AU3595799A - Substituted guanidines and diaminonitroethenes, their preparation and use - Google Patents

Description

WO 99/58497 PCT/DK99/00251 Substituted Guanidines and Diaminonitroethenes, their Preparation and Use FIELD OF THE INVENTION 5 The present invention relates to substituted guanidines and diaminonitroethenes, to methods for their preparation, to compositions comprising the compounds, to the use of these com pounds as medicaments and their use in therapy e.g. in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastroin testinal system and the endocrinological system. 10 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 15 ATP-sensitive (KATP-) channels which are regulated by changes in the intracellular con centration of adenosine triphosphate. The KATP-channels have been found in cells from vari ous tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, cen tral neurons and adenohypophysis cells. The channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth 20 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 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 25 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 compounds, ha ve been found to be able to relax vascular smooth muscles and have therefore been used 30 for the treatment of hypertension. In addition, potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.

WO 99/58497 PCT/DK99/00251 2 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 5 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. 10 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 15 channels of the beta-cell can be used in combination with other compounds which may be used to treat non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus. Examples of such compounds are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenclamide and glucagon like peptide ( GLP1), inhibitors of a-glucosidases and hepatic enzymes 20 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 25 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 30 R. et al. Endocrinol. 133, 705-712, 1993). It is expected that compounds 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. In EP 310545 and EP 306451 N-N'-substituted cyanoguanidines are claimed for the use as curing agent for epoxy resins.

WO 99/58497 PCT/DK99/00251 3 In WO 9211233, US 5525742-A, EP-747374-A1,EP 354553 and EP 405525 derivatives of the N-cyano-N'-aryl-N"-alkyl-guanidine type have been claimed as potassium channel acti vators related to smooth muscles. Cyanoguanidines have recently been described by K. Yoshizumi et al Chem. Pharm. Bull. 44 5 (11) 2042-2050 (1996) and K. Yoshizumi et al Chem. Pharm. Bull. 45 (12) 2005-2010 (1997). Derivatives of N-cyano-N'-aryl-N"-aryl-guanidines have been claimed in WO 9422807. N-aryl-N'-alkyl-2-nitro-1,1-ethenediamines have been described in U.S Pat. 4567.188 in J.Med.Chem 35 , 2327-2340 (1992) the synthesis of N-aryl-N'-alkyl-2-nitro-1,1 10 ethenediamine and N-heteroaryl-N'-alkyl-2-nitro-1, 1 -ethenediamine and their properties as agents for relaxation of smooth muscle are described . Fluorine-containing arylcyanoguanidines have been described by E. G. Belezertseva et al in Khim.-Farm. Zh. (1997), 31 (6), 11-13. 15 DESCRIPTION OF THE INVENTION The present invention relates to compounds of the general formula I:

R

3 2 R4 R 2N N H H R wherein 20 R' and R 2 are independently hydrogen, trifluoromethyl or halogen;

R

3 is trifluoromethyl, methoxy or halogen;

R

4 is straight or branched C 1

.

12 -alkyl,. C 2

-

12 -alkenyl, C 2

>

2 -alkynyl or C 3

-

8 -cycloalkyl optionally 25 substituted with C 3

-

8 -cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C 16 -alkoxy, C1 alkylthio, arylthio, C 16 -alkylamino, C 16 -dialkylamino, heteroaryl, heteroarylalkyl or aryl, any or heteroaryl group optionally being substituted with halogen or trifluoromethyl; or

R

4 is Y-R', Y being -0- or -N(R6)- WO 99/58497 PCT/DK99/00251 4

R

5 and R 6 are independently straight or branched C 1 12 -alkyl, C 2 .>-alkenyl, C 2 .>-alkynyl or C. 8 -cycloalkyl optionally substituted with C 38 -cycloalkyl, halogen, hydroxy, heteroaryl, heteroarylalkyl, aryloxy or aryl, any aryl or heteroaryl group optionally being substituted with halogen or trifluoromethyl; 5 or R 5 and R 6 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen,

C

1

.

6 -alkyl, hydroxy, C 1

.

6 -alkoxy, C 1

.

6 -alkoxy-C 6 -alkyl, nitro, amino, cyano, trifluoromethyl, Cj_ 6 -monoalkyl- or dialkylamino or oxo; 10 X is N-CN or CH-NO 2 ; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof. 15 The salts include pharmaceutically acceptable acid addition salts, pharmaceutically accepta ble metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malo nic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethane 20 sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like. The term "C 16 -alkoxy" as used herein, alone or in combination, refers to a straight or bran 25 ched monovalent substituent comprising a C 1 --alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy. The term "Ce 6 -alkylthio" as used herein, alone or in combination, refers to a straight or bran 30 ched monovalent substituent comprising a lower alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio.

WO 99/58497 PCT/DK99/00251 5 The term "cycloalkyl" as used herein refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclo hexyl. 5 The terms "C2- 12 -alkenyl" as used herein refers to an unsaturated hydrocarbon chain having 2-6 or 2-18 carbon atoms and one double bond such as e.g. vinyl, 1-propenyl, allyl, isopro penyl, n-butenyl, n-pentenyl and n-hexenyl. The term "C 2

.>

2 -alkynyl" as used herein refers to unsaturated hydrocarbons which contain 10 triple bonds, such as e.g. -C=CH, -C=CCH 3 , -CH 2 C=CH,

-CH

2

CH

2 C=CH, -CH(CH 3 )CaCH, and the like. The term "C 6 -alkoxy-C 6 -alkyl" as used herein refers to a group of 2-12 carbon atoms in terrupted by an 0 such as e.g. CH 2 -0-CH 3 , CH 2 -0-CH 2

-CH

3 , CH 2 -0-CH(CH 3

)

2 and the like. 15 The term "halogen" means fluorine, chlorine, bromine or iodine. The term "perhalomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl or triiodo methyl. 20 The terms "C 12 -alkyl", as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2 methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2 25 dimethylpropyl, 1, 2,2-trimethylpropyl and the like. The term "C 18 -alkyl" as used herein also includes secondary C 3

-

6 -alkyl and tertiary C4.

6 -alkyl. The term "C 1 .- monoalkylamino" as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a straight or branched, saturated hydrocarbon chain ha 30 ving the indicated number of carbon atoms such as e.g. methylamino, ethylamino, propyla mino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, 2 methylbutylamino, n-hexylamino, 4-methylpentylamino, neopentylamino, n-hexylamino, 2,2 dimethylpropylamino and the like.

