ITMI941466A1 - USE OF QUINOLINE DERIVATIVES - Google Patents
USE OF QUINOLINE DERIVATIVES Download PDFInfo
- Publication number
- ITMI941466A1 ITMI941466A1 IT001466A ITMI941466A ITMI941466A1 IT MI941466 A1 ITMI941466 A1 IT MI941466A1 IT 001466 A IT001466 A IT 001466A IT MI941466 A ITMI941466 A IT MI941466A IT MI941466 A1 ITMI941466 A1 IT MI941466A1
- Authority
- IT
- Italy
- Prior art keywords
- alkyl
- ring
- phenyl
- dissolved
- optionally substituted
- Prior art date
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- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 101001125071 Homo sapiens Neuromedin-K receptor Proteins 0.000 claims description 11
- 102100029409 Neuromedin-K receptor Human genes 0.000 claims description 10
- -1 linear or branched Chemical group 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 239000005557 antagonist Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims 1
- 125000005518 carboxamido group Chemical group 0.000 claims 1
- 239000002740 neurokinin 3 receptor antagonist Substances 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000007787 solid Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000008279 sol Substances 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 10
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- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
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- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- VQPZXHKKSOVFCH-UHFFFAOYSA-N 7-methoxy-2-phenylquinoline-4-carbonyl chloride Chemical compound N=1C2=CC(OC)=CC=C2C(C(Cl)=O)=CC=1C1=CC=CC=C1 VQPZXHKKSOVFCH-UHFFFAOYSA-N 0.000 description 5
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- 102000046798 Neurokinin B Human genes 0.000 description 5
- NHXYSAFTNPANFK-HDMCBQFHSA-N Neurokinin B Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O)C1=CC=CC=C1 NHXYSAFTNPANFK-HDMCBQFHSA-N 0.000 description 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000003141 Tachykinin Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 2
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
- C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
Description
Descrizione dell'invenzione industriale avente per titolo: "USO DI DERIVATI DI CHINOLINA" Description of the industrial invention entitled: "USE OF QUINOLINE DERIVATIVES"
La presente invenzione si riferisce all'uso di certi derivati di chinolina in medicina. The present invention relates to the use of certain quinoline derivatives in medicine.
La neurochinina B (NKB), un peptide dei mammiferi, appartiene alla famiglia dei peptidi della Tachichinina (TK) che comprende anche la sostanza P (SP) e la Neurochinina A (NKA). Evidenze farmacologiche e di biologia molecolare hanno dimostrato l'esistenza di tre sottotipi di recettore TK (NK1, NK2 e NK3): la NKB si lega preferenzialmente al recettore NK3 sebbene riconosca anche gli altri due recettori con affinità inferiore {Maggi et al., 1993, J. Autcn. Pharmacol., 13, 23-93) . Neurokinin B (NKB), a mammalian peptide, belongs to the tachykinin (TK) peptide family which also includes substance P (SP) and neurokinin A (NKA). Pharmacological and molecular biology evidence has shown the existence of three TK receptor subtypes (NK1, NK2 and NK3): NKB preferentially binds to the NK3 receptor although it also recognizes the other two receptors with lower affinity {Maggi et al., 1993 , J. Autcn. Pharmacol., 13, 23-93).
Sono noti antagonisti peptidici selettivi del recettore NK3 (Drapeau, 1990, Regul. Pept., 31, 125-135) e le evidenze disponibili sugli agonisti peptidici del recettore NK3 suggeriscono che NKB, attivando il recettore NK3, svolga un ruolo fondamentale nella modulazione dell'input neuronaie a livello di vie respiratorie, pelle, colonna vertebrale e vie nigro-striatali (Myers and Undem, 1993, J. Phisiol.,470, 665-679;Counture et al., 1993,Regul. Peptides, 46, 426-429; Mocarson and Krause, 1994, J. Neurosci., 14(2), 712-720; Arenas et al., 1991,J.Neurosci., 11, 2332-8). Selective peptide antagonists of the NK3 receptor are known (Drapeau, 1990, Regul. Pept., 31, 125-135) and the available evidence on peptide agonists of the NK3 receptor suggests that NKB, by activating the NK3 receptor, plays a fundamental role in the modulation of 'neuronal input at the level of the respiratory tract, skin, spine and nigro-striatal tract (Myers and Undem, 1993, J. Phisiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426 -429; Mocarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al., 1991, J.Neurosci., 11, 2332-8).
Tuttavia, la natura peptidica degli antagonisti noti, li rende probabilmente troppo labili, da un punto di vista metabolico, per servire come agenti terapeutici da un punto di vista pratico. However, the peptide nature of the known antagonists probably makes them too labile, from a metabolic point of view, to serve as therapeutic agents from a practical point of view.
Abbiano ora trovato che una classe di derivati chinolinici, alcuni dei quali seno composti già noti, seno attivi come antagonisti selettivi non peptidici del recettore NK3 e sono di gran lunga più stabili da un punto di vista metabolico dei noti antagonisti peptidici del recettore ΝΚ3. Quésti derivati seno di potenziale utilità terapeutica nel trattamento di malattie polmonari (asma, malattie polmonari croniche ostruttive -COPD-, iperreattività delle vie respiratorie, tosse), malattie della pelle e prurito (per esempio, dermatite atopica, vesciche, ustioni e bruciori cutanei), infiammazione neurogenica e malattie del sistema nervoso centrale (morbo di Parkinson, disturbi motori,ansia). We have now found that a class of quinoline derivatives, some of which are already known compounds, are active as selective non-peptide antagonists of the NK3 receptor and are far more stable from a metabolic point of view than the known peptide antagonists of the ΝΚ3 receptor. These sinus derivatives of potential therapeutic utility in the treatment of pulmonary diseases (asthma, chronic obstructive pulmonary diseases -COPD-, hyperreactivity of the respiratory tract, cough), skin diseases and itching (for example, atopic dermatitis, blisters, burns and skin burns) , neurogenic inflammation and central nervous system diseases (Parkinson's disease, motor disorders, anxiety).
Secondo la presente invenzione si fornisce un composto o un suo solvato o sale di formula (I) According to the present invention, a compound or a solvate or salt thereof of formula (I) is provided
in cui: in which:
Ar è un gruppo fenile o naftile eventualmente sostituito o un gruppo eterociclico singolo o fuso eventualmente sostituito, avente carattere aromatico, contenente da 5 a 12 atomi di anello e conprendente fino a 4 eternatomi nell'anello o in ciascun anello scelti fra S,0,N; Ar is an optionally substituted phenyl or naphthyl group or a single or fused heterocyclic group optionally substituted, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 eternatoms in the ring or in each ring selected from S, 0, N;
R è un fenile eventualmente sostituito, oppure un gruppo eterociclico ad anello singolo o fuso eventualmente sostituito, avente carattere aromatioo,contenente da 5 a 12 atomi di anello e comprendente fino a 4 eteroatomi nell'anello o in ciascun anello scelti fra S,0,N; oppure R è un gruppo CH-R4R5, in cui R is an optionally substituted phenyl, or a heterocyclic group with a single or fused ring optionally substituted, having an aromatic character, containing from 5 to 12 ring atoms and comprising up to 4 heteroatoms in the ring or in each ring selected from S, 0, N; or R is a CH-R4R5 group, where
R4 è idrogeno, C1-6 alchile, lineare o ramificato, C3-7 cicloalchile, C4-7 cicloalchilalchile, fenile eventualmente sostituito, anelli eteroaromatici a 5 membri eventualmente sostituiti contenenti fino a 4 eteroatomi scelti fra 0 oppure N, idrossi C1-6 alchile, anmino C1-6 alchile, C1-6 alchilantninoalchile, di C1-6 alchilantninoalchile, C1-6 acilanminoalchile, C1-6 alcossialchile, C1-6 alchilcarbonile, carbossi, C1-6 alcossicarbcnile, antninocarbcnile, C1-6 alchilantninocarbonile, di C1-6 alchilantninocarbonile,alogeno C1-6 alchile; R4 is hydrogen, C1-6 alkyl, linear or branched, C3-7 cycloalkyl, C4-7 cycloalkylalkyl, possibly substituted phenyl, 5-membered heteroaromatic rings possibly substituted containing up to 4 heteroatoms selected from 0 or N, hydroxy C1-6 alkyl , Amino C1-6 alkyl, C1-6 alkylanthininoalkyl, C1-6 alkylanthininoalkyl, C1-6 acylaninoalkyl, C1-6 alkoxyalkyl, C1-6 alkylcarbonyl, carboxy, C1-6 alkoxycarbonyl, C1-6 alkylanthininoalkyl, C1-6 alkyl 6 alkylanthninocarbonyl, C1-6 alkyl halogen;
e R5 è un C1-6 alchile lineare o ramificato o un gruppo (CH2)n-Ar1, dove n è 1,2 o 3 e Ar1 ha gli stessi significati di Ar, and R5 is a linear or branched C1-6 alkyl or an n-Ar1 (CH2) group, where n is 1,2 or 3 and Ar1 has the same meanings as Ar,
R1 è idrogeno o C1-6 alchile lineare o ramificato; R1 is hydrogen or linear or branched C1-6 alkyl;
R2 e R3, che possono essere uguali o diversi, sono indipendentemente idrogeno C1-6 alchile lineare o ramificato, C2-6 alchenile, arile, carbossanmido, sulfcnanmido, C1-6 alcossi, idrossi, alogeno, nitro, ciano, carbossi, C1-6 alcossicartoonile, trifluororoetile, con fino a 4 sostituenti R2 nel nucleo chinolinico; R2 and R3, which may be the same or different, are independently hydrogen C1-6 linear or branched alkyl, C2-6 alkenyl, aryl, carboxanmido, sulfcnanmido, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, C1- 6 alkoxycartoonyl, trifluororoethyl, with up to 4 R2 substituents in the quinolinic nucleus;
X è 0, S,H2, o N-C=N; X is 0, S, H2, or N-C = N;
per uso come sostanza terapeuticamente attiva. for use as a therapeutically active substance.
