DE1955682C3 - 2- [(MethylsulfinylVacetyl] pyridine and process for its preparation - Google Patents

2- [(MethylsulfinylVacetyl] pyridine and process for its preparation

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Publication number
DE1955682C3
DE1955682C3 DE1955682A DE1955682A DE1955682C3 DE 1955682 C3 DE1955682 C3 DE 1955682C3 DE 1955682 A DE1955682 A DE 1955682A DE 1955682 A DE1955682 A DE 1955682A DE 1955682 C3 DE1955682 C3 DE 1955682C3
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Prior art keywords
acid
pyridine
preparation
addition salts
pharmaceutically acceptable
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Expired
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DE1955682A
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German (de)
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DE1955682B2 (en
DE1955682A1 (en
Inventor
Glenn Curtis Dover Morrison
John Mendham Shavel Jun.
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Warner Lambert Co LLC
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Warner Lambert Pharmaceutical Co
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Publication of DE1955682A1 publication Critical patent/DE1955682A1/en
Publication of DE1955682B2 publication Critical patent/DE1955682B2/en
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Publication of DE1955682C3 publication Critical patent/DE1955682C3/en
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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
    • C07D213/24—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
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01C—PLANTING; SOWING; FERTILISING
    • A01C15/00—Fertiliser distributors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen 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
    • C07D213/24—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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24D—DOMESTIC- OR SPACE-HEATING SYSTEMS, e.g. CENTRAL HEATING SYSTEMS; DOMESTIC HOT-WATER SUPPLY SYSTEMS; ELEMENTS OR COMPONENTS THEREFOR
    • F24D13/00—Electric heating systems
    • F24D13/02—Electric heating systems solely using resistance heating, e.g. underfloor heating
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02B—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO BUILDINGS, e.g. HOUSING, HOUSE APPLIANCES OR RELATED END-USER APPLICATIONS
    • Y02B30/00—Energy efficient heating, ventilation or air conditioning [HVAC]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/10—Process efficiency

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Environmental Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Soil Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Thermal Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Combustion & Propulsion (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Die Erfindung betrifft den Gegenstand der Ansprüche. The invention relates to the subject matter of the claims.

Das biologische Profil dieser Verbindungen ist das folgende:The biological profile of these compounds is as follows:

Die Verbindungen inhibieren diejenigen Immunoreaktionen, die als zellbedingte, verzögerte Hypersensitivitäten eingeordnet werden. Diese letzteren schließen ein die späten, sekundären Migrationsläsionen bei Ratten, denen Freundsches Adjuvans injiziert wurde in Übereinstimmung mit den Techniken, wie sie in Brit. J. Pharmacol., 21, S. 127 — 136 (1962), und 24, S. 632 bis 640 (1965), beschrieben werden; die sensibilisierte Reaktion auf bakterielles Endotoxin, wie es in dem Milz-Zelltest gezeigt wird, vgl. lerne et. al., Cell-bound Antibodies. V/istar Institute Press, 1963, S. 109; die Abstoßung von Hauttransplantat bei Mäusen und Ratten und die Abstoßung von Brustdrüsengewebe bei Ratten, vgl. B i 11 i η g h a m, Transplantation of Cells and Tissues, Wistar Institute Press, 1961, S. 1; Kontakt und Protein-Hypersensitivitäten bei Meerschweinchen, Kaninchen und Ratten, vgl. Uhr, Physiol. Rev., 46, S. 359—419. Die erfindungsgemäßen Verbindungen zeigten in einem Dosisbereich von ca. 1 bis 1000 mg/kg, insbesondere bei 25 bis 100 mg/kg drei- bis viermal täglich oral oder durch Injektion verabreicht, abhängig von dem verwendeten Tier, Wirksamkeit, indem sie die verschiedenen Erscheinungsformen verzögerter Hypersensitivität der Immunoreaktion unterdrücken.The compounds inhibit those immunoreactions that are known as cell-related, delayed hypersensitivities be classified. These latter include the late secondary migratory lesions Rats injected with Freund's adjuvant in accordance with the techniques set out in Brit. J. Pharmacol., 21, pp. 127-136 (1962) and 24, pp. 632-640 (1965); the sensitized response to bacterial endotoxin, as in the spleen cell test is shown, see learn et. al., Cell-bound Antibodies. V / istar Institute Press, 1963, p. 109; the rejection of skin grafts in mice and rats and the Rejection of mammary gland tissue in rats, see B i 11 i η g h a m, Transplantation of Cells and Tissues, Wistar Institute Press, 1961, p. 1; Contact and protein hypersensitivities in guinea pigs, rabbits and rats, see Uhr, Physiol. Rev., 46, pp. 359-419. The compounds according to the invention showed in a dose range of approx. 1 to 1000 mg / kg, in particular at 25 to 100 mg / kg three to four times Administered orally or by injection daily, depending on the animal used, efficacy by the suppress various manifestations of delayed immunoreaction hypersensitivity.

