ES2573531T3 - Sales de amonio cuaternarias de omega-aminoalquilamidas de ácidos R-2-arilpropiónicos y composiciones farmacéuticas que las contienen - Google Patents

Sales de amonio cuaternarias de omega-aminoalquilamidas de ácidos R-2-arilpropiónicos y composiciones farmacéuticas que las contienen Download PDF

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ES2573531T3
ES2573531T3 ES02777207.8T ES02777207T ES2573531T3 ES 2573531 T3 ES2573531 T3 ES 2573531T3 ES 02777207 T ES02777207 T ES 02777207T ES 2573531 T3 ES2573531 T3 ES 2573531T3
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methyl
formula
phenyl
piperidinium
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Marcello Allegretti
Riccardo Bertini
Cinzia Bizzarri
Maria Candida Cesta
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Dompe Farmaceutici SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

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Abstract

Compuestos de (R)-2-aril-propionadima de fórmula (I):**Fórmula** en donde Ar se selecciona de: a) un Ara que se selecciona del grupo que consiste en 4-isobutilfenilo, 3-benzoil-fenilo; b) un grupo fenilo sustituido en 3 por isopropilo, c) un 2-(fenilamino)-fenilo de fórmula (III c):**Fórmula** en donde los sustituyentes P1 y P2 indican que los dos grupos fenilo tienen, cada uno independientemente, mono- o poli-sustituciones con grupos alquilo de C1-C4, alcoxi de C1-C3, cloro, flúor y/o trifluorometilo, R es hidrógeno; X es: - un alquileno de C1-C6 lineal, opcionalmente sustituido en C1 con un -CO2R4 en donde R4 es H; - un alquileno de C1-C6 lineal opcionalmente sustituido en C1 con un grupo -CONHR5 en donde R5 es OH; - (CH2)m-CO-NH-(CH2)n- en donde m y n son cada uno independientemente un número entero de 2 a 3; - -(CHR')-CONH-(CH2)n en donde n es un número entero de 2 a 3 y R' es un metilo, que tiene configuración absoluta R o S; - un grupo fenilo o fenilmetileno de fórmula:**Fórmula** - o X, junto con el átomo de N al que está unido y el grupo R1 forma un anillo azocicloalifático, el grupo NR1R2R3 representa un grupo trimetilamonio, trietilamonio, N-ciclohexilmetil-N,N-dimetilamonio, Nciclopentilamino- N,N-dimetilamonio, N-metil-1-piperidinio, N-etil-1-piperidinio, N-metil-4-morfolinio, N-metil-4- tiomorfolinio, N-bencil-N,N-dimetilamonio, N-alil-1-piperidinio, 4-oxo-N-metil-piperidinio, o X junto con el N amino al que está unido y con el grupo R1, forma un anillo heterocíclico de 5-6 miembros que contiene nitrógeno y los sustituyentes R2 y R3 representan independientemente un residuo de metilo o ciclohexilo, Z- representa un contraión farmacéuticamente aceptable de sales de amonio cuaternarias, o dichos compuestos son yoduro de (R)-{3-[2-(3-benzoilfenil)-propionilamino]propil}-N-isopropil-N,Ndimetilamonio o yoduro de (R)-{3-[2-(4-isobutilfenil)-propionilamino]propil}-N-etil-N,N-dimetilamonio.

