WO2013091282A1 - 一组木豆素结构类似化合物、制备方法和应用 - Google Patents

一组木豆素结构类似化合物、制备方法和应用 Download PDF

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WO2013091282A1
WO2013091282A1 PCT/CN2012/001711 CN2012001711W WO2013091282A1 WO 2013091282 A1 WO2013091282 A1 WO 2013091282A1 CN 2012001711 W CN2012001711 W CN 2012001711W WO 2013091282 A1 WO2013091282 A1 WO 2013091282A1
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isopentenyl
compound
methoxy
hydroxy
styryl
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PCT/CN2012/001711
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English (en)
French (fr)
Inventor
李卓荣
季兴跃
薛司徒
郑光辉
李玉环
陶佩珍
蒋建东
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中国医学科学院医药生物技术研究所
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Application filed by 中国医学科学院医药生物技术研究所 filed Critical 中国医学科学院医药生物技术研究所
Priority to US14/368,066 priority Critical patent/US9359298B2/en
Priority to JP2014547669A priority patent/JP6203746B2/ja
Priority to EP12859858.8A priority patent/EP2796442B1/en
Publication of WO2013091282A1 publication Critical patent/WO2013091282A1/zh

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
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    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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Definitions

  • the present invention relates to a group of xylenol structural similar compounds and a preparation method thereof, and to the compounds in antiviral and antibacterial infections, neuroprotective, anti-metabolic diseases (such as osteoporosis, hyperlipemia, hyperglycemia), etc. Applications, and pharmaceutical compositions containing such compounds as active ingredients and their use.
  • the present invention also relates to a chemical total synthesis preparation method of the natural products lignan, lignan A, and lignan C. Background technique
  • Bean (CaJanus caJan L.) is a leguminous genus of genus, has a wide range of medicinal properties.
  • the main function of pea seed is to treat liver and kidney edema, bloody sputum, hemorrhoids and so on, and the root of the pea has a heat-clearing and detoxifying effect.
  • the pigeonpea leaves have the effect of detoxification and swelling, and treat children with chickenpox and acne.
  • the pigeonpea leaves contain a large amount of terpenoids, such as lignan, lignan A, and lignan C (the chemical structure is shown in Figure 1). These compounds have a wide range of pharmacological effects, such as anti-osteoporosis.
  • Anthraquinone extract can effectively promote bone cell formation and inhibit bone cell absorption (see Journal of Pharmaceutical Sciences, 2007, 42 (4): 386 - 391); in the treatment of hyperlipidemia, the pigeonpea extract can be significantly Reduce abnormally elevated serum TC and TG and serum LDL-C levels (see CN101204418A, 2008.6.25.).
  • the extract of locust leaf mites also has anti-cerebral ischemia and hypoxia damage, and has protective effects on the stability of brain cell membrane and microvascular membrane in cerebral ischemia (see Chinese medicine and clinical pharmacology, 2006, 17 (3): 172 - 174).
  • the effect of lignan preparation on vascular permeability was significantly lower than that of the control group, and the inhibition rate was 38.96%.
  • the effect of the preparation on the pain of the mice found that the high- and low-dose group (200, 120 mg / kg) of the crotonin preparation can prolong the pain of the mice, and the length of the mice is more than doubled.
  • the lignan preparation has obvious analgesic effect.
  • the results of pharmacological studies of natural products show that lignan and pigeonpea leaf extract have extensive pharmacological effects. It has strong pharmacological activity (such as osteoporosis, hyperglycemia, hyperlipidemia, inflammation, tumor) for many major human diseases. In particular, it has a mechanism of action that regulates the balance of bone metabolism similar to estrogen (promotes bone formation and inhibits bone resorption), and has small side effects, and has in-depth research in China.
  • the present invention further expands the molecular structure diversity of the lignan compound by chemical means, synthesizes and optimizes the structure of the natural product; firstly synthesizes a large number of novel compounds having a stilbene structural skeleton, and synthesizes the obtained lignans.
  • the derivatives were screened for pharmacological activity, and the structure-activity relationship of the compounds was revealed.
  • the first study found that the compounds have a wide range of strong antiviral activities (such as anti-HIV, HCV, influenza and Cox).
  • the role of the compound of the present invention in neuroprotective and anti-metabolic diseases (such as osteoporosis, hyperlipidemia, hyperglycemia) is provided, which lays a foundation for optimization from active natural products to drug realization.
  • the invention also completes the total synthesis of lignan C for the first time; meanwhile, on the basis of patent 201010256856.7, another completely new synthetic route is proposed for lignan.
  • the present invention provides a xylenol structural analog compound having the formula I, II, III, IV, V or a pharmaceutically acceptable salt thereof
  • R represents a H, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted alkoxycarbonyl group or a carboxyl group.
  • it is selected from the group consisting of substituted phenyl, benzyl, phenethyl, really vinyl.
  • R 2 represents H, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted alkoxycarbonyl group or a carboxyl group.
  • it is selected from substituted styryl, benzyl, phenethyl, styryl.
  • R 3 represents H, a carboxyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted decanoyl group.
  • R4 represents H, a hydroxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted decanoyloxy group, a substituted or unsubstituted amino group or a ??, or an isoureido group.
  • R 5 represents H, a saturated or unsaturated hydrocarbon group, a substituted or unsubstituted aryl group, and an aromatic ring-substituted unsaturated hydrocarbon group.
  • it is selected from the group consisting of styryl, isopentenyl, isopentyl, decyl or 3,7,-dimercapto-2,6'-dienyl.
  • R 6 represents H, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, 13 ⁇ 4 , decyl or alkyl fluorenyl.
  • R 7 represents H, isopentenyl, isopentyl, 3,7'-dimethyloctyl-2',6,-dienyl, substituted or unsubstituted aryl, allyl, 13 ⁇ 4, A substituted or unsubstituted amino group.
  • R 8 and R 9 may be the same or different and may represent a hydrocarbon group of H, 1-18 carbons, respectively.
  • substitution may be, but is not limited to, substitution of alkane, alkoxy, hydroxy, alkyl, amino, decylamino.
  • substituted aryl may be, but is not limited to, a phenyl group substituted at various positions by a compound such as a ?, alkoxy group, a hydroxyl group, an alkyl group, an amino group and a substituted amino group.
  • heteromatic ring may be, but not limited to, a pyridine ring, a thiophene ring, a furan ring or the like.
  • the "hydrocarbyl group” may be, but not limited to, a linear or branched alkyl or cycloalkyl group having 1 to 18 carbon atoms, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. or their corresponding cycloalkyl groups. More preferably, it is a C1-C6 lower alkyl group.
  • Alkoxy may be, but is not limited to, an alkoxy group having from 1 to 18 carbon atoms, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutylene
  • Acyl may be, but is not limited to, a hydrocarbon substituted acyl or aryl acyl group having 1 to 18 carbons, such as formyl, acetyl, isopropyl acyl, n-propyl acyl, allyl acyl, cyclopropyl acyl , n-butyl acyl, isobutyl
  • alkoxycarbonyl or “ester group” may be, but not limited to, a hydrocarbon-substituted ester group (hydrocarbyl acyloxy) or aryl ester group having 1 to 18 carbons, such as a nonanoyloxy group, an acetoxy group, Isopropyloxy, n-propyloxy, allyloxy, cyclopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, uncle Butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, phenylacyloxy, fluorenylphenyloxy and the like.
  • a hydrocarbon-substituted ester group hydrocarbyl acyloxy
  • aryl ester group having 1 to 18 carbons such as a nonanoyloxy group, an acetoxy group, Isopropyloxy, n
  • aminoacyl or “aminodecanoyl” may be a mono- or di-substituted aminoacyl or aryl-aminoacyl group having from 1 to 18 carbons, such as N-methylaminoacyl, ethylaminoacyl, isopropyl Aminoacyl, n-propylaminoacyl, allylaminoacyl, cyclopropylaminoacyl, n-butylaminoacyl, isobutylaminoacyl, sec-butylaminoacyl, tert-butylaminoacyl, n-pentylaminoacyl , isoamylamino, n-hexylamino, isohexylamino, phenylamino, tolylamino and the like.
  • Halo or halogen can be fluoro, chloro, bromo or iodo.
  • the present invention also provides a method for synthesizing a xylenol structurally similar compound as shown in the general formula I, II, III, IV, V, as follows.
  • the present invention provides a method of synthesizing a compound of formula I:
  • R 3 is a carboxyl group, a hydroxyl group, R 6 is an alkoxy group, R 7 is H, and the remaining groups are as defined by the above formula
  • R 3 is an alkoxy (thio) decanoyl group or a substituted amino acyl group, and the remaining groups are as defined in the above formula, the synthesis method is as follows:
  • R l 5 R 2 , RA , R 5 , R 6 , R 7 have the same definitions as defined in the above-mentioned formulae, R 9 , a substituted or unsubstituted alkyl group of 1 to 18 carbons, substituted Or an unsubstituted aryl group, a heteroaryl group;
  • the condensing agent may be, but not limited to, DIC, DCC; or various inorganic or Lewis acids such as an ether solution of HCl, H 2 S0 4 , and BF 3 ;
  • the acylating agent may be, but not limited to, S0C1 2 , oxalyl chloride, etc.
  • the acid binding agent may be, but not limited to, an organic base such as DM AP or Et 3 N or NaOH, KOH, Na 2 C0. 3 , K 2 C0 3 and other inorganic bases;
  • the present invention also provides a method for preparing lignan A, as shown in Scheme 3:
  • the base may be, but not limited to, an inorganic base such as KOH, NaOH, K 2 C0 3 , Na 2 C0 3 , etc.
  • the acid may be, but not limited to, inorganic substances such as HC1, H 2 S0 4 , H 3 P0 4 , etc.
  • the acid, the solvent may be, but not limited to, water, various alcohols
  • An equipolar protic solvent or a polar aprotic solvent such as DMSO or DMF;
  • R 3 is a carboxyl group
  • R 4 is a hydroxyl group
  • R 6 is an alkoxy group
  • R 7 is a 13 ⁇ 4 element
  • the halogenating agent may be, but not limited to, S0 2 C1 2 , NCS (ie, N-chlorosuccinimide), NBS (ie, N-bromosuccinimide), Br 2, etc.
  • a halogenating reagent which may be, but not limited to, a halogenated hydrocarbon solvent such as CH 2 C1 2 , CHC1 3 , CC1 4 or the like, or MeOH, EtOH, AcOH, propanol, isopropanol, n-butanol, tert-butyl a polar protic solvent such as an alcohol, or a polar aprotic solvent such as acetonitrile or DMF; when the compound 12 is prepared: the alkylating agent may be, but not limited to, various
  • the sulfonate, the base to be used may be, but not limited to, an inorganic base such as sodium hydride, potassium hydride, calcium hydride, sodium metal, potassium hydroxide or sodium hydroxide; or an organic base such as sodium alkoxide or potassium t-butoxide;
  • the solvent used may be, but not limited to, an ether or an aromatic solvent;
  • the base may be, but not limited to, an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide or the like, or an organic base such as an amine, a sodium alkoxide or a potassium alkoxide;
  • the acid used may be but not It is limited to inorganic acids such as hydrochloric acid, sulfuric acid, etc., or organic acids such as acetic acid;
  • the solvent is water, alcohol or a mixed solvent containing active hydrogen;
  • the alkylating agent may be, but not limited to, various hydrocarbons, or sulfonates or sulfates of various alcohols, and the base used may be, but not limited to, sodium hydride, An inorganic base such as potassium hydride, calcium hydride, sodium metal, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate; or an organic base such as sodium alkoxide or potassium t-butoxide; the solvent used may be, but not limited to, polar a protic solvent, or a water or alcohol polar shield solvent; the method of Preparation 15 is the same as the hydrolysis condition of Route 4;
  • the present invention also provides a method for fully synthesizing lignan C, as shown in Scheme 6:
  • the coupling reagent may be, but not limited to, various saturated or unsaturated trialkyltin substitution reagents, organic boronic acids, organometallics (RLi, RMgX, RZnX, etc.); It is not limited to Pd-type catalysts such as Pd(OAc) 2 , Pd(dppf) 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , PdCl 2 (CH 3 CN) 2 ; the solvent may be, but not limited to, A polar aprotic solvent such as DMF or CH 3 CN, or an aromatic hydrocarbon solvent such as really, terpene, diphenyl or chlorobenzene;
  • the dehydrogenation reagent may be a Lewis acidic reagent (such as boron tribromide, boron trichloride, aluminum trichloride, trimethyl iodine silane, trimethyl bromo silane, etc.), and the reaction solvent may be It is, but not limited to, a hydrocarbon solvent, and the reaction temperature is -80-25 °C;
  • a Lewis acidic reagent such as boron tribromide, boron trichloride, aluminum trichloride, trimethyl iodine silane, trimethyl bromo silane, etc.
  • Scheme 7 The compound of formula I is reacted with a dealkylating reagent to give the target compound 20.
  • Said dealkylating agent can therefore, it is not limited to a protonic acid such as HI or HBr, or a Lewis acid such as A1X 3 or BX 3 , and the solvent may be, but not limited to, a halogenated hydrocarbon solvent, and the reaction temperature is -80-25 ° C; wherein R!, R 2 , R 5 , R 7 and R 8 are the same as defined in the above formula.
  • Route 9 a condensation of a derivative having a carboxyl group at the 1-position with a carbonyl diimidazole in an organic solvent to obtain the target product 22, which may be, but not limited to, an aprotic polar solvent such as acetone, DMF or DMSO, or a halogenated hydrocarbon solvent, wherein Ri, R 2 , R 4 , R 5 , R 6 , R 7 are the same as defined in the above formula;
  • a 2-hydroxyl derivative is condensed with an acid chloride under basic conditions to give the desired product 24, which may be, but not limited to, an organic base such as triethylamine, pyridine or diethylamine, or anhydrous.
  • An inorganic base such as potassium carbonate, sodium carbonate or KOH NaOH, wherein R 1 ; R 2 , R 3 , R 5 and R 6 R 7 are the same as defined in the above formula, and R 10 is a substituted or unobtained alkyl group, substituted or Unsubstituted heteroaryl ring, substituted or unsubstituted amino group;
  • the condensing agent may be, but not limited to, a condensing agent such as diethyl azodicarboxylate + triphenylphosphine, diisopropyl azodicarboxylate or triphenylphosphine;
  • the debenzylating agent may be, but not limited to, Zn+ammonium formate, Mg+ammonium formate, and the like;
  • a 2-hydroxyl derivative is reacted with an amino cyanide under acidic conditions to obtain the target compound 27.
  • the acidic condition may be, but not limited to, a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or methanesulfonic acid.
  • An organic acid such as trifluoroacetic acid, wherein Ri R 2 R 3 , R 5 and R 6 R 7 are the same as defined in the above formula; Further, when the fluorenyl acyloxy group and the remaining groups are as defined in the general formula, the synthesis method is as follows:
  • the conditions for preparing the compound 30 are identical to those for the preparation of the compound 28;
  • a benzo ring-terminated alkoxycarbonyl group is aminated in an organic solvent to give the target product 32.
  • the organic solvent may be, but not limited to, an alcohol solvent such as decyl alcohol, ethanol or isopropanol. Or a halogenated hydrocarbon solvent.
  • R!, R 2 , R 4 , R 5 , R 6 , R 7 are the same as defined in the above formula
  • R 8 is an alkyl group of 1 to 18 carbons; moreover, the present invention also provides a structure having the formula II a method for synthesizing a compound, wherein R 8 is a thiol group, such as a route
  • Route 17 Compound 1 is decarboxylated in the presence of an acid catalyst, an intramolecular addition product 33;
  • the acidic catalyst may be, but not limited to, a Lewis acid such as A1C1 3 , BC1 3 , BBr 3 , SiMe 3 I or the like, and the solvent may be, but not limited to, dichlorosilane, chloroform, chlorobenzene, etc. [3 ⁇ 4 hydrocarbons Solvent; reaction temperature is 0-80 ° C.
  • the present invention also provides a method of synthesizing a compound of the formula III, wherein R 9 is H, and R 8 is as defined in the above formula, as shown in Scheme 18:
  • Route 18 The lignan analog 1, hydrogenated under the catalysis of a Pd-type catalyst to obtain a product in which all hydrocarbon double bonds are reduced;
  • the Pd-based catalyst may be, but not limited to, a catalyst such as Pd/C, Pd/BaS0 4 or the like.
  • the reaction temperature is 0-50 ° C
  • the reaction pressure is 0-100 psi
  • the solvent may be, but not limited to, an alcohol solvent such as decyl alcohol, ethanol or propanol, or an acid solvent such as acetic acid, or benzene, benzene, An aromatic hydrocarbon solvent such as diphenylbenzene.
  • the present invention provides a method of synthesizing a compound having the structure of Formula IV, wherein R 8 , R 9 are as defined in the above formula, as shown in Scheme 19:
  • the method of Preparation 35 is consistent with the conditions of Route 18.
  • the method of Preparation 36 is identical to the alkylation conditions of Scheme 5, and the procedure for Preparation 37 is consistent with the hydrolysis conditions of Scheme 4.
  • the present invention provides a method of synthesizing a compound of the formula V wherein R 8 , R 9 and R 10 are alkyl groups of 1 to 18 carbons, as shown in Scheme 20:
  • the basic condition may be, but not limited to, sodium decoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide or the like, or inorganic base such as KOH, NaOH, K 2 C0 3 or the like.
  • the solvent may be, but not limited to, an alcohol solvent such as decyl alcohol or ethanol, or may be a polar aprotic solvent such as DMF or CH 3 CN;
  • the brominating reagent may be, but not limited to, liquid bromine, NBS, etc.
  • the solvent may be, but not limited to, a protic polar solvent such as ethanol, acetic acid or methanol, and the reaction temperature is o-io (rc;
  • the halogenating agent used may be, but not limited to, a mixture of N-bromosuccinimide (NBS) and dibenzoyl peroxide (BPO) or liquid bromine, or a mixture of sulfuryl chloride and BPO, sulfur. a mixture of an acid chloride and azobisisobutyronitrile (AIBN), a mixture of N-chlorosuccinimide (NSS) and BPO or AIBN, etc.;
  • the solvent used is, but not limited to, petroleum ether, carbon tetrachloride, etc. a polar solvent, or an aprotic polar solvent such as acetonitrile or chloroform;
  • the reaction temperature is from o ° c to the reflux temperature of the selected solvent, preferably the solvent reflux temperature;
  • the organophosphorus reagent is a phosphite triester, a triaryl phosphorus, etc., and the condensation reaction is in a solvent. It is carried out at reflux temperature or lower, but it is not excluded to be carried out under high temperature and high pressure;
  • the reaction solvent may be, but not limited to, an ether solvent and various polar aprotic solvents
  • the base catalyst may be, but not limited to, an inorganic base such as sodium hydride or potassium carbonate, or triethylamine, sodium decoxide or ethanol.
  • An organic base such as sodium, potassium t-butoxide or lithium diisopropylamine; the reaction temperature is -10 to 100 ° C, preferably the reflux temperature of the solvent;
  • the present invention also provides a novel synthetic route for the preparation of lignan, such as Route 21:
  • the method for preparing compound 48 is the same as the method for the preparation of step 42 of Scheme 20, the method for preparing 49 is the same as the condition for the preparation of 18 of Scheme 6, and the preparation of compound 8 is consistent with the preparation of compound 17 of Scheme 6.
  • the method for preparing compound 1 is consistent with the hydrolysis conditions of Scheme 4. .
  • the present invention synthesizes a large number of novel lignin analogs for the first time, and completes the chemical total synthesis of lignan C for the first time, and proposes another brand new synthetic route for lignan. .
  • the present invention is also the first to synthesize lignin derivatives and compounds such as lignin, lignin A, and lignin C in antiviral, neuroprotective, and anti-metabolic diseases (such as osteoporosis, hyperlipidemia, high
  • the pharmacological activity of blood glucose and the like was measured, and the activity of some compounds exceeded the lead lignin.
  • the results of the structure and pharmacological activity of the inventive compound are shown in Tables 1 and 2, respectively.
  • the antiviral activity of the compound of the invention was selected by cell culture method, and the compound has strong resistance.
  • the role of respiratory viruses shown in Table 1).
  • the anti-influenza activity of 24i, 26f, 29c, 31a 31b, 31c, 32, 46 and 47 is significantly stronger than that of the lead lignan, and the antiviral activity of the above-mentioned inventive compound compared with the clinical drug Tamiflu and Tamiflu
  • the present invention also relates to the use of the compound for inhibiting HIV, HCV virus, and the results are shown in Table 2, wherein, Compound 1, la, lb, lc, le, lf, li, lj, 11, ls, lu, lx, Ly, lz, la', lb', 8, 8a, 8e, 8f> 8j, 8s, 8t, 8u, 8v, 8w, 9e, 10, 10b, 10h, 10i, 10j, 101, 10m> 10o,
  • Compounds such as 10q, 10t, 23a, 23b, 29a, 31b, 31c 46 exhibit strong anti-HIV, HCV virus activity.
  • the present invention also relates to the use of the compound for neuroprotection (influence of PC 12 cell damage), and the protective effect of the compound on PC12 cells and rotenone-injured PC12 cells, and the results are shown in Table 3.
  • the compound of the invention has a clear protective effect on PC 12 cells and rotenone-injured PC 12 cells, wherein the compounds lp, lr, lu, lw, lz> la', lb', Id', 8d, 8m, 8p, 8q , 8w, 9e, 9g, 10c, 10j, 10k, 101, 10m, 10o, 10p, 10t, lOu and 10v, 10c', 10d', 21d, 24b, 24k, 24q, 27b, 32 are the most active.
  • the present invention also relates to the anti-osteoporosis effect of the compound. It has been reported in the literature that myzusin is a plant estrogen, and the anti-osteoporosis effect of natural products is related to its estrogen-like effect.
  • the invention confirms the protective effect of pure ligninin obtained by chemical means on osteoporosis in ovariectomized rats, and the results show that the anti-osteoporosis effect in the animal body is stronger than the clinical drug raloxifene.
