U.S. patent application number 15/178799 was filed with the patent office on 2016-09-29 for fluorescent pyrazine derivatives and methods of using the same in assessing renal function.
The applicant listed for this patent is MediBeacon Inc.. Invention is credited to Richard B. Dorshow, Dennis A. Moore, William L. Neumann, Raghavan Rajagopalan.
Application Number | 20160280666 15/178799 |
Document ID | / |
Family ID | 36570361 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160280666 |
Kind Code |
A1 |
Rajagopalan; Raghavan ; et
al. |
September 29, 2016 |
FLUORESCENT PYRAZINE DERIVATIVES AND METHODS OF USING THE SAME IN
ASSESSING RENAL FUNCTION
Abstract
The present invention relates to pyrazine derivatives such as
those represented by Formulas I and II. X.sup.1 to X.sup.4 of
Formulas I and II may be characterized as electron withdrawing
groups, while Y.sup.1 to Y.sup.4 of Formulas I and II may be
characterized as electron donating groups. Pyrazine derivatives of
the present invention may be utilized in assessing organ (e.g.,
kidney) function. In a particular example, an effective amount of a
pyrazine derivative that is capable of being renally cleared may be
administered into a patient's body. The pyrazine derivative may
capable of one or both absorbing and emanating spectral energy of
at least about 400 nm (e.g., visible and/or infrared light). At
least some of the derivative that is in the body may be exposed to
spectral energy and, in turn, spectral energy may emanate from the
derivative. This emanating spectral energy may be detected and
utilized to determine renal function of the patient.
##STR00001##
Inventors: |
Rajagopalan; Raghavan;
(Solon, OH) ; Dorshow; Richard B.; (St. Louis,
MO) ; Neumann; William L.; (St. Louis, MO) ;
Moore; Dennis A.; (St. Louis, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MediBeacon Inc. |
St. Louis |
MO |
US |
|
|
Family ID: |
36570361 |
Appl. No.: |
15/178799 |
Filed: |
June 10, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14047733 |
Oct 7, 2013 |
9376399 |
|
|
15178799 |
|
|
|
|
11721186 |
Jun 8, 2007 |
8778309 |
|
|
PCT/US05/46732 |
Dec 22, 2005 |
|
|
|
14047733 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 241/20 20130101;
A61K 49/0021 20130101; A61K 49/0004 20130101; A61K 31/4965
20130101; C07D 241/28 20130101; C07D 241/26 20130101; A61K 49/0052
20130101 |
International
Class: |
C07D 241/28 20060101
C07D241/28; C07D 241/26 20060101 C07D241/26 |
Claims
1.-8. (canceled)
9. The compound of Formula II, wherein: ##STR00029## each of
X.sup.3 and X.sup.4 is independently selected from the group
consisting of --CN, --CO.sub.2R.sup.20, --CONR.sup.21R.sup.22,
--COR.sup.23, --NO.sub.2, --SOR.sup.24, --SO.sub.2R.sup.25,
--SO.sub.2OR.sup.26 and --PO.sub.3R.sup.27R.sup.28. each of Y.sup.3
and Y.sup.4 is independently selected from the group consisting of
--OR.sup.29, --SR.sup.30, --NR.sup.31R.sup.32,
--N(R.sup.33)COR.sup.34 and ##STR00030## Z.sup.2 is selected from
the group consisting of a direct bond, --CR.sup.35R.sup.36--,
--O--, --NR.sup.37--, --NCOR.sup.38--, --S--, --SO-- and
--SO.sub.2.sup.-; each of R.sup.20 to R.sup.38 is independently
selected from the group consisting of hydrogen, C3-C6
polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, C5-C10 aryl, C5-C10 heteroaryl, --(CH.sub.2).sub.bOH,
--(CH.sub.2).sub.bCO.sub.2H, --(CH.sub.2).sub.bSO.sub.3H,
--(CH.sub.2).sub.bSO.sub.3.sup.-, --(CH.sub.2).sub.bOSO.sub.3H,
--(CH.sub.2).sub.bOSO.sub.3.sup.-, --(CH.sub.2).sub.bNHSO.sub.3H,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bPO.sub.3H.sub.2,
--(CH.sub.2).sub.bPO.sub.3H.sup.-,
--(CH.sub.2).sub.bPO.sub.3.sup..dbd.,
--(CH.sub.2).sub.bOPO.sub.3H.sub.2,
--(CH.sub.2).sub.bOPO.sub.3H.sup.- and
--(CH.sub.2).sub.bOPO.sub.3.sup..dbd.; R.sup.40 is selected from
the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C5-C10
heteroaryl, --(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H, --(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bOSO.sub.3H, --(CH.sub.2).sub.bOSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3H, --(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bPO.sub.3H.sub.2,
--(CH.sub.2).sub.bPO.sub.3H.sup.-,
--(CH.sub.2).sub.bPO.sub.3.sup..dbd.,
--(CH.sub.2).sub.bOPO.sub.3H.sub.2, --(CH.sub.2).sub.bOPO.sub.3H'
and --(CH.sub.2).sub.bOPO.sub.3.sup..dbd.; and b, p and q range
from 1 to 6; with the proviso that if: each of X.sup.3 and X.sup.4
is independently --CN, --CO.sub.2R.sup.20 or --CONR.sup.21R.sup.22;
each of Y.sup.3 and Y.sup.4 is independently --NR.sup.31R.sup.32,
or ##STR00031## and Z.sup.2 is a direct bond, then: each of
R.sup.20, R.sup.21, R.sup.22, R.sup.31 and R.sup.32 is
independently not hydrogen, C1-C10 alkyl or C1-C10 aryl; and p, q,
N and Z.sup.2 together do not form a 5- or 6-membered ring.
10. The compound of claim 9 wherein: each of X.sup.3 and X.sup.4 is
selected from the group consisting of --CN, --CO.sub.2R.sup.20 and
--CONR.sup.21R.sup.22; each of Y.sup.3 and Y.sup.4 is independently
--NR.sup.31R.sup.32 or ##STR00032## each of R.sup.20, R.sup.21,
R.sup.22, R.sup.31 and R.sup.32 is independently selected from the
group consisting of C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C5-C10 heteroaryl, --(CH.sub.2).sub.bOH,
--(CH.sub.2).sub.bCO.sub.2H, --(CH.sub.2)b.sub.aSO.sub.3H and
--(CH.sub.2)b.sub.aSO.sub.3.sup.-; each of R.sup.35 to R.sup.38 is
independently selected from the group consisting of hydrogen, C3-C6
polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, C5-C10 aryl, C5 to C10 heteroaryl,
--(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H and --(CH.sub.2).sub.bSO.sub.3.sup.-; p
is 1 or 2; and q is 1.
11. The compound of claim 10 wherein: each of X.sup.3 and X.sup.4
is --CN; Z.sup.2 is selected from the group consisting of a direct
bond, --O--, --NR.sup.37--, --NCOR.sup.38--, --S--, --SO-- and
--SO.sub.2--; each of R.sup.31 and R.sup.32 is independently
selected from the group consisting of C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
--(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H and --(CH.sub.2).sub.bSO.sub.3.sup.-;
and each of R.sup.37 and R.sup.38 is independently selected from
the group consisting of hydrogen, C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, --(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H and
--(CH.sub.2).sub.bSO.sub.3.sup.-.
12. The compound of claim 11 wherein: each of Y.sup.3 and Y.sup.4
is --NR.sup.31R.sup.32; and each of R.sup.31 and R.sup.32 is
--(CH.sub.2).sub.bCO.sub.2H.
13. The compound of claim 11 wherein: each of Y.sup.3 and Y.sup.4
is ##STR00033##
14. The compound of claim 10 wherein: each of X.sup.3 and X.sup.4
is --CO.sub.2R.sup.20; Z.sup.2 is selected from the group
consisting of a direct bond, --O--, --NR.sup.37--, --NCOR.sup.38--,
--S--, --SO-- and --SO.sub.2--; R.sup.20 is hydrogen; each of
R.sup.31 and R.sup.32 is independently selected from the group
consisting of C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
--(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H and --(CH.sub.2).sub.bSO.sub.3--; and
each of R.sup.37 and R.sup.38 is independently selected from the
group consisting of hydrogen, C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, --(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H and
--(CH.sub.2).sub.bSO.sub.3.sup.-.
15. The compound of claim 14 wherein: each of Y.sup.3 and Y.sup.4
is --NR.sup.31R.sup.32; and each of R.sup.31 and R.sup.32 is
--(CH.sub.2).sub.bCO.sub.2H.
16. The compound of claim 14 wherein each of Y.sup.3 and Y.sup.4 is
##STR00034##
17.-44. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pyrazine derivatives that
may be characterized as hydrophilic, small molecule dyes capable of
absorbing and/or emanating spectral energy in the visible and/or
near infrared spectrum. In addition, the present invention relates
to methods of using pyrazine derivatives in the monitoring of renal
function.
BACKGROUND
[0002] Acute renal failure (ARF) is a common ailment in patients
admitted to general medical-surgical hospitals. Approximately half
of the patients who develop ARF die, and survivors face marked
increases in morbidity and prolonged hospitalization [1]. Early
diagnosis is generally believed to be critical, because renal
failure is often asymptomatic and typically requires careful
tracking of renal function markers in the blood. Dynamic monitoring
of renal function of patients is highly desirable in order to
minimize the risk of acute renal failure brought about by various
clinical, physiological and pathological conditions [2-6]. Such
dynamic monitoring is particularly important in the case of
critically ill or injured patients, because a large percentage of
these patients tend to face the risk of multiple organ failure
(MOF) potentially resulting in death [7, 8]. MOF is a sequential
failure of the lungs, liver and kidneys and is incited by one or
more of acute lung injury (ALI), adult respiratory distress
syndrome (ARDS), hypermetabolism, hypotension, persistent
inflammatory focus and sepsis syndrome. The common histological
features of hypotension and shock leading to MOF generally include
tissue necrosis, vascular congestion, interstitial and cellular
edema, hemorrhage and microthrombi. These changes generally affect
the lungs, liver, kidneys, intestine, adrenal glands, brain and
pancreas in descending order of frequency [9]. The transition from
early stages of trauma to clinical MOF generally corresponds with a
particular degree of liver and renal failure as well as a change in
mortality risk from about 30% up to about 50% [10].
[0003] Traditionally, renal function of a patient has been
determined using crude measurements of the patient's urine output
and plasma creatinine levels [11-13]. These values are frequently
misleading because such values are affected by age, state of
hydration, renal perfusion, muscle mass, dietary intake, and many
other clinical and anthropometric variables. In addition, a single
value obtained several hours after sampling is difficult to
correlate with other important physiologic events such as blood
pressure, cardiac output, state of hydration and other specific
clinical events (e.g., hemorrhage, bacteremia, ventilator settings
and others).
[0004] With regard to conventional renal monitoring procedures, an
approximation of a patient's glomerular filtration rate (GFR) can
be made via a 24 hour urine collection procedure that (as the name
suggests) typically requires about 24 hours for urine collection,
several more hours for analysis, and a meticulous bedside
collection technique. Unfortunately, the undesirably late timing
and significant duration of this conventional procedure can reduce
the likelihood of effectively treating the patient and/or saving
the kidney(s). As a further drawback to this type of procedure,
repeat data tends to be equally as cumbersome to obtain as the
originally acquired data.
[0005] Occasionally, changes in serum creatinine of a patient must
be adjusted based on measurement values such as the patient's
urinary electrolytes and osmolality as well as derived calculations
such as "renal failure index" and/or "fractional excretion of
sodium." Such adjustments of serum creatinine undesirably tend to
require contemporaneous collection of additional samples of serum
and urine and, after some delay, further calculations. Frequently,
dosing of medication is adjusted for renal function and thus can be
equally as inaccurate, equally delayed, and as difficult to
reassess as the measurement values and calculations upon which the
dosing is based. Finally, clinical decisions in the critically ill
population are often equally as important in their timing as they
are in their accuracy.
[0006] Thus, there is a need to develop improved compositions,
devices and methods for measuring renal function (e.g., GFR) using
non-ionizing radiation. The availability of a real-time, accurate,
repeatable measure of renal excretion rate using exogenous markers
under a variety of circumstances would represent a substantial
improvement over any currently available or widely practiced
method. Moreover, since such an invention would depend heavily on
the renal elimination of the exogenous marker(s), the measurement
would ideally be absolute and would, thus, preferably require
little or no subjective interpretation based on age, muscle mass,
blood pressure and the like. Indeed, such an invention would enable
assessment of renal function under particular circumstances at
particular moments in time.
[0007] It is known that hydrophilic, anionic substances are
generally capable of being excreted by the kidneys [14]. Renal
clearance typically occurs via two pathways: glomerular filtration
and tubular secretion. Tubular secretion may be characterized as an
active transport process, and hence, the substances clearing via
this pathway typically exhibit specific properties with respect to
size, charge and lipophilicity.