Preferibilmente, Ar o R è fenile eventualmente sostituito da idrossi, alogeno,C1-6 alcossi o trifluororoetile. Preferably, Ar or R is phenyl optionally substituted by hydroxy, halogen, C1-6 alkoxy or trifluororoethyl.
Esenpi di alogeno sono cloro e fluoro, e un esempio di C1-6 alcossi è metossi. Examples of halogen are chlorine and fluorine, and an example of C1-6 alkoxy is methoxy.
Esempi di Ar o R come gruppo eterociclico sono furile, tienile, piridile,pirrile,tiazolile,indolile,benzofurile o benzotienile-Esempi di R4 sono i seguenti: Examples of Ar or R as a heterocyclic group are furyl, thienyl, pyridyl, pyrryl, thiazolyl, indolyl, benzofuryl or benzothienyl - Examples of R4 are as follows:
I composti di formula (I) o i loro sali o solvati seno preferibilmente in forma farmaceuticamente accettabile o sostanzialmente pura. Per forma farmaceuticamente accettabile si intende, fra l'altro, di un livello di purezza farmaceuticamente accettabile che esclude i normali additivi farmaceutici quali diluenti e veicoli e che non comprende materiale considerato tossico ai normali livelli di dosaggio. The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, a pharmaceutically acceptable level of purity which excludes normal pharmaceutical additives such as diluents and carriers and which does not include material considered to be toxic at normal dosage levels.
Una forma sostanzialmente pura conterrà generalmente almeno il 50% (esclusi i normali additivi farmaceutici), preferibilmente il 75%, più preferibilmente il 90% e ancora più preferibilmente il 95% del composto di formula (I)o il suo sale o solvato. A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and even more preferably 95% of the compound of formula (I) or its salt or solvate.
Una forma farmaceuticamente accettabile preferita è la forma cristallina, compresa tale forma in oonposizioni farmaceutiche. Nel caso di sali e solvati anche le porzioni ioniche e solventi aggiuntivi devono essere non tossici. A preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical compositions. In the case of salts and solvates, the ionic portions and additional solvents must also be non-toxic.
Esempi di sali farmaceuticamente accettabili di un composto di formula (I) comprendono i sali di addizione acida con acidi farmaceuticamente accettabili, per esenpio acido maleico, cloridrico, bromidrico, fosforico, acetico, fumarico, salicilico, citrico, lattico, mandelico, tartarico, succinico,benzoico,ascorbico e metansolfonico. Examples of pharmaceutically acceptable salts of a compound of formula (I) include acid addition salts with pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic acids. , benzoic, ascorbic and methanesulfonic.
Esempi di salvati farmaceuticamente accettabili di un composto di formula (I)conprendono gli idrati. Examples of pharmaceutically acceptable salvages of a compound of formula (I) include hydrates.
I conposti di formula (I) possono avere uno o più centri asimnetrici e pertanto possono esistere in più di una forma stereoisomera. L'invenzione comprende tutte tali forme nonché le loro miscele, racemati inclusi. The compounds of formula (I) can have one or more asymmetric centers and therefore can exist in more than one stereoisomeric form. The invention encompasses all such forms as well as their mixtures, including racemates.
I ccnposti di formula (I) sono noti oppure possono essere preparati da composti noti con metodi noti. The compounds of formula (I) are known or can be prepared from known compounds by known methods.
Composti di formula (I) , e i metodi per la loro preparazione, sono descritti nelle seguenti pubblicazioni: Compounds of formula (I), and the methods for their preparation, are described in the following publications:
Ger. Offen. DE 3,721,22 (Nippcn) 14-01-88, Chem. Abst. 109: 93604. Eur. Pat. Appi. EP 384,313 (BASF) , 29-08-90, Chem. Abst, 114: 209232U. Ger. Offen. DE 3,721,22 (Nippcn) 14-01-88, Chem. Abst. 109: 93604. Eur. Pat. Appi. EP 384,313 (BASF), 29-08-90, Chem. Abst, 114: 209232U.
- Jpn. Kokai Tokkio Koho JP 02,129,169 (Yoshitomi Pharm. Ind.), 17-05-90,Chem.Abst. 113:132029c. - Jpn. Kokai Tokkio Koho JP 02,129,169 (Yoshitomi Pharm. Ind.), 05-17-90, Chem.Abst. 113: 132029c.
- Acta Poi. Pharm., 34(3), 271, 1977. - Acta Poi. Pharm., 34 (3), 271, 1977.
Pharm. Sci,. 72(9), 1082, 1983. Pharm. Ski ,. 72 (9), 1082, 1983.
Indian J.Pharm.Sci., 50(5),269, 1988. Indian J.Pharm. Sci., 50 (5), 269, 1988.
Eur.J. Med.Chem.,27(9), 877, 1992. Eur.J. Med. Chem., 27 (9), 877, 1992.
L'attività dei ccnposti di formula (I) (i Composti) come antagonisti del recettore NK3 nelle prove standard indica che essi sono di potenziale utilità terapeutica nel trattamento di malattie polmonari (asma, COPD, iperreattività delle vie respiratorie, tosse), malattie della pelle e prurito (dermatite atopica, vesciche, ustioni e bruciori cutanei), infiammazione neurogenica e malattie del sistema nervoso centrale (morbo di Parkinson, disturbi motori, ansia) (di seguito indicate come "Condizioni"). The activity of compounds of formula (I) (the Compounds) as antagonists of the NK3 receptor in standard tests indicates that they are of potential therapeutic utility in the treatment of lung diseases (asthma, COPD, respiratory tract hyperreactivity, cough), skin and itching (atopic dermatitis, blisters, burns and skin burns), neurogenic inflammation and central nervous system diseases (Parkinson's disease, motor disorders, anxiety) (hereafter referred to as "Conditions").
La presente invenzione fornisce inoltre l'uso di un composto di formula (I), o di un suo sale o solvato farmaceuticamente accettabile, per la preparazione di un medicamento per il trattamento delle "Condizioni". The present invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of the "Conditions".
Un tale medicamento pud essere preparato miscelando un Conposto con un veicolo opportuno. Esso pud contenere un diluente, legante, riempitivo, disintegrante, agente aromatizzante, agente colorante, lubrificante o conservante in modo convenzionale. Such a medicament can be prepared by mixing a compound with a suitable vehicle. It may contain a diluent, binder, filler, disintegrant, flavoring agent, coloring agent, lubricant or preservative in a conventional manner.
Questi eccipienti convenzionali possono essere inpiegati per esenpio nella preparazione di conposizioni di noti agenti per il trattamento delle Condizioni. These conventional excipients may be employed for example in the preparation of compositions of known agents for the treatment of Conditions.
Preferibilmente, una ccnposizione farmaceutica è in forma di dosaggio unitario e in una forma adatta per l'uso nel canpo medico o veterinario. Per esenpio, tali preparazioni possono essere in forma confezioata acconpagnata da istruzioni scritte o stampate per l'uso come agente nel trattamento delle Condizioni. Preferably, a pharmaceutical composition is in unit dosage form and in a form suitable for use in the medical or veterinary field. For example, such preparations may be in packaged form accompanied by written or printed instructions for use as an agent in the treatment of the Conditions.
L'opportuno intervallo di dosaggio per i Composti dipende dal Conposto da inpiegarsi e dalla condizione del paziente. Esso dipenderà anche, fra l'altro, dal rapporto di potenza rispetto all'assorbimento e dalla frequenza e dalla via di somministrazione. The appropriate dosage range for the Compounds depends on the compound to be used and the condition of the patient. It will also depend, among other things, on the ratio of potency to absorption and on the frequency and route of administration.
I Composti possono essere formulati per somninistrazione per una qualunque via, e preferibilmente in forma di dosaggio unitario o in una forma che un paziente umano possa somministrare a sé stesso in un dosaggio singolo. Vantaggiosamente, la ccnposizione è adatta per somministrazione orale, rettale, topica, parenterale, endovenosa o intramuscolare.Le preparazioni possono essere formulate in modo da dare un lento rilascio del principio attivo. The Compounds may be formulated for administration by any route, and preferably in unit dosage form or in a form that a human patient can administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The preparations can be formulated in such a way as to give a slow release of the active principle.
