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AR053901A1 - PHYSICAL FORMS OF OXABISPIDINES N, N'- DISUSTITUIDAS - Google Patents

PHYSICAL FORMS OF OXABISPIDINES N, N'- DISUSTITUIDAS

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Publication number
AR053901A1
AR053901A1 ARP060102454A ARP060102454A AR053901A1 AR 053901 A1 AR053901 A1 AR 053901A1 AR P060102454 A ARP060102454 A AR P060102454A AR P060102454 A ARP060102454 A AR P060102454A AR 053901 A1 AR053901 A1 AR 053901A1
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AR
Argentina
Prior art keywords
alkyl
alkylene
represent
aryl
independently represent
Prior art date
Application number
ARP060102454A
Other languages
Spanish (es)
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Astrazeneca Ab
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Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of AR053901A1 publication Critical patent/AR053901A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08Bridged systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/06Antiarrhythmics

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Reivindicacion 1: Un material cristalino que consiste esencialmente en un compuesto de formula 1 o un solvato y/o sal farmacéuticamente aceptable del mismo, donde D representa alquileno C2-6 opcionalmente ramificado, R1 representa alquilo C1-6( opcionalmente sustituido con uno o más sustituyentes seleccionados entre -OH, halo, ciano, nitro y arilo) o arilo, R2 representa H, halo, alquilo C1-6, -OR5, -E-N(R6)R7 o junto con R3, representa = O; R3 representa H, alquilo C1-6 o junto con R2, representa = O; R5 representa H, alquilo C1-6, -E-arilo, -E-Het1, -C(O)R8a, -C(O)IR8b o -C(O)N(R9a)R9b; R6 representa H, alquilo C1-6, -E-arilo, -E-Het1, -C(O)R8a, -C(O)OR8b, -S(O)2R8c, -[C(O)]Pn(R9a) R9b o -C(NH)NH2; R7 representa H, alquilo C1-6, - E-arilo o -C(O)R8d; R8a a R8d representan independientemente, en cada caso, cuando se los utiliza en la presente, alquilo C1-6 (opcionalmente sustituido con uno o más sustituyentes seleccionados entre halo, arilo y Het2), arilo, Het3, o R8a y R8d representan independientemente H; R9a y R9b representan independientemente, en cada caso, cuando se los utiliza en la presente, H o alquilo C1-6 (opcionalmente sustituido con uno o más sustituyentes seleccionados entre halo, arilo y Het4), arilo, Het5 o juntos, representan alquileno C3-6, opcionalmente interrumpido por un átomo de O; E representa, en cada caso utilizado en la presente, un enlace directo o alquileno C1-4, p representa 1 o 2, AS representa un enlace directo, -J-, -J-N(R10a)-, - J-S(O)2N(R10b)-, -J-N(R10c)S(O)2- o -J-O-( donde, en estos cuatro ultimos grupos, J está unido al nitrogeno de la oxabispidina), B representa -Z-{[C(O)]aC(H)(R11ab-, -Z-[C(O)]cN( R11b)-, -Z-N(R11c)S(O)2-, -Z-S(O)2N(R11d)-, -Z-S(O)n-, -Z-O-(donde, en estos ultimos seis grupos, Z está unido al átomo de carbono que acarrea R2 y R3), -N(R11e)-Z-, -N(R11f)S(O)2-Z-, -S(O)2N(R11g)-Z- o N(R11h)C(O)O-Z- (donde, en estos cuatro ultimos grupos, Z está unido al grupo R4), J representa alquileno C1-6 opcionalmente interrumpido por -S(O)2N(R10d)- o -N(R10e)S(O)2- y/o opcionalmente sustituido con uno o más sustituyentes seleccionados entre -OH, halo y amino, Z representa un enlace directo o alquileno C1-4, opcionalmente interrumpido por - N(R11i)S(O)2- o -S(O)2N(R11J)-, a, b y c representan independientemente 0 o 1, n representa 0, 1 o 2, R10a a R10e representan independientemente, en cada caso en que se utilizan en la presente, H o alquilo C1-6, R11a representa H o junto con un solo sustituyente en posicion orto del grupo R4 ( orto con respecto a la posicion en la cual el grupo B está unido), R11a representa alquileno C2-4 opcionalmente interrumpido o terminado por O, S, N(H) o N(alquilo C1-6), R11b representa H, alquilo C1-6, o junto con un solo sustituyente en posicion orto del grupo R4( orto con respecto a la posicion en la cual el grupo B está unido), R11b representa alquileno C2-4, R11c a R11j representan independientemente, en cada caso en que se utilizan en la presente, H o alquilo C1-6, R4 representa fenilo o piridilo, ambos grupos estos que están opcionalmente