CA2167714A1 - Isoflavone derivatives - Google Patents
Isoflavone derivativesInfo
- Publication number
- CA2167714A1 CA2167714A1 CA002167714A CA2167714A CA2167714A1 CA 2167714 A1 CA2167714 A1 CA 2167714A1 CA 002167714 A CA002167714 A CA 002167714A CA 2167714 A CA2167714 A CA 2167714A CA 2167714 A1 CA2167714 A1 CA 2167714A1
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- Prior art keywords
- general formula
- group
- compounds
- isoflavone
- stand
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
The present invention relates to isoflavone, isoflavan-4-one and isoflavane derivative of general formula (1), their salts, pharmaceutical compositions containing the compounds of general formula (I), and to a process for preparing the same. In general formula (1), if n is 0, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 represent, C1-18alkyl substituted by alkylcarbonyl, carboxy, sulforic 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, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 represents C1-18alkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or pindino 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, R5 and R6 together stand for an oxo group or stand separately for hydrogen and the dotted line does not mean a chemical bond, R1 represents C1-18alkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy. alkoxy. phenyl optionally substituted by a halo atom, phenoxy, piperidino, moepholino 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; R4 stands for hydrogen or C1-4alkyl; R2 and R3 stand for hydrogen or C1-6alkoxy; R5 and R6 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. They are prepared by methods well known in the organic chemistry.
Description
wo 95/03293 2 1 6 7 7 1 4 PCT/HU94/00028 ~ .
ISOFLAVONE DERIVATIVES
The present invention relates to isoflavone, isoflavan-4-one and isoflavane derivaLhves of the general forrnula (I), S R5 R6 --~ R3 ( I ), RI~ R4 their salts, ph~ eelltic~l compositions co~ g the compounds of the general formula (I), and to a process for ~,e~aling ~he same.
The isoflavone derivatives of ~e general formula R
Rlo~l ~ (IA), the isoflavane-4-one derivatives of ~he general formula (R)lo 3 R3 (I13), ~e isoflavane derivatives of the general formula ~ R3 (IC) wo ss/032s3 2 2 1 6 7 7 1 4 PCT/~IU94/00028 form a narrower group of the compounds of the general formula (I).
In the general formula (I~
if n is 0, R5 and R6 together stand for an oxo group and the dotted line means a double bond, 5 Rl represents Cl l8aLkyl s~bstih~ted by aLkylcarbonyl, carboxy, sulfonicacid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (Cl-4alkYl)2N-(cH2)mco(cH2)p- or by (Cl 4alkyl)2N-(cH2)moco(cH2)p- group; or st~nds for C3 6cycloaLkyl or cycloaLkenyl; or 10 if n is 1, Rs and R6 together stand for an oxo group and the dotted line means a double bond, Rl represents Cl l8aLkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (Cl 4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3 6-cycloalkyl or cycloaLIcenyl or C2 6aLkenyl; or if n is O or 1, R5 and R6 together stand for an oxo group or stand s~lely for hydrogen and the dotted line does not mean a çhemic~l bond, Rl represents Cl l8aLlcyl optionally substitnte~l by aLkyl-carbonyl, aLkoxycarbonyl, carboxy, s -lfonic acid, hydroxy, alkoxy, phenyl optionally substituted by a halo atom, phenoxy, piperidino, morpholino or piridino or by a (Cl 4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3 6-cycloaLkyl or C2 6alkenyl;
R stands for Cl 8aLkyl, halogen, Cl 4aLkoxymethyl, C2 s-acyloxymethyl, or hydroxymethyl;
25 R4 stands for hydrogen or Cl 4aLkyl;
R2 and R3 stand for hydrogen or Cl 6aLkoxy;
R5 and ~6 together stand for an oxo group or separately stand for hydrogen;
the dotted line means a double bond being optionally present;
n isOorl;
30 m is an integer from 1 to 4; and p is an integer from 1 to 4.
The compounds of the general formula (I) can be used for the prevention and tre~tment of osteoporosis.
5 According to the invention the compounds of the general formula (IA) can be d by reacting ketones of the general formula 0 R2~ (III), n ~X c - CH2 RlO OH
wherein R, n, Rl, R2 and R3 are as defined for the general formula (1), a) with aLkyl orthoformate in the presence of a basic catalyst, or b) with hydrogen cyanide and/or cyanic salts in the presence of hydrohalides; or c) with alkyl formiate in the presence of an alkali metal; or d) with aLkyloxalylhalide, and the isoflavone ester thus obtained is, if desired, saponified and/or decarboxylated; or e) with organic carboxylic anhydride; or f) with N,N-dialkyl acid amide in the presence of phosphorous chloride; or g) by dehydrating 2-hydroxy-isoflavanone derivatives of the general formula0 R10~ C~ R3 (IV), and if desired, converting an Rl group into another Rl group, or forming an R group in a compound of the general formula (I), wherein R stands30 for hydrogen, and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt.
According to process variant a) of the present invention a suitably substituted ketone is reacted with alkyl orthoformiate, preferably ethyl ester, in an aprotic 35 solvent having a h~gh boiling point. As a solvent pyrrolidine, dimethyl formamide or diet~ylene glycol dimethyl ether is used. As a basic catalyst ~lerel~bly piperidine, morpholine, pyrrolidine and other secondary amines may be used.
WO 95/03293 4 2 1 6 7 7 1 4 PCT/I~U94/OllU8 According to process variant b) of the present invention the ketones are reactedwith hydrogen cyanide in an aprotic solvent in the presence of dry gaseous hydrochloric acid or other hydrohalogenic acids or Lewis acids. Non-basic aprotic solvents may also be used in the reaction, preferably diethyl ether or other diaLkyl 5 ethers. As catalyst zinc chloride or other Lewis acids may be used.
The reaction is carried out with hydrogen cyanide or an a~plu~liate salt thereof, ~rer~lably with zinc cyanide. The ll~ tule may be ~alul~L~d with dry gaseous hydrochloric acid and the substituted a-fon~iminn-2-hydroxyphenylbenzyl-ketone 10 chlorohydrates thus obtained are decomposed with aqueous trçatrnent - According to process variant c) of the present invention the ketones of the formula (m) are reacted with aLkyl formiates in the presence of an aLkali metal.One preferably proceeds by adding dropwise suitably sub~liluLed 2-hydroxyphenyl 15 -benzyl-ketone dissolved in ethyl formiate onto pulverized metallic sodium, then by decomposing the reaction ll~ ure with water and separating the isoflavone thus-obtained.
.
According to process variant d) of the present invention suitably substituted 20 2-hydroxy-phenyl benzyl k~tonçs are reacted with alkyl oxalyl h~litles A 2-alkoxycarbonyl-isoflavone delivilLiv~ is obt~ined, which is, if desired, converted into an isoflavone derivative unsubstituted in position 2 by hydrolyzing the ester group and by subsequent decarboxylation. This process variant can prt;~lably be calried out with methyl- or ethyl oxalyl chloride in the presence of a 25 basic acid binding agent in an a~rop,iate aprotic solvent, ~rerel~bly pyridine or another tertiary arr~ine.
According to process variant e) of the present invention the suitably substituted
ISOFLAVONE DERIVATIVES
The present invention relates to isoflavone, isoflavan-4-one and isoflavane derivaLhves of the general forrnula (I), S R5 R6 --~ R3 ( I ), RI~ R4 their salts, ph~ eelltic~l compositions co~ g the compounds of the general formula (I), and to a process for ~,e~aling ~he same.
The isoflavone derivatives of ~e general formula R
Rlo~l ~ (IA), the isoflavane-4-one derivatives of ~he general formula (R)lo 3 R3 (I13), ~e isoflavane derivatives of the general formula ~ R3 (IC) wo ss/032s3 2 2 1 6 7 7 1 4 PCT/~IU94/00028 form a narrower group of the compounds of the general formula (I).
