Five-membered heterocycles having biphenylsulfonyl substitution, process for their preparation, their use as a medicament or diagnostic, and medicament comprising them. Compounds of the formula I

The invention relates to compounds of the formula I
in which the symbols have the following meaning:
R1 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or xe2x80x94CaH2axe2x80x94, phenyl,
said xe2x80x94CaH2a-phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, 1, CF3, methyl, methoxy, hydroxyl and NR(8)R(9);
R(8) and R(9) independently of one another are H or (C1-C4)alkyl;
xe2x80x83a is zero, 1or 2;
or
R1 is xe2x80x94CbH2b-(C1-C9)heteroaryl, which is unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR(10)R(11);
R(10) and R(11) independently of one another are H or (C1-C4)alkyl;
b is zero, 1 or 2;
or
R1 is xe2x80x94CdH2dxe2x80x94(C3-C7)cycloalkyl;
xe2x80x83d is zero, 1 or 2;
R2 and R3
xe2x80x83independently of one another are hydrogen, F, Cl, Br, I, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, CH2OR17, CO-R6 or O-R7;
xe2x80x83R17 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
xe2x80x83R6 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR30 or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by 1-3 substituents selected from the group consistng of F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(31)R(32);
xe2x80x83R(31) and R(32) independently of one another are H or (C1-C4)-alkyl;
R30 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
xe2x80x83R7 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(12)R(13);
xe2x80x83R(12) and R(13) independently of one another are H or (C1-C4)-alkyl;
xe2x80x83or
xe2x80x83R7 is (C1-C9)heteroaryl,
xe2x80x83which is unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR(14)R(15);
xe2x80x83R(14) and R(15) independently of one another are H or (C1-C4)-alkyl;
or
R2 and R3
xe2x80x83independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CgH2g-phenyl,
said xe2x80x94CgH2g-phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(18)R(19);
R(18) and R(19) independently of one another are H or (C1-C4)alkyl;
xe2x80x83g is zero, 1 or 2;
or
R2 and R3
xe2x80x83independently of one another are xe2x80x94ClH2lxe2x80x94(C1xe2x80x94C9)heteroaryl,
which is unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR(20)R(21);
R(20) and R(21) independently of one another are H or (C1-C4)alkyl;
xe2x80x83I is zero, 1 or 2;
or
R2 and R3
xe2x80x83independently of one another are SOn-R22;
xe2x80x83n is zero, 1 or 2;
xe2x80x83R22 is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CsH2s-phenyl,
said xe2x80x94CsH2s-phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
R(34) and R(35) independently of one another are H or (C1-C4)-alkyl;
xe2x80x83s is zero, 1 or 2;
R4 and R5 independently of one another are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, SOp-R16, CO-R23 or O-R24;
xe2x80x83p is zero, 1 or 2;
xe2x80x83R16 is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(26)R(27);
xe2x80x83R(26) and R(27) independently of one another are H or (C1-C4)-alkyl;
xe2x80x83R23 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR25;
R25 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
xe2x80x83R24 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by 1-3 substituents selected from F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl and NR(28)R(29);
xe2x80x83R(28) and R(29) independently of one another are H or (C1-C4)-alkyl;
and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or xe2x80x94CaH2a-phenyl, said xe2x80x94CaH2a-phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(8)R(9);
R(8) and R(9) independently of one another are H or methyl;
xe2x80x83
a is zero or 1;
or
R1 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(10)R(11);
R(10) and R(11) independently of one another are H or methyl;
or
R1 is xe2x80x94CdH2dxe2x80x94(C3-C7)cycloalkyl;
xe2x80x83d is zero or 1;
R2 and R3
xe2x80x83independently of one another are hydrogen, F, Cl, Br, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, CH2OR17, CO-R6 or O-R7;
xe2x80x83R17 is hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
xe2x80x83R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl, said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(31)R(32);
xe2x80x83R(31) and R(32) independently of one another are H or methyl;
R30 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
xe2x80x83R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(12)R(13);
xe2x80x83R(12) and R(13) independently of one another are H or methyl;
xe2x80x83or
xe2x80x83R7 is (C1-C9)heteroaryl,
xe2x80x83which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(14)R(15);
xe2x80x83R(14) and R(15) independently of one another are H or methyl;
or
R2 and R3
xe2x80x83independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CgH2g-phenyl,
said xe2x80x94CgH2g-phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(18)R(19);
R(18) and R(19) independently of one another are H or methyl;
xe2x80x83g is zero or 1;
or
R2 and R3
xe2x80x83independently of one another are (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(20)R(21);
R(20) and R(21) independently of one another are H or methyl;
or
R2 and R3
xe2x80x83independently of one another are SOn-R22,
xe2x80x83n is zero, 1 or 2;
xe2x80x83R22 is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or xe2x80x94CsH2s-phenyl,
said xe2x80x94CsH2s-phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
R(34) and R(35) selected from H and methyl;
xe2x80x83s is zero or 1;
R4 and R5
xe2x80x83independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, SOpxe2x80x94R16, CO-R23 or O-R24;
xe2x80x83p is zero, 1 or 2;
xe2x80x83R16 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(26)R(27);
R(26) and R(27) independently of one another are H or methyl;
xe2x80x83R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25; R25 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
xe2x80x83R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by 12-2 substituents selected from F. Cl Br, CF3, methyl, methoxy, hydroxyl and NR(28)R(29);
R(28) and R(29) independently of one another are H or methyl;
and their physiologically tolerable salts.
Particularly preferred compounds of the formula I are those in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(8)R(9);
R(8) and R(9) independently of one another are H or methyl;
or
R1 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(10)R(11);
R(10) and R(11) independently of one another are H or methyl;
or
R1 is (C3-C7)cycloalkyl;
R2 and R3
xe2x80x83independently of one another are hydrogen, F, Cl, Br, CF3, xe2x80x94Cxe2x89xa1N, xe2x80x94NO2, CO-R6 or O-R7;
xe2x80x83R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl, said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(31)R(32);
xe2x80x83R(31) and R(32) independently of one another are H or methyl;
R30 is hydrogen or alkyl having 1, 2 or 3 carbon atoms
xe2x80x83R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(12)R(13);
xe2x80x83R(12) and R(13) independently of one another are H or methyl;
xe2x80x83or
xe2x80x83R7 is (C1-C9)heteroaryl,
xe2x80x83which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and
xe2x80x83NR(14)R(15); R4) and R(15) independently of one another are H or methyl;
or
R2 and R3
xe2x80x83independently of one another are alkyl having 1,2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(18)R(19);
R(18) and R(19) independently of one another are H or methyl;
or
R2 and R3
xe2x80x83independently of one another are (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3, methoxy, hydroxyl and NR(20)R(21);
R(20) and R(21) independently of one another are H or methyl;
or
R2 and R3
xe2x80x83independently of one another are SOn-R22;
xe2x80x83n is zero or 2;
xe2x80x83R22 is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
xe2x80x83R(34) and R(35) independently of one another are H or methyl;
R4 and R5 independently of one another are
xe2x80x83hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3, xe2x80x94CON, xe2x80x94NO2, SOp-R16, CO-R23 or O-R24;
xe2x80x83p is zero or 2;
xe2x80x83R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
xe2x80x83R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(28)R(29);
xe2x80x83R(28) and R(29) independently of one another are H or methyl;
xe2x80x83R1 6 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, methyl, methoxy, hydroxyl and NR(26)R(27);
xe2x80x83R(26) and R(27) independently of one another are H or methyl;
and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
R1 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
or
R1 is (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, CF3, CH3 and methoxy;
or
R1 is (C3-C7)cycloalkyl;
R2 and R3
xe2x80x83independently of one another are hydrogen, F, Cl, CF3, xe2x80x94Cxe2x89xa1N, CO-R6 or O-R7;
xe2x80x83R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl, said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
R30 is hydrogen, methyl or ethyl;
xe2x80x83R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
xe2x80x83or
xe2x80x83R7 is (C1-C9)heteroaryl,
xe2x80x83which is unsubstituted or substituted by one substituent selected from F, Cl, Br, CF3, CH3 and methoxy;
or
R2 and R3
xe2x80x83independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl,
said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
or
R2 and R3
xe2x80x83independently of one another are (C1-C9)heteroaryl,
which is unsubstituted or substituted by one substituent selected from F, Cl, CF3, CH3 and methoxy;
or
R2 and R3
xe2x80x83independently of one another are SOn-R22;
xe2x80x83n is zero or 2;
xe2x80x83R22 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by 1-2 substituents selected from F, Cl, CF3, methyl and methoxy;
R4 and R5
xe2x80x83independently of one another are hydrogen, methyl, F, Cl, CF3, xe2x80x94Cxe2x89xa1N, SO2-R16, CO-R23 or O-R24;
xe2x80x83R16 is alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by one substituent selected from F, Cl, CF3, methyl and methoxy;
xe2x80x83R23 is hydrogen, methyl or OR25; R25 is hydrogen, methyl or ethyl;
xe2x80x83R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
xe2x80x83said phenyl being unsubstituted or substituted by one substituent selected from F. Cl, CF3, methyl and methoxy;
and their physiologically tolerable salts.
In addition, preferred compounds of the formula I are those in which the radicals R1 1, R2, R3, R4 and R5 are as defined above, where R4 and R5 are not simultaneously hydrogen.
Alkyl can be straight-chain or branched.
Cycloalkyl is also understood as meaning alkyl-substituted rings. (C1-C9)Heteroaryl is understood as meaning in particular radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups (with formation of a five-membered aromatic ring) are replaced by S, NH or O. In addition, one or both atoms of the condensation site of bicyclic radicals (such as indolizinyl) can also be nitrogen atoms.
