Note: Descriptions are shown in the official language in which they were submitted.
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substituted Guanidines and Diaminonitroethenes their Preparation and Use
FIFI r~ OF THE INVENTION
The present invention relates to substituted guanidines and
diaminonitroethenes, to methods
for their preparation, to compositions comprising the compounds, to the use of
these com-
pounds as medicaments and their use in therapy e.g. in the treatment of
diseases of the
central nervous system, the cardiovascular system, the pulmonary system, the
gastroin-
testinal system and the endocrinological system.
Potassium channels play an important role in the physiological and
pharmacological control
of cellular membrane potential. Amongst the different types of potassium
channels are the
~5 ATP-sensitive (K,,,p-) channels which are regulated by changes in the
intracellular con-
centration of adenosine triphosphate. The K,,~-channels have been found in
cells from vari-
ous tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth
muscles, cen-
tral neurons and adenohypophysis cells. The channels have been associated with
diverse
cellular functions for example hormone secretion (insulin from pancreatic beta-
cells, growth
hormone and prolactin from adenohypophysis cells), vasodilation (in smooth
muscle cells),
cardiac action potential duration, neurotransmitter release in the central
nervous system.
Modulators of the KA.,p-channels have been found to be of importance for the
treatment of
various diseases. Certain sulphonylureas which have been used for the
treatment of non-
insulin-dependent diabetes mellitus act by stimulating insulin release through
an inhibition of
the K,,~ -channels on pancreatic beta-cells.
The potassium channel openers, which comprise a heterogeneous group of
compounds, ha-
ve been found to be able to relax vascular smooth muscles and have therefore
been used
for the treatment of hypertension.
In addition, potassium channel openers can be used as bronchodilators in the
treatment of
asthma and various other diseases.
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Furthermore, potassium channel openers have been shown to promote hairgrowth,
and
have been used for the treatment of baldness.
Potassium channel openers are also able to relax urinary bladder smooth muscle
and
therefore, can be used for the treatment of urinary incontinence. Potassium
channel openers
which relax smooth muscle of the uterus can be used for treatment of premature
labor. -
By acting on potassium channels of the central nervous system these compounds
can be
used for treatment of various neurological and psychiatric diseases such as
Alzheimer,
epilepsia and cerebral ischemia.
Further, the compounds are found to be useful in the treatment of benign
prostatic
hyperplasia, erectile dysfunction and in contraception.
Compounds of the present invention, which inhibit insulin secretion by
activating potassium
channels of the beta-cell can be used in combination with other compounds
which may be
used to treat non-insulin dependent diabetes mellitus and insulin dependent
diabetes
mellitus. Examples of such compounds are insulin, insulin sensitizers, such as
thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide,
glibenclamide
and glucagon like peptide ( GLP1), inhibitors of a-glucosidases and hepatic
enzymes
responsible for the biosynthesis of glucose.
Recently, it has been shown that Diazoxide (7-chloro-3-methyl-2H-1,2,4-
benzothiadiazine
1,1-dioxide) and certain 3-(alkylamino)-4H-pyrido[4,3-a]-1,2,4-thiadiazine 1,1-
dioxide
derivatives inhibit insulin release by an activation of K,,~-channels on
pancreatic beta-
cells (Pirotte B. et al. Biochem. Pharmacol, ~, 1381-1386 (1994); Pirotte B.
et al., J. Med.
Chem., ~, 3211-3213 (1993). Diazoxide has furthermore been shown to delay the
onset of
diabetes in BB-rats ( Vlahos WD et al. Metabolism 40, 39-46 (1991 )). In obese
zucker rats
diazoxide has been shown to decrease insulin secretion and increase insulin
receptor
binding and consequently improve glucose tolerance and decrease weight gain
(Alemzadeh
R. et al. Endocrinol. 1~,~, 705-712, 1993). It is expected that compounds
which activate KpTP-
channels can be used for treatment of diseases characterised by an
overproduction of
insulin and for the treatment and prevention of diabetes.
In EP 310545 and EP 306451 N-N'-substituted cyanoguanidines are claimed for
the use as
curing agent for epoxy resins.
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3
In WO 9211233. US 5525742-A, EP-747374-A1,EP 354553 and EP 405525 derivatives
of
the N-cyano-N'-aryl-N"-alkyl-guanidine type have been claimed as potassium
channel acti-
vators related to smooth muscles.
Cyanoguanidines have recently been described by K. Yoshizumi et al Chem.
Pharm. Bull. 44
(11) 2042-2050 (1996) and K. Yoshizumi et al Chem. Pharm. Bull. 45 (12) 2005-
2010
( 1997).
Derivatives of N-cyano-N'-aryl-N"-aryl-guanidines have been claimed in WO
9422807.
N-aryl-N'-alkyl-2-vitro-1,1-ethenediamines have been described in U.S Pat.
4567.188
In J.Med.Chem 35 , 2327-2340 (1992) the synthesis of N-aryl-N'-alkyl-2-vitro-
1,1-
ethenediamine and N-heteroaryl-N'-alkyl-2-vitro-1,1-ethenediamine and their
properties as
agents for relaxation of smooth muscle are described .
Fluorine-containing arylcyanoguanidines have been described by E. G.
Belezertseva et al in
Khim.-Farm. Zh. (1997), 31 (6), 11-13.
DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula I:
R3
X
~ R'
RZ / N~N~
H H
R'
wherein
R' and R2 are independently hydrogen, trifluoromethyl or halogen;
R3 is trifluoromethyl, methoxy or halogen;
R' is straight or branched C,.,2-alkyl,. Cz.,2-alkenyl, CT_,Z-alkynyl or C~-
cycloalkyl optionally
substituted with C~e-cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C,.6-
alkoxy, C,_6-
alkylthio, arylthio, C,.~-alkylamino, C,$-dialkylamino, heteroaryf,
heteroarylalkyl or aryl, any or
heteroaryl group optionally being substituted with halogen or trifluoromethyl;
or
R' is Y-R5, Y being -O- or -N(R6)- ;
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R5 and R6 are independently straight or branched C,_,2-alkyl, CZ_,2-alkenyl,
C2_,z-alkynyl or C,.
e-cycloalkyl optionally substituted with C~e-cycloalkyi, halogen, hydroxy,
heteroary(,
heteroarylalkyl, aryloxy or aryl, any aryl or heteroaryl group optionally
being substituted with
halogen or trifluoromethyl; . .
or RS and R6 together with the nitrogen atom form a 3-12 membered mono- or
bicyclic
system, in which one or more of the carbon atoms may be exchanged with
nitrogen, oxygen -'
or sulfur, each of these ring systems optionally being mono- or
polysubstituted with halogen,
C,.6-alkyl, hydroxy, C,_6-alkoxy, C,_6-alkoxy-C,.6-alkyl, nitro, amino, cyano,
trifluoromethyl, C,.
