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
- Authority
- AP
- ARIPO
- Prior art keywords
- disease
- accordance
- preparation
- pharmacological
- treatment
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 5
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 11
- 230000000144 pharmacologic effect Effects 0.000 claims description 9
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 claims description 9
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 8
- 229960001237 podophyllotoxin Drugs 0.000 claims description 8
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 claims description 8
- 201000004792 malaria Diseases 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000002054 transplantation Methods 0.000 claims description 5
- 241000196324 Embryophyta Species 0.000 claims description 4
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 3
- 241001495452 Podophyllum Species 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 241000700605 Viruses Species 0.000 claims description 3
- 230000032823 cell division Effects 0.000 claims description 3
- 230000036039 immunity Effects 0.000 claims description 3
- 230000001926 lymphatic effect Effects 0.000 claims description 3
- 244000005700 microbiome Species 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 244000000013 helminth Species 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 1
- 239000008196 pharmacological composition Substances 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 7
- 238000011835 investigation Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000009291 secondary effect Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- HSSDVCMYTACNSM-UHFFFAOYSA-N 5-hydroxy-9-(3,4,5-trimethoxyphenyl)-6h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC(C=2C3=CC=4OCOC=4C=C3C(O)=C3COC(=O)C3=2)=C1 HSSDVCMYTACNSM-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 244000221860 Podophyllum emodi Species 0.000 description 2
- 244000236480 Podophyllum peltatum Species 0.000 description 2
- 241000534944 Thia Species 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000002599 biostatic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000031864 metaphase Effects 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 241000894007 species Species 0.000 description 2
- ZGLXUQQMLLIKAN-CAYVGHNUSA-N (5s,5as,8as)-5-(3,4,5-trimethoxyphenyl)-5a,8,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-6-one Chemical compound COC1=C(OC)C(OC)=CC([C@H]2C3=CC=4OCOC=4C=C3C[C@H]3[C@H]2C(OC3)=O)=C1 ZGLXUQQMLLIKAN-CAYVGHNUSA-N 0.000 description 1
- ZGLXUQQMLLIKAN-UHFFFAOYSA-N Deoxypicropodophyllin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3CC3C2C(OC3)=O)=C1 ZGLXUQQMLLIKAN-UHFFFAOYSA-N 0.000 description 1
- 241000045500 Diseae Species 0.000 description 1
- 241000755710 Eilica Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- -1 P. emodi Wall Chemical compound 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 235000010169 Podophyllum emodi Nutrition 0.000 description 1
- 235000008562 Podophyllum peltatum Nutrition 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 244000004774 Sabina virginiana Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Virology (AREA)
- Transplantation (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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (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) | NO863329L (en) |
| PT (1) | PT81760B (en) |
| TN (1) | TNSN86004A1 (en) |
| WO (1) | WO1986004062A1 (en) |
| ZA (1) | ZA859881B (en) |
Families Citing this family (18)
| 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 |
| AU632796B2 (en) * | 1989-02-23 | 1993-01-14 | University Of North Carolina At Chapel Hill, The | Etoposide analogues |
| 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 |
| DE60233601D1 (en) * | 2001-06-19 | 2009-10-15 | Axelar Ab | Use of certain 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 |
| CN102083431A (en) * | 2008-06-23 | 2011-06-01 | 阿克塞拉公司 | Use of cyclolignans for the treatment of a hyperactive immune system |
| WO2013124380A1 (en) * | 2012-02-24 | 2013-08-29 | 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 |
| KR20210142152A (en) * | 2019-03-22 | 2021-11-24 | 인티그레이티드 나노테라퓨틱스 아이엔씨. | Lipid Conjugates Prepared from Scaffold Moieties |
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 AU AU53003/86A patent/AU585936B2/en not_active Ceased
- 1985-12-20 AT AT86900345T patent/ATE68186T1/en not_active IP Right Cessation
- 1985-12-20 DE DE8686900345T patent/DE3584370D1/en not_active Expired - Fee Related
- 1985-12-20 WO PCT/SE1985/000541 patent/WO1986004062A1/en not_active Ceased
- 1985-12-20 HU HU86777D patent/HU201672B/en not_active IP Right Cessation
- 1985-12-20 US US06/908,801 patent/US4788216A/en not_active Expired - Lifetime
- 1985-12-20 JP JP61500490A patent/JPH0720966B2/en not_active Expired - Lifetime
- 1985-12-20 EP EP86900345A patent/EP0207124B1/en not_active Expired - Lifetime
- 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 IL IL77456A patent/IL77456A/en unknown
- 1985-12-26 PT PT81760A patent/PT81760B/en not_active IP Right Cessation
- 1985-12-26 MA MA20828A patent/MA20602A1/en unknown
- 1985-12-27 GR GR853145A patent/GR853145B/el not_active IP Right Cessation
- 1985-12-27 CN CN85109666A patent/CN1006795B/en not_active Expired
- 1985-12-27 ES ES550504A patent/ES8701761A1/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 NO863329A patent/NO863329L/en unknown
- 1986-08-27 DK DK408186A patent/DK169506B1/en not_active IP Right Cessation
- 1986-08-27 FI FI863482A patent/FI89330C/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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