AP32A - Pharmaceutically active compounds and a method for its preparation - Google Patents
Pharmaceutically active compounds and a method for its preparation Download PDFInfo
- Publication number
- AP32A AP32A APAP/P/1985/000017A AP8500017A AP32A AP 32 A AP32 A AP 32A AP 8500017 A AP8500017 A AP 8500017A AP 32 A AP32 A AP 32A
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- AP
- ARIPO
- Prior art keywords
- disease
- accordance
- preparation
- pharmacological
- treatment
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Rheumatology (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Compounds consisting of
Description
Pharmaceutically active compound and a method for its preparation
Thia invention relates to pharmacologically active compoundi.Moreover, the invention concerns pharmacological preparations containing the compounds as well as the use of the compounds in the treatment of various diseases .
The compound according to the invention consists of podophy1lotoxin and derivatives thereof which have the formula
wherein Rj is H or OH and R2 is H or CH3 .
Podophy1lotoxin and its derivatives have been found to have a plurality of outstanding pharmacological effects. Thue, they suprsss the activity of lymphatic T-cells (killer cells) and can therefore be used to counteract reactions-of immunity and rejection at transplantations. Besides, they inhibit cell division in the meta phase and can therefore be used for treatment of pScrkxtic diseases. The compounds also have biocidal and biostatic effects against such microorganisms as plasmodia, fungi and viruses, and they can therefore be used in the treatment of parasitic diseases, such as malaria, and viral diseases.
Furthermore the compounds also act as anthelraintj.ce.
BAD ORIGINAL
The compound podophy11otoxiη is previously known and has been extracted from plants, mainly from the genus Podcp’.'.yl lum. However, the compound has not earlier beer, used in its highly pure form according to the present invention, which has made possible its use in new indication fields. In previous works, an impure extract from Podophyllum species, so-called podophy11ιn, has mostly been used, which has only contained 20-40 X of podophy11otoxin. Moreover, the extract contains a great number of other components such as desoxypodophyllotoxin, dehydropodophyllotoxin, 3- and g-peltatin etc., depending on from which species the extract has been ’recovered. Several of these other components have been found to be considerably mutageni c .
*
The compound podophy11otox in has the following physical data in its purs state:
Melting point: 183-1S4°C (substance free of solvent)
Optical rotation £a720D: - 132,5 (C 0.2 CHC13) Solubility in water: 120 mg/1
Podophy11otoxin and its derivatives can be extracted from plant parte, especially roots or rhizomes, from various species of the genus Podophyllum, such as P. emodi Wall, and P. peltatum L. The compound also occurs in other plant species, for
I example of the genus Juniperue such as J. virginiana L.
In the preparation of highly pure podophy1lotoxin gf- its derivatives according to the invention, and finely ground rhizomes of e.g. Podophyllum emodi or Podophyllum peltatum are extracted e.g. with ethyl
through silica gel. The desired fraction of podophyllotoxin and derivatives thereof ie thereafter chromatographed on acid alumina and yields a fraction substantially containing the five lignanee deoxypodophy1lot-:<m, podophy 11 o t oxon e , ι a op i c r cpodophy 1 1 ι n e , podophyllotoxin and 4'-demethy1podophy11otoxin . Podophyllotoxin or another desired derivative is isolated from this mixture through a caref ukchrona tography on eilica gel, after which the desired fraction ie recrystal11zed .
Highly pure podophy11otoxin and its derivatives accordidng to the invention have been found to have a number of excellent pharmacological, effects and can be used against several diseases. In accordance with this, the present invention also comprises pharmacological preparations which are characterized in that they contain podophyllotoxin and/or its derivatives together w_ one vi- m.vi ? pharraco logical.\γ acceptable carrier ma t e r i a 1s.
As carrier materials all those materials can be used which are known to be useful in the preparation of pharmacological preparations, provided they do not react unfavourably with the active compound or exert some unsuitable effect together therewith. The pharmacological preparations can be made for enteral, parenteral or dermal administration and they can for example be in the form of solid preparations such as tablets, powder, capsules, suppositories or vagitoriss, more or lees semi-liquid preparations such as ointments, gels or creams, or liquid preparations such as solutions, susper- ·'c- or emulsions. They may also contain additional conventional additives and also other therapeutically active agents. It is within the knowledge of one skilled in the art to prepare a
BAD ORIGINAL
Quitable compoebtion when the way of administration and other conditions for the administration are known.
The dose uaed can be established by one skilled in the art starting from conventional criteria such as the Beriouanasa of the illness, the way of administration, the patient's age and condition, etc.
