CA1327359C - Prostaglandin el derivatives as pharmacologically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration - Google Patents
Prostaglandin el derivatives as pharmacologically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administrationInfo
- Publication number
- CA1327359C CA1327359C CA000559004A CA559004A CA1327359C CA 1327359 C CA1327359 C CA 1327359C CA 000559004 A CA000559004 A CA 000559004A CA 559004 A CA559004 A CA 559004A CA 1327359 C CA1327359 C CA 1327359C
- Authority
- CA
- Canada
- Prior art keywords
- prostaglandin
- general formula
- treatment
- derivatives
- ulcers
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 title abstract description 12
- 239000013543 active substance Substances 0.000 title abstract description 8
- 150000003180 prostaglandins Chemical class 0.000 title description 8
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 4
- 206010065929 Cardiovascular insufficiency Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 206010061459 Gastrointestinal ulcer Diseases 0.000 claims description 5
- 206010018852 Haematoma Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 230000003779 hair growth Effects 0.000 claims description 5
- 201000001881 impotence Diseases 0.000 claims description 5
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 5
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 230000001771 impaired effect Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 4
- 238000002054 transplantation Methods 0.000 claims description 4
- 231100000397 ulcer Toxicity 0.000 claims description 4
- 239000000499 gel Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000011505 plaster Substances 0.000 claims description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 4
- 210000000056 organ Anatomy 0.000 claims 3
- 208000035475 disorder Diseases 0.000 claims 2
- 230000005764 inhibitory process Effects 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 229960000711 alprostadil Drugs 0.000 description 10
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 9
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- ROUDCKODIMKLNO-CTBSXBMHSA-N 6-oxoprostaglandin E1 Chemical class CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(O)=O ROUDCKODIMKLNO-CTBSXBMHSA-N 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- 206010040943 Skin Ulcer Diseases 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- LVDCZROIKIHUKJ-QZCLESEGSA-N ethyl 7-[(1r,2r,3r)-3-hydroxy-2-[(e,3s)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OCC LVDCZROIKIHUKJ-QZCLESEGSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- -1 tubes Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 206010060964 Arterial haemorrhage Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011340 continuous therapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- QLPYHQHJKMTHED-UHFFFAOYSA-N prostaglandin E1 methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(=O)OC QLPYHQHJKMTHED-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract:
The invention describes prostaglandin E1 derivatives as pharmacologically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration. The derivatives have the general formula:
The invention describes prostaglandin E1 derivatives as pharmacologically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration. The derivatives have the general formula:
Description
132735~
"Prostaglandin El Derivatives as Pharmacologically Active Agents, and Pharmaceutical Compositions Containing These Compounds, E~pecially ~or Transcutaneous Administration"
BACKGROUND OF THE INVENTION
The invention relates to prostaglandin E1 derivatives (PGE1 derivatives) as pharmacologically active agents and to pharmaceutical compositions - especially for transcutaneous application - which contain a PGEl derivative.
DE-A-27 53 986 published on July 6, 1978 to Upjohn Company and the corresponding US-A-4,205,178 issued on May 27, 1980 assigned to upjohn Company disclose 6-keto prostaglandin E1 derivatives, especially the 6-keto PGE1 methyl ester.
- A number of biological and pharmacological effects are described for these compounds. Various routes of administration are indicated for the various kinds of illnesses to be treated, e.g. oral, intravenous, subcutaneous, intra-arterial, buccal, rectal and intra-vaginal administration. Topical administration is described in connection with skin injuries or skin diseases at or near the site of the injury or disease.
A
13273~9 6-keto prostaglandin El derivatives are also described in DE-A-28 40 032 published on March 29, 1979 to Ono Pharmaceutical Company, in which the authors also refer to various fo:rms of pharmacological activity and administration.
