WO1995003040A1 - Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof - Google Patents

Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof Download PDF

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Publication number
WO1995003040A1
WO1995003040A1 PCT/HU1994/000027 HU9400027W WO9503040A1 WO 1995003040 A1 WO1995003040 A1 WO 1995003040A1 HU 9400027 W HU9400027 W HU 9400027W WO 9503040 A1 WO9503040 A1 WO 9503040A1
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Prior art keywords
hydrogen
stands
general formula
stand
alkyl
Prior art date
Application number
PCT/HU1994/000027
Other languages
French (fr)
Inventor
Mihály NÓGRÁDI
Ágnes GOTTSEGEN
Sándor ANTUS
János STRELISKY
Borbála VERMES
András WOLFNER
Ádám MAJOR
Tamás Szüts
Istvánné BENDEFFY
Tamásné Mármarosi
Original Assignee
Chinoin Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chinoin Ltd. filed Critical Chinoin Ltd.
Priority to AU72366/94A priority Critical patent/AU7236694A/en
Priority to EP94921775A priority patent/EP0717621A1/en
Priority to KR1019960700363A priority patent/KR960703600A/en
Publication of WO1995003040A1 publication Critical patent/WO1995003040A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom

Definitions

  • the present invention relates to pharmaceutical compositions containing as active agent isoflavone derivatives of the general formula
  • R 1 represents a C 2 personallyi 8 alkyl optionally substituted by C ⁇ galkoxy, hydroxyl, C ⁇ carbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C 1 -_ alkyl chain optionally substituted by a halo atom or a nitro group or C 2 .
  • R 2 and R 3 stand for hydrogen or C ⁇ alkoxy
  • R 4 stands for hydrogen, C ⁇ aUcyl or carboxyl
  • R 5 stands for hydrogen or C ⁇ alkyl
  • R 6 stands for hydrogen or, if R 5 stands for hydrogen, R 6 may also stand for methyl or hydroxymethyl, with the proviso that if R 2 , R 3 , R 4 , R 5 and R 6 stand for hydrogen, R 1 is other than isopropyl, or salt thereof.
  • the composition can be prepared by admixing an isoflavone derivative of the general formula (I), wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, prepared in a known manner, with filling, diluting and other auxiliary substances generally used in the pharmaceutical industry and formulating pharmaceutical compositions.
  • the compositions are suitable for the treatment of osteoporosis.
  • the compounds of the general formula (I) containing a hydrogen atom in the place ofR 6 are prepared by a) reacting ketones of the general formula
  • R 5 , R 1 , R 2 and R 3 are as defined above, with alkyl orthoformiate in the presence of a basic catalyst, or b) reacting ketones of the general formula
  • R 5 , R 1 , R 2 and R 3 as defined above, and optionally introducing into a compound of the general formula (I), wherein R 1 is hydrogen, an R 1 group other than hydrogen, if desired, converting an another R 1 group into another R 1 group and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt.
  • R 1 is hydrogen, an R 1 group other than hydrogen
  • converting an another R 1 group into another R 1 group and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt.
  • Hungarian Patent Specification No. 162,377 compounds of the general formula (I) containing a hydrogen atom in position 6 by halomethylation. The reduction is preferably carried out in the presence of metals, preferably zinc.
  • the compounds of the general formula (I) containing an alkoxy or hydroxymethyl group in position 6 are prepared either by replacing the halo atom of the halometfayl isoflavones prepares as described above by an alkoxy group by the aid of alcohols or by replacing said halo atom by an 0-acetyl group by the aid of sodium acetate and by subsequently converting the acetoxy group into a hydroxy group.
  • the active agents of the compositions according to the invention can be prepared in a known manner.
  • the term "known manner" comprises all the methods which could be learned from the literature until the date of priority.
  • the compounds of the general formula (I) and salts thereof exert a cholesterol level decreasing effect in the blood and they influence the metabolism, thus, the majority of these compounds show an anabolitic, while the others show a catabolitic effect.
  • osteoporosis is a disease which manifests itself frequently with women being in the menopause.
  • Oestrogenic preparations, calcitonine, vitamin D and other calcium-containing preparations are used for the treatment of osteoporosis. However, none of these preparations proved to be sufficiently effective against this disease.
  • Ipriflavone (7-Isopropoxy-isofiavone) is able to inhibit bone resoiption either in vitro or in vivo (Notoya, K. et al. Inhibitory effect of
  • Ipriflavone on pit formation in mouse unfractionated bone cells Calcif. Tissue Int. 51, (Supl. 1) 53-56 (1992); Notoya, K. et al. Inhibitory effect of Ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term cultures of mouse unfractionated bone cells, Calcif Tissue Int. 50, 314-319 (1992).
  • Ipriflavone also could increase the mineralization of the extracellular matrix of human bone cell cultures (Ref. Ecsedi, G.G.
  • the compounds of the general formula (I) can preferably be used in the form of capsules, tablets or tablets with prolonged effect. These pharmaceutical preparation can be made by methods known per se.
  • Example 1 Capsules A compound of the general formula (I) 200 mg colloidal silicic acid 20 mg talc 20 mg magnesium stearate 20 mg lactose 80 mg
  • a compound of the general formula (I) 200 mg magnesium stearate 4 mg talc 7 mg polyvinyl-pyrrolidone 13 mg lactose 60 mg potato starch 36 mg Esmaspreny (formaldehyde caseine) 60 mg

