Positive inotropic and lusitropic 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives, compositions and use

The present invention relates to novel positive inotropic and lusitropic 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives having positive inotropic and lusitropic properties which are useful in the treatment of warm-blooded animals suffering from Congestive Heart Failure. Pharmaceutical compositions containing said compounds as an active ingredient. Methods of preparing said compounds and pharmaceutical compositions.

BACKGROUND OF THE INVENTION 
In EP-A-O, 116,948, EP-A-O, 153,152 kand in U.S. Pat. Nos. 4,593,029 and 
4,670,434 there are described a number of imidazo[2,1-b]quinazolinones as 
phosphodiesterase inhibitors having positive inotropic properties. 
Analogous compounds are also disclosed in J. Med. Chem., 30, pp. 303-318 
(1987) and 31, pp. 145-152 (1988). 
DESCRIPTION OF THE INVENTION 
The present invention is concerned with novel 
3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives having the 
formula 
##STR1## 
the pharmaceutically acceptable addition salts thereof and the 
stereochemically isomeric forms thereof, wherein 
R is hydrogen, C.sub.1-6 alkyl, phenyl optionally substituted with from 1 
to 3 substituents each independently selected from halo, hydroxy, 
C.sub.1-6 alkyloxy, C.sub.1-6 alkyl or trifluoromethyl; pyridinyl; or 
thienyl optionally substituted with halo or C.sub.1-6 alkyl; 
R.sup.1 is hydrogen or C.sub.1-6 alkyl; 
R.sup.2 is hydrogen, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl or phenyl; or 
R.sup.1 and R.sup.2 taken together may also form a C.sub.1-5 alkanediyl 
radical; 
X is a radical of formula 
##STR2## 
R.sup.3 is hydrogen, tri(C.sub.1-6 alkyl)silyl or C.sub.1-6 alkyl 
optionally substituted with COOH, COOC.sub.1-4 alkyl, CONR.sup.5 R.sup.6 
or COOCH.sub.2 CONR.sup.7 R.sup.8 ; 
R.sup.4 is COOH, COOC.sub.1-4 alkyl, CONR.sup.5 R.sup.6, COOCH.sub.2 
CONR.sup.7 R.sup.8 or C.sub.1-6 alkyl optionally substituted with COOH, 
COOC.sub.1-4 alkyl, CONR.sup.5 R.sup.6 or COOCH.sub.2 CONR.sup.7 R.sup.8 ; 
R.sup.5 is hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, C.sub.1-4 
alkyloxyC.sub.1-4 alkyl, hydroxycarbonylC.sub.1-4 alkyl, C.sub.1-4 
alkyloxycarbonylC.sub.1-4 alkyl; 
R.sup.6 is hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl or C.sub.3-7 
cycloalkyl; or 
R.sup.5 and R.sup.6 taken together with the nitrogen atom to which they are 
attached may form a pyrrolidinyl, morpholinyl or piperazinyl ring, said 
piperazinyl ring being optionally substituted on the nitrogen atom with 
C.sub.1-4 alkyl or hydroxyC.sub.1-4 alkyl; and 
R.sup.7 and R.sup.8 each independently are hydrogen, C.sub.1-4 alkyl or 
hydroxyC.sub.1-4 alkyl. 
In the foregoing definitions the term halo defines fluoro, chloro, bromo 
and iodo; C.sub.1-4 alkyl defines straight and branched saturated 
hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for 
example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 
2-methylpropyl and 1,1-dimethylethyl; C.sub.1-6 alkyl defines C.sub.1-4 
alkyl and the higher homologs thereof such as, for example, pentyl, hexyl 
and the like; C.sub.3-7 cycloalkyl defines cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl and cycloheptyl; C.sub.1-5 alkanediyl defines 
straight and branch chained bivalent hydrocarbon radicals having from 1 to 
5 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 
1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,1-ethanediyl, 
1,1-propanediyl, 1,2-propanediyl and the like. Tri(C.sub.1-6 alkyl)silyl 
in particular may be trimethylsilyl, triethylsilyl, tert. 
butyldimethylsilyl and the like. 
Pharmaceutically acceptable addition salts as mentioned hereinabove 
comprise the therapeutically active non-toxic addition salt forms which 
the compounds of formula (I) are able to form. Said salt forms can 
conveniently be obtained by treating the base form of the compounds of 
formula (I) with appropriate acids such as inorganic acids, for example, 
hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, 
sulfuric acid, nitric acid, phosphoric acid and the like; or organic 
acids, such as, for example, acetic, propanoic, hydroxyacetic, 
2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, 
butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 
2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, 
methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, 
cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the 
like acids. Conversely the salt form can be converted by treatment with 
alkali into the free base form. 
The compounds of formula (I) containing acidic protons may also be 
converted into their therapeutically active non-toxic metal or amine 
addition salt forms by treatment with appropriate organic and inorganic 
bases. Appropriate base salt forms comprise, for example, the ammonium 
salts, the alkali and earth alkaline metal salts, e.g. the lithium, 
sodium, potassium, magnesium, calcium salts and the like, salts with 
organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine 
salts, and salts with amino acids such as, for example, arginine, lysine 
and the like. 
The term addition salt also comprises the hydrates and solvent addition 
forms which the compounds of formula (I) are able to form. Examples of 
such forms are e.g. hydrates, alcoholates and the like. 
The compounds of this invention may have several asymmetric carbon atoms in 
their structure. Each of these chiral centers may be indicated by the 
stereochemical descriptors R and S. The compounds of formula (I) wherein X 
is a radical of formula (b) or (c) may occur as mixtures of E- and Z-forms 
or as pure E-forms or pure Z-forms. This R and S notation and E and Z 
notation corresponds to the rules described in Pure Appl. Chem., 1976, 45, 
11-30. 
Pure stereochemically isomeric forms of the compounds of formula (I) may be 
obtained by the application of art-known procedures. Diastereoisomers may 
be separated by physical methods such as selective crystallization and 
chromatographic techniques, e.g. counter current distribution, liquid 
chromatography and the like; and enantiomers may be separated from each 
other following art-known resolution methods, for example, by the 
selective crystallization of their diastereomeric salts with chiral acids. 
Pure stereochemically isomeric forms may also be derived from the 
corresponding pure stereochemically isomeric forms of the appropriate 
starting materials, provided that the reactions occur stereospecifically. 
Preferably, if a specific stereoisomer is desired, said compound will be 
synthesized by stereospecific methods of preparation. These methods will 
advantageously employ enantiomerically pure starting materials. 
Stereochemically isomeric forms of the compounds of formula (I) are 
obviously intended to be included within the scope of the invention. 
A first group of interesting compounds are those compounds of formula (I) 
wherein R.sup.2 is hydrogen, C.sub.1-6 alkyl or hydroxyC.sub.1-6 alkyl; 
and/or R.sup.1 and R.sup.2 taken together may also form a C.sub.1-5 
alkanediyl radical; and/or R is phenyl optionally substituted with from 1 
to 3 substituents each independently selected from halo, hydroxy, 
C.sub.1-6 alkyloxy, C.sub.1-6 alkyl or trifluoromethyl. 
A second group of interesting compounds are those compounds of formula (I) 
wherein R.sup.2 is hydrogen, C.sub.1-6 alkyl or hydroxyC.sub.1-6 alkyl; 
and/or R.sup.1 and R.sup.2 taken together may also form a C.sub.1-5 
alkanediyl radical; and/or R is hydrogen, C.sub.1-6 alkyl or pyridinyl. 
A third group of interesting compounds are those compounds of formula (I) 
wherein R.sup.2 is hydrogen, C.sub.1-6 alkyl or hydroxyC.sub.1-6 alkyl; 
and/or R.sup.1 and R.sup.2 taken together may also form a C.sub.1-5 
alkanediyl radical; and/or R is thienyl. 
More interesting compounds are those interesting compounds wherein R.sup.1 
is hydrogen; and/or R.sup.2 is hydrogen or C.sub.1-6 alkyl; and/or R is 
phenyl optionally substituted with halo, C.sub.1-6 alkyloxy or C.sub.1-6 
alkyl; and/or X is a radical of formula (a), (b) or (c); and/or R.sup.5 is 
hydrogen or C.sub.1-4 alkyl; and/or R.sup.6 is C.sub.1-4 alkyl or 
C.sub.3-7 cycloalkyl. 
Other more interesting compounds are those interesting compounds wherein 
R.sup.1 is hydrogen; and/or R.sup.2 is hydrogen or C.sub.1-6 alkyl; and/or 
R is hydrogen, C.sub.1-6 alkyl or pyridinyl; and/or X is a radical of 
formula (a), (b) or (c); and/or R.sup.5 is hydrogen or C.sub.1-4 alkyl; 
and/or R.sup.6 is C.sub.1-4 alkyl or C.sub.3-7 cycloalkyl. 
Still other more interesting compounds are those interesting compounds 
wherein R.sup.1 is hydrogen; and/or R.sup.2 is hydrogen or C.sub.1-6 
alkyl; and/or R is thienyl; and/or X is a radical of formula (a), (b) or 
(c); and/or R.sup.5 is hydrogen or C.sub.1-4 alkyl; and/or R.sup.6 is 
C.sub.1-4 alkyl or C.sub.3-7 cycloalkyl. 
Particularly interesting compounds are those interesting compounds wherein 
R.sup.1 and R.sup.2 are hydrogen; and/or R is phenyl optionally 
substituted with fluoro, chloro, bromo, methoxy or methyl; and/or X is a 
radical of formula (a), (b) or (c); and/or R.sup.3 is hydrogen, C.sub.1-4 
alkyl substituted with COOC.sub.1-4 alkyl or with CONR.sup.5 R.sup.6, 
R.sup.5 being C.sub.1-4 alkyl and R.sup.6 being C.sub.5-7 cycloalkyl; 
and/or R.sup.4 is COOH, COOC.sub.1-4 alkyl or CONR.sup.5 R.sup.6, R.sup.5 
being C.sub.1-4 alkyl and R.sup.6 being C.sub.5-7 cycloalkyl. 
Other particularly interesting compounds are those interesting compounds 
wherein R.sup.1 and R.sup.2 are hydrogen; and/or R is hydrogen, C.sub.1-4 
alkyl or pyridinyl; and/or X is a radical of formula (a), (b) or (c); 
and/or R.sup.3 is hydrogen, C.sub.1-4 alkyl substituted with COOC.sub.1-4 
alkyl or with CONR.sup.5 R.sup.6, R.sup.5 being C.sub.1-4 alkyl and 
R.sup.6 being C.sub.1-4 alkyl and R.sup.6 being C.sub.5-7 cycloalkyl. 
Still other particularly interesting compounds are those interesting 
compounds wherein R.sup.1 and R.sup.2 are hydrogen; and/or R is thienyl; 
and/or X is radical of a formula (a), (b) or (c); and/or R.sup.3 is 
hydrogen, C.sub.1-4 alkyl substituted with COOC.sub.1-4 alkyl or with 
CONR.sup.5 R.sup.6, R.sup.5 being C.sub.1-4 alkyl and R.sup.6 being 
C.sub.5-7 cycloalkyl; and/or R.sup.4 is COOH, COOC.sub.1-4 alkyl or 
CONR.sup.5 R.sup.6, R.sup.5 being C.sub.1-4 alkyl and R.sup.6 being 
C.sub.5-7 cycloalkyl. 
The most interesting compounds within the present invention are: 
(E+Z)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2( 
1H)-one, 
(E)-N-cyclohexyl-N-methyl-2-[[[phenyl-(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- 
b]quinazolin-7-yl)methylene]amino]oxy]acetamide, 
(E)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1H 
)-one, 
(E)-N-cyclohexyl-N-methyl-2-[[[(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quina 
zolin-7-yl)methylene]amino]oxy]acetamide and 
(E+Z)-N-cyclohexyl-N-methyl-2-[[[(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]qui 
nazolin-7-yl)(2-thienyl)methylene]amino]oxy]acetamide, the pharmaceutically 
acceptable addition salts and the stereochemically isomeric forms thereof. 
In order to simplify the structural representation of the compounds and of 
some of the intermediates in the following preparations, the 
3,5-dihydro-imidazo[2,1-b]quinazolin-2(1H)-one moiety will hereinafter be 
represented by the symbol D. 
##STR3## 
The compounds of formula (I) can generally be prepared by cyclizing an 
intermediate of formula (II) with a reagent of formula (III) wherein 
W.sup.1 represents a leaving group such as, for example, trihalomethyl, 
e.g. trichloromethyl or a halide, in particular bromide, in a suitable 
solvent. 
##STR4## 
In formulae (II) and (IV) L represents a reactive leaving group such as, 
for example, C.sub.1-6 alkyloxy, phenyloxy, hydroxy, amino, imidazolyl and 
the like. Suitable solvents for said cyclization are, for example, water; 
aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and 
the like; alcohols, e.g. methanol, ethanol, 1-propanol, 2-propanol, 
1-butanol and the like, diols, e.g. 1,2-ethanediol and the like; dipolar 
aprotic solvents, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, 
hexamethylphosphor triamide and the like; ethers, e.g. tetrahydrofuran, 
1,1'-oxybisethane, 1,4-dioxane and the like; halogenated hydrocarbons, 
e.g. trichloromethane, tetrachloromethane and the like; and mixtures 
thereof. The reaction can conveniently be conducted by stirring the 
reactants initially at a low temperature such as between -10.degree. C. 
and 5.degree. C. and then at room temperature. In some instances the 
intermediate guanidine of formula (IV) may be isolated at this stage. In 
order to enhance the reaction rate of the second cyclization step it may 
be appropriate to heat the reaction mixture at an elevated temperature, in 
particular at the reflux temperature of the reaction mixture. 
The compounds of formula (I) may also be obtained by cyclizing an 
intermediate of formula (II) with N-cyanoimido-S,S-dimethyldithiocarbonate 
or with an Q-alkylisourea or S-alkylisothiourea wherein R.sup.9 is alkyl, 
thus yielding respectively a N-cyanoguanidine of formula (IV-a) or a 
N-alkyloxycarbonyl guanidine of formula (IV-b). 
##STR5## 
The N-cyanoguanidine of formula (IV-a) may be converted into compounds of 
formula (I) upon heating, preferably at the reflux temperature of the 
reaction mixture, in a suitable solvent such as an alkanol, e.g. ethanol, 
propanol, butanol and the like, and in the presence of an acid such as, 
for example, hydrochloric acid. The N-alkyloxycarbonyl guanidine of 
formula (IV-b) in turn, may be converted into compounds of formula (I) by 
base hydrolysis of the carbamate and subsequent cyclization in the 
presence of an acid, optionally at an enhanced temperature. 
In all of the foregoing and in the following preparations, the reaction 
products may be isolated from the reaction mixture and, if necessary, 
further purified according to methodologies generally known in the art. 
The compounds of formula (I) can also be prepared from a quinazoline 
derivative of formula (V) wherein L is a leaving group as defined 
hereinbefore and R.sup.9 is C.sub.1-6 alkyl or aryl, 
##STR6## 
by cyclization with ammonia or a salt thereof such as, for example, an 
ammonium halide, e.g. ammonium chloride; ammonium carbonate; ammonium 
acetate and the like ammonium salts, in a suitable reaction-inert solvent 
such as, for example, water, an alkanol, e.g. methanol, ethanol and the 
like, a carboxylic acid, e.g. acetic, propanoic acid and the like, or a 
mixture of such solvents. In order to enhance the rate of the reaction, it 
may be advantageous to heat the reaction mixture, in particular to the 
reflux temperature of the reaction mixture. 
The compounds of formula (I) wherein X is a radical of formula (b), said 
compounds being represented by formula (I-b), can be obtained by reacting 
a compound of formula (I) wherein X is a radical of formula (a), said 
compound being represented by formula (I-a), with an appropriate 
hydroxylamine derivative of formula (VI) or an acid addition salt thereof. 
##STR7## 
Said reaction can be carried out by stirring and heating the reagents in an 
appropriate solvent at an enhanced temperature, in particular the reflux 
temperature of the reaction mixture. Appropriate solvents are for example, 
aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and 
the like; halogenated hydrocarbons, e.g. trichloromethane, 
tetrachloromethane and the like; ethers, e.g. 1,1'-oxybisethane, 
tetrahydrofuran, 1,4-dioxane and the like; dipolar aprotic solvents, e.g. 
N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, pyridine and 
the like, or mixtures thereof. 
The compounds of formula (I) wherein X is a radical of formula (c), said 
compounds being represented by formula (I-c), may be prepared by reacting 
the compounds of formula (I-a) with a phosphorus ylide of formula (VII) 
(Wittig reaction) or with an ylide of formula (VIII) prepared from a 
phosphonate (Horner-Emmons reaction). 
##STR8## 
In formula (VIII) R" represents C.sub.1-6 alkyl. The reaction can 
conveniently be conducted by treating a phosphonium salt or a phosphonate 
with an appropriate base such as, for example, butyllithium, 
methyllithium, sodium amide, sodium hydride, a sodium or potassium 
alkoxide, sulfinylbis(methane) sodium salt and the like bases, under an 
inert atmosphere and in a reaction-inert solvent such as for example, a 
hydrocarbon, e.g. hexane, heptane, cyclohexane and the like; an ether, 
e.g. 1,1'oxybisethane, tetrahydrofuran, 1,2-dimethoxyethane and the like; 
a dipolar aprotic solvent, e.g. dimethylsulfoxide, hexamethylphosphor 
triamide, and the like solvents; and subsequently treating the thus 
obtained ylides (VII) or (VIII) with the compound of formula (I-a), 
optionally at a slightly enhanced temperature. 
