NO156608B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMIDES OF 4-AMINO ACID ACID. - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMIDES OF 4-AMINO ACID ACID. Download PDFInfo
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- NO156608B NO156608B NO812890A NO812890A NO156608B NO 156608 B NO156608 B NO 156608B NO 812890 A NO812890 A NO 812890A NO 812890 A NO812890 A NO 812890A NO 156608 B NO156608 B NO 156608B
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- carbon atoms
- acid
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- 150000001408 amides Chemical class 0.000 title claims abstract description 6
- 239000002253 acid Substances 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000001225 therapeutic effect Effects 0.000 title 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 2
- WCVPFJVXEXJFLB-UHFFFAOYSA-N 4-aminobutanamide Chemical class NCCCC(N)=O WCVPFJVXEXJFLB-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 4
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 2
- 125000005842 heteroatom Chemical group 0.000 abstract 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract 2
- 235000001014 amino acid Nutrition 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- -1 amide esters Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000001773 anti-convulsant effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 230000000147 hypnotic effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- IYGYMKDQCDOMRE-QRWMCTBCSA-N Bicculine Chemical compound O([C@H]1C2C3=CC=4OCOC=4C=C3CCN2C)C(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-QRWMCTBCSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- AACMFFIUYXGCOC-UHFFFAOYSA-N bicuculline Natural products CN1CCc2cc3OCOc3cc2C1C4OCc5c6OCOc6ccc45 AACMFFIUYXGCOC-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- IYGYMKDQCDOMRE-UHFFFAOYSA-N d-Bicucullin Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1OC(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000000803 paradoxical effect Effects 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 230000004622 sleep time Effects 0.000 description 2
- MVNDLBVMQJUQOA-UHFFFAOYSA-N 2-ethyl-3-methylpentanoic acid Chemical compound CCC(C)C(CC)C(O)=O MVNDLBVMQJUQOA-UHFFFAOYSA-N 0.000 description 1
- WCYPPYDWDMCZIU-UHFFFAOYSA-N 4-(butanoylamino)butanoic acid Chemical compound CCCC(=O)NCCCC(O)=O WCYPPYDWDMCZIU-UHFFFAOYSA-N 0.000 description 1
- BVAIRKQPJHMDNC-UHFFFAOYSA-N 4-(pentanoylamino)butanoic acid Chemical compound CCCCC(=O)NCCCC(O)=O BVAIRKQPJHMDNC-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- XDOLZJYETYVRKV-UHFFFAOYSA-N 7-Aminoheptanoic acid Chemical class NCCCCCCC(O)=O XDOLZJYETYVRKV-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010021033 Hypomenorrhoea Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000002920 convulsive effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Oppfinnelsen vedrører en fremgangsmåte for fremstilling av terapeutisk aktive amider av 4-aminosmørsyre, idet disse derivater spesielt har farmakologisk innvirkning på sentralnervesystemet. The invention relates to a method for the production of therapeutically active amides of 4-aminobutyric acid, these derivatives particularly having a pharmacological effect on the central nervous system.
De derivater som fremstilles i henhold til oppfinnelsen er produkter som tilsvarer den generelle formel: The derivatives produced according to the invention are products corresponding to the general formula:
hvor: where:
R er en rettkjedet eller forgrenet alkylgruppe med 1-7 karbonatomer, eller en cykloalkylgruppe; m er et helt tall som er 0-3; n er et helt tall som er 0-2, idet m+n er lik eller over 1; X er hydrogen, en alkylgruppe med 1-4 karbonatomer, en fenyl-alkylgruppe hvor fenylgruppen eventuelt er substituert med to metoksygrupper; og R2er hver for seg hydrogen, en rettkjedet eller forgrenet alkylgruppe med 1-18 karbonatomer, en benzylgruppe, en gruppe eller R^og R2danner, sammen med nitrogenatomet som de er knyttet til, en morfolin-, pyrrolidin-, pyridin-gruppe eller en gruppe Disse forbindelser viser interessante aktiviteter på sentralnervesystemet og kan spesielt anvendes som sedativer, beroligende midler, hypnotiske midler eller anksiolytiske midler. Fremgangsmåten i henhold til oppfinnelsen erkarakterisertved at en forbindelse med formel hvor m, n og X har den ovenfor angitte betydning, og R' er H eller lavere alkyl, omsettes med et syreklorid av formel R-COC1 for omdannelse av aminet til amid, idet reaksjonen utføres i et egnet løsnings-middel og i nærvær av en syreakseptor, og det oppnådde produkt utsettes for amidifisering ved hjelp av et amin av formel R is a straight-chain or branched alkyl group with 1-7 carbon atoms, or a cycloalkyl group; m is an integer that is 0-3; n is an integer that is 0-2, where m+n is equal to or greater than 1; X is hydrogen, an alkyl group with 1-4 carbon atoms, a phenyl-alkyl group where the phenyl group is optionally substituted with two methoxy groups; and R 2 are each hydrogen, a straight-chain or branched alkyl group of 1-18 carbon atoms, a benzyl group, a group or R^ and R 2 form, together with the nitrogen atom to which they are attached, a morpholine, pyrrolidine, pyridine group or a group These compounds show interesting activities on the central nervous system and can especially be used as sedatives, sedatives, hypnotics or anxiolytics. The method according to the invention is characterized in that a compound of the formula where m, n and X have the above-mentioned meaning, and R' is H or lower alkyl, is reacted with an acid chloride of the formula R-COC1 to convert the amine into an amide, as the reaction is carried out in a suitable solvent and in the presence of an acid acceptor, and the product obtained is subjected to amidification using an amine of formula
Reaksjonsskjemaet for fremgangsmåten i henhold til oppfinnelsen er altså som følger: The reaction scheme for the method according to the invention is thus as follows:
Ut fra aminosyrene eller esterne 1_ kjente forbindelser oppnår man syrene eller amidesterne 2 ved innvirkning av syreklorid R-C0C1 i et passende løsningsmiddel, for eksempel vann, eter eller en lavere alifatisk alkohol og i nærvær av en mineralsk eller organisk hydrogensyre-akseptor, og spesielt natriumkarbonat eller trietylamin. From the amino acids or esters 1_ known compounds, the acids or amide esters 2 are obtained by the action of acid chloride R-COC1 in a suitable solvent, for example water, ether or a lower aliphatic alcohol and in the presence of a mineral or organic hydrogen acid acceptor, and especially sodium carbonate or triethylamine.