WO 99/58497 PCT/DK99/00251 6 The term "C 1 .- dialkylamino" as used herein refers to an amino group wherein the two hy drogen atoms independently are substituted with a straight or branched, saturated hydrocar bon chain having the indicated number of carbon atoms; such as dimethylamino, N-ethyl-N methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n-pentyl)amino, 5 and the like. The term "3-12 membered mono- or bicyclic system" as used herein refers to a monovalent substituent of formula -NR 2

R

3 or -NR 11 R where R 2 and R 3 , or R 1 1 and R 1 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the 10 carbon atoms may be exchanged with nitrogen, oxygen or sulfur, such as 1-pyrrolidyl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7-azabicyclo[2.2.1]heptan-7 yl, tropanyl and the like. The term "aryl" as used herein refers to phenyl, 1-naphthyl, or 2-naphthyl. 15 The term "heteroaryl" as used herein, alone or in combination, refers to a monovalent sub stituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicy clic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazi 20 ne, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazo line, quinoxaline, indole, benzimidazole, benzofuran, pteridine, and purine. The term "arylalkyl" as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, 25 phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like. The term "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy. The term "arylalkoxy" as used herein refers to a C 1

.

6 -alkoxy group substituted with an aro 30 matic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like. The term "heteroarylalkyl" as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2- WO 99/58497 PCT/DK99/00251 7 furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl 1-(2-pyrimidyl)ethyl and the like. The term "aryithio" as used herein, alone or in combination, refers to an aryl group linked 5 through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono- or polysubstituted with C 1

.

6 -alkyl, halogen, hydroxy or C 1

.

6 -alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio, and the like. In a preferred embodiment of the invention R 3 is selected from trifluoromethyl and R 2 from 10 hydrogen or trifluoromethyl. In another preferred embodiment of the invention R 2 and R 3 are selected from halogen and

R

4 is branched C 112 -alkyl. 15 Further preferred compounds are those where R 2 and R 3 are selected from halogen and R 4 is C 5 -alkyl, branched at the C(2), C(3) or C(4) carbon atom counted from the attachment to the nitrogen atom, in particular compounds where R 2 and R 3 both are chloro. Preferred compounds of the invention are: 20 N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-methylbutyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-(4-pyridinyl)ethyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1,2,2-trimethylpropyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-cyclopentylpropyl)guanidine 25 N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-cyclopropylethyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(cyclopentyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1,2-dimethylpropyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-chlorobenzyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-chlorobenzyl)guanidine 30 N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentylpropyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-cyclopropylethyl)guanidine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(1,2,2-trimethylpropyl)-2-nitro-1 ,1 -ethenediamine WO 99/58497 PCT/DK99/00251 8 N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-methylbutyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-cyclopentylpropyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(2-cyclopropylethyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(cyclopentyl)-2-nitro- 1 -ethenediamine 5 N-(3,5-bis(trifluoromethyl)phenyl)-N'-((1,2-dimethylpropyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(2-chlorobenzyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-chlorobenzyl)-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(3-cyclopentylpropyl)-2-nitro-1, 1 -ethenediamine 10 N-(3,5-dichlorophenyl)-N'-(cyclopentyl)-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(2-chlorobenzy )-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(3-chlorobenzyI )-2-nitro-1,1-ethenediamine N-(3,5-dichlorophenyl)-N'-(2-cyclopropylethyl)-2-nitro-1, 1 -ethenediamine N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-(1,1 -dimethylpropyl)guanidine 15 N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1 -methylethyl)-guanidine N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-propyl-guanidine N-Cyano-N'-(3-trifluoromethylphenyl)-N"-cyclopentylguanidine N-Cyano-N'-isopropyl-N"-(3-trifluoromethylphenyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine 20 N-Cyano-N'-cyclopentyl-N"-(3,5-dichlorophenyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1 -methylethyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-propylguanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-methylbutyl)-guanidine N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine 25 N-Cyano-N'-(3-methoxy-5-trifluoromethylphenyl)-N"-(3-methylbutyl)guanidine The use of the following known compounds as medicaments and their use in therapy e.g. in the treatment of diseases in the endocrinological system is also a preferred embodiment of the invention: 30 N-Cyano-N'-(3-trifluoromethylphenyl)-N"-(1,2,2-trimethylpropyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,2,2-trimethylpropyl)-guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1 ,1-dimethylpropyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1, 1 -dimethylbutyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-t-pentylguanidine WO 99/58497 PCT/DK99/00251 9 N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1 -ethyl-1 -methylpropyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-t-butylguanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,1,2-trimethylpropyl)guanidine and N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1, 1 -diethylpropyl)guanidine. 5 The compounds of the present invention interact with the potassium channels and hence act as openers or blockers of the ATP-regulated potassium channels, which make them useful in the treatment of various diseases of the cardiovascular system, e.g. cerebral ischemia, hy pertension, ischemic heart diseases, angina pectoris and coronary heart diseases; the pul 10 monary system; the gastrointestinal system; the central nervous system and the endocrino logical system. Since some KATP-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 disor 15 ders such as subarachnoid haemorrhage and migraine. The compounds of the present invention may also be used for the treatment of diseases as sociated with decreased skeletal muscle blood flow such as Raynauds disease and inter mittent claudication. 20 Further, the compounds of the invention may be used for the treatment of chronic airway diseases, including asthma, and for treatment of detrusor muscle instability secondary to bladder outflow obstruction and therefore for kidney stones by aiding their passage along the urethra. 25 The present compounds could also be used for treatment of conditions associated with dis turbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compounds can be used for the treatment of premature labour and dysmenorrhea. 30 Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that such compounds can be used for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the management of pain.