Abstract

The present invention relates to pharmaceutical compositions containing as active agent isoflavone derivatives of general formula (I), wherein R1 represents a C¿2-18?alkyl optionally substituted by C1-6alkoxy, hydroxyl, C1-6carbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C1-3alkyl chain optionally substituted by a halo atom or a nitro group or C2-6alkenyl; R?2 and R3¿ stand for hydrogen or C¿1-6?alkoxy; R?4¿ stands for hydrogen, C¿1-6?alkyl or carboxyl; R?5¿ stands for hydrogen or C¿1-4?alkyl; R?6¿ stands for hydrogen or, if R5 stands for hydrogen, R6 may also stand for methyl or hydroxymethyl, with the proviso that if R?2, R3, R4, R5 and R6¿ stand for hydrogen, R1 is other than isopropyl, or salt thereof. The pharmaceutical compositions according to the invention are prepared by known methods and are suitable for the treatment of osteoporosis.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE AGENT ISOFLAVONE DERIVATIVES OR SALTS THEREOF
The present invention relates to pharmaceutical compositions containing as active agent isoflavone derivatives of the general formula
Figure imgf000003_0001
wherein
R1 represents a C2„i8alkyl optionally substituted by Cμgalkoxy, hydroxyl, Cμβcarbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C1-_ alkyl chain optionally substituted by a halo atom or a nitro group or C2.6alkenyl; R2 and R3 stand for hydrogen or C^alkoxy; R4 stands for hydrogen, C^aUcyl or carboxyl; R5 stands for hydrogen or C^alkyl; R6 stands for hydrogen or, if R5 stands for hydrogen, R6 may also stand for methyl or hydroxymethyl, with the proviso that if R2, R3, R4, R5 and R6 stand for hydrogen, R1 is other than isopropyl, or salt thereof. The composition can be prepared by admixing an isoflavone derivative of the general formula (I), wherein R1, R2, R3, R4 and R5 are as defined above, prepared in a known manner, with filling, diluting and other auxiliary substances generally used in the pharmaceutical industry and formulating pharmaceutical compositions. The compositions are suitable for the treatment of osteoporosis.
The compounds of the general formula (I) containing a hydrogen atom in the place ofR6 are prepared by a) reacting ketones of the general formula
(III) ,
Figure imgf000003_0002
wherein R5, R1, R2 and R3 are as defined above, with alkyl orthoformiate in the presence of a basic catalyst, or b) reacting ketones of the general formula
Figure imgf000004_0001
wherein R5, R1, R2 and R3 as defined above, with hydrogen cyanide and/or cyanic salts in the presence of a hydrohalogenic acid, or c) reacting ketones of the general formula (HI), wherein R5, R1, R2 and R3 as defined above, with alkyl formiate in the presence of an alkali metal, or d) reacting ketones of the general formula (El), wherein R5, R1, R2 and R3 as defined above, with alkyloxalkyl halide and, if desired, saponifying and/or decarboxylating the isoflavone ester thus obtained, or e) reacting ketones of the general formula (IH), wherein R5, R1, R2 and R3 as defined above, with organic carboxylic acid anhydride, or f) reacting ketones of the general formula (III), wherein R5, R1, R2 and R3 as defined above, with N,N-dialkyl acid amide in the presence of phosporous chloride, or g) dehydrating 2-hydroxy isoflavone derivatives of the general formula
Figure imgf000004_0002
wherein R5, R1, R2 and R3 as defined above, and optionally introducing into a compound of the general formula (I), wherein R1 is hydrogen, an R1 group other than hydrogen, if desired, converting an another R1 group into another R1 group and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt. (Hungarian Patent Specification No. 162,377) compounds of the general formula (I) containing a hydrogen atom in position 6 by halomethylation. The reduction is preferably carried out in the presence of metals, preferably zinc.
The compounds of the general formula (I) containing an alkoxy or hydroxymethyl group in position 6 are prepared either by replacing the halo atom of the halometfayl isoflavones prepares as described above by an alkoxy group by the aid of alcohols or by replacing said halo atom by an 0-acetyl group by the aid of sodium acetate and by subsequently converting the acetoxy group into a hydroxy group.
