DE2738822A1 - Epoxy-succinic acid mono:ester derivs. - are inhibitors of thiol-protease(s) and have antiinflammatory activity - Google Patents
Epoxy-succinic acid mono:ester derivs. - are inhibitors of thiol-protease(s) and have antiinflammatory activityInfo
- Publication number
- DE2738822A1 DE2738822A1 DE19772738822 DE2738822A DE2738822A1 DE 2738822 A1 DE2738822 A1 DE 2738822A1 DE 19772738822 DE19772738822 DE 19772738822 DE 2738822 A DE2738822 A DE 2738822A DE 2738822 A1 DE2738822 A1 DE 2738822A1
- Authority
- DE
- Germany
- Prior art keywords
- epoxysuccinate
- hydrogen
- compound according
- solution
- note
- 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.)
- Granted
Links
- DCEMCPAKSGRHCN-UHFFFAOYSA-N oxirane-2,3-dicarboxylic acid Chemical compound OC(=O)C1OC1C(O)=O DCEMCPAKSGRHCN-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 101710097834 Thiol protease Proteins 0.000 title abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 3
- 150000002148 esters Chemical class 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- -1 methyl hydrogen Chemical compound 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000004365 Protease Substances 0.000 abstract description 6
- 108090000526 Papain Proteins 0.000 abstract description 4
- 235000019834 papain Nutrition 0.000 abstract description 4
- 229940055729 papain Drugs 0.000 abstract description 4
- 102000005600 Cathepsins Human genes 0.000 abstract description 2
- 108010084457 Cathepsins Proteins 0.000 abstract description 2
- 208000009386 Experimental Arthritis Diseases 0.000 abstract description 2
- 108010004032 Bromelains Proteins 0.000 abstract 1
- 241000700159 Rattus Species 0.000 abstract 1
- 229940124639 Selective inhibitor Drugs 0.000 abstract 1
- 235000019835 bromelain Nutrition 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- 238000000921 elemental analysis Methods 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- MMUKXYWDBWHQBL-UHFFFAOYSA-N (4-nitrophenyl)methylthiourea Chemical class NC(=S)NCC1=CC=C([N+]([O-])=O)C=C1 MMUKXYWDBWHQBL-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000004593 Epoxy Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- ZCUFTCUMEDALHC-UHFFFAOYSA-N CC[K] Chemical compound CC[K] ZCUFTCUMEDALHC-UHFFFAOYSA-N 0.000 description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- NHOKPJQMAIMYJR-UHFFFAOYSA-N C(C#C)[K] Chemical compound C(C#C)[K] NHOKPJQMAIMYJR-UHFFFAOYSA-N 0.000 description 2
- LDHQTLHCMUOSDI-UHFFFAOYSA-N CCCCCCCCCCCC[K] Chemical compound CCCCCCCCCCCC[K] LDHQTLHCMUOSDI-UHFFFAOYSA-N 0.000 description 2
- IRDQNLLVRXMERV-UHFFFAOYSA-N CCCC[Na] Chemical compound CCCC[Na] IRDQNLLVRXMERV-UHFFFAOYSA-N 0.000 description 2
- ZJGPGQJYWPRTFO-UHFFFAOYSA-N CCC[K] Chemical compound CCC[K] ZJGPGQJYWPRTFO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- MKUSAUJRCWWAMK-UHFFFAOYSA-N [K]CC=C Chemical compound [K]CC=C MKUSAUJRCWWAMK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- KBGJIKKXNIQHQH-UHFFFAOYSA-N potassium;methanidylbenzene Chemical compound [K+].[CH2-]C1=CC=CC=C1 KBGJIKKXNIQHQH-UHFFFAOYSA-N 0.000 description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 2
- WPUCZXADEWUTRF-UHFFFAOYSA-N (4-nitrophenyl)methylthiourea;hydrochloride Chemical compound Cl.NC(=S)NCC1=CC=C([N+]([O-])=O)C=C1 WPUCZXADEWUTRF-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- BDOYKFSQFYNPKF-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O BDOYKFSQFYNPKF-UHFFFAOYSA-N 0.000 description 1
- KCMZYCFSSYXEQR-UHFFFAOYSA-N CCCC[K] Chemical compound CCCC[K] KCMZYCFSSYXEQR-UHFFFAOYSA-N 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical group S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010056079 Subtilisins Proteins 0.000 description 1
- 102000005158 Subtilisins Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- PLOSSHSFATUNTF-UHFFFAOYSA-N [K]C1=CC=CC=C1 Chemical compound [K]C1=CC=CC=C1 PLOSSHSFATUNTF-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- UNMLVGNWZDHBRA-UFAVQCRNSA-N alpha-L-Fucp-(1->3)-[alpha-D-Manp-(1->6)-[beta-D-Xylp-(1->2)]-beta-D-Manp-(1->4)-beta-D-GlcpNAc-(1->4)]-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO[C@@H]4[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)O3)O[C@H]3[C@@H]([C@@H](O)[C@H](O)CO3)O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O UNMLVGNWZDHBRA-UFAVQCRNSA-N 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- YQDHCCVUYCIGSW-LBPRGKRZSA-N ethyl (2s)-2-benzamido-5-(diaminomethylideneamino)pentanoate Chemical compound NC(=N)NCCC[C@@H](C(=O)OCC)NC(=O)C1=CC=CC=C1 YQDHCCVUYCIGSW-LBPRGKRZSA-N 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
Abstract
Description
Epoxysuccinsäuremonoester Epoxysuccinic acid monoesters
Die Erfindung betrifft einen neuen Epoxysuccinsäuremonoester der allgemeinen Formel worin R aus der Gruppe Alkyl mit bis zu 12 Kohlenstoffatomen, Allyl, Propargyl, Benzyl und Phenyl und deren Salzen gewählt wird.The invention relates to a new epoxysuccinic acid monoester of the general formula wherein R is selected from the group alkyl of up to 12 carbon atoms, allyl, propargyl, benzyl and phenyl and their salts.
