DK166320B - Eddikesyreesteren af haloperidol, fremgangsmaade til fremstilling heraf og farmaceutiske kompositioner deraf - Google Patents
Eddikesyreesteren af haloperidol, fremgangsmaade til fremstilling heraf og farmaceutiske kompositioner deraf Download PDFInfo
- Publication number
- DK166320B DK166320B DK479587A DK479587A DK166320B DK 166320 B DK166320 B DK 166320B DK 479587 A DK479587 A DK 479587A DK 479587 A DK479587 A DK 479587A DK 166320 B DK166320 B DK 166320B
- Authority
- DK
- Denmark
- Prior art keywords
- haloperidol
- acetic acid
- oil
- pharmaceutical composition
- hydroxy
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims abstract description 6
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 title abstract description 54
- 229960003878 haloperidol Drugs 0.000 title abstract description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title 3
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 150000002168 ethanoic acid esters Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000003921 oil Substances 0.000 claims abstract description 7
- 235000019198 oils Nutrition 0.000 claims abstract description 7
- 239000008159 sesame oil Substances 0.000 claims abstract description 6
- 235000011803 sesame oil Nutrition 0.000 claims abstract description 6
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 5
- 239000008158 vegetable oil Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- -1 4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl-1- (4-fluorophenyl) -butanone Chemical compound 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 3
- 239000002552 dosage form Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- XAMUDJHXFNRLCY-UHFFFAOYSA-N phenthoate Chemical compound CCOC(=O)C(SP(=S)(OC)OC)C1=CC=CC=C1 XAMUDJHXFNRLCY-UHFFFAOYSA-N 0.000 abstract 1
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 210000003205 muscle Anatomy 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 102000004420 Creatine Kinase Human genes 0.000 description 4
- 108010042126 Creatine kinase Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940064734 aminobenzoate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229940018560 citraconate Drugs 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001954 decanoic acid esters Chemical class 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N itaconic acid Chemical compound OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Anesthesiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
Description
DK 166320 B
Den foreliggende opfindelse angår den hidtil ukendte eddikesyreester af 4-(4-(4-chlorphenyl)-4-hydroxy-l-piperidinyl)-1-(4-fluor-phenyl)-1-butanon, med den i krav 1 angivne formel, såvelsom farmaceutisk acceptable syreadditionssalte deraf, en fremgangsmåde 5 til fremstilling af de nævnte forbindelser, samt farmaceutiske kompositioner deraf.
Forbindelsen 4-(4-(4-chlorphenyl)-4-hydroxy-l-piperidinyl)-1-(4 — fluorphenyl)-1-butanon med formlen 10 kendt under det generiske navn haloperidol (INN), har i mange år i stort omfang været anvendt som et neuroleptikum i behandlingen af psykotiske tilstande, herunder skizofreni.
Hidtil har haloperidol været administreret oralt i form af vandige injektionsopløsninger indeholdende haloperidol og mælkesyre. Desuden 15 beskrives i GB 2.054.371 A et meget længevirkende depotpræparat, bestående af dekansyreesteren af haloperidol i sesamolie, hvilket hævdes overraskende ikke at have den bivirkning at det fremkalder vævsirritation.
Endelig kendes fra US patentskrift nr. 3,408,356 Cg-C18-estere af 4'- 20 fluor-4- [4-hydroxy-4- (α,α,α-trifluortolyDpiperidinojbutyrophenon og beslægtede derivater at være længere virkende end de tilsvarende lavere estere'.
De ovennævnte estere med langkædede syrer giver altså angiveligt en lang virkningstid, idet virkningen dog først indtræder efter nogen 25 tid.
Den ovenfor nævnte vandige injektionsopløsning har en relativ kort virkning og anvendes derfor mest i patientens akutte fase, men har i de fleste tilfælde alvorlige bivirkninger, idet den i mange tilfælde forårsager nekroser i muskelvævet på injektionsstedet. Der er 30 følgeligt et behov for et kortvirkende injektionspræparat af haloperidol, som ikke forårsager de nævnte bivirkninger samtidig med at det giver en forholdsvis hurtigt indtrædende virkning.
DK 166320 B
2
Det har nu ifølge den foreliggende opfindelse vist sig, at ved at erstatte de · vandige opløsninger af haloperidol med opløsninger af den hidtil ukendte eddike-* syreester af haloperidol, eller et farmaceutisk akceptabelt syreadditionssalt deraf, i farmaceutisk akceptable olier, sker der praktisk taget ingen skade på 5 muskelvævet, samtidig med at der opnås en rimelig hurtig indsættelse af den antipsykotiske effekt med en varighed på 2-7 døgn.
