ME02863B - 5 - benzilizokinolinski derivati za liječenje srčanožilnih bolesti - Google Patents
5 - benzilizokinolinski derivati za liječenje srčanožilnih bolestiInfo
- Publication number
- ME02863B ME02863B MEP-2017-288A MEP2017288A ME02863B ME 02863 B ME02863 B ME 02863B ME P2017288 A MEP2017288 A ME P2017288A ME 02863 B ME02863 B ME 02863B
- Authority
- ME
- Montenegro
- Prior art keywords
- group
- pharmaceutically acceptable
- hydrates
- acceptable acid
- addition salts
- Prior art date
Links
- RYZAQUJQYMCPNV-UHFFFAOYSA-N 5-benzylisoquinoline Chemical class C(C1=CC=CC=C1)C1=C2C=CN=CC2=CC=C1 RYZAQUJQYMCPNV-UHFFFAOYSA-N 0.000 title 1
- 208000024172 Cardiovascular disease Diseases 0.000 title 1
- 239000002253 acid Substances 0.000 claims 27
- 150000004677 hydrates Chemical class 0.000 claims 27
- 150000001875 compounds Chemical class 0.000 claims 26
- 150000003839 salts Chemical class 0.000 claims 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 22
- 230000003287 optical effect Effects 0.000 claims 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims 6
- 125000005843 halogen group Chemical group 0.000 claims 5
- 230000002265 prevention Effects 0.000 claims 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 3
- 230000015572 biosynthetic process Effects 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- 229910052757 nitrogen Inorganic materials 0.000 claims 3
- 230000008569 process Effects 0.000 claims 3
- 238000003786 synthesis reaction Methods 0.000 claims 3
- 230000009885 systemic effect Effects 0.000 claims 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- TWASBYPJZBHZQJ-UHFFFAOYSA-N 1-methylcyclopentan-1-amine Chemical compound CC1(N)CCCC1 TWASBYPJZBHZQJ-UHFFFAOYSA-N 0.000 claims 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 208000037849 arterial hypertension Diseases 0.000 claims 2
- 210000001367 artery Anatomy 0.000 claims 2
- -1 atom hydrogen Chemical class 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 2
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 claims 2
- IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 claims 2
- 238000006722 reduction reaction Methods 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- BHRVKIXDBWVUEH-UHFFFAOYSA-N 2-amino-n-cyclopentylacetamide Chemical compound NCC(=O)NC1CCCC1 BHRVKIXDBWVUEH-UHFFFAOYSA-N 0.000 claims 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 201000006474 Brain Ischemia Diseases 0.000 claims 1
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 206010008120 Cerebral ischaemia Diseases 0.000 claims 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims 1
- 208000010228 Erectile Dysfunction Diseases 0.000 claims 1
- 208000010412 Glaucoma Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 claims 1
- 206010022489 Insulin Resistance Diseases 0.000 claims 1
- 206010072877 Intestinal fibrosis Diseases 0.000 claims 1
- 206010023421 Kidney fibrosis Diseases 0.000 claims 1
- 102000016349 Myosin Light Chains Human genes 0.000 claims 1
- 108010067385 Myosin Light Chains Proteins 0.000 claims 1
- 208000011623 Obstructive Lung disease Diseases 0.000 claims 1
- 101150111584 RHOA gene Proteins 0.000 claims 1
- 208000034189 Sclerosis Diseases 0.000 claims 1
- 208000005392 Spasm Diseases 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 claims 1
- 230000004913 activation Effects 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 208000007474 aortic aneurysm Diseases 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 230000009787 cardiac fibrosis Effects 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 206010008118 cerebral infarction Diseases 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 208000033679 diabetic kidney disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010061989 glomerulosclerosis Diseases 0.000 claims 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims 1
- 150000002430 hydrocarbons Chemical group 0.000 claims 1