6-monoalkyl- or dialkylamino or oxo;
X is N-CN or CH-NO2;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers, including a racemic mixture, or any tautomeric
form thereof.
The salts include pharmaceutically acceptable acid addition salts,
pharmaceutically accepta-
ble metal salts or optionally alkylated ammonium salts, such as hydrochloric,
hydrobromic,
hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichioroacetic, oxalic,
malefic, pyruvic, malo-
nic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic,
methanesulfonic, ethane
suifonic, picric and the like, and include acids related to the
pharmaceutically acceptable
salts listed in Journal of Pharmaceutical Science, ~, 2 (1977) and
incorporated herein by
reference, or lithium, sodium, potassium, magnesium and the like.
The term "C,.6-alkoxy" as used herein, alone or in combination, refers to a
straight or bran-
ched monovalent substituent comprising a C,.~-alkyl group linked through an
ether oxygen
having its free valence bond from the ether oxygen and having 1 to 6 carbon
atoms e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term "C,_6-alkylthio" as used herein, alone or in combination, refers to a
straight or bran-
ched monovalent substituent comprising a lower alkyl group linked through a
divalent sulfur
atom having its free valence bond from the sulfur atom and having 1 to 6
carbon atoms e.g.
methylthio, ethylthio, propylthio, butylthio, pentylthio.
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The term "cycloalkyl" as used herein refers to a radical of a saturated cyclic
hydrocarbon
with the indicated number of carbons such as cyclopropyl, cyclobutyl,
cyclopentyl, or cyclo-
hexyl.
The terms "CZ_,Z-alkenyl" as used herein refers to an unsaturated hydrocarbon
chain having
2-6 or 2-18 carbon atoms and one double bond such as e.g. vinyl, 1-propenyl,
allyl, isopro-
penyl, n-butenyl, n-pentenyl and n-hexenyl.
The teen "Cz_,Z-alkynyl" as used herein refers to unsaturated hydrocarbons
which contain
triple bonds, such as e.g. -C--=CH, -C---CCH3, -CH2C-_-_-CH,
-CHZCHZC=CH, -CH(CH3)C_--CH, and the like.
The term "C,.~-alkoxy-C,_6-alkyl" as used herein refers to a group of 2-12
carbon atoms in-
terrupted by an O such as e.g. CHZ-O-CH,, CH2-O-CHZ-CH,, CHZ-O-CH(CH3)2 and
the like.
The term "halogen" means fluorine, chlorine, bromine or iodine.
The term "pefialomethyl" means trifluoromethyl, trichloromethyl,
tribromomethyl or triiodo-
methyl.
The terms "C,_,2-alkyl", as used herein, alone or in combination, refers to a
straight or
branched, saturated hydrocarbon chain having the indicated number of carbon
atoms such
as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-
butyl, n-pentyl, 2-
methylbutyl, 3-methyibutyl, 4-methylpentyi, neopentyl, n-hexyl, 1,2-
dimethylpropyl, 2,2-
dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "C,_,e-alkyl" as
used herein also
includes secondary C~-alkyl and tertiary C,.~-alkyl.
The term "C,$-monoalkylamino" as used herein refers to an amino group wherein
one of the
hydrogen atoms is substituted with a straight or branched, saturated
hydrocarbon chain ha-
ving the indicated number of carbon atoms such as e.g. methylamino,
ethylamino, propyla-
mino, n-butyfamino, sec-butylamino, isobutylamino, tert-butylamino, n-
pentylamino, 2-
methylbutyiamino, n-hexyiamino, 4-methylpentylamino, neopentylamino, n-
hexylamino, 2,2-
dimethylpropylamino and the like.
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The term "C,_6-dialkyiamino" as used herein refers to an amino group wherein
the two hy-
drogen atoms independently are substituted with a straight or branched,
saturated hydrocar-
bon chain having the indicated number of carbon atoms; such as dimethylamino,
N-ethyl-N-
methylamino, diethylamino, dipropyiamino, N-(n-butyl)-N-methylamino, di(n-
pentyl)amino,
and the like.
The term "3-12 membered mono- or bicyclic system" as used herein refers to a
monovalent
substituent of formula -NRZR3 or -NR"R'2 where R2 and R', or R" and R'2
together with the
nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or
more of the
carbon atoms may be exchanged with nitrogen, oxygen or sulfur, such as 1-
pyrrolidyl,
piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7-
azabicyclo[2.2.1]heptan-7-
yl, tropanyl and the like.
The term "aryl" as used herein refers to phenyl, 1-naphthyi, or 2-naphthyl.
The term "heteroaryl" as used herein, alone or in combination, refers to a
monovalent sub-
stituent comprising a 5-8 membered monocyclic aromatic system or a 9-10
membered bicy-
clic aromatic system containing one or more heteroatoms selected from
nitrogen, oxygen
and sulfur, e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,
pyrimidine, pyridazi-
ne, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline,
isoquinoline, quinazo-
line, quinoxaline, indole, benzimidazole, benzofuran, pteridine, and purine.
The term "arylalkyl" as used herein refers to a straight or branched saturated
carbon chain
containing from 1 to 6 carbons substituted with an aromatic carbohydride; such
as benzyl,
phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
The term "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy or 2-
naphthyloxy.
The term "arylalkoxy" as used herein refers to a C,.~-alkoxy group substituted
with an aro-
matic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-
naphthylmethoxy,
2-(1-naphtyl)ethoxy and the like.
The term "heteroarylalkyl" as used herein refers to a straight or branched
saturated carbon
chain containing from 1 to 6 carbons substituted with a heteroaryl group; such
as (2-
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furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-
pyridyl)methyl, 1-methyl-
1-(2-pyrimidyl)ethyl and the like.
The term "arylthio" as used herein, alone or in combination, refers to an aryl
group linked
through a divalent sulfur atom having its free valence bond from the sulfur
atom, the aryl group
optionally being mono- or pofysubstituted with C,~-alkyl, halogen, hydroxy or
C,_6-aikoxy; e.g.
phenylthio, (4-methylphenyl)- thin, (2-chlorophenyl)thio, and the like. -
In a preferred embodiment of the invention R' is selected from trifluoromethyl
and R2 from
hydrogen or trifluoromethyl.
In another preferred embodiment of the invention RZ and R' are selected from
halogen and
R" is branched C,_,2-alkyl.
Further preferred compounds are those where RZ and R' are selected from
halogen and R°
is CS-alkyl, branched at the C(2), C(3) or C(4) carbon atom counted from the
attachment to
the nitrogen atom, in particular compounds where RZ and R' both are chloro.
