DE2428409C3 - S3'-Bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)-carbonodithioat, dessen pharmakologisch verträgliche Salze und Arzneimittel - Google Patents

S3'-Bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)-carbonodithioat, dessen pharmakologisch verträgliche Salze und Arzneimittel

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Publication number
DE2428409C3
DE2428409C3 DE2428409A DE2428409A DE2428409C3 DE 2428409 C3 DE2428409 C3 DE 2428409C3 DE 2428409 A DE2428409 A DE 2428409A DE 2428409 A DE2428409 A DE 2428409A DE 2428409 C3 DE2428409 C3 DE 2428409C3
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Germany
Prior art keywords
bis
methyl
hydroxymethyl
hydroxy
pyridylmethyl
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Expired
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DE2428409A
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English (en)
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DE2428409B2 (de
DE2428409A1 (de
Inventor
Conrad Peter Plainfield Dorn
Howard Holmdel Jones
Dennis Michael Whitehouse Station Mulvey
Tsung-Ying Westfield Shen
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Merck and Co Inc
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Merck and Co Inc
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Publication of DE2428409A1 publication Critical patent/DE2428409A1/de
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    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/63One oxygen atom
    • C07D213/65One oxygen atom attached in position 3 or 5
    • C07D213/66One 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D213/04Heterocyclic 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
    • C07D213/24Heterocyclic 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
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    • C07D213/04Heterocyclic 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
    • C07D213/24Heterocyclic 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
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    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/63One oxygen atom
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    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/62Oxygen or sulfur atoms
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    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02Heterocyclic 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
    • C07D213/89Heterocyclic 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
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    • C07D491/02Heterocyclic 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
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    • C07D497/04Ortho-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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