Description

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solvente se evapora después a presión reducida y el residuo se recoge en éter isopropílico. Se forma un precipitado blanco que se agita durante 6 horas. El precipitado se filtra y se seca al vacío a T=40ºC para dar el yoduro de R(-)-2[(4’-isobutil)fenil]-N-[3’’-N’-(N’-metil)piperidinopropil]-propionamida (0,114 g; 0,24 mmol) como un sólido céreo amarillo transparente. Rendimiento 84% [α]D = -12 (c = 0,7; CH3OH)1H-RMN (DMSO-d6) δ 8,05 (t, 1H, J= 6Hz, CONH); 7,25 (d, 2H, J=8Hz); 7,08 (d, 2H, J=8Hz); 3,55 (m, 1H); 3,25-3,02 (m, 8H); 2,90 (s, 3H); 2,38 (d, 2H, J=7Hz); 1,85-1,55 (m, 7H); 1,50 (m, 2H); 1,35 (d, 3H, J=7Hz); 0,88 (d, 6H, J=7Hz).
Los siguientes compuestos se prepararon usando el método descrito anteriormente
Yoduro de R(-)-{3-[2-(4’-isobutilfenil)-propionilamino]-propil}-trimetilamonio
p.f. 105-110ºC [α]D = -17 (c = 1,0; CH3OH)1H-RMN (CDCl3) δ 7,42 (d, 2H, J=8Hz); 7,20 (t, 1H, J=6Hz, CONH); 7,07 (d, 2H, J=8Hz); 3,83 (m, 1H); 3,77 (m, 2H); 3,55-3,20 (m, 2H); 3,18 (s, 9H); 2,40 (d, 2H, J=7Hz); 2,05 (m, 2H); 1,83 (m, 1H); 1,45 (d, 3H, J=7Hz); 0,9 (d, 6H, J=7Hz).
Yoduro de R(-)-{3-[2-(4’-isobutilfenil)-propionilamino]-butil}-trimetilamonio
p.f. 100-103ºC [α]D = -25 (c = 1,0; CH3OH)1H-RMN (CDCl3) δ 7,25 (d, 2H, J=8Hz); 7,09 (d, 2H, J=8Hz); 6,18 (s, 1H, CONH); 3,61 (m, 1H); 3,28 (m, 2H); 3,12 (m, 2H); 3,08 (s, 9H); 2,44 (d, 2H, J=7Hz); 1,81 (m, 1H); 1,75 (m, 4H); 1,50 (d, 3H, J=7Hz); 0,88 (d, 6H, J=7Hz).
Yoduro de R(-)-2-[(4’-isobutilfenil)-propionilamino]-1,1-dimetilpiperidinio
p.f. 80-85ºC [α]D = -7 (c = 1,2; CH3OH)1H-RMN (DMSO-d6) δ 7,91 (d, 1H, J=7Hz, CONH); 7,22 (d, 2H, J=8Hz); 7,08 (d, 2H, J=8Hz); 3,80 (m, 1H); 3,53 (m, 1H); 3,35-3,30 (m, 4H); 3,08 (s, 3H); 3,00 (s, 3H); 2,40 (d, 2H, J=7Hz); 1,95-1,65 (m, 5H); 1,3 (d, 3H, J=7Hz); 0,87 (d, 6H, J=7Hz).
Yoduro de R(-)-{3-[2-(4’-isobutilfenil)-propionilamino]-propil}-4-metilmorfolinio
p.f. 84-87ºC [α]D = -17 (c = 0,5; CH3OH)1H-RMN (CDCl3) δ 7,45 (d, 2H, J=8Hz); 7,02 (m, 3H, CONH + 2Har.); 4,25 (m, 2H); 3,92 (m, 1H); 3,88 (m, 1H); 3,80 (m, 1H); 3,53 (m, 1H); 3,35 (m, 2H); 3,15 (m, 1H); 3,00 (s, 3H); 2,92-2,70 (m, 4H); 2,40 (d, 2H, J=7Hz); 2,15 (m, 2H); 1,88 (m, 1H); 1,45 (d, 3H, J=7Hz); 0,92 (d, 6H, J=7Hz).
Yoduro de R(-)-2-[(4’-isobutilfenil)-N-(trimetilamoniometil)-metilamida]-propionamida
p.f. 70-72ºC [α]D = -18 (c = 1,0; CH3OH)1H-RMN (DMSO-d6) δ 7,22 (d, 2H, J=8Hz); 7,11 (d, 2H, J=8Hz); 6,25 (bs, 2H, CONH); 3,57 (m, 1H); 3,30 (m, 2H); 3,10 (s, 9H); 2,45 (d, 2H, J=7Hz); 2,40 (m, 2H); 1,88 (m, 1H); 1,75 (m, 2H); 1,52 (d, 3H, J=7Hz); 0,92 (d, 6H, J=7Hz).
Yoduro de R(-)-{3-[2-(3’-benzoilfenil)-propionilamino]-propil}-trimetilamonio
p.f. 62-65ºC [α]D = -16,3 (c = 1,0; CH3OH)1H-RMN (DMSO-d6) δ 8,20 (t, 1H, J=7Hz, CONH); 7,81-7,47 (m, 9H); 3,75 (m, 1H); 3,27-3,05 (m, 4H); 3,00 (s, 9H); 1,85 (m, 2H); 1,37 (d, 3H, J=7Hz).
Yoduro de R(-)-{3-[2-(3-benzoilfenil)-propionilamino]-propil)]-1-metilpiperidinio
p.f. 69-73ºC [α]D = -10 (c = 0,6; CH3OH) 1H-RMN (DMSO-d6) δ 8,18 (t, 1H, J=7Hz, CONH); 7,80-7,47 (m, 9H); 3,70 (m, 1H); 3,28-3,05 (m, 8H); 2,92 (s, 3H); 1,87-1,53 (m, 6H); 1,42 (m, 2H); 1,38 (d, 3H, J=7Hz).
Yoduro de R-{3-{2-[2-(2,6-diclorofenilamino)-fenil])-propionilamino}-propil)-trimetilamonio
[α]D = -15 (c = 1,0; CH3OH)
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Claims (1)

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ES02777207.8T 2001-09-28 2002-09-25 Sales de amonio cuaternarias de omega-aminoalquilamidas de ácidos R-2-arilpropiónicos y composiciones farmacéuticas que las contienen Expired - Lifetime ES2573531T3 (es)

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ITMI20010202 2001-09-28
IT2001MI002025A ITMI20012025A1 (it) 2001-09-28 2001-09-28 Sali di ammonio quaternari di omega-amminoalchilammidi di acidi r 2-aril-propionici e composizioni farmaceutiche che li contengono
PCT/EP2002/010746 WO2003029187A1 (en) 2001-09-28 2002-09-25 Quaternary ammonium salts of omega-aminoalkylamides of r-2-aryl-propionic acids and pharmaceutical compositions containing them

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