CA1245589A - Indanyl derivatives and process for their preparation - Google Patents
Indanyl derivatives and process for their preparationInfo
- Publication number
- CA1245589A CA1245589A CA000468691A CA468691A CA1245589A CA 1245589 A CA1245589 A CA 1245589A CA 000468691 A CA000468691 A CA 000468691A CA 468691 A CA468691 A CA 468691A CA 1245589 A CA1245589 A CA 1245589A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- indanyl
- compounds
- hydrogen
- chlorine
- 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
Links
Classifications
-
- 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
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/14—Fungi; Culture media therefor
- C12N1/145—Fungal isolates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
- C12R2001/66—Aspergillus
- C12R2001/685—Aspergillus niger
Abstract
ABSTRACT OF THE DISCLOSURE Indanyl compounds of the formula wherein R1 and R2 are hydrogen, fluorine or chlorine, is useful in the treatment of inflammatory and allergic diseases are prepared by fermenting indanyl compounds of the formula with a culture of Aspergillus niger or Polyporus tulipiferus.
Description
~z~s~9 `
INDAN~L D~KIVATIVE~ AND PROCESS FOR
lrH EIR PREPARAT10~
Backqround of the Invention This invention relates to novel pharmacologically active hydroxylated indanyl compounds, to a process for preparing such compounds and to pharmaceutical compositions containing those compounds.
Summary of the Invention In its process aspect, the present invention is a process for the preparation of indanyl compounds of the ~ormula l! R ~ ~
CH~50~NH
OH
wherein Rl and R2, independently chosen, are hydrogen fluorine, or chlorine, which comprises fermenting under aerobic conditions an indanyl derivative of the formula . O
F~ 2~3--D,~f />
.,~ CH~50 ., ,, ~Z~558~
in the presence of Asperaill~s ni~_r or Poly __us_ tulipiferus in a me~ium containin~ assimilable sources of carbon and nitrogen.
In another aspect, the present invention is the compounds there~y produced and pharmaceutical compositions containing those compounds.
Detailed Discussion The process of the invention is conducted under the conditions customarily employed in the microbiological hydroxylation of substrates with fungal cultures. First, the most favorable fermentation conditions are analytically determined, especially by means of thin-layer chromato-graphy, such as, for example, selection of the most advantageous nutrient medium, the suitable substrate solvent or suspension agent, the substrate concentration, the technical conditions, such as temperature, aeration, pH
value, and the optimum times for germination, substrate addition, and substrate contact on the enzyme of the microorganism.
It was found in this connection that it is advantageous !'~' to utilize concentrations of about 100 to 2,000 mg of substrate per liter of nutrient medium. The pH is preferably adjusted to a value in the range from 5 to 7.
The cultivation temperature lies in the range from 20 to 25 40 C, preferably 25-35C. For aeration, 0.5-5 liters of air is preferably supplied per minute per liter of culture broth. The conversion of the substrate is suitable monitored by analyses of sample extracts.
The Asper~illus niqer and PolYporus tulipiferus microorganisms utilized for the fermentation are readily available from conventional sources such as depositories, university collections, etc.
, . .
55~
Preferred strains are Asperqillus ni~ ATCC 10577 and NRRL 3228, and Polyporus tulipif~rus css 43148.
After ~erlnentation has taken place, the pro~ucts of fermentation are isolated by conventional means. Isolation can be accomplished, for example, by extracting the fermentation batches with a water-immiscible organic solv~nt, such as ethyl acetate, butyl acetate or methyl isobutyl ketone, concentrating the extracts, and purifying the resultant crude product optionally by chromatography and/or crystallization.
The compounds of this invention exhibit qood antiphlogistic activity. They also exhibit activity as analgesics, antidysmenorrheics, antipyretics, thrombocyte-aggregation-inhibitors and diuretics. It is noteworthy that these compounds having little eff~ct in inhibiting prostaglandin synthesis. A further advantage of these compounds is the large margin between therapeutic efficacy and undesirable side effects, particularly ulcerogenesis.
Consequently, the novel comounds of the present invention, in combination with the excipients usually employed in galenic pharmacy, are suitable for the treatment of a wide array of rheumatic type diseases, such as rheumatoid arthritis, osteo-arthritis and ankylosing spondylitis. They are also suitable for the treatment of bronchial asthma, hay fever, migraine and dysmenorrhea, and reduce the risk of thrombosis.