Podophy11 o t ox ι n and its derivatives according to the invention can be used for the treatment of a number of different diseases which can be summarized into the following groups. Non-restrιctive examples are given for each group.
1. Tropical diseases such as malaria and echizotomi a sis.
2. Skin diseases such as psoriasis, fungal infections and alopecia^areata.
3. Reactions of rejection at transplantations .
4. Collagenoees (connective tissue diseases) such <.’<= rha-jmilo id* i Afthi'i ti S , «Witsmic erythematosus dιaaeminatur, eclerodermy, polyartheritie nodosa and sarcoidosis.
5. Mental illness (caused by virue) such as demons and psychoses.
6. Neurological diseaees”euch as multiple sclerosis and myasthenia gravis.
The therapeutic effects on the diseases mentioned above are based on a number of acting mechanisms of podophy11otoxιn and its derivatives. Firstly, the compounds inhibit the activity of lymphatic T-cells (so-called killer cells) which is of importance to counteract reactions of rejection at transplantations. Furthermore, t' : - ·- «uounde counteract cell division in the metaphase which is of a great importance at certain skin diseases such as psoriatic states. The compounds have also a biocidal or biostatic effect against such
BAD ORIGINAL A microorganisms ar plaemodia, fungi and viruses, whereby a plurality of diseases caused by raicroorganisras as well as malaria can be treated. Finally, the compounds have also anthelmintic properties and can thus be used as agents again 31 helminths and other parasites.
Thus, in accordance with another aspect of the invention, it also comprises a method of treating states of illness caused by activity of the disease agents mentioned above and is characterized in that one or more of the compounds or a pharmacological preparation according to the invention is furnished to the organism attacked by the illness.
The organisms attacked by said illnesses may be humane or animals.
Podophyllotoxin and its derivatives according to the invention have been subjected to a number of pharmacological, toxicological and clinical investigations in ύΐα·ιΐ ij odto'ci'nh their thare.p-dutic nrooerhjes Thp results of these investigations are described in th6 foil owing .
Acute toxicity
The acute toxicity of podophyllotoxin has been determined on various test animals and by various ways of administration. The results appear from the following table 1.
AP 0 0 0 0 3 2
bad original
Acute toxicity
LD50 mg/kg
Table 1
Teel a η ϊ r. a 1
Way of Administration
| Rat | i . v . | 1 0 | |
| .'louse | 1 . v . | 20 | |
| Moua e | p. 0 . | 100 | |
| Ra t | derma 1 | 500 | |
| P. a b ϊ i t | derma 1 | 200 | |
| Effect acainst malaria | |||
| Th e | effect against malaria$wae | determined clini- | |
| ca1ly on | a number of patients which | had been | attacked |
| by the malaria parasite Plasmodium | foJ-C IPa.QjrS | . Podo- | |
| cfi » 1 1 1 ox | : n wa c a <Ίίη ·. n i s » m » <·«( in t | d · f f « r β π t | r) η n e » . |
the number of parasites in the patients was determined for each day and was noted as the number of asexual parasites per cubic millimeter of blood. The r β^άι 11 e appear from the foilwing table 2.
bad original
CSJ χ
Ο c· ο
ο
CL <
bad ORIGINAL s
Effect against reactions of immunity and rejection
Injection with a auapaneion of erythrocytes from aheep to mice causes formation of specific antibodies against this antigen. This reaction which normally is very strong requires u cooperation between different cell typos, substantially macrophages, T and B lymphocytes, and can easily be detected in the spleen of the test animal.;. This reaction can be inhibited in a dose-dopendent way by daily injections of podophyllotoxin after administration of erythrocytes.
A transplantation of skin to genetically different mice normally leads to a rejection within 10 days. It has been found in many cases that a markedly prolonged time of survival of 15 days and longer is obtained with animals treated with a compound according to the invention as compared with an untreated control group.
At investigations in vitro, it has also been found
,. . .'.,.'hy’lntnvin ’.nnibits the proliferation of cells caused by mitogenic lectins or cells from a non-related individual and also inhibits the development of cytotoxic cells. However, at markedly lower doses these effects increase. Other investigations show that cells treated with podophy1lotoxin could recover complete reactivity to these stimuli within 24 hours. Effect against psoriasis
A clinical investigation was carried out with totally 152 patients of an age between 19 and 71 years (mean value 46.1 years) afflicted with psoriasis vulgaris. The patients were divided into three groups of 50, 51 and 51 persons who were treated topically w’th » cream containing 0.1, 0.25 and 0.5 X of po phyllotoxin, reepectively. Each patient was treated only on a specific attacked area of the body while other attacked areas served as comparison. The severiBAD ORIGINAL ft ty of the attack wae judged at the etart of the treatment, and 2, 4, 8, 12 and 16 weeks after thia, no treatment being carried out during the laat period of 4 weeks. The investigation wae carried out with double blind technique and the results were treated statistically.
