U.S. patent application number 09/809952 was filed with the patent office on 2001-12-27 for substituted 3,3-diamino-2-propenenitriles, their preparation and use.
Invention is credited to Dorwald, Florencio Zaragoza, Hansen, John Bondo, Jorgensen, Anker Steen, Mogensen, John Patrick, Tagmose, Tina Moller.
Application Number | 20010056188 09/809952 |
Document ID | / |
Family ID | 46257620 |
Filed Date | 2001-12-27 |
United States Patent
Application |
20010056188 |
Kind Code |
A1 |
Hansen, John Bondo ; et
al. |
December 27, 2001 |
Substituted 3,3-diamino-2-propenenitriles, their preparation and
use
Abstract
Disclosed are substituted cyanoenamines, compositions containing
these compounds, and methods for preparing these compounds. These
compounds are useful in the treatment of diseases of the central
nervous system, the cardiovascular system, the pulmonary system,
the gastrointestinal system and the endocrinologic system.
Inventors: |
Hansen, John Bondo;
(Jyderup, DK) ; Tagmose, Tina Moller; (Ballerup,
DK) ; Mogensen, John Patrick; (Vanlose, DK) ;
Dorwald, Florencio Zaragoza; (Ballerup, DK) ;
Jorgensen, Anker Steen; (Kobenhavn O, DK) |
Correspondence
Address: |
Steve T. Zelson, Esq.
Novo Nordisk of North America, Inc.
405 Lexington Avenue, Suite 6400
New York
NY
10174-6401
US
|
Family ID: |
46257620 |
Appl. No.: |
09/809952 |
Filed: |
March 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09809952 |
Mar 16, 2001 |
|
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09433264 |
Nov 4, 1999 |
|
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60108728 |
Nov 17, 1998 |
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Current U.S.
Class: |
546/304 ;
558/397 |
Current CPC
Class: |
C07D 277/62 20130101;
C07D 317/66 20130101; C07C 317/48 20130101; C07C 2601/04 20170501;
C07C 2601/08 20170501 |
Class at
Publication: |
546/304 ;
558/397 |
International
Class: |
C07D 211/56; C07C
317/26 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 1998 |
DK |
PA 1998 01427 |
Claims
What is claimed is:
1. A compound selected from the group consisting of:
3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2-
,2-trimethylpropylamino)-2-propenenitrile
3-[3,5-bis(trifluoromethyl)pheny-
lamino]-2-(4-chlorophenylsulfonyl)-3-cyclopentylamino-2-propenenitrile
3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-isop-
ropylamino-2-propenenitrile 3-[3,
5-bis(trifuoromethyl)phenylamino]-2-(4-c-
hlorophenylsulfonyl)-3-cyclobutylamino-2-propenenitrile
3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-prop-
ylamino-2-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-(pyridin-3-ylamino)--
3-(1,2,2-trimethylpropylamino)-2-propenenitrile
2-(4-Chlorophenylsulfonyl)-
-3-(3,5-dichlorophenylamino)-3-(1,2,2-trimethylpropylamino)-2-propenenitri-
le
3-(Benzo[1,3]dioxol-5-ylamino)-2-(4-chloro-phenylsulfonyl)-3-(1,2,2-tri-
methyl-propylamino)-propenenitrile 3-(3,
5-Bis(trifluoromethyl)phenylamino-
)-2-methylsulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-(3,
5-dimethoxyphenylamino)-3-(1,2,2-trimeth-
ylpropylamino)-2-propenenitrile
3-[N-(3,5-bis(trifluoromethyl)phenyl)-N-me-
thylamino]-2-(4-chlorophenyls
ulfonyl)-3-(1,2,2-trimethylpropylamino)-2-pr- openenitrile
(1'S,2'S)-3-[2-Benzyloxycyclopentylamino]-3-[3,5-bis(trifluor-
omethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-2-propenenitrile
(1'R,
2'R)-3-[2-Benzyloxycyclopentylamino]-3-[3,5-bis(trifluoromethyl)phenylami-
no]-2-(4-chlorophenylsulfonyl)-2-propenenitrile
(S)-3-[3,5-Bis(trifluorome-
thyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2,2-trimethylpropylamino-
)-2-propenenitrile
(S)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chloro-
phenylsulfonyl)-3-(,2-dimethylpropylamino)-2-propenenitrile
(R)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3--
(1,2-dimethylpropylamino)-2-propenenitrile 3-[3,
5-Bis(trifluoromethyl)phe-
nylamino]-2-(4-chlorophenylsulfonyl)-3-(1,1-dimethylpropylamino)-2-propene-
nitrile
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfony)--
3-(5-cyclopropyl-2-methyl- 2H-pyrazol-3-ylamino)-2-propenenitrile
(R)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3--
(1,2,2-trimethylpropylamino)-2-propenenitrile
3-(3,5-Bis(trifluoromethyl)p-
henylamino)-3-isopropylamino-2-methylsulfonyl-propenenitrile
(R)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-methanesulfonyl-3-(1,2,2-tr-
imethylpropylamino)-2-propenenitrile
(S)-3-[3,5-bis(trifluoromethyl)phenyl-
amino]-2-methanesulfonyl-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-(3,
5-dimethoxyphenylamino)-3-(1,1-dimethylp-
ropylamino)-2-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyph-
enylamino)-3-cyclobutylamino-2-propenenitrile
3-(3,5-dimethoxyphenylamino)-
-2-methanesulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile
3-(3,5-dimethoxyphenylamino)-3-isopropyl-2-methanesulfonyl-propenenitrile
3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1-dimethyl-propylamino)-2-(4-chloro-p-
henylsulfonyl)-propenenitrile
3-(Benzo[1,3]dioxol-5-ylamino)-3-cyclobutyla-
mino-2-(4-chloro-phenylsulfonyl)-propenenitrile
2-(4-Chlorophenylsulfonyl)-
-3-(3,5-dichlorophenylamino)-3-(1,1-dimethylpropylamino)-2-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5-dichlorophenylamino)--
2-propenenitrile
3-sec-Butylamino-2-(4-chlorophenylsulfonyl)-3-(3,5-dichlo-
rophenylamino)-2-propenenitrile
2-Methylsulfonyl-3-(3-methoxy-5-trifluorom-
ethyl-phenylamino)-3-(1,2,2-trimethylpropylamino)-propenenitrile
3-(3-Fluoro-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-(1
,2,2-trimethylpropylamino)-propenenitrile
3-(4-Chlorophenylamino)-2-methy-
lsulfonyl-3-(1,2,2-trimethylpropylamino)-acrylonitrile
3-(Benzothiazol-6-ylamino)-3-(1,1-dimethyl-propylamino)-2-methylsulfonyl--
propenenitrile
3-(Benzo[1,3]dioxol-5-ylamino)-2-(2,2-dimethyl-propionyl)-3- -(1,
1-dimethyl-propylamino)-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-(-
3-cyanophenylamino)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-cyclopentylamino-2-pr-
openenitrile
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino-3-(1,2-dimet-
hylpropylamino)-2-propenenitrile
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-
-isopropylsulfonyl-3-(1,2,2-trimethylpropylamino)-propenenitrile
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-cyclopentyl-
amino-2-propenenitrile
3-(3,5-Bis(trifluoromethyl)phenylamino)-3-cyclobuty-
lamino-2-isopropylsulfonyl-2-propenenitrile
3-(3,5-Bis(trifluoromethyl)phe-
nylamino)-2-isopropylsulfonyl-3-(2-methyl)propylamino)-2-propenenitrile
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-(1,2,2-trimethylpropylamin-
o)-2-propenenitrile
3-Cyclopentylamino-2-isopropylsulfonyl-3-(3-methoxy)ph-
enylamino-2-propenenitrile
3-Cyclobutylamino-2-isopropylsulfonylamino-3-(3-
-methoxy)phenylamino-2-propenenitrile
2-Isopropylsulfonyl-3-(3-methoxy)phe-
nylamino-3-(2-methyl)propylamino)-2-propenenitrile
3-(1,1-Dimethyl)propyla-
mino)-2-isopropylsulfonyl-3-(3-methoxy)phenylamino-2-propenenitrile
2-Isopropylsulfonyl-3-(3-methoxy)phenylamino-3-tert.-butylamino-2-propene-
nitrile
3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1-dimethylpropylamino)-2-metha-
nesulfonyl-2-propenenitrile or a pharmaceutically acceptable salt
thereof.
2. A pharmaceutical composition comprising an effective amount of a
compound of claim 1, together with one or more pharmaceutically
acceptable carriers or diluents.
3. The pharmaceutical composition of claim 2 in the form of an oral
dosage unit or parenteral dosage unit.
4. The pharmaceutical composition of claim 2, wherein the compound
is administered as a dose in a range from about 0.05 mg to 1000 mg
per day.
5. The pharmaceutical composition of claim 4, wherein the compound
is administered as a dose in a range from about 0.1 mg to 500 mg
per day.
6. The pharmaceutical composition of claim 5, wherein the compound
is administered as a dose in a range from about 50 mg to 200 mg per
day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of Ser. No. 09/433,264
filed Nov. 4, 1999 and claims priority under 35 U.S.C. 119 of U.S.
provisional application No. 60/108,728 filed on Nov. 17, 1998, and
Danish application PA 1998 01427 filed on Nov. 5, 1998, the
contents of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to substituted
3,3-diamino-2-propenenitriles, in the following also referred to as
cyanoenamines, to methods for their preparation, to compositions
comprising the compounds, to the use of these compounds 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 gastrointestinal system and the
endocrinologic system.
[0003] 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 antidiabetic or
other pharmacologically active material, including compounds for
the treatment and/or prophylaxis of insulin resistance and diseases
wherein insulin resistance is the pathophysiological mechanism.
Suitable antidiabetics comprise insulin as well as orally active
hypoglycemic agents such as sulphonylureas, e.g. glibenclamide and
glipizide; biguanides, e.g. mefformin; benzoic acid derivatives,
e.g. repaglinide; and thiazolidinediones, e.g. troglitazone and
ciglitazone.
BACKGROUND OF THE INVENTION
[0004] Potassium channels play an important role in membrane
potential. Among the different types of potassium channels are the
ATP-sensitive (K.sub.ATP-) channels which are regulated by changes
in the intracellular concentration of adenosine triphosphate. The
K.sub.ATP-channels have been found in cells from various tissues
such as cardiac cells, pancreatic-cells, skeletal muscles, smooth
muscles, central neurones 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.
[0005] Modulators of the K.sub.ATP-channels have been found to be
of importance for the treatment of various diseases. Certain
sulfonylureas which have been used for the treatment of
non-insulin-dependent diabetes mellitus act by stimulating insulin
release through an inhibition of the K.sub.ATP-channels on
pancreatic beta-cells.
[0006] The potassium channel openers, which comprise a
heterogeneous group of compounds, have been found to be able to
relax vascular smooth muscles and have therefore been used for the
treatment of hypertension.
[0007] In addition, potassium channel openers can be used as
bronchodilators in the treatment of asthma and various other
diseases.
[0008] Furthermore, potassium channel openers have been shown to
promote hair growth, and have been used for the treatment of
baldness.
[0009] 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.
[0010] Since some K.sub.ATP-openers are able to antagonize
vasospasms in basilar or cerebral arteries the compounds of the
present invention can be used for the treatment of vasospastic
disorders such as subarachnoid hemorrhage and migraine.
[0011] Potassium channel openers hyperpolarizes neurons and inhibit
neurotransmitter release and it is expected that the present
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.
[0012] 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- -e]-1,2,4-thiadiazine
1,1-dioxide derivatives inhibit insulin release by an activation of
K.sub.ATP-channels on pancreatic beta-cells (Pirotte B. et al.
Biochem. Pharmacol, 47, 1381-1386 (1994); Pirotte B. et al., J.
Med. Chem., 36, 3211-3213 (1993). Diazoxide has furthermore been
shown to delay the onset of diabetes in BB-rats (Vlahos W D 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. 133, 705-712,
1993). It is expected that such potassium channel openers can be
used for treatment of diseases characterized by an overproduction
of insulin and for the treatment and prevention of diabetes.
