Micro Labs Exhibit 1051
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`LIPOPHILICITY
`
`Backgroud
`
`Crum—Brown and Fraser (1865)
`
`(I) = F(c)
`
`F : phgsioiogicai activitg
`c : chemical constitution
`
`Meger Overton hgpothesis.
`
`Hansch Equations.
`
`iogi/C = a iogP + b
`
`iogi/C = a(iogP)2 + biogP + c
`
`iogP : Lipophiiicitg,
`
`P: partition coefficient
`
`PARTITION COEFFICIENT or LIPOPHILICITY
`
`1. Direct mearsurement
`
`a. solvent system: "octanoi—water
`b. Temperature
`
`c. Purity
`
`2. AKUFVESgstem
`
`3. Reverse Phase TLC system
`
`Rm=log(I/Rf- i)’
`iogP=iogK+Rm K: constant from P=K(1/Rf— 1)
`
`4. HPLC
`
`k’ = ( tR — tO)/t0
`
`iogP = 109K + iog_i_<'
`
`Micro Labs Exhibit 1051-2
`
`Micro Labs Exhibit 1051-2
`
`

`

`CALCULATION of LIPOPHILICITY (partitiion coefficient)
`
`1. ii — method
`
`”I" = iOgPi ‘ iOgPo
`
`iogP = iogPo + 2 iii
`
`2. Hgdrophobic Fragmentai Constant f
`
`iogP = gain
`
`a,-
`f]-
`
`: incidence of a given fragment
`: hgdrophobic fragmentai constant
`
`iogP = Zaifi + c
`
`3. Moiecuiar Conneétivitg
`
`X“Zfi
`
`nxzzhgi .....59172,
`
`k-i=n
`
`8" = ZV — h
`
`ZV : number of valence electron
`
`‘
`
`h: number of hgdrogen atom attached
`
`:“X °‘ :71
`
`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)
`
`LIP OPHILICITY
`
`3. Progress in Drug Research 23, 97 (1979)
`
`U - 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 LE. 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
`
`Micro Labs Exhibit 1051-4
`
`

`

`Earl/V ex/W'ouen'ts.
`TABLE 5.1 : Narcosis of Mice.
`
`
`
`
`
`
`
`
`
` P N coil [1, ACthity
`
`Micro Labs Exhibit 1051-5
`
`0.01
`59300
`0.06
`100
`1.4
`Nitrous oxide
`0.01
`51700
`0.05
`65.0
`1.8
`Acetylene
`0.02
`6100
`0.06
`12.0
`1 1.6
`Dimethylether
`0.01
`5900
`0.07
`6.5
`14.0
`Methylchloride
`0.02
`1
`0.07
`5.8
`31.0
`Ethylene oxide
`0.02
`1730
`0.03
`5.0
`40.5
`Ethyl chloride
`0.03
`830
`0.07
`3.4
`50.0
`Diethyl ether
`' 0.03
`630
`0.08
`2.8
`75.0
`Methylal
`0.02
`725
`0.07
`1.9
`95.0
`Ethyl bromide
`0.05
`288
`0.06
`1.9
`100
`Dimethyl 30:18!
`0.07
`110
`0.05
`1.0
`120
`Diethyl formal
`0.02
`450
`0.05
`0.95
`130
`CHC1=CHCI
`0.02
`560
`0.07
`1.1
`160
`Carbon disulphide
`
`
`
`
`
`265 0.5 0.05 324Chloroform 0.01
`
`P = partition coefficient (oilzvapour); N = narcotic concentration (volume %);
`Con=conoentration (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 = mfg:s where pb the partial pressure in the anaesthetic
`mixture is calculated by multiplying the narcotic concentration by atmospheric
`pressure, e.g. {or diethyl formal p1 = 7&5 x 760 mm Hg.
`(From results of Meyer and Hemini, Biochim. Z. (1935), no. 277. p. 54.)
`
`57-71%”? .f
`
`flop/m QJ/‘HQ.
`
`TABLE 5.2: Activity of phenoxyacezic acids: C is the concentration
`producmg 10% growth of the Avena (grass) samples in the standard
`time; P 1:; the partition coeflicient; 7: is the effect of the substituent
`on log P, taking phenoxyacetic acid as standard,
`nd a is the effect of
`the substituent on the 'pK. of benzoic acid.
`
`Na
`
`
`
`‘
`.
`10 1c
`10 1,
`
`
`
`n (gale/J .Pa ,Subsutuenl (5155.?M
`
`
`3—CF3
`0.55
`6.8
`320
`1.09
`6 s
`4.0
`0.37
`168
`0.80
`6.3
`6.4
`3-1
`023
`325
`1.08
`6.1
`6.3
`4.1-"
`0.34
`43
`0.20
`5.0
`6.3
`3131
`0.23
`254
`0.97
`5.9
`6.0
`3.s1-‘5
`0.68
`1190
`1.64
`6.2
`6.0
`3-C1-
`0.23
`178
`0.82
`5.9
`5.7
`3-NO
`0.73
`29
`0.04
`5.7
`5.3
`3-sc113
`—0.05
`105
`0.59
`4.9
`5.3
`3-C,H5
`—0.15
`200
`0.37
`4.9
`5.3
`3-n-C3H7
`~05
`1:90
`1.52
`4.2
`4.7
`3-C>CH3
`—o.27
`36
`0.13
`3.1
`4.7
`300
`0.63
`16
`—0.23
`4.1
`4.5
`3-CH,
`—0.17
`75
`0.44
`4.3
`4.3
`3c113co
`0.52
`22
`—0.08
`4.5
`4.0
`3-F
`0.06
`41
`0.13
`4.2
`3.5
`H
`0.00
`27
`0.00
`3.4
`3.5
`3-01-1
`—0.36
`5
`—0.73
`—1.8
`3.7
`scoou
`0.27
`21
`—0.13
`3.5
`3.0
`hang
`—o.15
`3100
`2.03
`2.4
`0.0
`(From results of Hansch, Maloney. Fujita and Muir, Nature (1962), no. 194, p. 178.)
`
`Micro Labs Exhibit 1051-5
`
`

