HRP20110626T1 - Derivati benzotiazepina i njihova uporaba kao modulatora ampa i nmda receptora - Google Patents
Derivati benzotiazepina i njihova uporaba kao modulatora ampa i nmda receptora Download PDFInfo
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- HRP20110626T1 HRP20110626T1 HR20110626T HRP20110626T HRP20110626T1 HR P20110626 T1 HRP20110626 T1 HR P20110626T1 HR 20110626 T HR20110626 T HR 20110626T HR P20110626 T HRP20110626 T HR P20110626T HR P20110626 T1 HRP20110626 T1 HR P20110626T1
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- 102000003678 AMPA Receptors Human genes 0.000 title claims 2
- 108090000078 AMPA Receptors Proteins 0.000 title claims 2
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-N 0.000 title 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 title 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 title 1
- 150000007657 benzothiazepines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 17
- 125000005843 halogen group Chemical group 0.000 claims abstract 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract 6
- 125000003277 amino group Chemical group 0.000 claims abstract 5
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims abstract 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract 2
- -1 N-methylaminocarbonyl group Chemical group 0.000 claims 5
- 230000029936 alkylation Effects 0.000 claims 5
- 238000005804 alkylation reaction Methods 0.000 claims 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 4
- 229940100198 alkylating agent Drugs 0.000 claims 4
- 239000002168 alkylating agent Substances 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- 206010012289 Dementia Diseases 0.000 claims 2
- 239000004327 boric acid Substances 0.000 claims 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 230000004770 neurodegeneration Effects 0.000 claims 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims 2
- 230000003287 optical effect Effects 0.000 claims 2
- 238000000926 separation method Methods 0.000 claims 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- BZMMRNKDONDVIB-UHFFFAOYSA-N (1-ethoxycyclopropyl)oxy-trimethylsilane Chemical compound CCOC1(O[Si](C)(C)C)CC1 BZMMRNKDONDVIB-UHFFFAOYSA-N 0.000 claims 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 claims 1
- RTBXJPBWBIMMQZ-UHFFFAOYSA-N 3-[(1,1-dioxo-2,3,4,5-tetrahydro-1$l^{6},2,5-benzothiadiazepin-8-yl)oxy]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(OC=2C=C3S(=O)(=O)NCCNC3=CC=2)=C1 RTBXJPBWBIMMQZ-UHFFFAOYSA-N 0.000 claims 1
- DQGDFFMFRHJVHJ-UHFFFAOYSA-N 3-[(1,1-dioxo-2,3,4,5-tetrahydro-1$l^{6},2,5-benzothiadiazepin-8-yl)oxy]benzoic acid Chemical compound OC(=O)C1=CC=CC(OC=2C=C3S(=O)(=O)NCCNC3=CC=2)=C1 DQGDFFMFRHJVHJ-UHFFFAOYSA-N 0.000 claims 1
- ONLLJIGRRWECRE-UHFFFAOYSA-N 4-[(1,1-dioxo-2,3,4,5-tetrahydro-1$l^{6},2,5-benzothiadiazepin-8-yl)oxy]aniline Chemical compound C1=CC(N)=CC=C1OC1=CC=C(NCCNS2(=O)=O)C2=C1 ONLLJIGRRWECRE-UHFFFAOYSA-N 0.000 claims 1
- JKOKNPWVNITDHQ-UHFFFAOYSA-N 4-[(1,1-dioxo-2,3,4,5-tetrahydro-1$l^{6},2,5-benzothiadiazepin-8-yl)oxy]phenol Chemical compound C1=CC(O)=CC=C1OC1=CC=C(NCCNS2(=O)=O)C2=C1 JKOKNPWVNITDHQ-UHFFFAOYSA-N 0.000 claims 1
- WNYVYGICYQDPFZ-UHFFFAOYSA-N 4-[(5-methyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,5-benzothiadiazepin-8-yl)oxy]phenol Chemical compound C=1C=C2N(C)CCNS(=O)(=O)C2=CC=1OC1=CC=C(O)C=C1 WNYVYGICYQDPFZ-UHFFFAOYSA-N 0.000 claims 1
- WMTZBQNPKULSHB-UHFFFAOYSA-N 8-phenoxy-2,3,4,5-tetrahydro-1$l^{6},2,5-benzothiadiazepine 1,1-dioxide Chemical compound C1=C2S(=O)(=O)NCCNC2=CC=C1OC1=CC=CC=C1 WMTZBQNPKULSHB-UHFFFAOYSA-N 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 208000019901 Anxiety disease Diseases 0.000 claims 1
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 1
- 208000023105 Huntington disease Diseases 0.000 claims 1
- 208000006264 Korsakoff syndrome Diseases 0.000 claims 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims 1
- 201000004810 Vascular dementia Diseases 0.000 claims 1
