CN1401621A - Intermediate for preparing tricyclic compound and preparation method of intermediate - Google Patents

Intermediate for preparing tricyclic compound and preparation method of intermediate Download PDF

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CN1401621A
CN1401621A CN02141265A CN02141265A CN1401621A CN 1401621 A CN1401621 A CN 1401621A CN 02141265 A CN02141265 A CN 02141265A CN 02141265 A CN02141265 A CN 02141265A CN 1401621 A CN1401621 A CN 1401621A
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group
formula
compound
alk
benzo
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S·贝尔纳德
D·卡尼尔托
J·F·古尔维斯特
J·G·托伊施
J·克诺勒
H·U·斯蒂尔兹
V·维纳
S·C·伯达赖
T·R·加德克
R·S·麦多维尔
R·M·皮蒂
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Sanofi Aventis France
Genentech Inc
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Hoechst Marion Roussel
Genentech Inc
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    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
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Abstract

The invention discloses compounds of formula and acid and base addition salts and esters thereof, wherein R is1，R2，R3，R4，R5And G is as defined in the specification and the dotted line represents an optional second bond, processes for the preparation of said compounds, intermediates of such processes, the use of said compounds as medicaments and pharmaceutical compositions containing them.

Description

Be used to prepare intermediate and this intermediates preparation of tricyclic compound
The application is that application number is 97194806.2, and the applying date is dividing an application of the identical application for a patent for invention of the denomination of invention on March 20th, 1997 and the application's denomination of invention.
The present invention relates to new tricyclic compound, their preparation method and this method intermediate, they are as the purposes of medicine and the pharmaceutical composition that contains them.
The purpose of this invention is to provide general formula (I) compound and their bronsted lowry acids and bases bronsted lowry additive salt and their ester:
Figure A0214126500111
R wherein 1Representative-C ≡ C-[A]-[B]-COR 6,-CH=CH-[A]-[B]-COR 6,-(CH 2) 2-[A]-[B]-COR 6,-O-[A]-[B]-COR 6,-CH 2CO-[A]-[B]-COR 6Group ,-[A]-representative:
-derived from comprising the bivalent hydrocarbon radical that 1-12 carbon atom and 1-6 are selected from heteroatomic saturated or unsaturated, the straight or branched structure of oxygen, nitrogen or sulphur atom,
-or derived from the divalent group of saturated or unsaturated, the straight or branched acyclic hydrocarbous that comprises 1-12 carbon atom,
[B] represents phenyl, CH[Z] base, or singly-bound,
Z represents hydrogen atom, one of following groups: (D) 0-6-NRaRb, (D) 0-6-NH-SO 2-Rc, (D) 0-6-NH-CO 2-Rc, (D) 0-6-NH-CO-Rc, (D) 0-6-NH-SO 2-NH-Rc, (D) 0-6-NH-CO-NH-Rc, (D) 0-6-CO 2-Rc, (D) 0-6-SO 2-Rc, (D) 0-6-CO-Rc or (D) 0-6-Rc, wherein (D) 0-6Expression is derived from the divalent group of saturated or unsaturated, the straight or branched acyclic hydrocarbous that contains 0-6 carbon atom, Ra, Rb and Rc representative: hydrogen atom; (CH 2) 0-3-Ar base, wherein the Ar representative contains the isocyclic aryl of 6-18 carbon atom; (CH 2) 0-3-Het base, wherein the Het representative is selected from oxygen, the heteroatomic saturated or unsaturated aromatics of nitrogen or sulphur atom or the group of non-aromatic heterocyclic derived from containing 1-9 carbon atom and 1-5; (CH 2) 0-3-Alk base, wherein the Alk representative is derived from the group of the saturated or unsaturated straight chain, side chain or the ring-type non-aromatics that contain 1-12 carbon atom, group Het, Ar and Alk can be for unsubstituted or for replacing, perhaps Ra and Rb can also represent optionally to contain one or more and be selected from oxygen with the nitrogen-atoms that their institutes keys connect, the heteroatomic saturated or unsaturated aromatics of nitrogen or sulphur atom or non-aromatics nitrogen heterocyclic ring, this group can be that replace or unsubstituted.
-R 6Representation hydroxy, O-Alk, O-Ar, NH 2, NH-Alk, N (Alk) 2The amino acid whose remainder of group or L or D, the definition of Alk and Ar is the same, can be for that replace or unsubstituted.
-R 2And R 3Identical or different, and represent hydrogen atom, hydroxyl, O-Alk base or O-(CH 2) 0-3-Ar base, wherein the definition of Alk and Ar as above, perhaps R 2With R 3Formation-O-(CRdRe) together n-O-type ring, wherein n is integer 1-5, Rd and Re independently represent hydrogen atom separately, contain the alkyl of 1-6 carbon atom, or phenyl.
-R 4Represent hydrogen atom, halogen atom, one of following groups: hydroxyl, amino, nitro, cyano group, CF 3, contain the acyl group of 1-12 carbon atom or acyloxy, alkyl, alkenyl, alkynyl, alkylthio, alkoxyl group, alkylamino, dialkyl amido, dialkyl aminoalkyl, dialkyl amido alkoxyl group, wherein the term alkyl contains 1-6 carbon atom.
-R 5Represent hydrogen atom, hydroxyl, halogen atom, O-Alk group or O-(CH 2) 0-3-Ar group, wherein Alk and Ar as above define,
-G representative:
Formula G1 group:
Figure A0214126500121
Wherein Rh is hydrogen atom or (Alk) group as defined above, and the heterocycle of the following general formula of (Het ') representative:
Figure A0214126500122
Wherein (H) forms with the N=C-NH-unit and contains 1-9 carbon atom and 2-5 heteroatomic saturated or undersaturated list that is selected from oxygen, nitrogen and sulphur atom-or the remainder of bicyclic aromatic or non-aromatic heterocyclic, and this group can be that replace or unsubstituted,
-or NRaRb group (group G 2), the definition of Ra and Rb is the same,
-or define the same (Het) group (group G 3),
-or-NRh-C (=X)-and NHRc group (group G 4), wherein X is sulphur or Sauerstoffatom or NH, the definition of Rh and Rc is the same,
-or-NRh-SO 2Rc group (group G 5), wherein the definition of Rh and Rc is the same,
The optional second key of dotted line representative, and
R 1, R 2And R 3Can be positioned on 8,9 or 10 of the trinucleated.
Formula (I) compound refers to all possible single geometrical isomer and steric isomer and their form of mixtures.
Expression derive individual heteroatomic saturated or unsaturated, the straight or branched structure that is selected from oxygen, nitrogen or sulphur atom of a self-contained 1-12 carbon atom and 1-6 divalent group-[A]-group refers to the group derived from paraffinic hydrocarbons especially, wherein some carbon atoms of this paraffinic hydrocarbons are by oxygen or sulphur atom displacement, perhaps replaced: C=O by following groups, SO, SO 2, NH, N (Alk), NH-CO, N (Alk)-CO, CO-NH, CO-N (Alk), SO 2-NH, SO 2-N (Alk), wherein the definition of (Alk) is the same.Therefore, above-mentioned-[A]-group can be following groups :-CH 2-CH 2-O-CH 2-CH 2-,-CH 2-CH 2-N (CH 3)-CH 2-CH 2-,-CH 2-CH 2-C (O)-CH 2-CH 2-,-CH 2-C (O)-C (Me) 2-CH 2-.
When the divalent group of saturated or unsaturated, straight or branched acyclic hydrocarbous of a self-contained 1-12 carbon atom is derived in-[A]-representative, refer to formula-(CH especially 2) n-alkylidene group (wherein n represents the integer of 1-12), as-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-or-CH 2CH 2CH 2CH 2-, or such as-CH=CH-CH 2-or-C ≡ C-CH 2-and so on alkenylene or alkynylene.
When these divalent groups were branched group, they can be such as-CH (CH 3)-,-C (Me) 2,-CH 2-C (Me) 2-,-CH (Et)-,-CH (C ≡ CH)-or-C (C ≡ CH) (Et)-and so on group.
When [B] representative-Ph-divalent group, COR 6Group can be positioned at the neighbour, or contraposition on.Be preferably placed on the contraposition position.
As (D) 0-6Representative is during derived from the divalent group of saturated or unsaturated, the straight or branched acyclic hydrocarbous that contains 0-6 carbon atom, (D) 0-6Be selected from the above group described in [A].(D) 0Be meant that this group does not exist, promptly have covalent single bond again.(D) be preferably singly-bound or (CH 2) nGroup, wherein n is selected from 1,2 or 3 integer.
Work as Ra, Rb and Rc representative (CH 2) 0-3-Ar, (CH 2) 0-3-Het, (CH 2) 0-3During-Alk group, (CH 2) 0-3Represent singly-bound (with regard to (CH 2) 0), or group-CH 2-,-(CH 2) 2-or-(CH 2) 3-.
The term " (Ar) " that representative contains 6-18 carbon atom carbon ring aromatic yl group is meant group such as the phenyl derived from the aromatics cyclic hydrocarbon, naphthyl, phenanthryl, perhaps be group derived from fused bicyclic that contains phenyl ring or tricyclic hydrocarbon, as 2,3-indanyl, indenyl, dihydro naphthyl, tetralyl or fluorenyl.Interface is positioned at the phenyl ring part.Preferred phenyl.
Representative is selected from oxygen derived from containing 1-9 carbon atom and 1-5, and heteroatomic saturated or unsaturated, the aromatics of nitrogen or sulphur atom or the term " (Het) " of non-aromatic heterocyclic group refer to especially:
-monocyclic heterocycles base, for example, following groups: thienyl, furyl, pyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thiazolyl ， oxazolyl, furazan base, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazyl
-annelated heterocycles, for example, benzofuryl, benzothienyl, benzimidazolyl-, benzothiazolyl, naphtho-[2,3-b] thienyl, thianthrenyl, isobenzofuran-base, benzopyranyl, xanthenyl phenoxathiinyl (phenoxathiinyle), indolizine base, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl, 2 base, the naphthyridine base, quinoxalinyl, quinazolyl, the cinnolines base, pteridine radicals, carbazyl, β-Ka Lin base, acridyl, phenazinyl, phenothiazinyl ， phenoxazinyl, indolinyl, iso-dihydro-indole-group, imidazopyridyl, the imidazopyrimidine base perhaps can also be the fused polycycle system of above-mentioned monocyclic heterocycles formation, and for example furo [2,3-b] pyrroles or thieno-[2,3-b] furans
-or saturated heterocyclyl, tetramethyleneimine for example, piperidines, morpholine.
In addition, this term (Het) also comprises the group in above-mentioned (Het ').
Representative is derived from saturated or unsaturated, straight chain, the term of the group of side chain or ring-type non-aromatic hydrocarbon (Alk) is meant alkyl such as methyl, ethyl, propyl group, sec.-propyl under the acyclic hydrocarbous situation, butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl, 2-methyl amyl, 2, the 3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, the 3-ethyl pentyl group, just-octyl group, 2,2-dimethyl hexyl, 3,3-dimethyl hexyl, 3-methyl-3-ethyl pentyl group, nonyl, 2,4-dimethyl heptyl or just-decyl, alkenyl such as vinyl, propenyl, pseudoallyl, allyl group, the 2-methacrylic, butenyl or isobutenyl, or alkynyl such as ethynyl, proyl, propargyl, butynyl or isobutyl alkynyl; Under the cyclic group situation, be meant cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.
When the nitrogen-atoms that connects with their institute's keys as Ra and Rb is represented nitrogen heterocyclic ring, particularly following saturated heterocyclic: morpholine, piperidines, piperazine, tetramethyleneimine, or unsaturated heterocycle such as pyrimidine, pyridine or pyrazine.
Work as R 2, R 3, R 4And R 5When representative contains O-(Alk) group of 1-12 carbon atom, be preferably methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, allyl group oxygen base or alkynes propoxy-.Work as R 2, R 3, R 4And R 5Represent O-(CH 2) 0-3During-Ar base, be preferably benzene oxyethyl group and benzene propoxy-.
Work as R 2And R 3Formation-O-(CRdRe) together n(n is integer 1-5), finger-O-CH especially during-O-type ring 2-O, O-C (Me 2)-O, O-C (Ph 2)-O group.
R 2With R 3Must be in the ortho position relation.
Work as R 6(wherein Alk and Ar are replacement or unsubstituted), particularly one of following groups when representing O-Alk or O-Ar group: (C 1-C 8) alkoxyl group, (C 1-C 14) aryl (C 1-C 8) alkoxyl group, (C 6-C 14) aryloxy, (C 1-C 8) alkyl carboxyl oxygen base, (C 1-C 8) the dialkyl amino carbonyl methoxyl group, (C 6-C 14) aryl, (C 1-C 8) the dialkyl amino carbonyl methoxyl group.
When R6 represent NH-alk, NH (alk) 2Or during the NH-Ar group, one of following groups particularly: (C 1-C 8) alkylamino, two-(C 1-C 8) alkylamino, (C 6-C 14) aryl (C 2-C 8) alkylamino, (C 6-C 14) arylamino.
Work as R 6During the remainder of represented amino acid, it can be L or D amino acid.
L or D amino acid can be for natural or non-natural.They are preferably a-amino acid.For example, Houben-Weyl, The organic chemistry method (Methoden der organischen Chemie), Vol.XV/1 and 2, Georg Thieme Verlag, Stuttgart, the amino acid described in 1974: Aad, Abu, γ Abu, Abz, 2ABz, ∈ Aca, Ach, Acp, Adpd, Anb, Aib, β Aib, Ala, β Ala, Aala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, bLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, β Lys, Δ lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Δ pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, β Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val
Tia, Tle, Tly, Trp, Trta, Tyr, Val, tertiary butyl glycine (Tbg), neo-pentyl glycine (Npg), Cyclohexylglycine (Chg), Cyclohexylalanine (Cha), 2-thienyl alanine (Thia), 2,2-diphenyl amino acetate, 2-(right-tolyl) 2-phenylglycine, 2-(right-chloro-phenyl-) Padil
Perhaps also be
The 2-pyrrolidine acetic acid, 1,2,3,4-tetrahydroisoquinoline-3-acetate, Decahydroisoquinolinpreparation-3-acetate, octahydro isoindole-2-acetate, decahydroquinoline-2-acetate, octahydro cyclopenta [b] pyrroles-2-carboxylic acid, 2-azabicyclic [2,2,2] octane-3-carboxyl acid, 2-azabicyclic [2,2,1] heptane-3-carboxylic acid, 2-azabicyclic [3,1,0] hexane-3-carboxylic acid, 2-azaspiro [4,4] nonane-3-carboxylic acid, 2-azaspiro [4,5] decane-3-carboxylic acid, spiral shell (two rings [2,2,1] heptane)-2,3-tetramethyleneimine-5-carboxylic acid, spiral shell (two rings [2,2,2] 3-tetramethyleneimine-5-carboxylic acid octane)-2,, 2-aza-tricycle [4,3,0,16,9] decane-3-carboxylic acid, decahydro ring heptan is [b] pyrroles-2-carboxylic acid also, decahydro ring suffering is [c] pyrroles-2-carboxylic acid also, octahydro cyclopenta [c] pyrroles-2-carboxylic acid, octahydro isoindole-1-carboxylic acid, 2,3,3a, 4,6a-six hydrogen cyclopenta [b] pyrroles-2-carboxylic acids, 2,3,3a, 4,5,7a-six hydrogen Indoline-2-carboxylic acids, tetrahydro-thiazoles-4-carboxylic acid ， isoxazole alkyl-3-carboxylic acid, pyrazolidine-3-carboxylic acid, hydroxyl pyrrolidine-2-carboxylic acid, if suitable, these groups can be (referring to the following structural) that replaces:
Figure A0214126500171
Above-mentioned heterocycle remainder is known, for example, and referring to following patent or patent application:
US-A-4.344.949; US-A-4.374.847; US-A-4.350.704; EP-A-29.488; EP-A-31.741; EP-A-46.953; EP-A-49.605; EP-A-49.658; EP-A-50.800; EP-A-51.020; EP-A-52.870; EP-A-79.022; EP-A-84.164; EP-A-89.637; EP-A-90.341; EP-A-90.362; EP-A-105.102; EP-A-109.020; EP-A-111.873; EP-A-271,865 and EP-A-344,682.
