Novel carbamates of 2-ureado-6-hydroxy-pyridines have the structural formula ##STR1## wherein n is 0 to 20; R.sub.1 is hydrogen, alkyl which may be substituted, aryl which may be substituted; R.sub.2 is hydrogen, halogen, carboxylic, SO.sub.3 H, NO.sub.2, alkyl or aryl; R.sub.3 and R.sub.4 have the same meaning as R.sub.2 ; Z is N.dbd.C.dbd.O, N.dbd.C.dbd.S, carboxylic, primary or secondary amine and when n.dbd.O, Z may be ##STR2## wherein Q is hydroxyl, amino, carboxylic, sulfhydryl, isocyanato or isothiocyanato. The carbamates of 2-ureado-6-hydroxypyridines react with compounds of interest to form derivatives which will chelate metal ions such as radionuclides or lanthanides, resulting in the radioisotopic or fluorescent labeling of the compounds.

FIELD OF THE INVENTION 
This invention relates to novel carbamates of 2-ureado-6-hydroxypyridine. 
The ureado-carbamates of the invention are strong chelating agents which 
form stable chelates with various metal ions such as rare earth and 
transition metals useful in inter alia industrial extraction and 
purification or in ore analysis by well-known techniques. Moreover, the 
2-ureado-6-pyridine carbamates, according to this invention, are 
bi-functional making them useful inter alia in radioisotopic and 
fluorescent labeling of organic substrates. These bi-functional carbamates 
of 2-ureado-6-pyridinol have the ability to react with compounds of 
biological or clinical interest to form derivatives which will chelate 
with suitable metal ions such as radionuclides or lanthanides, resulting 
in the radioisotopic or fluorescent labeling of the compounds. 
The bi-functionality of the novel carbamates according to the invention 
make them particularly useful in analytical techniques for the detection 
and measurement of biological and clinical compounds of interest. Typical 
examples of such compounds are bacteria, viruses, protozoa, rickettsia, 
amino acids, peptides, proteins, enzymes, hormones and blood groups. The 
novel carbamates are also intended, in view of their peculiar 
bi-functionality, for use as imaging agents for investigating the function 
of organs in animals, including man. Furthermore, these bi-functional 
chelating agents can be used for the radioisotopic labeling of biological 
molecules. 
BACKGROUND OF THE INVENTION 
It is known that chelating agents such as ethylenediaminetetraacetic acid 
(EDTA), when chelated with a radionuclide, can be used in organ imaging. 
However, the complex of EDTA and a radionuclide is of limited use in 
certain organs where lipo-solubility is necessary. 
It is known that fluorescent groups such as fluorescein isothiocyanate can 
be introduced into biological or clinical compounds of interest. 
Analytical techniques employing fluorescein frequently lack the requisite 
sensitivity for the detection and measurement of nanomolar or picomolar 
levels of organic substrates. The lack in sensitivity of techniques which 
employ fluorescein is believed to be due to the high fluorescence 
background of biological fluids and to fluorescein's high degree of 
overlap in fluorescent excitation and emission spectra. 
It is an object of the present invention to provide carbamate compounds of 
2-ureado-6-hydroxypyridine which are strong chelating agents suitable for 
forming stable chelates, particularly with the rare earths, transition 
metals and radionuclides. 
It is also an object of the present invention to provide novel 
bi-functional carbamates of 2-ureado-6-hydroxypyridine which may be 
readily coupled to compounds of clinical or biological interest to provide 
derivatives which form stable complexes with suitable metal ions and which 
exhibit radioactivity or fluorescence. An object of this invention is to 
provide radioisotopic labeled compounds which exhibit rapid preferential 
location in animals regardless of liposolubility. It is a further object 
of the invention to provide fluorescent labeled compounds which circumvent 
the overlap of the excitation and emission spectra of known compounds and 
which exhibit limited background fluorescence. A further object of this 
invention is to provide novel chelates which will exhibit distinct 
fluorescence excitation and emission spectra corresponding to that of the 
specific metal ion which is chelated, which chelates are stable and not 
deleterious to the biological compounds of interest. Yet another object of 
this invention lies in the coupling of the novel moieties to form adducts 
with a broad spectra of biological and clinical compounds by facile and 
gentle chemical reactions. 
