HRP20030662A2 - Phosphodiesterase 4 inhibitors - Google Patents
Phosphodiesterase 4 inhibitors Download PDFInfo
- Publication number
- HRP20030662A2 HRP20030662A2 HR20030662A HRP20030662A HRP20030662A2 HR P20030662 A2 HRP20030662 A2 HR P20030662A2 HR 20030662 A HR20030662 A HR 20030662A HR P20030662 A HRP20030662 A HR P20030662A HR P20030662 A2 HRP20030662 A2 HR P20030662A2
- Authority
- HR
- Croatia
- Prior art keywords
- pyridylmethyl
- diphenylamine
- methoxy
- cyclopentyloxy
- substituted
- Prior art date
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- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title description 17
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 599
- -1 cyano, hydroxy Chemical group 0.000 claims description 371
- 125000000217 alkyl group Chemical group 0.000 claims description 208
- 150000001875 compounds Chemical class 0.000 claims description 197
- 125000004432 carbon atom Chemical group C* 0.000 claims description 176
- 229910052736 halogen Inorganic materials 0.000 claims description 157
- 150000002367 halogens Chemical class 0.000 claims description 157
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 110
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 93
- 125000003545 alkoxy group Chemical group 0.000 claims description 89
- 125000004043 oxo group Chemical group O=* 0.000 claims description 84
- 125000003118 aryl group Chemical group 0.000 claims description 81
- 125000006413 ring segment Chemical group 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 74
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 63
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 54
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 54
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 52
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 49
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
- 125000003282 alkyl amino group Chemical group 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 34
- 229920006395 saturated elastomer Polymers 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 26
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 26
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 24
- 125000002837 carbocyclic group Chemical group 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 20
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 19
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 18
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 18
- 125000004434 sulfur atom Chemical group 0.000 claims description 18
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 17
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 17
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 17
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 17
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 14
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 14
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
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- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 229940088598 enzyme Drugs 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 11
- PNIUJOQYAGLPHM-UHFFFAOYSA-N 3-[3-cyclopentyloxy-4-methoxy-n-(pyridin-3-ylmethyl)anilino]benzoic acid Chemical compound COC1=CC=C(N(CC=2C=NC=CC=2)C=2C=C(C=CC=2)C(O)=O)C=C1OC1CCCC1 PNIUJOQYAGLPHM-UHFFFAOYSA-N 0.000 claims description 11
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 11
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 10
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
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- 230000009467 reduction Effects 0.000 claims description 7
- 201000000980 schizophrenia Diseases 0.000 claims description 7
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- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- MYSNBAJHBYMBNT-UHFFFAOYSA-N n-[(3-cyclopentyloxy-4-methoxy-2h-pyridin-3-yl)methyl]-n-phenylaniline Chemical compound COC1=CC=NCC1(OC1CCCC1)CN(C=1C=CC=CC=1)C1=CC=CC=C1 MYSNBAJHBYMBNT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 6
- 125000005389 trialkylsiloxy group Chemical group 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- FDJBPHLXAYPMRF-UHFFFAOYSA-N 3-(3-cyclopentyloxy-4-methoxyanilino)benzoic acid Chemical compound C1=C(OC2CCCC2)C(OC)=CC=C1NC1=CC=CC(C(O)=O)=C1 FDJBPHLXAYPMRF-UHFFFAOYSA-N 0.000 claims description 5
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- RULLGLRZJAUWJC-UHFFFAOYSA-N 3-[3-(2,3-dihydro-1h-inden-2-yloxy)-4-methoxy-n-(pyridin-3-ylmethyl)anilino]benzoic acid Chemical compound C1=C(OC2CC3=CC=CC=C3C2)C(OC)=CC=C1N(C=1C=C(C=CC=1)C(O)=O)CC1=CC=CN=C1 RULLGLRZJAUWJC-UHFFFAOYSA-N 0.000 claims description 5
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- PFNVGWKABOYUIG-UHFFFAOYSA-N 4-[3-cyclopentyloxy-4-methoxy-n-(pyridin-3-ylmethyl)anilino]benzoic acid Chemical compound COC1=CC=C(N(CC=2C=NC=CC=2)C=2C=CC(=CC=2)C(O)=O)C=C1OC1CCCC1 PFNVGWKABOYUIG-UHFFFAOYSA-N 0.000 claims description 5
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Classifications
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- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C07C217/88—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/92—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the nitrogen atom of at least one of the amino groups being further bound to a carbon atom of a six-membered aromatic ring
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- 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
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
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- 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
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- 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
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Description
Ova prijava zahtijeva beneficiju U.S. Provisional application Serial No. 60/262,651, prijavljene 22. siječnja 2001., U. S. provisional application Serial No. 60/267,196, prijavljene 8. veljače, 2001., i U. S. Provisional application Serial No. 60/306,140, prijavljene 14. srpnja, 2001. This application claims the benefit of the U.S. Provisional application Serial No. 60/262,651, filed Jan. 22, 2001, U.S. provisional application Serial No. 60/267,196, filed Feb. 8, 2001, and U.S. Provisional application Serial No. 60/306,140, filed Jul. 14, 2001.
Polje izuma The field of invention
Ovaj izum se općenito odnosi na polje inhibicije enzima fosfodiesteraza 4 (PDE4). Određenije, ovaj izum se odnosi na selektivnu PDE4 inhibiciju novim spojevima, e. g., analozima N-supstituiranog anilina i difenilamina, na metode pripravljanja takvih spojeva, na smjese koje sadrže takve spojeve, i na metode njihovog korištenja. This invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically, this invention relates to selective PDE4 inhibition by novel compounds, e.g., analogs of N-substituted aniline and diphenylamine, to methods of preparing such compounds, to mixtures containing such compounds, and to methods of using them.
Pozadina izuma Background of the invention
Fosfodiesteraze specifične za cikličke nukleotide (PDEs) predstavljaju obitelj enzima koji kataliziraju hidrolizu raznih cikličkih nukleozid monofosfata (uključujući cAMP i cGMP). Ti ciklički nukleotidi djeluju kao sekundarni glasnici unutar stanica, te kao glasnici prenose impulse sa receptora stanične površine koji imaju vezane razne hormone i neurotransmitere. PDEs djeluju na reguliranju razine cikličkih nukleotida unutar stanica i održavanju homeostaze cikličkih nukleotida razlažući takve cikličke mononukleotide što rezultira završetkom njihove uloge glasnika. Cyclic nucleotide-specific phosphodiesterases (PDEs) are a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as secondary messengers inside the cells, and as messengers they transmit impulses from cell surface receptors that have various hormones and neurotransmitters bound to them. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by breaking down such cyclic mononucleotides resulting in the termination of their role as messengers.
PDE enzimi mogu se grupirati u jedanaest obitelji u skladu s njihovom specifičnošću prema hidrolizi cAMP-a ili cGMP-a, njihovom osjetljivošću na regulaciju kalcijem, kalmodulinom ili cGMP-om, i njihovom selektivnom inhibicijom raznim spojevima. Na primjer, PDE 1 je stimuliran Ca2+/kalmodulinom. PDE 2 je ovisan o cGMP-u, te je pronađen u srcu i nadbubrežnim žlijezdama. PDE 3 je ovisan o cGMP-u, a inhibicija tog enzima stvara pozitivno inotropično djelovanje. PDE 4 je specifičan za cAMP, a njegova inhibicija uzrokuje opuštanje dišnih puteva, protuupalno i antidepresivno djelovanje. Izgleda da je PDE 5 važan za regulaciju sadržaja cGMP-a u glatkom mišićju žila, te stoga PDE 5 inhibitori mogu imati kardiovaskularno djelovanje. Pošto PDEs posjeduju određene biokemijske značajke, vjerojatno su podvrgnute rasponu raznih oblika regulacije. PDE enzymes can be grouped into eleven families according to their specificity for hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin, or cGMP, and their selective inhibition by various compounds. For example, PDE 1 is stimulated by Ca2+/calmodulin. PDE 2 is cGMP-dependent and has been found in the heart and adrenal glands. PDE 3 is dependent on cGMP, and inhibition of this enzyme produces a positive inotropic effect. PDE 4 is specific for cAMP, and its inhibition causes airway relaxation, anti-inflammatory and antidepressant effects. PDE 5 appears to be important for the regulation of cGMP content in vascular smooth muscle, and therefore PDE 5 inhibitors may have cardiovascular effects. Since PDEs possess certain biochemical properties, they are likely to be subject to a range of different forms of regulation.
PDE4 je određen raznim kinetičkim značajkama uključujući niskom Michaelis konstantom za cAMP i osjetljivošću na određene lijekove. Obitelj PDE4 enzima se sastoji od četiri gena, što daje 4 izoforma PDE4 enzima, koji su označeni s PDE4A, PDE4B, PDE4C, i PDE4D [pogledaj: Wang et al., Expression, Purification, and Characterization human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234, 320-324 (1997)]. Dodatno su identificirane razne povezane ("splice") varijante svakog PDE4 izoforma. PDE4 is characterized by various kinetic features including a low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, giving rise to 4 isoforms of the PDE4 enzyme, designated PDE4A, PDE4B, PDE4C, and PDE4D [see: Wang et al., Expression, Purification, and Characterization of human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Crisp. Comm., 234, 320-324 (1997)]. In addition, various splice variants of each PDE4 isoform have been identified.
PDE4 izoenzimi su lokalizirani u citosolu stanica te nisu povezani ni s kojom poznatom membranoznom strukturom. PDE4 izoenzimi specifično inaktiviraju cAMP katalizirajući njegovu hidrolizu s adenozin 5'-monofosfata (AMP). Regulacija djelovanja cAMP-a je važna za mnoge biološke procese, uključujući upalu i pamćenje. Inhibitori PDE4 izoenzima kao što je rolipram, piklamilast, CDP-840 i ariflo su moćna protuupalna sredstva i stoga mogu biti korisna za tretiranje bolesti gdje je upala problematična, kao što je astma ili artritis. Dalje, rolipram poboljšava kognitivnu sposobnost štakora i miševa kod učenja paradigma. PDE4 isoenzymes are localized in the cytosol of cells and are not associated with any known membranous structure. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis with adenosine 5'-monophosphate (AMP). Regulation of cAMP action is important for many biological processes, including inflammation and memory. PDE4 isozyme inhibitors such as rolipram, piclamilast, CDP-840 and ariflo are potent anti-inflammatory agents and therefore may be useful for treating diseases where inflammation is problematic, such as asthma or arthritis. Furthermore, rolipram improves the cognitive performance of rats and mice in paradigm learning.
[image] [image]
rolipram piklamilast rolipram piclamilast
Dodatno takvim spojevima kao što je rolipram, derivati ksantina kao što je pentoksifilin, denbufilin, i teofilin inhibiraju PDE4 te su odnedavna dobili značajnu pažnju zbog njihovih učinaka na poboljšavanju kognicije. cAMP i cGMP su sekundarni glasnici koji posreduju stanične odgovore na mnoge različite hormone i neurotransmitere. Tako, do terapeutski značajnih učinaka može dovesti PDE inhibicija i rezultirajuće povećanje unutarstaničnog cAMP ili cGMP u ključnim stanicama, kao što su one locirane u živčanom sustavu i drugdje u tijelu. In addition to such compounds as rolipram, xanthine derivatives such as pentoxifylline, denbuphylline, and theophylline inhibit PDE4 and have recently received significant attention for their cognition-enhancing effects. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects can be achieved by PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body.
Rolipram, ranije u razvoju kao anti-depresiv, selektivno inhibira PDE4 enzim te je postao standardno sredstvo u klasifikaciji subtipova PDE enzima. Rani rad na PDE4 polju se fokusirao na depresiju i upalu, te je zatim bio proširen kako bi uključio indikacije kao što je demencija. [pogledaj "The PDE IV Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et al., Drugs of the Future 1992, 17(9): 799-807 za opći pregled). Dalji klinički razvoji roliprama i drugih PDE4 inhibitora prve generacije je bio prekinut zbog profila popratnih učinaka tih spojeva. Primarni popratni učinak kod primata je povraćanje, dok su primarni popratni učinci kod glodavaca testikularna degranulacija, slabljenje glatkog mišićja žila, psihotropni učinci, pojačano lučenje želučane kiseline te erozija stijenke želuca. Rolipram, earlier in development as an anti-depressant, selectively inhibits the PDE4 enzyme and has become the standard agent in the classification of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and was later expanded to include indications such as dementia. [see "The PDE IV Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et al., Drugs of the Future 1992, 17(9): 799-807 for a general review). Further clinical development of rolipram and other first-generation PDE4 inhibitors was halted due to the side effect profile of these compounds. The primary side effect in primates is vomiting, while the primary side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotropic effects, increased gastric acid secretion, and erosion of the stomach wall.
Sažetak izuma Summary of the invention
Ovaj izum se odnosi na nove spojeve, e. g., nove N-supstituirane anilin i difenilamin spojeve, koji inhibiraju PDE4 enzime, a osobito imaju poboljšane profile popratnih učinaka, e. g., relativno su ne-emetične (relativno ne izazivaju povraćanje), (e. g., u usporedbi s ranije raspravljenim spojevima kakve struka poznaje). Preferira se da spojevi selektivno inhibiraju PDE4 enzime. Spojevi ovog izuma u isto vrijeme olakšavaju ulazak u stanice, osobito stanice nervnog sustava. This invention relates to novel compounds, e.g., novel N-substituted aniline and diphenylamine compounds, which inhibit PDE4 enzymes, and in particular have improved side effect profiles, e.g., are relatively non-emetic (relatively non-emetic), (e.g., in compared to the previously discussed compounds known to the art). It is preferred that the compounds selectively inhibit PDE4 enzymes. The compounds of this invention at the same time facilitate entry into cells, especially cells of the nervous system.
Još dalje, ovaj izum pruža metode za sintetiziranje spojeva s takvim djelovanjem i selektivnošću kao i metode za (i odgovarajuće farmaceutske smjese za) tretiranje pacijenta, e. g., sisavaca, uključujući ljude, koji trebaju PDE inhibiciju, osobito PDE4 inhibiciju, za oboljenje koje uključuje povišene unutarstanične PDE 4 razine ili smanjene cAMP razine, e. g., koje uključuje neurološke sindrome, osobito ona stanja povezana sa slabljenjem pamćenja, najosobitije sa slabljenjem dugotrajnog pamćenja, gdje do takvog slabljenja pamćenja dolazi djelomice zbog katabolizma unutarstaničnih cAMP razina PDE 4 enzimima, ili gdje takvo slabljenje pamćenja može biti poboljšano učinkovitim inhibiranjem djelovanja PDE4 enzima. Still further, the present invention provides methods for synthesizing compounds with such activity and selectivity as well as methods for (and corresponding pharmaceutical compositions for) treating a patient, e.g., a mammal, including humans, in need of PDE inhibition, particularly PDE4 inhibition, for a disease involving elevated intracellular PDE 4 levels or reduced cAMP levels, e.g., which includes neurological syndromes, particularly those conditions associated with memory impairment, most notably long-term memory impairment, where such memory impairment occurs in part due to catabolism of intracellular cAMP levels by PDE 4 enzymes, or where such impairment memory can be improved by effectively inhibiting the action of the PDE4 enzyme.
U preferiranom aspektu, spojevi izuma olakšavaju takve bolesti inhibiranjem PDE4 enzima u dozama koje ne potiču povraćanje. In a preferred aspect, the compounds of the invention alleviate such diseases by inhibiting the PDE4 enzyme at doses that do not induce emesis.
Ovaj izum uključuje spojeve formule I: The present invention includes compounds of formula I:
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pri čemu whereby
R1 predstavlja alkil koji ima 1 do 4 ugljikovih atoma, koji je razgranat ili ravnolančan i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen (e. g.,CH3, CHF2, CF3, etc.); R1 represents an alkyl having 1 to 4 carbon atoms, which is branched or straight-chain and which is unsubstituted or substituted one or more times with: halogen (e.g., CH3, CHF2, CF3, etc.);
R2 predstavlja alkil koji ima 1 do 12, preferira se 1 do 8 ugljikovih atoma, koji je razgranat ili ravnolančan i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, hidroksi, cijano, C1-4-alkoksi, okso ili njihovim kombinacijama, te pri čemu su opcionalno jedna ili više -CH2CH2- grupa zamijenjeno u svakom slučaju s -CH=CH- ili -C≡C- (e. g., CH3,CHF2, CF3, metoksietil, etc.), R2 represents an alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or straight-chain and which is unsubstituted or substituted one or more times with: halogen, hydroxy, cyano, C1-4-alkoxy, oxo or combinations thereof , and optionally one or more -CH2CH2- groups are replaced in each case by -CH=CH- or -C≡C- (e.g., CH3,CHF2, CF3, methoxyethyl, etc.),
cikloalkil koji ima 3 do 10, preferira se 3 do 8 ugljikovih atoma, koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, hidroksi, okso, cijano, alkil koji ima 1 do 4 ugljikovih atoma, alkoksi koji ima 1 do 4 ugljikovih atoma, ili njihove kombinacije (e. g., ciklopentil), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times with: halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms atoms, or their combination (e.g., cyclopentyl),
cikloalkilalkil koji ima 4 do 16, preferira se 4 do 12 ugljikovih atoma, koji je nesupstituiran ili supstituiran u cikloalkil dijelu i/ili alkil dijelu jednom ili više puta s: halogen, okso, cijano, hidroksi, C1-4-alkil, C1-4-alkoksi ili njihovim kombinacijama (e. g., ciklopentilmetil, ciklopropilmetil, etc.), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl part and/or the alkyl part one or more times with: halogen, oxo, cyano, hydroxy, C1-4-alkyl, C1- 4-Alkoxy or their combinations (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),
aril koji ima 6 do 14 ugljikovih atoma, koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano, ili njihovim kombinacijama (e. g., metilfenil, metoksifenil, klorfenil, etc.), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted once or more with: halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorphenyl, etc.),
arilalkil u kojem aril dio ima 6 do 14 ugljikovih atoma, a alkil dio, koji je razgranat ili ravnolančan, ima 1 do 5 ugljikovih atoma, a koji arilalkil radikal je nesupstituiran ili je supstituiran u aril dijelu jednom ili više puta s: halogen, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, cijano, metilendioksi, etilendioksi, ili njihovim kombinacijama, a pri čemu su u alkil dijelu jedna ili više -CH2CH2- grupa svaka opcionalno zamijenjene s -CH=CH- ili -C≡C-, a jedna ili više -CH2-grupa su svaka opcionalno zamijenjene s -O- ili -NH- i/ili je alkil dio opcionalno supstituiran s: halogen, okso, hidroksi, cijano, ili njihovim kombinacijama (e. g., feniletil, fenilpropil, fenilbutil, metoksifeniletil, metoksifenilpropil, klorfeniletil, klorfenilpropil, feniletenil, fenoksietil, fenoksibutil, klorfenoksietil, klorfenilaminoetil, etc.), arylalkyl in which the aryl part has 6 to 14 carbon atoms and the alkyl part, which is branched or straight chain, has 1 to 5 carbon atoms, and which arylalkyl radical is unsubstituted or substituted in the aryl part one or more times with: halogen, CF3 . , and one or more -CH2-groups are each optionally substituted with -O- or -NH- and/or the alkyl moiety is optionally substituted with: halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl , methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),
djelomično nezasićena karbociklička grupa koja ima 5 do 14 ugljikovih atoma, koja je nesupstituirana ili supstituirana jednom ili više puta s: halogen, alkil, alkoksi, hidroksi, nitro, cijano, okso, ili njihovim kombinacijama (e. g., cikloheksenil, cikloheksadienil, indanil, tetrahidronaftenil, etc.), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times with: halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl , etc.),
heterociklička grupa, koja je zasićena, djelomično zasićena ili nezasićena, koja ima 5 do 10 atoma prstena u kojem najmanje 1 atom prstena je atom N, O ili S, koja je nesupstituirana ili supstituirana jednom ili više puta s: halogen, hidroksi, aril, alkil, alkoksi, cijano, trifluormetil, nitro, okso, ili njihovim kombinacijama (e. g., 3-tienil, 3-tetrahidrofuranil, 3-pirolil, etc.), ili a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times with: halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or
heterocikl-alkil grupa, pri čemu je heterociklički dio zasićen, djelomično zasićen ili nezasićen, te ima 5 do 10 atoma prstena u kojem najmanje 1 atom prstena je atom N, O ili S, a alkil dio je razgranat ili ravnolančan i ima 1 do 5 ugljikovih atoma, pri čemu je heterocikl-alkil grupa nesupstituirana ili supstituirana jednom ili više puta u heterocikličkom dijelu s: halogen, OCF3, hidroksi, aril, alkil, alkoksi, cijano, trifluormetil, nitro, okso, ili njihovim kombinacijama, pri čemu u alkil dijelu jedna ili više -CH2CH2- grupa su svaka opcionalno zamijenjene s -CH=CH- ili -C≡C-, a jedna ili više -CH2- grupa su svaka opcionalno zamijenjene s -O- ili -NH- i/ili je alkil dio opcionalno supstituiran s: halogen, okso, hidroksi, cijano, ili njihovim kombinacijama (e. g., piridiletil, pidridilpropil, metilpiperaziniletil, etc.); heterocycle-alkyl group, wherein the heterocyclic part is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl part is branched or straight chain and has 1 to 5 of carbon atoms, wherein the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic part with: halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or their combinations, wherein in alkyl part one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH2- groups are each optionally replaced by -O- or -NH- and/or is alkyl part optionally substituted with: halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pyridylpropyl, methylpiperazinylethyl, etc.);
R3predstavlja H, R3 represents H,
alkil koji ima 1 do 8, preferira se 1 do 4 ugljikovih atoma, koji je razgranat ili ravnolančan i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, cijano, C1-4-alkoksi, ili njihovim kombinacijama (e. g., metil, etil, propil, etc.), alkyl having 1 to 8, preferably 1 to 4, carbon atoms, which is branched or straight chain and which is unsubstituted or substituted one or more times with: halogen, cyano, C1-4-Alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),
djelomično nezasićena karbocikl-alkil grupa gdje karbociklički dio ima 5 do 14 ugljikovih atoma, a alkil dio koji je razgranat ili ravnolančan ima 1 do 5 ugljikovih atoma, i koja je nesupstituirana ili supstituirana u karbocikličkom dijelu jednom ili više puta s: halogen, alkil, alkoksi, nitro, cijano, okso, ili njihovim kombinacijama, a alkil dio je opcionalno supstituiran s: halogen, C1-4-alkoksi, cijano ili njihovim kombinacijama (e. g., cikloheksenilmetil, etc.), a partially unsaturated carbocycle-alkyl group where the carbocyclic part has 5 to 14 carbon atoms and the branched or straight-chain alkyl part has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic part one or more times with: halogen, alkyl, lkoxy, nitro, cyano, oxo, or their combinations, and the alkyl part is optionally substituted with: halogen, C1-4-alkoxy, cyano or their combinations (e.g., cyclohexenylmethyl, etc.),
arilalkil koji ima 7 do 19 ugljikovih atoma, pri čemu aril dio ima 6 do 14 ugljikovih atoma, a alkil dio, koji je razgranat ili ravnolančan, ima 1 do 5 ugljikovih atoma, pri čemu je arilalkil radikal nesupstituiran ili supstituiran, u aril dijelu, jednom ili više puta s: halogen, trifluormetil, CF30, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino i/ili koji je supstituiran u alkil dijelu s: halogen, cijano, ili metil (e. g., benzil, fenetil, fenpropil, metilbenzil, metoksibenzil, trifluormetil, benzil, metilendioksobenzil, etc.), ili arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms, and the alkyl portion, which is branched or straight chain, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times with: halogen, trifluoromethyl, CF30, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or which is substituted in the alkyl part with: halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl , methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), or
heteroarilalkil grupa, pri čemu heteroaril dio može biti djelomično ili potpuno zasićen te ima 5 do 10 atoma prstena u kojem najmanje 1 atom prstena je atom N, O ili S, a alkil dio, koji je razgranat ili ravnolančan, ima 1 do 5 ugljikovih atoma, pri čemu je heteroarilalkil grupa nesupstituirana ili supstituirana jednom ili više puta u heteroaril dijelu s: halogen, alkil, alkoksi, cijano, trifluormetil, CF30, nitro, okso, amino, alkilamino, dialkilamino, ili njihovim kombinacijama i/ili supstituirana u alkil dijelu s: halogen, cijano, ili metil ili njihovim kombinacijama (e. g., piridilmetil, piridilpropil, metilpiridilmetil, klorpiridilmetil, diklorpiridilmetil, tienilmetil, tiazolilmetil, kinolinilmetil, izokinolinilmetil, piperidinilmetil, furanilmetil, imidazolilmetil, metilimidazolilmetil, pirolilmetil, etc.); heteroarylalkyl group, wherein the heteroaryl part can be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl part, which is branched or straight chain, has 1 to 5 carbon atoms , wherein the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl part with: halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF30, nitro, oxo, amino, alkylamino, dialkylamino, or their combinations and/or substituted in the alkyl part with: halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);
R4predstavlja H, R4 represents H,
aril koji ima 6 do 14 ugljikovih atoma i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, alkil, alkenil, alkinil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluormetil, OCF3, amino, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (eg., hidroksimetil), hidroksamska kiselina, tetrazol-5-il, 2(-heterocikl)tetrazol-5-il (eg., 2-(2-tetrahidropiranil)tetrazol-5-il), hidroksialkoksi, karboksi, alkoksikarbonil (e. g., tert-butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi (eg.tert- butildimetilsililoksi), R5-1-, ili njihovim kombinacijama (e. g., supstituirani ili nesupstituirani fenil, naftil, i bifenil, kao što je fenil, metilfenil, klorfenil, fluorfenil, vinilfenil, cijanofenil, metilendioksofenil, etilfenil, diklorfenil, karboksifenil, etoksikarbonilfenil, dimetilfenil, hidroksimetilfenil, nitrofenil, aminofenil, etc.), ili aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times with: halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF3, amino, aminoalkyl, aminoalkyldialkylamino , hydroxyalkyl (eg, hydroxymethyl), hydroxamic acid, tetrazol-5-yl, 2(-heterocycl)tetrazol-5-yl (eg, 2-(2-tetrahydropyranyl)tetrazol-5-yl), hydroxy alkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. tert-butyldimethylsilyloxy), R5-1-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or
heteroaril koji ima 5 do 10 atoma prstena u kojem najmanje 1 atom prstena je heteroatom, koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluormetil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (eg., hidroksimetil), hidroksamska kiselina, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil (e. g., tert-butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi (eg. tert-butildimetilsililoksi), R5-1-, ili njihovim kombinacijama (e. g., piridil, tienil, pirazinil, kinolinil, izokinolinil, pirimidinil, imidazolil, tiazolil, etc.); heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times with: halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg, hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (eg, tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg tert-butyldimethylsilyloxy), R5-1-, or their combinations (eg, pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);
R5 predstavlja H, R5 represents H,
alkil koji ima 1 do 8, preferira se 1 do 4 ugljikovih atoma, koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, Cl-4-alkil, C1-4-alkoksi, okso, ili njihovim kombinacijama (e. g., metil, etil, propil, etc.), alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with: halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),
alkilamino ili dialkilamino pri čemu svaki alkil dio ima nezavisno 1 do 8, preferira se 1 do 4 ugljikovih atoma (e. g., dimetilamino, etc.), alkylamino or dialkylamino wherein each alkyl moiety independently has 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.),
djelomično nezasićena karbocikl-alkil grupa gdje karbociklički dio ima 5 do 14 ugljikovih atoma, a alkil dio ima 1 do 5 ugljikovih atoma, a koja je nesupstituirana ili supstituirana, preferira se u karbocikličkom dijelu, jednom ili više puta s: halogen, alkil, alkoksi, nitro, cijano, okso, ili njihovim kombinacijama (e. g., cikloheksenilmetil, etc.), a partially unsaturated carbocycle-alkyl group where the carbocyclic part has 5 to 14 carbon atoms and the alkyl part has 1 to 5 carbon atoms, and which is unsubstituted or substituted, preferably in the carbocyclic part, one or more times with: halogen, alkyl, alkoxy , nitro, cyano, oxo, or their combinations (e.g., cyclohexenylmethyl, etc.),
cikloalkil koji ima 3 do 10, preferira se 3 do 8 ugljikovih atoma, koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, hidroksi, okso, cijano, alkoksi, alkil koji ima 1 do 4 ugljikovih atoma, ili njihovim kombinacijama (e. g., ciklopentil), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times with: halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof (e.g. , cyclopentyl),
cikloalkilalkil koji ima 4 do 16, preferira se 4 do 12 ugljikovih atoma, koji je nesupstituiran ili supstituiran u cikloalkil dijelu i/ili alkil dijelu jednom ili više puta s: halogen, okso, cijano, hidroksi, alkil, alkoksi ili njihovim kombinacijama (e. g., ciklopentilmetil, ciklopropilmetil, etc.), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl part and/or alkyl part one or more times with: halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g. , cyclopentylmethyl, cyclopropylmethyl, etc.),
aril koji ima 6 do 14 ugljikovih atoma i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluormetil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (eg., hidroksimetil), hidroksamska kiselina,tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil (e.g., tert-butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, (e. g., supstituirani ili nesupstituirani fenil i naftil, metilfenil, klorfenil, fluorfenil, vinilfenil, cijanofenil, metilendioksofenil, etilfenil, diklorfenil, karboksifenil, etoksikarbonilfenil, dimetilfenil, hidroksimetilfenil, nitrofenil, aminofenil, etc.), aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times with: halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg ., hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl , chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),
arilalkil koji ima 7 do 19 ugljikovih atoma, pri čemu aril dio ima 6 do 14 ugljikovih atoma, a alkil dio, koji je razgranat ili ravnolančan, ima 1 do 5 ugljikovih atoma, pri čemu je arilalkil radikal nesupstituiran ili supstituiran, u aril dijelu, jednom ili više puta s: halogen, trifluormetil, CF3O, nitro, amino, alkil, alkoksi, amino, alkilamino, dialkilamino i/ili supstituiran u alkil dijelu s: halogen, cijano, ili metil (e. g., benzil, fenetil, fenpropil, metilbenzil, metoksibenzil, trifluormetil, benzil, metilendioksobenzil, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms, and the alkyl portion, which is branched or straight chain, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times with: halogen, trifluoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl part with: halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl , methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.),
heterociklička grupa, koja je zasićena, djelomično zasićena ili nezasićena, koja ima 5 do 10 atoma prstena u kojem najmanje 1 atom prstena je atom N, O ili S, koja je nesupstituirana ili supstituirana jednom ili više puta s: halogen, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluormetil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (eg., hidroksimetil), hidroksamska kiselina, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil (e. g.,tert-butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, ili njihovim kombinacijama (e. g., piridil, tienil, pirazinil, kinolinil, izokinolinil, pirimidinil, imidazolil, tiazolil, etc.), ili a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times with: halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazol-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or
heterocikl-alkil grupa, pri čemu je heterociklički dio zasićen, djelomično zasićen ili nezasićen, te ima 5 do 10 atoma prstena u kojem najmanje 1 atom prstena je atom N, O ili S i alkil dio, koji je razgranat ili ravnolančan te ima 1 do 5 ugljikovih atoma, pri čemu je heterocikl-alkil grupa nesupstituirana ili supstituirana jednom ili više puta u heterocikličkom dijelu s: halogen, alkil, alkoksi, cijano, trifluormetil, CF3O, nitro, okso, amino, alkilamino, dialkilamino, ili njihovim kombinacijama i/ili supstituirana u alkil dijelu s: halogen, cijano, ili metil, ili njihovim kombinacijama (e. g., piridilmetil, piridilpropil, metilpridilmetil, etc.); heterocycle-alkyl group, wherein the heterocyclic part is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom and the alkyl part, which is branched or straight chain and has 1 to 5 carbon atoms, whereby the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic part with: halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or their combinations and/ or substituted in the alkyl part with: halogen, cyano, or methyl, or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, etc.);
L predstavlja jednostruku vezu ili divalentni alifatski radikal koji ima 1 do 8 ugljikovih atoma pri čemu su jedna ili više -CH2- grupa svaka opcionalno zamijenjene s: -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, ili -NHCSNH- (e.g., -O-, CH2-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2CH2CH2-NH-CO-, -CH2-CH2-O-, -SO2-NH-CH2CH2-O-, -O-CH2CH2-O-, -CH2-NH-CO-, -CO-NH-CH2-, -SO2-NH-, -CH2-NH-SO2-, -CH2CH2CH2-SO2-NH-, etc.); a L represents a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms, where one or more -CH2- groups are each optionally replaced by: -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g., -O-, CH2-, -CO-, - CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2CH2CH2-NH-CO-, -CH2-CH2-O-, -SO2-NH-CH2CH2-O-, - O-CH2CH2-O-, -CH2-NH-CO-, -CO-NH-CH2-, -SO2-NH-, -CH2-NH-SO2-, -CH2CH2CH2-SO2-NH-, etc.); And
R6predstavlja H, R6 represents H,
alkil koji ima 1 do 8, preferira se 1 do 4 ugljikovih atoma, koji je razgranat ili ravnolančan i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, Cl-4-alkil, Cl-4-alkoksi, okso, ili njihovim kombinacijama (e. g., metil, etil, propil, etc.); alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or straight chain and which is unsubstituted or substituted one or more times with: halogen, C1-4-alkyl, C1-4-alkoxy, oxo, or their combinations (eg, methyl, ethyl, propyl, etc.);
pri čemu najmanje jedan od R3 i R4 ne predstavlja H; i wherein at least one of R3 and R4 does not represent H; and
njihove farmaceutski prihvatljive soli. their pharmaceutically acceptable salts.