[0008] Most of the substances that pass through the kidneys are
filtered through the glomerulus (a small intertwined group of
capillaries in the malpighian body of the kidney). Examples of
exogenous substances capable of clearing the kidney via glomerular
filtration (hereinafter referred to as "GFR agents") are shown in
FIG. 1 and include creatinine (1), o-iodohippuran (2), and
.sup.99mTc-DTPA (3) [15-17]. Examples of exogenous substance that
is capable of undergoing renal clearance via tubular secretion
include .sup.99mTc-MAG3 (4) and other substances known in the art
[15, 18, 19]. .sup.99mTc-MAG3 (4) is also widely used to assess
renal function though gamma scintigraphy as well as through renal
blood flow measurement. As one drawback to the substances
illustrated in FIG. 1, o-iodohippuran (2), .sup.99mTc-DTPA (3) and
.sup.99mTc-MAG3 (4) include radioisotopes to enable the same to be
detected. Even if non-radioactive analogs (e.g., such as an analog
of o-iodohippuran (2)) or other non-radioactive substances were to
be used for renal function monitoring, such monitoring would
require the use of undesirable ultraviolet radiation for excitation
of those substances.
[0009] Currently, no reliable, continuous, repeatable method for
the assessment of specific renal function using a non-radioactive,
exogenous renal agent is commercially available. Among the
non-radioactive methods, fluorescence measurement tends to offer
the greatest sensitivity. In principle, there are two general
approaches for designing fluorescent renal agents. The first
approach would involve enhancing the fluorescence of known renal
agents that are intrinsically poor emitters (e.g. lanthanide metal
complexes) [21, 22], and the second approach would involve
transforming highly fluorescent dyes (which are intrinsically
lipophilic) into hydrophilic, anionic species to force them to
clear via the kidneys.
[0010] Accordingly, it would be quite desirable to transform highly
fluorescent dyes into hydrophilic, anionic species. More
particularly, it would be quite desirable to identify appropriate,
small, fluorescent molecules and render such molecules hydrophilic.
Examples of dyes capable of absorbing light in the visible and/or
NIR regions are shown in FIG. 2. These dyes are often relatively
large in size, contain multiple aromatic rings, and are highly
lipophilic compared to the structures shown in FIG. 1. Large
lipophilic molecules almost always clear via the hepatobiliary
system and do not readily clear via renal pathways. For example,
FIG. 3 shows that tetrasulfonated cyanine dye (8 of FIG. 2)
exhibits a poor rate of clearance from the blood. In attempts to
circumvent this problem, some dyes have been conjugated to
polyanionic carriers [23, 24]. Although these dye-polymer
conjugates generally possess acceptable renal clearance properties,
such polymeric compounds have other drawbacks such as
polydispersity, manufacturing and quality control issues, and the
provocation of undesired immune responses that may preclude their
use as diagnostic and/or therapeutic substances. Accordingly,
development of small, hydrophilic dyes is quite desirable to enable
enhanced measurement of renal functioning and clearance.
SUMMARY
[0011] The present invention generally relates to the
transformation of fluorescent dyes into hydrophilic and/or anionic
species by substituting both electron withdrawing and electron
donating substituents (i.e., one or more of each) to the dyes. For
example, one aspect of the present invention is directed to rigid,
small molecules whose size is preferably similar to that of
creatinine or o-iodohippuran and rendering such molecules
hydrophilic by incorporating appropriate polar functionalities such
as hydroxyl, carboxyl, sulfonate, phosphonate and the like into
their backbones. Incidentally, the "backbone" of a molecule is a
term that is frequently used in the art to designate a central
portion or core of the molecular structure. For the purpose of this
invention, a "small molecule" is an aromatic or a heteroaromatic
compound: (1) that exhibits a molecular weight less than about 500
Daltons; (2) that is capable of absorbing spectral energy of at
least about 400 nm (e.g., visible and/or near infrared light); and
(3) that is capable of emanating spectral energy of at least about
400 nm (e.g., visible and/or near infrared light). Further, a
"rigid" molecule refers to a molecule that undergoes little, if
any, internal rotational movement. Pyrazine derivatives of the
invention may be desirable for renal applications because they tend
to be cleared from the body via the kidneys, may demonstrate strong
absorption and/or emission/fluorescence in the visible region, and
tend to exhibit significant Stokes shifts. These properties allow
great flexibility in both tuning the molecule to the desired
wavelength and introducing a wide variety of substituents to
improve clearance properties.
[0012] In a first aspect, the present invention is directed to
pyrazine derivatives of Formula I (below). With regard to Formula
I, X.sup.1 and X.sup.2 may, at least in some embodiments, be
characterized as electron withdrawing substituents, and each may
independently chosen from the group consisting of --CN,
--CO.sub.2R.sup.1, --CONR.sup.2R.sup.3, --COR.sup.4, --NO.sub.2,
--SOR.sup.5, --SO.sub.2R.sup.6, --SO.sub.2OR.sup.7 and
--PO.sub.3R.sup.8R.sup.9. Further, Y.sup.1 and Y.sup.2 may, at
least in some embodiments, be characterized as electron donating
substituents and may be independently chosen from the group
consisting of --OR.sup.10, --SR.sup.11, --NR.sup.12R.sup.13,
--N(R.sup.14)COR.sup.5 and substituents corresponding to Formula A
below. Z.sup.1 may be a direct bond, --CR.sup.16R.sup.17--, --O--,
--NR.sup.18--, --NCOR.sup.19--, --S--, --SO-- or --SO.sub.2--. "m"
and "n" may independently be any appropriate integers. For
instance, in some embodiments, each of "m" and "n" may
independently be between 1 and 6 (inclusive). As another example,
in some embodiments, each of "m" and "n" may independently be
between 1 and 3 (inclusive). R.sup.1 to R.sup.19 may be any
suitable substituents capable of enhancing biological and/or
physicochemical properties of pyrazine derivatives of Formula I.
For example, for renal function assessment, each of the R groups of
R.sup.1 to R.sup.19 may independently be any one of a hydrogen
atom, an anionic functional group (e.g., carboxylate, sulfonate,
sulfate, phopshonate and phosphate) and a hydrophilic functional
group (e.g., hydroxyl, carboxyl, sulfonyl, sulfonato and
phosphonato).
##STR00002##
[0013] A second aspect of the invention is directed to pyrazine
derivatives of Formula II. With regard to Formula II, X.sup.3 and
X.sup.4 may, at least in some embodiments, be characterized as
electron withdrawing substituents and may be independently chosen
from the group consisting of --CN, --CO.sub.2R.sup.20,
--CONR.sup.21R.sup.22, --COR.sup.23, --NO.sub.2, --SOR.sup.24,
--SO.sub.2R.sup.25, --S.sub.2OR.sup.26 and
--PO.sub.3R.sup.27R.sup.28. By contrast, Y.sup.3 and Y.sup.4 may,
at least in some embodiments, be characterized as electron donating
substituents and may be independently chosen from the group
consisting of --OR.sup.29, --SR.sup.30, --NR.sup.31R.sup.32,
--N(R.sup.33)COR.sup.34 and substituents corresponding to Formula B
below. Z.sup.2 is preferably a direct bond, --CR.sup.3SR.sup.36--,
--O--, --NR.sup.37--, --NCOR.sup.38--, --S--, --SO-- or
--SO.sub.2--. "p" and "q" may independently be any appropriate
integers. For instance, in some embodiments, each of "p" and "q"
may independently be between 1 and 6 (inclusive). As another
example, in some embodiments, each of "p" and "q" may independently
be between 1 and 3 (inclusive). R.sup.20 to R.sup.38 may be any
appropriate substituents capable of enhancing biological and/or
physicochemical properties of pyrazine derivatives of Formula II.
For example, for renal function assessment, each of the R groups of
R.sup.20 to R.sup.38 may independently be any one of a hydrogen
atom, an anionic functional group (e.g., carboxylate, sulfonate,
sulfate, phopshonate and phosphate) and a hydrophilic functional
group (e.g., hydroxyl, carboxyl, sulfonyl, sulfonato and
phosphonato).
##STR00003##
[0014] Yet a third aspect of the invention is directed to methods
of determining renal function using pyrazine derivatives such as
those described above with regard to Formulas I and II. In these
methods, an effective amount of a pyrazine derivative is
administered into the body of a patient (e.g., a mammal such as a
human or animal subject). Incidentally, an "effective amount"
herein generally refers to an amount of pyrazine derivative that is
sufficient to enable renal clearance to be analyzed. The
composition is exposed to at least one of visible and near infrared
light. Due to this exposure of the composition to the visible
and/or infrared light, the composition emanates spectral energy
that may be detected by appropriate detection equipment. This
spectral energy emanating from the composition may be detected
using an appropriate detection mechanism such as an invasive or
non-invasive optical probe. Herein, "emanating" or the like refers
to spectral energy that is emitted and/or fluoresced from a
composition of the invention. Renal function can be determined
based the spectral energy that is detected. For example, an initial
amount of the amount of composition present in the body of a
patient may be determined by a magnitude/intensity of light
emanated from the composition that is detected (e.g., in the
bloodstream). As the composition is cleared from the body, the
magnitude/intensity of detected light generally diminishes.
Accordingly, a rate at which this magnitude of detected light
diminishes may be correlated to a renal clearance rate of the
patient. This detection may be done periodically or in
substantially real time (providing a substantially continuous
monitoring of renal function). Indeed, methods of the present
invention enable renal function/clearance to be determined via
detecting a change and/or a rate of change of the detected
magnitude of spectral energy (indicative of an amount of the
composition that has not been cleared) from the portion of the
composition that remains in the body.
[0015] Yet a fourth aspect of the invention is directed to methods
for preparing 2,5-diaminopyrazine-3,6-dicarboxylic acid. In these
methods, a hydrolysis mixture including
2,4,6,8-tetrahydroxypyrimido(4,5-g)pteridine or a salt thereof is
irradiated with microwaves.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1: Structures of small molecule renal agents.
[0017] FIG. 2: Structures of conventional visible and NIR dyes.
[0018] FIG. 3: Blood clearance profile of cyanine tetrasulfonate
dye (8).
[0019] FIG. 4: Block diagram of an assembly for assessing renal
function.
[0020] FIG. 5: Graph showing renal clearance profile of a normal
rat.
[0021] FIG. 6: Graph showing renal clearance profile of a
bilaterally nephrectomized rat.
[0022] FIG. 7: Graph comparing data of FIGS. 5 and 6.
[0023] FIGS. 8A & 8B: Projection view of disodium
2,5-diamino-3,6-(dicarboxylato)pyrazine crystals prepared as set
forth in Example 16. FIG. 8A is a projection view of the molecule
with 50% thermal ellipsoids and FIG. 8B is projection view of the
molecule with 50% thermal ellipsoids and coordination sphere of the
Na atoms.
DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS
[0024] The present invention discloses renal function monitoring
compounds. An example of a particular compound of the invention
corresponds to Formula I below. In this exemplary embodiment,
X.sup.1 and X.sup.2 are electron withdrawing substituents
independently chosen from the group consisting of --CN,
--CO.sub.2R.sup.1, --CONR.sup.2R.sup.3, --COR.sup.4, --NO.sub.2,
--SOR.sup.5, --SO.sub.2R.sup.6, --SO.sub.2OR.sup.7 and
--PO.sub.3R.sup.8R.sup.9. Y.sup.1 and Y.sup.2 are independently
chosen from the group consisting of --OR.sup.10, --SR.sup.11,
--NR.sup.12R.sup.13, --N(R.sup.4)COR.sup.15 and substituents
represented by Formula A. Z.sup.1 is selected from the group
consisting of a direct bond, --CR.sup.16R.sup.17--, --O--,
--NR.sup.18--, --NCOR.sup.19--, --S--, --SO-- and --SO.sub.2--.
Each of the R groups of R.sup.1 to R.sup.19 are independently
selected from the group consisting of hydrogen, C3-C6
polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.aR.sup.40, C1-C10
alkyl, C5-C10 aryl, C5-C10 heteroaryl, --(CH.sub.2).sub.aOH,
--(CH.sub.2).sub.aCO.sub.2H, --(CH.sub.2).sub.aSO.sub.3H,
--(CH.sub.2).sub.aSO.sub.3.sup.-, --(CH.sub.2).sub.aOSO.sub.3H,
--(CH.sub.2).sub.aOSO.sub.3.sup.-, --(CH.sub.2).sub.aNHSO.sub.3H,
--(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--(CH.sub.2).sub.aPO.sub.3H.sub.2,
--(CH.sub.2).sub.aPO.sub.3H.sup.-,
--(CH.sub.2).sub.aPO.sub.3.sup.-, (CH.sub.2).sub.aOPO.sub.3H.sub.2,
--(CH.sub.2)OPO.sub.3H.sup.- and --(CH.sub.2).sub.aOPO.sub.3.
R.sup.40 is selected from the group consisting of hydrogen, C1-C10
alkyl, C5-C10 aryl, C5-C10 heteroaryl, --(CH.sub.2).sub.aOH,
--(CH.sub.2).sub.aCO.sub.2H, --(CH.sub.2).sub.aSO.sub.3H.sup.-,
--(CH.sub.2)SO.sub.3, --(CH.sub.2).sub.aOSO.sub.3H,
--(CH.sub.2).sub.aOSO.sub.3, --(CH.sub.2).sub.aNHSO.sub.3H,
--(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--(CH.sub.2).sub.aPO.sub.3H.sub.2,
--(CH.sub.2).sub.aPO.sub.3H.sup.-,
--(CH.sub.2).sub.aPO.sub.3.sup.-,
--(CH.sub.2).sub.aOPO.sub.3H.sub.2,
--(CH.sub.2).sub.aOPO.sub.3H.sup.- and --(CH.sub.2).sub.aOPO.sub.3.