SUMMARY OF THE INVENTION 
The 2-ureado-6-hydroxypyridine carbamates according to the invention have 
the structural formula 
##STR3## 
wherein n is 0 to 20; R.sub.1 is hydrogen, alkyl which may be substituted, 
or aryl which may be substituted; R.sub.2 is hydrogen, alkyl, aryl, 
halogen, carboxylic, SO.sub.3 H, or NO.sub.2 ; R.sub.3 and R.sub.4 have 
the same meaning as R.sub.2 ; Z is N.dbd.C.dbd.O, N.dbd.C.dbd.S, 
carboxylic, primary or secondary amine, and when n.dbd.O, Z may be 
##STR4## 
where Q is hydroxy, amino, carboxylic, sulfhydryl, isocyanato or 
isothiocyanato. 
As previously set forth, the excellent chelating properties of the 
carbamates of 2-ureado-6-hydroxypyridine, according to the invention, make 
them suitable for any known use where the formation of a stable chelate is 
desirous. For example, in fluorescent labelling techniques, such as 
fluorescent immunoassays, the chelated derivatives of the invention in 
remarkable contrast to the prior art exhibit little decay or loss of 
fluorescence and exhibit distinct separation of excitation and emission 
spectra. 
The novel carbamates of 2-ureado-6-hydroxypyridine of the present invention 
can be readily chelated with radioisotopic elements to provide 
radioisotopic probes which can be used as imaging agents for investigating 
the functioning of organs in animals including man. Furthermore, these 
radioactive probes can be used as therapeutic agents when short-lived 
radioactive nuclides can be localized in target areas. 
DETAILED DESCRIPTION OF THE INVENTION 
The carbamate compounds of 2-ureado-6-hydroxypyridine according to the 
invention are bi-functional. The 2-ureado-6-carbamato-pyridine moiety 
represented structurally as 
##STR5## 
acts as an ideal chelating agent due to the stability of the resulting 
complex. The remaining moiety of the invention compounds represented by 
the radical --(CH.sub.2).sub.n --Z where Z is an isothiocyanate, 
isocyanate, lactone or thiolactone moiety provides an active hydrogen 
bonding site and functions most suitably to promote coupling of the 
carbamate with other compounds of interest, including organic substrates. 
Depending upon the particular ureado-carbamate, the stable chelate formed 
may be either an ionic or coordinate bonded complex. 
The 2-ureado-6-carbamato pyridines of the invention are synthesized from 
2-amino-6-hydroxypyridine in three steps. For example, the reaction of 
2-amino-6-hydroxypyridine with a silylating agent such as 
hexamethyldisilazane affords a hydroxy blocked compound. An example is 
illustrated in the following equation: 
##STR6## 
This reaction is optionally performed in the presence of a solvent which 
is inert to the reaction partners, such as benzene, toluene, xylene, 
pyridine, or aliphatic or aromatic chlorinated hydrocarbons as esters, 
ketones, amides or ethers with methylene chloride being the preferred 
solvent. The temperature employed in the reaction may range from 5.degree. 
to 200.degree. C., with ambient temperature being preferrable. 
While the hexamethyldisilazane route has been employed, other silylating 
agents such as trimethylsilylacetamide, trimethylsilyltrifluoroacetamide 
or trimethylsilylchloride can be used. The use of trimethylsilylchloride 
for the silylation step may afford the ditrimethylsilylated compound in 
which both the hydroxy and the amine group at the 
2-amino-6-hydroxypyridine have been silylated. The following reaction for 
the trimethylsilylchloride method is illustrated: 
##STR7## 
It has been found that trimethylsilylation of the hydroxy group blocks its 
nucleophylic reactivity while the resulting trimethylsilylamine enhance 
the nucleophylic reactivity of the amine group against electrophyles. It 
is therefore of no disadvantage to disilylate the 
2-amino-6-hydroxypyridine in an effort to carry reactions of the amine 
group of the compound if one so wishes. 
The resulting 2-amino-6-trimethylsilyloxypyridine obtained from the 
silylation reaction has been used to synthesize the 
2-ureado-6-hydroxypyridine compounds of the invention. For example the 
reaction of 2-amino-6-trimethylsiloxy-pyridine with isocyanates of the 
general formula 
EQU R.sub.1 -N.dbd.C.dbd.O 
wherein R.sub.1 is alkyl which may be substituted, or aryl which may be 
substituted. An example is illustrated in the following equation: 
##STR8## 
The reaction with isocyanates is preferably carried out in the presence of 
a solvent which is inert to the reaction partners such as aromatic 
hydrocarbons, aliphatic or aromatic chlorinated hydrocarbons such as 
methylene chloride or chlorobenzene, ethers, ketones, amides or pyridine. 
