ME00129B - Triciklicnj benzodiazepini kao antagonisti receptora vazopresina - Google Patents
Triciklicnj benzodiazepini kao antagonisti receptora vazopresinaInfo
- Publication number
- ME00129B ME00129B MEP-2008-178A MEP17808A ME00129B ME 00129 B ME00129 B ME 00129B ME P17808 A MEP17808 A ME P17808A ME 00129 B ME00129 B ME 00129B
- Authority
- ME
- Montenegro
- Prior art keywords
- phenyl
- benzodiazepine
- benzamide
- tetrahydro
- carbonyl
- Prior art date
Links
- 229940049706 benzodiazepine Drugs 0.000 title abstract 3
- 150000001557 benzodiazepines Chemical class 0.000 title abstract 3
- 239000002536 vasopressin receptor antagonist Substances 0.000 title abstract 2
- 206010019280 Heart failures Diseases 0.000 claims abstract 9
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract 5
- 206010003225 Arteriospasm coronary Diseases 0.000 claims abstract 3
- 208000003890 Coronary Vasospasm Diseases 0.000 claims abstract 3
- 206010020772 Hypertension Diseases 0.000 claims abstract 3
- 208000007536 Thrombosis Diseases 0.000 claims abstract 3
- 206010047163 Vasospasm Diseases 0.000 claims abstract 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract 3
- 201000011634 coronary artery vasospasm Diseases 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims abstract 3
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract 3
- 206010016654 Fibrosis Diseases 0.000 claims abstract 2
- 230000007882 cirrhosis Effects 0.000 claims abstract 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 90
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 55
- 125000000217 alkyl group Chemical group 0.000 claims 18
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 15
- 150000001875 compounds Chemical class 0.000 claims 15
- 229910052736 halogen Inorganic materials 0.000 claims 14
- 150000002367 halogens Chemical group 0.000 claims 14
- 125000003118 aryl group Chemical group 0.000 claims 13
- 125000001424 substituent group Chemical group 0.000 claims 13
- 125000003545 alkoxy group Chemical group 0.000 claims 12
- 229910052739 hydrogen Inorganic materials 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 10
- 229910052731 fluorine Inorganic materials 0.000 claims 10
- 239000011737 fluorine Substances 0.000 claims 10
- 150000002431 hydrogen Chemical group 0.000 claims 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 8
- 150000003839 salts Chemical class 0.000 claims 7
- -1 cyano, hydroxy, amino Chemical group 0.000 claims 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 5
- 150000001336 alkenes Chemical class 0.000 claims 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 229910052801 chlorine Inorganic materials 0.000 claims 4
- 239000000460 chlorine Substances 0.000 claims 4
- 239000003814 drug Substances 0.000 claims 4
- 125000001624 naphthyl group Chemical group 0.000 claims 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 4
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 125000005842 heteroatom Chemical group 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 229910052717 sulfur Inorganic materials 0.000 claims 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- 201000006474 Brain Ischemia Diseases 0.000 claims 2
- 206010048962 Brain oedema Diseases 0.000 claims 2
- 206010016807 Fluid retention Diseases 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 208000001647 Renal Insufficiency Diseases 0.000 claims 2
- 208000006011 Stroke Diseases 0.000 claims 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 2
- 208000006752 brain edema Diseases 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 201000006370 kidney failure Diseases 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- 206010030113 Oedema Diseases 0.000 abstract 1
- 206010062237 Renal impairment Diseases 0.000 abstract 1
- 208000028867 ischemia Diseases 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 230000002792 vascular Effects 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Ovaj pronalazak se odnosi na triciklične benzodiazepine koji su korisni kao antagonisti receptora vazopresina prilikom tretiranja stanja koja obuhvataju povećanu vaskulamu rezistenciju i srčanu insuficijenciju. Opisani su takođe farmaceutski preparati koji sadrže triciklične benzodiazepine iz ovog pronalaska i postupci za tretiranje stanja kao što su hipertenzija, kongestivna srčana smetnja, srčana insuficijencija, koronarni vazospazam, srčana ishemija, ciroza jetre, bubrežni vazospazam, bubrežna smetnja, edem i ishemija mozga, moždani udar, tromboza ili retencija vode.
