NO178621B - Acid addition salts of optically active alanine anilide compounds and pharmaceutical compositions containing them - Google Patents
Acid addition salts of optically active alanine anilide compounds and pharmaceutical compositions containing them Download PDFInfo
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- NO178621B NO178621B NO920016A NO920016A NO178621B NO 178621 B NO178621 B NO 178621B NO 920016 A NO920016 A NO 920016A NO 920016 A NO920016 A NO 920016A NO 178621 B NO178621 B NO 178621B
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- optically active
- acid addition
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- dimethylphenyl
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- -1 alanine anilide compounds Chemical class 0.000 title claims description 26
- 239000002253 acid Substances 0.000 title claims description 20
- 150000003839 salts Chemical class 0.000 title claims description 20
- 235000004279 alanine Nutrition 0.000 title claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 206010003119 arrhythmia Diseases 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 208000031225 myocardial ischemia Diseases 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000005425 toluyl group Chemical group 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000013078 crystal Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- YYGZCHLVUTUNGZ-MRXNPFEDSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)-n-(3-pyridin-3-ylpropyl)propanamide Chemical compound CC=1C=CC=C(C)C=1N(C(=O)[C@H](N)C)CCCC1=CC=CN=C1 YYGZCHLVUTUNGZ-MRXNPFEDSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 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 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 229960001270 d- tartaric acid Drugs 0.000 description 4
- NTBIYBAYFBNTCD-KBPBESRZSA-N dibenzoyl (2s,3s)-2,3-dihydroxybutanedioate Chemical compound O=C([C@@H](O)[C@H](O)C(=O)OC(=O)C=1C=CC=CC=1)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-KBPBESRZSA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NTOIKDYVJIWVSU-WOJBJXKFSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-WOJBJXKFSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- UEJKXRPPKQFUDT-OMHPICJYSA-N (2R)-2-amino-N-(2,6-dimethylphenyl)-N-(3-pyridin-3-ylpropyl)propanamide (2R,3R)-2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical compound C(C1=CC=CC=C1)(=O)[C@@]([C@@](C(=O)O)(O)C(C1=CC=CC=C1)=O)(O)C(=O)O.N[C@@H](C(=O)N(CCCC=1C=NC=CC1)C1=C(C=CC=C1C)C)C UEJKXRPPKQFUDT-OMHPICJYSA-N 0.000 description 2
- DEUKDTGSUKHYQE-UHFFFAOYSA-N 2,6-dimethyl-n-(3-pyridin-3-ylpropyl)aniline Chemical compound CC1=CC=CC(C)=C1NCCCC1=CC=CN=C1 DEUKDTGSUKHYQE-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- VRHAQNTWKSVEEC-UHFFFAOYSA-N ethyl 1,3-dioxoisoindole-2-carboxylate Chemical compound C1=CC=C2C(=O)N(C(=O)OCC)C(=O)C2=C1 VRHAQNTWKSVEEC-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OZWUITKBAWTEAQ-ZCFIWIBFSA-N (2r)-2-(1,3-dioxoisoindol-2-yl)propanoic acid Chemical compound C1=CC=C2C(=O)N([C@H](C)C(O)=O)C(=O)C2=C1 OZWUITKBAWTEAQ-ZCFIWIBFSA-N 0.000 description 1
- RADYRPIQHFNFMA-PKLMIRHRSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)-n-(3-pyridin-3-ylpropyl)propanamide;hydrochloride Chemical compound Cl.CC=1C=CC=C(C)C=1N(C(=O)[C@H](N)C)CCCC1=CC=CN=C1 RADYRPIQHFNFMA-PKLMIRHRSA-N 0.000 description 1
- OMGLDTAERPJHLE-VEIFNGETSA-N (2r)-n-(2,6-dimethylphenyl)-2-(1,3-dioxoisoindol-2-yl)-n-(3-pyridin-3-ylpropyl)propanamide;hydrochloride Chemical compound Cl.O=C([C@H](N1C(C2=CC=CC=C2C1=O)=O)C)N(C=1C(=CC=CC=1C)C)CCCC1=CC=CN=C1 OMGLDTAERPJHLE-VEIFNGETSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 1
- CSJCEQXZVMIHRX-QZTJIDSGSA-N (2s,3s)-2,3-dibenzyl-2,3-dihydroxybutanedioic acid Chemical compound C([C@@](O)(C(=O)O)[C@@](O)(CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSJCEQXZVMIHRX-QZTJIDSGSA-N 0.000 description 1
- OZWUITKBAWTEAQ-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)propanoic acid Chemical compound C1=CC=C2C(=O)N(C(C)C(O)=O)C(=O)C2=C1 OZWUITKBAWTEAQ-UHFFFAOYSA-N 0.000 description 1
- NTLKAXQBFYZMAH-UHFFFAOYSA-N 2-methylpentanamide Chemical compound CCCC(C)C(N)=O NTLKAXQBFYZMAH-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000002763 arrhythmic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- DQPWXTNHZLGFIV-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-2-(1,3-dioxoisoindol-2-yl)-n-(3-pyridin-3-ylpropyl)propanamide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C)C(=O)N(C=1C(=CC=CC=1C)C)CCCC1=CC=CN=C1 DQPWXTNHZLGFIV-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- VHWJSJBTUWUEAL-UHFFFAOYSA-N propanamide;hydrochloride Chemical compound Cl.CCC(N)=O VHWJSJBTUWUEAL-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse vedrører et syreaddisjonssalt av en optisk aktiv alaninanilidforbindelse. The present invention relates to an acid addition salt of an optically active alanine anilide compound.