Heteroaryl is in particular furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl.
Stereocenters which may occur can have either the (R) or the (S) configuration.
Physiologically tolerable salts of compounds of the formula I are understood as being both their organic and inorganic salts, such as are described in Remington""s Pharmaceutical Sciences [17th Edition, page 1418 (1985)]. On account of the physical and chemical stability and the solubility, for acidic groups, inter alia, sodium, potassium, calcium and ammonium salts are preferred; for basic groups, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid, are preferred.
The invention also relates to a process for the preparation of the compounds of the formula I, and their physiologically tolerable salts, which comprises reacting a compound of the formula II
in which the radicals are as defined above and which are either known from J. Med. Chem. 1995, 38, 2357 or were prepared analogously, with cyanogen bromide. The reaction is carried out in a dipolar aprotic solvent which is stable to cyanogen bromide, for example acetonitrile, DMA, TMU or NMP, using a strong auxiliary base which is not very nucleophilic, such as, for example, K2CO3 or Cs2CO3. A suitable reaction temperature is a temperature from 0xc2x0 C. to the boiling point of the solvent used; a temperature from 60xc2x0 C. to 120 C. is preferred.
The invention furthermore relates to the use of a compound of the formula
in which:
a) X, Y and Z are, identically or differently, N or CR(102)
b) R(1) is
1. (C1-C10)alkyl, 2. (C3-C10)alkenyl, 3. (C3-C10)alkynyl, 4. xe2x80x94OR(103), 5. (C3-C8)cycloalkyl, 6. (C4-C10)cycloalkylalkyl, 7. (C5-C10)-cyclo-alkylalkenyl, 8. (C5-C10)cycloalkylalkynyl, 9. xe2x80x94(CH2)mxe2x80x94Bxe2x80x94(CH2)nxe2x80x94R(104), 10. -benzyl, 11. a radical defined as under b) 1., 2., 3. or 9., which is monosubstituted by CO2R(103), 12. a radical as defined under b) 1., 2., 3. or 9., in which 1 to all hydrogen atoms are substituted by fluorine, or 13. the radical defined under b) 10., which is substituted on the phenyl by 1 or 2 identical or different radicals from halogen, (C1-C4)alkoxy and nitro,
c) R(102) is
1. hydrogen, 2. halogen, 3. nitro, 4. CvF2v+1, 5. penta-fluorophenyl, 6. cyano, 7. xe2x80x94Oxe2x80x94R(106), 8. phenyl, 9. phenyl(C1-C3)alkyl, 10. (C1-C10)alkyl, 11. (C3-C10)alkenyl, 12. phenyl(C2-C6)alkenyl, 13. 1-imidazolyl(CH2)mxe2x80x94, 14. 1,2,3-triazolyl(CH2)nxe2x80x94, 15. tetrazolyl(CH2)mxe2x80x94, 16. xe2x80x94(CH2)0-1xe2x80x94CHR(107)xe2x80x94OR(105), 17. xe2x80x94(CH2)oxe2x80x94Oxe2x80x94COxe2x80x94R(103), 18. xe2x80x94(CH2)oxe2x80x94Sxe2x80x94R(106), 19. xe2x80x94S(O)rxe2x80x94R(119), 20. xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)mxe2x80x94CHR(103)xe2x80x94OR(106), 21. xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)mxe2x80x94COxe2x80x94R(108), 22. xe2x80x94COxe2x80x94R(108), 23. xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)mxe2x80x94Oxe2x80x94COxe2x80x94R(107), 24. xe2x80x94(CH2)mxe2x80x94CH(CH3)xe2x80x94COxe2x80x94R(108), 25. xe2x80x94(CH2)oxe2x80x94COxe2x80x94R(108), 26. xe2x80x94(CH2)oxe2x80x94Oxe2x80x94[Cxe2x95x90W]xe2x80x94NHxe2x80x94R(109), 27. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94[Cxe2x95x90W]xe2x80x94OR(109), 28. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94COxe2x80x94NHR(109), 29. xe2x80x94(CH2)oNR(107)xe2x80x94SO2R(109), 30. xe2x80x94(CH2)oxe2x80x94NR(107)xe2x80x94[Cxe2x95x90W]xe2x80x94R(109), 31. xe2x80x94(CH2)nF, 32. xe2x80x94(CH2)nxe2x80x94Oxe2x80x94NO2, 33. xe2x80x94CH2xe2x80x94N3, 34. xe2x80x94(CH2)nxe2x80x94NO2, 35. xe2x80x94CHxe2x89xa1Nxe2x80x94NR(105)R(107), 36. phthalimido(CH2)nxe2x80x94,
43. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)xe2x80x94CSxe2x80x94NR(106)R(109), 44. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)xe2x80x94COxe2x80x94NR(106)R(109), 45. xe2x80x94(CH2)oxe2x80x94SO2R(109), 46. a radical as defined under c) 8. or 9., which is substituted on the phenyl by 1 or 2 identical or different radicals from halogen, hydroxyl, methoxy, trifluoromethyl, CO2R(103) and phenyl, 47. a radical as defined under c) 10., 11. or 19., in which one to all hydrogen atoms are substituted by fluorine, 48. the radical defined under c) 14., which is substituted by 1 or 2 identical or different radicals from methoxycarbonyl and (C1-C4)alkyl, 49. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)xe2x80x94COxe2x80x94R(106), 50. xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NR(107)CSxe2x80x94R(106),
d) R(103) is
1. hydrogen, 2. (C1-C8)alkyl, 3. (C3-C8)cycloalkyl, 4. phenyl, 10 5. benzyl, 6. the radical defined under d) 2., in which 1 to all H atoms are substituted by fluorine;
e) R(104) is 1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. (C2-C4)-alkenyl or 5. (C2-C4)alkynyl;
f) R(105) is 1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. phenyl or 5. benzyl;
g) R(106) and R(109) are, identically or differently, 1. hydrogen, 2. (C1-C6)alkyl which is unsubstituted or substituted by 1-3 substituents selected from (C1-C6)alkoxy which for its part can be substituted by 1-3 radicals from hydroxyl, (C1-C6)alkoxy, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, (C2-C10)alkenyl, hydroxyl, amino, mono-(C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)-alkoxycarbonylamino, (C6-C12)aryl(C1-C4)alkoxycarbonylamino, (C6-C10)aryl, (C6-C10)aryl(C1-C3)alkyl, (C1-C3)heteroaryl, carboxyl and (C1-C4)alkoxycarbonyl; 3. (C3-C8)cycloalkyl,
where the cycloalkyl moiety is unsubstituted or substituted by 1-3 substituents selected from (C1-C4)alkyl and (C2-C4)alkenyl; 4. (C3-C8)cycloalkyl(C1-C3)alkyl, 5. (C6-C12)aryl, preferably phenyl, 6. (C6-C10)aryl(C1-C4)alkyl, 7. (C1-C9)heteroaryl,
which can be partially or completely hydrogenated,
8. a radical defined as under g) 5., 6., 7., 9., 15., 16., 17., 19., 20. or 21., substituted by 1 or 2 identical or different radicals selected from halogen, hydroxyl, (C1-C4)alkyl, methoxy, nitro, cyano, CO2R(103), trifluoromethyl, NR(111)R(112) and
9. (C1-C9)heteroaryl(C1-C3)alkyl,
where the heteroaryl moiety can be partially or completely hydrogenated,
10. (C1-C6)alkyl, in which 1 to all H atoms are substituted by fluorine,
11. (C2-C10)alkenyl, (C2-C10)-alkenoyl or (C2-C10)alkadienyl, 12. (C3-C8)cycloalkenyl, 13. (C3-C8)cycloalkenyl(C1-C3)alkyl, 14. bi- or tricyclic (C4-Cxe2x80x83)cycloalkenyl(C1-C4)alkyl,
which can also be substituted by 1-3 (C1-C4)-alkyl radicals;
15. (C6-C10)aryl(C1-C4)alkyl, 16. (C6-C10)aryl(C3-C6)-alkenyl, 17. (C1-C9)heteroaryl(C3-C6)alkenyl, 18. (C3-C6)alkynyl, 19. (C6-C10)aryl(C3-C6)alkynyl, 20. (C1-C9)heteroaryl(C3-C6)alkynyl, 21. R(106) and R(109) together with the nitrogen atom carrying them are a heteroaryl,
which can also be partially or completely hydrogenated;
h) R(107) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. (C6-C12)-aryl(C1-C6)alkyl, preferably benzyl, 5. phenyl or 6. (C1-C9)-heteroaryl;
i) R(108) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. phenyl-(CH2)qxe2x80x94, 5. OR(106), 6. NR(111)R(112) or 7.
j) R(110) is
cyano, nitro or CO2R(107);
k) R(111) and R(112) are,
identically or differently, 1. hydrogen, 2. (C1-C4)alkyl, 3. phenyl, 4. benzyl, or 5. xcex1-methylbenzyl;
l) D is NR(113), O or CH2;
m) R(113) is
hydrogen, (C1-C4)alkyl or phenyl;
n) A is biphenylyl,
which is unsubstituted or substituted by 1-4, preferably 1 to 2, identical or different substituents R(114) or R(115);
o) R(114) is
1. halogen, 2. nitroso, 3. nitro, 4. amino, 5. cyano, 6. hydroxyl, 7. (C1-C6)alkyl, 8. (C1-C4)alkanoyl, 9. (C1-C4)-alkanoyloxy, 10. CO2R(103), 11. methanesulfonylamino, 12. trifluoromethanesulfonylamino, 13. xe2x80x94COxe2x80x94NHxe2x80x94OR(109), 14. xe2x80x94SO2xe2x80x94NR(106)R(107), 15. xe2x80x94CH2xe2x80x94OR(107), 16. (C1-C9)-heteroaryl(CH2)qxe2x80x94, preferably 1-tetrazolyl, 17. (C7-C13)aroyl,
or
20. (C6-C12)aryl;
p) R(115) is
1. hydrogen, 2. (C1-C6)alkyl, 3. (C3-C8)cycloalkyl, 4. (C6-C12)-aryl, 5. (C7-C13)aroyl, 6. (C1-C4)alkoxy, 7. (C1-C4)-alkanoyloxy, 8. (C1-C9)heteroaryl, 9. CO2R(103), 10. halogen, 11. cyano, 12. nitro, 13. NR(106)R(107), 14. hydroxyl, 15. xe2x80x94COxe2x80x94NHxe2x80x94CHR(105)xe2x80x94CO2R(103), 16. sulfo, 17. xe2x80x94SO3R(103), 18. xe2x80x94SO2xe2x80x94NR(107)xe2x80x94COxe2x80x94NR(106)R(109) or xe2x80x94SO2xe2x80x94NR(107)xe2x80x94CSxe2x80x94NR(106)R(109), 19. xe2x80x94NR(107)xe2x80x94COxe2x80x94NR(106)xe2x80x94SO2xe2x80x94CH2-R(105), 20. xe2x80x94C(CF3)2OH, 21. phosphonooxy, 22. xe2x80x94PO3H2, 23. xe2x80x94NHxe2x80x94PO(OH)2, 24. xe2x80x94S(O)rR(106), 25. xe2x80x94COxe2x80x94R(108), 26. xe2x80x94COxe2x80x94NR(106)R(109), 27. xe2x80x94CR(120)(OH)xe2x80x94PO(OH)2, 28. the radical defined under o) 20.,
32. 5-tetrazolyl-NHxe2x80x94COxe2x80x94, 33. xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94CF3,
40. xe2x80x94COxe2x80x94NHxe2x80x94SO2-R(119), 41. xe2x80x94SO2xe2x80x94NHxe2x80x94COxe2x80x94R(106) or 42. the radical defined under p) 4., substituted by 1 or 2 identical or different radicals selected from halogen, cyano, nitro, NR(106)R(107) and hydroxyl; 43. R(115) together with R(114) is xe2x80x94COxe2x80x94NHxe2x80x94SO2xe2x80x94, 44. xe2x80x94SO2xe2x80x94NHxe2x80x94COxe2x80x94O-R(106), 45. xe2x80x94SO2xe2x80x94NHxe2x80x94SO2xe2x80x94NR(106)R(109), 46. xe2x80x94SO2xe2x80x94NHxe2x80x94SO2-R(106);
q) B is O, NR(107) or S;
r) W is O or S;
s) L is (C1-C3)alkanediyl;
t) R(116) is CO2R(103) or CH2CO2R(103);
u) R(117) is hydrogen, halogen, (C1-C4)alkyl or (C1-C4)alkoxy;
v) R(118) is hydrogen, (C1-C4)alkyl or phenyl;
w) R(119) is 1. (C1-C6)alkyl, 2. (C3-C8)cycloalkyl, 3. phenyl, 4. benzyl or 5. the radical defined under w) 1., in which one to all H atoms are substituted by fluorine,
x) T is 1. a single bond, 2. xe2x80x94COxe2x80x94, 3. xe2x80x94CH2xe2x80x94, 4. xe2x80x94Oxe2x80x94, 5. xe2x80x94Sxe2x80x94, 6. xe2x80x94NR(121)xe2x80x94, 7. xe2x80x94COxe2x80x94NR(121), 8. xe2x80x94NR(121)xe2x80x94COxe2x80x94, 9. xe2x80x94Oxe2x80x94CH2xe2x80x94, 10. xe2x80x94Cl2xe2x80x94, Oxe2x80x94, 11. xe2x80x94Sxe2x80x94CH2xe2x80x94, 12. xe2x80x94CH2xe2x80x94S, 13. xe2x80x94NHxe2x80x94CR(120)R(122), 14. xe2x80x94NR(121)xe2x80x94SO2, 15. SO2xe2x80x94NR(121)xe2x80x94, 16. xe2x80x94CR(120)R(122)xe2x80x94NH, 17. xe2x80x94CHxe2x95x90CHxe2x80x94, 18. xe2x80x94CFxe2x95x90CFxe2x80x94, 19. xe2x80x94CHxe2x95x90CFxe2x80x94, 20. xe2x80x94CFxe2x95x90CHxe2x80x94, 21. xe2x80x94CH2xe2x80x94CH2xe2x80x94, 22. xe2x80x94CF2xe2x80x94CF2xe2x80x94, 23. xe2x80x94CH[OR(103)]xe2x80x94, 24. xe2x80x94CH(OCOR(105))xe2x80x94, 25. xe2x80x94C[Nxe2x95x90R(123)]xe2x80x94 or 26. [R(124)O]xe2x80x94Cxe2x80x94[OR(125)]xe2x80x94
y) R(120) and R(122) are, identically or differently, hydrogen, (C1-C5)alkyl, phenyl, allyl or benzyl;
z) R(121) is hydrogen, (C1-C6)alkyl, benzyl or allyl;
axe2x80x2) R(123) is 1. NR(120)R(121), 2. ureido, 3. thioureido, 4. toluene-4-sulfonyl or 5. benzenesulfonylamino;
bxe2x80x2) R(124) and R(125) are, identically or differently, (C1-C4)alkyl or together xe2x80x94(CH2)q;
