Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-22
2002-04-02
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C514S407000, C514S466000, C514S523000, C514S866000
Reexamination Certificate
active
06365609
ABSTRACT:
FIELD OF THE INVENTION
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 endocrinological system.
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 hypoglycaemic agents such as sulphonylureas, e.g. glibenclamide and glipizide; biguanides e.g. metformin; benzoic acid derivatives, e.g. repaglinide;and thiazolidinediones, e.g. troglitazone and ciglitazone.
BACKGROUND OF THE INVENTION
Potassium channels play an important role in membrane potential. Among the different types of potassium channels are the ATP-sensitive (K
ATP
-)channels which are regulated by changes in the intracellular concentration of adenosine triphosphate. The K
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.
Modulators of the K
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
ATP
-channels on pancreatic beta-cells.
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.
In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
Furthermore, potassium channel openers have been shown to promote hair growth, 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 labour.
Since some K
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 haemorrhage and migraine.
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.
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
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 (Viahos 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 characterised by an overproduction of insulin and for the treatment and prevention of diabetes.
DESCRIPTION OF THE INVENTION
The present invention relates to substituted 3,3-diamino-2-propenenitriles, in the following also referred to as cyanoenamines, of the general formula I:
wherein
R
1
is alkyl optionally substituted with halogen, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; or 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, diarylamino, nitro, alkylsulfonyl, arylsulfonyl, cyano, alkoxycarbonyl or aminocarbonyl; or 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;
R
2
and R
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;
or R
2
and R
3
are linked together by —(CH
2
)
n
—, n being 4-7, provided that R
2
and R
3
cannot be hydrogen at the same time;
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;
or pharmaceutically acceptable salts thereof.
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.
The scope of the invention also includes all tautomeric forms of the compounds of formula I as well as metabolites or prodrugs.
In a preferred embodiment of the invention, Z is alkylsulfonyl or arylsulfonyl substituted with halogen. More preferred, Z is methylsulfonyl, isopropylsulfonyl or 4-chlorophenylsulfonyl.
In a further preferred embodiment of the invention, R
1
is optionally substituted aryl. More referred 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.
A preferred perhalomethyl group is trifluoromethyl. The most preferred phenyl substituents are 3,5-dichloro or 3,5-dialkoxy substituents.
In a further preferred embodiment of the invention, R
2
is cyclic alkyl with f
Dorwald Florencio Zaragoza
Hansen John Bondo
Jorgensen Anker Steen
Mogensen John Patrick
Tagmose Tina Moller
Green, Esq. Reza
Novo Nordisk A S
Stockton Laura L.
Waibel, Esq. Peter J.
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