De farmaceutiske kompositioner ifølge den foreliggende opfindelse fremstilles ved at opløse eller suspensere eddikesyreesteren af haloperidol, eller et farmaceutisk akceptabelt syreadditionssalt deraf, i en farmaceutisk akceptabel olie 10 under sterile betingelser. De foretrukne olier er af vegetabilsk oprindelse, såsom jordnøddeolie, sesamolie, bomuldsfrøolie, majsolie, sojabønneolie, olivenolie, og (R) især let vegetabilsk olie kendt under navnet Viscoleo' .
Ved fremgangsnåden ifølge opfindelsen behandles haloperidol med et reaktivt derivat af eddikesyre i et opløsningsmiddel, hvorpå den dannede eddikesyreester 15 af haloperidol isoleres i form af den frie base eller et farmaceutisk akceptabelt syreadditionssalt deraf.
Som reaktive derivater af eddikesyre kan især nævnes anhydrider eller syrehalo-genider, fortrinsvis acetylchlorid.
Opløsningsmidlet, som anvendes ved forestringen, kan fordelagtigt være pyridin 20 eller et inert organisk opløsningsmiddel indeholdende et syrebindende middel.
Forestringen gennemføres fortrinsvis, ved forhøjet temperatur såsom tilbagesvalingstemperatur.
Opfindelsen indbefatter også farmaceutisk akceptable salte af eddikesyreesteren af haloperidol dannet ud fra ugiftige organiske eller uorganiske syrer. Sådanne 25 salte fremstilles let på i og for sig kendt måde, såsom ved at omsætte haloperidol med enten den beregnede mængde af den organiske eller uorganiske syre i et med vand blandbart opløsningsmiddel, f.eks. acetone eller ethanol, med isolering af saltet ved koncentrering og afkøling, eller med et overskud af syren i et med vand ikke blandbart opløsningsmiddel, f.eks. ether, og påfølgende 30 udskillelse af det dannede salt. Eksempler på sådanne organiske salte er . maleatet, fumaratet, benzoatet, ascorbatet, embonatet, succinatet, oxalatet, bis-methylensalicylatet, methansulfonatet, ethandisulfonatet, acetatet, propionatet, tartratet, salicylatet, citratet, glukomatet, laktatet, maleinatet, 3
DK 166320B
mandelatet, cinnamatet, citrakonatet, aspartatet, stearatet, palmitatet, itakonatet, glykolatet, p-aminobenzoatet, glutamatet, benzensuifonatet og theophyJJinater. Eksempler på salte med uorganiske syrer er f.eks. hydrochloridet, hydrobromidet, sulfatet, fosfatet og nitratet. Naturligvis kan 5 disse salte også fremstilles ved den· klassiske metode af dobbeltomsætning af passende salte på i og for sig kendt måde.
Opfindelsen skal i det følgende illustreres ved nogle eksempler: EKSEMPEL 1 Μ 4-A cetoxy-M4-chlorphenyl)-1 -piper idinylM -(4-f luorphenyl)-1 -butanon 10 (Haloperidol-acetat) 4-(4-(4-Chlorphenyl)-4-hydroxy-l-piperidinyl)-l-(4-fluorphenyl)-l-butanon (20 g) og eddikesyreanhydrid (16 g) i 200 ml tør pyridin (KOH pellets) blev kogt under tilbagesvaiing i 2 timer. Blandingen hæidtes i 2 liter koldt vand (0°C) og ekstraheredes med 2x200 ml isopropylether. De samlede organiske faser tørredes 15 over MgSO^, og. opløsningsmidler afdampedes. Titelforbindelsen vandtes ved søjlekromatografi på silikagel (eluent, ethylacetat/dichlormethan/methanol, 1:1:1). Udbytte: 10,6 g (48%). Smp. 106-110°C ved krystallisation fra isopropylether. Hydrochloridet fældedes fra acetone. Smp. 215°C. Ifølge TLC analyse var indholdet af haloperidol 0,5%.
