Note: Descriptions are shown in the official language in which they were submitted.
_1_ ,
4-18815lA
Salts of hydrazones
The invention relates to acid addition salts of bases of formula I
X
r
R1 \ ( R Z (I)
TI
N~N.~~~N.--Rs
I I
R3 Ra
wherein A is a direct bond or -(CH2)n , wherein n is 1, ;? or 3; X is a
radical
-C(=Y)-NR6R~; Y is NRs, O or S; Z is NR9, O or S; each of Rl and R2,
independently of
the other, is hydrogen or one or more substituents other than hydrogen; each
of the
radicals R3, R4, R6, R8 and R9, independently of the others, is hydrogen or
lower alkyl;
and each of R~ and R~, independently of the other, is hydrogen, lower alkyl,
hydroxy,
etherified or esterified hydroxy or unsubstituted or mono- or di-substituted
amino;
with an acid [PA] that is a mono- or poly-protic acid selected from carbonic
acid, alkanoic
acids that are unsubstituted or mono- or poly-substituted, with the exception
of formic
acid, unsubstituted acetic acid, lysine and arginine; alkenoie acids that are
unsubstituted or
substituted, with the exception of unsubstituted fumaric acid;
cycloalkylcarboxylic acids,
arylcarboxylic acids, aryl-lower alkylcarboxylic acids, wherein lower alkyl is
unsubs-
tituted or substituted, aryl-lower alkenylcarboxylic acids,
heterocyclylcarboxylic acids,
alkanesulfonic acids that are unsubstituted or substituted, with the exception
of unsubstit-
uted methanesulfonic acid; aromatic sulfonic acids, alkylsulfuric acids, .N-
substituted
sulfamic acids, organic acids without carboxy, sulfo, sulfate or phospho
groups, and also
selected from pyrophosphoric acid and hydriodic acid, and tautomers thereof,
CA 02080545 2003-11-05
21489-8545
2
also to processes for the preparation of those acid addition
salts, to pharmaceutical compositions comprising those acid
addition salts, and to the use of those acid addition salts
in the therapeutic treatment of the human or animal body or
in the preparation of pharmaceutical compositions.
Tautomers may occur, for example, when Z is NR9 and
R3 and/or R4 and/or R5 are hydrogen:
the corresponding guanyl radical, shown in
formula I as -N (R3) -C (=Z) -NR4R5, may then, for example, also
be in the tautomeric form -N=C ( -ZH) -NR4R5, -N (R3) -C ( -ZH) =NRS
or -N (R3) -C (-ZH) =NR4.
If, for example, Y is NRB and if R6 and/or R~ is
hydrogen, then the corresponding amidine structure, defined
in formula I as X=-C(=Y)-NR6R7, may also occur in the
tautomeric form -C (-YH) =NR~ or -C (-YH) =NR6. The person
skilled in the art is familiar with the presence of those
and similar tautomers. All those tautomers are included in
the general formula I.
If A is a group - (CHZ) n- and RZ is other than
hydrogen, the substituent(s) corresponding to the radical R2
may also be linked to the carbon atoms of the group
- ( CH2 ) n- .
RZ is, for example, hydrogen or from 1 to 4
substituents other than hydrogen, especially hydrogen or 1
or 2 substituents other than hydrogen, and more especially
hydrogen or one substituent other than hydrogen.
R1 is, for example, hydrogen or from 1 to 3
substituents other than hydrogen, and especially hydrogen or
1 or 2 substituents other than hydrogen.
CA 02080545 2003-11-05
21489-8545
2a
According to one aspect of the present invention,
there is provided an acid addition salt of a base of formula
I, or a tautomer thereof,
X
Ri RZ
Z
(I)
~ .CwN~RS
I I
R3 R4
wherein A is a direct bond or -(CH2)n-, wherein n is 1, 2 or
3; X is a radical -C (=Y) -NR6R~; Y is NRB, O or S; Z is NR9, 0
or S; each of R1 and R2, independently of the other, is
hydrogen, lower alkyl, trifluoromethyl, cycloalkyl, aryl-
lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy,
aryloxy, acyloxy, halogen, amino, N-lower alkylamino, N,N-
di-lower alkylamino; acylamino, nitro, lower alkanoyl,
arylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl
(-CONH2), N-lower alkylcarbamoyl, N,N-di-lower
alkylcarbamoyl, N-arylcarbamoyl, cyano, mercapto, lower
alkylthio, lower alkylsulfonyl, sulfamoyl (-S02NH2), N-lower
alkylsulfamoyl or N,N-di-lower alkylsulfamoyl; each of the
radicals R3, R4, R6, RB and R9, independently of the others,
is hydrogen or lower alkyl; and each of RS and R-,,
independently of the other, is hydrogen, lower alkyl,
hydroxy, etherified or esterified hydroxy or unsubstituted
or mono-substituted amino, substituted by a substituent, or
di-substituted amino, substituted by two substituents,
selected from lower alkyl, lower alkenyl, oxa-; thio-; or
aza-lower alkenyl, and lower alkylpiperazino; with an acid
[PA] that is a mono- or poly-protic acid selected from
carbonic acid, alkanonic acids that are unsubstituted or
mono- or poly-substituted by one or more substituent
independently selected from hydroxy, carboxy, amino,
CA 02080545 2003-11-05
21489-8545
2b
mercapto, methylmercapto, phenyl, hydroxy-phenyl, naphthyl,
cyclohexyl, imidazolyl and indolyl, with the exception of
formic acid, unsubstituted acetic acid, lysine and arginine;
alkenoic acids that are unsubstituted or substituted by a
substituent independently selected from hydroxy and lower
alkyl, with the exception of unsubstituted fumaric acid;
cycloalkylcarboxylic acids; aryl carboxylic acids; aryl-
lower alkylcarboxylic acids, wherein lower alkyl is
unsubstituted or substituted by hydroxy; aryl-lower
alkenylcarboxylic acids, 5-12 ring atom
heterocyclylcarboxylic acids wherein the heteroatom is
selected from N, S and O, alkanesulfonic acids that are
unsubstituted or substituted by hydroxy or sulfo, with the
exception of unsubstituted methanesulfonic acid; aromatic
sulfonic acids, alkylsulfuric acids, N-substituted sulfamic
acids wherein the N-substituted is independently selected
from lower alkyl and cycloalkyl; organic acids without
carboxy, sulfo, sulfate or phospho groups but containing an
acid hydroxy group; and also selected from pyrophosphoric
acid and hydriodic acid; wherein aryl is phenyl or naphthyl
both of which may be unsubstituted or substituted by one or
more substituents selected from lower alkyl, lower alkoxy,
hydroxy, lower alkanoyloxy, nitro, amino, halogen,
trifluoromethyl, carboxy, lower alkoxycarbonyl, carbomyl, N-
lower alkylcarbamoyl, N,N-di-lower alkyl-carbamoyl, cyano,
lower alkanoyl, arylcarbonyl, lower alkylsulfonyl,
sulfamoyl, N-lower alkylsulfamoyl and N,N-di-lower
alkylsulfamoyl.
Within the framework of the present Application,
the general terms used hereinbefore and hereinafter have
preferably the following meanings:
The following definitions relate to the radicals
mentioned in the bases of formula I.
CA 02080545 2003-11-05
21489-8545
2c
Lower alkyl is, for example, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
neopentyl, n-hexyl or n-heptyl, preferably ethyl or methyl,
especially methyl.
2~~~~4 i
_3-
A substituent other than hydrogen is, for example, lower alkyl,
trifluoromethyl, cycloalkyl,
aryl-lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy; acyloxy,
for example
lower alkanoyloxy; halogen, amino, N-lower alkylamino, N,N-di-lower
alkylamino; acyl-
amino, for example lower alkanoylamino; nitro, lower alkanoyl, arylcarbonyl,
carboxy,
lower alkoxycarbonyl, carbamoyl (-CONH2), N-lower alkylcarbamoyl, N,N-di-lower
alkylcarbamoyl, N-arylcarbamoyl, cyano, mercapto, lower alkylthio, lower
allcylsulfonyl,
sulfamoyl (-S02NH2), N-lower alkylsulfamoyl or N,N-di-lower alkylsulfamoyl.
Aryl is, for example, phenyl or naphthyl, such as 1- or 2-naphthyl. The phenyl
and
naphthyl radicals may be unsubstituted or substituted, especially as indicated
below for
phenyl. Aryl is preferably phenyl that is unsubstituted or substituted by one
or more,
especially one or two, substituents selected from the group consisting of
lower alkyl,
lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, halogen,
trifluoromethyl,
carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower
alkyl-
carbamoyl, cyano, lower alkanoyl, arylcarbonyl, lower alkylsulfonyl,
sulfamoyl, N-lower
alkylsulfamoyl and N,N-di-lower alkylsulfamoyl. Aryl :is especially phenyl
that is unsub-
stituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen or by
trifluoro-
methyl, more especially phenyl.
Arylcarbonyl is, for example, benzoyl that is unsubstituted or substituted by
lower alkyl,
lower alkoxy, hydroxy, halogen or by trifluoromethyl, especially benzoyl.
Aryl-lower alkyl is, for example, phenyl-lower alkyl, especially benzyl.
Halogen is especially chlorine and bromine, but may also be fluorine or
iodine.
Lower alkmoyl is, for example, formyl, acetyl, propionyl or pivaloyl.
Cycloalkyl is preferably C3-Cg- and especially CS-Cb-cyclaalkyl, which is to
denote that it
contains from 3 to 8 and 5 or 6 ring carbon atoms, respectively. It may,
however, also be
substituted, for example by lower alkyl.
Etherified hydroxy is, for example, lower atkoxy. Esterified hydroxy is, for
example,
lower alkanoyloxy. Mono-substituted amino is, for example, lower alkylamino.
Di-substit-
uted amino is, for example, di-lower allcylamino, lower alkyleneamino, for
example
-4-
C4-C~- and, especially, Ca-CS-alkyleneamino, for example piperidino, or oxa-,
thia- or
aza-lower alkyleneamino, for example morpholino, thiomorpholino, piperazino or
4-lower
alkylpiperazino.
The following definitions relate to the acids [PA] ([PA] stands for "erotic
Acid"):
Alkanoic acids are especially Ct-C2oalkanoic acids with the exception of
formic acid and
unsubstituted acetic acid, preferably C2-C~alkanoic acids, such as propionic
acid, butyric
acid, isobutyric acid, pentanoic acid, hexanoic acid or heptanoic acid, or
also octanoic
acid, decanoic acid or dodecanoic acid, especially propionic acid or octanaic
acid, all of
those alkanoic acids being unsubstituted or substituted one or more times,
especially from
one to six times, preferably by hydroxy, either once, such as in glycolic
acid, lactic acid or
2-hydroxybutyric acid, or several times, for example up to five times, such as
in gluconic
acid or glucose monocarboxylic acid ("glucoheptonic acid"), by carboxy, for
example in
C2-C2oallcanoic di-acids, especially C2-C~alkanoic di-acids, such as in
succinic acid, or
'also adipic acid, pimelic acid, suberic acid or azelaic acid, by hydroxy and
carboxy, such
as in malic acid, tartaric acid, citric acid, glucaric acid or galactaric
acid, by amino or
amino and carboxy and/or by one or two radicals selected independently from
mercapto,
methylmercapto, hydroxy, phenyl, 4-hydroxyphenyl, naphthyl, cyclohexyl,
imidazolyl and
indolyl, such as in amino acids, lysine and arginine being excluded,
especially glutamic
acid or aspartic acid in the (D)-, (L)- or (D,L)-form, preferably the (D)- or
(L)-form, by
substituted amino or substituted amino and carboxy and/or by one or two
radicals selected
independently from mercapto (also in oxidised form as the corresponding
disulfide
consisting of two molecules of the corresponding mercaptan), methylmercapto,
hydroxy,
phenyl, 4-hydroxyphenyl, naphthyl, cyclohexyl, imidazolyl and indolyl, such as
in amino
acids, for example in N-mono- or N,N-di-lower alkylamino acids, such as N-
methyl-
glycine, or in N-lower alkanoylarnino acids, such as acetylaminoacetic acid (N-
acetyl-
glycine), N-acetylasparagine or N-acetylcystine, by oxo, such as in pyruvic
acid or aceto-
acetic acid, by phospho and amino, such as in phosphoserine, or by phospho and
hydroxy,
such as in 2- or 3-glycerophosphoric acid, glucose-6-.phosphoric acid, glucose-
1-phos-
phoric acid or fructose-1,6-bisphosphoric acid. Amino acids are especially a-
amino acids
which may be in the (D)-, (L)- or (D,L)-form, preferably the {L)- or (D)-form,
and, when
other centres of asymmetry are present, they may also be in the form of other
isomers, for
example selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-
OH),
norvaline (a-aminovaleric acid), leucine (H-Leu-OH), isoleucine {H-Ile-OH),
norleucine
(a-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (a-amino-'y-
hydroxy-
-s-
butyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-
OH)
(which may also be present in oxidised form as cystine), phenylalanine (H-Phe-
OH),
tyrosine (H-Tyr-OI-I), B-phenylserine (Q-hydroxyphenylalanine), phenylglycine,
a-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine,
tryptophan (H-Trp-OH), aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), amino-
malonic acid, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-
HisOH),
$-hydroxylysine, ornithine (a,8-diaminovaleric acid), a,y-diaminobutyric acid
and
a,13-diaminopropionic acid, and, unless otherwise indicated, from arginine (H-
Arg-OH)
and lysine (H-Lys-OH). Especially preferred amino acids are.glycine, serine,
cystine,
aspartic acid and glutamic acid, especially aspartic acid and glutamic acid.