Preferred compounds of the invention are:
N-Cyano-N'-(3,5-bis(triouoromethyl)phenyl)-N"-(3-methylbutyl)guanidine
N-Cyano-N'-(3,5-bis(tr'rfiuoromethyl)phenyl)-N"-(2-(4-
pyridinyl)ethyl)guanidine
N-Cyano-N'-(3,5-bis(trifluoromethyl)phenylrN"-( 1,2,2-
trimethylpropyl)guanidine
N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-cyclopentylpropyf)guanidine
N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-cyctopropylethyl)guanidine
N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(cyclopentyl)guanidine
N-Cyano-N'-(3, 5-bis(trifluoromethyl)phenyl)-N"-{ 1,2-dimethylpropyl)guanidine
N-Cyano-N'-(3,5-bis(triftuoromethyl)phenyl)-N"-(2-chlorobenzyi)guanidine
N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-{3-chlorobenzyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentylpropyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyi)-N"-(3-cyclopentyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-{2-cyclopropylethyl)guanidine
N-(3,5-bis(trifluoromethyl)phenyl)-N'-( 1,2, 2-trimethylpropyl)-2-vitro-1,1-
ethenediamine
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N-(3, 5-bis(trifluoromethyl)phenyl)-N'-(3-methylbutyl)-2-vitro-1,1-
ethenediamine
N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-cyclopentyipropyl)-2-vitro-1,1-
ethenediamine
N-(3,5-bis(trifluoromethyl)phenyl)-N'-(2-cyclopropylethyl)-2-nitro-l ,1-
ethenediamine
N-(3,5-bis(trifluoromethyl)phenyl)-N'-(cyclopentyl)-2-vitro-1,1-ethenediamine
_ .
N-(3,5-bis(trifluoromethyl)phenyl)-N'-((1,2-dimethylpropyl)-2-vitro-1,1-
ethenediamine
N-(3,5-bis(trifluoromethyl)phenyl)-N'-(2-chlorobenzyl)-2-vitro-1,1-
ethenediamine
N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-chlorobenzyl)-2-vitro-1,1-
ethenediamine
N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)-2-vitro-1,1-ethenediamine
N-(3,5-dichlorophenyl)-N'-(3-cyclopentylpropyl)-2-vitro-1,1-ethenediamine
N-(3,5-dichlorophenyl)-N'-{cyclopentyl}-2-vitro-1,1-ethenediamine
N-(3,5-dichlorophenyl)-N'-(2-chlorobenzyl )-2-vitro-1,1-ethenediamine
N-(3,5-dichlorophenyl}-N'-(3-chlorobenzyl )-2-vitro-1,1-ethenediamine
N-(3,5-dichlorophenyl)-N'-(2-cyclopropylethyl)-2-vitro-1,1-ethenediamine
N-Cyano-N'-[3, 5-bis(trifluoromethyl)phenyl]-N"-( 1,1-dimethylpropyl)guanidine
N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1-methylethyl)-guanidine
N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-propyl-guanidine
N-Cyano-N'-(3-trifluoromethyiphenyl)-N"-cyclopentylguanidine
N-Cyano-N'-isopropyl-N"-(3-trifluoromethylphenyl)guanidine
N-Cyano-N'-(3, 5-dichlorophenyl)-N"-{2-chlorobenzyl)guanidine
N-Cyano-N'-cyclopentyl-N"-(3,5-dichlorophenyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1-methylethyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-propylguanidine .
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-methylbutyl)-guanidine
N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine
N-Cyano-N'-(3-methoxy-5-trifluoromethylphenyl)-N"-(3-methylbutyl)guanidine
The use of the following known compounds as medicaments and their use in
therapy e.g. in
the treatment of diseases in the endocrinological system is also a preferred
embodiment of
the invention:
N-Cyano-N'-(3-trifluoromethylphenyl)-N"-(1,2,2-trimethylpropyl)guanidine
N-Cyano-N'-(3, 5-dichlorophenyl)-N"-( 1,2,2-trimethylpropyl)-guanidine
N-Cyano-N'-(3, 5-dichlorophenyl}-N"-{ 1,1-dimethylpropyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,1-dimethylbutyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-t-pentylguanidine
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N-Cyano-N'-(3, 5-dichlorophenyl)-N"-( 1-ethyl-1-methylpropyl)guanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-t-butylguanidine
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,1,2-trimethylpropyl)guanidine and
N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,1-diethylpropyl)guanidine.
The compounds of the present invention interact with the potassium channels
and hence act
as openers or blockers of the ATP-regulated potassium channels, which make
them useful in
the treatment of various diseases of the cardiovascular system, e.g. cerebral
ischemia, hy-
pertension, ischemic heart diseases, angina pectoris and coronary heart
diseases; the pul-
monary system; the gastrointestinal system; the central nervous system and the
endocrino-
logical system.
Since some KATP-openers are able to antagonize vasospasms in basifar or
cerebral arteries
the compounds of the present invention can be used for the treatment of
vasospastic disor-
ders such as subarachnoid haemorrhage and migraine.
The compounds of the present invention may also be used for the treatment of
diseases as-
sociated with decreased skeletal muscle blood flow such as Raynauds disease
and inter-
mittent claudication.
Further, the compounds of the invention may be used for the treatment of
chronic airway
diseases, including asthma, and for treatment of detrusor muscle instability
secondary to
bladder outflow obstruction and therefore for kidney stones by aiding their
passage along the
urethra.
The present compounds could also be used for treatment of conditions
associated with dis-
turbances in gastrointestinal mobility such as irritable bowel syndrome.
Additionally these
compounds can be used for the treatment of premature labour and dysmenorrhea.
Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter
release and
it is expected that such compounds can be used for the treatment of various
diseases of the
central nervous system, e.g. epilepsia, ischemia and neurodegenerative
diseases, and for
the management of pain.
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Further, potassium channel openers promote hairgrowth, therefore, the
compounds of the
present invention can be used for the treatment of baldness.
Potassium channel openers also relax urinary bladder smooth muscle, thus, the
compounds
5 of the present invention can be used for the treatment of urinary
incontinence.
In diseases such as nesidioblastosis and insulinoma in which a hypersecretion
of insulin
causes severe hypoglycemia the compounds of the present invention can be used
to reduce
insulin secretion. In obesity hyperinsulinemia and insulin resistance is very
frequently
10 encountered. This condition could lead to the development of non insulin
dependent
diabetes (NIDDM). It is expected that potassium channel openers, and hence the
compounds of the present invention, can be used for reducing the
hyperinsulinemia and
thereby prevent diabetes and reduce obesity. In overt NIDDM treatment of
hyperinsulinemia
with potassium channel openers, and hence the present compounds, can be of
benefit in
restoring glucose sensitivity and normal insulin secretions.
Owing to the efficiency of the present compounds to improve glucose
sensitivity they are
useful for the treatment and/or prevention of ailments and disorders involving
elevated plas-
ma blood glucose, such as hyperglycaemia. Furthermore, they may find use in
the treatment
and/or prevention of dyslipidemia, Type I diabetes, NIDDM,
hypertrigiyceridemia, syndrome
X, insulin resistance, impaired glucose tolerance, obesity, diabetic
dyslipidemia, hyperlipide-
mia and hypertension.