WO 99/58497 PCT/DK99/00251 10 Further, potassium channel openers promote hairgrowth, therefore, the compounds of the present invention can be used for the treatment of baldness. Potassium channel openers also relax urinary bladder smooth muscle, thus, the compounds 5 of the present invention can be used for the treatment of urinary incontinence. In diseases such as nesidioblastosis and insulinoma in which a hypersecretion of insulin causes severe hypoglycemia the compounds of the present invention can be used to reduce insulin secretion. In obesity hyperinsulinemia and insulin resistance is very frequently 10 encountered. This condition could lead to the development of non insulin dependent diabetes (NIDDM). It is expected that potassium channel openers, and hence the compounds of the present invention, can be used for reducing the hyperinsulinemia and thereby prevent diabetes and reduce obesity. In overt NIDDM treatment of hyperinsulinemia with potassium channel openers, and hence the present compounds, can be of benefit in 15 restoring glucose sensitivity and normal insulin secretions. Owing to the efficiency of the present compounds to improve glucose sensitivity they are useful for the treatment and/or prevention of ailments and disorders involving elevated plas ma blood glucose, such as hyperglycaemia. Furthermore, they may find use in the treatment 20 and/or prevention of dyslipidemia, Type I diabetes, NIDDM, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance, obesity, diabetic dyslipidemia, hyperlipide mia and hypertension. In early cases of insulin dependent diabetes (IDDM) or in prediabetic cases, potassium 25 channel openers and hence the present compounds can be used to induce pancreatic cell rest which may prevent the progression of the autoimmune disease. The potassium channel openers of the present invention can be administered in combination with an immunosuppressant or with an agent like nicotinamide, which will reduce 30 autoimmune degeneration of beta-cells. Combining beta-cell rest with a treatment protecting the beta-cells against cytokine mediated beta-cell impairment/cytotoxicity is another aspect of this invention.

WO 99/58497 PCT/DK99/00251 11 Insulin requiring or Type 1 diabetes (IDDM) as well as late onset IDDM (also known as type 1.5. e.g. non-insulin-requiring Type 2 (NIDDM) patients with autoreactivity against beta-cell epitopes that later turns insulin requiring) have circulating autoreactive monocy tes/lymphocytes that homes to the islets/beta-cells and releases their cytokines. Some of 5 these cytokines (e.g. interleukin-1b (IL-1b) , tumour necrosis factor a (TNFa) and interferon y (IFNy)) are specifically toxic to the beta-cells, e.g. through the induction of nitric oxide (NO) and other free radicals. Inhibition of this cytotoxicity, e.g. by co-administring nicotinamide (NA), a derivative hereof or other cytokine protective compounds to the prediabetic/diabetic patients treated with the PCO compound is an example of this aspect. Nicotinamide belongs 10 to the B-vitamin family and is derived from nicotinic acid by amidation of the carboxyl group. It processes none of nicotine's pharmacological properties. NA is converted into NAD+, which acts as a coenzyme for proteins involved in tissue respiration. NA has been proposed to influence several of the putative intracellular molecular events following immune attack on the beta-cells. Animal experiments and early non-blinded experiments in humans have indi 15 cated a protective role of this compound against IDDM as well as in cytokine/immune medi ated beta-cell destruction. Yet another aspect of this application concerns the use of a PCO compound alone or in combination with the inhibitor of cytokine/immune mediated beta-cell impairment , in trans plantation, e.g. islet transplantation into diabetes patients. The use of one or both of these 20 treatments may reduce the risk of rejection of the transplanted islets/beta-cells/engineered beta-cells/pancreas. Compounds of the present invention which act as blockers of KATP -channels can be used for the treatment of NIDDM. 25 Preferably, the compounds of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia and diabetes. Accordingly, in another aspect the invention relates to a compound of the general formula 1 30 or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically ac ceptable substance, preferably for use as a therapeutically acceptable substance in the tre atment of hyperinsulinaemia and treatment or prevention of diabetes.

WO 99/58497 PCT/DK99/00251 12 Furthermore, the invention also relates to the use of the inventive compounds of formula I as medicaments useful for treating hyperinsulinaemia and treating or preventing diabetes. Optionally, the pharmaceutical composition of the invention may comprise a compound of 5 formula I combined with one or more other pharmacologically active compounds, e.g. an an tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism. Suitable antidiabetics comprise insulin as well as orally ac tive hypoglycaemic agents such as sulphonylureas, e.g. glibenclamide and glipizide; bigua 10 nides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide;and thiazolidinediones, e.g. troglitazone and ciglitazone. The compounds of the present invention may be prepared by various methods known to those skilled in the art. For example the methods for preparation of 2-nitro-1,1 15 ethenediamines by Niemers et al. U.S Pat, 4,567,188 and P.W Manley et al. J.Med.Chem. 35, 2327-2340 (1992): R3 R3 R3

NO

2 NO 2

R

4

NH

2

NO

2 R2 NH2 S S_ R2 N S R2 N N'R 4 H H H R1 R1 R1 Or using the methods by H.J Petersen et al. J. Med. Chem. 21, 773-781 (1978) R3 R3 R3 N CN N CN R 4 NH2 N'CN R2 NH 2 Ph, 0 OPh R2 N O'Ph R2 N NR4 R1 R1 R1 20 R3 R3