In the general formula (I~
if n is 0, R5 and R6 together stand for an oxo group and the dotted line means a double bond, 5 Rl represents Cl l8aLkyl s~bstih~ted by aLkylcarbonyl, carboxy, sulfonicacid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (Cl-4alkYl)2N-(cH2)mco(cH2)p- or by (Cl 4alkyl)2N-(cH2)moco(cH2)p- group; or st~nds for C3 6cycloaLkyl or cycloaLkenyl; or 10 if n is 1, Rs and R6 together stand for an oxo group and the dotted line means a double bond, Rl represents Cl l8aLkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (Cl 4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3 6-cycloalkyl or cycloaLIcenyl or C2 6aLkenyl; or if n is O or 1, R5 and R6 together stand for an oxo group or stand s~lely for hydrogen and the dotted line does not mean a çhemic~l bond, Rl represents Cl l8aLlcyl optionally substitnte~l by aLkyl-carbonyl, aLkoxycarbonyl, carboxy, s -lfonic acid, hydroxy, alkoxy, phenyl optionally substituted by a halo atom, phenoxy, piperidino, morpholino or piridino or by a (Cl 4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3 6-cycloaLkyl or C2 6alkenyl;
R stands for Cl 8aLkyl, halogen, Cl 4aLkoxymethyl, C2 s-acyloxymethyl, or hydroxymethyl;
25 R4 stands for hydrogen or Cl 4aLkyl;
R2 and R3 stand for hydrogen or Cl 6aLkoxy;
R5 and ~6 together stand for an oxo group or separately stand for hydrogen;
the dotted line means a double bond being optionally present;
n isOorl;
30 m is an integer from 1 to 4; and p is an integer from 1 to 4.
The compounds of the general formula (I) can be used for the prevention and tre~tment of osteoporosis.
5 According to the invention the compounds of the general formula (IA) can be d by reacting ketones of the general formula 0 R2~ (III), n ~X c - CH2 RlO OH
wherein R, n, Rl, R2 and R3 are as defined for the general formula (1), a) with aLkyl orthoformate in the presence of a basic catalyst, or b) with hydrogen cyanide and/or cyanic salts in the presence of hydrohalides; or c) with alkyl formiate in the presence of an alkali metal; or d) with aLkyloxalylhalide, and the isoflavone ester thus obtained is, if desired, saponified and/or decarboxylated; or e) with organic carboxylic anhydride; or f) with N,N-dialkyl acid amide in the presence of phosphorous chloride; or g) by dehydrating 2-hydroxy-isoflavanone derivatives of the general formula0 R10~ C~ R3 (IV), and if desired, converting an Rl group into another Rl group, or forming an R group in a compound of the general formula (I), wherein R stands30 for hydrogen, and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt.
According to process variant a) of the present invention a suitably substituted ketone is reacted with alkyl orthoformiate, preferably ethyl ester, in an aprotic 35 solvent having a h~gh boiling point. As a solvent pyrrolidine, dimethyl formamide or diet~ylene glycol dimethyl ether is used. As a basic catalyst ~lerel~bly piperidine, morpholine, pyrrolidine and other secondary amines may be used.
WO 95/03293 4 2 1 6 7 7 1 4 PCT/I~U94/OllU8 According to process variant b) of the present invention the ketones are reactedwith hydrogen cyanide in an aprotic solvent in the presence of dry gaseous hydrochloric acid or other hydrohalogenic acids or Lewis acids. Non-basic aprotic solvents may also be used in the reaction, preferably diethyl ether or other diaLkyl 5 ethers. As catalyst zinc chloride or other Lewis acids may be used.
The reaction is carried out with hydrogen cyanide or an a~plu~liate salt thereof, ~rer~lably with zinc cyanide. The ll~ tule may be ~alul~L~d with dry gaseous hydrochloric acid and the substituted a-fon~iminn-2-hydroxyphenylbenzyl-ketone 10 chlorohydrates thus obtained are decomposed with aqueous trçatrnent - According to process variant c) of the present invention the ketones of the formula (m) are reacted with aLkyl formiates in the presence of an aLkali metal.One preferably proceeds by adding dropwise suitably sub~liluLed 2-hydroxyphenyl 15 -benzyl-ketone dissolved in ethyl formiate onto pulverized metallic sodium, then by decomposing the reaction ll~ ure with water and separating the isoflavone thus-obtained.
.
According to process variant d) of the present invention suitably substituted 20 2-hydroxy-phenyl benzyl k~tonçs are reacted with alkyl oxalyl h~litles A 2-alkoxycarbonyl-isoflavone delivilLiv~ is obt~ined, which is, if desired, converted into an isoflavone derivative unsubstituted in position 2 by hydrolyzing the ester group and by subsequent decarboxylation. This process variant can prt;~lably be calried out with methyl- or ethyl oxalyl chloride in the presence of a 25 basic acid binding agent in an a~rop,iate aprotic solvent, ~rerel~bly pyridine or another tertiary arr~ine.
According to process variant e) of the present invention the suitably substituted
2-hydroxy-phenyl benzyl ketone is reacted with organic acid anhydrides in the 30 presence of a basic catalyst. As an organic acid anhydride acetic, propionic or ben~oic anhydride can be used. The anhydride is heated in the presence of a basic catalyst, suitably an alkali salt of the acid component of the acid anhydride, or in the presence of tertiary amines, without solvent or in an aprotic solvent havinghigh boiling point, such as pyridine or dimethyl formamide.
According to process variant f) of the present invention the ketone is reacted with N,N-dialkyl acid arnides in the presence of phosphorus oxychloride, ple~,ably by heating the suitably sub~l ;t,lle~l 2-hydroxy-phenyl benzyl ketone wi~
wo 95/03293 5 2 1 6 7 7 1 4 PCT/HU94/00028 N,N-dialkyl acid amid (e.g. dime~yl formamide or dimethyl acetamide) and phosphorous oxychloride, using as solvent the N,N-diaLkyl acid amide itself.
According to process variant g) of the present invention 2-hydroxy-isoflavones of S the formula (IV) are dehydrated by he~ting or by w~ g in an acidic medium in polar solvent.
In the first step of the process according to the invention such derivatives may be obtained from the compounds of the formula (m) or aV) in which Rl stands for 10 hydrogen or it is not the Rl group which is required in the target product.
In these cases the Rl group is introduced into the place of the hydrogen atom or, respectively, an Rl group is converted into another Rl group.
This step can be carried out by the partial or total alkylation of the mono- or polyh~ydroxy-isoflavones, which aLkylation can plerel~bly be carried out by 15 reacting with aLkyl h~lides or substituted aLkyl halides, alkyl sulfonic lactones, aLkyl sulfates, olefines or epoxydes, preferably by heating the aLkylating agent in a suitable solvent, e.g. ketones, dimethyl fonn~mi~le or ethers co~ g a higher number of carbon atoms with the isoflavones to be aLkylated. In case of halogenspreferably an acid binding agent, such as alkali carbonate, and in case of aLkyl20 bromides and aLkyl chlorides preferably aLkali iodide is present.
This step can be carried out by the partial or total desacylation or the partial and total d!esaLtcylation of acyloxy and polyacyloxy, aLkyloxy and polyaLkyloxy isofla~ones. Acyloxy or polyacyloxy isoflavones are formed when process varia~lt e) is carried out with di- or polyhydroxy phenyl benzyl ketones cont~inin~;
25 a hydroxy group in position 2. The desacylation is ~l~f~ bly carried out in an acidic or basic medium in the presence of a polar solvent. This step can also becarried out by decarboxylating isoflavone-2-carboxylic acids. Isoflavone-2-carbo~ylic acids are formed during process variant d) and their decarboxylation is preferably carried out by heating with or without the presence of a catalyst, such as 30 copper dust.
The compounds of the general formula (IB), wherein R, n, Rl, R2, R3 and R4 are as defined for general formula (I) are prepared by the reduction of the compounds of the general formula (IA), wherein R, n, Rl, R2, R3 and R4 are as defined for 35 general formula (I). The reduction is carried out by catalytic hydrogenation or by using metal hydrides.
