HRP980584A2 - SUBSTITUTED 1,2,4-TRIAZOLO/3,4-a/ PHTHALAZINE - Google Patents
SUBSTITUTED 1,2,4-TRIAZOLO/3,4-a/ PHTHALAZINEInfo
- Publication number
- HRP980584A2 HRP980584A2 HRP980584A HRP980584A2 HR P980584 A2 HRP980584 A2 HR P980584A2 HR P980584 A HRP980584 A HR P980584A HR P980584 A2 HRP980584 A2 HR P980584A2
- Authority
- HR
- Croatia
- Prior art keywords
- phthalazine
- triazolo
- methylisoxazol
- methyloxy
- triazol
- Prior art date
Links
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title description 5
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 4
- SPKCNMWPMHLVKI-UHFFFAOYSA-N 5-methyl-3-[6-(2h-triazol-4-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4NN=NC=4)C4=CC=CC=C4C3=NN=2)=N1 SPKCNMWPMHLVKI-UHFFFAOYSA-N 0.000 claims description 3
- 230000003930 cognitive ability Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- PLXVYTOTPXPOPS-UHFFFAOYSA-N 3-[7-methoxy-6-(1-methyltriazol-4-yl)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-5-methyl-1,2-oxazole Chemical compound N12N=C(C=3N=NN(C)C=3)C=3C(OC)=CC=CC=3C2=NN=C1C=1C=C(C)ON=1 PLXVYTOTPXPOPS-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
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Description
Ovaj izum odnosi se na supstituirani derivat triazolo -piridazina, njegovu uporabu u terapiji, farmaceutske sastave koji ga sadrže i proces za njegovu proizvodnju. This invention relates to a substituted derivative of triazolo-pyridazine, its use in therapy, pharmaceutical compositions containing it and a process for its production.
Sada smo otkrili daje moguće dobiti lijekove s efektom pojačavanja spoznajne sposobnosti, koji se mogu koristiti s manjim rizikom od prokonvulzijskih efekata, ranije opisanim kod djelomičnih ili punih inverznih agonista benzodiazepin receptora. Preferiraju se inverzni agonisti α5 receptora koji su relativno neaktivni na mjestima vezivanja α1, α2 i α receptora. We have now discovered that it is possible to obtain cognitive-enhancing drugs that can be used with less risk of proconvulsant effects previously described with partial or full benzodiazepine receptor inverse agonists. Inverse α5 receptor agonists that are relatively inactive at the α1, α2 and α receptor binding sites are preferred.
Europske Patentne aplikacije 0085840 i 0134946 opisuju srodne serije derivata 1,2,4-triazolo[3,4-a]ftalazina koje imaju antianksiozno djelovanje. Međutim, nema naznaka u ovim publikacijama o spojevima ovog izuma, niti da spojevi naznačeni u navedenim aplikacijama imaju svojstvo pojačavanja spoznajnih sposobnosti. European Patent Applications 0085840 and 0134946 describe related series of 1,2,4-triazolo[3,4-a]phthalazine derivatives that have antianxiety activity. However, there is no indication in these publications about the compounds of the present invention, nor that the compounds indicated in said applications have cognitive enhancing properties.
Ovaj izum obuhvaća spoj formule: 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3,4-a]. This invention comprises a compound of the formula: 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4 -And].
Pojačavanje spoznajne sposobnosti može se dokazati testiranjem spoja u Morrisovom vodenom labirintu, kako je to opisano od McNamare i Skeltona, Psychobiology, 21:101-108. Funkcionalna efikasnost na raznim receptorskim podtipovima može se izračunati koristeći metodu opisanu u WO-A-9625948. Cognitive enhancement can be demonstrated by testing the compound in the Morris water maze, as described by McNamara and Skelton, Psychobiology, 21:101-108. Functional efficiency at various receptor subtypes can be calculated using the method described in WO-A-9625948.
Tako, npr. spoj iz ovog izuma može se koristiti u nizu poremećaja središnjeg živčanog sustava. Takvi poremećaji su delirij, demencija, i amnezija i drugi spoznajni poremećaji. Primjeri delirija su delirij uzrokovan zloporabom toksičnih supstanci ili apstinencije od njihovog korištenja, delirij uzrokovan multiplim etiologijama i nespecifični delirij. Primjeri demencije su: demencija Alzheimerovog tipa s ranim pojavljivanjem, koja može biti nekomplicirana ili s delirijem, halucinacijama ili depresivnim raspoloženjem; demencija Alzheimerovog tipa s kasnim pojavljivanjem, koja može biti nekomplicirana ili s delirijem, halucinacijama ili depresivnim raspoloženjem; vaskularna demencija, koja može biti nekomplicirana ili s delirijem, halucinacijama ili depresivnim raspoloženjem; demencija uzrokovana HIVom, demencija uslijed traume glave, demencija uzrokovana Parkinsonovom bolešću; demencija uzrokovana Huntingtonovom bolešću; demencija uzrokovana Pickovom bolešću; demencija uzrokovana Creutzfeld-Jakobsovom bolešću; demencija uzrokovana zloporabom supstanci trajno ili zbog multiplih etiologija; nespecifična demencija. Primjeri amnezijskih poremećaja su amnezijski poremećaji uzrokovani specifičnim medicinskim stanjem ili koji su uzrokovani zloporabom supstanci trajno ili nespecifični amnezijski poremećaji. Thus, for example, the compound of this invention can be used in a number of disorders of the central nervous system. Such disorders are delirium, dementia, and amnesia and other cognitive disorders. Examples of delirium are delirium caused by the abuse of toxic substances or abstinence from their use, delirium caused by multiple etiologies and non-specific delirium. Examples of dementia are: Alzheimer's type dementia with early onset, which may be uncomplicated or with delirium, hallucinations or depressed mood; late-onset dementia of the Alzheimer type, which may be uncomplicated or with delirium, hallucinations, or depressed mood; vascular dementia, which may be uncomplicated or with delirium, hallucinations, or depressed mood; dementia caused by HIV, dementia due to head trauma, dementia caused by Parkinson's disease; dementia caused by Huntington's disease; dementia caused by Pick's disease; dementia caused by Creutzfeld-Jakobs disease; dementia caused by substance abuse permanently or due to multiple etiologies; non-specific dementia. Examples of amnesic disorders are amnesic disorders caused by a specific medical condition or caused by persistent substance abuse or non-specific amnesic disorders.