H

2 X X R2 N N R2 N R4 R2 15 WR4H H R1 R1 X= NCN, CHNO 2 WO 99/58497 PCT/DK99/00251 13 The starting materials are either known compounds or compounds which may be prepared in analogy with the preparation of known compounds or in analogy with known methods as described in Kogyo Kagaku Zashi, 59,(6) 1-33 (1956) and Zh. Obshch. Khim., 35, 2055 5 (1965). PHARMACOLOGICAL METHODS The ability of the compounds to interact with potassium channels can be determined by vari 10 ous methods. When patch-clamp techniques (Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J., PlOgers Arch., 391, 85-100 (1981)) are used the ionic current through a single channel of a cell can be recorded. The activity of the compounds as potassium channel openers can also be measured as rela 15 xation of rat aorta rings according to the following procedure: A section of rat thoracic aorta between the aortic arch and the diaphragm was dissected out and mounted as ring preparations as described by Taylor P.D. et al , Brit J. Pharmacol, 111, 42-48 (1994). 20 After a 45 min. equilibration period under a tension of 2 g, the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephri ne. When the phenylephrine response reached a plateau, potential vasodilatory agents were added cumulatively to the bath in small volumes using half log molar increments at 2 min 25 intervals. Relaxation was expressed at the percentage of the contracted tension. The poten cy of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue. Relaxation of rat aorta rings 30 Example 1 EC 50 5.6 micro M 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 Ca 2 concentration accor ding to the method of Arkhammar P. et al. , J. Biol. Chem., 262, 5448-5454 (1987). 35 WO 99/58497 PCT/DK99/00251 14 An opening of KATP-channels will result in an efflux of potassium ions. By measuring the release of 86 Rb* (a radioactive potassium mimic) from e.g. beta-cells pre-incubated in the presence of seRb* the effect of compounds acting as potassium channel openers can be determined. The test expresses the ability of the compounds to regulate the secretion of 5 insulin from the beta-cells. 56 Rb* efflux from a B-cell line The RIN 5F cell line was grown in RPMI 1640 with Glutamax 1, supplemented with 10 % fetal 10 calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5 % CO 2 / 95 % air at 370C. The cells were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/mi 1 6 Rb* and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 I./well, and grown 24 hours before use in assay. 15 The plates were washed 4 times with Ringer buffer (150 mM NaCl, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCl 2 , 20 mM Sucrose, pH 7.1). Eighty pl Ringer buffer and 1 pI control- or test compound dissolved in DMSO was added. After incubation 1 h at room temperature with a lid, 50 pl of the supernatant was transferred to PicoPlates (Packard Instrument Company, 20 CT, USA) and 100 p.1 MicroScint40 (Packard Instrument Company, CT, USA) added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 1 2 P program. The calculation of EC 50 and Emax was done by SlideWrite (Advanced Graphics Software, Inc., 25 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 infinite concentration. EC 50 = c and Emax= d, when the curve is turned of at infinite concentrations. 30 Increased Rb-efflux in rin 5F cells Example 1 EC 5 0 2.6 micro M WO 99/58497 PCT/DK99/00251 15 The effect of KATP-channel modulators on pancreatic beta-cells can be determined by measu ring qualitative changes in membrane potential in the insulin producing cell line p-TC3 using fluorescence imaging techniques. The slow fluorescent membrane potential probe DiBAC was used. The cells were kept in 5 Ca 2 . -HEPES buffer supplemented with 10 mM glucose. After 5 s of each 60 s run the com pound was added. 48 wells were run in each set, taking about 1 h. The same cells were then run again, now adding 25 mM KCI after 5 s, and the depolarisation-induced increase in Di BAC fluorescence monitored for 55 s. 10 In addition the effect of KATP-channel modulators on pancreatic beta-cells can be determined by measuring the increase or decrease in insulin release from insulin producing beta-cell li nes or isolated islets. Effect of KATP-channel modulators can be measured using the following procedure: 15 The beta cells are cultured with change of media every three-four days. Cells are then seeded in 96 well microtiter dishes and cultured for three day at 38 0C, 5% C02 and 95% humidity. The cells are washed with NN -buffer (+10mM Hepes + 0.1% BSA) for one minute and glucose (final conc. 22 mM), IBMX (final conc.0.1mM) and compounds (final conc. from 5 x 20 10-5 M - 5 x 10-8 M) added. All cells are then incubated for three hours (38 C, 5% C02 and 95% humidity). Supernates are harvested into Greiner minisorb microtiter wells and frozen. Insulin is measu red using elisa-techniques. 25 The compounds according to the invention are effective over a wide dose range. In general satisfactory results are obtained with dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day. A most preferable dosage is about 1 mg to about 100 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be trea 30 ted, and the preference and experience of the physician or veterinarian in charge. The route of administration may be any route, which effectively transports the active com pound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, WO 99/58497 PCT/DK99/00251 16 transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred. Typical compositions include a compound of formula I or a pharmaceutically acceptable acid 5 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, conventio nal techniques for the preparation of pharmaceutical compositions may be used. For exam ple, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclo 10 sed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active com pound can be adsorbed on a granular solid container for example in a sachet. Some exam ples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxy 15 ethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulo se and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delay 20 ed release of the active ingredient after administration to the patient by employing procedu res well known in the art. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances 25 and the like, which do not deleteriously react with the active compounds. For parenteral application, particularly suitable are injectable solutions or suspensions, prefe rably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. 30 Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or cap sules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in ca ses where a sweetened vehicle can be employed.

WO 99/58497 PCT/DK99/00251 17 Generally, the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage. A typical tablet, appropriate for use in this method, may be prepared by conventional tablet 5 ting techniques and contains: Active compound 5.0 mg Lactosum 67.8 mg Ph.Eur. Avicel@ 31.4 mg 10 Amberlite@ 1.0 mg Magnesii stearas 0.25 mg Ph.Eur. EXAMPLES 15 The process of preparing the compounds of formula I is further illustrated in the following e xamples which, however, are not to be construed as limiting. EXAMPLE 1 20 N-Cyano-N'-(3.5-bis(trifluoromethyl)phenyl)-N"-(3-methylbutyl)guanidine a) N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea 25 A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5 bistrifluoromethylaniline (2 mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml) was stirred under nitrogen for 12 h. After concentration the residue was stirred with toluene (5 ml) for 2 h and the solid was collected by filtration giving 550 mg of N-(3,5-bis(trifluoromethyl)phenyl) 30 N'-cyano-O-phenylisourea (73.6%); 1 H-NMR (d 6 -DMSO): 6 7.25 (m, 5H), 7.95 (s, 1H), 8.15 (s, 2H), 11.2 (s, 1H). b) N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-methylbutyl)guanidine WO 99/58497 PCT/DK99/00251 18 A solution of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg), 3-methylbutylamine (1.15 mmol,100 mg) and triethylamine (1.5 mmol, 150 mg) in acetonitrile (2 ml) was stirred for 24 h at 60 0C. After concentration the residue was purified by column chromatography (heptane:ethyl acetate 1:1) to give the title compound (100 mg, 27%). 5 1 H-NMR (d 6 -DMSO): 6 0.9 (d, 6H),1.45 (q, 2H), 1.65 (m,1H), 3.3 (q,2H), 7.7 (t, 1H), 7.79 (s, 1H), 7.95 (s, 2H), 9.45 (s,1H). EXAMPLE 2 10 N-Cyano-N'-(3.5-bis(trifluoromethyl)phenyl)-N"-(2-(4-pyridinyl)ethyl)guanidine By following a procedure analogous to the one described in EXAMPLE 1 b, N-(3,5 bis(trifluoromethyl)-phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg) was treated with 4 (2-aminoethyl)pyridine (1.15 mmol,140.5 mg) to give 110 mg (27%) of the title product; 15 1 H-NMR (d 6 -DMSO): 6 3.0 (t, 2H), 3.75 (q,2H), 7.41 (d,2H), 7.89 (s,1H), 7.95 (s, 1H), 8.05 (s, 2H), 8.62 (d, 2H), 9.5 (s, 1H). EXAMPLE 3 20 N-Cyano-N'-(3.5-bis(trifluoromethyl)phenyl)-N"-(cyclopentyl)guanidine To a suspension of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.400 g, 1.1 mmol) in dry acetonitrile (2.5 ml) triethylamine (0.164 ml, 1.2 mmol) and cyclopentylami 25 ne (0.116 ml, 1.2 mmol) was added. The homogenous solution was stirred at 850C under N 2 for 3.5 h. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with water twice. The organic layer was dried (Na 2

