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Thermodynamic Acidity Constants of Some 3-Hydroxypropionic Acid Derivatives.

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317/84
877
Nonsteroidal Antiinflammatory Drugs
Literatur
1 I. C. Ivanov, P. B. Sulay und D. K. Dantchev, Liebigs Ann. Chem. 1983, 753.
2 D. K. Dantchev und I. C. Ivanov, Synthesis 1981, 227.
3 E. Stenhagen, S. AbrahamssonundF. W. McLafferty, AtlasofMassSpectralData,Vol. 1,p. 512,
Interscience, New York 1969; Registry of Mass Spectral Data, Vol. 1, p. 194, J. Wiley & Sons,
New York 1974.
4 H. Budzikiewicz, C. Djerassi und D. H. Williams, Mass Spectrometryof Organic Compounds, (a)
p. 569; (b) pp. 241, 578, Holden-Day Inc., San Francisco 1967.
5 K. Undheim und T. Hurum, Acta Chem. Scand. 26, 2075 (1972).
6 A. M. Duffield, C. Djerassi, G. Schroll und S . - 0 . Lawesson, Acta Chem. Scand. 20, 361
( 1966).
7 A. Selva, A. Gennaro und P. Caramella, Org. Mass Spectrom. 11, 117 (1976).
8 H. Budzikiewicz, C. Horstmann, K. Pufahl und K. Schreiber, Chem. Ber. 100, 2798 (1967).
9 R. J. Sundberg, The Chemistry of Indoles, p. 171, Academic Press, New York 1970.
10 S. A. Glickman und A. C. Cope, J. Am. Chem. SOC.67, 1017 (1945).
[Ph 8261
Arch. Pharm. (Weinheim) 317, 877-883 (1984)
Nonsteroidal Antiinflammatory Drugs (NSAID), XIV:’)
Thermodynamic Acidity Constants of Some 3-Hydroxypropionic
Acid Derivatives
Paolo De Maria, Adamo Fini*
Istituto di Scienze Chimiche dell’Univerist8, via S. Donato 15, 1-40127Bologna
Adriano Guarnieri and Lucilla Varoli
Istituto di Chimica Farmaceutica e Tossicologica dell’Universit8, via Belmeloro 6, 1-40126
Bologna
Eingegangen am 21. Juli 1983
The proton dissociation constants of 3-hydroxypropionic acids bearing the biphenylyl or the
cyclohexylphenylgroup in position 2 were determined potentiometricallyat 25 “C. Because of the low
solubility of the compounds in water, a DMSO/water mixture (80:20) (w/w), which is approximately
equimolar in its components, was used as the solvent. Acidity constants in pure water could be
estimated by means of a previously established linear free energy relationship. Substituent effects on
the acidity and on the hydrophilic hydrophobic balance of the molecules of the title acids are briefly
discussed.
03654233/84/1010-0877 $02.5010
8 Verlag Chemie GmbH, Weinheim 1964
878
De Mario, Fini, Guarnieri and Varoli
Arch. Pharm.
Nichtsteroidale Antiphlogistika, 14. Mitt.: Thermodynamische Dissoziationskonstanten von 3Hydroxy-propionsaure-Derivaten
Es wurde die Dissoziationskonstante der an C-3 substituierten 2-Biphenylyl(oder 2-Cyclohexylphenyl)-3-hydroxypropionsauren 1-31 potentiometrisch bestimmt. Wegen der geringen Uslichkeit der
Verbindungen in Wasser wurden die Messungen in einem fast aquimolaren 80:20-DMSOl
Wasser-Gemisch durchgefuhrt; die pKa-Werte wurden durch eine vorher bestimmte lineare
Freie-Energie-Beziehung in Wasser abgeschatzt. Substituenteneffekte auf die Aziditat und das
Verhaltnis zwischen hydrophilen und hydrophoben Molekulbestandteilen der betreffenden Sauren
werden kurz diskutiert.
The therapeutic effectiveness of a drug depends, "inter alia", on its serum concentration as
detected in patients under treatment. It is well known" that, among potential NSAID, only a
relatively small group of acidic compounds, showing a very high degree of binding to plasma-proteins,
can display pharmacological activity. In addition these drugs should have pKa's in water near 4>".
The actual pKa values are also necessary to determine intrinsic partition coefficientsand solubilitiesin
water of these compounds. Therefore pKa is a parameter of importance') to be known in order to
design andor to chose a molecule as a NSAID.