Le conposizioni possono,per esenpio, essere in forma di compresse, capsule,bustine, fiali, polveri, granuli,confetti, polveri ricostituitili o preparazioni liquide,per esenpio soluzioni o sospensioni, oppure supposte. The compositions can, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, dragees, reconstituted powders or liquid preparations, for example solutions or suspensions, or suppositories.
Le composizioni, per esempio quelle adatte per la somministrazione orale, possono contenere eccipienti convenzionali quali agenti leganti, per esempio sciroppo, acacia, gelatina, sorbitolo, adragante, o polivinilpirrolidone; eccipienti, per esempio lattosio, zucchero, amido di mais, fosfato di calcio, sorbitolo o glieina; lubrificanti per compressione, per esempio stearato di magnesio; disintegranti, per esempio amido, polivinilpirrolidone, amido sodio glicolato o cellulosa microcristallina; o agenti surfattenti farmaceuticamente accettabili quali sodio lauril solfato. The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; excipients, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glyein; compression lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable surfactants such as sodium lauryl sulfate.
Le Composizioni solide possano essere ottenute con metodi convenzionali di miscelazione, riempimento, compressione,o simili. The solid compositions can be obtained by conventional methods of mixing, filling, compression, or the like.
Possono essere usate operazioni ripetute di miscelazione per distribuire il principio attivo in quelle composizioni che impiegano grandi quantità di eccipienti. Quando la conposizione è sotto forma di compressa,polvere o pastiglia, si può impiegare ogni veicolo adatto per la formulazione di conposizioni farmaceutiche solide, ad esempio stearato di magnesio, amido, glucosio, lattosio, saccarosio, farina di riso e gesso. Le compresse possono essere rivestite secondo metodi ben noti nella normale pratica farmaceutica, in particolare con rivestimenti gastroresistenti. Le composizioni possono anche essere sotto forma di capsula da deglutire,per esempio di gelatina contenente il composto, se desiderato con un veicolo o altri eccipienti. Repeated mixing operations can be used to distribute the active ingredient in those compositions employing large amounts of excipients. When the composition is in tablet, powder or tablet form, any vehicle suitable for formulating solid pharmaceutical compositions, for example magnesium stearate, starch, glucose, lactose, sucrose, rice flour and gypsum, can be employed. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with gastro-resistant coatings. The compositions may also be in the form of a capsule to be swallowed, for example of gelatin containing the compound, if desired with a vehicle or other excipients.
Le Composizioni liquide per la somministrazione orale possono essere in forma di, per esempio, emulsioni, sciroppi o elisir oppure possono essere presentate come prodotto secco da ricostituire con acqua o altri opportuni veicoli prima dell'uso. Tali composizioni liquide possono contenere additivi convenzionali quali agenti sospendenti, per esempio sorbitolo, sciroppo,metilcellulosa, gelatina, idrossietilcellulosa,carbossimetilcellulosa, gel di stearato di alluminio, acidi grassi commestibili idrogenati; agenti emulsionanti, per esempio lecitina, sorbitan monooleato, o gomma acacia; veicoli acquosi o non acquosi, che comprendano oli commestibili, per esempio olio di mandorle, olio frazionato di cocco, esteri oleosi, per esempio esteri di glicerina o propilengliool oppure alcol etilico, glicerina, acqua o soluzione fisiologica salina; conservanti, per esempio metil o propil p-idrossibenzoato o acido sorbico; e se desiderato agenti aromatizzanti o coloranti convenzionali. The liquid compositions for oral administration can be in the form of, for example, emulsions, syrups or elixirs or they can be presented as a dry product to be reconstituted with water or other suitable vehicles before use. Such liquid compositions can contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fatty acids; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia gum; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerin or propylene glycol or ethyl alcohol, glycerin, water or physiological saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents.
I Composti possalo anche essere somministrati per via non orale. Secondo la normale pratica farmaceutica, le composizioni possono essere formulate, per esempio per somministrazione orale come supposta. Esse possono anche essere formulate, per la presentazione sotto forma iniettabile, in una soluzione, sospensione o emulsione acquosa o non acquosa in un liquido farmaceuticamente accettabile, per esempio acqua sterile apirogena o olio parenteralmente accettabile o una miscela di liquidi. Il liquido pud contenere agenti batteriostatici, antiossidanti o altri conservanti,tamponi o soluti per rendere la soluzione isotonica con il sangue, agenti ispessenti, agenti sospendenti o altri additivi farmaceuticamente accettabili. Tali forme saranno presentate in forma di dosaggio unitario quali fiale o dispositivi per iniezione a perdere o in forme multi-dose quali flaconi, dai quali può essere prelevata la dose appropriata o una forma solida o concentrata che può essere impiegata per preparare una formulazione iniettabile. The Compounds can also be administered non-orally. According to normal pharmaceutical practice, the compositions can be formulated, for example for oral administration as a suppository. They may also be formulated, for presentation in injectable form, in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogenic water or parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes to make the solution isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dosage form such as ampoules or disposable injection devices or in multi-dose forms such as bottles, from which the appropriate dose or a solid or concentrated form can be withdrawn which can be used to prepare an injectable formulation.
I Composti posscno anche essere somministrati per inalazione, per via nasale o orale. Tale somministrazione può essere effettuata con una formulazione spray che comprende un Composto e un opportuno veicolo, eventualmente sospeso,per esenpio,in un propellente idrocarburico. The Compounds can also be administered by inhalation, by the nasal or oral route. This administration can be carried out with a spray formulation which comprises a Compound and a suitable vehicle, optionally suspended, for example, in a hydrocarbon propellant.
Formulazioni spray preferite comprendono particelle di composto micronizzate in conbinazione con un surfattante, solvente o agente disperdente per prevenire la sedimentazione di particelle sospese. Preferibilmente, la granulometria è da 2 a 10 micron. Preferred spray formulations include micronized compound particles in combination with a surfactant, solvent or dispersing agent to prevent sedimentation of suspended particles. Preferably, the particle size is from 2 to 10 microns.
Un'ulteriore via di somninistrazione dei Composti comprende la somministrazione transdemica utilizzando una formulazione di cerotto. Una formulazione preferita ccnprende un Conposto disperso in un adesivo sensibile alla pressione che aderisce alla pelle permettendo così al conposto di diffondere dall'adesivo attraverso la pelle. Per una velocità costante di assorbimento percutaneo, possalo essere impiegati adesivi sensibili a pressione noti quali gamia naturale o silicone. A further route of administration of the Compounds includes transdemic administration using a patch formulation. A preferred formulation includes a compound dispersed in a pressure sensitive adhesive which adheres to the skin thereby allowing the compound to diffuse from the adhesive through the skin. For a constant rate of percutaneous absorption, known pressure sensitive adhesives such as natural gamia or silicone can be used.
Come sopra menzionato, la dose efficace del Composto dipende dal particolare Conposto inpiegato, dalle condizioni del paziente e dalla frequenza e via di somministrazione. Una dose unitaria conterrà generalmente da 20 a 1000 mg e preferibilmente conterrà da 30 a 500 mg, in particolare 50, 100, 150,200, 250, 300, 350, 400,450,o 500 mg. Le conposizioni possono essere somministrate una o più volte al giorno,per esenpio 2, 3 o 4 volte al giorno, e la dose giornaliera totale per un adulto da 70 Kg sarà normalmente nell'intervallo da 100 a 3000 mg. As mentioned above, the effective dose of the Compound depends on the particular Compound employed, the patient's condition, and the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150,200, 250, 300, 350, 400,450, or 500 mg. The compositions can be administered one or more times a day, e.g. 2, 3 or 4 times a day, and the total daily dose for a 70 kg adult will normally be in the range of 100 to 3000 mg.
Alternativamente la dose unitaria conterrà da 2 a 20 mg di ingrediente attivo e sarà somministrata in dosi multiple, se desiderato, per dare la dose giornaliera di cui sopra. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and will be administered in multiple doses, if desired, to give the above daily dose.
Se i Composti sono somministrati secondo l'invenzione non sono previsti effetti tossioologici inacettàbili. If the Compounds are administered according to the invention, no unacceptable toxicological effects are expected.
La presente invenzione fornisce anche un metodo per il trattamento e/o la profilassi delle Condizioni nei mamniferi, in particolare uomini, che conprende la somministrazione al mammifero che necessita di tale trattamento e/o profilassi di una dose efficace di un composto di formula (I)o di un suo sale o solvato farmaceuticamente accettabile. The present invention also provides a method for the treatment and / or prophylaxis of the Conditions in mammals, in particular men, which includes the administration to the mammal that requires such treatment and / or prophylaxis of an effective dose of a compound of formula (I ) or a pharmaceutically acceptable salt or solvate thereof.
