AP848A - 6-Phenylpyridyl-2-amine derivatives useful as NOS inhibitors. - Google Patents
6-Phenylpyridyl-2-amine derivatives useful as NOS inhibitors. Download PDFInfo
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- AP848A AP848A APAP/P/1997/001156A AP9701156A AP848A AP 848 A AP848 A AP 848A AP 9701156 A AP9701156 A AP 9701156A AP 848 A AP848 A AP 848A
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- 239000003112 inhibitor Substances 0.000 title abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims abstract 9
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims abstract 9
- 150000001875 compounds Chemical class 0.000 claims description 39
- -1 hydroxy, methyl Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 11
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229960005181 morphine Drugs 0.000 claims description 5
- 210000002569 neuron Anatomy 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- MNUHYQZBNHDABI-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexan-6-amine Chemical group C1NCC2C(N)C21 MNUHYQZBNHDABI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 9
- 125000001424 substituent group Chemical group 0.000 claims 9
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims 8
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims 8
- 230000001154 acute effect Effects 0.000 claims 8
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims 8
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 6
- 230000002401 inhibitory effect Effects 0.000 claims 6
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- 125000003118 aryl group Chemical group 0.000 claims 4
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- 239000000126 substance Substances 0.000 claims 4
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- 125000003282 alkyl amino group Chemical group 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 125000005843 halogen group Chemical group 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 208000006011 Stroke Diseases 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000002346 iodo group Chemical group I* 0.000 claims 2
- 125000001624 naphthyl group Chemical group 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims 2
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- XDWUSBKLDNVDDQ-UHFFFAOYSA-N 6-phenylpyridin-2-amine Chemical class NC1=CC=CC(C=2C=CC=CC=2)=N1 XDWUSBKLDNVDDQ-UHFFFAOYSA-N 0.000 abstract 1
- 210000003169 central nervous system Anatomy 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 82
- 238000005160 1H NMR spectroscopy Methods 0.000 description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 56
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 239000000047 product Substances 0.000 description 30
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
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- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 8
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- HTNVCPGFIZOGBR-UHFFFAOYSA-N 6-(4-piperidin-4-ylphenyl)pyridin-2-amine Chemical compound NC1=CC=CC(C=2C=CC(=CC=2)C2CCNCC2)=N1 HTNVCPGFIZOGBR-UHFFFAOYSA-N 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
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- C07D213/02—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
- 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
- C07D213/60—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 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
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Abstract
The present invention relates to 6-phenyl-pyridin-2-ylamine derivatives of the formula wherein G, R1 and R2 are defined as in the specification, that exhibit activity as nitric oxide synthase (NOS) inhibitors, to pharmaceutical compositions containing them and to their use in the treatment and prevention of central nervous system and other disorders.
Description
+/+: :++εοηΐ invsniioi/ sL»o rs+issto a /+++1 of !rih;b:lio+ NOS in, a +/+//: + :, i/dudiitg a +urns+ comprising -sdmir.is'sring to said ic+vimrl a NOS k+?ibh+g ©“ectivo /:+/:++1 cf a c+ /.po+i/c oft::? + /++/ i, or;; pi/s+ro/oao/o/Py +c/spt/+1a soil tbersof.
Tha +!+<+:+ i+vsnlion also rs+iss io e ρ'τ/+//·/+!+ΐ+5ί cofp+S!'in( /or I'o+'z;; cr preventing a condifior: oaioctod from the gro/p consisting of migrsine, innarnmntcry disc roes (ej\, S++////Q, strc'/c, o '.vie nnci chic-uc ++/,, ί+·ρε7θί+<η:Γ /dew, traumatic ::/:+/.. 1/:+2++:+0/ i+j+ry, Credo's csoass, u+orsiiv? colitis, scciic chock, rndupSe sclsrosis, +19-5 ++-0 ci-.:1 sd damsnfa, neurodigseeretivo disc-csss, neuron t+iicily, ALhsirnar's ois+nso, :++=+-;’ depcnc+ndss and c-deletions p+q,., cop+rd..=:10.:33 on drugs, alcohoi and nkxilne), i+nssi/, opiicpsy, //'/sty, p/yo+o+s, head i;+-+na, i+'/lt r+aplrctory distress syndrome (++=33), morphine induced tsl+rsrcs /+ ++h/n?/si cymptc-rns, :/53:-/+/3/00,1 ο+νε! + -3/02, o+aorirthri/o, :032:/3=+/: arthritis, oyi'ictiots, cii/lcd f+oliomycpalhy, ac/ife //'+/+! con; ir.jury, Huntington's ciss/ss, giou+cma, ir+ze'j+r dagsnsrn'don, oia+zrtic nevre ++hy, /'iabe-ic nephropathy and esneef in 0 ma:pm?.;!, iaNtrfi++ a human, oc-rsprising a NOS +::+/21/--1 e+a+ivc amount 0; s sor/cci+c' of the fcro/Ns , or 0 p/sfir+oc+b+iiy /0:.3/+bis ++’ ti-c+ro; /+:+ ? phs/r+acscticoily sees+-//ie ear+sr.
Tho present k'.v+ntii+i .;·'·+> palates w + rnsthod of tr+i/linp or ++/7=//:+9 / condition S5i3Ct=?+ from fi'-? group +3i:oi5t:ng cf m+ra+e, :=++mn+/:or/ =1+5+:53 (§+g, /++/+), ++0+/, £+:uta +/d = + /+/ + ///:, 1+-+3+://:/+ +50/+, .++///-=1=0 ;+·//+, /3/ +/+-+/ + + :// + :+/+/ ///3//2, /+' +/+· /: ++. --/+=:/ =-+ + +, /-- + +// /+ + /++ .+ +5 - = =--/./+1 / = / = + + οΓΐΛ-. loohiior ,χί- ΓοοοούΆ bhebhe-; -ο :bos& dssiss-s; bui In: οο οοί ess’ ) Ί . · · ,! . / ΐ ;>.'! ' >· - - . : . , ' ,' ι, g-hen s'scoss-sb::
sitidi'--s snci >v sind-ng spsa-w i'!S ' ' ' .- ' · -V
-i s:' : ' ’ ’.,''' · ’ '. TiOil si; ••.ss.rai iomb he ieae&si' scbsvses end 'feoueski’ -bib bbiaw ere seis-sd beve.
G3
Ί.
'Μ
I
I
ί ϋ
!A-b
-“Ν
h,Λ 'V, >
X-H
1. R3RR,;H RsRRiER R,: R?
• R / R / „ „'t! :,7
NH.
--···
RRRR <··G-a, q=1 X“CHS Y»WR3R4
YV '<>
Γ*\ \
-A J ν' ν ν \\ ιΓ 7 Η \J r
ί< Ύ-Λ
EuLi
2. NH2OH HCI
Ύ-.1
Γ-, I r\ \ r\
Y'
-N.
IA -d h,L·
-j- j
G=A, cpO, X~N Y-H
4' ί . ' si, ' ι ιί .. , ν me tatoa: munmertata;:
ί ' , , r ’' , '- .. , :4 be £>/ moi ίο χκχα tariHsd is ++ art.
, ο. , ' , , · > ~ ,, - w .
• j I’ , ,· < .·'.'··· ' ' U ! ο·.. ' ’ -· ·. . ' ο,· ' . ·. ’ίχ τ'\ . - ' - ’ ,·
Ο-C m -obooG DCnC In an m-wrota mrowta, prstaroroiy oleirof mho. οχ taxor ’ ίο 2-ί imvro. Coo-oomd Ηί η poeps+eo .:χ οοο-οίίπρ π rtata ο taxctac. com <CerC,.:o;oC'o.. o' Poo 0:001000- ::OP<0'poP'oj);-r<Pii-sii3[o'CCC(Cop; ip, a ntavsm contatatag + o3 , ,· ctaionaiiy :t·· .>, · 1 · ' 1 r> r 1 t ks abou, 150cC, ico about 1 u- 24 hours, ' 1 p ,' m > -. . ' ,- »1,,, 1 or joaik^dium-ivof' oxidation srate, roptataly with nimsyrune. 'tamtam prsfcrably totatato‘iphaoy'phcspuins palladium.
CoiTipptsnd IV is prepared by reacting IH with tosylmeihyilsocyan-sbe in ire orocsncs bi portaosium l-bioooode anti eibancl, In an tahsraa! solvent -meh as 1.4-Girnethoxytafiar:&, x, :, ternpeiaiurs from aboui -ItataC to about 100°C, for about l io 24 hours. Compound V Is prepared from IV by basic hydrolysis of sna nitrile using an tataril rneiai hydroxide in an ecuecus alcohol-cased solvent, such as aqueous etlisnoi, at s tontawmiure from about 25°C to abmx 125i5C, 'or abtxrt 30 minutes to 48 boros. Compound v < t λ ''em 7 by -tobytimftye 1 'p '4' , , >.-iCi, 0 v ! ''-Ci· + a dehydrating Gpsnt such us 3 carbodlifnlds, for example, tta-eihyl-ta-fdiGrataiyisminopiOpyi)csrbodiimide, in a solvent -nsi is r nsiogenatsa hydrocarbon -or 2 N.N-taitakytoroitto, such -rs Gimeuiyiformamtae, at 3 tomperators from sbout 0°C io about 100°C: for about 1 to 4b hours. Compound Vii is prepared from Vi by deblocking using hydroxyiarnine bydrocitaoride in an -aqueous or alcoholic solvent, preferably aqueous ethanol, si « tompGraum; from xboui 25°C io oporrt 100°C, for about 1 io 43 hours, arid rrtsy include ae&incking s protecting group such a tbs t-buioxycaitiony! croup by rosciion with iriflucroacsbc acid or a rotated po'yha'ogenated acetic aclcf cr a gaseous hydrogen halide such as HCI, in a hsiogensied hydrocarbon, ethereal sttamrU or eihyi acetate, at a temperature from taxxta -70°C to shout 100°C, for about 10 minutes to 24 hours.
The final compound in Scheme I, IB, wherein G-B, is prsparsta by reduction of Vii with borane, a trialkyl borane, alans, or iithlum aluminum hybrids In an ethereal solvent, such ss ethyl ether ortetrshydrofuran, at a temperature from about ta00°C to about 100°C, for about 30 minutes io 24 hours, and optionally using cesium fluoride and an slksli metal or alkaline earth carbonate in an aqueous alcoholic solvent, si s tamper;;,tore from shoot 25CC to about f25°C tor
1 io 72 pours.
Π π * -L.I
| 5 | RtX&r? | ;;g to SzXrms 2, ? | :?;??n?l ’-.?? | - p: ?. f 7: 0 IS 7- ?7 |
| bc'-romc Ok.:· -:? | 4 p?11?'?.???X | 7.,3 X /7: | t - I? ?- - ?? 0; C - 7: .,? | |
| ztzle, / X | 7/ ;y?'-'/y cz? | ? ri / of ; | -? 41? · - :,07.·// - | |
| trip;· ??? i | rina p?il: ??;.....? 7: 3? | ? ze ?·; ? | '7. : ·. m.-.-par;?? . ο | |
| to :?./?? 7 | ?. -??:_? . : ? --:.. .- | ? ο | I ': : -.? i.-??? t/- ? ? | |
| 1C | all;?! /rip | : :.7.7. Of ? .Υ??.?-? | 7 '·; ?' . : | : . -?- ? ·-;. o'? 7 .7 . ? |
| ;'3S2? 0-. ,----:, | ? X ;?: :li?i?Yy' m | ? X:' ? | .:- -?. ' . 3~3 7-? : ?--' | |
| zbou' ύ :?:, | . ...; ,- .: ι ,:-(-.3. ?j.? | 0 - | - - -: f.. :::7. t'lY- ' ? · | |
| based :??o?m, | S: -..h £? m/lum : | . < ?-?, :.:,7-077, -: ? .? . | ||
| soivent, vyy-lcei | 7 ,ttnol, &t ε itr? >£?;?..,? 7 ; | ,. '?? 7f: io cbeiX 77 7.' ? r o'. | ||
| 15 | hours. The ?; | tai compound in ? | ClY.ne 7, | ~. ?ri v,?r; i'i; ., i |
| prepared from | IX by deblocking 1 ·' | .n | (ine liyrii.jcnloiids in εη 2lc:i,777 - | |
| alcoholic so;?ertl, typically zzuool:.. | , 7333/ :.ri | i 07 0 Yore from about 27-0 >0 · |
7':) for Sib-out 1 ·ο 72 Nours.
In 7? process of Schema 2, the pm/: 7 - : ,~·; γ / /-mbs IX and 7 -:, X 7 m?\7
Comp·;.; nos of the formula !A-e v. herein Y is benz ! car. be conve. led ir-to ‘he c -res; .-or/ng compos -ris wherein Y is ether than benzyl by >;i .'.-.••nzyiatton using hydrogen cr -:-- ,er.;om formate ;r, the presence of a noble rr.etfX cat. .1/7, such as palladium, in r.O.o-real, halogenated hydrocaibon, alcoholic, or equeous olroholic solvent, &t ε /mpororij;? .'rm . °C o 1C0°C iortime from 30 minutes to 2- hours, x II·?·? by raJnciive aminat;·»n >-nth ·· ? oo 7‘:yi or aralkyl aldehyde in the presence o'; ? >: όο7όtide-based reonent ooch τ sodium cyarsotOrohydride or sedium iiiscetco-zyborchycdrie, if; an ehsresl, hdo/nr/d I ·: 'Ci?7>n, alcoholic, cr aqueous-alcoholic solvent, at a ic? /-:./ from C’C to 10C°C 'or a 7 ·-;·= 7'm to 72 hours.
Referring to Scheme Z, compound X is props red by reductive amina/T of 2-(430 bromophenylmethyO-pipeiidine with benz-skiXvyc;- --.7 a borc-hydrlde-t-asad re/ rit ouch sc sodium cyanoborohydride or sodium irioc.atc.xvbcro'-yriride, in an ethereal, I . by rmris? hydrocarbon, alcoholic, or aqueous-alcoholic s-.-lvsnt, 7 · temperature from /out 0-7 to she: · 10C°C for about 1 io 72 hours. Ccmpoumi X' is pmpered from compound X by rooctljn c. compouno X with an opganciiihium reagent, typically butyl lithium, followed by oriX'ion of the resulting organolithium reagent to 2-(2,5-dimethy*pyiTclyl)-pyrid;ne, in an ethereal sob. oni cucn as ethyl ether, at a temperature from about -70°C in about 1C0°C for about 30 minutes to 4S hours. The final compound in Scheme 3, ΙΑ-b, wherein G=A, n=1, e,=1 end Y is benzyl, is prepared from compound XI by deblocking with hydroxylamine hydrochloride in an aicor.oiic or aqueous-alcchciic soivont, typically aqueous ethcnol, at -i famperzture from about 25°C to about
125°C for about 1 to 72 hours.
U 0 ίis co. iccpcraYng cornpoucds ο fterapaarrfs of ins water ;AY- can Ljo aonvmted nda b iSSS'ek; Y !s 'Ssfcf ihSii 5-0100 sis Si'SOSCdSS CteS-ViteY siSOVs =Cs CO/iVSiYiS,; COtSSsSSSS ' 1 I ., - Ϊ '·.· , , ' ' ' - · '
Roieishg ic . : compeanY ΧΠ ia teepsrad ίππο Ybisins-Y'YY, ,1 > I , v ,-··’ !,‘iv scis is sis ,S-isiS; SCS OS K ρΥΥΥΥ','Ω so ·'. , . ' ·/, ’ , ι - fl . .
sssssss; ideas,S;c sX-sesl s' a Vwiwaratars irors sbess Yds’ is aa-na·. :Y5°C ids sYssi ‘i ?s -is hoars Comps-s<d ΥΥΐΠ is Shess tsonsrari free XU by macds:. m XU χ,.- encsiraft yfYeXaie or siossydo. ivs:sc';Hy the mospsiYine or pyissikiine <·^<··ζζ·.ΐ,, X s raorastst, iaamsaaYory hydmcsfsjom a _ - .... 1 · urc Yorn about 26°C to about 150°C tor show 1 ίο 7Y hours, Ytetewerf by an aqueous hydrciysis step. typi-osHy with squeous hydrociiioric acid, snd then reduction with hydrogen or Sinmoniom formate in id··· presence of s nobis --nets' caisiyst, such ss sraltedium, ir- sn ethereal, ι ; . ι I . ,. I ‘ I m ' O< d
0°C to .about ii)0°C for about 30 mirm-e? to 24 hours. The -final compound in Scheme 4, ,'A, whore G™A, q--i, X~CH. end Y-NfCR4, is pmpsred by > ' ·- k < , f >T -4'· with ammonia, a primary’ amine, or a secondary amine in the presence- of n borohydride-tessd reapSfC such -S sodium cyimoborohydride ex sodium trisc-otxcy'bc-rohydrsdfe, in on ethersai, haisy&noieci s·, srcmoCon, nicoheiic, or aqesous-teeohoiie aYvent, id y temperature from about
0°c to about <00°C for about 1 to 72 hours, idlcweti by debtecYIng with hyehOxyiamme hydronb'orideX! an alcoholic or oquaous-ascenosic εοΐ-rant, typics'iy aqueous eihsno!. at a temperatera irsm shout 25“C to about 125°C for about 1 to 72 houra.
•-te
RefoiTs ig to Schema 5, compoynd XIV is prepared from 3--(4-broinophariyl)-giuti?rio cted by - ' .· ii ‘ ' up. .e - c -,. ,; ι, ι ,e >'< “ ’ . ' ‘c' on ' ι · m , ·> , < «· ~f ;t *ici> d ι, or hsic-gensf&d hydroc-sit-on soivent, at a teraforasture mmn about 2‘iCO to about 130’C for about a to 43 hours, ioHowod by dehydration with C’C&tic ani.ydiide, or s similar dehydrsting nragent, χ ε temperature from about 25°C to about reflux for about 1 to 48 hours. Compound XV is prepared by reduction of XiV with brawns, borane insihy! mifitie, elane, or lithium siurninum hydride in en stnsreai or hydrocarbon soivenf 35 at a temperate; e from about 0°C to about 100°C for about 30 minutes to 43 hcurs. Compound XV! is prepared from compound XV by reaction of compound XV with an organolithium reagent, typically butyi lithium, fei'ovesti by addition of ths resulting organoiithium reagent io 2-(2,5othyl ether, at s iernpsratura from •~. The final corn-raund in Rcncme v my o, u> -/ >
byi)-pyridine, in an ethsrsai solvent, such c about lOO’C for about SO minutes to 43 n ., · 1 ’ .
fY-A, YaTioniurr tfote
-15an ethereal, halogenated hydrocarbon, ri cholic, or '-;-?eru: crierJo; · ·. frerr. G’C to 100°C for r time from ZZ min·.'..r ♦ ;:.· on.: 5 5:. hydrexyismine hydrochloride in on -'rohcrc o- r ._·icrL:. :c s.eMrmol, at 2 temperature from xri P5CC ·ο ·.' 1:.. 5SC fc .t 1
Compounds of the formu!? ,A- /51.:. :r r ··. nr. r.. , cr . br- converted into ihe a r.-log -:,,-.., .-ι.'./. y J,r ./, ' c: I: sfioe with an n'ky! or cralky' ckP'y ie / fh·-, ... .-- e, ,- <r /odium cyenoborohyririrfi c, --··-'.// 5-.:/- ;·-.·. /,/.,-ιΑΡΡ ;· .,
h.-d-nonrbon, aicohoiic, or sou: m/;-,:5,,. / J- /:./.,, -,-, - - -:,// r.y:.; •mt, s'. ;/ ; ///-0. atum by -1///.;;''/g /-/55 r,t iypP 0 cum 5, . h·- /:/-/
..J o 0 e. -r.·- 5, : .ο; ./.5.5 ,
2·;. en r ' ,, s: t : . Ο ' I ,
P. ' - ?k .·, time fi nm 1 to 72 hours.
The preparation cf other comer-..,dr of the /0.///5: ' net s,·.·-<' - -.!ly :.5////bo:. in he foregoing experimental section can .rccorr.pi' ;hed us:ng com / atiour 0: th- rs cti. ns described above that will be apparent to those skiriod in the art.
