`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
`LIPOPHILICITY
`
`Backgroud
`
`Crum-Brown and Fraser (1865)
`® = F(c)
`F : physiological activity
`c : chemical constitution
`
`Meyer Overton hypothesis.
`
`Hansch Equations.
`
`log!/C =alogP +b
`
`logi/C = a(logP)2 + blogP +c
`
`logP : Lipophilicity,
`
`P: partition coefficient
`
`PARTITION COEFFICIENT or LIPOPHILICITY
`
`1. Direct mearsurement
`a. solvent system: octanol-water
`b. Temperature
`c. Purity
`
`2. AKUFVE. System
`
`3. Reverse Phase TLC system
`
`Rm = 10g (1/Ry - 1)
`logP = 1logKk +Rm
`
` K: constant from P = K(1/Rr - 1)
`
`4. HPLC
`
`k’ =( ta - to)/to
`logP = logk + log k’
`
`Micro Labs Exhibit 1051-2
`
`Micro Labs Exhibit 1051-2
`
`
`
`CALCULATION of LIPOPHILICITY (partition coefficient)
`
`1. TT - method
`
`HF = logP; = logP,
`
`logP =logPg+ > Tk
`
`2. Hydrophobic Fragmental Constant f
`
`logP = >aif;
`
`: incidence of a given fragment
`aj
`f; : hydrophobic fragmental constant
`
`logP = Daify+e
`
`3. Molecular Connectivity
`
`X = Df
`nX => (8; —5,)172 ,
`
`k-ji=n
`
`6Y = ZY -h
`:
`
`ZY : number of valence electron
`h: number of hydrogen atom attached
`
`Xx © Di
`
`Micro Labs Exhibit 1051-3
`
`Micro Labs Exhibit 1051-3
`
`
`
`REFERENCES
`
`QSAR, HANSCH EQUATIONS
`
`1. S.K.S. Non Research Seminar abstract and references therein
`2.Acc.Chem. Res. 19, 392: (1986)
`
`LIPOPHILICITY
`
`3. Progress in Drug Research 23, 97 (1979)
`
`Tl - SYSTEM
`
`4.
`
`" Substituent Constants for Correlation Analysis in Chemistry
`and Biology” by C. Hansch and A. Leo (1979)
`
`f
`
`5. "The Hydrophobic Fragmental Constant" by R. F. Rekker (1977)
`
`MOLECULAR CONNECTIVITY
`
`6. "Molecular Connectivity in Chemistry and Drug Research" by
`L.B. Kier and L.H. Hall
`
`HPLC : J. Med. Chem. 19, 615 (1976)
`TLC:
`J. Med. Chem. 13, 511 (1970)
`AKUFVE: Chem. and Ind. 488 (1970)
`
`Micro Labs Exhibit 1051-4
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`Micro Labs Exhibit 1051-4
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`
`
`
` :Tasxe 5.1: Narcosis of Mice. |
`
`
`
` P N Con Ps Activity
`
`
`
`
`Nitrous oxide
`14
`100
`0.06
`59300
`0.01
`Acetylene
`1.8
`65.0
`0.05
`$1700
`0.01
`Dimethylether
`11.6
`12.0
`0.06
`6100
`0.02
`Methylchloride
`14.0
`6.5
`0.07
`5900
`0.01
`Ethylene oxide
`31.0
`58
`0.07
`1
`0.02
`Ethy!chloride
`40.5
`5.0
`0.08
`1780
`0.02
`Diethyl ether
`50.0
`3.4
`0.07
`830
`0.03
`
`Metbylal 630=—s«0.0375.0 2.8 0.08
`
`
`
`Ethyl bromide
`95.0
`1.9
`0.07
`725
`0.02
`Dimethy!acetal
`100
`19
`0.06
`288
`0.05
`Diethyl formal
`120
`1.0
`0.05
`110
`0.07
`CHCI=CHCI
`130
`0.95
`0.05
`450
`0.02
`Carbon disulphide
`160
`11
`0.07
`560
`0.02
`
`Chloroform i 265 0.5 0.05 324 0.01
`
`
`
`
`
`
`|
`
`P = partition coefficient (oil:vapour); N = narcotic concentration (volume %);
`Coi1 = concentration (molar) of the substance in olive oil which would be in
`equilibrium with the narcotic concentration; p,= saturated vapour pressure
`(mm Hg) at 37°C; Activity = p,/p, where p,, the partial pressure in the anaesthetic
`mixture is calculated by multiplying the narcotic concentration by atmospheric
`pressure, ¢.g. for diethyl formal p, = 7$5 x 760 mm Hg.
