HRP980319A2 - 3-substituted 3,4-dihydro-thieno/2,3-d/pyrimidine derivatives, their preparation and use - Google Patents
3-substituted 3,4-dihydro-thieno/2,3-d/pyrimidine derivatives, their preparation and useInfo
- Publication number
- HRP980319A2 HRP980319A2 HR19724980.9A HRP980319A HRP980319A2 HR P980319 A2 HRP980319 A2 HR P980319A2 HR P980319 A HRP980319 A HR P980319A HR P980319 A2 HRP980319 A2 HR P980319A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- thieno
- dihydro
- ethyl
- naphthyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 4
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title 1
- 150000003230 pyrimidines Chemical class 0.000 title 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 20
- -1 3-substituted 3,4-dihydrothieno[2,3-d]pyrimidine Chemical class 0.000 claims description 18
- 229940076279 serotonin Drugs 0.000 claims description 13
- 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 claims description 10
- 101710138639 5-hydroxytryptamine receptor 1B Proteins 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000004000 serotonin 1B antagonist Substances 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 230000008485 antagonism Effects 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000003727 serotonin 1A antagonist Substances 0.000 claims 1
- 230000000697 serotonin reuptake Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 102000007527 Autoreceptors Human genes 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- PLSWKLWKNFLBFC-UHFFFAOYSA-N n,n,5-trimethyl-4-oxo-3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound O=C1C=2C(C)=C(C(=O)N(C)C)SC=2N=CN1CCN(CC1)CCN1C1=CC=CC(C(F)(F)F)=C1 PLSWKLWKNFLBFC-UHFFFAOYSA-N 0.000 description 1
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- IURUXISVEIKINP-UHFFFAOYSA-N n,n-diethyl-5-methyl-4-oxo-3-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound O=C1C=2C(C)=C(C(=O)N(CC)CC)SC=2N=CN1CCN(CC1)CCN1C1=NC=CC=N1 IURUXISVEIKINP-UHFFFAOYSA-N 0.000 description 1
- YPEWWOUWRRQBAX-UHFFFAOYSA-N n,n-dimethyl-3-oxobutanamide Chemical compound CN(C)C(=O)CC(C)=O YPEWWOUWRRQBAX-UHFFFAOYSA-N 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Predloženi izum odnosi se na nove derivate 3,4-dihidrotieno[2,3-d]pirimidina, njihovo pripravljanje i upotrebu za proizvodnju aktivnih sastojaka za lijekove.
Klasični antidepresanti, i noviji selektivni inhibitori ponovnog uzimanja serotonina (SSRIs), razvijaju svoj učinak antidepresanta između ostalog inhibicijom aktivnog ponovnog uzimanja transmitera u presinaptičkim završecima živaca. Na nesreću, njihov antidepresantni učinak se uspostavlja najmanje tek tri tjedna nakon liječenja, i čak štoviše, pribl. 30% pacijenata je rezistentno prema terapiji.
Blokada presinaptičkih serotonin autoreceptora se povisuje, poništavajući negativno povezivanje, serotonin se oslobađa i time stvarna koncentracija transmitera u sinaptičkom procjepu. To povišenje koncentracije transmitera se smatra načelom antidepresantnog učinka. Taj mehanizam djelovanja razlikuje se od ranije poznatih antidepresanata koji aktiviraju oboje, presinaptičke i somatodendritičke autoreceptore i zbog toga imaju za posljedicu odgođeno uspostavljanje djelovanja, samo nakon dezensitizacije tih autoreceptora. Izravna blokada autoreceptora premošćuje taj učinak.
Prema sadašnjem saznanju presinaptički autoreceptor serotonina je 5-HT1B podtip (Fink et al., Arch. Pharmacol. 352 (1995), 451). Njegova selektivna blokada s 5-HT1B antagonistima povisuje oslobađanje serotonina u mozgu; G.W. Price et al., Behavioural Brain Research 73 (1996), 79-82; P.H. Hutson et al., Neuropharmacology Vol. 34, br. 4 (1995), 383-392.
Međutim, iznenađujuće, selektivni 5-HT1B antagonist GR 127 935 smanjuje oslobađanje serotonina u korteksu nakon sistemskog davanja. Jedno objašnjenje može biti stimulacija somatodentritičkih 5-HT1B receptora u području rafa oslobađanjem serotonina, koji inhibira brzinu zapaljenja serotonergnih neurona i stoga oslobađanje serotonina (M. Skingle et al., Neuropharmacology Vol. 34 br. 4 (1995), 377-382, 393-402).
Stoga je jedna strategija za premošćivanje autoinhibicijskih učinaka u serotonergnim područjima izvorno usmjerena na blokiranje presinaptičkih 5-HT1B receptora. Tu hipotezu podupiru opažanja da se učinak paroksetina na oslobađanje serotonina u lednoj rafe jezgri štakora pojačava s 5-HT1B receptor antagonistom GR 127 935 (Davidson i Stamford, Neuroscience Lett., 188 (1995), 41).