DESCRIPTION OF THE INVENTION
[0013] The present invention relates to substituted
3,3-diamino-2-propenenitriles, in the following also referred to as
cyanoenamines, of the general formula I: 1
[0014] wherein
[0015] R.sup.1 is alkyl optionally substituted with halogen,
hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino,
arylalkylamino or diarylamino; or
[0016] aralkyl optionally substituted with alkyl, trifluoromethyl,
aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy,
methylenedioxo, aryloxy, dialkylamino, alkylarylamino, diarylamino,
nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or
aminocarbonyl; or aryl optionally substituted with alkyl,
trifluoromethyl, aryl, a 5-,6- or 7-membered heterocyclic system,
halogen, alkoxy, methylenedioxo, aryloxy, dialkylamino,
alkylarylamino, diaryl-amino, nitro, alkylsulfonyl, arylsulfonyl,
cyano, alkoxycarbonyl or aminocarbonyl; or
[0017] a 5-,6- or 7-membered heterocyclic system optionally
substituted with alkyl, aryl, a 5-,6- or 7-mem be red heterocyclic
system, halogen, alkoxy, aryloxy, dial kylamino, alkylarylamino,
diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano,
alkoxycarbonyl or aminocarbonyl;
[0018] R.sup.2 and R.sup.3 are independently hydrogen, alkyl
optionally substituted with aryl, a 5-, 6- or 7-membered
heterocyclic system, halogen, hydroxy, alkoxy, aryloxy, alkylthio,
arylthio, dialkylamino, arylalkylamino or diarylamino; aryl,
optionally substituted with alkyl, aryl, a 5-, 6-or 7-membered
heterocyclic system, halogen, trifluoromethyl, alkoxy, aryloxy,
dialkylamino, alkylarylamino, diarylamino, nitro, alkylsulfonyl,
arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; a 5-, 6- or
7-membered heterocyclic system optionally substituted with alkyl,
aryl, a 5-,6- or 7-membered heterocyclic system, halogen, alkoxy,
aryloxy, dialkylamino, alkylarylamino, diarylamino, nitro,
alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or
aminocarbonyl;
[0019] or R.sup.2 and R.sup.3 are linked together by
--(CH.sub.2).sub.n-, n being 4-7,
[0020] provided that R.sup.2 and R.sup.3 cannot be hydrogen at the
same time;
[0021] Z is hydrogen, cyano, carbonylalkyl, alkoxycarbonyl,
optionally substituted aminocarbonyl, alkylsulfonyl or arylsulfonyl
optionally substituted with alkyl, aryl, a 5-, 6- or 7-membered
heterocyclic system, halogen, alkoxy, aryloxy, dialkylamino,
alkylarylamino, diarylamino, nitro, alkylsulfonyl, arylsulfonyl,
cyano, alkoxycarbonyl or aminocarbonyl; or arylsulfonyl optionally
substituted with alkyl, aryl, a 5-,6- or 7-membered heterocyclic
system, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino,
diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano,
alkoxycarbonyl or aminocarbonyl;
[0022] or pharmaceutically acceptable salts thereof.
[0023] Within its scope the invention includes all diastereomers
and enantiomers of compounds of formula I, some of which are
optically active, and also their mixtures including racemic mixture
thereof.
[0024] The scope of the invention also includes all tautomeric
forms of the compounds of formula I as well as metabolites or
prodrugs.
[0025] In a preferred embodiment of the invention, Z is
alkylsulfonyl or arylsulfonyl substituted with halogen. More
preferred, Z is methylsulfonyl, isopropylsulfonyl or
4-chlorophenylsulfonyl.
[0026] In a further preferred embodiment of the invention, R.sup.1
is optionally substituted aryl. More preferred optionally
substituted phenyl and most preferred phenyl substituted by one or
two perhalomethyl groups, one or two alkoxy groups, one or two
halogen groups or one or two cyano groups.
[0027] A preferred perhalomethyl group is trifluoromethyl.
[0028] The most preferred phenyl substituents are 3,5-dichloro or
3,5-dialkoxy substituents.
[0029] In a further preferred embodiment of the invention, R.sup.2
is cyclic alkyl with from 3 to 5 carbon atoms in the ring, most
preferred is cyclobutyl.
[0030] In another preferred embodiment of the invention, R.sup.2 is
1,1-dimethylpropyl.
[0031] A "metabolite" of a compound disclosed in this application
is an active derivative of a compound disclosed herein which is
produced when the compound is metabolized. Metabolites of compounds
disclosed herein can be identified either by administration of a
compound to a host and an analysis of blood samples from the host,
or by incubation of compounds with hepatic cells in vitro and
analysis of the incubant. A "prodrug" is a compound that either is
converted into a compound disclosed in the application in vivo or
has the same active metabolite as a compound disclosed in this
application.
[0032] The salts include pharmaceutically acceptable acid addition
salts, pharmaceutically acceptable metal salts or optionally
alkylated ammonium salts, such as hydrochloric, hydrobromic,
hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic,
oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric,
fumaric, mandelic, benzoic, cinnamic, methane-sulfonic, ethane
sulfonic, picric and the like, and include acids related to the
pharmaceutically acceptable salts listed in Journal of
Pharmaceutical Science, 66, 2 (1977) and incorporated herein by
reference, or lithium, sodium, potassium, magnesium and the
like.
[0033] The term "5-, 6- or 7-membered heterocyclic system" as used
herein refers to: a monocyclic unsaturated or saturated system
containing one, two or three hetero atoms selected from nitrogen,
oxygen and sulfur and having 5 members, e.g. pyrrole, furan,
thiophene, pyrroline, dihydrofuran, dihydrothiophene, imidazole,
imidazoline, pyrazole, pyrazoline, oxazole, thiazole, isoxazole,
isothiazole, 1,2,3-oxadiazole, furazan, 1,2,3-triazole,
1,2,3-thiadiazole or 2,1,3-thiadiazole; an aromatic monocyclic
system containing two or more nitrogen atoms and having 6 members,
e.g. pyrazine, pyrimidine, pyridazine, 1,2,4-triazine,
1,2,3-triazine or tetrazine; a non-aromatic monocyclic system
containing one or more hetero atoms selected from nitrogen, oxygen
and sulfur and having 6 or 7 members, e.g. pyran, thiopyran,
piperidine, dioxane, oxazine, isoxazine, dithiane, oxathine,
thiazine, piperazine, thiadiazine, dithiazine, oxadiazine or
oxoazepane.
[0034] Alkyl refers to lower straight, cyclic, bicyclic, fused or
branched alkyl having 1 to 15 carbon atoms, preferentially 1 to 6
carbon atoms. Aryl refers to phenyl or phenyl substituted with
alkyl or phenyl, or phenyl fused with cycloalkyl, or polycyclic
aromatic systems such as naphthyl, anthracenyl, phenanthrenyl,
fluorenyl, etc. Alkylene refers to lower straight, cyclic, fused or
branched alkylene having 1 to 15 carbon atoms, preferentially 1 to
6 carbon atoms. Alkoxy refers to --O-alkyl and aryloxy refers to
--O-aryl. Cyano refers to --CN, hydroxy refers to --OH, amino
refers to --NH.sub.2 and nitro refers to --NO.sub.2. Dialkylamino
refers to --N(alkyl).sub.2. Alkylarylamino refers to
--N(alkyl)(aryl) and diarylamino refers to --N(aryl).sub.2. Halogen
refers to --F, --Cl, --Br and --I. Aralkyl refers to
-alkylene-aryl. Alkylthio refers to --S-alkyl and arylthio refers
to --S-aryl. Alkoxycarbonyl refers to --CO--O-alkyl and
aminocarbonyl refers to --CO--N(alkyl).sub.2, --CO--N(alkyl)(aryl)
or --CO--N(aryl).sub.2. Carbonylalkyl refers to --CO-alkyl. A
leaving group refers to a group or atom capable of existing in
solution as a negatively charged species, or a positively charged
group or atom.
[0035] 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, hypertension, ischemic heart diseases, angina
pectoris and coronary heart diseases; the pulmonary system; the
gastrointestinal system; the central nervous system and the
endocrinologic system.
[0036] The compounds of the present invention may also be used for
the treatment of diseases associated with decreased skeletal muscle
blood flow such as Reynauds disease and intermittent
claudication.
[0037] 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 ureter. Potassium channel openers also relax
urinary bladder smooth muscle, thus, the compounds of the present
invention can be used for the treatment of urinary
incontinence.
[0038] The present compounds could also be used for treatment of
conditions associated with disturbances in gastrointestinal
mobility such as irritable bowel syndrome. Additionally these
compounds can be used for the treatment of premature labor and
dysmenorrhea.
[0039] Further, potassium channel openers promote hairgrowth,
therefore, the compounds of the present invention can be used for
the treatment of baldness.
[0040] 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 encountered. This condition could lead to the
development of noninsulin dependent diabetes (NIDDM). It is
expected that potassium channel openers and hence the compounds of
the present invention can be used for counteracting 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.
[0041] 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 betacell rest which may prevent the
progression of the autoimmune disease.
[0042] Compounds of the present invention which act as blockers of
KATP -channels can be used for the treatment of NIDDM.
[0043] Preferably, the compounds of the present invention may be
used for treatment or prevention of diseases of the endocrinologic
system such as hyperinsulinemia and diabetes.
[0044] 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 acceptable
substance, preferably for use as a therapeutically acceptable
substance in the treatment of hyperinsulinemia and treatment or
prevention of diabetes.
[0045] Furthermore, the invention also relates to the use of the
inventive compounds of formula I as medicaments useful for treating
hyperinsulinemia and treating or preventing diabetes .
[0046] In yet another aspect, the present invention relates to a
method of preparing compounds of the invention.
[0047] The method comprises synthesis of cyanoenamines by the
following reaction scheme: 2
[0048] Acceptor substituted acetonitriles were reacted with
isothiocyanates in the presence of a base. The resulting salts of
the adducts were treated with alkyl halide to give the
corresponding alkylsulfanyl propenenitriles, which were reacted
with primary and secondary amines to give cyanoenamines of formula
I.
PRIOR ART
[0049] Some derivatives of
2-cyano-3-(dimethylamino)-3-arylamino-2-propene- nitriles have been
claimed to be angiotensin II antagonists (EP 591891, Chem. Abstr.
1995, 122, 81364; Chem. Abstr. 1994, 121, 300890). Example: 3
[0050] Other compounds containing this substructural element have
been claimed to be antithrombotics (EP 547517, Chem. Abstr. 1993,
119, 249845; Chem. Abstr. 1993, 119, 180666), e.g.: 4
[0051] Several
3-(arylamino)-3-(alkylamino)-2-cyano-2-propenenitriles and
-2-acrylamides have been claimed as fungicides and herbicides (EP
10396, Chem. Abstr. 1982, 97, 140276; Chem. Abstr. 1980, 93,
144701), some examples being: 5
[0052] The reaction of amines RR'NH with mono-imidates of
malononitrile of the general formula NC--CH.sub.2--C(OR).dbd.NH
give compounds of the type RR'N--C(NH.sub.2).dbd.CH--CN, where one
of the two amino groups is limited to be NH.sub.2 (Cocco, M. T.;
Congiu, C.; Maccioni, A.; Plumitallo, A., J. Heterocycl. Chem.,
1989, 26,1859-1862; Klemm, K.; Pruesse, W.; Baron, L.; Daltrozzo,
E., Chem. Ber., 1981, 114, 2001-2018; Cocco, M. T.; Onnis, V.,
Synthesis, 1993, 2, 199-201; Fanshawe, W. J. et al., J. Org. Chem.,
1964, 29, 308-311; Troschuetz, R.; Dennstedt, T., Arch. Pharm.
(Weinheim Ger.), 1994, 327, 85-90).
[0053] A further method consists in the reaction of 0-alkylated
cyanoacetamides with aliphatic amines (G. J. Durant et al., patent,
CH 606026, Chem. Abstr. 1979, 90, 87449, G. J. Durant, patent, U.S.
Pat. No. 4,024,260, Chem. Abstr., 1977, 87, 135327). Also the
reaction of 3,3-dimethoxyacrylonitrile with amines, which can be
carried out stepwise in order to prepare compounds of the general
formula RR'N--C(NR"R'").dbd.CH--CN, has been reported (G. J.
Durant, patent, U.S. Pat. No. 4,277,485, Chem. Abstr., 1981, 95,
156591) and used for the preparation of ranitidine-analogues.
