美国专利US20010001100A1 Process for the isolation of galanthamine

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专利摘要:
The subject matter of the present invention concerns a process for the isolation of the alkaloid galanthamine; the galanthamine itself which has been produced according to this process; the use of the galanthamine thus produced in galenic preparations; and the galanthamine thus produced for treating narrow-angle glaucoma, Alzheimer's disease, as well as alcohol and nicotine dependence.
公开号:US20010001100A1
申请号:US09/741,436
申请日:2000-12-21
公开日:2001-05-10
发明作者:Thomas Hille；Hans-Rainer Hoffmann；Mirko Kreh；Rudolf Matusch
申请人:Thomas Hille；Hans-Rainer Hoffmann；Mirko Kreh；Rudolf Matusch；
IPC主号:C07D491-04

专利说明:
[1] 1. The present invention relates to a process for isolating the alkaloid galanthamnine; the galanthamine itself which has been produced by this process; the use of galanthamine thus manufactured in galenic preparations; as well as to galanthamine thus produced for the treatment of narrow-angle glaucoma, Alzheimer's disease, as well as alcohol and nicotine dependence.
[2] 2. Galanthamine (4a, 5, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-6 H-benzofuro-(3a, 3, 2-ef) - (2) benzazepine-6-ol) is a tetracyclic alkaloid which, owing to its pharmacological properties, belongs to the group of reversibly acting cholinesterase inhibitors. Its effects are similar to those of physostigmine and neostigmine. However, it also has own specific properties, for example, highly analgesic effects comparable to those of morphine. As a cholinesterase inhibitor the therapeutic range of galanthamine is three to six times broader, since it is not as toxic as physostigmine and neostigmine. This advantage compensates for its slightly lower cholinesterase-inhibiting action, relative to dosage. Galanthamine is used in poliomyelitis and different diseases of the nervous system, but mainly in the treatment of narrow-angle glaucoma and as antidote after curare applications. The use of galanthamine in the treatment of Alzheimer's disease is in an experimental stage. Lately, the treatment of alcohol and nicotine dependence has also been described (DE-OS 40 10 079, DE-OS 43 01 782).
[3] 3. The therapy of Alzheimer's disease, alcohol and nicotine dependence, as well as that of narrow-angle glaucoma requires long-acting drug forms adapted to the particular circumstances. This could be an eye ointment in the treatment of narrow-angle glaucoma. In the treatment of Alzheimer's disease, alcohol or nicotine dependence, complicated therapeutic plans or prolonged infusions are unsuitable for obvious reasons. In these diseases, a transdermal therapeutic system (TTS) is a suitable form, for example that described in DE-OS 43 01 783. Neither the intact skin nor the cornea permit absorption of active substance salts. For this reason it is not possible to use galanthamine hydrobromide or galanthamine hydrochloride with ointments or a TTS in the therapy of narrow-angle glaucoma, Alzheimer's disease, or alcohol or nicotine dependence. The pure galanthamine base must therefore be used.
[4] 4. An economically efficient synthesis of galanthamine base is not possible because of its complicated tetracyclic structure with three optically active carbon atoms. For this reason, galanthamine is usually isolated from plants belonging to Amaryllidaceae, for example, from galanthus species, such as the snowdrop or Leucojum aestivum. These plants have the advantage of comprising galanthamine in concentrations of up to 0.3% with only small amounts of companion alkaloids so that the extraction method described in DE-PS 11 93 061 can be used. However, both the galanthus species and Leucojum aestivum are protected. On the other hand, the extraction method described in DE-PS 11 93 061 preferably uses chlorohydrocarbons which have fallen into discredit for toxicological reasons. The Pharmacopoeias of the Western World therefore call for a limitation of the residual chlorohydrocarbon content to <10 ppm. In the preparation of drugs chlorohydrocarbons should therefore be avoided as far as possible. Moreover, in the known process, the solvent extract must be adsorbed to alumina to ensure separation of the resinous substances and companion alkaloids. From the solution obtained after filtering off the alumina, the galanthamine is then purified by galanthamine hydrobromide; this involves disposal of halogen salts. For the use in ointments or in a TTS, the galanthamine base must then additionally be liberated from this galanthamine hydrobromide.
[5] 5. It is accordingly the object of the present invention to provide a process for the isolation and purification of galanthamine, which does not have the drawbacks of the prior art processes. In particular, purification is to be facilitated, the use of chlorohydrocarbons and purification by means of galanthamine salts are to be avoided. The object is achieved according to the present invention by a process having the characterizing Features of claim 1. Preferred embodiments are characterized in the subclaims.
[6] 6. In detail, the subject matter of the present invention is a process for the isolation of galanthamine from biological material which is recovered from agriculturally cultivated amaryllidacea species or from those which are commonly regarded as “weeds” and are not protected, preferably from the bulbs of these plants. These amaryllidaceae include, for example, narcissi or crinum species. Particularly suitable are Narcissus pseudonarcissus “Carlton” or the Asian climber Crinum amabile. Although these plants only have a tenth of the galanthamine amount contained in the protected plants, and, moreover, have up to twelve companion alkaloids, the process according to the present invention surprisingly makes it possible to isolate galanthamine base therefrom with a purity suitable for the use in drugs.