Izum također obuhvaća farmaceutske sastave koji sadrže spoj opisan u izumu i farmaceutski prihvatlje nosače. Po mogućnosti, ovi sastavi su u jediničnim dozama kao što su tablete, pilule, kapsule, praškovi, granule, sterilne parenteralne otopine ili suspenzije, aerosol ili tekući sprejevi, kapi, ampule, povezi za kožu, naprave za auto-injekciju ili supozitoriji; za oralno, parenteralno, intranazalno pod-jezično ili rektakio uzimanje, ili za uzimanje inhalacijom ili insuflacijom. Za pripravu krutih sastava kao što su tablete, glavni aktivni sastojak se miješa sa farmaceutskim nosačem, npr. konvencionalnim sastojcima tableta kao što su kiikuruzni škrob, laktoza, sukroza, sorbitol, talk, stearinska kiselina, magnezij stearat, dikalcij fosfat, ili smole ili površinski aktivne supstance kao što su sorbitan monooleat, polietilen glikol, i drugi farmaceutski razrjeđivači kao voda, da se dobije kruti preformulacijski sastav, koji sadrži homogenu smjesu spoja iz ovog izuma ili njegove farmaceutski prihvatljive soli. Kada se kaže homogena preformulacijska smjesa, misli se na to da je aktivni sastojak ravnomjerno raspršen kroz sastav, tako da se sastav može dijeliti u doze jednakog učinka u obliku tableta, pilula i kapsula. Čvrsta preformulacijska smjesa se zatim dijeli u oblike jediničnih doza, kako je gore opisano, sa od 0.1 do 500 mg aktivnog sastojka ovog izuma. Tipične jedinične doze sadrže od 1 do 100 mg, npr. 1, 2, 5, 10, 25, 50 ili 100 mg aktivnog sastojka. Tablete ili pilule novog sastava mogu biti pakirane tako da pružaju prednosti produljenog djelovanja. Npr. tableta ili pilula može imati unutarnju i vanjsku dozu, ova druga u formi omotača prve. Dvije komponente mogu biti odvojene enteričnim slojem, koji se opire dezintegraciji u želucu i omogućava unutarnjoj komponenti da prođe netaknuta u duodenum ili da se oslobodi s odgodom. Različiti materijali mogu se koristiti za takve enterične slojeve ili premaze, kao što su polimerne kiseline i mješavine polimernih kiselina s materijalima kao što su shellac, cetilni alkohol i celuloza acetat. The invention also includes pharmaceutical compositions containing the compound described in the invention and pharmaceutically acceptable carriers. Preferably, these compositions are in unit doses such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, skin patches, auto-injection devices or suppositories; for oral, parenteral, intranasal sublingual or rectal administration, or for administration by inhalation or insufflation. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tablet ingredients such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or resins or surfactants. active substances such as sorbitan monooleate, polyethylene glycol, and other pharmaceutical diluents such as water, to obtain a solid preformulation composition, which contains a homogeneous mixture of the compound of this invention or its pharmaceutically acceptable salt. When we say a homogeneous preformulation mixture, we mean that the active ingredient is evenly dispersed throughout the composition, so that the composition can be divided into doses of equal effect in the form of tablets, pills and capsules. The solid preformulation mixture is then divided into unit dosage forms, as described above, containing from 0.1 to 500 mg of the active ingredient of the present invention. Typical unit doses contain from 1 to 100 mg, eg 1, 2, 5, 10, 25, 50 or 100 mg of the active ingredient. Tablets or pills of a new formulation may be packaged to provide the benefits of prolonged action. For example a tablet or pill can have an internal and an external dose, the latter in the form of an envelope of the former. The two components may be separated by an enteric layer, which resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be released with a delay. A variety of materials can be used for such enteric layers or coatings, such as polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.
Tekući oblici u kojima se novi sastav iz ovog izuma može ugraditi za uzimanje oralno ili injekcijom su vodene otopine, pogodno obojeni sirupi, vodene ili uljne suspenzije, emulzije s jestivim uljima kao što je ulje pamuka, sezama, kokosa ili kikirikija, kao i eliksiri i slični farmaceutski nosači. Pogodni agensi za disperziju i suspenziju za vodene suspenzije uključuju sintetske i prirodne smole, kao tragakant, akacija, alginat, dekstran, natrij karboksimetil celuloza, metil celuloza, polivinil-pirolidon ili želatina. Liquid forms in which the novel composition of the present invention can be incorporated for oral or injection are aqueous solutions, suitably colored syrups, aqueous or oily suspensions, emulsions with edible oils such as cottonseed, sesame, coconut or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing and suspending agents for aqueous suspensions include synthetic and natural resins such as tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone or gelatin.
Ovaj izum dalje obuhvaća korištenje sastava ovog izuma u proizvodnji lijeka za pojačavanje spoznajne sposobnosti, naročito kod osoba oboljelih od demencijskih bolesti kao što je Alzheimer. This invention further includes the use of the composition of this invention in the production of a medicine to enhance cognitive ability, especially in people suffering from dementia diseases such as Alzheimer's.
Za pojačavanje spoznajne sposobnosti, pogodna doza je od 0.01 mg do 250 mg/kg dnevno, po mogućnosti od 0.01 mg do 100 mg/kg dnevno, a naročito od 0.01 mg do 5 mg/kg tjelesne težine dnevno. Sastav se može uzimati u režimu od l do 4 puta dnevno. U nekim slučajevima, mogu se koristiti i doze izvan ovih granica. For enhancing cognitive ability, a suitable dose is from 0.01 mg to 250 mg/kg per day, preferably from 0.01 mg to 100 mg/kg per day, and especially from 0.01 mg to 5 mg/kg of body weight per day. The composition can be taken 1 to 4 times a day. In some cases, doses outside these limits can be used.