Syrene eller esterne amid 2 isoleres i reaksjonsblandingen og benyttes oftest slik de er uten rensning for det følgende trinn. The acids or esters amide 2 are isolated in the reaction mixture and are most often used as they are without purification for the following step.
Amidifiseringsreaksjonen av produkt 2 kan utføres i henhold til forskjellige metoder. The amidification reaction of product 2 can be carried out according to different methods.
Når R<1>er lavere alkyl, kan reaksjonen utføres i løsning i en lavere alifatisk alkohol eller ved å benytte et overskudd When R<1> is lower alkyl, the reaction can be carried out in solution in a lower aliphatic alcohol or by using an excess
av amin of amine
som løsningsmiddel. Man arbeider vanligvis as a solvent. One usually works
ved en temperatur som ligger mellom 0 og 50 C og i et tidsrom av fra 1 time til flere dager. at a temperature between 0 and 50 C and for a period of from 1 hour to several days.
Når R' er H kan man for eksempel omdanne denne syre til en lavere ester, i hvilket tilfelle man utfører reaksjonen som beskrevet ovenfor, for eksempel ved å omdanne denne syre til et blandet anhydrid. En slik omdannelse utføres ved at man lar syren reagere med etylklorformiat i nærvær av et alkalisk materiale, for eksempel trietylamin. Man arbeider i et passende løsningsmiddel, for eksempel tetrahydrofuran, ved en temperatur på fra 0 til 4 0°C og uten behov for å isolere dette blandede anhydrid. • When R' is H, this acid can for example be converted into a lower ester, in which case the reaction is carried out as described above, for example by converting this acid into a mixed anhydride. Such a conversion is carried out by allowing the acid to react with ethyl chloroformate in the presence of an alkaline material, for example triethylamine. One works in a suitable solvent, for example tetrahydrofuran, at a temperature of from 0 to 40°C and without the need to isolate this mixed anhydride. •
De følgende eksempler, som ikke er ment begrensende, gjør det lettere å forstå oppfinnelsens idé. The following examples, which are not meant to be limiting, make it easier to understand the idea of the invention.
Eksempel 1 Example 1
10- butyl- 4 , 9- diokso- 5, 10- diaza- tetradekar (CM 40039) 10-butyl-4,9-dioxo-5,10-diazatetradeca (CM 40039)
(I) R = CH3-(CH2)2-; m = n =1; X = H; Rx =R2= -(CH2)3CH3. (I) R = CH 3 -(CH 2 ) 2 -; m = n = 1; X = H; R x =R 2 = -(CH 2 ) 3 CH 3 .
a) Til en løsning av 10,3 g 4-aminosmørsyre i 110 ml a) To a solution of 10.3 g of 4-aminobutyric acid in 110 ml
av en vandig løsning av 2N natriumkarbonat avkjølt på is of an aqueous solution of 2N sodium carbonate cooled on ice
tilsetter man dråpevis under røring 11,7 g butyrylklorid. 11.7 g of butyryl chloride are added dropwise while stirring.
Etter at tilsetningen er ferdig, fortsetter agiteringen i After the addition is complete, the agitation continues i
4 timer. 4 hours.
Man vasker den vandige løsning med metylenklorid, sur- The aqueous solution is washed with methylene chloride, acid
gjør deretter vannfasen og metter med natriumklorid. Man ekstraherer med metylenklorid, tørker over natriumsulfat og inndamper til tørrhet under vakuum. Den faste inndampnings-rest røres tre ganger med 300 ml pentan, og tørkes under vakuum. Utbyttet er 9,1 g, som anvendes slik det er for den følgende operasjon. then make the water phase and saturate with sodium chloride. It is extracted with methylene chloride, dried over sodium sulphate and evaporated to dryness under vacuum. The solid evaporation residue is stirred three times with 300 ml of pentane and dried under vacuum. The yield is 9.1 g, which is used as is for the following operation.
b) Man oppløser den ovenfor oppnådde syre (9,1 g) i b) The acid obtained above (9.1 g) is dissolved in
200 ml tørt tetrahydrofuran. Man tilsetter 6,06 g trietylamin 200 ml dry tetrahydrofuran. 6.06 g of triethylamine is added
og 6,51 g etylklorformiat ved opprettholdelse av temperaturen under eller på 5°C. Man foretar røring i 1 time og tilsetter så dråpevis 7,74 g dibutylamin. Man lar dette henstå natten over under røring ved omgivelsestemperatur. and 6.51 g of ethyl chloroformate by maintaining the temperature below or at 5°C. Stirring is carried out for 1 hour and then 7.74 g of dibutylamine are added dropwise. This is allowed to stand overnight with stirring at ambient temperature.