  • the myzulin extract, the lignan, the lignan, and the lignan C have been extensively studied and reported for their antitumor, hypoglycemic, hypolipidemic, anti-inflammatory and analgesic effects.
  • the compound of the present invention is a structural analog of a natural product of lignan, lignan and lignan C as a lead compound, and the compound of the present invention has a similar antitumor, hypoglycemic, hypolipidemic, anti-inflammatory and analgesic effects. It is obvious. Accordingly, the present invention also relates to the use of the compound for anti-tumor, hypoglycemic, hypolipidemic, anti-inflammatory, analgesic and the like.
  • the present invention also provides a pharmaceutical composition for antiviral and bacterial infection, neuroprotection, antimetabolite disease (such as osteoporosis, hyperlipemia, hyperglycemia) and the like, the pharmaceutical composition comprising a therapeutically effective amount Said compound having the formula I, II, III, IV, V or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable pharmaceutical adjuvants.
  • the compound of the formula I, II, III, IV, V or a pharmaceutically acceptable salt thereof is used as an active ingredient in the pharmaceutical composition in an amount of from 0.1% to 99.5% by weight.
  • the pharmaceutical composition contains from 0.5% to 99.5% by weight of the active ingredient.
  • the present invention provides the use of the composition for the preparation of a medicament against bacteria and viral infections, neuroprotective, anti-metabolic diseases such as osteoporosis, hyperlipemia, hyperglycemia and the like.
  • Figure 1 shows the chemical structure of the pigeonpea extract.
  • the lignan (0.2 g, 0.59 mmol) was dissolved in dichloromethane (15 ml), DCC (0.15 g, 0, 71 mmol) was added, and the mixture was stirred at room temperature for 0.5 h, then cyclopropylamine (50 mg, 0.88 mmol) was added and reacted at room temperature for 3 h. , reflected. The solvent was distilled off and the residue was applied to a silica gel column (yield: 85%).
  • N-Mercapto-2-hydroxy-3-isopentenyl-4-methoxy-6-[(E)-stupyl]benzamide (23b) is synthesized according to compound 8, hydrazine.
  • the procedure of Example 178 gave the desired product as a white solid (80%).
  • the lignan 1 (O.lg, 0.29 mmol) was added to a hydrogenated acid (10 ml, 55%), and the mixture was heated to reflux for 2h. The organic layers were combined, and the organic layer was washed with water and brine.
  • the lignan (0.1 g, 0.29 mmol) was dissolved in 15 ml of absolute ethanol, and 10 mg of 5% Pd/C was added and hydrogenated at room temperature under a pressure of 70 psi for 4 h. After the completion of the reaction, the catalyst was filtered off, and the filtrate was evaporated to dryness to give the lignin double bond hydrogenated product (99 mg, 98%).
  • Methyl 2,4-dihydroxy-3-bromo-6-mercaptobenzoate (39 ) The compound 38 (10.0 g, 0.054 mol) was dissolved in glacial acetic acid (150 ml), and a solution of liquid bromine (19.9 g, 0.124 mol) in acetic acid (40 ml) was added dropwise at room temperature, and the mixture was allowed to react at room temperature for 12 h. After the reaction, the reaction solution was poured into ice water to precipitate a large amount of white solid, which was filtered, and the filter cake was washed with a large amount of water and dried.
  • MDCK cells were seeded in 96-well culture plates and placed in 5% CO 2 at 37 ° C for 24 hours. MDCK cells were added with influenza virus (A/H1N1, A/H3N2 or B/13/79 type) at about 100 TCID 50 , and the virus solution was decanted after adsorption at 37 ° C for 2 hours, and different dilutions of the compound of the present invention or positive control drug were separately added. Maintenance solution of ribavirin. At the same time, a virus-free control and a virus-infected cell control were set. When the degree of disease (C?E) of the virus control group was 4+ at 37 °C, the degree of cell lesion (CPE) of each group was observed (about 36 hours). The half-inhibitory concentration (IC 5 () ) of each sample against influenza virus was calculated, and the results are shown in Table 1.
  • influenza virus A/H1N1, A/H3N2 or B/13/79 type
  • VEro cells were seeded in 96-well culture plates. After 24 hours, the virus (Coxsackie B6 virus) was infected with about 100 TCID 50 , adsorbed for 2 hours, virus solution was discarded, and samples of the compound of the present invention containing different concentrations and positive control drug ribavirin were added.
  • RBV maintenance solution, at the same time set no virus control virus control and virus-free cell control, when the degree of disease control (CPE) of the virus control group reached 40 °, observe the degree of cell damage (CPE), using REED-MuEnch method
  • CPE degree of disease control
  • CPE degree of cell damage
  • the half-inhibitory concentration of the virus against the virus (IC 5C ) was calculated separately and the results are shown in Table 1.
  • the rotenone model was added to the complete medium cells with a final concentration of 4 ⁇ rotenone for 48 h, and the serum group was added with serum-free DMEM medium. The cells were 48h.
  • the dosing group was also divided into two groups. One group was modeled with rotenone, and the other group was modeled with desera, and 10 ⁇ M test compound was added at the same time as modeling. After 48 h, 10 ⁇ 15 mg/ml MTT was added. After 4 h, the supernatant was removed and 150 ⁇ l DMSO was added. The number of viable cells is expressed as the absorbance value at 570 nm.
  • Huh7.5 cells were seeded into 96-well plates at a density of 3 x 104 cells/cm2. After 24 hours of culture, cells were infected with HCV virus supernatant at 45 IU/cell, and treated with a drug solution or solvent control. After 72 hours of culture, the medium was aspirated, and total RNA was extracted with RNeasy Mini Kit. The expression level of HCV RNA was quantified by one-step real-time RT-PCR kit, and the inhibition rate of HCV was calculated by using the drug, and Reed-Muench was used. The method calculates half of the toxic concentration EC50. The activity of the compound against HCV is shown in Table 2.
  • MT-4 cells were infected with 100TCID50 HIV-1 prion at 37 °C for 1.5 h, then washed twice with medium, and made into 2 ⁇ 105 cells. mL-1, ⁇ inoculated into 96-well cell culture plates. At the same time, 3 times diluted different concentrations of the drug solution or 4 times diluted positive drug sputum solution were added, and 2 wells were repeated for each concentration, and a cell control group was set. The cells were cultured in a 37 ° C, 5% CO 2 and saturated humidity incubator. After 96 h of dosing, the supernatant was aspirated and the content of ⁇ 24 antigen was determined using a kit to calculate the IC50. The activity of the compound against HIV is shown in Table 2.

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Abstract

本发明提供了一组木豆素结构类似化合物、合成方法及其药理作用。本发明所提供的化合物具有通式I、II、III、IV和V的结构，本发明还提供了含有所述化合物作为活性成分的药物组合物；本发明化合物具有抗病毒和细菌感染、神经保护、抗代谢性疾病等药理活性，以及含有该类化合物作为活性组分的药物组合物的应用。本发明还提供了天然产物木豆素、木豆素A、木豆素C的化学全合成制备方法。本发明为今后深入研究与开发所说化合物作为临床药物的应用奠定了基础。

Description

一组木豆素结构类似化合物、 制备方法和应用 技术领域
本发明涉及一组木豆素结构类似化合物及其制备方法， 还涉及所述化合物在抗病 毒和抗细菌感染、 神经保护、 抗代谢性疾病 （如骨质疏松、 高血脂、 高血糖） 等的应 用， 以及含有该类化合物作为活性组分的药物组合物及其应用。 本发明还涉及天然产 物木豆素、 木豆素 A、 木豆素 C的化学全合成制备方法。 背景技术
木豆 （ CaJanus caJan L. ) 是豆科木豆属植物， 具有广泛的药用价值， 木豆种子主 要功用有治疗肝肾水肿、 血淋、 痔疮下血等， 木豆根具有清热解毒、 利湿止血、 止痛、 杀虫等功效， 主治咽喉肿痛、 痔疮下血、 血淋水肿、 小便不利等。 木豆叶则具有解毒 消肿功效， 主治小儿水痘、 痈疽疮毒等。木豆叶中含有大量的芪类化合物， 如木豆素， 木豆素 A， 木豆素 C (化学结构如图 1所示） ， 此类化合物具有广泛的药理作用， 如抗 骨质疏松， 芪类提取物能有效促进骨细胞形成及抑制骨细胞吸收的作用 （参见药学学 报， 2007， 42 (4): 386 - 391 ) ； 在治疗高脂血症方面， 木豆芪类提取物可明显降低异常 升高的血清 TC和 TG以及血清 LDL-C水平 （参见 CN101204418A, 2008.6.25. ) 。 此外， 木豆叶芪类提取物还具有抗脑缺血缺氧损伤作用， 对脑缺血时脑组织中脑细胞膜及微 血管膜的稳定性有保护作用 （参见 中药新药与临床药理，2006, 17(3): 172 - 174 )。
美国学者 （参见 David C. Hopp等 US2002/0058707 A1 ) 还研究了木豆素、 木豆素 A和木豆素 C 等木豆素结构类似物（如图 1所示）的降血糖作用， 结果表明该类化合物 均具有较好的降血糖作用， 而且毒副作用都较小。 木豆粗提物的抗炎和镇痛作用也得 到实验的验证 （参见孙邵美等中草药， 1995,26(3 : 147-148), 实验结果发现， 实验样品 木豆素制剂具有明显的抗炎作用， 效果强于水杨酸， 且抗炎作用呈现剂量依赖关系。 木豆素制剂对血管通透性的作用与对照组相比显著降低， 抑制率为 38.96%。 此外， 通 过木豆素制剂对小鼠痛阁的影响研究发现， 灌服木豆素制剂高低剂量组 （ 200、 120 mg/kg ) , 均能延长小鼠痛阔， 与给药前相比， 延长超过一倍， 说明木豆素制剂具有明 显的镇痛作用。 天然产物药理作用研究结果显示， 木豆素及木豆叶芪类提取物具有广泛的药理作 用， 对多种人类重大疾病具有较强的药理活性（如骨质疏松、 高血糖、 高血脂、 炎症、 肿瘤） 。 尤其是其具有与雌激素相似的调节骨代谢平衡的作用机制 （促进骨形成同时 抑制骨吸收） ， 而且毒副作用小， 在国内具有较深入的研究。
但是， 目前国内外有关木豆芪类物质的化学研究仍然局限在天然产物的提取、 分 离和结构鉴定等天然药物化学层面， 得到的具有明确结构的类似物的数量非常有限。 而且， 受药物来源的限制， 天然产物木豆素药理作用的深入研究难以展开。 本专利的 发明人在申请号 201010256856.7的中国发明专利中首次完成了木豆素及木豆素 A的全 合成， 为进一步拓展该类化合物分子结构的多样性提供了化学手段和基础。 发明内容
本发明首次通过化学手段，进一步拓展木豆素类化合物分子结构的多样性，合成、 优化天然产物结构； 首次合成了大量具有二苯乙烯结构骨架的新型化合物， 并对合成 得到的木豆素类衍生物进行药理作用活性筛选， 探究揭示该类化合物的构效关系； 首 次研究发现该类化合物具有广泛的强抗病毒的活性（如抗 HIV、 HCV、流感和 Cox等）。 同时， 提供了本发明化合物在神经保护、 抗代谢性疾病 （如骨质疏松、 高血脂、 高血 糖） 等方面的作用， 为从有活性的天然产物优化到药物的实现奠定了基础。
本发明还首次完成了木豆素 C的全合成；同时，在专利 201010256856.7的基础上， 对木豆素又提出了另一条全新的全合成路线。
为了达到上述目的， 本发明采用如下技术方案：
本发明提供了具有如通式 I 、 II、 III、 IV、 V所示的木豆素结构类似化合物或其 药用盐
Figure imgf000004_0001
式中 R,代表 H, 取代或未取代的芳基， 取代或未取代的杂芳基， 取代或未取代的 烃基， 取代或未取代芳烃基， 取代或者未取代的烷氧甲酰基或者羧基。 优选的， 选自 取代的苯基， 苄基， 苯乙基， 笨乙烯基。
R2代表 H, 取代或未取代的芳基， 取代或未取代的杂芳基， 取代或未取代的烃基， 取代或未取代芳烃基， 取代或者未取代的烷氧曱酰基或者羧基。 优选的， 选自取代的 笨基， 苄基， 苯乙基， 苯乙烯基。
R3代表 H, 羧基， 取代或者未取代的烷氧曱酰基， 取代或者未取代的氨甲酰基， 取代或者未取代的曱酰基。
R4代表 H， 羟基， 取代或者未取代的烷氧基， 取代或未取代的曱酰氧基， 取代或 者未取代的氨基或! ¾素， 或者异脲基。
R5代表 H, 饱和或不饱和烃基， 取代或未取代的芳基， 芳环取代的不饱和烃基。 优选的， 选自苯乙烯基， 异戊烯基， 异戊基， 浠丙基或 3，，7，-二曱基辛 -2，，6'-二烯基。
R6代表 H, 羟基， 取代或者未取代的烷氧基， 取代或未取代的氨基， 1¾素， 巯基 或烷石克基。
R7代表 H， 异戊烯基， 异戊基， 3，,7'-二甲基辛-2',6，-二烯基， 取代或未取代的芳 基， 烯丙基， 1¾素， 取代或未取代的氨基。
R8和 R9可以相同， 也可以不同， 可分别代表 H， 1-18个碳的烃基。
以上定义中所说的：
"取代" 可以是但不限于是由 素， 烷氧基， 羟基， 烷基， 氨基， 垸基氨基取代。 例如 "取代芳基" 可以是但不限于是： 由! ¾素， 烷氧基， 羟基， 烷基， 氨基及取代氨 基等取代于各种位置的苯基。
"杂芳环" 可以是但不限于是吡啶环， 噻吩环， 呋喃环等。
"烃基 "可以是但不限于是碳原子数在 1-18的直链或支链的烷基或环烷基，例如， 甲基、 乙基、 异丙基、 正丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 正戊基、 异戊基、 正己基、 异己基等或其相应的环烷基。 更优选为 C1-C6的低级烷基。
"烷氧基"可以是但不限于是碳原子数在 1-18的烷氧基， 例如， 甲氧基、 乙氧基、 异丙氧基、 正丙氧基、 正丁氧基、 异丁氧基、 仲丁氧基、 叔丁氧基、 正戊氧基、 异戊 氧基、 正己氧基、 异己氧基等。 更优选为 的低级烷氧基。
"酰基 "可以是但不限于是具有 1-18个碳的烃取代酰基或芳基酰基，例如甲酰基、 乙酰基、 异丙基酰基、 正丙基酰基、 烯丙基酰基、 环丙基酰基、 正丁基酰基、 异丁基 酰基、 仲丁基酰基、 叔丁基酰基、 正戊基酰基、 异戊基酰基、 正己基酰基、 异己基酰 基、 苯基酰基、 曱苯基酰基等。
"烷氧曱酰基" 或 "酯基" 可以是但不限于是具有 1-18个碳的烃取代酯基（烃基 酰氧基） 或芳基酯基， 例如曱酰氧基、 乙酰氧基、 异丙基酰氧基、 正丙基酰氧基、 烯 丙基酰氧基、 环丙基酰氧基、 正丁基酰氧基、 异丁基酰氧基、 仲丁基酰氧基、 叔丁基 酰氧基、 正戊基酰氧基、 异戊基酰氧基、 正己基酰氧基、 异己基酰氧基、 苯基酰氧基、 曱苯基酰氧基等。
"氨酰基" 或 "氨曱酰基" 可以是具有 1-18个碳的烃单取代或双取代的氨酰基 或芳基氨酰基， 例如 N-甲基氨酰基、 乙基氨酰基、 异丙基氨酰基、 正丙基氨酰基、 烯 丙基氨酰基、 环^基氨酰基、 正丁基氨酰基、 异丁基氨酰基、 仲丁基氨酰基、 叔丁基 氨酰基、 正戊基氨酰基、 异戊基氨酰基、 正己基氨酰基、 异己基氨酰基、 苯基氨酰基、 甲苯基氨酰基等。
"卤代，， 或 "卤素" 可以是氟、 氯、 溴或碘。
本发明还提供了如通式 I、 II、 III、 IV、 V所示的木豆素结构类似化合物的合成方 法， 具体如下。
本发明提供如通式 I所示化合物的合成方法：
当 R3 为羧基， 为羟基， R6为烷氧基， R7为 H, 而其余基团如上面通式所定义 时
Figure imgf000006_0001
路线 1 : 乙酰乙酸酯和二乙烯酮在碱性条件下缩合得到化合物 2 , 化合物 2在碱性 条件下在极性溶剂中烷基化生成 3， 3在非极性溶剂中发生自由基! ¾化反应生成化合物 4， 化合物 4与亚磷酸三酯缩合得到化合物 5 , 化合物 5与酮或醛反应得到化合物 6 , 化合物再在脱烷基试剂存在下脱烷基得到化合物 7， 化合物 7与! ¾代烃发生缩合反应 得到 8 (此时也得到氧烷基化产物 8' , 该化合物即是 为烷氧基， R5为氢， 其余各基 团定义如上的式 I化合物） ， 8水解得到通式 I化合物； 其中 R8. R9，R10为 1-18个碳 的取代或者未取代的烃基， R,， R2, R5,与前述各通式中的定义相同；
又， 当 R3 为烷氧（硫） 曱酰基或取代的氨曱酰基， 其余基团如上面通式所定义 时， 其合成方法如路线 2:
Figure imgf000007_0001
路线 2: 通式 I化合物与各种 R9，XH ( X=0 , S , N等）在缩合剂存在下缩合得到 化合物 9， 或者通式 I化合物与酰化剂生成酰氯， 再与各种 R9，XH在缚酸剂存在下缩 合得到化合物 9。 其中 Rl 5 R2, RA , R5， R6， R7其定义与前面所述各通式中的定义相 同， R9, 为 1 -18个碳的取代或者未取代的烷基， 取代或者未取代的芳基， 杂芳基； 其中， 所说的缩合剂可以是但不限于是 DIC， DCC; 或者是 HC1, H2S04, BF3 的乙醚溶液等各种无机酸或者路易斯酸； 所说的酰化剂可以是但不限于是 S0C12, 草 酰氯等，所说的缚酸剂可以是但不限于是 DM AP , Et3N等有机碱或者是 NaOH，KOH， Na2C03 , K2C03等各种无机碱；
又， 本发明还提供了木豆素 A的制备方法， 如路线 3所示：
Figure imgf000007_0002
8 10
路线 3为木豆素 A的合成方法 （ RfPh, R2=H, ^OH, R5=异戊烯基， R6=OME, R7=H， 化合物 10为木豆素 A ) , 化合物 8在碱性或酸性条件下， 在微波的辅助下脱羧 得到化合物 10 , 式中 Ri , R2， R4, R5 , R6, R7 , R9与前述通式所定义一样；
所说的碱可以是但不限于是 KOH , NaOH , K2C03 , Na2C03等无机碱， 所说的酸 可以是但不限于是 HC1， H2S04 , H3P04等无机酸， 溶剂可以是但不限于是水， 各种醇 等极性质子溶剂或者是 DMSO, DMF等极性非质子溶剂；
又， 当 R3 为羧基， R4为羟基， R6为烷氧基， R7为 1¾素， 其余基团如上面通式所 定义时， 其合成方法如路线 4:
Figure imgf000008_0001
7 11 12 13
路线 4: 化合物 7在有机溶剂中与 化试剂反应得到化合物 11， 化合物 11在碱性 条件下与烷基化试剂偶合得到化合物 12, 化合物 12在碱性或者酸性条件下水解得到 化合物 13; 其中 X为 F, CI, Br; R!， R2, R5， R8, R9的定义如前所述；