Nærmere bestemt vedrører foreliggende oppfinnelse et syreaddisjonssalt av en optisk aktiv alaninanilidforbindelse representert ved formelen: More specifically, the present invention relates to an acid addition salt of an optically active alanine anilide compound represented by the formula:
hvor R<1> er et hydrogenatom, en benzoylgruppe eller en toluoylgruppe; og karbonatomet merket med (R) betyr et karbonatom i form av R-konfigurasjonen. where R<1> is a hydrogen atom, a benzoyl group or a toluoyl group; and the carbon atom marked with (R) means a carbon atom in the form of the R configuration.
BAKGRUNN FOR OPPFINNELSEN BACKGROUND OF THE INVENTION
En farmakologisk aktiv forbindelse med et asymmetrisk karbonatom er blitt anvendt i form av en racemisk blanding som aktiv bestanddel, men i den senere tid anvendes en optisk aktiv forbindelse av den farmakologisk aktive forbindelse som aktiv bestanddel for å unngå bivirkninger. A pharmacologically active compound with an asymmetric carbon atom has been used in the form of a racemic mixture as active ingredient, but in recent times an optically active compound of the pharmacologically active compound is used as active ingredient to avoid side effects.
TEKNIKKENS STAND STATE OF THE ART
US patent nr. 4.696.930 beskriver substituerte anilin-forbindelser representert ved formelen: US Patent No. 4,696,930 describes substituted aniline compounds represented by the formula:
hvor Ri er alkylen'-NH2 eller alkylen'-A'; R2, R3 og R4 er uavhengig et hydrogenatom eller en metylgruppe; A og A' er uavhengig et usubstituert eller et lavere alkyl eller et arylsubstituert pyridinyl eller en pyrimidinylgruppe; alkylen og alkylen' er uavhengig en rett kjede av alkylendeler med 1-5 karbonatomer som eventuelt er substituert med en eller flere alkylsubstituenter med 1-5 karbonatomer, eller når et asymmetrisk karbonatom er tilstede, en enantiomer derav eller en racemisk blanding derav; eller farmasøytiske salter derav, hvilke forbindelser er nyttige som arythmiske midler. wherein R 1 is alkylene'-NH 2 or alkylene'-A'; R 2 , R 3 and R 4 are independently a hydrogen atom or a methyl group; A and A' are independently an unsubstituted or a lower alkyl or an aryl substituted pyridinyl or a pyrimidinyl group; alkylene and alkylene' are independently a straight chain of alkyl moieties with 1-5 carbon atoms optionally substituted with one or more alkyl substituents with 1-5 carbon atoms, or when an asymmetric carbon atom is present, an enantiomer thereof or a racemic mixture thereof; or pharmaceutical salts thereof, which compounds are useful as arrhythmic agents.
I virkeligheten beskrives racemisk-2-amino-N-(2.6-dimetylfenyl)-N-[3-pyridyl)propyl]propanamid som er nært beslektet med forbindelsene i foreliggende oppfinnelse, og som representeres ved formelen: In reality, racemic 2-amino-N-(2,6-dimethylphenyl)-N-[3-pyridyl)propyl]propanamide is described which is closely related to the compounds of the present invention, and which is represented by the formula:
er beskrevet. Imidlertid er forbindelsen med formel (IV) ovenfor et racemat, ikke en optisk aktiv forbindelse. is described. However, the compound of formula (IV) above is a racemate, not an optically active compound.
En optisk ren forbindelse av en alaninanilidforbindelse i fri form med formel (IV) er en oljeaktiv substans, derfor er det vanskelig å formulere en optisk ren forbindelse til et farmasøytisk preparat. An optically pure compound of an alanine anilide compound in free form with formula (IV) is an oil-active substance, therefore it is difficult to formulate an optically pure compound into a pharmaceutical preparation.