In early cases of insulin dependent diabetes (IDDM) or in prediabetic cases,
potassium
channel openers and hence the present compounds can be used to induce
pancreatic cell
rest which may prevent the progression of the autoimmune disease.
The potassium channel openers of the present invention can be administered in
combination
with an immunosuppressant or with an agent like nicotinamide, which will
reduce
autoimmune degeneration of beta-cells.
Combining beta-cell rest with a treatment protecting the beta-cells against
cytokine mediated
beta-cell impairmentlcytotoxicity is another aspect of this invention.
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Insulin requiring or Type 1 diabetes (IDDM) as well as late onset IDDM (also
known as type
1.5. e.g. non-insulin-requiring Type 2 (NIDDM) patients with autoreactivity
against beta-cell
epitopes that later turns insulin requiring) have circulating autoreactive
monocy-
tes/lymphocytes that homes to the islets/beta-cells and releases their
cytokines. Some of
these cytokines (e.g. interleukin-1 b (IL-1 b) , tumour necrosis factor a
(TNFa) and interferon y
(IFNy)) are specifically toxic to the beta-cells, e.g. through the induction
of nitric oxide (NO)
and other free radicals. Inhibition of this cytotoxicity, e.g. by co-
administring nicotinamide
(NA), a derivative hereof or other cytokine protective compounds to the
prediabeticldiabetic
patients treated with the PCO compound is an example of this aspect.
Nicotinamide belongs
to the B-vitamin family and is derived from nicotinic acid by amidation of the
carboxyl group.
It processes none of nicotine's pharmacological properties. NA is converted
into NAD+,
which acts as a coenzyme for proteins involved in tissue respiration. NA has
been proposed
to influence several of the putative intracellular molecular events following
immune attack on
the beta-cells. Animal experiments and early non-blinded experiments in humans
have indi-
Gated a protective role of this compound against IDDM as well as in
cytokinelimmune medi-
ated beta-cell destruction.
Yet another aspect of this application concerns the use of a PCO compound
alone or in
combination with the inhibitor of cytokine/immune mediated beta-cell
impairment , in trans-
plantation, e.g. islet transplantation into diabetes patients. The use of one
or both of these
treatments may reduce the risk of rejection of the transplanted isletslbeta-
cells/engineered
beta-cellslpancreas.
Compounds of the present invention which act as blockers of K,,~ -channels can
be used for
the treatment of NIDDM.
Preferably, the compounds of the present invention may be used for treatment
or prevention
of diseases of the endocrinological system such as hyperinsulinaemia and
diabetes.
Accordingly, in another aspect the invention relates to a compound of the
general formula I
or a pharmaceutically acceptable acid addition salt thereof for use as a
therapeutically ac-
ceptable substance, preferably for use as a therapeutically acceptable
substance in the tre-
atment of hyperinsulinaemia and treatment or prevention of diabetes.
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Furthermore, the invention also relates to the use of the inventive compounds
of formula I as
medicaments useful for treating hyperinsulinaemia and treating or preventing
diabetes.
Optionally, the pharmaceutical composition of the invention may comprise a
compound of
formula I combined with one or more other pharmacologically active compounds,
e.g. an an-
tidiabetic or other pharmacologically active material, including compounds for
the treatment
and/or prophyiaxis of insulin resistance and diseases wherein insulin
resistance is the
pathophysiological mechanism. Suitable antidiabetics comprise insulin as well
as orally ac-
tive hypoglycaemic agents such as sulphonylureas, e.g. glibenclamide and
glipizide; bigua-
nides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide;and
thiazolidinediones, e.g.
troglitazone and ciglitazone.
The compounds of the present invention may be prepared by various methods
known to
those skilled in the art. For example the methods for preparation of 2-vitro-
1,1-
ethenediamines by Niemers et al. U.S Pat, 4,567,188 and P.W Manley et al.
J.Med.Chem.
35, 2327-2340 (1992):
R3 R3 R3
NOZ ~ I ~ I NOZ R4NH2 I ~ ( NOZ
/ w i / i / ~N~R4
R2 ~ ~NH2 S S R2 ~ ~H S R2 ~ ~H H
R1 R1 R1
Or using the methods by H.J Petersen et al. J. Med. Chem. 21, 773-781 (1978)
R3 R3 R3
~CN ~CN R4NH2 ~CN
N ~ N w N
II R
NH2 Ph~O~O~Ph R2 I / N~O~Ph R2 I / N~H~ 4
H H
R1 R1 R1
R3 R3
H~ W X
,R4 ~ R2 ~ N~N~R4
R2 ~ ~ N / N H H
R1 R1
X= NCN, CHNOZ
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The starting materials are either known compounds or compounds which may be
prepared in
analogy with the preparation of known compounds or in analogy with known
methods as
described in Kogyo Kagaku Zashi, 59,(6) 1-33 (1956) and Zh. Obshch. Khim., 35,
2055
(1965).
PHARMACOLOGICAL METHODS
The ability of the compounds to interact with potassium channels can be
determined by vari-
ous methods. When patch-clamp techniques (Hamill O.P., Marty A., Neher E.,
Sakmann B.
and Sigworth F.J., Plugers Arch., ~, 85-100 (1981)) are used the ionic current
through a
single channel of a cell can be recorded.
The activity of the compounds as potassium channel openers can afso be
measured as rela-
xation of rat aorta rings according to the following procedure:
A section of rat thoracic aorta between the aortic arch and the diaphragm was
dissected out
and mounted as ring preparations as described by Taylor P.D. et al , Brit J.
Pharmacol, 111,
42-48 (1994).
After a 45 min. equilibration period under a tension of 2 g, the preparations
were contracted
to achieve 80% of the maximum response using the required concentration of
phenylephri-
ne. When the phenylephrine response reached a plateau, potential vasodilatory
agents were
added cumulatively to the bath in small volumes using half log molar
increments at 2 min
intervals. Relaxation was expressed at the percentage of the contracted
tension. The poten-
cy of a compound was expressed as the concentration required to evoke a 50%
relaxation of
the tissue.
Relaxation of rat aorta rings
Example 1 ECM 5.6 micro M
In the pancreatic b-cell the opening of the KAY-channels can be determined by
measuring
the subsequent change in the concentration of cytoplasmic free Ca2+
concentration accor-
ding to the method of Arkhammar P. et al. , J. Biol. Chem., ~, 5448-5454
(1987).
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An opening of KATP-channels will result in an efflux of potassium ions. By
measuring the
release of e6Rb' (a radioactive potassium mimic) from e.g. beta-cells pre-
incubated in the
presence of e6Rb' the effect of compounds acting as potassium channel openers
can be
determined. The test expresses the ability of the compounds to regulate the
secretion of
insulin from the beta-cells.
~Rb' efflux from a f3-cell line
The RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with
10 % fetal
calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5
% COZ /
95 % air at 37°C. The cells were detached with a Trypsin-EDTA solution
(from GibcoBRL,
Scotland, UK), resuspended in medium, added 1 mCi/ml 86Rb' and replated into
microtiter
plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a
density of
50000 cells/well in 100 ~I/well, and grown 24 hours before use in assay.