"m" and "n" independently fall within the range of 1 to 6 inclusive
in some embodiments, and independently fall within the range of 1
to 3 inclusive in some embodiments. "a" is an integer from 1 to 10
inclusive in some embodiments, and is an integer from 1 to 6
inclusive in some embodiments.
[0025] In some embodiments represented by Formula I, each of
X.sup.1 and X.sup.2 are --CN, --CO.sub.2R.sup.1 or
--CONR.sup.2R.sup.3, each of Y.sup.1 and Y.sup.2 are
--NR.sup.12R.sup.13 or the substituent of Formula A, and Z.sup.1 is
a direct bond. In such compositions, each of R.sup.1, R.sup.2,
R.sup.3, R.sup.12 and R.sup.13 is not hydrogen, C1-C10 alkyl or
C1-C10 aryl, and m, n, N and Z.sup.1 together do not form a 5- or
6-membered ring.
##STR00004##
[0026] In some embodiments represented by Formula I, X.sup.1 and
X.sup.2 are independently selected from the group consisting of
--CN, --CO.sub.2R.sup.1, --CONR.sup.2R.sup.3, --SO.sub.2R.sup.6 and
--SO.sub.2OR.sup.7. Further, Y.sup.1 and Y.sup.2 are independently
selected from the group consisting of --NR.sup.12R.sup.13,
--N(R.sup.14)COR.sup.is and substituents represented by Formula A.
Z.sup.1 is selected from the group consisting of a direct bond,
--CR.sup.16R.sup.17--, --O--, --NR.sup.18--, --NCOR.sup.19--,
--S--, --SO-- and --SO.sub.2--. The R groups of R.sup.1 to R.sup.19
are each independently selected from the group consisting of
hydrogen, C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.a--R.sup.40,
C1-C10 alkyl, C5-C10 heteroaryl, C5-C10 aryl, --(CH.sub.2).sub.aOH,
--(CH.sub.2).sub.aCO.sub.2H, --(CH.sub.2).sub.aSO.sub.3H and
--(CH.sub.2).sub.aSO.sub.3.sup.-. Further, "a", "m" and "n" fall
within a range from 1 to 3 inclusive.
[0027] In some embodiments represented by Formula I, X.sup.1 and
X.sup.2 are independently chosen from the group consisting of --CN,
--CO.sub.2R.sup.1 and --CONR.sup.2R.sup.3. Y.sup.1 and Y.sup.2 are
independently selected from the group consisting of
--NR.sup.2R.sup.13 and substituents represented by Formula A.
Z.sup.1 is selected from the group consisting of a direct bond,
--CR.sup.16R.sup.17--, --O--, --NR.sup.18--, --NCOR.sup.9--, --S--,
--SO-- and --SO.sub.2--. Each of the R groups of R.sup.1 to
R.sup.19 is independently selected from the group consisting of
hydrogen, C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.a--R.sup.4, C1-C10
alkyl, --(CH.sub.2).sub.aOH and --(CH.sub.2).sub.aCO.sub.2H.
Further, "a," "m" and "n" are within a range from 1 to 3
inclusive.
[0028] Another example of a particular compound of the invention
corresponds to Formula II below.
[0029] In this exemplary embodiment, X.sup.3 and X.sup.4 are
electron withdrawing substituents independently selected from the
group consisting of --CN, --CO.sub.2R.sup.20,
--CONR.sup.21R.sup.22, --COR.sup.23, --NO.sub.2, --SOR.sup.24,
--SO.sub.2R.sup.25, --SO.sub.2OR.sup.26 and
--PO.sub.3R.sup.27R.sup.28. Y.sup.3 and Y.sup.4 are electron
donating substituents independently selected from the group
consisting of --OR.sup.29, --SR.sup.30, --NR.sup.31R.sup.32,
--N(R.sup.33)COR.sup.34 and substituents represented by Formula B.
Z.sup.2 is selected from the group consisting of a direct bond,
--CR.sup.35R.sup.36--, --O--, --NR.sup.37--, --NCOR.sup.38--,
--S--, --SO--, and --SO.sub.2--. Each of the R groups of R.sup.20
to R.sup.38 are independently selected from the group consisting of
hydrogen, C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, C5-C10 aryl, C5-C10 heteroaryl, --(CH.sub.2).sub.bOH,
--(CH.sub.2).sub.bCO.sub.2H, --(CH.sub.2).sub.bSO.sub.3H,
--(CH.sub.2).sub.bSO.sub.3.sup.-, --(CH.sub.2).sub.bOSO.sub.3H,
--(CH.sub.2).sub.bOSO.sub.3.sup.-, --CH.sub.2).sub.bNHSO.sub.3H,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bPO.sub.3H.sub.2, --(CH.sub.2).sub.bPO.sub.3H,
--(CH.sub.2).sub.bPO.sub.3.sup.-,
--(CH.sub.2).sub.bOPO.sub.3H.sub.2, --(CH.sub.2).sub.bOPO.sub.3H
and --(CH.sub.2).sub.bOPO.sub.3. R.sup.40 is selected from the
group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C5-C10
heteroaryl, --(CH.sub.2).sub.bOH, --(CH.sub.2).sub.bCO.sub.2H,
--(CH.sub.2).sub.bSO.sub.3H, --(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bOSO.sub.3H, --(CH.sub.2).sub.bOSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3H, --(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bPO.sub.3H.sub.2,
--(CH.sub.2).sub.bPO.sub.3H.sup.-,
--(CH.sub.2).sub.bPO.sub.3.sup.-,
--(CH.sub.2).sub.bOPO.sub.3H.sub.2,
--(CH.sub.2).sub.bOPO.sub.3H.sup.- and --(CH.sub.2).sub.bOPO.sub.3.
"p" and "q" independently fall within the range of 1 to 6 inclusive
in some embodiments, and independently fall within the range of 1
to 3 inclusive in some embodiments. "b" is an integer from 1 to 10
inclusive in some embodiments, and is an integer from 1 to 6
inclusive in some embodiments.
[0030] In some embodiments represented by Formula II, X.sup.3 and
X.sup.4 are independently --CN, --CO.sub.2R.sup.20 or
--CONR.sup.21R.sup.22; Y.sup.3 and Y.sup.4 are independently
--NR.sup.31R.sup.32 or a substituent of Formula B; and Z.sup.2 is a
direct bond. In such embodiments, each of R.sup.20, R.sup.21,
R.sup.22, R.sup.31 and R.sup.32 is independently not hydrogen,
C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl or C1-C10 aryl. Further, p, q, N and Z.sup.2 together
do not form a 5- or 6-membered ring in such embodiments.
##STR00005##
[0031] In some embodiments represented by Formula II, X.sup.3 and
X.sup.4 are independently selected from the group consisting of
--CN, --CO.sub.2R.sup.20, --CONR.sup.21R.sup.22, --SO.sub.2R.sup.25
and --SO.sub.2R.sup.26. Y.sup.3 and Y.sup.4 are independently
selected from the group consisting of --NR.sup.31R.sup.32,
--N(R.sup.33)COR.sup.34 and substituents represented by Formula B.
Z.sup.2 is selected from the group consisting of a direct bond,
--CR.sup.35R.sup.36--, --O--, --NR.sup.37--, --NCOR.sup.38--,
--S--, --SO-- and --SO.sub.2--. Each of the R groups of R.sup.20 to
R.sup.38 are independently selected from the group consisting of
hydrogen, C3-C6 polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, C5-C10 aryl, C5-C10 heteroaryl --(CH.sub.2).sub.bOH,
--(CH.sub.2).sub.bCO.sub.2H, --(CH.sub.2).sub.bSO.sub.3H and
--(CH.sub.2).sub.bSO.sub.3.sup.-. In these embodiments, "b", "p"
and "q" independently range from 1 to 3 inclusive.
[0032] Some embodiments represented by Formula II have X.sup.3 and
X.sup.4 being independently selected from the group consisting of
--CN, --CO.sub.2R.sup.20 and --CONR.sup.21R.sup.22. Each of Y.sup.3
and Y.sup.4 may be --NR.sup.33R.sup.34 or a substituent represented
by Formula B. Z.sup.2 is selected from the group consisting of a
direct bond, --CR.sup.16R.sup.17, --O, --NR.sup.18, --NCOR.sup.19,
--S, --SO and --SO.sub.2. R.sup.20 to R.sup.38 are independently
selected from the group consisting of hydrogen, C3-C6
polyhydroxylated alkyl,
--((CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O).sub.b--R.sup.40,
C1-C10 alkyl, --(CH.sub.2).sub.bOH and --(CH.sub.2).sub.aCO.sub.2H.
"b", "p" and "q" independently range from 1 to 3 inclusive.
[0033] By way of example, and not by way of limitation, compounds
of Formula I and Formula II include the following (other exemplary
compounds include those described in Examples 1-16):
##STR00006## ##STR00007##
[0034] Syntheses of pyrazine derivatives, in general, has been
previously studied [27] and described [25, 26, 28, 29]. Preparation
procedures for at least some of the pyrazine derivatives disclosed
herein, using procedures similar to the cited references, are
described herein in Examples 1-8 and 12. Based on the cited
references and the disclosure herein, one of ordinary skill in the
art will be readily able to prepare compounds of the invention.
[0035] In accordance with one aspect of the present invention,
compounds corresponding to Formula I may be derived from
2,5-diaminopyrazine-3,6-dicarboxylic acid which, in turn, may be
derived from 5-aminouracil. For example, 5-aminouracil may be
treated with a ferricyanide in the presence of a base to form, as
an intermediate, 2,4,6,8-tetrahydroxypyrimido(4,5-g)pteridine (or a
salt thereof), the pteridine intermediate is heated and hydrolyzed
using a base, and the hydrolysate is then acidified to yield
2,5-diaminopyrazine-3,6-dicarboxylic as illustrated in Reaction
Scheme 1.
##STR00008##
[0036] wherein each Z is independently hydrogen or a monovalent
cation. For example, each Z may independently be hydrogen or an
alkali metal. In one exemplary embodiment, each Z is hydrogen. In
another exemplary embodiment, each Z is an alkali metal. In yet
another exemplary embodiment, each Z is lithium, sodium or
potassium, but they are different (e.g., one is potassium and the
other is lithium or sodium).
[0037] The series of reactions illustrated in Reaction Scheme 1 are
generally carried out in a suitable solvent. Typically, the
reactions will be carried out in an aqueous system.
[0038] In one embodiment, each equivalent of 5-aminouracil is
treated with about 3.0 equivalents of ferricyanide, and the
concentration of the base is about 0.5N in the reaction mixture.
The ferricyanide used to treat 5-aminouracil may be selected from
the group consisting of potassium ferricyanide
(K.sub.3Fe(CN).sub.6), lithium ferricyanide (Li.sub.3Fe(CN).sub.6),
sodium ferricyanide (Na.sub.3Fe(CN).sub.6), sodium potassium
ferricyanide, lithium sodium ferricyanide or lithium potassium
ferricyanide. Typically, the ferricyanide will be potassium
ferricyanide. The base used in combination with the ferricyanide is
preferably an alkali metal hydroxide, e.g., sodium or potassium
hydroxide. See, for example, Taylor et al., JACS, 77: 2243-2248
(1955).
[0039] In a preferred embodiment, the hydrolysis mixture is
irradiated with microwaves to heat the mixture as the
2,4,6,8-tetrahydroxypyrimido(4,5-g)pteridine (or salt thereof) is
hydrolyzed. At least in some embodiments, the microwaves will have
a frequency within the range of about 300 MHz to 30 GHz, and the
hydrolysis mixture (preferably an aqueous hydrolysis mixture) is
heated to a temperature within the range of about 120 to about
180.degree. C. for a period of about 30 to about 90 minutes. For
example, in some embodiments, the hydrolysis mixture will be
irradiated with microwaves to heat the hydrolysis mixture to a
temperature of about 120 to about 140.degree. C. for about 45 to
about 75 minutes. In addition to the
2,4,6,8-tetrahydroxypyrimido(4,5-g)pteridine (or salt thereof), the
hydrolysis mixture of at least some embodiments will typically
contain at least about 4.7 equivalents of a base, preferably an
alkali metal hydroxide (e.g., potassium or sodium hydroxide). The
resulting hydrolysate may then be acidified, preferably with a
mineral acid such as hydrochloric acid, sulfuric acid, or
phosphoric acid, more preferably hydrochloric acid, to provide
2,5-diaminopyrazine-3,6-dicarboxylate.
[0040] Methods for the conversion of
2,5-diaminopyrazine-3,6-dicarboxylic acid to other compositions
falling within Formula I are known to those of ordinary skill. For
example, corresponding 2,5-diaminopyrazine-3,6-diesters and
corresponding 2,5-Bis(N,N-dialkylamino) pyrazine-3,6-diesters may
be prepared by treating 2,5-diaminopyrazine-3,6-dicarboxylic acid
with the appropriate alkylating agent(s), for example, a mono- or
dialkyl halide as described in Kim et al., Dyes and Pigments, Vol.
39, pages 341-357 (1998). Alternatively, corresponding
2,5-diaminopyrazine-3,6-dithioesters or corresponding
2,5-Bis(N,N-dialkylamino) pyrazine-3,6-dithioesters may be prepared
by treating the 2,5-diaminopyrazine-3,6-dicarboxylic acid with a
thiol, or a thiol and the appropriate alkylating agent,
respectively, as described in Kim et al., Dyes and Pigments, Vol.