Zu den verzögerten Hypersensitivitäten der Immunoreaktionen, bei denen die erfindungsgemäßen Verbindungen verwendet werden können, gehören beispielsweise rheumatische Arthritis, ulcerative Colitis, Allergien. Haut- und Organ-Transplantationen, systemischer Lupus, glomerolare Nephritis und ähnliche. Was die Toxizität betrifft, so haben die erfindungsgemäßen Verbindungen besonders niedrige Toxizität, beispielsweise treten bei oraler Gabe von 5 g/kg oder bei intravenöser Injektion von 1 g/kg an Mäusen keine Todesfälle auf.On the delayed hypersensitivities of the immunoreactions, in which the compounds of the invention can be used include, for example rheumatoid arthritis, ulcerative colitis, allergies. Skin and organ transplants, systemic Lupus, glomerolar nephritis and the like. As for toxicity, those of the present invention have Compounds particularly low toxicity, for example, occur with oral administration of 5 g / kg or intravenous injection of 1 g / kg into mice did not result in any deaths.

6-Mercaptopurin ist die auf diesem Gebiet bisher meistverwendete Verbindung, wie sich z. B. aus Römpps Chemie-Lexikon, 7. Aufl., 1972, S. 2114, ergibt.6-mercaptopurine is the most widely used compound in this field to date, as is e.g. B. from Römpps Chemie-Lexikon, 7th ed., 1972, p. 2114, results.

Es kann aber festgestellt werden, daß das Überleben von Fremdtransplantaten wesentlich durch eine chemisehe Beeinflussung durch die erfindungsgemäßen Verbindungen verlängert wird, ohne daß die Antikörperbildung unterdrückt wird. Die erfindungsgemäßen Verbindungen waren nicht weniger effektiv bei der Ausdehnung der Lebensdauer der Transplantate als 6-Mercaptopurin, aber ungleich diesem unterdrückte es unter den gleichen Bedingungen nicht die Antikcrperproduktion. Es ergab sich auch, daß die Immunisierungsdauer, d. h. die Überlebensdauer, von Transplantaten bei den erfindungsgemäßen Verbindungen größer war als bei 6-Mercaptopurin. Außerdem ist die Toxizität etwa um das 7fache niedriger als bei 6-Mercaptopurin.It can be stated, however, that the survival of foreign transplants is essentially due to a chemical marriage The influence of the compounds according to the invention is prolonged without the formation of antibodies is suppressed. The compounds of the present invention were no less effective in this Extending the life of the grafts as 6-mercaptopurine, but unlike that suppressed it antibody production does not occur under the same conditions. It was also found that the duration of immunization, i.e. H. the survival time, of transplants the compounds according to the invention was greater than that of 6-mercaptopurine. Besides, the toxicity is about 7 times lower than 6-mercaptopurine.