Die Erfindung betrifft neue Epoxysuccinsäuremonoester und deren Salze, die eine ausgezeichnete, stark hemmende Wirkung nur gegen Thiolproteasen besitzen, gleichzeitig aber außerordentlich wenig toxisch sind.The invention relates to new epoxysuccinic acid monoesters and their salts, which have an excellent, strong inhibitory effect only against thiol proteases, at the same time, however, are extremely little toxic.
Die hier verwendeten Begriffe "Epoxysuccinsäure" und "Epoxysuccinat" bedeuten, wenn nichts anderes angegeben ist, daß beide Gruppen in der trans-Form vorliegen.The terms "epoxysuccinic acid" and "epoxysuccinate" used here mean, unless otherwise stated, that both groups are in the trans form are present.
In einer bevorzugten Ausführungsform der Erfindung wird Epoxysuccinsäurediester der allgemeinen Formel II worin R die oben angegebene Bedeutung hat, in einem organischen Lösungsmittel oder einem Gemisch aus organischen Lösungsmitteln und Wasser gelöst. Als organisches Lösungsmittel kann Aceton oder ein Alkohol, wie ein aliphatischer Alkohol mit bis zu 12 Kohlenstoffatomen, Benzylalkohol oder ein Gemisch dieser Alkohole verwendet werden. Zu der erhaltenen Lösung kann unter Eiskühlung oder bei Raumtemperatur ein Atzalkali, wie Kaliumhydroxid oder Natriumhydroxid, in dem genannten organischen Lösungsmittel zugegeben werden.In a preferred embodiment of the invention, epoxysuccinic acid diester of the general formula II wherein R has the meaning given above, dissolved in an organic solvent or a mixture of organic solvents and water. Acetone or an alcohol such as an aliphatic alcohol with up to 12 carbon atoms, benzyl alcohol or a mixture of these alcohols can be used as the organic solvent. An alkali metal, such as potassium hydroxide or sodium hydroxide, in the organic solvent mentioned can be added to the solution obtained with ice cooling or at room temperature.
Bei dieser Umsetzung müssen äquimolare Mengen des Atzalkali verwendet werden. Das erhaltene Gemisch kann 0,5 bis 2 Std.In this implementation, equimolar amounts of the caustic alkali must be used used will. The resulting mixture can be used for 0.5 to 2 hours.
gerührt werden, anschließend kann, wenn notwendig, Athyläther oder Petroläther zur Herstellung eines Alkalisalzes der Verbindung der Formel I als Niederschlag zugegeben werden. Der erhaltene Niederschlag kann durch Filtern gesammelt und durch Umkristallisierung gereinigt werden. Das Alkalimetallsalz kann mit einer anorganischen Säure, wie Schwefelsäure, angesäuert und mit einem organischen Lösungsmittel, wie Athylacetat oder Benzol extrahiert werden, was einen freien Epoxysuccinsäuremonoester der Formel I ergibt. Die meisten Verbindungen der Formel I sind jedoch so ölig, daß man sie am besten in der Form des Alkalimetallsalzes gewinnt. Zur genauen Fließpunktbestimmung können die Salze in die p-Nitrobenzylthiuroniumsalze umgewandelt werden.be stirred, then, if necessary, ethyl ether or Petroleum ether for the preparation of an alkali salt of the compound of formula I as a precipitate be admitted. The precipitate obtained can be collected and filtered through Recrystallization to be purified. The alkali metal salt can be combined with an inorganic Acid, such as sulfuric acid, acidified and with an organic solvent such as Ethyl acetate or benzene can be extracted, resulting in a free epoxysuccinic acid monoester of formula I results. Most of the compounds of formula I, however, are so oily that they are best obtained in the form of the alkali metal salt. For precise determination of the pour point the salts can be converted into the p-nitrobenzylthiuronium salts.
Die erfindungsgemäßen Verbindungen hemmen wirkungsvoll und spezifisch Thiolproteasen wie Papain, Bromelaine und einige Arten von Cathepsin, worin einige Schwefelwasserstoffreste essentiell für die Wirkung sind.The compounds according to the invention inhibit effectively and specifically Thiol proteases such as papain, bromelaine and some types of cathepsin, some in which Hydrogen sulfide residues are essential for the effect.
Die papainhemmende Wirkung der erfindungsgemäßen Verbindungen wurde wie folgt geprüft: Zu 0,5 ml einer Papainlösung (80 pg/mg, Sigma Chem. Co., 2x krist.) wurden 0,25 ml einer Lösung von 40 mmol/l Cystein in 20 mmol/l Dinatriumäthylendiamintetraessigsäurelösung, deren pH mit Natriumhydroxid auf 6,8 eingestellt war, sowie 0,25 ml von 33 mmol/l Phosphatpuffer (pH 6,8) mit oder ohne Hemmstoff gegeben. Nach 15 Minuten Inkubation bei 40°C wurde das erhaltene Gemisch zu 5 ml einer 1%gen Milchkaseinlösung in dem oben beschriebenen Puffer gegeben und nochmals 10 Minuten bei 40 OC inkubiert. Zu dem Gemisch wurden dann 5 ml 0,44 mol/l Trichloressigsäure gegeben, anschließend wurde mit Toyo Filterpapier Nr. 4 filtriert.The papain-inhibiting effect of the compounds according to the invention was tested as follows: To 0.5 ml of a papain solution (80 pg / mg, Sigma Chem. Co., 2x crystall.) 0.25 ml of a solution of 40 mmol / l cysteine in 20 mmol / l disodium ethylenediaminetetraacetic acid solution, whose pH was adjusted to 6.8 with sodium hydroxide, and 0.25 ml of 33 mmol / l phosphate buffer (pH 6.8) with or without an inhibitor. After 15 minutes Incubation at 40 ° C., the resulting mixture became 5 ml of a 1% milk casein solution given in the buffer described above and incubated again for 10 minutes at 40.degree. 5 ml of 0.44 mol / l trichloroacetic acid were then added to the mixture, then was filtered with Toyo No. 4 filter paper.