Preferira se daje sastav iz ovog izuma samljeven, npr. uporabom tučka i mužara ili njihovog industrijskog ekvivalenta, na veličinu čestica od 1 do 10 μM, a po mogućnosti manje od 5 μM, prije formulacije. Sastav se može mikronizirati ili sonizirati po metodama znanim u struci, ili nanoizirati po metodi iz US-A-5145684. It is preferred that the composition of the present invention is ground, eg using a pestle and mortar or their industrial equivalent, to a particle size of 1 to 10 μM, preferably less than 5 μM, prior to formulation. The composition can be micronized or sonicated by methods known in the art, or nanoized by the method of US-A-5145684.
Ovaj izum također obuhvaća proces za proizvodnju sastava ovog izuma, koji se sastoji od reakcije metiliranog reagensa, kao stoje litij heksametildisilazid sa 3-(5-metilizoksazol-3-il)-6-(1-H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a] ftalazinom. The present invention also encompasses a process for producing a composition of the present invention, which comprises reacting a methylated reagent such as lithium hexamethyldisilazide with 3-(5-methylisoxazol-3-yl)-6-(1-H-1,2,3-triazole -5-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine.
Reakcija se izvodi u otapalu kao što je DMF, obično na temperaturi ispod 0°C sa zagrijavanjem do sobne temperature i obično pod inertnim plinom kao što je dušik. Reakcijska smjesa se ostavlja 4-12 sati. Željeni proizvod se pročišćava od drugih proizvoda reakcije konvencionalnim tehnikama kao što je preparativna HPLC. The reaction is carried out in a solvent such as DMF, usually below 0°C with warming to room temperature and usually under an inert gas such as nitrogen. The reaction mixture is left for 4-12 hours. The desired product is purified from other reaction products by conventional techniques such as preparative HPLC.
Sastav u skladu s ovim izumom potencijalno inhibira vezivanje [3H]-flumazenila na mjesto vezivanja benzodiazepina ljudskog GABAAreceptora koji sadrži α5 podjedinicu stabilno izraženu u Ltk- stanicama. The composition according to the present invention potentially inhibits the binding of [3H]-flumazenil to the benzodiazepine binding site of the human GABAA receptor containing the α5 subunit stably expressed in Ltk cells.
Sastav iz pratećih Primjera je testiran i nađeno je da ima Ki vrijednost za dislokaciju [3H]Ro 15-1788 od α5 podjedinice ljudskog GABAAreceptora 100 nM ili manje. The composition of the accompanying Examples was tested and found to have a Ki value for the dislocation of [3H]Ro 15-1788 from the α5 subunit of the human GABAA receptor of 100 nM or less.
Sastav iz ovog izuma dokazano pojačava sposobnost spoznaje u testu štakora u vodenom labirintu (Morris, Learning and Motivation, 1981,12, 239ff). Daljnji detalji metodologije za dokazivanje pojačavanja spoznajne sposobnosti ovog izuma mogu se naći u WO-A-9625948. Ovo je dokazano na minimalnoj efektivnoj dozi od 0.3 mg/kg na kojoj spoj iz ovog izuma ima 40% zauzetost receptora. Također je dokazano na dozi od 3mg/kg. The composition of this invention has been proven to enhance cognition in rats in a water maze test (Morris, Learning and Motivation, 1981, 12, 239ff). Further details of the methodology for demonstrating the cognitive enhancement of this invention can be found in WO-A-9625948. This has been proven at a minimum effective dose of 0.3 mg/kg at which the compound of this invention has 40% receptor occupancy. It has also been proven at a dose of 3mg/kg.
Sastav iz ovog izuma može se pripraviti kako je opisano u sljedećim Primjerima. Precizni detalji reakcijskih uvjeta, te očigledne izmjene reakcijskog postupka su dostupne stručnjacima. The composition of this invention can be prepared as described in the following Examples. The precise details of the reaction conditions, and the obvious changes in the reaction procedure are available to those skilled in the art.
MEĐUPRODUKT 1 INTERMEDIATE PRODUCT 1
6-kloro-3-(5-metilizoksazol-3il)-1,2,4-triazolo[3.4-a] ftalazin 6-chloro-3-(5-methylisoxazol-3yl)-1,2,4-triazolo[3.4-a]phthalazine
a) 1-kloro-4-hidrazinoftalazin a) 1-chloro-4-hydrazinophthalazine
1,4-dikloroftalazin (20.0 g, 0.100 mola) je dodan u kipuću otopinu hidrazin monohidrata (37.3 ml, 0.785 mola) u etanolu (500 ml) i otopina je zagrijavana u refluksu 0.5 h. Otopina je ohlađena do sobne temperature i krutina sakupljena filtracijom i isprana eterom. Materijal je miješan s otopinom n-butanola i amonijaka (sp. gr. 0.91) i zagrijavan do otapanja krutine. Organski sloj je izdvojen, isparen in vacuo da se dobije naslovni hidrazin (11.5 g, 59%), 1H NMR (250 MHz, d6DMSO) 5 7.84 - 8.04 (3H, m, Ar-H), 8.20 (1H, m, Ar-H); MS(ES+) m/e 194[MH]+ 1,4-Dichlorophthalazine (20.0 g, 0.100 mol) was added to a boiling solution of hydrazine monohydrate (37.3 ml, 0.785 mol) in ethanol (500 ml) and the solution was heated at reflux for 0.5 h. The solution was cooled to room temperature and the solid collected by filtration and washed with ether. The material was mixed with a solution of n-butanol and ammonia (sp. gr. 0.91) and heated until the solid dissolved. The organic layer was separated, evaporated in vacuo to give the title hydrazine (11.5 g, 59%), 1H NMR (250 MHz, d6DMSO) δ 7.84 - 8.04 (3H, m, Ar-H), 8.20 (1H, m, Ar -H); MS(ES+) m/e 194[MH]+
b) 5-metilizoksazol-3-karboksilna kiselina b) 5-methylisoxazole-3-carboxylic acid
Smjesa acetonil acetona (10g, 88mmol) i dušične kiseline (sp.gr.1.42)/vode (2:3) (50ml) pažljivo je stavljena na refluks pod strujom dušika i zagrijavana 1 sat.Otopina je ohlađena na sobnu temperaturu i ostavljena preko noći. Rezultirajuća krutina je sakupljana filtracijom, isprana hladnom vodom (2x7ml) i heksanom, osušena in vacuo da se dobije naslovna kiselina (4.4g, 40%), 1HNMR (CDCl3) δ 2.50 (3H, d, J=0.8Hz, Me), 6.41 (1H, d,JM0.8Hz,Ar-H). A mixture of acetonyl acetone (10g, 88mmol) and nitric acid (sp.gr.1.42)/water (2:3) (50ml) was carefully refluxed under a stream of nitrogen and heated for 1 hour. The solution was cooled to room temperature and left over night. The resulting solid was collected by filtration, washed with cold water (2x7ml) and hexane, dried in vacuo to give the title acid (4.4g, 40%), 1HNMR (CDCl3) δ 2.50 (3H, d, J=0.8Hz, Me), 6.41 (1H, d, JM0.8Hz, Ar-H).