41, pages 183-191 (1999).
[0041] It is noteworthy that the alkylation of the electron
donating amino groups in cyano- or carboxypyrazines has a profound
effect on electronic transition of the pyrazine chromophore in that
the dialkylation of the amino group in
2,5-diamino-3,5-dicyanopyrazine produces large bathochromic shift
on the order of about 40-60 nm. It is also noteworthy that the
pyrrolidino and piperidino derivatives exhibit substantial
differences in their UV spectra (e.g., the former may tend to
exhibit a bathochromic shift of about 34 nm).
[0042] One protocol for assessing physiological function of renal
cells includes administering an effective amount of a pyrazine
derivative that is capable of being renally cleared into a body of
a patient. This pyrazine derivative is hydrophilic and capable of
absorbing and/or emanating spectral energy of at least about 400
nm. Examples of such pyrazine derivates are those represented by
Formulas I and II above. An appropriate dosage of the pyrazine
derivative that is administered to the patient is readily
determinable by one of ordinary skill in the art and may vary
according to such factors as clinical procedure contemplated,
solubility, bioavailabilty, and toxicity. By way of example, an
appropriate dosage generally ranges from about 1 nanomolar to about
100 micromolar. The administration of the pyrazine derivative to
the patient may occur in any of a number of appropriate fashions
including, but not limited to: (1) intravenous, intraperitoneal, or
subcutaneous injection or infusion; (2) oral administration; (3)
transdermal absorption through the skin; and (4) inhalation.
[0043] Still referring to the above-mentioned protocol, the
pyrazine derivative in the patient's body is exposed to spectral
energy of at least about 400 nm (preferably, visible and/or near
infrared light). This exposure of the pyrazine derivative to
spectral energy preferably occurs while the pyrazine derivative is
in the body (e.g., in the bloodstream). Due to this exposure of the
pyrazine derivative to the spectral energy, the pyrazine derivative
emanates spectral energy (e.g., visible and/or near infrared light)
that may be detected by appropriate detection equipment. The
spectral energy emanated from the pyrazine derivative tends to
exhibit a wavelength range greater than a wavelength range absorbed
by the pyrazine derivative. For example, if a composition of the
invention absorbs light of about 700 nm, the composition may emit
light of about 745 nm.
[0044] Detection of the pyrazine derivative (or more particularly,
the light emanating therefrom) may be achieved through optical
fluorescence, absorbance, light scattering or other related
procedures known in the art. In some embodiments, this detection of
the emanated spectral energy may be characterized as a collection
of the emanated spectral energy and a generation of electrical
signal indicative of the collected spectral energy. The
mechanism(s) utilized to detect the spectral energy from the
composition that is present in the body may be designed to detect
only selected wavelengths (or wavelength ranges) and/or may include
one or more appropriate spectral filters. Various catheters,
endoscopes, ear clips, hand bands, head bands, forehead sensors,
surface coils, finger probes and the like may be utilized to expose
the pyrazine derivatives to light and/or to detect the light
emanating therefrom [30]. This detection of spectral energy may be
accomplished at one or more times intermittently or may be
substantially continuous.
[0045] Renal function of the patient can be determined based on the
detected spectral energy. This can be achieved by using data
indicative of the detected spectral energy and generating an
intensity/time profile indicative of a clearance of the pyrazine
derivative from the body. This profile may be correlated to a
physiological or pathological condition. For example, the patient's
clearance profiles and/or clearance rates may be compared to known
clearance profiles and/or rates to assess the patient's renal
function and to diagnose the patient's physiological condition. In
the case of analyzing the presence of the pyrazine derivative in
bodily fluids, concentration/time curves may be generated and
analyzed (preferably in real time) using an appropriate
microprocessor to diagnose renal function.
[0046] Physiological function can be assessed by any of a number of
procedures such as any of the following or similar procedures alone
or in any combination: (1) comparing differences in manners in
which normal and impaired cells remove a composition of the
invention from the bloodstream; (2) measuring a rate or an
accumulation of a composition of the invention in the organs or
tissues; and (3) obtaining tomographic images of organs or tissues
having a composition of the invention associated therewith. For
example, blood pool clearance may be measured non-invasively from
convenient surface capillaries such as those found in an ear lobe
or a finger or can be measured invasively using an appropriate
instrument such as an endovascular catheter. Accumulation of a
composition of the invention within cells of interest can be
assessed in a similar fashion. Incidentally, a "composition" of the
invention refers to sterile formulations, aqueous formulations,
parenteral formulations and any other formulations including one or
more of the pyrazine derivatives of the invention. These
compositions of the invention may include pharmaceutically
acceptable diluents, carriers, adjuvants, preservatives,
excipients, buffers, and the like. The phrase "pharmaceutically
acceptable" means those formulations which are, within the scope of
sound medical judgment, suitable for use in contact with the
tissues of humans and animals without undue toxicity, irritation,
allergic response and the like, and are commensurate with a
reasonable benefit/risk ratio.
[0047] A modified pulmonary artery catheter may also be utilized
to, inter alia, make the desired measurements [32] of spectral
energy emanating from a composition of the invention. The ability
for a pulmonary catheter to detect spectral energy emanating from a
composition of the invention is a distinct improvement over current
pulmonary artery catheters that measure only intravascular
pressures, cardiac output and other derived measures of blood flow.
Traditionally, critically ill patients have been managed using only
the above-listed parameters, and their treatment has tended to be
dependent upon intermittent blood sampling and testing for
assessment of renal function. These traditional parameters provide
for discontinuous data and are frequently misleading in many
patient populations.
[0048] Modification of a standard pulmonary artery catheter only
requires making a fiber optic sensor thereof wavelength-specific.
Catheters that incorporate fiber optic technology for measuring
mixed venous oxygen saturation exist currently. In one
characterization, it may be said that the modified pulmonary artery
catheter incorporates a wavelength-specific optical sensor into a
tip of a standard pulmonary artery catheter. This
wavelength-specific optical sensor can be utilized to monitor renal
function specific elimination of a designed optically detectable
chemical-entity such as the compositions of the present invention.
Thus, by a method analogous to a dye dilution curve, real-time
renal function can be monitored by the disappearance/clearance of
an optically detected compound.
[0049] The following examples illustrate specific embodiments of
this invention. As would be apparent to skilled artisans, various
changes and modifications are possible and are contemplated within
the scope of the invention described.
Example 1
Prophetic
Preparation of
36-dicyano-2,5-[(N,N,N',N'-tetrakis(carboxymethyl)amino]pyrazine
##STR00009##
[0051] Step 1.
[0052] A stirring mixture of 2,5-diamino-3,6-dicyanopyrazine (10
mmol) and t-butyl bromoacetate (42 mmol) in distilled
dimethylacetamide (25 mL) is cooled in ice and subsequently treated
with powdered sodium hydroxide (50 mmol). After stirring at ambient
temperature for about 2 hours, the reaction mixture is treated
water (200 mL) and methylene chloride (100 mL). An organic layer of
the mixture is washed with copious water, next dried over sodium
sulfate, then filtered, and subsequently the filtrate evaporated in
vacuo. The crude product is then purified by flash chromatography
to give tetra-t-butyl ester.
[0053] Step 2.
[0054] The tetraester from Step 1 (10 mmol) is treated with 96%
formic acid (10 mL) and heated to boiling for about 1 minute and
kept at about 40-50.degree. C. for approximately 16 hours. The
reaction mixture is poured onto ether causing formation of a
precipitate. This resulting precipitate is separated from the ether
layer by decantation, and then purified by chromatography or
recrystallization.
Example 2
Prophetic
Preparation of
3,6-(N,N,N',N'-tetrakis(2-hydroxyethyl)aminopyrazine-2,5-dicarboxylic
acid
##STR00010##
[0056] Step 1.
[0057] The alkylation procedure is identical to the one in Step 1
of Example 1, except that 2-iodoethanol is used instead of
t-butylbromoacetate.
[0058] Step 2.
[0059] The dicyano compound from Step 1 (10 mmol) is dissolved in
concentrated sulfuric acid (10 mL) and stirred at ambient
temperature for about 3 hours. The reaction mixture is carefully
diluted with water (100 mL), and the product is collected by
filtration and subsequently dried to give the corresponding
carboxamide intermediate.
[0060] Step 3.
[0061] The biscarboxamide derivative from Step 2 (10 mmol) is
dissolved in potassium hydroxide solution (25 mmol in 25 mL of
water) and heated under reflux for about 3 hours. After cooling,
the solution is acidified with 1N HCl (25 mL). The product is
collected by filtration, dried, and purified by recyrstallization
or chromatography.
Preparation of
3,5-[(N,N,N',N'-tetrakis(2-hydroxyethyl)amino]-pyrazine-2,6-dicarboxylic
acid (compound of Formula II) can be accomplished in a similar
manner using 2,6-diamino-3,5-dicyanopyazine as the starting
material
[0062] Alternatively,
3,6-[(N,N,N',N'-tetrakis(2-hydroxyethyl)amino]pyrazine-2,5-dicarboxylic
acid may be prepared by N-alkylating
3,6-diaminopyrazine-2,5-dicarboxylic acid (Example 16) with
2-iodoethanol as described in Step 1.
Example 3
Prophetic
Preparation of 3,6-bis(N-azetadino)pyrazine-2,5-dicarboxylic
acid
##STR00011##
[0064] Step 1.
[0065] The alkylation procedure is substantially identical to the
one in Step 1 of Example 1, except that 1,3-dibromopropane is used
instead of t-butylbromoacetate.
[0066] Step 2.
[0067] The hydrolysis procedure is substantially identical to the
one in Step 2 of Example 2, except that the starting material is
3,6-dicyano-2,5-bis(N-azetadino)pyrazine.
[0068] Step 3.
[0069] The hydrolysis procedure is substantially identical to the
one in Step 3 of Example 2, except that the starting material is
3,6-bis(N-azetadino)-2,5-pyrazinedicarboxamide.
[0070] Preparation of 3,5-bis(N-azetadino)pyrazine-2,6-dicarboxylic
acid (compound of Formula II) can be accomplished in a similar
fashion using 2,6-diamino-3,5-dicyanopyazine as the starting
material.
[0071] Alternatively, 3,6-bis(N-azetadino)pyrazine-2,5-dicarboxylic
acid may be prepared by N-alkylating
3,6-diaminopyrazine-2,5-dicarboxylic acid (Example 16) with
1,3-dibromopropane as described in Step 1.
Example 4
Prophetic
Preparation of 3,6-bis(N-morpholino)pyrazine-2,5-dicarboxylic
acid
##STR00012##
[0073] Step 1.
[0074] The alkylation procedure is identical to the one in Step 1,
Example 1 except that bis(2-chloroethyl) ether is used instead of
t-butylbromoacetate.
[0075] Step 2.
[0076] The hydrolysis procedure is identical to the one in Step 2,
Example 2 except that the starting material is
3,6-dicyano-2,5-bis(N-morpholino)pyrazine.
[0077] Step 3.
[0078] The hydrolysis procedure is identical to the one in Step 3,
Example 2 except that the starting material is
3,6-bis(N-morpholino)-2,5-pyrazinedicarboxamide.
[0079] Preparation of
3,5-bis(N-morpholino)pyrazine-2,6-dicarboxylic acid (compound
belonging to Formula II) can be accomplished in the same manner
using 2,6-diamino-3,5-dicyanopyazine as the starting material.
[0080] Alternatively,
3,6-bis(N-morpholino)pyrazine-2,5-dicarboxylic acid may be prepared
by N-alkylating 3,6-diaminopyrazine-2,5-dicarboxylic acid (Example
16) with (2-chloroethyl) ether as described in Step 1.
Example 5
Prophetic
Preparation of 3,6-bis(N-piperazino)pyrazine-2,5-dicarboxylic
acid
##STR00013##
[0082] Step 1.
[0083] The alkylation procedure is identical to the one in Step 1,
Example 1 except that bis(2-chloroethyl) amine is used instead of
t-butylbromoacetate.
[0084] Step 2.
[0085] The hydrolysis procedure is identical to the one in Step 2,
Example 2 except that the starting material is
3,6-dicyano-2,5-bis(N-piperazino)pyrazine.
[0086] Step 3.
[0087] The hydrolysis procedure is identical to the one in Step 3,
Example 2 except that the starting material is
3,6-bis(N-piperazino)-2,5-pyrazinedicarboxamide.
[0088] Preparation of
3,5-bis(N-piperazino)pyrazine-2,6-dicarboxylic acid (compound
belonging to Formula II) can be accomplished in the same manner
using 2,6-diamino-3,5-dicyanopyazine as the starting material.
[0089] Alternatively,
3,6-bis(N-piperazino)pyrazine-2,5-dicarboxylic acid may be prepared
by N-alkylating 3,6-diaminopyrazine-2,5-dicarboxylic acid (Example
16) with bis(2-chloroethyl) amine as described in Step 1.
Example 6
Prophetic
Preparation of 3,6-bis(N-thiomorpholino)pyrazine-2,5-dicarboxylic
acid
##STR00014##
[0091] Step 1.
