DE1287588B - New curare-effective up to quarterly compounds - Google Patents

New curare-effective up to quarterly compounds

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Publication number
DE1287588B
DE1287588B DES113282A DES0113282A DE1287588B DE 1287588 B DE1287588 B DE 1287588B DE S113282 A DES113282 A DE S113282A DE S0113282 A DES0113282 A DE S0113282A DE 1287588 B DE1287588 B DE 1287588B
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Germany
Prior art keywords
compounds
curare
tropanium
bis
new
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DES113282A
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German (de)
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MUNNES
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MUNNES
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Priority to DES113282A priority Critical patent/DE1287588B/en
Publication of DE1287588B publication Critical patent/DE1287588B/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

Es ist bekannt, daß Verbindungen mit doppelter quartärer N-Funktion wertvolle physiologische Eigenschaften besitzen. It is known that compounds with a double quaternary N function have valuable physiological properties.

Von den bisquartären Folgeprodukten des 4,4'-Bishalogenmethylbiphenyls wurden bisher das Biphenylen-(4,4')-bis-(methyl-ammoniumchlorid) und das Bipenylen-(4,4')-bis-(methyl-trimethyl-ammoniumjodid) beschrieben (J. W a l k e r, J. Chem. Soc., London, 1950, s. 193 bis 197), die aber schwächer curarewirksam waren als d-Tubocurarin. Of the bisquaternary derivatives of 4,4'-bishalogenmethylbiphenyl were previously the biphenylene (4,4 ') - bis (methyl ammonium chloride) and the Bipenylene- (4,4 ') - bis- (methyl-trimethyl-ammonium iodide) (J. W a lker, J. Chem. Soc., London, 1950, pp. 193 to 197), but the were less effective than d-tubocurarine.

Die Erfindung betrifft neue curarewirksame bisquartäre Verbindungen der allgemeinen Formel in der R den N-(3-Tigloyloxy)-tropanium-, den N-(3- Benzoyloxy)- tropanium- oder den N-(3-Phenylacetoxy)-tropaniumrest und Hal ein Halogenatom bedeutet.The invention relates to new curare-active bisquaternary compounds of the general formula in which R denotes the N- (3-tigloyloxy) tropanium, the N- (3-benzoyloxy) tropanium or the N- (3-phenylacetoxy) tropanium radical and Hal denotes a halogen atom.

Die Verbindungen der allgemeinen Formel können in an sich bekannter Weise dadurch erhalten werden, daß ein 4,4'-Bis-halogenmethyl-biphenyl, vorzugsweise das 4,4'-bis-brommethyl-bphenyl, mit N-(3-Tigloyloxy)-, N-(3-Benzoyloxy)-oder N-(3-Phenylacetoxy)-tropan umgesetzt wird. The compounds of the general formula can be known per se Way can be obtained in that a 4,4'-bis-halomethyl-biphenyl, preferably 4,4'-bis-bromomethyl-bphenyl, with N- (3-tigloyloxy), N- (3-benzoyloxy) or N- (3-phenylacetoxy) tropane is implemented.

Die neuen Verbindungen besitzen wertvolle pharmakologische Eigenschaften und sind insbesondere curarewirksam. The new compounds have valuable pharmacological properties and are particularly effective in curare.

Ihre Toxizitäten und curarimimetische Wirkungen ergeben sich aus der folgenden Tabelle. DL501) Head-drop2) Relative Substanz Maus i. v. ED50 Kaninchen i. v. Curarewirkung3) µg/kg µg/kg d-Tubocurarinchlorid ............................. 130 150 1,0 Biphenylen-(4,4')-bis-[methl-(3a-phenylacetoxy)- tropaniumbromid] 75 40 3,1 Biphenylen-(4,4'-bis-[methyl-(3a-benzoyloxy)- tropaniumbromid] . 290 85 1,5 Biphenylen-(4,4')-bis-[methyl-(3ß-tigloyloxy)- tropaniumbromid]. .. . 1200 150 1,1 1) Berechnet nach K ä r b e r (Arch. exp. Pathol. Pharmakol., 162 [193], S. 480 bis 483).Their toxicities and curarimimetic effects are shown in the following table. DL501) Head-drop2) Relative Substance mouse iv ED50 rabbit iv Curare effect3) µg / kg µg / kg d-tubocurarine chloride ............................. 130 150 1.0 Biphenylene- (4,4 ') - bis- [methyl- (3a-phenylacetoxy) - tropanium bromide] 75 40 3.1 Biphenylene- (4,4'-bis- [methyl- (3a-benzoyloxy) - tropanium bromide]. 290 85 1.5 Biphenylene- (4,4 ') - bis- [methyl- (3ß-tigloyloxy) - tropanium bromide]. ... 1200 150 1.1 1) Calculated according to Kärber (Arch. Exp. Pathol. Pharmakol., 162 [193], pp. 480 to 483).