c) 6-kloro-3-(5-metilizoksazol-3-il)-1,2,4-triazolo[3.4-a] ftalazin c) 6-chloro-3-(5-methylisoxazol-3-yl)-1,2,4-triazolo[3.4-a]phthalazine
5-metilizoksazol-3-karboksilna kiselina (5.24 g, 41.3 mmol), bis(2-okso-3-oksazolidinil) fosfin klorid (10.5 g, 41.2 mmol) i trietilamin (11.5 ml, 82.5mmol) dodani su jedan za drugim u miješanu suspenziju 1-kloro-4-hidrazinftalazina (8.00g, 41.2mmol) u diklormetanu (11) na 0°C pod dušikom. Smjesa je miješana na 0°C 2 sata i na sobnoj temperaturi preko noći. Otapalo je ispareno in vacuo ostaci su izmrvljeni s vodom, ponovno filtrirani, isprani s hehsanom i osušeni in vacuo da se dobije ketohidrazin (11 g), MS (ES+) m/e 304 [MH]+. Otopina ketohidrazina (11 g), i trietilaminhidroklorida (2.2g, 20% w/w) u ksilenu (500ml) zagrijavana je na refluksu 3 sata. Smjesa je ohlađena na sobnu temperaturu i otapalo ispareno in vacuo. 5-Methylisoxazole-3-carboxylic acid (5.24 g, 41.3 mmol), bis(2-oxo-3-oxazolidinyl) phosphine chloride (10.5 g, 41.2 mmol) and triethylamine (11.5 ml, 82.5 mmol) were added one after another in stirred suspension of 1-chloro-4-hydrazinenaphthalazine (8.00g, 41.2mmol) in dichloromethane (11) at 0°C under nitrogen. The mixture was stirred at 0°C for 2 hours and at room temperature overnight. The solvent was evaporated in vacuo and the residue triturated with water, filtered again, washed with hexane and dried in vacuo to give ketohydrazine (11 g), MS (ES+) m/e 304 [MH]+. A solution of ketohydrazine (11 g) and triethylamine hydrochloride (2.2 g, 20% w/w) in xylene (500 ml) was heated at reflux for 3 hours. The mixture was cooled to room temperature and the solvent was evaporated in vacuo.
Ostatak je otopljen u diklormetanu, ispran s vodom (x2), osušen (MgSO4) i isparen in vacuo, i krutina je rekristalizirana (diklormetan/heksan) da se dobije naslovni spoj (6.8g, 58%) 1HNMR (360MHz, CDCl3) δ 2.59 (3H, s, Me), 6.90 The residue was dissolved in dichloromethane, washed with water (x2), dried (MgSO4) and evaporated in vacuo, and the solid recrystallized (dichloromethane/hexane) to give the title compound (6.8g, 58%) 1HNMR (360MHz, CDCl3) δ 2.59 (3H, s, Me), 6.90
(1H, s, Ar-H),7.95 (1H, m, Ar-H), 8.07 (1H, m, Ar-H), 8.34 (1H, m, Ar-H),8.78 (1H, s, Ar-H); (1H, s, Ar-H), 7.95 (1H, m, Ar-H), 8.07 (1H, m, Ar-H), 8.34 (1H, m, Ar-H), 8.78 (1H, s, Ar -H);
MS(ES+) m/e 286 [MH]+. MS(ES+) m/e 286 [MH]+.
REFERENTNI PRIMJER 1 REFERENCE EXAMPLE 1
3-(5-metilizoksazol-3il)-6-(2-piridil)metiloksi-1,2,4-triazolo[3,4-a]ftalazin 3-(5-methylisoxazol-3yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine
Natrij hidrid (244mg 60% disperzije u ulju, 6.10 mmol) je dodan u miješanu otopinu 2-piridilkarbinola (470 mg, 4.27 mmol) u DMF-u (60ml) na sobnoj temperaturi pod dušikom i smjesa je miješana 0.25 sata. Nakon toga, dodan je međuprodukt l (1160 mg, 4.07mmol) i smjesa je mješana 2 sata. Otapalo je odstranjeno in vacuo i ostatak je otopljen u diklormetanu, ispran vodom (x2), osušen (MgSO4) i isparen in vacuo. Brzom kromatografijom na silikagelu, eluacijom sa 3% metanol/diklormetanom zatim rekristalizacijom (diklormetan/heksan) dobiven je naslovni produkt (640mg, 44%), mp234-236°C; Sodium hydride (244mg 60% dispersion in oil, 6.10 mmol) was added to a stirred solution of 2-pyridylcarbinol (470 mg, 4.27 mmol) in DMF (60ml) at room temperature under nitrogen and the mixture was stirred for 0.25 hours. After that, intermediate 1 (1160 mg, 4.07 mmol) was added and the mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with water (x2), dried (MgSO4) and evaporated in vacuo. Flash chromatography on silica gel, eluting with 3% methanol/dichloromethane followed by recrystallization (dichloromethane/hexane) gave the title product (640mg, 44%), mp234-236°C;
1HNMR (360MHz, CDCl3) δ 2.59 (3H, d, J=0.8Hz,Me), 5.77 (2H, s, CH2), 6.82 (IH, d, J=0.8 Hz, Ar-H), 7.30 (1H, m, Ar-H), 7.74-7.85 (3H, m, Ar-H), 7.95 (1H, m, Ar-H), 8.33 (1H, d, J=7.8 Hz, Ar-H), 8.64-8.72 (2H, m, Ar-H), MS(ES+) m/e 359 [MH]+; Anal. nađeno:C, 62.93; H, 3.56; N, 22.94. C19H14N6O2 0.05(CH2Cl2) zahtijevano: 1HNMR (360MHz, CDCl3) δ 2.59 (3H, d, J=0.8Hz, Me), 5.77 (2H, s, CH2), 6.82 (IH, d, J=0.8Hz, Ar-H), 7.30 (1H, m, Ar-H), 7.74-7.85 (3H, m, Ar-H), 7.95 (1H, m, Ar-H), 8.33 (1H, d, J=7.8 Hz, Ar-H), 8.64-8.72 (2H, m, Ar-H), MS(ES+) m/e 359 [MH]+; Anal. found: C, 62.93; H, 3.56; N, 22.94. C19H14N6O2 0.05(CH2Cl2) required:
C, 63,10; H,3.92, N, 23.17%. C, 63.10; H, 3.92, N, 23.17%.