Alternatively the compounds of formula (I-c) may be prepared by reacting a 
compound of formula (I-a) with an organometallic reagent of formula (IX) 
wherein M represents a metal group such as, for example, lithium, 
halomagnesium, copper lithium and the like; and subsequently dehydrating 
the alcohol of formula (X), for example by treatment with an appropriate 
acid, e.g. hydrochloric or sulfuric acid in a solvent. 
##STR9## 
The organometallic reagent may conveniently be prepared following 
art-known methods by reacting an appropriate halide with a metal such as 
lithium or magnesium in a reaction-inert solvent such as, for example, an 
ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,2-dimethoxyethane and 
the like. 
The compounds of formula (I-b) wherein R.sup.3 is other than hydrogen, said 
radical being represented by formula R.sup.3-a and said compounds by 
formula (I-b-1) can also be obtained from compounds of formula (I-b) 
wherein R.sup.3 is hydrogen, said compounds being represented by formula 
(I-b-2), by O-alkylation or O-silylation with an appropriate alkylating or 
silylating reagent of formula R.sup.3-a -W.sup.2. 
##STR10## 
In said alkylating or silylating reagent, W.sup.2 represents a leaving 
group such as, for example, halo, e.g. chloro, bromo, iodo or sulfonyloxy, 
e.g. 4-methylbenzenesulfonyloxy, benzenesulfonyloxy, 
2-naphthalenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy 
and the like leaving groups. Said O-alkylation and O-silylation reaction 
can conveniently be conducted by stirring the reactants in a 
reaction-inert solvent in the presence of a base. Appropriate solvents are 
halogenated hydrocarbons such as, for example, dichloromethane, 
trichloromethane and the like; etherts, e.g. 1,1'-oxybisethane, 
tetrahydrofuran and the like; dipolar aprotic solvents, e.g. 
N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, acetonitrile; and 
the like solvents. Suitable bases are tertiairy amines such as, for 
example, N,N-diethylethanamine, 4-methylmorpholine, pyridine, 
tetramethylguanidine and the like. 
Furthermore, the compounds of formula (I-b-2) which may occur as E- or 
Z-forms, or mixtures thereof, may be isomerized by equilibration in an 
acidic medium. 
##STR11## 
The compounds of formula (I-b-1) wherein R.sup.3-a is tri(C.sub.1-6 
alkyl)silyl can be desilylated to the oximes of formula (I-b) by treatment 
with a fluoride salt such as, for example, potassium fluoride, tetrabutyl 
ammonium fluoride, or by reaction with hydrofluoric acid, in a solvent 
such as, an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran; or in an 
aqueous mixture thereof. As the compounds of formula (I-b-1) wherein 
R.sup.3-a is tri(C.sub.1-6 alkyl)silyl can easily be separated in the E- 
and Z-stereoisomers following art-known procedures such as selective 
crystallization and chromatography, and desilylated as described 
hereinabove, this sequence provides an efficient procedure for preparing 
those stereomers of (I-b) which can not be prepared by the isomerization 
procedure mentioned hereinabove. 
The compounds of formula (I-b-1) wherein R.sup.3-a is C.sub.1-6 alkyl 
substituted with COOH, COOC.sub.1-6 alkyl, CONR.sup.5 R.sup.6 or 
COOCH.sub.2 CONR.sup.7 R.sup.8 and the compounds of formula (I-c) wherein 
R.sup.4 is COOH, COOC.sub.1-4 alkyl, CONR.sup.5 R.sup.6, COOCH.sub.2 
CONR.sup.7 R.sup.8 or C.sub.1-6 alkyl substituted with COOH, COOC.sub.1-4 
alkyl, CONR.sup.5 R.sup.6 or COOCH.sub.2 CONR.sup.7 R.sup.8 can be 
converted into each other following art known procedures such as, for 
example, esterification, amidation, transesterification, transamidation, 
ester hydrolysis and the like methods. 
For example, the compounds wherein R.sup.3-a or R.sup.4 is C.sub.1-6 alkyl 
substituted with COOH or R.sup.4 is COOH may be converted into an ester 
wherein R.sup.3-a or R.sup.4 is C.sub.1-4 alkyl substituted with 
COOC.sub.1-4 alkyl or COOCH.sub.2 CONR.sup.7 R.sup.8, or R.sup.4 is 
COOC.sub.1-4 alkyl or COOCH.sub.2 CONR.sup.7 R.sup.8, or into an amide 
wherein R.sup.3-a or R.sup.4 is C.sub.1-6 alkyl substituted with 
CONR.sup.5 R.sup.6 or R.sup.4 is CONR.sup.5 R.sup.6 by treating the 
carboxylic acid with an alkanol of formula C.sub.1-4 alkyl-OH or an 
alcohol of formula HOCH.sub.2 CONR.sup.7 R.sup.8 or an amine of formula 
HNR.sup.5 R.sup.6 in the presence of a suitable reagent capable of forming 
esters and/or amides. Typical examples of such reagents are for example, 
dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide, phosphorus 
pentoxide, 1,1'-carbonylbis[1H-imidazole], 1,1'-sulfonylbis[1H-imidazole] 
and the like reagents. Alternatively, said carboxylic acids may be 
converted into suitable reactive functional derivatives thereof such as, 
for example, an acyl halide, symmetric or mixed anhydride, ester, amide, 
acyl azide, cyclic anhydride, lactone, lactam and the like derivatives 
before reaction with the alkanol C.sub.1-4 alkylOH, the alcohol of formula 
HOCH.sub.2 CONR.sup.7 R.sup.8 or the amine HNR.sup.5 R.sup.6. Said 
reactive functional derivatives may be prepared following art known 
methods, for example, by reacting the carboxylic acid with a halogenating 
reagent such as, for example, thionyl chloride, phosphorous trichloride, 
polyphosphorous acid, phosphoryl chloride, oxalyl chloride and the like, 
or by reacting said carboxylic acid with an acyl halide such as acetyl 
chloride and the like. Said reactive functional derivatives of the 
carboxylic acids may be generated in situ, or if desired, be isolated and 
further purified before reacting them with the alkanol C.sub.1-4 alkyl-OH, 
the alcohol of formula HOCH.sub.2 CONR.sup.7 R.sup.8 or the amine 
HNR.sup.5 R.sup.6. 
Said esterification and amidation reactions can conveniently be carried out 
by stirring the reactants, optionally in a suitable reaction-inert solvent 
such as, for example, a halogenated hydrocarbon, e.g. dichloromethane, 
trichloromethane and the like; an aromatic hydrocarbon, e.g. benzene, 
methylbenzene and the like; an ether, e.g. 1,1'-oxybisethane, 
tetrahydrofuran and the like; or a dipolar aprotic solvent, e.g. 
N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and the like. In 
some instances it may be appropriate to employ an excess of one of the 
reagents as solvent. The water, acid, alcohol or amine which is liberated 
during the course of the reaction may be removed from the reaction mixture 
by art-known procedures such as, for example, azeotropical distillation, 
complexation, salt formation and the like methods. In some instances 
particularly the addition of a suitable base such as, for example, an 
amine, e.g. N,N-diethylethanamine, 4-ethylmorpholine, pyridine or 
N,N-dimethyl-4-pyridinamine, may be appropriate. Further, in order to 
enhance the rate of the reaction, said acylation reaction may 
advantageously be conducted at a somewhat elevated temperature, in 
particular the reflux temperature of the reaction mixture. 
Transesterification may be accomplished by reacting a compound wherein 
R.sup.3-a or R.sup.4 is C.sub.1-6 alkyl substituted with COOC.sub.1-4 
alkyl or COOCH.sub.2 CONR.sup.7 R.sup.8 or R.sup.4 is COOC.sub.1-4 alkyl 
or COOCH.sub.2 CONR.sup.7 R.sup.8, with a different alkanol of formula 
C.sub.1-4 alkylOH or a different alcohol of formula HOCH.sub.2 CONR.sup.7 
R.sup.8. The equilibrium of the transesterification reaction may be 
shifted following art-known methods, e.g. by using an excess of said 
alcohol, or by distilling off the liberated alcohol. Transamination can be 
accomplished in a similar manner by reaction with an amine HNR.sup.5 
R.sup.6. 
The compounds wherein R.sup.3-a or R.sup.4 is C.sub.1-6 alkyl substituted 
with COOC.sub.1-4 alkyl or COOCH.sub.2 CONR.sup.7 R.sup.8 or R.sup.4 is 
COOC.sub.1-4 alkyl or COOCH.sub.2 CONR.sup.7 R.sup.8 can be hydrolysed to 
the corresponding compounds wherein R.sup.3-a or R.sup.4 is C.sub.1-6 
alkyl substituted with COOH or R.sup.4 is COOH. Said hydrolysis can 
conveniently be conducted by stirring and heating the ester in an aqueous 
and/or alcoholic medium, e.g. water, methanol, ethanol and the like, or 
mixtures thereof, in the presence of a base such as, for example, sodium 
hydroxide, potassium hydroxide, potassium carbonate and the like. In some 
instances, for example, the 1,1-dimethylethyl ester, said hydrolysis may 
also be effected by stirring and optionally heating in an acidic aqueous 
and/or alcoholic medium as defined hereinabove. 
Alternatively the compounds of formula (I-b-1) may be prepared from an 
intermediate of formula (XI) wherein W.sup.3 represents a suitable 
reactive leaving group such as, for example, halo, e.g. chloro, or 
acetate, by reaction with a reagent of formula (XII). 
##STR12## 
The compounds of formula (I) may also be prepared by cyclizing an 
intermediate of formula (XIII) or an intermediate of formula (XIV). 
##STR13## 
Following an alternative cyclization procedure, an intermediate of formula 
(XV) may also be converted into a compound of formula (I). 
##STR14## 
The compounds of formula (I) may also be formed from the quinazoline 
derivatives (XVI), (XVII) or (XVIII) by cyclization. 
##STR15## 
In all the above mentioned cyclization reactions, said cyclization may be 
carried out by stirring and if desired heating the intermediate starting 
material, optionally in a suitable reaction-inert solvent. Appropriate 
solvents for said cyclization reactions are for example, aromatic 
hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and the like; 
halogenated hydrocarbons, e.g. trichloromethane, tetrachloromethane, 
chlorobenzene and the like; ethers, e.g. 1,1'-oxybisethane, 
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methoxybenzene and the 
like; dipolar aprotic solvents, e.g. N,N-dimethylformamide, 
N,N-dimethylacetamide, dimethyl sulfoxide and the like; or mixtures of 
such solvents. The water, hydrohalic acid or ammonia which is liberated 
during the cyclization reaction may be removed from the reaction mixture 
by azeotropical destillation, destillation, complexation, salt formation 
and the like methods. 
All intermediates of the previous schemes as well as many of their 
precursors are novel and have especially been developed for conversion 
into the compounds of the present invention. Interesting are the novel 
intermediates of formula (II) and (IV), in particular these intermediates 
of formula (IV) wherein L is C.sub.1-6 alkyloxy, hydroxy or amino, the 
pharmaceutically acceptable acid and base addition salts thereof and the 
stereochemically isomeric forms thereof. 
The intermediates of formula (II) can be obtained from the corresponding 
nitro derivatives of formula (XIX) following art known reduction 
procedures. 
##STR16## 
For example, the nitro derivative of formula (XIX) may be reduced by 
catalystic hydrogenation in a suitable solvent, e.g. methanol or ethanol, 
in the presence of hydrogen and an appropriate catalyst, e.g. 
platinum-on-charcoal, palladium-on-charcoal, Raney nickel and the like, 
optionally at an increased temperature and/or pressure. In some instances 
it may be useful to add an appropriate catalyst poison such as thiophene 
to the reaction mixture. Alternatively, said nitro derivative may also be 
reduced by a reducing agent such as, for example, sodium sulfide, sodium 
hydrogen sulfide, sodium hydrosulfite, titanium trichloride, formic acid, 
N,N-diethylethanamine; iron ammonium chloride and the like. 
The intermediate nitro derivative (XIX) can be prepared from an 
intermediate of formula (XX) by reaction with an aminoacid (L=OH) or a 
derivative thereof (L=--O--C.sub.1-6 alkyl, --O--phenyl, -amino) of 
formula (XXI) and more particularly an acid addition salt thereof. 
##STR17## 
In formula (XX) W.sup.2 represents an appropriate leaving group as defined 
hereinabove. The above N-alkylation reaction can conveniently be conducted 
by stirring, and if desired heating, the reactants in a suitable 
reaction-inert solvent in the presence of a base. 
Suitable solvents are, for example, water; an aromatic solvent, e.g. 
benzene, methylbenzene, dimethylbenzene, chlorobenzene, methoxybenzene and 
the like; a C.sub.1-6 alkanol, e.g. methanol, ethanol, 1-butanol and the 
like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; an 
ester, e.g. ethylacetate, .gamma.-butyrolactone and the like; an ether, 
e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; a 
dipolar aprotic solvent, e.g. N,N-dimethylformamide, 
N,N-dimethylacetamide, dimethylsulfoxide, pyridine, 
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 
1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylurea, 
1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile and the like; or a 
mixture of such solvents. In order to set free the base form of (XXI) in 
case a salt form is used, and to neutralize the acid which is formed 
during the course of the reaction, an appropriate base may be added such 
as, for example, an alkali metal or an earth alkaline metal carbonate, 
hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or 
amide, e.g. sodium carbonate, sodium hydrogen carbonate, potassium 
carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium 
methoxide, sodium hydride, sodium amide and the like, or an organic base 
such as, for example, an amine, e.g. N,N-diethylethanamine, 
N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, 
1,4-diazabicyclo[2.2.2]octane, pyridine and the like. 
The intermediate of formula (XX) can be obtained from a benzylalcohol of 
formula (XXII) following art known procedures for converting hydroxy 
groups into reactive leaving groups. 
##STR18## 
Suitable procedures comprise, for example, converting the alcohol of 
formula (XXII) into sulfonyloxy esters by reaction with sulfonyl halides 
such as, for example, methanesulfonyl chloride, benzenesulfonyl chloride, 
4-methylbenzenesulfonyl chloride and the like reagents. Or, the alcohol of 
formula (XXII) can be converted into the corresponding halide by reaction 
with a halogenating reagent such as, for example, a hydrohalic acid, e.g. 
hydrochloric or hydrobromic acid, thionyl chloride, oxalyl chloride, 
phosphoryl chloride or bromide, phosphorous trichloride or tribromide, 
phosphorus pentachloride, triphenylphosphine with tetrachloromethane or 
tetrabromomethane and the like halogenating reagents. 
The intermediate benzylalcohol of formula (XXII) can be derived from a 
protected alcohol by art-known deprotection procedures. 
##STR19## 
In formula (XXIII) P may represent a suitable protective group such as, 
for example, tetrahydropyranyl, 2-methoxyethoxymethyl, 2-methoxypropyl, 
2-acetoxypropyl, 1-ethoxyethyl and the like; a trialkylsilyl group, e.g. 
trimethylsilyl, tert. butyldimethylsilyl and the like groups. Said 
deprotection reaction can easily be conducted following art-known methods 
of hydrolyzing acetals and silyl ethers, e.g. by acid hydrolysis in 
aqueous media. Conversely, the protected intermediates of formula (XXIII) 
may be obtained from the alkanols of formula (XXII) following art-known 
procedures for protecting hydroxy groups. Typically such protection 
reactions may comprise treatment with a vinylether, e.g. dihydropyran, in 
an inert solvent and in the presence of an acid catalyst; or O-alkylation 
or O-silylation with a suitable alkylating reagent such as, for example, a 
trialkylsilyl halide, e.g. trimethylsilylchloride, tert. 
butyldimethylsilylchloride; and the like protection reactions. 
The intermediates of formula (XXIII) wherein X is a radical of formula (b) 
or (c), said intermediates being represented by formulae (XXIII-b) and 
(XXIII-c), can easily be prepared from an intermediate of formula 
(XXIII-a) wherein X is O, following the procedures described above for the 
conversion of the compounds of formula (I-a) into the compounds of formula 
(I-b) and (I-c). 
##STR20## 
The intermediates of formula (XXIII-a) can be prepared from a cyanide of 
formula (XXIV) following art-known oxidation procedures such as described 
in J. Org. Chem., 1975, 40, 267. 
##STR21## 
The cyanides of formula (XXIV) can easily be obtained by an aromatic 
nucleophilic substitution reaction of a cyanide of formula (XXV) on a 
nitrobenzene of formula (XXVI). 
##STR22## 
In formula (XXVI) W.sup.4 represents a reactive leaving group such as, for 
example, halo, e.g. chloro or fluoro, nitro, 4-methylbenzenesulfonyloxy, 
phenyloxy, alkyloxy and the like groups known in the art to be good 
leaving groups in aromatic nucleophilic substitution reactions. Said 
aromatic nucleophilic substitution reaction can conveniently be conducted 
by stirring the reactants in the presence of a base in a reaction inert 
solvent such as for example, a dipolar aprotic solvent, e.g. 
