NIELSEN FLEMMING ELMELUND
HANSEN JOHN BONDO
HANSEN HOLGER CLAUS
PIROTTE BERNARD
BOVERIE STEPHANE
SOMERS FABIAN
LEBRUN PHILIPPE
MOGENSEN JOHN PATRICK
| WO1997049692A1 | 1997-12-31 |
| US5378704A | 1995-01-03 | |||
| DE1470316A1 | 1969-04-24 |
J. MED. CHEM., Volume 36, No. 21, 1993, BERNARD PIROTTE et al., "3-(Alkylamino)-4H-Pyrido 4,3-e -1,2,4-Thiadiazine 1,1-Dioxides as Powerful Inhibitors of Insulin Release from Rat Pancreatic B-Cells: A New Class of Potassium Channel Openers?", pages 3211-3213.
IL FARMACO-ED. SC., Volume 17, No. 12, 1962, E. GRANA et al., "Azione Cardiovascolare di Derivati del 1,2,4-Benzotiadiazin-1,1-Diossido", pages 974-987.
J. MED. CHEM., Volume 39, No. 4, 1996, PASCAL DE TULLIO et al., "3- and 4-Substituted 4H-Pyrido 4,3-3 -1,2,4-Thiadiazine 1,1-Dioxides as Potassium Channel Openers: Synthesis, Pharmacological Evaluation and Structure-Activity Relationships", pages 937-948.
ARZNEIM.-FORSCH./DRUG RES., Volume 31, No. 2, 1981, VON H. WOLLWEBER et al., "3-Amino-2H-1,2,4-Benzothiadiazin-1,1-Dioxi de mit Antihypertensiver und Potentieller Diabetongener Wirkung", pages 279-288.
TETRAHEDRON: ASYMMETRY., Volume 7, No. 9, 1996, ANNALISA TAIT et al., "Stereospecific Synthesis of 3- (2H-1,2,4-Benzothiadiazine-1,1-Dioxide-3-yl )thio -2-Methylpropanoic Acids", pages 2703-2706.
| 1. | A compound of the general formula I wherein Z is O, S, S (=O), S (=O) 2, S (=NR), S (=O) (=NR) or S (=NR) 2 wherein R is hydrogen; C, 6alkyl, C2 6alkenyl or C26alkynyl optionally monoor polysub stituted with halogen, hydroxy or C16alkoxy ; or C36cycloalkyl optionally monoor polysubstituted with C16alkyl, halogen, hydroxy or C, _6alkoxy; R3 is (C36cycloalkyl)C16alkyltheC36cycloalkylgroupoptionallybeingor monoor polysubstituted with C, _salkyl, halogen, hydroxy or C16alkoxy ; a 36 membered saturated ring system comprising one or more nitrogen, oxygenor sulfur atoms, optionally being monoor polysubstituted with halogen, cyano, trifluoromethyl, C16alkyl, C16alkoxy, C16alkoxyC16alkyl, aryl, arylalkyl, hydroxy, oxo, nitro, amino, C16monoalkyl or dialkylamino; or straight or branche C118alkyl, C218alkenyl or C2, 8aikynyl, each of the groups being optionally monoor polysubstituted with halogen, hydroxy, C16alkoxy, C16 alkylthio, C36cycloalkyl, nitro, amino, C16monoalkyl or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C,. 6alkoxycarbonyl, carbamoyl, formylamino, or C16alkylcarbonylamino, aryl, aryloxy, arylalkoxy, the aryl group optionally being monoor polysubstituted with C16 alkyl, perhalomethyl, halogen, hydroxy or C, 6alkoxy; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of the groups being optionally monoor polysubstituted with halogen, hydroxy, C, 6alkyl, C, 6alkoxy, aryloxy, arylalkoxy, nitro, amino, C16 monoalkylor dialkjrlamino, cyano, oxo, acyl or C16alkoxycarbonyl ; or is wherein n, m and p independently are 0,1,2 or 3 and R'° is hydrogen; hydroxy; C16 alkoxy; C36cycloalkyl optionally monoor polysubstituted with C16alkyl, halogen, hydroxy or C16alkoxy ; C, 6alkyl, C2 6alkenyl or C26alkynyl optionally monoor polysubstituted with halogen; R5, R6, R7, R3 independently are hydrogen, halogen; C118alkyl ; C36cycloalkyl ; hydroxy; Cl 6alkoxy; C16alkoxyC16alkyl ; nitro; amino; cyano; cyanomethyl; perhalomethyl; Cl6 monoalkylor dialkylamino; sulfamoyl; C, 6alkylthio; C16alkylsulfonyl ; C16alkylsulfinyl ; Cl 6alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, aryl, arylalkyl, aryloxy, the aryl group optionally being monoor polysubstituted with C, _salkyl, perhalomethyl, halogen, hydroxy or C16alkoxy ; C16alkoxycarbonyl ; C, 6alkoxycarbonylC, 6alkyl; carbamyl; carbamylmethyl; C, 6monoalkylor dialkylaminocarbonyl; C16monoalkyl or dialkylami nothiocarbonyl; ureido; C16monoalkyl or dialkylaminocarbonylamino, thiocarbamyl; thioureido; C16monoalkyl or dialkylaminothiocarbonylamino; C, 6monoalkylor dialky laminosulfonyl; carboxy; carboxyC, _6alkyl; acyl; formyl; or a 56 membered nitrogen, oxygen or sulfur containing ring, optionally substituted with C16alkyl or phenyl, the phenyl group optionally being monoor polysubstituted with C, _6alkyl, perhalomethyl, halogen, hydroxy or C16alkoxy ; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form. |
| 2. | A compound according to claim 1, wherein Z is S. |
| 3. | A compound according to claim 1 or 2 wherein one of R5, R6, R7 or R8 is halogen. |
| 4. | A compound according to anyone of the preceding claims wherein R7 is chloro. |
| 5. | A compound according to anyone of the preceding claims wherein R3 is straight or branche C118alkyl, C36cycloalkyl or (C3 6cycloalkyl) C, 6alkyl. |
| 6. | A compound selected from the following: 7chloro3isobutylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3cyclobutylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3cyclopentylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3(1phenylethyl)(1phenylethyl) sulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7bromo3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7fluoro3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6fluoro3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6, 8dichloro3isopropylsulfanyl4H1, 2,4benzothiadiazine 1,1dioxide 6,7dichloro3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6methoxy3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7methoxy3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7trifluoromethyl3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6trifluoromethyl3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3ethylsulfinyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3propylsulfinyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3isopropylsulfinyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3ethylsulfinimidoyl4H1,2,4benzothiadiazine 1,1dioxide 6fluoro3ethylsulfinimidoyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3ethylsulfonimidoyl4H1,2,4benzothiadiazine 1,1dioxide 7bromo3isopropoxy4H1,2,4benzothiadiazine 1,1dioxide 7fluoro3isopropoxy4H1,2,4benzothiadiazine 1,1dioxide 6fluoro3isopropoxy4H1,2,4benzothiadiazine 1,1dioxide 6,8dichloro3isopropoxy4H1,2,4benzothiadiazine 1,1dioxide 3isopropoxy6methoxy4H1,2,4benzothiadiazine 1,1dioxide 3isopropoxy7methoxy4H1,2,4benzothiadiazine 1,1dioxide 3isopropoxy7trifluoromethyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3cyclopropylmethylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 7chloro3cyclopropylmethoxy4H1,2,4benzothiadiazine 1,1dioxide 7Chloro3 (3trifluoromethylbenzylsulfanyl)4H1,2,4benzothiadiazine 1,1dioxide 7Chloro3 (3methylbut2enylsulfanyl)4H1, 2, 4benzothiadiazine 1,1dioxide 6bromo3isopropoxy4H1,2,4benzothiadiazine 1,1dioxide 6bromo3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6bromo3cyclopropylmethylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6bromo3cyclopropylmethoxy4H1,2,4benzothiadiazine 1,1dioxide 6bromo3isobutylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6bromo3cyclobutylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6bromo3cyclopentylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide 6bromo3(1phenylethyl)(1phenylethyl) sulfanyl4H1,2,4benzothiadiazine 1,1dioxide 3isopropoxy7methyl4H1,2,4benzothiadiazine 1,1dioxide 3isopropylsulfanyl7methyl4H1,2,4benzothiadiazine 1,1dioxide 3cyclopropylmethylsulfanyl7methyl4H1,2,4benzothiadiazine 1,1dioxide 3cyclopropylmethoxy7methyl4H1,2,4benzothiadiazine 1,1dioxide 3isobutylsulfanyl7methyl4H1,2,4benzothiadiazine 1,1dioxide 3cyclobutylsulfanyl7methyl4H1,2,4benzothiadiazine 1,1dioxide 3cyclopentylsulfanyl7methyl4H1,2,4benzothiadiazine 1,1dioxide 3(1phenylethyl)(1phenylethyl) sulfanyl7methyl4H1,2,4benzothiadiazine 1,1dioxide 3cyclopropylmethoxy7fluoro4H1,2,4benzothiadiazine 1,1dioxide7chloro3 cyclopentyloxy4H1,2,4benzothiadiazine 1,1dioxide7fluoro3ethylsulfanyl4H 1,2,4benzothiadiazine 1,1dioxide7fluoro3cyclopropylmethylsulfanyl4H1,2,4 benzothiadiazine 1,1dioxide7chloro3ethylsulfanyl4H1,2,4benzothiadiazine 1,1 dioxide7bromo3ethylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide7bromo3 cyclopropylmethylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide3ethylsulfanyl6 fluoro4H1,2,4benzothiadiazine 1,1dioxide3cyclopropylmethylsulfanyl6fluoro4H 1,2,4benzothiadiazine 1,1dioxide6chloro3ethylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide6chloro3isopropylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide6chloro 3cyclopropylmethylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide6chloro3 cyclobutylsulfanyl4H1,2,4benzothiadiazine 1,1dioxide6bromo3ethylsulfanyl4H 1,2,4benzothiadiazine 1,1dioxide7chloro3 (5chloro2methoxybenzyloxy)4H1,2,4 benzothiadiazine 1,1dioxide7chloro3cyclobutoxy4H1,2,4benzothiadiazine 1,1 dioxide7chloro3 (lphenyl) ethoxy4H1,2,4benzothiadiazine 1, 1dioxide. |
