1. A method for controlling a level of blood glucose in a patient using an extracorporeal blood circuit, said method comprising:
a. withdrawing blood from a vascular system in the patient to the extracorporeal circuit;
b. removing ultrafiltrate from the withdrawn blood in the circuit and passing the ultrafiltrate through an ultrafiltration passage;
c. determining a level of glucose present in the blood using a glucose sensor monitoring ultrafiltrate flowing through an ultrafiltration passage;
d. infusing insulin into the vascular system to control the blood glucose, wherein a rate of insulin infused is based on the determined level of glucose;
e. introducing a calibration solution into the ultrafiltrate passage; and
f. calibrating the glucose sensor based on a measurement made by the sensor of the calibration solution flowing through the ultrafiltrate passage.
2. A method as in claim 1 where a rate of infusion is adjusted based on a current level of glucose and a prior level of glucose.
3. A method as in claim 1 wherein at least a portion of the removed ultrafiltrate is infused into the vascular system.
4. A method as in claim 3 wherein the portion of the removed ultrafiltrate is returned to the withdrawn blood upstream of a filter removing the ultrafiltrate.
5. A method as in claim 1 further comprising introducing the calibration solution into the ultrafiltrate flow passage in a flow direction in the ultrafiltrate passage opposite to a flow direction of the ultrafiltrate in the ultrafiltrate passage.
6. A method as in claim 1 further comprising introducing the calibration solution from the ultrafiltrate passage into the withdrawn blood and upstream of a filter removing the ultrafiltrate.
7. A method as in claim 1 further comprising removing the calibration solution from the ultrafiltrate passage without introducing the calibration solution into the withdrawn blood.
8. A method as in claim 1 wherein the insulin is infused into the patient by first introducing the insulin into the withdrawn blood in the circuit.
9. A method as in claim 1 wherein an amount of calibration solution introduced into the ultrafiltrate passage is less than a volume of the ultrafiltrate passage.
10. A method as in claim 9 wherein the amount of calibration solution introduced into the ultrafiltrate passage is removed from the circuit without being introduced into the vascular system.
11. A method as in claim 1 further comprising blocking introduction of the calibration solution into the ultrafiltrate passage while ultrafiltrate is being removed from a filter in the circuit.
12. A method as in claim 11 further comprising of placing a spring loaded one way valve in the calibration solution line to block the calibration solution during removal of ultrafiltrate.
13. A method as in claim 1 wherein the infusion of the removed ultrafiltrate to the vascular system is interrupted while the calibration solution is introduced into the ultrafiltrate passage.
14. A method as in claim 1 further comprising preventing withdrawal of blood through a blood return passage in the circuit during introduction of the calibration solution in the ultrafiltrate passage.
15. A method as in claim 1 wherein the removal of ultrafiltrate and the introduction of the calibration solution is performed with a peristaltic pump acting on the ultrafiltrate passage, wherein the pump operates in opposite rotational direction to pump the ultrafiltrate and the calibration solution.
16. A method of claim 1, wherein calibrating the glucose sensor is based on a measurement made by the glucose sensor of the calibration solution flowing through the ultrafiltrate passage.
17. A method of claim 1 further comprising measuring the calibration solution with a reference glucose sensor and calibrating the glucose sensor based on the measurement made by the reference glucose sensor of the calibration solution during a calibration sequence.
18. A method of claim 17 wherein the glucose sensor measures a level of glucose present in the blood during the calibration sequence.
19. A method as in claim 1, wherein the step of introducing a calibration solution into the ultrafiltrate passage comprises introducing a calibration solution into the ultrafiltrate passage in a flow direction in the ultrafiltrate passage opposite to a flow direction of the ultrafiltrate in the ultrafiltrate passage.