In each of the reactions discussed or ϋί istrsied above, pnss-’re io- not critic.?! unless 0ti':3i\vise indicated. Pressures from about 0.5 atmospheres to cl rut 5 ctm/s/heres are generally acceptable, and ambient pressure, i.e,, about 1 atmosphere, is preferred as s matter of convenience.
The compounds of formulae· I (the active compounds of this invention’) wnich are basic in nature are capable of forming a wide variety of different salts, with various inorganic and organic acids. Although such salts must ba phcrmrceuticaliy scop-table for administration to animals, it is often desirable in practice to initially isolate a compound of Hie form vis I from the reaction mixture as a pharmaceuticrily unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alka'ins reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the active base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen miners! or organic add in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
The active compounds of this invention and their pharmaceutically acceptable salts an useful as NOS inhibitors i.e.. they possess the ability to inhibit the NOS enzyme in mammals, and therefore they are able to function as therapeutic agents in the treatment of the aforementioned disorders and diseases in an afflicted mammal.
The active compounds of this invention and their pharmaceutically scceptabie salts can be administered via either the ora!, parenteral or topicoi rentes, in general, these compounds are most desirably administered in dosages ranging from about 0.01 to about 250 mg per day, in f-.b
1,0
P*0 «* T
&*£*»·.
single or divided doses (Le.., from 1 to 4 doses per day), dthcugh variations vi'l =-ecessari!y occur depending upon the species, weight eric c'o'fitiilion of tr.e subjeci being ir/'Toti end the
ΡΡ f, Λ •‘ί ΰ~ pgilicuisr route of sd -ninistraLion chosen. However, ε dosage ievei tost, is in the range of about O.Q? my to about 21 mg pc? kg of body weight per day is moot ucsiraWy employee. Variations may nevertheless occur depending upon the species of snirnal being treated and its Individual response to said medicament, as vreH ss on the type of pharmaceutical formulation chaser. mfe the time perioh and inieivsi at which such admlsiisiretlon is carried cut. in some Instances, dcsage levels below the iovw limit of the aforesaid rsnoe rnny be more than adequate, whila in other easts still Sanger doses rosy ce employed without causing any harmful side effect, provided that : uch ferger doses arc first divided Info .severs! smsi* closes for administration ’itreudhoert the day.
The solve compounds of rite invention may be stiirlnsst&feti Hone or in combination '(δ wife pharrnacd.rficaiiy acceptable oorriers or diluents by eifeer of ife three remiss previously btok,sfed, and such stiff,irtlslrii'ilon may be corned out in single or muhsple Jcses. mors pafiicclarly, the novel therapeutic coenis of this invention can be otirnfeisfersd in a wide variety of different dosage forms, i.e., they may be combined with various phmrnsceuticvHy acceptable Inert carriers in the form of labiets, capsules, lozenges, troches, ham candies, powders, sprays,
2G creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. moreover, oral pharmaceutics’ compositions can he suitably sweetened ard/or flavored. in general, the therapeutically-sffective compounds of this invention are present fe such dosage forms at concentration levels ranging from shout 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystal’ine cellulose, sodium citrate, calcium ebarbonste, dicslcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), slginic add and certain complex si'icsiss, together with granulation binders like polyvinylpyrrolMone, sucrose, gelatin and aoada. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablstting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for ora! administration, the active ingredient may be combined with various sweetening or flavoring agents, coioring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents ss water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of an active compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may b? employed. The aqueous solutions should be ouitatiy buffered (preferably pH grester then d) if nccjsssiy end the liquid r£’?·
1C
Γϊ Λ
V diluent first rendered tectonic. These ap ' purposes. T o oily solutions are c/ii/T )00848 )ij:, /TT/nr are fo. ir, rr ITuPr, injeciion ρ·.!Γρ·.:.;ο<. The ·; τχ.ΧΤ/ o.' o’l rha.:; -eiul'· :-.u/af'e fcr ir.tmvenc ‘ injeevor.
' 2i”:j'c·;lsr end sub·-u'.aneo .- : s? .J':· conditio../ is roa-.a;
scce.ap'ish -a ay .-..:/be/' phsr.naceuticci tech T/:. .. a l./r ' 1
AdtiTic it is dso >. ssibie to s-'·..: Tb.,: ;he -/X>
hvcr.tion tr·pi··.?.::;/ when tr·;·i·:'!? atc;y cr-n'itio/s of 1; way of cr_m. js'-ies, pcL, , '. p ' -he.', oi;d.' -,..Ta : id th; T phfi.-.raciutic·'·' mcdice.
fhos' ' Tied in -.. ; art. c·-.:·. a.:a:'s ci '·'.·· pre at a i’aa may .·. dons :/. ' ”:,ce */,..· e.anc - :
The e.Try of coma·.·., at'. o.' he T, : tc jr.hiiJ. , ;C3 na ; la de'e? .Ta J ;.'T ~ procedures described in the Tere/T'a 7¾ rtThy of rorepou: ds ·..: th- f: ::/:/:/ I ;o inIT endothelial NOS may be d-Termincd by ντίης- the procedures de.; /ire·- by Schmbh et aL i.i proc, Mstl. Acad. Sci. U.S.A,, 88, pp. 335-229 (1901) and by Pc-llc/.k el 0., in Ρβ:ϊίΓ.Ϊ.Χ1£.ΑίΤ T Sci. U.S.A., 88, pp. 10480-10484 (19&1). The ability of compounds of lb a Trmij’na i to inhibit inducible NOS may be determined using the procedures d esc,·'bed by Schmidt et at,, in Pm·-,. Natl. Ac-ad, Sci. U.S.A,, 88 pp. 382-369 (T91) and by Garvey z, al. in J. PTI, Chem.. 283, pp. 26669-26673 (1994). The s'Jiiiy of the compounds of the formulae I to inlTbii neuronal NOS rnay be determined using the procedure described by Gredt snd Snyder in Proc. Natl. Acad. -Sci.
i
LLS.A,, 87. 682-685 (1930).
Of 100 compounds of the formula i that were tested, ail exhibited an !CK < 10 μΜ for inhibition of either inducible or neuronal NOS.
The present invention is illustrated by the following examples. It vii! be understood, however, that the invention is not limited to the specific details cf these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (Ή NMR) and C13 nuclear magnetic resonance spectra were measured for solutions in deuterochlorcforrn (CDCI3) or in CD3OD or CD2SOCD3 and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet, m, multiplet, b, broad.
EXAMPLE 1
P*·»
TSb g?
<
3-(2-f4’-(6-Amino-pyridin-2-v!)-biphenvl-4-vn-ethvfi-3-az?-bicyciof3.1.0lhex-€-ylamine 35 A. 2-(2,5-Dirnethyloyrroly!)-6-(4-bromophenyiT>-pyridine
To a 100 mL 3-necked round-bottomed flask equipped with septum and nitrogen (N2) inlet were added 3.54 gram (g) (15 mmol) 1,4-dibromobenzene and 15 mL dry ether. The solution was cooled to -70°C, and 6.25 mL (10 mmol) of a 1.6 M solution of butyl lithium in tetrahydrofuran added dropwise over 5 minutes. The reaction was stirred 5 minutes at -70°C, then warmed to room temperature over 15 minutes. To the resulting solution was added a solution of 1.72 g (10 mmol) 2-(2,S-dimethyipyrroiyQ-pyridin® in 5 mL ether, producing a deep
Ο Ο 0 fi / red coicr, and the reaction stirred 3 hours st room tempereture. It was then quenched with aqueous ammonium chloride- solution, taken up in oihyi acetate, end washed with aqueous ammonium chloride and brine, dried over sodium su'fste, and evaporst’id. The residue was chromatographed on siiics gel using hexane/ethy! acetate as eluant to afford 820 nig (25%) of an oil.
H-MMR (δ, CDCb): 2.30 (s, 8H), 6.03 (s, 2K), 7.20 (eid, J=1,8, 1H), 7.64 (m, 2H), 7.73 (dd, .1=1,8, 1H). 7.90 (dt. J=1,8, 1H), 8.00 (m, 2K).
13C-NMR (δ, CDCI3): 13.6, 107.2, 116.1, 120.2, 123.S, 127.0, 128.S, 132.0, 1337.3. 138.S, 151.8, 155.7.
. MS (%): 327/329 (100/98, BFW1, parent+1).
B. 2-(2.5-DimethvlpviTolvl)-e-(4-(4-formvlphenvl)ohenyi))-pvridine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
630 mg (1.93 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-bromophenyl)-pyridine, 283 mg (1.93 mmol) 4formyl phenylboronic acid, 317 mg (7.71 mmol) sodium carbonate, 112 mg (0.036 mmol) tetrakistriphenyiphosphine palladium, 3 mL. ethanol, and 1 mL water. The mixture was heated st reflux for 14 hours, -cooled, poured into water, and extracted into ethyl acetate. The organic layer was washed with brine, dried, and evaporate, and the residue chromatographed on silica gel using 25% wthyi acetate in hexane as eluant to afford 540 mg (50%) of the product 1H-WMR (δ CDCIs): 2-23 (s, SH), 5.94 (s, 2H), 7.17 (δ J=8, IK), 7.74 (m, 2K), 7.80 (m,
3H), 7.90 (t, J=3, 1H), 7.S3 (m, 2H), 8.19 (m, 2H), 10.05 (s, 1H).
13C-NMR (δ CDCfe): 13.5, 107,1, 118.4, 120.2, 127.6, 127.7, 130.3, 138.7, 140.5, 146,4,
156.0, 191.9.
MS (%): 353 (100, parent+1).
cs tn (X 30 C, 2-(2,5-Dimethvlpvrrolvl)-6-(4-(4-(cvanomethvl)phenvi)phenvr))-pyridine
To a 100 mL 3N round-bottomed flask equipped with septum and N2 inlet were added
354 mg (3.16 mmol) potassium t-butcxide and 5 mL dry 1,2-dimethoxyethane. The mixture as cooled in a -Q0°C bath (CHCI3/CO2), and a solution of 317 rng (1.62 mmol) tosylmethylisocyanide in 5 mL dry 1,2-dimethoxyethans added dropwise. After a few minutes, a solution of 540 mg (1.53 mmol) 2-(2,5-dimethylpyrmlyi)-S-(4-(4-farrny!phenyi)pheny!))-pyridine in 10 mL dry 1,2-dimethoxyethane was added dropwise, and stirring continued at -50°C for 50 minutes. Then 5 mL methanol was added and the reaction wanned and then refluxed for 15 minutes. The reaction was cooled and evaporated, and the residue taken up in water with 0.5 mL acetic acid and methylene chloride. The aqueous layer was reextracted with methylene chloride, and the combined organic layer washed with aqueous sodium bicarbonate solution, αρ ο δ ο ε ί, 8
-195 dried over sodium sulfate , and evaporated. The residue was chi'omrdographed cu siiica gel using 25% ethy! sce;ate io hexene se eluent to sffc-td 220 me (40%) of 13. product.
’H-NMR (δ, CDCb): 2.2? (s, CH), 3.7.7 (s, 2H), 5.UG (s, 2K), 7.17 (5. J-S, 1H), 7.41 (m, 2H), 7.6-7.7 (m, 4H), 7.79 (δ J=3, IK). 7.89 (t, -.=8, 1K), 8.17 (m, 7H).
13C-N;.-.R (5, CDCij): 12.6. 23.3, 107.!, 11,.3, 120.0, T'/.4, 127.5, ,27.8, 12&.5, 126.7, 10 129.3, 137.6, 7 58.7, V0.3, 1/-1.0, 151.3, -55.3.
MS 364 (100, pr.rent+1).
A byproduct ol'Jriy sf.-rth pre -fuel w.: - characteriz. -' ss 7.8 ox: zoic, .:0 mg (75,..):
D. 2-(2,5-Dimethvlpvrrolvi)-5-(4-(4-(carboxvmethvl)phenyl)phenyl))-pyridine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
220 mg (0.S06 mmol) 2-(2,5-dimeihylpyrroiyl)-8-(4-(4-(cyanomethyl)phenyI)phenyl))-pyrid!ne and 7 mL ethanol to form a s. lution at reflux. A 10% solution of sodium hydroxide in water was added slowly dropwise at reflux to maintain solution, requiring 30-60 minutes for 15 ml (snd a little further ethanol). Refluxing was maintained for a total of 2.5 hours. The reaction was cooled to 0cC and the pH adjusted with 6N hydrochloric acid to 1, and the reaction was extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium suifate, snd evaporated to afford the product as an oil, used directly in the next step.
1H-NMR (δ CDCI3): 2.24 (s, 6H), 3.70 (s, 2H). 5.95 (s, 2H), 7.14 (δ J=8, 1H), 7.38 (m,
2H), 7.61 (m, 2H), 7.68 (m, 2H), 7.77 (SJ=8, 1H), 7.87 (t, J=3, 1H), 8.13 (m, 2H).
13C-NMR (δ. CDCI3): 13.5, 20.8, 107.1, 118.4, 120.2, 127.3, 127.4, 128.7, 129.9, 132.9,
137.2, 138.8, 139.5, 141.6, 151.7, 156.4.
MS (%): 383 (100, parent+1).
E. 2-(2,5-DimethvlpvnOlvr)-6-f4-(4-(6-t-butvlcarboxarnido-3-aza-bicvclof3.1.01hex-3vlcarboxamido)methyl)phenyl)phenyi))-pyridine
To a 100 mL round-bottomed flask equipped with N2 inlet were added 420 mg (1.099 mmol) 2-(2,5-dimethylpyrroly()-6-(4-(4-(carboxymethyl)phenyl)phenyl))-pyridine, 218 mg (1.099 mmol) 3-aza-bicyclo[3.1.0]hex-6-y!amine t-butylcarbamate, 211 mg (1.099 mmol) EDAC, 10 mg
HOST, 7 mL dry acetonitrile, and 337 uL (2.42 mmo!) triethylamine. The reaction was stirred si
-205 room temperature for 20 hours evaporated, and the residue chromatographed on silica ge; using 5% methanol in methylene chloride as eluant to afford the product, 2S0 mg (45%).
Ή-NMR (δ, CDCfe): 1.69 (m, 2H), 2.22 (s, 6H), 3.4-3.9 (moKipiets, 7H), 4.97 (bs, 1H),
5.93 (s, 2H), 7. 12 (δ, J=8, 1H), 7.23 (m, 2K), 7.57 (m, 2K), 7.67 (m, 2H), 7.76 (δ, J=8, 1H), 7.85 (?, J=8, 1H). 8.7 2 (m, 2H).
'3C-NMR (δ, CDCfe): 13.5, 28.4, 42.0, 47.S, 48.8, 53.5, 79.5, 107.0 IIS.3, IIS.9, 127.3,
127.4, i28.7, 129.5, 134.0, 137.2, 138.7, 138.9, 141.6, 151.7, 156.2, I56.4, 769.3.
MS (%); 563 (100, parental).
F. 2-(3-f4'-(6-amino-pyridin-2-Yl)-biphenyl-4-yn)-3-aza-bicyclof3.1.01hex-615 ylamine acetamide
To a 100 mL round-bottomed flask, equipped with condenser and N2 inlet were added 250 mg (0.498 mmol) 2-(2,5-dimethylpyrrofyl)-6-(4-(4-(6-t-butyicait»oxamido-3-azabicyclo[3.1.0]hex-3-ylcarboxamido)rnethyi)phenyl)phenyl))-pyridine, 173 mg (2.49 mmoi) hydroxylamine hydrochloride, 1 mL water and 5 mL ethanol. The reaction was refluxed 40 hours, an additional 173 mg hydroxylamine hydrochloride and 5 mL ethanol added, and refluxing continued 24 hours. The reaction was cooled, poured into aqueous sodium bicarbonate solution, and extracted with a mixture of ethyf acetate and methanol, due to the limited solubility of the product in ethyl acetate. The organic layer was dried over sodium sulfate and evaporated.
The residue was taken up in δ mL dry methylene chloride and treated with 1.5 mL trillurooacetic acid at room temperature for 1.5 hours. The reaction was evaporated, taken up in 1 N hydrochloric acid, washed with ethyl acetate, then the pH adjusted to 10 with 1 N sodium hydroxide solution, and extracted with a mixture of ethyl acetate and rnethanol. The organic layer was dried over sodium sulfate and evaporated to afford 160 mg (84%) of the product as a low-melting solid.
1H-NMR (δ, CDCI3): 1.39 (bs, 2H), 1.78 (bs, 1H), 3.2-3.8 (multiplets, 2H), 3.41 (bs, 2H),
4.90 (bs, 1H), 6.30 (δ, J=8, 1H), 6.83 (δ, J=7.5, 1H), 7.06 (m, 2H), 7.29 (t, J==8, 1H), 7.38 (m, 2H), 7.44 (m, 2H), 7.69 (m, 2H).
13C-NMR (δ, CDCb); 25.0, 25.3, 34.9, 41.5, 107.6, 110.7, 126.8, 127.0, 127.1, 129.1, 35 133.2, 138.5, 129.0, 140.5, 155.3, 158.8, 170.6,
MS (%): 385 (100, parental).
co ' G· 3-{2-i4'-(5-Amino-Pvririin-2-YlY-biphenvl-4-vl]-ethvD-3-aza-bicvclof3.1.01hex-6-Ylamine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
160 mg (0.417 mmol) 3-{2-[4'-(6-amino-pyridin-2-yl)-biplienyl-4-y!l}-3-aza-bicyclo[3.1.0]hex-6ylamine acetamide, 5 mL dry tetrahydrofuran, and 0.625 mL of a 2 M solution of borane methyl
AP Ο Ο Ο 8 ·’
-215 sulfide in tetmhyd.'oiuran. ϊ region wus rfluxed 12 hours, and additional 0.625 mL portion of borar.e m.--.hyl 'vlfida r.d .«J dung v/iih a fev.· r.;L ioti...hyh.u(u.-:n, and refluxing continued 12 hours (due to the limited siicbuiiy of the c'oriir;· mtteris! in tetrahydrofuran). The reaction was cooled and evaporated, sod 20 ml. ethane1. 1 g sodium cvrtvrstc, and 1 g cesium fluoride added, and the mixture refluxed 14 hours. The roociion was ccoisd one evaporated, taken up in wster and othy! scjiaie/mc-hnnol. and the or, anic lay.:; r spamled, dried over sodium sulfate, and evaporated. The resulting s-'Lj. r!lg (6LT-) v/ss token up in methyls e ehloride/metLanoi/ather aril precipiiomo '.vim 1 1' HSi in eth-r, thr-n evo-noraied. The residue was triturated Iih tetrahydrofuran to a. ford 46 mg (24%) cis . /hito relic, mp 205cC (dec. above this point).
