NO851008L - PROCEDURE FOR PREPARING CHINA SALTS OF ANTIMALERIA COMPOUND MEFLOKIN. - Google Patents
PROCEDURE FOR PREPARING CHINA SALTS OF ANTIMALERIA COMPOUND MEFLOKIN.Info
- Publication number
- NO851008L NO851008L NO851008A NO851008A NO851008L NO 851008 L NO851008 L NO 851008L NO 851008 A NO851008 A NO 851008A NO 851008 A NO851008 A NO 851008A NO 851008 L NO851008 L NO 851008L
- Authority
- NO
- Norway
- Prior art keywords
- compound
- mefloquine
- salts
- meflokin
- antimaleria
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 9
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 claims description 9
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 claims description 9
- XEEQGYMUWCZPDN-UHFFFAOYSA-N [2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol Chemical compound C=1C(C(F)(F)F)=NC2=C(C(F)(F)F)C=CC=C2C=1C(O)C1CCCCN1 XEEQGYMUWCZPDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- XGGGTFWVLXTKEP-MRJKSXEKSA-N [[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethyl] (3R,5R)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylate Chemical group C1[C@H](C([C@@H](CC1(C(=O)OC(C1=CC(=NC2=C(C=CC=C12)C(F)(F)F)C(F)(F)F)C1NCCCC1)O)O)O)O XGGGTFWVLXTKEP-MRJKSXEKSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 16
- 229960001962 mefloquine Drugs 0.000 description 13
- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical class [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000000078 anti-malarial effect Effects 0.000 description 6
- WESWYMRNZNDGBX-YLCXCWDSSA-N Mefloquine hydrochloride Chemical compound Cl.C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 WESWYMRNZNDGBX-YLCXCWDSSA-N 0.000 description 5
- 229960005329 mefloquine hydrochloride Drugs 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 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
- 241000223960 Plasmodium falciparum Species 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000001563 schizont Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository 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
- 238000012360 testing method Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
Landscapes
- Compounds Of Unknown Constitution (AREA)
Description
Meflokin, a-2-piperidinyl-2,8-bis(trifluormetyl)-4-kinolin-metanol, er vist å oppvise antimalaria-aktivitet hos mennesker både mot klorokin-følsomme og -resistente stammer av Plasmodium falciparum. Mefloquine, α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinoline-methanol, has been shown to exhibit antimalarial activity in humans against both chloroquine-susceptible and -resistant strains of Plasmodium falciparum.
Denne oppfinnelse angår fremstilling av kinatsaltene av a-2-piperidiny1-2,8-bis(trifluormetyl)-4-kinolinmetanol. Disse salter oppviser en sterktøket oppløselighet under vandige betingelser og forbedret farmåkokinetisk profil mot malaria-forårsakende parasitter sammenlignet med hydrokloridsaltet beskrevet i litteraturen. This invention relates to the preparation of the quinate salts of α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. These salts show a greatly increased solubility under aqueous conditions and an improved pharmacokinetic profile against malaria-causing parasites compared to the hydrochloride salt described in the literature.
Forbindelsene med den følgende strukturformel (I):The compounds with the following structural formula (I):
hvor n er 1 eller 2, har en forbedret farmåkokinetisk profil mot malaria-forårsakende parasitter. En forbindelse med formel (I), meflokin-kinat (n er 1), er uventet oppløselig i vann på bakgrunn av den relative uoppløselighet av meflokin-hydroklorid i vann. I et sammenligningsforsøk ble oppløseligheten av meflokin-kinat vist å være 100 g/100 ml vann, og oppløseligheten av meflokin-hydroklorid var 1 g/100 ml vann. where n is 1 or 2, has an improved pharmacokinetic profile against malaria-causing parasites. A compound of formula (I), mefloquine quinate (n is 1), is unexpectedly soluble in water given the relative insolubility of mefloquine hydrochloride in water. In a comparative experiment, the solubility of mefloquine quinate was shown to be 100 g/100 ml of water, and the solubility of mefloquine hydrochloride was 1 g/100 ml of water.