`(From results of Meyer and Hemini, Biochim. Z. (1935), no. 277, p. 54.)
`
`Bazi nning of Soden GSAR,
`TABLE 5.2: Activity of phenoxyacetic acids: C is the concentration
`producing 10% growth of the Avena (grass) samples in the standard
`:
`time; P is the partition coefficient: n is the effect of the substituent
`
`on logP, taking phenoxyacetic acid as standard, and¢is the effect of :
`the substituent on the pK, ofbenzoic acid.
`
`i
`
`;
`
`log 1/C
`log 1/C
`.
`u
`P
`a
`Substituent
`(obs.)
`(calc.)
`fs)
`3-CF,
`0.55
`320
`1.09
`68
`65
`4]
`0.37
`168
`0.80
`63
`64
`31
`0.28
`325
`1.08
`6!
`63
`4F
`0.34
`43
`0.20
`5.0
`63
`3-Br
`0.23
`254
`0.97
`59
`6.0
`3.SF,
`0.68
`1190
`1.64
`62
`6.0
`3-Ch
`0.23
`178
`0.82
`59
`5.7
`3-NO,
`0.78
`29
`0.04
`5.7
`53
`3-SCH,
`—0.05
`105
`0.59
`49
`53
`3-C,H,
`-0.15
`200
`0.87
`49
`53
`3-n-CyH,
`-0.15
`390
`1.52
`42
`47
`3-OCH,
`~0.27
`36
`0.13
`31
`47
`3-CN
`0.63
`16
`-023
`41
`45
`3-CH,
`=0.17
`75
`0.44
`43
`43
`3-CH,CO
`0.52
`2
`—0.08
`45
`40
`3.5
`0.06
`41
`0.18
`42
`35
`H
`0.00
`27
`0.00
`34
`3/5
`3-OH
`—0.36
`5
`~0.73
`-18
`3.7
`3-COOH
`0.27
`21
`—0.13
`Bs
`3.0
`3-n-C,H,
`—0.15
`3100
`2.03
`24
`0.0
`(From results of Hansch, Maloney, Fujita and Muir, Nature (1962), no. 194, p. 178.)
`
`Micro Labs Exhibit 1051-5
`
`Micro Labs Exhibit 1051-5
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`
`
`Table9
`
`
`
`ftBiologicalactivityCompoundsabnrsRef.
