Tropone derivatives characterized by having a derivative of oxamic acid at positions 2 and/or 5 are disclosed. In addition, the tropone nucleus can be optionally further substituted. The foregoing compounds are useful for preventing or treating allergic conditions in a mammal. Methods for the preparation and use of said compounds are disclosed.

BACKGROUND OF THE INVENTION 
a. Field of the Invention 
This invention relates to novel tropone derivatives, to processes for their 
preparation, to methods for using said derivatives, and to therapeutically 
acceptable salts and compositions of said derivatives. 
More specifically, the present invention relates to novel troponyl-oxamic 
acid derivatives possessing valuable pharmacologic properties. For 
example, these derivatives are useful for preventing or treating allergic 
conditions in a mammal at dosages which do not elicit undesirable side 
effects. The combination of these pharmacologic properties render the 
troponyl-oxamic acid derivatives of the invention therapeutically useful. 
B. Description of the Prior Art 
A rather large number of reports dealing with tropone derivatives are 
available. The prior art relating to tropone derivatives is summarized in 
various reviews; for example, see the review by F. Pietra in Chem. Rev., 
73, 293 (1973). Another report describes a class of alkyl esters of 
5-aminotropolones which exhibit anti-neoplastic activity, see L. D. 
Donaruma, Canadian Patent No. 787,451, issued June 11, 1968. 
The tropone derivatives of the present invention are distinguished from the 
prior art compounds by the nature of the substituents on the tropone 
nucleus and by their pharmacologic properties. More specifically, the 
novel tropone derivatives of this invention are distinguished from the 
prior art compounds by having the tropone nucleus substituted with one or 
two oxamic acid derivatives. 
SUMMARY OF THE INVENTION 
The compounds of this invention are represented by formula I 
##STR1## 
in which R.sup.1 and R.sup.4 are the same or different selected from the 
group consisting of hydrogen, halo, trifluoromethyl, lower alkoxy, lower 
alkyl, phenyl, hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio, NR.sup.7 
R.sup.8 wherein R.sup.7 and R.sup.8 each is hydrogen or lower alkyl, or 
R.sup.7 is lower alkyl and R.sup.8 is p-toluenesulfonyl, and a radical of 
formula NR.sup.9 COCOOR.sup.10 wherein R.sup.9 and R.sup.10 each is 
hydrogen or lower alkyl; and R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are the 
same or different selected from the group consisting of hydrogen, halo, 
trifluoromethyl, lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy, 
mercapto, (2-carboxyphenyl)thio, and NR.sup.7 R.sup.8 wherein R.sup.7 and 
R.sup.8 each is hydrogen or lower alkyl; or R.sup.7 is lower alkyl and 
R.sup.8 is p-toluenesulfonyl; with the proviso that at least one of 
R.sup.1 and R.sup.4 must be a radical of formula NR.sup.9 COCOOR.sup.10 
wherein R.sup.9 and R.sup.10 are as defined herein. 
A preferred group of compounds of formula I are those in which at least 
three or R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are 
hydrogen. 
Another preferred group of compounds of this invention is represented by 
formula I in which 
a. R.sup.1 is a radical of formula NR.sup.9 COCOOR.sup.10 in which R.sup.9 
and R.sup.10 are the same or different and are hydrogen or lower alkyl, 
and R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are the same or 
different selected from the group consisting of hydrogen, lowr alkoxy and 
hydroxy; or 
b. R.sup.4 is a radical of formula NR.sup.9 COCOOR.sup.10 in which R.sup.9 
and R.sup.10 each is hydrogen or lower alkyl and R.sup.1, R.sup.2, 
R.sup.3, R.sup.5 and R.sup.6 are the same or different selected from the 
group consisting of hydrogen, lower alkoxy and hydroxy; or 
c. R.sup.1 and R.sup.4 are a radical of formula NR.sup.9 COCOOR.sup.10 
wherein R.sup.9 and R.sup.10 each is hydrogen or lower alkyl, and R.sup.2, 
R.sup.3, R.sup.5 and R.sup.6 are the same or different selected from the 
group consisting of hydrogen, lower alkoxy and hydroxy. 
Still another preferred group of compounds of this invention are 
represented by formula I in which 
a. R.sup.1 is a radical of formula NR.sup.9 COCOOR.sup.10 in which R.sup.9 
and R.sup.10 each is hydrogen or lower alkyl, and R.sup.2, R.sup.3, 
R.sup.4, R.sup.5 and R.sup.6 are the same or different selected from the 
group consisting of hydrogen, lower alkoxy and hydroxy , with the proviso 
that at least three of R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are 
hydrogen; or 
b. R.sup.4 is a radical of formula NR.sup.9 COCOOR.sup.10 in which R.sup.9 
and R.sup.10 each is hydrogen or lower alkyl, and R.sup.1, R.sup.2, 
R.sup.3, R.sup.5 and R.sup.6 are the same or different selected from the 
group consisting of hydrogen, lower alkoxy and hydroxy, with the proviso 
that at least three of R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are 
hydrogen; or 
c. R.sup.1 and R.sup.4 are a radical of formula NR.sup.9 COCOOR.sup.10 
wherein R.sup.9 and R.sup.10 each is hydrogen or lower alkyl; and R.sup.2, 
R.sup.3, R.sup.5 and R.sup.6 are the same or different selected from the 
group consisting of hydrogen, lower alkoxy and hydroxy, with the proviso 
that at least two of R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are hydrogen. 
The therapeutically acceptable salts of the compounds of formula I are also 
included within the scope of this invention. 
The compounds of this invention of formula I are prepared by a process 
comprising: condensing a compound of formula II 
##STR2## 
in which R.sup.11 and R.sup.14 are the same or different selected from the 
group consisting of hydrogen, halo, trifluoromethyl, lower alkoxy, lower 
alkyl, phenyl, hydroxy phenoxy, mercapto, (2-carboxyphenyl)thio, NR.sup.7 
R.sup.8 wherein R.sup.7 is lower alkyl and R.sup.8 is hydrogen, lower 
alkyl or p-toluenesulfonyl, and NHR.sup.9 wherein R.sup.9 is hydrogen or 
lower alkyl; and R.sup.12, R.sup.13, R.sup.15 and R.sup.16 are the same or 
different selected from the group consisting of hydrogen, halo, 
trifluoromethyl, lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy, 
mercapto, (2-carboxyphenyl)thio, and NR.sup.7 R.sup.8 wherein R.sup.7 is 
lower alkyl and R.sup.8 is hydrogen, lower alkyl or p-toluenesulfonyl; 
with the priviso that at least one of R.sup.11 and R.sup.14 must be 
NHR.sup.9, with a compound of formula III 
EQU halogen--COCOOR.sup.10 (III) 
in which R.sup.10 is lower alkyl and the halogen is bromine, chlorine or 
iodine in the presence of a proton acceptor to obtain the corresponding 
compound of formula I in which R.sup.1 and R.sup.4 are the same or 
different selected from the group consisting of hydrogen, halo, 
trifluoromethyl, lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy, 
mercapto, (2-carboxyphenyl)thio and NR.sup.7 R.sup.8 wherein R.sup.7 is 
lower alkyl and R.sup.8 is hydrogen, lower alkyl or p-toluenesulfonyl, and 
a radical of formula NR.sup.9 COCOOR.sup.10 wherein R.sup.9 is as defined 
herein and R.sup.10 is lower alkyl; and R.sup.2, R.sup.3, R.sup.5 and 
R.sup.6 are the same or different selected from the group consisting of 
hydrogen, halo, trifluoromethyl, lower alkoxy, lower alkyl, phenyl, 
hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio and NR.sup.7 R.sup.8 
wherein R.sup.7 is lower alkyl and R.sup.8 is hydrogen, lower alkyl or 
p-toluenesulfonyl; and, if desired and required, followed by 
transformation of the compound of formula I, prepared as described above, 
to other compounds of formula I by methods described herein. 