SO

4 ) and concentrated. The crude product was purified by flash chromatography using ethyl acetate/heptane 1:2 to give the title compound. Yield 82% (0.320 g). mp 156-1590C. 30 'H-NMR(CDCl 3 ): 6 8.87 (1H, broad s, NH); 7.78 (2H, s); 7.60 (1H, s); 5.50 (1H, broad d, NH); 4.20 (1H, sextet); 2.1 (2H, m); 1.75 (4H m); 1.55 ppm (2H, m). EXAMPLE 4 WO 99/58497 PCT/DK99/00251 19 N-Cyano-N'-(3.5-bis(trifluoromethyl)phenyl)-N"-(2-chlorobenzyl)guanidine By following a procedure analogous to the one described above in Examplel b, N-(3,5 bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.300 g, 0.8 mmol) was treated with 5 triethylamine (0.123 ml, 0.88 mmol) and 2-chlorobenzylamine (0.107 ml, 0.88 mmol) to give the title compound as a syrup. Yield 72% (0.234 g). 1 H-NMR(CDCl 3 ): 6 8.6 (1H, broad s, NH); 7.70 (3H, s); 7.45 (2H, m); 7.30 (2H,m); 5.85 (1H, broad s, NH); 4.60 (2H, d). 10 EXAMPLE 5 N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyll-N"-(1.2-dimethylpropyl)guanidine 15 a) N-[3.5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5-bis(trifluoromethyl)aniline (2 mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml) was stirred under nitrogen for 12 h. After concentration the residue was stirred with toluene (5 ml) for 2 h and the solid was collected by filtration giving 550 mg of N-[3,5 20 bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (73.6%); 1 H-NMR (d 6 -DMSO): 5 7.25 (m, 5H), 7.95 (s, 1H), 8.15 (s, 2H), 11.2 (s, 1H). b) N-Cyano-N'-[3.5-bis(trifluoromethyl)phenyll-N"-(1.2-dimethylpropyl)guanidine 25 A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 3-methyl-2-butylamine (0.88 mmol, 0.101 ml) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 7 h at 75 C. After concentration the residue was dis solved in ethyl acetate, washed with water, dried (Na 2

SO

4 ) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 4:1) to give the title com 30 pound (143 mg, 59%) as white crystals. Mp 134-136*C; El SP/MS: 366 (M+); 'H-NMR (CDCl 3 ): 5 0.92 (d, 6H),1.15 (d, 3H), 1.78 (m, 1H), 3.78 (m, 1H), 4.85 (br, 1H), 7.73 (br s, 3H), 8.0 ppm (br, 1H); MA calc for C1 5

H

1 6

F

6

N

4 : C 49.18%, H 4.40%, N 15.29%. Found: C 48.95%, H 4.38%, N 15.08%.

WO 99/58497 PCT/DK99/00251 20 EXAMPLE 6 N-Cyano-N'-[3.5-bis(trifluoromethyl)phenyl-N"-(1, 2.2-trimethylpropyl)guanidine A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 5 mg), 2-amino-3,3-dimethylbutane (0.88 mmol, 0.09 g) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 8 h at 75 *C. After concentration the residue was pu rified by column chromatography (heptane:ethyl acetate 2 :1) to give the title compound (140 mg, 46%) as white crystals. Mp 165.5-166.5*C; El SP/MS: 380 (M+); 1 H-NMR (CDC13): 6 0.92 (s, 9H),1.13 (d, 3H), 3.8 (m, 1H), 4.8 (br d, 1H), 7.74 (br s, 3H), 8.5 ppm (br, 1H); MA calc for 10 C 1 6H 18

F

6

N

4 : C 50.53%, H 4.77%, N 14.73%. Found: C 50.48%, H 4.74%, N 14.45%. EXAMPLE 7 15 N-Cyano-N'-[3.5-bis(trifluoromethyl)phenyl]-N"-(1, 1 -dimethylpropyl)guanidine A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.78 mmol, 290 mg), tert-amylamine (0.85 mmol, 0.100 ml) and triethylamine (0.85 mmol, 0.119 ml) in ace tonitrile (2 ml) was stirred for 25 h at 75 *C followed by work-up as described in EXAMPLE 5, b) to give the title compound (140 mg, 46%) as white crystals. Mp 149-1500C; El SP/MS: 20 366 (M+); 'H-NMR (CDCI 3 ): 8 0.85 (t, 3H),1.35 (s, 6H), 1.75 (q, 2H), 4.65 (br s, 1 H), 7.70 (br s, 3H), 8.95 ppm (br s, 1H); MA calc for C 15

H

1 6

F

6

N

4 . 0.15 H 2 0: C 49.37%, H 4.57%, N 14.76%. Found: C 49.72%, H 4.56%, N 14.76%. 25 EXAMPLE 8 N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1 -methylethyl)-guanidine N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and iso propylamine (1 ml) was stirred in a sealed flask for 19 h at 75 *C. After concentration the 30 residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2

SO

4 ) and concentrated. The residue was crystallised from ethyl acetate and heptane to give the title compound (114 mg, 45%) as white crystals. Mp 176-182*C; 1 H-NMR (CDCI 3 ): 6 1.25 (d, 6H), 4.07 (m, 1H), 5.5 (br d, 1H), 7.71 (br s, 1H), 7.75 (br s, 2H), 8.10 ppm (br, 1H); MA calc for C 13 Hl 2

F

6

N

4 : C 46.16%, H 3.58%, N 16.56%. Found: C 46.15%, H 3.64%, N 35 16.45%.

