2H，m)，2.85(2H，t，J＝7.3Hz)，3.03(1H，d，J＝7.8Hz)，3.85-3.90(1H，m)，4.13(1H，d，J＝2.4Hz)，4.18-4.22(1H，m)，4.44(1H，dd，J＝7.8，2.4Hz)，5.54-5.61(1H，m)，5.71-5.78(1H，m)，7.31(1H，dd，J＝8.3，2.0Hz)，7.39-7.46(2H，m)，7.59(1H，s)，7.75-7.80(3H，m).
The compound (22.0g) that forms is dissolved in the ethyl acetate (300ml).In the solution that forms, add 10% palladium-charcoal (1g), under nitrogen atmosphere, mixture was at room temperature stirred 9.5 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain colorless oil title compound (21.1g).(2) (2R, 3R)-3-tertiary butyloxycarbonyl ylmethoxy-3-hydroxyl-2-[5-(2-naphthyl) pentyloxy] benzyl propionate
The di tert butyl carbonate compound (21.1g) that (1) is obtained is dissolved in N, in the dinethylformamide (65ml).Under the frozen water cooling, and dropping diethyl methoxyl group borine in the solution that forms (the 1M tetrahydrofuran solution, 54ml).After 25 minutes, in reaction mixture, add sodium borohydride (2.09g), at room temperature stirred 2.5 hours.Reaction mixture is poured in the mixture of SODIUM PHOSPHATE, MONOBASIC (108g) and water (350ml), this mixture is cooled off with frozen water, add the trimethyl carbinol (43ml) and 2-methyl-2-butene (110ml) then.Add again Textone (80%, 102g) and water (220ml), the mixture that forms was at room temperature stirred 15 hours.In reaction mixture, add entry and ethyl acetate, isolate organic layer.With the organic layer that forms 1N salt acid elution, use anhydrous sodium sulfate drying.Decompression steams solvent.In resistates, add toluene and triethylamine, carry out azeotropic distillation again.Then, resistates is dissolved in N, dinethylformamide (200ml).Under the frozen water cooling, in the solution that forms, add triethylamine (13.9g) and bromotoluene (19.7g).The mixture that forms was at room temperature stirred 21 hours, then concentrating under reduced pressure.Resistates dilutes with ether, with 1N hydrochloric acid, 5% sodium bicarbonate aqueous solution and water washing, uses anhydrous sodium sulfate drying then.Decompression steams solvent, resistates silica gel chromatography (with 15-20% ethyl acetate-hexane wash-out), thus obtain light yellow oily title compound (13.95g).Mass (EI) m/Z:492 (M
+).
1H-NMR (CDCl
3) δ: 1.35-1.46 (2H, m), 1.47 (9H, s), 2.74 (2H, t, J=7.8Hz), 3.08 (1H, d, J=8.3Hz), 3.28-3.33 (1H, m), 3.71-3.76 (1H, m), 4.24 (1H, d, J=2.0Hz), 4.48 (1H, dd, J=7.8,2.0Hz), 5.21 (1H, d, J=12.1Hz), 5.26 (1H, d, J=12.1Hz), 7.29-7.44 (8H, m), 7.58 (1H, s), 7.74-7.80 (3H, m). (3) (2R, 3R)-and 3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
The diester (2.03g) that obtains in (2) is dissolved in the tetrahydrofuran (THF) (20ml).Under-70 ℃ or lower temperature, in the solution that forms, drip two trimethyl silyl amination potassium (toluene solution of 0.5M, 8.4ml).Then, be added dropwise to tetrahydrofuran (THF) (5ml) solution of bromo-acetic acid tert-butyl (1.05g) again, be warming up to room temperature subsequently.After in the mixture of reaction mixture being poured into 0.5N hydrochloric acid and ethyl acetate, isolate organic layer.The organic layer that forms is washed with saturated brine, use anhydrous sodium sulfate drying, decompression steams solvent.Resistates silica gel chromatography (with 15% ethyl acetate-hexane wash-out), thus colorless oil title compound (1.98g) obtained.Mass (EI) m/Z:606 (M
+).
1H-NMR (CDCl
3) δ: 1.50 (9H, s), 1.52 (9H, s), 1.45-1.85 (6H, m), 2.79 (2H, t, 7.81Hz), 3.25-3.45 (1H, m), 3.70-3.85 (1H, m), 4.06 (1H, d, J=6.6Hz), 4.33 (1H, d, J=6.6Hz), 4.42 (1H, d, J=2.9Hz), 4.53 (1H, d, J=2.9Hz), 7.28-7.45 (8H, m), 7.57 (1H, s), 7.73-7.80 (3H, m). (4) (2R, 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-carboxyl-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
Three esters (1.86g) that (3) are obtained are dissolved in the ethyl acetate (30ml), add 10% palladium-charcoal (0.1g) again.Under nitrogen atmosphere, the mixture that forms was at room temperature stirred 12.5 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain light yellow oily title compound (1.63g).Mass (FAB+) m/Z:599 (M+Na)
+, 517 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.38-1.51 (2H, m), 1.45 (9H, s), 1.48 (9H, s), 1.62-1.74 (4H, m), 2.75 (2H, t, J=7.5Hz), 3.45 (1H, dt, J=9.3,6.8Hz), 3.67 (1H, dt, K=9.3,6.8Hz), 4.02 (1H, d, J=16.1Hz), 4.31 (1H, d, J=16.1Hz), 4.36 (1H, d, J=2.7Hz), 4.37 (1H, d, J=2.7Hz), 7.30 (1H, dd, J=8.3,1.5Hz), 7.38-7.45 (2H, m), 7.57 (1H, s), and 7.74-7.80 (3H, m). embodiment 16 is dissolved in the 3-carboxylic compound (0.20g) that embodiment 15-(4) obtains in the methylene dichloride (20ml), under the frozen water cooling, add 5-(1, the 3-benzo dioxole-5-yl) amylamine (0.096g) that reference example 6 obtains again, I-hydroxybenzotriazole (0.053g) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.114g).The mixture that forms was at room temperature stirred 16 hours.The mixture that forms is used anhydrous sodium sulfate drying again with dilute hydrochloric acid and saturated brine washing.Decompression steams solvent.Resistates is with silica gel chromatography (with 25% ethyl acetate-hexane wash-out), thereby obtains the colorless oil compound (0.144g) of embodiment 16-a.
In the mode same with above-mentioned reacting phase, just replace 5-(1,3-benzo dioxole-5-yl) amylamines with reference example 7 and 8 corresponding sulfonamide derivativess respectively, make the compound of embodiment 16-b and 16-c.
Embodiment 17
The di tert butyl carbonate compound (0.144g) that embodiment 16-a is obtained is dissolved in the methylene dichloride (6ml), adds trifluoroacetic acid (4ml) again.The mixture that forms was at room temperature stirred 2 hours.Reaction mixture is evaporated to dried, thereby obtain the compound (0.136g) of colorless oil embodiment 17-a.
In reaction similar to the above, obtain compound 17-b and 17-c.
Embodiment 18 (2R, 3R)-3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-oxo butoxy] the propionic acid tert-butyl ester
(1) (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-)-crotyl oxygen base]-the 3-hydroxy-propionic acid tert-butyl ester
Under frozen water cooling, stir the N of L-(+)-tartrate di tert butyl carbonate (65.4g), dinethylformamide (350ml) solution, add again sodium hydride (60% oily dispersion liquid, 9.98g).The mixture that forms was stirred 15 minutes.Be added dropwise to the N with the 4-t-butyldimethylsilyloxy base-1-iodo-2-butylene (108.8g) of reference example 9, dinethylformamide (100ml) solution at room temperature stirs the mixture that forms 6.5 hours.After decompression steams solvent, in resistates, add entry, the mixture that forms is diluted with ether.Organic layer washs with saturated brine, uses anhydrous sodium sulfate drying.The resistates that obtains steams solvent by decompression, and with silica gel chromatography (with 16% ethyl acetate-hexane wash-out), thereby obtain light yellow oily title compound (62.1g).Mass (FAB+) m/Z:571 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.05 (9H, s), 1.48 (9H, s), 1.51 (9H, s), 3.06 (1H, d, J=8.3Hz), 3.92 (1H, dd, J=11.9,5.1Hz), 4.16 (1H, d, J=2.4Hz), and 4.18-4.22 (2H, m), 4.31 (1H, dd, J=12.2,4.9Hz), 4.46 (1H, dd, J=8.3,2.4Hz), 5.75-5.87 (2H, m), and 7.36-7.44 (6H, m), 7.65-7.67 (4H, m). (2) (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-the 3-hydroxy-propionic acid tert-butyl ester
The 2-butylene oxycompound (61.1g) that (1) is obtained is dissolved in the methyl alcohol (500ml).In the solution that forms, add 10% palladium-charcoal (3.0g), under nitrogen atmosphere, mixture was at room temperature stirred 3 days.After removing by filter palladium-charcoal, filtrate decompression is steamed solvent, obtain yellow oily title compound (56.8g).Mass (FAB+) m/Z:573 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.01 (9H, s), 1.47 (9H, s), 1.48 (9H, s), 1.53-1.70 (4H, m), 2.98 (1H, d, J=8.3Hz), 3.25-3.29 (1H, m), 3.47 (2H, d, J=5.9Hz), 3.71-3.77 (1H, m), 4.05 (1H, d, J=2.4Hz), 4.41 (1H, dd, J=8.3,2.4Hz), 7.34-7.42 (6H, m), 7.63 (4H, dd, J=7.8,1.5Hz). (3) (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-3-hydroxy-propionic acid benzyl ester
With with the identical mode of embodiment 15-(2), handle the di tert butyl carbonate compound (132.3g) that obtains in (2), thereby obtain colorless oil title compound (78.3g).Mass (FAB+) m/Z:607 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.03 (9H, s), 1.48 (9H, s), 1.52-1.72 (4H, m), 3.03 (1H, d, J=8.3Hz), and 3.29-3.34 (1H, m), 3.62-3.65 (2H, m), 3.75 (1H, dd, J=15.1,6.4Hz), 4.24 (1H, d, J=2.0Hz), 4.48 (1H, dd, J=8.3,2.4Hz), 5.21 (1H, d, J=12.2Hz), and 7.32-7.43 (11H, m), 7.63-7.65 (4H, m). (4) (2R, 3R)-and 3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-(tert-butyl diphenyl siloxy-) butoxy] the propionic acid tert-butyl ester
With with the identical mode of embodiment 15-(3), handle the diester compound (40.1g) that obtains in (3), thereby obtain colorless oil title compound (42.4g).
1H-NMR (CDCl
3) δ: 1.02 (9H, s), 1.44 (9H, s), 1.47 (9H, s), 1.56-1.63 (2H, m), 1.66-1.72 (2H, m), 3.29-3.34 (1H, m), 3.61-3.64 (2H, m), 3.70-3.74 (1H, m), 4.00 (1H, d, J=16.6Hz), 4.27 (1H, d, J=16.6Hz), 4.36 (1H, d, J=2.9Hz), 4.47 (1H, d, J=2.9Hz), 5.23 (1H, d, J=12.2Hz), 5.28 (1H, d, J=12.2Hz), 7.32-7.43 (11H, m), 7.63-7.65 (4H, m). (5) (2R, 3R)-and 3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-hydroxyl butoxy] the propionic acid tert-butyl ester
Be added dropwise to acetate (7.2ml) in tetrahydrofuran (THF) (200ml) solution of three ester cpds (30.1g) that in (4), obtain, then, (the 1M tetrahydrofuran solution 83.6ml), at room temperature stirred mixture 36 hours to add tetrabutyl ammonium fluoride under the frozen water cooling.The resistates that obtains by underpressure distillation, and with silica gel chromatography (with 50% ethyl acetate-hexane wash-out), thereby colorless oil title compound (17.0g) obtained.
1H-NMR (CDCl
3) δ: 1.40 (9H, s), 1.42 (9H, s), 1.61-1.70 (4H, m), 3.41 (1H, dt, J=8.8,5.9Hz), 3.61-3.69 (2H, m), 3.73-3.78 (1H, m), 4.00 (1H, d, J=16.6Hz), 4.26 (1H, d, J=16.6Hz), 4.37 (1H, d, J=3.4Hz), 4.58 (1H, d, J=3.4Hz), 5.24 (1H, d, J=12.2Hz), 5.29 (1H, d, J=12.2Hz), and 7.33-7.39 (3H, m), 7.42-7.45 (2H, m). (6) (2R, 3R)-and 3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-oxo butoxy] the propionic acid tert-butyl ester
Oxalyl chloride (2.0ml) is dissolved in the methylene dichloride (100ml).Methylene dichloride (10ml) solution that is added dropwise to methyl-sulphoxide (2.15ml) in the solution that forms lentamente is 65 ℃ or is lower than 65 ℃ to keep temperature.After stirring 10 minutes, in reaction mixture, be added dropwise to methylene dichloride (40ml) solution of the alkylol cpd that obtains in (5), restir 30 minutes.Then, be added dropwise to triethylamine, reaction mixture is warming up to room temperature again.Use dilute hydrochloric acid and saturated brine washing reaction mixture successively, use anhydrous sodium sulfate drying again.Decompression steams solvent, resistates silica gel chromatography (with 50% ethyl acetate-hexane wash-out), thus obtain colorless oil title compound (4.60g).
1H-NMR (CDCl
3) δ: 1.44 (9H, s), 1.48 (9H, s), 1.81-1.95 (2H, m), 2.59 (2H, t, J=7.1Hz), and 3.41-3.47 (1H, m), 3.66-3.71 (1H, m), 3.99 (1H, d, J=16.6Hz), 4.25 (1H, d, J=16.6Hz), 4.36 (1H, d, J=2.9Hz), 4.45 (1H, d, J=2.9Hz), 5.24 (1H, d, J=12.0Hz), 5.27 (1H, d, J=12.0Hz), 7.31-7.38 (3H, m), 7.42-7.52 (2H, m), 9.72 (1H, s). embodiment 19 is with (3 of reference example 10 preparations, 4-dimethyl benzene ylmethyl) triphenyl phosphonium chloride (0.55g) is suspended in the tetrahydrofuran (THF) (3ml), at room temperature be added dropwise to two trimethyl silyl amination potassium (the 0.5M toluene solution, 2.6ml).After stirring 10 minutes, add tetrahydrofuran (THF) (3ml) solution of the aldehyde cpd (0.30g) of embodiment 18-(6), and reaction mixture was stirred 1 hour.Use the ether diluted reaction mixture, use anhydrous sodium sulfate drying then.Decompression steams solvent.Resistates silica gel chromatography (with 17% ethyl acetate-hexane wash-out), thereby obtain colorless oil (2R, 3R)-and 3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(3, the 4-3,5-dimethylphenyl) penta-4-alkene-1-base oxygen base] the propionic acid tert-butyl ester (0.30g).
1H-NMR(CDCl
3)δ：1.43，1.44，1.46，1.48(total?18H，s?each)，1.71-1.79(2H，m)，2.17-2.25(7H，m)，2.30-2.38(1H，m)，3.32-3.40(1H，m)，3.71-3.79(1H，m)，4.00，4.01(total?1H，deach，J＝16.6/16.6Hz)，4.25，4.27(total?1H，deach，J＝16.6/16.6Hz)，4.37，4.38(total?1H，deach，J＝3.4，2.9Hz)，4.46，4.47(total?1H，d?each，J＝2.9，3.4Hz)，5.22-5.30(2H，m)，5.50-5.57，6.60-6.13(total?1H，m?each)，6.28-6.34(1H，m)，6.97-7.09(3H，m)，7.30-7.36(3H，m)，7.40-7.43(2H，m).
The compound (0.30g) that forms is dissolved in the ethanol (3ml).In the solution that forms, add 10% palladium-charcoal (0.03g), under nitrogen atmosphere, mixture was at room temperature stirred 17 hours.After removing by filter palladium-charcoal, the decompression steam solvent, thereby obtain colorless oil (2R, 3R)-3-tertbutyloxycarbonyl-3-tertiary butyloxycarbonyl ylmethoxy-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid.With the compound dissolution that forms in methylene dichloride (3ml).In the solution that forms, add 5-(2-naphthyl) amylamine hydrochloride (0.25g), I-hydroxybenzotriazole (0.020g) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.250g).The mixture that forms was at room temperature stirred 16 hours.Reaction mixture with dilute hydrochloric acid and saturated brine washing, is used anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates is with silica gel chromatography (with 25% ethyl acetate-hexane wash-out), thereby obtains the compound (0.15g) of colorless oil embodiment 19-a.
In mode same as the previously described embodiments, just with (3,4-dimethyl benzene ylmethyl) triphenyl phosphonium chloride (phosphonium salt that reference example 10 is answered mutually), thus the compound of acquisition embodiment 19-b to 19-o.
Embodiment 20
The di tert butyl carbonate compound (0.15g) that embodiment 19-a is obtained is dissolved in the methylene dichloride (2ml).In the solution that forms, add trifluoroacetic acid (1ml), mixture is at room temperature stirred 3 little.Decompression is concentrated into reaction mixture dried down, and resistates is dissolved in the ethanol (2ml).In the solution that forms, add 2N sodium hydroxide (0.22ml).Behind concentrating under reduced pressure, by solid collected by filtration, thus the embodiment 20-a compound (0.08g) of acquisition colorless solid shape.
The compound of embodiment 19-b to 19-o is similarly reacted, thereby obtain the compound of embodiment 20-b to 20-o respectively.
Embodiment 21 (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-(4-oxo butoxy) the propionic acid tert-butyl ester
(1) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-(4-hydroxyl butoxy)-3-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
The alkylol cpd (0.50g) of embodiment 18-5 is dissolved in the tetrahydrofuran (THF) (10ml).In the solution that forms, add 10% palladium-charcoal (0.05g), under nitrogen atmosphere, mixture was at room temperature stirred 2 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain colorless oil (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-carboxyl-3-(4-hydroxyl butoxy) propionic acid tert-butyl ester.
1H-NMR(CDCl
3)δ：1.46(9H，s)，1.50(9H，s)，1.69-1.80(2H，m)，1.82-1.89(2H，m)，3.55-3.59(1H，m)，3.63-3.77(3H，m)，3.97(1H，d，J＝15.6Hz)，4.30(1H，d，J＝15.6Hz)，4.32(1H，d，J＝2.5Hz)，4.36(1H，d，J＝2.5Hz).
With the compound dissolution that forms in methylene dichloride (10ml).In the solution that forms, add 5-(2-naphthyl) amylamine hydrochloride (0.26g), I-hydroxybenzotriazole (0.05g) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.24g).The mixture that forms was at room temperature stirred 16 hours.Reaction mixture with dilute hydrochloric acid and saturated brine washing, is used anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates silica gel chromatography (with 3% methyl alcohol-methylene dichloride wash-out), thus colorless oil title compound (0.515g) obtained.
1H-NMR (CDCl
3) δ: 1.42 (9H, s), 1.50 (9H, s), 1.54-1.63 (8H; m), 1.73 (2H, dt, J=7.8,7.3Hz); 2.77 (2H, t, J=7.8Hz), 3.31 (2H, dt; J=6.4,5.9Hz), 3.36-3.45 (1H, m), 3.48-3.53 (1H; m), 3.60 (2H, q, J=5.4Hz), 3.87 (1H; d, J=16.1Hz), 4.17 (1H, d, J=2.0Hz); 4.23 (1H, d, J=16.1Hz), 4.30 (1H, d; J=2.0Hz), 6.84 (1H, t, J=5.9Hz); 7.31 (1H, dd, J=8.3,1.6Hz); 7.40 (1H, dt, J=7.8,1.5Hz); 7.44 (1H, dt, J=7.8,1.5Hz); 7.60 (1H, s), 7.76 (1H, d; J=8.3Hz), 7.78 (1H, d, J=7.8Hz); 7.79 (1H, d, J=7.8Hz). and (2) (2R, 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-(4-oxo butoxy) the propionic acid tert-butyl ester
With the identical mode of embodiment 18-(6), handle the alkylol cpd (0.587g) that (1) obtains, thereby obtain light yellow oily title compound (0.444g).
1H-NMR (CDCl
3) δ: 1.37-1.45 (12H, m), 1.49 (9H, s); 1.53-1.63 (2H, m), 1.70-1.85 (4H, m); 2.42-2.47 (2H, m), 2.77 (2H, t; J=7.3Hz), and 3.25-3.40 (2H, m), 3.45-3.51 (2H; m), 3.87 (1H, d, J=16.1Hz); 4.15 (1H, d, J=2.4Hz), 4.21 (1H; d, J=16.1Hz), 4.29 (1H, d; J=2.4Hz), 6.70 (1H, broadt; J=5.5Hz), 7.31 (1H, dd; J=8.3,1.5Hz), 7.38-7.46 (2H; m), 7.59 (1H, s); 7.74-7.80 (3H, m). embodiment 22 (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3-chloro-4-aminomethyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Aldehyde (0.20g) in the mode Processing Example identical 21 acquisitions with embodiment 19-a; just adopt (3-chloro-4-aminomethyl phenyl methyl) triphenyl phosphonium chloride; thereby the acquisition colorless oil (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(3-chloro-4-aminomethyl phenyl) pentyloxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester (0.15g).
Mass(EI)m/Z：709(M
+).
1H-NMR(CDCl
3)δ：1.25-1.90(30H，m)，2.32(3H，s)，
2.49(2H，t，J＝7.3Hz)，2.76(2H，t，J＝7.3Hz)，3.30-3.65(4H，m)，
3.86(1H，d，J＝2.0Hz)，4.13-4.30(1H，m)，4.35-4.45(2H，m)，6.65-
6.75(1H，m)，6.85-7.20(3H，m)，7.26-7.50(3H，m)，7.58(1H，s)，
7.77-7.79(3H，m).
Handle the compound of formation according to embodiment 20 identical modes, thereby obtain the disodium salt (0.095g) of colorless solid shape title compound.Mass (FAB+) m/Z:664 (M+Na)
+, 642 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.20-1.85 (12H, m), 2.31 (3H, s), 2.48 (2H, t, J=7.3Hz), 2.75 (2H, t, J=7.3Hz), 3.20-3.60 (4H, m), 4.15 (1H, d, J=17.6Hz), 4.25 (1H, d, J=17.6Hz), 4.34 (1H, s), 4.58 (1H, s), 5.80-6.10 (3H, broad s), 6.80-7.25 (3H, m), 7.29 (1H, d, J=1.4Hz), 7.35-7.50 (2H, m), 7.56 (1H, s), 7.72-7.94 (3H, m). to C
33H
38ClNNa
2O
72.5H
2The ultimate analysis of O: calculated value: C, 57.68; H, 6.31; N, 2.04 measured values: C, 57.82; H, 5.91; N, 1.97 alkylol cpd (0.25g), N-(3 that embodiment 23 obtains embodiment 18-(5), the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide (0.18g) (reference example 11-a) and triphenyl phosphine (0.16g) are dissolved in the tetrahydrofuran (THF) (10ml), under frozen water cooling, be added dropwise to subsequently diethyl azodiformate (40% toluene solution, 0.43ml).After stirring 5 hours, decompression steams solvent.Resistates silica gel chromatography (with 25% ethyl acetate-hexane wash-out); thereby obtain (the 2R of colorless oil; 3R)-3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-[N-(3; the 4-3,5-dimethylphenyl)-and N-(2,4-dinitrophenyl alkylsulfonyl) amino] butoxy] the propionic acid tert-butyl ester (0.34g).