Another aspect of this invention involves a pharmaceutical composition 
comprising a compound of formula I or a therapeutically acceptable 
addition salt thereof, and a pharmaceutically acceptable carrier therefor. 
Still another aspect of this invention involves a method for preventing or 
treating allergic conditions in a mammal which comprises administering to 
said mammal an effective allergy alleviating amount of a compound of 
formula I or a therapeutically acceptable addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION 
The term "lower alkyl" as used herein contemplates both straight and 
branched chain alkyl radicals containing from one to six carbon atoms and 
includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl 
and the like. 
The term "lower alkoxy" as used herein contemplates both straight and 
branched chain alkoxy radicals containing from one to six carbon atoms and 
includes methoxy, ethoxy, isopropoxy, butoxy, hexanoxy and the like. 
The terms "halogen" and "halo" as used herein contemplate halogens and 
include fluorine, chlorine, bromine and iodine, unless stated otherwise. 
The term "lower alkanol" as used herein contemplates both straight and 
branched chain alkanols containing from one to six carbon atoms and 
includes methanol, ethanol, isopropanol, butanol, hexanol and the like. 
The acidic compounds of formula I in which R.sup.1 and/or R.sup.4 is a 
radical of formula NR.sup.9 COCOOR.sup.10 wherein R.sup.10 is hydrogen 
form salts with suitable therapeutically acceptable inorganic and organic 
bases. These derived salts possess the same activity as the parent acid 
and are included within the scope of this invention. The acid is 
transformed in excellent yield into the corresponding therapeutically 
acceptable salt by neutralization of said acid with the appropriate 
inorganic or organic base. The salts are administered in the same manner 
as the parent acid compounds. Suitable inorganic bases to form these salts 
include, for example, the hydroxides, carbonates, bicarbonates or 
alkoxides of the alkali metals or alkaline earth metals, for example, 
sodium, potassium, magnesium, calcium and the like. Suitable organic bases 
include the following amines; lower mono-, di- and trialkylamines , the 
alkyl radicals of which contain up to three carbon atoms, such as 
methylamine, dimethylamine, trimethylamine, ethylamine, di- and 
triethylamine, methylethylamine, and the like; mono-, di and 
trialkanolamines, the alkanol radicals of which contain up to three carbon 
atoms, for example, mono-, di- and triethanolamine; alkylene-diamines 
which contain up to six carbon atoms, such as hexamethylenediamine; cyclic 
saturated or unsaturated bases containing up to six carbon atoms, such as 
pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and 
N-hydroxyalkyl derivatives, such as N-methyl-morpholine and 
N-(2-hydroxyethyl)piperidine, as well as pyridine. Furthermore, there may 
be mentioned the corresponding quaternary salts, such as the tetraalkyl 
(for example tetramethyl), alkyl-alkanol (for example methyltrimethanol 
and trimethyl-monoethanol) and cyclic ammonium salts, for example the 
N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)morpholinium, 
N,N-dimethylmorpholinium, N-methyl-N-(2-hydroxyethyl)morpholinium, 
N,N-dimethylpiperidinium salts, which are characterized by having good 
water-solubility. In principle, however, there can be used all the 
ammonium salts which are physiologically compatible. 
The transformations to the salts can be carried out by a variety of methods 
known in the art. For example, in the case of the inorganic salts, it is 
preferred to dissolve the acid for formula I in water containing at least 
one equivalent amount of a hydroxide, carbonate, or bicarbonate 
corresponding to the inorganic salt desired. Advantageously, the reaction 
is performed in a water-miscible, inert organic solvent, for example, 
methanol, ethanol, dioxane, and the like in the presence of water. For 
example, such use of sodium hydroxide, sodium carbonate or sodium 
bicarbonate gives a solution of the sodium salt. Evaporation of the 
solution or addition of a water-miscible solvent of a more moderate 
polarity, for example, a lower alkanol, for instance, butanol, or a lower 
alkanone, for instance, ethyl methyl ketone, gives the solid inorganic 
salt if that form is desired. 
To produce an amine salt, the acid of formula I is dissolved in a suitable 
solvent of either moderate or lower polarity, for example, ethanol, 
methanol, ethyl acetate, diethyl ether and benzene. At least an equivalent 
amount of the amine corresponding to the desired cation is then added to 
that solution. If the resulting salt does not precipitate, it can usually 
be obtained in solid form by addition of a miscible diluent of lower 
polarity, for example, benzene or petroleum ether, or by evaporation. If 
the amine is relatively volatile, any excess can easily be removed by 
evaporation. It is preferred to use substantially equivalent amounts of 
the less volatile amines. 
Salts wherein the cation is quaternary ammonium are produced by mixing the 
acid of formula I with an equivalent amount of the corresponding 
quaternary ammonium hydroxide in water solution, followed by evaporation 
of the water. 
The basic compounds of formula I in which R.sup.1, R.sup.2, R.sup.3, 
R.sup.4, R.sup.5 and/or R.sup.6 is NR.sup.7 R.sup.8 wherein R.sup.7 and 
R.sup.8 are as defined herein form addition salts with suitable inorganic 
and organic acids. These salts possess the same activities as the parent 
base compound when administered to a mammal and may be utilized in the 
same manner. Suitable acids to form these salts include, for example the 
common mineral acids, hydrophalic, sulfuric or phosphoric, as well as the 
organic acids, formic, acetic, maleic, malic, citric, or tartaric acid, or 
acids which are sparingly soluble in body fluids and which impart 
slow-release properties to their respective salts such as pamoic or tannic 
acid or carboxymethyl cellulose. The addition salts thus obtained are the 
functional equivalent of the parent base compound in respect to their 
therapeutic use. Hence, these addition salts are included within the scope 
of this invention and are limited only by the requirement that the acids 
employed in forming the salts be therapeutically acceptable. 
Also included within the scope of this invention are the isomers of the 
compounds of formula I resulting from the asymmetric centers contained 
therein. 
Also included within the scope of this invention are the tautomeric forms 
of the compounds of formula I in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, 
R.sup.5 and/or R.sup.6 is hydroxy resulting from the keto-enol equilibrium 
contained therein. 
Anti-allergic Activity 
The compounds of this invention of formula I or therapeutically acceptable 
salts thereof are useful in the prevention or treatment of allergic 
reactions in a mammal upon oral or parenteral administration. 
More specifically, the compounds of this invention are useful for the 
prophylactic treatment as well as for the management of anaphylactic 
reactions and atopic allergic manifestations, for example, bronchial 
asthma, hay fever, allergic rhinitis, allergic conjunctivitis, food 
allergies, urticaria and the like, in a sensitized mammal. 
More specifically exemplified, the compounds of this invention are 
effective anti-allergic agents when tested using the passive cutaneous 
anaphylaxis (PCA) method, described by I. Mota, Immunology, 7, 681(1964). 