- NGXPOGBRTZWTBL-UHFFFAOYSA-N [3-[(1,1-dioxo-2,3,4,5-tetrahydro-1$l^{6},2,5-benzothiadiazepin-8-yl)oxy]phenyl]methanol Chemical compound OCC1=CC=CC(OC=2C=C3S(=O)(=O)NCCNC3=CC=2)=C1 NGXPOGBRTZWTBL-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 230000002490 cerebral effect Effects 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 230000003001 depressive effect Effects 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 206010015037 epilepsy Diseases 0.000 claims 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- 210000001652 frontal lobe Anatomy 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- KDGKTJGPFXIBEB-UHFFFAOYSA-N n-hydroxyformamide Chemical group ONC=O KDGKTJGPFXIBEB-UHFFFAOYSA-N 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000000750 progressive effect Effects 0.000 claims 1
- 238000006268 reductive amination reaction Methods 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 201000000980 schizophrenia Diseases 0.000 claims 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims 1
- 230000002739 subcortical effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/36—Seven-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- 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
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- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- 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
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- A61P25/16—Anti-Parkinson drugs
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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Abstract
Spojevi formule (I): naznačeni time, da: - R1 i R2, koji mogu biti jednaki ili različiti, svaki za sebe predstavlja atom vodika; atom halogena; ravnu ili razgrananu skupinu (C1-C6)alkil koja je nesupstituirana ili supstituirana s jednim ili više atoma halogena; ravnu ili razgrananu skupinu (C1-C6)alkoksi; ravnu ili razgrananu skupinu (C1-C6)alkiltio; ravnu ili razgrananu skupinu (C1-C6)alkoksikarbonil; karboksi skupinu; ravnu ili razgrananu skupinu (C1-C6)acil; hidroksi skupinu; ravnu ili razgrananu skupinu (C1-C6)hidroksialkil; cijano skupinu; nitro skupinu; amino skupinu koja je nesupstituirana ili supstituirana s jednom ili više ravnih ili razgrananih skupina (C1-C6)alkil; amino skupinu koja je supstituirana ravnom ili razgrananom skupinom (C1-C6)acil; aminokarbonilnu skupinu koja je nesupstituirana ili supstituirana s jednom ili više ravnih ili razgrananih skupina (C1-C6)alkil; aminosulfonilnom skupinom koja je nesupstituirana ili supstituirana s jednom ili više ravnih ili razgrananih skupina (C1-C6)alkil; skupinom (C1-C6)alkilsulfonilamino-(C1-C6)alkil u kojoj su alkilne skupine ravne ili razgranane; skupinu
Claims (11)
1. Spojevi formule (I):
[image]
naznačeni time, da:
- R1 i R2, koji mogu biti jednaki ili različiti, svaki za sebe predstavlja atom vodika; atom halogena; ravnu ili razgrananu skupinu (C1-C6)alkil koja je nesupstituirana ili supstituirana s jednim ili više atoma halogena; ravnu ili razgrananu skupinu (C1-C6)alkoksi; ravnu ili razgrananu skupinu (C1-C6)alkiltio; ravnu ili razgrananu skupinu (C1-C6)alkoksikarbonil; karboksi skupinu; ravnu ili razgrananu skupinu (C1-C6)acil; hidroksi skupinu; ravnu ili razgrananu skupinu (C1-C6)hidroksialkil; cijano skupinu; nitro skupinu; amino skupinu koja je nesupstituirana ili supstituirana s jednom ili više ravnih ili razgrananih skupina (C1-C6)alkil; amino skupinu koja je supstituirana ravnom ili razgrananom skupinom (C1-C6)acil; aminokarbonilnu skupinu koja je nesupstituirana ili supstituirana s jednom ili više ravnih ili razgrananih skupina (C1-C6)alkil; aminosulfonilnom skupinom koja je nesupstituirana ili supstituirana s jednom ili više ravnih ili razgrananih skupina (C1-C6)alkil; skupinom (C1-C6)alkilsulfonilamino-(C1-C6)alkil u kojoj su alkilne skupine ravne ili razgranane; skupinu N-hidroksikarboksamid ili skupinu benziloksi,
- R3 predstavlja atom vodika ili ravnu ili razgrananu skupinu (C1-C6)alkil, skupinu (C3-C8)cikloalkil ili skupinu (C3-C8)cikloalkil-(C1-C6)alkil u kojoj je alkilna skupina ravna ili razgranana,
- R4 predstavlja atom vodika ili ravnu ili razgrananu skupinu (C1-C6)alkil koja je nesupstituirana ili supstituirana s jednim ili više atoma halogena,
njihove optičke i pozicijske izomere te njihove adicijske soli s farmaceutski prihvatljivom kiselinom ili bazom.