1H-NMR (δ, CDCb): 1.33 (bs, 2H), 1.63 (bs, 1H), 2.60 (m, 2H), 2.71 (m, 2H), 3.05 (m,
2H), 3.59 (m, 2H), 4.56 (bs, 2H), 5.42 (δ, J=8, 1H), 7.08 (δ, 3=7.5, 1H), 7.22 (m, 2H), 7.4-7.5 (m, 3H), 7.S1 (m, 2H), 7.95 (m, 2H).
13C-NMR (δ, CDCb): 20.9, 32.2, 34.8, 55.0, 57.6, 107.4, 110.9, 126.9, 127.0, 128.9, 12S.0, 136.3, 138.3, 138.5, 139.4, 141.0, 155.6, 158.5.
MS (%): 371 (100, parent+1).
Anal. Calc’d for 3HCI3H2O: C 53.99, H 6.61, N 10.49. Fouhd: C 53.79, H
6.46, N 8.70.
EXAMPLE 2 un
6-[4'-(4-Phenethvi-piperazin-1-ylmethvf)-biphenyl-4-vn-pyridin-2-ylamine
A. 2-(2,5-DimethviDvrrolvl)-6-i4'-(4-phenethyl-piperazin-1-y!methvr)-biphenvl-4-vllpyridine
To a 100 mL round-bottomed flask equipped with N2 inlet were added 176 mg (0.50 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-(4’-formylbipheny!-4-yl))-pyridine (Example 1B), 105 mg (0.55 mmol) 2-phenyiethylpiperazine, 7 mL methanol, 30 uL (0.50 mmol) acetic acid, and 38 mg (0.60 mmol) sodium cyanoborohydride. The reaction was stirred at room temperature for 12 hours poured into aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 190 mg (72%) of an oil.
1H-NMR (δ, CDCb): 2.26 (s, 6H), 2.5-2.7 (m, 8H), 2.83 (m, 2H), 3.60 (s, 2H), 5.97 (s, 2H), 7.15 (δ, J=8, 1H), 7.2-7.3 (m, 5H), 7.44 (m, 2H), 7.62 (m, 2H), 7.72 (m, 2H), 7.79 (δ, J=8, 1H), 7.87 (t, J=8, 1H), 8.16 (m, 2H).
13C-NMR (δ, CDCb): 13.3, 33.7, 53.1, 53.2, 60.6, 62.8, 107.0, 118.2, 119.8, 126.1, 125.9, 127.4, 123.4, 123.7, 128.3, 129.3, 137.2, .137.7^136,9,139.3, 140.3, 141.9, 151.7, 156.5.
M,
MS (%): 527 (parent+I, 100).
Β. S-f4l-(4-Phenethvi-'piper3zin-1-v!melhvi)-biphenvl-4-vn-pyridin-2-yiair.ine
Tos 100 mL round-bottom 3d flask equipped with N2 inlet were added 190 mg (0.361 mmol) 2-(2,5-dimethylpyrroly!)-6-[4'-(4-phenethyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-pyridine,
126 mg.(1.81 mmol) hydroxylarnine hydrochloride, 1 mL water, and 5 mL ethanol. The reaction was heated at reflux for 3S hours followed by treatment with an additional 50 mg hydroxylarnine hydrochloride and refluxing for 24 hours. The reaction was cooled, poured into dilute aqueous hydrochloric scid, snd washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 1 N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was converted to the hydrochloride salt using 1 N HC! in ether to afford 110 mg (55%) of a solid, mp 267-269°C.
1K-NMR (δ, CDCb): 2.5-2.7 (m, 8H), 2.81 (m, 2H), 3.57 (s, 2H), 4.66 (bs, 2H), 6.42 (§, J=8, 1H), 7.10 (δ, J--7.5, 1H), 7.21 (m, 3H), 7.26 (m, 2H), 7.41 (m, 2H), 7.47 (t, J=8, 1H), 7.59 (m, 2H), 7.66 (m, 2H), 8.00 (m, 2H).
13C-NMR (δ, CDCb): 33.7, 53.1, 53.2, 60.6, 62.8, 107.2, 110.8, 126.1, 126.9, 127.2,
127.3, 128.4, 128.7, 129.7, 137.4, 138.4, 139.5, 140.4, 141.0, 155.7, 158.4.
MS (%): 449 (parent+1, 100).
Anal. Calc’d for C30K32N4 3HCI3/2H2O: C 61.59, H 6.55, N 9.58. Found: C 61.64, H 6.31, N 9.51.
25 EXAMPLE 3
3-f4'-(6-Amino-pyridin-2-vl)-biphenYl-4-ylmethyH-3-aza-bicyciof3.1.0lhex-6-vlamine Prepared as in Example 2, using 3-aza-bicyclo[3.1.0]hex-6-ylamine t-butyl carbamate for the reductive amination step (2A) in 67% yield as an oil:
’H-NMR (δ, CDCb): 1.46 (s, 9H), 1.52 (bs, 2H), 2.26 (s, 6H), 2.43 and 3.11 (multiplets,
4H), 2.94 (m, 1H), 3.61 (s, 2H), 5.97 (s, 2H), 7.14 (dd, J=1,8, 1H), 7.34 (m, 2H), 7.57 (m, 2H), 7.70 (m, 2H), 7.78 (δ, J=7, 1H), 7.87 (t, J=8, 1H), 8.16 (m, 2H).
13C-NMR (δ, CDCb): 13.6, 24.6, 28.4, 30.6, 54.2, 58.6, 107.0, 118.2, 119.8, 126.8,
127.1, 127.3, 127.5, 128.7, 128.9, 132.1, 137.1, 138.6, 138.9, 142.0, 151.7, 156.5.
MS (%): 535 (parent+1, 100).
followed by removal of the protecting groups with hydroxylarnine hydrochloride in aqueous ethanol (as in Example 2B) and treatment with trifluoroacetic acid in methylene chloride at room temperature for 3 hours to give overall 65% yield of the trifluoroacetate salt, triturated with tetrahydrofuran, mp 112-119°C:
• AP/P/ 9 7/01 156
AP 0 Ο Ο 8 4 8
-2310 1H-NMR (6, TrA salt in CDC!3): 2.33 (bs, 2H), 2.20 (bs, 1H), 3.29 (m, 2H), 3.70 (m, 2H), 4.41 (s, 2H), 6.93 (δ, J*8. 1H), 7.20 (δ, J=7.5, 1H), 7.60 (m, 2H), 7.78 (m, 2H). 7.83 (m, 2K), 7.98 ({. J~8, IK).
13CK (δ, TFA salt in CDCI3): 23.7,27.5, 57.1,60.1,6.9., 113.1, 113.0, 120.9, 130.0,
130.1, 132.7, 13-.4, 133.5, 143.5, 145.1, 146.7, 149.1, 157.9.
i .3(8-'; 35/(-«.;-3nt+1, 100).
A”: I. + vic'd for C2iH24N,'3(C2F3C2K)'1/2H2O: C 49.23, H 2.22, N 7.37. Found: 7 49.14, H 3.20, N 7.?,'.
EXAMPLE 4 15 3-f4'-(6-Am|,!)o-pyridin-2-vl)-biphenvl-3-vlmethvn-3-aza-bicyclo[3.1.0]hex-5-ylamine
A. 2-(2.5-DimethvlpYrrolvl)-6-(4-(3-tolyl)phenvl))-pvridine Prepared as in Example 1B using 3-tolyi boronic acid as an oil in 39% yield.
1H-NMR (δ, CDCI3) 2.32 (s, 6H), 2.49 (s, 3H), 6.03 (s, 2H), 7.19 (dd, J=1,8, 1H), 7.25 (m, 1H), 7.41 (t, J=7.5, 1H), 7.53 (m, 2H), 7.77 (m, 2H), 7.81 (dd, J=1,8, 1H), 7.90 (t, J=8, 1H),
8.21 (m, 2H).
13C-NMR (δ, CDCfe) 13.6, 21.7, 107.1, 118.3, 119.9, 124.3, 127.0, 127.4, 127.5, 127.9,
128.5, 128.7, 128.8, 137.2, 138.5, 138.7, 140.5, 142.3, 151.8, 156.5.
MS (%): 339 (parent+1,100).
B. 2-Phthamimido-6-(4-(3-tolyf)phenvl))-pyridtne
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
200 mg (0.592 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-(3-to!yl)phenyl))-pyridine, 206 mg (2.96 mmol) hydroxylamine hydrochloride, 4 mL ethanol and 1 mL water. The reaction was refluxed 36 hours cooled, and poured into dilute aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was separated, washed with brine, and dried. The residue, as a brown oil, 138 mg (90%), was taken up in 10 mL dry toluene and treated with 116 mg (0.531 mmol) N-carbethoxyphthalimide. The resulting solution was refluxed 20 hours cooled and evaporated. The residue was ch'omatographed on silica gel using hexane/ethyl acetate as eluant to give 130 mg (56% overall) of an oil.
1H-NMR (δ, CDCI3): 2.40 (s, 3H), 7.15 (m, 1H), 7.34 (m, 2H), 7.42 (m, 2H), 7.65 (m,
2H), 7.79 (m, 3H), 7.92 (m, 3H), 8.07 (m, 2H).
13C-NMR (δ, CDCI3): 21.6, 119.9, 120.1, 123.5, 123.9, 124.2, 122.2, 122.4, 127.5, 127.9; 128.3, 128.7, 131.9, 133.7, 134.2, 134.5, 135.3, 138.4, 139.0, 157.3, 166.8.
MS (%): 391 (parent+1, 100).
AP/P' 9 7/01
AP Ο Ο Ο 8 ί 8
-245 C- 3-f4'-(e-Phthalimido-pyriclin-2-yr)-bipheriyl-3-YlmethyB-3-az3-bicYclof3.1.01hex-6viamine t-butyi carbamate
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 130 mg (0.333 mmol) 2-phthamimido-6-(4-(3-toiyl)phenyl))-pyridine, 59 mg (0.333 mmol) Nbromosuccinimide, 10 mg diazo-bis(l-cyanocyclohexane), and 10 mL carbon tetrachloride. The reaction was refluxed 1 hour an additional 10 mg of diazo-bis(l-cyanocyciohexane) added, and refluxing continued 1 hour. The reaction was then cooled, filtered and evaporated.
The residue was taken up in 10 mL dry acetonitrile end treated with 86 mg (0.333 mmol) 3-sza-bicyclo[3.1.0]hex-6-y!amine and 28 mg (0.333 mmol) sodium bicarbonate. The reaction was refluxed 12 hours cooled, and evaporated. The residue was taken up in ethyl acetate and water, and the organic layer separated, washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 130 mg (67%) of an oil.
1H-NMR (δ, CDCi3): 1.38 (s, 9H), 1.6-1.8 (m, 2H), 3.2-3.5 (m, 5H), 3.57 (m, 2H), 7.15 (dd, J=1,8, 1H), 7.2-7.5 (m, 4H), 7.65 (m, 3H), 7.78 (m, 3H), 7.92 (m, 2H), 8.05 (m, 2H).
13C-NMR (δ, CDCI3): 28.3, 47.6, 50.5, 54.1, 62.1, 116.5, 118.8, 119.9, 120.1, 123.9,
126.5, 127.3, 127.4, 127.5, 128.8, 129.2, 131.8, 134.5, 136.4, 136.8, 138.9, 155.1, 157.2, 165.6, 166.7,169.6,169.8.
MS (%): 587 (parent+1, 100).
D. 3-f4,-(6-Amino-pyridin-2-yl)-biphenyl-3-ylmethyll-3-aza-bicycloi3.1.0lhex-6-vlamine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 130 mg (0.222 mmol) 3-[4'-(6-phthalimido-pyridin-2-yl)-biphenyi-3-ylmethyl]-3-azabicyclo[3.1,0]hex-6-ylamine t-buty! carbamate, 20 mL methanol and 0.3 mL hydrazine. The reaction was heated at 50°C for 2.5 hours cooled, and evaporated. The residue was taken up in ethyl acetate and washed with 0.2 N sodium hydroxide solution, water and brine, dried over sodium sulfate, and evaporated.
The residue, 110 mg, was taken up in 6 mL dry methylene chloride and treated with 1.5 mL trifluoroacetic acid at room temperature for 2 hours. The reaction was evaporated and taken up in ethyl acetate/0.3 N hydrochloric acid. The aqueous layer was separated, the pH adjusted to 10 with 6 N sodium hydroxide solution, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil was converted to the hydrochloride using 1 N HCl in ether and triturated with tetrahydrofuran to afford 21 mg (20%) of a solid, mp 184-196°C.
1H-NMR (δ, CDCIj): 1.37 (bs, 2H), 1.51 (bs, 1H), 2.46 and 3.02 (multiplets, 4H), 3.64 (s, • AP/P/ 9 7/01 156
2H), 4.50 (bs, 2H), 6.46 (δ, J=8, 1H), 7.13 (δ, 2H).
ΐ AAD LASTS [MARKS
APO Ο Ο 84i
-255 13C-NMR (δ, CDCI3): 14.0, 38.7, 54.5, 59.2, 107.1, 110.8, 115.1, 125.7, 126.8, 127.1,
127.3, 127.7, 128.6, 138.3, 138.5, 139.0, 140.6, 141.3, 155.7, 158.3.
MS (%): 357 (parent+1, 100).
EXAMPLE 5
2-Amino-N-i4'-(S-amino-pynidin-2-yf)-bi!?hfc nvi-3-yi1-propionamide
A. 2-f2.5-D;roethylpviTOlYl)-6-(4-(3-pi,.rophenvnphenvl))-pvridine
Prepared as in Example 13, using 3-niiropheny! boronic acid as an oil in 667· yield.
1H-NMR (δ, CDCi3): 2.24 (s, 6H), 5.96 (s, 2H), 7.15 (δ, J=8, 1H), 7.54 (t, J=S, 1H), 7.67 15 (m, 2H), 7.76 (m, 1H), 7.88 (m, 2H), 8.15 (m, 3H), 8.42 (bs, 1H).
13C-NMR (δ, CDCI3): 13.6, 107.3, 118.4, 120.2, 121.9, 123.2, 123.4, 127.6, 128.6, 129.9, 132.9, 138.5, 138.9, 139.2, 141.9, 148.7, 151.8, 155.8.
MS (%): 370 (parent+1, 100).
B. 2-(2,5-Dimethvlpvrrolvl)-6-(4-(3-aminophenvl)phenvl))-pyridine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 520 mg (1.41 mmol) 2-(2,5-dimethylpyrroiyl)-6-(4-(3-nitrophenyI)pheny!))-pyridine, 445 mg (7.05 mmol) ammonium formate, 10 mL ethanol, and 80 mg 10% palladium on carbon (a few mL 1,2dichloroethane added to dissolve fhe nitro compound). The reaction was refluxed 40 min, cooled, and filtered with ethanol through Celite. The filtrate was evaporated, taken up in ethyl acetate/dilute aqueous sodium hydroxide solution, and the organic layer separated and washed with brine, dried over sodium sulfate, and evaporated to an oil, 400 mg (84%).
1H-NMR (δ, CDCI3): 2.26 (s, 6H), 3.77 (bs, 2H), 5.99 (s, 2H), 6.67 (m, 1H), 6.92 (bs, 1H), 7.04 (m, 1H), 7.14 (m, 1H), 7.23 (t, J=8, 1H), 7.67 (m, 2H), 7.75 (δ, J=8, 1H), 7.84 (t, J=8,
1H), 8.14 (m, 2H).
13C-NMR (δ, CDCl3): 13.5, 107.0, 113.6, 114.4, 117.3, 118.2, 119.8, 127.1, 127.3,
128.6, 129.7, 137.1, 138.6, 141.4, 142.3, 147.0, 151.6, 156.4.
MS (%): 340 (parent+1, 100).
35 C. 2-(t-Butvlcarbamovlamino)-N-f4,-(6-(2.5-dimethvlpvmolvr)-pvridin-2-yl)-biphenvl-3-vl1propionamide
To a 100 mL round-bottomed flask equipped with N2 inlet were added 200 mg (0.590 mmol) 2-(2,5-dimethylpyrTolyl)-6-(4-(3-aminophenyl)phenyl))-pyridine, 117 mg (0.590 mmol) N-tbutoxycarbonylalanine, 113 mg (0.590 mmol) EDAC, 159 mg (1.30 mmol) 440 dimethylaminopyridine, and 10 mL dry acetonitrile. The reaction was stirred at room <O un
AP/P/ 9 7/01
AP Ο Ο Ο 8 4θ
-265 temperature for 12 hours evaporated, and the residue chromatographed on silica gel using methanol/methylene chloride as eluant to afford 230 mg (76%) of an oil.
’H-NMR (δ, CDCI3): 1.46 (s, 9H), 1.48 (δ, J=7, 3H), 2.24 (s, 6H), 4.55 (m, 1H), 5.62 (m, 1H), 5.96 (s, 2H), 7.11 (δ, J=8, 1H), 7.23 (m, 2H), 7.47 (m, 1H), 7.57 (m, 2H), 7.69 (m, 1H), 7.81 (m, 2K), 8.05 (m, 2H).
,3C-NMR (δ, CDCI3): 13.5, 18.0, 28.3, 50.9, 80.4, 106.9, 118.2, 118.9, 119.7, 122.6,
127.1. 127.3, 128.6 129.2, 137.2, 138.5, 138.6, 140.9, 141.4, 151.6, 156.3, 171.8.
MS (%): 511 (parent+1, 100).
. ..: -.us
- D· 2-Amino-N-[4'-(6-amino-pyridin-2-vi)-biphenyl-3-vH-propionamide 15 To a 100 ml. round-bottomed flask equipped with N2 inlet were added 230 mg (0.451 rnmol) 2-(t-butylcarbamoylamino)-N-[4'-(6-(2,5-dimethylpyrrolyl)-pyridin-2-yl)-biphenyl-3-yl]propionamide and 25 mL ethyl acetate. The solution was cooled to 0°C and saturated with HCI, then stirred at 0°C for 30 minutes and 1 hour at room temperature. The resulting precipitate was collected and dissolved in 20 mL methanol, treated with 1 mL water and 157 mg (2.255 mmol) hydroxylamine hydrochloride, and refluxed 2 days. The reaction was cooled, evaporated, and taken up in ethyl acetate/dilute hydrochloric acid. The aqueous layer was separated, the pH adjusted to 10 with 6 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The oil was taken up in methylene chloride, treated with decolorizing carbon, filtered through Celite, and evaporated. The resulting oil (90 mg) was converted to the hydrochloride salt using 1 N HCI in ether to afford a solid, 73 mg (40%), mp >215°C (dec.).
1H-NMR (δ, CDCI3): 1.39 (δ, J=7, 3H), 3.57 (q, J=7, 1H), 4.66 (bs, 2H), 6.40 (δ, J=8, 1H), 7.05 (δ, J=7.5, 1H), 7.34 (m, 2H), 7.43 (t, J=8, 1H), 7.62 (m, 4H), 7.93 (m, 2H), 9.57 (bs, 1H).
13C-NMR (δ, CDCI3): 21.5, 51.1, 107.2, 110.7, 117.9, 118.3, 122.6, 127.1, 127.2, 129.3,
138.3, 138.6, 140.6, 141.3, 155.4, 158.3, 173.9.
MS (%): 333 (parent+1, 100).
IR (KBr, cm.’1): 1657 (C=O).
EXAMPLE_6
2-Amino-N-f4’-(6-amino-pvridin-2-yl)-biphenyl-3-yn-3-phenvl-propionamide
Prepared as in Example 5, using t-butoxycarbonylphenylalanine, with the coupling step proceeding in 58% yield, and the deblocking in 57% yield to afford the product as the hydrochloride salt, mp 180-200°C (dec.)