sowie deren pharmakologiseh verträgliche Salze. 2. Arzneimittel, bestehend aus einer Verbindung gemäß Anspruch I und üblichen Träger-. Hilfs- und Verdünnungsmitteln.
R1OCHv
CH3
CH2OR2
Ii A ORl
-S-C-S-CH2-I[V7
in der Kx und R2 gleich oder verschieden sind und jeweils ein WasserstofTatom oder eine säureempfindliche Schutzgruppe (wie eine Tetrahydropyranylgruppe) bedeuten oder R, und R2 zusammen einen Rest der nachstehenden allgemeinen Formel bilden
Ungeachtet der intensiven Forschung der letzten zwei Jahrzehnte auf dem Gebiet der entzündungshemmenden Mittel besteht weiterhin Bedarf an einem wirksamen und gut verträglichen Arzneimittel gegen rhcumatoide Arthritis. Die herkömmlichen, keine Steroide darstellenden, gleichzeitig entzündungshemmend, analgctisch imduniipyrclisch wirkenden Mittel, wie Acetylsalicylsäurc, sowie viele neue, im Stadium klinischer Untersuchung stehende Arzneisioffe ermöglichen lediglich eine symptomatische Milderung des akuten Syndroms, sind jedoch nicht in der Lage, den Krankheilsverlauf zu ändern. Demgemäß haben die antirheumatischen Wirkungsweisen zweier aller Heilmittel, nämlich von Gold und D-Pcnicillamin. trotz ihrer potentiellen Nebenwirkungen in den letzten Jahren neues Interesse gefunden. Die klinische Wirksanikeil beider Heilmittel wurde an Hand sorgfältiger, an mehreren Stellen durchgeführter klinischer Untersuchungen neuerlich bestätigt. Mehrere Rheumatologen haben die Auffassung vertreten, daß eine D-penicillaminähnliehc Verbindung mil überdurchschnittlichen Eigenschaften die Medizin auf diesem bedeutsamen Gebiet außerordentlich bereichern würde.
Die Erfindung belriffi die Verbindung der Formel
CH7OH
f Y-CH1 S-C S
CH,
C Ή, Ο Η
OH
sowie deren pharmakologiseh vertragliche Salze.
Beispiele für pharmakologiseh verträgliehe Additionssal/e sind jene, die aus den üblicherweise in der l'harma/ie verwendeten Mineralsäuren und organischen Säuren, w ie SaI/-. Bromwassersiofl-. Schwelel-, Salpeter-. Malein-. l;nniar-. Wem- oder Bernsieinsiiure. hergestellt werden.
Das erlindungsgemäße S.S - Bis - {} - hvdroxv-4 - hvdrownicllnl - .1 - met In I - 5 - pvridvlmetlnl)-carin der R, und R4 gleich oder verschieden sind und je-
2) weils ein Wassersloffatom, einen C, -,-Alkylresl oder eine Phenylgruppc darstellen, mit verdünnter Mineralsäure bei 20 bis 50" C während 1 bis 5 Stunden hergestellt werden.
Die erfindungsgemäße Verbindung und deren Salze zeigen ein hohes Ausmaß an Wirksamkeit gegenüber rheumatoider Arthritis.
Wie der nachfolgende Verglcichsvcrsuch zeigt, entfalten zwei pharmakologiseh verträgliche Salze der crfindungsgemäßen Verbindung dieselbe Wirksam-
!■-. keil wie 5-Mcrcaptopyridoxin bei einem Drittel der Dosis. Die Toxizität der crlindungsgemäßcn Verbindung und ihrer pharmakologiseh verträglichen Salze ist ferner wesentlich geringer als jene von 5-Mcrcaplopyridoxin.
κι Die Erfindung betrifft ferner Arzneimittel, welche aus der erfindungsgemäßen Verbindung oder einem pharmakologiseh verträglichen Salz davon und üblichen Träger-, Hilfs- und Verdünnungsmitteln bestehen.
4") Man kann diese Arzneimittel für die obigen Zwecke oral, lokal, parenteral, mit Hilfe von Inhalalionssprays oder rektal in Form von Einheitsdosen verabfolgen. »Parenteral« schließt hier subkutane Injektionen, die intravenöse, intramuskuläre und intrasler-
")ii nale Injektion, die inlraartikuläre Verabfolgung sowie die Infusionsmethode ein. Außer für die Humanmedizin eignen sich die erlindungsgemüßcn Arzneimittel auch Tür die Behandlung von warmblütigen Tieren, wie Mäusen, Rallen, Pferden, Hunden, Katzen, Meer-
T) schweinchen oder Kaninchen.
Zur Behandlung der vorgenannten Erkrankungen können Dosen in der Größenordnung von I bis 140 mg/kg Körpergewicht/Tag angewendet werden. Im allgemeinen licgl die wirksame Dosis im Bereich
«ι von 5 bis 50 mg/kg Körpergewicht/Tag.