N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric 
traimide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 
1,3-dimethylimidazolidinone, 1,1,3,3-tetramethylurea, 
1-methyl-2-pyrrolidinone, nitrobenzene and the like solvents; or mixtures 
thereof. Appropriate bases are sodium hydride, sodium amide, 
sulfinylbis(methane) sodium salt and the like bases. It may be 
advantageous to add to the reaction mixture a crown ether, e.g. 
1,4,7,10,13,16-hexaoxacyclooctadecane and the like or a complexing agent 
such as for example, tris[2-(2-methoxyethoxy)]ethanamine and the like. 
Somewhat elevated temperatures may enhance the rate of the reaction. 
The intermediates of formula (XXII-a), wherein X is O, can alternatively be 
prepared by oxidizing an intermediate of formula (XXVII). 
##STR23## 
Said oxidation reaction can conveniently be conducted by stirring the 
reactants in water in the presence of an oxidizing agent such as, for 
example, hydrogen peroxide and the like. 
The intermediates of formula (XXVII) in turn can be obtained by the 
addition of an intermediate of formula (XXV) to 
2-hydroxymethylnitrobenzene. 
##STR24## 
Said addition reaction can conveniently be conducted by stirring the 
reactants in a reaction-inert solvent in the presence of an appropriate 
base. Suitable solvents are, for example, dipolar aprotic solvents, e.g. 
N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine 
and the like. Appropriate bases are sodium hydroxide, potassium hydroxide, 
sodium hydride, sodium amide, sulfinyl bis(methane) sodium salt and the 
like bases. 
The intermediates of formula (XXII-a) can also be obtained by the 
chemoselective reduction of an aldehyde of formula (XXVIII). 
##STR25## 
Suitable reductants for said selective reduction of the carboxaldehyde 
group are, for example, sodium borohydride, sodium cyanoborohydride, and 
the like. A particularly interesting mode of conducting said reduction 
comprises the addition of a rare-metal salt such as, for example, 
cerium(III)chloride, to the reaction in order to increase the selectivity. 
The aldehydes of formula (XXVIII) in turn can be obtained by hydrolyzing in 
an acidic aqueous medium an .alpha.-aminocyanide of formula (XXIX), 
wherein both R.sup.10 radicals represent an alkyl group such as methyl, 
ethyl and the like, or both R.sup.10 taken together form an alkanediyl 
radical such as, 1,2-ethanediyl, 1,3-propanediyl, 
2,2-dimethyl-1,3-propanediyl and the like. 
In formula (XXIX) and hereinafter the group -NR'R' represents a 
dialkylamino group or a heterocyclic radical such as, for example, 
morpholino, piperidino, pyrrolidino and the like groups. 
##STR26## 
The intermediates of formula (XXIX) in turn can be prepared by an aromatic 
nucleophilic substitution reaction on a nitrobenzene of formula (XXXI) as 
described hereinabove for the preparation of the intermediates of formula 
(XXIV). 
##STR27## 
The reagent of formula (XXX) can easily be prepared from an appropriate 
aldehyde by reaction with sodium cyanide, potassium cyanide and the like 
cyanides, in the presence of an amine HNR'R' and sodium hydrogen sulfite. 
Suitable solvents are for example, water, alkanols, e.g. methanol, ethanol 
and the like, and mixtures thereof. 
In a number of instances, the intermediates of formula (XIX) and (II) 
wherein X is O, said intermediates being represented by formula (XIX-a) 
and (II-a), can be derived directly from an intermediate of formula 
(XXVIII) by reductive N-alkylation with an amino acid derivative of 
formula (XXI) or a salt thereof. 
##STR28## 
Said reductive N-alkylation reaction can conveniently be conducted 
following art-known procedures, i.e. by stirring and optionally heating a 
mixture of the ingredients in a reaction-inert solvent in the presence of 
a suitable reductant and an equivalent of a base to set free the amino 
acid from its salt. Suitable bases are alkali metal carboxylates, e.g. 
sodium acetate, potassium acetate, potassium propionate and the like. For 
example, said mixture may be catalytically reduced in the presence of 
hydrogen and a hydrogenation catalyst such as palladium-on-charcoal, 
platinum-on-charcoal and the like, thus yielding an intermediate of 
formula (II-a). Alternatively, hydrides, e.g. sodium borohydride, sodium 
cyanoborohydride and the like; formic acid or a salt thereof, particularly 
the ammonium salt, may be employed to effect the desired reductive 
N-alkylation to an intermediate of formula (XIX-a). 
The thus obtained intermediates of formula (XIX-a) can further be converted 
into the corresponding free oxime derivatives wherein X is NOH, said 
intermediates being represented by formula (XIX-b), by reaction with 
hydroxylamine or a salt thereof in a lower alkanol such as, for example, 
methanol, ethanol, 1-propanol, 2-propanol and the like and a suitable base 
such as, for example, potassium fluoride, potassium acetate and the like. 
##STR29## 
The intermediates of formula (XIX-b) are particularly useful for 
O-alkylating or O-silylating the oxime group with a reagent of formula 
R.sup.3-a -W.sup.2 as described hereinbefore for the preparation of 
compounds of formula (I-b-1) from the compounds of formula (I-b-2). The 
intermediates of formula (XIX-b) may occur in their E- or Z-form or as 
mixtures thereof. Mixtures of said E- and Z-forms can be isomerized mainly 
to the E-form by stirring in a suitable solvent in the presence of an acid 
such as, for example, hydrochloric acid. Suitable solvents are, for 
example, alcohols, e.g. propanol, isopropanol and the like; ethers, e.g. 
1,4-dioxane, tetrahydrofuran and the like or mixtures of such solvents. 
The intermediates of formula (XXII) wherein X is NOH, said intermediates 
being represented by formula (XXII-b) can also be prepared by reducing an 
ester of formula (XXXII) wherein R.sup.11 represents alkyl. 
##STR30## 
Said reduction can conveniently be conducted by treating the ester in a 
reaction-inert solvent such as an ether, e.g. tetrahydrofuran, 
1,1'-oxybisethane and the like, with a reducing agent such as sodium 
borohydride. 
The intermediates of formula (XXXII) are obtained from the corresponding 
ketones or aldehydes (XXXIII) following procedures as described 
hereinabove for the preparation of the compounds of formula (I-b) from 
those of formula (I-a). 
The ketones may be prepared by reacting an organometallic compound R.sup.12 
-M, wherein R.sup.12 represents R but is other than hydrogen, and M is a 
metal group such as lithium, magnesium halide, copper lithium, with the 
aldehyde (XXXIII) and oxidizing the thus obtained alcohol to the ketone. 
##STR31## 
The aldehyde (XXXIII) is prepared following art-known procedures from the 
corresponding methyl group by oxidation to the carboxylic acid, reduction 
to the alcohol and oxidation to the aldehyde. 
The intermediates of formula (V) wherein X is O, said intermediates being 
represented by formula (V-a) can be prepared by N-alkylating an 
intermediate (XXXIV) with an appropriate acetate derivative (XXXV) wherein 
W and L are reactive leaving groups as defined hereinbefore. 
##STR32## 
The intermediate (XXXIV) in turn can be obtained from (XXXVI) by 
S-alkylation with an alkylhalide R.sup.9 -W, e.g. methyliodide, following 
art-known procedures. 
The intermediate (XXXVI) finally is prepared by the Friedel-Crafts 
acylation of 3,4-dihydro-2(1H)-quinazolinethione with a suitable acid 
halide (XXXVII) in the presence of an appropriate Lewis acid such as, for 
example, aluminum chloride, ferric chloride and the like, in a solvent, 
preferably a dipolar aprotic solvent, e.g. N,N-dimethylformamide, 
N,N-dimethylacetamide, hexamethylphosphoric triamide, 
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 
1,3-dimethylimidazolidinone, 1,1,3,3,-tetramethylurea and the like. 
##STR33## 
The compounds of formula (I), the pharmaceutically acceptable acid addition 
salts and stereochemically isomeric forms thereof, are potent inhibitors 
of the phosphodiesterase type III.sub.c (cardiotonic-sensitive PDE III) 
(also designated family III.sub.Al in the novel classification by J. A. 
Beavo and D. H. Reifsnyder, TIPS Reviews, April 1990, pp. 150-155) of 
warm-blooded animals, in particular humans. Inhibition of PDE III.sub.c 
leads to an elevation of cAMP in cardiac muscle, which in turn enhances 
sarcolemmal entry of Ca.sup.2+ into the cell, increases the release and 
reuptake of Ca.sup.2+ by the sarcoplasmic reticulum and probably also 
increases the sensitivity of contractile proteins to Ca.sup.2+. As a 
result an increased contractile force of the heart ensues (positive 
inotropy) as well as a faster relaxation of the heart (positive 
lusitropy). 
Particularly important is the observation that the positive inotropic and 
lusitropic effects generally do not coincide with a simultaneous increase 
of other haemodynamic variables such as heart rate and blood pressure. 
Concommittant increases of heart rate and/or blood pressure would indeed 
put extra strain on the heart and cancel the beneficial positive cardiac 
inotropy and lusitropy. In vivo experiments with the instant compounds of 
formula (I) show moderate systemic vasodilation and hence a decrease in 
blood pressure. The heart rate generally only increases at high doses. In 
all, the instant compounds of formula (I) dramatically increase cardiac 
output by cardiac positive inotropy and lusitropy and without major 
influence on heart rate and/or blood pressure. The novel intermediates of 
formula (IV) also are inhibitors of the phosphodiesterase type III.sub.c. 
Consequently, the subject compounds are considered to be valuable 
therapeutical drugs for treating warm-blooded animals, particularly 
humans, suffering from Congestive Heart Failure. Congestive Heart Failure 
is a pathophysiological state that is defined by the inability of the 
heart to pump adequate amounts of blood to the peripheral sites of the 
organism, with consequent failure to meet the metabolic requirement of the 
body. Said condition may result from a heart attack, infection of the 
heart, chronic hypertension, deficiencies in the operation of the heart 
valves and other disorders of the heart leading to Congestive Heart 
Failure. 
In view of their useful positive inotropic and lusitropic properties, the 
subject compounds may be formulated into various pharmaceutical forms for 
administration purposes. To prepare the pharmaceutical compositions of 
this invention, an effective amount of the particular compound, in base or 
acid addition salt form, as the active ingredient is combined in intimate 
admixture with a pharmaceutically acceptable carrier, which may take a 
wide variety of forms depending on the form of preparation desired for 
administration. These pharmaceutical compositions are desirably in unitary 
dosage form suitable, preferably, for administration orally, rectally, 
percutaneously, or by parenteral injection. For example, in preparing the 
compositions in oral dosage form, any of the usual pharmaceutical media 
may be employed, such as, for example, water, glycols, oils, alcohols and 
the like in the case of oral liquid preparations such as suspensions, 
syrups, elixirs and solutions: or solid carriers such as starches, sugars, 
kaolin, lubricants, binders, disintegrating agents and the like in the 
case of powders, pills, capsules and tablets. Because of their ease in 
administration, tablets and capsules represent the most advantageous oral 
dosage unit form, in which case solid pharmaceutical carriers are 
obviously employed. For parenteral compositions, the carrier will usually 
comprise sterile water, at least in large part, though other ingredients, 
for example, to aid solubility, may be included. Injectable solutions, for 
example, may be prepared in which the carrier comprises saline solution, 
glucose solution or a mixture of saline and glucose solution. Injectable 
suspensions may also be prepared in which case appropriate liquid 
carriers, suspending agents and the like may be employed. In the 
compositions suitable for percutaneous administration, the carrier 
optionally comprises a penetration enhancing agent and/or a suitable 
wettable agent, optionally combined with suitable additives of any nature 
in minor proportions, which additives do not cause any significant 
deleterious effects on the skin. Said additives may facilitate the 
administration to the skin and/or may be helpful for preparing the desired 
compositions. These compositions may be administered in various ways, 
e.g., as a transdermal patch, as a spot-on or as an ointment. Addition 
salts of the subject compounds are obviously more suitable in the 
preparation of aqueous compositions due to their increased water 
solubility. 
Especially noteworthy as complexants and/or solubilizers are 
.beta.-CD,2,6-dimethyl-.beta.-CD and in particular 
2-hydroxypropyl-.beta.-CD, 2-hydroxyethyl-.beta.-CD, 
2-hydroxyethyl-.gamma.-CD and 2-hydroxypropyl-.gamma.-CD. In the 
aforementioned cyclodextrin derivatives, the DS (degree of substitution, 
i.e. the average number of substituted hydroxy functions per glucose unit) 
preferably is in the range of 0.125 to 3, in particular 0.3 to 2, more in 
particular 0.3 to 1 and the MS (molar degree of substitution, i.e. the 
average number of moles of the substituting agent per glucose unit) is in 
the range of 0.125 to 10, in particular of 0.3 to 3 and more in particular 
0.3 to 1.5, preferably of 0.35 to 0.50. Said compositions may conveniently 
be prepared by dissolving the cyclodextrin or ether derivative thereof in 
water and adding thereto a subject compound as well as other adjuvants and 
components such as, for example, sodium chloride, potassium nitrate, 
glucose, mannitol, sorbitol, xylitol and buffers such as, for example, 
phosphate, acetate or citrate buffers; and optionally concentrating or 
drying the solution by evaporation under reduced pressure or by 
lyophilization. The amount of the cyclodextrin or ether derivative thereof 
in the final composition generally ranges from about 1% to about 40% by 
weight, particularly form 2.5% to 25% and more particularly from 5% to 
20%. 
It is especially advantageous to formulate the aforementioned 
pharmaceutical compositions in dosage unit form for ease of administration 
and uniformity of dosage. Dosage unit form as used in the specification 
and claims herein refers to physically discrete units suitable as unitary 
dosages, each unit containing a predetermined quantity of active 
ingredient calculated to produce the desired therapeutic effect in 
association with the required pharmaceutical carrier. Examples of such 
dosage unit forms are tablets (including scored or coated tablets), 
capsules, pills, powder packets, wafers, injectable solutions or 
suspensions and the like, and segregated multiples thereof. 
In view of the usefulness of the subject compounds in the treatment of 
Congestive Heart Failure it is evident that the present invention provides 
a method of treating warmblooded animals suffering from Congestive Heart 
Failure, said method comprising the systemic administration of a 
pharmaceutically effective amount of a compound of formula (I), an 
intermediate of formula (IV) or a pharmaceutically acceptable addition 
salt thereof in admixture with a pharmaceutical carrier. Those of skill in 
the treatment of Congestive Heart Failure could easily determine the 
effective daily amount from the test results presented here. In general it 
is contemplated that an effective daily amount would be from 0.01 mg/kg to 
4 mg/kg body weight, more preferably from 0.04 mg/kg to 2 mg/kg body 
weight. 
It is evident that said effective daily amount may be lowered or increased 
depending on the response of the treated subject and/or depending on the 
evaluation of the physician prescribing the compounds of the instant 
invention. The effective daily amount ranges mentioned hereinabove are 
therefore guidelines only and are not intended to limit the scope or use 
of the invention to any extent.

The following examples are intended to illustrate and not to limit the 
scope of the present invention. Unless otherwise stated all parts therein 
are by weight. 
EXPERIMENTAL T 
A. Preparation of Intermediates 
Example 1 
(a) A mixture of 25 parts of 5-chloro-2-nitrobenzenemethanol, 13.3 parts of 
dihydro-2H-pyran, 300 parts of dichloromethane and 0.28 parts of 
4-methylbenzenesulfonic acid was stirred for 2 hours at reflux 
temperature. After cooling, the reaction mixture was neutralized with 
sodium carbonate and stirred for 10 min. The whole was filtered and the 
filtrate was evaporated. The residue was co-evaporated with methylbenzene 
and then purified by column chromatography (silica gel; CHCl.sub.3). The 
eluent of the desired fraction was evaporated and the residue was 
co-evaporated with methylbenzene, yielding 36 parts (99.6%) of 
2-[(5-chloro-2-nitrophenyl)methoxy]tetrahydro-2H-pyran (interm. 1). 
(b) To a suspension of 7.13 parts of a sodium hydride dispersion 50% in 
mineral oil in 94 parts of N,N-dimethylacetamide there was added dropwise 
a solution of 9.1 parts of benzeneacetonitrile in 18.8 parts of 
N,N-dimethylacetamide. After hydrogen evolution had ceased, there were 
added 1.28 parts of 
N,N-di[2(2-methoxyethoxy)ethyl]-2-(2-methoxyethoxy)ethanamine and a 
solution of 20.2 parts of intermediate (1) in 28.2 parts of 
N,N-dimethylacetamide. After 15 min, the reaction mixture was poured into 
ice-water and the whole was neutralized. The product was extracted with 
dichloromethane and the extract was dried, filtered and evaporated, 
yielding 26.2 parts (100%) of 
4-nitro-.alpha.-phenyl-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzeneace 
tonitrile (interm. 2). 
(c) A mixture of 26.2 parts of intermediate (2), 10.2 parts of potassium 
carbonate and 376 parts of N,N-dimethylacetamide was aerated at room 
temperature, while stirring. The reaction mixture was poured into water 
and the product was extracted with 2,2'-oxybispropane. The extract was 
dried, filtered and evaporated, yielding 25 parts (98.6%) of 
[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]phenyl-methanone 
(interm. 3). 