Amino acids
may also be omitted from the definition of substituted aikanoic acids.
Alkenoic acids are, far example, C2-Ctoalkenoic di-acids that are
unsubstituted, such as
malefic acid, or substituted, preferably by hydroxy, such as in hydroxymaleic
acid
(tautomer: oxalacetic acid), or lower alkyl, for example methyl, such as in
methylmaleic
acid. Unsubstituted fumaric acid is excluded.
Cycloalkylcarboxylic acids are preferably C4-Ct2cycloalkylcarboxylic acids
wherein the
cycloalkyl radical is mono-, bi- or tri-cyclic, preferably monocyclic or
tricyclic, for
example cyclopentyl, cyclohexyl, cycloheptyl or adamantyl, and is, for
example, unsub-
stituted, such as in cyclohexanecarboxylic acid or adamantanecarboxylic acid.
In arylcarboxylic acids, the aryl radical has, for example, from 6 to 20,
preferably from S
to 14, carbon atoms, and is selected, for example, from phenyl, 1- or 2-
naphthyl and
indane, and is unsubstituted, such as in benzoic acid, or substituted,
preferably by from 1
to 3 radicals selected independently from lower alkyl,.such as methyl;
halogen, such as
fluarine, chlorine or bromine, hydroxy, Iower alkoxy, for example methoxy,
phenoxy,
lower allcanoyloxy, such as acetoxy, amino and carboxy, such as in salicylic
acid, 1- or 3-
hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethaxybenzoic acid, 2-
phenoxybenzoic
acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid or phthalic acid.
In aryl-lower alkylcarboxylic acids, aryl is as last defined for
arylcarboxylic acids and is
unsubstituted or substituted as defined there, and lower alkyl is preferably
methyl or ethyl,
lower alkyl being unsubstituted, such as in phenylacetic acid, or substituted,
for example
by hydroxy, such as in mandelic acid.
-6-
In aryl-lower alkenylcarboxylic acids, aryl is as last defined for
arylcarboxylic acids, and
lower alkenyl has preferably from 2 to 4 carbon atoms, such as in cinnamic
acid.
Heterocyclylcarboxylic acids contain, for example, heterocyclyl comprising
from one to
three rings, preferably one or two rings, that is saturated or partially or
completely unsatur-
ated, preferably saturated or unsaturated, and has from 5 to 12 ring atoms,
preferably from
to 7 ring atoms, which are selected from carbon and up to three hetero atams,
preferably
one or two hetero atoms being present, especially oxygen, nitrogen and/or
sulfur, espec-
Tally oxygen and nitrogen, heterocyclyl being, for example, pyrrolyl,
imidazolyl, pyr-
azolyl, oxazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl,
quinoxalinyl or a
completely or partially saturated derivative of those radicals, or pyranyl or
furanyl, and
being unsubstituted, such as in nicotinic acid or isonicotinic acid, or from
mono- to penta-
substituted, preferably by hydroxy and/or by hydroxy-lower alkyl, for example
hydroxy or
hydroxymethyl, such as in glucuronic acid or galacturonic acid.
Alkanesulfonic acids are especially C2-C2Qalkanesulfonic acids, preferably C2-
C~alkyl-
sulfonic acids, such as ethanesulfonic acid, that are unsubstituted or
substituted, preferably
by one or two radicals selected from hydroxy and sulfo, such as in 2-
hydroxyethane-
sulfonic acid, or alkanedisulfonic acids, for example lower alkanedisulfonic
acids, such as
ethane-1,2-disulfonic acid. Methanesulfonic acid is excluded.
In aromatic sulfonic acids, the aromatic residue is, for example, aryl as
defined for aryl-
carboxylic acids and is unsubstituted, such as in benzenesulfonic acid or 2-
naphthalene-
sulfonic acid, or is substituted as in arylcarboxylic acids, especially by
lower alkyl, for
example methyl, such as in 2-, 3- or 4-methylbenzenesulfonic acid, or by a
further sulfonyl
radical, such as in 1,3-benzenesulfonic acid or naphthalene-1,5-disulfonic
acid, such as,
especially, in 1,5-naphthalenedisulfonic acid.
Alkylsulfuric acids are especially Ct-C2oalkylsulfuric acids, especially lower
alkylsulfuric
acids, such as rnethylsulfuric acid or ethylsulfuric acid, or dodecylsulfuric
acid.
N-substituted sulfamic acids are, for example, N-cycloalkylsulfamic acids,
wherein cyclo-
all;yl is preferably C4-Ct2cycloalkyl and the cycloalkyl radical is mono-, bi-
or tri-cyclic,
for example cyclopentyl, cyclohexyl, cycloheptyl or adamantyl, preferably
monocyclic,
such as in N-cyclohexylsulfamic acid, or N-alkylsulfamic acids, preferably N-
lower alkyl-
sulfamic acid, such as methyl-, ethyl- or propyl-sulfamic acid.
C?rganic acids without carboxy, sulfo, sulfate or phospho groups contain, for
example,
acidic hydroxy groups, such as in ascorbic acid.
Important acids are carbonic acid, propionic acid, octanaic acid, decanoic
acid,
dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic
acid, glucose
monocarboxylic acid, succinic acid, adipic acid, pimelic acid, suberic acid,
azelaic acid,
malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid,
glutamic acid, aspartic
acid, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine, N-
acetylcystine,
pyruvic acid, acetoacenc acid, phosphoserine, 2- or 3-glycerophosphoric acid,
glucose-6-
phosphoric acid, glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid,
malefic acid,
hydroxymaleic acid, methylmaleic acid, cyclohexanecaxboxylic acid, adamantane-
carboxylic acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-
carboxylic acid,
3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-
amino-
salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic
acid, nicotinic
acid, isonicotinic acid, glucuronic acid, galacturonic acid, ethanesulfonic
acid, 2-hydroxy-
ethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-
naphthalene-
sulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3- or 4.-
methylbenzenesulfanic acid,
methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-
cyclohexylsulfamic acid,
methyl-, ethyl- or propyl-sulfamic acid, or ascorbic acid.
Very important acids are octanoic acid, succinic acid, adipic acid, salicylic
acid, benzene-
sulfonic acid, 1,5-naphthalenesulfonic acid or N-cyclohexylsulfamic acid, very
especially
salicylic acid or, more especially, adipic acid or benzenesulfonic acid.
Very important acids are equally tartaric acid, especially L-tartaric acid,
lactic acid or
citric acid.
The mentioned acids, especially if they contain several acidic groups of
differing acidity
that can dissociate protons, may also be in the form of mixed salts with
canons, fox
example alkali metal canons, such as sodium or potassium ions, alkali metal
salts, such as
magnesium salts, or zinc salts, the acid component before the reaction
yielding the
mentioned mixed sales containing at least one other dissociable proton, or
they may be
present in the resulting salts in a form in which not all protons are freed,
but at least one
proton has been transferred to the relevant base of formula I. For example,
carbonic acid
can be used in the form of a hydrogen carbonate salt, such as sodium or
potassium
2Q~~~~
_8_
hydrogen carbonate.
The acid addition salts of a base of formula I with an acid [PA] may also be
in the form of
hydrates. Crystals may also include other solvents used for crystallisation.
Depending on structural factors, the acid addition salts of the present
invention may be in
the form of isomeric mixtures or in the form of pure isomers. If, for example,
R2 is a
substituent other than hydrogen, the corresponding acid addition salts of
formula I may be
in the form of racemic salts or enantiomerically pure salts or also in the
form of diastereo-
isomeric salts, for example in the presence of acids having centres of
asymmetry, such as
the mentioned amino acids, lactic acid or tartaric acid.
The aim of the present invention is to provide novel acid addition salts of
pharma-
cologically acceptable compounds, which salts have a good solubility in
physiological
liquids and/or liquids that are similar to physiological liquids, such as
physiological saline
solution, mannitol solution or phosphate buffers, and/or goad absarbability in
the case of
enteral, such as oral, administration, for example by the formation of ion
pairs, such as
lipophilic ion pairs.
The acid addition salts according to the invention have valuable
pharmacologically
exploitable properties. They exhibit, especially, a stronr;, specific
inhibitory action on the
enzyme S-adenosylmethionine decarboxylase (SAMDC:). As a key enzyme, SAMDC
plays an important role in polyamine synthesis, which takes place in
practically all Bells of
mammals, including humans. SAIVIDC regulates the concentration of polyamine in
the
cell. Inhibition of the enzyme SAMDC results in a reduction in palyamine
concentration.
Because a reduction in polyamine concentration.brings about inhibition of cell
growth, it
is possible, by administering SAN117C-inhibiting substances, to inhibit the
growth of both
eukaryotic and prokaryotic cells and even to kill cells or to inhibit the
onset of cell differ-
entiation.
Inhibition of the enzyme SAMDC can be demonstrated, for example, using the
method of
H.G. Williams-Ashmann and A. Schenone, Biochem. Biophys. Res. Communs. 46, 288
(1972). The acid addition salts of the invention in this case exhibit ICSp
values as low as
0.005 ~.M or lower.
A further advantage of the acid addition salts according to the invention is
that, compared
-9-
with their strong inhibitory action on SAMDC, they inhibit diaminoxidase to
only a slight
extent and are well tolerated. According to J. Jaenne and D.R. Morris,
Biochem.
J. 218, 974 (1984), inhibition of diaminoxidase is unfavourable because it can
lead to the
accumulation of putrescine and indirect SAMDC-activation.
The acid addition salts of formula I can accordingly be used, for example, in
the treatment
of benign and malignant tumours. They can induce tumour regression and can
also prevent
the spread of tumour cells resulting in rnetastase formation, and also the
growth of micro-
metastases. They can also be used, far example, in the treatment of protozoa
infections,
such as, for example, trypanosomiasis, malaria or pulmonary inflammation
caused by
Pneumocystis carinii.
As selective SAMDC-inhibitors, the acid addition salts of bases of formula I
with an acid
[PA] can be used alone or also in combination with other pharmacologically
active
substances. A possible combination is, for example, one with (a) inhibitors of
other
enzymes of polyamine biosynthesis, for example ornithine decarboxylase
inhibitors,
(b) inhibitors of protein kinase C, (c) inhibitors of tyrosine protein kinase,
(d) cytokines,
(e) negative growth regulators, (f) aromatase inhibitors, (g) antioestrogens
or (h) conven-
tional cytostatic active substances.
The invention relates preferably to the acid addition salts of a base of
formula z wherein A
is a direct bond or -(CH2)n-, n being 1 or 2; X is a radicatl -C(=Y)-NR6R7; Y
is NRg, O or
S; Z is NR9, O or S; each of Rl and R2, independently of the other, is
hydrogen or one or
two substituents selected from the group consisting of lower alkyl,
trifluoromethyl, cyclo-
alkyl, aryl-lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy, arylaxy,
lower
alkanoyloxy, halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino,
lower
alkanoylamino, nitro, lower alkanoyl, arylcarbonyl, caxboxy, lower
alkaxycarbonyl,
carbamoyl, N-lower allcylcarbamoyl, N,N-di-lower alkylcarbamayl, N-
arylearbamoyl,
cyano, rnercapto, lower alkylthio, lower alkylsulfonyl, sulfamoyl, N-lower
alkylsulfamoyl
and N,N-di-lower alkylsulfamoyl, aryl being phenyl that is unsubstituted or
substituted by
lower alkyl, lower alkoxy, hydroxy, halogen or by trifluoramethyl; each of the
radicals R3,
R4, R6, R8 and R9; independently of the others, is hydrogen or lower alkyl;
and each of RS
and R~, independently of the other, is hydrogen, lower alkyl, hydroxy, lower
alkoxy, lower
alkanoyloxy, amino, lower alkylamino, di-lower aikylamino, lower alkyleneamino
or oxa-,
thia- or aza-lower alkyleneamino;
- to -
with an acid [PA] that is a mono- or poly-erotic acid selected from carbonic
acid, alkanoic
acids that are unsubstituted or mono- or poly-substituted, with the exception
of formic
acid, unsubstituted acetic acid, lysine and arginine; alkenoic acids that are
unsubstituted or
substituted, with the exception of fumaric acid; cycloalkylcarboxylic acids,
arylcarboxylic
acids, aryl-lower alkylcarboxylic acids, wherein lower alkyl is unsubstituted
or substit-
uted, aryl-lower alkenylcarboxylic acids, heterocyclylcarboxylic acids,
alkanesulfonic
acids that are unsubstituted or substituted, with the exception of
methanesulfonic acid;
arylsulfonic acids, alkylsulfuric acids, N-substituted sulfamic acids, organic
acids without
carboxy, sulfo, sulfate or phospho groups, and also selected from
pyrophosphoric acid and
hydriodic acid, for example one of the acids defined above as being important,
for
example one of the acids defined as being very important,
or tautomers thereof.