制备化合物 11时： 所说的卤化试剂可以是但不限于是 S02C12, NCS (即 N-氯代琥 珀酰亚胺） ， NBS (即 N-溴代琥珀酰亚胺） ， Br2等卤化试剂， 所说的溶剂可以是但 不限于是 CH2C12，CHC13, CC14等鹵代烃溶剂， 或者是 MeOH, EtOH, AcOH, 丙醇， 异丙醇， 正丁醇， 叔丁醇等极性质子溶剂， 或者是乙腈， DMF等极性非质子溶剂； 制备化合物 12时： 所述的烷基化试剂可以是但不限于是各种 |¾代烃， 或者是各种 醇的磺酸酯， 所使用的碱可以是但不限于是氢化钠、 氢化钾， 氢化钙， 金属钠、 氢氧 化钾， 氢氧化钠等无机碱， 或者是醇钠、 叔丁醇钾等有机碱； 所用溶剂可以是但不限 于是醚类或芳烃类溶剂；
制备化合物 13时： 所说的碱可以是但不限于是无机碱如碳酸钾、 氢氧化钠、 氢氧 化钾等， 或胺类、 醇钠、 醇钾等有机碱； 所用的酸可以为但不限于如盐酸、 硫酸等的 无机酸， 或如乙酸等的有机酸； 溶剂为水、 醇或含有活泼氢的混合溶剂等；
又， 当 R3 为羧基， R4和 R6为烷氧基， R7为 H， 其余基团如前述通式所定义时， 其合成方法如路线 5:
Figure imgf000008_0002
8 14 15 路线 5: 化合物 8在碱性条件下与烷基化试剂反应得到化合物 14, 化合物 14再在 碱性或酸性条件下水解得到化合物 15; 式中 R! , R2, R5 , R8, R9与前述通式所定义 一致， R8, 为 1-18个碳的烷基； 在制备化合物 14时： 所说的烷基化试剂可以是但不限于是各种 代烃， 或者是各 种醇的磺酸酯或硫酸酯， 所使用的碱可以是但不限于是氢化钠、 氢化钾， 氢化钙， 金 属钠、 氢氧化钾， 氢氧化钠， 碳酸钾， 碳酸钠等无机碱， 或者是醇钠、 叔丁醇钾等有 机碱； 所用溶剂可以是但不限于是极性非质子溶剂， 或者是水或醇类极性盾子溶剂； 制备 15的方法与路线 4的水解条件一样；
又， 本发明还提供了木豆素 C的全合成方法， 如路线 6所示：
Figure imgf000009_0001
路线 6为木豆素 C 的全合成路线 （R7=异戊烯基， R8=Me, R2=H, RfPh时， 化合物 19即为木豆素 C ) , 化合物 6经过! ¾化得到化合物 16, 16与偶合试剂在催化 剂存在下发生偶联反应得到化合物 17， 化合物 17与脱烃基试剂反应得到化合物 18, 18再脱羧得到化合物 19; 式中 R1 ; R2， R7, R8， R9与前述通式所定义一致；
在制备 16时的！ ¾化条件与路线 4的条件一致；
制备 17时：所说的偶合试剂可以是但不限于是各种饱和或不饱和的三烷基锡取代 试剂， 有机硼酸类， 有机金属类 (RLi， RMgX, RZnX等）； 所说的催化剂可以是不限 于是 Pd(OAc)2, Pd(dppf)2, Pd(PPh3)4, Pd2(dba)3, PdCl2(CH3CN)2等 Pd类催化剂； 溶剂可 以是但不限于是 DMF，CH3CN等极性非质子溶剂， 或者是笨， 曱苯， 二曱苯， 氯苯等 芳烃类溶剂；
制备 18时：所说的脱烃基试剂可以是为路易斯酸性试剂（如三溴化硼，三氯化硼， 三氯化铝， 三甲基碘硅烷， 三曱基溴硅烷等）， 反应溶剂可以是但不限于是烃类溶剂， 反应温度为 -80-25 °C ;
制备 19时脱羧的方法和路线 3的方法一致；
又， 当 R3 为羧基， 、 5=OH, 其余基团如前述通式所定义时， 其合成方法如 路线 7:
Figure imgf000009_0002
路线 7: 通式 I化合物与脱烷基试剂反应得到目标化合物 20。 所说的脱烷基试剂可 以是但不限于是 HI, HBr 等质子酸， 或者是 A1X3, BX3等路易斯酸， 溶剂可以是但不 限于是卤代烃溶剂， 反应温度 -80-25°C; 式中 R!, R2, R5， R7, R8与前述通式定义相 同。
又， 当 R3=R5=R7=H, 其余基团如前述通式所定义时， 其合成方法如路线 8:
Figure imgf000010_0001
路线 8: 取代苄基膦酸酯与酮缩合反应得到目标产物 21, 缩合反应的条件与制备化 合物 6的条件一致， 式中 R!, R2, ， R6与前述通式定义相同；
又， 当 R3= (1H-咪唑 -1-基）曱酰基， 其余基团如前述通式所定义时， 其合成方法如 路线 9:
Figure imgf000010_0002
路线 9: 1位为羧基的衍生物与羰基二咪唑在有机溶剂中缩合反应得到目标产物 22， 所说的有机溶剂可以是但不限于是丙酮， DMF， DMSO等非质子极性溶剂， 或者是卤 代烃溶剂， 式中 Ri, R2, R4, R5, R6, R7与前述通式定义相同；
又， 当 R3=N- (氨基曱酰基)氨曱酰基， 或者 N- (曱脒基)氨曱酰基， 其余基团如前述 通式所定义时， 其合成方法如路线 10:
Figure imgf000010_0003
23
路线 10:1位为烷氧曱酰基的衍生物与尿素（ X=0 )或者胍（ X=NH )在有机溶剂中 缩合反应得到目标产物 23， 所说的有机溶剂可以是但不限于是曱醇， 乙醇， 异丙醇等 醇类溶剂， 式中 X=0 或者 NH， R!， R2, R4， R5, R6, R7与前述通式定义相同； 又，当 取代曱酰氧基，其余基团如前述通式所定义时，其合成方法如路线 11:
Figure imgf000011_0001
24
路线 11:2位为羟基的衍生物在碱性条件下与酰氯缩合得到目标产物 24, 所说的碱 可以是但不限于是三乙胺，吡啶，二乙胺等有机碱，或者是无水碳酸钾，碳酸钠， KOH NaOH等无机碱， 式中 R1; R2, R3, R5, R6 R7与前述通式定义相同， R10为取代或 者未取得的烷基， 取代或者未取代的杂芳环， 取代或者未取代氨基；
又， 当 氨基甲氧基或者 （哌嗪 -2-基） 曱氧基， 其余基团如前述通式所定义时， 其合成方法如路线 12 (以氨基曱氧基为例， （哌嗪 -2-基） 曱氧基与此类似） ：
Figure imgf000011_0002
25 26 路线 12: 2位为羟基的衍生物在缩合剂存在下与 N-苄基氨基甲醇缩合得到化合物 25, 化合物 25再与脱苄基试剂反应得到目标产物 26, 式中 Ri R2, R3 R5, R6, R7与前 述通式定义相同；
制备化合物 25时，所说的缩合剂可以是但不限于是偶氮二甲酸二乙酯 +三苯基膦， 偶氮二曱酸二异丙酯 +三苯基膦等缩合剂；
制备化合物 26时， 所说的脱苄基试剂可以是但不限于是 Zn+甲酸铵， Mg+甲酸铵 等；
又， 当 R4 = 异脲基， 其余基团如前述通式所定义时， 其合成方法如路线 13:
Figure imgf000011_0003
路线 13: 2位为羟基的衍生物与胺基氰在酸性条件下反应得到目标化合物 27， 所 说的酸性条件可以是但不限于是盐酸， 硫酸， 磷酸等无机酸， 也可以是甲磺酸， 三氟 乙酸等有机酸， 式中 Ri R2 R3, R5, R6 R7与前述通式定义相同； 又，当 肼基曱酰氧基，其余基团如 述通式所定义时， 合成方法如路线 14:
Figure imgf000012_0001
28 29 路线 14: 2位为羟基的衍生物在碱性条件下与碳酰氯反应得到化合物 28 , 28再与肼在 碱性条件下缩合得到目标产物 29， 式中 R,， R2 , R3 , R5 , R6, R7与前述通式定义相同； 在制备化合物 28时， 所说的碱可以是但不限于是吡啶， 三乙胺， Ν,Ν-二曱基吡啶 等有机胺， 或者是碳酸钾， 碳酸钠， 氢氧化钾等无机碱；
在制备化合物 29时， 其条件和制备化合物 28时相似，
又， 当 羧基曱酰氧基， 其余基团如前述通式所定义时， 其合成方法如路线 15 :
Figure imgf000012_0002
30 31 路线 15:2位为羟基的衍生物与 2-氯 -2-羰基乙酸甲酯在碱性条件下缩合得到化合物 30， 化合物 30再水解得到目标产物 31， 式中 R!， R2， R3 , R5 , R6 , R7与前述通式定义相 同；
制备化合物 30的条件与制备化合物 28的条件一致；
制备化合物 31的条件与制备化合物 1的条件一致；
又， 当 R3=氨曱酰基， 其余基团如前述通式所定义时， 其合成方法如路线 16:
Figure imgf000012_0003
32
路线 16: 苯环一位为烷氧曱酰基的衍生物在有机溶剂中胺解得到目标产物 32 , 所 说的有机溶剂可以是但不限于是曱醇， 乙醇， 异丙醇等醇类溶剂， 或者是卤代烃类溶 剂。 式中， R! , R2, R4 , R5 , R6, R7与前述通式定义相同， R8，为 1 -18个碳的烷基； 此外， 本发明还提供了具有式 II结构化合物的合成方法， 其中 R8为曱基， 如路线
17:
Figure imgf000013_0001
路线 17: 化合物 1在酸催化剂存在下得到脱羧， 分子内加成产物 33;
所说的酸性催化剂可以是但不限于是 A1C13, BC13, BBr3, SiMe3I等路易斯酸， 溶剂 可以是但不限于是二氯曱烷， 三氯甲烷， 氯苯等 [¾代烃溶剂； 反应温度为 0-80°C。
此外， 本发明还提供了具有式 III结构化合物的合成方法， R9为 H, R8与前面通式 所述定义一致， 如路线 18:
Figure imgf000013_0002
路线 18: 木豆素类似物 1，在 Pd类催化剂催化下， 氢化得到所有烃双键被还原的产 物；
所说的 Pd类催化剂可以是但不限于是 Pd/C, Pd/BaS04等催化剂。反应温度为 0-50 °C , 反应压力为 0-100psi, 溶剂可以是但不限于是曱醇， 乙醇， 丙醇等醇类溶剂， 或 者是乙酸等酸类溶剂， 或者是曱苯， 苯， 二曱苯等芳烃类溶剂。
此外， 本发明还提供了具有式 IV结构化合物的合成方法， 其中 R8, R9与前面通式 所述定义一致， 如路线 19:
Figure imgf000013_0003
路线 19: 化合物 7经催化氢化得到化合物 35， 35再异戊烯基化得到化合物 36, 最后经水解得到 37;
制备 35的方法与路线 18的条件一致。 制备 36的方法与路线 5烷基化条件一致， 制备 37的方法与路线 4水解条件一致。
此外， 本发明还提供了具有式 V结构化合物的合成方法， 式中 R8, R9, R10为 1-18 个碳的烷基， 如路线 20:
Figure imgf000014_0001
Figure imgf000014_0002
47
路线 20: 乙酰乙酸酯与巴豆酸酯在碱性条件下缩合得到化合物 38 , 化合物 38再溴 化芳环化得到化合物 39， 化合物 39再烷基化得到化合物 40 , 化合物 40与 化试剂发 生自由基! ¾化反应得到化合物 41 , 化合物 41与有机膦试剂缩合得到化合物 42 , 42发 生偶联反应得到烷基化产物 43， 43再氢化得到化合物 44 , 进而在碱性条件下与苯甲 醛缩合得到化合物 45 , 46再发生脱烷基和水解反应得到化合物 47。
制备化合物 38时：所说的碱性条件可以是但不限于是曱醇钠，乙醇钠，叔丁醇钠， 叔丁醇钾等有机碱， 或者是 KOH， NaOH, K2C03等无机碱； 溶剂可以是但不限于曱 醇， 乙醇等醇类溶剂， 也可以是 DMF， CH3CN等极性非质子溶剂；
制备化合物 39时： 溴化试剂可以是但不限于是液溴， NBS等， 溶剂可以是但不限 于是乙醇， 乙酸， 甲醇等质子极性溶剂， 反应温度 o-io(rc ;
制备化合物 40的方法和路线 5烷基化条件一致；
制备化合物 41时： 所用的卤化剂可以是但不限于是 N-溴代琥珀酰亚胺（NBS ) 和过氧化二苯曱酰（BPO ) 的混合物或液溴， 或者硫酰氯和 BPO混合物、 硫酰氯和偶 氮二异丁腈 （ AIBN ) 的混合物、 N-氯代琥珀酰亚胺 （ NCS ) 和 BPO或 AIBN的混合 物等； 所用的溶剂是但不限于是石油醚、 四氯化碳等非极性溶剂， 或乙腈、 氯仿等非 质子极性溶剂； 反应温度为 o°c至所选溶剂回流温度， 优选为溶剂回流温度；
制备化合物 42时： 所述有机膦试剂为亚磷酸三酯、 三芳基磷等， 缩合反应在溶剂 回流温度或更低温度下进行， 但也不排除在高温高压下进行；
制备化合物 43的方法和路线 6制备 17—致；
制备化合物 44的方法与路线 18的条件一致；
制备 45时： 反应溶剂可以是但不限于是醚类溶剂以及各种极性非质子溶剂， 碱催 化剂可以是但不限于是氢化钠、 碳酸钾等无机碱或三乙胺、 曱醇钠、 乙醇钠、 叔丁醇 钾、 二异丙基胺基锂等有机碱； 反应温度为 -10-100 °C , 优选溶剂回流温度；
制备化合物 46的条件与路线 6制备 18的条件一致；
制备化合物 47的方法与路线 4水解条件一致。
此 ， 本发明还提供了一条制备木豆素的全新合成路线， 如路线 21 :
Figure imgf000015_0001
路线 21 : 式中 R8， R9，R10为 1 -18个碳的烷基， 当 R8=Me时， 化合物 1即为木豆 素；化合物 42的制备方法与路线 20—致，与苯曱醛在碱性条件下缩合得到化合物 48 , 48再脱烷基得到化合物 49， 49再经过烷基化、 水解得到化合物 1 ;
制备化合物 48的方法与路线 20制备 42的方法一致， 制备 49的方法与路线 6制 备 18的条件一致， 制备化合物 8与路线 6制备化合物 17条件一致； 制备化合物 1的 方法与路线 4水解条件一致。
发明效果： 按照以上所述路线和方法， 本发明首次合成了大量新型木豆素类似物， 首次完成了木豆素 C的化学全合成， 对木豆素又提出了另一条全新的全合成路线。 本 发明还首次对所合成的木豆素衍生物及木豆素、 木豆素 A、 木豆素 C等化合物在抗病 毒、 神经保护、 抗代谢性疾病 （如骨质疏松、 高血脂、 高血糖） 等的药理活性进行了 测定， 部分化合物的活性超过先导物木豆素。 发明化合物的结构及药理活性测定结果 分别见表 1、 表 2。
采用细胞培养法对发明化合物的抗病毒活性歸选发现， 该类化合物具有较强的抗 呼吸道病毒作用 （表 1所示）。 其中， 化合物 lf、 lh、 lk、 11、 lq、 lt、 lu、 lw la' 、 Id' 、 8e、 8f、 8h、 8o、 8x、 8a， 、 9d、 9e、 9f、 9h、 10、 10e、 10h、 10k、 101、 10m、 10q、 10w、 10x、 10y、 10z、 10a' 、 10c' 、 10f 、 10e， 、 10f， 、 10h' 、 20、 21k、 23a、 23b、 24d、 24e、 24f、 24g、 24i、 26f、 29c、 31a 31b、 31c, 32、 46及 47等抗 流感病毒活性明显强于先导物木豆素， 并且， 与临床药物达菲相比， 上述发明化合物 的抗病毒活性与达菲相当甚至更强。
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Ζ8ΖΪ60/εΐΟΖ OAV
Figure imgf000019_0001
Figure imgf000020_0001
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Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
1 0CH3
Figure imgf000030_0001
Figure imgf000031_0001
本发明还涉及所述化合物在抑制 HIV， HCV病毒方面的应用，其结果见表 2,其中， 化合物 1、 la、 lb、 lc、 le、 lf、 li、 lj、 11、 ls、 lu、 lx、 ly、 lz、 la' 、 lb' 、 8、 8a、 8e、 8f> 8j、 8s、 8t、 8u、 8v、 8w、 9e、 10、 10b、 10h、 10i、 10j、 101、 10m> 10o、
10q、 10t、 23a、 23b, 29a、 31b、 31c 46等化合物表现出了较强的抗 HIV, HCV病毒 的活性。
表 2. 所述化合物体外抑制 HIV, HCV病毒的活性
HCV HIV
编号
EC50 ( g/ml ) IC50 ( g/ml )
1 1.21 0.27
la 1.04 1.01
lb 0.67 1.22
lc 2.69 1.64
Id 3.31 1.86
le 0.47 2.70
If 0.53 1.45
Figure imgf000032_0001
llZ.lOO/ZTOZN3/X3d Ζ8ΖΪ60/εΐ0ί OAV
Figure imgf000033_0001
/u/u naoozssd O Z6sAV
Figure imgf000034_0001
37 12.20 2.09
46 0.77 2.51
47 1.47 1.13 本发明还涉及所述化合物在神经保护方面 （对 PC 12细胞损伤的影响） 的应用， 测 定化合物对去血清损伤 PC12细胞、鱼藤酮损伤 PC12细胞的保护作用， （结果见表 3 ) . 发明化合物对去血清损伤 PC 12细胞和鱼藤酮损伤 PC 12细胞均具有明保护作用，其中， 化合物 lp、 lr、 lu、 lw、 lz> la' 、 lb' 、 Id' 、 8d、 8m、 8p、 8q、 8w、 9e、 9g、 10c、 10j、 10k、 101、 10m、 10o、 10p、 10t、 lOu及 10v、 10c' 、 10d' 、 21d、 24b、 24k、 24q、 27b、 32等活性最强。
表 3 : 发明化合物的神经元保护作用
Figure imgf000035_0001
lz 91.6± 1.6 89.9 ±4.8 la' 88.7 ±4.9 87.2 ±4.3 lb' 88.9 + 1.9 87.2 ±6.31 lc， 85.9 ±4.7 85.6 ±3.8'
Id' 89.9 ±4.5 88.6 ±4.5
6 62.4 ±7.0 74.4 ±5.2
7 66.8 + 6.0 77.0 ±3.6
8' 40.0 + 3.6 74.3 + 5.0
8 76.6 + 5.8 78.9 + 5.7
8a 65.2 + 6.9 76.9 ±4.1
8b 75.1 ±3.6 80.7 + 6.4
8c 67.3土 10.0 71.9 + 6.1
8d 82.0 + 3.2 84.4 ±3.6
8e 58.5±8.7 74.5±3.8
8f 60.7±12.6 74. 1.8
8g 29.1±11.6 59.0±4.6
8h 35.4±10.6 72.4±4.3
8i 46.4±16.6 69.4±2.6
8j 34.4±3.2 63.6±5.0
81 51.1±17.0 64.7±1.8
8m 84.7 + 5.0 69.8 ±5.2
8n 53.7 ±3.8 78.0 ±9.2
8o 69.3 + 5.6 70.6 + 6.3
8p 82.3土 5.6 84.6 ±5.9
8q 79.8 ±5.8 80.5 + 6.5
8r 74.5 + 5.7 69.8 + 8.4
8s 79.8 + 5.2 76.8 ±5.4
8w 89.7 + 5.4 84.9 ±5.9
8x 79.8 ±2.6 76.5 ± 1.8
8y 49.8 ±2.6 48.9 ±6.5
8a， 87.9 ±2.5 88.0 + 6.9
9a 49.6±13.2 70.9±6.4
9b 42.9±11.3 74.5士 12.1
9c 47.9±11.4 62.9±3.8
9d 55.4±10.7 71.0±1.5
9e 91.3 ±2.4 90.8 ±4.3
9f 58.9 ±2.6 68.5 ±4.9
9g 89.4 ±2.3 87.4 ± 1.9
9h 84.5 ± 5.1 79.8 + 2.1
10 34.7 ±9.8 69.9 ±5.8
10a 78.2 ±4.1 79.8 + 5.6
10b 74.8 + 5.2 74.6 ±6.3
10c 81.6±2.6 80.3 ±6.2 d 79.3 ±5.4 78.9 + 6.1 e 65.3 ±2.3 70.2 ±8.1 f 74.5 ±6.5 76.5 ±8.0g 81.3 + 2.5 80.3 ±3.2h 65.8 ±9.2 67.8 ±8.5 i 78.5 ±7.4 79.1 ±7.2/ 82.3 +2.5 84.6 ±5.2k 85.6 + 3.2 84.6 ±2.4 1 81.3 ±2.9 84.6 ±6.2m 89.3 ±6.4 85.3 ±7.1η 79.6 + 2.8 78.6 ±3.2o 86.3 ±3.8 87.6 ±5.4p 84.6 ±2.7 86.7 ±9.1q 79.5 ± 1.4 76.8 ±5.8 r 68.5 ±2.4 58.4 ±6.5 s 78.5 ±6.3 79.8 ±3.5 t 84.9 ±2.5 85.6 ±6.3u 87.6 ±3.2 85.4 ±2.3v 85.2 ±4.1 87.1 ±2.5
79.1 +4.6 78.2 ±5.8x 78.9 ±4.6 78.9 ±5.4y 89.1 ±5.4 89.5 ±2.5z 84.6 ±3.9 87.0 ±5.1a' 86.3 ± 1.2 89.2 ±3.2b， 84.3 ±2.5 85.9 ±3.4c' 89.7 + 2.4 91.2±2.1d' 91.2 ±3.2 94.3 ± 5.4e' 87.9 ±4.7 88.9 ±2.8Γ 80.5 ±3.2 79.1 ±5.6g' 71.0 + 5.2 63.5 ±2.1h' 87.6 ±4.3 86.7 ±4.52 60.2 + 5.1 74.5 ±3.23 21.3 ±4.2 74.4土 6.44 69.7 ±5.6 73.7 ±8.55 74.1 ±2.5 83.1 +5.78 77.8 ±6.3 74.9 ±2.99 62.7 ±5.8 80.1 ±6.90 32.3±5.6 67.3土 3.1 a 81.2 + 2.4 80.5 ±2.3b 74.6 + 3.5 78.9 ±6.8d 88.7 ±6.3 89.8 ±2.8 e 85.6 ±4.2 87·4±2·5 g 80.2 ± 1.5 82.3 ±3.1 21h 74.8 ±2.6 71.2±3.8
21j 69.3 ±2.5 75.6 ±4.6
21k 74.5 ±5.8 71.3 + 8.0
22 87.8 ±2.9 85.6 + 1.6
23a 87.9 ±5.8 85.6 + 8.7
23b 79.8 ±4.6 81.3 + 5.0
24b 89.7 + 5.6 88.3 ±5.2
24e 87.2 ±2.4 86.9 + 5.8
24h 88.9 ±5.4 87.8 ±6.3
24k 89.6 ±2.3 85.6 ±2.1
24n 75.8 + 3.2 79.8 + 5.6
24q 92.3士 1.2 90.5 + 5.6
26b 88.2 + 4.1 89.7 + 6.3
26e 85.6 + 2.9 87.6 + 5.6
27b 91.5 ±6.1 92.3 ±2.6
29b 74.5 ±4.6 78.9 + 5.6
31b 88.6 ±2.6 80.5 ±6.4
32 94.5 ±2.3 92.3土 1.2
33 16.8 ±0.4 75.6±2.1
36 41.0士15.4 72.2±12.2
37 29.0±11.2 60.4±7.8
46 59.0±14.3 73.9±2.9
47 30·2±9·9 61.9±4.1 本发明还涉及所述化合物的抗骨质疏松作用。 文献报道， 木豆芪类化合物属于植 物雌激素， 天然产物的抗骨质疏松作用与其具有雌激素样作用有关。 本发明对通过化 学手段得到的木豆素纯品对去势大鼠骨质疏松保护效果进行了研究确证， 结果显示， 其在动物体内的抗骨质疏松效果强于临床药物雷诺昔芬。
另外， 正如发明背景所述， 木豆芪类提取物及木豆素、 木豆素 Α、 木豆素 C具有 抗肿瘤、 降血糖降血脂、 抗炎镇痛作用被广泛研究和报道。 本发明化合物是以天然产 物木豆素、 木豆素 Α及木豆素 C为先导化合物的结构类似物， 本发明化合物同时具有 先导物类似的抗肿瘤、 降血糖降血脂、 抗炎镇痛作用是显而易见的。 因此， 本发明还 涉及所述化合物在抗肿瘤、 降血糖降血脂、 抗炎镇痛等方面的应用。
并且， 本发明还提供一种用于抗病毒和细菌感染、 神经保护、 抗代谢性疾病（如骨 质疏松、 高血脂、 高血糖） 等的药物组合物， 该药物组合物中含有治疗有效量的所述 具有通式 I 、 II、 III、 IV、 V的化合物或其药用盐， 并含有一种或多种药学上可接受 的药物辅剂。 其中， 所述具有通式 I 、 II、 III、 IV、 V的化合物或其药用盐作为活性成分， 在该 药物组合物中的重量含量为 0.1 %-99.5%。 优选的， 该药物组合物中含有重量比为 0.5%-99.5%的活性成分。
进一步， 本发明提供所述组合物在制备抗细菌和病毒感染、 神经保护、 抗代谢性 疾病 （如骨质疏松、 高血脂、 高血糖） 等药物中的应用。 附图说明
图 1为木豆芪类提取物的化学结构。 具体实施方式
实施例 1
2, 4-二羟基 -6-曱基苯曱酸曱酯的制备（2 )
乙酰乙酸曱酯（ 50g, 0.43mol )溶于 300ml乙醚中，在室温加入 NaH (15.50g 0.45mol, 70%), 加毕， 在此温度滴加二乙烯酮 （37g, 0.45mol ) 的乙瞇溶液， 加毕， 在室温反 应 3-4h, 此时反应体系变为黄色混浊液。 终止反应， 将反应液加到 500ml 冰水混合液 中， 分出乙醚层， 水层用 50ml乙瞇萃取 2次， 合并乙醚层， 并用饱和食盐水洗， 无水 硫酸镁干燥过夜。 过滤， 旋蒸除去乙醚， 剩余物用石油醚： 乙酸乙酯 =8: 1过硅胶柱， 得到 35g ( 45% ) 白色固体即为目标产物。 'H-NMR(400M, DMSO-d6) δ (ppm): 2.26(s, 3H), 3.78(s, 3H), 6.14(d, J=2.4Hz, 1H), 6.16(d, J=2.4Hz, 1H), 9.95(s， 1H), 10.66(s, 1H) 实施例 2
2, 4-二曱氧基 -6-甲基苯曱酸曱酯的制备（3 )
化合物 2 ( 12g, 0.066mol )溶于 50ml 丙酮中， 加入碳酸钾 ( 27.3g, 0.198mol ) , 碘曱烷（28g, 0.198mol ) , 加热回流反应 3h， 停止反应， 反应液加入 100ml水中， 用 乙酸乙酯萃取（ 3 50ml ) ， 合并有机层， 有机层依次用 10% 的氢氧化钠溶液， 10%盐 酸， 饱和食盐水洗。 有机层用无水硫酸镁干燥。 过滤， 旋蒸除去溶剂， 得到无色油状 物， 用石油醚 /乙酸乙酯重结晶得到无色晶体 13.5g ( 97% )。 1H-NMR(400M, CDC13) δ (ppm): 2.28(s, 3H), 3.80(s, 6H), 3.88(s, 3H), 6.31 (s, 2H)
实施例 3
2-溴曱基 -4， 6-二曱氧基苯曱酸曱酯 （4 )
化合物 3 ( 10g, 0.0476mol )溶于 50ml 四氯化碳中， 氮气保护， 加热回流， 分批 加入 NBS(8.5g, 0.0476mol)+ BPO(0.1 1g, 0.476mmol)的混合物， 加完， 回流反应 lh。 停 止反应， 冷却， 过滤， 滤液旋干， 得浅黄色固体， 用无水乙醇重结晶得白色固体 1 1.3g ( 82% ) 。 1H-NMR(400M, CDC13) δ (ppm): 3.85(s, 3H)， 3.93(s， 3H), 3.96(s， 3H), 4.66(s， 2H), 6.47(s, 1 H), 6.74(s, 1H).