Videre er et saltsyresalt derav sterkt hydroskopisk, og vannet som finnes i nevnte forbindelse varierer avhengig av fuktigheten i atmosfæren, hvor forbindelsen oppbevares. I en atmosfære med høy fuktighet flyter forbindelsen bort. Følgelig har en nettovekt av nevnte forbindelse en tendens til å variere på grunn av dens hygroskopiske egenskap å absorbere fuktighet fra luften. Idet man tar i betraktning at et farmasøytisk preparat alltid må inneholde en aktiv bestanddel i et foreskrevet forhold for å oppnå den ventede effekt og sikkerhet, er nevnte forbindelse ikke nødvendigvis velegnet for fremstilling av farmasøytiske preparater. Furthermore, a hydrochloric acid salt thereof is strongly hygroscopic, and the water contained in said compound varies depending on the humidity of the atmosphere, where the compound is kept. In an atmosphere of high humidity, the compound floats away. Accordingly, a net weight of said compound tends to vary due to its hygroscopic property of absorbing moisture from the air. Considering that a pharmaceutical preparation must always contain an active ingredient in a prescribed ratio to achieve the expected effect and safety, said compound is not necessarily suitable for the production of pharmaceutical preparations.
Etter utstrakt forskning og eksperimentering har vi funnet at slike problemer ble helt løst ved å anvende forbindelsen med formel (I) ovenfor. Forbindelsen med formel (I) er nemlig ikke-hygroskopisk, og har således en konstant nettovekt og stabilitet uten å påvirkes av fuktigheten i luften. After extensive research and experimentation, we have found that such problems were completely solved by using the compound of formula (I) above. Namely, the compound with formula (I) is non-hygroscopic, and thus has a constant net weight and stability without being affected by the humidity in the air.
OPPSUMMERING AV OPPFINNELSEN SUMMARY OF THE INVENTION
En hensikt ved foreliggende oppfinnelse er å fremskaffe et syreaddisjonssalt av en optisk aktiv alaninanilidforbindelse med formel (I) som er nyttig i medisiner. An object of the present invention is to provide an acid addition salt of an optically active alanine anilide compound of formula (I) which is useful in medicines.
En ytterligere hensikt i foreliggende oppfinnelse er å frembringe et farmasøytisk preparat som inneholder en optisk aktiv alaninanilidforbindelse som aktiv bestanddel. A further aim of the present invention is to produce a pharmaceutical preparation which contains an optically active alanine anilide compound as active ingredient.
Andre hensikter, trekk og fordeler ved foreliggende oppfinnelse vil være åpenbare av følgende beskrivelse av oppfinnelsen. Other purposes, features and advantages of the present invention will be apparent from the following description of the invention.
DETALJERT BESKRIVELSE AV OPPFINNELSEN DETAILED DESCRIPTION OF THE INVENTION
Foreliggende oppfinnelse frembringer en optisk aktiv alaninanilidforbindelse som er nyttig i medisin for behandling av arythmia, trombose eller iskemiske hjertesykdommer. Spesifikt vedrører foreliggende oppfinnelse syreaddisjonssalter av den optisk aktive alaninanilidforbindelse med formel (I) som ikke har noen upraktiske egenskaper såsom hydroskopiske egenskaper ved fremstillingen av farmasøytiske preparater. The present invention provides an optically active alanine anilide compound which is useful in medicine for the treatment of arrhythmia, thrombosis or ischemic heart diseases. Specifically, the present invention relates to acid addition salts of the optically active alanine anilide compound of formula (I) which have no impractical properties such as hydroscopic properties in the preparation of pharmaceutical preparations.
Et syreaddisjonssalt av den optisk aktive alaninanilidforbindelse med formel (I) er nemlig ikke hygroskopisk og er stabil i en atmosfære som har ca. 50% relativ fuktighet ved ca. 25-26°C. An acid addition salt of the optically active alanine anilide compound of formula (I) is not hygroscopic and is stable in an atmosphere having approx. 50% relative humidity at approx. 25-26°C.
Følgelig har syreaddisjonssaltene alltid konstant nettovekt uten å påvirkes av fuktighet i luften, og farmasøytiske preparater som inneholder syreaddisjonssaltet, kan lett fremstilles, og de erholdte farmasøytiske preparater vil være av høy kvalitet. Consequently, the acid addition salts always have a constant net weight without being affected by humidity in the air, and pharmaceutical preparations containing the acid addition salt can be easily prepared, and the pharmaceutical preparations obtained will be of high quality.
