Note: Descriptions are shown in the official language in which they were submitted.
CA 02240845 1998-06-17
W O 97/23465 PCTlEP96/05766
New barbituric acid derivatives, processes for their production and
pharmaceutical agents containing these compounds
In normal tissue there is an equilibrium between synthesis and degradation.
Extracellular
matrix is degraded by proteases which belong to at least three groups of
matrix
metalloproteases. These are the collagenases, gelatinases and stromelysins.
Normally
there are specific inhibitors for these catabolic enzymes such as oc2
macroglobulines and
MMP (= tissue inhibitor of metalloproteases (MMP}) so that an excessive
degradation of
extracellular matrix does not occur. A related group of proteases is the
adamalysins. A
prominent member of the adamalysins is TACE (TNF-oc-converting enzyme}.
At least 11 different and yet highly homologous MMP species have been
characterized,
including the interstitial fibroblast collagenase (MMP-I, HFC), the neutrophil
coIlagenase (MMP-8, HNC), two gelatinases, stromelysins (such as HSL-I ) and
HPUMP (for a recent review, see Birkedal-Hansen, H., Moore, W.G.L, Bodden,
M.K.,
Windsor, L.J., Birkedal-Hansen; B., DeCarIo, A., Engler, 3.A., Critical Rev.
Oral
Biol.Med. (I993) 4, I97-250. These proteinases share a number of structural
and
functional features but differ somewhat in their substrate specificity. Only
HNC and HFC
are capable of cleaving type 1, II and III native triple-helical collagens at
a single bond
with the production of fragments 3/4 and I/4 of the native chain length. This
lowers the
collagen melting point and makes them accessible to further attack by other
matrix
degrading enzymes.
However, the uncontrolled excessive degradation of this matrix is a
characteristic of
many pathological states such as e.g. in the clinical picture of rheumatoid
arthritis,
3 0 osteoarthritis, multiple sclerosis, in the formation of tumour metastases,
corneal
ulceration, inflamative diseases and invasion and in diseases of the bone and
teeth.
It can be assumed that the pathogenesis of these clinical pictures can be
favourably
influenced by the administration of matrix metailoprotease inhibitors. A
number of
compounds in the meantime are known in the literature (see e.g. the review
article of
Nigel RA Beeley et al. Curr. Opin. they. Patents 4 (I), 7 (1994)) or are
described in the
patent literature, these mainly being peptides with a hydroxamic acid residue.
a thiol or
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phosphine group as a zinc binding group (see e.g. WO-A-9209563 by Glycomed, EP-
A-
497 192 by Hoffmann-LaRoche, WO-A-9005719 by British Biotechnology, EP-A-489
577 by Celltech, EP-A-320 I 18 by Beecham, US-A-459 5700 by Searle among
others).
Some of these compounds have a high activity as inhibitors of matrix
metalloproteases
but only have a very low oral availability.
It has now been found that the claimed new barbituric acid derivatives are
very
efficacious as matrix metalIo-protease inhibitors and have a good oral
availability.
The present invention therefore concerns substances of the general formula I
R~
R1 N-RS
Y Z
~~N N~~
(I)
X
in which
X, Y and Z are independently of one another oxygen, sulphur or NH,
Rl represents a group W-V
W is a valence dash or a straight-chained or branched C1-C8 alkyl or a CZ-C8
alkenyl
group which is optionally once or several times substituted,
V is an optionally substituted monocycle or bicycle which can contain one or
several
heteroatoms,
or
W-V is a Cl-C20 akyl group which can be interrupted by heteroatoms, one or
several
carbon atoms are optionally substituted, '
3 0 RZ and R3 represent hydrogen or one of the two represents lower alkyl or
lower acyl
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-3-
R4 and RS denote independently of each other for A-D wherein A represents a
dash~alkyl,
alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylaminocarbonyl, aminocarbonyl,
alkoxycarbonyl,
oxy-carbonyl, alkylaminothiocarbonyl, aminothio-carbonyl which is optionally
once or
several times substituted,
D represents a hydrogen, mono or bicycle, the monocycle or bicycle is
optionally once or
several times interrupted by heteroatoms and the monocycle or bicycle is once
or several
times substituted,
or
R4 and R5 together with the nitrogen atom to which they are bound represent a
ring
which optionally can be interrupted by a further N atom, said ring can be
condensed to a
monocycle or bicycle; said ring can optionally be substituted once or several
times
independently by the residues hydroxy, alkoxy, amino, alkylamino,
dialkylamino, nitril or
by E-G wherein E represents a dash alkyl, alkenyl, acyl, alkylsulfonyl,
sulfonyl,
alkylaminocarbonyl, aminocarbonyl, alkoxycarbonyl, oxy-carbonyl,
alkylaminothiocarbonyl, aminothiocarbonyl which is optionally substituted; G
represents
a hydrogen, mono or bicycle, the monocycle or bicycle is optionally once or
several times
2 0 interrupted by heteroatoms and the monocycle or bicycle is once or several
times
substituted,
pharmacologically acceptable salts or prodrugs thereof as well as the use of
these
compounds to produce pharmaceutical agents.
The monocycie listed in the case of RI, R4 and R~ is understood as saturated
or
unsaturated ring systems with 3 - 8, preferably 5 - 7 carbon atoms which can
optionally
be interrupted one or several times by heteroatoms such as nitrogen, oxygen or
sulphur
3 0 in particular a cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl,
thiamorpholinyl,
piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl,
pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl,
oxazolyl,
isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazoiyl residue. Lower
alkyl, alkoxy and
halogen come above ail into consideration as substituents.
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-4-
The bicycle listed under R1, R4 and R5, is understood to be a condensed
bicycle or a
bicycle of the type monocycle,-L-monocycle2, wherein L denotes a valence dash
C1-C4-
alkyl group, CZ-C4 an alkenyl group, an oxygen or -C(O)-group.
The bicycle is preferably a residue such as a naphthyl, tetrahydronaphthyl,
dekalinyl,
quinolinyl, isoquinolinyl, tetrahydroquino-linyl, tetrahydroisoquinolinyl,
indolyl,
bettzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl,
benzthiazolyI,
benzoxazolyl, purinyl, biphenyl or (4-phenoxy)phenyl residue and in particular
a
naphthyl, biphenyl, quinoiinyi, isoquinolinyt, tetrahydroquinolinyl, indolyl
or
benzimidazolyl residue.
The residues listed under R1, R4 and RS can optionally be substituted once or
several
times by halogen, hydroxy, thin, alkyl, hydroxyalkyi, alkoxy, alkylthio,
alkylsulfinyl,
alkyl-sulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido,
alkoxy-
carbonyl, amino or aminocarbonyl optionally substituted once or twice by lower
alkyl,
nitrite, oxo, thiocarboxamido, alkoyxythiocarbonyl, alkmercaptocarbonyl,
phosphono,
alkylphosphono, dialkylphosphono, alkylsulfonylamido, arylamino, aryl,
hetaryl, aryloxy,
arylthio, arylsulftnyl, arylsulfonyl or acyl.
2 0 In this case the halogen, hydroxy, oxo, thio, alkoxy, alkylthio, amino,
aminocarbonyl,
carboxyl and acyl groups are preferred.
Lower alkyl denotes C,-C~-Alkyl, preferred methyl, ethyl, propyl, isopropyl or
tert.-
butyl.
Lower acyl in the residues R2 and R3 above all denotes for -C{O)-C,-C6-alkyl
or -
C(O)H, preferred for an acetyl group.
The alkyl residues in R,, R4 and RS can optionally be interrupted once or
several time by
3 0 heteroatoms {O, S, NH).
Alkyl in the residues R4 and RS denotes as such or in combination with alkoxy,
alkylthio,
aryIsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl,
alkylamino,
alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl
a
straight-chained, branched, saturated or unsaturated residue with 1 - 11,
preferably 1 - 8
carbon atoms such as e.g. a methyl, ethyl, propyl, pentyl, octyl, allyl,
propargyl, 2,4-
pentadienyl, isopropyl, sec. butyl, 3-methylbutyl, 2-hydroxyhexyl and in
particular a
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-5-
methyl, propyl, isopropyl, pentyl, octyl, allyl, 3-methyibutyl, 2-hydroxyhexyl
and
propargyl residue.
Aryl, also in combination with aryloxy, arylthio, arylsulfonyl,
arylaminocarbonyl,
aryloxycarbonyl, arylaminothiocarbonyl is understood as a phenyl or naphthyl
residue
which can optionally be substituted in particular by halogen, lower alkyl or
alkoxy.
The C 1-C2p alkyl group listed for RI is a straight-chained or branched
saturated residue
such as e.g. a methyl, ethyl, propyl, butyl, pentyl, octyl, decyl, undecyl,
isobutyl, 3-
methylbutyl or 7-methyloctyl group. Hydroxy and amino residues come above all
into
consideration as substituents. The alkyl chains can be interrupted once or
several times
by oxygen, nitrogen or sulphur. The preferred heteroatom interruption is
oxygen (ether
linkage) or -C(O)NH- (amid linkage). The most preferred heteroatom interrupted
residues are -(CHZCH20}n-(CHZ)mH and n= 2 or 3 and m = I or 2.
W of R, is preferrabiy a methyl, ethyl, butyl or hexyi residue; V is in
particular a phenyl,
Pyridyf, imidazolyl residue which can optionally be substituted above all by
lower alkyl,
hydroxy, alkoxyamid, sulfonamide or halogen. The most preferred Rl residues
are C6-
C I2-A,lkyi residue or a -(CHZ)» C6H4-(CHz)mH residue, wherein m and n are
equal or
2 0 less than 8, the (CHz)-group is optionally interrupted by oxygen, sulfur,
or NH and one
or two carbons of the phenyl ring are substituted for N-heteroatoms. The
aikyI, aryl,
hetaryl groups are optionally substituted by small polar substituents.
The most preferred R, residues are n-Octyl, n-Decyl, Biphenyl or octyl or
decyl type
residues showing two or three oxygen heteroatoms like 2-(2-(2-methoxyethoxy)-
ethoxy}ethyl, 2-(2-ethoxyethoxy)ethyl or biphenyl-type residues showing one or
two
nitrogen heteroatoms. The bridging monocycle is optionally ortho substituted
and the
terminal monocycle of the biphenyl or biphenyl type residue is optionally
ortho or para
substituted by a small, polar substituent like NH2, -N02, -S02NHa, SOaCH3,
Acetyl,
3 0 Hydroxy, Methoxy, Ethoxy or Nitril-group. The para substitution of the
terminal
monocycle is more preferred.
Halogen is understood as chlorine, bromine, iodine and preferably chlorine.
3 5 The hetaryl residues listed for Rq. and RS denote preferred for a
pyridine, pyrazine,
piperazine, imidazole, thiazoie, thiophene or indole ring preferably a
pyridine, imidazole
and thiophene ring.
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-b-
The acyi residue listed for the residues R4 and RS is a residue with 1 - 10,
preferably 6 -
8 carbon atoms such as e.g. a hexanoyl or octanoyl residue. The alkyl group
can be
interrupted once or several times by heteroatoms or heteroatom groups like S,
O, NH,
SO,, amido or carbonyl. These residues can be substituted by amino groups,
alkyl
groups, aryl groups, arylalkyl groups, alkylamino groups, dialkyIamino groups,
alkoxy
groups and aromatic compounds. These are then amino acid residues preferably a
phenylalanine and tryptophan residue in this case.
If R4 and RS form a ring together with the nitrogen atom to which they are
bound, these
are 5 - 7-membered rings preferably a six-membered ring. The piperidine,
piperazine,
tetrahydroquinoiine and tetrahydroiso-quinoline, bicyclo(9.4.0)pentadecyl and
1,2,3,4-
tetrahydrobenzo(g)isoquinoline rings are preferred.
If compounds of the general formula I contain one or several asymmetric carbon
atoms,
the optically active compounds of the general formula I are also a subject
matter of the
present invention.
Independently of each other the preferred meaning for X, Y, Z is oxygen, for
Rz and R3
it is hydrogen. A more preferred combination is X, Y and Z equal each oxygen
and R2 is
2 0 identical to R3 and both mean hydrogen.
It is also preferred that R., and RS do not both represent hydrogen.
The term "several" means in connection with heteroatoms in monocycles or
bicycles
preferred one, two or three more preferred one or two, the most preferred
heteroatom is
nitrogen.
The term "several" means in connection with substituents or substitution
preferred one to
five, more preferred one, two or three most preferred one or two.
The term "heteroatom" in connection with alkyl or acyl groups means preferred
oxygen
3 0 or NH, more preferred oxygen.
Substitutions of monocycles or bicycles in R~, R4 and RS are halogen, nitro,
hydroxy,
alkoxy, amino, alkylamino, dialkylamino, halogenmethyi, dihalogenmethyl,
trihalogenmethyl, phosphono, aikylphosphono, dialkylphosphono, S02NH2,
S02NH(alkyl), SOZN(alkyi)z, SOZ(alkyl), acetyl, formyl, nitril, COOH,
COOalkyl, -
OC(O)alkyl, -NHC(O)Oalkyl, OC(O)O-aryl, -NHC(S)NH2, -NHC{S)NHaIkyl, -
NHC(O)-aryl.
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The preferred ring structure formed together with the nitrogen, Rø and R5, is
piperazin or
piperidin, both of which are substituted preferrably at the 4-position. In the
case of
piperidin the 4 position is optionally substituted by a second substitute
hydroxy, amino,
alkylamino, alkyiamino, dialkylamino or aIkoxy. The 4 position of piperidin
may also
form a double bond with the substituent of the 4 position.
Preferred substitution of the 4 position of piperidin or piperazin are 6-
membered
aromatic monocycles which are more preferred substituted in para position by
small
polar substitutions as hydroxy, lower alkoxy, amino, lower alkylamino, lower
dialkylamino, nitro, nitrilo, SOaNH2, SOzNH lower alkyl, SOz lower alkyl. The
6
membered aromatic monocycle is preferrably bound to the 4 position via a
valence bond
or a lower aikyI spacer.
