NO771033L - ANALOGICAL PROCEDURE FOR THE MANUFACTURE OF ((TENOYL-3) -4-PHENYL) -2-PROPION ACID WITH ANALGETIC, ANTI-INFLAMMATORIC AND ANTI-BLOOD PLATHOLIC COLLECTIVE EFFECT - Google Patents
ANALOGICAL PROCEDURE FOR THE MANUFACTURE OF ((TENOYL-3) -4-PHENYL) -2-PROPION ACID WITH ANALGETIC, ANTI-INFLAMMATORIC AND ANTI-BLOOD PLATHOLIC COLLECTIVE EFFECTInfo
- Publication number
- NO771033L NO771033L NO771033A NO771033A NO771033L NO 771033 L NO771033 L NO 771033L NO 771033 A NO771033 A NO 771033A NO 771033 A NO771033 A NO 771033A NO 771033 L NO771033 L NO 771033L
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- platholic
- inflammatoric
- tenoyl
- analgetic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 239000002253 acid Substances 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 5
- 230000000202 analgesic effect Effects 0.000 title description 4
- 230000003110 anti-inflammatory effect Effects 0.000 title description 3
- 239000008280 blood Substances 0.000 title 1
- 230000000694 effects Effects 0.000 title 1
- CICCQWCEJQLFAF-UHFFFAOYSA-N 2-[4-(thiophene-3-carbonyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CSC=C1 CICCQWCEJQLFAF-UHFFFAOYSA-N 0.000 claims description 6
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 3
- QTWBEVAYYDZLQL-UHFFFAOYSA-N thiophene-3-carbonyl chloride Chemical compound ClC(=O)C=1C=CSC=1 QTWBEVAYYDZLQL-UHFFFAOYSA-N 0.000 claims description 3
- REGOCDRDNZNRMC-UHFFFAOYSA-N 3-ethoxy-2-methyl-3-oxopropanoic acid Chemical compound CCOC(=O)C(C)C(O)=O REGOCDRDNZNRMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ARGIMADSKZUFOB-UHFFFAOYSA-N (4-fluorophenyl)-thiophen-3-ylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CSC=C1 ARGIMADSKZUFOB-UHFFFAOYSA-N 0.000 description 1
- JESGWURRAFBBPR-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-thiophen-3-ylethanone Chemical compound C1=CC(F)=CC=C1C(=O)CC1=CSC=C1 JESGWURRAFBBPR-UHFFFAOYSA-N 0.000 description 1
- BNZPXQWIYCIDMF-UHFFFAOYSA-N 4-[dimethylamino(phenyl)methyl]-5-methylpyrazol-3-one Chemical compound CN(C)C(C=1C(N=NC=1C)=O)C1=CC=CC=C1 BNZPXQWIYCIDMF-UHFFFAOYSA-N 0.000 description 1
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 1
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- AOLOWHMQPDPVDP-UHFFFAOYSA-N diethyl 2-methyl-2-[4-(thiophene-3-carbonyl)phenyl]propanedioate Chemical compound C1=CC(C(C)(C(=O)OCC)C(=O)OCC)=CC=C1C(=O)C1=CSC=C1 AOLOWHMQPDPVDP-UHFFFAOYSA-N 0.000 description 1
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- -1 ethyl 2-methyl-(4-(3-thenyl)-phenyl)malonate Chemical compound 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- WCNLCIJMFAJCPX-UHFFFAOYSA-N pethidine hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 WCNLCIJMFAJCPX-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Description
Foreliggende oppfinnelse vedrorer en analogifremgangsmåte The present invention relates to an analog method
for fremstilling av en ny analgetisk og antiinflammatorisk virkende substituert propionsyre, samt nodvendige mellompro-dukter for fremstilling av denne. Forbindelsen i folge fore-<!>liggende oppfinnelse er (( 3-tenoyl)-4-fenyl)-2-propionsyre for the production of a new analgesic and anti-inflammatory acting substituted propionic acid, as well as necessary intermediate products for the production of this. The compound according to the present invention is ((3-thenoyl)-4-phenyl)-2-propionic acid
med formelen: with the formula:
Denne forbindelsen har et asymmetrisk karbonatom og kan der-for spaltes ved anvendelse av kjente fremgangsmåter på om-rådet, særlig gjennom krystallisasjon av de salter som er-, holdes med en optisk aktiv organisk base. De erholdte aktive former danner en del av foreliggende oppfinnelse. This compound has an asymmetric carbon atom and can therefore be cleaved using methods known in the field, in particular through crystallization of the salts which are held with an optically active organic base. The active forms obtained form part of the present invention.
