The invention relates to novel inhibitors of human tryptase which are used in the pharmaceutical industry for the production of medicaments.

The invention relates to novel inhibitors of human tryptase which are used in the pharmaceutical industry for the production of medicaments.
Human tryptase is a serine proteinase which is the predominant protein present in human mast cells. The term tryptase covers four closely related enzymes (xcex1, I, II/xcex2, III; possessing 90 to 98% sequence identity) (cf. Miller et al., J. Clin. Invest. 84 (1989) 1188-1195; Miller et al., J. Clin. Invest. 86 (1990) 864-870; Vanderslice et al., Proc. Natl. Acad. Sci., USA 87 (1990) 3811-3815). With the exception of xcex1-tryptase (Schwartz et al., J. Clin. Invest. 96 (1995) 2702-2710; Sakai et al., J. Clin. Invest. 97 (1996) 988-995), the enzymes are activated intracellularly and stored in catalytically active form in secretory granules.
As compared with other known serine proteinases, such as trypsin or chymotrypsin, tryptase exhibits some exceptional properties (Schwartz et al., Methods Enzymol. 244, (1994), 88-100; G. H. Caughey, xe2x80x9cMast cell proteases in immunology and biology.xe2x80x9d Marcel Dekker, Inc., New York, 1995). Tryptase obtained from human tissue has a noncovalently linked tetrameric structure which has to be stabilized by heparin or other proteoglycans in order to be proteolytically active.
Low-molecular-weight compounds are described as tryptase inhibitors in the international applications WO 95/32945, WO 96/09297 and WO 98/04537.
It has now been found that the compounds of the formula I described in more detail below possess surprising and particularly advantageous properties.
The invention relates to compounds of the formula I
in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl, 1-4C-alkyl which is wholly or partially substituted by fluorine, or hydroxyl, or R1 and R2 together, and including the carbon atom to which they are bonded, are xe2x80x94C(O)xe2x80x94 or a 5- or 6-membered, optionally substituted cyclic hydrocarbon,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94S(O)2xe2x80x94,
T is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,
R7 is hydrogen, 1-4C-alkyl, phenyl or pyridyl,
R8 is 1-4C-alkoxy, N(R81)R82, piperidino or morpholino,
R81 and R82 are identical or different and are hydrogen or 1-4C-alkyl,
R9 is hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
n is 0, 1, 2 or 3,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or 2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms, the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
1-4C-Alkyl represents straight-chain or branched alkyl radicals having from 1 to 4 carbon atoms. The butyl, the iso-butyl, the sec-butyl, the tert-butyl, the propyl, the isopropyl, the ethyl and the methyl radical may be mentioned by way of example.
Examples of 1-4C-alkyl which is entirely or partially substituted by fluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropyl, the perfluoroethyl, the 1,2,2-trifluoroethyl, the 1,1,2,2-tetrafluoroethyl, the 2,2,2-trifluoroethyl, the trifluoromethyl and the difluoromethyl radicals.
Examples of a 5- or 6-membered cyclic hydrocarbon which may be mentioned are cyclopentane or cyclohexane.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having from 1 to 4 carbon atoms. The butoxy, the iso-butoxy, the sec-butoxy, the tert-butoxy, the propoxy, the isopropoxy and, preferably, the ethoxy and the methoxy radical may be mentioned by way of example.
1-4C-Alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene [xe2x80x94CH2xe2x80x94], the ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], the trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], the tetramethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], the 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94], the 1,1-dimethylethylene [xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94], the 2,2-dimethylethylene [xe2x80x94CH2xe2x80x94C(CH3)2xe2x80x94], the isopropylidene [xe2x80x94C(CH3)2xe2x80x94] or the 1-methylethylene [xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94] radical.
1-3C-Alkylene represents straight-chain or branched 1-3C-alkylene radicals, for example the methylene [xe2x80x94CH2xe2x80x94], the ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], the trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], the isopropylidene [xe2x80x94C(CH3)2xe2x80x94] or the 1-methylethylene [xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94] radical.
If m has the meaning 0, the group xe2x80x94(C(O))mxe2x80x94 is then a bond.
If p has the meaning 0, the group xe2x80x94(C(O))pxe2x80x94 is then a bond.
If n has the meaning 0, the group xe2x80x94(CH2)nxe2x80x94 is then a bond.
4-11C-Heteroaryl is an optionally substituted monocyclic or bicyclic aromatic hydrocarbon which contains from 4 to 11 C atoms and at least one ring nitrogen atom; in addition, one or more of the carbon atoms can be replaced by ring heteroatoms selected from the group O, N or S. In bicycles, at least one of the rings is aromatic. Pyrid-4-yl, pyrid-3-yl, pyrimidin-5-yl, imidazol-1-yl and benzimidazol-5-yl may be mentioned by way of example.
2-7C-Heterocycloalkyl is an optionally substituted monocyclic saturated or partially saturated hydrocarbon which contains from 2 to 7 C atoms and at least one ring nitrogen atom; in addition, one or more carbon atoms can be replaced by ring heteroatoms selected from the group O, N or S. Piperid-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl and morpholin-2-yl may be mentioned by way of example.
5-12C-Arylene is an optionally substituted divalent monocyclic or bicyclic aromatic hydrocarbon radical which possesses from 5 to 12 C atoms, with at least one of the rings being aromatic in the case of the bicyclic aromatic hydrocarbon radicals. The free valencies can both be located on the aromatic ring or on the nonaromatic ring, or one can be located on the aromatic ring and one on the nonaromatic ring. 1,4-Phenylene, 1,3-phenylene, 1,4-naphthylene and 2,6-naphthylene may be mentioned by way of example.
5-12C-Heteroarylene is an arylene radical, as previously defined, in which from 1 to 4 C atoms are replaced by heteroatoms selected from the group O, N and S. 2,5-Furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,5-benzofuranylene, 2,6-quinolinylene and 4,2-thiazolylene may be mentioned by way of example.
3-8C-Cycloalkylene is an, optionally substituted, divalent monocyclic saturated or partially saturated hydrocarbon radical which possesses from 3 to 8 C atoms. The 1,3-cyclopentylene, the 1,3-cyclohexylene and, preferably, the 1,4-cyclohexylene radical may be mentioned by way of example.
3-8C-Heterocycloalkylene is a cycloalkylene radical, as previously defined, in which from 1 to 3 C atoms are replaced by heteroatoms selected from the group O, N and S. The 1,4-piperidinylene, the 1,4-piperazinylene, the 2,5-pyrrolidinylene, the 4,2-imidazolidinylene and, preferably, the 4,1-piperidinylene radical may be mentioned by way of example.
1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. The methoxycarbonyl (CH3Oxe2x80x94C(O)xe2x80x94) and the ethoxycarbonyl (CH3CH2Oxe2x80x94C(O)xe2x80x94) radical may be mentioned by way of example.
1-4C-Alkylcarbonyloxy is a carbonyloxy group to which one of the abovementioned 1-4C-alkyl radicals is bonded. The acetoxy radical (CH3C(O)xe2x80x94Oxe2x80x94) may be mentioned by way of example.