In addition, amino acid can be ester or acid amides form, for example, and methyl ester, ethyl ester, isopropyl esters, isobutyl, tertiary butyl ester, benzyl ester, buserelin, Urea,amino-or omega-amino acid (C 2-C 8)-alkylamide.
At last, these amino acid whose functional groups can be protected.Suitable protecting group such as urethane protecting group, carboxyl-protecting group or Side chain protective group have been documented in Hubbuch, Kontakte (Merck) 1979, N ° 3, p.14-23 and Bullesbach, Kontakte (Merck) 1980, N ° 1, p.23-25. in.
For example, the protecting group that can mention comprises following: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO 2), Z (Hal n), Bobz, Iboc, Adpoc, Mboc, Acm, the tertiary butyl, Obzl, Onbzl, Ombzl, Bzl, Mob, Pic, Trt.
When G is a formula G1 group:
Figure A0214126500181
(Het ') is following general formula heterocycle:
Figure A0214126500182
Wherein (H) with the N=C-NH-unit form contain 1-9 carbon atom and 2-5 be selected from oxygen, nitrogen or sulphur atom heteroatomic saturated or unsaturated, single-or when bicyclic aromatics or non-aromatic heterocyclic, this group can be that replace or unsubstituted, and G1 especially represents following heterocycle:
Figure A0214126500191
Wherein p represents integer 1-4.
-when G representative-NRaRb group when (being called G2), Ra and Rb can be hydrogen atom, (CH 2) 0-3-Ar, (CH 2) 0-3-Het or (CH 2) 0-3-Alk group.Ar, Het and Alk group can also be defined following group and replace.
G2 is NH particularly 2, NH-Alk group such as NHMe, NHET, N (Alk) 2Group such as NMe 2, NEt 2, NMeEt, NH-(CH 2) 0-1-Ar group such as NHPh, NHCH 2Ph or NHCH 2Het group such as NHCH 2-pyrroles-2-base.
When Ra is a hydrogen atom or (Alk) when group and Rb are for (Het ') group, the availability of visible G1 group again.
When the nitrogen-atoms that connects with their institute's keys as Ra and Rb forms nitrogen heterocyclic ring, heterocyclic radical particularly mentioned above, these groups can be for that replace or unsubstituted.
-when G was (Het) base (group G 3), this group can be for that replace or unsubstituted, particularly above listed heterocycle, general formula particularly mentioned above (Het ') heterocycle.When this heterocycle connects by its nitrogen-atoms position, be also shown in wherein Ra and Rb and form the availability of heterocyclic G2 group with the nitrogen-atoms that is loaded with them.
-when G be-NRh-C (=X)-NHRc base (group G 4), or NRhSO 2During Rc base (group G 5) (wherein X is sulphur or Sauerstoffatom or NH, and the definition of Rh and Rc is the same), be specially one of following groups :-NH-C (=NH)-NH 2,-NH-C (=O)-NH 2Or-NH-C (=S)-NH 2,-NH-C (=NH)-NHCH 2-Ar for example-NH-C (=NH)-NHCH 2Ph ,-NH-C (=NH)-NHCH 2-Het ,-NH-C (=NH)-NHCH 2-Het ' ,-NH-C (=NH)-NH-Alk for example-NH-C (=NH)-NHCH 3, or-NH-SO 2Ph, Ar wherein, Het, Het ' or Alk group are replacement or unsubstituted.
(Alk), (Ar), (Het), (Het ') or the possible substituting group that forms on the heterocyclic NRaRb group are preferably following groups:
-halogen: fluorine, chlorine, bromine, iodine,
-contain alkyl, alkenyl, the alkynyl of 1-12 carbon atom, methyl for example, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, vinyl or allyl group; These groups itself are optional to be replaced by one or more halogen atoms (for example fluorine), trifluoromethyl for example,
-oxo, cyano group, nitro, formyl radical, carboxyl and the carboxyalkyl that contains 1-6 carbon atom, formamido group,
-contain the alkoxyl group such as the methoxyl group of 1-12 carbon atom, oxyethyl group, propoxy-, isopropoxy, butoxy,
-contain the alkylthio of 1-12 carbon atom, as methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, butylthio,
-amino contains the alkylamino of 1-12 carbon atom, and for example methylamino-or ethylamino contain the dialkyl amido of 2-24 carbon atom, dimethylamino for example, and diethylamino, methylethyl amino, these dialkyl amidos may be oxidised form,
-contain the aminoalkyl group of 1-12 carbon atom, for example amino methyl or aminoethyl,
-contain the dialkyl aminoalkyl of 3-25 carbon atom, for example dimethylamino methyl or ethyl,
-contain the dialkyl amido alkoxyl group of 3-25 carbon atom, dimethylamino oxyethyl group for example,
-contain the hydroxyl of the possible acidylate of 1-12 carbon atom, acetoxyl group for example,
-containing 1-12 carbon atom may be by for example acyl group of chlorine, iodine or fluorine atom replacement, for example formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, succinyl, valeryl, benzoyl.Also can mention chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide or trifluoroacetyl group.
-carbocyclic ring or heterocycle heteroaryl be phenyl for example, furyl, and thienyl, pyridyl or aralkyl such as benzyl, these groups itself may be replaced by halogen mentioned above, alkyl, alkoxyl group, alkylthio, aminoalkyl group or dialkyl amido.
Certainly, can there be one or more identical or different substituting groups.Just (Het), substituting group can be positioned on the position of NH group or carbon atom.
These substituting groups have also illustrated R 4Definition.
Should be appreciated that and work as R 1, R 2, R 3, R 4, R 5, R 6, Ra, Rb, when comprising alkyl as indicated above, aryl or heterocyclic radical among the Rc, they are identical or different independently of one another.
Natural expansion of the present invention is to the salt of formula (I) compound, for example, and when formula (I) compound comprises amino or aminoguanidine functional group, the salt that is become with following acid: hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, formic acid, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid, oxalic acid, Glyoxylic acid hydrate, aspartic acid, alkane sulfonic acid such as methane-or ethane sulfonic acid, aromatic hydrocarbons sulfonic acid is benzene-or tosic acid and aryl carboxylic acid for example, perhaps, and when formula (I) when compound contains acid functional group, the salt that is become with basic metal or alkaline-earth metal, the maybe ammonium salt that may replace.
The present invention also expands to the ester of formula (I) compound.
First preferred aspect in, theme of the present invention is the additive salt of above defined general formula corresponding to general formula (I ') (I) compound and bronsted lowry acids and bases bronsted lowry thereof and their ester
Figure A0214126500211
R ' wherein 1Represent one of following groups :-C ≡ C-[A ']-B ']-COR ' 6,-CH=CH-[A ']-[B ']-COR ' 6,-(CH 2) 2-[A ']-[B ']-COR ' 6,-O-[A ']-[B ']-COR ' 6,-CH 2CO-[A ']-[B]-COR ' 6,-[A ']-representative comprises divalent alkyl, alkenylene or the alkynylene of 1-6 carbon atom, [B '] represents CH (Z ') group or singly-bound,
Z ' represents hydrogen atom, one of following groups:
(CH 2) 0-6-NRaRb，(CH 2) 0-6-NH-SO 2-Rc，(CH 2) 0-6-NH-CO 2-Rc，
(CH 2) 0-6-NH-CO-Rc，(CH 2) 0-6-NH-SO 2-NH-Rc，
(CH 2) 0-6-NH-CO-NH-Rc，(CH 2) 0-6-CO 2-Rc，(CH 2) 0-6-SO 2-Rc，
(CH 2) 0-6-CO-Rc or (CH 2) 0-6-Rc, Ra, the definition of Rb and Rc is the same, R ' 6Represent OH, amino or contain 1-8 carbon atom and may be by one or more alkoxyl groups that are selected from the groups replacement of hydroxyl, amino, phenyl, alkylamino or dialkyl amido,
R ' 2And R ' 3Represent hydrogen atom or methoxyl group, and the definition of G is the same, dotted line is represented the second key chosen wantonly.
Second preferred aspect in, theme of the present invention is additive salt and their ester, the wherein R of general formula (I) compound and bronsted lowry acids and bases bronsted lowry thereof as defined above 6Represent one of following groups :-OH ,-OCH 3,-OCH 2CH 3,-O-(CH 2) 2-OH,
Figure A0214126500221
-O-(CH 2) 2-N-(CH 3) 2,-NH 2Or-O-(CH 2)-phenyl.
The 3rd preferred aspect in, theme of the present invention is additive salt and their ester, the wherein R of general formula (I) compound and bronsted lowry acids and bases bronsted lowry thereof as defined above 1Represent O-(CH 2) 0-6CH (Z ')-COOH or-(CH 2) 0-7-CH (Z ')-COOH group.
The 4th preferred aspect in, theme of the present invention is general formula (I) compound and the additive salt of bronsted lowry acids and bases bronsted lowry and their ester as defined above, wherein (Z ') is hydrogen atom.
The 5th preferred aspect in, theme of the present invention is general formula (I) compound and the additive salt of bronsted lowry acids and bases bronsted lowry and their ester as defined above, wherein (Z ') is (CH 2) 0-6-NH-CO 2-Rc or (CH 2) 0-6-NHRb group, and the definition of Rb and Rc is the same.
The 6th preferred aspect in, theme of the present invention is the additive salt and the ester of general formula (I) compound and bronsted lowry acids and bases bronsted lowry thereof as defined above, wherein Rb and Rc representative (CH 2) 0-3-Ar group, the definition of Ar is the same and can be for that replace or unsubstituted.
The 7th preferred aspect in, theme of the present invention is general formula (I) compound and the additive salt of bronsted lowry acids and bases bronsted lowry and their ester as defined above, wherein G be formula-NH-C (=NH)-the G4 group of NHRc, and the definition of Rc is the same.
The 8th preferred aspect in, theme of the present invention is general formula (I) compound and the additive salt of bronsted lowry acids and bases bronsted lowry and their ester as defined above, wherein G be NH-C (=NH)-NH 2The G4 group.
The 9th preferred aspect in, theme of the present invention is general formula (I) compound and the additive salt of bronsted lowry acids and bases bronsted lowry and their ester as defined above, wherein G for as defined above-NH-Het ' group, be in particular:
P is integer 2,3 or 4, and these heterocycles are replacement or unsubstituted.
The tenth preferred aspect in, theme of the present invention is general formula (I) compound and the additive salt of bronsted lowry acids and bases bronsted lowry and their ester as defined above, wherein G is a group:
P is integer 2,3 or 4.
The 11 preferred aspect in, the invention provides following general formula as defined above (I) compound:
-4-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid,
-5-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-valeric acid,
-5-((4-((amino imino methyl) hydrazono-)-8,10-dimethoxy-1,2,3,4,5,6-six hydrogen-9-benzo (e) Azulene base) oxygen base)-valeric acid,
-6-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-caproic acid,
-7-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-enanthic acid,
-5-((9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-8-benzo (e) Azulene base) oxygen base)-valeric acid,
-5-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-Valeric acid ethylester hydrochloride,
-4-((4-((amino imino methyl) hydrazono-)-8,9-dimethoxy-1,2,3,4,5,6-six hydrogen-10-benzo (e) Azulene base) oxygen base)-butyric acid,
-5-((4-((amino imino methyl) hydrazono-)-8,9-dimethoxy-1,2,3,4,5,6-six hydrogen-10-benzo (e) Azulene base) oxygen base)-valeric acid,
-5-((4-(((amino) carbonyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-valeric acid,
-5-((4-(((amino) thiocarbonyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-valeric acid,
-4-((4-((amino imino methyl) hydrazono-)-8,10-dimethoxy-1,2,3,4,5,6-six hydrogen-9-benzo (e) Azulene base) oxygen base)-butyric acid,
-6-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-caproic acid,
-5-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-3,3-dimethyl-4-oxo-valeric acid,
-5-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-3,3-dimethyl-4-oxo-valeric acid,
-5-((4-((amino imino methyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-valerate hydrochlorate,
-4-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid,
-5-((8-((amino imino methyl) hydrazono-)-6,7,8,9,10,11-six hydrogen-Azulene be (5,6-d)-1,3-benzodioxole-4-yl) oxygen base also)-valeric acid,
-5-((8-((amino imino methyl) hydrazono-)-2,2-phenylbenzene-6,7,8,9,10,11-six hydrogen-Azulene be (4,5-e)-(1,3)-benzodioxole-4-yl) oxygen base also)-valeric acid,
-4-((9,10-dimethoxy-4 '-((1,4,5,6-tetrahydrochysene-2-pyrimidyl) hydrazono-)-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid,
-2-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-acetate,
-3-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-propionic acid,
-4-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid,
-4-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid,
-O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo [e] Azulene base]-the N-[(benzyloxy) carbonyl]-the DL-homoserine,
-O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-1,2,3,4,5,6-six hydrogen-8-benzo [e] Azulene base]-the N-[(benzyloxy) carbonyl]-the DL-homoserine,
-O-[4-[(1,2,3,4-tetrahydrochysene-6-pyrimidyl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo [e] Azulene base]-the N-[(benzyloxy) carbonyl]-the DL-homoserine,
-O-(9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(1,4,5,6-tetrahydrochysene 2-pyrimidyl) hydrazono-]]-8-benzo [e] Azulene base] N-[(phenyl methoxyl group) carbonyl] (2, the 3-dihydroxypropyl) ester of DL-homoserine,
-O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-the N-[(8-quinolyl) alkylsulfonyl]-the DL-homoserine,
-O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[[3-[4-(3-pyridyl)-1H-imidazoles-1-yl] propoxy-] carbonyl]-hydrochloride of DL-homoserine,
-5-[[4-[(4,5-4-dihydro-4-oxo-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base] the oxygen base] valeric acid,
-O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(4,5,6,7-tetrahydrochysene-1H-1,3-diaza -2-yl) hydrazono-]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl] the DL-homoserine,
-O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(3a, 4,5,6,7, the hydrazono-of 7a-six hydrogen-1H-benzimidazolyl-2 radicals-yl)]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl] the DL-homoserine,
Theme of the present invention is the preparation method of general formula (I) compound equally, it is characterized in that making formula (II) compound:
Figure A0214126500261
R wherein 2, R 3, R 4And R 5As mentioned above, but be not hydroxyl,
In the presence of alkali, react with formula (F1) compound:
Hal-[A]-[B]-COR 6(F1) or in the presence of phosphine and diethylazodicarboxylate with formula (F ' 1) the compound reaction:
HO-[A]-[B]-COR 6(F ' 1) wherein Hal be halogen atom, [A], [B] and R 6Define the samely, [B] can also represent base
Figure A0214126500262
Wherein P is the amine functional group protecting group,
To obtain formula (IIIa) compound:
Perhaps react with activator earlier, in the presence of catalyzer, react then with formula (F2) compound:
To obtain formula (IIIb) compound:
Figure A0214126500273
Make formula (IIIa) or (IIIb) compound and the reaction of formula (F3) compound subsequently:
H 2N-G?????????????(F3)
Wherein the G definition is the same,
To obtain corresponding to the formula (IVa) of some formula (I) product and (IVb) compound:
Figure A0214126500281
Subsequently, if suitable, make these compounds carry out following reaction with suitable order:
-with alkali or acid-respons with the fracture ester, obtain corresponding acid,
-be suitable for partially or completely reducing R 1The reductive agent of unsaturated link(age) reaction in the group,
-react with the triple bond hydrated agent,
-react with the dealkylation agent,
-when [B] represents the CH-NHP group, with CO-R 6The deprotection agent reaction of the locational NH-P of β functional group,
-by CO-R 6The locational corresponding amine of β form NH-SO 2R C, NH-CO 2R C, NHCOR C, NH-SO 2-NH-R C, NH-CO-NHR CGroup, to obtain corresponding formula (I) compound, if suitable, these compounds can be done in order to obtain corresponding salt with acid or alkali, perhaps do in order to obtain corresponding ester with esterifying agent.