- 201000001421 hyperglycemia Diseases 0.000 claims 1
- 201000001881 impotence Diseases 0.000 claims 1
- 208000019423 liver disease Diseases 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 230000001575 pathological effect Effects 0.000 claims 1
- 230000007170 pathology Effects 0.000 claims 1
- 230000037361 pathway Effects 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- 230000026731 phosphorylation Effects 0.000 claims 1
- 238000006366 phosphorylation reaction Methods 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 208000005069 pulmonary fibrosis Diseases 0.000 claims 1
- 208000037803 restenosis Diseases 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- 239000010948 rhodium Substances 0.000 claims 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims 1
- 239000011435 rock Substances 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Reproductive Health (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
Claims (18)
1. Spoj formule (I) : naznačen time, da: - X predstavlja skupinu -C(=O), -CH(OH)- ili -CH2-, - Ri1 predstavlja atom vodika ili hidroksilnu skupinu, pri čemu se podrazumijeva da spoj formule (I) gdje Ri1 predstavlja hidroksilnu skupinu, može biti predstavljen sljedećim tautomeričkim oblikom: - Ri2 i Ri3, od kojih svaki može biti isti ili različit, svaki predstavlja atom vodika, (C1-C6)alkilnu skupinu ili atom halogena, - Ri6, Ri7 i Ri8, koji može biti isti ili različit, svaki predstavlja atom vodika ili atom halogena, - Ra1 i Ra5, koji može biti isti ili različit, svaki predstavlja atom vodika ili atom halogena, -O(C1-C6)alkilnu skupinu ili (C1-C6)alkilnu skupinu, - Ra2 predstavlja atom vodika ili halogena, hidroskilnu skupinu, -O(C1-C6)alkilnu skupinu, -(C1-C6)alkilnu skupinu, heterocikl koji ima od 3 do 7 članova prstena a sadrži dušik ili skupinu -O-(CH2)m-NR’R”, - Ra3 predstavlja atom vodika, -O(C1-C6)alkilnu skupinu, -( C1-C6)alkilnu skupinu, heterocikl koji ima od 3 do 7 članova prstena a sadrži dušik ili skupinu -CRy1Ry2NH(Ry3), - Ra4 predstavlja atom vodika ili halogena, -O(C1-C6)alkilnu skupinu, -(C1-C6)alkilnu skupinu ili skupinu -CRy1Ry2NH(Ry3), pri čemu se podrazumijeva da: • Ra1, Ra2, Ra3, Ra4 i Ra5 ne mogu istovremeno predstavljati vodikov atom, • Ra3 i Ra4 ne mogu istovremeno predstavljati skupinu -CRy1Ry2NH(Ry3), • Ra1 i Ra2 mogu zajedno s atomima ugljika koji ih nose tvoriti heterocikl koji ima od 4 do 7 članova prstena odabranog od tetrahidrofurana, 1,4-dioksana, tetrahidropirana, tetrahidro-2H-piran-4-amina i 1-(tetrahidro-2H-piran-4-il)metanamina i • Ra2 i Ra3 mogu zajedno s atomima ugljika koji ih nose tvoriti prsten ugljikovodika koji ima od 4 do 7 članova prstena koji je odabran od ciklopentana, ciklopentanamina, N-ciklopentilglicinamida i 1-metilciklopentanamina, - m je cijeli broj čija je vrijednost fiksirana na 1, 2 ili 3, - R’ i R’’, koji mogu biti isti ili različiti, svaki predstavljaju -( C1-C6)alkilnu skupinu ili zajedno s dušikovim atomom koji ih nosi tvore heterocikl koji ima od 3 do 7 članova prstena, - Ry1 predstavlja atom vodika, -(C1-C6)alkilnu skupinu, -CH2-cikloheksilnu skupinu ili 3-metoksifenilnu skupinu, - Ry2 predstavlja atom vodika ili -(C1-C6)alkilnu skupinu, - Ry3 predstavlja: • atom vodika, • skupinu -C(=O)-CHRy4-NHRy5 gdje Ry4 predstavlja atom vodika ili (C1-C6)alkilnu skupinu i Ry5 predstavlja atom vodika ili metilnu skupinu ili • -(C1-C6)alkilnu skupinu koja se može supstituirati hidroksilnom skupinom, -O(C1-C3)alkilnom skupinom, cikloheskilnom skupinom ili metilsulfonilnom skupinom, ili Ry1 i Ry2 zajedno s ugljikovim atomom koji ih nosi tvore skupinu ciklopropana, ciklobutana ili tetrahidropirana, ili Ry2 i Ry3 zajedno s ugljikovim i dušikovim atomima koji ih nose tvore, naime, skupinu pirolidina ili piperidina, njihove optičke izomere, gdje postoje i njihove adicijske soli s farmaceutski prihvatljivom kiselinom i hidratima istih.
2. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da X predstavlja skupinu -C(=O), njegove optičke izomere, gdje postoje i njihove adicijske soli s farmaceutski prihvatljivom kiselinom i hidratima istih.
3. Spoj formule (I) u skladu s patentnim zahtjevom 1 ili patentnim zahtjevom 2, naznačen time, da Ri1 predstavlja hidroksilnu skupinu, pri čemu je poznato da rečeni spoj može biti predstavljen u njegovom tautomeričkom obliku, optičkim izomerima, gdje postoje i njegovim adicijskim s farmaceutski prihvatljivom kiselinom i hidratima istih.
4. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time, da Ri2, Ri6, Ri7 i Ri8 svaki predstavlja atom vodika, njegove optičke izomere, gdje postoje i njihove adicijske soli s farmaceutski prihvatljivom kiselinom i hidratima istih.
5. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time, da Ra1 i Ra5 svaki predstavlja atom fluora, njegove optičke izomere, gdje postoje i njihove adicijske soli s farmaceutski prihvatljivom kiselinom i hidratima istih.
6. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time, da Ra3 ili Ra4 predstavlja skupinu -CRy1Ry2NH(Ry3), njegove optičke izomere, gdje postoje i njihove adicijske soli s farmaceutski prihvatljivom kiselinom i hidratima istih.
7.Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da: - Ry1 predstavlja atom vodika ili -(C1-C6)alkilnu skupinu, - Ry2 predstavlja -(C1-C6)alkilnu skupinu, - Ry3 predstavlja atom vodika, njegove optičke izomere, gdje postoje i njihove adicijske soli s farmaceutski prihvatljivom kiselinom i hidratima istih.
8. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da: - X predstavlja skupinu -C(=O)-, - Ri1 predstavlja atom vodika ili hidroskilnu skupinu, - Ri2, Ri6, Ri7 i Ri8 svaki predstavlja atom vodika i Ri3 predstavlja atom vodika ili (C1-C6)alkilnu skupinu, - Ra1 i Ra5, koji može biti isti ili različit, svaki predstavlja atom vodika ili fluora ili (C1-C6)alkilnu skupinu, - Ra2 predstavlja atom vodika ili -(C1-C6)alkilnu skupinu, - Ra3 predstavlja atom vodika, skupinu piperidina ili skupinu -CRy1Ry2NH(Ry3), - Ra4 predstavlja atom vodika ili skupinu -CRy1Ry2NH(Ry3), pri čemu se podrazumijeva da Ra3 i Ra4 ne mogu istovremeno predstavljati skupinu -CRy1Ry2NH(Ry3) te da: • kada Ra3 predstavlja skupinu -CRy1Ry2NH(Ry3), Ra1 i Ra2 zajedno s atomima ugljika koji ih nose mogu tvoriti skupinu tetrahidrofurana, 1,4-dioksana ili tetrahidropirana ili • kada Ra3 predstavlja atom atom vodika, Ra1 i Ra2 zajedno s atomima ugljika koji ih nose mogu tvoriti skupinu tetrahidro-2H-piran-4-amina ili 1-(tetrahidro-2H-piran-4-il)metanamina ili • Ra2 i Ra3 zajedno s atomima ugljika koji ih nose mogu tvoriti skupinu ciklopentanamina ili 1-metilciklopentanamina, - Ry1 predstavlja atom vodika, -(C1-C6)alkilnu skupinu ili -CH2-cikloheksilnu skupinu, - Ry2 predstavlja atom vodika ili -(C1-C6) alkilnu skupinu, - Ry3 predstavlja atom vodika ili -(C1-C6)alkilnu skupinu koji može biti supstituiran hidroskilnom skupinom, njihovim optičkim izomerima, gdje postoje i njihovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih.
9. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je odabran od: - [4-(1-aminoetil)-2,6-difluorfenil](izokinolin-5-il)metanonom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - [4-((1R)-1-aminoetil)-2,6-difluorfenil](izokinolin-5-il)metanonom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - [4-(1-aminoetil)-2,6-difluorfenil](1-hidroksiizokinolin-5-il)metanonom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 1-[3,5-difluoro-4-(izokinolin-5-ilmetil)fenil]etanaminom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - {4-[(1S)-1-aminoetil]-2,6-difluorfenil}(izokinolin-5-il)metanolom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - [4-(2-aminopropan-2-il)-2,6-difluorfenil](izokinolin-5-il)metanonom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-[4-(2-aminopropan-2-il)-2,6-difluorobenzoil]izokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-[4-(1-aminoetil)-2-fluoro-3-metoksibenzoil]izokinolin-1(2H)-onom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-({5-[(1R)-1-aminoetil]-3,4-dihidro-2H-kromen-8-il}karbonil)izokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-{4-[(1R)-1-aminoetil]-2-metilbenzoil}izokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-(2,6-difluoro-4-{1-[(2-hidroksietil)amino]etil}benzoil)izokinolin-1(2H)-onom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-{4-[(1R)-1-aminoetil]-2,6-difluorobenzoil}-4-metilizokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-{3-[(1R)-1-aminoetil]-2,6-difluorobenzoil}izokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-[(1-amino-4,6-difluoro-2,3-dihidro-1H-inden-5-il)karbonil]izokinolin-1(2H)-onom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-{[(3R)-3-amino-4,6-difluoro-2,3-dihidro-1H-inden-5-il]karbonil}izokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-({8-[(1R)-1-aminoetil]-2,3-dihidro-1,4-benzodioksin-5-il}karbonil)izokinolin-1(2H)-onom i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-[2,6-difluoro-4-(piperidin-2-il)benzoil]izokinolin-1(2H)-onom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-[4-(1-amino-2-cikloheksiletil)-2,6-difluorobenzoil]izokinolin-1(2H)-onom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih, - 5-{[4-(aminometil)-3,4-dihidro-2H-kromen-8-il]karbonil}izokinolin-1(2H)-onom i njegovim optičkim izomerima i njegovim adicijskim solima s farmaceutski prihvatljivom kiselinom i hidratima istih.
10. Postupak za sintezu spojeva formule (Ia), posebice u slučajevima spojeva formule (I) u skladu s patentnim zahtjevom 1 gdje X predstavlja skupinu -C(=O), naznačen time, da su spojevi formule (Ia) dobiveni počevši od spoja formule (II): koji se izlaže reakciji spajanja sa spojem formule (III): u nazočnosti katalizatora rodija ili paladija, fosfina i lužine u organskom otapalu kako bi se dobio spoj formule (Ia):
11. Postupak za sintezu spojeva formule (Ib), posebnih slučajeva spojeva formule (I) u skladu s patentnim zahtjevom 1 gdje X predstavlja skupinu -CH(OH)- : naznačen time, da su spojevi formule (Ib) dobiveni počevši od spojeva formule (Ia) u skladu s patentnim zahtjevom 10, uz pomoć redukcijske reakcije u nazočnosti natrijevog tetraborohidrida.