[7] 7. According to the present invention galanthamine-containing, biological material, which is preferably communicated and mixed with alkali powder, preferably with sodium hydroxide pellets, soda, potash, or similar salts suitable to liberate bases from biological material and to prepare pharmacological active substances, is extracted with toxicologically safe organic solvents, and the galanthamine from this extract is purified by means of liquid-liquid extraction. It is particularly important for the success of the process according to the present invention to maintain the pH-value in the first stage of the liquid-liquid extraction. The liquid-liquid extraction is carried out in a first stage at a pH of about 4, and in a second stage at a pH of about 9. In addition to concentrated ammonia, soda solution of another base may be used to adjust the pH-value. Diethyl ether or special boiling-point gasoline is used as toxicologically safe organic solvent. Special boiling-point gasoline is preferably used, with it a certain preliminary purification can be achieved. The solvent is removed; galanthamine is recrystallized from a suitable solvent, preferably from isopropanol. The white galanthamine base having a melting point of 129 to 130° C. is obtained. The purity of the galanthamine thus obtained is shown in the HPLC-chromatogram (FIG. 2).
[8] 8. This result is very amazing since the process according to DE-PS 11 93 061 used so far was found to be unsuitable to isolate galanthamine from biological material containing small amounts of galanthamine and up to 12 companion alkaloids. The process described in DE-PS 11 93 061 results in an emulsion which cannot be broken so that an extraction is rendered impossible. A slightly modified process resulted in an oily residue which, according to HPLC-chromatogram (FIG. 1), is contaminated by at least four substances.
[9] 9. It must therefore be regarded as a particular surprise that the free galanthamine base can be isolated in pure form and good yield from biological material comprising small amounts of galanthamine in addition to a large number of companion alkaloids by means of the simple process according to the present invention, without having to carry out any additional adsorption step to aluminum oxide.
[10] 10. The galanthamine base produced according to the present invention may be used for the treatment of narrow-angle glaucoma, Alzheimer's disease, or alcohol and nicotine dependence. In addition, the galanthamine base produced according to the present invention may be used in galenic preparations, such as ophthalmic ointments or transdermal therapeutic systems, which may also be used to treat the above-mentioned diseases.
[11] 11. The present invention is more particularly described in the examples that follow, which are intended to illustrate, but not to limit, the present invention: EXAMPLE 1
[12] 12. (Comparison):
[13] 13. In accordance with the process described in DE-PS 11 93 061, 10 kg air-dried, communicated bulbs of Narcissus pseudonarcissus “Carlton” is carefully mixed with 2.5 l of a 8% aqueous ammonia solution. The material swells; the whole batch pastes up. The addition of 23 l dichloroethane intended for extraction results in an emulsion which cannot be b.,token. EXAMPLE 2
[14] 14. (Comparison):
[15] 15. The process for the isolation of galanthamine known in the art (DE-PS 11 93 061) is modified. 10 kg air-dried, communicated bulbs of Narcissus pseudonarcissus “Carlton” is carefully mixed with 400 g sodium carbonate. 23 l dichloroethane is added. The mixture is allowed to stand for 10 hours; then the solvent is decanted. The bulbs are once again doused with 23 l dichloroethane which is decanted after 2 to 3 hours. After that, 17 l dichloroethane is added to the bulks for the third time; however, this is decanted immediately. The mixed dichloroethane extracts are extracted by means of 10% sulfuric acid (2×600 ml each; 2×300 ml each). The acidic extracts are mixed and purified from traces of dichloroethane by means of shaking out with diethyl ether. Under stirring and cooling to 15 to 20° C., about 200 ml of a 25% aqueous ammonia solution is then added up to alkaline litmus reaction. The pH is in the range of 7 to 8. Different from the indications in the art, the companion alkaloids do not precipitate. The alkaline solution is saturated with salt and extracted with diethyl ether. After evaporation of the ether, a negligible residue remains, which is also different from the indications in the art. The pH-value of the aqueous phase is set to about 14 by saturating it with potash. The aqueous phase is repeatedly extracted with diethyl ether. The mixed ether extracts are evaporated to dryness, the remaining galanthamine-containing residue is dissolved in acetone (50 ml). In contrast to the art, there is no precipitate. 350 ml acetone is replenished, 200 g aluminum oxide is added, and stirring is effected for 45 minutes. The aluminum oxide is filtered off and washed twice with 100 ml acetone each time. The mixed acetone solutions are evaporated to dryness. 1.3 g of an oily residue is obtained which is examined by means of HPLC. The chromatogram is shown in FIG. 1. The main peak, the galanthamine, is marked. It is clearly visible that the galanthamine thus isolated is contaminated by at least four substances. EXAMPLE 3
[16] 16. 100 kg air-dried, communicated bulbs of Narcissus pseudonarcissus “Carlton” is carefully mixed with 4 kg of sodium carbonate. The mixture is divided into three equal parts, and each is doused with 15 l special boiling-point gasoline 80/110. The mixtures are allowed to stand for 24 hours. The solvents are each renewed twice, collected, and evaporated to dryness in low vacuum. The extracts are placed in 2% aqueous sulfuric acid and adjusted to a pH of 4 with concentrated aqueous ammonia solution. Five extractions with diethyl ether follow. The aqueous phase is set to a pH of 9 with concentrated ammonia and extracted five times with diethyl ether. These ether fractions are collected, dried with sodium sulfate, and evaporated. 20 g of a slightly yellow, oily residue is obtained, which is recrystallized from hot isopropanol. 10 g of white galanthamine base having a melting point of 129-130° C. is obtained. Only one pealing is visible in the HPLC chromatogram (FIG. 2).