cxe2x80x2) Q is CH2, NH, O or S;
dxe2x80x2) m is 1, 2, 3, 4 or 5;
exe2x80x2) n is 1, 2, 3, 4 or 5;
fxe2x80x2) o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
gxe2x80x2) q is zero or 1;
hxe2x80x2) r is zero, 1 or 2;
ixe2x80x2) v is 1, 2, 3, 4, 5 or 6;
and of their physiologically tolerable salts for the production of a medicament for the treatment or prophylaxis of illnesses caused by ischemic conditions, and also for the production of a medicament for the treatment of impaired respiratory drive.
In addition, the invention relates to the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of illnesses caused by ischemic conditions;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of cardiac infarct;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of angina pectoris;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the heart:
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke;
and also the use of a compound of the formula I for the production of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and members;
and the use of a compound of the formula I for the production of a medicament for the treatment of states of shock;
and also the use of a compound of the formula I for the production of a medicament for use in surgical operations and organ transplantation;
and also the use of a compound of the formula I for the production of a medicament for the preservation and storage of transplants for surgical measures;
and also the use of a compound of the formula I for the production of a medicament for the treatment of illnesses in which cell proliferation is a primary or secondary cause; and thus their use for the production of an antiatherosclerotic or a composition against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, or prostate hyperplasia;
and also the use of a compound of the formula I for the production of a medicament for the treatment of impaired respiratory drive;
and also a pharmaceutical which comprises an efficacious amount of a compound of the formula I.
Compounds similar to the compounds of the formula I according to the invention are disclosed in U.S. Pat. Nos. 5,482,957 and 5,604,251. However, they do not have the sulfonylcyanamide side chain always present according to the invention. Imidazole derivatives as angiotensin 11 antagonists are also described in WO9523792, WO9523791, U.S. Pat. No. 5,391,732, EP-A 648763. In addition, in U.S. Pat. No. 5,281,614, triazole derivatives and, in WO 9220662 and in J. Med. Chem. (1994), 37 (17), 2808-2824, triazolinone derivatives are described as angiotensin 11 receptor antagonists. The known compounds are angiotensin II receptor antagonists of the subtype AT1, which action is not present or is only present to a small extent in the compounds I according to the invention.
The compounds of the formula I according to the invention exhibit very good antiarrhythmic properties, such as are important, for example, for the treatment of illnesses which occur in the case of oxygen deficiency symptoms. Because of their pharmacological properties, the compounds of the formula I are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias.
Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used, as a result of inhibition of the cellular Na+-dependent Clxe2x88x92/HCO3xe2x88x92 exchange mechanism or of the sodium/bicarbonate symporter, as a pharmaceutical for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. They protect organs which are acutely or chronically undersupplied with oxygen by reducing or preventing ischemically induced damage and are thus suitable as pharmaceuticals, for example in thrombosis, vasospasms, atherosclerosis or in surgical interventions (e.g. in kidney and liver organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and in the transfer to the recipient""s body) or acute kidney failure. The compounds of the formula I are also valuable pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart and also on peripheral vessels. Corresponding to their protective action against ischemically induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and of bacterial shock.
Moreover, the compounds of the formula I according to the invention are distinguished by strong inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of the vascular smooth muscle cells. Therefore the compounds of the formula I are suitable as valuable therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy.
It was found that inhibitors of the Na+-dependent Clxe2x88x92/HCO3xe2x88x92 exchanger or of the sodium/bicarbonate symporter can stimulate the respiration by an increase in the chemosensitivity of the respiratory chemoreceptors. These chemoreceptors are responsible to a considerable extent for the maintenance of an ordered respiratory activity. They are activated by hypoxia, pH decrease and rise in CO2 (hypercapnia) in the body and lead to an adjustment of the respiratory minute volume. During sleep, the respiration is particularly susceptible to disturbance and is dependent to a great extent on the activity of the chemoreceptors.
Improvement in the respiratory drive by stimulation of the chemoreceptors with substances which inhibit Na+-dependent Clxe2x88x92/HCO3xe2x88x92 exchange leads to an improvement in the respiration in the following clinical conditions and illnesses: disturbed central respiratory drive (e.g. central sleep apnea, cot death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in a high mountain region, obstructive and mixed forms of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.
Pharmaceuticals which contain a compound of the formula I can in this case be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred manner of administration being dependent on the particular symptoms of the disorder. The compounds of the formula I can in this case be used on their own or together with pharmaceutical auxiliaries, namely both in veterinary and in human medicine.
Auxiliaries which are suitable for the desired pharmaceutical formulation are familar to the person skilled in the art on the basis of his expert knowledge. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries, and other vehicles, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.
For an oral administration form, the active compounds are mixed with the additives suitable therefor, such as excipients, stabilizers or inert diluents, and brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefor such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension or emulsion. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and also a propellant gas. Such a preparation contains the active compound customarily in a concentration from approximately 0.1 to 10, in particular from approximately 0.3 to 3, % by weight.
The dose of the active compound of the formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I in the case of a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, to at most 10 mg/kg, preferably 1 mg/kg, of body weight. In the case of acute episodes of the illness, for example immediately after suffering a cardiac infarct, higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular in the case of i.v. administration, for example in the case of an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.
The compounds of the formula I can be employed as sole active compounds or in combination with other pharmacologically active compounds.
The compounds of the formula I and/or their physiologically tolerable salts can be employed to achieve an advantageous therapeutic action and, together with other pharmacologically active compounds, for the treatment or prophylaxis of the abovementioned symptoms, in particular for the treatment of cardiovascular disorders. Combination with inhibitors of the sodium/hydrogen exchanger (NHE) and/or with active substances from other classes of cardiovascular active compound is preferred.
The invention additionally relates very generally to the combination of a) NCBE inhibitors and/or their physiologically tolerable salts with NHE inhibitors and/or their physiologically tolerable salts; b) NCBE inhibitors and/or their physiologically tolerable salts with active substances from other classes of cardiovascular active compound and/or their physiologically tolerable salts and also c) of NCBE inhibitors and/or their physiologically tolerable salts with NHE inhibitors and/or their physiologically tolerable salts and with active substances from other classes of cardiovascular active compound and/or their physiologically tolerable salts. Preferred combinations are those in which NCBE inhibitors of the formula I and/or their physiologically tolerable salts are used.
The active compounds which are known and identified as NHE inhibitors are guanidine derivatives, preferably acylguanidine, inter alia such as are described in Edward J. Cragoe, Jr., xe2x80x9cDIURETICS, Chemistry, Pharmacology and Medicinexe2x80x9d, J. WILEY and Sons (1983), 303-341 or the NHE inhibitors mentioned in DE19737224.4. The disclosures of both of these documents are specifically incorporated by reference herein.
Suitable NHE inhibitors are, for example, also benzoylguanidines such as are described in U.S. Pat. No. 5,292,755, U.S. Pat. No. 5,373,024, U.S. Pat. No. 5,364,868, U.S. Pat. No. 5,591,754, U.S. Pat. No. 5,516,805, U.S. Pat. No. 5,559,153, U.S. Pat. No. 5,571,842, U.S. Pat. No. 5,641,792, U.S. Pat. No. 5,631,293, EP-A 577024, EP-A 602522, EP-A 602523, EP-A 603650, EP-A 604852, EP-A 612723, EP-A 627413, EP-A 628543, EP-A 640593, EP-A 640588, EP-A 702001, EP-A 713864, EP-A 723956, EP-A 754680, EP-A 765868, EP-A 774459, EP-A 794171, DE 19624178.2, DE 19713427.0; ortho-substituted benzoylguanidines, such as are described in EP-A 556673, EP-A 791577, EP-A 794172, DE 19624178.2; ortho-amino-substituted benzoylguanidines, such as are described in EP-A 690048; isoquinolines, such as are described in EP-A 590455; benzo-fused 5-membered ring heterocycles, such as are described in EP-A 639573; diacyl-substituted guanidines, such as are described in EP-A 640587; acylguanidines, such as are described in U.S. Pat. No. 5,547,953; phenyl-substituted alkyl- or alkenylcarboxylic acids bearing perfluoroalkyl groups, such as are described in U.S. Pat. No. 5,567,734, EP-A 688766; heteroaroylguanidines, such as are described in EP-A 676395; bicyclic heteroaroylguanidines, such as are described in EP-A 682017; indenoylguanidines, such as are described in EP-A 738712; benzyloxycarbonylguanidines, such as are described in EP-A 748795; phenyl-substituted alkenylcarboxylic acid guanidines bearing fluorophenyl groups, such as are described in EP-A 744397; substituted cinnamoylguanidines, such as are described in EP-A 755919; sulfonimidamides, such as are described in EP-A 771788; benzenedicarboxylic acid diguanidines, such as described in EP-A 774458, EP-A 