`Toxicity,redspidet0.087B33)2Narcosis,Alcohols0.668(+0.09)3.164140.978
`
`
`
`
`
`
`fungusMisc.compounds0.809(+0.04)0.28453.0.9850.174[33]2Hemolysis,Inhibition7.interdigitaleAcids0.757(+0.05)2.431140.9940.133[175]aToxicityvs.Madison517
`
`
`
`
`
`
`
`
`
`
`
`
`
`Narcosis,barnaclelarvaeAlcohols0.976(+0.09)0.584140.9900.14933)3InhibitionS.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`[33]aI100frogheartMisc.compounds0.903(+0.08)0.130330.9740.195[33]Ss(33)%IoarbaciaeggcelldivisionBarbiturates0.801(+0.12)1.076190,9600.171I,9cholinesterase,plasmaAlkylammoniumcompounds0.643(+0.09)—3.40670.9930.08933]=Bloodclothuman
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`[174]©InhibitionS.aureusHydroquinoneInhibitionS.aureusmonoethers0.823(+0.11)—1.02013,0.9820.196[33]3InhibitionS.typhosaAlcohols1.024(+0.06)—1.536150.9960.090[174]=:tadpolesMisc.compounds(£0.07)0.90957096220312[33]ee0.901
`
`
`
`
`
`
`
`
`dissolutionSubst.salicylicacids0.508(+0.06)1.492490.9280.204
`[176]&Hemolysis,erythrocytes[176]5<<bovineAlcoholsandesters0.901(+0.05)—0.238190.9930.096
`
`
`
`
`
`
`
`
`
`
`
`typhosaAlcoholsandketones0.940(+0.04)—0.430120,9980.067
`
`
`
`
`
`Alkylbromophenols(+0.08)—1.25813,0.9910.126[174]<$0.847
`
`
`
`
`
`
`
`rabbiterythrocytesAromaticcompounds1.085(+0.13)—0.430190.9740.133
`
`
`
`
`
`
`
`InhibitionliversuccinateoxidaseMisc.compounds0.80(+0.14)0.12140.9630.190{11]
`
`
`
`
`
`
`
`Bindingtohumanserum’)Penicillins0.550(+0.04)—1.060790.9580.191[29]
`
`
`
`
`
`
`
`
`InhibitionmusclesuccinateoxidaseMisc.compounds0.76(40.12)0.06140.9720.158(11)
`
`
`
`
`
`
`BindingtoBSAMisc.compounds(+0.07){11}0.7512.300420.9600.159
`
`
`
`
`
`
`Bindingtohumanserum?)Penicillins0.49(+0.05)—0.63790.9240.134{11]
`
`
`
`
`
`
`
`
`Linearrelationshipsbetweenbiologicalactivityandpartitioncoefficients,log1/C=alogP+b.
`
`
`
`*)xvaluesusedinsteadoflogPvalues.>)fvalues
`
`
`
`usedinsteadoflogPvalues.
`
`
`aKiatsaetiksiiaiaiclaes2e:cenMDdlicaihsh."alsYoactaPheadaiheanddaseiasavaciageeteadeemeceaamannstvaeaemammetimerPelitaeeSaiatld
`
`
`
`
`é
`
`9<93=#2<<xuwaa©pa°—2=
`
`aa2
`
`Micro Labs Exhibit 1051-6
`
`
`
`
`
`
`
`
`
`
`Adenosinedeaminase9-(1-Hydroxy-2-alkyl)-
`
`
`
`Parabolicrelationships.
`
`
`
`
`
`
`
`Hemolysis,rabbit
`
`
`
`Dihydrofolatereductase
`
`
`
`AntimalarialPhenanthreneamino-
`
`»)2-3optimum.
`
`°)MR-4optimum.