The anti-allergic activity of a given compound is measured in rats by its 
ability to inhibit the increase in vascular permeability at the site of 
injection of rat immunoglobulin E (IgE) followed by i.v. administration of 
the specific antigen. Evans blue is injected i.v. at the same time as the 
specific antigen, and the size of the wheal or of the area infiltrated 
with Evans blue is measured and compared with that of untreated controls. 
An effective anti-allergic agent will prevent or inhibit the release of 
inflammatory mediators (mainly serotonin and histamine from the mast 
cells) which causes an increase in vascular permeability and thus an 
infiltration of Evans blue surrounding the site of injection of IgE. The 
anti-allergic activity of the compounds of formula I is demonstrated by 
the reduction of the wheal size of sensitized skin tissue compared to that 
of control animals. A comparison of the anti-allergic activity of the 
compounds of this invention with the anti-allergic activity of a standard 
compound, such as disodium cromoglycate, indicates that the compounds of 
this invention function in the same manner as disodium cromoglycate by 
blocking the release of mediators from the mast cells responsible for the 
allergic reaction. 
When the compounds of formula I of this invention are used for suppressing 
allergic manifestations of anaphylactic reactions and atopic 
hypersensitivity in a mammal, they are used alone or in combination with 
pharmacologically acceptable carriers, the proportion of which is 
determined by the solubility and the chemical nature of the compound, 
chosen route of administration and standard biological practice. For 
example, they are administered parenterally by injection; orally; by the 
nasal route, for instance, as drops or aerosol; or by inhalation from an 
aerosol. 
In addition, the compounds of this invention can be administered in 
conjunction with common anti-allergics, for example, known compounds 
effecting anti-histaminic, analgesic, central nervous system depressant, 
anti-hypertensive, immunosupressive, anti-bradykinin, anti-serotonin or 
endocrinological responses. 
Therapeutic compositions containing the compounds of this invention are 
effective anti-allergic agents for preventing or relieving anaphylactic 
allergic manifestations at dosages of 0.1 mg to 100 mg/kg body weight when 
administered parenterally to a mammal. For administration to a mammal by 
parenteral injection, it is preferred to use the compounds of formula I in 
solution in a sterile aqueous vehicle which may also contain other solutes 
such as buffers or preservatives, as well as sufficient quantities of 
pharmaceutically acceptable salts or of glucose to make the solution 
isotonic. 
A number of the compounds of this invention of formula I are useful in the 
management of allergic reactions when administered orally at dosages of 
0.5 mg to 500 mg/kg body weight to a sensitized mammal. For example, the 
representative compounds of formula I, 
[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester (see 
Example 1), 
[N-(2-oxo-3,5,7-cycloheptatrien-1-yl)-N-methylamino]oxo-acetic acid ethyl 
ester (see Example 1), 
2,2'-[(2-oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-acetic acid] 
diethyl ester (see Example 6), 
[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid pentyl ester (see 
Example 31) and 
[(5-methoxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 
1-methylethyl ester (see Example 31), 
are effective anti-allergic agents when administered orally at dosages of 
1.0 mg to 100 mg/kg body weight. 
When the compounds of this invention are employed as anti-allergic agents 
in mammals, e.g. rats, orally effective, anti-allergic amounts of the 
compounds are administered to the mammal, either alone or combined with 
pharmaceutically acceptable excipients in a dosage form, i.e. capsule or 
tablet, or the compounds are administered orally in the form of solutions 
or suspensions. 
The tablet compositions contain the active ingredient in admixture with 
non-toxic pharmaceutical excipients known to be suitable in the 
manufacture of tablets. Suitable pharmaceutical excipients are, for 
example, starch, milk sugar, certain types of clay and so forth. The 
tablets may be uncoated or they may be coated by known techniques so as to 
delay disintegration and absorption in the gastrointestinal tract and 
thereby provide a sustained action over a longer period. 
The aqueous suspensions of the invention contain the active ingredient in 
admixture with one or more non-toxic pharmaceutical excipients known to be 
suitable in the manufacture of aqueous suspensions. Suitable excipients 
are, for example, methylcellulose, sodium alginate, gum acacia, lecithin 
and so forth. The aqueous suspensions may also contain one or more 
preservatives, one of more coloring agents, one or more flavoring agents 
and one or more sweetening agents. 
Non-aqueous suspensions may be formulated by suspending the active 
ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame 
oil, or coconut oil, or in a mineral oil, for example liquid paraffin, and 
the suspension may contain a thickening agent, for example beeswax, hard 
paraffin or cetyl alcohol. These compositions may also contain a 
sweetening agent, a flavoring agent and an anti-oxidant. 
The compounds of formula I can also be administered as nasal powders or 
insufflations. For such purpose the compounds are administered in finely 
divided solid form together with a pharmaceutically acceptable solid 
carrier, for example, a finely divided polyethylene glycol ("Carbowax 
1540") or finely divided lactose. Such compositions may also contain other 
excipients in finely divided solid form, for instance, preservatives, 
buffers, or surface active agents. 
When administering the compounds of this invention by inhalation from an 
aerosol, the compound of formula I is dissolved in water or ethanol and 
mixed with a volatile propellant, for example, dichlorotetrafluoroethane 
and dichlorodifluoromethane, and placed in a pressurized container having 
a metering valve to release a predetermined amount of material. 
The dosage of the compounds of this invention will vary with the form of 
administration and the particular compound chosen. Furthermore, it will 
vary with the particular host under treatment. Generally, treatment is 
initiated with small dosages substantially less than the optimum dose of 
the compound. Thereafter, the dosage is increased by small increments 
until the optimum effect under the circumstance is reached. In general, 
the compounds of this invention are most desirably administered at a 
concentration level that will generally afford effective results without 
causing any harmful or deleterious side effects, and preferably at a level 
that is in a range of from about 0.1 mg to about 500 mg per kilogram body 
weight, although as aforementioned variations will occur. However, a 
dosage level that is in the range of from about 0.5 mg to about 200 mg per 
kilogram body weight is most desirably employed in order to achieve 
effective results. 
Processes 
Useful and practical starting materials for the preparation of the 
compounds of this invention of formula I are the tropone derivatives of 
formula II 
##STR3## 
in which R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are 
as defined in the first instance. 
The tropone derivatives of formula II suitable as starting materials are 
described in a number of reports; for example, see the recent review on 
tropone derivatives, their preparation and their interconversions by F. 
Pietra, supra. Thus, the tropone derivatives suitable as starting 
materials are either known or they can be prepared by conventional means. 
The compounds of this invention of formula I are prepared by condensing the 
compound of formula II in which R.sup.11, R.sup.12, R.sup.13, R.sup.14, 
R.sup.15 and R.sup.16 are as defined in the first instance with one to ten 
molar equivalents, preferably one to three molar equivalents, of a 
compound of formula III. 
EQU halogen--COCOOR.sup.10 (III) 
in which R.sup.10 is lower alkyl and the halogen is bromine, chlorine or 
iodine in the presence of a proton acceptor to obtain the corresponding 
compound of formula I in which R.sup.1 and R.sup.4 are the same or 
different selected from the group consisting of hydrogen, halo, 
trifluoromethyl, lower alkoxy, lower alkyl, phenyl, hydroxy, phenoxy, 
mercapto, (2-carboxyphenyl)thio and NR.sup.7 R.sup.8 wherein R.sup.7 is 
lower alkyl and R.sup.8 is hydrogen, lower alkyl or p-toluenesulfonyl, and 
a radical of formula NR.sup.9 COCOOR.sup.10 wherein R.sup.9 is as defined 
herein and R.sup.10 is lower alkyl; and R.sup.2, R.sup.3, R.sup.5 and 
R.sup.6 are the same or different selected from the group consisting of 
hydrogen, halo, trifluoromethyl, lower alkoxy, lower alkyl, phenyl, 
hydroxy, phenoxy, mercapto, (2-carboxyphenyl)thio and NR.sup.7 R.sup.8 
wherein R.sup.7 is lower alkyl and R.sup.8 is hydrogen, lower alkyl or 
p-toluenesulfonyl. 
