Novel compounds of general formula (I) which have hemoregulatory activities and can be used to stimulate haematopoiesis and for the treatment of viral, fungal and bacterial infectious diseases. ##STR1##

FIELD OF THE INVENTION 
The present invention relates to novel compounds which have hemoregulatory 
activities and can be used to stimulate haematopoiesis and for the 
treatment of viral, fungal and bacterial infectious diseases. 
BACKGROUND OF THE INVENTION 
The haematopoietic system is a life-long cell renewal process whereby a 
defined stem cell population gives rise to a larger population of mature, 
differentiated blood cells (Dexter T M. Stem cells in normal growth and 
disease, Br Med J 1987; 195:1192-1194) of at least nine different cell 
lineages (erythrocytes, platelets, eosinophils, basophils, neutrophils, 
monocytes/macrophages, osteoclastes and lymphocytes) (Metcalf D. The 
Molecular Control of Blood Cells, 1988; Harvard University Press, 
Cambridge, Mass.). The stem cells are also ultimately responsible for 
regenerating the bone marrow following treatment with cytotoxic agents or 
following bone marrow transplantation. 
The major dose-limiting toxicities of most standard anti-neoplastic drugs 
are related to bone marrow suppression, which if severe and prolonged, can 
give rise to life-threatening infectious and haemorrhagic complications. 
Myelosuppression is predictable and has been reported to be dose-limiting 
in greater than 50% of single-agent Phase I trials cytotoxic compounds 
(Merrouche Y, Catimel G, Clavel M. Haematopoietic growth factors and 
chemoprotectants; should we move toward a two-step process for phase I 
trials in oncology? Ann Oncol 1993; 4:471-474). The risk of infection is 
directly related to the degree of myelosuppression as measured by the 
severity and duration of neutropenia (Brody G P, Buckley M, Sathe Y S, 
Freireich E J. Quantitative relationship between circulating leukocytes 
and infections with acute leukemia. Ann In Med 1965; 64:328-334). 
The control of haematopoiesis involves the interplay of a variety of 
cytokines and growth factors during various stages of the haematopoietic 
cascade, including early pluripotent stem cells and mature circulating 
effector cells. These regulatory molecules include granulocyte colony 
stimulating factor (G-CSF), granulocyte-macrophage stimulating factor 
(GM-CSF), macrophage-colony stimulating factor (M-CSF), and a variety of 
interleukines which have overlapping, additive and synergistic actions 
which play major roles in host defence. Mechanistically, this is 
accomplished by enhancing the production of granulocytes and macrophages, 
as well as by the activation of effector cell functions (Moore MAS. 
Haematopoietic growth factor interactions: in vitro and in vivo 
preclinical evaluation. Cancer Surveys 1990; 9:7-80). These co-ordinated 
activities support optimal host defences which are necessary for fighting 
bacterial, viral and fungal infections. 
Strategies to prevent or reduce the severity of neutropenia and 
myelotoxicity include the use of haematopoietic growth factors and/or 
other haematopoietic cytokines. Such treatments are becoming common 
practice, in that they offer the potential of increased doses of cytotoxic 
agents that may improve the therapeutic efficacy in antineoplastic agents, 
and reduce the morbidity associated with their use (Steward W P. 
Granulocyte and granulocyte-macrophage colony stimulating factors, Lancet 
1993; 342:153-157). Clinical studies have demonstrated the G-, GM- and/or 
M-CSF may reduce the duration of neutropenia, accelerate myeloid recovery 
and reduce neutropenia-associated infections and other infectious 
complications in patients with malignancies who are receiving cytotoxic 
chemotherapy or in high infectious-risk patients following bone marrow 
transplantation (Steward W P. Granulocyte and granulocyte-macrophage 
colony stimulating factors, Lancet 1993; 342:153-157 and Munn D H, Cheung 
N K V. Preclinical and clinical studies of macrophage colony-stimulating 
factor. Semin Oncol 1992; 19:395-407). 
We have now found certain novel compounds which have a stimulative effect 
on myelopoietic cells and are useful in the treatment and prevention of 
viral, fungal and bacterial diseases. 
SUMMARY OF THE INVENTION 
This invention comprises compounds, hereinafter represented as Formula (I), 
which have hemoregulatory activities and can be used to stimulate 
haematopoiesis and in the prevention and treatment of bacterial, viral and 
fungal diseases. 