The plates were washed 4 times with Ringer buffer {150 mM NaCI, 10 mM Hepes,
3.0 mM
KCI, 1.0 mM CaCIZ, 20 mM Sucrose, pH 7.1 ). Eighty ~I Ringer buffer and 1 wl
control- or test
compound dissolved in DMSO was added. After incubation 1 h at room temperature
with a
lid, 50 ul of the supernatant was transferred to PicoPlates (Packard
Instrument Company,
CT, USA) and 100 wl MicroScint40 (Packard Instrument Company, CT, USA) added.
The
plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1
min/well at
the 32P program.
The calculation of ECM and Em~ was done by SIideWrite (Advanced Graphics
Software, Inc.,
CA, USA) using a four parameter logistic curve: y = (a-d)/(1+(x/c)°)+d,
where a = the activity
estimated at concentration zero, b = a slope factor, c = the concentration at
the middle of the
curve and, d = the activity estimated at infinite concentration. ECM = c and
E",~= d, when the
curve is turned of at infinite concentrations.
Increased Rb-efflux in rin 5F cells
Example 1 ECM 2.6 micro M
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The effect of KAY-channel modulators on pancreatic beta-cells can be
determined by measu-
ring qualitative changes in membrane potential in the insulin producing cell
line (i-TC3 using
fluorescence imaging techniques.
The slow fluorescent membrane potential probe DiBAC was used. The cells were
kept in
Caz' -HEPES buffer supplemented with 10 mM glucose. After 5 s of each 60 s run
the com-
pound was added. 48 welts were run in each set, taking about 1 h. The same
cells were then
run again, now adding 25 mM KCI after 5 s, and the depolarisation-induced
increase in Di-
BAC fluorescence monitored for 55 s.
In addition the effect of KAY-channel modulators on pancreatic beta-cells can
be determined
by measuring the increase or decrease in insulin release from insulin
producing beta-cell li-
nes or isolated islets.
Effect of K,,~,-channel modulators can be measured using the following
procedure:
15 The beta cells are cultured with change of media every three-four days.
Cells are then seeded in 96 well microtiter dishes and cultured for three day
at 38 °C, 5%
COZ and 95% humidity.
The cells are washed with NN -buffer (+1 OmM Hepes + 0.1 % BSA) for one minute
and
glucose (final conc. 22 mM), IBMX (final concØlmM) and compounds (final
conc. from 5 x
10'5 M - 5 x 10'~ M) added. All cells are then incubated for three hours (38
°C, 5% C02 and
95% humidity).
Supernates are harvested into Greiner minisorb microtiter wells and frozen.
Insulin is measu-
red using elisa-techniques.
The compounds according to the invention are effective over a wide dose range.
In general
satisfactory results are obtained with dosages from about 0.05 to about 1000
mg, preferably
from about 0.1 to about 500 mg, per day. A most preferable dosage is about 1
mg to about
100 mg per day. The exact dosage will depend upon the mode of administration,
form in
which administered, the subject to be treated and the body weight of the
subject to be trea-
ted, and the preference and experience of the physician or veterinarian in
charge.
The route of administration may be any route, which effectively transports the
active com-
pound to the appropriate or desired site of action, such as oral or parenteral
e.g: rectal,
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transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral
route being
preferred.
Typical compositions include a compound of formula I or a pharmaceutically
acceptable acid
addition salt thereof, associated with a pharmaceutically acceptable excipient
which may be
a can-ier or a diluent or be diluted by a carrier, or enclosed within a
carrier which can be in
form of a capsule, sachet, paper or other container. In making the
compositions, conventio-
nal techniques for the preparation of pharmaceutical compositions may be used.
For exam-
ple, the active compound will usually be mixed with a carrier, or diluted by a
carrier, or enclo-
sed within a carrier which may be in the form of a ampoule, capsule, sachet,
paper, or other
container. When the carrier serves as a diluent, it may be solid, semi-solid,
or liquid material
which acts as a vehicle, excipient, or medium for the active compound. The
active com-
pound can be adsorbed on a granular solid container for example in a sachet.
Some exam-
pies of suitable carriers are water, salt solutions, alcohols, polyethylene
glycols, polyhydroxy-
ethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc,
sificic acid, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid esters,
hydroxymethylcellulo-
se and polyvinylpyrrolidone. The formulations may also include wetting agents,
emulsifying
and suspending agents, preserving agents, sweetening agents or flavouring
agents. The
formulations of the invention may be formulated so as to provide quick,
sustained, or delay-
ed release of the active ingredient after administration to the patient by
employing procedu-
res well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with
auxiliary
agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or
coloring substances
and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or
suspensions, prefe-
rably aqueous solutions with the active compound dissolved in polyhydroxyfated
castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or
binder or the like
are particularly suitable for oral application. Preferable carriers for
tablets, dragees, or cap-
sules include lactose, com starch, and/or potato starch. A syrup or elixir can
be used in ca-
ses where a sweetened vehicle can be employed.
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Generally, the compounds are dispensed in unit form comprising from about 1 to
about 100
mg in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet, appropriate for use in this method, may be prepared by
conventional tablet-
s ting techniques and contains:
Active compound 5.0 mg
Lactosum 67.8 mg Ph.Eur.
Avicel~ 31.4 mg
Amberlite~ 1.0 mg
Magnesii stearas 0.25 mg Ph.Eur.
The process of preparing the compounds of formula I is further illustrated in
the following e-
xamples which, however, are not to be construed as limiting.
N-Cyano-N'-(3.5-bis trifluoromethyl) henyl)~(3-methylbuty~auanidine
a) ~3.5-bis(trifluoromethyrl)~~y1}-N'-cyano-O-pb,~pyrlisourea
A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5
bistrifluoromethylaniline (2
mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml)
was stitred
under nitrogen for 12 h. After concentration the residue was stirred with
toluene (5 ml) for 2 h
and the solid was collected by filtration giving 550 mg of N-(3,5-
bis(trifluoromethyl)phenyl)-
N'-cyano-O-phenylisourea (73.6%);
'H-NMR (ds-DMSO): b 7.25 (m, 5H), 7.95 (s, 1 H), 8.15 (s, 2H), 11.2 (s, 1 H).
b) N-Cyano-N'- 3.5-bis(trifluoromethy!)pt~enX~jy'_-(3-methylbutyrf)quanidine
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A solution of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (1
mmol, 373 mg),
3-methylbutylamine (1.15 mmo1,100 mg) and triethylamine (1.5 mmol, 150 mg) in
acetonitrile
(2 ml) was stirred for 24 h at 60 °C. After concentration the residue
was purified by column
chromatography (heptane:ethyl acetate 1:1) to give the title compound (100 mg,
27%).
