8-(piperazin-1yl)- and 8-([1,4]diazepan-1yl)-xanthines, the preparation thereof and their use as pharmaceutical composition
The present invention relates to substituted xanthines of the general formula in which R 1 to R 3 and n are as defined in claims 1 to 8, their tautomers, their enantiomers, their diastereomers, their mixtures, their prodrugs and their salts, which have valuable pharmacological properties, in particular an inhibitory action on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
1. A compound of formula
wherein
R 1 is
(a) a heteroaryl-C 1-3 -alkyl group,
wherein heteroaryl is selected from the group consisting of phenylpyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl and phenanthridinyl which may be optionally substituted by R 10 , R 11 and R 12 ,
where R 10 is selected from hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, phenyl, cyano, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl group;
R 11 is selected from hydrogen, methyl, methoxy or cyano; and
R 12 is hydrogen or methyl,
or
(b) a naphthyl-C 1-3 -alkyl group, which may be substituted by R 13 and R 14 ,
where R 13 is selected from hydrogen, fluorine, chlorine, bromine methyl, difluoromethyl,
trifluoromethyl, cyano, methoxy, difluoromethoxy or trifluoromethoxy; and
R 14 is selected from hydrogen, methyl, methoxy or cyano;
R 2 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl;
R 3 is selected from 2-butyn-1-yl, 1-buten-1-yl, 2-buten-1-yl or 3-methyl-2-buten-1-yl and
n is 1 or 2;
or a tautomer, enantiomer, diastereomer, mixture, prodrug or salt thereof.
2. The compound of formula I according to claim 1 , wherein
R 1 is
(a) a heteroarylmethyl group,
wherein heteroaryl is selected from the group consisting of phenylpyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl and phenanthridinyl, which may be optionally substituted by R 10 , R 11 and R 12 ,
where R 10 is selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, phenyl, cyano, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl;
R 11 is selected from hydrogen, methyl or cyano; and
R 12 is selected from hydrogen or methyl,
or
(b) a naphthylmethyl group, which may optionally be substituted by R 13 and R 14 ,
where R 13 is selected from hydrogen, fluorine, chlorine, bromine, methyl, difluoromethyl,
trifluoromethyl, cyano, methoxy, difluoromethoxy or trifluoromethoxy; and
R 14 is selected from hydrogen, methyl or cyano;
R 2 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl;
R 3 is selected from 2-butyn-1-yl, 1-buten-1-yl, 2-buten-1-yl or 3-methyl-2-buten-1-yl;
and
n is 1 or 2;
or a tautomer, mixture or their salt thereof.
3. The compound of formula I according to claim 1 , wherein
R 1 is
(a) a heteroarylmethyl group,
where heteroaryl is selected from a group consisting of phenylpyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl or phenanthridinyl, which may optionally substituted by R 10 , R 11 and R 12 ,
where R 10 is selected from hydrogen, methyl, phenyl, cyano, methoxy, amino, methylamino, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl;
R 11 is selected from hydrogen, methyl or cyano; and
R 12 is selected from hydrogen or methyl,
or
(b) a naphthylmethyl group, which optionally may be substituted by R 13 and R 14 ,
where R 13 is selected from hydrogen, fluorine, methyl, cyano or methoxy; and
R 14 is selected from hydrogen, methyl or cyano;
R 2 is methyl;
R 3 is 2-butyn-1-yl;
and
n is 1 or 2;
or a tautomer, mixture or salt thereof.
4. The compound of formula I according to claim 1 , wherein
R 1 is methyl, which may be substituted by a fluoronaphthyl, methoxynaphthyl, cyanonaphthyl, dicyanonaphthyl, phenylpyrimidinyl, quinolinyl, fluoroquinolinyl, methylquinolinyl, cyanoquinolinyl, isoquinolinyl, methylisoquinolinyl, cyanoisoquinolinyl, quinazolinyl, methylquinazolinyl, phenylquinazolinyl, (dimethylamino)-quinazolinyl, (morpholin-4-yl)quinazolinyl, quinoxalinyl, methylquinoxalinyl, dimethylquinoxalinyl, trimethylquinoxalinyl, phenylquinoxalinyl or naphthyridinyl;
R 2 is methyl;
R 3 is 2-butyn-1-yl;
and
n is 1 or 2;
or a tautomer, mixture or salt thereof.
5. The compound of formula I according to claim 1 , wherein
R 1 is methyl, which may be substituted by a cyanoquinolinyl, methylisoquinolinyl, cyanoisoquinolinyl, quinazolinyl, methylquinazolinyl, phenylquinazolinyl, dimethylquinoxalinyl or naphthyridinyl group;
R 2 is methyl;
R 3 is 2-butyn-1-yl;
and
n is 1 or 2;
or a tautomer, mixture or salt thereof.
6. The compound of formula I according to any one of claims 1 to 5 , wherein
R 1 , R 2 and R 3 are as defined;
and
n is 1;
or a tautomer, mixture or salt thereof.
7. The compound of formula I according to any one of claims 1 to 5 , wherein
R 1 , R 2 and R 3 are as defined;
and
n is 2;
or a tautomer or salt thereof.
8. The compound of formula I according to claim 1 is selected from:
(a) 1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(piperazin-1-yl)-xanthine
(b) 1-[(4-Phenylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(piperazin-1-yl)-xanthine
(c) 1-[([1,5]-Naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(piperazin-1-yl)-xanthine
or a tautomer or salt thereof.
9. A physiologically tolerable salt of a compound according to one of claims l- 5 or 8 with at least one inorganic or organic acid.
10. A medicament comprising a compound according to claim 1 or a physiologically tolerable salt thereof in addition to one or more inert vehicles and/or diluents.
11. A method of treating at least one of diabetes mellitus type II and adiposity comprising administering to a patient in need thereof an effective amount of a compound according to claim 1 or a physiologically tolerable salt thereof.
12. A process for the preparation of the compounds of the general formula I according to claim 1 , wherein
a) a compound of the formula
in which
R 1 to R 3 are as defined in claim 1 , and
Z 1 is a leaving group selected from a chlorine or bromine atom, or a methanesulfonyl or methanesulfonyloxy group,
is reacted with piperazine or [1,4]diazepane or their salts, wherein, optionally, reactive groups optionally present in formula (II) are protected with a protective group during the reaction and the protective group is cleaved after the reaction, or
b) a compound of the formula
wherein R 1 , R 2 and R 3 are defined as mentioned in claim 1 , is deprotected by removing the tert-butyloxycarbonyl group.
13. The process according to claim 12 further comprising separating a compound thus obtained into its enantiomers and/or diastereomers.
14. The process according to claim 12 further comprising converting a compound thus obtained into at least one salt thereof with an inorganic or organic acid.
15. The process according to claim 13 further comprising converting a compound thus obtained into at least one salt thereof with an inorganic or organic acid.
16. A process for the preparation of the compounds of the formula I according to claim 1 , wherein
a) a compound of the formula
in which
R 1 to R 3 are defined in claim 1 , and
Z 1 is a leaving group,
is reacted with piperazine or [1,4]diazepane or their salts, wherein, optionally, reactive groups optionally present in formula (II) are protected with a protective group during the reaction and the protective group is cleaved after the reaction, or
b) a compound of the formula
wherein R 1 , R 2 and R 3 are as defined in claim 1 , is deprotected by removing the tert-butyloxycarbonyl group.