Several of the groups listed under M possess, either in themselves or due to their substitution, one or more chiral centers. The invention therefore encompasses both all the pure enantiomers and all the pure diastereomers and also their mixtures in any mixing ratio.
The groups Z1 and Z2, respectively, are located, by definition, between the groups B9 and B11 (-B9-Z1-B11-) and B10 and B12 (-B10-Z2-B12-), respectively. Correspondingly, in the divalent groups (e.g. 2,6-indolylene) which are mentioned by way of example, the first number is that of the site for linkage to the B9 or B10 group, respectively, and the second number is that of the site for linkage to the B11 or B12 group, respectively.
In the context of this application, the expression xe2x80x9cterminal nitrogen atomxe2x80x9d in each case refers to a nitrogen atom in the groups denoted X1, X2, Y1 and Y2.
If the groups X1 and/or X2 contain only one nitrogen atom, this nitrogen atom is the terminal nitrogen atom.
If the groups X1 and/or X2 contain a plurality of nitrogen atoms, the nitrogen atom which is located furthest from the atom via which the bond to groups B9 (B11) or B10 (B12) is effected is the terminal nitrogen atom.
If the groups Y1 and/or Y2 contain only one ring nitrogen atom, this ring nitrogen atom is the terminal nitrogen atom.
If the groups Y1 and/or Y2 contain a plurality of ring nitrogen atoms, the ring nitrogen atom which is located furthest from the atom via which the bond with the groups B9 or B10 is effected is the terminal nitrogen atom.
According to the invention, the direct route between the nitrogen atoms which act as terminal nitrogen atoms in the groups defined as X1 (Y1) or X2 (Y2) is the number of bonds which is obtained by counting the bonds which represent the shortest possible link between the terminal nitrogen atoms.
The following example is used to illustrate how the number of bonds on the direct route between two terminal nitrogen atoms is determined:
Here, the direct route encompasses 26 bonds.
The inhibitors according to the invention are bifunctional inhibitors, i.e. inhibitors having two reactive functional groups. These groups are such that they can bind specifically to active sites of tryptase. The two functional groups of the inhibitor preferably bind to active sites in different monomer subunits of the tryptase tetramer.
The inhibitors according to the invention are suitable for inhibiting human tryptase. Human tryptase is understood as meaning, in particular, the human enzyme xcex2-tryptase with the EC No. 184.108.40.206.
Depending on substitution, all acid addition salts or all salts with bases are suitable salts for compounds of the formula I. Those which may in particular be mentioned are the pharmacologically tolerated salts of the inorganic and organic acids which are customarily used in pharmacy. Suitable salts of this nature are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, with the acids being employed, when preparing the salt, in an equimolar quantity ratio or in a quantity ratio which differs from this depending on whether the acid is a monobasic or polybasic acid and on which salt is desired.
On the other hand, salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali (lithium, sodium or potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumin or guanidinium salts, with the bases also in this case being employed, when preparing the salt, in an equimolar quantity ratio, or in a quantity ratio which differs from this.
Salts which are not pharmacologically tolerated and which can, for example, initially arise as process products when producing the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerated salts using methods known to the skilled person.
The skilled person knows that the compounds according to the invention, and also their salts, when they are isolated in crystalline form, for example, can contain varying quantities of solvents. The invention therefore also encompasses all solvates and, in particular, all hydrates of the compounds of the formula I, as well as all solvates and, in particular, all hydrates of the salts of the compounds of the formula I.
One embodiment (embodiment a) of the compounds according to the invention of the formula I is that in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94 xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl, 1-4C-alkyl which is wholly or partially substituted by fluorine, or hydroxyl, or R1 and R2 together, and including the carbon atom to which they are bonded, are xe2x80x94C(O)xe2x80x94 or a 5- or 6-membered, optionally substituted cyclic hydrocarbon,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94S(O)2xe2x80x94,
R8 is 1-4C-alkoxy, N(81)R82, piperidino or morpholino,
R81 and R82 are identical or different and are hydrogen or 1-4C-alkyl,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or 2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
Compounds of embodiment a which are to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl, 1-4C-alkyl which is wholly or partially substituted by fluorine, or hydroxyl, or R1 and R2 together, and including the carbon atom to which they are bonded, are xe2x80x94C(O)xe2x80x94 or a 5- or 6-membered, optionally substituted cyclic hydrocarbon,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94S(O)2xe2x80x94,
R8 is 1-4C-alkoxy, N(R81)R82, piperidino or morpholino,
R81 and R82 are identical or different and are hydrogen or 1-4C-alkyl,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or straight-chain or branched 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
Y1 and Y2 are identical or different and are piperid-4-yl, piperid-3-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, 2-imidazolin-3-yl, 2-imidazolin-2-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 5-methylimidazol-4-yl, pyrid-4-yl, pyrid-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-4-yl, indol-3-yl, benzimidazol-4-yl or benzimidazol-5-yl,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene, 4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3, 6-indazolylene, 2, 6-quinolinylene, 2,5-benzofuranylene or 4,2-thiazolylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or carbonyl groups.
Compounds of embodiment a which are in particular to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94NHxe2x80x94C(O)xe2x80x94,
A3 and A4 are identical or different and are xe2x80x94C(O)-NHxe2x80x94 or are selected from the group
where W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond,
M is selected from one of the following groups
K1 is -B7-(C(O))m-B9-X1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or xe2x80x94CH2xe2x80x94 (methylene),
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-2C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are amino, amidino or guanidino,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-cyclohexylene or 1,4-piperazinylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or two carbonyl groups.
Preferred compounds of embodiment a are those in which
A1 and A2 are identical or different and are xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94NHxe2x80x94C(O)xe2x80x94,
A3 and A4 are identical or different and are xe2x80x94C(O)-NHxe2x80x94 or are selected from the group
where W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond,
M is selected from one of the following groups
K1 is -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or xe2x80x94CH2xe2x80x94 (methylene),
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or xe2x80x94CH2xe2x80x94 (methylene),
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are amino, amidino or guanidino,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-cyclohexylene or 1,4-piperazinylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or two carbonyl groups.