U skladu s daljim aspektom izuma pružen je rod novih spojeva u skladu s formulama II i III: In accordance with a further aspect of the invention, a class of new compounds according to formulas II and III is provided:
[image] [image]
pri čemu R1, R2, R3, i R4 su kao što su definirani gore. Spojevi tog podroda formule I ne samo da imaju inhibirajuće djelovanje na PDE4, nego su također korisni kao intermedijeri za pripravljanje spojeva formule I u kojoj R3 i R4 oba nisu H. wherein R1, R2, R3, and R4 are as defined above. Compounds of this subfamily of formula I not only have PDE4 inhibitory activity, but are also useful as intermediates for the preparation of compounds of formula I wherein R 3 and R 4 are both non-H.
Dodatno, preferirani spojevi formule I su oni podformule IV Additionally, preferred compounds of formula I are those of subformula IV
[image] [image]
pri čemu R1, R2, i R4 su kao što su definirani u formuli I, jedan od A, B i D je N, a drugi su C. Preferira se da B predstavlja N. Također, R4 predstavlja, preferira se, piridil ili fenil koji je u svakom slučaju supstituiran ili nesupstituiran. wherein R 1 , R 2 , and R 4 are as defined in formula I, one of A, B, and D is N and the other is C. It is preferred that B represents N. Also, R 4 is preferably pyridyl or phenyl which is in any case substituted or unsubstituted.
Ovaj izum također uključuje spojeve formule I': This invention also includes compounds of formula I':
[image] [image]
pri čemu whereby
R1predstavlja metoksi, F, Cl, CHF2 ili CF3 ; R1 represents methoxy, F, Cl, CHF2 or CF3;
R2predstavlja R2 represents
alkil koji ima 1 do 12 ugljikovih atoma, alkyl having 1 to 12 carbon atoms,
alkil koji ima 1 do 12 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, okso, cijano, ili njihovim kombinacijama, alkyl having 1 to 12 carbon atoms which is substituted one or more times with: halogen, oxo, cyano, or their combinations,
alkenil koji ima 2 do 12 ugljikovih atoma, alkenyl having 2 to 12 carbon atoms,
alkenil koji ima 2 do 12 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, okso, cijano ili njihovim kombinacijama, alkenyl having 2 to 12 carbon atoms which is substituted one or more times with: halogen, oxo, cyano or their combinations,
alkinil koji ima 2 do 12 ugljikovih atoma, alkynyl having 2 to 12 carbon atoms,
alkinil koji ima 2 do 12 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, okso, cijano ili njihovim kombinacijama, alkynyl having 2 to 12 carbon atoms which is substituted one or more times with: halogen, oxo, cyano or their combinations,
cikloalkil koji ima 3 do 10 ugljikovih atoma, cycloalkyl having 3 to 10 carbon atoms,
cikloalkil koji ima 3 do 10 ugljikovih atoma supstituiranih jednom ili više puta s: halogen, okso, alkil, ili njihovim kombinacijama, cycloalkyl having 3 to 10 carbon atoms substituted one or more times with: halogen, oxo, alkyl, or their combinations,
cikloalkilalkil koji ima 4 do 12 ugljikovih atoma, cycloalkylalkyl having 4 to 12 carbon atoms,
cikloalkilalkil koji ima 4 do 12 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, okso, alkil ili njihovim kombinacijama, cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or more times with: halogen, oxo, alkyl or combinations thereof,
djelomično nezasićena karbociklička grupa koja ima 5 do 14 ugljikovih atoma, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
djelomično nezasićena karbociklička grupa koja ima 5 do 14 ugljikovih atoma koja je supstituirana jednom ili više puta s: halogen, alkil, alkiloksi, nitro, cijano, okso, ili njihovim kombinacijama, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms that is substituted one or more times with: halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof,
arilalkil koji ima 7 do 26 ugljikovih atoma arylalkyl having 7 to 26 carbon atoms
arilalkil koji ima 7 do 26 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, alkil, alkoksi, nitro, cijano, okso, trifluormetil, ili njihovim kombinacijama, arylalkyl having 7 to 26 carbon atoms which is substituted one or more times with: halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof,
heteroarilalkil koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom, ili heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
supstituirani heteroarilalkil koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom i koji je supstituiran jednom ili više puta u heteroaril dijelu s: halogen, aril, alkil, alkoksi, cijano, trifluormetil, nitro, amino, alkilamino, dialkilamino ili njihovim kombinacijama i/ili supstituiran u alkil dijelu s: halogen, okso, cijano, ili njihovim kombinacijama; substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion with: halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or by their combinations and/or substituted in the alkyl part with: halogen, oxo, cyano, or their combinations;
X predstavlja O ili S; X represents O or S;
R3 predstavlja aril koji ima 6 do 14 ugljikovih atoma, R3 represents aryl having 6 to 14 carbon atoms,
aril koji ima 6 do 14 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, heteroaril koji je nesupstituiran ili supstituiran s: halogen, alkil ili alkoksi, ili njihovim kombinacijama, aryl having 6 to 14 carbon atoms that is substituted one or more times with: halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkyl, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio , alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted with: halogen, alkyl or alkoxy, or combinations thereof,
heteroaril koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom, ili heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
supstituirani heteroaril koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom koji je supstituiran jednom ili više puta s: halogen, aril, alkil, alkoksi, cijano, trifluormetil, nitro, okso, amino, alkilamino, dialkilamino ili njihovim kombinacijama; substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom substituted one or more times with: halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof ;
L predstavlja -NH-, -NR4-, -NHCH2-, -NR4CH2-, ili -CH2NR4-; a L represents -NH-, -NR4-, -NHCH2-, -NR4CH2-, or -CH2NR4-; And
R4 predstavlja alkil koji ima 1 do 12 ugljikovih atoma, R4 represents alkyl having 1 to 12 carbon atoms,
alkil koji ima 1 do 12 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, okso, cijano, ili njihovim kombinacijama, alkyl having 1 to 12 carbon atoms which is substituted one or more times with: halogen, oxo, cyano, or their combinations,
aril koji ima 6 do 14 ugljikovih atoma i koji je nesupstituiran ili supstituiran jednom ili više puta s: halogen, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi ili njihovim kombinacijama, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted once or more with: halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy or their combinations,
heteroaril koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom,
supstituirani heteroaril koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom i koji je supstituiran jednom ili više puta s: halogen, aril, alkil, alkoksi, cijano, trifluormetil, nitro, okso, amino, alkilamino, dialkilamino ili njihovim kombinacijama, substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times with: halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or their combinations,
arilalkil koji ima 7 do 16 ugljikovih atoma, arylalkyl having 7 to 16 carbon atoms,
arilalkil koji ima 7 do 16 ugljikovih atoma koji je supstituiran jednom ili više puta s: halogen, alkil, alkoksi, nitro, cijano, okso, trifluormetil, ili njihovim kombinacijama arylalkyl having 7 to 16 carbon atoms which is substituted one or more times with: halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof
heteroarilalkil koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom, ili heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
supstituirani heteroarilalkil koji ima 5 do 10 atoma prstena u kojem je najmanje 1 atom prstena heteroatom i koji je supstituiran jednom ili više puta u heteroaril dijelu s: halogen, aril, alkil, alkoksi, cijano, trifluormetil, nitro, okso, amino, alkilamino, dialkilamino ili njihovim kombinacijama i/ili supstituiran u alkil dijelu s: halogen, okso, cijano, ili njihovim kombinacijama; i substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl part with: halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or their combinations and/or substituted in the alkyl part with: halogen, oxo, cyano, or their combinations; and
njihove farmaceutski prihvatljive soli. their pharmaceutically acceptable salts.
Spojevi ovog izuma su učinkoviti u inhibiranju, ili moduliranju djelovanja PDE4 kod životinja, e. g., sisavaca, osobito ljudi. Ti spojevi pokazuju neurološko djelovanje, osobito gdje takvo djelovanje utječe na kogniciju, uključujući dugotrajno pamćenje. Ti spojevi će također biti učinkoviti za tretiranje bolesti gdje su ukljućene smanjene razine cAMP-a. To uključuje, ali nije time ograničeno, upalne bolesti. Ti spojevi mogu također djelovati kao antidepresivi, ili biti korisni kod tretiranja kognitivnih i negativnih simptoma šizofrenije. The compounds of this invention are effective in inhibiting or modulating the action of PDE4 in animals, e.g., mammals, especially humans. These compounds exhibit neurological activity, particularly where such activity affects cognition, including long-term memory. These compounds will also be effective for treating diseases where reduced levels of cAMP are involved. This includes, but is not limited to, inflammatory diseases. These compounds may also act as antidepressants, or be useful in treating the cognitive and negative symptoms of schizophrenia.
Analize za određivanje PDE inhibirajućeg djelovanja kao i selektivnosti PDE 4 inhibirajućeg djelovanja i selektivnosti inhibiranja PDE 4 izoenzima su poznate unutar struke. Pogledaj, e. g., US 6,136,821, čija je objava uključena ovdje referencom. Assays for determining PDE inhibitory activity as well as selectivity of PDE 4 inhibitory activity and selectivity of PDE 4 isoenzyme inhibition are known in the art. See, e.g., US 6,136,821, the disclosure of which is incorporated herein by reference.
U skladu s daljim aspektom izuma pruženi su spojevi korisni kao intermedijeri za proizvodnju ovdje opisanih PDE4 inhibitora (e. g., PDE4 inhibitori formule I) i/ili korisni za sintetiziranje radio-označenih analoga PDE4 inhibitora s u ovoj prijavi. In accordance with a further aspect of the invention, there are provided compounds useful as intermediates for the production of the PDE4 inhibitors described herein (e.g., PDE4 inhibitors of formula I) and/or useful for synthesizing radiolabeled analogs of the PDE4 inhibitors described herein.
Tako, pruženi su spojevi intermedijeri koji odgovaraju spojevima formule I, pri čemu R2, R3, i R4 su kao što su definirani ranije za formulu I, ali R1 predstavlja H, tert-butildimetilsilil-, ili prikladnu fenolnu zaštitnu grupu. Prikladne fenolne zaštitne grupe su opisane, na primjer; u Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. Ti intermedijeri su također korisni za sintetiziranje radio-označenih spojeva, kao što su oni gdje R1 predstavlja 3H3C-, 14CH3- ili 11CH3-, na primjer uklanjanjem zaštitne grupe i reagiranjem rezultirajućeg spoja u kojem R1 predstavlja H s prikladnim radio-označenim reagensima. Takvi radio-označeni spojevi su korisni za određivanje raspodijele spoja u tkivu kod životinja, kod studija PET prikaza, i za in vivo, ex vivo, i in vitro studije vezanja. Thus, there are provided intermediate compounds corresponding to compounds of formula I, wherein R 2 , R 3 , and R 4 are as defined earlier for formula I, but R 1 represents H, tert-butyldimethylsilyl-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example; in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for synthesizing radiolabelled compounds, such as those where R1 is 3H3C-, 14CH3- or 11CH3-, for example by removing the protecting group and reacting the resulting compound where R1 is H with suitable radiolabelled reagents. Such radiolabeled compounds are useful for determining the tissue distribution of the compound in animals, in PET imaging studies, and for in vivo, ex vivo, and in vitro binding studies.
Također se pružaju spojevi intermedijeri koji odgovaraju spojevima formule I, pri čemu R1, R3, i R4 su kao što su definirani ranije za formulu I, ali R2 predstavlja H, tert-butildimetilsililoksi-, ili prikladnu fenolnu zaštitnu grupu. Prikladne fenolne zaštitne grupe su opisane, na primjer, kod: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. Spojevi u kojima R2 predstavlja H su korisni kao intermedijeri, na primjer, kao skele za paralelne ili kombinatorijske kemijske primjene. Nadalje, ti spojevi su korisni za uvođenje radio-označivaća kao što je 3H, 14C, ili 11C. Also provided are intermediate compounds corresponding to compounds of formula I, wherein R 1 , R 3 , and R 4 are as defined above for formula I, but R 2 represents H, tert-butyldimethylsilyloxy-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example, in: Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. Compounds in which R2 is H are useful as intermediates, for example, as scaffolds for parallel or combinatorial chemical applications. Furthermore, these compounds are useful for introducing radiolabels such as 3H, 14C, or 11C.
Kao što je ranije opisano, spojevi u skladu s formulom II, pri čemu su Rl, R2 i R4 kao što je ranije opisano, su korisni intermedijeri za proizvodnju spojeva u skladu s formulom I gdje R3 nije H. As previously described, compounds of formula II, wherein R 1 , R 2 , and R 4 are as previously described, are useful intermediates for the production of compounds of formula I wherein R 3 is not H.
Također, kao što je ranije opisano, spojevi u skladu s formulom III, pri čemu Rl, R2 i R3 su kao što je ranije opisano, su korisni intermedijeri za proizvodnju spojeva u skladu s formulom I gdje R4 nije H. Also, as previously described, compounds of formula III, wherein R 1 , R 2 , and R 3 are as previously described, are useful intermediates for the production of compounds of formula I wherein R 4 is not H.
Halogen se ovdje odnosi na F, Cl, Br, i I. Preferirani halogeni su F i Cl. Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl.
Alkil, kao grupa ili supstituent per se ili kao dio grupe ili supstituenta (e. g., alkilamino, trialkilsililoksi, aminoalkil, hidroksialkil), predstavlja ravnolančani ili razgranati alifatski ugljikovodični radikal koji ima 1 do 12 ugljikovih atoma, preferira se 1 do 8 ugljikovih atoma, osobito 1 do 4 ugljikovih atoma. Prikladne alkil grupe uključuju metil, etil, propil, izopropil, butil, sec-butil, tert-butil, pentil, heksil, heptil, oktil, nonil, decil, undecil, i dodecil. Drugi primjeri prikladnih alkil grupa uključuju 1-, 2- ili 3-metilbutil, 1,1-, 1,2- ili 2,2-dimetilpropil, 1-etilpropil, 1-, 2-, 3- ili 4-metilpentil, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- ili 3,3-dimetilbutil, 1- ili 2-etilbutil, etilmetilpropil, trimetilpropil, metilheksil, dimetilpentil, etilpentil, etilmetilbutil, dimetilbutil, i slično. Alkyl, as a group or substituent per se or as part of a group or substituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), represents a straight-chain or branched aliphatic hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, especially 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1 ,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl , and similar.
Supstituirane alkil grupe su alkil grupe kao što je opisano gore koje su supstituirane na jednoj ili više pozicija s: halogeni, okso, hidroksil, C1-4-alkoksi i/ili cijano. Halogeni su preferirani supstituenti, osobito F i Cl. Substituted alkyl groups are alkyl groups as described above which are substituted in one or more positions with: halogens, oxo, hydroxyl, C1-4-Alkoxy and/or cyano. Halogens are preferred substituents, especially F and Cl.
Alkoksi predstavlja alkil-O- grupe, a alkoksialkoksi predstavlja alkil-O-alkil-O- grupe u kojima su alkil dijelovi u skladu s ranijom raspravom. Prikladne alkoksi i alkoksialkoksi grupe uključuju metoksi, etoksi, propoksi, butoksi, pentoksi, heksoksi, heptoksi, oktoksi metoksimetoksi etoksimetoksi, propoksimetoksi, i metoksietoksi. Preferirane alkoksi grupe su metoksi i etoksi. Slično, alkoksikarbonil predstavlja alkil-O-CO- u kojem je alkil dio u skladu s ranijom raspravom. Primjeri uključuju metoksikarbonil, etoksikarbonil, propoksikarbonil, i tert-butoksikarbonil. Alkoxy represents alkyl-O- groups and alkoxyalkoxy represents alkyl-O-alkyl-O- groups in which the alkyl moieties are in accordance with the earlier discussion. Suitable alkoxy and alkyloxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxymethoxy, and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl represents alkyl-O-CO- in which the alkyl moiety is consistent with the earlier discussion. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.
Cikloalkil predstavlja monociklički, biciklički ili triciklički nearomatski zasićeni ugljikovodični radikal koji ima 3 do 10 ugljikovih atoma, preferira se 3 do 8 ugljikovih atoma, osobito 3 do 6 ugljikovih atoma. Prikladne cikloalkil grupe uključuju ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, ciklooktil, norbornil, 1-dekalin, adamant-1-il, i adamant-2-il. Druge prikladne cikloalkil grupe uključuju spiropentil, biciklo[2.1.0]pentil, biciklo[3.1.0]heksil, spiro[2.4]heptil, spiro[2.5]oktil, biciklo[5.1.0]oktil, spiro[2.6]nonil, biciklo[2.2.0]heksil, spiro[3.3]heptil, biciklo[4.2.0]oktil, i spiro[3.5]nonil. Preferirane cikloalkil grupe su ciklopropil, ciklopentil i cikloheksil. Cikloalkil grupa može biti supstituirana, na primjer, supstituirana s: halogeni i/ili alkil grupe. Cycloalkyl is a monocyclic, bicyclic or tricyclic non-aromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo [2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be substituted, for example, substituted with: halogens and/or alkyl groups.
Cikloalkilalkil se odnosi na cikloalkil-alkil radikale u kojima su cikloalkil i alkil dijelovi u skladu s ranijim raspravama. Prikladni primjeri uključuju ciklopropilmetil i ciklopentilmetil. Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl moieties are consistent with the earlier discussions. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.
Aril, kao grupa ili supstituent per se ili kao dio grupe ili supstituenta, se odnosi na aromatski karbociklički radikal koji sadrži 6 do 14 ugljikovih atoma, preferira se 6 do 12 ugljikovih atoma, osobito 6 do 10 ugljikovih atoma. Prikladne aril grupe uključuju fenil, naftil i bifenil. Supstituirane aril grupe uključuju gore opisane aril grupe koje su supstituirane jednom ili više puta s, na primjer: halogen, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, i fenoksi. Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups that are substituted one or more times with, for example: halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, and phenoxy.
Arilalkil se odnosi na aril-alkil-radikal u kojem su aril i alkil dijelovi su u skladu s ranijim opisima. Prikladni primjeri uključuju benzil, 1-fenetil, 2-fenetil, fenpropil, fenbutil, fenpentil, i naftilmetil. Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl moieties are as previously described. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and naphthylmethyl.
Heteroaril se odnosi na aromatsku heterocikličku grupu koja ima jedan ili dva prstena i ukupni broj od 5 do 10 atoma prstena pri čemu je najmanje jedan od atoma prstena heteroatom. Preferira se da heteroaril grupa sadrži 1 do 3, osobito 1 ili 2, heteroatoma prstena koji su odabrani među: N, O i S. Prikladne heteroaril grupe uključuju furil, tienil, pirolil, pirazolil, imidazolil, triazolil, tetrazolil, ditialil, oksatialil, izoksazolil, oksazolil, tiazolil, izotiazolil, oksadiazolil, oksatriazolil, dioksazolil, oksatiazolil, tiadiazolil, piridil, piridazinil, pirimidinil, pirazinil, triazinil, oksazinil, izoksazinil, oksatiazinil, oksadiazinil, benzofuranil, izobenzofuranil, tionaftenil, izotionaftenil, indolil, izoindolil, indazolil, benzizoksazolil, benzoksazolil, benztiazolil, benzizotiazolil, purinil, benzopiranil, kinolinil, izokinolinil, cinolinil, kinazolinil, naftiridinil, i benzoksazinil, e. g., 2-tienil, 3-tienil, 2-, 3- ili 4-piridil, 2-, 3-, 4-, 5-, 6-, 7- ili 8-kinolinil, i 1-, 3-, 4-, 5-, 6-, 7- ili 8-izokinolinil. Heteroaryl refers to an aromatic heterocyclic group having one or two rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is a heteroatom. It is preferred that the heteroaryl group contains 1 to 3, especially 1 or 2, ring heteroatoms selected from: N, O and S. Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, oxathialyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3- , 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.
Supstituirani heteroaril se odnosi na heteroaril grupe opisane gore koje su supstituirane na jednom ili više mjesta s, na primjer: halogen, aril, alkil, alkoksi, karboksi, metilen, cijano, trifluormetil, nitro, okso, amino, alkilamino, i dialkilamino. Substituted heteroaryl refers to the heteroaryl groups described above that are substituted at one or more positions with, for example: halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.
Heterocikli uključuju heteroaril grupe kao što je opisano gore kao i nearomatske cikličke grupe koje sadrže najmanje jedan heteroatom u prstenu, preferira se odabran među: N, S i O, na primjer, tetrahidrofuranil, piperidinil, i pirolidinil. Heterocycles include heteroaryl groups as described above as well as non-aromatic cyclic groups containing at least one ring heteroatom, preferably selected from: N, S and O, for example, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl.
Heterocikl-alkil se odnosi na heterocikl-alkil- grupu gdje su heterociklički i alkil dijelovi u skladu s ranijim raspravama. Prikladni primjeri su piridilmetil, tienilmetil, pirimidinilmetil, pirazinilmetil, i izokinolinilmetil. Heterocycle-alkyl refers to a heterocycle-alkyl- group where the heterocyclic and alkyl moieties are consistent with the earlier discussions. Suitable examples are pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.
Djelomično nezasićene karbocikličke strukture su nearomatske monocikličke ili bicikličke strukture koje sadrže 5 do 14 ugljikovih atoma, preferira se 6 do 10 ugljikovih atoma, pri čemu struktura (strukture) prstena sadrži (sadrže) najmanje jednu C=C vezu. Prikladni primjeri su ciklopentenil, cikloheksenil, cikloheksadienil, tetrahidronaftenil i indan-2-il. Partially unsaturated carbocyclic structures are non-aromatic monocyclic or bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein the ring structure(s) contain(s) at least one C=C bond. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.
Alkenil se odnosi na ravnolančane ili razgranate alifatske radikale koji sadrže 2 do 12 ugljikovih atoma u kojem su jedna ili više -CH2-CH2- struktura svaka zamijenjene s -CH=CH-. Prikladne alkenil grupe su etenil, 1-propenil, 2-metiletenil, 1-buten, 2-buten, 1-pentenil, i 2-pentenil. Alkenyl refers to straight-chain or branched aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH2-CH2- structures have each been replaced by -CH=CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and 2-pentenyl.
Alkinil se odnosi na ravnolančane ili razgranate alifatske radikale koji sadrže 2 do 12 ugljikovih atoma u kojem su jedna ili više -CH2-CH2- struktura svaka zamijenjene s -C≡C-. Prikladne alkinil grupe su etinil, propinil, 1-butinil, i 2-butinil. Alkynyl refers to straight-chain or branched aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH2-CH2- structures are each replaced by -C≡C-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-butynyl.
Acil se odnosi na alkanoil radikale koji imaju 1 do 13 ugljikovih atoma u kojima alkil dio može biti supstituiran s: halogen, alkil, aril i/ili alkoksi, ili aroil radikale koji imaju 7 do 15 ugljikovih atoma u kojima aril dio može biti supstituiran s, na primjer: halogen, alkil i/ili alkoksi. Prikladne acil grupe uključuju formil, acetil, propionil, butanoil i benzoil. Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in which the alkyl part can be substituted with: halogen, alkyl, aryl and/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms in which the aryl part can be substituted with , for example: halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl.
Supstituirani radikali, preferira se, imaju 1 do 3 supstituenta, osobito 1 do 2 supstituenta. Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2 substituents.
Kod spojeva formule I, R1 predstavlja alkil grupu koja ima, preferira se, 1 do 4 ugljikovih atoma koja je opcionalno supstituirana s: halogen, preferira se fluor ili klor. Osobito, R1 predstavlja, preferira se, metil ili difluormetil. In the compounds of formula I, R1 represents an alkyl group having, preferably, 1 to 4 carbon atoms which is optionally substituted with: halogen, preferably fluorine or chlorine. In particular, R1 is preferably methyl or difluoromethyl.
R2 predstavlja, preferira se, cikloalkil, osobito ciklopentil. R 2 is preferably cycloalkyl, especially cyclopentyl.
R2 također predstavlja, preferira se, aril ili arilalkil, osobito supstituirani ili nesupstituirani fenil ili fenilalkil, kao što je fenil, metilfenil, metoksifenil, klorfenil, fenetil, fenpropil, fenbutil, feniletenil, fenoksietil, fenoksipropil, fenoksibutil, klorfeniletil, metoksifenil etil, klorfeniletenil, klorfenoksietil, klorfenipropil, metoksifenpropil, metoksifenbutil, klorfenbutil, nitrofenbutil, klorfenilaminoetil, i slično, R2 also represents, preferably, aryl or arylalkyl, especially substituted or unsubstituted phenyl or phenylalkyl, such as phenyl, methylphenyl, methoxyphenyl, chlorophenyl, phenethyl, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyl , chlorphenoxyethyl, chlorphenipropyl, methoxyphenpropyl, methoxyphenbutyl, chlorphenbutyl, nitrophenbutyl, chlorphenylaminoethyl, and the like,
R2 predstavlja također, preferira se, djelomično nezasićene karbocikličke grupe, koja je nesupstituirana ili supstituirana, osobito cikloheksenil, cikloheksadienil, indan-2-il. R2 also represents, preferably, partially unsaturated carbocyclic groups, which are unsubstituted or substituted, especially cyclohexenyl, cyclohexadienyl, indan-2-yl.
R2 predstavlja također, preferira se, alkil grupu koja ima 1 do 8 ugljikovih atoma, osobito 1 do 4 ugljikovih atoma, koja je supstituirana ili nesupstituirana, e. g., metil, difluormetil, trifluormetil, i metoksietil. R 2 represents also, preferably, an alkyl group having 1 to 8 carbon atoms, especially 1 to 4 carbon atoms, which is substituted or unsubstituted, e.g., methyl, difluoromethyl, trifluoromethyl, and methoxyethyl.
R2 predstavlja također, preferira se, heterocikličku ili heterocikl--alkil grupu, osobito radikale u kojima heterociklička grupa ima 5 do 6 atoma prstena i 1 do 2 hetero-atoma prstena odabrane među: N, O i S, e. g., tetrahidrofuranil, pirolidinil, pirolil, piridilmetil, piridiletil, piridilpropil, piperazinilmetil, piperaziniletil, metilpiperaziniletil i slično. R 2 represents also, preferably, a heterocyclic or heterocycl--alkyl group, especially radicals in which the heterocyclic group has 5 to 6 ring atoms and 1 to 2 hetero-ring atoms selected from: N, O and S, e.g., tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl and the like.
Preferirani R2 uključuju ciklopentil, tetrahidrofuranil, CHF2, metoksietil, ciklopropilmetil, fenetil, fenpropil, feniletenil, fenoksietil, fenoksibutil, fenilaminoetil, indan-2-il, piridiletil, i piridilpropil. Preferred R 2 include cyclopentyl, tetrahydrofuranyl, CHF 2 , methoxyethyl, cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl.
R3 predstavlja, preferira se, vodik, alkil koji ima 1 do 4 ugljikovih atoma (e. g., metil, etil, n-propil, ili n-butil), arilalkil (e. g., supstituirani ili nesupstituirani benzil, fenetil, i fenpropil), ili heteroarilalkil grupu (e. g., supstituirani ili nesupstituirani piridilmetil, furanilmetil, tienilmetil, pirolilmetil, pirimidinilmetil, tiazolilmetil, izokinolinilmetil i kinolinilmetil). Preferirani supstitueni za aril i heteroaril dijelove unutar R3 su F, Cl, CH3, C2H5, OCH3, i CN. R3 is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, or n-butyl), arylalkyl (e.g., substituted or unsubstituted benzyl, phenethyl, and phenpropyl), or heteroarylalkyl group (e.g., substituted or unsubstituted pyridylmethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl, isoquinolinylmethyl and quinolinylmethyl). Preferred substituents for the aryl and heteroaryl moieties within R 3 are F, Cl, CH 3 , C 2 H 5 , OCH 3 , and CN.
R4 predstavlja, preferira se, aril, ili heteroaril, osobito fenil, naftil, bifenil, furanil, pirazinil, pirimidinil, piridil, kinolinil, i izokinolinil, koji je u svakom slučaju nesupstituiran ili je supstituiran jednom ili više puta. Preferirani supstituenti su OH, F, Cl, CF3, alkil (kao što je metil ili etil), alkoksi (kao što je metoksi i etoksi), CN, vinil, CH2OH, CONHOH, CONH2, metilendioksi, COOH, i njihove kombinacije. R4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, and isoquinolinyl, which is in any case unsubstituted or substituted one or more times. Preferred substituents are OH, F, Cl, CF3, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH2OH, CONHOH, CONH2, methylenedioxy, COOH, and combinations thereof.