Die Extinktion des Filtrats wurde bei 280 nm abgelesen. Die prozentuale Hemmung wurde nach der Formel lOOx(B-A)/B berechnet, worin B die Absorption ohne Hemmstoff und A die Absorption mit Hemmstoff bedeuten. Die Hemmstoffmenge für 50% Hemmung wurde als ID50 ausgedrückt und ist in Tabelle 1 dargestellt.The absorbance of the filtrate was read at 280 nm. The percentage Inhibition was calculated according to the formula 100x (B-A) / B, where B is the absorption without Inhibitor and A denotes absorption with inhibitor. The amount of inhibitor for 50% Inhibition was expressed as ID50 and is shown in Table 1.
Tabelle 1 Verbindungen 1D50 (y) Methylhydrogenepoxys uccinat 12,20 Äthylkaliumepoxysuccinat 2,08 n-Propylkaliumepoxys uccinat 0,82 i-Propylkaliumepoxysuccinat 0,78 Allylkaliumepoxysuccinat 0,92 Propargylkaliumepoxysuccinat 1,45 n-Butylnatriumepoxysuccinat 0,29 n-Amylkaliumepoxysuccinat 0,34 n-Dodecylkaliumepoxysuccinat 0,14 Benzylkaliumepoxysuccinat 0,15 Phenylkaliumepoxysuccinat 2,72 Diäthylepoxysuccinat 39,10 Di-n-propylepoxysuccinat 25,35 Di-i-propylepoxysuccinat 30,50 Diallylpropylepoxysuccinat 17,65 n-Butylkalium-cis-epoxysuccinat >200,00 Tabelle 1 zeigt, daß die hemmende Wirkung der erfindungsgemäßen Epoxysuccinsäuremonoester signifikant höher ist, als die der Epoxysuccinsäurediester und des cis-Epoxysuccinat. Table 1 Compounds 1D50 (y) methyl hydrogen epoxysucinate 12.20 Ethyl potassium epoxysuccinate 2.08 n-propyl potassium epoxysuccinate 0.82 i-propyl potassium epoxysuccinate 0.78 allyl potassium epoxysuccinate 0.92 propargyl potassium epoxysuccinate 1.45 n-butyl sodium epoxysuccinate 0.29 n-amyl potassium epoxysuccinate 0.34 n-dodecyl potassium epoxysuccinate 0.14 benzyl potassium epoxysuccinate 0.15 phenylpotassium epoxysuccinate 2.72 diethyl epoxysuccinate 39.10 di-n-propylepoxysuccinate 25.35 di-i-propyl epoxysuccinate 30.50 diallyl propyl epoxysuccinate 17.65 n-butyl potassium cis-epoxysuccinate > 200.00 Table 1 shows that the inhibitory effect of the invention Epoxysuccinic acid monoester is significantly higher than that of the epoxysuccinic acid diester and the cis-epoxysuccinate.
Die erfindungsgemäßen Verbindungen besitzen ferner eine ausgezeichnete entzündungshemmende Wirkung. Sie zeigten signifikante Hemmung von Ratten-Adjuvansarthritis, nachgewiesen mit dem Verfahren von E. Fujihira et al., Pharmacometrics 4, 5, 897 (1970); Benzylhydrogenepoxysuccinat, Äthylhydrogenepoxysuccinat und Amylhydrogenepoxysuccinat zeigten z.B. nach Tag 20 bei wiederholter subkutaner Verabreichung von 100 mg/kg/Tag 55% bzw. 50% und 35% Hemmung.The compounds of the present invention also have excellent properties anti-inflammatory effect. They showed significant inhibition of rat adjuvant arthritis, detected with the method of E. Fujihira et al., Pharmacometrics 4, 5, 897 (1970); Benzyl hydrogen epoxysuccinate, ethyl hydrogen epoxysuccinate and amyl hydrogen epoxysuccinate showed e.g. after day 20 with repeated subcutaneous administration of 100 mg / kg / day 55%, 50% and 35% inhibition, respectively.
Die erfindungsgemäßen Verbindungen besitzen jedoch keine hemmende Wirkung gegen Kaseinproteolyse durch Trypsin, Chymotrypsin, Pepsin, saure Protease aus Peacilomyces varioti und Nagarse (Handelsname der Nagase Industry), Esterolyse von Benzoylargininäthylester durch Kallikrein und Fibrinolyse durch menschliches Plasmin.However, the compounds according to the invention do not have any inhibitory effects Action against casein proteolysis by trypsin, chymotrypsin, pepsin, acidic protease from Peacilomyces varioti and Nagarse (trade name of the Nagase Industry), esterolysis of benzoylarginine ethyl ester by kallikrein and fibrinolysis by human Plasmin.
Die erfindungsgemäßen Verbindungen zeigen bei Mäusen bei einer intraperitonealen Dosis von 2 g/kg keine Toxizität.The compounds according to the invention show in mice with an intraperitoneal Dose of 2 g / kg no toxicity.
Die folgenden Beispiele sollen die Erfindung näher erläutern.The following examples are intended to explain the invention in more detail.