At all three dosage levels, statistically significant improvements (p<0.001) were obtained regarding the seventy of the treated lesione with associated symptoms. Ae early as after a treatment time of two weeks, there was a statistically significant difference (p<0.001) between treated and untreated lesions, and this difference increased in the course of the treatment. At the fifth control, 70-75 X of the patients were free from symptoms or had^only mild ones, while only two of the patients showed the corresponding improvements for the untreated lesions. In the follow- · > -> ί ’ - ' q.o'V- I 7 » Ο ιή f r> rio t a r i p rn t ] on ncf'j Td « * to the severity or symptoms of the treated lesions.
Only 11 of the patients reported any secondary effects such as rash. These secondary effects disappeared after interruption of the treatment. Differences between the three treated groups regarding the number of cases with secondary effects are not statistically significant (p
Claims (7)
1. A process for the preparation of a ccmpcund podophyllotcxin or derivative thereof characterized in that plant portions of Podophyllum species are extracted with ethly acetate and the extract is concentrated and filtered through silica gel, after which it is chrcmatographed on acid alumina and the main fraction is chrcmatographed on silica gel, and the desired product is thereafter recrystallized.
2. A pharmacological carposition characterized in that it contains a compound according to claim 1 togehter with one or more pharmacologically acceptable carries.
3. The use of podophyllotoxin or derivative thereof having the pharmacological composition for the treatment of diseases caused by an inadequate activity of lymphatic T-cells, by cell division in the rreta phase, by microorganisms such as plasmodia and fungi, and/or by helminths.
4. The use in accordance with claim, 3 wherein said disease is a reaction of immunity or rejection, such as at transplantation.
5. The use in accordance with claim 3, wherein said disease is peoriasis.
6. The use in accordance with claim 3, wherein said disease is malaria.
7. The use in accordance with claim 3, wherein said disease is a virus disease.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8406660 | 1984-12-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP8500017A0 AP8500017A0 (en) | 1985-11-01 |
| AP32A true AP32A (en) | 1988-12-07 |
Family
ID=20358339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1985/000017A AP32A (en) | 1984-12-28 | 1985-12-23 | Pharmaceutically active compounds and a method for its preparation |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4788216A (en) |
| EP (1) | EP0207124B1 (en) |
| JP (2) | JPH0720966B2 (en) |
| CN (1) | CN1006795B (en) |
| AP (1) | AP32A (en) |
| AT (1) | ATE68186T1 (en) |
| AU (1) | AU585936B2 (en) |
| CA (1) | CA1255230A (en) |
| DE (1) | DE3584370D1 (en) |
| DK (1) | DK169506B1 (en) |
| DZ (1) | DZ876A1 (en) |
| EG (1) | EG17788A (en) |
| ES (1) | ES8701761A1 (en) |
| FI (1) | FI89330C (en) |
| GR (1) | GR853145B (en) |
| HU (1) | HU201672B (en) |
| IL (1) | IL77456A (en) |
| MA (1) | MA20602A1 (en) |
| NO (1) | NO863329D0 (en) |
| PT (1) | PT81760B (en) |
| TN (1) | TNSN86004A1 (en) |
| WO (1) | WO1986004062A1 (en) |
| ZA (1) | ZA859881B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4644072A (en) * | 1985-04-12 | 1987-02-17 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
| DE69033342T2 (en) * | 1989-02-23 | 2000-05-11 | University Of North Carolina At Chapel Hill, Chapel Hill | ETOPOSIDE ANALOGS |
| SE464167B (en) | 1989-07-31 | 1991-03-18 | Analytecon Sa | TOPICAL PHARMACEUTICAL PREPARATION OF PODOPHYLLOTOXIN |
| US5332811A (en) * | 1989-09-12 | 1994-07-26 | The University Of North Carolina At Chapel Hill | Etopside analogs |
| US5338867A (en) * | 1992-04-24 | 1994-08-16 | Genelabs Technologies, Inc. | Preparation of 4β- amino podophyllotoxin compounds |
| SE9301831D0 (en) * | 1993-05-28 | 1993-05-28 | Analytecon S A | PHARMACEUTICAL COMPOSITIONS |