2. Spojevi formule (I) u skladu s patentnim zahtjevom 1, naznačeni time, da skupina R1 predstavlja atom vodika ili hidroksi skupinu, hidroksimetilnu skupinu, etoksikarbonilnu skupinu, amino skupinu ili N-metilaminokarbonilnu skupinu.
3. Spojevi formule (I) u skladu bilo s patentnim zahtjevom 1 ili patentnim zahtjevom 2, naznačeni time, da je skupina R1 na meta ili para poziciji.
4. Spojevi formule (I) u skladu s bilo kojim patentnim zahtjevom 1 do 3, naznačeni time, da skupine R2 i R4 predstavljaju atome vodika.
5. Spojevi formule (I) u skladu s bilo kojim patentnim zahtjevom 1 do 4, naznačeni time, da skupina R3 predstavlja atom vodika ili metilnu skupinu.
6. Spojevi formule (I) u skladu s patentnim zahtjevom 1, naznačeni time, da su to spojevi:
• 8-fenoksi-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin 1,1-dioksid;
• 3-[(1,1-dioksido-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin-8-il)oksi]-benzoat;
• 3-[(1,1-dioksido-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin-8-il)oksi]-N-metil-benzamid;
• {3-[(1,1-dioksido-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin-8-il)oksi]fenil}-metanol;
• 4-[(1,1-dioksido-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin-8-il)oksi]fenol;
• 4-[(5-metil-l,l-dioksido-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin-8-il)oksi]-fenol;
• 4-[(1,1-dioksido-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin-8-il)oksi]anilin,
te njegove adicijske soli s farmaceutski prihvatljivom kiselinom ili bazom.
7. Postupak priprave spojeva formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da se kao početna tvar koristi spoj formule (II):
[image]
pri čemu R5 predstavlja ravnu ili razgrananu skupinu (C1-C6)alkoksi,
koja se izlaže reakciji s tionil kloridom u nazočnosti dimetilformamida , čime se dobiva spoj formule (III):
[image]
u kojem je R5 definirana jednako kao gore,
koji se zatim izlaže djelovanju spoja 2-kloretilamina u lužnatoj sredini, čime se dobiva spoj formule (IV):
[image]
u kojem je R5 definirana jednako kao gore,
koji se, nakon skidanja zaštite u kiseloj sredini, podvrgava cikliranju, čime se dobiva spoj formule (V):
[image]
u kojem je R5 definirana jednako kao gore,
koji se zatim izlaže djelovanju bor tribromida, čime se dobiva spoj formule (VI):
[image]
koji se podvrgava reakciji sa spojem borne kiseline formule (VII):
[image]
u kojem su R1 i R2 definirani kao u formuli (I),
čime se dobiva spoj formule (I/a), koji predstavlja poseban slučaj spojeva formule (I):
[image]
u kojem su R1 i R2 definirani jednako kao gore,
što predstavlja inačicu u postupku priprave spoja formule (I/a) koji se sastoji od uporabe-nakon stoje završen korak sprezanja sa spojem formule (VI) - uobičajenih kemijskih reakcija za naknadnu preinaku supstituenata spoja borne kiseline,
spoj formule (I/a), prema potrebi, može se podvrgnuti:
• bilo dvostrukoj alkilaciji na atomima dušika na pozicijama 2 i 5, djelovanjem jake baze u nazočnosti alkilacijskog sredstva R'-X, pri čemu R' predstavlja ravnu ili razgrananu skupinu (C1-C6)alkil, a X predstavlja atom halogena,