Claims (18)
1. Jedinjenje formule (I) ili (II): naznačeno time, što su m je ceo broj od 1 do 2, uz uslov da ako je m 1 ili 2, da je tada ”Het” u jedinjenju formule (II) stabilan peto- ili šesto-člani monociklični aromatični prstenasti sistem, sačinjen od atoma ugljenika i jednog heteroatoma, gde se heteroatom bira između N, O ili S, koji može biti spojen sa bilo kojim heteroatomom ili atomom ugljenika, a pri tome je nastali prstenasti sistem stabilan; A se bira iz grupe koju čine -C(O)-, S02 ili CH2; Y se bira iz grupe koju čine CH2 ili CH kao deo olefina; X se bira iz grupe koju čine CH2, CH kao deo olefina, NR3, S ili O; pod uslovom da ukoliko Y predstavlja CH kao deo olefina, tada X predstavlja CH kao deo olefina; Z se bira iz grupe koju čine N ili CH; R1 se bira iz grupe koju čine vodonik, alkil, alkoksi, halogen, aminoalkil ili nitro; Ar se bira između naftil, pri čemu je naftil opciono supstituisan sa jedan do tri supstituenta koji se nezavisno biraju između C1-C8salkil, C1-C8alkoksi, fluorovani C1-C8alkil, fluorovani C1-C8alkoksi, halogen, cijano, hidroksi, amino, nitro, C1-C4 alkilamino, C1-C4dialkilamino, pri čemu alkil grupe mogu biti iste ili različite; ili fenil, pri čemu je fenil opciono supstituisan sa jedan do tri supstituenta koji se nezavisno biraju između C1-C8alkil, C1-C8alkoksi, fluorovani C1-C8alkil, fluorovani C1-C8alkoksi, C1-C8aralkil (gde su opciono alkil ili aril delovi nezavisno supstituisani, stim da alkil deo može biti supstituisan sa najmanje jednim fluorom i/ili da aril deo može nezavisno biti supstituisan sa jedan do dva supstituenta koji se biraju između halogen, C1-C4alkil, C1-C6alkiltio ili hidroksil), C1-C8aralkoksi, gde su opciono alkoksi ili aril delovi nezavisno supstituisani, stim da alkoksi deo može biti supstituisan sa najmanje jednim fluorom i/ili da aril deo može nezavisno biti supstituisan sa jedan do dva supstituenta koji se biraju između halogen, C1-C4alkil, C1-C6alkiltio ili hidroksil), halogen, cijano, hidroksi, amino, nitro, C1-C8 alkilamino, C1-C4alkilamino (gde alkil grupe mogu biti iste ili različite), C1-C8 alkilsulfonil, C1-C8alkiltio, C1-C8alkilsulfinil, hetroaril, drugi fenil (gde je drugi fenil opciono supstiuisan sa jedan do dva supstituenta koji se nezavisno biraju između C1-C4alkil, C1-C4alkoksi, fluorovani C1-C4alkil, fluorovani C1-C4alkoksi, halogen, cijano, hidroksi, amino, nitro, C1-C4alkilamino, C1-C4alkilamino (gde alkil grupe mogu biti iste ili različite), C1-C4alkilsulfonil, C1-C4alkiltio ili C1-C4alkilsulfinil; R2 se bira iz grupe koju čine NR4COAr, NR4CO-heteroaril, NR4Ar, CH=CH-Ar, CF=CH-Ar, CH=CF-Ar, CCI=CH-Ar, CH=CCI-Ar, CH=CH-heteroaril, CF=CH-heteroaril, CH=CF-heteroaril, -CCI=CH-heteroaril, CH=CCI-heteroaril, OCH2-Ar, OCH2-heteroaril, SCH2-Ar ili NR4CH2Ar; R3 se bira iz grupe koju čine vodonik, acil, alkii, alkoksikarbonil, alkilsuffonil i arilsulfonil; R4 se bira iz grupe koju čine vodonik ili C1-C4aikil; R5 se bira iz grupe koju čine vodonik, C1-C4alkil, C1-C4 alkoksi, hlor, fluor, hidroksi, dialkilamino (gde alkii grupe mogu biti iste ili različite), trifluorometil i trifluorometoksi; i njihove farmaceutski prihvatljive soli.
