Substituted chiral allosteric hemoglobin modifiers

Details Substituted chiral allosteric hemoglobin modifiers Substituted chiral allosteric hemoglobin modifiers

2000-08-23

2002-11-26

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S008000, C560S019000, C560S031000, C560S032000, C560S070000, C514S563000

Reexamination Certificate

active

06486342

ABSTRACT:

DESCRIPTION
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to a family of allosteric effectors of hemoglobin and more specifically to chirality affects of allosteric effectors where the chiral carbon has a substituted carbon ring, a heteroatom ring, or different substituents. The invention includes several new potent enantiomers that are superior than their racemic mixture and other enantiomeric isomer, possessing different degrees of allosteric potency.
2. Background Description
Human hemoglobin (Hb) is a tetrameric allosteric protein comprised of two alpha and two beta chains and functions to deliver oxygen from the lungs to the many tissues of the body. The four subunits are arranged around a molecular two fold axis creating a central water cavity. As an allosteric protein, Hb exists in an equilibrium between two states, the relaxed (R) or oxy-state and the tense (T) or deoxy-state. In the oxy-state, the water cavity is narrow and the subunits have fewer and weaker bonds between them (i.e., relaxed). However, in the deoxy-state, the water cavity is larger, and the subunits are tightly tethered together by salt bridges (i.e., tense). The allosteric equilibrium can be influenced by allosteric modifiers. Such molecules can increase the oxygen affinity of Hb shifting the allosteric equilibrium toward oxy-Hb or decrease the affinity of oxygen, shifting the equilibrium to the deoxy-Hb. Modifiers that decrease the oxygen affinity act by adding constraints to the T-state. Oxygen affinity decreasing agents have several potential applications including radiosensitization of tumors, enhancement of oxygen delivery to hypoxic and ischemic tissues, and shelf-life prolongation of stored blood.
The gap between the &bgr; subunits is wide enough for 2,3-diphosphoglycerate (2,3-DPG), a naturally occuring allosteric modifier, to dock in and bind, forming additional salt bridges that further stabilize the deoxy state. Therefore, compounds that lower the affinity of oxygen for Hb do so by strengthening the existing salt bridges or by adding new ones to the tense state.
Several synthetic agents have been reported to lower the affinity of oxygen for Hb. In the search for an antisickling agent, Abraham and coworkers discovered the antilipidemic drug, clofibric acid, that lowered the oxygen affinity of Hb. Perutz and Poyart followed with a report that bezafibrate, another antilipidemic agent, was also a right-shifting compound, more potent than DPG and clofibric acid. Lalezari and coworkers demonstrated that shortening the four atom bridge to a three atom urea bridge produced even more potent allosteric modifiers, but their potential as clinical agents was limited due to loss of activity in the presence of serum albumin.
It has been proposed that influencing the allosteric equilibrium of hemogobin is a viable avenue of attack for treating diseases. The conversion of hemoglobin to a low affinity state is believed to have general utility in a variety of disease states where tissues suffer from low oxygen tension, such as ischemia and radio sensitization of tumors. Several synthetic compounds have been identified which have utility in the allosteric regulation of hemoglobin and other proteins.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a family of compounds which allosterically modifies hemoglobin such that hemoglobin is present in blood in a lower oxygen affinity state.
It is therefore an object of the present invention to provide synthetic agents that can enhance the oxygenation of tissues. Enhancement of oxygenation has several potential therapeutic applications: (1) radio-sensitization of tumors, (2) treatment of stroke and cerebral traumas, (3) shelf-life prolongation of stored blood, (4) treatment of angina and myocardial infarcation, and (5) reduction of surgical blood loss and blood transfusions.
Currently, two of the most potent oxygen-affinity decreasing agents developed by Abraham et al. are shown as RSR13 and JP7 in Table I below. The high resolution crystal structure of the RSR13-Hb complex has been determined. The small molecule binds near the top of the &agr; subunits and points down the central water cavity to the &agr;,&bgr;-subunit interfaces making several important interactions with the protein. RSR46, KDD86, and RSR4 shown in Table I are also oxygen affinity decreasing agents.
TABLE I
Name
Compound
1
RSR13

