EP0000538A1 - 6,7-Dihydro-5H,13H-quinazolino(3,2-a) (1,4)benzodiazépine-5,13-diones, procédé pour leur préparation et leur application comme médicaments. - Google Patents

6,7-Dihydro-5H,13H-quinazolino(3,2-a) (1,4)benzodiazépine-5,13-diones, procédé pour leur préparation et leur application comme médicaments. Download PDF

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Publication number
EP0000538A1
EP0000538A1 EP78100425A EP78100425A EP0000538A1 EP 0000538 A1 EP0000538 A1 EP 0000538A1 EP 78100425 A EP78100425 A EP 78100425A EP 78100425 A EP78100425 A EP 78100425A EP 0000538 A1 EP0000538 A1 EP 0000538A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
groups
phenyl
alkoxy
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.)
Withdrawn
Application number
EP78100425A
Other languages
German (de)
English (en)
Inventor
Karl Heinrich Dr. Mayer
Helmut Dr. Heitzer
Friedrich Prof.Dr. Hoffmeister
Arend Dr Heise
Stanislav Dr. Kazda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE19772733681 external-priority patent/DE2733681A1/de
Priority claimed from DE19772758875 external-priority patent/DE2758875A1/de
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0000538A1 publication Critical patent/EP0000538A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3