2. Jedinjenje prema Zahtevu 1, naznačeno time, što se ”Het” bira iz grupe koju čine tiofen, furan, pirol i piridin; A predstavlja -C(O)-; Ar je naftil, pri čemu je naftil opciono supstituisan sa jednim do tri supstituenta koji se nezavisno biraju između trifluorometil, trifluorometoksi, -NH-C1-C4alkil ili -N-(C1-C4alkil)2 (gde alkil grupe mogu biti iste ili različite); R2 je NR4COAr; R4 se bira iz grupe koju čine vodonik i metil; i njegove farmaceutski prihvatljive soli.
3. Jedinjenje prema Zahtevu 1, naznačeno time, što R4 predstavlja vodonik; i njegove farmaceutski prihvatljive soli.
4. Jedinjenje prema Zahtevu 1, naznačeno time, što ima formulu (III): gde se R1 bira iz grupe koju čine vodonik, CrC4alkil, CrC4alkoksi, halogen amino C1-C4alkil i nitro; R2 je NHCOAr; R3 se bira iz grupe koju čine vodonik, acil, C1-C4alkil, C1-C4alkilsutfonil i arilsulfonil; R5 se bira iz grupe koju čine vodoni, C1-C4alkil, C1-C4alkoksi, hlor, fluor, trifluorometil i trifluorometoksi; i njegove farmaceutski prihvatjive soli.
5. Jedinjenje prema Zahtevu 4, naznačeno time, što se X bira između CH2, CH kao dela olefina, O ili S; Z je CH; Ar je fenil, pri čemu je fenil opciono supstituisan sa jedan do tri supstituenta koji se nezavisno biraju između C1-C8 alkil, C1-C8alkoksi, fluorovani C1-C8alkil, fluorovani C1-C8alkoksi, C1-C8aralkil (gde su opciono alkil ili aril delovi nezavisno supstituisani, s tim da alkil deo može biti supstituisan sa najmanje jednim fluorom i/ili da aril deo može nezavisno biti supstituisan sa jedan do dva supstituenta koji se biraju između halogen, C1-C4alkil, C1-C8alkiltio ili hidroksil), C1-C8aralkoksi, gde su opciono alkoksi ili aril delovi nezavisno supstituisani , stim da alkoksi deo može biti supstituisan sa najmanje jednim fluorom i/ili da aril deo može nezavisno biti supstituisan sa jedan do dva supstituenta koji se biraju između halogen, C1-C4alkil, C1-C6alkiltio ili hidroksil), halogen, cijano, hidroksi, amino, nitro, C1-C8 alkilamino, C1-C8 dialkilamino (gde alkil grupe mogu biti iste ili različite), C1-C8 alkilsulfonil, C1-C8alkiltio, C1-C8alkilsulfinil, hetroaril, drugi fenil (gde je drugi fenil opciono supstiuisan sa jedan do dva supstituenta koji se nezavisno biraju između C1-C4alkil, C1-C4alkoksi, fluorovani C1-C4 alkil, fluorovani C1-C4alkoksi, halogen, cijano, hidroksi, amino, nitro, C1-C4 alkilamino, C1-C4dialkilamino (gde alkil grupe mogu biti iste ili različite), C1-C4alkilsulfonil, C1-C4alkiltio ili C1-C4 alkilsulfinil; i njegove farmaceutski prihvatljive soli.
