CH634302A5 - Verfahren zur herstellung neuer mercaptomethylpyridin-derivate. - Google Patents

Verfahren zur herstellung neuer mercaptomethylpyridin-derivate. Download PDF

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Publication number
CH634302A5
CH634302A5 CH303278A CH303278A CH634302A5 CH 634302 A5 CH634302 A5 CH 634302A5 CH 303278 A CH303278 A CH 303278A CH 303278 A CH303278 A CH 303278A CH 634302 A5 CH634302 A5 CH 634302A5
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CH
Switzerland
Prior art keywords
derivatives
mercaptomethylpyridin
producing new
compound
acid
Prior art date
Application number
CH303278A
Other languages
English (en)
Inventor
Tsung-Ying Shen
Howard Jones
Dennis Michael Mulvey
Conrad Peter Dorn
Original Assignee
Merck & Co Inc
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Filing date
Publication date
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of CH634302A5 publication Critical patent/CH634302A5/de

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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 to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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 to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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 to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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 to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pain & Pain Management (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

634302
2
PATENTANSPRUCH Ein Verfahren zur Herstellung einer neuen Verbindung der Formel
CH-OH
OH
:H_— S— C— S—CH.
HO
2
CH
CH
bzw. ihrer pharmazeutisch annehmbaren Säureadditionssalze, dadurch gekennzeichnet, dass man 5-Mercaptopyridoxin mit p-Nitrophenylchlorformiat oder Phosgen umsetzt und eine erhaltene Verbindung gegebenenfalls in entsprechende Salze überführt.
Die vorliegende Erfindung bezieht sich auf ein Verfahren zur Herstellung von neuen Mercaptomethylpyridin-Derivaten, die als aktive Komponente in Arzneimitteln verwendet werden können, insbesondere zur Behandlung von rheumatoider Arthritis.
Vor allem bezieht sich die vorliegende Erfindung auf ein Verfahren zur Herstellung einer neuen Verbindung der folgenden Formel:
OH
HO
:H_— S - C— S— CH
2
CH
CH
und ihrer pharmazeutisch annehmbaren Säureadditionssalze.
Das erfindungsgemässe Verfahren zur Herstellung dieser Verbindung ist dadurch gekennzeichnet, dass man 5-Mercaptopyridoxin mit p-Nitrophenylchlorformiat oder Phosgen umsetzt und eine erhaltene Verbindung gegebenenfalls in die entsprechenden Säureadditionssalze überführt.
Pharmazeutisch annehmbare Säureadditionssalze umfassen diejenigen, die aus anorganischen sowie auch aus organischen Säuren hergestellt werden können, wobei diese Säuren im allgemeinen in der pharmazeutischen Praxis Anwendung finden. Es handelt sich insbesondere um Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Maleinsäure, Fumarsäure, Weinsäure oder Bernsteinsäure. Ebenfalls können Salze von Alkalimetallen der Mer-captangruppe sowie zweiwertige Metallkomplexe der Mer-captogruppe, wie z.B. mit Calcium oder mit Magnesium, eingesetzt werden.
Trotz der Tatsache, dass in den letzten zwei Jahrzehnten ausgedehnte Untersuchungen über gegen Entzündungen wirksame Mittel durchgeführt wurden, besteht immer noch eine dringende Notwendigkeit ein Mittel für eine wirksame Behandlung von rheumatoider Arthritis zu finden, das ebenfalls eine gute Verträglichkeit aufweist. Die üblichen, gegen Entzündungen wirksamen, analgetisch und antipyretisch wirkenden Mittel auf nicht-steroider Basis, wie z.B. Aspirin und auch viele andere experimentell neue Medikamente mit einer klinischen Bewertung, sind nur auf eine solche Weise wirksam, dass sie eine symptomatische Linderung des aktuten Krankheitsbildes bewirken, aber sie weisen nicht die Fähigkeit auf, den Verlauf der Krankheit zu ändern. Als Folge dieser Tatsache haben die antirheumatischen Wirksamkeiten der beiden alten Arzneimittel, nämlich Gold und D-Penicill-amin, trotz ihrer potentiellen Nebenwirkungen erneute Beachtung in den letzten Jahren gefunden. Die klinische