(d) A mixture of 50 parts of intermediate (3), 1.9 parts of 
4-methylbenzenesulfonic acid and 400 parts of methanol was stirred at room 
temperature. The reaction mixture was neutralized with sodium carbonate, 
stirred at room temperature for 15 min and filtered. The filtrate was 
evaporated and the residue was stirred in a mixture of water and 
2,2'-oxybispropane for 15 min. The whole was washed with NaCl (sat.), 
dried, filtered and evaporated. The residue was co-evaporated with 
methylbenzene and was then purified by column chromatography (silica gel; 
CHCl.sub.3 /CH.sub.3 OH 98:2). The eluent of the desired fractions was 
evaporated and the residue was crystallized from a mixture of 
methylbenzene and hexane. The product was filtered off, washed with a 
mixture of hexane and methylbenzene and with hexane, and dried in vacuo at 
40.degree.-50.degree. C., yielding 9.7 parts (25.9%) of 
[3-(hydroxymethyl)-4-nitrophenyl]phenylmethanone; mp. 71.3.degree. C. 
(interm. 4). 
(e) To a stirred and cooled (0.degree. C.) mixture of 27.5 parts of 
intermediate (4), 11.9 parts of N,N-diethylethanamine and 650 parts of 
dichloromethane there were added dropwise 13.3 parts of methanesulfonyl 
chloride. The reaction mixture was partitioned between dichloromethane and 
water. The organic layer was separated, dried, filtered and evaporated, 
yielding 36 parts (100%) of 5-benzoyl-2-nitrobenzenemethanol 
methanesulfonate (ester). 
To a stirred amount of 385 parts of dimethyl sulfoxide were added 22.3 
parts of ethyl glycine monohydrochloride. When a clear solution was 
obtained, there were added 13.4 parts of sodium hydrogen carbonate and, 
after stirring for 15 min, 70 parts of molecular sieve 4 .ANG.. Stirring 
was continued for 15 min. Next there were added dropwise a solution of 
34.3 parts of 5-benzoyl-2-nitrobenzenemethanol methanesulfonate (ester) in 
77 parts of dimethyl sulfoxide. This reaction mixture was used as such for 
the preparation of intermediate (6). Theoretical yield: 28 parts (100%) of 
[3-(chloromethyl)-4-nitrophenyl]phenylmethanone (interm. 5) 
(f) To the reaction mixture, obtained in the preparation of intermediate 
(5), there were added 9 parts of sodium hydrogen carbonate. The whole was 
stirred overnight at 50.degree. C. and was then poured into 1000 parts of 
water. The precipitate was filtered off and stirred in 2-propanone for 15 
min. This solution was filtered and the filtrate was evaporated. The 
residue was taken up in methylbenzene and the whole was washed with water, 
dried, filtered and evaporated. The residue was purified by column 
chromatography (silica gel; CHCl.sub.3 /C.sub.2 H.sub.5 OH 98:2). The 
eluent of the desired fractions was evaporated, yielding 23.7 parts 
(68.2%) of ethyl N-[(5-benzoyl-2-nitrophenyl)methyl]glycine (interm. 6). 
(g) A mixture of 3.7 parts of intermediate (6), 2 parts of a solution of 
thiophene in methanol and 119 parts of ethanol was hydrogenated at normal 
pressure and at room temperature with 2 parts of platinum-on-charcoal 
catalyst 5%. After the calculated amount of hydrogen was taken up, the 
catalyst was filtered off and the filtrate was evaporated. The residue was 
co-evaporated with methylbenzene, yielding 3.19 parts (95%) of ethyl 
N-[(2-amino-5-benzoylphenyl)methyl]glycine (interm. 7). 
Example 2 
(a) To a stirred solution of 21.2 parts of intermediate (5) in 158 parts of 
acetonitrile, there were added successively 17.9 parts of ethyl 
.beta.-alanine monohydrochloride and 20.4 parts of N,N-diethylethanamine. 
Stirring was continued overnight at 50.degree. C. The reaction mixture was 
filtered and the filtrate was evaporated. The residue was partitioned 
between NaCl (sat.) and dichloromethane. The organic layer was separated, 
dried, filtered and evaporated. The residue was purified by column 
chromatography (silica gel; CHCl.sub.3 /C.sub.2 H.sub.5 OH 99:1). The 
eluent of the desired fraction was evaporated and the residue was 
co-evaporated with methylbenzene, yielding 15.3 parts (55.8%) of ethyl 
N-[(5-benzoyl-2-nitrophenyl)methyl]-.beta.-alanine (interm. 8). 
(b) A mixture of 15.3 parts of intermediate (8), 2 parts of a solution of 
thiophene in methanol 4% and 198 parts of ethanol was hydrogenated at 
normal pressure and room temperature with 5 parts of palladium-on-charcoal 
catalyst 5%. After the calculated amount of hydrogen was taken up, the 
catalyst was filtered off and the filtrate was evaporated. The residue was 
co-evaporated with methylbenzene, yielding 12.8 parts (93.4%) of ethyl 
N-[(2-amino-5-benzoylphenyl)methyl]-.beta.-alanine (interm. 9). 
In a similar manner there were also prepared: 
methyl N-[(2-amino-5-benzoylphenyl)methyl]-2-methylalanine (interm. 10) and 
ethyl 1-[[(2-amino-5-benzoylphenyl)methyl]amino]cyclopropanecarboxylate 
(interm. 11). 
Example 3 
(a) A mixture of 20 parts of intermediate (3), 4.45 parts of hydroxylamine 
monohydrochloride and 98 parts of pyridine was stirred for a few hours at 
reflux temperature. The solvent was evaporated and the residue was 
purified by column chromatography (silica gel; CHCl.sub.3 /CH.sub.3 OH 
98:2). The eluent of the first and second fraction was evaporated and the 
residues were separately co-evaporated with ethanol (3.times.) and with 
methylbenzene (1.times.). From the second fraction there were obtained 4.8 
parts (30.2%) of product. The first fraction was chromatographed again 
(silica gel; CHCl.sub.3 /CH.sub.3 OH 98:2) and evaporation of the eluent 
yielded an additional 9 parts (56.4%) of product. Total yield: 13.8 parts 
(86.6%) of (E+Z)-[3-(hydroxymethyl)-4-nitrophenyl]phenylmethanone, oxime 
(interm. 12). 
(b) To a stirred solution of 11.3 parts of intermediate (12) in 245 parts 
of N,N-dimethylformamide there were added portionwise 1.99 parts of a 
sodium hydride dispersion 50% in mineral oil. Stirring at room temperature 
was continued for 1/2 hour and then there were added at once 6.9 parts of 
ethyl 2-bromoacetate. After stirring overnight at room temperature, the 
reaction mixture was poured into NaCl (sat.). The product was extracted 
with 2,2'-oxybispropane and the extract was washed with water, dried, 
filtered and evaporated. The residue was purified by column chromatography 
(silica gel; CHCl.sub.3). The eluent of the desired fraction was 
evaporated and the residue was co-evaporated with methylbenzene, yielding 
8.9 parts (59.8%) of ethyl 
(E+Z)-2-[[[[3-(hydroxymethyl)-4-nitrophenyl]phenylmethylene]amino]oxy]acet 
ate (interm. 13). 
(c) To a stirred and cooled (0.degree. C.) mixture of 8.9 parts of 
intermediate (13), 2.6 parts of N,N-diethylethanamine and 260 parts of 
dichloromethane there were added dropwise 2.84 parts of methanesulfonyl 
chloride. Stirring was continued at 0.degree. C. and the mixture was 
allowed to reach room temperature overnight. The product was extracted 
with 130 parts of dichloromethane and the extract was washed with water 
(2.times.), dried, filtered and evaporated. The residue was co-evaporated 
with methylbenzene, yielding 9.3 parts (100%) of a mixture of ethyl 
(E+Z)-2-[[[[3-(chloro-methyl)-4-nitrophenyl]phenylmethylene]amino]oxy]acet 
ate (interm. 14) and ethyl 
(E+Z)-2-[[[[3-[(methylsulfonyloxy)methyl]-4-nitrophenyl]phenylmethylene]am 
ino]oxy]acetate (interm. 15) (15:85). 
(d) A mixture of 9.3 parts of intermediate (14) and intermediate (15) in 
132 parts of dimethyl sulfoxide, 5.15 parts of ethyl glycine 
monohydrochloride and 7.7 parts of N,N-diethylethanamine was stirred at 
50.degree.-60.degree. C. The reaction mixture was poured into NaCl (sat.) 
and the product was extracted with 2,2'-oxybispropane. The extract was 
washed with water (2.times.), dried, filtered and evaporated. The residue 
was co-evaporated with methylbenzene (2.times.), yielding 6.6 parts (60%) 
of ethyl 
(E+Z)-[[5-[[(2-ethoxy-2-oxoethoxy)imino]phenylmethyl]-2-nitrophenyl]methyl 
]glycine (interm. 16). 
(e) A mixture of 6.6 parts of intermediate (16), 4 parts of a solution of 
thiophene in methanol and 200 parts of ethanol was hydrogenated at normal 
pressure and at room temperature with 2 parts of platinum-on-charcoal 
catalyst 5%. After the calculated amount of hydrogen was taken up, the 
catalyst was filtered off and the filtrate was evaporated. The residue was 
co-evaporated with methylbenzene, yielding 5.9 parts (96.4%) of ethyl 
(E+Z)-N-[[2-amino-5-[[(2-ethoxy-2-oxoethoxy)imino]phenylmethyl]phenyl]meth 
yl]glycine (interm. 17). 
In a similar manner there were also prepared: 
ethyl 
(E)-N-[[2-amino-5-[[[[6-(cyclohexylmethylamino)-6-oxohexyl]oxy]imino]pheny 
lmethyl]phenyl]methyl]glycine (interm. 18) and 
ethyl 
(E+Z)-5-[[[[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]phenylmet 
hylene]amino]oxy]pentanoate (interm. 19). 
Example 4 
To a suspension of 39.3 parts of intermediate (12) in 395 parts of 
2-methyl-2-propanol there were added 23 ml of a solution of potassium 
hydroxide in ethanol and 23.1 parts of ethyl 2-propenoate. The whole was 
stirred for 3 days at 40.degree. C. The reaction mixture was filtered and 
the filtrate was evaporated. The residue was purified by column 
chromatography (silica gel; CH.sub.2 Cl.sub.2 /CHOH 98:2). The eluent of 
the desired fraction was evaporated, yielding 29.9 parts (57.4%) of ethyl 
(E+Z)-3-[[[[3-(hydroxymethyl)-4-nitrophenyl]phenylmethylene]amino]oxy]prop 
anoate (interm. 20). 
Following the reaction procedure described in Example 3(c), (d) and (e), 
intermediate (20) was converted into ethyl 
(E+Z)-3-[[[[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]phenylmet 
hylene]amino]oxy]propanoate (interm. 21). 
Example 5 
(a) To a stirred mixture of 20 parts of intermediate (3) in 98 parts of 
pyridine, there were added 4.45 parts of hydroxylamine monohydrochloride. 
The whole was refluxed for a few hours and was then evaporated. The 
residue was purified by column chromatography (silica gel; CHCl.sub.3 
/CH.sub.3 OH 98:2). The eluent of the desired fraction was evaporated and 
the residue was co-evaporated with ethanol (3.times.) and methylbenzene 
(1.times.). The product was chromatographed again (silica gel; CHCl.sub.3 
/CH.sub.3 OH 100:0.fwdarw.98:2). Evaporation of the eluent yielded 6.4 
parts (30.7%) 
(E+Z)-[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]phenylmetha 
none, oxime (interm. 22). 
(b) To a stirred mixture of 6.4 parts of intermediate (22) in 44 parts of 
dimethyl sulfoxide, there were added 3.29 parts of potassium carbonate and 
4.53 parts of 2-chloro-N-cyclohexyl-N-methylacetamide. Stirring was 
continued overnight at room temperature. The reaction mixture was poured 
into NaCl (sat.) and the product was extracted with dichloromethane. The 
extract was dried, filtered and evaporated, yielding 10 parts (100%) of 
(E+Z)-N-cyclohexyl-N-methyl-2-[[[[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)ox 
y]methyl]phenyl]phenylmethylene]amino]oxy]acetamide (interm. 23). 
(c) A solution of 12.55 parts of intermediate (23) in 200 parts of methanol 
was treated with 0.45 parts of 4-methylbenzenesulfonic acid and stirred at 
room temperature. The reaction mixture was neutralized with sodium 
carbonate and stirred for 10 min. The whole was filtered and the filtrate 
was evaporated. The residue was purified by column chromatography (silica 
gel; CHCl.sub.3 /CH.sub.3 OH 98:2). The eluent of the desired fractions 
was evaporated and the residue was co-evaporated with ethanol (2.times.) 
and with methylbenzene (2.times.), yielding 8.6 parts (82.2%) of 
(E+Z)-N-cyclohexyl-2-[[[[3-(hydroxymethyl)-4-nitro-phenyl]phenylmethylene] 
amino]oxy]-N-methylacetamide (interm. 24). Following the reaction procedure 
described in Example 3 (c), (d) and (e), intermediate (24) was converted 
into ethyl 
(E+Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]phenylm 
ethyl]phenyl]methyl]glycine (interm. 25). In a similar manner there was 
also prepared ethyl (E+Z)-4-[[[[4-amino-3 
-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]phenylmethylene]amino]oxy]buta 
noate (interm. 26). 
Example 6 
(a) To a cooled (10.degree. C.) mixture of 12.96 parts of a dispersion of 
sodium hydride in mineral oil (50%) in 801 parts of tetrahydrofuran there 
were added 60.5 parts of ethyl (diethoxyphosphinyl)acetate under a 
nitrogen atmosphere. After stirring for 20 min at 10.degree.-15.degree. 
C., there was added a solution of 42 parts of intermediate (3) in 45 parts 
of tetrahydrofuran under nitrogen. Stirring was continued overnight at 
60.degree. C. The reaction mixture was poured into ice-water and the 
product was extracted with dichloromethane. The extract was dried, 
filtered and evaporated and the residue was co-evaporated with 
methylbenzene, yielding 55 parts (100%) of ethyl 
(E+Z)-3-[4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]-3-phenyl 
-2-propenoate (interm. 27). 
(b) A mixture of 50.6 parts of intermediate (27), 2.3 parts of 
4-methylbenzenesulfonic acid and 395 parts of methanol was stirred for 20 
hours at room temperature. The reaction mixture was neutralized with 
sodium carbonate and stirred for 5 min. The whole was filtered and the 
filtrate was evaporated. The residue was dissolved in dichloromethane and 
this solution was washed with water, dried, filtered and evaporated. The 
residue was purified by column chromatography (silica gel; CH.sub.2 
Cl.sub.2). The eluent of the desired fraction was evaporated, yielding 28 
parts (69.5%) of ethyl 
(E+Z)-3-[3-(hydroxymethyl)-4-nitrophenyl]-3-phenyl-2-propenoate (interm. 
28). 
(c) To a cooled (0.degree.-5.degree. C.) solution of 28 parts of 
intermediate (28) and 9.7 parts of N,N-diethylethanamine in 665 parts of 
dichloromethane there were added dropwise 10.4 parts of methanesulfonyl 
chloride. After stirring for 1/2 hour at 0.degree.-5.degree. C., the 
reaction mixture was washed with water, dried, filtered and evaporated. 
The residue was purified by column chromatography (silica gel; CH.sub.2 
Cl.sub.2). The eluent of the desired fraction was evaporated and the 
residue was co-evaporated with methylbenzene, yielding 27 parts (77.4%) of 
ethyl 
(E+Z)-3-[3-[[(methylsulfonyl)oxy]methyl]-4-nitrophenyl]-3-phenyl-2-propeno 
ate (interm. 29). 
(d) To a solution of 27 parts of intermediate (29) in 237 parts of 
acetonitrile, there were added successively 14 parts of ethyl glycine 
monohydrochloride and 17 parts of N,N-diethylethanamine. The whole was 
stirred overnight at 50.degree. C. and then evaporated. The residue was 
taken up in dichloromethane. This solution was washed with water, dried, 
filtered and evaporated, yielding 26 parts (94.1%) of ethyl 
(E+Z)-3-[3-[[(2-ethoxy-2-oxoethyl)amino]methyl]-4-nitrophenyl]-3-phenyl-2- 
propenoate (interm. 30). 
(e) A mixture of 26 parts of intermediate (30), 18 parts of iron powder, 
17.4 parts of ammonium chloride, 596 parts of trichloromethane and 200 
parts of water was refluxed for 2 days. The reaction mixture was filtered 
over diatomaceous earth. The trichloromethane layer of the filtrate was 
separated, dried, filtered and evaporated. The residue was purified by 
column chromatography (silica gel; CH.sub.2 Cl.sub.2 /CH.sub.3 OH 99:1). 
The eluent of the desired fraction was evaporated and the residue was 
co-evaporated with methylbenzene, yielding 18 parts (72.4%) of ethyl 
(E+Z)-3-[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]-3-phenyl-2- 
propenoate (interm. 31). 