Druga strategija uključuje blokadu obaju tipova autoreceptora, naime 5-HT1A receptora, da se pojačaju da bi neuronski signali, i 5-HT1B-receptori, da se poveća terminalno oslobađanje serotonina (Starkey i Skingle, Neuropharmacology 33, (3-4) (1994), 393).
5-HT1B/D antagonisti, sami ili povezani na antagonističku komponentu 5-HT1B receptora, trebali bi stoga uzrokovati pojačano oslobađanja serotonina u mozgu i zbog toga se mogu korisno povezati s terapijom depresija i srodnih psiholoških poremećaja.
Sada je pronađeno da derivati 3-supstituiranog 3,4-dihidrotieno[2,3-d]-pirimidina formule I
[image]
u kojoj
R1 i R2 predstavljaju vodikov atom ili C1-C4-alkilnu skupinu,
R3 predstavlja fenil, piridil, pirimidinil ili pirazinilnu skupinu koja nije supstituirana ili je mono ili disupstituirana s halogenim atomima, C1-C4-alkilnom, trifluormetilnom, trifluormetoksi, hidroksi, C1-C4-alkoksi, amino, monometilamino, dimetilamino, cijano ili nitro skupinama i koji mogu biti fuzionirane na benzenovu jezgru s halogenim atomima, C1-C4-alkilnom, hidroksi, trifluormetilnom, C1-C4-alkoksi, amino, cijano ili nitro skupinama, i mogu sadržavati 1 dušikov atom, ili na petero- ili šesteročlani prsten, koji može sadržavati 1-2 kisikova atoma,
A je NH ili kisikov atom,
Y je CH2, CH2-CH2, CH2-CH2-CH2 ili CH2-CH,
Z je dušikov atom, ugljikov atom ili CH, pri čemu veza između Y i Z može biti dvostruka veza, i
n je 2, 3 ili 4,
i njihove soli s fiziološki podnošljivim kiselinama imaju dragocjena farmakološka svojstva.
Posebno prednosni spojevi su oni u kojima
R1 i R2 predstavljaju metil,
R3 predstavlja o-metoksifenil, 1-naftil, 2-metoksi-1-naftil, 2-metil-1-naftil
A je kisikov atom,
Y je CH2-CH2,
Z je dušikov atom, i n je 2 ili 3.
Novi spojevi formule I mogu se proizvesti reakcijom spoja formule II
[image]
u kojoj R1 ima gore navedeno značenje, R3 je cijano skupina ili C1-3-alkilkarboksilna esterska skupina, a R4 je
C1-3-alkil, s primarnim aminom formule III
[image]
u kojoj R ima gore navedeno značenje, i pretvorbom na taj način dobivenog spoja u odgovarajuću adicijsku sol fiziološki podnošljive kiseline.
Reakcija se uspješno provodi u inertnom organskom otapalu, posebno u nižem alkoholu, npr. metanolu ili etanolu, ili u cikličkom zasićenom eteru, posebno u tetrahidrofuranu ili dioksanu.
Reakcija se u pravilu provodi pri temperaturi od 20 do 110°C, posebno od 60 do 90°C, i općenito je gotova za 1 do 10 sati.
Alternativno, spoj formule II
[image]
u kojoj R1 ima gore navedeno značenje, R3 je cijano skupina ili C1-3-alkilkarboksilna esterska skupina, a R4 je
C1-3-alkil, reagira s primarnim amino alkoholom formule IV
[image]
u inertnom otapalu, ponajprije alkoholima kao etanolu, pri temperaturi od 60 do 120°C, čime se dobije proizvod ciklizacije V (X = OH)
[image]
koji se zatim pretvara sa sredstvom za halogeniranje, npr. s tionil kloridom ili s bromovodičnom kiselinom, u organskom otapalu kao što je halogenirani ugljikovodik ili bez otapala pri temperaturi od sobne temperature do 100°C u odgovarajući halogeni derivat V (X = Cl, Br).
Konačno, halogeni derivat formule V (X = Cl, Br) reagira s aminom formule VI
[image]
u kojoj Y, Z i R imaju gore navedena značenja, čime se dobije novi krajnji proizvod formule I. Ta se reakcija odvija najbolje u inertnom organskom otapalu, ponajprije toluenu ili ksilenu, u prisutnosti baze, npr. kalijevog karbonata ili kalijevog hidroksida, pri 60°C do 150°C.
Novi spojevi prema izumu formule I mogu se očistiti prekristalizacijom iz uobičajenih organskih otapala, ponajprije iz nižeg alkohola, kao etanola, ili kromatografijom u koloni.