Dodatno, kada R4 predstavlja aril, osobito fenil, preferirani supstituenti uključuju R5-1-, e. g., R5-, R5-O-, R5-CO-, R5-NH-CO-, R5-S02-NH-, R5-SO2-NH-alkilen-O-, NH2-alkil-NH-CO-, R5-alkilen-NH-CO-, alkil-CO-NH-alkil- kao i metil, etil, Cl, F, CN, OCH3, CF3, amino, nitro, HOCH2 i COOH. Additionally, when R4 is aryl, especially phenyl, preferred substituents include R5-1-, e.g., R5-, R5-O-, R5-CO-, R5-NH-CO-, R5-SO2-NH-, R5-SO2 -NH-alkylene-O-, NH2-alkyl-NH-CO-, R5-alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl, Cl, F, CN, OCH3, CF3, amino, nitro, HOCH2 and COOH.
Kada R4 predstavlja aril supstituiran s R5-SO2-NH- preferira se da predstavlja supstituiranu fenil grupu a R5,preferira se, predstavlja metil, etil, propil ili fenil. When R4 represents aryl substituted with R5-SO2-NH-, it is preferred that it represents a substituted phenyl group and R5, preferably, represents methyl, ethyl, propyl or phenyl.
Kada R4 predstavlja aril supstituiran s R5-SO2-NH-alkilen-O- preferira se da predstavlja supstituirani fenil. Kod takvih slučajeva, R5, preferira se, predstavlja metil, etil, propil ili fenil, a alkilen, preferira se, predstavlja -CH2-, -CH2CH2- ili -CH2CH2CH2-. When R4 represents aryl substituted by R5-SO2-NH-alkylene-O- it is preferred that it represents substituted phenyl. In such cases, R5 is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably -CH2-, -CH2CH2- or -CH2CH2CH2-.
Kada R4 predstavlja aril supstituiran s R5-1-, preferira se da predstavlja supstituirani fenil. Kod takvih slučajeva, preferirane R5 grupe uključuju tetrazolil, oksazinil, piperazinil, metilpiperazinil, piridil, metilpiridil, pirolinil, metilpirolinil, piperadinil, ili metilpiperadinil, a L, preferira se, predstavlja jednostruku vezu, -O-, -CO-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-O , -CH2CH2-O-, -CH2CH2CH2-O-, -CH2-NH-CH2CH2-O-, -CO-NH- ili -NH-CO-. When R4 represents aryl substituted by R5-1-, it is preferred that it represents substituted phenyl. In such cases, preferred R5 groups include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and L preferably represents a single bond, -O-, -CO-, -CH2- , -CH2CH2-, -CH2CH2CH2-, -CH2-O , -CH2CH2-O-, -CH2CH2CH2-O-, -CH2-NH-CH2CH2-O-, -CO-NH- or -NH-CO-.
Dodatno, preferirani PDE4 inhibitori u skladu s izumom su spojevi opisani podformulama Ia-Ih koje odgovaraju formuli I ali pokazuju slijedeće preferirane grupe: Additionally, preferred PDE4 inhibitors according to the invention are compounds described by subformulas Ia-Ih which correspond to formula I but show the following preferred groups:
Ia R1 predstavlja metil ili CHF2; And R 1 represents methyl or CHF 2 ;
R2 predstavlja alkil, alkenil, alkinil, cikloalkil, arilalkil, heterocikl-alkil, cikloalkilalkil, aril, ili heterocikl, u svakom slučaju supstituiran ili nesupstituiran; R 2 represents alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heterocycle, in each case substituted or unsubstituted;
R3 predstavlja H, alkil, arilalkil ili heteroarilalkil, u svakom slučaju supstituiran ili nesupstituiran; a R 3 represents H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; And
R4 predstavlja aril ili heteroaril, u svakom slučaju supstituiran ili nesupstituiran. R 4 represents aryl or heteroaryl, in each case substituted or unsubstituted.
Ib R3 predstavlja heteroarilalkil koji je supstituiran ili nesupstituiran. Ib R 3 represents heteroarylalkyl which is substituted or unsubstituted.
Ic R1 predstavlja metil ili CHF2 ; a Ic R1 represents methyl or CHF2; And
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil). R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl).
Id R1 predstavlja metil ili CHF2; Id R1 represents methyl or CHF2;
R2 predstavlja ciklopentil; R 2 represents cyclopentyl;
R3 predstavlja heteroarilalkil, u svakom slučaju supstituiran ili nesupstituiran; a R 3 represents heteroarylalkyl, in each case substituted or unsubstituted; And
R4 predstavlja supstituirani ili nesupstituirani aril ili heteroaril. R4 represents substituted or unsubstituted aryl or heteroaryl.
Ie R1 predstavlja metil; If R1 represents methyl;
R2 predstavlja ciklopentil; a R 2 represents cyclopentyl; And
R3 predstavlja heteroarilalkil koji je supstituiran ili nesupstituiran. R 3 represents heteroarylalkyl which is substituted or unsubstituted.
If R1 predstavlja metil; If R 1 represents methyl;
R2 predstavlja ciklopentil; R 2 represents cyclopentyl;
R3 predstavlja heteroarilalkil koji je supstituiran ili nesupstituiran; a R 3 represents heteroarylalkyl which is substituted or unsubstituted; And
R4 predstavlja fenil koji je supstituiran ili nesupstituiran. R 4 represents phenyl which is substituted or unsubstituted.
Ig R1 predstavlja metil; Ig R1 represents methyl;
R2 predstavlja ciklopentil; R 2 represents cyclopentyl;
R3 predstavlja piridilmetil, fenetil, benzil, tienilmetil, piridilpropil, piperidinilmetil, ili pirazinilmetil, koji je u svakom slučaju supstituiran ili nesupstituiran, ili metil, etil, ili propil ; a R 3 represents pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsubstituted, or methyl, ethyl, or propyl; And
R4 predstavlja fenil ili fenil supstituiran s 1 do 3 supstituenta. R 4 represents phenyl or phenyl substituted with 1 to 3 substituents.
Ih R1 predstavlja metil; Their R1 is methyl;
R2 predstavlja ciklopentil; R 2 represents cyclopentyl;
R3 predstavlja piridilmetil, fenetil, benzil, tienilmetil, piridilpropil, piperidinilmetil, pirazinilmetil, koji je u svakom slučaju supstituiran ili nesupstituiran, ili metil, etil, ili propil ; a R 3 represents pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsubstituted, or methyl, ethyl, or propyl; And
R4 predstavlja fenil, naftil, bifenil, piridil, pirimidinil, tiazolil, pirazinil, kinolinil, ili izokinolinil, u svakom slučaju supstituiran ili nesupstituiran. R 4 represents phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.
Dodatno, preferirani PDE4 inhibitori u skladu s izumom su spojevi opisani podformulama IIa-IId koje odgovaraju formuli II ali pokazuju slijedeće preferirane grupe: Additionally, preferred PDE4 inhibitors according to the invention are compounds described by subformulas IIa-IId which correspond to formula II but show the following preferred groups:
IIa R1 predstavlja metil ili CHF2; IIa R1 represents methyl or CHF2;
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil); a R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl); And
R4 predstavlja fenil, naftil, piridil, kinolinil, ili izokinolinil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 4 represents phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
IIb R1 predstavlja metil ili CHF2 ; IIb R1 represents methyl or CHF2;
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil); a R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl); And
R4 predstavlja fenil koji je nesupstituiran ili supstituiran s: metil, etil, metoksi, Cl, F, CF3, vinil, cijano, amino, karboksi, hidroksimetil, ili etilsulfonamido, ili predstavlja 3-piridil koji je nesupstituiran ili supstituiran s karboksi ili alkoksikarbonil. R4 represents phenyl which is unsubstituted or substituted by: methyl, ethyl, methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or represents 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
IIc R1 predstavlja metil; IIc R1 is methyl;
R2 predstavlja ciklopentil; a R 2 represents cyclopentyl; And
R4 predstavlja fenil, naftil, piridil, kinolinil, ili izokinolinil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 4 represents phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
IId R1 predstavlja metil; IId R1 is methyl;
R2 predstavlja ciklopentil; a R 2 represents cyclopentyl; And
R4 predstavlja fenil koji je nesupstituiran ili supstituiran s: metil, etil, metoksi, Cl, F, CF3, vinil, cijano, amino, karboksi, hidroksimetil, ili etilsulfonamido, ili predstavlja 3-piridil koji je nesupstituiran ili supstituiran s karboksi ili alkoksikarbonil. R4 represents phenyl which is unsubstituted or substituted by: methyl, ethyl, methoxy, Cl, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or represents 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
Dodatno, preferirani PDE4 inhibitori u skladu s izumom su spojevi opisani podformulama IIIa-IIId koje odgovaraju formuli III ali pokazuju slijedeće preferirane grupe: Additionally, preferred PDE4 inhibitors according to the invention are compounds described by subformulas IIIa-IIId which correspond to formula III but show the following preferred groups:
IIIa R1 predstavlja metil ili CHF2 ; IIIa R1 represents methyl or CHF2;
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil); a R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl); And
R3 predstavlja benzil, fenetil, cikloheksenilmetil, furanilmetil, tienilmetil, piridilmetil, kinolinimetil, izokinolinilmetil, tiazolilmetil, ili pirolilmetil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 3 represents benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinmethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which is in each case substituted or unsubstituted.
IIIb R1 predstavlja metil ili CHF2 ; IIIb R1 represents methyl or CHF2;
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil); a R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl); And
R3 predstavlja pirazinilmetil, pirimidinilmetil ili piridilmetil, koji je u svakom nesupstituiran ili supstituiran. R 3 represents pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, each of which is unsubstituted or substituted.
IIIc R1 predstavlja metil; IIIc R1 is methyl;
R2 predstavlja ciklopentil; a R 2 represents cyclopentyl; And
R3 predstavlja benzil, fenetil, cikloheksenilmetil, furanilmetil, tienilmetil, pirazinilmetil, pirimidinilmetil, piridilmetil, kinolinimetil, izokinolinilmetil, izoimidazolil, tiazolilmetil, ili pirolilmetil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 3 represents benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinylmethyl, isoquinolinylmethyl, isoimidazolyl, thiazolylmethyl, or pyrrolylmethyl, which is in each case substituted or unsubstituted.
IIId R1 predstavlja metil; IIId R1 is methyl;
R2 predstavlja ciklopentil; a R 2 represents cyclopentyl; And
R3 predstavlja pirazinilmetil ili piridilmetil, koji je u svakom nesupstituiran ili supstituiran. R 3 represents pyrazinylmethyl or pyridylmethyl, each of which is unsubstituted or substituted.
Dodatno, preferirani PDE4 inhibitors u skladu s izumom su spojevi opisani podformulama IVa-IVp koje odgovaraju formuli IV ali pokazuju slijedeće preferirane grupe: Additionally, preferred PDE4 inhibitors according to the invention are compounds described by subformulas IVa-IVp which correspond to formula IV but show the following preferred groups:
IVa R1 predstavlja metil ili CHF2. IVa R1 represents methyl or CHF2.
IVb R1 predstavlja metil ili CHF2, a IVb R1 represents methyl or CHF2, a
B predstavlja N. B represents N.
IVc R1 predstavlja metil ili CHF2, a IVc R1 represents methyl or CHF2, a
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil). R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl).
IVd R1 predstavlja metil ili CHF2, IVd R1 represents methyl or CHF2,
B predstavlja N, a B represents N, a
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil). R 2 represents cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl).
IVe R1 predstavlja metil ili CHF2, a IVe R1 represents methyl or CHF2, a
R4 predstavlja 3-piridil ili fenil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 4 represents 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVf R1 predstavlja metil ili CHF2, IVf R1 represents methyl or CHF2,
B predstavlja N, a B represents N, a
R4 predstavlja 3-piridil ili fenil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 4 represents 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVg R1 predstavlja metil ili CHF2, IVg R1 represents methyl or CHF2,
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito(3R)-tetrahidrofuranil), a R2 represents cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and
R4 predstavlja 3-piridil ili fenil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 4 represents 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVh R1 predstavlja metil ili CHF2, IVh R1 represents methyl or CHF2,
B predstavlja N, B represents N,
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil), a R2 represents cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and
R4 predstavlja 3-piridil ili fenil, koji je u svakom slučaju supstituiran ili nesupstituiran. R 4 represents 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVi R1 predstavlja metil ili CHF2, a IVi R1 represents methyl or CHF2, a
R4 predstavlja fenil koji je supstituiran na poziciji 3 ili 4. R4 represents phenyl which is substituted in position 3 or 4.
IVj R1 predstavlja metil ili CHF2, IVj R1 represents methyl or CHF2,
B predstavlja N, a B represents N, a
R4 predstavlja fenil koji je supstituiran na poziciji 3 ili 4. R4 represents phenyl which is substituted in position 3 or 4.
IVk R1 predstavlja metil ili CHF2, IVk R1 represents methyl or CHF2,
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil), a R2 represents cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and
R4 predstavlja fenil koji je supstituiran na poziciji 3 ili 4. R4 represents phenyl which is substituted in position 3 or 4.
IVl R1 predstavlja metil ili CHF2, IVl R1 represents methyl or CHF2,
B predstavlja N, B represents N,
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil), a R2 represents cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and
R4 predstavlja fenil koji je supstituiran na poziciji 3 ili 4. R4 represents phenyl which is substituted in position 3 or 4.
IVm R1 predstavlja metil ili CHF2, a IVm R1 represents methyl or CHF2, a
R4 predstavlja 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3-etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil, ili 4-hidroksimetil-fenil. R4 represents 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVn R1 predstavlja metil ili CHF2, IVn R1 represents methyl or CHF2,
B predstavlja N, a B represents N, a
R4 predstavlja 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3 etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil, ili 4-hidroksimetil-fenil. R4 represents 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4 -COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVo R1 predstavlja metil ili CHF2, IVo R1 represents methyl or CHF2,
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil), a R2 represents cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and
R4 predstavlja 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3 etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil, ili 4-hidroksimetil-fenil. R4 represents 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4 -COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
IVp R1 predstavlja metil ili CHF2, IVp R1 represents methyl or CHF2,
B predstavlja N, B represents N,
R2 predstavlja ciklopentil, CHF2, ciklopropilmetil, piridiletil (osobito 2-piridiletil), ili tetrahidrofuranil (osobito (3R)-tetrahidrofuranil), a R2 represents cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (especially 2-pyridylethyl), or tetrahydrofuranyl (especially (3R)-tetrahydrofuranyl), and
R4 predstavlja 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3-etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 3-nitro-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil, ili 4-hidroksimetil fenil. R4 represents 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro- phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl phenyl.
Preferirani aspekti uključuju farmaceutske smjese koje sadrže spoj ovog izuma i farmaceutski prihvatljiv nosač te, opcionalno, druga djelatna sredstva kao što je dolje raspravljeno; metodu inhibiranja PDE4 enzima, osobito izoenzima, e. g., kako je određen konvencionalnom analizom ili kako je opisan ovdje, ili in vitro ili in vivo (kod životinje, e.g., kod modela životinje, ili kod sisavca ili kod čovjeka); metoda za tretiranje neuroloških sindroma, e. g., gubitak pamćenja, osobito dugotrajnog pamćenja, slabljenje kognicije ili njeno propadanje, slabljenje pamćenja, etc. metoda za tretiranje oboljenja moduliranih djelovanjem PDE4, kod sisavca, e. g., čovjeka, e. g., onih ovdje spomenutih. Preferred aspects include pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier and, optionally, other active agents as discussed below; a method of inhibiting a PDE4 enzyme, particularly an isoenzyme, e.g., as determined by a conventional assay or as described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); method for treating neurological syndromes, e.g., loss of memory, especially long-term memory, weakening of cognition or its deterioration, weakening of memory, etc. a method for treating diseases modulated by the action of PDE4, in a mammal, e.g., a human, e.g., those mentioned herein.
Spojevi ovog izuma se mogu pripraviti na konvencionalni način. Neki od postupaka koji se mogu koristiti su opisani dolje. Sve početne tvari su poznate ili se mogu pripraviti na konvencionalni način iz poznatih početnih tvari The compounds of this invention can be prepared in a conventional manner. Some of the procedures that can be used are described below. All starting materials are known or can be prepared in a conventional manner from known starting materials
SHEMA 1 SCHEME 1
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Početni nitrofenoli tipa 1 su ili komercijalno dostupni (e. g., R1 = CH3) ili pripravljeni pomoću objavljenih postupaka (e. g., R1 = CHF2 ili oba R1 i R2 = CHF2, pogledaj Mueller, Klaus-Helmut. Eur. Pat. Appl. (1994), 8 pp. CODEN:EPXXDW EP 626361A1 ; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN:JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Victor. Int. Simp. Wood. Pulping Chem., 1995, 8th, 3, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN: PIXXD2 WO 9623754 A1 19960808). Anilin intermedijeri 3 su proizvedeni u dva koraka; prvo, adicijska reakcija pruža intermedijer 2, nakon čega slijedi redukcija nitro grupe. Nitro spojevi intermedijeri 2 mogu se pripraviti brojnim objavljenim postupcima, kao Mitsunobu reakcijama ili standardnim reakcijama alkilacije. Spojevi gdje R2 predstavlja aril ili heteroaril mogu se pripraviti reakcijama kataliziranima bakrom s aril ili heteroaril jodidima pod Ullman uvjetima ili spajajući aril-, vinil-, ili heteroaril-borove kiseline s fenolom 2 u prisustvu bakrovog katalizatora (e. g., Cu(OAc)2) i baze kao što je TEA. Mitsunobu reakcija između odgovarajuće supstituiranog nitrofenola i primarnog ili sekundarnog alkohola korištenjem azodikarboksilata (e. g., DEAD, DIAD), i prikladnih fosfina (e. g., Ph3P, Bu3P) pruža alkilirane nitrofenole 2. Mitsunobu reakcije se općenito izvode u aprotičnim otapalima kao što je diklormetan ili THF. Alternativno, alkilacija se može postići reakcijom između odgovarajuće supstituiranog nitrofenola i alkil halogenida u prisustvu baze (e. g.,K2CO3 ili NaH) u polarnom aprotičnom otapalu (e. g., DMF ili CH3CN). The starting nitrophenols of type 1 are either commercially available (e.g., R1 = CH3) or prepared using published procedures (e.g., R1 = CHF2 or both R1 and R2 = CHF2, see Mueller, Klaus-Helmut. Eur. Pat. Appl. (1994) , 8 pp. CODEN:EPXXDW EP 626361A1 ; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN:JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov. , Victor. Int. Symp. Wood. Pulping Chem., 1995, 8th, 3, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN : PIXXD2 WO 9623754 A1 19960808). Aniline intermediates 3 were produced in two steps; first, an addition reaction affords intermediate 2, followed by reduction of the nitro group. Nitro compounds intermediates 2 can be prepared by numerous published methods, such as Mitsunobu reactions or standard alkylation reactions. Compounds where R2 is aryl or heteroaryl can be prepared by copper-catalyzed reactions with aryl or heteroaryl iodides under Ullman conditions or by coupling aryl-, vinyl-, or heteroaryl-boronic acids with phenol 2 in the presence of a copper catalyst (e.g., Cu(OAc)2) and bases such as TEA. A Mitsunobu reaction between an appropriately substituted nitrophenol and a primary or secondary alcohol using azodicarboxylates (e.g., DEAD, DIAD), and suitable phosphines (e.g., Ph3P, Bu3P) provides alkylated nitrophenols 2. Mitsunobu reactions are generally performed in aprotic solvents such as dichloromethane or THF . Alternatively, alkylation can be achieved by reaction between an appropriately substituted nitrophenol and an alkyl halide in the presence of a base (eg, K2CO3 or NaH) in a polar aprotic solvent (eg, DMF or CH3CN).
Nitrokateholi 2 su nakon toga reducirani do odgovarajućih anilina 3 metodom standardnom u struci kao što je hidrogenacija korištenjem prikladnog katalizatora (e. g., Pd na ugljiku) u polarnom protičnom otapalu (e. g., MeOH ili EtOH) pod atmosferom vodika. Alternativno, nitrokateholi 3 mogu biti reducirani korištenjem izvora hidrida (e. g., NaBH4) i katalizatora prijelaznog metala (e. g., NiCl2, Pd na ugljiku) ili korištenjem metala (e. g., Zn, Sn, Fe) u otopinama mineralnih kiselina (e. g., HCl) kako bi se proizveli odgovarajući anilini. Općenito polarna protična otapala kao što je etanol ili metanol su korištena u tim reakcijama. The nitrocatechols 2 are then reduced to the corresponding anilines 3 by a method standard in the art such as hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., MeOH or EtOH) under a hydrogen atmosphere. Alternatively, nitrocatechols 3 can be reduced using a hydride source (e.g., NaBH4) and a transition metal catalyst (e.g., NiCl2, Pd on carbon) or using a metal (e.g., Zn, Sn, Fe) in mineral acid solutions (e.g., HCl) as the corresponding anilines would be produced. Generally polar protic solvents such as ethanol or methanol are used in these reactions.
N-Arilalkilanilini 4 su sintetizirani u struci standardnim metodama kao što je reakcija reduktivne aminacije, reakcija alkilacije, ili redukcijom odgovarajućih amida. Na primjer, reakcija reduktivne aminacije aril ili arilalkil aldehida s odgovarajuće supstituiranim anilinima u prisustvu reducirajućeg sredstva s borhidridom kao što je NaBH4 ili NaBH3CN s kiselim katalizatorom kao što je octena kiselina ili pTsOH pruža željene N-arilalkilaniline. Te se reakcije općenito odigravaju u polarnim protičnim otapalima kao što je metanol, etanol, izopropanol, n-propanol i slično. N-Arylalkylanilines 4 are synthesized in the art by standard methods such as reductive amination reaction, alkylation reaction, or reduction of the corresponding amides. For example, the reductive amination reaction of aryl or arylalkyl aldehydes with appropriately substituted anilines in the presence of a borohydride reducing agent such as NaBH4 or NaBH3CN with an acid catalyst such as acetic acid or pTsOH affords the desired N-arylalkylanilines. These reactions generally take place in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like.
N-arilalkilanilini 4 odmah prolaze N-arilaciju metodama standardim u struci uključujući Ullman reakciju vezanja, vezanje katalizirano metalom, ili reakciju aromatske nukleofilne supstitucije. Na primjer, metalom katalizirana reakcija između N-benzilanilina i aril halogenida korištenjem paladij katalizatora, (e. g., Pd2dba3), i opsežnim elektronima bogatog fosfin liganda (e. g., tributilfosfin), i prikladne baze (e. g., NaOtBu) pruža N-arilalkildifenilamine. Niklovi i bakrovi katalizatori su također uključeni. Otapala korisna u tim reakcijama uključuju apolarna aprotična otapala kao što je toluen, benzen, ksileni, tetrahidrofuran, i eter. Kada se sintetiziraju spojevi tipa 5 pri čemu R4 predstavlja alkoksikarbonilfenil, prednosno je da je amin 4 vezan s 1.1 ekvivalenata tert-butil 3-jodbenzena, te da se koristi 22 mol % (tBu)3P, 5.5 mol % Pd2(dba)3 i 1.3 ekvivalenta tBuONa. N -Arylalkylanilines 4 readily undergo N -arylation by methods standard in the art including Ullman coupling reaction, metal catalyzed coupling, or aromatic nucleophilic substitution reaction. For example, the metal-catalyzed reaction between N-benzylaniline and aryl halides using a palladium catalyst, (e.g., Pd2dba3), and an extensive electron-rich phosphine ligand (e.g., tributylphosphine), and a suitable base (e.g., NaOtBu) provides N-arylalkyldiphenylamines. Nickel and copper catalysts are also included. Solvents useful in these reactions include apolar aprotic solvents such as toluene, benzene, xylenes, tetrahydrofuran, and ether. When synthesizing compounds of type 5 where R4 is alkoxycarbonylphenyl, it is preferable that amine 4 is bound with 1.1 equivalents of tert-butyl 3-iodobenzene, and that 22 mol % (tBu)3P, 5.5 mol % Pd2(dba)3 and 1.3 equivalents of tBuON.
SHEMA 2 SCHEME 2
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Intermedijeri karboksilnog estera 6 mogu biti hidrolizirani pod kiselim ili bazičnim uvjetima kako bi dali odgovarajuće karboksilne kiseline 7. Na primjer, etil ester (R5 = Et) može biti hidroliziran korištenjem smjese vodene baze (e. g., NaOH, KOH) i otapala koji se može miješati s vodom (e. g., EtOH, THF). Dok t-butil esteri (R5 = t-butil) mogu biti hidrolizirani korištenjem vodene kiseline (e. g., HCl, mravlja kiselina, TFA) u organskom otapalu koje se može miješati s vodom, ako je neophodno. Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7. For example, an ethyl ester (R5 = Et) can be hydrolyzed using a mixture of an aqueous base (e.g., NaOH, KOH) and a miscible solvent. with water (e.g., EtOH, THF). Whereas t-butyl esters (R5 = t-butyl) can be hydrolyzed using aqueous acid (eg, HCl, formic acid, TFA) in an organic solvent that can be mixed with water, if necessary.
SHEMA 3 SCHEME 3
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Vezanje zaštićenih tetrazol brom ili jodbenzena (e. g., 5-(3-jodfenil)-2-(2-tetrahidropiran)tetrazol) s N-supstituiranim derivatima anilina 4 daje THP-zaštićene tetrazole 8. Hidroliza THP-zaštićenih tetrazola 8 može biti postignuta korištenjem vodene kiseline, kao što je HCl u vodi i otapala koje se može miješati kao što je THF ili EtOH kako bi dala tetrazole 9. Dalje, THP tetrazoli 8 se također mogu oksidativno vezati korištenjem reagenasa kao što je CAN i DDQ u halogeniranim ugljikovodičnim otapalima kao što je diklormetan, kloroform, dikloretan i slično kako bi se dobili tetrazoli 9. Coupling of protected tetrazole bromines or iodobenzenes (e.g., 5-(3-iodophenyl)-2-(2-tetrahydropyran)tetrazole) with N-substituted aniline derivatives 4 gives THP-protected tetrazoles 8. Hydrolysis of THP-protected tetrazoles 8 can be achieved using aqueous acids such as HCl in water and miscible solvents such as THF or EtOH to give tetrazoles 9. Further, THP tetrazoles 8 can also be oxidatively coupled using reagents such as CAN and DDQ in halogenated hydrocarbon solvents such as which is dichloromethane, chloroform, dichloroethane and the like to obtain tetrazoles 9.
Alternativno, tetrazol analozi 9 mogu se pripraviti iz odgovarajućih nitrila tretiranjem s azid ionom (e. g.,KN3, NaN3, etc.) i izvorom protona (e. g., NH4Cl) u polarnom aprotičnom otapalu kao što je DMF. Oni se također mogu pripraviti tretiranjem s azid ionom i Lewis kiselinom (e. g., ZnBr2) u vodi, korištenjem su-otapala koje se može miješati s vodom kao što je izopropanol ako je neophodno. Druga metoda pripravljanja je tretiranje nitrila s kositrovim ili silikon azidima (e. g., Me3SiN3, Bu3SnN3) u aprotičnom organskom otapalu kao što je benzen, toluen, diklormetan, dikloretan, eter, THF, i slično. Alternatively, tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with an azide ion (e.g., KN3, NaN3, etc.) and a proton source (e.g., NH4Cl) in a polar aprotic solvent such as DMF. They can also be prepared by treatment with the azide ion and a Lewis acid (eg, ZnBr 2 ) in water, using a water-miscible co-solvent such as isopropanol if necessary. Another preparation method is to treat nitriles with tin or silicon azides (eg, Me3SiN3, Bu3SnN3) in an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like.
SHEMA 4 SCHEME 4
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[ključ uz shemu 4: toluene = toluen] [key to scheme 4: toluene = toluene]
Difenilamini 10 mogu se pripraviti vezanjem odgovarajuće supstituiranih anilina 3, kao što je 3-ciklopentiloksi-4-metoksianilin, s arilborovim kiselinama u prisustvu baze kao što je trietilamin i bakrovog katalizatora kao što je bakrov acetat (kao što je opisano u: Chan et al, Tetrahedron Lett., 39, 2933-2936 (1998)). Općenito, halogenirana otapala kao što je diklormetan, kloroform, dikloretan, i slično kao i apolarna aprotična otapala kao što je benzen, toluen, ili ksilen se koriste. Takvi difenilamini (e. g., 10) mogu, više se preferira, biti sintetizirani reakcijama aminacije kataliziranima metalom. Na primjer, reakcija odgovarajuće supstituiranog anilina 3 s arilhalogenidom u prisustvu baze (e. g., K3PO4, CsCO3, ili NaOtBu) i paladijevog ili niklovog katalizatora, na primjer Pd(dppf)Cl2, ligand (e. g., dppf) i baza (e. g., NaOtBu) (JACS. 1996, 118, 7217) ili s Pd2dba3, opsežnim elektronima bogati fosfin kao što je P(tBu)3, i baza (e. g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) pruža željene difenilamine 10. Otapala koja su najčešće korištena u tom tipu reakcije uključuju apolarna aprotična otapala kao što je benzen, toluen, tetrahidrofuran, eter, i slično. Diphenylamines 10 can be prepared by coupling appropriately substituted anilines 3, such as 3-cyclopentyloxy-4-methoxyaniline, with arylboronic acids in the presence of a base such as triethylamine and a copper catalyst such as copper acetate (as described in: Chan et al , Tetrahedron Lett., 39, 2933-2936 (1998)). Generally, halogenated solvents such as dichloromethane, chloroform, dichloroethane, and the like as well as apolar aprotic solvents such as benzene, toluene, or xylene are used. Such diphenylamines (eg, 10) can, more preferably, be synthesized by metal-catalyzed amination reactions. For example, the reaction of an appropriately substituted aniline 3 with an aryl halide in the presence of a base (e.g., K3PO4, CsCO3, or NaOtBu) and a palladium or nickel catalyst, for example Pd(dppf)Cl2, a ligand (e.g., dppf), and a base (e.g., NaOtBu) (JACS. 1996, 118, 7217) or with Pd2dba3, an extensive electron-rich phosphine such as P(tBu)3, and a base (e.g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired diphenylamines 10 Solvents most commonly used in this type of reaction include apolar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, and the like.
Difenilamini 10 mogu tada biti alkilirani s raznim alkil halogenidima ili arilalkil halogenidima kao što je, ali koji time nisu ograničeni, jodmetan, etilbromid, benzilklorid, 3-(klormetil)piridin, 4-(klormetil)-2,6-diklorpiridin, i 4-(brommetil)benzojeva kiselina, ili njihove soli, u prisustvu nenukleofilne baze kao što je natrijev hidrid, kalijev heksametildisilazid ili kalijev diizopropilamid kako bi se dobili N-supstituirani difenilamini 5. Otapala korisna u toj reakciji uključuju aprotična otapala kao što je benzen, toluen, tetrahidrofuran, eter, DMF, i slično. Diphenylamines 10 can then be alkylated with various alkyl halides or arylalkyl halides such as, but not limited to, iodomethane, ethyl bromide, benzyl chloride, 3-(chloromethyl)pyridine, 4-(chloromethyl)-2,6-dichloropyridine, and 4 -(bromomethyl)benzoic acid, or salts thereof, in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide or potassium diisopropylamide to give N-substituted diphenylamines 5. Solvents useful in this reaction include aprotic solvents such as benzene, toluene , tetrahydrofuran, ether, DMF, and the like.