Man filtrerer det uløselige materiale og fordamper løsningsmidlet til tørrhet. Man tar inndampningsresten opp i eter og vasker løsningen med en fortynnet saltsyreløsning, hvoretter man tilsetter en fortynnet natriumkarbonatløsning og til slutt en vandig løsning som er mettet med natriumklorid. Man tørker eterløsningen over natriumsulfat, fordamper løsningsmidlet til tørrhet og destillerer inndampningsresten under .vakuum. Man oppnår 6,2 g av en blekgul væske. Kokepunkt ved 0,01 mm:170°C. The insoluble material is filtered and the solvent is evaporated to dryness. The evaporation residue is taken up in ether and the solution is washed with a dilute hydrochloric acid solution, after which a dilute sodium carbonate solution is added and finally an aqueous solution saturated with sodium chloride. The ether solution is dried over sodium sulphate, the solvent is evaporated to dryness and the evaporation residue is distilled under vacuum. 6.2 g of a pale yellow liquid is obtained. Boiling point at 0.01 mm: 170°C.
Eksempel 2 Example 2
Man arbeider som angitt i eksempel 1, men varierer aminet som ble anvendt i avsnitt b). One works as indicated in example 1, but varies the amine that was used in section b).
Man oppnår således produktene (I) :R = CH3(CH2)2, m = n = The products (I) are thus obtained: R = CH3(CH2)2, m = n =
1, X = H, som fremkommer av tabell I nedenunder. 1, X = H, which appears from table I below.
Eksempel 3 Example 3
Man arbeider som angitt i eksempel 1, men varierer på You work as indicated in example 1, but vary on
den ene side det anvendte syreklorid i første trinn og eventuelt, på den annen side, det amin som anvendes i annet trinn. on the one hand the acid chloride used in the first step and possibly, on the other hand, the amine used in the second step.
Man oppnår således produktene (I) som er beskrevet i The products (I) described in are thus obtained
tabell II nedenunder. table II below.
Eksempel 4 Example 4
5- butyl- 12- etyl- 13- metyl- 6, ll- diokso- 5, 10- diaza- pentadekan 5- butyl- 12- ethyl- 13- methyl- 6, ll- dioxo- 5, 10- diaza-pentadecane
(CM 40195) (CM 40195)
a) Til 9,18 g av benzylester-hydrokloridet av 4-amino-smørsyre oppløst i 100 ml tetrahydrofuran tilsettes 8,08 g a) To 9.18 g of the benzyl ester hydrochloride of 4-aminobutyric acid dissolved in 100 ml of tetrahydrofuran, add 8.08 g
trietylamin. Man avkjøler ved hjelp av isbad og tilsetter så, dråpevis, 6,5 g av syrekloridet av 2-etyl-3-metyl-pentansyre. Man lar dette stå natten over under røring ved omgivelsestemperatur og filtrerer så reaksjonsblandingen og fordamper løsningsmidlet til tørrhet. triethylamine. Cool using an ice bath and then add, dropwise, 6.5 g of the acid chloride of 2-ethyl-3-methyl-pentanoic acid. This is allowed to stand overnight with stirring at ambient temperature and then the reaction mixture is filtered and the solvent is evaporated to dryness.
Man tar inndampningsresten opp i etylacetat, vasker med vann og så med en fortynnet natriumkarbonat-løsning, på nytt med vann og så med en fortynnet saltsyreløsning og endelig med en mettet natriumkloridløsning. Man tørker løsningen over natriumsulfat og fordamper løsningsmidlet til tørrhet under vakuum. The evaporation residue is taken up in ethyl acetate, washed with water and then with a dilute sodium carbonate solution, again with water and then with a dilute hydrochloric acid solution and finally with a saturated sodium chloride solution. The solution is dried over sodium sulfate and the solvent is evaporated to dryness under vacuum.
Man oppnår således 11 g av benzylesteren av 7-etyl-8-metyl-. 6-okso-5-aza-l-dekansyre. Man oppløser denne ester (11 g) 11 g of the benzyl ester of 7-ethyl-8-methyl- are thus obtained. 6-oxo-5-aza-1-decanoic acid. This ester (11 g) is dissolved
i 150 ml etanol (96 %) og hydrogenerer ved atmosfæretrykk i nærvær av 1 g palladium over karbon med 10 % palladium. Etter at reaksjonen er ferdig, filtrerer man katalysatoren og inndamper til tørrhet under vakuum. Til inndampningsresten som er tatt opp i 100 ml vannfri eter tilsetter man 6 g dicyklo-heksylamin og lar dette henstå en natt ved 0°C. Man avvanner det dannede salt og vasker det med eter, vekt: 7,8 g. in 150 ml of ethanol (96%) and hydrogenate at atmospheric pressure in the presence of 1 g of palladium over carbon with 10% palladium. After the reaction is complete, the catalyst is filtered and evaporated to dryness under vacuum. To the evaporation residue which has been taken up in 100 ml of anhydrous ether, 6 g of dicyclohexylamine are added and this is allowed to stand overnight at 0°C. The formed salt is dewatered and washed with ether, weight: 7.8 g.