L'attività dei Conposti, come leganti del recettore NK3, è determinata dalla loro capacità di inibire il legame dei leganti radiomarcati del recettore NK3 [<125>I] Me-Phe<7>]-NKB o [<3>]-Senktide, ai recettori NKg di cavia e umani (Renzetti et al., 1991, Neurcpeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem.Biophys. Res.Conmun.,198(3),967-972). The activity of the Compounds, as ligands of the NK3 receptor, is determined by their ability to inhibit the binding of the radiolabeled ligands of the NK3 receptor [<125> I] Me-Phe <7>] -NKB or [<3>] -Senktide , to guinea pig and human NKg receptors (Renzetti et al., 1991, Neurcpeptide, 18, 104-114; Buell et al, 1992, FEBS, 299 (1), 90-95; Chung et al, 1994, Biochem.Biophys . Res.Conmun., 198 (3), 967-972).
Le prove di legame impiegate permettono la determinazione della concentrazione di ogni singolo conposto necessaria per ridurre del 50% il legame specifico di [<125>I]-[Me-Phe<7>]-NKB e [<3>]-Senktide al recettore NK3 in condizioni di equilibrio. Le prove di legame forniscono per ogni composto saggiato medie di valori di IC50 di 2-5 esperimenti separati effettuati in triplicato o in quadruplicato. The binding tests used allow the determination of the concentration of each single compound necessary to reduce by 50% the specific bond of [<125> I] - [Me-Phe <7>] -NKB and [<3>] -Senktide al NK3 receptor in equilibrium conditions. The binding tests provide for each compound tested averages of IC50 values of 2-5 separate experiments carried out in triplicate or in quadruplicate.
I conposti più potenti hanno valori di IC50 nell'intervallo da 100 a 1000 nM; per esempio il composto dell'Esempio 8 mostra un valore di IC50 di 620 nM (n-3)nelle membrane corticali di cavia, per spiazzamento di [<l25>I]-[Me-Phe<7>]-NKB. The more potent compounds have IC50 values in the range from 100 to 1000 nM; for example the compound of Example 8 shows an IC50 value of 620 nM (n-3) in the cortical membranes of guinea pigs, due to displacement of [<125> I] - [Me-Phe <7>] -NKB.
L'attività NKg-antagonista dei Ccnposti è determinata dalla loro abilità di inibire la contrazione dell'ileo di cavia indotta da Senktide (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) e la mobilizzazione di Ca<++ >mediante recettori NK3 umani (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). La prova funzionale sulla cavia fornisce per ogni composto saggiato inedie di valori di KB di 3-8 esperimenti separati, dove KB è la concentrazione di ogni singolo comtposto necessaroa per produrre uno spostamento verso destra di due volte nella curva dose-risposta di Senktide. The NKg-antagonist activity of CC compounds is determined by their ability to inhibit Senktide-induced contraction of guinea pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and mobilization of Ca <++> by human NK3 receptors (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). The functional test on the guinea pig provides for each compound tested inedited KB values from 3-8 separate experiments, where KB is the concentration of each single compound needed to produce a two-fold rightward shift in the Senktide dose-response curve.
Le prove funzionali sui recettori umani permettono la determinazione della concentrazione di ogni singolo composto necessaria per ridurre del 50% (valori di IC50) la mobilizzazione di Ca<++ >indotta dall'agonista NKB. In questa prova i Composti si comportano cane antagonisti. The functional tests on human receptors allow the determination of the concentration of each single compound necessary to reduce by 50% (IC50 values) the mobilization of Ca <++> induced by the NKB agonist. In this test the Compounds behave as antagonistic dogs.
Il potenziale terapeutico dei Conposti nel trattamento delle Condizioni può essere valutato impiegando modelli di malattia nei roditori. The therapeutic potential of Compounds in the treatment of the Conditions can be assessed using disease models in rodents.
Le seguenti Descrizioni illustrano le preparazioni degli intermedi, mentre gli Esenpi illustrano la preparazione dei Conposti. I Composti degli Esenpi seno riassunti in Tabella. The following Descriptions illustrate the preparations of the intermediates, while the Exemplars illustrate the preparation of the Compounds. The Compounds of the Examples are summarized in the Table.
DESCRIZIONE 1 DESCRIPTION 1
2-fenil-4-chinolincarbonil cloruro 2-phenyl-4-quinolincarbonyl chloride
11,7 mi (136,3mmoli) di ossalil cloruro vengono sciolti in 150 mi di CH2Cl2· La soluzione viene raffreddata a -10°C e si aggiungono, in più porzioni, 20 g (80,2 mmoli) di acido 2-fenil-4 -chino lincarbossilico, commercialmente disponibile. La miscela di reazione viene lasciata a sè, a temperatura ambiente , per tutta la notte e poi evaporata a secco sotto vuoto. Si ottengono 22 g del prodotto desiderato, utilizzato senza ulteriori purificazioni. 11.7 ml (136.3 mmoles) of oxalyl chloride are dissolved in 150 ml of CH2Cl2 The solution is cooled to -10 ° C and 20 g (80.2 mmol) of 2-phenyl acid are added in several portions. -4 -quino lincarboxylic, commercially available. The reaction mixture is left alone, at room temperature, for the whole night and then evaporated to dryness under vacuum. 22 g of the desired product are obtained, used without further purification.
DESCRIZIONE 2 DESCRIPTION 2
addo 2-fenil-7-metossi-4-chinolincart)Ossilico addo 2-phenyl-7-methoxy-4-quinolincart) Oxyl
5 g (28,2 mnoli) di 6-metossiisatina, 4 mi (33,8 mmoli) di acetofenone e 5,2 g (92,6 mmoli) di idrossido di potassio vengono sciolti in 22,9 mi di EtOH assoluto e la sospensione viene scaldata a 80<e>C per 42 ore. La miscela di reazione viene raffreddata, vengono aggiunti 50 mi di acqua e la soluzione viene estratta con 50 mi di Et2O. La fase acquosa, raffreddata con ghiaccio, viene acidificata a pH 1 ccn HCl al 37% e il precipitato viene raccolto per filtrazione, lavato con acqua e asciugato sotto vuoto a 40°C. Si ottengono 7,0 g del prodotto desiderato. 5 g (28.2 mmol) of 6-methoxyisatin, 4 ml (33.8 mmol) of acetophenone and 5.2 g (92.6 mmol) of potassium hydroxide are dissolved in 22.9 ml of absolute EtOH and suspension is heated at 80 <e> C for 42 hours. The reaction mixture is cooled, 50 ml of water are added and the solution is extracted with 50 ml of Et2O. The aqueous phase, cooled with ice, is acidified to pH 1 ccn HCl at 37% and the precipitate is collected by filtration, washed with water and dried under vacuum at 40 ° C. 7.0 g of the desired product are obtained.
DESCRIZIONE 3 DESCRIPTION 3
2-fenil-7-metossi-4-ctrinolincarbonil cloruro 2-phenyl-7-methoxy-4-ctrinolincarbonyl chloride
2,8 mi (32,3 imoli) di ossalil cloruro vengono sciolti in 60 mi di CH2C12. La soluzione viene raffreddata a -10°C e vengono aggiunti, in più porzioni, 6 g (19,0 limoli) di acido 2-fenil-7-metossicchinolinearbossilico. La miscela di reazione viene lasciata a se', a temperatura anbiente, per tutta la notte e poi evaporata a secco sotto vuoto. Si ottengono 7,0 g del prodotto desiderato, utilizzato senza ulteriori purificazioni. 2.8 ml (32.3 imoles) of oxalyl chloride are dissolved in 60 ml of CH 2 Cl 12. The solution is cooled to -10 ° C and 6 g (19.0 limols) of 2-phenyl-7-methoxychinolinearboxylic acid are added in several portions. The reaction mixture is left alone, at room temperature, for the whole night and then evaporated to dryness under vacuum. 7.0 g of the desired product are obtained, used without further purifications.
DESCRIZIONE 4 DESCRIPTION 4
acido 2-fenil-7-idrossi-4-chinolincarbossilico iodidrato 2-phenyl-7-hydroxy-4-quinolincarboxylic acid iodide
1,5 g (5,4 mmoli) di acido 2-fenil-7-metossi-4-chinolincarbossilioo vengono aggiunti, in più porzioni, a 50 mi di HI al 57%. La miscela di reazione viene scaldata a ricadere sotto vigorosa agitazione magnetica per 5 ore e poi evaporata a secco sotto vuoto per fornire 2,1 g del prodotto desiderato. 1.5 g (5.4 mmoles) of 2-phenyl-7-methoxy-4-quinolincarboxylic acid are added, in several portions, to 50 ml of 57% HI. The reaction mixture is refluxed under vigorous magnetic stirring for 5 hours and then evaporated to dryness under vacuum to yield 2.1 g of the desired product.
