HRP20030710A2 - Inhibitor of monoamine uptake - Google Patents
Inhibitor of monoamine uptake Download PDFInfo
- Publication number
- HRP20030710A2 HRP20030710A2 HR20030710A HRP20030710A HRP20030710A2 HR P20030710 A2 HRP20030710 A2 HR P20030710A2 HR 20030710 A HR20030710 A HR 20030710A HR P20030710 A HRP20030710 A HR P20030710A HR P20030710 A2 HRP20030710 A2 HR P20030710A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- phenyl
- oxy
- aminopropane
- compound
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 55
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 12
- 229940076279 serotonin Drugs 0.000 claims description 11
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 9
- 229960002748 norepinephrine Drugs 0.000 claims description 9
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- VQXJIFJNGPGACE-UNTBIKODSA-N 3-methyl-4-[(1r)-3-(methylamino)-1-phenylpropoxy]phenol;hydrochloride Chemical group Cl.O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(O)C=C1C VQXJIFJNGPGACE-UNTBIKODSA-N 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- PPXQPRLGNSJNJM-QGZVFWFLSA-N 4-Hydroxyatomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(O)C=C1C PPXQPRLGNSJNJM-QGZVFWFLSA-N 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
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- 239000002904 solvent Substances 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
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- 230000002503 metabolic effect Effects 0.000 description 10
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- 150000008378 aryl ethers Chemical class 0.000 description 9
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- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 5
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- 239000000706 filtrate Substances 0.000 description 5
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- 238000010561 standard procedure Methods 0.000 description 5
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- JZFUHAGLMZWKTF-UHFFFAOYSA-N 3-chloro-1-phenylpropan-1-ol Chemical compound ClCCC(O)C1=CC=CC=C1 JZFUHAGLMZWKTF-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
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- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- VHGCDTVCOLNTBX-UHFFFAOYSA-N n-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=CC=C1C VHGCDTVCOLNTBX-UHFFFAOYSA-N 0.000 description 4
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- 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 2
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- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- QXFHPLPMTXEJPV-UHFFFAOYSA-N octane-1-sulfonic acid;sodium Chemical compound [Na].CCCCCCCCS(O)(=O)=O QXFHPLPMTXEJPV-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- 229960002888 oxitriptan Drugs 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 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
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229930010796 primary metabolite Natural products 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
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- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000021193 standardized breakfast Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001738 temporomandibular joint Anatomy 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
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Description
Povezanost između ponovne pohrane monoamina i broja neuroloških poremećaja kod sisavaca je ustanovljena, i 3-ariloksi-3-supstituirani-1-aminopropani su pokazali značajnu raznolikost u svojoj sposobnosti da inhibiraju ponovnu pohranu monoamina. Određeni članovi razreda 3-ariloksi-3-supstituiranih-1-aminopropana su našli primjenu u liječenju neuroloških poremećaja. Fluoksetin, N-metil-3-((4-trifluormetilfenil)oksi)-3-fenil-1-aminopropan hidroklorid, na primjer, je selektivni inhibitor ponovne pohrane serotonina koji je naišao na odlično prihvaćanje na tržištu za liječenje depresije i odobren je za liječenje nekoliko drugih poremećaja. Atomoksetin, (-)-N-metil-3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorid, je selektivni inhibitor ponovne pohrane norepinefrina, koji se klinički ispituje za liječenje poremećaja nedostatka pažnje/hiperaktivosti. Duloksetin, (+)-N-metil-3-(1-naftaleniloksi)-3-(2-tienil)-1-aminopropan hidroklorid, inhibira ponovnu pohranu i norepinefrina i serotonina i trenutno je u kliničkom procjenjivanju za liječenje depresije. Ti spojevi su među mnogim 3-ariloksi-3-supstituiranim-1-aminopropanima opisanim u U.S. Patentima #4,018,895, 4,194,009, 4,314,081, 4,956,388, i 5,023,269. Međutim, korisnost hidroksiliranog 3-fenoksi-3-fenil-1-aminopropana do sada nije prepoznata.
Ovaj izum pruža spoj formule I:
[image]
ili njegovu farmaceutski prihvatljivu sol.
Ovaj izum također pruža farmaceutski pripravak koji sadržava, zajedno s farmaceutski prihvatljivim nosačem, razrjeđivačem ili ekscipijentom, spoj formule I.
Ovaj izum pruža postupak za inhibiranje ponovne pohrane norepinefrina i serotonina kod sisavaca, koji uključuje davanje sisavcu, kojem je potrebno takvo inhibiranje, farmaceutske djelotvorne količine spoja formule I.
Daljnje ostvarenje ovog izuma je postupak za inhibiranje ponovne pohrane norepinefrina i serotonina kod sisavaca, za liječenje raznih poremećaja koji su povezani sa smanjenom neurotransmisijom serotonina i/ili norepinefrina kod sisavaca. Ti poremećaji uključuju: depresiju, migrensku bol, bulimiju, predmenstrualni sindrom ili sindrom kasne lutealne faze, alkoholizam, zloupotrebu duhana, panični poremećaj, anksioznost, opću bol, post-traumatski sindrom, gubitak pamćenja, staračku demenciju, socijalnu fobiju, hiperaktivni poremećaj nedostatka pažnje, psorijazu, poremećaj opozicijskog otpora, poremećaj provođenja, granični poremećaj ličnosti, opsesivno kompulzivni poremećaj, poremećaj kroničnog umora, preranu ejakulaciju, erektilne poteškoće, anoreksiju nervosu, poremećaje spavanja, autizam, mutizam, alergijski rinitis, simptome prehlade, narkolepsiju, inkontinenciju, trihotilomaniju, trigeminalnu neuralgiju, zubobolju ili disfunkcijsku bol temperomandibularnog zgloba. Bilo koji od tih postupaka upotrebljava spoj formule I.
Ovaj izum također pruža upotrebu spoja formule I za proizvodnju lijeka za inhibiciju ponovne pohrane norepinefrina i serotonina. Dodatno, ovaj izum pruža farmaceutski pripravak prilagođen za inhibiciju ponovne pohrane serotonina i norepinefrina, koji sadrži spoj formule I ili njegov metabolički prekursor.