Particularly preferred compounds of embodiment a are bis{4-[4-(4-aminomethylcyclohexanoyl)piperazin-1-yl]-carbonyl}-4,4xe2x80x2-diaminodiphenyl ether, bis{4-[(3-aminomethyl)benzoylpiperazin-1-yl]carbonyl}-4,4xe2x80x2-diaminodiphenyl ether, di{4-[4-(4-aminomethyl)cyclohexanoyl-amino]piperidin-1-ylcarbamoyl}cyclohexylmethane, 2,2-bis[4-(4-guanidinylbenzylamino)carbonylmethoxyphenyl]-propane, 2,2-bis[4-(10-amino-3,6-diaza-2,5-dioxodecyloxyphenyl] propane and 2,2-bis{4-[4-(4-aminomethylbenzylcarbamoyl)-1-piperazinylcarbonyloxy]phenyl}propane, and also the salts of these compounds.
Another embodiment (embodiment b) of the compounds according to the invention of the formula I is that in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94O- or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are hydrogen, 1-4C-alkyl, 1-4C-alkyl which is wholly or partially substituted by fluorine, or hydroxyl, or R1 and R2 together, and including the carbon atom to which they are bonded, are xe2x80x94C(O)xe2x80x94 or a 5- or 6-membered, optionally substituted cyclic hydrocarbon,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94S(O)2xe2x80x94,
T is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,
R7 is hydrogen, 1-4C-alkyl, phenyl or pyridyl,
R9 is hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
n is 0, 1, 2 or 3,
K1 is -B7-(C(O)) B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or 2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
Compounds of embodiment b which are to be emphasized are, on the one hand, those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O).xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are 1-4C-alkyl which is wholly or partially substituted by fluorine, or R1 and R2 together, and including the carbon atom to which they are bonded, are a 5- or 6-membered, optionally substituted cyclic hydrocarbon,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94S(O)2xe2x80x94,
T is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,
R7 is pyridyl,
K1 is -B7-(C(O)) -B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or 2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
On the other hand, compounds of embodiment b which are to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are 1-4C-alkyl or together, and including the carbon atom to which they are bonded, are carbonyl,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94Sxe2x80x94 (sulfur),
T is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,
R7 is hydrogen, 1-4C-alkyl or phenyl,
K1 is -B7-(C(O) )m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are pyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
Compounds of embodiment b which are furthermore to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
R9 is hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
n is 0, 1, 2 or 3,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7- (C (O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl
Y1 and Y2 are identical or different and are pyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thioncarbonyl group.
Compounds of embodiment b which are in particular to be emphasized are, on the one hand, those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are 1-4C-alkyl which is wholly or partially substituted by fluorine, or R1 and R2 together, and including the carbon atom to which they are bonded, are a 5- or 6-membered, optionally substituted cyclic hydrocarbon,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94S(O)2xe2x80x94,
T is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,
R7 is pyridyl,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
Y1 and Y2 are identical or different and are piperid-4-yl, piperid-3-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, 2-imidazolin-3-yl, 2-imidazolin-2-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 5-methylimidazol-4-yl, pyrid-4-yl, pyrid-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-4-yl, indol-3-yl, benzimidazol-4-yl or benzimidazol-5-yl,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene, 4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or 4,2-thiazolylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or two carbonyl groups.
Compounds of embodiment b which are in particular to be emphasized are, on the other hand, compounds of the formula I in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R1 and R2 are identical or different and are 1-4C-alkyl or together, and including the carbon atom to which they are bonded, are carbonyl,
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
E is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
G is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94Sxe2x80x94 (sulfur),
T is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or a bond,
R5 and R6 are identical or different and are hydrogen or 1-4C-alkyl,
R7 is hydrogen, 1-4C-alkyl or phenyl,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9 Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2, B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl, Y1 and Y2 are identical or different and are pyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene, 4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or 4,2-thiazolylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or two carbonyl groups.
Compounds of embodiment b which are in particular to be emphasized are furthermore those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
R3 and R4 are identical or different and are hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
R9 is hydrogen or one, two or three identical or different 1-4C-alkyl radicals,
n is 0, 1, 2 or 3,
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are pyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene, 4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or 4,2-thiazolylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or two carbonyl groups.
Compounds of embodiment b which are in particular to be emphasized are, in addition, pyridine-2,6-dicarbobis[4-(3-aminomethylbenzoyl)-1-piperazide], pyridine-2,6-dicarbobis[4-(trans-4-aminomethylcyclohexanoyl)-1-piperazide], 2,6-dimethyl-4-phenylpyridine-3,5-dicarbobis[4-(3-aminomethylbenzoyl)-1-piperazide], pyridine-2,6-dicarbobis[4-(3-aminomethylbenzoylamino)-1-piperidide] and pyridine-2,6-dicarbobis[4-(4-aminomethylcyclohexylcarbonylamino)-1-piperidide], and also the salts of these compounds.
A further embodiment (embodiment c) of the compounds of the formula I is that in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1 B11 X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-4C-heteroaryl or 2-7C-heterocycloalkyl radical which contains at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
Compounds of embodiment c which are to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
U is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene),
V is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene), and
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
where
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7-(C(O))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or l-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are pyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene or 3-8C-heterocycloalkylene,
with each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl additionally, for its part, being able to be substituted by one, two or three substituents selected from the group hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms, two carbonyl groups or one carbonyl group and one thiocarbonyl group.