DESCRIZIONE 5 DESCRIPTION 5
2-fenil-4-idrossimetil-7-metossichinolina 2-phenyl-4-hydroxymethyl-7-methoxyquinoline
15 g (50,4 mmoli) di 2-fenil-7-metossi-4-chinolincarbonil cloruro vengono sospesi, sotto azoto, in 300 mi di THF anidro. La miscela di reazione viene raffreddata a -78°C e vengano gocciolati 80 mi (80,0 nmoli) di Li(t-BuO)3AiH (sol. 1M in THF).La soluzione viene mantenuta a -78 °C per 2 ore e poi a temperatura ambiente per tutta la notte. 15 g (50.4 mmoles) of 2-phenyl-7-methoxy-4-quinolincarbonyl chloride are suspended, under nitrogen, in 300 ml of anhydrous THF. The reaction mixture is cooled to -78 ° C and 80 ml (80.0 nmoles) of Li (t-BuO) 3AiH (sol. 1M in THF) are dropped. The solution is kept at -78 ° C for 2 hours and then at room temperature overnight.
La miscela di reazione viene raffreddata oon un bagno di ghiaccio e spenta con 150 mi di H2o; il solvente viene evaporato sotto vuoto, si aggiungono 100 mi di CH2C2 e si filtra su celite. La fase organica viene separata, seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto per ottenere 6,0 g del prodotto desiderato. The reaction mixture is cooled in an ice bath and quenched with 150 ml of H2o; the solvent is evaporated under vacuum, 100 ml of CH2C2 are added and it is filtered on celite. The organic phase is separated, dried over Na2SO4, filtered and evaporated to dryness under vacuum to obtain 6.0 g of the desired product.
Altri 2,3 g di prodotto vengono ottenuti lavando ripetutamente i sali di alluminio con AcCEt e CH2C12. Another 2.3 g of product are obtained by repeatedly washing the aluminum salts with AcCEt and CH2C12.
DESCRIZIONE 6 DESCRIPTION 6
2-fenil-7-metossi-4-chinolincarbaldeide 2-phenyl-7-methoxy-4-quinolincarbaldehyde
6,0 g (46,0 nmoli) di Mn02 vengono sospesi, sotto azoto, in 150 mi di CH2C12 anidro. 6.0 g (46.0 nmoles) of Mn02 are suspended, under nitrogen, in 150 ml of anhydrous CH2C12.
3,3 g (12,4 nmoli) del prodotto della Descrizione 5, sciolti in 500 mi di CH2C12 anidro, vengono aggiunti goccia a goccia e la miscela di reazione viene tenuta sotto agitazione magnetica per 2 giorni. Si aggiungono 1,0 g (11,5 mmoli) di Mn02 e si agitata per 1 giorno; si aggiungono 0,5 g (5,7 «moli) di Mn02 e si agitata per un giorno; si aggiungano altri 0,5 g (5,7 nnoli) di MnO2 e si agitata per un altro giorno. 3.3 g (12.4 nmoles) of the product of Description 5, dissolved in 500 ml of anhydrous CH2Cl2, are added dropwise and the reaction mixture is kept under magnetic stirring for 2 days. 1.0 g (11.5 mmoles) of Mn02 are added and the mixture is stirred for 1 day; 0.5 g (5.7 mole) of MnO2 are added and the mixture is stirred for one day; another 0.5 g (5.7 nnoles) of MnO2 are added and the mixture is stirred for another day.
La miscela viene filtrata su celite e il solvente evaporato a secco sotto vuoto; il residuo viene triturato con i-Pr2O per fornire 2,7 g del prodotto desiderato. The mixture is filtered on celite and the solvent evaporated to dryness under vacuum; the residue is triturated with i-Pr2O to give 2.7 g of the desired product.
DESCRIZIONE 7 DESCRIPTION 7
2-f enil-4- ( N-benzil ) iflininometil-7Hnetossichinolina 2-f enyl-4- (N-benzyl) iflininomethyl-7Hnetoxyquinoline
1,0 g (3,8 nnoli) del prodotto della Descrizione 6 e 0,44 g (4,1 imtoli) di benzilanmina vengono sciolti in 30 mi di toluene; viene aggiunta una quantità catalitica di acido paratoluensolfonico (PTSA) e la soluzione viene scaldata a ricadere per 36 ore, distillando via l'acqua formatasi con un apparato di Dean-Stark. 1.0 g (3.8 nols) of the product of Description 6 and 0.44 g (4.1 mmoles) of benzylanine are dissolved in 30 ml of toluene; a catalytic quantity of paratoluenesulfonic acid (PTSA) is added and the solution is heated under reflux for 36 hours, distilling away the water formed with a Dean-Stark apparatus.
La miscela di reazione viene evaporata a secco sotto vuoto per dare 1,5 g del prodotto desiderato,usato senza ulteriori purificazioni.ESEMPIO 1 The reaction mixture is evaporated to dryness under vacuum to give 1.5 g of the desired product, used without further purification. EXAMPLE 1
N-(2-netossicart)onilfenil)-2-fenilchinolina-4-carbossanmide N- (2-netoxycart) onylphenyl) -2-phenylquinoline-4-carboxanmide
2,0 g (8,0 mmoli) di acido 2-fenil-4-chinolincarbossilico vengono sciolti, sotto azoto, in 70 mi di THF anidro e 30 mi di CH3CN. 2.0 g (8.0 mmoles) of 2-phenyl-4-quinolincarboxylic acid are dissolved, under nitrogen, in 70 ml of anhydrous THF and 30 ml of CH3CN.
Si aggiungono 1,21 g (8,0 imoli) di antranilato di metile e 2,5 g (18,5 imoli) di N-idrossibenzotriazolo (ΗOΒΤ) e la miscela di reazione viene raffreddata a 0°C. 1.21 g (8.0 imoles) of methyl anthranilate and 2.5 g (18.5 imoles) of N-hydroxybenzotriazole (ΗOΒΤ) are added and the reaction mixture is cooled to 0 ° C.
Si gocciolano 1,81 g (8,8 amoli) di DOC, sciolti in 10 ml di anidro,e la soluzicne viene tenuta tra 0 e 5C per 1 ora e a temperatura ambiente per 2 ore. La dieicloesilurea che precipita viene filtrata via e la soluzione viene evaporata a secco sotto vuoto. Il residuo viene sciolto in CH2CI2 e lavato ccn acqua, sol. sat. di NaHC3, acido citrico al 5%, sol. sat. di NaHCO3 e sol. sat. di NaCl. La fase organica separata viene seccata su ed evaporata a secco sotto vuoto; il residuo viene sciolto in 20 mi di CH2CI2 e lasciato a se' per tutta la notte. Precipita dell'altra dicicloesilurea che viene filtrata via. 1.81 g (8.8 amoles) of DOC are dropped, dissolved in 10 ml of anhydrous, and the solution is kept between 0 and 5 ° C for 1 hour and at room temperature for 2 hours. The precipitating dieyclohexylurea is filtered off and the solution evaporated to dryness in vacuo. The residue is dissolved in CH2CI2 and washed with water, sol. sat. of NaHC3, 5% citric acid, sol. sat. of NaHCO3 and sol. sat. of NaCl. The separated organic phase is dried up and evaporated to dryness under vacuum; the residue is dissolved in 20 ml of CH2Cl2 and left to stand overnight. The other dicyclohexylurea precipitates and is filtered off.
La soluzione viene evaporata a secco sotto vuoto ed il residuo purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando come eluente una miscela di esano/AcQEt 1:1 contenente lo 0,5% di NH4CH (al 28%) per ottenere 0,45 g di prodotto purificato, che viene triturato con i-PrO e poi ricristallizzato con i-PrOH a fornire 0,34 g del prodotto desiderato. The solution is evaporated to dryness under vacuum and the residue purified by flash chromatography on silica gel (230-400 mesh), using as eluent a mixture of hexane / AcQEt 1: 1 containing 0.5% NH4CH (28% ) to obtain 0.45 g of purified product, which is triturated with i-PrO and then recrystallized with i-PrOH to give 0.34 g of the desired product.
ESaiPIO 2 EXAMPLE 2
(R,S)-N-[(l-metossicarbonil-2-fenil)etil]-2-fenilchinolina-4- (R, S) -N - [(1-methoxycarbonyl-2-phenyl) ethyl] -2-phenylquinoline-4-
2,0 g (7,8 aiuoli) di cloridrato dell'estere metilico della (D,L) fenilalanina e 2,7 mi (19,5 mmoli) di trietilammina (TEA) vengono sciolti, sotto azoto, in 50 ml di una miscela 1:1 di CH2C12 anidro e CH3CN. In questa soluzione, raffreddata con un bagno di ghiaccio, vengono gocciolati 2,0 g (7,8 mmoli) di 2-fenil-4-chinolincarbcnil cloruro, sciolti in 50 mi di una miscela 1:4 di CH2C1 anidro e DMF, e la reazione viene mantenuta tra 0° e 5°C per 1 ora e poi a temperatura ambiente per tutta la notte. 2.0 g (7.8 aluols) of (D, L) phenylalanine methyl ester hydrochloride and 2.7 ml (19.5 mmol) of triethylamine (TEA) are dissolved, under nitrogen, in 50 ml of a 1: 1 mixture of anhydrous CH2C12 and CH3CN. In this solution, cooled with an ice bath, 2.0 g (7.8 mmoles) of 2-phenyl-4-quinolincarbene chloride are dropped, dissolved in 50 ml of a 1: 4 mixture of anhydrous CH2Cl and DMF, and the reaction is maintained between 0 ° and 5 ° C for 1 hour and then at room temperature for the whole night.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo viene sciolto in AcQEt e lavato due volte con una sol. sat. di NaH003. La fase organica separata viene seccata su Na2S04, filtrata ed evaporata a secco sotto vuoto. L'olio residuo viene cristallizzato due volte da AcQEt per fornire 1,6 g del prodotto desiderato cane solido grigio. The reaction mixture is evaporated to dryness under vacuum and the residue is dissolved in AcQEt and washed twice with a sol. sat. of NaH003. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum. The residual oil is crystallized twice by AcQEt to yield 1.6 g of the desired gray solid product.