(f) A mixture of 13.2 parts of intermediate (30) and 119 parts of ethanol 
was hydrogenated at normal pressure and room temperature with 2 parts of 
platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen 
was taken up, the catalyst was filtered off and the filtrate was 
evaporated. The residue was purified by column chromatography (silica gel; 
CHCl.sub.3 /C.sub.2 H.sub.5 OH 98:2). The eluent of the (E)-isomer 
fraction was evaporated, yielding 4.3 parts (35.1%) of ethyl 
(E)-3-[4-amino-3-[[(2-ethoxy-2-oxoethyl)-amino]methyl]phenyl]-3-phenyl-2-p 
ropenoate (interm. 32). 
(g) To a cooled (0.degree.-5.degree. C.) solution of 39.1 parts of 
intermediate (28), 18.2 parts of N,N-diethylethanamine and 333 parts of 
dichloromethane there was added dropwise a solution of 16.5 parts of 
methanesulfonyl chloride in 40 parts of dichloromethane. After stirring 
for 15 min at 0.degree.-5.degree. C., the reaction mixture was poured into 
ice-water. The organic layer was separated, dried, filtered and 
evaporated. The residue was stirred with activated charcoal in 
1,1'-oxybisethane. This solution was filtered and concentrated. The 
crystallized product was filtered off and purified by column 
chromatography (silica gel; CHCl.sub.3 /C.sub.2 H.sub.5 OH 98:2). The 
eluent of the desired fraction was evaporated and the residue was 
crystallized from 1,1'-oxybisethane (2x). The product was filtered off and 
dried, yielding 16.8 parts (34.5%) of ethyl 
(Z)-3-[3-[[(methylsulfonyl)oxy]methyl]-4-nitrophenyl]-3-phenyl-2-propenoat 
e; mp. 87.8.degree. C. (interm. 33). 
Following the reaction procedures described in steps (d) and (f) 
hereinbefore, intermediate (33) was converted into ethyl 
(Z)-3-[4-amino-3-[[(2-ethoxy-2-oxoethyl)amino]methyl]phenyl]-3-phenyl-2-pr 
openoate (interm. 34). 
Example 7 
(a) To a stirred amount of 1076 parts of N,N-dimethylacetamide there were 
added successively 63.24 parts of a dispersion of sodium hydride in 
mineral oil (50%) and a solution of 92.46 parts of 
4-fluorobenzeneacetonitrile in 47 parts of N,N-dimethylacetamide. After 
hydrogen evolution had ceased, there were added dropwise 9.85 parts of 
N,N-di[2-(2-methoxyethoxy)ethyl]-2-(2-methoxyethoxy)ethanamine and a 
solution of 179.19 parts of intermediate (1) in 94 parts of 
N,N-dimethylacetamide. The mixture was stirred for 15 min. and then 
partitioned between ice-water and dichloromethane. After neutralization 
with formic acid, the product was extracted with dichloromethane. The 
extract was dried, filtered and concentrated, yielding theoretically 244.5 
parts (100%) of 
.alpha.-(4-fluorophenyl)-4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl] 
benzeneacetonitrile in solution (interm. 35). 
(b) A mixture of 244.2 parts of intermediate (35), 100.9 parts of sodium 
carbonate and 1316 parts of N,N-dimethylacetamide was aerated at room 
temperature for 48 hours, while stirring. The reaction mixture was poured 
into 3000 parts of water and the whole was extracted with 
2,2'-oxybispropane. The formed solid was filtered off, recrystallized from 
2-propanol and dried in vacuo, yielding a first fraction of 58.5 parts 
(24.7%) of product. The organic layer of the filtrate was separated, 
dried, filtered and evaporated. The residue was stirred in hexane, 
filtered off and dried, yielding an additional 157 parts (66.2%) of 
product. Total yield: 215.5 parts (90.9%) of (4-fluorophenyl) 
[4-nitro-3-[[(tetrahydro-2H-2-pyranyl)oxy]methyl]phenyl]methanone; mp. 
105.4.degree. C. (interm. 36). Following the reaction procedures described 
in Example 1 (d), (e); Example 3 (d) and Example 2 (b), intermediate (36) 
was converted into ethyl 
N-[[2-amino-5-(4-fluorobenzoyl)phenyl]methyl]glycine (interm. 37). 
Similarly, following the reaction procedures described in Example 1 (d); 
Example 5 (a), (b); Example 1 (e); Example 2 (a) and Example 1 (g), 
intermediate (36) was also converted into ethyl 
(E)-N-[[2-amino-5-[[[2-[(cyclohexyl)methylamino]-2-oxoethoxy]imino](4-fluo 
rophenyl)methyl]phenyl]methyl]glycine (interm. 38). 
Following the reaction procedures described in Example 1(d), (e); Example 
2(a) and (b), intermediate (36) was converted into ethyl 
(E+Z)-N-[[2-amino-5-[[[2-[(cyclohexyl)methylamino]-2-oxoethoxy]imino](4-fl 
uorophenyl)methyl]phenyl]methyl]glycine (interm. 39). 
Example 8 
(a) To a stirred and cooled (&lt;15.degree. C.) mixture of 134 parts of 
potassium hydroxide and 940 parts of pyridine were added portionwise 92 
parts of 2-nitrobenzenemethanol. Next there were added 132.5 parts of 
4-methoxybenzeneacetonitrile and stirring was continued for 4 hours at 
room temperature. The reaction mixture was diluted with 3000 parts of 
ice-water and the whole was acidified with 1270 parts of hydrochloric 
acid. The precipitate was filtered off, stirred overnight in methylbenzene 
and dried in vacuo at 60.degree. C., yielding 128.8 parts (50.7%) of 
.alpha.-[4-(hydroxyimino)-3-(hydroxymethyl)-2,5-cyclohexadien-1-ylidene]-4 
-methoxybenzeneacetonitrile (interm. 40). 
(b) To a stirred solution of 340 parts of potassium hydroxide in 1700 parts 
of water there were added 66.4 parts of intermediate (40). Next a solution 
of 394 parts of hydrogen peroxide in 500 parts of water was added 
dropwise. Stirring was continued for 3 hours and then the product was 
extracted with a mixture of trichloromethane and methanol (90:10). The 
extract was dried, filtered and evaporated. The residue was purified by 
column chromatography (silica gel; CHCl.sub.3). The eluent of the desired 
fractions was collected and the residue was stirred in 2,2'-oxybispropane. 
The product was filtered off and dried, yielding 21.7 parts (32.8%) of 
[3-(hydroxymethyl)-4-nitrophenyl](4-methoxyphenyl)-methanone; mp. 
116.5.degree. C. (interm. 41). 
Following the reaction procedure described in Example 3 (c), (d) and (e), 
intermediate (41) was converted into ethyl 
N-[[2-amino-5-(4-methoxybenzoyl)phenyl]methyl]glycine (interm. 42). 
Example 9 
(a) A mixture of 14.7 parts of 5-chloro-2-nitrobenzaldehyde, 13.3 parts of 
trimethoxymethane, 0.15 parts of 4-methylbenzenesulfonic acid and 64 parts 
of methanol was stirred at reflux temperature. After cooling, the reaction 
mixture was neutralized with sodium carbonate and stirred for 5 min. The 
whole was filtered and the filtrate was evaporated, yielding 18.3 parts 
(99.7%) of 4-chloro-2-(dimethoxymethyl)-1-nitrobenzene (interm. 43). 
(b) A solution of 78.1 parts of sodium hydrogen sulfite in 400 parts of 
water was stirred for 15 min at 20.degree. C. under a nitrogen atmosphere. 
After cooling to -5.degree. C., there were added portionwise 100 parts of 
4-bromobenzaldehyde and stirring was continued for 20 min at 10.degree. C. 
Next there were added portionwise 65.3 parts of morpholine and, after 
stirring for 15 min, a solution of 26.9 parts of sodium cyanide in 90 
parts of water. The mixture was stirred for 22 hours at 50.degree. C. and 
was then treated with 8.7 parts of a sodium hydroxide solution 50%. The 
product was filtered off, washed with water and dried in vacuo at 
50.degree. C., yielding 138.5 parts (98.5%) of 
.alpha.(4-bromophenyl)-4-morpholineacetonitrile (interm. 44). 
(c) To a stirred solution of 21.1 parts of a sodium hydride dispersion 50% 
in mineral oil in 940 parts of N,N-dimethylformamide there was added 
dropwise a solution of 112.5 parts of intermediate (44) in 207 parts of 
N,N-dimethylformamide under a nitrogen atmosphere. After stirring for 2 
hours and subsequent cooling to 0.degree.-5.degree. C., there was added 
dropwise a solution of 94.9 parts of intermediate (43) in 263 parts of 
N,N-dimethylformamide. Stirring was continued for 45 min at room 
temperature. The reaction mixture was poured into ice-water. The 
precipitate was filtered off and dissolved in 2,2'-oxybispropane. This 
solution was washed with water, dried and filtered. The filtrate was left 
to crystallize, yielding two crops of respectively 60.2 parts and 36.3 
parts of product. Addition of dichloromethane to the mother liquor yielded 
a third crop of 77.7 parts of product. Total yield: 174.2 parts (91.4%) of 
.alpha.-(4-bromophenyl)-.alpha.-[3-(dimethoxymethyl)-4-nitrophenyl]-4-morp 
holineacetonitrile; mp. 142.8.degree. C. (interm. 45). 
(d) To a stirred mixture of 390 parts of 2-propanol, saturated with 
hydrochloric acid and 350 parts of water there was added dropwise a 
solution of 172.4 parts of intermediate (45) in 361 parts of 1,4-dioxane. 
After refluxing for 3 hours and stirring at room temperature overnight, 
the precipitate was filtered off (*) and taken up in a mixture of methanol 
and dichloromethane. The whole was basified with NH.sub.4 OH (aq.), washed 
with water, dried, filtered and evaporated, yielding a first fraction of 
83 parts (62.2%) of product. The filtrate (*) was evaporated. The residue 
was taken up in water and the whole was extracted with dichloromethane. 
The extract was washed with water, dried, filtered, evaporated. The 
residue was co-evaporated with methylbenzene and stirred in 
2,2'-oxybispropane. The product was filtered off and dried in vacuo at 
40.degree. C., yielding an additional 4.5 parts (3.4%) of product. Total 
yield: 87.5 parts (65.6%) of 5-(4-bromobenzoyl)-2-nitro-benzaldehyde; mp. 
150.9.degree. C. (interm. 46). 
(e) To a stirred and cooled (ice-bath) solution of 83 parts of intermediate 
(46), 11.2 parts of cerium(III)chloride heptahydrate and 1540 parts of 
dimethyl sulfoxide there were added portionwise 2.5 parts of sodium 
tetrahydroborate. After stirring for 10 min, there was added an ammonium 
chloride solution. The product was successively extracted with 
2,2'-oxybispropane (3x) and with dichloromethane (2x). The combined 
extracts were washed with water, dried, filtered and evaporated. The 
residue was purified twice by column chromatography (silica gel; CH.sub.2 
Cl.sub.2 /CH.sub.3 OH 99.5:0.5). The eluent of the desired fraction was 
evaporated, yielding 56.4 parts (67.1%) of (4-bromophenyl) 
[3-(hydroxymethyl)-4-nitrophenyl]methanone (interm. 47). 
Following the reaction procedure described in Example 3 (c), (d) and (e), 
intermediate (47) was converted into ethyl 
N-[[2-amino-5-(4-bromobenzoyl)phenyl]methyl]glycine (interm. 48). 
In a similar manner there were also prepared: 
ethyl N-[[2-amino-5-(3-methoxybenzoyl)phenyl]methyl]glycine (interm. 49), 
ethyl N-[[2-amino-5-(4-methylbenzoyl)phenyl]methyl]glycine (interm. 50), 
ethyl N-[[2-amino-5-(3,4-dimethoxybenzoyl)phenyl]methyl]glycine (interm. 
51), 
ethyl [[2-amino-5-(4-chlorobenzoyl)phenyl]methyl]glycine (interm. 52). 
Following the reaction procedures described in Examples 5 (a), (b); Example 
3 (c), (d) and (e), intermediate (47) was also converted into ethyl 
(E+Z)-N-[[2-amino-5-[(4-bromophenyl)[[2-(cyclohexylmethylamino)-2-oxoethox 
y]imino]methyl]phenyl]methyl]glycine (interm. 53). 
Example 10 
(a) 106 Parts of N,N-dimethylformamide were added dropwise to 650 parts of 
aluminum chloride and the solution was stirred for 15 min at 75.degree. C. 
There were added portionwise 112 parts of 
3,4-dihydro-2(1H)-quinazolinethione and, after stirring for 15 min at 
75.degree. C., 136 parts of 3-pyridinylcarbonyl chloride hydrochloride. 
Stirring at 75.degree. C. was continued overnight and then the mixture was 
poured into 2500 parts of ice-water. The precipitate was filtered off and 
stirred for 13 hours in a mixture of ice-water and 1530 parts of a sodium 
hydroxide solution 50%. The product was filtered off, washed with water 
and dried, yielding 150 parts (82%) of (3-pyridinyl) 
(1,2,3,4-tetrahydro-2-thioxo-6-quinazolinyl)methanone; (decomp.) (interm. 
54). 
(b) A mixture of 2.7 parts of intermediate (54), 89 parts of 
tetrahydrofuran, 18.8 parts of N,N-dimethylformamide and 1.45 parts of 
iodomethane was stirred for 18 hours at room temperature. The reaction 
mixture was filtered and the filtrate was neutralized with ammonium 
hydroxide. The product was extracted with dichloromethane. The extract was 
dried, filtered and evaporated. The residue was purified by column 
chromatography (silica gel; CH.sub.2 Cl.sub.2 /CH.sub.3 OH(NH.sub.3) 
95:5). The eluent of the desired fraction was evaporated and the residue 
was crystallized from 2,2'-oxybispropane. The product was filtered off and 
dried, yielding 1.75 parts (61.8%) of 
[3,4-dihydro-2-(methylthio)-6-quinazolinyl] (3-pyridinyl)methanone; mp. 
155.8.degree. C. (interm. 55). 
(c) To a solution of 8.5 parts of intermediate (55) in 47 parts of 
N,N-dimethylformamide there were added 1.4 parts of a dispersion of sodium 
hydride in mineral oil (50%). After stirring for 20 min at room 
temperature, there was added dropwise a solution of 6.12 parts of methyl 
2-bromoacetate in 9.4 parts of N,N-dimethylformamide. Stirring at room 
temperature was continued for 1/2 hour. The reaction mixture was diluted 
with water and the product was extracted with methylbenzene. The organic 
layer was in its turn extracted with diluted hydrochloric acid. The 
aqueous layer was basified with sodium hydroxide and extracted with 
methylbenzene. The extract was dried, filtered and evaporated and the 
residue was purified by column chromatography (silica gel; CH.sub.3 
C.sub.6 H.sub.5 /CH.sub.3 CN 75:25). The eluent of the desired fraction 
was evaporated and the residue was crystallized from 1,1'-oxybisethane. 
The product was filtered off and dried, yielding 1.9 parts (13.3%) of 
methyl 
3.4-dihydro-2-(methylthio)-6-(3-pyridinylcarbonyl)-3-quinazolineacetate; 
mp. 113.6.degree. C. (interm. 56). 
Example 11 
(a) A mixture of 26.7 parts of ethyl 
N-[[5-(4-methylbenzoyl)-2-nitrophenyl]methyl]glycine (which is a precursor 
to intermediate 50 in Example 9), 6.25 parts of hydroxylamine 
monohydrochloride, 5.25 parts of potassium fluoride and 395 parts of 
ethanol was stirred for 22 hours at reflux temperature. The reaction 
mixture was evaporated and the residue was dissolved in ethyl acetate. The 
whole was washed with sodium hydrogen carbonate solution 10% and with 
water. The organic layer was dried, filtered and evaporated and the 
residue was purified by column chromatography (silica gel; CH.sub.2 
Cl.sub.2 /CH.sub.3 OH 98:2). The eluent of the E- and Z-isomer fractions 
was evaporated and the residue was crystallized from 2,2'-oxybispropane, 
yielding 3.7 parts of product. The mother liquor was evaporated and the 
residue was isomerized in a mixture of 1,4-dioxane and 2-propanol, 
saturated with HCl, by stirring overnight. The solvent was evaporated and 
the residue was stirred in water. After neutralizing with NaHCO.sub.3 10%, 
the product was extracted with dichloromethane. The extract was dried, 
filtered and evaporated and the residue was crystallized from 
2,2'-oxybispropane, yielding 2 additional fractions of resp. 3.6 parts and 
1.2 parts of product. The three fractions were recrystallized from a 
mixture of ethyl acetate and 2,2'-oxybispropane, yielding 5.3 parts (19%) 
of ethyl (E)-N-[[5-[(hydroxyimino) 
(4-methylphenyl)methyl]-2-nitrophenyl]methyl]glycine (interm. 57). 
(b) To a stirred mixture of 5.3 parts of intermediate (57) in 89 parts of 
tetrahydrofuran there were added 1.8 parts of 2-methyl-2-propanol, 
potassium salt and, after 5 min, 0.44 parts of 
N,N-di[2-(2-methoxyethoxy)ethyl]-2-(2-methoxyethoxy)ethanamine. Next there 
was added dropwise a solution of 3 parts of 
2-chloro-N-cyclohexyl-N-methyl-acetamide in 44.5 parts of tetrahydrofuran. 