774457; diarylcarboxylic acid diguanidines, such as are described in EP-A 787717; substituted thiophenylalkenylcarboxylic acid guanidines, such as are described in EP-A 790245; bis-ortho-substituted benzoylguanidines, such as are described in DE 19621319.3; substituted 1- or 2-naphthylguanidines, such as are described in DE 19621482.3 and DE 19621483.1; indanylideneacetylguanidines, such as are described in EP 96112275.1; phenyl-substituted alkenylcarboxylic acid guanidines such as are described in DE 19633966.9; aminopiperidylbenzoylguanidines, such as are described in EP 667341; heterocycloxybenzylguanidines, such as are described in EP-A 694537; ortho-substituted benzoylguanidines, such as are described in EP704431; ortho-substituted alkylbenzylguanidines, such as are described in EP-A 699660; ortho-substituted heterocyclylbenzoylguanidines, such as are described in EP-A 699666; ortho-substituted 5-methylsulfonylbenzoylguanidines, such as are described in EP-A 708088; ortho-substituted 5-alkylsulfonylbenzoylguanidines having 4-amino substituents, such as are described in EP-A 723963; ortho-substituted 5-alkylsulfonylbenzoylguanidines having 4-mercapto substituents, such as are described in EP-A 743301; 4-sulfonyl- or 4-sulfinylbenzylguanidines, such as are described in EP-A 758644; alkenylbenzoylguanidines, such as are described in EP-A 760365; benzoylguanidines having fused, cyclic sulfones, such as are described in DE 19548708; benzoyl-, polycyclic aroyl- and heteroaroylguanidines, such as are described in WO 9426709; 3-aryl/heteroarylbenzoylguanidines, such as are described in WO 9604241; 3-phenylbenzoylguanidines having a basic amide in the 5-position, such as are described in WO 9725310; 3-dihalothienyl- or 3-dihalophenylbenzoylguanidines having a basic substituent in the 5-position, such as are described in WO 9727183; 3-methylsulfonylbenzoylguanidines having certain amino substituents in the 4-position, such as are described in WO 9512584; amiloride derivatives, such as are described in WO 9512592; 3-methylsulfonyl-benzoylguanidines having certain amino substituents in the 4-position, such as are described in WO 9726253; indoloylguanidines, such as are described in EP-A 622356 and EP-A 708091; indoloylguanidines having a fused additional ring system, such as are described in EP 787728; methylguanidine derivatives, such as are described in WO 9504052; 1,4-benzoxazinoylguanidines, such as are described in EP-A 719766; 5-bromo-2-naphthoylguanidines, such as are described in JP 8225513; quinoline-4-carbonylguanidines having a phenyl radical in the 2-position, such as are described in EP-A 726254; cinnamoylguanidines, such as are described in JP 09059245; propenoylguanidines having a naphthalene substituent, such as are described in JP 9067332; propenoylguanidines having indole substituents, such as are described in JP 9067340; or heteroaryl-substituted acryloylguanidines, such as are described in WO 9711055, and their physiologically tolerable salts. The disclosures of all of these documents are specifically incorporated by reference herein.
Preferred NHE inhibitors are the compounds emphasized as preferred in the publications mentioned. Very particularly preferred compounds are cariporide (HOE642), HOE 694, EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032, and their physiologically tolerable salts. Most preferred is cariporide or its physiologically tolerable salt.
Examples of classes of active compounds having cardiovascular activity which can be combined advantageously with NCBE inhibitors therapeutically or can additionally be combined with combinations of NCBE inhibitors and NHE inhibitors are beta-receptor blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, loop diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists, such as are employed, for example, in lowering of the blood pressure, and also cardiac glycosides or other agents increasing the contractile force in the treatment of cardiac insufficiency and of congestive heart failures, and also antiarrhythmics of the classes I-IV, nitrates, KATP openers, KATP blockers, inhibitors of the veratridine-activatable sodium channel, etc. For example, the following are thus suitable: the beta-blockers propanolol, atenolol, metoprolol; the calcium antagonists diltiazem hydrochloride, verapamil hydrochloride, nifedipine; the ACE inhibitors captopril, enalapril, ramipril; trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; the angiotensin II receptor antagonists losartan, valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan; the loop diuretics furosemide, piretanide, torasemide; the thiazide diuretics hydrochlorothiazide, metolazone, indapamide; the potassium-sparing diuretics amiloride, triamterene, spironolactone; the cardiac glycosides digoxin, digitoxin, strophanthin; the antiarrhythmics amiodarone, sotalol, bretylium, flecainide; the nitrate glycerol trinitrate; the K+(ATP) openers cromakalim, lemakalim, nocorandil, pinacidil, minoxidil; the inhibitors of the veratridine-activatable Nat channel.
An example of such a particularly advantageous combination component with NCBE inhibitors are blockers of the non-inactivating sodium channel (veratridine-activatable sodium channel). The combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel (veratridine-activatable sodium channel) are suitable for infarct and reinfarct prophylaxis and infarct treatment and also for the treatment of angina pectoris and the inhibition of ischemically induced cardiac arrhythmias, tachycardia and the formation and maintenance of ventricular fibrillation, the combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel also preventively inhibiting or greatly decreasing the pathophysiological processes in the formation of ischemically induced damage. Because of their enhanced protective actions against pathological hypoxic and ischemic situations, the combinations according to the invention of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are used, as a result of enhanced inhibition of the Na+ influx into the cell, as pharmaceuticals for the treatment of all acute or chronic damage induced by ischemia or diseases induced primarily or secondarily thereby. This relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example, also during storage thereof in physiological bath fluids, and also during transfer to the recipient""s body. The combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are likewise valuable, protectively acting pharmaceuticals when carrying out angioplastic surgical interventions, for example on the heart, and also on peripheral vessels. In accordance with their protective action against ischemically induced damage, the combinations of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable for the treatment of stroke or of cerebral edema. Moreover, the combinations according to the invention of an NCBE inhibitor with a blocker of the non-inactivating sodium channel are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
Beside administration as a fixed combination, the invention also relates to the simultaneous, separate or sequential administration of NCBE inhibitors with NHE inhibitors and/or an additional active substance from another class of cardiovascular active compound for the treatment of the abovementioned diseases.
The invention additionally relates to a pharmaceutical preparation comprising a) an NCBE inhibitor and an NHE inhibitor and/or their physiologically tolerable salts; or b) an NCBE inhibitor and additionally an active substance from another class of cardiovascular active compound and/or their physiologically tolerable salts; or c) an NCBE inhibitor, an NHE inhibitor and additionally an active substance from another class of cardiovascular active compound, and/or their physiologically tolerable salts.
Preferred pharmaceutical preparations are those which contain a compound of the formula I and/or its physiologically tolerable salt as an NCBE inhibitor.
By combined administration, the effect of one combination component can be potentiated by the respective other component, i.e. the action and/or duration of action of a combination or preparation according to the invention is stronger or longer-lasting than the action and/or the duration of action of the respective individual components (synergistic effect). In the case of combined administration, this leads to a lowering of the dose of the respective combination component, compared with individual administration. The combinations and preparations according to the invention accordingly have the advantage that the amounts of active compound to be administered can be significantly reduced and undesirable side effects can be eliminated or greatly reduced.
The invention furthermore relates to a commercial pack, comprising as pharmaceutical active compound a) an NCBE inhibitor and an NHE inhibitor and/or their physiologically tolerable salts; or b) an NCBE inhibitor and additionally an active substance from another class of cardiovascular active compound and/or their physiologically tolerable salts; or c) an NCBE inhibitor, an NHE inhibitor and additionally an active substance from another class of cardiovascular active compound and/or their physiologically tolerable salts, in each case together with instructions for the use of these active compounds in combination for simultaneous, separate or sequential administration in the treatment or prophylaxis of the abovementioned syndromes, in particular for the treatment of cardiovascular disorders.
Preferred commercial packs are those which contain compounds of the formula I as NCBE inhibitors.
The pharmaceutical preparations according to the invention can be prepared, for example, by either intensively mixing the individual components as powders, or by dissolving the individual components in the suitable solvents such as, for example, a lower alcohol and then removing the solvent.
The weight ratio of NCBE inhibitor to the NHE inhibitor or the substance having cardiovascular activity in the combinations and preparations according to the invention is expediently 1:0.01 to 1:100, preferably 1:0.1 to 1:10.
The combination and preparations according to the invention contain a total of preferably 0.5-99.5% by weight, in particular 4-99% by weight, of these active compounds.
When used according to the invention in mammals, preferably in man, the doses of the various active compound components vary, for example, in the range from 0.001 to 100 mg/kg/day.
The sulfonamide starting material is dissolved in 10 ml/mmol of anhydrous acetonitrile, 3 mol equivalents of K2CO3 and one mol equivalent of a 5 N solution of BrCN in acetonitrile are added dropwise and the mixture is heated under reflux until conversion is complete (typical reaction time 1-6 hours). The reaction mixture is then chromatographed on silica gel without further working up.