The active agents of the compositions according to the invention can be prepared in a known manner. The term "known manner" comprises all the methods which could be learned from the literature until the date of priority.
According to the Hungarian Patent Specification No. 162,377 the compounds of the general formula (I) and salts thereof exert a cholesterol level decreasing effect in the blood and they influence the metabolism, thus, the majority of these compounds show an anabolitic, while the others show a catabolitic effect.
It is known that osteoporosis is a disease which manifests itself frequently with women being in the menopause.
Oestrogenic preparations, calcitonine, vitamin D and other calcium-containing preparations are used for the treatment of osteoporosis. However, none of these preparations proved to be sufficiently effective against this disease.
We have found that the compounds of the general formula (I) and salts thereof can effectively be used for the prophylaxis and treatment of osteoporosis.
It is known that Ipriflavone (7-Isopropoxy-isofiavone) is able to inhibit bone resoiption either in vitro or in vivo (Notoya, K. et al. Inhibitory effect of
Ipriflavone on pit formation in mouse unfractionated bone cells, Calcif. Tissue Int. 51, (Supl. 1) 53-56 (1992); Notoya, K. et al. Inhibitory effect of Ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term 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 mineralization of the extracellular matrix of human bone cell cultures (Ref. Ecsedi, G.G. Model for in vitro investigation of bone mineralization, Agents and Actions 41, 84-85 (1994.) To estimate the effectiveness of the compoimds of the general Formula (I) on bone formation an in vitro mineralization model was developed. Under certain circumstances cultures of partially selected (osteoblast-enriched) human bone cells originated from either nasal bone of adults or foetus femur produce Type I collagene, bone specific proteins (e.g. osteocalcin), prostanoides (PGE2, PGF2α, PGI2, etc. and accumulate calcium into the synthesized matrix (Ref: Ecsedi, G.G., Characterization 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-inoculated at a density of 2* 10Λ4 cells per well 96-well plates. On the day 3 the treatments were started with the compound of the Formula I at two concentrations, 10Λ-8 and 10Λ-10 M. Because ethanolic 10Λ-5 and 10Λ-7 M stock solutions of the compounds were used in the treatments all culture media contained 0J % ethanol including the Controls. Media were changed on each 2-3 day. The treatments were finished on the day 21, the total calcium (Ca) and DNA content of the 6-parallel samples were measured by Boehringer Test Combination (MPR3) and the spectrofluorometric 3,5-diaminobenzoic acid (DABA) 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%)
Name of Concentration Ca DNA Ca/DNA
Compound [-log M] % % %
Ipriflavone 8 121 100 121
(7-isopropoxy- 10 111 108 103 isoflavone)
CH- 16693 8 143 109 131
(7-n-nonyloxy- 10 108 103 104
-isoflavone) covered by the general Formula (I)
CH-2793 8 116 103 113
(7-n-propoxy- 10 180 106 168
-isoflavone) covered by the general Formula (I) In the treatment the compounds of the general formula (I) can preferably be used in the form of capsules, tablets or tablets with prolonged effect. These pharmaceutical preparation can be made by methods known per se.
The invention is elucidated in detail by the following non-limiting examples. The following compositions are prepared in a known manner:
Example 1 Capsules A compound of the general formula (I) 200 mg colloidal silicic acid 20 mg talc 20 mg magnesium stearate 20 mg lactose 80 mg
Example 2 Tablets
A compound of the general formula (I) 200 mg magnesium stearate 4 mg talc 7 mg polyvinyl-pyrrolidone 13 mg lactose 60 mg potato starch 36 mg Esmaspreny (formaldehyde caseine) 60 mg