In practicing the above condensation it is preferable to use an inert 
solvent as a reaction medium. Suitable solvents include benzene, toluene, 
chloroform, methylene chloride, lower alkyl ketones (i.e. 2-propanone, 
2-butanone and 3-pentanone) and the like. However, if the reactants are 
mutually soluble, the solvent can be omitted without deleterious effects. 
Suitable proton acceptors include the organic bases, or amines for 
instance, triethylamine, pyridine, N-ethylmorpholine, 
1,5-diazabicyclo[3.4.0]nonene-5 and the like, as well as the inorganic 
bases, preferably the alkali metal hydroxides, carbonates, hydrides, 
amides and alkoxides, for example, sodium ethoxide, sodium hydroxide, 
potassium hydroxide, potassium carbonate, sodium methoxide and the like. 
The preferred proton acceptors employed are the organic bases or amines. 
The amount of the organic bases can vary from one molar equivalent to a 
large molar excess. When a large molar excess is used, the organic base 
can also serve as the solvent for the condensation. 
The duration and temperature of the condensation are not critical; however, 
the preferred time is from about ten minutes to about 2 days and the 
temperature can range from about -10.degree. C to 100.degree. C or the 
boiling point of the reaction mixture, preferably from about 20.degree. C 
to the boiling point of the reaction mixture. The compounds of formula I 
are separated from the reaction mixture by conventional means, for 
example, evaporation, filtration, extraction, chromatography and/or 
crystallization. 
The compounds of formula I obtained from the above described condensation 
can be further reacted to obtain other compounds of formula I by methods 
described hereinafter. 
For instance the compound of formula I in which at least one of R.sup.1, 
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is lower alkoxy or halo can 
be reacted with a molar excess of ammonia or an amine of formula HNR.sup.7 
R.sup.8 in which R.sup.7 and R.sup.8 are as defined herein to obtain the 
corresponding compound of formula I in which at least one of R.sup.1, 
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is NR.sup.7 R.sup.8 in 
which R.sup.7 and R.sup.8 are as defined herein. The reaction is conducted 
either using the amine of formula HNR.sup.7 R.sup.8 as solvent or a 
suitable solvent can be selected from water and a lower alkanol (i.e. 
methanol, ethanol and the like). Suitable conditions for the reaction are 
a temperature of from about -50.degree. C to about 100.degree. C, 
preferably 0.degree. to 100.degree. C, for about ten minutes to 12 hours. 
If the temperature necessary for reaction is above the boiling point of 
the reaction mixture, the reaction can be conducted at the desired 
temperature in a pressure vessel without deleterious effects. 
The compound of formula I, prepared as above, in which at least one of 
R.sup.1 and R.sup.4 is a radical of formula NR.sup.9 COCOOR.sup.10 wherein 
R.sup.9 is as defined herein and R.sup.10 is lower alkyl can be hydrolyzed 
to obtain the corresponding acidic compound of formula I in which the 
corresponding R.sup.1 and R.sup.4 is a radical of formula NR.sup.9 
COCOOR.sup.10 wherein R.sup.9 is as defined herein and R.sup.10 is 
hydrogen. The preferred method of hydrolysis comprises the use of 0.1 to 
2.0 molar equivalents, preferably 0.5 to 1.0 molar equivalents, of a mild 
alkali, for example a suitable mild alkali selected from the bicarbonates 
and acetates of sodium or potassium, in an inert solvent, for instance, 
water, a lower alkanol (i.e. methanol or ethanol) or mixtures thereof, at 
a temperature of about 20.degree. to 120.degree. C for about 1 to 10 
hours. Acidification of the reaction mixture with a dilute mineral acid, 
such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, 
gives the corresponding acidic compound of formula I. 
In addition, a number of the compounds of formula I are readily converted 
to other compounds of formula I. In some cases it is convenient and 
preferable to prepare a specific compound of formula I by the 
transformation of another compound of formula I. Examples of such 
interconversions of the compound of formula I are described hereinafter. 
For example, the acidic compound of formula I described above (i.e. R.sup.1 
and/or R.sup.4 is a radical of formula NR.sup.9 COCOOR.sup.10 wherein 
R.sup.9 is as defined herein and R.sup.10 is hydrogen) is readily 
esterified to obtain the corresponding ester of formula I (i.e. R.sup.1 
and/or R.sup.4 is a radical of formula NR.sup.9 COCOOR.sup.10 wherein 
R.sup.9 is as defined herein and R.sup.10 is lower alkyl). Suitable 
esterification conditions include a variety of methods; for example, ester 
exchange, treatment with diazomethane, or conversion of the acid to the 
corresponding activated carbonyl (i.e., acid halide, anhydride, 
succinimio, imidazolide and the like), followed by treatment of the latter 
with an appropriate lower alkanol, see also L. F. Fieser and M. Fieser, 
"Advanced Organic Chemistry," Reinhold Publishing Corporation, New York 
1961, pp. 370-381. 
A preferred and convenient method of esterification comprises dissolving 
the acidic compound of formula I in an inert solvent, preferably 
dimethylsulfoxide, in the presence of one to ten molar equivalents of a 
mild base, for example, sodium or potassium carbonate. One to three molar 
equivalents of a lower alkyl bromide or chloride is added and the solution 
is maintained at a temperature of about 20.degree. to 100.degree. C, 
preferably at about 40.degree. to 80.degree. C, for about 30 minutes to 5 
hours. 
The compound of formula I in which at least one of R.sup.1, R.sup.2, 
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is hydroxy can be alkylated to 
obtain the corresponding compound of formula I in which the corresponding 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is alkoxy. The 
alkylation is conveniently carried out by reacting said hydroxy compound 
with one to five molar equivalents of a di(lower)alkyl sulfate in the 
presence of one to five molar equivalents of a mild alkali, for instance 
sodium or potassium carbonate in an inert solvent, for example, a lower 
alkyl ketone, preferably 2-butanone, 2-propanone and the like. The 
alkylation is conducted at a temperature from about 30.degree. C to the 
boiling point of the reaction mixture for about 30 minutes to ten hours. 
A useful alternative method of esterification or alkylation comprises 
reacting the acidic or hydroxy compound of formula I with an excess of a 
diazoalkane, for instance diazomethane, diazoethane and the like, in an 
inert solvent, e.g. diethyl ether or methanol. 
The compound of formula I in which at least one of R.sup.1, R.sup.2, 
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is lower alkoxy, chlorine, bromine 
or iodine can be reacted with sodium sulfhydrate in an inert solvent, 
preferably a lower alkanol (i.e. methanol, ethanol and the like) to obtain 
the corresponding compound of formula I in which the corresponding 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 is mercapto. This 
reaction is preferably carried out at a temperature of from about 
-70.degree. C to about 30.degree. C for about 1 to 10 hours. 
The following examples illustrate further this invention. 