These compounds are useful in the restoration of leukocytes in patients 
with lowered cell counts resulting from a variety of clinical situations, 
such as surgical induced myelosuppression, AIDS, ARDS, congenital 
myelodysplacis, bone marrow and organ transplants; in the protection of 
patients with leukopenia from infection; in the treatment of severely 
burned patients and in the amelioration of the myelosuppression observed 
with some cell-cycle specific antiviral agents and in the treatment of 
infections in patients who have had bone marrow transplants, especially 
those with graft versus host disease, in the treatment of tuberculosis and 
in the treatment of fevers of unknown origin in humans and animals. The 
compounds are also useful in the treatment and prevention of viral, fungal 
and bacterial diseases, particularly Candida, Herpes and hepatitis in both 
immunosuppressed and "normal" subjects. 
These compounds may also be used in combination with the monomers of 
co-pending U.S. application Ser. No. 07/799,465 and U.S. Pat. No. 
4,499,081, incorporated by reference herein, to provide alternating peaks 
of high and low activity in the bone marrow cells, thus augmenting the 
natural circadian rhythm of haematopoiesis. In this way, cytostatic 
therapy can be given at periods of low bone marrow activity, thus reducing 
the risk of bone marrow damage, while regeneration will be promoted by the 
succeeding peak of activity. This invention is also a pharmaceutical 
composition, which comprises a compound of Formula (I) and a 
pharmaceutically acceptable carrier. 
This invention further constitutes a method for stimulating the 
myelopoietic system of an animal, including humans, which comprises 
administering to an animal in need thereof, an effective amount of a 
compound of Formula (I). 
This invention also constitutes a method for preventing and treating viral, 
fungal and bacterial infections including sepsis in immunosuppressed and 
normal animals, including humans, which comprises administering to an 
animal in need thereof, an effective amount of a compound of Formula (I). 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the invention are represented by structural Formula I 
##STR2## 
wherein: A.sub.1 equals A.sub.2 and denotes a group Z--(CH.sub.2).sub.k 
--(NR'").sub.q, wherein 
Z is a 4-10 membered mono- or bicyclic heterocyclic ring system containing 
up to four heteroatoms N, O, S in the ring in which at least one 
heteroatom is N, and wherein the ring is substituted or unsubstituted by 
one or two C.sub.1-4 alkyl, F, Cl, Br, I, C.sub.1-4 alkoxy, 
(CH.sub.2).sub.m R.sub.4, oxo, oxime, O--C.sub.1-4 alkyloxime, hydroxy, 
N(R.sub.3).sub.2, acylamino or aminoacyl groups, 8, 9, 10 membered 
monocyclic ring systems being excluded; 
R' and R" are the same and are hydrogen, C.sub.1-4 alkylC(O)R.sub.4, 
C.sub.1-4 alkyl or R' and R" are benzyl which is optionally substituted by 
one or two C.sub.1-4 alkyl, C.sub.1-4 alkoxy, F, Cl, I, Br, OH, or 
N(R.sub.3).sub.2 ; 
k is an integer from 0 to 4; 
R'" denotes Hydrogen, C.sub.1-4 -alkyl or C.sub.1-4 -alkylcarboxylic acid; 
q is an integer from 0 to 1; 
Q denotes a group 
##STR3## 
wherein: B.sub.1 equals B.sub.2 and denotes halogen, --(CH.sub.2).sub.m 
--CN, --(CH.sub.2).sub.m+1 --R.sup.2, --(CH.sub.2).sub.m --R.sup.3, 
--(CH.sub.2).sub.m --COR.sup.2 or --(CH.sub.2).sub.m --COR.sup.3 ; 
R.sup.2 denotes --OR.sup.3, --N(R.sup.3).sub.2, --SR.sup.3 ; 
R.sup.3 is independently hydrogen, C.sub.1 -C.sub.4 -alkyl or benzyl; 
m is independently an integer from 0 to 4; 
C.sub.1 equals C.sub.2 and denotes halogen, --(CH.sub.2).sub.n --CN, 
--(CH.sub.2).sub.n+1 --R.sup.4, --(CH.sub.2).sub.n --R.sup.5, 
--(CH.sub.2).sub.n --COR.sup.4 or --(CH.sub.2).sub.n --COR.sup.5 ; 
R.sup.4 is independently --OR.sup.5, --N(R.sup.5).sub.2, --SR.sup.5 ; 
R.sup.5 is independently hydrogen, C.sub.1 -C.sub.4 -alkyl or benzyl; 
n is independently an integer from 0 to 4; 
D denotes --(CH.sub.2).sub.x --E--(CH.sub.2).sub.y --; wherein 
E denotes a mono- or bicyclic aromatic or nonaromatic ring system 
consisting of 5-10 carbon atoms containing up to 4 heteroatoms N, O or S 
in the ring, which is optionally mono-, poly or mixed substituted by 
alkyl, alkoxy, oxo, alkoxyalky, hydroxy, amino or dialkylamino; and 
x and y independently denote an integer from 0 to 5; with the proviso that 
B.sub.1 is not identical to C.sub.1 and B.sub.2 is not identical to C.sub.2 
; and pharmaceutically acceptable salts thereof. 