1H-NMR (CDCl
3) δ: 1.44 (9H, s), 1.47 (9H, s), 1.49-1.65 (4H, m), 2.21 (3H, s), 2.24 (3H, s), 3.36 (1H, dd, J=8.8,5.9Hz), 3.66-3.81 (3H, m), 3.96 (1H, d, J=16.6Hz), 4.24 (1H, d, J=16.6Hz), 4.35 (1H, d, J=2.9Hz), 4.45 (1H, d, J=2.9Hz), 5.23 (1H, d, J=12.2Hz), 5.27 (1H, d, J=12.2Hz), 6.82 (1H, d, J=8.3Hz), 6.96 (1H, s), 7.06 (1H, d, J=8.3Hz), 7.29-7.34 (3H, m), 7.40-7.43 (2H, m), 7.72 (1H, d, J=8.8Hz), 8.27 (1H, d, J=8.8Hz), 8.40 (1H, s). the compound (0.34g) that forms is dissolved in the methylene dichloride (5ml).In the solution that forms, add Thiovanic acid (0.05ml) and triethylamine (0.2ml), mixture was at room temperature stirred 0.5 hour.Reaction mixture with 5% sodium bicarbonate aqueous solution and dilute hydrochloric acid washing, is used anhydrous sodium sulfate drying then.Decompression steams solvent, resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thereby obtain colorless oil (2R, 3R)-3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy] the propionic acid tert-butyl ester (0.25g).
1H-NMR (CDCl
3) δ: 1.44 (9H, s), 1.47 (9H, s), 1.63-1.69 (4H, m), 2.13 (3H, s), 2.18 (3H, s), 3.06 (2H, t, J=6.4Hz), 3.36-3.42 (1H, m), 3.72-3.77 (1H, m), 4.00 (1H, d, J=16.6Hz), 4.27 (1H, d, J=16.6Hz), 4.38 (1H, d, J=2.9Hz), 4.48 (1H, d, J=2.9Hz), 5.25 (1H, d, J=12.2Hz), 5.29 (1H, d, J=12.2Hz), 6.35 (1H, dd, J=8.3,2.0Hz), 6.41 (1H, d, J=2.0Hz), 6.90 (1H, d, J=8.3Hz), 7.31-7.38 (3H, m), 7.41-7.44 (2H, m). the compound (0.25g) that forms is dissolved in the ethanol (3ml).In the solution that forms, add 10% palladium-charcoal (0.03g), under nitrogen atmosphere, mixture was at room temperature stirred 17 hours.After removing by filter palladium-charcoal, the decompression steam solvent, thereby obtain colorless oil (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-carboxyl-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy] the propionic acid tert-butyl ester.
1H-NMR(CDCl
3)δ：1.43(9H，s)，1.50(9H，s)，1.71-1.88(4H，m)，2.14(3H，s)，2.17(3H，s)，3.23-3.35(2H，m)，3.52-3.59(1H，m)，3.77-3.85(1H，m)，3.94(1H，d，J＝16.1Hz)，4.21(1H，d，J＝16.1Hz)，4.25(1H，d，J＝2.0Hz)，4.53(1H，d，J＝2.0Hz)，6.97(1H，d，J＝7.8Hz)，7.05(1H，s)，7.06(1H，d，J＝7.8Hz).
With the compound dissolution that forms in methylene dichloride (3ml).In the solution that forms, add 5-(2-naphthyl) amylamine hydrochloride (0.12g), I-hydroxybenzotriazole (0.02g) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.11g).The mixture that forms was at room temperature stirred 16 hours.Reaction mixture with dilute hydrochloric acid and saturated brine washing, is used anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates is with silica gel chromatography (with 25% ethyl acetate-hexane wash-out), thereby obtains the compound (0.136g) of colorless oil embodiment 23-a.
In mode same as the previously described embodiments, have only employing N-(3, the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide (the corresponding sulfone amide derivative of reference example 11) reacts, thereby obtains the compound of example 23-b to 23-i.
Embodiment 24
The compound (0.136g) of embodiment 23-a is dissolved in the methylene dichloride (3ml).In the solution that forms, add trifluoroacetic acid (2ml), mixture was at room temperature stirred 3 hours.Reaction mixture is evaporated to dried.Then, resistates is carried out purifying with high performance liquid chromatography (" SensyuPak ODS-5251-SH " is with 65: 35 (V/V) wash-outs of acetonitrile-0.1% trifluoroacetic acid), thereby obtain the compound (0.076g) of light yellow solid shape embodiment 24-a.
React the compound of embodiment 23-b to 23-i in mode same as the previously described embodiments, thereby obtain the compound of embodiment 24-b to 24-i respectively.
Embodiment 25 is with the alkylol cpd (0.15g) of embodiment 21-(1), the N-of reference example 11-j (3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide (0.10g) and triphenyl phosphine (0.09g) are dissolved in the tetrahydrofuran (THF) (3ml), under frozen water cooling, be added dropwise to again diethyl azodiformate (40% toluene solution, 0.15ml).After stirring 12 hours, decompression steams solvent.Resistates silica gel chromatography (with 30% ethyl acetate-hexane wash-out); thereby obtain (the 2R of colorless oil; 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-[4-[N-(3-chloro-4-aminomethyl phenyl)-N-(2,4-dinitrophenyl alkylsulfonyl) amino] butoxy]-3-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester (0.18g).
1H-NMR(CDCl
3)δ：1.37-1.50(4H，m)，1.42(9H，s)，1.47(9H，s)，1.52-1.60(4H，m)，1.68-1.76(2H，m)，2.35(3H，s)，2.76(2H，t，J＝7.8Hz)，3.29(2H，q，J＝6.8Hz)，3.32-3.38(1H，m)，3.45-3.50(1H，m)，3.68-3.82(2H，m)，3.87(1H，d，J＝15.6Hz)，4.14(1H，d，J＝2.4Hz)，4.22(1H，d，J＝15.6Hz)，4.30(1H，d，J＝2.4Hz)，6.74(1H，t，J＝5.9Hz)，??6.97(1H，dd，J＝8.3，2.0Hz)，7.17(1H，d，J＝2.0Hz)，??7.30(1H，dd，J＝8.8，1.5Hz)，7.38(1H，dt，J＝6.8，1.5Hz)，??7.42(1H，dt，J＝6.8，1.5Hz)，7.57(1H，s)，7.72-7.78(4H，m)，??8.26(1H，dd，J＝8.8，2.0Hz)，8.40(1H，d，J＝2.0Hz).
The compound (0.18g) that forms is dissolved in the methylene dichloride (3ml).In the solution that forms, add mercaptoethanol acid (0.04ml) and triethylamine (0.12ml), mixture was at room temperature stirred 0.5 hour.Reaction mixture with 5% sodium bicarbonate aqueous solution and dilute hydrochloric acid washing, is used anhydrous sodium sulfate drying then.Decompression steams solvent, and resistates is with silica gel chromatography (with 50% ethyl acetate-hexane wash-out), thereby obtains the compound (0.128g) of colorless oil embodiment 25-j.
In mode same as the previously described embodiments, have only employing N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide (the corresponding sulfone amide derivative of reference example 11) reacts, thereby obtains the compound of example 25-k to 25-m.
Embodiment 26
The compound (0.128g) of embodiment 25-j is dissolved in the methylene dichloride (2ml).In the solution that forms, add trifluoroacetic acid (1ml), mixture was at room temperature stirred 3 hours.Reaction mixture is evaporated to dried.Then, resistates is carried out purifying with high performance liquid chromatography (" SensyuPak ODS-5251-SH " is with 65: 35 (V/V) wash-outs of acetonitrile-0.1% trifluoroacetic acid), thereby obtain the compound (0.08g) of light yellow solid shape embodiment 26-j.
React the compound of embodiment 25-k to 25-m in mode same as the previously described embodiments, thereby obtain the compound of embodiment 26-k to 26-m respectively.
Embodiment 27 (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl]-3-(4-oxo butoxy) the propionic acid tert-butyl ester
Diester compound (23.6g) with mode Processing Example 18-(3) acquisition identical with embodiment 18-(4), just adopt ethyl bromoacetate to replace bromo-acetic acid tert-butyl, thereby obtain colorless oil (2R, 3R)-3-carbobenzoxy-(Cbz)-3-[4-(tert-butyl diphenyl siloxy-) butoxy]-2-ethoxycarbonyl methoxy propyl tert-butyl acrylate (24.1g).Mass(FAB+)m/Z：715(M+Na)
+.
1H-NMR(CDCl
3)δ：1.02(9H，s)，1.24(3H，t，J＝7.1Hz)，1.47(9H，s)，1.55-1.62(1H，m)，1.66-2.04(2H，m)，3.29-3.34(1H，m)，3.62(2H，t，J＝6.1Hz)，3.70-3.75(1H，m)，4.12-4.19(3H，m)，4.37(1H，d，J＝16.6Hz)，4.38(1H，d，J＝2.9Hz)，4.48(1H，d，J＝2.9Hz)，5.23(1H，d，J＝12.0Hz)，5.27(1H，d，J＝12.0Hz)，7.31-7.41(11H，m)，7.63-7.65(4H，m).
Handle the siloxy-compound (22.7g) of formation in the mode identical with embodiment 18-(5), thus obtain colorless oil (2R, 3R)-3-carbobenzoxy-(Cbz)-2-ethoxycarbonyl methoxyl group-3-(4-hydroxyl butoxy) propionic acid tert-butyl ester (14.0g).Mass(FAB+)m/Z：455(M+H)
+.
1H-NMR(CDCl
3)δ：1.25(3H，t，J＝7.1Hz)，1.48(9H，s)，1.62-1.70(4H，m)，3.41(1H，dt，J＝9.3，5.9Hz)，3.56-3.63(2H，m)，3.75(1H，dt，J＝8.8，5.9Hz)，4.11-4.19(3H，m)，4.35-4.40(2H，m)，4.48(1H，d，J＝2.9Hz)，5.23(1H，d，J＝12.2Hz)，5.29(1H，d，J＝12.2Hz)，7.33-7.39(3H，m)，7.41-7.43(2H，m).
Handle the alkylol cpd (30.8g) of formation in the mode identical with embodiment 21-(1), thereby obtain (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-(4-hydroxyl butoxy)-3-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester.Mass(EI)m/Z：559(M)
+.
1H-NMR(CDCl
3)δ：1.23(3H，t，J＝7.1Hz)，1.39-1.46(4H，m)，1.50(9H，s)，1.52-1.63(6H，m)，1.73(2H，m)，2.77(2H，t，J＝7.8Hz)，3.24-3.39(2H，m)，3.40-3.45(1H，m)，3.48-3.52(1H，m)，3.58-3.62(1H，m)，4.01(1H，d，J＝16.1Hz)，4.15(2H，m)，4.19(1H，d，J＝2.4Hz)，4.33(1H，d，J＝2.9Hz)，4.35(1H，d，J＝16.1Hz)，6.77-6.80(1H，m)，7.32(1H，dd，J＝8.3，1.5Hz)，7.39-7.46(2H，m)，7.60(1H，s)，7.75-7.80(3H，m).
Handle the alkylol cpd (14.28g) of formation in the mode identical, thereby obtain colorless oil title compound (12.4g) with embodiment 18-(6).Mass (EI) m/Z:557 (M
+).
1H-NMR (CDCl
3) δ: 1.23 (3H, t, J=7.3Hz), 1.36-1.44 (2H; m), 1.50 (9H, s), 1.56-1.62 (2H; m), and 1.70-1.78 (1H, m), 1.80-1.86 (1H; m), and 2.42-2.47 (2H, m), 2.78 (1H; t, J=7.6Hz), 3.26-3.40 (3H, m); 3.46-3.51 (1H, m), 4.00 (1H, d; J=16.1Hz), and 4.10-4.18 (3H, m), 4.32 (1H; d, J=2.9Hz), 4.34 (1H, d; J=15.6Hz), 6.63 (1H, t, J=5.4Hz); 7.31-7.33 (1H, m), 7.39-7.46 (2H, m); 7.60 (1H, s), 7.75-7.80 (3H, m); 9.70 (1H, s). embodiment 28 (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
(1) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
In the mode identical with embodiment 29, the aldehyde cpd (0.6g) that Processing Example 27 obtains, thus obtain colorless oil title compound (0.47g).(2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) penta-4-alkene-1-base oxygen base]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid tert-butyl ester Mass (EI) m/Z:659 (M
+).
1H-NMR (CDCl
3) δ: 1.22 (3H, t, J=7.1Hz), 1.34-1.41 (2H, m); 1.49 (9H, s), 1.48-1.60 (2H, m), 1.67-1.76 (2H; m), and 2.17-2.22 (8H, m), 2.74 (2H; t, J=7.8Hz), 3.21-3.30 (2H, m); 3.42-3.55 (2H, m), 4.02,4.03 (total 1H; d each, J=16.1/16.6Hz), 4.09-4.18 (2H, m); 4.19 (1H, d, J=2.4Hz), 4.33; 4.35 (total 1H, deach, J=16.1/16.1Hz), 4.34 (1H; d, J=2.0Hz), 6.07 (1H, dt; J=16.1,6.8Hz), 6.29 (1H, d; J=16.1Hz), 6.69 (1H, t, J=5.9Hz); 6.97-7.08 (3H, m), 7.28-7.30 (2H, m); 7.38-7.45 (2H, m), 7.57 (1H, s); 7.73-7.79 (3H, m). (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid tert-butyl ester Mass (EI) m/Z:661 (M
+).
1H-NMR (CDCl
3) δ: 1.20-1.32 (5H, m), 1.34-1.43 (2H, m), 1.49 (9H; s), and 1.50-1.60 (6H, m), 1.68-1.76 (2H, m); 2.20 (3H, s), 2.21 (3H, s), 2.50 (2H; t, J=7.8Hz), 2.76 (2H, t, J=7.6Hz); 3.23-3.50 (4H, m), 4.02 (1H, d, J=16.1Hz); 4.12-4.19 (3H, m), 4.33 (1H, d, J=2.0Hz); 4.34 (1H, d, J=16.1Hz), 6.67 (1H; t, J=5.9Hz), 6.87 (1H, d; J=7.6Hz), 6.91 (1H, s), 7.01 (1H; d, J=7.6Hz), 7.28-7.31 (1H, m); 7.37-7.45 (2H, m), 7.58 (1H, s); 7.73-7.79 (3H, m). (2) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
The diester compound (0.22g) that (1) is obtained is dissolved in the methylene dichloride (1ml).In the solution that forms, add trifluoroacetic acid (0.5ml), mixture was at room temperature stirred 1 hour.Carry out the processing of " DIAION HP20 " post with under reduced pressure being concentrated into the resistates of doing and obtaining, and use the acetonitrile wash-out.The resistates that common concentrating under reduced pressure is obtained is dissolved in the ether.The solution anhydrous sodium sulfate drying that forms, be evaporated to then dried, thereby obtain colorless oil title compound (0.18g).Mass (EI) m/Z:605 (M
+).
1H-NMR (CDCl
3) δ: 1.25-1.43 (7H, m), 1.50-1.62 (6H, m), 1.70-1.78 (2H; m), 2.20 (3H, s), 2.22 (3H; s), 2.51 (2H, t, J=7.6Hz); 2.77 (2H, t, J=7.6Hz), 3.27-3.32 (2H; m), and 3.45-3.51 (2H, m), 4.10 (1H; d, J=17.1Hz), 4.25 (2H, q; J=7.1Hz), 4.34 (1H, d, J=17.1Hz); 4.37 (1H, d, J=2.0Hz), 4.54 (1H; d, J=2.0Hz), 6.80 (1H, t; J=5.9Hz), 6.88 (1H, d, J=7.6Hz); 6.92 (1H, s), 7.02 (1H, d; J=7.6Hz), 7.30 (1H, dd, J=8.3; 1.5Hz), 7.38-7.46 (2H, m), 7.58 (1H; s), 7.74-7.80 (3H, m). embodiment 29 (2R, 3R)-3-[5-(2-benzoxazolyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Handle in the mode identical, just adopt 2-(benzoxazole ylmethyl) three phenyl phosphonium bromides to replace (3,4-dimethyl benzene ylmethyl) phosphonium chloride, thereby obtain the colorless oil title compound with embodiment 28.(1) (2R, 3R)-3-[5-(2-benzoxazolyl)-4-pentenyl oxygen base]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
1H-NMR (CDCl
3) δ: 1.23 (3H, t, J=7.3Hz), 1.37-1.42 (2H, m); 1.55 (9H, s), 1.52-1.59 (2H, m), 1.67-1.79 (4H; m), and 2.28-2.36 (2H, m), 2.75 (2H, t; J=7.6Hz), and 3.25-3.39 (2H, m), 3.45 (1H, dt; J=9.3,6.4Hz), 3.55 (1H, dt; J=9.3,6.2Hz), 4.02 (1H, d; J=16.1Hz), 4.16 (2H, m), 4.21 (1H; d, J=2.4Hz), 4.34 (1H, d; J=2.0Hz), 4.37 (1H, d, J=16.1Hz); 6.42 (1H, d, J=15.6Hz), 6.63-6.66 (1H; m), and 6.91-6.99 (1H, m), 7.28-7.31 (2H; m), and 7.39-7.47 (4H, m), 7.58 (1H; s), 7.66 (1H, dd, J=5.9; 3.4Hz), 7.73-7.79 (3H, m). (2) (2R, 3R)-3-[5-(2-benzoxazolyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid tert-butyl ester Mass (EI) m/Z:674 (M
+).
1H-NMR (CDCl
3) δ: 1.21-1.28 (3H, m), 1.37-1.45 (4H, m); 1.49 (9H, s), 1.51-1.64 (2H, m); 1.67-1.75 (2H, m), 1.81-1.89 (2H, m); 2.75 (2H, t, J=7.6Hz), 2.89 (2H; t, J=7.6Hz), 3.24-3.36 (2H, m); 3.39 (1H, dt, J=9.8,6.6Hz); 3.47 (1H, dt, J=9.8,6.5Hz); 4.00 (1H, d, J=16.1Hz), 4.10-4.16 (2H; m), 4.18 (1H, d, J=2.4Hz); 4.33 (1H, d, J=2.4Hz), 4.35 (1H; d, J=16.1Hz), 6.67 (1H, t; J=5.9Hz), and 7.27-7.31 (2H, m), 7.33-7.47 (4H; m), 7.58 (1H, s), 7.63-7.66 (1H; m), 7.73-7.79 (3H, m). (3) (2R, 3R)-3-[5-(2-benzoxazolyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid Mass (FAB+) m/Z:619 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26 (3H, t, J=7.3Hz), 1.36-1.44 (3H, m), and 1.56-1.61 (4H, m), 1.70-1.77 (2H, m), and 1.82-1.91 (2H, m), 2.77 (2H, t, J=7.6Hz), 2.96 (2H, dt, J=7.3,3.4Hz), 3.30 (2H, q, J=6.8Hz), and 3.44-3.48 (1H, m), 3.57-3.62 (1H, m), and 4.18-4.28 (4H, m), 4.35 (1H, d, J=2.4Hz), 4.56 (1H, d, J=2.4Hz), 6.74 (1H, t, J=5.9Hz), 7.29-7.32 (2H, m), 7.38-7.49 (4H, m), 7.59 (1H, s), 7.67-7.69 (1H, m), 7.74-7.80 (3H, m). embodiment 30 (2R, 3R)-2-carboxyl methoxyl group-10-(2-naphthyl)-3-[5-(2-naphthyl) pentyloxy]-4-oxo capric acid
(1) (2R, 3R)-3-carbobenzoxy-(Cbz)-2-t-butyldimethylsilyloxy base-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
The compound (1.05g) that embodiment 15-(2) is obtained is dissolved in N, in the dinethylformamide (10ml).In the solution that forms, add imidazoles (0.29g) and tertiary butyl chloride for dimethylsilane (0.61g), mixture was at room temperature stirred 3 days.Use the ethyl acetate diluted reaction mixture, use 0.5N hydrochloric acid and water washing reaction mixture successively, use anhydrous sodium sulfate drying.Decompression steams solvent, resistates silica gel chromatography (with 3% ethyl acetate-hexane wash-out), thus obtain colorless oil title compound (1.25g).Mass (FAB+) m/Z:629 (M+Na)
+.
1H-NMR (CDCl
3) δ: 0.02 (3H, s), 0.11 (3H, s); 0.87 (9H, s), 1.34-1.40 (2H, m); 1.45 (9H, s), 1.57-1.70 (4H, m); 2.72 (2H, t, J=7.6Hz), 3.34-3.40 (1H; m), and 3.62-3.68 (1H, m), 4.25 (1H; d, J=4.2Hz), 4.52 (1H, d; J=4.2Hz), 5.11 (1H, d, J=12.5Hz); 5.21 (1H, d, J=12.5Hz), 7.28-7.45 (8H; m), 7.57 (1H, s); 7.73-7.78 (3H, m). (2) (2R, 3R)-and 2-t-butyldimethylsilyloxy base-3-(N-methoxyl group-N-methylamino formyl radical)-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
Add the 10% palladium-charcoal of catalytic amount in ethanol (8ml) solution of the silyl ether compound (0.38g) that obtains to (1), under nitrogen atmosphere, mixture was at room temperature stirred 15 hours.Reaction mixture dilutes with methylene dichloride, and removes by filter palladium-charcoal.Decompression steams solvent, thus the acquisition colorless oil (2R, 3R)-2-t-butyldimethylsilyloxy base-3-carboxyl-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.33g).With the compound dissolution that forms in tetrahydrofuran (THF) (8ml).Under-15 ℃, in the solution that forms, add N-methylmorpholine (0.08ml) and isobutyl chlorocarbonate (0.1ml) successively, mixture was stirred 7 minutes under same temperature.Then, add N in batches, the N of O-dimethyl hydroxyl amine hydrochlorate (0.069g) and N-methylmorpholine (0.08ml), dinethylformamide (5ml) solution is warming up to room temperature gradually with the mixture that forms.After stirring 1 hour,, use extracted with diethyl ether water layer three times with ether and 10% hydrochloric acid diluted reaction mixture.Organic layer after the merging washs with saturated brine, uses anhydrous sodium sulfate drying.Then, decompression steams solvent.Resistates silica gel chromatography (with 17% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.24g) obtained.
1H-NMR (CDCl
3) δ: 0.05 (6H, s), 0.79 (9H, s), 1.34 (9H; s), and 1.20-1.70 (6H, m), 2.64 (2H, t; J=7.3Hz), 3.08 (3H, broad s), 3.20-3.55 (2H; m), 3.60 (3H, s), 4.26 (1H; d, J=6.3Hz), 4.42 (1H, d; J=6.4Hz), and 7.18-7.75 (7H, m). (3) (2R, 3R)-and 2-hydroxyl-3-(N-methoxyl group-N-methylamino formyl radical)-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
(tetrahydrofuran solution of 1M 1ml), at room temperature stirred mixture 12 hours to add tetrabutyl ammonium fluoride in tetrahydrofuran (THF) (8ml) solution of the silyl ether compound (0.23g) that obtains in (2).Reaction mixture is diluted with ethyl acetate, add entry then.Water layer ethyl acetate extraction three times.Organic layer after the merging washs with saturated brine.Decompression steams solvent.
Resistates silica gel chromatography (with 25% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.16g) obtained.
1H-NMR (CDCl
3) δ: 1.30-1.78 (6H, m), 1.50 (9H, s); 2.75 (2H, t, J=7.8Hz), 3.10 (1H; d, J=9.3Hz), 3.20-3.30 (1H, m); 3.25 (3H, s), 3.58-3.70 (1H, m); 3.73 (3H, s), 4.44-4.50 (2H, m); 7.27-7.85 (7H, m). (4) (2R, 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-(N-methoxyl group-N-methylamino formyl radical)-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester
At room temperature, the N of the 2-oxy-compound (0.15g) that in (3), obtains, (60% oily dispersion liquid 0.017g) and bromo-acetic acid tert-butyl, stirs mixture 12 hours under uniform temp to add sodium hydride in dinethylformamide (3ml) solution.Reaction mixture is diluted with ethyl acetate, and add 10% hydrochloric acid.Then, water layer ethyl acetate extraction three times.Organic layer after the merging washs with saturated brine.Decompression steams solvent, resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus obtain colorless oil title compound (0.125g).