6. Jedinjenje formule (IV): naznačeno time, što R1 se bira iz grupe koju čine vodonik, C1-C4alkil, C1-C4alkoksi, halogen, amino C1-C4alkil i nitro; R5 se bira iz grupe koju čine vodonik, C1-C4alkil, C1-C4alkoksi, hlor, fluor, trifluorometil i trifluorometoksi; R6 se bira iz grupe koju čine fenil (gde je fenil opciono supstituisan sa jedan do dva supstituenta koji se nezavisno biraju između C1-C4alkil, C1-C4 alkoksi, fluorovani C1-C4alkil, fluorovani alkoksi, halogen, cijano, hidroksi, amino, nitro, C1-C4alkilamino, C1-C4dialkilamino (gde alkil grupe mogu biti iste ili različite), C1-C4alkilsulfonil, C1-C4alkiltio ili C1-C4alkilsulfinil); aralkil (gde su gde su opciono alkil ili aril delovi nezavisno supstituisani, stim da alkil deo može biti supstituisan sa najmanje jednim fluorom i/iii da aril deo može nezavisno biti supstituisan sa jedan do dva supstituenta koji se biraju između halogen, C1-C4alkil, C1-C4alkiltio ili hidroksil), i aralkoksi (gde su opciono alkoksi ili aril delovi nezavisno supstituisani, stim da alkoksi deo može biti supstituisan sa najmanje jednim fluorom i/ili da aril deo može nezavisno biti supstituisan sa jedan do dva supstituenta koji se biraju između halogen, C1-C4 alkil, C1-C6alkiltio ili hidroksil); i R7 se nezavisno bira iz grupe koju čine vodonik, fluor, hlor, hidroksil, C1-C6alkil, C1-C6alkoksi i njihove kombinacije, gde R7 predstavlja jednu do četiri grupe koje se nezavisno biraju; i njegove farmaceutski prihvatljive soli.
7. Jedinjenje prema Zahtevu 1, naznačeno time, što se bira iz grupe koju čine: 10-[4-[[(2-bifenil)karbonil]amino]benzoil]-10,11 -dihidro-5H-piperidino[2,1 -c][1,4]benzodiazepin; 10-[4-[[(2-bifenil)karbonil]amino]benzoil]-10,11 -dihidro-5H-(tetrahidropiridino)[2,1-c][1,4]benzodiazepin; (R,S)-2-fenil-N-[4-(1,3,4,12a-tetrahidro-6/-/-[1,4]tiazino[4,3-a][1,4]-benzodiazepin-11 (12H-il-karbonil)fenil]benzamid; (S)-2-fenil-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1,4]oksazino[4,3-a][1,4]-benzodiazepin-11 (12/-0-il-karbonil)fenil]benzamid; (S)-2-(4-hidroksifenil)-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (S)-2-fenil-4-hidroksi-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (S)-2-(3-hidroksifenil)-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (S)-2-fenil-5-hidroksi-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-(4-metil-tienil)-4-fluoro-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2,6-dimetil-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2,3<iimetil-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (RS)-2-(4-metil-fenil)-N-[4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R)-2-fenil-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[3-metoksi-4-(1,3,4,12a-tetrahidro-6H-[1t4]oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[2-metoksi-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2,3,4,5-tetrafluoro-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-hloro-5-trifluorometil-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-fluoro-3-hloro-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R, S)-2-(difluorometiltio)-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R, S)-2-fenil-N-[4-(1,3,4,12a-tetrahidro-6 