Syreaddisjonssaltene av de optisk aktive alaninanilidfor-bindelser med formelen (I) ifølge foreliggende oppfinnelse, utøver anti-arythmiske aktiviteter, tromboxan A2-syntease-hemmende aktiviteter og blodplateaggresjonshemmende aktiviteter på samme måte som et racemat med formel (IV) eller et syreaddisjonsalt derav, og de er således nyttige som medisiner ved behandling av arythmia, trombose og iskemiske hj ertesykdommer. The acid addition salts of the optically active alanine anilide compounds of formula (I) according to the present invention exert anti-arrhythmic activities, thromboxane A2-synthase-inhibiting activities and platelet-aggression-inhibiting activities in the same way as a racemate of formula (IV) or an acid addition salt thereof, and they are thus useful as medicines in the treatment of arrhythmia, thrombosis and ischemic heart diseases.
Syreaddisjonssaltene med formel (I) ifølge foreliggende oppfinnelse kan fremstilles ved å behandle et fritt amin av The acid addition salts of formula (I) according to the present invention can be prepared by treating a free amine of
en optiske aktiv alaninanilidforbindelse eller et racemat med optisk aktive vinsyrederivater, såsom D-vinsyre, dibensoyl-D-vinsyre, eller ditoluol-D-vinsyre, og deretter hvis nødvendig ved fraksjonell krystallisering av nevnte ubehandlede an optically active alanine anilide compound or a racemate with optically active tartaric acid derivatives, such as D-tartaric acid, dibenzoyl-D-tartaric acid, or ditoluene-D-tartaric acid, and then if necessary by fractional crystallization of said untreated
syreaddisjonssalt i henhold til normal praksis. acid addition salt according to normal practice.
Forbindelsen med formel (IV) kan fremstilles på lignende måte som beskrevet i det tidligere nevnte US patent 4.696.930. For eksempel omsettes N-karboetoksyftalimid med alanin for å erholde 2-ftalimidopropionsyre, og reaksjonsproduktet omdannes til et reaktivt funksjonelt derivat derav, såsom et syreklorid, og syrekloridet omsettes med N-[3-(3-pyridyl)-propyl]-2,6-dimetylanilin for å erholde 2-ftalimido-N-(2,6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]-propanamid, og deretter behandles produktet med en base, såsom etylamin, for å fremstille et ønsket produkt med formel (IV). The compound of formula (IV) can be prepared in a similar manner as described in the previously mentioned US patent 4,696,930. For example, N-carboethoxyphthalimide is reacted with alanine to obtain 2-phthalimidopropionic acid, and the reaction product is converted to a reactive functional derivative thereof, such as an acid chloride, and the acid chloride is reacted with N-[3-(3-pyridyl)-propyl]-2,6 -dimethylaniline to obtain 2-phthalimido-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]-propanamide, and then the product is treated with a base such as ethylamine to produce a desired product of formula (IV).
Ved fremstillingen av forbindelsen med (IV) som er beskrevet ovenfor, kan, hvis det optisk aktive D-alanin anvendes som utgangsmateriale, en ønsket optisk aktiv forbindelse erholdes med høy renhet. Hvis den fremstilte forbindelse anvendes som utgangsmateriale for å fremstille syreaddisjonssaltene med formel (I), kan et ønsket syreaddisjonssalt renses fra det erholdte ubehandlede syreaddisjonssalt ved en meget enkel renseprosess. In the preparation of the compound with (IV) described above, if the optically active D-alanine is used as starting material, a desired optically active compound can be obtained with high purity. If the prepared compound is used as starting material to prepare the acid addition salts of formula (I), a desired acid addition salt can be purified from the obtained untreated acid addition salt by a very simple purification process.
Blant foreliggende syreaddisjonssalter er (R)-2-amino-N-(2,6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]-propanamid D-tartrat representert ved formelen (II): Among the present acid addition salts, (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]-propanamide D-tartrate is represented by the formula (II):
hvor karbonatomet merket med (R) har den samme betydning som beskrevet ovenfor, ytterst gunstig. where the carbon atom marked with (R) has the same meaning as described above, extremely beneficial.
Når syreaddisjonssaltene med formel (I) ifølge foreliggende oppfinnelse anvendes i behandlingen av en pasient, kan ethvert farmasøytisk preparat som inneholder forbindelsen som aktiv bestanddel, såsom tabletter, kapsler, pulvere, granuler, siruper og injiserbare preparater, formuleres og administreres oralt eller parenteralt. Disse farmasøytiske preparater kan formuleres i henhold til konvensjonelle formu-leringsmetoder. When the acid addition salts of formula (I) according to the present invention are used in the treatment of a patient, any pharmaceutical preparation containing the compound as active ingredient, such as tablets, capsules, powders, granules, syrups and injectable preparations, can be formulated and administered orally or parenterally. These pharmaceutical preparations can be formulated according to conventional formulation methods.