Especially preferred are the acid addition salts of a base of formula I
wherein A is a direct
bond or -(CH~n , wherein n is 1 or 2; X is a radical -C(=Y)-NR6R7; Y is NH, O
or S; Z is
NH, O or S; each of Rr and R2, independently of the other, is hydrogen or one
or two
substituents selected from the group consisting of lower alkyl,
trifluoromethyl, phenyl-
lower alkyl, hydroxy, lower alkoxy and halogen; the radicals R3, R4 and R6 are
hydrogen;
and each of RS and R~, independently of the ather, is hydrogen, lower alkyl,
hydroxy or
amino; with an acid [PA] that is a mono- or poly-erotic acid selected from
carbonic acid,
alkanoic acids that are unsubstituted or mono- or poly-substituted, with the
exception of
formic acid, unsubstituted acetic acid, lysine and arginine; alkenoic acids
that are unsub-
stituted or substituted, with the exception of fumaric acid;
cycloalkylcarboxylic acids,
arylcarboxylic acids, aryl-lower alkylcarboxylic acids, wherein lower alkyl is
unsubs-
tituted or substituted, aryl-lower alkenylcarboxylic acids,
heterocyclylcarboxylic acids,
alkanesulfonic acids that are unsubstituted or substituted, with the exception
of methane-
sulfonic acid; aromatic sulfonic acids, alkylsulfuric acids, N-substituted
sulfamic acids,
organic acids without carboxy, sulfo, sulfate or phospho groups, and also
selected from
pyrophosphoric acid and hydriodic acid, for example one of the acids defined
above as
being important, for example one of the acids defined as being vry important;
or tautomers thereof.
More especially preferred are the acid addition salts of a base of formula I
wherein A is a
direct bond or -CH2-; X is a radical -C(=Y)-NR6R~; Y is NI-I or S; Z is NH; Rl
is
-11-
hydrogen or one or two substituents selected from the group consisting of
lower alkyl,
hydroxy, lower alkoxy and halogen; R2 is hydrogen or lower alkyl; the radicals
R3, R4 and
R6 are hydrogen; and each of R5 and R~, independently of the other, is
hydrogen, lower
alkyl or hydroxy; with an acid [PA] that is as defined above, for example one
of the acids
defined above as being important, for example one of the acids defined as
being very
important; or tautomers thereof.
Most especially preferred are the acid addition salts of bases of formula I
wherein A is a
direct bond; X is a radical -C(=NH)-NH2; Z is NH; Rl is hydrogen or one or two
substit-
uents selected from the group consisting of lower alkyl, hydroxy and lower
alkoxy; the
radicals R2, R3 and R4 are hydrogen; and RS is hydrogen or hydroxy; with an
acid [PA]
that is as defined above, for example one of the acids defined above as being
important,
especially one of the acids defined as being very important; or tautomers
thexeof.
As sub-groups of a group of acid addition salts of bases of formula I with
acids (PA],
attention is drawn to:
(a) acid addition salts of bases of formula I wherein A is a direct bond; (b)
acid addition
salts of bases of formula I wherein X is a radical -C(=NCI)-NH2; (c) acid
addition salts of
bases of formula I wherein Z is NH, R4 is hydrogen, and RS is hydrogen or
hydroxy; and
(d) acid addition salts of bases of formula I wherein Rt and RZ are hydrogen;
each of the
other radicals being as defined; with acids [PA] selected from one of the
groupings
mentioned above, for example from the acids defined above as being very
important; or
tautomers thereof.
The invention relates more especially to the acid addition salts of bases of
formula I
wherein A is a direct bond; X is a radical -C(=NH)-NH2; Z is NH; acid each of
Rt, R2, R3,
R4 and R5 is hydrogen; and (PA] is selected from the above-mentioned acids, or
is prefer-
ably one of the acids defined above as being important, for example one of the
acids
defined as being very important, for example an acid selected from N-
cyclohexylsulfamic
acid, octanoic acid, salicylic acid and benzenesulfonic acid, such as
salicylic acid.
The invention relates more especially also to the acid addition salts of bases
of formula I
wherein A is a direct bond; X is a radical -C(=NH)-NH2; Z is, NH; and each of
R1, R2, R3,
R4 and RS is hydrogen; and [PA] is preferably one of the acids defined above
as being
very important, especially selected from tartaric acid, more especially L-
tartaric acid,
-12-
lactic acid and citric acid.
Most strongly preferred are the acid addition salts of bases of formula I
mentioned in the
Examples with an acid [PA].
The acid addition salts of bases of formula I with an acid [PA] are prepared
in accordance
with processes lGnown per se, for example as follows:
a) a tease of formula I
X
.~ A
R1 I R2
(I),
Z
i II
N~NiC~N~Rs
I i
R3 R4
wherein the radicals are as defined for acid addition salts of bases of
formula I, is reacted
with an acid [PA], (PA] being as defined above, or
b) a compound of the formula
X
A
R~ \ ~ ~ R2
~C
i
W1 W2
wherein the group CW1W2 is carbonyl, functionally modified carbonyl or
protected
carbonyl and A, X, Rl and R2 are as defined for acid addition salts of formula
I, is
condensed with an amine of the formula
-13-
Z
H2N~.N~C'~NiRS (III)>
R3 R4
wherein Z, R3, R4 and R5 are as defined for acid addition salts of bases of
formula I, in the
presence of an acid [PA] that is as defined, or
c) in a compound of the formula
W3
A
Rt_ ~ R2
II
NwN.~C.,.N~R5
I i
R3 R4
whexein W3 is a radical that can be converted into a group X in a base of
.formula I and A,
Z, Rt, R2, R3, R4 and RS are as defined under formula I, the xadical W3 is
converted into
the group X in the presence of an acid [PA] that is as defined above; or
d) any desired acid addition salt of a base of formula I with an acid that
does not fall
within the definition of [PA] is converted into an acid addition salt of a
base of formula I
with an acid [PA] that is as defined above;
and, if desired, a resulting acid addition salt of a base of formula I with an
acid [PA] is
converted into a different acid addition salt of a base of formula I with an
acid [PA],
and/or, if desired, isomeric mixtures are separated into the individual
isomers.
In the following more detailed description of processes a)-d), each of the
symbols A, X, Y,
Z, Rt-R9 and [PA] is as defined in the definition of the acid addition salts
of bases of
formula I with acids [PA], unless otherwise indicated.
Process a
- 14-
The reaction of a base of formula I with an acid [PA] to form the;
corresponding acid
addition salt is carried out in accordance with methods known her se for the
formation of
acid addition salts of basic compounds.
The reaction to form the acid addition salt takes place, for example, in
solvents, especially
in organic solvents, more especially in polar organic solvents, most
especially in esters,
for example lower alkanoyl-lower alkyl esters, such as acetic acid ethyl
ester, in amides,
for example N,N-di-lower alkyl-lower alkanoylamides, such as
dimethylformamide, in
alcohols, for example hydroxy-lower alkanes, such as methanol, ethanol,
ethylene glycol
or glycerol, or aryl alcohols, such as phenols, for example phenol, or in
dimethyl
sulfoxide, in the absence or presence of water, preferably in the absence of
water. The
reaction in alcohols, such as the last-mentioned hydroxy-lower alkanes, is
especially
preferred.
The reaction takes place, for example, in free solution but may also be
carried out using
chromatographic columns, for example by gel Fltration, or using ion
exchangers, or via
semi-permeable membranes by osmotic processes.
The reaction is carried out at temperatures from the :free;zing point to the
boiling point of
the solutions concerned, preferably at from 0 to 50°C, especially from
20 to 40°C, for
example at room temperature, in the presence or absence of a protective gas,
such as
nitrogen ox argon.
The compounds of formula I and the acids [PA] are used in suitable molar
ratios, or the
acid [PA] is used in excess. The individual components are used preferably in
the molar
ratio corresponding to the ratio of the molarity of the base of formula I and
the acid [PA]
in the acid addition salts according to the invention.
The resulting salts precipitate, for example, spontaneously, in some cases
only after
cooling, or they are precipitated by the addition of solvents, especially non-
polar solvents,
for example ethers, such as diethyl ether, or water and/or are obtained by
partial or
complete concentration by evaporation.
Process b
There may be mentioned as functionally modified or protected carbonyl CW1W2,
for
2~~fl~~
-15-
example: di-lower alkoxymethyl, Cl-~2alkylenedioxymethyl, dihalamethyl, di-
lower
alkylthiomethyl or Ct-C2alkylenedithiomethyl.
The group CW1W2 in the compounds of formula II is preferably in the form of
free
carbonyl.
The condensation reaction according to Process b) is effected under the
conditions known
her se for the formation of hydrazones and is carried out in the presence of
an acid [PA]
that at the same time acts as a catalyst. The amount of [PA] is preferably
such that the
reacting amino group in the compound of formula III is protonated to such a
slight extent
that it is still reactive. For that purpose, the starting compounds, provided
they contain
salt-forming groups, are used especially preferably in the form of salts of
the acid [PA]
which are, if desired, formed in situ either from the free compounds or salts
of readily
volatile acids, such as hydrohalic acids, for example HBr or HCl, formic acid,
acetic acid
or carbonic acid (in the form of the carbonate salt or hydrogen carbonate
salt), it also
being possible for the reaction to take place, for example, in the presence of
a catalytically
active small excess of the acid [PA]. The solvent used is preferably one of
the solvents
mentioned under Process a), especially an aqueous solvent, such as water, at
preferred
temperatures of from 20°C up to the boiling point of the reaction
mixture concerned,
especially at the boiling point of the mixture concerned, in the presence or
absence of a
protective gas, such as nitrogen or argon. Suitable for compounds of formula
II are those
protected carbonyl groups CW1W2 that pass over into free carbonyl under the
conditions
of the condensation reaction.
For the preparation of acid addition salts from a base of formula I wherein RS
is amino,
and from an acid [PA], it is expedient to use the compound of formula III in
excess.
PPOCeSS C
In the intermediates of formula IV, W3 is, for example, free or functionally
modified
carboxy, especially halocarbonyl, cyano, imino-lower alkoxycarbonyl, imino-
lower alkyl-
thiolcarbonyl or thiocarbamoyl.
In the preparation of amidines of formula I (Y~ NR8), the group W3 in a
compound of
formula IV may be, for example: an acid addition salt of an imino-lower alkyl
ester (~
imino-lower alkyl ether) or imino-lower alkyl thiol ester with one of the
mentioned acids,
~Q8~5~
-16-
for example -C(=NH)-OC2H5 ~ [PA] or -C(=NH)-SC2H5 ~ [PA], respectively, also
thio-
carbamoyl or cyano.
By reacting an imino-lower alkyl ester of formula IV (in the form of a salt of
one of the
acids [PA], as defined above) with ammonia or primary or secondary amines, the
unsub-
stituted or mono- or di-substituted acid addition salts, respectively, of the
corresponding
amidines according to formula I are obtained. Cyano compounds of formula IV
can be
converted, for example, by reaction with a primary or secondary (di-)lower
alkyl-
ammonium salt of one of the mentioned acids [PA] into an unsubstituted or mono-
or di-
substituted acid addition salt of an amidine of formula I.
In the preparation of carbamoyl-substituted bases of formula I (Y'-_°
O) as constituents of
acid addition salts with acids [PA], the group Wg in a compound of formula IV
may be,
for example: carboxy, halocarbonyl (for example -COCl) or lower
allcoxycarbonyl. The
formation of unsubstituted or mono- or di-substituted carbamoyl-substituted
bases of
formula I as constituents of acid addition salts with an acid [PA] from
corresponding inter-
mediates of formula IV, wherein W3 is carboxy, halacarbonyl or lower
alkoxycarbonyl, by
reaction with ammonia or primary or secondary amines, respectively, is known
her se. The
corresponding acid addition salts of the bases of formula I can be obtained
directly from
the reaction mixture by precipitation, that is to say, by acidifying a, fox
example, alkaline
or neutral reaction mixture with one of the mentioned acids [PA].
In the preparation of acid addition salts with carbamoyl-substituted bases of
formula I
(Y~ O), the group W3 in a compound of formula IV may be, for example, cyano.
Inter-
mediates of formula IV wherein W3 is cyano can be converted, for example, by
partial
hydrolysis in the manner of a Graf Bitter reaction, or by way of carboxylic
acid ester
imide salts of the relevant acids [PA], into unsubstituted or mono- or di-
substituted
carbamoyl-substituted bases of formula I as canstituents of acid addition
salts. The
conditions of the hydrolysis of the cyano intermediates may be so chosen that
the reaction
is discontinued at the stage of the amide. Especially suitable for that
purpose is hydrolysis
with one of the acids [PA], as defined above, especially with the stronger of
the acids
mentioned there having a pK~, of S 5, at room temperature or with heating, for
example to
the boiling temperature or up to 150°C, in the presence of a non-
aqueous solvent or of a
solvent containing a stoichiometric amount of water.