Prostaglandin E1 (PGEl) and 6-keto prostaglandin El (6-k PGE1) can be used for the treatment of several diseases. These diseases include peripheral occlusive diseases, complications in arteriosclerosis such as Meniere's disease or acute loss o~
hearing, acute myocardial infarctation, unstable angina pectoris, acute ischaemic strokes, impotence, bronchial asthma, impaired hair growth and rejection following kidney transplants; see H.
Sinzinger and W. Rogatti, Prostaglandin El in atherosclerosis, Springer Verlag Berlin - Heidelberg - New York, 1986 S. Schrey, PGE1, Therapie der arteriellen VerschluBkrankheit, Universitatsdruckerei and Verlag Dr. C~ Wolf und Sohn, Munich, ; 1985. PGEl is used for the treatment of chronic arterial occlusive diseases in phase III and IV. This condition calls for intra-arterial or intravenous infusion which results in a severe limitation in the use of PGEl, as the infusion iq not~only a strain on the patient, but also involves a certain risk o~
arterial haemorrhage. Neither route of administration (i.a. and i.v.) is suitable for continuous therapy in ambulatory patient care. However, long-term administration would be most appropriate for these diseases. The oral administration of PGEl is always problematic as either the very low bio-availability rule~ out such administration, or the typical undesired effects (nauRea, vomiting, diarrhoea) are prohibitive due to the high concentration of the drug in the gastrointestinal track when orally a~ministered.
SUMMARY OF_THE INVENTION
The object underlying the invention is to provide P&E1 and PGE1 derivatives as pharmaceutical compositions or pharma-cologically active agents. The PGE1 derivatives, which ( 13273~9 were especially developed as pharmacologically active agents ; for transcutaneous adminstration, are absorbed by the skin and subsequently split by hydrolases into prostaglandin E1 or 6-keto PGBl and alcohol. The PGEl derivatives thus fulfill the . requirements of the "Pro-Drug" concept and avoid the ; disadvantages of PGEl and 6-keto PGE1 when adminstered arterially, intravenously or orally.
` The subject matter of the invention is therefore prosta-glandin E1 derivatives of the general formula I
.~,, O Rl ,~~ COOR2 tI) ' ~
HO O'H
in which R1 is a hydrogen atom and R2 is a Cl_4 alkyl residue, ~;~ as pharmacologically active agents.
i A further subject matter of the invention is a pharmaceu-tical composition containing a prostaglandin E1 derivative ac-~; cording to formula I.
,.:
~' Still a further subject matter of the invention is the use of prostaglandin El derivatives of general formula I, O Rl ,~ ~,~~ COOR2 ` ~ (I~
HO
in which R1 is a hydrogen atom (PGE1) or a carbonyl oxygenatom (6-k-PGE1) and R2 is a C1_4 alkyl residue for the preparation of a pharmaceutical composition to be administered transcutaneously.
` 13273~9 BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 shows the absorption rate of PGE1 and PGEl ethyl -ester which has been determined as the cumulative urinary excretion following transcutaneous administration.
DETAILED DESCRI TION
' Specific examples of alkyl residues are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl group.
Due to the non-toxicity of the fragments, the preferred group R2 is the ethyl group.
-The preparation of the compounds of general formula I is carried out according to methods known per se via esterifica-tion of PGEl and 6-k PGEl. The methyl and ethyl ester, for in-stance, are pr~pared by reacting the same with diazomethane or diazoethane; also see Ch. J. Sih et al., J. Am. Chem. Soc., Vol. 97 (1975), pp. 857 to 865.
;
The compounds of general formula I can be used to treat circulatory insufficiencies, for instance of the brain, the heart and the extremities, to inhibit platelet aggregation (~hrombocyte aggregation), impotence and to treat allergic reactions such as bronchial asthma, rejection following transplantations and impaired hair growth. Typical examples of deficiencies in the cerebral blood supply are transitory cerebral ischaemia, acute loss of hearing, vertigo cauæed by circulatory insufficiencies and ischaemic strokes. Typical examples of deficiencies in the myocardial blood supply are angina pectoris and myocardial infarction. Typical examples of deficiencies in the blood supply of the extremities are 1~73~
periphal arterial circulatory insufficiencies in arteriosclerosis and Raynaud's disease and Raynaud's syndrom.