In the case that R4 is hydrogen a lower alkyl a lower alkylaryl, then RS is
preferred a acyl
derivate preferrably substituted with a monocyle or lower alkylaryl; or a -
CHRso-CHRsI-
NRsz-Rs3 wherein Rso and Rs 1 denote independently of each other for hydrogen,
lower
alkyl a lower alkoxy. Rs2 denotes for hydrogen or lower alkyl, Rs3 denotes a 6-
membered aromatic monocycle which is optionally once or several times
substituted and
bound to the nitogen preferrably via a valence bond or a lower alkyl spacer.
The most preferred combination of meanings in general formula I are
X equals Y equals Z equals oxygen and
R2 equals Rz equals hydrogen and
Rl equals n-Octyl, n-Decyl, Biphenyl or octyl or decyl type residues showing
two or
2 5 three oxygen heteroatoms like 2-(2-(2-methoxyethoxy)-ethoxy)ethyl, 2-(2-
ethoxyethoxy)ethyl or biphenyl-type residues showing one or two nitrogen
heteroatoms;
wherein the bridging monocycIe is optionally ortho substituted and the
terminal
monocycle of the biphenyl or biphenyl type residue is optionally ortho or
preferred para
substituted by a small, polar substituent like NHZ, -N02, -SOZNH2, SOzCH3,
Acetyl,
3 0 Hydroxy, Methoxy, Ethoxy or Nitril-group and
R4 and Rs form together with the nitrogen to which they are bound a piperazin
or
piperidin both of which are substituted in the 4 position with a phenyl,
pyridyl or
pyrazidyl ring which is preferred para substituted by a small polar
substituent; in the case
of piperidin the 4 position may be additionally sustituted by hydroxy, lower
alkoxy, nitril
3 5 or amin which may be mono- or disubstituted by lower alkyl.
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_g_
Compounds of the general formula I can be synthesized by well-known processes
preferably in that
a) compounds of the general formula II
'
R1 T
Y Z
~~N~N~~
{II)
X
in which X, Y, Z, R 1, R2 and R3 have the above-mentioned meanings and T
represents a
leaving group such as Hal or OS02Rb,Hai denoting chlorine, bromine or iodine
and R6
denoting an aryl or a methyl residue, are reacted with a compound of the
general formula
III
~ R4
HN
Rs
(III)
in which R4 and RS have the meanings stated above and optionally converted
into
pharmacologically acceptable salts or
b) compounds of the general formula IV
R4
Ri N-Rs
Y Z
OR.~ OR., {IV)
in which RI, R4 and RS have the above-mentioned meanings, Y and Z
independently of
one another represent oxygen, sulphur or a NH group and R~ = methyl, ethyl or
phenyl,
2 5 is reacted with a compound of the general formula V
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WO 97/23465 PCT/EP96/05766
-9
- X (V)
~ in which R2, R3 and X have the above-mentioned meanings and optionally
convened
into pharmacologically acceptable salts
or
n the case that R4 and/or RS represent an acyl, alkylsulfonyl, arylsulfonyl,
alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl,
alkylaminothiocarbonyl or arylaminothiocarbonyl residue
c) a compound of the general formula VI
Rt ~a
Y Z
~~N~N~~
(VI)
X
20
in which X, Y, Z, R1, R2 and R3 have the above-mentioned meanings, is reacted
with a
compound of the general formula VII or VIII
Rg D Hal (VII) RSN-- CwA (VIII)
in which Rg represents an optionally substituted alkyl or aryl residue, D =
C{O), O-C{O),
S02 or a valency dash. Hal = chlorine, bromine or iodine and A represents
oxygen or
sulphur
2 5 and optionally converted into pharmacologically acceptable salts.
Compounds of the general formula II are known in the literature. Thus for
example
2,4,6-pyrimidine triones brominated in the 5-position can be synthesized by
reacting the
appropriate bromomalonic acid dialkyl esters with urea (e.g. Acta Chim. Acad.
Sci.
3 0 Hung. 107 (~), 13 9 ( I 98 I )). The corresponding brominated or
chlorinated compounds of
the general formula II can be obtained by reacting 2,4,6-pyrimidine-triones
substituted by
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_ 10_
R1 in the 5-position with bromine (analogous to J. pr. Chemie 136, 329 (1933)
or J.
Chem. Soc. 1931, 1870) or sulfuryl chloride (J. Chem. Soc. 1938. 1622). In the
same
manner one can synthesize the 2-imino-4,6-pyrimidine-diones of the general
formula II
correspondingly halogenated in the 5-position analogously to Collect. Czech.
Comm. 48
( 1 ), 299 ( I933). The reaction of 2-this-4,6-pyrimidine-diones substituted
by RI in the 5-
position with bromine in glacial acetic acid (analogously to Am. Chem. J. 34,
186} leads
to the compounds of the general formula II correspondingly brominated in the 5-
position.
1 o Amines of the general formula III are commercially available or are
usually known in the
literature.
Compounds of the general formula IV are reacted according to known methods
with
ureas (see for example J. Med. Chem. 10, 1078 (1967} or Helvetica Chim. Acta
34. 459
( 1959) or Pharmacie 3 8 ( I ), 65 ( 1983 )), thioureas (see for example
Indian J. Chem. 24
(10), 1094 (1985} or 3. Het. Chem. 18 (3), 635 (1981)) or guanidines (see for
example
Collect. Czech. Chem. Comm. 45 (12), 3583 {1980)) ofthe general formula V.
The reactions are usually carried out in an alcohol such as methanol, ethanol
or butanol
2 0 in the presence of an appropriate sodium alcoholate at temperatures
between 40°C and
100°C and in the case of the guanidines also at temperatures of up to
200°C (under
pressure). In the case of the thioureas the process is frequently earned out
in the
presence of acetyl chloride (also as a solvent}.
Compounds ofthe general formula IV are known from the literature or can be
produced
according to processes known from the literature. They can be synthesized for
example
by weak acidic hydrolysis of the corresponding bislactim ethers (see J. Chem.
Soc.
Chem. Comm. 5, 400 (1990)). Other methods of synthesis are for example
described in
Farmaco Ed. Sci. 31 (7), 478 ( 1976) or Aust. J. Chem., 23 (6), 1229 (1970).
Ureas, thioureas and guanidines of the general formula V are commercially
available.
Compounds of the general formula VI can easily be synthesized by reacting an
appropriate substituted acetamidomalonic ester according to process b) and
subsequent
hydrolytic cleavage of the acetyl group {see Can. J. Chem. 42 {3), 605
(1964)).
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Carboxylic acid chlorides of the general formula VII are known or can be
synthesized by
generally known methods from the corresponding carboxylic acids. The reaction
is
usually carried out with thionyl chloride or phosphorus tribromide or
phosphorus
pentabromide or pentachloride in inert solvents such as dichloromethane,
diethyl ether,
dioxane or tetrahydrofuran at temperatures of 0°C to 50°C,
preferably between 20°C and
40°C.
Chloroformic acid esters of the general formula VII are known in the
literature or can be
obtained by generally known methods from the corresponding alcohols by
reaction with
phosgene or diphosgene. The reaction proceeds in inert solvents such as e.g.
diethyl
ether, dichloromethane, dioxane, tetrahydrofuran or toluene at temperatures
between -
20°C and 20°C. In the case of phosgene the reaction is carried
out in the presence of
bases, usually tertiary amines such as e.g. triethylamine or pyridine.
Suifonic acid chlorides of the general formula VII are known or can be
synthesized
analogously to described methods from the corresponding sulfonic acids by
reaction with
phosphorus pentachloride or thionyl chloride. The reaction is usually carned
out in an
inert solvent such as e.g. dimethylformamide or also without a solvent at
temperatures of
20°C to 180°C, preferably at 50°C to 100°C.
Isocyanates of the general formula VIII are known or can be synthesized by
methods
known in the literature. Thus for example appropriate alkyl halogenides of the
general
formula Rg-Hal can be reacted with potassium cyanate analogously to Synthesis
1978,
760. Further methods are to react an acid amide of the general formula Rg-
CONH2 with
2 5 oxalyl chloride, to thermally decompose an acid azide of the general
formula Rg-CON3
or to react an amine of the general formula Rg-NH2 with phosgene (analogously
to Ann.
Chem. 562, 110).
Isothiocyanates of the general formula VIII are known in the literature or can
be
3 0 synthesized analogously to known processes. An amine of the general
formula Rg-NH2
is preferably allowed to react with carbon disulphide under alkaline
conditions
analogously to Chem. Ber. 74 1375.
The reaction of carboxylic acid halogenides, sulfonic acid halogenides or
chloroformic
3 5 acid esters of the general formula VII with amines of the general formula
VI is usually
carried out in a solvent such as dichloromethane, dimethylformamide or
pyridine with
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- 12
addition of an auxiliary base such as triethylamine or 4-dimethylaminopyridine
at a
temperature between -10°C and 50°C, preferably at room
temperature.
Compounds of the general formula I can contain one or several chiral centres
and can
then be present in a racemic or in an optically active form. The racemates can
be
separated according to known methods into the enantiomers. Preferably
diastereomeric
salts which can be separated by crystallization are formed from the racemic
mixtures by
reaction with an optically active acid such as e.g. D- or L-tartaric acid,
mandelic acid.
malic acid, lactic acid or camphorsulfonic acid or with an optically active
amine such as
e.g. D- or L-oc-phenyl-ethylamine, ephedrine, quinidine or cinchonidine.
Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts,
acetates or
hydrochlorides are mainly used as pharmacologically acceptable salts which are
produced
in the usual manner e.g. by tritrating the compounds with inorganic or organic
bases or
inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous
ammonia,
C 1-C4-alkyl-amines such as e.g. triethylamine or hydrochloric acid. The salts
are usually
purified by reprecipitation from water/acetone.
The new substances of formula 1 and salts thereof according to the invention
can be
2 0 administered enterally or parenterally in a liquid or solid form. In this
connection all the
usual forms of administration come into consideration such as for example
tablets,
capsules, coated tablets, syrups, solutions, suspension etc. Water which
contains
additives such as stabilizers, solubilizers and buffers that are usual in
injection solutions is
preferably used as the injection medium.
Such additives are e.g. tartrate and citrate buffer, ethanol, complexing
agents (such a
ethylenediaminetetra-acetic acid and non-toxic salts thereof), high-molecular
polymers
(such as liquid polyethylene oxide) to regulate viscosity. Liquid earner
substances for
injection solutions have to be sterile and are preferably dispensed into
ampoules. Solid
3 0 carrier substances are e.g. starch, lactose, mannitol, methylcellulose,
talcum, highly
dispersed silicic acids, higher molecular fatty acids (such as stearic acid),
gelatins, agar-
agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid
high-
molecular polymers (such as polyethylene glycols); suitable preparations for
oral
application can optionally also contain flavourings and sweeteners.
The dosage can depend on various factors such as manner of administration,
species, age
and/or individual state of health. The doses to be administered daily are
about 10-1000
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-13
mg/human, preferably 100-500 mg/human and can be taken singly or distributed
over
several administrations.
Prodrugs of the compounds of the invention are such which are converted in
vivo to the
pharmacological active compound. The most common prodrugs are carboxylic acid
esters.