| 7. | Compound according to any one of the preceding ciaims which acts as openers of the KATPregulated potassium channes. |
| 8. | A method of preparing a compound of formula 1, characterized in a) reacting a compound of formula II : wherein Y is O or S and R5, R6,R7 and R8 are as defined above with a compound of formula lil<BR> <BR> R3X (IiI) in the presence of a base, wherein R3 is as defined above and X is a leaving group selected from sulfate, chloro, bromo or iodo to form a compound of the general formula I wherein Z is O or S, or b) reacting a compound of formula li: wherein Y is O and R5, R6,R7 and R8 are as defined above with a diazo compound of formulaIV R'R"CN2 (IV) wherein R'and R"together as two substituents on methyl form a group R'R"CH meeting the criteria defined above for R3, to form a compound of the general formula I wherein Z is O and R3 is R'R"CH) or c) reacting a compound of formula V: wherein R5, R6, R'and Ra are as defined above and Q is a leaving group selected from chloro, bromo, iodo, amino, trimethylamino, imidazol1yl, methylsulfanyl, methylsulfinyl or methylsulfonyl with a compound of formula VI : R3YH (VI) in the presence of a base, wherein R3 is as defined above and Y is O or S to form a compound of the general formula I wherein Z is O or S, or d) reacting a compound of formula Vil: wherein R3, R5, R6,R7 and R8 are as defined above with an oxidizing agent to form a compound of the general formula I wherein Z is S (=O) or S (=O)2, or e) reacting a compound of formula Vil: wherein R3, R5) R6, R7 and R8 are as defined above with an aminating agent, to form a compound of the general formula VIII wherein n is 1 or 2, or f) reacting a compound of formula VII: wherein R3, R5, R6, R'and R8 are as defined above with an aminating agent and subse quently an oxidizing agent, or vice versa, to form a compound of the general formula I wherein Z is S (=O) (=NR), or g) reacting a compound of formula IX wherein R5, R6,R7 and R8 are as defined above with CS2 in the presence of a base to give the corresponding sulfonylimino carbodithioate which in turn is treated with an alkylating agent of formula III R3X(III) wherein R3 is as defined above and X is a leaving group selected from sulfate, chloro, bromo or iodo to form a compound of formula X which by ringclosure forms a compound of the general formula 1, or h) reacting a compound of formula XI wherein R3, R5, Rs, R'and R$ are as defined above and PG is a protecting group selected from substituted benzyl, with chlorosulfonyl isocyanate (CISOZ NCO) and subsequent ring closure folliowed by removal of the protecting group to form a compound of formula 1. |
| 9. | A pharmaceutical composition comprising a compound according to any of the claim 16 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluent. |
| 10. | A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as hyperinsulinaemia and diabetes comprising a compound according to any of the claims 16 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluent. |
| 11. | The pharmaceutical composition according to claim 9 or 10 in the form of an oral dosage unit or parenteral dosage unit. |
| 12. | A pharmaceutical composition according to claim 9 or 10 wherein said compound is administered as a dose in a range from about 0.05 to 1000, preferably from about 0.1 to 500 and especially in the range from 50 to 200 mg per day. |
| 13. | A compound according to any one of the claims 16 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use. |
| 14. | A compound according to any one of the claims 16 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes. |
| 15. | The use of a compound according to any one of the claims 16 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament. |
| 16. | The use of a compound according to any of the claims 16 for preparing a medicament. |
| 17. | The use of a compound according to any one of the claims 16 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes. |
| 18. | A method of treating or preventing diseases of the endocrinological system, such as hyperinsulinaemia and diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims 16 to said subject. |
| 19. | A process for the manufacture of a medicament, particular to be used in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes which process comprising bringing a compound of formula I according to any of the claims 16 or a pharmaceutically acceptable salt thereof into a galenic dosage form. |
| 20. | Any novel feature or combination of features as described herein. |
BACKGROUND OF THE INVENTION Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential. Amongst the different types of potassium channels are the ATP-sensitive (KATp-) channels which are regulated by changes in the intracellular concentration of adenosine triphosphate. The KATp-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, neurotransmitter reiease in the central nervous system.
Modulators of the KATP-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 KATP-channels on pancreatic beta-cells.
The potassium channel openers, which comprise a heterogeneous group of compound, 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 labour.
By acting on potassium channels of the central nervous system these compound can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsy and cerebral ischemia.
Further, the compound are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception.
Compound of the present invention, which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with other compound which may be used to treat non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus. Examples of such compound are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenclamide and glucagon like peptide (GLP1), inhibitors of a-glucosidases and hepatic enzymes responsible for the biosynthesis of glucose.
Recently, it has been shown that Diazoxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide) and certain 3- (alkylamino)-4H-pyrido [4, 3-e]-1,2,4-thiadiazine 1,1-dioxide derivatives inhibit insulin release by an activation of KATP-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 WD et al. Metabolism 40,39-46 (1991)). In obese zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R. et al. Endocrinol. 133,705-712,1993). It is expected that compound which activate KATp-channels can be used for treatment of diseases characterised-by an overproduction of insulin and for the treatment and prevention of diabetes.
EP 618 209 discloses a class of pyridothiadiazine derivatives having an alkyl or an alkylamino group in position 3 of the thiadiazine ring. These compound are claimed to be agonists at the AMPA-glutamate receptor.
In J. Med. Chem. 1980,23,575-577 the synthesis of 4 (5)-amino-and formylaminoimidazo- 5 (4) carboxamide and their properties as agents of chemotherapeutic value are described.
Especially, the compound 3-aminoimidazo [4,5-e]-1,2,4-thiadiazine 1,1-dioxide and N- benzoylaminoimidazo [4,5-e]-1,2,4-thiadiazine 1,1-dioxide are shown.