Wirksamkeit der genannten beiden Medikamte wurde durch Ausführung gut kontrollierter, klinischer Studien in den verschiedensten Zentren abermals bestätigt. Verschiedene Rheumatologen. haben ihrer Meinung Ausdruck gegeben, dass eine Verbindung, die dem D-Penicillamin ähnlich sein würde, einen wertvollen Beitrag für die Medizin in diesem wichtigen Feld darstellen würde. Aus diesem Grund ist die Entdeckung sehr wichtig, dass viele der bekannten Mercaptomethylpyri-dine sowie auch die neuen Mercaptomethylpyridine der vorliegenden Erfindung in ausserordentlichem Massstab eine Aktivität gegen anti-rheumatoide Arthritis aufweisen.
Zur Feststellung dieser Eigenschaften wurden die erfin-dungsgemäss erhaltenen Verbindungen auf oralem oder topischem Wege, auf parenterale Weise, durch eine Inhalationsspray oder auch als rectal in Dosierungs-Einheitsformulie-rungen verabreicht, welche die üblichen, nicht toxischen, pharmazeutisch annehmbaren Trägermaterialien, Zusatzstoffe und andere Trägerstoffe enthielten. Der hier verwendete Ausdruck «parenteral» bezieht sich auf subcutane Injektionen, intravenöse, intramuskuläre oder intrasternale Injektionen, sowie auch auf intraarticulare oder Infusions-Verabreichungs-methoden. Zusätzlich zu der Behandlung warmblütiger Tiere, wie z.B. Mäuse, Ratten, Pferde, Hunde, Katzen, Meerschweinchen, Kaninchen u.s.w., ist die neue Verbindung ebenfalls bei der Behandlung von Menschen wirksam.
Dosierungsniveaus in einer Grössenordnung von 1 mg bis 140 mg pro Kilogramm Körpergewicht pro Tag sind bei der Behandlung der weiter oben beschriebenen Zustände nützlich. Im allgemeinen wird eine wirksame Dose in einem Bereich von 5 bis 50 mg pro Kilogramm Körpergewicht pro Tag betragen.
Es wird jedoch selbstverständlich sein, dass das spezifische Dosierungsniveau für einen beliebigen Patienten von einer Vielfalt von Faktoren abhängig sein wird, einschliesslich der Aktivität der speziell verwendeten Verbindung, abhängig von dem Alter, dem Körpergewicht, dem allgemeinen Gesundheitszustand, dem Geschlecht, der Diät, der Zeit der Verabreichung, dem Weg der Verabreichung, dem Ausscheidungsweg, der Kombination verschiedener Medikamente und dem Schwerheitsgrad der besonderen Krankheit, die behandelt werden soll.
Bei einer bevorzugten Ausführungsform des erfindungs-gemässen Verfahrens wird 2-Methyl-3-hydroxy-4-hydroxy-methyl-5-mercaptomethylpyridin mit p-Nitrophenylchlorformiat in einem aprotischen Lösungsmittel, wie z.B. Tetra-hydrofuran, Äther, Glyme, Diglyme oder anderen, bei einer Temperatur von 0 bis 10°C 1 bis 3 Stunden lang umgesetzt, gefolgt von einer Erwärmung bei 20 bis 50°C.
Beispiel
Bis-[2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5--methylthio ]-carbonat
Eine Lösung von 0,1 Mol 5-Mercaptopyridoxin in 100 ml trockenem Tetrahydrofuran wird bei einer Temperatur von 0 bis 5°C gerührt, während welcher Zeit man 0,1 Mol P-Nitrophenylchlorformiat in 10 ml trockenem Tetrahydrofuran im Laufe einer Stunde hinzufügt. Nach einer weiteren Stunde wird die Lösung bei einer Temperatur von 10°C auf 10 ml eingedampft. Falls nötig, kann man das sich als Zwischenprodukt gebildete p-Nitrophenylmonothiocarbonat von 5-Mercaptopyridoxin durch Filtration während dieser Stufe isolieren.
Es besteht aber auch die Möglichkeit, weitere 0,1 Mol von 5-Mercaptopyridoxin vor dem Verdampfen hinzuzufügen u. die Tetrahydrofuran-Lösung auf eine Temperatur von 40°C zu erwärmen. Verdampfung, gefolgt von einer Extraktion des s
io
15
20
25
30
35
40
45
50
55
60
65
3
Dithiocarbonates im Äthylacetat (3 x 100 ml) aus einer gesättigten wässrigen Bicarbonatlösung wird durch das Trocknen der organischen Schicht über Magnesiumsulfat gefolgt. Die organische Schicht wird filtriert und zur Trockne eingedampft. Man chromatographiert das rohe Produkt an einer 5
634302
Silikagelkolonne mit den Massen 2 in. x 2 ft., unter Verwendung von Lösungen von Methylchlorid-Methanol als Eluiermittel, wobei man die folgende Verbindung erhält: Bis--[2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methylthio]--carbonat.
v
CH303278A 1973-06-15 1978-03-20 Verfahren zur herstellung neuer mercaptomethylpyridin-derivate. CH634302A5 (de)

