CN1129445A - Isoflavone derivatives - Google Patents
Isoflavone derivatives Download PDFInfo
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- CN1129445A CN1129445A CN94193107A CN94193107A CN1129445A CN 1129445 A CN1129445 A CN 1129445A CN 94193107 A CN94193107 A CN 94193107A CN 94193107 A CN94193107 A CN 94193107A CN 1129445 A CN1129445 A CN 1129445A
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- general formula
- group
- alkyl
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- isoflavones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
- C07D311/38—2,3-Dihydro derivatives, e.g. isoflavanones
Abstract
The present invention relates to isoflavone, isoflavan-4-one and isoflavane derivatives of general formula (I), their salts, pharmaceutical compositions containing the compounds of general formula (I), and to a process for preparing the same. In general formula (I), if n is 0, R<5> and R<6> together stand for an oxo group and the dotted line means a double bond, R<1> represents C1-18alkyl substituted by alkylcarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (C1-4alkyl)2N-(CH2)mCO(CH2)p- or by (C1-4alkyl)2N-(CH2)mOCO(CH2)p- group; or stands for C3-6cycloalkyl or cycloalkenyl; or if n is 1, R<5> and R<6> together stand for an oxo group and the dotted line means a double bond, R<1> represents C1-18alkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (C1-4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3-6-cycloalkyl or cycloalkenyl or C2-6alkenyl; or if n is 0 or 1, R<5> and R<6> together stand for an oxo group or stand separately for hydrogen and the dotted line does not mean a chemical bond, R<1> represents C1-18alkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, alkoxy, phenyl optionally substituted by a halo atom, phenoxy, piperidino, morpholino or piridino or by a (C1-4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3-6-cycloalkyl or C2-6alkenyl; or R stands for C1-8alkyl, halogen, C1-4alkoxymethyl, C2-5-acyloxymethyl, or hydroxymethyl; R<4> stands for hydrogen or C1-4alkyl; R<2> and R<3> stand for hydrogen or C1-6alkoxy; R<5> and R<6> together stand for an oxo group or separately stand for hydrogen; the dotted line means a double bond being optionally present; n is 0 or 1; m is an integer from 1 to 4; and p is an integer from 1 to 4. The compounds of general formula (I) can be used for the prevention and treatment of osteoporosis.
Description
The present invention relates to isoflavones, different Huang-4-ketone and the isoflavan derivative of general formula (I),
Their salt contains the pharmaceutical composition of the compound of general formula (I), and relates to their preparation method.
The isoflavone derivative of following general formula
Different Huang-4-the ketone derivatives of following general formula
The isoflavan derivative of following general formula
Constitute the compound of less one group of general formula (I).
In general formula (I):
If n is 0, R
5And R
6Represent that together oxo group and dotted line refer to two keys,
R
1Representative is by alkyl-carbonyl, carboxyl, sulfonic group, hydroxyl, phenoxy group, piperidino-(1-position only), morpholino or pyrido or by (C
1-4Alkyl)
2N-(CH
2)
mCO (CH
2)
p-or by (C
1-4Alkyl)
2N-(CH
2)
mOCO (CH
2)
pThe C that-group replaces
1-18Alkyl; Or expression C
3-6Cycloalkyl or cycloalkenyl group; Perhaps
If n is 1, R
5And R
6Represent that together oxo group and dotted line refer to two keys,
R
1Represent arbitrariness ground by alkyl-carbonyl, alkoxy carbonyl, carboxyl, sulfonic group, hydroxyl, phenoxy group, piperidino-(1-position only), morpholino or pyrido or by (C
1-4Alkyl)
2N-(CH
2)
mCO (CH
2)
pThe C that-group replaces
1-18Alkyl; Or expression C
3-6Cycloalkyl or cycloalkenyl group or C
2-6Alkenyl; Perhaps
If n is 0 or 1, R
5And R
6Represent oxo group together or represent that independently hydrogen and dotted line are not meant chemical bond,
R
1Phenyl, phenoxy group, piperidino-(1-position only), morpholino or the pyrido or the quilt (C that represent arbitrariness ground to be replaced by halogen atom by alkyl-carbonyl, alkoxy carbonyl, carboxyl, sulfonic group, hydroxyl, alkoxyl group, arbitrariness ground
1-4Alkyl)
2N-(CH
2)
mCO (CH
2)
pThe C that-group replaces
1-18Alkyl; Or expression C
3-6Cycloalkyl or C
2-6Alkenyl;
R represents C
1-8Alkyl, halogen, C
1-4Alkoxy methyl, C
2-5Acyloxy methyl or methylol;
R
4Expression hydrogen or C
1-4Alkyl;
R
2And R
3Expression hydrogen or C
1-6Alkoxyl group;
R
5And R
6Represent oxo group together or represent hydrogen individually;
Dotted line refers to two keys that arbitrariness exists;
N is 0 or 1;
M is the integer of 1-4; With
P is the integer of 1-4.
The compound of general formula (I) is used for preventing and the treatment osteoporosis.