The temperature employed may range from 5.degree. to 150.degree. C. with 
ambient temperature being preferable. Deblocking of the 6-hydroxyl group 
can be easily achieved by the addition of alcohol or water, with known 
techniques such as crystallization or liquid or thin-layer chromatography 
can be employed for the purification. 
While the isocyanate route of urea synthesis is preferred, the 
6-hydroxy-2-pyridyl ureas can be synthesized by alternative methods 
utilizing either phosgene or chloroformic acid esters. In the phosgene 
method, an amine of the general formula 
EQU R.sub.1 --NH.sub.2 
wherein R.sub.1 as defined above, is reacted with phosgene to form the 
carbamic acid chloride. The so formed carbamic acid chloride is then 
reacted in situ with 6-trimethylsilyloxy-2-aminopyridine to form the 
desired urea. 
The chloroformic acid method involves the reaction of 
6-trimethylsilyloxy-2-aminopyridine with chloroformic acid esters, such as 
ethylchloroformate, benzylchloroformate or isobutylchloroformate, and then 
reacting the product obtained with an amine of the general formula: 
EQU R.sub.1 --NH.sub.2 
wherein R.sub.1 is as defined above. 
The bifunctional carbamates of 2-ureado-6-hydroxypyridine of the invention 
are synthesized using known techniques. For example, by the reaction of 
2-ureado-6-hydroxypyridine, whose synthesis is described above with a 
bi-functional isocyanate of the general formula: 
EQU O.dbd.C.dbd.N--(CH.sub.2).sub.n --Z 
wherein when n is O, Z is thiolactone, lactone or succinic anhydride, and 
when n is 1 to 20, Z is isocyanate, isothiocyanate, blocked carboxylic or 
benezene derivative such as 
##STR9## 
where Q is blocked primary or secondary amine, blocked carboxylic, 
isocyanate or isothiocyanate, is preferred. 
An example is illustrated in the following equation: 
##STR10## 
The synthesis is optionally performed in the presence of a solvent which 
is inert to the isocyanato radical such as chlorinated aromatic or 
aliphatic hydrocarbons, aromatic hydrocarbon, e.g., benzene, toluene, 
xylene or esters, ketones and amides. The preferred solvent is pyridine. 
The temperature employed in the synthesis may range from 5.degree. to 
150.degree. C. with ambient temperature being preferred. Also, if desired, 
any of the several types of catalysts known to be useful in forming 
urethanes can be employed. Useful catalysts include tertiary amines, salts 
or organic acids with a variety of metals such as alkali metals and the 
like. 
While the isocyanate route of carbamate synthesis is preferred, the 
bi-functional carbamate of 2-ureado-6-hydroxypyridine can be synthesized 
by alternate methods, utilizing either phosgene or chloroformic acid 
esters which are described in the 6-hydroxy-2-pyridyl urea synthesis. In 
the phosgene method, an amine of the general formula 
EQU H.sub.2 N--(CH.sub.2).sub.n --Z 
wherein n is 0 to 20 and Z is as defined above, is reacted with phosgene to 
form carbamic acid chloride. The so-formed carbamic acid chloride is then 
reacted in situ with 2-ureado-6-hydroxypyridine to form the desired 
carbamate. 
The method utilizing chloroformic acid esters involves the reaction of 
2-ureado-6-hydroxypyridine with isobutylchloroformate and then reacting 
the resulting product with an amine of the general formula 
EQU H.sub.2 N--(CH.sub.2).sub.n --Z 
wherein n is 0 to 20 and Z is as defined above. Other chloroformic acid 
esters such as benzylchloroformate, etherchloroformate and the like can be 
utilized in this method of carbamate synthesis. 
The 2-ureado-6-hydroxypyridine carbamates of the invention may be reacted 
with any compound of interest capable of reacting with the Z radical. For 
example, any compound containing (in the clinical sense) an active 
hydrogen group may be coupled to the carbamates, e.g., any compound 
containing a hydroxyl, amino, sulfhydryl or carboxylic group can be 
utilized. Accordingly, with regard to organic or biological compound of 
interest, a wide number of amino acids, peptides, proteins, enzymes, 
steroids, drugs, pesticides, various natural products, plant and animal 
hormones, polyamines, viruses, bacterial cells and other matabolites 
contain groups reactive with the Z radicals. 