`
`
`
` 2/.lu-2(bePf)bibffiftereccncrenesnmneneeaecaeTmtsoCve¢Table13tennant
`
`
`
`
`
`
`AntileukemicactivityAryl-3,3-dialkyl-triazenes(logP)?,logP,o+,MR-2,6,E-R-1.18610.8360.191[223]-——————————SESESEeeeee
`
`
`
`
`
`Toxicity,mouseEthers(logP)*,logP1.91250,8640.208(34]
`
`
`
`
`
`activityalkylcarbinolsn*,mw,-X,Y,o-X,Y4.421020.9080.263[183,221]
`AntimalarialactivityQuinazolinesn*,x,1-6,1-8-1-102.82600.9060.427[198]
`
`
`
`
`
`
`
`
`
`
`
`AntimalarialactivityMisc.aminoalkylcarbinolsn*,2,1-X,Y,o0-X,Y4.12120.8600.319[183,222]
`
`
`
`
`
`erythrocytes=Benzene(logP)?,logP5.52170.9830.11734,176]derivatives
`
`
`
`
`
`
`Gastricabsorption,ratAcids(logP)?,logP1.9790.9520.129[22]
`
`
`
`
`
`
`
`Anaestheticactivity,mouseEthers(logP)?,logP2.34270,9600.107[34,220]
`
`
`
`
`
`
`
`
`
`Analgesicactivity,mousep-SubstitutedacetanilidesR2,,Ry,0,2813,0.9560.127[108,116]
`
`
`
`
`
`
`
`Hypnosis,mouseN,N’-Diacylureas(logP)?,logP1.6913°0.9180.079[34,216]
`
`
`
`
`
`
`
`Hypnosis,mouseBarbiturates(logP)?,logP1.8013.0.9690.098[216]
`
`
`
`
`
`Hypnosis,(yy,'yTA120.9830.067{5}rabbitBarbiturates
`
`
`
`
`
`
`
`Hemolysis,erythrocytesestersRiRy0.45140.9540.173[108,112]ratTestosterone
`
`
`
`
`
`
`Hypnosis,mouse1,1-Dialkylpropynols(logP)’,logP2.0990.9440.096{(34]
`
`
`
`
`
`
`ChymotrypsininhibitionMisc.compoundsMR2,MR,|-1-1-519.913660.9400.292[218]
`
`
`
`
`
`inhibitionDiaminotriazines(n-3),2-3,MR-43.5830.9050.328[196]
`
`
`
`
`
`
`InhibitionS.hemolyticusPhenols(logP)’,logP9.65320.9830.161[34]
`
`
`
`
`
`
`inhibitionDiaminotriazinesMR-4,I-1-1-64.792440.923.0.377[197,219]
`
`
`
`
`InhibitionS.aureusHalogenatedphenols('x)?,by9.09490.9770.20[149]
`
`
`
`
`
`
`Hypnosis,rabbitBarbiturates(logP),logP1.96100.9510.071(34]
`
`
`
`
`
`
`inhibitionM.smegmatisPhenols(logPy’,logP1,33330.9810.160[34]
`
`
`
`
`
`
`InhibitionC.albicansPhenols(logP)?,logP8.41130,997.0.078(34]
`
`
`
`
`
`
`
`ChymotrypsininhibitionMise.compoundsMR?MR,I-I-I-417.7103.0.9440.290[195]
`
`
`
`
`
`inhibitionadenines(logP)?,logP3.6490.9960.097[34]
`
`
`
`
`BiologicalactivityCompoundsParameters")Optimum=nrsRef.
`
`
`
`
`
`PASEagagr?abePIRFSO9°8B29FS.8BERETEBS2Ver
`FERRERSaC223BoBBee-aGekestkegs
`Dihydrofolatereductase(n-3)%,2-3,(MR-4)?,2.9%
`
`
`
`
`
`
`
`
`
`
`*)Forassignmentexplanationofparametersseeoriginalreferences.and
`
`—PSASFRGUMSFReSYsaao5~3SpBpamQ“So8e058S88S58Boee8s2b8s&BeeSEoEB&woeewseaeSeaegRPBsFseesREELSOSS
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`
`Aytanoe Snip ¢
`
`Micro Labs Exhibit 1051-7
`
`Micro Labs Exhibit 1051-7
`
`
`
`
`Bilinear odek
`
`Log1/C
`
`permission of the copyright owner).
`
`Figure 15
`Irritant activity of
`phorbol-12, 13-diesters, fitted with
`the parabolic model (- - -) [eq. (139)]
`andthe bilinear model (——) [eq.