[0054] Moreover, the reaction of 3,3-dichloroacrylonitrile with
amines has been reported to give cyanoenamines of the general
structure (RR'N).sub.2C.dbd.CH--CN, with two identical
amine-moieties RR'N-- (Hashimoto et al., J. Org. Chem., 1970, 35,
828-831; Takeda Chem.lnd.Ltd., JP 7022328, 1970, Chem.Abstr., 73,
98434z). In addition to these, some special methods for the
synthesis of these compounds have been described (e.g. Sasaki, T.;
Kojima, A. J. Chem. Soc. Sec. C, 1970, 476-480; Clark, J., Parvizi,
B., Southon, I. W., J. Chem. Soc., Perkin Trans. 1, 1976, 125-130;
Smith; Kline and French Lab. Lim, FR 2229417, DE 2423813, Chem.
Abstr., 82, 170943; Meyer; K., Justus Liebigs Ann. Chem., 1978,
1491; Elagamey, A. G. A.; El-Taweel, F. M. A., J. Prakt. Chem.,
1991, 333, 333-338).
[0055] For the preparation of 2-acceptor-substituted
3,3-bis(alkyl/arylamino)-2-propenenitriles, several different
synthetic methods have been described (Elvidge, J. A. et al., J.
Chem. Soc., Perkin Trans, I, 1983, 1741-1744; Yatsishin, A. A. et
al., Zh. Org. Khim. 1979, 15,1381-1384; Hartke, K., Angew. Chem.
1964, 76, 781)
PHARMACOLOGICAL METHODS
[0056] The ability of the compounds to interact with potassium
channels can be determined by various methods. When patch-clamp
techniques (Hamill O. P., Marty A., Nefer E., Sakman B. and
Sigworth F. J., Plugers Arch. 1981, 391, 85-100) are used the ionic
current through a single channel of a cell can be recorded.
[0057] The activity of the compounds as potassium channel openers
can also be measured as relaxation of rat aortas rings according to
the following procedure:
[0058] 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., 1994, 111,
42-48.
[0059] 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 phenylephrine. 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 potency of a compound was expressed as the
concentration required to evoke a 50% relaxation of the tissue.
[0060] In the pancreatic beta-cell the opening of the
K.sub.ATP-channels can be determined by measuring the subsequent
change in the concentration of cytoplasmic free Ca.sup.2+
concentration according to the method of Arkhammer P. et al. , J.
Biol. Chem. 1987, 262, 5448-5454.
[0061] .sup.86Rb.sup.+ efflux from a .beta.-cell Line
[0062] 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% CO.sub.2/95% air at
37.degree. C. The cells were detached with a Trypsin-EDTA solution
(from GibcoBRL, Scotland, UK), resuspended in medium, added 1
mCi/mL .sup.86Rb.sup.+ and replated into microtiter plates (96 well
cluster 3596, sterile, from Costar Corporation, Mass., USA) at a
density of 50000 cells/well in 100 .mu.l/well, and grown 24 hours
before use in assay.
[0063] The plates were washed 4 times with Ringer buffer (150 mM
NaCl, 10 mM Hepes, 3.0 mM KCl, 1.0 mM CaCl.sub.2, 20 mM sucrose, pH
7.1). Eighty .mu.L Ringer buffer and 1 .mu.L control- or test
compound dissolved in DMSO was added. After incubation 1 h at room
temperature with a lid, 50 .mu.L of the supernatant was transferred
to PicoPlates (Packard Instrument Company, Conn., USA) and 100
.mu.L MicroScint4o (Packard Instrument Company, Conn., USA) added.
The plates were counted in TopCount (Packard Instrument Company,
CT, USA) for 1 min/well at the .sup.32P program.
[0064] The calculation of EC.sub.50 and E.sub.max was done by
SlideWrite (Advanced Graphics Software, Inc., Calif., USA) using a
four parameter logistic curve: y=(a-d)/(1+(x/c).sup.b)+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. EC.sub.50=c and E.sub.max=d,
when the curve is turned of at infinite concentrations.
[0065] In addition the effect of K.sub.ATP-channel modulators on
pancreatic beta-cells can be determined by measuring the increase
or decrease in insulin release from insulin producing beta-cell
lines or isolated islets.
[0066] Effect of K.sub.ATP-channel modulators can be measured using
the following procedure:
[0067] The beta cells are cultured with change of media every
three-four days.
[0068] Cells are then seeded in 96 well microtiter dishes and
cultured for three day at 38.degree. C., 5% CO.sub.2 and 95%
humidity.
[0069] The cells are washed with NN -buffer (+10 mM Hepes+0.1% BSA)
for one minute and glucose (final conc. 22 mM), IBMX (final
conc.0.1 mM) and compounds (final conc. from 5.times.10.sup.-5
M-5.times.10.sup.-8 M) added. All cells are then incubated for
three hours (38.degree. C., 5% CO.sub.2 and 95% humidity).
[0070] Supernates are harvested into Greiner minisorb microtiter
wells and frozen. Insulin is measured using elisa-techniques.
[0071] The compounds of the present invention shows high
selectivity of the insulin release test compared to the relaxation
of rat aorta rings test.
[0072] The compounds according to the invention are effective over
a wide dosage range. In general satisfactory results are obtained
with dosages from about 0.05 mg to about 1000 mg, preferably from
about 0.1 mg to about 500 mg, per day. A most preferable dosage is
about 5 mg to about 200 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
treated, and the preference and experience of the physician or
veterinarian in charge.
[0073] The route of administration may be any route, which
effectively transports the active compound to the appropriate or
desired site of action, such as oral or parenteral e.g. rectal,
transdermal, subcutaneous, intravenous, intramuscular or
intranasal, the oral route being preferred.
[0074] 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 carrier
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, conventional techniques for
the preparation of pharmaceutical compositions may be used. For
example, the active compound will usually be mixed with a carrier,
or diluted by a carrier, or enclosed 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 compound can be
adsorbed on a granular solid container for example in a sachet.
Some examples of suitable carriers are water, salt solutions,
alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,
gelatine, lactose, amylose, magnesium stearate, talc, silicic acid,
fatty acid monoglycerides and diglycerides, pentaerythritol fatty
acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The
formulations may also include wetting agents, emulsifying and
suspending agents, preserving agents, sweetening agents or
flavoring agents. The formulations of the invention may be
formulated so as to provide quick, sustained, or delayed release of
the active ingredient after administration to the patient by
employing procedures well known in the art.
[0075] 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.
[0076] For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
[0077] 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 capsules include lactose, corn starch, and/or potato
starch. A syrup or elixir can be used in cases where a sweetened
vehicle can be employed.
[0078] A typical tablet, appropriate for use in this method, may be
prepared by conventional tabletting techniques and contains:
1 Active compound 5.0 mg Lactosum 67.8 mg Ph.Eur. Avicel .RTM. 31.4
mg Amberlite .RTM. 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.
[0079] Due to their high degree of activity, the compounds of the
invention may be administered to a mammal, especially a human, in
need of such treatment, prevention, elimination, alleviation or
amelioration of various diseases as mentioned above and especially
of diseases of the endocrinologic system such as hyperinsulinemia
and diabetes. Such mammals include also animals, both domestic
animals, e.g. household pets, and non-domestic animals such as
wildlife.
EXAMPLES
[0080] The process of preparing the compounds of formula I is
further illustrated in the following examples which, however, are
not to be construed as limiting.
Example 1
3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(1,2,-
2-trimethylpropylamino)-2-propenenitrile
[0081] 1)
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfony-
l)-3-methylsulfanyl-2-propenenitrile
[0082] To a solution of 4-chlorophenylsulfonylacetonitrile (1.10 g,
5.10 mmol) in dry acetone (12 ml) first dry potassium carbonate
(1.41 g, 10.2 mmol) and then 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (1,44 g, 5.31 mmol) were added. The resulting
mixture was stirred at room temperature under nitrogen for 1 h, and
then filtered. To the filtrate a solution of sodium
hydrogencarbonate (0.86 g) in water (15 ml) and methyl iodide
(0.945 ml, 15.3 mmol) was added. The mixture was stirred at room
temperature for 3.5 h. Then pH was adjusted to .about.4 with 1N
HCl. The precipitate was filtered off and washed with water to give
2.39 g (93%) of the title compound. Recrystallisation could be done
from ethyl acetate/heptane 1:3. Mp 150.5-152.5.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=2.25 (s, 3H), 7.57 (d, 2H), 7.79
(s, 2H), 7.83 (s, 1H), 7.88 (d, 2H), 10.0 (br s, 1H); MA calc for
C.sub.18H.sub.11CIF.sub.6- N.sub.2O.sub.2S.sub.2: C.sub.43.17%, H
2.21%, N 5.59%. Found: C.sub.43.25%, H 2.16%, N 5.59%.
[0083] 2)
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfony-
l)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
[0084]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred
in 1,2,2-trimethylpropylamine (1 ml) for 19 h at 75.degree. C.
under nitrogen. The reaction mixture was concentrated and the
residue dissolved in DCM, washed twice with 1N aqueous HCl and once
with water. The organic phase was dried (sodium sulfate) and
concentrated. The residue was crystallised from ethyl
acetate/heptane 1:3 to give 225 mg (68%) of the title compound. Mp
155.5-158.5.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H), 7.40 (s, 2H), 7.50
(d, 2H), 7.70 (s, 1H), 7.82 (d, 2H); MA calc for
C.sub.23H.sub.22CIF.sub.6N.sub.3O.sub.2S: C.sub.49.87%, H 4.00%, N
7.59%. Found: C.sub.49.86%, H 4.29%, N 7.55%.
Example 2
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-cyclo-
pentylamino-2-propenenitrile
[0085]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred
in cyclopentylamine (2 ml) at 80.degree. C. for 2 h and at room
temperature for 16 h under nitrogen. Work up as descriped in
Example 1, 2) gave 305 mg (71%) of the title compound as pale
yellow crystals. Mp 199-200.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=1.4-1.65 (m, 4H), 1.65-1.85 (m, 4H), 3.56
(sextet, 1H), 7.42 (s, 2H), 7.49 (d, 2H), 7.67 (s, 1H), 7.78 (d,
2H); MA calc for C.sub.22H.sub.18CIF.sub.6N.s- ub.3O.sub.2S:
C.sub.49.12%, H 3.37%, N 7.18%. Found: C.sub.48.93%, H 3.31%, N
7.58%.
Example 3
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-isopr-
opylamino-2-propenenitrile
[0086]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred
in isopropylamine (2 ml) at 80.degree. C. in a sealed flask for 20
h. Work up as described in Example 1, 2) gave 254 mg (62%) of the
title compound as white crystals. Mp 197-198.5.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=1.5 (d, 6H), 3.37 (m, 1H), 7.42
(s, 2H), 7.48 (d, 2H), 7.67 (s, 1H), 7.79 (d, 2H); MA calc for
C.sub.20H.sub.16CIF.sub.6N.s- ub.3O.sub.2S: C.sub.46.93%, H 3.15%,
N 8.21%. Found: C.sub.47.16%, H 3.14%, N 8.10%.
Example 4
3-[3,
5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-cycl-
obutylamino-2-propenenitrile
[0087]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl
)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred
in cyclobutylamine (0.70 ml) at 60.degree. C. for 20 h. Work up as
described in Example 1, 2) gave 354 mg (85%) of the title compound
as white crystals. Mp 190.5-193.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=1.5 (m, 2H), 1.72 (m, 1H), 2.0 (m, 3H), 3.63
(sextet, 1H), 7.42 (s, 2H), 7.48 (d, 2H), 7.67 (s, 1H), 7.79 (d,
2H); MA calc for C.sub.21H.sub.16CIF.sub.6N.sub.3O.sub.2S:
C.sub.48.15%, H 3.08%, N 8.02%. Found: C.sub.48.38%, H 3.09%, N
7.96%.
Example 5
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-propy-
lamino-2-propenenitrile
[0088]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)--
3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred
in n-propylamine (1.0 ml) at 75.degree. C. in a sealed flask for 19
h. Work up as described in Example 1, 2) gave 266 mg (65%) of the
title compound as white crystals. Mp 196.5-198.5.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=0.9 (t, 3H), 1.55 (p, 2H), 2.88
(q, 2H), 7.40 (s, 2H), 7.48 (d, 2H), 7.68 (s, 1H), 7.81 (d, 2H); MA
calc for C.sub.20H.sub.16CIF.sub.6N.sub.3O.sub.2S: C 46.93%, H
3.15%, N 8.21%. Found: C 46.82%, H 3.19%, N 8.10%.