Sadašnji izum dalje pruža postupak za dobivanje spoja formule I, koji sadrži sljedeće korake:
a) spajanje spoja formule (i)
[image]
gdje "Pg" je zaštitna skupina kisika, s 1-klor-3-fenil-3-hidroksipropanom, da se dobije spoj formule (ii):
[image]
gdje "Pg" je zaštitna skupina kisika;
b) reakcija spoja formule (ii) s izvorom jodidnog iona, da se dobije spoj formule (iii):
[image]
gdje "Pg" je zaštitna skupina kisika;
c) reakcija spoja formule (iii) s metilaminom, da se dobije R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan; i
a) po potrebi obrađivanje R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana s farmaceutski prihvatljivom kiselinom.
Sadašnji izum također pruža postupak za dobivanje spoja formule I koji sadrži sljedeće korake:
a) spajanje spoja formule (i)
[image]
gdje "Pg" je zaštitna skupina kisika, sa (S)-1-fenil-3-metilaminopropan-1-olom, da se dobije spoj formule (iv):
[image]
gdje "Pg" je zaštitna skupina kisika;
b) reakcija spoja formule (iv) sa sredstvom za uklanjanje zaštite, da se dobije R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan; i
a) po potrebi obrađivanje R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana s farmaceutski prihvatljivom kiselinom.
Spojevi formula (ii), (iii), i (iv) su korisni međuprodukti za dobivanje spojeva formule I, s predstavljaju daljnja ostvarenja sadašnjeg izuma.
Spoj formule I se općenito označava kao R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan. Zbog toga što je taj spoj amin, bazičan je po prirodi i prema tome reagira s bilo kojom od anorganskih i organskih kiselina da bi formirao farmaceutski prihvatljive kisele adicijske soli. Poželjno je prevesti slobodni amin u farmaceutski prihvatljivu kiselu adicijsku sol radi lakoće rukovanja i primjene. Kiseline koje se obično upotrebljavaju za stvaranje soli su anorganske kiseline, kao npr. kloridna kiselina, bromidna kiselina, jodidna kiselina, sulfatna kiselina, fosfatna kiselina, i slično, i organske kiseline, kao npr. p-toluensulfonska kiselina, metansulfonska kiselina, oksalna kiselina, p-bromfenilsulfonska kiselina, karbonatna kiselina, sukcinska kiselina, limunska kiselina, benzojeva kiselina, octena kiselina i slično. Primjeri takvih farmaceutski prihvatljivih soli su prema tome sulfat, pirosulfat, bisulfat, sulfit, bisulfit, fosfat, monohidrogenfosfat, dihidrogenfosfat, metafosfat, pirofosfat, klorid, bromid, jodid, acetat, propionat, dekanoat, kaprilat, akrilat, formijat, izobutirat, kapronat, heptanoat, propiolat, oksalat, malonat, sukcinat, suberat, sebakat, fumarat, maleat, butil-1,4-dioat, heksin-1,6-dioat, benzoat, klorbenzoat, metilbenzoat, dinitrobenzoat, hidroksibenzoat, metoksibenzoat, ftalat, sulfonat, ksilensulfonat, fenilacetat, fenilpropionat, fenilbutirat, citrat, laktat, α-hidroksibutirat, glikolat, tartarat, metansulfonat, propansulfonat, naftalen-1-sulfonat, naftalen-2-sulfonat, mandelat i slično. Poželjne farmaceutski prihvatljive soli su one formirane sa kloridnom i oksalnom kiselinom.
Spoj formule I je kiralan, i može se pripraviti kiralnom kromatografijom racemičnih ili enantiomerno obogaćenih oblika spoja formule I, ili frakcijskom kristalizacijom soli dobivenih od racemičnog ili enantiomerno obogaćenog slobodnog amina i kiralne kiseline. Alternativno, slobodni amin može reagirati s kiralnim pomoćnim sredstvom i enantiomeri se odvojiti kromatografijom, nakon koje slijedi uklanjanje kiralnog pomoćnog sredstva da se regenerira slobodni amin. Dalje, odvajanje enantiomera se može izvesti u bilo kojoj prikladnoj točki u sintezi spojeva iz izuma. Poželjno, spojevi iz izuma se pripravljaju počevši od kiralnog početnog materijala.
Sadašnji izum pruža postupak za inhibiranje ponovne pohrane serotonina i norepinefrina. Ti mehanizmi djeluju kod sisavaca, i poželjni sisavac je čovjek.
Strukturna klasa 3-ariloksi-3-supstituiranih-1-aminopropanskih spojeva je povijesno bila privlačan cilj za sintezu, i u literaturi je opisano nekoliko korisnih sinteza. Sinteza atomoksetina (R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan, ranije poznat kao tomoksetin) i fluoksetina, na primjer, su opisane u Tetrahedron Letters, 30(39), 5207 (1989); Tetrahedron Letters, 35(9), 1339 (1997); WO 99/18947; WO 00/58262; i WO 00/61540. R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan se može prikladno pripraviti kako je ilustrirano u sljedećoj shemi gdje "Pg" zaštitna skupina kisika i "X" je ili klor ili NHMe.
[image]
Potrebni fenoli formule (i) mogu se pripraviti iz komercijalno dostupnog metilhidrokinona uvođenjem odgovarajuće zaštitne skupine kisika standardnim sintetskim postupcima. Prikladne zaštitne skupine kisika za fenole su dobro poznate stručnjaku i opisane su u Greene i Wuts (Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, New York (1999)). Poželjne zaštitne skupine za postupak iz sadašnjeg izuma su alkanoil esteri i silil eteri. Naročito poželjne zaštitne skupine kisika su acetil, tert-butoksikarbonil, i tert-butildimetilsilil. Upotreba tert-butoksikarbonila je naročito poželjna.
Spojevi formule (v) su dobro poznati u struci i mogu se pripraviti standardnim sintetskim postupcima. Sinteze 1-fenil-1-hidroksi-3-klorpropana (v, X = Cl) su opisali Corey i Reichard (Tetrahedron Letters, 30(39), 5207-5210 (1989)); Srebnik, i sur. (Journal of Organic Chemistry, 53, 2916-2020 (1988)); i Schneider i Georgens (Tetrahedron Asymmetry, 3(4), 525-528 (1992)). Sinteze 1-fenil-1-hidroksi-3-klorpropana (v, X = NHMe) su opisali Koenig i Mitchell (Tetrahedron Letters, 35(9), 1339-1342 (1994)); Gao i Sharpless (Journal of Organic Chemistry, 53, 4081-4084 (1988)); i u EP 0 909 754 A1.