20. A method as in claim 1, wherein wherein the removal of ultrafiltrate and the introduction of the calibration solution is performed with a peristaltic pump acting on the ultrafiltrate passage, wherein the pump operates in opposite rotational directions to pump the ultrafiltrate and the calibration solution.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of Formula I:
A\u2014B
or pharmaceutically acceptable salts thereof, wherein
A represents
B represents
X and Y independently at each occurrence are selected from NH, N, C, or CH, such that at least one of X and Y always represents N or NH; and
Z represents C or N; provided that, (i) when Z represents N, R7 represents H or C(\u2550NH)NH2;
R1 represents OH, halogen, COOH, COO\u2014C1-4 alkyl, O\u2014(CH2)0-1\u2014Ph, CH2OR10, C1-6 halogenated alkyl, O\u2014(CH2)1-4\u2014CO\u2014N(R10)2, SC1-4 alkyl, NHSO2C1-4alkyl, SO2\u2014OH, O\u2014SO2\u2014OH, O\u2014SO2\u2014O\u2014C1-4 alkyl, OP(O)(OH)2, or OP(O)(OH)OC1-4 alkyl;
R2, R3, R4 and R5 independently at each occurance occurrence represent H, SH, OR10, halogen, COOR10, CONR11R12, optionally substituted aryl, optionally substituted heterocyclyl, C4-14 cycloalkyl-C1-4 alkyl, C1-4 alkyl aryl, optionally substituted C1-4 straight chain, branched or cyclo alkyl, O\u2014(CH2)2-6\u2014NR10\u2014(CH2)0-3\u2014R24, NR10R24, (CH2)1-4\u2014NR33R34, (CH2)1-4\u2014COOR33, O\u2014(CH2)1-3\u2014CO-het, O\u2014(CH2)1-2\u2014NH\u2014CO-aryl, O\u2014(CH2)1-2\u2014NR10\u2014CO\u2014NR10R33, O\u2014(CH2)0-2\u2014C(O)\u2014NR33R34, O\u2014(CH2)1-4\u2014COOR10, O\u2014(CH2)1-3-het-R32, O-optionally substituted cycloalkyl, O\u2014(CH2)1-4\u2014NR10\u2014COO-t-butyl, O\u2014(CH2)1-4-NR10R33, O\u2014(CH2)1-4\u2014NR10\u2014C(O)\u2014C0-3-alkyl-optionally substituted aryl, O-substituted cycloalkyl, O\u2014(CH2)0-6-optionally substituted aryl, (CH2)1-4\u2014NH\u2014C(O)O\u2014(CH2)1-4\u2014PhR13R14, NO2, O\u2014(CH2)0-4\u2014C(O)\u2014NH-tetrahydro carboline, NR10R28, O\u2014(CH2)1-3-optionally substituted het, CH2COOCH3, CH\u2550CH\u2014COOCH3, 5-amidino benzimidazole,
alternatively R2 and R3 taken together form
R6 and R9 independently at each occurrence represents H, halogen, cyano, C1-4 alkyl, C1-4 halogenated alkyl, NO2, O-aryl or OR11;
R7 and R8 independently at each occurrence represent OH, CF3, H, NO2, C1-4 alkyl, OC1-4 alkyl, O-aryl, halogen, or cyano, or a basic group selected from guanidino, C(\u2550NH)N(R10)2, C(\u2550NH)\u2014NH\u2014NH2, C(\u2550O)NH2, 2-imidazoline, N-amidinomorpholine, N-amidino piperidine, 4-hydroxy-N-amidino piperidine, N-amidino pyrrolidine, tetrahydro pyrimidine, and thiazolidin-3-yl-methylideneamine; with the proviso that one, but not both, of R7 and R8 represents a basic group;
R10 independently at each occurrence represents H, (CH2)0-2-aryl, C1-4 halo alkyl, or C1-14 straight chain, branched or cyclo alkyl, and alternatively, when one atom is substituted with two R10 groups, the atom along with the R10 groups can form a five to 10 membered ring structure;
R11 and R12 independently at each occurrence represent H or C1-4 alkyl;