Unfortunately most potential NSAIDs object of the present series of investigationsare, in the form
of undissociated acids, such insoluble materials in water as to prevent direct potentiometric
determination of reliable pKa values in water. The absence of suitable UV-visible absorption bands in
the acids andor conjugate bases makes also optical methods of pKa determination') unapplicable for
those compounds.
Nevertheless pKa* of thermodynamic significance (i. e. directly comparable with values
in dilute aqueous solution, as free from liquid-junction potentials and from other empirical
factors) are now easily accessible in some organic solvents and aqueous-organic mixtures').
Following Kreevoy et al.%") we have recently") used a DMSOIwater (80:20) (w/w) mixture
for acidity constants (pKa*) determinations and have shown that the selection of this
mixed solvent is quite convenient both from ~hemical'~)
and pharmacological points of
view14).
In addition we have shown") that, for acids of similar structure, the following
LFER
pKa = -0.71
+ 0.66 pKa*
(es. 1)
where pKa* is the value in aqueous DMSO and pKa is the corresponding value in water,
holds over more than five pKa* units at 25 "C.
Therefore, if the pKa* of a given potential NSAID is known, the corresponding pKa in
water can be "estimated", within the limits of equation 1,with a high degree of confidence
(for statistical treatment of equation 1, see")).
In parallel with pharmacological tests, we have thought it to be interesting to measure
pKa* values of a number of substituted 3-hydroxypropionic acids, to further estimate the
corresponding pKa's in water and finally to calculate their log P (partition coefficient)
values by means of the recentI5)fragmentation constants method.
31 7/84
879
Nonsteroidal Antiinflammatory Drugs
The general structure of the compounds under investigation may be represented as
follows:
PH
Z-FY-7XH-CooH
where Xis a 4-biphenylyl or 4-cyclohexylphenylgroup and both Y and Z are substituents of
different nature as reported in Table 1. Three hydroxycycloalkyl-biphenylylaceticacids
23-25 were also investigated, as reported in table 1.
Table 1: Thermodynamic Acid Dissociation Constants of Antiinflammatory Series of Arylaliphatic
Acids 1-31
~
~
Y
Z
~
pKa* pKa
logP
7.59
7.38
7.17
7.34
7.42
7.57
7.03
7.52
7.43
7.50
7.56
7.42
7.39
7.50
7.21
7.20
2.46
3.19
3.70
3.70
4.70
4.10
2.68
3.47
3.45
3.45
3.45
4.10
4.10
4.10
3.61
3.64
Y
pKa* pKa
2
logP
A) X = biphenylyl
1H
2H
3H
4H
5 H
6H
7H
8H
9H
10 H
11 H
12 H
13 H
14 H
15 H
16 H
methyl
ethyl
n-propyl
i-propyl
cyclohexyl
benzyl
2-f~yl
phenyl
oCH30-phenyl
mCH30-phenyl
pCH3O-phenyl
oCH3-phenyl
mCH3-phenyl
pCH3-phenyl
o-F-phenyl
m-F-phenyl
4.30
4.16
4.02
4.13
4.19
4.29
3.93
4.25
4.19
4.28
4.28
4.19
4.17
4.24
4.05
4.04
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
H
p-F-phenyl
7.17
H
pC1-phenyl
7.43
H
plr-phenyl
7.46
methyl methyl
6.78
ethyl
methyl
6.25
methyl phenyl
6.20
-cyclopentyl6.60
c y clohexyl6.51
-4-methylcyclohexyl6.30
B) X = cyclohexylphenyl
H
methyl
7.46
methyl methyl
6.78
H
phenyl
7.50
H
pCH3-phenyl 7.42
H
pC1-phenyl
7.55
H
p-Br-phenyl 7.60
Maximum standard deviation =
k
4.02
4.19
4.21
3.76
3.41
3.38
3.65
3.59
3.45
3.61
4.10
4.33
3.12
4.50
4.13
3.76
4.20
4.86
4.21 3.51
3.76 4.17
4.24 4.52
4.18 5.15
4.27 5.23
4.30 5.38
0.02
We thank CNR (Rome) for financial support and Dr. S. Burnelli for assistance in synthesis of some of
the compounds.