Doseringen av forbindelsen kan bestemmes i henhold til kjønn, alder og kroppsvekt hos pasienten, arten og graden av sykdom-men, og kan være 1-1000 mg pr. dag ved oral administrasjon til en voksen person, og 0,1-100 mg pr. dag ved parenteral administrasjon til en voksen person. The dosage of the compound can be determined according to the gender, age and body weight of the patient, the nature and degree of the disease, and can be 1-1000 mg per day by oral administration to an adult, and 0.1-100 mg per day by parenteral administration to an adult.
Foreliggende oppfinnelse illustreres ytterligere i mer detalj ved hjelp av følgende eksempler og referanseeksempler. Smeltepunktene for de erholdte produkter ble ikke korrigert. Produktenes optiske renhet ble fastslått ved kiral HPLC [kolonne: SUMICHIRAL OA-4600 (Sumitomo Chemical Co., Ltd.) 5 fim, 4 mm i.d. x 25 cm; Eluent: n-hexan : dikloretan : etanol = 80:15:5; strømningshastighet: 1.0 ml/min; Deteksjon: UV 260 nm]. Prøvene ble behandlet med eddiksyreanhydrid for å erholde acetatene derav før kromato-grafering. The present invention is further illustrated in more detail by means of the following examples and reference examples. The melting points for the products obtained were not corrected. The optical purity of the products was determined by chiral HPLC [column: SUMICHIRAL OA-4600 (Sumitomo Chemical Co., Ltd.) 5 µm, 4 mm i.d. x 25 cm; Eluent: n-hexane : dichloroethane : ethanol = 80:15:5; flow rate: 1.0 ml/min; Detection: UV 260 nm]. The samples were treated with acetic anhydride to obtain the acetates thereof before chromatography.
Referanseeksempel 1 Reference example 1
( R)- 2- Ftalimidopropionsvre ( R )- 2- Phthalimidopropionic acid
Til en oppløsning av 50 g D-alanin i 500 ml vann ble det tilsatt 78 ml trietylamin, og 123 g N-karbetoksyftalimid ble tilsatt blandingen i små porsjoner under iskjøling, og blandingen ble omrørt i de følgende 3 0 minutter. Utfelt materia-le ble filtrert av, og filtratet ble surgjort til pH 1-2 med 6N-saltsyre og avkjølt til 5°C for å utfelle krystaller. Krystallene ble oppsamlet ved filtrering og ble vasket to ganger med 100 ml vann og tørket ved 40°C under redusert trykk, hvilket ga 93 g (R)-2-ftalimidopropionsyre som hvite krystaller. To a solution of 50 g of D-alanine in 500 ml of water was added 78 ml of triethylamine, and 123 g of N-carbethoxyphthalimide was added to the mixture in small portions under ice cooling, and the mixture was stirred for the following 30 minutes. Precipitated material was filtered off, and the filtrate was acidified to pH 1-2 with 6N hydrochloric acid and cooled to 5°C to precipitate crystals. The crystals were collected by filtration and were washed twice with 100 ml of water and dried at 40°C under reduced pressure to give 93 g of (R)-2-phthalimidopropionic acid as white crystals.
Referanseeksempel 2 Reference example 2
( R)- 2- Ftalimido- N-( 2, 6- dimetylfenyl- N- T3-( 3- pyridvl) propyl1 - propanamid- hvdroklorid ( R )- 2- Phthalimido- N-( 2, 6- dimethylphenyl- N- T3-( 3- pyridyl) propyl 1 - propanamide- hydrochloride
Til en suspensjon av 10 g av (R)-2-ftalimidoproionisk syre i 10 ml tionylklorid ble det tilsatt 1.8 ml tørt dimetylform-amid, og blandingen ble omrørt i 5 timer ved værelsestemperatur. Løsningsmidlet ble innblandet i vakuum, og 50 ml tørt dikloretan ble tilsatt til residuet, og blandingen ble konsentrert i vakuum. Den samme fremgangsmåte ble gjentatt to ganger for å fjerne overskuddet av tionylklorid fullstendig og for å oppnå et syreklorid. To a suspension of 10 g of (R)-2-phthalimidoproionic acid in 10 ml of thionyl chloride, 1.8 ml of dry dimethylformamide was added, and the mixture was stirred for 5 hours at room temperature. The solvent was mixed in vacuo, and 50 mL of dry dichloroethane was added to the residue, and the mixture was concentrated in vacuo. The same procedure was repeated twice to completely remove the excess thionyl chloride and to obtain an acid chloride.