., The compounds of general formula I can also be used to treat gastrointestinal ulcers and ulcers o~ the skin. Typical examples of gastrointestinal ulcers are ulcus ventriculi, duo-denal ulcers and ulcerative colitis (Crohn's disease). A typi-cal example of a skin ulcer is ulcus cruris. The compounds of general formula I have a cyto-protective effect. The cells ex-hibit increased resistance to noxious stimuli.
The compounds of general formula I can further be used to treat haematomas, especially surface haematomas.
In addition to transcutaneous administration, the com-pounds of general formula I can also be administered by inhalation, intravenously and intra-arterially and in each case incorporated into microsomes.
The preparation of pharmaceutical compositions is carried out according to conventional methods. For the preparation of pharmaceutical compositions to be administered transcu-taneously, the compounds of general formula I can be mixed with a gel, ointment or liquid vehicle either with or without various solvents and stabilizers. The packages used are sprays, tubes, ampules and individual doses. Once applied to the skin either with or without an additional occlusive dressing, the active agent is absorbed.
The compounds of general formula I can also be placed either with or without stabilizers and solvents onto a plaster and can then be applied as such.
The conversion of the ethyl ester to PGEl in the human body was demonstrated in the following way: an isotopically labelled P&El e~hyl ester was applied in the manner described abo~e. The isotopically labelled urinary metabolites were 13273~9 .
separated with HPLC and compared with the retention time of the main metabolite of PGEl (7~-hydroxy-5,11-diketo-tetranorprosta-1,20-dioic acid). It was found that after administration of the PGEl ethyl ester, the main metabolite was identical to the main meta~olite after administration of PGE1. This proves that the PGE1 ethyl ester is a pro-drug of PGE1.
The following examples illustrate the invention.
E X A M P L E
The preparation of prostaglandin El ethylester.
Excess diazoethane in diethyl ether ~17 mg/ml; 0.3 mmol) is added to 500 ~g PGEl (1.31 ~mol) in 500 ~1 ethanol under stirring and cooling. The reaction mixture is taken out of the cooler and is stirred until it reaches room temperature.
Stirring is then continued for a further 30 minutes. The excess diazoethane and the ethanol are removed at room temperature by a stream of nitrogen. The product is purified by high-pressure liquid chromatography (RP 18).
In the same manner and with excess diazoethane, 500 ~g of 6-keto PGEl in 500 ~1 of ethanol are reacted and processed in diethyl ether. The ester is purified by high-pressure liquid chromatography (RP 18).
~ X A ~ P L E 2 250 ~g of prostaglandin El ethyl ester together with an isotopically labelled PGEl-ethyl-ester in 250 ~1 of ethanol were worked into 2 g of a gel vehicle of the composition as indicated below. The gel was applied to the upper arm and 1327~9 rubbed in for 1 minute. The application area was covered with a plastic foil.
.~
.~One week later, 250 ~g of prostaglandin El together with an isotopically labelled PGEl in 250 ~1 of ethanol were mixed with 2 g of a gel vehicle of the composition as indicated below. It, too, was applied to the upper arm and rubbbed in for 1 minute.
Measurement of the absorbed quantity was carried out by determining the isotopically labelled prostaglandin metabolites in the urine. For this, the total urine was -collected in portions from the beginning of the application onwards. Four hours after the application, the plastic film was removed and the excess gel wiped off. As can be seen in Fig. 1, the absorption rate of PGE1 ethyl ester (23 %) was clearly better than that of PGE1 (approx. 4 ~).
:.
The gel vehicle was prepared according to the following recipe:
;
Isopropanol 40.0 g Diisopropyl adipate0.5 g Carbopol ~40 2.0 g j Trometamol 1.91 g ~ Purified waterad 100.0 g `~The isopropanol can also be exchanged for ethanol.