According to the present invention, the compound of general formula (IA) can obtain by following reaction: allow the ketone of following general formula
R wherein, n, R
1, R
2And R
3It is the same with the definition in the general formula (I),
A) react in the presence of alkaline catalysts with alkyl orthoformate, or
B) react in the presence of hydrohalogen with prussic acid and/or cyanate; Or
C) react in the presence of basic metal with alkyl formate, or
D) with the reaction of alkoxalyl halogen, if desired, so the isoflavones ester that obtains is by saponification and/or decarboxylation; Or
E) with the organic carboxyl acid anhydride reactant; Or
F) and N, the N-dialkyl amide reacts in the presence of phosphorus chloride; Perhaps
G) the 2-hydroxyl-isoflavone derivative with following general formula dewaters:
And, if desired, with R
1Groups converted becomes another R
1Group, or form R group in general formula (I) compound, wherein R represents hydrogen and if desired, the compound of the general formula (I) that obtains is like this changed into its salt or it is dissociated out from its salt.
The method according to this invention subform a), the ketone of suitable replacement and alkyl orthoformate, preferred ethyl ester reacts in high boiling aprotonic solvent.As solvent, can use tetramethyleneimine, dimethyl formamide or diglyme.As alkaline catalysts, preferably use piperidines, morpholine, tetramethyleneimine and other secondary amine class.
The method according to this invention subform b), aldehydes and prussic acid react in the presence of dry gaseous state spirit of salt or other haloid acid or Lewis acid in aprotonic solvent.In reaction, also can use the aprotonic solvent of non-alkalescence, preferred ether or other dialkyl ether.As catalyzer, can use zinc chloride or other Lewis acid.
With prussic acid or its suitable salt, preferred zinc cyanide carries out this reaction.This mixture is saturated with dry gaseous state spirit of salt, and the α-formimino of resulting replacement-2-hydroxy phenyl benzyl-ketone hydrochloride decomposes after water treatment.
The method according to this invention subform c), the ketone of general formula (III) and alkyl formate react in the presence of basic metal.Preferably carry out in the following manner: the 2-hydroxy phenyl benzyl-ketone that will be dissolved in the suitable replacement in the ethyl formate is added drop-wise on the atomizing sodium Metal 99.5, then water decomposition reaction mixture and isolate the isoflavones that is obtained.
The method according to this invention subform d), the 2-hydroxyl-phenylbenzyl ketone of suitable replacement and alkoxalyl halogen reaction.Obtain 2-alkoxy carbonyl-isoflavone derivative, if desired,, convert it at 2 unsubstituted isoflavone derivatives by the hydrolysis ester group with by decarboxylation subsequently.This method subform is enough methyl of energy or ethyl oxalyl chloride preferably, in the presence of alkaline acid binding agent, carries out in suitable aprotonic solvent, preferred pyridine or another kind of tertiary amine.
The method according to this invention subform e), the 2-hydroxyl-phenylpropiophenone of suitable replacement and organic acid anhydride react in the presence of alkaline catalysts.As organic acid anhydride, can use diacetyl oxide, propionic anhydride or benzoyl oxide.Acid anhydrides is at alkaline catalysts, and is solvent-free or in high boiling aprotonic solvent such as pyridine or dimethyl formamide in the presence of an alkali metal salt of the acid constituents of this acid anhydrides or in the presence of tertiary amines more suitably, heats.
The method according to this invention subform f), ketone and N, the N-dialkyl amide reacts in the presence of phosphoryl chloride, preferred mode is to allow the 2-hydroxyl-phenylpropiophenone and the N of suitable replacement, N-dialkyl amide (for example dimethyl formamide or N,N-DIMETHYLACETAMIDE) and phosphoryl chloride heat together, N, N-dialkyl amide itself is as solvent.
The method according to this invention subform g), the 2-hydroxyl-isoflavones of structural formula (IV) by the heating or by in polar solvent in acidic medium mild heat dewater.
In the first step of the inventive method, this analog derivative can obtain from structural formula (III) or compound (IV), wherein R
1Expression hydrogen or be not the needed R of target product
1Base.In these cases, R
1Group is introduced in the position of hydrogen atom, or R
1Group is converted into another R
1Group.This step can be undertaken by the part or all of alkylation of list or poly-hydroxy isoflavones, this alkylated reaction is preferably by allowing it and alkylogen or substituted alkyl halogen, the alkylsulphonic acid lactone, the alkyl sodium sulfate ester, alkene or epoxide reaction carry out, preferred mode is to allow alkylating reagent and the institute alkylating isoflavones of wanting at suitable solvent, and for example ketone, dimethyl formamide or contain in the ethers of more carbon atom heats together.Under the situation of halogen, preferably there is acid binding agent, as alkaline carbonate with under the situation of alkyl bromide and alkyl chloride, preferably there is alkaline metal iodide.This step can be by acyloxy and many acyloxy, the part or all of deacylated tRNA of alkoxyl group and many alkoxyl groups isoflavones or partly or entirely take off alkyl and carry out.Carry out method subform e when being used in 2 two or poly-hydroxy phenyl benzyl ketones of going up hydroxyl) time, acyloxy or many acyloxy isoflavones formed.De-acyl reaction is preferably carrying out in acidity or alkaline medium in the presence of the polar solvent.This step also can be by carrying out isoflavones-2-carboxylic acid decarboxylation.At method subform d) in form isoflavones-2-carboxylic acid, their decarboxylic reaction is preferably undertaken by heating being with or without in the presence of catalyzer such as the copper scale.