Compounds of embodiment c which are in particular to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group
where
W is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
M is selected from one of the following groups
K1 is -B7-(C(O))m-B9-X1, -B7-(C(O))m-B9-Y1 or -B7- (C ))m-B9-Z1-B11-X1,
K2 is -B8-(C(O))p-B10-X2, -B8-(C(O))p-B10-Y2 or -B8-(C(O))p-B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-3C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups
where
R10 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are pyrrolidin-2-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyridazin-4-yl, indol-3-yl or morpholin-2-yl,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene, 4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 6-methyl-5,2-pyridinylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or 4,2-thiazolylene,
and in which 24 to 40 bonds must be present on the direct route between the terminal nitrogen atoms,
the salts of these compounds, and also the N-oxides of the heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes which contain a nitrogen atom, and their salts,
with all those compounds being excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 assume the meaning of a bond, with this thereby resulting in the direct linkage of two heteroatoms or two carbonyl groups.
The compounds of the formula I are composed of a large number of divalent building blocks (M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, Z1 and Z2). In principle, they can be synthesized starting from any one of these building blocks. In the case of compounds of the formula I which are constructed to a large extent symmetrically, preference is given to starting the synthesis with the central building block M; by contrast, it can be advantageous to synthesize compounds of the formula I which are predominantly asymmetrical starting with one of the end groups K1 or K2.
In this connection, the building blocks are always linked together in accordance with the same pattern, which is known per se to the skilled person.
The skilled person knows that the compounds of the formula I can be synthesized building block by building block; alternatively, relatively large fragments, consisting of several individual building blocks, can first of all be constructed, with these fragments then being assembled into the whole molecule.
Amino [xe2x80x94NHxe2x80x94], ether [xe2x80x94Oxe2x80x94], thioether [xe2x80x94Sxe2x80x94], keto [xe2x80x94C(O)xe2x80x94], thioketo [xe2x80x94C(S)xe2x80x94], sulfonyl [xe2x80x94S(O)2xe2x80x94], ester [xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94], amide [xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94], sulfonamide [xe2x80x94SO2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94SO2xe2x80x94], carbamate [xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94], carbamide (xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94) or carbonate [xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94] bridges occur in the compounds of the formula I as a result of the meanings which the individual building blocks of the compounds of the formula I can assume.
The manner in which such bridges are prepared is known per se to the skilled person, and suitable methods, and starting compounds for preparing them, are described, for example, in March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Third Edition, 1985, John Wiley and Sons.
For example, ether and thioether bridges can be prepared by the method of Williamson.
Keto or thioketo bridges can, for example, be introduced as components of larger building blocks, such as 1,3-dichloroacetone.
Sulfonyl bridges can be obtained, for example, by oxidizing thioether bridges.
A large number of methods are known for synthesizing ester bridges. Mention may be made here, by way of example, of the reaction of acids with alcohols, preferably using H2SO4 or p-toluenesulfonic acid as catalyst; or with the addition of a water-extracting agent, such as a molecular sieve or a carbodiimide. The reaction of acid chlorides with alcohols may also be mentioned at this point.
There is also a large number of known methods for preparing amide bridges. The reaction of acid chlorides with primary or secondary amines may be mentioned here as an example. In addition, reference may also be made to all the methods which have been developed for peptide chemistry. Correspondingly, sulfonamide bridges can be synthesized from sulfonyl chlorides and primary or secondary amines.
Carbamate bridges can be prepared, for example, by reacting chlorocarbonic esters with amines. The chlorocarbonic esters can, for their part, be synthesized from alcohols and phosgene.
The addition of alcohols to isocyanates constitutes another variant for synthesizing carbamate bridges.
In a similar way to carbamate bridges, carbonate bridges can be prepared from chlorocarbonic esters by reacting them with alcohols (instead of amines).
Carbamide bridges can be prepared, for example, by reacting isocyanates with amines.
It is also possible to convert compounds of the formula I by derivatization into other compounds of the formula I. Thus, for example, compounds of the formula I which have a nitrogen-containing heteroaryl or heterocycloalkyl building block can be converted by oxidation into the corresponding N-oxides.
The N oxidation is effected in a manner with which the skilled person is also familiar, for example using hydrogen peroxide in methanol or m-chloroperoxybenzoic acid in dichloromethane at room temperature. The skilled person is familiar, on the basis of his specialist knowledge, with the detailed reaction conditions which are required for carrying out the method.
It is furthermore known to a person skilled in the art that, if a starting material or intermediate contains a plurality of reactive centers, it may be required to protect one or more reactive centers temporarily by protective groups so that a reaction can take place selectively at the desired reaction center. A detailed description of how a large number of proven protective groups are used is given, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
The substances according to the invention are isolated and purified in a manner known per se, for example by the solvent being distilled off in vacuo and the resulting residue being recrystallized from a suitable solvent or being subjected to one of the customary purification methods such as column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol), which contains the desired acid or base, or to which the desired acid or base is subsequently added. The salts are isolated by filtering, reprecipitation or precipitation with a substance which does not dissolve the addition salt, or by evaporating off the solvent. Resulting salts can be converted, by alkalizing or acidifying, into the free compounds, which can be converted into salts once again. In this way, salts which are not tolerated pharmacologically can be converted into salts which are tolerated pharmacologically.
The preparation of compounds of the formula I may be demonstrated, by way of example, with the aid of the following Examples 1 to 12 and FIGS. 1 to 12. Other compounds of the formula I can be prepared analogously or using the methods which are cited above and which are known per se to the skilled person.
FIGS. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 show formula schemes for preparing bifunctional inhibitors according to the invention.