Definitions

  • the present invention relates to new 6,7-dihydro-5H, 13H-quinazolino [3,2-a] [1,4] benzodiazepin-5,13-dione, a process for their preparation and their use as a medicament, preferably as substances that act on the central nervous system, in particular as cerebral anti-ischemic, antiamnetic, learning, performance and memory-improving, tranquilizing, analgesic and antipyretic active substances.
  • the benzodiazepine derivatives of the formula (I) according to the invention surprisingly show very strong effects on the central nervous system, in particular very good cerebral anti-ischemic, antiamnetic, learning, performance and memory-improving, tranquilizing, analgesic and antipyretic properties and thus represent an enrichment of the pharmaceutical industry.
  • reaction scheme shows examples of reactions of individual reaction partners that can be used according to the invention: Examples of subsequent reaction steps which may follow:
  • R 1 and R 5 preferably represent one or two substituents from the group hydrogen, alkyl, hydroxy, alkoxy, nitro, amino, dialkylamino, acylamino, alkoxycarbonylamino, halogen, trifluoromethyl, carboxy, alkoxycarbonyl , Aminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, dialkylaminosulfonyl, where halogen in particular represents fluorine, chlorine and bromine and the alkyl, alkoxy and acyl radicals mentioned contain 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms.
  • the 2-alkyl-3-aryl-4H-quinazolin-4-ones of the formula II to be used as starting materials are known or can be prepared by known processes (cf. J.Amer.Chem. Soc. 68 (1946), 542 / J.org.Chem. 14 (1949), 967 / J.Gen. Chem. (Engl. Trans.) 30 (1960), 2333 and 34 (1964), 848 / Chem.Abstr. 52 (1958), 9147 / J.pr.Chem. (4) 14 (1961), 84 / drug research 13 (1963) 688 / J.Med.Chem. 20 (1977), 379 / Synthesis 1977, 309).
  • R 2 preferably represents an optionally substituted alkyl radical having 1 to 10, in particular 1 to 6, carbon atoms, an optionally substituted aralkyl radical having 1 to 6 carbon atoms in the alkyl part, in particular benzyl or phenethyl, an optionally substituted one Phenyl radical, a heterocycloalkyl radical with 1 to 6 carbon atoms in the alkyl part and 4 to 8 ring members and 1 to 3 heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur in the heteroaryl part, to which a phenyl ring can also be fused.
  • R 2 alkyl are hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, Alkylaminocarbonylamino and sulfo groups, where carboxy and sulfo groups can also be present in the form of salts with inorganic and organic acids.
  • alkyl radicals in dialkylamino groups can also be closed in themselves or via a hetero atom from the group consisting of oxygen, sulfur or via an NH, N-alkyl, N-acyl or N- alkoxycarbonyl group to form a 4- to 8-membered ring.
  • Alkyl, alkoxy and acyl radicals mentioned in the possible substituents preferably contain 1 to 4, in particular 1 to 2, carbon atoms.
  • R 2 aralkyl and phenyl are in respective aryl part halogen, in particular chlorine and bromine, trifluoromethyl, hydroxy, alkoxy, nitro and alkyl.
  • the primary amines of Fornel (III) to be used as starting materials are known or can be prepared by known processes.
  • Methylamine isobutylamine, 2-ethylhexylamine, 4-methylcyclohexylamine, 2-norbornylamine, allylamine, propargylamine, propylenediamine, 1-amino - 2-diethylaminoethane, ethanolamine, 3-atoxypropylamine, aminoacetic acid ethyl ester, aminopropionitrylamine, aminopropyl aminomethylamine, aminopropionitrylamine, 2,4-dichlorobenzylamine, 4-chlorophenylethylamine, 3-ethoxyaniline, 4-diethylaminoaniline, 2-aminomethylfuran, 4-aminomethylpyridine, N-aminoethyl-N'-methylpiperazine, N-aminobutylthiomorpholine-1,1-dioxide, 1 Aminomethylisoquinoline, 1-aminopropyl-1,2,3-triazole.
  • alkyl represents, for example, methyl, ethyl, n- and isopropyl, n-, iso- and tert-butyl, h- and iso-hexyl, decyl, hexadecyl, allyl, propargyl, cyclohexyl.
  • Alkoxy stands for example for methoxy, ethoxy, n- and iso - propoxy, n-, iso- and tert-butoxy, allyloxy, cyclobutyloxy.
  • Alkylamino and dialkylamino are, for example, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, n- and iso-propylamino, n-, iso- and tert-butylamino, n- and iso-dipropylamino, n-, iso- and tert-dibutylamino, allylamino, diallylamino - dialkylamino also for pyrrolidino, piperidino, cyclohexylimino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, tetrahydroquinolino,.
  • Acylamino stands for example for formylamino, acetylamino, propionylamino, n- and iso-butyrylamino, valeroylamino, iso-valeroylamino, pivaloylamino.
  • Alkoxycarbonyl stands for example for methoxycarbonyl, ethoxycarbonyl, n- and iso-propoxycarbonyl, n-, iso- and tert-butoxycarbonyl, allyloxycarbonyl, cyclohexyloxycarbonyl.
  • Aralkyl stands for example for benzyl, 4-chlorobenzyl, 2,6-dichlorobenzyl, 3-bromobenzyl, 2-methoxybenzyl, 3-hydroxybenzyl, 2,4,6-trimethylbenzyl, phenylethyl, 4-chlorophenylethyl, phenylpropyl, phenylbutyl.
  • Aryl stands for example for phenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2-methylphenyl, 4-xthylphenyl, 3,4-dimethylphenyl, 3-hydroxyphenyl , 2-methoxyphenyl,; 4-ethoxyphenyl, 2-methoxy-5-chlorophenyl, 2,5-diethoxyphenyl, 4-aminosulfonylphenyl, 3-dimethylaminophenyl, 3-xthylaminophenyl, 3-ethylamino-4-methylphenyl.
  • Heteroaryl stands for example for furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, thiazine, indole, benzimidazole, benzoxazole, benz thiazole, indazole, quinoline, isoquinoline, quinazoline, cninoxaline, benzotriazine, phthalazine.
  • All organic solvents which are inert to the respective reactants are suitable as solubilizers.
