DE1909665B - 4-aminomethyl-bicyclo square bracket on 2,2,2 square bracket to-oct-2-en-lcarboxylic acid, its salts and antifibrinolytic agents - Google Patents
4-aminomethyl-bicyclo square bracket on 2,2,2 square bracket to-oct-2-en-lcarboxylic acid, its salts and antifibrinolytic agentsInfo
- Publication number
- DE1909665B DE1909665B DE1909665B DE 1909665 B DE1909665 B DE 1909665B DE 1909665 B DE1909665 B DE 1909665B
- Authority
- DE
- Germany
- Prior art keywords
- oct
- square bracket
- salts
- bicyclo
- aminomethyl
- 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.)
- Pending
Links
- 239000011780 sodium chloride Substances 0.000 title claims description 7
- 150000003839 salts Chemical class 0.000 title claims description 5
- 239000002253 acid Substances 0.000 title description 2
- 239000000504 antifibrinolytic agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 5
- ZLHZYQNFVKZWOE-UHFFFAOYSA-N NCC12C=CC(CC1)(CC2)C(=O)O Chemical compound NCC12C=CC(CC1)(CC2)C(=O)O ZLHZYQNFVKZWOE-UHFFFAOYSA-N 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- -1 alkali metal salt Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000035507 absorption Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- SLXKOJJOQWFEFD-UHFFFAOYSA-N Aminocaproic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 3
- QCTBMLYLENLHLA-UHFFFAOYSA-N Aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- WNJHQPYESZTVKU-UHFFFAOYSA-N C(C)(=O)NCC12C=CC(CC1)(CC2)C(=O)O Chemical compound C(C)(=O)NCC12C=CC(CC1)(CC2)C(=O)O WNJHQPYESZTVKU-UHFFFAOYSA-N 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 2
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940090052 4-aminomethylbenzoic acid Drugs 0.000 description 1
- XRZWVSXEDRYQGC-UHFFFAOYSA-N 4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1CCCCC1 XRZWVSXEDRYQGC-UHFFFAOYSA-N 0.000 description 1
- GYDJEQRTZSCIOI-UHFFFAOYSA-N AMCHA Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000002173 Dizziness Diseases 0.000 description 1
- 206010018987 Haemorrhage Diseases 0.000 description 1
- 210000002216 Heart Anatomy 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000007106 Menorrhagia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- LRQKBLKVPFOOQJ-UHFFFAOYSA-N Norleucine Chemical compound CCCCC(N)C(O)=O LRQKBLKVPFOOQJ-UHFFFAOYSA-N 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- 229940012957 Plasmin Drugs 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 229960005202 Streptokinase Drugs 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 241000212749 Zesius chrysomallus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003375 aminomethylbenzoic acid Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 1
- 229910000424 chromium(II) oxide Inorganic materials 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000008286 diarrhea Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000000896 plasminic Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
Description
In jüngster Zeit haben antifibnnolytische Mittel d h Drogen, die die Aktivierung von Plasminogen unter Bildung von Plasmin inhibieren Interesse erregt Derartige Drogen werden ζ Β angewendet bei Personen, die sich chirurgischen Eingriffen (beispielsweise chirurgischen Herz- Lunge- und Prostataeingnffen) unterziehen müssen, bei Hamorrhagiegefahr bei der Entbindung, bei Menorrhagie und bei vielen anderen Krankheitsbildern (vgl Acta Medica Scand Suppl 448 Bd 180, 1966)Recently, antifibnolytic agents have been used That is, drugs that inhibit the activation of plasminogen to form plasmin have aroused interest Such drugs are ζ Β used by people undergoing surgical procedures (for example have to undergo surgical heart, lung and prostate interventions) if there is a risk of hemorrhage in childbirth, in menorrhagia, and in many other clinical pictures (see Acta Medica Scand Suppl 448 Vol 180, 1966)