The carbamates of 2-ureado-6-hydroxypyridine can be bound to organic 
substrates by utilizing known process conditions. It is suitable, for 
example, to prepare the adduct by reaction in a solvent, if desired, at a 
temperature ranging from 0.degree. to about 150.degree. C. Representative 
examples of useful solvents include pyridine, formamide, tetrahydrofuran, 
triethylamine, dimethylformamide, ethers, methylene chloride, water and 
aqueous media. 
The conditions selected should be such as to insure that the structure of 
the compound of interest will not be degraded or otherwise adversely 
effected. For this reason, it is preferable to utilize as mild conditions 
as possible. 
The 2-ureado-6-hydroxypyridine carbamates of the invention may be coupled 
to biological molecules or clinical compounds of interest through the Z 
moiety in various ways to form adducts. For example, when the Z moiety is 
isothiocyanate, coupling occurs readily with proteins, such as antibodies, 
enzymes and amino acids and other biological molecules having an amine 
group which are receptive to an amide linkage. The following reaction for 
the isothiocyanato carbamate is illustrated: 
##STR11## 
where R is an organic substrate containing a functional amine group having 
an active hydrogen. The coupling is carried out in a variety of solvents 
depending on the nature of the organic substrate. Coupling with proteins, 
for example, is carried out in buffers such as carbamates, phosphates or 
citrates. The pH of the reaction may range from 1 to 12, but a pH of 8 to 
10 is preferred. The reaction time and temperature are approximately 
selected depending on the stability and nature of the protein. The 
preferred reaction time is 1 to 24 hours and the preferred temperature is 
about 4.degree. C. to ambient. 
Since proteins may have more than one amino group, it is possible that more 
than one 2-ureado-6-carbamatopyridines can be coupled. The coupling of one 
to five 2-ureado-pyridine carbamates is preferred. The ratio of 
2-ureado-6-hydroxypyridine carbamates to the number of proteins coupled 
can be controlled by the amount of the pyridyl carbamate used. 
Coupling with organic substrates bearing functional amino groups and which 
are not susceptible to organic solvents is carried out in pyridine, 
dimethylformamide, chlorinated hydrocarbons, ethers, ureas, amides and a 
variety of solvents which are inert to the reaction partners. 
When the Z moiety is thiolactone, coupling occurs readily with proteins and 
other biological molecules having an amine group with an active hydrogen, 
which are receptive to an amide linkage. The following equation 
illustrates this type of reaction: 
##STR12## 
where R is an organic substrate containing a functional amine group having 
an active hydrogen. The conditions for the thiolactone coupling are 
similar to the conditions used for the coupling of 
isothiocyanato-2-ureado-pyridyl carbamate. 
When the Z moiety is isocyanate, as in 
2-ureado-6-isocyanatohexyl-pyridyl-carbamate, the resulting carbamate is 
wellsuited to coupling with biological molecules which have hydroxyl 
reactive groups such as digoxin, cortisol, estradiol and, in general, 
drugs or hormones having reactive hydroxyl groups. This, however, does not 
exclude coupling to compounds with other reactive groups. Typically, for 
example, any compound containing an hydroxyl, amino, sulfhydryl or 
carboxylic group can be utilized. For example, ethanol can be coupled to 
2-ureado-6-isocyanatohexyl-pyridyl-carbamate in accordance with the 
invention by a carbamate bond as shown in the following equation: 
##STR13## 
Many compounds of interest contain more than one radical reactive with the 
isocyanate moiety, resulting in the formation of more than one species. 
This can be minimized and even avoided by utilizing particular blocking 
and deblocking techniques. For example, 11-amino-undecanoic acid possesses 
one amino and one carboxylic group, both of which can react with 
isocyanate radicals. In order to minimize the reactive sites, it is 
necessary to block the carboxylic group with trimethylsilyl radicals. It 
has been discovered that the employment of this procedure results only in 
the production of a single species consistent with a structure having a 
2-ureado-6-carbamatopyridine linked to the 11-amino group of the 
11-amino-undecanoic acid. Deblocking of the carboxylic group is 
accomplished by using water or methanol. Where the reaction provides more 
than one species, conventional separation techniques (e.g., thin layer 
chromatography or crystallization) can be employed. 