ESEMPIO 3 EXAMPLE 3
4-[(N-benzil)amminometil]-2-fenil-7-metossichinolina dicloridrato 4 - [(N-benzyl) aminomethyl] -2-phenyl-7-methoxyquinoline dihydrochloride
1,3 g (3,7 limoli) del prodotto grezzo della Descrizione 7 vengono sciolti, sotto azoto, in 60 mi di AcCH. La miscela di reazione viene raffreddata a 20° C e, in circa 15 minuti, vengano aggiunti 2,0 g (9,4 mmoli) di Na(AcO)3BH; la reazione viene mantenuta a temperatura ambiente per tutta la notte. 1.3 g (3.7 limols) of the crude product of Description 7 are dissolved, under nitrogen, in 60 ml of AcCH. The reaction mixture is cooled to 20 ° C and, in about 15 minutes, 2.0 g (9.4 mmoles) of Na (AcO) 3BH are added; the reaction is kept at room temperature overnight.
Vengano aggiunti altri 1,5 g (7,0 nmoli) di Na(AcO)3BH, poi la miscela di reazione viene evaporata a seoco sotto vuoto. Il residuo viene sciolto in CH2C1 e lavato con NaHCO3 e HjO; la fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a seoco sotto vuoto. Another 1.5 g (7.0 nmoles) of Na (AcO) 3BH are added, then the reaction mixture is evaporated under vacuum. The residue is dissolved in CH2C1 and washed with NaHCO3 and HjO; the separated organic phase is dried over Na2SO4, filtered and evaporated to temperature under vacuum.
Il prodotto grezzo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando come eluente una miscela di esano/AcCEt 3:2 contenente lo 0,5% di NH4OH (al 28%) . Il solido purificato viene sciolto in Et2o e acidificato con HCl/Et20; il precipitato viene filtrato e triturato con una miscela di i-PrOH/i-Pr2o 1:1 per ottenere 0,1 g del prodotto desiderato. The crude product is purified by flash chromatography on silica gel (230-400 mesh), using as eluent a mixture of hexane / AcCEt 3: 2 containing 0.5% NH4OH (28%). The purified solid is dissolved in Et2o and acidified with HCl / Et20; the precipitate is filtered and triturated with a 1: 1 i-PrOH / i-Pr2o mixture to obtain 0.1 g of the desired product.
ESEMPIO 4 EXAMPLE 4
B-benzi-2-fenil-7-idrossichi∞lina— 4-carbossanmide B-benzi-2-phenyl-7-hydroxyline— 4-carboxanmide
0,85 g (3,0 mmoli) di acido 2-fenil-7-idrossi-4-chinolincarbossilico grezzo vengono sciolti, sotto azoto, in 15 mi di CH2C1 anidro; si aggiungono 0,52 g (3,3 mmoli) di N,N'-carbcnildiimidazolo e la miscela di reazione viene mantenuta a tenperatura ambiente per 3 ore. 0.85 g (3.0 mmoles) of crude 2-phenyl-7-hydroxy-4-quinolincarboxylic acid are dissolved, under nitrogen, in 15 ml of anhydrous CH2Cl; 0.52 g (3.3 mmoles) of N, N'-carbcnyldiimidazole are added and the reaction mixture is kept at room temperature for 3 hours.
Si gocciolano 0,65 ml (5,9 mnoli) di benzilamnina sciolta in 5 mi di CH2C1 anidro e la soluzione viene mantenuta a tenperatura ambiente per 6 giorni e poi evaporata a secco sotto vuoto. Il prodotto grezzo viene lavato con CH2C1 caldo e con MeCH ed il residuo viene raccolto per filtrazione. 0.65 ml (5.9 mnoles) of benzylamine dissolved in 5 ml of anhydrous CH2C1 are added dropwise and the solution is kept at room temperature for 6 days and then evaporated to dryness under vacuum. The crude product is washed with hot CH2Cl and with MeCH and the residue is collected by filtration.
Il filtrato viene sciolto in una miscela di CHCl3 (200 mi)/MeCH (8 mi)e lavato con H2o (10 mi).La fase organica estratta viene seccata su Νa2SO4 filtrata, evaporata a secco sotto vuoto e triturata con 5 mi di MeOH caldo per ottenere 0,045 g del prodotto desiderato. The filtrate is dissolved in a mixture of CHCl3 (200 ml) / MeCH (8 ml) and washed with H2o (10 ml). The extracted organic phase is dried over filtered Νa2SO4, evaporated to dryness under vacuum and triturated with 5 ml of MeOH hot to obtain 0.045 g of the desired product.
ESEMPIO 5 EXAMPLE 5
N-{3,4-dimetossibenzil)-2-fenil-7-metossichinolina-4-carbossaramide 1,5 g (9,0 mmoli) di 3,4-dimetossibenzilanmina e 1,2 g (9,0 mmoli} di carbonato di potassio anidro vengono sciolti, sotto azoto, in 40 mi di DMF anidra. Si gocciolano nella soluzione raffreddata con un bagno di ghiaccio 1,3 g (4,5 mmoli) di 2-fenil-7-metossi-4-chinolincarbonil cloruro sciolti in 30 mi di DMF anidra e la reazione viene mantenuta tra 0" e 5°C per 1 ora e poi a temperatura ambiente per tutta la notte. La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in AcQEt e lavato due volte con NaHCO3 sol. sat.. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. N- {3,4-dimethoxybenzyl) -2-phenyl-7-methoxyquinoline-4-carboxaramide 1.5 g (9.0 mmol) of 3,4-dimethoxybenzylanine and 1.2 g (9.0 mmol} of carbonate of anhydrous potassium are dissolved, under nitrogen, in 40 ml of anhydrous DMF. 1.3 g (4.5 mmoles) of dissolved 2-phenyl-7-methoxy-4-quinolincarbonyl chloride are dropped into the solution cooled with an ice bath in 30 ml of anhydrous DMF and the reaction is maintained between 0 "and 5 ° C for 1 hour and then at room temperature for the whole night. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in AcQEt and washed two times with NaHCO3 sat. sol .. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum.
L'olio residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando oome eluente una miscela di esano/AcGEt 6:4 contenente lo 0,2% di NH4OH (al 28%) . Il solido purificato (250 mg) viene cristallizzato da una miscela di AcOEt/toluene/EtOH per ottenere 114 mg del prodotto desiderato come solido giallo. The residual oil is purified by flash chromatography on silica gel (230-400 mesh), using as eluent a mixture of hexane / AcGEt 6: 4 containing 0.2% NH4OH (at 28%). The purified solid (250 mg) is crystallized from a mixture of AcOEt / toluene / EtOH to obtain 114 mg of the desired product as a yellow solid.
ESHPIO 6 ESHPIO 6
N-[3,5-bis(trifluorometil )benzil]—2-fenil—7-metossichinolina—4— carbossanmide N- [3,5-bis (trifluoromethyl) benzyl] —2-phenyl — 7-methoxyquinoline — 4— carboxanmide
2,0 g (6,6 nmoli) di 3,5-bistrifluorometilbenzilaninina e 1,0 g (6,6 imoli) di carbonato di potassio anidro vengono sospesi in 40 mi di DMF anidra. Nella soluzione raffreddata a 0°C vengono gocciolati 1,0 g (3,3 mmoli) di 2-fenil-7-metossi-4-chinolincarbonil cloruro sciolti in 30 mi di DMF anidra e la reazione viene mantenuta a tenperatura ambiente per tutta la notte. 2.0 g (6.6 nmoles) of 3,5-bistrifluoromethylbenzylaninine and 1.0 g (6.6 imoles) of anhydrous potassium carbonate are suspended in 40 ml of anhydrous DMF. 1.0 g (3.3 mmoles) of 2-phenyl-7-methoxy-4-quinolincarbonyl chloride dissolved in 30 ml of anhydrous DMF are dropped into the solution cooled to 0 ° C and the reaction is kept at room temperature for the whole night.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in H2o ed estratto ccn AcCKt; la fase organica separata viene seccata su Na2S04, filtrata ed evaporata a secco sotto vuoto. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in H2o and extracted with AcCKt; the separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum.