56
O
CD a
APO Ο Ο 8 4 8
-275 1H-NMR (δ, CDCI3): 2.81 and 3.37 (multiplets, 2H), 3.74 (dd, J=4,9, IH), 4.62 (bs, 2H),
6.43 (δ, J=8, 1H), 7.10 (δ, J=7.5, IH), 7.2-7.4 (m, 3H), 7.47 (t, J=8, 1H), 7.65 (m, 3H), 7.97 (m, 2H), 9.53 (bs, 1H).
13C-NMR (δ, CDCI3): 40.6, 56.8, 107.2 ,110.3, 113.0, 118.5, 122.8, 126.9, 127.0, 127.1,
127.2, 128.8, 129.2, 129.4, 1137.6, 138.1, 138.4, 138.6, 140.7, 141.4, 155.4, 158.2, 172.4.
MS (%): 409 (parent+1, 100).
EXAMPLE 7
6-i4-(1-Benzyl-t,2.5,6-tetr3hvGro-pyridin-3-vi)-phenyn-pyridin-2-vlamine
:)
A. 2-(2,5-Dimethylpyrrolyl)-6-[4-(pyrid-3-yl)-phenyn-pyridine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
271 mg (2.20 mmol) 3-pyridylboronic acid (Rec. Tray. Chim.. 93, 21 (1974)), 720 mg (2.20 mmoi) 2-(2,5-dimethylpyrroly!)-6-(4-bromophenyl)-pyridine, 933 mg (8.81 mmo!) sodium carbonate, 128 mg (0.110 mmol) tetrakistriphenylphosphine palladium, 9 mL ethanol, and 1 mL water. The mixture was refluxed 20 hours 100 mg 3-pyridiylboronic acid added, and refluxing continued for 2 hours. The reaction was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanoi/methylene chloride as eluant to afford the product as an oil, 350 mg (49%).
1H-NMR (δ, CDCI3): 2.25 (s, 6H), 5.97 (s, 2H), 7.12 (δ, J=8, 1H), 7.31 (dd, J=5,8, 1H),
7.64 (m, 2H), 7.74 (δ, J=8, 1H), 7.83 (m, 2H), 8.16 (m, 2H), 8.59 (m, 1H), 8.90 (m, 1H).
13C-NMR (δ, CDCi3): 13.6, 107.2, 118.3, 120.1, 123.7, 127.4, 127.6, 128.1, 128.6, 129.1, 134.2, 135.9, 138.6, 138.8, 148.2, 148.5, 128.8, 151.8, 156.0.
MS (%): 326 (parent+1, 100).
AP/P/ 9 7/01 156
B. 2-(2,5-Dimethvlpyrrolvl)-6-f4-(1-benzyl-1.2.5.6-tetrahvdro-pvridin-3-vf)-phenvl1pyridine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 350 mg (1.077 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4-(pyrid-3-yi)-phenyl]-pyridine, 10 mLdry acetonitrile, and 128 uL (1.077 mmol) benzyl bromide. The reaction was heated at 70°C for 14 hours cooled, evaporated, and the residue taken up in 5 mL ethanol and 4 mL water, and treated with 149 mg (2.37 mmoi) sodium cyanoborohydride (a few mL dichloromethane was added to improve solubility). The reaction was stirred at room temperature for 20 hours poured into dilute aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, dnd^evaporated/The resTdufTwas I OP F'ATFL’TS
AP 0 0 0 8 4 8
| 5 | chromatographed on silica gel using methanol/methylene chloride as eluant to afford two product fractions: 2-(2,5-dimethylpyrroiyl)-6-[4-(1 -benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridine as an oil, 135 mg (30%): 1H-NMR (δ, CDCIj): 2.26 (s, 6H), 2.41 (m, 2H), 2.67 (m, 2H), 3.45 (m, 2H), 3.76 (s, 2H), |
| 10 | 5.98 (s, 2H), 6.28 (bs, 1H), 7.13 (δ, J=8, 1H), 7.3-7.5 (m, 7H), 7.73 (5, J=8, 1H), 7.85 (t, J=8, 1H), 8.05 (m, 2H). 13C-NMR (δ, CDCb): 13.6, 26.6, 49.2, 54.6, 62.9,107.0, 118.1, 11S.7, 123.5, 125.2, |
| :, 15 Q | 126.9, 127.2, 128.4, 128.7, 129.3, 134.8, 135.9, 138.2, 138.6, 141.1, 151.7, 156.5. MS (%): 420 (parent+1, 100), and 2-(2,5-dimethylpyrrolyl)-6-[4-(1-benzyl-piperidin-3-yl)-phenyl]-pyridine, 170 mg (37.5%): 1H-NMR (δ, CDCb): 1.82 (m, 4H), 2.23 (s, 6H), 2.67 (m, 1H), 2.9-3.1 (m, 4H), 3.66 (s, 2H), 5.95 (s, 2H), 7.12 (5, J=8, 1H), 7.2-7.5 (m, 7H), 7.73 (δ, J=8, 1H), 7.86 (t, J=8, 1H), 8.01 (m, 2H). 13C-NMR (δ, CDCb): 13.6, 25.2, 31.3, 42.3, 53.5, 60.3,63.2, 107.0, 118.2, 119.7, 127.1, |
| 20 | 127.6, 127.7, 128.4, 128.5, 128.7, 129.5, 129.9, 133.3, 136.7, 138.7, 151.6, 156.7. MS (%): 420 (parent+1, 100). |
| 25 1 | C. 6-r4-(1-BenzYl-1,2,5.6-tetrahydro-Dvridin-3-Yl)-phenvn-Dvridin-2-viamine To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 135 mg (0.322 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4-(1 -benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)phenyl]-pyridine, 112 mg (1.61 mmol) hydroxylamine hydrochloride, 5 mL ethanol, and 1 mL water. The reaction was refluxed 40 hours cooled, and the resulting precipitate, 6-(4-(1 -benzyl- 1, 2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridin-2-ylamine clihydrochloride, filtered and dried, 22 mg (16.5%), mp 270-272°C. Additional material was recovered from the filtrate, 60 mg (55%) of |
| 30 | the free base as an oil. |
| 35 | 1H-NMR (δ, CDCb): 2.35 (m, 2H), 2.64 (m, 2H), 3.40 (m, 2H), 3.71 (s, 2H), 4.58 (bs, 2H), 6.21 (bs, 1H), 6.40 (δ, J=8, 1H), 7.04 (δ, J=7.5, 1H), 7.2-7.4 (m, 7H), 7.45 (t, J=8, 1H), 7.84 (m, 2H). 13C-NMR (δ, CDCb): 26.5, 49.1, 54.6, .62.8, 107.1, 110.7, 122.9, 125.0, 126.7, 126.8, 127.1, 128.3, 129.3, 134.9, 138.1, 138.2, 138.3, 138.4, 155.8. MS (%): 342 (parent+1, 100). Anal. Calc'd for C23H23N32HCM/2H2O: C 65.25, H 6.19, N 9.92. Found: C 65.62, H 6.42, N 9.93. |
D'.;V • AP/P/ 9 7/01 156
APO0 0 8 4 8
-29EXAMPLE 8
6-i4-(1-Benzyl-piperidin-3-vl)-phenvn-pyridin-2-ylamine
Prepared as in Example 7C using the intermediate from Example 7B, to afford 50 mg (30%) of a solid, mp 55-70°C.
1H-NMR (δ, CDCIj): 1.75 (m, 2H), 2.0 (m, 2H), 2.62 (m, 1H), 2.8-3.0 (m, 4H), 3.55 (s,
2H), 4.53 (bs, 2H), 6.40 (δ, J=8, 1H), 7.05 (δ, J=8, 1H), 7.2-7.4 (m, 7H)?7.44 (t, J=8, 1H), 7.82 (m, 2H).
13C-NMR (δ, CDCI3): 25.7, 31.7, 42.7, 53.7, 61.0, 63.6, 105.9, 110.7, 126.8, 127.0,
127.5, 128.2, 128.3, 129.2, 129.3, 133.8, 137.8, 138.3, 145.7, 156.1, 158.3.
MS (%): 344 (parent+1, 100).
EXAMPLE 9
644-(1-Benzvl-piperidin-2-ylmethyl)-phenyn-pyridin-2-vlamine
A. N-Benzyl-2-(4-bromobenzyl)-piperidine
To a 100 mL round-bottomed flask equipped with N2 inlet were added 250 mg (0.984 mmol) 2-(4-bromobenzyI)-piperidine (prepared as described in Tetrahedron Letters. 7, 631 (1977)), 110 uL (1.08 mmol) benzaldehyde, 7 mL methanol, 74 mg (1.18 mmol) sodium cyanoborohydride, and a few drops of acetic acid. The reaction was stirred at room temperature, followed by additional benzaldehyde, sodium cyanoborohydride, and acetic acid, for a total of 16 hours then poured into dilute aqueous sodium bicarbonate solution, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methyiene chloride as eluant, and the product further purified by conversion to the hydrochloride salt in ether followed by basification using aqueous sodium hydroxide solution to afford 175 mg (52%) of an oil.
1H-NMR (δ, CDCI3): 1.29 (m, 2H), 1.53 (m, 3H), 1.6 (m, 1H), 2.26 and 2.79 (multiplets, 2H), 2.60 (m, 2H), 3.15 (dd, J=3,12, 1H), 3.77 (Abq, J=13.5, Dn = 41, 2H), 7.00 (m, 1H), 7.2-7.4 (m, 8H).
13C-NMR (δ, CDCI3); 22.4, 24.9, 28.9, 36.0, 51.0, 58.2, 61.5, 127.0,127.2, 127.6, 128.3, 35 128.5, 129.2, 131.1, 131.4, 139.0, 140.9.
MS (%): 344/346 (parent+1, Br^/Br*1,100).
CO to o
-«·«.
r^ **·-*.
r £X <
‘ B. 2-(2,5-Dimethvlpvrrolyl)-6-f4-(1-benzvl-piperidin-2-ylmethvl)-phenvll-pvridine
To a 100 mL 3N round-bottomed flask equipped with septum and N2 inlet were added
175 mg (0.509 mmol) N-benzyl-2-(4-bromobenzyl)-piperidine and 7 mL dry ether. The solution was cooled to -70°C, and 0.38 mL (0.610 mmol) of a 1.6 M solution of butyl lithium in hexane
-305 added dropwise over 1 minutes. The reaction was stirred at -70°C for 5 min, then warmed to room temperature over 20 minutes. To the stirring reaction was then added a soiution of 105 mg (0.610 mmol) 2-(2,5-dimethylpyrrolyi)-pyridine in 5 mL dry ether, and the reaction, turning dark orange, was stirred at room temperature for 4 hours then quenched with aqueous ammonium chloride solution. After extraction into ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate for 16 hours to effect air-oxidation to the pyridine, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 36 mg (16%) of an oil.
1H-NMR (δ, CDCb): 1.30 (m, 2H), 1.55 (m, 3H), 1.64 (m, 1H), 2.22 (s, 6H), 2.6-2.S (m, 4H), 3.11 and 3.25 (multiplets, 1H), 3.54 and 4.07 (multiplets, 2H), 5.93 (s, 2H), 7.01 (δ, J=8,
1H), 7.2-7.4 (m. 7H), 7.72 (δ, J=8, 1H), 7.85 (t, J=8, 1H), 7.98 (m, 2H).
13C-NMR (δ, CDCI3): 13.5, 22.3, 25.0, 29.0, 50.8, 58.2, 61.5, 65.2, 106.9, 118.1, 119.6,
126.9, 127.0, 127.6, 128.3, 128.5, 128.7, 129.0, 129.1, 129.8, 131.1, 131.3, 138.5, 141.5, 155.5, 157.0.
MS (%): 436 (parent+1, 100).
C. 6-[4-(1-Benzvl-piperidin-2-ylmethyl)-phenvn-pyridin-2-ylamine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 36 mg (0.0827 mmol) 2-(2,5-dimethylpymolyl)-6-[4-(1-benzyl-piperidin-2-ylmethyl)-phenyi]-pyridine, 29 mg (0.414 mmol) hydroxylamine hydrochloride, 4 mL ethanol and 1 mL water. The reaction was refluxed 84 h (additional hydroxylamine hydrochloride was used to complete the reaction), cooled, poured into dilute hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide soiution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil was converted to the hydrochloride salt using 1 N HCI in ether to afford a solid, 17 mg (48%), mp 70-85°C.
1H-NMR (δ, CDCI3): 1.32 (m, 2H), 1.52 (m, 3H), 1.63 (m, 1H), 2.6-2.8 (m, 2H), 3.21 (m, 1H), 3.53 (m, 2H), 4.08 (m, 2H), 4.50 (bs, 2H), 6.42 (δ, J=8, 1H), 7.05 (δ, J=7.5, 1H). 7.2-7.4 (m, 7H), 7.47 (t, J=8, 1H), 7.81 (m, 2H).
13C-NMR (δ, CDCI3): 22.4, 23.8, 25.3, 36.2, 38.7, 50.9, 61.8, 106.8, 110.8, 126.7, 126.8, 35 128.2, 128.8, 128.9, 129.0, 129.6, 131.1, 131.3, 138.3, 141.0, 156.2, 158.6.
MS (%): 358 (parent+1,100).
Anal. Calc’d for C24H27N32HCI 3H2O: C 59.50, H 7.28, N 8.67. Found: C 59.54, H 6.98, N 7.32.
AP/”/ 9 7/01 156
ΑΡΟ η π g 4 8
-31EXAMPLE 10
6-(4-f1-(2,2-DiphenYl-ethyl)-piperidin-2-ylmethyil-phenyiPpyridin-2-ylamine Prepared as in Example 9, using diphenylacetaldehyde in the step analogous to 9A,
59% yield, followed by a 33% yield in the organolithium addition, and a 31% yield in the deblocking to afford the product as the dihydrochloride salt, mp 168-180°C.
1K-NMR (δ, CDCI3): 1.4-1.7 (m, 6H), 2.4-3.4 (series of multiplets, 8H), 4.49 (bs, 2H),
6.43 (δ, J=8, 1H), 7.04 (δ, J=7.5, 1H), 7.11 (m, 2H), 7.2-7.4 (m, 10H), 7.47 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCb): 23.0, 23.8, 29.7, 38.7, 49.5, 50.5, 59.6, 61.6, 106.8, 110.8, 126.2,
126.7,128.3,129.5,130.9,138.4,141.9,144.0,156.0,158.2.
MS (%): 448 (parent+1, 100).
EXAMPLE 11
6-f3-(2-DimethYlamino-cvclopentvlmethvl)-phenyn-PYridin-2-ylamine
A. 2-(4-((2-(2,5-Dimethvlpvrrolyl))-pyrid-6-yl)benzvlidene)cvclopentanone
To a 100 mL round-bottomed flask equipped with Dean-Stark trap topped with a condenser arid N2 inlet were added 552 mg (2.0 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4formylphenyl)-pyridine, 20 mL benzene, 0.384 mL (2.4 mmol) 4-morpholino-1 -cyclohexene, and 10 mg camphorsulfonic acid. The solution was refluxed with removal of water for 13 hours cooled, and 25 mL 3N hydrochloric acid added. The mixture was stirred at room temperature for
1 hour then diluted with ethyl acetate and water. The organic layer was separated, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated. The crude oil solidified on standing, 460 mg (~100%), and was used directly in the next step.
1H-NMR (δ, CDCb): 1.95 (m, 2H), 2.195 (s, 6H), 2.33 (t, J=8, 2H), 2.91 (m, 2H), 5.91 (s, 2H), 7.09 (δ, J=8, 1H), 7.36 (bs, 1H), 7.55 (m, 2H), 7.71 (δ, J=8, 1H), 7.81 (t, J=8, 1H), 8.07 (m.
2H).
13C-NMR (δ, CDCb): 13.5, 20.0, 29.3, 37.6, 107.1, 118.4, 120.1, 127.0, 128.2, 128.1,
130.8, 131.2, 136.4, 136.7, 138.8, 151.7, 155.6.
MS (%): 343 (parent+1, 100).
AP/F/ 9 7/01 156
B. 2-(4-((2-(2.5-DimethvlpyrrolvD)-pyrid-6-vl)benzyl)cvclopentanone
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added the crude material from above (2 mmol) and 4 mL 1,2-dichloroethane. After dissolution, 25 mL ethanol was added, followed by 631 mg (10 mmol) ammonium formate and 100 mg 10% palladium-on-carbon. The mixture was refluxed 1 hours then treated with additional ammonium formate and palladium-on-carbon (Pd-C) and refluxed foryi^fl^TfleTefactiorTwas-then;cooled and filtered through Celite with ethanol and methylene Ihlori^GiTR^iTiffftfe^asSevaQorated, I j
- ΐ L· t!:C<8!)7 !
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taken up in ethyl acetate and aqueous sodium bicarbonate solution, the organic layer separated, washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 410 mg (60% overall) of a foam.
1H-NMR (δ, CDCI3): 1.56 (m, 1H), 1.70 (m, 1H), 1.93 (m, 1H), 2.06 (m, 2H), 2.24 (s, 10 6H), 2.29 (m, 1H), 2.36 (m, 1H), 2.61 (m, 1H), 3.19 (dd, J=4,14, 1H), 5.95 (s, 2H), 7.10 (δ, J=8,
1H), 7.27 (m, 2H), 7.71 (δ, J=8, 1H), 7.83 (t, J=8, 1H), 8.01 (m, 2H).
13C-NMR (δ, CDCI3): 13.5, 20.5 29.0, 35.3, 38.1, 50.8, 107.0, 118.1, 119.6, 126.9,
128.5, 129.3, 136.3, 138.7, 141.5, 151.6, 156.6.
IR (neat, cm.'j: 1735 (C=O).
MS (%): 345 (parent+1, 100).
C. 2-(2,5-Dimethvlpyrroivl)-6-f3-(2-dimethvlamino-cvclopentvlmethyl)-phenvll-pyridine To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 205 mg (0.596 mmol) 2-(4-((2-(2,5-dimethylpyrrolyl))-pyrid-6-yI)benzyl)cyclopentanone, 10 mL methanol,
486 mg (5.96 mmol) dimethylamine hydrochloride, 45 mg (0.715 mmol) sodium cyanoborohydride*, and 41 uL (0.715 mmol) acetic acid. The reaction was heated at 50°C for 40 hours, cooled, and poured into aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride (with a small amount of triethylamine) as eluant to afford both diastereomers as an oil Less polar diastereomer, 140 mg (63%):
1H-NMR (δ, CDCI3): 1.51 (m, 2H), 1.63 (m, 2H), 1.86 (m, 2Η),δ 2.22 (s, 6H), 2.28 (m, 3H), 2.33 (s, 6H), 2.99 (m, 1H), 5.93 (s, 2H), 7.10 (δ, J=8,1H), 7.27 (m, 2H), 7.71 (δ, J=8, 1H),
7.83 (t, J=8, 1H), 7.99 (m, 2H).
13C-NMR (δ, CDCI3): 13.4, 20.3, 27.3, 28.2, 32.4, 42.8, 45.3, 71.8, 106.8, 118.0, 119.4,
126.7, 128.6, 129.4,135.7, 138.4, 143.8,151.5, 156.8.
MS (%): 374 (parent+1, 100).
More polar diastereomer, 10 mg (4%):
1H-NMR (δ, CDCI3): 1.5-1.8 (m, 6H), 2.20 (s, 6H), 2.32 (s, 6H), 2.45 (dd, J=10,14, 1H), 35 2.60 (m, 2H), 2.95 (dd, J=5,13.5, 1H), 5.91 (s, 2H), 7.10 (δ, J=8, 1H), 7.27 (m, 2H), 7.71 (δ, J=8,
1H), 7.84 (t, J=8, 1H), 7.97 (m, 2H).