Odgovarajući fenol (i) se spaja ili s 1-fenil-1-hidroksi-3-klorpropanom (v, X = Cl), ili s 1-fenil-1-hidroksi-3-(metilamino)propanom (v, X = NHMe) u prisutnosti dialkil azodikarboksilata i trifenilfosfina u standardnim Mitsunobu uvjetima spajanja, da se dobije ili aril eter (ii) ili aril eter (iv), pojedinačno. ̧Tipično, otopina ekvivalenta fenola (i) i ekvivalenta alkohola (v) se spoje u prikladnom otapalu s oko 1,0 do 1,1 ekvivalentom trifenilfosfina. Prikladna otapala uključuju bilo koje otapalo koje otapa dovoljnu količinu reaktanata da se omogući odvijanje reakcije bez značajnog ometanja željene reakcije. Prikladna otapala uključuju dioksan, dietil eter, i tetrahidrofuran. Poželjno otapalo je tetrahidrofuran. Ova otopina se ohladi na temperaturu od oko -5 °C do oko 5 °C, poželjno od oko 0 °C do oko 5 °C. Reakcijska smjesa se održava pod inertnom atmosferom bilo dušika ili argona. Reakcijskoj smjesi se doda oko 1,0 do oko 1,5 ekvivalent, poželjno 1,1 ekvivalent, dialkil azodikarboksilata, poželjno diizopropil azodikarboksilata. Dobivena smjesa zatim reagira od oko 1 sat do oko 24 sata, i zatim se željeni aril eter izolira i pročisti standardnim tehnikama.
Otopina aril etera (ii) u odgovarajućem otapalu, poželjno acetonu, se obrađuje s jodidnim ionom, od oko jednog molarnog ekvivalenta do velikog suviška. Prihvatljiv je bilo koji izvor jodidnog iona koji je kompatibilan s odabranim otapalom i aril eterom (ii). Poželjni izvori jodidnog iona uključuju natrij i kalij jodid. Natrij jodid je poželjni izvor jodidnog iona. Dobiveni aril eter (iii) se izolira i pročisti standardnim tehnikama.
Otopina aril etera (iii) u prikladnom otapalu, tipično tetrahidrofuranu, reagira s metilaminom, od oko jednog ekvivalenta do velikog suviška. Metilamin se može dodati kao plin, kondenzirati u reakcijsku smjesu kao tekućina, ili dodati kao vodena otopina reakcijskoj smjesi. Kad je dodavanje završeno, reaktanti zajedno reagiraju od oko 1 sat do oko 24 sata. Željeni amin se zatim izolira i pročisti standardnim tehnikama.
Stručnjak će prepoznati da se u ovom koraku dobiva, ovisno o prirodi određene upotrijebljene zaštitne skupine kisika (Pg), ili spoj formule (iv) ili R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan. Na primjer, kad Pg je acetil, zaštitna skupina se uklanja za vrijeme koraka aminacije.
Kad se određena zaštitna skupina (Pg) spoja formule (iv) mora ukloniti u odvojenom koraku, stručnjak će razumjeti da specifični uvjeti za regeneriranje fenolne skupine ovise o prirodi zaštitne skupine. Standardni postupci za uklanjanje zaštitnih skupina kisika su opisani u Greene i Wuts, iznad. Kad Pg je tert-butildimetilsilil, na primjer, zaštitna skupina se prikladno uklanja obrađivanjem početnog silil etera (iv) s izvorom fluoridnog iona u prikladnom otapalu. Alternativno, kad Pg je tert-butoksikarbonil, zaštitna skupina se prikladno uklanja obrađivanjem s kiselinom, tipično kloridnom kiselinom. Dobiveni R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan se može zatim izolirati i pročistiti standardnim tehnikama.
Sljedeće priprave i primjeri specifičnije prikazuju ostvarenja sadašnjeg izuma i dobivanje R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana.
Priprava I
4-acetoksi-2-metilfenol
Acetahidrid (4,73 g, 4,37 mL, 46,3 mmol) se dodaje kap po kap smjesi 4-hidroksi-2-metilfenola (5 g, 46,3 mmol) i cezij karbonata (15,1 g, 46,3 mmol) u acetonitrilu (50 mL). Nakon miješanja preko noći, smjesa se filtrira i filtrat se koncentrira pod sniženim tlakom. Ostatak se podvrgne kromatografiji na silikagelu, eluiranjem sa smjesom 5:1 pentana:etil acetata. Frakcije koje sadržavaju produkt se sjedine i koncentriraju pod sniženim tlakom da se dobije 0,24 g (3%) željenog spoja.
1H-NMR (CDCl3) δ 1,54 (1H, bs), 2,18 (3H, s), 2,22 (3H, s), 6,59 (1H, m), 6,82 (1H, m).
Priprava II
(S)-3-klor-1-fenil-1-propanol
Otopini (S)-1-fenil-1,3-propandiola (125 g, 0,822 mol) u metil tert-butil eteru (500 mL) se doda trietilamin (135 mL). Reakcijska smjesa se ohladi do 0 °C i dodaje se otopina 4-brombenzensulfonil klorida (230 g, 0,92 mol) u metil tert-butil eteru (300 mL) i tetrahidrofuranu (300 mL), kap po kap tijekom 3 sata. Nakon dodavanja, reakcijska smjesa se ostavi da reagira pri 0 °C tri sata i zatim se ugrije do sobne temperature. Nakon miješanja na sobnoj temperaturi 18 sati, doda se menziltrietilamonij klorid (210 g, 0,92 mol) i dobivena smjesa se zagrijava pri 55 °C tri sata. Reakcijska smjesa se ohladi do sobne temperature i zatim razrijedi s vodom. Nakon odvajanja organske faze, vodena faza se ekstrahira dva puta s dietil eterom. Sjedinjeni organski ekstrakt se ispere s 1,0 N kloridnom kiselinom, zasićenim vodenim natrij bikarbonatom, vodom, zasićenim vodenim natrij kloridom, osuši iznad magnezij sulfata, i koncentrira pod sniženim tlakom da se dobije žućkasto-bijela krutina (160 g). Krutina se podvrgne kromatografiji na silikagelu, razvijajući s etil acetatom/heksanom (1:9), da se dobije 110 grama (80%) naslovnog spoja.