sustituidos con uno o más sustituyentes seleccionados entre -OH, ciano, halo, nitro, alquilo C1-6 ( opcionalmente terminado en -N(H)C(O)OR12a), alcoxi C1-6, -N(R13a)R13b, -C(O)R13c, -C(O)OR13d, -C(O)N(R13e)R13f, -N(R13g)C(O)R13h, -N(R13i)C(O)N(R13j)R13k, -N(R13M)S(O)2R12b, -S(O)2N(R13n)R13o, -S(O)2R12c, -OS(O)2R12d, y/o arilo, y un sustituyente en posicion orto (orto con respecto a la union de B) puede (i) junto con R11a, representar alquileno C2-4 opcionalmente interrumpido o terminado por O, S, N(H) o N(alquilo C1-6) o (ii) junto con R11b, representar alquileno C2-4, R12a a R12d representar independientemente alquilo C1-6, R13a y R13b representar independientemente H, alquilo C1-6 o juntos representan alquileno C3-6, dado lugar a un anillo de cuatro a siete miembros con contenido de nitrogeno, R13c a R13o representar independientemente H o alquilo C1-6 y Het1 a Het5 representar independientemente, en cada caso en que se utiliza en la presente, grupos heterocíclicos de cinco a doce miembros que contienen uno o más heteroátomos seleccionados entre oxígeno, nitrogeno y/o azufre, donde los grupos heterocíclicos que están opcionalmente sustituido con uno o más sustituyentes seleccionados entre =O, -OH, ciano, halo, nitro, alquilo C1-6, alcoxi C1-6, arilo, ariloxi, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, - C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -S(O)2N(R14i)(R14J) y/o -N(R14k)S(O)2R14l; R14a a R14l representan independientemente alquilo C1-6, arilo o R14a a R14k representan independientemente H, siempre que (a) D no represente 1,1-alquileno C2-6, (b) cuando R3 representa H o alquilo C1-6 y A representa -J- N(R10a)- o -J-O-, luego (i) J no represente alquileno C1 o 1,1-alquileno C2-6 y (ii) B no represente -N(R11b)-, -N(R11c)S(O)2-, -S(O)n-, -O-, -N(R11e)-Z-, -N(R11f)S(O)2-Z- o -N(R11h)C(O)O-Z-; y (c) cuando R2 representa -OR5 o -E-N(R6)R7 en los cuales E representa un enlace directo, luego, (i) A no represente un enlace directo -J-N(R10a)-, -J-S(O)2N(R12b)- o -J-O-; y (ii) B no representa -N(R11b)-, -N(R11c)S(O)2, -S(O)n-, -O-, -N(R11e)-Z, -N(R11f)S(O2)-Z- o -N(R11h)C(O)O-Z y (d) cuando A representa -J-N(R10c)S(O)2, luego J no represente alquileno C1 o 1,1-alquileno C2-6 y (e) cuando R3 representa H o alquilo C1-6 y A representa -J-S(O)2N(R10b), luego B no represente -N(R11b)-, -n(R11c)S(O)2-, -S(O)n-, -O-, -N(R11e)-Z-, - N(R11f)S(O)2-Z- o -N(R11h)C(O)-Z-, y donde cada grupo arilo y ariloxi, a menos que se indique expresamente lo contrario, está opcionalmente sustituido, donde el metal cristalino se caracteriza por tener un área superficial de menos de 0,7 m2g-1. También se presentan procesos para la preparacion de dichos materiales cristalinos.Claim 1: A crystalline material consisting essentially of a compound of formula 1 or a pharmaceutically acceptable solvate and / or salt thereof, wherein D represents optionally branched C2-6 alkylene, R1 represents C1-6 alkyl (optionally substituted with one or more substituents selected from -OH, halo, cyano, nitro and aryl) or aryl, R2 represents H, halo, C1-6 alkyl, -OR5, -EN (R6) R7 or together with R3, represents = O; R3 represents H, C1-6 alkyl or together with R2, represents = O; R5 represents H, C1-6 alkyl, -E-aryl, -E-Het1, -C (O) R8a, -C (O) IR8b or -C (O) N (R9a) R9b; R6 represents H, C1-6 alkyl, -E-aryl, -E-Het1, -C (O) R8a, -C (O) OR8b, -S (O) 2R8c, - [C (O)] Pn (R9a ) R9b or -C (NH) NH2; R7 represents H, C1-6 alkyl, - E-aryl or -C (O) R8d; R8a to R8d independently represent, in each case, when used herein, C1-6 alkyl (optionally substituted with one or more substituents selected from halo, aryl and Het2), aryl, Het3, or R8a and R8d independently represent H ; R9a and R9b independently represent, in each case, when used herein, H or C1-6 alkyl (optionally substituted with one or more substituents selected from halo, aryl and Het4), aryl, Het5 or together, represent C3 alkylene -6, optionally interrupted by an O atom; E represents, in each case used herein, a direct bond or C1-4 alkylene, p represents 1 or 2, AS represents a direct bond, -J-, -JN (R10a) -, - JS (O) 2N ( R10b) -, -JN (R10c) S (O) 2- or -JO- (where, in these last four