13C-NMR (δ, CDCI3): 13.4, 23.5 27.5, 30.85, 41.0, 42.3, 43.3, 72.1, 106.8, 118.0, 119.5,
126.8, 128.6, 129.4, 136.0, 138.4, 142.7,151.5, 156.7.
MS (%): 374 (parent+1, 100).
D. 6-f3-(2-Dimethy[amino-cyclopentylmethvl)-phgnvll-pyridin-2-ylamine un
APO Ο Ο 8 4 8
-335 To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
140 mg (0.375 mmol) 2-(2,5-dimethylpyrrolyl)-6-[3-(2-dimethylamino-cyclopentylmethyl)phenylj-pyridine, 9 mL ethanol, 1 mL water, and 261 mg (3.75 mmol) hydroxylamine hydrochloride. The reaction was refluxed 24 hours treated with additional hydroxylamine hydrochloride, and refluxed a further 12 hours. It was then cooled, poured into dilute aqueous hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6N sodium hydroxide solution, and extracted with two portions of ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (109 mg, 98.5%) was converted to the hydrochloride salt using 1N HCl in ether to afford 115 mg (83%) of a white solid, mp 60-80°C.
. T-, 15 1H-NMR (δ, CDCI3): 1.49 (m, 2H), 1.58 (m, 2H), 1.82 (m, 2H), 2.23 (m, 2H), 2.29 (s,
6H), 2.3 (m, 1H), 2.94 (δ, J=9.6, 1H), 4.57 (bs, 2H), 6.38 (δ, J=8, 1H), 7.02 (δ, J=8, 1H), 7.20 (m, 2H), 7.43 (t, J=8, 1H), 7.80 (m, 2H).
13C-NMR (δ, CDCI3): 20.3, 27.3, 28.2, 32.3, 42.8, 45.3, 71.9, 106.7, 110.6, 126.6, 129.2,137.1, 138.2, 142.8, 156.2, 158.2.
MS (%): 296 (parent+1, 100).
EXAMPLE 12
6-f3-(2-(4-Methylpiperazin-1-vl)-cvclopentvlmethyD-phenvn-pyridin-2-vlamine Prepared as in Example 11, using N-methylpiperazine, to afford a 64% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 212-224°C.
’H-NMR (δ, CDCI3): 1.44 (m, 2H), 1.51 (m, 2Ηχ 1.7-1.8 (m, 2H). 2.21 (m, 2H), 2.25 (s, ) 6H), 2.3 (m, 1H), 2.4-2.6 (m, 8H), 2.88 (m, 1H), 4.60 (bs, 2H), 6.34 (δ, J=8, 1H), 6.99 (δ, J=8,
1H), 7.16 (m, 2H), 7.40 (t, J=8, 1H), 7.77 (m, 2H).
13C-NMR (δ, CDCI3): 20.1, 27.3, 27.4, 32.5, 42.1, 46.0, 52.7, 55.1, 70.0, 106.7, 110.5, 30 126.6,129.1,137.0,138.2,142.8,156.1,158.2.
MS (%): 351 (parent+1,100).
EXAMPLE 13
6-[4-(Piperidin-4-vn-phenvn-pyridin-2-vlamine
A. N-Benzvl-4-(4-bromophenvl)piperidine
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 4.77 g (17.72 mmol) 3-(4-bromophenyl)glutaric anhydride (prepared as described in J. Org. Chem.. 21, 704 (1956)), 1.90 g (17.72 mmol) benzylamine, and 80 mL toluene. The reaction 40 was refluxed 1.5 hours cooled, and concentrated. The residui anhydride, and heated at 100°C for 16 hours then cooled an?
was taken up in 80 mL acetic I evaporated several finTeTWith pATEMTS I AND TkADE MARKS
f.!4 L-pinn
ΑΡ/Γ7 9 7 / 0 1 1 5 6
1997 tOXCYi77 ,V
AP000848
-345 toluene to remove excess acetic anhydride. The residue was dissolved in 80 mL dry tetrahydrofuran and treated with 40 mL (80 mmoi) of a 2 N solution of borane methyl sulfide in tetrahydrofuran. The reaction was refluxed 18 hours cooled, and evaporated, then dissolved in 80 mL ethanol and treated with 3.5 g sodium carbonate and 3.5 g cesium fluoride. The reaction was refluxed 16 hours cooled, and concentrated. The residue was taken up in water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 2.94 g (50%) of an oil.
1H-NMR (δ, CDCI3): 1.78 (m, 4H), 2.08 (m, 2H), 2.47 (m, 1H), 3.02 (m, 2H). 3.56 (s, 2H), 7.10 (d, J=8, 1H), 7.2-7.4 (m, 5H), 7.41 (d, J=8, 2H).
13C-NMR (δ, CDCI3): 33.4, 42.2, 54.1, 63.5, 119.7, 127.0, 128.2, 128.7, 129.2, 131.4,
138.4, 145.5.
MS (%): 328/330 (parent, Bp/Br®1, 15/19), 91 (100).
B. N-Benzvl-4-(4-(2-(2.5-dimethvlpvrrolvl)pyrid-6-vl)phenvl) piperidine
To a 125 mL three-necked round-bottomed flask equipped with septum and N2 inlet . were added 2.93 g (8.88 mmol) N-bertzyl-4-(4-bromophenyl)piperidine and 30 mL dry ether.
The solution was cooled to -70°C, and 6.66 mL (10.65 mmoi) of a 1.6 N solution of butyl lithium in hexane added dropwise over 5 minutes. After stirring a further 5 minutes at -70°C, the solution was warmed slowly to room temperature over 25 minutes. A solution of 1.83 g (10.65 mmol) 2-(2,5-dimethylpyrrolyl)pyridine in 10 mL dry ether was then added dropwise over 5 minutes, and the reaction, which turned slowly dark red, stirred at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride solution, partitioned between ethyl acetate and water, and the organic layer separated, washed with brine, and dried over sodium sulfate, allowing it to stand overnight to effect rearomatization of the pyridine ring. After evaporation of the solvent, the residue was chromatographed on silica gel using ethyl acetate/hexane followed by methanol/methylene chloride as eluant to afford 1.21 g (32%) of an oil.
1H-NMR (δ, CDCI3): 1.86 (m, 4H), 2.16 (m, 2H), 2.23 (s, 6H), 2.58 (m, 1H), 3.05 (m, 2H), 3.59 (s, 2H), 5.95 (s, 2H), 7.12 (d, J=8, 1H), 7.2-7.4 (m, 7H), 7.73 (d, J=7, 1H), 7.85 (t, J=8,
1H), 8.03 (m, 2H).
13C-NMR (δ, CDCI3); 13.5, 33.4, 42.5, 54.2, 63.5, 106.9, 118.1, 119.6, 127.1, 127.3, 128.2, 128.7, 129.3, 131.4, 136.3, 138.3, 138.5,148.0, 151.7, 156.8.
MS (%); 422 (parent+1, 26), 91 (100).
C. 4-(4-(2-(2.5-Dimethvlpyrrolvt)pvrid-6-vt)phenvi)piperidine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added
1.21 g (2.87 mmol) N-benzyl-4-(4-(2-(2,5-dirnethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 30 mL . ΑΡ/Γ/ 9 7/01 156
AP Ο Ο Ο 8 4 Β
ethanol, 0.90 g (14.37 mmol) ammonium formate, and 140 mg 10% palladium-on-carbon (PdC). The reaction was refluxed 1 hour treated with additional ammonium formate and Pd-C, and refluxed 3 hours. It was then cooled and filtered through Celite with ethanol and methylene chloride. The filtrate was evaporated, taken up in ethyl acetate and aqueous sodium bicarbonate solution, and the organic layer separated, washed with brine, dried over sodium sulfate, and evaporated to afford 734 mg (77%) of an oil.
1H-NMR (δ, CDCI3): 1.80 (m, 4H), 2.20 (s, 6H), 2.69 (m, 1H)?2.78 (m, 2H), 3.23 (m,
2H), 3.68 (bs, 1H), 5.92 (s, 2H), 7.10 (d, J=8, 1H), 7.32 (m, 2H), 7.71 (d, J=8, 1H), 7.84 (t, J=8, 1H), 8.01 (m, 2H).
13C-NMR (δ, CDCI3): 13.5, 33.7, 42.5, 46.7, 106.9, 118.1, 119.6, 127.2, 128.5, 128.7, 15 136.4,138.5,147.7,151.7,156.8.
MS (%): 332 (parent+1,100).
D. 6-f4-(Piperidin-4-vl)-phenvn-Pvridin-2-ylarnine
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 100 mg (0.302 mmol) 4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 10 mL ethanol, 1 mL water, and 417 mg (6.04 mmol) hydroxylamine hydrochloride. The reaction was refluxed 20 hours cooled, and poured into dilute aqueous hydrochloric acid, then washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (77 mg, 100%) was converted to the hydrochloride salt using HCI in, ether to afford a tan solid, 32 mg (32%), mp dec. above 150°C.
1H-NMR (δ, CDCI3): 1.63 (m, 2H), 1.80 (m, 2H), 2.60 (m, 1H), 2.68 (m, 2H), 3.14 (m,
2H), 4.68 (bs, 2H), 6.36 (d, J=8, 1H), 6.97 (d, J=7.5, 1H), 7.22 (m, 2H), 7.41 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCI3): 34.1, 42.5, 46.8, 106.9, 110.5, 126.9, 128.3, 137.6, 138.2, 147.0,
155.9, 158.3.
MS (%): 254 (parent+1,100).
EXAMPLE 14
AP/P/ 9 7/01 156
6-f3-(2-(N-Cvclohexvlamino)-cvclopentvlmethvD-phenvn-pyridin-2-vlamine 35 Prepared as in Example 11, using cyclohexylamine, to afford a 76% yield of the less polar isomer after separation of isomers, assigned the cis stereochemistry, as the hydrochloride salt, mp 198-205°C.
' 1H-NMR (δ, CDCI3): 1.0-1.9 (m, 16H), 2.21 (m, 1H), 2.34 (m, 1H), 2.45 (m, 1H), 2.82 (dd, J=5,13, 1H, assigned cis stereochemistry), 3.21 (m, 1H), 4.52 (broad s, 2H, Nth), 6-40 (d,
J=8,1H), 7.04 (d, J=8,1H), 7.23 (m, 2H), 7.45 (t, J=8,1H), 7.81 (m, 2H).
APOΟ Ο 8 A 8
-365 13C-NMR (δ, CDCI3): 20.6, 25.2, 26.1, 28.3, 31.1, 33.9, 34.1, 43.8, 54.9, 58.3, 106.7,
110.6, 126.6, 129.1, 137.0, 138.2, 142.7, 156.2, 158.1.
MS (%): 350 (parent+1, 100).
Anal. Calc’d. for C23H31N32HCIH2O: C 62.72, H 8.01, N 9.54. Found: C 62.66, H 8.12,
N 8.83.
EXAMPLE 15
Vs?
6-[3-(2-(N-Cvclohexvlamino)-cvclooentylmethyl)-phenyn-pyridin-2-vlamine
Prepared as in Example 11, using cyclohexylamine, to afford a 85% yield of the more polar isomer after separation of isomers, assigned the trans stereochemistry, as the hydrochloride salt, mp 175-185°C.
1H-NMR (δ, CDCb): 0.9-1.4 (m, 6H), 1.5-2.0 (m, 11H), 2.33 (m, 1H), 2.52 (dd, J=8.5,13, 1H assigned trans stereochemistry), 2.81 (m, 2H), 4.56 (broad s, 2H, NH?). 6.38 (d, J=8, 1H), 7.02 (d, J=8, 1H), 7.21 (m, 2H), 7.43 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCb): 22.5, 25.1, 25.2, 26.0, 30.7, 33.3, 33.6, 34.5, 40.3, 48.0, 55.2, 20 61.6, 106.7, 110.6, 126.6, 129.1, 137.2, 138.2, 141.9, 156.1, 158.2.
MS (%): 350 (parent+1, 100).
Anal. Calc’d for C23H3nN32HCI 3/2H2O: C 61.46, H 8.07, N 9.35. Found: C 61.78, H 8.01, N 9.12.
EXAMPLE 16 25
6-f3-(2-(N-Phenethvlamtno)-cyclopentvlmethyl)-phenvn-pvridin-2-yiamine
Prepared as in Example 11, using phenethyiamine, to afford a 85% yield of the less polar isomer after separation of isomers, assigned the cis stereochemistry, as the hydrochloride salt, mp 170-185°C.
1H-NMR (δ, CDCb): 1.52 (m, 6H), 1.75 (m, 2H), 2.20 (m, 1H), 2.36 (dd, J=10,13, 1H),
2.7-3.0 (m, 4H), 4.53 (broad s, 2H, Nli), 6.41 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.14 (m, 2H), 7.27.3 (m, 5H), 7.46 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCI3): 21.2, 28.9, 30.7, 34.2, 36.7, 44.6, 49.9, 61.7, 106.9, 110.8, 126.3,
126.8, 128.6, 128.9, 139.1, 137.3, 138.4, 140.4, 142.7, 156.3,158.3.
MS (%): 372 (parent+1,100).
Anal. Calc’d for CzsHjgNs ZHCI 5/3H2O: C 63.29, H 7.29, N 8.86. Found: C 63.31, H 7.35, N 8.66.
EXAMPLE 17
AP/P/ 9 7/01 156
6-[3-(2-(N-Phenethylamino)-cvclopentvlroethyl)-phenvlbPYridin-2-vlamine
AP Ο Ο Ο 8 4 8
-375 Prepared as in Example 11, using phenethylamine, to afford a 85% yield of the more polar isomer after separation of isomers, assigned the trans stereochemistry, as the hydrochloride salt, mp 110-130°C.
1H-NMR (δ, CDCb): 1.29 (m, 2H), 1.40 (m, 1H), 1.59 (m, 2H), 1.75 (m, 1H), 1.93 (m, 2H), 2.51 (dd, J=8.5,13,1H), 2.6-2.8 (m, 5H), 4.55 (broad s, 2H, Nth), 6.40 (d, J=8, 1H), 7.05 (d,
J=8, 1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.81 (m, 2H).
13C-NMR (δ, CDCIs): 22.5, 30.8, 32.6, 36.4, 40.3, 47.6, 49.70, 64.5, 106.8, 110.6, 126.0,
126.6, 128.3, 128.6, 129.0, 137.25, 138.2, 140.0, 141.8, 156.0, 158.2.
MS (%): 372 (parent+1, 100).
Anal. Calc’d for C25H29N32HCI3/2H2O: C 63.69, H 7.27, N 8.91. Found: C 63.80, H 15 7.41, N 8.53.
EXAMPLE 18
6-f3-(2-(4-MethYlpiberazin-1-yl)-cyclohexvlmethvl)-phenvn-pyridin-2-vlamine Prepared as in Example 11, using N-methylpiperazine, to afford a 96% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 195-208°C.
1H-NMR (δ, CDCIs): 1.1-1.6 (m, 8H), 1.8-1.9 (m, 3H), 2.27 (s, 3H), 2.4-2.7 (m, 8H), 2.90 (m, 1H), 4.53 (broad s, 2H, Nth), 6.40 (d, J=8,1H), 7.02 (d, J=8, 1H), 7.18 (m, 2H), 7.45 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCIs): 13.8, 24.5, 25.7, 26.9, 30.5, 37.2, 45.9, 50.1, 55.5, 65.8, 106.7, 25 110.6, 126.6, 129.1, 137.0, 138.2, 143.1, 156.2, 158.i.
MS (%): 365 (parent+1,100).
Anal. Calc’d for C23H32N4 3HCI 5/2H202/3(C4H1oO): C 57.26, H 8.11, N 10.41. Found: C 57.15, H 7.81, N 10.11.
EXAMPLE 19 30
6-f3-(2-(N-benzylamino)-cyclohexylmethyl)-phenvn-pyridin-2-ylamine
Prepared as in Example 11, using benzylamine, to afford a 72% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 170-185°C.
1H-NMR (δ, CDCIs): 1.3-1.4 (m, 4H), 1.6-1.8 (m, 4H), 2.57 (dd, J=9,13, 2H), 2.73 (m,
1H), 2.84 (m, 1H), 3.77 (dd, J=9,38, 2H), 4.58 (broad s, 2H, Nth). 6.40 (d, J=8, 1H), 7.05 (d,
J=8, 1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).
13C-NMR (δ, CDCIs): 25.2, 25.6, 27.0, 28.6, 39.0, 50.8, 51.3, 56.1, 60.1, 106.7, 110.6, 126.5* 126.6, 128.1, 128.3,129.5,137.1, 138.3, 141.2, 141.9, 142.5, 156.2,158.2.
MS (%): 372 (parent+1,100).
Anal. Calc’d for C25H29NS2HCI 3/2H2O: C 63.69, H 7.27, N 8.91. Found: C 64.03, H 7.25, N 8.90.
ΑΡ/Γ7 9 7/01 156
AP ο ο Ο 8 4 8
-38EXAMPLE 20
6-(4-f2-(2-EthoxY-ethylamino)-cvclohexylmethvH-phenvl}-pyridin-2-ylaroine Prepared as in Example 11, using 2-ethoxyethylamine, to afford a 100% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 70-90°C.
1H-NMR (δ, CDCI3): 1.21 (t, J=8, 3H), 1.2-1.7 (m, 8H), 2.5-2.9 (multiplets, 3H), 3.4-3.6 (m, 7H), 4.54 (broad s, 2H, Nth), 6.39 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.22 (m, 2H), 7.44 (t, J=8, 1H), 7.80 (m, 2H).
13C-NMR (δ, CDCb): 15.2, 26.9, 28.7, 30.4, 32.2, 46.2, 46.8, 57.0, 60.5, 66.25, 70.1,
106.7, 110.6, 126.5, 129.3, 167.0, 138.2, 141.6, 142.4, 156.2, 158.2.
MS (%): 354 (parent+1, 100).
Anal. Calc’d for C22H31N3O2HCI 9H2O: C 44.90, H 8.73, N 7.14. Found: C 44.69, H 8.82, N 6.82.
EXAMPLE 21
20 6-r4-(2-(4-Benzvlpjperazin-1-vl)-cyclohexylmethyl)-phenvl1-pvridin-2-Ylamine
Prepared as in Example 11, using N-benzylpiperazine, to afford a 67% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 205-215°C.
1H-NMR (δ, CDCb): 1.0-1.8 (m, 8H), 1.8-1.9 (m, 3H), 2.4-2.6 (m, 8H), 2.02 (m, 1H),
3.51 (singlets, 2H), 4.53 (bs, 2H, Nth), 6.40 (d, J=8,1H), 7.03 (d. J=7, 1H), 7.1-7.3 (m, 7H), 7.45 25 (t, J=7.5, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCb): 19.8, 24.5, 25.7, 26.9, 30.5, 37.2, 50.1, 53.0, 53.5, 63.1, 65.9,
106.7, 110.6, 126.6, 126.9, 128.1, 129.1, 129.2, 137.0, 138.0,138.2, 143.1, 156.2, 158.1.
MS (%): 441 (parent+1,100).
Anal. Calc’d for C^F^Nx 3HCI 3/2H2O: C 60.36, H 7.34, N 9.71. Found: C 60.53, H 30 7.35, N 8.97.