20 De følgende eksempler illustrerer de farmaceutiske kompositioner ifølge opfindelsen: EKSEMPEL 2
Haloperidol acetat 5 gram
Tynd vegetabilsk olie 25 BP (Viscoleo® ) ad 100 ml
EKSEMPEl· S
Haloperidol acetat 2 gram
Sesamolie BP ad 100 ml 4
DK 166320B
EKSEMPEL '4
Haloperidol acetat 3 gram
Tynd vegetabilsk olie BP ad 100 ml EKSEMPEL 5 5 Haloperidol acetat 10 gram
Olivenolie ad 100 ml EKSEMPEL 6
Haloperidol acetat 5 gram
Sesamolie BP ad 100 ml . 10 Opløsningerne ifølge eksemplerne 2-6 fremstilles under sterile betingelser og fyldes i passende beholdere såsom ampuller eller hætteglas, hver indeholdende 1-3 mi opløsning.
De farmaceutiske kompositioner ifølge opfindelsen administreres hensigtsmæssigt i enhedsdoser i ampuller eller hætteglas, idet opløsningen eller suspensionen 13 indeholder fra 1 mg til 100 mg aktiv substans pr. ml opløsning eller suspension.
Nogle af de ovennævnte kompositioner i eksemplerne 2-6 blev testet for deres evne til at beskytte hunde mod opkastning forårsaget af apomorfin. Testen har været beskrevet af Janssen, P.A.J., Niemegeers, C.J.E. og K.H.L. Scheelekens, Arzneimittel-Forschung, 1965, 15, 1196-1201.
20 Der fandtes god beskyttelse sammenlignet med tilsvarende injektioner af vandige opløsninger af uesterificeret haloperidol. Der fandtes således klar beskyttelse fra få timer efter injektion til ca.· 7 dage efter, ved en dosis på 4 mg/kg,· og fra få timer til ca. 8 dage ved en dosis på 8 mg/kg.
DK 166320 B
5
Den lokale toxicitet på injektionsstedet blev testet i grise.
2 ml af prøveopløsningen blev injiceret intramuskulært. Tre dage efter injektionen blev grisene bedøvet og dræbt ved overskæring af hovedpulsåren. Makroskopiske forandringer på injektionsstedet noteredes, og mængden af 5 ødelagt eller beskadiget muskelvæv blev bestemt ved måling af formindskelse i kreatinphosphokinase (CK). Medens kompositionerne ifølge den foreliggende opfindelse kun viste svag formindskelse af CK i ca. 0,15 - Ο,ΨΟ g muskelvæv, og næsten ingen makroskopiske ændringer, viste den tilsvarende test med en kommercial 0,5% vandig opløsning af haloperidol som laktatet en formindskelse 10 af CK på omkring 6g muskelvæv med udtalte makroskopiske forandringer af nekrotisk muskelvæv skarpt afgrænset fra omliggende sundt væv.
Claims (2)
- 5 Eddikesyreesteren af 4-(4-(4-chlorphenyl)-4-hydroxy-l-piperidinyl-l- (4-fluorphenyl)-butanon. -3- En injicerbar farmaceutisk komposition, der som aktiv bestanddel indeholder en effektiv mængde af en forbindelse ifølge krav 1 eller 2, i en farmaceutisk acceptabel olie, eventuelt sammen med andre 10 farmaceutiske hjælpestoffer. -4- En farmaceutisk komposition ifølge krav 3, hvori den aktive bestanddel er forbindelsen ifølge krav 2. -5- En farmaceutisk komposition ifølge krav 3 eller 4, i enhedsdoseform, hvori den aktive bestanddel er til stede i en mængde fra 1 mg til 15 100 mg pr. ml opløsning eller suspension. DK 166320B -6- En farmaceutiske komposition ifølge ethvert af kravene 3-5, hvori olien er sesamolie. -7- En farmaceutisk komposition ifølge ethvert af kravene 3-5, hvori olien er tynd. vegetabilsk olie, Viscoleo ®. -8-
- 5 Fremgangsmåde til fremstilling af eddikesyreesteren af 4-(M4-chlorphenylM-hydroxy-l-piperidinyl)-l-(^-fluorphenyl)-l-butanon, eller et farmaceutisk akceptabelt syreadditionssalt deraf, kendetegnet ved, at ΜΜΨ-chlorphenyl)-4-hydroxy-1 -piperidinyl)-1 -(4-fluorphenyl)-1 -butanon behandles med et reaktivt derivat af eddikesyre, hvorpå den dannede ester isoleres som den frie 10 base eller et farmaceutisk akceptabelt syreadditionssalt deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8621892 | 1986-09-11 | ||