The compound of general formula (IB), R wherein, n, R
1, R
2, R
3And R
4The same with the definition in the general formula (I), be by with the also preparation originally of the compound of general formula (IA), R wherein, n, R
1, R
2, R
3And R
4The same with the definition in the general formula (I).By catalytic hydrogenation or by using metal hydride to carry out reduction reaction.
Under the situation of catalytic hydrogenation, use noble metal catalyst, preferably be carried on the palladium catalyst on the gac, reduction reaction is carried out in organic solvent, preferably carries out in acetone.
As the title complex metal hydride, preferably use diisobutyl aluminium hydride and reduction to be reflected under the low temperature (70 ℃) and carry out.The compound of general formula (IC), R wherein, n, R
1, R
2, R
3And R
4The same with the definition in the general formula (I), be by in the presence of precious metal or nickel catalyzator, the compound for catalysis hydrogenation of general formula (IB) being prepared R in the formula, n, R
1, R
2, R
3And R
4The same with the definition in the general formula (I).Reduction reaction is carried out in preferred acetate or the ethyl acetate preferably at polar solvent.
The compound of general formula (I), wherein R
1Expression is by the alkyl of carboxyl substituted, is that the hydrolysis of ester group of those compounds of the alkyl by will containing the alkoxy carbonyl substituted prepares.Hydrolysis reaction preferably carries out in acidic medium, and the most handy rudimentary organic acid carries out in the presence of strong acid catalyst.
The compound that contains the general formula (IA) of methyl on 6 is by with the also preparation originally of monochloromethyl isoflavones, wherein this monochloromethyl isoflavones be from a kind of on 6 the compound of the general formula (IA) of hydrogen atoms carry out halomethylation reaction and obtain.Reduction reaction preferably at metal, be preferably in the presence of the zinc and carry out.
General formula (I) compound that contains alkoxyl group or methylol on 6 prepares in the following way: perhaps by means of alcohol; replace the halogen atom of the monochloromethyl isoflavones for preparing according to the above mode with alkoxyl group; perhaps by means of sodium acetate; replace this halogen atom with the O-ethanoyl, subsequently acetoxyl group is changed into the OH base.
We find the compound of general formula (I) and salt can be used for preventing effectively and the treatment osteoporosis.
Known 7-isopropoxy isoflavones (Ipriflavone) can suppress to absorb in the bone (Notoya again in external or body, people such as K, Inhibitory effect of Ipriflavoneon pit formation in mouse unfractionated bone cells, Calcif.Tis-sue Int.51, (Supl.1) 53-56 (1992); Notoya, K. wait the people, Inhibito-ry effect of Ipriflavone on osteoclast-mediated bone resorptionand new osteoclast formation in long-term cultures of mouseunfractionated bone cells, Calcif Tissue Int.50,314-319 (1992)).On the other hand, known Ipriflavone can also improve the mineralization degree of extracellular matrix of human body osteocyte culture (with reference to Ecsedi, G.G.Model in vitroinvestigation of bone mineralization, Agents and Actions 41,84-85 (1994)).
In order to estimate general formula (I) compound, set up an external mineralising model to osteoplastic effect.Under some environment, culture from (rich synthetic bone cell) human body osteocyte grownup's nasal bone or fetal femur, that part is selected can produce type i collagen albumen, bone specific proteins class (for example osteocalcin), prostanoid (PGE2, PGE2a, PGI2 etc.) and with calcium run up to (reference: Ecsedi in the synthetic matrix, G.G., Characteri-zation of cells of human nasal bone cell cultures, 4th Int.Sympo-sium on Osteoporosis, 27 March-2 April, 1993 Hong Kong; Ab-str.no.534).Method: the cell of subculture 8-12 (the common the 8th or the 9th) drips inoculation with the density in 2*10^4 the every hole of cell (plates in 96 holes).At the 3rd day, handle with two kinds of concentration 10^-8 and 10^-10M with the compound of general formula I.Because the ethanol 10^-5 of this compound and 10^-7M storage liquid are used for handling, all culture media comprise contrast, contain 0.1% ethanol.Changed medium in every 2-3 days.This is handled at the 21st day and finishes, by Boehringer Test Combination (MPR3) and 3,5-diaminobenzoic acid (DABA) spectrofluorimetry method is measured total calcium (Ca) content and the dna content of 6 parallel sample respectively, thereby calculates ratio Ca/DNA.