Certain of the indanyl compounds of the invention, surprisingly additionally exhibit pronounced antiulcerogenic and tumor-inhibiting activity.
Pharmaceutical dosage composition containing these compounds are produced in the usual way by blending the active compounds with suitable additives, excipients, and flavoring agents into the desired forms of administration, . . .
,.
~LZ~55~
sucll as tablets, dragees, capsules, solutions, inhalants, etc. Especially suitable for oral administration are tablets, dragees, and capsules which contain, ~or example, 1-250 mg of active compound and 50 mg to 2 mg of a pharmacologically inert carrier, such as, for example, lactose, amylose, talc, gelatin, magnesium stearate, and similar materials, as well as the usual additives.
The starting compounds for the process of this invention are known or can be prepared in a manner known per se.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
~1:
55~
Example 1 A 2-liter Erlen~neyer flask filled with 500 ml o~ a sterile, aqueous nutrient solution containing 3.0~ glucose 1.0~ corn steep liquor 0.2% sodium nitrate 0.1% potassium dihydrogen phosphate 0.2~ dipotassium hydrogen phosphate 0.05~ magnesium sulfate heptahydrate 0.002% iron (II) sulfate heptahydrate 0.05~ potassium chloride is inoculated with an agar slant of the strain Asperqillus niqer ATCC 10577 or ~2_rqillus n ger NRRL 3228 and shaken for 60 hours at 28C.
The contents o the flask are then transferred under sterile conditions into a 20-liter preliminary fermentor charged with 15 liters of the same nutrient solution. With the addition of silicone SH as a defrother, germination is effected at 29C and a pressure of 0.7 bar (over atmospheric) with aeration (15 liters per minute) and agitation t220 rpm) for a period of 24 hours.
' Thereafter, 0.9 liter of its contents is withdrawn from the preliminary fermentor under sterile conditions and used to inoculate a 20-liter main fermentor containing 14 liters of the nutrient medium described above~ After an incubating phase of 12 hours under preliminary fermentor conditions, a sterile solution of 3.0 g of N-[l-oxo-6-phenoxyindan-5-yl]methanesulfonamide in 60 ml of dimethylformamide is added thereto, and fermentation is carried out under the above indicated conditions for 48 hours.
The culture broth is then extracted twice with 10 liter portions of methyl isobutyl ketone, the extract ;., ~2~5~9 concentrated ~n~er vac~um, and the resid~e chro~atogr~phed over a silica ~el column by means o- dichlorornethane-acetone gradients. On recrystalli~ation ~rom acetone-diisopropyl ether, there is obtained 1.74 q of ~-[1-oxo-3~-hydroxy-6-phenoxyindan-5-yl]-methanesul~on~mide, mp 148-15~C.
Example 2 Using the conditions of Example 1 and using the microorganism Polyporus tulipiferus CBS 43148, 3.0 g of N-[l-oxo-6(2,4-difluorophenoxy)indan-5-yl]methanesulfonamide is hydroxylated for a period of 46 hours. After working up the reaction mixture and purifying the cruide product by column chromatography on silica gel, 0.96 g of ~-[1-oxo-3~-hydroxy-6-(2,4-difluorophenoxy)indan-5-yl]methanesulfon-amide is obtained in the form of a colorless oil whichcrystllizes after standing for several days in a refrigerator; mp 83-86C.
.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
,,
INDAN~L D~KIVATIVE~ AND PROCESS FOR
lrH EIR PREPARAT10~
Backqround of the Invention This invention relates to novel pharmacologically active hydroxylated indanyl compounds, to a process for preparing such compounds and to pharmaceutical compositions containing those compounds.
Summary of the Invention In its process aspect, the present invention is a process for the preparation of indanyl compounds of the ~ormula l! R ~ ~
CH~50~NH
OH
wherein Rl and R2, independently chosen, are hydrogen fluorine, or chlorine, which comprises fermenting under aerobic conditions an indanyl derivative of the formula . O
F~ 2~3--D,~f />
.,~ CH~50 ., ,, ~Z~558~
in the presence of Asperaill~s ni~_r or Poly __us_ tulipiferus in a me~ium containin~ assimilable sources of carbon and nitrogen.