Slobodni derivati 3-supstituiranog pirido[3’,4’:4,5]tieno[2,3-d]pirimidina formule I mogu se na uobičajen način prevesti u kiselinske adicijske soli u otopini sa stehiometrijskom količinom odgovarajuće kiseline. Primjeri farmaceutski podnošljivih kiselina jesu solna kiselina, fosforna kiselina, sumporna kiselina, metansulfonska kiselina, sulfaminska kiselina, maleinska kiselina, fumarna kiselina, oksalna kiselina, vinska kiselina ili limunska kiselina.
S tim u skladu izum se također odnosi na terapeutski sastav koji kao aktivnu tvar sadrži spoj formule I ili njegovu farmakološki podnošljivu kiselinsku adicijsku sol, pored uobičajenih nosača i sredstava za razrjeđivanje, te na upotrebu novih spojeva pri suzbijanju bolesti.
Spojevi prema izumu mogu se dati na uobičajen način oralno ili parenteralno, intravenski ili intramuskularno. Doziranje ovisi o starosti, stanju i težini pacijenta, te o načinu davanja. U pravilu kod oralnog davanja dnevna doza aktivne tvari iznosi od pribl. 1 i 100 mg/kg tjelesne težine i od 0,1 i 10 mg/kg tjelesne težine kod parenteralnog davanja.
Novi spojevi mogu se primijeniti u uobičajenim krutim ili tekućim farmaceutskim oblicima, npr. kao neprevučene
ili (s filmom) prevučene tablete, kapsule, puderi, granule, čepići, otopine, masti, kreme ili sprejevi. Oni se proizvode na uobičajen način. Pri tome se aktivne tvari mogu preraditi s uobičajenim farmaceutskim pomoćnim sredstvima kao što su veziva za tablete, punila, konzervansi, sredstva za rastvaranje tableta, sredstva za regulaciju tecivosti, omekšivači, kvasila, sredstva za dispergiranje, emulgatori, otapala, sredstva usporavanje oslobađanja aktivne tvari, antioksidanti i/ili potisni plinovi (usporedi H. Sucker et al., Pharmaceutische Technologie, Thieme-Verlag, Stuttgart, 1978). Tako dobiveni oblici za davanje sadrže aktivnu tvar normalno količinom od 1 do 99 mas. %.
Tvari formule II do VI, potrebne kao polazne tvari za sintezu novih spojeva, su poznate ili se mogu sintetizirati postupcima opisanim u literaturi iz analognih polaznih materijala (F. Sauter i P. Stanetty, Monatsh. Chem. (1975), 106(5), 1111-1116; K. Gewald et al., Chem. Ber. 99, 94-100, (1966), Njemačka patentna prijava br. 196 36769.7).
Novi spojevi imaju visoki afinitet prema receptorima serotonina 5-HT1B, 5-HT1D i 5-HT1A. Pri tome, afinitet prema tim receptorima je otprilike jednake veličine, barem istog reda veličine. Nadalje, nekoliko spojeva prema izumu pokazuju dobru inhibiciju ponovnog uzimanja serotonina, koji je načelno prisutna kod većine antidepresanata.
Ti spojevi su prikladni kao lijekovi za liječenje patofizioloških stanja kod kojih je snižena koncentracija serotonina i kod kojih se u okviru terapije želi ciljano blokirati aktivnost presinaptičkih receptora 5-HT1B, 5-HT1D i 5-HT1A, a da se pri tome ne utječe jako na druge receptore. Takovo bolesno stanje je primjerice depresija.
Spojevi predloženog izuma mogu se također upotrijebiti i za liječenje poremećaja raspoloženja uvjetovanog središnjom nervozom, kao što su sezonski osjećajni poremećaji i distimije. Tu spadaju također i stanja straha, kao opći strah, napad panike, sociofobija, opsesivno-kompulzivne neuroze i simptomi post-traumatskog stresa, poremećaji pamćenja, uključiv demenciju, amneziju i gubitak pamćenja zbog starosti, kao i psihogene poremećaje uzimanja hrane kao što je neurotična anoreksija i neurotična bulimija.
Osim toga, spojevi prema izumu mogu se upotrijebiti za liječenje endokrinih bolesti, kao hiperprolaktinemije, kao i za liječenje vazospazmi (naročito moždanih krvnih žila), hipertenzije i gastrointestinalnih poremećaja, koji su povezani s poremećajima motiliteta i sekrecije. Daljenje područje primjene su seksulani poremećaji.