Within the sense of the present invention the following barbituric acid
derivatives are
preferred in addition to the compounds mentioned in the examples and compounds
that
can be derived by combining all meanings of substituents mentioned in the
claims:
1. 5-(N-benzyl-N-octyl}-5-phenyl-barbituric acid
2. 5-(N-benzyl-N-phenethyl)-5-phenyl-barbituric acid
3. 5-(N-benzyl-N-[2-(4-pyridyl)ethyl)]-5-phenyl-barbituric acid
4. 5-(N-benzyl-N-[2-(3-pyridyl)ethyl]-5-phenyl-barbituric acid
5. 5-(N-benzyI-N-[2-(2-pyridyl)ethyl]-5-phenyl-barbituric acid
6. S-(N-benzyl-N-[2-(2-thiophenyl)ethyl]-5-phenyl-barbituric acid
7. 5-[N-(3-methylbutyl)-N-(3-phenylpropyl)]-5-phenyl-barbituric acid
8. 5-(N-benzyl-N-[3-(4-pyridyl)propyl])-5-phenyl-barbituric acid
2 0 9. 5-(N-benzyl-N-[2-(2-imidazolyi)ethyl])-5-phenyl-barbituric acid
10. 5-(N-benzyl-N-[2-{ I -imidazolyl)ethyl])-5-phenyl-barbituric acid
11. 5-{N-butyl-N-phenylalaninyl)-5-phenyl-barbituric acid
12. 5-(N-butyl-N-tryptophanyl)-5-phenyl-barbituric acid
13. 5-(N-benzyi-N-cyclohexyl)-5-phenyl-barbituric acid
14. 5-[N-benzyl-N-(2-pyridyl)]-5-phenyl-barbituric acid
15. 5-[N-butyl-N-(4-piperidinyl)]-5-phenyl-barbituric acid
16. 5-[N-benzyl-N-(2-imidazolyl)]-5-phenyl-barbituric acid
17. 5-(N-octyl-N-phenyl)-5-phenyl-barbituric acid
18. 5-[N-(2-naphthyl)-N-propyl]-5-phenyl-barbituric acid
3 0 19. 5-[N-(4-tetrahydroquinolinyl)-N-propyl]-5-phenyl-barbituric acid
20. 5-[N-benzyl-N-(2-thiophenyl)]-5-phenyl-barbituric acid
21. 5-[N-(3-methylbutyl)-N-[3-(4-pyridyl)propyl)]-5-phenyl-barbituric acid
22. 5-[N-(7-methyloctyl)-N-[3-(2-pyridyl)propyl)]-5-phenyl-barbituric acid
23. 5-{N-(2-hydroxyhexyl)-N-[3-(3-pyridyl)propyl])-5-phenyl-barbituric acid
3 5 24. 5-(N-benzyl-N-hexanoyl)-5-phenyl-barbituric acid
25. 5-(N-benzyl-N-octanoyl)-5-phenyl-barbituric acid
26. 5-(N-benzyl-N-octanesulfonyl)-5-phenyl-barbituric acid
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27. 5-[N-butyl-N-(2-naphthylsulfonyl)]-5-phenyl-barbituric acid
28. 5-(N-hexyloxycarbonyl-N-propyl)-5-phenyl-barbituric acid
29. 5-(N-(4-methoxy-phenylsulfonyl)-N-hexyl]-5-phenyl-barbituric acid
30. ~-[N-(4-butoxy-phenylsulfonyl)]-N-hexyI]-5-phenyl-barbituric acid
31. 5-[N-benzyl-N-(2-phenethyl)]-5-(4-pyridyl) barbituric acid
32. 5-[N-benzyl-N-(2-phenethyl)]-5-(2-pyridyl) barbituric acid
33. 5-(N,N-dipentyl)-5-(4-piperidinyl)barbituric acid
34. 5-(N,N-dioctyl)-5-(2-thiophenyl)barbituric acid
35. 5-{N-benzyl-N-[2-(2-pyridyl)ethyl]-5-{3-imidazolyl) barbituric acid
36. 5-[1-(4-hydroxy)piperidinyl]-5-(4-pyridyl) barbituric acid
37. 5-[ I -{4-hydroxy)piperidinyl]-5-(3-pyridyl) barbituric acid
38. 5-[I-(4-hydroxy)piperidinyl]-5-(2-pyridyl) barbituric acid
39. 5-[1-(4-hydroxy)piperidinyl]-5-(4-piperidinyl} barbituric acid
40. 5-[ 1-(4-hydroxy)piperidinyl]-5-{2-thiophenyl) barbituric acid
41. 5-[1-(4-hydroxy)piperidinyl]-5-(4-imidazolyl) barbituric acid
42. 5-benzyl-5-[ I -{4-hydroxy)piperidinyl]barbituric acid
43. 5-[1-(4-hydroxy)piperidinyl]-5-(2-phenethyl) barbituric acid
44. 5-[I-{4-hydroxy)piperidinyl]-5-(I-naphthyl) barbituric acid
45. 5-[ 1-(4-hydroxy)piperidinyl]-5-(2-naphthyl) barbituric acid
2 0 46. 5-(2-quinolinyl)-5-[ 1-(4-hydroxy)piperidinyl] barbituric acid
47. 5-[i-(4-hydroxy)piperidinyl]-5-(1-isoquinolinyl) barbituric acid
48. 5-[I-(4-hydroxy)piperidinyl]-5-(2-tetrahydro-quinolinyl)barbituric acid
49. 5-(2-indolyl)-5-[ 1-(4-hydroxy)piperidinyl] barbituric acid
50. 5-(2-benzimidazoiyl)-5-[i-(4-hydroxy)piperidinyI] barbituric acid
2 5 51. 5-( 1-[4-(2-hydroxyethyl)piperazinyl])-5-octyl-barbituric acid
52. 5-decyl-5-(1-[4-(2-hydroxyethyl)piperazinyl]) barbituric acid
53. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-undecyl-barbituric acid
54. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(7-methyl-octyl)barbituric acid
55. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-(8-hydroxy-octyl)barbituric acid
3 0 56. 5-(8-aminooctyl)-5-( I-[4-(2-hydroxyethyl) piperazinyl])barbituric
acid
57. 5-(1-[4-(2-hydroxyethyl}piperazinyl])-5-(2-phen-ethyl)barbituric acid
58. 5-(1-[4-(2-hydroxyethyl)piperazinyl])-5-{4-phenyl-butyl)barbituric acid
59. 5-{1-[4-(2-hydroxyethyl)piperazinyl])-5-{6-phenyl-hexyl}barbituric acid
60. 5-( I -[4-(2-hydroxyethyl)piperazinyl])-5-[6-(4-
methylphenyl)hexyl]barbituric
3 5 acid
61. 5-{I-[4-(2-hydroxyethyl)piperazinyl])-5-(2-pyridylmethyl)barbituric acid
62. 5-{1-[4-(2-hydroxyethyl)piperazinyl])-S-(4-imidazolylmethyl}barbituric
acid
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63. 5-(I-[4-(2-hydroxyethyl)piperazinyl])-S-(I-imidazolylmethyl)barbituric
acid
64. 5-phenyl-5-( 1-(4-propyl)piperazinyl]barbituric acid
6S. S-phenyl-S-( 1-tetrahydroquinoiinyl)barbituric acid
66. S-phenyl-5-(1-tetrahydroisoquinolinyl)barbituric acid
67. S-phenyl-5-[2-(1,2,3,4-tetrahydrobenzo(g)iso-quinolinyl]barbituric acid
68. S-[2-(Z-aza-bicyclo[9.4.0]pentadecyl)]-S-phenyl-barbituric acid
69. S-[2-(2,11-diaza-12-oxo-bicyclo[9.4.0]pentadecyl)]-5-phenyl-barbituric
acid
70. 5-{1-[4-(I-oxo-propyl)]piperidinyl)-5-phenyl-barbituric acid
71. S-[I-(3-oxo-4-propyl)]piperidinyl]-5-phenyl-barbituric acid
72. 5-phenyl-5-[1-(4-propyl)piperazinyl]barbituric acid
73. S-[I-(3,S-dihydroxy-4-propyl)piperidinyl]-S-phenyl-barbituric acid
74. 5-(4-chlorophenyl}-5-[I-(4-hydroxy)piperidinyl] barbituric acid
75. 5-{4-chlorobenzyl)-5-[1-(4-hydroxy)piperidinyl] barbituric acid
76. S-[1-(4-hydroxy)piperidinyl]-5-(4-methoxybenzyl) barbituric acid
77. 3-methyl-5-[ 1-(4-hydroxy}piperidinyl]-S-phenyl-barbituric acid
78. 1-isopropyl-5-[ I-{4-hydroxy)piperidinyl]-5-phenyl-barbituric acid
79. 3-acetyl-5-[1-(4-hydroxy)piperidinyl]-5-phenyl-barbituric acid
80. S-[1-{4-methoxy)piperidinyl]-5-phenyl-2-thio-barbituric acid
81. 2-imino-5-[1-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid
82. 5-[1-(4-methoxy)piperidinyl]-S-phenyl-2,4,6-triimino-barbituric acid
83. 4,6-diimino-5-[I-(4-methoxy)piperidinyl]-5-phenyl-barbituric acid
84. 5-[1-{4-methoxy)piperidinyl]-5-phenyl-2,4,6-trithio-barbituric acid
8S. 5-(6-aminohexyl}-S-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
86. 5-{6-formylaminohexyl)-5-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
87. 5-{6-acetylaminohexyl}-S-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
88. S-j7-(ethoxycarbonyl}heptyl]-S-[N-(2-hydroxyethyl)piperazinyl]barbituric
acid
89. S-(8-hydro:~yoctyl)-5-[N-(2-hydroxyethyi)piperazinyl]barbituric acid
90. S-(7-carboxyheptyl)-5-[N-{2-hydroxyethyl)piperazinyl]barbituric acid
9I. S-[7-(aminocarbonyl)heptyl]-S-[N-{2-hydroxyethyl)piperazinyl]barbituric
acid
3 0 92. 5-[3-((aminocarbonylmethyl)aminocarbonyl)propyl]-S-[N-(2-hydroxyethyl)-
piperazinyl]barbituric acid
93. S-[6-(methylamino)hexyl]-S-[N-(4-nitrophenyl)piperazinyl]barbituric acid
94. S-[4-(n-propyloxy)butyl]-S-[N-(4-nitrophenyl)piperazinyl]barbituric acid
95. 5-[2-{2-(2-methoxyethoxy)ethoxy)ethyl]-S-[N-(4-
3 5 nitrophenyl)piperazinyl]barbituric acid
96. 5-[2-(2-(ethoxy)ethoxy)ethyl]-5-[N-(4-nitrophenyi)piperazinyl]barbituric
acid
97. S-decyl-5-[N-(4-nitrophenyi)piperazinyl]barbituric acid
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98. 5-octyl-5-[N-(4-(hydroxysulphonyl)phenyl)piperazinyl]barbituric acid
99. 5-octyl-5-[N-(4-(aminosulphonyl)phenyl)piperazinyl]barbituric acid
100. 5-octyl-5-[N-(4-cyanophenyl}piperazinyl]barbituric acid '
101. 5-octyl-5-[N-(4-carboxyphenyl)piperazinyl]barbituric acid
102. 5-octyl-5-[N-(4-(buthoxycarbonyl)phenyl)piperazinyl]barbituric acid
103. S-octyl-5-[N-(4-(amidino)phenyl)piperazinyl]barbituric acid
104. 5-octyl-5-[N-(4-(aminothiocarbonyl)phenyl)piperazinyl]barbituric acid
105. 5-octyl-5-[N-{4-(methylsulphonyl)phenyi)piperazinyl]barbituric acid
106. 5-octyl-5-[N-(4-(aminocarbonyl)phenyl)piperazinyl]barbituric acid
107. 5-octyl-5-jN-(4-{methylcarbonyl)phenyl)piperazinyl]barbituric acid
108. 5-octyl-5-[N-{4-(dimethylphosphonyl}phenyl)piperazinyl]barbituric acid
109. 5-octyl-5-[N-(4-(amino)phenyl)piperazinyl]barbituric acid
110. 5-octyi-5-jN-(4-{acetylamino)phenyl)piperazinyl]barbituric acid
1 i 1. 5-octyl-5-[N-(4-(trifluoroacetyiamino)phenyl}piperazinyl]barbituric
acid
112. S-octyl-5-[N-(4-(methylsulphonylamino)phenyl)piperazinyl]barbituric acid
113. 5-octyl-5-[N-{5-nitropyrid-2-yI)piperazinyl]barbituric acid
114. 5-octyl-5-[N-{N-oxypyrid-4-yl)piperazinyl]barbituric acid
115. 5-octyl-5-[N-(4-(5-triazolyl)phenyl)piperazinyl]barbituric acid
116. 5-octyl-5-[(N-benzoyl-N-benzyl)amino]barbituric acid
2 0 117. 5-[4-(phenyl)phenyl]-5-j(N-benzoyl-N-benzyl)amino]barbituric acid
118. S-(4-[4-Nitrophenyl)piperazinyl])-5-octyl-barbituric acid
119. N-Benzyl-3-(4-nitro-phenyl)-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
S-yl)-acrylamide
120. 5-[4-(phenyl)phenyl]-5-[(N-benzoyl-N-benzyl)amino]-barbituric acid
121. N-Benzyl-2-(3-bromo-phenyl)-N-{2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
5-yl)-acetamide
Ezample 1
5-(1-f4-(2-H~xyethyl)piperazinyll)-5-phenyl-barbituric acid
5-Bromo-5-phenyl barbituric acid (Acta Chim. Acad. Sci. Hung. 107 139-45
(1981)) (7
mmol) and N-(2-hydroxy-ethyl)-piperazine (8 mmol) are suspended in 40 ml
absolute
ethanol. After 3 hours under reflux it is concentrated in a vacuum. The
residue is purified
by chromatography on silica gel (ethyl acetate/methanol 3 :1 ). Colourless
crystals are
obtained by recrystallization from isopropanol. Yield 56 %; Fp. 238-
40°C (decomp.).
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Example 2
S-(1-f4~-(4-Methylphenyl methyllpiperaziny,,-S-phenyl-barbituric acid
' S-Bromo-S-phenyl-barbituric acid (7 mmol) and N-(methyl-p-tolyl)-piperazin
(8 mmol)
are suspended in 40 ml absolute ethanol. After 2 hours under reflux it is
concentrated in
a vacuum. The residue is triturated with diethyl ether, sucked ofd rewashed
with 20 ml
diethyl ether and dried. The crude product is purified by chromatography on
silica gel
(acetone). One obtains colourless crystals. Yield 72 %; Fp. 247-48°C.
Example 3
~1-I[4-(4-(4-Meth~Iphenyl))butyll~aerazin~l-5-phenyl-barbituric acid _.
4-(p-Tolyl)-butyl bromide
The compound is prepared analogously to the literature. Synth. Commun.
22(20}2945-8
( 1992). Yield 91 % colourless oil.
Phenyl-(4-{p-tolyl)-butyl)-malonic acid diethyl ester
Phenylmalonic acid diethyl ester (8.8 mmol) dissolved in S ml absolute
tetrahydrofuran is
2 0 added dropwise to 20 ml absolute tetrahydrofuran and sodium hydride (9.7
mmoI). Then
4-p-tolylbutyl bromide (8.8 mmol) dissolved in 10 ml absolute tetrahydrofuran
is added
after 1 S minutes. It is heated for 3 days under reflux. The solvent is
concentrated in a
vacuum. The residue is taken up in SO ml ethyl acetate and extracted with 2 x
SO ml
water. The organic phase is dried over magnesium sulfate, filtered and
concentrated by
2 5 evaporation. It is purified by chromatography on silica gel (heptane/ethyl
acetate 9:1 ).
Yield SS % colourless oil.
S-1-f4-(4-(4-meth ly phen~ 1)i )butyllpinerazinyl)-5=phenyl-barbituric acid
Urea (4.6 mmol) and phenyl-(4-(p-tolyl)-butyt)-malonic acid diethyl ester (3.1
mmol) are
3 0 added to a solution of sodium ethylate (6.2 mmol) in absolute ethanol. It
is heated for 12
hours under reflux, then concentrated in a vacuum and the residue is taken up
in 1 S ml
water. The mixture is adjusted to pH 1-2 with 6 N hydrochloric acid and
extracted with
2 x 30 ml ethyl acetate. The organic phase is dried over magnesium sulfate,
filtered and
concentrated by evaporation. The residue is purified by chromatography on
silica gel
3 5 (heptane/ethyl acetate 3 :1 ). Yield 46 % colourless crystals; Fp. 163-
S°C.