Claims

Claims:
1. A pharmaceutical composition for the treatment of osteoporosis, which comprises as active ingredient a therapeutically active amount of a compound of the general
Figure imgf000008_0001
wherein
R1 represents a C2_18alkyl optionally substituted by C galkoxy, hydroxyl,
C gcarbalkoxy, phenyl, benzoyl or a halo atom; phenylalkyl containing a C^alkyl chain optionally substituted by a halo atom or a nitro group or C2_6alkenyl; R2 and R3 stand for hydrogen or C^alkoxy; R4 stands for hydrogen, C galkyl or carboxyl; R5 stands for hydrogen or C^alkyl; R6 stands for hydrogen or, if R5 stands for hydrogen, R6 may also stand for methyl or hydroxymethyl, with the proviso that if R2, R3, R4, R5 and R6 stand for hydrogen, R1 is other than isopropyl, in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutical additives and auxiliary agent.
2. Use of compounds of the general formula (I), wherein R1, R2, R3, R4 and R5 are as defined in claim 1, for formulating pharmaceutical compositions for the treatment of osteoporosis.
3. Method of treatment of osteoporosis of an affected human or animal subject, which comprises the step of administering in an effective amount a compound of the general formula (I), wherein R1, R2, R3, R4 and R5 are as defined in claim 1, in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutical additives and auxiliary agent.
PCT/HU1994/000027 1993-07-20 1994-07-18 Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof WO1995003040A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU72366/94A AU7236694A (en) 1993-07-20 1994-07-18 Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof
EP94921775A EP0717621A1 (en) 1993-07-20 1994-07-18 Pharmaceutical compositions containing as active agent isoflavone derivatives or salts thereof
KR1019960700363A KR960703600A (en) 1993-07-20 1994-07-18 PHARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE AGENT ISOFLAVONE DERIVATIVES OR SALTS THEREOF

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU2082/93 1993-07-20
HU9302082A HUT68396A (en) 1993-07-20 1993-07-20 Method for preparing pharmaceutical preparation containing isoflavone derivative or salt of it

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WO1995003040A1 true WO1995003040A1 (en) 1995-02-02

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EP (1) EP0717621A1 (en)
KR (1) KR960703600A (en)
CN (1) CN1129398A (en)
AU (1) AU7236694A (en)
HU (1) HUT68396A (en)
WO (1) WO1995003040A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029403A1 (en) * 1997-01-03 1998-07-09 Chiesi Farmaceutici S.P.A. Isoflavone derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
KR100436220B1 (en) * 2001-08-30 2004-06-12 주식회사 네패스 Organic polymers for bottom antireflective coating, processes for preparing the same, and compositions containing the same
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101331913B (en) * 2008-07-22 2011-03-16 广东新南都饲料科技有限公司 Use of isoflavone with substituent at intermedium ring 2 position as animal feed additives