EXAMPLE I 
[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Ethyl Ester; I 
(R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 and R.sup.2, R.sup.3, R.sup.4, R.sup.5 
and R.sup.6 = H) 
A solution of ethyl oxalyl chloride (0.30 g) in pyridine (15 ml) is added 
to a solution of 2-amino-2,4,6-cycloheptatrien-1-one [0.242 g, described 
by T. Nozoe et al., Proc. Japan Acad. 27, 556-560 (1951), CA 46, 7559 g] 
in pyridine (0.5 ml). The mixture is heated until a solution forms and the 
solution is stirred at room temperature for 45 minutes. Water is added and 
collection of the precipitate gives the title compound, mp 114.degree. C. 
In the same manner but replacing 2-amino-2,4,6-cycloheptatrien-1-one with 
an equivalent amount of 2-methylamino-2,4,6-cycloheptatrien-1-one 
[described by N. Soma et al., Chem. Pharm. Bull., 13, 457-64 (1965)], 
[N-(2-oxo-3,5,7-cycloheptatrien-1-yl)-N-methylamino]oxo-acetic acid ethyl 
ester, mp 70.degree.-71.degree. C, is obtained. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
EXAMPLE 2 
[(3-Bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Ethyl 
Ester; I (R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 ; R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 = H and R.sup.6 = Br) 
A solution of 7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one [1.0 g, 
described by T. Nozol et al., Proc. Japan Acad., 27, 556-60 (1951), (CA 
46, 7560c)] in methanol (30 ml) is cooled to -20.degree. C and saturated 
with gaseous ammonia. The reaction mixture is heated in a pressure bottle 
at 80.degree. C for 4 hours and cooled to -70.degree. C. The bottle is 
opened and the solvent is removed under reduced pressure. The residue is 
boiled with ethyl acetate and the ethyl acetate extract is evaporated to 
give 2-amino-7-bromo-2,4,6-cycloheptatrien-1-one. 
A solution of the latter compound (0.800 g) in pyridine (10 ml) is cooled 
to 0.degree. C and ethyl oxalyl chloride (0.544 g) is added dropwise. The 
mixture is stirred at 0.degree. C for 1 hour and at room temperature for 2 
hours. The solvent is removed under reduced pressure and the residue is 
crystallized from methanol-acetone to give the title compound, mp 
161.degree.-163.degree. C. 
In the same manner but replacing 
7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one with an equivalent amount of 
5-chloro-2-methoxy-2,4,6-cycloheptatrien-1-one [described by T. Sato, 
Nippon Kagaku Zasski, 80, 1171-4 (1959), (CA 55, 4389c)], 
[(5-chloro-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl 
ester, mp 178.degree.-179.degree. C, is obtained. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
EXAMPLE 3 
[(3-Phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Ethyl 
Ester; 1 (R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 ; R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 = H and R.sup.6 = OC.sub.6 H.sub.5) 
a. A mixture of 2-hydroxy-3-phenoxy-2,4,6-cycloheptatrien-1-one [13.0 g, 
described by Y. Kitahara, Sci. Repts. Tohoku Univ. First Ser., 39, 265-74 
(1956), (CA 51, 12874f)], potassium carbonate (28.9 g), dimethylsulfate 
(26.5 g) and methyl ethyl ketone (680 ml) is heated at reflux for two 
hours. The hot mixture is filtered and the filtrate is evaporated under 
reduced pressure. The residue is subjected to chromatography on silica gel 
using ether. The appropriate fractions of the eluate are combined and 
evaporated to give 2-methoxy-3-phenoxy-2,4,6-cycloheptatrien-1-one and 
2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one. 
b. A solution of 2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one (2.0 g, 
described above) in methanol (30 ml) is cooled to -25.degree. C and 
saturated with gaseous ammonia. The mixture is heated in a pressure bottle 
at 80.degree. C for 4 hours and cooled to -70.degree. C. The bottle is 
opened and the solvent is removed under reduced pressure. The residue is 
crystallized from ethyl acetate to give 
2-amino-7-phenoxy-2,4,6-cycloheptatrien-1-one. 
In the same manner but replacing 
2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one with an equivalent amount 
of 2-methoxy-3-phenoxy-2,4,6-cycloheptatrien-1-one [described above in 
(a)], 2-amino-3-phenoxy-2,4,6-cycloheptatrien-1-one is obtained. 
c. A solution of 2-amino-7-phenoxy-2,4.6-cycloheptatrien-1-one [1.38 g, 
described above in (b)] in pyridine (50 ml) is cooled to 0.degree. C and 
ethyl oxalyl chloride (0.980 g) is added dropwise. The mixture is stirred 
at 0.degree. C for 1 hour and at room temperature for 2 hours. Most of the 
solvent is removed under reduced pressure and water (200 ml) is added. The 
precipitate is collected and crystallized from ethyl acetate to give the 
title compound, mp 145.degree.-145.5.degree. C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
In the same manner but replacing 
2-amino-7-phenoxy-2-amino-3-phenoxy-2,4,6-cycloheptatrine-1-one [described 
above in (b))], [(7-phenoxy-2-oxo-3,5,7-cycloheptatrien-1-one 
yl)amino]oxo-acetic acid ethyl ester, mp 121.degree.-122.degree. C, is 
obtained. 
EXAMPLE 4 
8 (5-Hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Ethyl 
Ester; I (R.sup.1 = OH, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 = H and 
R.sup.4 =NH-CO-COOC.sub.2 H.sub.5) 
Ethyl oxalyl chloride (1.36 g ) is added dropwise to a solution at 
0.degree. C of 5-amino-2-hydroxy-2,4,6-cycloheptatrien-1-one [0.680 g, 
described by T. Nozoe et al., Sci. Repts. Tohoku Univ. 1, 35, 274-82 
(1952)] in pyridine (15 ml). After 30 min. the reaction mixture is allowed 
to reach room temperature. The solvent is removed under reduced pressure 
and the residue is dissolved in methylene chloride. The solution is washed 
with water, dried, evaporated and the residue is crystallized from ethyl 
acetate to give the title compound,mp 186.degree.-187.degree. C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of ethyl oxalyl bromide, the title compound is obtained. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount oxalyl chloride or propyl oxalyl bromide 
[(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl]amino]oxo-acetic acid methyl 
ester and [(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic 
acid propyl ester are obtained respectively. 
EXAMPLE 5 
[(3-Hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Ethyl 
Ester; 1 (R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 ; R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 = H and R.sup.6 = OH 
The hot solutions of 3-bromo-2-hydroxy-2,4,6-cycloheptatriene-1-one (30.0 
g) in methanol (2000 ml) and cupric accetate (18.0 g) in methanol (2000 
ml) are mixed and the precipitate is collected to give 
3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1 -one copper complex. 
A mixture of the latter compound (11.65 g), potassium p-toluenesulfonamide 
(15.7 g) and pyridine (150 ml) is heated at reflux for 16 hours. The 
pyridine is evaporated under reduced pressure and chloroform is added to 
the residue. The precipitate is collected and washed with chloroform. The 
precipitate is suspended in chloroform and 2N sulfuric acid (40 ml) 
followed by the addition of hydrogen sulfide gas until the copper complex 
is decomposed. The precipitate is removed by filtration and the organic 
phase of the filtrate is separated. The organic phase is dried over sodium 
sulfate and evaporated. The residue is mixed with methanol and the 
precipitate is collected to obtain 
2-hydroxy-3-[[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one, 
mp 177.degree.-179.degree. C. 