De nye forbindelser fremstilles hensiktsmessig ved at kinasyre (1,3,4,5-tetrahydroksycykloheksankarboksylsyre) omsettes med meflokin (fri base) (II): The new compounds are suitably prepared by reacting quinic acid (1,3,4,5-tetrahydroxycyclohexanecarboxylic acid) with mefloquine (free base) (II):
i et inert oppløsningsmiddel. Den anvendte mengde kinasyre ved denne omsetning kan være mellom 0,75 og 2,25 mol pr. mol meflokin (II), men 1,0 til 2,0 mol kinasyre foretrekkes. Meflokin (II) blandes med den passende mengde kinasyre (50% vandig oppløsning), og det inerte oppløsningsmiddel tilsettes for å frembringe oppløs-ning av reaksjonskomponentene ved en temperatur valgt i området fra omgivelsestemperatur til 100°C. Reaksjonsoppløsningen fil-treres og filtratet oppvarmes under redusert trykk opp til 100°C for å fjerne oppløsningsmidlet. Ved konsentrering til tørrhet størkner en forbindelse med formel (I), og den oppsamles og tørkes. in an inert solvent. The amount of quinic acid used in this reaction can be between 0.75 and 2.25 mol per moles of mefloquine (II), but 1.0 to 2.0 moles of quinic acid is preferred. Mefloquine (II) is mixed with the appropriate amount of quinic acid (50% aqueous solution), and the inert solvent is added to produce dissolution of the reaction components at a temperature selected in the range from ambient temperature to 100°C. The reaction solution is filtered and the filtrate is heated under reduced pressure to 100°C to remove the solvent. On concentration to dryness, a compound of formula (I) solidifies, and it is collected and dried.
Eksempler på inerte oppløsningsmidler som anvendes ved fremgangsmåten, er alkoholer, så som metanol, etanol, isopropanol og lignende, og amider så som dimetylformamid og dimetylacetamid. Examples of inert solvents used in the method are alcohols, such as methanol, ethanol, isopropanol and the like, and amides such as dimethylformamide and dimethylacetamide.
Meflokin (II) er en kjent forbindelse og fremstilles i henhold til generelle fremgangsmåter. Mefloquine (II) is a known compound and is prepared according to general methods.
Antimalaria-aktiviteten hos forbindelsene fremstilt ifølge oppfinnelsen påvises med standard farmakologiske in vitro forsøks-metoder mot P. falciparum. The antimalarial activity of the compounds produced according to the invention is demonstrated with standard pharmacological in vitro test methods against P. falciparum.
Antimalaria-aktiviteten hos a-2-piperidinyl-2,8-bis(trifluor-metyl) -4-kinolinmetanol-kinat (meflokin-kinat) eller bikinat ble fastslått under anvendelse av fremgangsmåten beskrevet av Lebras et al. i American Journal of Tropical Medicine and Hygiene, Vol. 32 (3) side 447-451 (1983). Meflokin-kinat ble sammenlignet med meflokin-hydroklorid mot to stammer av P. falciparum fra menneske-isolater. Resultatene fraLebras<1>s metoden uttrykt som ICV (hemmende konsentrasjon ble beregnet ved hjelp av det enkle diagram over den prosentvise modning av schizontene som funksjon av log konsentrasjonen av prøvemidlet) er vist nedenfor: The antimalarial activity of α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol quinate (mefloquine quinate) or bicinate was determined using the method described by Lebras et al. in American Journal of Tropical Medicine and Hygiene, Vol. 32 (3) pages 447-451 (1983). Mefloquine quinate was compared with mefloquine hydrochloride against two strains of P. falciparum from human isolates. The results from Lebras<1>'s method expressed as ICV (inhibitory concentration was calculated using the simple diagram of the percentage maturation of the schizonts as a function of the log concentration of the test agent) are shown below:
Meflokin-kinat er ved denne standard in vitro prøvemetode funnet å ha en effektivitet som kan sammenlignes med effektiviteten av meflokin-hydroklorid. Eftersom imidlertid den vandige oppløs-elighet av meflokin-kinat er så overraskende mye høyere enn for meflokin-hydroklorid, vil dets farmakokinetiske profil forbedres. By this standard in vitro test method, mefloquine quinate has been found to have an efficacy comparable to that of mefloquine hydrochloride. However, since the aqueous solubility of mefloquine quinate is so surprisingly much higher than that of mefloquine hydrochloride, its pharmacokinetic profile will be improved.
Meflokin-bikinat har en 1C5Qpå 100 nM/1 mot FCM17 stammer (vest afrikanske klorokin-følsomme). Mefloquine bicinate has an 1C5Q of 100 nM/1 against FCM17 strains (West African chloroquine sensitive).
Farmasøytiske preparater inneholdende en forbindelse medPharmaceutical preparations containing a compound with
formel (I) med antimalaria-aktivitet fremstilles i vanlige enhets-doseformer ved å innarbeide den kjemiske forbindelse i et ugiftig, farmasøytisk bæremiddel i henhold til vanlige metoder. En ugiftig mengde av nevnte aktive bestanddel velges, som er tilstrekkelig til å frembringe den ønskede kjemoterapeutiske aktivitet hos et individ, dyr eller menneske, uten uakseptabel giftighet. formula (I) with antimalarial activity is prepared in conventional unit dosage forms by incorporating the chemical compound in a non-toxic pharmaceutical carrier according to conventional methods. A non-toxic amount of said active ingredient is selected, which is sufficient to produce the desired chemotherapeutic activity in an individual, animal or human, without unacceptable toxicity.