In another aspect, the present invention is the compounds there~y produced and pharmaceutical compositions containing those compounds.
Detailed Discussion The process of the invention is conducted under the conditions customarily employed in the microbiological hydroxylation of substrates with fungal cultures. First, the most favorable fermentation conditions are analytically determined, especially by means of thin-layer chromato-graphy, such as, for example, selection of the most advantageous nutrient medium, the suitable substrate solvent or suspension agent, the substrate concentration, the technical conditions, such as temperature, aeration, pH
value, and the optimum times for germination, substrate addition, and substrate contact on the enzyme of the microorganism.
It was found in this connection that it is advantageous !'~' to utilize concentrations of about 100 to 2,000 mg of substrate per liter of nutrient medium. The pH is preferably adjusted to a value in the range from 5 to 7.
The cultivation temperature lies in the range from 20 to 25 40 C, preferably 25-35C. For aeration, 0.5-5 liters of air is preferably supplied per minute per liter of culture broth. The conversion of the substrate is suitable monitored by analyses of sample extracts.
The Asper~illus niqer and PolYporus tulipiferus microorganisms utilized for the fermentation are readily available from conventional sources such as depositories, university collections, etc.
, . .
55~
Preferred strains are Asperqillus ni~ ATCC 10577 and NRRL 3228, and Polyporus tulipif~rus css 43148.
After ~erlnentation has taken place, the pro~ucts of fermentation are isolated by conventional means. Isolation can be accomplished, for example, by extracting the fermentation batches with a water-immiscible organic solv~nt, such as ethyl acetate, butyl acetate or methyl isobutyl ketone, concentrating the extracts, and purifying the resultant crude product optionally by chromatography and/or crystallization.
The compounds of this invention exhibit qood antiphlogistic activity. They also exhibit activity as analgesics, antidysmenorrheics, antipyretics, thrombocyte-aggregation-inhibitors and diuretics. It is noteworthy that these compounds having little eff~ct in inhibiting prostaglandin synthesis. A further advantage of these compounds is the large margin between therapeutic efficacy and undesirable side effects, particularly ulcerogenesis.
Consequently, the novel comounds of the present invention, in combination with the excipients usually employed in galenic pharmacy, are suitable for the treatment of a wide array of rheumatic type diseases, such as rheumatoid arthritis, osteo-arthritis and ankylosing spondylitis. They are also suitable for the treatment of bronchial asthma, hay fever, migraine and dysmenorrhea, and reduce the risk of thrombosis.
Certain of the indanyl compounds of the invention, surprisingly additionally exhibit pronounced antiulcerogenic and tumor-inhibiting activity.
Pharmaceutical dosage composition containing these compounds are produced in the usual way by blending the active compounds with suitable additives, excipients, and flavoring agents into the desired forms of administration, . . .
,.
~LZ~55~
sucll as tablets, dragees, capsules, solutions, inhalants, etc. Especially suitable for oral administration are tablets, dragees, and capsules which contain, ~or example, 1-250 mg of active compound and 50 mg to 2 mg of a pharmacologically inert carrier, such as, for example, lactose, amylose, talc, gelatin, magnesium stearate, and similar materials, as well as the usual additives.
The starting compounds for the process of this invention are known or can be prepared in a manner known per se.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
~1:
55~
Example 1 A 2-liter Erlen~neyer flask filled with 500 ml o~ a sterile, aqueous nutrient solution containing 3.0~ glucose 1.0~ corn steep liquor 0.2% sodium nitrate 0.1% potassium dihydrogen phosphate 0.2~ dipotassium hydrogen phosphate 0.05~ magnesium sulfate heptahydrate 0.002% iron (II) sulfate heptahydrate 0.05~ potassium chloride is inoculated with an agar slant of the strain Asperqillus niqer ATCC 10577 or ~2_rqillus n ger NRRL 3228 and shaken for 60 hours at 28C.
The contents o the flask are then transferred under sterile conditions into a 20-liter preliminary fermentor charged with 15 liters of the same nutrient solution. With the addition of silicone SH as a defrother, germination is effected at 29C and a pressure of 0.7 bar (over atmospheric) with aeration (15 liters per minute) and agitation t220 rpm) for a period of 24 hours.