groups, J is bound to oxabispidine nitrogen), B represents -Z - {[C (O)] aC (H) (R11ab-, -Z- [C (O)] cN (R11b) -, -ZN (R11c) S (O) 2-, -ZS (O) 2N (R11d) -, -ZS (O ) n-, -ZO- (where, in these last six groups, Z is attached to the carbon atom that carries R2 and R3), -N (R11e) -Z-, -N (R11f) S (O) 2- Z-, -S (O) 2N (R11g) -Z- or N (R11h) C (O) OZ- (where, in these last four groups, Z is linked to group R4), J represents optionally C1-6 alkylene interrupted by -S (O) 2N (R10d) - or -N (R10e) S (O) 2- and / or optionally substituted with one or more substituents selected from -OH, halo and amino, Z represents a direct bond or alkylene C1-4, optionally interrupted by - N (R11i) S (O) 2- or -S (O) 2N (R11J) -, a, b and c independently represent 0 or 1, n represents 0, 1 or 2, R10a to R10e independently represent, in each case in which they are used herein, H or C1-6 alkyl, R11a represents H or together with a single ortho substituent of the R4 group (ortho with respect to the position in the which group B is attached), R11a represents C2-4 alkylene optionally interrupted or terminated by O, S, N (H) or N (C1-6 alkyl), R11b represents H, C1-6 alkyl, or together with a single ortho substituent of group R4 (ortho with respect to the position in which group B is attached), R11b represents C2-4 alkylene, R11c to R11j independently represent, in each case in which they are used herein, H or C1-6 alkyl, R4 represents phenyl or pyridyl, both of which are optionally substituted with one or more substituents selected from -OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated in -N (H) C (O ) OR12a), C1-6 alkoxy, -N (R13a) R13b, -C (O) R13c, -C (O) OR13d, -C (O) N (R13e) R13f, -N (R13g) C (O) R13h, -N (R13i) C (O) N (R13 j) R13k, -N (R13M) S (O) 2R12b, -S (O) 2N (R13n) R13o, -S (O) 2R12c, -OS (O) 2R12d, and / or aryl, and a substituent in position ortho (ortho with respect to the union of B) may (i) together with R11a, represent C2-4 alkylene optionally interrupted or terminated by O, S, N (H) or N (C1-6 alkyl) or (ii) together with R11b, represent C2-4 alkylene, R12a to R12d independently represent C1-6 alkyl, R13a and R13b independently represent H, C1-6 alkyl or together represent C3-6 alkylene, resulting in a four to seven membered ring containing of nitrogen, R13c to R13o independently represent H or C1-6 alkyl and Het1 to Het5 independently represent, in each case in which it is used herein, five to twelve member heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur, where the heterocyclic groups that are optionally substituted with one or more substituents selected from = O, -OH, cyano, halo, nitro, a C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, -N (R14a) R14b, -C (O) R14c, -C (O) OR14d, - C (O) N (R14e) R14f, -N (R14g ) C (O) R14h, -S (O) 2N (R14i) (R14J) and / or -N (R14k) S (O) 2R14l; R14a to R14l independently represent C1-6 alkyl, aryl or R14a to R14k independently represent H, provided that (a) D does not represent 1,1-C2-6 alkylene, (b) when R3 represents H or C1-6 alkyl and A represents -J- N (R10a) - or -JO-, then (i) J does not represent C1 alkylene or 1,1-C2-6 alkylene and (ii) B does not represent -N (R11b) -, -N (R11c ) S (O) 2-, -S (O) n-, -O-, -N (R11e) -Z-, -N (R11f) S (O) 2-Z- or -N (R11h) C ( O) OZ-; and (c) when R2 represents -OR5 or -EN (R6) R7 in which E represents a direct link, then, (i) A does not represent a direct link -JN (R10a) -, -JS (O) 2N ( R12b) - or -JO-; and (ii) B does not represent -N (R11b) -, -N (R11c) S (O) 2, -S (O) n-, -O-, -N (R11e) -Z, -N (R11f) S (O2) -Z- or -N (R11h) C (O) OZ and (d) when A represents -JN (R10c) S (O) 2, then J does not represent C1 alkylene or 1,1-C2 alkylene- 6 and (e) when R3 represents H or C1-6 alkyl and A represents -JS (O) 2N (R10b), then B does not represent -N (R11b) -, -n (R11c) S (O) 2-, -S (O) n-, -O-, -N (R11e) -Z-, - N (R11f) S (O) 2-Z- or -N (R11h) C (O) -Z-, and where each aryl and aryloxy group, unless expressly stated otherwise, is optionally substituted, where the crystalline metal is characterized by having a surface area of less than 0.7 m2g-1. Processes for the preparation of said crystalline materials are also presented.

