Derivatives oxadiazole, thiadiazole or triazole, which are inhibitors of serine proteases, and containing pharmaceutical compositions

 

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms. Compounds according to the invention are inhibitors of serine proteases, including elastase human neutrophils. Also proposed farmacevticheskaja composition for the inhibition of serine proteases. 7 C. and 12 C. p. F.-ly, 39 ill. , 2 PL.

Description text in facsimile form (see graphic part)

moreover, the specified connection selected from the group consisting of

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(3,5-dimethylbenzyl)-1,2,4-oxadiazolyl]-carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(3,5-dimethoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(Unselectable)-L-poured-N-[1-(3-[5-(3,5-DATEFORMAT-benzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(3-methylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(4-phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(3-phenylbenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[-5-(3-phenoxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3[5-(3,5-diphenylmethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(4-dimethylaminobenzoyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(biphenylether)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(1-naphthylmethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(2-naphthylmethyl)-1,2,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(3,4-methylenedioxybenzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(3-pyridylmethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(morpholino-N-ethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(dimethylamino-N-ethylene)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(carbomethoxyamino)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(adamantylamine)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(3-[5-(cyclohexylmethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

2. Derived oxadiazole formulas

where X represents O;

Y - N;

R1- alkyl, substituted dialkylamino the Ohm, selected from N and O;

R2and R3independently from each other H or alkyl;

And denotes-C(O)-, -S(O)2-, -OC(O)-;

R4- alkyl, cycloalkyl containing one or more heteroatoms selected from N and O, (C5-C12)aryl, optionally containing as the heteroatom one N atom and optionally substituted by alkoxygroup.

3. Connection on p. 2, selected from the group consisting of

3-pyridylcarbonyl-L-poured-N-[1-(3-[5-(3-trifloromethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

methyloxycarbonyl-L-poured-N-[1-(3-[5-(3-trifloromethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide

isopropoxycarbonyl-L-poured-N-[1-(3-[5-(3-trifloromethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

4-pyridylmethylamine-L-poured-N-[1-(3-[5-(3-trifluoromethyl-benzyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide or

methylsulphonyl-L-poured-N-[1-(3-[5-(3-trifloromethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

4. Derived oxadiazole formulas

where X represents N;

Y - O;

R1- alkyl; dialkylamino, arylalkyl, optionally substituted alkyl, halogenation or di which means a direct link, -C(O)-, -S(O)2-, -OC(O)-;

R4- alkyl, cycloalkyl containing one or more heteroatoms selected from N or O; and (C5-C12)aryl, optionally containing as the heteroatom one N atom, or arylalkyl, optionally containing as the heteroatom one atom n

5. Connection on p. 4, selected from the group consisting of

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-propylamide,

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-dimethylamino-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl] carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl] carbonyl-1-methylethyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-(3-trifloromethyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide, (benzyloxycarbonyl)-L-poured-N-[1-(2-[5-(4-dimethylaminobenzoyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

(benzyloxycarbonyl)-L-poured-N-[1-(2-[5-(1-naphthylmethyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylp the yl]-L-prolinamide,

methyloxycarbonyl-L-poured-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

isopropoxycarbonyl-L-poured-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

4-pyridylmethylamine-L-poured-N-[1-(3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

methylsulphonyl-L-poured-N-[1-(3-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

phenylsulfonyl-L-poured-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

methylsulphonyl-L-poured-N-[l-(3-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide,

methylsulphonyl-L-poured-N-[1-(3-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-L-prolinamide.

6. Derived oxadiazole, thiadiazole or triazole of the formula

where X and Y independently of one another - O, S or N, provided that at least one of X or Y is N;

R1- alkyl, arylalkyl, optionally substituted alkyl or halogenation;

R2and R3independently from each other H or alkyl;

In is-C(O)-;

R6- soy is

where R’2and R’3- N; R13- H, alkyl, aryl, optionally substituted with halogen or alkyl or containing as the heteroatom one atom N: or 3, 4-methylenedioxybenzyl; R14- N, amino, arylalkylamines; R15- H, alkyl, halogen, alkoxy and W is O, S or N.