Max-Planck-Gesellschaft zur Fordrungder Wisenschaften, e.V.

Byk Gulden Lomberg Chemische Fabrik GmbH


A method and a system for analyzing traffic on a website are disclosed, the website being arranged on a server. The method comprises the steps of allowing a plurality of visitors to visit the website; for each visit, registering a sequence of pages viewed by the visitor and/or actions performed by the visitor during the visit; for each visit, monitoring navigations and/or actions performed by the visitor during the visit while accumulating value points in accordance with content viewed by the visitor and actions performed by the visitor, and in accordance with predefined value point settings associated with content of the website, thereby obtaining an accumulated value point score for the visit; and defining a set of visits from the plurality of visits. Path patterns are built based on the visits of the set of visits, where the registered sequences form the path patterns, the path patterns including one or more full path patterns, each full path pattern corresponding to a complete registered sequence of at least one visit, and for each full path pattern, a total path value is calculated being the sum of accumulated value point scores for all visits with registered sequences forming said full path pattern.

For website owners it is often desirable to be able to analyse the traffic on a website, e.g. in order to determine which visitor behaviour leads to increased value for the website owner, and which visitor behaviour does not. By gaining such knowledge, the website owner may adjust or redesign the website in a manner which encourages the value creating or increasing behaviour.
Various analytic tools exist which provide the website owner with information regarding the amount of traffic on the website, including the origin of the traffic. Google® Analytics is one example of such a tool. However, these tools provide no information regarding the quality of the traffic, i.e. it is not possible to derive which part of the traffic was successful with respect to achieving the goals of the website owner.
U.S. Pat. No. 7,020,643 B2 discloses a system and method for extracting funnels from at least one input clickstream representing an ordered path of successively viewed web pages. The clickstreams are stored in one or more tree structures in one scan, then traverses each tree structure to identify funnels satisfying input criteria, such as depth criteria, width criteria, starting page criteria or end page criteria.

Method and a system for analysing traffic on a website by means of path analysis

Abstract: Correlated information regarding the paths followed by the visitors and the value generated by the visitors during their visits is thereby obtained. This can be used for investigating which paths generate value for the website owner, and which do not. The website may then be adjusted to encourage value generating behavior.


In a commercial transaction system, a magnetic stripe data card is used to interact with a point of sale (POS) terminal, equipped with a card reader/writer device, a computer system, and a display device, and an input means for entering cost information, to conduct coinless transactions with cash or paper bill currency. The POS terminal is capable of processing data which includes comparing the fractional transaction cost of the goods and/or services to be purchased with an existing balance of change stored on the magnetic stripe data card, and updating the balance of change at the end of the transaction. In a preferred embodiment of the present invention, when the balance of change associated with the card does not cover the fractional dollar cost of the transaction, the system provides a change renewal algorithm which automatically increases the balance on the card by an amount equal to the difference between the cost of the transaction and the next highest whole dollar amount. This difference is also added to the transaction cost raising it to the next highest whole dollar amount. Likewise, when the balance of change stored on the card does cover the fractional dollar cost of the transaction, the system provides a change depletion algorithm which automatically decreases the balance on the card by an amount equal to the fractional dollar cost of the transaction. This amount is also deducted from the transaction cost lowering it to the next lowest whole dollar amount. In either case, whether the balance of change stored on the card is greater than, or less than or equal to, the fractional dollar cost of the transaction, the fractional dollar cost of the transaction, or the difference between 1.0 and the fractional dollar cost of the transaction, is automatically debited from or credited to both the balance on the card and the total cost of the transaction, respectively, thereby resulting in a whole dollar cost for the transaction. The lack of any fractional cost for the transaction eliminates the requirement to exchange coins of any denomination while conducting commercial transactions with cash or paper bill currency.

