Tryptase inhibitors

Details Tryptase inhibitors Tryptase inhibitors

2002-05-03

2004-01-06

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252110, C540S460000

Reexamination Certificate

active

06673786

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel tryptase inhibitors which are used in the pharmaceutical industry for preparing medicaments.
KNOWN TECHNICAL BACKGROUND
The international applications WO95/32945, WO96/09297, WO98/04537, WO99/12918 and WO99/24395 describe low-molecular-weight compounds for use as tryptase inhibitors.
DESCRIPTION OF THE INVENTION
It has now been found that the compounds of the formula I, which are described in more detail below, have surprising and particularly advantageous properties.
The invention provides compounds of the formula I
in which
A1 and A2 are identical or different and are —C(O)—, —NH—, —O— (oxygen), —S— (sulfur), —S(O)
2
—, —S(O)
2
—NH—, —NH—S(O)
2
—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O— or a bond,
A3 and A4 are identical or different and are —C(O)—, —O—, —S—, —NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected from the group consisting of
where
E is —O— (oxygen), —S— (sulfur) or —CH
2
— (methylene),
G is —O— (oxygen) or —CH
2
— (methylene), and
T is the group —C(O)— or a bond,
A5 and A6 are identical or different and are —C(O)—, —NH—, —O—, —S—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—, —C(O)—O—, —NH—C(O)—NH— or a bond,
M is the following central building block
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 1-4C-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
R8 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or 2-7C-heterocycloalkyl radical containing at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene 3-8C-heterocycloalkylene,
where each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl may additionally for its part be substituted by one, two or three substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and where on the direct route between the terminal nitrogen atoms 20 to 40, preferably 25 to 40, bonds have to be present,
the salts of these compounds, and the N-oxides of the nitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 may assume the meaning of a bond resulting in the direct linkage of two heteroatoms or two carbonyl groups.
1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
1-4C-Alkoxycarbonyl represents a carbonyl group to which is attached one of the above-mentioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl [CH
3
O—C(O)—] and the ethoxycarbonyl [CH
3
CH
2
O—C(O)—] radicals.
1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which is attached one of the above-mentioned 1-4C-alkyl radicals. An example which may be mentioned is the acetoxy [CH
3
C(O)—O—] radical.
For the purpose of the invention, halogen is bromine, chlorine and fluorine.
1-4C-Alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene (—CH
2
—), ethylene (—CH
2
—CH
2
—), trimethylene (—CH
2
—CH
2
—CH
2
—), tetramethylene (—CH
2
—CH
2
—CH
2
—CH
2
—), 1,2-dimethylethylene [—CH(CH
3
)—CH(CH
3
)—], 1,1-dimethylethylene [—C(CH
3
)
2
—CH
2
—], 2,2-dimethylethylene [—CH
2
—C(CH
3
)
2
—], isopropylidene [—C(CH
3
)
2
—] or the 1-methylethylene [—CH(CH
3
)—CH
2
—] radicals.
If m is 0, the group —(C(O))
m
— is a bond.
If p is 0, the group —(C(O))
p
— is a bond.
4-11C-Heteroaryl represents a—if desired substituted—mono- or bicyclic aromatic hydrocarbon which contains 4 to 11 carbon atoms and at least one ring nitrogen atom; in addition, one or more of the carbon atoms may be replaced by ring heteroatoms selected from the group consisting of O, N and S. In the case of bicycles, at least one of the rings is aromatic. Examples which may be mentioned are pyrid-4-yl, pyrid-3-yl, pyrimidin-5-yl, imidazol-1-yl and benzimidazol-5-yl.
2-7C-Heterocycloalkyl represents a—if desired substituted—monocyclic saturated or partially saturated hydrocarbon which contains 2 to 7 carbon atoms and at least one ring nitrogen atom; in addition, one or more carbon atoms may be replaced by ring heteroatoms selected from the group consisting of O, N and S. Examples which may be mentioned are piperid4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, lmidazolidin-4-yl and morpholin-2-yl.
5-12C-Arylene represents a—if desired substituted—divalent mono- or bicyclic aromatic hydrocarbon radical having 5 to 12 carbon atoms, where in the case of bicyclic aromatic hydrocarbon radicals at least one of the rings is aromatic. The free valencies can both be located at the aromatic, both at the nonaromatic or one at the aromatic and one at the nonaromatic ring. Examples which may be mentioned are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene and 2,6-naphthylene.
5-12C-Heteroarylene represents an arylene radical as defined above in which 1 to 4 carbon atoms are replaced by heteroatoms selected from the group consisting of O, N and S. Examples which may be mentioned are 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.
3-8C-Cycloalkylene represents a—if desired substituted—divalent monocyclic saturated or partially saturated hydrocarbon radical having 3 to 8 carbon atoms. Examples which may be mentioned are the 1,3-cyclopentylene, the 1,3-cyclohexylene and preferably the 1,4-cyclohexylene radicals.
3-8C-Heterocycloalkylene represents a cycloalkylene radical as defined above in which 1 to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, N and S. Examples which may be mentioned are the 1,4-piperidinylene, 1,4-piperazinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene and preferably the 4,1-piperidinylene radicals.
Preferred meanings of the groups X1 and X2 are amino, aminocarbonyl, amidino and guanidino.
By definition, the groups Z1 and Z2 are located between the groups B9 and B11 (—B9-Z1-B11-) and B10 and B12 (—B10-Z2-B12-), respectively. Accordingly, in the divalent groupings mentioned by way of example (for example 2,6-indolylene), the first number indicates the point of attachment to the group B9 and B10, respectively, and the second number indicates the point of attachment to the group B11 and B12, respectively.
The definitions of M, A3, A4, X1 and X2 contain chemical formulae, such as, for example,
Here, bonds which are unattached on one side mean that the building block is attached at this site to the remainder of the molecule. Bonds which are unattached on both sides mean that this building block has a plurality of sites via which the building block can be attached to the remainder of the molecule.
In the context of this application, the term terminal nitrogen atom means in each case a nitrogen atom in the groups designated X1, X2, Y1 and Y2.
If the group X1 or X2 contains only one nitrogen at

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