Example 6
2-(4-Chlorophenylsulfonyl)-3-(pyridin-3-ylamino)-3-(1,2,2-trimethylpropyla-
mino)- 2-propenenitrile
[0089] 1)
2-(4-Chlorophenylsulfonyl)-3-methylsulfanyl-3-(pyridin-3-ylamino-
)-2-propenenitrile
[0090] To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g,
4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate
(1.28 g, 9.3 mmol) and then pyridin-3-yl isothiocyanate (0.663 g,
4.9 mmol) were added. The resulting mixture was stirred at room
temperature under nitrogen for 4 h, and then filtered. To the
filtrate methyl iodide (0.315 ml, 5.1 mmol) was added. The mixture
was stirred at room temperature for 16 h. The reaction mixture was
concentrated and the residue was taken up into ethyl acetate and
water. The organic layer was washed with 1N aqueous HCl (2.times.).
The organic phase was dried (sodium sulfate) and concentrated. The
residue was purified by flash chromatography using heptanelethyl
acetate 1:2 as eluent and recrystallisation in ethyl acetate to
give 294 mg (16%) of the title compound. Mp 181-182.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=2.20 (s, 3H), 7.36 (dd,
1H), 7.54 (dm, 2H), 7.6 (m, 1H), 7.88 (dm, 2H), 8.55 (m, 2H), 9.85
(br s, 1H); EI SP/MS: 365 (M+).
[0091] 2)
2-(4-Chlorophenylsulfonyl)-3-(pyridin-3-ylamino)-3-(1,2,2-trimet-
hylpropylamino)-2-propenenitrile
[0092]
2-(4-Chloro-phenylsulfonyl)-3-methylsulfanyl-3-(pyridin-3-ylamino)--
2-propenenitrile (0.186 g, 0.5 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 22 h at 100.degree. C. under
nitrogen. The reaction mixture was concentrated. The residue was
dissolved in DCM, washed with water, dried (sodium sulfate) and
concentrated. The crude product was purified by flash
chromatography using ethyl acetate as eluent to give 124 mg (58%)
of the title compound as a syrup, which could be crystallised from
ethyl acetate/heptane 2:1 to give 65 mg (30%). Mp 172-174.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=0.85 (s, 9H), 0.9 (d,
3H), 3.03 (m, 1H), 7.35 (m, 2H), 7.48 (d, 2H), 7.80 (d, 2H), 8.33
(br s, 1H), 8.5 (br s, 1H).
Example 7
2-(4-Chlorophenylsulfonyl)-3-(3, 5-dichlorophenylamino)-3-(1,
2,2-trimethylpropylamino)-2-propenenitrile
[0093] 1)
2-(4-Chlorophenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methyls-
ulfanyl-2-propenenitrile
[0094] To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g,
4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate
(1.28 g, 9.3 mmol) and then 3,5-dichlorophenyl isothiocyanate (0.99
g, 4.9 mmol) were added. The resulting mixture was stirred at room
temperature under nitrogen for 4 h, and then filtered. To the
filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture
was stirred at room temperature for 45 min. Then pH was adjusted to
1 with 1N aqueous HCl. The precipitate was filtered off and washed
with water to give 1.86 g (93%) of a crude product.
Recrystallisation from ethyl acetatelheptane (1:1) gave 1.42 g
(72%) of the title compound contaminated with
4-chlorophenylsulfonylaceto- nitrile. Mp 128-131.degree. C. .sup.1H
NMR (200 MHz, CDCl.sub.3): .delta.=2.25 (s, 3H), 7.20 (d, 2H), 7.30
(t, 1H), 7.55 (d, 2H), 7.85 (d, 2H), 9.80 (br s, 1H); EI SP/MS: 434
(M+), 436 (M+2).
[0095] 2)
2-(4-Chlorophenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-(1,2,2--
trimethylpropylamino)-2-propenenitrile
[0096]
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsul-
fanyl-2-propenenitrile (0.347 g, 0.8 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 22 h at 100.degree. C. under
nitrogen in a sealed flask. Work up as described in Example 1, 2)
gave 235 mg (60%) of the title compound. Mp 163-169.degree. C.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.9 (s, 9H), 1.0 (d,
3H), 3.05 (m, 1H), 6.85 (br s, 2H), 7.2 (br s, 1H), 7.50 (d, 2H),
7.78 (d, 2H); EI SP/MS: 485 (M+), 487 (M+2), 489 (M+4), 491
(M+6).
Example 8
3-(Benzo[1,3]dioxol-5-ylamino)-2-(4-chlorophenylsulfonyl)-3-(1,2,2-trimeth-
ylpropylamino)- 2-propenenitrile
[0097] 1)
3-(Benzo[1,3]dioxol-5-ylamino)-2-(4-chlorophenylsulfonyl)-3-meth-
ylsulfanyl-2-propenenitrile
[0098] To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g,
4.64 mmol) in dry acetone (10 ml) first dry potassium carbonate
(1.28 g, 9.3 mmol) and then 3,4-methylenedioxyphenyl isothiocyanate
(0.87 g, 4.9 mmol) were added. The resulting mixture was stirred at
room temperature under nitrogen for 4 h, and then filtered. To the
filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture
was stirred at room temperature for 50 min. Then pH was adjusted to
1 with 1N aqueous HCl. The precipitate was filtered off and washed
with water to give 1.12 g (59%) of the title compound. Mp
196-200.degree. C. .sup.1 H NMR (200 MHz, CDCl.sub.3): .delta.=2.22
(s, 3H), 6.05 (s, 2H), 6.68 (m, 2H), 6.80 (d, 1H), 7.53 (d, 2H),
7.87 (d, 2H), 9.80 (br s, 1H); EI SP/MS: 408 (M+).
[0099] 2)
3-(Benzo[1,3]dioxol-5-ylamino)-2-(4-chlorophenylsulfonyl)-3-(1,2-
,2-trimethyl-propylamino)- 2-propenenitrile
[0100]
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chlorophenylsulfonyl)-3-methylsu-
lfanyl-2-propenenitrile (0.327 g, 0.8 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 22 h at 100.degree. C. under
nitrogen in a sealed flask. Work up as described in Example 1, 2)
gave 182 mg (49%) of the title compound. Mp 160.5-162.degree. C.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.78 (s, 9H), 0.9 (d,
3H), 3.22 (m, 1H), 6.0 (br s, 2H), 6.48 (m, 2H), 6.78 (br d, 1H),
7.48 (d,2H), 7.83 (d, 2H). MA
C.sub.22H.sub.24CIN.sub.3O.sub.4S.0.30H.sub.2O (corrected
bruttoformula); calc 56.54%C.sub.5.31%H 8.99%N; found
56.47%C.sub.5.25%H 8.90%N
Example 9
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methylsulfonyl-3-(1,2,2-trimethy-
lpropylamino)-propenenitrile
[0101] 1)
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methanesulfonyl-3-meth-
ylsulfanyl-2-propenenitrile
[0102] To a solution of methanesulfonylacetonitrile (0.55 g, 4.6
mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g,
9.3 mmol) and then 3,5-bis(trifluorornethyl)phenyl isothiocyanate
(1,32 g, 4.7 mmol) were added. The resulting mixture was stirred at
room temperature under nitrogen for 4 h, and then filtered. To the
filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture
was stirred at room temperature for 2 h. The reaction mixture was
filtered and the filtrate was concentrated. The residue was
dissolved in dichloromethane and washed with water. The organic
layer was dried (sodium sulfate) and concentrated. The residue was
recrystallised from ethyl acetate/heptane 1:2 to give the title
compound (1.55 g, 83%). Mp 129-131.degree. C. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=2.35 (s, 3H), 3.25 (s, 3H), 7.77 (s, 2H), 7.80
(s, 1H)H), 9.90 (br s, 1H); EI SP/MS: 404 (M+).
[0103] 2)
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methylsulfonyl-3-(1,2,-
2-trimethylpropylamino)propenenitrile
[0104]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methylsulfonyl-3-methylsu-
lfanyl-2-propenenitrile (0.225 g, 0.56 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 22 h at 100.degree. C. under
nitrogen in a sealed flask. The reaction mixture was concentrated
and the residue dissolved in DCM, washed twice with 1N aqueous HCl
and once with water. The organic phase was dried (sodium sulfate)
and concentrated. The residue was crystallised from ethyl
acetate/heptane 1:4 to give 146 mg (57%) of the title compound. Mp
184.5-188.5.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=0.9 (s, 9H), 1.03 (d, 3H), 3.0 (m, 1H), 7.52 (s, 2H), 7.68
(s, 1H); EI SP/MS: 457 (M+).
Example 10
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-(1,2,2-trimethyl-
propylamino)-2-propenenitrile
[0105] 1)
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methyl-
sulfanyl-2-propenenitrile
[0106] To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g,
4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate
(1.28 g, 9.3 mmol) and then 3,5-dimethoxyphenyl isothiocyanate
(0.96 g, 4.9 mmol) were added. The resulting mixture was stirred at
room temperature under nitrogen for 2 h 15 min and then filtered.
To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The
mixture was stirred at room temperature for 4 h. The reaction
mixture was concentrated. The residue was dissolved in DCM, washed
with water, dried (Na.sub.2SO.sub.4) and concentrated. The residue
was crystallised from ethyl acetate/heptane 1:2 to give 1.27 g
(65%) of the title compound. Mp 119.5-123.degree. C.; .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta.=2.29 (s, 3H), 3.80 (s, 6H), 3.36 (m,
3H), 7.53 (d, 2H), 7.87 (d, 2H), 9.82 (brs, 1H); EI SP/MS: 424
(M+).
[0107] 2)
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-(1,2,2-
-trimethylpropylamino)- 2-propenenitrile
[0108] 2-(4-Chlorophenylsulfonyl)-3-(3,
5-dimethoxyphenylamino)-3-methylsu- lfanyl-2-propenenitrile (0.34
g, 0.8 mmol) was stirred in 1 ,2,2-trimethylpropylamine (1 ml) for
22 h at 75.degree. C. under nitrogen. Work up as described in
EXAMPLE 1, 2) gave 264 mg (72%) of the title compound. Mp
177.5-179.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=0.82 (s, 9H), 0.95 (d, 3H), 3.2 (m, 1H), 6.13 (d, 2H), 6.32
(t, 1H), 7.45 (d, 2H), 7.82 (d, 2H); EI SP/MS: 478 (M+).
Example 11
3-[N-(3,5-bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chlorophenylsulf-
onyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
[0109] 1)
3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chloro-
phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile
[0110] To a solution of 4-chlorophenylsulfonylacetonitrile (1.10 g,
5.1 mmol) in dry acetone (12 ml) first dry potassium carbonate
(1.41 g, 10.2 mmol) and then 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (1,44 g, 5.3 mmol) were added. The resulting mixture
was stirred at room temperature under nitrogen. After 2 h methyl
iodide (3.80 ml, 61.2 mmol) was added. The mixture was stirred at
room temperature for 18 h, followed by filtration and
concentration. Crystallisation from ethyl acetate/heptane 1:3 gave
0.52 g (20%) of the title compound. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=2.40 (s, 3H), 3.65 (s, 3H), 7.36 (s, 2H), 7.42
(d, 2H), 7.58 (s, 1H), 7.65 (d, 2H);); EI SP/MS: 514 (M+).
[0111] 2)
3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chloro-
phenylsulfonyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
[0112] To a solution of
3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamin-
o]-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile
(0.300 g, 0.58 mmol) in dry acetonitrile (2 ml) was added
1,2,2-trimethylpropylamin- e (0.12 g) and dry triethylamine (89
.mu.l). The mixture was stirred for 68 h at 80.degree. C. under
nitrogen. The reaction mixture was concentrated. Purification by
flash chromatography using ethyl acetate/heptane 1:4 and 1:3 as
eluent gave a syrup (142 mg) which was crystallised in
ethanol/water to give 110 mg (33%) of the title compound. Mp
151.5-154.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=0.9
(s, 9H), 1.10 (d, 3H), 3.10 (m, 1H), 3.30 (s, 3H), 7.10 (s, 2H),
7.46 (s, 1H), 7.55 (d, 2H), 7.85 (d, 2H), 8.1 (brd, 1H); MA calc
for C.sub.24H.sub.24CIF.sub.6N.sub.3O.sub.2S: C.sub.50.75%, H
4.26%, N 7.40%, Cl 6.24%. Found: C.sub.50.79%, H 4.28%, N 7.24%, Cl
6.19%.