With formula Hal-[A]-[B]-COR 6(F1) reaction of compound is preferably carried out in the non-proton dipole solvent such as dimethyl formamide having in the presence of mineral alkali such as salt of wormwood or the yellow soda ash.Hal is preferably the chlorine or bromine atom.
With formula HO-[A]-[B]-COR 6(F ' 1) be reflected at the phosphine such as triphenyl phosphine and reagent such as diethylazodicarboxylate (DEAD) of compound exist down and carry out in to protonic solvent such as methylene dichloride.
With formula H-C ≡ C-[A]-[B]-COR 6(F2) reaction of compound at first in the presence of alkali such as pyridine with activator suc as formula (CF 3SO 2) 2O trifluoromethanesulfonic acid anhydride reactant is to obtain corresponding formula (OSO 2CF 3) triflate, then at palladium derivative (Pd 0) as Pd (PPh 3) 4Carry out under existing.
With NH 2The reaction of-G (F3) can be carried out under condition of no solvent or in alcoholic solvent such as ethanol or butanols.Synthon (Synthon) NH 2-G is optional to use example hydrochloric acid salt or hydrobromate with salt form.
The saponification reaction of ester functional group is by for example carrying out in tetrahydrofuran (THF) or lower alcohol such as methyl alcohol or ethanol with alkali metal base such as soda or salt of wormwood.The cracking of ester also can be carried out in acidic medium according to method known to those skilled in the art.
The reduction of unsaturated link(age) can be by reducing with the hydrogen effect in the presence of catalyzer such as palladium-charcoal or rhodium catalyst such as Wilkinson reagent fully, perhaps can also by with palladium or the barium sulfate agency part reduction (alkynylene be reduced into alkenylene) of poisoned catalyst as being poisoned by pyridine or triethylamine.
By-C ≡ C-[A]-[B]-COR 6Obtain-CH 2CO-[A]-[B]-COR 6The hydration reaction of group is preferably by being used for carrying out with water in the presence of Mercury bisulfate.
Obtain wherein R 2, R 3, R 4Or R 5The dealkylation of the formula of representation hydroxy (I) compound is reflected under aluminum chloride or the boron tribromide existence and carries out.
COR 6The α position on NH 2([B] represents CH-NH 2Or CH-NH 2, functionalization HCl) carries out according to known standard method in the organic chemistry.
Form NHSO by corresponding amine 2R CReaction preferably by alkali for example in the presence of the triethylamine with R CSO 2Hal is used for carrying out.
Form NHCO by corresponding amine 2R CReaction preferably press described carrying out: at first in the presence of sodium bicarbonate with triphosgene reaction to obtain the intermediate isocyanic ester, then according to Organic chemistry is assorted Will(J.Org.Chem), 61, method of putting down in writing among the 3929-3934 and R CThe OH reaction.
Salt-forming reaction can be carried out under normal condition.For example, be salify R 1Terminal CO 2The H group is operated in the presence of sodium salt such as yellow soda ash or sodium bicarbonate or saleratus.
Equally, the salt-forming reaction of the amine that can represent with G or aminoguanidine and acid is also carried out under normal condition.For example, operate with spirit of salt (for example its ethereal solution).
The optionally esterify of product is reflected under the standard conditions well known by persons skilled in the art and carries out.
Operation is usually by carrying out formula (I) acid or its functional derivatives and the reagent react that can import ester group, the non exhaustive example of the wherein said ester group R that sees above 6Definition described in.
General formula (F1), (F ' 1), (F2), (F3) compound is known or prepares according to method known to those skilled in the art.
The connection order of differential responses reagent can also change.That is to say, formula (II) compound can be reacted with formula F3 compound earlier, to obtain intermediate formula (IIIc) product:
And then with gained formula (IIIc) compound and formula (F1), (F ' 1) or (F2) reaction to obtain corresponding formula (IVa) and (IVb) product.
In this case, be necessary the G group in formula (IIIc) product is protected, adding (F1) then, (F ' 1) or (F2) afterwards again according to well known to a person skilled in the art method deprotection (T.W.Greene Protecting group in the organic synthesis(Protective Group inOrganic Synthesis), John, Wiley and Sons Inc.1991).
CO-R 6The β position on the deprotection reaction of NH-P ([B] represents the CH-NHP group) can also carry out according to the method for well known to a person skilled in the art, particularly represent CO as P 2During the tBu group, can for example be used for carrying out by decarboxylic reaction with hydrochloric acid.
Bone is constantly carrying out comprising the dynamic process of bone resorption and bone forming.These processes mediate by specific cells.Bone forming is the result that scleroblast causes the mineral apposition, and the absorption of bone then is the result that osteoclast dissolves this ground substance of bone.Bone refers to that osteoporosis is characterised in that this ground substance of bone dryness takes off mistake.Activate sophisticated osteoclast after being adhered to ground substance of bone by absorbing sclerotin at adhesion district internal secretion proteolytic ferment and proton, the result forms depression or cave on the surface of bone after osteoclast breaks away from bone.
Formula (I) compound and pharmaceutically acceptable additive salt thereof have useful pharmacological properties.These compounds suppress the bone resorption by the osteoclast mediation.
Therefore, The compounds of this invention can be used for treating ground substance of bone and takes off the disease of becoming homeless and causing, osteoporosis Evil hypercalcemia particularly, the osteopenia that the bone that results from shifts, periodontitis, hyperparathyroidism, corrode around the rheumatic arthritis joint, Paget's disease is because transfixion, glucocorticoid treatment or osteopenia male or that the female sex hormones shortage is brought out.
They also can be used for treating inflammation, cancer and comprise atherosclerosis, and restenosis recurs in interior cardiovascular diseases.
At last, The compounds of this invention also can be used as angiogenesis inhibitor, thereby can be used for treating tumour (by suppressing their neovascularity nucleus formation), diabetic retinopathy and ephrosis.
Research in recent years shows, osteoclast fixing 6 integrin-mediated by acceptor on bone.
Integrin is receptor-mediated cell/cell, especially be the superfamily receptors of cell/matrix adhesion process, particularly including as the α 2b β 3 of platelet receptor (Parenogen) with as the α ν β 3 of Vitronectic receptor, and bone sialoprotein such as osteopontin and thrombospondin.
These heterodimer protein receptors of forming by two kinds of α of subunit and β to divalent ion as Ca particularly 2+Have fixedly site, and to having recognition site by the predetermined part of its subunit's character.
α ν beta 3 receptor is a kind ofly to comprise endotheliocyte at many cells, and smooth muscle cell, osteoclast and cancer cells all have the transmembrane glycoprotein of expression in interior cell, so The compounds of this invention has multiple potential use.
The expression of α ν beta 3 receptor on the osteoclast film is the basis of adhesion/absorption process, helps the group structure of cytoskeleton, and relevant with osteoporosis (Ross etc., Journal of biological chemistry(J.Biol.Chem.), 1987,262,7703).
The expression of α ν beta 3 receptor in arterial smooth muscle cell can stimulate them towards neointima direction migration, so cause forming atherosclerosis and postangioplasty restenosis (Brown etc., Cardiovascular research(Cardiovascular Res.) (1994), 28,1815).
Endotheliocyte secretion somatomedin, they impel endothelium to carry out mitotic division, help to form neovascularity (vasculogenesis).The blood vessel primary stimuli causes neovascularization.Therefore, the antagonist of beta 2 integrin alpha ν β 3 can cause that by the former blood vessel apoptosis of induction of vascular cancer disappears.(Brook etc., Cell(Cell) (1994) 79,1157).
The native ligand of beta 2 integrin alpha ν β 3 all includes RGD unit (Arg-Gly-Asp).Comprise unitary peptide of this RGD and anti-α ν β 3 antibody with its suppress tooth absorb, prevent osteoclast stick on the mineralising matrix ability and known (Horton etc., Experimental cell research(Exp.Cell.Res.) (1991), 195,368).
Separation also contains the RGD unit from the echiststin of snake venom, and this peptide is said to be the inhibitor that osteoclast is adhered to bone, therefore be vitro tissue cultivate (Sato etc., Cytobiology is assorted Will(J.Cell.Biol.) (1990), 111,1713) and living rats (Fisher etc., In Eccrisology (Endocrionlogy) (1993), 132, the 1441) potent inhibitor of bone resorption.
Particularly, the ester of formula (I) compound and pharmaceutically acceptable additive salt thereof and they is by suppressing with their combining of native ligand Vitronectic receptor α ν β 3 or containing vitronectin as part (α ν β 1, α ν β 5, α 2b β 3) other integrin has affinity.
Therefore, this character makes The compounds of this invention can be used for prevention or treatment some diseases, and the pathologic basis of these diseases is by can be with due to interactional part of Vitronectic receptor or the cell.
These compounds are also to having activity by other integrin of RGD tripeptide sequence and its ligand interaction.Make The compounds of this invention have like this to can be used for and treat pharmacological properties with these receptor related pathology illnesss.
Therefore, this activity to integrin makes The compounds of this invention be suitable for treating multiple disease, for example above or magazine Dermot Cox DN﹠amp; 8 (4) Mays nineteen ninety-five of P, the illness described in the 197-205 (this article in fit among the application).
Therefore, theme of the present invention provides formula (I) compound and pharmaceutically acceptable additive salt and its ester as medicine.
In medicine of the present invention, it is worth mentioning the described compound of experimental section especially.
In these products, theme of the present invention is particularly as medicine, above listed formula (I) compound.
Dosage is according to subject illness, route of administration and changing: for example, oral administration dosage can be 1mg-1000mg/ days concerning the adult.
The present invention also expands to as activeconstituents, contains a kind of pharmaceutical composition of medicine mentioned above at least.
Formula (I) compound can be by digestion, and parenteral or local approach (for example through the skin approach) use.They can be mixed with simple or the sweet tablet tablet, capsule, and granule, suppository, vaginal suppository, injection, ointment, creme, gelifying agent, microspheres agent is received globule, migration agent, the patch agent, they are all according to routine recurrence preparation.
One or more activeconstituentss can with together fusion of normally used vehicle in these pharmaceutical compositions, described vehicle such as talcum, gum arabic, lactose, starch, Magnesium Stearate, Oleum Cocois, moisture or first water vehicle, animal or plant source fatty substance, paraffin derivative, glycol, various wetting agents, dispersion agent or emulsifying agent, sanitas.
Hydroxyl is positioned on the position 10 in the formula (II), and is positioned at the R on the position 8 2With the R that is positioned on the position 9 3Represent O-(Alk) or O-(CH 2) 0-3-Ar group, R 4With R 5The compound that is hydrogen atom is according to european patent application N ° 0729933 and the hereinafter preparation of method described in the experimental section (preparation example 2).
Two kinds of other positional isomerss can prepare in the following manner:
Make formula (IIA) compound:
Figure A0214126500331
With dealkylation agent reaction, to obtain formula (IIB) compound:
Make formula (IIB) compound subsequently:
Perhaps in alkaline medium, react with the glycerol protection agent, so that selectivity obtains formula (IIC) compound:
Figure A0214126500333
Wherein P represents the remainder of glycerol protection agent,
Then make this compound successively with the deprotection agent reaction of deprotection agent, alkylating agent and the phenol of phenol protective material, glycol, to obtain formula (IID) compound, promptly OH is positioned at three replacement formula (II) compounds on 8:
Figure A0214126500341
Perhaps react with phenol protective material, alkylating agent and deprotection agent successively, to obtain formula (IIE) compound, promptly OH is positioned at three replacement formula (II) compounds on 9:
The dealkylation agent preferably refers to the reagent such as boron tribromide or aluminum chloride.
The glycerol protection agent of reacting with formula (IIB) product can be boron derivative such as boric acid, and trialkyl borate (for example trimethyl borate or triethyl) perhaps can also be borax.
The phenol protective material specifically refers to halogenide, as methylsulfonyl chlorine or bromine or tolylsulfonyl chlorine or bromine, perhaps also refers to henzylate derivative such as toluenesulphonic acids benzyl ester or methylsulfonic acid benzyl ester.
The glycol deprotection agent specifically refers to the strong acid example hydrochloric acid, and sulfuric acid or tosic acid under the situation with the boron derivative protection, perhaps also have oxygenant, for example hydrogen peroxide.
Alkylating agent is meant the well known by persons skilled in the art any standard reagent that is used for the alkylating phenol compounds.That for example, can mention comprises alkylogen such as methyl or ethyl chloride, alkyl sodium sulfate ester such as sulfuric acid methyl or ethyl ester, or diazomethane.
Deprotection agent is meant such as soda, the alkali of salt of wormwood or yellow soda ash or salt of wormwood and so on.
R in the formula (II) 2, R 3, R 4And R 5Single substitution product of representing hydrogen atom is according to the similar approach preparation described in the european patent application N ° 0729933:
(i) make formula (a) compound:
Figure A0214126500351
Wherein O-(Alk) be positioned at alkyl carboxyl between or contraposition, definition (Alk) is the same,
With halogenating agent reaction, obtaining corresponding acyl halide,
(ii) with gained acyl halide and formula (b) reagent react:
Wherein the identical or different and representative of R (I) and R (II) contains the alkyl of 1-6 carbon atom, and perhaps R (I) and R (II) represent to choose wantonly with the nitrogen-atoms of their keys companies of institute and contain another and be selected from O and heteroatomic 5 or 6 yuan of saturated or unsaturated heterocycles of N,
To obtain formula (c) compound:
Figure A0214126500353
(iii) make the reaction of gained formula (c) compound and halogenating agent, obtain formula (d) compound:
Figure A0214126500361
Hal wherein 1Represent halogen atom,
(iv), obtain formula (e) compound with gained formula (d) compound and Lewis acid reaction:
(v) with gained formula (e) compound and dealkylation agent reaction, to obtain formula (IIF) product, i.e. the single substitution product of Yu Qi formula (II):
Figure A0214126500363
R wherein 2Represent O-(Alk) or O-(CH 2) 0-3-Ar, R 3, R 4And R 5Be hydrogen atom and OH, and R 2The two substitution products of formula (II) that are positioned on 8,9 or 10 can be the initial substance preparation with formula (a ') compound according to method mentioned above:
Wherein O-(Alk) and R 2Be positioned at alkyl carboxyl between or in the contraposition, R 2For O-(Alk) or-(CH 2) 0-3-Ar group.Above-mentioned initial substance is reacted (i) successively, (ii), (iii), (iv) and (v), finally obtain formula (IIG) product, i.e. the two substitution products of Yu Qi formula (II):
Figure A0214126500372
Be for example thionyl chloride with the halogenating agent of formula (a) or (a ') compound reaction, oxalyl chloride or for preparing well known to those skilled in the art any other reagent that acyl halide is used.
Formula (b) reagent is by cyclopentanone and secondary amine (for example diethylamine, piperidines, piperazine or and preferred morpholine) preparation.Operate under strong acid catalyst (for example tosic acid) existence and carry out.
The reaction of formula (b) enamine and acyl halide is preferably carried out in the presence of tertiary amine such as triethylamine or pyridine.
The halogenating agent that replaces the equivalent reaction with formula (c) compound or its formula (c ') two can be for example thionyl chloride, phosgene, phosphoryl chloride or (preferably) oxalyl chloride.