Um die Verbindungen zu verwenden, können sie mit inerten pharmazeutischen Trägern, wie Laktose, Mannitol, Stärke, verdünnt werden und in Dosiseinheitsformen, wie Tabletten, Kapseln und ähnliche geformt werden. Für die parenterale Verabreichung können diese Verbindungen mit einem inerten, parentalverträglichen Träger, wie Wasser, Salzlösung, Sesamöl und ähnliche, formuliert werden. Diese verschiedenen pharmazeutischen Dosiseinheitsformen werden nach bekannten pharmazeutischen Methoden zusammengestellt. To use the compounds, they can be mixed with inert pharmaceutical carriers such as lactose, mannitol, Starch, can be diluted and formed into unit dosage forms such as tablets, capsules, and the like will. For parenteral administration, these compounds can be mixed with an inert, parentally compatible Carriers such as water, saline, sesame oil and the like can be formulated. These different Pharmaceutical unit dosage forms are composed according to known pharmaceutical methods.

Gemäß der Erfindung wird die freie Verbindung hergestellt, indem ein niedermolekularer Ester der Picolinsäure mit Dimethylsulfoxyd in Gegenwart einer starken Base, wie Natriumamid, Natriumhydrid oder Kalium-t-butylat, umgesetzt wird. Allgemein wird die Reaktion mit oder ohne Lösungsmittel bei einer Temperatur von ca. 20 bis 9O0C ausgeführt. Das Reaktionsprodukt wird durch übliche Methoden isoliert.According to the invention, the free compound is prepared by reacting a low molecular weight ester of picolinic acid with dimethyl sulfoxide in the presence of a strong base such as sodium amide, sodium hydride or potassium t-butoxide. Generally, the reaction is carried out with or without solvent at a temperature of about 20 to 9O 0 C. The reaction product is isolated by customary methods.

Die freie Base kann in ihre pharmazeutisch annehmbaren nichttoxischen Säureadditionssalze durch übliche Verfahren übergeführt werden. Beispiele für nichttoxische Säureadditionssalze sind solche, die mit Essigsäure, Maleinsäure, Fumarsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Apfelsäure, Zimtsäure, SuI-fonsäure, Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure und Salpetersäure gebildet werden. Die Säureadditionssalze können auf übliche Weise hergestellt werden, indem man eine Lösung oder Suspension der feien Base in einem organischen Lösungsmittel mit der gewünschten Säure behandelt und dann das Salz gewinnt, das im allgemeinen durch Kristallisation isoliert wird.The free base can pass into its pharmaceutically acceptable non-toxic acid addition salts usual procedures are transferred. Examples of non-toxic acid addition salts are those with Acetic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, cinnamic acid, sulfonic acid, Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid are formed. The acid addition salts can be prepared in a conventional manner by adding a Solution or suspension of the free base in an organic solvent with the desired acid treated and then recovered the salt, which is generally isolated by crystallization.

Beispielexample

Ein Gemisch aus 24 g Natriumhydrid-Dispersion inA mixture of 24 g of sodium hydride dispersion in

bo Mineralöl und 270 ml Dimethylsulfoxyd wurde 1 Std. bei 700C erhitzt. Zu der entstehenden Lösung gab man 36,2 g Äthylpicolinat unter Kühlen, so daß die Temperatur unterhalb von 3O0C gehalten wurde. Nach Beendigung der Zugabe wurde eine weitere Stunde beiBo mineral oil and 270 ml of dimethyl sulfoxide were heated at 70 ° C. for 1 hour. To the resulting solution, 36.2 g was Äthylpicolinat under cooling so that the temperature was kept below 3O 0 C. After the addition was complete, a further hour was at

hi Zimmertemperatur gerührt. Die Reaktionsn;ischung wurde in 500 ml Eiswasser gegeben, filtriert, und der pH-Wert der Lösung wurde mit konzentrierter Chlorwasserstoffsäure auf 8 eingestellt. Die Lösungstirred at room temperature. The reaction mixture was poured into 500 ml of ice water, filtered, and the pH of the solution was concentrated with Hydrochloric acid adjusted to 8. The solution

ι 3 4ι 3 4

wurde viermal mit 500 ml Teilen Chloroform extrahiert festen Stoffes, Fp. 69,5 bis 71,5°C. Weitere Umkristalli-was extracted four times with 500 ml portions of chloroform. Solid matter, m.p. 69.5-71.5 ° C. Further recrystalline

Die vereinigten Chloroformschichten wurden über sation lieferte die analysenreine Probe, Fp. 71 bis72°C.The combined chloroform layers were ionized to yield the analytically pure sample, melting point 71 to 72 ° C.