SHEMA 5 SCHEME 5
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Karboksilne kiseline 7 mogu biti dalje manipulirane kako bi oblikovale karboksamide 11 korištenjem metode standardne u struci. Na primjer, karboksilna kiselina može biti tretirana s prikladnim primarnim ili sekundarnim aminom, u prisustvu prikladnog reagensa za vezanje kao što je BOP, pyBOP ili DCC, i baze kao što je Et3Nili DIEA kako bi se dobio karboksamid. Te se reakcije općenito odigravaju u apolarnom aprotičnom otapalu kao što je diklormetan, kloroform, ili dikloretan. Carboxylic acids 7 can be further manipulated to form carboxamides 11 using methods standard in the art. For example, a carboxylic acid can be treated with a suitable primary or secondary amine, in the presence of a suitable coupling reagent such as BOP, pyBOP or DCC, and a base such as Et 3 N or DIEA to give the carboxamide. These reactions are generally carried out in an apolar aprotic solvent such as dichloromethane, chloroform, or dichloroethane.
Karboksilni esteri 6 ili kiseline 7 mogu biti reducirani korištenjem metode standardne u struci kako bi dali odgovarajuće karboksaldehide ili hidroksimetil analoge. Na primjer, aril etil ester (e. g., struktura 6, R5 = etil) može biti tretiran s odgovarajućim reducirajućim sredstvom (e. g., LAH, DIBAL, etc.) u aprotičnom otapalu kao što je eter ili THF, kako bi se proizveli odgovarajući karboksaldehidi ili hidroksimetil analozi. Takvi aldehidi i alkoholi mogu biti dalje derivirani metodama standardnima u struci. Carboxylic esters 6 or acids 7 can be reduced using methods standard in the art to give the corresponding carboxaldehydes or hydroxymethyl analogs. For example, an aryl ethyl ester (e.g., structure 6, R5 = ethyl) can be treated with an appropriate reducing agent (e.g., LAH, DIBAL, etc.) in an aprotic solvent such as ether or THF to produce the corresponding carboxaldehydes or hydroxymethyl analogs. Such aldehydes and alcohols can be further derivatized by methods standard in the art.
Slično, karboksamidi (e. g., struktura 11) i nitrili mogu biti reducirani korištenjem metode standardne u struci kako bi dali odgovarajuće supstituirane amine ili aminometil analoge. Na primjer, aril karboksamid 11 može biti reduciran s odgovarajućim reducirajućim sredstvom (e. g., LAH) u aprotičnom otapalu (e. g., benzen, toluen, eter, THF, etc.) kako bi dao odgovarajući supstituirani aminometil analog. Međutim, redukcija aril nitrila daje odgovarajući primarni aminometil analog. Similarly, carboxamides (e.g., structure 11) and nitriles can be reduced using methods standard in the art to give the corresponding substituted amines or aminomethyl analogs. For example, aryl carboxamide 11 can be reduced with an appropriate reducing agent (e.g., LAH) in an aprotic solvent (e.g., benzene, toluene, ether, THF, etc.) to give the corresponding substituted aminomethyl analog. However, reduction of the aryl nitrile gives the corresponding primary aminomethyl analog.
SHEMA 6 SCHEME 6
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Nitrobenzen spojevi 12 mogu biti reducirani do odgovarajućih anilina 13 metodama standardnima u struci kao što je hidrogenacija korištenjem prikladnog katalizatora (e. g., Pd na ugljiku) u polarnom protičnom otapalu (e. g., EtOH, MeOH, etc.). Nitrobenzeni 12 mogu također biti reducirani korištenjem izvora hidrida (e. g., NaBH4) i katalizatora prijelaznog metala (e. g., NiCl2, Pd na ugljiku) u polarnom protičnom otapalu kao što je EtOH, kako bi se proizveli odgovarajući anilini 13. Ti anilini mogu zatim dalje biti supstituirani metodama standardnima u struci. Na primjer, anilini tipa 13 mogu biti alkilirani, acilirani, ili sulfonirani kako bi dali odgovarajuće N-alkil amine, karboksamide (e. g., struktura 15) odnosno sulfonamide (e. g., struktura 14). Na primjer, sulfonamid se može pripraviti iz anilina i odgovarajućeg sulfonil halogenida ili sulfonskog anhidrida (e. g., MeSO2Cl, EtSO2Cl, BnSO2Cl, PhSO2Cl, etc.) u prisustvu baze (e. g., Et3N, piridin, DIEA, etc.). Prikladna otapala za tu reakciju uključuju apolarna aprotična otapala kao što je diklormetan, kloroform, eter, i slično. Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by methods standard in the art such as hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 12 can also be reduced using a hydride source (e.g., NaBH4) and a transition metal catalyst (e.g., NiCl2, Pd on carbon) in a polar protic solvent such as EtOH to produce the corresponding anilines 13. These anilines can then be further substituted by methods standard in the profession. For example, anilines of type 13 can be alkylated, acylated, or sulfonated to give the corresponding N-alkyl amines, carboxamides (e.g., structure 15 ), or sulfonamides (e.g., structure 14 ), respectively. For example, a sulfonamide can be prepared from aniline and the corresponding sulfonyl halide or sulfonic anhydride (e.g., MeSO2Cl, EtSO2Cl, BnSO2Cl, PhSO2Cl, etc.) in the presence of a base (e.g., Et3N, pyridine, DIEA, etc.). Suitable solvents for this reaction include apolar aprotic solvents such as dichloromethane, chloroform, ether, and the like.
SHEMA 7 SCHEME 7
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Trialkilsilileteri tipa 16 su pripravljeni kako je opisano u Shemi 1. Tert-butildimetilsilil zaštićeni katehol intermedijeri 16 su lako odzaštićeni brojnim metodama iz literature (pogledaj Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 273-276.) kao što je korištenjem izvora fluorid iona (e. g., Bu4NF) u aprotičnom otapalu kao što je eter ili THF; ili pod kiselim uvjetima (e. g., KF, 48% HBr, DMF). Rezultirajući fenol 17, koji predstavlja vrlo koristan sintetički intermedijer, može tada biti alkiliran metodama standardnima u struci i na sličan način kao što je opisan za alkilaciju nitrofenola 2 u Shemi 1. Na primjer, Mitsunobu reakcijom, reakcijom s alkil halogenidom u prisustvu baze, ili Ullman tipom aril vezanja ili reakcijom s vinil-, aril- ili heteroarilborovim kiselinama u prisustvu bakrovog katalizatora. The trialkylsilyl ethers of type 16 were prepared as described in Scheme 1. The tert-butyldimethylsilyl protected catechol intermediates 16 were readily deprotected by a number of literature methods (see Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 273-276) such as by using a fluoride ion source (eg, Bu4NF) in an aprotic solvent such as ether or THF; or under acidic conditions (e.g., KF, 48% HBr, DMF). The resulting phenol 17, which is a very useful synthetic intermediate, can then be alkylated by methods standard in the art and in a manner similar to that described for the alkylation of nitrophenol 2 in Scheme 1. For example, by the Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or Ullman type of aryl bond or reaction with vinyl-, aryl- or heteroarylboronic acids in the presence of a copper catalyst.
SHEMA 8 SCHEME 8
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Haloalkoksi intermedijeri 18, pripravljeni alkilacijom odgovarajućeg fenola, mogu biti alkilirani reakcijama sa supstituiranim aminima, alkoholima, ili tiolima u prisustvu baze kako bi dali analoge kao što je 19. Na primjer, alkil halogenid može biti aminiran s odgovarajućim primarnim ili sekundarnim aminom i bazom kao što je K2CO3, u polarnom aprotičnom otapalu kao što je THF, DMF, ili CH3CN. Haloalkoxy intermediates 18, prepared by alkylation of the corresponding phenol, can be alkylated by reactions with substituted amines, alcohols, or thiols in the presence of base to give analogs such as 19. For example, an alkyl halide can be aminated with an appropriate primary or secondary amine and base as which is K2CO3, in a polar aprotic solvent such as THF, DMF, or CH3CN.
Mnogi od tih postupaka sinteze su opisani potpunije u donjim primjerima. Many of these synthesis procedures are described more fully in the examples below.
Uobičajeno vješti stručnjak će prepoznati da neki od spojeva Formula (I) i (I') mogu postojati u različitim geometrijskim izomernim oblicima. Dodatno, neki od spojeva ovog izuma posjeduju jedan ili više asimetričnih ugljikovih atoma te tako mogu postojati u obliku optičkih izomera, kao i u obliku svojih racemskih ili neracemskih smjesa, i u obliku diastereomera i diastereomerskih smjesa inter alia. Svi ti spojevi, uključujući cis izomere, trans izomere, diastereomerske smjese, racemate, neracemske smjese enantiomera, i, u osnovi čiste i čiste enantiomere, su unutar područja ovog izuma. U osnovi čisti enantiomeri sadrže ne više od 5% t/t odgovarajućeg suprotnog enantiomera, preferira se ne više od 2%, a najviše se preferira ne više od 1%. One of ordinary skill will recognize that some of the compounds of Formulas (I) and (I') may exist in different geometric isomeric forms. In addition, some of the compounds of this invention possess one or more asymmetric carbon atoms and thus can exist in the form of optical isomers, as well as in the form of their racemic or non-racemic mixtures, and in the form of diastereomers and diastereomeric mixtures inter alia. All such compounds, including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, and, essentially pure and pure enantiomers, are within the scope of this invention. Essentially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, and most preferably no more than 1%.
Optički izomeri se mogu dobiti otapljanjem racemske smjese u skladu s konvencionalnim postupcima, na primjer, stvaranjem diastereoizomernih soli korištenjem optički aktivne kiseline ili baze ili stvaranjem kovalentnih diastereomera. Primjeri odgovarajućih kiselina su vinska, diacetilvinska, dibenzoilvinska, ditoluoilvinska i kamforsulfonska kiselina. Smjese diastereoizomera mogu biti odvojene u njihove individualne diastereomere na osnovu njihovih fizikalnih i/ili kemijskih razlika metodama poznatim vještim stručnjacima, na primjer, kromatografijom ili frakcijskom kristalizacijom. Optički aktivne baze ili kiseline su tada oslobođene iz odvojenih diastereomernih soli. Drugačiji postupak za odvajanje optičkih izomera uključuje korištenje kiralne kromatografije (e. g., kiralni HPLC stupci), sa ili bez konvencionalnog deriviranja, optimalno odabran kako bi do najveće moguće mjere povećao odvajanje enantiomera. Prikladni kiralni HPLC stupci su proizvedeni od tvrtke Diacel, e. g., Chiracel OD i Chiracel OJ među mnogim drugima, koji se svi mogu rutinski odabrati. Enzimatska odvajanja, sa ili bez derivatizacije, su također korisna. Optički aktivni spojevi formula I i I' se mogu na isti način dobiti kiralnim sintezama korištenjem optički aktivnih početnih tvari. Optical isomers can be obtained by resolving the racemic mixture according to conventional procedures, for example, by forming diastereoisomeric salts using an optically active acid or base or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluenetartaric and camphorsulfonic acids. Mixtures of diastereomers can be separated into their individual diastereomers based on their physical and/or chemical differences by methods known to those skilled in the art, for example, chromatography or fractional crystallization. Optically active bases or acids are then liberated from the separated diastereomeric salts. A different procedure for separating optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, optimally chosen to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all of which can be routinely selected. Enzymatic separations, with or without derivatization, are also useful. Optically active compounds of formulas I and I' can be obtained in the same way by chiral syntheses using optically active starting substances.
Ovaj izum se također odnosi na korisne oblike spojeva kako su ovdje objavljeni, kao što su farmaceutski prihvatljive soli i prolijekovi svih spojeva ovog izuma. Farmaceutski prihvatljive soli uključuju one dobivene reagiranjem glavnog spoja, koji funkcionira kao baza, s anorganskom ili organskom kiselinom da oblikuju sol, na primjer, soli klorovodične kiseline, sumporne kiseline, fosforne kiseline, metan sulfonske kiseline, kamfor sulfonske kiseline, oksalne kiseline, jabučne kiseline, jantarne kiseline i limunske kiseline. Farmaceutski prihvatljive soli također uključuju one u kojima glavni spoj funkcionira kao kiselina te je reagirana s odgovarajućom bazom kako bi oblikovale, e. g., natrijeve, kalijeve, kalcijeve, magnezijeve, amonijeve, i kolinske soli. Vješti stručnjak će dalje prepoznati da se kisele adicijske soli zahtjevanih spojeva mogu pripraviti reakcijom spojeva s odgovarajućom anorganskom ili organskom kiselinom via bilo koje od brojnih poznatih metoda. Alternativno, soli alkalijskih i zemno alkalijskih metala su pripravljene reagiranjem spojeva izuma s odgovarajućom bazom via raznih poznatih metoda. This invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all the compounds of this invention. Pharmaceutically acceptable salts include those obtained by reacting the parent compound, which functions as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, malic acid , succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the parent compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. The skilled artisan will further recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with an appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
Slijedeći su dalji primjeri kiselih soli koje se mogu dobiti reakcijom s anorganskim ili organskim kiselinama: acetati, adipati, alginati, citrati, aspartati, benzoati, benzensulfonati, bisulfati, butirati, kamforati, diglukonati, ciklopentanpropionati, dodecilsulfati, etansulfonati, glukoheptanoati, glicerofosfati, hemisulfati, heptanoati, heksanoati, fumarati, hidrobromidi, hidrojodidi, 2-hidroksi-etansulfonati, laktati, maleati, metansulfonati, nikotinati, 2-naftalensulfonati, oksalati, palmoati, pektinati, persulfati, 3-fenilpropionati, pikrati, pivalati, propionati, sukcinati, tartarati, tiocijanati, tosilati, mesilati i undekanoati. The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates ) , thiocyanates, tosylates, mesylates and undecanoates.
Preferira se da su oblikovane soli farmaceutski prihvatljive za davanje sisavcima. Ipak, farmaceutski neprihvatljive soli spojeva su prikladne kao intermedijeri, na primjer, za izoliranje spoja kao soli i tada prevođenjem soli natrag do spoja slobodne baze tretiranjem s alkalnim reagensom. slobodna baza može tada, ako je željeno, biti prevedena do farmaceutski prihvatljive kisele adicijske soli. It is preferred that the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, to isolate the compound as a salt and then convert the salt back to the free base compound by treatment with an alkaline reagent. the free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
Spojevi izuma mogu biti davani sami ili kao djelatni sastojak formulacije. Tako, ovaj izum također uključuje farmaceutske smjese spojeva formula I ili I' koje sadrže, na primjer, jedan ili više farmaceutski prihvatljivih nosača. The compounds of the invention can be administered alone or as an active ingredient in the formulation. Thus, this invention also includes pharmaceutical mixtures of compounds of formula I or I' containing, for example, one or more pharmaceutically acceptable carriers.
Dostupne su brojne standardne reference koje opisuju postupke za pripravljanje raznih formulacija prikladnih za davanje spojeva u skladu s izumom. Primjeri mogućih formulacija i pripravaka su sadržani u, na primjer, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (posljednje izdanje); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) posljednje izdanje, objavljenima od strane Marcel Dekker, inc., kao i Remington's Pharmaceutical Sciences (Artur Osol, editor), 1553-1593 (posljednje izdanje). A number of standard references are available which describe procedures for the preparation of various formulations suitable for administration of the compounds of the invention. Examples of possible formulations and preparations are contained in, for example, the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (latest edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) last edition, published by Marcel Dekker, inc., as well as Remington's Pharmaceutical Sciences (Artur Osol, editor), 1553-1593 (last edition).
S obzirom na njihov visoki stupanj PDE4 inhibicije, spojevi ovog izuma mogu biti davani bilo kome koji potrebuje ili želi PDE4 inhibiciju, i/ili poboljšavanje kognicije. Davanje se može postići u skladu s potrebama pacijenta, na primjer, oralno, nazalno, parenteralno (subkutano, intravenozno, intramuskularno, intrasternalno i infuzijom), inhalacijom, rektalno, vaginalno, prema potrebi, lokalno, transdermalno, i okularnim davanjem. Given their high degree of PDE4 inhibition, the compounds of this invention can be administered to anyone in need or desire for PDE4 inhibition, and/or cognition enhancement. Administration can be accomplished according to the needs of the patient, for example, oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal, and infusion), inhalation, rectal, vaginal, as needed, topical, transdermal, and ocular administration.
Razni kruti oralni oblici doziranja se mogu koristiti za davanje spojeva izuma uključujući takve krute oblike kao što su: tablete, gelkapsule, kapsule, kaplete, granule, pastile i prašci u rinfuzi. Spojevi ovog izuma mogu biti davani sami ili u kombinaciji s raznim farmaceutski prihvatljivim nosačima, diluentima (kao što je saharoza, manitol, laktoza, škrobovi) i ekscipijentima poznatima u struci, uključujući, ali bez da su time ograničeni, sredstva za suspendiranje, sredstva za topljivost, sredstva za puferiranje, veziva, dezintegranti, konzervansi, bojila, poboljšivači okusa, lubrikanti i slično. Kapsule, tablete i gelovi s vremenskim otpuštanjem, su također prednosni za davanje spojeva ovog izuma. A variety of solid oral dosage forms can be used to administer the compounds of the invention including such solid forms as: tablets, gelcapsules, capsules, caplets, granules, lozenges and bulk powders. The compounds of this invention may be administered alone or in combination with a variety of pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including, but not limited to, suspending agents, solubility, buffering agents, binders, disintegrants, preservatives, dyes, flavor enhancers, lubricants and the like. Time-release capsules, tablets, and gels are also preferred for administering the compounds of this invention.
Razni tekući oralni oblici doziranja se mogu također koristiti za davanje spojeva izuma, uključujući vodene i ne-vodene otopine, emulzije, suspenzije, sirupe, i eliksire. Takvi oblici doziranja mogu također sadržavati prikladne inertne razrjeđivaće poznate u struci kao što je voda i prikladne ekscipijente poznate u struci kao što su konzervansi, sredstva za močenje (okvašivači), sladila, poboljšivači okusa, kao i sredstva za emulzificiranje i/ili suspendiranje spojeva izuma. Spojevi ovog izuma se mogu injektirati, na primjer, intravenozno, u obliku izotonične sterilne otopine. Drugi su pripravci također mogući. Various liquid oral dosage forms may also be used to administer the compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms may also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavor enhancers, as well as agents for emulsifying and/or suspending the compounds of the invention. . The compounds of this invention can be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
Supozitoriji za rektalno davanje spojeva ovog izuma mogu se pripraviti miješanjem spoja s prikladnim ekscipijentom kao što je kakako maslac, salicilati i polietilen glikoli. Formulacije za vaginalno davanje mogu biti u obliku pesara, tampona, kreme, gela, paste, pjene, ili formule za raspršivanje koje sadrže, dodatno djelatnom sastojku, takve prikladne nosače kao što su oni poznati u struci. Suppositories for rectal administration of the compounds of this invention may be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such suitable carriers as are known in the art.
Za lokalno davanje farmaceutska smjesa može biti u obliku krema, pomasti, masti (ulja za masažu), losiona, emulzija, suspenzija, gelova, otopina, pasta, prašaka, sprejeva, i kapi prikladnih za davanje na kožu, u oko, uho ili nos. Lokalno davanje može također uključivati transdermalno davanje via načina kao što su transdermalni flasteri. For local administration, the pharmaceutical mixture can be in the form of creams, ointments, ointments (massage oil), lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear, or nose. . Topical administration may also include transdermal administration via routes such as transdermal patches.
Aerosol formulacije prikladne za davanje via inhalacije također mogu biti napravljene. Na primjer, za tretman poremećaja respiratornog trakta, spojevi u skladu s izumom mogu biti davani inhalacijom u obliku praška (e. g., mikroniziranog) ili u obliku atomiziranih otopina ili suspenzija. Aerosol formulacija može biti postavljena u prihvatljiv propelant pod pritiskom. Aerosol formulations suitable for administration via inhalation can also be made. For example, for the treatment of respiratory tract disorders, compounds according to the invention may be administered by inhalation in powder form (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation may be placed in an acceptable propellant under pressure.
Spojevi mogu biti davani kao jedina djelatna sredstva ili u kombinaciji s drugim farmaceutskim sredstvima kao što su druga sredstva koja se koriste u tretmanu slabljenja kognicije i/ili u tretmanu psihoze, e. g., drugi PDE4 inhibitori, blokatori kalcijevog kanala, kolinergički lijekovi, modulatori adenozinskog receptora, amfakini NMDA-R modulatori, mGluR modulatori, i inhibitori kolinesteraze (e. g., donepezil, rivastigimin, i glantanamin). U takvim kombinacijama, svaki djelatni sastojak može biti davan ili u skladu s njihovim uobičajenim rasponom doziranja ili u dozi ispod njihovog uobičajenog raspona doziranja. The compounds may be administered as sole active agents or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators , amphakines, NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigmine, and glantanamine). In such combinations, each active ingredient may be administered either in accordance with their usual dosage range or at a dose below their usual dosage range.
Ovaj izum dalje uključuje metode tretmana koje uključuju inhibiciju PDE4 enzima. Tako, ovaj izum uključuje metode selektivne inhibicije PDE4 enzima kod životinja, e. g., sisavaca, osobito ljudi, pri čemu takva inhibicija ima terapeutski učinak, kao onda kada takva inhibicija može olakšati stanja koja uključuju neurološke sindrome, kao što je gubitak pamćenja, osobito dugotrajnog pamćenja. Takve metode uključuju davanje životinji kojoj on treba, osobito sisavcu, najosobitije čovjeku, inhibirajuću količinu spoja, samog ili kao dio formulacije, kako je ovdje objavljeno. The present invention further includes methods of treatment involving inhibition of the PDE4 enzyme. Thus, the present invention includes methods of selectively inhibiting the PDE4 enzyme in animals, e.g., mammals, especially humans, wherein such inhibition has a therapeutic effect, such as when such inhibition can alleviate conditions involving neurological syndromes, such as memory loss, particularly long-term memory . Such methods include administering to an animal in need thereof, particularly a mammal, most particularly a human, an inhibiting amount of the compound, alone or as part of a formulation, as disclosed herein.
Stanje slabljenja pamćenja se manifestira slabljenjem sposobnosti da se nauči nova informacija i/ili nemogućnošću da se prisjeti ranije naučene informacije. Slabljenje pamćenja je primarni simptom demencije te također može biti simptom povezan s takvim bolestima kao što je Alzheimerova bolest, šizofrenija, Parkinsonova bolest, Huntingtonova bolest, Pickova bolest, Creutzfeld-Jakobova bolest, HIV, kardiovaskularna bolest, i trauma glave kao i propadanje kognitivnih sposobnosti povezano sa starošću. The condition of memory impairment is manifested by the weakening of the ability to learn new information and/or the inability to recall previously learned information. Memory loss is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma as well as cognitive decline. related to old age.
Demencije su bolesti koje uključuju gubitak pamćenja i dodatno intelektualno slabljenje odvojeno od pamćenja. Ovaj izum uključuje metode za tretiranje pacijenata koji pate od slabljenja pamćenja u svim oblicima demencije. Demencije su klasificirane u skladu s njihovim uzrokom i uključuju: neurodegenerativne demencije (e. g., Alzheimerova, Parkinsonova bolest, Huntingtonova bolest, Pickova bolest), vaskularne (e. g., infarkti, krvarenja, srčani poremećaji), miješano vaskularne i Alzheimerova, bakterijski meningitis, Creutzfeld-Jacobova Bolest, multipla skleroza, traumatske (e. g., subduralni hematom ili traumatska ozljeda mozga), zarazne (e.g., HIV), genetičke (downov sindrom), toksičke (e.g., teški metali, alkohol, neki lijekovi), metaboličke (e.g., manjak vitamina B12 ili folata), CNS hipoksia, Cushingova bolest, psihijatrjske (e. g., depresija i šizofrenija), i hidrocefalus. Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The present invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhages, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld- Jacob's disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some drugs), metabolic (e.g., vitamin deficiency B12 or folate), CNS hypoxia, Cushing's disease, psychiatric (eg, depression and schizophrenia), and hydrocephalus.
Ovaj izum uključuje metode za postupanje s gubitkom pamćenja koji je odvojen od demencije, uključujući blago slabljenje kognicije (MCI) i propadanje kognitivnih sposobnosti povezano sa starošću. Ovaj izum uključuje metode za tretman slabljenja pamćenja kao rezultata bolesti. U drugoj primjeni, izum uključuje metode za postupanje s gubitkom pamćenja koji je rezultirao iz korištenja općih anestetika, kemoterapije, tretmana zračenjem, post-kirurške traume, i terapeutske intervencije. The present invention includes methods for treating memory loss separate from dementia, including mild cognitive decline (MCI) and age-related cognitive decline. The present invention includes methods for treating memory impairment as a result of disease. In another application, the invention includes methods for treating memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, and therapeutic intervention.
Spojevi se mogu koristiti za tretiranje psihijatrijskih stanja uključujući: šizofrenija, bipolarna ili manična depresija, velika depresija, i ovisnost o lijekovim i morfinu. Ti spojevi mogu poboljšati budnost. PDE4 inhibitori se mogu koristiti za povišenje razina cAMP-a i za sprječavanje neurona da prođu apoptozu. PDE4 inhibitori su, također je poznato, protuupalni. Kombinacija anti-apoptotskih i protuupalnih značajki čine te spojeve korisnima za tretiranje neurodegeneracije koja rezultira iz bilo koje bolesti ili ozljede, uključujući udar, ozljede leđne moždine, neurogenezu, Alzheimerovu bolest, multiplu sklerozu, amilolaterosklerozu (ALS), i multiplu sistemsku atrofiju (MSA). The compounds can be used to treat psychiatric conditions including: schizophrenia, bipolar or manic depression, major depression, and drug and morphine addiction. These compounds can improve alertness. PDE4 inhibitors can be used to increase cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to be anti-inflammatory. The combination of anti-apoptotic and anti-inflammatory properties make these compounds useful for treating neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amyloid atherosclerosis (ALS), and multiple system atrophy (MSA). .
Tako, u skladu s preferiranim aspektom, ovaj izum uključuje metode tretiranja pacijenata koji pate od slabljenja pamćenja zbog, na primjer, Alzheimerove bolesti, šizofrenija, Parkinsonove bolesti, Huntingtonove bolesti, Pickove bolesti, Creutzfeld-Jakobove bolesti, depresije, starenja, traume glave, udara, CNS hipoksije, cerebralne senilnosti, multiinfarktne demencije i drugih neuroloških stanja uključujući akutne neuronske bolesti, kao i od HIV-a i kardiovaskularnih bolesti, koje sadrže davanje učinkovite količine spoja u skladu s formulom (I) ili (I') ili njihovih farmaceutski prihvatljivih soli. Thus, in accordance with a preferred aspect, the present invention includes methods of treating patients suffering from memory impairment due to, for example, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multi-infarct dementia and other neurological conditions including acute neuronal diseases, as well as from HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to formula (I) or (I') or their pharmaceutical acceptable salts.
Spojevi ovog izuma se također mogu koristiti u metodi tretiranja pacijenata koji pate od oboljenja karakteriziranih smanjenjem NMDA funkcije, kao što je šizofrenija. Spojevi se također mogu koristiti za tretiranje psihoze karakterizirane povišenim razinama PDE4, na primjer, razni oblici depresije, kao što je manična depresija, velika depresija, i depresija povezana s psihijatrijskim i neurološkim poremećajima. The compounds of the present invention can also be used in a method of treating patients suffering from diseases characterized by a reduction in NMDA function, such as schizophrenia. The compounds can also be used to treat psychosis characterized by elevated levels of PDE4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychiatric and neurological disorders.
Kao što je spomenuto, spojevi izuma također pokazuju protuupalno djelovanje. Kao rezultat, spojevi izuma su korisni u tretmanu raznih alergijskih i upalnih bolesti, osobito oboljenja karakteriziranih smanjenjem razina cikličkog AMP-a i/ili povišenim razinama fosfodiesteraze 4. Tako, u skladu s daljim aspektom izuma, pruža se metoda tretiranja alergijskih i upalnih oboljenja, koja sadrži davanje učinkovite količine spoja u skladu s formulama (I) ili (I') ili njihovih farmaceutski prihvatljivih soli. Takva oboljenja uključuju: astma, kronični brohitis, kronična opstruktivna plućna bolest (COPD), atopični dermatitis, urtikarija, arergijski rinitis, alergijski konjunktivitis, proljetni konjunktivitis, eozinofilni granulom, psorijaza, upalni artritis, reumatoidni artritis, septički šok, ulcerativni kolitis, Crohnova bolest, reperfuzijska ozljeda miokarda i mozga, kronični glomerulonefritis, endotoksički šok, sindrom respiratornog stresa odraslih, cistična fibroza, arterijska restenoza, arteroskleroza, keratoza, reumatoidni spondilitis, osteoartritis, vrućica, dijabetes mellitus, pneumokonioza, kronična opstruktivna bolest dišnih puteva, kronična opstruktivna plućna bolest, toksički i alergijski kontaktni ekcem, atopični ekcem, seboreični ekcem, lichen simplex, opekotine od sunca, pruritis u anogenitalnom području, alopecia areata, hipertrofični ožiljci, diskoidni lupus eritematozus, sistemski lupus eritematozus, folikularne i piodermije velike površine, endogene i egzogene akne, akne rozacea, Beghetova bolest, anafilaktoidna purpura nefritis, upalna bolest crijeva, leukemija, multipla skleroza, gastrointestinalne bolesti, autoimune bolesti i slično. As mentioned, the compounds of the invention also exhibit anti-inflammatory activity. As a result, the compounds of the invention are useful in the treatment of various allergic and inflammatory diseases, particularly diseases characterized by decreased levels of cyclic AMP and/or elevated levels of phosphodiesterase 4. Thus, in accordance with a further aspect of the invention, there is provided a method of treating allergic and inflammatory diseases, comprising administering an effective amount of a compound according to formulas (I) or (I') or a pharmaceutically acceptable salt thereof. Such conditions include: asthma, chronic brochitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease , myocardial and brain reperfusion injury, chronic glomerulonephritis, endotoxic shock, adult respiratory stress syndrome, cystic fibrosis, arterial restenosis, arteriosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, fever, diabetes mellitus, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease , toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and pyodermas of a large area, endogenous and exogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like.
PDE4 inhibitori za tretiranje astme, kroničnog brohitisa, psorijaze, alergijskog rinitisa, i drugih upalnih bolesti, i za inhibiranje faktora nekroze tumora su poznati unutar struke. Pogledaj, e. g., WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651, i US 5,935,9778. Te reference također opisuju analize za određivanje djelovanja PDE4 inhibicije, i metode za sintetiziranje takvih spojeva. Potpune objave tih dokumenata su ovdje uključene referencom. PDE4 inhibitors for treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factor are known in the art. See, e.g., WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651, and US 5,935,9778. These references also describe assays for determining PDE4 inhibitory activity, and methods for synthesizing such compounds. The full disclosures of those documents are incorporated herein by reference.