Using the Graf Bitter reaction it is also possible to prepare the acid
addition salts of
-17-
N-substituted amides of formula I from nitrites of formula IV. To that end,
the nitrites are
reacted in the presence of a, preferably relatively strong (pKA of <_ 5), acid
[PA] with
compounds that can form carbenium ions in the acidic medium, that is to say,
for example,
with olefins, such as propylene, or alcohols, such as ethanol.
The carboxylic acid ester imides are obtained, for example, by acid-catalysed
addition of
alcohols to the nitrites of formula TV. The acid addition salts of the amides
of formula I
are obtained from the ester imides i.n the manner of a Pinner cleavage by
thermal
decomposition of the ester imide salts with acids [PA] at temperatures above
approx-
imately $0°C.
Acid addition salts of bases of formula I, wherein X is a radical -C(=NH)-
NR6R~, with
acids [PA] can also be obtained by reacting compounds of formula IV or the
acid addition
salts thereof with one of the above-mentioned acids [PA] wherein W3 is the
radical
-C(=S)-NH2, with S-alkylation, for example with tri-lower alkyloxonium
tetrafluoro-
borate, and subsequent reaction with an ammonia salt of one of the mentioned
acids [PA]
or with a corresponding acid addition salt of an amine of the formula NHR6R~
and one of
the mentioned acids [PA].
The reactions indicated under c) can, unless otherwise indicated, be carried
out under
reaction conditions known per se, in the absence or, generally, in the
presence of solvents
or diluents, preferably those that are inert towards the reagents used and
dissolve those
reagents, in the absence or presence of catalysts, condensation agents or
neutralising
agents, depending on the type of reaction and/or reactants, at ieduced, normal
or elevated
temperature, for example in a temperature range of from approximately -
70°C to approx-
imately 130°C, preferably from approximately.-20°C to
approximately 150°C, for
example at room temperature or at the boiling point of the solvent used in the
reaction
mixture concerned, under atmospheric pressure or in a closed vessel, where
appropriate
under pressure, and/or in an inert atmosphere, far example under a nitrogen
atmosphere.
Process d
The reaction of any desired acid addition salt of a base of formula I with an
acid that does
not fall within the definition of [PA] is carried out in accordance with the
customary
methods for converting salts.
~(~~~~~
-18-
Acids that do not fall within the definition of [PA] include all other erotic
acids, for
example.organic acids that do not fall within the definition of [PA], such as
formic acid,
acetic acid and methanesulfonic acid, or inorganic acids, such as sulfuric
acid, hydrohalic
acids, such as HF, HCl, HBr or HI, also hydrazoic acid or phosphoric acid. The
salts of
hydrohalic acids are especially preferred.
The reaction of such salts of acids that do not fall within the definition of
[PA] to form the
acid addition salt of an acid [PA] is corned out, for example, in solvents,
especially in
organic solvents, more especially in polar organic solvents, most especially
in esters, for
example lower alkanoyl-lower allcyl esters, such as acetic acid ethyl ester,
in amides, for
example N,N-di-lower alkyl-lower alkanoylamides, such as dimethylformamide, in
alcohols, for example hydroxy-lower alkanes, such as methanol, ethanol,
ethylene glycol
or glycerol, or aryl alcohols, such as phenols, far example phenol, or in
dimethyl
sulfoxide, in the absence or :presence of water, preferably in the absence of
water. The
reaction in alcohols, such as the last-mentioned hydroxy-lower alkanes, is
especially
preferred.
The reaction can also be carried out by way of the free bases of formula I
which are
prepared, for example, by converting the acid salt, used as starting material,
of a base of
formula I with an acid that does not fall within the definition of [PA], with
the aid of a
base, for example a hydroxy base, such as an alkali hydroxide, for example
NaOH or
KOH, in aqueous solution in the presence or absence of an organic solvent,
such as
defined under a), into the free base; the subsequent conversion of the free
base is carried
out, for example, as described under Process a).
The compounds of formula I and the acids [PA] are used in the mentioned
reactions in
suitable molar ratios, or the acid [PA] is used in excess. The individual
components are
used preferably in the molar ratio corresponding to the ratio of the molarity
of the base of
formula I and the acid [PA] in the acid addition salts according to the
invention.
The reaction is carried out at temperatures from the freezing point to the
boiling point of
the solutions concerned, preferably at from 0 to 50°C, especially from
20 to 40°C, for
example at room temperature, in the presence or absence of a protective gas,
such as
nitrogen or argon.
The resulting salts precipitate, for example, spontaneously, in some cases
only after
- 19-
cooling, or they are precipitated by the addition of solvents, especially non-
polar solvents,
for example ethers, such as diethyl ether, ar water and/or are obtained by
partial or
complete concentration by evaporation.
Additional~rocess measures
Acid addition salts of a base of formula I with an acid [PA] can be converted
into acid
addition salts of other bases of formula I and/or of other acids [PA],
processes known per
se being used.
That can be effected, for example, by converting the acid [PA], the base of
formula I or
both components of the acid addition salt.
For example, the acid component [PA] can be exchanged, either directly by
conversion
into the free base in the presence of the acid [PA] to be introduced, which
may, for
example, be used in excess, or indirectly by converting the base of formula I
contained in
the acid addition salt used as starting material into the free base, for
example by reacting
the acid addition salt, used as starting material, of the base of formula I
with a base, espec-
ially a hydroxy base, such as an alkali hydroxide, for example NaOH or KOI-l,
in aqueous
solution in the presence or, preferably, absence of an organic solvent, as
defined under a),
and by subsequent conversion of the free base in accordance with Process a)
into a
different acid addition salt of formula I, also by dialysis, by means of ion
exchangers or by
gel chromatography.
Also the base of formula I within an acid addition salt comprising abase of
formula Land
an acid [PA] can be converted into a different base according to formula I.
For example, the bases of formula I wherein X is a radical -C(=S)-NH2 can be
converted
by S-alkylation, for example with tri-lower alkyloxonium tetrafluoroborate,
and
subsequent reaction with an ammonium salt from the acid [PA], contained in the
original
acid addition salt, and ammonia itself or an amine of the formula NHR6R~ into
other bases
of formula I wherein X is a radical -C(=NH)-NR6R~, the acid component in the
resulting
acid addition salts being the same as before.
A base of formula I within acid addition salts with an acid [PA] wherein X is
a radical of
~~d0~~ i
-20-
the formula -C(=NI-I)-NH-OH can be converted by reaction in the presence of a
base, such
as triethylamine, and an oxidisable reagent, such as iron pentacarbonyl, in an
organic
solvent, such as tetrahydrofuran, at elevated temperatures, preferably the
boiling point of
the reaction mixture, and subsequent reaction of the resulting product with
the same acid
(PA] into acid addition salts of a base of fozmula I wherein X is the radical -
C(=NH)-NH2,
[PA] being unchanged with respect to the starting salt.
Isomeric mixtures obtainable according to the invention can be separated in a
manner
known her se into the individual isomers. For example, racemates can be
separated by the
formation of salts with optically pure salt-forming reagents and separation of
the
diastereoisomeric mixture so obtainable, for example by means of fractional
crystal-
lisation or by chromatography on optically active column materials.
In the process of the present invention, it is preferable to use those
starting materials that
lead to the acid addition salts described at the beginning as being especially
valuable.
The invention relates also to those forms of the process in which a compound
obtainable
as intermediate at any stage of the process is used as starting material and
the remaining
process steps are carried out, or in which a starting material is formed under
the reaction
conditions or is used in the form of a derivative, for example a salt,
thereof.
Pharmaceutical compositions:
The present invention relates also to pharmaceutical compositions that
comprise as active
ingredient one of the pharmacologically active acid addition salts of a base
of formula I
with an acid [PA]. Compositions for enteral, especially.oral, and parenteral
administration
are especially preferred. The compositions comprise the active ingredient
alone or, prefer-
ably, together with at least one pharmaceutically acceptable carrier. The dose
of the active
ingredient depends on the disorder to be treated and on the species and its
age, weight and
individual condition, and also on the method of administration.
The pharmaceutical compositions comprise from approximately 0.1 % to
approximately
95 % active ingredient, single dosage forms of administration comprising
preferably from
approximately 1 % to approximately 90 % and non-single dosage forms of
administration
comprising preferably from approximately 0.1 % to approximately 20 % active
ingredient.
Unit dose forms, such as dragees, tablets or capsules, comprise from
approximately 1 mg
~~g~~ ~~
-21-
to approximately 500 mg of the active ingredient.
The pharmaceutical compositions of the present invention are prepared in a
manner known
per se, for example by means of conventional mixing, granulating,
confectioning,
dissolving or lyophilising processes. For example, pharn~aceutical
compositions for oral
administration can be obtained by combining the active ingredient with one or
more solid
carriers, optionally granulating a resulting mixture, and processing the
mixture or
granules, if desired or necessary after the addition of further excipients, to
form tablets or
dragee cores.
Suitable carriers are especially fillers, such as sugars, for example lactose,
saccharose,
mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for
example
tricalcium phosphate or calcium hydrogen phosphate, also binders, such as
starches, for
example corn, wheat, rice or potato starch, methylcellulose,
hydroxypropylmethyl-
cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or,
if desired,
disintegrators, such as the above-mentioned starches, also carboxymethyl
starch, cross-
linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium
alginate.
Further excipients are especially flow-conditioners and lubricants, for
example silicic acid,
talc, stearic acid or salts thereof, such as magnesium or calcium stearate,
and/or paly-
ethylene glycol, orderivatives thereof.
Dragee cores may be provided with suitable enteric or non-enteric coatings,
there being
used, inter alia, concentrated sugar solutions that may contain gum arabic,
talc, polyvinyl-
pyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in
suitable
organic solvents or solvent mixtures or, for the preparation of
enteric~coatings, solutions of
suitable cellulose preparations, such as acetylcellulose phthalate or
hydroxypropylmethyl-
cellulose phthalate. Colourings or pigments may be added to the tablets or
dragee
coatings, for example for identification purposes or to indicate different
doses of active
ingredient.
Orally administrable pharmaceutical compositions axe also dry-filled capsules
consisting
of gelatin, and also soft sealed capsules consisting of gelatin and a
plasticiser, such as
glycerol or sorbitol. The dry-filled capsules tnay contain the active
ingredient in the form
of granules, for example in admixture with fillers, such as corn starch,
binders and/or
glidants, such as talc or magnesium stearate, and optionally stabilisers. In
soft capsules,
-22-
the active ingredient is preferably dissolved or suspended in suitable liquid
excipients,
such as fatty oils, paraffin oil or liquid polyethylene glycols, to which
stabilisers may also
be added.
Further oral forms of administration are, for example, syrups prepared in
customary
manner that comprise the active ingredient, for example, in suspended form and
in a
concentration of approximately from 0.1 % to 10 %, preferably approximately 1
% or in a
similar concentration that, for example, on measuring off 5 or 10 ml, gives a
suitable
individual dose. Also suitable are, for example, pulvezulent or liquid
concentrates for the
preparation of shakes, for example in milk. Such concentrates can also be
packed in
amounts for individual doses.
Suitable rectally administrable pharmaceutical compositions ace, for example,
supposi-
tories that consist of a combination of the active ingredient and a
suppository base.
Suitable as suppository base are, for example, natural or synthetic
triglycerides, paraffin
hydrocarbons, polyethylene glycols or higher alkanols.
Suitable for parenteral administration are especially aqueous solutions of an
active
ingredient in water-soluble form, for example a water-soluble salt, or aqueous
injection
suspensions containing viscosity-increasing substances, for example sodium
carboxy-
methylcellulose, sorbitol and/or dextran and optionally stabilisers. The
active ingredient,
optionally together with excipients, may also be in the form of a lyophilisate
and may be
dissolved before parenteral administratian by the addition of suitable
solvents. An isotonic
solution for infusion can be prepared especially by the addition of suitable
salts, such as
NaCI, buffers, such as phosphate buffers, for example with sodium as counter-
ion, and/or
sugar alcohols, such as mannitol, it being optionally possible for others of
the mentioned
excipients also to be present.
Solutions, as used, for example, for parenteral administration, may also be
used in the
form of infusion solutions.
The invention relates also to a method of treating the above-mentioned
diseased states,
caused especially by a lack of S-adenosylmethionine decarboxylase-inhibition,
which
respond to treatment with an inhibitor of S-adenosylmethionine decarboxylase.
The acid
addition salts of the present invention may be administered prophylactically
or thera-
peutically, especially in amounts that are suitable for inhibiting S-
adenosylmethionine
-23-
decarboxylase, and they are used preferably in the form of pharmaceutical
compositions.
In the case of a body weight of approximately 70 kg, a daily dose, especially
one that is
effective against the mentioned diseases, of from approximately 1 mg to
approximately
1000 mg, preferably approximately from 25 to 100 mg in the case of oral
administration or
approximately from 2 to 50 mg in the case of parenteral administration, of an
acid addition
salt of the present invention is administered, for example to a warm-blooded
animal, such
as a human, that is in need of such treatment because it is suffering from a
protozoa
infection or from tumours.