1H-NMR (CDCl
3) δ: 1.35-1.73 (6H, m), 1.44 (9H, S), 1.48 (9H, s), 2.76 (2H, t, J=7.3Hz), 3.25 (3H, broad s), 3.32-3.42 (1H, m), and 3.55-3.68 (1H, m), 3.72 (3H, s), and 4.00-4.60 (4H, m), 7.26-7.83 (7H, m). (5) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-10-(2-naphthyl)-3-[5-(2-naphthyl) pentyloxy]-the 4-oxo capric acid tert-butyl ester
The iodine of MAGNESIUM METAL (0.48g) and catalytic amount is added in the tetrahydrofuran (THF) (5ml), under stirring and room temperature, in the mixture that forms, add tetrahydrofuran (THF) (2ml) solution of 6-(2-naphthyl) hexyl bromide (0.58g).Reaction mixture is heated to 60 ℃, and under this temperature, mixture was stirred 5 minutes.Then, reaction mixture is cooled to room temperature, restir is 3 hours under this temperature, thereby obtains 6-(2-naphthyl) hexyl magnesium bromide.At room temperature, add 6-(2-naphthyl) hexyl bromination magnesium solution (2ml) in tetrahydrofuran (THF) (3ml) solution of the hydroxamate (0.045g) that in (4), obtains, at room temperature, restir 4 hours.After adding 10% hydrochloric acid, the mixture that forms is diluted with ethyl acetate.Water layer ethyl acetate extraction three times.Organic layer after the merging with saturated sodium bicarbonate aqueous solution and saturated brine washing, is used dried over mgso successively.Then, decompression steams solvent.Resistates silica gel chromatography (with 7% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.0013g) obtained.Mass (FD) m/Z:710 (M)
+.
1H-NMR (CDCl
3) δ: 1.71-1.78 (14H, m), 2.60-2.90 (6H, m), 3.40-3.70 (2H, m), 4.00-4.60 (4H, m), 7.25-7.83 (14H, m). (6) (2R, 3R)-2-carboxyl methoxyl group-10-(2-naphthyl)-3-[5-(2-naphthyl) pentyloxy]-4-oxo capric acid
Add trifluoroacetic acid (0.3ml) in methylene dichloride (5ml) solution of the di tert butyl carbonate (0.0011g) that in (5), obtains, mixture was at room temperature stirred 12 hours.After finishing reaction, decompression steams solvent, thereby obtains the title compound (0.0009g) of colorless oil.Mass (FAB+) m/Z:621 (M+Na)
+.
1H-NMR (CDCl
3) δ: 1.20-1.65 (14H, m), 1.39 (9H, s), 1.41 (9H; s), and 2.49-2.78 (6H, m), 3.23-3.50 (2H, m); 3.81 (1H, d, J=16.1Hz), 4.19 (1H; d, J=16.1Hz), 3.98 (1H, d; J=2.9Hz), (1H, d, J=2.9Hz); 7.20-7.75 (14H, m). embodiment 31 (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
(1) (2R, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-3,5-dimethylphenyl) penta-2-alkene-1-base oxygen base]-the 3-hydroxy-propionic acid tert-butyl ester
L (+)-tartrate di tert butyl carbonate (19.7g) is dissolved in N, in the N-methylene dichloride (300ml), under the frozen water cooling and stirring, the adding sodium hydride (60% oily dispersion liquid, 3.0g).After 5 minutes, in 15 minutes, be added dropwise to the N of 5-(3, the 4-3,5-dimethylphenyl) penta-2-alkene-1-base iodine (22.5g) (reference example 13), dinethylformamide (100ml) solution.When being heated to room temperature,, be poured into then in the mixture under the frozen water cooling of saturated brine and ethyl acetate reaction mixture restir 80 minutes.Isolate organic layer, use the saturated brine washed twice, use anhydrous sodium sulfate drying.Decompression steams solvent then.Resistates silica gel chromatography (with 15% ethyl acetate-hexane wash-out), thus colorless oil title compound (14.0g) obtained.Mass (FAB+) m/Z:457 (M+Na)
+.
1H-NMR (CDCl
3) δ: 1.49 (9H, s), 1.50 (9H, s), 2.22 (3H, s), 2.23 (3H, s), 2.29-2.35 (2H, m), and 2.59-2.63 (2H, m), 3.04 (1H, d, J=8.3Hz), 3.85-3.90 (1H, m), 4.12 (1H, d, J=2.4Hz), 4.17-4.22 (1H, m), 4.44 (1H, dd, J=8.3,2.4Hz), 5.45-5.58 (1H, m), 5.61-5.75 (1H, m), 6.89 (1H, dd, J=7.8,1.5Hz), 6.93 (1H, s), 7.03 (1H, d, J=7.8Hz). (2) (2R, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-the 3-hydroxy-propionic acid tert-butyl ester
The olefin(e) compound (14.0g) that (1) is obtained is dissolved in ethyl acetate (200ml).In the solution that forms, add 10% palladium-charcoal (0.8g), under nitrogen atmosphere, mixture was at room temperature stirred 14.5 hours.After removing by filter palladium-charcoal, filtrate is used anhydrous sodium sulfate drying, decompression steams solvent then, thereby obtains colorless oil title compound (13.97g).MS (EI) m/Z:436 (M)
+.
1H-NMR (CDCl
3) δ: 1.34-1.41 (2H, m), 1.45-1.65 (22H, m), 2.22 (3H, s), 2.23 (3H, s), 2.52 (2H, t, J=7.8Hz), 3.01 (1H, d, J=8.8Hz), 3.26-3.31 (1H, m), and 3.69-3.75 (1H, m), 4.06 (1H, t, J=0.98Hz), 4.41-4.44 (1H, m), 6.89 (1H, d, J=7.6Hz), 6.93 (1H, s), 7.02 (1H, d, J=7.6Hz). (3) (2R, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-hydroxy-propionic acid benzyl ester
The di tert butyl carbonate (13.93g) that obtains in (2) is dissolved in N, dinethylformamide (45ml), subsequently, under the frozen water cooling, in 15 minutes, be added dropwise to diethyl methoxyl group borine (the 1M tetrahydrofuran solution, 37ml).After 40 minutes, add sodium borohydride (1.45g), the mixture that forms was at room temperature stirred 4.5 hours.Reaction mixture is poured in the mixture of frozen water refrigerative SODIUM PHOSPHATE, MONOBASIC (75g) and water (250ml), added the trimethyl carbinol (30ml) and 2-methyl-2-butene (76ml) then.(80%, aqueous solution 75g) (150ml) at room temperature stirred the mixture that forms 15.5 hours to add Textone again.In reaction mixture, add entry (400ml) and ethyl acetate (400ml), isolate organic layer.The organic layer that forms is washed with 1N hydrochloric acid (700ml), use anhydrous sodium sulfate drying.Decompression steams solvent.In resistates, add toluene and triethylamine, carry out azeotropic distillation again.Then, resistates is dissolved in N, dinethylformamide (150ml).Under the frozen water cooling, in the solution that forms, add triethylamine (13ml) and bromotoluene (10.9g).The mixture that forms was at room temperature stirred 20.5 hours, and reaction mixture dilutes with ethyl acetate, with 1N hydrochloric acid, 5% sodium bicarbonate aqueous solution and water washing, uses anhydrous sodium sulfate drying then.Decompression steams solvent, resistates silica gel chromatography (with 15% ethyl acetate-hexane wash-out), thus obtain light yellow oily title compound (6.35g).MS(FAB+)m/Z：493(M+Na)
+.
1H-NMR(CDCl
3)δ：1.30-1.40(2H，m)，1.48(9H，s)，1.55-1.63(4H，m)，2.21(3H，s)，2.23(3H，s)，2.50(2H，t，J＝7.8Hz)，3.09(1H，d，J＝8.3Hz)，3.31(1H，dt，J＝8.8，6.8Hz)，3.73(1H，dt，J＝8.8，6.4Hz)，4.24(1H，d，J＝2.4Hz)，4.48(1H，d，J＝8.3，2.4Hz)，5.21(1H，d，J＝12.2Hz)，5.26(1H，d，J＝12.2Hz)，6.88(1H，d，J＝7.6Hz)，6.88(1H，d，J＝7.6Hz)，6.92(1H，s)，7.02(1H，d，J＝7.6Hz)，7.32-7.38(5H，m).
(4) (2R, 3R)-3-benzyloxycarbonyl-2-t-butyldimethylsilyloxy base-3[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
The oxy-compound (1.58g) that obtains in (3) is dissolved in N, in the dinethylformamide (25ml).In the solution that forms, add imidazoles (0.46g) and tertiary butyl chloride for dimethylsilane (0.91g), mixture was at room temperature stirred 27 hours.Reaction mixture is poured in the water, extracted with the ethyl acetate dilution.Extraction liquid is used anhydrous sodium sulfate drying with dilute hydrochloric acid and saturated brine washing.Decompression steams solvent, resistates silica gel chromatography (with 3% ethyl acetate-hexane wash-out), thus obtain colorless oil title compound (1.56g).MS (FAB+) m/Z:607 (M+Na)
+, 585 (M+H)
+.
1H-NMR (CDCl
3) δ: 0.017 (3H, s), 0.112 (3H, s), 0.88 (9H, s), 1.25-1.34 (2H, m), 1.45 (9H, s), 1.51-1.61 (4H, m), 2.21 (3H, s), 2.22 (3H, s), 2.48 (2H, t, J=7.6Hz), 3.36 (1H, dt, J=9.3,7.1Hz), 3.64 (1H, dt, J=9.3,7.1Hz), 4.25 (1H, d, J=3.9Hz), 4.52 (1H, d, J=3.9Hz), 5.11 (1H, d, J=12.2Hz), 5.21 (1H, d, J=12.2Hz), 6.87 (1H, d, J=7.8Hz), 6.91 (1H, s), 7.02 (1H, d, J=7.8Hz), 7.31-7.37 (5H, m). (5) (2R, 3R)-and 3-tertbutyloxycarbonyl-3-t-butyldimethylsilyloxy base-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
The diester compound (1.50g) that obtains in (4) is dissolved in the ethyl acetate (20ml).In the solution that forms, add 10% palladium-charcoal (0.09g), under nitrogen atmosphere, mixture was at room temperature stirred 17 hours.After removing by filter palladium-charcoal, filtrate is used anhydrous sodium sulfate drying.Decompression steams solvent, thereby obtains colorless oil title compound (1.35g).MS (FAB+) m/Z:495 (M+H)
+.
1H-NMR (CDCl
3) δ: 0.04 (3H, s), 0.11 (3H, s); 0.88 (9H, s), 1.30-1.38 (2H, m); 1.48 (9H, s), 1.56-1.66 (4H, m); 2.21 (3H, s), 2.23 (3H, s); 2.52 (2H, t, J=7.8Hz), 3.48-3.60 (2H; m), 4.29 (1H, d, J=2.9Hz); 4.49 (1H, d, J=2.9Hz), 6.88 (1H; d, J=7.8Hz), 6.92 (1H; s), 7.02 (1H, d; J=7.8Hz). (6) (2R, 3R)-2-t-butyldimethylsilyloxy base-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With propionic acid (0.25g), methyl [5-(2-naphthyl) amylamine (free alkali that obtains in (5), 0.15g) (reference example 14-(2)) and I-hydroxybenzotriazole (23mg) be dissolved in the methylene dichloride (10ml), adds 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (0.29g) in the frozen water cooling and under stirring again.After the mixture that forms at room temperature stirred 14.5 hours, with the reaction mixture concentrating under reduced pressure.In resistates, add entry, the mixture that forms is extracted with ethyl acetate.Extraction liquid with dilute hydrochloric acid and saturated brine washing, is used anhydrous sodium sulfate drying successively again.Decompression steams solvent.Resistates silica gel chromatography (with 10% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.25g) obtained.MS (FAB+) m/Z:726 (M+Na)
+, 704 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.032,0.035 (total 3H, seach); 0.089,0.096 (total 3H, s each), 0.89 (9H; s), and 1.25-1.40 (4H, m), 1.43; (1.44 total 9H, s each), 1.51-1.60 (6H; m), and 1.68-1.76 (2H, m); 2.20 (3H, s), 2.21 (3H; s), 2.50 (2H, t; J=7.6Hz), 2.76 (2H, t; J=7.6Hz), 2.87,3.14 (total3H; s each), 3.02-3.08,3.27-3.61; (3.74-3.81 total 4H, m each), 4.34; 4.36 (1H, d, each; J=5.9/4.9Hz), 4.44,4.48 (1H; d, each, J=5.9/4.9Hz); 6.86-6.88 (1H, m), 6.91 (1H; s), and 6.99-7.02 (1H, m); 7.30 (1H, dd, J=8.3; 1.5Hz), 7.37-7.51 (2H, m); 7.58 (1H, s), 7.73-7.79 (3H; m). (7) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
The 2-t-butyldimethylsilyloxy based compound (0.22g) that (6) are obtained is dissolved in the tetrahydrofuran (THF) (6ml).(the 1M tetrahydrofuran solution 0.56ml), at room temperature stirred mixture 2 days to add acetate (38g) and tetrabutyl ammonium fluoride in the solution that forms.Decompression steams solvent.Resistates silica gel chromatography (with 35% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.16g) obtained.MS (FAB+) m/Z:512 (M+Na)
+, 590 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.30-1.40 (4H, m), 1.40-1.64 (15H; m), and 1.70-1.76 (2H, m), 2.21 (3H; s), 2.22 (3H, s), 2.50 (2H; t, J=7.6Hz), 2.76 (2H, t; J=7.1Hz), 2.92,3.12 (total3H, s each); 3.24-3.33 (2H, m), 3.41-3.59 (2H, m); 4.30-4.41 (2H, m), 6.87 (1H, d; J=7.3Hz), 6.91 (1H, s), 7.01 (1H; d, J=7.8Hz), 7.30 (1H, d; J=8.1Hz), and 7.38-7.45 (2H, m); 7.58 (1H, s), 7.74-7.79 (3H; m). (8) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
The tert-butyl ester compound (153mg) that obtains in (7) is dissolved in the methylene dichloride (1.5ml), mixture was at room temperature stirred 5 hours.Then, decompression steams solvent.In resistates, add toluene, the mixture that forms is carried out azeotropic distillation three times.Behind the drying under reduced pressure, obtain the title compound (133mg) of colorless oil.MS (FAB+) m/Z:556 (M+Na)
+, 534 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.26-1.40 (4H, m), 1.51-1.66 (6H; m), and 1.68-1.78 (2H, m), 2.20 (3H; s), 2.22 (3H, s), 2.49-2.52 (2H; m), and 2.74-2.80 (2H, m), 2.95; (3.06 total 3H, s each), and 3.29-3.41 (3H, m); 3.48-3.55 (1H, m), 4.34,4.39 (total 1H; deach, J=2.9/2.9Hz), 4.57,4.60 (total 1H; d each,, J=2.9/2.9Hz); 6.87 (1H, d, J=7.8Hz); 6.92 (1H, s), 7.01 (1H; d, J=7.8Hz), 7.30 (1H; d, J=8.3Hz), 7.38-7.45 (2H; m), 7.58 (1H, s); 7.75-7.80 (3H, m). embodiment 32 (2R, 3R)-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
(1) (2R, 3R)-3-[4-(tert-butyl diphenyl siloxy-) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With embodiment 27 obtain (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-3-ethoxycarbonyl methoxy propyl acid benzyl ester (2.5g) is dissolved in the tetrahydrofuran (THF) (50ml).In the solution that forms, add 10% palladium-charcoal (0.5g), under nitrogen atmosphere, mixture was at room temperature stirred 4.5 hours.After removing by filter palladium-charcoal, decompression steams solvent, thereby the acquisition colorless oil (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-3-ethoxycarbonyl methoxypropionic acid.
The compound dissolution that forms in methylene dichloride (50ml), is added methyl [5-(2-naphthyl) amylamine (free alkali, 0.82g) (reference example 14-(2)) and I-hydroxybenzotriazole (0.1g).Under the frozen water cooling and stirring, in the mixture that forms, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (1.04g).After the mixture that forms at room temperature stirred 3 days, add entry, extract with methylene dichloride.Extraction liquid washs with saturated brine, uses anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates silica gel chromatography (with 15% ethyl acetate-hexane wash-out), thus oily title compound (1.67g) obtained.Mass (EI) m/Z:811 (M)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.03 (9H, s), 1.23 (3H, t; J=7.3Hz), and 1.32-1.40 (2H, m), 1.45,1.46 (total 9H; seach), and 1.54-1.76 (8H, m), 2.76 (2H; dd, J=7.8,7.3Hz), 2.90; (3.16 total 3H, s each), and 3.26-3.62 (4H, m); 3.63 (2H, t, J=6.4Hz), 4.06 (1H; d, J=16.1Hz), 4.11-4.20 (2H, m); 4.29-4.35 (1H, m), 4.39 (1H, d; J=16.1Hz), 4.50 (2/3H, d, J=4.4Hz); 4.52 (1/3H, d, J=5.8Hz), 7.27-7.44 (9H; m), 7.58 (1H, s), 7.64 (4H; d, J=5.9Hz), 7.73 (1H, d; J=8.3Hz), 7.75 (1H, d, J=8.8Hz); 7.76 (1H, d, J=8.8Hz). and (2) (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[4-hydroxyl butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
Handle the tert-butyl diphenyl siloxy-compound (1.67g) that obtains in (1) in the mode identical, thereby obtain oily title compound (1.05g) with embodiment 18-(5).Mass (EI) m/Z:573 (M)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.25 (3H, t, J=6.8Hz); 1.30-1.41 (2H, m), 1.45,1.47 (total 9H; s each), and 1.52-1.68 (6H, m), 1.70-1.78 (2H; m), 2.77 (2H, t, J=7.8Hz); 2.91,3.16 (total 3H, seach), 3.28-3.60 (6H; m), and 4.07-4.21 (3H, m), 4.30-4.38 (4/3H; m), 4.38 (2/3H, d, J=16.6Hz); 4.50 (2/3H, d, J=5.4Hz), 4.52 (1/3H; d, J=5.4Hz), 7.32 (1H, d; J=8.3Hz), and 7.38-7.47 (2H, m); 7.60 (1H, s), 7.75 (1H; d, J=8.3Hz), 7.77 (1H; d, J=7.8Hz), 7.79 (1H; d, J=7.8Hz). (3) (2R, 3R)-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
Handle the alkylol cpd (0.25g) that obtains in (2) in the mode identical, thereby obtain oily title compound (0.42g) with embodiment 25.Mass (EI) m/Z:696 (M)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.24 (3H, t, J=7.3Hz); 1.32-1.39 (2H, m), 1.44,1.46 (total 9H; s each), and 1.50-1.67 (6H, m), 1.69-1.76 (2H; m), 2.22 (3H, s), 2.76 (2H; t, J=7.3Hz), 2.91; (3.15 total 3H, s each), 3.26-3.68 (6H; m) .4.09 (2/3H, d, J=16.1Hz); 4.14-4.22 (7/3H, m), 4.33 (1H; d, J=4.9Hz), 4.36 (1/3H; d, J=16.1Hz), 4.38 (2/3H; d, J=16.1Hz), 4.50 (2/3H; d, J=4.9Hz), 4.52 (1/3H; d, J=4.9Hz), 6.37 (1/3H; dd, J=7.8,2.0Hz); 6.39 (2/3H, d, J=8.3; 2.4Hz), 6.58 (1H, s); (6.59 1H, broad s), 6.94 (2/3H; d, J=8.3Hz), 6.95 (1/3H; d, J=7.8Hz), 7.30 (1H; d, J=8.3Hz), 7.39 (1H; dt, J=6.8,2.0Hz); 7.42 (1H, dt, J=6.8; 2.0Hz), 7.58 (1H, s); 7.73-7.79 (3H, m). (4) (2R, 3R)-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Handle the diester compound (0.42g) that obtains in (3) in the mode identical, thereby obtain light yellow oily title compound (0.048g) with embodiment 26.Mass (FAB+) m/Z:641 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.19 (3H, t, J=6.8Hz); 1.34-1.45 (2H, m), 1.60-1.80 (8H, m); 2.31,2.34 (total 3H, s each), 2.77; 2.79 (total 2H, t each, J=7.8/7.8Hz), 3.00; (3.13 total3H, s each), 3.10-3.16 (6H; m), 3.94 (1/3H, d; J=17.1Hz), 3.96 (2/3H, d; J=15.8Hz), 4.03 (2/3H, d; J=15.8Hz), 4.10 (2H, q; J=6.8Hz), 4.40 (1/3H, d; J=2.9Hz), 4.50 (2/3H, d; J=2.4Hz), 4.70 (1H, broad s); 7.19 (2/3H, d, J=7.8Hz); 7.22 (1/3H, d, J=8.3Hz); 7.28-7.35 (2H, m), 7.51 (1H; s), 7.58 (2/3H, s); 7.59 (1/3H, s), 7.74 (1H; d, J=8.3Hz), 7.76 (1H; d, J=8.3Hz), 7.78 (1H; d, J=8.3Hz). (5) (2R, 3R)-2-carboxyl methoxyl group-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Handle the mono ethyl ester compound that obtains in (4) in the mode identical with embodiment 39-(4), with high performance liquid chromatography (" Sensyu Pak ODS-5251-SH ", with 65: 35 (V/V) wash-outs of acetonitrile-0.1% trifluoroacetic acid) replace " DIAION HP20 " column chromatography to carry out purifying, thus obtain light yellow amorphous solid shape title compound (0.048g).MS(FAB+)m/Z：613(M+H)
+。To C
33H
41ClN
2O
70.7CF
3COOH1.2H
2The ultimate analysis of O: calculated value: C, 57.82; H, 6.22; Cl, 4.96; F, 5.58; N, 3.92 measured values: C, 58.11; H, 6.10; Cl, 5.66; F, 5.36; N, 3.51 embodiment 33 (1) (4R, 5R)-4-tertbutyloxycarbonyl-3,6-two oxa-s-5-[N-[5-(2-naphthyl) amyl group] formamyl]-11-(2-naphthyl) undecanoic acid
With embodiment 3-(3) obtain (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-N-[5-(2-naphthyl) amyl group] formamyl]-3-[5-(2-naphthyl) pentyloxy] the propionic acid tert-butyl ester (0.85g) is dissolved in the ethanol (5ml).At room temperature, in the solution that forms, add 1N aqueous sodium hydroxide solution (1.4ml), mixture was stirred 12 hours.Then, decompression steams solvent.The hydrochloric acid and the methylene dichloride of adding 10% in resistates, water layer dichloromethane extraction three times.Merge organic layer and use anhydrous magnesium sulfate drying.Decompression steams solvent, thereby obtains colorless oil title compound (0.67g).The compound that forms can not purifiedly be directly used in next step reaction.(2) carboxylic acid (110) that (1) is obtained is dissolved in the methylene dichloride (5ml), adds morpholine (35mg), I-hydroxybenzotriazole (50mg) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (35.5mg) again under the frozen water cooling.The mixture that forms was stirred 18 hours.In reaction mixture, add 10% aqueous hydrochloric acid and methylene dichloride.Water layer dichloromethane extraction three times.Organic layer after the merging is used anhydrous magnesium sulfate drying with saturated sodium bicarbonate aqueous solution and saturated brine washing.Decompression steams solvent, resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus obtain colorless oil embodiment 33-a compound (55mg).
In the mode same, only be to use corresponding sulfonamide derivatives to replace morpholine to react, thereby synthesize the compound of embodiment 33-b to 33-k respectively with above-mentioned reacting phase.
Embodiment 34
At the tert-butyl ester compound of the mode Processing Example 33 identical, thereby obtain the compound of embodiment 34-a to 34-k respectively with embodiment 17.