The Lewis acid that is used for cyclisation formula (d) compound or its formula (d ') two replacement equivalents is for example aluminum chloride, titanium tetrachloride, or preferred iron(ic) chloride, or tin tetrachloride.As previous reaction, this reaction also can for example have halogenated solvent (for example methylene dichloride, chloroform or ethylene dichloride) to carry out under existing.
Being used for dealkylation formula (e) compound or its formula (e ') two replaces equivalents and is preferably aluminum chloride or boron tribromide with the reagent that obtains corresponding phenolic compound.
R wherein 4Not for the formula of hydrogen atom (II) product according to well known to a person skilled in the art that fragrance parent electricity and nucleophilic substitution standard method prepare.
R wherein 5Formula (II) product that is not hydrogen atom is according to method known to those skilled in the art, and particularly the method preparation described in the european patent application N ° 0729933 is promptly carried out halogenating reaction earlier, subsequently with water and suitable alcohol reaction.
R wherein 5For existing formula (II) product of two keys between hydrogen atom and position 1-2 according to well known to a person skilled in the art method, the particularly preparation of the method described in the european patent application N ° 0729933 promptly prepares by dewatering in the anhydrous acidic medium or taking off oxyalkylation.
Wherein the junction between the ring at the ring at 5 places, position and 7 places, position be saturated formula (II) product can according to the standard method for hydrogenation particularly in the presence of palladium-charcoal the corresponding two keys of hydrogenation prepare.
R 4, R 5Importing and hydrogenation preferably at formula (IIA), (IID), (IIE), (IIF) or (IIG) carry out on the compound.
Wherein be in the R of ortho position relation 2And R 3Form as mentioned above-O-(CRdRe) nFormula (II) product of-O type ring also can be according to well known to a person skilled in the art method, the particularly hereinafter described method preparation of experimental section.
Theme of the present invention also relates to the formula (IIIa) as intermediate product, (IIIb), (IIIc) and (II) product, certainly, formula (IIc) compound and following compounds are excluded:
-2,3,5,6-tetrahydrochysene-9,10-dimethoxy-8-hydroxyl-benzo [e] Azulene-4 (1H)-ketone,
With
2,3,5,6-tetrahydrochysene-8,9-dimethoxy-10-hydroxyl-benzo [e] Azulene-4 (1H)-ketone.
The preparation of these two compounds experimental section that sees below.
The following example is used to illustrate the present invention, but the present invention is not limited thereto.
Preparation example 1: 2,3,5,6-tetrahydrochysene-8,9,10-trihydroxy--benzo [e]-Azulene-4 (1H)-ketone
Steps A: 3,4,5-trimethoxy-phenylpropionic acid
Get 6.8g salt of wormwood and be added to 21.44g 3,4, in the solution of 5-trimethoxyphenyl vinylformic acid and 45ml water, contained in the presence of the gac of 10% palladium under 1200-1300 millibar pressure hydrogenation 1 hour at 1.8g then, absorb 2.1l hydrogen.Filtering reacting medium, that continues washes with water, and with 50ml hydrochloric acid (2N) acidifying.After the separation, residue is washed with water, then drying under reduced pressure at room temperature.Obtain 19.8g expection product (M.P.=102-103 ℃) like this.
IR spectrum (CHCl 3)
Carbonyl: { 1712cm -1(max) fragrant skeleton: { 1592cm -1
{1740cm -1(sh)???????????????{1510cm -1
NMR spectrum (CDCl 3)
‖
2,69(t)}＝C-CH 2-CH 2-CO???3,83(s)}3H 3CO-C-
2,91(t)}????????????????3,85(s)}
6.43 (s) fragrant proton 2H
10.50 (m) the proton 1H of reactivity
Step B: 3,4,5-trimethoxy-phenylpropyl alcohol acyl chlorides
With the solution of 6g steps A products therefrom in 21ml methylene dichloride 1.5g dried over mgso, after the filtration, reaction mixture to 5 ℃ adds the 2.2ml thionyl chloride, at room temperature stirs gained solution then 20 hours.Reduction vaporization continues to carry twice secretly with hexanaphthene to doing, and collects 6.46g expection product like this.(M.P.＝60℃)。
Step C: 2-[3-(3,4, the 5-trimethoxyphenyl)-1-oxopropyl]-cyclopentanone
Under+5 ℃, in 1 hour 30 minutes introversive be cooled to 5 ℃ comprise 2.4ml 1-(N-morpholinyl) cyclopentenes (its preparation sees below described), add the solution of 4.27g step B products therefrom in the 15ml methylene dichloride in the solution of 2.31ml triethylamine and 15ml methylene dichloride.In+5 ℃ of following stirring reaction media 1 hour, in the temperature reaction medium, add 10ml 2N hydrochloric acid then, then stirred at ambient temperature 1 hour, decantation, water and saturated solution of sodium bicarbonate wash successively, drying, filtering also, reduction vaporization obtains 5g expection product to doing.This crude product is pressed described mode purifying: be dissolved in 10 volumes of acetic acid ethyl esters, extract with the N soda solution, alkali is acidified to pH1 with concentrated hydrochloric acid then with the ethyl acetate washing, and that continues use dichloromethane extraction, and dry and reduction vaporization is to dried.Collect the 2.75g purified product.
IR spectrum (CHCl 3):
Carbonyl: { 1741cm -1Aromatics skeleton: { 1592cm -1
{1709cm -1??????????????????????????{1509cm -1
Carbonyl: { 1658cm -1
+ C=C {～1610cm -1The OH that comprises chelated forms
NMR spectrum (CDCl 3)
6.41 (s) fragrant proton, 2H (integration baseline)
3.81 (s) 3.82 (s) } common 9H
3.83 (s) 3.85 (s) } 4 types of CH 3O-C=
1.86(m)CH 2-CH 2-CH 2～1.5H
1.95-2,95 (m) altogether～7.5H, comprise a few types=C-CH 2
3.26(t)～0.40???CO-CH-CH 2
|
CO
The H of (11.2 m is wide) reactivity
The preparation of used 1-(N-morpholinyl)-cyclopentenes among the step C
With 100ml hexanaphthene, 20ml cyclopentanone, 50ml morpholine and 100mg right-solution that toluenesulphonic acids constitutes stirred under reflux state 4 hours 30 minutes, removed formed water simultaneously.After the solvent evaporated under reduced pressure, under 12-13 millibar pressure, distill, collect the required product of 27.44g (B.P.=83 ℃).
Step D: 1-(2-chloro-1-cyclopentenes-1-yl)-3-(3,4, the 5-trimethoxyphenyl) third-1-ketone
Under the room temperature, in the solution of 23g step C products therefrom and the formation of 230ml chloroform, add the 13ml oxalyl chloride.Reaction mixture at room temperature stirred 3 hours, concentrating under reduced pressure then, and continue to carry secretly twice with hexanaphthene.Obtain the 28g crude product.Then in 50ml hexanaphthene and 50ml di-isopropyl ether mixture after partial concentration the above-mentioned crude product of recrystallization.Separate out crystallization,, obtain 16.24g expection product behind the drying under reduced pressure with the diisopropyl ether washing.(M.P.＝93℃)。
IR spectrum (CHCl 3):
1659cm -1: carbonyl
1599cm -1
1586cm -1: C=C+ fragrance skeleton
1508cm -1
NMR spectrum CDCl 3
1.93 (m): center C H 2
(m)-2.81 2.69 (m): the C-CH of cyclopentenes 2-C=proton
2.85 (t, and J=7.5)-3.08 (t, J=7.5): all the other=C-CH 2-C proton
2.44：CH 3-C＝
3.68-3.81: all OCH 3Proton
6.59-6.68 (d, j=2): the fragrant CH=that a digit pair is closed
7.31-7.80 (d, j=8): fragrant proton
Step e: 2,3,5,6-tetrahydrochysene-8,9,10-trimethoxy-benzo [e] Azulene-4 (1H)-ketone
With 900mg step D products therefrom, 9ml 1,2-ethylene dichloride and 0.9ml tin chloride at room temperature together stirred 20 hours.Add the 9ml frozen water then, decantation mixture, and washing with water, and then once with dichloromethane extraction, that continues uses dried over mgso, filter and reduction vaporization to doing, obtain 1g expection (rough) product.By silica gel chromatography purifying gained crude product, adopt the hexanaphthene wash-out that contains 10% and 25% ethyl acetate successively.After concentrating, collect the 700mg product, crystallization in the 5ml normal hexane then is cooled to 0 ℃, separates, and with a small amount of normal hexane washing, drying under reduced pressure at room temperature then obtains 630mg and expects product.
(M.P.＝101-102℃)。
NMR spectrum (CDCl 3):
1.86 (m) center C H 2
2.65(dd)2H}????????????????????????????3.84}
2.72 (t) all the other CH of 2H} 2Proton 3.86}OMe proton
2.84(dd)2H}????????????????????????????3.90}
3.06??2H}
6.59 (s) fragrant H
Step F: 2,3,5,6-tetrahydrochysene-8,9,10-trihydroxy--benzo [e] Azulene-4 (1H)-ketone
As described in the step B of preparation example 1a, operate the demethylation product that obtains expecting.
Preparation example 1a: 2,3,5,6-tetrahydrochysene-8,9,10-trihydroxy--benzo [e] Azulene-4 (1H)-ketone
Steps A: 2,3,5,6-tetrahydrochysene-8,9,10-trimethoxy-benzo [e] Azulene-4 (1H)-ketone
With the product of 60g preparation example 2 gained, 600ml 1, the 2-ethylene dichloride, and 342ml 2N soda, 1.2g Tetrabutyl amonium bromide and 33ml methyl-sulfate stirred under 20 ℃ 2 hours 30 minutes together.Add the methyl-sulfate of 39ml triethylamine then, and stirred 1 hour down at 20 ℃ ± 2 ℃ with decomposing excessive.Add the 342ml softening water subsequently, stirred 15 minutes down at 20 ℃+2 ℃ again, decantation then, with water with 1, (2 * 120ml) extractions of 2-ethylene dichloride.Merge 1,2-ethylene dichloride phase is used 4 * 240ml softening water, 1 * 300ml N hydrochloric acid, 3 * 240ml softening water washing (till for neutrality) successively.The organic phase dried over sodium sulfate that merges, filtration also is concentrated into the 480ml resid vol at 83 ℃ of following normal pressures.
Step B: 2,3,5,6-tetrahydrochysene-8,9,10-trihydroxy--benzo [e] Azulene-4 (1H)-ketone
With the 480ml solution of gained in the step (A) with 102.3g Aluminum chloride anhydrous reflux 1 hour.Heat-eliminating medium to 0 ℃ ± 2 ℃ added in 2 hours then and is cooled to about 0 ℃ 600ml softening water and 192ml bright sulfur acid (dense) mixture in advance, during keep the reaction medium temperature to be lower than 20 ℃.Under 20 ℃ ± 2 ℃, in 5 minutes, add the 300ml softening water, and stirred 16 hours down at 20 ℃ ± 2 ℃, the separation that continues, with 1,2-ethylene dichloride washed twice, each 60ml, then with the softening water washing, drying under reduced pressure obtains 52.2g expection product.
Preparation example 2: 8,9-dimethoxy-10-hydroxyl-2,3,5,6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone
Steps A: 3,4-dimethoxy-5-[[(4-aminomethyl phenyl)-alkylsulfonyl] the oxygen base]-phenylpropionic acid
As described in preparation example 1 steps A; adopt 29.76g 3; 4-dimethoxy-5-[[[(4-aminomethyl phenyl)-and alkylsulfonyl] the oxygen base] phenyl]-styracin (its preparation sees below described), 43.5g salt of wormwood, 60ml methyl alcohol and 1.48g gac (containing 10% palladium) are operated.Obtain 28.33g expection product, be colourless crystallization (M.P.=48-149 ℃).
UV spectrum (EtOH)
For M=380.4
max?226nm?????ε＝22100
infl?263nm????ε＝2000
infl?269nm????ε＝2400
max?274nm?????ε＝2800
infl?279nm????ε＝2500
infl?307nm????ε＝450
NMR spectrum (CDCl 3)
2,45(s)CH 3-
2,61(m)＝C-CH 2-CH 2-C＝?????3,68(s)2CH 3O-C＝
2,86(m)??????????????????????3,81(s)
6,61(d，j＝2)????????????????7,32(dl)H 3?H 5
6,65(d，j＝2)H 4?H 6?????????7,80(dl)H 2?H 6
Step B: 3,4-dimethoxy-5-[[(4-aminomethyl phenyl)-alkylsulfonyl] the oxygen base]-the phenylpropyl alcohol carboxylic acid halides
As described in preparation example 1 step B, with 1.9g steps A products therefrom, 9.5ml methylene dichloride and 0.7ml thionyl chloride are operated.Obtain 2.2.4g expection product, this product is directly used in the next step.
Step C: 2-[3-[3,4-dimethoxy-5-[[(4-p-methoxy-phenyl) alkylsulfonyl] the oxygen base] phenyl]-the 1-oxopropyl]-cyclopentanone
As described in preparation example 1 step C, be starting raw material with the acyl chlorides of 2.24g step B gained, and use 770mg 1-(N-morpholinyl)-cyclopentenes (made among the preparation example 1 step C) that 6ml methylene dichloride and 0.77ml triethylamine are operated.After with the diisopropyl ether recrystallization, obtain 1.27g expection product (M.p.=84 ℃).
IR spectrum (CHCl 3)
Carbonyl: { 1742cm -1O-SO 3{ 1374cm -1
{1709cm -1??1178cm -1??1658cm -1
C=C+ fragrance skeleton { 1608cm -11599cm -11586cm -11508cm -1
NMR spectrum (CDCl 3)
2.44(s)??CH 3-O
3.67(s)?????????}2OCH 3
3.79(s)??3.81(s)}
6.59-6.65 (m) fragrant 2H (ortho position of O)
7.32(wd)??H 3??H 5
7.89(wd)??H 2??H 6
(13.58 wide m) enol form OH
1.8-3.4 (m) other proton of 10-11H
UV spectrum
1-EtOH (+diox) is for M=446.52
max?225nm????ε＝23000
max?282nm????ε＝7900
infl?270，277，290，300，313nm
2-EtOH(0.1N?NaOH)
mzx?310nm????ε＝21600
infl268，272，276nm
Step D: 1-(2-chloro-1-cyclopentenes-1-yl)-3-[3,4-dimethoxy-5-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base]-phenyl]-third-1-ketone
As described in preparation example 1 step D, adopt 8.7g step C products therefrom, 70ml chloroform and 3.5ml oxalyl chloride are operated.After the diisopropyl ether crystallization, obtain 7.75g expection product (M.P.=73 ℃).This product is directly used in the next step.
By with 2.5 volumes methylene chloride and 5 volume diisopropyl ether recrystallizations, that continues is concentrated to 3 volumes, separate, with the diisopropyl ether washing and at room temperature drying under reduced pressure obtain analytic sample (M.P.=77-78 ℃).
IR spectrum (CHCl 3)
Carbonyl: { 1659cm -1
Fragrance C=C:{1599cm -1-1586cm -1-1508cm -1
UV spectrum (EtOH)
max?227nm??????ε＝26100
infl?248nm?????ε＝12800
infl?272nm?????ε＝5300
infl?280nm?????ε＝3200
infl?320nm
NMR spectrum (CDCl 3)
1.93 (m) center-C-CH 2-C-}
2.69(m)}C-CH 2-C＝?????}
2.81(m)}????????????}
2.85 (t, J=7.5) } remaining=C-CH 2-C proton
3.08(t，J＝7.5)}
2.44?CH 3-C＝
3.68}OCH 3Proton
3.81}
6.59 (d, J=2) fragrant CH
6.68 (d, J=2) between digit pair close
7.31(d，J＝8)}
7.80(d，J＝8)}
Step e: 8,9-dimethoxy-10-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base]-2,3,5,6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone
Under the room temperature,, add 1.65g 98% iron(ic) chloride in the 2-dichloroethane solution at the 50ml 1 of 2.32g step C products therefrom.Mixture at room temperature stirred 48 hours, and in the impouring mixture of ice and water, vigorous stirring 15 minutes is used dichloromethane extraction then then.Extracting solution water and saturated aqueous sodium chloride are washed successively.Drying and reduction vaporization obtain the 2.15g crude product, silica gel column chromatography after extremely doing, with the hexanaphthene wash-out that contains 50% ethyl acetate, collect the 1.8g product,, obtain 720mg expection product (M.P.=138 ℃) they chromatographies and with chloroform/diisopropyl ether mixture recrystallization once more.