In the table of formula I compound below, data provide with the percentage ratio with respect to the mean value of control value (100%)
| Concentration compound title [log M] | ???Ca ???％ | ??DNA ??％ | ?Ca/DNA ????％ |
| Ipriflavone 8 (7-isopropoxy-10 isoflavones) | ??121 ??111 | ??100 ??108 | ????121 ????103 |
| CH-16693 8 (7-(1-hexamethylene-10 2-alkene oxygen base)-isoflavones) | ??110 ??131 | ???97 ??107 | ????113 ????124 |
The compound of general formula (I) can be used for the treatment of with the dosage form that contains acceptable solid on activeconstituents and inert, atoxic, the pharmacology or liquid diluent or carrier.If desired, said preparation can contain the known substance of biologically active, as VITAMIN, and amino acid, Lipotril, inorganic acid salt, trace element etc.As carrier, can use talcum, gelatin, lime carbonate, Magnesium Stearate, starch, water, polyalkylene glycol etc.Said composition can be mixed with solid preparation (for example tablet, drageeing, capsule, suppository etc.) or liquid (for example solution, suspension or emulsion) preparation.
Illustrate in greater detail the present invention among the indefiniteness embodiment below.
Embodiment 1
The 10g 7-hydroxyisoflavone, 10ml monochloroacetone and 8g salt of wormwood stir in 120ml acetone, mixture boiled 5 hours.The reaction mixture dilute with water filters out throw out and recrystallization from acetate.Obtain 8.5g 7-(2-oxopropyl) isoflavones, m.p.:174-175 ℃.
By similar mode, get from 7-hydroxyisoflavone and corresponding alkylogen or substituted alkyl stew in soy sauce:
7-(2,3-dihydroxyl-1-propoxy-)-isoflavones (FL 230), m.p.:164-165 ℃,
7-(3-ethoxy carbonyl-propoxy-)-isoflavones (FL 283), m.p.:124-125 ℃,
7-(2-phenoxy group oxyethyl group)-isoflavones (FL 273), m.p.:195-197 ℃ and
7-(1-ethoxy carbonyl-1-oxygen in last of the ten Heavenly stems base)-isoflavones (FL 279), m.p.:97-99 ℃.
Use 3-methyl isophthalic acid-butyl bromide, from 7-hydroxyl-3 ', 4 '-dimethoxy-isoflavones makes 7-(3-methyl isophthalic acid-butoxy)-isoflavones (FL 191), m.p.:107-108 ℃.
Obtain from 7-hydroxyl-8-methyl-isoflavones: 7-oxyethyl group-8-methyl-isoflavones (FL 315), m.p.:129-130 ℃, 7-(ethoxycarbonyl methoxyl group)-8-methyl-isoflavones (FL 316), m.p.:137-139 ℃, and 7-(4-oxo-1-pentyloxy)-isoflavones (FL 501), m.p.:143-145 ℃.
Embodiment 2
16g 6-n-hexyl-7-hydroxyl-isoflavones, the mixture of 14ml isopropyl bromide and 70ml dimethyl formamide stirred 4 hours down at 90 ℃ in the presence of 16g salt of wormwood.
In the reaction mixture impouring 500ml water, isolate product, then recrystallization from 80% aqueous methanol.Obtain 15g 6-n-hexyl-7-(1-methyl ethoxy)-isoflavones, m.p.:37-39 ℃.
Make 6-n-hexyl-7-oxyethyl group-isoflavones (FL 319) in a similar manner, m.p.:57-59 ℃ and 6-n-hexyl-7-(2-methyl isophthalic acid-propoxy-)-isoflavones (FL 321), m.p.:65-67 ℃.
Allow 6-chloro-7-hydroxyl-isoflavones and alkylogen react, make following compound:
7-oxyethyl group-6-chloro-isoflavones (FL 322), m.p.:162-164 ℃,
7-(1-methyl ethoxy)-6-chloro-isoflavones (FL 323), m.p.:156-158 ℃,
7-(2-methyl isophthalic acid-propoxy-)-6-chloro-isoflavones (FL 324), m.p.:170-172 ℃,
7-(2-third-1-base-oxygen base)-different Huang-4-ketone (FL 238), m.p.:76-78 ℃ and
7-(4-nitro-benzyloxy)-different Huang-4-ketone (FL 239), m.p.:100-102 ℃.
Embodiment 3
6.5g 7-n-hexadecane oxygen base-isoflavones is carrying out hydrogenation in the presence of 3.0g 10% palladium/activated-carbon catalyst, in 1200ml acetone, till the hydrogen absorbed dose is 1.2 equimolar amounts.Filter out catalyzer, solution evaporates.Resistates is recrystallization from the mixture of methyl alcohol and acetone, obtains 5.3g 7-n-hexadecane oxygen base-different Huang-4-ketone, m.p.:90-92 ℃.
In a similar manner, make 7-oxyethyl group-5-methyl-different Huang-4-ketone (FL 299), m.p.:97-98 ℃ from 7-oxyethyl group-5-methyl-isoflavones.
By hydrogenation, till the hydrogen absorbed dose is 2.2 equimolar amounts, make 7-cyclohexyl-different Huang-4-ketone (FL 312), m.p.:119-120 ℃ from 7-(1-hexamethylene-2-alkene oxygen base)-isoflavones (FL 286).
Embodiment 4
The solution of 14g 7-isopropoxy-isoflavones in 160ml acetate carries out hydrogenation in the presence of 5% palladium/activated-carbon catalyst, till the hydrogen absorbed dose is 3 equimolar amounts.Filter out catalyzer, solvent evaporated, resistates is recrystallization from methyl alcohol.Obtain 10g 7-(1-methyl ethoxy)-isoflavan (FL 199), m.p.:93-95 ℃.