`(140)]; approximate standard
`deviations are indicated for each
`value (reprinted from [224] with
`
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`
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`Micro Labs Exhibit 1051-8
`
`Micro Labs Exhibit 1051-8
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`
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`Micro Labs Exhibit 1051-9
`
`Micro Labs Exhibit 1051-9
`
`
`
`
`Del CTeH
`
`ru
`
`Lend / AaAnNMS
`
`Substituent/substructure
`Ty
`2.87
`Aromatic-COOH
`Aromatic-OH
`2.60
`—CONH-—
`. 2.56
`—SO,NH-—
`1.93
`Aliphatic-OH
`1.82
`Aliphatic-NH,
`1.33
`Aromatic—NH,
`1.18
`-NR,R,(R,, R,+H)
`0.55
`2
`0.45
`>Cc=0
`0.31
`—C=N
`0.23
`—O=
`0.11
`ortho-Substitution to -OH, —COOH, —-NR R,
`— 0.62
`
`
`Table 3
`
`Hydrophobic fragmental constants fand x valuesofselected substructures and
`
`substituents.
`
`Fragment
`
`Fragmental constants f
`Rekker[6]
`aliph.
`arom.
`
`Leo etal. [62]
`aliph,
`arom.
`
`n benzene
`
`0.175
`0.702
`0.530
`0.235
`0.15
`1.886
`1.688
`1.431
`
`0.23
`0.89
`0.66
`0.43
`0.20
`1.90
`
`H
`CH,
`CH,
`CH
`Cc
`C.H
`C,H,
`C,H,
`0.14
`0.37
`— 0.38
`0.399
`— 0.462
`F
`0.71
`0.94
`0.06
`0.922
`0.061,
`Cl
`0.86
`1.09
`0.20
`1.131
`0.270
`Br
`1.12
`1.35
`0.60
`1.448
`0.587
`I
`— 0.67
`— 0.40
`— 1.64
`— 0.343
`— 1.491
`OH
`—0.57
`— 1.81
`— 0.433
`— 1.581.
`—O-
`— 0.32
`— 0.03
`— 1.09
`— 0.093
`— 0.954
`COOH
`= 1.23
`— 1.00
`— 1.54
`— 0.854
`— 1.428
`NH,
`— 1:03
`—2.11
`— 0.964
`= 11825
`NH
`
`
`
`
`
`NO, —126=-0.02e_ 0.939 ~0.078 — 0.28
`a hy
`CONH, ~*\"¢1
`~1,979
`— 1.109
`—2.18
`— 1.26
`— 1.49
`[A
`>C=0
`— 1.703
`— 0.842
`= 1.90
`— 0.32
`CF,
`0.757
`1.331
`0.88
`C=N
`— 1.066
`— 0.205
`— 1.28
`— 0.34
`— 0.57
`SH
`0.00
`0.62
`0.39
`—-S-
`—0.51
`0.11
`— 0.79
`0.03
`
`Correction factors
`Rekker
`Leo etal.
`
`— 0.12
`Proximity effect |
`f, (chain)
`0.861
`— 0.09
`Proximityeffect 2
`0.574
`f, (cyclic)
`=0.13
`H onelectronegative group
`0.287
`Chain branching
`= 0/22
`Aryl conjugation
`0.28
`Group branching
`Condensed aromatic system
`0.31
`
`
`0.00
`0.56
`
`1.96
`
`Micro Labs Exhibit 1051-10
`
`Micro Labs Exhibit 1051-10
`
`
`
`Molecutir
`
`connec “Purky
`
`L
`
`Table 6
`Heteroatom valence delta values 6° (5, 131, 135].
`
`Group
`o°
`Group
`~°
`5°
`
`—NH,
`3
`~OH
`5
`
`—-NH-
`_N-
`-Ne—
`“NH
`=N-
`>N®=(aitro)
`
`4
`5
`6
`4
`5
`6
`
`=O=
`=0
`~-S-
`oh
`a
`Br
`
`5
`,
`=N
`*) Empirical values, derived from molarrefractivity.
`
`>) Calculated from 6°= an Z=atomic number[131].
`
`I
`
`6
`6
`0.944°)
`3.58*)
`0.690*), 0.70)
`0.2542), 0.25)
`
`0.085), 0.152")
`
`\
`
`|
`
`|
`|
`
`/
`
`Micro Labs Exhibit 1051-11
`
`Micro Labs Exhibit 1051-11
`
`