WO 99/58497 PCT/DK99/00251 21 EXAMPLE 9 N-Cyano-N'-[3.5-bis(trifluoromethyl)phenyll-N"-propyl-quanidine 5 N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and n propylamine (1 ml) was stirred in a sealed flask for 19 h at 75 0C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2

SO

4 ) and concentrated. The residue was purified by flash chromatography (ethyl acetate / heptane 1:2) to give the title compound (90 mg, 28%) as white crystals. Mp 142.5-143.5*C; 10 1 H-NMR (CDCl 3 ): 6 0.95 (t, 3H), 1.65 (sextet, 2H), 3.35 (q, 2H), 5.45 (br, 1H), 7.68 (br s, 1H), 7.80 (br s, 2H), 8.35 ppm (br, 1H); MA calc for C 13 Hl 2

F

6

N

4 : C 46.16%, H 3.58%, N 16.56%. Found: C 46.31%, H 3.65%, N 16.23%. 15 EXAMPLE 10 N-Cyano-N'-(3-trifluoromethylphenyl)-N"-cyclopentylguanidine a) N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea 20 To a solution of 3-trifluoromethylaniline (11 mmol, 1.37 ml) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g), and triethylamine (11 mmol, 1.53 ml) were added. The mixture was stirred under nitrogen for 23 h. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was 25 stirred with toluene and the solid was collected by filtration giving 1.42 g of N-(3 trifluoromethylphenyl)-N'-cyano-O-phenylisourea (50%); 'H-NMR (CDC13): 6 7.13 (d, 2H), 7.30 (t, 1H), 7,42 (t, 2H), 7.43 (d, 2H), 7.60 (m, 1H), 7.68 (s, 1 H), 9.3 ppm (br s, 1 H). El SP/MS: 305 (M+). 30 b) N-Cyano-N'-(3-trifluoromethylphenyl)-N"-cyclopentylquanidine N-(3-Trifluoromethylphenyl)-N'-cyano-O-phenylisourea (1 mmol, 290 mg) was stirred for 19 h at 80 *C in cyclopentylamine (1 ml). After concentration of the cold reaction mixture, the residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried 35 (Na 2

SO

4 ) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 3:1) to give the title compound (205 mg, 68%) as a syrup. Crystallisa- WO 99/58497 PCT/DK99/00251 22 tion from heptane:ethyl acetate 2:1 gave 147mg (49%). Mp 111.5-113*C; 'H-NMR (CDCI 3 ): 6 1.42 (m, 2H),1.65 (m, 4H), 2.05 (m, 2H), 4.12 (sextet, 1H), 4.85 (br, 1H), 7.35 (br s, 1H), 7.5 ppm (m, 4H); MA calc for C 14

H

15

F

3

N

4 : C 56.75%, H 5.10%, N 18.91%. Found: C 56.48%, H 5.08%, N 18.65%. 5 EXAMPLE 11 N-Cyano-N'-isopropyl-N"-(3-trifluoromethylphenyl)quanidine 10 To a solution of N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 286 mg) in dry acetonitrile (2 ml), isopropylamine (0.184 ml) and triethylamine (0.150 ml) were added. The mixture was stirred for 42 h at room temperature under nitrogen. After concentration the 15 residue was purified by flash chromatography (ethyl acetate / heptane 1:2) to give the title compound (210 mg, 79%) as a syrup. Crystallisation from ethyl acetate / heptane 1:3 gave white crystals (165 mg, 62%). Mp 109-111*C; 1 H-NMR (CDCl 3 ): 6 1.20 (d, 6H), 4.05 (m, 1H), 4.67 (br d, 1 H), 7.42 (m, 1 H), 7.50 (s, 1 H), 7.55 (m, 2H), 7.68 ppm (br, 1 H); MA calc for

C

12

H

13

F

3

N

4 : C 53.33%, H 4.85%, N 20.73%. Found: C 53.61%, H 4.92%, N 20.67%. 20 EXAMPLE 12 N-Cyano-N'-(3.5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine 25 a) N-Cyano-N'-(3.5-dichlorophenyl)-O-phenylisourea 30 To a solution of 3,5-dichloroaniline (11 mmol,1.79 g) in dichloromethane (25 ml), diphenyl cyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 65 h at room temperature. After concen tration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 2.04 g of 35 the title compound (67%); 1 H-NMR (CDCl3): 6 7.12 (d, 2H), 7.22 (s, 1H), 7,35 (m, 3H), 7.45 (d, 2H), 9.4 ppm (br s, 1 H). El SP/MS: 305 (M+), 307 (M+2), 309 (M+4). b) N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine WO 99/58497 PCT/DK99/00251 23 To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry acetonitrile (2 ml), 2-chlorobenzylamine (0.9 mmol, 0.108 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 2% h at 82*C under nitrogen. After concentration 5 the residue was recrystallised from ethyl acetate to give the title compound (208 mg, 72%). Mp 186-187.5*C; 1 H-NMR (CDCI 3 ): 8 4.54 (d, 2H), 5.53 (br, 1H), 7.15 (m, 2H), 7.3 (m, 3H), 7.4 (m, 2H), 7.75 ppm (br, 1 H); El SP/MS: 394 (M+). MA calc for C 1 5 HlCl 3

N

4 : C 50.95%, H 3.14%, N 15.84%. Found: C 50.68%, H 3.10%, N 15.49%. 10 EXAMPLE 13 N-Cyano-N'-cyclopentyl-N"-(3.5-dichlorophenyl)guanidine To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry 15 acetonitrile (2 ml), cyclopentylamine (0.9 mmol, 0.089 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 2% h at 820C under nitrogen. After concentration the residue was purified by flash chromatography (ethyl acetate / heptane 1:2) to give the title compound (160 mg, 66%) as crystals. Mp 147.5-148.5*C; 1 H-NMR (CDCl 3 ): 6 1.45 (m, 2H), 1.65 (m, 4H), 2.05 (m, 2H), 4.11 (sextet, 1H), 5.1 (br, 1H), 7.2 (m, 3H), 8.02 ppm (br, 1H); El 20 SP/MS: 296 (M+), 298 (M+2), 300 (M+4). MA calc for C 13

H

14 Cl 2

N

4 : C 52.54%, H 4.75%, N 18.85%. Found: C 52.17%, H 4.71%, N 18.50%. EXAMPLE 14 25 N-Cyano-N'-(3.5-dichlorophenyl)-N"-(1 -methylethyl)guanidine N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and isopropylamine (1 ml) was stirred in a sealed flask for 19 h at 75 C. After concentration the residue was dis 30 solved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2

SO

4 ) and concentrated. The residue was crystallised from ethyl acetate / heptane 1:3 to give the title compound (115 mg, 43%) as white crystals. Mp 156-158.50C; 1 H-NMR (CDC 3 ): 6 1.21 (d, 6H), 4.03 (m, 1H), 4.70 (br d, 1H), 7.16 (m, 2H), 7.29 (m, 1H), 7.47 ppm (br, 1H); MA calc for

C

11

H

1 C1 2

N

4 : C 48.73%, H 4.46%, N 20.66%. Found: C 48.76%, H 4.49%, N 20.38%.