'H-NMR (ds-DMSO): 8 0.9 (d, 6H),1.45 (q, 2H), 1.65 (m,lH), 3.3 (q,2H), 7.7 (t,
1H), 7.79 (s,
1 H), 7.95 (s, 2H), 9.45 (s,1 H).
EXAMPLE 2
N-C ny~ oN'-(3 5-bis(trifluoromethy~ohenyy-N"-(2-(4-ovridinyl~ethy~auanidine
By following a procedure analogous to the one described in EXAMPLE 1 b, N-(3,5-
bis(trifluoromethyl)-phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg) was
treated with 4-
(2-aminoethyl)pyridine (1.15 mmo1,140.5 mg) to give 110 mg (27%) of the title
product;
'H-NMR (ds-DMSO): & 3.0 (t, 2H), 3.75 (q,2H), 7.41 (d,2H), 7.89 (s,1 H), 7.95
(s, 1 H), 8.05 (s,
2H), 8.62 (d, 2H), 9.5 (s, 1 H).
N-Cyano-N'-(3.5-bis(trifluoromethyl)phenyl)-N"-(cyclol en ()guanidine
To a suspension of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea
(0.400 g,
1.1 mmol) in dry acetonitrile (2.5 ml) triethylamine (0.164 ml, 1.2 mmol) and
cyclopentylami-
ne (0.116 ml, 1.2 mmol) was added. The homogenous solution was stirred at
85°C under NZ
for 3.5 h. The solvent was evaporated, and the residue was dissolved in ethyl
acetate and
washed with water twice. The organic layer was dried (Na2S0,) and
concentrated. The crude
product was purified by flash chromatography using ethyl acetate/heptane 1:2
to give the
title compound. Yield 82% (0.320 g). mp 156-159°C.
'H-NMR(CDCI3): b 8.87 (1H, broad s, NH); 7.78 (2H, s); 7.60 (1H, s); 5.50 (1H,
broad d, NH);
4.20 (1 H, sextet); 2.1 (2H, m); 1.75 (4H m); 1.55 ppm (2H, m).
EXAMPLE 4
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N-C~ano-N'-l3 5-bis(trifluoromethy~~eny~-N"-(2-chlorobenzyl)guanidine
By following a procedure analogous to the one described above in Example1 b, N-
(3,5-
bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.300 g, 0.8 mmol) was
treated with
triethylamine (0.123 ml, 0.88 mmol) and 2-chlorobenzylamine (0.107 ml, 0.88
mmol) to give
the title compound as a syrup. Yield 72% (0.234 g).
'H-NMR(CDCI3): S 8.6 (1H, broad s, NH); 7.70 (3H, s); 7.45 (2H, m); 7.30
(2H,m); 5.85 (1H,
broad s, NH); 4.60 (2H, d).
EXAMPLE 5
N-Cyano-N'-j3.5-bis(trifluoromethyl)ohenyl]-~ 1.2-dimethyt~~y~auanidine
a) N-j3.5-bis(trifluoromethyrl)p~gpy~,~~y n~ o-O-~pylisourea
A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5-
bis(trifluoromethyl)aniline
(2 mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml)
was
stirred under nitrogen for 12 h. After concentration the residue was stin-ed
with toluene (5 ml)
for 2 h and the solid was collected by filtration giving 550 mg of N-[3,5-
bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (73.6%);
'H-NMR (de-DMSO): 8 7.25 (m, 5H), 7.95 (s, 1 H), 8.15 (s, 2H), 11.2 (s, 1 H).
b) N-Cyrano-N'-[3.5-bis trifluoromethyl)~henyrll-N"-(1.2-
dimethyloropyllauanidine
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8
mmol, 300
mg), 3-methyl-2-butylamine (0.88 mmol, 0.101 ml) and triethylamine (0.88 mmol,
0.123 ml)
in acetonitrile (2 ml) was stirred for 7 h at 75 °C. After
concentration the residue was dis-
solved in ethyl acetate, washed with water, dried (NaZSO,) and concentrated.
The residue
was purified by column chromatography (heptane:ethyl acetate 4:1 ) to give the
title com-
pound (143 mg, 59%) as white crystals. Mp 134-136°C; EI SP/MS: 366
(M+); 'H-NMR
(CDCI3): 8 0.92 (d, 6H),1.15 (d, 3H), 1.78 (m, 1 H), 3.78 (m, 1 H), 4.85 (br,
1 H), 7.73 (br s, 3H),
8.0 ppm (br, 1 H); MA calc for C,SH,6F6N,: C 49.18%, H 4.40%, N 15.29%. Found:
C 48.95%,
H 4.38%, N 15.08%.
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EXAMPLE 6
N-Cyano-N'-j3.5-bis trifluoromethyl)phenyl]-N"-(1.2.2-
trimethylprop~L)guanidine
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8
mmol, 300
5 mg), 2-amino-3,3-dimethylbutane (0.88 mmol, 0.09 g) and triethytamine (0.88
mmol, 0.123
ml) in acetonitrile (2 ml) was stirred for 8 h at 75 °C. After
concentration the residue was pu-
rified by column chromatography (heptane:ethyl acetate 2 :1) to give the title
compound (140
mg, 46%) as white crystals. Mp 165.5-166.5°C; E! SP/MS: 380 (M+); 'H-
NMR (CDCI3): b 0.92
(s, 9H),1.13 (d, 3H), 3.8 (m, 1 H), 4.8 (br d, 1 H), 7.74 (br s, 3H), 8.5 ppm
(br, 1 H); MA calc for
10 C,6H,eF6N,: C 50.53%, H 4.77%, N 14.73%. Found: C 50.48%, H 4.74%, N
14.45%.
15 N-Cyano-N'-'[3.5-bis(trifluoromethyl)~~hen»]-N"-(1.1-
dimethyrl~Qyrl)guanidine
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea
(0.78 mmol, 290
mg), tert-amylamine (0.85 mmol, 0.100 ml) and triethylamine (0.85 mmol, 0.119
ml) in ace-
tonitrile (2 ml) was stirred for 25 h at 75 °C followed by work-up as
described in EXAMPLE 5,
b) to give the title compound (140 mg, 46%) as white crystals. Mp 149-
150°C; EI SPIMS:
20 366 (M+);'H-NMR (CDCI3): 8 0.85 (t, 3H),1.35 (s, 6H), 1.75 (q, 2H), 4.65
(br s, 1H), 7.70 (br s,
3H), 8.95 ppm (br s, 1 H); MA calc for C,SH,6F6N,. 0.15 H20: C 49.37%, H
4.57%, N 14.76%.
Found: C 49.72%, H 4.56%, N 14.76%.
EXAMPLE 8
N-Cyano-N'-(3.5-bis~(trifluoromethyl)pheny! -~1-methylethyrl)-guanidine
N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350
mg) and iso-
propylamine (1 ml) was stirred in a sealed flask for 19 h at 75 °C.