EXAMPLE 22
AP/P/ 9 7/01 156
6-[4-(2-(4-(N-lsopropvlacetamido)piDerazin-1-yl)-cyclohexvlmethvl)-ohenvll-pvridin-2ylamine
Prepared as in Example 11, using N-(N-isopropylacetamido)piperazine, to afford a 94% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 180-200°C (dec.).
’ 1H-NMR (δ, CDCb): 1.147 and 1.148 (doublets, J=6, 6H), 1.2-1.8 (m, 11H), 2.6 (broad m, 8H), 2.95 (s, 2H), 4.088 and 4.092 (heptets, J=6,1H), 4.53 (broad s, 2H, Nth), 6.40 (d, J=8,
1H), 7.02 (d,J=8,1H), 7.17 (m,2H), 7.45 (t,J=8,1H), 7.79 (m,2H).
ΑΡΟ Ο Ο 8 4 8
-395 13C-NMR (δ, CDCI3): 22.75, 24.5, 25.7,26.1, 30.6, 60.5, 50.2, 53.8, 61.5, 65.8, 106.7,
110.6, 126.6, 129.1, 137.0, 138.2, 143.0, 156.1, 158.2, 169.2.
MS (%): 450 (parent+1, 100).
Anal. Calc’d forC27H39N50 3HCH/2H20 (C4H1oO): C 57.98, H 8.32, N 10.91. Found: C 57.77, H 7.90, N 10.85.
EXAMPLE 23
6-f4-((2-(PhenethvD-i2.2.nbicvclohept-1-vl)methvl)-phenvl]-pyridin-2-vlamine
Prepared as in Example 11, using N-phenethylamine, to afford a 73% yield of the product assigned the trans stereochemistry, mp 195-204°C (dec.).
1H-NMR (δ, CDCI3): 1.2-1.4 (m, 4H), 1.58 (m, 2H), 1.94 (broad s, 1H), 2.27 (m, 1H),
2.33 (broad s, 1H), 2.4904 (dd, J=10,14, 2H), 2.7-2.8 (m, 4H), 3.10 (dd, J=4,11, 1H, assigned trans stereochemistry), 4.54 (bs, 2H, NHz), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.2-7.3 (m, 5H), 7.27 (m, 2H), 7.46 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCI3): 20.3, 22.4, 31.7, 36.6, 37.3, 39.9, 40.7, 43.3, 50.1, 59.3, 106.8,
110.7, 126.1, 126.7, 128.4, 128.7, 128.9, 137.1, 138.3, 140.4, 142.8, 156.2, 158.2.
MS (%): 398 (parent+1, 100).
Anal. Calc’d for C27H31N32HCIH2O: C 66.39, H 7.22, N 8.60. Found: C 66.00, H 7.22,
N 8.60.
EXAMPLE 24
6-f4-((2-(3-aza-bicvclof3.1.01hex-6-ylamino)-f2.2.nbicvclohept-1-vDmethvl)-phenvnpyridin-2-vlamine
Prepared as in Example 11, using 3-aza-bicycloI3.1.0]hex-6-yIamine, to afford a 78% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 248-260°C (dec.).
1H-NMR (δ, CDCI3): 1.04 (broad d, J=9, 2H), 1.29 (m, 4H), 1.53 (m, 2H), 1.59 (broad s, 1H), 1.89 (broad s, 1H), 2.12 (m, 1H), 2.21 (ddd, J=3,14, 24, 2H), 2.48 (broad s, 1H), 2.78 (dd, J=4,13,1H assigned trans stereochemistry), 3.02 (m, 4H), 4.55 (broad s, 2K, NH?). 6.39 (d, J=8, 1H), 7.02 (d, J=7.5,1H), 7.19 (m, 2H), 7.44 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCI3): 22.4, 25.5, 25.6, 27.35, 32.5, 36.3, 36.8, 38.3, 41.3, 49.5, 52.6,
53.6, 106.8, 110.6, 126.7, 128.9, 137.1,138.3, 142.5, 156.2, 158.3.
MS (%): 375 (parent+1,100).
Anal. Calc’d for ^Η^^ΗΰΙΊ/ΣΗζΟΊ/Σ^Η^Ο): C 58.92, H 7.42, N 10.57. Found: C 59.02, H 7.50, N 10.64.
•AP/P/ 9 7/01 156
000848
-40EXAMPLE 25
6-f2-(N-Phenethvlamino)-5-phenvl-cvclohexvlmethYl)methvl)-phenvn-pvridin-2-vlamine
Prepared as in Example 11, using N-phenethylamine, to afford a 77.5% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 178-192°C (dec.).
1H-NMR (δ, CDCI3): 1.2-1.5 (m, 6H), 2.2-2.5 (m, 3H), 2.84 (m, 4H), 3.03 (m, 1H), 3.13 (m, 1H), 4.49 (broad s, 2H, Nfch), 6.41 (d, J=8, 1H), 7.02 (d, J=7.5 (1H), 7.2-7.4 (m, 12H), 7.46 (t, J=8, 1H), 7.74 (m, 2H).
13C-NMR (δ, CDCb): 32.6, 33.0, 36.7, 338.7, 38.8, 43.8, 44.7, 48.1, 60.4, 106.8, 110.8,
125.9, 126.3, 126.6, 126.8, 128.3, 128.5, 128.8, 129.6, 137.3, 138.3, 140.1, 141.0, 146.8, 156.2T
158.2.
MS (%): 462 (parent+1, 100).
Anal. Calc’d for C3?H35N3 2HCH/2CH2Cb (C<,H10O): C 66.41, H 7.48, N 6.37. Found: C 66.42, H 7.29, N 6.17.
EXAMPLE 26
6-f4-((2-(Phenethvl)-f2.2.nbicvclohept-1-yl)methyl)-phenvn-pvridin-2-ylamine Prepared as in Example 11, using N-phenethylamine, to afford a 96% yield of the product assigned the cis stereochemistry, mp 170-180°C (dec.).
1H-NMR (δ, CDCb): 1.08 (m, 1H), 1.15 (m, 1H), 1.2-1.4 (m, 4H),1.57 (m, 2H), 1.68 (m,
1H), 2.0-2.2 (m, 2H), 2.61 (m, 1H). 2.69 (m, 4H), 2.77 (m, 1H), 4.50 (broad s, 2H, Nfch), 6.42 (d,
J=8, 1H), 7.05 (d, J=8, 1H), 7.12 (m, 2H), 7.22 (m, 5H). 7.47 (t, J=8, 1H), 7.81 (m 2H).
13C-NMR (δ, CDCb): 22.1, 27.4, 36.4, 36.6, 37.1, 39.0, 41.7, 49.7, 52.5, 68.5, 106.8,
110.7, 126.0, 126.7, 128.4,128.6, 128.9,137.3, 138.3, 140.1,142.3, 156.1,158.2.
MS (%): 398 (parent+1,100).
Anal. Calc’d for CzyHaiN^HCI H2O1/2(C4Hi0O): C 66.28, H 7.67, N 8.00. Found: C
66.57, H 7.41, N 7.64.
EXAMPLE 27
64((2-(3-aza-biCYClof3.1.01hex-6-vlamino)-5-phenvl-cvclohexvlmethyl)methvD-phenvll35 Pvridin-2-ylamine
Prepared as in Example 11, using 3-aza-bicyclo[3.1.0]hex-6-ylamino, to afford a 56% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 200-220°C (dec.).
1H-NMR (δ, CDCI3): 1.2-3.2 (multiplets for 18H), 4.53 and 4.58 (broad singlets, 2H, 40 Nfch), 6.40 and 6.44 (doublets, J=8, 1H), 7.02 and 7.05 (doublets, J=7.5, 1H), 7.16 (m, 2H), 7.25 (m, 5H), 7.40 and 7.45 (triplets, J=8,1H), 7.89 and 7.87 (multiplets, 2H).
• AP/P' 9 7/01 156
APO Ο Ο 8 4 8
-415 13C-NMR (δ, CDCI3): 25.3, 26.1, 30.9, 32.9, 34.6, 37.1, 39.9, 53.0, 64.9, 66.5, 106.8,
107.2, 110.8, 110.9, 125.9, 126.8, 127.0, 127.1, 128.3, 129.2, 138.4, 138.5, 156.2, 158.2.
MS (%): 439 (parent+1, 100).
EXAMPLE 28
N-Methvl-(2-aminopvrid-6-yl-benzylidene)-oxindole
Prepared as in Example 11, using N-methyioxindoie, to afford a 100% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 170-175°C (dec.).
1H-NMR (δ, CDCIs): 3.26 (s, 3H), 4.60 (broad s, 2H, Νϋ), 6.47 (d, J=8, 1H), 6.80 (d, J=8, 1H), 6.86 (t, J=8, 1H), 7.12 (d, J=8, 1H), 7.24 (m, 1H), 7.50 (t, J=8, 1H), 7.70 (m, 2H), 7.85 (s, 1H), 8.02 (m, 2H).
13C-NMR (δ, CDCI3): 26.1, 107.7, 108.1, 110.9, 121.1, 121.7, 122..8 126.8, 127.1,
129.7, 132.3, 135.0, 136.7, 138.4, 140.6, 144.1, 154.9, 158.3, 168.45.
MS (%): 328 (parent+1,100).
Anal. Calc’d for C2iH17N3O1/4H2O: C 76.00, H 5.31, N 12.66. Found: C 75.93, H 5.30, 20 N 11.87.
EXAMPLE 29
N-Methyl-(2-aminopvrid-6-vl-berizYl)-oxindole
Prepared by reduction of Example 28, to afford a 60% yield of the product as a mixture 25 of diastereomers as the hydrochloride salt, mp 45-55°C (dec.).
1H-NMR (δ, CDCb): 2.91 (dd, J=10,14, 1H), 3.14 (s, 3H), 3.52 (dd, J=4,14, 1H), 3.73 (m, 1H), 4.53 (broad s, 2H, Nth), 6.42 (d, J=8, 1H), 6.725 (d, J=8, 1H), 6.80 (m 1H), 6.88 (t, J=7.5,1H), 7.05 (d, J=8,1H), 7.21 (m, 3H), 7.46 (t, J=7.5,1H), 7.81 (m, 2H).
13C-NMR (δ, CDCfe): 26.1, 36.5, 47.0, 107.0, 107.9, 110.7, 122.1, 124.6, 126.7, 127.9, 30 129.6, 138.0, 138.3, 138.5, 144.2, 155.7, 158.3, 177.0.
MS (%): 330 (parent+1,100).
EXAMPLE 30 • AP/P/ 9 7/01 156
N-(2-Dimethvlaminoethvl)-(2-aminopvrid-6-vl-benzvlidene)-oxindole 35 Prepared as in Example 28, using N-(2-dimethylaminoethyl)oxindole, to afford a 91% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp 165-190°C (dec.).
1H-NMR (δ, CDCI3): 2.33 (s, 6H), 2.59 (t, J=7, 2H), 3.90 (t, J=7, 2H), 4.55 (broad s, 2H, Nth), 6.48 (d, J=8, 1H), 6.85 (m, 2H), 7.14 (d, J=7^*1T^^24Rfnr2W)R^MVJ=8, 1H), 7.71 (m, 2H), 7.85 (s, 1H), 8.02 (m. 2H).
&GGRW O PATENTS X ' .'I? ϊ' RE MARKS
DEC 1937
?. ROVCY'77
-425 13C-NMR (δ, CDCI3): 37.6, 45.1, 55.6, 107.0, 107.7, 110.4, 121.1, 122.4, 125.9, 126.2,
129.1, 131.7, 136.3, 137.8, 157.6. Not all carbons were visible in this scan due to limited compound solubility.
MS (%): 385 (parent+1, 100).
Anal. Calc’d for C24H24N4O2HCI H2O: C 60.63, H 5.94, N 11.78. Found: C 60.61, H
6.13, N 10.12.
EXAMPLE 31
N-(2-Dimethvlaminoethvl)-(2-aminopyrid-6-vl-benzyl)-oxindole
Prepared by reduction of Example30 using palladium-catalyzed ammonium formate, to 15 afford a 97% yield of the product as a mixture of diastereomers as the hydrochloride salt, mp
120-135°C (dec.).
1H-NMR (δ, CDCI3): 2.25 (s, 6H), 2.39 9m, 2H), 2.95 (dd, J=9,14,1H), 3.48 (dd, J=4,14, 1H), 3.7-3.9 (m, 3H), 4.47 (broad s, 2H, NH2), 6.42 (d, J=8, 1H), 7.76 (d, J=8, 1H), 6.84 (m, 1H), 6.89 (t, J=7, 1H), 7.05 (d, J=7.5, 1H), 7.18 (m, 2H), 7.25 (m, 1H), 7.46 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCI3): 36.5, 38.2, 45.6, 46.9, 55.9, 107.0, 108.1, 110.7, 122.0, 124.7,
126.6, 127.9, 128.4, 129.7, 130.9, 138.0, 138.3, 143.5, 155.8, 158.2, 176.8.
MS (%): 387 (parent+1, 100).
EXAMPLE 32
6-f(N-5-ls0xazolvlmethvl)-4-(pi peridin-4-vt)-phenvn-pvridin-2-vlamine
Prepared from Example 13, using 5-bromomethylisoxazole to alkylate 6-[4-(piperidin-4yl)-phenyl]-pyridin-2-ylamine, in ethyl acetate, in 90%, mp 122-127°C.
1H-NMR (δ, CDCI3): 1.81 (m, 4H), 2.18 (m, 2H), 2.485 (m, 1H), 3.00 (m, 2H), 3.735 (s,
2H), 4.57 (broad s, 2H, Nth), 6.17 (d, J=1.5, 1H), 6.38 (d, J=8, 1H), 7.01 (d, J=8, 1H), 7.24 (m, 30 2H), 7.43 (t, J=8, 1H), 7.81 (m, 2H), 8.18 (d, J=1.7, 1H).
13C-NMR (δ, CDCI3): 33.2, 41.8, 53.4, 53.9, 102.4, 106.8, 110.6, 126.8, 126.9, 137.7,
138.2, 146.4, 150.1, 155.9, 158.2, 168.9.
MS (%): 335 (parent+1,100).
Anal. Calc’d for CjoH^O 1/4(C4H8O2): C 70.76, H 6.79, N 15.72. Found: C 70.83, H 35 6.62, N 15.73.
AP/P/ 9 7/01 156
AP Ο Ο Ο 8 4 8
-43EXAMPLE 33
6-f(N-Acetamido)-4-(piperidin-4-vl)-phenvn-Dvridin-2-vlamine
Prepared from Example 13, using iodoacetamide to alkylate 6-[4-(piperidin-4-yl)phenyl]-pyridin-2-ylamine, in 55%, mp224-227°C.
1H-NMR (δ, DMSO-de): 1.76 (m, 2H), 2.17 (m, 1H), 2.51 (m, 2H), 2.88 (s, 2H), 2.91 (m,
4H), 5.94 (d, J=4.5, 1H), 6.39 (d, J=8, 1H), 7.01 (d, J=7, 1H), 7.19 (m, 1H), 7.30 (m, 2H), 7.44 (t, J=8, 1H), 7.90 (m, 2H).
13C-NMR (δ, DMSO-de): 33.0, 41.1, 54.0, 61.7, 106.7, 108.0, 126.3, 126.8, 137.3, 137.9,146.5,154.3,159.4,172.0.
MS (%): 311 (parent+1,100).
Anal. Calc'd for Ο^Ηζ^ΟΊ/ΣΗζΟ: C 67.69, H 7.26, N 17.54. Found: C 67.96, H 7.03, N 17.37.
EXAMPLE 34
6-f(N-Benzovlmethvl)-4-(piperidin-4-vi)-phenvll-Pvridin-2-vlamine
Prepared from Example 13, using phenacyl bromide to alkylate 6-[4-(piperidin-4-yl)phenyl]-pyridin-2-ylamine, in 75%, mp 180-200°C as the hydrochloride salt.
1H-NMR (δ, CDCI3): 1.8-2.0 (m, 4H), 2.27 (m, 2H), 2.55 (m, 1H), 3.12 (m, 2H), 3.85 (s,
2H), 4.57 (broad s, 2H, NH2), 6.40 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.28 (m, 2H), 7.45 (m, 3H), .25 7.55 (t, J=7.5, 1H), 7.83 (m, 2H), 8.01 (m, 2H).
13C-NMR (δ, CDCI3): 33.2, 42.0, 54.6, 64.8, 106.8, 110.6, 126.8, 127.0, 128.1, 128.5,
133.1, 136.1, 137.6, 138.3,146.7, 155.9,158.1, 196.7.
MS (%): 372 (parent+1,100).
Anal. Calc’d for C24H25N3O 2HCI 3/4H2O: C 62.95, H 6.27, N 9.18. Found: C 63.13, H 30 6.38, N 9.07.
EXAMPLE 35
ΑΡ/Γ/ 9 7/01 156
6-f(N-(3.4-Dimethoxvbenzvi))-4-(piperidin-4-vD-phenvn-pyridin-2-vlamine
Prepared from Example 13, using 3,4-dimethoxybenzyl bromide to alkylate 6-[4(piperidin-4-yl)-phenyi]-pyridin-2-ylamine, in 89%, mp 150-165°C as the hydrochloride salt.
1H-NMR (δ, CDCI3): 1.85 (m, 4H), 2.18 (m, 2H), 2.54 (m, 1H), 3.06 (m, 2H), 3.56 (s,
2H), 3.86 (s, 3H), 3.89 (s, 3H), 4.6 (broad s, 2H), 6.40 (d, J=8,1H), 6.82 (m, 2H), 6.95 (m, 1H), 7.02(d, J=7.5, 1H), 7.27 (m, 2H), 7.45 (t, J=8,1H), 7.82 (m, 2H).
13C-NMR (δ, CDCI3): 32.9, 42.2, 53.8, 55.91, 55.935, 60.4, 62.8, 106.9, 1110.7, 110.8,
112.6,121.7,126.9, 127.1,137.7,138.3,146.6, 148.3,156.1,1 of PATENTS
Aa’D 7PADP Ma.F
P* nrr
1997 vi 77 'WZ
AP Ο Ο Ο 8 4 3
-445 MS (%): 404 (parent+1, 100).
Anal. Calc’d for C25H29N3O22HCI7/4H2O: C 59.11, H 6.85, N 8.27. Found: C 59.19, H 6.92, N 8.21.
EXAMPLE 36
6-iYN-(3,4-Methylenedioxvbenzyl))-4-(piperidin-4-vl)-phenvn-pyridin-2-ylamine:
Prepared from Example 13, using 3,4-methylenedioxybenzyl bromide to alkylate 6-(4(piperidin-4-yl)-phenylJ-pyridin-2-y!amine, in 82%, mp 15O-165°C as the hydrochloride salt.
1H-NMR (δ, CDCfe): 1.87 (m, 4H), 2.11 (m, 2H), 2.53 (m, 1H), 3.05 (m, 2H), 3.51 (s,
2H), 5.94 (s, 2H), 6.41 (d, J=8,1H), 6.76 (m, 2H), 6.89 (s, 1H), 7.02 (d, J=7.5,1H), 7.27 (m, 2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H).
13C-NMR (δ, CDCfe):33.0, 42.2, 53.8, 62.8, 100.9, 106.9, 107.9, 109.8, 110.7, 122.6,
126.9, 127.1, 131.4, 137.7, 138.4, 146.7, 147.6, 156.1, 158.3.
MS (%): 388 (parent+1,100).
Anal. Calc’d for C24H25N3O23/2H2O2HCI: C 59.14, H 6.20, N 8.62. Found: C 59.22, H 6.32, N 8.53.