IR spectrum (CHCl 3)
Carbonyl: { 1650cm -1
{1599cm -1
C＝C+???{1556cm -1
Fragrance skeleton { 1512cm -1-1498cm -1
UV spectrum (EtOH)
max?230nm?????ε＝25300
infl?254nm????ε＝9400
max?323nm?????ε＝10300
NMR spectrum (CDCl 3)
～1.61 (m) are center C H (2H) 2
～2.41?Ph-CH 3
～2.50-2.80????CH 2-C＝
|
3.88 (s) } OCH 3Proton
3.90(s)}
6.74?H4
7.21(d)}C-Ph-SO 2
7.64(d)}
Step F: 8,9-dimethoxy-10-hydroxyl-2,3,5,6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone
With step e products therefrom above the 350g, 1750ml methyl alcohol, the mixture heating up of the pure caustic soda lye of 350ml softening water and 350ml (concentrating) refluxed 2 hours.The cooling reaction medium added the 467ml concentrated hydrochloric acid then to about 2 ℃ ± 2 ℃ in 45 minutes, during to keep temperature be 2 ℃ ± 2 ℃.In 10 minutes, add the 1645ml softening water subsequently, and holding temperature is 2 ℃ ± 2 ℃.Separate out formed crystallization, clarify washing 5 times with the 700ml softening water down at every turn, then at 40 ℃ of following drying under reduced pressure, to obtain 199.1g expection product at 20 ℃.
3 of preparation example 2 beginning uses, 4-dimethoxy-5-[[(4-aminomethyl phenyl) alkylsulfonyl] The oxygen base]-system of styracinBe equipped with
Steps A: 3,4-dimethoxy-5-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base] methyl benzoate
In room temperature and under stirring, in the mixture of 10 minutes inherent 200g gallic acid methyl esters and 2 liters of methylene dichloride, add the 303ml triethylamine.After the dissolving, the cooling reaction medium added the 130ml dichlorodimethylsilane under this temperature in 1 hour, then further stirred 30 minutes under this temperature then to 0-5 ℃.Under keeping 0-5 ℃, in 25 minutes, add the 303.2ml triethylamine, in 15 minutes, add the 227.6g toluene sulfonyl chloride then.Continue down to stir 1 hour at 0-5 ℃, under agitation in 10 minutes, add 200ml acetate then earlier, add the 500ml softening water then, during temperature rise to 20-22 ℃, and 20 ℃ of continuous down stirrings 15 minutes.Decompression is steamed with constant volume (3.3l) down and is removed methylene dichloride; and substitute them with softening water; stirred 2 hours down at 20 ℃; separate then; wash with softening water; obtain 523g (Wen Chong) 3,4-dihydroxyl-5[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base] methyl benzoate (3-tosyl group Methylgallate).The gained damp product is dissolved in 2.17l soda (2N) and the 2.17l methylene dichloride.Be stirred to dissolving at 20 ℃, add the 18g Tetrabutyl amonium bromide down at 20 ℃ then, in 15 minutes, adding the 237ml methyl-sulfate under 20 ℃ more subsequently.Reaction medium stirred 1.5 hours down at 20-22 ℃.Adding the 78ml triethylamine under 20-22 ℃ and stirring under 20-22 ℃ and spend the night, the decantation that continues is also used the washing of 400ml softening water.Add the pure acetate of 20ml in organic phase, the stirring that continues 15 minutes adds the 400ml softening water, thereafter decantation.At first under normal pressure, concentrate, then the organic phase that concentrating under reduced pressure merges under 40mmHg under 60 ℃ of outside temperatures as for.Carry secretly with 400ml methyl alcohol, the no water extract with gained is dissolved in 600ml methyl alcohol then, and reflux to product dissolves fully, and that continues is cooled to 0-5 ℃, stirs 1 hour under this temperature.After the separation ,-10 ℃ of following washed twice, at 40 ℃ of following drying under reduced pressure, obtain 330.4g 3 then, 4-dimethoxy-5-[[(4-aminomethyl phenyl with 200ml methyl alcohol) alkylsulfonyl] the oxygen base] methyl benzoate.With this crude product 330ml toluene recrystallization.After stirring 2 hours under-10 ℃, to separate, the usefulness 82ml toluene wash twice that continues is cooled to-15 ℃, then at 40 ℃ of following drying under reduced pressure, obtains the pure expection product of 230.3g.
Step B: 3,4-dimethoxy-5-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base] styracin
A) 600ml toluene is cooled to 0 ℃, adds 202ml70%Vitride down at 0 ℃ then Toluene solution, and in 1 hour, adding the 67.6ml morpholine under 0-2 ℃, temperature rises to 18 ℃.The solution that so obtains is used for next step at once.
B) alkylsulfonyl with 3 of gained in the 200g steps A, 4-dimethoxy-5-[[(4-aminomethyl phenyl)] the oxygen base] methyl benzoate and 1400ml toluene stirs 10 minutes till the dissolving fully together at 20-22 ℃.The reagent solution of gained in 1 hour, add under 10 ℃.The continuous stirring 1 hour, temperature rises to 18 ℃.Be pre-cooling to 10 ℃ the 200ml vitriol oil and the solution of 1000ml softening water adding in little in 1 under 10 ℃.Stirred 16 hours at 20 ℃, decantation organic phase then, with the washing of 5 * 200ml softening water, drying, filtration and with 3 * 100ml washed with dichloromethane.The intermediate aldehydes solution that so obtains is directly used in the next step.
C) the intermediate aldehydes solution that will obtain above, 200ml 2-picoline, 120g propanedioic acid and 20ml piperidines heat 16 hours (removing methylene dichloride simultaneously under normal pressure) together under 70 ℃ ± 2 ℃.The cooling reaction medium is keeping under this temperature to 20-22 ℃, adds 200ml concentrated hydrochloric acid and 400ml soften aqueous solution in 15 minutes.After 2 hours, be cooled to 0 ℃ 20-22 ℃ of stirring, separate out formed crystallization,, and, obtain 171.7g expection product 3,4-dimethoxy-5-[[(4-aminomethyl phenyl at 40 ℃ of following drying under reduced pressure with the softening water washing) alkylsulfonyl] the oxygen base]-styracin.
Preparation example 3: 9,10-dimethoxy-8-hydroxyl-2,3,5,6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone
Steps A: 9,10-dihydroxyl-8-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base]-2,3,5,6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone
With 30g according to preparation example 1 or 1a make 2,3,5,6-tetrahydrochysene-8,9,10-trihydroxy--benzo [e] Azulene-4 (1H)-ketone, 300ml tetrahydrofuran (THF), 60ml triethylamine and 12.9ml trimethyl borate stirred 1 hour 30 minutes down at 20 ℃ ± 2 ℃ together.Adding 30g toluene sulfonyl chloride also stirred 16 hours under 20 ℃ ± 2 ℃, stirred 10 minutes at 20 ℃ ± 2 ℃ then, reaction medium is poured in the mixture of the 900ml softening water that stirring and 159ml concentrated hydrochloric acid, adds 90ml tetrahydrofuran (THF) and 60ml methylene dichloride then.Stirred gained solution 1 hour at 20 ℃, add the 150ml methylene dichloride then, and continue to stir 15 minutes, the decantation that continues extracts with 2 * 75ml methylene dichloride again.The organic phase that merges is also extracted with the 75ml methylene dichloride with 4 * 150ml softening water washing, decantation again, is evaporated to when being distilled to 50 ℃ to stop under 20 millibars of pressure, obtains 47.6g expection product.
Step B: 9,10-dimethoxy-8-[[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base]-2,3,5,6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone
47.6g is gone up the step products therefrom, the 300ml methylene dichloride, 300ml soda (2N), 0.6g Tetrabutyl amonium bromide and 30ml methyl-sulfate stirred under 20 ℃ 16 hours together.Add the methyl-sulfate of 30ml triethylamine with decomposing excessive then, further stirring reaction medium is 1 hour under 20 ℃ ± 2 ℃, adds the 150ml softening water then, continues to stir 15 minutes, subsequently decantation.Water extracts with 2 * 75ml methylene dichloride again, the organic phase that merges is used 3 * 120ml softening water and 120ml N hydrochloric acid and the washing of 3 * 120ml softening water successively, merge organic phase and use dried over sodium sulfate, then at 20 ℃ ± 2 ℃ and stir adding 120g silica gel (60 order) in 1 hour down, and 20 ℃ of further down stirrings 1 hour, then filter, with washed with dichloromethane and be evaporated to driedly at 50 ℃, obtain 47.4g expection product.This crude product is by with 390ml ethyl alcohol recrystallization purifying, distill out 90ml ethanol after, stirred 3 hours down at 0 ℃ ± 2 ℃.Make it dry, 0 ℃ of washing down,, obtain 41.1g expection product (M.P.=129 ℃) then at 40 ℃ of drying under reduced pressure with 30ml ethanol.
Step C: 9,10-dimethoxy-8-hydroxyl-2,3,5,6-tetrahydro benzo [e] Azulene-4 (1H)-ketone
To containing 9 of 10g step B gained, 10-dimethoxy-8-(((4-aminomethyl phenyl) alkylsulfonyl) oxygen base)-2,3,5 adds 4.5g salt of wormwood and 10ml triethylamine successively in the suspension of 6-tetrahydrochysene-benzo [e] Azulene-4 (1H)-ketone and 100ml methyl alcohol.Heating reflux reaction medium 1 hour adds the acidifying of 20ml acetate, adds 20ml water then.Extract with methylene dichloride, the washing extracting solution removes solvent under reduced pressure under 40 ℃, obtains 5.7g expection product.
Preparation example 4: 2,3,5,6-tetrahydrochysene-8-hydroxyl-9-methoxyl group-benzo [e] Azulene-4 (1H)-ketone and 2,3,5,6-tetrahydrochysene-9-hydroxyl-8-methoxyl group-benzo [e] Azulene-4 (1H)-ketone
Operate in the mode that is equal to preparation example 2 step B, C, D, E and F, but adopt 3-(3,4-dimethoxy-phenyl) propionic acid is a starting raw material, obtain the crude product that 1.08g comprises monohydroxylated product mixtures (8-OH/9-OMe and 9-OH/8-OMe), it is separated by silica gel chromatography, use cyclohexane/ethyl acetate mixture (7/3) to be eluent.Thereby obtain following two kinds of positional isomerss:
8-OH/9-OMe 0.494g Rf (cyclohexane/ethyl acetate 6/4)=0.42
8-OMe/9-OH 0.041g Rg (cyclohexane/ethyl acetate 6/4)=0.33
Preparation example 5: 2,3,5,6-tetrahydrochysene-8-hydroxyl-10-methoxyl group-benzo [e] Azulene-4 (1H)-ketone and 2,3,5,6-tetrahydrochysene-10-hydroxyl-8-methoxyl group-benzo [e] Azulene-4 (1H)-ketone
Operate in the mode that is equal to preparation example 2 step B, C, D, E and F, but adopt 3-(3, the 5-Dimethoxyphenyl) propionic acid is a starting raw material, obtain the mixture that 1.428g comprises monohydroxylated product (8-OH/10-OMe and 10-OH/8-OMe) and dihydroxy product (8-OH/10-OH), separate by silica gel chromatography then, use cyclohexane/ethyl acetate mixture (7/3) wash-out.
Preparation example 6: 2,3,5,6-tetrahydrochysene-9-hydroxyl-benzo [e] Azulene-4 (1H)-ketone
Operating in the mode that is equal to preparation example 2 step B, C, D, E and F, is starting raw material but adopt 3-(4-p-methoxy-phenyl) propionic acid, obtains 0.448g expection product.Adopt boron tribromide to carry out demethylating reaction subsequently.
(Rf=0.15 cyclohexane/ethyl acetate 7/3).
Preparation example 7: 2,3,5,6-tetrahydrochysene-8-hydroxyl-benzo [e] Azulene-4 (1H)-ketone
Operating in the mode that is equal to preparation example 2 step B, C, D, E and F, is starting raw material but adopt 10.0g 3-(3-p-methoxy-phenyl) propionic acid.Obtain 2.9g expection product.Adopt boron tribromide to carry out demethylating reaction subsequently.
(Rf=0.15 dichloromethane/ethyl acetate 95/5).
Preparation example 8: (DL)-4-bromo-2-(phenyl methoxycarbonyl amino) methyl-butyrate
The 200ml acetic acid solution of 25g 2-amino-4-butyrolactam hydrobromate was stirred under 120 ℃ 18 hours in sealed vessel with 24% gaseous hydrogen bromic acid.The cooling reaction medium arrives room temperature, and returns to atmospheric pressure environment, then concentrating under reduced pressure.Residue is dissolved in 200ml methyl alcohol, logical then spirit of salt air-flow 2 hours, during keep temperature to be lower than 35 ℃.Remove solvent under reduced pressure, and the 2-amino-4-bromo-butyric acid methyl esters that obtains is dissolved in 250ml acetone and the 100ml water again, subsequently this solution is neutralized with 2N soda, slowly add the 35ml chloroformic acid benzyl ester then.Stirred 48 hours, ethyl acetate extraction is used in the filtration that continues, and removes solvent under reduced pressure, and residue is by silica gel column chromatography (eluent: hexanaphthene-ethyl acetate 7-3), reclaim 27.9g expection product.M.P.＝90℃。
Preparation example 9: 4-bromo-2-(tert-butoxycarbonyl amino) methyl-butyrate
2-amino-4-bromo-butyric acid methyl esters of getting 8 preparations of 5.7g preparation example stirred 48 hours under 24ml triethylamine and 9g tert-Butyl dicarbonate room temperature in 120ml methyl alcohol.Steaming desolventizes, the water-soluble and methylene dichloride with residue, and dichloromethane extraction is used in the filtration that continues, steams once more to desolventize, and silica gel column chromatography gained residue (eluent: pimelinketone-ACOEt-TEA 7-3-0.5), obtain 1.575g expection product, Rf=0.52.
Preparation example 10: 4-(3-pyrimidyl)-1H-imidazoles-1-propyl alcohol
The 505mg sodium ethylate is mixed in the 12.5ml dimethyl formamide, add 1g3-(1H-imidazol-4 yl) pyrimidine and 0.64ml propylene chlorohydrin then successively, and stirred 16 hours down at 55 ℃.Remove solvent subsequently under reduced pressure, and chromatography gained residue (eluent: CH 2Cl 2-MeOH 98-2), reclaim 1.015g expection product.
IR spectrum (CHCl 3)
OH 3626cm -1+ association peak
Heterocycle 1601,1578,1551,1499cm -1
Preparation example 11: six hydrogen-2H-1,3-diaza -2-ketone hydrazone
To comprise the 3.3g nitroguanidine, 7ml water, the suspension of 3.47g salt of wormwood and 5g diamines dihydrochloride heated 1 hour down at 65-70 ℃; Add 10.5g zinc, at room temperature stirred then 30 minutes, add 2ml acetate subsequently, in 40 ℃ of heating total overall reaction things 1 hour, the filtration that continues added 3g ammonium chloride and 4g sodium bicarbonate then successively again.Extract with methylene dichloride, remove solvent under reduced pressure, and by silica gel column chromatography gained residue (eluent: CH 2Cl 2-MeOH-NH 4OH 8-4-2), reclaim 1.650g expection product.