2
JP7

3
RSR46

4
RSR4

5
KDD86
Specifically, compounds having substituted chiral centers and the structures:
wherein R
1
and R
2
are selected from the group comprising CH
3
, Cl, and 5 carbon cyclics; R
3
is selected from the group comprising H, OH, and OC
2
H
5
; R
4
and R
5
are selected from the group comprising CH
3
, cyclics containing CH
3
substituents, OCH
3
, C
2
H
5
, phenyl and substituted phenyl; and wherein R
4
and R
5
are not the same, and
wherein R
1
is selected from the group comprising H, CH
3
, CH(CH
3
)
2
, CH
2
Ph, CH
2
CH(CH
3
)
2
, CH(CH
3
)C
2
H
5
, CH
2
CH
2
COOH, CH
2
COOH, CH
2
tryptophan, CH
2
Indole, CH
2
PhOH, CH
2
OH, CH
2
SCH
3
, (Me)
2
SMe, (CH
2
)
3
, CH
2
SCH
2
Ph, CH(OH)CH
3
, (CH
2
)
4
NHOCOCH
2
Ph, and (CH
2
)
4
NH
2
.
Where R
3
is selected from the group comprising H, CH
3
, CH(CH
3
)
2
, CH
2
Ph, CH
2
CH(CH
3
)
2
, CH(CH
3
)C
2
H
5
, CH
2
CH
2
COOH, CH
2
COOH, CH
2
tryptophan, CH
2
Indole, CH
2
PhOH, CH
2
OH, CH
2
SCH
3
, (Me)
2
SMe, (CH
2
)
3
, CH
2
SCH
2
Ph, CH(OH)CH
3
, (CH
2
)
4
NHOCOCH
2
Ph, (CH
2
)
4
NH
2
etc. have been identified as being allosteric effectors of hemoglobin.
Investigation of the effect of stereochemistry on activity and binding conformation shows that the existence of a chiral center affects the allosteric activity. Specifically, a chiral center was introduced in compounds having the general structures of RSR13, JP7, RSR4, RSR46 and KDD86 (shown in Table I). The new chiral molecules (class B) were prepared by replacing either one of the gem dimethyl groups of Table I compounds with other alkyl/alkanoic, un/substituted cycloalkyl/cycloalkanoic, substituted aromaatic groups or by condensing the carboxylate group of the parent.molecule (Table 1 compounds) with various D and L isomers of amino acids such as alanine, valine, asparagine, cysteine, glutamic acid, phenylalanine, glycine, histidine, leucine, isoleucine, proline, arginine, serine, threonine, tryptophan, tyrosine, and lysine (class C).
The synthesis of the compounds (class B) involves central intermediate amidophenols: 4-[[(3,5-dimethylanilino)carbonyl]methyl]phenol, 4-[[(5-indanyl)carbonyl]methyl]phenol, and 4-[[(3-chloro-5-methylanilino)carbonyl]methyl]phenol, where 3,5 dimethylaniline or 5-aminoindan is condensed with 4-hydroxyphenylacetic acid in refluxing xylene over a three-day period. While 3,5-dimethylaniline and 5-aminoindan were both readily available.
The scheme 1 above as well the schemes 2 and 3 shown below were utilized to produce the corresponding racemates.
The previously reported &agr;-aryloxyisobutyric acid analogs were obtained via reaction of amidophenols with acetone-chloroform in the presence of sodium hydroxide. In this process, the appropriate ketone is substituted for acetone in tetrahydrofuran to obtain the proposed compounds 1-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-3-methylcyclopentane carboxylic acid, 2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy-2-methylbutanoic acid 1-4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentane carboxylic acid, 4-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]tetrahydro-2H-4-pyrancarboxylic acid, 3-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methyltretrahydro-3-furan carboxylic acid, 2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-3-methoxy-2-methylpropanoic acid, 2-[4-[[(3,5-dimethylanilino)carbonyl&rsq

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