1H-NMR (CDCl3) (400 MHz) δ: 2,20 (m, 1H), 2,45 (m, 1H), 3,60 (m, 1H), 3,75 (m, 1H), 4,95 (m, 1H), 7,45 (m, 5H).
MS(FAB): m/z = 172,0 (10%), 154 (10%), 132 (25%), 117 (5%), 107 (100%), 79 (54%), 77 (45%), 51 (19%).
Priprava III
4-((tert-butoksikarbonil)oksi)-2-metilfenol
Di-tert-butoksikarbonat (52,4 g, 0,24 mol) u tetrahidrofuranu (100 mL) se dodaje kap po kap otopini metilhidrokinona (99,2 g, 0,80 mol) i dimetilaminopiridina (4,8 g, 4,0 mmol) u dietil eteru (1,1 L) na sobnoj temperaturi. Nakon miješanja 40 minuta, reakcija se prekine sa 1 N kloridnom kiselinom (200 mL). Organski sloj se odvoji, ispere sa zasićenim vodenim natrij kloridom (200 mL), osuši iznad natrij sulfata i koncentrira do sirovog ulja koje se skrutne stajanjem. Pročišćavanjem sirove krutine Biotage Flash 75 kromatografijom, razvijajući sa 94/6 heksanom/etil acetatom (94/6) se dobije žućkasto-bijela krutina koja se prekristalizira iz diklormetana/heksana (15/85), da se dobije 28,5 (53%) naslovnog spoja.
1H-NMR (CDCl3) δ: (300 MHz) 1,55 (s, 9H), 2,22 (s, 3H), 4,76 (s, 1H), 6,68 (d, J = 8,78 Hz, 1H), 6,85 (dd, J = 8,78 Hz i 2,92 Hz, 1H), 6,92 (d, J = 2,92 Hz, 1H).
MS(FAB): m/z = 225,3, 211,3, 169,3, 155,2, 124,2.
Primjer 1
R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan oksalat
(R)-3-klor-1-fenil-1-(2-metil-4-acetoksifenoksi)propan
Otopina (S)-(-)-3-klor-1-fenil-1-propanola (0,204 g, 1,20 mmol), 4-acetoksi-2-metilfenola (0,200 g, 1,20 mmol) i trifenilfosfina (0,346 g, 1,32 mmol) u 10 mL tetrahidrofurana se ohladi na 0-5 °C pod argonom. Ova smjesa se obrađuje, kap po kap, s di-izopropilazodikarboksilatom (0,26 mL, 1,32 mmol) u tetrahidrofuranu (2 mL). Dobivena smjesa se miješa 1 sat pri 0-5 °C i zatim se ostavi da se ugrije do sobne temperature. Nakon reagiranja na sobnoj temperaturi preko noći, reakcijska smjesa se koncentrira pod sniženim tlakom i ostatak se triturira s 10%-tnim etil acetatom u pentanu i miješa dok suspendirana krutina ne bude kristalna. Suspenzija se filtrira i regenerirana kristalna krutina ispere s 10%-tnim etil acetatom u pentanu. Sjedinjeni filtrat se koncentrira pod sniženim tlakom i ostatak se podvrgne kromatografiji na silikagelu, razvijajući s toluenom. Frakcije koje sadržavaju produkt se sjedine i koncentriraju pod sniženim tlakom da se dobije 0,205 g(54%) željenog spoja kao blijedo žutog ulja.
MS(FD): m/e = 318 (M+)
(R)-3-jod-1-fenil-1-(2-metil-4-acetoksifenoksi)propan
Smjesa (R)-3-klor-1-fenil-1-(2-metil-4-acetoksifenoksi)propana (0,200 g, 0,63 mmol) i 15 mL acetona zasićenog s kalij jodidom se miješa pod refluksom ispod argona preko noći. Reakcijska smjesa se izlije u 50 mL dietil etera i dobivena suspenzija se filtrira. Filtrat se ispere sa zasićenim vodenim natrij hidrogensulfitom, zatim s vodom. Preostala organska faza se osuši iznad magnezij sulfata i koncentrira pod sniženim tlakom da se dobije 0,18 g, (70%) željenog spoja kao bezbojnog ulja.
MS(FD): m/e = 410 (M+)
Aminiranje
Smjesa (R)-3-jod-1-fenil-1-(2-metil-4-acetoksifenoksi)propana (0,180 g, 0,44 mmol) i 40%-tnog vodenog metilamina (5 mL, 71 mmol) u 15 mL tetrahidrofurana se miješa na sobnoj temperaturi preko noći. Reakcijska smjesa se koncentrira pod sniženim tlakom i ostatak razdijeli između vode i etil acetata, Etil acetatna faza se ispere s vodom, osuši iznad magnezij sulfata, i koncentrira pod sniženim tlakom. Ostatak se otopi u etil acetatu i obrađuje s oksalnom kiselinom (0,04 g, 0,44 mmol). Dobivena bijela krutina se regenerira filtracijom, ispere s etil acetatom i osuši pod sniženim tlakom da se dobije 0,107 g (67%) naslovnog spoja.
MS(FD): m/e = 271 (M+)
EA: Izračunato za C19H23NO6: Teorijski: C, 63,15, H, 6,41, N, 3,88. Ustanovljeno: C, 63,32, H, 6,59, N, 3,99.