R20 represents R24, C1-4-alkyl, (CH2)1-3-biphenyl, (CH2)1-4\u2014Ph\u2014N(SO2\u2014C1-2-alkyl)2, (CH2)1-4\u2014NH\u2014C(O)\u2014R24, (CH2)1-4\u2014NH\u2014SO2\u2014R24, halogen, COOR10, (CH2)1-4\u2014Ph\u2014N(SO2\u2014C1-2alkyl), (CH2)1-4\u2014NR10\u2014C(O)\u2014R24, (CH2)1-4\u2014NR10\u2014SO2\u2014R24, (CH2)1-4-het, (CH2)1-4\u2014CON(R10)2, (CH2)1-4\u2014N(R10)\u2014C(O)\u2014NR10R24, (CH2)1-4\u2014N(R10)\u2014C(S)\u2014NR10R24, or (CH2)1-3\u2014COOH;
R24 represents R10, (CH2)1-4-optionally substituted aryl, (CH2)0-4R10, CO\u2014(CH2)1-2\u2014N(R10)2, CO(CH2)1-4\u2014OR10, (CH2)1-4\u2014COOR10, (CH2)0-4\u2014N(R10)2, SO2R10, COR10, CON(R10)2, (CH2)0-4-aryl-COOR10, (CH2)0-4-aryl-N(R10)2, or (CH2)1-4-het-aryl;
R28 represents (CH2)1-2\u2014Ph\u2014O\u2014(CH2)0-2-het-R30, C(O)-het, CH2\u2014Ph\u2014CH2-het-(R30)1-3; (CH2)1-4-cyclohexyl-R31, CH2\u2014Ph\u2014O\u2014Ph\u2014(R30)1-2, CH2\u2014(CH2OH)-het-R30, CH2\u2014Ph\u2014O-cycloalkyl-R31, CH2-het-C(O)\u2014CH2-het-R30, or CH2\u2014Ph\u2014O\u2014(CH2)\u2014O-het-R30;
R30 represents SO2N(R10)2, H, NHOH, amidino, or C(\u2550NH)CH3;
R31 represents R30, amino-amidino, NH\u2014C(\u2550NH)CH3 or R10;
R32 represents H, C(O)\u2014CH2\u2014NH2, or C(O)\u2014CH(CH(CH3)2)\u2014NH2;
R33 and R34 independently at each occurrence represent R10, (CH2)0-4\u2014Ar, optionally substituted aryl, (CH2)0-4 optionally substituted heteroaryl, (CH2)1-4\u2014CN, (CH2)1-4\u2014N(R10)2, (CH2)1-4\u2014OH, (CH2)1-4\u2014SO2\u2014N(R10)2; alternatively,
R33 and R34 along with the nitrogen atom that they are attached form a 4 to 14 atom ring structure selected from tetrahydro-1H-carboline; 6,7-dialkoxyoxy-2-substituted 1,2,3,4-tetrahydro-isoquinoline,
R35 represents R10, SO2\u2014R10, COR10, or CONHR10;
E represents a bond, S(O)0-2, O or NR10;
W1, W2, W3 and W4 independently represent C or N; and
Q, Q1, Q2, Q3, L1, L2, L3 and L4 independently at each occurrence represent N-natural or unnatural amino acid side chain, CHR10, O, NH, S(O)0-2, N\u2014C(O)\u2014NHR10, SO2\u2014N(R10)2, N\u2014C(O)\u2014NH\u2014(CH2)1-4\u2014R26, NR10, N-heteroaryl, N\u2014C(\u2550NH)\u2014NHR10, or N\u2014C(\u2550NH)C1-4 alkyl;
R26 represents OH, NH2, or SH;
provided that, (i) when R1=OH; R7=amidine; R2, R6, R8, R9 and R20 each represent H; and R3, R4, R5 are independently chosen from H, CH3 and halogen, then only one of R3, R4, and R5 represents H; (ii) when R1=OH; R7=amidine; R2, R3, R4, R5 and R20 each represent H; and R6, R8, R9 are independently chosen from H, CH3, and halogen, then only one of R6, R8, and R9 represents H; (iii) at least two of W1, W2, W3 and W4 represent C and at least one of W1, W2, W3 and W4 represent N; and (iv) when R1=OH; R7=amidine; and R2, R3, R4, R5, R6, R8 and R9, represent H, R20 cannot be CH3.
2. A compound of claim 1 wherein
R1 represents OH, O\u2014Ph, COOH or P(O)(OH)2;
R7 represents CONH2, CN, C(\u2550NH)\u2014NH\u2014NH2, NH\u2014C(\u2550NH)\u2014NH2 or C(\u2550NH)\u2014NH2;
R20 represents H, C1-2 alkyl, (CH2)1-4-optionally substituted aryl, (CH2)1-4-het; (CH2)1-4\u2014N(R10)2, (CH2)1-4\u2014CON(R10)2, (CH2)1-4\u2014NR10\u2014C(O)\u2014R24, (CH2)1-4\u2014NR10\u2014SO2\u2014R24, or (CH2)1-3\u2014COOH.
3. A compound of claim 2 wherein
A represents
B represents
X and Y represent N; and
R7 represents \u2014CONH2 or C(\u2550NH)\u2014NH2.