WO 99/58497 PCT/DK99/00251 24 EXAMPLE 15 5 N-Cyano-N'-(3.5-dichlorophenyl)-N"-propylguanidine N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and n-propylamine (1 ml) was stirred in a sealed flask for 19 h at 75 C. After concentration the residue was dis solved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2

SO

4 ) and concentrated. The residue was purified by flash chromatography (ethyl acetate / heptane 10 1:3) to give the title compound (60 mg, 23%) as white crystals. Mp 141-143*C; 1 H-NMR

(CDCI

3 ): a 0.92 (d, 6H), 1.58 (sextet, 2H), 3.25 (q, 1H), 5.1 (br, 1H), 7.19 (m, 2H), 7.25 (m, 1H), 7.95 ppm (br, 1 H); MA calc for CHl 2 Cl 2

N

4 : C 48.73%, H 4.46%, N 20.66%. Found: C 49.02%, H 4.55%, N 20.27%. 15 EXAMPLE 16 N-Cyano-N'-(3.5-dichlorophenyl)-N"-(3-methylbutyl)-guanidine To N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) in dry acetonitrile 20 (2 ml), 3-methylbutylamine (2.16 mmol, 0.255 ml) and triethylamine (1.08 mmol, 0.150 ml) were added. The reaction mixture was stirred for 16 h at 850C under nitrogen. The precipi tated material was filtered off and recrystallised from ethyl acetate to give the title compound (160 mg, 54%) as white crystals. Mp 146.5-1451.5*C; 'H-NMR (CDCl 3 ): 8 0.94 (d, 6H), 1.43 (q, 2H), 1.6 (m, 1H), 3.31 (q, 2H), 4.9 (br, 1H), 7.18 (br s, 2H), 7.29 (br s, 1H), 7.5 ppm (br, 25 1H); MA calc for C 1 3 Hl 6 Cl 2

N

4 : C 52.19%, H 5.39%, N 18.73%. Found: C 52.23%, H 5.51%, N 18.60%. EXAMPLE 17 30 N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea To a solution of 3-methyloxy-5-trifluoromethylaniline (11 mmol, 2.10 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) WO 99/58497 PCT/DK99/00251 25 were added. The reaction mixture was stirred under nitrogen for 16 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was purified by flash chromatography (ethyl acetate / heptane 1:2) to give 0.413 g of the title compound (12%); Mp 168.5-169.5*C; 'H-NMR (CDCl3): 6 5 3.83 (s, 3H), 7.00 (s, 1H), 7.14 (m, 3H), 7,23 (s, 1H), 7.32 (t, 1H), 7.43 ppm (t, 2H), 8.7 (br s, 1H). El SP/MS: 335 (M+). 10 N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine To a solution of N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea (0.52 mmol, 175 mg) in dry acetonitrile (1 ml), cyclopentylamine (1.04 mmol, 0.113 ml) and tri 15 ethylamine (0.080 ml) were added. The mixture was stirred for 19 h at 750C under nitrogen. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2

SO

4 ) and concentrated. The residue was purified by flash chro matography (ethyl acetate / heptane 1:2) to give a syrup. Crystallisation from ethyl acetate / heptane 1:4 gave grey crystals (110 mg, 65%). Mp 101-102'C; 1 H-NMR (CDC 3 ): 6 1.40 (m, 20 2H), 1.65 (m, 4H), 2.02 (m, 2H), 4.13 (sextet, 1H), 5.05 (br, 1H), 6.96 (s, 1H), 7.00 (s, 1H), 7.03 (s, 1H), 8.15 ppm (br, 1H); El SP/MS: 326 (M+). EXAMPLE 18 25 N-Cyano-N'-(3-methoxy-5-trifluoromethylphenyl)-N"-(3-methylbutyl)guanidine To a solution of N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea (0.6 mmol, 200 mg) in dry acetonitrile (1 ml), 3-methylbutylamine (1.31 mmol, 0.152 ml) and triethylamine (0.66 mmol, 0.091 ml) were added. The mixture was stirred for 19 h at 750C 30 under nitrogen. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCI (2x), water, dried (Na 2

SO

4 ) and concentrated. Crystallisation from ethyl acetate / heptane 1:3 gave white crystals (160 mg, 81%). Mp 105.5 -108.5*C; 'H-NMR

(CDCI

3 ): 6 0.90 (d, 6H), 1.42 (q, 2H), 1.6 (m, 1 H), 3.32 (q, 2H), 3.85 (s, 3H), 4.9 (br, 1 H), 6.94 (brs, 1 H), 7.04 (s, 2H), 7.33 ppm (br s, 1 H); MA calc for C 15 Hj 9

F

3

N

4 0: C 54.87%, H 5.83%, N 35 17.06%. Found: C 55.08%, H 5.97%, N 16.68%.

Claims (20)

1. A compound of the -general formula I R 3 2 R 4 R 2N N H H 5 R wherein R 1 and R 2 are independently hydrogen, trifluoromethyl or halogen; 10 R 3 is trifluoromethyl, methoxy or halogen; R 4 is straight or branched Cr 1 2 -alkyl, C 2 2 -alkenyl, C 21 2 -alkynyl or C 3 8 -cycloalkyl optionally substituted with C 38 -cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C 1 . 6 -alkoxy, C 6 alkylthio, arylthio, C 16 -alkylamino, C 1 -,dialkylamino, heteroaryl, heteroarylalkyl or aryl, any of 15 the heteroaryl groups being optionally substituted with halogen or trifluoromethyl; or R 4 is Y-R', Y being -0- or -N(R6)- ; R 5 and R 6 are independently straight or branched Cr 12 -alkyl, C 212 -alkenyl, C 2 - 12 -alkynyl or C 3 . 8 -cycloalkyl optionally substituted with C 38 -cycloalkyl, halogen, hydroxy, heteroaryl, 20 heteroarylalkyl, aryloxy or aryl, any of the aryl or heteroaryl groups being optionally substituted with halogen or trifluoromethyl; or R' and R 6 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, 25 C 1 . 6 -alkyl, hydroxy, C 16 -alkoxy, C 1 . 6 -alkoxy-C 1 . 6 -alkyl, nitro, amino, cyano, trifluoromethyl, C1 6 -monoalkyl- or dialkylamino or oxo; X is N-CN or CH-NO 2 ; WO 99/58497 PCT/DK99/00251 27 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof.