Preparation example 12: 3a, 4,5,6,7,7a-six hydrogen-2-(rosickyite base)-1H-benzoglyoxaline one hydrobromate
The reflux dissolving extremely fully in 20ml ethanol with 1g octahydro-2H-benzimidazolyl-2 radicals-thioketones and 1.3ml N-PROPYLE BROMIDE.Remove solvent under reduced pressure, and residue is dissolved in a small amount of methylene dichloride.Add isopropyl ether then, remove solvent once more under reduced pressure, and in isopropyl ether recrystallization, make dehydration, and in addition dry (yield 95%).
M.P.＝136℃。
Embodiment 1: 7-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene be (e) Azulene-8-yl also) oxygen base)-enanthic acid
Steps A7-(4-oxo)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene be (e) Azulene-8-yl also) the oxygen base)-Methylheptanoate
To contain 0.684g 2,, 3,5,6-tetrahydrochysene-8-hydroxyl-9,10-dimethoxy-benzo [e] Azulene-4 (1H)-ketone (preparation example 3), 12ml dimethyl formamide (DMF), 12ml tetrahydrofuran (THF) (THF), the suspension of 0.7g salt of wormwood and 0.835g 7-bromine Methylheptanoate stirred 4 hours down at 40 ℃.After the reduction vaporization,, use methylene dichloride (CH by silica gel column chromatography gained crude product 2Cl 2)/acetone mixture (95/5) wash-out.Obtain the 1.000g refined products, be yellow oil.
Rf CH 2Cl 2/ acetone 95/5:0.5
IR(CHCl 3)
C＝O??1732cm -1
0Me???1438cm -1
Conjugation ketone 1641cm -1
C＝C??1592cm -1，1557cm -1，1492cm -1
+ fragrant skeleton
Step B: 7-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-benzo (e) Azulene-8-yl) oxygen base)-Methylheptanoate
The suspension that will contain the rapid A product of 0.5g previous step, 5ml ethanol and 0.330g aminoguanidine monohydrochloride at room temperature stirred 48 hours, removed solvent under reduced pressure, and the gained crude product by the silica gel chromatography purifying, is used CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide mixture (80/20/4) wash-out.Thereby obtain the 0.466g purified product, be the white foam form.
Rf CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide 80/20/4:0.8
IR(Nujol)
NH/NH 23495cm -1, 3155cm -1+ association peak
C＝O??1731cm -1
C＝N??1674cm -1
C＝C??1625cm -1
Fragrance skeleton: 1595cm -1(F)
NH/NH 2?1534cm -1，1491cm -1
Step C: 7-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene be (e) Azulene-8-yl also) oxygen base)-enanthic acid
The solution that will contain 0.44g previous step products therefrom, 5ml ethanol and 2ml 1N soda at room temperature stirred 3 hours, then with the neutralization of 2ml 1N hydrochloric acid.Behind the reduction vaporization, the gained crude product by the silica gel chromatography purifying, is used CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide mixture (80/20/4) wash-out.Obtain the refining product of 0.192g with recrystallizing methanol.
Rf CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide 80/20/4:0.17
NMR (D 2O+1 drips 1N soda)
3.92wt?2H???C H 2-O
2.17t?2H????C H 2-COOH
134m?4H
1.55m 2H center C H 2+ CH 2-C=
1.70m?4H
2.50-2.90m?8H
6.62s 1H fragrance H 7
3.64s，3H?OC H 3
3.73s?3H??OC H 3
Trace analysis
% calculated value C 62.86 H 7.47 N 12.21
% measured value C 62.9 H 7.5 N 12.1
In the mode that is equal to embodiment 1 steps A, B and C, adopt 2,3,5,6-tetrahydrochysene-8-hydroxyl-9,10-dimethoxy benzo [e] Azulene-4 (1H)-ketone (preparation example 3) and different alkylating agent and G-NH 2Operate for starting raw material, prepare following formula (I) product:
Embodiment 2: 4-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene be (e) Azulene-8-yl also) oxygen base) butyric acid
Embodiment 3: 4-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene be (e) Azulene-8-yl also) oxygen base) valeric acid
Embodiment 4: 5-((4-(((amino) carbonyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base) valeric acid
Embodiment 5: 6-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base) caproic acid
Embodiment 6: oxygen base 5-(9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-8-benzo (e) Azulene base))-valeric acid
Embodiment 7: 5-((4-(((amino) thiocarbonyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base) valeric acid
Embodiment 8: 6-(4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-caproic acid
Embodiment 9: 5-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-3,3-dimethyl-4-oxopentanoie acid
Embodiment 10: 5-(4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-3,3-dimethyl-4-oxopentanoie acid
Embodiment 11: 4-(4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid
Embodiment 12: 4-((9,10-dimethoxy-4 '-((1,4,5,6-tetrahydrochysene-2-pyrimidyl) hydrazono-)-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid
Embodiment 13: 2-(4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-acetate
Embodiment 14: 3-(4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-propionic acid
(1) methylene chloride/ammonia 80/20/4
Embodiment 15: 5-((4-(((amino) iminomethyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenzene be (e) Azulene-8-yl also) oxygen base) valerate hydrochlorate
Get 86mg embodiment 3 products and 2ml water and 4l 0.1N mixed in hydrochloric acid, after several minutes, the freeze-drying medium obtains 91mg expection salt.
Embodiment 16: 4-((4-(((amino) iminomethyl) hydrazono-)-8,9-dimethoxy-1,2,3,4,5,6-six hydrogen-10-benzo (e) Azulene base) oxygen base) butyric acid
Embodiment 17: 5-((4-(((amino) iminomethyl) hydrazono-)-8,9-dimethoxy-1,2,3,4,5,6-six hydrogen-10-benzo (e) Azulene base) oxygen base) valeric acid
As embodiment 1 steps A, B and C are described to be operated, but with 2,3,5,6-tetrahydrochysene-10-hydroxyl-8,9-dimethoxy-benzo [e] Azulene-4-(1H)-ketone (preparation example 2) is a starting material.
Embodiment Starting material Alkylate G-NH 2 Note
16 (II) A Br-(CH 2) 3-CO 2Et H 2N-NH-C(＝NH)-NH 2.HCl 0,07
17 (II) A Br-(CH 2) 4-CO 2Et H 2N-NH-C(＝NH)-NH 2.HCl 0,07
Embodiment 18: 4-((4-(((amino) iminomethyl) hydrazono-)-8,10-dimethoxy-1,2,3,4,5,6-six hydrogen-9-benzo (e) Azulene base) oxygen base) butyric acid
Embodiment 19: 5-((4-(((amino) iminomethyl) hydrazono-)-8,10-dimethoxy-1,2,3,4,5,6-six hydrogen-9-benzo (e) Azulene base) oxygen base) valeric acid
As embodiment 1 steps A, B and C are described to be operated, but with 2,3,5,6-tetrahydrochysene-9-hydroxyl-8,10-dimethoxy-benzo [e] Azulene-4-(1H)-ketone is starting material.
Embodiment Starting material Alkylate ?G-NH 2 Note
18 (II) E1 ?Br-(CH 2) 3-CO 2Et ?H 2N-NH-C(＝NH)-NH 2.HCl 0,10
19 (II) E1 ?Br-(CH 2) 4-CO 2Et ?H 2N-NH-C(＝NH)-NH 2.HCl 0,07
Embodiment 20: 4-((4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-1,2,3,4,5,6-six hydrogen-9-benzo (e) Azulene base) oxygen base)-butyric acid
Steps A: 4-(4-oxo)-1,2,3,4,5, the 6-hexahydrobenzene is (e) Azulene-9-yl also) the oxygen base)-butyric acid
To contain 0.6g 2,3,5,6-tetrahydrochysene-9-hydroxyl-benzo [e] Azulene-4 (1H)-ketone (preparation example 6), 12ml dimethyl formamide (DMF), 12ml tetrahydrofuran (THF) (THF), the suspension of 0.7g salt of wormwood and 0.7ml bromo-butyric acid ethyl ester at room temperature stirs and spends the night.Behind the reduction vaporization, silica gel column chromatography gained crude product uses dichloromethane mixture (methylene dichloride/acetone 95/5) wash-out.Obtain the 0.608mg purified product like this, be the yellow oil form.
IR(CHCl 3)
C＝O???????1728cm -1
Conjugation ketone 1641cm -1
Fragrance C=C 1610cm -1, 1590cm -1, 1569cm -1, 1449cm -1
Step B: 4-((4-((4,5-dihydro-1H-tetrahydroglyoxaline-2-yl) hydrazono-)-1,2,3,4,5, the 6-hexahydrobenzene is (e) Azulene-9-yl also) oxygen base)-ethyl butyrate
Product with 608mg above-mentioned steps A, the following cyclic amino guanidine of 10ml butanols and 600mg hydrobromate: (4,5-dihydro-1H-tetrahydroglyoxaline-2-yl)-hydrazine, together stirring and refluxing is 24 hours, remove solvent under reduced pressure, and with the gained crude product by the silica gel chromatography purifying, with methylene chloride (MeOH)/ammonium hydroxide mixture (80/20/4) wash-out.Obtain 0.604g expection product.
IR(CHCl 3)
＝C-NH-????3451cm -1
C=O 1728cm -1(ester)
C=N+C=C+ aromatic base: 1627cm -1(F), 1568cm -1, 1548cm -1, 1497cm -1, 1488cm -1
Step C: 7-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-1,2,3,4,5, the 6-hexahydrobenzene is (e) Azulene-9-yl also) the oxygen base)-butyric acid
To contain 0.604g back product, 8ml ethanol, the solution of 5ml tetrahydrofuran (THF) and 2ml 2N soda at room temperature stirred 4 hours, added the neutralization of 2ml hydrochloric acid then.Behind the reduction vaporization, crude product by the silica gel chromatography purifying, is used methylene dichloride (CH 2Cl 2)/methyl alcohol (MeOH)/ammonium hydroxide mixture (80/20/4) wash-out.Obtain the purified product of 0.298g with recrystallizing methanol.
Rf (methylene chloride/ammonium hydroxide 80/20/4): 0.2
NMR (D 2O+1 drips 1N soda)
1.71(w)2H??????O-CH 2-C H 2-CH 2-CO
1.96 (m) CH of 2H position 2 (cyclopentenes) 2
2.30(t)2H??????CH 2-CO
2.50-2.75?8H???C H 2-C＝
3.45(ws)4H?????C H 2-N＝
3.89(wt)2H???????Ph-O-C H 2-C
6.70 (m) 2H H 10And H 8
7.00(d，J＝8)????H 7
Embodiment 21: 4-(4-((4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base) oxygen base)-butyric acid
Operation is carried out as described in embodiment 20, but with 0.856g 2,3,5,6-tetrahydrochysene-8-hydroxyl-benzo [e] Azulene-4 (1H)-ketone (preparation example 7) is starting raw material, obtains 0.299g expection product.
Rf (methylene chloride/ammonium hydroxide 80/20/4): 0.27
Embodiment 22: 5-((8-(((amino) iminomethyl) hydrazono-)-6,7,8,9,10,11-six hydrogen-Azulene be (5,6-d)-1,3-benzodioxole-4-yl) oxygen base also)-valeric acid
Steps A: 5-(((4-oxo)-9,10-dihydroxyl-1,2,3,4,5,6-six hydrogen-benzo (e) Azulene-9-yl) oxygen base) Valeric acid ethylester
1) protection
Under the inert atmosphere, at 10g 2,3,5, add 4.42ml trimethoxy boric acid ester and 20.4ml triethylamine in the 6-tetrahydrochysene-8,9, the 100ml tetrahydrofuran solution of 10-trihydroxy--benzo [e] Azulene-4 (1H)-ketone (preparation example 1), maintain the temperature at during this time between 37-39 ℃, then stirred reaction mixture 3 hours at room temperature.
2) alkylation and deprotection
Then, add 9.7ml 5-bromine Valeric acid ethylester, 100ml dimethyl formamide and 8.4g salt of wormwood, and under 60 ℃, stirred 2 days.Add 120ml water and 50ml 36N concentrated hydrochloric acid reaction mixture then, restir 1 hour adds ethyl acetate then, separates organic phase and water.With the after scouring organic phase, dry and reduction vaporization.The gained crude product is by the silica gel chromatography purifying, with cyclohexane/ethyl acetate mixture (70/30) wash-out.Obtain 5.2g expection clean product.
Rf (methylene chloride 95/5)=0.82
Rf (cyclohexane/ethyl acetate 70/30)=0.23
Step B: 5-(((8-oxo)-6,7,8,9,10,11-six hydrogen Azulene be (5,6-d)-1,3-benzodioxole-4-yl) oxygen base also))-Valeric acid ethylester
Under 60 ℃, with 2.5g previous step product, the 17ml dimethyl formamide, 3.6g CsF and 1.4ml methylene bromide together mixed under inert atmosphere 1 hour.After filtration and the washed with methanol, carry out reduction vaporization, and the gained crude product is passed through the silica gel chromatography purifying, with cyclohexane/ethyl acetate mixture (85/15) wash-out.Obtain 1.73g expection clean product.
(M.P.＝118℃)
Rf (cyclohexane/ethyl acetate 80/20)=0.25
Step C: 5-((8-((amino) iminomethyl) hydrazono-)-6,7,8,9,10,11-six hydrogen-Azulene be (5,6-d)-1,3-benzodioxole-4-yl) oxygen base also)-Valeric acid ethylester
551mg is gone up step products therefrom and 467mg aminoguanidine monohydrochloride together mix at 120 ℃ and spend the night, carry out chromatogram purification then, with methylene chloride/ammonium hydroxide mixture (80/20/4) wash-out.Obtain 174mg expection product.
Rf (methylene chloride/ammonium hydroxide 80/20/4) 0.98
Step D: 5-((8-(((amino) iminomethyl) hydrazono-)-6,7,8,9,10,11-six hydrogen-Azulene be (5,6-d)-1,3-benzodioxole-4-yl) oxygen base also) valeric acid
274mg is upward gone on foot products therefrom and 1.86ml 1N soda solution at room temperature together mixed 1 hour 30 minutes, use 1N hydrochloric acid soln neutralise mixt then, and reduction vaporization.Crude product is by chromatogram purification, with methylene chloride/ammonium hydroxide mixture (80/20/4) wash-out.Obtain 141mg expection product.
Rf (methylene chloride/ammonium hydroxide 80/20/4) 0.23
NMR(DMSO)
1.55-1.9(m)??4H??????????O-CH 2-C H 2-C H 2-CH 2-CO
1.55-1.9 (m) CH of 2H position 2 (cyclopentenes) 2
2.26(t)??2H??????????????C H 2-CO
2.65-3.00(m)??8H?????????C H 2-C＝
4.07(t)??2H??????????????O-C H 2-CH 2-
5.95(s)??2H??????????????-O-C H 2-O
6.61(m)??1H??????????????H 8
Active H (m, wide) NH-C (=NH)-NH 2
Embodiment 23: 5-((8-(((amino) iminomethyl) hydrazono-)-2,2-phenylbenzene-6,7,8,9,10,11-six hydrogen-Azulene be (4,5-e)-1,3-benzodioxole-4-yl) oxygen base also)-valeric acid
As above an embodiment is described operates, but is starting raw material with last embodiment steps A products therefrom of 374mg and 0.19ml phenylbenzene methylene dichloride.Obtain 198mg expection product.