Citations (9)

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FR846M (en) * 1960-01-19 1961-10-02
US3352754A (en) * 1960-01-19 1967-11-14 Sarec S A Therapeutic compositions comprising isoflavone compounds
DE2166458A1 (en) * 1970-05-27 1974-10-03 Chinoin Gyogyszer Es Vegyeszet METABOLIC MEANS
US3864362A (en) * 1970-05-27 1975-02-04 Chinoin Gyogyszer Es Vegyeszet Iso flavones
US3949085A (en) * 1970-05-27 1976-04-06 Chinoin Gyogyszer-Es Vegyeszeti Termakek Gyara Rt Anabolic-weight-gain promoting compositions containing isoflavone derivatives and method using same
AT339130B (en) * 1971-10-20 1977-10-10 Chinoin Gyogyszer Es Vegyeszet WEIGHT INCREASING FEED ADDITIVE
US4163746A (en) * 1973-07-09 1979-08-07 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Metabolic 5-methyl-isoflavone-derivatives, process for the preparation thereof and compositions containing the same
US4166862A (en) * 1971-05-25 1979-09-04 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Animal feed containing anabolic isoflavones
DE3446246A1 (en) * 1983-12-21 1985-07-11 Takeda Chemical Industries, Ltd., Osaka USE OF 3-PHENYL-4H-1-BENZOPYRAN-4-ON DERIVATIVES FOR THE PREVENTION AND TREATMENT OF OSTEOPOROSIS

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR846M (en) * 1960-01-19 1961-10-02
US3352754A (en) * 1960-01-19 1967-11-14 Sarec S A Therapeutic compositions comprising isoflavone compounds
DE2166458A1 (en) * 1970-05-27 1974-10-03 Chinoin Gyogyszer Es Vegyeszet METABOLIC MEANS
US3864362A (en) * 1970-05-27 1975-02-04 Chinoin Gyogyszer Es Vegyeszet Iso flavones
US3949085A (en) * 1970-05-27 1976-04-06 Chinoin Gyogyszer-Es Vegyeszeti Termakek Gyara Rt Anabolic-weight-gain promoting compositions containing isoflavone derivatives and method using same
US4166862A (en) * 1971-05-25 1979-09-04 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Animal feed containing anabolic isoflavones
AT339130B (en) * 1971-10-20 1977-10-10 Chinoin Gyogyszer Es Vegyeszet WEIGHT INCREASING FEED ADDITIVE
US4163746A (en) * 1973-07-09 1979-08-07 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Metabolic 5-methyl-isoflavone-derivatives, process for the preparation thereof and compositions containing the same
DE3446246A1 (en) * 1983-12-21 1985-07-11 Takeda Chemical Industries, Ltd., Osaka USE OF 3-PHENYL-4H-1-BENZOPYRAN-4-ON DERIVATIVES FOR THE PREVENTION AND TREATMENT OF OSTEOPOROSIS

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Title
Soviet Inventions Illustrated, Section CH, week C 15, 21 May 1980 (21.05.80), Derwent Publications LTD London, B 02; & SU,A,682 099 (CHINOIN GYOGYSZER). *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029403A1 (en) * 1997-01-03 1998-07-09 Chiesi Farmaceutici S.P.A. Isoflavone derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
KR100436220B1 (en) * 2001-08-30 2004-06-12 주식회사 네패스 Organic polymers for bottom antireflective coating, processes for preparing the same, and compositions containing the same
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
WO2007099432A3 (en) * 2006-02-28 2007-11-22 Council Scient Ind Res Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof
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

Also Published As

Publication number Publication date
EP0717621A1 (en) 1996-06-26
AU7236694A (en) 1995-02-20
HU9302082D0 (en) 1993-10-28
CN1129398A (en) 1996-08-21
HUT68396A (en) 1995-04-25
KR960703600A (en) 1996-08-31

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