Slijedeći primjeri služe za objašnjenje izuma:
A Pripravljanje polaznih materijala
a) 2-amino-3-karboetoksi-5-metil-5-dimetilkarbamoil-tiofen
82,8 ml (775 mmolova) etil cijanoacetata i 24,8 g (755 mmolova) sumpornog praha doda se k 100 g (755 mmolova) N,N-dimetilacetoacetamida u 400 ml etanola i zatim, uz snažno miješanje i u atmosferi dušika, doda se kap po kap 90 ml (647 mmolova) trietilamina. Nakon 1 sata smjesu se refluktira 8 sati i zatim se pusti miješati preko noći pri sobnoj temperaturi. Smjesu se zgusne pod smanjenim tlakom, ostatak se preuzme u 2 l vode, pH se namjesti na 9, i izvrše se dvije ekstrakcije s metilen kloridom. Organsku fazu se osuši i zgusne i zatim se sirov proizvod (70 g) očisti otapanjem u 200 ml kipućeg etil acetata. Krutu tvar, koja se istaloži nakon miješanja preko noći, se odfiltrira odsisavanjem nakon hlađenja na ledenoj kupelji i ispere nekoliko puta s hladnim etil acetatom. Izolirano je 39,0 g (20%) proizvoda kao sive krute tvari s talištem pri 122-124°C.
b) 2-etoksimetilenamino-3-karboetoksi-4-metil-5-dimetilkarbamoiltiofen
2,0 ml octenog anhidrida doda se k 30,6 g (119 mmolova) 2-amino-3-karboetoksi-5-metil-4-metil-5-dimetil-karbamoil-tiofena u 150 ml trietil ortoformata i refluktira se 2 sata u atmosferi dušika. Smjesu se zatim potpuno ispari na rotacijskom isparivaču pri 80°C. Dobije se 35,6 g (96%) sirovog proizvoda kao tamnog ulja koje je dovoljno čisto za slijedeću reakciju.
c) 3-(2-hidroksietil)-5-metil-6-dimetilkarbamoiltieno[2,3-d]pirimidin-4-on
8,0 ml (133 mmola) etanolamina doda se k 35,6 g (114 mmolova) 2-etoksimetilenamino-3-karboetoksi-4-metil-5-dimetilkarbamoiltiofena u 200 ml etanola i refluktira se 2 sata. Zatim se smjesu zgusne pod smanjenim tlakom. Izolirano je 29,9 g (93%) tamnog viskoznog ulja.
d) 3-(2-kloretil)-5-metil-6-dimetilkarbamoiltieno[2,3-d]pirimidin-4-on
29,9 g (106 mmolova) 3- (2-hidroksietil)-5-metil-6-dimetilkarbamoiltieno[2,3-d]pirimidin-4-ona u 200 ml 1,2-dikloretana grije se pod refluksom (polagano otapanje) i zatim se doda kap po kap 12,7 ml (175 mmolova) tionil klorida u 20 ml 1,2-diklormetana. Refluktira se 1 sat i zatim se reakcijsku smjesu ohladi i zgusne. Sirov proizvod se podijeli između metilen klorida i vode pri pH 9. Nakon sušenja i zgušnjavanja iz organske faze se izolira 44,1 g (83%) proizvoda kao tamnog ulja koje se očisti kromatografijom na koloni (silika gel, sredstvo ispiranje etil acetat). Izolirano je 23,8 g (76%) proizvoda s talištem pri 120-122°C.
Drugi C1-4-mono- ili dialkilkarbamoil derivati formule II i V mogu se proizvesti postupcima opisanim pod a) do d).
e) N-(1-naftil)piperazin
83,2 g (966 mmolova) piperazina, 38,0 g (339 mmolova) kalijevog terc.butoksida i 50,0 g (241 mmol) 1-brom-naftalena doda se k mješavini od 5,4 g (24,2 mmola) paladijevog acetata i 14,7 g (48,3 mmola) tri-o-tolil-fosfina u 500 ml ksilena, i smjesu se refluktira 10 sati uz snažno miješanje u atmosferi dušika. Zatim se smjesu razrijedi s metilen kloridom, neotopljen ostatak se odfiltrira, i filtrat se zgusne. Sirov proizvod se očisti kromatografijom na koloni (silika gel, sredstvo za ispiranje THF/metanol/amonijak 85/13/2). Izolirano je 21,5 g (42%) proizvoda s talištem pri 84-86°C.
f) N-(2-metil-1-naftil)piperazin
14,7 g (82,7 mmola) bis(2-kloretil)amina x HCl doda se k 13,0 g (82,7 mmola) 1-amino-2-metilnaftalena u 100 ml klorbenzena i refluktira se 90 sati u atmosferi dušika. Zatim se smjesu zgusne i podijeli između metilen klorida i vode pri pH 9, organsku fazu se osuši i zgusne. Sirov proizvod se očisti kromatografijom na koloni (silika gel, sredstvo za ispiranje THF/metanol/amonijak 85/13/2). Izolirano je 11,6 g (62%) proizvoda.