The invention relates also to a pharmaceutical composition that is suitable
for adminis-
tration to a mammal, for example a human, for the prevention or treatment of a
disease
that responds to treatment with an inhibitor of S-adenosylmethionine
decarboxylase,
especially a tumour disease or a protozoa infection, which composition
comprises an
amount of an acid addition salt of formula I, or tautomers thereof, that is
effective in the
inhibition of S-adenosylmethionine decarboxylase, and a pharmaceutically
acceptable
carrier.
Starting Compounds:
The protic acids [PA) are known, can be pxepared in accordance with processes
known Qer
se or are commercially available.
The starting compounds of foiznula I are prepared in accordance with processes
known her
se, for example as follows:
(i) a compound of formula II as defined under Process a) is condensed with an
amine of
formula III as defined under Process a), or
(ii) in a compound of formula IV as defined under Process c), the radical W3
is converted
into the group X,
and, if desired, a resulting compound of formula I is converted into a
different compound
of formula I, and/or, if desired, a resulting salt is converted into the free
compound or into
a different salt, and/or, if desired, a resulting free compound of formula I
having salt-
forming properties is converted into a salt.
-24-
In the following more detailed description of Processes i)-ii), each of the
symbols A, X, Y,
Z, Rl-R~ and [PA] occurring in formulae is as defined for acid addition salts
of bases of
formula I with acids [PA], unless otherwise indicated.
Process (i):
There may be mentioned as functionally modified or protected carbonyl CWtW2,
for
example: di-lower alkoxymethyl, Cl-C2alkylenedioxymethyl, dihalomethyl, di-
lower
alkylthiomethyl or Cl-C2alkylenedithiomethyl.
The group CW1W~ in the compounds of formula II is preferably in the form of
free
carbonyl.
The condensation reaction according to Process a) is carried out under the
conditions
known per se for the formation of hydrazones. It is preferably catalysed by an
acid. In
compounds of formula II, suitable protected carbonyl groups CW1W2 are those
that pass
over into free carbonyl under the conditions of the condensation reaction.
1~or the preparation of compounds of formula I wherein RS is amino, it is
expedient to use
the compound of formula III in excess.
The intermediates of formula I wherein Y in the radical X is NH are obtained,
for
example, by first converting a compound of formula V
CN
r A
R1 I R2 (V)
C
i ~
W~ W2
into the corresponding thiocarboxamide [-C(=S)-NHz] by treatment with hydrogen
sulfide.
The thiocarboxamide can also be obtained by other methods starting from the
analogous
carboxamide [-C( =O)-NH2], for example by reaction with Lawesson's reagent
[2,4-bis(4-
methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane]. The thiocarboxamides
are
S-alkyiated, for example, with lower alkyl iodide or tri-lower alkyloxonium
tetrafluoro-
-25-
borate, and thus converted into imino-lower alkylthiol ester hydroiodides [-
C(=NH)S-
alkyl ~ Hl] or tetrafluoroborates, respectively, which can be readily
converted into the
desired carboximidamides of formula I by reaction with ammonia or amines of
the
formula IVI-IRSR~, respectively, [see S. Fatai (Ed.), The Chemistry of
Amidines and
Imidates, Wiley, London etc. 1975, p. 303-304.
The preparation of the carboxamides of formula II from the cyano compounds of
formula V takes place analogously to the preparation, described below in
connection with
Process (ii), of carboxamides of formula I from cyano compounds of formula N
and is
described in detail there.
Another possible method of preparing the compounds of formula II is to treat a
compound
of formula V, wherein the group CW1W2 is as defined under formula II, for
example with
ethanol and hydrochloric acid in, for example, chloroform or diethyl ether, to
form the
corresponding iminoethyl ester hydrochloride which can be converted into the
desired
carboximidamide of formula II, for example, by reaction with ammonia or a
primary or
secondary amine of the formula NHR~R~ and, far example, methanol. That method
may,
however, fail in some cases owing to steric hindrance by the group A or Rl.
The starting compounds of formula V are known her se or are prepared
analogously to the
known compounds.
The compounds of formula V can be prepared, for example, by intramolecular
Friedel-Crafts acylation of c~-phenyl-lower alkanoic acids of formula VI,
Wd
O
/ A~~ (VI)
Rt I q2 OOH
v
wherein W4 is cyano or a cyano precursor, or acid derivatives thereof, for
example acid
chlorides or acid anhydrides. There may be used as catalysts in the case of
fxee acids, for
example, polyphosphoric acid, and, in the case of acid chlorides or acid
anhydrides, for
example A1C13.
-26-
In that reaction it is preferable to use compounds of formula VI wherein W4 is
not cyano
but a precursor of cyano, for example halogen, especially bromine, or
protected amino, for
example acetylamino. After the cyclisation step, the cyano precursors can be
converted
into cyano in a manner known her se, for example: bromine can be converted by
reaction
with copper(I) cyanide, or acetylamino can be converted by removal of the
acetyl-
protecting group, diazotisation and reaction with copper(I) cyanide.
Compounds of formula V wherein the group CW1W2 is carbonyl can also be
prepared, for
example, by oxidation, for example with chromium trioxide (Cr03), from the
corres-
ponding non-carbonyl compounds of formula VII
Wa
A
R1 ( R2 (VII)
H H
wherein W~ is cyano or a cyano precursor as defined above. If a cyano
precursor is used, it
is again to be converted, after completion of oxidation, into cyano, for
example as
indicated above.
Another possible method of preparing the compounds of formula V wherein the
group
CW1W2 is carbonyl is to start from compounds of formula II wherein X is
hydrogen and
to introduce the cyano group, for example, by a reaction sequence analogous to
US Patent
3 956 363, Example 10, which comprises nitration, reduction of the nitro group
to amino,
diazotisation and reaction with copper(I) cyanide. (Sandmeyer reaetion)_
The preparation of amino-guanidines, -ureas and -thioureas of formula III is
known her se.
Amino(thio)ureas ['~ semi(thio)carbazides] are prepared, for example, in a
manner
analogous to corresponding simple (thio)ureas, there being used, for example,
instead of
amines, the corresponding hydrazines of the formula H2N-NHRg, which are
reacted, for
example, with an isocyanate of the formula R4N=C=O or RSN=C=O, an
isothiocyanate of
the formula R4N=C=S or R5N=C=S, a carbamoyl chloride of the formula R4R5N-COCI
or
a thiocarbamoyl chloride of the formula RaRSN-CSCI. Also possible is, for
example, the
reaction of a hydrazine of the formula I32N-NIIR3 with an acyl isothiocyanate,
for
example acetyl isothiocyanate, and subsequent acidic hydrolysis.
~f~~~~!~
-27-
Aminoguanidines of formula III wherein 2 is NR9 and R3, R4, RS and R9 are as
defined
under formula I are known her se and can be prepared, for example, from
corresponding
aminothioureas of formula III by converting the latter by alkylation, for
example with an
alkyl p-toluenesulfonate or an alkyl halide, into the corresponding S-
alkylisothiuronium
salts and reacting those salts with an amine of the formula NHR4R5.
Process (ii):
In the intermediates of formula IV, W3 is, for example, free or functionally
modified
carboxy, especially halocarbonyl, cyano, imino-lower alkoxycarbonyl, imino-
lower alkyl-
thiolcarbonyl or thiocarbamoyl.
In the preparation of amidines of formula II (Y~ NR$), the group W3 in a
compound of
formula IV may be, for example: an acid addition salt of an imino-lower alkyl
ester
( ~ imino-lower alkyl ether) or imino-lower alkylthiol ester, for example
-C(=NH)-OC2H5 ~ HCI or -C(=NH)-SC2H5 ~ >:II, respectively, or cyano.
By reacting an imino-lower alkyl ester of formula IV (in the form of a salt)
with ammonia
or primary or secondary amines, the unsubstituted or mono- or di-substituted
amidines,
respectively, of formula I are obtained. Cyano compounds of formula IV can be
converted,
for example, by reaction with an alkali metal amide, for example KI~I2, or by
reaction
with a primary or secondary (di-)lower alkylammonium halide, for example
~NH3CH3 CI ~~ into an unsubstituted or mono- or di-substituted amidine of
formula I.
In the preparation of carbamoyl compounds of formula I (Y~__ O), the group W3
in a
compound of formula IV may be, for example: carboxy, halocarbonyl (for example
-COCl), lower alkoxycarbonyl or cyano. The formation of unsubstituted or mono-
or di-
substituted carbamoyl compounds of formula I from corresponding intermediates
of
formula IV, wherein W3 is carboxy, halocarbonyl or lower alkoxycarbonyl, by
reaction
with ammonia or primary or secondary amines, respectively, is known ~ se.
Inter-
mediates of formula IV wherein W3 is cyano can be converted, far example, by
partial
hydrolysis, in the manner of a Graf Ritter reaction, or by way of carboxylic
acid ester
imide salts, into unsubstituted or mono- or di-substituted carbamoyl compounds
of
formula I. In the hydrolysis of the cyano intermediates, the conditions may be
so chosen
-28-
that the reaction is discontinued at the amide stage. Suitable for that
purpose is especially
hydrolysis with acids, for example with 80 % sulfuric acid (with heating),
polyphosphoric
acid (at 110-150°C), hydrobromic acid/glacial acetic acid (at room
temperature, in the
presence of formic acid or without further solvent) or HCl gas in ethereal
solution
followed by the addition of water or aqueous hydrochloric acid, or reaction
with boron
halides.
Using the Graf Ritter reaction it is also possible to produce N-substituted
amides from
nitrites of formula IV. To that end, the nitrites are reacted in the presence
of a strong acid,
especially 85-90 % sulfuric acid, or also polyphosphoric acid, formic acid,
boron
trifluoride or other Lewis acids, with the exception of aluminium chloride,
with
compounds that can form carbenium ions in the acidic medium, that is to say,
for example,
with olefins, such as propylene, or alcohols, such as ethanol.
The carboxylic acid ester imides are obtained, for example, by acid-catalysed
addition of
alcohols to the nitrites of formula IV. The amides are obtained from the ester
imides in the
manner of a Dinner cleavage by thermal decomposition of the ester imide salts
at tempera-
tures above approximately 80°C.
Compounds of formula IV wherein W3 is cyano can be prepared, for example, by
reacting
a compound of formula V with a compound of formula BI in accordance with
Process ii).
The other compounds of formula IV wherein W3 is free carboxy or carboxy
functionally
modified in another manner can be prepared from compounds of formula IV
wherein W3
is cyano in a manner known per se or as described abave.
Compounds of foamula I wherein X is a radical -C(=NI-i)-NR6R~ can also be
obtained by
reacting compounds of formula IV wherein W3 is a radical -C(=S)-NH2, with S-
alkylation,
for example with tri-lower alkyloxonium tetrafluoroborate, and by subsequent
reaction
with ammonia or an amine of the formula NHR6R~ or a corresponding ammonium
salt, for
example the chloride.
Compounds of formula I can be converted into different compounds of formula I.
For example, compounds of formula I wherein X is a radical -C(=S)-NH2 can be
converted by S-alkylation, for example with tri-lower alkyloxonium
tetrafluoroborate, and
subsequent reaction with ammonia or an amine of the formula NHR6R~, or
especially with
-29-
a corresponding ammonium salt thereof, into compounds of formula I wherein X
is a
radical -C(=NH)-NRbR~.
Compounds of formula I wherein X is an N-hydroxyamidino radical -C(=NRg)-NHOH
can be converted, for example, by reaction with iron pentacarbonyl [Fe(CO)5]
into
different compounds of formula I wherein X is an analogous amidino radical
-C(=NR$)-NH2 (see, for example, J. Chem. Soc. Chem. Commun. 1975, 761).
Free compounds of formula I that have salt-foaming properties and that are
obtainable in
accordance with the process can be converted in a manner known her se into
their salts:
for example, compounds having basic properties can be converted by treatment
with acids,
either with the erotic acids [PA] themselves or preferably with other erotic
acids, for
example organic acids that do not fall within the definition of [PA], such as
formic acid,
acetic acid and rnethanesulfonic acid, or inorganic acids, such as sulfuric
acid, hydrohalic
acids, such as HF, HCI, HBr or HI, also hydrazoic acid or phosphoric acid.
Flydrohalic
acids are especially preferred. The reaction takes place, for example,
analogously to
Process a) for the preparation of acid addition salts of bases of formula I
with acids [PA].
The acid addition salts of bases of formula I, especially those with erotic
acids other than
[PA], can also be converted into the free compounds. That can be effected, for
example,
by conversion into the free base, for example by reaction of the salt of a
compound of
formula I used as starting material with a hydroxy base, such as an alkali
metal hydroxide,
for example NaOH or KOH, in aqueous solution in the presence or, preferably,
absence of
an organic solvent, as defined under a), also by dialysis, using ion
exchangers or by gel
chromatography.
The preparation of starting compounds of formulae II, T(I and IV is carried
out as indicated
in the more detailed description of Processes i) and ii).
Owing to the close relationship between the compounds of formulae I, II, III,
IV and also
V, VI and VII in free form and, insofar as the mentioned compounds contain
salt-forming
groups, in the form of salts, hereinbefore and hereinafter the free compounds
and their
salts are also to be understood as being the corresponding salts, for example
acid addition
salts or also salts with bases, and the free compounds, respectively, where
appropriate and
where the context so allows.