In a similar manner, prepare 7-(2-methyl isophthalic acid-propoxy-)-isoflavan (FL 248) from corresponding isoflavones respectively, m.p.:97-99 ℃, 7-(n-hexadecane oxygen base)-isoflavan, m.p.:90-92 ℃.
By hydrogenation, till the hydrogen absorbed dose is 4 equimolar amounts, make 7-cyclohexyl-isoflavan, m.p.:90-92 ℃ from 7-(1-hexamethylene-2-alkene oxygen base)-isoflavones.
Embodiment 5
2.38g 7-hydroxyl-isoflavones and 1.94g propane sultone are dissolved in 25ml 1% methanol solution of sodium methylate.Mixture kept 48 hours, isolated precipitated product by suction function (filtration) then, and recrystallization from water obtains 3.0g 7-(3-alkylsulfonyl-1-propoxy-)-isoflavones sodium salt, and its fusing point is higher than 350 ℃.
Make from corresponding 7-hydroxyl-isoflavone derivative in a similar manner:
7-(3-alkylsulfonyl-1-propoxy-)-8-methyl-isoflavones sodium salt (FL318), m.p.:＞350 ℃,
6-chloro-7-(3-alkylsulfonyl-1-propoxy-)-isoflavones (FL 346), m.p.＞350 ℃,
5-methyl-7-(3-sulfo group-1-propoxy-)-isoflavones sodium salt (FL502), m.p.:＞320 ℃ and
7-(3-sulfo group-1-propoxy-)-2-methyl-isoflavones sodium salt (FL291), m.p.:＞350 ℃.
Embodiment 6
16.5g 7-(3-methoxycarbonyl-1-propoxy-)-isoflavones was boiled 9 hours under refluxing in the mixture of 165ml Glacial acetic acid, 8.5ml water and the 1.0ml vitriol oil.When mixture is cooled, be settled out free acid (m.p.:188-190 ℃), obtain free acid by suction, be dissolved in the 300ml methyl alcohol, this solution is neutralized to pH-8 with the 1N sodium methoxide solution.Isolate the sedimentary 7-of 13.1g (3-carboxyl-1-propoxy-)-isoflavones sodium salt, m.p. by suction (filtration):＞320 ℃.
In a similar manner from corresponding ester class preparation:
7-(1-carboxyl-1-propoxy-)-isoflavones, m.p.:197-200 ℃ and its sodium salt (FL 282) and
7-(1-carboxyl-1-oxygen in last of the ten Heavenly stems base)-isoflavones, m.p.:124-126 ℃ and its salt (FL 280).
Embodiment 7
9g 7-isopropoxy-isoflavones and 3.2g Paraformaldehyde 96 stirred 3 hours under the situation of introducing anhydrous gaseous hydrogen chloric acid continuously in 70 ℃ in the mixture of 80ml Glacial acetic acid and 40ml concentrated hydrochloric acid.At second day, this solution was partly evaporated, and went out throw out and recrystallization from methyl alcohol by isolated at suction.In the solution of 7-isopropoxy-8-chloromethyl-isoflavones (m.p.:123-124 ℃) that is obtained and 50ml benzene, under the boiling condition, add the normal sodium methylate of 1N.The refrigerative solution with water is vibrated several times and is evaporated.Resistates is recrystallization from methyl alcohol, obtains 7g 7-isopropoxy-8-methoxymethyl-isoflavones, m.p.:92-93 ℃.
In a similar manner, make 7-methoxyl group-8-methoxymethyl-isoflavones (FL 308) from 7-methoxyl group-isoflavones.
Embodiment 8
In the suspension of 7.5g 7-methoxyl group-8-chloromethyl-isoflavones and 45ml Glacial acetic acid, in 3 hours, add 3.0g zinc bits.After further stirring 8 hours, use the warm water diluted reaction mixture, go out throw out by isolated at suction, recrystallization from ethanol obtains 5.1g 7-methoxyl group-8-methyl-isoflavones, m.p.:133-135 ℃.
Embodiment 9
36.2g 2-hydroxyl-4-(3-phenoxy group-1-propoxy-)-phenylpropiophenone, 22g ethyl orthoformate and 5g morpholine boiled in the 200ml dimethyl formamide 8 hours.The ethanol that forms in reaction process is removed by fractionation plant, the most of solvent of vacuum-evaporation then, and resistates dilutes with dilute hydrochloric acid.Filter crude product, recrystallization from acetone obtains 32g 7-(3-phenoxy group-1-propoxy-)-isoflavones (FL 230), m.p.:123-125 ℃.
Embodiment 10
9.8g 7-(3-chloro-1-propoxy-)-isoflavones was boiled in the 55ml 2-butanone 14 hours in the presence of 5.5g salt of wormwood and 0.5g potassiumiodide with the 4.1ml piperidines.Filtered while hot is fallen inorganic salt, and the cooling back goes out precipitated product and recrystallization from methyl alcohol by isolated at suction.Obtain 7-(3-(1-piperidines)-propoxy-)-isoflavones (FL118) of 6.0g, m.p.:138-139 ℃.