实施例 4
2-亚磷酸二乙酯曱基 -4， 6-二曱氧基苯曱酸曱酯 （ 5 )
化合物 4 ( 12g, 0.0326mol ) 与亚磷酸三乙酯 （ 10.83g, 0.065mol ) 的混合物， 加 热回流反应 2h。停止反应，冷却，减压蒸去过量的亚磷酸三乙酯，剩余物用二氯曱烷： 曱醇 =40: 1过硅胶柱得到白色固体 12.8g ( 92% ) 。 'H-NMR(400M, CDC13) δ (ppm): 1.26(t, J=6.4Hz, 6H), 3.78(d, J=22.8Hz, 2H)， 3.80(s, 3H), 3.90(s, 3H), 3.92(s, 3H)， 4.02(q, J=6.4Hz, 4H), 6.43(s, 1 H), 6.76(s, 1 H).
实施例 5
2 , 4-二曱氧基 -6-[(E)-苯乙烯基]苯曱酸甲酯 （6 )
化合物 5 ( 10g， 0.0289mol )溶于 100ml四氢呋喃中，加入 NaH(1.09g, 0.0318mol) , 苯甲醛（ 3.68g, 0.0347mol ) ,加热回流反应 2h,停止反应，反应液加入到 200ml水中， 用乙酸乙酯萃取（3 100ml )，合并有机层，有机层用饱和食盐水洗， 无水硫酸镁干燥。 过滤，旋蒸去除溶剂，剩余油状物用石油醚 /乙酸乙酯重结晶得到无色晶体 6.2g( 72% )。 1H-NMR(400M, CDC13) δ (ppm): 3.83(s, 3H), 3.88(s, 3H), 3.92(s, 3H)， 6.42(s, 1H)， 6.77(s, 1H), 7.06(dd, J=16Hz, 2H)， 7.29(m， 1H), 7.35(t, J=7.2Hz, 2H), 7.47(d, J=7.2Hz, 2H).
实施例 6
2-羟基 -4-甲氧基 -6-[(E)-苯乙烯基]笨曱酸曱酯 （ 7 )
化合物 6 ( 6g, 0.0201mol )溶于 50ml二氯曱烷中， 在 0°C时滴加 BBr3的二氯甲烷 溶液（24ml， 1 M ) ， 滴完， 室温反应 lh, 停止反应。 反应液用水洗， 无水硫酸镁干 燥。 过滤， 旋蒸除去溶剂， 剩余物用石油醚 /乙醚过硅胶柱得到白色固体 5.4g (95%)。 1H-NMR(400M, CDC13) δ (ppm): 3.79(s, 3H), 3.82(s， 3H), 6.40(d, J=2.4Hz, 1H)， 6.80(d, J=2.4Hz, 1H), 7.15(dd, J=16Hz, 2H)， 7.28(t, J=7.2Hz, 1H), 7.38(t, J=7.2Hz, 2H), 7.52(d, J=7.2Hz, 2H), 10.28(s, 1 H).
实施例 Ί
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-笨乙浠基]苯曱酸甲酯 （8 )
化合物 7 ( 5g, 0.0176mol ) 溶于 50ml乙醚中， 加入金属钠 （ 0.43g, 0.0184mol ) ， 室温搅拌 4h， 加入异戊烯基溴 （ 3.2g， 0.021 1mol ) , 回流反应 4h, 停止反应， 反应液 •(HI '«ι)59'ΐΐ '(HI
Figure imgf000041_0001
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实施例 45
2, 4-二甲氧基 -6-[(E)-2- (噻吩 -2-基）乙烯基]笨甲酸甲酯 （6j )
以 2-噻吩甲醛为原料， 以实施例 5类似的方法得到化合物， 白色固体 (83%)。
1HNMR (400 MHz, CDC13): 3.82(s, 3H)， 3.84(s, 3H), 3.86(s, 3H), 6.40(s, IH), 6.70(s, 1H)， 6.90(d, J= 15.6Hz, IH), 6.99(t, J=4.0Hz, IH), 7.07(d, J=4.0Hz, 1H)， 7.14(d， J=4.0Hz, IH), 7.24(d,J= 15.6Hz, IH).
实施例 46
2-羟基 -4-甲氧基 -6-[(E)-2- (噻吩 -2-基）乙烯基]苯甲酸甲酯 （7j )
以化合物 6j为原料，按实施例 6的方法反应得到化合物，白色固体 (78%)。 1H NMR (400 MHz, CDC13): 3.84(s, 3H), 3.96(s， 3H), 6.43(s, IH), 6.60(s, IH), 6.95(d， J=15.6Hz, IH), 7.01(d, J=4.4Hz， IH), 7.06(t, J=4.4Hz, 1H)， , 7.21(d, J=4.4Hz, IH), 7.55(d, J=15.6Hz， IH), 11.68(s, IH).
实施例 47
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2- (噻吩 -2-基）乙烯基]苯曱酸曱酯 （ 8j ) 以化合物 7j为原料， 按照实施例 7的方法得到化合物， 白色固体 (60%)。 1H NMR (400 MHz, DMSO-d6): 1.68(s, 3H), 1.78(s, 3H)， 3.36(d, J=7.2Hz, 2H), 3.91(s, 3H), 3.95(s, 3H), 5.21(t,J=7.2Hz, 1H)， 6.58(s, IH), 6.92(d, J=16.0Hz, IH), 7.01(t, J=4.0Hz, IH), 7.06(d, J=4.0Hz, IH),， 7.20(d, J=4.0Hz, IH), 7.57(d, J=16.0Hz, IH), 11.67(s, IH).
实施例 48
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2- (噻吩 -2-基）乙烯基]苯甲酸 （ lj )
以化合物 8j为原料， 按照实施例 8的方法得到化合物， 白色固体 (89%)。 1HNMR (400 MHz, DMSO-d6): 1.61(s, 3H), 1.72(s, 3H), 3.24(d, J=7.2Hz, 2H)， 3,91(s， 3H)， 5.11(t, J=7.2Hz, IH), 6.79(s, 1H)， 7.06(dd, Jl-3.2Hz, J2=4.0Hz, IH), 7.18(d, J=3.2Hz, 1H)， 7.26(d,J=15.6Hz, 1H)， 7.46(d, J=4.0Hz, 1H)， 7.67(d, J=15.6Hz, IH), 12.30(br, 1H)， 14.10(br, IH).
实施例 49
2, 4-二曱氧基 -6-[(£)-3， -苯基丙 -Γ -烯基]苯甲酸曱酯 （6k)
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HZ.l00/il0iNJ/X3d Z8Z160/£10Z OAV 2-羟基 -3-(3， ，7， -二甲基辛 -2， ，6， -二烯基) -4-曱氧基 -6-[(E)-苯乙烯基]苯甲酸曱酯 ( 8o )
以化合物 7及 3',7，-二甲基辛 -2，，6'-二烯基溴为原料，按照实施例 7的方法得到化 合物， 浅黄色油状物 (60%)。 Ή NMR (400 MHz, CDCl3): 1.57(s, 3H), 1.64(s, 3H), 1.78(s, 3H), 2.03(m, 4H), 3.78(d, J=6.8Hz, 2H), 3.91 (s， 3H), 3.92(s， 3H), 5.07(t, J=6.8Hz, IH), 5.22(t, J=6.8Hz, IH), 6.61 (s, IH), 6.78(d, J=l 6.0Hz, 1H)， 7.28(t, J=7.6Hz, 1H)， 7.37(t, J=7.6Hz, 2H)， 7.50(d, J=7.6Hz, 2H), 7.72(d, J=l 6.0Hz, IH), 1 1.66(s， IH).
实施例 66
2—羟基—3-(3，，7， -二甲基辛 -2， ，6， -二烯基) -4-曱氧基 -6-[(E)-苯乙烯基]笨甲酸（ l o ) 以化合物 8o为原料，按照实施例 8的方法得到化合物， 白色固体 (89%)。 1H NMR
(400 MHz, CDC13): 1.56(s, 3H), 1.64(s， 3H), 1.79(s, 3H), 2.03(m, 4H), 3.27(d, J=6.4Hz， 2H), 3.88(s, 3H), 5.07(t, J=6.4Hz, IH), 5.18(t, J=6.8Hz, 1H)， 6.42(s, 1H)， 6.66(d， J=16.0Hz IH), 7.24(t, J=7.6Hz, 1H)， 7.29(t, J=7.6Hz， 2H), 7.4 l (d, J=7.6Hz， 2H), 7.77(d, J=l 6.0Hz, IH).
实施例 67
2, 4-二曱氧基 -6-[(E)-2-环己基乙烯基]笨曱酸曱酯 （ 6p )
以环己基曱醛为原料，按照实施例 5类似的方法得到化合物，无色油状液体（ 84% )。 1H NMR (400 MHz, CDC13): 1.39(m, 5H), 1.60(m, 5H)， 2.20(m, IH), 3.80(s, 6H)， 3.90(s, 3H), 6.03(d, J=16.0Hz, 1H)， 6.48(s, IH), 6.70(s, IH), 6.98(d, J=l 6.0Hz, IH).
实施例 68
2—羟基—4-甲氧基 -6-[(E)-2-环己基乙烯基]苯曱酸曱酯 （ 7p )
以化合物 6p为原料，按照实施例 6类似的方法得到化合物，无色油状液体（ 89% )。 'H NMR (400 MHz, CDC13): 1.40(m, 5H), 1.62(m, 5H)， 2.19(m, IH), 3.80(s, 3H), 3.90(s, 3H), 6.08(d, J=16.0Hz, 1H)， 6.46(s, 1 H)， 6.75(s, IH), 6.97(d, J=16.0Hz, IH), 1 1.66(s, IH). 实施例 69
2—羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-环己基乙烯基]苯甲酸曱酯 （ 8p )
以化合物 7p为原料，按照实施例 7类似的方法得到化合物，无色油状液体（ 59% )。 1H NMR (400 MHz, CDCI3): 1.35(m, 5H)， 1.59(m, 5H), 1.68(s, 3H), 1.79(s, 3H), 2.19(m, IH), 3.35(d, J-7.2Hz, 2H), 3.80(s, 3H), 3.88(s, 3H), 5.21 (t, J=7.2Hz, IH), 6.60(s, 1H)， 6.75(d, J=16.0Hz, IH), 7.30(d, J=16.0Hz, IH), 1 1.78(s, IH).
实施例 70 .
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Il.100/Z10ZN3/X3d Ζ8ΖΪ60/εΐΟΖ OAV 以 2-曱酰基 -4,6-二曱氧基吡啶为原料， 按照实施例 5的方法得到化合物， 白色固 体（ 75% )。 1H NMR (400 MHz, DMSO-d6): 3.87 (s, 9H).3.94 (s， 6H)， 6.24 (s， IH), 6.26 (s, IH), 6.50 (s， IH), 6.69 (s, IH), 7.08 (d, J=l 6.0Hz, IH), 7.72 (d, J=16.0Hz, IH).
实施例 102
2-羟基 -4-曱氧基 -6-[(E)-2-(4,6-二甲氧基吡啶 -2-基）乙烯基]苯曱酸曱酯 （ 7x ) 以化合物 6x 为原料，按照实施例 6的方法得到化合物，白色固体（ 85% )。 1H NMR (400 MHz, DMSO-d6): 3.87 (s, 3H)， 3.91(s,3H)， 3.94 (s, 6H), 6.23 (s, IH), 6.27 (s, IH), 6.48 (s, IH), 6.70 (s, IH), 7.12 (d,J=l 6.0Hz, IH), 7.52 (d,J=l 6.0Hz, IH), 11.21(s, IH). 实施例 103
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-(4，6-二曱氧基吡啶 -2-基）乙烯基]笨甲酸曱酯（ 8x ) 以化合物 7x 为原料，按照实施例 7的方法得到化合物，白色固体（ 65% )。 1H NMR (400 MHz, DMSO-d6): 1.85(s, 3H), 1.90(s, 3H)， 3.43(d, J= 7.6Hz, 2H), 3.89 (s, 3H), 3.91(s, 3H), 3.92 (s, 6H)，， 5.21(t, J = 7.6Hz, IH), 6.23 (s, IH), 6.27 (s, IH), 6.70 (s， IH), 7.13 (d,J= 16.0Hz, IH), 7.50(d, J=16.0Hz, IH), 10.21(s, IH).
实施例 104
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-(4,6-二曱氧基吡啶 -2-基）乙烯基]苯曱酸（ lz ) 以化合物 8x 为原料，按照实施例 8的方法得到化合物，白色固体（ 85%)。 1HNMR (400 MHz, DMSO-d6): 1.88(s, 3H), 1.95(s, 3H), 3.40(d, J= 7.6Hz, 2H), 3.91(s, 3H), 3.94 (s, 6H)，， 5.23(t, J= 7.6Hz, IH), 6.22 (s, IH), 6.28 (s, IH), 6.72 (s， IH), 7.16 (d, J=16.0Hz， IH), 7.50(d， J= 16.0Hz, 1H)， 10.29(s, IH), 12.45(s, IH).
实施例 105
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-(4，6-二羟基吡啶 -2-基）乙浠基]笨曱酸（ la，） 以化合物 lz 为原料，按照实施例 6的方法得到化合物，白色固体（ 65%)。 1HNMR (400 MHz, DMSO-d6): 1.88(s, 3H)， 1.95(s, 3H), 3.40(d,J= 7.6Hz, 2H), 3.91(s, 3H), 5.23(t, J=7.6Hz, IH), 6.22 (s, IH), 6.28 (s, IH), 6.72 (s， 1H)， 7.16 (d, J=l 6.0Hz, IH), 7.50(d, J=l 6.0Hz, IH), 10.21(s, IH), 10.29(s, IH), 11.10 (s， IH), 12.45(s, IH).
实施例 106
2,4-二曱氧基 -6-[(E)-2-(6-甲氧基吡啶 -2-基）乙烯基]苯曱酸甲酯 （ 6y )
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Ζ8ΖΪ60/εΐΟΖ OAV 实施例 116
N-环丙基 -2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酰胺 （ 9d )
将木豆素（0.2g， 0.59mmol)溶于二氯曱烷 (15ml), 加入 DCC(0.15g, 0,71mmol), 室 温搅拌 0.5h, 加入环丙胺 (50mg, 0.88mmol), 室温反应 3h, 反映毕。 蒸出容剂， 剩余 物过硅胶柱得到白色固体（85%)。 Ή NMR (400 MHz, CDC13): 0.48(m, 2H), 0.83(m, 2H), 1.68(s, 3H)， 1.79(s, 3H), 2.88(m, IH), 3.37(d, J=7.2Hz, 2H), 3.89(s, 3H)， 5.22(t, J=7.2Hz, IH), 6.23(br, IH), 6.46(s, 1H)， 6.89(d, J=l 6.0Hz, IH), 7.24(d, J=l 6.0Hz, IH), 7.33 (t, J=7.6Hz, IH), 7.41(t， J=7.6Hz, 2H), 7.47(d, J=7.6Hz, 2H).
实施例 117
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯甲酸 2,3-二羟基丙酯 （ 9e ) 以甘油为原料， 按照实施列 116的方法得到目标产物， 白色固体（65%)。 1HNMR (400 MHz, CDC13): 1.82(s, 3H), 1.91(s, 3H), 3.22(d,J= 7.6Hz, 2H), 3.56(m, IH), 3.73(s, 3H), 3.81(m， IH), 3.90(m, 1H)， 4.28(m, IH), 4.53(m, lH),4.78(s, IH), 4.81(s, IH), 5.22(t, J=7.6Hz, IH), 6.70(s, 1H)， 6.82(d， J= 16.0Hz, IH), 7.26(d,J= 16.0Hz, 1H)， 7.30(d,J = 8.0Hz, IH), 7.42(d,J= 8.0Hz, 2H)， 7.45(t,J= 8.0Hz, 2H), 9.98(s, IH).
实施例 118
N- (哌啶 -4-基） -2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(£)-苯乙烯基]笨曱酰胺 （9f) 以为哌啶 -4-胺原料， 按照实施列 116的方法得到目标产物， 白色固体 （ 60% ) 。
IH NMR (400 MHz, CDC13): 1.68(s, 3H), 1.76(m, 4H), 1.79(s, 3H), 2.74(m, 4H)， 3.22(d, J= 7.6Hz, 2H), 3.60(m 1H)， 3.73(s, 3H), 4.52(s, IH), 5.21 (t， J = 7.6Hz, IH), 6.68(s, IH),
6.82(d,J= 16.0Hz, IH), 7.24(d,J= 16.0Hz, 1H)， 7.32(d, J= 8.0Hz, IH), 7.45(d， J= 8.0Hz:
2H), 7.48(t, J= 8.0Hz, 2H), 8.45(s, IH), 9.98(s, IH).
实施例 119
N-苯基 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酰胺 （9g)
以苯胺为原料， 按照实施列 116的方法得到目标产物， 白色固体（78%)。 1HNMR
(400 MHz, CDC13): 1.78(s, 3H), 1.79(s, 3H), 3.26(d, J= 7.6Hz， 2H), 3.73(s, 3H), 5.20(t,J = 7.6Hz， IH), 6.69(s, IH), 6.84(d,J= 16.0Hz, IH), 7.28(d,J= 16.0Hz, IH), 7.32(m,
3H),7.45(m, 5H), 7.70(d, J=7.2Hz, 2H)， 9.89(s, 1H)， 10.35(s, IH).