PDE4 inhibitori se mogu koristiti za sprječavanje ili poboljšanje osteoporoze, kao antibiotik, za tretman kardiovaskularne bolesti mobiliziranjem kolesterola iz aterosklerotskih lezija, za tretiranje reumatoidnog artritisa (RA), za dugoročnu inhibiciju proliferacije mezenhimalnih stanica nakon transplantacije, za tretman urinarne opstrukcije sekundarne za benignu hiperplaziju prostate, za potiskivanje kemotaksije i smanjenje invazije stanica raka debelog crijeva, za tretman kronične limfocitne leukemije B stanica (B-CLL), za inhibiciju kontrakcija maternice, za umanjivanje plućne vaskularne ishemije-reperfuzijske ozljede (IRI), za hidraciju rožnice, za inhibiciju IL-2R ekspresije te time ukidanje HIV-1 DNA nuklearnog unosa u memorijske T stanice, za povećavanje sekrecije inzulina potaknute glukozom, i kod prevencije i tretmana kolitisa, i za inhibiranje degranulacije masnih stanica. PDE4 inhibitors can be used to prevent or improve osteoporosis, as an antibiotic, to treat cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (RA), for long-term inhibition of mesenchymal cell proliferation after transplantation, to treat urinary obstruction secondary to benign prostatic hyperplasia , for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (B-CLL), for inhibition of uterine contractions, for reduction of pulmonary vascular ischemia-reperfusion injury (IRI), for corneal hydration, for inhibition of IL- 2R expression and thereby abolishment of HIV-1 DNA nuclear entry into memory T cells, to increase glucose-stimulated insulin secretion, both in the prevention and treatment of colitis, and to inhibit fat cell degranulation.
Spojevi ovog izuma mogu biti davani kao jedino djelatno sredstvo ili u kombinaciji s drugim farmaceutskim sredstvima kao što su druga sredstva korištena u tretmanu kognitivnog poremećaja i/ili u tretmanu psihoze, e. g., drugi PDE4 inhibitori, blokatori kalcijevog kanala, kolinergički lijekovi, modulatori receptora adenozina, amfakini NMDA-R modulatori, mGluR modulatori, i inhibitori kolinesteraze (e. g., donepezil, rivastigimin, i glantanamin). U takvim kombinacijama, svaki djelatni sastojak može biti davan ili u skladu s njihovim uobičajenim rasponom doziranja ili u dozi ispod njihovog uobičajenog raspona doziranja. The compounds of this invention may be administered as a single active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, cholinergic drugs, adenosine receptor modulators , amphakines, NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigmine, and glantanamine). In such combinations, each active ingredient may be administered either in accordance with their usual dosage range or at a dose below their usual dosage range.
Doziranja spojeva ovog izuma zavise o raznim činiocima uključujući osobiti sindrom koji treba biti tretiran, ozbiljnost simptoma, način davanja, učestalost intervala doziranja, određeni spoj koji se koristiti, učinkovitost, toksikološki profil, farmakokinetički profil spoja, i prisustvo bilo kojeg štetnog popratnog učinka, među drugim razmatranjima. The dosages of the compounds of this invention depend on various factors including the particular syndrome to be treated, severity of symptoms, route of administration, frequency of dosing intervals, particular compound to be used, efficacy, toxicological profile, pharmacokinetic profile of the compound, and the presence of any adverse side effects, among other considerations.
Spojevi izuma se tipično daju u razinama doziranja i u skladu s uobičajenim postupkom kod sisavaca za PDE4 inhibitore kao što su poznati spojevi spomenuti gore. Na primjer, spojevi mogu biti davani, u jednostrukoj ili višestrukim dozama, oralnim davanjem u razini doziranja od, na primjer, 0.01-100 mg/kg dnevno, preferira se 0.1-70 mg/kg dnevno, osobito 0.5-10 mg/kg dnevno. Jedinični oblik doziranja može sadržavati, na primjer, 0.1-50 mg djelatnog spoja. Za intravenozno davanje, spojevi mogu biti davani, u jednostrukoj ili višestrukim dozama, u razini doziranja od, na primjer, 0.001-50 mg/kg dnevno, preferira se 0.001-10 mg/kg dnevno, osobito 0.01-1 mg/kg dnevno. Jedinični oblik doziranja može sadržavati, na primjer, 0.1-10 mg djelatnog spoja. The compounds of the invention are typically administered at dosage levels and in accordance with conventional mammalian practice for PDE4 inhibitors such as the known compounds mentioned above. For example, the compounds may be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.01-100 mg/kg per day, preferably 0.1-70 mg/kg per day, particularly 0.5-10 mg/kg per day . The unit dosage form may contain, for example, 0.1-50 mg of the active compound. For intravenous administration, the compounds may be administered, in single or multiple doses, at a dosage level of, for example, 0.001-50 mg/kg per day, preferably 0.001-10 mg/kg per day, particularly 0.01-1 mg/kg per day. The unit dosage form may contain, for example, 0.1-10 mg of the active compound.
Kod provođenja postupaka ovog izuma, jasno je da treba shvatiti da upućivanja na osobite pufere, medije, reagense, stanice, uvjete postavljanja u kulturu i slično, ne trebaju biti ograničavajuća, ali ih treba pročitati kako bi se uključili svi povezani materijali koje će uobičajeno vješt stručnjak prepoznati kao od interesa ili vrijednosti u osobitom kontekstu u kojem je ta rasprava predstavljena. Na primjer, često je moguće zamijeniti jedan puferski sistem ili medij za kulturu drugim i dalje postići slične, ako ne identične, rezultate. Vješti stručnjak će imati dovoljno znanja o takvim suitavima i metodologijama kako bi bio u mogućnosti, bez prekomjernih eksperimenata, da napravi takve zamjene kakve će optimalno služiti svojoj svrsi kod korištenja metoda i postupaka koji su ovdje objavljeni. In practicing the methods of the present invention, it is to be understood that references to particular buffers, media, reagents, cells, culture conditions, and the like are not intended to be limiting, but should be read to include all related materials that will be readily apparent to one of ordinary skill in the art. recognized by the expert as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. The skilled artisan will have sufficient knowledge of such suites and methodologies to be able, without undue experimentation, to make such substitutions as will optimally serve his purpose when using the methods and procedures disclosed herein.
Ovaj izum će sada biti dalje opisan pomoću slijedećih neograničavajućih primjera. Kod primjene objave tih primjera, treba jasno držati na umu da će se drugi i različiti aspekti metoda objavljenih u skladu s ovim izumom bez sumnje nametnuti sami stručnjaku koji je vješt u relevantnoj struci. This invention will now be further described by means of the following non-limiting examples. In applying the disclosure of these examples, it should be clearly kept in mind that other and various aspects of the methods disclosed in accordance with the present invention will no doubt be apparent to one skilled in the relevant art.
U prethodnim i u slijedećim primjerima, sve su temperature navedene neispravljene u stupnjevima Celzijusa; te, osim ako nije drugačije naznačeno, svi dijelovi i postoci su težinski. In the previous and following examples, all temperatures are listed uncorrected in degrees Celsius; and, unless otherwise noted, all parts and percentages are by weight.
Potpune objave svih prijava, patenata i publikacija, citiranih gore i dolje, su ovdje uključene referencom. The entire disclosures of all applications, patents and publications cited above and below are incorporated herein by reference.
PRIMJER 1A EXAMPLE 1A
1-Ciklopentiloksi-2-metoksi-5-nitrobenzen 1-Cyclopentyloxy-2-methoxy-5-nitrobenzene
Suspenziji 2-metoksi-5-nitrofenola (525g, 3.104 mol) i kalijevog karbonata (643.5g, 4.66 mol) u dimetilformamidu (1 L), pod N2 zaštitom, je bio dodan ciklopentil bromid (499.2 mL, 4.66 mol). Suspenzija je bila grijana do 100°C 6h. Kalijev karbonat (85.8g, 0.62 mol) i ciklopentil bromid (50 mL, 0.46 mol) su bili dodani. Suspenzija je bila grijana do 100°C 4h. TLC je pokazao da je reakcija bila gotova (9:1 DCM : MeOH). Reakcijska smjesa je bila ohlađena do sobne temperature i razrijeđena s vodom (3L) i eterom (3L). Slojevi su bili odvojeni i vodeni sloj je bio reekstrahiran s eterom (2L). Kombinirani organski slojevi su bili isprani s 1N NaOH (2L), vodom (2L), i rasolom (2L). Organski sloj je bio sušen nad natrijevim sulfatom, filtriran, i isparen. Rezultirajuća krutina je bila učinjena azeotropnom s toluenom (2 x 300 mL) kako bi se dobilo 736.7 g (prinos 99.6%) kao žuta krutina. Cyclopentyl bromide (499.2 mL, 4.66 mol) was added to a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium carbonate (643.5g, 4.66 mol) in dimethylformamide (1 L), under N2 protection. The suspension was heated to 100°C for 6 hours. Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100°C for 4 hours. TLC showed that the reaction was complete (9:1 DCM : MeOH). The reaction mixture was cooled to room temperature and diluted with water (3L) and ether (3L). The layers were separated and the aqueous layer was back-extracted with ether (2L). The combined organic layers were washed with 1N NaOH (2L), water (2L), and brine (2L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with toluene (2 x 300 mL) to give 736.7 g (yield 99.6%) as a yellow solid.
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 1-Ciklopropilmetoksi-2-metoksi-5-nitrobenzen a) 1-Cyclopropylmethoxy-2-methoxy-5-nitrobenzene
b) 1-Ciklopentoksi-2-difluormetoksi-5-nitrobenzen b) 1-Cyclopentoxy-2-difluoromethoxy-5-nitrobenzene
c) 1-Ciklopropilmetoksi-2-difluormetoksi-5-nitrobenzen c) 1-Cyclopropylmethoxy-2-difluoromethoxy-5-nitrobenzene
PRIMJER 1B EXAMPLE 1B
2-Metoksi-5-nitro-1-((3R)-tetrahidrofuriloksi)benzen 2-Methoxy-5-nitro-1-((3R)-tetrahydrofuryloxy)benzene
Smjesi 2-metoksi-5-nitrofenola (1.69 g, 10 mmol), trifenilfosfina (5.24 g, 20 mmol) i 3-(R)-hidroksitetrahidrofurana (1.80 g, 20 mmol) u bezvodnom tetrahidrofuranu (40 mL) je bio dodan u kapima, uz miješanje, diizopropilazodikarboksilat (4.0 mL, 20 mmol) i smjesa je puštena da se miješa pri sobnoj temperaturi 16 h. Smjesa je bila razrijeđena s eterom (150 mL) i isprana s 2N NaOH (3 x 50 mL) i rasolom (50 mL), (MgSO4) i koncentrirana u vakuumu. Sirovi talog je bio pročišćen "flash" kromatografijom u stupcu nad silika gelom (Biotage Flash 40M) eluiranjem s 20%-tnim etil acetatom u heksanima kako bi dao 1.05 g proizvoda. A mixture of 2-methoxy-5-nitrophenol (1.69 g, 10 mmol), triphenylphosphine (5.24 g, 20 mmol) and 3-(R)-hydroxytetrahydrofuran (1.80 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added to diisopropylazodicarboxylate (4.0 mL, 20 mmol) was added dropwise, with stirring, and the mixture was allowed to stir at room temperature for 16 h. The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50 mL) and brine (50 mL), (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by flash column chromatography over silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes to give 1.05 g of product.
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 2-Metoksi-5-nitro-1-(3-tetrahidrofuriloksi)benzen a) 2-Methoxy-5-nitro-1-(3-tetrahydrofuryloxy)benzene
b) 2-Metoksi-5-nitro-1-((3S)-tetrahidrofuriloksi)benzen b) 2-Methoxy-5-nitro-1-((3S)-tetrahydrofuryloxy)benzene
c) 2-Difluormetoksi-5-nitro-1-(3-tetrahidrofuriloksi)benzen c) 2-Difluoromethoxy-5-nitro-1-(3-tetrahydrofuryloxy)benzene
d) 2-Difluormetoksi-5-nitro-1-((3R)-tetrahidrofuriloksi)benzen d) 2-Difluoromethoxy-5-nitro-1-((3R)-tetrahydrofuryloxy)benzene
e) 2-Difluormetoksi-5-nitro-1-((3S)-tetrahidrofuriloksi)benzen e) 2-Difluoromethoxy-5-nitro-1-((3S)-tetrahydrofuryloxy)benzene
f) 2-Metoksi-5-nitro-1-(3-fenpropiloksi)benzen f) 2-Methoxy-5-nitro-1-(3-phenpropyloxy)benzene
g) 1-(2-Indaniloksi)-4-metoksi-5-nitrobenzen g) 1-(2-Indanyloxy)-4-methoxy-5-nitrobenzene
PRIMJER 1C EXAMPLE 1C
1-(tert-Butildimetilsilil)oksi-2-metoksi-5-nitrobenzen 1-(tert-Butyldimethylsilyl)oxy-2-methoxy-5-nitrobenzene
Smjesi 2-metoksi-5-nitrofenola (1.53 g, 9.0 mmol) i imidazola (1.08 g, 15.9 mmol) u bezvodnom DMF-u (40 mL) je bio dodan, uz miješanje, tert-butildimetilsilil klorid (2.05 g, 13.6 mmol) te je smjesa puštena da se miješa pri sobnoj temperaturi 16 h. Otapalo je bilo uklonjeno u vakuumu, a talog je bio otopljen u 40 mL 50%-tnog etil acetata u heksanima i filtriran kroz 10 g silika gela. Silika gel je bio ispran s dodatnih 200 mL 50%-tnog etil acetata u heksanima, a filtrati su bili kombinirani i koncentrirani u vakuumu kako bi dali 2.01 g proizvoda kao brončanu kristalnu krutinu. 1H NMR (CDCl3) δ 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J = 2.8 Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H). To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 g, 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol). ) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removed in vacuo and the precipitate was dissolved in 40 mL of 50% ethyl acetate in hexanes and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50% ethyl acetate in hexanes, and the filtrates were combined and concentrated in vacuo to give 2.01 g of product as a bronze crystalline solid. 1H NMR (CDCl3) δ 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J = 2.8 Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H) , 1.00 (s, 9H), 0.18 (s, 6H).
PRIMJER 2 EXAMPLE 2
3-Ciklopentiloksi-4-metoksianiline 3-Cyclopentyloxy-4-methoxyanilines
Suspenziji 10% Pd na aktiviranom ugljiku (25g) u etanolu (4L), pod N2 zaštitom, je bio dodan 1-ciklopentiloksi-2-metoksi-5-nitrobenzen (250 g, 1.054 mol). Reakcijska smjesa je bila odplinjena pod vakuumom tri puta. Reakcijska smjesa je bila snažno miješana dok je vodik (plin) pušten da teče nad reakcijskom smjesom. Nakon 4h reakcija je bila završena pomoću TLC (5:1 heks:EA). Reakcijska smjesa je bila filtrirana kroz jastučić celita, a celit je bio ispran s dodatnim etanolom. Otapalo je bilo uklonjeno u vakuumu da bi se dobilo 208.38g (prinos 95%) 3-ciklopentiloksi-4-metoksianilina kao crvene tekućine. 1H NMR (CDCl3) d 6.85 (d. J = 8.4Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (p, J= 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81(m, 6H), 1.61-1.55 (m, 2H). To a suspension of 10% Pd on activated carbon (25g) in ethanol (4L), under N2 protection, was added 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250g, 1.054 mol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen (gas) was allowed to flow over the reaction mixture. After 4 h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite, and the celite was washed with additional ethanol. The solvent was removed in vacuo to give 208.38g (yield 95%) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid. 1H NMR (CDCl3) d 6.85 (d. J = 8.4Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (p, J = 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81 (m, 6H), 1.61-1.55 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-difluormetoksianilin a) 3-Cyclopentyloxy-4-difluoromethoxyaniline
b) 3-Ciklopropilmetoksi-2-metoksianilin b) 3-Cyclopropylmethoxy-2-methoxyaniline
c) 3-Ciklopropilmetoksi-4-difluormetoksianilin c) 3-Cyclopropylmethoxy-4-difluoromethoxyaniline
d) 4-Metoksi-3-((3R)-tetrahidrofuriloksi)anilin d) 4-Methoxy-3-((3R)-tetrahydrofuryloxy)aniline
e) 4-Metoksi-3-(tetrahidrofuriloksi)anilin e) 4-Methoxy-3-(tetrahydrofuryloxy)aniline
f) 4-Metoksi-3-((3S)-tetrahidrofuriloksi)anilin f) 4-Methoxy-3-((3S)-tetrahydrofuryloxy)aniline
g) 4-Difluormetoksi-3-(3-tetrahidrofuriloksi)anilin g) 4-Difluoromethoxy-3-(3-tetrahydrofuryloxy)aniline
h) 4-Difluormetoksi-3-((3R)-tetrahidrofuriloksi)anilin h) 4-Difluoromethoxy-3-((3R)-tetrahydrofuryloxy)aniline
i) 4-Difluormetoksi-3-((3S)-tetrahidrofuriloksi)anilin i) 4-Difluoromethoxy-3-((3S)-tetrahydrofuryloxy)aniline
j) 3-(tert-Butildimetilsilil)oksi-4-metoksianilin j) 3-(tert-Butyldimethylsilyl)oxy-4-methoxyaniline
k) 4-Metoksi-3-(3-fenpropiloksi)anilin k) 4-Methoxy-3-(3-phenpropyloxy)aniline
l) 3-(2-Indaniloksi)-4-metoksianilin l) 3-(2-Indanyloxy)-4-methoxyaniline
PRIMJER 3 EXAMPLE 3
3-Ciklopentil-4-metoksi-N-(3-piridilmetil)anilin 3-Cyclopentyl-4-methoxy-N-(3-pyridylmethyl)aniline
Smjesi 3-piridinkarboksaldehida (106.55 g, 0.995 mol) u metanolu (5L) je bilo dodano 3-ciklopentiloksi-4-metoksianilin (208.38g, 1.005 mol) i monohidrat p-toluensulfonske kiseline (200 mg). Reakcijska smjesa je bila miješana 4h. Tikvica je tada bila ohlađena do 0°C, a natrijev borhidrid (37.64 g, 2.3 mol) je bio dodan u dijelovima kroz 4h. Reakcijska smjesa je puštena da se zagrije do sobne temperature kroz 16h uz miješanje. TLC je pokazao da je reakcija bila dovršena (1 : 3 heks:EA). Otapalo je bilo ispareno dok nije ostalo približno 0.5L guste otopine. Gusta otopina je bila razrijeđena s vodom (1L) i ekstrahirana s etil acetatom (2 x 2L). Kombinirani organski slojevi su bili isprani s rasolom (500 mL), sušeni nad natrijevim sulfatom, i koncentrirani kako bi se dobilo 300g (prinos 100%) željenog proizvoda kao smeđu viskoznu tekućinu. 1H NMR (CDCl3) d 8.61-8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 (s, 1H), 6.13 (dd, J = 2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H), 1.88-1.70 (m, 6H), 1.65-1.45 (m, 2H). To a mixture of 3-pyridinecarboxaldehyde (106.55 g, 0.995 mol) in methanol (5 L) was added 3-cyclopentyloxy-4-methoxyaniline (208.38 g, 1.005 mol) and p-toluenesulfonic acid monohydrate (200 mg). The reaction mixture was stirred for 4 h. The flask was then cooled to 0°C, and sodium borohydride (37.64 g, 2.3 mol) was added in portions over 4 h. The reaction mixture was allowed to warm to room temperature over 16h with stirring. TLC showed that the reaction was complete (1 : 3 hex:EA). The solvent was evaporated until approximately 0.5L of thick solution remained. The thick solution was diluted with water (1L) and extracted with ethyl acetate (2 x 2L). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to give 300 g (100% yield) of the desired product as a brown viscous liquid. 1H NMR (CDCl3) d 8.61-8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 (s, 1H) ), 6.13 (dd, J = 2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H), 1.88-1.70 (m, 6H ), 1.65-1.45 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-metoksi-N-(3-tienilmetil)anilin a) 3-Cyclopentyloxy-4-methoxy-N-(3-thienylmethyl)aniline
b) 3-Ciklopentiloksi-4-metoksi-N-(4-piridilmetil)anilin b) 3-Cyclopentyloxy-4-methoxy-N-(4-pyridylmethyl)aniline
c) 3-Ciklopentiloksi-N-(2,6-diklor-4-piridilmetil)-4-metoksianilin c) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxyaniline
d) 3-Ciklopentiloksi-4-metoksi-N-(2-kinolinilmetil)anilin d) 3-Cyclopentyloxy-4-methoxy-N-(2-quinolinylmethyl)aniline
e) 3-Ciklopentiloksi-4-metoksi-N-(3-kinolinilmetil)anilin e) 3-Cyclopentyloxy-4-methoxy-N-(3-quinolinylmethyl)aniline
f) 3-Ciklopentiloksi-4-metoksi-N-(4-kinolinilmetil)anilin f) 3-Cyclopentyloxy-4-methoxy-N-(4-quinolinylmethyl)aniline
g) 3-Ciklopentiloksi-4-metoksi-N-(2-pirazinilmetil)anilin g) 3-Cyclopentyloxy-4-methoxy-N-(2-pyrazinylmethyl)aniline
h) 4-Metoksi-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)anilin h) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)aniline
i) 4-Metoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)anilin i) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)aniline
j) 4-Metoksi-N-(3-piridilmetil)-3-((3S)-tetrahidrofuriloksi)anilin j) 4-Methoxy-N-(3-pyridylmethyl)-3-((3S)-tetrahydrofuryloxy)aniline
k) 3-Ciklopropilmetoksi-4-difluormetoksi-N-(3-piridilmetil)anilin k) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)aniline
l) 3-Ciklopentiloksi-4-difluormetoksi-N-(3-piridilmetil)anilin l) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)aniline
m) 4-Difluormetoksi-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)anilin m) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)aniline
n) 4-Difluormetoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)anilin n) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)aniline
o) 3,4-Bis(difluormetoksi)-N-(3-piridilmetil)anilin o) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)aniline
p) 3-tert-Butildimetilsililoksi-4-metoksi-N-(3-piridilmetil)anilin p) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)aniline
q) 3-Ciklopentiloksi-4-metoksi-N-(2-piridilmetil)anilin q) 3-Cyclopentyloxy-4-methoxy-N-(2-pyridylmethyl)aniline
r) 3-Ciklopentiloksi-4-metoksi-N-[1-(2-fenetil)]anilin r) 3-Cyclopentyloxy-4-methoxy-N-[1-(2-phenethyl)]aniline
s) N-Benzil-3-ciklopentiloksi-4-metoksianilin s) N-Benzyl-3-cyclopentyloxy-4-methoxyaniline
t) N-[(Cikloheks-1-en-1-il) metil]-3-ciklopentiloksi-4-metoksianilin t) N-[(Cyclohex-1-en-1-yl) methyl]-3-cyclopentyloxy-4-methoxyaniline
u) 3-Ciklopentiloksi-4-metoksi-N-(3,4,5-trimetoksibenzil)anilin u) 3-Cyclopentyloxy-4-methoxy-N-(3,4,5-trimethoxybenzyl)aniline
v) N-[(Cikloheks-3-en-1-il) metil]-3-ciklopentiloksi-4-metoksianilin v) N-[(Cyclohex-3-en-1-yl) methyl]-3-cyclopentyloxy-4-methoxyaniline
w) 3-Ciklopentiloksi-4-metoksi-N-(2,4,6-trimetilbenzil)anilin w) 3-Cyclopentyloxy-4-methoxy-N-(2,4,6-trimethylbenzyl)aniline
x) 3-Ciklopentiloksi-4-metoksi-N-(2-metilbenzil)anilin x) 3-Cyclopentyloxy-4-methoxy-N-(2-methylbenzyl)aniline
y) 3-Ciklopentiloksi-4-metoksi-N-(2-trifluormetilbenzil)anilin y) 3-Cyclopentyloxy-4-methoxy-N-(2-trifluoromethylbenzyl)aniline
z) 3-Ciklopentiloksi-4-metoksi-N-((3,4-metilendioksi)benzil)anilin z) 3-Cyclopentyloxy-4-methoxy-N-((3,4-methylenedioxy)benzyl)aniline
aa) 3-Ciklopentiloksi-N-(2-hidroksi-3-metoksilbenzil)-4-metoksianilin aa) 3-Cyclopentyloxy-N-(2-hydroxy-3-methoxylbenzyl)-4-methoxyaniline
bb) 3-Ciklopentiloksi-N-(3-furilmetil)-4-metoksianilin bb) 3-Cyclopentyloxy-N-(3-furylmethyl)-4-methoxyaniline
cc) 3-Ciklopentiloksi-4-metoksi-N-(3-metilbenzil)anilin cc) 3-Cyclopentyloxy-4-methoxy-N-(3-methylbenzyl)aniline
dd) 3-Ciklopentiloksi-4-metoksi-N-(2-metoksibenzil)anilin dd) 3-Cyclopentyloxy-4-methoxy-N-(2-methoxybenzyl)aniline
ee) 3-Ciklopentiloksi-4-metoksi-N-(3-klorbenzil)anilin ee) 3-Cyclopentyloxy-4-methoxy-N-(3-chlorobenzyl)aniline
ff) 3-Ciklopentiloksi-4-metoksi-N-(3-metoksibenzil)anilin ff) 3-Cyclopentyloxy-4-methoxy-N-(3-methoxybenzyl)aniline
gg) 3-Ciklopentiloksi-4-metoksi-N-(2-klorbenzil)anilin gg) 3-Cyclopentyloxy-4-methoxy-N-(2-chlorobenzyl)aniline
hh) 3-Ciklopentiloksi-4-metoksi-N-(3-metilbenzil)anilin hh) 3-Cyclopentyloxy-4-methoxy-N-(3-methylbenzyl)aniline
ii) 4-Metoksi-3-(3-fenpropiloksi)-N-(4-piridilmetil)anilin ii) 4-Methoxy-3-(3-phenpropyloxy)-N-(4-pyridylmethyl)aniline
jj) N-(2,6-Diklor-4-piridilmetil)-3-(2-indaniloksi)-4-metoksianilin jj) N-(2,6-Dichloro-4-pyridylmethyl)-3-(2-indanyloxy)-4-methoxyaniline
kk) 4-Metoksi-3-(3-fenpropiloksi)-N-(2-piridilmetil)anilin kk) 4-Methoxy-3-(3-phenpropyloxy)-N-(2-pyridylmethyl)aniline
ll) N-(2,6-Diklor-4-piridilmetil)-4-metoksi-3-(3-fenpropiloksi)anilin ll) N-(2,6-Dichloro-4-pyridylmethyl)-4-methoxy-3-(3-phenpropyloxy)aniline
mm) 4-Metoksi-3-(3-fenpropiloksi)-N-(3-piridilmetil)anilin mm) 4-Methoxy-3-(3-phenpropyloxy)-N-(3-pyridylmethyl)aniline
nn) 3-Ciklopentiloksi-4-metoksi-N-(2-tienilmetil)anilin nn) 3-Cyclopentyloxy-4-methoxy-N-(2-thienylmethyl)aniline
oo) 3-(2-Indaniloksi)-4-metoksi-N-(3-tienilmetil)anilin oo) 3-(2-Indanyloxy)-4-methoxy-N-(3-thienylmethyl)aniline
pp) 4-Metoksi-3-(3-fenpropiloksi)-N-(3-tienilmetil)anilin pp) 4-Methoxy-3-(3-phenpropyloxy)-N-(3-thienylmethyl)aniline
qq) 3-(2-Indaniloksi)-4-metoksi-N-(2-piridilmetil)anilin qq) 3-(2-Indanyloxy)-4-methoxy-N-(2-pyridylmethyl)aniline
rr) 3-(2-Indaniloksi)-4-metoksi-N-(3-piridilmetil)anilin rr) 3-(2-Indanyloxy)-4-methoxy-N-(3-pyridylmethyl)aniline
ss) 3-(2-Indaniloksi)-4-metoksi-N-(4-piridilmetil)anilin ss) 3-(2-Indanyloxy)-4-methoxy-N-(4-pyridylmethyl)aniline
tt) 3-Ciklopentiloksi-4-metoksi-N-(3-piperidinmetil)anilin tt) 3-Cyclopentyloxy-4-methoxy-N-(3-piperidinemethyl)aniline
uu) 3-Ciklopentiloksi-4-metoksi-N-(3-(l-tert-butiloksikarbonil)piperidinmetil)anilin uu) 3-Cyclopentyloxy-4-methoxy-N-(3-(1-tert-butyloxycarbonyl)piperidinemethyl)aniline
vv) 3-Ciklopentiloksi-4-metoksi-N-(6-metil-2-piridilmetil)anilin vv) 3-Cyclopentyloxy-4-methoxy-N-(6-methyl-2-pyridylmethyl)aniline
ww) N-(2-Klor-3-piridilmetil)-3-ciklopentiloksi-4-metoksianilin ww) N-(2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline
xx) N-(2-Klor-5-piridilmetil)-3-ciklopentiloksi-4-metoksianilin xx) N-(2-Chloro-5-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline
yy) 3-Ciklopentiloksi-4-metoksi-N-(2-tiazolilmetil)aniline yy) 3-Cyclopentyloxy-4-methoxy-N-(2-thiazolylmethyl)anilines
PRIMJER 4 EXAMPLE 4
3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
U tikvicu od 100 mL, koja je sušena u pečnici te isplahnuta argonom je bilo dodano slijedećim redom 0.59 g (6.10 mmol) NaOtBu, 360 mg Pd2dba3, 20 mL toluena, 0.14 mL P(tBu)3, i 20 mL otopine 1.3 g (4.36 mmol) N-(3-piridilmetil)-3-ciklopentiloksi-4-metoksianilina u toluenu. Uz miješanje, 3.1 g (15 mmol) jodbenzena je bilo dodano u kapima te je smjesa bila miješana 18 sati. Reakcijska smjesa je bila razrijeđena s EtOAc i isprana dvaput s H2O i ekstrahirana s 3 x 15 mL 3N HCl. Kombinirani kiseli ekstrakti su bili isprani s 15 mL EtOAc i tada pažljivo neutralizirani s 6N NaOH do pH većeg od 12. Bazična otopina je bila ekstrahirana s 2 x 15 mL EtOAc, a kombinirane organske frakcije su nakon toga bile isprane s 15 mL H2O i rasolom, sušene (MgSO4), i koncentrirane. Talog je bio pročišćen kromatografijom nad silika gelom (Biotage Flash 40M) eluiranjem s 25%-tnim EtOAc u heksanima. Materijal je bio dalje pročišćen pomoću kristalizacije iz heksana kako bi dao 550 mg bijele krutine. 1H NMR (CDCl3) d 8.61 (s, 1H), 8.49 (d, 1H, J= 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7.30-7.10 (m, 3H), 6.90-6.80(m, 4H), 6.80-6.60(m, 2H), 4.94 (s, 2H), 4.64 (p, 1H, J= 4.1 Hz), 3.84 (s, 3H), 1.86-1.70(m, 6H), 1.65-1.45(m, 2H). In a 100 mL flask, which was dried in an oven and purged with argon, 0.59 g (6.10 mmol) of NaOtBu, 360 mg of Pd2dba3, 20 mL of toluene, 0.14 mL of P(tBu)3, and 20 mL of a solution of 1.3 g ( 4.36 mmol) of N-(3-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline in toluene. With stirring, 3.1 g (15 mmol) of iodobenzene was added dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with H 2 O and extracted with 3 x 15 mL 3N HCl. The combined acid extracts were washed with 15 mL EtOAc and then carefully neutralized with 6N NaOH to a pH greater than 12. The base solution was extracted with 2 x 15 mL EtOAc, and the combined organic fractions were then washed with 15 mL H2O and brine. , dried (MgSO4), and concentrated. The precipitate was purified by chromatography over silica gel (Biotage Flash 40M) eluting with 25% EtOAc in hexanes. The material was further purified by crystallization from hexane to give 550 mg of a white solid. 1H NMR (CDCl3) d 8.61 (s, 1H), 8.49 (d, 1H, J= 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7.30-7.10 (m, 3H), 6.90-6.80(m, 4H), 6.80-6.60(m, 2H), 4.94 (s, 2H), 4.64 (p, 1H, J= 4.1 Hz), 3.84 (s, 3H), 1.86-1.70(m, 6H), 1.65-1.45 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-metoksi-2'-metil-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-4-methoxy-2'-methyl-N-(3-pyridylmethyl)diphenylamine