Experimental Part
Materials
Acids 1-31 were synthesized by addition of the appropriate carbonyl compound to an anhydrous THF
solution of the acetic acid derivative in the presence of n-butyllithium as previously described16)and
recrystallized to constant m. pa Purification of DMSO and preparation of the solutions were as
previously described”).
880
De Maria, Fini, Guarnieri and Varoli
Arch. Pharm.
Determination of acidity constants
Thermodynamic acidity constant Ka* for the equilibrium HA % H@ + A@ of a general uncharged
acid HA in an organic solvent or in an aqueous mixture of the organic solvent can be represented by
equation 2
eq. 2
where the asterisk means that the activity coefficients y refer to infinite dilution in the actual solvent
and c are molar concentrations.
The activity coefficients y* of ionic species can be calculated from the Davies equation 3 (or from
similar expressions”)):
log y_+ = -Az211’*/ (1
+ I l n ) + Az21/3
eq. 3
while the activity coefficient of the neutral species can be assumed to be unity. In equation3, I is the
from
ionic strength of the solution and the Debye-Hiickel function A can be ~alculated’~’
equation 4
A=
1.825 *106d’/2
eq. 4
(DT) 3/2
where T is the absolute temp., D and d are the dielectric constant and the density of the solvent resp.
For the DMSOIwater mixture, A is 0.710 at 25°C.
cH@values to be inserted in equation 2 can, in principle, be obtained by equation 5
pH* = -log cHo - log Y * ~ @
eq. 5
where the hydrogen ion activity corresponds to the actual reading of the pH-meter provided that the
apparatus were standardized against buffer of known pH* in the solvent under investigation. As
buffer of known pH* are not avalaible for DMSOIwater mixture, the apparatus (Radiometer pH M
26, assembled with a glass electrode, a saturated calomel electrode and an ABU 111 automatic
burette), was standardized against Robinson-Stokes aqueous buffersm).Then the electrodes were
calibrated with solutions of perchloric acid of known. activity in DMSO/water (80:20) (wlw) as
previously described”). Under these conditions the glass electrode is responsive’” and the actual
readings p q e a d ,could be related to thermodynamic pH* values by means of the calibration curve of
equation 6.
pH* = 1.39 + 1.13 pHread
eq. 6
Finally the buffer ratio cA@/cAH (eq. 2) was calculated from the stoichiometric composition of the
solutions alongside the potentiometric titration with standard NaOH in DMSO/water. The initial
concentration of the NSAID acid was in the range 0.5-1.0. W 2 M in all cases.
Calculation of the partition coeficients
Log P value calculationswere performed by the fragment addition method developed by Hansch and
acids were used as
Experimental values of log P for phenylpropionic”) and biphenylyla~etic’~)
31 7/84
Nonsteroidal Antiinflammatory Drugs
881
reference values. Values for the various substituents have been derived from the experimental log P
values reported for the parent compounds in the n-octanouwatersystem''). Most of log P values have
been experimentally confirmed in the same solvent system: they have been found not to differ more
than & 0.1 units.
Discussion
The pKa* values in DMSO/water of the acids under investigation are collected in
Table 1.Substituents X and Z modify the acidity in the qualitative direction expected from
their known stereo-electronic effectsz3).In particular the present, as well as our previous
results in this series, show that a biphenylyl group, both in position 312)and in position 2
(Table 1)enhances the acidity compared to 3-hydroxybutyric acid") in DMSO/water. This
can be accounted for by the electron-attracting inductive effect (a= 0.06)24)of this
substituent. An analogous effect, as discussed by King (p. 168of 2 5 ) ) , exerted by the phenyl
group makes both phenylacetic and p-phenylpropionic acids stronger than the corresponding fatty acids in water. However it appears that this acid strengthening effect of the
biphenylyl group is approximately 0.7pKa* units less effective in position 2 than in
position 3 in the hydroxypropionic acid derivatives in DMSO/water, and this cannot be
attributed to any simple through-bonds inductive effect of the biphenylyl group. The
observed trend could be tentatively explained by the reduced solvation of the charged
conjugate base of NSAID neutral acid due to the closeness of the strongly hydrophobic
biphenylyl group in position 2.
Both acidity and pharmacological activity are affected by substitution into the phenyl
group of compound 8 ( X = C,H,). As expected in view of the reaction type and the
distance of the substituents from the reaction center, the substituents affect the acidity of
the compounds 8-19 only to a low degree.