Primjer 2
R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan hidroklorid
(R)-3-klor-1-fenil-1-(2-metil-4-O-tert-butoksikarboksi-fenoksi)propan
Osušena u sušioniku, trogrla, 2-litarska tikvica okruglog dna se napuni sa (S)-3-klor-1-fenil-propanolom (52 g, 304 mmol), 4-((tert-butoksikarbonil)oksi)-2-metilfenolom (73,86 g, 329 mmol), trifenilfosfinom (87,36 g, 333 mmol) i bezvodnim tetrahidrofuranom (600 mL). Reakcijska smjesa se ohladi do 0 °C, i dodaje se otopina diizopropilazadikarboksilata (76 mL, 365 mmol) u suhom tetrahidrofuranu (100 mL) tijekom 6 sati. Reakcijska smjesa se miješa dodatna dva sata pri 0 °C i zatim ostavi da se postepeno ugrije do sobne temperature. Reakcijska smjesa se dalje miješa na sobnoj temperaturi 24 sata i reakcijska smjesa se koncentrira pod sniženim tlakom. Ostatak se obrađuje s 2 L 9:1 pentana:etil acetata. Dobivena suspenzija se pohrani pri -20 °C 24 sata i netopljive tvari se uklone filtracijom. Talog se ispere sa 9:1 pentanom:etil acetatom (200 mL). Sjedinjeni filtrat se koncentrira pod sniženim tlakom. Sirovi ostatak (150 g) se pročisti pomoću 150 flash Biotage prethodno napunjenog stupca, razvijajući s 3%-tnim etil acetatom u heksanu, da se dobije (R)-3-klor-1-fenil-1-(2-metil-4-((tert-butoksikarbonil)oksi)-fenoksi)propan (100 g), s 85%-tnim prinosom.
1H-NMR (CDCl3) δ: (400 MHz) 1,50 (s, 9H), 2,20 (m, 1H), 2,27 (s, 3H), 2,46 (m, 1H), 3,60 (m, 1H), 3,76 (m, 1H), 5,31 (m, 1H), 6,56 (d, J = 8,8 Hz, 1H), 6,72 (m, 1H), 7,24 (m, 1H), 7,32 (s, 4H).
13C-NMR (CDCl3) δ: 15,27, 16,59, 27,69, 41,25, 41,48, 83,20, 113,15, 113,71, 118,42, 118,84, 122,21, 123,42, 125,39, 125,81, 127,93 128,17, 128,80, 140,77, 144,29, 152,46, 153,44.
MS(FAB): m/z = 376,145.
EA: Izračunato za C21H25ClO4: C, 66,93; H, 6,69; Cl, 9,41. Ustanovljeno: C, 66,94, H, 6,74; Cl, 9,67.
(R)-3-jod-1-fenil-1-(2-metil-4-((tert-butoksikarbonil)-oksi)fenoksi)propan
Suha 1-litrena tikvica okruglog dna se napuni sa (R)-3-klor-1-fenil-1-(2-metil-4-((tert-butoksikarbonil)oksi)-fenoksi)propanom (18,00 g, 47,80 mmol), natrij jodidom (90,0 g, 600 mmol) i 2-butanonom (550 mL). Reakcijska tikvica se zaštiti do svjetla. Reakcijska smjesa se miješa na temperaturi refluksa pod dušikom 16 sati. Smjesa se ohladi do sobne temperature i izlije u eter (1 L). Netopljive anorganske soli (bijeli talog) se uklone filtracijom. Filtrat se koncentrira pod sniženim tlakom i sirovi ostatak se otopi u dietil eteru (1 L). Eterski sloj se ispere sa hladnom zasićenom otopinom natrij bisulfita (2 × 200 mL), vodom i zasićenim vodenim natrij kloridom. Organski sloj se osuši iznad bezvodnog magnezij sulfata i koncentrira pod sniženim tlakom. Ostatak se podvrgne flash kromatografiji, razvijajući s 20%-tnim etil acetatom u heksanu, da se dobije 20,5 g (91%) željenog spoja.
1H-NMR (CDCl3, 400 MHz) δ 1,56 (s, 9H), 2,30 (s, 3H), 2,40 (m, 1H), 2,50 (m, 1H), 3,25 (m, 1H), 3,35 (m, 1H), 5,21 (m, 1H), 6,55 (d, J = 8,8 Hz, 1H), 6,75 (m, 1H), 6,95 (d, J = 2,4 Hz, 1H), 7,25 (m, 1H), 7,37 (m, 4H).
MS(FAB): m/z = 468,0 (100%), 342 (10%).
EA: Izračunato za C21H25IO4: C, 53,86, H, 5,38. Ustanovljeno: C, 53,36, H, 4,79.
Aminiranje / Uklanjanje zaštite / Formiranje soli
(R)-3-jod-1-fenil-1-(2-metil-4-((tert-butoksikarbonil)oksi)fenoksi)propan (20,0 g, 42,66 mmol) se otopi u bezvodnom tetrahidrofuranu (100 mL). Otopina se obrađuje s metilaminom (300 mL, 2M otopina u tetrahidrofuranu) pod atmosferom dušika, i reakcija se miješa na sobnoj temperaturi 15 sati, u kojem vremenu se reakcijska smjesa koncentrira do suhoće. Ostatak se obrađuje s etil acetatom i hladnom vodom. Dva sloja se odvoje. Vodeni sloj se ekstrahira s etil acetatom. Sjedinjeni organski sloj se ispere potpuno s hladnom zasićenom otopinom natrij bisulfita, hladnom vodom, osuši iznad magnezij sulfata, i koncentrira pod sniženim tlakom. Ostatak se otopi u etil acetatu. Otopina se ekstrahira s ledenom 0,1 N kloridnom kiselinom. Liofilizacijom vodene otopine se dobije žuta krutina koja se otopi u metanolu, i pusti kroz kratki stupac aktivnog ugljena, Norit, prašak 100 oka (2% ugljen). Otapalo se ukloni i dobivena hidrokloridna sol se istaloži nakon trituriranja s minimalnom količinom vode. Hidrokloridna sol se prekristalizira iz vode, da se dobije željeni produkt (7,22 g, 55%).
1H-NMR (DMSO 300 MHz) δ 2,12 (m, 1H), 2,15 (s, 3H), 2,20 (m, 1H), 2,49 (s, 3H), 2,99 (m, 2H), 5,31 (m, 1H), 6,33 (dd, J = 8,7 Hz i 2,56 Hz, 1H), 6,51 (m, 1H), 7,29 (m, 1H), 7,34 (m, 5H), 8,77 (s, 1H), 8,85 (br s, 1H).
MS(FAB): m/z = 272,4.
EA: Izračunato za C17H21NO2·HCl: C, 66,33, H, 7,20, N, 4,55, Cl, 11,52. Ustanovljeno: C, 66,23, H; 7,22, , 5,37, Cl, 11,23.