Natriumsulfat getrocknet und das Lösungsmittel wurdeSodium sulfate dried and the solvent was added

entfernt Schließlich wurde der Rückstand im Hochva- Analyse fur CsH9NO2S:Finally, the residue was removed in the Hochva Analysis for CsH 9 NO 2 S:

kuum auf einem Dampfbad abgestreift Kristallisation 5 Berechnet: C 52,44, H 4,95, N 7,64, S 17,50%;vacuum stripped on a steam bath Crystallization 5 Calculated: C 52.44, H 4.95, N 7.64, S 17.50%;

des Rückstands aus Äthylacetat lieferte 25 g (57%) eines gefunden: C 52,51, H 4,93, N 7,69, S 17,68%.the residue from ethyl acetate yielded 25 g (57%) of one found: C 52.51, H 4.93, N 7.69, S 17.68%.

Claims (4)

Patentansprüche:
1.2-[(Methylsulfinyl)-acetyl]-pyridin der FormelPatent claims:
1.2 - [(Methylsulfinyl) acetyl] pyridine of the formula und seine pharmazeutisch annehmbaren Säureadditionssalze. and its pharmaceutically acceptable acid addition salts. 2. Verfahren zur Herstellung von Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß man einen niedermolekularen Ester der Picolinsäure mit Dimethylsulfoxid in Gegenwart einer starken Base umsetzt und gewünschtenfalls die so entstandene Verbindung in üblicher Weise in ihre pharmazeutisch annehmbaren Säureadditionssalze überführt.2. Process for the preparation of compounds according to claim 1, characterized in that a low molecular weight ester of picolinic acid with dimethyl sulfoxide in the presence of a strong one Base converts and, if desired, the compound formed in this way in the usual way in their converted to pharmaceutically acceptable acid addition salts. 3. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, daß als starke Base Natriumamid, Natriumhydrid oder Kalium-t-butylat verwendet wird.3. The method according to claim 2, characterized in that the strong base is sodium amide, sodium hydride or potassium t-butoxide is used. 4. Pharmazeutische Zusammensetzungen, enthaltend als Wirkstoff eine Verbindung nach Anspruch 1 neben üblichen Träger- und Hilfsstoffen.4. Pharmaceutical compositions containing a compound according to claim 1 as active ingredient in addition to the usual carriers and auxiliaries.
DE1955682A 1968-11-06 1969-11-05 2- [(MethylsulfinylVacetyl] pyridine and process for its preparation Expired DE1955682C3 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US77394168A 1968-11-06 1968-11-06

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DE1955682A1 DE1955682A1 (en) 1970-06-04
DE1955682B2 DE1955682B2 (en) 1978-01-26
DE1955682C3 true DE1955682C3 (en) 1978-09-21

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DE (1) DE1955682C3 (en)
DK (1) DK135764B (en)
FR (1) FR2024803B1 (en)
GB (1) GB1244098A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725420A (en) * 1970-09-28 1973-04-03 Warner Lambert Co Pyridyl-{62 -hydroxysulfoxides and sulfones and derivatives

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DE1955682B2 (en) 1978-01-26
FR2024803B1 (en) 1973-12-21
DK135764B (en) 1977-06-20
GB1244098A (en) 1971-08-25
DK135764C (en) 1977-11-21
DE1955682A1 (en) 1970-06-04
FR2024803A1 (en) 1970-09-04

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