-30-
The preparation of salts, for example of the compounds of formulae II, III and
IV having
salt-forming groups, is carried out analogously to the preparation of salts of
the bases of
formula I (Process a)).
The compounds, including their salts, can also be obtained in the form of
hydrates, or their
crystals may include, for example, the solvent used for crystallisation.
Isomeric mixtures obtainable in accordance with Process i) or ii) can be
separated in a
manner known her se into the individual isomers. For example, racemates can be
separated by the formation of salts with optically pure salt-forming reagents
and
separation of the diastereoisomeric mixture so obtainable, for example by
means of
fractional crystallisation.
The above reactions given under Process i) or ii) can be carried out under
reaction
conditions known per se, in the absence or, generally, presence of solvents or
diluents,
preferably those that are inert towards the reagents used and dissolve those
reagents, in the
absence or presence of catalysts, condensation agents or neutralising agents,
depending on
the type of reaction and/or the reactants at reduced, normal or elevated
temperature, for
example in a temperature range of from approximately -70°C to
approximately 190°C,
preferably from approximately -20°C to approximately 150°C, for
example at room
temperature or at the boiling point of the solvent used in the reaction
mixture concerned,
under atmospheric pressuxe or in a closed vessel, where appropriate under
pressure, and/or
in an inert atmosphere, for example under a nitrogen atmosphere.
The preparation of some starting compounds of formula I is described below for
purely
illustrative purposes. Temperatures are given in degrees Celsius: The
following abbrev-
iations are used: abs. = absolute (anhydrous); D20 = deuterised water; DMF =
N,N-di-
methylformamide; DMSO-d6 = perdeuterised dimethyl sulfoxide; ether = diethyl
ether;
ethyl acetate = acetic acid ethyl ester, IR = infrared spectroscopy; m.p. =
melting point;
THF = tetrahydrofuran; MS (FAB) = mass spectrum ("Fast Atom Bombardment").
1) Starting Coanpound A:
4-Axrrino-1-indanone-2'-afnidinohydrazone dihydrochloride
A solution of 3.8 g (27.9 mmol) of aminoguanidine hydrogen carbonate in 200 ml
of water
and 14.7 ml of 2N hydrochloric acid is heated to 60° and, with
stirring, a solution of 5.85 g
(27.8 mmol) of 4-amidino-1-indanone hydrochloride in 200 ml of methanol is
added over
-31-
the course of 30 min. The reaction mixture is boiled under reflex for 24 h
and, after
cooling, is concentrated to dryness by evaporation. The residue is suspended
in 50 ml of
ethanol, filtered, washed with ethanol and ether and dried to yield the title
compound
which contains 1 mol of water of crystallisation, m.p. a330°; MS(FAB):
(M+H)~=231;
1H-NMR (D20): s=8.08 (d,lH); 7.75 (d,lH); 7.58 (t,lH); 3.35 (m,2H); 2.96
(m,2H).
The precursors are prepared as follows:
(a) 4-Thiocarbamoyl-1-indanone
A solution of 12.1 g (77 mmol) of 4-cyano-1-indanone [Coll. Czechoslov. Chem.
Commun. 43, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of
triethylamine
is saturated for 3 h at 40° with hydrogen sulfide and stirred for a
further 16 h at that same
temperature. After cooling, the reaction mixture is concentrated to dryness by
evaporation
and 300 ml of water are added to the residue. The yellow product which
crystallises out is
filtered off with suction, washed with water, dried and recrystallised from
ethyl acetate to
yield the title compound, m.p. 197° (decomposition).
(b) 4-Amidino-1-indanone hydrochloride
10.8 g (54 mmol) of triethyloxonium tetrafluoroborate are added at room
temperature and
under argon to a solution of 9.8 g (51.3 mmol) of 4-thiorarbamoyl-1-indanone
in S00 rnl
of abs. methylene chloride. After 16 h, a mixture of 4.2 g of potassium
carbonate and
4.2 ml of water is added to the reaction solution. The reaction mixture is
then stirred
briefly and filtered and the filtrate is washed with water. The organic phase
is dried over
magnesium sulfate, filtered and concentrated by evaporation. The resulting
crude
ethylthioimino ether is dissolved in 160 ml of abs. ethanol; 3.3 g (60 mmol)
of ammonium
chloride are added and the reaction mixture is heated under reflex for 20 h.
After cooling,
it is concentrated to dryness by evaporation and the title compound is
purified by
chromatography on 1000 ml of Amberlite~ ER-180 resin (water as eluant) and
recrystal-
lined from ethanol/ether, m.p. 2I5-218° (decompositian).
2) Starting Compound B:
4-Amidino-1-indanone-2'-{N-hydroxyamidino)-hydrazone dihydrochloride
A solution of 394 mg (1.5 mmol) of 1-amino-3-hydroxyguanidine-4-
toluenesulfonate in
6 ml of water and 0.75 ml (1.5 mmol) of 2N hydrochloric acid is added to a
solution of
316 mg (1.5 mmol) of 4-amidino-1-indanone hydrochloride (see precursor 1 b)
under
Starting Compound A) in 7 ml of methanol and the reaction mixture is heated
for 2 h
-32-
under reflux and stirred for 16 h at room temperature. It is then concentrated
by evapor-
ation and the residue is purified by chromatography (Pharmacia column SR-28-
100) on
silica gel OPTI-UP C12~ (water as eluant, 5 ml-fractions, rate of flow 27.5
ml/h). The
contents of fractions 58-78 are combined and concentrated by evaporation and
the residue
is crystallised from ethanol to yield the title compound in the form of wax-
like crystals,
MS (FAB): (M+H)+ = 247; tH-NMR (D20): s=8.06 (d,1H); 7.73 (d,1H); 7.58 (t,lH);
3.36
(m,2H); 2.98 (m,2H).
3) Starting Compound C:
5-Amidino-1-tetralone-2'-amidinohydrazone dihydrochloride
0.675 g (3 mmol) of 5-amidino-1-tetralone hydrochloride is added to a solution
of 0.41 g
(3 mmol) of aminoguanidine hydrogen carbonate in 31.5 ml of O.1N hydrochloric
acid and
the batch is heated for 72 h under reflux. After cooling, it is concentrated
to dryness by
evaporation and the title compound is recrystallised from methanol/ether, m.p.
>250°;
MS (FAB): (M+H)+ = 245; 1H-NMR (DMSO-db): s =11.3 (s, 1H); 9.5 (m,4H); 8.65
(d,lH); 7.92 (m,3I-I); 7.52 (d,lH); 7.46 (t,ll3); 2.7-2.85 (m,4H); 1.9 (rn,4I-
I).
The precursors are prepared as follows:
(a) 5-Cyano-1-tetralone
0.41 g (4.5 mmol) of copper(I) cyanide is added to a solution of 1.0 g (4.4
mmol) of
5-bromo-1-tetralone [J. Org. Chem. 49, 4226 (19$4)] in 1.3 ml of DMF and the
reaction
mixture is stirred for 6 h at 160°. It is then cooled to 80° and
a solution of 1.6 g of iron(III)
chloride hexahydrate in 2.5 ml of water and 0.44 ml of concentrated
hydrochloric acid is
added. The reaction mixture is then stirred for 45 minutes, cooled, diluted
with water and
extracted with toluene. The organic phase.is washed with water; dried over
magnesium
sulfate, filtered and concentrated by evaporation to yield the title compound
in the form of
yellow-orange crystals, IR (CH~C12): 2220, 1690 cm-1; 1H-NMR (CDCl3): S = 8.26
'(q,lH); 7.81 (q,lH); 7.43 (t,lH); 3.21 (t,2H); 2.72 (t,2H); 2.23 (m,2H).
(b) 5-Thiocarbamoyl-1-tetralone
Analogously to the process described for Starting Compound.A under 1 a), 10.6
g
(62 mmol) of 5-cyano-1-tetralone in 200 ml of pyridine and 8.6 ml of
triethylamine are
treated with hydrogen sulfide and worked up to yield the title compound in the
form of
yellow crystals, rn.p. 200-205°.
-33-
(c) 5Amidino-1-tetralone hydrochloride
Analogously to the process described for Starting Compound A under 1 b), 8.6 g
(42 mmol) of 5-thiocarbamoyl-1-tetralone are treated with 8.8 g (44 mmol) of
triethyl-
oxonium tetrafluoroborate and 2.6 g (49 mmol) of ammonium chloride to yield
the title
compound in the form of pale pink crystals, MS (FAB): (M+H)-~ = 189.
4) Starting Compound D:
4-Thiocarbamoyl-1-indanone-2'-arnidinohydrazone hydrochloride
1.36 g (10 mmol) of aminoguanidine hydrogen carbonate and 10 ml of 2N
hydrochloric
acid are added to a solution of 1.9 g (10 mmol) of 4-thiocarbamoyl-1-indanone
(prepared
as described under Starting Compound A, 1 a)) in 50 ml of ethanol and the
reaction
mixture is heated under reflex for 24 h. After cooling, it is concentrated to
dryness by
evaporation to yield the title compound.
5) Starting Compound ~:
4-(N-Iiydroxyamidino)-I-indanone-2'-amidinohydrazone dihydrochloride
0.2 g (3 mmol) of hydroxylatnine hydrochloride is suspended in 1 ml of abs,
ethanol, and
2 ml of a 1N sodium ethoxide solution in ethanol are added. The mixture is
stirred for 1 h
and filtered. A solution of 0.26 g (1 mmol) of 4-cyano-1-indanone-2'-
amidinohydrazone
hydrochloride (see below under 18 a)) in 2 ml of water is added to the
filtrate, and the
reaction mixture is heated under reflex for 6 h. After cooling, it is
concentrated by evapor-
ation and the title compound is crystallised from water, m.p. >250°; tH-
NMR
(DMSO-d6 + D20): b = 8.12 (m,lH); ?.55 (m,2H); 3.22 (m,2H); 2.83 (m,2H).
6) Starting Compound F:
4-Amidino-2-methyl-1-indanone-2'-amidinohydrazone dihydrochlaride
A solution of 1.0 g (5.0 mmol) of 4-amidino-2-methyl-1-indanone hydrochloride
and
0.68 g (5.0 mmol) of aminoguanidine hydrogen carbonate in 10 ml of 0.5N
hydrochloric
acid is stirred for 120 h at 25°. The product which crystallises out is
filtered off with
suction, washed with a small amount of water and dried to yield the title
compound,
m.p. >250°; MS (FAB): (M + H)t = 245; tH-NMR (D20): 8 = 7.95 (d,lH);
7.66 (d,lH);
7.48 (t,lH); 3.45 (m,2H); 2.85 (d,lH); 1.12 (d,3H).
The precursors are prepared as follows:
(a) 4-Thiocai:bamoyl-2-methyl-1-indanone
_34_
Analogously to the process described for Starting Compound A under 1 a), 11.1
g
(65 mmol) of 4-cyano-2-methyl-1-indanone [see US Patent 3 95b 363] in 200 ml
of
pyridine and 9.7 ml of triethylamine are treated with hydrogen sulfide and
worked up to
yield the title compound in the form of yellow crystals, m.p. 195-198°
(decomposition);
tH-NMR (DMSO-d6): 8 = 9.61 (s,lH); 7.71 (m,2H); 7.48 (m,lH); 3.48 (m,lH); 2.81
(m,2H); 1.23 (s,3H); 1.19 (s,3H).
(b) 4-Amidino-2-methyl-1-indanone hydrochloride
Analogously to the process described for Starting Compound A under 1 b), 10.2
g
(50 mmol) of 4-thiocarbamoyl-2-methyl-1-indanone are treated with 11.0 g (55
mmol) of
triethyloxonium tetxafluoroborate and 3.2 g (60 mmol) of ammonium chloride to
yield the
title compound in the form of pink crystals, which is further reacted
directly.
7) Starting Compound G:
S-Amidino-6-methoxy-1-tetralone-2'-amidinohydrazone dihydrochloride
Analogously to Starting Compound A under 1) the title compound is prepared
starting
fxom 5-cyano-6-methoxy-1-tetralone [Chem. Pharm. Bull. 31, 2329 (1983)].
8) Starting Compound I-t:
4-Amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihxdrochloride
Analogously to Starting Compound C, the title compound is prepared stating
from 4-
bromo-6-methoxy-7-methyl-1-indanone (J. Chem. Soc. Perkin Trans. 1 1974,
1911).
9) Starting Compound I:
4-Amidino-6,7-dimethyl-1-indanone-2'-amidinohydrazone dihydrochioride
Analogously to Starting Compound A under 1), the title compound is prepared
starting
from 4-amidino-6,7-dimethyl-1-indanone hydrochloride, m.p. >240°C; MS
(FAB):
(M+I-I)~ = 259; lI-I-NMR (D20): S = 7.43 (s,lH); 3.12 (m,2H); 2.75 (m,2H);
2.43 (s,3H);
2.24 (s,3H).
The precursors are prepared as follows:
(a) 4-Cyano-6,7-dimethyl-1-indanone
A mixture of 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J. Het.