Det således oppnådde salt oppløses i 100 ml vann. Man avkjøler løsningen i is og surgjør med konsentrert saltsyre til pH = 1,5. Man metter løsningen med natriumklorid og ekstraherer med etylacetat. Man vasker den organiske løsning tre ganger med en mettet natriumkloridløsning, tørker over natriumsulfat og inndamper til tørrhet. The salt thus obtained is dissolved in 100 ml of water. The solution is cooled in ice and acidified with concentrated hydrochloric acid to pH = 1.5. The solution is saturated with sodium chloride and extracted with ethyl acetate. The organic solution is washed three times with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness.
Man oppnår således 3,9 g av 7-etyl-8-metyl-6-okso-5-aza-l-dekansyre. 3.9 g of 7-ethyl-8-methyl-6-oxo-5-aza-1-decanoic acid is thus obtained.
b) I henhold til den teknikk som er beskrevet i eksempel b) According to the technique described in the example
1 b), lar man dibutylamin reagere med denne syre. På samme 1 b), dibutylamine is allowed to react with this acid. On the same
måte oppnår man CM 40195 i form av en olje; kp./0,01 mm : 200°C. way one obtains CM 40195 in the form of an oil; kp./0.01 mm : 200°C.
Eksempel 5 Example 5
4, 12- diokso- 5, 13- diaza- heptadekan (CM 40387) 4, 12- dioxo- 5, 13- diaza-heptadecane (CM 40387)
a) Til en isavkjølt løsning av 5,2 g 7-aminoheptansyrer a) To an ice-cooled solution of 5.2 g of 7-aminoheptanoic acids
i 80 ml 4N natriumkarbonat tilsetter man langsomt under røring in 80 ml of 4N sodium carbonate is added slowly while stirring
4,8 g butyrylklorid. Man fortsetter med agiteringen i 4 timer og surgjør så til pH = 2 med saltsyre. Man ekstraherer med etylacetat, tørker løsningen over natriumsulfat og fordamper løsningsmidlet til tørrhet under vakuum. 4.8 g of butyryl chloride. Agitation is continued for 4 hours and then acidified to pH = 2 with hydrochloric acid. Extract with ethyl acetate, dry the solution over sodium sulphate and evaporate the solvent to dryness under vacuum.
Man oppnår 4,2 g av en olje som krystalliserer. Man re-krystalliserer i heksan; smp.: 68°C. 4.2 g of an oil which crystallizes is obtained. One re-crystallises in hexane; m.p.: 68°C.
b) Til løsningen av 2,3 g av den oppnådde syre, beskrevet ovenfor, i 30 ml tørt tetrahydrofuran tilsetter man 1,1 g b) To the solution of 2.3 g of the obtained acid, described above, in 30 ml of dry tetrahydrofuran, 1.1 g is added
trietylamin og deretter 1,2 g etylklorformiat. Man lar dette omrøres i 2 timer og tilsetter løsningen deretter langsomt 0,85 g butylamin i 5 ml tetrahydrofuran. Man fortsetter om-røringen i 15 timer ved omgivelsestemperatur og tilsetter så vann og ekstraherer med etylacetat. Man vasker den organiske løsning med en løsning av natriumkarbonat, tørker over natriumsulfat og fordamper løsningsmidlet til tørrhet. Inndampningsresten rekrystalliseres i acetonitril; smp. 132°C: triethylamine and then 1.2 g of ethyl chloroformate. This is allowed to stir for 2 hours and then slowly 0.85 g of butylamine in 5 ml of tetrahydrofuran is added to the solution. Stirring is continued for 15 hours at ambient temperature and water is then added and extracted with ethyl acetate. The organic solution is washed with a solution of sodium carbonate, dried over sodium sulfate and the solvent is evaporated to dryness. The evaporation residue is recrystallized in acetonitrile; m.p. 132°C:
Eksempel 6 Example 6
Ved å arbeide som angitt i eksempel 5 og gå ut fra forskjellige aminosyrer 1. og ved å variere reaktantene R-COC1 og By working as indicated in example 5 and starting from different amino acids 1. and by varying the reactants R-COC1 and
oppnår man produktene (I) som er beskrevet i tabell the products (I) described in the table are obtained
III nedenunder. III below.
Eksempel 7 Example 7
2, 7- diokso- l, 6- diaza- dekan (CM 40401) 2, 7- dioxo-l, 6- diaza- decane (CM 40401)
(I) R = CH (CH2)2-; m = n = 1; X = H; Rx = R2 = H. (I) R = CH (CH 2 ) 2 -; m = n = 1; X = H; Rx = R2 = H.
a) Til en løsning av 17 g 6-okso-5-aza-l-nonansyre (oppnådd i henhold til eksempel 1 a) ovenfor) i 500 ml absolutt a) To a solution of 17 g of 6-oxo-5-aza-l-nonanoic acid (obtained according to Example 1 a) above) in 500 ml absolute
etanol tilsetter man 10 ml konsentrert svovelsyre og rører i 4 timer ved omgivelsestemperatur. Man inndamper løsnings-midlet ved 30°C under vakuum og tar resten opp i isvann. Man nøytraliserer ved tilsetning av natriumbikarbonat og ekstraherer deretter med metylenklorid. Man tørker over natrium- ethanol, add 10 ml of concentrated sulfuric acid and stir for 4 hours at ambient temperature. The solvent is evaporated at 30°C under vacuum and the residue taken up in ice water. Neutralize by adding sodium bicarbonate and then extract with methylene chloride. It is dried over sodium
sulfat og inndamper til tørrhet. sulfate and evaporate to dryness.