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Application Number Priority Date Filing Date Title
US36877473A 1973-06-15 1973-06-15
US05/470,231 US3971797A (en) 1973-06-15 1974-05-16 S,S'-bis(pyridylmethyl)-carbonodithioates

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CH812274A CH613951A5 (de) 1973-06-15 1974-06-13
CH821974A CH610305A5 (de) 1973-06-15 1974-06-14
CH303278A CH634302A5 (de) 1973-06-15 1978-03-20 Verfahren zur herstellung neuer mercaptomethylpyridin-derivate.
CH972578A CH618428A5 (de) 1973-06-15 1978-09-18

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AR (1) AR203749A1 (de)
BG (1) BG24408A3 (de)
CA (1) CA1037956A (de)
CH (4) CH613951A5 (de)
DD (1) DD113001A5 (de)
DE (2) DE2428294A1 (de)
DK (1) DK148595C (de)
ES (1) ES427277A1 (de)
FI (1) FI58775C (de)
FR (2) FR2233056B1 (de)
GB (2) GB1466386A (de)
IE (1) IE39467B1 (de)
IL (1) IL44998A (de)
LU (1) LU70342A1 (de)
NL (2) NL7407618A (de)
NO (1) NO144149C (de)
PH (1) PH10366A (de)
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US4061759A (en) * 1975-05-19 1977-12-06 Merck & Co., Inc. Ethenyl and ethynyl mercaptoalkyl pyridines
CH655110A5 (de) * 1982-09-03 1986-03-27 Otsuka Pharma Co Ltd Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten.
EP0640072B1 (de) * 1992-05-15 2000-08-23 Btg International Limited Pyridinderivate als Hydroxylase- und Lyase-Inhibitoren
GB2266887B (en) * 1992-05-15 1996-04-17 British Tech Group Substituted pyridines,their preparation and pharmaceutical use
GB201718148D0 (en) * 2017-11-02 2017-12-20 Ipotts Ltd Hair cutting comb
GB2603007B (en) * 2021-01-26 2023-01-11 Pickuls Gizmo Ltd A hair cutting guide

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US3515726A (en) * 1968-10-16 1970-06-02 Olin Mathieson 2,2'-bis(pyridyl-n-oxide) dithiolcarbonates and trithiocarbonates

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NL185841B (nl) 1990-03-01
RO71434A (ro) 1981-08-17
CA1037956A (en) 1978-09-05
NO144149C (no) 1981-07-01
DE2428409A1 (de) 1975-01-09
DE2428409B2 (de) 1978-11-30
FR2233056A1 (de) 1975-01-10
GB1466386A (en) 1977-03-09
DE2428294A1 (de) 1975-01-09
JPS5747189B2 (de) 1982-10-07
LU70342A1 (de) 1975-03-27
FR2233056B1 (de) 1977-10-28
BG24408A3 (en) 1978-02-10
DD113001A5 (de) 1975-05-12
IL44998A (en) 1977-10-31
IE39467B1 (en) 1978-10-11
FR2233057B1 (de) 1978-03-24
DE2428409C3 (de) 1979-08-09
DK303274A (de) 1975-02-10
IL44998A0 (en) 1974-09-10
NL185841C (nl) 1990-08-01
CH613951A5 (de) 1979-10-31
AR203749A1 (es) 1975-10-15
AU7004174A (en) 1975-12-18
IE39467L (en) 1974-12-15
JPS5032181A (de) 1975-03-28
JPS5032180A (de) 1975-03-28
NO144149B (no) 1981-03-23
FI58775C (fi) 1981-04-10
ES427277A1 (es) 1976-09-16
CH610305A5 (de) 1979-04-12
FI58775B (fi) 1980-12-31
NO742042L (de) 1975-05-05
SE411346B (sv) 1979-12-17
US3971797A (en) 1976-07-27
DK148595C (da) 1986-01-27
JPS5387363A (en) 1978-08-01
FI168574A (de) 1974-12-16
PH10366A (en) 1977-01-18
GB1466295A (en) 1977-03-02
SE7407296L (de) 1974-12-16
NL7407616A (de) 1974-12-17
RO70852A (ro) 1981-08-17
DK148595B (da) 1985-08-12
FR2233057A1 (de) 1975-01-10
CH618428A5 (de) 1980-07-31
NL7407618A (de) 1974-12-17

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