Chem. 24,
677 (1987)] and 7.3 g (82 mmol) of copper(I) cyanide in 18 ml of DMF is
stirred for 6 h at
170°. The reaction mixture is then cooled to 100° and 200 ml of
toluene and a solution of
-35-
31.2 g of iron(III) chloride hexahydrate in 47 ml of water and 8.2 ml of
concentrated
hydrochloric acid are added in succession. The reaction mixture is stirred for
20 min at
70°, cooled and diluted with toluene and water. The organic phase is
separated off, washed
with water, a semi-saturated sodium hydrogen carbonate solution and again with
water,
dried and concentrated by evaporation. The residue is crystallised from ethyl
acetate and
ether and corresponds to the title compound. Beige crystals are obtained of
m.p. 160-163°;
IR (CH2Cl2): 2220, 1710 cm t.
(b) 4-lfiiocarbamo_,~-6,7-dimethyl-1-indanone
Analogously to the process described for Starting Compound A under 1 a), 10 g
(54.1 mmol) of 4-cyano-6,7-dimethyl-1-indanone in 200 ml of pyridine and 7.5
ml of
triethylamine are treated with hydrogen sulfide and worked up to yield the
title compound
in the form of yellow crystals, m.p. 207-208°; 1H-NMR (DMSO-d6): 8 =
10.03 (s,lH);
9.49 (s,lH); 7.49 (s,ll-I); 3.12 (m,2H); 2.61 (m,2H); 2.54 (s,3H); 2.29
(s,3H).
(c) 4-Amidino-6,7-dimethyl-1-indanone hydrochloride
Analogously to the process described for Starting Compound A under 1 b), 4.4 g
(20 mmol) of 4-thiocarbamoyl-6,7-dimethyl-1-indanone are txeated with 4.26 g
(21 mmol)
of triethyloxonium tetrafluoroborate and 1.2 g (24 mmol) of ammonium chloride
to yield
the title compound in the form of beige crystals.
10) Starting Compound J:
4-Amidino-7-hydroxy-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride
Analogously to Starting Compound C, the title compound is prepared starting
from
4-bromo-7-hydroxy-3-methyl-1-indanone [Indian J. Chem. Sect. B 24B, 1061
(1985)].
11) Starting Compound I~:
4-(Methylamidino)-1-indanone-2'-amidinohydrazone dihydrochloride
Analogously to the process described for Starting Compaund A under 1 b), 4-
thio-
carbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (Starting CarnpoundD)
is
reacted with triethyloxonium tetrafluoroborate and methylammonium chloride to
yield the
title compound.
12) Starting Compound L:
4-Amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazone dihydrochloride
0.73 g (2.7 mmol) of 4-amidino-6,7-dimethoxy-1-indanone hydrochloride is added
to a
2~~~~~
-36-
solution of 0.4 g (3 mmol) of aminoguanidine hydrogen carbonate in 6 ml of
0.5N hydro-
chloric acid and the batch is stirred for 24 h at 50°. After cooling,
the product which
crystallises out is filtered off with suction, washed with a small amount of
water and dried
to yield the title compound, m.p. >220°; MS (FAB): (M + H)+ = 291; 1H-
NMR (D20):
8 = 7.45 (s,lH); 3.97 (s,6H); 3.27 (m,2H); 2.98 (m,2H).
The precursors are prepared as follows:
(a) 4-Cyano-6,7-dimethoxy-1-indanone
A mixture of 6.57 g (24.2 mmol) of 4-bromo-6,7-dimethoxy-1-indanone (Can. J.
Chem.
57, 1603(1979)] and 2.5 g (28 mmol) of copper(I) cyanide in 7 ml of DMF is
stirred for
5.75 h at 170°. The reaction mixture is then cooled to 100° and
70 ml of toluene and a
solution of 9.7 g (36 mmol) of iron(III) chloride hexahydrate in 15.6 ml of
water and
3.5 ml of concentrated hydrochloric acid are added in succession. The reaction
mixture is
then stirred for 30 min at 80°, cooled and diluted with toluene and
water. The organic
phase is separated off, washed with water, a semi-saturated sodium hydrogen
carbonate
solution and again with water, dried and concentrated by evaporation. The
residue is
distilled at 150-160°/0.1 mbar in a bulb tube distilling apparatus and
corresponds to the
title compound, m.p. 150°; IR (CH2C12): 2220, 1710 cm-t; tH-NMR
(CDC13): 8 = 7.33
(s,lH); 4.12 (s,3H); 3.90 (s,3H); 3.19 (m,2H); 2.76 (m,2H).
(b) 4-Thiocarbamoyl-6,7-dimethoxv-1-indanone
Analogously to the process described for Starting Compound A under 1 a), 3.7 g
(17 mmol) of 4-cyano-6,7-dimethoxy-1-indanone in 100 ml of pyridine and 2.4 ml
of
triethylamine are treated with hydrogen sulfide and worked up to yield the
title compound
in the form of pale yellow crystals, m.p. 196-199°; IH-NMR (DMSO-d6): S
=10.06
(s,lH); 9.50 (s,lH); 7.41 (s,lH); 3.84 (s,6H); 3.13 (m,2H); 2.63 (m,2H).
(c) 4-r'lmidino-6,7-dimethoxy-1-indanone hydrochloride
Analogously to the process described for Starting Compound A under 1 b), 3.3 g
(13 mmol) of 4-thiocarbarnoyl-6,7-dimethoxy-1-indanone are treated with 2.8 g
(14 mmol) of triethyloxonium tetrafluoroborate and 0.8 g (15 mmol) of ammonium
chloride to yield the title compound in the form of beige crystals, m.p.
188° (with decomp-
osition); tH-NMR (DMSO-d6): 8 = 9.4 (s,3H); 7.63 (s,lH); 3.92 (s,3H); 3.89
(s,3H); 3.18
(m,2H); 2.68 (m,2H).
-37-
13) Starting Compound M:
4-Amidino-6-methyl-1-indanone-B'-amidinohydrazone dihydrochloride
Analogously to Starting Compound C, the title compound is prepared starting
from
4-bromo-6-methyl-1-indanone (Bull. Soc. Chim. France 1964, 3103), m.p. >
250°C;
MS (FAB): (M + H)+ = 245; tH-NMR (D20): 8= 7.89 (s, 1H); 7.62 (s, 1H); 3.34
(t, 2H);
2.96 (t, 2H); 2.45 (s, 3H).
14) Starting Compound N:
4-Amidino-3-methyl-~-indanone-2'-amidinohydrazone dihydrochloride
300 mg (2.3 mmol) of aminaguanidine hydrogen carbonate in 4 ml of 0.5N
hydrochloric
acid are added to a solution of 300 mg (1.3 mmol) of 4-amidino-3-methyl-1-
indanone
hydrochloride in 6 ml of water and the reaction mixture is stirred for 24 h at
80°. It is then
cooled and concentrated by evaporation and the residue is purified by
chromatography on
180 ml of Amberlite~ ER-180 resin using water as eluant. The title compound is
recrystallised from methanol/ether, m.p. >250°; Rp = O.:18 (silica gel,
methylene chloride/-
methanol/concentrated ammonia 5:3:1); MS (FAB): (M + I-I)t = 245; 1H-NMR
(D20):
b=7.97 (d,lH); 7.64 (d,lH); 7.49 (t,lH); 3.86 (m,lH); 3.17 (q,lH); 2.49
(d,lH); 1.24
(d,3H).
The precursors are prepared as follows:
(a) 4-C,yano-3-methyl-1-indanone
A mixture of 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J. Org, Chem.
22, 1019
(1957)] and L14 g (I2.7 mmol) of copper(I) cyanide in 2.5 ml of DMF is stirred
for 6 h at
170°. The reaction mixture is then cooled to 100° and 50 m1 of
toluene and a solution of
4.5 g (16.5 mmol) of iron(III) chloride hexahydrate in 7 ml of water and 1.7
ml of concen-
traced hydrochloric acid are added in succession. The reaction mixture is then
stirred for
20 min at 70°, cooled and diluted with toluene and water. The organic
phase is separated
off, washed with water, a semi-saturated sodium hydrogen carbonate solution
and again
with water, dried and concentrated by evaporation. The residue is distilled at
100-120°/-
0.05 mbar in a bulb tube distilling apparatus and corresponds to the title
compound,
m.p. 109-111°; IR (CH2C12): 2220, 1710 cm-1; 1H-NMR (CDC13): 8 = 7.92
(m,2H); 7.52
(t,lH); 3.73 (m,lH); 3.03 (q,lH); 2.40 (q,ll-T); 1.55 (d,3H).
(b) 4-Thiocarbamoyl-3-methyl-1-indanone
Analogously to the process described for Starting Compound A under 1 a), 1.45
g
2~Q~
-38-
(8.47 mmol) of 4-cyano-3-methyl-1-indanone in 25 ml of pyridine and 1.2 ml of
triethyl-
amine are treated with hydrogen sulfide and worked up to yield the title
compound in the
form of pale yellow crystals, m.p. 198-200°; tH-NMR (DMSO-db): b = 9.78
(s,lH); 7.65
(m,2H); 7.46 (m,lH); 3.98 (m,lH); 2.95 (q,lH); 2.26 (q,lH); 1.25 (d,3H).
(c) 4-Amidino-3-methyl-1-indanone hydrochloride
Analogously to the process described for Starting Compound A under 1 b), 0.96
g
(4.68 mmol) of 4-thiocarbamoyl-3-methyl-1-indanone is treated with 1.0 g (4.93
mmol) of
triethyloxonium tetrafluoroborate and 0.3 g (6 mmol) of ammonium chloride to
yield the
title compound in the form of beige crystals, tH-NMR (DMSO-d6): 8 = 9.59
(s,4H); 7.65
(m,2H); 7.46 (m,lH); 3.98 (m,lH); 2.95 (q,lH); 2.26 (q,lH); 1.25 (d,3H).
15) Starting Compound O:
4-Amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride
3-(2-bromophenyl)-2-ethylpropionic acid (German Patent 2 733 868) is cyclised
at
elevated temperature with polyphosphoric acid to form the corresponding 1-
indanone
which is converted :into the title compound analogously to the process
described for
Starting Compound C. M.p. >250°C; MS (FAB): (M+H)+= 259; tH-NMR (D20):
8=7.96
(d,1H); 7.65 (d,1I-I); 7.48 (t, l l-I); 2.95-3.48 (m,3H); 1.3-~ 1.8 (m,2H);
0.83 (t,3H).
16) Starting Compound P:
4-Amidino-2-n-butyl-1-indanone-2'-arnidinohydrazone dihydrochloride
3-(2-bromophenyl)-2-n-butylpropionic acid (German Patent 2 733 868) is
cyclised at
elevated temperature with polyphosphoric acid to form the corresponding 1-
indanone
which is converted into the title compound analogously to the process
described for
Starting Compound C.
Further processes for the preparation of Starting Compound A) (4-amidino-1-
indanone-2'-
amidinohydrazone dihydrochloride):
17) Analogously to the process described for Starting Compound A under 1 b), 4-
thio-
carbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (Starting Compound D)
is
reacted with triethyloxonium tetrafluoroborate and ammonium chloride to yield
Starting
Compaund A, m.p. >330°; MS (FAI3): (M+H)~= 231; t1H-NMR (D20): s=8.08
(d,lH);
7.75 (d,lH); 7.58 (t,lH); 3.35 (m,2H); 2.96 (m,2I-I).
-39-
18) 1.2 ml of a 1N sodium methoxide solution in methanol are added to a
solution of
0.26 g (1 mmol) of 4-cyano-1-indanone-2'-amidinohydrazone hydrochloride in 5
ml of
abs, methanol and the reaction mixture is heated under reflux for 16 h. After
cooling,
0.16 g (3 mmol) of solid ammonium chloride is added to the reaction mixture
and stirring
is effected for 1 h at 60°. The reaction mixture is then concentrated
by evaporation and the
residue is crystallised from dilute ethanol to yield Starting Compound A, m.p.
>330°.
The precursor is prepared as follows:
(a) 4-Cyano-1-indanone-2'-amidinoh~drazone hydrochloride
Analogously to the process mentioned for Starting Compound A under 1), 314 mg
(2 mmol) of 4-cyano-1-indanone are dissolved in 20 ml of methanol. A solution
of 272 mg
(2 mmol) of aminoguanidine hydrogen carbonate in 9 ml of water and 1 ml of 2N
hydro-
chloric acid is added and the reaction mixture is stirred under reflux for 4
days. After
cooling, it is concentrated to dryness by evaporation and the residue is
crystallised from
water to yield the title compound, m.p. >230°; 1H-NMR (DMSO-d6/D20):
s=8.16 (d,ll-I);
7.9 (d,lH); 7.55 (t,lH); 3.28 (m,2H); 2.9 (m,2H); IR (Nujol (paraffin)): 2190
cm t (CN).
19) 9.45 g (44.9 mmol) of 4-amidino-1-indanone hydrochloride (see under
Starting
Compound A, 1 b)) are added to a solution of 6.12 g (4-'i mmol) of
aminoguanidine
hydrogen carbonate in 100 ml of water and 46 ml of 1N hydrochloric acid and
the batch is
stirred for 24 h at 24°. The product which crystallises out is filtered
off with suction,
washed with a small amount of water and recrystallised from 300 ml of water to
yield
Starting Compound A, which contains 1 mol of water of crystallisation, m.p.