Beispiel 1 Zu einer Lösung von 2,4 g Dimethylepoxysuccinat in 45 ml Methanol wurde unter Eiskühlung eine Lösung von 0,84 g Kaliumhydroxid in 8,4 ml Methanol gegeben. Das Gemisch wurde 2 Stunden gerührt und im Vakuum konzentriert. Der Rückstand wurde in 30 ml Wasser gelöst und mit konzentrierter Schwefelsäure angesäuert. Die erhaltene Lösung wurde 5x mit 30 ml Athylacetat extrahiert. Die Athylacetatschichten wurden zusammengegeben und zur Trockne konzentriert. Die Umkristallisierung des Rückstandes aus Chloroform-hexan ergab 1,31 g (48%) Methylhydrogenepoxysuccinat als weiße Plättchen. Fp. 85-86 OC.Example 1 To a solution of 2.4 g of dimethyl epoxysuccinate in 45 ml Methanol became a solution of 0.84 g of potassium hydroxide in 8.4 ml while cooling with ice Given methanol. The mixture was stirred for 2 hours and concentrated in vacuo. The residue was dissolved in 30 ml of water and washed with concentrated sulfuric acid acidified. The resulting solution was extracted 5 times with 30 ml of ethyl acetate. the Ethyl acetate layers were combined and concentrated to dryness. The recrystallization the residue from chloroform-hexane gave 1.31 g (48%) of methyl hydrogen epoxysuccinate as white plates. M.p. 85-86 OC.
IRKBr(cm 1): 1760 (Ester), 1715 (-COOH), 900 (Epoxid). NMR(CDCl3): ß 3,77 (2H, s, 3,88 (3H, s, O-CH3), 9,95 (1H, s, COOH).IRKBr (cm 1): 1760 (ester), 1715 (-COOH), 900 (epoxy). NMR (CDCl3): β 3.77 (2H, s, 3.88 (3H, s, O-CH3), 9.95 (1H, s, COOH).
Elementaranalyse: Berechnet für C5H605: C 41,1; H 4,13.Elemental analysis: Calculated for C5H605: C 41.1; H 4.13.
Gefunden: C 40,9; H 4,18.Found: C, 40.9; H 4.18.
Beispiel 2 Zu einer Lösung von 9 g Diäthylepoxysuccinat in 30 ml Athanol wurden 2,7 g Kaliumhydroxid in 72 ml Athanol unter Eiskühlung gegeben. Das Gemisch wurde 2 Stunden gerührt und der abgelagerte Feststoff durch Filtrieren gesammelt. Der RUckstand wurde mit einer kleinen Menge Wasser gewaschen und getrocknet. Die Umkristallisierung des Rückstandes aus wässrigem Äthanol ergab 6,8 g (72,58) Athylkaliumepoxysuccinat als weiße Prismen.Example 2 To a solution of 9 g of diethyl epoxysuccinate in 30 ml of ethanol 2.7 g of potassium hydroxide in 72 ml of ethanol were added while cooling with ice. The mixture was stirred for 2 hours and the deposited solid collected by filtration. The residue was washed with a small amount of water and dried. the Recrystallization of the residue from aqueous Ethanol yielded 6.8 g (72.58) ethyl potassium epoxysuccinate as white prisms.
IRKBr(cm 1): 1735 (Ester), 1620 (-COOK), 905 (Epoxid).IRKBr (cm 1): 1735 (ester), 1620 (-COOK), 905 (epoxy).
NMR(D20): 6 1,3 (3H, t, J = 7,0 Hz, -CH3), 3,59 (2H, d.d, J = 2,0 Hz, 4,29 (2H, q, J = 7,0 Hz, -O-CH2).NMR (D20): 6 1.3 (3H, t, J = 7.0 Hz, -CH3), 3.59 (2H, dd, J = 2.0 Hz, 4.29 (2H, q, J = 7.0 Hz, -O-CH2).
Elementaranalyse: Berechnet für C6H705K: C 36,35; H 3,55.Elemental analysis: Calculated for C6H705K: C 36.35; H 3.55.
Gefunden: C 36,17; H 3,61.Found: C, 36.17; H 3.61.
Das p-Nitrobenzylthiuroniumsalz des Athylhydrogenepoxysuccinat hatte einen Schmelzpunkt bei 159-160 °C.The p-nitrobenzylthiuronium salt of ethyl hydrogen epoxysuccinate had a melting point of 159-160 ° C.
Elementaranalyse: Berechnet für C14Hl7N307S: C 45,28; H 4,61; N 11,32.Elemental analysis: Calculated for C14H17N307S: C, 45.28; H 4.61; N 11.32.
Gefunden: C 45,10; H 4,59; N 11,15.Found: C, 45.10; H 4.59; N 11.15.
Die Umwansilung des Kaliumsalzes in das p-Nitrobenzylthiuroniumsalz wurde wie folgt durchgeführt: Zu einer Lösung von 1,5 ml Wasser und 3,5 ml Äthanol wurden 450 mg p-Nitrobenzylthioharnstoffhydrochlorid und 450 mg Athylkaliumepoxysuccinat gegeben und unter Erwärmen gelöst. Nach Abkühlen der Lösung wurden die darin erhaltenen Kristalle durch Filtrieren gesammelt und aus wässrigem Äthanol zu p-Nitrobenzylthiuroniumsalz des Äthylhydrogenepoxysuccinat umkristallisiert.The conversion of the potassium salt into the p-nitrobenzylthiuronium salt was carried out as follows: To a solution of 1.5 ml of water and 3.5 ml of ethanol were 450 mg of p-nitrobenzylthiourea hydrochloride and 450 mg of ethyl potassium epoxysuccinate given and dissolved with heating. After the solution was cooled, those obtained therein were obtained Crystals collected by filtration and converted from aqueous ethanol to p-nitrobenzylthiuronium salt of the ethyl hydrogen epoxysuccinate recrystallized.