实施例 120
N-对氯苯基 2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]笨曱酰胺 （9h) 以对氯苯胺为原料， 按照实施列 116的方法得到目标产物， 白色固体 （85%) 。 IH NMR (400 MHz, CDC13): 1.79(s, 3H), 1.82(s, 3H), 3.24(d, J= 7.6Hz, 2H), 3.78(s, 3H), 5.21(t,J= 7.6Hz， 1H), 6.65(s, 1H), 6.82(d,J= 16.0Hz, 1H), 7.24(d,J= 16.0Hz, 1H), 7.30(t. J= 7.6Hz, 1H), 7.44(m， 6H)， 7.66(d, J=7.2Hz, 2H), 9.98(s, 1H), 10.36(s, 1H).
实施例 121
木豆素 A (10)
化合物 8( lg, 2.84mmol)溶于 10ml 乙醇和 5ml 水中，加入 KOH( 0.5g, 8.5mmol ), 微波反应 lh (30W, 25psi, 100°C ) , 反应毕。 反应液加入 50ml水中， 用 10% 的盐 酸调节 pH小于 2， 用乙酸乙酯萃取（ 3 X30ml) , 合并有机层， 有机层再用饱和食盐 水洗， 无水硫酸镁干燥过夜。 次日过滤， 浓缩得浅黄色固体， 再用石油醚 /乙酸乙酯过 硅胶柱，得到白色固体 0.66g (80 1HNMR (400 MHz, CDC13): 1.75(s, 3H)， 1.82(s, 3H), 3.41(d, J= 6.8Hz, 2H), 3.87(s, 3H), 5.24(m, 2H), 6.64(s， 1H), 6.66(s, 1H), 7.02(dd,
J=l 6.0Hz, 2H), 7.28(t, J=7.2Hz, 1H), 7.35(t， J= 7.2Hz, 2H), 7.50(d, J= 7.2Hz, 2H).
实施例 122
2-异戊烯基 -3-甲氧基 -5-[(E)-(4，-氟苯乙烯基)]苯酚（ 10a)
以化合物 8a 为原料， 按照实施例 121类似的方法得到目标化合物， 白色固体 ( 75% ) 。 1H NMR (400 MHz, CDC13): 1.76(s, 3H)， 1.79(s, 3H), 3.35 (d, J= 6.8Hz, 2H), 3.88(s, 3H), 5.21(m, 2H), 6.64(s, 1H), 6.67(s, 1H), 7.02(dd, J=16.0Hz, 2H), 7.40(d,
J=8.4Hz， 2H), 7.48(d, J=8.4Hz, 2H), 11.20(s, 1H).
实施例 123
2-异戊烯基 -3-曱氧基 -5-[(E)-2，-氯笨乙烯基]苯酚（ 10b)
以化合物 8b 为原料， 按照实施例 121类似的方法得到目标化合物， 白色固体
( 76% ) 。 1H NMR (400 MHz, CDC13): 1.61(s, 3H), 1.71(s, 3H)， 3.25(d, J=7.2Hz， 2H), 3.90(s, 3H), 5.11(t,J=7.2Hz, 1H), 6.37(s, 1H), 6.33(s, 1H), 7.13(d, J=16.0Hz, 1H), 7.35(m, 2H), 7.47(d, J=7.6Hz, 1H), 7.74(d. J=7.6Hz, 1H), 7.86(d, J=l 6.0Hz, 1H), 11.61(s, 1H). 实施例 124
2-异戊烯基 -3-曱氧基 -5-[(E)-4，-曱氧基苯乙烯基]苯酚 （ 10c)
以化合物 8c 为原料， 按照实施例 121类似的方法得到目标化合物， 白色固体 ( 73% ) 。 'Η NMR (400 MHz, CDCI3): 1.68(s, 3H), 1.79(s, 3H), 3.35(d， J=6.8Hz, 2H), 3.87(s, 3H), 3.94(s, 3H), 5.23(t, J=6.8Hz， 1H), 6.33(s, 1H), 6.38(s, 1H), 6.78(d, J=l 6.0Hz, 1H), 6.92(d,J=8.4Hz, 2H), 7.48(d， J=8.4Hz， 2H), 7.68(d, J=16.0Hz, 1H), 11.58(s, 1H). 实施例 125
2-异戊烯基 -3-甲氧基 -5-[(E)-2，，6， -二曱氧基苯乙烯基]苯酚（ 10d) on οε
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Figure imgf000065_0002
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Figure imgf000066_0004
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Figure imgf000066_0006
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Figure imgf000067_0001
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Figure imgf000067_0002
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Figure imgf000067_0003
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Figure imgf000067_0007
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Figure imgf000068_0001
•(HI 's)ie-n
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Figure imgf000068_0002
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Figure imgf000068_0005
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Figure imgf000068_0006
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Figure imgf000069_0001
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Figure imgf000069_0002
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Figure imgf000069_0003
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Figure imgf000069_0004
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Figure imgf000069_0005
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's)6 l '(HI 's) 1Γ8 '(HI 0'9t =/"P)0S-. '(HI L= 'V)iY L '(HI ' 0'91=/> 'Ρ) 6ΓΑ '(HI 'ζΗ9Κ'Ρ)9ΐ·Α '(HI 's)0fr'9 '(HI 's) S "9 '(HI ¾9'/, ¾03'S '(H£ 's) 16
Tl.100/Z10ZN3/X3d Z8Z160/C10Z OAV 'HNMR (400 MHz, CDC13): 1.79(s, 3H), 1.84(s, 3H), 3.41(d, J= 7.6Hz, 2H), 3.82 (s, 3H), 5.20(t, J= 7.6Hz, 1H), 6.54(d,J= 7.2Hz, 1H), 6.57 (d,J= 7.2 Hz, 1H), 6.38 (s, 1H), 6.45(s, 1H)， 7.24 (d,J= 16.0Hz, 1H), 7.39 (t, J=7.6Hz, 1H), 7.52 (d,J= 16.0Hz, 1H)， 9.89(s, 1H). 实施例 155
2-烯丙基 -3-甲氧基 -5-[(E)-苯乙烯基]笨酚（ 10h， )
以化合物 Id，为原料，按照实施例 121类似的方法得到目标化合物，白色固体（ 80%)。 Ή NMR (400 MHz, CDC13): 3.24(d, J=7.6Hz, 2H), 3.77(s, 3H), 4.91 (dd, Jl = 16.0Hz, J2=12.0Hz, 1H), 4.93(dd, Jl= 6.4Hz, Jl = 12.0Hz, 1H)， 6.30(m, 1H), 6.32(s, 1H), 6.38(s, 1H), 6.82(d,J= 16.0Hz, 1H), 7.31(m, 2H), 7.45(d，J= 7.6Hz, 2H), 7.51(t, J= 7.6Hz, 2H), 9.88(s, 1H).
实施例 156
2—羟基—4-曱氧基 -5-氯 -6-[(E)-苯乙烯基]苯曱酸曱酯 （ 11 )
化合物 7 (12g, 0.042mol)溶于无水乙瞇（150ml), 在室温滴加硫酰氯（11.2g,
0.084mol), 滴完， 回流反应 3h， 反应毕。 冷却至 0°C， 有白色固体析出， 过滤得目标 产物，白色固体（11.4g, 85%)。 1H NMR (400 MHz, CDCl3):3.82(s, 3H), 3.94(s， 3H)， 6.48(d, J=l 6.0Hz, 1H), 6.52(s， 1H), 7.20(d, J=l 6.0Hz, 1H), 7.30(t, J=8.0Hz, 1H), 7.38(t, J=8.0Hz, 2H), 7.50(d, J=8.0Hz, 2H),
实施例 157
2_羟基 _3_异戊烯基— 4—曱氧基 5—氯 _6-[(E)-苯乙烯基]苯曱酸甲酯 （ 12)
以化合物 11为原料， 按照实施例 7的方法得到化合物， 白色固体 (61%)。 1HNMR
(400 MHz, CDC13): 1.63(s, 3H), 1.73(s, 3H), 3.36(d, J=6.8Hz, 2H), 3.73(s, 3H), 3.79(s, 3H), 5.15(t,J=6.8Hz, 1H)， 6.38(d, J=16.4Hz, 1H), 7.14(d, J=16.4Hz, 1H), 7.22(t, J=8.0Hz, 1H), 7.30(t, J=8.0Hz, 2H), 7.41(d, J=8.0Hz, 2H), 10.85(s， 1H).
实施例 158
2-羟基 -3-异戊烯基- 4-甲氧基 -5-氯 -6-[(E)-苯乙烯基]苯曱酸 （ 13)
以化合物 12为原料，按照实施例 8的方法得到化合物 , 白色固体 (86%)。 1HNMR (400 MHz, CDC13): 1.70(s, 3H), 1.80(s, 3H), 3.43(d, J=6.8Hz, 2H)， 3.88(s， 3H), 5.21(t, J=6.8Hz, 1H), 6.59(d,J=16.4Hz, 1H)， 7.18(d, J=16.4Hz, 1H), 7.33(t, J=8.0Hz, 1H), 7.38(t, J=8.0Hz, 2H), 7.51(d,J=8.0Hz, 2H)， 11.32(s, 1H).
实施例 159
2, 4-二曱氧基 -3-异戊烯基 --6-[(E)-笨乙烯基]苯甲酸曱酯 （ 14)
Figure imgf000071_0001
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Figure imgf000072_0001
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Figure imgf000072_0003
991
iUZ 'ΖΗ9·乙 =
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Figure imgf000072_0005
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'1)86 '(Η ^)Z £ '(Ηζ '^ΗΖ'ί 'Ρ)θ3 '(Η£ 'S) //I '(Η£ 's)6n:(9P-OSWa 'ζ謂 001^)
Η, °(%8Α) ' ^令 W [ι? ^ ^ ^ ί ¾ 81
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Figure imgf000072_0006
'1)9Γ '(Ηΐ 'ΖΗ0"91=/"Ρ)6Γ. '(HI ^)LY9 '(HI ¾0'91=/* 'Ρ)£^9 '(HI ^ΥίΥ9=Γ Όό6 '(Η£ 's)9A '(He 's) 9 '(Η 'Ρ)Ζ £ '(Η9 's)6S"l :(9P-0SW I 'ζ謂 OOt^) ¾WNH,
Z8Z160/C10Z OAV 的方法得到目标产物， 浅黄色固体（ 79% )。 Ή NMR (400 MHz, DMSO-d6): 2.08(s, 3H)， 3.73(s, 3H), 3.80(s, 6H)， 6.23(s, 1H), 6.84(s, 2H)， 6.92(d, J= 16.0Hz, 1H)， 6.99(d,J = 16.0Hz, 1H)， 7.07(d, J=7.6Hz, 1H)， 7.12(d, J= 7.6Hz, 1H)， 7.14(s, 1H).
实施例 169
1,3-二甲氧基 -5-[(E)-3-羟基 -4-曱氧基苯乙烯基]苯（21d)
化合物 21c(5.0g， 0.015mol) 溶于无水曱醇 (50ml) 中， 加入曱醇钠 （ 1.41g， 0.024mol ) , 回流反应 3h,反应毕，反应液加入冰水中，用稀盐酸调节 ρΗ 小于 2， 乙酸乙 酯萃取 3次， 合并有机层， 无水硫酸镁干燥。 过滤， 浓缩， 剩余物用石油醚 /乙酸乙酯 重结晶得到目标产物， 白色固体 ( 3.70g, 85% )。 lH NMR (400 MHz, DMSO-d6): 3.75(s, 3H), 3.81(s, 6H), 6.24(s, 1H), 6.86(s, 2H), 6.93(d, J= 16.0Hz, 1H), 7.01(d,J= 16.0Hz, 1H) 7.08(d, J=7.6Hz, 1H), 7.13(d,J- 7.6Hz, 1H)， 7.15(s, 1H), 9.89(s, 1H).
实施例 170
1，3-二羟基 -5-[(E)-3，4-二羟基苯乙烯基]苯 （ 21e )
以 21d为原料， 按照实施例 6的方法得到目标产物， 白色固体 （ 75%) 。 1HNMR (400 MHz, DMSO-d6): 6.24(s, 1H), 6.87(s, 2H), 6.94(d,J= 16.0Hz, 1H), 7.03(d,J = 16.0Hz, 1H), 7.09(d, J=7.6Hz, 1H), 7.15(d,J= 7.6Hz, 1H)， 7.18(s, 1H)， 9.89(s, 3H)， 10.02(s, 1H).
实施例 171
1,3-二甲氧基 -5-[ (E) -2- ( 3,5-二乙酰氧基苯基） 丙小烯基]苯（21f)
以 3,5-二甲氧基苄基膦酸二乙酯与 3,4-二乙酰氧基笨曱醛为原料， 按照实施例 5 的方法得到目标产物， 白色固体 （74%) 。 1HNMR(400 MHz, DMSO-d6): 1.72(s, 3H), 2.06(s, 3H), 2.08(s, 3H), 3.78(s, 6H)， 6.22(s, 1H), 6.71(s, 1H), 6.84(s, 2H), 7.04(s, 2H), 7.15(s， 1H).
实施例 172
1，3-二曱氧基 -5-[ (E) -2- ( 3,5-二羟基笨基） 丙 -1-烯基]苯（21g)
以 21f为原料，按照实施例 169的方法得到目标产物， 白色固体（90%)。 'HNMR (400 MHz, DMSO-d6): 1.73(s, 3H), 3.75(s, 6H), 6.21(s, 1H), 6.72(s, 1H)， 6.83(s, 2H), 7.06(s, 2H), 7.13(s, 1H)， 9.87(s, 1H), 9.98(s, 1H).
实施例 173
1,3-二羟基 -5-[ ( E) -2- ( 3，5-二羟基苯基） 丙 -1-烯基]苯（21h)
以 21 g为原料， 按照实施例 6的方法得到目标产物， 白色固体（ 78% ) 。 1H NMR (400 MHz, DMSO-d6): 1.75(s, 3H), 6.23(s, 1H), 6.77(s, 1H), 6.85(s, 2H), 7.01(s, 2H), 7.12(s, 1H), 9.89(s, 2H), 10.02(s, 2H).
实施例 174
1，3-二曱氧基 -5-[ (E) -3,4，5-三乙酰氧基苯乙烯基]笨 ( 21i)
以 3,5-二曱氧基苄基膦酸二乙酯与 3，4,5-三乙酰氧基苯曱醛为原料， 按照实施例 5 的方法得到目标产物， 白色固体 （75%) 。 1H NMR (400 MHz, DMSO-d6): 2.08(s， 9H), 3.77(s, 6H), 6.22(s, 1H), 6.84(s， 2H), 6.91(d，J= 16.0Hz, 1H), 6.92(d,J= 16.0Hz, 1H), 7.01(s, 2H).
实施例 175
1,3-二甲氧基 -5-[ (E) -3,4，5-三羟基苯乙烯基]苯 (21j )
以 21i为原料， 按照实施例 169的方法得到目标产物， 白色固体（ 88%)。 1HNMR
(400 MHz, DMSO-d6): 3.78(s, 6H)， 6.21(s， 1H), 6.85(s， 2H)， 6.90(d,J= 16.0Hz, 1H), 6.92(d，J= 16.0Hz, 1H), 7.02(s, 2H), 9.89(s, 1H), 9.92(s, 2H).
实施例 176
1,3-二羟基 -5-[ (E) -3，4,5-三羟基苯乙烯基]苯 ( 21k)
以 21j为原料， 按照实施例 6的方法得到目标产物， 白色固体（ 75%) 。 1HNMR
(400 MHz, DMSO-d6): 6.24(s, 1H), 6.83(s, 2H)， 6.91(d,J= 16.0Hz, 1H), 6.93(d,J = 16.0Hz, 1H), 7.05(s, 2H), 9.89(s, 1H), 9.92(s, 2H), 10.02(s, 2H).
实施例 177
[(E)- (2-羟基 -3-异戊烯基 -4甲氧基 -6-苯乙烯基苯基 )[(1H-咪唑 -1-基）曱酮 （22) 木豆素（ l.Og, 2.96mmol)溶于氯仿中 （20ml) , 加入 CaCl2(0.39g, 3.55mmol)， 羰 基二咪唑 （0.58g, 3.56mmol) , 室温反应 4-6h, 反应毕， 先后用稀盐酸， 饱和食盐水 洗有几层， 无水硫酸镁干燥， 过滤， 浓缩。 剩余物过硅胶柱得到目标产物， 白色固体 ( l.Og, 87% )。 'Η NMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.85(s, 3H), 3.22(d, J-7.6Hz, 2H), 3.78(s, 3H)， 5.21(t, J= 7.6Hz, 1H), 6.70(s, 1H)， 6.82(d,J= 16.0Hz， 1H),7.28 (d,J = 16.0Hz, 1H), 7.30(m, 2H), 7.42(d,J= 7.6Hz, 2H), 7.44(t, J=7.6Hz, 2H), 7.70(d,J= 8.0Hz, 1H), 8.27(s, 1H)， 9.98(s， 1H).
实施例 178
N-胺甲酰基 -2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酰胺 （ 23a) 化合物 8( l.Og, 2.96mmol)溶于无水乙醇 (20ml)中，加入尿素（0.27g, 4.44mmol )， 回流反应 12h, 反应毕， 反应液倒入冰水中， 并用乙酸乙酯萃取三次， 合并有几层， 无水硫酸镁干燥，过滤，浓缩，剩余物过硅胶柱得到目标产物，白色固体（ 0.89g, 80% )。 Ή NMR (400 MHz, DMSO-d6): 1.79(s, 3H)， 1.82(s, 3H)， 3.34(d， J=7.6Hz， 2H), 3.83(s, 3H), 5.2 l(t, J= 7.6Hz, 1H), 6.20(s, 2H)， 6.65(s, 1H), 6.81(d,J= 16.0Hz, lH),7.26(d, J = 16.0Hz, 1H), 7.32(d,J= 7.6Hz， 1H), 7.43(d， J= 7.6Hz, 2H), 7.45(t, J=7.6Hz, 2H), 9.89(s, 1H), 11.77(s, 1H).
实施例 179
N-曱脒基 -2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-笨乙烯基]苯曱酰胺（ 23b ) 以化合物 8,胍为原料，按照实施例 178的方法得到目标产物， 白色固体（ 80%)。 1HNMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.81(s， 3H), 3.32(d, J=7.6Hz, 2H), 3.79(s, 3H), 5.20(t,J= 7.6Hz, 1H)， 5.52(s, 1H)， 6.45(s， 2H), 6.69(s, 1H)， 6.80(d,J= 16.0Hz， lH),7.27(d, J= 16.0Hz, 1H), 7.30(d, J= 7.6Hz， 1H), 7.38(d,J= 7.6Hz, 2H), 7.42(t, J=7.6Hz， 2H), 8.23(s, 1H), 9.89(s, 1H).
实施例 180
2-氨基乙酰氧基 -3-异戊烯基 -4-曱氧基 -6-[(E>苯乙烯基]苯甲酸曱酯 (24a) 化合物 8 ( 1.5g, 4.26mmol) , 三乙胺 （ 1.3g， 12.8mmol ) 溶于二氯甲烷中， 在（TC 滴加氨基乙酰氯的二氯甲烷溶液（由氨基乙酸 (0.48g, 6.39mmol)和二氯亚砜反应制的）， 滴完， 室温反应 8-10h, 反应毕。 有机层用水洗， 稀盐酸洗， 饱和食盐水洗， 无水硫酸 镁干燥，过滤，浓缩，剩余物过硅胶柱得到目标产物， 白色固体（ 1.36g, 78%)。 'HNMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.81(s， 3H), 3.32(d, J=7.6Hz, 2H), 3.59(s, 2H), 3.73(s, 3H), 3.88(s, 3H)， 5.12(s, 2H), 5.20(t, J= 7.6Hz， 1H), 6.72(s, 1H), 6.82(d,J= 16.0Hz, lH),7.26(d,J= 16.0Hz, 1H), 7.32(d,J= 7.6Hz, 1H)， 7.42 (d, J= 7.6Hz, 2H), 7.48(t, J=7.6Hz, 2H).
实施例 181
2-氨基乙酰氧基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]笨甲酸 (24b)
以化合物 1为原料， 按照实施例 180的方法得到目标产物， 白色固体 （ 80%) 。 1H NMR (400 MHz, DMSO-d6): 1.79(s, 3H), 1.83(s, 3H), 3.33(d, J=7.6Hz， 2H), 3.57(s, 2H)， 3.78(s, 3H)， 5.11(s, 2H), 5.22(t,J= 7.6Hz, 1H), 6.73(s, 1H), 6.80(d,J= 16.0Hz, lH),7.26(d,J- 16.0Hz, 1H), 7.33(d,J= 7.6Hz, 1H), 7.43 (d,J=7.6Hz, 2H), 7.45(t, J=7.6Hz, 2H), 12.32(s, 1H).