b) 3-Ciklopentiloksi-4-metoksi-3'-metil-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine
c) 3-Ciklopentiloksi-4-metoksi-4'-metil-N-(3-piridilmetil)difenilamin c) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl)diphenylamine
d) 3-Ciklopentiloksi-4'-etil-4-metoksi-N-(3-piridilmetil)difenilamin d) 3-Cyclopentyloxy-4'-ethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine
e) 3'-Klor-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin e) 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
f) 4'-Klor-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin f) 4'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
g) 3-Ciklopentiloksi-2',4-dimetoksi-N-(3-piridilmetil)difenilamin g) 3-Cyclopentyloxy-2',4-dimethoxy-N-(3-pyridylmethyl)diphenylamine
h) 3-Ciklopentiloksi-3',4-dimetoksi-N-(3-piridilmetil)difenilamin i h) 3-Cyclopentyloxy-3',4-dimethoxy-N-(3-pyridylmethyl)diphenylamine and
i) 3-Ciklopentiloksi-4,4'-dimetoksi-N-(3-piridilmetil)difenilamin i) 3-Cyclopentyloxy-4,4'-dimethoxy-N-(3-pyridylmethyl)diphenylamine
j) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-3'-trifluormetildifenilamin j) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine
k) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-4'-trifluormetildifenilamin k) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-trifluoromethyldiphenylamine
l) 3-Ciklopentiloksi-3'-fluor-4-metoksi-N-(3-piridilmetil)difenilamin l) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
m) 3-Ciklopentiloksi-4'-fluor-4-metoksi-N-(3-piridilmetil)difenilamin m) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
n) 3-Ciklopentiloksi-4-metoksi-3'-fenil-N-(3-piridilmetil)difenilamin n) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-N-(3-pyridylmethyl)diphenylamine
o) 3-Ciklopentiloksi-4-metoksi-4'-fenil-N-(3-piridilmetil)difenilamin o) 3-Cyclopentyloxy-4-methoxy-4'-phenyl-N-(3-pyridylmethyl)diphenylamine
p) 3'-Cijano-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin p) 3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
q) 4'-Cijano-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin q) 4'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
r) Etil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoat r) Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
s) Etil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-4-aminobenzoat s) Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoate
t) 3-Ciklopentiloksi-4-metoksi-3'-nitro-N-(3-piridilmetil)difenilamin t) 3-Cyclopentyloxy-4-methoxy-3'-nitro-N-(3-pyridylmethyl)diphenylamine
u) 3-Ciklopentiloksi-4-metoksi-4'-nitro-N-(3-piridilmetil)difenilamin u) 3-Cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl)diphenylamine
v) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-1-naftilamin v) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-1-naphthylamine
w) 3-Ciklopentiloksi-2',3'-dimetil-4-metoksi-N-(3-piridilmetil)difenilamin w) 3-Cyclopentyloxy-2',3'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine
x) 3-Ciklopentiloksi-2',4'-dimetil-4-metoksi-N-(3-piridilmetil)difenilamin x) 3-Cyclopentyloxy-2',4'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine
y) 3-Ciklopentiloksi-2',5'-dimetil-4-metoksi-N-(3-piridilmetil)difenilamin y) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine
z) 3-Ciklopentiloksi-3',4'-dimetil-4-metoksi-N-(3-piridilmetil)difenilamin z) 3-Cyclopentyloxy-3',4'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine
aa) 3-Ciklopentiloksi-2',3'-diklor-4-metoksi-N-(3-piridilmetil)difenilamin aa) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
bb) 3-Ciklopentiloksi-3',4'-diklor-4-metoksi-N-(3-piridilmetil)difenilamin bb) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
cc) 3-Ciklopentiloksi-3',5'-diklor-4-metoksi-N-(3-piridilmetil)difenilamin cc) 3-Cyclopentyloxy-3',5'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
dd) 3'-Klor-3-ciklopentiloksi-4'-fluor-4-metoksi-N-(3-piridilmetil)difenilamin dd) 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
ee) 4'-Klor-3-ciklopentiloksi-3'-fluor-4-metoksi-N-(3-piridilmetil)difenilamin ee) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
ff) 4'-Klor-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-3'-trifluormetildifenilamin ff) 4'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine
gg) 3-Ciklopentiloksi-4-metoksi-N-(3-tienilmetil)difenilamin gg) 3-Cyclopentyloxy-4-methoxy-N-(3-thienylmethyl)diphenylamine
hh) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-tienilmetil)-1-naftilamin hh) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-thienylmethyl)-1-naphthylamine
ii) 3-Ciklopentiloksi-2',3'-diklor-4-metoksi-N-(3-tienilmetil)difenilamin ii) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxy-N-(3-thienylmethyl)diphenylamine
jj) 3-Ciklopentiloksi-4-metoksi-4'-metil-N-(4-piridilmetil)difenilamin jj) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(4-pyridylmethyl)diphenylamine
kk) 3-Ciklopentiloksi-N-(2,6-diklor-4-piridilmetil)-4-metoksi-3'-metildifenilamin kk) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxy-3'-methyldiphenylamine
ll) 2'-Klor-3-ciklopentiloksi-N-(2,6-diklor-4-piridilmetil)-4-metoksidifenilamin ll) 2'-Chloro-3-cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine
mm) 3-Ciklopentiloksi-N-(2,6-diklor-4-piridilmetil)-4-metoksidifenilamin mm) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine
nn) 3-Ciklopentiloksi-4-metoksi-N-(6-metil-2-piridilmetil)difenilamin nn) 3-Cyclopentyloxy-4-methoxy-N-(6-methyl-2-pyridylmethyl)diphenylamine
oo) 3-Ciklopentiloksi-4-metoksi-N-(3-kinolinilmetil)difenilamin oo) 3-Cyclopentyloxy-4-methoxy-N-(3-quinolinylmethyl)diphenylamine
pp) 3-Ciklopentiloksi-4-metoksi-N-(4-kinolinilmetil)difenilamin pp) 3-Cyclopentyloxy-4-methoxy-N-(4-quinolinylmethyl)diphenylamine
qq) 3-Ciklopentiloksi-4-metoksi-N-(2-pirazinilmetil)difenilamin qq) 3-Cyclopentyloxy-4-methoxy-N-(2-pyrazinylmethyl)diphenylamine
rr) 4-Metoksi-3'-metil-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin rr) 4-Methoxy-3'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
ss) 4-Metoksi-4'-metil-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin ss) 4-Methoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
tt) 4,4'-Dimetoksi-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin tt) 4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
uu) 3'-Klor-4-metoksi-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin uu) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
vv) 4-Metoksi-4'-(4-metilpiperazin-1-ilkarbonil)-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin vv) 4-Methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
ww) 3'-Cijano-4-metoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin ww) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
xx) 3'-Cijano-4-metoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin xx) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
yy) 3-Ciklopropilmetoksi-4-difluormetoksi-N-(3-piridilmetil)difenilamin yy) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine
zz) 3-Ciklopentiloksi-4-difluormetoksi-N-(3-piridilmetil)difenilamin zz) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine
aaa) 4-Difluormetoksi-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin aaa) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
bbb) 3,4-Bis(difluormetoksi)-N-(3-piridilmetil)difenilamin bbb) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine
ccc) 4-Difluormetoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin ccc) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
ddd) 3'-Cijano-4-difluormetoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin ddd) 3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
eee) 3'-Klor-4-difluormetoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin eee) 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
fff) Etil N-(3-ciklopropilmetoksi-4-difluormetoksifenil)-N-(3-piridilmetil)-3-aminobenzoat fff) Ethyl N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
ggg) 3-Ciklopentiloksi-4-metoksi-3'-(4-metilpiperazin-1-ilkarbonil)-N-(3-piridilmetil)difenilamin ggg) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine
hhh) 3-Ciklopentiloksi-4-metoksi-4'-(4-metilpiperazin-1-ilkarbonil)-N-(3-piridilmetil)difenilamin hhh) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine
iii) 3'-tert-Butildimetilsililoksi-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin iii) 3'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
jjj) 4'-tert-Butildimetilsililoksi-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin jjj) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
kkk) tert-Butil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoat kkk) tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
lll) Etil N-(3-ciklopentiloksi-4-difluormetoksifenil)-N-(3-piridilmetil)-3-aminobenzoat lll) Ethyl N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
mmm) Etil N-(4-difluormetoksi-3-(3-tetrahidrofuriloksi)fenil)-N-(3-piridilmetil)-3-aminobenzoat mmm) Ethyl N-(4-difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
nnn) Etil N-(3,4-Bis(difluormetoksi)fenil)-N-(3-piridilmetil)-3-aminobenzoat nnn) Ethyl N-(3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
ooo) Etil N-(4-metoksi-3-((3R)-tetrahidrofuriloksi)fenil)-N-(3-piridilmetil)-3-aminobenzoat ooo) Ethyl N-(4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
ppp) Etil N-(3-ciklopropilmetoksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoat ppp) Ethyl N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
qqq) 3-Ciklopentiloksi-4-metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin qqq) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
rrr) 3-Ciklopentiloksi-4-metoksi-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin rrr) 3-Cyclopentyloxy-4-methoxy-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
sss) 4-Metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin sss) 4-Methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
ttt) 3-Ciklopropilmetoksi-4-metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin ttt) 3-Cyclopropylmethoxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
uuu) 4-Difluormetoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin uuu) 4-Difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine
vvv) 3-Ciklopropilmetoksi-4-difluormetoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin vvv) 3-Cyclopropylmethoxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
www) 3-Ciklopentiloksi-4-difluormetoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin www) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
xxx) 3-Ciklopropilmetoksi-4-difluormetoksi-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin xxx) 3-Cyclopropylmethoxy-4-difluoromethoxy-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
yyy)Bis-(3,4-difluormetoksi)-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin yyy) Bis-(3,4-difluoromethoxy)-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine
zzz) 3-tert-Butildimetilsililoksi-4-metoksi-N-(3-piridilmetil)difenilamin zzz) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
aaaa) 3-tert-Butildimetilsililoksi-3'-klor-4-metoksi-N-(3-piridilmetil)difenilamin aaaa) 3-tert-Butyldimethylsilyloxy-3'-chloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
bbbb) Etil N-(3-tert-butildimetilsililoksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoat bbbb) Ethyl N-(3-tert-butyldimethylsilyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
cccc) 3-Ciklopentiloksi-2'-klor-4-metoksi-N-(3-piridilmetil)difenilamin cccc) 3-Cyclopentyloxy-2'-chloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
dddd) 3-(2-indaniloksi)-4-metoksi-N-(3-piridilmetil)difenilamin dddd) 3-(2-indanyloxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
PRIMJER 5 EXAMPLE 5
N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
Otopina 6.5 g etil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoata u 50 mL EtOH je bila tretirana s 10 mL 6N NaOH. Smjesa je puštena da stoji 6 sati, koncentrirana, i razrijeđena s 50 mL H2O. Vodena smjesa je bila ekstrahirana s 2 x 50 mL etera, zakiseljena s AcOH do pH 3, i ekstrahirana s 2 x 50 mL EtOAc. Kombinirane EtOAc frakcije su bile isprane s 25 mL H20 i 25 mL rasola, sušene (MgSO4), i koncentrirane. Talog je bio pročišćen kromatografijom preko Si02 (35 g RediSep® stupac) korištenjem linearnog gradijenta EtOAc i heksana kao protočno sredstvo (eluant) (50% EtOAc na 70% EtOAc kroz 20 minuta) kako bi dao 4.8 g proizvoda žute krutine nakon sušenja u vakuumu 12 h pri 60°C. 1H NMR (CDCl3) d 11.15 (bs, 1H), 8.70-8.55(m, 2H), 7.77-6.71(m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8 Hz, 1H), 3.84 (s, 3H), 1.86-1.70(m, 6H), 1.65-1.45(m, 2H). A solution of 6.5 g of ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate in 50 mL of EtOH was treated with 10 mL of 6N NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 mL of H2O. The aqueous mixture was extracted with 2 x 50 mL ether, acidified with AcOH to pH 3, and extracted with 2 x 50 mL EtOAc. The combined EtOAc fractions were washed with 25 mL H 2 O and 25 mL brine, dried (MgSO 4 ), and concentrated. The residue was purified by chromatography over SiO2 (35 g RediSep® column) using a linear gradient of EtOAc and hexanes as eluent (50% EtOAc to 70% EtOAc over 20 min) to give 4.8 g of the product as a yellow solid after drying in vacuo 12 h at 60°C. 1H NMR (CDCl3) d 11.15 (bs, 1H), 8.70-8.55(m, 2H), 7.77-6.71(m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8 Hz, 1H), 3.84 (s, 3H), 1.86-1.70(m, 6H), 1.65-1.45(m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-4-aminobenzojeva kiselina a) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid
b) N-(3-Ciklopentiloksi-4-difluormetoksifenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina b) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
c) N-[4-Difluormetoksi-3-(3-tetrahidrofuriloksi)fenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina c) N-[4-Difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
d) N-3,4-Bis (difluormetoksi)fenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina d) N-3,4-Bis (difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
e) N-[4-Metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina e) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
f) N-(3-Ciklopropilmetoksi-4-metoksifenil)-N-(3-piridilmetil)-4-aminobenzojeva kiselina f) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid
g) N-(3-Ciklopropilmetoksi-4-difluormetoksifenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina g) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
h) N-(3-Ciklopentiloksi-4-metoksifenil)-3-aminobenzojeva kiselina h) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid
i) N-[3-(4-Klorfenil)prop-1-iloksi-4-metoksifenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina i) N-[3-(4-Chlorophenyl)prop-1-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
j) N-(3-Ciklopropilmetoksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina j) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
k) N-[3-(2-Indaniloksi)-4-metoksifenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina k) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
l) N-[4-Metoksi-3-(3-tetrahidrofuriloksi)fenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina l) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
m) N-[4-Metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina m) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
n) N-[3-(2-Metoksietoksi)-4-metoksifenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina n) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
o) N-[4-Metoksi-3-(2-(2-piridil) Etil)oksifenil]-N-(3-piridilmetil)-3-aminobenzojeva kiselina o) N-[4-Methoxy-3-(2-(2-pyridyl) Ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid
PRIMJER 6 EXAMPLE 6
N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-2-aminobenzojeva kiselina N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2-aminobenzoic acid
Tert-Butil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-2-aminobenzoat (60 mg, 0.13 mmol) je bio uzet u 2 mL 98%-tne mravlje kiseline i grijan pri 40°C 4 h. Mravlja kiselina je bila uklonjena u vakuumu, a talog je bio napunjen na stupac silika gela (RediSep, 4.2 g). Proizvod je bio eluiran s linearnim gradijentom od 40% EtOAc u heksanima do 60% EtOAc u heksanima kroz 15 minuta kako bi se dobilo 16 mg proizvoda kao smeđa krutina.1H NMR (CDCl3) d 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8), 7.67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d,lH, J = 8.7), 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J = 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40(m, 2H). Tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2-aminobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL of 98% formic acid and heated at 40° C 4 h. The formic acid was removed in vacuo, and the precipitate was loaded onto a silica gel column (RediSep, 4.2 g). The product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to give 16 mg of product as a brown solid. 1H NMR (CDCl3) d 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8), 7.67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H, J = 8.7), 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J = 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina a) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
b) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-6-aminonikotinska kiselina b) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid
PRIMJER 7 EXAMPLE 7
3-Ciklopropilmetoksi-4-difluorometoksi-N-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
3-Ciklopropilmetoksi-4-difluormetoksi-N-(3-piridilmetil)-4'-[2-(2-tetrahidropiranil)-2H-tetrazol-5-il]difenilamin (1.5 g, 0.26 mmol) je bio otopljen u THF-u (5 mL), a 3 mL 1N HCl je bilo dodano. Nakon 6 h pri sobnoj temperaturi, smjesa je bila neutralizirana do pH = 5 sa zasićenim vodenim natrijevim bikarbonatom i ekstrahirana s EtOAc (3 x 50 mL). EtOAc ekstrakti su bili kombinirani, isprani rasolom (50 mL), sušeni (MgSO4), i koncentrirani u vakuumu. Sirovi talog je bio napunjen na RediSep stupac (10 g, silika gel), a proizvod je bio eluiran korištenjem linearnog gradijenta od 0% MeOH u EtOAc do 5% MeOH u EtOAc kroz 20 min kako bi dao 0.96 g proizvoda kao bijeli prah.1H NMR (CDCl3) d 8.55 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.65 (d, 1H, 8.0 Hz), 7.21 (dd, 1H, J = 4.9 Hz, 8.0 Hz), 7.18 (d, 1H, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.87 (dd, 1H, J = 8.6 Hz, 2.5 Hz), 6.75 (t, 1H, J = 75.5 Hz), 5.14 (s, 2H), 3.82 (d, 2H, J = 6.9 Hz), 1.23 (m, 1H), 0.60 (m, 2H),0.33 (m, 2H). 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-[2-(2-tetrahydropyranyl)-2H-tetrazol-5-yl]diphenylamine (1.5 g, 0.26 mmol) was dissolved in THF- in (5 mL), and 3 mL of 1N HCl was added. After 6 h at room temperature, the mixture was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with EtOAc (3 x 50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (10 g, silica gel) and the product was eluted using a linear gradient from 0% MeOH in EtOAc to 5% MeOH in EtOAc over 20 min to give 0.96 g of the product as a white powder.1H NMR (CDCl3) d 8.55 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.65 (d, 1H, 8.0 Hz), 7.21 (dd, 1H, J = 4.9 Hz, 8.0 Hz), 7.18 (d, 1H, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.87 (dd, 1H, J = 8.6 Hz, 2.5 Hz), 6.75 (t, 1H, J = 75.5 Hz), 5.14 (s , 2H), 3.82 (d, 2H, J = 6.9 Hz), 1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin a) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
b) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-3'-(2H-tetrazol-5-il)difenilamin b) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine
c) 4-Metoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)-4'-(2H-tetrazol-5-il)difenilamin c) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5-yl)diphenylamine
d) 3-Ciklopropilmetiloksi-4-metoksi-N-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin d) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
e) 4-Difluormetoksi-N-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)-4'-(2H-tetrazol-5-il)difenilamin e) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5-yl)diphenylamine
f) 3-Ciklopentiloksi-4-diflurometoksi-N-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin f) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
g) 3-Ciklopropilmetiloksi-4-difluormetoksi-N-(3-piridilmetil)-3'-(2H-tetrazol-5-il)difenilamin g) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine
h) Bis-3,4-difluormetoksi-N-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin h) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
PRIMJER 8 (Metoda A) EXAMPLE 8 (Method A)
3-Ciklopentiloksi-4-metoksidifenilamin 3-Cyclopentyloxy-4-methoxydiphenylamine
Metoda A. (Ref. Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P., Tetrahedron Lett., 1998, 39, 2933-2936.). Gusta otopina 207 mg 4-metoksi-3-ciklopentiloksianilina, 280 mg fenilborove kiseline, 182 mg Cu(OAc)2, 280 μL Et3N i 4.0 mL CH2Cl2 je bila miješana 20 h na sobnoj temperaturi. Crna smjesa je bila filtrirana kroz zemlju kremenjaču, eluirajući s CH2Cl2, koncentrirana, i pročišćena kromatografijom preko Si02 korištenjem EtOAc/Heksani (15/85) kao protočno sredstvo (eluant) kako bi dala 75 mg željenog proizvoda. 1H NMR (CDCl3) d 7.26-7.20(m, 2H), 6.94-6.63(m, 6H), 5.50 (s, 1H), 4.71(m, 1H), 3.82 (s, 3H), 1.89-1.54 (m, 8H). Method A. (Ref. Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P., Tetrahedron Lett., 1998, 39, 2933-2936.). A thick solution of 207 mg of 4-methoxy-3-cyclopentyloxyaniline, 280 mg of phenylboric acid, 182 mg of Cu(OAc)2, 280 μL of Et3N and 4.0 mL of CH2Cl2 was stirred for 20 h at room temperature. The black mixture was filtered through silica, eluting with CH 2 Cl 2 , concentrated, and purified by chromatography over SiO 2 using EtOAc/Hexanes (15/85) as the eluant to give 75 mg of the desired product. 1H NMR (CDCl3) d 7.26-7.20(m, 2H), 6.94-6.63(m, 6H), 5.50 (s, 1H), 4.71(m, 1H), 3.82 (s, 3H), 1.89-1.54 (m , 8H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-3',4-dimetoksidifenilamin a) 3-Cyclopentyloxy-3',4-dimethoxydiphenylamine
b) 3'-Klor-3-ciklopentiloksi-4-metoksidifenilamin b) 3'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
c) 3-Ciklopentiloksi-4-metoksi-3'metildifenilamin c) 3-Cyclopentyloxy-4-methoxy-3'methyldiphenylamine
d) 3-Ciklopentiloksi-4'-fluor-4-metoksidifenilamin d) 3-Cyclopentyloxy-4'-fluoro-4-methoxydiphenylamine
e) 3-Ciklopentiloksi-4-metoksi-4'-vinildifenilamin e) 3-Cyclopentyloxy-4-methoxy-4'-vinyldiphenylamine
f) 3'-Cijano-3-ciklopentiloksi-4-metoksidifenilamin f) 3'-Cyano-3-cyclopentyloxy-4-methoxydiphenylamine
g) 4'-Klor-3-ciklopentiloksi-4-metoksidifenilamin g) 4'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
h) 3-Ciklopentiloksi-4,4'-dimetoksidifenilamin h) 3-Cyclopentyloxy-4,4'-dimethoxydiphenylamine
i) 3-Ciklopentiloksi-4-metoksi-2'-metildifenilamin i) 3-Cyclopentyloxy-4-methoxy-2'-methyldiphenylamine
j) 3-Ciklopentiloksi-4-metoksi-4'-metildifenilamin j) 3-Cyclopentyloxy-4-methoxy-4'-methyldiphenylamine
k) 2'-Klor-3-ciklopentiloksi-4-metoksidifenilamin k) 2'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
l) 3-Ciklopentiloksi-2',4-dimetoksidifenilamin l) 3-Cyclopentyloxy-2',4-dimethoxydiphenylamine
m) 3-Ciklopentiloksi-4-metoksi-3'-trifluormetildifenilamin m) 3-Cyclopentyloxy-4-methoxy-3'-trifluoromethyldiphenylamine
n) 3-Ciklopentiloksi-4-metoksi-4'-trifluormetildifenilamin n) 3-Cyclopentyloxy-4-methoxy-4'-trifluoromethyldiphenylamine
o) 3-Ciklopentiloksi-2',5'-dimetil-4-metoksidifenilamin o) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxydiphenylamine
PRIMJER 8 (Metoda B) EXAMPLE 8 (Method B)
3-Ciklopentiloksi-4-metoksidifenilamin 3-Cyclopentyloxy-4-methoxydiphenylamine
Metoda B (Angerw Chem. Int. Ed., 1995,34(17), 1348-1351.) Smjesa 207 mg 3-ciklopentiloksi-4-metoksianilina, 204 mg jodbenzena, 115 mg NaOtBu, 9 mg Pd2(dba)3, 12 mg P(o-tol)3 i 7 mL toluena je bilo kombinirano i grijano uz miješanje do 100°C 4h. Smjesa je bila ohlađena do sobne temperature, razrijeđena s 25 mL EtOAc i isprana s 10 mL H2O, 10 mL rasola, sušena (MgSO4) i koncentrirana. Talog je bio pročišćen kromatografijom preko Si02 korištenjem EtOAc/heksana (5/95) kao protočno sredstvo (eluant) kako bi se dobilo 84 mg željenog proizvoda. Method B (Angerw Chem. Int. Ed., 1995,34(17), 1348-1351.) A mixture of 207 mg of 3-cyclopentyloxy-4-methoxyaniline, 204 mg of iodobenzene, 115 mg of NaOtBu, 9 mg of Pd2(dba)3, 12 mg of P(o-tol)3 and 7 mL of toluene were combined and heated with stirring to 100°C for 4 h. The mixture was cooled to room temperature, diluted with 25 mL EtOAc and washed with 10 mL H 2 O, 10 mL brine, dried (MgSO 4 ) and concentrated. The residue was purified by chromatography over SiO 2 using EtOAc/hexanes (5/95) as eluant to give 84 mg of the desired product.
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-metoksi-2',4'-dimetildifenilamin a) 3-Cyclopentyloxy-4-methoxy-2',4'-dimethyldiphenylamine
b) 3-Ciklopentiloksi-2',5'-dimetil-4-metoksidifenilamin b) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxydiphenylamine
c) 3-Ciklopentiloksi-2',3'-dimetil-4-metoksidifenilamin c) 3-Cyclopentyloxy-2',3'-dimethyl-4-methoxydiphenylamine
d) 3-Ciklopentiloksi-3',4'-dimetil-4-metoksidifenilamin d) 3-Cyclopentyloxy-3',4'-dimethyl-4-methoxydiphenylamine
e) 3-Ciklopentiloksi-3',4'-metilendioksidifenilamin e) 3-Cyclopentyloxy-3',4'-methylenedioxydiphenylamine
f) 4'-tert-Butil-3-ciklopentiloksi-4-metoksidifenilamin f) 4'-tert-Butyl-3-cyclopentyloxy-4-methoxydiphenylamine
g) 3-Ciklopentiloksi-3',4'-diklor-4-metoksidifenilamin g) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxydiphenylamine
h) 3-Ciklopentiloksi-2',3'-diklor-4-metoksidifenilamin h) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxydiphenylamine
PRIMJER 8 (Metoda C) EXAMPLE 8 (Method C)
3-Ciklopentiloksi-2',4,5'-trimetoksidifenilamin 3-Cyclopentyloxy-2',4,5'-trimethoxydiphenylamine
Metoda C. Smjesi Pd(dppf)Cl2 (0.025 mmol, 5mol%), dppf (0.075 mmol, 3dppf/Pd) i NaOtBu (0.70 mmol, 1.4 ekvivalenta) i 1.0 mL THF je bio dodan 1-brom-2,5-dimetoksibenzen (0.55 mmol, 1.1 ekvivalenta) nakon čega je slijedilo 1.0 mL 0.5M otopine 3-ciklopentiloksi-4-metoksianilina u THF-u. Smjesa je bila grijana do 60°C 3 sata i razrijeđena s eterom i isprana s H2O i rasolom, sušena (MgSO4), i koncentrirana. Sirovi talog je bio pročišćen kromatografijom preko silika gela (Biotage Flash 12) eluiranjem s 15% EtOAc u heksanima. Method C. To a mixture of Pd(dppf)Cl2 (0.025 mmol, 5mol%), dppf (0.075 mmol, 3dppf/Pd) and NaOtBu (0.70 mmol, 1.4 equiv) and 1.0 mL of THF was added 1-bromo-2,5- dimethoxybenzene (0.55 mmol, 1.1 equiv) followed by 1.0 mL of a 0.5 M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was heated to 60°C for 3 hours and diluted with ether and washed with H 2 O and brine, dried (MgSO 4 ), and concentrated. The crude residue was purified by chromatography over silica gel (Biotage Flash 12) eluting with 15% EtOAc in hexanes.
