EP0525145A1 - Verfahren zur herstellung von ergolin-derivaten - Google Patents
Verfahren zur herstellung von ergolin-derivatenInfo
- Publication number
- EP0525145A1 EP0525145A1 EP19920903931 EP92903931A EP0525145A1 EP 0525145 A1 EP0525145 A1 EP 0525145A1 EP 19920903931 EP19920903931 EP 19920903931 EP 92903931 A EP92903931 A EP 92903931A EP 0525145 A1 EP0525145 A1 EP 0525145A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- general formula
- alkyl group
- meaning
- streptomyces
- 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.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
-
- 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/886—Streptomyces
Definitions
- the invention relates to a process for the preparation of ergoline derivatives of the general formula I.
- bonds ._ ___ j represent two single bonds or a double bond, and a bondschreib ⁇ .
- R. denotes a hydrogen atom or an alkyl group with 1-6 carbon atoms
- R symbolizes a hydrogen atom or an alkyl group with 1-6 carbon atoms
- R_ represents a carboxyl group or a grouping of the formula
- R in the meaning of hydrogen or an alkyl radical with 1-6 carbon atoms which may be substituted by a hydroxyl group, and R .. and R - in the meaning of a 1--.
- Alkyl group containing carbon atoms and Q represents an oxygen atom or sulfur atom, which is characterized in that an ergoline derivative of the general formula II
- R-, R_ have the meaning given above, with a
- the ergoline derivatives of the general formula I are known to be valuable intermediates, for example for the synthesis of the pharmacologically active ergoline derivatives of the general formula III
- R represents an alkyl radical having 2 to 6 carbon atoms, can be used (EP-B 0021206; EP-A 0351 352 and J. Med. Chem. Ü, 1985. 1252-1255).
- the process according to the invention makes it possible to carry out the ergoline derivatives of the general formula I in a much simpler manner and under much more environmentally friendly conditions than is possible using the conventional processes (J. Med. Chem., -21. 1985, 1252-1255 ).
- the process according to the invention is carried out under the same fermentation conditions which are also used in the known microbiological conversions of substrates with bacterial cultures.
- Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide, or aqueous mineral acids such as phosphoric acid or sulfuric acid.
- the Emulsification of the substrate can be effected, for example, by dissolving it in micronized form or in a water-miscible solvent (such as methanol, ethanol, acetone, glycol monoethyl ether, dimethylformamide or dimethylsulfox d) with strong turbulence in (preferably decalcified) water, which contains the usual emulsification aids.
- Suitable emulsification aids are nonionic emulsifiers, such as, for example, ethyleneoxy adducts or fatty acid esters of polyglycols.
- the commercially available wetting agents Tegin®, Tween® and Span® may be mentioned as examples of suitable emulsifiers.
- the optimal substrate concentration, substrate addition time and fermentation time depend on the type of substrate and microorganism used and the fermentation conditions. As is generally necessary in the case of microbiological substrate conversions, these variables must be determined in individual cases by preliminary tests as are known to the person skilled in the art.
- the stem forms reddish to purple substrate mycelium and whitish spores.
- the culture flask is incubated for 48 hours at 30 ° C and 180 revolutions per minute.
- the flask is inoculated with 50 ml of culture from the culture flask. Then 0.5 g of Lysergklarea id / Isolysergklareamid added and the flask incubated at 30 ° C and 180 revolutions per minute for 5 days.
- the culture broth is mixed with 500 ml of 2.1 Z NaOH and 23 Z NaCl and extracted with 1 1 chloroform.
- the chloroform phase is concentrated on a rotary evaporator and then fractionated on a silica gel column (volume 500 ml).
- Ethylene chloride: ethanol: diethylamine in a ratio of 75: 25: 0.1 is used as flow agent.
- the fractions containing the desired product are pooled, evaporated to dryness and precipitated with ethylene chloride. 0.25 g of 9, 10-didehydro-ergolinyl-8 ⁇ -carboxamide is obtained.
- the structure is confirmed by NMR and IR spectroscopy.
- the N-6 demethylation of lysergic acid amide / isolysergic acid amide is carried out with Streptomyces roseochromogenes IFO 3363.
- the cultivation, substrate production, fermentation and workup are carried out as indicated in Example 1.
- the yield is 0.3 g.
- N-6 demethylation of lisuride is carried out with Streptomyces purpurascens DSM 40310.
- the cultivation, fermentation and work-up are carried out as described in Example 1.