According to process variant f) of the present invention the ketone is reacted with N,N-dialkyl acid arnides in the presence of phosphorus oxychloride, ple~,ably by heating the suitably sub~l ;t,lle~l 2-hydroxy-phenyl benzyl ketone wi~
wo 95/03293 5 2 1 6 7 7 1 4 PCT/HU94/00028 N,N-dialkyl acid amid (e.g. dime~yl formamide or dimethyl acetamide) and phosphorous oxychloride, using as solvent the N,N-diaLkyl acid amide itself.
According to process variant g) of the present invention 2-hydroxy-isoflavones of S the formula (IV) are dehydrated by he~ting or by w~ g in an acidic medium in polar solvent.
In the first step of the process according to the invention such derivatives may be obtained from the compounds of the formula (m) or aV) in which Rl stands for 10 hydrogen or it is not the Rl group which is required in the target product.
In these cases the Rl group is introduced into the place of the hydrogen atom or, respectively, an Rl group is converted into another Rl group.
This step can be carried out by the partial or total alkylation of the mono- or polyh~ydroxy-isoflavones, which aLkylation can plerel~bly be carried out by 15 reacting with aLkyl h~lides or substituted aLkyl halides, alkyl sulfonic lactones, aLkyl sulfates, olefines or epoxydes, preferably by heating the aLkylating agent in a suitable solvent, e.g. ketones, dimethyl fonn~mi~le or ethers co~ g a higher number of carbon atoms with the isoflavones to be aLkylated. In case of halogenspreferably an acid binding agent, such as alkali carbonate, and in case of aLkyl20 bromides and aLkyl chlorides preferably aLkali iodide is present.
This step can be carried out by the partial or total desacylation or the partial and total d!esaLtcylation of acyloxy and polyacyloxy, aLkyloxy and polyaLkyloxy isofla~ones. Acyloxy or polyacyloxy isoflavones are formed when process varia~lt e) is carried out with di- or polyhydroxy phenyl benzyl ketones cont~inin~;
25 a hydroxy group in position 2. The desacylation is ~l~f~ bly carried out in an acidic or basic medium in the presence of a polar solvent. This step can also becarried out by decarboxylating isoflavone-2-carboxylic acids. Isoflavone-2-carbo~ylic acids are formed during process variant d) and their decarboxylation is preferably carried out by heating with or without the presence of a catalyst, such as 30 copper dust.
The compounds of the general formula (IB), wherein R, n, Rl, R2, R3 and R4 are as defined for general formula (I) are prepared by the reduction of the compounds of the general formula (IA), wherein R, n, Rl, R2, R3 and R4 are as defined for 35 general formula (I). The reduction is carried out by catalytic hydrogenation or by using metal hydrides.
3 6 PCT/HU94/000-8 In the case of the catalytic hydrogenation a nobel metal catalyst, l,lere.~bly ap~ lm on charcoal catalyst is used and the reduction is carried out in an organic solvent, preferably in acetone.
As a comrle~ metal hydride, preferably diisobutyl ~l,.. ~il.. hydride is used and the reduction is carried out at a low temperature (-70 C).
The compounds of the general form~ (IC), wherein R, n, Rl, R2, R3 and R4 are as defined for general formula (I) are ~re~ed aby the catalytic hydrogenation ofthe compounds of the general form~ (IB), wherein R, n, Rl, R2, R3 and R4 are as 10 defined for general formula (I), in the presence of a noble metal or nickel catalyst.
The reduction is preferably carried out in a polar solvent, preferably acetic acid or ethyl acetate.
The compounds of the general formula (I), wherein Rl stands for aL~cyl substituted 15 by carboxy are prepared by hydrolysing the ester group of the compounds co..~ as Rl an aLkyl group substituted by alkoxyc~bullyl. The hydrolysis is preferably carried out in an acidic medium, ~rert.~bly with lower organic acids in the presence of a strong acid catalyst.
20 The compounds of the general formula (IA) co~ a methyl group in position 6 are ~rep~ed by the reduction of halomethyl isoflavones obtained from the compounds of the general formula (LA) co.~ a hydrogen atom in position by h~lomethylation. The reduction is carried out preferably in the presence of metals, ~i~r~lably zinc.
The compounds of the general formula (I) co~ an aLkoxy or hydroxymethyl group in position 6 are pie~d either by replacing the halo atom of the halomethyl isoflavones prepared as described above with an aLkoxy group by the aid of alcohols or by replacing said halo atom with an 0-acetyl group by the aid of 30 sodium acetate and by subsequently converting the acetûxy group into an OH
group.
We have found ~at the compounds of ~e general formula (I) and salts thereof can effectively be used for the prophylaxis and the tre~l~nent of osteoporosis.
35 It is known that Ipriflavone (7-Isopropoxy-isoflavone) is able to inhibit bone resorption either in vitro or in vivo (Notoya, K. et al. Inhibitory effect of Ipriflavone on pit formation in mouse unfractionated bone cells, CalciTissue Int.
51, (Supl. l) 53-56 (1992); Notoya, K. et al. Inhibitory effect of Ipriflavone on osteoclast-me~ te~l bone resorption and new osteoclast formation in long-term ~ WO 95/03293 7 2 1 6 7 7 1 4 PCT/~IU94/00028 cultures of mouse unfractionated bone cells, Calcif Tissue Int. 50, 314-319 (1992).
On the other hand, it is known that Ipriflavone also could increase the miner~li7~tinn of the extracellular matrix of human bone cell cultures (Ref. Ecsedi, G.G. Model for in vitro investigation of bone mineralization, Agents and Actions41, 84~85 (1994.) To estim~tç the effectiveness of the compounds of the general Form~ (I) on bone r~ l;on an in vitro mineralization model was developed. Under certain cirCl~rnct~nces cultures of partially selected (osteoblast-enriçhed) hllm~n bone cells origin~te~1 from either nasal bone of adults or foetus femur produce Type I
coll~gene, bone specific proteins (e.g. osteocalcin), prostanoides (PGE2, PGF2a,PGI2, etc. and accnm~ te calcium into the synthesi7erl matrix (Re: Ecsedi, G.G., Chara~ on of cells of human nasal bone cell cultures, 4th Int. Symposium on Osteoporosis, 27 March- 2 April, 1993 Hong Kong; Abstr. no. 534).
Method, Cells of subcultures 8-12 (usually 8th or 9th) were drop-inoc~ te~ at a density of 2*10A4 cells per well 96-well plates. On the day 3 the tre~tment~ were started with the compound of the Formula I at two concentrations, lOA-8 and lOA-10 M. Because ethanolic loA 5 and loA 7 M stock solutions of the compounds were used in the tre~tmentc all culture media cont~ined 0.1 % ethanol in~ lin~ the Controls. Media were changed on each 2-3 day. The tre~1mentc were fini~hed on the day 21, ~e total c~lcil~m (Ca) and DNA content of the 6-parallels~mples were me~nred by Boehringer Test Combination (~R3) and the spectrofluorometric 3~5-~ minobenzoic acid (DA~A~ method, respectively, then the ratios, Ca/DNA were calculated.
In the table of the compounds of Formula I below, data are given in percentages compared to the average of the Control value (100%) Nameof Concentration Ca DNA Ca/DNA
Compound [-log M] % % %
Ipriflavone 8 121 100 121 ` (7-isopropoxy- 10 111 108 103 isoflavone) (7-(-1 cyclohex- 10 131 107 124 2-enyloxy)-isoflavone) The compounds of the general formula (I) may be lltili7t?(1 in the therapy in the form of ~r~alions co,.~ g the active ingredient together with inert, non-toxic, ph~ reutically acceptable solid or liquid ~ n~ntc or carriers.
If desired, the ~ ~alions can contain biologically active known substances such S as vi~llil-c, amino acids, choline chloride, salts of mineral acids, trace elemen~c etc. As carriers talc, ~el~tine, calcium carbonate, magnesium stearate, starch, water, polyaLkylene glycols etc. may be used. The compositions may be fonm~l~tçd as solid (e.g. tablets, dragées, capsules, suppositories etc.) or liquid (e.g. solution, suspension or emulsion) preparations.