Man oppnår 16 g av den ønskede etylester. 16 g of the desired ethyl ester are obtained.
b) Man innfører de 16 g etylester som ble oppnådd ovenfor, i 300 ml av en løsning av 16 % ammoniakk i metanol. Man b) The 16 g of ethyl ester obtained above are introduced into 300 ml of a solution of 16% ammonia in methanol. Mon
rører i 5 timer ved omgivelsestemperatur. Man inndamper løsningsmidlet til tørrhet og tar inndampningsresten opp i eter. Man avvanner det faste stoff og vasker med acetonitril. stir for 5 hours at ambient temperature. The solvent is evaporated to dryness and the evaporation residue is taken up in ether. The solid is dewatered and washed with acetonitrile.
Man oppnår ufarvede krystaller (10 g); smp. 135°C (acetonitril). Colorless crystals (10 g) are obtained; m.p. 135°C (acetonitrile).
Eksempel 8 Example 8
6 - ( 3, 4- dimetoksy- benzy l)- 4, 9- diokso- 5, 10- diaza- tetradekan 6 - (3, 4- dimethoxy- benzyl)- 4, 9- dioxo- 5, 10- diaza- tetradecane
Ved å erstatte, i den første reaksjon, 4-klorbenzoyl-kloridet med en ekvivalent mengde av butyrylklorid. By replacing, in the first reaction, the 4-chlorobenzoyl chloride with an equivalent amount of butyryl chloride.
På samme måte oppnår man den ønskede forbindelse i form av et farveløst faststoff; smp.: 152°C. In the same way, the desired compound is obtained in the form of a colorless solid; m.p.: 152°C.
De produkter som er oppnådd, ble underkastet forskjellige prøver vedrørende deres farmakologiske aktivitet og spesielt deres innvirkning på det sentrale nervesystem. The products obtained were subjected to various tests concerning their pharmacological activity and in particular their impact on the central nervous system.
A) - Farmakologisk aktivitet A) - Pharmacological activity
1) - Sedativ og hypnotisk effekt 1) - Sedative and hypnotic effect
a) Aktografisk studium a) Actographic study
Målingen av aktografi utføres på mus 45 min. etter The measurement of actography is carried out on mice for 45 min. after
administrering av produktet. Man arbeider med grupper på administration of the product. You work with groups on
12 dyr, og hvert av dem er isolert i 10 min. før målingen. Telling av poeng utføres ved avskjæring av to lysbunter som er perpendikulære. 12 animals, and each of them is isolated for 10 min. before the measurement. Counting of points is carried out by cutting off two beams of light that are perpendicular.
I tabell IV nedenunder er de oppnådde resultater samlet som vedrører forskjellige produkter fremstilt i henhold til oppfinnelsen, administrert i en dose av 500 mg/kg pr. oralt. Resultatene er uttrykt som prosent variasjon av de poeng som er oppnådd i forhold til de ikke-behandlede kontrolldyr. In Table IV below, the results obtained are collected which relate to different products manufactured according to the invention, administered in a dose of 500 mg/kg per orally. The results are expressed as percentage variation of the points obtained in relation to the non-treated control animals.
Man kan konstatere at produktene fordeler seg i to grupper: - produkter som fremkaller hypomotilitet, slik som 40217, 40039, 40271, 40272, 40319; i det tilfelle hvor de behandlede dyr viser et tap av snurefleks, hvilket gir et uttrykk for den riktige bedøvelseeffekt av produktet, har man notert PRR; It can be seen that the products fall into two groups: - products that induce hypomotility, such as 40217, 40039, 40271, 40272, 40319; in the case where the treated animals show a loss of turning reflex, which gives an expression of the correct anesthetic effect of the product, PRR has been noted;
- slike produkter som fremkaller hypermotilitet, slik som 40142, 40398, 40397, 40404, 40253, 40355, 40209; for å presisere de oppnådde resultater er studiet for to produkter gjentatt i effektiv dose i henhold til den samme fremgangsmåte. - such products that induce hypermotility, such as 40142, 40398, 40397, 40404, 40253, 40355, 40209; in order to clarify the results obtained, the study for two products has been repeated in an effective dose according to the same procedure.
De oppnådde resultater er samlet i tabell V nedenunder. The results obtained are collected in table V below.
b) Potensialisering av pentobarbital bedøvelse b) Potentiation of pentobarbital anesthesia
De produkter som skulle studeres, ble administrert per os The products to be studied were administered by us
til mus i en dose av 500 mg/kg, 1 time før pentobarbitalet ble injisert intraperitonealt i en mengde av 20 mg/kg. to mice at a dose of 500 mg/kg, 1 hour before the pentobarbital was injected intraperitoneally in an amount of 20 mg/kg.
Man bestemmer den prosent av dyrene som har mistet snu-refleksen. Resultatene er uttrykt i prosent eller, i noen til-feller, i effektiv dose 50 (DE 50) eller som dose som fremkaller bedøvelse hos 50 % av de behandlede dyr. The percentage of animals that have lost the turning reflex is determined. The results are expressed as a percentage or, in some cases, in effective dose 50 (DE 50 ) or as the dose that induces anesthesia in 50% of the treated animals.
Resultatene er angitt i tabell VI nedenunder. The results are set out in Table VI below.
c) Elektroencefalografisk studium c) Electroencephalographic study
For bedre å forstå den hypnotiske aktivitet av forbindelser To better understand the hypnotic activity of compounds
som fremstilles i henhold til oppfinnelsen, ble det gjort et elektroencefalografisk studium på ett av dem, dvs. CM 40039. which are produced according to the invention, an electroencephalographic study was carried out on one of them, i.e. CM 40039.