Likeledes danner de salter som erholdes med en organisk eller mineralsk base som kan anvendes ved human terapi, også en del av oppfinnelsen. Similarly, the salts obtained with an organic or mineral base which can be used in human therapy also form part of the invention.
Denne syren kan fremstilles ved alkalisk hydrolyse av etyl-2-metyl-(4-(3-tenyol)-fenyl)malonat med formelen This acid can be prepared by alkaline hydrolysis of ethyl 2-methyl-(4-(3-thenyl)-phenyl)malonate with the formula
og dekarboxylering. and decarboxylation.
Det nye mellomproduktet utgjor en del av oppfinnelsen. Det fremstilles fortrinnsvis ved alkoylering av fluorfenyltenylmetanonen med etyl-2-metyl-malonat i et dipolært aprotisk losningsmiddel i nærvær av en sterk base. The new intermediate product forms part of the invention. It is preferably prepared by alkylation of the fluorophenylthenylmethanone with ethyl 2-methylmalonate in a dipolar aprotic solvent in the presence of a strong base.
Fluorfenyltenylmetanonen med formelen The fluorophenylthenylmethanone with the formula
er et nytt mellomprodukt, som utgjor en del av oppfinnelsen. Det kan fremstilles ved kondensasjon av 3-tenoylklorid med fluorbensen under de betingelser som anvendes ved Friedel-. is a new intermediate product, which forms part of the invention. It can be prepared by condensation of 3-thenoyl chloride with fluorobenzene under the conditions used in Friedel-.
Crafts reaksjonen. Craft's reaction.
Dessuten har 2-(4-(3-tenoyl)-fenyl)-propionsyren vist seg å ha en særskilt interesse som et analgetisk og antiinflammatorisk middel og antiaggregeringsmiddel for blodplater. Moreover, the 2-(4-(3-thenoyl)-phenyl)-propionic acid has been shown to be of particular interest as an analgesic and anti-inflammatory agent and anti-aggregation agent for blood platelets.
Den analgetiske aktiviteten er påvist ved det forsoket som anvender eddiksyre på mus (Siegmund-metoden modifisert av Koster, Anderson og Debeer). Den aktive dosen 50 (mg/kg) The analgesic activity has been demonstrated in the experiment using acetic acid on mice (Siegmund method modified by Koster, Anderson and Debeer). The active dose 50 (mg/kg)
er lik 9 for 2-(4-(3-tenoyl)-fenyl)-propionsyren, mens aspirin (acetylsalicylsyre) ved dette forsoket hår et DA^^på 130., pyramidon (fenyldimetylaminodimetylpyrazolon) har et DA^Qpå 32 og petidin (etyl-l-metyl-4-fenyl-4-piperidin-karboxylathydroklorid) har et DA^Qpå 17. is equal to 9 for the 2-(4-(3-thenoyl)-phenyl)-propionic acid, while aspirin (acetylsalicylic acid) in this tested hair has a DA^^ of 130., pyramidone (phenyldimethylaminodimethylpyrazolone) has a DA^Q of 32 and pethidine ( ethyl 1-methyl-4-phenyl-4-piperidine carboxylate hydrochloride) has a DA^Q of 17.
Den antiinflammatoriske aktiviteten som bestemmes blant annet ved odemaforsoket med anvendelse av karragenin og rotter The anti-inflammatory activity determined, among other things, in the edema experiment using carrageenan and rats
(Winter og Coll-Proc-Soc Exp. Biol. Med. 1972 III, 544-547) (Winter and Coll-Proc-Soc Exp. Biol. Med. 1972 III, 544-547)
har vist seg å være utmerket. Den aktive dosen 30 (mg/kg) for 2-(4-0-tenoyl)fenyl)-propionsyren er 5, mens fénylbuta-zonets (1,3-difenyl-3,5-dioxo-4n-butyl-pyrazolidin) er 50 og pyramidons er 82. has proven to be excellent. The active dose 30 (mg/kg) for 2-(4-0-thenoyl)phenyl)-propionic acid is 5, while that of phenylbutazone (1,3-diphenyl-3,5-dioxo-4n-butyl-pyrazolidine) is 50 and pyramidons are 82.