H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[3-hloro^-(1,3,4,12a-tetrahidro-6R-[1,4]oksazino[4,3-a][1,4]-5-okso-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[2-hidroksi-4-(1,3,4,12a-tetrahidro-6H- [1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[3-hidroksi-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-metil-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6R-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12R)-il-karbonil)fenil]benzamid; (R, S)-2-(4-metil-fenil)-N-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karboni!)fenil]benzamid; (R, S)-2-metil-N-[4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-metil-N-[3-metil-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-(4-metil-fenil)-N-[3-metil-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[3-metil-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-(4-metil-fenil)-N-[3-fluoro-4-(1,3,4,12a-tetrahidro-6H-[1.4] oksazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R, S)-2-fenil-N-[4-(8-metoksi-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid, (R;S)-2-fenil-N-[4-(8-fluoro-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R, S)-2-fenil-N-[4-(8,9-dimetoksi-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[4-(9-hloro-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid, (R,S)-2-fenil-N-[4-(8,9-difluoro-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[4-(8-metil-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[4-(8-hloro-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[3-hloro-4-(8-fluoro-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R, S)-2-fenil-N-[4-(10-metil-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-fenil-N-[4-(10-metoksi-1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-3,5-dimetil-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; (R,S)-2-jodo-3-metil-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11(12H)-il-karbonil)fenil]benzamid; (R,S)-3,5-dihloro-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11(12/-/)-il-karbonil)fenil]benzamid; (R,S)-2-metil-3-jodo-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11(12^-il-karbonil)fenil]benzamid; (/R,S)-2-fluorofenil-A/-[4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12/-/)-il-karbonil)fenil]benzamid; (S)-2-fenil-A/-[3-dimetilamino-4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12/-/)-il-karbonil)fenil]benzamid; (S)-2-fenil-A/-[3-hloro-4-(1,3,4,12a-tetrahidro-6H-[1.4] tiazino[4,3-a][1,4]-benzodiazepin-11 (12H)-il-karbonil)fenil]benzamid; i njihove farmaceutski prihvatljive soli.
8. Jedinjenje, naznačeno time, što ima formulu (V):
9. Jedinjenje, naznačeno time, štoima formulu (VI):
10. Farmaceutski preparat, naznačen time, što sadrži farmaceutski prihvatljiv nosač i jedinjenje prema Zahtevu 1.
11. Farmaceutski preparat, naznačen time, što se dobija mešanjem jedinjenja prema Zahtevu 1 i farmaceutski prihvatljivog nosača.
12. Farmaceutski preparat, naznačen time, što se dobija granuliranjem jedinjenja prema Zahtevu 1 i farmaceutski prihvatljivog nosača.
13. Upotreba jedinjenja prema Zahtevu 1 u postupku dobijanja leka za tretiranje hipertenzije, kongestivne srčane smetnje, srčane insuficijencije, koronarnog vazospazma, srčane ishemije, ciroze jetre, bubrežnog vazospazma, bubrežne smetnje, edema i ishemije mozga, moždanog udara, tromboze ili retencije vode.
14. Upotreba prema Zahtevu 13, što je pomenuti lek za tretiranje kongestivne srčane smetnje.
15. Upotreba prema Zahtevu 14, što je terapeutski efikasna količina jedinjenja od oko 0,1 do oko 300 mg/kg/dan.
16. Upotreba preparata prema Zahtevu 6 u postupku za dobijanje leka za tretiranje hipertenzije, kongestivne srčane smetnje, srčane insuficijencije, koronarnog vazospazma, srčane ishemije, ciroze jetre, bubrežnog vazospazma, bubrežne smetnje, edema i ishemije mozga, moždanog udara, tromboze ili retencije vode.