Forbindelsen 40039 er studert i en dose av 350 mg/kg p.o. hos tre rotter. Etter en tilvenningsperiode på 10 dager (tidsrom med lys fra klokken åtte til klokken tyve og tidsrom i mørke fra klokken tyve til klokken åtte) ble dyrene registrert i 5 dager med løsningsmidlet (gummiarabikum, 10 %), og deretter registrert i 4 dager hvor de fikk produktet klokken ni hver morgen. Etter denne kroniske administrering ble dyrene registrert i 5 følgende dager (kontrollperiode). Compound 40039 has been studied at a dose of 350 mg/kg p.o. in three rats. After a habituation period of 10 days (light period from eight o'clock to midnight and dark period from midnight to eight o'clock), the animals were recorded for 5 days with the solvent (gum arabic, 10%), and then recorded for 4 days where they received the product at nine o'clock every morning. After this chronic administration, the animals were recorded for 5 following days (control period).
Resultater: Results:
Dyrene ble registrert liver 24. time. Det statistiske studium gjelder et tidsrom på 24 timer. Man gjør en global analyse over de tre rotter ved kumulering av de 15 kontrolldager, de 12 dager med behandling og de 15 dager for kontroll. I hver timegruppe på 24 timer vurderer man våkentiden (EV), sovetiden (SL), den paradoksale søvn (SP), den 'totale søvn (ST), såvel som forholdet (i prosent) paradoksal søvn/total søvn (SP/ST) The animals were registered alive at the 24th hour. The statistical study covers a period of 24 hours. A global analysis is made of the three rats by cumulating the 15 control days, the 12 days of treatment and the 15 days of control. In each hour group of 24 hours, the waking time (EV), sleep time (SL), the paradoxical sleep (SP), the 'total sleep (ST), as well as the ratio (in percent) paradoxical sleep/total sleep (SP/ST) are assessed
(tabell VII nedenunder). (Table VII below).
I hver periode av studiet har registreringene ikke avslørt morfologiske modifikasjoner av det encefalografiske diagram. In each period of the study, the recordings did not reveal morphological modifications of the encephalographic diagram.
Forbindelsen fremkaller en reduksjon av oppvåknings-signifikans (-8,1 %) som samsvarer med en signifikant økning av lett søvn (+6,6 %). The compound induces a decrease in arousal significance (-8.1%) that corresponds to a significant increase in light sleep (+6.6%).
Denne effekt vedvarer i kontrollfasen. This effect persists in the control phase.
2) - Antikonvulsiv effekt 2) - Anticonvulsant effect
Den antikonvulsive effekt ble bestemt i forhold til konvulsive kriser fremkalt av elektrosjokk eller ved hjelp av bicucullin. The anticonvulsant effect was determined in relation to convulsive crises induced by electroshock or by means of bicuculline.
Elektrosjokket (12,5 V i 0,5 sek.) er utført på musen The electroshock (12.5 V for 0.5 sec.) is applied to the mouse
60 min. etter administrering av forbindelsen ad oral vei. 60 min. after administration of the compound orally.
Bicucullinet administreres til musen intravenøst i en The bicuculline is administered to the mouse intravenously in a
mengde av 1 mg/kg, 60 min. etter at den fqrbindelse som skal studeres, er gitt per os. Man noterer den oppnådde beskyttelses-effekt i forhold til toniske kriser. amount of 1 mg/kg, 60 min. after the connection to be studied has been given per us. The protective effect achieved in relation to tonic crises is noted.
Ved å arbeide med forskjellige grupper av dyr med forskjellige doser av den forbindelse som skal studeres, kan man bestemme den effektive median-dose (DE 50).'By working with different groups of animals with different doses of the compound to be studied, one can determine the effective median dose (DE 50).'
Resultatene er samlet i tabell VIII nedenunder og viser The results are collected in table VIII below and show
de rene antikonvulsive egenskaper for de studerte produkter. the pure anticonvulsant properties of the studied products.
B) - Biokjemisk studium B) - Biochemical study
a) Effekt på GABA- graden ( 4- aminosmørsyre) a) Effect on the GABA level (4-aminobutyric acid)
Forbindelsen 40039 ble administrert 30 min. før musen Compound 40039 was administered 30 min. before the mouse
ble drept. GABA-graden ble vurdert på hele hjernen (gruppe med 6 dyr) (se tabell IX nedenunder). was killed. The GABA level was assessed on the whole brain (group of 6 animals) (see Table IX below).
Forbindelsen 40039 fremkaller hurtig økning av GABA- Compound 40039 induces a rapid increase in GABA-
graden i den totale hjerne hos musen. degree in the total brain of the mouse.
b) Effekt på den sentrale dopaminergi b) Effect on the central dopaminergy
Effekten av forbindelsene på den sentrale dopaminergi The effect of the compounds on the central dopaminergy
aktivitet ble studert ved hjelp av akkumulering av homovanillinsyre over et tidsrom på 24 timer etter administrering av forbindelsene til mus. activity was studied by means of the accumulation of homovanillic acid over a period of 24 hours after administration of the compounds to mice.
Mengden av homovanillinsyre (HVA) vurderes i hele hjernen, idet dyrene får en injeksjon av probenecid (200 mg/kg i.p.) The amount of homovanillic acid (HVA) is assessed in the whole brain, as the animals receive an injection of probenecid (200 mg/kg i.p.)
1 time 30 min. før de avlives (gruppe med 10 dyr). 1 hour 30 min. before they are killed (group of 10 animals).