Preparatene vil inneholde den aktive bestanddel i en slik effek-The preparations will contain the active ingredient in such an effect
tiv, men ugiftig mengde valgt i området fra ca. 125 mg til ca.tive, but non-toxic quantity chosen in the range from approx. 125 mg to approx.
1000 mg aktiv bestanddel pr. enhetsdose, men denne mengde er av-hengig av den spesielle biologiske aktivitet som ønskes, forbind-elsens aktivitet og pasientens tilstand. 1000 mg of active ingredient per unit dose, but this amount depends on the particular biological activity that is desired, the activity of the compound and the patient's condition.
En rekke forskjellige farmasøytiske former kan anvendes.A number of different pharmaceutical forms can be used.
Hvis således et fast bæremiddel for oral administrering anvendes, kan preparatet tabletteres, anbringes i en hard gelatinkapsel i pulver- eller pellet-form, eller i form av en stikkpille, tablett eller pastill. Mengden av fast bæremiddel vil variere i stor ut-strekning, men vil fortrinnsvis være fra ca. 125 mg til ca. 500 mg. Hvis et flytende bæremiddel anvendes, vil preparatet være i form If a solid carrier for oral administration is thus used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a suppository, tablet or lozenge. The amount of solid carrier will vary widely, but will preferably be from approx. 125 mg to approx. 500 mg. If a liquid carrier is used, the preparation will be in form
av en sirup, emulsjon, myk gelatinkapsel, steril, injiserbar væske så som en ampulle, eller en vandig oppløsning eller ikke-vandig, flytende suspensjon. På bakgrunn av oppløseligheten av meflokin-kinat, fremstilles lett vandige oppløsninger og anvendes som et sterilt, injiserbart flytende preparat. of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous solution or non-aqueous liquid suspension. Based on the solubility of mefloquine quinate, easily aqueous solutions are prepared and used as a sterile, injectable liquid preparation.
De farmasøytiske preparater fremstilles under anvendelse avThe pharmaceutical preparations are produced using
de vanlige metoder for fremstilling av legemiddelpreparater, inn-befattet blanding, granulering og komprimering når dette er nød-vendig, eller vekselvis blanding og oppløsning av bestanddelene når dette passer for å oppnå det ønskede sluttprodukt. the usual methods for the production of medicinal preparations, including mixing, granulation and compression when necessary, or alternately mixing and dissolving the components when this is appropriate to achieve the desired end product.
Antimalaria-aktivitet kan oppnås, helbredende eller forebyg-gende, ved at det til et individ som har behov for slik aktivitet, administreres internt en forbindelse med formel (I), vanligvis sammen med et farmasøytisk bæremiddel, i en ugiftig mengde som er tilstrekkelig til å frembringe nevnte aktivitet som beskrevet oven-for. Administreringsveien kan være en hvilken som helst vei som effektivt transporterer den aktive forbindelse til virkningstedet som skal påvirkes i kroppen, så som oralt eller parenteralt. Hensiktsmessig administreres en enkel oral dose eller like orale doser flere ganger daglig så som fra 1-3 ganger daglig, idet den daglige dosemengde velges fra ca. 125 mg til ca. 1000 mg. Alter-nativt administreres en enkel parenteral dose én gang daglig med en daglig dosemengde svarende til den man benytter ved oral administrering. Antimalarial activity may be obtained, curatively or prophylactically, by administering internally to an individual in need of such activity a compound of formula (I), usually together with a pharmaceutical carrier, in a non-toxic amount sufficient to to produce said activity as described above. The route of administration can be any route that effectively transports the active compound to the site of action to be affected in the body, such as orally or parenterally. Appropriately, a single oral dose or equal oral doses are administered several times a day, such as from 1-3 times a day, with the daily dose being selected from approx. 125 mg to approx. 1000 mg. Alternatively, a single parenteral dose is administered once a day with a daily dose equivalent to that used for oral administration.
De følgende eksempler illustrerer fremstillingen av en forbindelse med formel (I) og dens innføring i farmasøytiske preparater. The following examples illustrate the preparation of a compound of formula (I) and its introduction into pharmaceutical preparations.