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) N-(3-Ciklopentiloksi-4-metoksifenil)-3-piridilamin a) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-pyridylamine
b) 3-Ciklopentiloksi-2',4',4-trimetoksidifenilamin b) 3-Cyclopentyloxy-2',4',4-trimethoxydiphenylamine
c) N-(3-Ciklopentiloksi-4-metoksifenil)-2-piridilamin c) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine
d) N-(3-Ciklopentiloksi-4-metoksifenil)-8-kinolinilamin d) N-(3-Cyclopentyloxy-4-methoxyphenyl)-8-quinolinylamine
e) N-(3-Ciklopentiloksi-4-metoksifenil)-2-naftilamin e) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-naphthylamine
f) N-(3-Ciklopentiloksi-4-metoksifenil)-1-naftilamin f) N-(3-Cyclopentyloxy-4-methoxyphenyl)-1-naphthylamine
g) 3-Ciklopentiloksi-4'-etil-4-metoksidifenilamin g) 3-Cyclopentyloxy-4'-ethyl-4-methoxydiphenylamine
h) 3-Ciklopentiloksi-2'-fluor-4-metoksi-5'-metildifenilamin h) 3-Cyclopentyloxy-2'-fluoro-4-methoxy-5'-methyldiphenylamine
i) 3-Ciklopentiloksi-3'-fluor-4-metoksi-4'-metildifenilamin i) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-4'-methyldiphenylamine
j) N-(3-Ciklopentiloksi-4-metoksifenil)-2-pirimidinilamin j) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrimidinylamine
k) 3-Ciklopentiloksi-3',5'-diklor-4-metoksidifenilamin k) 3-Cyclopentyloxy-3',5'-dichloro-4-methoxydiphenylamine
l) 3-Ciklopentiloksi-2'-etil-4-metoksidifenilamin l) 3-Cyclopentyloxy-2'-ethyl-4-methoxydiphenylamine
m) 4'-Klor-3-ciklopentiloksi-3'-fluor-4-metoksidifenilamin m) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxydiphenylamine
n) N-(3-Ciklopentiloksi-4-metoksifenil)-4-izokinolinilamin n) N-(3-Cyclopentyloxy-4-methoxyphenyl)-4-isoquinolinylamine
o) N-(3-Ciklopentiloksi-4-metoksifenil)-2-pirazinilamin o) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrazinylamine
p) N-(3-Ciklopentiloksi-4-metoksifenil)-5-pirimidinilamin p) N-(3-Cyclopentyloxy-4-methoxyphenyl)-5-pyrimidinylamine
q) N-(3-Ciklopentiloksi-4-metoksifenil)-1-izokinolinilamin q) N-(3-Cyclopentyloxy-4-methoxyphenyl)-1-isoquinolinylamine
r) N-(3-Ciklopentiloksi-4-metoksifenil)-3-kinolinilamin r) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-quinolinylamine
s) N-(3-Ciklopentiloksi-4-metoksifenil)-4-piridilamin s) N-(3-Cyclopentyloxy-4-methoxyphenyl)-4-pyridylamine
t) N-(3-Ciklopentiloksi-4-difluormetoksifenil)-3-piridilamin t) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-3-pyridylamine
u) N-(3-Ciklopropilmetiloksi-4-metoksifenil)-3-piridilamin u) N-(3-Cyclopropylmethyloxy-4-methoxyphenyl)-3-pyridylamine
v) N-(3-Ciklopropilmetiloksi-4-difluormetoksifenil)-3-piridilamin v) N-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenyl)-3-pyridylamine
w) N-(4-Metoksi-3-(3R)-tetrahidrofuriloksifenil)-3-piridilamin w) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-3-pyridylamine
x) N-(4-Difluormetoksi-3-(3R)-tetrahidrofuriloksifenil)-3-piridilamin x) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-3-pyridylamine
y) Etil N-(3-ciklopentiloksi-4-metoksifenil)-3-aminobenzoat y) Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoate
z) 3-Ciklopentiloksi-4'-(N,N-dimetilamino)-4-metoksidifenilamin z) 3-Cyclopentyloxy-4'-(N,N-dimethylamino)-4-methoxydiphenylamine
aa) N-(3-Ciklopentiloksi-4-metoksifenil)-3-(6-metokspiridil)amin aa) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(6-methoxypyridyl)amine
bb) Metil N-(3-ciklopentiloksi-4-metoksifenil)-2-aminonikotinat bb) Methyl N-(3-cyclopentyloxy-4-methoxyphenyl)-2-aminonicotinate
cc)tert-Butil N-(3-ciklopentiloksi-4-metoksifenil)-6-aminonikotinat cc) tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-6-aminonicotinate
dd) 2'-Amino-3-ciklopentiloksi-4-metoksidifenilamin dd) 2'-Amino-3-cyclopentyloxy-4-methoxydiphenylamine
ee) 3-Ciklopentiloksi-4-metoksi-3'-(1-ftalimido)difenilamin ee) 3-Cyclopentyloxy-4-methoxy-3'-(1-phthalimido)diphenylamine
ff) 3-Ciklopentiloksi-4-metoksi-3'-[2-(2-tetrahidropiranil)-2H-tetrazol-5-il] difenilamin ff) 3-Cyclopentyloxy-4-methoxy-3'-[2-(2-tetrahydropyranyl)-2H-tetrazol-5-yl] diphenylamine
PRIMJER 9 (Metoda A) EXAMPLE 9 (Method A)
3-Ciklopentiloksi-4-metoksi-N-metildifenilamin 3-Cyclopentyloxy-4-methoxy-N-methyldiphenylamine
Otopini 3-ciklopentiloksi-4-metoksidifenilamina (70 mg, 0.25 mmol) u 3 mL THF-a pri 0°C je bilo dodano 0.55 mL 0.5 M KN(TMS)2 u toluenu. Otopina je bila miješana pri 0°C 0.5 h, a 2.0 ekvivalenta jodmetana je bilo dodano te je reakcijska smjesa bila grijana do sobne temperature. Nakon što je reakcija završila, kako je pokazano pomoću TLC, 10 mL EtOAc je bilo dodano, a smjesa je bila isprana s 3 mL H2O, 3 mL rasola, sušena (MgSO4) i koncentrirana. Sirovi talog je bio pročišćen pomoću kromatografije u stupcu (Biotage flash 12) korištenjem 5% EtOAc u heksanima kao protočno sredstvo (eluant). To a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol) in 3 mL of THF at 0°C was added 0.55 mL of 0.5 M KN(TMS)2 in toluene. The solution was stirred at 0°C for 0.5 h, and 2.0 equivalents of iodomethane were added and the reaction mixture was warmed to room temperature. After the reaction was complete, as indicated by TLC, 10 mL of EtOAc was added, and the mixture was washed with 3 mL of H 2 O, 3 mL of brine, dried (MgSO 4 ), and concentrated. The crude residue was purified by column chromatography (Biotage flash 12) using 5% EtOAc in hexanes as eluent.
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-N-etil-4-metoksidifenilamin a) 3-Cyclopentyloxy-N-ethyl-4-methoxydiphenylamine
b) 3-Ciklopentiloksi-4-metoksi-N-(1-propil)difenilamin b) 3-Cyclopentyloxy-4-methoxy-N-(1-propyl)diphenylamine
c) 3-Ciklopentiloksi-4-metoksi-N-[1-(3-fenpropil)]difenilamin c) 3-Cyclopentyloxy-4-methoxy-N-[1-(3-phenpropyl)]diphenylamine
d) N-Benzil-3-ciklopentiloksi-4-metoksidifenilamin d) N-Benzyl-3-cyclopentyloxy-4-methoxydiphenylamine
e) 3-Ciklopentiloksi-4-metoksi-N-(4-piridilmetil)difenilamin e) 3-Cyclopentyloxy-4-methoxy-N-(4-pyridylmethyl)diphenylamine
f) 3-Ciklopentiloksi-4-metoksi-N-(2-piridilmetil)difenilamin f) 3-Cyclopentyloxy-4-methoxy-N-(2-pyridylmethyl)diphenylamine
g) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin g) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
h) 3-Ciklopentiloksi-4-metoksi-N-[3-(3-piridil)-1-propil]difenilamin h) 3-Cyclopentyloxy-4-methoxy-N-[3-(3-pyridyl)-1-propyl]diphenylamine
i) N-(3-Ciklopentiloksi-4-metoksifenil)-N-etil-4-izokinolinilamin i) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-ethyl-4-isoquinolinylamine
j) N-(3-Ciklopentiloksi-4-metoksifenil)-N-benzil-4-izokinolinilamin j) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-benzyl-4-isoquinolinylamine
k) N-(3-Ciklopentiloksi-4-metoksifenil)-N-metil-4-izokinolinilamin k) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-methyl-4-isoquinolinylamine
l) N-(3-Ciklopentiloksi-4-metoksifenil)-N-propil-4-izokinolinilamin l) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-propyl-4-isoquinolinylamine
m) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(4-izokinolinil)-N-(4-piridilmetil)amin m) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(4-pyridylmethyl)amine
n) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(4-izokinolinil)-N-(3-piridilmetil)amin n) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3-pyridylmethyl)amine
o) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-N-(5-pirimidinil)amin o) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5-pyrimidinyl)amine
p) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(2-pirazinil)-N-(3-piridilmetil)amin p) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl)amine
q) N-(3-Ciklopentiloksi-4-piridilmetil)-N-(2-piridil)-N-(3-piridilmetil)amin q) N-(3-Cyclopentyloxy-4-pyridylmethyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine
r) N-(3-Ciklopentiloksi-4-metoksifenil)-N-(3-piridil)-N-(3-piridilmetil)amin r) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
s) N-(3-Ciklopenliloksi-4-metoksifenil)-N-(4-piridil)-N-(3-piridilmetil)amin s) N-(3-Cyclophenyloxy-4-methoxyphenyl)-N-(4-pyridyl)-N-(3-pyridylmethyl)amine
t)tert-Butil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-6-aminonikotinat t)tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinate
u) N-(3-Ciklopropilmetoksi-4-metoksifenil)-N-(3-piridil)-N-(3-piridilmetil)amin u) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
v) N-(4-Metoksi-3-(3R)-tetrahidrofuriloksifenil)-N-(3-piridil)-N-(3-piridilmetil)amin v) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
w) N-(3-Ciklopentiloksi-4-difluormetoksifenil)-N-(3-piridil)-N-(3-piridilmetil)amin w) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
x) N-(3-Ciklopropilmetoksi-4-difluormetoksifenil)-N-(3-piridil)-N-(3-piridilmetil)amin x) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
y) N-(4-Difluormetoksi-3-(3R)-tetrahidrofuriloksifenil)-N-(3-piridil)-N-(3-piridilmetil)amin y) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine
z) N-(4-Klor-3-piridilmetil)-N-(3-ciklopentiloksi-4-metoksifenil)-N-(2-piridil)amin z) N-(4-Chloro-3-pyridylmethyl)-N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)amine
aa) N-(3-ciklopentiloksi-4-metoksifenil)-N-(4-metil-3-piridilmetil)-N-(2-piridil)amin aa) N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(4-methyl-3-pyridylmethyl)-N-(2-pyridyl)amine
bb) 3-Ciklopentiloksi-4-metoksi-N-(2-tiazolilmetil)difenilamin bb) 3-Cyclopentyloxy-4-methoxy-N-(2-thiazolylmethyl)diphenylamine
cc) N-(2-Klor-3-piridilmetil)-3-ciklopentiloksi-4-metoksidifenilamin cc) N-(2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxydiphenylamine
dd) N-(6-Klor-3-piridilmetil)-3-ciklopentiloksi-4-metoksidifenilamin dd) N-(6-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxydiphenylamine
PRIMJER 9 (Metoda B) EXAMPLE 9 (Method B)
N-4-Klor-3-piridilmetil)-N-(3-ciklopentil-4-metoksifenil)-N-(2-piridil)amin N-4-Chloro-3-pyridylmethyl)-N-(3-cyclopentyl-4-methoxyphenyl)-N-(2-pyridyl)amine
Otopini (3-ciklopentiloksi-4-metoksifenil)-2-piridilamina (30 mg, 0.10 mmol) i 4-klorpikolil klorid hidroklorida (50 mg, 0.25 mmol) je bilo otopljeno u DMF-u (1 mL), a natrijev hidrid (50 mg 60%-tna disperzija mineralnog ulja, 1.3 mmol) je bio dodan u malim dijelovima. Nakon miješanja lh pri sobnoj temperaturi, smjesa je bila prelivena u 25 mL ledene vode. Smjesa je bila ekstrahirana s EtOAc (2 x 15 mL), a EtOAc ekstrakti su bili kombinirani, isprani s rasolom (15 mL), sušeni (MgSO4), i koncentrirani u vakuumu. Sirovi talog je bio napunjen na RediSep stupac (4.2 g, silika gel), a proizvod je bio eluiran s 15% EtOAc u heksanima kako bi dali 20 mg proizvoda kao žutu kristalnu krutinu. 1H NMR (CDCl3) d 8.61 (s, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33(m, 1H), 7.25(m, 1H), 6.83 (d, 1H, J = 8.5), 6.75 (d, 1H, J = 8.5), 6,71 (s, 1H), 6.62 (m, 1H), 6.42 (d, 1H, J = 8.6), 5.31 (s, 2H), 4.63(p, 1H, J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45(m, 2H). A solution of (3-cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine (30 mg, 0.10 mmol) and 4-chloropicolyl chloride hydrochloride (50 mg, 0.25 mmol) was dissolved in DMF (1 mL), and sodium hydride ( 50 mg of 60% mineral oil dispersion, 1.3 mmol) was added in small portions. After stirring for 1 h at room temperature, the mixture was poured into 25 mL of ice water. The mixture was extracted with EtOAc (2 x 15 mL), and the EtOAc extracts were combined, washed with brine (15 mL), dried (MgSO 4 ), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of product as a yellow crystalline solid. 1H NMR (CDCl3) d 8.61 (s, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33(m, 1H), 7.25(m, 1H), 6.83 (d, 1H, J = 8.5), 6.75 (d, 1H, J = 8.5), 6.71 (s, 1H), 6.62 (m, 1H), 6.42 (d, 1H, J = 8.6), 5.31 ( s, 2H), 4.63(p, 1H, J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45(m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3,4-Bis(difluormetoksi)-N-(4-klor-3-piridilmetil)-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)difenilamin a) 3,4-Bis(difluoromethoxy)-N-(4-chloro-3-pyridylmethyl)-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)diphenylamine
b) 3,4-Bis(difluormetoksi)-N-(4-metil-3-piridilmetil)-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)difenilamin b) 3,4-Bis(difluoromethoxy)-N-(4-methyl-3-pyridylmethyl)-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)diphenylamine
PRIMJER 10 EXAMPLE 10
3-Ciklopentiloksi-4-metoksianilino-N-(3-piridilmetil)-N-3- (4-piridil)benzamid 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide
Otopini N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzojeve kiseline (20 mg, 0.05 mmol) i pyBOP-a (40 mg. 0.08 mmol) u CH2Cl2 (2 mL) pri sobnoj temperaturi je bio dodan diizopropiletilamin (20 L, 0.11 mmol). Nakon miješanja 15 min, 4-aminopiridin (15 mg, 0.15 mmol) je bio dodan, a smjesa je puštena da se miješa 16 h. Smjesa je bila razrijeđena s EtOAc (25 mL) i isprana s vodom (2 x 15 mL) i rasolom (15 mL), sušena (MgSO4), i koncentrirana u vakuumu. Sirovi talog je bio napunjen na RediSep stupac (4.2 g, silika gel), a proizvod je bio eluiran s linearnim gradijentom od 40% EtOAc u heksanima do 60% EtOAc u heksanima kroz 15 min kako bi dao 22 mg proizvoda. 1H NMR (CDCl3) d 8.70-8.40(m, 3H), 8.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55(m, 2H), 7.30-7.20(m, 1H), 6.88 (d, 2H, J = 8.5), 6.80-6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). Solutions of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg, 0.08 mmol) in CH2Cl2 (2 mL) at diisopropylethylamine (20 L, 0.11 mmol) was added at room temperature. After stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added, and the mixture was allowed to stir for 16 h. The mixture was diluted with EtOAc (25 mL) and washed with water (2 x 15 mL) and brine (15 mL), dried (MgSO 4 ), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to give 22 mg of product. 1H NMR (CDCl3) d 8.70-8.40(m, 3H), 8.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55(m, 2H), 7.30-7.20(m, 1H), 6.88 (d, 2H, J = 8.5), 6.80-6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70 ( m, 6H), 1.65-1.45 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-(3-Ciklopentiloksi-4-metoksianilino)-N-(3-piridilmetil)-N-3-[3-(N,N-dimetilamino)prop-1-il] benzamid a) 3-(3-Cyclopentyloxy-4-methoxyanilino)-N-(3-pyridylmethyl)-N-3-[3-(N,N-dimethylamino)prop-1-yl] benzamide
b) 3-Ciklopentiloksi-4-metoksi-3'-(4-metilpiperazin-1-ilkarbonil)-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine
c) 3-Ciklopentiloksi-4-difluormetoksi-4'-(4-metilpiperazin-1-ilkarbonil)-N-(3-piridilmetil)difenilamin c) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)diphenylamine
d) 3-Ciklopentiloksi-4-metoksi-4'-(4-metilpiperazin-1-ilkarbonil)-N-(3-piridilmetil)-3-(3-tetrahidrofuraniloksi)-difenilamin d) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)-N-(3-pyridylmethyl)-3-(3-tetrahydrofuranyloxy)-diphenylamine
PRIMJER 11 EXAMPLE 11
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano u Primjeru 2: The following compounds were prepared in a similar manner as described in Example 2:
a) 4'-Amino-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin a) 4'-Amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3'-Amino-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin b) 3'-Amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
c) 3'-Amino-3-ciklopropilmetoksi-4-metoksi-N-(3-piridilmetil)difenilamin c) 3'-Amino-3-cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
d) 3'-Amino-4-metoksi-N-(3-piridilmetil)-3-[(3R)-tetrahidrofuriloksi] difenilamin d) 3'-Amino-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
PRIMJER 12 EXAMPLE 12
3-Ciklopentiloksi-4'-metansulfonilamino-4-metoksi-N-(3-piridilmetil)-difenilamin 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)-diphenylamine
Otopini 4'-amino-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-difenilamina (47 mg, 0.12 mmol) u CH2Cl2 (2 mL) pri sobnoj temperaturi je bio dodan piridin (20 mikrolitara, 0.24 mmol) nakon čega je slijedio metansulfonil klorid (15 mikrolitara, 0.18 mmol) i smjesa je puštena da stoji pri sobnoj temperaturi 16 h. Smjesa je bila razrijeđena s eterom (50 mL) i isprana s vodom (25 mL) i rasolom (25 mL), sušena (MgSO4), i koncentrirana. Sirovi talog je bio pročišćen "flash" kromatografijom u stupcu (4.2 g RediSep stupac, silika gel) eluiranjem s linearnim gradijentom od 45% EtOAc u heksanima do 60% EtOAc u heksanima kroz 20 min kako bi se dobilo 41 mg proizvoda. 1H NMR (CDCl3) d 8.51 (s, 1H), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H, 7.9 Hz), 7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 Hz), 6.80-6.60(m, 6H), 4.82 (s, 2H), 4.56 (p, 1H, J = 4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86-1.70(m, 6H), 1.65-1.45 (m, 2H). To a solution of 4'-amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-diphenylamine (47 mg, 0.12 mmol) in CH2Cl2 (2 mL) at room temperature was added pyridine (20 microliters, 0.24 mmol). followed by methanesulfonyl chloride (15 microliters, 0.18 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was diluted with ether (50 mL) and washed with water (25 mL) and brine (25 mL), dried (MgSO 4 ), and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with a linear gradient from 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 min to give 41 mg of product. 1H NMR (CDCl3) d 8.51 (s, 1H), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H, 7.9 Hz), 7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 Hz), 6.80-6.60(m, 6H), 4.82 (s, 2H), 4.56 (p, 1H, J = 4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86-1.70( m, 6H), 1.65-1.45 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-3'-etansulfonilamino-4-metoksi-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-Ciklopentiloksi-4-metoksi-3'-(1-propansulfonilamino)-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4-methoxy-3'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine
c) 3'-(1-Butansulfonilamino)-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin c) 3'-(1-Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
d) 3'-Benzilsulfonilamino-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin d) 3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
e) 3'-Acetamido-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin e) 3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
f) 3-Ciklopentiloksi-4'-etansulfonilamino-4-metoksi-N-(3-piridilmetil)difenilamin f) 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine
g) 3-Ciklopentiloksi-4-metoksi-4'-(1-propansulfonilamino)-N-(3-piridilmetil)difenilamin g) 3-Cyclopentyloxy-4-methoxy-4'-(1-propanesulfonylamino)-N-(3-pyridylmethyl)diphenylamine
h) 3-Ciklopropilmetoksi-3'-etansulfonilamino-4-metoksi-N-(3-piridilmetil)difenilamin h) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)diphenylamine
i) 4-Difluormetoksi-3'-etansulfonilamino-N-(3-piridilmetil)-3-[(3R)-tetrahidrofuriloksi]difenilamin i) 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine
PRIMJER 13 EXAMPLE 13
3-Ciklopentiloksi-4-metoksi-3'-hidroksimetil-N-(3-piridilmetil)difenilamin 3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine
Otopini Etil N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoata (50 mg, 0.11 mmol) u THF-u (5 mL) pri 0°C je bio dodan u kapima, uz miješanje, 2.5M diizobutilaluminijev hidrid u toluenu (0.4 mL, 1.00 mmol). Smjesa je bila miješana pri 0°C 1 h, a suvišak diizobutilaluminijevog hidrida je bio neutraliziran pomoću dodatka 5 kapi EtOAc u smjesu. Smjesa je bila koncentrirana, a talog je bio particioniran između CH2Cl2 (50 mL) i vode (50 mL). Slojevi su bili odvojeni, a vodeni sloj je bio ekstrahiran s CH2Cl2 (2 x 10 mL). Organski ekstrakti su bili kombinirani i isprani s rasolom (50 mL), sušeni (MgSO4), i koncentrirani. Sirovi talog je bio pročišćen "flash" kromatografijom u stupcu (4.2 g RediSep stupac, silika gel) eluiranjem s 300 mL 50% EtOAc u heksanima, zatim 100% EtOAc kako bi dao 15 mg proizvoda 1H NMR (CDCl3) d 8.51 (s, 1H), 8.40 (br, 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05(m, 3H), 6.80-6.60 (m,5H), 4.85 (s, 2H), 4.56 (p, 1H, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H). Solutions of ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate (50 mg, 0.11 mmol) in THF (5 mL) at 0 °C was added dropwise, with stirring, 2.5M diisobutylaluminum hydride in toluene (0.4 mL, 1.00 mmol). The mixture was stirred at 0°C for 1 h, and excess diisobutylaluminum hydride was neutralized by adding 5 drops of EtOAc to the mixture. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The organic extracts were combined and washed with brine (50 mL), dried (MgSO4), and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with 300 mL of 50% EtOAc in hexanes, then 100% EtOAc to give 15 mg of product 1H NMR (CDCl3) d 8.51 (s, 1H), 8.40 (br, 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, 5H), 4.85 (s, 2H), 4.56 (p, 1H , J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-metoksi-4'-hidroksimetil-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine
PRIMJER 14 EXAMPLE 14
3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
Otopini N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzonitrila (100 mg, 0.25 mmol) u DMF-u (3 mL) je bilo dodano NaN3 (163 mg, 2.5 mmol) i NH4Cl (135 mg, 2.5 mmol) te je smjesa bila miješana pri 120°C 6h. Smjesa je bila ohlađena do sobne temperature, razrijeđena s vodom (50 mL) i ekstrahirana s EtOAc (2 x 25 mL). EtOAc ekstrakti su bili kombinirani, isprani s vodom (25 mL) i rasolom (25 mL), sušeni (MgSO4), i koncentrirani u vakuumu. Talog je bio napunjen na RediSep stupac (4.2 g, silika gel) i eluiran s linearnim gradijentom od 50% do 75% EtOAc u heksanima kako bi se dobilo 12 mg proizvoda. 1H NMR (CDCl3) d 12.50 (br, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz), 7.36 (m, 1H), 6.80-6.60 (m,5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H). To a solution of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzonitrile (100 mg, 0.25 mmol) in DMF (3 mL) was added NaN3 (163 mg, 2.5 mmol). and NH4Cl (135 mg, 2.5 mmol) and the mixture was stirred at 120°C for 6 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). The EtOAc extracts were combined, washed with water (25 mL) and brine (25 mL), dried (MgSO 4 ), and concentrated in vacuo. The precipitate was loaded onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient of 50% to 75% EtOAc in hexanes to give 12 mg of product. 1H NMR (CDCl3) d 12.50 (br, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz), 7.36 (m, 1H), 6.80-6.60 (m, 5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).
PRIMJER 15 EXAMPLE 15
3-Ciklopentiloksi-4-metoksi-4'-(4-metil-1-piperazinilmetil)-N-(3-piridilmetil)difenilamin 3-Cyclopentyloxy-4-methoxy-4'-(4-methyl-1-piperazinylmethyl)-N-(3-pyridylmethyl)diphenylamine
Otopini 3-ciklopentiloksi-4-metoksi-4'-(4-metilpiperazin-1-ilkarbonil)difenilamina (100 mg, 0.20 mmol) u THF-u (5 mL) je bio pažljivo dodan, uz miješanje, litijev aluminijev hidrid (50 mg, 1.3 mmol). Smjesa je bila miješana 15 min, a par kapi EtOAc je bilo pažljivo dodano da se neutralizira suvišak hidrida. Voda (50 mL) i CH2Cl2 (50 mL) su bili dodani i smjese su bile filtrirane kroz Celit. CH2Cl2 sloj je bio odvojen, ispran s rasolom (25 mL), sušen (MgSO4), i koncentriran u vakuumu. Sirovi talog je bio pročišćen na ISCO RediSep stupcu (4.2 g, zemlja kremenjača) eluiranjem s gradijentom od 5% MeOH u EtOAc do 15% MeOH u EtOAc kako bi se dobilo 60 mg proizvoda kao svijetlo žuto ulje.1H NMR (CDCl3) d 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73(m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 Hz), 3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20(m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45(m, 2H). To a solution of 3-cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-1-ylcarbonyl)diphenylamine (100 mg, 0.20 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydride (50 mg, 1.3 mmol). The mixture was stirred for 15 min, and a few drops of EtOAc were carefully added to neutralize the excess hydride. Water (50 mL) and CH 2 Cl 2 (50 mL) were added and the mixture was filtered through Celite. The CH 2 Cl 2 layer was separated, washed with brine (25 mL), dried (MgSO 4 ), and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g, silica earth) eluting with a gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 60 mg of product as a light yellow oil. 1H NMR (CDCl3) d 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73(m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 Hz), 3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20(m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45(m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-4-metoksi-3'-(4-metil-1-piperazinilmetil) N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-4-methoxy-3'-(4-methyl-1-piperazinylmethyl) N-(3-pyridylmethyl)diphenylamine
PRIMJER 16 EXAMPLE 16
3'-Aminometil-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin 3'-Aminomethyl-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
Otopini N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzonitrila (50 mg, 0.12 mmol) u THF-u (5 mL) je bio pažljivo dodan, uz miješanje, litijev aluminijev hidrid (20 mg, 0.52 mmol). Smjesa je bila miješana 4 h, a par kapi vode su bile pažljivo dodane kako bi se neutralizirao suvišak hidrida. Voda (50 mL) i CH2Cl2 (50 mL) su bili dodani te su smjese bile filtrirane kroz Celit. CH2Cl2 sloj je bio odvojen, ispran s rasolom (25 mL), sušen (MgSO4), i koncentriran u vakuumu. Sirovi talog je bio pročišćen na ISCO RediSep stupcu (4.2 g, zemlja kremenjača) eluiranjem s 10% MeOH u EtOAc kako bi se dobilo 20 mg proizvoda. 1H NMR (CDCl3) d 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65(m, 6H), 4.94 (s, 2H), 4.63 (p, 1H, J =, 4.1 Hz), 3.83 (s, 3H), 3.75(m, 2H), 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65-1.45(m, 2H). To a solution of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzonitrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydride (20 mg, 0.52 mmol). The mixture was stirred for 4 h, and a few drops of water were carefully added to neutralize the excess hydride. Water (50 mL) and CH 2 Cl 2 (50 mL) were added and the mixture was filtered through Celite. The CH 2 Cl 2 layer was separated, washed with brine (25 mL), dried (MgSO 4 ), and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g, diatomaceous earth) eluting with 10% MeOH in EtOAc to afford 20 mg of product. 1H NMR (CDCl3) d 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65(m, 6H), 4.94 ( s, 2H), 4.63 (p, 1H, J =, 4.1 Hz), 3.83 (s, 3H), 3.75(m, 2H), 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65- 1.45(m, 2H).
PRIMJER 17 EXAMPLE 17
3-Hidroksi-4-metoksi-N-(3-piridilmetil)difenilamin 3-Hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
Otopini 3-(tert-butildimetilsiloksi)-N-(3-piridilmetil)-4-metoksidifenilamina (1.20 g, 2.85 mmol) u THF-u (40 mL) pri 0°C, je bilo dodano 1.0M tetrabutilamonijevog fluorida u THF-u (10 mL, 10 mmol). Smjesa je bila miješana pri 0°C 30 min. Voda (50 mL) je bila dodana te je smjesa bila ekstrahirana s eterom (3 x 25 mL). Eterski ekstrakti su bili kombinirani i isprani s vodom (3 x 25 mL) i rasolom (25 mL), sušeni (MgSO4), i koncentrirani u vakuumu. Talog je bio trituriran s heksanima i sakupljen pomoću vakuumske filtracije kako bi dao 0.85 g proizvoda 1H NMR (CDCl3) d 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10(m, 3H), 6.90-6.65(m, 5H), 6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H), 3.86 (s, 3H). To a solution of 3-(tert-butyldimethylsiloxy)-N-(3-pyridylmethyl)-4-methoxydiphenylamine (1.20 g, 2.85 mmol) in THF (40 mL) at 0°C was added 1.0 M tetrabutylammonium fluoride in THF- in (10 mL, 10 mmol). The mixture was stirred at 0°C for 30 min. Water (50 mL) was added and the mixture was extracted with ether (3 x 25 mL). The ether extracts were combined and washed with water (3 x 25 mL) and brine (25 mL), dried (MgSO4), and concentrated in vacuo. The precipitate was triturated with hexanes and collected by vacuum filtration to give 0.85 g of product 1H NMR (CDCl3) d 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 3H), 6.90-6.65(m, 5H), 6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H), 3.86 (s, 3H) .