Z in the above Formula (I) denotes an optionally substituted pyrrolyl, 
isopyrrolyl, pyrazolyl, isoimidazolyl, triazolyl, iosxazolyl, oxazolyl, 
thiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 
pyrazinyl, pyrrolidinyl, piperazinyl, triazinyl, morpholinyl, indolyl, 
indoleninyl, isobenzazolyl, pyrindinyl, ioindazolyl, indoxazinyl, 
benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, 
naphthyridinyl, pyridopyridinyl, tetrahydroquinolinyl, 
tetrahydroisoquinolinyl, quinoxalinyl, indolinyl, pyrrolidonyl, 
imidazolyl, imidazolidinyl, imidazolinyl, piperidyl, tetrazolyl, 
quinuclidinyl, azetidinyl, or purinyl. 
Possible substituents for Z are C.sub.1-4 alkyl, C.sub.1-4 alkoxy, 
C.sub.1-4 alkoxy-C.sub.1-4 -alkyl, oxo, oxime, O--C.sub.1-4 -alkyloxime, 
hydroxy, amino, C.sub.1-4 -alkylamino, di-C.sub.1-4 -alkylamino, acylamino 
and aminoacyl 
R.sup.3, as well as R.sup.5, denotes hydrogen, methyl, ethyl, propyl, 
i-propyl, butyl and benzyl. 
E in the above Formula (I) denotes an optionally substituted phenyl, 
indenyl, naphthyl, pyrrolyl, isopyrrolyl, pyrazolyl, isoimidazolyl, 
triazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, piperazinyl, 
triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, 
indolyl, indoleninyl, isobenzazolyl, pyrindinyl, pyranopyrrolyl, 
isoindazolyl, indoxazinyl, benzoxazolyl, anthianilyl, quinolinyl, 
isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridinyl 
or benzoxazinyl. 
Preferred compounds are those wherein Z is pyridinyl, pyrimidinyl, 
pyrazinyl, pyridazinyl, quinolinyl, tetrahydroquinolinyl, azetidinyl, or 
pyrrolidinyl. 
More preferred compounds are those wherein Z is 2-pyridinyl, 2-pyrimidinyl, 
2-pyrazinyl, 2-pyrrolidon-5-yl, or pyrrolidinyl. 
Preferred substituents for Z are methyl, ethyl, methoxy, methoxymethyl, 
oxo, oxime, hydroxy, amino, ethylamino or dimethylamino. 
Preferred groups R' and R" are hydrogen, methyl and ethyl. 
Preferred groups E are optionally substituted phenyl, indenyl, naphthyl, 
pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, pyrrolidinyl, pyridinyl, 
naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl or 
cinnolinyl. 
Alkyl groups may be straight or branched. 
The compounds of the present invention may contain one ore more asymmetric 
carbon atoms and may exist in racemic and optically active forms. All the 
compounds and diastereomers are contemplated to be within the scope of the 
present compounds. 
Especially preferred is: 
##STR4## 
Methods of Preparation 
Compounds of Formula (1) wherein E, R', R", R'", C.sub.1, C.sub.2, B.sub.1, 
B.sub.2, A.sub.1, A.sub.2, Z, k, m, n, x and y are defined as in Formula 
(I) are prepared by methods analogous to those described in Scheme 1. 