>330°; MS
(FAI3): (M + H)* = 231; tH-NMR (DZO): S = 8.08 (d,1H); 7.75 (d,lH); 7.58
(t,lH); 3.35
(m,2H); 2.96 (m,2H).
20) A mixture of 0.32 g (1 mmol) of 4-(N-hydroxyamidino)-1-indanone-2'-amidino-
hydrazone dihydrochloride (Starting Compound E), 0.36 ml (2 mmol) of
triethylamine and
0.2 g (1 mmol) of iron pentacarbonyl in 10 ml of abs. THF is boiled under
reflux for 16 h.
The reaction mixture is then concentrated by evaporation and the residue is
crystallised
from dilute hydrochloric acid to yield Starting Compound A, m.p. >330°.
21) Starting Compound Q:
4-Amidino-2-propylindanone-1-amidinohydrazone dihydc°ochlosidc
Analogously to Starting Compound O, the title compound is prepared starting
from
2~~~~~~
-40-
2-bromobenzyl bromide and malonic acid diethyl ester, m.p. >250°C; MS
(FAB):
(M+H)+=273; tH-NMR (D20): 8=7.98 (d,lH); 7.67 (m,lH); 7.49 (t,lH); 3.44
(m,2H);
3.01 (m,lH); 1.1-1.75 (m,4H); 0.81 (t,3H).
Examples
The following Examples serve to illustrate the invention but do not limit the
scope thereof
in any way.
Temperatures are given in degrees Celsius (°C). If no temperature is
indicated, the
reaction concerned is carried out at room temperature. If concentration by
evaporation is
carried out, a rotary evaporator is used unless otherwise indicated.
The values for proton nuclear magnetic resonance spectroscopy are given in ppm
("parts
per million") based on tetramethylsilane (8 = 0) as the internal standard. d =
doublet,
s = singlet, t = triplet, m = multiplet.
In the case of elemental analyses, the empirical formula, the molecular
weight, and
calculated and found analysis values are indicated.
The shortened forms and abbreviations used have the following meanings:
anal. elemental analysis
calc. calculated
Dz0 dideuterium oxide
DMSO-d6 completely deuterised dimethyl
sulfoxide
1H-NMR proton nuclear magnetic resonance
spectroscopy
m.p. melting point
decomp, with decomposition
Example 1: 4-Amidino-1-indanone-2'-amidinohydrazone dicyclamate
A solution of 717 mg (4 mmol) of N-cyclohexylsulfamic acid in 20 ml of
methanol is
added to a solution of 460 mg (2 mmol) of 4-amidinointianone-1-
amidinohydrazone in
80 ml of methanol and the batch is concentrated to dryness by evaporation. The
residue is
dissolved in ethanol and crystallised by the addition of diethyl ether to
yield the title
-41-
compound, m.p. 210° (decomp.); 1~I-NMR (D20): 8 7.97 {d,ll-I); 7.64
(d,lH); 7.47 (t,lH);
3.25 (m,2H); 2.9 (m,4H); 1-2 (m,20H); anal. for C23H4oN8O6S2 (588.75): calc.
46.92% C,
6.85% H, 19.03% N, found 46.5% C, 6.9% H, 19.0% N.
The starting material is prepared as follows:
a) 4-Amidino-1-indanone-2'-amidinohydrazone
9.63 g (30 mmol) of 4-amidino-1~-indanone-2'-amidinohydrazone dihydrochloride
(Starting Compound A, prepared in accordance with one of the processes
described under
"Starting Compounds", for example in accordance with 16)) are dissolved in 900
ml of
distilled water heated to 70-80°C and cooled to 10°C. 30 ml of
2N sodium hydroxide
solution are added dropwise to the resulting solution with stirnng. The
pxoduct which
separates out is filtered off with suction, washed with a small amount of ice-
water and
dried to yield the title compound, m.p. 250° (decomp.).
Example 2: 4-Amidino-1-indanone-2'-amidino~drazone dioctanoate
631 p.l (4 mmol) of octanoic acid are added to a solution of 460 mg (2 mmol)
of
4-amidinoindanone-1-amidinohydrazone (Example 1 a)) in 80 ml of methanol and
the
batch is concentrated to dryness by evaporation. The residue is dissolved in
ethanol and
crystallised by the addition of diethyl ether to yield the title compound,
m.p. 190°
(decomp.); 1H-NMR {DMSO-d6): 8 8.03 (d,lH); 7.52 (d,lH); 7.47 (t,lH); 3.19
(m,2H);
2.85 (m,2H); 1.98 (t,4H); 1.42 (m,4H); 1.19 (s,24I-I); 0.81 (t,6H); anal, for
C2~H46N6O4
(518.70): calc. 62.52% C, 8.94% H, 16.20% N, found 62.3% C, 8.9% H, 16.2% N.
Exam lp a 3: 4-Amidino-1-indanone-2'-amidinohydrazone disalicylate
A solution of 830 mg (6 mmol) of salicylic acid in SO ml of ethanol is added
to a solution
of 690 mg (3 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1 a)) in
100 ml
of methanol and the reaction mixture is concentrated to half the volume by
evaporation.
70 ml of water are added to the solution, whereupon the title compound
crystallises out,
m.p. 206-9° (decomp.); anal. far C~fI2~N6O6 (507.1): calc. 59.13% C,
5.19% H,
16.55% N, found 59.3% C, 5.2% H, 16.8% N.
Example 4: 4-Amidino-1-indanone-2'-amidinohydrazone dibenzenesulfonate
A solution of 975 mg (6 mmol) of benzenesulfonic acid in SO ml of methanol is
added to a
solution of 690 mg (3 mmol) of 4-amidinoindanone-1-amidinohydrazone (Example 1
a))
~~D~~e~~~
-42-
in 100 ml of methanol and the batch is concentrated to dryness by evaporation.
T'he
residue is crystallised from ethanol to yield the title compound, m.p.
>250° (decornp.);
tH-NMR (D20): 8 7.38-7.95 (m,l6H); 3.21 (m,2H); 2.78 (m,2H); anal, for
C23H26Ns~s52
(546.63): calc. 50.54% C, 4.79% H, 15.37% N, found 50.4% C, 4.8% H, 15.6% N.
Example S: further salts
Example 5a: 4-Amidino-1-indanone-2'-amidinohydrazone succinate
A solution of 472 mg (4 mmol) of succinic acid in 120 ml of methanol is added
to a
solution of 920 mg (4 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in
120 ml of methanol. The product which crystallises out is filtered off with
suction,
washed with a small amount of methanol and dried to yield the title compound,
m.p. 200° (decomp.); anal. for C15H2oNs~a'1.04 H20 (367.10): calc.
49.08% C,
6.06% H, 22.89% N, found 49.13% C, 6.07% H, 23.04% N.
Example 5b: 4-Amidino-1-indanone-2'-amidinohydrazone adinate
A solution of 146 mg (1 mmol) of adipic acid in 25 ml of ethanol is added to a
solution of 230 mg (1 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in 30
ml
of methanol. The product which crystallises out is filtered off with suction,
washed
with a small amount of ethanol and dried to yield the title compound, m.p.
20U°
(decomp.); anal. for Cl~H2aNs04 0.25 H20 (380.9:Z): calc. 53.60% C, 6.48% H,
22.06% N, found 53.79% C, 6.73% H, 21.93% N.
Example 5c: 4-Amidino-1-indanone-2'-amidinohydrazone-1,5-naphthalene di-
sulfonate
A solution of 1.49 g (4 mmol) of 1,5-naphthalene disulfonic acid in 100 ml of
methanol is added to a solution of 920 mg (4.mmo1) of 4-amidino-1-indanone-2'-
amidinohydrazone in 120 ml of methanol. The product which crystallises out is
filtered off with suction, washed with a small amount of methanol and dried to
yield
the title compound, m.p. >250°; anal, for C21HZZNs06S2 2.36 H20
(561.09): talc.
44.95% C, 4.80% H, 14.98% N, found 45.06% C, 4.98% H, 15.21% N.
Example 5d: 4-Amidino-1-indanone-2'-amidinohydrazone ethane disulfonate
Analogously to any one of the Examples given hereinbefore and hereinafter, 4-
amidino-1-indanone-2'-amidinohydrazone is converted into the tide compound
using
1,2-ethanedisulfonic acid.
~~~~~sl.~
-43-
Example Se: 4-Amidino-1-indanone-2'-amidinohydrazone L-tartrate
A solution of 600 mg (4 mmol) of L-(+)-tartaric acid in 100 ml of methanol is
added
to a solution of 920 mg (4 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone
in
120 ml of methanol. The product which crystallises aut is filtered off with
suction,
washed with a small amount of methanol and dried to yield the title compound,
m.p. 190° (decomp.); anal. for C15H2oNs~6'0.26 H20 (385.04): calc.
46.79% C,
5.37% H, 21.83% N9 found 46.83% C, 5.43% I-I, 21.87% N.
Example Sf: 4-Amidino-1-indanone-2'-amidinohydrazone citrate
A solution of 210 mg (1 mmol) of citric acid in 10 ml of methanol is added to
a
solution of 230 mg (1 mmol) of 4-amidino-1-indanone-2'-amidinohydrazone in 30
ml
of methanol. The product which crystallises out is filtered off with suction,
washed
with a small amount of methanol and dried to yield the title compound, m.p.
>220°
(decornp.); anal. for C1~H22N60~ (422.40): calc. 48.34% C, 5.25% H, 19.90% N,
found 48.23% C, 5.33% H, 20.07% N.
Example 5~: 4-Amidino-1-indanone-2'-amidinohydrazone dilactate
Analogously to to any one of the Examples given hereinbefore and hereinafter,
4-amidino-1-indanone-2'-amidinohydrazone is converted into the title compound
using lactic acid.
Example 6:
Analogously to any one of the above Examples, the following starting compounds
can be
converted into the acid addition salts of octanoic acid, succinic acid, adipic
acid, salicylic
acid, cyclohexylsulfamic acid, ethanedisulfonic acid, benzenesulfonic acid;
cittic acid,
tartaric acid grad 1,5-naphthalenedisulfonic acid:
a) 4-amidino-1-indanone-2'-(N-hydroxyamidino)-hydrazone dihydrochloride
(Starting
Compound B);
b) 5-Amidino-1-tetralone-2'-amidinohydrazone dihydrochloride (Starting
Compound C);
c) 4-Thiocarbamoyl-1-indanone-2'-arnidinohydrazone hydrochloride (Starting
Compound
D);
-44-
d) 4-(N-Hydroxyamidino)-Z-indanone-2'-amidinohydrazone dihydrochloride
(Starting
Compound E);
e) 4-Amidino-2-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting
Compound F);
f7 5-Amidino-6-methoxy-1-tetxalone-2'-amidinohydrazone dihydrochloride
(Starting
Compound G);
g) 4-Amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazone dihydrochloride
(Starting Compound H);
h) 4-Amidino-6,7-dimethyl-1-indanone-2'-amidinohydrazone dihydrochloride
(Starting
Compound I);
i) 4-Amidino-7-hydroxy-3-methyl-I-indanone-2'-amidinohydrazone dihydrochloride
(Starting Compound J);
j) 4-(Methylamidino)-1-indanone-2'-amidinohydrazone dihydrochloride (Starting
Compound K);
k) 4-Amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazone dihydrochloride
(Starting
Compound L);
1) 4-Amidino-6-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting
Compound M);
m) 4-Amidino-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting
Compound N);
n) 4-Amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride (Starting
Compound O);
o) 4-Amidino-2-n-butyl-1-indanone-2'-amidinohydrazone dihydrachloride
(Starting
Compound P).
-45-
p) 4-Amidino-2-n-propyl-indanone-1-amidinohydrazone (Starting Compound Q):
Example 7: Capsules, each containing 0.25 g of active ingredient, for example
one of the
acid addition salts of Examples 1-6, can be prepared as follows:
Composition (for 5000 capsules)
active ingredient 1250
g
talc 180
g
wheat starch 120
g
magnesium stearate80 g
lactose 20 g
The pulvenalent substances are forced through a sieve having a mesh size of
0.6 mm and
mixed. 0.33 g portions of the mixture are introduced into gelatin capsules by
means of a
capsule-filling machine.
Example 8: 10 000 tablets, each comprising 5 mg of active ingredient, for
example one of
the acid addition salts prepared in Examples 1-6, are prepaxed:
Composition:
active ingredient 50.00 g
lactose 2535.00 g
corn starch 125.00 g
polyethylene glycol 150.00 g
6000
magnesium stearate 40.00 g
purified water quantum satis
Method: All of the pulverulent constituents are passed through a sieve having
a mesh size
of 0.6 mm. The active ingredient, the lactose, the magnesium stearate and half
of the
starch are then mixed in a suitable mixer. The other half of the starch is
suspended in
65 ml of water and the resulting suspension is added to a boiling solution of
the poly-
ethylene glycol in 260 ml of water. The resulting paste is added to the powder
mixture and
granulated, where appropriate with the addition of more water. The granules
are dried
overnight at 35°C, forced through a sieve having a mesh size of 1.2 mm
and compressed
to form tablets having a breaking notch.