DESCRIPTION OF THE INVENTION The present invention relates to 1,2,4-benzothiadiazine derivatives of the general formula 1 : wherein Z is O, S, S (=O), S (=O) 2, S (=NR), S (=O) (=NR) or S (=NR) 2 wherein R is hydrogen; C1-6-alkyl, C2-6-alkenyl or C24-alkynyl optionally mono-or polysub- stituted with halogen, hydroxy or C1-6-alkoxy ; or C3-6-cycloalkyl optionally mono-or polysubstituted with C, _6-alkyl, halogen, hydroxy or C, 4-alkoxy; R3 is C3-6-cycloalkyl or (C3-6-cycloalkyl)C1-6-alkyl the C.-cycloalkyl group optionally being mono-or polysubstituted with C, _s-alkyl, halogen, hydroxy or C1-6-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, C1-6-alkyl, C1-6-alkoxy, C1-6alkoxy-C1-6-alkyl, aryl, arylalkyl, hydroxy, oxo, nitro, amino, C1-6-monoalkyl
or dialkylamino ; or straight or branche C1-18-alkyl, C2-18-alkenyl or C2, 8-alkynyl, each of the groups being optionally mono-or polysubstituted with halogen, hydroxy, C, 6-aikoxy, C, 6- alkylthio, C3-8cycloalkyl, nitro, amino, C, 6-monoalkyl-or dialkylamino, cyano, oxo, formyl, acyl, carboxy, formylamino,orC1-6-alkylcarbonylamino,carbamoyl, aryl, aryloxy, arylalkoxy, the aryl group optionally being mono-or polysubstituted with C1-6- alkyl, perhalomethyl, halogen, hydroxy or C, _6-alkoxy; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of the groups being optionally mono-or polysubstituted with halogen, hydroxy, Cl. 6-alkyl, C1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, C1-6- monoalkyl-or dialkylamino, cyano, oxo, acyl or C1-6-alkoxycarbonyl ; or R3 is wherein n, m and p independently are 0,1,2 or 3 and R'° is hydrogen; hydroxy; C1-6- alkoxy; C3-6-cycloalkyl optionally mono-or polysubstituted with C, _6-alkyl, halogen, hydroxy or C, _s alkoxy; C1-6-alkyl, C2-6-alkenyl or C2 6-alkynyl optionally mono-or polysubstituted with halogen; R5, R6, R7, R3 independently are hydrogen, halogen; C"8-alkyl; C3-6-cycloalkyl ; hydroxy; Cl- 6-alkoxy; Cl-6-alkoxy-Cl. 6-alkyl; nitro; amino; cyano; cyanomethyl; perhalomethyl; C1-6- monoalkyl-or dialkylamino; sulfamoyl; C1-6-alkylthio ; C1-6-alkylsulfonyl ; C1-6-alkylsulfinyl ; Cl- 6-alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, aryl, arylalkyl, aryloxy, the aryl group optionally being mono-or polysubstituted with C, _6-alkyl, perhalomethyl, halogen, hydroxy or C1-6-alkoxy ; C1-6-alkoxycarbonyl ; C, 6-alkoxycarbonyl-C, 6-alkyl; carbamyl; carbamylmethyl; C, 6-monoalkyl-or dialkylaminocarbonyl; C, 6-monoalkyl-or dialkylami- nothiocarbonyl; ureido; C, 6-monoalkyi-or dialkylaminocarbonylamino, thiocarbamyl; thioureido; C, 6-monoalkyl-or dialkylaminothiocarbonylamino; C, 6-monoalkyl-or dialky- laminosulfonyl; carboxy; carboxy-C, _s-alkyl; acyl; formyl; or a 5-6 membered nitrogen, oxygen or sulfur containing ring, optionally substituted with Cl. 6-alkyl or phenyl, the phenyl
group optionally being mono-or polysubstituted with C, _6-alkyl, perhalomethyl, halogen, hydroxy or C, _6-alkoxy; or a salt thereof with a pharmaceutically acceptable acid or base.
Within its scope the invention inclues all optical isomers of compound of formula 1, some of which are optically active, and also their mixtures including racemic mixture thereof.
The scope of the invention also inclues all tautomeric forms of the compound of formula I.
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 pharmaceuti- cally acceptable salts listed in Journal of Pharmaceutical Science, 66,2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
The term"C,. 6-alkoxy"as used herein, alone or in combination, refers to a straight or branche monovalent substituent comprising a C, 6-aikyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e. g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term"C, 4-alkylthio"as used herein, alone or in combination, refers to a straight or branche monovalent substituent comprising a lower alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e. g. methylthio, ethylthio, propylthio, butylthio, pentylthio.
The terms"C2 6-alkenyl"and"C2, 8-alkenyl"as used herein refers to an unsaturated hydrocarbon chain having 2-6 or 2-18 carbon atoms and one double bond such as e. g. vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.
The term"C3 6-cycloalkyl"as used herein refers to a radical of a saturated cyclic hydrocar- bon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The terms "C2-6-alkynyl" and "C2-18-alkynyl" as used herein refers to unsaturated hydrocar- bons which contain triple bonds, such as e. g.-C=CH,-C_CCH3,-CH2C_CH, -CH2CH2C_CH,-CH (CH3) C_CH, and the like.
The term"C, 6-alkoxy-C, 6-alkyl"as used herein refers to a group of 2-12 carbon atoms interrupted by an O such as e. g. CH2-O-CH3, CH2-O-CH2-CH3, CH2-O-CH (CH3) 2 and the like.
The term"halogen"means fluorine, chlorine,-bromine or iodine.
The term"perhalomethyl"means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
The terms "C1-6-alkyl", "C1-12-alkyl" and "C1-18-alkyl" as used herein, alone or in combination, refers to a straight or branche, saturated hydrocarbon chain having the indicated number of carbon atoms such as e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term"C, _, 8-alkyl" as used herein also inclues secondary C3.6-alkyl and tertiary C4-6-alkyl, The term"C,. 6-monoalkylamino"as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a straight or branche, saturated hydrocarbon chain having the indicated number of carbon atoms such as e. g. methylamino, ethylamino, propylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, 2-methylbutylamino, n-hexylamino, 4-methylpentylamino, neopentylamino, n-hexylamino, 2,2-dimethylpropylamino and the like.
The term "C1-4-dialkylamino" as used herein refers to an amino group wherein the two hydrogen atoms independently are substituted with a straight or branche, saturated
hydrocarbon chain having the indicated number of carbon atoms; such as dimethylamino, N-ethyl-N-methylamino, diethylamino, dipropylamino, N- (n-butyl)-N-methylamino, di (n- pentyl) amino, and the like.
The term"acyl"as used herein refers to a monovalent substituent comprising a C, _s-alkyl group linked through a carbonyl group; such as e. g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, and the like.
The term"C, _6-alkoxycarbonyl"as used herein refers to a monovalent substituent comprising a C, _6-alkoxy group linked through a carbonyl group; such as e. g. methoxycar- bonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbol-iyl, sec- butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
The ter"3-6 membered saturated ring system"as used herein refers to a monovalent substituent comprising a monocyclic saturated system containing one or more hetero atoms selected from nitrogen, oxygen and sulfur and having 3-6 members and having its free valence from a carbon atom, e. g. 2-pyrrolidyl, 4-piperidyl, 3-morpholinyl, 1,4-dioxan-2- yl, 5-oxazolidinyl, 4-isoxazolidinyl, or 2-thiomorpholinyl.
The term"bicycloalkyl"as used herein refers to a monovalent substituent comprising a bicyclic structure made of 6-12 carbon atoms such as e. g. 2-norbornyl, 7-norbornyl, 2- bicyclo [2.2.2joctyl, and 9-bicyclo [3.3.1jnonanyl.
The term"aryl"as used herein refers to phenyl, 1-naphthyl, or 2-naphthyl.