Rf (methylene chloride/ammonium hydroxide 80/20/4)=0.17
Embodiment 24: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the DL-homoserine
Steps A: the O-[(4-oxo)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-DL-homoserine methyl esters
Under the room temperature, with 0.6g 2,3,5,6-tetrahydrochysene-8-hydroxyl-9,10-dimethoxy-benzo [e] Azulene-4 (1H)-ketone (preparation example 3), 10ml dimethyl formamide (DMF), the 10ml tetrahydrofuran (THF), 1g salt of wormwood and 0.867g stir together and spend the night as (DL)-4-bromo-2-(the phenyl methoxycarbonyl amino) methyl-butyrate that makes as described in the preparation example 8.After the reduction vaporization, the silica gel column chromatography crude product is with methylene dichloride (CH 2Cl 2)/acetone mixture (95/5) wash-out.Obtain the 1.166g refined products thus, be yellow oil.
IR(CHCl 3)
C＝O?1740cm -1(sh.)，1721cm -1
Conjugation ketone 1642cm -1
Fragrance C=C 1593cm -1, 1559cm -1, 1508cm -1, 1493cm -1
Step B: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)--9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-DL-homoserine methyl esters
With 539mg steps A product, the following cyclic amino guanidine of 15ml butanols and 600mg hydrobromate: (4,5-dihydro-1H-imidazoles-2-yl)-hydrazine, under 120 ℃, stirred together 24 hours, remove solvent then under reduced pressure, and crude product is passed through the silica gel chromatography purifying, use CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide mixture (80/20/4) wash-out.Obtain 0.641g expection product thus.
IR(CHCl 3)
=C-NH-3451cm -1+ association peak
C＝O?????1740cm -1(sh.)，1720cm -1(max)
C=N+C=C+ fragrance skeleton+acid amides II:1667cm -1(F), 1606cm -1, 1508cm -1, 1490cm -1.
Step C: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the DL-homoserine
The solution that will contain 0.6g previous step products therefrom, 10ml ethanol and 2ml 2N soda at room temperature stirred 2 hours, then with the neutralization of 2ml hydrochloric acid.After the reduction vaporization, crude product by the silica gel chromatography purifying, is used CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide mixture (80/20/4) wash-out.After with recrystallizing methanol, obtain the 0.349g refined products like this.
Rf CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide 80/20/4:0.37
Embodiment 25: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-)-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the DL-homoserine
Operate by the method that is equal to embodiment 24, but wherein use 0.428g 2,3,5,6-tetrahydrochysene-9-hydroxyl-benzo [e] Azulene-4 (1H)-ketone (preparation example 7) is starting raw material.Obtain 245mg expection product.
Rf CH 2Cl 2/ methyl alcohol (MeOH)/ammonium hydroxide 80/20/4:0.5
Embodiment 26: O-[4-[(1,2,3,4-tetrahydrochysene-6-pyrimidyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the DL-homoserine
Steps A: O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(1,4,5,6-tetrahydrochysene-2-pyrimidyl) hydrazono-]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-hydrobromate of DL-homoserine methyl esters
As described in embodiment 24 step B, be that raw material is operated with 200mg as the solution and 74.5mg tetrahydrochysene-2 (1H)-pyrimidone hydrazone one hydrobromate of product in the 2ml butanols that obtains as described in embodiment 24 steps A, and reflux 16 hours.Make reaction medium return to room temperature subsequently, extract with methylene dichloride, dry extraction liquid removes solvent then under reduced pressure, obtains 152mg expection product.
Step B: O-[4-[(1,2,3,4-tetrahydrochysene-6-pyrimidyl) hydrazono-)-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the DL-homoserine
As described in embodiment 24 step C, the solution of steps A products therefrom in 1.3ml ethanol and 0.43ml N soda is operated above the employing 131mg.Add N hydrochloric acid neutralization reaction medium, steaming desolventizes then.After filtration with drying after, obtain 78mg expection product.M.P.＝172℃。
NMR spectrum (CDCl 3)
1.90 (m) CH of (2H) position 9 2
2.03 (m) center C H 2
2.36(m)(2H)
2.60-3.00 (8H)=C-CH 2Proton
3.48 (wm) (4H)=N-CH 2Proton
3.77 (s) 3.78 (s) (9H)=the C-OMe proton
4.01(m)(1H)4.17?????Φ-O-CH 2
4.67(p)???????????????-C-CH-N-C＝
514(ws)???????????????COO-CH 2-Φ
6.13(d)???????????????＝C-NH-CH
6.49(ws)??????????????H 4
≈7.36(m)(5H)?????????Φ-C
Embodiment 27: O-(9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(1,4,5,6-tetrahydrochysene-2-pyrimidyl] hydrazono-]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-DL-homoserine (2, the 3-dihydroxypropyl) ester
Steps A: O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(1,4,5,6-tetrahydrochysene-2-pyrimidyl) hydrazono-]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-DL-homoserine [(2,2-dimethyl-1,3-dioxolane-4-yl) methyl] ester
0.3g is cooled to 0 ℃ as solution, 96mg 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and the 68mg I-hydroxybenzotriazole hydrate of product in 1ml dimethyl formamide and 1ml methylene dichloride that makes as described in the embodiment 26.Stirred the mixture under the room temperature 30 minutes, and added 0.06ml solketal, and continue to stir 3 hours 30 minutes.The thin up reaction medium extracts with methylene dichloride, and the 0.6g crude product of gained is carried out silica gel chromatography purifying (eluent: CHCl 2-MeOH 90-10) reclaims.Obtain 0.352g expection product.
IR spectrum (CHCl 3)
NH??????????????????3400cm -1
C＝O????????????????1745(sh)，1719cm -1
C＝N，C＝C??????????}
The fragrance skeleton, acid amides II} 1672 (F), 1645,1597,1565 (f), 1507,1492cm -1
Step B: O-(9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(1,4,5,6-tetrahydrochysene-2-pyrimidyl) hydrazono-]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-DL-homoserine (2, the 3-dihydroxypropyl) ester
0.320g steps A products therefrom was stirred 6 hours under room temperature in 3ml ethanol and 1ml 2N hydrochloric acid.Behind the evaporating solvent, carry out silica gel column chromatography (eluent: CH 2Cl 2-MeOH-NH 4OH80-20-4), obtain 0.112g expection product.
NMR spectrum (CDCl 3)
1.88(m)(2H)???????????}
1.98 center C H 2CH with position 9 2
2.36??????????????????}
2.60-3.10(8H)?????????＝C-CH 2
3.43(m)(4H)???????????＝N-N-CH 2
3.79(s)???????????????}
3.81??????????????????}Φ-OMe
3.60-3.90?????????????O-CH 2-CH-O
≈4.00-4.30???????????}COO-CH 2-CH
}Φ-O-CH 2-CH 2
4.64(m)(1H)???????????＝C-CH-N-C＝
5.13(s)???????????????COO-CH 2-Φ
6.53(s)???????????????H 4
7.20-7.38 Φ-C proton
Embodiment 28: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-the N-[(8-quinolyl) alkylsulfonyl]-the DL-homoserine
Steps A: O-(9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-oxo-8-benzo (e) Azulene base)-N-[(1,1-dimethyl oxyethyl group) carbonyl]-DL-homoserine methyl esters
With 4.1g by the preparation example 3 described products that make and 5g by the preparation example 9 described products that make in 50ml dimethyl formamide and 50ml tetrahydrofuran (THF), exist down in 5g salt of wormwood and Dimethylamino pyridine, at room temperature stirred 65 hours.Remove solvent then under reduced pressure, residue is by silica gel chromatography purifying (eluent: CH 2Cl 2-acetone 95-5), obtain 7.3g expection product.
IR spectrum (CDCl 3)
＝C-NH???????????3430cm -1
C=O 1744cm -1(methyl esters)
1710cm -1(NH-BOC)
1648cm -1(conjugation ketone)
Fragrance skeleton+acid amides II 1593,1559,1493cm -1
Step B: a hydrochloride of O-(9,10-dimethoxy-1,2,3,4,5,6-tetrahydrochysene-4-oxo-8-benzo (e) Azulene base)-DL-homoserine methyl esters
The ethyl acetate solution of 10ml spirit of salt is added in the 10ml ethyl acetate solution of the made product of 6g steps A in three batches, at room temperature stirred then 16 hours.Remove solvent under reduced pressure, obtain 0.656g expection product, this product is directly used in the next step.
Step C: alkylsulfonyl O-(9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-oxo-8-benzo (e) Azulene base)-N-[(8-quinolyl)]-the DL-homoserine
The 0.656g product of gained of last step is dissolved in the 5ml methylene dichloride, adds 1ml triethylamine and 0.638g 8-chlorosulfonyl quinoline, and at room temperature stirred 2 hours.After the solvent evaporated under reduced pressure, carry out silica gel column chromatography (eluent: CHCl 2-MeOH 95-5), obtain 0.956g expection product.
Step D: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-the N-[(8-quinolyl) alkylsulfonyl]-DL-homoserine methyl esters
With the product of 0.9g previous step A, the following cyclic amino guanidine of 5ml butanols and 0.6g hydrobromate: (4,5-dihydro-1H-imidazoles-2-yl) hydrazine, stirred 16 hours at 120 ℃ together, remove solvent then under reduced pressure, obtain 0.786g expection product, this product is directly used in the next step.
Step e: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-the N-[(8-quinolyl) alkylsulfonyl]-the DL-homoserine
To contain the rapid products therefrom of 0.786g previous step, the solution of 5ml methyl alcohol and 2ml 2N soda at room temperature stirred 2 hours, added the neutralization of 2ml 2N hydrochloric acid then, and continued to stir 10 minutes.Behind the reduction vaporization, the gained crude product by the silica gel chromatography purifying, is used CH 2Cl 2-methanol-hydrogen ammonium oxide mixture (80-20-4) wash-out.After recrystallizing methanol, obtaining 0.438g expection product.
Rf＝0.40(CH 2Cl 2-MeOH-NH 4OH?80-20-4)。
NMR spectrum (DMSO):
1.81 (ws) CH of position 9 2
2.40-3.20=C-CH 2Proton
3.35 (w)=N-CH 2Proton,
3.55 (ws)=the C-OMe proton
6.63(ws)??????????????????????H 4
7.58(dd)??????????????????????H′ 3
7.67(t)???????????????????????H′ 6
8.19 (d), 8.29 (d) H ' 5And H ' 7
8.45(d)???????????????????????H 4
8.90(d)???????????????????????H 2
7.31(ws)?????????????}
7.97 active H
10.40(f)?????????????}
12.62????????}
Embodiment 29: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[[3-[4-(3-pyridyl)-1H-imidazoles-1-yl] propoxy-] carbonyl]-hydrochloride of DL-homoserine
Steps A: 4-[[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-oxo-8-benzo (e) Azulene base] the oxygen base]-2-isocyanato methyl-butyrate
Under 0 ℃, the amine of 450mg embodiment 28 step B gained was stirred 10 minutes in 10.2ml saturated solution of sodium bicarbonate and 10.2ml methylene dichloride.Add the 2ml dichloromethane solution of 204mg triphosgene then in the organic phase of reaction medium, stirred 10 minutes, use dichloromethane extraction then, dry extraction liquid removes solvent under reduced pressure, obtains 430mg expection product, and this product is directly used in the next step.
Step B: O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-oxo-8-benzo (e) Azulene base]-N-[[3-[4-(3-pyridyl)-1H-imidazoles-1-yl] propoxy-] carbonyl]-the DL-homoserine
The 20ml dichloromethane solution of 430mg steps A products therefrom is cooled to 0 ℃, adds the 10ml dichloromethane solution of 414mg such as preparation example 10 made alcohol.Make the reaction medium temperature return to room temperature, stirred 48 hours, remove solvent then under reduced pressure, residue is by alumina column chromatography (eluent: CH 2Cl 2-MeOH), reclaim 298mg expection product.
Step C: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[[3-[4-(3-pyridyl)-1H-imidazoles-1-yl] propoxy-] carbonyl]-hydrobromate of DL-homoserine
As described in embodiment 24 step B, be that starting raw material is operated with the solution of the 13ml butanols of step B products therefrom above the 277mg and 164mg cyclic amino guanidine hydrobromate.Through alumina column chromatography (eluent: CH 2Cl 2-MeOH 95-5) after, obtains 289mg expection product.
IR spectrum (CHCl 3)
C＝O??????1746(sh)??1723(max)cm -1
Conjugated system }
+ fragrant skeleton } 1668,1625 (F), 1599 (sh), 1551,1509,1489cm -1
+ acid amides II }
OH?????????3618cm -1
Step D: O-[4-[(4,5-dihydro-1H-imidazoles-2-yl) diazanyl]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base]-N-[[3-[4-(3-pyridyl)-1H-imidazoles-1-yl] propoxy-] carbonyl]-hydrochloride of DL-homoserine
Add 0.3ml N soda solution in the solution on 277mg in the 10ml ethanol of step C products therefrom, stirred 30 minutes, and added 10ml water again, use N hydrochloric acid acidizing reaction medium then to pH2.5, remove solvent under reduced pressure, residue is by silica gel column chromatography (eluent: CH 2Cl 2-MeOH-NH 4OH 40-10-2), reduction vaporization filtrate is dissolved in isopropyl ether with residue, leaches precipitation, obtains 126mg expection product after the drying.
NMR spectrum (DMSO)
1.78(m)(2H)?????????}
1.90-2.30(m)(2H)????}????3-CH 2
1.60-2.90(m)(8H)?????????CH 2-C＝
3.53(ws)(≈4H)???????????N-CH 2-CH 2-N
3.69(s)，3.71(s)?????????CH 3O-C＝
3.90-4.20 (m) (7-8H) CH 2And CH
6.73(s)??????????????????H 4
(7.20 d, wide) CO-NH-CH-
7.35(dd)?????????????????H′ 5
8.04(d)??????????????????H′ 4
8.37(wd)?????????????????H′ 6
8.94(ws)?????????????????H′ 2
7.72 (s), 7.80 (s) CH=imidazoles
Embodiment 30: 5-[[4-[(4,5-dihydro-4-oxo-1H-imidazoles-2-yl) hydrazono-]-9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-8-benzo (e) Azulene base] the oxygen base] valeric acid
Under the room temperature, the 6ml alcoholic acid solution of 300mg embodiment 3 steps A products therefroms is mixed with 61mg sodium bicarbonate and 0.7ml ethyl bromoacetate.Steaming desolventizes, silica gel column chromatography residue (eluent: CH 2Cl 2-MeOH 95-5), obtain 139mg intermediate ethyl ester.Get this ester of 110mg and 1ml ethanol mixed at room temperature 2 hours in the presence of 0.5ml 2N soda.After adopting 2N hydrochloric acid neutralization reaction medium, leach formed throw out, drying reclaims 44mg expection product.
NMR spectrum (DMSO)
≈ 1.73 (m) is center C H (6H) 2CH with position 9 2
2.30 (t) (2H)=C-CH 2(chain)
2.30-3.20???????????＝C-CH 2
3.73(s)，3.75(s)????Φ-OMe
3.83(ws)????????????＝C-N-CH 2-C＝
4.02(t)?????????????Φ-O-CH 2
6.76(s)?????????????H 4
7.20(ws)(1H)????????}
(ws) 8.28 (1H) } active H
12.04(1H)???????????}
Embodiment 31: O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(4,5,6,7-tetrahydrochysene-1H-1,3-diaza -2-yl) hydrazono-]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the D-homoserine
The 5ml butanol solution of the made product of 1g embodiment 24 steps A and 0.9g preparation example 11 made cyclic amino guanidines were together mixed under 130 ℃ 16 hours.Solvent evaporated under reduced pressure, residue is by silica gel column chromatography (eluent: CH 2Cl 2-MeOH 90-10), obtain the 0.8g intermediate ester.Then this product was at room temperature stirred 1 hour 30 minutes with 2ml 2N soda in 3ml methyl alcohol.After adopting 2N hydrochloric acid neutralization reaction medium, solvent evaporated under reduced pressure, residue is again by silica gel column chromatography (eluent: CH 2Cl 2-MeOH-NH 4OH 90-15-2), reclaim 0.22g expection product.