7. Connection under item 6, selected from the group consisting of

(2S,5S)-5-amino-1,2,4,5,6,7-hexahydroazepin-[3,2,1]-indol-4-one-carbonyl-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]-ndimethylacetamide,

2-oxo-5-phenyl-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-oxo-5-(4-chlorophenyl)-1,4-benzodiazepine-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-oxo-5-(4-triptoreline)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

3-(R,S)-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

3-(R,S)-amino-2-oxo-5-phenyl-1,4-(2’-chlorobenzothiazole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

2-oxo-5-phenyl-1,4-(2’-dimethylaminobenzoate)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

(R,S)-3-amino-2-OK

(R,S)-3-amino-2-oxo-5-(2-chlorophenyl)-1,4-(2’-chlorobenzothiazole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

(R,S)-3-benzyloxycarbonylamino-2-oxo-5-(2-chlorophenyl)-1,4-(2’-chlorobenzothiazole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

3-(R,S)-amino-2-oxo-5-(2-chlorophenyl)-1,4-(2’-chlorobenzothiazole)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

3-(R,S)-amino-2-oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

2-oxo-5-(2-pyridyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-oxo-5-(4-piperidinyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

3-(R,S)-amino-2-oxo-5-methyl-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl] ndimethylacetamide,

2-oxo-5-(3,4-methylenedioxyphenyl)-1,4-benzodiazepine-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

3-(R,S)-amino-2-oxo-5-methyl-1,4-(2’,3’-methylenedioxy)-benzodiazepine)-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

3-(R,S-amino-2-oxo-5-methyl-1,4-(1-topantispyware or triazole of the formula

where X and Y independently of one another - O, S or N, provided that at least one of X and Y represents N;

R1- arylalkyl, optionally substituted alkyl or halogenation;

R2and R3independently from each other or together are - H or alkyl;

In is-C(O)- or-OC(O)-;

R6the compound of formula (I)

where m and n independently from each other 0 or 1; D is a direct bond or valine; And denotes a direct bond, -C(O)-, -OC(O)-; R14is alkyl or arylalkyl, or R6- arylalkyl.

9. Connection on p. 8, representing benzyloxycarbonyl-L-poured-(1,2,3,4-tetrahydroisoquinoline-3-N-[1-(2-[5(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]amide.

10. Derived oxadiazole, thiadiazole or triazole of the formula

where X and Y independently of one another - O, S or N, provided that at least one of X and Y represents N;

R1- alkyl, optionally substituted by dialkylamino;

alkylsilane; and (C5-C12)arylalkyl, optionally substituted alkyl, halogenation or alkoxy; and (C5-C12)aryl, optionally substituted ALK is independently from each other H or alkyl;

R2’ and R’3- N.;

R11, R12and E together form a monocyclic or bicyclic ring corresponding to one of the following formulas:

where V1and V3- C; V2and V4independently represent C or N; R13is hydrogen, halogen; R14is hydrogen, amino, arylalkyl; And denotes a direct bond, -OC(O)NH;

where W1- S; W2and W3- C; V4- N; R14- amino; And denotes a direct link;

where W represents S, SO or S; N = 0 or 1; G represents CO(O)NH - or a direct bond; R13is hydrogen, aryl, optionally substituted with halogen, or arylalkyl; R14is hydrogen, amino or arylalkyl;

where R13- arylalkyl, optionally containing as the heteroatom one N atom or CH=R15where R15- pyridyl, phenyl or benzyl, optionally substituted with halogen, dialkylamino or-C(O)och3; and R14- H, CH3C(O) alkyl, arylalkyl; cycloalkenyl, containing two heteroatoms selected from N and O; 3,4-atlantooccipital;

where C(R16)(R17), where R16and R17independently of one another denote hydrogen, alkyl; aryl, optionally substituted by hydroxy or dialkylamino and optionally containing as the heteroatom one atom of N, arylalkyl, optionally substituted, dialkylamino and optionally containing as the heteroatom one N atom; V represents N; W is - NR13where R13- H, alkyl, arylalkyl or cycloalkyl, containing two heteroatoms selected from N and O; Y represents NR13or C(R16)(R17), where R13, R16and R17defined above;

where W denotes NR13where R13- cycloalkyl containing as the heteroatom one atom N

where R14"And denotes hydrogen, amino, CbzNH, CH3OS(O)-; R13is hydrogen or cycloalkyl containing as the heteroatom one N atom;

where A is R13denotes phenyl or-C(O)phenyl; R14is hydrogen;

where A is R13denotes phenyl or-C(O)phenyl; R14is hydrogen;

11. Connection on p. 10, in which R11, R12and E together form a ring structure of formula (I) or (Ia):

R13is hydrogen, halogen;

R14is hydrogen, amino, arylalkyl;

And denotes a direct bond, -OC(O)NH;

in the formula (Ia) W1denote S;

W2and W3;

V4N;

or R14represents amino and a - direct connection.