g) 4-(1-piperazinil)kinolin
4,51 g (21,7 mmola) 4-bromizokinolina, 4,65 g (25,0 mmolova) 4-butil piperazin-N-karboksilata, 0,1 g (0,11 mmola) tris(dibenzilidenaceton)dipaladija, 0,11 g (0,18 mmola) 2,2'-bis (difenilfosfino)-1,1’-binaftila i 2,92 g (30,4 mmolova) natrijevog t-butoksida pomiješa se u 50 ml toluena i miješa se 2 sata pri 75°C. Reakcijsku smjesu se doda k led/natrijevom kloridu i ekstrahira se s etil acetatom, organsku fazu se osuši preko natrijevog sulfata i otapalo se odstrani na rotacijskom isparivaču. Proizvod iskristalizira i odfiltrira se odsisavanjem i ispere s pentanom. Dobiveno je 5,5 g (81%) Boc-zaštićenog piperazina (talište: 111°C). Od te tvari uzme se 5,5 g (16,6 mmolova) u 17 ml diklormetana i pri 0°C polako se doda 17 ml (0,22 mmola) trifluoroctene kiseline. Smjesu se pusti miješati 4 sata pri 0°C, prelije se na led-vodu i ekstrahira s diklormetanom. Vodenu fazu se profiltrira, učini alkalnom i ekstrahira s diklormetanom. Nakon sušenja preko natrijevog sulfata i odstranjivanja glavnine otapala, razrijedi se s dietil eterom i hidroklorid se istaloži s eterskom solnom kiselinom. Dobiveno je 3,2 g (67%) proizvoda s talištem pri 293-294°C.
Daljnji piperazinski derivati (vidi primjere) koji nisu obznanjeni u literaturi (vidi također Njemačku patentnu prijavu 19636769.7) proizvedeni su postupcima kako je opisano u e), f) i g).
B Pripravljanje krajnjih proizvoda
Primjer 1
3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metoksi-fenil)-1-piperazinil) etil]tieno[2,3-d]pirimidin-4-on
1,9 g (8,0 mmolova) 1-(2-aminoetil)-4-(2-metoksi-fenil)piperazina doda se k 2,4 g (7,8 mmolova) 2-etoksi-metilenamino-3-karbetoksi-4-metil-5-dimetilkarbamoil-tiofena u 30 ml etanola i refluktira se 2 sata. Proizvod iskristalizira nakon stajanja preko noći i odfiltrira se odsisavanjem i ispere s malo etanola. Izolirano je 2,2 g (62%) proizvoda s talištem pri 188-190°C.
Primjer 2
3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2,3-dimetilfenil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on
1,1 g (5,0 mmolova) 1- (2,3-dimetilfenil) piperazin hidroklorida i 1,54 ml (11 mmolova) trietilamina doda se k 1,5 g (5,0 mmolova) 3-(2-kloretil)-5-metil-6-dimetil-karbamoiltieno[2,3-d]pirimidin-4-ona u 15 ml dimetilformamida i grije se pri 125°C u atmosferi dušika ukupno 3 sata. Izlije se u vodu i zatim se ekstrahira s etil acetatom, organsku fazu se ekstrahira s razrijeđenom solnom kiselinom pri pH 2, tako dobivenu vodenu fazu se učini bazičnom s razrijeđenom otopinom natrijevog hidroksida. Sirov proizvod se ekstrahira s diklormetanom i nakon sušenja preko natrijevog sulfata otapalo se odstrani pod smanjenim tlakom. Uljasti ostatak kristalizira iz malo metanola i odfiltrira se odsisavanjem. Na taj način dobiveno je 0,7 g (31%) proizvoda s talištem pri 160-161°C.
Analogno primjerima 1 i 2 proizvedeni su slijedeći spojevi:
3. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(1-naftil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on,
talište 190-191°C;
4. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metil-1-naftil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on, talište 178-180°C;
5. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metoksi-1-naftil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on x H2O, talište 153-155°C (raspadanje);
6. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metilfenil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
7. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(3-trifluormetilfenil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on, talište 146°C;
8. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-klorfenil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
9. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-pirimidinil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on x 2 HCl x 4 H2O, talište 180-182°C (raspadanje);
10. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-piridinil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
11. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-kinolinil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on;
12. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(3,5-diklorfenil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
13. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(5-tetralinil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on,
talište 174°C;
14. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(4-indanil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on,
talište 153°C;
15. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-cijanofenil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on,
talište 210°C (hidroklorid);
16. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(4-izokinolinil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on;
17. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-pirimidinil)-1-piperazinil)propil]tieno[2,3-d]pirimidin-4-on x 2 HCl x 4 H2O, talište 209-211°C (raspadanje);
18. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metoksifenil)-1-piperidinil)etil]tieno[2,3-d]pirimidin-4-on;
19. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metoksifenil)-3,4-dehidro-1-piperidinil)etil]tieno[2,3-d]-pirimidin-4-on;
20. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(1-naftil)-1-piperidinil)etil]tieno[2,3-d]-pirimidin-4-on;
21. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2-metoksi-1-naftil)-3,4-dehidro-1-piperidinil)etil]tieno [2,3-d]-pirimidin-4-on;
22. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(1-naftil)-1,4-heksahidro-1,4-diazepin-1-il)etil]tieno[2,3-d]-pirimidin-4-on, talište 225-230°C (hidroklorid);
23. 3,4-dihidro-5-metil-6-karbamoil-3-[2-(4-(1-naftil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
24. 3,4-dihidro-5-metil-6-karbamoil-3-[2-(4-(2-pirimidinil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
25. 3,4-dihidro-5-metil-6-dietilkarbamoil-3-[2-(4-(2-metoksifenil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on;
26. 3,4-dihidro-5-metil-6-dietilkarbamoil-3-[2-(4-(1-naftil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
27. 3,4-dihidro-5-metil-6-dietilkarbamoil-3-[2-(4-(2-pirimidinil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on;
28. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(4-kinazolinil)-1-piperazinil)etil]tieno[2,3-d]-pirimidin-4-on, talište 295-300°C (hidroklorid);
29. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2,4-dimetoksifenil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on, talište 170-171°C;
30. 3,4-dihidro-5-metil-6-dimetilkarbamoil-3-[2-(4-(2,5-dimetilfenil)-1-piperazinil)etil]tieno[2,3-d]pirimidin-4-on, talište 90-91°C;
31. 3,4-dihidro-5-metil-6-dietilkarbamoil-3-[2-(4-(1-naftil)-3,4-dehidro-1-piperidinil)etil]tieno[2,3-d]pirimidin-4-on, MS: m+ = 509,1.