The invention is elucidated in more detail in the following non-limitin~ examples.
Example 1 10 g of 7-hydroxy-isoflavone, 10 ml of chloro~setone and 8 g of pot~csillm carbonate are stirred in 120 ml of acetone and the ~ e is boiled for 5 hours.
The reaction ~~ is diluted with water, the precipil~le is filtered off and recryst~lli7e-1 from acetic acid. 8.5 g of 7-(2-oxopropyl)-isoflavone are obtained, m.p.: 174-175 C.
7-(2,3-dihydroxy-1-propyloxy)-isoflavone (FL 230), m.p.: 164-165 C, 7-(3-ethoxycarbonyl-propyloxy~isoflavone (FL 283), m.p.: 124-125 C, 7-(2-pheno~cyethoxy~isoflavone (FL 273), m.p. 195-197 C, and 7-(1-ethoxycarbonyl-1-decyloxy~isoflavone (FL 279), m.p.: 97-99 C
are ~ ed in a similar way from 7-hydroxy-isoflavone and the corresponding aLkyl halide or sul)~Liluled aLkyl halide.
7-(3-methyl-1-butyloxy)-isoflavone (FL 191), m.p.: 107-108 C, is ~repa~ed from 7-hydroxy-3',4'-dimethoxy-isoflavone by using 3-methyl-1-butylbromid.
7-ethoxy-8-methyl-isoflavone (FL 315), m.p.: 129-130 C, 7-(carbethoxymethoxy)-8-methyl-isoflavone (FL 316), m.p.: 137-139 C, and 7~4-oxo-1-pentyloxy)-isoflavone (FL 501), m.p.: 143-145 C, are obtained from 7-hydroxy-8-methyl-isoflavone.
Example 2 A ~ e of 16 g of 6-n-hexyl-7-hydroxy-isoflavone, 14 ml of isopropylbromide and 70 ml of dimethylformamide are stirred for 4 hours at a temperature of 90 C in the presence of 16 g of potassium carbonate.
The reaction ~i~ e is poured into 500 ml of water, the product is separated, then recryst~ e.l from 80% aqueous medlanol. 15 g of 6-n-hexyl-7-(1-methyle~oxy)-~ WO 95/03293 9 2 1 6 7 7 1 4 PCT/HU94100028 -isoflavone are obtained, m.p. 37-39 C.
6-n-hexyl-7-ethoxy-isoflavone (FL 319), m.p.: 57-59 C, and 6-n-hexyl-7--(2-methyl-1-propyloxy)-isoflavone (FL 321), m.p.: 65-67 C, are prepared in a similar way.
S By reacting 6-chloro-7-hydroxy-isoflavones with alkyl h~lides with the following compounds are prepared:
7-ethoxy-6-chloro-isoflavone (FL 322), m.p.: 162-164 C, 7-(1-methylethoxy)-6-chloro-isoflavone (FL 323), m.p.: 156-158 C, 7-(2-methyl-1-propyloxy)-6-chloro-isoflavone (FL 324), m.p.: 170-172 C, 7-(2-propen-1-yloxy)-isoflavan-4-one (FL 238), m.p.: 76-78 C and 7-(4-nitro-benzyloxy)-isoflavan-4-one (FL 239), m.p.: 100-102 C.
Example 3 6.5 g of 7-n-hex~ecyloxy-isoflavone are hydrog~n~te~l in 1200 ml of ~cetone in the presence of 3.0 g of 10 % palladium on charcoal catalyst until a hydrogen uptake of 1.2 equimolar amount. The catalyst is filtered off and the solution is cv~or~Lcd. The residue is recryst~lli7e~1 from a ~llixLu~c of methanol and ~t~etone to obtain 5.3 g of 7-n-hçx~-lecyloxy-isoflavon~one, m.p.: 90-92 C.7-et_oxy-5-methyl-isoflavan~-one (FL 299), m.p.: 97-98 C, is l)l~cd in a similar way from 7-ethoxy-5-methyl-iso~avone.
7-cyclohexyl-isoflavan-4-one (FL 312), m.p.: 119-120 C, is p~arcd from 7-(1-cyclohex-2-enyloxy)-isoflavone (FL 286) by hydrogenation until a hydrogen ptake of 2.2 equimolar amount.
Example 4 A solution of 14 g of 7-isopropyloxy-isoflavone in 160 ml of acetic acid is hydrogenated in the presence of 5% p~ lm on charcoal catalyst until a hydrogen uptake of 3 equimolar amount. The catalyst is filtered off, the solvent is evaporated and the residue is recryst~lli7e~1 from methanol. 10 g of 7-(1-methylethoxy)-isoflavane (FLl99) is obtained, m.p.: 93-95 C
7-(2-methyl-1-propyloxy)-isoflavane (FL 248), m.p.: 97-99 C, 7-(n-h~ (lecyloxy)-isoflavan, m.p.: 90-92 C, are ~icpa.cd in a similar way from the - collcspollding isoflavones.
7-cyclohexyl-isoflavane, m.p.: 90-92 C, is prepared from 7-(1--cyclohex-2-enyloxy)-isoflavone by hydrogenation until a hydrogen uptake of
As a comrle~ metal hydride, preferably diisobutyl ~l,.. ~il.. hydride is used and the reduction is carried out at a low temperature (-70 C).
The compounds of the general form~ (IC), wherein R, n, Rl, R2, R3 and R4 are as defined for general formula (I) are ~re~ed aby the catalytic hydrogenation ofthe compounds of the general form~ (IB), wherein R, n, Rl, R2, R3 and R4 are as 10 defined for general formula (I), in the presence of a noble metal or nickel catalyst.
The reduction is preferably carried out in a polar solvent, preferably acetic acid or ethyl acetate.
The compounds of the general formula (I), wherein Rl stands for aL~cyl substituted 15 by carboxy are prepared by hydrolysing the ester group of the compounds co..~ as Rl an aLkyl group substituted by alkoxyc~bullyl. The hydrolysis is preferably carried out in an acidic medium, ~rert.~bly with lower organic acids in the presence of a strong acid catalyst.
20 The compounds of the general formula (IA) co~ a methyl group in position 6 are ~rep~ed by the reduction of halomethyl isoflavones obtained from the compounds of the general formula (LA) co.~ a hydrogen atom in position by h~lomethylation. The reduction is carried out preferably in the presence of metals, ~i~r~lably zinc.
The compounds of the general formula (I) co~ an aLkoxy or hydroxymethyl group in position 6 are pie~d either by replacing the halo atom of the halomethyl isoflavones prepared as described above with an aLkoxy group by the aid of alcohols or by replacing said halo atom with an 0-acetyl group by the aid of 30 sodium acetate and by subsequently converting the acetûxy group into an OH
group.
We have found ~at the compounds of ~e general formula (I) and salts thereof can effectively be used for the prophylaxis and the tre~l~nent of osteoporosis.
35 It is known that Ipriflavone (7-Isopropoxy-isoflavone) is able to inhibit bone resorption either in vitro or in vivo (Notoya, K. et al. Inhibitory effect of Ipriflavone on pit formation in mouse unfractionated bone cells, CalciTissue Int.
51, (Supl. l) 53-56 (1992); Notoya, K. et al. Inhibitory effect of Ipriflavone on osteoclast-me~ te~l bone resorption and new osteoclast formation in long-term ~ WO 95/03293 7 2 1 6 7 7 1 4 PCT/~IU94/00028 cultures of mouse unfractionated bone cells, Calcif Tissue Int. 50, 314-319 (1992).