The 2-ureado-6-carbamatopyridine moiety of this invention is receptive to 
chelation and may be advantageously utilized in any of the several known 
techniques involving radioisotopic or fluorescent competitive binding to 
detect and measure the compound of interest. Adducts of 
2-ureado-6-carbamatopyridine and biological molecules complexed with 
radionuclides such as technetium 99 can be used in vivo for diagnostic or 
therapeutic purposes. The particular 2-ureado-6-carbamatopyridine adducts 
used will be dependent upon the type of tagging required by the technique 
of choice and the technique selected will be determined by the results 
required. Suitable ions, including radioisotopic ions, for chelating the 
compounds of the invention are ions of the lanthanide series of elements, 
e.g., the rare earths and ions of the transition metals. Illustrative 
examples are lanthanum, indium, europium, scandium, terbium, beryllium, 
technisium, cobalt and gallium ions. It is preferred to use a lanthanide 
ion for fluorescent labeling of organic substrates. It is preferred to use 
technisium-99 or indium-111 ions for radioisotopic labeling of organic 
substrates. The following examples are illustrative, but not in 
limitation, of the present invention:

EXAMPLE 1 
2-(N-butylureado)-6-hydroxypyridine 
The chemical formula of 2-(N-butylureado)-6-hydroxypyridine is shown below. 
##STR14## 
A mixture of 2.2 grams (0.02 mols) of 2-amino-6-hydroxypyridine suspended 
in 20 milliliters of dry methylene chloride and 9.0 milliliters of 
hexamethyldisilazane was stirred at ambient temperature for about 24 
hours. The homogeneous reaction mixture formed was evaporated to dryness 
using trap to trap distillation and the resulting residue was dissolved in 
10 milliliter of dry pyridine. To this was added 2.5 milliliter (0.022 
mols) of n-butylisocyanate and the mixture stirred at ambient temperature 
for about 24 hours. The pyridine and excess n-butylisocyanate was then 
removed in vacuo at ambient temperature and the crude reaction mixture was 
washed with water. 3.1 grams of product dried in a stream of air was 
obtained. The product analyzed by infrared spectroscopy showed bands at 
(nujol) 3.0 (NH), 3.10-3.15 (OH), 5.88 and 6.03 (urea carbonyl), 6.3.mu. 
(aromatic). 
EXAMPLE 2 
2-(N-phenylureado)-6-hydroxypyridine 
The chemical formula of 2-(N-phenylureado)-6-hydroxypyridine is shown 
below. 
##STR15## 
A mixture of 1.1 grams (0.01 mols) of 2-amino-6-hydroxypyridine suspended 
in 10 milliliter of dry pyridine and 5.0 milliliter of 
hexamethyldisilazane was stirred at ambient temperature for about 24 
hours. The solvent and excess of hexamethyldisilazane was then removed 
using trap to trap distillation and the resulting residue was dissolved in 
10 milliliters of dry Pyridine. To this was added 1.5 milliliters (0.013 
mols) of phenylisocyanate and the mixture stirred at ambient temperature 
for about 24 hours. The pyridine was then removed in vacuo and the crude 
reaction product crystallized from methanol gave 2.1 grams of product. The 
product analyzed by infrared spectroscopy showed bands at (nujol) 3.03 
(NH), 6.0 (urea carbonyl), 6.25, 6.40, 6.53, 7.58, 7.9, 8.13, 8.30, 8.70 
.mu.. 
EXAMPLE 3 
2-(N-butylureado)-6-(N-5-isothiocyanatopentylcarbamato)-pyridine 
The chemical formual of 2-ureado-6-isothiocyanatopentylcarbamato pyridine 
is shown below. 
##STR16## 
A mixture of 210 milligrams (0.001 mols) of 
2-(N-butylureado)-6-hydroxypyridine and 0.3 milliliter of 
1-isocyanato-5-isothiocyanato-pentane were mixed in 3.0 milliliter of dry 
pyridine and stirred at ambient temperature for five days. The pyridine 
was then removed in vacuo and the crude reaction mixture was washed with 
50% ether-hexane to remove excess of 1-isocyanato-5-isothiocyanatopentane. 