Ved inhiberingen av erytem på grunn av UV hos marsvin In the inhibition of erythema due to UV in guinea pigs
(C.V. Winder, J. Wax, V. Burr et al, Arch. Int. Pharm. (1958), 116-261 har. 2-(4-(3-tenoyl)-fenyl)-propionsyre vist seg å være 30 ggr mer aktiv enn aspirin. Ved 5 mg/kg er beskyttelsen hos dyret fullstendig'og er av samme størrelsesorden som det som frembringes av indometacin (1-(4-klorbensoyl)-5-metoxi-2-metylindol-3-eddiksyre) eller ketoprofen (2-(3'-bensoylfenyl)-propionsyre). (C.V. Winder, J. Wax, V. Burr et al, Arch. Int. Pharm. (1958), 116-261. 2-(4-(3-thenoyl)-phenyl)-propionic acid has been shown to be 30 times more active than aspirin At 5 mg/kg the protection in the animal is complete and is of the same order of magnitude as that produced by indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid) or ketoprofen (2-(3'-benzoylphenyl)-propionic acid).
2-(4-(3-tenoyl)-fenyl)-propionsyre inhiberer in vito og in vivo aggregeringen av plasmaplatene hos en kanin, der aggregering indoseres av 5-adenosindifosfat (A D P) og kollagen. Den metoden som anvendes for å styrke den farmakologiske egenskapen, er basert på den som er beskrevet av Born (Journal of Physiology - 1952) og ved hjelp av en Mustard aggregometex. Resultatet 2-(4-(3-thenoyl)-phenyl)-propionic acid inhibits in vitro and in vivo the aggregation of rabbit plasma platelets, where aggregation is induced by 5-adenosine diphosphate (ADP) and collagen. The method used to strengthen the pharmacological property is based on that described by Born (Journal of Physiology - 1952) and using a Mustard aggregometex. The result
angis med en faktor som erholdes fra forholdet: den minste aktive konsentrasjonen (i mikromol) av standard over den sva-keste, aktive konsentrasjonen av produktet. (Med aktiv konsentrasjon, menes den konsentrasjon som gir en 50% eller hbyere is indicated by a factor obtained from the ratio: the least active concentration (in micromoles) of the standard over the weakest, active concentration of the product. (By active concentration, is meant the concentration that gives a 50% or higher
inhibering av aggregeringen). inhibition of the aggregation).
De farmasoytiske komposisjonene som inneholder forbindelsen The pharmaceutical compositions containing the compound
i folge foreliggende oppfinnelse som aktiv bestanddel, enten i form av base eller i form av et organisk eller mineralsk salt, kan foreligge i form av tabletter, piller, kapsler, sukkerovertrukne piller, vannholdige suspensjoner, injiser-bare losninger, aerosoler, sirup og lignende. -Tablettene kan eventuelt gjores gastroresistente:ved overtrekning med et cellulosederivat. according to the present invention as an active ingredient, either in the form of a base or in the form of an organic or mineral salt, can be in the form of tablets, pills, capsules, sugar-coated pills, aqueous suspensions, injectable solutions, aerosols, syrups and the like . - The tablets can optionally be made gastro-resistant: by coating with a cellulose derivative.
De farmasøytiske komposisjonene som inneholder syref orbindels.en i folge foreliggende oppfinnelse som aktiv bestanddel og en fysikalsk akseptabel fast eller flytende farmasoytisk bærer The pharmaceutical compositions containing an acid compound according to the present invention as active ingredient and a physically acceptable solid or liquid pharmaceutical carrier
eller fortynningsmiddel, muliggjor daglige administrerings-dosér av aktiv bestanddel på 20-1000 mg. or diluent, enables daily administration doses of active ingredient of 20-1000 mg.
I det folgende er det gitt et eksempel som illustrerer uten begrensende hensikt de forskjellige fremstillingstrinn ved fremstillingen av den nye syren i folge oppfinnelsen. In the following, an example is given which illustrates, without limiting intent, the various production steps in the production of the new acid according to the invention.
r r
Eksempelet folger. The example follows.