Det erholdte syreklorid ble oppløst i 50 ml tørt dikloretan, og en oppløsning av 9.97 g N-[3-(3-pyridyl)propyl]-2.6-dimet-ylanilin i 5 ml tørt dikloretan ble tilsatt dråpevis til oppløsningen, idet man holdt temperaturen i oppløsningen ved 3-5°C, og deretter ble reaksjonsblandingen omrørt ved værelsestemperatur over natten. The acid chloride obtained was dissolved in 50 ml of dry dichloroethane, and a solution of 9.97 g of N-[3-(3-pyridyl)propyl]-2,6-dimethylaniline in 5 ml of dry dichloroethane was added dropwise to the solution, maintaining the temperature in the solution at 3-5°C, and then the reaction mixture was stirred at room temperature overnight.
Felningen ble filtrert av og vasket to ganger med 50 ml tørt dikloretan, filtratet ble konsentrert i vakuum, hvilket ga 22,6 g (R)-2-ftalimid-N-(2.6-dimetylfenyl)-N[3-(3-pyridyl)-propyl] propanamidhydroklorid som en amorft pulver. The precipitate was filtered off and washed twice with 50 ml of dry dichloroethane, the filtrate was concentrated in vacuo to give 22.6 g of (R)-2-phthalimide-N-(2,6-dimethylphenyl)-N[3-(3-pyridyl )-propyl] propanamide hydrochloride as an amorphous powder.
Optisk renhet: 98% ee Optical purity: 98% ee
IR (KBr) : vco 1715, 1660 cm-<1>IR (KBr) : vco 1715, 1660 cm-<1>
Referanseeksempel 3 Reference example 3
( R)- 2- Amino- N-( 2. 6- dimetvlfenvl- N- f3-( 3- Pvridvl) propvll pro<p>anamid ( R )- 2- Amino- N-( 2. 6- dimethylphenyl- N- 3-( 3- Pvridyl) propyl pro<p>anamide
Til en oppløsning av 22,6 g (R)-2-ftalimido-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamidhydroklorid erholdt i referanseeksempel 2 i 113 ml metanol ble det tilsatt 82 ml 40% metylaminmetanoloppløsning, og reaksjonsblandingen ble omrørt over natten. Løsningsmidlet ble inndampet i vakuum, residuet ble oppløst i 100 ml 2N-saltsyre, og løsningen ble vasket to ganger med 70 ml metylenklorid. Det vandige sjikt ble nøytralisert til pH 8 med natriumbikarbonat, og løsningen ble ekstrahert 3 ganger med 70 ml metylenklorid. To a solution of 22.6 g of (R)-2-phthalimido-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide hydrochloride obtained in reference example 2 in 113 ml of methanol was added 82 ml 40% methylamine methanol solution, and the reaction mixture was stirred overnight. The solvent was evaporated in vacuo, the residue was dissolved in 100 ml of 2N hydrochloric acid, and the solution was washed twice with 70 ml of methylene chloride. The aqueous layer was neutralized to pH 8 with sodium bicarbonate, and the solution was extracted 3 times with 70 ml of methylene chloride.
Det organiske sjikt ble vasket med vann og tørket over vannfritt natriumsulfat, og løsningsmidlet ble inndampet i vakuum hvilket ga 8,4 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamid. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to give 8.4 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl )propyl]propanamide.
Eksempel 1 Example 1
( R)- 2- Amino- N-( 2. 6- dimetylfenyl)- N- T3- pvridvl) propvllpropan-amid D- tartrat ( R )- 2- Amino- N-( 2. 6- dimethylphenyl)- N- T3- pvridvl) propylpropane-amide D- tartrate
En blanding av 8,4 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamid og 3,2 g D-vinsyre ble oppløst i 33,5 ml 3% vandig etanol, og en autentisk prøve ble innkimet, og oppløsningen fikk stå over natten ved værelsestemperatur. A mixture of 8.4 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide and 3.2 g of D-tartaric acid was dissolved in 33.5 ml of 3% aqueous ethanol, and an authentic sample was collected, and the solution was allowed to stand overnight at room temperature.
De utfelte krystaller ble oppsamlet ved filtrering og tørket under redusert trykk ved 60°C hvilket ga 8,2 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamid D tartrat som hvite krystaller. The precipitated crystals were collected by filtration and dried under reduced pressure at 60°C to give 8.2 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl] propanamide D tartrate as white crystals.
