Urea derivatives of substituted nortropanes, medicaments containing such compounds and their use

1. A compound of formula (I)

wherein

R 1 denotes phenyl

wherein said phenyl is optionally substituted with one R 2 substituent,

R 2 denotes fluorine, methyl, isopropyl, methoxy, trifluoromethoxy, phenoxy, methoxycarbonyl, and methoxymethyl,

V is CY 5 Y 6 or O,

W is CY 7 Y 8 ,

X is absent or is CY 11 Y 12 ,

Y 1 to Y 12 , which may be identical and/or different, independently of each other denote hydrogen, methyl, trifluoromethyl, hydroxymethyl, 2-hydroxyprop-2-yl, hydroxy, methoxy, cyano, methoxycarbonyl, ethoxycarbonyl, and aminocarbonyl,

or a tautomer thereof, stereoisomer or mixture thereof, or salt thereof.

2. The compound of claim 1 of formula

wherein the ethylene bridge and the residue R 1 are situated on the same face of the piperidine ring.

3. The compound according to claim 2 , selected from the group consisting of:

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-pyrrolidin-1-yl-methanone

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-morpholin-4-yl-methanone

endo-N-{1-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carbonyl]-piperidin-4-yl}-acetamide

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4-hydroxy-piperidin-1-yl)-methanone

endo-1-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carbonyl]-piperidine-4-carboxylic acid amide

endo-1-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carbonyl]-piperidine-4-carboxylic acid ethyl ester

endo-1-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carbonyl]-piperidine-4-carboxylic acid

endo-1-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carbonyl]-piperidine-4-carbonitrile

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4-methoxy-piperidin-1-yl)-methanone

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4-hydroxy-4-trifluoromethyl-piperidin-1-yl)-methanone

endo-1-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carbonyl]-piperidine-4-carboxylic acid methyl ester

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3-hydroxymethyl-piperidin-1-yl)-methanone

endo-[3-(4-Methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

endo-Piperidin-1-yl-(3-p-tolyl-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone

endo-Piperidin-1-yl-[3-(4-trifluoromethoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

endo-[3-(4-Isopropyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

endo-[3-(4-Phenoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

endo-4-[8-(Piperidine-1-carbonyl)-8-aza-bi-cyclo[3.2.1]oct-3-yl]-benzoic acid methyl ester

endo-[3-(4-Methoxymethyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

endo-[3-(2-Methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

endo-Piperidin-1-yl-(3-o-tolyl-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone

endo-[3-(3-Methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-piperidin-1-yl-methanone

or salt thereof.

4. A physiologically acceptable salt of a compound according to claim 1 with an inorganic or organic acid or base.

5. A pharmaceutical composition containing a therapeutically effective amount of compound according to claim 1 , or a physiologically acceptable salt with an inorganic or organic acid or base, optionally together with one or more inert carriers and/or diluents.

6. A method of treating type 2 diabetes mellitus comprising administering a therapeutically effective amount of a compound according to claim 1 , or a physiologically acceptable salt with an inorganic or organic acid or base.

7. A method of administering a pharmaceutical composition according to claim 5 , for the treatment of type 2 diabetes mellitus.

8. Process for preparing a compound of formula I according to claim 1 , or a physiologically acceptable salt with an inorganic or organic acid or base, characterized in that

an amine of formula III

wherein the group R 1 is defined as hereinbefore and hereinafter,

or an amine of formula IV

wherein the groups Y 1 to Y 4 , V, W, and X are defined as hereinbefore and hereinafter,

is reacted with a carbonic acid derivative of the formula Y—CO—Y, yielding a compound either of formula V or VI as intermediate

wherein the groups R 1 , Y 1 to Y 4 , V, W, and X are defined as hereinbefore and hereinafter and

wherein Y is a leaving group and denotes fluorine, chlorine, bromine, cyano, C 1-9 -alkoxy, C 2-6 -alkenyloxy, C 2-6 -alkynyloxy, aryloxy, heteroaryloxy, C 1-8 -alkylsulfanyl, heteroar-N-yl, arylotriazol-1-yloxy, heteroarylotriazol-1-yloxy, 3-methyl-imidazol-1-yl, succinyl-N-oxy, di-(C 1-4 -alkyl)aminocarbonyloxy, pyrrol-1-ylcarbonyloxy, piperidin-1-yl-carbonyloxy, morpholin-4-ylcarbonyloxy, arylsulfanyl, or hetero-arylsulfanyl,

while the alkyl, alkenyl, and alkynyl groups mentioned in the definition of the above group are optionally substituted with one or more substituents, preferably with one to five substituents, independently of each other selected from fluorine, chlorine, C 1-3 -alkyl, or C 1-3 -alkoxy,

while the aryl groups mentioned in the definition of the above group denote phenyl or naphthyl and the heteroaryl groups mentioned in the definition of the above group denote pyridinyl, pyrimidinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, whilst both the aryl and heteroaryl groups are optionally substituted with one or more substituents, preferably with one to five, independently of each other selected from fluorine, chlorine, bromine, C 1-3 -alkyl, C 1-3 -alkyloxy, nitro, cyano, or di-(C 1-3 -alkyl)-amino,

while the two Y in Y—CO—Y may be identical or different,

while the second Y to be replaced may also be transformed into a more reactive Y after the first Y is replaced with one of the two amines,

while the intermediates of formula V and VI are optionally isolated and optionally purified, before being subsequently reacted with the other amine of the formula III or IV to yield a compound of the formula I;

the reactions are conducted optionally in the presence of an organic base or an inorganic base, and/or an additive between −10 and 120° C. in solvents selected from tetrahydrofuran, 1,2-dimethoxyethane, ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, benzene, and hexanes;

and, if necessary any protective group used in the reactions described above is cleaved concurrently or subsequently;

if desired a compound of formula I thus obtained is resolved into its stereoisomers;

if desired a compound of formula I thus obtained is converted into a physiologically acceptable salt thereof.