On the other hand, it is known that Ipriflavone also could increase the miner~li7~tinn of the extracellular matrix of human bone cell cultures (Ref. Ecsedi, G.G. Model for in vitro investigation of bone mineralization, Agents and Actions41, 84~85 (1994.) To estim~tç the effectiveness of the compounds of the general Form~ (I) on bone r~ l;on an in vitro mineralization model was developed. Under certain cirCl~rnct~nces cultures of partially selected (osteoblast-enriçhed) hllm~n bone cells origin~te~1 from either nasal bone of adults or foetus femur produce Type I
coll~gene, bone specific proteins (e.g. osteocalcin), prostanoides (PGE2, PGF2a,PGI2, etc. and accnm~ te calcium into the synthesi7erl matrix (Re: Ecsedi, G.G., Chara~ on of cells of human nasal bone cell cultures, 4th Int. Symposium on Osteoporosis, 27 March- 2 April, 1993 Hong Kong; Abstr. no. 534).
Method, Cells of subcultures 8-12 (usually 8th or 9th) were drop-inoc~ te~ at a density of 2*10A4 cells per well 96-well plates. On the day 3 the tre~tment~ were started with the compound of the Formula I at two concentrations, lOA-8 and lOA-10 M. Because ethanolic loA 5 and loA 7 M stock solutions of the compounds were used in the tre~tmentc all culture media cont~ined 0.1 % ethanol in~ lin~ the Controls. Media were changed on each 2-3 day. The tre~1mentc were fini~hed on the day 21, ~e total c~lcil~m (Ca) and DNA content of the 6-parallels~mples were me~nred by Boehringer Test Combination (~R3) and the spectrofluorometric 3~5-~ minobenzoic acid (DA~A~ method, respectively, then the ratios, Ca/DNA were calculated.
In the table of the compounds of Formula I below, data are given in percentages compared to the average of the Control value (100%) Nameof Concentration Ca DNA Ca/DNA
Compound [-log M] % % %
Ipriflavone 8 121 100 121 ` (7-isopropoxy- 10 111 108 103 isoflavone) (7-(-1 cyclohex- 10 131 107 124 2-enyloxy)-isoflavone) The compounds of the general formula (I) may be lltili7t?(1 in the therapy in the form of ~r~alions co,.~ g the active ingredient together with inert, non-toxic, ph~ reutically acceptable solid or liquid ~ n~ntc or carriers.
If desired, the ~ ~alions can contain biologically active known substances such S as vi~llil-c, amino acids, choline chloride, salts of mineral acids, trace elemen~c etc. As carriers talc, ~el~tine, calcium carbonate, magnesium stearate, starch, water, polyaLkylene glycols etc. may be used. The compositions may be fonm~l~tçd as solid (e.g. tablets, dragées, capsules, suppositories etc.) or liquid (e.g. solution, suspension or emulsion) preparations.
The invention is elucidated in more detail in the following non-limitin~ examples.
Example 1 10 g of 7-hydroxy-isoflavone, 10 ml of chloro~setone and 8 g of pot~csillm carbonate are stirred in 120 ml of acetone and the ~ e is boiled for 5 hours.
The reaction ~~ is diluted with water, the precipil~le is filtered off and recryst~lli7e-1 from acetic acid. 8.5 g of 7-(2-oxopropyl)-isoflavone are obtained, m.p.: 174-175 C.
7-(2,3-dihydroxy-1-propyloxy)-isoflavone (FL 230), m.p.: 164-165 C, 7-(3-ethoxycarbonyl-propyloxy~isoflavone (FL 283), m.p.: 124-125 C, 7-(2-pheno~cyethoxy~isoflavone (FL 273), m.p. 195-197 C, and 7-(1-ethoxycarbonyl-1-decyloxy~isoflavone (FL 279), m.p.: 97-99 C
are ~ ed in a similar way from 7-hydroxy-isoflavone and the corresponding aLkyl halide or sul)~Liluled aLkyl halide.
7-(3-methyl-1-butyloxy)-isoflavone (FL 191), m.p.: 107-108 C, is ~repa~ed from 7-hydroxy-3',4'-dimethoxy-isoflavone by using 3-methyl-1-butylbromid.
7-ethoxy-8-methyl-isoflavone (FL 315), m.p.: 129-130 C, 7-(carbethoxymethoxy)-8-methyl-isoflavone (FL 316), m.p.: 137-139 C, and 7~4-oxo-1-pentyloxy)-isoflavone (FL 501), m.p.: 143-145 C, are obtained from 7-hydroxy-8-methyl-isoflavone.
Example 2 A ~ e of 16 g of 6-n-hexyl-7-hydroxy-isoflavone, 14 ml of isopropylbromide and 70 ml of dimethylformamide are stirred for 4 hours at a temperature of 90 C in the presence of 16 g of potassium carbonate.
The reaction ~i~ e is poured into 500 ml of water, the product is separated, then recryst~ e.l from 80% aqueous medlanol. 15 g of 6-n-hexyl-7-(1-methyle~oxy)-~ WO 95/03293 9 2 1 6 7 7 1 4 PCT/HU94100028 -isoflavone are obtained, m.p. 37-39 C.
6-n-hexyl-7-ethoxy-isoflavone (FL 319), m.p.: 57-59 C, and 6-n-hexyl-7--(2-methyl-1-propyloxy)-isoflavone (FL 321), m.p.: 65-67 C, are prepared in a similar way.
S By reacting 6-chloro-7-hydroxy-isoflavones with alkyl h~lides with the following compounds are prepared:
7-ethoxy-6-chloro-isoflavone (FL 322), m.p.: 162-164 C, 7-(1-methylethoxy)-6-chloro-isoflavone (FL 323), m.p.: 156-158 C, 7-(2-methyl-1-propyloxy)-6-chloro-isoflavone (FL 324), m.p.: 170-172 C, 7-(2-propen-1-yloxy)-isoflavan-4-one (FL 238), m.p.: 76-78 C and 7-(4-nitro-benzyloxy)-isoflavan-4-one (FL 239), m.p.: 100-102 C.
Example 3 6.5 g of 7-n-hex~ecyloxy-isoflavone are hydrog~n~te~l in 1200 ml of ~cetone in the presence of 3.0 g of 10 % palladium on charcoal catalyst until a hydrogen uptake of 1.2 equimolar amount. The catalyst is filtered off and the solution is cv~or~Lcd. The residue is recryst~lli7e~1 from a ~llixLu~c of methanol and ~t~etone to obtain 5.3 g of 7-n-hçx~-lecyloxy-isoflavon~one, m.p.: 90-92 C.7-et_oxy-5-methyl-isoflavan~-one (FL 299), m.p.: 97-98 C, is l)l~cd in a similar way from 7-ethoxy-5-methyl-iso~avone.
7-cyclohexyl-isoflavan-4-one (FL 312), m.p.: 119-120 C, is p~arcd from 7-(1-cyclohex-2-enyloxy)-isoflavone (FL 286) by hydrogenation until a hydrogen ptake of 2.2 equimolar amount.
Example 4 A solution of 14 g of 7-isopropyloxy-isoflavone in 160 ml of acetic acid is hydrogenated in the presence of 5% p~ lm on charcoal catalyst until a hydrogen uptake of 3 equimolar amount. The catalyst is filtered off, the solvent is evaporated and the residue is recryst~lli7e~1 from methanol. 10 g of 7-(1-methylethoxy)-isoflavane (FLl99) is obtained, m.p.: 93-95 C
7-(2-methyl-1-propyloxy)-isoflavane (FL 248), m.p.: 97-99 C, 7-(n-h~ (lecyloxy)-isoflavan, m.p.: 90-92 C, are ~icpa.cd in a similar way from the - collcspollding isoflavones.