The water, alcohol and diisopropyl adipate are mixed, the carbopol is dispersed in this mixture and left to swell. The gel is neutralized with the aqueous trometamol-solution.
"Prostaglandin El Derivatives as Pharmacologically Active Agents, and Pharmaceutical Compositions Containing These Compounds, E~pecially ~or Transcutaneous Administration"
BACKGROUND OF THE INVENTION
The invention relates to prostaglandin E1 derivatives (PGE1 derivatives) as pharmacologically active agents and to pharmaceutical compositions - especially for transcutaneous application - which contain a PGEl derivative.
DE-A-27 53 986 published on July 6, 1978 to Upjohn Company and the corresponding US-A-4,205,178 issued on May 27, 1980 assigned to upjohn Company disclose 6-keto prostaglandin E1 derivatives, especially the 6-keto PGE1 methyl ester.
- A number of biological and pharmacological effects are described for these compounds. Various routes of administration are indicated for the various kinds of illnesses to be treated, e.g. oral, intravenous, subcutaneous, intra-arterial, buccal, rectal and intra-vaginal administration. Topical administration is described in connection with skin injuries or skin diseases at or near the site of the injury or disease.
A
13273~9 6-keto prostaglandin El derivatives are also described in DE-A-28 40 032 published on March 29, 1979 to Ono Pharmaceutical Company, in which the authors also refer to various fo:rms of pharmacological activity and administration.
Prostaglandin E1 (PGEl) and 6-keto prostaglandin El (6-k PGE1) can be used for the treatment of several diseases. These diseases include peripheral occlusive diseases, complications in arteriosclerosis such as Meniere's disease or acute loss o~
hearing, acute myocardial infarctation, unstable angina pectoris, acute ischaemic strokes, impotence, bronchial asthma, impaired hair growth and rejection following kidney transplants; see H.
Sinzinger and W. Rogatti, Prostaglandin El in atherosclerosis, Springer Verlag Berlin - Heidelberg - New York, 1986 S. Schrey, PGE1, Therapie der arteriellen VerschluBkrankheit, Universitatsdruckerei and Verlag Dr. C~ Wolf und Sohn, Munich, ; 1985. PGEl is used for the treatment of chronic arterial occlusive diseases in phase III and IV. This condition calls for intra-arterial or intravenous infusion which results in a severe limitation in the use of PGEl, as the infusion iq not~only a strain on the patient, but also involves a certain risk o~
arterial haemorrhage. Neither route of administration (i.a. and i.v.) is suitable for continuous therapy in ambulatory patient care. However, long-term administration would be most appropriate for these diseases. The oral administration of PGEl is always problematic as either the very low bio-availability rule~ out such administration, or the typical undesired effects (nauRea, vomiting, diarrhoea) are prohibitive due to the high concentration of the drug in the gastrointestinal track when orally a~ministered.
SUMMARY OF_THE INVENTION
The object underlying the invention is to provide P&E1 and PGE1 derivatives as pharmaceutical compositions or pharma-cologically active agents. The PGE1 derivatives, which ( 13273~9 were especially developed as pharmacologically active agents ; for transcutaneous adminstration, are absorbed by the skin and subsequently split by hydrolases into prostaglandin E1 or 6-keto PGBl and alcohol. The PGEl derivatives thus fulfill the . requirements of the "Pro-Drug" concept and avoid the ; disadvantages of PGEl and 6-keto PGE1 when adminstered arterially, intravenously or orally.
` The subject matter of the invention is therefore prosta-glandin E1 derivatives of the general formula I
.~,, O Rl ,~~ COOR2 tI) ' ~
HO O'H
in which R1 is a hydrogen atom and R2 is a Cl_4 alkyl residue, ~;~ as pharmacologically active agents.
i A further subject matter of the invention is a pharmaceu-tical composition containing a prostaglandin E1 derivative ac-~; cording to formula I.