It is well established that acid-base equilibria are strongly dependent upon the solvent
and that total "solvent effects" may be related to acid-base properties and dielectric
constant of the actual solvent"). In particular the addition of DMSO to water commonly
progressively decreases28)the acidity of uncharged acids, although to a different extent
depending upon the particular acids (e. g. carboxylic acid^"*^); phenols3'); benzenethiol~'~)
etc.).
However it is likely that, within a group of acids of similar structure, relative acid
strenghts are approximately the same in water and different solvent systemsz7).In fact pKa
in water and pKa* in the solvent appear to be often linearly related for several classes of
acidic compounds. In particular we have recently shown12) this to be the case for 15
carboxylic acids in DMSO/water (80:20) (w/w) at 25 "C (see equation 1).
From equation 1the pKa in water at 25 "C of any unsoluble NSAID acid can therefore be
"estimated", provided that the corresponding thermodynamic pKa* in 80 70DMSO is
accurately known at the same temperature. pKa's in water "estimated" according to
equation 1 are reported in Table 1. As these values are probably reliable to f0.08 pKa
units, they are useful for most chemical, analytical and pharmacological purposes.
It can be seen that the substituents X and 2, suitably introduced with the aim of fulfilling
the best physical and chemical properties for pharmacological activity3'), keep pKa values
882
De Maria, Fini, Guarnieri and Varoli
Arch. Pharm.
in water for all of the investigated acids well within the range 3-4. This particular acidity
has been considereds5) critical for pharmacological activity of NSAIDs of similar
structure.
In addition the substituent should modify the hydrophilic-hydrophobic balance of the
molecule hopefully in the direction of favourable partition coefficients for a rapid
absorption.
For instance both ibufenac and indometacine, very commonly used as antiinflammatory
drugs, bear a strongly hydrophobic p-isobutylphenyl and arylidenindenyl group, resp.
Log P values reported in Table 1 clearly point to a more favourable partition in the
organic than in the aqueous phase for all of the presently investigated NSAIDs.
In particular log P values of the phenylcyclohexyl derivatives tend to be higher than
those of the corresponding biphenylyl substituted NSAIDs and this can account for some
instances of enhancement of the antiinflammatory activity of the cyclohexyl
References
1 XIII: A. Guarnieri, S. Burnelli, L. Varoli, G. Fabbri, G. Scapini, M. Sarret and D. Bertoli,
Farmaco Ed. Sci. 38, 686 (1983).
2 K. Brune, P. Graf and M. Glatt, in Future Trends in Inflammation, Vol. 2, Eds. J. P. Giraud,
D. A. Willoughby and G. P. Velo, Birkhauser Verlag, Basel 1975.
3 H. Levitan and J. L. Barker, Science 176, 1423 (1972).
4 A. Goldstein, L. Aronow and S. M. Kolman, Principles of Drug Action, Harper and Row, New
York 1969.
5 H. Terada, S. Muraoka and T. Fujita, J. Med. Chem. 17, 330 (1974).
6 D. W. Newton and R. B. KIuza, Drug Intell. Clin. Pharm. 12, 546 (1978).
7 A. Albert and E. P. Serjeant, The Determination of Ionization Constants, Chapman and Hall,
London 1971.
8 D. D. Perrin and B. Dempsey, Buffer for pH and Metal Ion Control, Chapman and Hall, London
1974.
9 E. H. Baughman and M. Kreevoy, J. Phys. Chem. 78, 421 (1974).
10 R. Eliason and M. Kreevoy, J. Phys. Chem. 78, 2658 (1974).
11 A. I. Hassid, M. Kreevoy and T. M. Laing, J. Chem. SOC.Faraday Trans. 1 10, 72 (1975).
12 P. De Maria, A. Fini, A. Guarnieri and L. Varoli, Arch. Pharm. (Weinheim) 316, 559
(1983).
13 I. Kolthoff and T. B. Reddy, Inorg. Chem. I , 189 (1962).
14 N.A. David, Annu. Rev. Pharmacol. 12, 353 (1972).
15 C. Hansch and A. J. Leo, Substituent Constants for Correlation Analysis in Chemistry and
Biology, J. Wiley and Sons, New York 1979.
16 A. Guarnieri, S. Burnelli, G. Scapini, L. Varoli, I. Busacchi, B. Lumachi and G. Bossoni, Eur. J.
Med. Chem. Chim. Ther. 17,509 (1981).