7-cyclohexyl-isoflavane, m.p.: 90-92 C, is prepared from 7-(1--cyclohex-2-enyloxy)-isoflavone by hydrogenation until a hydrogen uptake of
4 equimolar amount.
wo 95/03293 2 1 6 7 7 1 4 PCT/HUg4/00028 Example S
2.38 g of 7-hydroxy-isoflavone and 1.94 g of propane sulfone are dissolved in 25 ml of 1% methanolic sodium methylate. The nLixLule is let stand for 48 hours, then the precipiL~l~d product is separated by suction and recryst~lli7e~1 from S water to obtain 3.0 g of 7-(3-sulfonyl-1-propyloxy)-isoflavone sodium salt which melts above 350 C
7-(3-sulfonyl-1-propyloxy)-8-methyl-isoflavone sodium salt (FL 318), m.p.: above 350 C, 6-chloro-7-(3-sulfonyl-1-propyloxy)-isoflavone (FL 346), m.p.: above 350 C,
wo 95/03293 2 1 6 7 7 1 4 PCT/HUg4/00028 Example S
2.38 g of 7-hydroxy-isoflavone and 1.94 g of propane sulfone are dissolved in 25 ml of 1% methanolic sodium methylate. The nLixLule is let stand for 48 hours, then the precipiL~l~d product is separated by suction and recryst~lli7e~1 from S water to obtain 3.0 g of 7-(3-sulfonyl-1-propyloxy)-isoflavone sodium salt which melts above 350 C
7-(3-sulfonyl-1-propyloxy)-8-methyl-isoflavone sodium salt (FL 318), m.p.: above 350 C, 6-chloro-7-(3-sulfonyl-1-propyloxy)-isoflavone (FL 346), m.p.: above 350 C,
5-methyl-7-(3-sulfo-1-propyloxy)-isoflavone sodiurn salt (FL 502), m.p.: above 320 C, and 7-(3-sulfo-1-propyloxy)-2-methyl-isoflavone sodium salt (FL 291), m.p.: above 350 C
are ~ t;d in a similar way from the corresponding 7-hydroxy-isoflavone derivatives.
Example 6 16.5 g of 7-(3-carbomethoxy-1-proplyoxy)-isoflavone are boiled for 9 hours under reflux in a ~Lult; of 165 ml of glacial acetic acid, 8.5 ml of water and 1.0 ml of conc~ ed slllfilric acid. The free acid (m.p.: 188-190 C) preci~ lt;swhen the ~ixlult; is cooled, said acid is remo~ed by suction, dissolved in 300 rnl of methanol and the solution is nel~tr~li7e~l to pH-8 with lN sodium methylate solution. The pl~cipil~led 7-(3-carboxy-1-propyloxy)-isoflavone sodium salt is separated by snction in an amount of 13.1 g, m.p.: above 320 C.
7-(1-carboxy-1-propyloxy)-isoflavone, m.p.: 197-200 C and its sodium salt (FL 282) and 7-(1-carboxy-1-decyloxy)-isoflavone, m.p.: 124-126 C, and its sodium salt (FL 280) are prepared in a similar way from the corresponding esters.
Example 7 9 g of 7-isopropyloxy-isoflavone and 3.2 g of paraformaldehyde are stirred for 3 hours at a temperature of 70 C in a mixture of 80 ml of glacial acetic acid and 40 ml of concentrated hydrochloric acid under continuous introducing of anhydrous gaseous hydrochloric acid. On the next day the solution is partially evaporated, the pre~ is separated by suction and recryst~ e~l from methanol. To the solution of the 7-isopropoxy-8-chloromethyl-isoflavone, m.p.: 123-124 C, thus obtained with 50 ml of benzene an equivalent amount of wo 9S/03293 11 2 1 6 7 7 1 4 PCT/HU94/00028 lN sodium methylate is added under boiling. The cooled solution is ch~kçn several times with water and evaporated. The residue is recrysf~ e~l from methanol to obtain 7 g of 7-isopropoxy-8-methoxymethyl-isoflavone, m.p.: 92-93 C.
7-methoxy-8-methoxymethyl-isoflavone (FL 308) is prepared from 7-methoxy-isoflavone in a similar way.
Example 8 To a suspension of 7.5 g of 7-methoxy-8-chloromethyl-isoflavone with 45 ml of glacial acetic acid 3.0 of zinc dust is added within 3 hours. After a further stirling for 8 hours the reaction ~ e is diluted with warm water, the precipilat~
is separated by suction and recryst~ l from ethanol. 5.1 g of 7-methoxy-8--methyl-isoflavone are obtained, m.p.: 133-135 C.
Example 9 36.2 g of 2-hydroxy-4-(3-phenoxy-1-propyloxy)-phenylbenzyl-ketone, 22 g of ethyl orthoformiate and S g of morpholine are boiled in 200 ml of dimethyl form~mi-le for 8 hours. The ethanol formed during the reaction is removed through a fr~c~tion~hnp~ ~tt~t~hmen~, then a great part of the solvent is evaporated in vacuo and the residue is diluted with diluted aqueous hydrochloric acid.
The raw product is filtered offand recryst~lli7P~1 from ~cetone to obtain 32 g of 7 (3-plh~noxy-1-propyloxy)-isoflavone (FL 230), m.p.: 123-125 C.
Example 10 9.8 g of 7-(3-chloro-1-propyloxy)-isoflavone are boiled with 4.1 ml of piperidine in 55 ml of 2-bnt~none in the presence of 5.5 g of pot~ccinm carbonate and 0.5 g of pot~ccillm iodide for 14 hours. The inorganic salts are filtered off while hot and after cooling the precipi~l~:d product is se~aled by suction and recryst~lli7e~1 from methanol. 7-[3-(1-piperidine)-propyloxy]-isoflavone (FL 118) is obtained in an amount of 6.0 g, m.p.: 138-139 C.
7-[3-(1-morpholinyl)-propyloxy~-isoflavone (FL 117) is obtained in a simil~ way, m.p.: 162-163 C.
Example 11 18.5 g of 7-(10-ethoxycarbonyl-1-decyloxy)-isoflavone are boiled in a n~ e of 180 ml of glacial acetic acid, 10 ml of water and 3 ml of concentrated sulfuric acid for 4 hours. The next day the precipilal~d 7-(10-carboxy-1-decyloxy)-isoflavone, m.p.: 118-120 C, is separated by suction, dissolved in a 4: 1 mixture of acetone and methanol and the solution is adjusted to pH 8 by the aid of 10%
wo 95/03293 12 2 1 6 7 7 ~ 4 PCT/~IU94/00018 sodium hydroxyde. The precipitated salt is separated by suction and washed with the solvent mixture. 7-(10-carboxy-1-decyloxy)-isoflavone sodium salt (FL 295) is obtained in an amount of 10.6 g, which melts above 360 C.
7-(5-carboxy-1-pentyloxy)-isoflavone, m.p.: 146-148 C, is obtained from 7-(5-carbethoxy-1-pentyloxy)-isoflavone in a similar way and then the co,lesponding sodium salt (FL 302) which melts above 360 C.
Example 12 3.0 g of 7-methoxy-isoflavone are dissolved in 30 ml of chloroforrn and then 2.0 g of sulfurylchloride are added to the solution. The l~ Lul~ is boiled for an hour, evaporated, then the residue is recryst~lli7P~1 from a 1~ c; of chlorofo,m and ethanol. 8-chloro-7-methoxy-isoflavone (FL 501) is obtained in anamountof22.5g,m.p.: 181-182C.
In a similar way 7-ethoxy-isoflavone, m.p.: 144-145 C, is ~r~ ed from 7-ethoxy-isoflavone, 8-chloro-7-(2-propyloxy)-isoflavone, m.p.: 167-169 C, from 7-(2-propyloxy)-isoflavone and 8-chloro-2-methyl-7-methoxy-isoflavone (FL 517), m.p.: 17~178 C, from 2-methyl-7-methoxy-isoflavone.
Example 13 2.0 g of 7-(carbethoxymethoxy)-isoflavone are dissolved in 10 ml of diethylamino ethanol, 2.0 g of pot~cillTn carbonate are added to the solution and the ~ix LLue is boiled for 5 hours under st~ ng then poured into a ~ e of ice and 2% hydrochloric acid. The product is sepa~aled by s-~ction and recryst~lli7e~1 from a ~ e of methanol and acetone. 7-(N,N-diethylaminoethoxy--carbonylmethoxy)-isoflavone (FL 105) is obtained in an amount of 1.5 g, m.p.: 227-228 C.
7 (N,N-diethylaminoethoxy-carbonylmethoxy)-2-methyl-isoflavone (FL 104), m.p.: 190-192 C, is plep~ed in a similar way from 7-(carbethoxymethoxy)-2-methyl-isoflavone .