A solution of the latter compound (5.0 g) in conc. sulfuric acid (25 ml) is 
stirred at room temperature for 16 hours. The solution is poured on ice, 
neutralized with sodium carbonate and extracted with chloroform. The 
solvent is removed by evaporation to give a residue of 
3-amino-2-hydroxy-2,4,6-cycloheptatrien-1-one [the latter compound is 
described in Sci. Repts. Tohoku Univ. First Ser., 39, 83-91 (1956)]. 
To a solution of the latter compound (1.19 g) and triethylamine (1.1 g) in 
methylene chloride (25 ml) at room temperature, ethyl oxalyl chloride 
(1.27 g) in methylene chloride (5 ml) is added dropwise. The mixture is 
stirred for four hours and washed with water. The organic phase is dried 
over sodium sulfate and evaporated. The residue crystallized from ethyl 
acetate to give the title compound, mp 158.degree.-159.degree. C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
EXAMPLE 6 
2,2'[(2-Oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-acetic acid] 
Diethyl Ester; I (R.sup.1 and R.sup.4 = NH-CO-COOC.sub.2 H.sub.5 and 
R.sup.2, R.sup.3, R.sup.5 and R.sup.6 = H) 
Conc. ammonium hydroxide solution (50 ml) is added dropwise to a suspension 
of 2-hydroxy-5-nitroso-2,4,6-cycloheptatrien-1-one [10 g, described by T. 
Nozoe et al., Sci. Repts. Tohoku Univ., 35, 274-82 (1952), (CA 47 329la)] 
collected and washed with water then acetone to give 
2-amino-5-nitroso-2,4,6-cycloheptatrien-1-one. 
A mixture of the latter compound (5.0 g) and 5% palladium on charcoal (1.5 
g) in ethanol (2000 ml) is stirred rapidly under an atmosphere of hydrogen 
for 12 minutes (hydrogen absorbed is 1600 ml). The mixture is filtered and 
the filtrate is evaporated to give 
2,5-diamino-2,4,6-cycloheptatrien-1-one. 
The latter compound is dissolved in pyridine (150 ml), cooled to 0.degree. 
C and ethyl oxalyl chloride (9.55 g) is added dropwise. The reaction 
mixture is warmed to room temperature and stirred for two hours. Half of 
the pyridine is evaporated under reduced pressure and the residue is added 
to water (400 ml). The precipitate is collected, crystallized from ethyl 
acetate and subjected to chromatography on silica gel using ethyl acetate 
for elution. The eluates are evaporated and the residue is crystallized 
from ethyl acetate to give the title compound, mp 217.degree.-218.degree. 
C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl choride, the methyl and propyl esters of 
the title compound are obtained. 
EXAMPLE 7 
[(6-Methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Ethyl 
Ester; I (R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 ; R.sup.2, R.sup.4, R.sup.5 
and R.sup.6 = H and R.sup.3 = OCH.sub.3) 
a. A solution of 3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1-one [27.5 g, 
described by T. Toda et al., Nippon Hagaku Zasshi, 88, 1234-5 (1967), (CA 
68 101342)] and sodium methoxide (prepared from 12.6 g of sodium in 
methanol followed by evaporation of the methanol) in dimethyl sulfoxide 
(300 ml) is heated at 80.degree. C for 1 hour. The solution is cooled 
poured on ice, acidified with 2N sulfuric acid and extracted with ethyl 
acetate. The organic extract is washed with brine, dried over sodium 
sulfate and evaporated. The residue is crystallized from ethyl 
acetate-hexane to give 2-hydroxy-3-methoxy-2,4,6-cycloheptatrien-1-one. 
Evaporation of the mother liquors gives 
2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one. 
b. A mixture of 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one (described 
above, 13 g), potassium carbonate (23.6 g), dimethyl sulfate (21.6 g) and 
2-butanone (130 ml) is heated at reflux for 3 hours. The mixture is 
filtered and the filtrate is evaporated. The residue is subjected to 
chromatography on silica gel using acetone-ethyl acetate (1:1) and 
evaporation of the eluates gives 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one 
and 2,6-dimethoxy-2,4,6-cycloheptatrien-1-one. 
In the same manner but replacing 
2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one with an equivalent amount 
of 2-hydroxy-3-methoxy-2, 4,6-cycloheptatrien-1-one [(described above in 
(a)], 2,3-dimethoxy-2,4,6-cycloheptatrine-1-one and 
2,7-dimethoxy-2,4,6-cycloheptatrine-1-one are obtained. 
c. A solution of 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one [described above 
in (b),2.4 g] in methanol (70 ml) is cooled to -25.degree. C and saturated 
with ammonia gas. The solution is heated in a pressure bottle at 
80.degree. C for 4 hours and cooled to -70.degree. C. The pressure bottle 
is opened and the solvent is evaporated to give 
2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one. 
In the same manner but replacing 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one 
with an equivalent amount of 2,6-dimethoxy-2,4,6-cycloheptatrien-1-one 
with an equivalent amount of 2,6-dimethoxy-2,4,6cycloheptatrien-1-one or 
2,3-dimethoxy-2,4,6-cycloheptatrien-1one, 
2-amino-6-methoxy-2,4,6-cycloheptatrien-1-one and 
2-amino-3-methoxy-2,4,6-cycloheptatrien-1-one are obtained, respectively. 
d. A solution of ethyl oxalyl chloride (2.16 g) in methylene chloride (25 
ml) is added dropwise to a solution of 
2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one [described above in (c), 2.9 
g] and triethylamine (1.84 g) in methylene chloride (50 ml). The mixture 
was stirred at room temperature for 3 hours, washed with water, dried over 
sodium sulfate and evaporated. The residue is subjected to chromatography 
on silica gel using ethyl acetate-hexane (2:3). The eluates are evaporated 
to give the title compound, mp 132.degree.-134.degree. C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
In the same manner but replacing 
2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one with an equivalent amount of 
2-amino-6-methoxy-2,4,6-cycloheptatrien-1-one or 
2-amino-3-methoxy-2,4,6-cycloheptatrien-1-one, 
[(4-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl 
ester, mp 157.degree.-158.degree. C, and 
[(7-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl 
ester are obtained, respectively. 
In the same amount but replacing dimethyl sulfate with an equivalent amount 
of diethyl sulfate, 
[(6-ethoxy-2-oxo-3,5,7-cycloheptatrien-1yl)amino]oxo-acetic acid ethyl 
ester is obtained. 
EXAMPLE 8 
[[7-Oxo-4-[(2-carboxyphenyl)thio]-1,3,5-cycloheptatrien-1-yl]amino]oxoaceti 
c acid Ethyl Ester; I (R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 ; R.sup.2, 
R.sup.3, R.sup.5 and R.sup.6 = H and R.sup.4 = 2-carboxyphenylthio) 
A solution of 
5-[(2-carboxyphenyl)thio]-2-methoxy-2,4,6-cycloheptatrien-1-one (1.0 g, 
prepared from 5-chloro-2-methoxy-2,4,6-cycloheptatrien-1-one and 
2-mercaptobenzoic acid) in methanol (30 ml) at -25.degree. C is saturated 
with ammonia gas. The solution is heated in a pressure bottle at 
80.degree. C for 8 hours and cooled to -70.degree. C. The bottle is opened 
and the solvent is evaporated to give 
2-amino-5-[(2-caboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one. 
A solution of ethyl oxalyl chloride (1.0 g) in methylene chloride (10 ml) 
is added dropwise to a suspension of 
2-amino-5-[(2-carboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one (1.0 g) and 
triethylamine (0.74 g) in methylene chloride (30 ml). The mixture is 
stirred at room temperature for 30 minutes, washed with water, dried over 
sodium sulfate and evaporated. The residue is crystallized from ethyl 
acetate to give the title compound, mp 225.degree.-228.degree. C. 