1. Field of Invention
This invention relates to a commercial transaction system and method, and more specifically, to a system and method for conducting cash-payment transactions without the use of coins.
2. Related Art
Presently, there are billions of dollars worth of coins, or change, estimated to be lying around and not being used. Spare coins end up in jars or dresser drawers, get lost, or are simply thrown away. The reason change accumulates is that a person must physically carry coins to conduct day-to-day transactions. These transactions include buying goods and/or services from supermarket cashiers, vending machines, parking meters, laundry machines, toll machines, photocopiers, and the like. Although there are several methods in the art which specifically eliminate the use of both paper currency and coins (cash), such as credit cards, debit cards, pre-valued vending cards, and more recently, integrated circuit (IC) cards, none of these methods attempt to eliminate the use of coins with paper currency transactions at the point of sale.
Credit and debit card systems are examples of cashless transactions where a financial institution extends credit or debit to a cardholder to cover purchases from participating merchants. In a credit card system, a financial institution pays the merchant the purchase price less a service charge fee and later bills the cardholder for the purchase price. In contrast, with a debit card system, a financial institution directly deducts the purchase price from the cardholder's bank account. In either case, it is necessary for a financial institution, e.g., a bank, to mediate the transaction. Typically, these transactions need to be attended by a salesperson who calls a processing center via a dial-up modem to obtain authorization, and verifies the cardholder's signature to prevent fraud. This involves significant transaction costs which may be acceptable for large purchases, but is not cost effective for relatively small purchases. In addition, access to financial institutions by telephone lines can lead to security problems, and to an inability to transfer transaction data in the case of a communications link failure. These techniques are also open to human error, and moreover require a large number of steps in collecting and processing the data.
Further examples of cashless transactions involve the use of pre-valued vending cards or integrated circuit (IC) cards. A subway system such as the Washington D.C. Metro system utilizes such pre-valued vending cards. A certain amount of money or cash value is purchased and stored on the card, and subsequently used to purchase goods and services. Each time a purchase is made, the card is debited for the cost of that item. Payment by this pre-valued method, however, entails that the purchaser go to a different specified location to increase the balance on the card with additional money. With IC cards, value must also be loaded at a separate terminal which is typically in communication with one or more financial entities having access to the designated account of the cardholder for authorization of the transfer of value to the IC card. Therefore, a disadvantage of pre-valued vending cards and IC cards is the need to find a separate terminal from which to add value to a card.
Another disadvantage is that conventional pre-valued vending cards can only be used in a closed system, and cannot be utilized by the card user outside the system to freely spend his pre-paid amount. Also, the cards are used until exhausted and then discarded, which contributes to excess environmental waste. In contrast, conventional IC cards have the advantage of being re-valued once their balance is depleted, but like credit and debit cards, added security measures must be taken, and complicated encryption codes must be incorporated into the transaction process to prevent unauthorized or fraudulent access to a cardholder's account. Again, this involves significant transaction costs.
Due to the aforementioned disadvantages of conventional methods for conducting cashless commercial transactions, consumers must still rely heavily on the use of cash, particularly in conducting transactions of relatively small monetary value. As a result, it is necessary to either manually or automatically exchange coins during cash transactions, and this requires that an inventory of coins be kept on hand. Individual cash transactions are burdened by this need to provide and manage coins. It is inconvenient, costly, and time consuming for customers, clerks, and financial institutions alike. The growing popularity of coin-handling and coin-sorting devices is further evidence of the present need to relieve this burden.
Therefore, there is a need for a convenient, cost-effective, open system for eliminating the need to exchange coins with commercial cash transactions at the point of sale. Further, there is a need for a system and method for conducting cash-payment transactions without the use of coins and without requiring a user to access a separate terminal for managing a balance on a storage device.

System and method for conducting coinless transactions


A self-centering spring assembly including a liquid spring having a cylinder and a piston, a casing slidably mounted on the cylinder and having the outer end of the piston connected thereto, a first pivotal connector between an extension of the cylinder and a bracket member and a second pivotal connection between a member extending laterally of the casing and an external member, the second pivotal connection lying outwardly of the first pivotal connection.. The foregoing basic structure plus a liquid spring axially mounted thereon. The foregoing basic structure plus a resilient rubber sleeve mounted between the liquid spring and an external sleeve which supports a member.

The present invention relates to an improved self-centering spring assembly and to constructions containing at least one such assembly.
By way of background, self-centering spring units are known, one of which is disclosed in prior U.S. Pat. No. 3,438,512. It is with an improved self-centering spring assembly and constructions containing such assembly that the present invention is concerned.

Self-centering liquid spring assembly and constructions thereof


A method and apparatus for counting Media Access Control (MAC) address moves at line rate is described. According to one embodiment of the invention, a line card in a network bridge receives a frame at a port having a source MAC address that is associated with a different port of the network bridge. The line card signals a control card of the network bridge that the source MAC address has moved. The control card processes the source MAC address move and increments a MAC address move counter. If the MAC address move counter exceeds a MAC address move count threshold for a given time interval, the control card signals each line card in the network bridge to count each frame they receive on any port having that source MAC address. Other methods and apparatuses are also described.

1. Field
Embodiments of the invention relate to the field of network processing; and more specifically, to counting Media Access Control (MAC) addresses moves.
2. Background
A layer 2 network bridge (data link layer in the Open Systems Interconnection Basic Reference Model (OSI MODEL), ISO/IEC 7498-1, Nov. 15, 1994) is a device used to connect multiple computing devices from one network to other network(s). The bridge scans incoming data frames for the source MAC address and the destination MAC address. A MAC address is typically a globally unique address of a physical network interface card inside a computing device and usually does not change for the life of the computing device.
A network bridge dynamically builds a forwarding structure based upon the source MAC addresses of the frames it receives and the ports associated with those MAC addresses. A typical architecture of a network bridge includes at least one control card and multiple line cards. The control card includes a parent bridge forwarding structure which stores a master version of the associations between MAC addresses and ports. The control card distributes the content of the parent bridge forwarding structure to each of the line cards (e.g., to child bridge forwarding structures). Thus, each line card typically has an equivalent child bridge forwarding structure that reflects the information in the parent bridge forwarding structure.
Upon receiving a frame, a processor on the line card performs a lookup in its child bridge forwarding structure to determine if the source MAC address is associated with the port the frame was received on. A source MAC address miss is determined if the source MAC address is not associated with the port the frame was received on. For example, a source MAC address miss exists if the MAC address is associated with a different port than the frame was received on, or if the MAC address is not associated with any ports. If the MAC address is associated with a different port than the frame was received on, the source MAC address has moved. This is referred to as a source MAC address move (e.g., the source MAC address has moved between ports). Source MAC address moves may occur for expected (legitimate) reasons (e.g., the computing device associated with that source MAC address has physically moved locations) and/or unexpected (illegitimate) reasons (e.g., a bridge forwarding loop). A bridge forwarding loop may cause many source MAC address misses in a short amount of time (e.g., at line rate). If there is a source MAC address miss (e.g., either the MAC has moved, or the MAC is unknown) the line card sends a source MAC address miss message to the central processing unit (CPU) of the control card. The CPU updates the parent bridge forwarding structure and distributes the update to each of the line cards, and increments a source MAC address move counter (in case the source MAC has moved to a different port). Depending on the load on the CPU, this process may take several seconds.
Applications exist that attempt to prevent bridge forwarding loops. For example, the Spanning Tree Protocol (STP) (described in Institute of Electrical and Electronics Engineers (IEEE) standard 802.1D, Jun. 9, 2004) is a commonly used scheme to prevent network loops. A STP application, when performed correctly, may prevent a bridge forwarding loop by blocking one or more ports. However, in some circumstances, a STP application or other network loop prevention applications are unable to prevent a bridge forwarding loop. For example, STP must be configured at each of the ports of the network in the bridge to prevent bridge forwarding loops. On some occasions, a network administrator may incorrectly configure STP which may lead to STP not being configured on each of the ports. As another example, other types of bugs (hardware or software), and/or other configuration errors, cause the loop prevention application to fail (i.e., to not detect the loop).
As an additional safeguard to the loop prevention applications, many network bridges also perform a source MAC address move detection application. Typically, the source MAC address move detection applications blocks ports in a similar fashion as a STP application to resolve a bridge forwarding loop. Since not all source MAC address moves are for unexpected reasons, the source MAC address move detection algorithm is not performed until a certain threshold of source MAC address moves are met over a given time interval (e.g., five source address MAC moves in a period of time of 5 seconds). Typically a CPU in the control card of the network bridge counts the source address MAC moves and determines whether to execute the MAC address move detection application.