The term"heteroaryl"as used herein, alone or in combination, refers to a monovalent substituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e. g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine, and purine.
The term"arylalkyl"as used herein refers to a straight or branche saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2- (l-naphtyl) ethyl and the like.
The term"aryloxy"as used herein refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.
The term"arylalkoxy"as used herein refers to a C, _6-alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2- (l-naphtyl) ethoxy and the like.
The term"Cl. 6-alkylsulfonyl" as'used herein refers to a monovalent substituent comprising a C, _6-alkyl group linked through a sulfonyl group such as e. g. methylsulfonyl, ethylsul- fonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl, 3- methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopentylsulfonyl, n- hexylsulfonyl and 2,2-dimethylpropylsulfonyl.
The term"C, _6-monoalkylaminosulfonyl"as used herein refers to a monovalent substituent comprising a C1-6-monoalkylamino group linked through a sulfonyl group such as e. g. methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, sec-butylaminosulfonyl, isobutylaminosulfonyl, tert- butylaminosulfonyl, n-pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3- methylbutylaminosulfonyl, n-hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopenty- laminosulfonyl, n-hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
The term"C, _6-dialkylaminosulfonyl"as used herein refers to a monovalent substituent comprising a C, _s-dialkylamino group linked through a sulfonyl group such as dimethylami- nosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, N- (n-butyl)-N-methylaminosulfonyl, di (n-pentyl) aminosulfonyl, and the like.
The term"C, 4-alkylsulfinyl"as used herein refers to a monovalent substituent comprising a straight or branche C1-6-alkyl group linked through a sulfinyl group (-S (=O)-); such as e. g. methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, and the like.
The term"C, 4-alkylcarbonylamino"as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group, such as e. g : acetamido, propiona- mido, isopropylcarbonylamino, and the like.
The term" (C-cycloalkyl) C,-alkyl" as used herein, alone or in combination, refers to a straight or branche, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubstituted with a C3-6-cycloalkyl group, the cycloalkyl group optionally being mono-or polysubstituted with C, 4-alkyl, halogen, hydroxy or Cl-6-alkoxy; such as e. g. cyclopropylme- thyl, (1-methylcyclopropyl) methyl, 1- (cyclopropyl) ethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
The term"arylthio"as used herein, alone or in combination, refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono-or polysubstituted with C1-6-alkyl, halogen, hydroxy or C, 4- alkoxy; e. g. phenylthio, (4-methylphenyl)-thio, (2-chlorophenyl) thio, and the like.
The term"arylsulfinyl"as used herein refers to an aryl group linked through a sulfinyl group (- S (=O)-), the aryl group optionally being mono-or polysubstituted with C, 4-alkyl, halogen, hydroxy or C1-6-alkoxy ; such as e. g. phenylsulfinyl, (4-chlorophenyl) sulfinyl, and the like.
The term"arylsulfonyl"as used herein refers to an aryl group linked through a sulfonyl group, the aryl group optionally being mono-or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy ; such as e. g. phenylsulfonyl, tosyl, and the like.
The term "C1-6-monoalkylaminocarbonyl" as used herein refers to a monovalent substituent comprising a C1-6-monoalkylamino group linked through a carbonyl group such as e. g. methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert- butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3- methylbutylamino-carbonyl, n-hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neo- pentylaminocarbonyl, n-hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl.
The term "C1-6-dialkylaminocarbonyl" as used herein refers to a monovalent substituent comprising a C, 4-dialkylamino group linked through a carbonyl group such as dimethylami- nocarbonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N- (n-butyl)-N-methylaminocarbonyl, di (n-pentyl) aminocarbonyl, and the like.
The term"C, 4-monoalkylaminocarbonylamino"as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a C1-6-monoalkylaminocarbonyl group, e. g. methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec-butylaminocarbonylamino, isobutylaminocarbonylamino, tert-butylaminocarbonylamino, and 2- methylbutylaminocarbonylamino.
The term"C, 4-dialkylaminocarbonylamino"as used herein refers to an aminagroup wherein one of the hydrogen atoms is substituted with a C1-6dialkylaminocarbonyl group, such as dimethylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethyla- minocarbonylamino, dipropylaminocarbonylamino, N-(n-butyl)-N- methylaminocarbonylamino, di (n-pentyl) aminocarbonylamino, and the like.
The term"5-or 6-membered nitrogen, oxygen or sulfur containing ring"as used herein refers to a monovalent substituent comprising a monocyclic unsaturated or saturated system containing one or more nitrogen, oxygen or sulfur atoms and having 5 or 6 members, e. g. pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, primidi- nyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazotyl, thiadiazolyl, 1,3-dioxolanyl, and 1,4-dioxolanyl.
Preferred compound of the invention are: 7-chloro-3-isobutylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-cyclobutylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-cyclopentylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-(1-phenylethyl)(1-phenylethyl) sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-bromo-3-isopropylsulfanyl4H-1,2,4-benzothiadiazine 1,1-dioxide
7-fluoro-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-fluoro-3-isopropylsulfanyl4H-1,2,4-benzothiadiazine 1,1-dioxide 6,8-dichloro-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6,7-dichloro-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-methoxy-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-methoxy-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-trifluoromethyl-3-isopropylsulfanyl4H-1,2,4-benzothiadiazi ne 1,1-dioxide 6-trifluoromethyl-3-isopropylsulfanyl-4H-1,2,4-benzothiadiaz ine 1,1-dioxide 7-chloro-3-ethylsulfinyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-propylsulfinyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-isopropylsulfinyl-4H-1,2,4-benzo'hiadiazine 1,1-dioxide 7-chloro-3-ethylsulfinimidoyl4H-1,2,4-benzothiadiazine 1,1-dioxide 6-fluoro-3-ethylsulfinimidoyl4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-ethylsulfonimidoyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-bromo-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-fluoro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-fluoro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 6,8-dichloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-isopropoxy-6-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-isopropoxy-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-isopropoxy-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-chloro-3-cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazi ne 1,1-dioxide 7-chloro-3-cyclopropylmethoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 7-Chloro-3- (3-trifluoromethylbenzylsulfanyl)-4H-1, 2, 4-benzothiadiazine 1,1-dioxide 7-Chloro-3- (3-methyl-but-2-enylsulfanyl)-4H-1, 2, 4-benzothiadiazine 1,1-dioxide 6-bromo-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-bromo-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-bromo-3-cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazin e 1,1-dioxide 6-bromo-3-cyclopropylmethoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-bromo-3-isobutylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-bromo-3-cyclobutylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-bromo-3-cyclopentylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 6-bromo-3-(1-phenylethyl)(1-phenylethyl) sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
3-isopropoxy-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-isopropylsulfanyl-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-cyclopropylmethylsulfanyl-7-methyl-4H-1,2,4-benzothiadiazi ne 1,1-dioxide 3-cyclopropylmethoxy-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-isobutylsulfanyl-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-cyclobutylsulfanyl-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-cyclopentylsulfanyl-7-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 3-(1-phenylethyl) sulfanyl-7-methyl4H-1,(1-phenylethyl) sulfanyl-7-methyl4H-1, 2,4-benzothiadiazine 1,1-dioxide 3-cyclopropylmethoxy-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide7-chloro-3- cyclopentyloxy-4H-1,2,4-benzothiadiazine 1,1-dioxide7-fluoro-3-ethylsulfanyl-4H- 1,2,4-benzothiadiazine 1,1-dioxide7-fluoro-3-cyclopropylmethylsulfanyl-4H-1,2,4- benzothiadiazine 1,1-dioxide7-chloro-3-ethylsulfanyl-4H-1,2,4-benzothiadiazin e 1,1- . dioxide7-bromo-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide7-bromo-3- cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide3-ethylsulfanyl-6- fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide3-cyclopropylmethylsulfanyl-6-fluoro-4H- 1,2,4-benzothiadiazine 1,1-dioxide6-chloro-3-ethylsulfanyl-4H-1,2,4-benzothiadiazin e 1,1-dioxide6-chloro-3-isopropylsulfanyl-4H-1,2,4-benzothiadi azine 1,1-dioxide6-chloro- 3-cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide6-chloro-3- cyclobutylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide6-bromo-3-ethylsulfanyl-4H- 1,2,4-benzothiadiazine 1,1-dioxide7-chloro-3- (5-chloro-2-methoxybenzyloxy)-4H-1, 2,4- benzothiadiazine 1,1-dioxide7-chloro-3-cyclobutoxy-4H-1,2,4-benzothiadiazine 1,1- dioxide7-chloro-3- (1-phenyl) ethoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide The compound 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 endocrinological system.