Claims (6)
1. Derivati 3-supstituiranog 3,4-dihidrotieno[2,3-d]pirimidina formule I
[image]
naznačeni time, da
R1 i R2 predstavljaju vodikov atom ili C1-C4-alkilnu skupinu,
R3 predstavlja fenil, piridil, pirimidinil ili pirazinilnu skupinu koja nije supstituirana ili je mono ili disupstituirana s halogenim atomima, C1-C4-alkilnom, trifluormetilnom, trifluormetoksi, hidroksi, C1-C4-alkoksi, amino, monometilamino, dimetilamino, cijano ili nitro skupinama i koji mogu biti fuzionirane na benzenovu jezgru s halogenim atomima, C1-C4-alkilnom, hidroksi, trifluormetilnom, C1-C4-alkoksi, amino, cijano ili nitro skupinama, i mogu sadržavati 1 dušikov atom, ili na petero- ili šesteročlani prsten, koji može sadržavati 1-2 kisikova atoma,
A je NH ili kisikov atom,
Y je CH2, CH2-CH2, CH2-CH2-CH2 ili CH2-CH,
Z je dušikov atom, ugljikov atom ili CH, pri čemu veza između Y i Z može biti dvostruka veza, i
n je 2, 3 ili 4, te njihove fiziološki podnošljive soli.
2. Spoj prema zahtjevu 1, naznačen time, da
R1 i R2 predstavljaju metil,
R3 predstavlja o-metoksifenil, 1-naftil, 2-metoksi-1-naftil, 2-metil-1-naftil,
A je kisikov atom,
Y j e CH2-CH2,
Z je dušikov atom, i
n je 2 ili 3.
3. Upotreba spoja prema zahtjevima 1-2, naznačena time, da se on koristi za proizvodnju lijekova.
4. Upotreba prema zahtjevu 3, naznačena time, da se spoj koristi za liječenje depresija i srodnih zdravstvenih poremećaja.