Abstract: in which the symbols have the meanings indicated in the claims, have outstanding antiarrhythmic properties and exhibit a cardioprotective component. They can preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias. Moreover, they have a potent inhibitory action on the proliferation of cells.


This invention relates to the integration of visual information, anatomic constraints, prior shape knowledge, and level set representations for the segmentation of medical images. An embodiment according to the present invention comprises a level set variational framework that uses a bi-directional boundary flow, an intensity-based regional component that maximizes the a posteriori segmentation probability, a physiology-based module that constrains the solution space and a term that accounts for shape-driven consistency. All modules are expressed in an energetic form and the resulting objective function is optimized using a gradient descent method.

Cardiovascular diseases are one of the leading causes of death in United States. The development of new technologies to diagnose cardiovascular diseases has led to a decline of the mortality rate. Magnetic resonance imaging ("MRI") provides time varying three dimensional imagery of the heart that can be processed using Computer Vision techniques. The three dimensional imagery can then be used for diagnostic purposes. Therefore, physicians are interested in identifying heart chambers using three dimensional imagery so that this information can be used for diagnostic purposes.
In medical applications the areas of interest in the image domain are actual anatomic structures. The segmentation result is constrained according to some a priori high level knowledge of an anatomic structure, such as, forms, relative positions, and motion over time.
The extraction of accurate results is a requirement in medical applications. Therefore, predominately boundary-based methods, enforced by some region-based segmentation modules, have been employed to cope with the segmentation task. These methods can be classified into two categories. The first category is parametric methods that determine the segmentation map by fitting a boundary template to the image. The second category is non-parametric methods that are based on the propagation of regular curves under the influence of local image characteristics.
Parametric methods have real-time performance and can deal with incomplete data and slight deformations due to shape-driven constraints. However, such methods primarily refer to boundary information and require complicated models to deal with important shape deformations while topological changes cannot be handled.
Non-Parametric methods can deal with important shape deformations and topological changes. At the same time these methods do not require a priori knowledge. However, non-parametric methods do not have a robust behavior due to the presence of noise and are time consuming.
Identifying heart chambers, in particular, the endocardium and the epicardium, is a challenging problem in medical image analysis. Furthermore, measuring ventricular blood volume, ventricular wall mass, ventricular wall motion and wall thickening properties over various stages of a cardiac cycle are powerful diagnostic tools that are studied in medical image analysis. The left ventricle is of particular interest because it pumps oxygenated blood out of the heart to distant tissue in the entire body. The information space refers to physically corrupted data. Small parts, for example, papillary muscles, of an endocardium do not have the same intensity properties as its dominant parts. At the same time, the separation, that is, boundaries, of the epicardium and the rest of the heart is practically impossible to detect in some areas, due to lack of information.
A need exists for a unified mathematical framework that makes optimal use of visual information, translates high level application constraints into low level segmentation modules, is able to deal with lack of visual information, and is able to deal with physically corrupted data.