实施例 182
2-异戊烯基 -3-氨基乙酰氧基 -5-[(E)苯乙烯基]苯曱醚 （ 24c )
以化合物 10为为原料，按照实施例 180的方法得到目标产物， 白色固体（ 79% )。 = /"ρ)6/,·9 '(HI ^)Z 9 '(HI ' ^L = f ^ίΖ'ζ '(Η£ 'S)68 '(He 'S) '£ '(H3 ¾9'.=/ 0£
'p) re-e '(He 's)so'z; '(He 's)e8"i '(HE 'S) 6/,Ί :(9P-oswa 'z腿 oot^) ¾wNHt-(%28)
981 ^ ^
^SVL '(HI ςζ
'ζΗ0·9ΐ =/"P)A 'A'(Hl ¾0'91 =/" 'Ρ)6//9 '(HI 's)ll7'9 '(HI 's)S£'9 '(HI =f ¾ 3"S
'(HI 's)3g '(He 's)8. '(ΗΓ ui)t7g-£ '(H3 'ZH9K 'Ρ) Ζ ί '(HZ ^)ZST '(H£ 's)e8'l '(H£ 's) 6乙 ·ΐ '(Η3 'ui) -l '(HZ 'ui)69'l :(9P-OSW I 'z顯 OOt 腦 N Ht ° ( %58 )
581 ί'
(HI 's)tT31 '(HS
'(HI 'ΖΗ0·9ΐ = 'Ρ)6Γ乙' (HI 'ζΗ0·9ΐ = 'Ρ)6/.'9 '(HI 's)W9 '(HI 9·乙 ^Γ^Ζ ξ
'(HI 's)eg '(He 's)8乙 ·ε '(ΗΙ'∞)βξτ 9'乙 =* 'ρ)εε·ε '(ΗΣ; )08·3 '(He 's)£8i
'(Η 's) 6Ζ Ϊ '(HZ: '(Η3 ^)89Ί :(9P_OSWa 'z画 OOt) Ή顺 ° ( %18 ) ^tU ST
Figure imgf000076_0001
1钟 WW
w)^ -(3 ]-9-节¾ -t^- ^-e-(-fU^ -z- ^)-z
'(HI 'ζΗ0·9ΐ =f 'Ρ) Γ/ (ΗΙ '¾0'91 =Γ 'P)l8"9 '(HI 's) '9 '(HI 9·乙 ^Γ^Ι ξ 01 '(HI 's)9g K 's)88-e '(HE 'S)8 '(HI' ra)gg-£ '(HS 9 'ρ) ·ε '(HZ; '(He S)178-1 '(H£ 's) 08· I '(HZ: '^)S l '« Ζ9·Ι :(9P_OSW I ^UW OOfr) ΉΝΜ Η,'(%8Ζ.)^[11 ^ ί^'^^ M 081 t ^ ¾' ¼ ^ ^ ^ " -^ ^ 8
'(HZ 'ZH9" .=/* ^)6VL
'(HZ 'ZH9' = "P) '(HI 'ΖΗ9·Α = "Ρ)ζ Ά '(HI ¾0'91 =/" 'Ρ)½·.'(Ηΐ ¾091
= /"P)l8"9 '(HI 's)6e'9 '(HI 's)9£'9 '(HI 'ZH97_ =f Ί)ΐ '5 '(H3 's)£rg '(H£ 'S)9 '(H3
'S)6S '(HZ; 'ΖΗ9·乙 'ρ) 'ε '(HE '(H 's) 08Ί： (卯 -os a 'z腦 OOW ¾WNH,
Z8Z160/C10Z OAV 7.45(t, J=7.6Hz, 2H).
实施例 187
2- (吡咯 -2-曱酰氧基 )-3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯甲酸 (24h) 以化合物 1及乙酰氯为原料， 按照实施例 180的方法得到目标产物， 白色固体 ( 85% ) 。 1H NMR (400 MHz, DMSO-d6): 1.77 (s, 3H), 1.85(s, 3H), 2.07(s, 3H), 3.34 (d， J=7.6Hz, 2H), 3.78(s, 3H), 5.25(t,J= 7.6Hz, 1H), 6.70(s, 1H), 6.79(d,J= 16.0Hz, lH),7.28(d,J= 16.0Hz, 1H)， 7.32(d， J= 7.6Hz， 1H), 7.45 (d,J=7.6Hz, 2H), 7.49(t, J=7.6Hz， 2H), 12.54(s, 1H).
实施例 188
2-异戊烯基 -3- (吡咯 -2-甲酰氧基) -5-[(E)-苯乙烯基]苯曱醚 （24i)
以化合物 10及乙酰氯为原料， 按照实施例 180的方法得到目标产物， 白色固体 ( 87% ) 。 1H NMR (400 MHz, DMSO-d6): 1.79(s, 3H), 1.83(s, 3H), 2.08(s, 3H), 3.38 (d, J=7.6Hz, 2H), 3.78(s, 3H), 5.23(t, J= 7.6Hz, 1H), 6.37(s, lH),6.40(s, 1H), 6.78(d,J = 16.0Hz, lH),7.27(d, J= 16.0Hz, 1H), 7.31(d,J= 7.6Hz, 1H), 7.43 (d,J= 7.6Hz, 2H)， 7.48(t, J=7.6Hz, 2H).
实施例 189
2- (吡啶 -3-甲酰氧基 )-3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙晞基]苯甲酸曱酯 (24j) 以化合物 8以及吡啶 -3-曱酰氯为原料，按照实施例 180的方法得到目标产物，白色 固体 (86%).1H NMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.83(s, 3H), 3.34 (d， J=7.6Hz, 2H), 3.78(s, 3H), 3.89(s, 3H)， 5.23(t,J= 7.6Hz, 1H)， 6.70(s, 1H), 6.78(d,J= 16.0Hz, lH),7.27(d,J= 16.0Hz, 1H), 7.3 l(d, J= 7.6Hz, 1H), 7.43 (d, J= 7.6Hz， 2H), 7.48(m, 3H),
8.17(d,J=8.0Hz, 1H), 8.71(d, J-8.0Hz, 1H), 9.04(s, 1H).
实施例 190
2- (吡啶 -3-曱酰氧基 )-3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸 (24k) 以化合物 1及吡啶 -3-曱酰氯为原料， 按照实施例 180的方法得到目标产物， 白色 固体 ( 84% )。 1H NMR (400 MHz, DMSO-d6): 1.79(s, 3H)， 1.84(s, 3H), 3.35 (d, J=7.6Hz, 2H), 3.78(s, 3H), 5.22(t, J= 7.6Hz, 1H), 6.72(s, 1H), 6.79(d,J= 16.0Hz, lH),7.28(d, J = 16.0Hz, 1H), 7.32(d, J= 7.6Hz, 1H), 7.44 (d,J= 7.6Hz, 2H), 7.47(m, 3H)， 8.16(d， J =8.0Hz， 1H), 8.73(d,J=8.0Hz, 1H), 9.08(s, 1H), 12.32(s, 1H).
实施例 191
2-异戊烯基 -3- (吡啶 -3-曱酰氧基) -5-[(E)-笨乙烯基]笨曱醚 （ 241 ) 'ρ) ζζτ '(He 's) 8'i '(HE 'S)S 'I :(9P-oswa
Figure imgf000078_0001
¾ oe K i^-^^ 08ΐ ^ ^ ¾' ¼ ^ ^ f ^ - r- ?«> ^-H 1 ^ΥΔ 8
(dW)镪 ^ 玄 ^ 玄 -(3 ]-9-~f 卞 ¾^H-("f ¾ ^- - « -Ηΐ)-3
S61 Ϊ^ ^
■(HZ ^WL^f^iVL ΉΖ 'ZH9 = Γ'ν)ΖΥί '(HI 'ΖΗ9·Λ =f iV)0Z'L '(HI ¾0'91 =Γίν)ίΓί '(Ηΐ ¾0"91 = "P)t8"9 '(HI iZ 's)g 9 '(HI 's)tl7-9 '(HI 'ZH9' = 9乙' S '(Η£ 'S)S '£ '(Ηζ 'ΖΗ9·乙 = 'Ρ) Ρ£'£ '(Ηζ 's)62 :(Η9
Figure imgf000078_0002
g
Figure imgf000078_0003
t^^^gfl'^'^^^t^^^ i -Ν'Ν ¾Τ 01 ΥΔ
( ow ) ¾ 玄 [^ 玄- ( ) ( 节 -Ν'Ν)-ε- ^^ ^-3
Figure imgf000078_0004
•(HI 's)3£ l '(Η3 'ΖΗ9·乙 = *
'(Η 'ZH9' . = "P) 乙 '(HI =/·'Ρ)ΐΓ/_ '(HI ¾091 = 'Ρ)9Γ/ (ΗΙ ¾0'91 =Γ
'Ρ)08·9 '(HI 's)0/9 '(HI 9' =/"l)£3'S '(H ^)Z £ '(H3 9'乙= 'Ρ) ξΖ '(HZ 's)l£'e ;(H9 's)8 '(He 's)乙 8· 1 '(HE I :(卯 -OS 'z丽 OOt^) ¾匪 H, ° ( %S8 ) ^IB^^
g
Figure imgf000078_0005
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S
Figure imgf000078_0006
Figure imgf000078_0007
^^ tk -N'N)-3
•(HI 's)e0'6 '(HI 'zH0'8- "P) -8 '(HI ¾0'8= 'Ρ)^Γ8 ξ '(Η£ ^)9VL UZ 'ΖΗ9·Α = " 'Ρ) ZVL '(Ηΐ 9·乙 = 'Ρ)0ΓΛ '(Ηΐ ¾0'91 = "Ρ)/.Γ/,'(Ηΐ
'ζΗ0·9ΐ = "P)6."9 '(HI 's)g -9 '(HI 's) i '9 '(HI 'ΖΗ9·乙 = >'l)8^'S '(Η£ 's)e/.' '(Η3 ZH9KP) ϋ '(Η£ 's)S8"l '(H 's) 'I :(9P-OSWd 'z丽 OOt 謂 NH, °(%Z.8 ) ^囟 ^
Figure imgf000078_0008
ll.l00/Zl0iN3/X3d J8Z160/£T0Z OAV 16.0Hz, 1H)， 7.26(d,J= 16.0Hz， 1H), 7.31(d, J= 7.6Hz, 1H), 7.43 (d，J= 7·6Ηζ， 2H), 7.47(t,J= 7.6Hz, 2H),8.06(s, 1H), 8.34(s, 1H)， 9.21(s, 1H).
实施例 196
2-(1Η-咪唑 -2-甲酰氧基 )-3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸 (24q) 以化合物 1及 1H-咪唑 -2-曱酰氯为原料， 按照实施例 180的方法得到目标产物， 白色固体 （ 85% ) 。 1H NMR (400 MHz, DMSO-d6): 1.79(s, 3H), 1.83(s, 3H), 3.26 (d， J=7.6Hz, 2H), 3.75(s, 3H), 5.23(t, J= 7.6Hz, 1H)， 6.70(s, 1H), 6.80(d，J= 16.0Hz, 1H), 7.24(d,J= 16.0Hz, 1H), 7.30(d,J= 7.6Hz, 1H), 7.42 (d,J= 7.6Hz, 2H), 7.45(t,J= 7.6Hz, 2H)， 8.06(s, 1H), 8.32(s, lH)，8.98(s, 1H), 12.32(s, 1H).
实施例 197
2-异戊烯基 -3-(1Η-咪唑 -2-曱酖氧基) -5-[(E)-苯乙烯基]苯曱醚 （ 24r )
以化合物 10及 1H-咪唑 -2-甲酰氯为原料， 按照实施例 180的方法得到目标产物， 白色固体 ( 79% ) 。 1H NMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.82(s, 3H), 3.25 (d, J-7.6Hz, 2H), 3.73(s, 3H), 5.20(t, J- 7.6Hz, 1H)， 6.32(s， 1H), 6.38(s, 1H), 6.80(d,J = 16.0Hz, 1H), 7.25(d,J= 16.0Hz, 1H), 7.31(d, J = 7.6Hz, 1H), 7.43 (d,J=7.6Hz, 2H), 7.47(t,J= 7.6Hz, 2H), 8.07(s, 1H), 8.35(s, 1H), 9.02 (s， 1H).
实施例 198
2- (N-苄基胺甲氧基) -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯甲酸甲酯 (25a) 化合物 8( l.Og, 2.84mmol)， N-苄基曱醇胺（ 0.50g, 3.70mmol ) , 三苯基膦（ 0.97g， 3.70mmol ),溶于无水 THF(40ml)中，在 0。C 滴加 DEAD(0.6g， 3.70mmol)的 THF溶液， 滴完， 室温反应 4-6小时， 反应毕， 反应液加入饱和食盐水中， 乙酸乙酯萃取， 合并 有机层， 无水硫酸镁干燥， 过滤， 浓缩， 剩余物过硅胶柱得目标产物， 白色固体（ 1.04g， 78% ) 。 1H NMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.82(s, 3H), 3.22(d,J= 7.6Hz, 2H), 3.75(s, 3H), 3.81(s, 2H), 3.88(s, 3H)， 4.56(s, 1H), 5.21(t, J=7.6Hz, 1H), 5.30(s, 2H), 6.50(s, 1H), 6.82(d,J= 16.0Hz, 1H), 7.28(d,J= 16.0Hz, 1H)， 7.32(m, 6H), 7.45(m, 4H).
实施例 199
2-胺曱氧基 -3-异戊烯基 -4-曱氧基 -6-[(E)-笨乙烯基]苯曱酸甲酯 （ 26a )
化合物 25a( l.Og, 2.12mmol) ,溶于乙醇 (20ml)中,加入锌粉（0.42g， 6.36mmol ) , 曱酸铵（ 0.20g， 3.18mmol)， 室温搅拌反应 10h,反应毕， 过滤除去不溶物， 滤液浓缩， 过柱得到目标产物，白色固体（ 0.73g, 90%)。 1H NMR (400 MHz, DMSO-d6): 1.77(s, 3H), 1.82(s, 3H), 3.26(d,J= 7.6Hz, 2H), 3.75(s, 3H), 3.89(s, 3H), 4.21(s, 2H), 5.21(t, J=7.6Hz, 'ZH9A = \Γ 'ΡΡ)^ΐ '(Η£ 's)68 '(Η£ ^)9Li '(Ηΐ '^)9£'£ '(Η3 'ΖΗ9·乙 =f iV)iZ'i Οί m '^)L9 '(HZ ^)£9T '(He 's)l8"l '(Η£ 's)6Z/I :(9P-0S W OOt^) 醒 Ht 。 ( %乙 6 ) ^ ^ t^ B 003 ½ "Si¥ ^^ΥΛ
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HZ.100/Z10ZN3/X3J Z8Z160/£10J OAV 7.24(d,J= 16.0Hz, IH), 7.29(t,J= 7.6Hz, IH), 7.37 (d,J= 7.6Hz, 2H), 7.45(t， J= 7.6Hz, 2H).
实施例 204
2- (哌嗪 -2-基） 甲氧基 -3-异戊烯基- 4-曱氧基 -6-[ (E) -苯乙烯基]苯甲酸（26e) 以化合物 26d为原料， 按照实施例 8的方法得到目标产物， 白色固体 （ 90% ) 。
1H NMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.82(s, 3H), 2.61(m, 2H), 2.65(m, 4H)， 3.22(d,J= 7.6Hz, 2H), 3.37(m, IH), 3.78(s, 3H), 4.12(dd, Jl = 7.6Hz, J2=12.0Hz, 2H), 4.51(s, 2H), 5.23(t, J=7.6Hz, IH), 6.60(s, IH), 6.81(d, J= 16.0Hz, 1H)， 7.25(d,J= 16.0Hz, IH), 7.31(t,J= 7.6Hz， 1H)， 7.35 (d,J= 7.6Hz, 2H), 7.42(t, J= 7.6Hz, 2H), 12.35(s, IH). 实施例 205
2-异戊烯基 -3- (哌嗪 -2-基） 甲氧基 -5-[(E)-苯乙烯基]苯甲醚 （26f)
以化合物 26d为原料， 按照实施例 113的方法得到目标产物， 白色固体（ 68%)。 'HNMR (400 MHz, DMSO-d6): 1.79(s, 3H)， 1.81(s, 3H), 2.63(m, 2H), 2.67(m, 4H), 3.25(d,J= 7.6Hz, 2H), 3.39(m, IH), 3.79(s, 3H), 4.1 l(dd, Jl = 7.6Hz, J2=12.0Hz, 2H), 4.48 (s， 2H), 5.21(t, J=7.6Hz, 1H)， 6.29(s, 1H)， 6.35(s, IH), 6.79(d， J= 16.0Hz, IH), 7.24(d J= 16.0Hz, IH), 7.28(t,J= 7.6Hz, IH), 7.37 (d, J= 7.6Hz, 2H), 7.41(t,J= 7.6Hz, 2H). 实施例 206
2-异脲基 -3-异戊烯基 -4-曱氧基 -6-[ (E) -苯乙烯基]苯曱酸曱酯 (27a)
化合物 8 ( l.Og, 2.84mmol ) , 胺基氰 ( 0.24g, 5.68mmol )溶于乙醚 (20ml)中， 在 0 °C时通氯化氢气体， lh后， 室温反应 6h, 反应毕， 反应液用水洗， 饱和食盐水洗， 无 水； 酸镁干燥，过滤，浓缩，剩余物过柱得到目标产物，白色固体（ 0.88g, 79% )。 1H NMR (400 MHz, DMSO-d6): 1.79(s， 3H), 1.81(s, 3H), 3.22(d, J=7.6Hz, 2H), 3.78(s, 3H), 3.89(s, 3H), 4.21(s, IH), 4.85(s, IH), 5.24(t， J= 7.6Hz， IH), 6.68(s, IH), 6.80(d,J= 16.0Hz, IH), 7.24(d,J= 16.0Hz, IH), 7.30(t, J= 7.6Hz, 1H)， 7.35 (d， J= 7.6Hz， 2H), 7.47(t,J= 7.6Hz, 2H).
实施例 207
2-异脲基 -3-异戊烯基 -4-曱氧基 -6-[ (E) -苯乙烯基]苯曱酸 (27b)
以化合物 1为原料， 按照实施例 206的方法， 得到目标产物， 白色固体（ 75%)。 1H NMR (400 MHz, DMSO-d6): 1.80(s, 3H), 1.83(s, 3H)， 3.29(d, J=7.6Hz, 2H), 3.73(s, 3H), 4.18(s, IH), 4.80(s, IH), 5.23(t,J= 7.6Hz， IH), 6.60(s, IH), 6.75(d,J= 16.0Hz, IH) 7.18(d,J= 16.0Hz, IH), 7.29(t,J= 7.6Hz, IH), 7.38 (d，J= 7.6Hz， 2H), 7.45(t,J= 7.6Hz: 2H), 12.21(s, 1H).
实施例 208
2-异戊烯基 -3-异脲基 -5-[ (E) -笨乙烯基]苯曱醚 (27c)
以化合物 9为原料， 按照实施例 206的方法， 得到目标产物， 白色固体（ 74% )。 1HNMR (400 MHz, DMSO-d6): 1.81(s, 3H), 1.82(s, 3H), 3.23(d, J=7.6Hz, 2H), 3.75(s, 3H), 4.13(s, 1H), 4.65(s, 1H), 5.20(t,J= 7.6Hz， IH), 6.35(s, 1H)， 6.42(s, 1H), 6.78(d,J = 16.0Hz, IH), 7.19(d,J= 16.0Hz, IH), 7.24(t, J= 7.6Hz, IH), 7.34 (d,J= 7.6Hz, 2H), 7.39(t,J= 7.6Hz, 2H), 7.45(t， J= 7.6Hz, 2H).
实施例 209
2-肼曱酰氧基 --3-异戊烯基 -4-曱氧基 -6-[ (E) -苯乙烯基]苯曱酸曱酯 （29a) 化合物 8 ( 1.0g， 2.84mmol) , 三乙胺 （ 0.43g， 4.26mmol ) , 溶于二氯甲烷 (30ml) 中， 于 0°C滴加氯曱酰氯 （ 0.40g, 3.98mmol) , 滴完， 室温反应 4h, 反应毕， 反应液 降温至 0°C， 緩慢滴加肼 (0.2g, 5.68mmol)的二氯曱烷溶液， 滴完， 室温反应， 反应毕， 反应液先后用水， 稀盐酸， 饱和食盐水洗， 无水硫酸镁干燥。 过滤， 浓缩， 剩余物过 柱得到目标产物， 白色固体 (0.87g, 75%)。 1H NMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.81(s, 3H)， 3.24(d, J=7.6Hz, 2H), 3.78(s, 3H), 3.87(s, 3H), 4.25(s, 2H), 6.73(s, 1H)， 6.79(d, J= 16.0Hz, IH), 7.24(d, J= 16.0Hz, IH), 7.34 (d,J= 7.6Hz， 2H), 7.39(t,J= 7.6Hz, 2H)， 7.42(s, IH), 7.45(t,J= 7.6Hz, 2H).
实施例 210
2-肼曱酰氧基 --3-异戊烯基 -4-曱氧基 -6-[ (E) -苯乙烯基]苯曱酸（29b)
以化合物 1为原料， 按照实施例 209的方法， 得到目标产物， 白色固体（ 74%)。 Ή NMR (400 MHz, DMSO-d6): 1.77(s, 3H), 1.80(s, 3H), 3.25(d, J=7.6Hz, 2H), 3.78(s, 3H), 4.12(s, 2H), 6.70(s, IH), 6.82(d,J= 16.0Hz, IH), 7.26(d,J= 16.0Hz, IH), 7.30 (d， J = 7.6Hz, 2H)， 7.34(t,J= 7.6Hz, 2H)， 7.38 (s, IH), 7.42(t, J= 7.6Hz, 2H), 12.13(s, IH).
实施例 211
2-异戊烯基 -3-肼曱酰氧基 -5-[ (E) -苯乙烯基]笨曱醚 （29c)
以化合物 9为原料， 按照实施例 209的方法， 得到目标产物， 白色固体（ 74% )。 1H NMR (400 MHz, DMSO-d6): 1.78(s, 3H)， 1.81(s, 3H)， 3.26(d, J=7.6Hz， 2H), 3.79(s, 3H), 4.18(s, 2H), 6.28(s, IH), 6.32(s, IH), 6.80(d, J= 16.0Hz, 1H)， 7.23(d,J= 16.0Hz, IH), 7.29 (d， J = 7.6Hz， 2H), 7.32(t， J = 7.6Hz， 2H), 7.39 (s, 1 H), 7.43(t, J = 7.6Hz, 2H).
实施例 212 913 n ^
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Z8Z160/C10Z OAV J-7.6Hz, 2H), 3.67(s, 3H), 3.75(s, 3H)， 5.21(t,J= 7.6Hz, 1H)， 6.37(s, IH), 6.42(s, IH), 6.81(d,J= 16.0Hz, IH), 7.23(d,J= 16.0Hz, IH), 7.29(t, J= 7.6Hz, 2H), 7.35 (s， 1H)， 7.45(t,J= 7.6Hz, 2H).