`

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`Micro Labs Exhibit 1051-6
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`

`

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`Micro Labs Exhibit 1051-7
`
`Micro Labs Exhibit 1051-7
`
`
`

`

`permission of the copyright owner).
`
`Figure 15
`Irritant activity of
`phorbol-IZ‘ l3-diesters. fitted with
`the parabolic model (— - —) [eq. ( [39)]
`and the bilinear model (—) [eq.
`(140)]; approximate standard
`deviations are indicated for each
`value (reprinted from [224} with
`
`5
`
`g
`ll
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`200
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`100
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`5
`a.Q
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`
`Chain Length
`
`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
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`
`
`

`

`ae/Eofea’
`
`mm. / W/CWJ
`
`1'77
`
`IH
`Substituent/substructure
`2.87
`Aromatic—C0011
`2.60
`Aromatic—OH
`. 2.56
`—CONH—
`1.93
`—SOZNH—
`1.82
`Aliphatic—OH
`1.33
`Aliphatic—NH2
`1.18
`Aromatic—NH2
`0.55
`—NR,R2 (RI, R24: H)
`0.45
`—NO2
`0.31
`: C=O
`0.23
`—CEN
`0J1
`-0-
`ortha-Substitution to —OH, —COOH, ~NRIR2
`— 0.62
`
`
`I
`
`Table 3
`Hydrophobic fragmental constants fand 7: values ofselected substructures and
`substituents.
`
`Fragment
`
`Fragmental constants f
`Rekker [6]
`aliph.
`
`arom.
`
`Leo et a1. [62]
`aliph.
`arom.
`
`H
`CH3
`CH2
`CH
`C
`C6H5
`C6114
`CGH3
`
`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
`
`fl benzene
`1511
`
`0 00
`036
`
`1.96
`
`0.14
`0.71
`0.86
`1.12
`-0.67
`
`— 032
`~ 1.23
`
`— 0.28
`— 1.49
`
`0.88
`'—057
`0.39
`
`0.37
`— 0.38
`0.399
`— 0.462
`F
`0.94
`0.06
`0.922
`0.061
`C1
`1.09
`0.20
`1.131
`0.270
`Br
`1.35
`0.60
`1.448
`0.587
`I
`— 0.40
`— 1.64
`— 0.343
`— 1.491~
`OH
`—O.57
`— 1.81
`—0.433
`— 1.581.
`—O—
`— 0.03
`— 1.09
`— 0.093
`— 0.954
`COOH
`— 1.00
`— 1.54
`—0.854
`— 1.428
`NH2
`— 1.03
`——2.11
`—0.964
`— 1.825
`NH
`— 0.02
`— 1.26
`-— 0.078
`0
`— 0.939
`N02
`—126
`~2J8
`—1J09
`CONH2 “\.(1 —1970
`— 0.32
`— 1.90
`— 0.842
`>C=0
`— 1.703
`.
`1.331
`CF3
`0.757
`— 0.34
`— 1.28
`— 0.205
`CEN
`— 1.066
`0.62
`SH
`0.00
`0.03
`— 0.79
`0.11
`—S—
`— 0.51
`
`Correction factors
`Rekker
`I
`Leo et a1.
`
`Proximity effect 1
`0.861
`fb (chain)
`Proximity effect 2
`0.574
`FD (cyclic)
`H on electronegative group
`0.287
`Chain branching
`Aryl conjugation
`0.28
`Group branching
`Condensed aromatic system b
`0.31
`
`— 0.12
`— 0.09
`— 0.13
`— 0.22
`
`
`
`Micro Labs Exhibit 1051-10
`
`Micro Labs Exhibit 1051-10
`
`

`

`Mo /e MM m-fiec T/I'V/‘K/
`/
`
`Table 6
`Heteroatom valence delta values 6" [5, 131, l3S].
`
`
`Group
`6"
`Group
`"
`6”
`
`
`~NH2
`-NH—
`-111—
`—Ill0—
`=IiiH
`=N—
`> N$= (nitro)
`
`'
`
`3
`4
`5
`6
`4
`5
`6
`
`-.-0H
`—O—
`=0
`—S—-
`=§=
`Ci
`Br
`
`5
`6
`6
`0.944“)
`3.58“)
`0.690“), 0.70”)
`0.2543), 0.25b)
`
`0
`0.0853), 0.152”)
`I
`5
`EN
`————_._—__———_—_
`
`a) Empirical values, derived from molar reframivity.
`
`Z"— h
`b) Calculated from 6“= Z Z"; Z = atomic number [131].
`
`3
`
`g
`
`1‘
`'3
`
`/
`
`Micro Labs Exhibit 1051-11
`
`Micro Labs Exhibit 1051-11
`
`