Beispiel 3 Zu einer Lösung von 8 g Di-n-propylepoxysuccinat in 50 ml n-Propanol wurde eine Lösung von 2,07 g Kaliumhydroxid in 40 ml n-Propanol gegeben. Das Gemisch wurde dann wie in Beispiel 2 behandelt und ergab 5,1 g (65%) n-Propylkaliumepoxysuccinat.Example 3 To a solution of 8 g of di-n-propylepoxysuccinate in 50 A solution of 2.07 g of potassium hydroxide in 40 ml of n-propanol was added to ml of n-propanol. The mixture was then treated as in Example 2 to give 5.1 g (65%) of n-propyl potassium epoxysuccinate.
IRKBr(cm 1): 1735 (Ester), 1620 (-COOK), 900 (Epoxid).IRKBr (cm 1): 1735 (ester), 1620 (-COOK), 900 (epoxy).
NMR(D20): 6 0,95 (3H, t, J = 6,6 Hz, CH3), 1,7 (2H, m, 3,58 (2H, d.d, J = 2 Hz, 4,2 (2H, t, J = 6,2 Hz, -O-CH2- ) .NMR (D20): 6 0.95 (3H, t, J = 6.6 Hz, CH3), 1.7 (2H, m, 3.58 (2H, dd, J = 2 Hz, 4.2 (2H, t, J = 6.2 Hz, -O-CH2-).
Elementaranalyse: Berechnet für CH2 C7H905K: C 39,61; H 4,27.Elemental analysis: Calculated for CH2 C7H905K: C 39.61; H 4.27.
Gefunden: C 38,35; H 4,33.Found: C, 38.35; H 4.33.
Das p-Nitrobenzylthiuroniumsalz des n-Propylhydrogenepoxysuccinat hatte einen Schmelzpunkt bei 156 OC.The p-nitrobenzylthiuronium salt of n-propyl hydrogen epoxysuccinate had a melting point of 156 ° C.
Elementaranalyse: Berechnet für C15HlgN307S: C 46,75; H 4,97; N 10,90.Elemental analysis: Calculated for C15HlgN307S: C 46.75; H 4.97; N 10.90.
Gefunden: C 46,66; H 4,83; N 10,74.Found: C, 46.66; H 4.83; N 10.74.
Beispiel 4 Zu einer Lösung von Di-i-propylepoxysuccinat in 30 ml i-Propanol wurde unter Eiskühlung eine Lösung von 1,4 g Kaliumhydroxid in 28 ml i-Propanol gegeben. Das Gemisch wurde dann wie in Beispiel 2 behandelt und ergab 3,7 g (70%) i-Propylkaliumepoxysuccinat.Example 4 To a solution of di-i-propyl epoxysuccinate in 30 ml of i-propanol a solution of 1.4 g of potassium hydroxide in 28 ml of i-propanol was obtained while cooling with ice given. The mixture was then treated as in Example 2 to give 3.7 g (70%) i-propyl potassium epoxysuccinate.
IRBr(cm1): 1730 (Ester), 1620 (-COOK), 905 (Epoxid).IRBr (cm1): 1730 (ester), 1620 (-COOK), 905 (epoxy).
NMR(D20): 6 1,31 (6H, d, J = 6,2 Hz, CH3), 3,57 (2H, dd, J = 2,0 Hz, 5,10 (1H, m, J = 6,2 Hz, O-CH-).NMR (D20): 6 1.31 (6H, d, J = 6.2 Hz, CH3), 3.57 (2H, dd, J = 2.0 Hz, 5.10 (1H, m, J = 6.2 Hz, O-CH-).
Elementaranalyse: Berechnet für C7H905K: C 39,61; H 4,27.Elemental analysis: Calculated for C7H905K: C 39.61; H 4.27.
Gefunden: C 38,95; H 4,40.Found: C 38.95; H 4.40.
Das p-Nitrobenzylthiuroniumsalz des i-Propylhydrogenepoxysuccinat hatte einen Schmelzpunkt bei 170 OC Elementaranalyse: Berechnet für C15HlgN307S: C 46,75; H 4,97; N 10,90.The p-nitrobenzylthiuronium salt of i-propyl hydrogen epoxysuccinate had a melting point of 170 OC Elemental analysis: Calculated for C15HlgN307S: C 46.75; H 4.97; N 10.90.
Gefunden: C 46,66; H 4,83; N 10,59.Found: C, 46.66; H 4.83; N 10.59.
Beispiel 5 Zu einer Lösung von 6,36 g Diallylepoxysuccinat in 50 ml Allylalkohol wurde unter Eiskühlung eine Lösung von 1,68 g Kaliumhydroxid in 30 ml Allylalkohol gegeben. Das Gemisch wurde eine Stunde gerührt. Der erhaltene Niederschlag wurde durch Filtrieren gesammelt, mit einer kleinen Menge Aceton gewaschen, getrocknet und aus wässrigem Aceton zu 5,0 g (79,8%) Allylkaliumepoxysuccinat umkristallisiert.Example 5 To a solution of 6.36 g of diallylepoxysuccinate in 50 ml Allyl alcohol became a solution of 1.68 g of potassium hydroxide in 30 while cooling with ice ml of allyl alcohol. The mixture was stirred for one hour. The precipitate obtained was collected by filtration, washed with a small amount of acetone, dried and recrystallized from aqueous acetone to give 5.0 g (79.8%) allyl potassium epoxysuccinate.