De to forbindelser fremkaller effekter nær HVA-verdien, The two compounds induce effects close to the HVA value,
idet de spesielt fremkallerøkning av konsentrasjonen 4 timer etter at de er administrert, og en sterk senkning 24 timer etter at de er administrert (se tabell X nedenunder). in that they particularly cause an increase in concentration 4 hours after they are administered, and a strong lowering 24 hours after they are administered (see Table X below).
c) Akutt toksisitet c) Acute toxicity
De forbindelser som skal studeres, administreres ad The compounds to be studied are administered ad
oral vei med doser på 500 og 1000 mg/kg til grupper av mus. Man observerer musene i 24 timer og registrerer deres dødelighet. oral route with doses of 500 and 1000 mg/kg to groups of mice. The mice are observed for 24 hours and their mortality recorded.
Resultatene, uttrykt i prosent dødelighet, fremgår av tabell XI nedenunder. The results, expressed in percentage mortality, appear in Table XI below.
Resultatene indikerer at i endose på 500 mg/kg har alle The results indicate that in a single dose of 500 mg/kg, all have
de studerte forbindelser ikke vist noe tegn på akutt toksisitet. Ved 1000 mg/kg, meget forhøyet dose, viser noen forbindelser en"toksisitet på 100 %, men i de fleste til- the studied compounds showed no sign of acute toxicity. At 1000 mg/kg, a very elevated dose, some compounds show a "toxicity of 100%, but in most at-
feller forblir den akutte toksisitet svak eller null. In other cases, the acute toxicity remains weak or zero.
De således utførte forsøk viser at forbindelsene som fremstilles i henhold til oppfinnelsen presenterer en sammen-setning av farmakologiske egenskaper som er interessante, The experiments thus carried out show that the compounds produced according to the invention present a combination of pharmacological properties which are interesting,
og de har svak toksisitet. Følgelig kan de benyttes i den humane terapi, spesielt for behandling av neurologiske og psykiske affekter. and they have low toxicity. Consequently, they can be used in human therapy, especially for the treatment of neurological and psychological affections.
De forbindelser som fremstilles i henhold til oppfinnelsen, kan spesielt anvendes for behandling av sinns- eller adferds-forstyrrelser: nervøsitet, irritabilitet såvel som for behandling av angst-tilstander og søvnløshet. The compounds produced according to the invention can be used in particular for the treatment of mental or behavioral disorders: nervousness, irritability as well as for the treatment of anxiety states and insomnia.
Disse forbindelser kan administreres ad oral vei eller injiseres. De farmasøytiske preparater kan være i fast eller flytende form og for eksempel ha form av tabletter, kapsler, granulat, suppositorier eller injiserbare preparater. These compounds can be administered orally or injected. The pharmaceutical preparations can be in solid or liquid form and, for example, take the form of tablets, capsules, granules, suppositories or injectable preparations.
Posologien kan variere innen vide grenser, spesielt' av-hengig av typen og hvor alvorlig lidelsen er som skal behandles, og at etter administreringsmåte. Oftest hos voksne personer, ad oral vei, vil dosen ligge mellom 0,100 og 1 g pr. dag, eventuelt fordelt på flere ganger. The dosage can vary within wide limits, especially depending on the type and severity of the disorder to be treated, and that according to the method of administration. Most often in adults, orally, the dose will be between 0.100 and 1 g per day, possibly divided into several times.
I det følgende skal det bringes en del eksempler på farma-søytiske preparater. In the following, a number of examples of pharmaceutical preparations will be given.
Kapsler Capsules
T abletter Pills
Claims (3)
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Application Number | Priority Date | Filing Date | Title |
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FR8018609A FR2489319A1 (en) | 1980-08-27 | 1980-08-27 | DERIVATIVES OF AMINO-4 BUTYRIC ACID AND MEDICAMENTS, PARTICULARLY ACTIVE ON THE CENTRAL NERVOUS SYSTEM, CONTAINING |
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Publication Number | Publication Date |
---|---|
NO812890L NO812890L (en) | 1982-03-01 |
NO156608B true NO156608B (en) | 1987-07-13 |
NO156608C NO156608C (en) | 1987-10-21 |
Family
ID=9245433
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO812890A NO156608C (en) | 1980-08-27 | 1981-08-26 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMIDES OF 4-AMINO ACID ACID. |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0046707B1 (en) |
JP (1) | JPS5772949A (en) |
AT (1) | ATE21099T1 (en) |
AU (1) | AU547392B2 (en) |
CA (1) | CA1208230A (en) |
DE (1) | DE3175030D1 (en) |
DK (1) | DK378781A (en) |
ES (1) | ES8206445A1 (en) |
FR (1) | FR2489319A1 (en) |
GR (1) | GR75299B (en) |
IE (1) | IE52415B1 (en) |
NO (1) | NO156608C (en) |