- N-6 demethylation of lisuride is carried out with Streptomyces roseochromogenes IFO 3363.
- the cultivation, fermentation and work-up are carried out as indicated in Example 1; substrate production is carried out as described in Example 4.
- the yield is 0.45 g.
- the N-6 demethylation of terguride is carried out with Streptomyces purpurascens DSM 40310.
- the cultivation, fermentation and workup are carried out as indicated in Example 1.
- To prepare the substrate 1 g of terguride is dissolved in 50 ml of 10% Ziger ⁇ PO ⁇ and sterile filtered.
- the N-6 demethylation of terguride is carried out with Streptomyces roseochromogenes IFO 3411.
- the cultivation, fermentation and work-up is carried out as indicated in Example 1; substrate production is carried out as described in Example 6.
- the yield is about 80% of theory.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4104379 | 1991-02-08 | ||
DE4104379 | 1991-02-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0525145A1 true EP0525145A1 (de) | 1993-02-03 |
Family
ID=6424967
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19920903931 Ceased EP0525145A1 (de) | 1991-02-08 | 1992-02-06 | Verfahren zur herstellung von ergolin-derivaten |
Country Status (10)
Country | Link |
---|---|
US (1) | US5371000A (de) |
EP (1) | EP0525145A1 (de) |
JP (1) | JPH05507722A (de) |
AU (1) | AU1226192A (de) |
CA (1) | CA2080119A1 (de) |
CZ (1) | CZ283099B6 (de) |
FI (1) | FI102546B1 (de) |
HU (1) | HU212766B (de) |
SK (1) | SK279827B6 (de) |
WO (1) | WO1992013857A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070243240A9 (en) * | 2000-08-24 | 2007-10-18 | Fred Windt-Hanke | Transdermal therapeutic system |
DE10053397A1 (de) * | 2000-10-20 | 2002-05-02 | Schering Ag | Verwendung eines dopaminergen Wirkstoffes zur Behandlung von dopaminerg behandelbaren Erkrankungen |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK338789A (da) * | 1988-07-15 | 1990-01-16 | Schering Ag | 2-substituerede ergolinylurinstofderivater og fremgangsmaade til fremstilling deraf, deres anvendelse som laegemidler samt mellemprodukter til fremstilling deraf |
-
1992
- 1992-02-06 EP EP19920903931 patent/EP0525145A1/de not_active Ceased
- 1992-02-06 AU AU12261/92A patent/AU1226192A/en not_active Abandoned
- 1992-02-06 WO PCT/DE1992/000088 patent/WO1992013857A1/de not_active Application Discontinuation
- 1992-02-06 US US07/930,692 patent/US5371000A/en not_active Expired - Fee Related
- 1992-02-06 CA CA002080119A patent/CA2080119A1/en not_active Abandoned
- 1992-02-06 JP JP92503914A patent/JPH05507722A/ja active Pending
- 1992-02-06 HU HU9203176A patent/HU212766B/hu not_active IP Right Cessation
- 1992-02-07 CZ CS92355A patent/CZ283099B6/cs not_active IP Right Cessation
- 1992-02-07 SK SK355-92A patent/SK279827B6/sk unknown
- 1992-10-06 FI FI924504A patent/FI102546B1/fi active
Non-Patent Citations (1)
Title |
---|
See references of WO9213857A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2080119A1 (en) | 1992-08-09 |
JPH05507722A (ja) | 1993-11-04 |
FI924504A0 (fi) | 1992-10-06 |
SK279827B6 (sk) | 1999-04-13 |
FI924504A (fi) | 1992-10-06 |
AU1226192A (en) | 1992-09-07 |
US5371000A (en) | 1994-12-06 |
CZ283099B6 (cs) | 1998-01-14 |
HU212766B (en) | 1996-11-28 |
CS35592A3 (en) | 1992-08-12 |
WO1992013857A1 (de) | 1992-08-20 |
FI102546B (fi) | 1998-12-31 |
HUT65671A (en) | 1994-07-28 |
FI102546B1 (fi) | 1998-12-31 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19920811 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: HAFFER, GREGOR, DR. Inventor name: NICKISCH, KLAUS, DR. Inventor name: WEBER, ALFRED, DR. Inventor name: KENNECKE, MARIO, DR. Inventor name: HUMMEL-MARQUARDT, HEIDI, DR. |
|
17Q | First examination report despatched |
Effective date: 19961115 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
18R | Application refused |
Effective date: 19990919 |