Embodiment 35 (1) (2R, 3R)-2-carbobenzoxy-(Cbz) methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
(2R with embodiment 31-(7) acquisition; 3R)-3-[5-(3; the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester (0.19g) is dissolved in the tetrahydrofuran (THF) (5ml);-78 ℃ and stir under; be added dropwise to two trimethyl silyl amination potassium (the 0.5M tetrahydrofuran solution, 0.85ml).After being heated to 0 ℃, stirred 10 minutes, again reaction mixture is cooled to-78 ℃.Add benzyl acetate bromide (0.1ml), the mixture that forms was stirred 2 hours.In reaction mixture, add 10% aqueous hydrochloric acid, extract with ethyl acetate.Extraction liquid washes with water, uses anhydrous sodium sulfate drying then.Decompression steams solvent.Resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.22g) obtained.MS (FAB+) m/Z:760 (M+Na)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.22-1.78 (21H, m), 2.18-2.23 (6H; m), and 2.43-2.79 (4H, m), 2.87 (0.9H; s), 3.12 (2.1H, s), 3.13-3.80 (4H; m), and 4.05-4.52 (4H, m), 5.08-5.18 (2H; m), and 6.83-7.85 (15H, m). (2) (4R; 5R)-and tertbutyloxycarbonyl-11-(3, the 4-3,5-dimethylphenyl)-3,6-two oxa-s-5-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] undecanoic acid
The benzyl ester (0.22g) that obtains in (1) is dissolved in the ethanol (5ml).In the solution that forms, add 10% palladium-charcoal (0.01g), under nitrogen atmosphere, mixture was at room temperature stirred 5 hours.After removing by filter palladium-charcoal, filtrate is used anhydrous sodium sulfate drying.Decompression steams solvent, thereby obtains colorless oil title compound (0.15g).MS (FAB+) m/Z:670 (M+Na)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.25-1.82 (21H, m), 2.21 (3H; s), and 2.45-2.57 (2H, m), 2.70-2.82 (2H; m), 2.95 (2H, s), 3.08 (4H; s), and 3.20-3.62 (4H, m); 4.08-4.65 (4H, m), 6.81-7.82 (10H; m). (3) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-methoxyl group formamyl) methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
The carboxylic acid (99mg), O-methyl hydroxy amine hydrochloric acid salt (20mg) and the I-hydroxybenzotriazole (5mg) that obtain in (2) are dissolved in the methylene dichloride (6ml).In the solution that forms, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (33mg).The mixture that forms was at room temperature stirred 16 hours.Reaction mixture is carried out concentrating under reduced pressure.In resistates, add dilute hydrochloric acid, the mixture that forms is extracted with methylene dichloride.Extraction liquid washs with saturated brine, uses anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates silica gel chromatography (with 75% ethyl acetate-hexane wash-out), thus oily title compound (60mg) obtained.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.10-1.90 (12H, m); 2.10-2.30 (6H, m), 2.40-2.57 (2H; m), and 2.66-2.83 (2H, m); 2.94 (1H; s), 3.09 (2H, s); 3.20-3.70 (7H; m), and 4.00-4.60 (4H, m); 6.75-7.82 (10H; m), and 10.50-10.67 (1H, m). (4) (2R; 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-(N-methoxyl group formamyl) methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Add trifluoroacetic acid (1ml) in methylene dichloride (2ml) solution (2ml) of the tert-butyl ester (58mg) that in (3), obtains, mixture was at room temperature stirred 12 hours.Reaction mixture is evaporated to dried.Carry out purifying with high performance liquid chromatography (" Sensyu Pak ODS-5251-SH " is with 8: 2 (V/V) wash-outs of acetonitrile-0.1% trifluoroacetic acid), thereby obtain colorless oil shape title compound (27mg).MS (FAB+) m/Z:621 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.20-1.80 (12H, m), 2.19-2.24 (6H; m), and 2.43-2.58 (2H, m); 2.70-2.81 (2H, m), 2.89-3.12 (3H; m), and 3.20-3.90 (7H, m); 4.08-4.72 (4H, m), 6.80-7.86 (10H; m). embodiment 36 (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
Handle in the mode identical, just adopt (3, the 4-dichlorophenylmethyl) three phenyl phosphonium bromides to replace (3,4-dimethyl benzene ylmethyl) triphenyl phosphonium chloride, thereby obtain the colorless oil title compound with embodiment 28.(1) (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid tert-butyl ester Mass (EI) m/Z:701 (M)
+.
1H-NMR (CDCl
3) δ: 1.23 (3H, t, J=7.4Hz), 1.49 (9H; s), and 1.27-1.65 (10H, m), 1.65-1.74 (2H; m), 2.51 (2H, t, J=7.4Hz); 2.76 (2H, t, J=7.4Hz), 3.25-3.55 (3H; m), 3.90 (1H, d, J=6.1Hz); 4.10-4.20 (3H, m), 4.30-4.40 (2H, m); 6.65 (1H, t, J=5.8Hz), 6.95 (1H; dd, J=8.3,2.0Hz), 7.21-7.45 (6H; m), 7.58 (1H, s), 7.73-7.79 (3H; m). (2) (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid Mass (EI) m/Z:645 (M)
+.
1H-NMR (CDCl
3) δ: 1.28 (3H, t, J=7.3Hz), 1.35-1.80 (12H; m), 2.53 (2H, t, J=7.3Hz); 2.77 (2H, t, J=7.3Hz), 3.28-3.33 (2H; m), and 3.47-3.60 (2H, m), 4.09 (1H; d, J=17.6Hz), 4.25 (2H, q; J=7.3Hz), and 4.30-4.40 (2H, m), 4.55 (1H; d, J=1.5Hz), 6.75-6.90 (1H; m), 6.98 (1H, dd; J=8.3,2.0Hz), 7.20-7.35 (3H; m), and 7.35-7.50 (2H, m); 7.58 (1H, s), 7.70-7.85 (3H; m). embodiment 37 (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid disodium
(1) (2R, 3R)-3-carbobenzoxy-(Cbz)-2-tertiary butyloxycarbonyl oxygen base-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
(2R with embodiment 31-(3) acquisition, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-hydroxy-propionic acid benzyl ester (1.20g) is dissolved in the tetrahydrofuran (THF) (12ml), subsequently,-70 ℃ or the cooling of lower temperature and under agitation, in 5 minutes, be added dropwise to two trimethyl silyl amination potassium (the 1M toluene solution, 5.2ml).After 5 minutes, in 5 minutes, be added dropwise to tetrahydrofuran (THF) (3ml) solution of bromo-acetic acid tert-butyl (0.64g).Remove cryostat.Reaction mixture was stirred 75 minutes, and be heated to room temperature simultaneously, reaction mixture is poured in the mixture of 0.5N hydrochloric acid and ethyl acetate.Isolate organic layer,, use anhydrous sodium sulfate drying with the saturated brine washing.Decompression steams solvent.Resistates silica gel chromatography (with 10% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.93g) obtained.MS (FAB+) m/Z:607 (M+Na)
+, 585 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.32-1.39 (2H, m), 1.44 (9H, s), 1.47 (9H, s), 1.51-1.65 (4H, m), 2.21 (3H, s), 2.22 (3H, s), 2.49 (2H, t, J=7.8Hz), 3.28-3.33 (1H, m), 3.67-3.73 (1H, m), 4.00 (1H, d, J=16.6Hz), 4.26 (1H, d, J=16.6Hz), 4.36 (1H, d, J=2.9Hz), 4.46 (1H, d, J=2.9Hz), 5.24 (1H, d, J=12.0Hz), 5.27 (1H, d, J=12.0Hz), 6.88 (1H, d, J=7.6Hz), 6.92 (1H, s), 7.02 (1H, d, J=7.6Hz), 7.31-7.37 (3H, m), 7.41-7.44 (2H, m). (2) (2R, 3R)-and 3-tertbutyloxycarbonyl-3-tertiary butyloxycarbonyl ylmethoxy-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
With the identical mode of embodiment 31-(5), the 3-carbobenzoxy-(Cbz) compound colorless oil title compound that obtains by (1).MS (FAB+) m/Z:495 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.27-1.68 (24H, m), 2.22 (3H, s); 2.23 (3H, s), 2.52 (2H; t, J=7.6Hz), 3.41-3.50 (1H; m), and 3.60-3.70 (1H, m); 4.00 (1H, d, J=16.1Hz); 4.33 (1H, d, J=16.1Hz); 4.36 (1H, s), 6.88 (1H; d, J=7.3Hz), 6.92 (1H; s), 7.02 (1H, d; J=7.3Hz). (3) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With with the identical mode of embodiment 31-(6), propionic acid (103mg) the preparation colorless oil title compound (139mg) that obtains by (2).MS (FAB+) m/Z:726 (M+Na)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.30-1.80 (30H, m), 2.15-2.25 (6H; m), and 2.42-2.54 (2H, m), 2.70-2.80 (2H; m), 2.91,3.19 (total 3H; s each), and 3.25-3.63 (4H, m); 3.87-4.50 (4H, m), 6.80-7.83 (10H; m). (4) (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid disodium
The diester compound (139mg) that obtains in (3) is dissolved in the methylene dichloride (3ml).In the solution that forms, add trifluoroacetic acid (0.6ml), mixture was at room temperature stirred 18 hours.Be dissolved in the ethanol (2ml) being evaporated to the dried resistates that obtains.In the solution that forms, add 1N sodium hydroxide (0.4ml), be evaporated to the mixture that forms dried.Resistates carries out purifying (carrying out wash-out with the water that contains acetonitrile) with " DIAION HP20 " column chromatography, thereby obtains colorless solid shape title compound (76mg).MS (FAB+) m/Z:658 (M+Na)
+, 636 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.20-1.82 (12H, m), 2.04-2.25 (6H, m), 2.40-2.80 (4H, m), 2.82-3.14 (3H, m), 3.24-4.71 (8H, m), 6.72-7.81 (10H, m). to C
35H
43NNa
2O
70.4H
2The ultimate analysis of O: calculated value: C, 65.39; H, 6.87; N, 2.18 measured values: C, 65.55; H, 6.97; N, 2.06 embodiment 38 (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
(1) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
The 2-oxy-compound (204mg) that embodiment 31-(7) is obtained is dissolved in the tetrahydrofuran (THF) (6ml), under-78 ℃ of cooling and stirring, be added dropwise to two trimethyl silyl amination potassium (the 1M toluene solution, 0.8ml).After stirring 20 minutes, add ethyl bromoacetate (0.1ml).Remove ice bath, make reaction mixture be warming up to 0 ℃.The hydrochloric acid of adding 10% extracts with ethyl acetate then in reaction mixture.Extraction liquid with saturated sodium bicarbonate aqueous solution and saturated brine washing, is used anhydrous sodium sulfate drying successively then.Decompression steams solvent.Resistates silica gel chromatography (with 33% ethyl acetate-hexane wash-out), thus colorless oil title compound (203mg) obtained.MS (FAB+) m/Z:698 (M+Na)
+, 620 (M-tert-Bu+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.22-1.27 (3H, m), 1.31-1.41 (4H, m); 1.45,1.47 (total 9H, s each), and 1.52-1.64 (6H, m); 1.67-1.76 (2H, m), 2.20 (3H, s), 2.21 (3H; s), and 2.48-2.52 (2H, m), 2.74-2.79 (2H; m), 2.90,3.13 (total 3H, s each); 3.25-3.66 (4H, m), 4.07 (1H, dd; J=16.6Hz), and 4.14-4.21 (2H, m), 4.30-4.33 (1H; m), 4.36,4.39 (total 1H, d each; J=16.6/16.6Hz), 4.48,4.51 (total 1H, d each; J=4.9,5.9Hz), 6.87 (1H, d; J=7.3Hz), 6.92 (1H, s), 7.01 (1H; d, J=7.3Hz), 7.31 (1H, dd; J=8.3,2.0Hz), 7.58 (1H, s); 7.74-7.79 (3H, m). (2) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
In the mode identical, prepare the title compound (180mg) of colorless oil by the diester compound (197mg) of above-mentioned acquisition with embodiment 28-2.MS (FAB+) m/Z:642 (M+Na)
+, 620 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.25-1.42 (7H, m), 1.52-1.61 (6H; m), and 1.70-1.79 (2H, m), 2.20 (3H; s), 2.22 (3H, s), 2.48-2.53 (2H; m), and 2.74-2.80 (2H, m), 2.96; (3.11 total 3H, s each), and 3.30-3.50 (4H, m); 4.22,4.25 (total 2H, q each, J=7.3/7.3Hz); 4.351,4.357 (total 2H, s each), 4.42; 4.44 (total 1H, deach, J=6.1/6.1Hz), 4.66; 4.70 (total 1H, d each, J=6.1/6.1Hz), 6.87-6.89 (1H; m), 6.92 (1H, s), 7.01 (1H; d, J=7.3Hz), 7.30 (1H, d; J=8.3Hz), and 7.37-7.46 (2H, m); 7.58 (1H, s), 7.74-7.80 (3H; m). embodiment 39 (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid disodium
(1) (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl]-3-(4-oxo butoxy) the propionic acid tert-butyl ester
With the identical mode of embodiment 18-(6); by embodiment 32-(2) obtain (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-(4-hydroxyl butoxy)-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester prepares the colorless oil title compound.
1H-NMR (CDCl
3) δ: 1.25 (3H, t, J=7.1Hz), 1.33-1.41 (2H; m), 1.44,1.47 (total 9H, s each); 1.55-1.66 (1H, m), 1.70-1.77 (2H, m); 1.82-1.88 (3H, m), 2.50 (2H, t; J=7.3Hz), and 2.74-2.81 (2H, m), 2.90; (3.14 total 3H, s each), and 3.25-3.63 (3H, m); 3.73-3.76 (1H, m), 4.10 (0.9H, d; J=16.1Hz), and 4.13-4.20 (2.1H, m); 4.31-4.39 (2H, m), 4.48-4.51 (1H; m), 7.32 (1H, d; J=8.3Hz), and 7.38-7.46 (2H, m); 7.59 (1H, s), 7.74-7.80 (3H; m), 9.71,9.73 (total1H; s each). (2) (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
(3, the 4-dichlorophenylmethyl) three phenyl phosphonium bromides (530mg) are dissolved in the tetrahydrofuran (THF) (25ml), under-78 ℃ of cooling and stirring, be added dropwise to two trimethyl silyl amination potassium (the 1M toluene solution, 0.84ml).After stirring 5 minutes, in reaction mixture, be added dropwise to 3-(the 4-oxo butoxy) compound (300mg) that (1) obtains.The mixture that forms was stirred 4 hours, and be warming up to room temperature simultaneously.Use the ethyl acetate diluted reaction mixture, and water and saturated brine washing successively, anhydrous magnesium sulfate drying used.Decompression steams solvent.Resistates silica gel chromatography (with 33% ethyl acetate-hexane wash-out); thereby obtain colorless oil (2R; 3R)-3-[5-(3, the 4-dichlorophenyl) penta-4-alkene-1-base oxygen base]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester (217mg).MS (FAB+) m/Z:736 (M+Na)
+, 714 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.17-1.27 (3H, m), 1.27-1.80 (17H, m), 2.18-2.38 (2H, m), 2.70-2.80 (2H, m), 2.90,2.91,3.13,3.17 (total 3H, s each), and 3.21-3.68 (4H, m), 4.02-4.42 (5H, m), and 4.44-4.55 (1H, m), 5.60-5.70, (6.10-6.30 total2H, m each), 7.00-7.82 (10H, m).
The compound (217mg) that forms is dissolved in the tetrahydrofuran (THF) (40ml).In the solution that forms, add 10% palladium-charcoal (20mg), under nitrogen atmosphere, mixture was at room temperature stirred 3 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried.Resistates silica gel chromatography (with 50% ethyl acetate-hexane wash-out), thus colorless oil title compound (168mg) obtained.MS (FAB+) m/Z:716 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.20-1.80 (24H, m); 2.45-2.56 (2H, m), 2.70-2.80 (2H; m), 2.91,3.16 (total 3H; s each), and 3.23-3.63 (4H, m); 4.01-4.23 (3H, m), 4.28-4.52 (3H; m), and 6.90-7.00 (1H, m); 7.16-7.32 (3H, m), 7.35-7.47 (2H; m), 7.58 (1H, s); 7.72-7.83 (3H; m). (3) (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
The diester compound (168mg) that (2) are obtained is dissolved in the methylene dichloride (5ml).In the solution that forms, add trifluoroacetic acid (0.5ml), mixture was at room temperature stirred 8 hours.Reaction mixture is evaporated to dried, thereby obtain colorless oil title compound (161mg).MS (FAB+) m/Z:682 (M+Na)
+, 660 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.19-1.81 (15H, m); 2.45-2.60 (2H, m), 2.70-2.80 (2H; m), 2.97,3.15 (total 3H; s each), and 3.26-3.53 (4H, m); 4.16-4.41 (4H, m), 4.45-4.50 (1H; m), 4.64,4.66 (total 1H; d each; J=6.3Hz), and 6.90-7.00 (1H, m); 7.20-8.00 (9H; m). (4) (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid disodium
The monoester compound (57mg) that (3) are obtained is dissolved in the tetrahydrofuran (THF) (3ml).In the solution that forms, add 1N sodium hydroxide (0.18ml), mixture was at room temperature stirred 16 hours.Decompression steams solvent then.Resistates carries out purifying (carrying out wash-out with the water that contains acetonitrile) with " DIAION HP20 " column chromatography, thereby obtains colorless solid shape title compound (55mg).MS (FAB+) m/Z:698 (M+Na)
+, 676 (M+H)
+.
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 1.13-1.73 (12H, m), 2.42-2.52 (2H, m), 2.63-2.73 (2H, m), 2.83,3.02 (total 3H, s each), 3.20-3.45 (4H, m), 3.50-3.60 (1H, m), 3.79, (3.82 total 1H, broads each), and 4.02-4.12 (1H, m), 4.55-4.61 (1H, m), and 6.95-7.03 (1H, m), 7.21-7.35 (4H, m), 7.52 (1H, s), 7.61-7.70 (3H, m). to C
33H
37Cl
2NNa
2O1.5H
2The ultimate analysis of O: calculated value: C, 56.34; H, 5.73; Cl, 10.08; N, 1.99 measured values; C, 56.12; H, 5.80; Cl, 10.30; N, 1.74 embodiment 40 (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
(1) (2R, 3R)-3-carbobenzoxy-(Cbz)-2-hydroxyl-3-(4-hydroxyl butoxy) propionic acid tert-butyl ester
With embodiment 18-(3) obtain (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-3-hydroxy-propionic acid benzyl ester (657mg) is dissolved in the tetrahydrofuran (THF) (5ml).Under the frozen water cooling, (the 1M tetrahydrofuran solution 1.5ml), at room temperature stirred mixture 24 hours to add acetate (0.1ml) and tetrabutyl ammonium fluoride in the solution that forms.Decompression steams solvent.Resistates silica gel chromatography (with 75% ethyl acetate-hexane wash-out), thus colorless oil title compound (377mg) obtained.MS (EI) m/Z:368 (M
+).
1H-NMR (CDCl
3) δ: 1.49 (9H, s), 1.51-1.72 (6H, m), 3.37-3.41 (1H, m), 3.62-3.65 (2H, m), 3.76-3.80 (1H, m), 4.25 (1H, d, J=2.5Hz), and 4.43-4.60 (1H, m), 5.22 (1H, d, J=12.2Hz), 5.28 (1H, d, J=12.2Hz), and 7.30-7.45 (5H, m). (2) (2R, 3R)-3-carbobenzoxy-(Cbz)-2-hydroxyl-3-(4-oxo butoxy) propionic acid tert-butyl ester
With with the identical mode of embodiment 18-(6), the crude product (2.63g) of alkylol cpd (3.75g) the preparation title compound that obtains by (1).MS (EI) m/Z:367 (M
++ 1).
1H-NMR (CDCl
3) δ: 1.49 (9H, s), 1.80-1.97 (2H, m), 2.52-2.62 (2H, m), 3.09 (1H, d, J=8.3Hz), and 3.35-3.48 (1H, m), 3.65-3.78 (1H, m), 4.24 (1H, d, J=2.5Hz), 4.50 (1H, dd, J=7.8,2.5Hz), 5.20 (1H, d, J=12.2Hz), 5.25 (1H, d, J=12.2Hz), 7.30-7.45 (5H, m), 9.73 (1H, s). (3) (2R, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-dichlorophenyl) penta-4-alkene-1-base oxygen base]-3-hydroxy-propionic acid benzyl ester
With with the identical mode of embodiment 39-(2), 3-(the 4-oxo butoxy) compound (2.63g) that (2) are obtained carries out the Wittig reaction, thereby obtains colorless oil title compound (2.82g).MS (EI) m/Z:508 (M
+).
1H-NMR (CDCl
3) δ: 1.47 (9H, s), 1.49 (9H, s), and 1.69-1.80 (2H, m), 2.25-2.45 (2H, m), 3.09 (1H, m), and 3.25-3.45 (1H, m), 3.72-3.84 (1H, m), 4.22-4.27 (1H, m), and 4.46-4.52 (1H, m), 5.15-5.35 (2H, m), 5.65-5.75 (1H, m), and 6.10-6.36 (1H, m), 7.05-7.50 (8H, m). and (4) (2R, 3R)-3-carbobenzoxy-(Cbz)-2-(t-butyldimethylsilyloxy base)-3-[5-(3, the 4-dichlorophenyl) penta-4-alkene-1-base oxygen base] the propionic acid tert-butyl ester
With with the identical mode of embodiment 31-(4), by oxy-compound (2.82g) preparation colorless oil title compound (3.42g) that obtains in (3).MS (EI) m/Z:622 (M
+).
1H-NMR (CDCl
3) δ: 0.01 (3H, s), 0.11 (3H, s), 0.77 (9H, s), 0.78 (9H, s), 1.34,1.36 (total 9H, s each), 1.55-1.75 (2H, m), and 2.05-2.30 (2H, m), 3.30-3.3.45 (1H, m), and 3.55-3.70 (1H, m), 4.16-4.19 (1H, m), 4.43-4.46 (1H, m), and 4.98-5.02 (1H, m), 5.65-5.75 (1H, m), 6.05-6,25 (1H, m), 6.95-7.40 (8H, m). and (5) (2R, 3R)-3-tertbutyloxycarbonyl-3-(t-butyldimethylsilyloxy base)-2-[5-(3, the 4-dichlorophenyl) pentyloxy] propionic acid
With with the identical mode of embodiment 31-(5), diester compound (1.80g) the preparation title compound (1.50g) that obtains by (4).MS (EI) m/Z:535 (M
++ 1).
1H-NMR (CDCl
3) δ: 0.08 (3H, s), 0.10 (3H, s); 0.76 (10H, s), 1.20-1.30 (2H; m), 1.36 (9H, s); 1.46-1.60 (4H, m), 2.43 (2H; t, J=7.3Hz), 3.35-3.45 (1H; m), and 3.46-3.52 (1H, m); 4.17 (1H, d, J=2.9Hz); 4.39 (1H, d, J=2.9Hz); 6.87 (1H, m), 7.08-7.18 (2H; m). (6) (2R, 3R)-2-(t-butyldimethylsilyloxy base)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
With with the identical mode of embodiment 31-(6), propionic acid (1.50g) the preparation colorless oil title compound (1.46g) that obtains by (5).MS (EI) m/Z:744 (M
++ 1).
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.08 (3H, s), 0.14 (3H; s), 0.86 (9H, s), 1.15-1.40 (4H; m), 1.41 (9H, s), 1.45-1.65 (8H; m), and 1.65-1.80 (2H, m), 2.40-2.55 (2H; m), and 2.65-2.75 (2H, m), 2.85 (3H; s), 3.10 (3H, s), 3.20-3.60 (2H; m), and 4.25-4.50 (2H, m), 6.85-6.95 (1H; m), and 7.15-7.30 (3H, m), 7.35-7.45 (2H; m), 7.56 (1H, s), 7.60-7.70 (3H; m). (7) (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With with the identical mode of embodiment 31-(7), amide compound (1.32g) the preparation colorless oil title compound (1.02g) that obtains by (6).MS (EI) m/Z:629 (M
+).