• EKSEMPEL [ • EXAMPLE [
1. trinn: 1 step:
(4-fluorfenyl)-(3-tenyl)metanon (formel III) (4-fluorophenyl)-(3-thenyl)methanone (formula III)
C1;LH7FOS MW = 206,17 C1;LH7FOS MW = 206.17
Til en løsning av 42,5 g (0,29 mol) 3-tiofenkarbonylklorid i To a solution of 42.5 g (0.29 mol) of 3-thiophenecarbonyl chloride i
315 ml fluorbensen ble 57 g.(0,42 mol) vannfritt aluminium-klorid tilsatt i-små porsjoner under samtidig omroring og 315 ml of fluorobenzene, 57 g (0.42 mol) of anhydrous aluminum chloride were added in small portions while simultaneously stirring and
kjoling i ett isbad. Reaksjonen er noe exoterm og temperaturen oker til 10°C. Blandingen varmes deretter i lopet av 45 minutter til 60°C og kokes ved tilbakelop i 15 minutter. Etter kjoling helles blandingen i isvann, og folges av extra-hering med kloroform., Den organiske fasen vaskes med en 5% natriumhydrogénkarbonatlosning og torkes over Na2S04. Etter fordamping av løsningsmiddelet og destillasjon under vakuum erholdes 18,3 g (utbytte 30%), kokepunkt 0,25 mm: 125-130°C; dressing in an ice bath. The reaction is somewhat exothermic and the temperature rises to 10°C. The mixture is then heated over the course of 45 minutes to 60°C and refluxed for 15 minutes. After cooling, the mixture is poured into ice water, followed by extraction with chloroform. The organic phase is washed with a 5% sodium bicarbonate solution and dried over Na 2 SO 4 . After evaporation of the solvent and distillation under vacuum, 18.3 g are obtained (yield 30%), boiling point 0.25 mm: 125-130°C;
smeltepunkt 74°C (hexan) IR: C = 0 1660 cm"<1>" melting point 74°C (hexane) IR: C = 0 1660 cm"<1>"
2. trinn: 2nd step:
Dietyl-2-metyl-2(4-(3-tenoyl)fenyl)-malonat (formel II) C19H20°5 S Mv = 360'35-Diethyl 2-methyl-2(4-(3-thenoyl)phenyl)-malonate (formula II) C19H20°5 S Mv = 360'35-
14,4 g (0,083 mol) dietyl-2-metyl-malonat ble satt dråpevis ved romtemperatur til eh natriumhydridsuspension: 4 g 50% suspension (0,083 mol), i 83 ml nydestillert hexametylfosfor-triamid . Reaksjonen er noe exoterm. 17,1 g (0,083 mol) av (4-fluorfenyl)-(3-tienyl)-metanon ble tilsatt deretter i små porsjoner. Temperaturen okes deretter i lopet av 10 timer 14.4 g (0.083 mol) of diethyl 2-methyl malonate was added dropwise at room temperature to eh sodium hydride suspension: 4 g of 50% suspension (0.083 mol), in 83 ml of freshly distilled hexamethylphosphoric triamide. The reaction is somewhat exothermic. 17.1 g (0.083 mol) of (4-fluorophenyl)-(3-thienyl)-methanone was then added in small portions. The temperature is then increased over the course of 10 hours
til 100°C. Deretter fortynnes med 300 ml berisen, fulgt av to 100°C. Then dilute with 300 ml of berisen, followed by
vask med H20 og torking over IS^SO^. Etter fordamping av løsningsmiddelet og vakuumdestillasjon erholdes en gul olje. washing with H 2 O and drying over IS^SO^. After evaporation of the solvent and vacuum distillation, a yellow oil is obtained.