Il residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando come eluente una miscela di esano/AcCEt 65:35 contenente lo 0,2% di NH4OH (al 28%) per ottenere 0,4 g del prodotto desiderato. The residue is purified by flash chromatography on silica gel (230-400 mesh), using as eluent a mixture of hexane / AcCEt 65:35 containing 0.2% NH4OH (at 28%) to obtain 0.4 g of the desired product.
ESfflPIO 7 EXAMPLE 7
N-(2-piridilinetil)—2-fenil—7-netossichinolina-4-carbossaninide N- (2-pyridylinethyl) -2-phenyl-7-netoxyquinoline-4-carboxaninide
1,3 mi (12,6 muoli) di 2-ainninanetilpiridina e 1,7 g (12,6 imoli) di carbonato di potassio anidro vengono sospesi, sotto azoto, in 25 mi di CH2CI2 anidro. Nella soluzione raffreddata con un bagno di ghiaccio vengono gocciolati 1,9 g (6,3 limoli) di 2-fenil-7-metossi-4-chinolincarbonil cloruro sciolti in 30 mi di CH2C1 anidro e la reazione viene mantenuta tra 0° e 5°C per 1 ora e poi a tenperatura anbiente per tutta la notte. 1.3 ml (12.6 muoles) of 2-ainninanethylpyridine and 1.7 g (12.6 imoles) of anhydrous potassium carbonate are suspended, under nitrogen, in 25 ml of anhydrous CH2CI2. 1.9 g (6.3 limols) of 2-phenyl-7-methoxy-4-quinolincarbonyl chloride dissolved in 30 ml of anhydrous CH2C1 are dropped into the solution cooled with an ice bath and the reaction is maintained between 0 ° and 5 ° C for 1 hour and then at room temperature for the whole night.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in AcCEt e lavato due volte con una sol. sat. di NaHGO3. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. L'olio residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando cane eluente AcOEt. Il solido purificato viene triturato con i-Pr2o, filtrato, lavato e seccato per ottenere 1,8 g del prodotto desiderato come solido bianco. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in AcCEt and washed twice with a sol. sat. by NaHGO3. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum. The residual oil is purified by flash chromatography on silica gel (230-400 mesh), using the eluent AcOEt. The purified solid is triturated with i-Pr2o, filtered, washed and dried to obtain 1.8 g of the desired product as a white solid.
LC/MS (flusso d'iniezione; interfaccia termospray; eluente acqua/acetonitrile 50:50, 0.05% TFA,sorgente 250°C):370 (MH)+. LC / MS (injection flow; thermospray interface; water / acetonitrile eluent 50:50, 0.05% TFA, source 250 ° C): 370 (MH) +.
ESEMPI 8 EXAMPLES 8
N-benzil-2-fenilchinolina-4-carbossaninide N-benzyl-2-phenylquinoline-4-carboxaninide
2,6 mi (24,0 mnoli) di benzilaitmina e 3,3 g (24,0 irrnoli) di carbonato di potassio anidro vengono sciolti, sotto azoto, in 20 mi di DMF anidra. Nella soluzione raffreddata con un bagno di ghiaccio vengono gocciolati 3,1 g (12,0 mmoli) di 2-fenil-4-chinolincarbonil cloruro sciolti in 40 mi di DMF anidra e la reazione viene mantenuta tra 0° e 5°C per 1 ora e poi a tenperatura ambiente per tutta la notte. 2.6 ml (24.0 mnoles) of benzylaithmin and 3.3 g (24.0 mnoles) of anhydrous potassium carbonate are dissolved, under nitrogen, in 20 ml of anhydrous DMF. 3.1 g (12.0 mmoles) of 2-phenyl-4-quinolincarbonyl chloride dissolved in 40 ml of anhydrous DMF are dropped into the solution cooled with an ice bath and the reaction is maintained between 0 ° and 5 ° C for 1 now and then at room temperature all night.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in AcOEt e lavato due volte con una sol. sat. di NaHCO3. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. L'olio residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando come eluente una miscela di esano/AcGEt 80:20 contenente lo 0,5% di NH4OH (al 28%). Il solido purificato viene cristallizzato da AcOEt, filtrato, lavato e seccato per ottenere 2,7 g del prodotto desiderato come solido bianco. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in AcOEt and washed twice with a sol. sat. of NaHCO3. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum. The residual oil is purified by flash chromatography on silica gel (230-400 mesh), using as eluent a mixture of hexane / AcGEt 80:20 containing 0.5% NH4OH (28%). The purified solid is crystallized from AcOEt, filtered, washed and dried to obtain 2.7 g of the desired product as a white solid.
ESEMPIO 9 EXAMPLE 9
N-fenil-2-fenil-7-metossichinolina-4-cartiossammide N-phenyl-2-phenyl-7-methoxyquinoline-4-cartyoxamide
1,7 mi (18,8 mmoli) di anilina e 2,5 g (18,8 mmoli) di carbonato di potassio anidro vengono sciolti, sotto azoto, in 15 ml di DMF anidra. Nella soluzione raffreddata con un bagno di ghiaccio vengalo gocciolati 2,9 g (9,4 mmoli) di 2-fenil-7-metossi-4-chinolincarbcnil cloruro sciolti in 40 mi di DMF anidra e la reazione viene mantenuta tra 0° e 5°C per 1 ora e poi a temperatura ambiente per tutta la notte. 1.7 ml (18.8 mmoles) of aniline and 2.5 g (18.8 mmoles) of anhydrous potassium carbonate are dissolved, under nitrogen, in 15 ml of anhydrous DMF. 2.9 g (9.4 mmoles) of 2-phenyl-7-methoxy-4-quinolincarbene chloride dissolved in 40 ml of anhydrous DMF are dropped into the solution cooled with an ice bath and the reaction is maintained between 0 ° and 5. ° C for 1 hour and then at room temperature overnight.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in AcOEt e lavato due volte con una sol. sat. di NaHCO3. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. L'olio residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando come eluente una miscela di esano/AcCEt 80:20 c(ritenente lo 0,5% di NH4CH (al 28%). Il solido purificato viene cristallizzato da toluene, filtrato, lavato e seccato per ottenere 1,9 g del prodotto desiderato come solido bianco. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in AcOEt and washed twice with a sol. sat. of NaHCO3. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum. The residual oil is purified by flash chromatography on silica gel (230-400 mesh), using a mixture of hexane / AcCEt 80:20 c (retaining 0.5% NH4CH (at 28%) as eluent. purified it is crystallized from toluene, filtered, washed and dried to obtain 1.9 g of the desired product as a white solid.
ESEMPIO 10 EXAMPLE 10
N-(2-metossibenzil)-2-fenil-7-metossichinolina-4-carbossammide N- (2-methoxybenzyl) -2-phenyl-7-methoxyquinoline-4-carboxamide
1,6 mi (12,6 mmoli) di 2-metossihenzilammina e 1,7 g (12,6 rimoli) di carbonato di potassio anidro vengono sciolti, sotto azoto, in 10 ml di DMF anidra. Nella soluzione raffreddata con un bagno di ghiaccio vengono gocciolati 1,9 g (6,3 mmoli) di 2-fenil-7-metossi-4-chinolincarbonii cloruro sciolti in 30 mi di DMF anidra e la reazione viene mantenuta tra 0° e 5°C per 1 ora e poi a temperatura ambiente per tutta la notte. 1.6 ml (12.6 mmoles) of 2-methoxyhenzylamine and 1.7 g (12.6 rimoles) of anhydrous potassium carbonate are dissolved, under nitrogen, in 10 ml of anhydrous DMF. 1.9 g (6.3 mmoles) of 2-phenyl-7-methoxy-4-quinolincarbonium chloride dissolved in 30 ml of anhydrous DMF are dropped into the solution cooled with an ice bath and the reaction is maintained between 0 ° and 5 ° C for 1 hour and then at room temperature overnight.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in AcOEt e lavato due volte con una sol. sat. di NaHCO3. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. L'olio residuo viene purificata mediante cromatografia flash su gel di silice (230-400 mesh) usando come eluente una miscela di esano/AcCEt 50:50. 11 solido purificato viene triturato con i-Pr2O, filtrato, lavato e seccato per ottenere 0,4 g del prodotto desiderato come solido giallo. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in AcOEt and washed twice with a sol. sat. of NaHCO3. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum. The residual oil is purified by flash chromatography on silica gel (230-400 mesh) using a mixture of hexane / AcCEt 50:50 as eluent. The purified solid is triturated with i-Pr2O, filtered, washed and dried to obtain 0.4 g of the desired product as a yellow solid.
LC/MS (flusso d'iniezione; interfaccia termospray; eluente acqua/acetonitrile 40:60,0.05% TFA,sorgente 250°C): 399 (MH)+. LC / MS (injection flow; thermospray interface; eluent water / acetonitrile 40: 60,0.05% TFA, source 250 ° C): 399 (MH) +.