Obtain 7-(3-(1-morpholinyl)-propoxy-)-isoflavones (FL117) in a similar manner, m.p.:162-163 ℃.
Embodiment 11
18.5g 7-(10-ethoxy carbonyl-1-oxygen in last of the ten Heavenly stems base)-isoflavones was boiled 4 hours in the mixture of 180ml Glacial acetic acid, 10ml water and the 3ml vitriol oil.Went out sedimentary 7-(10-carboxyl-1-oxygen in last of the ten Heavenly stems base)-isoflavones by isolated at suction in second day, m.p.:118-120 ℃, be dissolved in 4: 1 mixtures of acetone and methyl alcohol, this solution transfers to pH8 with 10% sodium hydroxide.By the sedimentary salt of isolated at suction, and wash with solvent mixture.Obtain 7-(10-carboxyl-1-oxygen in last of the ten Heavenly stems base)-isoflavones sodium salt (FL295) of 10.6g, its fusing point＞360 ℃.
In a similar manner, obtain 7-(5-carboxyl-1-pentyloxy)-isoflavones, m.p.:146-148 ℃, then, obtain corresponding sodium salts (FL 302), its fusing point＞360 ℃ from 7-(5-ethoxycarbonyl-1-pentyloxy)-isoflavones.
Embodiment 12
3.0g 7-methoxyl group-isoflavones is dissolved in the 30ml chloroform, then, the 2.0g SULPHURYL CHLORIDE is added in this solution.Mixture boiled 1 hour, evaporation, resistates recrystallization from 1: 1 mixture of chloroform and alcoholic acid then.Obtain 8-chloro-7-methoxyl group-isoflavones (FL 501) of 22.5g, m.p.:181-182 ℃.
By similar mode, make 7-oxyethyl group-isoflavones from 7-oxyethyl group-isoflavones, m.p.:144-145 ℃, make 8-chloro-7-(2-propoxy-)-isoflavones from 7-(2-propoxy-)-isoflavones, m.p.:167-169 ℃, and make 8-chloro-2-methyl-7-methoxyl group-isoflavones (FL517), m.p.:176-178 ℃ from 2-methyl-7-methoxyl group-isoflavones.
Embodiment 13
2.0g 7-(ethoxycarbonyl methoxyl group)-isoflavones is dissolved in the 10ml diethylaminoethanol, and 2.0g salt of wormwood adds in this solution, and allows this mixture under agitation boil 5 hours, then in the mixture of impouring ice and 2% hydrochloric acid.Go out product by isolated at suction, recrystallization from the mixture of methyl alcohol and acetone.Obtain 7-(N, N-diethylamino ethoxy carbonyl methoxyl group)-isoflavones (FL 105) of 1.5g, m.p.:227-228 ℃.
In a similar manner, make 7-(N, N-diethylamino ethoxy-carbonyl methoxyl group)-2-methyl-isoflavones (FL104), m.p.:190-192 ℃ from 7-(ethoxycarbonyl methoxyl group)-2-methyl-isoflavones.
Embodiment 14
16.0g 8-chloromethyl-7-methoxyl group-isoflavones and 11.4g anhydrous sodium acetate boiled in the 80ml diacetyl oxide 4 hours.In the reaction mixture impouring water, filtering-depositing product, recrystallization from acetate.Obtain 8-acetoxy-methyl-7-methoxyl group-isoflavones (FL 509) of 11.7g, m.p.:195-197 ℃.
In a similar manner, make 8-acetoxy-methyl-7-(2-propoxy-)-isoflavones (FL 521), m.p.:107-109 ℃ from 8-chloromethyl-7-(2-propoxy-)-isoflavones.