EXAMPLE 37
6-[(N-(2-FurvDmethvB-4-(piperidin-4-vl)-phenvll-pvridin-2-vlamine
Prepared from Example 13, using furfuryl bromide to alkylate 6-[4-(piperidin-4-yl)25 phenyl]-pyridin-2-ylamine, in 100%, mp 75-95°C as the hydrochloride salt.
1H-NMR (δ. CDCfe): 1.8-1.9 (m, 4H), 2.11 (m, 2H), 2.49 (m, 1H), 3.02 (m, 2H), 3.56 (s,
2H), 4.6 (broad s, 2H, NJi), 6.21 (m, 1H), 6.30 (m, 1H), 6.38 (d, J=8, 1H), 7.00 (d, J=7.5, 1H), 7.25 (m, 2H), 7.37 (m, 1H), 7.43 (t, J=7.5,1H). 7.80 (m, 2H).
13C-NMR (δ, CDCfe): 33.1, 42.1, 53.8, 55.0, 136.8 128.8, 110.0, 110.6 126.8, 127.0, 30 137.6, 138.2, 142.1, 146.7, 151.6, 156.0, 158.2.
MS (%): 334 (parent+1,100).
Anal. Calc’d for C21H23N3O2HCI3/4H2O: C 57.60, H 6.56, N 9.60. Found: C 57.66, H 6.69, N 9.47.
EXAMPLE 38 35
N-[4'-(6-Amino-pyridin-2-vl)-biphenvl-4-vlmethvl1-5.e-dimethoxv-1.2.3.4tetrahvdroisoquinoline
Prepared as in Example 2, using 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline for the reductive amination step, with a 88% yield for the final deblocking, mp 205-209’C:
• AP/FV 9 7 / 0 1 1 56
APO Ο Ο 8 4 8
-455 1H-NMR (δ, CDCI3): 2.72 (m, 2H), 2.77 (m, 2H), 3.52 (s, 2H), 3.66 (s, 2H), 3.72 (s, 3H),
3.75 (s, 3H), 3.8 (broad s, 2H), 6.39 (d, J=8, 1H), 6.43 (s, 1H), 6.53 (s, 1H), 6.98 (d, J=7.5, 1H),
7.3-7.4 (m, 3H), 7.5-7.7 (m, 4H), 7.85 (m, 2H).
13C-NMR (δ, CDCI3; 28.2, 50.6, 55.4, 55.8, 62.2, 107.5, 139.5, 110.9, 111.4, 125.9,
126.1, 126.9, 127.0, 127.3, 129.9, 136.7, 138.5, 138.6, 140.9, 147.2, 147.5, 155.5, 158.6.
MS (%): 452 (parent+1, 100).
Anal. Calc'd for C29H29N3O2 1/2H2O: C 75.63, H 6.57, N 9.12. Found: C 75.75, H 6.37,
N 9.20.
EXAMPLE 39
6-f(N-(5-lsothiazolvl)methvl)-4-(piperidin-4-vl)-phenvn-pyridin-2-vlamine
Prepared from Example 13, using 5-isothiazolyl bromide to alkylate 6-[4-(piperidin-4~yI)phenyl}-pyridin-2-ylamine, in 95%, mp 140-145°C.
1H-NMR (5, CDCI3): 1.795 (m, 4H), 2.16 (m, 2H), 2.49 (m, 1H), 3.02 (m, 4H), 3.835 (s,
2H), 6.385 (d, J=8, 1H), 6.96 (d, J=7.5, 1H), 7.06 (s, 1H), 7.24 (m, 2H), 7.42 (t, J=8, 1H), 7.75 20 (m, 2H), 8.35 (s, 1H).
13C-NMR (δ, CDCI3): 33.1, 41.9, 54.1, 55.4, 107.1, 110.75, 122.2, 126.9, 127.0, 1337.6,
138.4, 146.5, 155.9, 157.4, 158.3, 166.6.
MS (%): 351 (parent+1,100).
Anal. Calc’d for CzoH^S I^HzO: C 66.82, H 6.45, N 15.58. Found: C 67.08, H 6.51, 25 N 15.23.
EXAMPLE 40 ‘ AP/P/ 9 7/01 156
6-f(N-(5-Thiazolvl)methvl)-4-(piperidin-4-vi)-phenvn-Pvridin-2-vlamine
Prepared from Example 13, using 5-thiazolyl bromide to alkylate 6-[4-(piperidin-4-yl)30 phenyl]-pyridin-2-ylamine, in 99%, mp 151-154°C.
1H-NMR (δ, CDCI3): 1.81 (m, 4H), 2.145 (m, 2H), 2.50 (m, 1H). 3.00 (m, 2H), 3.77 (s,
2H), 4.57 (broad s, 2H, Nik), 6-39 (d, J=8, 1H), 7.01 (d, J=7, 1H), 7.25 (m, 2H), 7.44 (t, J=8, 1H), 7.70 (s, 1H), 7.81 (m, 2H), 8.74 (s, 1H).
13C-NMR (δ, CDCI3): 33.2, 42.1, 53.8, 54.3, 106.8, 110.6, 126.8, 127.0, 136.4, 137.6, 35 138.3, 141.7, 146.6, 153.3, 156.0, 158.2.
MS (%): 351 (parent+1,100).
Anal. Calc’d for CzoH^S: C 68.54, H 6.33, N 15.99. Found: C 68.21, H 6.49, N
15.63.
^000848
-46EXAMPLE 41
6-f(N-(2-PYridv0methvD-4-(piperidin-4-vl)-phenvn-pyridin-2-yiamine
Prepared from Example 13, using 2-pyridyl bromide to alkylate 6-[4-(piperidin-4-yl)phenyl]-pyridin-2-ylamine, in 97%, mp 180-190°C as the hydrochloride salt.
1H-NMR (δ, CDCb): 1.82 (m, 4H), 2.19 (m, 2H), 2.53 (m, 1H), 3.02 (m, 2H), 3.69 (s,
2H), 4.54 (broad s, 2H, Nfch), 6.38 (d, J=8,1H), 7.02 (d, J=7.5, 1H), 7.14 (m, 1H), 7.26 (m, 2H), 7.43 (m, 2H), 7.64 (t, J=8, 1H), 7.81 (m, 2H), 8.55 (m, 1H).
13C-NMR (δ, CDCb): 33.2, 42.2, 54.4, 64.9, 106.8, 110.6, 121.9, 123.2, 126.8, 127.0,
136.3, 137.6, 138.2, 146.8, 149.1, 156.0, 158.2, 158.7.
MS (%): 345 (parent+1, 100).
Anal. Calc’d for C22H24N42HCI7/4H2O: C 58.86, H 6.62, N 12.48. Found: C 58.99, H 6.66, N 12.24.
EXAMPLE 42
6-[fN-(3-Pvridyl)methvl)-4-(piperidin-4-vi)-phenvn-Pvridin-2-viamine
Prepared from Example 13, using 3-pyridyl bromide to alkylate 6-[4-(piperidin-4-yl)phenyl]-pyridin-2-ylamine, in 86%, mp 202-215°C as the hydrochloride salt.
1H-NMR (δ, CDCIa): 1.81 (m, 4H), 2.10 (m, 2H), 2.51 (m, 1H), 2.96 (m, 2H), 3.53 (s,
2H), 4.625 (broad s, 2H, NH2). 6.38 (d, J=8, 1H), 7.01 (d, J=7.5,1H), 7.24 (m, 3H), 7.43 (t, J=8, 25 1H), 7.69 (m, 1H), 7.82 (m,2H), 8.49 (m,1H), 8.54 (m,1H).
13C-NMR (δ, CDCb): 33.1, 42.1, 54.1, 60.4, 106.8, 110.6, 123.3, 126.8, 127.0, 133.7, 136.8, 137.6, 138.3, 146.6, 148.4, 150.3, 155.9, 158.2.
MS (%): 345 (parent+1,100).
Anal. Calc’d for C22H24N4 3HCI3/2H2O: C 54.95, H 6.29, N 11.65. Found: C 54.93, H 30 6.51, N 11.31.
EXAMPLE 43
AP/P/ 9 7/01 156
6-f(N-(2-lmidazolYl)methvD-4-(piperidin-4-vD-phenvn-pvridin-2-ylamine
Prepared from Example 13, using 2-imidazolyl aldehyde to reductively aminate 6-[435 (piperidin-4-yl)-phenyi}-pyridin-2-ylamine, in 88%, mp 160-163°C.
1H-NMR (δ, CDCI3): 1.81 (m, 4H), 2.28 (m, 2H), 2.54 (m, 1H), 3.00 (m, 2H), 3.75 (broad s, 2H), 6.395 (d, J=8, 1H), 6.94 (m, 1H), 7.00 (d, J=7.5, 1H), 7.20 (m, 2H), 7.43 (t, J=8, 1H), 7.79 (m, 2H).
13C-NMR (δ, CDCb):32.6, 41.6, 54.0, 55.7, 107.0, 110.7, 127.0, 137.9, 138.4, 146.0, 40 155.9, 158.3.
AP Ο Ο Ο 8 4 θ
-475 MS (%): 334 (parent+1, 100).
Anal. Calc’d for C20H23N51/2H2CO3: C 67.56, H 6.64, N 19.22. Found: C 67.48, H 6.89, N 18.91.
EXAMPLE 44
6-f(N-(4-lmidazolvf)methvl)-4-(piperidin-4-vl)-phenyll-pvridin-2-ylamine
Prepared from Example 13, using 4-imidazolyl aldehyde to reductively aminate 6-[4(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 92%, mp >210°C (dec.) as the hydrochloride salt.
1H-NMR (δ, CDCI3): 1.74 (m, 4H), 2.07 (m, 2H), 2.5 (m, 1H), 2.97 (m, 2H), 3.47 (s, 2H),
5.94 (broad s, 2H, NHj), 6.39 (d, J=8, 1H), 6.90 (broad s, 1H), 7.00 (d, J=7.4, 1H), 7.27 (m, 2H), 15 7.42 (t, J=8, 1H), 7.56 (m, 1H), 7.88 (m, 2H).
13C-NMR (δ, CDCb): 32.8, 41.4, 53.3, 54.1, 106.7, 108.0, 126.3, 126.7, 137.3, 137.9,
146.5, 154.3, 159.5.
MS (%): 334 (parent+1,100).
Anal. Calc’d for CzoH^Ns l^hbCCb: C 67.56, H 6.64, N 19.22. Found: C 67.99, H 6.72, 20 N 19.07.
EXAMPLE 45
6-f(N-(4-Pvridvl)methvl)-4-(piperidin-4-vl)-phenvn-Pvridin-2-vlamine
Prepared from Example 13, using 4-pyridine carboxaldehyde to reductively aminate 625 [4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 74%, mp 158-163°C as the hydrochloride salt.
1H-NMR (δ, CDCb): 1.81 (m, 4H), 2.10 (m, 2H), 2.52 (m, 1H), 2.94 (m, 2H), 3.51 (s,
2H), 4.57 (broad s, 2H, ΝΗτ), 6.39 (d, J=8, 1H), 7.02 (d, J=7, 1H), 7.28 (m, 4H), 7.43 (t, J=8, 1H), 7.83 (m, 2H), 8.52 (m, 2H).
13C-NMR (δ, CDCb): 33.4, 42.2, 54.4, 62.1, 106.9, 110.7, 123.9, 126.9, 127.1, 137.7, 30 138.3, 146.7, 148.1, 149.7, 156.0, 158.3.
MS (%): 345 (parent+1,100).
Anal. Calc’d for C22H24N4 5/4H2O: C 72.00, H 7.28, N 15.27. Found: C 72.23, H 6.97, N 15.47.
EXAMPLE 46 35
6-f(N-(2-Furyl)methvl)-4-(pvrrolidin-3-vl)-phenvn-pyridin-2-vlamine
ΑΡ/Γ/ 9 7/01 156
A. Diethvl-4-r2-(2.5-dimethvlpvrrolyl)-6-pyridvnbenzvlidenemalonate To a 125 mL round-bottomed fiask equipped with N2 inlet were added 3.3 g (11.96 ampieuBK fl .9 g (11.96 mmol) 2-(2I5-dimethylpyrroIyl)-6-(4-(4,-formylbiphenyl-4-yl))-pyridine mmol) diethyl malonate, 60 mL benzene, 51 mg (O.q 1 enzoic acid.
APO Ο Ο 8 4 8
-485 The reaction was refluxed overnight, cooled, and poured into water and ethyl acetate. The organic layer was washed with 1N hydrochloric acid, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate to afford the product as a yellow oil, 4.32 g (86.5%).
1H-NMR (δ, CDCh): 1.31 (t, J=7, 3H), 1.34 (t, J=7, 3H), 2.21 (s, 6H), 4.33 (q, J=7, 2H), 10 4.35 (q, J=7, 2H), 5.93 (s, 2H), 7.17 (d, J=8, 1H), 7.55 (m, 2H), 7.77 (m, 2H), 7.87 (t, J=8, 1H),
8.09 (m, 2H).
13C-NMR (δ, CDCIs): 13.5, 14.0, 14.2, 61.7, 61.8, 106.1, 118.5, 120.5, 126.7, 127.2,
128.6, 129.9, 130.1, 133.7, 138.8, 140.2, 141.3, 151.8, 155.6, 164.1, 166.7.
IR (neat, cm.'1): 1727 (C=Q).
,5¾ 15 MS (%): 419 (parent+1,100).
B. Ethvl-3-[2-(2.5-dimethvlpvrrolvl)-6-pyridvllPhenvl-3-cvano-propionate
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 4.32 g (10.33 mmol) diethyl-4-[2-(2,5-dimethylpymolyl)-6-pyridyl]benzylidenemalonate and 100 mL ethanol. To the stirring solution was added a solution of 672 mg (10.33 mmol) potassium cyanide in 2.6 mL water, and the reaction heated at 60°C overnight. The reaction was cooled and quenched with dilute hydrochloric acid, then taken up in ethyl acetate and washed with acid and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluant to afford 3.00 g (78%) of an oil.
1H-NMR (δ, CDCIs): 2.21 (s. 6H), 2.96 (m, 2H). 3.71 (s, 3H), 4.355 (t, J=7, 1H), 5.93 (s,
2H), 7.17 (d, J=8, 1H), 7.47 (m, 2H), 7.74 (d, J=8, 1H), 7.89 (t, J=8, 1H). 8.09 (m, 2H).
| 13C-NMR (δ, CDCIs): 13.5, 32.9, 39.7, 52.4, 107.1, 118.4, 113.75, 120.3, 127.8, 128.6, © 135·4' 138·8· 151·8· 155·8’ 169·5·
IR (neat, cm/1): 2244 (CN), 1739 (C=O).
MS (%): 374 (parent+1,100).
C. 2-(2,5-Dimethvlpvrrolvl)-6-f4-(2-oxo-pvrrolidin-3-vl)-phenvn-pvridine
To a 125 mL round-bottomed flask equipped with condenser and N2 inlet were added
2.84 g (7.61 mmol) ethyl-3-[2-(2,5-dimethylpyrrolyl)-6-pyridyl]phenyl-3-cyano-propionate, 50 mL ethanol, and 1 mL concentrated hydrochloric acid. The solution was heated as 700 mg 10% palladium-on-carbon and 2.4 g (38.07 mmol) ammonium formate were added, and the reaction heated at 80°C for 4.75 hours, with additional catalyst and ammonium formate at 1 hour intervals. The reaction was cooled and filtered through Celite, and the filtrate evaporated. The residue was taken up in ethyl acetate, washed with aqueous sodium hydroxide, dried over sodium sulfate, and evaporated. The residue was taken up in 50 mL dry toluene, treated with 5 mL triethylamine, and heated at reflux for 1 hour. The reaction was then cooled, washed with •AP/F/ 9 7/01 156
ΑΡΟ 0 0 8 4 8
-495 dilute aqueous hydrochloric acid and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford 204.5 mg (8.1%) of an oil.
1H-NMR (δ, CDCI3): 2.21 (s, 6H), 2.64 (AB, J=8.5, 17, Dn=94, 2H), 3.43 (dd, J=7,9, 1H), 3.73 (m, 1H), 3.80 (m, 1H), 5.92 (s, 2H), 7.02 (bs, 1H), 7.13 (d, J=8, 1H), 7.34 (m, 2H), 7.72 (d,
J=8, 1H), 7.86 (t, J=8, 1H), 8.04 (m, 2K).
13C-NMR (δ, CDCI3): 13.5, 38.0, 40.0, 49.5, 107.0, 118.2, 11^9, 127.2, 127.4, 128.7,
137.3, 138.7, 143.5, 151.7, 156.3, 177.8.
IR (neat, cm.·1): 1708 and 1685 (C=O).
MS (%): 332 (parent+1, 100).
D. 2-(2,5-DimethvlpvnOlvl)-6-f4-(pvrrolidin-3-vl)-phenvn-pyridine
To a 125 mL round-bottomed flask equipped with condenser and N2 inlet were added
230 mg (1.73 mmol) aluminum chloride and 8 mL dry tetrahydrofuran. The solution was cooled to 0°C, and 4.04 mL (4.04 mmol) of a 1.0 M solution was lithium aluminum hydride in tetrahydrofuran was added. The reaction was stirred 20 minutes at room temperature, and cooled to -70°C. The reaction was treated with a solution of 191 mg (0.577 mmol) 2-(2,5dimethylpyrrolyl)-6-[4-(pyrrolidin-3-yl)-phenyl]-pyridine in 2 mL dry tetrahydrofuran, and stirred 1 hour at -70°C and 14 hours at room temperature. The reaction was carefully quenched with dilute aqueous hydrochloric acid, then taken up in methylene chloride and aqueous sodium hydroxide solution, and the combined organic layer washed with water, dried over sodium sulfate, and evaporated to afford 145 mg (79%) of an oil.
1H-NMR (δ, CDCI3): 1.90 (m, 1H), 2.21 (s, 6H), 2.27 (m, 1H), 2.89 (dd, J=8,10, 1H), 3.11 (m, 1H), 3.19 (m, 1H), 3.28 (t. J=8, 1H), 3.40 (dd, J=8,10, 1K), 3.5 (bs, 1H), 5.92 (s, 2H),
7.10 (d, J=8, 1H), 7.33 (m, 2H), 7.70 (d, J=8, 1H), 7.83 (t, J=8,1H), 8.00 (m, 2H).
13C-NMR (δ, CDCI3): 13.5, 34.4, 45.3, 47.2, 54.8, 106.9, 118.1, 119.7, 125.5, 127.1,
127.2, 127.4, 127.6, 128.6, 136.5, 138.6, 145.3,151.6,156.6.
MS (%): 318 (parent+1,100).
E. 2-(2.5-DimethvlPvrrolv[)-6-f(N-(2-furyl)methvD-4-(pvrTOlidin-3-vl)-phenvn-pvridine
Prepared using the procedure in Example 43 to carry out the reductive amination with furfural, in 65% yield as an oil.
1H-NMR (δ, CDCI3): 1.92 (m, 1H), 2.21 (s, 6H), 2.36 (m, 1H), 2.59 (t, J=9,1H), 2.78 (m, 1H), 2.97 (m, 1H), 3.18 (t, J=9, 1H), 3.44 (m, 1H), 3.75 (Ab,, J=14, Dn=19, 2H), 5.92 (s, 2H),
6.24 (d, J=3, 1H), 6.32 (dd, J=2,3, 1H), 7.10 (d, J=8, 1H), 7.34 (m, 2H), 7.38 (d, J=2, 1H), 7.70 (d, J=8,1H), 7.83 (t, J=8,1H), 7.99 (m, 2H).