4. A compound of claim 3 wherein
R1 represents OH, \u2014COOH, or O\u2014P(O)(OH)2;
R2 and R3 independently represent halogen, H, C1-4 alkyl, Ph, toluyl, OH, O\u2014(CH2)1-2\u2014C(O)\u2014NH\u2014(CH2)1-2\u2014CN, O\u2014(CH2)1-3\u2014Ph-p-OCH3, O\u2014CH2\u2014C(O)\u2014NH\u2014(CH2)1-2\u2014CH\u2014(CH3)2, O\u2014CH2\u2014C(O)\u2014NH\u2014(CH2)\u2014Ph, O\u2014CH2\u2014C(O)\u2014NH\u2014(CH2)\u2014Ph-pCH3, O\u2014C1-3 alkyl, O\u2014(CH2)0-2\u2014Ph\u2014R10, O\u2014CH2\u2014C(O)\u2014NH\u2014(CH2)2\u2014H, Ph\u2014C1-3 alkyl, Ph\u2014N(R10)2, O\u2014(CH2)1-3-het, O\u2014(CH2)1-3\u2014Ph-halo, O\u2014(CH2)1-3\u2014NHSO2Ph\u2014R10, O\u2014(CH2)1-3\u2014NHCO\u2014(CH2)0-2\u2014Ph, O\u2014CH2\u2014C(O)\u2014NH\u2014CH2\u2014COO\u2014C(CH3)3, O\u2014(CH2)2\u2014NHC(O)\u2014CH2\u2014NH2, \u2014OPh, O\u2014(CH2)1-3\u2014NH-het, O\u2014(CH2)2\u2014NH\u2014C(O)-pyridyl, O\u2014(CH2)2\u2014NH\u2014C(O)\u2014NH-benzyl, O\u2014(CH2)2-cyclohexyl, O\u2014(CH2)2\u2014NH\u2014C(O)\u2014(CH2)2\u2014CONH2, O\u2014(CH2)2\u2014NH\u2014C(O)\u2014CH2\u2014OCH3, thiophene, pyridyl or O\u2014(CH2)2-pyridyl;
alternatively R2 and R3 taken together form
R4 represents halogen, H, NO2, C1-2-alkyl, CH\u2550CH\u2014COOCH3, NHSO2C1-2 alkyl, NHCO-het, (CH2)1-3\u2014COOR10, (CH2)1-3\u2014CONH\u2014(CH2)1-3-pyridyl, or (CH2)1-3\u2014CONH\u2014(CH2)1-3-dichlorophenyl;
R5 represents H;
R6 represents H;
R7 represents C(\u2550NH)\u2014NH2 or NH(\u2550NH)NH2;
R8 represents H, halogen, OR10, CF3, or C(\u2550NH)\u2014NH2;
R9 represents H or halogen; and
R20 represents H.
5. A compound of claim 4 wherein
R1 represents OH, or COOH;
R2 represents H, halogen, OH, phenyl, O\u2014(CH2)1-3\u2014Ph, imidazolyl, 5-amidino benzimidazolyl, O\u2014(CH2)1-2\u2014C(O)\u2014NH\u2014C1-6 alkyl, or O\u2014CH2\u2014C(O)\u2014NH\u2014CH2\u2014Ph;
R3 represents H, O\u2014CH2\u2014COOH, O\u2014CH2\u2014C(O)O\u2014C2H5, O\u2014CH2\u2014C(O)\u2014NH\u2014(CH2)1-4-aryl, O\u2014(CH2)1-4\u2014NH\u2014C(O)-naphthyl, CONH2, O\u2014(CH2)1-2\u2014C(O)N(R10)\u2014(CH2)1-3\u2014Ph\u2014R13R14, O\u2014CH2\u2014C(O)\u2014N(R10)\u2014CH2-piperanyl, O\u2014CH2\u2014C(O)\u2014NH\u2014CH2-indoyl, (CH2)0-4-aryl,
R4 represents H, \u2014CH3, halogen, \u2014OCH3,\u2014(CH2)1-2COOR10, \u2014COOH, \u2014NO2, \u2014OH, aryl,
R5 represents H;
R6 represents H;
R7 represents \u2014C(O)\u2014NH2 or \u2014C(\u2550NH)\u2014NH2;
R8 represents H, Cl, F, OH or OCH3;
R9 represents H; and
R13 and R14 independently at each occurrence represents H, halogen, \u2014OC1-2 alkyl, \u2014CF3, or \u2014C1-4 alkyl; and
R15 represents H,
R20 represents H or \u2014CH2\u2014Ph.
6. A compound selected from
3-3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4hydroxy-phenyl-N-phenethyl-propionamide;
3-4-(6-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenyl-N-(2,3-dichloro-benzyl)-propionamide;
2-4(6-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy-N-(2,3-dichloro-benzyl)-acetamide;
3-3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl-N-2-(2,4-dichloro-phenyl)-ethyl-propionamide;
3-3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl-N-(2-pyridin-2-yl-ethyl)-propionamide;
3-3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl-N-(3-phenyl-propyl)-propionamide;
2-4-(6-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy-N-naphthalen-1-ylmethyl-acetamide;
2-(3\u2032-Amino-5-chloro-2-hydroxy-biphenyl-3-yl)-3H-benzoimidazole-5-carboxamidine;
3-3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl-propionic acid;
2-(3,5-Bis-hydroperoxy-2-hydroxy-phenyl)-3H-benzoimidazole -5-carboxamidine;
2-4-(5-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy-N-(3-chloro-benzyl)-acetamide;
N-Benzyl-3-3-bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl-propionamide;
2-(3,5-Dibromo-2,4-dihydroxy-phenyl)-3H-benzoimidazole-5-carboxamidine;
2-(2-Hydroxy-biphenyl-3-yl)-3H-benzoimidazole-5-carboxamidine;
2-(5-Chloro-2-hydroxy-biphenyl-3-yl)-3H-benzoimidazole-5-carboxamidine;
2-(2-Hydroxy-3-phenethyloxy-phenyl)-3H-benzoimidazole-5-carboxamidine;
N-(3-Bromo-benzyl)-2-4-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy-acetamide;
2-{3-1-(3-Amino-propionyl)-pyrrolidin-2-ylmethoxy-2-hydroxy-phenyl}-3H-benzoimidazole-5-carboxamidine;
2-(5-Chloro-2-hydroxy-3-pyridin-3-yl-phenyl)-1H-benzoimidazole-5-carboxamidine;
2-3-(5-Carbamimidoyl-1H-benzoimidazol-2-yl)-2-hydroxy-phenyl-3,4,6,7-tetrahydro-imidazo4,5-cpyridine-5-carboxamidine;
2-3-(1-Aminoacetyl-pyrrolidin-2-ylmethoxy)-2-hydroxy-phenyl-3H-benzoimidazole-5-carboxamidine;
2-(2-Hydroxy-3-phenoxy-phenyl)-3H-benzoimidazole-5-carboxamidine;
2-2-Hydroxy-3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl-1H-benzoimidazole-5-carboxamidine;
2-3-(1-Aminoacetyl-piperidin-3-ylmethoxy)-2-hydroxy-phenyl-1H-benzoimidazole-5-carboxamidine;
2-{3-1-(2-Amino-3-methyl-butyryl)-pyrrolidin-2-ylmethoxy-2-hydroxy-phenyl}-1H-benzoimidazole-5-carboxamidine;
2-2-Hydroxy-3-(1-hydroxyacetyl-pyrrolidin-2-ylmethoxy)-phenyl-1H-benzoimidazole-5-carboxamidine;
2-(2-Hydroxy-5-iodo-3-methoxy-phenyl)-1H-benzoimidazole-5-carboxamidine;
2-{3-1-(2-Amino-3-methyl-butyryl)-pyrrolidin-2-ylmethoxy-2-hydroxy-phenyl}-3H-benzoimidazole-5-carboxamidine;
2-(2-Hydroxy-5-{4-1-(1-imino-ethyl)-piperidin-4-yloxy-benzylamino}-phenyl)-3H-benzoimidazole-5-carboxamidine; compound with methane;
2-(2-Hydroxy-5-{4-1-(1-imino-ethyl)-piperidin-3-ylmethoxy-benzylamino}-phenyl)-3H-benzoimidazole-5-carboxamidine;
2-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3H-benzoimidazole-5-carboxamidine;
3-2,6-Dibromo-4-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy-propionic acid;
3-2,6-Dibromo-4-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy-propionic acid ethyl ester; and
2-3-Bromo-2-hydroxy-5-(3-methoxy-but-3-enyl)-phenyl-3H-benzoimidazole-5-carboxamidine;
or a stereoisomer or pharmaceutically acceptable salt form thereof.
7. A compound of claim 1 wherein A represents
B represents
X represents C; and
Y represents NH.
8. A compound of claim 7 wherein
R1 represents \u2014OH, \u2014COOH, or P(O)(OH)2;
R2 represents H, halogen, R10, -aryl, heteroaryl, \u2014C1-2-alkyl, COOH, \u2014OC1-2-alkyl or \u2014O\u2014(CH2)0-2-aryl;
R3 represents H or \u2014O\u2014(CH2)1-3\u2014COOH;
alternatively R2 and R3 taken together represent
R4 represents H, C1-4 alkyl, \u2014(CH2)1-4\u2014COOH, \u2014(CH2)1-4\u2014COOC1-2-alkyl, halogen, \u2014(CH2)1-2\u2014CONH2, \u2014CONH2, \u2014NO2, \u2014O\u2014C1-2 alkyl, or \u2014OH;
R5 represents H, C1-3 alkyl or \u2014COOH;
R6 represents H, halogen, or \u2014C1-3 alkyl;
R7 represents \u2014C(O)\u2014NH2, \u2014C(\u2550NH)\u2014NH\u2014NH2, or amidino;
R8 represents H, or halogen; and
R20 represents H, \u2014(CH2)1-4\u2014Ph\u2014N(SO2\u2014C1-2alkyl), \u2014(CH2)1-4\u2014NR10\u2014C(O)\u2014R24, \u2014(CH2)1-4\u2014NR10\u2014SO2\u2014R24, \u2014(CH2)1-4-het, \u2014(CH2)1-4\u2014CON(R10)2, \u2014(CH2)1-4\u2014N(R10)\u2014C(O\u2014NR10R24, \u2014(CH2)1-4\u2014N(R10)\u2014C(S)\u2014NR10R24, \u2014C1-2-alkyl, \u2014(CH2)1-4-optionally substituted aryl, \u2014(CH2)1-4-het; \u2014(CH2)1-3\u2014N(R10)2; \u2014(CH2)1-4\u2014CON(R10)2, or \u2014(CH2)1-3\u2014COOH.
9. A compound of claim 8 wherein the compound is selected from
3-Benzyl-2-(3-chloro-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
3-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-propionic acid;
3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-acetic acid;
6-Chloro-2-(3,5-dichloro-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
3-Bromo-5-(5-carbamimidoyl-1H-indol-2-yl)-4-hydroxy-benzamide;
2-(3,5-Dichloro-2-hydroxy-phenyl)-1H-indole-5carboxamidine;
3-(4-Amino-benzyl)-2-(3-bromo-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
2-(2-Hydroxy-biphenyl-3-yl)-1H-indole-5-carboxamidine;
2-(3-Bromo-2-hydroxy-5-nitro-phenyl)-1H-indole-5-carboxamidine;
2-(5-Hydroxy-2,3-dihydro-benzo1,4dioxin-6-yl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(3,5-difluoro-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(3,5-dibromo-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
3-Bromo-5-(5-carbamimidoyl-1H-indol-2-yl)-4-hydroxy-phenyl-acetic acid;
3-Benzyl-2-(5-chloro-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
2-3-Bromo-5-(5-carbamimidoyl-1H-indol-2-yl)-4-hydroxy-phenyl-acetamide;
2-(3,5-Difluoro-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
2-(3,5-Dibromo-2-hydroxy-phenyl)-1H-indole-5-carboxamidine;
2-(2-Hydroxy-5-methyl-biphenyl-3-yl)-1H-indole-5-carboxamidine;
2-(2-Hydroxy-5,4\u2032-dimethyl-biphenyl-3-yl)-1H-indole-5-carboxamidine;
2-(3-Bromo-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(3-bromo-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(3-chloro-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(2-hydroxy-3,5-dimethyl-phenyl)-1H-indole-5-carboxamidine;
2-(3,5-Dibromo-2-hydroxy-phenyl)-3-methyl-1H-indole-5-carboxamidine;
2-(2-Hydroxy-5-methyl-3-thiophen-2-yl-phenyl)-1H-indole-5-carboxamidine;
2-2-(3-Bromo-2-hydroxy-5-methyl-phenyl)-5-carbamimidoyl-1H-indol-3-yl-acetamide;
3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-acetic acid methyl ester;
3-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-propionic acid methyl ester;
3-(3-Amino-benzyl)-2-(3-bromo-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
2-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3-(3-nitro-benzyl)-1H-indole-5-carboxamidine;
3-(3-Amino-benzyl)-2-(2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
3-Benzyl-2-(3-chloro-2-hydroxy-5-methyl-phenyl)-1H-indole-5-carboxamidine;
6-Chloro-2-{5-2-(1,1-dioxo-1-thiomorpholin-4-yl)-2-oxo-ethyl-2-hydroxy-biphenyl-3-yl}-1H-indole-5-carboxamidine;
2-5-(5-Carbamimidoyl-6-chloro-1H-indol-2-yl)-6-hydroxy-biphenyl-3-yl-N-(2-piperidin-1-yl-ethyl)-acetamide;
6-Chloro-2-{2-hydroxy-5-2-(2-methoxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl-biphenyl-3-yl}-1H-indole-5-carboxamidine;
6-Chloro-2-{2-hydroxy-5-2-oxo-3-(tetrahydro-furan-2-yl)-propyl-biphenyl-3-yl}-1H-indole-5-carboxamidine;
2-5-(5-Carbamimidoyl-6-chloro-1H-indol-2-yl)-6-hydroxy-biphenyl-3-yl-N-(tetrahydro-furan-2-ylmethyl)-acetamide;
2-5-(5-Carbamimidoyl-6-chloro-1H-indol-2-yl)-6-hydroxy-biphenyl-3-yl-N-(3-methoxy-propyl)-acetamide;
Morpholine-4-carboxylic acid {2-5-(5-carbamimidoyl-6-chloro-1H-indol-2-yl)-6-hydroxy-biphenyl-3-yloxy-ethyl}-amide;
Phosphoric acid mono-{2-3-(3-benzyl-5-carbami midoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-ethyl} ester;
2-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-N-{4-1-(1-imino-ethyl)-piperidin-4-yloxy-phenyl}-acetamide;
4-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-butyric acid;
2-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo4-hydroxy-phenyl-acetamide;
2-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-N,N-dimethyl-acetamide;
3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-acetic acid;
3-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-pentanedioic acid bis-(2-morpholin-4-yl-ethyl)-amide;
3-3-(3-Benzyl-5-carbamimidoyl-1H-indol-2-yl)-5-bromo-4-hydroxy-phenyl-propionamide; and
2-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-benzyl)-1H-indole-5-carboxamidine;
or a stereoisomer or pharmaceutically acceptable salt form thereof.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof.
12. A method for treating or preventing a arterial thromboembolism, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula:
A\u2014B
or pharmaceutically acceptable salts thereof, wherein
A represents
B represents
X and Y independently at each occurrence are selected from NH, N, C, or CH, such that at least one of X and Y always represents N or NH; and
Z represents C or N; provided that, (i) when Z represents N, R7 represents H or C(\u2550NH)NH2;
R1 represents OH, halogen, COOH, COO\u2014O1-4 alkyl, O\u2014(CH2)0-1\u2014Ph, N(R10)2, CH2OR10, C1-6-halogenated alkyl, O\u2014(CH2)1-4\u2014CO\u2014N(R10)2, SC1-4 alkyl, NHSO2C1-4alkyl, SO2\u2014OH, O\u2014SO2\u2014OH, O\u2014SO2\u2014O\u2014C1-4 alkyl, OP(O)(OH)2, or OP(O)(OH)OC1-4 alkyl;
R2, R3, R4, and R5 independently at each occurrence represent H, SH, OR10, halogen, COOR10, CONR11R12, optionally substituted aryl, optionally substituted heterocyclyl, C4-14 cycloalkyl-C1-4 alkyl, C1-4 alkyl aryl, optionally substituted C1-14 straight chain, branched or cyclo alkyl, O\u2014(CH2)2-6\u2014NR10\u2014(CH2)0-3\u2014R24, NR10R24, (CH2)1-4\u2014NR33R34, (CH2)1-4\u2014COOR33, O\u2014(CH2)1-3\u2014N\u2014CO-het, O\u2014(CH2)1-2\u2014NH\u2014CO-aryl, O\u2014(CH2)1-2\u2014NR10\u2014CO\u2014NR10R33, O\u2014(CH2)0-2\u2014C(O)\u2014NR33R34, O\u2014(CH2)1-4\u2014COOR10, O\u2014(CH2)1-3-het\u2014R32, O-optionally substituted cycloalkyl, O\u2014(CH2)1-4\u2014NR10\u2014COO-t-butyl, O\u2014(CH2)1-4\u2014NR10R33, O\u2014(CH2)1-4\u2014NR10\u2014C(O)\u2014C0-3-alkyl-optionally substituted aryl, O-substituted cycloalkyl, O\u2014(CH2)0-6-optionally substituted aryl, (CH2)1-4\u2014NH\u2014C(O)O\u2014(CH2)1-4\u2014PhR13R14, NO2, O\u2014(CH2)0-4\u2014C(O)\u2014NH-tetrahydro carboline, NR10R28, O\u2014(CH2)1-3-optionally substituted het, CH2COOCH3, CH\u2550CH\u2014COOCH3, 5-amidino benzimidazole,
alternatively R2 and R3 taken together form
R6 and R9 independently at each occurrence represents H, halogen, cyano, C1-4 alkyl, C1-4 halogenated alkyl, NO2, O-aryl or OR11;
R7 and R8 independently at each occurrence represent OH, CF3, H, NO2, C1-4 alkyl, OC1-4 alkyl, O-aryl, halogen, or cyano, or a basic group selected from guanidino, C(\u2550NH)N(R10)2, C(\u2550NH)\u2014NH\u2014NH2, C(\u2550O)NH2, 2-imidazoline, N-amidinomorpholine, N-amidino piperidine, 4-hydroxy-N-amidino piperidine, N-amidino pyrrolidine, tetrahydro pyrimidine, and thiazolidin-3-yl-methylideneamine; with the proviso that one, but not both, of R7 and R8 represents a basic group;
R10 independently at each occurrence represents H, (CH2)0-2-aryl, C1-4 halo alkyl, or C1-14 straight chain, branched or cyclo alkyl, and alternatively, when one atom is substituted with two R10 groups, the atom alone with the R10 groups can form a five to 10 membered rind structure;
R11 and R12 independently at each occurrence represent H or C1-4 alkyl;
R20 represents R24, C1-4-alkyl, (CH2)1-3-biphenyl, (CH2)1-4\u2014Ph\u2014N(SO2\u2014C1-2-alkyl)2, (CH2)1-4\u2014NH\u2014C(O)\u2014R24, (CH2)1-4\u2014NH\u2014SO2\u2014R24, halogen, COOR10, (CH2)1-4\u2014Ph\u2014N(SO2\u2014C1-2alkyl), (CH2)1-4\u2014NR10\u2014C(O)\u2014R24, (CH2)1-4\u2014NR10\u2014SO2\u2014R24, (CH2)1-4-het, (CH2)1-4\u2014CON(R10)2, (CH2)1-4\u2014N(R10)\u2014C(O)\u2014NR10R24, (CH2)1-4\u2014N(R10)\u2014C(S)\u2014NR10R24, or (CH2)1-3\u2014COOH;
R24 represents R10, (CH2)1-4-optionally substituted aryl, (CH2)0-4OR10, CO\u2014(CH2)1-2\u2014N(R10)2, CO(CH2)1-4\u2014OR10, (CH2)1-4\u2014COOR10, (CH2)0-4\u2014N(R10)2, SO2R10, COR10, CON(R10)2, (CH2)0-4-aryl-COOR10, (CH2)0-4-aryl-N(R10)2, or (CH2)1-4-het-aryl;
R28 represents (CH2)1-2\u2014Ph\u2014O\u2014CH2)0-2-het\u2014R30, C(O)-het, CH2\u2014Ph\u2014CH2-het-(R30)1-3; (CH2)1-4-cyclohexyl-R31, CH2\u2014Ph\u2014O\u2014Ph\u2014(R30)1-2, CH2\u2014(CH2OH)-het\u2014R30, CH2\u2014Ph\u2014O-cycloalkyl-R31, CH2-het-C(O)\u2014CH2-het-R30, or CH2\u2014Ph\u2014O\u2014(CH2)\u2014O-het-R30;
R30 represents SO2N(R10)2, H, NHOH, amidino, or C(\u2550NH)CH3;
R31 represents R30, amino-amidino, NH\u2014C(\u2550NH)CH3 or R10;
R32 represents H, C(O)\u2014CH2\u2014NH2, or C(O)\u2014CH(CH(CH3)2)\u2014NH2;
R33 and R34 independently at each occurrence represent R10, (CH2)0-4\u2014Ar, optionally substituted aryl, (CH2)0-4 optionally substituted heteroaryl, (CH2)1-4\u2014CN, (CH2)1-4\u2014N(R10)2, (CH2)1-4\u2014OH, (CH2)1-4\u2014SO\u2014N(R10)2; alternatively,
R33 and R34 along with the nitrogen atom that they are attached form a 4 to 14 atom ring structure selected from tetrahydro-1H-carboline; 6,7-dialkoxyoxy-2-substituted 1,2,3,4-tetrahydro-isoquinoline,
R35 represents R10, SO2\u2014R10, COR10, or CONHR10;
E represents a bond, S(O)0-2, O or NR10;
W1, W2, W3 and W4 independently represent C or N; and
Q, Q1, Q2, Q3, L1, L2, L3 and L4 independently at each occurrence represent N-natural or unnatural amino acid side chain, CHR10, O, NH, S(O)0-2, N\u2014C(O)\u2014NHR10, SO2\u2014N(R10)2, N\u2014C(O)\u2014NH\u2014(CH2)1-4\u2014R26, NR10, N-heteroarl, N\u2014C(\u2550NH)\u2014NHR10, or N\u2014C(\u2550NH)C1-4 alkyl;
R26 represents OH, NH2, or SH;
provided that, (i) when R1=OH; R7=amidine; R2, R6, R8, R9, and R20 each represent H; and R3, R4, R5 are independently chosen from H, CH3, and halogen, then only one of R3, R4, and R5 represents H; (ii) when R1=OH; R7=amidine; R2, R3, R4, R5, and R20 each represent H; and R6, R8, R9 are independently chosen from H, CH3, and halogen, then only one of R6, R8, and R9 represents H; (iii) at least two of W1, W2, W3 and W4 represent C and at least one of W1, W2, W3 and W4 represent N; and (iv) when R1=OH; R7=amidine; and R2, R3, R4, R5, R6, R8, and R9, represent H, R20 cannot be CH3, or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 wherein A represents
B represents
X represents C; and
Y represents NH.