In the same manner but replacing 
2-amino-5-[(2-carboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one with an 
equivalent amount of 
5-amino-2-[(2-carboxyphenyl)thio]-7-methyl-2,4,6-cycloheptatrien-1-one or 
2-methylamino-6-[(2-carboxyphenyl)thio]-4-phenyl-2,4,6-cycloheptarien-1-on 
e, 
[[5-oxo-4-[(2-carboxyphenyl)thio]-6-methyl-1,3,6-cycloheptatrien-1-yl]-ami 
no]oxo-acetic acid ethyl ester and 
[N-[7-oxo-5-[(2-carboxyphenyl)thio]-3-phenyl-1,3,5-cycloheptatrien-1-yl]-N 
-methylamino]oxo-acetic acid ethyl are obtained, respectively. 
EXAMPLE 9 
[[3-[N-[(4-Methylphenyl)sulfonyl]-N-methylamino]-2-oxo-3,5,7-cycloheptatrie 
n-1-yl]amino]oxo-acetic Acid Ethyl Ester; I [R.sup.1 = NH-CO-COOC.sub.2 
H.sub.5 ; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 = H and R.sup.6 = 
[N-(4-methylphenyl)sulfonyl]-N-methylamino] 
a. A mixture of 
2-hydroxy-3-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-o 
ne (14.5 g), potassium carbonate (12.5 g), dimethyl sulfate (12.5 g) and 
2-butanone (145 ml) is heated at reflux for 1 hour. The mixture is 
filtered and the precipitate is washed with water and suspended in ethyl 
actate. Hydrochloric acid (10%) is added until the solution is acidic. The 
organic phase is collected and dried over sodium sulfate. Evaporation of 
the solvent and crystallization of the residue from ethyl acetate-hexane 
gives 
2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-on 
e, mp 163.degree.-164.degree. C. The above filtrate is evaporated and the 
residue is subjected to chromatography on silica gel using ethyl 
acetate-hexane (3:1). Evaporation of the eluates are crystallization of 
the residue from ethyl acetate gives 
2-methoxy-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptat 
rien-1-one, mp 101.degree.-102.degree. C and 
2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptat 
rien-1-one, mp 94.5.degree. C. 
b. A solution at -25.degree. C of 
2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6cycloheptatr 
ien-1-one (described above, 4.0 g) in methanol (40 ml) is saturated with 
ammonia gas and heated in a pressure bottle at 80.degree. C for 4 hours. 
The solution is cooled to -70.degree. C, the bottle is opened and the 
solvent is evaporated to yield 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
en-1-one, mp 221.degree.-222.degree. C. 
In the same manner but replacing 
2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptat 
rien-1-one with an equivalent amount of 
2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-o 
ne or 
2-methoxy-3-[N-[(4-methylphenyl)-sulfonyl]-N-methylamino]-2,4,6-cyclohepta 
trien-1-one, 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one 
and 
2-amino-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
en-1one are obtained respectively. 
c. A solution of ethyl oxalyl chloride (0.475 g) in methylene chloride (10 
ml) is added dropwise to a solution of 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
ene-1-one (described above, 0.87 g) and triethylamino (0.354 g) in 
methylene chloride (10 ml). The solution is stirred at room temperature 
for 2 hours, washed with water, dried over sodium sulfate and evaporated. 
The residue is crystallized from ethyl acetate-hexane to give the title 
compound, mp 148.5.degree.-150.degree. C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
In the same manner but replacing 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
en-1-one with an equivalent amount of 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one 
or 
2-amino-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
en-1-one, 
[[3-[N-[(4-methylphenyl)sulfonyl]amino]-2-oxo-3,5,7-cycloheptatrien-1-yl]a 
mino]oxo-acetic acid ethyl ester and 
[[7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2-oxo-3,5,7-cycloheptatri 
en-1-yl]amino]oxo-acetic acid ethyl ester are obtained respectively. 
In the same manner but replacing dimethyl sulfate with an equivalent amount 
of diethyl sulfate, the title compound is obtained. 
EXAMPLE 10 
[(3-Methylamino-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid 
Ethyl Ester; I (R.sup.1 = NH-CO-COOC.sub.2 H.sub.5 ; R.sup.2, R.sup.3, 
R.sup.4 and R.sup.5 = H and R.sup.6 = NHCH.sub.3) 
A solution of 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
en-1-one [described in Example 9 (b), 2.53 g] in conc. sulfuric acid (25 
ml) is heated at 75.degree. C for 1 hour and added to ice. The ice-mixture 
is neutralized with sat. sodium carbonate solution and extracted with 
chloroform. The organic extract is dried over sodium sulfate and 
evaporated to give 2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one. 
A solution of ethyl oxalyl chloride (2.46 g) in methylene chloride (10 ml) 
is added dropwise to a solution of 
2-amino-7-methylamino-2,4,6-cycloheptatrien-1-one (1.32 g) and 
triethylamine (1.95 g) in methylene chloride (15 ml). The mixture is 
heated at reflux for 3 hours, washed with water, dried over sodium sulfate 
and evaporated. The residue is subjected to chromatography on silica gel 
using acetone-hexane (3:7) and the eluates are evaporated to give the 
title compound, mp 178.degree.-181.degree. C. 
In the same manner but replacing ethyl oxalyl chloride with an equivalent 
amount of methyl or propyl oxalyl chloride, the methyl and propyl esters 
of the title compound are obtained. 
In the same manner but replacing 
2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatri 
en-1-one with an equivalent amount of 
2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-on 
e [described in Example 
(9a)],[(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 
ethyl ester, mp 164.degree.-167.degree. C, is obtained. 
By following a procedure selected from Examples 1 to 10 using the 
appropriate starting material of formula II and the appropriate compound 
of formula III in which R.sup.10 is lower alkyl, other compounds of 
formula I in which at least one of R.sup.1 and R.sup.4 is NR.sup.9 
COCOOR.sup.10 wherein R.sup.9 is as defined herein and R.sup.10 is lower 
alkyl are obtained. Examples of the latter compounds of formula I are 
listed as products in Table I together with the appropriate starting 
material of formula II used for the preparation of the compound of formula 
I. 
TABLE1 
__________________________________________________________________________ 
Product: 
[(prefix listed below)-cycloheptatrien-l-yl 
)amino]- 
Starting Material of Formula 11 
oxo-acetic acid (suffix listed below)] 
Ex. 