##STR5## 
a) butyllithium, THF; b) conc. HCl, dioxane/ethanol; c) DCC, HOBt, 
CH.sub.2 Cl.sub.2 ; 
d) NaOH, dioxane/ethanol 
(2S)-2,5-Dihydro-3,6-diethoxyisopropylpyrazine (1 in Scheme 1) is coupled 
with an appropriate dielectrophile, such as 2 in Scheme 1, using a strong 
base (such as butyllithium) in a suitable solvent (such as THF) to give 3 
in Scheme 1. Hydrolysis and ring-opening under standard acidic conditions 
(such as diluted HCl) in a suitable solvent (such as dioxane/ethanol) 
leads to a diamine, such as 4 in Scheme 1, which is then bis-acylated with 
appropriate heterocyclic acids, such as 5 in Scheme 1, using an activating 
agent (such as DCC) and a strong base (such as HOBt) in an aprotic polar 
solvent (such as CH.sub.2 Cl.sub.2). Optionable hydrolysis of the ester 
under standard basic conditions (such as NaOH) in a suitable solvent (such 
as dioxane/ethanol) furnishes the product 7 in Scheme 1. 
In order to use a compound of the Formula (I) or a pharmaceutically 
acceptable salt thereof for the treatment of humans and other mammals it 
is normally formulated in accordance with pharmaceutical practice as a 
pharmaceutical composition. 
According to a still further feature of the present invention there are 
provided pharmaceutical compositions comprising as active ingredient one 
or more compounds of Formula (I) as herein before defined or 
physiologically compatible salts thereof, in association with a 
pharmaceutical carrier or excipient. The compositions according to the 
invention may be presented for example, in a form suitable for oral, 
nasal, parenteral or rectal administration. 
As used herein, the term "pharmaceutical" includes veterinary applications 
of the invention. These peptides may be encapsulated, tableted or prepared 
in an emulsion or syrup for oral administration. Pharmaceutically 
acceptable solid or liquid carriers may be added to enhance or stabilize 
the composition, or to facilitate preparation of the composition. Liquid 
carriers include syrup, peanut oil, olive oil, glycerin, saline and water. 
Solid carriers include starch, lactose, calcium sulfate dihydrate, terra 
alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or 
gelatin. The carrier may also include a sustained release material such as 
glyceryl monostearate or glyceryl distearate, alone or with a wax. The 
amount of solid carrier varies, but, preferably will be between about 20 
mg to about 1 g per dosage unit. The pharmaceutical preparations are made 
following the conventional techniques of pharmacy involving milling, 
mixing and filling for hard gelatin capsule forms. Capsules containing one 
or several active ingredients may be produced, for example, by mixing the 
active ingredients with inert carriers, such as lactose or sorbitol, and 
filling the mixture into gelatin capsules. Organ specific carrier systems 
may also be used. 
Alternately pharmaceutical compositions of the peptides of this invention 
or derivatives thereof, may be formulated as solutions of lyophilized 
powders for parenteral administration. Powders may be reconstituted by 
addition of a suitable diluent or other pharmaceutically acceptable 
carrier prior to use. The liquid formulation is generally a buffered, 
isotonic, aqueous solution. Examples of suitable diluents are normal 
isotonic saline solution, standard 5% dextrose in water or buffered sodium 
or ammonium acetate solution. Such formulation is especially suitable for 
parenteral administration, but may also be used for oral administration 
and contained in a metered dose inhaler or nebulizer for insufflation. It 
may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, 
hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride 
or sodium citrate. 
For rectal administration, a pulverized powder of the peptides of this 
invention may be combined with excipients such as cocoa butter, glycerin, 
gelatin or polyethylene glycols and molded into a suppository. The 
pulverized powders may also be compounded with oily preparation, gel, 
cream or emulsion, buffered or unbuffered, and administered through a 
transdermal patch. 
Nasal sprays may be formulated similarly in aqueous solution and packed 
into spray containers either with an aerosol propellant or provided with 
means for manual compression. 
Dosage units containing the compounds of this invention preferably contain 
0.05-50 mg, for example 0.05-5 mg of the compound of Formula (I) or of the 
salt thereof. 
According to a still further feature of the present invention there is 
provided a method of stimulation of myelopoiesis which comprises 
administering an effective amount of a pharmaceutical composition as 
hereinbefore defined to a subject. 
No unacceptable toxicological effects are expected when compounds of the 
invention are administered in accordance with the present invention. 
The biological activity of the compounds of Formula (I) is demonstrated by 
the following tests. 
Induction of Hematopoietic Synergistic Activity in Stromal Cells 
The murine bone marrow derived from stromal cell line C6.4 is grown in 12 
well pates in RPMI 1640 with 10% FBS. Upon reaching confluence, the C6.4 
cells are washed and the media exchanged with fresh RPMI 1640 without FBS. 