Since some KATp-openers are able to antagonize vasospasms in basilar or cerebral arteries the compound of the present invention can be used for the treatment of vaso- spastic disorders such as subarachnoid haemorrhage and migraine.
The compound of the present invention may also be used for the treatment of diseases associated with decreased skeletal muscle blood flow such as Raynauds disease and intermittent claudication.
Further, the compound of the invention may be used for the treatment of chronic airway diseases, including asthma, and for treatment of detrusor muscle instability secondary to bladder outflow obstruction and therefore for kidney stones by aiding their passage along the urethra.
The present compound could also be used for treatment of conditions associated with disturbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compound can be used for the treatment of premature labour and dysmenorrhea.
Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that such compound 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.
Further, potassium channel openers promote hairgrowth, therefore, the compound of the present invention can be used for the treatment of baldness.
Potassium channel openers also relax urinary bladder smooth muscle, thus, the compound of the present invention can be used for the treatment of urinary incontinence.
In diseases such as nesidioblastosis and insulinoma in which a hypersecretion of insulin causes severe hypoglycemia the compound 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 compound of the present invention, can be used for reducing the hyperinsulinemia and thereby prevent diabetes and reduce obesity. In overt NIDDM treatment of hyperinsulinemia with potassium channel openers, and hence the present compound,
can be of benefit in restoring glucose sensitivity and normal insulin secretions.
In early cases of insulin dependent diabetes (IDDM) or in prediabetic cases, potassium channel openers and hence the present compound can be used to induce pancreatic cell rest which may prevent the progression of the autoimmune disease.
The potassium channel openers of the present invention can be administered in combination with an immunosuppressant or with an agent like nicotinamide, which will reduce autoimmune degeneration of beta-cells.
Combining beta-cell rest with a treatment prctecting the beta-cells against cytokine mediated beta-cell impairment/cytotoxicity is another aspect of this invention.
Insulin requiring or Type 1 diabetes (IDDM) as well as late onset IDDM (also known as type 1.5. e. g. non-insulin-requiring Type 2 (NIIDM) patients with autoreactivity against beta-cell epitopes that later turns insulin requiring) have circulating autoreactive mono- cytes/lymphocytes that homes to the islets/beta-cells and releases their cytokines. Some of these cytokines (e. g. interleukin-1 b (I L-1 b), tumour necrosis factor a (TNFa) and interferon g (IFNg)) are specifically toxic to the beta-cells, e. g. through the induction of nitric oxide (NO) and other free radicals. Inhibition of this cytotoxicity, e. g. by co- administring nicotinamide (NA), a derivative hereof or other cytokine protective com- pounds to the prediabetic/diabetic patients treated with the PCO compound is an example of this aspect. Nicotinamide belongs to the B-vitamin family and is derived from nicotinic acid by amidation of the carboxyl group. It processes none of nicotine's pharmacological properties. NA is converted into NAD+, which acts as a coenzyme for proteins involved in tissue respiration. NA has been propose to influence several of the putative intracellular molecular events following immune attack on the beta-cells. Animal experiments and early non-blinded experiments in humans have indicated a protective role of this compound against IDDM as well as in cytokine/immune mediated beta-cell destruction.
Yet another aspect of this application concerns the use of a PCO compound alone or in combination with the inhibitor of cytokine/immune mediated beta-cell impairment, in transplantation, e. g. islet transplantation into diabetes patients. The use of one or both of these treatments may reduce the risk of rejection of the transplanted islets/beta- cells/engineered beta-cells/pancreas.
Compound of the present invention which act as blockers of KATP-channels can be used for the treatment of NIDDM.
Preferably, the compound of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia and diabetes.
Accordingly, in another aspect the invention relates to a compound of the general formula I or a pharmaceuticaliy acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinaemia and treatment or prevention of diabetes.
Furthermore, the invention also relates to the use of the inventive compound of formula I as medicaments useful for treating hyperinsulinaemia and treating or preventing diabetes.
Optionally, the pharmaceutical composition of the invention may comprise a com- pound of formula I combine with one or more other pharmacologically active compound, e. g. an antidiabetic or other pharmacologically active material, including compound 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 sulphony- lureas, e. g. glibenclamide and glipizide; biguanides, e. g. metformin; benzoic acid derivatives, e. g. repaglinide; and thiazolidinediones, e. g. troglitazone and ciglitazone.
In yet another aspect, the present invention relates to methods of preparing the above mentioned compound. The methods comprises: a) reacting a compound of formula 11:
wherein Y is O or S and R5, Rs, R'and Re are as defined above with a compound of formula III R3-X(III) wherein R3 is as defined above and X is a leaving group such as halogen or sulfate, preferentially chloro, bromo or iodo to form a compound of the general formula I wherein Z is O or S. The rection may be carried out in a suitable solvent and in the presence of a base. b) reacting a compound of formula li: wherein Y is O and R5, Rs, R'and R8 are as defined above with a diazo compound of formula IV R'R"CNZ (IV) wherein R'and R"together as two substituents on methyl form a group R'R"CH meeting the criteria defined above for R3, to form a compound of the general formula I wherein Z is R3isR'R"CH.and c) reacting a compound of formula V:
wherein R5, Rs, R'and Re are as defined above and Q is a leaving group such as halogen, preferentially chloro, bromo, iodo; amino, trimethylamino, imidazol-1-yl, methylsulfanyl, methylsulfinyl or methylsulfonyl with a compound of formula VI : R3YH(VI) wherein R3 is as defined above and Y is O or S to form a compound of the general formula I wherein Z is O or S. The rection may be carried out in a suitable solvent and in the presence of a base. d) reacting a compound of formula VII : wherein R3, R5, R6, R7 and R8 are as defined above with an oxidizing agent to form a compound of the general formula I wherein Z is S (=O) or S (=O) 2. e) reacting a compound of formula VII :
wherein R3,R5,R5,R7 and R8 are as defined above with an aminating agent according to known procedures, see e. g. P. D. Kennenwell, J. B. Taylor, Chem. Soc. Rev. (1980) 477- 498 and P. D. Kennenwell, J. B. Taylor, Chem. Soc. Rev. (1975) 189-209, to form a compound of the general formula VIII wherein n is 1 or 2.
D reacting a compound of formula Vil: wherein R3,R5,R6,R7 and R8 are as defined above with an aminating agent and subse- quently an oxidizing agent, or vice versa, according to known procedures, e. g. P. D.
Kennenwell, J. B. Taylor, Chem. Soc. Rev. (1980) 477-498 and P. D. Kennenwell, J. B.
Taylor, Chem. Soc. Rev. (1975) 189-209, to form a compound of the general formula I wherein Z is S (=O) (=NR). g) reacting a compound of formula IX
wherein R5, R6, R'and Re are as defined above with CS2 in the presence of a base to give the corresponding sulfonylimino carbodithioate which in turn is treated with an alkylating agent of formula III R3-X(III) wherein R3 is as defined above and X is a leaving group such as halogen or sulfate, preferentially chloro, bromo or iodo to form a compound of formula X
which by ring-closure, e. g. by treatment with phosgene in a suitable solvent, forms a compound of the general formula 1. h) reacting a compound of formula Xi
wherein R3) R5, Rs, R'and R$ are as defined above and PG is a protecting group, e. g. substituted benzyl, with chlorosulfonyl isocyanate (CI-S02-NCO) and subsequent ring closure foillowed by removal of the protecting group to form a compound of formula 1.