Example 14 16.0 g of 8-chloromethyl-7-methoxy-isoflavone and 11.4 g of anhydrous sodium acetate are boiled in 80 ml of acetic anhydride for 4 hours. The reactione is poured onto water, the pre~ aled product is filtered off and recryst~lli7;ç-1 from acetic acid. 8-acetoxymethyl-7-methoxy-isoflavone (FL 509) is obtained in an amount of 11.7 g, m.p.: 195-197 C.
8-acetoxymethyl-7-(2-propyloxy)-isoflavone (FL 521), m.p.: 107-109 C, is ~ ,~ed from 8-chloromethyl-7-(2-propyloxy)-isoflavone in a similar way.
are ~ t;d in a similar way from the corresponding 7-hydroxy-isoflavone derivatives.
Example 6 16.5 g of 7-(3-carbomethoxy-1-proplyoxy)-isoflavone are boiled for 9 hours under reflux in a ~Lult; of 165 ml of glacial acetic acid, 8.5 ml of water and 1.0 ml of conc~ ed slllfilric acid. The free acid (m.p.: 188-190 C) preci~ lt;swhen the ~ixlult; is cooled, said acid is remo~ed by suction, dissolved in 300 rnl of methanol and the solution is nel~tr~li7e~l to pH-8 with lN sodium methylate solution. The pl~cipil~led 7-(3-carboxy-1-propyloxy)-isoflavone sodium salt is separated by snction in an amount of 13.1 g, m.p.: above 320 C.
7-(1-carboxy-1-propyloxy)-isoflavone, m.p.: 197-200 C and its sodium salt (FL 282) and 7-(1-carboxy-1-decyloxy)-isoflavone, m.p.: 124-126 C, and its sodium salt (FL 280) are prepared in a similar way from the corresponding esters.
Example 7 9 g of 7-isopropyloxy-isoflavone and 3.2 g of paraformaldehyde are stirred for 3 hours at a temperature of 70 C in a mixture of 80 ml of glacial acetic acid and 40 ml of concentrated hydrochloric acid under continuous introducing of anhydrous gaseous hydrochloric acid. On the next day the solution is partially evaporated, the pre~ is separated by suction and recryst~ e~l from methanol. To the solution of the 7-isopropoxy-8-chloromethyl-isoflavone, m.p.: 123-124 C, thus obtained with 50 ml of benzene an equivalent amount of wo 9S/03293 11 2 1 6 7 7 1 4 PCT/HU94/00028 lN sodium methylate is added under boiling. The cooled solution is ch~kçn several times with water and evaporated. The residue is recrysf~ e~l from methanol to obtain 7 g of 7-isopropoxy-8-methoxymethyl-isoflavone, m.p.: 92-93 C.
7-methoxy-8-methoxymethyl-isoflavone (FL 308) is prepared from 7-methoxy-isoflavone in a similar way.
Example 8 To a suspension of 7.5 g of 7-methoxy-8-chloromethyl-isoflavone with 45 ml of glacial acetic acid 3.0 of zinc dust is added within 3 hours. After a further stirling for 8 hours the reaction ~ e is diluted with warm water, the precipilat~
is separated by suction and recryst~ l from ethanol. 5.1 g of 7-methoxy-8--methyl-isoflavone are obtained, m.p.: 133-135 C.
Example 9 36.2 g of 2-hydroxy-4-(3-phenoxy-1-propyloxy)-phenylbenzyl-ketone, 22 g of ethyl orthoformiate and S g of morpholine are boiled in 200 ml of dimethyl form~mi-le for 8 hours. The ethanol formed during the reaction is removed through a fr~c~tion~hnp~ ~tt~t~hmen~, then a great part of the solvent is evaporated in vacuo and the residue is diluted with diluted aqueous hydrochloric acid.
The raw product is filtered offand recryst~lli7P~1 from ~cetone to obtain 32 g of 7 (3-plh~noxy-1-propyloxy)-isoflavone (FL 230), m.p.: 123-125 C.
Example 10 9.8 g of 7-(3-chloro-1-propyloxy)-isoflavone are boiled with 4.1 ml of piperidine in 55 ml of 2-bnt~none in the presence of 5.5 g of pot~ccinm carbonate and 0.5 g of pot~ccillm iodide for 14 hours. The inorganic salts are filtered off while hot and after cooling the precipi~l~:d product is se~aled by suction and recryst~lli7e~1 from methanol. 7-[3-(1-piperidine)-propyloxy]-isoflavone (FL 118) is obtained in an amount of 6.0 g, m.p.: 138-139 C.
7-[3-(1-morpholinyl)-propyloxy~-isoflavone (FL 117) is obtained in a simil~ way, m.p.: 162-163 C.
Example 11 18.5 g of 7-(10-ethoxycarbonyl-1-decyloxy)-isoflavone are boiled in a n~ e of 180 ml of glacial acetic acid, 10 ml of water and 3 ml of concentrated sulfuric acid for 4 hours. The next day the precipilal~d 7-(10-carboxy-1-decyloxy)-isoflavone, m.p.: 118-120 C, is separated by suction, dissolved in a 4: 1 mixture of acetone and methanol and the solution is adjusted to pH 8 by the aid of 10%
wo 95/03293 12 2 1 6 7 7 ~ 4 PCT/~IU94/00018 sodium hydroxyde. The precipitated salt is separated by suction and washed with the solvent mixture. 7-(10-carboxy-1-decyloxy)-isoflavone sodium salt (FL 295) is obtained in an amount of 10.6 g, which melts above 360 C.
7-(5-carboxy-1-pentyloxy)-isoflavone, m.p.: 146-148 C, is obtained from 7-(5-carbethoxy-1-pentyloxy)-isoflavone in a similar way and then the co,lesponding sodium salt (FL 302) which melts above 360 C.
Example 12 3.0 g of 7-methoxy-isoflavone are dissolved in 30 ml of chloroforrn and then 2.0 g of sulfurylchloride are added to the solution. The l~ Lul~ is boiled for an hour, evaporated, then the residue is recryst~lli7P~1 from a 1~ c; of chlorofo,m and ethanol. 8-chloro-7-methoxy-isoflavone (FL 501) is obtained in anamountof22.5g,m.p.: 181-182C.
In a similar way 7-ethoxy-isoflavone, m.p.: 144-145 C, is ~r~ ed from 7-ethoxy-isoflavone, 8-chloro-7-(2-propyloxy)-isoflavone, m.p.: 167-169 C, from 7-(2-propyloxy)-isoflavone and 8-chloro-2-methyl-7-methoxy-isoflavone (FL 517), m.p.: 17~178 C, from 2-methyl-7-methoxy-isoflavone.
Example 13 2.0 g of 7-(carbethoxymethoxy)-isoflavone are dissolved in 10 ml of diethylamino ethanol, 2.0 g of pot~cillTn carbonate are added to the solution and the ~ix LLue is boiled for 5 hours under st~ ng then poured into a ~ e of ice and 2% hydrochloric acid. The product is sepa~aled by s-~ction and recryst~lli7e~1 from a ~ e of methanol and acetone. 7-(N,N-diethylaminoethoxy--carbonylmethoxy)-isoflavone (FL 105) is obtained in an amount of 1.5 g, m.p.: 227-228 C.
7 (N,N-diethylaminoethoxy-carbonylmethoxy)-2-methyl-isoflavone (FL 104), m.p.: 190-192 C, is plep~ed in a similar way from 7-(carbethoxymethoxy)-2-methyl-isoflavone .
Example 14 16.0 g of 8-chloromethyl-7-methoxy-isoflavone and 11.4 g of anhydrous sodium acetate are boiled in 80 ml of acetic anhydride for 4 hours. The reactione is poured onto water, the pre~ aled product is filtered off and recryst~lli7;ç-1 from acetic acid. 8-acetoxymethyl-7-methoxy-isoflavone (FL 509) is obtained in an amount of 11.7 g, m.p.: 195-197 C.