[0092] A mixture of the tetralcohol product from Step 1, Example 2,
(10 mmol), and triethylamine (44 mmol) in anhydrous tetrahydrofuran
(50 mL) cooled to 0.degree. C. and treated with methanesulfonyl
chloride (42 mmol) added in portion in such a manner that the
temperature is maintained at 0 to 15.degree. C. After the addition,
the reaction mixture is stirred at ambient temperature for 16
hours. The reaction mixture is then filtered and the filtrate taken
to dryness under reduced pressure.
[0093] The residue is then redissolved in methanol (20 mL) and
treated with sodium sulfide (22 mmol). The reaction mixture is then
heated under reflux for 16 hours and poured onto water (100 mL) and
extracted with ethyl acetate. The combined organic layer is washed
with copious water, dried over sodium sulfate, filtered, and the
filtrate evaporated in vacuo. The crude product is then purified by
flash chromatography to give the bis(thiomorpholino)pyrazine
diester.
[0094] Step 2.
[0095] The hydrolysis procedure is identical to the one in Step 2,
Example 2 except that the starting material is
3,6-dicyano-2,5-bis(N-thiomorpholino)pyrazine.
[0096] Step 3.
[0097] The hydrolysis procedure is identical to the one in Step 3,
Example 2 except that the starting material is
3,6-bis(N-thiomorpholino)-2,5-pyrazinedicarboxamide.
[0098] Preparation of
3,5-bis(N-thiomorpholino)pyrazine-2,6-dicarboxylic acid (compound
belonging to Formula II) can be accomplished in the same manner
using 2,6-diamino-3,5-dicyanopyazine as the starting material.
Example 7
Prophetic
Preparation of 3,6-bis(N-thiomorpholino)pyrazine-2,5-dicarboxylic
acid S-oxide
##STR00015##
[0100] Step 1.
[0101] The bis(thiomorpholino)pyrazine derivative from Step 3,
Example 6 (5 mmol) is dissolved in methanol (20 mL) and treated
with m-chloroperoxybenzoic acid (11 mmol) and heated under reflux
for 16 hours. The reaction mixture poured onto saturated sodium
bicarbonate (20 mL) and extracted with methylene chloride. The
combined organic layer is washed with brine, dried over sodium
sulfate, filtered, and the filtrate evaporated in vacuo. The crude
product is purified by chromatography or recrystallization.
[0102] Step 2.
[0103] The procedure is identical to Step 2, Example 6 except that
thiomorpholino-S-oxide is used in this experiment.
[0104] Preparation of
3,5-bis(N-thiomorpholino)pyrazine-2,6-dicarboxylic acid S-oxide
(compound belonging to Formula II) can be accomplished in the same
manner using 2,6-diamino-3,5-dicyanopyazine as the starting
material, followed by hydrolysis of the nitrile as outlined in
Example 1, Step 2 or Example 2, Steps 2 and 3.
Example 8
Prophetic
Preparation of 2,5-dicyano-3,6-bis(N-thiomorpholino)pyrazine
S,S-dioxide
##STR00016##
[0106] Step 1.
[0107] The procedure is identical to Step 1, Example 7 except that
thiomorpholino-S-oxide is used in this experiment.
[0108] Step 2.
[0109] The procedure is identical to Step 2, Example 6 except that
thiomorpholino-S,S-dioxide is used in this experiment.
Example 9
Prophetic
[0110] Protocol for Assessing Renal Function.
[0111] An example of an in vivo renal monitoring assembly 10 is
shown in FIG. 4 and includes a light source 12 and a data
processing. The light source 12 generally includes or is
interconnected with an appropriate device for exposing at least a
portion of a patient's body to light therefrom. Examples of
appropriate devices that may be interconnected with or be a part of
the light source 12 include, but are not limited to, catheters,
endoscopes, fiber optics, ear clips, hand bands, head bands,
forehead sensors, surface coils, and finger probes. Indeed, any of
a number of devices capable of emitting visible and/or near
infrared light of the light source may be employed in the renal
monitoring assembly 10.
[0112] Still referring to FIG. 4, the data processing system 14 of
the renal monitoring assembly 10 may be any appropriate system
capable of detecting spectral energy and processing data indicative
of the spectral energy. For instance, the data processing system 14
may include one or more lenses (e.g., to direct and/or focus
spectral energy), one or more filters (e.g., to filter out
undesired wavelengths of spectral energy), a photodiode (e.g., to
collect the spectral energy and convert the same into electrical
signal indicative of the detected spectral energy), an amplifier
(e.g., to amplify electrical signal from the photodiode), and a
processing unit (e.g., to process the electrical signal from the
photodiode). This data processing system 14 is preferably
configured to manipulate collected spectral data and generate an
intensity/time profile and/or a concentration/time curve indicative
of renal clearance of a pyrazine composition of the present
invention from the patient 20. Indeed, the data processing system
14 may be configured to generate appropriate renal function data by
comparing differences in manners in which normal and impaired cells
remove the pyrazine composition from the bloodstream, to determine
a rate or an accumulation of the composition in organs or tissues
of the patient 20, and/or to provide tomographic images of organs
or tissues having the pyrazine composition associated
therewith.
[0113] In one protocol for determining renal function, an effective
amount of a composition including a pyrazine derivative of the
invention is administered to the patient. At least a portion of the
body of the patient 20 is exposed to visible and/or near infrared
light from the light source 12 as indicated by arrow 16. For
instance, the light from the light source 12 may be delivered via a
fiber optic that is affixed to an ear of the patient 20. The
patient may be exposed to the light from the light source 12 before
or after administration of the composition to the patient 20. In
some cases, it may be beneficial to generate a background or
baseline reading of light being emitted from the body of the
patient 20 (due to exposure to the light from the light source 12)
before administering the composition to the patient 20. When the
pyrazine derivative(s) of the composition that are in the body of
the patient 20 are exposed to the light from the light source 12,
the pyrazine derivative(s) emanate light (indicated by arrow 18)
that is detected/collected by the data processing system 14.
Initially, administration of the composition to the patient 20
generally enables an initial spectral signal indicative of the
initial content of the pyrazine derivative(s) in the patient 20.
The spectral signal then tends to decay as a function of time as
the pyrazine derivative(s) is cleared from the patient 20. This
decay in the spectral signal as a function of time is indicative of
the patient's renal function. For example, in a first patient
exhibiting healthy/normal renal function, the spectral signal may
decay back to a baseline in a time of T. However, a spectral signal
indicative of a second patient exhibiting deficient renal function
may decay back to a baseline in a time of T+4 hours. As such, the
patient 20 may be exposed to the light from the light source 12 for
any amount of time appropriate for providing the desired renal
function data. Likewise, the data processing system 14 may be
allowed to collect/detect spectral energy for any amount of time
appropriate for providing the desired renal function data.
Example 10
Actual
Assessment of Renal Function of Normal Rat
[0114] Incident laser light having a wavelength of about 470 nm was
delivered from a fiber optic bundle to the ear of an anesthetized
Sprague-Dawley rat. While the light was being directed at the ear,
data was being acquired using a photodector to detect fluorescence
coming from within the ear. A background reading of fluorescence
was obtained prior to administration of the pyrazine agent. Next,
the pyrazine agent (in this case, 2 ml of a 0.4 mg/ml solution of
3,6-diaminopyrazine-2,5-dicarboxylic acid in PBS) (Example 16) was
administered into the rat through a bolus injection in the lateral
tail vein. As shown in FIG. 5, shortly after the injection, the
detected fluorescence signal rapidly increased to a peak value. The
signal then decayed as a function of time indicating the dye being
cleared from the bloodstream (in this case, over a duration of a
little over 20 minutes).
##STR00017##
[0115] The blood clearance time profiles reported herein were
assumed to follow a two compartment pharmacokinetic model. The
fluorescent signal (arising from the dye concentration in the
blood) as a function of time was therefore fit to a double
exponential decay. The equation employed to fit the data was:
S=Ae.sup.-t/.tau..sub.1+Be.sup.-t/.tau..sub.2+C (1)
where S is the fluorescent light intensity signal measured, t is
the time point of the measurement, and e refers to the mathematical
constant having a numerical value of about 2.71828182846. The decay
times .tau..sub.1 and .tau..sub.2, and the constants A, B, and C
are deduced from the fitting procedure. The non-linear regression
analysis package within SigmaPlot.RTM. (Systat Software Inc.,
Richmond, Calif.) was employed to fit data to Eq. (1). In Examples
10 and 11, .tau..sub.1 represents the time constant for
vascular-extracellular fluid equilibrium, and .tau..sub.2
represents the dye clearance from the blood.
Example 11
Actual
Assessment of Renal Function of Bilaterally Nephrectomized Rat
[0116] An anesthetized Sprague-Dawley rat was bilaterally
nephrectomized. Incident laser light having a wavelength of about
470 nm was delivered from a fiber optic bundle to the ear of rat.
While the light was being directed at the ear, data was being
acquired using a photodector to detect fluorescence coming from
within the ear. A background reading of fluorescence was obtained
prior to administration of the pyrazine agent. Next, the pyrazine
agent (again, in this case, 2 ml of a 0.4 mg/ml solution of
3,6-diaminopyrazine-2,5-dicarboxylic acid in PBS) was administered
into the rat through a bolus injection in the lateral tail vein. As
shown in FIG. 6, shortly after the injection, the detected
fluorescence signal rapidly increased to a peak value. However, in
this case, the pyrazine agent did not clear, indicating that the
agent is capable of being renally cleared. A comparison between the
rat that exhibited normal kidney function (FIG. 5) and the rat that
had a bilateral nephectomy (FIG. 6) is shown in FIG. 7.
Incidentally, experiments similar to those of Examples 10 and 11
can be utilized to determine whether or not other proposed agents
are capable of being renally cleared.
Example 12
Actual
Preparation of
3,6-dicyano-25-[(N,N,N',N'-tetrakis(carboxymethyl)amino]pyrazine
##STR00018##
[0118] Step 1.
[0119] A stirring mixture of 2,5-diamino-3,6-dicyanopyrazine (1
mmol) and t-butyl bromoacetate (16 mmol) in dimethylacetamide (5
mL) was cooled in an ice-water-bath and subsequently treated with
powdered NaOH (6 mmol). The contents were allowed to warm to
ambient temperature over 1 h, then the reaction mixture was treated
with deionized water (50 mL). This aqueous mixture was extracted
twice with methylene chloride (50 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo to afford an oil. This oil was purified by flash
chromatography to give the tetra-t-butyl ester.
[0120] Step 2.
[0121] The tetraester from Step 1 (0.86 mmol) was heated in glacial
acetic acid (50 mL) for 24 hours, then was allowed to cool to
ambient temperature. The solution was filtered and concentrated in
vacuo to afford an oil. The oil was purified by preparative HPLC to
afford the title compound.
Example 13
Prophetic
Preparation of
2,6-dicyano-3,5-[(N,N,N',N'-tetrakis(hydroxyethyl)amino]pyrazine
##STR00019##
[0123] To a stirring solution of mixture of tetracyanopyrazine (10
mmol) in tetrahydrofuran (25 mL) is treated with dropwise addition
of diethanolamine (50 mmol) over 30 minutes. After the addition,
the mixture is stirred at ambient temperature for additional 1
hour. The crude product is collected by filtration and purified by
chromatography or recrystallization.
Example 14
Prophetic
Preparation of
2,6-dicyano-3.5-[(N,N'-bis(hydroxyethyl)amino]pyrazine
##STR00020##
[0125] The procedure is identical to Example 13 except that
aminopropanediol is used in instead of diethanolamine.
Example 15
Prophetic
Preparation of 2,6-dicyano-3,5-[(N,N'-bis(prolyl)amino]pyrazine
##STR00021##
[0127] The procedure is identical to Example 13 except that proline
is used in instead of diethanolamine.
Example 16
Actual
Synthesis of 3,6-diaminopyrazine-2,5-dicarboxylic acid
##STR00022##
[0129] Dipotassium 2,4,6,8-tetrahydroxypyrimido(4,5-g)pteridine was
prepared by treating 5-aminouracil with potassium ferricyanide in
the presence of potassium hydroxide as described in Taylor et al.,
JACS, 77: 2243-2248 (1955).
[0130] In each of two Teflon reaction vessels was placed 0.5 g
dipotassium 2,4,6,8-tetrahydroxypyrimido[4,5g]pteridine and a
solution consisting of 0.3-0.4 g sodium hydroxide in about 10 mL
deionized water. The vessels were secured in the microwave reactor
and allowed to react for one hour at 170.degree. C., generating ca.
100 psi pressure, for one hour. The vessels were allowed to cool in
the microwave to ca. 50.degree. C. and the contents filtered to
remove a small amount of solid residue. The bright yellow filtrate
was transferred to a 250 mL round-bottom flask equipped with a
large magnetic stir bar.
[0131] With stirring, the pH was adjusted to ca. 3 with
concentrated HCl. A large amount of red precipitate formed. A few
more drops of acid was added and the solid collected by filtration
on a glass frit, washed with cold 1.times.10 mL 1N HCl, 2.times.30
mL acetonitrile and 1.times.30 mL diethyl ether, suctioned dry and
transferred to a vacuum oven, vacuum drying overnight at
45-50.degree. C. Yield 0.48 g (79%). C13 NMR (D.sub.2O/NaOD,
external TMS reference) .delta. 132.35, 147.32, 171.68.