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3'-Klor-3-hidroksi-4-metoksi-N-(3-piridilmetil)difenilamin a) 3'-Chloro-3-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) Etil N-(3-hidroksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoat b) Ethyl N-(3-hydroxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
PRIMJER 18 (Metoda B) EXAMPLE 18 (Method B)
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano u Primjeru 1B: The following compounds were prepared in a similar manner as described in Example 1B:
a) 3-[3-(4-Klorfenil)prop-1-iloksi]-4-metoksi-N-(3-piridilmetil)difenilamin a) 3-[3-(4-Chlorophenyl)prop-1-yloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-[2-(4-Klorfenil)etoksi]-4-metoksi-N-(3-piridilmetil)difenilamin b) 3-[2-(4-Chlorophenyl)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
c) 4-Metoksi-3-(4-fenoksibut-1-il)oksi-N-(3-piridilmetil)difenilamin c) 4-Methoxy-3-(4-phenoxybut-1-yl)oxy-N-(3-pyridylmethyl)diphenylamine
d) 4-Metoksi-N-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin d) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine
e) 4-Metoksi-3-[3-(4-metoksifenil)prop-1-il]oksi-N-(3-piridilmetil)difenilamin e) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-1-yl]oxy-N-(3-pyridylmethyl)diphenylamine
f) 4-Metoksi-3-[3-(4-piridil)prop-1-il]oksi-N-(3-piridilmetil)difenilamin f) 4-Methoxy-3-[3-(4-pyridyl)prop-1-yl]oxy-N-(3-pyridylmethyl)diphenylamine
g) 4-Metoksi-3-[2-(4-metoksifenil)etoksi]-N-(3-piridilmetil)difenilamin g) 4-Methoxy-3-[2-(4-methoxyphenyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
h) 4-Metoksi-3-(4-fenilbut-1-il)oksi-N-(3-piridilmetil)difenilamini) h) 4-Methoxy-3-(4-phenylbut-1-yl)oxy-N-(3-pyridylmethyl)diphenylamines)
i)Metoksi-3-[4-(4-metoksifenil)but-1-il]oksi-N-(3-piridilmetil)difenilamin i) Methoxy-3-[4-(4-methoxyphenyl)but-1-yl]oxy-N-(3-pyridylmethyl)diphenylamine
j) 4-Metoksi-3-[4-(4-nitrofenil)but-1-il]oksi-N-(3-piridilmetil)difenilamin j) 4-Methoxy-3-[4-(4-nitrophenyl)but-1-yl]oxy-N-(3-pyridylmethyl)diphenylamine
k) 4-Metoksi-3-[2-(2-piridil)etoksi]-N-(3-piridilmetil)difenilamin k) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
l) 4-Metoksi-3-[2-(4-piridil)etoksi]-N-(3-piridilmetil)difenilamin l) 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
m) 4-Metoksi-3-[3-(2-piridil)prop-1-il]oksi-N-(3-piridilmetil)difenilamin m) 4-Methoxy-3-[3-(2-pyridyl)prop-1-yl]oxy-N-(3-pyridylmethyl)diphenylamine
n) 4-Metoksi-3-(2-metoksietoksi)-N-(3-piridilmetil)difenilamin n) 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine
o) 3-Ciklopropilmetoksi-4-metoksi-N-(3-piridilmetil)difenilamin o) 3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
p) 4-Metoksi-3-(1-metilpirolidin-3-il)oksi-N-(3-piridilmetil)difenilamin p) 4-Methoxy-3-(1-methylpyrrolidin-3-yl)oxy-N-(3-pyridylmethyl)diphenylamine
q) 4-Metoksi-3-(l-metilpiperidin-4-il)oksi-N-(3-piridilmetil)difenilamin q) 4-Methoxy-3-(1-methylpiperidin-4-yl)oxy-N-(3-pyridylmethyl)diphenylamine
r) 4-Metoksi-N-(3-piridilmetil)-3-[(3S)-tetrahidrofuriloksi]difenilamin r) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3S)-tetrahydrofuryloxy]diphenylamine
s) 4-Metoksi-N-(3-piridilmetil)-3-[(3R)-tetrahidrofuriloksi]difenilamin s) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine
t) 3'-Klor-4-metoksi-3-[2-(2-piridil)etoksi]-N-(3-piridilmetil)difenilamin t) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
u) 3'-Klor-4-metoksi-3-[2-(4-piridil)etoksi]-N-(3-piridilmetil)difenilamin u) 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
v) 3'-Klor-4-metoksi-3-(2-metoksietoksi)-N-(3-piridilmetil)difenilamin v) 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine
w) 3'-Klor-4-metoksi-N-(3-piridilmetil)-3-[(3R)-tetrahidrofuriloksi] difenilamin w) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy] diphenylamine
x) 3-Cikloheksiloksi-4-metoksi-N-(3-piridilmetil)difenilamin x) 3-Cyclohexyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
y) 3-Cikloheptiloksi-4-metoksi-N-(3-piridilmetil)difenilamin y) 3-Cycloheptyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
z) 3-(2-Ciklopropiletoksi)-4-metoksi-N-(3-piridilmetil)difenilamin z) 3-(2-Cyclopropylethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
aa) 3-Ciklopentilmetoksi-4-metoksi-N-(3-piridilmetil)difenilamin aa) 3-Cyclopentylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
bb) Etil N-[3-(4-klorfenil)prop-1-iloksi-4-metoksifenil]-N-(3-piridilmetil)-3-aminobenzoat bb) Ethyl N-[3-(4-chlorophenyl)prop-1-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoate
cc) Etil N-(3-ciklopropilmetoksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzoat cc) Ethyl N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
dd) Etil N-(3-ciklopropilmetoksi-4-difluormetoksifenil)-N-(3-piridilmetil)-3-aminobenzoat dd) Ethyl N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate
ee) Etil N-[3-(2-indaniloksi)-4-metoksifenil]-N-(3-piridilmetil)-3-aminobenzoat ee) Ethyl N-[3-(2-indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoate
ff) Etil N-[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-N-(3-piridilmetil)-3-aminobenzoat ff) Ethyl N-[4-methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoate
gg) Etil N-[4-metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-N-(3-piridilmetil)-3-aminobenzoat gg) Ethyl N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoate
hh) Etil N-[3-(2-metoksietoksi)-4-metoksifenil]-N-(3-piridilmetil)-3-aminobenzoat hh) Ethyl N-[3-(2-methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoate
ii) Etil N-[4-metoksi-3-(2-(2-piridil) Etil)oksifenil]-N-(3-piridilmetil)-3-aminobenzoat ii) Ethyl N-[4-methoxy-3-(2-(2-pyridyl) Ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoate
PRIMJER 18 (Metoda C) EXAMPLE 18 (Method C)
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano u Primjeru 8A vezanjem fenola s borovom kiselinom prije nego vezanjem anilina s borovom kiselinom: The following compounds were prepared in a similar manner as described in Example 8A by coupling phenol with boric acid rather than coupling aniline with boric acid:
a) 4-Metoksi-3-(4-metoksifenoksi)-N-(3-piridilmetil)difenilamin a) 4-Methoxy-3-(4-methoxyphenoxy)-N-(3-pyridylmethyl)diphenylamine
b) 4-Metoksi-3-fenoksi-N-(3-piridilmetil)difenilamin b) 4-Methoxy-3-phenoxy-N-(3-pyridylmethyl)diphenylamine
c) 4-Metoksi-3-(4-metilfenoksi)-N-(3-piridilmetil)difenilamin c) 4-Methoxy-3-(4-methylphenoxy)-N-(3-pyridylmethyl)diphenylamine
d) 3-(4-Klorfenoksi)-4-metoksi-N-(3-piridilmetil)difenilamin d) 3-(4-Chlorophenoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
e) 3-[2-(4-Klorfenil) Eteniloksi]-4-metoksi-N-(3-piridilmetil)difenilamin e) 3-[2-(4-Chlorophenyl)Ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
PRIMJER 19 EXAMPLE 19
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano u Primjeru 17: The following compounds were prepared in a similar manner as described in Example 17:
a) 3-Ciklopentiloksi-3'-hidroksi-4-metoksi-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-Ciklopentiloksi-4'-hidroksi-4-metoksi-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
c) 3-Ciklopropilmetoksi-4'-hidroksi-4-metoksi-N-(3-piridilmetil)difenilamin c) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
PRIMJER 20 (Metoda A) EXAMPLE 20 (Method A)
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano u Primjeru 1A : The following compounds were prepared in a similar manner as described in Example 1A:
a) 3'-(2-Brometoksi)-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin a) 3'-(2-Bromothoxy)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
PRIMJER 20 (Metoda B) EXAMPLE 20 (Method B)
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano u Primjeru 1B : The following compounds were prepared in a similar manner as described in Example 1B:
a) 3-Ciklopentiloksi-4'-(2-metoksietoksi)-4-metoksi-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-Ciklopentiloksi-4'-(3-metil-1-butoksi)-4-metoksi-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4'-(3-methyl-1-butoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
c) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-4'-[(3S)-tetrahidrofuraniloksi]-difenilamin c) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-[(3S)-tetrahydrofuranyloxy]-diphenylamine
d) 3-Ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-4'-[(3R)-tetrahidrofuraniloksi]-difenilamin d) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-[(3R)-tetrahydrofuranyloxy]-diphenylamine
e) 3-Ciklopentiloksi-4'-ciklopropilmetoksi-4-metoksi-N-(3-piridilmetil)difenilamin e) 3-Cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
f) 4'-Cikloheksiletoksi-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin f) 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
g) 4'-Ciklopentiletoksi-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin g) 4'-Cyclopentylethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
h) 3-Ciklopentiloksi-4-metoksi-4'-(1-metilpiperidin-4-iloksi)-N-(3-piridilmetil)difenilamin h) 3-Cyclopentyloxy-4-methoxy-4'-(1-methylpiperidin-4-yloxy)-N-(3-pyridylmethyl)diphenylamine
i) 3-Ciklopentiloksi-4-metoksi-4'-(1-metilpirolidin-3-iloksi)-N-(3-piridilmetil)difenilamin i) 3-Cyclopentyloxy-4-methoxy-4'-(1-methylpyrrolidin-3-yloxy)-N-(3-pyridylmethyl)diphenylamine
j) 3-Ciklopentiloksi-4-metoksi-4'-[2-(1-metilpirolidin-2-il)etoksi]-N-(3-piridilmetil)difenilamin j) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-methylpyrrolidin-2-yl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
k) 3-Ciklopentiloksi-4-metoksi-4'-[2-(1-pirolidiniletoksi)-N-(3-piridilmetil)difenilamin k) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-pyrrolidinylethoxy)-N-(3-pyridylmethyl)diphenylamine
l) 3-Ciklopentiloksi-4-metoksi-4'-[2-(6-metilpiridil)metoksi)-N-(3-piridilmetil)difenilamin l) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-N-(3-pyridylmethyl)diphenylamine
m) 3-Ciklopentiloksi-4-metoksi-4'-[3-(1-metilpiperidinil)metoksi]-N-(3-piridilmetil)difenilamin m) 3-Cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine
n) 3-Ciklopentiloksi-4-metoksi-4'-[2-(1-metilpiperidinil)metoksi]-N-(3-piridilmetil)difenilamin n) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-methylpiperidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine
o) 3-Ciklopentiloksi-4-metoksi-4'-[2-(5-oksopirolidinil)metoksi]-N-(3-piridilmetil)difenilamin o) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3-pyridylmethyl)diphenylamine
p) 4'-[1-(3-Brompropil)oksi]-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin p) 4'-[1-(3-Bromopropyl)oxy]-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
q) 3-Ciklopentiloksi-4-metoksi-4'-[2-(N-ftalimido)etoksi]-N-(3-piridilmetil)difenilamin q) 3-Cyclopentyloxy-4-methoxy-4'-[2-(N-phthalimido)ethoxy]-N-(3-pyridylmethyl)diphenylamine
PRIMJER 21 EXAMPLE 21
3-Ciklopentiloksi-4-metoksi-3'-[2-(l-piperidinil)etoksi]-N-(3-piridilmetil)difenilamin 3-Cyclopentyloxy-4-methoxy-3'-[2-(1-piperidinyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
Otopini 3'-(2-brometoksi)-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamina (17 mg, 0.03 mmol) u acetonitrilu (1 mL) je bio dodan kalijev karbonat (25 mg, 0.18 mmol) i piperidin (5 μL, 0.05 mmol) te je smjesa bila miješana pri 60°C 4 h. Smjesa je bila particionirana između vode (50 mL) i EtOAc (50 mL). Slojevi su bili odvojeni, a organski sloj je bio ispran s vodom (25 mL) i rasolom (25 mL), sušen (MgSO4), i koncentriran in vacuo. Talog je bio napunjen na ISCO RediSep stupac (4.2 g, zemlja kremenjača), a stupac je bio eluiran s linearnim gradijentom od 5% MeOH u EtOAc do 15% MeOH u EtOAc kako bi dao 11 mg proizvoda 1H NMR (CDCl3) d 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26-7.20(m, 1H), 7.06 (t, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 9.2 Hz), 6.75-6.68(m, 2H), 6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz), 4.00 (t, 2H, J = 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70(m, 6H), 1.86-1.70(m, 6H), 1.65-1.45(m, 2H). To a solution of 3'-(2-bromomethoxy)-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine (17 mg, 0.03 mmol) in acetonitrile (1 mL) was added potassium carbonate (25 mg, 0.18 mmol) ) and piperidine (5 μL, 0.05 mmol) and the mixture was stirred at 60°C for 4 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated, and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO4), and concentrated in vacuo. The precipitate was loaded onto an ISCO RediSep column (4.2 g, silica earth), and the column was eluted with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11 mg of product 1H NMR (CDCl3) d 8.59 ( s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26-7.20(m, 1H), 7.06 (t, 1H, J = 8.6 Hz), 6.81 (d , 1H, J = 9.2 Hz), 6.75-6.68(m, 2H), 6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz), 4.00 (t, 2H, J = 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70(m, 6H), 1.86-1.70(m, 6H ), 1.65-1.45(m, 2H).
Slijedeći spojevi su bili pripravljeni na sličan način kao što je opisano gore: The following compounds were prepared in a similar manner as described above:
a) 3-Ciklopentiloksi-3'-[2-(1-imidazolil)etoksi]-4-metoksi-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-3'-[2-(1-imidazolyl)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-Ciklopentiloksi-4-metoksi-3'-[2-(1-metilpiperazin-4-il)etoksi]-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4-methoxy-3'-[2-(1-methylpiperazin-4-yl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
c) 3-Ciklopentiloksi-4-metoksi-4'-[3-(2-metilpiperazin-4-il)propoksi]-N-(3-piridilmetil)difenilamin c) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-methylpiperazin-4-yl)propoxy]-N-(3-pyridylmethyl)diphenylamine
d) 3-Ciklopentiloksi-4-metoksi-4'-[3-(1-metilpiperazin-4-il)propoksi]-N-(3-piridilmetil)difenilamin d) 3-Cyclopentyloxy-4-methoxy-4'-[3-(1-methylpiperazin-4-yl)propoxy]-N-(3-pyridylmethyl)diphenylamine
e) 3-Ciklopentiloksi-4-metoksi-4'-[3-(2-morfolin-4-iletilamino)propoksi]-N-(3-piridilmetil)difenilamin e) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-morpholin-4-ylethylamino)propoxy]-N-(3-pyridylmethyl)diphenylamine
f) 4-Metoksi-3-(2-fenoksietoksi)-N-(3-piridilmetil)difenilamin f) 4-Methoxy-3-(2-phenoxyethoxy)-N-(3-pyridylmethyl)diphenylamine
g) 3-[2-(4-Klorfenoksi)etoksi)-4-metoksi-N-(3-piridilmetil)difenilamin g) 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
h) 4-Metoksi-3-(2-pirolidin-1-il)etoksi-N-(3-piridilmetil)difenilamin h) 4-Methoxy-3-(2-pyrrolidin-1-yl)ethoxy-N-(3-pyridylmethyl)diphenylamine
i) 4-Metoksi-3-(2-(4-metilpiperazin-1-il)etoksi)-N-(3-piridilmetil)difenilamin i) 4-Methoxy-3-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(3-pyridylmethyl)diphenylamine
j) 3-[2-(4-Klorfenilamino)etoksi]-4-metoksi-N-(3-piridilmetil)difenilamin j) 3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
PRIMJER 22 EXAMPLE 22
4'-Aminoetoksi-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin 4'-Aminoethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
Otopini N-(3-piridilmetil)-3'-[2-(2-ftalimido)etoksi]-3-ciklopentiloksi-4-metoksidifenilamina (0.39 g, 0.69 mmol) u MeOH (5 mL) je bio dodan hidrazin hidrat (1.0 mL, 20 mmol). Nakon 6 h pri sobnoj temperaturi, EtOAc je bio dodan (50 mL), a precipitat je bio odfiltriran. Filtrat je bio ispran s vodom (25 mL) i rasolom (25 mL), sušen (MgSO4), i koncentriran in vacuo. Talog je bio napunjen na ISCO RediSep stupac (10 g, zemlja kremenjača). Stupac je bio ispran s 10% MeOH u EtOAc (200 mL), a proizvod je bio eluiran s 50% MeOH u EtOAc kako bi dao 0.21 g.1H NMR (CDCl3) d 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.7 Hz), 7.20-7.10(m, lH), 6.91 (d, 2H,J = 9.0 Hz), 6.78 (d, 2H,J = 9.0 Hz), 6.70 (d, 1H, J = 8.6 Hz), 6.50-6.35(m, 2H), 4.82 (s, 2H), 4.54 (p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H). To a solution of N-(3-pyridylmethyl)-3'-[2-(2-phthalimido)ethoxy]-3-cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol) in MeOH (5 mL) was added hydrazine hydrate (1.0 mL, 20 mmol). After 6 h at room temperature, EtOAc was added (50 mL) and the precipitate was filtered off. The filtrate was washed with water (25 mL) and brine (25 mL), dried (MgSO4), and concentrated in vacuo. The precipitate was loaded onto an ISCO RediSep column (10 g, silica earth). The column was washed with 10% MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH in EtOAc to give 0.21 g. 1H NMR (CDCl3) d 8.55 (s, 1H), 8.42 (d, 1H , J = 3.8 Hz), 7.62 (d, 1H, 7.7 Hz), 7.20-7.10(m, 1H), 6.91 (d, 2H,J = 9.0 Hz), 6.78 (d, 2H,J = 9.0 Hz), 6.70 (d, 1H, J = 8.6 Hz), 6.50-6.35(m, 2H), 4.82 (s, 2H), 4.54 (p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz ), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H).
PRIMJER 23 EXAMPLE 23
Slijedeći su spojevi bili pripravljeni na sličan način kao što je opisano u Primjeru 12: The following compounds were prepared in a similar manner as described in Example 12:
a) 3-Ciklopentiloksi-4'-(2-metansulfonilamino)etoksi-4-metoksi-N-(3-piridilmetil)difenilamin a) 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
b) 3-Ciklopentiloksi-4'-(2-etansulfonilamino)etoksi-4-metoksi-N-(3-piridilmetil)difenilamin b) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
c) 3-Ciklopentiloksi-4-metoksi-4'-[2-(2-propansulfonilamino)etoksi]-N-(3-piridilmetil)difenilamin c) 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N-(3-pyridylmethyl)diphenylamine
d) 3-Ciklopentiloksi-4-metoksi-4'-[2-(1-propansulfonilamino)etoksi]-N-(3-piridilmetil)difenilamin d) 3-Cyclopentyloxy-4-methoxy-4'-[2-(1-propanesulfonylamino)ethoxy]-N-(3-pyridylmethyl)diphenylamine
e) 4'-[2-(1-Butansulfonilamino)etoksi]-3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin e) 4'-[2-(1-Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
PRIMJER 24 EXAMPLE 24
In vitro mjerenje inhibicijskog djelovanja fosfodiesteraze tipa 4 In vitro measurement of phosphodiesterase type 4 inhibitory activity
Humana PDE4 je bila dobivena iz bakulovirusom (baculovirus) zaraženih Sf9 stanica koje ekspresiranju rekombinantni enzim. cDNA koja kodira hPDE-4D6 je bila subklonirana u bakulovirus vektor. Stanice kukaca (Sf9) su bile zaražene bakulovirusom, a stanice su bile postavljene u kulturu dok nije došlo do ekspresije proteina. Bakulovirusom zaražene stanice su bile lizirane, a lizat je bio korišten kao izvor hPDE-4D6 enzima. Enzim je bio djelomično pročišćen korištenjem DEAE kromatografije s izmjenom iona. Taj postupak se može ponoviti korištenjem cDNA koja kodira druge PDE-4 enzime. Human PDE4 was obtained from baculovirus-infected Sf9 cells expressing the recombinant enzyme. The cDNA encoding hPDE-4D6 was subcloned into a baculovirus vector. Insect cells (Sf9) were infected with baculovirus, and the cells were placed in culture until protein expression occurred. Baculovirus-infected cells were lysed, and the lysate was used as a source of hPDE-4D6 enzyme. The enzyme was partially purified using DEAE ion exchange chromatography. This process can be repeated using cDNA encoding other PDE-4 enzymes.
Analiza: Analysis:
Fosfodiesteraze tipa 4 prevode ciklički adenozin monofosfat (cAMP) u 5'-adenozin monofosfat (5'-AMP). Nukleotidaza prevodi 5'-AMP u adenozin. Stoga, kombinirano djelovanje PDE4 i nukleotidaze prevodi cAMP u adenozine. Adenozin se lako odvaja od cAMP pomoću neutralih stupaca s glinicom. Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine. Therefore, the combined action of PDE4 and nucleotidase converts cAMP to adenosine. Adenosine is easily separated from cAMP using neutral alumina columns.
Inhibitori fosfodiesteraze blokiraju prevođenje cAMP-a u adenozin u ovoj analizi; kao posljedica toga, PDE4 inhibitori uzrokuju smanjenje adenozina. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; as a consequence, PDE4 inhibitors cause a decrease in adenosine.
Stanični lizati (40 ul) koji ekspresiraju hPDE-4D6 su bili kombinirani s 50 ul smjese za analizu i 10 ul inhibitora, te su inkubirani 12 min pri sobnoj temperaturi. Konačne koncentracije komponenata analize su bile: 0.4 ug enzima, 10mM Tris-HCl (pH 7.5), 10mM MgCl2, 3 uM cAMP, 0.002 U 5'-nukleotidaze, i 3 x 104 cpm [3H]cAMP-a. Reakcija je bila zaustavljena dodavanjem 100 μl kipuće 5mN HCl. Alikvot od 75 μl reakcijske smjese je bio prenesen iz svake jažice do stupaca s glinicom (Multiplate; Millipore). Označeni adenozin je bio eluiran u OptiPlate okretanjem pri 2000 rpm 2 min; 150 μl scintilacijske tekućine po jažici je bilo dodano u OptiPlate. Ploča je bila zapečaćena, tresena približno 30 min, a cpm [3H] adenozina je bio određen korištenjem Wallac Trifluks®. Cell lysates (40 µl) expressing hPDE-4D6 were combined with 50 µl assay mixture and 10 µl inhibitor, and incubated for 12 min at room temperature. The final concentrations of the analysis components were: 0.4 µg enzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 3 µM cAMP, 0.002 U 5'-nucleotidase, and 3 x 104 cpm [3H]cAMP. The reaction was stopped by adding 100 μl boiling 5mN HCl. An aliquot of 75 μl of the reaction mixture was transferred from each well to alumina columns (Multiplate; Millipore). Labeled adenosine was eluted in the OptiPlate by spinning at 2000 rpm for 2 min; 150 μl of scintillation fluid per well was added to the OptiPlate. The plate was sealed, shaken for approximately 30 min, and cpm [3H] adenosine was determined using Wallac Trifluks®.
Svi test spojevi su otopljeni u 100% DMSO i razrijeđeni u analizu tako da je konačna koncentracija DMSO-a 0.1%. DMSO ne utječe na djelovanje enzima pri toj koncentraciji. All test compounds were dissolved in 100% DMSO and diluted for analysis so that the final DMSO concentration was 0.1%. DMSO does not affect the activity of the enzyme at this concentration.
Smanjenje koncentracije adenozina je indikativna za inhibiciju PDE djelovanja. pIC50 vrijednosti su bile određene pregledom (screening) 6 do 12 koncentracija spoja koje se kreću od 0.1 nM do 10.000 nM i tada izrađivanjem grafikona koncentracije lijeka u ovisnosti o koncentraciji 3H-adenozina. Nelinearni regresijski softver (Assay Explorer®) je bio korišten za procjenu pIC50 vrijednosti. A decrease in the concentration of adenosine is indicative of the inhibition of PDE action. pIC50 values were determined by screening 6 to 12 compound concentrations ranging from 0.1 nM to 10,000 nM and then creating a graph of drug concentration as a function of 3H-adenosine concentration. Nonlinear regression software (Assay Explorer®) was used to estimate pIC50 values.
PRIMJER 25 (Metoda A) EXAMPLE 25 (Method A)
Pasivno izbjegavanje kod štakora, in vivo test za učenje i pamćenje Passive avoidance in rats, an in vivo test for learning and memory
Test je bio izveden kao što je ranije opisano (Zhang, H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198-204.). Uređaj (model E10-16SC, Coulbourn Instruments, Allentown, PA) se sastojao od prostorije s dva odjeljka, pri čemu je jedan, osvijetljeni, povezan s drugim, koji je zamračen, pomoću vrata s giljotinom. Pod u zamračenom odjeljku se sastojao od nehrđajućih čeličnih štapića kroz koje se može izdati strujni udar u noge iz stalnog izvora struje. Sve su eksperimentalne grupe bile prvo naviknute na uređaj dan prije početka eksperimenta. Za vrijeme treninga, štakor (mužjak Spraque-Dawley (Harlan) koji teži od 250 do 350 g) je bio postavljen u osvijetljeni odjeljak, okrenut od zatvorenih vrata s giljotinom 1 minutu prije nego su vrata dignuta. Zabilježena je latencija za ulazak u zamračeni odjeljak. Nakon što je štakor ušao u zamračeni odjeljak, vrata su bila zatvorena, a bio je davan strujni šok od 0.5 mA, 3 sekunde. Dvadeset četiri sata kasnije, štakoru je bilo dano 0.1 mg/kg MK-801 ili slane otopine, 30 minuta prije injektiranja slane otopine ili test spoja (doziranog od 0.1 do 2.5 mg/kg, i. p.), što je bilo 30 minuta prije početka retencijskog testa. Štakor je ponovno bio postavljen u osvijetljeni odjeljak s otvorenim vratima s giljotinom. Latencija za ulazak u zamračeni odjeljak je bila zabilježena do 180 sekundi, u kojem je vremenu ispitivanje završeno. The test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204.). The apparatus (model E10-16SC, Coulbourn Instruments, Allentown, PA) consisted of a room with two compartments, one, illuminated, connected to the other, which was darkened, by means of a guillotine door. The floor in the darkened compartment consisted of stainless steel rods through which electric shocks could be delivered to the legs from a constant current source. All experimental groups were first accustomed to the device one day before the start of the experiment. During training, a rat (male Spraque-Dawley (Harlan) weighing 250 to 350 g) was placed in a lighted compartment, facing away from a closed guillotine door for 1 min before the door was opened. Latency to enter the darkened compartment was recorded. After the rat entered the darkened compartment, the door was closed, and an electric shock of 0.5 mA was given for 3 seconds. Twenty-four hours later, the rat was given 0.1 mg/kg of MK-801 or saline, 30 min before the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 min before the start of the retention test. The rat was again placed in the lighted compartment with the guillotine door open. Latency to enter the darkened compartment was recorded for up to 180 seconds, at which time the trial ended.
Svi podaci su bili analizirani analizama varijanci (ANOVA); individualne usporedbe su bile učinjene korištenjem Kewman-Keuls testova. Obični štakori trebali su manje od 30 sekunda, u prosjeku, da prijeđu iz osvijetljenog odjeljka u zamračeni odjeljak. Ipak, 24 sata nakon izlaganja strujnom šoku, većina štakora predtretiranih s prijenosnikom nisu ponovno ušli u zamračeni odjeljak; prosječna latencija je bila povećana do 175 sekunda (p < 0.001). Predtretman s MK-801 (0.1 mg/kg) značajno reducira tu latenciju kada se usporedi s prijenosnikom (p < 0.001). Taj amnestički učinak MK-801 je obrnut na statistički značajan način pomoću aktualnih test spojeva na način ovisan o dozi (e. g.,3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin, učinkoviti raspon za doziranje = 0.5 do 2.5 mg/kg, i. p.; i N-(3-ciklopentiloksi-4-metoksifenil)-N-(3-piridilmetil)-3-aminobenzojeva kiselina, učinkoviti raspon za doziranje = 0.1 do 2.5 mg/kg, ip). All data were analyzed by analysis of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Normal rats took less than 30 seconds, on average, to move from the lighted compartment to the darkened compartment. However, 24 hours after electric shock exposure, the majority of vehicle-pretreated rats did not re-enter the darkened compartment; the average latency was increased to 175 seconds (p < 0.001). Pretreatment with MK-801 (0.1 mg/kg) significantly reduced this latency when compared to vehicle (p < 0.001). This amnestic effect of MK-801 was reversed in a statistically significant manner by the actual test compounds in a dose-dependent manner (e.g., 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, effective dosage range = 0.5 to 2.5 mg /kg, i.p.; and N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, effective dosage range = 0.1 to 2.5 mg/kg, i.p.).
PRIMJER 25 (Metoda B) EXAMPLE 25 (Method B)
Zadatak za štakore u labirintu s radijalnim kracima, in vivo test za učenje i pamćenje The radial arm maze task for rats, an in vivo test for learning and memory
Test je bio izveden kao što je ranije opisano (Zhang, H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198-204.). Pet dana nakon početnog smještaja, štakori (mužjaci Spraque-Dawley (Harlan) koji su težili 250 do 350 g) su bili postavljeni u osmokračni radijalni labirint (svaki krak je bio 60 x 10 x 12 cm visok; labirint je bio podignut 70 cm iznad tla) sa svrhom aklimatizacije dva dana. Štakori su tada bili postavljeni individualno u sređište labirinta 5 minuta s peletima hrane postavljenima blizu posuda s hranom, i zatim, slijedeći dan, u posude na kraju krakova; dnevno su vođene dvije sesije. Zatim su u četiri slučajno odabrana kraka tada bili postavljeni mamci (jedan pelet u svaki krak). Štakor je bio ograničen na središnju platformu (26 cm u dijametru) 15 sekunda, te je tada pušten da se slobodno kreće kroz cijeli labirint dok ne sakupi sve pelete hrane ili dok ne prođe 10 minuta, što god se dogodi ranije. Četiri parametra su bila bilježena: 1) greške radnog pamćenja, i. e., ulasci u krakove koji su bili opremljeni mamcima ali koji su već bili posjećeni u istom testu; 2) greške referentnog pamćenja, i. e., ulasci u krakove koji nisu bili opremljeni mamcima; 3) ukupni ulasci u krakove; i 4) trajanje testa (sekunde), i. e., vrijeme potrošeno za skupljanje svih peleta u labirintu. Ako je radno pamćenje bilo nula, a prosječne greške referentnog pamćenja manje od jednom u pet pokušaja za redom, štakori počinju s testovima za lijek. MK-801 ili slana otopina su bili injektirani 15 minuta prije prijenosnika ili testiranog sredstva, koje je bilo dano 45 minuta prije testa. Eksperimenti su bili izvedeni u osvijetljenoj prostoriji, koja je sadržavala nekoliko vanlabirintnih vizualnih znakova. The test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204.). Five days after initial housing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) were placed in an eight-arm radial maze (each arm was 60 x 10 x 12 cm high; the maze was elevated 70 cm above soil) with the purpose of acclimatization for two days. The rats were then placed individually in the center of the maze for 5 min with food pellets placed near the food dishes, and then, the next day, in the dishes at the end of the arms; two sessions were conducted daily. Baits were then placed in four randomly selected arms (one pellet in each arm). The rat was confined to the central platform (26 cm in diameter) for 15 seconds, and then allowed to move freely through the entire maze until all food pellets were collected or until 10 minutes had elapsed, whichever occurred first. Four parameters were recorded: 1) working memory errors, i.e., entries into arms that were equipped with lures but which had already been visited in the same test; 2) referential memory errors, i.e., entering arms that were not equipped with lures; 3) total entries into the branches; and 4) test duration (seconds), i.e., time spent collecting all pellets in the maze. If working memory was zero and mean reference memory errors were less than once in five consecutive trials, rats began drug testing. MK-801 or saline was injected 15 min before vehicle or test agent, which was given 45 min before the test. The experiments were performed in a lighted room, which contained several extra-maze visual cues.
Svi su podaci bili analizirani analizama varijanci (ANOVA); individualne usporedbe su bile učinjene korištenjem Kewman-Keuls testova. U Usporedbi s kontrolom, MK-801 (0.1 mg/kg, i. p.) je povećao frekvencije i grešaka radnog pamćenja i grešaka referentnog pamćenja (p < 0.01). Taj je amnestički učinak MK-801 na radno pamćenje obrnut na statistički značajan način davanjem aktualnih test spojeva na način ovisan o dozi (e. g., 3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)difenilamin, Učinkovita doza = 2.5 mg/kg, i. p.; p < 0.01) All data were analyzed by analysis of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Compared to control, MK-801 (0.1 mg/kg, i.p.) increased the frequency of both working memory errors and reference memory errors (p < 0.01). This amnestic effect of MK-801 on working memory was reversed in a statistically significant manner by administration of the actual test compounds in a dose-dependent manner (e.g., 3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine, Effective dose = 2.5 mg/ kg, i.p.; p < 0.01)
Prethodni se primjeri mogu ponoviti sa sličnim uspjehom zamijenjujući generičke ili specifično opisane reaktante i/ili uvjete rada ovog izuma za one korištene u prethodnim primjerima. The preceding examples may be repeated with similar success by substituting the generic or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Dok je izum bio opisan s obzirom na proizvodnju i osobite spojeve, jasno je da se mogu učiniti varijacije i modifikacije izuma bez da se udaljava od duha ili područja izuma. While the invention has been described with respect to manufacture and particular compounds, it is clear that variations and modifications can be made to the invention without departing from the spirit or scope of the invention.
Podnosi se zahtjev za: A request is submitted for:
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