The starting materials are either known compound or compound which may be prepared in analogy with the preparation of known compound or in analogy with known methods as described by e. g. Huang B.-S., et al., J. Med. Chem., 23,575-7 (1980), Ofitserov V. 1. et al., Khim. Geterotsikl. Soedin., 1119-22 (russ.) (1976), Topliss J. G., U. S.
3,641,017 (1972), Kotovskaya S. K. et al., Khim.-Farm. Zh., 13,54-57 (russ.) (1979), Meyer R. F., J. Heterocycl. Chem., 6,407-408 (1969), Hattori M., Yoneda M., Goto M., Bull. Chem. Soc. Jap., 46,1890-1 (1973), Williams T. R. and Cram D. J., J. Org. Chem., 38,20-26 (1973), T. Iwakawa, H. Tamura, Y. Hayase, Chem. Pharm. Bull. 38 (4), 1075-6 (1990), F. E. Nielsen, H. C. Hansen, J. B. Hansen, T. M. Tagmose, PCT Int. Appl. WO 97/ 26265, M. E. Arranz, S. Vega, Heterocycles 45,1767-1774 (1997).
PHARMACOLOGICAL METHODS The ability of the compound to interact with potassium channels can be determined by various methods. When patch-clamp techniques (Hamill O. P., Marty A., Neher E., Sakmann B. and Sigworth F. J., PlügersArch., 391,85-100 (1981)) are used the ionic current through a single channel of a cell can be recorde.
The activity of the compound as potassium channel openers can also be measured as relaxation of rat aorta rings according to the following procedure: A section of rat thoracic aorta between the aortic arch and the diaphragm was dissected out and mounted as ring preparations as described by Taylor P. D. et al, Brit J. Pharma-
col, 111,42-48 (1994).
After a 45 min. equilibration period under a tension of 2 g, the preparations were con- tracted to achieve 80% of the maximum response using the required concentration of phenylephrine. When the phenylephrine response reached a plateau, potential vasodila- tory 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 contracte tension. The potency of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue.
In the pancreatic b-cell the opening of the KATP-channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Cl 21 concentration according to the method of Arkhammar P. et al., J. Biol. Chem., 262,5448-5454 (1987).
-6Rb+ efflux from a ß-cell line The RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10 % fetal calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5 % C02/95 % air at 37°C. The cells were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/mi 86Rb+ and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 pI/well, and grown 24 hours before use in assay.
The plates were washed 4 times with Ringer buffer (150 mM NaCI, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCl2, 20 mM Sucrose, pH 7.1). Eighty pI Ringer buffer and 1 pI control-or test compound dissolve in DMSO was added. After incubation 1 h at room temperature with a lid, 50 ti of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 pLI MicroScint40 (Packard Instrument Company, CT, USA) added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32P program.
The calculation of EC50 and EmaX was done by SlideWrite (Advanced Graphics Software, Inc., CA, USA) using a four parameter logistic curve: y = (a-d)/ (1+ (x/c) 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 infinie concentration. EC50 = c and EmaX = d, when the curve is turned of at infinie concentrations.
The compound according to the invention are effective over a wide dose range. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day. A most preferable dosage is about 1 mg to about 100 mg per day. The exact dosage will depend upon the mode of administra- tion, 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.
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 beingpreferred.
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 enclose 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 enclose 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 adsorbe on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alco- hols, 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, preser- ving agents, sweetening agents or flavouring 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.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring sub- stances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolve in polyhydroxylated castor oil.
Tables, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tables, 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.
Generally, the compound are dispense in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains: Active compound 5.0 mg Lactosum 67.8 mg Ph. Eur.
AvicelQ) 31.4 mg Amberlite 1.0 mg Magnesii stearas 0.25 mg Ph. Eur.
EXAMPLES The process of preparing the compound of formula I is further illustrated in the following examples which, however, are not to be construed as limiting.
Intermediates General procedure for the preparation of 2,3-dihydro-3-oxo-4H-1,2,4-benzothiadiazine 1,1-dioxides The compound were obtained as described by Girard (Y. Girard et al., J. Chem. Soc.
Perkin I, 1043,1979) using nitromethane as the solvent for the rection of the appropriate aniline with chlorosulfonyl isocyanate. The crude product was purifie by dissolution in a 5 % w/v aqueous solution of sodium hydrogen carbonate (20-30 mL/g) or in a 2.5 % w/v methanol-wåter 1: 1 solution of sodium hydrogen carbonate (40-60 mL/g). The resulting suspension or solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 0 with 12N HCI. The precipitate was collecte by filtration, washed with water and dried (yields: 40-60 %).
In this way compound previously described as well as the following new compound could be made: 7-Fluoro-2,3-dihydro-3-oxo-4H-1,2,4-benzothiadiazine 1,1-dioxide; mp 275-277 OC 6-Fluoro-2,3-dihydro-3-oxo-4H-1,2,4-benzothiadiazine 1,1-dioxide The crude compound which contains the 8-fluoro-substituted derivative as a contai- nent was purifie by successive crystallization in hot water and methanol-ether. The compound however may contain a residual trace of the 8-fluoro-substituted derivative and is used without further purification; mp 260-262 OC 6-Bromo-2,3-dihydro-3-oxo-4H-1,2,4-benzothiadiazine 1,1-dioxide The crude compound which contains the 8-bromo-substituted derivative as a contai- nent was purifie by successive crystallization in hot water (two fold); mp >300 °C General procedure for the preparation of 3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxides
The appropriate 2,3-dihydro-3-oxo-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.1 mol) and phosporus pentasulfide (40-60 g) in anhydrous pyridine (250-300 mL) was reffuxed for 4-10 h (until completion of the rection monitored by t. l. c.). The solvent was removed by distillation under reduced pressure. The residue was dissolve in 2.5M NaOH (600 mL). The solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 0 with 12N HCI. The precipitate was collecte by filtration, washed with water and dissolve in a hot 5 % w/v aqueous solution of sodium hydrogen carbonate (400-600 mL) or in a 2.5 % w/v methanol-water 1: 1 solution of sodium hydrogen carbonate (800 mL). The resulting suspension was treated with charcoal, filtered, and the filtrate was adjusted to pH 0. The precipitate was collecte by filtration, washed with water and dried (yields: 60-80%).
In this way compound previously described as well as the following new compound could be made: 7-Bromo-2,3-dihydro-3-thioxo-4H-1,2,4-benzothiadiazine 1,1-dioxide; mp 209-211 °C 7-Fluoro-2,3-dihydro-3-thioxo-4H-1,2,4-benzothiadiazine 1,1-dioxide; mp 193-195 OC 6-Bromo-2,3-dihydro-3-thioxo-4H-1,2,4-benzothiadiazine 1,1-dioxide; mp 210-218 OC 6-Fluoro-2,3-dihydro-3-thioxo-4H-1,2,4-benzothiadiazine 1,1-dioxide; mp 246-248 °C The process of preparing the compound of formula I is further illustrated in the following examples which, however, are not to be construed as limiting.
General procedure for the preparation of 3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides The appropriate 3-thioxo-2,3-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.05 mol) was dissolve in a mixture of aqueous 2.5% w/v sodium hydrogen carbonate (280mL) and methanol (280 mL) and supplemented with an excess of methyl iodide (0.35 mol).
After stirring for 30-60 min (until completion of the rection monitored by t. l. c.), the resulting suspension was adjusted to pH 6. The suspension was concentrated to a
volume of 300 mL by distillation under reduced pressure. The precipitate was collecte by filtration, washed with water and dried (yields: 80-95%). In this way the following five compound were prepared: EXAMPLE1 7-lodo-3-methylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dioxide mp 271-273 °C.
EXAMPLE2 7-Fluoro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dioxi de mp 265-268 OC.
EXAMPLE 3 7-Methyl-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide mp 275-278 °C EXAMPLE4 7-Methoxy-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide mp 270-276 OC.
EXAMPLE5 5-Chloro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dioxi de mp 208-210 °C.