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.15-1.80 (23H, m), 2.40-2.55 (2H, m); 2.70-2.85 (2H, m), 2.93 (3H, s); 3.11 (3H, s), 3.20-3.40 (4H, m); 4.25-4.50 (2H, m), 6.90-7.00 (1H, m); 7.15-7.50 (5H, m), 7.59 (1H, s); 7.75-7.80 (3H, m). (8) (2R, 3R)-3-[5-(3, the 4-dichlorophenyl) pentyloxy]-2-hydroxyl-3-[N-methyl-N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
With with the identical mode of embodiment 31-(8), tert-butyl ester compound (353mg) the preparation colorless oil title compound (300mg) that obtains by (7).MS (FAB+) m/Z:574 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.25-1.85 (14H, m); 2.45-2.60 (2H, m), 2.75-2.85 (2H; t, J=7.8Hz), 2.97 (3H; s), 3.07 (3H, s); 3.30-3.50 (3H, m), 4.34-4.38 (1H; m), and 4.60-4.62 (1H, m); 6.90-7.00 (1H, m), 7.20-7.35 (4H; m), and 7.35-7.60 (2H, m); 7.58 (1H, s), 7.72-7.80 (3H; m). and embodiment 41 (2R, 3R)-2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group] formamyl-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
(1) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-hydroxyl amyl group] the formamyl propionic acid tert-butyl ester
(2R with embodiment 37-(2) acquisition, 3R)-and 3-tertbutyloxycarbonyl-3-tertiary butyloxycarbonyl ylmethoxy-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid (174mg), 5-hydroxyl amylamine (45mg) and 4-Dimethylamino pyridine (54mg) be dissolved in the methylene dichloride (10ml).In the solution that forms, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (84mg), mixture was at room temperature stirred 18 hours.Use the methylene dichloride diluted reaction mixture, with 1N hydrochloric acid and saturated brine washing, use anhydrous sodium sulfate drying successively.Decompression steams solvent, resistates silica gel chromatography (with 2-3% methyl alcohol-methylene dichloride wash-out), thus obtain light yellow oily title compound (130mg).MS (FAB+) m/Z:580 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26-1.65 (12H, m), 1.44 (9H, s), 1.50 (9H; s), 2.22 (3H, s), 2.23 (3H, s); 2.52 (2H, t, J=7.6Hz), 3.26 (1H; m), 3.37 (1H, m), 3.43 (1H; m), 3.53 (1H, m), 3.62 (2H; dd, J=11.7,5.9Hz), 3.88 (1H; d, J=15.9Hz), 4.18 (1H, d; J=2.0Hz), 4.27 (1H, d, J=15.9Hz); 4.32 (1H, d, J=2.0Hz), 6.76 (1H; t, J=5.9Hz), 6.88 (1H, d; J=7.6Hz), 6.93 (1H, s) .7.03 (1H, d; J=7.6Hz). (2) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-[N-(3-chloro-4-aminomethyl phenyl)-N-(2,4-dinitrophenyl alkylsulfonyl) amino] amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, the alkylol cpd (130mg) that (1) is obtained is with N-(3-chloro-4-aminomethyl phenyl)-2, and 4-dinitrobenzene sulphonamide, triphenyl phosphine and diethyl azodiformate are handled, and obtain yellow oily title compound (80mg).MS (FAB+) m/Z:933 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.24-1.64 (12H, m), 1.42 (9H, s), 1.50 (9H; s), 2.22 (3H, s), 2.23 (3H, s); 2.37 (3H, s), 2.51 (2H, t, J=7.8Hz); 3.26 (2H, m), 3.43 (1H, m), 3.52 (1H; m), 3.75 (2H, t, J=7.1Hz); 3.88 (1H, d, J=15.6Hz), 4.17 (1H; d, J=2.0Hz), 4.25 (1H, d; J=15.6Hz), 4.32 (1H, d, J=2.0Hz); 6.73 (1H, t, J=5.9Hz), 6.87 (1H; d, J=7.8Hz), 6.92 (1H, s); 7.00 (2H, m), 7.20 (2H, m); 7.74 (1H, d, J=8.8Hz), 8.29 (1H; dd, J=8.8,2.0Hz), 8.44 (1H; d, J=2.4Hz). (3) (2R, 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, handle 2 of acquisition in (2) with mercaptoethanol acid and triethylamine, 4-dinitrophenyl sulfonyl compound (80mg), thus obtain light yellow oily title compound (29mg).MS (FAB+) m/Z:703 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26-1.73 (12H, m), 1.43 (9H, s), 1.50 (9H; s), 2.22 (3H, s), 2.23 (6H, s); 2.51 (2H, t, J=7.8Hz), 3.05 (2H, t; J=7.1Hz), 3.27 (1H, m), 3.35 (1H, m); 3.43 (1H, m), 3.51 (1H, m), 3.63 (1H; broad), 3.88 (1H, d, J=5.9Hz); 4.18 (1H, d, J=2.4Hz), 4.27 (1H; d, J=15.9Hz), 4.32 (1H, d; J=2.4Hz), 6.40 (1H, dd, J=8.3; 2.4Hz), 6.58 (1H, d, J=2.4Hz); 6.76 (1H, t, J=5.9Hz), 6.87 (1H; d, J=7.6Hz), 6.92 (1H, s); 6.96 (1H, d, J=8.3Hz), 7.02 (1H; d, J=7.6Hz). (4) (2R, 3R)-and 2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group] formamyl]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
In the mode identical, by diester compound (29mg) preparation light yellow oily title compound (18mg) that obtains in (3) with embodiment 26.MS (FAB+) m/Z:591 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.26-1.69 (12H, m), 2.20 (6H; s), 2.34 (3H, s); 2.47 (2H, m), 3.04-3.49 (6H; m), and 4.25-4.54 (4H, m); 5.49 (3H, broad), 6.86-7.49 (7H; m). embodiment 42 (2R, 3R)-2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
(1) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-hydroxyl amyl group]-the N-methylamino formyl radical propionic acid tert-butyl ester
Handle in the mode identical, just adopt (5-hydroxyl amyl group) methylamine (47mg) of reference example 15 to replace 5-hydroxyl amylamine, thereby obtain title compound (110mg) with embodiment 41-(1).MS (FAB+) m/Z:594 (M+H)
+.
1H-NMR (CDCl
3, rotation and structure body mixture) and δ: 1.25-1.72 (12H, m), 1.45 (9H; s), 1.47 (9H, s), 2.22 (3H; s), 2.23 (3H, s); 2.51 (2H, t, J=7.8Hz); 2.91,3.20 (total 3H, s each); 3.35-3.65 (6H, m), 3.94-4.52 (4H; m), 6.88 (1H, d; J=7.3Hz), 6.93 (1H, s); 7.02 (1H, d, J=7.3Hz). (2) (2R; 3R)-and 2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-[N-(3-chloro-4-aminomethyl phenyl)-N-(2,4-dinitrophenyl alkylsulfonyl) amino] amyl group-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, the alkylol cpd (100mg) that (1) is obtained is with N-(3-chloro-4-aminomethyl phenyl)-2, and 4-dinitrobenzene sulphonamide, triphenyl phosphine and diethyl azodiformate are handled, and obtain yellow oily title compound (101mg).MS (FAB+) m/Z:947 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.26-1.61 (12H, m), 1.43 (9H; s), 1.47 (9H, s), 2.22 (3H; s), 2.23 (3H, s), 2.37 (3H; s), 2.51 (2H, t, J=7.6Hz); 2.91,3.18 (total 3H, s each), 3.20-3.77 (6H; m), and 3.93-4.49 (4H, m), 6.87 (1H; d, J=7.3Hz), 6.92 (1H, s); 6.98-7.03 (2H, m), 7.20 (2H, d; J=7.8Hz), 7.74 (1H, d, J=8.6Hz); 8.30 (1H, dd, J=8.6; 2.1Hz), 8.44 (1H, d; J=2.1Hz). (3) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, handle 2 of acquisition in (2) with mercaptoethanol acid and triethylamine, 4-dinitrophenyl sulfonyl compound (101mg), thus obtain light yellow oily title compound (35mg).MS (FAB+) m/Z:717 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.29-1.62 (12H, m), 1.44 (9H; s), 1.47 (9H, s), 2.22 (3H; s), 2.23 (6H, s), 2.50 (2H; t, J=7.8Hz), 2.91,3.19 (total 3H; s each), and 3.02-3.61 (6H, m), 3.66 (1H; broad), and 3.92-4.49 (4H, m), 6.40 (1H; dd, J=8.3,2.0Hz), 6.59 (1H; t, J=2.7Hz), 6.87 (1H; d, J=7.8Hz), 6.92 (1H; s), 6.96 (1H, d; J=8.3Hz), 7.02 (1H, d; J=7.8Hz). (4) (2R, 3R)-2-carboxyl methoxyl group-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
In the mode identical, by diester compound (35mg) preparation light yellow oily title compound (25mg) that obtains in (3) with embodiment 26.MS (FAB+) m/Z:605 (M+H)
+.
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 1.24-1.70 (12H, m), 2.19 (3H, s), 2.21 (3H, s), 2.35 (3H, s), 2.49 (2H, m), 2.93,3.17 (total 3H, s each), 3.17-3.67 (6H, m), 4.11-4.30 (4H, m), 4.44 (1H, broad), 4.50 (1H, broad), 4.64 (1H, broad), 6.83-7.35 (6H, m). to C
32H
45ClNa
2O
7CF
3CO
2The ultimate analysis of H: calculated value: C, 56.78; H, 6.45; N, 3.90 measured values: C, 56.48; H, 6.78; N, 3.93 embodiment 43 (2R, 3R)-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-hydroxyl-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
(1) (2R, 3R)-3-[4-(tert-butyl diphenyl siloxy-) butoxy]-2-hydroxyl-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With embodiment 18-(3) obtain (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-3-hydroxy-propionic acid benzyl ester (1.0g) is dissolved in the ethanol (50ml).In the solution that forms, add 10% palladium-charcoal (0.1g), under nitrogen atmosphere, mixture was at room temperature stirred 10 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain colorless oil (2R, 3R)-3-tertbutyloxycarbonyl-2-[4-(tert-butyl diphenyl siloxy-) butoxy]-3-hydroxy-propionic acid (0.994g).
MS(FAB+)m/Z：539(M+Na)
+，517(M+H)
+.
The propionic acid (0.994g) that forms is dissolved in the methylene dichloride (30ml), under the frozen water cooling, [5-(2-naphthyl) amylamine hydrochloride (761mg) (reference example 14), triethylamine (0.4ml), I-hydroxybenzotriazole (260mg) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (553mg) at room temperature stirred mixture 14 hours to add methyl in the solution that forms.Reaction mixture washes with water, uses anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates silica gel chromatography (with 33% ethyl acetate-hexane wash-out), thus oily title compound (890mg) obtained.MS (FAB+) m/Z:726 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.03 (9H, s); 1.30-1.79 (19H, m), 2.77 (2H; t, J=7.6Hz), 2.93; 3.12 (total 3H, seach), 3.24-3.67 (6H; m), and 4.25-4.44 (2H, m); 7.27-7.82 (17H, m). (2) (2R, 3R)-and 2-hydroxyl-3-(4-hydroxyl butoxy)-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With with the identical mode of embodiment 18-(5), 4-(tert-butyl diphenyl siloxy-) butoxy compound that is obtained by (1) prepares colorless oil title compound (494mg).MS (FAB+) m/Z:510 (M+Na)
+, 488 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.94 (1H, t, J=7.3Hz); 1.28-1.82 (19H, m), 2.67-2.85 (3H; m), 2.94,3.11 (total 3H; s each), and 3.26-3.68 (6H, m); 4.25-4.47 (2H, m), 7.26-7.84 (7H; m). (3) (2R, 3R)-3-[4-[N-(3-chloro-4-aminomethyl phenyl)-N-(2,4-dinitrophenyl alkylsulfonyl) amino] butoxy]-2-hydroxyl-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, with N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, triphenyl phosphine and azodicarbonic acid diethyl ester are handled the alkylol cpd (398mg) that (2) obtain, thereby obtain light yellow oily title compound (482mg).MS (FAB+) m/Z:841 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.29-1.80 (19H, m); 2.72-2.83 (2H, m), 2.94; (3.09 total 3H, s each), 3.22-3.58 (4H; m), and 3.68-3.83 (2H, m); 4.25-4.44 (2H, m), 6.97 (1H; d; J=8.3Hz), and 7.15-7.82 (10H, m); 8.27 (1H; d, J=8.8Hz), 8.41 (1H; s). (4) (2R, 3R)-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-hydroxyl-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, handle 2 of (3) acquisition with mercaptoethanol acid and triethylamine, 4-dinitrophenyl sulfonyl compound (582mg), thus obtain light yellow oily title compound (348mg).MS (FAB+) m/Z:633 (M+Na)
+, 611 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.31-1.81 (19H, m), 2.23 (3H; s), 2.77 (2H, t, J=6.8Hz); 2.94,3.11 (total 3H, s each), 2.98-3.08 (2H; m), and 3.24-3.71 (5H, m), 4.25-4.44 (2H; m), and 6.34-6.43 (1H, m), 6.58 (1H; s), 6.96 (1H, d; J=8,3Hz), 7.31 (1H; d, J=8.3Hz), 7.35-7.51 (2H; m), 7.58 (1H, s); 7.71-7.80 (3H, m). (5) (2R, 3R)-3-[4-(3-chloro-4-aminomethyl phenyl amino) butoxy]-2-hydroxyl-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] propionic acid
The ester cpds (91mg) that (4) are obtained is dissolved in the methylene dichloride (5ml).In the solution that forms, add trifluoroacetic acid (1ml), mixture was at room temperature stirred 7 hours.Under reduced pressure be concentrated into reaction mixture dried.Resistates carries out purifying (with the aqueous solution wash-out of 80% acetonitrile) with " DIAION HP20 " column chromatography, thereby obtains colourless thickness oily title compound (85mg).MS (FAB+) m/Z:555 (M+H)
+.
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 1.07 (1H, t, J=6.8Hz), 1.42-1.98 (10H, m), 2.35 (3H, s), 2.95 (2H, t, J=7.6Hz), 3.07, (3.30 total 3H, s each), and 3.12-3.20 (2H, m), 3.45-3.75 (4H, m), and 4.50-4.55 (1H, m), 4.64,4.71 (total 1H, deach, J=3.4Hz), 6.63-6.70 (1H, m), 6.81 (1H, s), and 7.10-7.15 (1H, m), 7.45-7.95 (7H, m). to C
31H
39ClNa
2O
50.5H
2The ultimate analysis of O: calculated value: C, 66.00; H, 7.13; N, 4.97 measured values: C, 66.09; H, 7.21; N, 5.08 embodiment 44 (2R, 3R)-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2 hydroxy propanoic acid
(1) (2R, 3R)-2-t-butyldimethylsilyloxy base-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-(5-hydroxyl amyl group)-N-methylamino formyl radical] the propionic acid tert-butyl ester
Handle in the mode identical, just adopt (5-hydroxyl amyl group) methylamine (117mg) of reference example 15 to replace methyl [5-(2-naphthyl) amyl group] amine, thereby obtain light yellow oily title compound (440mg) with embodiment 31-(6).MS (FAB+) m/Z:616 (M+Na)
+, 594 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.04 (3H, s), 0.11 (3H; s), 0.90 (9H, s), 1.26-1.64 (12H; m), 1.46 (9H, s), 2.23 (3H; s), 2.24 (3H, s); 2.52 (2H, m), 3.06-3.52 (4H; m), 2.90,3.19 (taotal3H; s each), and 3.58-3.65 (2H, m); 4.39 (1H, m), 4.46-4.50 (1H; m), 6.89 (1H, d; J=7.8Hz), 6.94 (1H, s); 7.04 (1H, d, J=7.8Hz). (2) (2R; 3R)-and 2-t-butyldimethylsilyloxy base-3-[N-[5-[N-(3-chloro-4-aminomethyl phenyl)-N-(2,4-dinitrophenyl alkylsulfonyl) amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, with N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, triphenyl phosphine and azodicarbonic acid diethyl ester are handled the alkylol cpd that is obtained by (1), obtain yellow oily title compound (167mg).MS (FAB+) m/Z:969 (M+Na)
+, 947 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.03 (3H, s), 0.10 (3H; s), 0.89 (9H, s), 1.24-1.62 (12H; m), 1.45 (9H, s), 2.22 (3H; s), 2.23 (3H, s), 2.37 (3H; s), and 2.47-2.53 (2H, m), 3.03-3.54 (4H; m), 2.87,3.17 (total 3H, s each); 3.76 (2H, t, J=7.1Hz), 4.36 (1H; d, J=4.9Hz), 4.47 (1H, d; J=4.9Hz), and 6.87-6.89 (1H, m), 6.92 (1H; s), and 6.99-7.03 (2H, m), 7.20 (2H; d, J=2.0Hz), 7.73 (1H, d; J=8.8Hz), 8.29 (1H, dd, J=8.8; 2.4Hz), 8.44 (1H, d; J=2.4Hz). (3) (2R, 3R)-2-t-butyldimethylsilyloxy base-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino)-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, handle 2 of (2) acquisition with mercaptoethanol acid and triethylamine, 4-dinitrophenyl sulfonyl compound (167mg), thus obtain light yellow oily title compound (110mg).MS (FAB+) m/Z:739 (M+Na)
+, 717 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.04 (3H, s), 0.11 (3H, s); 0.90 (9H, s), 1.29-1.64 (12H, m); 1.45 (9H, s), 2.22 (3H, s); 2.23 (3H, s), 2.24 (3H, s); 2.50 (2H, t, J=7.6Hz), 3.02-3.64 (6H; m), 2.89,3.17 (total 3H, s each); 4.32-4.39 (1H, m), 4.45 (4.50 (1H, m); 6.40 (1H, d, J=8.1,2.4Hz); 6.59 (1H, t, J=2.4Hz), 6.88 (1H; d, J=7.3Hz), 6.92 (1H, s); 6.97 (1H, d, J=8.1Hz), 7.02 (1H; d, J=7.3Hz). (4) (2R, 3R)-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3,4-dimethylbenzene phenyl) pentyloxy]-the 2 hydroxy propanoic acid tert-butyl ester
The 2-t-butyldimethylsilyloxy based compound (110mg) that (3) are obtained is dissolved in the tetrahydrofuran (THF) (5ml).Under the frozen water cooling, (the 1M tetrahydrofuran solution 1.53ml), at room temperature stirred mixture 3 hours to add tetrabutyl ammonium fluoride in the solution that forms.Reaction mixture is separated into methylene dichloride-moisture saturated ammonium chloride.The water layer dichloromethane extraction.Merge organic layer, with 1N hydrochloric acid and saturated brine washing, then, use anhydrous sodium sulfate drying successively.Resistates silica gel chromatography (with 66% ethyl acetate-hexane wash-out), thus light yellow oily title compound (73mg) obtained.MS (FAB+) m/Z:625 (M+Na)
+, 603 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.34-1.41 (3H, m), 1.50 (9H; s), and 1.54-1.65 (9H, m), 2.22 (3H; s), 2.23 (3H, s), 2.51 (2H; t, J=7.8Hz), 3.05 (2H, t; J=6.6Hz), 2.94,3.15 (total3H, s each); 3.30-3.36 (2H, m), 3.47-3.58 (2H, m); 4.37 (1H, m), 4.42 (1H, m); 6.40 (1H, dd, J=8.1,2.4Hz); 6.58 (1H, d, J=2.4Hz), 6.88 (1H; d, J=7.8Hz), 6.92 (1H, s); 6.96 (1H, d, J=8.1Hz), 7.02 (1H; d, J=7.8Hz). (5) (2R, 3R)-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2 hydroxy propanoic acid
In the mode identical with embodiment 26, the title compound (61mg) of ester cpds (73mg) the preparation yellow amorphous substance that obtains by (4).MS (FAB+) m/Z:569 (M+Na)
+, 547 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) δ: 0.92-1.73 (12H, m), 2.21 (3H, s), 2.22 (3H, s), 2.32 (3H, s), 2.36 (2H, t, J=7.6Hz), 2.93, (3.08 total 3H, s each), and 2.82-3.40 (5H, m), 4.05-4.11 (1H, m), 4.54 (1H, m), 4.60 (1H, broad), 6.82 (1H, d, J=7.8Hz), 6.88 (1H, s), 7.00 (1H, d, J=7.8Hz), 7.22 (1H, d, J=7.8Hz), 7.37 (1H, d, J=7.8Hz), 7.56 (1H, s), 8.37 (2H, broad). to C
30H
43ClN
2O
5.CF
3CO
2H0.5H
2The ultimate analysis of O: calculated value: C, 57.35; H, 6.77; N, 4.18 measured values: C, 57.15; H, 6.72; N, 3.99 embodiment 45 (2R, 3R)-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2 hydroxy propanoic acid
Handle in the mode identical with embodiment 44, just adopt N-(3, the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, thus obtain light yellow amorphous title compound.MS (FAB+) m/Z:527 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.87-1.63 (12H, m), 2.21 (6H; s), 2.22 (3H, s), 2.24 (3H; s), 2.34 (2H, t, J=7.8Hz); 2.92,3.08 (total 3H, s each), 2.80-3.30 (5H; m), 4.12 (1H, m), 4.56 (1H; broad), 4.59 (1H, broad); 6.81 (1H, d, J=7.8Hz); 6.87 (1H, s), 7.00 (1H; d, J=7.8Hz), 7.14 (1H; d, J=7.8Hz), 7.31 (1H; d, J=7.8Hz), 7.34 (1H; s). embodiment 46 (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-hydroxyl-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
Handle in the mode identical with embodiment 44, just adopt N-(5-indanyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, thus obtain light yellow amorphous title compound.MS (FAB+) m/Z:539 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.87-1.63 (12H, m), 2.05 (2H; dt, J=14.7,7.3Hz), 2.21 (3H; s), 2.22 (3H, s), 2.35 (2H; t, J=7.6Hz), 3.08 (3H, s); 2.79-3.31 (9H, m), 4.15 (1H, m); 4.57-4.60 (2H, m), 6.81 (1H, d; J=7.3Hz), 6.87 (1H, s), 7.00 (1H; d, J=7.3Hz), 7.22 (1H, d; J=7.8Hz), 7.34 (1H, d, J=7.8Hz); 7.42 (1H, s). embodiment 47 (2R, 3R)-2-carboxyl methoxyl group-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] propyl group
(1) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-(t-butyldimethylsilyloxy base) butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With with the identical mode of embodiment 37-(1); (2R with bromo-acetic acid tert-butyl Processing Example 43-(1) acquisition; 3R)-3-[4-(tert-butyl diphenyl siloxy-) butoxy]-2-hydroxyl-3-[N-methyl-[N-[5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester (1.2g), thus obtain colorless oil title compound (1.5g).MS (FAB+) m/Z:840 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.02 (9H, s); 1.27-1.75 (28H, m), 2.76 (2H; t, J=7.8Hz), 2.89; 3.17 (total 3H, seach), 3.29-3.66 (6H; m), 3.92,4.03 (total 1H; deach, J=16.1/16.6Hz), 4.20-4.33 (2H; m); 4.48,4.50 (total 1H, deach; J=4.4/5.8Hz); 7.27-7.80 (17H, m). (2) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-hydroxyl butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
With with the identical method of embodiment 18-(5), 4-(tert-butyl diphenyl siloxy-) butoxy compound (1.5g) the preparation colorless oil title compound (0.96g) that obtains by (1).MS (FAB+) m/Z:602 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.31-1.80 (28H, m); 2.74-2.83 (2H, m), 2.91; (3.16 total 3H, s each), 3.30-3.68 (6H; m), 3.95,4.04 (total 1H; d each, J=16.1/16.1Hz), 4.22; 4.25 (total1H, d each, J=16.1; 16.1Hz), 4.29-4.35 (1H, m); 4.47-4.53 (1H, m), 7.31 (1H; d, J=8.3Hz), 7.35-7.50 (2H; m), 7.60 (1H, s); 7.72-7.88 (3H, m). (3) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-[N-(3; the 4-3,5-dimethylphenyl)-and N-(2,4-dinitrophenyl alkylsulfonyl) amino] butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, handle the alkylol cpd (0.20g) that obtains by (2) with triphenyl phosphine and azodicarbonic acid diethyl ester, just with N-(3, the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, thus light yellow oily title compound (0.24g) obtained.MS (FAB+) m/Z:957 (M+Na)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.30-1.87 (28H, m), 2.19 (3H; s), 2.22 (3H, s), 2.72-2.91 (2H; m), 2.89,3.13 (total 3H, s each); 3.24-3.60 (4H, m), 3.73 (2H, t; J=6.8Hz), 3.92,4.01 (total 1H; J=16.1/16.1Hz), and 4.16-4.31 (2H, m); 4.45,4.48 (total 1H, d each; J=4.9/5.9Hz), 6.80 (1H, d; J=7.8Hz), 6.94 (1H, s); 7.01-7.06 (1H, m), 7.27-7.33 (1H; m), and 7.36-7.46 (2H, m); 7.56-7.80 (5H, m), 8.17; 8.23 (1H, m), 8.35-8.40 (1H; m). (4) (2R, 3R)-2-tertiary butyloxycarbonyl ylmethoxy-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] the propionic acid tert-butyl ester
In the mode identical with embodiment 25, handle 2 of acquisition in (3) with Thiovanic acid acid and triethylamine, 4-dinitrophenyl sulfonyl compound (0.24g), thus obtain light yellow oily title compound (0.19g).MS (FAB+) m/Z:705 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.30-1.78 (28H, m), 2.13 (3H; s), 2.17 (3H, s), 2.72-2.80 (2H; m), 2.90,3.16 (total3H, s each); 3.02-3.08 (2H, m), 3.28-3.67 (4H, m); 3.94,4.03 (total 1H, d each, J=16.1/16.6Hz); 4.20-4.32 (2H, m), 4.49,4.51 (total 1H; d each, J=4.9/5.9Hz), 6.32-6.38 (1H, m); 6.41 (1H, s), 6.90 (1H, d; J=8.3Hz), 7.31 (1H, dd, J=8.8; 1.5Hz), 7.36-7.47 (2H, m); 7.58 (1H, s), 7.72-7.81 (3H; m). (5) (2R, 3R)-2-carboxyl methoxyl group-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] propionic acid
With with the identical mode of embodiment 43-(5), diester compound (0.19g) the preparation colourless thickness buttery title compound (0.15g) that obtains by (4).