Confluent cell layers of murine C6.4 cells are treated with compound. Cell 
free supernatants are collected 18 hours later. Supernatants are 
fractionated with a Centricon-30 molecular weight cut-off membrane. C6.4 
cell hematopoietic synergistic factor (HSF) activity is measured in a 
murine CFU-C assay. 
CFU-C Assay 
Bone marrow cells are obtained from C57B1/6 female mice and suspended in 
RPMI 1640 with 10% FBS. Bone marrow cells (7.5E+4 cells/mL) are cultured 
with sub optimal levels of CFU plus dilutions of test C6.4 cell 30K-E 
supernatants from above in a standard murine soft agar CFU-C assay. Cell 
aggregates &gt;50 cells are counted as colonies. The number of agar colonies 
counted is proportional to the amount of HSF present within the C6.4 bone 
marrow stromal line supernatant. 
Effector Cell Function Assay 
Female C57B1 mice are administered test compound PO daily for 8 days. 
Resident peritoneal exudate cells (PEC) utilized ex vivo from treated or 
untreated mice are harvested with cold calcium and magnesium-free DPBS 
supplemented with heparin and antibiotics within 2-4 hours following the 
last injection. Adherent PEM populations are prepared by incubating 
standardized PEC suspensions in microtiter dishes for 2 hours at 
37.degree. C. (5% CO.sub.2) and removing nonadherent cells by washing the 
wells with warm buffer. 
The superoxide dismutase-inhibitable (SOD) superoxide released by effector 
cells in response to a in vitro stimulation by phorbol myristate acetate 
(PMA) (100-200 nM) or pre-opsonized (autologous sera) live C. albicans 
(E:T=1:10) are quantitated in a microtiter ferricytochrome c reduction 
assay. The assay is performed in the presence of 1% gelatin/HBSS and 80 
.mu.M ferricytochrome c in a total volume of 200 .mu.L/well. The nmoles of 
cytochrome c reduced/well is calculated from spectrophotometric readings 
(550 nm) taken following a 1 hour incubation at 37.degree. C. (5% 
CO.sub.2). The amount of SOD-inhibitable cytochrome c reduced is 
determined by the inclusion of wells containing SOD (200 U/well). Baseline 
superoxide release is determined in the absence of stimuli. Experimental 
data are expressed as a percentage of the control group.

EXAMPLE 1 
1,4-Bis-(2-(2-pyridylcarbonylamino)-2-carboxy-(2R)-ethyl)-benzene 
##STR6## 
Preparation of 
a,a'-Bis-((2S,5R)-2,5-dihydro-3,6-diethoxy-2-isopropyl-5-pyrazine)-p-xylen 
e 
##STR7## 
(2S)-2,5-Dihydro-3,6-diethoxyisopropylpyrazine (2.03 g; 9.6 mmol) was 
dissolved in THF (150 ml) and a 1.6 M solution of butyllithium in hexane 
was added at -78.degree. C. (6.0 ml; 9.6 mmol). After 1 h at -78.degree. 
C. a solution of the dielectrophile (a,a'-dibromo-p-xylene, 3.8 g, 9.6 
mmol) in 30 ml THF was added dropwise and the mixture was allowed to come 
to room temperature overnight. After hydrolysis of the mixture by pouring 
it on a 1 M phosphate buffer solution (240 ml, pH 7.2), the mixture was 
extracted with diethyl ether (3.times.200 ml) and the combined organic 
layers were dried over MgSO.sub.4. After filtration and drying (Na.sub.2 
SO.sub.4), the solvents were removed on the rotary evaporator and the 
residue was dried under vacuum. 
Purification: flash chromatography: petrol ether/ethyl acetate 9/0.5. 
Yield: 1.8 g, 24% (oil) 
Preparation of 1,4-Bis-(2-amino-2-ethyloxycarbonyl-(2R)-ethyl)-benzene 
##STR8## 
a,a'-Bis-((2S,5R)-2,5-dihydro-3,6-diethoxy-2-isopropyl-5-pyrazine)-p-xylene 
(1.80 g; 3.40 mmol) was dissolved in dioxane (80 ml) and EtOH (160 ml) and 
a solution of conc. HCl (6.25 ml, 75.0 mmol) in water (160 ml) was added 
dropwise. The mixture was stirred overnight and the organic solvents were 
stripped off. A conc. aqueous ammonia solution was added until a pH of 9 
was reached and the aqueous layer was extracted with chloroform 
(3.times.80 ml). The combined organic layers were dried (MgSO.sub.4), 
filtered and the solvent was removed. Remaining ValOEt was removed by 
Kugelrohr distillation (room temperature, 0.05 Torr) to yield 
1,4-Bis-(2-amino-2-ethyloxycarbonyl-(2R)-ethyl)-benzene (1.04g, 100%). 