权利要求:
Claims (26)
[1" id="US-20010001100-A1-CLM-00001] 1. A process for the isolation of galanthamine characterized in that galanthamine-containing, biological material is extracted with toxicologically safe organic solvents and that the galanthamine from this extract is purified by means of liquid-liquid extraction, said liquid-liquid extraction being carried out in the first stage at a pH-value of about 4.
[2" id="US-20010001100-A1-CLM-00002] 2. The process according to
claim 1 characterized in that the biological material is communicated and mixed with alkali powder prior to the extraction.
[3" id="US-20010001100-A1-CLM-00003] 3. The process according to any one of claims 1 or 2 characterized in that the liquid-liquid extraction in carried out in the second stage at a pH-value of about 9.
[4" id="US-20010001100-A1-CLM-00004] 4. The process according to any one of
claims 1 to
3 characterized in that sodium carbonate is used as alkali powder.
[5" id="US-20010001100-A1-CLM-00005] 5. The process according to any one of
claims 1 to
4 characterized in that diethyl ether or special boiling-point gasoline is used as toxicologically safe organic solvent, special boiling-point gasoline being preferred.
[6" id="US-20010001100-A1-CLM-00006] 6. The process according to any one of
claims 1 to
5 characterized in that the obtained galanthamine is recrystallized from a suitable solvent.
[7" id="US-20010001100-A1-CLM-00007] 7. The process according to
claim 6 characterized in that Isopropanol is used as solvent.
[8" id="US-20010001100-A1-CLM-00008] 8. The process according parts of amaryllidaceae, are used as biological material.
[9" id="US-20010001100-A1-CLM-00009] 9. The process according to
claim 8 characterized in that bulbs are used as plant parts.
[10" id="US-20010001100-A1-CLM-00010] 10. The process according to any one of
claims 1 to
9 characterized in that narcissi species or crinum species are used as amaryllidaceae.
[11" id="US-20010001100-A1-CLM-00011] 11. The process according to
claim 10 characterized in that as narcissi species narcicissus pseudonarcissus “Carlton”, or as crinum species Crinum amabile are used.
[12" id="US-20010001100-A1-CLM-00012] 12. Galanthamine in pharmaceutical quality with a purity of ≧99%, produced according to a process in accordance with any one of
claims 1 to
11 .
[13" id="US-20010001100-A1-CLM-00013] 13. Galenic administration forms characterized by a content of galanthamine in accordance with
claim 12 .
[14" id="US-20010001100-A1-CLM-00014] 14. The use of the galanthiamine according to
claim 12 for the production of ophthalmic ointments.
[15" id="US-20010001100-A1-CLM-00015] 15. The use of the galanthamine according to
claim 12 for the production of transdermal therapeutic systems.
[16" id="US-20010001100-A1-CLM-00016] 16. The use of the galanthamine according to
claim 12 for the production of a drug for the treatment of narrow-angle glaucoma.
[17" id="US-20010001100-A1-CLM-00017] 17. The use of the galanthamine according to
claim 12 for the production of a drug for the treatment of Alzheimer's disease.
[18" id="US-20010001100-A1-CLM-00018] 18. The use of the galanthamine according to
claim 12 for the production of a drug for the treatment of alcohol dependence.
[19" id="US-20010001100-A1-CLM-00019] 19. The use of the galanthamine according to
claim 12 for the production of a drug for the treatment of nicotine dependence.
[20" id="US-20010001100-A1-CLM-00020] 20. A pharmaceutical preparation characterized in that it comprises galanthamine according to
claim 12 in addition to pharmaceutical adjuvants known per se.
[21" id="US-20010001100-A1-CLM-00021] 21. The pharmaceutical preparation according to
claim 20 for topical application.
[22" id="US-20010001100-A1-CLM-00022] 22. The pharmaceutical preparation according to
claim 20 or
21 for the treatment of narrow-angle glaucoma.
[23" id="US-20010001100-A1-CLM-00023] 23. The pharmaceutical preparation according to
claim 20 or
21 for the treatment of Alzheimer's disease.
[24" id="US-20010001100-A1-CLM-00024] 24. The pharmaceutical preparation according to
claim 20 or
21 for the treatment of alcohol dependence.
[25" id="US-20010001100-A1-CLM-00025] 25. The pharmaceutical preparation according to
claim 20 or
21 for the treatment of nicotine dependence.
[26" id="US-20010001100-A1-CLM-00026] 26. A process for the therapeutic treatment of the human organism characterized in that galanthamine according to
claim 12 or a pharmaceutical preparation according to any one of claims 20 or 21 is used.