,.:
~' Still a further subject matter of the invention is the use of prostaglandin El derivatives of general formula I, O Rl ,~ ~,~~ COOR2 ` ~ (I~
HO
in which R1 is a hydrogen atom (PGE1) or a carbonyl oxygenatom (6-k-PGE1) and R2 is a C1_4 alkyl residue for the preparation of a pharmaceutical composition to be administered transcutaneously.
` 13273~9 BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 shows the absorption rate of PGE1 and PGEl ethyl -ester which has been determined as the cumulative urinary excretion following transcutaneous administration.
DETAILED DESCRI TION
' Specific examples of alkyl residues are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl group.
Due to the non-toxicity of the fragments, the preferred group R2 is the ethyl group.
-The preparation of the compounds of general formula I is carried out according to methods known per se via esterifica-tion of PGEl and 6-k PGEl. The methyl and ethyl ester, for in-stance, are pr~pared by reacting the same with diazomethane or diazoethane; also see Ch. J. Sih et al., J. Am. Chem. Soc., Vol. 97 (1975), pp. 857 to 865.
;
The compounds of general formula I can be used to treat circulatory insufficiencies, for instance of the brain, the heart and the extremities, to inhibit platelet aggregation (~hrombocyte aggregation), impotence and to treat allergic reactions such as bronchial asthma, rejection following transplantations and impaired hair growth. Typical examples of deficiencies in the cerebral blood supply are transitory cerebral ischaemia, acute loss of hearing, vertigo cauæed by circulatory insufficiencies and ischaemic strokes. Typical examples of deficiencies in the myocardial blood supply are angina pectoris and myocardial infarction. Typical examples of deficiencies in the blood supply of the extremities are 1~73~
periphal arterial circulatory insufficiencies in arteriosclerosis and Raynaud's disease and Raynaud's syndrom.
., The compounds of general formula I can also be used to treat gastrointestinal ulcers and ulcers o~ the skin. Typical examples of gastrointestinal ulcers are ulcus ventriculi, duo-denal ulcers and ulcerative colitis (Crohn's disease). A typi-cal example of a skin ulcer is ulcus cruris. The compounds of general formula I have a cyto-protective effect. The cells ex-hibit increased resistance to noxious stimuli.
The compounds of general formula I can further be used to treat haematomas, especially surface haematomas.
In addition to transcutaneous administration, the com-pounds of general formula I can also be administered by inhalation, intravenously and intra-arterially and in each case incorporated into microsomes.
The preparation of pharmaceutical compositions is carried out according to conventional methods. For the preparation of pharmaceutical compositions to be administered transcu-taneously, the compounds of general formula I can be mixed with a gel, ointment or liquid vehicle either with or without various solvents and stabilizers. The packages used are sprays, tubes, ampules and individual doses. Once applied to the skin either with or without an additional occlusive dressing, the active agent is absorbed.
The compounds of general formula I can also be placed either with or without stabilizers and solvents onto a plaster and can then be applied as such.
The conversion of the ethyl ester to PGEl in the human body was demonstrated in the following way: an isotopically labelled P&El e~hyl ester was applied in the manner described abo~e. The isotopically labelled urinary metabolites were 13273~9 .
separated with HPLC and compared with the retention time of the main metabolite of PGEl (7~-hydroxy-5,11-diketo-tetranorprosta-1,20-dioic acid). It was found that after administration of the PGEl ethyl ester, the main metabolite was identical to the main meta~olite after administration of PGE1. This proves that the PGE1 ethyl ester is a pro-drug of PGE1.
The following examples illustrate the invention.
E X A M P L E
The preparation of prostaglandin El ethylester.
Excess diazoethane in diethyl ether ~17 mg/ml; 0.3 mmol) is added to 500 ~g PGEl (1.31 ~mol) in 500 ~1 ethanol under stirring and cooling. The reaction mixture is taken out of the cooler and is stirred until it reaches room temperature.