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Example 4
S-( 1-(4-(2-Hydrox~yl)~peridinyll -5-phenyl-barbituric acid
14.6 g {50 mmol) phenylmalonic acid diethyl ester and subsequently 10 g (166
mmol)
urea are slowly added to I .3 g sodium in 40 ml methanol while stirring. It is
heated for 2
hours while slightly boiling. In this process a precipitate forms. It is
cooled to 10-IS°C,
subsequently slowly admixed with I 2.9 g { 100 mmol) 4-(2-
hydroxyethyl)piperidine, 13.8
g ( I 00 mmol) potassium carbonate and 2.87 ml ( I I2.3 mmol) bromine. The
mixture is
stirred for 2 hours at 10-15°C, then slowly heated to boiling and
boiled for 1 hour under
reflux. After cooling it is poured onto 240 ml In nitric acid, the solution is
washed once
with toluene and neutralized with a saturated sodium acetate solution. A
greasy mass
precipitates which is taken up in hot ethanol. The hot solution is treated
with active
carbon and admixed with warm water until turbidity starts. After cooling the
crystals are
suction filtered. Yield: 7.3 g = 44 %; Fp.: 222-223°C.
Example 5
S-Phenyl-5-(1=piperidinyl)barbituric acid
5-Phenyl-5-( I-piperidinyl)barbituric acid in a yield of 92 %; Fp.: 244-
246°C is obtained
analogously to example 4 using piperidine instead of 4-(2-hydroxyethyl)
piperidine.
2 o Example 6
5-(1-(4-Hydroxy)~ eridinyl]-5-phenyl-barbituric acid _ __
5-[I-(4-Hydroxy)piperidinyI]-5-phenyl-barbituric acid in a yield of39 %; Fp.:
241-242°C
(from ethanol) is obtained analogously to example 4 using 4-hydroxy-piperidine
instead
of 4-(2-hydroxyethyi)piperidine.
Example 7
5-[1-(4 4-Dirnethyl~p~eridin~l-5-phenyl-barbituric acid __
5-[1-(4,4-Dimethyl)piperidinyl]-5-phenyl-barbituric acid in a yield of 69 %;
Fp.: 238-
240°C (from ethanol/water) is obtained analogously to example 4 using
4,4-dimethyl-
3 0 piperidine instead of 4-(2-hydroxyethyl)piperidine.
Example 8
5-jl-(4-Methyl)-piperidinyil-5-phenyl-barbituric acid
5-[ 1-{4-Methyl)piperidinyl]-5-phenyl-barbituric acid in a yield of 87 %; Fp.:
208-209°C
(from methanol/water} is obtained analogously to example 4 using 4-methyl-
piperidine
instead of 4-(2-hydroxyethyi)piperidine.
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Example 9
5-f 1-(4-Methoxy)piperidinyll-5-phenyl-barbituric acid
5-[1-{4-Methoxy)piperidinyi]-5-phenyl-barbituric acid in a yield of 67 %; Fp.:
184-185°C
(from ethanol/water) is obtained analogously to example 4 using 4-methoxy-
piperidine
instead of 4-(2-hydroxyethyl) piperidine.
Example 10
5-Ethyl-5-f 1-(4-methyl piperidinyllbarbituric acid
14.1 g (75 mmol) ethylmalonic acid diethyl ester and subsequently 15 g (264
mmol) urea
is slowly added to 1.95 g sodium in 60 ml methanol while stirring. After
boiling for 2
hours a precipitate forms. It is cooled to 10-15°C and successively
slowly admixed with
g (15 mmol) 4-methylpiperidine, 21 g {150 mmol) potassium carbonate and 4.3
nnl
( I 68 mmol) bromine. The mixture is stirred for 2 hours at this temperature,
slowly
heated to boiling and heated for 1 hour under reflux. After cooling it is
poured onto 360
15 ml 1 N nitric acid, the solution is washed once with toluene and admixed
with an excess
of saturated sodium acetate solution. The precipitated precipitate is
recrystalIized from
ethanol with addition of active carbon. Yield: 4.4 g = 23 %; Fp.: 194-
195°C.
Example 11
2 0 5-Ethyl-5-'[ 1-(4-methoxy)piperidinyl~barbituric acid
5-Ethyl-5-[ I-{4-methoxy)piperidinyi]barbituric acid in a yield of 15 %; Fp.:
201-202°C
(from ethanol) is obtained analogously to example 10 using 4-methoxypiperidine
instead
of 4-methyipiperidine.
Example i2
5-Etl~l-5-(1-(4-h dy roxy~piperidinyl]barbituric acid
5-Ethyl-5-{I-(4-hydroxy)piperidinyl]barbituric acid in a yield of 5 %; Fp.: 1
IO-112°C
(from ethanol) is obtained analogously to example 10 when using 4-
hydroxypiperidine
instead of 4-methoxypiperidine.
Example 13
5-Ethyl-5-[~4-(2-hydroxyeth~)piperidinyl)]barbituric acid
_ 5-Ethyl-5-[1-(4-(2-hydroxyethyi)piperidinyl)]barbituric acid in a yield of
17 %; Fp.: 238-
240°C (from methanol) is obtained analogously to example 10 using 4-(2-
3 5 hydroxyethyl)piperidine instead of 4-methylpiperidine.
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Example 14
~4-methox~phenyl)-5-[N-(2-hydroxvethyl)piperazinyl]barbituric acid
a) preparation of ethyl 4-methoxyphenylacetate
A solution of 4-methoxyphenylacetic acid (2 g) and para-toluensulfonic acid
(230 mg) in
30 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under
reduced
pressure and the residue is suspended in a saturated aqueous solution of
sodium
hydrogencarbonate and extracted twice with ethyl acetate. The organic extracts
are
collected, washed with water and dried over sodium sulfate to give, after
evaporation of
the solvent under reduced pressure, 2.14 g of the product.
b) preparation of ethyl 4-methoxyphenyl malonate
A mixture of ethyl 4-methoxyphenylacetate (27.8 g) and sodium (3.68 g) in 90
ml of
diethyicarbonate is refluxed for 3 hours, then the solvent is evaporated under
reduced
pressure and the residue is diluted with water and neutralized with acetic
acid. The
aqueous phase is extracted twice with diethyl ether. The organic extracts are
pooled and
washed twice with 1 N sodium hydroxide and once with water, then the organic
phase is
dried over sodium sulfate and concentrated to dryness. 34.2 g of the product
are
obtained.
c) preparation of 5-(4-methoxyphenyl)barbituric acid
To a solution of 660 mg of sodium in 50 ml of ethanol are added 3.86 g of
ethyl 4-
methoxyphenyl malonate and 1.28 g of urea. The reaction mixture is refluxed
far 3
hours. A white solid separates, which is collected by filtration and
redissolved in 15 ml of
water. The solution is acidified to pH = 1-2 by adding 6 N hydrochloric acid.
A white
solid separates, which is filtered and washed on the filter with water. After
drying under
vacuum at 50°C for several hours, 2.28 g of the product are obtained.
d) preparation of 5-bromo-5-(4-methoxyphenyl)barbituric acid
3 0 To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 3 mi of
water,
cooled to 0-5°C with ice bath, are added 136 p.l of 48% hydrobromic
acid and 56 p.I of
bromine, dropwise. After 1 hour at a temperature below 10°C, the solid
which separated
is collected by filtration and washed on the filter with water. The solid is
dried for several
hours under vacuum at 50°C, to give 283 mg of the product.
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e) preparation of the title compound
A solution of 5-bromo-5-(4-methoxyphenyl)barbituric acid ( 1 I .5 g) and N-(2-
hydroxyethyl) piperazine ( I 5.755 g) in 260 ml of methanol is refluxed for
about 2 hours,
then the solid which separated is collected by filtration, redissolved in 100
ml of
methanol and heated at reflux for I hour. The solid is filtered again and
dried at 80°C
under vacuum to give 9 g of the product containing 8-9% of methanol. The solid
is
dissolved in 40 ml of 1 N hydrochloric acid, then the solution is basified
with 3.42 g of
sodium hydrogencarbonate and cooled at 0-5°C for 4 hours. The product
is recovered by
filtration and it is dried under vacuum at 80°C for sevaral hours, to
give 8.55 g of the
pure product, m.p. 247-248°C.
'H-NMR in d6-DMSO: 2.36 ppm (m, 6H); 2.55 ppm (m, 4H); 3.44 ppm (q, ZH); 3.74
ppm (s, 3H); 4.33 ppm (t, I H); 6.95 ppm (d, 2H); 7.3 ppm (d, 2H); 11.54 ppm
(br s,
2H).
Example 15
5-[3-(4-methoxyphenyl)propyl]-5-[4-(2-hydroxyethyl)piperazinyl] barbituric
acid
a) preparation of 3-(4-methoxyphenyl)propionyl chloride
2 0 To a suspension of 3-(4-methoxyphenyl)propioruc acid ( 10 g) in 150 ml of
toluene are
added 8 ml of thionyl chloride and the mixture is heated to 65°C for 4
hours. The solvent
is evaporated off under reduced pressure and the residue is redissolved in
toluene and
concentrated to dryness. Such steo is repeated twice. 11 g of the product are
obtained as
a yellow oil.
b) preparation of 5-{3-(4-methoxyphenyi)propionyl]barbituric acid
To a suspension of barbituric acid (6.4 g) in 48 mi of pyridine are added
dropwise 11 g
of 3-(4-methoxyphenyl)propionyl chloride and the mixture is stirred at room
temperature
3 0 for 18 hours. The reaction mixture is then poured into ice and acidified
to pH = 1 by
adding 6 N hydrochloric acid. A solid precipitates, which is filtered and
resuspended in
methanol. The suspension is kept under stirring for 15 minutes, then the solid
is
recovered by filtration to give 12.2 g of the product. m.p. 248-250°C.
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c) preparation of 5-[3-(4-methoxyphenyl)propyl]barbituric acid
To a suspension of 10 g of 5-[3-(4-methoxyphenyl)propionyl]barbituric acid in
100 ml of
acetic acid are added portionwise 4.5 g of sodium cyanoborohydride, then the
mixture is
heated to 60°C. After 1 hour the reaction mixture is cooled to room
temperature and
poured into ice. After 30 minutes a solid is recovered by filtration, which is
dried under
vacuum at 50°C to give 8.74 g ofthe product, m.p. 195-197°C.
d) preparation of 5-bromo-5-[3-(4-methoxyphenyl)propyl]barbituric acid
A mixture of 5-[3-(4-methoxyphenyl)propyt]barbituric acid (2.5 g), N-
bromosuccinimide
{2 g) and dibenzoyl peroxide (catalytic amount) in I 10 ml of carbon
tetrachloride is
refluxed for about 1 hour, then the solid which separated is filtered. The
solid is
redissolved in ethyl acetate and filtered through a silica gel cake in order
to eliminate the
succinimide residue. The organic phase is then concentrated to dryness and the
residue is
crystallized from diethylether/carbon tetrachloride mixture. A pale yellow
solid separates
which is filtered and dried under vacuum at 60°C to give 2.8 g of the
product, m.p. 1 I3-
114°C.
e} preparation ofthe title compound
A mixture of 5-bromo-5-[3-(4-methoxyphenyl)propyl]barbituric acid (710 mg) and
N-(2-
hydroxyethyl}piperazine (281 mg) in ZS mI of ethanol is refluxed for 4 hours.
The solvent
is evaporated under reduced pressure and the residue is partitioned between 1
N
hydrochloric acid and ethyl acetate. The aqueous phase is basified to pH =6-7
and
extracted with ethyl acetate. The organic phase is concentrated to dryness and
the
residue is crystallized from ethyl acetate to give 30 mg of the product.
'H-NMR in d6-DMSO: 1.32 ppm (m, 2H); 1.86 ppm (m, ZH); 2.33 ppm (m, 6H); 2.45
ppm (m, 2H); 2.53 ppm (m, 4H); 3.43 ppm (q, 2H); 3.7 ppm (s, 3H); 4.35 ppm (t,
1H);
3 0 6.8 ppm (d, 2H); 7.04 ppm (d, 2H); I 1.53 ppm {br s, 2H).
Example 16
5-phen~-[4-(2-hvdroxyethylidene~piperidin~lbarbituric acid
a) preparation of 4-(ethoxycarbonylmethyiidene)piperidine
To a suspension of sodium hydride (2.6 g) in 30 ml oftetrahydrofuran, cooled
to 0°C
and kept under nitrogen atmosphere, 13 ml of triethylphosphonoacetate,
dissolved in I 0
ml of tetrahydrofuran, are added dropwise. The temperature is then brought to
room
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temperature and the stirring is continued for 30 minutes. The mixture is again
cooled to
0°C and it is added dropwise with a solution obtained by adding
portionwise to a
solution of 4-piperidone monohydrate hydrochloride ( 10 g) in THF 2.6 g of
sodium
hydride. filtered to eliminate the sodium chloride which formed. At the end of
the
addition, the temperature is brought to room temperature and the stirring is
continued
for 20 hours. The solvent is then evaporated under reduced pressure and the
residue is
redissolved in ethyl acetate and washed with I N hydrochloric acid. The
aqueous phase is
extracted with ethyl acetate and chloroform, then it is basified to pH = 9-10
by adding
20% sodium hydroxide and it is extractedb with chloroform. The aqueous phase
is then
salted and extracted again with chloroform three times. The pooled extracts
are dried
over sodium sulfate and evaporated to give 7.1 g of the product as a yellow
oil.
b) preparation of 4-(hydroxyethylidene)piperidine
A solution of I 5 ml of DIBAL ( 1.5 M solution in toluene) in 20 ml of toluene
is added
dropwise with 0.976 g of 4-(ethoxycarbonyimethylidene)piperidine, dissolved in
few
milliliter of toluene. The reaction mixture is stirred at room temperature for
2 hours, then
it is cooled to 0-5°C and added dropwise with methanol, until the gaz
development is
seen. The mixture is concentrated to a little volume and diethyl ether is
added: a white
solid separates, which is filtered ofl' The organic phase is concentrated to
dryness,
2 0 redissolved in diethyl ether and again filtered. The clear solution is
concentrated to
dryness to give 500 mg of the product.
c) preparation of the title compound
A mixture of 5-bromo-5-phenylbarbituric acid (2.45 g), 4-
(hydroxyethylidene)piperidine
2 5 ( 1.053 g) and triethylamine { 1.15 mI) in 50 ml of ethanol is refluxed
for 2 hours. The
solvent is evaporated under reduced pressure and the residue is purified by
silica gel
chromatography (40 g; eluent: ethyl acetate/petroleum ether 8:2), to give 450
mg of the
product.