Preparation of 
1,4-Bis-(2-(2-pyridylcarbonylamino)-2-ethyloxycarbonyl-(2R)-ethyl)-benzene 
##STR9## 
Picolinic acid (1.90 g; 7.2 mmol) was suspended in 100 ml dichloromethane 
and a solution of 1,4-bis-(2-amino-2-ethyloxycarbonyl-(2R)-ethyl)-benzene 
(1.10 g, 3.6 mmol) was added. The clear solution was cooled to 0.degree. 
C. and HOBt (1,31 g, 8.3 mmol) and DCC (1.59 g, 7.7 mmol) were added. The 
reaction mixture came to room temperature overnight and was extracted with 
4% NaHCO.sub.3 solution. The combined organic layers were dried over 
MgSO.sub.4, filtered and the solvent was removed. The residue was purified 
by flash chromatography (silica gel; petrol ether/ethyl acetate 1/2) to 
yield 
1,4-Bis-(2-(2-pyridylcarbonylamino)-2-ethyloxycarbonyl-(2R)-ethyl)-benzene 
as semicrystalline compound (1.40 g, 76%). 
Preparation of 
1,4-Bis-(2-(2-2-pyridylcarbonylamino)-2-carboxy-(2R)-ethyl)-benzene 
To a cooled (0.degree. C.) solution of 
1,4-bis-(2-(2-pyridylcarbonylamino)-2-ethyloxycarbonyl-(2R)-ethyl)-benzene 
(1.40 g; 2.70 mmol) in dioxane (4 ml) and EtOH (4 ml) an aqueous 2N NaOH 
solution (4 ml, 8.0 mmol) and water (2 ml) was added. The mixture was 
allowed to come to r.t. overnight. The solution was concentrated to 
approximately 5 ml under reduced pressure and the pH of the residual 
solution was adjusted to pH 3 by addition of aqueous 4N HCl, whereupon an 
oil separated. The mixture was extracted with ethyl acetate (3.times.15 
ml). The combined organic layer was dried (MgSO.sub.4), concentrated and 
the residue purified by: flash chromatography (chloroform/MeOH/HOAc 8/2/1) 
to yield 1,4-Bis-(2-(2-pyridylcarbonylamino)-2-carboxy-(2R)-ethyl)-benzene 
(1.1 g, 70%). 
.sup.1 H NMR (400 MHz, d.sub.6 -DMSO) d 8.59 (m, 4H), 7.96 (m, 4H), 7.57 
(m, 4H), 7.08 (s, 4H), 4.66 (m, 2H), 3.15 (m, 4H); 
.sup.13 C NMR (100 MHz, d.sub.6 -DMSO) d 172.7, 163.4, 149.5, 148.6, 137.9, 
135.7, 129.1, 126.8, 121.9, 53.6, 36.3; 
C.sub.24 H.sub.22 N.sub.4 O.sub.6 ; MW 462.47. 
EXAMPLE 2 
1,4-Bis-(2-(2-pyridylcarbonylamino)-2-ethyloxycarbonyl-(2R)-ethyl)-benzene 
This compound was synthesized analogous to Example 1, except that the last 
step (hydrolysis of the ester) was omitted. 
.sup.1 H NMR (400 MHz, CDCl.sub.3) d 8.51 (m, 2H), 8.45 (d, 2H, 8.1 Hz), 
8.13 (d, 2H, J=7.7 Hz), 7.81 (m, 2H), 7.40 (m, 2H), 7.10 (s, 4H), 5.00 (m, 
2H), 4.14 (m, 4H), 3.18 (d, 4H, J=6.2 Hz), 1.19 (t, 6H, J=7.1 Hz); 
.sup.13 C NMR (100 MHz, CDCl.sub.3) d 171.3, 163.939 149.5, 148.3, 137.2, 
134.9, 129.5, 126.3, 122.2, 61.4, 53.5, 38.0, 14.1.