Stirring was continued for 3 hours at room temperature. The reaction 
mixture was evaporated and the residue was taken up in water. The product 
was extracted with a mixture of dichloromethane and methanol (90:10). The 
extract was dried, filtered and evaporated. The residue was purified by 
column chromatography (silica gel; CH.sub.3 COOC.sub.2 H.sub.5 /hexane 
50:50). The eluent of the desired fraction was evaporated, yielding 5.7 
parts (77.6%) of ethyl 
(E)-N-[[5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](4-methylphenyl)m 
ethyl]-2-nitrophenyl]methyl]glycine (interm 58). 
(c) A mixture of 5.7 parts of intermediate (58), 2 parts of a solution of 
thiophene in methanol 4% and 119 parts of ethanol was hydrogenated at 
normal pressure and room temperature with 3 parts of platinum-on-charcoal 
catalyst 5%. After the calculated amount of hydrogen was taken up, the 
catalyst was filtered off and the filtrate was evaporated, yielding 5.1 
parts (94.6%) of ethyl 
(E)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](4-methyl 
phenyl)methyl]phenyl]methyl]glycine (interm. 59). 
Example 12 
(a) To a stirred and cooled (0.degree. C.; 2-propanone/dry ice) solution of 
54.4 parts of methyl 5-methyl-2-nitrobenzoate in 405 parts of acetic 
anhydride and 394 parts of acetic acid were added dropwise 110 parts of 
sulfuric acid and portionwise 83.6 parts of chromium(VI)oxide. Stirring 
was continued for 1/2 hour at 0.degree.-10.degree. C. and overnight at 
room temperature. The reaction mixture was poured into ice-water and the 
whole was treated with dichloromethane. The precipitate which formed, was 
filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 
80.degree. C., yielding 30.2 parts (48.1%) of product. The dichloromethane 
layer was separated and extracted with a sodium hydrogen carbonate 
solution and the aqueous extract was acidified with HCl 2N. The 
precipitate was filtered off and treated similarly as before, yielding an 
additional 5 parts (8.0%) of product. Total yield: 35.2 parts (56.1%) of 
2-nitro-1,5-benzenedicarboxylic acid, 1-methyl ester; mp. 197.5.degree. 
C. (interm. 60). 
From the dichloromethane layer there was also obtained methyl 
5-[bis(acetyloxy)methyl]-2-nitrobenzoate; mp. 102.3.degree. C. (interm. 
61). 
(b) To a cooled (-18.degree. C.; 2-propanone/dry ice) solution of 5.63 
parts of intermediate (60) in 44.5 parts of tetrahydrofuran there were 
added dropwise 10.7 parts of a solution of dimethylsulfide borane complex 
in tetrahydrofuran 2M. The mixture was allowed to warm to room temperature 
and was then refluxed for 2 hours. There were added 23.7 parts of methanol 
and refluxing was continued for 10 min. The reaction mixture was 
evaporated and the residue was taken up in 2,2'-oxybispropane. This 
solution was successively washed with water, Na.sub.2 CO.sub.3 5% and 
water and was then dried, filtered and evaporated. The residual syrup was 
left overnight to crystallize. The product was recrystallized from 
2,2'-oxybispropane, filtered off, washed with 2,2'-oxybispropane and dried 
in vacuo at room temperature, yielding 2.1 parts (39.8%) of product. 
Evaporation of the mother liquor yielded an additional 1.9 parts (36.0%) 
of product. Total yield: 4.0 parts (75.8%) of methyl 5 
-(hydroxymethyl)-2-nitrobenzoate; mp. 54.5.degree. C. (interm. 62). 
(c) A mixture of 1.9 parts of intermediate (62), 7.8 parts of 
manganese(IV)oxide and 133 parts of dichloromethane was stirred over 
weekend at room temperature. The reaction mixture was filtered over 
diatomaceous earth. To the filtrate there was added methylbenzene and the 
whole was filtered again. The filtrate was evaporated, yielding 1.42 parts 
(75.4%) of methyl 5-formyl-2-nitrobenzoate; mp. 76.7.degree. C. (interm. 
63). Hydrolysis of intermediate (61) in an aqueous acidic medium also 
yielded methyl 5-formyl-2-nitrobenzoate (interm. 63). 
(d) A mixture of 22 parts of intermediate (63), 8.4 parts of hydroxylamine 
monohydrochloride and 147 parts of pyridine was heated at 80.degree. C. 
for 2 hours. The solvent was evaporated and the residual oil was 
partitioned between water and 2,2'-oxybispropane. The organic layer was 
separated, washed successively with water, HCl 1N, water, NaHCO.sub.3 5% 
and water, and was then dried, filtered and evaporated. The residue was 
dried in vacuo at 60.degree. C., yielding 19.8 parts (80.3%) of methyl 
(E)-5-[(hydroxyimino)methyl]-2-nitrobenzoate; mp. 116.0.degree. C. 
(interm. 64). 
(e) To a refluxing mixture of 18.3 parts of intermediate (64), 12.37 parts 
of sodium tetrahydroborate and 320 parts of tetrahydrofuran there were 
added dropwise 56.9 parts of methanol. After refluxing for 1 hour, the 
reaction mixture was poured into ice-water. The whole was acidified with 
hydrochloric acid 2N and then extracted with dichloromethane. The extract 
was washed successively with water, NaHCO.sub.3 5% and water, and was then 
dried, filtered and evaporated. The residue was purified by column 
chromatography (silica gel; CH.sub.2 Cl.sub.2 /CH.sub.3 OH/THF 90:5:5). 
The eluent of the desired fraction was evaporated and the residue was 
washed with 2,2'-oxybispropane and dried in vacuo at 60.degree. C., 
yielding 12.6 parts (78.6%) of (E)-3-(hydroxymethyl)-4-nitro-benzaldehyde, 
oxime; mp. 128.9.degree. C. (interm. 65). 
Example 13 
(a) To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of 
ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 
100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following 
the procedure described in Example 9 or Example 14. After stirring for 1/2 
hour, there were added portionwise 9.4 parts of sodium 
cyanotrihydroborate. Stirring was continued for 1/2 hour at room 
temperature. The reaction mixture was evaporated and the residue was 
partitioned between water and dichloromethane. The organic layer was 
separated, washed with water, dried, filtered and evaporated. The residue 
was purified by column chromatography (silica gel; CH.sub.2 Cl.sub.2 
/C.sub.2 H.sub.5 OH 99:1). The eluent of the desired fraction was 
evaporated, yielding 71 parts (56.2%) of ethyl 
N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66). 
(b) A mixture of 68 parts of intermediate (66), 14 parts of hydroxylamine 
monohydrochloride, 11.6 parts of potassium fluoride and 790 parts of 
ethanol was stirred for 3 hours at reflux temperature. After cooling, the 
reaction mixture was filtered. The precipitate was rinsed with ethanol and 
the combined filtrates were evaporated. The residue was taken up in a 
mixture of ethyl acetate and water and the whole was neutralized with 
NaHCO.sub.3 10%. The organic layer was separated, washed with water, 
dried, filtered and evaporated, yielding 51.4 parts of product (E/Z isomer 
mixture) (1). From the aqueous layer, a precipitate was filtered off, 
which was washed with 2,2'-oxybispropane and dried in vacuo at 60.degree. 
C., yielding an additional 8.7 parts of product (mainly Z-isomer) (2). 
Total yield: 60.1 parts (86.1%) of (E/Z) isomer mixture, which can be 
separated by column chromatography. A fraction of (1) was crystallized 
from 2-propanone to obtain a small amount of pure ethyl (E)-N-[[5-[( 
3-bromophenyl) (hydroxyimino)methyl]-2-nitrophenyl]methyl]glycine; mp. 
131.2.degree. C. (interm. 68). Crystallization of (2) from ethyl acetate 
yielded a small amount of pure ethyl (Z)-N-[[5-[(3-bromophenyl) 
(hydroxyimino)methyl]-2-nitrophenyl]methyl]glycine; mp. 149.8.degree. C. 
(interm. 67). 
(c) To a stirred solution of 5.3 parts of intermediate (68) in 89 parts of 
tetrahydrofuran there were added 1.46 parts of 2-methyl-2-propanol, 
potassium salt and, after 5 min, 0.38 parts of 
2-(methoxyethoxy)-N,N-bis[2-(methoxyethoxy)ethyl]ethanamine and a solution 
of 2.46 parts of chloro-N-cyclohexyl-N-methylacetamide in some 
tetrahydrofuran. Stirring was continued for 20 min. The reaction mixture 
was evaporated and the residue was stirred in water. The product was 
extracted with a mixture of ethanol and dichloromethane (10:90). The 
extract was dried, filtered and evaporated and the residue was purified by 
column chromatography (silica gel; hexane/CH.sub.3 COOC.sub.2 H.sub.5 
50:50). The eluent of the desired fraction was evaporated and the residue 
was co-evaporated with methylbenzene, yielding 5 parts (70.7%) of ethyl 
(E)-N-[[5-[(3-bromophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]me 
thyl]-2-nitrophenyl]methyl]glycine (interm. 69). 
(d) A mixture of 5 parts of intermediate (69), 2 parts of a solution of 
thiophene in methanol 4% and 158 parts of ethanol was hydrogenated 
overnight at normal pressure and room temperature with 2 parts of 
palladium-on-charcoal catalyst 10%. After the calculated amount of 
hydrogen was taken up, the catalyst was filtered off and the filtrate was 
evaporated. The residue was co-evaporated with methylbenzene, yielding 4.6 
parts (96.7%) of ethyl 
(E)-N-[[2-amino-5-[(3-bromophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy] 
imino]methyl]phenyl]methyl]glycine (intermediate 70). 
In a similar manner there were also prepared: 
ethyl 
(Z)-N-[[2-amino-5-[[[(3-bromophenyl)-2-(cyclohexylmethylamino)-2-oxoethoxy 
]imino]methyl]phenyl]methyl]glycine (interm. 71); 
ethyl 
(E)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]-[4-(trif 
luoromethyl)phenyl]methyl]phenyl]methyl]glycine (interm. 72); 
ethyl 
(E+Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]-(3-met 
hylphenyl)methyl]phenyl]methyl]glycine (interm. 73); 
ethyl 
(Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]-(3-methy 
lphenyl)methyl]phenyl]methyl]glycine (interm. 74); 
ethyl 
(Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino]-[4-(trif 
luoromethyl)phenyl]methyl]phenyl]methyl]glycine (interm. 75); 
ethyl 
(Z)-N-[[2-amino-5-[(3-chlorophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy 
]imino]methyl]phenyl]methyl]glycine (interm. 76); 
ethyl 
(E)-N-[[2-amino-5-[(3-chlorophenyl)[[2-(cyclohexylmethylamino)-2-oxoethoxy 
]imino]methyl]phenyl]methyl]glycine (interm. 77); 
ethyl 
(E)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](3-methox 
yphenyl)methyl]phenyl]methyl]glycine (interm. 78); and 
ethyl 
(Z)-N-[[2-amino-5-[[[2-(cyclohexylmethylamino)-2-oxoethoxy]imino](2-thieny 
l)methyl]phenyl]methyl]glycine (interm. 79). 
Example 14 
(a) 81.6 Parts of a dispersion of sodium hydride in mineral oil (50%) were 
stirred in hexane to remove the oil. The solvent was decanted and to the 
residue there were added 825 parts of dimethyl sulfoxide. While stirring 
at room temperature, there were added dropwise a solution of 92.3 parts of 
2-thiopheneacetonitrile in 138 parts of dimethyl sulfoxide (when 
necessary, cooling on ice) and next a solution of 173.7 parts of 
intermediate (43) in 138 parts of dimethyl sulfoxide. Stirring at room 
temperature was continued overnight. The crude reaction mixture was used 
as such for further synthesis. Yield: 238.8 parts (100%) of 
.alpha.-[3-(dimethoxymethyl)-4-nitrophenyl]-2-thiopheneacetonitrile 
(interm. 80). 
(b) A mixture of 238.8 parts of intermediate (80), 40.8 parts of a 
dispersion of sodium hydride in mineral oil (50%) and 1100 parts of 
dimethyl sulfoxide was stirred at room temperature, while air was bubbled 
through for a week and oxygen for 40 hours. The reaction mixture was 
poured into ice-water and the product was extracted with dichloromethane. 
The extract was dried, filtered and evaporated. The residue was stirred in 
water and the whole was re-extracted with dichloromethane. The extract was 
dried, filtered and evaporated and the residue was purified by column 
chromatography (silica gel; CH.sub.2 Cl.sub.2). The eluent of the desired 
fraction was evaporated, yielding 181.5 parts (78.7%) of 
[3-(dimethoxymethyl)-4-nitrophenyl](2-thienyl)methanone (interm. 81). 
(c) A mixture of 181.5 parts of intermediate (81), 468 parts of 2-propanol 
saturated with hydrochloric acid, 371 parts of 1,4-dioxane and 240 parts 
of water was stirred for 18 hours at reflux temperature. After cooling, 
the precipitate was filtered off, washed with 2-propanol and 
2,2'-oxybispropane and dried, yielding 89.7 parts (58.2%) of product. The 
filtrate was concentrated to obtain further precipitation. The precipitate 
was filtered off, washed successively with 2-propanol, diluted NH.sub.4 
OH, water, 2-propanol and 2,2'-oxybispropane, and dried, yielding an 
additional 25.4 parts (16.5%) of product. Total yield: 115.1 parts (74.7%) 
of 2-nitro-5-(2-thienylcarbonyl)benzaldehyde (interm. 82). 
In a similar manner there was also prepared 
2-nitro-5-[4-(trifluoromethyl)benzoyl]benzaldehyde; mp. 119.5.degree. C. 
(interm. 83) 
B. Preparation of the final compounds 
Example 15 
To a stirred and cooled (0.degree.-5.degree. C.) solution of 3.19 parts of 
intermediate (7) in 40 parts of ethanol there was added dropwise a 
solution of 1.13 parts of bromocyanide in 8 parts of ethanol. Stirring was 
continued overnight at room temperature and for 3 hours at reflux 
temperature. After cooling, the reaction mixture was treated with 
methanol, saturated with ammonia. The precipitate was filtered off, washed 
with ethanol, stirred in water and boiled in ethanol. The impure product 
was filtered off, washed with ethanol and 2,2'-oxybispropane and 
recrystallized from a mixture of 16 parts of methanol and 75 parts of 
N,N-dimethylformamide. The product was filtered off, washed with methanol 
and 2,2'-oxybispropane and dried in vacuo at 70.degree.-75.degree. C., 
yielding 1.08 parts (36.3%) of 
7-benzoyl-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one; mp. &gt;300.degree. 
C. (comp. 1). 
Example 16 
To a stirred and cooled (0.degree. C.) solution of 9.5 parts of 
intermediate (25) in 160 parts of ethanol there was added dropwise a 
solution of 2.08 parts of bromocyanide in ethanol. Stirring was continued 
for 1/2 hour at 0.degree. C., for 1 hour at room temperature and for 2 
hours at reflux temperature. The reaction mixture was evaporated and the 
residue was partitioned between NaCl (sat.) and dichloromethane. After 
neutralization with a sodium hydroxide solution, the product was extracted 
with dichloromethane. The extract was dried, filtered and evaporated. The 
residue was purified twice by column chromatography (silica gel; 
CHCl.sub.3 /CH.sub.3 OH/CH.sub.3 OH(NH.sub.3) 98:1:1; HPLC; silica gel; 
CHCl.sub.3 /CH.sub.3 OH 93:7). The first and second fraction were 
separately evaporated and the residues were crystallized from ethyl 
acetate. The products obtained from both fractions were filtered off, 
washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo at 
60.degree. C., yielding resp. 2.92 parts (32.2%) of 
(Z)-N-cyclohexyl-N-methyl-2-[[ 
[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)methylene]am 
ino]-oxy]-acetamide; mp. 173.4.degree. C. (comp. 10) and 2.4 parts (26.3%) 
of 
(E)-N-cyclohexyl-N-methyl-2-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- 
b]quinazolin-7-yl)methylene]amino]oxy]acetamide; mp. 202.2.degree. C. 
(comp. 9). 
Example 17 
To a stirred suspension of 16 parts of compound (1) in 440 parts of 
pyridine there were added 4.17 parts of hydroxylamine monohydrochloride. 
Stirring was continued for 4 hours at reflux temperature. The precipitate 
was filtered off (*), washed with pyridine, stirred in water and washed 
successively with water, 2-propanol and 2,2'-oxybispropane. The product 
was filtered off and dried in vacuo at 100.degree. C., yielding a first 
fraction of 9.6 parts (57.1%) of product (E/Z=75/25); mp. &gt;300.degree. C. 
The filtrate (*) was evaporated and the residue was treated in the same 
manner as the precipitate hereinbefore, yielding an additional 5.5 parts 
(32.7%) of product. Total yield: 15.1 parts (89.8%) of 
(E+Z)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2 
(1H)-one (comp. 2). 