After concentration the
residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x),
water, dried
(Na2S04) and concentrated. The residue was crystallised from ethyl acetate and
heptane to
give the title compound (114 mg, 45%) as white crystals. Mp 176-182°C;
'H-NMR (CDCI3): 8
1.25 (d, 6H), 4.07 (m, 1 H), 5.5 (br d, 1 H), 7.71 (br s, 1 H), 7.75 (br s,
2H), 8.10 ppm (br, 1 H);
MA calc for C,3H,2F6N4: C 46.16%, H 3.58%, N 16.56%. Found: C 46.15%, H 3.64%,
N
16.45%.
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N-yano-N'-[3.5-bis(trifluoromethy~~~henyl~N"-RroRyl-guanidine
N-(3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350
mg) and n-
propylamine (1 ml) was stirred in a sealed flask for 19 h at 75 °C.
After concentration the
residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x),
water, dried
(NazSO,) and concentrated. The residue was purified by flash chromatography
(ethyl acetate
/ heptane 1:2) to give the title compound (90 mg, 28%) as white crystals. Mp
142.5-143.5°C;
'H-NMR (CDCI,): 8 0.95 (t, 3H), 1.65 (sextet, 2H), 3.35 (q, 2H), 5.45 (br,
1H), 7.68 (br s, 1 H),
7.80 (br s, 2H), 8.35 ppm (br, 1 H); MA calc for C,3H,ZFgN,: C 46.16%; H
3.58%, N 16.56%.
Found: C 46.31 %, H 3.65%, N 16.23%.
Jy-Cyrano-N'- ,3-trifluoromethyl enyrl)-N"-~,~y~ e~rlauanidine
a) ~3-trifluorometh~~, -ZN--cyano-O,chenvlisourea
To a solution of 3-trifluoromethylaniline (11 mmol, 1.37 ml) in
dichloromethane (25 ml),
diphenylcyanocarbonimidate (10 mmol, 2.38 g), and triethylamine {11 mmol, 1.53
ml) were
added. The mixture was stirred under nitrogen for 23 h. After concentration
the residue was
stirred with water, the water was decanted followed by concentration. The
residue was
stirred with toluene and the solid was collected by filtration giving 1.42 g
of N-{3-
trifluoromethylphenyl)-N'-cyano-O-phenylisourea (50%);
' H-NMR (CDCI3): 8 7.13 (d, 2H), 7.30 (t, 1 H), 7,42 (t, 2H), 7.43 (d, 2H),
7.60 (m, 1 H), 7.68 (s,
1 H), 9.3 ppm (br s, 1 H). E1 SP/MS: 305 (M+).
b) N-Cyano-N'-{3-trifluoromethyl~yjl-N"-cyclopeni~lguanidine
N-(3-Trifluoromethylphenyl)-N'-cyano-O-phenylisourea (1 mmol, 290 mg) was
stirred for 19 h
at 80 °C in cyclopentylamine (1 ml). After concentration of the cold
reaction mixture, the
residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x),
water, dried
(Na2S0,) and concentrated. The residue was purified by column chromatography
(heptane:ethyl acetate 3:1 ) to give the title compound (205 mg, 68%) as a
syrup. Crystallisa-
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tion from heptane:ethyl acetate 2:1 gave 147mg (49%). Mp 111.5-113°C;
'H-NMR (CDC13): 8
1.42 (m, 2H),1.65 (m, 4H), 2.05 (m, 2H), 4.12 (sextet, 1 H), 4.85 (br, 1 H),
7.35 (br s, 1 H), 7.5
ppm (m, 4H); MA calc for C"H,SF3N4: C 56.75%, H 5.10%, N 18.91 %. Found: C
56.48%, H
5.08%, N 18.65%.
EXAMPLE 11
N-Cyano-N'-iso~r_ooyl-N"-~(3-trifluoromethyi~h gn_yrl)guanidine
To a solution of N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea (0.98
mmol, 286 mg)
in dry acetonitrile (2 ml), isopropylamine (0.184 ml) and triethylamine (0.150
ml) were added.
The mixture was stirred for 42 h at room temperature under nitrogen. After
concentration the
residue was purified by flash chromatography (ethyl acetate l heptane 1:2) to
give the title
compound (210 mg, 79%) as a syrup. Crystallisation from ethyl acetate I
heptane 1:3 gave
white crystals ( 165 mg, 62%). Mp 109-111 °C; ' H-NMR (CDCI3): 81.20
(d, 6H), 4.05 (m, 1 H),
4.67 (br d, 1 H), 7.42 (m, 1 H), 7.50 (s, 1 H), 7.55 (m, 2H), 7.68 ppm (br, 1
H); MA calc for
C,ZH,3F3N,: C 53.33%, H 4.85%, N 20.73%. Found: C 53.61 %, H 4.92%, N 20.67%.
N-C no-N'-(3.5-dichloroohenyl)-N"-(2-chlorobenzyl~guanidine
~ N-Cyano-N'-~(3.5-dichiorophenyl)-O-p~yriisourea
To a solution of 3,5-dichloroaniline (11 mmol,1.79 g) in dichloromethane (25
ml), diphenyl-
cyanocarbonimidate (10 mmol, 2.38 g} and triethylamine (11 mmol, 1.53 ml) were
added.
The reaction mixture was stirred under nitrogen for 65 h at room temperature.
After concen-
tration the residue was stirred with water, the water was decanted followed by
concentration.
The residue was stirred with toluene and the solid was collected by filtration
giving 2.04 g of
the title compound (67%); 'H-NMR (CDCI3): b 7.12 (d, 2H), 7.22 (s, 1H), 7,35
(m, 3H), 7.45
(d, 2H), 9.4 ppm (br s, 1 H). EI SPIMS: 305 (M+), 307 (M+2), 309 (M+4).
b) N-Cyano-N'-~,5-dichlorophenyl)-N"-{2-chlorobenzyrl)guanidine
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To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol,
250 mg) in dry
acetonitrile (2 ml), 2-chlorobenzylamine (0.9 mmol, 0.108 rnl) and
triethylamine (0.125 ml)
were added. The mixture was stirred for 2'/z h at 82°C under nitrogen.
After concentration
the residue was recrystallised from ethyl acetate to give the title compound
(208 mg, 72%).
Mp 186-187.5°C; 'H-NMR (CDCI3): 8 4.54 (d, 2H), 5.53 (br, 1 H), 7.15
(m, 2H), 7.3 (m, 3H), 7.4
(m, 2H), 7.75 ppm (br, 1 H); EI SPIMS: 394 (M+). MA calc for C,SH"CI,N,: C
50.95%, H
3.14%, N 15.84%. Found: C 50.68%, H 3.10%, N 15.49%.