' Thereafter, 0.9 liter of its contents is withdrawn from the preliminary fermentor under sterile conditions and used to inoculate a 20-liter main fermentor containing 14 liters of the nutrient medium described above~ After an incubating phase of 12 hours under preliminary fermentor conditions, a sterile solution of 3.0 g of N-[l-oxo-6-phenoxyindan-5-yl]methanesulfonamide in 60 ml of dimethylformamide is added thereto, and fermentation is carried out under the above indicated conditions for 48 hours.
The culture broth is then extracted twice with 10 liter portions of methyl isobutyl ketone, the extract ;., ~2~5~9 concentrated ~n~er vac~um, and the resid~e chro~atogr~phed over a silica ~el column by means o- dichlorornethane-acetone gradients. On recrystalli~ation ~rom acetone-diisopropyl ether, there is obtained 1.74 q of ~-[1-oxo-3~-hydroxy-6-phenoxyindan-5-yl]-methanesul~on~mide, mp 148-15~C.
Example 2 Using the conditions of Example 1 and using the microorganism Polyporus tulipiferus CBS 43148, 3.0 g of N-[l-oxo-6(2,4-difluorophenoxy)indan-5-yl]methanesulfonamide is hydroxylated for a period of 46 hours. After working up the reaction mixture and purifying the cruide product by column chromatography on silica gel, 0.96 g of ~-[1-oxo-3~-hydroxy-6-(2,4-difluorophenoxy)indan-5-yl]methanesulfon-amide is obtained in the form of a colorless oil whichcrystllizes after standing for several days in a refrigerator; mp 83-86C.
.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
,,
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula wherein R1 and R2, independently chosen, are hydrogen, fluorine or chlorine.
2. N-[1-oxo-3.beta.-hydroxy-6-phynoxyindan-5-yl]methane-sulfonamide, a compound according to claim 1.
3. N-[1-oxo-3.beta.-hydroxy-6-(2,4-difluorophynoxy)indan-5-yl]methanesulfonamide, a compound according to claim 1.
4. A process for the preparation of indanyl compounds of the formula wherein R1 and R2, independently chosen, are hydrogen, fluorine, chlorine, which comprises fermenting under aerobic conditions an indanyl derivative of the formula in the presence of Aspergillus niger or Polyporus tulipiferus in a medium containing assimilable sources of carbon and nitrogen.
5. A composition comprising an indanyl derivative of the formula wherein R1 and R2, independently chosen are hydrogen, fluorine or chlorine, and a pharmaceutically acceptable carrier therefor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3343331.3 | 1983-11-28 | ||
| DE19833343331 DE3343331A1 (en) | 1983-11-28 | 1983-11-28 | METHOD FOR PRODUCING INDANYL DERIVATIVES AND THE USE THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1245589A true CA1245589A (en) | 1988-11-29 |
Family
ID=6215683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000468691A Expired CA1245589A (en) | 1983-11-28 | 1984-11-27 | Indanyl derivatives and process for their preparation |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4696948A (en) |
| EP (1) | EP0143403B1 (en) |
| JP (1) | JPS60199394A (en) |
| AT (1) | ATE62511T1 (en) |
| AU (1) | AU568701B2 (en) |
| CA (1) | CA1245589A (en) |
| CS (1) | CS244844B2 (en) |
| DD (1) | DD229153A5 (en) |
| DE (2) | DE3343331A1 (en) |
| DK (1) | DK561484A (en) |
| ES (1) | ES8600736A1 (en) |
| FI (1) | FI77893C (en) |
| GR (1) | GR81056B (en) |
| HU (1) | HU193238B (en) |
| IL (1) | IL73657A (en) |
| NO (1) | NO164845C (en) |
| PT (1) | PT79556B (en) |