Example 18 
A mixture of 2.01 parts of compound (2), 6 parts of 2-propanol, saturated 
with hydrochloric acid and 62 parts of 1,4-dioxane was stirred for 4 hours 
at room temperature. Gaseous hydrogen chloride was bubbled through the 
reaction mixture, while cooling in an ice-bath. Stirring was continued 
overnight at room temperature. The precipitate was filtered off, washed 
with 2,2'-oxybispropane and stirred in water. The aqueous layer was 
treated with an ammonium hydroxide solution and stirred for 10 min. The 
precipitate filtered off, washed with water and purified by column 
chromatography (HPLC; silica gel; H.sub.2 O/CH.sub.3 OH (0.5% 
(NH.sub.4).sub.2 CO.sub.3)). The eluent of the desired fractions was 
evaporated and the residue was stirred in water. The product was filtered 
off, washed with water and dried in vacuo at 70.degree.-90.degree. C., 
yielding 0.867 parts (41.3%) of 
(E)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2(1 
H)-one; mp. &gt;300.degree. C. (comp. 3). 
Example 19 
(a) A mixture of 8.5 parts of compound (2), 110 parts of dimethyl 
sulfoxide, 8.36 parts of 1,1-dimethylethylchlorodimethylsilane and 7.56 
parts of 1H-imidazole was stirred for 10 min. at 60.degree. C. The 
reaction mixture was poured into 500 parts of water and the whole was 
extracted with 2,2'-oxybispropane. The extract was dried, filtered and 
evaporated. The residue was crystallized from methanol, washed with 
methanol and dried, yielding a first fraction of 7.1 parts (60.9%) of 
product. Evaporation of the mother liquor yielded an additional 4.6 parts 
(39.5%) of product. 
Total yield: 11.7 parts (.apprxeq.100%) of 
(E+Z)-7-[[[(1,1-dimethylethyl)dimethylsiloxy]imino]phenylmethyl]-3,5-dihyd 
roimidazo[2,1-b]quinazolin-2(1H)-one; mp. 254.7.degree. C. (comp. 5). 
(b) Compound (5) was separated into its pure E and Z isomers by column 
chromatography (HPLC; silicagel .gamma.aminopropyl; (C.sub.2 
H.sub.5).sub.2 O)/CH.sub.3 CN/THF/H.sub.2 O 46.5:5:46.5:2). The eluent of 
the separated E- and Z-isomer fractions was evaporated and the residues 
were chromatographed again (HPLC; .gamma.-aminopropyl; CH.sub.2 Cl.sub.2 
/CH.sub.3 OH 96:4). The products were dried in vacuo, yielding 3.3 parts 
(19.7%) of 
(E)-7-[[[[(1,1-dimethylethyl)dimethylsilyl]oxy]imino]phenylmethyl]-3,5-dih 
ydroimidazo[2,1-b]quinazolin-2(1H)-one; mp. 221.0.degree. C. (comp. 18) and 
0.9 parts (5.4%) of 
(Z)-7-[[[[(1,1-dimethylethyl)dimethylsilyl]oxy]imino]phenylmethyl]-3,5-dih 
ydroimidazo[2,1-b]quinazolin-2(1H)-one; mp. &gt;250.degree. C. (decomp.) 
(comp. 19). 
(c) To a mixture of 0.103 parts of compound (19) and 4.45 parts of 
tetrahydrofuran there were added 0.53 parts of a solution of 
tetrabutylammonium fluoride in tetrahydrofuran 1M. After stirring for 10 
min at room temperature, the reaction mixture was evaporated and the 
residue was taken up in water. The solid was filtered off, washed with 
water and boiled in methanol. The product was filtered off, washed with 
methanol and 2,2'-oxybispropane and dried in vacuo at 80.degree. C., 
yielding 0.033 parts (35.9%) of 
(Z)-3,5-dihydro-7-[(hydroxyimino)phenylmethyl]imidazo[2,1-b]quinazolin-2-( 
1H)-one; mp. &gt;250.degree. C. (comp. 15). 
Example 20 
(a) A solution of 0.3 parts of compound (6), 2.5 parts of a sodium 
hydroxide solution 1N and 2 parts of methanol was stirred for 1 hour at 
room temperature. There were added 2.5 parts of a hydrochloric acid 
solution 1N. The precipitated product was filtered off, washed with water 
and methanol and crystallized from methanol. The product was filtered off, 
washed with methanol and 2,2'-oxybispropane and dried in vacuo at 
60.degree. C., yielding 0.15 parts (53.7%) of 
(E+Z)-2-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)me 
thylene]amino]oxy]acetic acid; mp. 253.0.degree. C. (E/Z=75/25) (comp. 7). 
(b) Compound 56 was prepared from compound 37 in a similar manner, but 
without organic solvent (methanol) and with stirring at 60.degree. C. for 
1 hour. 
Example 21 
(a) A mixture of 10.7 parts of compound (28), 78.4 parts of a sodium 
hydroxide solution 1N and 59.3 parts of ethanol was stirred overnight at 
room temperature. The aqueous layer was extracted with dichloromethane and 
then acidified to pH 5 with HCl 2N. The product was filtered off, washed 
with water, co-evaporated with a mixture of methanol and methylbenzene and 
with methylbenzene, boiled in methanol, washed with a mixture of methanol 
and 2,2'-oxybispropane and dried at 60.degree. C., yielding 2.1 parts 
(21.4%) of 
(E+Z)-4-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)me 
thylene]amino]oxy]butanoic acid; mp. 268.5.degree. C. (comp. 31). 
(b) To a stirred solution of 1.9 parts of compound (31) in 303 parts of 
dimethyl sulfoxide there were added 1.5 parts of 
1,1'-carbonylbis[1H-imidazole]. After stirring for 10 min at room 
temperature, for 2 hours at 60.degree. C. and for 1/2 hour at 80.degree. 
C., there were added 4.7 parts of N-methylcyclohexanamine. Stirring was 
continued overnight at 80.degree. C. The reaction mixture was poured into 
water and the whole was acidified to pH 5 with acetic acid 10%. The 
product was extracted with dichloromethane and the extract was washed with 
water, dried, filtered and evaporated. The residue was purified twice by 
column chromatography (silica gel; CH.sub.3 COOC.sub.2 H.sub.5 /CH.sub.3 
OH 95:5; CH.sub.2 Cl.sub.2 /CH.sub.3 OH 95:5). The eluent of the desired 
fraction was evaporated and the residue was co-evaporated with 
methylbenzene. The E and Z isomers were separated by HPLC (Licroprep 
amino; CHCl.sub.3). The two fractions were evaporated and the residues 
stirred in water and dried in vacuo at 70.degree. C., yielding 0.05 parts 
(2.1%) of 
(E)-N-cyclohexyl-N-methyl-4-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- 
b]quinazolin-7-yl)methylene]amino]oxy]butanamide (comp. 33) and 0.03 parts 
(1.3%) of 
(Z)-N-cyclohexyl-N-methyl-4-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- 
b]quinazolin-7-yl)methylene]amino]oxy]butanamide (comp. 34). 
Example 22 
A mixture of 1.96 parts of intermediate (56), 20 parts of ammonium acetate 
and 2.1 parts of acetic acid was stirred for 45 min at 130.degree. C. The 
reaction mixture was diluted with water. The precipitate was filtered off, 
stirred in N,N-dimethylformamide and methanol and was then dissolved in 20 
ml of formic acid. After filtration, there was added tetrahydrofuran to 
enhance precipitation. The product was filtered off and dried in vacuo at 
85.degree. C., yielding 0.9 parts (56.0%) of 
1,5-dihydro-7-(3-pyridinylcarbonyl)imidazo[2,1-b]quinazolin-2(3H)-one; mp. 
275.1.degree. C. (comp. 39). 
Example 23 
To a mixture of 1 part of compound (65) and 9.4 parts of 
N,N-dimethylformamide there were added dropwise 0.4 parts of thionyl 
chloride. After stirring for 5 min, there were added at once 2.03 parts of 
N-methylcyclohexanamine. The whole was stirred for 5 min and was then 
evaporated. The residue was stirred in water, filtered off and purified by 
column chromatography (silica gel; CHCl.sub.3 /CH.sub.3 OH 95:5). The 
eluent of the desired fraction was evaporated and the residue was 
crystallized from 2-propanol. The product was filtered off, washed with 
2-propanol and 1,1'-oxybisethane and dried, yielding 0.4 parts (31.1%) of 
(E)-N-cyclohexyl-3-(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl) 
-N-methyl-3-phenyl-2-propenamide; mp. 204.degree. C. (decomp.) (comp. 67). 
Example 24 
(a) 133 Parts of dichloromethane were stirred while gaseous hydrochloric 
acid was bubbled through for 1 min. There were added portionwise 4.6 parts 
of compound (59) and gaseous hydrochloric acid was passed through for 1 
more min. After the dropwise addition of 1.36 parts of thionyl chloride, 
the whole was stirred at reflux temperature for 40 min. The reaction 
mixture was evaporated and the residue was co-evaporated with 
methylbenzene, yielding 4.9 parts (94.0%) of 
(E/Z)-5-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolin-7-yl)me 
thylene]amino]oxy]pentanoyl chloride monohydrochloride (interm. 84). 
(b) To a stirred solution of 6.0 parts of N-methylcyclohexanamine and 160 
parts of dichloromethane there were added portionwise 5.9 parts of 
intermediate (84). Stirring was continued for 1 hour at room temperature. 
The reaction mixture was poured into water and the product was extracted 
with dichloromethane. The extract was washed with water, dried, filtered 
and evaporated. The residue was purified by column chromatography (silica 
gel; CH.sub.2 Cl.sub.2 /CH.sub.3 OH 92.5:7.5) and then separated into its 
E and Z isomers by HPLC (silica gel; .gamma.-aminopropyl; 
c.hexane/(C.sub.2 H.sub.5).sub.2 O/CH.sub.3 OH/H.sub.2 O 45:45:10:1). The 
E isomer fraction was crystallized from 2-propanol. The product was 
filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 
50.degree. C., yielding 0.12 parts (1.81%) of 
(E)-N-cyclohexyl-N-methyl-5-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- 
b]quinazolin-7-yl)methylene]amino]oxy]pentanamide; mp. 189.9.degree. C. 
(comp. 61). The Z isomer fraction was stirred in 2,2'-oxybispropane. The 
product was filtered off, washed with 2,2'-oxybispropane and dried in 
vacuo at 40.degree. C., yielding 0.42 parts (6.23%) of 
(Z)-N-cyclohexyl-N-methyl-5-[[[phenyl(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- 
b]quinazolin-7-yl)methylene]amino]oxy]pentanamide hemihydrate; mp. 
104.1.degree. C. (comp. 60). 
All compounds listed in Tables 1 and 2 were prepared following methods of 
preparation described in Examples 15-24, as is indicated in the column Ex. 
No. 
TABLE 1 
__________________________________________________________________________ 
##STR34## 
Comp. 
Ex. 
No. No. 
R X R.sup.1 
Physical Data 
__________________________________________________________________________ 
1 15 C.sub.6 H.sub.5 
O H mp. &gt;300.degree. C. 
2 17 C.sub.6 H.sub.5 
NOH H (E+Z)/mp. &gt;300.degree. C.(dec.) 
3 18 C.sub.6 H.sub.5 
NOH H (E)/mp. 279.7.degree. C. 
4 17 C.sub.6 H.sub.5 
NOCH.sub.3 H (E+Z)/mp. 265.0.degree. C.(dec.) 
5 19a 
C.sub.6 H.sub.5 
NOSi(CH.sub.3).sub.2 (t-C.sub.4 H.sub.9) 
H (E+Z)/mp. 254.7.degree. C. 
6 16 C.sub.6 H.sub.5 
NOCH.sub.2 COOC.sub.2 H.sub.5 
H (E+Z)/mp. 251.7.degree. C. 
7 20a 
C.sub.6 H.sub.5 
NOCH.sub.2COOH H (E+Z)/mp. 253.0.degree. C. 
8 16 C.sub.6 H.sub.5 
##STR35## H (E+Z)/HCl/1/2 (CH.sub.3).sub.2 CHOH 
mp.169.8.degree. C. 
9 16 C.sub.6 H.sub.5 
##STR36## H (E)/mp. 202.2.degree. C. 
10 16 C.sub.6 H.sub.5 
##STR37## H (Z)/mp. 173.4.degree. C. 
11 15 C.sub.6 H.sub.5 
O CH.sub.3 
mp. &gt;300.degree. C. 
12 15 4-CH.sub.3 OC.sub.6 H.sub.4 
O H mp. 260.degree. C.(dec.) 
13 17 4-CH.sub.3 OC.sub.6 H.sub.4 
NOH H (E+Z)/1/2 H.sub.2 O 
mp. 290.8.degree. C. 
14 15 4-FC.sub.6 H.sub.4 
O H mp. &gt;300.degree. C.(dec.) 
15 19c 
C.sub.6 H.sub.5 
NOH H (Z)/mp. &gt;250.degree. C. 
16 17 4-BrC.sub.6 H.sub.4 
NOH H (E+Z:55/45)/mp. &gt;300.degree. C. 
17 15 4-BrC.sub.6 H.sub.4 
O H mp. &gt;300.degree. C. 
18 19b 
C.sub.6 H.sub.5 
NOSi(CH.sub.3).sub.2 (t-C.sub.4 H.sub.9) 
H (E)/mp. 221.degree. C. 
19 19b 
C.sub.6 H.sub.5 
NOSi(CH.sub.3).sub.2 (t-C.sub.4 H.sub.9) 
H (Z)/mp. &gt;250.0.degree. C. 
20 15 4-CH.sub.3C.sub.6 H.sub.4 
O H mp. &gt;300.degree. C.(dec.) 
21 15 3-CH.sub.3 OC.sub.6 H.sub.4 
O H mp. 280.degree. C. 
22 17 4-FC.sub.6 H.sub.4 
NOH H (E+Z)/mp. 274.2.degree. C. 
23 17 4-CH.sub.3C.sub.6 H.sub.4 
NOH H (E+Z)/mp. 271.2.degree. C. 
24 15 3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 
O H mp. &gt;300.degree. C. 
25 17 3-CH.sub.3 OC.sub.6 H.sub.4 
NOH H (E+Z)/mp. &gt;300.degree. C. 
26 17 3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 
NOH H (E+Z)/mp. 216.6.degree. C. 
27 15 4-ClC.sub.6 H.sub.4 
O H mp. 260.degree. C.(dec.) 
28 16 C.sub.6 H.sub.5 
NO(CH.sub.2).sub.3 COOC.sub.2 H.sub.5 
H (E+Z)/mp. 190.0.degree. C. 
29 17 4-ClC.sub.6 H.sub.4 
NOH H (E+Z)/1/2 H.sub.2 O/ 
mp. &gt;300.degree. C.(dec.) 
30 16 C.sub.6 H.sub.5 
##STR38## H (E)/mp. 151.2.degree. C. 
31 21a 
C.sub.6 H.sub.5 
NO(CH.sub.2).sub.3COOH 
H (E+Z)/mp. 268.5.degree. C. 
32 16 C.sub.6 H.sub.5 
CHCOOC.sub.2 H.sub.5 
H mp. 228.6.degree. C. 
33 21b 
C.sub.6 H.sub.5 
##STR39## H (E) 
34 21b 
C.sub.6 H.sub.5 
##STR40## H (Z) 
35 16 4-BrC.sub.6 H.sub.4 
##STR41## H (E)/mp. 229.3.degree. C. 
36 16 C.sub.6 H.sub.5 
NO(CH.sub.2).sub.4 COOC.sub.2 H.sub.5 
H (E+Z)/mp. 139.8.degree. C. 
37 16 C.sub.6 H.sub.5 
NO(CH.sub.2).sub.2 COOC.sub.2 H.sub.5 
H (E+Z)/mp. 185.2.degree. C. 
38 16 4-FC.sub.6 H.sub.4 
##STR42## H (E)/3/2H.sub. 2 O/mp. 205.6.degree. 
C. 
39 22 3-pyridinyl 
O H mp. 275.1.degree. C. 
40 17 3-pyridinyl 
NOH H (E+Z)/1/2 H.sub.2 O/mp. 
279.4.degree. C. 
41 16 4-FC.sub.6 H.sub.4 
##STR43## H (E+Z)/1/2 H.sub.2 O/mp. 
240.2.degree. C. 
42 16 4-CH.sub.3C.sub.6 H.sub.4 
##STR44## H (E)/1/2 H.sub.2 O/mp. 189.3.degree. 
C. 
43 16 3-BrC.sub.6 H.sub.4 
##STR45## H (E)/1/2 H.sub.2 O/mp. 198.4.degree. 
C. 
44 16 3-BrC.sub.6 H.sub.4 
##STR46## H (Z)/1/2 H.sub.2 O/mp. 200.0.degree. 
C. 
45 16 H 
##STR47## H (E)/mp. 241.degree. C. 
46 16 4-ClC.sub.6 H.sub.4 
##STR48## H E/1/2 H.sub.2 O/mp. 207.4.degree. 
C. 
47 16 4-CF.sub.3C.sub.6 H.sub.4 
##STR49## H Z/mp. 195.8.degree. C. 
48 16 4-CF.sub.3C.sub.6 H.sub.4 
##STR50## H E/mp. 229.7.degree. C. 
49 16 3-CH.sub.3 OC.sub.6 H.sub.4 
##STR51## H Z/1/2 H.sub.2 O/mp. 155.2.degree. 
C. 