NZ (1) | NZ198110A (en) |
PT (1) | PT73558B (en) |
ZA (1) | ZA815662B (en) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1340902C (en) * | 1985-02-15 | 2000-02-22 | Harold L. Kohn | Amino acid derivative anticonvulsant |
US5654301A (en) * | 1985-02-15 | 1997-08-05 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
US5378729A (en) * | 1985-02-15 | 1995-01-03 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
CA1320734C (en) * | 1986-02-04 | 1993-07-27 | Suntory Limited | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
US5198458A (en) * | 1986-02-04 | 1993-03-30 | Suntory Limited | Pyrrolidineamide derivatives of acylamino acid and pharmaceutical composition containing the same |
NZ222045A (en) * | 1986-08-21 | 1989-10-27 | Res Corp Technologies Inc | From diamides up to tetrapeptides for use as anticanvulsants |
US4992472A (en) * | 1987-06-16 | 1991-02-12 | The United States Of America As Represented By The Department Of Health And Human Services | Chemical differentiating agents |
US5770625A (en) * | 1988-02-08 | 1998-06-23 | The Trustees Of Columbia University In The City Of New York | Butyryl-tyrosinyl spermine, analogs thereof and methods of preparing and using same |
DE3915755A1 (en) * | 1989-05-13 | 1990-11-29 | Bayer Ag | FUNGICIDAL AGENTS AND SUBSTITUTED AMINO ACID DERIVATIVES AND THE PRODUCTION THEREOF |
DE3915756A1 (en) * | 1989-05-13 | 1990-11-29 | Bayer Ag | CYCLOPROPANOYLAMINOSAEUREAMID DERIVATIVES |
JPH03506045A (en) * | 1989-05-19 | 1991-12-26 | リサーチ・コーポレイション・テクノロジーズ・インコーポレイテッド | Amino acid derivative anticonvulsant |
DE4102042A1 (en) * | 1991-01-24 | 1992-07-30 | Bayer Ag | SUBSTITUTED AMINO ACID DERIVATIVES THEIR PRODUCTION AND USE AS FUNGICIDES |
US5585358A (en) * | 1993-07-06 | 1996-12-17 | Yissum Research Development Corporation Of The Hebrew University Of Jerusalem | Derivatives of valproic acid amides and 2-valproenoic acid amides, method of making and use thereof as anticonvulsant agents |
US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
IL114483A0 (en) * | 1994-07-12 | 1995-11-27 | Yissum Res Dev Co | Glycinamide derivatives pharmaceutical compositions containing the same and methods utilizing the same |
CA2378955A1 (en) * | 1999-08-10 | 2001-02-15 | Uab Research Foundation | Use of gaba agonists for treatment of spastic disorders, convulsions, and epilepsy |
CZ2004266A3 (en) | 2000-07-21 | 2005-02-16 | Teva Pharmaceutical Industries, Ltd. | Use of amide derivatives of valproic and 2-valproenic acids for treating mania-induced bipolar disorder |
EP1604656A1 (en) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Novel use of peptide compounds for treating amyotrophic lateral sclerosis (ALS) |
US7632836B2 (en) * | 2006-11-30 | 2009-12-15 | Cenerx Biopharma, Inc. | Dialkylamino alkyl esters of pivagabine as medicaments for the treatment of central nervous system disorders |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB732415A (en) * | 1952-07-12 | 1955-06-22 | Ruhrchemie Ag | Process for the production of aroylated aminocarboxylic acids |
US3022314A (en) * | 1955-06-20 | 1962-02-20 | Upjohn Co | Alpha-phenyl-omega-amino-alkanamides |
IE33790B1 (en) * | 1968-06-04 | 1974-10-30 | Beecham Group Ltd | Derivatives of n-acylaminoacid amides |
-
1980
- 1980-08-27 FR FR8018609A patent/FR2489319A1/en active Granted
-
1981
- 1981-08-11 GR GR65767A patent/GR75299B/el unknown
- 1981-08-11 IE IE1835/81A patent/IE52415B1/en unknown
- 1981-08-13 DE DE8181401299T patent/DE3175030D1/en not_active Expired
- 1981-08-13 EP EP81401299A patent/EP0046707B1/en not_active Expired
- 1981-08-13 AT AT81401299T patent/ATE21099T1/en not_active IP Right Cessation
- 1981-08-17 ZA ZA815662A patent/ZA815662B/en unknown
- 1981-08-18 AU AU74259/81A patent/AU547392B2/en not_active Ceased
- 1981-08-20 NZ NZ198110A patent/NZ198110A/en unknown
- 1981-08-21 CA CA000384370A patent/CA1208230A/en not_active Expired
- 1981-08-24 PT PT73558A patent/PT73558B/en unknown
- 1981-08-26 DK DK378781A patent/DK378781A/en not_active Application Discontinuation
- 1981-08-26 JP JP56132669A patent/JPS5772949A/en active Pending
- 1981-08-26 ES ES505004A patent/ES8206445A1/en not_active Expired
- 1981-08-26 NO NO812890A patent/NO156608C/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA815662B (en) | 1982-08-25 |
CA1208230A (en) | 1986-07-22 |
JPS5772949A (en) | 1982-05-07 |
IE811835L (en) | 1982-02-27 |
ES505004A0 (en) | 1982-08-16 |
EP0046707B1 (en) | 1986-07-30 |
DE3175030D1 (en) | 1986-09-04 |
DK378781A (en) | 1982-02-28 |
IE52415B1 (en) | 1987-10-28 |
GR75299B (en) | 1984-07-13 |
PT73558A (en) | 1981-09-01 |
NO156608C (en) | 1987-10-21 |
AU547392B2 (en) | 1985-10-17 |
NZ198110A (en) | 1984-12-14 |
FR2489319A1 (en) | 1982-03-05 |
AU7425981A (en) | 1982-03-04 |
FR2489319B1 (en) | 1984-04-06 |
PT73558B (en) | 1982-11-03 |
NO812890L (en) | 1982-03-01 |
ES8206445A1 (en) | 1982-08-16 |
ATE21099T1 (en) | 1986-08-15 |
EP0046707A1 (en) | 1982-03-03 |
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