Stirring is then continued for a further 30 minutes. The excess diazoethane and the ethanol are removed at room temperature by a stream of nitrogen. The product is purified by high-pressure liquid chromatography (RP 18).
In the same manner and with excess diazoethane, 500 ~g of 6-keto PGEl in 500 ~1 of ethanol are reacted and processed in diethyl ether. The ester is purified by high-pressure liquid chromatography (RP 18).
~ X A ~ P L E 2 250 ~g of prostaglandin El ethyl ester together with an isotopically labelled PGEl-ethyl-ester in 250 ~1 of ethanol were worked into 2 g of a gel vehicle of the composition as indicated below. The gel was applied to the upper arm and 1327~9 rubbed in for 1 minute. The application area was covered with a plastic foil.
.~
.~One week later, 250 ~g of prostaglandin El together with an isotopically labelled PGEl in 250 ~1 of ethanol were mixed with 2 g of a gel vehicle of the composition as indicated below. It, too, was applied to the upper arm and rubbbed in for 1 minute.
Measurement of the absorbed quantity was carried out by determining the isotopically labelled prostaglandin metabolites in the urine. For this, the total urine was -collected in portions from the beginning of the application onwards. Four hours after the application, the plastic film was removed and the excess gel wiped off. As can be seen in Fig. 1, the absorption rate of PGE1 ethyl ester (23 %) was clearly better than that of PGE1 (approx. 4 ~).
:.
The gel vehicle was prepared according to the following recipe:
;
Isopropanol 40.0 g Diisopropyl adipate0.5 g Carbopol ~40 2.0 g j Trometamol 1.91 g ~ Purified waterad 100.0 g `~The isopropanol can also be exchanged for ethanol.
The water, alcohol and diisopropyl adipate are mixed, the carbopol is dispersed in this mixture and left to swell. The gel is neutralized with the aqueous trometamol-solution.
Claims (13)
1. A transdermal pharmaceutical composition comprising:
prostaglandin E1 derivative of general formula I, (I) in which R1 is hydrogen, or R1 and the hydrogen atom gem thereto are replaced by a carbonyl oxygen atom, and R2 is a C1-4 alkyl residue; and, wherein said derivative is present in a transdermally deliverable amount in combination with a transdermally effective carrier.
prostaglandin E1 derivative of general formula I, (I) in which R1 is hydrogen, or R1 and the hydrogen atom gem thereto are replaced by a carbonyl oxygen atom, and R2 is a C1-4 alkyl residue; and, wherein said derivative is present in a transdermally deliverable amount in combination with a transdermally effective carrier.
2. The transdermal pharmaceutical composition of claim 1 wherein R2 is an ethyl group.
3. The composition of claim 1 wherein the transdermally effective carrier comprises a substance selected from the group consisting of gels, ointments and liquid vehicles.
4. The composition of Claim 1 wherein the transdermally effective carrier comprises plaster.
5. The composition of claim 1 for the treatment of circulatory insufficiencies.
6. Use of prostaglandin E1 derivatives of general formula I, (I) in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2 is a C1-4 alkyl residue, for the preparation of a pharma-ceutical composition to be administered transcutaneously.
7. The use according to claim 6, wherein R2 is an ethyl group.
8. The use according to claim 6 or 7, wherein the pharmaceutical composition is for the treatment of circulatory insufficiencies, of impotence, for the inhibition of platelet aggregation, for the treatment of bronchial asthma, of gastrointestinal ulcers and ulcers of the skin, of haematomas, of impaired hair growth or of rejections following transplantations of an organ.
9. The use of prostaglandin E1 derivatives of general formula I, (I) in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2 is a C1-4 alkyl residue, for the treatment of a disorder by transcutaneous application, said disorder being selected from the group consisting of circulatory insufficiencies, impotence, platelet aggregation, bronchial asthma, gastrointestinal ulcers, ulcers of the skin, haematomas, impair hair growth and rejection following transplantation or an organ.