Example 12
(1'S,
2'S)-3-[2-Benzyloxycyclopentylamino]-3-[3,5-bis(trifluoromethyl)phen-
ylamino]-2-(4-chlorophenylsulfonyl)-2-propenenitrile
[0113] 3-(3,5-Bis(trifluoromethyl
)phenylamino)-2-(4-chlorophenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.150 g, 0.3 mmol) was stirred
in (1S,2S)-2-benzyloxycyclopentylamine (0.3 ml) at 80.degree. C. in
a sealed flask for 20 h. Work up as described in Example 1, 2) gave
108 mg (53%) of the title compound as white crystals. .sup.1 H NMR
(300 MHz, CDCl.sub.3): .delta.=1.6-1.75 (m, 4H), 2.05 (m, 2H), 3.9
(m,1H), 4.1 (m, 1H), 4.5 (dd, 2H), 7.15 (s, 1H), 7.2 (m, 6H), 7.5
(d, 2H), 7.7 (m, 3H), 8.2 (s, 1H), 9.8 (s, 1H).
Example 13
(1'R,
2'R)-3-[2-Benzyloxycyclopentylamino]-3-[3,5-bis(trifluoromethyl)phen-
ylamino]-2-(4-chlorophenylsulfonyl)-2-propenenitrile
[0114]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)--
3-methylsulfanyl-2-propenenitrile (0.150 g, 0.3 mmol) was stirred
in (1R,2R)-2-benzyloxycyclopentylamine (0.3 ml) at 80.degree. C. in
a sealed flask for 20 h. Work up as described in Example 1, 2) gave
106 mg (51%) of the title compound as white crystals. .sup.1 H NMR
(300 MHz, CDCl.sub.3): .delta.=1.6-1.75 (m, 4H), 2.0 (m, 2H), 3.85
(m,1H), 4.15 (m, 1H), 4.5 (dd, 2H), 6.9 (s, 1H), 7.15-7.30 (m, 6H),
7.35 (d, 1H), 7.5 (d, 2H), 7.7 (d, 1H),8.5 (br s, 1H).
Example 14
(S)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(-
1,2,2-trimethylpropylamino)-2-propenenitrile
[0115]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)--
3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred
in (S)-1,2,2-trimethylpropylamine (0.2 ml) at 80.degree. C. in a
sealed flask for 20 h. Work up as described in Example 1, 2) gave
25 mg (11%) of the title compound as white crystals. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta.=0.95 (s, 9H), 1.15 (d, 3H), 3.0 (m,
1H), 7.40 (s, 2H), 7.50 (d, 2H), 7.70 (s, 1H), 7.82 (d, 2H).
Example 15
(S)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(-
1,2-dimethylpropylamino)-2-propenenitrile
[0116]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred
in (S)-1,2-dimethylpropylamine (0.2 ml) at 80.degree. C. in a
sealed flask for 20 h. Work up as described in Example 1, 2) gave
40 mg (18%) of the title compound as white crystals. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta.=0.85 (dd, 6H), 1.05 (d, 3H), 1.7 (m,
1H) 3.10 (m, 1H), 7.43 (s, 2H), 7.48 (d, 2H), 7.70 (s, 1H), 7.80
(d, 2H).
Example 16
(R)-3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulfonyl)-3-(-
1,2-dimethylpropylamino)-2-propenenitrile
[0117]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)--
3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred
in (R)-1,2-dimethylpropylamine (0.2 ml) at 80.degree. C. in a
sealed flask for 20 h. Work up as described in Example 1, 2) gave
30 mg (13%) of the title compound as white crystals.
[0118] .sup.1H NMR (300 MHz, CDCl.sub.3): d=0.9 (dd, 6H), 1.05 (d,
3H), 1.7 (m, 1H),3.15 (m,1H) 7.45 (s, 2H), 7.50 (d, 2H), 7.65 (s,
1H), 7.79 (d, 2H).
Example 17
Synthesis of
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulf-
onyl)- 3-(1,1-dimethylpropylamino)-2-propenenitrile
[0119]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred
in 1,1-dimethylpropylamine (1 ml) for 40 h at 60.degree. C. and for
43 h at 110.degree. C. under nitrogen. The reaction mixture was
concentrated and the residue dissolved in DCM, washed twice with 1N
aqueous HCl and once with water. The organic phase was dried
(sodium sulfate) and concentrated. The residue was purified by
flash chromatography using from ethyl acetate/heptane 1:2 as eluent
followed recrystallisation from ethyl acetate/heptane 1:2 to give
25 mg (8%) of the title compound. Mp 205-207.degree. C. .sup.1H NMR
(200 MHz, CDCl3): .delta.=0.98 (t, 3H), 1.54 (s, 6H), 1.68 (q, 2H),
7.10 (s, 2H), 7.53 (d, 2H), 7.60 (s, 1H), 7.81 (d, 2H); EI SP/MS:
539 (M+).
Example 18
Synthesis of
3-[3,5-Bis(trifluoromethyl)phenylamino]-2-(4-chlorophenylsulf-
onyl)-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-2-propenenitrile
[0120] To a solution of
3-(3,5-bis(trifluoromethyl)phenylamino)-2-(4-chlor-
o-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6
mmol) in dry acetonitrile (1.0 ml), triethylamine (0.100 ml, 0.7
mmol) and 5-amino-3-cyclopropyl-1-methyl pyrazole (0.100 g, 0.7
mmol) were added. The reaction mixture was stirred for 41 h at
80.degree. C. under nitrogen and then concentrated. The residue was
worked up as described in Example 17,2) to give 90 mg (25%) of the
title compound. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.7 (m,
2H), 0.9 (m, 2H), 1.85 (m, 1H), 3.5 (s, 3H), 5.3 (s, 1H), 5.4 (s,
1H), 5.85 (s, 1H), 7.28 (s, 2H), 7.53 (d, 2H), 7.63 (s, 1H), 7.8
(d, 2H); El SP/MS: 589 (M+).
Example 19
Synthesis of
(R)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-(4-chlorophenyl-
sulfonyl)-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
[0121]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-
-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred
in (R)-1,2,2-trimethylpropylamine (1 ml) for 17 h at 75.degree. C.
under nitrogen. Work-up as described in Example 17, 2) gave 131 mg
(39%) of the title compound. Mp 164-165.degree. C. .sup.1H NMR (200
MHz, CDCl.sub.3): .delta.=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H),
7.37 (s, 2H), 7.50 (d, 2H), 7.68 (s, 1H), 7.80 (d, 2H); Analysis:
calc. for C.sub.23H.sub.22CIF.sub.6N.sub.3O.sub.2S: C.sub.49.87%, H
4.00%, N 7.59%. Found: C.sub.49.95%, H 4.15%, N 7.48%.
Example 20
Synthesis of
3-(3,5-Bis(trifluoromethyl)phenylamino)-3-isopropylamino-2-me-
thylsulfonyl-propenenitrile
[0122]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methanesulfonyl-3-methyls-
ulfanyl-2-propenenitrile (0.323 g, 0.8 mmol) was stirred in
isopropylamine (1 ml) for 17 h at 75.degree. C. under nitrogen.
Work-up as described in Example 17, 2) without chromatography gave
247 mg (74%) of the title compound. Mp 188.5-191.degree. C. .sup.1H
NMR (200 MHz, CDCl.sub.3): .delta.=1.15 (d, 6H), 3.15 (s, 3H), 3.40
(m, 1H), 7.56 (s, 2H), 7.68 (s, 1H). Analysis: caic. for
C.sub.15H.sub.15F.sub.6N.sub.3O.sub.2S: C.sub.43.38%, H 3.64%, N
10.12%. Found: C.sub.43.52%, H 3.63%, N 9.98%.
Example 21
Synthesis of
(R)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-methanesulfonyl-
-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
[0123]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2methanesulfonyl)-3-methyls-
ulfanyl-2-propenenitrile (0.250 g, 0.6 mmol) was stirred in
(R)-1,2,2trimethylpropylamine (1 ml) for 17 h at 75.degree. C. and
17 h at 100.degree. C. under nitrogen. Work-up as described in
Example 17, 2) without chromatography gave 104 mg (38%) of the
title compound. Mp 181-181.5.degree. C. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=0.9 (s, 9H), 1.03 (d, 3H), 3.0 (m, 1H), 3.15
(s, 3H), 7.52 (s, 2H), 7.71 (s, 1H); Analysis: calc. for
C.sub.18H.sub.21F.sub.6N.sub.3O.sub.2S: C.sub.47.26%, H 4.63%, N
9.19%. Found: C.sub.47.43%, H 4.75%, N 9.12%.
Example 22
Synthesis of
(S)-3-[3,5-bis(trifluoromethyl)phenylamino]-2-methanesulfonyl-
-3-(1,2,2-trimethylpropylamino)-2-propenenitrile
[0124]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methanesulfonyl)-3-methyl-
sulfanyl-2-propenenitrile (0.250 g, 0.6 mmol) was stirred in
(S)-1,2,2-trimethylpropylamine (1 ml) for 19 h at 75.degree. C. and
4 days at room temperature under nitrogen. Work-up as described in
Example 17, 2 ) without chromatography gave 71 mg (26%) of the
title compound. Mp 180.5-181.5.degree. C. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=0.9 (s, 9H), 1.03 (d, 3H), 3.0 (m, 1H), 3.15
(s, 3H), 7.52 (s, 2H), 7.71 (s, 1H); Analysis: calc. for
C.sub.18H.sub.21F.sub.6N.sub.3O.sub.2S: C.sub.47.26%, H 4.63%, N
9.19%. Found: C.sub.47.48%, H 4.76%, N 9.18%.
Example 23
Synthesis of
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-(1,-
1-dimethylpropylamino)-2-propenenitrile
[0125]
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methylsul-
fanyl-2-propenenitrile (0.30 g, 0.7 mmol) was stirred in
1,1-dimethylpropylamine (1 ml) for 17 h at 100.degree. C. in a
sealed flask under nitrogen. Work-up as described in Example 17, 2)
without chromatography gave 84 mg (26%) of the title compound. Mp
189-190.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.95
(t, 3H), 1.35 (s, 6H), 1.65 (q, 2H), 3.62 (s, 6H), 5.88 (d, 2H),
6.20 (t, 1H) 6.45 (br s, 1H), 7.0 (br s, 1H), 7.50 (dt, 2H), 7.83
(dt, 2H); Analysis: calc. for C.sub.22H.sub.26CIN.sub.30.sub.4S:
C.sub.59.96%, H 5.65%, N 9.06%. Found: C.sub.56.82%, H 5.64%, N
8.90%.
Example 24
Synthesis of
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-cyc-
lobutylamino-2-propenenitrile
[0126] 4-(Chlorophenylsulfonyl)-3-(3,5-d
imethoxyphenylamino)-3-methylsulf- anyl-2-propenenitrile (0.99 g,
2.4 mmol), cyclobutylamine (0.60 ml, 7.2 mmol) and acetonitrile (4
ml) was stirred for 17 h at 100.degree. C. in a sealed flask under
nitrogen. Work-up as described in Example 17, 2) without
chromatography gave 0.90 g (83%) of the title compound. Mp
163.5-164.5.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=1.6 (m, 2H), 1.85 (m, 2H), 2.1 (m, 2H), 3.77 (s, 6H), 3.8
(m, 1H), 6.12 (d, 2H), 6.32 (t, 1H), 7.47 (dt, 2H), 7.81 (dt, 2H);
Analysis: calc. for C.sub.21H.sub.22CIN.sub.3O.sub.4S: C 56.31%, H
4.95%, N 9.38%. Found: C.sub.56.40%, H 4.99%, N 9.30%.