| GB868621892A GB8621892D0 (en) | 1986-09-11 | 1986-09-11 | Organic compound |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK479587D0 DK479587D0 (da) | 1987-09-11 |
| DK479587A DK479587A (da) | 1988-03-12 |
| DK166320B true DK166320B (da) | 1993-04-05 |
| DK166320C DK166320C (da) | 1993-08-23 |
Family
ID=10604021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK479587A DK166320C (da) | 1986-09-11 | 1987-09-11 | Eddikesyreesteren af haloperidol, fremgangsmaade til fremstilling heraf og farmaceutiske kompositioner deraf |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4855307A (da) |
| EP (1) | EP0260070B1 (da) |
| JP (1) | JPS6377857A (da) |
| AT (1) | ATE92917T1 (da) |
| AU (1) | AU591334B2 (da) |
| DE (1) | DE3786966T2 (da) |
| DK (1) | DK166320C (da) |
| ES (1) | ES2058120T3 (da) |
| FI (1) | FI88155C (da) |
| GB (1) | GB8621892D0 (da) |
| IE (1) | IE60902B1 (da) |
| IL (1) | IL83819A (da) |
| NO (1) | NO169893C (da) |
| NZ (1) | NZ221711A (da) |
| PT (1) | PT85678B (da) |
| ZA (1) | ZA876819B (da) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3742580C1 (de) * | 1987-12-16 | 1989-05-11 | Schaper & Bruemmer Gmbh | Verwendung des alpha,alpha-Diphenyl-alpha-(3-carboxy-propionyloxy)-essigsaeure-4-(N-methylpiperidyl)-esters zur Behandlung hypertoner Funktionszustaende im Bereich der Harnblase |
| US5776963A (en) | 1989-05-19 | 1998-07-07 | Hoechst Marion Roussel, Inc. | 3-(heteroaryl)-1- (2,3-dihydro-1h-isoindol-2-yl)alkyl!pyrrolidines and 3-(heteroaryl)-1- (2,3-dihydro-1h-indol-1-yl)alkyl!pyrrolidines and related compounds and their therapeutic untility |
| DK238190D0 (da) * | 1990-10-03 | 1990-10-03 | Lundbeck & Co As H | Depotderivater |
| ATE348808T1 (de) | 2000-03-06 | 2007-01-15 | Acadia Pharm Inc | Azacyclische verbindungen zur verwendung in der behandlung von mit serotonin verwandten krankheiten |
| EP1787984B1 (en) * | 2000-03-06 | 2016-10-19 | Acadia Pharmaceuticals Inc. | Azacyclic compounds for use in the treatment of serotonin related diseases |
| WO2003057698A2 (en) | 2001-12-28 | 2003-07-17 | Acadia Pharmaceuticals, Inc. | Spiroazacyclic compounds as monoamine receptor modulators |
| US7538222B2 (en) | 2002-06-24 | 2009-05-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| WO2004000808A2 (en) | 2002-06-24 | 2003-12-31 | Acadia Pharmaceuticals Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| US7253186B2 (en) | 2002-06-24 | 2007-08-07 | Carl-Magnus Andersson | N-substituted piperidine derivatives as serotonin receptor agents |
| SI1587789T1 (sl) | 2003-01-16 | 2009-02-28 | Acadia Pharm Inc | Selektivni inverzni agonisti serotoninskega 2A/2Creceptorja kot terapevtiki za nevrodegenerativne bolezni |
| US7820695B2 (en) | 2004-05-21 | 2010-10-26 | Acadia Pharmaceuticals, Inc. | Selective serotonin receptor inverse agonists as therapeutics for disease |
| US20050261278A1 (en) | 2004-05-21 | 2005-11-24 | Weiner David M | Selective serotonin receptor inverse agonists as therapeutics for disease |
| ES2412207T3 (es) | 2004-09-27 | 2013-07-10 | Acadia Pharmaceuticals Inc. | Forma cristalina de hemitartrato de N-(4-fluorobencil)-N-(1-metilpiperidin-4-il)-N'-(4-(2-metilpropiloxi)fenilmetil)carbamida |
| US7790899B2 (en) | 2004-09-27 | 2010-09-07 | Acadia Pharmaceuticals, Inc. | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
| AU2008228833B9 (en) | 2007-03-19 | 2013-10-24 | Acadia Pharmaceuticals Inc. | Combinations of 5-HT2A inverse agonists and antagonists with antipsychotics |