Vekt: 12,1 g (utbytte 40,6%), kokepunkt 0,4 mm: 190-200°C IR: vC = 0 1660 cm<-1>(keton) Weight: 12.1 g (yield 40.6%), boiling point 0.4 mm: 190-200°C IR: vC = 0 1660 cm<-1>(ketone)
VC = 0 1750 cm<-1>(éstrar) VC = 0 1750 cm<-1>(Estra)
NMR (CC14) : NMR (CC14) :
<S (ppm) : 6 protoner ved 1,25 (triplett J = 7 eps) <S (ppm) : 6 protons at 1.25 (triplet J = 7 eps)
3 protoner ved 1,95 (singlett) 3 protons at 1.95 (singlet)
4 protoner ved 4,3 (kvartett J = 7 eps) 4 protons at 4.3 (quartet J = 7 eps)
7 protoner, fra 7,3, til 8 (topp) 7 protons, from 7.3, to 8 (top)
3. trinn: 3rd step:
2-"(4- (3-tenoyl) -f enyl) -propionsyre (formel I) 2-(4-(3-thenoyl)-phenyl)-propionic acid (formula I)
<C>11H12°3 3 Mv = 260'30 <C>11H12°3 3 Mv = 260'30
12,1 g (3,3xlO~<2>mol) dietyl-2-metyl-2-((3,4-tenoylfenyl)--malonat og 80 ml åv en 5% yannholdig natriumhydrbxidlosning tilbakelopskokes i 6 timer. Etter kjoling og vask av los-ningen med bensen, ble den vannholdige fasen surgjort med 1/2 HC1. Den dannede oljen ble .extrahert med kloroform. Etter torking over Na2S0^og fordamping av losnirigsmiddelét erholdes 9 g av en tykk olje, og denne ble omkrystallisert: 3,4 g avet hvitt fast stoff erholdtes: 12.1 g (3.3x10~<2>mol) diethyl 2-methyl-2-((3,4-thenoylphenyl)-malonate and 80 ml of a 5% aqueous sodium hydroxide solution are refluxed for 6 hours. After cooling and washing the solution with benzene, the aqueous phase was acidified with 1/2 HCl. The oil formed was extracted with chloroform. After drying over Na2SO4 and evaporation of the solvent, 9 g of a thick oil were obtained, and this was recrystallized: 3.4 g of white solid was obtained:
Smp = 99-105°C; (^-0-<) ; utbytte: 39,5%' Mp = 99-105°C; (^-0-<) ; yield: 39.5%'
IR: -k>.C=0: 1650 cm<-1>(keton) IR: -k>.C=0: 1650 cm<-1>(ketone)
VC=0: 1730 cm<-1>(syra). VC=0: 1730 cm<-1>(acid).
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7608470A FR2345148A1 (en) | 1976-03-24 | 1976-03-24 | NEW SUBSTITUTE PROPIONIC ACID, PREPARATION AND APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO771033L true NO771033L (en) | 1977-09-27 |
Family
ID=9170850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO771033A NO771033L (en) | 1976-03-24 | 1977-03-23 | ANALOGICAL PROCEDURE FOR THE MANUFACTURE OF ((TENOYL-3) -4-PHENYL) -2-PROPION ACID WITH ANALGETIC, ANTI-INFLAMMATORIC AND ANTI-BLOOD PLATHOLIC COLLECTIVE EFFECT |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS52139057A (en) |
| AR (1) | AR212262A1 (en) |
| AT (1) | AT358026B (en) |
| AU (1) | AU2351877A (en) |
| BE (1) | BE852463A (en) |
| CA (1) | CA1102343A (en) |
| CH (1) | CH597220A5 (en) |
| CS (1) | CS199667B2 (en) |
| DD (1) | DD128778A5 (en) |
| DE (1) | DE2711585A1 (en) |
| DK (1) | DK128077A (en) |
| ES (1) | ES457112A1 (en) |
| FR (1) | FR2345148A1 (en) |
| GB (1) | GB1517688A (en) |
| HU (1) | HU176990B (en) |
| IE (1) | IE44660B1 (en) |
| IL (1) | IL51720A0 (en) |
| IT (1) | IT1115272B (en) |
| MX (1) | MX4565E (en) |
| NL (1) | NL7703215A (en) |
| NO (1) | NO771033L (en) |
| OA (1) | OA06109A (en) |
| SE (1) | SE7703317L (en) |
| SU (1) | SU657748A3 (en) |
| YU (1) | YU65377A (en) |
| ZA (1) | ZA771724B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2030131B (en) * | 1978-09-12 | 1982-12-22 | Taiyo Pharma Ind | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