Example 25
Synthesis of 3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-(1,
2,2-trimethylpropylamino)-propenenitrile
[0127] 1)
3-(3,5-Dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl--
2-propenenitrile
[0128] To a solution of methanesulfonylacetonitrile (0.55 g, 4.6
mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g,
9.3 mmol) and then 3,5-dimethoxyphenyl isothiocyanate (0.96 g, 4.9
mmol) were added. The resulting mixture was stirred at room
temperature under nitrogen for 23 h, then filtered and washed with
ethanol. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was
added. The mixture was stirred at room temperature for 4 h. The
reaction mixture was filtered and the filtrate was concentrated.
The residue was dissolved in dichloromethane and washed with water.
The organic layer was dried (sodium sulfate) and concentrated. The
residue was recrystallised from ethyl acetate to give the title
compound (0.728 g, 48%). .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=2.27 (s, 3H), 3.19 (s, 3H), 3.80 (s, 6H), 6.48 (t, 1H),
6.44 (d, 2H) EI SP/MS: 328 (M+).
[0129] 2)
3-(3,5-Dimethoxyphenylamino)-2-methanesulfonyl-3-(1,2,2-trimethy-
lpropvlamino)propenenitrile
[0130]
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-p-
ropenenitrile (0.263 g, 0.8 mmol) was stirred in
1,2,2-trimethylpropylamin- e (1 ml) for 17 h at 75.degree. C. under
nitrogen. Work-up as described in Example 17, 2) gave the title
compound as a syrup, 262 mg (86%). .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=0.85 (s, 9H), 1.01 (d, 3H), 3.12 (s, 3H), 3.26
(m, 1H), 3.78 (s, 6H), 6.25 (d, 2H), 6.35 (t, 1H); EI SP/MS: 381
(M+).
Example 26
Synthesis of
3-(3,5-dimethoxyphenylamino)-3-isopropyl-2-methanesulfonyl-pr-
openenitrile
[0131]
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-p-
ropenenitrile (0.263 g, 0.8 mmol) was stirred in isopropylamine (1
ml) for 17 h at 75.degree. C. under nitrogen. Work-up as described
in Example 17, 2) to give the title compound syrup, 209 mg (77%).
Mp 135-136.5.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=1.15 (s, 6H), 3.10 (s, 3H), 3.5 (m, 1H), 3.78 (s, 6H), 6.25
(br s, 2H), 6.33 (br s, 1H); Analysis: calc. for
C.sub.15H.sub.21N.sub.3O.sub.4S: C.sub.53.08%, H 6.24%, N 12.38%.
Found: C.sub.53.38%, H 6.26%, N 12.31%.
Example 27
Synthesis of 3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,
1-dimethyl-propylamino)--
2-(4-chloro-phenylsulfonyl)-propenenitrile
[0132] 1)
3-(Benzor1,31dioxol-5-ylamino)-2-(4-chlorophenylsulfonyl)-3-meth-
ylsulfanyl-2-propenenitrile
[0133] To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g,
4.64 mmol) in dry acetone (10 ml) first dry potassium carbonate
(1.28 g, 9.3 mmol) and then 3,4-methylenedioxyphenyl isothiocyanate
(0.87 g, 4.9 mmol) were added. The resulting mixture was stirred at
room temperature under nitrogen for 4 h, and then filtered. To the
filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture
was stirred at room temperature for 50 min. Then pH was adjusted to
1 with 1N aqueous HCl. The precipitate was filtered off and washed
with water to give 1.12 g (59%) of the title compound. Mp
196-200.degree. C. (decomp.); .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=2.22 (s, 3H), 6.05 (s, 2H), 6.68 (m, 2H), 6.80 (d, 1H),
7.53 (d, 2H), 7.87 (d, 2H), 9.80 (br s, 1H); EI SP/MS: 408
(M+).
[0134] 2)
3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1-dimethyl-propylamino)-2-(4-
-chlorophenylsulfonyl)-propenenitrile
[0135]
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chloro-phenylsulfonyl)-3-methyls-
ulfanyl-2-propenenitrile (0.327 g, 0.8 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 17 h at 100.degree. C. under
nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2)
without chromatography gave 81 mg (26%) of the title compound. Mp
169-170.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.95
(t, 3H), 1.37 (s, 6H), 1.65 (q, 2H), 5.98 (s, 1H), 6.2 (m, 2H),
6.45 (br s, 1H), 6.66 (d, 1H), 6.98 (br s, I H), 7.50 (d, 2H), 7.80
(d, 2H). Analysis: calc. for C.sub.21H.sub.22CIN.sub.3O.sub.4S
0.50H.sub.2O (corrected formula): C.sub.55.20%, H 5.07%, N 9.20%;
Found: C.sub.55.18%, H 4.90%, N 8.90%.
Example 28
Synthesis of
3-(Benzo[1,3]dioxol-5-ylamino)-3-cyclobutylamino-2-(4-chlorop-
henylsulfonyl)-propenenitrile
[0136]
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chloro-phenylsulfonyl)-3-methyls-
ulfanyl-2-propenenitrile (0.29 g, 0.7 mmol) was stirred in
cyclobutylamine (0.6 ml 7.0 mmol) for 17 h at 100.degree. C. under
nitrogen in a sealed flask. The reaction mixture was concentrated
and the residue was crystallised from ethyl acetate to give 88 mg
(29%) of the title compound. Mp 189.50C. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=1.6 (m, 2H), 1.75 (m, 2H), 2.05 (m, 2H), 3.80
(m, 1H), 6.02 (s, 2H), 6.5 (m, 2H), 6.79 (d, 2H), 7.50 (dt, 2H),
7.83 (dt, 2H). Analysis: calc. for
C.sub.20H.sub.18CIN.sub.3O.sub.4S: C.sub.55.62%, H 4.20%, N 9.73%;
Found: C.sub.55.59%, H 4.21%, N 9.59%.
Example 29
Synthesis of
2-(4-Chlorophenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-(1,1-
-dimethylpropylamino)-2-propenenitrile
[0137]
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsul-
fanyl-2-propenenitrile (0.359 g, 0.8 mmol) was stirred in
1,2,2-trimethylpropylamine (0.125 ml) for 22 h at 50.degree. C. and
for 18 h at 80.degree. C. under nitrogen in a sealed flask. Work-up
as described in EXAMPLE 17, 2) gave 64 mg (17%) of the title
compound. Mp 189-191.5.degree. C. (EtOAc). .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=0.99 (t, 3H), 1.38 (s, 6H), 1.68 (q, 2H), 6.26
(br s, 1H), 6.50 (d, 2H), 7.10 (t, 1H), 7.55 (dt, 2H), 7.81 (dt,
2H); El SP/MS: 475 (M+4), 473 (M+2), 471 (M+).
Example 30
Synthesis of
2-(4-Chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5-dichlorop-
henylamino)-2-propenenitrile
[0138]
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsul-
fanyl-2-propenenitrile (0.90 g, 2.1 mmol), cyclobutylamine (0.50
ml, 6.3 mmol) and acetonitrile (2 ml) were stirred for 40 h at
100.degree. C. under nitrogen in a sealed flask. Work-up as
described in EXAMPLE 17, 2) gave 0.47 g (49%) of the title
compound. 179.5-181.5.degree. C. (EtOAc) .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=1.65 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 3.65
(sextet, 1H), 6.88 (d, 2H), 7.18 (t, 1H), 7.47 (d, 2H), 7.78 (d,
2H); EI SP/MS: 459 (M+4), 357 (M+2) 455 (M+).
Example 31
Synthesis of
3-sec-Butylamino-2-(4-chlorophenylsulfonyl)-3-(3,5-dichloroph-
enylamino)-2-propenenitrile
[0139] 2-(4-Chloro-phenylsulfonyl)-3-(3,5-d
ichlorophenylamino)-3-methylsu- lfanyl-2-propenenitrile (0.50 g,
1.2 mmol) was stirred in 2-aminobutane (1 ml) for 17h at
100.degree. C. under nitrogen in a sealed flask. Work-up as
described in EXAMPLE 17, 2) without chromatography gave 0.38 g
(69%) of the title compound. Mp 150-152.degree. C. .sup.1H NMR (200
MHz, CDCl.sub.3): .delta.=0.85 (t, 3H), 1.06 (d, 3H), 1.48 (p, 2H),
3.25 (m, 1H), 6.90 (d, 2H), 7.20 (t, 1H), 7.47 (d, 2H), 7.78 (d,
2H); EI SP/MS: 457 (M+), 459 (M+2), 461 (M+4).
Example 32
Synthesis of
3-(3-Methoxy-5-trifluoromethyl-phenylamino)-2-methylsulfonyl--
3-(1,2,2-trimethylpropylamino)-propenenitrile
[0140] 1)
3-(3-Methoxy-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-m-
ethylsulfanyl-propenenitrile
[0141] To a solution of 3-methoxy-5-trifluoromethyl-anilin (1.50 g,
7.8 mmol) in dry ethyl acetate (10 ml) thiophosgene (0.20 ml, 2.6
mmol) was added dropwise. After stirring for 1.5 h at 75.degree. C.
the reaction mixture was cooled on an ice bath and then filtered.
The filtrate was concentrated. The residue was dissolved in dry
acetone (5 ml) and added to a suspension of
methanesulfonylacetonitrile (0.34 g, 2.6 mmol) and dry potassium
carbonate (0.72 g, 5.2 mmol) in dry acetone (5 ml). The resulting
mixture was stirred at room temperature under nitrogen for 19 h,
and then filtered. To the filtrate methyl iodide (0.49 ml, 7.8
mmol) was added. The mixture was stirred at room temperature for
1.5 h. The reaction mixture was concentrated and the residue was
taken up into dichloromethane and water. The organic layer was
washed with water (2.times.), dried (sodium sulfate) and
concentrated. The residue was recrystallised from ethyl acetate to
give 0.70 g (73%) of the title compound. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=2.28 (s, 3H), 3.22 (s, 3H), 3,87 (s, 3H), 7.0
(t, 1H), 7.05 (br s, 1H), 7.14 (br s, 1H), 9.8 (br s, 1H); El
SP/MS: 366 (M-2).
[0142] 2)
3-(3-Methoxy-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-(-
1,2,2-trimethylpropylamino)-acrylonitrile
[0143]
3-(3-Methoxy-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-meth-
ylsulfanyl-propenenitrile (0.22 g, 0.6 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 17 h at 75.degree. C. under
nitrogen. Work-up as described in EXAMPLE 17, 2) without
chromatography gave 100 mg (40%) of the title compound. Mp
110-113.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.87
(s, 9H), 1.01 (d, 3H), 3.08 (m, 1H), 3.10 (s, 3H), 3.87 (s, 3H),
6.81 (br s, 1H), 6.95 (br s, 1H), 6.97 (br s, 1H); Analysis: calc.
for C.sub.18H.sub.24N.sub.3O.sub.3S: C.sub.51.54%, H 5.77%, N
10.02%; Found: C.sub.51.77%, H 6.05%, N 9.80%.
Example 33
Synthesis of
3-(3-Fluoro-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-
-(1,2,2-trimethylpropylamino)-propenenitrile
[0144] 1)
3-(3-Fluoro-5-trifluoromethylphenylamino)-2-methylsulfonyl-3-met-
hylsulfanyl-propenenitrile
[0145] To a solution of 3-fluoro-5-trifluoromethyl-anilin (1.50 g,
8.3 mmol) in dry ethyl acetate (5 ml) thiophosgene (0.215 ml, 2.8
mmol) was added dropwise. After stirring for 1.5 h at 75.degree.
C., the reaction mixture was cooled on an ice bath and then
filtered. The filtrate was concentrated. The residue was dissolved
in dry acetone (5 ml) and added to a suspension of
methanesulfonylacetonitrile (0.33 g, 2.8 mmol) and dry potassium
carbonate (0.77 g, 5.6 mmol) in dry acetone (5 ml). The resulting
mixture was stirred at room temperature under nitrogen for 22 h,
and then filtered. To the filtrate methyl iodide (0.525 ml, 8.4
mmol) was added. The mixture was stirred at room temperature for 2
h. The reaction mixture was filtered, the filtrate was concentrated
and the residue was taken up into dichloromethane and water. The
organic layer was washed with water (2.times.), dried (sodium
sulfate) and concentrated. The residue was recrystallised from
ethyl acetate to give 0.297 g (30%) of the title compound. .sup.1H
NMR (200 MHz, CDCl.sub.3): .delta.=2.32 (s, 3H), 3.21 (s, 3H), 7.28
(s, 1H), 7.32 (br s, 1H), 7.37 (br s, 1H), 9.85 (br s, 1H); El
SP/MS: 354 (M+).