  • These preferably include aliphatic alcohols such as methanol, ethanol, isopropanol or butanol, ethers such as tetrahydrofuran, dioxane, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, glycols such as ethylene glycol, propylene glycol, diethylene glycol and corresponding ethers with aliphatic alcohols such as diethylene glycol, xylene alcohol, tolylene glycol, xylene alcohol, tolylene glycol, xylene alcohol, tolylene alcohol, tolylene glycol, xylene glycol, xylene glycol, ethyl ether, tolylene alcohol, tolylene alcohol, tolylene glycol, xylene alcohol, tolylene glycol, xylene glycol, xylene glycol, xylene glycol Halogenated hydrocarbons such
  • the reaction can be carried out at normal pressure but also at elevated pressure.
  • increased pressure may be required for the reaction.
  • reaction temperatures can be varied within a wide range. In general, temperatures between 20 and 250 ° C, preferably between 20 and 18 0 o C , especially between 40 and 150 ° C.
  • All customary acid binders can be used as acid binders. These include inorganic bases such as alkali and alkaline earth hydroxides, e.g. Sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, alkali or alkaline earth carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, amides such as sodium amide and organic bases such as tertiary amines, e.g. Triethylamine, N, N-dimethylaniline, pyridines, quinolines and isoquinolines.
  • an excess of the reactant ammonia or primary amine can also advantageously be used in the reaction.
  • 1 mol of 2-alkyl-3-aryl-4H-quinazolin-4-one of the formula (II) is at least 1 mol of ammonia or primary amine of the formula (III) and at least 1 mol of one of the acid binders mentioned.
  • the starting materials generally go completely or partially into solution, while the end products crystallize out.
  • the deposition of the end products can be accelerated by cooling and / or by adding precipitants such as water, lower aliphatic ethers such as diethyl ether or dibutyl ether or lower aliphatic hydrocarbons such as petroleum ether or mineral spirits.
  • the new compounds according to the invention are substances which can be used as medicaments. You can use it be administered, for example intravenously, intramuscularly, subcutaneously, orally or intravaginally.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, capsules, dragées, pills, granules, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • auxiliary substances are:
  • Non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol), solid carriers such as natural rock powder (e.g. kaolins, clays, talc, chalk), ground synthetic minerals (for example highly disperse silica, silicates), sugars (for example sucrose, lactose and glucose), emulsifiers such as nonionic and anionic emulsifiers (for example, polyethylene fatty acid ester, polyoxyethylene.
  • paraffins e.g. petroleum fractions
  • vegetable oils e.g. peanut / sesame oil
  • alcohols e.g. ethyl alcohol, glycerin
  • glycols e.g. propylene glycol, polyethylene glycol
  • solid carriers such as natural rock powder (e.g.
  • ettalkoholtechnik F alkylsulfonates and Arylaulfonate
  • Dis Pergierstoff eg lignin, methyl cellulose, starch and polyvinylpyrrolidone
  • lubricants eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
  • the application is carried out in the usual way, preferably orally or parenterally.
  • tablets can of course also contain additives such as sodium citrate, calcium carbonate and calcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like, in addition to the carriers mentioned.
  • Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
  • the active ingredients can be mixed with various flavor enhancers or colorants in addition to the abovementioned auxiliaries.
  • solutions of the active ingredients can be used using suitable liquid carrier materials.
  • suitable liquid carrier materials include: caustic soda, potash lye, ethanolamine, diethanolamine, triethanolamine, aminotris hydroxymethyl methane, glucosamine, N-methylglucosamine.
  • Such salts can also be of greater importance for the oral use of the compounds according to the invention, in that they accelerate or delay the absorption as desired.
  • examples may be mentioned: magnesium salts, calcium salts, aluminum salts and iron salts.
  • Example 1 a Analogously to Example 1 a) are obtained from 0.05 mole of 2-chloromethyl-3- (2-methoxycarbonyl-phenyl) -6-trifluoromethyl-4H-quinazolin-4-one (m.p. 169 -. 170 0) and 50 ml of liquid ammonia in 150 ml dioxane in 3 hours at 50 ° 36 th. 11-trifluoromethyl-A. Mp 190-192 ° (from toluene).
  • Example 1 a Analogously to Example 1 a) are obtained from 0.05 mole of 2-chloromethyl-3- (2-methoxycarbonyl-5-nitro-phenyl) -4H-quinazolin-4-one (mp 158 -. 159 0) and 50 ml of liquid ammonia in 150 ml of o-dichlorobenzene in 3 hours at 60 ° 35% of theory Th. 2-nitro-A. Mp 276 - 277 ° dec. (from glacial acetic acid).
  • Example 13 Analogously to Example 13, from 0.05 mol of the reaction product from Example 5 and 60 ml of pyrocarbonate in 20 minutes at 120-130 0 80% d. Th. 6-Athoxycarbonyl-3-chloro-A. M.p. 189-191 0 (also ethanol).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP78100425A 1977-07-26 1978-07-18 6,7-Dihydro-5H,13H-quinazolino(3,2-a) (1,4)benzodiazépine-5,13-diones, procédé pour leur préparation et leur application comme médicaments. Withdrawn EP0000538A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE2733681 1977-07-26
DE19772733681 DE2733681A1 (de) 1977-07-26 1977-07-26 6,7-dihydro-5h, 13h-chinazolino eckige klammer auf 3,2-a eckige klammer zu eckige klammer auf 1,4 eckige klammer zu benzodiazepin-5,13-dione, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DE19772758875 DE2758875A1 (de) 1977-12-30 1977-12-30 6,7-dihydro-5h,13h-chinazolino eckige klammer auf 3,2-a eckige klammer zu eckige klammer auf 1,4 eckige klammer zu benzodiazepin-5,13-dione, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DE2758875 1977-12-30