| GB9422947D0 (en) * | 1994-11-14 | 1995-01-04 | Univ Salamanca | Immunosuppressive cyclolignan derivatives |
| US6051721A (en) * | 1997-10-02 | 2000-04-18 | The Board Of Regents Of The University Of Nebraska | Ring E-modified analogues of(-)-podophyllotoxin and etoposide and a method for their synthesis |
| FI105152B (en) | 1998-07-17 | 2000-06-30 | Eero Saarela | Local pain relief procedure |
| US6143304A (en) * | 1999-08-17 | 2000-11-07 | The University Of Mississippi | Enhanced yield of podophyllotoxin from natural products through in situ conversion methods |
| KR20040030686A (en) * | 2001-06-19 | 2004-04-09 | 악셀라르 아베 | New use or cyclolignans and new cyclolignans |
| SE0102168D0 (en) | 2001-06-19 | 2001-06-19 | Karolinska Innovations Ab | New use and new compounds |
| SE0203746D0 (en) * | 2002-12-18 | 2002-12-18 | Karolinska Innovations Ab | New compounds |
| US20110178050A1 (en) * | 2008-06-23 | 2011-07-21 | Axelar Ab | Use of cyclolignans for the treatment of a hyperactive immune system |
| EP2817007A1 (en) * | 2012-02-24 | 2014-12-31 | Nestec S.A. | Peltatin for the treatment of chronic inflammatory disorders |
| WO2015028456A1 (en) * | 2013-08-28 | 2015-03-05 | Nestec S.A. | PPAR modulators |
| JOP20190254A1 (en) | 2017-04-27 | 2019-10-27 | Pharma Mar Sa | Antitumoral compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634459A (en) * | 1964-08-12 | 1972-01-11 | Sandoz Ltd | Epipodophyllotoxin derivatives |
| US4122092A (en) * | 1977-08-25 | 1978-10-24 | University Of Rochester | Total synthesis of (±)-picropodophyllone and (±)-4'-demethylpicropodophyllone |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA635769A (en) * | 1962-01-30 | Rutschmann Jurg | Amides of podophyllic acid and picropodophyllic acid | |
| US4567253A (en) * | 1984-02-03 | 1986-01-28 | Tony Durst | 2-Substituted derivatives of podophyllotoxin and etoposide |
| GB8424269D0 (en) * | 1984-09-26 | 1984-10-31 | Pharma Medica As | Isolation and purification of podophyllotoxin |
-
1985
- 1985-12-20 DE DE8686900345T patent/DE3584370D1/en not_active Expired - Fee Related
- 1985-12-20 JP JP61500490A patent/JPH0720966B2/en not_active Expired - Lifetime
- 1985-12-20 AT AT86900345T patent/ATE68186T1/en not_active IP Right Cessation
- 1985-12-20 EP EP86900345A patent/EP0207124B1/en not_active Expired - Lifetime
- 1985-12-20 AU AU53003/86A patent/AU585936B2/en not_active Ceased
- 1985-12-20 WO PCT/SE1985/000541 patent/WO1986004062A1/en active IP Right Grant
- 1985-12-20 US US06/908,801 patent/US4788216A/en not_active Expired - Lifetime
- 1985-12-20 HU HU86777D patent/HU201672B/en not_active IP Right Cessation
- 1985-12-23 AP APAP/P/1985/000017A patent/AP32A/en active
- 1985-12-24 CA CA000498645A patent/CA1255230A/en not_active Expired
- 1985-12-25 EG EG828/85A patent/EG17788A/en active
- 1985-12-26 MA MA20828A patent/MA20602A1/en unknown
- 1985-12-26 PT PT81760A patent/PT81760B/en not_active IP Right Cessation
- 1985-12-26 IL IL77456A patent/IL77456A/en unknown
- 1985-12-27 GR GR853145A patent/GR853145B/el not_active IP Right Cessation
- 1985-12-27 ES ES550504A patent/ES8701761A1/en not_active Expired
- 1985-12-27 CN CN85109666A patent/CN1006795B/en not_active Expired
- 1985-12-28 DZ DZ850275A patent/DZ876A1/en active
- 1985-12-30 ZA ZA859881A patent/ZA859881B/en unknown
-
1986
- 1986-01-09 TN TNTNSN86004A patent/TNSN86004A1/en unknown
- 1986-08-19 NO NO1986863329A patent/NO863329D0/en unknown
- 1986-08-27 FI FI863482A patent/FI89330C/en not_active IP Right Cessation
- 1986-08-27 DK DK408186A patent/DK169506B1/en not_active IP Right Cessation
-
1994
- 1994-10-14 JP JP6274258A patent/JP2572558B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634459A (en) * | 1964-08-12 | 1972-01-11 | Sandoz Ltd | Epipodophyllotoxin derivatives |
| US4122092A (en) * | 1977-08-25 | 1978-10-24 | University Of Rochester | Total synthesis of (±)-picropodophyllone and (±)-4'-demethylpicropodophyllone |
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