12. Connection on p. 11, selected from the group consisting of

2-[(6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-pyridyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl-)-2-(R)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl)-N-[1-(2[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-phenyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]-ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(4-methoxyphenyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]acetylmuramyl]ndimethylacetamide; or

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethyl-3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(5)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethyl-3,4-dihydroxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]ndimethylacetamide,

2-[6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-)-1,3,4-])-2-232D/chr/945.gif">-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(,-dimethyl-3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-(benzyloxycarbonyl)amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-methyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-isopropyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl ideasall]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]ndimethylacetamide,

2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide;

2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(tert-butyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R)-methylpropyl]ndimethylacetamide,

2-[5-(methylsulphonyl)amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide;

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazole who drank)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl] ndimethylacetamide,

2-[6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(1-methylcyclopropyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[6-oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide

2-[6-oxo-2-phenyl-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(4-forfinal)-1,6-dihydro-1-pyridinyl]-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(5)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-thienyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-[5-amino-6-oxo-2-(3-pyridyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide; or

2-[5-amino-6-oxo-2-(3-pyrid who was Salil]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide.

13. Connection on p. 10, in which R11, R12and E together form a ring of formula (V)

where W is S, SO or S;

N = 0 or 1;

G denotes CO(O)NH - or a direct link;

R13is hydrogen, aryl, optionally substituted with halogen, or arylalkyl;

R14is hydrogen, amino or arylalkyl.

14. Connection on p. 10, in which R11, R12and E together form a ring of formula (VI) or (VIa)

where in formula (VI) R13- arylalkyl, optionally containing as the heteroatom one N atom or CH=R15where R15- pyridyl, phenyl or benzyl, optionally substituted with halogen, dialkylamino or-C(O)och3;

R14- H, CH3C(O) alkyl, arylalkyl, cycloalkenyl, containing two heteroatoms selected from N and O; 3,4-atlantooccipital;

in the formula (VIa) R13- aryl or arylalkyl;

R14- H, Cbz.

15. Connection on p. 14, selected from the group consisting of

4-[1-(3-atlantooccipital)-3-(R)-benzylpiperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

2-(R,S)-[6-(methylene-4-pyridyl)piperazine-2,5-dione]-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide.

16. Carmoly (IX) or (Ha)

where in the formula (IX) U denotes C(O) or C(R16)(R17), where R16and R17independently of one another denote hydrogen, alkyl; aryl, optionally substituted by hydroxy or dialkylamino and optionally containing as the heteroatom one atom of N, arylalkyl, optionally substituted, dialkylamino and optionally containing as the heteroatom one N atom;

V denotes N;

W - NR13where R13- H, alkyl, arylalkyl, or cycloalkyl, containing two heteroatoms selected from N and O;

Y - NR13or C(R16)(R17), where R13, R16and R17defined above;

in the formula (Ha) W denotes NR13where R13- cycloalkyl containing as the heteroatom one atom n

17. Connection on p. 16, selected from the group consisting of

4-(S)-(2-isobutyl)-2.5-imidazolidinedione-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4-(S)-(2-isobutyl)-2.5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4-(R)-isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4-(S)-(2-isobutyl)-2.5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4-(R)-isopropyl-2,5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

[4-(R,S)-(4-dimethylaminophenyl)]-2.5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4-(R,S)-phenyl-2,5-imidazolidinedione-N-[1-(3-[5-(3-trifloromethyl)-1,2,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

[4-(R,S)-(4-pyridyl)-4-(R,S)-N-Succinimidyl]-2.5-imidazolidinedione-N-[l-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

[4-(R,S)-(2-pyridyl)-4-(R,S)-methyl]-2.5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4,4-diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4,4-diphenyl-2,5-imidazolidinedione-N-[1-(2-[5-(3,4-methylenedioxybenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide,

4-(R)-(3-indolylmethane)-2.5-imidazolidinedione-N-[1-(2-[5-tert-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(5)-methylpropyl]ndimethylacetamide,

4-(R)-(3-indolylmethane)-2.5-imidazolidinedione-N-[1-(2-[5-(,-dimethylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-metalpro the Nile)-2-(R,S)-methylpropyl]ndimethylacetamide,

1-(N-morpholinoethyl)-5-(R,S)-phenyl-2,4-imidazolidinedione-N-[l-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide; or

1-(N-morpholinoethyl)-5-(S)-benzyl-2,4-imidazolidinedione-N-[l-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(R,S)-methylpropyl]ndimethylacetamide,

5-(R,S)-phenyl-1-methyl-2,4-imidazolidinedione-N-[1-(2-[5-(3-methylbenzyl)-1,3,4-oxadiazolyl]carbonyl)-2-(S)-methylpropyl]ndimethylacetamide.

18. Connection PP.1, 2, 4, 6, 8 or 10 for the preparation of a pharmaceutical composition effective in inhibiting one or more proteases, preferably an elastase-specific elastase human neutrophils.

19. Pharmaceutical composition for the inhibition of serine proteases containing one or more compounds according to paragraphs.1, 2, 4, 6, 8, or 10 and a pharmaceutically acceptable carrier.

Priority points and attributes:

06.12.1996 - PP.1-19;

04.12.1997 - clarification of signs on PP.1-19 claims.

 

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