~y-Cvano-N'-cyrcfopen yl-N"-(3.5-dichloro~ohenyl)guanidine
To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol,
250 mg) in dry
acetonitriie (2 ml), cyclopentylamine (0.9 mmol, 0.089 ml) and triethylamine
(0.125 ml) were
added. The mixture was stirred for 2'/Z h at 82°C under nitrogen. After
concentration the
residue was purified by flash chromatography (ethyl acetate / heptane 1:2) to
give the title
compound (160 mg, 66%) as crystals. Mp 147.5-148.5°C; 'H-NMR (CDCI3): b
1.45 (m, 2H),
1.65 (m, 4H), 2.05 (m, 2H), 4.11 (sextet, 1 H), 5.1 (br, 1 H), 7.2 (m, 3H),
8.02 ppm (br, 1 H); EI
SP/MS: 296 (M+), 298 (M+2), 300 (M+4). MA calc for C,3H"CIZN,: C 52.54%, H
4.75%, N
18.85%. Found: C 52.17%, H 4.71 %, N 18.50%.
N-Cv ano-N'- 3.5-dichlorophenyl)-N"-(1-methylethyrl)guanidine
N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and
isopropylamine
(1 ml) was stirred in a sealed flask for 19 h at 75 °C. After
concentration the residue was dis-
solved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried
(Na2S0,) and
concentrated. The residue was crystallised from ethyl acetate I heptane 1:3 to
give the title
compound (115 mg, 43%) as white crystals. Mp 156-158.5°C; 'H-NMR
(CDCI,): S 1.21 (d,
6H), 4.03 (m, 1 H), 4.70 (br d, 1 H), 7.16 (m, 2H), 7.29 (m, 1 H), 7.47 ppm
(br, 1 H); MA calc for
C"H,zCIZN,: C 48.73%, H 4.46%, N 20.66%. Found: C 48.76%, H 4.49%, N 20.38%.
CA 02331299 2000-11-02
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24
EXA,MQLE 15
N-Cyano-N'- 3.5-dichlorophenyrl}-N"-~~ropylguanidine
N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and n-
propylamine
(1 ml) was stirred in a sealed flask for 19 h at 75 °C. After
concentration the residue was dis-
solved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried
(Na2S0,) and
concentrated. The residue was purrfied by flash chromatography (ethyl acetate
/ heptane
1:3) to give the title compound (60 mg, 23%) as white crystals. Mp 141-
143°C; 'H-NMR
(CDCI3): 8 0.92 (d, 6H}, 1.58 (sextet, 2H), 3.25 (q, 1 H), 5.1 (br, 1 H), 7.19
(m, 2H), 7.25 (m, 1 H),
7.95 ppm (br, 1 H); MA talc for C"H,ZCIZN,: C 48.73%, H 4.46%, N 20.66%.
Found: C
49.02%, H 4.55%, N 20.27%.
N-Cyano-N'-(3.5-dichloro~~~)-~3-methyrlbufyrl)~-guanidine
To N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) in dry
acetonitrile
(2 ml), 3-methylbutylamine (2.16 mmol, 0.255 ml) and triethylamine (1.08 mmol,
0.150 ml)
were added. The reaction mixture was stirred for 16 h at 85°C under
nitrogen. The precipi-
tated material was filtered off and recrystallised from ethyl acetate to give
the title compound
(160 mg, 54%) as white crystals. Mp 146.5-1451.5°C;'H-NMR (CDCI3): 8
0.94 (d, 6H), 1.43
(q, 2H), 1.6 (m, 1 H), 3.31 (q, 2H), 4.9 (br, 1 H), 7.18 (br s, 2H), 7.29 (br
s, 1 H), 7.5 ppm (br,
1 H); MA talc for C,3H,BCI2N,: C 52.19%, H 5.39%, N 18.73%. Found: C 52.23%, H
5.51 %, N
18.60%.
N-Cyano-N'-cyclopentyrl-N"-(3-methyl-5-trifluoromethy~Zp, rJ,yl)guanidine
N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea
To a solution of 3-methyloxy-5-trifluoromethylaniline (11 mmol, 2.10 g) in
dichloromethane
(25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11
mmol, 1.53 ml)
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were added. The reaction mixture was stirred under nitrogen for 16 h at room
temperature.
After concentration the residue was stirred with water, the water was decanted
followed by
concentration. The residue was purified by flash chromatography (ethyl acetate
I heptane
1:2) to give 0.413 g of the title compound (12%); Mp 168.5-169.5°C;'H-
NMR (CDCI3): b
5 3.83 (s, 3H), 7.00 (s, 1 H), 7.14 (m, 3H), 7,23 (s, 1 H), 7.32 (t, 1 H),
7.43 ppm (t, 2H), 8.7 (br s,
1 H). El SPIMS: 335 (M+).
10 N-Gvano-N'-cvcio en yl N"-{3-methyloxy-5-trifluoromethviohenvllquanidine
To a solution of N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-
phenylisourea (0.52
mmol, 175 mg) in dry acetonitrile (1 ml), cyclopentylamine (1.04 mmol, 0.113
ml) and tri-
15 ethylamine (0.080 ml) were added. The mixture was stirred for 19 h at
75°C under nitrogen.
After concentration the residue was dissolved in dichloromethane, washed with
1 N aqueous
HCI (2x), water, dried (Na2S0,) and concentrated. The residue was purfied by
flash chro-
matography (ethyl acetate I heptane 1:2) to give a syrup. Crystallisation from
ethyl acetate I
heptane 1:4 gave grey crystals (110 mg, 65%). Mp 101-102°C;'H-NMR
(CDCI3): 81.40 (m,
20 2H), 1.65 (m, 4H), 2.02 (m, 2H), 4.13 (sextet, 1 H), 5.05 (br, 1 H~ 6.96
(s, 1 H), 7.00 (s, 1 H),
7.03 (s, 1 H), 8.15 ppm (br, 1 H); EI SP/MS: 326 (M+).
Jy-y na o-N'-{3-methoxv-5-trifluoromethyrlnhenyl)-N"-{3-methylb~yrl)guanidine
To a solution of N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-
phenylisourea (0.6
mmol, 200 mg) in dry acetonitrile (1 ml), 3-methylbutylamine (1.31 mmol, 0.152
ml) and
triethyiamine (0.66 mmol, 0.091 ml) were added. The mixture was stirred for 19
h at 75°C
under nitrogen. After concentration the residue was dissolved in
dichloromethane, washed
with 1 N aqueous HCI (2x), water, dried (Na2S04) and concentrated.
Crystallisation from
ethyl acetate I heptane 1:3 gave white crystals (160 mg, 81%). Mp 105.5 -
108.5°C; 'H-NMR
(CDCI3): 8 0.90 (d, 6H), 1.42 (q, 2H), 1.6 (m, 1 H), 3.32 (q, 2H), 3.85 (s,
3H), 4.9 (br, 1 H), 6.94
(brs, 1 H), 7.04 (s, 2H), 7.33 ppm (br s, 1 H); MA calc for C,SH,9F,N,0: C
54.87%, H 5.83%, N
17.06%. Found: C 55.08%, H 5.97%, N 16.68%.