[0132] An aliquot of the bright yellow solution was concentrated in
vacuo resulting in the formation of two sets of crystals: red
needles and yellow blocks. X-Ray crystallography revealed that both
crystals are disodium 2,5-diamino-3,6-(dicarboxylato)pyrazine. The
crystal data and structure refinement for the two sets of crystals
are set forth in Tables 1R-6R (red crystals) and Tables 1Y-6Y
(yellow blocks). Their structures are shown in FIGS. 8A (projection
view of the molecule with 50% thermal ellipsoids) and 8B
(projection view of the molecule with 50% thermal ellipsoids and
coordination sphere of the Na atoms).
Example 17
Prophetic
Preparation of 2,5-dicyano
3,6-[(N,N'-bis(2,3-dihydroxyhydroxypropyl)amino]-pyrazine
##STR00023##
[0134] The alkylation procedure is identical to the one in Step 1
of Example 1, except that 3-bromo-1,2-propanediol is used instead
of t-butylbromoacetate.
Example 18
Prophetic
Preparation of
3,6-[(N,N'-bis(23-dihydroxypropyl)amino]pyrazine-2,5-dicarboxylic
acid
##STR00024##
[0136] Step 1.
[0137] The alkylation procedure is identical to the one in Step 1
of Example 1, except that 3-bromo-1,2-propanediol is used instead
of t-butylbromoacetate.
[0138] Step 2.
[0139] The hydrolysis procedure is identical to the one in Step 2
of Example 2, except that the starting material is the cyano
compound in Example 17.
[0140] Step 3.
[0141] The hydrolysis procedure is identical to the one in Step
3.
Example 19
Prophetic
Preparation of 2,5-dicyano
3,6-[(N,N'-bis(23-dihydroxyhydroxypropyl)amino]-N,N'-dimethylaminopyrazin-
e
##STR00025##
[0143] The cyano compound (10 mmol) from Example 17 is dissolved in
dimethylformamide (10 mL) and treated with dimethylsulfate (30
mmol). The mixture is heated at 100.degree. C. for 4 hours and
triturated with acetone (100 mL). The crude product is then
collected and purified by either crystallization or
chromatography.
Example 20
Prophetic
Preparation of
3,6-[(N,N-bis(dimethylamino]pyrazine-2,5-dicarboxylic acid
##STR00026##
[0145] The title compound is prepared by the hydrolysis of the
corresponding dicyano compound by the procedure described in Steps
2 and 3 of Example 2.
Example 21
Prophetic
Preparation of 2,5-dicyano
3,6-[(N,N'-bis(2-sulfonatoethyl)amino]-pyrazine
##STR00027##
[0147] The alkylation procedure is identical to the one in Step 1
of Example 1, except that taurine (2-aminoethanesulfonate) is used
instead of t-butylbromoacetate.
Example 22
Prophetic
Preparation of
2,5-bis[(N,N'-(2-sulfonato)ethyl]carbamoyl-3,6-[(N,N-bis-(dimethylamino)]-
pyrazine
##STR00028##
[0149] A mixture of the diacid in Example 20 (10 mmol), taurine (22
mmol) and the water-soluble carbodiimide, EDC
(ethyldimethylaminopropylcarbodiimide) (25 mmol) in water/DMF (1:1)
is stirred at ambient temperature for 16 hours. The solvent is
evaporated in vacuo and the crude product is purified by
chromatography.
TABLE-US-00001 TABLE 1Y Crystal data and structure refinement for
dm16005 (yellow). Identification code m16005/lt/B3401P021-yellow
Empirical formula C3H8N2NaO5 Formula weight 175.10 Temperature
100(2) K Wavelength 0.71073 .ANG. Crystal system Monoclinic Space
group P2.sub.1/c Unit cell dimensions a = 10.5000(10) .ANG. .alpha.
= 90.degree.. b = 5.2583(5) .ANG. .beta. = 103.207(4).degree.. c =
13.0181(11) .ANG. .gamma. = 90.degree.. Volume 699.75(11)
.ANG..sup.3 Z 4 Density (calculated) 1.662 Mg/m.sup.3 Absorption
coefficient 0.204 mm.sup.-1 F (000) 364 Crystal size 0.23 .times.
0.19 .times. 0.13 mm.sup.3 Theta range for data collection 1.99 to
39.00.degree.. Index ranges -18 .ltoreq. h .ltoreq. 17, -9 .ltoreq.
k .ltoreq. 9, -22 .ltoreq. l .ltoreq. 23 Reflections collected
17310 Independent reflections 4040 [R(int) = 0.04] Completeness to
theta = 39.00.degree. 99.4% Absorption correction Semi-empirical
from equivalents Max. and min. transmission 0.9739 and 0.9545
Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 4040/0/132 Goodness-of-fit on F.sup.2
1.045 Final R indices [I > 2sigma(I)] R1 = 0.0365, wR2 = 0.0924
R indices (all data) R1 = 0.0514, wR2 = 0.1005 Largest diff. peak
and hole 0.744 and -0.309 e .ANG..sup.-3
TABLE-US-00002 TABLE 2Y Atomic coordinates (.times.10.sup.4) and
equivalent isotropic displacement parameters (.ANG..sup.2 .times.
10.sup.3) for dm16005. U(eq) is defined as one third of the trace
of the orthogonalized U.sup.ij tensor. x y z U(eq) Na(1) 5013(1)
585(1) 3712(1) 10(1) O(1) 6904(1) 3242(1) 4474(1) 11(1) O(2)
8116(1) 5088(1) 3474(1) 13(1) O(3) 6108(1) -1620(1) 2599(1) 11(1)
O(4) 3129(1) -2477(1) 3412(1) 14(1) O(5) 3823(1) 2092(1) 4915(1)
11(1) N(1) 8824(1) -4(1) 5294(1) 10(1) N(2) 9494(1) -3201(2)
6512(1) 18(1) C(1) 7933(1) 3462(1) 4135(1) 9(1) C(2) 9036(1)
1636(1) 4569(1) 9(1) C(3) 9759(1) -1648(1) 5744(1) 10(1)
TABLE-US-00003 TABLE 3Y Bond lengths [.ANG.] and angles [.degree.]
for dm16005. Na(1)--O(3) 2.3511(6) Na(1)--O(5) 2.3532(6)
Na(1)--O(3)#1 2.3533(7) Na(1)--O(5)#2 2.3815(7) Na(1)--O(1)
2.4457(6) Na(1)--O(4) 2.5110(7) Na(1)--Na(1)#2 3.4155(7)
Na(1)--Na(1)#3 4.1027(5) Na(1)--Na(1)#1 4.1027(5) O(1)--C(1)
1.2618(8) O(2)--C(1) 1.2592(9) O(3)--Na(1)#3 2.3534(7) O(3)--H(3A)
0.869(15) O(3)--H(3B) 0.823(15) O(4)--H(4A) 0.878(17) O(4)--H(4B)
0.827(17) O(5)--Na(1)#2 2.3814(7) O(5)--H(5A) 0.874(16) O(5)--H(5B)
0.871(14) N(1)--C(2) 1.3339(9) N(1)--C(3) 1.3385(9) N(2)--C(3)
1.3687(10) N(2)--H(2A) 0.862(14) N(2)--H(2B) 0.891(14) C(1)--C(2)
1.5105(10) C(2)--C(3)#4 1.4153(10) C(3)--C(2)#4 1.4152(10)
O(3)--Na(1)--O(5) 170.15(2) O(3)--Na(1)--O(3)#1 95.449(17)
O(5)--Na(1)--O(3)#1 91.07(2) O(3)--Na(1)--O(5)#2 86.08(2)
O(5)--Na(1)--O(5)#2 87.66(2) O(3)#1--Na(1)--O(5)#2 177.57(2)
O(3)--Na(1)--O(1) 93.75(2) O(5)--Na(1)--O(1) 92.47(2)
O(3)#1--Na(1)--O(1) 99.33(2) O(5)#2--Na(1)--O(1) 78.66(2)
O(3)--Na(1)--O(4) 93.84(2) O(5)--Na(1)--O(4) 78.47(2)
O(3)#1--Na(1)--O(4) 92.42(2) O(5)#2--Na(1)--O(4) 89.36(2)
O(1)--Na(1)--O(4) 165.33(2) O(3)--Na(1)--Na(1)#2 129.13(2)
O(5)--Na(1)--Na(1)#2 44.160(16) O(3)#1--Na(1)--Na(1)#2 135.20(2)
O(5)#2--Na(1)--Na(1)#2 43.502(15) O(1)--Na(1)--Na(1)#2 83.835(18)
O(4)--Na(1)--Na(1)#2 81.636(18) O(3)--Na(1)--Na(1)#3 29.317(15)
O(5)--Na(1)--Na(1)#3 144.77(2) O(3)#1--Na(1)--Na(1)#3 85.888(19)
O(5)#2--Na(1)--Na(1)#3 96.338(17) O(1)--Na(1)--Na(1)#3 122.678(18)
O(4)--Na(1)--Na(1)#3 66.623(15) Na(1)#2--Na(1)--Na(1)#3 129.770(12)
O(3)--Na(1)--Na(1)#1 76.118(19) O(5)--Na(1)--Na(1)#1 112.639(17)
O(3)#1--Na(1)--Na(1)#1 29.285(14) O(5)#2--Na(1)--Na(1)#1 150.22(2)
O(1)--Na(1)--Na(1)#1 78.905(15) O(4)--Na(1)--Na(1)#1 115.15(2)
Na(1)#2--Na(1)--Na(1)#1 150.502(13) Na(1)#3--Na(1)--Na(1)#1
79.709(13) C(1)--O(1)--Na(1) 126.28(5) Na(1)--O(3)--Na(1)#3
121.40(3) Na(1)--O(3)--H(3A) 116.0(10) Na(1)#3--O(3)--H(3A)
102.3(10) Na(1)--O(3)--H(3B) 105.9(10) Na(1)#3--O(3)--H(3B)
105.7(10) H(3A)--O(3)--H(3B) 103.9(13) Na(1)--O(4)--H(4A) 98.7(11)
Na(1)--O(4)--H(4B) 102.9(11) H(4A)--O(4)--H(4B) 109.9(14)
Na(1)--O(5)--Na(1)#2 92.34(2) Na(1)--O(5)--H(5A) 114.6(11)
Na(1)#2--O(5)--H(5A) 97.3(10) Na(1)--O(5)--H(5B) 131.9(9)
Na(1)#2--O(5)--H(5B) 111.0(9) H(5A)--O(5)--H(5B) 103.8(13)
C(2)--N(1)--C(3) 120.18(6) C(3)--N(2)--H(2A) 119.5(9)
C(3)--N(2)--H(2B) 117.4(9) H(2A)--N(2)--H(2B) 115.5(12)
O(2)--C(1)--O(1) 125.27(7) O(2)--C(1)--C(2) 117.65(6)
O(1)--C(1)--C(2) 117.08(6) N(1)--C(2)--C(3)#4 120.73(6)
N(1)--C(2)--C(1) 116.00(6) C(3)#4--C(2)--C(1) 123.27(6)
N(1)--C(3)--N(2) 116.98(6) N(1)--C(3)--C(2)#4 119.09(6)
N(2)--C(3)--C(2)#4 123.90(7) Symmetry transformations used to
generate equivalent atoms: #1-x + 1, y + 1/2, -z + 1/2 #2-x + 1,
-y, -z + 1 #3-x + 1, y - 1/2, -z + 1/2 #4-x + 2, -y, -z + 1
TABLE-US-00004 TABLE 4Y Anisotropic displacement parameters
(.ANG..sup.2 .times. 10.sup.3) for dm16005. The anisotropic
displacement factor exponent takes the form: -2.pi..sup.2[h.sup.2
a*.sup.2U.sup.11 + . . . + 2 h k a* b* U.sup.12] U.sup.11 U.sup.22
U.sup.33 U.sup.23 U.sup.13 U.sup.12 Na(1) 10(1) 11(1) 11(1) 0(1)
3(1) 1(1) O(1) 8(1) 10(1) 14(1) 0(1) 4(1) 1(1) O(2) 12(1) 13(1)
15(1) 5(1) 4(1) 3(1) O(3) 12(1) 11(1) 11(1) 1(1) 3(1) 2(1) O(4)
17(1) 14(1) 12(1) 0(1) 5(1) 2(1) O(5) 11(1) 10(1) 14(1) -1(1) 5(1)
1(1) N(1) 8(1) 10(1) 12(1) 2(1) 3(1) 2(1) N(2) 12(1) 20(1) 23(1)
13(1) 9(1) 6(1) C(1) 8(1) 9(1) 10(1) -1(1) 1(1) 1(1) C(2) 8(1) 9(1)
10(1) 1(1) 2(1) 1(1) C(3) 9(1) 11(1) 12(1) 2(1) 4(1) 1(1)
TABLE-US-00005 TABLE 5Y Hydrogen coordinates (.times.10.sup.4) and
isotropic displacement parameters (.ANG..sup.2 .times. 10.sup.3)
for dm16005. x y z U(eq) H(3A) 6776(14) -2530(30) 2911(12) 29(4)
H(3B) 6428(13) -520(30) 2284(11) 29(3) H(4A) 2538(16) -1520(30)
3001(14) 40(4) H(4B) 2966(15) -2590(30) 4003(14) 34(4) H(5A)
3053(15) 1390(30) 4852(13) 36(4) H(5B) 3726(12) 3610(30) 5152(11)
25(3) H(2A) 9998(13) -4480(30) 6728(11) 22(3) H(2B) 8657(14)
-3410(30) 6531(11) 30(3)
TABLE-US-00006 TABLE 6Y Torsion angles [.degree.] for dm16005.