Hs sei jedoch festgestellt, daß die spezielle Dosis für jeden bestimmten Patienten von den verschiedensten Faktoren abhängt, beispielsweise von der Wirksamkeil der eingesetzten speziellen Verbindung.
ι-■ vom Aller. Körpergewicht, allgemeinen Gesundheitszustand. Gcsclilechl. von der Kost, vom Verahfolgungszeitpunkl und -weg. von der Ausscheidungslieschw indiukcit. Arzneistolfkombinaiion und Schwere
der jeweiligen Erkrankung, welcher die Therapie gilt. Das nachstehende Beispiel erläutert die Erfindung.
Beispiel
S,S'-Bis-(3-hydroxy-4-hydroxymethyl-
2-methyl-5-pyridyimethyl)-carbonodithioat-
dihydrochlorid-monohydrat
Stufe A
Herstellung von S,S'-Bis-(2,2,8-lrimethyl-
4H-l,3-dioxino[4,5-c]pyridin-5-yl-methyl)-
carbonodithioat
Eine eisgekühlte Lösung von 4,5 g 5-Mercaptomethyl-2,2,8-trimelhyl-4H-l,3-dioxino[4,5-c]pyridin in 50 ml wasserfreiem Pyridin wird tropfenweise mit 10 ml einer 12,5prozentigen Phosgenlösung in Benzol versetzt. Man läßt das Reaklionsgemisch sich auf Raumtemperatur erwärmen und rührt 3 Stunden, wonach man den Ansatz im Vakuum eindampft. Der Rückstand wird einer Extraktion mit Benzol und gesättigter Natriumbicarbonallösung unterworfen. Die Benzolschicht wird abgetrennt, mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum eingedampft. Man Chromatographien den erhaltenen Rückstand an 250 g Kicsclgcl. Die Elution mit Äther ergibt 3,59 g S,S'-Bis-(2,2,8-lrimcthyl-4H- 1,3-dioxino[4,5 - c]pyridin - 5 - yl - methyl)- earbonodithioal vom Fp. 88 bis WC.
Stufe B
Herstellung von S,S'-Bis-(3-hydroxy-4-hydroxymcthyl-2-mcthyl-5-pyridylmelhyl)-carboiuidithioal-dihydrochlorid-monohydrat
Eine Lösung von 0,2 g S,S'-Bis-|2,2,8-lrimelhyl-4H- l^-dioxiiio^.S-cJpyridin-S-yl-mclhyll-carbonodilhioat in 0,9 ml eiskalter konzentrierter Salzsäure wird 5 Minuten kalt gerührt und anschließend mil 2,5 ml Methanol verdünnt. Beim Abkühlen in Eis/ Aceton bildet sich ein kristalliner Niederschlug, den man abliltricrt. Man erhält 0,12 g S,S'-Bis-(3-hydroxy-4-hydroxymcthyl-2-mclhyl-5-pyridylmethyl)-carbonodithioat-dihydrochlorid-monohydrat vom Fp. 125 bis 130 C.
Der nachstehende Vcrglcichsvcrsuch veranschaulich I die überlegene Wirksamkeil der crfindimgsgcmüüen Verbindungen gegenüber einem bekannten Wirkstoff, nämlich S-Mcrcaptopyridoxin.
Vergleichsversuch
Gruppen von 4 Meerschweinchen erhielten oral zur Zeit 0 30 mg/kg oder 90 mg/kg der 'lötverbindung. Jedes Tier erhielt eine zweite Dosis der Tesl-
Dosis Durch % Inhi
messer bierung
Erythem
(mg/kg) (mm)
._„ 11,1 -
90 7,6 32
30 7,2 36
verbindung in der gleichen Menge 17 Stunden später. Eine Stunde nach Gabe der zweiten Dosis der Testverbindung erhielt jedes Tier intradermal Lymphokine (lösliche Proteinmittler, freigesetzt durch sensibilisierte Lymphocyten bei Kontakt mit Antigen). 22 Stunden später wurde an der Injektionsstelle der Umfang des Erythems gemessen.
|0 Behandlung
Salz
5-Mercaptopyridoxin
S,S'-Bis-(3-hydroxy-
4-hydroxymethyl-
2-methyl-5-pyridylmcthyU-carbono-
dithioat-dihydrochlorid
S,S'-Bis-(3-hydroxy- 30 7,5 34*)
4-hydroxymethyl-,r 2-methyl-5-pyridyl-
melhyO-carbono-
dithioat-sulfat-
halbhydral
·) Statistische Signifikanz P < 0,05.
Sowohl das Sulfat als auch das Dihydrochlorid
von S,S'-Bis-(3-hydroxy-4-hydroxymcthyl-2-melhyl-5-pyridylmethyl)-carbonodithioat zeigen also etwa die
η gleiche Wirksamkeit wie 5-Mercaptopyridoxin bei einem Drittel der Dosis des 5-Mercaptopyridoxins.
Die geringere Toxizität der erfindungsgemäßen Verbindung und ihrer Salze geht aus der nachstehenden Gegenüberstellung hervor:
LD51, (weibliche Mäuse des Stammes CF1S orale Gabe in Wasser)
Dihydrochlorid der erfindungs-
4. gemäßen Verbindung 6910 mg/kg
5-Mercaplopyridoxin-
hydrochlorid 1250 mg/kg
LD5n (weibliche Mäuse des Stammes CF1S orale Gabe in I %iger wäßriger Methylcellulose)
Hrfindungsgemäße
Verbindung >685O mg kg
Sulfat-Halbhydrat der
erlindungsgemäßen Verbindung 8870 mg/kg