2. A compound of the general formula I 5 R

3 X 2 R4 R 2N N H H R wherein R 1 and R 2 are independently hydrogen, trifluoromethyl or halogen; 10 R 3 is trifluoromethyl, methoxy or halogen; R 4 is straight or branched C- 12 -alkyl, C 2 -1-alkenyl, C2- 1 2 -alkynyl or C 3 - 8 -cycloalkyl optionally substituted with C 3 -- cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C 6 -alkoxy, C, 15 alkylthio, arylthio, C 6 -alkylamino, C 1 _ 6 -dialkylamino, heteroaryl, heteroarylalkyl or aryl, any of the heteroaryl groups being optionally substituted with halogen or trifluoromethyl; or R 4 is Y-R', Y being -0- or -N(R")- ; R' and R' are independently straight or branched C- 12 -alkyl, C 2 - 12 -alkenyl, C 2 -1-alkynyl or C 3 20 8 -cycloalkyl optionally substituted with C 38 -cycloalkyl, halogen, hydroxy, heteroaryl, heteroarylalkyl, aryloxy or aryl, any of the aryl or heteroaryl groups being optionally substituted with halogen or trifluoromethyl; or R 5 and R 6 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen 25 or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C 1 . 6 -alkyl, hydroxy, C 16 -alkoxy, C 1 . 6 -alkoxy-Cl. 6 -alkyl, nitro, amino, cyano, trifluoromethyl, Cj. 6 -monoalkyl- or dialkylamino or oxo; X is N-CN or CH-N0 2 ; 30 WO 99/58497 PCT/DK99/00251 28 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof provided that the following compounds are not included: N-Cyano-N'-(3-trifluoromethylphenyl)-N"-(1,2,2-trimethylpropyl)guanidine 5 N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,2,2-trimethylpropyl)-guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,1 -dimethylpropyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1, 1 -dimethylbutyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-t-pentylguanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1-ethyl-1 -methylpropyl)guanidine 10 N-Cyano-N'-(3,5-dichlorophenyl)-N"-t-butylguanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1, 1, 2-trimethylpropyl)guanidine and N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1,1 -diethylpropyl)guanidine. 15 3. A compound according to claim 1 or 2, wherein R' is hydrogen, R 2 is hydrogen or trifluoromethyl and R 3 is trifluoromethyl.

4. A compound according to claim 3, wherein R 2 is hydrogen. 20

5. A compound according to claim 1 or 2, wherein R 1 is hydrogen and R 2 and R 3 are chloro.

6. A compound according to claim 5 wherein R 4 is branched C 112 -alkyl. 25

7. A compound selected from the following: N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-methylbutyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-(4-pyridinyl)ethyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1,2,2-trimethylpropyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-cyclopentylpropyl)guanidine 30 N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-cyclopropylethyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(cyclopentyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1,2-dimethylpropyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-chlorobenzyl)guanidine N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-chlorobenzyl)guanidine WO 99/58497 PCT/DK99/00251 29 N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentylpropyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-cyclopropylethyl)guanidine 5 N-(3,5-bis(trifluoromethyl)phenyl)-N'-(1,2,2-trimethylpropyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-methylbutyl)-2-nitro-1 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-cyclopentylpropyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(2-cyclopropylethyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(cyclopentyl)-2-nitro- 1 -ethenediamine 10 N-(3,5-bis(trifluoromethyl)phenyl)-N'-((1,2-dimethylpropyl)-2-nitro-1 ,1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(2-chlorobenzyl)-2-nitro-1, 1 -ethenediamine N-(3,5-bis(trifluoromethyl)phenyl)-N'-(3-chlorobenzyl)-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(3-cyclopentylpropyl)-2-nitro-1, 1 -ethenediamine 15 N-(3,5-dichlorophenyl)-N'-(cyclopentyl)-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(2-chlorobenzyl )-2-nitro-1,1-ethenediamine N-(3,5-dichlorophenyl)-N'-(3-chlorobenzyl )-2-nitro-1, 1 -ethenediamine N-(3,5-dichlorophenyl)-N'-(2-cyclopropylethyl)-2-nitro-1, 1 -ethenediamine N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-(1 1 -dimethylpropyl)guanidine 20 N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1 -methylethyl)-guanidine N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-propyl-guanidine N-Cyano-N'-(3-trifluoromethylphenyl)-N"-cyclopentylguanidine N-Cyano-N'-isopropyl-N"-(3-trifluoromethylphenyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl)guanidine 25 N-Cyano-N'-cyclopentyl-N"-(3,5-dichlorophenyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(1 -methylethyl)guanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-propylguanidine N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-methylbutyl)-guanidine N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine 30 N-Cyano-N'-(3-methoxy-5-trifluoromethylphenyl)-N"-(3-methylbutyl)guanidine or a salt thereof with a pharmaceutically acceptable acid or base.

8. Compounds according to any one of the preceding claims which acts as modulators of the KATP-regulated potassium channels. WO 99/58497 PCT/DK99/00251 30

9. A pharmaceutical composition comprising a compound according to any of the claim 1 - 7 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 5 tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.

10. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as impaired glucose tolerance, hyperinsulinaemia and diabetes comprising a compound according to any of the claims 1 - 7 or a pharmaceutical 10 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 diluents.

11. The pharmaceutical composition according to claim 9 or 10 in the form of an oral 15 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. 20

13. A compound according to any one of the claims 1 - 7 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. 25

14. A compund according to any one of the claims 1 - 7 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, 30 such as impaired glucose tolerance, hyperinsulinaemia and diabetes.

15. The use of a compound according to any one of the claims 1 - 7 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or WO 99/58497 PCT/DK99/00251 31 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 1 - 7 for preparing a 5 medicament.

17. The use of a compound according to any one of the claims 1 - 7 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 10 tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as impaired glucose tolerance, hyperinsulinaemia and diabetes.

18. A method of treating or preventing diseases of the endocrinological system, such as 15 impaired glucose tolerance, hyperinsulinaemia and diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims 1 - 7 to said subject.

19. A process for the manufacture of a medicament, particular to be used in the 20 treatment or prevention of diseases of the endocrinological system, such as impaired glucose tolerance, hyperinsulinaemia and diabetes which process comprising bringing a compound of formula I according to any of the claims 1 - 7 or a pharmaceutically acceptable salt thereof into a galenic dosage form. 25

20. Any novel feature or combination of features as described herein.