12. Postupak za sintezu spojeva formule (Ic), posebnih slučajeva spojeva formule (I) u skladu s patentnim zahtjevom 1 gdje X predstavlja skupinu -CH2- naznačen time, da su spojevi formule (Ic) dobiveni počevši od spojeva formule (Ib) u skladu s patentnim zahtjevom 11, uz pomoć redukcijske reakcije u nazočnosti trifluoroctene kiseline i trietilsilana.
13. Farmaceutski pripravak koji kao djelatni sastojak sadrži spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 9, naznačen time, da je u kombinaciji s jednim ili više inertnih, ne-toksičnih, farmaceutski prihvatljivih ekscipijensa ili nosača.
14. Farmaceutski pripravak u skladu s patentnim zahtjevom 13, naznačen time, da je za uporabu u liječenju ili sprječavanju patoloških stanja koji su posljedica aktiviranja RhoA/ROCK puta i fosforilacije lakog lanca miozina.
15. Farmaceutski pripravak za uporabu u skladu s patentnim zahtjevom 14, naznačen time, da se koristi u liječenju ili sprječavanju sistemske arterijske hipertenzije, plućne arterijske hipertenzije, angine, infarkta miokarda, restenoze postangioplastike, aortalnog aneurizma, okluzije perifernih arterija, ateroskleroze, srčane fibroze i zatajenja srca.
16. Farmaceutski pripravak za uporabu u skladu s patentnim zahtjevom 15, naznačen time, da se koristi u liječenju ili sprječavanju sistemske arterijske hipertenzije.
17. Farmaceutski pripravak za uporabu u skladu s patentnim zahtjevom 14, naznačen time, se koristi u liječenju ili sprječavanju glaukoma i patologije rožnice.
18. Farmaceutski pripravak za uporabu u skladu s patentnim zahtjevom 14, naznačen time, da se koristi u liječenju ili sprječavanju erektilne disfunkcije, opstruktivne plućne bolesti, post-radijacijske crijevne fibroze, sistemske kožne skleroze, plućne fibroze povezane s plućnom arterijskom hipertenzijom, bolesti jetre, fibroze bubrega i glomerularne skleroze, dijabetesa, hiperglikemije, inzulinske rezistancije, dijabetičke nefropatije koja je izazvana ili nije izazvana hipertenzijom, bolesti tromboze, grčenja arterija mozga koje dovodi do moždane ishemije.
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| FR1451389A FR3017868A1 (fr) | 2014-02-21 | 2014-02-21 | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| PCT/FR2015/050415 WO2015124877A1 (fr) | 2014-02-21 | 2015-02-20 | Dérivés de 5-benzylisoquinoléine pour le traitement de maladies cardiovasculaires |
| EP15709289.1A EP3107900B1 (fr) | 2014-02-21 | 2015-02-20 | Dérivés de 5-benzylisoquinoléine pour le traitement de maladies cardiovasculaires |
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| BRPI0720986A2 (pt) | 2006-12-27 | 2014-03-11 | Sanofi Aventis | Derivados de isoquinolina e isoquinolinona substituídos |
| MX2009005964A (es) | 2006-12-27 | 2009-06-15 | Sanofi Aventis | Derivados de isoquinolina sustituidos con cicloalquilamina. |
| CL2008000973A1 (es) * | 2007-04-05 | 2009-01-02 | Astrazeneca Ab | Compuestos derivados de 1-oxo-isoquinolina; procedimiento de preparación; composición farmacéutica; y su uso en el tratamiento de enfermedades pulmonares obstructvas crónicas (epoc) y asma. |
| MY153756A (en) | 2008-06-24 | 2015-03-13 | Sanofi Aventis | Bi-and polycyclic substituted isoquinoline and isoquinoline derivatives as rho kinase inhibitors |
| MY153615A (en) | 2008-06-24 | 2015-02-27 | Sanofi Aventis | 6-substituted isoquinolines and isoquinolinones |
| CA2728137C (en) | 2008-06-24 | 2016-10-18 | Sanofi-Aventis | Substituted isoquinolines and isoquinolinones as rho kinase inhibitors |
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