Integration of visual information, anatomic constraints and prior shape knowledge for medical segmentations


Embodiments herein relate to a method in a radio base station for transmitting an information signal in a radio communications network. The radio base station is arranged to operate in a time structure associated with a clock and arranged to transmit an information signal associated with the time structure. The radio base station is in the radio communications network. The radio base station transmits the information signal repeatedly with a first frequency over a first period of time. Then, the radio base station transmits the same information signal repeatedly with a second frequency over a second period of time, wherein the first frequency is lower than the second frequency and the first period of time is longer than the second period of time.

In today's radio communications networks a number of different technologies are used, such as Long Term Evolution (LTE), LTE-Advanced, 3rd Generation Partnership Project (3GPP) Wideband Code Division Multiple Access (WCDMA), Global System for Mobile communications/Enhanced Data rate for GSM Evolution (GSM/EDGE), Worldwide Interoperability for Microwave Access (WiMax), or Ultra Mobile Broadband (UMB), just to mention a few possible implementations. A radio communications network comprises radio base stations providing radio coverage over at least one respective geographical area forming a cell. User equipments (UE) are served in the cells by the respective radio base station and are communicating with respective radio base station. The user equipments transmit data over an air or radio interface to the radio base stations in uplink (UL) transmissions and the radio base stations transmit data over an air or radio interface to the user equipments in downlink (DL) transmissions.
Today there are approximately 5 billion connectable devices in the radio communication networks. One vision for the future is that communication becomes so cheap so that network communication capabilities can be built into almost every small device or object. In the future the radio communications networks may need to serve up to 50 billion, or even 500 billion devices. The use cases that are currently being studied for a "500B vision" are: mass monitoring, e.g. of agricultural fields, energy infrastructure, and parking lots; mass controlling, e.g. of traffic lights, building automation, and lamps; object tracking, e.g. of baggage, parcels, and keys; personal health care, e.g. heart rate monitoring.
In a vision it is assumed that every small device can communicate. Most devices will be sending and/or receiving small amounts of data and for many devices the energy consumption will be the most important design limitation. For simple devices, such as small sensors, the battery might need to last for several years, since replacing the batteries more often than that will simply be prohibitively expensive. The devices need to be cheap and hence we assume that the typical device battery will have limited capacity, e.g. in the order of a standard AAA battery.
For many simple devices the energy consumption in the receiving circuits of the simple device will be dominating simply because the simple device does not transmit very often. The receiver (RX) radio front-end of the simple device is dominating in energy consumption and it is particularly expensive for the simple device to have the RX radio front-end activated. Typically the simple device in idle mode needs to activate the RX radio front-end when e.g. receiving data, listening for paging transmissions from the network, and/or performing radio measurements. During sleep mode the RX radio front-end, the RX base band, and the fine clock e.g. the local oscillator, can all be turned off and only a coarse clock that is used to wake up the simple device when the simple device need to be active. The coarse clock can be made extremely power efficient but the accuracy is typically rather poor.
The energy consumption in the radio communications network is dominated by the power amplifiers in the radio base stations. In order to reduce network energy consumption in future systems it is important to design for as much support of Discontinuous Transmission (DTX) as possible since the transmitters are then silent, which also leads to increased intervals of Discontinuous Reception (DRX). The mandatory overhead transmissions that do not relate to user plane data shall preferably transmitted only in short bursts every 10-100 ms or so, such as synchronization signal transmissions, a paging message, cell specific reference signals, master information block on a Physical Broadcast Channel (PBCH), or transmissions of higher layer system information blocks.
In order to reduce the energy consumption in the devices being in idle mode increased paging intervals is beneficial. For ultra-low power devices for Machine-to-Machine (M2M) communication the paging intervals can be measured in minutes or hours rather than seconds. Since the power required for the receiving device, also referred to as a user equipment, to have the RX radio front-end in active mode is so significant, it is important to keep the wake-up period required to receive a paging message as short as possible. Typically the RX radio front-end is active for 1-2 ms which is considered acceptable to read a paging message.
The problem is that long DRX cycles cause a significant timing uncertainty in the user equipment due to the fact that the coarse clock that is running in the idle mode is of low accuracy. Long DTX periods in the radio base stations and long DRX periods in the user equipments are wanted for the purpose of reducing energy consumption. It turns out that short wakeup periods in the user equipments are difficult to match with long DTX periods since the user equipments cannot quickly find the network timing, i.e. the synchronization clock of the network, when the network is not continuously transmitting the timing information.
In case the user equipment wakes up to read a paging message with an uncertain timing, then the period the user equipment receives transmissions needs to be long in order to capture the paging message transmitted from the network to activate the user equipment.
Today one may try and solve the problem by using shorter DRX cycles in the user equipments. This reduces the time the user equipment can be in sleep mode and hence it has the drawback of high energy consumption in the mobile terminal. Alternatively, the user equipment may keep the RX radio front-end active until it receives an overhead transmission carrying an information signal associated with the time structure in the radio base station, such as a synchronization signal transmission or the actual paging message, from the radio base station. This method increases the time the user equipment needs to have the RX radio front-end in active mode and hence it has the drawback of high energy consumption in the user equipment. Furthermore, the radio base station may transmit the information signal, such as synchronization signals, more often. This limits the applicability of network DTX in the radio base station and hence it has the drawback of high energy consumption in radio base station. Thus, the different solutions known in prior art require increased energy consumption in the radio communications network or in the user equipments.

Radio base station, user equipment and methods therein


A vector-matrix multiplier in which a matrix is stored in an electron trapping material by exposing the material to visible light passed through a liquid crystal device, which acts as a mask. The visible light raises electrons in the electron trapping material to a higher energy level at the exposed locations. Infrared light is then passed through the liquid crystal device to form an input vector, which is projected onto the electron trapping material. The infrared light releases electrons from the higher energy level, resulting in emission of a pattern of visible light. The emission of visible light from the electron trapping material forms an output representing the product of the input vector and the matrix.

1. Field of the Invention
The present invention relates to optical signal processing using electron trapping materials and, more specifically, to the use of electron trapping materials in a compact optical vector-matrix multiplier system.
2. Description of the Related Art
The capabilities of electron trapping materials having been demonstrated in various disciplines of optical signal processing. For example, the application of electron trapping materials to parallel Boolean logic has been reported by S. Jutamulia, G. M. Storti, J. Lindmayer, and W. Seiderman in "Application of Electron trapping (ET) Materials to Optical Parallel Logic Processing," Proc. SPIE. 1151, 83, 1989. The use of electron trapping materials in memory devices has been demonstrated by S. Jutamulia, J. Lindmayer, and G. Storti in "Optical Pattern Recognition and Associative Memory Using Electron trapping Materials," Proc. SPIE 1053, 67, 1989. Recently, the capabilities of electron trapping materials applied to Hopfield type neural networks has been discussed by S. Jutamulia, G. M. Storti, J. Lindmayer, W. Seiderman in "Optical Neural Nelectron trappingwork Digital Multi-Value Processor with Learning Capability Using Electron trapping Materials," Proc. SPIE 1215, 457, 1990.
A neural network model is basically represented by a matrix-vector multiplication. J. J. Hopfield, "Neural Networks and Physical Systems with Emergent Collective Computational Abilities", Proc. Natl. Acad. Sci. USA, 79, 2554-2558 (1982). Vector-matrix multiplication can be performed optically by converting the vector into matrix form, forming an image of that matrix, and optically multiplying that image with the image of a vector. The conversion of a vector into a matrix is accomplished by the following interconnection matrix T.sub.ij : ##EQU1## where V.sub.i and V.sub.j are the ith and jth elements of the vector, and where i and j represent the row and column of the matrix elements.
For example, the vector (1,0,0,1,1) will convert into the matrix: ##EQU2##
Electron trapping materials are useful in performing optical multiplications. As described in A. D. McAulay, "Optical Orthogonal Neural Network Associative Memory with Luminescent Rebroadcasting Devices," Int. Joint Conf. Neu. Net. IEEE--89CH2765--G, Volume III, 483-485 (1985), multiplication can be performed by writing one image, say A, onto an electron trapping material using visible light, and then reading with IR light in a pattern representing the second image B. The output luminescent at each pixel position is proportional to the analog product of the read intensity at that pixel and the stored value at that pixel.
While the prior techniques for optical vector-matrix multiplication such as disclosed by McAulay have been successfully demonstrated, they use fan-out and fan-in lenses and thus require precise optical alignment and take up a considerable amount of space. Accordingly, optical vector-matrix multiplication has been limited to laboratory bench top systems. Thus, a need exists for a vector-matrix multiplier which is compact, rugged and which can actually be implemented in an optical computer.