| EP0046337A3 (en) * | 1980-08-20 | 1982-09-15 | Imperial Chemical Industries Plc | Triazole compounds, a process for preparing them, their use as plant and pharmaceutical fungicides and as plant growth regulators and compositions containing them |
| GB2181728B (en) * | 1985-10-21 | 1990-01-24 | Indian Drugs & Pharma | 4-(3-thienyl)phenylalkanoic acids and derivatives and process for their preparation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1007643A (en) * | 1972-10-24 | 1977-03-29 | Janssen Pharmaceutica Naamloze Vennootschap | Aroyl-substituted phenylacetic acid derivatives |
-
1976
- 1976-03-24 FR FR7608470A patent/FR2345148A1/en active Granted
-
1977
- 1977-03-11 YU YU00653/77A patent/YU65377A/en unknown
- 1977-03-15 AT AT176577A patent/AT358026B/en not_active IP Right Cessation
- 1977-03-15 BE BE175792A patent/BE852463A/en not_active IP Right Cessation
- 1977-03-17 DE DE19772711585 patent/DE2711585A1/en not_active Withdrawn
- 1977-03-18 CS CS771807A patent/CS199667B2/en unknown
- 1977-03-21 IT IT7721461A patent/IT1115272B/en active
- 1977-03-21 CA CA274,355A patent/CA1102343A/en not_active Expired
- 1977-03-22 CH CH359977A patent/CH597220A5/xx not_active IP Right Cessation
- 1977-03-22 IL IL51720A patent/IL51720A0/en unknown
- 1977-03-22 ZA ZA00771724A patent/ZA771724B/en unknown
- 1977-03-23 AU AU23518/77A patent/AU2351877A/en not_active Expired
- 1977-03-23 DK DK128077A patent/DK128077A/en not_active Application Discontinuation
- 1977-03-23 MX MX775559U patent/MX4565E/en unknown
- 1977-03-23 GB GB12327/77A patent/GB1517688A/en not_active Expired
- 1977-03-23 NO NO771033A patent/NO771033L/en unknown
- 1977-03-23 SE SE7703317A patent/SE7703317L/en unknown
- 1977-03-23 ES ES457112A patent/ES457112A1/en not_active Expired
- 1977-03-23 SU SU772462808A patent/SU657748A3/en active
- 1977-03-23 IE IE616/77A patent/IE44660B1/en unknown
- 1977-03-23 HU HU77LI310A patent/HU176990B/en unknown
- 1977-03-24 DD DD7700198055A patent/DD128778A5/en unknown
- 1977-03-24 JP JP3164377A patent/JPS52139057A/en active Pending
- 1977-03-24 NL NL7703215A patent/NL7703215A/en not_active Application Discontinuation
- 1977-03-24 AR AR266969A patent/AR212262A1/en active
- 1977-03-28 OA OA56120A patent/OA06109A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR212262A1 (en) | 1978-06-15 |
| JPS52139057A (en) | 1977-11-19 |
| ZA771724B (en) | 1978-02-22 |
| AT358026B (en) | 1980-08-11 |
| NL7703215A (en) | 1977-09-27 |
| IL51720A0 (en) | 1977-05-31 |
| CA1102343A (en) | 1981-06-02 |
| CH597220A5 (en) | 1978-03-31 |
| BE852463A (en) | 1977-09-15 |
| IT1115272B (en) | 1986-02-03 |
| CS199667B2 (en) | 1980-07-31 |
| ATA176577A (en) | 1980-01-15 |
| MX4565E (en) | 1982-06-17 |
| FR2345148B1 (en) | 1978-10-20 |
| OA06109A (en) | 1981-06-30 |
| SU657748A3 (en) | 1979-04-15 |
| SE7703317L (en) | 1977-09-25 |
| DE2711585A1 (en) | 1977-09-29 |
| DD128778A5 (en) | 1977-12-07 |
| IE44660L (en) | 1977-09-24 |
| AU2351877A (en) | 1978-09-28 |
| YU65377A (en) | 1983-01-21 |
| DK128077A (en) | 1977-09-25 |
| FR2345148A1 (en) | 1977-10-21 |
| HU176990B (en) | 1981-06-28 |
| GB1517688A (en) | 1978-07-12 |
| ES457112A1 (en) | 1978-03-01 |
| IE44660B1 (en) | 1982-02-10 |
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