5. Upotreba spoja prema zahtjevima 1-2, naznačena time, da se on koristi kao selektivni 5-HT1B i 5-HT1A antagonist.
6. Upotreba prema zahtjevu 5, naznačena time, da se selektivni serotonin antagonizam nadopunjuje inhibcijom ponovnog uzimanja serotonina.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19724980A DE19724980A1 (de) | 1997-06-13 | 1997-06-13 | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
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| Publication Number | Publication Date |
|---|---|
| HRP980319A2 true HRP980319A2 (en) | 1999-04-30 |
Family
ID=7832352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR19724980.9A HRP980319A2 (en) | 1997-06-13 | 1998-06-12 | 3-substituted 3,4-dihydro-thieno/2,3-d/pyrimidine derivatives, their preparation and use |
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| Country | Link |
|---|---|
| US (1) | US6159962A (hr) |
| EP (1) | EP0988306B1 (hr) |
| JP (1) | JP2002504103A (hr) |
| KR (1) | KR20010013696A (hr) |
| CN (1) | CN1260797A (hr) |
| AR (1) | AR015712A1 (hr) |
| AT (1) | ATE244720T1 (hr) |
| AU (1) | AU749320B2 (hr) |
| BG (1) | BG103900A (hr) |
| BR (1) | BR9810017A (hr) |
| CA (1) | CA2293816A1 (hr) |
| CO (1) | CO4940507A1 (hr) |
| CZ (1) | CZ290464B6 (hr) |
| DE (2) | DE19724980A1 (hr) |
| HR (1) | HRP980319A2 (hr) |
| HU (1) | HUP0002902A3 (hr) |
| ID (1) | ID23421A (hr) |
| IL (1) | IL132967A0 (hr) |
| NO (1) | NO996043L (hr) |
| NZ (1) | NZ502238A (hr) |
| PL (1) | PL337453A1 (hr) |
| SK (1) | SK168499A3 (hr) |
| TR (1) | TR199903062T2 (hr) |
| WO (1) | WO1998056792A1 (hr) |
| ZA (1) | ZA985121B (hr) |
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|---|---|---|---|---|
| ATE491689T1 (de) * | 1997-10-27 | 2011-01-15 | Neurosearch As | Heteroaryl diazacycloalkane als cholinergische ligande für nikotin-acetylcholin-rezeptoren |
| DE19900545A1 (de) * | 1999-01-11 | 2000-07-13 | Basf Ag | Verwendung von Pyrimidinderivaten zur Prophylaxe und Therapie der zerebralen Ischämie |
| EP1266898A4 (en) * | 2000-02-29 | 2003-05-21 | Takeda Chemical Industries Ltd | PROCESSES FOR PRODUCING THIENOPYRAMIDINE DERIVATIVES |
| DE10031389A1 (de) * | 2000-07-03 | 2002-01-17 | Knoll Ag | Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie |
| DE10259382A1 (de) * | 2002-12-18 | 2004-07-01 | Abbott Gmbh & Co. Kg | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-4-on-Derivate, ihre Herstellung und Verwendung |
| US20050222175A1 (en) * | 2004-03-31 | 2005-10-06 | Dhanoa Dale S | New piperidinylamino-thieno[2,3-D] pyrimidine compounds |
| US7612078B2 (en) * | 2003-03-31 | 2009-11-03 | Epix Delaware, Inc. | Piperidinylamino-thieno[2,3-D] pyrimidine compounds |
| BRPI0408988A (pt) * | 2003-03-31 | 2006-03-28 | Predix Pharmaceuticals Holding | composto de piperidinilamino-tieno[2,3-d]pirimidina |
| US7488736B2 (en) * | 2004-05-17 | 2009-02-10 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
| US7598265B2 (en) * | 2004-09-30 | 2009-10-06 | Epix Delaware, Inc. | Compositions and methods for treating CNS disorders |
| US7407966B2 (en) * | 2004-10-07 | 2008-08-05 | Epix Delaware, Inc. | Thienopyridinone compounds and methods of treatment |
| US7576211B2 (en) * | 2004-09-30 | 2009-08-18 | Epix Delaware, Inc. | Synthesis of thienopyridinone compounds and related intermediates |
| US8349850B2 (en) | 2006-03-28 | 2013-01-08 | Atir Holding S.A. | Heterocyclic compounds and uses thereof in the treatment of sexual disorders |
| EP2896624B1 (en) * | 2007-03-28 | 2016-07-13 | Atir Holding S.A. | Heterotricyclic compounds as serotonergic and/or dopaminergic agents and uses thereof |
| WO2008138126A1 (en) * | 2007-05-09 | 2008-11-20 | Neuromed Pharmaceuticals Ltd. | Bicyclic pyrimidine derivatives as calcium channel blockers |
| US8114894B2 (en) * | 2008-12-03 | 2012-02-14 | Nanotherapeutics, Inc. | Bicyclic compounds and methods of making and using same |
| WO2011024873A1 (ja) * | 2009-08-26 | 2011-03-03 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
| CA2832822A1 (en) | 2011-04-10 | 2012-10-18 | Atir Holding S.A. | Heterocyclic compounds and uses thereof in the treatment of sexual disorders |
| US9671052B2 (en) | 2015-10-27 | 2017-06-06 | Whirlpool Corporation | Collet securing device for joining two fluid lines and providing lateral support at the connection of the two fluid lines |