Eksempel 2 Example 2
( R) - 2- Amino- N- ( 2 . 6- dimetylf enyl) - N- \ 3 - Opyridyl) propvll pro-panamid- dibezovl- D- tartrat ( R) - 2- Amino- N-( 2 . 6- dimethylphenyl) - N- \ 3 - Opyridyl) propvll propanamide- dibezovl- D- tartrate
En blanding av 10 g (RS)-2-amino-N-(2.6-dimetylfenyl)-N-[3-pyridyl)propyl]propanamid og 11,5 g dibenzyol-D-vinsyre ble oppløst i 100 ml etanol, og en autentisk prøve ble innkimet og løsningen fikk stå over natten ved 60°C. De utfelte krystaller ble oppsamlet ved filtrering og tørket, hvilket ga 9,92 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)-propyl]propanamid-dibenzoyl-D-tartrat. A mixture of 10 g of (RS)-2-amino-N-(2,6-dimethylphenyl)-N-[3-pyridyl)propyl]propanamide and 11.5 g of dibenzyl-D-tartaric acid was dissolved in 100 ml of ethanol, and a authentic sample was entered and the solution was allowed to stand overnight at 60°C. The precipitated crystals were collected by filtration and dried to give 9.92 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)-propyl]propanamide-dibenzoyl-D -tartrate.
(Utbytte: 46,1%; optisk renhet: 92,6% ee) (Yield: 46.1%; optical purity: 92.6% ee)
Krystallene ble oppløst i en løsningsmiddelblanding av 100 ml kloroform og 200 ml etanol, og løsningen ble oppvarmet under tilbakeløp for å fjerne kloroformen fullstendig. Etanol ble tilsatt til den gjenværende blanding for å få en etanolløs-ning på ca. 200 ml i volum, og løsningen fikk stå over natten ved 60°C. De utfelte krystaller ble oppsamlet ved filtrering og tørket, hvilket ga 8,18 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamid-dibenzoyl-D-tartrat. The crystals were dissolved in a solvent mixture of 100 ml chloroform and 200 ml ethanol, and the solution was heated under reflux to completely remove the chloroform. Ethanol was added to the remaining mixture to obtain an ethanol solution of approx. 200 ml in volume, and the solution was allowed to stand overnight at 60°C. The precipitated crystals were collected by filtration and dried to give 8.18 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide-dibenzoyl-D- tartrate.
Eksempel 3 Example 3
( R)- 2- Amino- N-( 2. 6- dimetvlfenyl)- N-[ 3 -( 3- pyridvl) propyl 1 pro-panamid D- tartrat ( R )- 2- Amino- N-( 2. 6- dimethylphenyl)- N-[ 3 -( 3- pyridyl) propyl 1-propanamide D- tartrate
En mettet vandig natriumbikarbonatløsning på 50 ml ble tilsatt til 8,18 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamid dibenzoyl D-tartrat (optisk renhet: 100% ee) erholdt i eksempel 2, og blandingen ble ekstrahert tre ganger med 50 ml, 2 0 ml og 20 ml metylklorid. A saturated aqueous sodium bicarbonate solution of 50 ml was added to 8.18 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide dibenzoyl D-tartrate (optical purity : 100% ee) obtained in Example 2, and the mixture was extracted three times with 50 ml, 20 ml and 20 ml of methyl chloride.
Det organiske sjikt ble vasket etter hverandre med en mettet vandig natriumbikarbonatløsning og vann og ble tørket over vannfritt natriumsulfat. Løsningsmidlet ble inndampet i vakuum og ga 3,90 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)-propyl]propanamid. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and water and was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 3.90 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide.
En blanding av 3,90 g av det frie amin erholdt ovenfor og 1,86 g D-vinsyre ble oppløst i 15 ml 3% vandig etanol, og en autenstisk prøve ble innkimet i løsningen, og løsningen fikk stå over natten ved værelsestemperatur. A mixture of 3.90 g of the free amine obtained above and 1.86 g of D-tartaric acid was dissolved in 15 ml of 3% aqueous ethanol, and an authentic sample was placed in the solution, and the solution was allowed to stand overnight at room temperature.
De utfelte krystaller ble oppsamlet ved filtrering og tørket hvilket ga 5,84 g (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3 -(3 - pyridyl)propyl]propanamid D-tartrat. Smeltepunktet og den optiske rotasjon for produktet var identisk med verdiene for forbindelsen fremstilt i eksempel 1. The precipitated crystals were collected by filtration and dried to give 5.84 g of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide D-tartrate. The melting point and optical rotation of the product were identical to the values for the compound prepared in Example 1.