čime se dobiva spoj formule (I/b), koji predstavlja poseban slučaj spojeva formule (I):
[image]
u kojem su Ri, R2 i R' definirani jednako kao gore,
• ili alkilacijom na atomu dušika koji se nalazi na poziciji 2, djelovanjem baze u nazočnosti alkilacijskog sredstva R'4-X, pri čemu R'4 predstavlja ravnu ili razgrananu skupinu (C1-C6)alkil koja je nesupstituirana ili supstituirana s jednim ili više atoma halogena, a X predstavlja atom halogena,
čime se dobiva spoj formule (l/c), koji predstavlja poseban slučaj spojeva formule (I):
[image]
u kojem su R1, R2 i R'4 definirani jednako kao gore,
koji se po izboru može podvrgnuti alkilaciji na atomu dušika koji se nalazi na poziciji 5, djelovanjem baze u nazočnosti alkilacijskog sredstva R'3-X, pri čemu R'3 predstavlja ravnu ili razgrananu skupinu (C1-C6)alkil, skupinu (C3-C8)cikloalkil ili skupinu (C3-C8)cikloalkil-(C1-C6)alkil u kojoj je alkilni dio ravan ili razgranan, a X predstavlja atom halogena,
čime se dobiva spoj formule (I/d):
[image]
u kojem su Ri, R2, R'3 i R'4 definirani jednako kao gore,
• ili alternativno, alkilacijom na atomu dušika koji se nalazi na poziciji 5, putem reakcije reduktivne aminacije s redukcijskim sredstvom poput natrij triacetoksiborhidrida ili cijanoborhidrida u nazočnosti:
- bilo [(1-etoksiciklopropil)oksi]trimetilsilana,
- ili spoja formule(VIII):
R''3CHO (VIII),
u kojem R"3 predstavlja atom vodika ili ravnu ili razgrananu skupinu (C1-C5)alkil, skupinu (C3-C8)cikloalkil ili skupinu (C3-C8)cikloalkil-(C1-C5)alkil u kojoj je alkilni dio ravan ili razgranan,
- ili alternativno, spoja formule (IX):
[image]
u kojem 0 ≤ n ≤ 4, čime se dobiva spoj formule (I/e), koji predstavlja poseban slučaj spojeva formule (I):
[image]
u kojem R'"3 predstavlja ravnu ili razgrananu skupinu (C1-C6)alkil, skupinu (C3-C8)cikloalkil ili skupinu (C3-C8)cikloalkil-(C1-C6)alkil u kojoj je alkilni dio ravan ili razgranan, a R1 i R2 definirani su jednako kao gore,
koji se po izboru može podvrgnuti alkilaciji na atomu dušika koji se nalazi na poziciji 2, djelovanjem baze u nazočnosti alkilacijskog sredstva R"4-X, pri čemu R"4 predstavlja ravnu ili razgrananu skupinu (C1-C6)alkil koja je nesupstituirana ili supstituirana s jednim ili više atoma halogena, a X predstavlja atom halogena,
čime se dobiva spoj formule (I/f):
[image]
u kojem su R1, R2, R'''3 i R''4 definirani jednako kao gore,
spojevi formula (I/a) do (I/f), koji predstavljaju sve spojeve formule (I), mogu se zatim pročišćavati uobičajenom tehnikom razdvajanja, prema potrebi prevoditi u svoje adicijske soli s farmaceutski prihvatljivom kiselinom ili bazom te prema potrebi razdvajati, u svoje optičke i pozicijske izomere, ako takvi postoje, uobičajenim tehnikama razdvajanja.
8. Spoj formule (VI) u skladu s patentnim zahtjevom 7:
[image]
naznačen time, da se koristi kao međuspoj u sintezi spojeva formule (I).
9. Farmaceutski pripravci, naznačeni time, da kao djelatno sredstvo sadrže spoj u skladu s bilo kojim patentnim zahtjevom od 1 do 6, u kombinaciji s jednim ili više farmaceutski prihvatljivih, neotrovnih, inertnih nosača.