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 1.40-1.60 (4H, m), 1.77-2.08 (6H, m), 2.37,2.40,2.43,2.60 (total 6H, s each), 2.92,3.00 (total 2H, t each, J=7.3/7.3Hz), 3.12, (3.30 total3H, s each), and 3.50-3.80 (4H, m), 4.00-4.08 (4H, m), 4.39,4.47 (total 1H, broad s each), 4.91, (4.94 total 1H, broads each), and 7.29-2.98 (10H, m). to C
34H
44N
2O
71/3H
2The ultimate analysis of O: calculated value: C, 68.21; H, 7.53; N, 4.68 measured values: C, 68.04; H, 7.60; N, 4.74 embodiment 48 (2R, 3R)-2-carboxyl methoxyl group-3-[4-(5-indanyl amino) butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] propionic acid
React in the mode identical with embodiment 47, just adopt N-(5-indanyl)-2,4-dinitrobenzene sulphonamide replaces N-(3, the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide, thus obtain colourless thickness oily title compound.MS (FAB+) m/Z:605 (M+H)
+.
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 1.42-2.32 (12H, m), 2.88-3.24 (6H, m), 3.12, (3.30 total 3H, s each), and 3.42-3.80 (4H, m), 3.98-4.10 (4H, m), 4.36-4.50 (1H, m), 4.85-4.98 (1H, m), 7.32-7.98 (10H, m). to C
35H
44N
2O
71/2H
2The ultimate analysis of O: calculated value: C, 68.50; H, 7.39; N, 4.56 measured values: C, 68.56; H, 7.35; N, 4.62 embodiment 49 (2R, 3R)-3-[4-(3,4-3,5-dimethylphenyl amino) butoxy]-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] propionic acid
React in the mode identical with embodiment 32, just adopt N-(3, the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, thus obtain colourless thickness oily title compound.MS (FAB+) m/Z:621 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.15-1.22 (3H, m); 1.24-2.00 (10H, m), 2.21; 2.23,2.26,2.27 (total 6H; s each), and 2.73-2.82 (2H, m); 3.01,3.12 (total 3H, s each); 3.15-3.78 (6H, m), 3.88 (1H; d, J=16.6Hz), 3.96 (1H; d, J=16.6Hz), 4.07 (2H; q, J=7.0Hz), 4.39; (4.49 total 1H, broad each), 4.72; (4.72 total 1H, broad each), 7.10-7.83 (10H; m). embodiment 50 (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl]-3-[4-(3-aminomethyl phenyl amino) butoxy] propionic acid
React in the mode identical with embodiment 32, just adopt N-(3-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, thus obtain colourless thickness oily title compound.MS (FAB+) m/Z:607 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.05-2.00 (13H, m), 2.34; 2.38 (total 3H, seach), 2.72-2.84 (2H; m), 3.01,3.12 (total 3H; s each), and 3.18-3.80 (6H, m); 3.85 (1H, d, J=16.1Hz); 3.93 (1H, d, J=16.1Hz); 4.06 (2H, q, J=6.8Hz); 4.39,4.49 (total 1H, broad each); 4.70-4.76 (1H, m), 7.15-7.82 (11H; m). embodiment 51 (2R, 3R)-2-ethoxycarbonyl methoxyl group-3-[4-(5-indanyl amino) butoxy]-3-[N-methyl-N-(5-(2-naphthyl) amyl group] formamyl] propionic acid
React in the mode identical with embodiment 32, just adopt N-(5-indanyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2,4-dinitrobenzene sulphonamide, thus obtain light yellow thickness oily title compound.MS (FAB+) m/Z:633 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.16-1.82 (13H, m), 1.98-2.08 (2H; m), and 2.72-2.88 (6H, m); 2.96,3.12 (total 3H, s each); 3.03-3.15 (2H, m), 3.30-3.63 (4H; m), and 4.02-4.40 (5H, m); 4.68-4.73 (1H, m), 6.76 (1H; d, J=7.3Hz), 6.85 (1H; s), 7.07 (1H, d; J=7.3Hz), 7.30 (1H, d; J=8.3Hz), and 7.37-7.48 (2H, m); 7.59 (1H, s), 7.72-7.83 (3H; m). embodiment 52 (2R, 3R)-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxypropionic acid
(1) (2R, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-ethoxycarbonyl methoxy propyl acid benzyl ester
With the 2-oxy-compound (1.07g) of mode Processing Example 31-(3) acquisition identical, thereby obtain colorless oil title compound (0.82g) with embodiment 38-(1).MS (FAB+) m/Z:579 (M+Na)
+.
1H-NMR (CDCl
3) δ: 1.24 (3H, t, J=7.1Hz), 1.31-1.38 (2H, m), 1.47 (9H, s), 1.53-1.65 (4H, m), 2.21 (3H, s), 2.22 (3H, s), 2.49 (2H, t, J=7.8Hz), 3.28-3.34 (1H, m), 3.70 (1H, dt, J=8.8,6.8Hz), 4.11-4.19 (1H, m), 4.37 (1H, d, J=2.9Hz), 4.48 (1H, d, J=2.9Hz), 5.24 (1H, d, J=12.2Hz), 5.27 (1H, d, J=12.2Hz), 6.87 (1H, d, J=7.8Hz), 6.92 (1H, s), 7.01 (1H, d, J=7.8Hz), 7.31-7.36 (3H, m), 7.40-7.51 (2H, m). (2) (2R, 3R)-3-tertbutyloxycarbonyl-2-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-ethoxycarbonyl methoxypropionic acid
With with the identical mode of embodiment 31-(5), by three ester cpds (0.80g) preparation colorless oil title compound (0.68g) that obtains in (1).MS (FAB+) m/Z:489 (M+Na)
+.
1H-NMR (CDCl
3) δ: 1.26 (3H, t, J=7.1Hz), 1.32-1.39 (2H, m); 1.50 (9H, s), 1.54-1.65 (4H, m); 2.21 (3H, s), 2.23 (3H, s); 2.51 (2H, t, J=7.6Hz), 3.44 (1H; dt, J=8.8,6.8Hz), 3.66 (1H; dt, J=8.8,6.8Hz), 4.15 (1H; d, J=16.6Hz), 4.19 (2H, q; J=6.8Hz), 4.37 (1H, d, J=2.9Hz); 4.40 (1H, d, J=2.9Hz), 4.41 (1H; d, J=16.6Hz), 6.87 (1H, d; J=7.8Hz), 6.92 (1H, s), 7.02 (1H; d, J=7.8Hz). (3) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-(5-hydroxyl amyl group)-N-methylamino formyl radical] the propionic acid tert-butyl ester
With with the identical mode of embodiment 41-(1), just (the 5-hydroxyl amyl group) methylamine (0.37g) with reference example 15 replaces 5-hydroxyl amylamine, carboxylic acid cpd (1.05g) the preparation title compound (1.19g) that is obtained by (2).MS (FAB+) m/Z:566 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.26 (3H, t, J=7.1Hz); 1.33-1.63 (12H, m), 1.47 (9H, s); 2.22 (3H, s), 2.23 (3H, s); 2.51 (2H, t, J=7.8Hz), 2.91; (3.19 total 3H, s each), 3.33-3.48 (3H; m), and 3.53-3.62 (3H, m); 4.07-4.53 (6H, m), 6.88 (1H; d, J=7.3Hz), 6.93 (1H; s), 7.02 (1H, d; J=7.3Hz). (4) (2R, 3R)-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxy propyl tert-butyl acrylate
In the mode identical, by alkylol cpd (0.23g) preparation light yellow oily title compound (0.11g) that obtains in (3) with embodiment 25.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.23-1.67 (15H, m), 1.47 (9H; s), 2.21 (3H, s), 2.22 (3H; s), 2.23 (3H, s), 2.51 (2H; t, J=7.8Hz), 2.91,3.19 (total 3H; s each), and 3.02-3.08 (2H, m), 3.31-3.64 (4H; m), 3.64 (1H, broad), 4.06-4.53 (6H; m), 6.40 (1H, dd, J=8.3; 2.4Hz), 6.58 (1H, d, J=2.4Hz); 6.87 (1H, d, J=7.3Hz), 6.92 (1H; s), 6.96 (1H, d; J=8.3Hz), 7.02 (1H, d; J=7.3Hz). (5) (2R, 3R)-3-[N-[5-(3-chloro-4-aminomethyl phenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxypropionic acid
In the mode identical, by diester compound (60mg) preparation light yellow thickness oily title compound (41mg) that obtains in (4) with embodiment 26.MS (FAB+) m/Z:633 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 1.21-1.72 (15H, m), 2.22 (3H; s), 2.23 (3H, s), 2.33 (3H; s), 2.49 (2H, t, J=7.6Hz); 2.95,3.13 (total 3H, s each), 3.08-3.75 (6H; m), and 4.18-4.64 (6H, m); 6.88 (1H, d, J=7.5Hz); 6.93 (1H, s), 7.02 (1H; d, J=7.5Hz), 7.12-7.31 (3H; m), 8.18 (2H, broad). embodiment 53 (2R; 3R)-2-carboxyl methoxyl group-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid
(1) (2R, 3R)-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxypropionic acid
In the mode identical with embodiment 52, just with N-(3, the 4-3,5-dimethylphenyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-aminomethyl phenyl)-2, and 4-dinitrobenzene sulphonamide obtains colourless thickness oily title compound.MS (FAB+) m/Z:613 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.87-1.55 (10H, m), 1.26 (3H, t; J=7.1Hz), 1.72 (2H, broad), 2.21 (3H; s), 2.23 (6H, s), 2.24 (3H; s), 2.49 (2H, t, J=7.6Hz); 3.04 (1H, broad), 2.92,3.11 (total 3H; s each), 3.26 (2H, broad), 3.47 (2H; broad), 3.76 (1H, broad), 4.18-4.36 (2H; m), 4.20 (2H, q, J=7.1Hz); 4.41 (1H, d, J=6.4Hz), 4.60 (1H; d, J=6.4Hz), 6.87 (1H, d; J=7.3Hz), 6.92 (1H, s), 7.02 (1H; d, J=7.8Hz), 7.13 (1H, d; J=7.8Hz), and 7.18-7.23 (2H, m), 10.07 (2H; broad). (2) (2R, 3R)-2-carboxyl methoxyl group-3-[N-[5-(3,4-3,5-dimethylphenyl amino) amyl group]-N-methylamino formyl radical]-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy] propionic acid is dissolved in the ethyl ester compound (95mg) that obtains in (1) in the tetrahydrofuran (THF) (2ml).In the solution that forms, add 1N sodium hydroxide (0.46ml), mixture was at room temperature stirred 1 hour.In reaction mixture, add 1N hydrochloric acid (0.55ml), reaction mixture is under reduced pressure concentrated.Resistates carries out purifying (using the acetonitrile wash-out) with " DIAION HP20 " column chromatography, thereby obtains light yellow oily title compound (34mg).MS (FAB+) m/Z:585 (M+H)
+.
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 0.88-1.67 (12H, m), 2.18 (3H; s), 2.19 (3H, s), 2.20 (3H; s), 2.22 (3H, s), 2.47 (2H; t, J=7.6Hz), 2.91,3.15 (total 3H; s each), and 3.17-3.61 (6H, m), 4.17 (2H; s), 4.30,4.34 (total 1H, deach; J=4.9/4.9Hz), 4.60 (1H, d, J=4.9Hz); 6.78-7.09 (2H, m), 6.83 (1H; d, J=7.8Hz), 6.89 (1H; s), 6.96 (1H, d; J=7.8Hz), 7.07 (1H, d; J=7.8Hz). embodiment 54 (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
(1) (2R, 3R)-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-2-ethoxycarbonyl methoxyl group-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
React in the mode identical with embodiment 52, just with N-(5-indanyl)-2,4-dinitrobenzene sulphonamide replaces N-(3-chloro-4-methyl)-2,4-dinitrobenzene sulphonamide, thus obtain colourless thickness oily title compound.MS (FAB+) m/Z:625 (M+H)
+.
1H-NMR (CDCl
3, the rotational isomer mixture) and δ: 0.86-1.56 (10H, m), 1.26 (3H, t; J=7.0Hz), 1.73 (2H, broad s), 2.08 (2H; t, J=7.3Hz), 2.21 (3H, s); 2.23 (3H, s), 2.48 (2H, t; J=7.6Hz), and 2.86-2.92 (4H, m), 3.05 (1H; m), 2.92,3.12 (total 3H, s each); (3.27 2H, broad s), 3.48 (2H, broad s); 3.77 (1H, m), 4.19 (2H, q; J=7.0Hz), and 4.24-4.36 (2H, m), 4.41 (1H; broad), 4.60 (1H, d, J=5.4Hz); 6.87 (1H, d, J=7.3Hz), 6.92 (1H; s), 7.01 (1H, d, J=7.3Hz); 7.22 (2H, m), 7.32 (1H, s); 9.02 (2H, broad). (2) (2R, 3R)-2-carboxyl methoxyl group-3-[5-(3, the 4-3,5-dimethylphenyl) pentyloxy]-3-[N-[5-(5-indanyl amino) amyl group]-N-methylamino formyl radical] propionic acid
With with the identical mode of embodiment 53-(2), by the title compound of the light yellow oily of ethyl ester compound that obtains in (1).MS (FAB+) m/Z:597 (M+H)
+.
1H-NMR (CD
3OD, the rotational isomer mixture) δ: 0.88-1.68 (12H, m), 2.04 (2H, t, J=7.1Hz), 2.19 (3H, s), 2.20 (3H, s), 2.47 (2H, t, J=7.3Hz), and 2.81-2.85 (4H, m), 2.92,3.15 (total 3H, seach), 3.26-3.60 (6H, m), 4.16 (2H, s), 4.31 (1H, broad), 4.62 (1H, broad), 6.82-6.84 (2H, m), 6.89 (1H, s), 6.96 (1H, d, J=6.8Hz), 7.06 (1H, d, J=7.8Hz), 7.13 (1H, d, J=6.8Hz). reference example 1L-tartrate tertiary butyl benzyl ester
L-tartrate (5.0g) is suspended in the methylene dichloride (50ml), under the frozen water cooling, is added dropwise to the O-tertiary butyl-N, N '-di-isopropyl isourea (10.0g) subsequently.After at room temperature stirring 16 hours, filtering insoluble solid from filtrate, decompression steams solvent.Resistates is dissolved in the dimethyl formamide (100ml).In the solution that forms, add triethylamine (8.3ml), and then be added dropwise to bromotoluene (5.9ml).After at room temperature stirring 3 hours, reaction mixture is poured in the frozen water, used ethyl acetate extraction again.The extraction liquid anhydrous sodium sulfate drying.Decompression steams solvent then.Resistates carries out crystallization with a spot of ethyl acetate and hexane again, thereby obtains colourless crystallization shape title compound (1.56g) with silica gel chromatography (20% ethyl acetate-hexane wash-out).Fusing point: 72-74 ℃ [α]
D 25+ 14.3 ° (c=1.00, acetone)
1H-NMR (CDCl
3) δ: 1.50 (9H, s), 3.07 (1H, d, J=7.8Hz), 3.19 (1H, d, J=6.3Hz), 4.44 (1H, dd, J=6.3,2.0Hz), 4.54 (1H, dd, J=7.8,2.0Hz), 5.28 (1H, d, J=12.2Hz), 5.29 (1H, d, J=12.2Hz), 7.34-7.38 (5H, m). to C
15H
20O
6Ultimate analysis: calculated value: C, 60.80; H, 6.80 measured values: C, 60.95; H, 6.71 reference examples, 2 synthetic tartrate Ethylbenzyl ester (1) L ethyl tartrate sodium
Under frozen water cooling, in the ethanolic soln (100ml) of-(+)-diethyl tartrate (25g), add 2N aqueous sodium hydroxide solution (47.5ml), with mixture stirring 2 hours.By filtering the crystallization that collecting precipitation goes out, thereby obtain colourless crystallization shape title compound (15.0g).Fusing point: 201-203 ℃
1H-NMR (CD
3OD) δ: 1.25-1.30 (3H, m), 3.30 (2H, broad s), 3.33 (1H, d, J=6.8Hz), 4.15-4.30 (2H, m), 4.52 (1H, d, J=6.8Hz). (2) L-tartrate Ethylbenzyl ester
L-ethyl tartrate sodium (8.15g) is dissolved in N, in the dinethylformamide (30ml), under the frozen water cooling, in the solution that forms, adds triethylamine (7.7ml) and bromotoluene (6.6ml).The mixture overnight that forms is stirred.With ether (500ml) diluted reaction mixture, anhydrous sodium sulfate drying is used in water and saturated brine washing successively.Decompression steams solvent, resistates silica gel chromatography (50% ethyl acetate-hexane wash-out), thus obtain colorless oil title compound (6.68g).
1H-NMR (CDCl
3) δ: 1.31 (3H, t, J=7.3Hz), 3.17 (2H, m), 4.30 (2H, q, J=7.3Hz), 4.55-4.60 (2H, m), 5.27 (1H, d, J=12.2Hz), 5.31 (1H, d, J=12.2Hz), 7.33-7.39 (5H, m). reference example 35-(2-naphthyl)-pentenyl alcohol
(60% oily dispersion liquid 2.0g) is suspended in the tetrahydrofuran (THF) (50ml), is added dropwise to tetrahydrofuran (THF) (50ml) solution of diethyl phosphoryl ethyl acetate (11.4g) again with sodium hydride.After gas stopped to volatilize 30 minutes, be added dropwise to tetrahydrofuran (THF) (50ml) solution of 3-(2-naphthyl) propionic aldehyde (8.95g).After at room temperature stirring 30 minutes, with the reaction mixture concentrating under reduced pressure.Add entry in concentrated solution, the mixture of formation extracts with ethyl acetate.Extraction liquid washs with saturated brine, uses anhydrous sodium sulfate drying.Decompression steams solvent, thereby obtains oily 5-(2-naphthyl)-pentenyl alcohol (14g).
1H-NMR(CDCl
3)δ：1.27(3H，t，J＝7.3Hz)，2.58-2.64(2H，m)，2.93(2H，t，J＝7.3Hz)，4.17(2H，q，J＝7.3Hz)，5.86(1H，d，J＝15.6Hz)，7.03(1H，dt，J＝15.6，6.8Hz)，7.31(1H，dd，J＝8.3，1.5Hz)，7.40-7.47(2H，m)，7.61(1H，s)，7.76-7.81(3H，m).
With the compound dissolution that forms in tetrahydrofuran (THF) (140ml), under the frozen water cooling, in 40 minutes, be added dropwise to again the diisobutyl alanate (the 1M hexane solution, 120ml).After stirring 1 hour, reaction mixture is warming up to room temperature, add sodium sulfate decahydrate (60g).Continue to stir 1 hour.The filtering insoluble substance washs with tetrahydrofuran (THF) again.Merging filtrate and washing lotion, decompression steams solvent.Resistates silica gel chromatography (with 30-40% ethyl acetate-hexane wash-out), thus colourless crystallization shape title compound (8.10g) obtained.Fusing point: 51-52 ℃ Mass (EI) m/Z:212 (M
+).
1H-NMR (CDCl
3) δ: 2.44-2.49 (2H, m), 2.87 (2H, t, J=7.3Hz), 4.06-4.09 (2H, m), 5.69-5.80 (2H, m), 7.32 (1H, dd, J=8.3,1.5Hz), 7.39-7.47 (2H, m), 7.61 (1H, s), 7.76-7.81 (3H, m). to C
15H
16The ultimate analysis of O: calculated value: C, 84.86; H, 7.60 measured values: C, 84.65; H, 7.62 (2) 5-(2-naphthyl)-pentenyl iodine
Alkylol cpd (12.8g) and sodium iodide (10.85g) that (1) is obtained are dissolved in the acetonitrile (140ml), are added dropwise to chloro trimethyl silane (9.1ml) again.After at room temperature stirring 40 minutes, reaction mixture is poured in the water, used extracted with diethyl ether.Extraction liquid is used anhydrous sodium sulfate drying with sodium thiosulfate solution and saturated brine washing.Decompression steams solvent.Resistates silica gel chromatography (with 3% ethyl acetate-hexane wash-out), thus light yellow oily title compound (18.6g) obtained.
1H-NMR (CDCl
3) δ: 2.41-2.46 (2H, m), 2.85 (2H, t, J=7.3Hz), and 3.81-3.89 (2H, m), 5.71-5.81 (2H, m), 7.30 (1H, dd, J=8.3,1.5Hz), 7.39-7.47 (2H, m), 7.60 (1H, s), 7.75-7.81 (3H, m). reference example 4 (2R, 3S)-4-hydroxyl-3-methoxymethoxy-2-[5-(2-naphthyl) pentyloxy] tert-butyl acetate
(1) (3R, 4S)-4-hydroxyl-3-[5-(2-naphthyl) pentyloxy]-dihydro-2 (3H)-furanone
With 3,4-O-isopropylidene-L-threonic acid methyl esters (19.4g) is dissolved in N, in the dinethylformamide (300ml), add again in room temperature and under stirring sodium hydride (60% oily dispersion liquid, 4.10g).In the mixture that forms, be added dropwise to the N of 5-(2-naphthyl)-pentenyl iodine (33.0g), dinethylformamide (50ml) solution, and the mixture that forms stirred 2 hours.Use the ether diluted reaction mixture, add water sepn and go out organic layer.With organic layer water and the saturated brine washing that forms, use anhydrous sodium sulfate drying.Then, decompression steams solvent.Resistates carries out partial purification (with 1: 2 ethyl acetate-hexane wash-out) with silica gel column chromatography, thereby obtains colorless oil 3,4-O-isopropylidene-2-O-[5-(2-naphthyl)-pentenyl]-L-threonic acid methyl esters (17.1g).
With the compound dissolution that forms in the mixture of methyl alcohol (200ml) and tetrahydrofuran (THF) (200ml).In the solution that forms, add the 10% palladium-charcoal of catalytic amount, mixture was stirred 6 days under nitrogen atmosphere and room temperature.Filtration catalizer, filtrate is carried out underpressure distillation, thereby obtains oily 3,4-O-isopropylidene-2-O-[5-(2-naphthyl)-2-amyl group]-L-threonic acid methyl esters.
With the compound dissolution that forms in methylene dichloride (100ml).In the solution that forms, add trifluoroacetic acid (5ml), mixture was at room temperature stirred 19 hours.Under reduced pressure be concentrated into reaction mixture dried.Resistates silica gel chromatography (with 2: 3 ethyl acetate-hexane wash-outs), thus colorless oil title compound (5.78g) obtained.