REFERENTNI PRIMJER 2 REFERENCE EXAMPLE 2
6-(6-bromopiridin-2-il)metiloksi-3-(5-metilizoksazol-3-il)-1,2,4-triazolo[3.4-a] ftalazin 6-(6-bromopyridin-2-yl)methyloxy-3-(5-methylisoxazol-3-yl)-1,2,4-triazolo[3.4-a]phthalazine
Naslovni spoj pripravljen je iz međuprodukta 1 i 2-bromopiridin-6-metanola (Tetrahedron Lett, 1996, 50, 2537) prema postupku iz referentnog primjera 1. Produkt je izoliran dodavanjem vode u reakcijsku smjesu i rezultirajući talog je profiltriran. Brzom kromatografijom na silikagelu, eluacijom sa etilacetatom, i rekristalizacijom (etilacetat/metanol) dobiven je naslovni ftalazin, mp 247.5-249°C; 1HNMR (360MHz, CDCl3) δ 2.61 (3H, d, J=0.7 Hz,Me), 5.73 (2H, s, CH2), 6.82 (1H, d, J=0.7 Hz, Ar-H), 7.48 (1H, d, J=7.8 Hz, Ar-H), 7.84 (1H, t,J=8.4 Hz, Ar-H), 7.98 (1H, t, J=8.4Hz, Ar-H), 8.31 (1H, d, J=8.5 Hz, Ar-H), 8.70 (1H, d, Ar-H), MS(ES+) m/e 437 [MH]+; The title compound was prepared from intermediate 1 and 2-bromopyridine-6-methanol (Tetrahedron Lett, 1996, 50, 2537) according to the procedure of reference example 1. The product was isolated by adding water to the reaction mixture and the resulting precipitate was filtered. Flash chromatography on silica gel, elution with ethyl acetate, and recrystallization (ethyl acetate/methanol) gave the title phthalazine, mp 247.5-249°C; 1HNMR (360MHz, CDCl3) δ 2.61 (3H, d, J=0.7 Hz, Me), 5.73 (2H, s, CH2), 6.82 (1H, d, J=0.7 Hz, Ar-H), 7.48 (1H, d, J=7.8 Hz, Ar-H), 7.84 (1H, t, J=8.4 Hz, Ar-H), 7.98 (1H, t, J=8.4Hz, Ar-H), 8.31 (1H, d, J=8.5 Hz, Ar-H), 8.70 (1H, d, Ar-H), MS(ES+) m/e 437 [MH]+;
Anal. nađeno: C, 52.27; H, 2.85; N, 19.14. C19H13N6O2 Br.0.1 (H2O) zahtijevano: C, 51.98;H,3.03,N, 18.60%. Anal. found: C, 52.27; H, 2.85; N, 19.14. C19H13N6O2 Br.0.1 (H2O) required: C, 51.98; H, 3.03, N, 18.60%.
