Tryptase inhibitors

Details Tryptase inhibitors Tryptase inhibitors

2000-10-20

2002-12-03

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S255010, C514S255050, C544S357000, C544S358000, C544S398000, C544S402000, C546S001000, C546S186000, C546S244000, C546S246000, C546S248000

Reexamination Certificate

active

06489327

ABSTRACT:

APPLICATION OF THE INVENTION
The invention relates to novel inhibitors of human tryptase which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
Human tryptase is a serine proteinase which is the predominant protein present in human mast cells. The term tryptase covers four closely related enzymes (&agr;, I, II/&bgr;, 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 &agr;-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, “Mast cell proteases in immunology and biology.” 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.
DESCRIPTION OF THE INVENTION
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 —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)—, —C(S)—, —O—, —S—, —NH—, —O—C(O)—, —C(O)—O—, —C(O)—NH—, —NH—C(O)— or a bond, or are selected from the group
where
U is —O— (oxygen) or —CH
2
— (methylene),
V is —O— (oxygen), —S— (sulfur) or —CH
2
— (methylene), and
W 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— 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 —C(O)— 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 —CH
2
—, —O— or a bond,
G is —S—, —O— or —S(O)
2
—,
T is —CH
2
—, —O— 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 [—CH
2
—], the ethylene [—CH
2
—CH
2
—], the trimethylene [—CH
2
—CH
2
—CH
2
—], the tetramethylene [—CH
2
—CH
2
—CH
2
—CH
2
—], the 1,2-dimethylethylene [—CH(CH
3
)—CH(CH
3
)—], the 1,1-dimethylethylene [—C(CH
3
)
2
—CH
2
—], the 2,2-dimethylethylene [—CH
2
—C(CH
3
)
2
—], the isopropylidene [—C(CH
3
)
2
—] or the 1-methylethylene [—CH(CH
3
)—CH
2
—] radical.
1-3C-Alkylene represents straight-chain or branched 1-3C-alkylene radicals, for example the methylene [—CH
2
—], the ethylene [—CH
2
—CH
2
—], the trimethylene [—CH
2
—CH
2
—CH
2
—], the isopropylidene [—C(CH
3
)
2
—] or the 1-methylethylene [—CH(CH
3
)—CH
2
—] radical.
If m has the meaning 0, the group —(C(O))
m
— is then a bond.
If p has the meaning 0, the group —(C(O))
p
— is then a bond.
If n has the meaning 0, the group —(CH
2
)
n
— 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 t

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