Claims (17)
1. prepare the compound of general formula (I) and the method for salt thereof,
Wherein
If n is 0, R
5And R
6Represent that together oxo group and dotted line refer to two keys,
R
1Representative is by alkyl-carbonyl, carboxyl, sulfonic group, hydroxyl, phenoxy group, piperidino-(1-position only), morpholino or pyrido or by (C
1-4Alkyl)
2N-(CH
2)
mCO (CH
2)
p-or by (C
1-4Alkyl)
2N-(CH
2)
mOCO (CH
2)
pThe C that-group replaces
1-C
18Alkyl; Or expression C
3-6Cycloalkyl or cycloalkenyl group; Perhaps
If n is 1, R
5And R
6Represent that together oxo group and dotted line refer to two keys,
R
1Represent arbitrariness ground by alkyl-carbonyl, alkoxy carbonyl, carboxyl, sulfonic group, hydroxyl, phenoxy group, piperidino-(1-position only), morpholino or pyrido or by (C
1-4Alkyl)
2N-(CH
2)
mCO (CH
2)
pThe C that-group replaces
1-C
18Alkyl; Or expression C
3-6Cycloalkyl or cycloalkenyl group or C
2-6Alkenyl; Perhaps
If n is 0 or 1, R
5And R
6Represent oxo group together or represent that independently hydrogen and dotted line are not meant chemical bond,
R
1Phenyl, phenoxy group, piperidino-(1-position only), morpholino or the pyrido or the quilt (C that represent arbitrariness ground to be replaced by halogen atom by alkyl-carbonyl, alkoxy carbonyl, carboxyl, sulfonic group, hydroxyl, alkoxyl group, arbitrariness ground
1-4Alkyl)
2N-(CH
2)
mCO (CH
2)
pThe C that-group replaces
1-18Alkyl; Or expression C
3-6Cycloalkyl or C
2-6Alkenyl;
R represents C
1-8Alkyl, halogen, C
1-4Alkoxy methyl, C
2-5Acyloxy methyl or methylol;
R
4Expression hydrogen or C
1-4Alkyl;
R
2And R
3Expression hydrogen or C
1-6Alkoxyl group;
R
5And R
6Represent oxo group together or represent hydrogen individually;
Dotted line refers to two keys that arbitrariness exists;
N is 0 or 1;
M is the integer of 1-4; With
P is the integer of 1-4,
It is characterized in that:
1) in order to prepare general formula (IA) compound:
R wherein, n, R
1, R
2And R
3The same with the definition of front, this compound constitutes group's general formula (I) compound, allows the ketone of general formula (III):
R wherein, n, R
1, R
2And R
3It is the same with the definition in the general formula (I),
A) react in the presence of alkaline catalysts with alkyl orthoformate, or
B) react in the presence of haloid acid with prussic acid and/or cyanate; Or
C) react in the presence of basic metal with alkyl formate, or
D) with the reaction of alkoxalyl halogen, if desired, so the isoflavones ester that obtains is by saponification and/or decarboxylation; Or
E) with the organic carboxyl acid anhydride reactant; Or
F) and N, the N-dialkyl amide reacts in the presence of phosphorus chloride;
Perhaps
G) the 2-hydroxyl-isoflavone derivative with following general formula dewaters:
Perhaps
2) in order to prepare the compound of general formula (IB):
R wherein, n, R
1, R
2, R
3And R
4The same with the definition of front, this compound constitutes general formula (I) compound of a group, with general formula (IA) compound, and R wherein, n, R
1, R
2, R
3And R
4The same with the definition of front, reduction,
Perhaps
3) in order to prepare the compound of general formula (IC):
R wherein, n, R
1, R
2, R
3And R
4The same with the definition of front, this compound constitutes general formula (I) compound of a group, with the compound of general formula (IB), and R wherein, n, R
1, R
2, R
3And R
4The same with the definition of front, by the catalytic hydrogenation reduction,
And, if desired, R
1Be converted to another R in the definition in front
1Group,
Or on the R position, contain and form the R group in general formula (I) compound of a hydrogen atom,
And if desired, the general formula that is obtained (I) compound is converted to its salt or dissociates out from its salt.
2. according to subform method a)～f) of claim 1, it is characterized in that the starting raw material of 2-hydroxyl-4-alkoxyl phenyl benzyl ketone as general formula (III).
3. according to desired method in the claim 2, be characterised in that the starting raw material of 2-hydroxyl-4-isopropyl phenyl benzyl ketone as general formula (III).
4. according to a) desired method of the subform of claim 1, be characterised in that and use piperidines, morpholine or tetramethyleneimine as alkaline catalysts.
5. according to the subform b of claim 1) desired method, be characterised in that in aprotonic solvent, preferably in dialkyl ether or another kind of dialkyl ether, carry out this reaction.
6. according to the desired method of claim 5, be characterised in that in the presence of Lewis acid, preferably in the presence of zinc chloride, carry out this reaction.
7. according to the subform c of claim 1) desired method, be characterised in that sodium is used as basic metal.
8. according to the subform e of claim 1) desired method, be characterised in that and use diacetyl oxide, propionic anhydride or benzoyl oxide as organic acid anhydride.
9. desired according to Claim 8 method is characterised in that in the presence of alkaline catalysts, preferably in the presence of an alkali metal salt of the acid constituents of this acid anhydrides or carry out this reaction in the presence of a kind of tertiary amine.
10. according to the subform f of claim 1) desired method, be characterised in that and use dimethyl formamide or N,N-DIMETHYLACETAMIDE, the N-dialkyl amide as N.
11. the desired method subform g according to claim 1) is characterised in that and carries out dehydration reaction in acidic medium.
12., be characterised in that by using alkylogen, alkyl sodium sulfate ester, alkylsulphonic acid lactone, alkene or epoxide with R according to the desired method of claim 1
1Contain general formula (I) alkylation of a hydrogen atom on the position and introduce R
1Group.
13. the subform 2 according to claim 1) desired method is characterised in that by catalytic hydrogenation or by using metal hydride to carry out reduction reaction.
14. the subform 3 according to claim 1) desired method is characterised in that as catalyzer, uses nickel or noble metal catalyst.
15. the method for pharmaceutical compositions is characterized in that allowing the compound of general formula (I), wherein R
1, R, R
2, R
3, R
4, R
5, R
6, n, m, p is the same with the definition in the claim 1 with dotted line, or its salt and inert, atoxic, pharmaceutically acceptable solid or liquid diluent or carrier and other vehicle mix and be mixed with pharmaceutical composition.