1H-NMR (CDCl
3) δ: 1.40-1.48 (2H, m), 1.64-1.78 (4H, m), 2.12-2.17 (1H, broad s), 2.78 (2H, t, J=7.3Hz), 3.49 (1H, s), 3.62 (1H, dt, J=9.3,6.4Hz), 4.40-4.44 (2H, m), 7.32 (1H, dd, J=8.3,1.9Hz), 7.35-7.45 (2H, m), 7.60 (1H, s), 7.70-7.90 (3H, m). (2) (3R, 4S)-4-methoxymethoxy-3-[5-(2-naphthyl) pentyloxy]-dihydro-2 (3H)-furanone
The lactone compound (5.78g) that (1) is obtained is dissolved in the methylene dichloride (60ml).In the solution that forms, add diisopropyl ethyl amine (6ml) and chloro methyl ether (3.5ml), mixture was stirred 24 hours under the frozen water cooling.Use the ether diluted reaction mixture, anhydrous sodium sulfate drying is used in water and saturated brine washing successively.Decompression steams solvent, resistates silica gel chromatography (with 1: 4 ethyl acetate-hexane wash-out), thus obtain oily title compound (4.88g).Mass (EI) m/Z:358 (M
+).
1H-NMR (CDCl
3) δ: 1.42-1.48 (2H, m), 1.65-1.73 (4H, m), 2.78 (2H, t, J=7.8Hz), 3.35 (3H, s), 3.62 (1H, dd, J=6.8,2.4Hz), 3.96 (1H, dd, J=6.8,2.4Hz), 4.02-4.10 (1H, m), 4.07 (1H, d, J=6.4Hz), 4.29 (1H, dt, J=6.4,6.4Hz), 4.48 (1H, dd, J=9.3,6.4Hz), 4.63 (1H, d, J=6.8Hz), 4.71 (1H, d, J=6.8Hz), 7.32 (1H, dd, J=8.3,1.5Hz), 7.40-7.46 (2H, m), 7.60 (1H, s), and 7.75-7.80 (3H, m). (3) (2R, 3S)-and 4-hydroxyl-3-methoxymethoxy-2-[5-(2-naphthyl) pentyloxy] tert-butyl acetate
The methoxymethoxy compound (4.88g) that obtains in (2) is dissolved in the tetrahydrofuran (THF) (8ml).In the solution that forms, add 2N aqueous sodium hydroxide solution (8ml), mixture was at room temperature stirred 3 hours.In reaction mixture, add 10% hydrochloric acid and carry out acidifying, with the mixture extracted with diethyl ether that forms.The extraction liquid anhydrous sodium sulfate drying.Decompression steams solvent then, thus the acquisition oily (2R, 3S)-4-hydroxyl-3-methoxymethoxy-2-[5-(2-naphthyl) pentyloxy] butyric acid.
The compound dissolution that forms in tetrahydrofuran (THF) (50ml), is added dropwise to the O-tertiary butyl-N, N '-di-isopropyl isourea (17ml) in the solution that forms.After at room temperature stirring 15 hours, decompression steams solvent.Resistates silica gel chromatography (with 1: 3 ethyl acetate-hexane wash-out), thus oily title compound (3.96g) obtained.Mass (EI) m/Z:432 (M
+).
1H-NMR (CDCl
3) δ: 1.42-1.52 (2H, m), 1.47 (9H, s), 1.60-1.78 (4H, m), 2.77 (2H, t, J=7.5Hz), 2.98 (1H, dd, J=9.2,3.4Hz), 3.29 (1H, dd, J=8.8,6.8Hz), 3.40 (3H, s), 3.68-3.78 (3H, m), 3.89 (1H, s), 3.84-3.96 (1H, m), 4.60 (1H, d, J=6.8Hz), 4.71 (1H, d, J=6.8Hz), 7.32 (1H, dd, J=8.3Hz, 1.5Hz), 7.38-7.46 (2H, m), 7.60 (1H, s), 7.74-7.78 (3H, m). reference example 55-(2-naphthyl) amylamine
In the ethanolic soln (100ml) of 5-(2-naphthyl)-2-pentenoic acid ethyl ester (1.25g) that reference example 3-(1) obtains, add 10% palladium-charcoal (125g), under nitrogen atmosphere, mixture was at room temperature stirred 5.5 hours.After removing by filter palladium-charcoal, decompression steams solvent.Resistates silica gel chromatography (with 50% ethyl acetate-hexane wash-out), thus 5-(2-naphthyl) Valeric acid ethylester (1.24g) obtained.Under frozen water cooling, tetrahydrofuran (THF) (10ml) drips of solution of the compound (1.18g) that forms is added in tetrahydrofuran (THF) (10ml) suspension of lithium aluminium hydride (190mg), mixture was stirred 1.5 hours.In reaction mixture, add sodium sulfate decahydrate (1.6g), the mixture that forms was stirred 30 minutes.After reaction mixture is filtered, filtrate is carried out concentrating under reduced pressure.Resistates silica gel chromatography (with 33% ethyl acetate-hexane wash-out), thus colorless solid shape 5-(2-naphthyl) amylalcohol (0.98g) obtained.Mass(EI)m/Z：214(M
+).
1H-NMR(CDCl
3)δ：1.23(1H，t，J＝5.4Hz)，1.40-1.49(2H，m)，1.58-1.68(2H，m)，1.70-1.80(2H，m)，2.79(2H，t，J＝7.6Hz)，3.64(2H，dd，J＝12.7，7.3Hz)，7.33(1H，dd，J＝8.8，2.0Hz)，7.37-7.47(2H，m)，7.61(1H，s)，7.75-7.85(3H，m).
The alkylol cpd (0.96g), phthalic imidine (0.99g) and the triphenyl phosphine (1.76g) that form are dissolved in the tetrahydrofuran (THF) (100ml).Under the frozen water cooling, in the solution that forms, be added dropwise to diethyl azodiformate (1.06ml).After at room temperature stirring 18 hours, decompression steams solvent.Resistates silica gel chromatography (with 33% ethyl acetate-hexane wash-out), thereby obtain colourless crystallization shape 1-[5-(2-naphthyl) amyl group] phthalic imidine (1.53g).Mass(EI)m/Z：343(M
+).
1H-NNR(CDCl
3)δ：1.37-1.47(2H，m)，1.68-1.80(4H，m)，2.77(2H，t，J＝7.3Hz)，3.68(2H，t，J＝7.3Hz)，7.28-7.85(12H，m)
In ethanol (20ml) solution of the phthalimide compound (0.90g) that forms, add hydrazine hydrate (0.26ml), reflux 2.5 hours.After the cooling, the crystallization that filtering is settled out concentrates filtrate decompression.In resistates, add aqueous sodium hydroxide solution, extract with ethyl acetate again.Extraction liquid washs with saturated brine, uses anhydrous sodium sulfate drying again.Steam solvent, thereby obtain light yellow oily title compound (0.53g).Mass(EI+)m/z：213(M
+).
1H-NMR(CDCl
3)δ：1.34-1.54(6H，m)，1.68-1.76(2H，m)，2.68(2H，t，J＝7.1Hz)，2.77(2H，t，J＝7.6Hz)，7.32(1H，dd，J＝8.0，2.0Hz)，7.38-7.46(2H，m)，7.59(1H，s)，7.71-7.81(3H，m).
In the ethanolic soln of the compound that forms, add concentrated hydrochloric acid, concentrating under reduced pressure again, thus obtain the hydrochloride (colourless crystallization) of title compound.Fusing point: 180-181 ℃ to C
15H
20The ultimate analysis of ClN: calculated value: C, 72.13; H, 8.07; Cl, 14.19; N, 5.61 measured values: C, 71.77; H, 8.04; Cl, 14.12; N, 5.30
In the mode identical with reference example 5, just adopt 5-(1,3-benzo dioxole-5-yl) amylalcohol, 5-(2-[4-morpholinodithio base) amylalcohol and 5-(2-benzoxazolyl) amylalcohol replace 5-(2-naphthyl) amylalcohol, obtain the compound of reference example 6-8 respectively.Reference example 65-(1,3-benzo dioxole-5-yl) amylamine (1) 1-[5-(1,3-benzo dioxole-5-yl) amyl group] phthalic imidine Mass (FAB+) m/Z:337 (M
+).
1H-NMR (CDCl
3) δ: 1.30-1.40 (2H, m), 1.55-1.75 (4H, m), 2.52 (2H, t, J=7.6Hz), 3.67 (2H, t, J=7.3Hz), 5.90 (2H, s), 6.59 (1H, dd, J=7.8,1.0Hz), 6.45 (1H, s), 6.69 (1H, d, J=7.8Hz), and 7.68-7.87 (4H, m). (2) 5-(1,3-benzo dioxole-5-yl) amylamine Mass (EI) m/Z:207 (M
+).
1H-NMR (CDCl
3) δ: 1.28-1.62 (8H, m), 2.53 (2H, t, J=7.8Hz), 2.69 (2H, t, J=7.1Hz), 5.91 (2H, s), 6.61 (1H, dd, J=7.8,1.5Hz), 6.67 (1H, d, J=1.5Hz), 6.72 (1H.d.J=7.8Hz). reference example 75-(2-[4-morpholinodithio base) amylamine (1) 1-[5-(2-[4-morpholinodithio base) amyl group] phthalic imidine Mass (FAB+) m/Z:351 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.33-1.45 (2H, m), 1.60-1.70 (2H, m), 1.78-1.88 (2H, m), 3.05-3.12 (2H, m), 3.55-3.62 (2H, m), 7.35-8.00 (8H, m) (2) 5-(2-[4-morpholinodithio base) amylamine
1H-NMR (CDCl
3) δ: 1.42-1.60 (4H, m), 1.85-2.00 (2H, m), and 2.68-2.78 (2H, m), 3.10-3.20 (2H, m), 7.32-7.50 (2H, m), 7.84 (1H, d, J=8.3Hz), 7.96 (1H, d, J=7.8Hz). reference example 85-(2-benzoxazolyl) amylamine (1) 5-(2-benzoxazolyl) amylalcohol
Monoethyl adipatee (2.0g) is dissolved in the benzene (20ml), under the frozen water cooling, to wherein being added dropwise to oxalyl chloride (5ml).After stirring 1 hour, reaction mixture is evaporated to dried.In resistates, add benzene, carry out azeotropic distillation twice.Resistates is dissolved in the toluene (30ml).Add 2-amino-phenol (1.25g) in the solution that forms, reheat refluxed 16 hours.After the cooling, reaction mixture is washed with water, use anhydrous sodium sulfate drying.Decompression steams solvent.Resistates silica gel chromatography (with 33% ethyl acetate-hexane wash-out), thus light yellow solid shape 5-(2-benzoxazolyl) Valeric acid ethylester (1.11g) obtained.Mass(FAB+)m/Z：248(M+H)
+.
1H-NMR(CDCl
3)δ：1.25(3H，t，J＝7.3Hz)，1.70-1.83(2H，m)，1.90-2.00(2H，m)，2.38(2H，t，J＝7.6Hz)，2.96(2H，t，J＝7.6Hz)，4.12(2H，q，J＝7.3Hz)，7.27-7.00(4H，m).
The ethyl ester (1.11g) that forms is dissolved in the tetrahydrofuran (THF) (50ml).Under-78 ℃, (the 0.95M hexane solution 12ml), stirs mixture 1 hour to add diisobutyl aluminium hydride in the solution that forms.In reaction mixture, add the sodium sulfate decahydrate, reaction mixture is warming up to room temperature.Behind the filtering insoluble substance, filtrate is carried out underpressure distillation.Resistates silica gel chromatography (with 50% ethyl acetate-hexane wash-out), thus light yellow solid shape title compound (0.62g) obtained.Mass (FAB+) m/Z:206 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.45-1.70 (4H, m), 1.85-2.10 (3H, m), 2.95 (2H, t, J=7.6Hz), 3.67 (2H, t, J=6.3Hz), 7.27-7.30 (2H, m), and 7.45-7.50 (1H, m), 7.65-7.70 (1H, m). (2) 1-[5-(2-benzoxazolyl) amyl group] phthalic imidine
1H-NMR (CDCl
3) δ: 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 2.93 (2H, t, J=7.6Hz), 3.73 (2H, t, J=7.1Hz), 7.22-7.88 (8H, m). (3) 5-(2-benzoxazolyl) amylamine Mass (FAB+) m/Z:335 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.40-1.60 (4H, m), 1.85-2.06 (4H, m), 2.70-2.80 (2H, m), 2.90-3.00 (2H, M), 7.25-7.70 (4H, m). reference example 94-tert-butyl diphenyl siloxy--1-iodo-2-butylene
Under the frozen water cooling, in methylene dichloride (800ml) solution of triphenyl phosphine (152.4g) and imidazoles (55.4g), be added dropwise to methylene dichloride (1200ml) solution of iodine powder (148.5g).After stirring 30 minutes under the frozen water cooling, be added dropwise to methylene dichloride (500ml) solution of (Z)-4-tert-butyl diphenyl siloxy--2-butylene-1-alcohol (148.4g).After stirring 4 hours, add sodium thiosulfate solution to isolate organic layer.Organic layer washs with saturated brine, uses anhydrous sodium sulfate drying again.Decompression steams solvent.Resistates silica gel chromatography (with 17% ethyl acetate-hexane wash-out), thus yellow oily title compound (164.0g) obtained.
1H-NMR (CDCl
3) δ: 0.99 (9Hs), 3.86 (2H, d, J=7.8Hz), 4.11 (2H, d, J=4.4Hz), 5.71 (1H, dt, J=15.1,4.4Hz), 5.96 (1H, dt, J=15.1,7.8Hz), 7.30-7.37 (6H, m), 7.59-7.61 (4H, m). reference example 10 (3,4-dimethyl benzene ylmethyl) triphenyl phosphonium chloride
With 3, the mixture heating up of 4-3,5-dimethylphenyl methyl chloride (15.5g), triphenyl phosphine (26.2g) and o-Xylol (200ml) refluxed 16 hours.After the cooling,,,, standby decompression and 60 ℃ dry 7 hours down with the ether washing by filter collecting insoluble solid.
Adopt similar mode, only replace 3 with corresponding chlorinated thing or bromide, 4-3,5-dimethylphenyl methyl chloride prepares following substances respectively: (2-Chlorophenylmethyl) triphenyl phosphonium chloride, (3, the 4-dichlorophenylmethyl) three phenyl phosphonium bromides, (4-trifluorophenyl methyl) three phenyl phosphonium bromides, [(1,3-benzo dioxole-5-yl) methyl] three phenyl phosphonium bromides, (2-benzoxazole ylmethyl) three phenyl phosphonium bromides, (2-[4-morpholinodithio ylmethyl) three phenyl phosphonium bromides and (3-chloro-4-aminomethyl phenyl methyl) triphenyl phosphonium chloride.
Triphenyl phosphonium salt outside it is above-mentioned is commercially available.Reference example 11
With 3,5-xylidine (2.0g) is dissolved in the methylene dichloride (30ml), adds 2,4-dinitrophenyl chloride (5.3g) and pyridine (1.6ml) again under the frozen water cooling.After at room temperature stirring 3 hours,, use anhydrous sodium sulfate drying with reaction mixture water and saturated brine washing.Isolate resistates, and with silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thereby obtain the compound (4.63g) of yellow solid shape reference example 11-c.
Adopt similar mode to react, just replace 3,5-xylidine, thereby embodiment 11a, b and d to m that acquisition will be described below with corresponding aniline.
Reference example 126-(2-naphthyl) hexyl bromide
Beta naphthal (10.0g) is dissolved in the methylene dichloride (100ml), under the frozen water cooling, adds diisopropyl ethyl amine (15ml) and trifluoromethanesulfanhydride anhydride (20g) successively again.After at room temperature stirring 6 hours, use the ether diluted reaction mixture, wash with water then.After with anhydrous sodium sulfate drying, decompression steams solvent.Resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus colorless oil trifluoromethanesulfonic acid 2-naphthalene ester (19.1g) obtained.
The compound (19.1g) that forms is dissolved in the triethylamine (200ml).In the solution that forms, add 5-hexin-1-alcohol (7.0g), cupric iodide (I) (0.18g) and two (triphenyl phosphine) palladium chlorides (0.4g), mixture was stirred 10 hours down at 60 ℃.After with the ether dilution, the filtering insoluble substance.Filtrate is carried out concentrating under reduced pressure, and resistates carries out partial purification (with 20% ethyl acetate-hexane wash-out) with silica gel column chromatography, thereby obtains oily 6-(2-naphthyl)-5-hexin-1-alcohol (14.5g).
With the compound dissolution that forms in ethanol (100ml).In the solution that forms, add 10% palladium-charcoal (0.5g), under nitrogen atmosphere, mixture was at room temperature stirred 24 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried.Resistates silica gel chromatography (with 17% ethyl acetate-hexane wash-out), thus oily 6-(2-naphthyl)-1-hexanol (8.0g) obtained.
The compound (6.6g) that forms is dissolved in the methylene dichloride (100ml).In the solution that forms, add dibromo triphenyl phosphine (14.6g) and imidazoles (2.0g), mixture was at room temperature stirred 6 hours.After with the ether dilution, the filtering insoluble substance.Filtrate is carried out concentrating under reduced pressure, resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus obtain oily title compound (7.0g).
1H-NMR (CDCl
3) δ: 1.30-1.90 (8H, m), 2.78 (2H, t, J=7.3Hz), 3.40 (2H, t, J=6.8Hz), 7.28-7.50 (3H, m), 7.61 (1H, s), 7.72-7.85 (3H, m). reference example 135-(3, the 4-3,5-dimethylphenyl) penta-2-alkene-1-base iodide
(1) 3-(3, the 4-3,5-dimethylphenyl)-2-alkynes third-1-alcohol
To two (triphenyl phosphine) palladiums (II) of 4-iodo o-Xylol (30g), dichloro (1.81g), cupric iodide (I) adding 2-alkynes third-1-alcohol (10.9g) (0.49g) and in the mixture of triethylamine (500ml), mixture was stirred 21 hours under argon atmospher and room temperature.Adopt diatomite filtering insoluble substance, and use hexane wash.Merging filtrate and washing lotion are carried out underpressure distillation.Resistates silica gel chromatography (with 20% ethyl acetate-hexane wash-out), thus yellow oily title compound (21.2g) obtained.MS (EI) m/Z:160 (M
+).
1H-NMR (CDCl
3) δ: 1.80 (1H, t, J=6.4Hz), 2.22 (3Hs), 2.24 (3H, s), 4.48 (2H, d, J=6.4Hz), 7.06 (1H, d, J=7.6Hz), 7.17 (1H, d, J=7.6Hz), 7.22 (1H, s). (2) 3-(3, the 4-3,5-dimethylphenyl)-1-propyl alcohol
With 3-(3, the 4-3,5-dimethylphenyl)--2-alkynes third-1-alcohol (21.1g) is dissolved in ethanol (300ml).In the solution that forms, add 10% palladium-charcoal (0.5g), under nitrogen atmosphere, mixture was at room temperature stirred 3 days.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried.Resistates is dissolved in the methylene dichloride, uses anhydrous sodium sulfate drying again.Decompression steams solvent, thereby obtains colorless oil title compound (20.3g).MS (EI+) m/Z:164 (M
+).
1H-NMR (CDCl
3) δ: 1.83-1.90 (2H, m), 2.22 (3H, s), 2.23 (3H, s), 2.63 (2H, t, J=7.8Hz), 3.66 (2H, t, J=6.6Hz), 6.93 (1H, d, J=7.6Hz), 6.97 (1H, s), 7.04 (1H, d, J=7.6Hz). (3) 3-(3, the 4-3,5-dimethylphenyl) propionic aldehyde
Oxalyl chloride (12.9ml) is added in the methylene dichloride (200ml), be cooled to-78 ℃ and stirring.In 55 minutes, be added dropwise to methylene dichloride (50ml) solution of methyl-sulphoxide (17.4ml), with the mixture restir that forms 15 minutes.In 1 hour, be added dropwise to methylene dichloride (150ml) solution of 3-(3, the 4-3,5-dimethylphenyl)-1-propyl alcohol (20.2g) again, the mixture that forms was stirred 50 minutes.Be added dropwise to triethylamine (86ml), the mixture that forms was stirred 15 minutes.After stirring 1 hour under the frozen water cooling, add entry (500ml) and isolate organic layer.The organic layer that forms with dilute hydrochloric acid and saturated brine washing, is used anhydrous sodium sulfate drying successively.Then, decompression steams solvent.Resistates silica gel chromatography (with 5% ethyl acetate-hexane wash-out), thus light yellow oily title compound (16.9g) obtained.MS (EI) m/Z:162 (M
+).
1H-NMR (CDCl
3) δ: 2.22 (3H, s), 2.23 (3H, s), 2.72-2.76 (2H, m), 2.87 (2H, t, J=7.6Hz), 6.91-6.93 (1H, m), 6.96 (1H, s), 7.05 (1H, d, J=7.3Hz), 9.81 (1H, t, J=1.5Hz). (4) 5-(3, the 4-3,5-dimethylphenyl) penta-2-olefin(e) acid ethyl ester
With with the identical mode of reference example 3-(1), adopt 3-(3, the 4-3,5-dimethylphenyl) propionic aldehyde that obtains in (3) to synthesize, thereby obtain light yellow oily title compound (22.1g).MS (EI) m/Z:232 (M
+).
1H-NMR (CDCl
3) δ: 1.28 (3H, t, J=7.3Hz), 2.22 (3H, s), 2.23 (3H, s), 2.46-2.52 (2H, m), 2.46-2.52 (2H, m), 2.70 (2H, t, J=7.8Hz), 4.18 (2H, q, J=7.3Hz), 5.85 (1H, d, J=15.6Hz), 6.91 (1H, d, J=7.8Hz), 6.95-7.05 (3H, m) (5) 5-(3, the 4-3,5-dimethylphenyl) penta-2-alkene-1-alcohol
With with the identical mode of reference example 3-(1), adopt 5-(3, the 4-3,5-dimethylphenyl) penta-2-olefin(e) acid ethyl ester (22.0g) that obtains in (4) to synthesize, thereby obtain colorless oil title compound (15.4g).MS (EI) m/Z:190 (M
+).
1H-NMR (CDCl
3) δ: 2.22 (3H, s), 2.23 (3H, s), 2.31-2.37 (2H, m), 2.63 (2H, t, J=7.8Hz), and 4.03-4.11 (2H, m), 5.66-5.74 (2H, m), 6.91 (1H, d, J=7.6Hz), 6.95 (1H, s), 7.04 (1H, d, J=7.6Hz). (6) 5-(3, the 4-3,5-dimethylphenyl) penta-2-alkene-1-base iodide
With with the identical mode of reference example 3-(1), adopt 5-(3, the 4-3,5-dimethylphenyl) penta-2-alkene-1-alcohol (15.4g) that obtains in (5) to synthesize, thereby obtain light yellow oily title compound (23.5g).MS (EI) m/Z:300 (M
+).
1H-NMR (CDCl
3) δ: 2.22 (3H, s), 2.23 (3H, s), 2.30-2.34 (2H, m), 2.61 (2H, t, J=7.8Hz), 3.86 (2H, dd, J=4.9,2.0Hz), 5.73-5.7 6 (2H, m), 6.90 (1H, d, J=7.6Hz), 6.93 (1H, s), 7.04 (1H, d, J=7.6Hz). reference example 14 methyl [5-(2-naphthyl) amyl group] amine hydrochlorate
(1) N-[5-(2-naphthyl) amyl group] urethanum
Reference example 5 synthetic [5-(2-naphthyl) amyl group] amine hydrochlorate (20g) is suspended in the methylene dichloride (200ml), under agitation adds triethylamine (20g) again.Under the frozen water cooling, in 5 minutes, in reaction mixture, drip chlorocarbonic acid ethyl ester (10.5g), the mixture that forms was at room temperature stirred 2 hours.Decompression steams solvent.Resistates is dissolved in the ethyl acetate.The solution that forms is washed with dilute hydrochloric acid, 5% sodium bicarbonate and saturated brine, use anhydrous sodium sulfate drying.Decompression steams solvent, resistates silica gel chromatography (with 30% ethyl acetate-hexane wash-out), thus obtain colourless crystallization shape title compound (19.5g).Fusing point: 44-46 ℃ MS (EI) m/Z:285 (M
+).