10. The use according to claim 9 wherein R2 is an ethyl group.
11. Process for the preparation of a pharmaceutical composition for transcutaneous administration containing a prostaglandin E1 derivative of general formula I
(I) in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2 is a C14 alkyl residue, characterized in that a prostaglandin E1 derivative of general formula I is combined with a carrier substance or adjuvant suitable for transcutaneous administration.
(I) in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2 is a C14 alkyl residue, characterized in that a prostaglandin E1 derivative of general formula I is combined with a carrier substance or adjuvant suitable for transcutaneous administration.
12. A process according to claim 11, wherein R2 is the ethyl group.
13. A process according to claim 11 or 12, wherein the pharmaceutical composition for transcutaneous administration is determined for the treatment of circulatory insufficiencies, of impotence, for the inhibition of platelet aggregation, for the treatment of bronchial asthma, of gastrointestinal ulcers and ulcers of the skin, of haematomas, of impaired hair growth or of rejections following transplantations of an organ.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3704825.2 | 1987-02-16 | ||
| DE19873704825 DE3704825A1 (en) | 1987-02-16 | 1987-02-16 | PROSTAGLANDIN E1 DERIVATIVES AS PHARMACEUTICAL ACTIVE SUBSTANCES AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, IN PARTICULAR FOR TRANSCUTANEAL USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1327359C true CA1327359C (en) | 1994-03-01 |
Family
ID=6321070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000559004A Expired - Fee Related CA1327359C (en) | 1987-02-16 | 1988-02-16 | Prostaglandin el derivatives as pharmacologically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0292643B1 (en) |
| JP (1) | JPS63246331A (en) |
| AT (1) | ATE80616T1 (en) |
| AU (2) | AU623336B2 (en) |
| CA (1) | CA1327359C (en) |
| DE (2) | DE3704825A1 (en) |
| DK (1) | DK173552B1 (en) |
| ES (1) | ES2043696T3 (en) |
| GR (1) | GR3005743T3 (en) |
| HU (1) | HU199687B (en) |
| ZA (1) | ZA881053B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2939569A (en) * | 1957-10-16 | 1960-06-07 | Gay W Roach | Cotton weighing machine |
| AU674054B2 (en) * | 1993-02-03 | 1996-12-05 | Teijin Limited | Dermatologic preparation composition containing isocarbacyclin as active ingredient |
| SG66248A1 (en) * | 1993-02-03 | 1999-07-20 | Teijin Ltd | External skin treatment agent composition containing prostacyclins as active ingredient |
| US6007836A (en) * | 1993-05-28 | 1999-12-28 | Vericade, Inc. | Transdermal vasodilator |
| FR2812191B1 (en) * | 2000-07-28 | 2003-10-17 | Oreal | USE OF PROSTAGLANDIN E2 RECEPTOR AGONISTS (EP-3) TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS |
| FR2812193B1 (en) * | 2000-07-28 | 2003-10-24 | Oreal | USE OF AN ANTAGONIST OF PROSTAGLANDIN EP-2 AND / OR EP-4 RECEPTORS TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS |
| FR2812190B1 (en) * | 2000-07-28 | 2003-01-31 | Oreal | USE OF NON-PROSTANOIC AGONISTS OF EP-2 AND / OR EP-4 PROSTAGLANDIN RECEPTORS AS A COSMETIC AGENT FOR MITIGATING, DECREASING OR STOPPING HAIR AND HAIR LOSS |