17 G. B. Cox, P. de Maria and A. Fini, Gazz. Chim. Ital. 106, 817 (1976).
18 C. W. Davies, Ion Association, Buttenvorths, London 1962.
19 R. G. Bates, in Solute Solvent Interactions, chap. 11, Eds. J. F. Coetzee and C. D. Richtie, M.
Dekker, New York 1969.
20 R. A. Robinson and R. H. Stokes, Electrolyte Solution, 2nd Ed., Buttenvorths, London
1965.
21 B. G. Cox and A. Gibson, Faraday Symp. Chem. SOC.10, 8 (1975).
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Borkornplexe yon Malon- und Dithiornalondiirnidsaureestern
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M. Kuchhr, V. Rejolec and 0. Ntmectk, Drugs Fut. 7, 179 (1982).
J. Hine, Physical Organic Chemistry, McGraw-Hill Book Company, Inc., New York 1962.
M. Charton, Progr. Phys. Org. Chem. 13, 119 (1981).
E. J. King, Acid Base Equilibria, in The International Encyclopedia of Physical Chemistry and
Chemical Physics, E. A. Guggenheim, J. E. Mayer and F. C. Thompkins Eds., The Mac Maan
Company, New York 1965.
26 R. W. Taft jr., J. Phys. Chem. 64, 1805 (1960).
27 R. P. Bell, The Proton in Chemistry, 2nd, Ed., chap. 4, Chapman and Hall, London 1969.
28 C.D. Richtie, in Solute Solvent Interaction, chap. 4, J.F. Coetzee and C.D. Richtie Eds., M.
Dekker, New York 1969.
29 I. M. Kolthoff and M. K. Chantooni, J. Am. Chem. SOC.93, 3843 (1971).
30 N. M. Ballash, E. B. Robertson and M. D. Sokolowski, Trans. Faraday SOC.66, 2622 (1970).
31 J. C. Halle, R. Gaboriaud and R. School, Bull. SOC.Chim. Fr. 1970,2047.
32 T. Y. Shen, Chim. Ther. 2, 459 (1967).
33 N. N., Chem. Eng. News 45, 10 (1967).
22
23
24
25
[Ph 8271
Arch. Pharm. (Weinheim) 317, 883-890 (1984)
Borkomplexe von Malondiimidsaureestern und
Dithiomalondiimidsaureestern
Barbara Krug und Klaus Hartke*
Institut fur Pharmazeutische Chemie der Universitat Marburg, Marbacher Weg 6,
D-3550 MarburdLahn
Eingegangen am 22. Juli 1983
Malondiimidsaure-diethylester (2) bildet rnit Bortrifluoridetherat entweder das 4,6-Diethoxy2,2-difluor-3-aza-l-azonia-2-borato-4,6-cyclohexadien
(5) oder dessen Tetrafluoroborat 4. Analog
kondensiert 2 mit Diphenylborsaure-ethylester(7a), Triethylboran (7b) und Borsauretrimethylester
(7c) zu den Neutralkomplexen Ba-c, die sich zum Teil rnit Tetrafluorborsaure zu den Salzen 9a, b
protonieren lassen. Die Umsetzung von Dithiomalondiimidsaure-dimethylester,der in der tautomeren Form 12 vorliegt, liefert mit 7 die Neutralkomplexe 13a-c bzw. nach Protonierung die
Tetrafluoroborate 14a, b.
Boron Complexes of Malonodiimidates and Dithiomalonodiimidates
Diethyl malonodiimidate (2) reacts with boron trifluoride etherate to form 4,6-diethoxy-2,2difluoro-3-aza-l-azonia-2-borato-4,6-cyclohexadiene
(5) or its tetrafluoroborate (4). In a similar
manner, 2 condenses with ethyl diphenyl borate (7a), triethylborane (7b) or trimethyl borate (7c) to
give the neutral complexes BM. These can be partially protonated with HBF4to yield the salts 913,b.
Reaction of 7 with dimethyl dithiomalonodiimidate, which exists in the tautomeric form U ,leads to
the isolation of the neutral complexes 13a-c. Protonation of Wa, b with HBF, yields the
tetrafluoroborates 14a, b.
03654233/84/101(M883 $ 02.50/0
8 Verlag Chemie GmbH, Weinheim 1984
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