MEĐUPRODUKT 2 INTERMEDIATE PRODUCT 2
6-hidroksi-3-(5-metilizoksazol-3-il)-1,2.4-[3,4-a] ftalazin 6-hydroxy-3-(5-methylisoxazol-3-yl)-1,2.4-[3,4-a] phthalazine
Otopina natrij hidroksida (0.67g,17 mmol) u vodi (7.5ml) dodana je u mješanu otopinu međuprodukta 1 (1.0 g, 3.5 mmol) u dioksanu (37.5 ml) i zatim je ta smjesa zagrijavana u refluksu 4 sata. Otapalo je ispareno in vacuo a otatak je podjeljen između vode i dietiletera. Vodeni sloj je odijeljen, ispran sa eterom (x1) a zatim zakiseljen sa 2N klorovodičnom kiselinom dok se ne postigne pH2. Krutina koja se istaložila iz otopine je profiltrirana i vodeni filtrat ekstrahiran sa diklormetanom (x3). Kombinirani ekstrakti su osušeni (MgSO4) i ispareni in vacuo i kombinirani s talogom daju naslovni produkt (0.45 g, 48%), 1HNMR ( 250 MHz, d6 -DMSO) δ 2.58 (3H, d, J=0.7 Hz,Me), 7.07 (1H, d, J=0.9 Hz, Ar-H), 7.94 (1H, m, Ar-H), 8.08 (1H, m, Ar-H), 8.24 (1H, d, J=7.4 Hz, Ar-H), 8.54(1H, d, J=7.4Hz, Ar-H), 13.32 (IH, br s, MH); MS(ES+)m/e268[MH]+; A solution of sodium hydroxide (0.67g, 17 mmol) in water (7.5 ml) was added to a mixed solution of intermediate 1 (1.0 g, 3.5 mmol) in dioxane (37.5 ml) and then the mixture was heated under reflux for 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and diethyl ether. The aqueous layer was separated, washed with ether (x1) and then acidified with 2N hydrochloric acid until pH2 was reached. The solid that precipitated from the solution was filtered and the aqueous filtrate extracted with dichloromethane (x3). The combined extracts were dried (MgSO4) and evaporated in vacuo and combined with the residue to give the title product (0.45 g, 48%), 1HNMR (250 MHz, d6 -DMSO) δ 2.58 (3H, d, J=0.7 Hz, Me), 7.07 (1H, d, J=0.9 Hz, Ar-H), 7.94 (1H, m, Ar-H), 8.08 (1H, m, Ar-H), 8.24 (1H, d, J=7.4 Hz, Ar -H), 8.54(1H, d, J=7.4Hz, Ar-H), 13.32 (IH, br s, MH); MS(ES+)m/e268[MH]+;
REFERENTNI PRIMJER 3 REFERENCE EXAMPLE 3
3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il) metiloksi-1,2,4-triazolo [3.4-a] ftalazin 3-(5-methylisoxazol-3-yl)-6-(1H-1,2,3-triazol-5-yl) methyloxy-1,2,4-triazolo [3.4-a] phthalazine
a) 5-formil-1-[2-(trimetilsilil)etoksi]metil-1,2,3-triazol a) 5-formyl-1-[2-(trimethylsilyl)ethoxy]methyl-1,2,3-triazole
n-butil litij (6.8ml u 1.6M otopini heksana, 10.9 mmol) dodan je u kapima nakon 0.08 h u miješanu otopinu 1-[2(trimetilsilil)etoksi]metil-1,2,3-triazola (J.Heterocykl. Chem., 1992, 29,1203) (2.077 g, 10.42 mmol) u THF-u (30ml) na -78°C pod dušikom. Otopina je zagrijana do -68°C nakon 0.067h, zatim ponovno ohlađena na -78°C i dodan je DMF (0.9ml,11.6 mmol). Smjesa je zagrijana na sobnu temperaturu i mješana 16.5h. Zatim je dodana zasićena otopina amonij klorida (50ml) i reakcijska smjesa ekstrahirana s dietileterom (3x80ml). Kombinirani eterski ekstrakti su osušeni (MgSO4), ispareni in vacuo, a ostatak je kromatografiran na silika gelu, eluiran sa 30% etilacetat/heksanom, da se dobije naslovni triazol (1.713g, 72%), 1HNMR ( 360 MHz, CDCl3) δ 0.01 (9H, s, Me3Si), 0.92-0.99 (2H, m, CH2), 3.64-3.69 (2H, m, CH2), 6.05 (2H, s, CH2), 8.31 (1H, s, Ar-H), 10.12 (1H, s, CHO). n-Butyl lithium (6.8ml in 1.6M hexane solution, 10.9 mmol) was added dropwise after 0.08 h to a stirred solution of 1-[2(trimethylsilyl)ethoxy]methyl-1,2,3-triazole (J.Heterocycl. Chem. , 1992, 29, 1203) (2.077 g, 10.42 mmol) in THF (30ml) at -78°C under nitrogen. The solution was heated to -68°C after 0.067h, then cooled again to -78°C and DMF (0.9ml, 11.6 mmol) was added. The mixture was heated to room temperature and mixed for 16.5 hours. Then a saturated solution of ammonium chloride (50ml) was added and the reaction mixture was extracted with diethyl ether (3x80ml). The combined ether extracts were dried (MgSO4), evaporated in vacuo, and the residue chromatographed on silica gel, eluting with 30% ethyl acetate/hexane, to give the title triazole (1.713g, 72%), 1HNMR (360 MHz, CDCl3) δ 0.01 (9H, s, Me3Si), 0.92-0.99 (2H, m, CH2), 3.64-3.69 (2H, m, CH2), 6.05 (2H, s, CH2), 8.31 (1H, s, Ar-H) , 10.12 (1H, s, CHO).
b) 5-hidroksimetil-1-[2-(trimetilsilil)etoksi]metil-1,2,3-triazol b) 5-hydroxymethyl-1-[2-(trimethylsilyl)ethoxy]methyl-1,2,3-triazole
Natrij borohidrid (0.284g, 7.51mmol) dodan je u mješanu otopinu prethodnog triazola (1.704g, 7.495mmol)u metanolu (8ml) na 0°C pod dušikom. Smjesa je mješana na 0°C 0.5 h i na sobnoj temperaturi 0.5h. Zatim je dodana voda i smjesa je podjeljena između diklormetana i zasićene otopine soli. Vodeni sloj je odjeljen i zatim ekstrahiran s diklormetanom (x2). Kombinirani organski slojevi su osušeni ((MgSO4) i ispareni in vacuo a ostatak kromatografiran na silikagelu, eluiran sa 70% etilacetat/heksanom da se dobije naslovni produkt (1.34g,78%), 1HNMR ( 360 MHz, CDCl3) δ 0.00 (9H, s, Me3Si), 0.90-0.95 (2H, m, CH2), 3.58-3.63 (2H, m, CH2), 4.84 (2H, s, CH2), 5.80 (2H, s, CH2), 7.68 (1H, s, Ar-H). Sodium borohydride (0.284g, 7.51mmol) was added to a stirred solution of the preceding triazole (1.704g, 7.495mmol) in methanol (8ml) at 0°C under nitrogen. The mixture was mixed at 0°C for 0.5 h and at room temperature for 0.5 h. Water was then added and the mixture was partitioned between dichloromethane and brine. The aqueous layer was separated and then extracted with dichloromethane (x2). The combined organic layers were dried ((MgSO4) and evaporated in vacuo and the residue chromatographed on silica gel, eluting with 70% ethyl acetate/hexane to give the title product (1.34g, 78%), 1HNMR (360 MHz, CDCl3) δ 0.00 (9H , s, Me3Si), 0.90-0.95 (2H, m, CH2), 3.58-3.63 (2H, m, CH2), 4.84 (2H, s, CH2), 5.80 (2H, s, CH2), 7.68 (1H, s, Ar-H).