[0146] 2)
3-(3-Fluoro-5-trifluoromethyl-phenylamino)-2-methylsulfonyl-3-(1-
,2,2-trimethylpropylamino)-propenenitrile
[0147]
3-(3-Fluoro-5-trifluoromethylphenylamino)-2-methylsulfonyl-3-methyl-
sulfanyl-propenenitrile (0.176 g, 0.5 mmol) was stirred in
1,2,2-trimethylpropylamine (1 ml) for 17 h at 75.degree. C. under
nitrogen. Work-up as described in EXAMPLE 17, 2) without
chromatography gave 98 mg (49%) of the title compound. Mp
183-185.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.87
(s, 9H), 1.03 (d, 3H), 3.05 (m, 1H), 3.13 (s, 3H) 7.02 (brd, 1H),
7.15 (m, 2H); EI SP/MS: 407 (M+).
Example 34
Synthesis of
3-(4-Chlorophenylamino)-2-methylsulfonyl-3-(1,2,2-trimethylpr-
opylamino)-acrylonitrile
[0148] 1)
3-(4-Chlorophenylamino)-2-methylsulfonyl-3-methylsulfanyl-propen-
enitrile
[0149] To a solution of methanesulfonylacetonitrile (0.55 g, 4.9
mmol) in dry acetone (5 ml) first dry potassium carbonate (1.28 g,
9.3 mmol) and then 4-chlorophenyl isothiocyanate (0.78 g, 4.6 mmol)
were added. The resulting mixture was stirred at room temperature
under nitrogen for 22 h, and then filtered. To the filtrate methyl
iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at
room temperature for 2 h. The precipitate was filtered off, the
filtrate was concentrated. The residue was taken up into
dichloromethane and water. The organic layer was washed with water
(2.times.), dried (sodium sulfate) and concentrated.
Crystallisation from ethyl acetate gave 1.114 g (80%) of the title
compound. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=2.25 (s, 3H),
3.20 /s, 3H), 7.25 (d, 2H), 7.41 (d, 2H), 9.70 (br s, 1H); EI
SP/MS: 302 (M+), 304 (M+2).
[0150] 2)
3-(4-Chlorophenylamino)-2-methylsulfonyl-3-(1,2,2-trimethylpropy-
lamino)-propenenitrile
[0151]
3-(4-Chlorophenylamino)-2-methylsulfonyl-3-methylsulfanyl-propeneni-
trile (0.242 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine
(1 ml) for 17 h at 75.degree. C. under nitrogen. Work-up as
described in EXAMPLE 17, 2) without chromatography gave 0.240 g
(85%) of the title compound. Mp 160.5-161.5.degree. C. .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta.=0.87 (s, 9H), 0.97 (d, 3H), 3.1 (m,
4H), 7.07 (d, 1H), 7.49 (d, 2H); Analysis: calc. for
C.sub.16H.sub.22CIN.sub.3O.sub.2S: C.sub.54.00%, H 6.23%, N 11.81%;
Found: C.sub.54.26%, H 6.33%, N 11.76%.
Example 35
Synthesis of
3-(Benzothiazol-6-ylamino)-3-(1,1-dimethyl-propylamino)-2-met-
hylsulfonyl-propenenitrile
[0152] 1)
3-(benzothiazol-6-ylamino)-2-methylsulfonyl-3-methylsulfanyl-pro-
penenitrile
[0153] To a solution of 6-aminobenzothiazole (1.00 g, 6.7 mmol) in
dry ethyl acetate (10 ml) thiophosgene (0.170 ml, 2.2 mmol) was
added dropwise. After stirring for 1.5 h at 75.degree. C., the
reaction mixture was cooled on an ice bath and then filtered. The
filtrate was concentrated. The residue was dissolved in dry acetone
(5 ml) and added to a suspension of methanesulfonylacetonitrile
(0.264 g, 2.2 mmol) and dry potassium carbonate (0.61 g, 4.4 mmol)
in dry acetone (10 ml). The resulting mixture was stirred at room
temperature under nitrogen for 70 h, and then filtered. To the
filtrate methyl iodide (0.415 ml, 6.7 mmol) was added. The mixture
was stirred at room temperature for 4.5 h. The reaction mixture was
filtered, the filtrate was concentrated and the residue was taken
up into dichloromethane and water. The organic layer was washed
with water (2.times.), dried (sodium sulfate) and concentrated. The
residue was recrystallised from ethyl acetate to give 0.219 g (11%)
of the title compound. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=2.25 (s, 3H), 3.20 (s, 3H), 7.45 (dd,1H), 7.93 (d, 1H),
8.16 (d, 1H), 9.05 (s, 1H), 9.95 (brs, 1H); EI SP/MS: 325 (M+).
[0154] 2)
3-(Benzothiazol-6-ylamino)-3-(1,1-dimethyl-propylamino)-2-methyl-
sulfonyl-propenenitrile
[0155]
3-(Benzothiazol-6-ylamino)-2-methylsulfonyl-3-methylsulfanyl-propen-
enitrile (0.167 g, 0.5 mmol) was stirred in 1,1-dimethylpropylamine
(0.5 ml) for 17 h at 100.degree. C. under nitrogen in a sealed
flask. Work-up as described in EXAMPLE 17, 2) without
chromatography gave 60 mg (33%) of the title compound. Mp
112-114.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=1.00
(t, 3H), 1.39 (s, 6H), 1.65 (q, 2H), 3.12 (s, 3H) 7.29 (dd, 1H),
7.70 (d, 1H), 8.13 (d, 1H), 9.0 (s, 1H); EI SP/MS: 364 (M+).
Example 36
Synthesis of
3-(Benzo[1,3]dioxol-5-ylamino)-2-(2,2-dimethyl-propionyl)-3-(-
1,1-dimethyl-propylamino)-propenenitrile
[0156] 1)
3-(Benzo[1,3]dioxol-5-ylamino)-2-(2,2-dimethyl-propionyl)-3-meth-
ylsulfanyl-propenenitrile
[0157] To a solution of 4,4-dimethyl-3-oxopentanenitrile (0.626 g,
5.0 mmol) in dry acetone (10 ml) first potassium carbonate (1.38 g,
10 mmol) and then 3,4-methylendioxyphenyl isothiocyanate (0.941 g,
5.3 mmol) were added. The resulting mixture was stirred at room
temperature under nitrogen for 72 h, and then filtered. To the
filtrate methyl iodide (0.93 ml, 15 mmol) was added. The mixture
was stirred at room temperature for 45 min. The precipitate was
filtered off and the filtrate was concentrated. The residue was
taken up into dichloromethane and water. The organic layer was
washed with water (2.times.), dried (sodium sulfate) and
concentrated. Crystallisation from ethyl acetate/heptane 1:1 gave
1.56 g (98%) of the title compound. Mp 139-141.degree. C.; .sup.1H
NMR (200 MHz, CDCl.sub.3). .delta.=1.40 (s, 9H), 2.28 (s, 3H), 6.03
(s, 2H), 6.75 (dd, 1H), 6.8 (m, 2H), 13.5 (br s, 1H); EI SP/MS: 318
(M+).
[0158] 2)
3-(Benzo[1,3]dioxol-5-ylamino)-2-(2,2-dimethyl-propionyl)-3-(1,1-
-dimethyl-propylamino)-propenenitrile
[0159]
3-(Benzo[1,3]dioxol-5-ylamino)-2-(2,2-dimethyl-propionyl)-3-methyls-
ulfanyl-propenenitrile (0.500 g, 1.6 mmol) 1,1-dimethylpropylamine
(0.275 ml, 2.4 mmol), triethylamine (0.335 ml, 2.4 mmol) in
acetonitrile (1 ml) were stirred for 65 h at 100.degree. C. under
nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2)
without chromatography gave 0.130 g (23%) of the title compound. Mp
161-165.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.96
(t, 3H), 1.30 (s, 9H), 1.35 (s, 6H), 1.65 (q, 2H), 5.98 (s, 2H),
6.57 (dd, 1H), 6.65 (d, 1H), 6.77 (d, 1H), 9.9 (br s, 1H); EI
SP/MS: 357 (M+).
Example 37
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-(1,
2,2-trimethylpropylamino)-2-propenenitrile
[0160] 1)
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfan-
yl-2-propenenitrile
[0161] A solution of 4-chlorophenylsulfonylacetonitrile (1.0 g,
4.64 mmol) in dry acetone (10 ml) was stirred while dry potassium
carbonate (1.28 g, 9.28 mmol) and 3-cyanophenyl isothiocyanate
(0.78 g, 4.87 mmol) were added. The resulting mixture was stirred
at room temperature under nitrogen for 20 h. Excess of potassium
carbonate was filtered off, methyl iodide (0.859 ml, 13.9 mmol) was
added to the filtrate, and stirring was continued for 3 h. The
mixture was evaporated and the residue was dissolved in
dichloromethane and extracted with water and brine. The organic
phase was dried over magnesium sulphate, filtered and evaporated to
afford 1.74 g (96%) of the title compound as golden brown crystals.
Mp 168-170.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=2.22 (s, 3H), 7.50-7.68 (m, 6H), 7.84-7.93(m, 2H),9.89
(brs, 1H).
[0162] 2)
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-(1,2,2-trime-
thylpropylamino)-2-propenenitrile
[0163]
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl--
2-propenenitrile (0.300 g, 0.6 mmol) was stirred in
2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100.degree. C. under
nitrogen in a sealed flask. The reaction mixture was concentrated
and the residue dissolved in dichloromethane, washed twice with 1N
aqueous HCl, once with brine, and once with water. The organic
phase was dried (sodium sulphate) and concentrated. The residue was
trituated with ether to afford a white crystalline substance which
was further purified by flash chromatography (SiO.sub.2) using
heptane/ethyl acetate (1:1) to yield 85 mg (25%) of the title
compound. Mp 80-82.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=0.90 (s, 9H), 1.02 (d, 3H), 3.02 (m, 1H), 7.27 (s, 2H),
7.47 (d, 2H), 7.51 (d,2H), 7.81 (d, 2H);
Example 38
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-cyclopentylamino-2-pro-
penenitrile
[0164]
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl--
2-propenenitrile (0.300 g, 0.6 mmol) was stirred in
cyclopentylamine (1 ml) for 48 h at 100.degree. C. under nitrogen
in a sealed flask. Work up as described in Example 1, 2) gave 51 mg
(16%) of the title compound as light brown crystals. .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta.=1.43-1.54 (m, 4H), 1.68-1.78 (m,
4H), 3.64 (sextet, 1H), 7.07 (d, 1H), 7.21 (s, 1H), 7.40-7.55 (m,
6H), 7.77 (dd, 2H)
Example 39
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino-3-(1,2-dimethylpropylamin-
o)-2-propenenitrile
[0165]
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl--
2-propenenitrile (0.300 g, 0.6 mmol) was stirred in
cyclopentylamine (1 ml) for 48 h at 100.degree. C. under nitrogen
in a sealed flask. Work up as described in Example 37, 2) gave 44
mg (13%) of the title compound as white crystals. .sup.1H NMR (200
MHz, CDCl.sub.3): .delta.=0.85 (dd, 6H), 1.01 (d, 3H), 1.67 (m,
1H), 3.13 (m,1H) 7.20-7.25 (m, 2H), 7.44-7.50 (m, 2H), 7.49 (d,
2H), 7.79 (d, 2H).
Example 40
3-(3, 5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-(1,
2,2-trimethylpropylamino)-propenenitrile
[0166] 1)
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-me-
thylsulfanyl-2-propenenitrile
[0167] A solution of 2-propanesulphonylacetonitrile (4.0 g, 27.2
mmol) in dry acetone (50 ml) was stirred while dry potassium
carbonate (7.52 g, 54.4 mmol) and 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (7.72 g, 4.87 mmol) were added. The resulting
mixture was stirred at room temperature under nitrogen for 20 h.