O(3)--Na(1)--O(1)--C(1) 11.94(6) O(5)--Na(1)--O(1)--C(1) -175.71(6)
O(3)#1--Na(1)--O(1)--C(1) -84.22(6) O(5)#2--Na(1)--O(1)--C(1)
97.17(6) O(4)--Na(1)--O(1)--C(1) 132.96(9)
Na(1)#2--Na(1)--O(1)--C(1) 140.92(6) Na(1)#3--Na(1)--O(1)--C(1)
6.88(6) Na(1)#1--Na(1)--O(1)--C(1) -63.12(6)
O(5)--Na(1)--O(3)--Na(1)#3 59.71(15) O(3)#1--Na(1)--O(3)--Na(1)#3
-71.52(4) O(5)#2--Na(1)--O(3)--Na(1)#3 110.37(3)
O(1)--Na(1)--O(3)--Na(1)#3 -171.28(3) O(4)--Na(1)--O(3)--Na(1)#3
21.28(3) Na(1)#2--Na(1)--O(3)--Na(1)#3 103.62(3)
Na(1)#1--Na(1)--O(3)--Na(1)#3 -93.69(3) O(3)--Na(1)--O(5)--Na(1)#2
50.56(15) O(3)#1--Na(1)--O(5)--Na(1)#2 -177.93(2)
O(5)#2--Na(1)--O(5)--Na(1)#2 0.0 O(1)--Na(1)--O(5)--Na(1)#2
-78.54(2) O(4)--Na(1)--O(5)--Na(1)#2 89.82(2)
Na(1)#3--Na(1)--O(5)--Na(1)#2 97.68(3)
Na(1)#1--Na(1)--O(5)--Na(1)#2 -157.54(2) Na(1)--O(1)--C(1)--O(2)
90.49(8) Na(1)--O(1)--C(1)--C(2) -90.07(7) C(3)--N(1)--C(2)--C(3)#4
0.69(12) C(3)--N(1)--C(2)--C(1) -178.18(6) O(2)--C(1)--C(2)--N(1)
177.82(6) O(1)--C(1)--C(2)--N(1) -1.66(9) O(2)--C(1)--C(2)--C(3)#4
-1.02(10) O(1)--C(1)--C(2)--C(3)#4 179.50(7) C(2)--N(1)--C(3)--N(2)
177.38(7) C(2)--N(1)--C(3)--C(2)#4 -0.67(12) Symmetry
transformations used to generate equivalent atoms: #1-x + 1, y +
1/2, -z + 1/2 #2-x + 1, -y, -z + 1 #3-x + 1, y - 1/2, -z + 1/2 #4-x
+ 2, -y, -z + 1
TABLE-US-00007 TABLE 1R Crystal data and structure refinement for
dm16105. Identification code m16105/lt/B3401P021-red Empirical
formula C.sub.6H.sub.8N.sub.4Na2O.sub.6 Formula weight 278.14
Temperature 100(2) K Wavelength 0.71073 .ANG. Crystal system
Monoclinic Space group C2/c Unit cell dimensions a = 20.549(6)
.ANG. .alpha. = 90.degree.. b = 3.5198(9) .ANG. .beta. =
100.56(2).degree.. c = 13.289(4) .ANG. .gamma. = 90.degree.. Volume
944.9(5) .ANG..sup.3 Z 4 Density (calculated) 1.955 Mg/m.sup.3
Absorption coefficient 0.245 mm.sup.-1 F (000) 568 Crystal size
0.15 .times. 0.08 .times. 0.03 mm.sup.3 Theta range for data
collection 2.02 to 23.29.degree.. Index ranges -22 .ltoreq. h
.ltoreq. 22, -3 .ltoreq. k .ltoreq. 3, -14 .ltoreq. l .ltoreq. 14
Reflections collected 5401 Independent reflections 673 [R(int) =
0.11] Completeness to theta = 23.29.degree. 99.9% Absorption
correction None Max. and min. transmission 0.9927 and 0.9641
Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 673/1/94 Goodness-of-fit on F.sup.2
1.128 Final R indices [I > 2sigma(I)] R1 = 0.0656, wR2 = 0.1678
R indices (all data) R1 = 0.1011, wR2 = 0.1953 Largest diff. peak
and hole 0.553 and -0.459 e .ANG..sup.-3
TABLE-US-00008 TABLE 2R Atomic coordinates (.times.10.sup.4) and
equivalent isotropic displacement parameters (.ANG..sup.2 .times.
10.sup.3) for dm16105. U(eq) is defined as one third of the trace
of the orthogonalized U.sup.ij tensor. x y z U(eq) Na(1) 0 4107(10)
-2500 18(1) Na(2) 2500 2500 0 18(1) O(1) 1044(2) 5915(13) -1625(3)
18(1) O(2) 1697(2) 7546(12) -166(3) 17(1) O(3) 2678(2) 1457(16)
1788(3) 23(1) N(1) -24(2) 8853(15) -999(3) 14(1) N(2) -1135(3)
10283(16) -1427(4) 17(1) C(1) 1146(3) 7295(18) -736(5) 14(2) C(2)
548(3) 8715(18) -334(4) 14(1) C(3) -579(3) 10076(18) -695(4)
14(1)
TABLE-US-00009 TABLE 3R Bond lengths [.ANG.] and angles [.degree.]
for dm16105. Na(1)--O(1) 2.334(4) Na(1)--O(1)#1 2.334(4)
Na(1)--N(1) 2.609(5) Na(1)--N(1)#1 2.609(5) Na(1)--N(1)#2 2.727(5)
Na(1)--N(1)#3 2.727(5) Na(1)--Na(1)#3 3.5198(9) Na(1)--Na(1)#4
3.5198(9) Na(2)--O(3)#5 2.365(5) Na(2)--O(3) 2.365(5) Na(2)--O(2)#6
2.383(4) Na(2)--O(2)#3 2.383(4) Na(2)--O(2)#5 2.407(4) Na(2)--O(2)
2.407(4) Na(2)--Na(2)#3 3.5198(9) Na(2)--Na(2)#4 3.5198(9)
Na(2)--H(3A) 2.63(7) O(1)--C(1) 1.259(7) O(2)--C(1) 1.244(7)
O(2)--Na(2)#4 2.383(4) O(3)--H(3A) 0.96(8) O(3)--H(3B) 0.84(11)
N(1)--C(2) 1.335(8) N(1)--C(3) 1.350(8) N(1)--Na(1)#4 2.727(5)
N(2)--C(3) 1.359(7) N(2)--H(2A) 0.87(4) N(2)--H(2B) 0.87(4)
C(1)--C(2) 1.512(9) C(2)--C(3)#7 1.422(9) C(3)--C(2)#7 1.422(9)
O(1)--Na(1)--O(1)#1 148.4(3) O(1)--Na(1)--N(1) 65.72(16)
O(1)#1--Na(1)--N(1) 93.56(17) O(1)--Na(1)--N(1)#1 93.56(17)
O(1)#1--Na(1)--N(1)#1 65.72(16) N(1)--Na(1)--N(1)#1 100.4(2)
O(1)--Na(1)--N(1)#2 114.29(16) O(1)#1--Na(1)--N(1)#2 87.62(15)
N(1)--Na(1)--N(1)#2 177.1(2) N(1)#1--Na(1)--N(1)#2 82.51(13)
O(1)--Na(1)--N(1)#3 87.62(15) O(1)#1--Na(1)--N(1)#3 114.29(16)
N(1)--Na(1)--N(1)#3 82.51(13) N(1)#1--Na(1)--N(1)#3 177.1(2)
N(1)#2--Na(1)--N(1)#3 94.6(2) O(1)--Na(1)--Na(1)#3 105.83(14)
O(1)#1--Na(1)--Na(1)#3 105.82(14) N(1)--Na(1)--Na(1)#3 129.81(12)
N(1)#1--Na(1)--Na(1)#3 129.81(12) N(1)#2--Na(1)--Na(1)#3 47.30(12)
N(1)#3--Na(1)--Na(1)#3 47.30(12) O(1)--Na(1)--Na(1)#4 74.18(14)
O(1)#1--Na(1)--Na(1)#4 74.17(14) N(1)--Na(1)--Na(1)#4 50.19(12)
N(1)#1--Na(1)--Na(1)#4 50.19(12) N(1)#2--Na(1)--Na(1)#4 132.70(12)
N(1)#3--Na(1)--Na(1)#4 132.70(12) Na(1)#3--Na(1)--Na(1)#4
179.998(1) O(3)#5--Na(2)--O(3) 180.0 .sup. O(3)#5--Na(2)--O(2)#6
87.51(15) O(3)--Na(2)--O(2)#6 92.49(15) O(3)#5--Na(2)--O(2)#3
92.49(15) O(3)--Na(2)--O(2)#3 87.51(15) O(2)#6--Na(2)--O(2)#3 180.0
.sup. O(3)#5--Na(2)--O(2)#5 100.60(16) O(3)--Na(2)--O(2)#5
79.40(16) O(2)#6--Na(2)--O(2)#5 94.58(14) O(2)#3--Na(2)--O(2)#5
85.42(14) O(3)#5--Na(2)--O(2) 79.40(16) O(3)--Na(2)--O(2)
100.60(16) O(2)#6--Na(2)--O(2) 85.42(14) O(2)#3--Na(2)--O(2)
94.58(14) O(2)#5--Na(2)--O(2) 180.0 .sup. O(3)#5--Na(2)--Na(2)#3
98.93(14) O(3)--Na(2)--Na(2)#3 81.07(14) O(2)#6--Na(2)--Na(2)#3
137.03(10) O(2)#3--Na(2)--Na(2)#3 42.97(10) O(2)#5--Na(2)--Na(2)#3
42.45(10) O(2)--Na(2)--Na(2)#3 137.55(10) O(3)#5--Na(2)--Na(2)#4
81.07(14) O(3)--Na(2)--Na(2)#4 98.93(14) O(2)#6--Na(2)--Na(2)#4
42.97(10) O(2)#3--Na(2)--Na(2)#4 137.02(10) O(2)#5--Na(2)--Na(2)#4
137.56(10) O(2)--Na(2)--Na(2)#4 42.45(10) Na(2)#3--Na(2)--Na(2)#4
180.0 .sup. O(3)#5--Na(2)--H(3A) 158.6(17) O(3)--Na(2)--H(3A)
21.4(17) O(2)#6--Na(2)--H(3A) 79.2(18) O(2)#3--Na(2)--H(3A)
100.8(18) O(2)#5--Na(2)--H(3A) 64.3(18) O(2)--Na(2)--H(3A)
115.7(18) Na(2)#3--Na(2)--H(3A) 80.3(18) Na(2)#4--Na(2)--H(3A)
99.7(18) C(1)--O(1)--Na(1) 123.5(4) C(1)--O(2)--Na(2)#4 130.2(4)
C(1)--O(2)--Na(2) 122.4(4) Na(2)#4--O(2)--Na(2) 94.58(14)
Na(2)--O(3)--H(3A) 95(4) Na(2)--O(3)--H(3B) 125(7)
H(3A)--O(3)--H(3B) 99(8) C(2)--N(1)--C(3) 120.2(5)
C(2)--N(1)--Na(1) 110.2(4) C(3)--N(1)--Na(1) 124.6(4)
C(2)--N(1)--Na(1)#4 112.2(4) C(3)--N(1)--Na(1)#4 97.6(4)
Na(1)--N(1)--Na(1)#4 82.51(13) C(3)--N(2)--H(2A) 114(4)
C(3)--N(2)--H(2B) 118(4) H(2A)--N(2)--H(2B) 123(6) O(2)--C(1)--O(1)
125.1(6) O(2)--C(1)--C(2) 118.0(5) O(1)--C(1)--C(2) 116.9(5)
N(1)--C(2)--C(3)#7 120.4(6) N(1)--C(2)--C(1) 116.9(5)
C(3)#7--C(2)--C(1) 122.8(5) N(1)--C(3)--N(2) 116.7(5)
N(1)--C(3)--C(2)#7 119.4(5) N(2)--C(3)--C(2)#7 123.8(6) Symmetry
transformations used to generate equivalent atoms: #1-x, y, -z -
1/2 #2-x, y - 1, -z - 1/2 #3x, y - 1, z #4x, y + 1, z #5-x + 1/2,
-y + 1/2, -z #6-x + 1/2, -y + 3/2, -z #7-x, -y + 2, -z
TABLE-US-00010 TABLE 4R Anisotropic displacement parameters
(.ANG..sup.2 .times. 10.sup.3) for dm16105. The anisotropic
displacement factor exponent takes the form: -2.pi..sup.2[h.sup.2
a*.sup.2U.sup.11 + . . . + 2 h k a* b* U.sup.12] U.sup.11 U.sup.22
U.sup.33 U.sup.23 U.sup.13 U.sup.12 Na(1) 23(2) 12(2) 19(2) 0 3(1)
0 Na(2) 19(2) 12(2) 24(2) 2(2) 5(2) -1(2) O(1) 21(2) 16(3) 17(2)
-3(2) 3(2) 1(2) O(2) 20(3) 9(3) 22(2) 0(2) 2(2) 2(2) O(3) 20(3)
25(3) 25(3) -1(2) 7(2) -2(2) N(1) 17(3) 2(3) 22(3) 0(2) 4(2) -1(2)
N(2) 20(3) 13(4) 19(3) -4(3) 4(3) 3(3) C(1) 16(4) 2(4) 22(4) 5(3)
3(3) -2(3) C(2) 19(3) 3(3) 20(2) 5(2) 1(2) -1(2) C(3) 19(3) 3(3)
20(2) 5(2) 1(2) -1(2)
TABLE-US-00011 TABLE 5R Hydrogen coordinates (.times.10.sup.4) and
isotropic displacement parameters (.ANG..sup.2 .times. 10.sup.3)
for dm16105. x y z U(eq) H(3A) 3150(40) 1200(200) 1860(50) 40(20)
H(3B) 2660(50) 3100(300) 2230(70) 80(40) H(2A) -1120(30) 8900(170)
-1960(40) 14(17) H(2B) -1510(20) 10860(180) -1240(40) 10(16)
TABLE-US-00012 TABLE 6R Torsion angles [.degree.] for dm16105.