| FR2812192B1 (en) * | 2000-07-28 | 2003-01-31 | Oreal | USE OF PROSTAGLANDIN EP-3 RECEPTOR ANTAGONISTS AS A COSMETIC AGENT FOR MITIGATING, REDUCING OR STOPPING HAIR AND HAIR LOSS |
| KR20050119187A (en) * | 2003-04-02 | 2005-12-20 | 넥스메드 홀딩스 인코포레이티드 | Prostaglandin compositions and their use for the treatment of vasospasm |
| IT1402047B1 (en) * | 2010-10-19 | 2013-08-28 | Cross Pharma Sa | USE OF MEXIPROSTIL IN THE TREATMENT OF INTESTINAL INFLAMMATORY DISEASES |
| US8940794B2 (en) | 2011-04-07 | 2015-01-27 | Nexmed Holdings, Inc. | Methods and compositions for treating Raynaud's disease |
| US10383839B2 (en) * | 2011-06-30 | 2019-08-20 | Johnson & Johnson Vision Care, Inc. | Esters for treatment of ocular inflammatory conditions |
| ITRM20120036A1 (en) * | 2012-02-02 | 2013-08-03 | Robert Davis Steigerwalt Jr | TRANSDERMAL APPLICATION OF PROSTAGLANDINE E1 FOR THE TREATMENT OF OCULAR ISCHEMIA. |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3735005A (en) * | 1970-08-19 | 1973-05-22 | Alza Corp | Method for preparing a viable platelet concentrate |
| AU511711B2 (en) * | 1976-12-30 | 1980-09-04 | Upjohn Company, The | 6-Oxo and 5, 6-Dihalo prostaglandin analogues |
| US4205178A (en) * | 1976-12-30 | 1980-05-27 | The Upjohn Company | 6-Keto prostaglandin E-type compounds |
| JPS6022710B2 (en) * | 1977-09-16 | 1985-06-03 | 小野薬品工業株式会社 | Prostaglandin-like compounds |
| JPS59216820A (en) * | 1983-05-20 | 1984-12-06 | Taisho Pharmaceut Co Ltd | Fat emulsion of prostaglandin |
| US4707495A (en) * | 1985-10-28 | 1987-11-17 | Ortho Pharmaceutical | Peptic ulcer treatment method |
-
1987
- 1987-02-16 DE DE19873704825 patent/DE3704825A1/en not_active Withdrawn
-
1988
- 1988-02-15 ES ES88102189T patent/ES2043696T3/en not_active Expired - Lifetime
- 1988-02-15 DK DK198800775A patent/DK173552B1/en not_active IP Right Cessation
- 1988-02-15 AT AT88102189T patent/ATE80616T1/en not_active IP Right Cessation
- 1988-02-15 JP JP63032571A patent/JPS63246331A/en active Pending
- 1988-02-15 DE DE88102189T patent/DE3874610D1/de not_active Expired - Lifetime
- 1988-02-15 EP EP88102189A patent/EP0292643B1/en not_active Expired - Lifetime
- 1988-02-16 AU AU11766/88A patent/AU623336B2/en not_active Ceased
- 1988-02-16 HU HU88742A patent/HU199687B/en not_active IP Right Cessation
- 1988-02-16 ZA ZA881053A patent/ZA881053B/en unknown
- 1988-02-16 CA CA000559004A patent/CA1327359C/en not_active Expired - Fee Related
-
1992
- 1992-04-24 AU AU15184/92A patent/AU649130B2/en not_active Ceased
- 1992-09-17 GR GR920402069T patent/GR3005743T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR3005743T3 (en) | 1993-06-07 |
| AU1176688A (en) | 1988-08-18 |
| AU623336B2 (en) | 1992-05-14 |
| DE3704825A1 (en) | 1988-08-25 |
| HU199687B (en) | 1990-03-28 |
| ES2043696T3 (en) | 1994-01-01 |
| DK77588D0 (en) | 1988-02-15 |
| DK173552B1 (en) | 2001-02-26 |
| DK77588A (en) | 1988-08-17 |
| DE3874610D1 (en) | 1992-10-22 |
| HUT46224A (en) | 1988-10-28 |
| ZA881053B (en) | 1988-08-12 |
| EP0292643B1 (en) | 1992-09-16 |
| AU649130B2 (en) | 1994-05-12 |
| EP0292643A1 (en) | 1988-11-30 |
| ATE80616T1 (en) | 1992-10-15 |
| AU1518492A (en) | 1992-06-25 |
| JPS63246331A (en) | 1988-10-13 |
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