实施例 217
2-异戊烯基 -3-羧基曱酰氧基 -5-[ (E) -苯乙烯基]苯曱醚 （31c)
以化合物 30c， 按照实施例 213的方法得到目标产物， 白色固体（ 85%)。 1HNMR (400 MHz, DMSO-d6): 1.78(s, 3H), 1.82(s, 3H), 3.26(d, J=7.6Hz, 2H), 3.78(s, 3H), 5.23(t, J= 7.6Hz， 1H)， 6.34(s, IH), 6.41(s, IH), 6.80(d,J= 16.0Hz, IH), 7.25(d, J= 16.0Hz, IH), 7.29(t, J= 7.6Hz， 2H), 7.37 (s, 1H)， 7.44(t, J= 7.6Hz, 2H), 12.54(s, IH).
实施例 218
2—羟基—3-异戊烯基 -4-曱氧基 -6-[ (E) -苯乙烯基]苯曱酰胺 (32)
化合物 8 ( l.Og, 2.84mmol)溶于氨的曱醇溶液（ 10%, 10ml) , 回流反应 4-6h， 反 应毕， 反应液加入冰水中， 乙酸乙酯萃取， 无水硫酸镁干燥。 过滤， 浓缩， 过柱得到 目标产物， 白色固体（ 0.86g, 92% )。 1H NMR (400 MHz, DMSO-d6): 1.79(s, 3H), 1.81 (s, 3H), 3.25(d,J=7.6Hz, 2H), 3.77(s, 3H), 5.20(t, J= 7.6Hz， IH), 6.68(s, IH), 6.80(d,J =
16.0Hz, IH), 7.24(d, J= 16.0Hz, IH), 7.29(t, J= 7.6Hz, 2H), 7.36(s, IH), 7.44(t,J= 7·6Ηζ: 2H), 7.90(s, 2H).
实施例 219
2,4-二羟基 -3-异戊烯基 -6-[(E)-苯乙烯基]苯曱酸（ 33 )
木豆素 1 ( O.lg, 0.29mmol) 加入到氢埃酸中 （ 10ml，55%) , 加热回流反应 2h, 反应毕， 冷却， 反应液用乙酸乙酯萃取（ 3x30ml) 。 合并有机层， 有机层先后用水， 饱和食盐水洗。 无水硫酸镁干燥， 过滤， 旋蒸出去溶剂， 剩余物用石油醚 /乙酸乙酯重 结晶得到白色固体（ 66mg， 70% )。 1H NMR (400 MHz, DMSO-d6): 1.65(s, 3H), 1.78(s, 3H): 3.32(d,J=7.6Hz, 2H), 5.23(t, J=7.6Hz, IH), 6.59(s, IH), 6.82(d, J=l 6.0Hz, IH), 7.22(d, J=l 6.0Hz, IH), 7.28(t, J=7.6Hz, IH), 7.38(t, J=7.6Hz, 2H), 7.52(d, J=7.6Hz, 2H), 10.35(s, IH), 11.32(s， IH), 12.30(br, IH).
实施例 220
木豆素双键氢化产物（34)
木豆素 （0.1g， 0.29mmol)溶于 15ml 无水乙醇中，加入 10mg5%的 Pd/C,于室温， 70psi 压力下氢化 4h。 反应毕， 过滤出去催化剂， 滤液蒸干即得到木豆素双键氢化产 物 99mg( 98% )。 Ή NMR (400 MHz, CDC13): 0.95(d, J=6.4Hz， 6H), 1.36(m, 2H), 1.58(m, 1H), 2.63(t, J=7.6Hz, 2H), 2.92(t, J=7.6Hz， 2H)， 3.26(t, J=7.6Hz， 2H), 3.78(s, 3H), 6.19(s, 1H)， 7.20(d, J=7.2Hz, 2H),7.30(m, 3H), 10.5(br, 1H), 1 1.63(s, 1H).
实施例 221
2—羟基—4—曱氧基—6—苯乙基苯甲酸曱酯 （35 )
化合物 7 (5.0g， 0.0176mol)， 溶于无水乙醇（50ml), 加入 Pd/C(0.25g), 在室温， 50psi 条件下氢化 3h. 反应毕， 过滤除去催化剂， 滤液蒸千得到白色固体（ 97% )。 1H NMR (400 MHz, DMSO-d6):2.77(m, 2H), 2.84(m, 2H), 3.70(s, 3H), 3.80(s, 3H), 6.30(d, J=2.4Hz: 1H), 6.33(d, J=2.4Hz, 1H)， 7.18(m, 3H), 7.27(t, J=7.6Hz, 2H), 10.35(s, 1H).
实施例 222
2-羟基 -3-异戊烯基 -4-甲氧基 -6-苯乙基苯曱酸甲酯 （36 )
以化合物 35为原料， 按照实施例 7的方法得到化合物， 白色固体 (65%)。 1H NM (400 MHz, CDC13): 1.67(s, 3H), 1.78(s, 3H), 2.84(t， J=8.0Hz, 2H)， 3.18(t, J=8.0Hz, 2H), 3.33(d, J=7.2Hz， 2H)， 3.79(s, 3H), 3.95(s, 3H), 5.20(t, J=7.2Hz， 1H)， 6.21(s, 1H)， 7.20(m, 3H), 7.30(t, J=7.2Hz, 2H)， 1 1.70(s, 1H).
实施例 223
2-羟基 -3-异戊烯基 -4-曱氧基 -6-苯乙基苯曱酸 （37 )
以化合物 36为原料， 按照实施例 8的方法得到化合物， 白色固体 (87%)。 'H NMR (400 MHz, DMSO-d6): 1.59 (s， 3H), 1.69(s， 3H), 2.80(t, J=7.6Hz, 2H), 3.12(t, J=7.6Hz, 2H), 3.21(d, J=6.8Hz, 2H), 3.78(s, 3H)， 5.10(t, J=6.8Hz, 1H)， 6.45(s, 1H), 7.17 (t, J=7.2Hz, 1H)， 7.22(d, J=7.2Hz, 2H), 7.28(t, J=7.2Hz, 2H)， 12.47(br, 1H), 13.95(br, 1H).
实施例 224
2-羰基 -4-羟基 -6-曱基环己 -3-烯碳酸曱酯 （ 38 )
金属钠（ 3.1g, 0.134mol )溶于无水曱醇 （200ml)，在室温加入乙酰乙酸甲酯（ 12.0g, 0.103mol ) , 与巴豆酸曱酯 （ 12.4g, 0.124mol ) , 加完， 回流反应 6h， 反应毕， 蒸出 大部分曱醇， 剩余物加入到冰水 (200ml), 用乙酸乙酯萃取 （3X50ml), 水层用 15%的 稀盐酸调节 pH 小于 2, 再用乙酸乙酯萃取 （3X50ml)。 合并有机层， 有机层用饱和食 盐水洗， 无水 MgS04 干燥。 过滤， 蒸干溶剂， 剩余物用石油醚 /乙酸乙酯重结晶得到 白色固体（13.2g, 70%)。 1H NMR (400 MHz, DMSO-d6): 0.94(d, J=6.0Hz, 3H), 2.32(m, 3H), 3.09(d, J=9.2Hz, 1H), 3.63(s, 3H)， 5.21 (s, 1 H), 11.37(s, 1 H).
实施例 225
2,4-二羟基 -3-溴 -6曱基苯曱酸甲酯 （39 ) 化合物 38(10.0g, 0.054mol) 溶于冰乙酸（150ml) , 在室温下滴加液溴（19.9g, 0.124mol)的乙酸 (40ml)溶液， 滴完， 在室温下反应 12h。 反应毕， 反应液倒入冰水中， 析出大量白色固体， 过滤， 滤饼用大量水洗， 干燥。 所得固体进一步用石油醚 /乙酸乙 酯过硅胶柱得到较纯产物，白色固体 (5.6g, 40%) Ή NMR (400 MHz, DMSO-d6): 2.2 l (s, 3H)， 3.86(s, 3H), 6.41 (s, 1H), 10.98(s, 1H)， 1 1.72(s, 1H).
实施例 226
2,4-二甲氧基 -3-溴 -6甲基苯曱酸曱酯 （ 40 )
以化合物 39为原料， 按照实施例 2的方法得到产物， 白色固体 (95%)。 1H NMR (400 MHz, CDC13): 2.30(s, 3H), 3.86(s, 3H), 3.89(s, 3H)， 3.91 (s, 3H), 6.52(s， 1 H).
实施例 227
2,4-二甲氧基 -3-溴 -6溴曱基苯甲酸曱酯 （41 )
以化合物 40为原料， 按照实施例 3的方法得到产物， 白色固体 (82%)。 1H NMR (400 MHz, CDCI3): 3.90(s, 3H), 3.94(s, 3H), 3.96(s, 3H), 4.53(s, 2H), 6.73(s, 1 H).
实施例 228
2,4-二甲氧基 -3-溴 -6-亚磷酸二乙酯曱基苯曱酸甲酯 （42 )
以化合物 41为原料， 按照实施例 4的方法得到产物， 白色固体 (86%)。 1H NMR (400 MHz, CDCI3): 3.90(s, 3H), 3.94(s, 3H), 3.96(s, 3H), 4.53(s, 2H), 6.73(s, 1H).
实施例 229
2，4-二甲氧基 -3-异戊烯基 -6-亚磷酸二乙酯曱基笨甲酸曱酯 （ 43 )
以化合物 42为原料，按照实施例 162的方法得到产物，无色油状物 （78%)。1H NMR
(400 MHz, CDCl3): 1.26(t, J-7.2Hz, 6H)， 3.29(d, J=22.4Hz, 2H), 3.87(s, 3H), 3.92(s, 6H), 4.02(q, J=7.2Hz, 4H)， 6.78(s， 1H).
实施例 230
2,4-二曱氧基 -3-异戊基 -6-亚磷酸二乙酯曱基苯甲酸曱酯 （ 44 )
以化合物 43为原料，按照实施例 220的方法得到产物，无色油状物 （92%)。 1H NMR
(400 MHz, CDC13): 0.88(d, J=6.4Hz, 6H), 1.26(t, J=7.2Hz, 6H), 1.37(m, 2H)， 1.63(m, 1 H), 2.58(t, J=8.0Hz, 2H), 3.32(d, J=21.6Hz, 2H)， 3.76(s, 3H), 3.83(s, 3H), 3.91 (s，3H), 4.02(q, J=7.2Hz, 4H)， 6.71 (s, 1H).
实施例 231
2,4-二甲氧基 -3-异戊基 -6-[(E)-苯乙浠基]笨曱酸曱酯 （45 )
以化合物 44为原料，按照实施例 5的方法得到产物，无色油状物 （80%)。 1H NMR
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实施例 237
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-笨乙烯基]苯甲酸 （ 1， 木豆素）
以化合物 8为原料， 按照实施例 8的方法得到目标产物， 白色固体 （92%)。
'H-NMR(400M, CDC13) δ (ppm):1.61(s, 3H), 1.71(s, 3H), 3.24(d, J=6.8Hz, 2H),3.91(s, 3H), 5.12(t,J=6.8Hz, 1H)， 6.78(s， 1H), 7.00(d, J=16Hz, 1H), 7.27(t, J=7.2Hz, 1H), 7.38(t, J=7.2Hz, 2H), 7.52(d, J=7.2Hz, 2H), 7.84(d， J=16Hz, 1H)， 12.28(s, 1H). ESI-MS m/z: 361.14318 [M+Na]+ (Calcd for C21H2204Na:361.14158 ).
实验例 1 抗流感病毒活性测定
MDCK细胞接种 96孔培养板， 置于 5%C02, 37°C 培养 24小时。 MDCK细胞加 入流感病毒 (A/H1N1、 A/H3N2或 B/13/79型）约 100TCID50, 37°C吸附 2小时后倾去病 毒液， 分别加入不同稀释度的本发明化合物或阳性对照药利巴韦林的维持液。 同时设 不加药的病毒对照和无病毒感染的细胞对照， 37°C培养待病毒对照组病变程度（ C?E ) 达 4+时观察各组细胞病变程度（CPE) (约 36小时） ， 计算各样品抗流感病毒半数 抑制浓度 (IC5()), 结果参见表 1。
实验例 2 抗柯萨奇 （CoxaskiEs) 病毒活性测定
VEro细胞种 96孔培养板， 24小时后感染病毒（柯萨奇 B6病毒）约 100TCID50, 吸附 2小时， 弃病毒液， 加入含有不同浓度的本发明化合物样品及阳性对照药利巴韦 林 （RBV) 的维持液， 同时设不加药的病毒对照和无病毒感染的细胞对照， 待病毒对 照组病变程度（ CPE)达 4十时观察各组细胞病变程度（ CPE) , 用 REEd-MuEnch法分 别计算样品对病毒的半数抑制浓度 （IC5C) , 结果列入表 1。
实验例 3 神经元保护活性测定 （对鱼藤酮、 去血清损伤 PC12细胞的保护作用） 取铺满单层的 PC12细胞（模拟神经元细胞） ， 弃去原培养液， 加入 5%FBS、 5% 马血清的 完全培养液，用吸管轻轻吹打使细胞分散完全，以 5 X 104个 /ml密度， 每孔 100 μ 1接种于预先用多聚赖氨酸（ 0.1mg/ml) ) 处理过的 96培养板中， 培养 24h 即可用于实验。 实验分为空白组、 模型组和加药组。 空白组给予完全培养基， 模型组 包括鱼藤酮组和去血清组， 其中鱼籐酮造模组是加入终浓度为 4μΜ鱼藤酮的完全培 养基作用细胞 48h, 去血清组为加入无血清 DMEM培养基作用细胞 48h。 加药组也分 为两组， 一组以鱼藤酮造模组为模型， 另一组以去血清组为模型， 均在造模的同时加 入 10 μ M受试化合物。 48h后加入 10 μ 15mg/ml MTT, 4h后去上清，加入 150 μ 1 DMSO, 以 570nm吸光度值表示存活细胞数。
所述化合物对去血清损伤 PC12细胞， 鱼藤酮损伤 PC12细胞的保护作用见表 3。 实验例 4抗丙肝病毒 (HCV)活性测定
Huh7.5细胞以 3 x 104 cells/cm2的密度接种到 96孔板中， 培养 24h后， 用 HCV病 毒上清液以 45IU/cell感染细胞， 同时加入药液或溶剂对照处理。 培养 72h后， 吸弃培 养基，用 RNeasy Mini Kit提取细胞内总 RNA, HCV RNA表达水平用 one-step real-time RT-PCR kit定量检测， 用计算药物对 HCV的抑制率， 并用 Reed-Muench法计算半数 有毒浓度 EC50。 所述化合物抗 HCV的活性见表 2。
实验例 5 抗艾滋病毒 (HIV)活性测定
MT - 4细胞用 100TCID50 HIV-1 ΙΠΒ病毒 37°C吸附感染 1.5h后用培养基洗涤 2 次， 用培养液配制成 2x 105细胞. mL-1 , ΙΟΟμΙ^接种于 96孔细胞培养板内， 同时分别 加 3倍稀释的不同浓度的药液或 4倍稀释的阳性药 ΑΖΤ药液， 每个浓度重复 2孔， 设 细胞对照组。置 37°C、 5%C02和饱和湿度培养箱内培养，于加药 96h后吸上清 ΙΟΟμ 用试剂盒测定 Ρ24抗原的含量， 计算 IC50。 所述化合物抗 HIV的活性见表 2。

Claims

权 利 要 求
Figure imgf000090_0001
式中 代表 H， 取代或未取代的芳基， 取代或未取代的杂芳基， 取代或未取代的 烃基， 取代或未取代芳烃基， 取代或者未取代的烷氧甲酰基或者羧基；
R2代表 H， 取代或未取代的芳基， 取代或未取代的杂芳基， 取代或未取代的烃基， 取代或未取代芳烃基， 取代或者未取代的烷氧甲酰基或者羧基；
R3代表 H, 羧基， 取代或者未取代的烷氧曱酰基， 取代或者未取代的氨甲酰基， 取 代或者未取代的甲酰基；
R4代表 H, 羟基， 取代或者未取代的烷氧基， 取代或未取代的曱酰氧基， 取代或 者未取代的氨基或! ¾素， 或者异脲基；
R5代表 H, 饱和或不饱和烃基， 取代或未取代的芳基， 芳环取代的不饱和烃基； R6代表 H, 羟基， 取代或者未取代的烷氧基， 取代或未取代的氨基， 1¾素， 巯基 或烷疏基；
R7代表 H， 异戊烯基， 异戊基， 3'，7'-二曱基辛 -2',6，-二烯基， 取代或未取代的芳 基， 烯丙基， ！¾素， 取代或未取代的氨基；
R8和 R9可以相同， 也可以不同， 可分别代表 H， 1 -18个碳的烃基。
2. 如权利要求 1所述的化合物， 其中， Ri选自取代的苯基， 苄基， 苯乙基， 苯乙烯基；
R2选自取代的苯基， 苄基， 苯乙基， 苯乙烯基；
R5选自笨乙烯基， 异戊烯基， 异戊基， 烯丙基， 3，，7 '-二曱基辛 -2',6'-二烯基。 3. 如权利要求 1所述的化合物， 为：
2 , 4-二曱氧基 -6-[(E)-苯乙烯基]苯甲酸曱酯；
2-羟基 -4-曱氧基 -6-[(£)-笨乙烯基]苯曱酸甲酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E) -苯乙烯基]苯曱酸曱酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E) -4， -氟笨乙烯基]笨曱酸甲酯；
2-羟基 -3 -异戊烯基 -4-曱氧基 -6- [(E) -4， -氟笨乙烯基]苯曱酸；
2-羟基 -3 -异戊烯基 -4-曱氧基 -6- [(E)- - 2' -氯苯乙烯基]笨甲酸曱酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- - 2， -氯苯乙烯基]苯曱酸；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E) -4， -甲氧基笨乙烯基]苯曱酸曱酯；
2-羟基 -3 -异戊烯基 -4-曱氧基 -6- [(E)- -4， -曱氧基苯乙烯基]苯甲酸；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- •2， ，6， -二曱氧基苯乙烯基]苯甲酸甲酯
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- - 2， ，6' -二曱氧基苯乙烯基]笨曱酸；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- ■2' -曱基苯乙烯基]苯甲酸曱酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- -2， -甲基苯乙烯基]苯甲酸；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- -3， -甲基苯乙烯基]苯甲酸曱酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- -3， -曱基苯乙烯基]苯甲酸；
2-羟基 -3 -异戊烯基 -4-曱氧基 -6- [(E)- -4， -曱基苯乙烯基]苯曱酸甲酯；
2-羟基 -3 -异戊烯基 -4-曱氧基 -6- [(E)- •4， -曱基苯乙烯基]苯曱酸；
2-羟基 -3 -异戊烯基 -4-曱氧基 -6- [(E)- -丁 -1 -烯基]苯曱酸曱酯；
2-羟基 -3- -异戊烯基 -4-甲氧基 -6- [(E)- -丁 -1 -烯基]苯曱酸；
2-羟基 -3- -异戊烯基 -4-曱氧基 -6— [(E)- 2， -苯基丙 -Γ -烯基]苯甲酸曱酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- -2， -苯基丙 -Γ -烯基]苯甲酸；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- -2- (噻吩 -2-基）乙烯基]苯曱酸曱酯；
2-羟基 -3 -异戊烯基 -4-甲氧基 -6- [(E)- -2- (噻吩 -2-基）乙烯基]苯曱酸；
2-羟基 -3- -异戊浠基 -4-甲氧基 -6- [(E)- 3' -苯基丙 -Γ -烯基]笨甲酸曱酯；
2-羟基 -3- -异戊烯基 -4-曱氧基 -6- [(E)- 3， -苯基丙 -Γ -烯基]苯曱酸；
2-羟基 -3- -异戊烯基 -4-曱氧基 -6- [(E)- 4， -苯基丁 - Γ -烯基]笨曱酸甲酯； 2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-4， -苯基丁 -1， -晞基]苯甲酸； 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(Γ E, 3' E)- V ,3， -苯丁二烯基]苯曱酸甲酯； 2-羟基 -3-异戊浠基 -4-甲氧基 -6-[(1 ' E, 3， E)- V ,3' -苯丁二烯基]笨曱酸;
2-羟基 -3-异戊烯基 -4-曱氧基 -6-(4，-甲基环亚己基甲基)苯曱酸曱酯；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-(4，-曱基环亚己基曱基)笨甲酸；
2-羟基 -3-(3， ,7' -二曱基辛 -2' ,6' -二烯基) -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸甲酯; 2-羟基 -3-(3， ,7' -二曱基辛 -2， ,6' -二浠基) -4-曱氧基 -6-[(E)-笨乙烯基]苯曱酸; 2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-环己基乙烯基]苯曱酸曱酯；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-环己基乙烯基]苯曱酸；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-4，-乙酰氧基苯乙烯基]苯曱酸甲酯；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-4，-羟基笨乙烯基]苯甲酸甲酯；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2- (吡啶 -4-基）乙烯基]苯曱酸甲酯；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2- (吡啶 -4-基）乙烯基]苯曱酸；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-曱酯基苯乙烯基]苯甲酸曱酯；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-甲酯基苯乙烯基]苯甲酸；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酸乙酯；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酸异丙酯；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-笨乙烯基]苯曱酸叔丁酯；
N-环丙基 -2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯甲酰胺；
2-异戊烯基 -3-曱氧基 -5-[(E)-4，-氟苯乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(£)-2，-氯苯乙浠基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[(E)-4，-曱氧基苯乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(E)- 2，， 6， -二曱氧基苯乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-2，-曱基苯乙烯基]笨酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-3，-曱基苯乙浠基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[(E)-4，-曱基苯乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-丁 -1 -烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-2，-笨基丙 -Γ-烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[((E)-2- (噻吩 -2-基）乙烯基]苯盼；