IRNujol(cm-1): 1740 (Ester), 1625 (COOK), 900 (Epoxid).IRNujol (cm-1): 1740 (ester), 1625 (COOK), 900 (epoxy).
NMR(D2O): # 3,58 (2H, dd, J = 2,0 Hz, 4,7 (2H, d, J = 6,0 Hz, -O-CH2-), 5,0-5,6 (2H, m, -C = CH2), 6,0 (1H, m, -CH = CH2).NMR (D2O): # 3.58 (2H, dd, J = 2.0 Hz, 4.7 (2H, d, J = 6.0 Hz, -O-CH2-), 5.0-5.6 (2H, m, -C = CH2), 6.0 (1H, m, -CH = CH2).
Elementaranalyse: Berechnet für C7H705K: C 39,99; H 3,35.Elemental analysis: Calculated for C7H705K: C 39.99; H 3.35.
Gefunden: C 39,10; H 3,60.Found: C, 39.10; H 3.60.
Das p-Nitrobenzylthiuroniumsalz des Allylhydrogenepoxysuccinat schmolz bei 147 OC.The p-nitrobenzylthiuronium salt of allyl hydrogen epoxysuccinate melted at 147 OC.
Elementaranalyse: Berechnet für C15H17N307S: C 46,99; H 4,47; N 10,96.Elemental analysis: Calculated for C15H17N307S: C 46.99; H 4.47; N 10.96.
Gefunden: C 46,80; H 4,55; N 10,72.Found: C, 46.80; H 4.55; N 10.72.
Beispiel 6 Zu einer Lösung von 4,16 g Dipropargylepoxysuccinat in 50 ml Propargylalkohol wurde unter Eiskühlung eine Lösung von 1,12 g Kaliumhydroxid in 50 ml Propargylalkohol gegeben.Example 6 To a solution of 4.16 g of dipropargylepoxysuccinate in 50 ml of propargyl alcohol became a solution of 1.12 g of potassium hydroxide while cooling with ice given in 50 ml of propargyl alcohol.
Das Gemisch wurde eine Stunde gerührt. Der so erhaltenen Niederschlag wurde mit einer kleinen Menge Aceton gewaschen, getrocknet und aus wässrigem Aceton zu 3,4 g (82%) Propargylkaliumepoxysuccinat umkristallisiert.The mixture was stirred for one hour. The precipitate thus obtained was washed with a small amount of acetone, dried and extracted from aqueous acetone recrystallized to 3.4 g (82%) propargyl potassium epoxysuccinate.
In (cm 1): 3250 (H-C-C), 2140 (CC), 1750 (Ester), 1630 Nuol (COOK), 900 (Epoxid).In (cm 1): 3250 (H-C-C), 2140 (CC), 1750 (Ester), 1630 Nuol (COOK), 900 (epoxy).
NMR(D20): S 2,98 (1H, t, J t 2,5 Hz, CtCH), 3,63 (2H, dd, J = 2,0 Hz, 4,86 (2H, d, J = 2,5 Hz, -O-CH2-CiCH).NMR (D20): S 2.98 (1H, t, J t 2.5 Hz, CtCH), 3.63 (2H, dd, J = 2.0 Hz, 4.86 (2H, d, J = 2.5 Hz, -O-CH2-CiCH).
Berechnet für C7H505: C 40,38; H 2,42.Calculated for C7H505: C, 40.38; H 2.42.
Gefunden: C 40,15; H 2,49.Found: C, 40.15; H 2.49.
Das p-Nitrobenzylthiuroniumsalz des Propargylhydrogenepoxysuccinat schmolz bei 151-152 OC.The p-nitrobenzylthiuronium salt of propargyl hydrogen epoxysuccinate melted at 151-152 OC.
Beispiel 8 Zu einer Lösung von 5 g Dibenzylepoxysuccinat in 100 ml Benzylalkohol wurde unter Eiskühlung eine Lösung von 0,896 g Kaliumhydroxid in 12,8 ml Benzylalkohol gegeben. Das Gemisch wurde 2 Stunden gerührt. Der erhaltene Niederschlag wurde durch Filtrieren gesammelt, mit Ather gewaschen, getrocknet und aus wässrigem Aceton zu 3,4 g (90%) Benzylkaliumepoxysuccinat umkristallisiert.Example 8 To a solution of 5 g of dibenzyl epoxysuccinate in 100 ml Benzyl alcohol became a solution of 0.896 g of potassium hydroxide in 12.8 g with ice cooling ml of benzyl alcohol. The mixture was stirred for 2 hours. The precipitate obtained was collected by filtration, washed with ether, dried, and extracted from aqueous Recrystallized acetone to 3.4 g (90%) benzyl potassium epoxysuccinate.
IRNujol(cm i): 1743 (Ester), 1620 (COOK), 1500 (aromatisch), 902 (Epoxid).IRNujol (cm i): 1743 (ester), 1620 (COOK), 1500 (aromatic), 902 (epoxy).
NMR(D20): 6 3,56 (2H, dd, J = 2,0 Hz, 5,24 (2H, s, 7,44 (5H, s, Elementaranalyse: Berechnet für C1lH905K: C 50,75; H 3,48.NMR (D20): 6 3.56 (2H, dd, J = 2.0 Hz, 5.24 (2H, s, 7.44 (5H, s, Elemental analysis: Calculated for C1H905K: C 50.75; H 3.48.
Gefunden: C 49,84; H 3,56.Found: C, 49.84; H 3.56.
Das p-Nitrobenzylthiuroniumsalz des Benzylhydrogenepoxysuccinat schmolz bei 164 OC.The p-nitrobenzylthiuronium salt of benzyl hydrogen epoxysuccinate melted at 164 OC.