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同族专利:

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DK1095656T3|2003-12-08|

CA2215351C|2005-01-11|

AU5108896A|1996-10-08|

JPH11505519A|1999-05-21|

KR100427093B1|2004-07-31|

PT815112E|2002-01-30|

CZ283597A3|1997-12-17|

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EP1095656A2|2001-05-02|

IL117371D0|1996-07-23|

EP1095656A3|2001-05-16|

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DK0815112T3|2001-11-12|

CZ294722B6|2005-03-16|

US20020028802A1|2002-03-07|

NO316380B1|2004-01-19|

AU707203B2|1999-07-08|

SK283861B6|2004-03-02|

DE59610680D1|2003-09-25|

IL117371A|2000-01-31|

US20030012831A1|2003-01-16|

NZ304008A|1998-09-24|

US6617452B2|2003-09-09|

WO1996029332A1|1996-09-26|

EP0815112B1|2001-08-08|

NO974119D0|1997-09-08|

JP3863180B2|2006-12-27|

CA2215351A1|1996-09-26|

EP0815112A1|1998-01-07|

DE59607450D1|2001-09-13|

US6335328B2|2002-01-01|

CN1088460C|2002-07-31|

PT1095656E|2004-01-30|

EP1095656B1|2003-08-20|

ZA962140B|1996-09-16|

SK123597A3|1998-02-04|

CN1178533A|1998-04-08|

PL322463A1|1998-02-02|

HU9802234A3|2000-03-28|

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法律状态:
2001-12-13| STCF| Information on status: patent grant|Free format text: PATENTED CASE |

2005-06-27| FPAY| Fee payment|Year of fee payment: 4 |

2009-06-26| FPAY| Fee payment|Year of fee payment: 8 |

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优先权:

申请号 | 申请日 | 专利标题

DE19509663A|DE19509663A1|1995-03-17|1995-03-17|Process for the isolation of galanthamine|

DE19509663||1995-03-17||

DE19509663.0||1995-03-17||

US08/913,461|US5877172A|1995-03-17|1996-03-14|Process for isolating galanthamine|

US09/130,883|US6194404B1|1995-03-17|1998-08-07|Process for the isolation of galanthamine|

US09/741,436|US6335328B2|1995-03-17|2000-12-21|Process for the isolation of galanthamine|US09/741,436| US6335328B2|1995-03-17|2000-12-21|Process for the isolation of galanthamine|

US09/986,792| US6573376B2|1995-03-17|2001-11-09|Process for the isolation of galanthamine|

US10/241,585| US6617452B2|1995-03-17|2002-09-12|Process for the isolation of galanthamine|

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