Method and apparatus to count MAC moves at line rate


In the design of a structured ASIC device that is intended to be functionally equivalent to a programmed FPGA, an initial design for the structured ASIC may be modified in any of several ways to improve various aspects of its performance. For example, for critical or near-critical parts of the structured ASIC design, attempts may be made to permute inputs to improve performance. Alternatively or in addition, Shannon's decomposition or other decomposition may be attempted to move a critical input closer to the output of a cell. Another possible modification is replacement of high-speed adders with slower-speed adders in non-critical parts of the structured ASIC design.

This invention relates to the design of application-specific integrated circuits ("ASICs"). More particularly, the invention relates to the design of ASICs of the type known as structured ASICs that are intended to be functionally equivalent to a field-programmable gate array ("FPGA") that has been programmed in a particular way.
FPGAs are relatively general-purpose integrated circuit devices that can be programmed to perform any of many different functions such as logic. After a design has been implemented and proven in an FPGA, it may be desirable to migrate that design to a structured ASIC. A structured ASIC is an integrated circuit that always has the same basic structure, but that has several layers that can be customized to cause the structured ASIC to implement particular functions. For example, many of the masks used to make a particular type of structured ASIC are the same or substantially the same for all ASIC products of that type. A few of the masks can be customized to give any one of those products a particular set of functions. These functions can be those that have been proven to work in a programmed FPGA. Using a structured ASIC to replicate an FPGA in this way (as opposed to attempting to design an unstructured ASIC, completely "from scratch", for this purpose) has a number of advantages. These include faster design turn-around, lower design cost, less risk that the ASIC design will not be a good functional equivalent of the FPGA design, etc.
References such as the following show examples of structured ASICs and methods for converting FPGA designs to structured ASIC implementations of those designs: Foo U.S. patent application Ser. No. 10/861,585, filed Jun. 4, 2004; Chua et al. U.S. patent application Ser. No. 10/884,460, filed Jul. 2, 2004; Yuan et al. U.S. patent application Ser. No. 10/916,305, filed Aug. 11, 2004; Schleicher et al. U.S. patent application Ser. No. 11/050,607, filed Feb. 3, 2005; Pedersen et al. U.S. patent application Ser. No. 11/072,560, filed Mar. 3, 2005; Schleicher et al. U.S. patent application Ser. No. 11/097,633, filed Apr. 1, 2005; Yuan et al. U.S. patent application Ser. No. 11/101,949, filed Apr. 8, 2005; Park et al. U.S. patent application Ser. No. 11/108,370, filed Apr. 18, 2005; Park et al. U.S. patent application Ser. No. 11/115,641, filed Apr. 27, 2005; Lim et al. U.S. patent application Ser. No. 11/141,867, filed May 31, 2005; and Tan et al. U.S. patent application Ser. No. 11/141,941, filed May 31, 2005. (All of these references are assigned to the same assignee as this disclosure, and references identified as patent applications are co-pending with this disclosure.) As at least some of these references show, programmed-FPGA-to-structured-ASIC conversion methods frequently include use of libraries of structured ASIC cells that are known to be equivalent to particular programmed FPGA functions or cells.
There are several respects in which the known methods of converting an FPGA design to a functionally equivalent structured ASIC design could be improved. For example, the known methods do not attempt to permute the inputs to structured ASIC library cells to try to achieve better timing performance. Nor do the known methods attempt to decompose a structured ASIC library cell for similar purposes. Still another possible deficiency of known programmed-FPGA-to-structured-ASIC conversion methods is that the known methods tend to implement all adders in the structured ASIC using two-bit adder cells. These may be more costly (e.g., in terms of area occupied and power consumed) than is warranted in all cases.

Methods for improved structured ASIC design


A display device is disclosed. The display device comprises a display panel, a backlight unit, and a processor for driving the backlight unit so as to provide light to the display panel, wherein the processor is capable of acquiring a current duty for driving the backlight unit, on the basis of pixel information of an area excluding a text area in an input image, and driving the backlight unit on the basis of the acquired current duty.

A liquid crystal display is configured to form a liquid crystal layer having anisotropic dielectric constant on upper and lower transparent insulating substrates, and change a molecular arrangement of a liquid crystal material by adjusting an intensity of an electric field formed in the liquid crystal layer, thereby displaying a desired image by adjusting the amount of light transmitted to the transparent insulating substrate.
A thin film transistor liquid crystal display (TFT LCD) that uses a thin film transistor (TFT) as a switching element is mainly used as a liquid crystal display, and the liquid crystal display is composed of a liquid crystal panel that displays an image composed of pixels divided into cross-arranged gate lines and data lines, a driver that drives the liquid crystal panel, a backlight unit that supplies light to the liquid crystal panel, and a color filter that transmits light supplied to the liquid crystal panel.
However, power consumption of light source of the backlight unit and an inverter circuit for driving the light source is almost half of a total power consumption of the liquid crystal display. Accordingly, a method of reducing the power consumption of the backlight unit is effective in order to reduce the power consumption of the liquid crystal display apparatus. A backlight dimming method is most widely used as a method for reducing power consumption of the backlight unit.
According to the backlight dimming method, a current value for backlight dimming is determined based on pixel information of an image, but there is a problem in that the current value may be determined too high when a high-gradation text such as subtitles is included in an image.