1H-NMR in d6-DMSO: 2.13 ppm {m, 4H); 2.55 ppm (m, 4H); 3.89 ppm (d, 2H); 4.46
30 ppm (br s, 1H); 5.24 ppm (t, IH); 7.42 ppm (m, SH); 11.6 ppm (br s, 2H).
50 mg of 5-phenyl-5-[4-(2-hydroxyethyl)-1,2,5,6-tetrahydropyridinyl]barbituric
acid as a
side product are also recovered.
1H-1'JMR in d6-DMSO: 1.96 ppm (m, 2H); 2.09 ppm (t, 2H); 2.64 ppm (t, 2H);
3.00
35 ppm {m, 2H); 3.47 ppm (q, 2H); 4.43 ppm (t, IH); 5.3 ppm (m, 1H); 7.4 ppm
(s, SH);
11.63 ppm {br s, 2H).
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Example 17
5-phenyl-5-jN-(2-hydroxyethyl)~perazin~l-2-thiobarbituric acid
a) preparation of diethyl 2-bromo-2-phenylmalonate
To a solution of diethyl 2-phenylmalonate ( 15 mI) in 200 ml of
tetrahydrofuran, kept at
0°C and under nitrogen atmosphere, 3.475 g of sodium hydride are added
and the
mixture is kept 30 minutes under stirring at 0°C, then it is brought to
room temperature.
After cooling again to 0°C, the reaction mixture is added with 14.3
g of N-
bromosuccinimide. After about 15 minutes, the white solid which separated is
filtered off
and the filtrate is concentrated to dryness to give a residue which is
redissolved in
chloroform and dried over sodium sulfate. The solvent is evaporated under
reduced
pressure to give 15.66 g of the product.
b) preparation of diethyl 2-phenyl-2-[4-(2-hydroxyethyl)piperazinyl]malonate
A solution of diethyl 2-bromo-2-phenylmalonate ( 16.8 g) in I 50 ml of
dimethylsulfoxide
is heated to 90-100°C, then N-(2-hydroxyethyl)piperazine (27.9 g) is
added and the
reaction mixture is heated for additional 4 hours. The mixture is poured into
water and
extracted with ethyl acetate three times. The pooled organic extracts are
washed with 1
N hydrochloric acid. The aqueous phase is basified with 1 N sodium hydroxide
to pH =
2 0 8-9 and it is extracted twice with ethyl acetate. The organic extracts are
collected and are
washed with a saturated aqueous solution of sodium chloride and dried over
sodium
sulfate. After removal of the solvent under reduced pressure, the residue is
crystallized
from diethylether/petroleum ether 1:1 to give 6.5 g of the product, m.p. 63-
64°C.
2 5 c) preparation of the title compound
To a solution of sodium (27 mg) in 3 ml of ethanol are added 218 mg of diethyl
2-
phenyl-2-[4-(2-hydroxyethyl)piperazinyl]malonate and 288 mg of thiourea, then
the
mixture is refluxed for about 13 hours. The reaction mixture is cooled to room
temperature and 140 p.l of acetic acid are added, then the solvent is
evaporated under
3 0 reduced pressure. The residue is redissolved in a ethyl acetatelmethanol
9:1 mixture. The
solid which separates is filtered off and the filtrate is concentrated to
dryness and purified
by silica gel chromatography (eluent: from ethyl acetate to ethyl
acetate/methanol 9:1 ),
to give, after crystallization from ethyl acetate, 30 mg of the product, m.p.
>250°C.
35 1H-NMR in d6-DMSO: 2.4 ppm (m, 6H); 2.59 ppm (m, 4H); 3.46 ppm (q, 2H); 4.4
ppm (t, 1H); 7.4 ppm (m, SH); 12.5 ppm (br s, 2H).
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Example 18
5-phenyl-5-[N-(2-hvdroxyeth~)piperazinyl]-2-azobarbituric acid
To a solution of sodium (70 mg) in 5 ml of ethanol are added 218 mg of diethyl
2-
phenyl-2-[4-(2-hydroxyethyl)piperazinyl]malonate (example 4 - step b) and 172
mg
guanidine hydrochloride and the mixture is refluxed for 8 hours. Further 57 mg
of
guanidine hydrochloride are added and the mixture is refluxed for additional 6
hours. The
temperature is brought to room temperature and acetic acid is added until
neutralization
occurs, then the solid which is formed is filtered ofd The filtrate is
concentrated to
dryness and redissolved in ethanol, from which by adding of ethyl acetate a
solid
separates. After 1 hour at -4°C the white solid is recovered by
filtration and it is
recrystallized from methanol (2 ml), to give, after drying under vacuum at
90°C for 4
hours, 78 mg of the product, m.p. >250°C.
1H-NMR in d6-I~M50: 2.33 ppm (m, 6H); 2.54 ppm (m, 4H); 3.41 ppm (t, ZH); 4.33
ppm (br s, 1H); 7.00 ppm (br s, 1H); 7.33 ppm (m, SH); 7.5 ppm (br s, 1H); l
I.4 ppm
(br s, 1H).
Example 19
2 0 5-benzyl-5-fN-(2-hvdroxyeth~~~erazinyl]barbituric acid -
a) preparation of 5-benzylidenebarbituric
A suspension of 5 g of barbituric acid in 50 ml of water is heated until a
compklete
dissolution occurs, then it is added with 4.3 ml of benzaldheide. The mixture
is refluxed
for 1 hour, then the solid which separated is filtered, washed several times
with water
and dried under vacuum at 100°C, to give 8. I7 g of the product, m.p.
>258°C.
b) preparation of 5-benzylbarbituric acid
To a suspension of 5-benzylidenebarbituric acid (4 g) in 200 ml of methanol
are added
portionwise 1.4 g of sodium borohydride. After 10 minutes from the end of the
addition,
3 0 100 ml of water are added and the mixture is acidified with 1 N
hydrochloric acid to pH
= 2. The solvent is evaporated off and the aqueous phase is extracted with
ethyl acetate.
The pooled extracts are dried over sodium sulfate and concentrated to dryness.
3.6 g of
the product crystallize, m.p. 207-209°C.
3 5 c) preparation of 5-bromo-5-benzylbarbituric acid
To a suspension of 5-benzylbarbituric acid (1.7 g) in 15 ml of water, cooled
to 0-5°C, I
ml of 48% hydrobromic acid are added, followed by the addition dropwise of
0.437 ml
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of bromine into the reaction mixture. After 1 hour under stirring at a
temperature below
10°C. the solid which formed is separated by filtration and washed with
water. 2.17 g of
the product are obtained. m.p. 164-166°C.
d) preparation of the title compound
A solution of S-bromo-S-benzylbarbituric acid (2.15 g) and N-(2-
hydroxyethyl)piperazine in 50 ml of ethanol is refluxed for 4 hours, then it
is cooled to
room temperature and added with 4 ml of triethylamine. The solvent is
evaporated off
and the white residue is redissolved in a ethyl acetate/methanol 3:1 mixture.
An ornage
solid crystallizes, which is recovered by filtration. After recrystallization
from ethanol
0.62 g of the product are obtained, m.p. 243-246°C.
tH-NMR in d6-DMSO: 2.43 ppm (t, 2H); 2.58 ppm (m, 4H); 3.03 ppm (m, 4H); 3.34
ppm (s, 2H); 3.49 ppm (q, 2H); 4.5 ppm (t, 1H); 7.13 ppm (m, SH); 8.8 ppm (br
s, 2H).
Example 20
S-[N-(2-hydrox~~piperazin lei-5-(4-h d~ roxXphenyl)barbituric acid
a) preparation of 5-(4-hydroxyphenyl)barbituric acid
To a suspension of S-(4-methoxyphenyl)barbituric acid (222 mg) in S ml of
methylene .
2 0 chloride, kept at -S/-10°C and under nitrogen atmosphere, is
dropped a solution of boron
tribromide (473 p.I) in 2 ml of methylene chloride. The stirring is continued
for additional
2 hours at -5°C, then the temperature is brought to room temperature
and stirnng is
continued for further 20 hours. The reaction mixture is again cooled to
0°C with an ice
bath and it is basified to pH = 9-10 by adding dropwise 5% sodium hydroxide.
The
aqueous phase is separated, filtered through a celite plug, cooled with ice
bath and
acidified to pH = 1 with 37% hydrochloric acid. A white solid separates which
after 1
hour is separated by filtration and dried under vacuum at 60°C to give
215 mg of the
product.
3 0 b) preparation of 5-[4-(tertbutyldimethylsilyloxy)phenyl]barbituric acid
To a solution of 5-(4-hydroxyphenyl)barbituric acid (1.9 g) and tertbutyl
dimethylsilyl
chloride (4.68 g) in 20 ml of anhydrous dimethylformamide are added 4.4 g of
imidazole
and the mixture is heated to 55°C for 5 hours. The temperature is then
brought to room
temperature and the reaction mixture is poured into 1 N hydrochloric acid and
extracted
3 5 twice with ethyl acetate. The pooled organic extracts are washed with
water and dried
over sodium sulfate. By concentration of the solution a white solid separates,
which is
kept at 0°C overnight, then it is filtered to give 2.185 g of the
product.
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c) prepay anon of 5-bromo-5-[(4-tertbutyldimethylsilyloxy)phenyl]barbituric
acid
To a suspension of 5-[4-{tertbutyldimethylsilyloxy)phenyl]barbituric acid (330
mg) and
dibenzoyl peroxide (catalytic amount) in 10 ml of carbon tetrachloride are
added 210 mg
of N-bromosuccinimide. The mixture is stirred at room temperature for 1 hour,
then the
solvent is evaporated off and the residue is purified by silica gel
chromatography (eluent:
petroleum ether/ethyl acetate 8:2), to give 260 mg of the product.
d) preparation of 5-[N-(2-hydroxyethyl)piperazinyl]-S-[(4-
tertbutyldimethylsilyloxy}phenyl]barbituric acid
A solution of 5-bromo-5-[(4-tertbutyldimethylsilyloxy)phenyl]barbituric acid
(260 mg)
and N-(2-hydroxyethyl)piperazine (98 mg) in 5 ml of ethanol is refluxed for 1
hour, then
it is brought to room temperature and added with 0.3 ml of triethylamine. The
solvent is
evaporated off and the residue is purified by silica gel chromatography (25 g;
eluent:
ethyl acetate/methanol 3 :1 ), to give, after crystallization from ethyl
acetate, 170 mg of
the product, m.p. 220-221°C.
e) preparation of the title compound
A mixture of 5-[N-(2-hydroxyethyl)piperazinyl]-5-[(4-
tertbutyldimethylsilyloxy)phenyl]barbituric acid ( 148 mg), tetrabutylammonium
fluoride
2 0 ( 1.1 M in THF; 0.6 ml) and acetic acid (290 pl) in 10 mi of
tetrahydrofuran, kept at 0°C,
is stin-ed for 2 hours 30 minutes, then the solvent is evaporated off and the
residue is
purified by silica gel chromatography ( 12 g; eluent: ethyl acetate/methanol 3
:1 ), to give,
after crystallization from ethyl acetate and recrystailization from ethyl
acetate/methanol
mixture, 40 mg of the product, m.p. >25°C.
'H-NMIt in d6-DMSO: 2.37 ppm {m, 6H); 2.55 ppm (m, 4H); 3.45 ppm (q, 2H); 4.35
ppm (t, 1H); 6.76 ppm {d, ZH); 7.17 ppm (d, 2H); 9.72 ppm (s, iH); 11.47 ppm
(br s,
2H).
Ezample 21
3 0 5-[N-(2-hydrox r~ eth~~perazinyll-5-(3-hydroxyphenyl)barbituric acid
a) preparation of ethyl 3-hydroxyphenylacetate
A suspension of 3-hydroxyphenylacetic acid {5.4 g) and para-toluensulfonic
acid (650
mg) in 80 ml of ethanol is refluxed for 4 hours, then the solvent is
evaporated off and the
3 5 residue is dissolved in ethyl acetate and washed twice with a saturated
aqueous solution
of sodium hydrogencarbonate. The organic phase is dried over sodium sulfate
and the
solvent is evaporated off to give 6.08 g of the product as a yellow oil.
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b} preparation of ethyl 3-(tertbutyldimethylsilyioxy)phenylacetate
To a solution of ethyl 3-hydroxyphenylacetate (6 g) and tertbutyldimethylsilyl
chloride
(6 g) in 80 ml of anhydrous dimethylformamide are added 5.66 g of imidazole
and the
mixture is stirred at room temperature for I hour 30 minutes. The reaction
mixture is
then poured into water and extracted twice with ethyl acetate. The pooled
organic
extracts are dried over sodium sulfate and concentrated to dryness to give 10
g of the
product as a yellow oil.
c} preparation of diethyl 3-(tertbutyldimethylsilyloxy)phenylmalonate
To a solution of ethyl 3-(tertbutyldimethylsilyloxy)phenylacetate ( 10 g) in
25 ml of
diethyicarbonate are added portionwise 0.86 g of sodium and the mixture is
refluxed for
2 hours. The solvent is evaporated off and the residue is poured into water
(90 ml). The
pH is adjusted to pH = 6 with acetic acid and the mixture is extracted with
diethyl ether.