Ein bekanntes antifibnnolytisches Mittel, im Vergleich mit dem neuere Mittel im allgemeinen getestet werden, ist f -Aminocapronsäure, bekannt als EACA Ein Nachteil dieses Mittels sind die erforderlichen sehr hohen Dosierungen, die in manchen Fallen 3 bis 6 g oder mehr alle 4 bis 6 Stunden betragen Außerdem sind Nebeneffekte, wie Schwindel, Brechreiz und Diarrhöe beobachtet worden Vor kurzem sind zwei stärkere Mittel beschrieben worden, namhch Trans -A- aminomethylcyclohexancarbonsaure (AMCHA) und 4-Aminomethylbenzoesaure (PAMBA) Von beiden wird angegeben, daß sie sowohl bei Tests in vitro als auch bei Tests in vivo aktiver sind als EACA (vgl Scand J Haemat, Bd 2 [1965], S 230, und Acta Pharmacol et Toxicol, Bd 22 [1965], S 340, beide Literaturstellen betreffen AMCHA)A well-known anti-fibnolytic agent against which newer agents are generally tested is α-aminocaproic acid, known as EACA. A disadvantage of this agent is the very high dosages required, in some cases 3 to 6 g or more every 4 to 6 hours been amount addition, side effects such as dizziness, nausea and diarrhea observed recently, two more agents have been described, namhch Trans -A- aminomethylcyclohexancarbonsaure (AMCHA) and 4-Aminomethylbenzoesaure (PAMBA) of both is stated that they both tests in vitro as well as in tests in vivo are more active than EACA (cf. Scand J Haemat, Vol. 2 [1965], p. 230, and Acta Pharmacol et Toxicol, Vol. 22 [1965], p. 340, both references refer to AMCHA)
Gegenstand der Erfindung ist 4-Aminomethylbicyclo-[2,2,2]-okt-2-en-l-carbonsaure der FormelThe invention relates to 4-aminomethylbicyclo- [2,2,2] -oct-2-en-1-carboxylic acid the formula
COOHCOOH
CH2NH2 CH 2 NH 2
Die erfindungsgemaße Verbindung wird entweder oral oder intravenös verabreicht, wobei der orale Weg bevorzugt istThe compound of the invention is either administered orally or intravenously, the oral route being preferred
Die erhndungsgemaße Verbindung kann in jedem pharmazeutisch vertraglichen Trager in Form von Pillen Tabletten oder Kapseln verwendet werden Die pharmazeutisch vertraglichen Salze, sowohl der Aminogruppe, beispielsweise Hydrochlond, Hydrobromid, Sulfat, Citrat oder Tartrat, als auch derThe connection according to the invention can be in any pharmaceutically acceptable carriers in the form of pills tablets or capsules can be used The pharmaceutically acceptable salts, both of the amino group, for example hydrochloride, hydrobromide, Sulfate, citrate or tartrate, as well as the
ίο Carboxygruppe, beispielsweise Alkalimetallsalz oder Erdalkalimetallsalz, sind ohne weiteres verwendbar insbesondere in injizierbaren Mittelnίο carboxy group, for example alkali metal salt or Alkaline earth metal salts are readily useful, particularly in injectables
Die erfindungsgemaße Verbindung zeigt bei Tests in vitro etwa die 30fache Wirkung von EACA die 8fache Wirkung von PAMBA und die 3fache Wirkung von AMCHA, wie aus dem nachfolgenden Versuchsbericht hervorgehtThe compound of the invention shows when tested in vitro about 30 times the effect of EACA 8-fold effect of PAMBA and 3-fold effect of AMCHA, as from the following Test report emerges
VersuchsberichtTest report
Es wurde die Hemmung der Auflosung von Gennsel bestimmt Hierzu wurden zunächst menschliche Fibnngerinsel hergestellt durch Zugabe von Thrombin zu einer Standardmenge von menschlichem Fibnnogen menschlichem Plasminogen und Streptokinase Man muß die Zeit fur vollständige Auflosung bei 37 C in Anwesenheit und in Abwesenheit von Inhibitoren Die Wirkung des bekannten Inhibitors f-Aminocapronsäure wurde gleich 1 gesetzt Der Vergleich der Substanzen erfolgte auf molarer BasisIt became the inhibition of the dissolution of Gennsel To this end, human fibrous islets were first produced by adding thrombin to a standard amount of human fibnogen, human plasminogen and streptokinase One must have the time for complete dissolution at 37 C in the presence and in the absence of Inhibitors The effect of the known inhibitor f-aminocaproic acid was set equal to 1 Der Comparison of the substances was done on a molar basis