16. the compound of general formula (I)
And salt.
17. contain the pharmaceutical composition of general formula (I) compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2083/93 | 1993-07-20 | ||
| HU9302083A HUT68558A (en) | 1993-07-20 | 1993-07-20 | Method for preparing isoflavon derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1129445A true CN1129445A (en) | 1996-08-21 |
Family
ID=10983803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94193107A Pending CN1129445A (en) | 1993-07-20 | 1994-07-19 | Isoflavone derivatives |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0710234A1 (en) |
| KR (1) | KR960703888A (en) |
| CN (1) | CN1129445A (en) |
| AU (1) | AU7236794A (en) |
| CA (2) | CA2167597A1 (en) |
| HU (1) | HUT68558A (en) |
| WO (1) | WO1995003293A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100564370C (en) * | 1999-02-15 | 2009-12-02 | 诺沃根研究有限公司 | The preparation of isoflavone derivative |
| CN102964322A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Isoflavone or flavonoid aliphatic ether derivates, preparation method and medical application thereof |
| CN108264506A (en) * | 2018-01-17 | 2018-07-10 | 中国药科大学 | Novel isoflavone derivative, preparation method and medical usage |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6087366A (en) * | 1996-03-07 | 2000-07-11 | The Trustees Of Columbia University In The City Of New York | Use of flavopiridol or a pharmaceutically acceptable salt thereof for inhibiting cell damage or cell death |
| IT1289154B1 (en) * | 1997-01-03 | 1998-09-29 | Chiesi Farma Spa | ISOFLAVONE DERIVATIVES THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| US6146668A (en) | 1997-04-28 | 2000-11-14 | Novogen, Inc. | Preparation of isoflavones from legumes |
| KR20000001793A (en) * | 1998-06-13 | 2000-01-15 | 이경하 | Novel benzopyran or thiobenzopyran derivatives |
| AUPQ266199A0 (en) | 1999-09-06 | 1999-09-30 | Novogen Research Pty Ltd | Compositions and therapeutic methods involving isoflavones and analogues thereof |
| KR100408231B1 (en) * | 2000-08-14 | 2003-12-01 | 한국 한의학 연구원 | Flavonoid derivateives for prevention and treatment of osteoporosis |
| AUPR363301A0 (en) | 2001-03-08 | 2001-04-05 | Novogen Research Pty Ltd | Dimeric isoflavones |
| AU2003255232A1 (en) | 2002-08-07 | 2004-02-25 | University Of Mississippi | Antigiardial agents and use thereof |
| GB0412768D0 (en) * | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
| GB0412769D0 (en) | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
| JP2009536610A (en) * | 2006-02-28 | 2009-10-15 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | Pharmaceutical composition for the prevention / treatment of bone disease and preparation method thereof |
| TWI324514B (en) | 2008-02-26 | 2010-05-11 | Univ Kaohsiung Medical | Isoflavone derivatives and pharmaceutical compositions comprising the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6054379A (en) * | 1983-09-05 | 1985-03-28 | Takeda Chem Ind Ltd | Novel 4h-1-benzopyran-4-one derivative, its preparation and its use |
| AU631860B2 (en) * | 1990-04-06 | 1992-12-10 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara | An improved process for the preparation of substituted isoflavone derivatives |
-
1993
- 1993-07-20 HU HU9302083A patent/HUT68558A/en unknown
-
1994
- 1994-07-18 CA CA002167597A patent/CA2167597A1/en not_active Abandoned
- 1994-07-19 AU AU72367/94A patent/AU7236794A/en not_active Abandoned
- 1994-07-19 WO PCT/HU1994/000028 patent/WO1995003293A1/en not_active Application Discontinuation
- 1994-07-19 CN CN94193107A patent/CN1129445A/en active Pending
- 1994-07-19 CA CA002167714A patent/CA2167714A1/en not_active Abandoned
- 1994-07-19 EP EP94921776A patent/EP0710234A1/en not_active Withdrawn
-
1996
- 1996-01-19 KR KR1019960700364A patent/KR960703888A/en not_active Application Discontinuation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100564370C (en) * | 1999-02-15 | 2009-12-02 | 诺沃根研究有限公司 | The preparation of isoflavone derivative |
| CN102964322A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Isoflavone or flavonoid aliphatic ether derivates, preparation method and medical application thereof |
| CN108264506A (en) * | 2018-01-17 | 2018-07-10 | 中国药科大学 | Novel isoflavone derivative, preparation method and medical usage |
| CN108264506B (en) * | 2018-01-17 | 2021-01-26 | 中国药科大学 | Isoflavone derivative, preparation method and medical application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7236794A (en) | 1995-02-20 |
| HUT68558A (en) | 1995-06-28 |
| WO1995003293A1 (en) | 1995-02-02 |
| CA2167597A1 (en) | 1995-02-02 |
| CA2167714A1 (en) | 1995-02-02 |
| EP0710234A1 (en) | 1996-05-08 |
| KR960703888A (en) | 1996-08-31 |
| HU9302083D0 (en) | 1993-10-28 |
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