The organic phase is dried over sodium sulfate and cocentrated to dryness to
give 10 g
of an orange oil which is purified by silica gel chromatography (eluent:
petroleum
ether/ethyl acetate 95:5}, to give 2.45 of the product.
d) preparation of 5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituric acid
To a solution of diethyl 3-(tertbutyldimethylsilyloxy)phenylmalonate ( I .5 g)
in 1 S ml of
2 0 ethanol are added 0.445 g of sodium ethoxide and 0.295 g of urea and the
mixture is
refluxed for 3 hours. The reaction mixture is cooled to room temperature and
the solid
formed is filtered. The solid is redissolved in water, the pH is adjusted to
pH = I-2 with
6 N hydrochloric acid and the soild which precipitates is recovered by
filtration. The
flitrate is concentrated to eliminate the ethanol, then the solution is
basified and extracted
2 5 with ethyl acetate. The organic phase is concentrated to dryness to give
250 mg of
residue which is pooled with the solid previously filtered (350 mg). The
residue so
obtained contains a mixture of the product along with the de-silyiated
derivative.
Such a residue (550 mg) is dissolved in 5 ml of anhydrous dimethylformamide
and 790
3 0 mg of tertbutyldimethylsilyl chloride and 745 mg of imidazole are
successively added.
The mixture is heated to 55°C for 5 hours. Furher 75 mg of imidazole
and 79 mg of
tertbutyldimethylsily! chloride are added and the heating is continued for an
additional
hour. The reaction mixture is then poured into 1 N hydrochloric acid and
extracted three
times with ethyl acetate. The pooled organic extracts are washed with water
and dried
3 5 over sodium sulfate. The solution is concentrated and a white solid
precipitates. 710 mg
of the product are recovered by filtration.
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e) preparation of 5-[3-(tertbutyldimethylsilyloxy)phenyl]-5-bromobarbituric
acid
A mixture of S-[3-(tertbutyldimethylsilyloxy)phenyl]barbituric acid (680 mg),
N-
bromosuccinimide (432 mg) and dibenzoyl peroxide (catalytic amount) in 10 ml
of
carbon tetrachloride are stirred at room temperature for 1 hour. The solvent
is
evaporated off and the residue is purified by silica gel chromatography
(eluent: ethyl
acetate/hexane 7:3) to give 550 mg ofthe product, m.p. 170-I72°C.
~ preparation of S-[N-(2-hydroxyethyl)piperazinyl]-S-[3-
(tertbutyldimethylsilyloxy)phenyl]barbituric acid
A solution of 5-[3-(tertbutyldimethylsilyloxy)phenylj-5-bromobarbituric acid
(444 mg)
and N-(2-hydroxyethyl)piperazine (420 mg) in 10 ml of methanol is stirred at
room
temperature for 5 hours, then the solvent is evaporated ofd and the residue is
purified by
silica gel chromatography ( 13 g; eluent: ethyl acetate/methanol 3:1), to give
70 mg of the
product.
1S
g) preparation of the title compound
To a solution of 5-[N-{2-hydroxyethyl)piperazinyl]-5-[3-
(tertbutyldimethyisilyloxy)phenyl]barbituric acid (170 mg) in I2 ml of
tetrahydrofuran,
kept at 0°C and under nitrogen atmosphere, are added 333 p.l of acetic
acid and 0.69 ml
2 0 of tetrabutylammonium fluoride. The mixture is stirred for 3 hours then
the solvent is
evaporated off and the residue is purified by silica gel chromatography { I 5
g; eluent:
ethyl acetate/methanol 4:1 ), to give, after crystallization from methanol, 3
S mg of the
product, m.p. 219-221 °C.
1H-NMR in d6-DMSO: 2.37 ppm (m, 6H}; 2.59 ppm (m, 4H); 3.45 ppm (q, 2H); 4.35
25 ppm (t, 1H); 6.74 ppm (m, 2H); 6.92 ppm (t, IH}; 7.18 ppm (t, 1H); 9.62 ppm
(s, IH);
1 I.54 ppm (br s, 2H).
Example 22
5-LTl-(2-hydroxyeth r~l piperazinyl]-5-(4-methylt~henyl~barbituric acid
a) preparation of S-(4-methylphenyl)barbituric acid
To a solution of sodium ( I 84 mg) in I 2 mI of ethanol are added 0.95 ml of
diethyl 2-(4-
methylphenyl)malonate and 360 mg of urea. then the mixture is refluxed for 3
hours. A
white solid separates, which is filtered and redissolved in 4 ml of water. The
solution is
acidified to pH = 1-2 by adding 6 N hydrochloric acid. A white solid
separates, which is
collected by filtration, washed with I 5 ml of water and dried under vacuum.
619 mg of
the product are obtained, m.p. 27I°C.
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b) preparation of S-bromo-S-(4-methylphenyl)barbituric acid
To a suspension of 5-(4-methylphenyl)barbituric acid (218 mg) in 2 ml of
water, kept at
I 0°C under stirring, I 36 p.I of 48% hydrobromic acid are added, then
S6 p.l of brominr
are dropped and the stirring is continued for 3 hours. The precipitate which
formed is
recovered by filtration and washed with water. then it is dried under vacuum
to give 270
mg of the product, m.p. 210-213°C.
c) preparation of the title compound
A solution of S-bromo-5-(4-methylphenyi)barbituric acid (3.1 g} and of N-(2-
hydroxyethyl) piperazine ( I .S3 g) in 60 ml of ethanol is refluxed for 3
hours. The solvent
is evaporated ofd' and the residue is dissolved in I N hydrochloric acid and
washed twice
with ethyl acetate, The aqueous phase is basified with 1 N sodium hydroxide
and
extracted with ethyl acetate. The organic extracts are concentrated to dryness
and the
residue is purified by silica gel chromatography ( i 00 g; eluent: ethyl
acetate/methanol
3 :1 ), to give, after evaporation of the solvent, 1.97 g of the product as
hydrobromide.
The free base is obtained by treating an ethyl acetate suspension (200 ml) of
the salt with
SO ml of a saturated aqueous solution of sodium hydrogencarbonate and by
extraction of
the aqueous phase with ethyl acetate. By concentrating to dryness the pooled
organic
2 0 extracts 1. I 8 g of theproduct are obtained.
'H-NMR in d6-DMSO: 2.3 ppm (s, 3H); 2.35 ppm (m, 6I~; 2.57 ppm (m, 4H); 3.45
ppm (q, 2H); 4.35 ppm (t, IH); 7.19 ppm (d, ZH); 7.28 ppm (d, 2H); 1 I.SS ppm
(br s,
2H).
Example 23
S-octyl-S-[N-(2-hydroxyethyl)piperazinyl]barbituric acid
a) preparation of diethyl 2-octylmalonate
3 0 To a solution of 2.63 of sodium in 100 ml of ethanol is added dropwise a
solution of
19. I ml of diethylmalonate in 10 ml of ethanol. The mixture is successively
added with
20.4 ml of 1-bromooctane dissolved in 10 ml of ethanol, then the mixture is
refluxed for
6 hours. The reaction mixture is concentrated to a little volume and the
residue is
partitioned between a saturated aqueous solution of sodium hydrogenphosphate
(200 ml)
3 5 and ethyl acetate (200 ml). The organic phase is washed with 7S ml of
water and 7S ml
of saturated aqueous solution of sodium chloride, dried over sodium sulfate
and
concentrated to dryness. to give 3 I .8 g of the product as an oil.
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1H-NMR in CDCI3: 0.80-0.95 ppm (m. 3H); 1.15-1.40 ppm (m, 18H); 1.88 ppm (q,
2H); 3.33 ppm (t, 1H); 4.19 ppm (q, 4H).
b) preparation of 5-octylbarbituric acid
To a solution of sodium (5.32 g) in 400 ml of anhydrous ethanol is added a
solution of
diethyl 2-octylmalonate (31.5 g) in 50 ml of ethanol and successively 10.27 g
of urea,
then the mixture is refluxed for 2 hours 30 minutes. The mixture is rapidly
cooled to
room temperature and the solid which was formed is recovered by filtration and
washed
with diethyl ether. The solid is then dissolved in 200 ml of water and
acidified with 6 N
hydrochloric acid until pH I .5-2 is reached. A solid separates. The mixture
is added with
200 ml of ethyl acetate and it is stirred for 2 hours, then it is added with
additional 800
ml of warm ethyl acetate. The organic phase is separated and the aqueous phase
is
washed with 200 ml of ethyl acetate.The pooled organic phases are washed with
250 ml
of saturated aqueous solution of sodium chloride, dried over sodium sulfate
and
concentrated to dryness. 21.03 g of the product are obtained.
1H-NMR in d6-DMSO: 0.77-0.80 ppm (m, 3H); 1.23 ppm (s, 12H); 1.80-1.95 ppm {m,
2H); 3.52 ppm (t, 1H); 1 1.15 ppm (s, ZH).
c) preparation of 5-bromo-5-octylbarbituric acid
2 0 To a suspension of 5-octylbarbituric acid (20 g) in 120 ml of water,
cooled at 0-5°C, are
added 12 ml of 48% hydrobromic acid and successively are dropped 4.72 ml of
bromine.
Ater 2 hours under stirring, the white solid which separated is recovered by f
ltration,
washed with water and partitioned between 200 ml of diethyl ether and 100 ml
of water.
The aqueous phase is extracted with additional 50 ml of diethyl ether. The
pooled
2 5 organic phases are washed with 75 ml of saturated aqueous solution of
sodium chloride,
dried over sodium sulfate and concentrated to dryness. 25.8 g of the product
as white
solid are obtained.
IH-NMR in d6-DMSO: 0.78-0.90 ppm (m, 3H); 1.10-I.38 ppm (m, 12H); 2.20-2.34
ppm (m, 2H); 1 1.80 ppm (s, 2H).
d) preparation of the title compound
To a solution of 5-bromo-5-octylbarbituric acid (23.52 g) in 70 ml of
dimethylsulfoxide,
kept under nitrogen atmosphere and at a temperature of 5-10°C, is
dropped N-(2-
hydroxyethyl}piperazine (36.2 ml), then the mixture is stirred at room
temperature for 2
3 5 hours 30 minutes. The reaction mixture is poured into water ( 1 1) under
stirring and
cooling with an ice bath. The white solid which separates is recovered by
filtration,
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washed with water and dried under vacuum at 40°C, to give, after
crystallization from
ethanol { 140 ml) I 0.91 g of the product as a white solid, m.p. 183-
184°C.
1H-NMR in d6-DMSO: 0.75-0.88 ppm {m, 3H); 0.90-1.10 ppm (m, 2H); 1.12-1.30 ppm
(m, lOH); 1.75-1.90 ppm (m, 2H); 2.23-2.40 ppm (m, 6H); 2.45-2.60 ppm (m, 4H);
3.45
ppm (br t, 2H); 4.35 ppm (br s, 1H); I 1.55 ppm (s, 2H).
Example 24
5-naphtyl-5- ~2-h~yeth~)piperazinyllbarhituric acid
a) preparation of ethyl 2-naphtylacetate
To a solution of 2-naphtylacetic acid {5 g} in 50 ml of ethanol are added 0.5
g of para-
toluensulfonic acid, then the reaction mixture is refluxed for about 4 hours.
The solvent
is evaporated off and the residue is dissolved in diethyl ether, washed twice
with a
saturated aqueous solution of sodium hydrogencarbonate and once with brine,
then the
pooled organic extracts are dried over sodium sulfate and concentrated to
dryness. 5.64
g of the product as a yellow oil are obtained.
b) preparation of diethyl 2-naphtylmalonate
2 0 To a solution of ethyl 2-naphtylacetate (2 g) in 23.3 ml of
diethylcarbonate, kept under
stirring and at room temperature, are added portionwise 0.232 g of sodium. The
reaction
mixture is refluxed for 2 hours 30 minutes, then it is concentrated in order
to eliminate
the not reacted diethylcarbonate and it is added with 20 ml of cold water. The
resulting
mixture is acidified with acetic acid until weak acidity is reached, then it
is extracted
three times with diethyl ether. The pooled organic extracts are dried over
sodium sulfate
and the solvent is evaporated off, to give, after recrystallization from
diethyl ether ( 19
ml), 1.0I S g of the product as a white solid.
c) preparation of 5-naphtylbarbituric acid
3 0 A solution of sodium (0.32 g) in 30 ml of anhydrous ethanol is added with
diethyl 2-
naphtylmalonate (2 g} and successively with urea (0.63 g). The mixture is
refluxed for 2
hours, then the solid which separated is recovered by filtration, then it is
dissolved in 7
ml of water and acidified to pH = 1 with 6 N hydrochloric acid. A white solid
precipitates which, after 30 minutes under stirring, is filtered and washed
with water. The
3 5 solid is dried overnight under vacuum at 40°C, to give 0.96 g of
the product.
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d} preparation of 5-bromo-5-naphtylbarbituric acid
A suspension of 5-naphtylbarbituric acid (0.2 g) in 1.5 ml of 95% ethanol,
cooled at 0°C
and kept under stirring, is added dropwise with 48% hydrobromic acid (0.5 ml)
and
successively with 4.4 pl of bromine. After 4 hours under stirring at room
temperature the
solid is filtered and washed with water, then it is dried under vacuum at
40°C overnight.
0.25 g of the product are obtained.
e) preparation of the title compound
To a suspension of 5-bromo-5-naphtylbarbituric acid (0.24 g) in 3.5 mI of
ethanol is
added a solution of N-(2-hydroxyethyl)piperazione (0.1 I2 g) in 1.5 ml of
ethanol. The
reaction mixture is refluxed for 5 hours, then it is cooled to room
temperature and the
solid which separates is filtered off. The filtrate is added with 100 p.l of
triethylamine,
then the solvent is evaporated off to give 0.364 g of a solid, which is
recrystallized from
a mixture of methanoi (4.5 ml) and ethyl acetate (10 ml). The obtained solid
(70 mg) is
washed under stirring with an ethyl acetate/water mixture for 2 hours and
dried under
vacuum at 40°C for 8 hours, to give 60 mg of the product.
'H-NMR in d6-DMSO: 2.3-2.5 ppm (m, 6H); 2.6 ppm (m, 4H); 3.45 ppm (m, ZH);
4.35
ppm (t, 1 H); 7.4-8. I ppm (m, 7H); 11.65 ppm (s, 2H).