| US10557469B2 (en) | 2016-03-22 | 2020-02-11 | Whirlpool Corporation | Multi-outlet fluid flow system for an appliance incorporating a bi-directional motor |
| US10655266B2 (en) | 2016-11-30 | 2020-05-19 | Whirlpool Corporation | Lint processing fluid pump for a laundry appliance |
| US10619289B2 (en) | 2017-02-27 | 2020-04-14 | Whirlpool Corporation | Self cleaning diverter valve |
| US10662574B2 (en) | 2017-02-27 | 2020-05-26 | Whirlpool Corporation | Self cleaning heater exchanger plate |
| US10480117B2 (en) | 2017-02-27 | 2019-11-19 | Whirlpool Corporation | Self cleaning sump cover |
| US10634412B2 (en) | 2017-04-10 | 2020-04-28 | Whirlpool Corporation | Concealed upstream air tower guide vanes |
| WO2020183011A1 (en) | 2019-03-14 | 2020-09-17 | Institut Curie | Htr1d inhibitors and uses thereof in the treatment of cancer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5001130A (en) * | 1988-02-18 | 1991-03-19 | Bristol-Myers Company | Psychotropic heterobicycloalkylpiperazine derivatives |
| US4835157A (en) * | 1988-03-15 | 1989-05-30 | Ortho Pharmaceutical Corporation | Thieno- and furopyrimidine-2,4-dione piperidine derivatives as serotonin antagonists and alpha adrenergic blocking agents |
| DE19636769A1 (de) * | 1996-09-10 | 1998-03-12 | Basf Ag | 3-Substituierte Pyrido [4',3':4,5]thieno[2,3-d]pyrimidin-Derivate, ihre Herstellung und Verwendung |
-
1997
- 1997-06-13 DE DE19724980A patent/DE19724980A1/de not_active Withdrawn
-
1998
- 1998-05-28 ID IDW991496A patent/ID23421A/id unknown
- 1998-05-29 JP JP50145899A patent/JP2002504103A/ja active Pending
- 1998-05-29 DE DE59808992T patent/DE59808992D1/de not_active Expired - Fee Related
- 1998-05-29 CN CN98806146A patent/CN1260797A/zh active Pending
- 1998-05-29 CA CA002293816A patent/CA2293816A1/en not_active Abandoned
- 1998-05-29 PL PL98337453A patent/PL337453A1/xx not_active Application Discontinuation
- 1998-05-29 TR TR1999/03062T patent/TR199903062T2/xx unknown
- 1998-05-29 US US09/445,222 patent/US6159962A/en not_active Expired - Lifetime
- 1998-05-29 KR KR1019997011711A patent/KR20010013696A/ko not_active Application Discontinuation
- 1998-05-29 CZ CZ19994431A patent/CZ290464B6/cs not_active IP Right Cessation
- 1998-05-29 WO PCT/EP1998/003230 patent/WO1998056792A1/de active IP Right Grant
- 1998-05-29 EP EP98929405A patent/EP0988306B1/de not_active Expired - Lifetime
- 1998-05-29 HU HU0002902A patent/HUP0002902A3/hu unknown
- 1998-05-29 AU AU79176/98A patent/AU749320B2/en not_active Ceased
- 1998-05-29 BR BR9810017-3A patent/BR9810017A/pt not_active IP Right Cessation
- 1998-05-29 AT AT98929405T patent/ATE244720T1/de not_active IP Right Cessation
- 1998-05-29 IL IL13296798A patent/IL132967A0/xx unknown
- 1998-05-29 NZ NZ502238A patent/NZ502238A/xx unknown
- 1998-05-29 SK SK1684-99A patent/SK168499A3/sk unknown
- 1998-06-11 AR ARP980102769A patent/AR015712A1/es not_active Application Discontinuation
- 1998-06-11 CO CO98033545A patent/CO4940507A1/es unknown
- 1998-06-12 HR HR19724980.9A patent/HRP980319A2/hr not_active Application Discontinuation
- 1998-06-12 ZA ZA9805121A patent/ZA985121B/xx unknown
-
1999
- 1999-11-17 BG BG103900A patent/BG103900A/xx unknown
- 1999-12-08 NO NO996043A patent/NO996043L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0002902A3 (en) | 2002-09-30 |
| EP0988306B1 (de) | 2003-07-09 |
| HUP0002902A2 (hu) | 2001-02-28 |
| BR9810017A (pt) | 2000-09-19 |
| CO4940507A1 (es) | 2000-07-24 |
| AR015712A1 (es) | 2001-05-16 |
| KR20010013696A (ko) | 2001-02-26 |
| BG103900A (en) | 2000-06-30 |
| NO996043D0 (no) | 1999-12-08 |
| AU7917698A (en) | 1998-12-30 |
| ID23421A (id) | 2000-04-20 |
| US6159962A (en) | 2000-12-12 |
| JP2002504103A (ja) | 2002-02-05 |
| CZ443199A3 (cs) | 2000-06-14 |
| EP0988306A1 (de) | 2000-03-29 |
| CN1260797A (zh) | 2000-07-19 |
| DE59808992D1 (de) | 2003-08-14 |
| NZ502238A (en) | 2001-02-23 |
| PL337453A1 (en) | 2000-08-14 |
| IL132967A0 (en) | 2001-03-19 |
| ATE244720T1 (de) | 2003-07-15 |
| WO1998056792A1 (de) | 1998-12-17 |
| TR199903062T2 (xx) | 2000-06-21 |
| ZA985121B (en) | 1999-12-13 |
| SK168499A3 (en) | 2000-05-16 |
| AU749320B2 (en) | 2002-06-20 |
| CA2293816A1 (en) | 1998-12-17 |
| CZ290464B6 (cs) | 2002-07-17 |
| DE19724980A1 (de) | 1998-12-17 |
| NO996043L (no) | 1999-12-08 |
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