Excess of potassium carbonate was filtered off, methyl iodide (5.08
ml, 81.6 mmol) was added to the filtrate, and stirring was
continued for 48 h. The mixture was evaporated and the residue was
dissolved in dichloromethane and extracted with water and brine.
The organic phase was dried over magnesium sulphate, filtered and
evaporated to afford 11.65 g (99%) of the title compound as
yellowish brown crystals. Mp 130-133.degree. C. .sup.1H NMR (200
MHz, CDCl.sub.3): .delta.=1.47 (d, 6H), 2.35 (s, 3H), 3.44 (heptet,
1H), 7.73 (s, 2H), 7.80 (s, 1H), 10.10 (br s, 1H);
[0168] 2)
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-(1-
,2,2-trimethylpropylamino)-propenenitrile
[0169]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methy-
lsulfanyl-2-propenenitrile (0.500 g, 0.6 mmol) was stirred in
2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100.degree. C. under
nitrogen in a sealed flask. The reaction mixture was concentrated
and the residue dissolved in dichloromethane, washed twice with 1N
aqueous HCl, once with brine, and once with water. The organic
phase was dried (sodium sulphate) and evaporated to afford 450 mg
(80%) of the title compound as pale yellow crystals. Mp
177-180.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.89
(s, 9H), 1.04 (d, 3H), 1.40 (d, 6H), 2.97 (m, 1H), 3.27 (m, 1H),
7.50 (s, 2H), 7.67 (s, 1H), 9.16 (brs, 1H);
Example 41
3-(3,
5-Bis(trifluoromethyl)phenyamino)-2-isopropylsulfonyl-3-cyclopentyla-
mino- 2-propenenitrile
[0170]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropysulfonyl-3-methyl-
sulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in
cyclopentylamine (2 ml) for 24 h at 80.degree. C. under nitrogen in
a sealed flask. Work up as described in Example 40, 2) gave 540 mg
(99%) of the title compound as white crystals. Mp 172-173.degree.
C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=1.41 (d, 6H),
1.40-1.57 (m, 4H), 1.74-1.93 (m, 4H), 3.25 (heptet, 1H), 3.56 (m,
1H), 7.54 (s, 2H), 7.67 (s, 1H), 7.94 (br s, 1H), 9.22 (br s,
1H)
Example 42
3-(3,5-Bis(trifluoromethyl)phenylamino)-3-cyclobutylamino-2-isopropylsulfo-
nyl- 2-propenenitrile
[0171]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methy-
lsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in
cyclobutylamine (2 ml) for 24 h at 80.degree. C. under nitrogen in
a sealed flask. Work up as described in Example 40, 2) gave 470 mg
(89%) of the title compound as white crystals. Mp 148-150.degree.
C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=1.38 (d, 6H),
1.49-1.85 (m, 2H), 2.02 (q, 4H), 3.26 (heptet, 1H), 3.53-3.77
(m,1H), 7.46 (s, 2H), 7.64 (s, 1H), 7.96-8.14 (m, 1H), 9.17 (brs,
IH)
Example 43
3-(3,
5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-(2-methyl)p-
ropylamino)-2-propenenitrile
[0172]
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methy-
lsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in
cyclopentylamine (2 ml) for 24 h at 80.degree. C. under nitrogen in
a sealed flask. Work up as described in Example 40, 2) gave 460 mg
(87%) of the title compound as white crystals. Mp 160-163.degree.
C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.91 (d, 6H), 1.42
(d, 6H), 1.74-1.94 (m, 1H), 2.73 (t, 2H) 3.26 (heptet,1H), 7.47 (s,
2H), 7.65 (s, I H), 7.94-8.12 (m, 1H), 9.26 (brs 1H).
Example 44
2-lsopropylsulfonyl-3-(3-methoxyphenylamino)-3-(1, 2,
2-trimethylpropylamino)- 2-propenenitrile
[0173] 1)
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2--
propenenitrile
[0174] A solution of 2-propanesulfonylacetonitrile (2.0 g, 13.6
mmol) in dry acetone (25 ml) was stirred while dry potassium
carbonate (1.28 g, 9.28 mmol) and 3-methoxyphenyl isothiocyanate
(2.36 g, 14.3 mmol) were added. The resulting mixture was stirred
at room temperature under nitrogen for 20 h. Excess of potassium
carbonate was filtered off, methyl iodide (2.54 ml, 40.8 mmol) was
added to the filtrate, and stirring was continued for 60 h. The
mixture was evaporated and the residue was dissolved in
dichloromethane and extracted with water and brine. The organic
phase was dried over magnesium sulphate, filtered and evaporated to
afford 4.40 g (99%) of the title compound as yellow crystals. Mp
107-110.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=1.44
(d, 6H), 2.22 (s, 3H), 3.36 (heptet, 1H), 3.83 (s, 3H), 6.81 (m,
1H), 6.85 (dd, 1H), 6.87 (dd, 1H), 7.32 (dd, 1H), 9.91 (br s,
1H).
[0175] 2)
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-(1,2,2-trimethylp-
ropylamino)-2-propenenitrile
[0176]
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfany-1,2,2--
propenenitrile (0.500 g, 1.53 mmol) was stirred in
2-amino-3,3-dimethylbut- ane (2 ml) for 48 h at 100.degree. C.
under nitrogen in a sealed flask. The reaction mixture was
concentrated and the residue dissolved in dichloromethane, washed
twice with 1N aqueous HCl, once with brine, and once with water.
The organic phase was dried (sodium sulphate) and evaporated to
afford 450 mg (80%) of the title compound as white crystals. Mp
59-62.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.84
(s, 9H), 0.96 (d, 3H), 1.40 (d, 6H), 3.00-3.33 (m, 2H), 3.82 (s,
3H), 6.64 (dd, 1H), 6.70 (dd, 1H), 6.81 (dd, 1H), 7.31 (dd, 1H),
7.73-7.94 (m, 1H) 8.95 (br s, 1H).
Example 45
3-Cyclopentylamino-2-isopropylsulfonyl-3-(3-methoxy)phenylamino-2-propenen-
itrile
[0177]
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-pro-
penenitrile (0.500 g, 1.53 mmol) was stirred in cyclopentylamine (2
ml) for 48 h at 100.degree. C. under nitrogen in a sealed flask.
Work up as described in Example 44, 2) gave 490 mg (88%) of the as
yellow crystals. Mp 81-85.degree. C. .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.=1.4 (d, 6H), 1.44-1.82 (m, 9H), 3.26 (sextet,
1H), 3.82 (s, 3H), 6.63 (m, 1H), 6.69 (dd, 1H), 6.77 (dd, 1H), 7.27
(dd, 1H), 8.99 (br s, 1H).
Example 46
3-Cyclobutylamino-2-isopropylsulfonylamino-3-(3-methoxy)phenylamino-2-prop-
enenitrile
[0178]
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-pro-
penenitrile (0.500 g, 1.53 mmol) was stirred in cyclobutylamine (2
ml) for 48 h at 100.degree. C. under nitrogen in a sealed flask.
Work up as described in Example 44, 2) gave 510 mg (95%) of the
title compound as white crystals. Mp 152-155.degree. C. .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta.=1.39 (d, 6H), 1.52-2.23 (m, 7H),
3.25 (hextet, 1H), 3.81 (s, 3H), 6.61 (m, 1H), 6.66 (dd, 1H), 6.77
(dd, 1H), 7.77 (dd, 1H), 7.75-8.03 (m, 1H), 8.96 (br s, 1H)
Example 47
2-Isopropylsulfonyl-3-(3-methoxy)phenylamino-3-(2-methyl)propylamino)-2-pr-
openenitrile
[0179]
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-pro-
penenitrile (0.500 g, 1.53 mmol) was stirred in isobutylamine (2
ml) for 48 h at 100.degree. C. under nitrogen in a sealed flask.
Work up as described in Example 44, 2) gave 410 mg (76%) of the
title compound as yellow crystals. Mp 138-141.degree. C. .sup.1H
NMR (200 MHz, CDCl.sub.3): .delta.=0.87 (d, 6H), 1.39 (d, 6H),
1.66-1.85 (m, 1H), 2.69-2.90 (m, 2H), 3.25 (heptet, 1H), 3.81 (s,
3H), 6.60 (m, 1H), 6.65 (dd, 1H), 6.75 (dd, 1H), 7.26 (dd, 1H),
7.63-7.98 (m, 1H), 9.01 (br s 1H).
Example 48
3-(1,-Dimethyl)propylamino)-2-isopropylsulfonyl-3-(3-methoxy)phenylamino-2-
-propenenitrile
[0180]
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-pro-
penenitrile (0.500 g, 1.53 mmol) was stirred in
1,1-dimethylpropylamine (2 ml) for 48 h at 100.degree. C. under
nitrogen in a sealed flask. Work up as described in Example 44, 2)
gave 410 mg (73%) of the title compound as yellow crystals. Mp
130-134.degree. C. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=0.96
(t, 3H), 1.33 (s, 6H), 1.43 (d, 6H), 1.58 (q, 2H), 3.27 (heptet,
1H), 3.81 (s, 3H), 6.65 (s, 1H), 6.70 (d, 1H), 6.75 (d, 1H), 7.28
(dd, 1H).
Example 49
2-Isopropylsulfonyl-3-(3-methoxy)phenylamino-3-tert.-butylamino-2-propenen-
itrile
[0181]
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-pro-
penenitrile (0.500 g, 1.53 mmol) was stirred in tert.-butylamine (2
ml) for 48 h at 100.degree. C. under nitrogen in a sealed flask.
Work up as described in Example 44, 2) gave 440 mg (82%) of the
title compound as yellowish brown crystals. Mp 130-134.degree. C.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=1.36 (s, 9H), 1.42 (d,
6H), 3.25 (heptet, 1H), 3.79 (s, 3H), 6.67 (m, 1H), 6.71 (dd, I H),
6.75 (dd, 1H), 7.28 (dd, 1H).
Example 50
3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1-dimethylpropylamino)-2-methanesulfon-
yl- 2-propenenitrile
[0182] 1)
3-(Benzo[1,3]dioxol-5-ylamino)-2-methanesulfonyl-3-methylsulfany-
l-2-propenenitrile
[0183] A solution of methanesulfonylacetonitrile (2.85 g, 23.9
mmol) in dry acetone (50 ml) was stirred while dry potassium
carbonate (6.61 g, 47.8 mmol) and 3,4-methylenedioxyphenyl
isothiocyanate (4.50 g, 25.1 mmol) were added. The resulting
mixture was stirred at room temperature under nitrogen for 20 h.
Excess of potassium carbonate was filtered off, methyl iodide (4.43
ml, 71.8 mmol) was added to the filtrate, and stirring was
continued for 4 h at 50.degree. C. The mixture was evaporated and
the residue was dissolved in dichloromethane and extracted with
water and brine. The organic phase was dried over magnesium
sulphate, filtered and evaporated to afford 4.88 g (65%) of the
title compound as golden brown crystals. Mp 168-170.degree. C.
.sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta.=2.30 (s, 3H), 3.33 (s,
3H), 6.06 (s, 2H), 6.79 (dd, 1H), 6.94 (d, 1H), 6.97 (d, I H), 9.98
(br s, 1H).
[0184] 2)
3-(Benzo[1,3]dioxol-5-ylamino)-3-(1,1-dimethylpropylamino)-2-met-
hanesulfonyl-2-propenenitrile
[0185] A mixture of
3-(benzo[1,3]dioxol-5-ylamino)-2-methanesulfonyl-3-met-
hylsulfanyl-2-propenenitrile (0.800 g, 2.5 mmol) and
1,1-dimethylpropylamine (2.92 ml) in 10 ml of acetonitrile was
stirred and refluxed for one week under nitrogen. The reaction
mixture was concentrated and the residue dissolved in
dichloromethane, washed twice with 1N aqueous HCl, once with brine,
and trice with water. The organic phase was dried (sodium sulphate)
and evaporated to afford the title compound as white crystals. Mp
86-88.degree. C. .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta.=0.90
(t, 3H), 1.34 (s, 6H), 1.70 (q, 2H), 3.04 (s, 3H), 6.66 (s, 2H),
6.66 (dd, 1H), 6.74 (d, 1H), 6.88 (d, 1H), 7.21 (s, 1H). 8.19 (s,
1H).
* * * * *