O(1)#1--Na(1)--O(1)--C(1) 72.9(5) N(1)--Na(1)--O(1)--C(1) 20.0(5)
N(1)#1--Na(1)--O(1)--C(1) 119.8(5) N(1)#2--Na(1)--O(1)--C(1)
-156.9(5) N(1)#3--Na(1)--O(1)--C(1) -62.9(5)
Na(1)#3--Na(1)--O(1)--C(1) -107.1(5) Na(1)#4--Na(1)--O(1)--C(1)
72.9(5) O(3)#5--Na(2)--O(2)--C(1) 56.5(4) O(3)--Na(2)--O(2)--C(1)
-123.5(4) O(2)#6--Na(2)--O(2)--C(1) 144.8(5)
O(2)#3--Na(2)--O(2)--C(1) -35.2(5) O(2)#5--Na(2)--O(2)--C(1) 8(7)
Na(2)#3--Na(2)--O(2)--C(1) -35.2(5) Na(2)#4--Na(2)--O(2)--C(1)
144.8(5) O(3)#5--Na(2)--O(2)--Na(2)#4 -88.32(16)
O(3)--Na(2)--O(2)--Na(2)#4 91.68(16) O(2)#6--Na(2)--O(2)--Na(2)#4
0.0.sup. O(2)#3--Na(2)--O(2)--Na(2)#4 180.0 .sup.
O(2)#5--Na(2)--O(2)--Na(2)#4 -137(6) Na(2)#3--Na(2)--O(2)--Na(2)#4
180.0 .sup. O(1)--Na(1)--N(1)--C(2) -21.7(4)
O(1)#1--Na(1)--N(1)--C(2) -176.9(4) N(1)#1--Na(1)--N(1)--C(2)
-110.9(4) N(1)#2--Na(1)--N(1)--C(2) 69.1(4)
N(1)#3--Na(1)--N(1)--C(2) 69.1(4) Na(1)#3--Na(1)--N(1)--C(2)
69.1(4) Na(1)#4--Na(1)--N(1)--C(2) -110.9(4)
O(1)--Na(1)--N(1)--C(3) -176.7(5) O(1)#1--Na(1)--N(1)--C(3) 28.1(5)
N(1)#1--Na(1)--N(1)--C(3) 94.1(5) N(1)#2--Na(1)--N(1)--C(3)
-85.9(5) N(1)#3--Na(1)--N(1)--C(3) -85.9(5)
Na(1)#3--Na(1)--N(1)--C(3) -85.9(5) Na(1)#4--Na(1)--N(1)--C(3)
94.1(5) O(1)--Na(1)--N(1)--Na(1)#4 89.24(16)
O(1)#1--Na(1)--N(1)--Na(1)#4 -65.95(15)
N(1)#1--Na(1)--N(1)--Na(1)#4 0.002(1) N(1)#2--Na(1)--N(1)--Na(1)#4
179.998(11) N(1)#3--Na(1)--N(1)--Na(1)#4 180.0 .sup.
Na(1)#3--Na(1)--N(1)--Na(1)#4 180.0 .sup. Na(2)#4--O(2)--C(1)--O(1)
89.2(7) Na(2)--O(2)--C(1)--O(1) -42.1(8) Na(2)#4--O(2)--C(1)--C(2)
-91.4(6) Na(2)--O(2)--C(1)--C(2) 137.3(5) Na(1)--O(1)--C(1)--O(2)
164.0(5) Na(1)--O(1)--C(1)--C(2) -15.3(8) C(3)--N(1)--C(2)--C(3)#7
-1.2(10) Na(1)--N(1)--C(2)--C(3)#7 -157.5(5)
Na(1)#4--N(1)--C(2)--C(3)#7 112.5(5) C(3)--N(1)--C(2)--C(1)
179.8(5) Na(1)--N(1)--C(2)--C(1) 23.5(7) Na(1)#4--N(1)--C(2)--C(1)
-66.5(6) O(2)--C(1)--C(2)--N(1) 172.0(5) O(1)--C(1)--C(2)--N(1)
-8.6(9) O(2)--C(1)--C(2)--C(3)#7 -7.0(9) O(1)--C(1)--C(2)--C(3)#7
172.4(6) C(2)--N(1)--C(3)--N(2) 177.4(5) Na(1)--N(1)--C(3)--N(2)
-30.0(8) Na(1)#4--N(1)--C(3)--N(2) 56.1(6) C(2)--N(1)--C(3)--C(2)#7
1.2(10) Na(1)--N(1)--C(3)--C(2)#7 153.9(4)
Na(1)#4--N(1)--C(3)--C(2)#7 -120.0(5) Symmetry transformations used
to generate equivalent atoms: #1-x, y, -z - 1/2 #2-x, y - 1, -z -
1/2 #3x, y - 1, z #4x, y + 1, z #5-x + 1/2, -y + 1/2, -z #6-x +
1/2, -y + 3/2, -z #7-x, -y + 2, -z
[0150] Various publications are referenced throughout this
disclosure by Arabic numerals in brackets. A full citation
corresponding to each reference number is listed below. The
disclosures of these publications are herein incorporated by
reference in their entireties.
REFERENCES
[0151] 1. Nally, J. V. Acute renal failure in hospitalized
patients. Cleveland Clinic Journal of Medicine 2002, 69(7),
569-574. [0152] 2. C. A. Rabito, L. S. T. Fang, and A. C. Waltman.
Renal function in patients at risk with contrast material-induced
acute renal failure: Noninvasive real-time monitoring. Radiology
1993, 186, 851-854. [0153] 3. N. L. Tilney, and J. M. Lazarus.
Acute renal failure in surgical patients: Causes, clinical
patterns, and care. Surgical Clinics of North America 1983, 63,
357-377. [0154] 4. B. E. VanZee, W. E. Hoy, and J. R. Jaenike.
Renal injury associated with intravenous pyelography in
non-diabetic and diabetic patients. Annals of Internal Medicine
1978, 89, 51-54. [0155] 5. S. Lundqvist, G. Edbom, S. Groth, U.
Stendahl, and S.-O. Hietala. Iohexol clearance for renal function
measurement in gynecologic cancer patients. Acta Radiologica 1996,
37, 582-586. [0156] 6. P. Guesry, L. Kaufman, S. Orloff, J. A.
Nelson, S. Swann, and M. Holliday. Measurement of glomerular
filtration rate by fluorescent excitation of non-radioactive
meglumine iothalamate. Clinical Nephrology 1975, 3, 134-138).
[0157] 7. C. C. Baker et al. Epidemiology of Trauma Deaths.
American Journal of Surgery 1980, 144-150. [0158] 8. R. G.
Lobenhoffer et al. Treatment Results of Patients with Multiple
Trauma: An Analysis of 3406 Cases Treated Between 1972 and 1991 at
a German Level I Trauma Center. Journal of Trauma 1995, 38, 70-77.
[0159] 9. J. Coalson, Pathology of Sepsis, Septic Shock, and
Multiple Organ Failure. In New Horizons: Multiple Organ Failure, D.
J. Bihari and F. B. Cerra, (Eds). Society of Critical Care
Medicine, Fullerton, Calif., 1986, pp. 27-59. [0160] 10. F. B.
Cerra, Multiple Organ Failure Syndrome. In New Horizons: Multiple
Organ Failure, D. J Bihari and F. B. Cerra, (Eds). Society of
Critical Care Medicine, Fullerton, Calif., 1989, pp. 1-24. [0161]
11. R. Muller-Suur, and C. Muller-Suur. Glomerular filtration and
tubular secretion of MAG.sub.3 in rat kidney. Journal of Nuclear
Medicine 1989, 30, 1986-1991). [0162] 12. P. D. Dollan, E. L.
Alpen, and G. B. Theil. A clinical appraisal of the plasma
concentration and endogenous clearance of creatinine. American
Journal of Medicine 1962, 32, 65-79. [0163] 13. J. B. Henry (Ed).
Clinical Diagnosis and Management by Laboratory Methods, 17th
Edition, W.B. Saunders, Philadelphia, Pa., 1984. [0164] 14. F.
Roch-Ramel, K. Besseghir, and II. Murer. Renal excretion and
tubular transport of organic anions and cations. In Handbook of
Physiology, Section 8, Neurological Physiology, Vol. II, E. E.
Windhager, Editor, pp. 2189-2262. Oxford University Press: New
York, 1992 [0165] 15. D. L. Nosco and J. A. Beaty-Nosco. Chemistry
of technetium radiopharmaceuticals 1: Chemistry behind the
development of technetium-99m compounds to determine kidney
function. Coordination Chemistry Reviews 1999, 184, 91-123. [0166]
16. P. L. Choyke, H. A. Austin, and J. A. Frank. Hydrated clearance
of gadolinium-DTPA as a measurement of glomerular filtration rate.
Kidney International 1992, 41, 1595-1598. [0167] 17. N. Lewis, R.
Kerr, and C. Van Buren. Comparative evaluation of urographic
contrast media, inulin, and .sup.99mTc-DTPA clearance methods for
determination of glomerular filtration rate in clinical
transplantation. Transplantation 1989, 48, 790-796). [0168] 18. W.
N. Tauxe. Tubular Function. In Nuclear Medicine in Clinical Urology
and Nephrology, W. N. Tauxe and E. V. Dubovsky, Editors, pp.
77-105, Appleton Century Crofts: East Norwalk, 1985. [0169] 19. A.
R. Fritzberg et al. Mercaptoacetylglycylglycyglycine. Journal of
Nuclear Medicine 1986, 27, 111-120. [0170] 20. G. Ekanoyan and N.
W. Levin. In Clinical Practice Guidelines for Chronic Kidney
Disease: Evaluation, Classification, and Stratification (K/DOQI).
National Kidney Foundation: Washington, D.C. 2002, pp. 1-22. [0171]
21. Ozaki, H. et al. Sensitization of europium(III) luminescence by
DTPA derivatives. Chemistry Letters 2000, 312-313. [0172] 22.
Rabito, C. Fluorescent agents for real-time measurement of organ
function. 2002; U.S. Pat. No. 6,440,389. [0173] 23. R. Rajagopalan,
R. et al. Polyionic fluorescent bioconjugates as composition agents
for continuous monitoring of renal function. In Molecular Imaging:
Reporters, Dyes, Markers, and Instrumentation, A. Priezzhev, T.
Asakura, and J. D. Briers, Editors, Proceedings of SPIE, 2000,
3924. [0174] 24. Dorshow, R. B. et al. Noninvasive renal function
assessment by fluorescence detection. In Biomedical Optical
Spectroscopy and Diagnostics, Trends in Optics and Photonics Series
22, E. M Sevick-Muraca, J. A. Izatt, and M. N. Ediger, Editors, pp.
54-56, Optical Society of America, Washington D.C., 1998. [0175]
25. Shirai, K. et al Synthesis and fluorescent properties of
2,5-diamino-3,6-dicyanopyrazine dyes. Dyes and Pigments 1998,
39(1), 49-68. [0176] 26. Kim, J. H. et al. Self-assembling of
aminopyrazine fluorescent dyes and their solid state spectra. Dyes
and Pigments 1998, 39(4), 341-357. [0177] 27. Barlin, G. B. The
pyrazines. In The Chemistry of Heterocyclic Compounds. A.
Weissberger and E. C.
[0178] Taylor, Eds. John Wiley & Sons, New York: 1982. [0179]
28. Donald, D. S. Synthesis of 3,5-diaminopyrazinoic acid from
3,5-diamino-2,6-dicyanopyrazine and intermediates. 1976; U.S. Pat.
No. 3,948,895. [0180] 29. Donald, D. S. Diaminosubstituted
dicyanopyrzines and process. 1974; U.S. Pat. No. 3,814,757. [0181]
30. Muller et al. Eds, Medical Optical Tomography, SPIE Volume
IS11, 1993. [0182] 31. R. B. Dorshow et al. Non-Invasive
Fluorescence Detection of Hepatic and Renal Function, Bull. Am.
Phys. Soc. 1997, 42, 681. [0183] 32. R. B. Dorshow et al.
Monitoring Physiological Function by Detection of Exogenous
Fluorescent Contrast Agents. In Optical Diagnostics of Biological
Fluids IV, A. Priezzhev and T. Asakura, Editors, Proceedings of
SPIE 1999, 3599, 2-8).
* * * * *