17. Upotreba prema zahtevu 16, što je pomenuti lek za tretiranje kongestivne srčane smetnje.
18. Upotreba prema Zahtevu 17, što je terapeutski efikasna količina jedinjenja oko 0,1 do oko 300 mg/kg/dan.
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| PCT/US1999/030423 WO2000043398A2 (en) | 1999-01-19 | 1999-12-21 | Tricyclic benzodiazepines as vasopressin receptor antagonists |
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| US3860600A (en) | 1972-07-10 | 1975-01-14 | Sterling Drug Inc | Octahydropyrrido{8 2,1-c{9 {8 1,4{9 benzodiazepines |
| US5516774A (en) * | 1993-07-29 | 1996-05-14 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
| US5521173A (en) * | 1995-01-17 | 1996-05-28 | American Home Products Corporation | Tricyclic benzazepine vasopressin antagonists |
| EP0987266A4 (en) | 1997-03-31 | 2000-07-26 | Wakamoto Pharma Co Ltd | BIPHENYL DERIVATIVES AND MEDICINAL COMPOSITIONS |
| CN1183134C (zh) * | 1997-07-30 | 2005-01-05 | 惠氏公司 | 三环后叶加压素激动剂 |
| ES2207333T7 (es) * | 1999-01-19 | 2009-06-18 | Orto-Mcneil Pharmaceutical, Inc. | Benzodiazepinas triciclicas utilizadas como antagonistas del receptor de la vasopresina. |
-
1999
- 1999-12-21 ES ES99966495T patent/ES2207333T7/es active Active
- 1999-12-21 WO PCT/US1999/030423 patent/WO2000043398A2/en not_active Ceased
- 1999-12-21 KR KR1020017009039A patent/KR100771184B1/ko not_active Expired - Fee Related
- 1999-12-21 DE DE69911259T patent/DE69911259T4/de not_active Expired - Lifetime
- 1999-12-21 HK HK02100064.9A patent/HK1038361B/en not_active IP Right Cessation
- 1999-12-21 BR BRPI9917086A patent/BRPI9917086B8/pt not_active IP Right Cessation
- 1999-12-21 TR TR2001/02069T patent/TR200102069T2/xx unknown
- 1999-12-21 ME MEP-2008-178A patent/ME00129B/me unknown
- 1999-12-21 PT PT99966495T patent/PT1147115E/pt unknown
- 1999-12-21 HU HU0105034A patent/HU229074B1/hu not_active IP Right Cessation
- 1999-12-21 CA CA002360767A patent/CA2360767C/en not_active Expired - Fee Related
- 1999-12-21 AU AU22014/00A patent/AU772397B2/en not_active Ceased
- 1999-12-21 IL IL14427099A patent/IL144270A0/xx unknown
- 1999-12-21 CN CNB998164887A patent/CN1174986C/zh not_active Expired - Fee Related
- 1999-12-21 UA UA2001075136A patent/UA70984C2/uk unknown
- 1999-12-21 CZ CZ20012598A patent/CZ302647B6/cs not_active IP Right Cessation
- 1999-12-21 AT AT99966495T patent/ATE249465T1/de active
- 1999-12-21 EP EP99966495A patent/EP1147115B3/en not_active Expired - Lifetime
- 1999-12-21 DK DK99966495T patent/DK1147115T5/da active
- 1999-12-21 DE DE69911259A patent/DE69911259D1/de not_active Expired - Lifetime
- 1999-12-21 PL PL349778A patent/PL205704B1/pl unknown
- 1999-12-21 NZ NZ512960A patent/NZ512960A/en not_active IP Right Cessation
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2000
- 2000-01-18 AR ARP000100214A patent/AR035837A1/es active IP Right Grant
- 2000-01-19 MY MYPI20000169A patent/MY128065A/en unknown
- 2000-02-24 TW TW089100772A patent/TWI289564B/zh not_active IP Right Cessation
- 2000-12-21 RS YUP-519/01A patent/RS50820B/sr unknown
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2001
- 2001-07-11 IL IL144270A patent/IL144270A/en not_active IP Right Cessation
- 2001-07-16 NO NO20013515A patent/NO327896B1/no not_active IP Right Cessation
- 2001-07-24 US US09/911,605 patent/US6713475B2/en not_active Expired - Lifetime
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2004
- 2004-02-10 US US10/775,675 patent/US7317005B2/en not_active Expired - Fee Related
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