EXAMPLE6 7-Chloro-3-cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazi ne1,1-dioxide
Sodium bicarbonate (84mg, 1 mmol) was added to a solution of 7-chloro-2H-1,2,4- benzothiadiazine-3 (4H)-thione 1,1-dioxide (249 mg, 1 mmol) and bromomethylcyclo- propane (135 mg, 1 mmol) in dry DMF (2 ml). The rection mixture was stirred for 48 h at 60 OC and concentrated in vacuo. The residue was treated with water (2 mi) and the solid was collecte by filtration and dried giving 130 mg (43%) of the title compound; mp 214-215 °C, 1H-NMR (d6-DMSO): 0.36 (m, 2H), 0.57 (m, 2H), 1.13 (m, 1 H), 3.09 (d, 2H), 7.29 (d, 1 H), 7.75 (dd, 1 H), 7.84 (d, 1 H), 12.65 (s, 1 H).
EXAMPLE7 7-Chloro-3-(3-trifluoromethylbenzylsulfanyl)-4H-1, 2,4-benzothiadiazine 1,1-dioxide By following a procedure analogous to the one described in EXAMPLE 6,3- trifluoromethylbenzyl bromide (239 mg, 1 mmol) was treated with 7-chloro-2H-1,2,4- benzothiadiazine-3 (4H)-thione 1,1-dioxide (249 mg, 1 mmol) to give 110 mg (27.4%) of the title compound; mp > 220 IC, 1 H-NMR (d6-DMSO): 3.0 (t, 2H), 3.75 (q, 2H), 7.41 (d, 2H), 7.89 (s, 1 H), 7.95 (s, 1 H), 8.05 (s, 2H), 8.62 (d, 2H), 9.5 (s, 1 H).
EXAMPLE8 7-Chloro-3- (3-methyl-but-2-enylsulfanyl)-4H-1, 2, 4-benzothiadiazine 1,1-dioxide By following a procedure analogous to the one described in EXAMPLE 6,3,3- dimethylallyl bromide (149 mg, 1 mmol) was treated with 7-chloro-2H-1,2,4- benzothiadiazine-3 (4H)-thione 1,1-dioxide (249 mg, 1 mmol) to give 90 mg (28.5%) of the title compound; mp: 170-172 °C, 1H-NMR (d6-DMSO): 1.68 (2xs, 6H), 3.82 (dd, 2H), 5.32 (m, 1H), 7.30 (d, 1H), 7.70 (dd, 1H), 7.83 (d, 1H), 12.65 (s, 1H).
General procedure for the preparation of 3-alkoxy-4H-1,2,4-benzothiadiazine 1,1- dioxides The appropriate 2,3-dihydro-3-oxo-4H-1,2,4-benzothiadiazine 1,1-dioxide (1.0 g) was dissolve in a solution of NaOH (1.0 equiv.) in methanol (10 mL) and stirred for 10 min. The solvent was removed by distillation under reduced pressure and the residue (sodium salt of the starting compound) was dissolve in DMF (20 mL). The approriate
alkyl haiide (1.5-2.0 equiv.) was added to the solution and the mixture was heated at 70-80 °C for 4-6 h (until completion of the rection checked by t. l. c.). Two com- pounds were usually formed: the title compound: 3-alkoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide, and the compound of N-alkylation: 2-alkyl-2,3-dihydro-3-oxo-4H-1,2,4- benzothiadiazine1,1-dioxide.
The solvent was removed by distillation under reduced pressure and the residue was suspende in distille water (30 mL). The suspension was adjusted to pH 14 with NaOH 5% w/v in water. The insoluble material was eliminated by filtration and the filtrate was treated with charcoal and filtered. The filtrate was carefully adjusted to pH 10 and the resulting precipitate (essentially the compound of N-alkylation) was collecte by filtration. The filtrate was ådjusted to pH 1 and the resulting precipitate (the compound of O-alkylation) was collecte by filtration, washed with water and dried.
In this way the following five compound were prepared: EXAMPLE9 7-Fluoro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate The title compound was obtained from 7-fluoro-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp 200-205 °C, IR (KBr): 3594, 3532,2988,1591,1543,1499,1317,1287,1260,1167,1092 cm-1.
EXAMPLE10 3-Cyclopropylmethoxy-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide hemihydrate The title compound was obtained from 7-fluoro-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopropylmethyl bromide; mp 153-156 °C, IR (KBr- ): 3478,3249,1618,1584,1538,1494,1368,1314,1256,1159 cm-1
EXAMPLE 11 3-Isopropoxy-7-methyl-4H-1, 2,4-benzothiadiazine 1,1-dioxide monohydrate The title compound was obtained from 7-methyl-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp212-215 °C, IR (KBr): 3574, 3519,2984,1589,1532,1501,1311,1281,1265,1169 cm-1.
EXAMPLE12 3-Isopropoxy-7-methoxy-4H-1, 2,4-benzothiadiazine 1,1-dioxide monohydrate The title compound was obtained from 7-methoxy-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp 162-176 °C, IR (KBr): 3570, 3513,3053,2983,1586,1541,1504,1318,1279,1170,1095 cm-1.
EXAMPLE13 7-Chloro-3-cyclopentyloxy-4H-1,2,4-benzothiadiazine 1,1-dioxide The title compound was obtained from 7-chloro-3-oxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopentyl bromide. The compound was purifie by refluxing in ethyl acetate for 20 min. The suspension was cooled and the insoluble material was collecte by filtration, washed with ethyl acetate and dried; mp >300 °C, IR (KBr): 3253,3188,3104,2952,2875,1617,1601,1580,1521,1480, 1337,1297,1252,1158, 1104cm-1.
General procedure for the preparation of 3-alkylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides
The appropriate 2,3-dihydro-3-thioxo-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.5 g) was dissolve (or suspende) in a mixture of acetonitrile (13 mL) and DMF (1 mL) and then supplemented with anhydrous potassium carbonate (0.5 g) and an excess of the appropriate alkyl halide (1.0-1.5 mL). The suspension was stirred at room tempera- ture for 24-72 h (until completion of the rection checked by t. l. c.). The solvent and the excess of the reagent were removed by distillation under reduced pressure and the residue was dissolve in a dilute (1-2%) aqueous or hydromethanolic 1: 1 solution of NaOH (10-20 mL). The solution was treated with charcoal, filtered off, and the filtrate was adjusted to pH 5-6. The resulting precipitate was collecte by filtration, washed with water and dried.
In this way the following seventeen compound were prepared: EXAMPLE14 7-Fluoro-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate The title compound was obtained from 7-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and ethyl bromide; mp 205-208 °C, IR (KBr): 3603, 3536,3078,3056,2980,2946,1634,1609,1564,1527,1494,1287,1268, 1233, 1197, cm-1.1134 EXAMPLE15 7-Fluoro-3-isopropylsulf anyl-4H-1,2,4-benzothiadiazine 1,1-dioxide hemihydrate The title compound was obtained from 7-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp 190-193 °C, IR (KBr): 3580, 3517,2976,2932,1563,1525,1492,1291,1266,1224,1193, 1156, 1134 cm-1.
EXAMPLE 16 3-Cyclopropylmethylsulfanyl-7-fluoro-4H-1,2,4-benzothiadiazi ne1,1-dioxide The title compound was obtained from 7-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopropylmethyl bromide; mp 218-224 °C, IR (KBr): 3237,3073,1552,1521,1487,1303,1260,1224, 1193, 1150, 1130 cm-1.
EXAMPLE17 74Chloro-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide The title compound was obtained from 7-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and ethyl bromide; mp 252-255 °C, IR (KBr): 3233, 3186,3090,1605,1555,1516,1477,1294,1254,1203,1156,1143,1108 cm-1.
EXAMPLE18 7-Bromo-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dioxide The title compound was obtained from 7-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and ethyl bromide; mp 277-278 °C, IR (KBr): 3234, 3184,3084,1608,1598,1552,1513,1478,1293,1252,1202,1156,1144, 1092 cm-1.