Elementaranalyse: Berechnet für ClgH19N307S: C 52,65; H 4,42; N 9,70.Elemental analysis: Calculated for ClgH19N307S: C, 52.65; H 4.42; N 9.70.
Gefunden: C 52,37; H 4,26; N 9,48.Found: C, 52.37; H 4.26; N 9.48.
BeisPiel 9 Zu einer Lösung von 4,68 g Didodecylepoxysuccinat in 40 ml Dodecylalkohol wurde bei Raumtemperatur eine Lösung von 0,56 g Kaliumhydroxid in 4 ml Methanol gegeben. Das Gemisch Elementaranalyse: Berechnet für C15Hl5N307S: C 47,24; H 3,96; N 11,02.EXAMPLE 9 To a solution of 4.68 g didodecyl epoxysuccinate in 40 ml of dodecyl alcohol became a solution of 0.56 g of potassium hydroxide at room temperature given in 4 ml of methanol. The mixture Elemental analysis: calculated for C15H15N307S: C, 47.24; H 3.96; N 11.02.
Gefunden: C 46,96; H 4,08; N 10,84.Found: C, 46.96; H 4.08; N 10.84.
Beispiel 7 Zu einer Lösung von 4,88 g Di-n-butylepoxysuccinat in 40 ml n-Butanol wurde unter Eiskühlung eine Lösung von 0,8 g Natriumhydroxid in 10 ml n-Butanol gegeben. Das Gemisch wurde eine Stunde gerührt und zu dem Petroläther gegeben. Der so erhaltene Niederschlag wurde durch Filtrieren gesammelt, mit einer kleinen Menge Aceton gewaschen, getrocknet und aus wässrigem Aceton zu 3,53 g (84%) n-Butylnatriumepoxysuccinat umkristallisiert.Example 7 To a solution of 4.88 g of di-n-butyl epoxysuccinate in 40 ml of n-butanol was a solution of 0.8 g of sodium hydroxide in 10 while cooling with ice ml of n-butanol added. The mixture was stirred for one hour and added to the petroleum ether given. The precipitate thus obtained was collected by filtration with a small amount of acetone washed, dried and extracted from aqueous acetone to 3.53 g (84%) n-Butyl sodium epoxysuccinate recrystallized.
IRNujol (cm-1): 1730 (Ester), 1640, 1610 (COONa), 900 (Epoxid). NMR(D2O): 0,9 (3H, t, J = 6,0 Hz, CH), 1-2 (4H, m, -CH2-CH2-\ 3,54 (2H, dd, J = 2,0 Hz, 4,22 (2H, t, J = 6,0 Hz, -O-CH2- ) Elementaranalyse: Berechnet für C8H110 5Na: C 45,72; H 5,28.IRNujol (cm-1): 1730 (ester), 1640, 1610 (COONa), 900 (epoxy). NMR (D20): 0.9 (3H, t, J = 6.0 Hz, CH), 1-2 (4H, m, -CH2-CH2- \ 3.54 (2H, dd, J = 2.0 Hz, 4.22 (2H, t, J = 6.0 Hz, -O-CH2-) Elemental analysis: Calculated for C8H110 5Na: C, 45.72; H 5.28.
Gefunden: C 45,54; H 5,43.Found: C, 45.54; H 5.43.
Das p-Nitrobenzylthiuroniumsalz des n-Butylhydrogenepoxysuccinat schmolz bei 155 OC Elementaranalyse für C16H2lN307S: C 48,11; H 5,30; N 10,52.The p-nitrobenzylthiuronium salt of n-butyl hydrogen epoxysuccinate melted at 155 ° C. Elemental analysis for C16H2IN307S: C, 48.11; H 5.30; N 10.52.
Gefunden: C 47,86; H 5,51; N 10,50.Found: C, 47.86; H 5.51; N 10.50.
wurde wie in Beispiel 2 behandelt und ergab 0,7 g (23,5%) Dodecylkaliumepoxysuccinat als weiße Nadeln.was treated as in Example 2 to give 0.7 g (23.5%) of dodecyl potassium epoxysuccinate than white needles.
IRKBr (cm-1) 1): 1745 (Ester), 1600 (COOK), 890 (Epoxid).IRKBr (cm-1) 1): 1745 (ester), 1600 (COOK), 890 (epoxy).
NMR(D20): 6 0,89 (3H, t, J = 6 Hz, CH3), 1,32 (22H, m, -(CH2)11-), 3,52 (2H, dd, J = 2 Hz 4,18 (2H, t, J = 7 Hz, O-CH2-).NMR (D20): 6 0.89 (3H, t, J = 6 Hz, CH3), 1.32 (22H, m, - (CH2) 11-), 3.52 (2H, dd, J = 2 Hz 4.18 (2H, t, J = 7 Hz, O-CH2-).
Elementaranalyse: Berechnet für C16H2705K: C 56,77; H 8,04.Elemental analysis: Calculated for C16H2705K: C 56.77; H 8.04.
Gefunden: C 55,95; H 8,75.Found: C, 55.95; H 8.75.
Das p-Nitrobenzylthiuroniumsalz des Dodecylhydrogenepoxysuccinat schmolz bei 141 OC.The p-nitrobenzylthiuronium salt of dodecyl hydrogen epoxysuccinate melted at 141 OC.
Elementaranalyse: Berechnet für C24H37N307S: C 56,34; H 7,29; N 8,21.Elemental analysis: Calculated for C24H37N307S: C, 56.34; H 7.29; N 8.21.
Gefunden: C 56,20; H 7,31; N 8,15.Found: C, 56.20; H 7.31; N 8.15.