und deren Salzeand their salts
Die Erfindung betrifft außerdem antifibnnolytische Mittel, welche aus diesen Verbindungen und pharmazeutisch üblichen Tragerstoffen bestehenThe invention also relates to antifungal agents made from these compounds and pharmaceutically common carrier materials exist
Die erfindungsgemaße Verbindung wird bei pathologischen fibnnolytischen Zustanden bei Saugetieren oder beim Menschen oral in einer Dosis von 1 bis 20, vorzugsweise 2 bis 8 mg/kg Korpergewicht pro Tag gegebenThe compound according to the invention is used in pathological fibnnolytic conditions in mammals or in humans orally in a dose of 1 to 20, preferably given 2 to 8 mg / kg body weight per day
NrNo
Verbindungconnection
WirksamkeilEffective wedge
-t--t-
f -Aminocapronsäuref -aminocaproic acid
4-Aminomethylbenzoesaure4-aminomethylbenzoic acid
Trans-4-aminomethylcyclohexancarbonsaure Trans-4-aminomethylcyclohexanecarboxylic acid
4-Aminomethyl-bicyclo-[2,2,2]-okt-2-en-1 -carbonsaure 4-aminomethyl-bicyclo- [2.2.2] -oct-2-en-1 -carboxylic acid
3,7 10,33.7 10.3
3737
Die Verbindungen 1 bis 3 sind bekannte Verbindüngen die Verbindung 4 ist die erfindungsgemaße Verbindung Der Versuchsbencht zeigt, daß die erfindungsgemaße Verbindung weit wirksamer ist als die fur den gleichen Zweck bekannten Verbindungen Die Herstellung der erfindungsgemaßen Verbindung ist im nachfolgenden Beispiel erläutert Man geht dabei aus von 4-Carboxamido-bicyclo-[2 2 2]-okt-2-en-l-carbonsauremethylester (hergestellt nach Journ Org Chem, Bd 32 [1967], S 3344)Compounds 1 to 3 are known compounds compound 4 is that according to the invention The test bench shows that the invention Compound is far more effective than the compounds known for the same purpose The preparation of the compound according to the invention is illustrated in the following example from 4-carboxamido-bicyclo- [2 2 2] -oct-2-en-1-carboxylic acid methyl ester (prepared according to Journ Org Chem, Vol. 32 [1967], p. 3344)
Herstellung von l-Aminomethyl-4-hydroxymethylbicyclo-[2,2,2]-okt-2-en (II)Preparation of l-aminomethyl-4-hydroxymethylbicyclo- [2,2,2] -oct-2-ene (II)
COOCH,COOCH,
CONH,CONH,
(I)(I)
LiAlHLiAlH
CH, OHCH, OH
Verbindung (II)Connection (II)
(CH3CO)2O(CH 3 CO) 2 O
PyndinPyndin
CH,OHCH, OH
CH2NHCOCH3
(III)CH 2 NHCOCH 3
(III)
Zu 0,85 g (5,1OmMoI) l-Aminomethyl-4-hydroxymethylbicyclo-[2,2,2]-okt-2-en (II), gelost m 15 ml trockenem Pyndin, werden im Verlauf von 30 Minuten 0,46 g (4,5OmMoI) Essigsaureanhydnd in 10 ml Pyndin gegeben Die Mischung wird über Nacht bei Raumtemperatur gerührt. Nach der Entfernung des Pyndins im Vakuum wird das zurückbleibende Ol m 50 ml Essigsdureathylester aufgenommen, es wird zweimal mit 5 ml 3n-HCl und zweimal mit 5 ml gesättigtem Natnumbicarbonat extrahiert, über Magnesiumsulfat getrocknet, filtriert und zu einem Ol eingedampft, das sich rasch verfestigt Bei der Umknstallisation aus Acetonitril wird eine Spur Diacetat entfernt, wobei sich die kristalline N-Acetylverbindung mit einem F = 137 bis 139°C (594 mg, 56%) ergibt Ein Infrarotspektrum zeigt die erwarteten Amid- und Hydroxylabsorptionen Das NMR-Spektrum (CDCl3) zeigt die folgenden Peaks. AB-Quartett, Mitte bei 1,37 ppm (8 Protonen), Singlet bei 2,00 ppm (3 Protonen, Acetyl), Doublet, Mitte bei 3,34 ppm (J = 6 Hz) (2 Protonen, CH2N), Singlet bei 3,61 ppm (2 Protonen, CH2O), breite Absorption, Mitte bei 5,8 ppm (NH), AB-Quartett