2 0 Example 25
5-(4'-biphenyl)-5-!Tt-(2-hydrox~yl)piperazinyl]barhituric acid
a) preparation of ethyl (4'-biphenyl)acetate
A suspension of (4'-biphenyl)acetic acid (6.4 g) in 60 ml of ethanol is added
with 1.1 g
of para-toluensulfonic acid. then the reaction mixture is refluxed for 4 hours
30 minutes.
The solvent is evaporated ofd the residue is dissolved in diethyl ether and
the resulting
organic phase is washed three times with a saturated aqueous solution of
sodium
hydrogencarbonate and once with brine. The organic phase is then dried over
sodium
sulfate and the solvent is evaporated off to give 7.1 g of the product as a
yellow oil.
b) preparation of diethyl (4'-biphenyl)malonate
A solution of ethyl (4'-biphenyl)acetate (7.1 g) in 60 m1 of diethylcarbonate,
kept under
nitrogen atmosphere, is added portionwise with sodium (0.734 g), then it is
heated at
I20°C for 3 hours. The solvent is evaporated off and the residue is
dissolved in 65 mI of
3 5 cold water and acidified with acetic acid until pH = 5-6 is reached. The
aqueous phase is
then extracted three times with diethyl ether and the pooled organic extracts
are dried
over sodium sulfate and concentrated to dryness. The residue is purified by
silica gel
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chromatography (eluent: petroleum ether/diethyl ether 9.4:0.6) to give 7.05 g
of the
product, m.p. 51-53°C.
c) preparation of 5-(4'-biphenyl)barbituric acid
A solution of sodium (0.322 g) in 40 ml of anhydrous ethanol is added with
diethyl (4'-
biphenyI)malonate (2.2 g) and successively with urea (0.63 g). The reaction
mixture is
refluxed for 3 hours 30 minutes, then it is cooled to room temperature and the
solid is
recovered by filtration. The obtained solid is redissolved in 40 ml of warm
water and the
resulting aqueous phase is acidified to pH = 1 with 6 N hydrochloric acid. The
solid
which separates is kept I 5 minutes under stirnng, then it is filtered and
dried under
vacuum at 60°C. 1.1 g of the product are obtained, m.p. >240°C.
d) preparation of 5-bromo-5-{4'-biphenyl)barbituric acid
A suspension of 5-(4'-biphenyl)harbituric acid (0.28 g) in 1.4 ml of water,
cooled at 0°C
and kept under stirring, is added dropwise with 0.14 ml of 48% hydrobromic
acid and
successively with 55.5 p.l of bromine. The temperature is then brought to room
temperature and the stirring is continiued for 1 hour. The suspended solid is
recovered by
filtration, washed with water and dried under vacuum at 60°C for 2
hours, to give 0.336
of the product, m.p. 203-205°C.
e) preparation of the title compound
To a suspension of 5-bromo-5-(4'-biphenyl}barbituric acid (0.323 g) in 4.4 ml
of ethanol
0.14 g of N-(2-hydroxyethyl)piperazine are added and the reaction mixture is
refluxed
for 2 hours. The suspended solid is filtered off and the resulting clear
solution is treated
2 5 with 125 p.l of triethyiamine, then the solvent is evaporated off. The
residue is
redissolved in 2 ml of ethanol, from which crystallizes a solid which is
stirred for 30
minutes, then it is filtered. The residue is recrystallized from ethanol to
give 100 mg of
the pure product, m.p. 225-226°C.
1H-NMR in d6-DMSO: 2.3-2.5 ppm (m, 6H); 2.65 ppm (m, 4H); 3.45 ppm (m, 2H);
4.4
ppm (s, 1H); 7.3-7.8 ppm (m, 9H); 11.6 ppm (s, 2H).
Example 26
5-(4'-biphenyl)-5-IN-(4-nitrophenyl)piperazinyljbarbituric acid
A solution of 5-bromo-5-(4'-biphenyl)barbituric acid (0.359 g; example 25,
step d) in 9
ml of methanol is added with 0.622 g of N-(4-nitrophenyl)piperazine and the
mixture is
refluxed for about 2 hours. The solvent is evaporated off and the residue is
partitioned
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between water and ethyl acetate. The organic phase is separated, washed with
brine and
dried over sodium sulfate. The solvent is then evaporated under reduced
pressure to give
0.74 g of a residue which is purified by silica gel chromatography (eluent:
methylene
chloride/acetone 9:1) to give 400 mg of the product, m.p. 181°C.
'H-NMR in d6-DMSO: 2.8 ppm (m, 4H); 3.5 ppm (m, 4H); 7.00 ppm (d, 2H); 7.3-
7.85
ppm (m, 9H); 8.05 ppm (d, 2H); 11.7 ppm (s, 2H).
Ezarnipte 27
5-(4'phenoxyphenyl)-5-[N-(2-h~xyethyl)piperazin~barbituric acid
a) preparation of N-[(4'-phenoxybenzyl)thiocarbonyl]morpholine
A mixture of (4'-phenoxyphenyl)methyiketone ( 19.1 g), morpholine (20 ml} and
sulphur
(4.32 g) is refluxed for 24 hours, then it is extracted with diethyl ether.
The organic
phase is concentrated to dryness to give, after crystallization form a
petroleum
ether/ethyl acetate mixture 8:2 (600 ml), 12.2 g of the product, m.p. 75-
77°C.
b) preparation of (4'-phenoxyphenyl)acetic acid
A suspension of N-[(4'-phenoxybenzyl)thiocarbonyi]morpholine ( 1.725 g) in 87
ml of
2 0 10% potassium hydroxide is refluxed for 8 hours 30 minutes, then the
reaction mixture is
brought to room temperature and acidified with 1N hydrochloric acid. A white
solid
separates, which is stirred for 30 minutes and filtered. The solid is washed
with water
and dried under vacuum, to give 1.095 g of the product, m.p. 70-72°C.
c) preparation of ethyl (4'-phenoxyphenyl)acetate
To a suspension of (4'-phenoxyphenyl)acetic acid (0.456 g) in 4 ml of ethanol
is added
para-toluensulfonic acid (0.076 g) and the resulting mixture is refluxed for 2
hours. The
solvent is evaporated off, the residue is dissolved in diethyl ether and the
organic phase is
washed with saturated aqueous solution of sodium hydrogencarbonate and then
with
3 0 brine. The organic phase is dried over sodium sulfate and concentrated to
dryness to give
0.458 g of the product as a brown oil.
d) preparation of 5-(4'-phenoxyphenyl}barbituric acid
A soultion of sodium ethoxide (0.27 g} in 3 mi of anhydrous ethanol is added
with 0.657
3 5 g of ethyl (4'-phenoxyphenyl)acetate dissolved in 5 ml of ethanol, then
with urea (0.18
g). The reaction mixture is refluxed for 2 hours 30 minutes, then it is cooled
to room
temperature and the suspended solid is filtered. The solid is redissolved in 8
ml of water
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and the solution is acidified with I N hydrochloric acid. The solid which
separates is
recovered by filtration to give 0.165 g ofthe product, m.p. >240°C.
e) preparation of 5-bromo-5-(4'-phenoxyphenyl)barbituric acid
To a suspension of 5-(4'-phenoxyphenyl)barbituric acid (48 mg)in 0.23 ml of
water,
cooled at 0°C and under stirring, are added 23 p,l of 48% hydrobromic
acid and
successively 9 p.l of bromine. After 2 hours at room temperature additional 9
p.l of ,
bromine are added and stirring is continued for 2 hours. The suspended solid
is then
filtered and washed with water, to give, after drying under vacuum at
60°C, 57 mg of the
product, m.p. 125-127°C.
f) preparation of the title compound
A solution of 5-bromo-5-(4'-phenoxyphenyl)barbituric acid (50 mg) in 0.2 ml of
methanol is added dropwise with a solution of N-(2-hydroxyethyl)piperazine (52
mg) in
0.6 ml of methanol and the mixture is stirred for 2 hours. The white
precipitate is
recovered by filtration and dried under vacuum at 60°C overnight. 42.6
mg of the
product are obtained, m.p. >240°C.
1H-NMR in d6-DMSO: 2.2-2.45 ppm (m, 6H); 2.55 ppm (m, 4H); 3.45 ppm (m, 2H);
2 0 4.4 ppm (t, I H); 6.9-7.7 ppm (m, 9H); I 1.6 ppm (s, 2H).
Example 28
5-decyl-5-[N-(2-hydroxyethyllpiperazi~l]barbituric acid
a) preparation of diethyl decylmalonate
A solution of sodium (0.46 g) in 10 of anhydrous ethanol is added with 3.35 ml
of diethyl
malonate in 3 ml of ethanol and successively with a solution of decylbromide
(4.15 mI) in
3 ml of ethanol.The reaction mixture is refluxed for 4 hours, then the
precipitate is
filtered off and the filtrate is concentrated to dryness. The residue is
redissolved in a
3 0 saturated aqueous solution of sodium hydrogensulfate and it is extracted
with ethyl
acetate. The organic extract is dried over sodium sulfate and the solvent is
evaporated
off. The resulting residue is used as such in the successive reaction.
b) preparation of 5-decylbarbituric acid
3 5 To a solution of diethyl decylmalonate of step a) in 40 ml of ethanol are
added 2.72 g of
sodium ethoxide and then 1.8 g of urea. The reaction mixture is refluxed for 2
hours,
then the precipitate is filtered and redissolved in 40 ml of water. The
resulting aqueous
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solution is acidified with 6 N hydrochloric acid. The solid which separates is
recovered
by filtration and dried under vacuum at 40°C overnight. to give 2.152 g
of the product,
m.p. 190°C.
c) preparation of 5-bromo-5-decylbarbituric acid
To a suspension of 5-decylbarbituric acid (0.537 g) in 2.9 ml of water are
added under
stirring a.t room temperature 0.29 ml of 48% hydrobromic acid. The mixture is
cooled to
0°C and 0.113 ml of bromine are dropped. The reaction mixture is
stirred at room
temperature for 1 hour 30 minutes, then the white precipitate is filtered and
it is washed
1o with water. The solid is partitioned between water and diethyl ether, the
organic phase is
separated, washed with brine and finally dried over sodium sulfate. By
evaporation of the
solvent under reduced pressure 0.62 g of the product are recovered.
d) preparation of the title compound
To a solution of 5-bromo-5-decylbarbituric acid (0.619 g) in 1.3 ml of
dimethylsulfoxide,
kept under stirnng at 0°C, a solution of 0.93 g of N-(2-
hydroxyethyl)piperazine in 0.7 ml
of dimethylsulfoxide is added dropwise, then the reaction mixture is stirred
at room
temperature for 1 hour. The mixture is then cooled to 0°C and added
with 30 ml of
water. A white solid separates, which is kept under stirring for 1 hour, then
is filtered and
2 0 dried under vacuum at 50°C. 0.309 g of the product are obtained,
m.p. 181-182°C.
1H-NMR in d6-D1VIS0: 0.85 ppm (t, 3H); 0.9-1.1 ppm (m, 2H); 1.i5-1.4 ppm (m,
14H); 1.8-1.9 ppm (m, 2H); 2.2-2.45 ppm (m, 6H); 2.55 ppm (m, 4H); 3.45 ppm
(m,
2H); 4.35 ppm (t, 1H); I 1.55 ppm (s, 2H).
Example 29
5-hexdecyl-5-[N-(2-h d~oxyethyl)t~iperazine]barbituric acid
The title compound was prepared in an analogous manner like the compound of
example
28.
Example 30
5-eicoxyl-5-[N-(2-hydroxyethyl)pinerazine]barbituric acid
The title compound was prepared in an analogous manner like the compound of
example
28.
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Example 31
S-(4-butoxyphenyl)-5-[4-(2-hydroxyphenyl)piperazinylJbarbituric acid
m.p. 184-I 85°
H-N.M.R. in d6-DMSO: 0.91 ppm (t, 3H); 1.4 ppm {m, 2H); 1.67 ppm (m, 2H}; 2,36
ppm (m, 6H); 2.55 ppm {m, 4H; 3.44 ppm (q, ZH); 3.95 ppm (t, 2H); 4.37 ppm (t,
IH);
6.95 ppm {d, 2H); 7.28 ppm (d, 2H); I 1.5 ppm (br. s, 2H).
The compound is prepared as described in Example 14. The only difference is in
the
preparation of the starting material ethyl 4-butoxyphenyl acetate, which can
be prepared
starting from 4-hydroxyphenylacetic acid by esterification with ethanol (see
example 14-
a) and subsequent alkylation of ethyl 4-hydroxyphenyl acetate with butyl
bromide
alkylation of ethyl 4-hydroxyphenyl acetate with butyl bromide, according to
know
methodologies.
Example 32
The pathway of production as described in the specification and examplified in
the
previous examples the following compounds are synthesized. They are
characterized by
mass spectroscopy.