Publications (1)

Publication Number Publication Date
EP0000538A1 true EP0000538A1 (fr) 1979-02-07

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ID=25772398

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100425A Withdrawn EP0000538A1 (fr) 1977-07-26 1978-07-18 6,7-Dihydro-5H,13H-quinazolino(3,2-a) (1,4)benzodiazépine-5,13-diones, procédé pour leur préparation et leur application comme médicaments.

Country Status (9)

Country Link
US (1) US4187306A (fr)
EP (1) EP0000538A1 (fr)
JP (1) JPS5424896A (fr)
AU (1) AU3828478A (fr)
DK (1) DK330378A (fr)
ES (1) ES471985A1 (fr)
FI (1) FI782318A (fr)
IL (1) IL55207A0 (fr)
IT (1) IT7826042A0 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190588A1 (fr) * 1985-01-25 1986-08-13 Merck & Co. Inc. Quinazolino-1,4-benzodiazépine-6,9-diones, procédés pour leur préparation et compositions pharmaceutiques les contenant
RU2815382C2 (ru) * 2019-03-05 2024-03-13 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Пентациклическое гетероциклическое соединение

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4530790A (en) * 1982-12-27 1985-07-23 Merck & Co., Inc. Cholecystokinin antagonists
US4559338A (en) * 1985-01-25 1985-12-17 Merck & Co., Inc. Soluble quinazolino-1,4-benzodiazepin-5,13-dione derivatives
US4563451A (en) * 1985-01-25 1986-01-07 Merck & Co., Inc. Quinazolino-1,4-benzodiazepin-5,13-diones
US4735941A (en) * 1986-12-23 1988-04-05 Merck & Co., Inc. 1,4-benzodiazepines with 5- and 6-membered heterocyclic rings, useful as gastrointestinal and CNS agents
EP0272868A1 (fr) * 1986-12-23 1988-06-29 Merck & Co. Inc. 1,4-Benzodiazépines avec hétérocycles à 6 chaînons
US5670640A (en) * 1996-02-02 1997-09-23 Hoffmann-La Roche Inc. Process for the manufacture of imidazodiazepine derivatives
AR112788A1 (es) 2017-09-07 2019-12-11 Eisai R&D Man Co Ltd Compuesto pentacíclico
KR20210135223A (ko) * 2019-03-05 2021-11-12 에자이 알앤드디 매니지먼트 가부시키가이샤 펜타시클릭 화합물의 염 및 이의 결정
EP3936190A4 (fr) * 2019-03-05 2022-11-16 Eisai R&D Management Co., Ltd. Composé hétérocyclique pentacyclique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3280117A (en) * 1964-04-20 1966-10-18 Sandoz Ag Tricyclic quinazolinones

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3651046A (en) * 1969-01-30 1972-03-21 Hoffmann La Roche Quinazolino-benzodiazepines and methods for the preparation thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3280117A (en) * 1964-04-20 1966-10-18 Sandoz Ag Tricyclic quinazolinones

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190588A1 (fr) * 1985-01-25 1986-08-13 Merck & Co. Inc. Quinazolino-1,4-benzodiazépine-6,9-diones, procédés pour leur préparation et compositions pharmaceutiques les contenant
RU2815382C2 (ru) * 2019-03-05 2024-03-13 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Пентациклическое гетероциклическое соединение

Also Published As

Publication number Publication date
IL55207A0 (en) 1978-09-29
FI782318A (fi) 1979-01-27
ES471985A1 (es) 1979-10-01
US4187306A (en) 1980-02-05
JPS5424896A (en) 1979-02-24
IT7826042A0 (it) 1978-07-24
AU3828478A (en) 1980-01-31
DK330378A (da) 1979-01-27

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Inventor name: HOFFMEISTER, FRIEDRICH, PROF.DR.

Inventor name: KAZDA, STANISLAV, DR.

Inventor name: MAYER, KARL HEINRICH, DR.

Inventor name: HEITZER, HELMUT, DR.

Inventor name: HEISE, AREND, DR