Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-06-17
2001-06-05
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S012000
Reexamination Certificate
active
06242443
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 119 of Danish application 0693/96 filed Jun. 21, 1996, and 1451/96 filed Dec. 19, 1996, the contents of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to 1,2,4-benzothiadiazine derivatives, 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.
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 neurons and adenohypophysis cells. The channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmifter 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 sulphonylureas which have been used for the treatment of non-insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the K
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 hairgrowth, and have been used for the treatment of baldness.
Potassium channel openers are also able to relax urinary bladder smooth muscle and therefore, can be used for the treatment of urinary incontinence. Potassium channel openers which relax smooth muscle of the uterus can be used for treatment of premature labor.
By acting on potassium channels of the central nervous system these compounds can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia.
Further, the compounds are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception.
Compounds of the present invention, which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with compounds which reduce blood glucose levels. Examples of such compounds are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenclamide and glucagon like peptide (GLP1), inhibitors of &agr;-glucosidases and hepatic enzymes responsible for the biosynthesis of glucose, and glucagon.
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 (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 compounds which activate K
ATP
-channels can be used for treatment of diseases characterised by an overproduction of insulin and for the treatment and prevention of diabetes.
The following compounds are known from the literature:
3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-isobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
(2-ethylhexylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
cyclopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
cyclohexylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
7-chloro-3-(1,2,2-trimethylpropylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
7-chloro-3-(1,2-dimethylpropylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
7-chloro-3-(1-methylpropylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
7-chloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
7-chloro-3-cyclohexylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
6-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
6-chloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
6,7-dichloro-3-cyclopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-isobutylamino-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-cyclopentylamino-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-cyclohexylamino-6-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
(N-cyclohexyl-N-methylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-cyclohexylamino-4-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-cyclohexylamino-2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide.
DESCRIPTION OF THE INVENTION
The present invention relates to 1,2,4-benzothiadiazine derivatives of the general formula I:
wherein
R
1
and R
5
independently can be hydrogen; hydroxy; C
1-6
-alkoxy; C
3-6
-cycloalkyl optionally mono- or polysubstituted with C
1-6
-alkyl, halogen, hydroxy or C
1-6
-alkoxy; or C
1-6
-alkyl, C
2-6
-alkenyl or C
2-4
-alkynyl optionally mono- or polysubstituted with halogen and R
4
is hydrogen; or
R
4
together with R
5
represent one of the bonds in a double bond between the atoms 2 and 3 of formula I and R
1
is as defined above; or
R
4
together with R
1
represent one of the bonds in a double bond between the atoms 3 and 4 of formula I and R
5
is as defined above;
D represents —S(═O)
2
— or —S(═O)—;
R
2
is hydrogen; hydroxy; C
1-6
-alkoxy; C
3-6
-cycloalkyl optionally mono- or polysubstituted with C
1-6
-alkyl, halogen, hydroxy or C
1-6
-alkoxy; or C
1-6
-alkyl, C
2-6
-alkenyl or C
2-6
-alkynyl optionally mono- or polysubstituted with halogen;
R
3
is R
8
; —OR
8
; —C(═X
1
)R
8
; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally mono- or polysubstituted with halogen, hydroxy, C
1-6
-alkyl, C
1-6
-alkoxy, aryloxy, arylalkoxy, nitro, amino, C
1-6
-monoalkyl- or dialkylamino, cyano, oxo, acyl or C
1-6
-alkoxycarbonyl;
wherein R
8
is hydrogen; C
3-6
-cycloalkyl or (C
3-6
-cycloalkyl)C
1-6
-alkyl the C
3-6
-cycloalkyl group optionally being mono- or polysubstituted with C
1-6
-alkyl, halogen, hydroxy or C
1-6
-alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms, optionally being mono- or polysubstituted with halogen, cyano, trifluoromethyl, C
1-6
-alkyl, C
1-6
-alkoxy, C
1-6
-alkoxy-C
1-6
-alkyl, aryl, arylalkyl, hydroxy, oxo, nitro, amino, C
1-6
-monoalkyl or dialkylamino; or straight or branched C
1-8
-alkyl optionally mono- or polysubstituted with halogen, hydroxy, C
1-6
-alkoxy, C
1-6
-alkylthio, C
3-6
-cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C
1-6
-monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C
1-6
-alkoxycarbonyl, carbamoyl, formylamino, or C
1-6
-alkylcarbonylamino;
X
1
is O or S;
R
3
is
wherein n,m,p independently can be 0,1,2,3 and R
10
is hydrogen; hydroxy; C
1-6
-alkoxy; C
3-6
-cycloalkyl optionally mono- or polysubstituted with C
1-6
-alkyl, halogen, hydroxy or C
1-6
-alkoxy; or C
1-6
-alkenyl or C
2-6
-alkynyl optiona
De Tullio Pascal
Delarge Jacques
Hansen Holger Claus
Hansen John Bondo
Lebrun Philippe
Ford John M.
Novo Nordisk AIS
Rozek, Esq. Carol E.
Zelson, Esq. Steve T.
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