Svi spojevi o kojima se radi su oralno dostupni i normalno se primjenjuju oralno, i prema tome oralna primjena je poželjna. Međutim, oralna primjena nije jedini put, čak ni jedini poželjni put. Na primjer, transdermalna primjena može biti vrlo poželjna za pacijente koji su zaboravljivi ili nemarni kad je u pitanju uzimanje oralnog lijeka. Spojevi formule I se mogu također primijeniti perkutanim, intravenskim, intramuskularnim, intranazalnim ili intrarektalnim putem, u određenim okolnostima. Put primjene se može mijenjati na bilo koji način, ograničen je fizikalnim svojstvima lijeka, prikladnošću za pacijenta i njegovatelja, i drugim relevantnim okolnostima (Remington's Pharmaceutical Sciences, 18. izdanje, Mack Publishing Co. (1990)).
Farmaceutski pripravci se pripravljaju na način koji je dobro poznat u farmaceutskoj struci. Nosač ili ekscipijens može biti čvrsti, polučvrsti, ili tekući materijal koji može služiti kao nosač ili medij za aktivni sastojak. Prikladni nosači ili ekscipijenti su dobro poznati u struci. Farmaceutski pripravak može biti prilagođen za oralnu, inhalacijsku, parenteralnu, ili lokalnu upotrebu i može se dati pacijentu u obliku tableta, kapsula, aerosola, inhalacija, supozitorija, otopina, suspenzija, ili slično.
Spojevi iz sadašnjeg izuma se mogu primijeniti oralno, na primjer, s inertnim razrjeđivačem ili u kapsulama ili komprimirani u tablete. Za svrhu oralne terapijske primjene, spojevi se mogu uklopiti s ekscipijentima i upotrijebiti u obliku tableta, pastila, kapsula, eliksira, suspenzija, sirupa, hostija, guma za žvakanje i slično. Ti pripravci bi trebali sadržavati najmanje 4% spoja iz sadašnjeg izuma, kao aktivni sastojak, ali udio može varirati ovisno o određenom obliku i može prikladno biti između 4% i oko 70% mase jedinice. Količina spoja prisutnog u pripravcima je takva, da se postigne odgovarajuće doziranje. Poželjne sastave i pripravke prema sadašnjem izumu može odrediti stručnjak područja.
Tablete, pilule, kapsule, pastile, i slično, mogu također sadržavati jednu ili više od sljedećih pomoćnih tvari: veziva, kao što je mikrokristalna celuloza, smola tragakant ili želatina; ekscipijente kao što je škrob ili laktoza, sredstva za raspadanje kao što su alginska kiselina, Primogel, kukuruzni škrob i slično, lubrikante kao što je magnezij stearat ili Sterotex; sredstva za kliženje kao što je koloidni silicij dioksid; mogu se dodati i zaslađivači kao što je saharoza ili saharin, ili sredstvo za aromatiziranje kao što je pepermint, metil salicilat ili aroma naranče. Kad je dozirni oblik kapsula, može sadržavati, uz tvari gornjeg tipa, tekući nosač kao što je polietilen glikol ili masno ulje.
Drugi dozirni oblici mogu sadržavati razne druge tvari koje modificiraju fizikalna svojstva dozirnog oblika kao, na primjer, ovojnice. Dakle, tablete ili pilule mogu biti obložene šećerom, šelakom, ili drugim sredstvima za oblaganje. Sirup može sadržavati, uz spojeve iz izuma, saharozu kao zaslađivač i određene konzervanse, boje i bojila i arome. Tvari koje se upotrebljavaju za pripravljanje tih raznih pripravaka bi trebale biti farmaceutski čiste i netoksične u upotrijebljenim količinama.
Pripravak koristan za primjenu R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida (atomoksetina), metaboličkog prekursora R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana sadrži suhu smjesu R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida s razrjeđivačem i lubrikantom. Škrob, kao npr. preželatinizirani kukuruzni škrob, je prikladni razrjeđivač, i silikonsko ulje, kao npr. dimetikon, je prikladan lubrikant za upotrebu u tvrdim želatinskim kapsulama. Dobivaju se odgovarajući pripravci koji sadržavaju oko 0,4 do 26% R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida, oko 73 do 99% škroba, i oko 0,2 do 1,0% silikonskog ulja. Sljedeće tablice prikazuju naročito poželjne pripravke:
[image]
[image]
Za svrhu parenteralne terapijske primjene, spojevi iz sadašnjeg izuma se mogu uklopiti u otopinu ili suspenziju. Ti pripravci tipično sadržavaju najmanje 0,1% spoja iz izuma, ali udio može varirati između 0,1 i oko 90% njegove mase. Količina spoja formule I prisutnog u takvim pripravcima je takva, da se postigne odgovarajuće doziranje. Otopine ili suspenzije mogu također uključivati jedno ili više do sljedećih pomoćnih sredstava: sterilne razrjeđivače kao što je voda za injekcije, otopina soli, fiksirana ulja, polietilen glikole, glicerin, propilen glikol ili druga sintetska otapala; antibakterijska sredstva kao što je benzil alkohol ili metil paraben; antioksidante kao što je askorbinska kiselina ili natrij bisulfit; sredstva za keliranje kao što je etilen diamintetraoctena kiselina; pufere kao što su acetati, citrati ili fosfati, i sredstva za podešavanje toničnosti, kao što je natrij klorid ili dekstroza. Parenteralni pripravak može biti stavljen u ampule, jednokratne šprice ili višedozirne bočice načinjene od stakla ili plastike. Poželjne sastave i pripravke može odrediti stručnjak u tom području.
Spojevi iz sadašnjeg izuma se mogu također primijeniti lokalno, i kad se to čini, nosaš može prikladno sadržavati bazu otopine, masti ili gela. Baza, na primjer, može sadržavati jednu ili više od sljedećih tvari: vazelin, lanolin, polietilen glikole, pčelinji vosak, mineralno ulje, razrjeđivače kao što su voda i alkohol, emulgatore, i stabilizatore. Lokalni pripravci mogu sadržavati koncentraciju spoja formule I, ili njegove farmaceutske soli, od oko 0,1 do oko 10% mas/v (mase po jedinici volumena).