ARP060102454A 2005-06-20 2006-06-12 PHYSICAL FORMS OF OXABISPIDINES N, N'- DISUSTITUIDAS AR053901A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
SE0501428 2005-06-20

Publications (1)

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AR053901A1 true AR053901A1 (en) 2007-05-23

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AR (1) AR053901A1 (en)
TW (1) TW200740828A (en)
WO (1) WO2006137772A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180194769A1 (en) 2015-07-06 2018-07-12 Rodin Therapeutics, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
DK3570834T3 (en) 2017-01-11 2022-02-28 Alkermes Inc Bicyclic inhibitors of histone deacetylase
AU2018313094A1 (en) 2017-08-07 2020-02-20 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9903759D0 (en) * 1999-10-18 1999-10-18 Astra Ab Pharmaceutically active compounds
AR030756A1 (en) * 2000-10-02 2003-09-03 Astrazeneca Ab COMPOUND OF OXABISPIDINE USEFUL IN THE TREATMENT OF CARDIAC ARRITMIES
SE0101327D0 (en) * 2001-04-12 2001-04-12 Astrazeneca Ab New crystalline forms
SE0101324D0 (en) * 2001-04-12 2001-04-12 Astrazeneca Ab New process
SE0201374D0 (en) * 2002-05-06 2002-05-06 Astrazeneca Ab Pharmaceutical combination
SE0201662D0 (en) * 2002-05-31 2002-05-31 Astrazeneca Ab Pharmaceutical combination
GB0223712D0 (en) * 2002-10-14 2002-11-20 Astrazeneca Ab Chemical intermediate

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