10. Farmaceutski pripravci u skladu s patentnim zahtjevom 9, naznačeni time, da se koriste za proizvodnju lijekova koji se koriste kao modulatori AMPA receptora i antagonisti NMDA receptora.
11. Farmaceutski pripravci u skladu s patentnim zahtjevom 9, naznačeni time, da se koriste za proizvodnju lijekova koji se koriste za liječenje ili prevenciju progresivnih neurodegenerativnih bolesti, Alzheimerove bolesti, Parkinsonove bolesti, Pickove bolesti, Huntingtonove koreje, Korsakoffljeve bolesti, shizofrenije, akutnih neurodegenerativnih bolesti, demencije frontalnog režnja i subkortikalne demencije, vaskularnih demencija, epilepsije, cerebralnih vaskularnih incidenata te depresivnih i anksioznih stanja.
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| FR0901300A FR2943342B1 (fr) | 2009-03-20 | 2009-03-20 | Nouveaux derives de benzothiadiazepines,leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
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| CA2774715C (en) | 2009-07-27 | 2018-04-03 | Gilead Sciences, Inc. | Fused heterocyclic compounds as ion channel modulators |
| CN103096977B (zh) | 2010-07-02 | 2017-02-15 | 吉利德科学公司 | 作为离子通道调节剂的稠杂环化合物 |
| PE20131116A1 (es) | 2010-08-10 | 2013-10-24 | Takeda Pharmaceutical | Compuestos heterociclicos potenciadores de ampa |
| CA2834164A1 (en) | 2011-05-10 | 2012-11-15 | Gilead Sciences, Inc. | Fused benzoxazinones as ion channel modulators |
| NO3175985T3 (hr) | 2011-07-01 | 2018-04-28 | ||
| AU2015224425B2 (en) * | 2011-07-01 | 2017-02-09 | Gilead Sciences, Inc. | Fused benzoxazepinones as ion channel modulators |
| TWI478908B (zh) * | 2011-07-01 | 2015-04-01 | Gilead Sciences Inc | 作為離子通道調節劑之稠合雜環化合物 |
| US9493484B2 (en) | 2012-02-08 | 2016-11-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compound and use thereof |
| CN111518055A (zh) * | 2020-05-16 | 2020-08-11 | 西安都创医药科技有限公司 | 一种苯并硫氮杂卓氧化物的制备方法及其制备的产品及其应用 |
| CN111548325A (zh) * | 2020-05-16 | 2020-08-18 | 西安都创医药科技有限公司 | 一种卤代苯并硫氮杂卓化合物的制备方法及其制备的产品及其应用 |
| CN111620838A (zh) * | 2020-05-16 | 2020-09-04 | 西安都创医药科技有限公司 | 一种氯代苯并硫氮杂卓化合物的制备方法及其制备的产品及其应用 |
| CN111574475B (zh) * | 2020-06-03 | 2022-09-20 | 西安都创医药科技有限公司 | 卤代苯并硫杂卓氧化物的制备方法及其制备的产品及其应用 |
| CN115368363B (zh) * | 2021-05-17 | 2024-02-20 | 中山大学 | 一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用 |
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| AU3957093A (en) * | 1992-04-15 | 1993-11-18 | Rhone-Poulenc Rorer S.A. | 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxyl ic acid derivatives, preparation thereof and drugs containing same |
| WO1999041246A1 (en) * | 1998-02-11 | 1999-08-19 | Du Pont Pharmaceuticals Company | Novel cyclic sulfonamide derivatives as metalloproteinase inhibitors |
| EP1071426A2 (en) * | 1998-02-18 | 2001-01-31 | Neurosearch A/S | Novel compounds and their use as positive ampa receptor modulators |
| US6156746A (en) * | 1998-08-25 | 2000-12-05 | Bristol-Myers Squibb Company | 1,2,5-benzothiadiazepine-1,1-dioxides with n-2 imidazolylalkyl substituents |
| GB0209467D0 (en) * | 2002-04-25 | 2002-06-05 | Astrazeneca Ab | Chemical compounds |
| DE10300973A1 (de) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Carbonsäuren und deren Ester, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| FR2877338B1 (fr) * | 2004-11-03 | 2007-01-26 | Servier Lab | Nouveaux derives de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR2879201B1 (fr) * | 2004-12-10 | 2007-02-16 | Servier Lab | Nouveaux derives de benzothiazine et benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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