Stručnjak će razumjeti da se R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan može dobiti prevođenjem, na primjer enzimskom ili kiselom katalizom, metaboličkih prekursora R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana. Metabolički prekursor R-(-)-N-metil 3-((2-metil-4-hidroksifenil)-oksi)-3-fenil-1-aminopropana je spoj je spoj koji se prevodi u R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan in vivo nakon primjene metaboličkog prekursora sisavcu. Prema tome, uz postupke opisane u prethodnim odlomcima, primjena R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana se može također postići primjenjivanjem metaboličkog prekursora R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana. Takav metabolički prekursor bi se primjenjivao u dozama koje bi proizvele djelotvornu inhibiciju ponovne pohrane serotonina i norepinefrina bez uzrokovanja štetnih ili neželjenih učinaka.
Metabolički prekursori R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana uključuju estere karboksilne kiseline, sulfonatne estere, aminokiselinske estere, i etere hidroksi skupine spoja formule I.
Dalje, otkriveno je da se R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan može dobiti enzimskom konverzijom R-(-)-N-metil 3-((2-metil-fenil)oksi)-3-fenil-1-aminopropana, atomoksetina, in vivo. Prema tome, poželjni postupak sistemske primjene R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana je oralna primjena sisavcima R-(-)-N-metil 3-((2-metil-fenil)oksi)-3-fenil-1-aminopropan hidroklorida, atomoksetina. To jest, sistemska primjena R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana se može poželjno postići oralnom primjenom sisavcima R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida, atomoksetina, kao metaboličkog prekursora R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana.
Ispitivanje monoamina mikrodijalizom
Sprague-Dawley štakorima (Harlan ili Charles River) mase 270-300 grama se kirurški implantiraju sonde za mikrodijalizu, pod kloralhidratnom/pentobarbitalskom anestezijom (170 i 36 mg/kg i.p. u 30% propilen glikola, 14% etanola), kako su opisali Perry i Fuller. (Perry i Fuller, Effect of fluoxetine on serotonin and dopamine concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytryptophan, Life Sci., 50, 1683-90 (1992)). David Kopf stereotaktični instrument se upotrijebi za implantiranje sonde unilateralno u hipotalamus, na koordinatama rostralno -1,5 mm, lateralno -1,3 mm, i ventralno -9,0 mm (Paxinos i Watson, 1986). Nakon 48-satnog perioda oporavka, štakori se stave u veliku plastičnu posudu s montiranim tekućim sustavom prstena za okretanje (CMA/120 sustav za slobodno kretanje životinja, Bioanalytical Systems, West Lafayette, IN). Filtrirana umjetna cerebrospinalna tekućina (CSF) (150 mM NaCl, 3,0 mM KCl, 1,7 mM CaCl2, i 0,9 mM MgCl2) se pusti kroz sondu brzinom od 1,0 ml/min. Linija izlaza dijalizata se namjesti na deset-portni HPLC ventil s 20 μl-petljom. Na kraju svakog 30-minutnog perioda uzimanja uzoraka, dijalizat sakupljen u petlji se injicira u analitički stupac (Spherisorb 3 μ ODS2, 2X150 mm, Keystone Scientific).
Postupak upotrijebljen za mjerenje monoamina su opisali Perry i Fuller (1992). Ukratko, dijalizat sakupljen u 20 μl petlji se ispituje na 5-HT i Ne. 20 μl injekcija ide u stupac s mobilnom fazom koja odvaja NE i 5.HT: 75 mM kalij acetat, 0,5 mM etilendiamintetraoctena kiselina, 1,4 mM natrij oktansulfonska kiselina i 8% metanol, pH 4,9. Mobilna faza za aminski stupac se pušta pomoću pumpe s programiranim protokom, početnom brzinom protoka od 0,2 ml/min, povećavajući do 0,3 ml/min nakon 5 min, zatim ponovnim smanjivanjem do 0,2 ml/min nakon 26 min, s ukupnim vremenom pokusa od 30 min. Programiranje protoka se upotrebljava da se 5-HT eluira unutar vremenskog perioda od 25 min. Elektrokemijski detektor (EG&G, Model 400) za aminski stupac se namjesti na potencijal od 400 mV i osjetljivost od 0,2 nA/V. Bazična razina se mjeri najmanje 90 minuta prije primjene lijeka. Lijekovi se priprave u filtriranoj deioniziranoj vodi (volumen 0,25-0,3 ml) za primjenu u željenim dozama.
R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan je ispitan uglavnom kako je opisano iznad, i ustanovljeno je da inhibira ponovnu pohranu i serotonina (Ki = 43 nM) i norepinefrina (Ki = 3,0 nM).
Metabolizam R-(-)-N-metil 3-((2-metil-4-fenil)oksi)-3-fenil-1-aminopropana do R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana kod ljudi
Otvorena studija je provedena na sedam zdravih muškaraca, prije studije je CYP2D6 genotip identificiran kao EM (dobri metabolizator) ili PM (slabi metabolizator). CYP2D6 je enzim s genetičkim polimorfizmom, koji rezultira s najmanje 2 populacije osoba s bilo aktivnim ili slabim metaboličkim sposobnostima. većina ljudi su označeni kao "dobri metabolizatori" (EM) i imaju "normalnu" CYP2D6 aktivnost. Mutacije ili uništenje CYP2D6 gena nastaje kod manjeg broja ljudi (5% do 10% bijelaca; 1% azijata), koji su poznati kao "slabi metabolizatori" (PM) CYP2D6 supstrata.
Višestruke 20-mg doze R-(-)-N-metil 3-((2-metil-fenil)oksi)-3-fenil-1-aminopropana su primjenjivane dvaput dnevno tijekom 5 dana, nakon toga je slijedila jedna radio-označena 20-mg doza atomoksetina (stvarna doza 19.66 mg), ujutro 6. dana. Radio-označeni [3-14C]-R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan je dna kao 20-mg kapsule R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida koji je sadržavao dovoljnu količinu [3-14C]-R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida, da se dobije doza od približno 3,7 Mbq (100 μCi).