Driving display apparatus and method acquiring current duty to drive backlight unit based on excluding text area in input image


A loose-leaf sheet (1) according to the present invention comprises a base sheet (3) having a binding margin (7) adjacent one edge thereof, and release sheet members (4) affixed onto at least one of opposite faces of the base sheet (3), each of the release sheet members (4) being releasable at least once. A multiplicity of such loose-leaf sheets (1) are bound together to form a systematic notebook such as a memorandum book.

Memorandum books, in general, have pages with special formats allowing items to be entered therein sortingly by their contents or in the order of their occurrences thereby facilitating orderly entries of different information in different pages. A so-called "systematic memorandum book" is currently the most developed form of memorandum book. Such systematic memorandum book includes special pages having, for example, a schedule column, memorandum column, check list column, client column, account column, diary column and a like column.
These memorandum books have unique utility which is different from that of electronic notebook devices or like devices because the memorandum books enables immediate entry, fast reading-through and offers excellent portability, and because actual writing makes the user hard to forget the matter thus written down.
When an item is to be entered in a conventional memorandum book, the user requires time to sort the item in his or her mind and select a page having a suitable format prior to the entry. Thus, a mere entry involves cumbersome operations such as turning pages.
Further, if the user selects a wrong page, the user has to post an entered item to a right page later with a substantial loss of time and labor.
Additionally, entries of sorted items into different pages make it rather difficult to find out only certain items, for example, unfinished items.
Generally, a finished item is deleted by being entirely marked with a cross mark (X) or struck through with two lines. For this reason, it may be impossible to confirm again the content of an item thus deleted. Also, if unfinished items and finished items are left as mingled, there would arise problems such as oversight of any unfinished item.
With such a conventional memorandum book, the user may have to post items once entered when he or she wishes to put interrelated items together, to separate finished items from unfinished items so as to rearrange the entered items, or to change the order of items entered in one page. In such case the posting work imposes very much labor on the user and, as well, the pages in which the items thus posted had been originally entered may become useless.
The present invention has been accomplished in view of the foregoing circumstances. Accordingly, it is an object of the present invention to provide a loose-leaf sheet and a systematic notebook which allow the user to put items in a desired order with extreme ease while saving time and labor required for posting operations, prevent the user from overlooking any unfinished item, and avoid the occurrence of any useless page thereby enhancing their usefulness.

Loose-leaf sheet and systematic notebook

Kabushiki Kaisha Nishiwaki Keisan Center


In one embodiment, a power reception device includes a load circuit, to which a first signal having a first power value is supplied from a first resonance circuit connected to a power reception coil, and a first transceiver which transmits the first power value to a power transmission device. The power transmission device includes a second resonance circuit including a plurality of inductors and capacitors to which a second signal having a second power value is input, a power transmission coil connected to the second resonance circuit, a second transceiver which receives the first power value from the first transceiver, and a first control circuit which calculates power transmission efficiency using the first power value and the second power value and adjusts at least one of inductance values of the inductors and/or at least one of capacitance values of the capacitors based on the power transmission efficiency.

Recently, wireless power transmission technology to perform non-contact transmission of power wirelessly using a power transmission coil and a power reception coil is adopted to a wide range of devices such as an IC card and a portable phone. A power transmission characteristic significantly varies depending on a positional relationship between the power transmission coil and the power reception coil. Therefore, actually, the positional relationship between the coils is fixed by means of a cradle and the like and a distance between the coils is limited to 0 cm to approximately few cm.
In order to realize a transmission distance not shorter than few tens of cm without limiting the positional relationship between the coils, it is required to detect the transmission characteristics different according to the position of the coils to adjust a circuit parameter. Therefore, a method of improving power transmission efficiency by adjusting a tuning capacitor by deriving an electromagnetic coupling coefficient by a circuit sensor and a table provided in a power transmission device is suggested.
The transmission characteristic is detected by detecting only a state of a resonance circuit in the power transmission device by a method of adjusting the power described above, so that an operational state of a power reception device is not understood. Therefore, there is a problem that correct transmission characteristic cannot be detected and sufficient power transmission efficiency cannot be obtained when the transmission distance is extended and the electromagnetic coupling coefficient becomes smaller.


A shoe liner adapted to selectively couple to a vertical, rear, interior wall of a shoe includes a natural fabric body that is an elongated ovoid shape having a foot side and an opposite shoe side. The shoe side includes an adhesive back adapted to selectively adhere to the vertical backwall interior side of the shoe. The shoe liner further includes an interior chamber defined between the foot side and shoe side layers. The interior chamber is adapted to hold a volume of cotton batting filler material. The exterior surfaces of the shoe liner are made from a natural material and are available in a myriad of colors, textures, and patterns.

There are some known insert devices for shoes. Most known devices are designed to be used underneath the foot, placed inside the shoe, on top of the sole of the shoe and are used to pad or absorb shock, or to absorb odors, or both. One representative reference of this type of shoe insert is U.S. Published Pat. App. No. 2013/0055592 to Elsenbach published on Mar. 7, 2013.
Another type of shoe insert, known as heel liners, are presently available for sale by the Dr. Scholl's Company of Memphis Tenn. under the brand name of "Sole Expressions Heel Liners". Another product is distributed by ETC Group, Inc. of New York, N.Y. under the brand of "feet treats". And yet another is branded as "Heavenly Healz" and is sold by Footpetals.com.
However, known shoe inserts have some inherent limitations including that they do not absorb perspiration, are not environmentally friendly to produce or dispose of, are not economical to produce, and are not comfortable. Therefore, there remains a need for a system, device, and method that provides increased comfort, is more economical to produce, and are more environmentally friendly both to produce and to dispose.