c) 3-(5-metilizoksazol-3-il)-6-{1-[2-(trimetilsili)etoksi]metil-1,2,3-triazol-5-il}metiloksi-1,2,4-triazolo[3.4-a] ftalazin c) 3-(5-methylisoxazol-3-yl)-6-{1-[2-(trimethylsilyl)ethoxy]methyl-1,2,3-triazol-5-yl}methyloxy-1,2,4-triazol [3.4-a] Phthalazine
Naslovni spoj je pripravljen iz međuprodukta 1 i prethodnog alkohola prema postupku opisanom u Primjeru 10,1HNMR (360 MHz, CDCl3) δ 0.00 (9H, s, Me3Si), 0.88-0.93 (2H, m, CH2), 2.63 (3H, s, Me), 3.61-3.66 (2H, m, CH2), 5.92 (2H, s, CH2), 5.97 (2H, s, CH2), 6.89 (1H, s, Ar-H), 7.86(1H, m, Ar-H), 8.02 (1H,d, J=7.7 Hz, Ar-H), 8.18 (1H, s, Ar-H), 8.23 (1H,d, J=8.0 Hz, Ar-H), 8.76 (1H, d, J=8.0 Hz, Ar-H); MS (ES+) m/e 479[MH]+. The title compound was prepared from intermediate 1 and the previous alcohol according to the procedure described in Example 10, 1HNMR (360 MHz, CDCl3) δ 0.00 (9H, s, Me3Si), 0.88-0.93 (2H, m, CH2), 2.63 (3H, s , Me), 3.61-3.66 (2H, m, CH2), 5.92 (2H, s, CH2), 5.97 (2H, s, CH2), 6.89 (1H, s, Ar-H), 7.86(1H, m, Ar-H), 8.02 (1H,d, J=7.7 Hz, Ar-H), 8.18 (1H, s, Ar-H), 8.23 (1H,d, J=8.0 Hz, Ar-H), 8.76 ( 1H, d, J=8.0 Hz, Ar-H); MS (ES+) m/e 479[MH]+.
d) 3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a] ftalazin d) 3-(5-methylisoxazol-3-yl)-6-(1H-1,2,3-triazol-5-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine
Smjesa prethodnog produkta, etanol (10 ml) i 2N HCl (20ml) zagrijavani su na 50°C 15.25h. pH otopine je naravnan na pH 12 sa zasićenom otopinom natrijkarbonata i otapalo je ispareno in vacuo. Ostatak je azeotropiran sa etanolom (x2) i kromatografiran na silikagelu, eluiran sa 0-4% metanol/diklormetanom (gradijent eluacije), da se dobije naslovni produkt, 1HNMR ( 400 MHz, CDCl3) δ 2.65 (3H, s, Me), 5.73 (2H, s, CH2), 7.02 (1H, s, Ar-H), 7.87 (1H, t, J=7.8 Hz, Ar-H), 7.99-8.03 (2H, m, 2 od Ar-H), 8.24 (1H,d, J=8.2 Hz, Ar-H), 8.72 (1H, d, J=7.9 Hz, Ar-H); MS (ES+). m/e 349 [MH]+. A mixture of the previous product, ethanol (10 ml) and 2N HCl (20 ml) was heated at 50°C for 15.25 h. The pH of the solution was adjusted to pH 12 with saturated sodium carbonate solution and the solvent was evaporated in vacuo. The residue was azeotroped with ethanol (x2) and chromatographed on silica gel, eluting with 0-4% methanol/dichloromethane (gradient elution), to give the title product, 1HNMR ( 400 MHz, CDCl3 ) δ 2.65 (3H, s, Me), 5.73 (2H, s, CH2), 7.02 (1H, s, Ar-H), 7.87 (1H, t, J=7.8 Hz, Ar-H), 7.99-8.03 (2H, m, 2 from Ar-H) , 8.24 (1H, d, J=8.2 Hz, Ar-H), 8.72 (1H, d, J=7.9 Hz, Ar-H); MS (ES+). m/e 349 [MH]+.
Primjer 1 Example 1
3-(5-metilizoksazol-3-il)-6-(1metil-1,2.3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a] ftalazin. 3-(5-metilizoksazol-3-il)- 6-(2-metil-1,2,3-friazol-4-il)metiloksi-1,2,4-triazolo[3.4-a] ftalazin i 3-(5-metilizoksazol- 3-il)-6-(1metil-1,2,3- triazol- 4 -il)metiloksi-1,2,4-triazolo[3.4-a] ftalazin 3-(5-Methylisoxazol-3-yl)-6-(1methyl-1,2.3-triazol-5-yl)methyloxy-1,2,4-triazolo[3,4-a] phthalazine. 3-(5-methylisoxazol-3-yl)-6-(2-methyl-1,2,3-friazol-4-yl)methyloxy-1,2,4-triazolo[3.4-a] phthalazine and 3-( 5-methylisoxazol-3-yl)-6-(1methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3.4-a]phthalazine
Litij heksametildisilazid (1.63ml u 1M otopini THF (1.63mmol) dodan je u kapima u mješanu otopinu 3-(5-metilizoksazol-3-il)-6-(1H-1,2,3-triazol-5-il)metiloksi-1,2,4-triazolo[3,4-a] ftalazina (241mg, 0.626mmol) pripravljenog kao u referentnom primjeru 3, u DMF-u (50ml) na -31°C pod dušikom. Smjesa je zagrijana na -23°C nakon 1.5h, dodan je metil jodid (0,10 ml, 1.8 mmol) u kapima i reakcijska smjesa je ostavljena da se zagrije do sobne temperature preko noći. Zatim je dodana voda i ispareno otapalo in vacuo. Ostatak je podjeljen između diklormetana i vode i vodena faza odjeljena re-ekstrakcijom s diklormetanom (x1). Kombinirani organski ekstrakti su isprani s otpinom soli (x1), osušeni (MgSO4) i ispareni in vacuo. Kromatografijom ostataka na silikagelu, eluacijom sa 0.5% metanol/diklormetanom (gradijent eluacije), i dalje pomoću preparativne HPLC (YMC Sil kolona, 250x20mm) eluacijom sa 