bei 6,18 ppm (J = 9 Hz) (2 Protonen, Vinylgruppe)0, 46 g (4.5OmMoI) of acetic anhydride are added to 10 ml of pyndine. The mixture is stirred at room temperature overnight. After the pyndine has been removed in vacuo, the remaining oil is taken up in 50 ml of ethyl acetate, extracted twice with 5 ml of 3N HCl and twice with 5 ml of saturated sodium bicarbonate, dried over magnesium sulphate, filtered and evaporated to an oil which solidifies rapidly A trace of diacetate is removed during the conversion from acetonitrile, giving the crystalline N-acetyl compound with a melting point = 137 to 139 ° C. (594 mg, 56%). An infrared spectrum shows the expected amide and hydroxyl absorptions. The NMR spectrum (CDCl 3 ) shows the following peaks. AB quartet, middle at 1.37 ppm (8 protons), singlet at 2.00 ppm (3 protons, acetyl), doublet, middle at 3.34 ppm (J = 6 Hz) (2 protons, CH 2 N) , Singlet at 3.61 ppm (2 protons, CH 2 O), broad absorption, middle at 5.8 ppm (NH), AB quartet at 6.18 ppm (J = 9 Hz) (2 protons, vinyl group)
Herstellung von 4-Acetamidomethylbicyclo-[2,2,2]-okt-2-en-l-carbonsaure (IV)Preparation of 4-acetamidomethylbicyclo- [2,2,2] -oct-2-en-1-carboxylic acid (IV)
Verbindung (III)Compound (III)
COOHCOOH
Γ I ,Γ I,
CrO3 CrO 3
Zu 1,52 g (4OmMoI) Lithiumaluminiumhydrid in 50 ml trockenem, am Rückfluß gehaltenen Tetrahydrofuran wird tropfenweise unter Ruhren eine Losung von 1,90 g (9,1OmMoI) 4-Carboxamido-bicyclo -1_2,2,2] - okt- 2- en -1 - carbonsauremethy lester (I) gegeben Wenn die Zugabe vollständig ist (Dauer 1 Stunde) wird die Mischung 10 Stunden lang gerührt und am Ruckfluß gehalten überschüssiges Lithiumaluminiumhydnd wird durch vorsichtige Zugabe von Wasser zersetzt, das Tetrahydrofuran wird im Vakuum entfernt, und die wäßrige Losung wird mit Kahumhydroxyd basisch gestellt und kontinuierlich mit Äther extrahiert Trocknen der Ätherextrakte mit Magnesiumsulfat Filtrieren und Entfernung des Äthers im Vakuum ergibt ein basisches, farbloses viskoses Ol in einer Menge von 0,85 g (56%) Nach der Entfernung von Losungsmitteln im Hochvakuum wird das Material ohne weitere Reinigung direkt fur die N-Acetyherung verwendet.To 1.52 g (40mMoI) lithium aluminum hydride in 50 ml of dry, refluxed tetrahydrofuran is added dropwise with stirring Solution of 1.90 g (9.1OmmoI) of 4-carboxamido-bicyclo -1_2,2,2] - oct- 2- en -1 - methyl carboxylate (I) given When the addition is complete (duration 1 hour) the mixture is stirred for 10 hours and refluxed excess lithium aluminum hydride is decomposed by careful addition of water, the tetrahydrofuran is in vacuo removed, and the aqueous solution is treated with potassium hydroxide made basic and extracted continuously with ether, drying the ether extracts with Magnesium sulfate. Filtration and removal of the ether in vacuo gives a basic, colorless one viscous oil in an amount of 0.85 g (56%) after removal of solvents in a high vacuum the material is used directly for N-acetylation without further purification.
Herstellung von l-Acetamidomethyl-4-hydroxymethylbicyclo-[2,2,2]-okt-2-en (III)Preparation of l-acetamidomethyl-4-hydroxymethylbicyclo- [2,2,2] -oct-2-ene (III)
H2SO4, (CH3J2COH 2 SO 4 , (CH 3 J 2 CO
(IV)(IV)
CH9NHCOCH,CH 9 NHCOCH,