8-acetoxymethyl-7-(2-propyloxy)-isoflavone (FL 521), m.p.: 107-109 C, is ~ ,~ed from 8-chloromethyl-7-(2-propyloxy)-isoflavone in a similar way.
Claims (17)
1. Process for the preparation of compounds of the general formula (I), and salts thereof, wherein if n is 0, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 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, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 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, R5 and R6 together stand for an oxo group or stand separately for hydrogen and the dotted line does not mean a chemical bond, R1 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;
R4 stands for hydrogen or C1-4alkyl;
R2 and R3 stand for hydrogen or C1-6alkoxy;
R5 and R6 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.
characterized in that 1) for the preparation of compounds of the general formula (IA), wherein R, n, R1, R2 and R3 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), ketones of the general formula (III), wherein R, n, R1, R2 and R3 are as defined for the general formula (I), are reacted a) with alkyl orthoformate in the presence of a basic catalyst, or b) with hydrogen cyanide and/or cyanic salts in the presence of hydrohalogenic acid; or c) with alkyl formiate in the presence of an alkali metal, or d) with alkyloxalyl halide, and the isoflavone ester thus obtained is, if desired, saponified and/or decarboxylated; or e) with organic carboxylic anhydride; or f) with N,N-dialkyl acid amide in the presence of phosphorous chloride; or g) 2-hydroxy-isoflavanone derivatives of the general formula (IV), are dehydrated, or 2) for the preparation of compounds of the general formula (IB), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), compounds of the general formula (IA), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, aresubjected to reduction, or 3) for the preparation of compounds of the general formula (IC), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), compounds of the general formula (IB), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, arereduced by catalytic hydrogenation, and, if desired, an R1 is converted into another R1 group within the definitions of the preamble, or an R group is formed in a compound of the general formula (I) containing a hydrogen atom in the place of R, and, if desired, a compound of the general formula (I) thus obtained is converted into its salt or is set free from its salt.
R4 stands for hydrogen or C1-4alkyl;
R2 and R3 stand for hydrogen or C1-6alkoxy;
R5 and R6 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.
characterized in that 1) for the preparation of compounds of the general formula (IA), wherein R, n, R1, R2 and R3 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), ketones of the general formula (III), wherein R, n, R1, R2 and R3 are as defined for the general formula (I), are reacted a) with alkyl orthoformate in the presence of a basic catalyst, or b) with hydrogen cyanide and/or cyanic salts in the presence of hydrohalogenic acid; or c) with alkyl formiate in the presence of an alkali metal, or d) with alkyloxalyl halide, and the isoflavone ester thus obtained is, if desired, saponified and/or decarboxylated; or e) with organic carboxylic anhydride; or f) with N,N-dialkyl acid amide in the presence of phosphorous chloride; or g) 2-hydroxy-isoflavanone derivatives of the general formula (IV), are dehydrated, or 2) for the preparation of compounds of the general formula (IB), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), compounds of the general formula (IA), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, aresubjected to reduction, or 3) for the preparation of compounds of the general formula (IC), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), compounds of the general formula (IB), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, arereduced by catalytic hydrogenation, and, if desired, an R1 is converted into another R1 group within the definitions of the preamble, or an R group is formed in a compound of the general formula (I) containing a hydrogen atom in the place of R, and, if desired, a compound of the general formula (I) thus obtained is converted into its salt or is set free from its salt.
2. Processes according to variants a) to f) of claim 1, characterized by using 2-hydroxy-4-alkoxyphenylbenzyl-ketone as a starting material of the general formula (III).
3. A process as claimed in claim 2, characterized by using 2-hydroxy-4-isopropoxyphenylbenzyl-ketone as starting material of the general formula (III).
4. A process as claimed in variant a) of claim 1, characterized by using piperidine, morpholine or pyrrolidine as basic catalyst.
5. A process as claimed in variant b9 of claim 1, characterized by carrying out the reaction in an aprotic solvent, preferably in dialkyl ether or another dialkyl ether.
6. A process as claimed in claim 5, characterized by carrying out the reaction in the presence of Lewis acids, preferably in the presence of zinc chloride.
7. A process as claimed in variant c) of claim 1, characterized by using sodium as an alkali metal.
8. A process as claimed in variant e) of claim 1, characterized by using acetic anhydride, propionic anhydride or benzoic anhydride as organic acid anhydride.
9. A process as claimed in claim 8, characterized by carrying out the reaction in the presence of a basic catalyst, preferably in the presence of the alkali salt of the acid component of the acid anhydride or a tertiary amine.
10. A process as claimed in variant f) of claim 1, characterized by using dimethylformamide or dimethylacetamide as N,N-dialkyl acid amide.
11. A process as claimed in variant g) of claim 1, characterized by carrying out the dehydration in an acidic medium.
12. A process as claimed in claim 1, characterized by introducing the group by alkylating the compounds of the general formula (I) containing a hydrogen atom in the place of R1 witih alkyl halides, alkyl sulfates, alkyl sulfonic lactones, olefines or epoxydes.
13. A process as claimed in variant 2) of claim 1, characterized by carrying out the reduction by catalytic hydrogenation or by using metal hydrides.
14. A process as claimed in variant 3) of claim 1, characterized by using as catalyst nickel or a noble metal catalyst.
15. A process for the preparation of pharmaceutical compositions, characterized by admixing a compound of the general formula (I) wherein R1, R, R2, R3 R4, R5, R6, n, m, p and the dotted line are as defined in claim 1, or a salts thereof, with inert, non-toxic, pharmaceutically acceptable solid or liquid diluents or carriers and other excipients and formulating pharmaceutical compositions.
16. Compounds of the general formula (I), and salts thereof.
17. Pharmaceutical compositions containing compounds of the general formula (I).
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 |
|---|---|
| CA2167714A1 true CA2167714A1 (en) | 1995-02-02 |
Family
ID=10983803
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002167597A Abandoned CA2167597A1 (en) | 1993-07-20 | 1994-07-18 | Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof |
| CA002167714A Abandoned CA2167714A1 (en) | 1993-07-20 | 1994-07-19 | Isoflavone derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002167597A Abandoned CA2167597A1 (en) | 1993-07-20 | 1994-07-18 | Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof |
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) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| AUPP868599A0 (en) * | 1999-02-15 | 1999-03-11 | Novogen Research Pty Ltd | Production of isoflavone 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 |
| US7468445B2 (en) | 2002-08-07 | 2008-12-23 | University Of Mississippi | Antigiardial agents and use thereof |
| GB0412769D0 (en) | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
| GB0412768D0 (en) * | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
| WO2007099432A2 (en) * | 2006-02-28 | 2007-09-07 | Council Of Scientific And Industrial Research | Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof |
| TWI324514B (en) | 2008-02-26 | 2010-05-11 | Univ Kaohsiung Medical | Isoflavone derivatives and pharmaceutical compositions comprising the same |
| 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 |
| CN108264506B (en) * | 2018-01-17 | 2021-01-26 | 中国药科大学 | Isoflavone derivative, preparation method and medical application thereof |
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| 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 |
| EP0478558B1 (en) * | 1990-04-06 | 1994-02-02 | CHINOIN Gyògyszer és Vegyészeti Termékek Gyára RT. | 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 EP EP94921776A patent/EP0710234A1/en not_active Withdrawn
- 1994-07-19 CN CN94193107A patent/CN1129445A/en active Pending
- 1994-07-19 CA CA002167714A patent/CA2167714A1/en not_active Abandoned
-
1996
- 1996-01-19 KR KR1019960700364A patent/KR960703888A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU7236794A (en) | 1995-02-20 |
| HUT68558A (en) | 1995-06-28 |
| CN1129445A (en) | 1996-08-21 |
| EP0710234A1 (en) | 1996-05-08 |
| KR960703888A (en) | 1996-08-31 |
| WO1995003293A1 (en) | 1995-02-02 |
| CA2167597A1 (en) | 1995-02-02 |
| HU9302083D0 (en) | 1993-10-28 |
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