| ZA (1) | ZA849287B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0753725B2 (en) * | 1987-10-08 | 1995-06-07 | 富山化学工業株式会社 | 4H-1-benzopyran-4-one derivative and its salt, their production method and anti-inflammatory agent containing them |
| US5409944A (en) * | 1993-03-12 | 1995-04-25 | Merck Frosst Canada, Inc. | Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase |
| US5500359A (en) * | 1993-09-27 | 1996-03-19 | Solvay Enzymes, Inc. | Method for producing a therapeautic composition for papillomavirus-induced tumors with aspergillus niger |
| AU4479096A (en) * | 1995-01-31 | 1996-08-21 | Merck Frosst Canada Inc. | 5-methanesulfonamido-3h-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2965279D1 (en) * | 1978-07-27 | 1983-06-01 | Schering Ag | Indanyl derivatives, process for their preparation and pharmaceutical compositions containing these compounds |
| DE3103372A1 (en) * | 1981-01-27 | 1982-09-02 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW INDANYL DERIVATIVES, THEIR PRODUCTION AND USE |
| DE3208079A1 (en) * | 1982-03-04 | 1983-09-08 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW INDANYL DERIVATIVES, THEIR PRODUCTION AND USE |
-
1983
- 1983-11-28 DE DE19833343331 patent/DE3343331A1/en not_active Withdrawn
-
1984
- 1984-11-15 EP EP84113813A patent/EP0143403B1/en not_active Expired - Lifetime
- 1984-11-15 AT AT84113813T patent/ATE62511T1/en not_active IP Right Cessation
- 1984-11-15 DE DE8484113813T patent/DE3484422D1/en not_active Expired - Lifetime
- 1984-11-23 AU AU35844/84A patent/AU568701B2/en not_active Ceased
- 1984-11-26 DD DD84269890A patent/DD229153A5/en not_active IP Right Cessation
- 1984-11-26 ES ES537971A patent/ES8600736A1/en not_active Expired
- 1984-11-27 NO NO844702A patent/NO164845C/en unknown
- 1984-11-27 HU HU844385A patent/HU193238B/en not_active IP Right Cessation
- 1984-11-27 DK DK561484A patent/DK561484A/en not_active Application Discontinuation
- 1984-11-27 CA CA000468691A patent/CA1245589A/en not_active Expired
- 1984-11-27 PT PT79556A patent/PT79556B/en not_active IP Right Cessation
- 1984-11-27 GR GR81056A patent/GR81056B/en unknown
- 1984-11-27 FI FI844644A patent/FI77893C/en not_active IP Right Cessation
- 1984-11-28 IL IL73657A patent/IL73657A/en unknown
- 1984-11-28 US US06/675,596 patent/US4696948A/en not_active Expired - Fee Related
- 1984-11-28 ZA ZA849287A patent/ZA849287B/en unknown
- 1984-11-28 JP JP59249837A patent/JPS60199394A/en active Granted
- 1984-11-28 CS CS849122A patent/CS244844B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS244844B2 (en) | 1986-08-14 |
| HUT36499A (en) | 1985-09-30 |
| JPS60199394A (en) | 1985-10-08 |
| AU3584484A (en) | 1985-06-06 |
| DE3343331A1 (en) | 1985-06-05 |
| NO164845C (en) | 1990-11-21 |
| DK561484D0 (en) | 1984-11-27 |
| FI844644A0 (en) | 1984-11-27 |
| FI77893C (en) | 1989-05-10 |
| NO164845B (en) | 1990-08-13 |
| EP0143403A3 (en) | 1987-07-22 |
| DE3484422D1 (en) | 1991-05-16 |
| US4696948A (en) | 1987-09-29 |
| ZA849287B (en) | 1985-07-31 |
| ES537971A0 (en) | 1985-11-01 |
| JPH054069B2 (en) | 1993-01-19 |
| HU193238B (en) | 1987-08-28 |
| AU568701B2 (en) | 1988-01-07 |
| GR81056B (en) | 1985-03-26 |
| EP0143403A2 (en) | 1985-06-05 |
| IL73657A0 (en) | 1985-02-28 |
| PT79556B (en) | 1986-09-15 |
| ATE62511T1 (en) | 1991-04-15 |
| EP0143403B1 (en) | 1991-04-10 |
| FI844644L (en) | 1985-05-29 |
| IL73657A (en) | 1987-10-30 |
| DK561484A (en) | 1985-05-29 |
| DD229153A5 (en) | 1985-10-30 |
| PT79556A (en) | 1984-12-01 |
| ES8600736A1 (en) | 1985-11-01 |
| FI77893B (en) | 1989-01-31 |
| NO844702L (en) | 1985-05-29 |
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