32.Name MW , exp.
mass
O1 N-(2,4,6-Trioxo-5-phenyl-hexahydro-pyrimidin-5-yl}-323.3 323
benzamide
02 3-(3,4-Dimethoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl-409.4 409
hexahydro-pyrimidin-5-yi)-acrylanvde
03 3-(3,4,5-Tnmethoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl-439.4 439
hexahydro-pyrimidin-5-yl)-acrylamide
04 3-Phenyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-351.4 351
yl)-propionamide
OS 5-Phenyl-pentanoic acid (2,4,6-trioxo-5-phenyl-hexahydro-379.4 379
pyrimidin-5-yl)-amide
06 2-{4-Nitro-phenyl}-N-(2,4,6-trioxo-5-phenyl-hexahydro-382.3 382
pyrimidin-5-yl)-acetamide
07 3-Benzenesulfonyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-415.4 415
pyrimidin-5-yl}-propionamide
08 2-(4-Bromomethyi-phenyl)-N-(2,4,6-trioxo-5-phenyl-430.3 429
hexahydro-pyrimidin-5-yl)-acetamide
09 2-Naphthalen-2-yl-N-(2,4,6-trioxo-5-phenyl-hexahydro-387.4 387
pyrimidin-5-yl)-acetamide
10 2-(3-Chloro-phenyl)-N-(2,4,6-trioxo-5-phenyl-hexahydro-371.8 371
pyrimidin-5-yl}-acetamide
11 3-(2-Methoxy-phenyl}-N-(2,4,6-trioxo-5-phenyl-381.4 381
hexahydro-pyrimidin-5-yl)-propionamide
12 3-(4-Methoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl-381.4 381
hexahydro-pyrimidin-5-yl)-propionamide
13 2-(3-Bromo-phenyl)-N-(2,4,6-trioxo-S-phenyl-hexahydro-416.2 415
pyrimidin-5-yl)-acetamide
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14 3-Phenyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-349.3
349
yl)-acrylamide
I S 4-Bromo-N-{2 4,6-trioxo-5-phenyl-hexahydro-pyrimidin-402.2 401
' S-yl)-benzamide
16 3-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-337.3 337
5-yl)-benzamide
' 17 4-Methylsulfanyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-369.4 369
pyrimidin-5-yl)-benzamide
18 3-Chloro-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-357.8
357
yl)-benzamide
19 4-Chloro-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-357.8
357
yl)-benzamide
20 3,4-Dimethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-351.4 351
pyrimidin-5-yl)-benzamide
21 3,5-Dimethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-351.4 351
pyrimidin-5-yl)-benzamide
22 4-Ethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-367.4 367
5-yl)-benzamide
23 4-Cyano-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-348.3 348
yl)-benzamide
24 3-Methoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-353.3 353
5-yl)-benzamide
25 4-Methoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-353.3 353
5-yl)-benzamide
26 2-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-337.3 337
5-yl)-benzamide
27 2,4-Difluoro-N-(2,4,6-trioxo-5-phenyl-hexahydro-359.3 359
pyrimidin-5-yl)-benzamide
28 N-(2,4,6-Trioaco-5-phenyl-hexahydro-pyrimidin-5-yl)-324.3 324
isonicotinamide
29 Naphthalene-1-carboxylic acid (2,4,6-trioxo-5-phenyl-373.4 373
hexahydro-pyrimidin-5-yl)-amide
30 1-(4-Fluoro-phenyl)-3-(2,4,6-trioxo-5-phenyl-hexahydro-356.3 356
pyrimidin-5-yi)-urea
31 3-(4-Methoxy-phenyl)-N-(2,4,6-trioxo-5-phenyl-379.4 379
hexahydro-pyrimidin-5-yl}-acrylamide
32 1-(3-Trifluoromethyl-phenyl)-3-(2,4,6-trioxo-5-phenyl-406.3 406
hexahydro-pyrimidin-5-yl}-urea
33 3-(4-Chioro-phenyl)-N-{2,4,6-trioxo-5-phenyl-hexahydro-383.8 383
pyrimidin-5-yl)-acrylamide
34 1-(2,4-Dichloro-phenyl}-3-(2,4,6-trioxo-5-phenyl-407.2 406
hexahydro-pyrimidin-5-yl)-urea
35 1-(3,4-Dichloro-phenyl)-3-(2,4,6-trioxo-5-phenyl-407.2 406
hexahydro-pyrimidin-5-yl)-urea
3b I-{Chlor-phenyl)-3-(2,4,6-trioxo-5-phenyl-hexahydro-372.7 372
pyrimidin-5-yl)-urea
37 I-{4-Methoxy-phenyl)-3-{2,4,6-trioxo-5-phenyl-368.4 368
hexahydro-pyrimidin-5-yl)-urea
38 1-Phenyl-3-{2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-338.3
338
yl)-urea
39 Naphthalene-2-carboxylic acid (2,4,6-trioxo-5-phenyl-373.4 373
hexahydro-pyrimidin-5-yl}-amide
40 IH-Indole-5-carboxylic acid (2,4,6-trioxo-5-phenyl-362.3 362
hexahydro-pyrimidin-5-yl)-amide
41 N-(2,4,6-Tnoxo-5-phenyl-hexahydro-pyrimidin-5-yl)-366.3 366
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- 40 -
terephthalamide
42 4-Sulfamoyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-
402.4 402
pyrimidin-5-yl)-benzamide
43 4-Methyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
337.3 337
5-yl)-benzamide
44 4-Ethyl-N-{2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-
351.4 351
yl)-benzamide
45 4-Methyl-N-{2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
373.4 373
5-yl)-benzenesulfonamide
46 4-Bromo-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
438.3 437
5-yl)-benzenesulfonamide
47 2-Trifluoromethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-
427.4 427
pyrimidin-5-yl)-benzenesulfonamide
48 5-Phenyl-5-(4-phenyl-piperidin-I-y1)-pyrimidine-2,4,6-
363.4 363
trione
49 2,3-Dimethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-
383.4 383
pyrimidin-5-yl)-benzamide
50 2,3-Dimethyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-
351.4 351
pyrimidin-5-yl)-benzamide
51 4-Hydroxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
339.3 411
5-yl)-benzamide silyl.
52 3,4-Dimethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-
383.4 383
pyrimidin-5-yl)-benzamide
53 3-Dimethylanuno-N-(2,4,6-trioxo-5-phenyl-hexahydro-
366.4 366
pyrimidin-5-yl)-benzamide
54 3-tent-Butyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-
379.4 379
pyrimidin-5-yl)-benzamide
55 3,4-Dimethoxy-2-nitro-N-(2,4,6-trioxo-5-phenyl-
428.4 428
+
hexahydro-pyrimidin-5-yl)-benzamide FAB
56 4-Butoxy-3-methoxy-N-{2,4,6-trioxo-5-phenyl-hexahydro-
425.4 425
+
pyrimidin-5-yl)-benzamide FAB
57 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic
379.4 379
acid +
(2,4,6-
trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-amide
FAB
58 1H-Indole-4-carboxylic 362.3 362
acid
{2,4,6-trioxo-5-phenyl-
hexahydro-pyrimidin-5-yl)-amide
59 4-Methyl-3-sulfamoyl-N-{2,4,6-trioxo-5-phenyl-
416.4 416
hexahydro-pyrimidin-5-yl)-benzamide
60 Acetic 440.4 440
acid +
6-methyl-2-nitro-3-(2,4,6-trioxo-5-phenyl-
hexahydro-pyrimidin-5-yIcarbamoyl)-phenyl FAB
ester
61 Carbonic 441.4 441
acid +
ethyl
ester
2-methoxy-4-(2,4,6-trioxo-5-
phenyl-hexahydro-pyrimidin-5-ylcarbamoyl)-phenyl
FAB
ester
62 2-Bromo-3-nitro-N-(2,4,6-trioxo-5-phenyl-hexahydro-
447.2 446
pyrimidin-5-yI)-benzamide
63 "4-Chloro-3-sulfamoyl-N-(2,4,6-trioxo-5-phenyl-
436.8 436
hexahydro-pyrimidin-5-yl)-benzamide e"
65 3-tert-Butyl-2-hydroxy-N-(2,4,6-trioxo-5-phenyl-395.4 395
hexahydro-pyrimidin-5-yl)-benzamide
66 4'-Benzyloxy-biphenyl-3-carboxylic 505.5 505
acid +
(2,4,6-trioxo-5-
phenyl-hexahydro-pyrimidein-5-yl)-amide FAB
67 3-Cyano-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-5-
348.3 348
yl)-benzamide
68 3-Bromo-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
402.2 401
5-yl)-benzamide
69 3-Phenoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-
415.4 415
+
S-yl)-benzamide FA.B
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70 3-Benzoyl-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-427.4 427
5-yl)-benzamide
71 3-Trifluoromethyi-N-(2,4,6-trioxo-5-phenyl-hexahydro-391.3 391
pyrimidin-5-yl)-benzamide
72 N-(2,4,6-Trioxo-5-phenyl-hexahydro-pyrimidin-5-yl)-381.3 381
isophthalamic acid methyl ester
73 9H-Fluorene-1-carboxylic acid (2,4,6-trioxo-5-phenyl-4I 1.4 411
hexahydro-pyrimidin-5-yl)-amide
74 9-Oxo-9H-fluorene-1-carboxylic acid (2,4,6-trioxo-5-425.4 425
phenyl-hexahydro-pyrimidin-5-yl)-amide
75 5-Phenyl-5-(4-phenyl-piperazin-1-yl)-pyrimidine-2,4,6-364.4 364
triune
76 5-Phenyl-5-[4-(2-trifluoromethyl-phenyl)-piperazin-1-yl]-432.4
432
pyrimidine-2,4,6-triune
77 5-j4-{4-Nitro-phenyl)-piperazin-1-yl]-5-phenyl-pyrimidine-409.4
409
2,4,6-triune
78 5-(4-Phenethyl-piperazin-1-yl)-5-phenyl-pyrimidine-2,4,6-392.5
392
triune
79 5-[4-(3-Methoxy-phenyl)-piperazin-1-yl]-5-phenyl-394.4 394
pyrimidine-2,4,6-triune
80 3-Acetylamino-N-(2,4,6-trioxo-5-phenyl-hexahydro-380.4 380
pyrimidin-5-yl)-benzamide
81 Acetic acid 3-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-381.3
381
S-ylcarbamoyl)-phenyl ester
82 3-Ethoxy-N-(2,4,6-trioxo-5-phenyl-hexahydro-pyrimidin-367.4 367
5-yl)-benzamide
83 5-Phenyl-5-(4-pyridin-4-yl-piperazin-1-yl)-pyrimidine-365.4 365
2,4,6-triune
84 5-Phenyl-5-j4-{3-trifluoromethyl-phenyl)-piperazin-1-yl]-432.4
432
pyrimidine-2,4,6-triune
85 5-j4-(4-Methoxy-phenyl)-piperazin-1-yI]-S-phenyl-394.4 394
pyrimidine-2,4,6-triune
86 5-(4-Benzhydryl-piperazin- i -yl)-5-phenyl-pyrimidine-454.5 454
+
2,4,6-triune F~
87 5-Phenyl-5-[4-(3-phenyl-allyl)-piperazin-1-yl]-pyrimidine-404.5
404
+
2,4,6-triune F~
88 5-Phenyl-5-(2-pyrrolidin-1-yl-ethylamino)-pyrimidine-3 i 6.4 316
2,4,6-triune
89 5-[2-(3H-Imidazol-4-yl)-ethylamino]-5-phenyl-pyrimidine-313.3 313
+
2,4,6-triune F~
Ezample 33
In order to determine the inhibition of MMPs, for example HNC, the catalytic
domain
(isolation and purification see for example Schnierer, S., Kleine, T., Gote,
T., HiIIemann,
A., Knauper, V., Tschesche, H.,Biochem. Biophys. Res. Common. (1993) 19I, 319-
326}
is incubated with inhibitors having various concentrations. Subsequently, the
initial
reaction rate in the conversion of a standard substrate is measured in a
manner analogous
to Grams F. et al., FEBS 335 (I993) 76-80).
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The results are evaluated by plotting the reciprocal reaction rate against the
concentration of the inhibitor. The inhibition constant (Ki) is obtained as
the negative
section of the abscissis by the graphical method according to Dixon, M.,
Biochem. J.
(1953) 55, 170-202.
The synthetic collagenase substrate is a heptapeptide which is coupled, at the
C-
terminus, with DNP (dinitrophenol). Said DNP residue quenches by steric
hindrance the
fluorescence of the adjacent tryptophane of the heptapeptide. After cleavage
of a
tripeptide which includes the DNP group, the tryptophane fluorescence
increases. The
proteolytic cleavage of the substrate therefore can be measured by the
fluorescence
value.
a) First method
The assay was performed at 25 °C in a freshly prepared 50 mM Tris
buffer (pH 8.0)
treated with dithiozone to remove traces of heavy metals. 4 mM CaClz was added
and
the buffer saturated wtih argon. Stock solutions of adamalysin II were
prepared by
centrifugation of the protein from ~.n ammonium sulfate suspension and
subsequent
dissolution in the assay buffer. Stock solutions of collagenase were diluted
with the assay
buffer. Enzyme concentrations were determined by uv measurements (sago = 2.8
104 M-1
crri', s288: 2.2 104 M' . cm') and the stock solutions were stored in the
cold.-This
solution was diluted 1:100 to obtain the final 16 nM assay concentration. The
fluorogenic substrate DNP-ProLeu-Gly-LeuTrp-Ala-D-Arg-NHZ with a Km of 52 pM
was used at a concentration of 21.4 pM; for the K; determination a 12.8 pM
concentration has also been used. Substrate fluorescence was measured at an
excitation
and emission wavelength of ~, = 320 and 420 nm, respectively, on a
spectrofluorimeter
(Perkin Elmer, Model 650-40) equipped with a thermostated cell holder.
Substrate
hydrolysis was monitored for 10 min. immediately after adding the enzyme. All
reactions
were performed at least in triplicate. The K; values-of the inhibitors were
calculated from
the intersection point of the straight lines obtained by the plots of v~/v;
vs. [concentration
3 0 of inhibitor], whereas ICto values were calculated from plots of
v;/v° [concentration of
inhibitor] by non-linear regression with simple robust weighting.
b) Second method
3 5 Assay buffer:
50 mM Tris/HCI pH 7.6 (Tris= Tris-(hydroxymethyl)-aminomethan)
100 mM NaCI/ 10 mM CaC 12/5 % MeQH {ff necessary)
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Enzyme: 8 nM catalytic domain (Met80-G1y242) of human neutrophil collagenase
Substrate: 10 microM DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2
Total assay volume: I ml
A solution of the enzyme and inhibitor in assay buffer (25 °C) was
prepared. The
reaction was started directly by giving the substrate into the solution. The
cleavage of the
flourogenic substrate was followed by flourescence spectroscopy with an
excitation and
envision wavelength of 280 and 350 nm, respectively. The ICso value was
caicuIated as
the inhibitor concentration, which is necessary to decrease the velocity of
the reaction to
the half in comparison to the reaction without inhibitor.
Table 1 shows the ICso values found.
Table 1: IC50 Values of MMP-Inhibitor (MMP-8
Compound IC-50 nM
examle 32.74 890
referred 150
no.
120
examle 25 140
examIe 23 110
examIe 20 860
examle 32.77 160
referred 60
no.
118
examle 28 320
examle 26 15