Približno 12 sati nakon jutarnje doze u danima 1 do 5, druga 20-mg kapsula je primijenjena sa 240 mL vode. Ova večernja doza je primijenjena najmanje 30 minuta nakon laganog večernjeg obroka. Ujutro 6. dana, kapsula od 20 mg R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida koji sadrži 100 μCi [3-14C]-R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida, je dana oralno sa 240 mL vode 30 minuta nakon završetka standardiziranog doručka.
Uzorci pune krvi su uzeti od EM subjekata 12 sati prije i neposredno prije primjene [3-14C]-R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida (preddozirni kontrolni uzorak), i približno 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, i 72 sata nakon doziranja. Uzorci pune krvi su sakupljeni od PM subjekata 12 sati prije i neposredno prije primjene [3-14C]-R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida (preddozirni kontrolni uzorak), i približno 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, i 216 sati nakon doziranja. Uzorci pune krvi (približno 12 mL) su sakupljani u svakoj vremenskoj točki u staklene epruvete koje su sadržavale heparin kao antikoagulans. Uzorci pune krvi su pohranjeni u ledu do centrifugiranja. Za dobivanje plazme, krv je centrifugirana na približno 3000 okr/min približno 15 minuta, na približno 4 °C unutar 1 sat od sakupljanja. Alikvoti plazme su uzimani za određivanje radioekvivalentnih koncentracija. Preostala plazma je pohranjena na približno -70 °C prije ispitivanja na koncentraciju konjugiranog i nekonjugiranog N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropana, R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana, 3-((2-metilfenil)oksi)-3-fenil-1-aminopropana ili profiliranje metabolita.
Uzorci heparinizirane ljudske plazme se analiziraju na N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan, R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan, i upotrebom validiranog APCI LC/MS/MS (kemijska ionizacija na atmosferskom tlaku, tekućinska kromatografija/masena spektrometrija/masena spektrometrija) postupka na koncentracijama od 1,00 do 800,00 ng/mL za N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan i R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan, i 2,50 do 2000,00 ng/mL za 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan. Daljnja analiza je provedena upotrebom validiranog APCI LC/MS/MS postupka manjeg opsega, na koncentracijama od 1,00 do 100,00 ng/mL za N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan i R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan i 0,25 do 25,00 ng/mL za R-(-)-3-((2-metilfenil)oksi)-3-fenil-1-aminopropan.
Primarni metabolit R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida proizveden kod CYP2D6 EM i PM subjekata je R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan. EM subjekti su metabolizirali 85% R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida do R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana. PM subjekti su metabolizirali 40% R-(-)-N-metil 3-((2-metilfenil)oksi)-3-fenil-1-aminopropan hidroklorida do R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropana.
Claims (6)
1. Spoj, naznačen time, što ima formulu I:
[image]
ili njegova farmaceutski prihvatljiva sol.
2. Spoj, naznačen time, što je R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan hidroklorid.
3. Farmaceutski pripravak, naznačen time, što sadrži spoj formule I:
[image]
ili njegovu farmaceutski prihvatljivu sol, zajedno s farmaceutski prihvatljivim nosačem, razrjeđivačem ili ekscipijentom.
4. Farmaceutski pripravak prema zahtjevu 3, naznačen time, što spoj formule I je R-(-)-N-metil 3-((2-metil-4-hidroksifenil)oksi)-3-fenil-1-aminopropan hidroklorid.
5. Postupak za inhibiranje ponovne pohrane norepinefrina i serotonina kod sisavaca, naznačen time, što sadrži davanje sisavcu, kojem je potrebna takva inhibicija, farmaceutski djelotvorne količine spoja formule I:
[image]
ili njegove farmaceutski prihvatljive soli.
6. Postupak prema zahtjevu 5, naznačen time, što spoj formule I se primjenjuje sistemski.
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| WO2005020976A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of pervasive developmental disorders with norepinephrine reuptake inhibitors |
| CA2548304A1 (en) * | 2003-12-12 | 2005-07-07 | Eli Lilly And Company | Selective norepinephrine reuptake inhibitors for the treatment of hot flashes, impulse control disorders and personality change due to a general medical condition |
| WO2011027359A2 (en) * | 2009-07-30 | 2011-03-10 | Matrix Laboratories Ltd | Novel process for the preparation of 4-hydroxy atomoxetine |
| WO2012020418A1 (en) | 2010-08-12 | 2012-02-16 | Matrix Laboratories Ltd | Novel polymorphs of 4-hydroxy atomoxetine hydrochloride |
| DE102013022397A1 (de) | 2013-12-19 | 2016-07-07 | Metrax Gmbh | Vorrichtung zur Unterstützung eines Ersthelfers bei der Herzdruckmassage |
| GR1008819B (el) | 2015-05-22 | 2016-08-01 | Φαρματεν Ανωνυμος Βιομηχανικη Και Εμπορικη Εταιρεια Φαρμακευτικων Ιατρικων Και Καλλυντικων Προϊοντων | Φαρμακευτικο σκευασμα που περιλαμβανει ατομοξετινη και μεθοδος παρασκευης αυτου |
| CN107935848B (zh) * | 2017-11-21 | 2020-12-22 | 中国农业科学院兰州畜牧与兽药研究所 | 一种六茜素衍生物及其制备方法和应用 |
| KR20210084481A (ko) * | 2018-10-31 | 2021-07-07 | 애프니메드, 인코포레이티드 (델라웨어) | 수면 무호흡증의 치료 방법 및 조성물 |
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| FR2432500A1 (fr) * | 1978-02-24 | 1980-02-29 | Roussel Uclaf | Nouveaux derives de la benzene propanamine et leurs sels, procede de preparation et application a titre de medicaments |
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| TW514634B (en) | 1997-10-14 | 2002-12-21 | Lilly Co Eli | Process to make chiral compounds |
| WO2000058262A1 (en) | 1999-03-29 | 2000-10-05 | Eli Lilly And Company | Stereospecific method for preparing tomoxetine and intermediates thereof |
| WO2000061540A1 (en) | 1999-04-09 | 2000-10-19 | Eli Lilly And Company | Methods for preparing 3-aryloxy-3-arylpropylamines and intermediates thereof |
| EA200300567A1 (ru) * | 2000-11-15 | 2004-10-28 | Эли Лилли Энд Компани | Лечение состояний тревоги |
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