EXAMPLE19 7-Bromo-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
The title compound was obtained from 7-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp 240-246 °C, IR (KBr): 3237, 3186,3089,1608,1597,1552,1511,1476,1297,1248,1201,1154, 1145,1091 cm-1.
EXAMPLE20 7-Bromo-3-cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazin e1,1-dioxide The title compound was obtained from 7-bromo-3-thioxo-2, 3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopropylmethyl bromide; mp 242-244 °C, IR (KBr): 3233,3183,3088,3012,1607,1598,1553,1517,1478,1296,1253, 1201,1157, 1146,1091 cm-1.
EXAMPLE21 6-Fluoro-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dioxid e The title compound was obtained from 6-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and ethyl bromide; mp 218-220 °C, IR (KBr): 3238, 3200,3153,3107,3081,1617,1558,1477,1297,1268,1206,1154, 1121 cm-1.
EXAMPLE22 3-Cyclopropylmethylsulfanyl-6-fluoro-4H-1,2,4-benzothiadiazi ne1,1-dioxide The title compound was obtained from 6-fluoro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopropylmethyl bromide; mp 208-211 °C, IR (KBr): 3237,3200,3155,3104,3075,1616,1557,1478,1301,1208,1155, 1121 cm-1.
EXAMPLE 23 6-Chioro-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide The title compound was obtained from 6-chloro-3-thioxo-2, 3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and ethyl bromide; mp 233-240 °C, IR (KBr): 3230, 3180,3099,3068,1605,1595,1557,1471,1297,1197, 1160, 1138,1096 cm-1.
EXAMPLE24 6-Chloro-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine1,1-di oxide The title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp 249-253 °C, IR (KBr): 3251, 3082,2967,1606,1553,1466,1300,1198, 1157, 1136,1090 cm-1.
EXAMPLE25 6-Chloro-3-cyclopropylmethylsulfanyl-4H-1,2,4-benzothiadiazi ne1,1-dioxide The title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclopropylmethyl bromide; mp 212-217 °C, IR (KBr): 3232,3179,3097,3064,1594,1555> 1471,1303,1196,1160, 1137,1095 cm-1.
EXAMPLE26 6-Chloro-3-cyclobutylsulfanyl-4H-1,2,4-benzothiadiazine1,1-d ioxide
The title compound was obtained from 6-chloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclobutyl bromide; mp 251-254 °C, IR (KBr): 3224, 3173,3064,2984,1606,1552,1463,1300,1196, 1157, 1121,1088 cm-1.
EXAMPLE27 6-Bromo-3-ethylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dioxide The title compound was obtained from B-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and ethyl bromide; mp 269-273 °C, IR (KBr): 3232, 3177,3078,3056,2984,1603,1557,1518,1465,1293,1202,1159,1140, 1082 cm-1.
EXAMPLE28 6-Bromo-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine1,1-dio xide The title compound was obtained from 6-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; mp 244-252 °C, IR (KBr): 3239, 3178,3073,2970,2927,1597,1552,1465,1291, 1198, 1163, 1137, 1082 cm-1.
EXAMPLE29 6-Bromo-3-cyclobutylsulfanyl-4H-1,2,4-benzothiadiazine1,1-di oxide The title compound was obtained from 6-bromo-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and cyclobutyl bromide; mp 265-270 °C, IR (KBr): 3224, 3168,3071, 2980,1592,1548,1460,1300,1196, 1157, 1119,1077 cm-1.
EXAMPLE 30 6,7-Dichloro-3-isopropylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide The title compound was obtained from 6,7-dichloro-3-thioxo-2,3-dihydro-4H-1,2,4- benzothiadiazine 1,1-dioxide and isopropyl iodide; m. p.: >300°C, IR (KBr): 3252, 3183,3089,1612,1557,1459,1303,1286,1160 cm-1.
General procedure for the preparation of 3-alkylsulfinyl-4H-1,2,4-benzothiadiazine 1,1- dioxides The appropriate 3-alkylsulfanyl*4H-1,2,4-benzothiadiazine 1,1-dioxide (1.0 mmol) was suspende in distille water (25 mL) and supplemented with sodium carbonate (1.1 mmol) and a few drops of dilute NaOH until complete dissolution. Bromine (1.1 mmol) was then added under vigorous stirring and the resulting suspension was stirred for 30 min. at room temperature. The suspension was adjusted to pH 4-5 and the insoluble material was collecte by filtration, washed with water and dried. The crude com- pound was recrystallized in the appropriate solvent.
In this way the following compound was prepared: EXAMPLE31 7-Chloro-3-isopropylsulfinyl-4H-1,2,4-benzothiadiazine 1,1-dioxide The title compound was obtained from the rection of 7-chloro-3-isopropylsulfanyl-4H- 1,2,4-benzothiadiazine 1,1-dioxide with bromine in alkaline medium as described above. The crude compound was purifie by stirring in methanol. The insoluble material was collecte by filtration and suspende in diethylether (two fold). The insoluble compound was collecte by filtration, washed with diethylether and dried; mp 257-260 °C, IR (KBr): 3148,2977,1606,1570,1507,1477,1326,1173, 1110,1060,1028 cm-1.
EXAMPLE 32 7-Chloro-3-cyclopentyloxy-4H-1, 2,4-benzothiadiazine 1.1-dioxide A solution of 7-chloro-2H-1,2, 4-benzothiadiazin-3(4H)-one 1,1-dioxide sodium salt (0.75 g), cyclopentyl bromide (1.55 moi), and potassium tert-butoxide (0.17 g) in dry DMF (3 mi) was heated at 55-60 °C for 48 h. The solvent was evaporated and the residue was triturated with 25 ml of water. The precipitate was collecte by filtration, washed with water and dried. Recrystallization from methanol gave the title com- pound as white crystals; mp 332 - 34 °C, 1H-NMR(DMSO-d6) # :(ppm) 12.20 (br, 1 H), 7.82 (d, J = 2 Hz, 1 H), 7.70 (dd, 1 H), 7.29 (d, J = 9 Hz, 1 H), 5.41-5.28 (m, 1 H), 2.1-1.5 (m, 8H).
EXAMPLE 33 7-Chloro-3-(5-chloro-2-methoxybenzyloxy)-4H-1,2 4-benzothiadiazine 1.1-dioxide The title compound was prepared from 7-chloro-2H-1,2,4-benzothiadiazin-3 (4H)-one 1,1-dioxide sodium salt and 5-chloro-2-methoxybenzyl chloride by a procedure analogous to the procedure described in example 32;'H-NMR (DMSO-ds) 8 (ppm): 12.40 (s, 1 H), 7.85 (d, J = 2 Hz, 1 H), 7.71 (dd, 1 H), 7.55 (d, J = 2 Hz, 1 H), 7.46 (dd, 1 H), 7.28 (d, J = 6 Hz, 1 H), 7.11 (d, J = 6 Hz, 1 H), 5.32 (s, 2H), 3.83 (s, 3H), IR(KBr) v [cm-11 = 3237,3175,3104,3043,2941,2844,1621,1601,1581,1486, 1400,1330,1298,1254,1167,1128,1107,1017.
EXAMPLE 34 7-Chloro-3-cyclopropylmethoxy-4H-1. 2. 4-benzothiadiazlne 1.1-dioxide The title compound was prepared from 7-chloro-2H-1,2, 4-benzothiadiazin-3(4H)-one 1,1-dioxide sodium salt and cyclopropylmethyl bromide by a procedure analogous to the procedure described in example 32 ; 1H-MR(DMSO-d6) # (ppm) : 12.35 (br, 1 H), 7.82 (d, J = 2Hz), 7.71 (dd, 1H), 7.29 (d, J = 9 Hz, 1 H), 4.18 (d, J = 7 Hz), 1.35- 1.13 (m, 1 H), 0.68-0.35 (m, 4H), IR (KBR) v [cm-11 = 3251,3187,3107,3029, 1619,1602,1583,1525,1480,1387,1353,1297,1252,1162,1107,974.