5% metanol/1-klorbutanom odjeljeni su izomeri triazola: Lithium hexamethyldisilazide (1.63ml in 1M THF solution (1.63mmol) was added dropwise to a mixed solution of 3-(5-methylisoxazol-3-yl)-6-(1H-1,2,3-triazol-5-yl)methyloxy -1,2,4-triazolo[3,4-a]phthalazine (241mg, 0.626mmol) prepared as in Reference Example 3, in DMF (50ml) at -31°C under nitrogen.The mixture was warmed to -23 °C after 1.5 h, methyl iodide (0.10 mL, 1.8 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. Water was then added and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and water and the aqueous phase separated by re-extraction with dichloromethane (x1). The combined organic extracts were washed with brine (x1), dried (MgSO4) and evaporated in vacuo. Chromatography of the residue on silica gel, eluting with 0.5% methanol/dichloromethane (gradient elution), and further using preparative HPLC (YMC Sil column, 250x20mm) by elution with 5% methanol/1-chlorobutane, the triazole isomers were separated:
Izomer najmanjeg polariteta: 3-(5-metilizoksazol-3-il)-6-(2-metil-1,2,3-triazol-4-il)metiloksi-1,2.4-triazolo[3.4-a] ftalazin 1HNMR ( 400 MHz, CDCl3) δ 2.59 (3H, s, Me),4.21 (3H, s,Me),5.73 (2H, s, CH2), 6.89 (IH, s, Ar-H), 7.79 (IH, m, Ar-H), 7.94 (IH, m, Ar-H), 8.10 (1H, s, Ar-H), 8.22 (1H,d, J=8.0 Hz, Ar-H), 8.67 (1H, d, J=8.0 Hz, Ar-H); MS (ES+) m/e 363 [MH]+. Isomer of least polarity: 3-(5-methylisoxazol-3-yl)-6-(2-methyl-1,2,3-triazol-4-yl)methyloxy-1,2.4-triazolo[3.4-a] phthalazine 1HNMR ( 400 MHz, CDCl3) δ 2.59 (3H, s, Me), 4.21 (3H, s, Me), 5.73 (2H, s, CH2), 6.89 (IH, s, Ar-H), 7.79 (IH, m, Ar-H), 7.94 (IH, m, Ar-H), 8.10 (1H, s, Ar-H), 8.22 (1H, d, J=8.0 Hz, Ar-H), 8.67 (1H, d, J =8.0 Hz, Ar-H); MS (ES+) m/e 363 [MH]+.
Izomer srednjeg polariteta: 3-(5-metilizoksazol-3-il)-6-(1-metil-1,2,3-triazol-4-il)metiloksi-1,2,4-triazolo[3.4-a] ftalazin 1HNMR ( 400 MHz, CDCl3) δ 2.60 (3H, s, Me), 4.09 (3H, s,Me), 5.78 (2H, s, CH2), 6.90(1H, d, J=8.0 Hz, Ar-H), 7.80(1H, m, Ar-H),7.94(1H, m, Ar-H), 8.25 (1H,d, J=8.0 Hz, Ar-H), 8.65 (1H,d, J=8.0 Hz, Ar-H), 8.73 (1H, s, Ar-H); MS (ES+) m/e 363 [MH]+. Medium polarity isomer: 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3.4-a] phthalazine 1HNMR (400 MHz, CDCl3) δ 2.60 (3H, s, Me), 4.09 (3H, s, Me), 5.78 (2H, s, CH2), 6.90 (1H, d, J=8.0 Hz, Ar-H) , 7.80(1H, m, Ar-H), 7.94(1H, m, Ar-H), 8.25 (1H,d, J=8.0 Hz, Ar-H), 8.65 (1H,d, J=8.0 Hz, Ar-H), 8.73 (1H, s, Ar-H); MS (ES+) m/e 363 [MH]+.
Izomer jakog polariteta (HPLC sistem otapala): 3-(5-metilizoksazol- 3-il)-6-(1-metil-1,2,3- triazol-5-il) metiloksi-1,2,4-triazolo[3.4-a] ftalazin Isomer of strong polarity (HPLC solvent system): 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-5-yl)methyloxy-1,2,4-triazolo[ 3.4-a] Phthalazine
1HNMR ( 400 MHz, CDCl3) δ 2.56 (3H, s, Me), 4.19 (3H, s,Me), 5.76 (2H, s, CH2), 6.82 (1H, s, Ar-H), 7.80 (1H, m, Ar-H), 7.96 (1H, m, Ar-H), 8.04 (1H, s, Ar-H), 8.12 (1H, d, J=8.8 Hz, Ar-H), 8.67(1H, d, J=8.0 Hz, Ar-H); MS (ES+) m/e 363 [MH]+. 1HNMR (400 MHz, CDCl3) δ 2.56 (3H, s, Me), 4.19 (3H, s, Me), 5.76 (2H, s, CH2), 6.82 (1H, s, Ar-H), 7.80 (1H, m, Ar-H), 7.96 (1H, m, Ar-H), 8.04 (1H, s, Ar-H), 8.12 (1H, d, J=8.8 Hz, Ar-H), 8.67(1H, d , J=8.0 Hz, Ar-H); MS (ES+) m/e 363 [MH]+.
Claims (4)
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| GBGB9803992.8A GB9803992D0 (en) | 1998-02-25 | 1998-02-25 | Therapeutic agents |
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| CO (1) | CO5011102A1 (en) |
| DZ (1) | DZ2644A1 (en) |
| GB (1) | GB9803992D0 (en) |
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| ZA (1) | ZA989317B (en) |
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1998
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- 1998-10-30 PE PE00102598A patent/PE128999A1/en not_active Application Discontinuation
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| PE128999A1 (en) | 1999-12-16 |
| TW487710B (en) | 2002-05-21 |
| DZ2644A1 (en) | 2003-03-15 |
| GB9803992D0 (en) | 1998-04-22 |
| CO5011102A1 (en) | 2001-02-28 |
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