350 milligrams of solid product was obtained. The product characterized by 
infrared spectroscopy showed bands at (nujol) 3.0 (NH), 4.75 
(N.dbd.C.dbd.S), 5.80 (carbamate carbonyl), 5.90.mu. (urea carbonyl). 
EXAMPLE 4 
2-(N-phenylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine 
The chemical formula of 
2-(N-phenylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine is shown 
below. 
##STR17## 
A mixture of 100 milligrams of 2-(N-phenylureado)-6-hydroxypyridine and 
1.0 milliliter of 1,6-diisocyanatohexane (excess) were mixed in 10 
milliliters of dry pyridine and the mixture was allowed to stir at ambient 
temperature for three days. The pyridine was then removed in vacuo at 
ambient temperature and the crude reaction mixture was washed with dry 
ether to remove unreacted diisocyanato hexane. 
Since the isocyanato moiety was susceptible to hydrolysis, the product was 
used in its crude form. 160 Milligrams of 
2-(N-phenylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine was obtained. 
IR (pyridine) analysis showed bands at 4.45 (N.dbd.C.dbd.O), 5.7 and 
5.8.mu. (carbamate and urea carbonyls). 
EXAMPLE 5 
Coupling of 2-(N-phenylureado)6-(N'-isocyanatohexylcarbamato)-pyridine to 
ethanol 
The chemical formula of the adduct formed by coupling 
2-(N-phenylureado)6-(isocyanatohexylcarbamato)-pyridine to ethanol is 
shown below. 
##STR18## 
A mixture of 160 milligrams of 
2-(N-phenylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine, prepared in 
accordance with Example 4, was mixed with 5.0 milliliters of absolute 
ethanol in 3.0 milliliters of dry pyridine and the mixture stirred at 
ambient temperature for about 24 hours. The pyridine and other volatiles 
were removed in vacuo and gave 185 milligrams of the product. The product 
characterized by infrared spectroscopy (neat smear) gave bands at 3.0 
(NH), 5.9 broad (carbonyls), 6.45, 7.9, 8.75, and 9.7.mu.. 
EXAMPLE 6 
2-(N-n-butylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine 
The chemical formula of 
2-(N-n-butylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine is shown 
below. 
##STR19## 
A mixture of 210 milligrams of 2-(N-n-butylureado)-6-hydroxypyridine 
prepared in accordance with Example 1 and 0.5 milliliters of 
1,6-diisocyanatohexane dissolved in 5.0 milliliters of dry pyridine was 
allowed to stir at ambient temperature for 3 days. The pyridine was then 
removed in vacuo and the crude reaction mixture was washed with hexane two 
times and with 50% hexane-ether to remove unreacted diisocyanatohexane. 
Since the isocyanato moiety was susceptible to hydrolysis, the product was 
used in its crude form. 350 Milligrams of 
2-(N-n-butylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine was obtained. 
IR (pyridine) analysis showed bands at 4.45.mu. (--N.dbd.C.dbd.O), 5.7.mu. 
(carbamate carbonyl), 5.9.mu. (urea carbonyl). 
EXAMPLE 7 
Coupling of 2-(N-n-butylureado)6-(N'-isocyanatohexylcarbamato)-pyridine to 
11-aminoundecanoic acid 
The chemical formula of the adduct formed by coupling 
2-(N-n-butylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine to 
11-aminoundecanoic acid is shown below. 
##STR20## 
A mixture of 300 milligrams (0.0015 mols) of 11-aminoundecanoic acid 
suspended in 5 ml of dry pyridine and 1.0 milliliter of 
hexamethyldisilazane was allowed to stir at about 100.degree. C. for one 
hour. The solvent and excess of hexamethyldisilazane were then removed 
using trap to trap distillation and the resulting residue was dissolved in 
3.0 milliliter of dry pyridine. Using a syringe, the pyridine solution was 
transferred to a flask containing 350 milligrams of 
2-(N-n-butylureado)-6-(N'-isocyanatohexylcarbamato)-pyridine prepared in 
accordance with Example 6. The mixture was stirred at ambient temperature 
for 48 days. The solvent was then removed in vacuo and the flask content 
was dissolved in methanol and filtered. The filtrate, evaporated to 
dryness, gave 470 mg of the adduct.