Eksempel 1Example 1
Fremstilling av oc- 2- piperidinyl- 2 , 8- bis ( trif luormetyl)- 4-kinolinmetanol- kinat ( Forbindelse A) Preparation of oc-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanolquinate (Compound A)
Til en 50% vandig oppløsning av kinasyre (1,9 g) ved omgivelsestemperatur under omrøring ble satt a-2-piperidinyl-2,8-bis(tri-fluormetyl)-4-kinolinmetanol (1 g). Til blandingen ble satt etanol (10 ml), og blandingen ble oppvarmet til ca. 40°C for å frembringe oppløsning. Oppløsningen ble derefter filtrert, og etanolen og vann ble fjernet under vakuum til tørrhet. Det ønskede produkt stivnet som et hvitt, krystallinsk materiale med et smeltepunkt på 180°C og var oppløselig i vann. Elementaranalyse er som følger: To a 50% aqueous solution of quinic acid (1.9 g) at ambient temperature with stirring was added α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinoline methanol (1 g). Ethanol (10 ml) was added to the mixture, and the mixture was heated to approx. 40°C to produce solution. The solution was then filtered, and the ethanol and water were removed under vacuum to dryness. The desired product solidified as a white crystalline material with a melting point of 180°C and was soluble in water. Elemental analysis is as follows:
Tilsvarende fremstilles bikinatet under anvendelse av 2,0 mol kinasyre, med et smeltepunkt på 180°C med dekomponering. Similarly, the bicinate is prepared using 2.0 mol of quinic acid, with a melting point of 180°C with decomposition.
Eksempel 2Example 2
Som en spesiell illustrasjon på et preparat oppløses en aktiv bestanddel, så som en del av forbindelse A, i 20 deler vann og administreres oralt i en dose på 4 mg/kg til et individ som har behov for behandling mot malaria. As a particular illustration of a preparation, an active ingredient, such as a portion of compound A, is dissolved in 20 parts of water and administered orally at a dose of 4 mg/kg to an individual in need of antimalarial treatment.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO851008A NO851008L (en) | 1985-03-14 | 1985-03-14 | PROCEDURE FOR PREPARING CHINA SALTS OF ANTIMALERIA COMPOUND MEFLOKIN. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO851008A NO851008L (en) | 1985-03-14 | 1985-03-14 | PROCEDURE FOR PREPARING CHINA SALTS OF ANTIMALERIA COMPOUND MEFLOKIN. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO851008L true NO851008L (en) | 1986-09-15 |
Family
ID=19888178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO851008A NO851008L (en) | 1985-03-14 | 1985-03-14 | PROCEDURE FOR PREPARING CHINA SALTS OF ANTIMALERIA COMPOUND MEFLOKIN. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO851008L (en) |
-
1985
- 1985-03-14 NO NO851008A patent/NO851008L/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4161595A (en) | Levulinic acid salt | |
| KR850001883B1 (en) | Method for preparing crystalline benzothiazine dioxide salts | |
| NZ208417A (en) | Orally administrable compositions having improved release of antidiabetic substances | |
| US5739167A (en) | Desferrioxamine-B salts and their use as orally effective iron chelators | |
| JPH0248526A (en) | Indomethacin injection and production thereof | |
| US4073895A (en) | Isopropylamino pyrimidine orthophosphate | |
| EP0046506B1 (en) | Vincamine saccharinate and drug containing it | |
| US4818767A (en) | Quinate salts of antimalarial phenanthrenemethanol compounds | |
| US4973553A (en) | Salt or organogermanium compound and medicine containing the same | |
| EP1037888B1 (en) | (e)-3-[1-n-butyl- 5-[2-(2-carboxyphenyl)methoxy- 4-chlorophenyl]-1h- pyrazol-4-yl]-2- [(5- methoxy-2,3- dihydrobenzofuran-6-yl)methyl]- prop-2-enoic acid monoargininyl salt | |
| NO851008L (en) | PROCEDURE FOR PREPARING CHINA SALTS OF ANTIMALERIA COMPOUND MEFLOKIN. | |
| US4521424A (en) | Quinate salts of the antimalarial compound mefloquine | |
| CZ20014269A3 (en) | Polymorphs of crystalline azabicyclo[2.2.2]octan-3-amine-citrate and pharmaceutical preparations in which they are comprised | |
| JPH10507446A (en) | Bis-2-aminopyridines, methods for their production and their use for controlling parasite infection | |
| JPS62294616A (en) | Fungicidal drug, manufacture and therapy | |
| KR100364941B1 (en) | Novel crystal forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine | |
| JPS6350355B2 (en) | ||
| US4507288A (en) | β-Glycerophosphate salts of antimalarial phenanthrenemethanol compounds | |
| US3459854A (en) | Tetracycline cyclohexyl sulphamate and process for preparation | |
| EP0138374B1 (en) | Salts of antimalarial phenanthrenemethanol compounds | |
| DD249186A1 (en) | METHOD OF MANUFACTURING A NEW GLIBENCLAMID MEDICAMENT WITH HIGHER BIODEGRADABILITY | |
| EP0078431A1 (en) | Methyl 3-acetamido-2-(5-methoxy-indol-3-yl) propanoate | |
| JPS59508B2 (en) | 2 3- Chikan -4- Fusokandiyouaminosulfonylbenzenesulfonamide | |
| HU195209B (en) | Process for producing mefloquine-quinate salts with antimalarian effect and pharmaceutical preparations comprising the same | |
| JPS6089453A (en) | Antimalarial salt of phenanthrene methanol compound |