2-异戊烯基 -3-甲氧基 -5-[(E)-3，-苯基丙 -Γ-烯基]苯酚； 2-异戊烯基 -3-曱氧基 -5-[( E)-4，-苯基丁 -Γ-烯基]笨酚；
2-异戊烯基 -3-甲氧基 -5-[ ( VE, 3'E)-1 ',3，-苯丁二烯基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[ 4，-甲基环亚己基甲基]苯酚；
2-异戊烯基 -3-(3，，7，-二甲基辛 -2，， 6，-二烯基 )-5-[(E)-苯乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(£)-2-环己基乙烯基]笨酚；
2-异戊烯基 -3-甲氧基 -5- [(E)-4，-羟基苯乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(E)- (吡啶 -4-基）乙烯基]笨酚；
2-异戊烯基 -3-曱氧基 -4-氯 -5-[(E)-苯乙烯基]苯酚；
2-异戊浠基 -3-甲氧基 -5-[(E)-苯乙烯基]笨甲醚；
2-异戊基 -3-甲氧基 -5-笨乙基苯酚；
2-异戊烯基 -3-曱氧基 -5-苯乙基苯臉；
2-异戊基 -3-曱氧基 -5-[(E)-苯乙烯基]苯酚；
2-羟基 -3-异戊烯基 -4-甲氧基 -5-氯 -6-[(E)-苯乙烯基]苯曱酸甲酯；
2-羟基 -3-异戊烯基 -4-甲氧基 -5-氯 -6-[(E)-苯乙烯基]苯甲酸；
2， 4-二甲氧基 -3-异戊烯基- -6-[(E)-苯乙烯基]苯甲酸甲酯；
2-甲氧基 -3-异戊烯基 -4-曱氧基 -6-[(£)-笨乙烯基]笨甲酸；
2-羟基—4—甲氧基 _5_异戊烯基 _6— [( —苯乙烯基]苯曱酸曱酯；
2,2-二甲基 -5-曱氧基 -7- [(E)-苯乙烯基]苯并 4氢吡喃；
2，4-二羟基 -3-异戊烯基 -6-[(E)-苯乙烯基]苯曱酸；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-苯乙基苯曱酸曱酯；
2_羟基—3·异戊浠基 _4-甲氧基 -6-苯乙基苯曱酸；
2—羟基 -4-曱氧基 -3-异戊基 -6-[(E)-苯乙烯基]笨曱酸曱酯；
2-羟基 -4-曱氧基 -3-异戊基 -6-[(E)-苯乙晞基]笨曱酸；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-笨乙烯基]苯甲酸甲酯；
2-幾基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2- (吡啶 -2-基）乙烯基]苯曱酸甲酯；
2-羟基—3-异戊烯基 -4-甲氧基 -6-[ (E)-2- (吡啶 -2-基）乙烯基]苯甲酸；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)- (3,4,5-三曱氧基苯乙烯基)]笨曱酸甲酯； 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)- (3,4,5-三曱氧基苯乙烯基)]苯甲酸；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[ (E)-2-(4-曱氧基吡啶 -2-基）乙烯基]苯甲酸曱酯; 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[ (E)-2-(4-曱氧基吡啶 -2-基）乙烯基]笨甲酸； 2-羟基 -3-异戊烯基 _4-曱氧基 -6-[ (E)-2-(4-羟基吡啶 -2-基）乙烯基]苯甲酸；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-(3-甲氧基吡啶 -2-基）乙烯基]苯甲酸曱酯； 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-(3-曱氧基吡啶 -2-基）乙烯基]苯甲酸；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E) -2-(3-羟基吡啶 -2-基）乙烯基]苯曱酸；
2-羟基 -3-异戊烯基 -4-曱氧基 -6- [(E)-2-(4,6-二曱氧基吡啶 -2-基）乙烯基]苯甲酸曱酯;
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-(4,6-二曱氧基吡啶 -2-基）乙烯基]笨曱酸； 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-(4，6-二羟基吡啶 -2-基）乙烯基]苯甲酸； 2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-(6-甲氧基吡啶 -2-基）乙烯基]苯甲酸甲酯； 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-2-(6-甲氧基吡啶 -2-基）乙烯基]苯甲酸；
2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-2-(6-羟基吡啶 -2-基）乙烯基]苯甲酸；
2-羟基 -3-烯丙基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸甲酯；
2-羟基 -3-烯丙基 -4-曱氧基 -6-[(E)-苯乙烯基]苯甲酸；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸 2,3-二羟基丙酯；
N-苯基 2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯甲酰胺；
N-对氯笨基 2-羟基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酰胺；
2-异戊烯基 -3-甲氧基 -5-[(E)-2- (吡啶 -2-基） 乙烯基]笨酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-3,4,5-三曱氧基苯乙烯基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[(E)-2- ( 4-曱氧基吡啶 -2-基） 乙烯基]笨酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-2- ( 4-羟基吡啶 -2-基） 乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-2- ( 3-曱氧基吡啶 -2-基） 乙烯基]笨酚；
2-异戊烯基 -3-曱氧基 -5-[(E)-2- ( 3-羟基吡啶 -2-基） 乙烯基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[(£)-2- ( 2,4-二甲氧基 p比啶 -2-基） 乙烯基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[(E)-2- ( 2,4-二羟基吡啶 -2-基） 乙烯基]苯酚；
2-异戊烯基 -3-曱氧基 -5-[(£)-2- ( 2-曱氧基吡啶 -2-基） 乙烯基]苯酚；
2-异戊烯基 -3-甲氧基 -5-[(E)-2- ( 2-羟基吡啶 -2-基） 乙烯基]苯酚；
2—烯丙基—3-曱氧基 -5-[(E)-笨乙烯基]笨酚；
1 ,3-二曱氧基 -5-[(E)-3-苯基丙 -1 -烯基]笨；
1，3-二羟基—5-[(E)-3-笨基丙 -1 -浠基]笨；
1 ,3-二曱氧基 -5-[(E)-3-乙酰氧基 -4-曱氧基苯乙烯基]苯；
1，3-二曱氧基 -5-[(E)-3-羟基 -4-曱氧基苯乙烯基]苯； 1，3-二羟基 -5-[(E)-3，4-二羟基苯乙烯基]苯；
1 ,3-二曱氧基 -5-[ ( E ) -2- ( 3,5-二乙跣氧基笨基） 丙 -1 -烯基]苯；
1 ,3-二甲氧基 -5-[ ( E ) -2- ( 3,5-二羟基苯基） 丙小烯基]笨；
1，3-二羟基 -5-[ ( E ) -2- ( 3,5-二羟基笨基) 丙- 烯基]苯；
1，3-二曱氧基 -5-[ ( E ) -3，4，5-三乙酰氧基笨乙烯基]笨；
1 ,3-二甲氧基 -5-[ ( E ) -3,4,5-三羟基笨乙烯基]笨;
1 ,
3-二羟基 -5-[ ( E ) -3,4,5-三羟基苯乙烯基]苯；
[(2-羟基 -3-异戊烯基 -4曱氧基 -6-(E)-苯乙烯基苯基 )](1H-咪唑 -1 -基）曱酮； N-胺曱酰基 -2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酰胺； N-曱脒基 -2-羟基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯甲酰胺；
2-氨基乙酰氧基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酸甲酯；
2-氨基乙酰氧基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酸；
2-异戊烯基 -3-氨基乙酰氧基 -5-[(E)-笨乙烯基]苯曱醚；
2- (吡咯 -2-甲酰氧基 )-3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙晞基]苯曱酸曱酯； 2- (吡咯 -2-曱酰氧基 )-3-异戊烯基 -4-甲氧基 -6- [(E)-苯乙烯基]苯曱酸；
2-异戊烯基 -3- (吡咯 -2-甲酰氧基 )-5-[(E)-苯乙烯基]笨甲醚；
2-乙酰氧基 -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸曱酯；
2- (吡咯 -2-甲酰氧基) -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯甲酸；
2-异戊烯基 -3- (吡咯 -2-曱酰氧基) -5-[(E)-苯乙烯基]苯甲醚；
2- (吡啶 -3-甲酰氧基 )-3-异戊烯基 -4-曱氧基 -6-[(E)-笨乙烯基]苯曱酸曱酯； 2- (吡啶 -3-甲酰氧基) -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酸；
2-异戊烯基 -3- (吡啶 -3-甲酰氧基) -5[(E)-笨乙烯基]苯曱醚；
2-(N，N-二甲基乙酰氧基 )-3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯甲酸甲酯; 2-(N,N-二曱基乙酰氧基) -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙烯基]苯曱酸； 2-异戊烯基 -3-(N，N-二曱基乙酰氧基) -5-[(E)-苯乙烯基]苯甲醚；
2-(1 H-咪唑 -2-曱酰氧基 )-3-异戊烯基 -4-曱氧基 -6- [(E)-笨乙烯基]苯曱酸曱酯； 2-( 1Η-咪唑 -2-曱酰氧基) -3-异戊烯基 -4-曱氧基 -6-[(E)-苯乙浠基]苯曱酸； 2-异戊烯基 -3-(1Η-咪唑 -2-甲酰氧基 )-5-[(E)-苯乙烯基]笨甲醚；
2- ( N-苄基胺曱氧基） -3-异戊烯基 -4-曱氧基 -6- [(E)-笨乙烯基]笨甲酸甲酯; 2-胺曱氧基 -3-异戊烯基 -4-甲氧基 -6-[(E)-苯乙烯基]苯曱酸甲酯； 2-胺曱氧基 -3-异戊烯基 -4-甲氧基 -6- [(E)-苯乙浠基]苯甲酸；
2-异戊烯基 -3-胺曱氧基 -5-[(E)-苯乙烯基]苯曱醚；
2- ( 1,4-二苄基哌嗪 -2-基） 曱氧基 -3-异戊烯基 -4-曱氧基 -6-[(E)-笨乙晞基]苯曱酸曱 酯；
2- (哌嗪 -2-基） 曱氧基 -3-异戊烯基 -4-甲氧基 -6-[ ( E) -苯乙烯基]苯曱酸曱酯； 2- (哌嗪 -2-基） 曱氧基 -3-异戊烯基 -4-甲氧基 -6-[ ( E) -苯乙烯基]苯曱酸； 2-异戊烯基 -3- (哌嗪 -2-基） 曱氧基 -5-[(E)-苯乙烯基]苯曱醚；
2-异脲基 -3-异戊烯基 -4-甲氧基 -6-[ ( E) -苯乙烯基]苯甲酸曱酯；
2-异脲基 -3-异戊烯基 -4-甲氧基 -6-[ ( E) -苯乙烯基]苯甲酸；
2-异戊烯基 -3-异脲基 -5-[ ( E) -苯乙烯基]苯曱醚；
2-肼曱酰氧基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙烯基]苯曱酸曱酯；
2-肼曱酰氧基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙烯基]苯曱酸；
2-异戊烯基 -3-肼曱酰氧基 -5-[ ( E) -苯乙烯基]苯曱醚；
2-曱酯基甲酰氧基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙烯基]苯曱酸曱酯；
2-羧基曱酰氧基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙烯基]苯曱酸曱酯；
2-曱酯基曱酰氧基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙浠基]苯曱酸；
2-羧基甲酰氧基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙烯基]苯曱酸；
2-异戊烯基 -3-曱酯基曱酰氧基 -5-[ ( E) -苯乙烯基]苯曱醚；
2-异戊烯基 -3-羧基曱酰氧基 -5-[ ( E) -苯乙烯基]笨甲醚；
2-羟基 -3-异戊烯基 -4-曱氧基 -6-[ ( E) -苯乙烯基]苯甲酰胺。
4. 制备权利要求 1中具有通式 （ I ) 所示结构的化合物， 如通式 I所示化合物的 合成方法：
当 R3 为羧基， 为羟基， R6为烷氧基， R7为 H， 而其余基团如上面通式所定义 时其合成方法如路线 1:
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000097_0003
路线 1 : 乙酰乙酸酯和二乙烯酮在碱性条件下缩合得到化合物 2, 化合物 2在碱性 条件下在极性溶剂中烷基化生成 3 , 3在非极性溶剂中发生自由基！ ¾化反应生成化合物 4， 化合物 4与亚磷酸三酯缩合得到化合物 5, 化合物 5与酮或醛反应得到化合物 6, 化合物再在脱烷基试剂存在下脱烷基得到化合物 7, 化合物 7与 代烃发生缩合反应 得到 8 (此时也得到氧烷基化产物 8'， 该化合物即是 为烷氧基， R5为氢， 其余各基 团定义如上的式 I化合物） ， 8水解得到通式 I化合物； 其中 R8. R9，R10为 1-18个碳 的取代或者未取代的烃基， R2, R5，与前述各通式中的定义相同；
又， 当 R3 为烷氧（硫）曱酰基或取代氨曱酰基， 其余基团如上面通式所定义时， 其合成方法如路线 2:
Figure imgf000097_0004
路线 2: 通式 I化合物与各种 R9,XH ( X=0, S , N等）在缩合剂存在下缩合得到 化合物 9， 或者通式 I化合物与酰化剂生成酰氯， 再与各种 R9，XH在缚酸剂存在下缩 合得到化合物 9; 其中 R2, R4 , R5， R6， R7其定义与前面所述各通式中的定义相 同， R9, 为 1-18个碳的取代或者未取代的烷基， 取代或者未取代的芳基， 杂芳基； 又， 本发明还提供了木豆素 A的制备方法， 如路线 3所示：
Figure imgf000098_0001
8 10
路线 3为木豆素 A的合成方法 （ RfPh, R2=H, R4=OH, R5=异戊烯基， R6=OM£,
R7=H, 化合物 10为木豆素 A ) , 化合物 8在碱性或酸性条件下， 在微波的辅助下脱羧 得到化合物 10， 式中 Ri , R2, R4 , R5 , R6, R7, R9与前述通式所定义一样；
又， 当 R3 为羧基， 为羟基， R6为烷氧基， R7为卤素， 其余基团如上面通式所 定义时， 其合成方法如路线 4:
Figure imgf000098_0002
路线 4: 化合物 7在有机溶剂中与! ¾化试剂反应得到化合物 11， 化合物 11在碱性 条件下与烷基化试剂偶合得到化合物 12, 化合物 12在碱性或者酸性条件下水解得到 化合物 13; 其中 X为 F, CI, Br; Rl 5 R2, R5， R8， R9的定义如前所述；
又， 当 R3 为羧基， 和 R6为烷氧基， R7为 H, 其余基团如前述通式所定义时， 其合成方法如路线 5:
Figure imgf000098_0003
8 14 15 路线 5: 化合物 8在碱性条件下与烷基化试剂反应得到化合物 14， 化合物 14再在 碱性或酸性条件下水解得到化合物 15; 式中 R2， R5， R8, R9与前述通式所定义 一致， R8， 为 1-18个碳的烷基；
又， 本发明还提供了木豆素 C的全合成方法， 如路线 6所示：
Figure imgf000098_0004
路线 6为木豆素 C 的全合成路线 （R7=异戊烯基， R8=Me, R2=H, RfPh时, 化合物 19即为木豆素 C ) ， 化合物 6经过 化得到化合物 16， 16与偶合试剂在催化 剂存在下发生偶联反应得到化合物 17, 化合物 17与脱烃基试剂反应得到化合物 18, 18再脱羧得到化合物 19; 式中 Ri , R2, R7， R8, R9与前述通式所定义一致；
又， 当 R3 为羧基， R4、 R5=OH, 其余基团如前述通式所定义时， 其合成方法如 路线 7:
Figure imgf000099_0001
路线 7: 通式 I化合物与脱烷基试剂反应得到目标化合物 20; 式中 R!， R2， R: R7, R8与前述通式定义相同；
又， 当 R3=R5=R7=H, 其余基团如前述通式所定义时， 其合成方法如路线 8:
Figure imgf000099_0002
路线 8: 取代苄基膦酸酯与酮缩合反应得到目标产物 21， 式中 R! , R2， R4 , R6与 前述通式定义相同；
又， 当 R3= (1H-咪唑 -1-基）曱酰基， 其余基团如前述通式所定义时， 其合成方法如 路线 9:
Figure imgf000099_0003
路线 9: 1位为羧基的衍生物与羰基二咪唑缩合反应得到目标产物 22 , 式中 ， R2, R4 , R5 , R6, R7与前述通式定义相同；
又， 当 R3=N- (氨基甲酰基)氨甲酰基， 或者 N- (甲脒基)氨甲酰基， 其余基团如前述 通式所定义时， 其合成方法如路线 10:
Figure imgf000100_0001
路线 10:1位为烷氧曱酰基的衍生物与尿素（X=0)或者胍（X=NH)缩合反应得到 目标产物 23， 式中 X=0 或者 NH, Rj, R2, R4, R5， R6, R7与前述通式定义相同； 又，当 取代曱酰氧基，其余基团如前述通式所定义时，其合成方法如路线 11:
Figure imgf000100_0002
24
路线 11:2位为羟基的衍生物在碱性条件下与酰氯缩合得到 标产物 24， 式中 R!, R2， R3, R5, R6, R7与前述通式定义相同， Rt。为取代或者未取得的烷基， 取代或者 未取代的杂芳环， 取代或者未取代氨基；
又， 当 FU=氨基甲氧基或者 （哌嗪 -2-基） 曱氧基， 其余基团如前述通式所定义时， 其合成方法如路线 12 (以氨基 为例， （哌嗪 -2-基） 曱氧基与此类似） ：
Figure imgf000100_0003
25 26 路线 12: 2位为羟基的衍生物与 N-苄基氨基甲醇缩合得到化合物 25, 化合物 25再脱 苄基得到目标产物 26, 式中 Rl R2, R3， R5， R6, R7与前述通式定义相同；
又， 当 异脲基， 其余基团如前述通式所定义时， 其合成方法如路线 13:
Figure imgf000100_0004
路线 13: 2位为羟基的衍生物与胺基氰反应得到目标化合物 27， 式中 R1; R2, R3, R5， R6, R7与前述通式定义相同； 又，当 肼基甲酰氧基，其余基团如前述通式所定义时，其合成方法如路线 14:
Figure imgf000101_0001
28 29 路线 14: 2位为羟基的衍生物与碳酰氯反应得到化合物 28， 28再与肼缩合得到目标产 物 29， 式中 R2, R3， R5， R6， R7与前述通式定义相同；
又， 当 羧基甲酰氧基， 其余基团如前述通式所定义时， 其合成方法如路线 15:
Figure imgf000101_0002
30 31 路线 15: 2位为羟基的衍生物与 2-氯 -2-羰基乙酸曱酯在碱性条件下缩合得到化合物 30, 化合物 30再水解得到 标产物 31, 式中 R!, R2, R3, R5, R6, R7与前述通式定义相 同；
又， 当 R3=氨曱酰基， 其余基团如前述通式所定义时， 其合成方法如路线 16:
Figure imgf000101_0003
路线 16: 苯环一位为烷氧甲酰基的衍生物胺解得到目标产物 32, 式中， R2， R4, R5， R6， R7与前述通式定义相同， R8，为 1-18个碳的烷基；
5. 制备权利要求 1 中具有通式（II)所示结构的化合物， 其中 R8与前面通式所述 定义一致， 如路线 17:
Figure imgf000101_0004
33 路线 17: 化合物 1在酸催化剂存在下得到脱羧， 分子内加成产物 33。
6. 权利要求 1中具有通式 （III) 所示结构的化合物， R9为 H, R8与前面通式所述 定义一致， 如路线 18:
Figure imgf000102_0001
路线 18: 木豆素类似物 1，在 Pd类催化剂催化下， 氢化得到所有烃双键被还原的产 物。
7. 权利要求 1 中具有通式（IV ) 所示结构的化合物， 其中 R8， R9与前面通式所述 定义一致， 如路 19:
Figure imgf000102_0002
路线 19: 化合物 7经催化氢化得到化合物 35, 35再异戊烯基化得到化合物 36, 最 后经水解得到 37。
8. 权利要求 1中具有通式（V )所示结构的化合物， 式中 R8, R9, R10为 1-18个碳 的烷基， 如路线 20:
Figure imgf000102_0003
47
路线 20: 乙酰乙酸酯与巴豆酸酯在碱性条件下缩合得到化合物 38，化合物 38再溴 化芳环化得到化合物 39， 化合物 39再烷基化得到化合物 40, 化合物 40与！ ¾化试剂发 生自由基 (¾化反应得到化合物 41 , 化合物 41与有机膦试剂缩合得到化合物 42 , 42发 生偶联反应得到烷基化产物 43， 43再氢化得到化合物 44， 进而在碱性条件下与苯甲 醛缩合得到化合物 45 , 46再发生脱烷基和水解反应得到化合物 47。
9. 一 法， 如路线 21 :
Figure imgf000103_0001
路线 21 : 式中 R8 , R9，R10为 18个碳的烷基， 当 R8=Me时， 化合物 1即为木豆 素；化合物 42的制备方法与路线 20—致，与苯曱醛在碱性条件下缩合得到化合物 48 , 48再脱烷基得到化合物 49, 49再经过烷基化、 水解得到化合物 1。
10. 权利要求 1中具有通式 I 、 II、 III、 IV、 V所示结构的芪类化合物或其药用盐 在制备抗细菌和病毒感染、 神经保护、 抗代谢性疾病等药物中的应用， 所述代谢性疾 病包括骨质疏松、 高血脂或高血糖。
1 1. 一种用于抗细菌和病毒感染、 神经保护、 抗代谢性疾病等的药物组合物， 其特 征在于， 该药物组合物中含有治疗有效量的权利要求 1所述具有通式 I 、 II、 III、 IV、 V的化合物或其药用盐， 并含有一种或多种药学上可接受的药物辅剂， 所述代谢性疾 病包括骨质疏松、 高血脂或高血糖。
12. 如权利要求 1 1所述的药物组合物。 其中， 所述具有通式 I 、 II、 III、 IV、 V的 化合物或其药用盐作为活性成分， 在该药物组合物中的重量含量为 0.1%-99.5%。
13. 如权利要求 12所述的药物组合物， 其中， 该药物组合物中含有重量比为 0.5%-99.5%的活性成分。
14. 如权利要求 1 1所述组合物在制备抗细菌和病毒感染、 神经保护、 抗代谢性疾 病等药物中的应用， 所述代谢性疾病包括骨质疏松、 高血脂或高血糖。
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