Embodiment 32: O-[9,10-dimethoxy-1,2,3,4,5,6-six hydrogen-4-[(3a, 4,5,6,7, the hydrazono-of 7a-six hydrogen-1H-benzimidazolyl-2 radicals-yl)]-8-benzo (e) Azulene base]-N-[(phenyl methoxyl group) carbonyl]-the DL-homoserine
As described in embodiment 24 step B and C, be that raw material is operated with the made product of 200mg embodiment 24 steps A and 176mg such as preparation example 12 made cyclic amino guanidines.Reclaim the 102mg intermediate ester, wherein get this intermediate of 100mg and carry out saponification reaction, obtain 59mg expection product.
Rf＝0.24(CH 2Cl 2-MeOH-NH 4OH?85-15-3)。
Pharmaceutical composition
Prepare the corresponding tablet that contains following component:
-embodiment 1 product 50mg
-tablet excipient (talcum, starch, Magnesium Stearate) SQ
Add to 120mg
The pharmaceutical research of product of the present invention
1-research product of the present invention is to vitronectin/Vitronectic receptor (α νβ 3) the bonded restraining effect:
Scheme
With 100 μ l people vitronectin solution (2 μ g/ml) (referring to Yatohgo etc., Cell., Structure and fraction 13:281-292 (1988)) (with the dilution of coating damping fluid) 4 ℃ down coating MaxiSorp 96-orifice plates spend the night.
Second day, inhale and to remove thing in the hole, then room temperature fixed ligands (vitronectin) 1 hour (referring to fixing damping fluid) under mild stirring.
Thing six times (referring to lavation buffer solution) in the washing hole adds in each hole then successively:
-40 μ l cultivate damping fluid,
-10 μ l are test-manufactured the thing diluent,
(product 50/50 DMSO-H 2The O dilution)
-50 μ l people α νβ 3Acceptor is (referring to Pyteal Deng enzyme method(Methods Enzymol) (1987) 144:475) (with cultivating the damping fluid dilution, extent of dilution is according to acceptor group and part adjustment).
Under mild stirring, with part, people α νβ 3Acceptor and test-manufactured thing and at room temperature cultivated 3 hours.
Washing hole is six times once more, and then at 100 μ l antibody 4B12-HRP, the antibody that is coupled to peroxidase exists down cultivates 2 hours (4B12-HRP antibody wherein is with cultivating the damping fluid dilution, and extent of dilution is adjusted according to the acceptor group) in the room temperature mild stirring.
Washing hole six times is showed medicine box (TMB MicrowellPeroxidase Substrate System Kirkegaard:Ref.Cat.50-76-00) test ligand-receptors bind by peroxidase then.
This medicine box comprise one bottle of substrate (3,3 ', 5,5 ＇-tetramethyl benzidine, 0.4g/l) and one bottle of B (0.02%H 2O 2Citrate trianion/citrate buffer solution solution).Face the time spent one volume A liquid is mixed with a volume B liquid, distribute reaction mixture with 100 μ l/ holes amount then.For vitronectin/α νβ 3Carry out enzymatic reaction in 12 hours, add 100 μ l 1M phosphoric acid then and stop cultivating.In 450nm place measuring light density.
Damping fluid:
-coating damping fluid: carbonate 0.05M, NaOH pH9.6
-fixing damping fluid: the PBS (pH7.4) that contains 0.5%BSA
-lavation buffer solution: the PBS (pH7.4) that contains 0.05% polysorbas20
-cultivation damping fluid:
·50mM?TRIS?pH7.4
·0.5％BSA
0.05% polysorbas20
·1mM?MnCl 2
·50μM?CaCl 2
·50μM?MgCl 2
·100mM?NaCl.
The result represents:
Draw people's vitronectin bonded percentage ratio and test-manufactured the logarithmic function curve of substrate concentration as each.
For each product, obtain its IC by following formula 50:
IC 50＝(BO+Bmin)/2
BO=does not have the maximum combined under the spawn existence
The minimum combination of Bmin=in the presence of the maximum concentration product.
2.-mouse braincap test
Principle
To pregnant female mice injection tracer dosage 45Ca (CaCl 2), so that discharge by measurement newborn mice skull lid 45C studies bone resorption.
Purpose
The in vitro study molecule is to the activity of bone resorption.
Product
1) test-manufactured thing:
Excipient: DMSO, H 2O/BSA (0.1%)
Dosage: variable (screening 10 μ M)
2) contrast product:
Echiststin (referring to .H-9010-BACHEM)
Excipient: H 2O/BSA
Dosage: 10 μ M
3) radiotracer:
CaCl 2Aqueous solution form 45Ca-is referring to CES3 AMWESHAM or NEZ-013 NEN.
Excipient: physiological serum
Dosage: 25 μ Ci/ mouse/0.4ml
Substratum
Add containing of 0.1%BSA and penicillin/Streptomycin sulphate of phenol red (referring to 041-01535M/GIBCO) CMRL 1066.
Method
1) to pregnant mouse (OF1, strain: injection Switzerland) 45Ca
A) preparation label solution:
190 μ l mother liquor of calcium (2mci/ml) are added in the 6ml physiological serum.
B) injection:
As gestation the 17th day, by intravenous route to the above-mentioned solution of injected in mice 400 μ l, i.e. 25 μ Ci/ mouse.
2) remove tissue (skull lid)
Newborn mice birth back the 6th day, sacrificed by decapitation is got head then, cuts skin along collare to forehead.Go out the skull lid with scissor cut, and utilize cutter skull to be cut into two half braincaps that are equal to fully (is positioned at the left side, and another is positioned at the right side) along parietal bone.With comparing, another then is used for test and is studied product with one of them.
3) " flushing " phase
Each half braincap is placed in the hole of 24 orifice plates (its mesopore contains the 1ml substratum) on the 100 μ m polyethylene and nylex support, contact fully with the bottom, hole avoiding.After 24 hours, the polyethylene support that is loaded with braincap is moved into contains 1ml fresh culture and being test-manufactured in the new 24-orifice plate of thing or their solvent.From each hole of first block of plate, take out 200 μ l substratum, carry out the radiocounting first time (A value).
This substratum changes feasible and shifts out relevant mechanical stress and eliminate.
4) " absorption " phase again
To organize with research after product contact 48 hours, and from every hole, take out 200 μ l substratum and count (B value), from substratum, disengage during the so-called absorption phase again to be determined at 45The Ca amount.
Then braincap is sloughed mineral substance fully in 1ml 5% trichoroacetic acid(TCA).Shifting out 200 μ l after the digestion again counts to measure remaining calcium amount (C value) in the bone.
The result represents
According to the following formula equation, calculate the bone resorption percentage ratio of per half braincap:
% bone resorption=dpm B/dpm (A+B+C) * 100
The summation of dpm A+B+C is represented to shift out in every bone parts on the same day 45The incorporation of Ca.
For measuring the effect of product, for every bit, the ratio of computing hole and the bone resorption percentage ratio of corresponding control wells.If product suppresses bone resorption, the numerical value that then can find to be called absorptive index between 0 to 1, otherwise, if product is strengthened bone resorption, then above-mentioned numerical value＞1.Calculate 6 exponential mean values (because of every group of 6 points) of every kind of product then, obtain an index of every kind of product.If deduct this index value with 1,, also can be expressed as the percentage form just obtain the inhibiting rate of product.
In addition, by the absorptive index of comparison point/again, carry out statistical procedures (Student T-check).
The result
Embodiment Competitive Vn/VR ((α νβ 3) in conjunction with test IC 50(μM) Mouse braincap inhibiting rate (10 μ M concentration) %
Embodiment 2 0.45 19
Embodiment 3 2.1 -
Embodiment 6 0.11 7.5
Embodiment 8 2.79 -
Embodiment 10 0.8 8
Embodiment 11 0.05 7
Embodiment 22 2.36 -
Embodiment 12 0.35 12
Embodiment 14 0.75 14
Embodiment 24 0.03 18
Embodiment 20 0.079 11
Embodiment 21 0.037 -
Embodiment 25 0.013 26
Embodiment 26 0.006 30
Embodiment 27 0.170 39
Embodiment 28 0.015 27
Embodiment 29 0.028 18
Embodiment 31 0.055 20
Embodiment 32 0.035 -

Claims (4)

1. the preparation method of the compound of following general formula (II),
Figure A0214126500021
R wherein 2, R 3, R 4And R 5For hydrogen atom and OH are positioned on 8,9 or 10,
It is characterized in that,
(i) make the compound of formula (a):
Figure A0214126500022
Wherein O-(Alk) be positioned at alkyl carboxyl between or contraposition, and Alk representative is derived from the group of saturated or unsaturated, the straight chain that contains 1-12 carbon atom, side chain or ring-type non-aromatics, the Alk group can be replacement or unsubstituted,
With the halogenating agent reaction, obtain corresponding acyl halide,
(ii) with resulting acyl halide and formula (b) reagent react:
Figure A0214126500023
Wherein the identical or different and representative of R (I) and R (II) contains the alkyl of 1-6 carbon atom, and perhaps R (I) and R (II) represent to choose wantonly with the nitrogen-atoms of their institute's key chains and contain another and be selected from O and heteroatomic 5 or 6 yuan of saturated or unsaturated heterocycles of N,
Obtain formula (c) compound:
(iii) make the reaction of gained formula (c) compound and halogenating agent, obtain formula (d) compound:
Hal wherein 1Represent halogen atom,
(iv) make formula (d) compound and the Lewis acid reaction of gained, obtain formula (e) compound:
Figure A0214126500033
(v) with gained formula (e) compound and dealkylation reagent react, obtain formula (IIF) product, i.e. the single substitution product of Yu Qi formula (II):
Figure A0214126500041
2. the preparation method of the compound of following general formula (II),
R wherein 2Represent OAlk group or O-(CH 2) 0-3-Ar group, wherein the definition of Alk is with claim 1, and the Ar representative contains the isocyclic aryl of 6-18 carbon atom, and Ar can be replacement or unsubstituted,
R 3, R 4And R 5Be hydrogen atom and OH, and R 2Be positioned on 8,9 or 10,
It is characterized in that,
With formula (a ') compound
R wherein 2And O-Alk be positioned at alkyl carboxyl between or in the contraposition,
Reaction in carry out claim 1 successively (i), (ii), (iii), (iv) and (v), obtain formula (IIG) product, i.e. the two substitution products of Yu Qi formula (II):
Figure A0214126500052
3. the preparation method of the compound of following general formula (II),
Figure A0214126500061
R wherein 2And R 3Represent O-(Alk) or O-(CH 2) 0-3-(Ar) group, wherein the definition of Alk and Ar is with claim 1, R 4And R 5Be hydrogen atom, OH is positioned on 9, it is characterized in that, makes formula (IIA) compound:
With dealkylation agent reaction, to obtain formula (IIB) compound:
Figure A0214126500063
Make formula (IIB) compound subsequently:
Perhaps in alkaline medium, react with the glycerol protection agent, so that selectivity obtains formula (IIC) compound:
Wherein P represents the remainder of glycerol protection agent,
Then make this compound successively with the deprotection agent reaction of deprotection agent, alkylating agent and the phenol of phenol protective material, glycol, to obtain formula (IID) compound, promptly OH is positioned at trisubstituted formula (II) compound on 8:
Perhaps successively with phenol protective material, alkylating agent and deprotection reaction, to obtain formula (IIE) compound, promptly OH is positioned at trisubstituted formula (II) compound on 9:
4. following general formula (II), (IIIa), (IIIb) and compound (IIIc):
Figure A0214126500091
R wherein 1Representative-C ≡ C-[A]-[B]-COR 6,-CH=CH-[A]-[B]-COR 6,-(CH 2) 2-[A]-[B]-COR 6,-O-[A]-[B]-COR 6,-CH 2CO-[A]-[B]-COR 6Group ,-[A]-representative:
The bivalent hydrocarbon radical of-heteroatomic saturated or unsaturated, the straight or branched structure that is selected from oxygen, nitrogen or sulphur atom of deriving a self-contained 1-12 carbon atom and 1-6,
-or the divalent group of saturated or unsaturated, the straight or branched acyclic hydrocarbous of the self-contained 1-12 carbon atom of deriving,
[B] represents phenyl, CH[Z] group, or singly-bound,
Z represents hydrogen atom, one of following groups: (D) 0-6-NRaRb, (D) 0-6-NH-SO 2-Rc, (D) 0-6-NH-CO 2-Rc, (D) 0-6-NH-CO-Rc, (D) 0-6-NH-SO 2-NH-Rc, (D) 0-6-NH-CO-NH-Rc, (D) 0-6-CO 2-Rc, (D) 0-6-SO 2-Rc, (D) 0-6-CO-Rc or (D) 0-6-Rc, wherein (D) 0-6Expression is derived from the divalent group of saturated or unsaturated, the straight or branched acyclic hydrocarbous that contains 0-6 carbon atom,
Ra, Rb and Rc representative: hydrogen atom; (CH 2) 0-3-Ar base, wherein the Ar representative contains the isocyclic aryl of 6-18 carbon atom; (CH 2) 0-3-Het base, wherein Het representative is derived from containing the individual oxygen that is selected from of 1-9 carbon atom and 1-5, heteroatomic saturated or unsaturated, the aromatics of nitrogen or sulphur atom or the group of non-aromatic heterocyclic; (CH 2) 0-3-Alk base, wherein Alk representative is derived from the group of saturated or unsaturated, the straight chain that contains 1-12 carbon atom, side chain or ring-type non-aromatics, group Het, Ar and Alk can be for unsubstituted or for replacing, perhaps Ra and Rb can also represent optionally to contain one or more and be selected from oxygen with the nitrogen-atoms that they were connected, the heteroatomic saturated or unsaturated aromatics of nitrogen or sulphur atom or non-aromatics nitrogen heterocyclic ring, this group can be that replace or unsubstituted
-R 6Representation hydroxy, O-Alk, O-Ar, NH 2, NH-Alk, N (Alk) 2The amino acid whose remainder of group or L or D, the definition of Alk and Ar is the same, and is replacement or unsubstituted,
-R 2And R 3Identical or different, perhaps represent hydrogen atom, O-Alk base or O-(CH 2) 0-3-Ar base, wherein the definition of Alk and Ar is the same, perhaps R 2With R 3Formation-O-(CRdRe) together n-O-type ring, wherein n is integer 1-5, Rd and Re independently represent hydrogen atom separately, contain the alkyl of 1-6 carbon atom, or phenyl,
-R 4Represent hydrogen atom, halogen atom, one of following groups: amino, nitro, cyano group, CF 3, contain the acyl group of 1-12 carbon atom or acyloxy, alkyl, alkenyl, alkynyl, alkylthio, alkoxyl group, alkylamino, dialkyl amido, dialkyl aminoalkyl, dialkyl amido alkoxyl group, wherein the term alkyl comprises 1-6 carbon atom,
-R 5Represent hydrogen atom, halogen atom, O-Alk group or O-(CH 2) 0-3-Ar group, wherein Alk and Ar as above define,
But the compound that does not comprise following formula (IIc):
Figure A0214126500101
Wherein P represents the remainder of glycerol protection agent,
Do not comprise following compound yet:
-2,3,5,6-tetrahydrochysene-9,10-dimethoxy-8-hydroxyl-benzo [e]-4 (1H)-ketone difficult to understand,
-2,3,5,6-tetrahydrochysene-8,9-dimethoxy-8-hydroxyl-benzo [e]-4 (1H)-ketone difficult to understand.
CN02141265A 1996-03-20 2002-06-27 Intermediate for preparing tricyclic compound and preparation method of intermediate Pending CN1401621A (en)

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