Beispiel 1( Zu einer Lösung von 2,48 g Diphenylepoxysuccinat in 50 ml Aceton wurde unter Eiskühlung eine Lösung von 0,56 g Kaliumhydroxid in 2 ml Wasser gegeben. Die erhaltene Lösung wurde wie in Beispiel 1 beschrieben behandelt und ergab o,45 g (22%) Phenylhydrogenepoxysuccinat. Fp. 135-136 OC.Example 1 (To a solution of 2.48 g of diphenyl epoxysuccinate in 50 ml of acetone became a solution of 0.56 g of potassium hydroxide in 2 ml of water while cooling with ice given. The resulting solution was treated as described in Example 1 and yielded 0.45 g (22%) phenyl hydrogen epoxysuccinate. M.p. 135-136 OC.
IRNujol(cm-1): 3030, 1765 (Ester), 1710 (COOH), 1590, 1490 (aromatisch), 900 (Epoxid).IRNujol (cm-1): 3030, 1765 (ester), 1710 (COOH), 1590, 1490 (aromatic), 900 (epoxy).
NMR( (CD3)2CO): 6 3,85 (2H, dd, J = 2,0 Hz, 7,3 (5H, 8,25 (H, breit,-COOH).NMR ((CD3) 2CO): 6 3.85 (2H, dd, J = 2.0 Hz, 7.3 (5H, 8.25 (H, broad, -COOH).
Elementaranalyse: Berechnet für C10H8O5: C 57,69; H 3,87.Elemental analysis: Calculated for C10H8O5: C, 57.69; H 3.87.
Gefunden: C 57,67; H 3,99.Found: C, 57.67; H 3.99.
BeisPiel 11 Zu einer Lösung von 8,16 g Di-n-amylepoxysuccinat in 3 ml n-Amylalkohol wurde unter Eiskühlung eine Lösung von 1,68 g Kaliumhydroxid in 12 ml Amylalkohol gegeben. Das Gemisch wurde 40 Minuten gerührt und zu Petroläther gegeben. Nach KUhlung bei -10 °C wurden die gewonnenen Kristalle gesammelt und mit Petroläther gewaschen, was 2,6 g (368) n-Amylkaliumepoxysuccinat ergab.EXAMPLE 11 To a solution of 8.16 g of di-n-amylepoxysuccinate in 3 ml of n-amyl alcohol was a solution of 1.68 g of potassium hydroxide in Given 12 ml of amyl alcohol. The mixture was stirred for 40 minutes and added to petroleum ether given. After cooling at -10 ° C, the crystals obtained were collected and mixed with Washed petroleum ether to give 2.6 g (368) n-amyl potassium epoxysuccinate.
IRNujOl(¢m 1): 1740 (Ester), 1620 (COOK), 900 (Epoxid).IRNujOl ([m 1): 1740 (ester), 1620 (COOK), 900 (epoxy).
NMR(D20): 6 0,85 (3H, t, J = 6,0 Hz, CH3), 1-2 (6H, m, -CH2-), 3,53 (2H, d.d, J = 2,0 Hz, 4,19 (2H, t, J = 6 Hz, O-CH2).NMR (D20): 6 0.85 (3H, t, J = 6.0 Hz, CH3), 1-2 (6H, m, -CH2-), 3.53 (2H, dd, J = 2.0 Hz, 4.19 (2H, t, J = 6 Hz, O-CH2).
Elementaranalyse: Berechnet für CgH1305K: C 44,98; H 5,45.Elemental analysis: Calculated for CgH1305K: C, 44.98; H 5.45.
Gefund-n:-;C 44,25; H 5,88.Found-n: -; C, 44.25; H 5.88.
Das p-Nitrobenzylthiuroniumsalz des n-Amylhydrogenepoxysuccinat schmolz bei 143 00.The p-nitrobenzylthiuronium salt of n-amyl hydrogen epoxysuccinate melted at 143 00.
Elementarßnalyse: Berechnet für C17H23N307S: C 49,39; H 5,61; N 10,16.Elemental Analysis: Calculated for C17H23N307S: C 49.39; H 5.61; N 10.16.
Gefunden: C 49,19; H 5,60; N 9,91.Found: C, 49.19; H 5.60; N 9.91.
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772738822 DE2738822A1 (en) | 1977-08-29 | 1977-08-29 | Epoxy-succinic acid mono:ester derivs. - are inhibitors of thiol-protease(s) and have antiinflammatory activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772738822 DE2738822A1 (en) | 1977-08-29 | 1977-08-29 | Epoxy-succinic acid mono:ester derivs. - are inhibitors of thiol-protease(s) and have antiinflammatory activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2738822A1 true DE2738822A1 (en) | 1979-03-22 |
| DE2738822C2 DE2738822C2 (en) | 1988-03-17 |
Family
ID=6017542
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19772738822 Granted DE2738822A1 (en) | 1977-08-29 | 1977-08-29 | Epoxy-succinic acid mono:ester derivs. - are inhibitors of thiol-protease(s) and have antiinflammatory activity |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2738822A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115895752A (en) * | 2021-09-30 | 2023-04-04 | 中国石油化工股份有限公司 | Antiwear additive, preparation method thereof and application thereof in oil products |
-
1977
- 1977-08-29 DE DE19772738822 patent/DE2738822A1/en active Granted
Non-Patent Citations (1)
| Title |
|---|
| C.A. Bd.87, 1977, 68129 a * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115895752A (en) * | 2021-09-30 | 2023-04-04 | 中国石油化工股份有限公司 | Antiwear additive, preparation method thereof and application thereof in oil products |
| WO2023051747A1 (en) * | 2021-09-30 | 2023-04-06 | 中国石油化工股份有限公司 | Lubricity improver and application thereof in oil product |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2738822C2 (en) | 1988-03-17 |
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