Claims (1)

Patentansprüche:
1. S,S'-Bis-(3-hydroxy-4-hydroxymethyI-2-methyl-5-pyridylmethyl)-ca;bonodithioat der Formel
CH,OH
CH,OH
HO—/ V-CH1-S-C-S-CH,
bonodithioat kann durch Hydrolyse einer Verbindung der nachstehenden allgemeinen Formel
DE2428409A 1973-06-15 1974-06-12 S3'-Bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)-carbonodithioat, dessen pharmakologisch verträgliche Salze und Arzneimittel Expired DE2428409C3 (de)

Applications Claiming Priority (2)

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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Publication Number Publication Date
DE2428409A1 DE2428409A1 (de) 1975-01-09
DE2428409B2 DE2428409B2 (de) 1978-11-30
DE2428409C3 true DE2428409C3 (de) 1979-08-09

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DE2428409A Expired DE2428409C3 (de) 1973-06-15 1974-06-12 S3'-Bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)-carbonodithioat, dessen pharmakologisch verträgliche Salze und Arzneimittel
DE19742428294 Ceased DE2428294A1 (de) 1973-06-15 1974-06-12 Mercaptomethylpyridine und derivate derselben

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DE19742428294 Ceased DE2428294A1 (de) 1973-06-15 1974-06-12 Mercaptomethylpyridine und derivate derselben

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US (1) US3971797A (de)
JP (3) JPS5032180A (de)
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CA (1) CA1037956A (de)
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IL (1) IL44998A (de)
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NL (2) NL185841C (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.
GB2266887B (en) * 1992-05-15 1996-04-17 British Tech Group Substituted pyridines,their preparation and pharmaceutical use
KR100235976B1 (ko) * 1992-05-15 1999-12-15 말콤 카터, 리차드 케이쓰 퍼시 치환된 피리딘 화합물,이것들의 제조방법 및 약제학적 사용방법
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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FI58775B (fi) 1980-12-31
AR203749A1 (es) 1975-10-15
SE411346B (sv) 1979-12-17
CH634302A5 (de) 1983-01-31
RO70852A (ro) 1981-08-17
DD113001A5 (de) 1975-05-12
NO144149C (no) 1981-07-01
LU70342A1 (de) 1975-03-27
AU7004174A (en) 1975-12-18
JPS5387363A (en) 1978-08-01
US3971797A (en) 1976-07-27
NO144149B (no) 1981-03-23
NL7407618A (de) 1974-12-17
CH618428A5 (de) 1980-07-31
DK303274A (de) 1975-02-10
FI58775C (fi) 1981-04-10
GB1466295A (en) 1977-03-02
FR2233057A1 (de) 1975-01-10
IE39467B1 (en) 1978-10-11
SE7407296L (de) 1974-12-16
NL185841C (nl) 1990-08-01
FR2233056B1 (de) 1977-10-28
CH613951A5 (de) 1979-10-31
NL7407616A (de) 1974-12-17
PH10366A (en) 1977-01-18
BG24408A3 (en) 1978-02-10
NL185841B (nl) 1990-03-01
RO71434A (ro) 1981-08-17
FI168574A (de) 1974-12-16
GB1466386A (en) 1977-03-09
FR2233056A1 (de) 1975-01-10
JPS5032181A (de) 1975-03-28
CA1037956A (en) 1978-09-05
CH610305A5 (de) 1979-04-12
DE2428409B2 (de) 1978-11-30
DK148595C (da) 1986-01-27
JPS5032180A (de) 1975-03-28
JPS5747189B2 (de) 1982-10-07
DE2428409A1 (de) 1975-01-09
DK148595B (da) 1985-08-12
NO742042L (de) 1975-05-05
IL44998A (en) 1977-10-31
FR2233057B1 (de) 1978-03-24
ES427277A1 (es) 1976-09-16
IL44998A0 (en) 1974-09-10
IE39467L (en) 1974-12-15
DE2428294A1 (de) 1975-01-09

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