Eksempel 4 Example 4
( R) - 2- Amino- N-( 2. 6- dimetylfenyl)- N- T3- pyridvl) propyllpropan-amid- di- p- t oluovl- D- t art rat (R) - 2- Amino- N-(2.6- dimethylphenyl)- N- T3- pyridvl) propylpropane-amide- di- p- t oluovl- D- t artrat
En blanding av 500 mg (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3 - pyridyl)propyl]propanamid og 620 mg di-p-toluoyl-D-vinsyre ble oppløst i 5 ml isopropanol, og en autentisk prøve ble innsådd i oppløsningen, og løsningen fikk stå over natten ved værelsestemperatur. De utfelte krystaller ble oppsamlet ved filtrering og tørket ved 50°C hvilket ga 608 mg (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl] propanamid-di-p-toluoyl-D-tartrat som hvite krystaller. A mixture of 500 mg of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-pyridyl)propyl]propanamide and 620 mg of di-p-toluoyl-D-tartaric acid was dissolved in 5 ml of isopropanol, and an authentic sample was inoculated into the solution and the solution was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration and dried at 50°C to give 608 mg of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide-di-p -toluoyl-D-tartrate as white crystals.
Referanseeksempel 4 Reference example 4
Bestemmelse av hy<g>roskopisitet Determination of hy<g>roscopicity
Hygroskopisiteten av (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-(3-pyridyl)propyl]propanamid-hydroklorid (heretter omtalt som hydrokloridet av forbindelsen i R-form); D-tartratet, dibenzoyl-D-tartratet og di-p-toluoyl-D-tartratet av (R)-2-amino-N-(2.6-dimetylfenyl)-N-[3-pyridyl)-propyl]propanamid (heretter omtalt som D-tartratet av forbindelsen i R-form, dibenzoyl-D-tartratet av R-formforbindelsen, og di-p-toluoyl-D-tartratet av R-formforbindelsen respektivt, ble bestemt som følger. The hygroscopicity of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propanamide hydrochloride (hereinafter referred to as the hydrochloride of the compound in R form); The D-tartrate, the dibenzoyl-D-tartrate and the di-p-toluoyl-D-tartrate of (R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-pyridyl)-propyl]propanamide (hereinafter as the D-tartrate of the R-form compound, the dibenzoyl-D-tartrate of the R-form compound, and the di-p-toluoyl-D-tartrate of the R-form compound, respectively, were determined as follows.
Hver prøve ble oppveid til ca. 0,1 g eller 0,2 g i en veie-skål med en diameter på ca. 2,5-3,0 cm. Each sample was weighed to approx. 0.1 g or 0.2 g in a weighing dish with a diameter of approx. 2.5-3.0 cm.
Prøvene fikk stå i et konstant fuktighetspar som inneholdt en mettet vandig kalsiumnitratløsning og hadde 51% relativ fuktighet ved ca. 25-26°C. The samples were allowed to stand in a constant humidity chamber containing a saturated aqueous calcium nitrate solution and had 51% relative humidity at approx. 25-26°C.
En forandring i vekten av hver prøve ved henstand ble målt, og hygroskopisiteten for hver prøve ble bestemt i henhold til følgende ligning. A change in the weight of each sample upon standing was measured, and the hygroscopicity of each sample was determined according to the following equation.
Vl1: Vekten av en tom vektstål (g) Vl1: Weight of an empty barbell (g)
W2: Vekten av vektskålen med en prøve før henstand (g) W3: Vekten av vektskålen med en prøve etter henstand (g) W2: The weight of the balance with a sample before the delay (g) W3: The weight of the balance with a sample after the delay (g)
Hygroskopisiteten (%) i D-tartratet av R-formforbindelsen (prøve B) og dibenzoyl-D-tartratet av R-formforbindelsen (prøve C) og di-p-toluoyl-D-tartratet av R-formforbindelsen (prøve D) sammenlignet med hydrokloridet av R-formforbindelsen (prøve A). The hygroscopicity (%) of the D-tartrate of the R-form compound (sample B) and the dibenzoyl-D-tartrate of the R-form compound (sample C) and the di-p-toluoyl-D-tartrate of the R-form compound (sample D) compared to the hydrochloride of the R-form compound (sample A).
Claims (5)
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NO920016A NO178621C (en) | 1992-01-02 | 1992-01-02 | Acid addition salts of optically active alanine anilide compounds and pharmaceutical compositions containing them |
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NO920016A NO178621C (en) | 1992-01-02 | 1992-01-02 | Acid addition salts of optically active alanine anilide compounds and pharmaceutical compositions containing them |
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NO920016L NO920016L (en) | 1993-07-05 |
NO178621B true NO178621B (en) | 1996-01-22 |
NO178621C NO178621C (en) | 1996-05-02 |
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