Compact vector-matrix multiplier system employing electron trapping materials


When engaged, an articulation controller automatically adjusts an angle of articulation between a front frame and a rear frame of a motor grader based on a steering angle of the front wheels. If a groundspeed of the motor grader exceeds a threshold groundspeed, the articulation controller enters a mode that only allows decreasing the angle of articulation of the motor grader. When the angle of articulation reaches zero, the articulation controller disengages until the groundspeed is reduced below the threshold groundspeed.

An articulated machine, such as a motor grader, is a versatile apparatus for road work, ditch work, site preparation and other surface contouring and finishing tasks. The versatility of a motor grader is provided in large part by its multiple course setting and course change options. In particular, a motor grader typically includes a steering function implemented via steerable ground engaging wheels while also allowing some degree of course correction or steering via lateral arching or articulation of the machine frame. In this manner, for example, a motor grader may be steered and articulated to follow a curve without driving the rear wheels across the area inside the curve and disturbing the just graded area.
As should be recognized from the above, motor graders, and other articulated machines, are complex pieces of heavy machinery and are operatively complex. Controlling a motor grader includes numerous hand-operated controls to steer the front wheels, position the blade, control articulation, control auxiliary devices such as rippers and plows, and various displays for monitoring machine conditions and/or functions. Control of a motor grader requires highly skilled and focused operators to position the blade while controlling steering.
Automatic articulation control can help relieve an operator of an articulated machine from the moment-to-moment monitoring of articulation while making turns but for reasons including safety, such system may be disengaged under different conditions, such as when the speed of a vehicle exceeds a threshold speed. For example, U.S. Patent Application Publication 2011/0035109 ("Steering System with Automated Articulation Control") describes a system wherein machine articulation is automatically controlled based on machine steering. The system of the '109 publication adjusts machine articulation to follow steering angles and commands, thereby maintaining tracking between the front and rear wheels of the machine. Automated articulation should be automatically disengaged when the ground speed of the machine exceeds a limit.
However, there may be situations in which the automatic disengagement of the automated articulation control function may leave the machine in an undesirable articulated position, such as when increasing speed past the limit or other condition while executing a turn. Further, automatic disengagement of the automatic articulation control function may require that an operator manually re-engage the automatic articulation control function after the condition clears, which can both distract the operator and leave the automatic articulation control function disabled longer than may be necessary or desirable.

Automatic articulation behavior during error and high speed conditions


A process for preparing a bioabsorbable sheet preparation holding thrombin is provided. A process for preparing a bioabsorbable sheet preparation holding thrombin which comprises immersing a bioabsorbable sheet consisting of polyglycolic acid in a thrombin solution containing thrombin as an active ingredient, glycerol as a softening agent, Tween 80 as a permeating agent, and optionally histidine and trehalose as a stabilizing agent followed by drying to hold thrombin on said bioabsorbable sheet, and a bioabsorbable sheet preparation holding thrombin prepared by said process.

Thrombin is an enzyme that is involved in blood coagulation and is indispensable to maintenance and progress of life such as formation of hemostatic thrombus or treatment of injury. Thrombin is normally present in blood in the form of inactive prothrombin but is activated by the coagulation system triggered by, for instance, platelets or damage in tissue cells to convert fibrinogen in a soluble form into insoluble fibrin useful for hemostasis and treatment of injury. A hemostatic utilizing this principle has widely been applied in clinical scenes.
Although thrombin has been used as an active ingredient of a hemostatic, with the conventional hemostatic in the form of liquid, hemostasis by pressing or closing by pressing to a spot of gushing hemorrhage or oozing hemorrhage is not possible and therefore bleeding cannot be stopped.
Aiming at hemostasis of such gushing hemorrhage or oozing hemorrhage, there have been attempts to develop a sheet-type hemostatic where thrombin, fibrinogen and/or a coagulation factor is held on a collagen sponge, a non-woven fabric consisting of alginic acid or polyglycolic acid, or other bioabsorbable supports consisting of gelatin or hydrogel (e.g. see Patent references 1, 2, 3, 4, 5, 6 and 7).
However, most of the sheet hemostatic have not yet been put into practical usage due to problems that they are thick and lack flexibility since, when applied to a closing spot of organs in their dry form, rigidity of supports per se may adversely affect to thereby make it difficult to closely contact with a spot of injury, thus failing to exert sufficient adhesive effect.
A unique product of a sheet-type fibrin adhesive that has been commercially available is one where fibrinogen and bovine thrombin are held on a support consisting of equine collagen (product name: TachoComb/CSL Behling) (e.g. see Patent reference 8). However, this adhesive still has room for improvement in handling and removal of risk factors in view of its thickness (about 3 mm) and inclusion of components derived from animals.
On the other hand, there are several reports on a stabilizing agent to thrombin. For instance, approaches for preserving thrombin with stability has been reported by comprising a salt of an organic carboxylic acid (e.g. see Patent reference 9) or glycerol (e.g. see Patent references 10, 11 and 12) for a liquid preparation, or by comprising a sugar, a basic amino acid and a liquid organic acid (e.g. see Patent reference 13), or gelatin, glycine and a sugar (e.g. see Patent reference 14), or an aliphatic polybasic carboxylic acid and albumin (e.g. see Patent reference 15), or human serum albumin and an amino acid (e.g. see Patent reference 16) for a dry preparation packed in a vial or in an aluminum pouch package. However, in case of a sheet-type preparation, mere stabilization of thrombin cannot attain an object.
When a sheet preparation is used, it is sometimes made round or folded so that it may touch closely a spot of injury. Therefore, for avoiding breakage of a sheet or leakage of thrombin constituent due to forces imposed, it is necessary to improve flexibility or thrombin-holding property of a sheet.
For instance, the thrombin preparation comprising a sugar, a basic amino acid and a liquid organic acid as described above is not suited for a sheet-type preparation since flexibility is lost when the thrombin preparation is held on a sheet. Also, when a non-woven fabric is immersed in a thrombin solution and is simply subject to lyophilization, thrombin is not held on the non-woven fabric. In order to solve the problems, a technique is reported that a non-woven fabric made of chitin as a support is immersed alternately in three solutions, i.e. a solution of an acidic high molecular weight compound such as chondroitin sulfate, alginic acid or hyaluronic acid, a solution of a basic high molecular weight compound such as chitosan, and a thrombin solution, to hold thrombin, followed by drying in vacuum or with ventilation to prepare a sheet-like hemostatic or a sheet-like medicament for injury (e.g. see Patent reference 17). However, with such technique of alternate absorption, even if flexibility of a sheet could be secured, reduction of the activity of thrombin would be unavoidable and handling in production is cumbersome. Accordingly, development of a more efficient process for preparation is desired.
Patent reference 1: Japanese Patent Publication No. 61-59737
Patent reference 2: Japanese Patent Publication No. 05-163157
Patent reference 3: Japanese Patent Publication No. 2002-515300
Patent reference 4: U.S. Pat. No. 4,453,939
Patent reference 5: Japanese Patent Publication No. 9-504719
Patent reference 6: Japanese Patent Publication No. 2000-510357
Patent reference 7: Japanese Patent Publication No. 2001-513368
Patent reference 8: European Patent 0059265
Patent reference 9: Japanese Patent Publication No. 56-39782
Patent reference 10: Japanese Patent Publication No. 62-106028
Patent reference 11: Japanese Patent Publication No. 7-64747
Patent reference 12: Japanese Patent Publication No. 63-192723
Patent reference 13: Japanese Patent Publication No. 2-53732
Patent reference 14: Japanese Patent Publication No. 7-165604
Patent reference 15: Japanese Patent Publication No. 2002-193832
Patent reference 16: Japanese Patent Publication No. 2006-117678
Patent reference 17: Japanese Patent Publication No. 2006-306759

Process for preparing bioabsorbable sheet preparation holding thrombin

THE CHEMO-SERO-THERAPEUTIC RESEARCH INSTITUTE


The present invention provides an apparatus for multiplexing a plurality of light waves with different wavelengths. The apparatus includes a laser sub-assembly, a multiplexer sub-assembly, and a receptacle sub-assembly. The laser sub-assembly includes a plurality of lasers for radiating a plurality of light waves of different wavelengths. The plurality of light waves are multiplexed in the multiplexer sub-assembly. The multiplexed light waves are coupled to an optical fiber by the receptacle sub-assembly.