50 16 3-ClC.sub.6 H.sub.4 
##STR52## H Z/1/2 H.sub.2 O/mp. 216.7.degree. 
C. 
51 16 3-ClC.sub.6 H.sub.4 
##STR53## H E/1/2 H.sub.2 O/mp. 189.4.degree. 
C. 
52 16 3-CH.sub.3 OC.sub.6 H.sub.4 
##STR54## H E/1/2 H.sub.2 O/mp. 169.9.degree. 
C. 
53 16 2-thienyl 
##STR55## H (E+Z)/mp. 204.9.degree. C. 
54 16 3-CH.sub.3C.sub.6 H.sub.4 
##STR56## H E/H.sub.2 O/mp. 150.0.degree. C. 
55 16 3-CH.sub.3C.sub.6 H.sub.4 
##STR57## H Z/1/2 H.sub.2 O/mp. 161.0.degree. 
C. 
56 20b 
C.sub.6 H.sub.5 
NO(CH.sub.2).sub.2 COOH 
H (E+Z) 
57 24 C.sub.6 H.sub.5 
##STR58## H Z/1/2 H.sub.2 O/mp. 186.7.degree. 
C. 
58 24 C.sub.6 H.sub.5 
##STR59## H E/1/2 H.sub.2 O/mp. 140.8.degree. 
C. 
59 21a 
C.sub.6 H.sub.5 
NO(CH.sub.2).sub.4COOH 
H (E+Z) 
60 24b 
C.sub.6 H.sub.5 
##STR60## H Z/1/2 H.sub.2 O/mp. 104.1.degree. 
C. 
61 24b 
C.sub.6 H.sub.5 
##STR61## H E/mp. 189.9.degree. C. 
__________________________________________________________________________ 
TABLE 2 
__________________________________________________________________________ 
##STR62## 
Comp. 
Ex. 
No. No. 
X R.sup.1 
R.sup.2 
Physical Data 
__________________________________________________________________________ 
62 16 CHCOOC.sub.2 H.sub.5 
H H (Z)/mp. 259.9.degree. C. 
63 16 CHCOOC.sub.2 H.sub.5 
H H (E)/mp. 279.2.degree. C. 
64 21a 
CHCOOH H H (Z)/mp. &gt;300.degree. C. 
65 21a 
CHCOOH H H (E)/ 
66 23 
##STR63## H H (Z)/1/2 H.sub.2 O/mp. 219.4.degree. C. 
67 23 
##STR64## H H (E)/mp. 204.degree. C. 
68 15 O CH.sub.2CH.sub.2 
mp. &gt;300.degree. C. 
69 17 NOH CH.sub.2CH.sub.2 
(E+Z)/mp. &gt;300.degree. C. 
70 15 O CH.sub.3 
CH.sub.3 
mp. &gt;300.degree. C. 
71 17 NOH CH.sub.3 
CH.sub.3 
(E+Z)/mp. 295.0.degree. C. 
__________________________________________________________________________ 
(C) Pharmacological examples 
The positive inotropic and lusitropic effect of the instant compounds were 
assessed by an in vitro assay system to detect inhibiting effect on the 
phosphodiesterase type III.sub.c and in an in vivo experiment in 
closed-chest anaestetized dogs by monitoring cardiac and haemodynamic 
effects of an intravenous infusion of the instant compounds. 
Example 25 
Inhibition of Phosphodiesterase type III.sub.c (PDE III.sub.c) 
The incubation mixture (pH 7.1) (200 .mu.l) contained 50 mM 
4-morpholinopropanesulfonic acid (MOPS), 1 mM 
ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA), 6 mM magnesium 
chloride, 0.25 mg/ml bovine serum albumin, 1.2 .mu.M .sup.3 H-cAMP (310 
mCi/mmole) and the phosphodiesterase type III.sub.c, and was prepared by 
dilution with water of a stock solution of MOPS, EGTA, MgCl.sub.2, BSA and 
.sup.3 H-cAMP (50 .mu.l) and 2 to 50 .mu.l of a solution of 
phosphodiesterase type III.sub.c, depending on the enzymatic activity. A 
protein concentration was chosen that showed a linear increase of 
phosphodiesterase activity during an incubation period of 10 minutes at 
37.degree. C. 
When the effect of different compounds on phosphodiesterase activity was 
tested, the medium without cAMP was incubated with the compound(s) or its 
carrier (DMSO-1% final concentration) for 5 min. The enzymatic reaction 
was started by addition of .sup.3 H-cAMP and stopped 10 min later after 
transferring the tubes in a waterbath at 100.degree. C. for 40 sec. After 
cooling to room temperature, alkaline phosphatase (0.25 .mu.g/ml) was 
added and the mixture was left at room temperature for 20 min. The mixture 
was subsequently applied to a 1 ml DEAE-Sephadex A-25 column (pasteur 
pipet) and washed twice with 3 ml 20 mM Tris-HCl at pH 7.4. The .sup.3 
H-labelled reaction products in the eluate were quantified by liquid 
scintillation counting. 
The inhibiting effect of the present compounds on canine heart and human 
platelet phosphodiesterase PDE III.sub.c was measured at different 
concentrations of the instant compounds. The IC.sub.50 values were 
calculated graphically from the thus obtained inhibition values. Table 3 
shows available IC.sub.50 values of the present compounds on canine heart 
and human platelet PDE III.sub.c. 
TABLE 3 
______________________________________ 
Human Platelet 
Comp. Canine heart PDE III.sub.c 
PDE III.sub.c 
No. IC.sub.50 (10.sup.-6 M) 
IC.sub.50 (10.sup.-6 M) 
______________________________________ 
1 0.55 -- 
2 0.44 0.19 
3 0.44 0.19 
4 0.37 -- 
5 0.06 -- 
6 0.46 0.38 
8 0.17 0.058 
9 0.064 0.025 
10 0.21 0.14 
12 0.28 -- 
13 0.36 -- 
14 0.49 0.52 
15 0.34 -- 
16 0.26 -- 
17 0.36 -- 
20 0.21 -- 
21 0.145 -- 
22 0.41 -- 
23 0.23 -- 
24 0.19 0.34 
25 0.20 -- 
26 0.19 -- 
27 0.30 -- 
28 0.22 -- 
29 0.19 -- 
30 0.14 -- 
31 0.62 -- 
32 0.26 0.084 
33 0.047 -- 
34 0.078 -- 
35 0.051 -- 
36 0.09 -- 
37 0.12 -- 
38 0.076 -- 
R 85.906 
40 0.93 -- 
R 86.134 
41 0.12 -- 
R 86.260 
42 0.081 -- 
R 86.313 
43 0.15 -- 
R 86.282 
44 0.045 -- 
R 86.251 
45 0.025 -- 
R 86.275 
46 0.067 -- 
R 86.325 
48 0.74 -- 
R 86.388 
49 0.041 -- 
R 86.620 
52 0.04 -- 
R 86.602 
53 0.01 -- 
R 86.756 
54 0.15 -- 
R 86.759 
55 0.089 -- 
R 86.838 
57 0.15 -- 
R 86.839 
58 0.05 -- 
R 86.856 
60 0.24 -- 
R 86.847 
61 0.1 -- 
R 86.033 
62 0.49 -- 
R 86.130 
63 0.38 -- 
R 86.399 
65 0.65 -- 
R 86.400 
67 0.39 -- 
______________________________________ 
-- = not yet tested 
Example 26 
Positive inotropy and lusitropy, blood pressure and heart rate in dogs 
Compound (9) was dissolved in 20% hydroxypropyl beta cyclodextrine ether 
slightly acidified with 1N HCl, in a concentration of 1 mg.ml.sup.-1 (pH 
5.5). The experiments were performed on 7 mongrel dogs of either sex and 
varying age, ranging in body weight from 27 to 33 kg (median 30 kg). The 
animals were intravenously anaesthetized with a mixture of 0.015 
mg.kg.sup.-1 scopolamine and 0.05 mg.kg.sup.-1 lofentanil. The animals 
were intubated with a cuffed endotracheal tube. Intermittent positive 
pressure ventilation was performed with a mixture of pressurized air and 
oxygen (60/40), using a volume-controlled ventilator (Siemens Elema). In 
the control period the CO.sub.2 concentration in the expired air (ET 
CO.sub.2), as determined with a capnograph (Gould Godart), was kept at 5 
vol% by adjustment of the respiratory volume (resp.rate=20 
breaths.min.sup.-1). A continuous intravenous infusion of 0.5 
mg.kg.sup.-1.h.sup.-1 of etomidate was started immediately after 
induction. Body temperature was monitored with a thermistor positioned in 
the pulmonary artery. To prevent blood clotting heparine, 1000 
IU.kg.sup.-1 i.v., was administered. 
The electrocardiogram (ECG) was derived from limb leads (standard lead 2). 
Left ventricular (LVP) and ascending aortic blood pressure (AoP) were 
measured by retrograde catheterisation via the femoral arteries with high 
fidelity cathetertip micromanometers (Honeywell). The other femoral vein 
was cannulated for injection of saline at room temperature into the right 
atrium and for injection of compound (9). Peak ascending aortic blood flow 
velocity was measured through the right carotid artery with an 
electromagnetic catheter-tip probe connected to a square wave 
electromagnetic flow meter (Janssen Scientific Instruments). The following 
variables --inter alia-- were calculated on-line, usually at 1 min 
intervals: heart rate (HR), diastolic (AoPd) aortic blood pressure, left 
ventricular end-diastolic pressure (LVEDP), the maximum positive and 
maximum negative rate of change of isovolumic LVP (LV dp/dt.sub.max and 
.sub.min, respectively), the maximum positive first derivative divided by 
the actually developed pressure in the left ventricle (LV dp/dt.sub.max 
/Pd). The time constant (T) of relaxation was measured with the use of an 
exponential analysis that also estimated the asymptote. After a recorded 
control period of 20 min the intravenous infusion of compound (9) was 
started at a rate of 0.005 mg.kg.sup.-1 over 120 min. In the wash-out 
period the effects were followed for 75 min. 
Compound (9) has positive inotropic properties, starting after 10 min of 
infusion (0.05 mg.kg.sup.-1 total dose), as indicated by the pronounced 
and significant increase in the variables related to cardiac performance 
(LV dp/dt.sub.max, LV dp/dt.sub.max /Pd), in the presence of no change or 
even a slight decrease in left ventricular end-diastolic pressure 
(preload) and no change in heart rate. Compound (9) has positive 
lusitropic properties, as evidenced by the significant decrease in the 
time constant of relaxation starting after 10 min of infusion (0.05 
mg.kg.sup.-1 total dose). Systemic and pulmonary peripheral vascular 
resistance decrease significantly starting after 20 min of infusion of the 
compound (0.10 mg.kg.sup.-1 total dose). This indicates that compound (9) 
has also additional systemic and pulmonary vasodilatory properties. This 
unloading of the heart occurs without altering heart rate, but with 
concomitant increase in cardiac output. These positive inotropic and 
lusitropic, and vasodilatory effects of the compound (9) are long-lasting, 
since the changes in the variables last for more than 75 min after 
stopping the infusion of a total dose of 0.60 mg.kg.sup.-1. 
Following the same procedure, a dose-related increase in cardiac inotropy 
and lusitropy associated with a dose-related systemic vasodilation and an 
increase in cardiac output, without changing the heart rate, was observed 
upon slow infusion (0.005 mg kg.sup.-1 min.sup.-1) of compound (3) for two 
hours and lasted for more than 90 minutes after stopping the infusion. 
Table 4 shows the % changes in haemodynamic variables measured after 
cumulative intravenous bolus administration of some of the present 
compounds in mongrel dogs (maximum end-dose is shown in mg kg.sup.-1). The 
variable AoPd (diastolic aortic blood pressure) shows the decrease in 
blood pressure (vasodilation), HR the influence of the present compounds 
on the heart rate, LV dp/dt.sub.max /Pd (the maximum positive rate of 
change of isovolumic left ventricular pressure divided by the actually 
developed pressure in the left ventricle) shows the positive inotropic 
effect and T (decrease in the time constant of relaxation) is a measure 
for positive lusitropy. 
TABLE 4 
______________________________________ 
% changes in haemodynamic variables 
Comp. end-dose 
No. AoPd HR LVdp/dt.sub.max /Pd 
T mg kg.sup.-1 
______________________________________ 
2 -10 15 102 -38 0.16 
6 -13 9 31 -15 0.16 
8 0 0 29 -45 0.16 
10 -5 0 18 -13 0.16 
12 0 10 57.5 -10 0.16 
13 0 -10 45 -27 0.16 
14 0 5 35 -16 0.08 
______________________________________ 
D. Composition examples 
The following formulations exemplify typical pharmaceutical compositions in 
dosage unit form suitable for systemic or topical administration to 
warm-blooded animals in accordance with the present invention. "Active 
ingredient" (A.I.) as used throughout these examples relates to a compound 
of formula (I), a pharmaceutically acceptable acid addition salt or a 
stereochemically isomeric form thereof. 
Example 27 
Oral drops 
500 g of the A.I. is dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 
l of the polyethylene glycol at 60.degree..about.80.degree. C. After 
cooling to 30.degree..about.40.degree. C. there are added 35 l of 
polyethylene glycol and the mixture is stirred well. Then there is added a 
solution of 1750 g of sodium saccharin in 2.5 l of purified water and 
while stirring there are added 2.5 l of cocoa flavor and polyethylene 
glycol q.s. to a volume of 50 l, providing an oral drop solution 
comprising 10 mg/ml of the A.I. The resulting solution is filled into 
suitable containers. 
Example 28 
Oral solution 
9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are 
dissolved in 4 l of boiling purified water. In 3 l of this solution are 
dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g 
of the A.I. The latter solution is combined with the remaining part of the 
former solution and 12 l of 1,2,3-propanetriol and 3 l of sorbitol 70% 
solution are added thereto. 40 g of sodium saccharin are dissolved in 0.5 
l of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. 
The latter solution is combined with the former, water is added q.s. to a 
volume of 20 l providing an oral solution comprising 5 mg of the A.I. per 
teaspoonful (5 ml). The resulting solution is filled in suitable 
containers. 
Example 29 
Capsules 
20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 
g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously 
stirred together. The resulting mixture is subsequently filled into 1000 
suitable hardened gelatin capsules, each comprising 20 mg of the A.I. 
Example 30 
Film-coated tablets 
Preparation of tablet core 
A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed 
well and thereafter humidified with a solution of 5 g sodium dodecyl 
sulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90.RTM.) in about 200 ml 
of water. The wet powder mixture is sieved, dried and sieved again. Then 
there are added 100 g microcrystalline cellulose (Avicel.RTM.) and 15 g 
hydrogenated vegetable oil (Sterotex.RTM.). The whole is mixed well and 
compressed into tablets, giving 10.000 tablets, each comprising 10 mg of 
the active ingredient. 
Coating 
To a solution of 10 g methyl cellulose (Methocel 60 HG.RTM.) in 75 ml of 
denaturated ethanol there is added a solution of 5 g of ethyl cellulose 
(Ethocel 22 cps.RTM.) in 150 ml of dichloromethane. Then there are added 
75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of 
polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. 
The latter solution is added to the former and then there are added 2.5 g 
of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of 
concentrated colour suspension (Opaspray K-1-2109.RTM.) and the whole is 
homogenated. The tablet cores are coated with the thus obtained mixture in 
a coating apparatus. 
Example 31 
Injectable solution 
1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate are 
dissolved in about 0.5 l of boiling water for injection. After cooling to 
about 50.degree. C. there are added while stirring 4 g lactic acid, 0.05 g 
propylene glycol and 4 g of the A.I. The solution is cooled to room 
temperature and supplemented with water for injection q.s. ad 11 volume, 
giving a solution of 4 mg A.I. per ml. The solution is sterilized by 
filtration (U.S.P.XVII p. 811) and filled in sterile containers. 
Example 32 
Suppositories 
3 g A.I. is dissolved in a solution of 3 g 2,3-dihydroxybutanedioic acid in 
25 ml polyethylene glycol 400. 12 g surfactant (SPAN.RTM.) and 
triglycerides (Witepsol 555.RTM.) q.s. ad 300 g are molten together. The 
latter mixture is mixed well with the former solution. The thus obtained 
mixture is poured into moulds at a temperature of 37.degree.-38.degree. C. 
to form 100 suppositories each containing 30 mg of the A.I. 
Example 33 
Injectable solution 
60 g of A.I. and 12 g of benzylalcohol are mixed well and sesame oil is 
added q.s. ad 1 l, giving a solution comprising 60 mg/ml of A.I. The 
solution is sterilized and filled in sterile containers. 
Example 34 
Injectable solution 
350 g of hydroxypropyl-.beta.-cyclodextrin is dissolved in 2.81 of water. 
There are added successively 80.5 g of hydrochloric acid 0.1N and 1.75 g 
of (E)-N-cyclohexyl-N-methyl-2-[[[phenyl-(1,2,3,5-tetrahydro-2-oxoimidazo[ 
2,1-b]-quinazolin-7-yl)methylene]-amino]oxy]acetamide. The whole is stirred 
until a clear solution is obtained and then the acidity is adjusted with 
sodium hydroxide 1N to pH 6. The solution is diluted with water to 3.5 l, 
thus yielding an injectable solution containing 0.5 mg/ml of A.I.