Zu 209 mg (1,OmMoI) l-Acetamidomethyl-4-hydroxymethylbicyclo-[2,2,2]-okt-2-en (III), gelost in 15 ml Aceton mit 100C, werden im Verlauf von 15 Minuten 0,60 ml 2,67molares Jones-Reagens in 0,10-ml-Anteilen zusammen mit 30 ml Aceton gegeben, wobei die Temperatur zwischen 10 und 15° C gehalten wird Nachdem fur weitere 30 Minuten bei dieser Temperatur gerührt worden ist, werden 2 Tropfen Isopropanol zugegeben, um das überschüssige Oxydationsmittel zu zerstören Schließlich werden 50 ml Wasser zugesetzt, um die niedergeschlagenen Salze zu losen Nach der Entfernung des Acetons im Vakuum wird das Produkt durch kontinuierliche Extraktion der wäßrigen Schicht mit Äther gewonnen Nach Trocknen über Magnesiumsulfat bleibt beim Verdampfen des Äthers die Amidosaure zurück Umkristallisieren aus Acetonitril ergibt das Produkt in Form von Nadeln mit einem F = 220 bis 225° C Ein NMR-Spektrum des Materials zeigt die folgenden Absorptionen (CF3COOH) komplexes Multiplet, 1,2 bis 2,2 ppm (8 Protonen. Ring). Singlet, 2,58 ppm (3 Protonen, Acetyl), Doublet 3,73 ppm (J = 6 Hz) (2 Protonen, CH2N), AB-Quartett 6,47 ppm (J = 8,5 Hz) (2 Protonen, Vinyl), breites Singlet bei 8,7 ppm (1 Proton, NH)To 209 mg (1, OmMoI) l-acetamidomethyl-4-hydroxymethylbicyclo- [2,2,2] -oct-2-ene (III), dissolved in 15 ml acetone at 10 0 C, 0 Add 60 ml of 2.67 molar Jones reagent in 0.10 ml portions together with 30 ml of acetone, keeping the temperature between 10 and 15 ° C. After stirring for a further 30 minutes at this temperature, 2 drops Isopropanol is added to destroy the excess oxidizing agent.Finally, 50 ml of water are added to dissolve the precipitated salts.After removing the acetone in vacuo, the product is obtained by continuously extracting the aqueous layer with ether Recrystallization of the amido acid from acetonitrile gives the product in the form of needles with an F = 220 to 225 ° C. An NMR spectrum of the material shows the following absorptions (CF 3 COOH) complex multiplet, 1.2 to 2.2 ppm (8 Protons, rin G). Singlet, 2.58 ppm (3 protons, acetyl), doublet 3.73 ppm (J = 6 Hz) (2 protons, CH 2 N), AB-quartet 6.47 ppm (J = 8.5 Hz) (2 Protons, vinyl), broad singlet at 8.7 ppm (1 proton, NH)
Herstellung von 4-Aminomethylbicyclo-[2,2,2]-okt-2-on-l-carbonsaure (V)Preparation of 4-aminomethylbicyclo- [2,2,2] -oct-2-one-1-carboxylic acid (V)
Verbindung (IV)Compound (IV)
I)HCl I) HCl
2) Dowex-1-Acetat2) Dowex-1 acetate
COOHCOOH
CH,NH,CH, NH,
Zu 183 mg (0,82 mMol) 4-Acetamidomethylbicyclo-[2,2,2]-okt-2-en-1-carbonsäure (IV) werden 20 ml Äthanol und 40 ml 6 η-Chlor wasserstoffsaure gegeben Es wird über Nacht am Ruckfluß gehalten, wonach beim Eindampfen im Vakuum das rohe Aminosaurehydrochlond als weißer Feststoff zurückbleibt Durch Leiten über Dowex-1-Acetat wird das Material in die freie Aminosäure umgewandelt, die aus Wasser-Aceton-Mischungen umkristallisiert wird Die reine Saure (V) mit einem F = 269 bis 27 Γ C (Zersetzung) erweist sich bei der Dunnschichtchromatographie an Silicagel in zwei Losungsmittelsystemen als homogen und wird mit Ninhydnn als roter Fleck festgestellt (3 1 1 Butanol zu Essigsaure zu H2O, Rf = 0,7, 8 1 1 CHCl3 CH3OH Essigsaure, Rf = 0,15) Ein NMR-Spektrum (D2O) zeigt die erwarteten Absorptionen komplexes Multiplet 1,0 bis 2,0 ppm (8 Protonen, Kern), Singlet, 3,12 ppm (2 Protonen, CH2N), AB-Quartett, 6,32 ppm (J = 8,5 Hz) (2 Protonen, Vinyl)20 ml of ethanol and 40 ml of 6η-hydrochloric acid are added to 183 mg (0.82 mmol) of 4-acetamidomethylbicyclo- [2.2.2] -oct-2-en-1-carboxylic acid (IV). It is added overnight kept under reflux, after which the crude amino acid hydrochloride remains as a white solid on evaporation in vacuo. The material is converted into the free amino acid, which is recrystallized from water-acetone mixtures F = 269 to 27 Γ C (decomposition) proves to be homogeneous in thin-layer chromatography on silica gel in two solvent systems and is determined as a red spot with ninhydnn (3 1 1 butanol to acetic acid to H 2 O, Rf = 0.7, 8 1 1 CHCl 3 CH 3 OH acetic acid, Rf = 0.15) An NMR spectrum (D 2 O) shows the expected absorptions complex multiplet 1.0 to 2.0 ppm (8 protons, nucleus), singlet, 3.12 ppm (2 protons, CH 2 N), AB-quartet, 6.32 ppm (J = 8.5 Hz) (2 protons, vinyl)
Claims (2)
Family
ID=
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