The present invention relates generally to optical communication devices. More specifically, the present invention relates to an optical multiplexing and transmitting assembly.
An optical multiplexing and transmitting assembly is used for transmitting large amounts of information or data at high speeds through an optical fiber. In multiplexing, two or more signals are combined into a single bit stream by an optical multiplexer. The signals can be individually recovered from the single bit stream, transmitted through an optical fiber, by a demultiplexer.
Currently known optical fibers have core diameters of 50-100 micron for multimode optical fibers, and of less than 10 microns for single-mode optical fibers. These optical fibers are connected to the various optical elements of the optical multiplexing and transmitting assembly. The locations of optical elements need to be fixed in space with sub-micron accuracies and need to be maintained to sub-micron accuracies over time and over temperature excursions. Therefore, there is a need for an optical multiplexing and transmitting assembly that has optical elements fixed at precise locations with sub-micron accuracy, to effectively transmit information or data through optical fibers.


A universal handle for medical instruments includes a first member movably disposed within a housing for detachably mounting a first medical instrument, a bias member for moving the first member toward a retracted or extended position near one end of the housing, a locking mechanism for engaging the first member in the retracted or extended position to prevent the bias member from moving the first member into the retracted or extended position, and a releasing mechanism including an operating member movable in response to a reduction in force acting on a component of the handle for triggering release of the locking mechanism to permit the bias member to move the first member to the retracted or extended position. A second member for detachably mounting a second medical instrument can be held stationary relative to the housing or can be movably disposed within the housing between extended and retracted positions. Opposite ends of the universal handle can be configured to provide at least one of a retracting and a protruding function as desired.

1. Field of the Invention
The present invention relates to medical procedures and instruments and, more particularly, to a universal handle providing a retracting and/or a protruding function for medical instruments.
2. Brief Description of the Related Art
Penetrating instruments are widely used in medical procedures to gain access to anatomical cavities ranging in size from the abdomen to small blood vessels, such as veins and arteries, epidural, pleural and subarachnoid spaces, heart ventricles and spinal and synovial cavities. Use of penetrating instruments has become an extremely popular and important first step in endoscopic, or minimally invasive, surgery to establish an endoscopic portal for many various procedures, such as laproscopic procedures in the abdominal cavity. Such penetrating instruments typically include a cannula or portal sleeve and a penetrating member disposed within the cannula and having a sharp tip for penetrating an anatomical cavity wall with the force required to penetrate the cavity wall being dependent upon the type and thickness of the tissue forming the cavity wall. Once the wall is penetrated, it is desirable to protect the sharp tip of the penetrating member from inadvertent contact with or injury to tissue or organ structures in or forming the cavity in that, once penetration is achieved, the lack of tissue resistance can result in the sharp tip traveling too far into the cavity and injuring adjacent tissue or organ structures.
Various safety penetrating instruments have been proposed, generally falling into protruding and retracting categories. In protruding safety penetrating instruments, a safety member is spring-biased to protrude beyond the tip of the penetrating member in response to the reduced force on the distal end of the safety member upon entering into the anatomical cavity. The safety member can be disposed around the penetrating member in which case the safety member is frequently referred to as a shield, or the safety member can be disposed within the penetrating member in which case the safety member is frequently referred to as a probe. In retracting safety penetrating instruments, the penetrating member is retracted into the cannula upon entry into the anatomical cavity in response to distal movement of a component of the safety penetrating instrument such as the penetrating member, the cannula, a probe or a safety member such as a shield or probe.
A disadvantage of safety penetrating instruments in general is that relatively complex mechanisms are required to retract a penetrating member or protrude a safety member such that integral construction of the safety penetrating instruments requires sterilization or disposal of the entire unit after use, significantly increasing the cost of utilizing such instruments. Another disadvantage of the prior art instruments is that penetrating components, such as the penetrating member and safety member, are not interchangeable between penetrating instruments. As such, if the type or size of a penetrating component is not correct for the application, an entirely new safety penetrating instrument must be selected. Moreover, there is no flexibility to selectively match a particular penetrating component with a particular protruding or retracting power.

Universal handle for medical instruments


In this butterfly valve (10) provided with: a main body (11); valve shafts (13, 14); and a valve body (30) that is rotatable with respect to the main body, the valve body is formed integrally from a core material (32) and a contour forming member (31) that is formed from a synthetic resin material and that encircles the core material and forms the contour of the valve body. The valve body has bearing holes (33, 34) that support the valve shafts, the contour forming member has a bearing inner peripheral part (36) that forms at least a part of the inner peripheral surface of each of the bearing holes, the contour forming member is formed continuously with the bearing inner peripheral part, and the core material has a bearing reinforcing part (35) that supports the bearing inner peripheral part of the contour forming member, radially outside from the rotation axis of the valve body.

A butterfly valve is used for controlling the flow of hydrochloric acid or other corrosive fluid. To raise the corrosion resistance and chemical resistance of such a butterfly valve, the past practice has been to form the valve body from a plastic material. Further, in recent years, larger sizes of butterfly valves with valve bodies formed from plastic materials and higher temperatures of the ranges of usage temperatures have been particularly sought. However, with a valve body made of a plastic material, as the temperature of the fluid circulating through the butterfly valve rises or as the size of the butterfly valve becomes larger, it gradually becomes more difficult to obtain the required strength. In particular, when the valve body is a type supported by a valve shaft divided into two parts, the stress occurring at the bearing hole of the valve body supporting the valve shaft becomes higher and as a result sometimes the problem arises of the bearing hole deforming.
To deal with the above-mentioned problem, as described in PTL 1, the conventional practice has been to reinforce a plastic valve body with a metal core member sealed inside it.


An algorithm for finding regions of interest (ROI) in images and photos based on an information driven approach in which sub-blocks of an image are analyzed for information content or compressibility based on the discrete cosine transform. The sub-blocks of low compressibility are grouped into ROIs using a morphological technique. Unlike other algorithms that are geared for highly specific types of ROI (e.g. face detection), the method of the present invention is generally applicable to arbitrary images and photos. A center-weighted variation of the algorithm can produce better results for certain photo applications. The algorithm can be used with several other image applications, including Stained-Glass collages and Pan-and-Scan presentations.

1. Field of the Invention
The current invention relates generally to digital image processing, and more particularly to finding regions of interest in natural and synthetic images.
2. Description of the Related Art
A tremendous amount of digital images and photos are being created with the ubiquitous digital cameras, camera cell phones and PDAs. An important challenge is figuring out ways to manage and visualize collections of images and photos. In the case of photos, small sets from events such as social gatherings and travels are especially prevalent. Another factor is viewing images on small displays and mobile devices, when it is helpful to provide ways to condense the images.
In U.S. patent application Ser. No. 10/815,389, entitled "EXTRACTING VIDEO REGIONS OF INTEREST" and U.S. patent application Ser. No. 10/815,354, entitled "GENERATING A HIGHLY CONDENSED VISUAL SUMMARY", a method was disclosed to summarize and condense a video using a Stained-Glass Visualization, which shows a video using a storyboard generated from regions of interest (ROI) in the key frames of the highly ranked video segments. The ROIs are laid out and the gaps are filled by extending the ROIs using a Voronoi technique. This produces irregular boundaries and the result looks like a stained glass. Along with the visualization method, an algorithm was provided for finding the ROIs in a video segment based on motion analysis.
The Stained-Glass visualization is applicable to photos and images, producing a collage from a given set of images. Photo collages can be used in many ways. For example, a wallet-sized collage of family members can be displayed on a PDA or cell phone. Larger collages of a party can be put on a Web page and shared with friends. Poster sized collages of scenic photos from a vacation can be printed and framed.
Our earlier algorithm for finding ROIs in videos, being based on motion analysis, does not work for still images. What is needed is a method for finding ROIs in images and photos such that collections of images and photos can be managed and visualized and presented on large and small displays.

This patent is subject to a terminal disclaimer.

Determining regions of interest in photographs and images