AP/P/ 9 7/01 156
APO Ο Ο 8 4 8
-505 13C-NMR (δ, CDCI3): 13.4, 33.0, 43.1, 51.7, 54.1, 61.4, 106.8, 108.2, 110.1, 118.0,
119.6, 126.9, 127.1, 127.3, 128.7, 130.8, 136.3, 138.5,142.1,146.05, 151.5, 152.0, 156.6.
MS (%): 398 (parent+1, 100).
F. 6-[(N-(2-Furvl)methvl)-4-(PYiT0lidin-3-vl)-phenYn-pvridin-2-Ylamine
Prepared as in Example 11D, in 77% yield, mp 60-70’C as the hydrochloride salt.
1H-NMR (δ, CDCI3): 1.90 (m, 1H), 2.34 (m, 1H), 2.51 (t, J=9, 1H), 2.70 (m, 1H), 2.93 (m, 1H), 3.13 (t, J=9, 1H), 3.65 (m, 1H), 3.69 (Abq, J=14, Dn=21, 2H), 4.55 (bs, 2H, NFfe), 6.19 (d, J=3, 1H), 6.30 (dd, J=2,3, 1H), 6.40 (d, J=8, 1H), 7.02 (d, J=7, 1H), 7.29 (m, 2H), 7.36 (m, 1H), 7.45 (t, J=8, 1H), 7.81 (m, 2H).
13C-NMR (δ, CDCI3): 33.1, 43.1, 52.0, 54.2, 61.75, 106.8, 107.7, 110.0, 110.6, 126.8,
127.1, 127.4, 167.6, 138.3, 141.9, 145.5, 152.6, 155.9, 158.2.
MS (%): 320 (parent+1,100).
Anal. Calc’d for C20H21N3O 2HCI5/3H2O: C 56.88, H 6.28, N 9.95. Found: C 56.67, H 6.11, N 10.15.
EXAMPLE 47 *
6-[iN-(2-Methvl)propvl)-4-(pyiTolidin-3-vD-phenyn-pyridin-2-vlamine
Prepared as in Example 46, using isobutyraldehyde, with a 73% yield in the final deblocking step to afford the product as a solid, mp 55-70°C.
1H-NMR (δ, CDCI3): 0.93 (d, J=6.5, 6H), 1.76 (m, 1H), 1.87 (m, 1H), 2.2-2.4 (m, 3H),
2.49 (dd, J=8,9, 1H), 2.64 (m, 1H), 2.76 (m, 1H), 2.98 (t, J=9, 1H), 3.37 (h, J=7, 1H), 4.56 (bs, 2H, NFh), 6.40 (d, J=8, 1H), 7.03 (d. J=7.5, 1H), 7.32 (m, 2H), 7.45 (t, J=8, 1H), 7.81 (m, 2H).
13C-NMR (5, CDCI3): 21.0, 27.4, 33.2, 43.0, 54.9, 62.4, 64.9,106.8,110.7, 126.8,127.5, 137.5, 138.3, 146.4, 156.0, 158.2.
MS (%): 296 (parent+1.100).
Anal. Calc’d for Ci9H25N3 2HCI2H2O: C 56.43, H 7.73, N 10.39. Found: C 56.13, H 7.52, N 10.40.
AP/?/ 9 7/01 156
EXAMPLE 48 35
8-f4-(6-Amino-pvridin-2-vl)-phenvn-3-isobutvl-3-aza-bicvclof3.2.noctan-8-ol
A. 844-(6-(2,5-DimethvlpvnOlYD-pvridtn-2-vl)-Phenvn-3-benzvl-3-aza-bicyclof3.2.noctan8-ol
To a 125 mL 3-necked round-bottomed flask equipped with septum and N2 inlet were added 1.86 g (5.70 mmol) 6-bromo-2-(2,5-dirnethylpyrrolyl)-pyridine and 40 mL dry
AP000848
-515 tetrahydrofuran. The solution was cooled to -60°C, and 2.73 mL (6.84 mmol) of a 2.5M solution of butyl lithium in hexane was added dropwise and the solution stimed 10 min at -60°C. Then a solution of 1.47 g (6.84 mmol) 3-benyl-3-aza-bicycio[3.2.1]octan-8-one in 15 mL dry tetrahydrofuran was added dropwise, and the reaction stirred at -60°C for 10 minutes, and then at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride solution and taken up in ethyl acetate. The organic layer was separated and washed with more aqueous ammonium chloride solution and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol and methylene chloride to afford 413 mg (16%) of a yellow oil which solidified, mp 58-68°C.
1H-NMR (δ, CDCI3): 1.45 (m, 2H), 1.84 (m, 2H), 2.22 (s, 6H), 2.46 (bs, 2H), 2.66 (m,
2H), 2.92 (m, 2H), 3.64 (s, 2H), 5.94 (s, 2H), 7.14 (d, J=8, 1H), 7.2-7.4 (m, 5H), 7.959 (m, 2H),
7.74 (d, J=8, 1H), 7.865 (t, J=8, 1H), 8.065 (m, 2H).
13C-NMR (δ, CDCI3): 13.5, 25.5, 41.8, 54.0, 61.8, 78.9, 107.0, 118.3, 120.0, 125.9, 126.8, 127.1, 128.2, 128.7, 137.6, 138.6, 151.7, 156.4.
MS (%): 464 (parent+1, 100).
B. 8-f4-(6-(2.5-Dimethvlpyrroivl)-pvridin-2-yl)-phenvn-3-aza-bicvcloi3.2.noctan-8-ol
Prepared as in Example 13C in 73% yield as a solid, mp 185-190°C.
1H-NMR (δ, CDCfe): 1.52 (m, 4H), 2.19 (s, 6H), 2.35 (m, 2H), 2.53 (m, 2H), 3.48 (m,
2H), 5.91 (s, 2H), 7.12 (d, J=8, 1H), 7.55 (m, 2H), 7.72 (d, J=8, 1H), 7.85 (t, J=8, 1H), 8.04 (m,
2H).
13C-NMR (5, CDCl3): 13.5, 24.7, 42.0, 47.1, 78.9, 107.0, 118.3, 119.9, 125.6, 127.1,
128.6, 137.5, 138.6, 147.1, 151.7, 156.4.
MS (%): 374 (parent+1,100).
Anal. Calc’d for C24H27N3O1/4(C4H8O3): C 75.92, H 7.39, N 10.62. Found: C 76.13, H
7.37, N 10.33.
APT/ 9 7/01 156
C. 8-i4-(6-amino-pYridin-2-Yl)-phenvn-3-aza-bicyclof3.2.noctan-8-ol
Prepared as in Example 11D in 84% yield as a solid, mp 108-120°C.
1H-NMR (δ, CDCI3): 1.46 (m, 4H), 2.29 (m, 2H), 2.47 (m, 2H), 3.39 (m, 2H), 4.635 (bs,
2H, NHs), 6.365 (d, J=8,1H), 6.94 (d, J=7.5,1H), 7.41 (t, J=8,1H), 7.44 (m, 2H), 7.75 (m, 2H).
13C-NMR (δ, CDCI3): 24.4, 41.5, 46.7, 78.3, 107.3, 110.8, 125.3, 125.5, 126.9, 138.4,
138.6, 145.8, 155.6, 158.4.
MS (%): 296 (parent+1,100).
HRMS Calc’d for C18H21N3O: 286.1763. Found:
I 'ss®
-525 D, 8-F4-(6-Amino-pvridin-2-vl)-phenvn-3-isobutyl-3-aza-bicycloi3.2.11octan-8-ol
Prepared as in Example 47 in 27% yield, mp 167-200°C.
1H-NMR (δ, CDCI3): 0.90 (d, J=6, 6H), 1.39 (m, 2H), 1.8 (broad m, 3H), 2.2 (broad m,
2H), 2.425 (bs, 2H), 2.64 (m, 2H), 2.83 (m. 2H). 4.51 (bs, 2H, Nth), 6.42 (d, J=8, 1H), 7.04 (d,
J=7.5, 1H), 7.465 (t, J=8, 1H), 7.52 (m, 2H), 7.86 (m, 2H).
13C-NMR (δ, CDCI3): 20.8, 25.15, 25.6, 41.5, 54.4, 65.6, 78.45, 107.4, 111.1, 125.6,
127.0, 138.6, 138.8, 155.7, 158.4.
MS (%): 352 (parent+1,100).
Anal. Calc’d for C22H29N3O2HCIH2O: C 57.64, H 7.26, N 9.17. Found: C 57.60, H 7.34, N 8.84.
EXAMPLE 49
8-r4-(6-Amino-pvridin-2-vl)-phenvi1-3-furan-2-vlmethvl-3-aza-bicyclof3.2.noctan-8-ol
Prepared as in Example 48, using furfural, with a 33% yield in the final deblocking step to afford the product as a solid, mp 187-202°C.
1H-NMR (δ, CDCI3): 1.41 (m, 2H), 1.78 (m, 2H), 2.435 (m, 2H), 2.65 (m, 2H), 3.00 (m,
2H), 3.68 (s, 2H), 4.52 (bs, 2H, NH2), 6.24 (d, J=3, 1H), 6.32'(dd, J=2,3, 1H), 6.415 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.37 (d, J=2,1H), 7.46 (t, J=8, 1H), 7.50 (m, 2H), 7.84 (m, 2H).
13C-NMR (δ, CDCI3): 25.1, 41.5, 53.6, 53.8, 78.5, 107.3, 108.6, 110.1, 111.0, 125.6, 127.0 138.4, 139.0, 141.9, 145.1, 155.6, 158.3.
MS (%): 376 (parent+1,100).
Anal. Calc’d for C23H25N3O22HCIH2O: C 59.23, H 6.27, N 9.01. Found: C 59.17, H I 6.50, N 8.71.
EXAMPLE 50
CO tn
Ps.
U a
8-f4-(6-Amino-pvridin-2-yl)-phenvn-3-benzvl-3-aza-biCYclof3.2.1loctan-8-ol
Prepared as in Example 46, deblocking after step A. to afford the product as a solid, mp
185-200°C (dec.).
1H-NMR (δ, CDCI3): 1.41 (m, 2H), 1.79 (m, 2H), 2.41 (bs, 2H), 2.63 (m, 2H), 2.91 (m, 2H), 3.62 (s, 2H), 4.58 (bs, 2H, NH2), 6.41 (d, J=8, 1H), 7.02 (d, J=7.5, 1H), 7.23 (m, 1H), 7.31 (m, 2H), 7.37 (m, 2H), 7.45 (t, J=8, 1H). 7.51 (m, 2H), 7.83 (m. 2H).
13C-NMR (5, CDCI3): 25.4, 41.7, 54.0, 61.8, 78.7, 107.3, 111.0, 125.6, 126.8, 127.0,
128.2, 128.8, 138.4,138.9, 145.4, 155.7, 158.3.
MS (%): 386 (parent+1,100).
Anal. Calc’d for C25H27N301/4CH2CI21/2(C4H1oO): C 63.34, H 6.73, N 8.13. Found: C 40 63.11, H 6.44, N 8.12.
APO 0 0 8 4 8
Η.,νιιτζ now particularly described and '53' ascertained my/our said invention and in w'nal manner the same is to be perl 01 med
I/we declare that what I/we claim is —
Claims (11)
10 wherein n is zero or one, x is N or CH q is zero, one or two and wherein R3 and R4 are selected, independently, from hydrogen, hydroxy, methyl and methoxy; and G is a group of the formula
NR3R4 (A) (B) wherein n is zero or one;
15 Y is NR3R4, (CrC^alkyl or aralkyl, wherein the aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl moiety is straight or branched and contains from 1 to 6 carbon atoms, and wherein said (CrC6)alkyl and the aryl moiety of said aralkyl may be substituted with from one to thoursee substituents, preferably from zero to two substituents, that are selected, independently, from halo (e.g.. chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano, amino, (CrC4)alkoxy and
20 (CrC4) alkylamino;
X is N when Y is (CKCS) alkyl, aralkyl, or substituted (CrC6)alkyl, and X is CH when Y is
NR3R4;
q is zero, one or two; m is zero, one or two; and
25 R3 and R4 are selected, independently, from (CrC6) alkyl, tetrahydronaphthalene and aralkyl, wherein the aryl moiety of said aralkyl Is phenyl or naphthyl and the alkyl moiety is straight or branched and contains from 1 to 6 carbon atoms, and wherein said (C^Cs) alkyl and said tetrahydronaphthalene and the aryl moiety of said aralkyl may optionally be substituted with from one to thoursee substituents, preferably from zero to two substituents, that are selected,
ART/ 9 7/01 156
APΟ Ο Ο 84 8
5 independently, from halo (e.g.. chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano, amino, (CiCi) alkoxy, and (CpCb) alkylamino;
or R3 and R4 form, together with the nitrogen to which they are attached, a piperazine, piperidine or pymolidine ring or an azabicyclic ring containing from 6 to 14 ring members, from 1 to 3 of which are nitrogen and the rest of which are carbon;
10 or a pharmaceutically acceptable salt of such compound.
2. A compound according to claim 1, wherein q is zero or orie.
3. A compound according to claim 1, wherein NR3R4 is a piperidine, piperazine or pyrrolidine ring or a 3-aza-bicyclo[3.1.0]hex-6-ylamine ring, and wherein said piperazine, piperidine and pyrrolidine rings may optionally be 15 substituted with one or more substituents, preferably with from zero to two substituents, that are selected, independently, from amino, (Ci-C6) alkylamino, [di-(CrC6)alkyl]amino, phenyl substituted 5 to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of any of the foregoing substituents may optionally be
20 substituted with one or more substituents, preferably with from zero to two substituents, that are selected, independently, from halo, ,(Ci-C3)alkyl, (CrC^alkoxy, nitro, amino, cyano, CF3 and OCF3;
and the pharmaceutically acceptable salts of such compounds.
4. A compound according to claim 1 wherein NR3R4 is 4-pheny!ethylpiperazin-1-yl,
25 4-methylpiperazin-1-yl, phenethylamino, or 3-aza-bicyclo[3.1.0]hex-6-ylamine.
5. A compound according to claim 1 wherein NR3R4 is a group of the formula
H
AP/P/ 9 7/01 156 wherein NR5R6 is NH2.
30
6. A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine inflammatory diseases, stroke, acute and choursonic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety,
35 psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine · induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthoursitis, rheumatoid
APO Ο Ο 8 4 8
5 arthoursitis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington’s disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephoursopathy and cancer in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating or preventing such condition and a pharmaceutically acceptable carrier.
10
7. A method of treating or preventing a condition selected from the group consisting of migraine inflammatory diseases, stroke, acute and choursonic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety,
15 psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthoursitis, rheumatoid arthoursitis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson’s disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephoursopathy and cancer in a mammal, comprising administering to said mammal an amount
20 of a compound according to claim 1, that is effective in treating or preventing such condition.
8. A pharmaceutical composition for inhibiting nitric oxide synthase (NOS) in a mammal, according to claim 1, comprising a NOS inhibiting effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.
9. A method of inhibiting NOS in a mammal, comprising administering to said 25 mammal a NOS inhibiting effective amount of a compound according to claim 1.
10. A pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, stroke, acute and choursonic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron
30 toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthoursitis, rheumatoid arthoursitis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington’s disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic
35 nephoursopathy and cancer in a mammal, comprising a NOS inhibiting effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
11. A method of treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases, stroke, acute and choursonic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock,
40 multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, •AP/F/ 9 7/01156
APO Ο Ο 8 4 8
-565 psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthoursitis, rheumatoid arthoursitis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington’s disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephoursopathy and cancer in a mammal, comprising administering to said mammal a NOS
10 inhibiting effective amount of a compound according to claim 1.
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| US3279396P | 1996-12-06 | 1996-12-06 | |
| PCT/IB1997/001446 WO1998024766A1 (en) | 1996-12-06 | 1997-11-17 | 6-phenylpyridyl-2-amine derivatives useful as nos inhibitors |
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| ATE261942T1 (en) * | 1996-03-29 | 2004-04-15 | Pfizer | 6-PHENYLPYRIDINE DERIVATIVES |
| US20010049379A1 (en) | 1997-08-27 | 2001-12-06 | Lowe John Adams | 2-aminopyridines containing fused ring substituents |
| HN1998000118A (en) | 1997-08-27 | 1999-02-09 | Pfizer Prod Inc | 2 - AMINOPYRIDINES CONTAINING SUBSTITUTES FOR CONDENSED RINGS. |
| HN1998000125A (en) * | 1997-08-28 | 1999-02-09 | Pfizer Prod Inc | 2-AMINOPYRIDIDS WITH BRANCHED ALCOXY SUBSTITUTES |
| HRP20000825A2 (en) | 1998-06-03 | 2001-12-31 | Pfizer Prod Inc | 2-aminopyridines containing fused ring substituents as nitric oxide synthase inhibitors |
| FR2780971B1 (en) * | 1998-07-08 | 2001-09-28 | Sod Conseils Rech Applic | NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR APPLICATION AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2791674A1 (en) * | 1999-04-02 | 2000-10-06 | Sod Conseils Rech Applic | NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| AR019190A1 (en) * | 1998-07-08 | 2001-12-26 | Sod Conseils Rech Applic | DERIVATIVES OF 2-AMINOPIRIDINES, INTERMEDIATE PRODUCTS FOR THEIR PREPARATION, DRUGS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE TO PREPARE DRUGS |
| CA2340200A1 (en) * | 1998-08-11 | 2000-02-24 | John Adams Lowe Iii | New pharmaceutical uses for nos inhibitors |
| SE9803710L (en) | 1998-09-25 | 2000-03-26 | A & Science Invest Ab | Use of certain substances for the treatment of nerve root damage |
| US7115557B2 (en) | 1998-09-25 | 2006-10-03 | Sciaticon Ab | Use of certain drugs for treating nerve root injury |
| BR0008569A (en) | 1999-02-25 | 2002-01-22 | Pfizer Prod Inc | 2-aminopyridines containing fused rings as substituents |
| US7008954B1 (en) * | 1999-07-23 | 2006-03-07 | Shionogi & Co., Ltd. | Th2 differentiation inhibitors |
| FR2804429B1 (en) * | 2000-01-31 | 2003-05-09 | Adir | NOVEL 4-SULFONAMIDE PIPERIDINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
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| CN114206843A (en) * | 2019-06-14 | 2022-03-18 | Srx心脏有限责任公司 | Compounds for modulating proprotein convertase subtilisin/Kexin type 9(PCSK9) |
| US12115154B2 (en) * | 2020-12-16 | 2024-10-15 | Srx Cardio, Llc | Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) |
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| WO1992014780A1 (en) | 1991-02-19 | 1992-09-03 | Akzo N.V. | Stabilized carbon monoxide-olefin copolymers |
| WO1994014780A1 (en) * | 1992-12-18 | 1994-07-07 | The Wellcome Foundation Limited | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors |
| US5621004A (en) | 1994-06-03 | 1997-04-15 | Robert W. Dunn | Method for treating emesis |
| WO1996018616A1 (en) * | 1994-12-12 | 1996-06-20 | Merck & Co., Inc. | Substituted 2-aminopyridines as inhibitors of nitric oxide synthase |
| ATE261942T1 (en) * | 1996-03-29 | 2004-04-15 | Pfizer | 6-PHENYLPYRIDINE DERIVATIVES |
| US6093743A (en) | 1998-06-23 | 2000-07-25 | Medinox Inc. | Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor |
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