2) Nach V a r n e y, L i n e g a r und H o l a d a y (J. Pharmacol. exp. therapeut., 97 [1949], S. 72 bis 83).2) According to V a r n e y, L i n e g a r and H o l a d a y (J. Pharmacol. exp. therapeut., 97 [1949], pp. 72 to 83).

3) Am Nerv-Muskelapparat der Katze nach G y ö r g y, D ò d a und N á d o r (Arzneimittel-Forsch., 11 [1961], S. 444 bis 448).3) On the nerve-muscle apparatus of the cat according to G y ö r g y, D ò d a and N á d o r (Arzneimittel-Forsch., 11 [1961], pp. 444 to 448).

Bezüglich einer monoquartären Verbindung, nämlich dem 4-Biphenylyl-methyl-atropiniumbromid, ist aus der Literatur (K, N á d o r und L. G y e r m e k Arzneimittel-Forsch., 8, [1958], S. 336 bis 340) bekannt, daß eine Curarewirkung an Nerv-Muskel-Präparaten von Katzen erst mit hohen Dosen erhalten wird, die bereits im toxischen Bereich liegen. With regard to a mono-quaternary compound, namely 4-biphenylyl-methyl-atropinium bromide, is from the literature (K, N á d o r and L. G y e r m e k Arzneimittel-Forsch., 8, [1958], pp. 336 to 340) known that a curare effect on nerve-muscle preparations is only received by cats with high doses that are already in the toxic range lie.

Beispiel I Biphenylen-(4,4')-bis-[methyl-N-(3ß-tigloyoxy) tropaniumbromid] 10 g N-(3gS-Tigloyloxy)-tropan in 100 ml Aceton und 5 g 4,4'-Bis-brommethyl-biphenyl in 50 ml Aceton gelöst werden zusammengegeben und längere Zeit stehengelassen. Der entstandene Kristallbrei wird abgenutscht, mit Aceton nachgewaschen und getrocknet. Durch mehrmaliges Umkristallisieren aus ethanol oder durch mehrmaliges Aufkochen mit Aceton erhält man eine reine, papierchromatographisch einheitliche, kristalline Substanz vom Schmelzpunkt: 253 bis 256°C (Zersetzung). Ausbeute: 70 bis 80%. Example I Biphenylene- (4,4 ') - bis- [methyl-N- (3ß-tigloyoxy) tropanium bromide] 10 g of N- (3gS-tigloyloxy) -tropane in 100 ml of acetone and 5 g of 4,4'-bis-bromomethyl-biphenyl dissolved in 50 ml of acetone are combined and left to stand for a long time. Of the The resulting crystal slurry is filtered off with suction, washed with acetone and dried. By repeated recrystallization from ethanol or by repeated boiling with acetone, a pure, crystalline one which is uniform according to paper chromatography is obtained Melting point substance: 253 to 256 ° C (decomposition). Yield: 70 to 80%.

C10H54Br3N2O4 # CH3OH (818,7): Berechnet ... C 60,14, H 7,14, Br 19.52; gefunden .. C 60,22, H 6,94, Br 18,99.C10H54Br3N2O4 # CH3OH (818.7): Calculated ... C 60.14, H 7.14, Br 19.52; found .. C 60.22, H 6.94, Br 18.99.

Molekulargewicht 817,5 (titrimetrisch). Molecular weight 817.5 (titrimetric).