R.sup.11 
R.sup.12 
R.sup.13 
R.sup.14 
R.sup.15 
R.sup.16 
Prefix/Suffix 
__________________________________________________________________________ 
11 H H H NH.sub.2 
Br CH.sub.3 
[(2-bromo-3-methyl-4-oxo-2,5,7 / / ethyl 
ester 
12 NHCH.sub.3 
H CH.sub.3 
H C.sub.6 H.sub.5 
H [N-methyl-N-(6-methyl-2-oxo-4-phenyl-3,5,7 
/ / ethyl ester 
13 NH.sub.2 
H H OC.sub.2 H.sub.5 
H I. [(5-ethoxy-3-iodo-2-oxo-3,5,7 / / methyl 
ester 
14 NH.sub.2 
H H NHCH.sub.3 
CH.sub.3 
H [[5-[N-(2-ethoxy-1,2-dioxoethyl)methylamino 
]-4-methyl- 
2-oxo-3,5,7// ethyl ester 
15 H C.sub.3 H.sub.7 
H NH.sub.2 
H CF.sub.3 
[(2-oxo-7-propyl-3-trifluoromethyl-3,5,7 
// methyl ester 
16 NH.sub.2 
C.sub.5 H.sub.1 
H H H OC.sub.3 H.sub.7 
[(2-oxo-7-pentyl-3-propoxy-3,5,7 // propyl 
ester 
17 NHC.sub.3 H.sub.9 
H OH F H H [N-butyl-N-(5-fluoro-6-hydroxy-2-oxo-3,5,7 
// propyl ester 
18 NHC.sub.3 H.sub.7 
H H NH.sub.2 
H OC.sub.6 H.sub.5 
[[5-[N-(2-ethoxy-1,2-dioxoethyl)propylamino 
] -4-oxo-3- 
phenoxy-1,5,7// ethyl ester 
19 OC.sub.2 H.sub.5 
H C.sub.4 H.sub.9 
NHC.sub.2 H.sub.5 
H H [N-ethyl-N-(7-butyl-5-ethoxy-4-xo-2,5,7 // 
methyl ester 
20 H OCH.sub.3 
H NH.sub.2 
H OH [(3-hydroxy-6-methoxy-4-oxo-2,5,7 // ethyl 
ester 
21 H SH H NH.sub.2 
C.sub.2 H.sub.5 
H [(2-ethyl-6-mercapto-4-oxo-2,5,7 // propyl 
ester 
22 NH.sub.2 
H Cl H OH H [(6-chloro-4-hydroxy-2-oxo-3,5,7 // ethyl 
ester 
23 NHC.sub.4 H.sub.9 
H OC.sub.6 H.sub.5 
H H SH [N-butyl-N-(3-mercapto-2-oxo-6-phenoxy-3,5, 
7 // 
methyl ester 
24 CF.sub.3 
Br H NH.sub.2 
H H [(6-bromo-4-oxo-5-trifluoromethyl-2,5,7 
// 
ethyl ester 
25 NH.sub.2 
H H N(CH.sub.3).sub.2 
Cl H [(4-chloro-5-dimethylamino-2-oxo-3,5,7 // 
ethyl ester 
26 NH.sub.2 
H OC.sub.2 H.sub.5 
H H N(C.sub.3 H.sub.7).sub.2 
[(6-ethoxy-3-dipropylamino-2-oxo-3,5,7 // 
methyl ester 
27 N(C.sub.2 H.sub.5).sub.2 
CH.sub.3 
OH NH.sub.2 
H H [(5-diethylamino-7-hydroxy-6-methyl-4-oxo-2 
,5,7 // 
ethtyl ester 
28 NH.sub. 2 
SH H H N(CH.sub.3) 
H [[4-(N-ethyl-N-methylamino)-7-mercapto-2-ox 
o-3,5,7 
(C.sub.2 H.sub.5) 
// propyl ester 
__________________________________________________________________________ 
EXAMPLE 29 
[(5-Methoxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Methyl 
Ester; I (R.sup.1 = OCH.sub.3 ; R.sup.2, R.sup.3, R.sup.5 and R.sup.6 = H 
and R.sup.4 = NH-CO-COOCH.sub.3) 
[(5-Hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl 
ester (4.1 g, described in Example 4) is dissolved in boiling methanol 
(500 ml) and the mixture is cooled to room temperature and reacted with a 
solution of diazomethane in ether (ca. 351 ml). The reaction mixture is 
stirred for one hour until all the solid is reacted with diazomethane. The 
solvent is removed under reduced pressure and the residue is crystallized 
from methanol to give the title compound, mp 198.degree.-200.degree. C. 
In the same manner but replacing 
[(5-hydroxy-4-oxo-2,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl 
ester with an equivalent amount of 
[(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl 
ester (described in Example 5), 
[(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid methyl 
ester is obtained. 
EXAMPLE 30 
[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid; I (R.sup.1 = 
NH-CO-COOH and R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 = H) 
A solution of potassium acetate (0.98 g) in water (5 ml) is added to a 
suspension of [(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 
ethyl ester (2.21 g, described in Example 1) in water (15 ml) and the 
resulting mixture is heated at 100.degree. C for 5 hours. The mixture is 
cooled, diluted with water, charcoalized and filtered. The filtrate is 
acidified with 10% hydrochloric acid and the precipitate is collected to 
give the title compound, mp 193.degree.-194.degree. C. 
In the same manner but replacing potassium acetate with an equivalent 
amount of sodium bicarbonate or potassium carbonate, the title compound is 
obtained. 
In the same manner but replacing the starting material 
[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester with 
other esters of formula I, other acids of formula I are obtained. For 
example, replacing the starting material with the title compound of 
Examples 2,3,5,6,7,8,14 and 23, the following acids of formula I are 
obtained respectively: 
[(3-bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, 
[(3-phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, 
[(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, 
2,2'[(2-oxo-3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-acetic acid], 
[(6-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, 
[(3-methylamino-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, 
[[5-[N-(carboxycarbonyl)-N-methylamino]-4-methyl-2-oxo-3,5,7-cycloheptatri 
en-1-yl]amino]oxo-acetic acid and 
[N-(3-mercapto-2-oxo-6-phenoxy-3,5,7-cycloheptatrien-1-yl)-N-butylamino]ox 
o-acetic acid. 
EXAMPLE 31 
[(2-Oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic Acid Pentyl Ester; I 
(R.sup.1 = NH-CO-COOC.sub.5 H.sub.11 and R.sup.2, R.sup.3, R.sup.4, 
R.sup.5 and R.sup.6 = H 
A solution of [(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 
(1.54 g, described in Example 30) and potassium carbonate (0.82 g) in 
dimethylsulfoxide (8 ml) is stirred at room temperature for 15 minutes. A 
solution of 5 -bromopentane (1.52 ml) in dimethylsulfoxide (8 ml) is added 
and the resulting mixture is stirred at 80.degree. C for 40 minutes. The 
mixture is cooled to room temperature and poured over ice. The mixture is 
stirred for ten minutes and the precipitate is collected by filtration. 
The precipitate is dissolved in ether, treated with charcoal and 
crystallized by the addition of hexane to give the title compound, mp 
87.degree.-89.degree. C. 
In the same manner but replacing the alkyl halide, 5-bromopentane, with an 
equivalent amount of 2-bromopropane or 2-bromo-2-methylpropane, 
[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 1-methylethyl 
ester, mp 91.degree.-93.degree. C and 
[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 1,1-dimethylethyl 
ester, mp 76.degree.-78.degree. C, are obtained respectively. 
In the same manner but replacing the starting material, 
[(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid, with other acids 
of formula I and using an appropriate alkyl halide other esters of formula 
I are obtained. For example, replacing the starting material with an acid 
described in Example 30, the following esters of formula I are obtained. 
[(3-bromo-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 
2-methylpropyl ester, 
[(3-phenoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid hexyl 
ester, 
2,2'-[(2-oxo,3,5,7-cycloheptatrien-1,5-diyl)diimino]bis[2-oxo-acetic acid] 
dipropyl ester, 
[(6-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid 
1,1-dimethylethyl ester and [[5-[N-2-butoxy-1,2-dioxoethyl)methyl 
amino]-4-methyl-2-oxo-3,5,7-cycloheptatrien-1-yl]amino]oxo-acetic acid 
butyl ester.