| HUE055763T2 (hu) | 2015-07-20 | 2021-12-28 | Acadia Pharm Inc | Eljárás N-(4-fluorbenzil)-N-(1-metilpiperidin-4-il)-N'-(4-(2-metil-propil-oxi)fenil-metil)karbamid vagy ennek tartarát-sója és C polimorf formája elõállítására |
| WO2017165635A1 (en) | 2016-03-25 | 2017-09-28 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome p450 modulators |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US11464768B2 (en) | 2016-12-20 | 2022-10-11 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis |
| WO2018200977A1 (en) | 2017-04-28 | 2018-11-01 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| EP3675827A1 (en) | 2017-08-30 | 2020-07-08 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB895309A (en) * | 1959-11-18 | 1962-05-02 | Res Lab Dr C Janssen Nv | Pyrrolidine and piperidine derivatives |
| US3408356A (en) * | 1965-08-31 | 1968-10-29 | Squibb & Sons Inc | Long chain esters of 4'-fluoro-4-[4-hydroxy-4-(alpha, alpha, alpha-trifluorotolyl)piperi-dino]butyrophenone and the like |
| DE1695194A1 (de) * | 1966-07-11 | 1971-03-18 | Hoffmann La Roche | Verfahren zur Herstellung von Piperidinderivaten |
| US4070473A (en) * | 1973-01-26 | 1978-01-24 | Ab Ferrosan | Piperidino-butyrophenones |
| JPS568318A (en) * | 1979-06-28 | 1981-01-28 | Janssen Pharmaceutica Nv | Non oral long acting composition of haloperidol and bromperidol derivative |
-
1986
- 1986-09-11 GB GB868621892A patent/GB8621892D0/en active Pending
-
1987
- 1987-09-03 AT AT87307799T patent/ATE92917T1/de not_active IP Right Cessation
- 1987-09-03 ES ES87307799T patent/ES2058120T3/es not_active Expired - Lifetime
- 1987-09-03 EP EP87307799A patent/EP0260070B1/en not_active Expired - Lifetime
- 1987-09-03 DE DE87307799T patent/DE3786966T2/de not_active Expired - Lifetime
- 1987-09-03 IE IE236687A patent/IE60902B1/en not_active IP Right Cessation
- 1987-09-04 US US07/093,404 patent/US4855307A/en not_active Expired - Lifetime
- 1987-09-08 IL IL83819A patent/IL83819A/xx not_active IP Right Cessation
- 1987-09-08 NZ NZ221711A patent/NZ221711A/xx unknown
- 1987-09-10 AU AU78232/87A patent/AU591334B2/en not_active Ceased
- 1987-09-10 PT PT85678A patent/PT85678B/pt not_active IP Right Cessation
- 1987-09-10 NO NO873785A patent/NO169893C/no unknown
- 1987-09-10 FI FI873924A patent/FI88155C/fi not_active IP Right Cessation
- 1987-09-11 DK DK479587A patent/DK166320C/da not_active IP Right Cessation
- 1987-09-11 ZA ZA876819A patent/ZA876819B/xx unknown
- 1987-09-11 JP JP62226744A patent/JPS6377857A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IE60902B1 (en) | 1994-08-24 |
| US4855307A (en) | 1989-08-08 |
| EP0260070B1 (en) | 1993-08-11 |
| JPS6377857A (ja) | 1988-04-08 |
| FI873924L (fi) | 1988-03-12 |
| ATE92917T1 (de) | 1993-08-15 |
| PT85678B (pt) | 1990-05-31 |
| PT85678A (en) | 1987-10-01 |
| DK479587A (da) | 1988-03-12 |
| AU7823287A (en) | 1988-03-17 |
| IL83819A0 (en) | 1988-02-29 |
| NO873785L (no) | 1988-03-14 |
| DE3786966T2 (de) | 1994-03-17 |
| DK166320C (da) | 1993-08-23 |
| AU591334B2 (en) | 1989-11-30 |
| EP0260070A1 (en) | 1988-03-16 |
| IL83819A (en) | 1992-02-16 |
| FI88155C (fi) | 1993-04-13 |
| NO169893C (no) | 1992-08-19 |
| GB8621892D0 (en) | 1986-10-15 |
| ZA876819B (en) | 1988-06-29 |
| NO169893B (no) | 1992-05-11 |
| DK479587D0 (da) | 1987-09-11 |
| FI88155B (fi) | 1992-12-31 |
| NZ221711A (en) | 1989-11-28 |
| ES2058120T3 (es) | 1994-11-01 |
| IE872366L (en) | 1988-03-11 |
| FI873924A0 (fi) | 1987-09-10 |
| NO873785D0 (no) | 1987-09-10 |
| DE3786966D1 (de) | 1993-09-16 |
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |