AR043677A1 - ARIL AND HETEROARIL SUBSTITUTED POLICICLIC URACILES USEFUL FOR THE SELECTIVE INHIBITION OF THE COAGULATION WATERFALL - Google Patents
ARIL AND HETEROARIL SUBSTITUTED POLICICLIC URACILES USEFUL FOR THE SELECTIVE INHIBITION OF THE COAGULATION WATERFALLInfo
- Publication number
- AR043677A1 AR043677A1 ARP000102449A ARP000102449A AR043677A1 AR 043677 A1 AR043677 A1 AR 043677A1 AR P000102449 A ARP000102449 A AR P000102449A AR P000102449 A ARP000102449 A AR P000102449A AR 043677 A1 AR043677 A1 AR 043677A1
- Authority
- AR
- Argentina
- Prior art keywords
- group
- hydride
- indenyl
- independently selected
- alkyl
- Prior art date
Links
- 230000015271 coagulation Effects 0.000 title abstract 2
- 238000005345 coagulation Methods 0.000 title abstract 2
- 230000005764 inhibitory process Effects 0.000 title 1
- 229910052799 carbon Inorganic materials 0.000 abstract 19
- -1 amidino, guanidino Chemical group 0.000 abstract 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 14
- 150000004678 hydrides Chemical class 0.000 abstract 12
- 125000000217 alkyl group Chemical group 0.000 abstract 11
- 229910052757 nitrogen Inorganic materials 0.000 abstract 11
- 229910052760 oxygen Inorganic materials 0.000 abstract 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 9
- 125000001188 haloalkyl group Chemical group 0.000 abstract 8
- 229910052717 sulfur Inorganic materials 0.000 abstract 8
- 125000003282 alkyl amino group Chemical group 0.000 abstract 7
- 125000001475 halogen functional group Chemical group 0.000 abstract 7
- 125000004429 atom Chemical group 0.000 abstract 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 5
- 125000003342 alkenyl group Chemical group 0.000 abstract 4
- 125000003545 alkoxy group Chemical group 0.000 abstract 3
- 125000000033 alkoxyamino group Chemical group 0.000 abstract 3
- 125000004414 alkyl thio group Chemical group 0.000 abstract 3
- 150000001721 carbon Chemical group 0.000 abstract 3
- 150000001875 compounds Chemical class 0.000 abstract 3
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 3
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 3
- 125000004438 haloalkoxy group Chemical group 0.000 abstract 3
- 125000004995 haloalkylthio group Chemical group 0.000 abstract 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 abstract 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 abstract 2
- 125000006294 amino alkylene group Chemical group 0.000 abstract 2
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 2
- 125000001589 carboacyl group Chemical group 0.000 abstract 2
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 abstract 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 abstract 2
- 125000004076 pyridyl group Chemical group 0.000 abstract 2
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 abstract 1
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical group OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 abstract 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 abstract 1
- WFBHRSAKANVBKH-UHFFFAOYSA-N N-hydroxyguanidine Chemical compound NC(=N)NO WFBHRSAKANVBKH-UHFFFAOYSA-N 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract 1
- 125000004423 acyloxy group Chemical group 0.000 abstract 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 abstract 1
- 125000005422 alkyl sulfonamido group Chemical group 0.000 abstract 1
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 abstract 1
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract 1
- 125000005466 alkylenyl group Chemical group 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 239000003146 anticoagulant agent Substances 0.000 abstract 1
- 229940127219 anticoagulant drug Drugs 0.000 abstract 1
- 125000003435 aroyl group Chemical group 0.000 abstract 1
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 125000005518 carboxamido group Chemical group 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 125000004181 carboxyalkyl group Chemical group 0.000 abstract 1
- 208000026106 cerebrovascular disease Diseases 0.000 abstract 1
- 208000029078 coronary artery disease Diseases 0.000 abstract 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000000262 haloalkenyl group Chemical group 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 abstract 1
- 125000002757 morpholinyl group Chemical group 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 229920006395 saturated elastomer Polymers 0.000 abstract 1
- 239000003001 serine protease inhibitor Substances 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract 1
- 230000001732 thrombotic effect Effects 0.000 abstract 1
- 125000004665 trialkylsilyl group Chemical group 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Compuestos de aril y heteroaril uracilos policíclicos substituidos útiles como inhibidores de serina proteasas de la cascada de coagulación y compuestos, composiciones y métodos de terapia anticoagulante para el tratamiento y prevención de diversas afecciones trombóticas que incluyen enfermedades de la arteria coronaria y enfermedades cerebrovasculares. Reivindicación1: Un compuesto caracterizado porque tiene la fórmula (1) o una sal farmacéuticamente aceptable del mismo, donde B es la fórmula (2): donde D1, D2, J1, J2 y K1 se seleccionan independientemente del grupo formado por C, N, O, S y un enlace covalente con las siguientes condiciones: que no más de uno sea un enlace covalente, no más de uno entre D1, D2, J1, J2 y K1 sea O, no más de uno entre D1, D2, J1, J2 y K1 sea S, uno entre D1, D2, J1, J2 y K1 debe ser un enlace covalente cuando dos entre D1, D2, J1, J2 y K1 son O y S, y no más de cuatro entre D1, D2, J1, J2 y K1 sean N; R9, R10, R11, R12, R13, R32, R33, R34, R35, y R36 se seleccionan independientemente del grupo formado por hidruro, acetamido, haloacetamido, amidino, guanidino, alquilendioxi, haloalquiltio, alcanoiloxi, alcoxi, alcoxialquilo, haloalcoxilalquilo, hidroxi, amino, alcoxiamino, nitro, alquilamino inferior, alquiltio, alquiltioalquilo, alquilsulfinilo, alquilsulfonilo, alquilsulfonilalquilo, arilo, aralquilo, cicloalquilo, cicloalquilalquilo, heteroarilo, heterociclilo, alquilsulfonamido, alquilaminosulfonilo, amidosulfonilo, monoalquilo amidosulfonilo, dialquilo amidosulfonilo, alcanoilo, haloalcanoilo, alquilo, alquenilo, halo, haloalquilo, haloalquenilo, haloalcoxi, hidroxihaloalquilo, hidroxialquilo, aminoalquilo, haloalcoxialquilo, carboxialquilo, carboalcoxi, carboxi, carboxamido, carboxamidoalquilo, y ciano; R16, R19, R32, R33, R34, R35, y R36 son independientemente optativamente Qb siempre que no más de uno entre R16 y R19 sea Qb al mismo tiempo y que Qb sea Qbe; B optativamente se selecciona del grupo formado por hidruro, trialquilsililo, alquilo C2-8, alquilenilo C3-8, alquenilo C3-8, alquinilo C3-8, y haloalquilo C2-8, donde cada miembro del grupo B puede estar substituido optativamente en cualquier carbono distante hasta 6 átomos inclusive desde el punto de unión entre B y A con uno o más del grupo formado por R32, R33, R34, R35, y R36; B se selecciona optativamente del grupo formado por cicloalquilo C3-12 y heterociclilo C4-9 saturado, donde cada átomo de carbono está optativamente substituido con R33, un carbono del anillo distinto del carbono del anillo del punto de unión de B con A está optativamente substituido con oxo siempre que no más de un carbono del anillo esté substituido por oxo al mismo tiempo, carbonos del anillo y un nitrógeno adyacentes al átomo de carbono del punto de unión están optativamente substituidos con R9 o R13, un átomo de carbono o nitrógeno del anillo adyacente a la posición R9 y distante dos átomos desde el punto de unión está optativamente substituido con R10, un carbono o nitrógeno del anillo adyacente a la posición R13 y distante dos átomos desde el punto de unión está optativamente substituido con R12, un carbono o nitrógeno del anillo distante tres átomos desde el punto de unión y adyacente a la posición R10 está optativamente substituido con R11, un carbono o nitrógeno del anillo distante tres átomos desde el punto de unión y adyacente a la posición R12 está optativamente substituido con R33, y un carbono o nitrógeno del anillo distante cuatro átomos desde el punto de unión y adyacente a las posiciones R11 y R33 está optativamente substituido con R34; A se selecciona del grupo formado por un enlace simple covalente, (W7)rr-(CH(R15))pa y (CH(R15))pa-(W7)rr donde rr es un entero seleccionado entre 0 y 1, pa es un entero seleccionado entre 0 y 6, y W7 se selecciona del grupo formado por O, S, C(O), (R7)NC(O), (R7)NC(S), y N(R7) siempre que no más de uno del grupo formado por rr y pa sea 0 al mismo tiempo; R7 se selecciona del grupo formado por hidruro, hidroxi, y alquilo; R15 se selecciona formado por hidruro, hidroxi, halo, alquilo, y haloalquilo; [Psi] se selecciona del grupo formado por NH y NOH; M se selecciona del grupo formado por N y R1-C; R1 se selecciona del grupo formado por hidruro, alquilo, alquenilo, ciano, halo, haloalquilo, haloalcoxi, haloalquiltio, amino, aminoalquilo, alquilamino, amidino, hidroxi, hidroxiamino, alcoxi, hidroxialquilo, alcoxiamino, tiol, y alquiltio; R2 is Z0-Q; Z0 se selecciona del grupo formado por un enlace simple covalente, (CR41R42)q donde q es un entero seleccionado entre 1 y 3, (CH(R41))g-W0-(CH(R42))p donde g y p son enteros seleccionados independientemente entre 0 y 3 y W0 se selecciona del grupo formado por O, S, C(O), S(O), N(R41), y ON(R41), y (CH(R41))e-W22-(CH(R42)h donde e y h son enteros seleccionados entre 0 y 1 y W22 se selecciona del grupo formado por CR41-CR42, 1,2-ciclopropilo, 1,2-ciclobutilo, 1,2-ciclohexilo, 1,3-ciclohexilo, 1,2-ciclopentilo, 1,3-ciclopentilo, 2,3-morfolinilo, 2,4-morfolinilo, 2,6-morfolinilo, 3,4-morfolinilo, 3,5 morfolinilo, 1,2-piperazinilo, 1,3-piperazinilo, 2,3-piperazinilo, 2,6-piperazinilo, 1,2-piperidinilo, 1,3-piperidinilo, 2,3-piperidinilo, 2,4-piperidinilo, 2,6-piperidinilo, 3,4-piperidinilo, 1,2-pirrolidinilo, 1,3-pirrolidinilo, 2,3-pirrolidinilo, 2,4-pirrolidinilo, 2,5-pirrolidinilo, 3,4-pirrolidinilo, 2,3-tetrahidrofuranilo, 2,4-tetrahidrofuranilo, 2,5-tetrahidrofuranilo, y 3,4-tetrahidrofuranilo, siempre que Z0 esté unido directamente al anillo de pirazinona; R41 y R42 se seleccionan independientemente del grupo formado por amidino, hidroxiamino, hidruro, hidroxi, amino, y alquilo; Q se selecciona del grupo formado por hidruro, siempre que Z0 es distinto de un enlace simple covalente, y la fórmula (3) donde D1, D2, J1, J2 y K1 se seleccionan independientemente del grupo formado por C, N, O, S y un enlace covalente con las siguientes condiciones: que no más de uno sea un enlace covalente, no más de uno entre D1, D2, J1, J2 y K1 sea O, no más de uno de D1, D2, J1, J2 y K1 sea S, uno entre D1, D2, J1, J2 y K1 debe ser un enlace covalente cuando dos entre D1, D2, J1, J2 y K1 son O y S, y no más de cuatro entre D1, D2, J1, J2 y K1 sean N, siempre que R9, R10, R11, R12, y R13 se seleccionan independientemente de modo de mantener la naturaleza tetravalente del carbono, la naturaleza trivalente del nitrógeno, la naturaleza divalente del azufre, y la naturaleza divalente del oxígeno; K es (CR4aR4b)n donde n es un entero seleccionado entre 1 y 2; R4a y R4b se seleccionan independientemente del grupo formado por halo, hidruro, hidroxialquilo, alquilo, alcoxialquilo, alquiltioalquilo, y haloalquilo; E0 es E1, cuando K es (CR4aR4b)n donde E1 se selecciona del grupo formado por un enlace simple covalente, C(O), C(S), C(O)N(R7), (R7)NC(O), S(O)2, (R7)NS(O)2, y S(O)2N(R7); Y0 es la fórmula (4) donde D5, D6, J5 y J6 se seleccionan independientemente del grupo formado por C, N, O, S y un enlace covalente con las siguientes condiciones: que no más de uno sea un enlace covalente, K2 es C, no más de uno entre D5, D6, J5 y J6 es O, no más de uno entre D5, D6, J5 y J6 es S, uno entre D5, D6, J5 y J6 debe ser un enlace covalente cuando dos entre D5, D6, J5 y J6 son O y S, y que no más de cuatro entre D5, D6, J5 y J6 sean N; R16, R17, R18, y R19 se seleccionan independientemente del grupo formado por hidruro, amidino, guanidino, carboxi, haloalquiltio, alcoxi, hidroxi, amino, nitro, alcoxiamino, alquilamino inferior, alquiltio, alquilsulfinilo, alquilsulfonilo, alcanoilo, haloalcanoilo, alquilo, alquenilo, halo, haloalquilo, haloalcoxi, hidroxialquilo, alquilamino, haloalcoxialquilo, carboalcoxi, y ciano; Qb se selecciona del grupo formado por NR20R21, aminoalquilenilo, Qbe donde Qbe es hidruro, N(R26)C(NR25)N(R23)(R24), y C(NR25)NR23R24, con las siguientes condiciones: que no más de uno entre R20 y R21 sea hidroxi, amino, alquilamino, o dialquilamino al mismo tiempo y que no más de uno entre R23 y R24 sea hidroxi, amino, alquilamino, o dialquilamino al mismo tiempo; R20, R21, R23, R24, R25, y R26 se seleccionan independientemente del grupo formado por hidruro, alquilo, hidroxi, aminoalquilenilo, amino, dialquilamino, alquilamino, e hidroxialquilo; Qs se selecciona del grupo formado por un enlace simple covalente, (CR37R38)b donde b es un entero seleccionado entre 1 y 4, y (CH(R14))c-W1-(CH(R15))d donde c y d son enteros independientemente seleccionados entre 1 y 3 y W1 se selecciona del grupo formado por C(O)N(R14), (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, y N(R14), con las siguientes condiciones: que R14 se selecciona entre los grupos distintos de halo cuando están unidos directamente a N y que (CR37R38)b, y (CH(R14))c están unidos a E0; R14 se selecciona del grupo formado por hidruro, halo, alquilo, y haloalquilo; R37 y R38 se seleccionan independientemente del grupo formado por hidruro, alquilo, y haloalquilo; R38 optativamente se selecciona del grupo formado por aroilo y heteroaroilo; Y0 es optativamente Qb-Qss donde Qss es (CH(R14))e-W2-(CH(R15))h, donde e y h son enteros seleccionados independientemente entre 1 y 2 y W2 es CR4a=CR4b siempre que (CH(R14))e esté unido a E0; Y0 optativamente se selecciona del grupo formado por Qb-Qssss y Qb-Qssssr donde Qssss es (CH(R38))r-W5 y Qssssr es (CH(R38))r-W6, r es un entero seleccionado entre 1 y 2, y W5 y W6 se seleccionan independientemente del grupo formado por 1,4-indenilo, 1,5-indenilo, 1,6-indenilo, 1,7-indenilo, 2,7-indenilo, 2,6-indenilo, 2,5-indenilo, 2,4-indenilo, 3,4-indenilo, 3,5-indenilo, 3,6-indenilo, 3,7-indenilo, 2,4benzofuranilo, 2,5-benzofuranilo, 2,6-benzofuranilo, 2,7-benzofuranilo, 3,4-benzofuranilo, 3,5-benzofuranilo, 3,6-benzofuranilo, 3,7-benzofuranilo, 2,4benzotiofenilo, 2,5-benzotiofenilo, 2,6-benzotiofenilo, 2,7-benzotiofenilo, 3,4-benzotiofenilo, 3,5-benzotiofenilo, 3,6-benzotiofenilo, 3,7-benzotiofenilo, 2,7-imidazo(1,2-a)piridinilo, 3,4-imidazo(1,2-a)piridinilo, 3,5-imidazo(1,2-a)piridiniCompounds of substituted polycyclic aryl and heteroaryl uracils useful as coagulation cascade serine protease inhibitors and compounds, compositions and methods of anticoagulant therapy for the treatment and prevention of various thrombotic conditions including coronary artery diseases and cerebrovascular diseases. Claim 1: A compound characterized in that it has the formula (1) or a pharmaceutically acceptable salt thereof, where B is the formula (2): wherein D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, Or, S and a covalent bond with the following conditions: that no more than one is a covalent bond, no more than one between D1, D2, J1, J2 and K1 is O, no more than one between D1, D2, J1, J2 and K1 is S, one between D1, D2, J1, J2 and K1 must be a covalent bond when two between D1, D2, J1, J2 and K1 are O and S, and no more than four between D1, D2, J1 , J2 and K1 are N; R9, R10, R11, R12, R13, R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydride, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, , amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, amidosulfonyl dialkyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano; R16, R19, R32, R33, R34, R35, and R36 are optionally independently Qb as long as no more than one between R16 and R19 is Qb at the same time and Qb is Qbe; B is optionally selected from the group consisting of hydride, trialkylsilyl, C2-8 alkyl, C3-8 alkylenyl, C3-8 alkenyl, C3-8 alkynyl, and C2-8 haloalkyl, where each member of group B can be optionally substituted at any distant carbon up to 6 atoms including from the point of union between B and A with one or more of the group consisting of R32, R33, R34, R35, and R36; B is optionally selected from the group consisting of C3-12 cycloalkyl and saturated C4-9 heterocyclyl, where each carbon atom is optionally substituted with R33, a carbon of the ring other than the carbon of the ring of the junction point of B with A is optionally substituted with oxo provided that no more than one carbon of the ring is substituted by oxo at the same time, carbons of the ring and a nitrogen adjacent to the carbon atom of the junction point are optionally substituted with R9 or R13, a carbon atom or nitrogen of the ring adjacent to position R9 and distant two atoms from the point of attachment is optionally substituted with R10, a carbon or nitrogen of the ring adjacent to position R13 and distant two atoms from the point of attachment is optionally substituted with R12, a carbon or nitrogen of the ring distant three atoms from the point of attachment and adjacent to the position R10 is optionally substituted with R11, a carbon or nitrogen from the ring distant three atoms from the point of attachment and adjacent to position R12 is optionally substituted with R33, and a carbon or nitrogen from the ring distant four atoms from the point of attachment and adjacent to positions R11 and R33 is optionally substituted with R34; A is selected from the group consisting of a covalent single bond, (W7) rr- (CH (R15)) pa and (CH (R15)) pa- (W7) rr where rr is an integer selected from 0 to 1, pa is an integer selected between 0 and 6, and W7 is selected from the group consisting of O, S, C (O), (R7) NC (O), (R7) NC (S), and N (R7) provided that no more of one of the group formed by rr and pa be 0 at the same time; R7 is selected from the group consisting of hydride, hydroxy, and alkyl; R15 is selected consisting of hydride, hydroxy, halo, alkyl, and haloalkyl; [Psi] is selected from the group consisting of NH and NOH; M is selected from the group consisting of N and R1-C; R1 is selected from the group consisting of hydride, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R2 is Z0-Q; Z0 is selected from the group consisting of a covalent single bond, (CR41R42) q where q is an integer selected from 1 to 3, (CH (R41)) g-W0- (CH (R42)) p where g and are independently selected integers between 0 and 3 and W0 is selected from the group consisting of O, S, C (O), S (O), N (R41), and ON (R41), and (CH (R41)) e-W22- (CH (R42) h where e and h are integers selected between 0 and 1 and W22 is selected from the group consisting of CR41-CR42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1 , 2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5 morpholinyl, 1,2-piperazinyl, 1,3- piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2, 5-tetrahydrofuranyl, and 3,4-tetrahydrof uranyl, provided that Z0 is directly attached to the pyrazinone ring; R41 and R42 are independently selected from the group consisting of amidino, hydroxyamino, hydride, hydroxy, amino, and alkyl; Q is selected from the group formed by hydride, provided that Z0 is different from a single covalent bond, and the formula (3) where D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the following conditions: that no more than one is a covalent bond, no more than one between D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 let S, one between D1, D2, J1, J2 and K1 must be a covalent bond when two between D1, D2, J1, J2 and K1 are O and S, and no more than four between D1, D2, J1, J2 and K1 are N, provided that R9, R10, R11, R12, and R13 are independently selected so as to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; K is (CR4aR4b) n where n is an integer selected from 1 to 2; R4a and R4b are independently selected from the group consisting of halo, hydride, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E0 is E1, when K is (CR4aR4b) n where E1 is selected from the group consisting of a covalent single bond, C (O), C (S), C (O) N (R7), (R7) NC (O) , S (O) 2, (R7) NS (O) 2, and S (O) 2N (R7); Y0 is the formula (4) where D5, D6, J5 and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the following conditions: that no more than one is a covalent bond, K2 is C, no more than one between D5, D6, J5 and J6 is O, no more than one between D5, D6, J5 and J6 is S, one between D5, D6, J5 and J6 must be a covalent bond when two between D5 , D6, J5 and J6 are O and S, and no more than four between D5, D6, J5 and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydride, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy, and cyano; Qb is selected from the group consisting of NR20R21, aminoalkylene, Qbe where Qbe is hydride, N (R26) C (NR25) N (R23) (R24), and C (NR25) NR23R24, with the following conditions: not more than one between R20 and R21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one between R23 and R24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; R20, R21, R23, R24, R25, and R26 are independently selected from the group consisting of hydride, alkyl, hydroxy, aminoalkylene, amino, dialkylamino, alkylamino, and hydroxyalkyl; Qs is selected from the group consisting of a covalent single bond, (CR37R38) b where b is an integer selected from 1 to 4, and (CH (R14)) c-W1- (CH (R15)) d where c and d are integers independently selected between 1 and 3 and W1 is selected from the group consisting of C (O) N (R14), (R14) NC (O), S (O), S (O) 2, S (O) 2N (R14), N (R14) S (O) 2, and N (R14), with the following conditions: that R14 is selected from groups other than halo when directly attached to N and that (CR37R38) b, and (CH (R14) ) c are attached to E0; R14 is selected from the group consisting of hydride, halo, alkyl, and haloalkyl; R37 and R38 are independently selected from the group consisting of hydride, alkyl, and haloalkyl; R38 is optionally selected from the group consisting of aroyl and heteroaroyl; Y0 is optionally Qb-Qss where Qss is (CH (R14)) e-W2- (CH (R15)) h, where e and h are integers independently selected between 1 and 2 and W2 is CR4a = CR4b provided that (CH (R14) ) e is linked to E0; Y0 is optionally selected from the group consisting of Qb-Qssss and Qb-Qssssr where Qssss is (CH (R38)) r-W5 and Qssssr is (CH (R38)) r-W6, r is an integer selected from 1 to 2, and W5 and W6 are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5 -indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2 , 7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl , 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a ) pyridinyl, 3,5-imidazo (1,2-a) pyridini
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| Application Number | Priority Date | Filing Date | Title |
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| US13495799P | 1999-05-19 | 1999-05-19 |
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| JP (1) | JP2002544263A (en) |
| KR (1) | KR20010113969A (en) |
| CN (1) | CN1152023C (en) |
| AR (1) | AR043677A1 (en) |
| AU (1) | AU771740B2 (en) |
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| NZ (1) | NZ514877A (en) |
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| US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
| US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
| US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
| US6458952B1 (en) * | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
| US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
| US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
| US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
| WO2001055119A2 (en) | 2000-01-25 | 2001-08-02 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| AU2004200664B2 (en) * | 2000-01-25 | 2007-08-16 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| WO2001068605A1 (en) | 2000-03-13 | 2001-09-20 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
| CA2405306A1 (en) | 2000-04-05 | 2001-10-18 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
| WO2001077097A2 (en) | 2000-04-05 | 2001-10-18 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
| US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
| US6710058B2 (en) | 2000-11-06 | 2004-03-23 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
| US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
| US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
| CA2430037A1 (en) | 2000-11-20 | 2002-05-30 | Michael S. South | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
| US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
| BR0213092A (en) | 2001-10-03 | 2004-10-19 | Pharmacia Corp | 6-element heterocyclic compounds useful for selective inhibition of coagulation cascade |
| TW200307667A (en) | 2002-05-06 | 2003-12-16 | Bristol Myers Squibb Co | Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors |
| GB0622472D0 (en) * | 2006-11-10 | 2006-12-20 | Addex Pharmaceuticals Sa | Novel heterocyclic derivatives |
| BR112014012892B1 (en) | 2011-11-29 | 2022-12-20 | Perosphere Inc | ANTICOAGULANT REVERSAL COMPOUNDS AND PHARMACEUTICAL COMPOSITION INCLUDING SAID COMPOUNDS |
| AU2020396565C1 (en) * | 2019-12-04 | 2025-05-15 | Omeros Corporation | MASP-2 inhibitors and methods of use |
| CN116410143A (en) * | 2021-12-29 | 2023-07-11 | 杭州奥默医药股份有限公司 | A kind of multi-substituted uracil derivative and its preparation method and application |
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| MX9704439A (en) * | 1994-12-13 | 1997-10-31 | Corvas Int Inc | Aromatic heterocyclic derivatives as enzyme inhibitors. |
| MXPA01011804A (en) * | 1999-05-19 | 2003-09-04 | Pharmacia Corp | Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants. |
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| BR0011273A (en) | 2002-06-18 |
| JP2002544263A (en) | 2002-12-24 |
| ZA200400450B (en) | 2004-09-29 |
| EP1178971A1 (en) | 2002-02-13 |
| CA2373610A1 (en) | 2000-11-23 |
| NZ514877A (en) | 2004-10-29 |
| UY26157A1 (en) | 2000-12-29 |
| AU4972400A (en) | 2000-12-05 |
| AU771740B2 (en) | 2004-04-01 |
| CN1152023C (en) | 2004-06-02 |
| WO2000069833A1 (en) | 2000-11-23 |
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| PE20010217A1 (en) | 2001-03-07 |
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