1H-NMR (CDCl
3) δ: 1.22 (3H, t, J=6.8Hz), 1.35-1.42 (2H, m), 1.50-1.58 (2H, m), 1.69-1.75 (2H, m), 2.77 (2H, t, J=7.6Hz), 3.10-3.19 (2H, m), 4.09 (2H, q, J=6.8Hz), 4.35-4.63 (1H, broad), 7.31 (1H, d, J=8.3Hz), 7.39-7.46 (2H, m), 7.59 (1H, s), (3H is m) to C for 7.75-7.80
18H
23NO
2Ultimate analysis: calculated value: C, 75.76; H, 8.12; N, 4.91 measured values: C, 75.68; H, 8.12; N, 4.86
(2) methyl [5-(2-naphthyl) amyl group] amine hydrochlorate
Lithium aluminium hydride (7.78g) is suspended in the methylene dichloride (200ml), under agitation is added dropwise to tetrahydrofuran (THF) (80ml) solution of the carbamate (19.49g) of (1) acquisition again., reaction mixture is cooled off and stirring after 4.5 hours in reflux with frozen water.Add the lithium aluminium hydride of sodium sulfate decahydrate, restir 30 minutes with decomposing excessive in batches.Remove insoluble substance by diatomite filtration, wash with tetrahydrofuran (THF).Merging filtrate and washing lotion are carried out underpressure distillation with mixture, thereby obtain the free alkali of title compound.
The free alkali that forms is dissolved in the ethanol (200ml), in the solution that forms, adds concentrated hydrochloric acid (7ml).The mixture that forms is carried out concentrating under reduced pressure.In enriched material, add ether, by filtering the solid that collecting precipitation goes out, thereby obtain colourless crystallization shape title compound (14.8g).Fusing point: 150-158 ℃ MS (FAB+) m/Z:228 (free alkali+H)
+ 1H-NMR (CD
3OD) δ: 1.40-1.49 (2H, m), 1.67-1.82 (4H, m), 2.65 (3H, s), 2.82 (2H, t, J=7.3Hz), 2.95 (2H, t, J=7.6Hz), 7.31-7.45 (3H, m), 7.63 (1H, s), 7.72-7.79 (3H, m). to C
16H
22The ultimate analysis of ClN: calculated value: C, 72.86; H, 8.41; Cl, 13.44; N, 5.31 measured values: C, 72.71; H, 8.42; Cl, 13.38; N, 5.29 reference examples 15 (5-hydroxyl amyl group) methylamine
(1) N-(5-hydroxyl amyl group)-N-methyl carbamic acid benzyl ester
With the identical mode of reference example 14-(1), handle 5-hydroxyl amylamine (1.03g), obtain N-(5-hydroxyl amyl group) urethanum (1.74g).Handle the compound (0.74g) of formation in the mode identical with reference example 14-(2), thus obtain (5-hydroxyl amyl group) methylamine crude product (free alkali, 0.68g).With the compound dissolution that forms in methylene dichloride (8ml).Under the frozen water cooling, in the solution that forms, add triethylamine (0.6ml) and chlorocarbonic acid benzyl ester (0.6ml), mixture was at room temperature stirred 1 day.Reaction mixture is carried out concentrating under reduced pressure, resistates is dissolved in the ethyl acetate.The solution that forms is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine successively, use anhydrous sodium sulfate drying again.Then, decompression steams solvent.Resistates silica gel chromatography (with 33-50% ethyl acetate-hexane wash-out), thus colorless oil title compound (0.64g) obtained.
1H-NMR (CDCl
3) δ: 1.37-1.61 (6H, m), 2.92 (3H, s), 3.30 (2H, m), 3.58-3.64 (2H, m), 5.12 (2H, s), 7.35 (5H, s). (2) (5-hydroxyl amyl group) methylamine
The carbamate compounds (0.64g) that (1) is obtained is dissolved in the methyl alcohol (10ml).In the solution that forms, add 10% palladium-charcoal (64mg), under nitrogen atmosphere, mixture was at room temperature stirred 8 hours.After removing by filter palladium-charcoal, filtrate decompression is concentrated into dried, thereby obtain light yellow oily title compound (0.28g).MS (FAB+) m/Z:118 (M+H)
+.
1H-NMR (CDCl
3) δ: 1.38-1.63 (6H, m), 1.79 (1H, broad), 2.43 (3H, s), 2.59 (2H, t, J=7.1Hz), 3.64 (2H, m). experiment
Confirm that by following method the squalene synthetase of all cpds of the present invention in rat liver suppresses active and the synthetic activity that suppresses of cholesterol.1. squalene synthetase suppresses active
(1) enzyme source preparation
According to described methods such as Schechter (" journal of biological chemistry " (Jounal ofBiological Chemistry), the 267th volume, the 8628-8635 page or leaf, 1992) be that the microsome composition that the HepG2 cell obtains prepares as the active enzyme of measured angular squalene synthetase source, by human hepatocyte's oncocyte.
Particularly, at first with HepG2 cell homogenizing, homogenization process is comprising 0.3M sucrose, 1mM dithiothreitol (DTT) (DTT), 1mM sodium ethylene diamine tetracetate (EDT) and various proteinase inhibitor, and the pH value is adjusted in 10mM N-2-hydroxyethyl piperazine-N '-2 ethane sulfonic aicd salt (HEPES) damping fluid of 7.4 and carries out.The mixture that forms is carried out centrifugation, under 2,000 * g, carried out 5 minutes, under 10,000 * g, carried out 15 minutes again.The proteinase inhibitor that is adopted is phenyl methanesulfonamide acyl fluorides (PMSF), bright proteolytic enzyme skin and the Trypsin inhibitor,Trasylol of pressing down, and they is added respectively to make last concentration be 1mM, 10 μ M and 5 μ g/ml.After centrifugal, with supernatant liquor under 105,000 * g centrifugal 60 minutes again.The throw out that is obtained is suspended in the 20mM phosphoric acid buffer (pH7.4), and this damping fluid comprises 1mMDTT, 1mM EDTA and above-mentioned proteinase inhibitor, and the suspension that forms is passed through centrifugal 30 minutes washed twice under 105,000 * g.Then, throw out is suspended in the 20mM phosphoric acid buffer (pH7.4), this damping fluid comprises 1mMDTT, 1mM EDTA again, and the suspension that forms is carried out similar centrifugal treating.The throw out of Huo Deing promptly can be used as the microsome composition of measuring enzymic activity at last.
(2) the measured angular squalene synthetase suppresses active
Equally according to described methods such as Schechter (" journal of biological chemistry " (Jounal ofBiological Chemistry), the 267th volume, 8628-8635 page or leaf, 1992), the activity of measured angular squalene synthetase.
Particularly, the trial drug that will be dissolved in water or the methyl-sulphoxide (DMSO) adds in the enzyme reaction mixture (50 μ l) totally, described enzyme reaction mixture comprises 5mM nicotinamid adenin dinucleotid phosphat ester reduction form (NADPH), 5mM 3-[(3-courage amido propyl group) diformazan ammonium] propane sulfonate (CHAPS), the 10mM Potassium monofluoride, the 10mM magnesium chloride, 10mM DTT, 1 μ g/mlNB-598 (a kind of squalene epoxidase inhibitor, as described in following document: " journal of biological chemistry " (Jounal of Biological Chemistry), the 265th volume, the 18075-18078 page or leaf, 1990), 50mM HEPES damping fluid (pH7.4), 0.01-0.1 μ g HepG2 cytomicrosome preparation and 5 μ M[
3H] farnesylpyrophosphate, subsequently, 37 ℃ of down reactions 20 minutes (reaction to the enzyme reaction mixture, add [
3H] farnesylpyrophosphate begins, described mixture is 37 ℃ of pre-down cultivations 10 minutes).Add 5 μ l 1M EDTA (pH9.2) and stop enzyme reaction.The ethanolic soln that in mixture, adds 0.5% squalene of 5 μ l.From the mixture that forms, get 40 μ l points on the thin-layer chromatography sheet of plastic back, launch with 5% toluene-95% hexane.After the drying, the thin-layer chromatography sheet is placed in the iodine vapor develops the color, thereby differentiate the bands of a spectrum of squalene.Use the scissors cutting of bands, place it in the bottle, add the Aquasol-2 (New englandNuclear Reserach Product Inc./USA) of 10ml.By the liquid scintillation counter measurement radioactivity.It is active in suppressing 50% concentration (IC when mixing radioactivity in the squalene that squalene synthetase suppresses
50, volumetric molar concentration) and expression.2. the synthetic activity (1) that suppresses of cholesterol prepares rat hepatocytes in rat hepatocytes
By original position collagenase perfusion method isolating hepatocytes from rats'liver.Particularly, the Sodital sodium solution of male SD rat intraperitoneal administration 50mg/ml to 6 ages in week makes its anesthesia.After implementing laparotomy and cannulation by portal vein, driving under the haemal strand spare, kill rat by excision bottom vena cava.Be fed into Hanks solution (pH7.2) from intubate, this solution comprises the ethyleneglycolbis(2-aminoethylether)tetraacetic acid (EGTA) of 2% albumin, 0.5mM and the HEPES of 10mM, and rate of flooding is 0.5ml/s, and the time is 5 minutes.Then, change another kind of Hanks solution again and pour into, this Hanks solution (pH7.5) comprises the calcium chloride of 0.05% collagenase, 4mM and the HEPES of 10mM, and this time infusion time is 15-20 minute.After confirming that the collagenase digesting of capacity is arranged, hepatic tissue is placed on the Petri dish, on it, add DulbeccoShi modification Eagle ' s (DEM) substratum of 30ml, by suction cell is disperseed.Adopt cell filter to remove indigested tissue.With the centrifugation 1 minute under 600rpm of the cell suspending liquid that forms.The DME substratum that adds 30ml in throw out is with cell dispersion again, centrifugation 1 minute under 600rpm again.By centrifugal repeat these washing process three times after, hepatocyte suspension be suspended in comprise in the DME substratum that 10% lipoprotein lacks serum (LPDS).The suspension that forms is seeded on 6 orifice plates that are purchased, in hole density 1 * 10
6Apply collagen under the cells/well onboard, later on plate is placed on overnight incubation in the carbonic acid gas insulation can (5% carbon dioxide, 37 ℃).
(2) measure the synthetic activity that suppresses of cholesterol
In the liver cell measurement cholesterol of employing preparation in the above described manner [
14C]-the radioactive picked-up of acetate, and the synthetic activity that suppresses of the cholesterol of evaluation test medicine.
Particularly, replace hepatocyte culture medium, it was cultivated 1 hour in the carbonic acid gas insulation can with the 25mM HEPES-10%LPDS-DME substratum (pH7.4) that comprises trial drug.Add then, [
14C] sodium acetate, making ultimate density is 1 μ Ci/ml.In the carbonic acid gas insulation can, cultivate after 1 hour again, remove cell culture medium.Cell is dissolved in the 1ml 0.1N aqueous sodium hydroxide solution with phosphate buffered saline (PBS) (pH7.2) washing three times again.A part (10 μ l) that forms cell lysates is carried out protein according to the Lowry method to be measured.In rest part, add 2ml ethanol and 0.5ml 50% potassium hydroxide aqueous solution, again in 75 ℃ of following saponification 1 hour.After saponification is finished, in sample, add as internal standard substance [
3H] cholesterol 50,000dpm.Add the 4.5ml sherwood oil down ice-cooled, the mixture that forms is acutely mixed, thereby extract unsaponified lipoid.The petroleum ether layer that forms is transferred in another test tube, under nitrogen gas stream, is evaporated to driedly, be dissolved in again and comprise in the cholesteric 50 μ l methylene chloride-methanols (2: 1) of 10mg/ml.The solution that forms is placed on the thin-layer chromatography sheet of plastic back, launch with toluene-ethyl acetate (3: 1).After finishing expansion, with the sheet drying, place it in the iodine vapor again and develop the color, thereby differentiate cholesteric bands of a spectrum.Use the scissors cutting of bands, place it in the flicker bottle.Aquasol-2 to wherein adding 10ml passes through liquid scintillation counter measurement
14C and
3The H radioactivity.
The cholesterol of trial drug is synthetic to suppress active in following method calculating.At first, measure as internal standard substance add [
3H] the cholesterol radioactivity, according to the result, proofread and correct the deviation of employing sherwood oil between sample aspect the percentage extraction and sample according to following formula:
In cholesterol [
14C] acetate radioactive picked-up (dpm)=
14The radioactive observed value of C * 50,000 (dpm)/
3The radioactive observed value of H (dpm)
According to above-mentioned value,
14The proteinic picked-up value of C radioactivity/unit (unit: dpm/mg protein) adopt the protein concn measuring result of cell lysates to determine.Concentration (IC when the synthetic inhibition activity of the cholesterol of trial drug is absorbed into cholesteric radioactivity by inhibition 50%
50, volumetric molar concentration) and expression.3. experimental result
The squalene synthetase of embodiment 1 compound that records by aforesaid method 1 suppresses active (IC
50) be 0.3nM.About the compound among the embodiment with at the compound described in following two pieces of patents; promptly; (2S)-2-[N-{ (1S; 2R)-3-(3; the 4-dichlorophenyl)-and 1-methyl-2-(2-naphthoyl oxygen base) propyl group } formamyl) methyl] succsinic acid (compd A) (the flat 7-138214 of TOHKEMY) and N-[(3R; 5S)-7-chloro-5-(2-chloro-phenyl-)-1-neo-pentyl-2-oxo-1; 2; 3; 5-tetrahydrochysene-4; 1-benzo oxygen azatropylidene-3-ethanoyl] Padil (compd B) (EP567026A), by method 2 the synthetic restraining effect of its cholesterol in rat hepatocytes is compared (table 1).
Table 1
The synthetic restraining effect of cholesterol in rat hepatocytes
| Compound number | ????IC 50(10 -6M) |
| Embodiment 1 | ????0.15 |
| Embodiment 20-n | ????0.03 |
| Embodiment 48 | ????0.019 |
| Compd A | ????0.32 |
| Compd B | ????0.39 |
As mentioned above, confirmed that compound of the present invention has excellent squalene synthetase inhibition activity and the synthetic inhibition of cholesterol is active.
Compound exhibits of the present invention goes out the potential squalene synthetase and suppresses active, thereby can be used as treatment and prevention hypercholesterolemia, hyperlipoidemia or arteriosclerotic medicine.
Claims (28)
1, by propionyl derivative or its salt of the replacement of following formula (1) expression:
Wherein
X
1For can esterified carboxyl, tetrazolium-5-base, phosphonic acids or sulfonic acid group;
Y
1For singly-bound ,-O-or-N (R
1)-, wherein, R
1Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl;
A
1, A
2And A
3In at least a be the group of following formula (2) expression:
-R
2-a
1-R
3-a
2→ (2) wherein
R
2For replacing or bivalent hydrocarbon radical unsubstituted, that have 2-12 carbon atom R
3Be singly-bound, perhaps replace or bivalent hydrocarbon radical unsubstituted, that have 1-12 carbon atom a
1And a
2Be independently singly-bound ,-S-,-SO-,-SO
2-,-SO
2NH-,-O-,-N (R
4)-, wherein, R
4Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl ,-CON (R
5)-, wherein, R
5Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl ,-C (=O)-or Si (R
6) (R
7)-, wherein, R
6And R
7Independently for replacing or unsubstituted alkyl → expression and Q
1, Q
2Or Q
3Key, A
1, A
2Or A
3In remaining one or both identical or different, each is the group of following formula (3) expression independently:
-R
8-a
3-R
9-a
4→ (3) wherein
R
8And R
9Be singly-bound independently, perhaps replace or bivalent hydrocarbon radical unsubstituted, that have 1-12 carbon atom a
3And a
4Be independently singly-bound ,-S-,-SO-,-SO
2-,-SO
2NH-,-O-,-N (R
10)-, wherein, R
10Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl ,-CON (R
11)-, wherein, R
11Be hydrogen atom, hydroxyl or replacement or unsubstituted alkyl ,-C (=O)-or Si (R
12) (R
13)-, wherein, R
12And R
13Independently for replacing or unsubstituted alkyl → expression and Q
1, Q
2Or Q
3Key;
Q
1, Q
2Or Q
3In at least a for replacement or unsubstituted cyclic hydrocarbon radical or replacement or unsubstituted heterocyclic radical, Q
1, Q
2Or Q
3In remaining one or both be independently hydrogen atom, can esterified carboxyl, replacement or unsubstituted alkyl or replacement or unsubstituted heterocyclic.
2, according to propionyl derivative or its salt of the replacement of claim 1, wherein, X
1For can esterified carboxyl.
3, according to propionyl derivative or its salt of the replacement of claim 1 or 2, wherein, A
1, A
2And A
3In one or both represent by following formula (2a) independently:
-R
2-a
1→ (2a) wherein, R
2, a
1With → identical with aforementioned definitions, A
1, A
2And A
3In remaining one or both identical or different, and represent by following formula (3a) independently:
-R
8-a
3-R
9-a
4→ (3a) wherein, R
8, R
9, a
3, a
4With → identical with aforementioned definitions.
4, according to each propionyl derivative or its salt of replacement of claim 1-3, it is represented by following formula (1A):
Wherein
R
14Be hydrogen atom or ester residue,
R
8aAnd R
8bIdentical or different, have independently with to R
8Define identical definition,
a
3aAnd a
3bIdentical or different, have independently with to a
3Define identical definition,
R
9aAnd R
9bIdentical or different, have independently with to R
9Define identical definition,
a
4aAnd a
4bIdentical or different, have independently with to a
4Define identical definition,
Q
1aFor replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic,
Q
2aAnd Q
3aIn a kind of be hydrogen atom or can esterified carboxyl, another kind of for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic; With
Y
1, a
1And R
2Identical with aforementioned definitions.
5, according to each propionyl derivative or its salt of replacement of claim 1-4, wherein, in formula (1A), Q
1aAnd Q
2aIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic Q
3aBe hydrogen atom or can esterified carboxyl.
6, want propionyl derivative or its salt of 4 or 5 replacement according to right, wherein, in formula (1A), group Y
1For-(NR
1)-, wherein, R
1Identical with aforementioned definitions.
7, want propionyl derivative or its salt of 4 or 5 replacement according to right, wherein, in formula (1A), group Y
1For-(NR
1)-, wherein, R
1Be hydrogen atom or alkyl.
8, according to each propionyl derivative or its salt of replacement of claim 4-7, wherein, in formula (1A), group-R
8a-a
3a-R
9a-and-R
8b-a
3b-R
9b-identical or different, each is independently for replacing or unsubstituted divalence C
1-12Alkyl.
9, according to each propionyl derivative or its salt of replacement of claim 4-8, wherein, in formula (1A), group-R
8b-a
3b-R
9b-a
4b→ be singly-bound or C
1-3Alkylidene group.
10, according to each propionyl derivative or its salt of replacement of claim 4-8, wherein, in formula (1A), group-R
8b-a
3b-R
9b-a
4b→ be singly-bound.
11, according to each propionyl derivative or its salt of replacement of claim 4-8, wherein, in formula (1A), group-R
8b-a
3b-R
9b-a
4b→ be methylene radical.
12, according to each propionyl derivative or its salt of replacement of claim 4-11, wherein, in formula (1A), group a
1For singly-bound or-(NR
4)-, wherein, R
4Identical with aforementioned definitions.
13, according to each propionyl derivative or its salt of replacement of claim 4-11, wherein, in formula (1A), group a
1Be singly-bound.
14, according to each propionyl derivative or its salt of replacement of claim 4-11, wherein, in formula (1A), group a
1For-(NR
4)-, wherein, R
4Identical with aforementioned definitions.
15, according to each propionyl derivative or its salt of replacement of claim 4-11, wherein, in formula (1A), group a
1For-(NR
4)-, wherein, R
4Be hydrogen atom.
16, according to each propionyl derivative or its salt of replacement of claim 4-15, wherein, in formula (1A), group a
4aFor singly-bound or-(NR
10)-, wherein, R
10Identical with aforementioned definitions.
17, according to each propionyl derivative or its salt of replacement of claim 4-15, wherein, in formula (1A), group a
4aBe singly-bound.
18, according to each propionyl derivative or its salt of replacement of claim 4-15, wherein, in formula (1A), group a
4aFor-(NR
10)-, wherein, R
10Identical with aforementioned definitions.
19, according to each propionyl derivative or its salt of replacement of claim 4-15, wherein, in formula (1A), group a
4aFor-(NR
10)-, wherein, R
10Be hydrogen atom.
20, according to propionyl derivative or its salt of the replacement of claim 4, wherein, in formula (1A),
R
14Be hydrogen atom or ester residue,
Q
1aAnd Q
2aIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic,
Q
3aBe hydrogen atom or can esterified carboxyl,
a
1For singly-bound or-(NR
4)-, wherein, R
4It is identical with aforementioned definitions,
R
2Be replacement or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom,
Y
1For-(NR
1)-, wherein, R
1It is identical with aforementioned definitions,
Group-R
8a-a
3a-R
9a-be to replace or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom,
a
4aFor singly-bound or-(NR
10)-, wherein, R
10It is identical with aforementioned definitions,
R
8bHave with to R
6Define identical definition,
a
3bHave with to a
3Define identical definition,
R
9bHave with to R
9Define identical definition,
a
4bHave with to a
4Define identical definition.
21, according to propionyl derivative or its salt of the replacement of claim 4, wherein, in formula (1A),
R
14Be hydrogen atom or ester residue,
Q
1aAnd Q
2aIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic,
Q
3aBe hydrogen atom or can esterified carboxyl,
a
1For singly-bound or-(NR
4)-, wherein, R
4It is identical with aforementioned definitions,
R
2Be replacement or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom,
Y
1For-(NR
1)-, wherein, R
1It is identical with aforementioned definitions,
Group-R
8a-a
3a-R
9a-be to replace or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom,
a
4aFor singly-bound or-(NR
10)-, wherein, R
10It is identical with aforementioned definitions,
Group-R
8b-a
3b-R
9b-a
4bBe singly-bound, replacement or unsubstituted bivalent hydrocarbon radical with 1-12 carbon atom.
22, according to each propionyl derivative or its salt of replacement of claim 1-3, it is represented by following formula (1B):
Wherein
R
15Be hydrogen atom or ester residue, R
16Be hydrogen atom, perhaps replace or unsubstituted alkyl,
Q
2bAnd Q
3bIdentical or different, independently for replacing or unsubstituted cyclic hydrocarbon radical, perhaps replace or unsubstituted heterocyclic and
Y
1, R
2, R
8, R
9, a
1, a
3And a
4Identical with aforementioned definitions.
23, medicine, it comprises each propionyl derivative or its salt of replacement as the claim 1-22 of effective constituent.
24, according to the medicine of claim 23, it can treat and/or prevent hypercholesterolemia, hyperlipoidemia or arteriosclerosis.
25, pharmaceutical composition, it comprises each propionyl derivative or its salt and pharmaceutically acceptable carrier of replacement of claim 1-22.
26, claim 1-22 each the propionyl derivative of replacement or its salt as the purposes of medicine.
27, according to the purposes of claim 26, wherein, medicine can be used for treating and/or preventing hypercholesterolemia, hyperlipoidemia or arteriosclerosis.
28, a kind of treatment hypercholesterolemia, hyperlipoidemia or arteriosclerotic method comprise giving claim 1-22 each propionyl derivative or its salt of replacement.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97181034 CN1241994A (en) | 1996-12-27 | 1997-12-26 | Substituted propionyl derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP350673/96 | 1996-12-27 | ||
| CN 97181034 CN1241994A (en) | 1996-12-27 | 1997-12-26 | Substituted propionyl derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1241994A true CN1241994A (en) | 2000-01-19 |
Family
ID=5178043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97181034 Pending CN1241994A (en) | 1996-12-27 | 1997-12-26 | Substituted propionyl derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1241994A (en) |
-
1997
- 1997-12-26 CN CN 97181034 patent/CN1241994A/en active Pending
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