ESEMPIO 11 EXAMPLE 11
N-fenetil-2-fenil-7-metossichinolina-4-carbossapinide N-phenethyl-2-phenyl-7-methoxyquinoline-4-carboxapinide
2,4 mi (18,8 mmoli) di fenetilamnina e 2,5 g (18,8 limoli) di carbonato di potassio anidro vengono sciolti, sotto azoto, in 15 mi di DMF anidra. Nella soluzione raffreddata con un bagno di ghiaccio vengono gocciolati 2,9 g (9,4 mmoli) di 2-fenil-7-metossi-4-chinolincarbonil cloruro sciolti in 40 mi di DMF anidra e la reazione viene mantenuta tra 0° e 5°C per 1 ora e poi a tenperatura ambiente per tutta la notte. 2.4 ml (18.8 mmoles) of phenethylamine and 2.5 g (18.8 limols) of anhydrous potassium carbonate are dissolved, under nitrogen, in 15 ml of anhydrous DMF. 2.9 g (9.4 mmoles) of 2-phenyl-7-methoxy-4-quinolincarbonyl chloride dissolved in 40 ml of anhydrous DMF are dropped into the solution cooled with an ice bath and the reaction is maintained between 0 ° and 5 ° C for 1 hour and then at room temperature for the whole night.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in AcOEt e lavato due volte con una sol. sat. di NaHCO3. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in AcOEt and washed twice with a sol. sat. of NaHCO3. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum.
L'olio residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh),usando cerne eluente una miscela di esano/AcCEt 80:20 contenente lo 0,5% di NH4OH (al 28%). Il solido purificato viene cristallizzato da toluene,filtrato, lavato e seccato per ottenere 2,3 g del prodotto desiderato cene solido bianco. The residual oil is purified by flash chromatography on silica gel (230-400 mesh), using an eluent mixture of hexane / AcCEt 80:20 containing 0.5% NH4OH (28%). The purified solid is crystallized from toluene, filtered, washed and dried to obtain 2.3 g of the desired white solid product.
Esavio 12 Hexavius 12
N-benzil -2-fenil-7- metossichinolina-4-cart)ossammide N-benzyl-2-phenyl-7-methoxyquinoline-4-cart) oxamide
0,5 g (1,6 mmoli) di acido 2-fenil-7-metossi-4-chinolincarbossilico e 0,3 g (2,1mmoli) di Ν,Ν'-carbcnildiimidazolo vengano sciolti, sotto azoto, in 10 ml di THF anidro e la soluzione viene mantenuta sotto agitazione magnetica per 3 ore. Si aggiungono 0,4 mi (2,4 mmoli) di benzilamnina e la soluzione viene tenuta a tenperatura ambiente per tutta la notte. 0.5 g (1.6 mmol) of 2-phenyl-7-methoxy-4-quinolincarboxylic acid and 0.3 g (2.1 mmol) of Ν, Ν'-carboxyldiimidazole are dissolved, under nitrogen, in 10 ml of THF anhydrous and the solution is kept under magnetic stirring for 3 hours. 0.4 ml (2.4 mmoles) of benzylamine are added and the solution is kept at room temperature overnight.
La miscela di reazione viene evaporata a secco sotto vuoto ed il residuo sciolto in Et20 e lavato due volte con una sol. sat. di NaHCO3. La fase organica separata viene seccata su Na2SO4, filtrata ed evaporata a secco sotto vuoto. L'olio residuo viene purificato mediante cromatografia flash su gel di silice (230-400 mesh), usando come eluente una miscela di esano/EtQAc 80:20 contenente lo 0,5% di NH4CH (al 28%). Il solido purificato viene triturato con i-Pr2O, filtrato, lavato e seccato per ottenere 0,33 g del prodotto desiderato cane solido bianco. The reaction mixture is evaporated to dryness under vacuum and the residue dissolved in Et20 and washed twice with a sol. sat. of NaHCO3. The separated organic phase is dried over Na2SO4, filtered and evaporated to dryness under vacuum. The residual oil is purified by flash chromatography on silica gel (230-400 mesh), using as eluent an 80:20 hexane / EtQAc mixture containing 0.5% NH4CH (28%). The purified solid is triturated with i-Pr2O, filtered, washed and dried to obtain 0.33 g of the desired white solid product.
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ES2236757T3 (en) * | 1995-11-24 | 2005-07-16 | Glaxosmithkline S.P.A. | DERIVATIVES OF QUINOLINA. |
GB9524137D0 (en) * | 1995-11-24 | 1996-01-24 | Smithkline Beecham Spa | Novel compounds |
AR004735A1 (en) * | 1995-11-24 | 1999-03-10 | Smithkline Beecham Spa | CHINOLEIN 4-AMIDO SUBSTITUTED, A PROCEDURE FOR ITS PREPARATION, A PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM AND THE USE OF THE SAME FOR THE PREPARATION OF A MEDICINAL PRODUCT. |
GB9524104D0 (en) | 1995-11-24 | 1996-01-24 | Smithkline Beecham Spa | Novel compounds |
JP4444375B2 (en) * | 1997-03-14 | 2010-03-31 | スミスクライン・ビーチャム・コーポレイション | Novel quinoline- and naphthalenecarboxamides, pharmaceutical compositions and methods of inhibiting calpain |
GB9819382D0 (en) * | 1998-09-04 | 1998-10-28 | Cerebrus Ltd | Chemical compounds I |
GB9825554D0 (en) * | 1998-11-20 | 1999-01-13 | Smithkline Beecham Spa | Novel Compounds |
DE60018707T2 (en) * | 1999-01-25 | 2006-02-09 | Smithkline Beecham Corp. | ANTI-ANDROGENES AND METHOD FOR THE TREATMENT OF DISEASES |
ATE247652T1 (en) * | 1999-03-29 | 2003-09-15 | Neurogen Corp | 4-SUBSTITUTED QUINOLINE DERIVATIVES AS NK-3 AND/OR GABA(A) RECEPTOR LIGANDS |
AU4802500A (en) | 1999-04-26 | 2000-11-10 | Neurogen Corporation | 2-aminoquinolinecarboxamides: neurokinin receptor ligands |
US6511987B1 (en) | 1999-11-12 | 2003-01-28 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
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US6310212B1 (en) | 2000-03-28 | 2001-10-30 | Neurogen Corporation | 4-substituted quinoline derivatives |
WO2002013825A1 (en) * | 2000-08-11 | 2002-02-21 | Smithkline Beecham P.L.C. | Novel pharmaceutical use of quinnoline derivatives |
GB0109122D0 (en) * | 2001-04-11 | 2001-05-30 | Smithkline Beecham Spa | Novel compounds |
EP1531849A2 (en) | 2002-05-24 | 2005-05-25 | Nathan C. Maier | System and method for inhibiting cellular proliferation with tachykinins |
GB0303086D0 (en) * | 2003-02-11 | 2003-03-19 | Merck Sharp & Dohme | New compounds |
GB0419192D0 (en) | 2004-08-27 | 2004-09-29 | Merck Sharp & Dohme | Therapeutic agents |
KR101238525B1 (en) * | 2004-12-31 | 2013-02-28 | 레디 유에스 테라퓨틱스 인코포레이티드 | Novel benzylamine derivatives as cetp inhibitors |
KR20080016591A (en) * | 2005-06-03 | 2008-02-21 | 아스트라제네카 아베 | Quinoline derivatives as nk3 antagonists |
GB0515580D0 (en) | 2005-07-29 | 2005-09-07 | Merck Sharp & Dohme | Therapeutic compounds |
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EP2986293A1 (en) | 2013-04-19 | 2016-02-24 | Astrazeneca AB | A nk3 receptor antagonist compound (nk3ra) for use in a method for the treatment of polycystic ovary syndrome (pcos) |
TWI636046B (en) | 2013-05-17 | 2018-09-21 | 美國禮來大藥廠 | Phenoxyethyl dihydro-1h-isoquinoline compounds |
WO2015094912A1 (en) | 2013-12-17 | 2015-06-25 | Eli Lilly And Company | Dimethylbenzoic acid compounds |
US10189788B2 (en) | 2014-09-09 | 2019-01-29 | Bayer Pharma Aktiengesellschaft | Substituted N,2-diarylquinoline-4-carboxamides and the use thereof as anti-inflammatory agents |
WO2016146602A1 (en) | 2015-03-18 | 2016-09-22 | Bayer Pharma Aktiengesellschaft | Substituted n-bicyclo-2-aryl-quinolin-4-carboxamides and use thereof |
WO2017153235A1 (en) | 2016-03-09 | 2017-09-14 | Bayer Pharma Aktiengesellschaft | Substituted n-cyclo-3-aryl-1-naphthamides and use thereof |
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WO2017153231A1 (en) | 2016-03-09 | 2017-09-14 | Bayer Pharma Aktiengesellschaft | Substituted n-cyclo-2-aryl-isoquinolinone-4-carboxamides and use thereof |
EA201992386A1 (en) * | 2017-04-10 | 2020-03-27 | Байер Акциенгезельшафт | SUBSTITUTED N-ARILETHYL-2-ARILKHINOLIN-4-CARBOXAMIDES AND THEIR APPLICATION |
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