B e i s p i e l 2 Biphenylen-(4, 4')-bis-[methyl-N-(3"-benzoyloxy)-tropaniumbromid] 10 g N-(3<£-Benzoyloxy)-tropan werden entsprechend Beispiel 1 umgesetzt. Ausbeute: 70 bis 80%; Schmelzpunkt: 281 bis 282"C (Zersetzung). B e i s p i e l 2 biphenylene- (4, 4 ') - bis- [methyl-N- (3 "-benzoyloxy) tropanium bromide] 10 g of N- (3 <£ -Benzoyloxy) -tropane are converted according to Example 1. Yield: 70 to 80%; Melting point: 281 to 282 "C (decomposition).

C14H50Br2N2O1 (830,8): Berechnet.. C 63,61, H 6,07, Br 19,24; gefunden C 63,10, H 6,23, Br 19.47.C14H50Br2N2O1 (830.8): Calculated. C 63.61, H 6.07, Br 19.24; found C 63.10, H 6.23, Br 19.47.

Molekulargewicht 822,5 (titrimetrisch). Molecular weight 822.5 (titrimetric).

Beispiel 3 Biphenylen-(4, 4')-bis-[melhyl-N-(3"-phenylacetoxy)-tropaniumbromid] N-(3a-Phenylacetoxy)-tropan wird entsprechend Beispiel 1 umgesetzt. Ausbeute: 80%; Schmelzpumkt: 234 bis 236"C (Zersetzung). Example 3 Biphenylene- (4, 4 ') - bis- [methyl-N- (3 "-phenylacetoxy) tropanium bromide] N- (3a-phenylacetoxy) tropane is reacted according to Example 1. Yield: 80%; Melting point: 234 to 236 "C (decomposition).

C10H51Br2N2O1 (858.7): Berechnet . . C 64,33, H 6,34; gefunden . . C 64,39, H 6,48.C10H51Br2N2O1 (858.7): calculated. . C 64.33, H 6.34; found . . C 64.39, H 6.48.

Molekulargewicht 864,0 (titrimetrisch). Molecular weight 864.0 (titrimetric).

Beispiel 4 Biphenylen-(4,4')-bis-[methyl-N-(3ß-benzoyloxy) tropaniumbromid] N-(3ß-Benzoyloxy)-tropaniumbromid wird entsprechend Beispiel I umgesetzt. Ausbeute: 50 bis 60%; Schmelzpunkt: oberhalb 310°C. Example 4 Biphenylene- (4,4 ') - bis- [methyl-N- (3β-benzoyloxy) tropanium bromide] N- (3β-Benzoyloxy) tropanium bromide is reacted according to Example I. Yield: 50 to 60%; Melting point: above 310 ° C.

C11H50Br2N2O4 (830,8): Berechnet. . C 63,61, H 6,07; gefunden . . C 63,30, H 6,28.C11H50Br2N2O4 (830.8): calculated. . C 63.61, H 6.07; found . . C 63.30, H 6.28.

Molekulargewicht 824,3 (titrimetrisch). Molecular weight 824.3 (titrimetric).

Claims (1)

Patentanspruch: Bisquartäre Verbindungen der allgemeinen Formel in der R den N-(3-Tigloyloxy)-tropanium-, den N-(3-Benzoyloxy)-tropanium-oder den N-(3-Phenylacetoxy)-tropaniumrest und Hal ein Halogenatom bedeutet.Claim: Bisquaternary compounds of the general formula in which R denotes the N- (3-tigloyloxy) -tropanium, the N- (3-benzoyloxy) -tropanium or the N- (3-phenylacetoxy) -tropanium radical and Hal denotes a halogen atom.
DES113282A 1962-12-01 1962-12-01 New curare-effective up to quarterly compounds Pending DE1287588B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DES113282A DE1287588B (en) 1962-12-01 1962-12-01 New curare-effective up to quarterly compounds

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021854A1 (en) * 1997-10-24 1999-05-06 Newlaxant Llc Bis-quaternary ammonium derivatives as neuromuscular relaxants

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021854A1 (en) * 1997-10-24 1999-05-06 Newlaxant Llc Bis-quaternary ammonium derivatives as neuromuscular relaxants
US5990124A (en) * 1997-10-24 1999-11-23 Gyermek; Laszlo Neuromuscular relaxants
US6274757B1 (en) 1997-10-24 2001-08-14 Newlaxant Llc Neuromuscular relaxants
US6274623B1 (en) 1997-10-24 2001-08-14 Newlaxant Llc Neuromuscular relaxants

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